A Study to Assess the Efficacy, Safety, and Tolerability of KPL-716 in Reducing Pruritus in Chronic Pruritic Diseases

• Sponsor: Kiniksa Pharmaceuticals, Ltd. (Industry)
• Overall Status: Completed
• CT.gov ID: NCT03858634
• Collaborator: (none)
• Enrollment: 58
• Locations: 19
• Arms: 2
• Actual Duration (Months): 12.4
• Patients Per Site: 3.1
• Patients Per Site Per Month: 0.2

Study Details

Study Description

Brief Summary

Participants with diseases characterized by chronic pruritus experiencing moderate to severe pruritus will be enrolled in this pilot Phase 2 study.

The diseases characterized by chronic pruritus investigated in this pilot study currently include chronic idiopathic urticaria (CIU), chronic idiopathic pruritus (CIP), lichen planus (LP), lichen simplex chronicus (LSC) and plaque psoriasis (PPs).

Condition or Disease	Intervention/Treatment	Phase
Chronic Idiopathic Urticaria; Chronic Idiopathic Pruritus; Lichen Planus; Lichen Simplex Chronicus; Plaque Psoriasis	Drug: KPL-716; Drug: Placebo	Phase 2

Study Design

• Study Type: Interventional
• Actual Enrollment: 58 participants
• Allocation: Randomized
• Intervention Model: Parallel Assignment
• Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
• Primary Purpose: Treatment
• Official Title: KPL-716-C202: A Phase 2 Randomized, Double-Blind, Placebo-Controlled Pilot Study to Investigate the Efficacy, Safety, and Tolerability of KPL-716 in Reducing Pruritus in Diseases Characterized by Chronic Pruritus
• Actual Study Start Date: May 29, 2019
• Actual Primary Completion Date: Apr 1, 2020
• Actual Study Completion Date: Jun 8, 2020

Arms and Interventions

Arm	Intervention/Treatment
Experimental: KPL-716 Weekly for 8 weeks	Drug: KPL-716; A loading dose of KPL-716 720 mg (2x maintenance dose) administered via 2 subcutaneous (SC) injections within 30 minutes on Day 1. All subsequent doses of KPL-716 (360 mg maintenance dose) administered via a single SC injection.; Other Names: vixarelimab
Placebo Comparator: Placebo Weekly for 8 weeks	Drug: Placebo; Placebo dose administered via 2 SC injections within 30 minutes on Day 1. All subsequent doses of placebo administered via a single SC injection.

Outcome Measures

Primary Outcome Measures

1. Change From Baseline in Weekly Average WI-NRS at Week 8 [Baseline, Week 8]

   WI-NRS score: Participants were asked daily to assign a numerical score to the intensity of their most severe (worst) pruritus in the past 24 hours using a scale from 0 to 10, with 0 indicating no pruritus and 10 indicating the worst imaginable pruritus. Daily scores were averaged for a weekly score. A negative change from Baseline indicates improvement.

2. Percent Change From Baseline in Weekly Average WI-NRS at Week 8 [Baseline, Week 8]

   WI-NRS score: Participants were asked daily to assign a numerical score to the intensity of their most severe (worst) pruritus in the past 24 hours using a scale from 0 to 10, with 0 indicating no pruritus and 10 indicating the worst imaginable pruritus. Daily scores were averaged for a weekly score. A negative change from Baseline indicates improvement.

Secondary Outcome Measures

1. Change From Baseline in Weekly Average WI-NRS Over Time [Baseline, Weeks 1-18]

   WI-NRS score: Participants were asked daily to assign a numerical score to the intensity of their most severe (worst) pruritus in the past 24 hours using a scale from 0 to 10, with 0 indicating no pruritus and 10 indicating the worst imaginable pruritus. Daily scores were averaged for a weekly score. A negative change from Baseline indicates improvement.

2. Percent Change From Baseline in Weekly Average WI-NRS Over Time [Baseline, Weeks 1-18]

   WI-NRS score: Participants were asked daily to assign a numerical score to the intensity of their most severe (worst) pruritus in the past 24 hours using a scale from 0 to 10, with 0 indicating no pruritus and 10 indicating the worst imaginable pruritus. Daily scores were averaged for a weekly score. A negative change from Baseline indicates improvement.

3. Change From Baseline in Pruritus Visual Analog Scale (VAS) Over Time [Baseline, Weeks 1-8, 10, 12, 14, 16, 18]

   Participants were asked to place a line perpendicular to the VAS line at the point that represents the intensity of their average pruritus experienced over the previous 3 days using a scale from 0 to 10, with 0 indicating no pruritus and 10 indicating the worst imaginable pruritus.

4. Percent Change From Baseline in Pruritus VAS Over Time [Baseline, Weeks 1-8, 10, 12, 14, 16, 18]

   Participants were asked to place a line perpendicular to the VAS line at the point that represents the intensity of their average pruritus experienced over the previous 3 days using a scale from 0 to 10, with 0 indicating no pruritus and 10 indicating the worst imaginable pruritus.

5. Change From Baseline in 5-D Pruritus Total Score Over Time [Baseline, Weeks 2, 4, 6, 8, 10, 12, 14, 16, 18]

   This tool evaluates pruritus in 5 domains: duration, degree, direction, disability and distribution. Duration, degree and direction each consist of 1 item. The disability domain contains 4 items and the distribution domain includes 16 items. The first 4 domains are measured on a 5-point Likert scale. The scores from each domain are added together to obtain a total 5-D score ranging from 5 (no pruritus) and 25 (most severe pruritus).

6. Percent Change From Baseline in 5-D Pruritus Total Score Over Time [Baseline, Weeks 2, 4, 6, 8, 10, 12, 14, 16, 18]

   This tool evaluates pruritus in 5 domains: duration, degree, direction, disability and distribution. Duration, degree and direction each consist of 1 item. The disability domain contains 4 items and the distribution domain includes 16 items. The first 4 domains are measured on a 5-point Likert scale. The scores from each domain are added together to obtain a total 5-D score ranging from 5 (no pruritus) and 25 (most severe pruritus).

7. Percentage of Participants Achieving ≥4-Point Reduction From Baseline in Weekly Average WI-NRS Over Time [Baseline, Weeks 1-18]

   WI-NRS score: Participants were asked daily to assign a numerical score to the intensity of their most severe (worst) pruritus in the past 24 hours using a scale from 0 to 10, with 0 indicating no pruritus and 10 indicating the worst imaginable pruritus. Daily scores were averaged for a weekly score. A negative change from Baseline indicates improvement.

8. Change From Baseline in Weekly Average Itch Severity Score: CIU Cohort Only [Baseline, Weeks 1-18]

   Participants were asked daily to self-assess the intensity of their pruritus on a Weekly Average Itch Severity Score, which is a Component of Urticaria Activity Score 7 (UAS7). The score for pruritis was graded from 0 (none) to 3 (intense), which was averaged over 7 consecutive days. The greater the severity of the disease the higher the score. Per protocol, the UAS7 tool was completed only by participants in the CIU Cohort.

9. Percent Change From Baseline in Weekly Average Itch Severity Score: CIU Cohort Only [Baseline, Weeks 1-18]

   Participants were asked daily to self-assess the intensity of their pruritus on a Weekly Average Itch Severity Score, which is a Component of Urticaria Activity Score 7 (UAS7). The score for pruritis was graded from 0 (none) to 3 (intense), which was averaged over 7 consecutive days. The greater the severity of the disease the higher the score. Per protocol, the UAS7 tool was completed only by participants in the CIU Cohort

10. Change From Baseline in Sleep Loss VAS Over Time [Baseline, Weeks 1-8, 10, 12, 14, 16, 18]

    Participants were asked to place a line perpendicular to the VAS line at the point that represents the intensity of their average sleeplessness experienced over the previous 3 nights using a scale from 0 to 10, with 0 indicating no sleeplessness and 10 indicating the worst imaginable sleeplessness at every visit.

11. Percent Change From Baseline in Sleep Loss VAS Over Time [Baseline, Weeks 1-8, 10, 12, 14, 16, 18]

    Participants were asked to place a line perpendicular to the VAS line at the point that represents the intensity of their average sleeplessness experienced over the previous 3 nights using a scale from 0 to 10, with 0 indicating no sleeplessness and 10 indicating the worst imaginable sleeplessness at every visit.

12. Change From Baseline in Weekly Average of Difficulty Falling Asleep Numerical Rating Scale (NRS) Over Time [Baseline, Weeks 1-18]

    Participants were asked daily to assign a numerical score to the intensity of their difficulty falling asleep last night due to itch using a scale from 0 to 10, with 0 indicating not difficult at all and 10 indicating extremely difficult.

13. Percent Change From Baseline in Weekly Average of Difficulty Falling Asleep NRS Over Time [Baseline, Weeks 1-18]

    Participants were asked daily to assign a numerical score to the intensity of their difficulty falling asleep last night due to itch using a scale from 0 to 10, with 0 indicating not difficult at all and 10 indicating extremely difficult.

14. Change From Baseline in Weekly Average of Sleep Quality NRS Over Time [Baseline, Weeks 1-18]

    Participants were asked daily to assign a numerical score to the quality of their sleep in the previous night using a scale from 0 to 10, with 0 indicating best possible sleep and 10 indicating worst possible sleep.

15. Percent Change From Baseline in Weekly Average of Sleep Quality NRS Over Time [Baseline, Weeks 1-18]

    Participants were asked daily to assign a numerical score to the quality of their sleep in the previous night using a scale from 0 to 10, with 0 indicating best possible sleep and 10 indicating worst possible sleep.

16. Change From Baseline in Dermatology Life Quality Index (DLQI) Total Score Over Time [Baseline, Weeks 4, 8, 12, 16, 18]

    The DLQI is a 10-question questionnaire that considers symptoms and feelings, daily activities, leisure, school, personal relationships, and treatment. Each question, except question 7, is answered on a scale of 0 to 3 (0 for not at all, 1 for a little, 2 for a lot, and 3 for very much), taking into account the previous week. For question 7: participants were asked "Over the last week, has your skin prevented you from working or studying?" If answered yes, score=3; If no, a second question will be asked: "Over the last week how much has your skin been a problem at work or studying?" If further answered a lot, score=2; if a little, score=1; if not at all or not relevant, score=0. The DLQI total score is defined as the sum of all 10-question scores with minimum of 0 meaning no effect on quality of life and 30 meaning extremely large effect.

17. Percent Change From Baseline in DLQI Total Score Over Time [Baseline, Weeks 4, 8, 12, 16, 18]

    The DLQI is a 10-question questionnaire that considers symptoms and feelings, daily activities, leisure, school, personal relationships, and treatment. Each question, except question 7, is answered on a scale of 0 to 3 (0 for not at all, 1 for a little, 2 for a lot, and 3 for very much), taking into account the previous week. For question 7: participants were asked "Over the last week, has your skin prevented you from working or studying?" If answered yes, score=3; If no, a second question will be asked: "Over the last week how much has your skin been a problem at work or studying?" If further answered a lot, score=2; if a little, score=1; if not at all or not relevant, score=0. The DLQI total score is defined as the sum of all 10-question scores with minimum of 0 meaning no effect on quality of life and 30 meaning extremely large effect.

18. Change From Baseline in ItchyQoL Total Score Over Time [Baseline, Weeks 4, 8, 12, 16, 18]

    ItchyQoL focuses on impact of pruritus on daily activities and on the level of psychological stress. It contains 22 items. The frequency items are scored using a 5-point Likert scale ranging from "never" to "all the time". The bother items are scored from 1 (not bothered) to 5 (severely bothered). The recall period in ItchyQoL is the past week. The ItchyQoL total score is defined as the sum of all 22-items scores. Total scores can be classified as little (0-30), mild (31-50), moderate (51-80), and severe (81-110).

19. Percent Change From Baseline in ItchyQoL Total Score Over Time [Baseline, Weeks 4, 8, 12, 16, 18]

    ItchyQoL focuses on impact of pruritus on daily activities and on the level of psychological stress. It contains 22 items. The frequency items are scored using a 5-point Likert scale ranging from "never" to "all the time". The bother items are scored from 1 (not bothered) to 5 (severely bothered). The recall period in ItchyQoL is the past week. The ItchyQoL total score is defined as the sum of all 22-items scores. Total scores can be classified as little (0-30), mild (31-50), moderate (51-80), and severe (81-110).

Eligibility Criteria

Criteria

• Ages Eligible for Study: 18 Years to 75 Years
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

Inclusion Criteria:

1. Male or female aged 18 to 75 years

2. Have clinical diagnosis of chronic idiopathic urticaria (CIU), chronic idiopathic pruritus (CIP), lichen planus (LP), lichen simplex chronicus (LSC) and plaque psoriasis (PPs) for at least 6 months

3. Moderate to severe pruritus

4. Female participants of childbearing potential must have a negative pregnancy test, be nonlactating, and have agreed to use a highly effective method of contraception, as specified in the protocol, from the Screening Visit until 10 weeks after final study drug administration

5. Able to comprehend and willing to sign an Informed Consent Form and able to abide by the study restrictions and comply with all study procedures for the duration of the study

Exclusion Criteria:

1. Use of prohibited medications within the indicated timeframe from Day 1 to the End of Study

2. Is currently using medication known to cause pruritus

3. Has any inflammatory, pruritic, and/or fibrotic skin condition other than the diagnosis that defines inclusion

4. Laboratory abnormalities that fall outside the windows specified in the protocol at the Screening Visit

5. Has an active infection, including skin infection

6. Any medical or psychiatric condition which, in the opinion of the Investigator or the Sponsor, may place the participant at increased risk as a result of study participation, interfere with study participation or study assessments, affect compliance with study requirements, or complicate interpretation of study results

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	Site 106	Anniston	Alabama	United States	36207
2	Site 110	Phoenix	Arizona	United States	85032
3	Site 114	Hot Springs	Arkansas	United States	71913
4	Site 103	Los Angeles	California	United States	90045
5	Site 108	Clearwater	Florida	United States	33756
6	Site 120	Gainesville	Florida	United States	32610
7	Site 113	Sweetwater	Florida	United States	33172
8	Site 116	Sandy Springs	Georgia	United States	30328
9	Site 105	Normal	Illinois	United States	61761
10	Site 112	Plainfield	Indiana	United States	46168
11	Site 119	New Orleans	Louisiana	United States	70115
12	Site 109	Fort Gratiot	Michigan	United States	48059
13	Site 121	Omaha	Nebraska	United States	68144
14	Site 123	New York	New York	United States	10012
15	Site 115	Johnston	Rhode Island	United States	02919
16	Site 102	Houston	Texas	United States	77004
17	Site 104	Pflugerville	Texas	United States	78660
18	Site 101	San Antonio	Texas	United States	78213
19	Site 122	Spokane	Washington	United States	99202

Sponsors and Collaborators

• Kiniksa Pharmaceuticals, Ltd.

Investigators

• Study Director: John Paolini, M.D., Kiniksa Pharmaceuticals, Ltd.

Study Documents (Full-Text)

• Study Protocol - Jan 28, 2019
• Statistical Analysis Plan - Apr 13, 2020

More Information

Publications

None provided.

• Responsible Party: Kiniksa Pharmaceuticals, Ltd.
• ClinicalTrials.gov Identifier: NCT03858634
• Other Study ID Numbers: KPL-716-C202
• First Posted: Mar 1, 2019
• Last Update Posted: Dec 28, 2021
• Last Verified: Nov 1, 2021

• Individual Participant Data (IPD) Sharing Statement: No
• Plan to Share IPD: No
• Studies a U.S. FDA-regulated Drug Product: Yes
• Studies a U.S. FDA-regulated Device Product: No
• Keywords provided by Kiniksa Pharmaceuticals, Ltd.: pruritus, chronic pruritus, moderate to severe
• Additional relevant MeSH terms: Psoriasis; Pruritus; Urticaria; Lichen Planus; Chronic Urticaria; Neurodermatitis

Study Results

Participant Flow

Pre-assignment Detail

This study assigned participants to active treatment or placebo in 5 individual disease-specific cohorts: chronic idiopathic urticaria (CIU), chronic idiopathic pruritus (CIP), lichen planus (LP), lichen simplex chronicus (LSC) and plaque psoriasis (PPs). The participant flow data are presented by combined cohorts for public reporting purposes because the low numbers of participants in the individual disease-specific cohorts may cause re-identification concerns if presented separately.

Arm/Group Title	KPL-716	Placebo
Arm/Group Description	KPL-716 weekly for 8 weeks	Placebo weekly for 8 weeks
Period Title: Overall Study
STARTED	39	19
Participants With Chronic Idiopathic Urticaria (CIU)	4	2
Participants With Chronic Idiopathic Pruritus (CIP)	14	9
Participants With Lichen Planus (LP)	3	0
Participants With Lichen Simplex Chronicus (LSC)	4	1
Participants With Plaque Psoriasis (PPs)	14	7
COMPLETED	36	17
NOT COMPLETED	3	2

Baseline Characteristics

Arm/Group Title	KPL-716	Placebo	Total
Arm/Group Description	KPL-716 weekly for 8 weeks	Placebo weekly for 8 weeks	Total of all reporting groups
Overall Participants	39	19	58
Age (years) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [years]	53.1 (11.51)	53.3 (13.94)	53.2 (12.24)
Sex: Female, Male (Count of Participants)
Female	27 69.2%	14 73.7%	41 70.7%
Male	12 30.8%	5 26.3%	17 29.3%
Race/Ethnicity, Customized (Count of Participants)
White	34 87.2%	14 73.7%	48 82.8%
Black or African American	4 10.3%	4 21.1%	8 13.8%
Asian	1 2.6%	1 5.3%	2 3.4%
Race/Ethnicity, Customized (Count of Participants)
Hispanic or Latino	20 51.3%	5 26.3%	25 43.1%
Not Hispanic or Latino	19 48.7%	14 73.7%	33 56.9%
Weekly Average of Daily Worst Itch-Numeric Rating Scale (WI-NRS) (score on a scale) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [score on a scale]	8.1 (0.93)	8.3 (1.14)	8.2 (1.00)

Outcome Measures

1. Primary Outcome

Title	Change From Baseline in Weekly Average WI-NRS at Week 8
Description	WI-NRS score: Participants were asked daily to assign a numerical score to the intensity of their most severe (worst) pruritus in the past 24 hours using a scale from 0 to 10, with 0 indicating no pruritus and 10 indicating the worst imaginable pruritus. Daily scores were averaged for a weekly score. A negative change from Baseline indicates improvement.
Time Frame	Baseline, Week 8

Outcome Measure Data

Analysis Population Description

Modified intent to treat (mITT) set: all randomized participants who received at least 1 dose of KPL-716 or placebo and had at least 1 post-baseline efficacy assessment in the double-blind treatment period. Missing data were imputed using the last observation carried forward (LOCF) method.

Arm/Group Title	KPL-716: CIU Cohort	Placebo: CIU Cohort	KPL-716: CIP Cohort	Placebo: CIP Cohort	KPL-716: LP Cohort	Placebo: LP Cohort	KPL-716: LSC Cohort	Placebo: LSC Cohort	KPL-716: PPs Cohort	Placebo: PPs Cohort
Arm/Group Description	Participants with CIU received KPL-716 weekly for 8 weeks	Participants with CIU received placebo weekly for 8 weeks	Participants with CIP received KPL-716 weekly for 8 weeks	Participants with CIP received placebo weekly for 8 weeks	Participants with LP received KPL-716 weekly for 8 weeks	Participants with LP received placebo weekly for 8 weeks	Participants with LSC received KPL-716 weekly for 8 weeks	Participants with LSC received placebo weekly for 8 weeks	Participants with PPs received KPL-716 weekly for 8 weeks	Participants with PPs received placebo weekly for 8 weeks
Measure Participants	4	2	14	9	3	0	4	1	14	7
Least Squares Mean (Standard Error) [score on a scale]	-4.3 (1.84)	-1.1 (2.66)	-4.3 (0.77)	-3.7 (0.96)	-3.1 (0.82)	-6.9 (0.81)	0.7 (1.84)	-5.6 (0.69)	-2.5 (0.98)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	KPL-716: CIU Cohort, Placebo: CIU Cohort
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.3980
	Comments	Calculated from an ANCOVA model including treatment as factor and baseline values as covariate.
	Method	ANCOVA
	Comments
Method of Estimation	Estimation Parameter	Least squares (LS) mean difference
	Estimated Value	-3.3
	Confidence Interval	(2-Sided) 80%; -8.68 to 2.17
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 3.31
	Estimation Comments

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	KPL-716: CIP Cohort, Placebo: CIP Cohort
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.6653
	Comments	Calculated from an ANCOVA model including treatment as factor and baseline values as covariate.
	Method	ANCOVA
	Comments
Method of Estimation	Estimation Parameter	LS mean difference
	Estimated Value	-0.5
	Confidence Interval	(2-Sided) 80%; -2.17 to 1.09
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 1.23
	Estimation Comments

Statistical Analysis 3

Statistical Analysis Overview	Comparison Group Selection	KPL-716: LSC Cohort, Placebo: LSC Cohort
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.0711
	Comments	Calculated from an ANCOVA model including treatment as factor and baseline values as covariate.
	Method	ANCOVA
	Comments
Method of Estimation	Estimation Parameter	LS mean difference
	Estimated Value	-7.6
	Confidence Interval	(2-Sided) 80%; -11.63 to -3.56
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 2.14
	Estimation Comments

Statistical Analysis 4

Statistical Analysis Overview	Comparison Group Selection	KPL-716: PPs Cohort, Placebo: PPs Cohort
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.0186
	Comments	Calculated from an ANCOVA model including treatment as factor and baseline values as covariate.
	Method	ANCOVA
	Comments
Method of Estimation	Estimation Parameter	LS mean difference
	Estimated Value	-3.1
	Confidence Interval	(2-Sided) 80%; -4.70 to -1.51
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 1.20
	Estimation Comments

2. Secondary Outcome

Title	Change From Baseline in Weekly Average WI-NRS Over Time
Description	WI-NRS score: Participants were asked daily to assign a numerical score to the intensity of their most severe (worst) pruritus in the past 24 hours using a scale from 0 to 10, with 0 indicating no pruritus and 10 indicating the worst imaginable pruritus. Daily scores were averaged for a weekly score. A negative change from Baseline indicates improvement.
Time Frame	Baseline, Weeks 1-18

Outcome Measure Data

Analysis Population Description

Modified intent to treat (mITT) set: all randomized participants who received at least 1 dose of KPL-716 or placebo and had at least 1 post-baseline efficacy assessment in the double-blind treatment period. Missing data were imputed using the last observation carried forward (LOCF) method. Once a participant started treatment period (through Week 8), missing data in treatment period were imputed. Once a participant started the follow up (FU) period, missing data in FU period were imputed.

Arm/Group Title	KPL-716: CIU Cohort	Placebo: CIU Cohort	KPL-716: CIP Cohort	Placebo: CIP Cohort	KPL-716: LP Cohort	Placebo: LP Cohort	KPL-716: LSC Cohort	Placebo: LSC Cohort	KPL-716: PPs Cohort	Placebo: PPs Cohort
Arm/Group Description	Participants with CIU received KPL-716 weekly for 8 weeks	Participants with CIU received placebo weekly for 8 weeks	Participants with CIP received KPL-716 weekly for 8 weeks	Participants with CIP received placebo weekly for 8 weeks	Participants with LP received KPL-716 weekly for 8 weeks	Participants with LP received placebo weekly for 8 weeks	Participants with LSC received KPL-716 weekly for 8 weeks	Participants with LSC received placebo weekly for 8 weeks	Participants with PPs received KPL-716 weekly for 8 weeks	Participants with PPs received placebo weekly for 8 weeks
Measure Participants	4	2	14	9	3	0	4	1	14	7
Change at Week 1	-1.9 (0.59)	-0.9 (0.86)	-1.6 (0.55)	-1.4 (0.45)	-0.2 (0.13)	-3.0 (1.23)	-0.9 (NA)	-0.7 (0.17)	-0.2 (0.16)
Change at Week 2	-3.0 (0.79)	-1.3 (1.29)	-3.0 (0.60)	-2.9 (0.63)	-0.5 (0.58)	-4.0 (1.64)	-1.0 (NA)	-1.5 (0.27)	-0.7 (0.26)
Change at Week 3	-3.8 (1.25)	-1.6 (1.64)	-3.5 (0.61)	-2.4 (0.72)	-1.2 (0.99)	-4.6 (1.73)	-1.4 (NA)	-2.6 (0.39)	-0.9 (0.33)
Change at Week 4	-3.9 (1.59)	-1.5 (1.50)	-3.5 (0.64)	-3.0 (0.85)	-2.3 (1.78)	-5.0 (1.48)	-2.4 (NA)	-3.4 (0.48)	-1.2 (0.63)
Change at Week 5	-4.4 (1.83)	-1.6 (1.64)	-4.1 (0.73)	-3.1 (0.88)	-2.5 (1.91)	-5.4 (1.58)	-2.0 (NA)	-4.4 (0.65)	-1.5 (0.88)
Change at Week 6	-4.6 (1.72)	-1.8 (1.79)	-4.2 (0.74)	-3.7 (0.92)	-2.7 (1.90)	-5.8 (1.58)	-2.6 (NA)	-4.7 (0.65)	-1.6 (0.81)
Change at Week 7	-4.4 (1.75)	-2.6 (2.64)	-4.4 (0.77)	-3.7 (0.81)	-3.1 (1.94)	-6.3 (1.48)	-2.3 (NA)	-5.1 (0.69)	-1.9 (0.91)
Change at Week 8	-4.1 (1.84)	-1.6 (1.57)	-4.3 (0.75)	-3.7 (0.94)	-3.1 (1.94)	-6.0 (1.61)	-2.7 (NA)	-5.6 (0.66)	-2.5 (1.07)
Change at Week 9	-4.1 (1.73)	-1.6 (1.57)	-4.6 (0.88)	-3.8 (0.76)	-5.0 (1.00)	-6.0 (1.76)	-3.3 (NA)	-5.7 (0.70)	-2.5 (1.21)
Change at Week 10	-4.1 (1.69)	-2.2 (2.21)	-4.3 (0.87)	-4.7 (0.64)	-5.0 (1.00)	-6.3 (1.46)	-3.0 (NA)	-5.6 (0.75)	-2.2 (1.23)
Change at Week 11	-4.1 (1.74)	-2.2 (2.21)	-4.4 (0.90)	-4.9 (0.75)	-5.0 (1.00)	-6.3 (1.42)	-2.9 (NA)	-5.4 (0.78)	-2.2 (1.22)
Change at Week 12	-4.5 (1.72)	-2.2 (2.21)	-4.4 (0.86)	-4.3 (0.76)	-5.3 (0.71)	-6.5 (1.27)	-2.7 (NA)	-5.3 (0.80)	-2.2 (1.21)
Change at Week 13	-3.9 (1.85)	-2.2 (2.21)	-4.4 (0.83)	-4.2 (0.86)	-5.5 (0.50)	-6.6 (1.32)	-2.0 (NA)	-5.5 (0.83)	-2.3 (1.22)
Change at Week 14	-3.8 (1.75)	-2.2 (2.21)	-4.5 (0.80)	-4.1 (0.92)	-5.5 (0.50)	-6.4 (1.42)	-1.9 (NA)	-5.6 (0.81)	-2.3 (1.21)
Change at Week 15	-4.4 (1.68)	-2.2 (2.21)	-4.2 (0.85)	-3.8 (0.91)	-5.5 (0.50)	-6.8 (1.23)	-2.0 (NA)	-5.4 (0.86)	-2.6 (1.35)
Change at Week 16	-4.1 (1.74)	-2.2 (2.21)	-4.3 (0.87)	-3.5 (0.96)	-5.5 (0.50)	-6.6 (1.25)	-1.6 (NA)	-5.3 (0.86)	-2.6 (1.33)
Change at Week 17	-4.5 (1.81)	-2.2 (2.21)	-4.5 (0.89)	-3.4 (0.97)	-5.5 (0.50)	-6.8 (1.11)	-1.4 (NA)	-5.0 (0.99)	-2.7 (1.38)
Change at Week 18	-4.4 (1.67)	-2.2 (2.21)	-4.3 (0.97)	-3.4 (1.06)	-5.6 (0.57)	-6.9 (1.01)	-1.4 (NA)	-5.0 (1.01)	-2.7 (1.39)

3. Secondary Outcome

Title	Percent Change From Baseline in Weekly Average WI-NRS Over Time
Description	WI-NRS score: Participants were asked daily to assign a numerical score to the intensity of their most severe (worst) pruritus in the past 24 hours using a scale from 0 to 10, with 0 indicating no pruritus and 10 indicating the worst imaginable pruritus. Daily scores were averaged for a weekly score. A negative change from Baseline indicates improvement.
Time Frame	Baseline, Weeks 1-18

Outcome Measure Data

Analysis Population Description

Modified intent to treat (mITT) set: all randomized participants who received at least 1 dose of KPL-716 or placebo and had at least 1 post-baseline efficacy assessment in the double-blind treatment period. Missing data were imputed using the last observation carried forward (LOCF) method. Once a participant started treatment period (through Week 8), missing data in treatment period were imputed. Once a participant started the follow up (FU) period, missing data in FU period were imputed.

Arm/Group Title	KPL-716: CIU Cohort	Placebo: CIU Cohort	KPL-716: CIP Cohort	Placebo: CIP Cohort	KPL-716: LP Cohort	Placebo: LP Cohort	KPL-716: LSC Cohort	Placebo: LSC Cohort	KPL-716: PPs Cohort	Placebo: PPs Cohort
Arm/Group Description	Participants with CIU received KPL-716 weekly for 8 weeks	Participants with CIU received placebo weekly for 8 weeks	Participants with CIP received KPL-716 weekly for 8 weeks	Participants with CIP received placebo weekly for 8 weeks	Participants with LP received KPL-716 weekly for 8 weeks	Participants with LP received placebo weekly for 8 weeks	Participants with LSC received KPL-716 weekly for 8 weeks	Participants with LSC received placebo weekly for 8 weeks	Participants with PPs received KPL-716 weekly for 8 weeks	Participants with PPs received placebo weekly for 8 weeks
Measure Participants	4	2	14	9	3	0	4	1	14	7
Change at Week 1	-23.5 (8.22)	-16.2 (11.84)	-19.5 (6.57)	-18.3 (8.20)	-2.4 (2.19)	-44.2 (12.54)	16.9 (28.60)	-8.8 (1.84)	-3.4 (2.61)
Change at Week 2	-37.2 (12.11)	-20.6 (17.45)	-36.7 (7.42)	-36.5 (9.25)	-6.1 (4.37)	-59.8 (10.80)	29.3 (24.62)	-17.8 (3.16)	-8.4 (4.46)
Change at Week 3	-46.9 (18.33)	-25.0 (26.41)	-43.4 (7.37)	-31.5 (9.19)	-15.0 (8.02)	-67.9 (12.89)	25.9 (29.39)	-31.2 (4.14)	-11.2 (5.86)
Change at Week 4	-48.9 (19.96)	-20.0 (28.76)	-43.9 (7.92)	-38.4 (9.87)	-29.3 (18.23)	-71.7 (9.93)	8.0 (22.65)	-41.7 (5.63)	-14.5 (7.96)
Change at Week 5	-54.7 (23.35)	-22.0 (33.65)	-51.6 (8.70)	-40.6 (10.84)	-31.1 (20.41)	-76.9 (13.08)	13.8 (29.81)	-53.0 (7.11)	-17.7 (10.05)
Change at Week 6	-57.3 (21.58)	-23.8 (31.10)	-52.3 (9.11)	-47.9 (11.36)	-33.5 (17.50)	-81.5 (13.07)	7.0 (29.80)	-56.5 (6.88)	-18.7 (9.72)
Change at Week 7	-53.6 (24.07)	-36.4 (34.67)	-54.3 (8.98)	-48.1 (11.19)	-39.4 (10.21)	-87.4 (11.02)	7.8 (25.13)	-60.6 (7.48)	-22.5 (10.57)
Change at Week 8	-50.7 (21.56)	-19.0 (31.07)	-52.4 (9.32)	-48.8 (11.63)	-39.4 (10.21)	-85.0 (11.76)	7.0 (26.80)	-66.5 (7.78)	-29.0 (11.00)
Change at Week 9	-51.1 (19.68)	-19.0 (28.35)	-55.7 (9.95)	-48.6 (11.50)	-62.5 (12.50)	-85.2 (14.00)	4.0 (31.91)	-68.1 (8.42)	-28.5 (11.91)
Change at Week 10	-50.0 (20.26)	-27.9 (29.19)	-52.6 (9.40)	-58.7 (10.86)	-62.5 (12.50)	-86.8 (11.34)	-1.2 (25.85)	-67.0 (8.73)	-24.5 (12.35)
Change at Week 11	-50.4 (20.87)	-27.3 (30.07)	-52.8 (9.91)	-61.4 (11.45)	-62.5 (12.50)	-86.6 (10.72)	-0.4 (24.44)	-64.1 (8.66)	-24.8 (12.25)
Change at Week 12	-55.4 (21.36)	-28.2 (30.77)	-53.9 (9.88)	-53.2 (11.42)	-66.1 (8.93)	-89.0 (8.84)	-2.8 (20.15)	-62.2 (8.85)	-24.8 (12.52)
Change at Week 13	-47.2 (22.72)	-27.6 (32.73)	-53.8 (10.04)	-52.2 (11.59)	-68.8 (6.25)	-90.1 (10.04)	6.1 (22.89)	-64.9 (9.22)	-25.2 (13.03)
Change at Week 14	-46.8 (20.94)	-27.7 (30.17)	-55.3 (10.15)	-51.4 (11.72)	-68.8 (6.25)	-88.8 (10.85)	10.7 (24.74)	-65.9 (9.17)	-26.1 (12.97)
Change at Week 15	-53.6 (20.68)	-28.2 (29.79)	-50.8 (10.54)	-49.0 (12.18)	-68.8 (6.25)	-91.8 (9.58)	3.0 (21.85)	-63.7 (9.87)	-29.5 (13.96)
Change at Week 16	-50.0 (21.31)	-28.0 (30.70)	-51.7 (10.86)	-44.7 (12.54)	-68.8 (6.25)	-90.6 (9.28)	9.1 (21.17)	-62.7 (9.81)	-29.3 (13.88)
Change at Week 17	-55.0 (23.07)	-28.7 (33.24)	-54.2 (11.00)	-43.7 (12.70)	-68.8 (6.25)	-92.2 (8.10)	6.8 (18.46)	-58.0 (11.35)	-30.8 (16.05)
Change at Week 18	-54.5 (20.93)	-28.9 (30.15)	-51.5 (12.05)	-43.7 (13.92)	-69.6 (7.14)	-92.1 (6.42)	4.1 (14.63)	-58.1 (11.43)	-31.1 (16.17)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	KPL-716: CIU Cohort, Placebo: CIU Cohort
	Comments	Change at Week 1
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.6533
	Comments	Calculated from an ANCOVA model including treatment as factor and baseline values as covariate.
	Method	ANCOVA
	Comments
Method of Estimation	Estimation Parameter	LS mean difference
	Estimated Value	-7.3
	Confidence Interval	(2-Sided) 80%; -31.52 to 16.84
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 14.76
	Estimation Comments

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	KPL-716: CIP Cohort, Placebo: CIP Cohort
	Comments	Change at Week 1
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.9077
	Comments	Calculated from an ANCOVA model including treatment as factor and baseline values as covariate.
	Method	ANCOVA
	Comments
Method of Estimation	Estimation Parameter	LS mean difference
	Estimated Value	-1.2
	Confidence Interval	(2-Sided) 80%; -15.16 to 12.69
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 10.51
	Estimation Comments

Statistical Analysis 3

Statistical Analysis Overview	Comparison Group Selection	KPL-716: LSC Cohort, Placebo: LSC Cohort
	Comments	Change at Week 1
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.2065
	Comments	Calculated from an ANCOVA model including treatment as factor and baseline values as covariate.
	Method	ANCOVA
	Comments
Method of Estimation	Estimation Parameter	LS mean difference
	Estimated Value	-61.2
	Confidence Interval	(2-Sided) 80%; -123.73 to 1.39
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 33.18
	Estimation Comments

Statistical Analysis 4

Statistical Analysis Overview	Comparison Group Selection	KPL-716: PPs Cohort, Placebo: PPs Cohort
	Comments	Change at Week 1
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.1133
	Comments	Calculated from an ANCOVA model including treatment as factor and baseline values as covariate.
	Method	ANCOVA
	Comments
Method of Estimation	Estimation Parameter	LS mean difference
	Estimated Value	-5.3
	Confidence Interval	(2-Sided) 80%; -9.56 to -1.07
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 3.19
	Estimation Comments

Statistical Analysis 5

Statistical Analysis Overview	Comparison Group Selection	KPL-716: CIU Cohort, Placebo: CIU Cohort
	Comments	Change at Week 2
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.4997
	Comments	Calculated from an ANCOVA model including treatment as factor and baseline values as covariate.
	Method	ANCOVA
	Comments
Method of Estimation	Estimation Parameter	LS mean difference
	Estimated Value	-16.7
	Confidence Interval	(2-Sided) 80%; -52.29 to 18.98
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 21.76
	Estimation Comments

Statistical Analysis 6

Statistical Analysis Overview	Comparison Group Selection	KPL-716: CIP Cohort, Placebo: CIP Cohort
	Comments	Change at Week 2
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.9919
	Comments	Calculated from an ANCOVA model including treatment as factor and baseline values as covariate.
	Method	ANCOVA
	Comments
Method of Estimation	Estimation Parameter	LS mean difference
	Estimated Value	-0.1
	Confidence Interval	(2-Sided) 80%; -15.83 to 15.59
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 11.85
	Estimation Comments

Statistical Analysis 7

Statistical Analysis Overview	Comparison Group Selection	KPL-716: LSC Cohort, Placebo: LSC Cohort
	Comments	Change at Week 2
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.0891
	Comments	Calculated from an ANCOVA model including treatment as factor and baseline values as covariate.
	Method	ANCOVA
	Comments
Method of Estimation	Estimation Parameter	LS mean difference
	Estimated Value	-89.2
	Confidence Interval	(2-Sided) 80%; -143.03 to -35.31
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 28.56
	Estimation Comments

Statistical Analysis 8

Statistical Analysis Overview	Comparison Group Selection	KPL-716: PPs Cohort, Placebo: PPs Cohort
	Comments	Change at Week 2
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.1029
	Comments	Calculated from an ANCOVA model including treatment as factor and baseline values as covariate.
	Method	ANCOVA
	Comments
Method of Estimation	Estimation Parameter	LS mean difference
	Estimated Value	-9.4
	Confidence Interval	(2-Sided) 80%; -16.67 to -2.12
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 5.47
	Estimation Comments

Statistical Analysis 9

Statistical Analysis Overview	Comparison Group Selection	KPL-716: CIU Cohort, Placebo: CIU Cohort
	Comments	Change at Week 3
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.5538
	Comments	Calculated from an ANCOVA model including treatment as factor and baseline values as covariate.
	Method	ANCOVA
	Comments
Method of Estimation	Estimation Parameter	LS mean difference
	Estimated Value	-21.9
	Confidence Interval	(2-Sided) 80%; -75.82 to 32.05
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 32.93
	Estimation Comments

Statistical Analysis 10

Statistical Analysis Overview	Comparison Group Selection	KPL-716: CIP Cohort, Placebo: CIP Cohort
	Comments	Change at Week 3
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.3252
	Comments	Calculated from an ANCOVA model including treatment as factor and baseline values as covariate.
	Method	ANCOVA
	Comments
Method of Estimation	Estimation Parameter	LS mean difference
	Estimated Value	-11.9
	Confidence Interval	(2-Sided) 80%; -27.51 to 3.73
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 11.78
	Estimation Comments

Statistical Analysis 11

Statistical Analysis Overview	Comparison Group Selection	KPL-716: LSC Cohort, Placebo: LSC Cohort
	Comments	Change at Week 3
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.1106
	Comments	Calculated from an ANCOVA model including treatment as factor and baseline values as covariate.
	Method	ANCOVA
	Comments
Method of Estimation	Estimation Parameter	LS mean difference
	Estimated Value	-93.8
	Confidence Interval	(2-Sided) 80%; -158.11 to -29.52
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 34.10
	Estimation Comments

Statistical Analysis 12

Statistical Analysis Overview	Comparison Group Selection	KPL-716: PPs Cohort, Placebo: PPs Cohort
	Comments	Change at Week 3
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.0123
	Comments	Calculated from an ANCOVA model including treatment as factor and baseline values as covariate.
	Method	ANCOVA
	Comments
Method of Estimation	Estimation Parameter	LS mean difference
	Estimated Value	-19.9
	Confidence Interval	(2-Sided) 80%; -29.48 to -10.40
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 7.17
	Estimation Comments

Statistical Analysis 13

Statistical Analysis Overview	Comparison Group Selection	KPL-716: CIU Cohort, Placebo: CIU Cohort
	Comments	Change at Week 4
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.4791
	Comments	Calculated from an ANCOVA model including treatment as factor and baseline values as covariate.
	Method	ANCOVA
	Comments
Method of Estimation	Estimation Parameter	LS mean difference
	Estimated Value	-28.9
	Confidence Interval	(2-Sided) 80%; -87.63 to 29.81
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 35.86
	Estimation Comments

Statistical Analysis 14

Statistical Analysis Overview	Comparison Group Selection	KPL-716: CIP Cohort, Placebo: CIP Cohort
	Comments	Change at Week 4
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.6684
	Comments	Calculated from an ANCOVA model including treatment as factor and baseline values as covariate.
	Method	ANCOVA
	Comments
Method of Estimation	Estimation Parameter	LS mean difference
	Estimated Value	-5.5
	Confidence Interval	(2-Sided) 80%; -22.28 to 11.27
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 12.66
	Estimation Comments

Statistical Analysis 15

Statistical Analysis Overview	Comparison Group Selection	KPL-716: LSC Cohort, Placebo: LSC Cohort
	Comments	Change at Week 4
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.0937
	Comments	Calculated from an ANCOVA model including treatment as factor and baseline values as covariate.
	Method	ANCOVA
	Comments
Method of Estimation	Estimation Parameter	LS mean difference
	Estimated Value	-79.7
	Confidence Interval	(2-Sided) 80%; -129.22 to -30.13
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 26.28
	Estimation Comments

Statistical Analysis 16

Statistical Analysis Overview	Comparison Group Selection	KPL-716: PPs Cohort, Placebo: PPs Cohort
	Comments	Change at Week 4
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.0120
	Comments	Calculated from an ANCOVA model including treatment as factor and baseline values as covariate.
	Method	ANCOVA
	Comments
Method of Estimation	Estimation Parameter	LS mean difference
	Estimated Value	-27.2
	Confidence Interval	(2-Sided) 80%; -40.21 to -14.27
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 9.75
	Estimation Comments

Statistical Analysis 17

Statistical Analysis Overview	Comparison Group Selection	KPL-716: CIU Cohort, Placebo: CIU Cohort
	Comments	Change at Week 5
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.4927
	Comments	Calculated from an ANCOVA model including treatment as factor and baseline values as covariate.
	Method	ANCOVA
	Comments
Method of Estimation	Estimation Parameter	LS mean difference
	Estimated Value	-32.7
	Confidence Interval	(2-Sided) 80%; -101.39 to 36.02
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 41.95
	Estimation Comments

Statistical Analysis 18

Statistical Analysis Overview	Comparison Group Selection	KPL-716: CIP Cohort, Placebo: CIP Cohort
	Comments	Change at Week 5
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.4409
	Comments	Calculated from an ANCOVA model including treatment as factor and baseline values as covariate.
	Method	ANCOVA
	Comments
Method of Estimation	Estimation Parameter	LS mean difference
	Estimated Value	-10.9
	Confidence Interval	(2-Sided) 80%; -29.35 to 7.49
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 13.90
	Estimation Comments

Statistical Analysis 19

Statistical Analysis Overview	Comparison Group Selection	KPL-716: LSC Cohort, Placebo: LSC Cohort
	Comments	Change at Week 5
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.1197
	Comments	Calculated from an ANCOVA model including treatment as factor and baseline values as covariate.
	Method	ANCOVA
	Comments
Method of Estimation	Estimation Parameter	LS mean difference
	Estimated Value	-90.7
	Confidence Interval	(2-Sided) 80%; -155.96 to -25.54
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 34.58
	Estimation Comments

Statistical Analysis 20

Statistical Analysis Overview	Comparison Group Selection	KPL-716: PPs Cohort, Placebo: PPs Cohort
	Comments	Change at Week 5
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.0102
	Comments	Calculated from an ANCOVA model including treatment as factor and baseline values as covariate.
	Method	ANOVA
	Comments
Method of Estimation	Estimation Parameter	LS mean difference
	Estimated Value	-35.3
	Confidence Interval	(2-Sided) 80%; -51.68 to -18.92
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 12.31
	Estimation Comments

Statistical Analysis 21

Statistical Analysis Overview	Comparison Group Selection	KPL-716: CIU Cohort, Placebo: CIU Cohort
	Comments	Change at Week 6
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.4515
	Comments	Calculated from an ANCOVA model including treatment as factor and baseline values as covariate.
	Method	ANCOVA
	Comments
Method of Estimation	Estimation Parameter	LS mean difference
	Estimated Value	-33.5
	Confidence Interval	(2-Sided) 80%; -96.97 to 30.02
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 38.77
	Estimation Comments

Statistical Analysis 22

Statistical Analysis Overview	Comparison Group Selection	KPL-716: CIP Cohort, Placebo: CIP Cohort
	Comments	Change at Week 6
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.7623
	Comments	Calculated from an ANCOVA model including treatment as factor and baseline values as covariate.
	Method	ANCOVA
	Comments
Method of Estimation	Estimation Parameter	LS mean difference
	Estimated Value	-4.5
	Confidence Interval	(2-Sided) 80%; -23.76 to 14.83
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 14.56
	Estimation Comments

Statistical Analysis 23

Statistical Analysis Overview	Comparison Group Selection	KPL-716: LSC Cohort, Placebo: LSC Cohort
	Comments	Change at Week 6
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.1247
	Comments	Calculated from an ANCOVA model including treatment as factor and baseline values as covariate.
	Method	ANCOVA
	Comments
Method of Estimation	Estimation Parameter	LS mean difference
	Estimated Value	-88.5
	Confidence Interval	(2-Sided) 80%; -153.65 to -23.29
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 34.57
	Estimation Comments

Statistical Analysis 24

Statistical Analysis Overview	Comparison Group Selection	KPL-716: PPs Cohort, Placebo: PPs Cohort
	Comments	Change at Week 6
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.0053
	Comments	Calculated from an ANCOVA model including treatment as factor and baseline values as covariate.
	Method	ANCOVA
	Comments
Method of Estimation	Estimation Parameter	LS mean difference
	Estimated Value	-37.7
	Confidence Interval	(2-Sided) 80%; -53.59 to -21.90
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 11.91
	Estimation Comments

Statistical Analysis 25

Statistical Analysis Overview	Comparison Group Selection	KPL-716: CIU Cohort, Placebo: CIU Cohort
	Comments	Change at Week 7
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.7177
	Comments	Calculated from an ANCOVA model including treatment as factor and baseline values as covariate.
	Method	ANCOVA
	Comments
Method of Estimation	Estimation Parameter	LS mean difference
	Estimated Value	-17.2
	Confidence Interval	(2-Sided) 80%; -87.97 to 53.62
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 43.23
	Estimation Comments

Statistical Analysis 26

Statistical Analysis Overview	Comparison Group Selection	KPL-716: CIP Cohort, Placebo: CIP Cohort
	Comments	Change at Week 7
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.6682
	Comments	Calculated from an ANCOVA model including treatment as factor and baseline values as covariate.
	Method	ANCOVA
	Comments
Method of Estimation	Estimation Parameter	LS mean difference
	Estimated Value	-6.2
	Confidence Interval	(2-Sided) 80%; -25.26 to 12.78
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 14.35
	Estimation Comments

Statistical Analysis 27

Statistical Analysis Overview	Comparison Group Selection	KPL-716: LSC Cohort, Placebo: LSC Cohort
	Comments	Change at Week 7
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.0823
	Comments	Calculated from an ANCOVA model including treatment as factor and baseline values as covariate.
	Method	ANCOVA
	Comments
Method of Estimation	Estimation Parameter	LS mean difference
	Estimated Value	-95.2
	Confidence Interval	(2-Sided) 80%; -150.21 to -40.24
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 29.16
	Estimation Comments

Statistical Analysis 28

Statistical Analysis Overview	Comparison Group Selection	KPL-716: PPs Cohort, Placebo: PPs Cohort
	Comments	Change at Week 7
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.0087
	Comments	Calculated from an ANCOVA model including treatment as factor and baseline values as covariate.
	Method	ANCOVA
	Comments
Method of Estimation	Estimation Parameter	LS mean difference
	Estimated Value	-38.1
	Confidence Interval	(2-Sided) 80%; -55.38 to -20.92
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 12.95
	Estimation Comments

Statistical Analysis 29

Statistical Analysis Overview	Comparison Group Selection	KPL-716: CIU Cohort, Placebo: CIU Cohort
	Comments	Change at Week 8
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.4734
	Comments	Calculated from an ANCOVA model including treatment as factor and baseline values as covariate.
	Method	ANCOVA
	Comments
Method of Estimation	Estimation Parameter	LS mean difference
	Estimated Value	-31.7
	Confidence Interval	(2-Sided) 80%; -95.11 to 31.76
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 38.73
	Estimation Comments

Statistical Analysis 30

Statistical Analysis Overview	Comparison Group Selection	KPL-716: CIP Cohort, Placebo: CIP Cohort
	Comments	Change at Week 8
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.8130
	Comments	Calculated from an ANCOVA model including treatment as factor and baseline values as covariate.
	Method	ANCOVA
	Comments
Method of Estimation	Estimation Parameter	LS mean difference
	Estimated Value	-3.6
	Confidence Interval	(2-Sided) 80%; -23.33 to 16.18
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 14.91
	Estimation Comments

Statistical Analysis 31

Statistical Analysis Overview	Comparison Group Selection	KPL-716: LSC Cohort, Placebo: LSC Cohort
	Comments	Change at Week 8
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.0979
	Comments	Calculated from an ANCOVA model including treatment as factor and baseline values as covariate.
	Method	ANCOVA
	Comments
Method of Estimation	Estimation Parameter	LS mean difference
	Estimated Value	-92.0
	Confidence Interval	(2-Sided) 80%; -150.60 to -33.32
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 31.10
	Estimation Comments

Statistical Analysis 32

Statistical Analysis Overview	Comparison Group Selection	KPL-716: PPs Cohort, Placebo: PPs Cohort
	Comments	Change at Week 8
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.0122
	Comments	Calculated from an ANCOVA model including treatment as factor and baseline values as covariate.
	Method	ANCOVA
	Comments
Method of Estimation	Estimation Parameter	LS mean difference
	Estimated Value	-37.5
	Confidence Interval	(2-Sided) 80%; -55.48 to -19.61
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 13.48
	Estimation Comments

Statistical Analysis 33

Statistical Analysis Overview	Comparison Group Selection	KPL-716: CIU Cohort, Placebo: CIU Cohort
	Comments	Change at Week 9
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.4310
	Comments	Calculated from an ANCOVA model including treatment as factor and baseline values as covariate.
	Method	ANCOVA
	Comments
Method of Estimation	Estimation Parameter	LS mean difference
	Estimated Value	-32.1
	Confidence Interval	(2-Sided) 80%; -89.98 to 25.81
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 35.35
	Estimation Comments

Statistical Analysis 34

Statistical Analysis Overview	Comparison Group Selection	KPL-716: CIP Cohort, Placebo: CIP Cohort
	Comments	Change at Week 9
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.6452
	Comments	Calculated from an ANCOVA model including treatment as factor and baseline values as covariate.
	Method	ANCOVA
	Comments
Method of Estimation	Estimation Parameter	LS mean difference
	Estimated Value	-7.1
	Confidence Interval	(2-Sided) 80%; -27.38 to 13.12
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 15.22
	Estimation Comments

Statistical Analysis 35

Statistical Analysis Overview	Comparison Group Selection	KPL-716: LSC Cohort, Placebo: LSC Cohort
	Comments	Change at Week 9
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.1375
	Comments	Calculated from an ANCOVA model including treatment as factor and baseline values as covariate.
	Method	ANCOVA
	Comments
Method of Estimation	Estimation Parameter	LS mean difference
	Estimated Value	-89.2
	Confidence Interval	(2-Sided) 80%; -159.04 to -19.44
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 37.02
	Estimation Comments

Statistical Analysis 36

Statistical Analysis Overview	Comparison Group Selection	KPL-716: PPs Cohort, Placebo: PPs Cohort
	Comments	Change at Week 9
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.0143
	Comments	Calculated from an ANCOVA model including treatment as factor and baseline values as covariate.
	Method	ANCOVA
	Comments
Method of Estimation	Estimation Parameter	LS mean difference
	Estimated Value	-39.6
	Confidence Interval	(2-Sided) 80%; -58.97 to -20.15
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 14.59
	Estimation Comments

Statistical Analysis 37

Statistical Analysis Overview	Comparison Group Selection	KPL-716: CIU Cohort, Placebo: CIU Cohort
	Comments	Change at Week 10
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.5867
	Comments	Calculated from an ANCOVA model including treatment as factor and baseline values as covariate.
	Method	ANCOVA
	Comments
Method of Estimation	Estimation Parameter	LS mean difference
	Estimated Value	-22.1
	Confidence Interval	(2-Sided) 80%; -81.70 to 37.52
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 36.40
	Estimation Comments

Statistical Analysis 38

Statistical Analysis Overview	Comparison Group Selection	KPL-716: CIP Cohort, Placebo: CIP Cohort
	Comments	Change at Week 10
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.6745
	Comments	Calculated from an ANCOVA model including treatment as factor and baseline values as covariate.
	Method	ANCOVA
	Comments
Method of Estimation	Estimation Parameter	LS mean difference
	Estimated Value	6.1
	Confidence Interval	(2-Sided) 80%; -12.99 to 25.27
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 14.38
	Estimation Comments

Statistical Analysis 39

Statistical Analysis Overview	Comparison Group Selection	KPL-716: LSC Cohort, Placebo: LSC Cohort
	Comments	Change at Week 10
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.1039
	Comments	Calculated from an ANCOVA model including treatment as factor and baseline values as covariate.
	Method	ANCOVA
	Comments
Method of Estimation	Estimation Parameter	LS mean difference
	Estimated Value	-85.6
	Confidence Interval	(2-Sided) 80%; -142.18 to -29.09
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 29.99
	Estimation Comments

Statistical Analysis 40

Statistical Analysis Overview	Comparison Group Selection	KPL-716: PPs Cohort, Placebo: PPs Cohort
	Comments	Change at Week 10
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.0116
	Comments	Calculated from an ANCOVA model including treatment as factor and baseline values as covariate.
	Method	ANCOVA
	Comments
Method of Estimation	Estimation Parameter	LS mean difference
	Estimated Value	-42.5
	Confidence Interval	(2-Sided) 80%; -62.60 to -22.36
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 15.12
	Estimation Comments

Statistical Analysis 41

Statistical Analysis Overview	Comparison Group Selection	KPL-716: CIU Cohort, Placebo: CIU Cohort
	Comments	Change at Week 11
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.5807
	Comments	Calculated from an ANCOVA model including treatment as factor and baseline values as covariate.
	Method	ANCOVA
	Comments
Method of Estimation	Estimation Parameter	LS mean difference
	Estimated Value	-23.1
	Confidence Interval	(2-Sided) 80%; -84.55 to 38.26
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 37.49
	Estimation Comments

Statistical Analysis 42

Statistical Analysis Overview	Comparison Group Selection	KPL-716: CIP Cohort, Placebo: CIP Cohort
	Comments	Change at Week 11
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.5765
	Comments	Calculated from an ANCOVA model including treatment as factor and baseline values as covariate.
	Method	ANCOVA
	Comments
Method of Estimation	Estimation Parameter	LS mean difference
	Estimated Value	8.6
	Confidence Interval	(2-Sided) 80%; -11.55 to 28.80
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 15.16
	Estimation Comments

Statistical Analysis 43

Statistical Analysis Overview	Comparison Group Selection	KPL-716: LSC Cohort, Placebo: LSC Cohort
	Comments	Change at Week 11
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.0933
	Comments	Calculated from an ANCOVA model including treatment as factor and baseline values as covariate.
	Method	ANCOVA
	Comments
Method of Estimation	Estimation Parameter	LS mean difference
	Estimated Value	-86.2
	Confidence Interval	(2-Sided) 80%; -139.70 to -32.75
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 28.36
	Estimation Comments

Statistical Analysis 44

Statistical Analysis Overview	Comparison Group Selection	KPL-716: PPs Cohort, Placebo: PPs Cohort
	Comments	Change at Week 11
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.0173
	Comments	Calculated from an ANCOVA model including treatment as factor and baseline values as covariate.
	Method	ANCOVA
	Comments
Method of Estimation	Estimation Parameter	LS mean difference
	Estimated Value	-39.3
	Confidence Interval	(2-Sided) 80%; -59.29 to -19.37
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 45

Statistical Analysis Overview	Comparison Group Selection	KPL-716: CIU Cohort, Placebo: CIU Cohort
	Comments	Change at Week 12
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.5293
	Comments	Calculated from an ANCOVA model including treatment as factor and baseline values as covariate.
	Method	ANCOVA
	Comments
Method of Estimation	Estimation Parameter	LS mean difference
	Estimated Value	-27.2
	Confidence Interval	(2-Sided) 80%; -90.04 to 35.62
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 38.36
	Estimation Comments

Statistical Analysis 46

Statistical Analysis Overview	Comparison Group Selection	KPL-716: CIP Cohort, Placebo: CIP Cohort
	Comments	Change at Week 12
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.9676
	Comments	Calculated from an ANCOVA model including treatment as factor and baseline values as covariate.
	Method	ANCOVA
	Comments
Method of Estimation	Estimation Parameter	LS mean difference
	Estimated Value	-0.6
	Confidence Interval	(2-Sided) 80%; -20.73 to 19.49
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 15.12
	Estimation Comments

Statistical Analysis 47

Statistical Analysis Overview	Comparison Group Selection	KPL-716: LSC Cohort, Placebo: LSC Cohort
	Comments	Change at Week 12
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.0663
	Comments	Calculated from an ANCOVA model including treatment as factor and baseline values as covariate.
	Method	ANCOVA
	Comments
Method of Estimation	Estimation Parameter	LS mean difference
	Estimated Value	-86.2
	Confidence Interval	(2-Sided) 80%; -130.27 to -42.11
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 23.38
	Estimation Comments

Statistical Analysis 48

Statistical Analysis Overview	Comparison Group Selection	KPL-716: PPs Cohort, Placebo: PPs Cohort
	Comments	Change at Week 12
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.0252
	Comments	Calculated from an ANCOVA model including treatment as factor and baseline values as covariate.
	Method	ANCOVA
	Comments
Method of Estimation	Estimation Parameter	LS mean difference
	Estimated Value	-37.4
	Confidence Interval	(2-Sided) 80%; -57.81 to -17.02
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 15.33
	Estimation Comments

Statistical Analysis 49

Statistical Analysis Overview	Comparison Group Selection	KPL-716: CIU Cohort, Placebo: CIU Cohort
	Comments	Change at Week 13
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.6637
	Comments	Calculated from an ANCOVA model including treatment as factor and baseline values as covariate.
	Method	ANCOVA
	Comments
Method of Estimation	Estimation Parameter	LS mean difference
	Estimated Value	-19.6
	Confidence Interval	(2-Sided) 80%; -86.45 to 47.22
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 40.81
	Estimation Comments

Statistical Analysis 50

Statistical Analysis Overview	Comparison Group Selection	KPL-716: CIP Cohort, Placebo: CIP Cohort
	Comments	Change at Week 13
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.9173
	Comments	Calculated from an ANCOVA model including treatment as factor and baseline values as covariate.
	Method	ANCOVA
	Comments
Method of Estimation	Estimation Parameter	LS mean difference
	Estimated Value	-1.6
	Confidence Interval	(2-Sided) 80%; -22.04 to 18.81
	Parameter Dispersion	Type: Standard Deviation; Value: 15.35
	Estimation Comments

Statistical Analysis 51

Statistical Analysis Overview	Comparison Group Selection	KPL-716: LSC Cohort, Placebo: LSC Cohort
	Comments	Change at Week 13
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.0685
	Comments	Calculated from an ANCOVA model including treatment as factor and baseline values as covariate.
	Method	ANCOVA
	Comments
Method of Estimation	Estimation Parameter	LS mean difference
	Estimated Value	-96.2
	Confidence Interval	(2-Sided) 80%; -146.23 to -46.10
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 26.55
	Estimation Comments

Statistical Analysis 52

Statistical Analysis Overview	Comparison Group Selection	KPL-716: PPs Cohort, Placebo: PPs Cohort
	Comments	Change at Week 13
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.0230
	Comments	Calculated from an ANCOVA model including treatment as factor and baseline values as covariate.
	Method	ANCOVA
	Comments
Method of Estimation	Estimation Parameter	LS mean difference
	Estimated Value	-39.7
	Confidence Interval	(2-Sided) 80%; -60.91 to -18.44
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 15.96
	Estimation Comments

Statistical Analysis 53

Statistical Analysis Overview	Comparison Group Selection	KPL-716: CIU Cohort, Placebo: CIU Cohort
	Comments	Change at Week 14
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.6471
	Comments	Calculated from an ANCOVA model including treatment as factor and baseline values as covariate.
	Method	ANCOVA
	Comments
Method of Estimation	Estimation Parameter	LS mean difference
	Estimated Value	-19.1
	Confidence Interval	(2-Sided) 80%; -80.69 to 42.54
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 37.62
	Estimation Comments

Statistical Analysis 54

Statistical Analysis Overview	Comparison Group Selection	KPL-716: CIP Cohort, Placebo: CIP Cohort
	Comments	Change at Week 14
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.8044
	Comments	Calculated from an ANCOVA model including treatment as factor and baseline values as covariate.
	Method	ANCOVA
	Comments
Method of Estimation	Estimation Parameter	LS mean difference
	Estimated Value	-3.9
	Confidence Interval	(2-Sided) 80%; -24.56 to 16.75
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 15.52
	Estimation Comments

Statistical Analysis 55

Statistical Analysis Overview	Comparison Group Selection	KPL-716: LSC Cohort, Placebo: LSC Cohort
	Comments	Change at Week 14
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.0741
	Comments	Calculated from an ANCOVA model including treatment as factor and baseline values as covariate.
	Method	ANCOVA
	Comments
Method of Estimation	Estimation Parameter	LS mean difference
	Estimated Value	-99.5
	Confidence Interval	(2-Sided) 80%; -153.63 to -45.37
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 28.71
	Estimation Comments

Statistical Analysis 56

Statistical Analysis Overview	Comparison Group Selection	KPL-716: PPs Cohort, Placebo: PPs Cohort
	Comments	Change at Week 14
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.0219
	Comments	Calculated from an ANCOVA model including treatment as factor and baseline values as covariate.
	Method	ANCOVA
	Comments
Method of Estimation	Estimation Parameter	LS mean difference
	Estimated Value	-39.9
	Confidence Interval	(2-Sided) 80%; -61.00 to -18.72
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 15.89
	Estimation Comments

Statistical Analysis 57

Statistical Analysis Overview	Comparison Group Selection	KPL-716: CIU Cohort, Placebo: CIU Cohort
	Comments	Change at Week 15
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.5436
	Comments	Calculated from an ANCOVA model including treatment as factor and baseline values as covariate.
	Method	ANCOVA
	Comments
Method of Estimation	Estimation Parameter	LS mean difference
	Estimated Value	-25.4
	Confidence Interval	(2-Sided) 80%; -86.21 to 35.46
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 37.15
	Estimation Comments

Statistical Analysis 58

Statistical Analysis Overview	Comparison Group Selection	KPL-716: CIP Cohort, Placebo: CIP Cohort
	Comments	Change at Week 15
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.9149
	Comments	Calculated from an ANCOVA model including treatment as factor and baseline values as covariate.
	Method	ANCOVA
	Comments
Method of Estimation	Estimation Parameter	LS mean difference
	Estimated Value	-1.7
	Confidence Interval	(2-Sided) 80%; -23.20 to 19.71
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 16.13
	Estimation Comments

Statistical Analysis 59

Statistical Analysis Overview	Comparison Group Selection	KPL-716: LSC Cohort, Placebo: LSC Cohort
	Comments	Change at Week 15
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.0646
	Comments	Calculated from an ANCOVA model including treatment as factor and baseline values as covariate.
	Method	ANCOVA
	Comments
Method of Estimation	Estimation Parameter	LS mean difference
	Estimated Value	-94.8
	Confidence Interval	(2-Sided) 80%; -142.63 to -47.05
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 25.34
	Estimation Comments

Statistical Analysis 60

Statistical Analysis Overview	Comparison Group Selection	KPL-716: PPs Cohort, Placebo: PPs Cohort
	Comments	Change at Week 15
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.0611
	Comments	Calculated from an ANCOVA model including treatment as factor and baseline values as covariate.
	Method	ANCOVA
	Comments
Method of Estimation	Estimation Parameter	LS mean difference
	Estimated Value	-34.2
	Confidence Interval	(2-Sided) 80%; -56.89 to -11.41
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 17.09
	Estimation Comments

Statistical Analysis 61

Statistical Analysis Overview	Comparison Group Selection	KPL-716: CIU Cohort, Placebo: CIU Cohort
	Comments	Change at Week 16
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.6060
	Comments	Calculated from an ANCOVA model including treatment as factor and baseline values as covariate.
	Method	ANCOVA
	Comments
Method of Estimation	Estimation Parameter	LS mean difference
	Estimated Value	-22.0
	Confidence Interval	(2-Sided) 80%; -84.68 to 40.71
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 38.28
	Estimation Comments

Statistical Analysis 62

Statistical Analysis Overview	Comparison Group Selection	KPL-716: CIP Cohort, Placebo: CIP Cohort
	Comments	Change at Week 16
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.6823
	Comments	Calculated from an ANCOVA model including treatment as factor and baseline values as covariate.
	Method	ANCOVA
	Comments
Method of Estimation	Estimation Parameter	LS mean difference
	Estimated Value	-6.9
	Confidence Interval	(2-Sided) 80%; -29.00 to 15.18
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 16.61
	Estimation Comments

Statistical Analysis 63

Statistical Analysis Overview	Comparison Group Selection	KPL-716: LSC Cohort, Placebo: LSC Cohort
	Comments	Change at Week 16
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.0556
	Comments	Calculated from an ANCOVA model including treatment as factor and baseline values as covariate.
	Method	ANCOVA
	Comments
Method of Estimation	Estimation Parameter	LS mean difference
	Estimated Value	-99.7
	Confidence Interval	(2-Sided) 80%; -146.02 to -53.41
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 24.56
	Estimation Comments

Statistical Analysis 64

Statistical Analysis Overview	Comparison Group Selection	KPL-716: PPs Cohort, Placebo: PPs Cohort
	Comments	Change at Week 16
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.0652
	Comments	Calculated from an ANCOVA model including treatment as factor and baseline values as covariate.
	Method	ANCOVA
	Comments
Method of Estimation	Estimation Parameter	LS mean difference
	Estimated Value	-33.4
	Confidence Interval	(2-Sided) 80%; -55.98 to -10.76
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 16.99
	Estimation Comments

Statistical Analysis 65

Statistical Analysis Overview	Comparison Group Selection	KPL-716: CIU Cohort, Placebo: CIU Cohort
	Comments	Change at Week 17
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.5714
	Comments	Calculated from an ANCOVA model including treatment as factor and baseline values as covariate.
	Method	ANCOVA
	Comments
Method of Estimation	Estimation Parameter	LS mean difference
	Estimated Value	-26.3
	Confidence Interval	(2-Sided) 80%; -94.14 to 41.62
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 41.45
	Estimation Comments

Statistical Analysis 66

Statistical Analysis Overview	Comparison Group Selection	KPL-716: CIP Cohort, Placebo: CIP Cohort
	Comments	Change at Week 17
	Type of Statistical Test	Other
	Comments
Statistical Test of Hypothesis	p-Value	0.5386
	Comments	Calculated from an ANCOVA model including treatment as factor and baseline values as covariate.
	Method	ANCOVA
	Comments
Method of Estimation	Estimation Parameter	LS mean difference
	Estimated Value	-10.5
	Confidence Interval	(2-Sided) 80%; -32.93 to 11.83
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 16.82
	Estimation Comments

Statistical Analysis 67

Statistical Analysis Overview	Comparison Group Selection	KPL-716: LSC Cohort, Placebo: LSC Cohort
	Comments	Change at Week 17
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.0438
	Comments	Calculated from an ANCOVA model including treatment as factor and baseline values as covariate.
	Method	ANCOVA
	Comments
Method of Estimation	Estimation Parameter	LS mean difference
	Estimated Value	-99.0
	Confidence Interval	(2-Sided) 80%; -139.35 to -58.60
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 21.41
	Estimation Comments

Statistical Analysis 68

Statistical Analysis Overview	Comparison Group Selection	KPL-716: PPs Cohort, Placebo: PPs Cohort
	Comments	Change at Week 17
	Type of Statistical Test	Other
	Comments
Statistical Test of Hypothesis	p-Value	0.1829
	Comments	Calculated from an ANCOVA model including treatment as factor and baseline values as covariate.
	Method	ANCOVA
	Comments
Method of Estimation	Estimation Parameter	LS mean difference
	Estimated Value	-27.2
	Confidence Interval	(2-Sided) 80%; -53.38 to -1.08
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 19.66
	Estimation Comments

Statistical Analysis 69

Statistical Analysis Overview	Comparison Group Selection	KPL-716: CIU Cohort, Placebo: CIU Cohort
	Comments	Change at Week 18
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.5443
	Comments	Calculated from an ANCOVA model including treatment as factor and baseline values as covariate.
	Method	ANCOVA
	Comments
Method of Estimation	Estimation Parameter	LS mean difference
	Estimated Value	-25.6
	Confidence Interval	(2-Sided) 80%; -87.20 to 35.94
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 37.59
	Estimation Comments

Statistical Analysis 70

Statistical Analysis Overview	Comparison Group Selection	KPL-716: CIP Cohort, Placebo: CIP Cohort
	Comments	Change at Week 18
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.6748
	Comments	Calculated from an ANCOVA model including treatment as factor and baseline values as covariate.
	Method	ANCOVA
	Comments
Method of Estimation	Estimation Parameter	LS mean difference
	Estimated Value	-7.9
	Confidence Interval	(2-Sided) 80%; -32.39 to 16.66
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 18.43
	Estimation Comments

Statistical Analysis 71

Statistical Analysis Overview	Comparison Group Selection	KPL-716: LSC Cohort, Placebo: LSC Cohort
	Comments	Change at Week 18
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.0297
	Comments	Calculated from an ANCOVA model including treatment as factor and baseline values as covariate.
	Method	ANCOVA
	Comments
Method of Estimation	Estimation Parameter	LS mean difference
	Estimated Value	-96.2
	Confidence Interval	(2-Sided) 80%; -128.19 to -64.19
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 16.97
	Estimation Comments

Statistical Analysis 72

Statistical Analysis Overview	Comparison Group Selection	KPL-716: PPs Cohort, Placebo: PPs Cohort
	Comments	Change at Week 18
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.1899
	Comments	Calculated from an ANCOVA model including treatment as factor and baseline values as covariate.
	Method	ANCOVA
	Comments
Method of Estimation	Estimation Parameter	LS mean difference
	Estimated Value	-27.0
	Confidence Interval	(2-Sided) 80%; -53.33 to -0.63
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 19.80
	Estimation Comments

4. Secondary Outcome

Title	Change From Baseline in Pruritus Visual Analog Scale (VAS) Over Time
Description	Participants were asked to place a line perpendicular to the VAS line at the point that represents the intensity of their average pruritus experienced over the previous 3 days using a scale from 0 to 10, with 0 indicating no pruritus and 10 indicating the worst imaginable pruritus.
Time Frame	Baseline, Weeks 1-8, 10, 12, 14, 16, 18

Outcome Measure Data

Analysis Population Description

Modified intent to treat (mITT) set: all randomized participants who received at least 1 dose of KPL-716 or placebo and had at least 1 post-baseline efficacy assessment in the double-blind treatment period. Missing data were imputed using the last observation carried forward (LOCF) method. Once a participant started treatment period (through Week 8), missing data in treatment period were imputed. Once a participant started the follow up (FU) period, missing data in FU period were imputed.

Arm/Group Title	KPL-716: CIU Cohort	Placebo: CIU Cohort	KPL-716: CIP Cohort	Placebo: CIP Cohort	KPL-716: LP Cohort	Placebo: LP Cohort	KPL-716: LSC Cohort	Placebo: LSC Cohort	KPL-716: PPs Cohort	Placebo: PPs Cohort
Arm/Group Description	Participants with CIU received KPL-716 weekly for 8 weeks	Participants with CIU received placebo weekly for 8 weeks	Participants with CIP received KPL-716 weekly for 8 weeks	Participants with CIP received placebo weekly for 8 weeks	Participants with LP received KPL-716 weekly for 8 weeks	Participants with LP received placebo weekly for 8 weeks	Participants with LSC received KPL-716 weekly for 8 weeks	Participants with LSC received placebo weekly for 8 weeks	Participants with PPs received KPL-716 weekly for 8 weeks	Participants with PPs received placebo weekly for 8 weeks
Measure Participants	4	2	14	9	3	0	4	1	14	7
Change at Week 1	-1.7 (0.98)	0.0 (0.00)	-1.3 (0.79)	-2.0 (0.78)	-0.4 (0.26)	-4.0 (1.61)	-0.7 (NA)	-1.3 (0.29)	-0.3 (0.28)
Change at Week 2	-2.8 (1.43)	0.0 (0.00)	-3.0 (0.96)	-2.6 (0.62)	-0.4 (0.19)	-4.4 (1.80)	-1.0 (NA)	-2.2 (0.55)	-0.7 (0.31)
Change at Week 3	-3.3 (1.52)	-0.1 (0.10)	-3.2 (1.09)	-3.4 (0.97)	-2.0 (1.36)	-5.2 (1.85)	-2.2 (NA)	-3.4 (0.55)	-0.9 (0.81)
Change at Week 4	-4.3 (1.67)	0.0 (0.00)	-3.7 (0.94)	-3.9 (0.95)	-2.8 (1.88)	-5.3 (1.66)	-2.2 (NA)	-4.3 (0.54)	-1.4 (0.94)
Change at Week 5	-5.2 (1.82)	0.0 (0.00)	-4.5 (1.01)	-4.7 (0.88)	-3.0 (1.86)	-5.7 (1.67)	-3.7 (NA)	-4.3 (0.51)	-1.6 (0.99)
Change at Week 6	-4.4 (1.88)	0.0 (0.00)	-4.5 (1.00)	-4.2 (1.07)	-3.1 (1.85)	-5.9 (1.57)	-2.0 (NA)	-5.2 (0.54)	-1.9 (1.05)
Change at Week 7	-5.1 (1.78)	-0.1 (0.10)	-4.7 (1.05)	-4.7 (0.88)	-3.3 (1.85)	-6.1 (1.45)	-1.4 (NA)	-5.3 (0.57)	-2.1 (1.27)
Change at Week 8	-4.2 (2.00)	0.0 (0.00)	-4.4 (1.03)	-4.3 (0.95)	-3.3 (1.85)	-6.0 (1.42)	-1.8 (NA)	-5.8 (0.61)	-2.2 (1.29)
Change at Week 10	-4.8 (1.86)	0.0 (0.00)	-4.2 (1.07)	-5.8 (0.58)	-5.6 (0.85)	-6.2 (1.50)	-3.5 (NA)	-5.9 (0.66)	-3.1 (1.36)
Change at Week 12	-4.1 (2.11)	0.0 (0.00)	-4.7 (1.10)	-4.8 (1.18)	-5.1 (1.30)	-6.3 (1.37)	-3.5 (NA)	-5.6 (0.71)	-3.8 (1.26)
Change at Week 14	-3.5 (2.19)	0.0 (0.00)	-5.0 (1.00)	-4.2 (1.06)	-5.3 (1.10)	-6.4 (1.31)	-1.4 (NA)	-5.8 (0.75)	-3.6 (1.37)
Change at Week 16	-4.5 (1.91)	-0.1 (0.05)	-4.2 (1.07)	-4.0 (1.13)	-5.6 (0.85)	-6.6 (1.12)	-0.8 (NA)	-5.6 (0.79)	-3.5 (1.41)
Change at Week 18	-3.9 (2.07)	0.0 (0.00)	-4.2 (1.22)	-3.6 (1.20)	-5.6 (2.40)	-7.0 (0.74)	-0.9 (NA)	-5.4 (0.90)	-3.9 (1.31)

5. Secondary Outcome

Title	Percent Change From Baseline in Pruritus VAS Over Time
Description	Participants were asked to place a line perpendicular to the VAS line at the point that represents the intensity of their average pruritus experienced over the previous 3 days using a scale from 0 to 10, with 0 indicating no pruritus and 10 indicating the worst imaginable pruritus.
Time Frame	Baseline, Weeks 1-8, 10, 12, 14, 16, 18

Outcome Measure Data

Analysis Population Description

Modified intent to treat (mITT) set: all randomized participants who received at least 1 dose of KPL-716 or placebo and had at least 1 post-baseline efficacy assessment in the double-blind treatment period. Missing data were imputed using the last observation carried forward (LOCF) method. Once a participant started treatment period (through Week 8), missing data in treatment period were imputed. Once a participant started the follow up (FU) period, missing data in FU period were imputed.

Arm/Group Title	KPL-716: CIU Cohort	Placebo: CIU Cohort	KPL-716: CIP Cohort	Placebo: CIP Cohort	KPL-716: LP Cohort	Placebo: LP Cohort	KPL-716: LSC Cohort	Placebo: LSC Cohort	KPL-716: PPs Cohort	Placebo: PPs Cohort
Arm/Group Description	Participants with CIU received KPL-716 weekly for 8 weeks	Participants with CIU received placebo weekly for 8 weeks	Participants with CIP received KPL-716 weekly for 8 weeks	Participants with CIP received placebo weekly for 8 weeks	Participants with LP received KPL-716 weekly for 8 weeks	Participants with LP received placebo weekly for 8 weeks	Participants with LSC received KPL-716 weekly for 8 weeks	Participants with LSC received placebo weekly for 8 weeks	Participants with PPs received KPL-716 weekly for 8 weeks	Participants with PPs received placebo weekly for 8 weeks
Measure Participants	4	2	14	9	3	0	4	1	14	7
Change at Week 1	-23.6 (13.76)	-8.3 (19.72)	-15.3 (9.17)	-24.8 (11.44)	-5.3 (1.80)	-76.1 (27.14)	90.9 (85.95)	-15.4 (3.19)	-4.6 (4.52)
Change at Week 2	-37.4 (19.67)	-4.3 (28.19)	-34.2 (9.66)	-32.8 (12.04)	-5.1 (3.22)	-79.6 (34.28)	81.3 (108.56)	-24.2 (5.50)	-10.1 (7.78)
Change at Week 3	-43.3 (19.79)	-2.6 (28.36)	-37.4 (12.12)	-44.5 (15.12)	-26.2 (8.32)	-97.1 (28.92)	96.7 (91.57)	-40.6 (6.26)	-10.3 (8.87)
Change at Week 4	-54.9 (19.93)	-0.9 (28.57)	-44.4 (10.57)	-50.7 (13.18)	-37.3 (12.60)	-93.6 (28.13)	74.8 (89.08)	-52.7 (6.55)	-16.0 (9.27)
Change at Week 5	-66.3 (21.37)	-0.2 (30.63)	-54.1 (10.84)	-60.4 (13.52)	-40.0 (15.97)	-99.4 (26.68)	64.0 (84.47)	-52.5 (6.54)	-19.1 (9.26)
Change at Week 6	-57.2 (22.58)	-1.2 (32.37)	-53.0 (11.31)	-52.4 (14.11)	-41.6 (17.99)	-101.0 (24.68)	76.3 (78.14)	-63.5 (6.90)	-21.5 (9.77)
Change at Week 7	-65.7 (18.99)	0.1 (27.22)	-55.7 (10.97)	-60.8 (13.68)	-44.3 (21.36)	-101.8 (22.55)	73.6 (71.40)	-64.6 (7.89)	-25.4 (11.18)
Change at Week 8	-54.1 (22.59)	-0.4 (32.38)	-52.1 (11.11)	-55.0 (13.86)	-44.3 (21.36)	-99.2 (23.11)	63.8 (73.18)	-70.9 (8.44)	-25.2 (11.96)
Change at Week 10	-61.6 (20.31)	0.7 (29.11)	-50.7 (10.73)	-72.2 (12.39)	-76.9 (0.00)	-103.9 (22.62)	57.5 (71.64)	-70.6 (8.32)	-36.2 (12.71)
Change at Week 12	-51.9 (21.21)	3.3 (30.40)	-56.3 (12.44)	-58.7 (14.37)	-69.7 (0.00)	-102.9 (21.13)	46.3 (66.92)	-67.6 (8.32)	-45.5 (12.71)
Change at Week 14	-44.2 (20.40)	4.4 (29.24)	-60.8 (11.32)	-51.2 (13.07)	-72.9 (0.00)	-103.3 (19.74)	64.5 (62.52)	-69.6 (8.91)	-42.5 (13.61)
Change at Week 16	-56.8 (14.02)	5.1 (20.09)	-49.5 (11.91)	-48.9 (13.75)	-76.9 (0.00)	-102.0 (16.87)	57.2 (53.41)	-68.1 (9.43)	-41.6 (14.40)
Change at Week 18	-47.8 (14.97)	6.8 (21.45)	-49.1 (13.66)	-45.0 (15.77)	-74.6 (0.00)	-101.3 (9.93)	29.5 (31.43)	-64.5 (10.23)	-46.0 (15.63)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	KPL-716: CIU Cohort, Placebo: CIU Cohort
	Comments	Change at Week 1
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.5763
	Comments	Calculated from an ANCOVA model including treatment as factor and baseline values as covariate.
	Method	ANCOVA
	Comments
Method of Estimation	Estimation Parameter	LS mean difference
	Estimated Value	-15.3
	Confidence Interval	(2-Sided) 80%; -55.37 to 24.78
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 24.47
	Estimation Comments

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	KPL-716: CIP Cohort, Placebo: CIP Cohort
	Comments	Change at Week 1
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.5214
	Comments	Calculated from an ANCOVA model including treatment as factor and baseline values as covariate.
	Method	ANCOVA
	Comments
Method of Estimation	Estimation Parameter	LS mean difference
	Estimated Value	9.6
	Confidence Interval	(2-Sided) 80%; -9.86 to 29.01
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 14.66
	Estimation Comments

Statistical Analysis 3

Statistical Analysis Overview	Comparison Group Selection	KPL-716: LSC Cohort, Placebo: LSC Cohort
	Comments	Change at Week 1
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.2536
	Comments	Calculated from an ANCOVA model including treatment as factor and baseline values as covariate.
	Method	ANCOVA
	Comments
Method of Estimation	Estimation Parameter	LS mean difference
	Estimated Value	-167.0
	Confidence Interval	(2-Sided) 80%; -365.51 to 31.54
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 105.28
	Estimation Comments

Statistical Analysis 4

Statistical Analysis Overview	Comparison Group Selection	KPL-716: PPs Cohort, Placebo: PPs Cohort
	Comments	Change at Week 1
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.0670
	Comments	Calculated from an ANCOVA model including treatment as factor and baseline values as covariate.
	Method	ANCOVA
	Comments
Method of Estimation	Estimation Parameter	LS mean difference
	Estimated Value	-10.8
	Confidence Interval	(2-Sided) 80%; -18.20 to -3.44
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 5.55
	Estimation Comments

Statistical Analysis 5

Statistical Analysis Overview	Comparison Group Selection	KPL-716: CIU Cohort, Placebo: CIU Cohort
	Comments	Change at Week 2
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.4133
	Comments	Calculated from an ANCOVA model including treatment as factor and baseline values as covariate.
	Method	ANCOVA
	Comments
Method of Estimation	Estimation Parameter	LS mean difference
	Estimated Value	-33.1
	Confidence Interval	(2-Sided) 80%; -90.43 to 24.15
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 34.98
	Estimation Comments

Statistical Analysis 6

Statistical Analysis Overview	Comparison Group Selection	KPL-716: CIP Cohort, Placebo: CIP Cohort
	Comments	Change at Week 2
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.9305
	Comments
	Method	ANCOVA
	Comments
Method of Estimation	Estimation Parameter	LS mean difference
	Estimated Value	-1.4
	Confidence Interval	(2-Sided) 80%; -21.83 to 19.11
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 15.44
	Estimation Comments

Statistical Analysis 7

Statistical Analysis Overview	Comparison Group Selection	KPL-716: LSC Cohort, Placebo: LSC Cohort
	Comments	Change at Week 2
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.3499
	Comments	Calculated from an ANCOVA model including treatment as factor and baseline values as covariate.
	Method	ANCOVA
	Comments
Method of Estimation	Estimation Parameter	LS mean difference
	Estimated Value	-160.9
	Confidence Interval	(2-Sided) 80%; -411.65 to 89.86
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 132.98
	Estimation Comments

Statistical Analysis 8

Statistical Analysis Overview	Comparison Group Selection	KPL-716: PPs Cohort, Placebo: PPs Cohort
	Comments	Change at Week 2
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.1588
	Comments	Calculated from an ANCOVA model including treatment as factor and baseline values as covariate.
	Method	ANCOVA
	Comments
Method of Estimation	Estimation Parameter	LS mean difference
	Estimated Value	-14.0
	Confidence Interval	(2-Sided) 80%; -26.74 to -1.33
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 9.55
	Estimation Comments

Statistical Analysis 9

Statistical Analysis Overview	Comparison Group Selection	KPL-716: CIU Cohort, Placebo: CIU Cohort
	Comments	Change at Week 3
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.3319
	Comments	Calculated from an ANCOVA model including treatment as factor and baseline values as covariate.
	Method	ANCOVA
	Comments
Method of Estimation	Estimation Parameter	LS mean difference
	Estimated Value	-40.6
	Confidence Interval	(2-Sided) 80%; -98.26 to 17.00
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 35.19
	Estimation Comments

Statistical Analysis 10

Statistical Analysis Overview	Comparison Group Selection	KPL-716: CIP Cohort, Placebo: CIP Cohort
	Comments	Change at Week 3
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.7179
	Comments	Calculated from an ANCOVA model including treatment as factor and baseline values as covariate.
	Method	ANCOVA
	Comments
Method of Estimation	Estimation Parameter	LS mean difference
	Estimated Value	7.1
	Confidence Interval	(2-Sided) 80%; -18.59 to 32.80
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 19.39
	Estimation Comments

Statistical Analysis 11

Statistical Analysis Overview	Comparison Group Selection	KPL-716: LSC Cohort, Placebo: LSC Cohort
	Comments	Change at Week 3
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.2261
	Comments	Calculated from an ANCOVA model including treatment as factor and baseline values as covariate.
	Method	ANCOVA
	Comments
Method of Estimation	Estimation Parameter	LS mean difference
	Estimated Value	-193.8
	Confidence Interval	(2-Sided) 80%; -405.34 to 17.67
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 112.17
	Estimation Comments

Statistical Analysis 12

Statistical Analysis Overview	Comparison Group Selection	KPL-716: PPs Cohort, Placebo: PPs Cohort
	Comments	Change at Week 3
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.0123
	Comments	Calculated from an ANCOVA model including treatment as factor and baseline values as covariate.
	Method	ANCOVA
	Comments
Method of Estimation	Estimation Parameter	LS mean difference
	Estimated Value	-30.3
	Confidence Interval	(2-Sided) 80%; -44.75 to -15.80
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 10.88
	Estimation Comments

Statistical Analysis 13

Statistical Analysis Overview	Comparison Group Selection	KPL-716: CIU Cohort, Placebo: CIU Cohort
	Comments	Change at Week 4
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.2253
	Comments	Calculated from an ANCOVA model including treatment as factor and baseline values as covariate.
	Method	ANCOVA
	Comments
Method of Estimation	Estimation Parameter	LS mean difference
	Estimated Value	-54.0
	Confidence Interval	(2-Sided) 80%; -112.02 to 4.09
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 35.45
	Estimation Comments

Statistical Analysis 14

Statistical Analysis Overview	Comparison Group Selection	KPL-716: CIP Cohort, Placebo: CIP Cohort
	Comments	Change at Week 4
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.7149
	Comments	Calculated from an ANCOVA model including treatment as factor and baseline values as covariate.
	Method	ANCOVA
	Comments
Method of Estimation	Estimation Parameter	LS mean difference
	Estimated Value	6.3
	Confidence Interval	(2-Sided) 80%; -16.14 to 28.66
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 16.90
	Estimation Comments

Statistical Analysis 15

Statistical Analysis Overview	Comparison Group Selection	KPL-716: LSC Cohort, Placebo: LSC Cohort
	Comments	Change at Week 4
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.2627
	Comments	Calculated from an ANCOVA model including treatment as factor and baseline values as covariate.
	Method	ANCOVA
	Comments
Method of Estimation	Estimation Parameter	LS mean difference
	Estimated Value	-168.4
	Confidence Interval	(2-Sided) 80%; -374.16 to 37.36
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 109.12
	Estimation Comments

Statistical Analysis 16

Statistical Analysis Overview	Comparison Group Selection	KPL-716: PPs Cohort, Placebo: PPs Cohort
	Comments	Change at Week 4
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.0047
	Comments	Calculated from an ANCOVA model including treatment as factor and baseline values as covariate.
	Method	ANCOVA
	Comments
Method of Estimation	Estimation Parameter	LS mean difference
	Estimated Value	-36.7
	Confidence Interval	(2-Sided) 80%; -51.87 to -21.60
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 11.38
	Estimation Comments

Statistical Analysis 17

Statistical Analysis Overview	Comparison Group Selection	KPL-716: CIU Cohort, Placebo: CIU Cohort
	Comments	Change at Week 5
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.1803
	Comments	Calculated from an ANCOVA model including treatment as factor and baseline values as covariate.
	Method	ANCOVA
	Comments
Method of Estimation	Estimation Parameter	LS mean difference
	Estimated Value	-66.1
	Confidence Interval	(2-Sided) 80%; -128.37 to -3.88
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 38.01
	Estimation Comments

Statistical Analysis 18

Statistical Analysis Overview	Comparison Group Selection	KPL-716: CIP Cohort, Placebo: CIP Cohort
	Comments	Change at Week 5
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.7174
	Comments	Calculated from an ANCOVA model including treatment as factor and baseline values as covariate.
	Method	ANCOVA
	Comments
Method of Estimation	Estimation Parameter	LS mean difference
	Estimated Value	6.4
	Confidence Interval	(2-Sided) 80%; -16.62 to 29.35
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 17.34
	Estimation Comments

Statistical Analysis 19

Statistical Analysis Overview	Comparison Group Selection	KPL-716: LSC Cohort, Placebo: LSC Cohort
	Comments	Change at Week 5
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.2551
	Comments	Calculated from an ANCOVA model including treatment as factor and baseline values as covariate.
	Method	ANCOVA
	Comments
Method of Estimation	Estimation Parameter	LS mean difference
	Estimated Value	-163.4
	Confidence Interval	(2-Sided) 80%; -358.51 to 31.72
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 103.47
	Estimation Comments

Statistical Analysis 20

Statistical Analysis Overview	Comparison Group Selection	KPL-716: PPs Cohort, Placebo: PPs Cohort
	Comments	Change at Week 5
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.0086
	Comments	Calculated from an ANCOVA model including treatment as factor and baseline values as covariate.
	Method	ANCOVA
	Comments
Method of Estimation	Estimation Parameter	LS mean difference
	Estimated Value	-33.5
	Confidence Interval	(2-Sided) 80%; -48.58 to -18.36
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 11.36
	Estimation Comments

Statistical Analysis 21

Statistical Analysis Overview	Comparison Group Selection	KPL-716: CIU Cohort, Placebo: CIU Cohort
	Comments	Change at Week 6
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.2576
	Comments	Calculated from an ANCOVA model including treatment as factor and baseline values as covariate.
	Method	ANCOVA
	Comments
Method of Estimation	Estimation Parameter	LS mean difference
	Estimated Value	-56.0
	Confidence Interval	(2-Sided) 80%; -121.78 to 9.78
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 40.16
	Estimation Comments

Statistical Analysis 22

Statistical Analysis Overview	Comparison Group Selection	KPL-716: CIP Cohort, Placebo: CIP Cohort
	Comments	Change at Week 6
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.9722
	Comments	Calculated from an ANCOVA model including treatment as factor and baseline values as covariate.
	Method	ANCOVA
	Comments
Method of Estimation	Estimation Parameter	LS mean difference
	Estimated Value	-0.6
	Confidence Interval	(2-Sided) 80%; -24.62 to 23.34
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 18.09
	Estimation Comments

Statistical Analysis 23

Statistical Analysis Overview	Comparison Group Selection	KPL-716: LSC Cohort, Placebo: LSC Cohort
	Comments	Change at Week 6
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.2051
	Comments	Calculated from an ANCOVA model including treatment as factor and baseline values as covariate.
	Method	ANCOVA
	Comments
Method of Estimation	Estimation Parameter	LS mean difference
	Estimated Value	-177.4
	Confidence Interval	(2-Sided) 80%; -357.85 to 3.13
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 95.72
	Estimation Comments

Statistical Analysis 24

Statistical Analysis Overview	Comparison Group Selection	KPL-716: PPs Cohort, Placebo: PPs Cohort
	Comments	Change at Week 6
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.0025
	Comments	Calculated from an ANCOVA model including treatment as factor and baseline values as covariate.
	Method	ANCOVA
	Comments
Method of Estimation	Estimation Parameter	LS mean difference
	Estimated Value	-42.0
	Confidence Interval	(2-Sided) 80%; -57.98 to -26.08
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 11.99
	Estimation Comments

Statistical Analysis 25

Statistical Analysis Overview	Comparison Group Selection	KPL-716: CIU Cohort, Placebo: CIU Cohort
	Comments	Change at Week 7
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.1465
	Comments	Calculated from an ANCOVA model including treatment as factor and baseline values as covariate.
	Method	ANCOVA
	Comments
Method of Estimation	Estimation Parameter	LS mean difference
	Estimated Value	-65.8
	Confidence Interval	(2-Sided) 80%; -121.14 to -10.50
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 33.78
	Estimation Comments

Statistical Analysis 26

Statistical Analysis Overview	Comparison Group Selection	KPL-716: CIP Cohort, Placebo: CIP Cohort
	Comments	Change at Week 7
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.7734
	Comments	Calculated from an ANCOVA model including treatment as factor and baseline values as covariate.
	Method	ANCOVA
	Comments
Method of Estimation	Estimation Parameter	LS mean difference
	Estimated Value	5.1
	Confidence Interval	(2-Sided) 80%; -18.13 to 28.37
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 17.54
	Estimation Comments

Statistical Analysis 27

Statistical Analysis Overview	Comparison Group Selection	KPL-716: LSC Cohort, Placebo: LSC Cohort
	Comments	Change at Week 7
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.1826
	Comments	Calculated from an ANCOVA model including treatment as factor and baseline values as covariate.
	Method	ANCOVA
	Comments
Method of Estimation	Estimation Parameter	LS mean difference
	Estimated Value	-175.5
	Confidence Interval	(2-Sided) 80%; -340.37 to -10.56
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 87.45
	Estimation Comments

Statistical Analysis 28

Statistical Analysis Overview	Comparison Group Selection	KPL-716: PPs Cohort, Placebo: PPs Cohort
	Comments	Change at Week 7
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.0105
	Comments	Calculated from an ANCOVA model including treatment as factor and baseline values as covariate.
	Method	ANCOVA
	Comments
Method of Estimation	Estimation Parameter	LS mean difference
	Estimated Value	-39.2
	Confidence Interval	(2-Sided) 80%; -57.40 to -20.93
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 13.71
	Estimation Comments

Statistical Analysis 29

Statistical Analysis Overview	Comparison Group Selection	KPL-716: CIU Cohort, Placebo: CIU Cohort
	Comments	Change at Week 8
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.2737
	Comments	Calculated from an ANCOVA model including treatment as factor and baseline values as covariate.
	Method	ANCOVA
	Comments
Method of Estimation	Estimation Parameter	LS mean difference
	Estimated Value	-53.7
	Confidence Interval	(2-Sided) 80%; -119.49 to 12.09
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 40.17
	Estimation Comments

Statistical Analysis 30

Statistical Analysis Overview	Comparison Group Selection	KPL-716: CIP Cohort, Placebo: CIP Cohort
	Comments	Change at Week 8
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.8692
	Comments	Calculated from an ANCOVA model including treatment as factor and baseline values as covariate.
	Method	ANCOVA
	Comments
Method of Estimation	Estimation Parameter	LS mean difference
	Estimated Value	3.0
	Confidence Interval	(2-Sided) 80%; -20.59 to 26.52
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 17.77
	Estimation Comments

Statistical Analysis 31

Statistical Analysis Overview	Comparison Group Selection	KPL-716: LSC Cohort, Placebo: LSC Cohort
	Comments	Change at Week 8
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.2106
	Comments	Calculated from an ANCOVA model including treatment as factor and baseline values as covariate.
	Method	ANCOVA
	Comments
Method of Estimation	Estimation Parameter	LS mean difference
	Estimated Value	-163.0
	Confidence Interval	(2-Sided) 80%; -332.06 to 5.99
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 89.64
	Estimation Comments

Statistical Analysis 32

Statistical Analysis Overview	Comparison Group Selection	KPL-716: PPs Cohort, Placebo: PPs Cohort
	Comments	Change at Week 8
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.0060
	Comments	Calculated from an ANCOVA model including treatment as factor and baseline values as covariate.
	Method	ANCOVA
	Comments
Method of Estimation	Estimation Parameter	LS mean difference
	Estimated Value	-45.7
	Confidence Interval	(2-Sided) 80%; -65.19 to -26.14
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 14.67
	Estimation Comments

Statistical Analysis 33

Statistical Analysis Overview	Comparison Group Selection	KPL-716: CIU Cohort, Placebo: CIU Cohort
	Comments	Change at Week 10
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.1831
	Comments	Calculated from an ANCOVA model including treatment as factor and baseline values as covariate.
	Method	ANCOVA
	Comments
Method of Estimation	Estimation Parameter	LS mean difference
	Estimated Value	-62.3
	Confidence Interval	(2-Sided) 80%; -121.44 to -3.13
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 36.12
	Estimation Comments

Statistical Analysis 34

Statistical Analysis Overview	Comparison Group Selection	KPL-716: CIP Cohort, Placebo: CIP Cohort
	Comments	Change at Week 10
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.2061
	Comments	Calculated from an ANCOVA model including treatment as factor and baseline values as covariate.
	Method	ANCOVA
	Comments
Method of Estimation	Estimation Parameter	LS mean difference
	Estimated Value	21.5
	Confidence Interval	(2-Sided) 80%; -0.31 to 43.30
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 16.39
	Estimation Comments

Statistical Analysis 35

Statistical Analysis Overview	Comparison Group Selection	KPL-716: LSC Cohort, Placebo: LSC Cohort
	Comments	Change at Week 10
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.2073
	Comments	Calculated from an ANCOVA model including treatment as factor and baseline values as covariate.
	Method	ANCOVA
	Comments
Method of Estimation	Estimation Parameter	LS mean difference
	Estimated Value	-161.4
	Confidence Interval	(2-Sided) 80%; -326.83 to 4.12
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 87.75
	Estimation Comments

Statistical Analysis 36

Statistical Analysis Overview	Comparison Group Selection	KPL-716: PPs Cohort, Placebo: PPs Cohort
	Comments	Change at Week 10
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.0371
	Comments	Calculated from an ANCOVA model including treatment as factor and baseline values as covariate.
	Method	ANCOVA
	Comments
Method of Estimation	Estimation Parameter	LS mean difference
	Estimated Value	-34.4
	Confidence Interval	(2-Sided) 80%; -54.62 to -14.10
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 15.19
	Estimation Comments

Statistical Analysis 37

Statistical Analysis Overview	Comparison Group Selection	KPL-716: CIU Cohort, Placebo: CIU Cohort
	Comments	Change at Week 12
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.2393
	Comments	Calculated from an ANCOVA model including treatment as factor and baseline values as covariate.
	Method	ANCOVA
	Comments
Method of Estimation	Estimation Parameter	LS mean difference
	Estimated Value	-55.2
	Confidence Interval	(2-Sided) 80%; -117.01 to 6.54
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 37.72
	Estimation Comments

Statistical Analysis 38

Statistical Analysis Overview	Comparison Group Selection	KPL-716: CIP Cohort, Placebo: CIP Cohort
	Comments	Change at Week 12
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.9019
	Comments	Calculated from an ANCOVA model including treatment as factor and baseline values as covariate.
	Method	ANCOVA
	Comments
Method of Estimation	Estimation Parameter	LS mean difference
	Estimated Value	2.4
	Confidence Interval	(2-Sided) 80%; -22.91 to 27.67
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 19.01
	Estimation Comments

Statistical Analysis 39

Statistical Analysis Overview	Comparison Group Selection	KPL-716: LSC Cohort, Placebo: LSC Cohort
	Comments	Change at Week 12
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.2103
	Comments	Calculated from an ANCOVA model including treatment as factor and baseline values as covariate.
	Method	ANCOVA
	Comments
Method of Estimation	Estimation Parameter	LS mean difference
	Estimated Value	-149.2
	Confidence Interval	(2-Sided) 80%; -303.77 to 5.35
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 81.97
	Estimation Comments

Statistical Analysis 40

Statistical Analysis Overview	Comparison Group Selection	KPL-716: PPs Cohort, Placebo: PPs Cohort
	Comments	Change at Week 12
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.1634
	Comments	Calculated from an ANCOVA model including treatment as factor and baseline values as covariate.
	Method	ANCOVA
	Comments
Method of Estimation	Estimation Parameter	LS mean difference
	Estimated Value	-22.1
	Confidence Interval	(2-Sided) 80%; -42.40 to -1.88
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 15.20
	Estimation Comments

Statistical Analysis 41

Statistical Analysis Overview	Comparison Group Selection	KPL-716: CIU Cohort, Placebo: CIU Cohort
	Comments	Change at Week 14
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.2727
	Comments	Calculated from an ANCOVA model including treatment as factor and baseline values as covariate.
	Method	ANCOVA
	Comments
Method of Estimation	Estimation Parameter	LS mean difference
	Estimated Value	-48.6
	Confidence Interval	(2-Sided) 80%; -108.04 to 10.80
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 36.28
	Estimation Comments

Statistical Analysis 42

Statistical Analysis Overview	Comparison Group Selection	KPL-716: CIP Cohort, Placebo: CIP Cohort
	Comments	Change at Week 14
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.5839
	Comments	Calculated from an ANCOVA model including treatment as factor and baseline values as covariate.
	Method	ANCOVA
	Comments
Method of Estimation	Estimation Parameter	LS mean difference
	Estimated Value	-9.6
	Confidence Interval	(2-Sided) 80%; -32.65 to 13.36
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 17.29
	Estimation Comments

Statistical Analysis 43

Statistical Analysis Overview	Comparison Group Selection	KPL-716: LSC Cohort, Placebo: LSC Cohort
	Comments	Change at Week 14
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.1597
	Comments	Calculated from an ANCOVA model including treatment as factor and baseline values as covariate.
	Method	ANCOVA
	Comments
Method of Estimation	Estimation Parameter	LS mean difference
	Estimated Value	-167.8
	Confidence Interval	(2-Sided) 80%; -312.25 to -23.45
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 76.58
	Estimation Comments

Statistical Analysis 44

Statistical Analysis Overview	Comparison Group Selection	KPL-716: PPs Cohort, Placebo: PPs Cohort
	Comments	Change at Week 14
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.1138
	Comments	Calculated from an ANCOVA model including treatment as factor and baseline values as covariate.
	Method	ANCOVA
	Comments
Method of Estimation	Estimation Parameter	LS mean difference
	Estimated Value	-27.1
	Confidence Interval	(2-Sided) 80%; -48.81 to -5.43
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 16.27
	Estimation Comments

Statistical Analysis 45

Statistical Analysis Overview	Comparison Group Selection	KPL-716: CIU Cohort, Placebo: CIU Cohort
	Comments	Change at Week 16
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.0888
	Comments	Calculated from an ANCOVA model including treatment as factor and baseline values as covariate.
	Method	ANCOVA
	Comments
Method of Estimation	Estimation Parameter	LS mean difference
	Estimated Value	-62.0
	Confidence Interval	(2-Sided) 80%; -102.78 to -21.13
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 24.93
	Estimation Comments

Statistical Analysis 46

Statistical Analysis Overview	Comparison Group Selection	KPL-716: CIP Cohort, Placebo: CIP Cohort
	Comments	Change at Week 16
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.9741
	Comments	Calculated from an ANCOVA model including treatment as factor and baseline values as covariate.
	Method	ANCOVA
	Comments
Method of Estimation	Estimation Parameter	LS mean difference
	Estimated Value	-0.6
	Confidence Interval	(2-Sided) 80%; -24.79 to 23.60
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 18.19
	Estimation Comments

Statistical Analysis 47

Statistical Analysis Overview	Comparison Group Selection	KPL-716: LSC Cohort, Placebo: LSC Cohort
	Comments	Change at Week 16
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.1354
	Comments	Calculated from an ANCOVA model including treatment as factor and baseline values as covariate.
	Method	ANCOVA
	Comments
Method of Estimation	Estimation Parameter	LS mean difference
	Estimated Value	-159.2
	Confidence Interval	(2-Sided) 80%; -282.59 to -35.87
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 65.42
	Estimation Comments

Statistical Analysis 48

Statistical Analysis Overview	Comparison Group Selection	KPL-716: PPs Cohort, Placebo: PPs Cohort
	Comments	Change at Week 16
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.1425
	Comments	Calculated from an ANCOVA model including treatment as factor and baseline values as covariate.
	Method	ANCOVA
	Comments
Method of Estimation	Estimation Parameter	LS mean difference
	Estimated Value	-26.5
	Confidence Interval	(2-Sided) 80%; -49.41 to -3.52
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 17.21
	Estimation Comments

Statistical Analysis 49

Statistical Analysis Overview	Comparison Group Selection	KPL-716: CIU Cohort, Placebo: CIU Cohort
	Comments	Change at Week 18
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.1326
	Comments	Calculated from an ANCOVA model including treatment as factor and baseline values as covariate.
	Method	ANCOVA
	Comments
Method of Estimation	Estimation Parameter	LS mean difference
	Estimated Value	-54.6
	Confidence Interval	(2-Sided) 80%; -98.18 to -11.01
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 26.61
	Estimation Comments

Statistical Analysis 50

Statistical Analysis Overview	Comparison Group Selection	KPL-716: CIP Cohort, Placebo: CIP Cohort
	Comments	Change at Week 18
	Type of Statistical Test	Other
	Comments
Statistical Test of Hypothesis	p-Value	0.8433
	Comments	Calculated from an ANCOVA model including treatment as factor and baseline values as covariate.
	Method	ANCOVA
	Comments
Method of Estimation	Estimation Parameter	LS mean difference
	Estimated Value	-4.2
	Confidence Interval	(2-Sided) 80%; -31.95 to 23.58
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 20.87
	Estimation Comments

Statistical Analysis 51

Statistical Analysis Overview	Comparison Group Selection	KPL-716: LSC Cohort, Placebo: LSC Cohort
	Comments	Change at Week 18
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.0768
	Comments	Calculated from an ANCOVA model including treatment as factor and baseline values as covariate.
	Method	ANCOVA
	Comments
Method of Estimation	Estimation Parameter	LS mean difference
	Estimated Value	-130.8
	Confidence Interval	(2-Sided) 80%; -203.39 to -58.19
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 38.50
	Estimation Comments

Statistical Analysis 52

Statistical Analysis Overview	Comparison Group Selection	KPL-716: PPs Cohort, Placebo: PPs Cohort
	Comments	Change at Week 18
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.3341
	Comments	Calculated from an ANCOVA model including treatment as factor and baseline values as covariate.
	Method	ANCOVA
	Comments
Method of Estimation	Estimation Parameter	LS mean difference
	Estimated Value	-18.6
	Confidence Interval	(2-Sided) 80%; -43.49 to 6.34
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 18.69
	Estimation Comments

6. Secondary Outcome

Title	Change From Baseline in 5-D Pruritus Total Score Over Time
Description	This tool evaluates pruritus in 5 domains: duration, degree, direction, disability and distribution. Duration, degree and direction each consist of 1 item. The disability domain contains 4 items and the distribution domain includes 16 items. The first 4 domains are measured on a 5-point Likert scale. The scores from each domain are added together to obtain a total 5-D score ranging from 5 (no pruritus) and 25 (most severe pruritus).
Time Frame	Baseline, Weeks 2, 4, 6, 8, 10, 12, 14, 16, 18

Outcome Measure Data

Analysis Population Description

Modified intent to treat (mITT) set: all randomized participants who received at least 1 dose of KPL-716 or placebo and had at least 1 post-baseline efficacy assessment in the double-blind treatment period. Missing data were imputed using the last observation carried forward (LOCF) method. Once a participant started treatment period (through Week 8), missing data in treatment period were imputed. Once a participant started the follow up (FU) period, missing data in FU period were imputed.

Arm/Group Title	KPL-716: CIU Cohort	Placebo: CIU Cohort	KPL-716: CIP Cohort	Placebo: CIP Cohort	KPL-716: LP Cohort	Placebo: LP Cohort	KPL-716: LSC Cohort	Placebo: LSC Cohort	KPL-716: PPs Cohort	Placebo: PPs Cohort
Arm/Group Description	Participants with CIU received KPL-716 weekly for 8 weeks	Participants with CIU received placebo weekly for 8 weeks	Participants with CIP received KPL-716 weekly for 8 weeks	Participants with CIP received placebo weekly for 8 weeks	Participants with LP received KPL-716 weekly for 8 weeks	Participants with LP received placebo weekly for 8 weeks	Participants with LSC received KPL-716 weekly for 8 weeks	Participants with LSC received placebo weekly for 8 weeks	Participants with PPs received KPL-716 weekly for 8 weeks	Participants with PPs received placebo weekly for 8 weeks
Measure Participants	4	2	14	9	3	0	4	1	14	7
Change at Week 2	-6.3 (2.78)	0.0 (0.00)	-4.4 (1.06)	-4.0 (1.35)	-2.3 (1.20)	-6.8 (2.10)	-4.0 (NA)	-5.0 (1.19)	-3.6 (1.29)
Change at Week 4	-8.5 (2.02)	0.5 (0.50)	-4.5 (1.27)	-5.4 (1.65)	-7.3 (4.06)	-7.3 (2.78)	-4.0 (NA)	-7.7 (1.05)	-4.1 (1.81)
Change at Week 6	-8.3 (2.17)	0.5 (0.50)	-6.6 (1.23)	-5.8 (1.47)	-8.0 (4.16)	-8.5 (2.90)	-7.0 (NA)	-8.2 (1.05)	-5.0 (1.79)
Change at Week 8	-7.5 (2.22)	-0.5 (0.50)	-6.5 (1.32)	-6.8 (1.23)	-8.0 (4.16)	-8.8 (2.95)	-7.0 (NA)	-9.4 (1.09)	-5.0 (1.75)
Change at Week 10	-8.0 (1.68)	-1.0 (1.00)	-6.6 (1.50)	-7.9 (0.63)	-12.0 (2.00)	-9.5 (2.87)	-7.0 (NA)	-9.4 (1.46)	-6.0 (1.81)
Change at Week 12	-7.0 (2.42)	0.0 (0.00)	-6.3 (1.33)	-6.3 (1.04)	-12.0 (2.00)	-9.8 (2.63)	-8.0 (NA)	-9.6 (1.32)	-6.3 (1.71)
Change at Week 14	-4.0 (3.37)	0.0 (0.00)	-6.7 (1.08)	-6.1 (1.17)	-12.0 (2.00)	-9.5 (2.87)	-4.0 (NA)	-9.6 (1.53)	-6.5 (1.78)
Change at Week 16	-7.8 (2.10)	0.5 (0.50)	-7.1 (1.77)	-5.0 (1.47)	-11.5 (2.50)	-10.0 (2.38)	-2.0 (NA)	-9.6 (1.48)	-7.2 (1.97)
Change at Week 18	-6.5 (2.50)	0.5 (0.50)	-6.3 (1.82)	-4.6 (1.42)	-13.5 (3.50)	-10.0 (2.38)	-2.0 (NA)	-8.9 (1.57)	-7.0 (1.65)

7. Secondary Outcome

Title	Percent Change From Baseline in 5-D Pruritus Total Score Over Time
Description	This tool evaluates pruritus in 5 domains: duration, degree, direction, disability and distribution. Duration, degree and direction each consist of 1 item. The disability domain contains 4 items and the distribution domain includes 16 items. The first 4 domains are measured on a 5-point Likert scale. The scores from each domain are added together to obtain a total 5-D score ranging from 5 (no pruritus) and 25 (most severe pruritus).
Time Frame	Baseline, Weeks 2, 4, 6, 8, 10, 12, 14, 16, 18

Outcome Measure Data

Analysis Population Description

Modified intent to treat (mITT) set: all randomized participants who received at least 1 dose of KPL-716 or placebo and had at least 1 post-baseline efficacy assessment in the double-blind treatment period. Missing data were imputed using the last observation carried forward (LOCF) method. Once a participant started treatment period (through Week 8), missing data in treatment period were imputed. Once a participant started the follow up (FU) period, missing data in FU period were imputed.

Arm/Group Title	KPL-716: CIU Cohort	Placebo: CIU Cohort	KPL-716: CIP Cohort	Placebo: CIP Cohort	KPL-716: LP Cohort	Placebo: LP Cohort	KPL-716: LSC Cohort	Placebo: LSC Cohort	KPL-716: PPs Cohort	Placebo: PPs Cohort
Arm/Group Description	Participants with CIU received KPL-716 weekly for 8 weeks	Participants with CIU received placebo weekly for 8 weeks	Participants with CIP received KPL-716 weekly for 8 weeks	Participants with CIP received placebo weekly for 8 weeks	Participants with LP received KPL-716 weekly for 8 weeks	Participants with LP received placebo weekly for 8 weeks	Participants with LSC received KPL-716 weekly for 8 weeks	Participants with LSC received placebo weekly for 8 weeks	Participants with PPs received KPL-716 weekly for 8 weeks	Participants with PPs received placebo weekly for 8 weeks
Measure Participants	4	2	14	9	3	0	4	1	14	7
Change at Week 2	-31.3 (13.40)	0.0 (18.98)	-24.2 (6.00)	-20.6 (7.48)	-11.8 (8.46)	-44.0 (3.43)	8.4 (8.04)	-25.4 (5.38)	-18.8 (7.61)
Change at Week 4	-42.7 (9.40)	2.4 (13.31)	-24.1 (7.03)	-29.2 (8.77)	-35.1 (12.38)	-49.1 (2.09)	23.0 (4.90)	-40.3 (5.55)	-20.8 (7.85)
Change at Week 6	-41.4 (10.22)	2.3 (14.48)	-35.9 (6.66)	-31.6 (8.31)	-38.8 (17.46)	-56.5 (1.49)	9.1 (3.49)	-43.3 (5.67)	-25.9 (8.02)
Change at Week 8	-37.7 (10.85)	-2.2 (15.36)	-34.4 (6.30)	-37.2 (7.85)	-38.8 (17.46)	-58.1 (0.83)	10.1 (1.95)	-49.1 (5.49)	-25.7 (7.77)
Change at Week 10	-40.1 (8.46)	-4.5 (11.98)	-35.2 (6.47)	-43.1 (7.48)	-58.2 (0.00)	-62.1 (3.76)	6.6 (8.82)	-49.1 (6.55)	-29.6 (10.06)
Change at Week 12	-33.3 (9.21)	-0.8 (13.05)	-33.5 (6.64)	-34.4 (7.66)	-58.2 (0.00)	-62.8 (3.53)	-3.4 (8.28)	-50.2 (5.86)	-31.4 (9.00)
Change at Week 14	-17.9 (14.08)	-1.1 (19.95)	-36.2 (5.83)	-33.3 (6.74)	-58.2 (0.00)	-62.1 (3.76)	20.2 (8.82)	-49.7 (7.04)	-33.1 (10.81)
Change at Week 16	-37.7 (8.29)	1.7 (11.74)	-37.0 (8.29)	-27.8 (9.57)	-55.4 (0.00)	-63.6 (3.33)	18.5 (7.81)	-49.9 (7.08)	-36.8 (10.88)
Change at Week 18	-31.3 (10.41)	1.6 (14.75)	-32.9 (8.83)	-25.0 (10.19)	-64.7 (0.00)	-63.6 (3.33)	18.5 (7.81)	-46.6 (7.43)	-35.5 (11.41)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	KPL-716: CIU Cohort, Placebo: CIU Cohort
	Comments	Change at Week 2
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.4995
	Comments	Calculated from an ANCOVA model including treatment as factor and baseline values as covariate.
	Method	ANCOVA
	Comments
Method of Estimation	Estimation Parameter	LS mean difference
	Estimated Value	-40.9
	Confidence Interval	(2-Sided) 80%; -166.52 to 84.74
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 40.82
	Estimation Comments

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	KPL-716: CIP Cohort, Placebo: CIP Cohort
	Comments	Change at Week 2
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.7071
	Comments	Calculated from an ANCOVA model including treatment as factor and baseline values as covariate.
	Method	ANCOVA
	Comments
Method of Estimation	Estimation Parameter	LS mean difference
	Estimated Value	-3.7
	Confidence Interval	(2-Sided) 80%; -16.37 to 9.06
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 9.59
	Estimation Comments

Statistical Analysis 3

Statistical Analysis Overview	Comparison Group Selection	KPL-716: LSC Cohort, Placebo: LSC Cohort
	Comments	Change at Week 2
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.0305
	Comments	Calculated from an ANCOVA model including treatment as factor and baseline values as covariate.
	Method	ANCOVA
	Comments
Method of Estimation	Estimation Parameter	LS mean difference
	Estimated Value	-52.5
	Confidence Interval	(2-Sided) 80%; -70.18 to -34.77
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 9.39
	Estimation Comments

Statistical Analysis 4

Statistical Analysis Overview	Comparison Group Selection	KPL-716: PPs Cohort, Placebo: PPs Cohort
	Comments	Change at Week 2
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.4884
	Comments	Calculated from an ANCOVA model including treatment as factor and baseline values as covariate.
	Method	ANCOVA
	Comments
Method of Estimation	Estimation Parameter	LS mean difference
	Estimated Value	-6.6
	Confidence Interval	(2-Sided) 80%; -19.01 to 5.81
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 9.33
	Estimation Comments

Statistical Analysis 5

Statistical Analysis Overview	Comparison Group Selection	KPL-716: CIU Cohort, Placebo: CIU Cohort
	Comments	Change at Week 4
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.2885
	Comments	Calculated from an ANCOVA model including treatment as factor and baseline values as covariate.
	Method	ANCOVA
	Comments
Method of Estimation	Estimation Parameter	LS mean difference
	Estimated Value	-45.3
	Confidence Interval	(2-Sided) 80%; -104.93 to 14.35
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 31.63
	Estimation Comments

Statistical Analysis 6

Statistical Analysis Overview	Comparison Group Selection	KPL-716: CIP Cohort, Placebo: CIP Cohort
	Comments	Change at Week 4
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.6505
	Comments	Calculated from an ANCOVA model including treatment as factor and baseline values as covariate.
	Method	ANCOVA
	Comments
Method of Estimation	Estimation Parameter	LS mean difference
	Estimated Value	5.2
	Confidence Interval	(2-Sided) 80%; -9.73 to 20.06
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 11.24
	Estimation Comments

Statistical Analysis 7

Statistical Analysis Overview	Comparison Group Selection	KPL-716: LSC Cohort, Placebo: LSC Cohort
	Comments	Change at Week 4
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.0062
	Comments	Calculated from an ANCOVA model including treatment as factor and baseline values as covariate.
	Method	ANCOVA
	Comments
Method of Estimation	Estimation Parameter	LS mean difference
	Estimated Value	-72.1
	Confidence Interval	(2-Sided) 80%; -82.91 to -61.34
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 5.72
	Estimation Comments

Statistical Analysis 8

Statistical Analysis Overview	Comparison Group Selection	KPL-716: PPs Cohort, Placebo: PPs Cohort
	Comments	Change at Week 4
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.0571
	Comments	Calculated from an ANCOVA model including treatment as factor and baseline values as covariate.
	Method	ANCOVA
	Comments
Method of Estimation	Estimation Parameter	LS mean difference
	Estimated Value	-19.6
	Confidence Interval	(2-Sided) 80%; -32.34 to -6.76
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 9.62
	Estimation Comments

Statistical Analysis 9

Statistical Analysis Overview	Comparison Group Selection	KPL-716: CIU Cohort, Placebo: CIU Cohort
	Comments	Change at Week 6
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value
	Comments
	Method
	Comments
Method of Estimation	Estimation Parameter	LS mean difference
	Estimated Value	-50.1
	Confidence Interval	(2-Sided) %; to
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 0.00
	Estimation Comments

Statistical Analysis 10

Statistical Analysis Overview	Comparison Group Selection	KPL-716: CIP Cohort, Placebo: CIP Cohort
	Comments	Change at Week 6
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.6927
	Comments	Calculated from an ANCOVA model including treatment as factor and baseline values as covariate.
	Method	ANCOVA
	Comments
Method of Estimation	Estimation Parameter	LS mean difference
	Estimated Value	-4.3
	Confidence Interval	(2-Sided) 80%; -18.38 to 9.84
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 10.65
	Estimation Comments

Statistical Analysis 11

Statistical Analysis Overview	Comparison Group Selection	KPL-716: LSC Cohort, Placebo: LSC Cohort
	Comments	Change at Week 6
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.0038
	Comments	Calculated from an ANCOVA model including treatment as factor and baseline values as covariate.
	Method	ANCOVA
	Comments
Method of Estimation	Estimation Parameter	LS mean difference
	Estimated Value	-65.6
	Confidence Interval	(2-Sided) 80%; -73.33 to -57.94
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 4.08
	Estimation Comments

Statistical Analysis 12

Statistical Analysis Overview	Comparison Group Selection	KPL-716: PPs Cohort, Placebo: PPs Cohort
	Comments	Change at Week 6
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.0940
	Comments	Calculated from an ANCOVA model including treatment as factor and baseline values as covariate.
	Method	ANCOVA
	Comments
Method of Estimation	Estimation Parameter	LS mean difference
	Estimated Value	-17.4
	Confidence Interval	(2-Sided) 80%; -30.43 to -4.30
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 9.82
	Estimation Comments

Statistical Analysis 13

Statistical Analysis Overview	Comparison Group Selection	KPL-716: CIU Cohort, Placebo: CIU Cohort
	Comments	Change at Week 8
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.1694
	Comments	Calculated from an ANCOVA model including treatment as factor and baseline values as covariate.
	Method	ANCOVA
	Comments
Method of Estimation	Estimation Parameter	LS mean difference
	Estimated Value	-72.4
	Confidence Interval	(2-Sided) 80%; -133.10 to -11.65
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 19.73
	Estimation Comments

Statistical Analysis 14

Statistical Analysis Overview	Comparison Group Selection	KPL-716: CIP Cohort, Placebo: CIP Cohort
	Comments	Change at Week 8
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.7811
	Comments	Calculated from an ANCOVA model including treatment as factor and baseline values as covariate.
	Method	ANCOVA
	Comments
Method of Estimation	Estimation Parameter	LS mean difference
	Estimated Value	2.8
	Confidence Interval	(2-Sided) 80%; -10.50 to 16.18
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 10.07
	Estimation Comments

Statistical Analysis 15

Statistical Analysis Overview	Comparison Group Selection	KPL-716: LSC Cohort, Placebo: LSC Cohort
	Comments	Change at Week 8
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.0011
	Comments	Calculated from an ANCOVA model including treatment as factor and baseline values as covariate.
	Method	ANCOVA
	Comments
Method of Estimation	Estimation Parameter	LS mean difference
	Estimated Value	-68.2
	Confidence Interval	(2-Sided) 80%; -72.51 to -63.91
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 2.28
	Estimation Comments

Statistical Analysis 16

Statistical Analysis Overview	Comparison Group Selection	KPL-716: PPs Cohort, Placebo: PPs Cohort
	Comments	Change at Week 8
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.0245
	Comments	Calculated from an ANCOVA model including treatment as factor and baseline values as covariate.
	Method	ANCOVA
	Comments
Method of Estimation	Estimation Parameter	LS mean difference
	Estimated Value	-23.4
	Confidence Interval	(2-Sided) 80%; -36.02 to -10.70
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 9.52
	Estimation Comments

Statistical Analysis 17

Statistical Analysis Overview	Comparison Group Selection	KPL-716: CIU Cohort, Placebo: CIU Cohort
	Comments	Change at Week 10
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.0603
	Comments	Calculated from an ANCOVA model including treatment as factor and baseline values as covariate.
	Method	ANCOVA
	Comments
Method of Estimation	Estimation Parameter	LS mean difference
	Estimated Value	-61.8
	Confidence Interval	(2-Sided) 80%; -79.88 to -43.74
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 5.87
	Estimation Comments

Statistical Analysis 18

Statistical Analysis Overview	Comparison Group Selection	KPL-716: CIP Cohort, Placebo: CIP Cohort
	Comments	Change at Week 10
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.4365
	Comments	Calculated from an ANCOVA model including treatment as factor and baseline values as covariate.
	Method	ANCOVA
	Comments
Method of Estimation	Estimation Parameter	LS mean difference
	Estimated Value	7.9
	Confidence Interval	(2-Sided) 80%; -5.29 to 21.04
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 9.89
	Estimation Comments

Statistical Analysis 19

Statistical Analysis Overview	Comparison Group Selection	KPL-716: LSC Cohort, Placebo: LSC Cohort
	Comments	Change at Week 10
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.0218
	Comments	Calculated from an ANCOVA model including treatment as factor and baseline values as covariate.
	Method	ANCOVA
	Comments
Method of Estimation	Estimation Parameter	LS mean difference
	Estimated Value	-68.7
	Confidence Interval	(2-Sided) 80%; -88.11 to -49.26
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 10.30
	Estimation Comments

Statistical Analysis 20

Statistical Analysis Overview	Comparison Group Selection	KPL-716: PPs Cohort, Placebo: PPs Cohort
	Comments	Change at Week 10
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.1238
	Comments	Calculated from an ANCOVA model including treatment as factor and baseline values as covariate.
	Method	ANCOVA
	Comments
Method of Estimation	Estimation Parameter	LS mean difference
	Estimated Value	-19.5
	Confidence Interval	(2-Sided) 80%; -35.65 to -3.45
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 12.07
	Estimation Comments

Statistical Analysis 21

Statistical Analysis Overview	Comparison Group Selection	KPL-716: CIU Cohort, Placebo: CIU Cohort
	Comments	Change at Week 12
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.1437
	Comments	Calculated from an ANCOVA model including treatment as factor and baseline values as covariate.
	Method	ANCOVA
	Comments
Method of Estimation	Estimation Parameter	LS mean difference
	Estimated Value	-54.8
	Confidence Interval	(2-Sided) 80%; -98.88 to -10.72
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 23.38
	Estimation Comments

Statistical Analysis 22

Statistical Analysis Overview	Comparison Group Selection	KPL-716: CIP Cohort, Placebo: CIP Cohort
	Comments	Change at Week 12
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.9279
	Comments	Calculated from an ANCOVA model including treatment as factor and baseline values as covariate.
	Method	ANCOVA
	Comments
Method of Estimation	Estimation Parameter	LS mean difference
	Estimated Value	0.9
	Confidence Interval	(2-Sided) 80%; -12.56 to 14.43
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 10.14
	Estimation Comments

Statistical Analysis 23

Statistical Analysis Overview	Comparison Group Selection	KPL-716: LSC Cohort, Placebo: LSC Cohort
	Comments	Change at Week 12
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.0254
	Comments	Calculated from an ANCOVA model including treatment as factor and baseline values as covariate.
	Method	ANCOVA
	Comments
Method of Estimation	Estimation Parameter	LS mean difference
	Estimated Value	-59.5
	Confidence Interval	(2-Sided) 80%; -77.69 to -41.24
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 9.67
	Estimation Comments

Statistical Analysis 24

Statistical Analysis Overview	Comparison Group Selection	KPL-716: PPs Cohort, Placebo: PPs Cohort
	Comments	Change at Week 12
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.0994
	Comments	Calculated from an ANCOVA model including treatment as factor and baseline values as covariate.
	Method	ANCOVA
	Comments
Method of Estimation	Estimation Parameter	LS mean difference
	Estimated Value	-18.8
	Confidence Interval	(2-Sided) 80%; -33.23 to -4.43
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 10.80
	Estimation Comments

Statistical Analysis 25

Statistical Analysis Overview	Comparison Group Selection	KPL-716: CIU Cohort, Placebo: CIU Cohort
	Comments	Change at Week 14
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.3656
	Comments	Calculated from an ANCOVA model including treatment as factor and baseline values as covariate.
	Method	ANCOVA
	Comments
Method of Estimation	Estimation Parameter	LS mean difference
	Estimated Value	-45.7
	Confidence Interval	(2-Sided) 80%; -119.90 to 28.54
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 39.36
	Estimation Comments

Statistical Analysis 26

Statistical Analysis Overview	Comparison Group Selection	KPL-716: CIP Cohort, Placebo: CIP Cohort
	Comments	Change at Week 14
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.7465
	Comments	Calculated from an ANCOVA model including treatment as factor and baseline values as covariate.
	Method	ANCOVA
	Comments
Method of Estimation	Estimation Parameter	LS mean difference
	Estimated Value	-2.9
	Confidence Interval	(2-Sided) 80%; -14.79 to 8.94
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 8.92
	Estimation Comments

Statistical Analysis 27

Statistical Analysis Overview	Comparison Group Selection	KPL-716: LSC Cohort, Placebo: LSC Cohort
	Comments	Change at Week 14
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.0153
	Comments	Calculated from an ANCOVA model including treatment as factor and baseline values as covariate.
	Method	ANCOVA
	Comments
Method of Estimation	Estimation Parameter	LS mean difference
	Estimated Value	-82.3
	Confidence Interval	(2-Sided) 80%; -101.75 to -62.90
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 10.30
	Estimation Comments

Statistical Analysis 28

Statistical Analysis Overview	Comparison Group Selection	KPL-716: PPs Cohort, Placebo: PPs Cohort
	Comments	Change at Week 14
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.2184
	Comments	Calculated from an ANCOVA model including treatment as factor and baseline values as covariate.
	Method	ANCOVA
	Comments
Method of Estimation	Estimation Parameter	LS mean difference
	Estimated Value	-16.6
	Confidence Interval	(2-Sided) 80%; -33.88 to 0.72
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 12.97
	Estimation Comments

Statistical Analysis 29

Statistical Analysis Overview	Comparison Group Selection	KPL-716: CIU Cohort, Placebo: CIU Cohort
	Comments	Change at Week 16
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.7726
	Comments	Calculated from an ANCOVA model including treatment as factor and baseline values as covariate.
	Method	ANCOVA
	Comments
Method of Estimation	Estimation Parameter	LS mean difference
	Estimated Value	-8.1
	Confidence Interval	(2-Sided) 80%; -50.37 to 34.07
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 25.78
	Estimation Comments

Statistical Analysis 30

Statistical Analysis Overview	Comparison Group Selection	KPL-716: CIP Cohort, Placebo: CIP Cohort
	Comments	Change at Week 16
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.4760
	Comments	Calculated from an ANCOVA model including treatment as factor and baseline values as covariate.
	Method	ANCOVA
	Comments
Method of Estimation	Estimation Parameter	LS mean difference
	Estimated Value	-9.2
	Confidence Interval	(2-Sided) 80%; -26.07 to 7.63
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 12.66
	Estimation Comments

Statistical Analysis 31

Statistical Analysis Overview	Comparison Group Selection	KPL-716: LSC Cohort, Placebo: LSC Cohort
	Comments	Change at Week 16
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.0121
	Comments	Calculated from an ANCOVA model including treatment as factor and baseline values as covariate.
	Method	ANCOVA
	Comments
Method of Estimation	Estimation Parameter	LS mean difference
	Estimated Value	-82.1
	Confidence Interval	(2-Sided) 80%; -99.26 to -64.87
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 9.12
	Estimation Comments

Statistical Analysis 32

Statistical Analysis Overview	Comparison Group Selection	KPL-716: PPs Cohort, Placebo: PPs Cohort
	Comments	Change at Week 16
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.3329
	Comments	Calculated from an ANCOVA model including treatment as factor and baseline values as covariate.
	Method	ANCOVA
	Comments
Method of Estimation	Estimation Parameter	LS mean difference
	Estimated Value	-13.0
	Confidence Interval	(2-Sided) 80%; -30.43 to 4.40
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 13.06
	Estimation Comments

Statistical Analysis 33

Statistical Analysis Overview	Comparison Group Selection	KPL-716: CIU Cohort, Placebo: CIU Cohort
	Comments	Change at Week 18
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.9564
	Comments	Calculated from an ANCOVA model including treatment as factor and baseline values as covariate.
	Method	ANCOVA
	Comments
Method of Estimation	Estimation Parameter	LS mean difference
	Estimated Value	-1.7
	Confidence Interval	(2-Sided) 80%; -48.31 to 44.92
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 28.46
	Estimation Comments

Statistical Analysis 34

Statistical Analysis Overview	Comparison Group Selection	KPL-716: CIP Cohort, Placebo: CIP Cohort
	Comments	Change at Week 18
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.5661
	Comments	Calculated from an ANCOVA model including treatment as factor and baseline values as covariate.
	Method	ANCOVA
	Comments
Method of Estimation	Estimation Parameter	LS mean difference
	Estimated Value	-7.9
	Confidence Interval	(2-Sided) 80%; -25.84 to 10.06
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 13.49
	Estimation Comments

Statistical Analysis 35

Statistical Analysis Overview	Comparison Group Selection	KPL-716: LSC Cohort, Placebo: LSC Cohort
	Comments	Change at Week 18
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.0121
	Comments	Calculated from an ANCOVA model including treatment as factor and baseline values as covariate.
	Method	ANCOVA
	Comments
Method of Estimation	Estimation Parameter	LS mean difference
	Estimated Value	-82.1
	Confidence Interval	(2-Sided) 80%; -99.26 to -64.87
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 9.12
	Estimation Comments

Statistical Analysis 36

Statistical Analysis Overview	Comparison Group Selection	KPL-716: PPs Cohort, Placebo: PPs Cohort
	Comments	Change at Week 18
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.4275
	Comments	Calculated from an ANCOVA model including treatment as factor and baseline values as covariate.
	Method	ANCOVA
	Comments
Method of Estimation	Estimation Parameter	LS mean difference
	Estimated Value	-11.1
	Confidence Interval	(2-Sided) 80%; -29.40 to 7.13
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 13.70
	Estimation Comments

8. Secondary Outcome

Title	Percentage of Participants Achieving ≥4-Point Reduction From Baseline in Weekly Average WI-NRS Over Time
Description	WI-NRS score: Participants were asked daily to assign a numerical score to the intensity of their most severe (worst) pruritus in the past 24 hours using a scale from 0 to 10, with 0 indicating no pruritus and 10 indicating the worst imaginable pruritus. Daily scores were averaged for a weekly score. A negative change from Baseline indicates improvement.
Time Frame	Baseline, Weeks 1-18

Outcome Measure Data

Analysis Population Description

Modified intent to treat (mITT) set: all randomized participants who received at least 1 dose of KPL-716 or placebo and had at least 1 post-baseline efficacy assessment in the double-blind treatment period. Missing data were imputed using the last observation carried forward (LOCF) method. Once a participant started treatment period (through Week 8), missing data in treatment period were imputed. Once a participant started the follow up (FU) period, missing data in FU period were imputed.

Arm/Group Title	KPL-716: CIU Cohort	Placebo: CIU Cohort	KPL-716: CIP Cohort	Placebo: CIP Cohort	KPL-716: LP Cohort	Placebo: LP Cohort	KPL-716: LSC Cohort	Placebo: LSC Cohort	KPL-716: PPs Cohort	Placebo: PPs Cohort
Arm/Group Description	Participants with CIU received KPL-716 weekly for 8 weeks	Participants with CIU received placebo weekly for 8 weeks	Participants with CIP received KPL-716 weekly for 8 weeks	Participants with CIP received placebo weekly for 8 weeks	Participants with LP received KPL-716 weekly for 8 weeks	Participants with LP received placebo weekly for 8 weeks	Participants with LSC received KPL-716 weekly for 8 weeks	Participants with LSC received placebo weekly for 8 weeks	Participants with PPs received KPL-716 weekly for 8 weeks	Participants with PPs received placebo weekly for 8 weeks
Measure Participants	4	2	14	9	3	0	4	1	14	7
Change at Week 1	0.0 0%	0.0 0%	21.4 36.9%	11.1 NaN	0.0 NaN	50.0 NaN	0.0 NaN	0.0 NaN	0.0 NaN
Change at Week 2	50.0 128.2%	0.0 0%	28.6 49.3%	33.3 NaN	0.0 NaN	50.0 NaN	0.0 NaN	0.0 NaN	0.0 NaN
Change at Week 3	50.0 128.2%	0.0 0%	42.9 74%	33.3 NaN	0.0 NaN	50.0 NaN	0.0 NaN	21.4 NaN	0.0 NaN
Change at Week 4	50.0 128.2%	0.0 0%	42.9 74%	44.4 NaN	33.3 NaN	75.0 NaN	0.0 NaN	42.9 NaN	14.3 NaN
Change at Week 5	50.0 128.2%	0.0 0%	50.0 86.2%	44.4 NaN	33.3 NaN	75.0 NaN	0.0 NaN	50.0 NaN	14.3 NaN
Change at Week 6	50.0 128.2%	0.0 0%	57.1 98.4%	66.7 NaN	33.3 NaN	75.0 NaN	0.0 NaN	57.1 NaN	14.3 NaN
Change at Week 7	50.0 128.2%	50.0 263.2%	57.1 98.4%	55.6 NaN	66.7 NaN	75.0 NaN	0.0 NaN	64.3 NaN	14.3 NaN
Change at Week 8	50.0 128.2%	0.0 0%	57.1 98.4%	66.7 NaN	66.7 NaN	75.0 NaN	0.0 NaN	71.4 NaN	28.6 NaN
Change at Week 9	50.0 128.2%	0.0 0%	58.3 100.5%	55.6 NaN	100.0 NaN	75.0 NaN	0.0 NaN	78.6 NaN	28.6 NaN
Change at Week 10	25.0 64.1%	50.0 263.2%	50.0 86.2%	77.8 NaN	100.0 NaN	75.0 NaN	0.0 NaN	78.6 NaN	14.3 NaN
Change at Week 11	50.0 128.2%	50.0 263.2%	58.3 100.5%	77.8 NaN	100.0 NaN	75.0 NaN	0.0 NaN	64.3 NaN	14.3 NaN
Change at Week 12	50.0 128.2%	50.0 263.2%	58.3 100.5%	66.7 NaN	100.0 NaN	75.0 NaN	0.0 NaN	64.3 NaN	14.3 NaN
Change at Week 13	25.0 64.1%	50.0 263.2%	58.3 100.5%	55.6 NaN	100.0 NaN	75.0 NaN	0.0 NaN	71.4 NaN	14.3 NaN
Change at Week 14	25.0 64.1%	50.0 263.2%	58.3 100.5%	55.6 NaN	100.0 NaN	75.0 NaN	0.0 NaN	71.4 NaN	14.3 NaN
Change at Week 15	50.0 128.2%	50.0 263.2%	50.0 86.2%	44.4 NaN	100.0 NaN	75.0 NaN	0.0 NaN	71.4 NaN	28.6 NaN
Change at Week 16	25.0 64.1%	50.0 263.2%	58.3 100.5%	44.4 NaN	100.0 NaN	75.0 NaN	0.0 NaN	71.4 NaN	28.6 NaN
Change at Week 17	75.0 192.3%	50.0 263.2%	50.0 86.2%	44.4 NaN	100.0 NaN	75.0 NaN	0.0 NaN	71.4 NaN	28.6 NaN
Change at Week 18	75.0 192.3%	50.0 263.2%	58.3 100.5%	44.4 NaN	100.0 NaN	100.0 NaN	0.0 NaN	71.4 NaN	28.6 NaN

9. Secondary Outcome

Title	Change From Baseline in Weekly Average Itch Severity Score: CIU Cohort Only
Description	Participants were asked daily to self-assess the intensity of their pruritus on a Weekly Average Itch Severity Score, which is a Component of Urticaria Activity Score 7 (UAS7). The score for pruritis was graded from 0 (none) to 3 (intense), which was averaged over 7 consecutive days. The greater the severity of the disease the higher the score. Per protocol, the UAS7 tool was completed only by participants in the CIU Cohort.
Time Frame	Baseline, Weeks 1-18

Outcome Measure Data

Analysis Population Description

Modified intent to treat (mITT) set: all randomized participants who received at least 1 dose of KPL-716 or placebo and had at least 1 post-baseline efficacy assessment in the double-blind treatment period. Missing data were imputed using the last observation carried forward (LOCF) method. Once a participant started treatment period (through Week 8), missing data in treatment period were imputed. Once a participant started the follow up (FU) period, missing data in FU period were imputed.

Arm/Group Title	KPL-716: CIU Cohort	Placebo: CIU Cohort
Arm/Group Description	Participants with CIU received KPL-716 weekly for 8 weeks	Participants with CIU received placebo weekly for 8 weeks
Measure Participants	4	2
Change at Week 1	-0.7 (0.13)	0.3 (0.29)
Change at Week 2	-0.9 (0.15)	-0.2 (0.21)
Change at Week 3	-1.0 (0.36)	-0.4 (0.36)
Change at Week 4	-1.2 (0.30)	-0.2 (0.21)
Change at Week 5	-1.2 (0.28)	-0.2 (0.21)
Change at Week 6	-1.4 (0.22)	-0.1 (0.14)
Change at Week 7	-1.1 (0.30)	-0.4 (0.43)
Change at Week 8	-0.8 (0.40)	-0.1 (0.14)
Change at Week 9	-1.2 (0.27)	-0.1 (0.14)
Change at Week 10	-1.1 (0.35)	-0.5 (0.50)
Change at Week 11	-1.0 (0.39)	-0.6 (0.57)
Change at Week 12	-1.0 (0.39)	-0.6 (0.57)
Change at Week 13	-0.7 (0.44)	-0.6 (0.57)
Change at Week 14	-0.9 (0.41)	-0.6 (0.57)
Change at Week 15	-1.1 (0.38)	-0.6 (0.57)
Change at Week 16	-0.9 (0.39)	-0.6 (0.57)
Change at Week 17	-1.1 (0.35)	-0.6 (0.57)
Change at Week 18	-1.3 (0.24)	-0.6 (0.57)

10. Secondary Outcome

Title	Percent Change From Baseline in Weekly Average Itch Severity Score: CIU Cohort Only
Description	Participants were asked daily to self-assess the intensity of their pruritus on a Weekly Average Itch Severity Score, which is a Component of Urticaria Activity Score 7 (UAS7). The score for pruritis was graded from 0 (none) to 3 (intense), which was averaged over 7 consecutive days. The greater the severity of the disease the higher the score. Per protocol, the UAS7 tool was completed only by participants in the CIU Cohort
Time Frame	Baseline, Weeks 1-18

Outcome Measure Data

Analysis Population Description

Modified intent to treat (mITT) set: all randomized participants who received at least 1 dose of KPL-716 or placebo and had at least 1 post-baseline efficacy assessment in the double-blind treatment period. Missing data were imputed using the last observation carried forward (LOCF) method. Once a participant started treatment period (through Week 8), missing data in treatment period were imputed. Once a participant started the follow up (FU) period, missing data in FU period were imputed.

Arm/Group Title	KPL-716: CIU Cohort	Placebo: CIU Cohort
Arm/Group Description	Participants with CIU received KPL-716 weekly for 8 weeks	Participants with CIU received placebo weekly for 8 weeks
Measure Participants	4	2
Change at Week 1	-26.6 (5.36)	-13.3 (13.33)
Change at Week 2	-36.4 (4.94)	-10.0 (10.00)
Change at Week 3	-40.8 (11.29)	-16.7 (16.67)
Change at Week 4	-45.5 (8.82)	-10.0 (10.00)
Change at Week 5	-48.7 (8.76)	-10.0 (10.00)
Change at Week 6	-54.6 (5.27)	-6.7 (6.67)
Change at Week 7	-43.8 (8.48)	-20.0 (20.00)
Change at Week 8	-31.5 (12.83)	-6.7 (6.67)
Change at Week 9	-48.3 (6.99)	-6.7 (6.67)
Change at Week 10	-41.5 (11.05)	-23.3 (23.33)
Change at Week 11	-36.9 (12.65)	-26.7 (26.67)
Change at Week 12	-38.4 (13.06)	-26.7 (26.67)
Change at Week 13	-26.4 (14.24)	-26.7 (26.67)
Change at Week 14	-33.7 (13.07)	-26.7 (26.67)
Change at Week 15	-41.4 (12.71)	-26.7 (26.67)
Change at Week 16	-33.8 (12.37)	-26.7 (26.67)
Change at Week 17	-44.0 (11.58)	-26.7 (26.67)
Change at Week 18	-51.5 (5.65)	-26.7 (26.67)

11. Secondary Outcome

Title	Change From Baseline in Sleep Loss VAS Over Time
Description	Participants were asked to place a line perpendicular to the VAS line at the point that represents the intensity of their average sleeplessness experienced over the previous 3 nights using a scale from 0 to 10, with 0 indicating no sleeplessness and 10 indicating the worst imaginable sleeplessness at every visit.
Time Frame	Baseline, Weeks 1-8, 10, 12, 14, 16, 18

Outcome Measure Data

Analysis Population Description

Modified intent to treat (mITT) set: all randomized participants who received at least 1 dose of KPL-716 or placebo and had at least 1 post-baseline efficacy assessment in the double-blind treatment period. Missing data were imputed using the last observation carried forward (LOCF) method. Once a participant started treatment period (through Week 8), missing data in treatment period were imputed. Once a participant started the follow up (FU) period, missing data in FU period were imputed.

Arm/Group Title	KPL-716: CIU Cohort	Placebo: CIU Cohort	KPL-716: CIP Cohort	Placebo: CIP Cohort	KPL-716: LP Cohort	Placebo: LP Cohort	KPL-716: LSC Cohort	Placebo: LSC Cohort	KPL-716: PPs Cohort	Placebo: PPs Cohort
Arm/Group Description	Participants with CIU received KPL-716 weekly for 8 weeks	Participants with CIU received placebo weekly for 8 weeks	Participants with CIP received KPL-716 weekly for 8 weeks	Participants with CIP received placebo weekly for 8 weeks	Participants with LP received KPL-716 weekly for 8 weeks	Participants with LP received placebo weekly for 8 weeks	Participants with LSC received KPL-716 weekly for 8 weeks	Participants with LSC received placebo weekly for 8 weeks	Participants with PPs received KPL-716 weekly for 8 weeks	Participants with PPs received placebo weekly for 8 weeks
Measure Participants	4	2	14	9	3	0	4	1	14	7
Change at Week 1	-1.6 (1.12)	0.1 (0.10)	0.4 (0.78)	-2.1 (1.17)	-0.4 (0.31)	-2.8 (1.81)	0.1 (NA)	-1.2 (0.25)	-0.1 (0.35)
Change at Week 2	-3.1 (1.46)	0.1 (0.10)	-1.0 (0.60)	-2.6 (0.71)	-0.3 (0.15)	-3.4 (1.98)	0.0 (NA)	-2.1 (0.48)	-0.4 (0.58)
Change at Week 3	-2.4 (1.86)	0.1 (0.10)	-1.6 (0.70)	-3.6 (0.95)	-2.1 (1.49)	-4.1 (1.97)	-0.1 (NA)	-3.0 (0.62)	-1.0 (0.75)
Change at Week 4	-2.9 (2.30)	0.1 (0.10)	-1.5 (0.80)	-3.4 (0.86)	-2.9 (1.87)	-4.2 (1.81)	-0.1 (NA)	-3.7 (0.62)	-0.3 (1.30)
Change at Week 5	-3.5 (2.34)	0.1 (0.10)	-2.0 (0.72)	-3.9 (0.96)	-3.1 (1.85)	-4.4 (1.75)	-2.6 (NA)	-4.0 (0.59)	-1.2 (1.14)
Change at Week 6	-2.9 (2.69)	0.1 (0.10)	-2.3 (0.74)	-3.6 (0.83)	-3.1 (1.85)	-5.0 (1.46)	-1.3 (NA)	-4.6 (0.56)	-1.6 (1.20)
Change at Week 7	-3.7 (2.16)	0.0 (0.00)	-2.1 (0.67)	-3.9 (0.79)	-3.4 (1.86)	-5.2 (1.33)	-1.0 (NA)	-4.9 (0.58)	-1.8 (1.34)
Change at Week 8	-3.3 (2.48)	0.1 (0.05)	-2.1 (0.67)	-3.8 (0.91)	-3.4 (1.86)	-5.3 (1.27)	-1.0 (NA)	-5.4 (0.59)	-2.1 (1.29)
Change at Week 10	-3.8 (2.20)	0.1 (0.10)	-1.7 (0.66)	-5.4 (0.80)	-5.5 (0.90)	-5.3 (1.29)	-2.4 (NA)	-5.4 (0.63)	-3.1 (1.36)
Change at Week 12	-3.3 (2.14)	0.1 (0.05)	-1.6 (0.73)	-4.3 (0.88)	-5.3 (1.15)	-5.2 (1.32)	-2.3 (NA)	-5.2 (0.68)	-3.2 (1.41)
Change at Week 14	-3.0 (2.36)	0.1 (0.10)	-1.7 (0.67)	-4.9 (0.72)	-5.3 (1.15)	-5.2 (1.33)	-0.1 (NA)	-5.3 (0.70)	-3.0 (1.49)
Change at Week 16	-3.5 (2.14)	0.1 (0.10)	-1.5 (0.78)	-4.0 (1.02)	-5.6 (0.85)	-5.4 (1.23)	-0.4 (NA)	-5.1 (0.75)	-2.8 (1.51)
Change at Week 18	-2.9 (2.28)	0.1 (0.05)	-1.4 (0.84)	-3.1 (1.03)	-5.7 (2.25)	-5.6 (1.11)	-0.6 (NA)	-4.9 (0.90)	-3.3 (1.42)

12. Secondary Outcome

Title	Percent Change From Baseline in Sleep Loss VAS Over Time
Description	Participants were asked to place a line perpendicular to the VAS line at the point that represents the intensity of their average sleeplessness experienced over the previous 3 nights using a scale from 0 to 10, with 0 indicating no sleeplessness and 10 indicating the worst imaginable sleeplessness at every visit.
Time Frame	Baseline, Weeks 1-8, 10, 12, 14, 16, 18

Outcome Measure Data

Analysis Population Description

Modified intent to treat (mITT) set: all randomized participants who received at least 1 dose of KPL-716 or placebo and had at least 1 post-baseline efficacy assessment in the double-blind treatment period. Missing data were imputed using the last observation carried forward (LOCF) method. Once a participant started treatment period (through Week 8), missing data in treatment period were imputed. Once a participant started the follow up (FU) period, missing data in FU period were imputed.

Arm/Group Title	KPL-716: CIU Cohort	Placebo: CIU Cohort	KPL-716: CIP Cohort	Placebo: CIP Cohort	KPL-716: LP Cohort	Placebo: LP Cohort	KPL-716: LSC Cohort	Placebo: LSC Cohort	KPL-716: PPs Cohort	Placebo: PPs Cohort
Arm/Group Description	Participants with CIU received KPL-716 weekly for 8 weeks	Participants with CIU received placebo weekly for 8 weeks	Participants with CIP received KPL-716 weekly for 8 weeks	Participants with CIP received placebo weekly for 8 weeks	Participants with LP received KPL-716 weekly for 8 weeks	Participants with LP received placebo weekly for 8 weeks	Participants with LSC received KPL-716 weekly for 8 weeks	Participants with LSC received placebo weekly for 8 weeks	Participants with PPs received KPL-716 weekly for 8 weeks	Participants with PPs received placebo weekly for 8 weeks
Measure Participants	4	2	14	9	3	0	4	1	14	7
Change at Week 1	-25.1 (20.89)	2.9 (31.37)	484.2 (401.19)	108.2 (483.26)	-5.1 (1.04)	-45.5 (27.70)	22.2 (62.96)	-12.7 (5.20)	-0.3 (7.56)
Change at Week 2	-49.5 (20.04)	9.9 (30.10)	12.4 (30.69)	-27.1 (36.97)	-4.1 (2.48)	-55.1 (29.83)	22.1 (67.80)	-23.9 (8.20)	-5.1 (11.91)
Change at Week 3	-38.1 (25.21)	17.1 (37.85)	9.9 (44.29)	-47.7 (53.35)	-27.6 (7.82)	-66.1 (33.17)	0.8 (75.41)	-34.7 (7.29)	-16.9 (10.59)
Change at Week 4	-46.8 (28.92)	22.4 (43.43)	244.8 (239.53)	15.4 (288.53)	-38.5 (13.99)	-67.0 (28.94)	4.2 (65.78)	-37.9 (11.30)	2.4 (16.42)
Change at Week 5	-56.5 (27.85)	22.2 (41.82)	8.2 (50.36)	-52.6 (60.66)	-41.1 (17.26)	-70.4 (28.63)	-28.9 (65.09)	-47.2 (9.43)	-15.7 (13.70)
Change at Week 6	-47.6 (34.25)	27.1 (51.43)	-39.8 (14.56)	-61.6 (17.54)	-41.6 (17.91)	-79.2 (21.45)	-15.2 (48.76)	-59.4 (8.54)	-21.7 (12.42)
Change at Week 7	-60.0 (22.57)	19.5 (33.89)	-17.8 (29.08)	-61.5 (35.03)	-45.3 (22.49)	-83.1 (18.68)	-14.4 (42.45)	-62.3 (10.19)	-24.3 (14.80)
Change at Week 8	-54.0 (29.23)	24.2 (43.90)	-26.8 (24.06)	-58.4 (28.98)	-45.3 (22.49)	-83.9 (17.07)	-14.3 (38.81)	-69.3 (9.15)	-29.0 (13.29)
Change at Week 10	-60.3 (23.36)	20.9 (35.07)	-43.8 (8.58)	-86.7 (9.51)	-75.0 (0.00)	-84.2 (17.92)	-31.1 (40.73)	-68.2 (8.29)	-39.9 (12.85)
Change at Week 12	-53.6 (13.58)	23.7 (20.39)	45.6 (82.52)	-43.2 (91.47)	-71.1 (0.00)	-83.4 (18.87)	-30.2 (42.89)	-66.1 (8.84)	-41.9 (13.71)
Change at Week 14	-49.5 (19.46)	27.2 (29.21)	-30.1 (14.43)	-75.6 (15.99)	-71.1 (0.00)	-83.0 (19.35)	-6.5 (43.97)	-68.6 (9.28)	-38.0 (14.39)
Change at Week 16	-57.0 (17.00)	22.9 (25.53)	-34.4 (15.61)	-69.0 (17.30)	-75.7 (0.00)	-85.9 (16.02)	-8.9 (36.40)	-66.0 (9.77)	-36.7 (15.16)
Change at Week 18	-47.3 (11.94)	27.7 (17.93)	-23.3 (15.15)	-56.1 (16.79)	-74.7 (0.00)	-89.9 (11.26)	-9.8 (25.59)	-61.6 (11.11)	-43.6 (17.22)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	KPL-716: CIU Cohort, Placebo: CIU Cohort
	Comments	Change at Week 1
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.5403
	Comments	Calculated from an ANCOVA model including treatment as factor and baseline values as covariate.
	Method	ANCOVA
	Comments
Method of Estimation	Estimation Parameter	LS mean difference
	Estimated Value	-27.9
	Confidence Interval	(2-Sided) 80%; -94.32 to 38.46
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 40.54
	Estimation Comments

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	KPL-716: CIP Cohort, Placebo: CIP Cohort
	Comments	Change at Week 1
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.5587
	Comments	Calculated from an ANCOVA model including treatment as factor and baseline values as covariate.
	Method	ANCOVA
	Comments
Method of Estimation	Estimation Parameter	LS mean difference
	Estimated Value	376.1
	Confidence Interval	(2-Sided) 80%; -462.83 to 1214.97
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 631.83
	Estimation Comments

Statistical Analysis 3

Statistical Analysis Overview	Comparison Group Selection	KPL-716: LSC Cohort, Placebo: LSC Cohort
	Comments	Change at Week 1
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.4516
	Comments	Calculated from an ANCOVA model including treatment as factor and baseline values as covariate.
	Method	ANCOVA
	Comments
Method of Estimation	Estimation Parameter	LS mean difference
	Estimated Value	-67.7
	Confidence Interval	(2-Sided) 80%; -205.33 to 69.93
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 72.99
	Estimation Comments

Statistical Analysis 4

Statistical Analysis Overview	Comparison Group Selection	KPL-716: PPs Cohort, Placebo: PPs Cohort
	Comments	Change at Week 1
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.2052
	Comments	Calculated from an ANCOVA model including treatment as factor and baseline values as covariate.
	Method	ANCOVA
	Comments
Method of Estimation	Estimation Parameter	LS mean difference
	Estimated Value	-12.5
	Confidence Interval	(2-Sided) 80%; -25.13 to 0.15
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 9.50
	Estimation Comments

Statistical Analysis 5

Statistical Analysis Overview	Comparison Group Selection	KPL-716: CIU Cohort, Placebo: CIU Cohort
	Comments	Change at Week 2
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.2240
	Comments	Calculated from an ANCOVA model including treatment as factor and baseline values as covariate.
	Method	ANCOVA
	Comments
Method of Estimation	Estimation Parameter	LS mean difference
	Estimated Value	-59.4
	Confidence Interval	(2-Sided) 80%; -123.09 to 4.28
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 38.89
	Estimation Comments

Statistical Analysis 6

Statistical Analysis Overview	Comparison Group Selection	KPL-716: CIP Cohort, Placebo: CIP Cohort
	Comments	Change at Week 2
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.4242
	Comments	Calculated from an ANCOVA model including treatment as factor and baseline values as covariate.
	Method	ANCOVA
	Comments
Method of Estimation	Estimation Parameter	LS mean difference
	Estimated Value	39.5
	Confidence Interval	(2-Sided) 80%; -24.70 to 103.65
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 48.33
	Estimation Comments

Statistical Analysis 7

Statistical Analysis Overview	Comparison Group Selection	KPL-716: LSC Cohort, Placebo: LSC Cohort
	Comments	Change at Week 2
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.4295
	Comments	Calculated from an ANCOVA model including treatment as factor and baseline values as covariate.
	Method	ANCOVA
	Comments
Method of Estimation	Estimation Parameter	LS mean difference
	Estimated Value	-77.2
	Confidence Interval	(2-Sided) 80%; -225.44 to 71.01
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 78.61
	Estimation Comments

Statistical Analysis 8

Statistical Analysis Overview	Comparison Group Selection	KPL-716: PPs Cohort, Placebo: PPs Cohort
	Comments	Change at Week 2
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.2272
	Comments	Calculated from an ANCOVA model including treatment as factor and baseline values as covariate.
	Method	ANCOVA
	Comments
Method of Estimation	Estimation Parameter	LS mean difference
	Estimated Value	-18.7
	Confidence Interval	(2-Sided) 80%; -38.64 to 1.20
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 14.97
	Estimation Comments

Statistical Analysis 9

Statistical Analysis Overview	Comparison Group Selection	KPL-716: CIU Cohort, Placebo: CIU Cohort
	Comments	Change at Week 3
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.3416
	Comments	Calculated from an ANCOVA model including treatment as factor and baseline values as covariate.
	Method	ANCOVA
	Comments
Method of Estimation	Estimation Parameter	LS mean difference
	Estimated Value	-55.1
	Confidence Interval	(2-Sided) 80%; -135.23 to 24.95
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 48.90
	Estimation Comments

Statistical Analysis 10

Statistical Analysis Overview	Comparison Group Selection	KPL-716: CIP Cohort, Placebo: CIP Cohort
	Comments	Change at Week 3
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.4192
	Comments	Calculated from an ANCOVA model including treatment as factor and baseline values as covariate.
	Method	ANCOVA
	Comments
Method of Estimation	Estimation Parameter	LS mean difference
	Estimated Value	57.6
	Confidence Interval	(2-Sided) 80%; -35.02 to 150.19
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 69.75
	Estimation Comments

Statistical Analysis 11

Statistical Analysis Overview	Comparison Group Selection	KPL-716: LSC Cohort, Placebo: LSC Cohort
	Comments	Change at Week 3
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.5245
	Comments	Calculated from an ANCOVA model including treatment as factor and baseline values as covariate.
	Method	ANCOVA
	Comments
Method of Estimation	Estimation Parameter	LS mean difference
	Estimated Value	-66.8
	Confidence Interval	(2-Sided) 80%; -231.66 to 98.02
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 87.42
	Estimation Comments

Statistical Analysis 12

Statistical Analysis Overview	Comparison Group Selection	KPL-716: PPs Cohort, Placebo: PPs Cohort
	Comments	Change at Week 3
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.1988
	Comments	Calculated from an ANCOVA model including treatment as factor and baseline values as covariate.
	Method	ANCOVA
	Comments
Method of Estimation	Estimation Parameter	LS mean difference
	Estimated Value	-17.8
	Confidence Interval	(2-Sided) 80%; -35.47 to -0.05
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 13.31
	Estimation Comments

Statistical Analysis 13

Statistical Analysis Overview	Comparison Group Selection	KPL-716: CIU Cohort, Placebo: CIU Cohort
	Comments	Change at Week 4
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.3054
	Comments	Calculated from an ANCOVA model including treatment as factor and baseline values as covariate.
	Method	ANCOVA
	Comments
Method of Estimation	Estimation Parameter	LS mean difference
	Estimated Value	-69.2
	Confidence Interval	(2-Sided) 80%; -161.08 to 22.72
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 56.11
	Estimation Comments

Statistical Analysis 14

Statistical Analysis Overview	Comparison Group Selection	KPL-716: CIP Cohort, Placebo: CIP Cohort
	Comments	Change at Week 4
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.5504
	Comments	Calculated from an ANCOVA model including treatment as factor and baseline values as covariate.
	Method	ANCOVA
	Comments
Method of Estimation	Estimation Parameter	LS mean difference
	Estimated Value	229.4
	Confidence Interval	(2-Sided) 80%; -271.51 to 730.22
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 377.23
	Estimation Comments

Statistical Analysis 15

Statistical Analysis Overview	Comparison Group Selection	KPL-716: LSC Cohort, Placebo: LSC Cohort
	Comments	Change at Week 4
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.4493
	Comments	Calculated from an ANCOVA model including treatment as factor and baseline values as covariate.
	Method	ANCOVA
	Comments
Method of Estimation	Estimation Parameter	LS mean difference
	Estimated Value	-71.2
	Confidence Interval	(2-Sided) 80%; -214.96 to 72.65
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 76.27
	Estimation Comments

Statistical Analysis 16

Statistical Analysis Overview	Comparison Group Selection	KPL-716: PPs Cohort, Placebo: PPs Cohort
	Comments	Change at Week 4
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.0665
	Comments	Calculated from an ANCOVA model including treatment as factor and baseline values as covariate.
	Method	ANCOVA
	Comments
Method of Estimation	Estimation Parameter	LS mean difference
	Estimated Value	-40.3
	Confidence Interval	(2-Sided) 80%; -67.74 to -12.85
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 20.63
	Estimation Comments

Statistical Analysis 17

Statistical Analysis Overview	Comparison Group Selection	KPL-716: CIU Cohort, Placebo: CIU Cohort
	Comments	Change at Week 5
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.2411
	Comments	Calculated from an ANCOVA model including treatment as factor and baseline values as covariate.
	Method	ANCOVA
	Comments
Method of Estimation	Estimation Parameter	LS mean difference
	Estimated Value	-78.7
	Confidence Interval	(2-Sided) 80%; -167.25 to 9.75
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 54.04
	Estimation Comments

Statistical Analysis 18

Statistical Analysis Overview	Comparison Group Selection	KPL-716: CIP Cohort, Placebo: CIP Cohort
	Comments	Change at Week 5
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.4528
	Comments	Calculated from an ANCOVA model including treatment as factor and baseline values as covariate.
	Method	ANCOVA
	Comments
Method of Estimation	Estimation Parameter	LS mean difference
	Estimated Value	60.8
	Confidence Interval	(2-Sided) 80%; -44.51 to 166.08
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 79.30
	Estimation Comments

Statistical Analysis 19

Statistical Analysis Overview	Comparison Group Selection	KPL-716: LSC Cohort, Placebo: LSC Cohort
	Comments	Change at Week 5
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.6381
	Comments	Calculated from an ANCOVA model including treatment as factor and baseline values as covariate.
	Method	ANCOVA
	Comments
Method of Estimation	Estimation Parameter	LS mean difference
	Estimated Value	-41.4
	Confidence Interval	(2-Sided) 80%; -183.72 to 100.85
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 75.46
	Estimation Comments

Statistical Analysis 20

Statistical Analysis Overview	Comparison Group Selection	KPL-716: PPs Cohort, Placebo: PPs Cohort
	Comments	Change at Week 5
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.0837
	Comments	Calculated from an ANCOVA model including treatment as factor and baseline values as covariate.
	Method	ANCOVA
	Comments
Method of Estimation	Estimation Parameter	LS mean difference
	Estimated Value	-31.5
	Confidence Interval	(2-Sided) 80%; -54.44 to -8.62
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 17.22
	Estimation Comments

Statistical Analysis 21

Statistical Analysis Overview	Comparison Group Selection	KPL-716: CIU Cohort, Placebo: CIU Cohort
	Comments	Change at Week 6
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.3428
	Comments	Calculated from an ANCOVA model including treatment as factor and baseline values as covariate.
	Method	ANCOVA
	Comments
Method of Estimation	Estimation Parameter	LS mean difference
	Estimated Value	-74.7
	Confidence Interval	(2-Sided) 80%; -183.53 to 34.13
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 66.45
	Estimation Comments

Statistical Analysis 22

Statistical Analysis Overview	Comparison Group Selection	KPL-716: CIP Cohort, Placebo: CIP Cohort
	Comments	Change at Week 6
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.3533
	Comments	Calculated from an ANCOVA model including treatment as factor and baseline values as covariate.
	Method	ANCOVA
	Comments
Method of Estimation	Estimation Parameter	LS Mean Difference
	Estimated Value	21.8
	Confidence Interval	(2-Sided) 80%; -8.63 to 52.27
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 22.93
	Estimation Comments

Statistical Analysis 23

Statistical Analysis Overview	Comparison Group Selection	KPL-716: LSC Cohort, Placebo: LSC Cohort
	Comments	Change at Week 6
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.3755
	Comments	Calculated from an ANCOVA model including treatment as factor and baseline values as covariate.
	Method	ANCOVA
	Comments
Method of Estimation	Estimation Parameter	LS Mean Difference
	Estimated Value	-63.9
	Confidence Interval	(2-Sided) 80%; -170.51 to 42.66
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 56.53
	Estimation Comments

Statistical Analysis 24

Statistical Analysis Overview	Comparison Group Selection	KPL-716: PPs Cohort, Placebo: PPs Cohort
	Comments	Change at Week 6
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.0268
	Comments	Calculated from an ANCOVA model including treatment as factor and baseline values as covariate.
	Method	ANCOVA
	Comments
Method of Estimation	Estimation Parameter	LS Mean Difference
	Estimated Value	-37.6
	Confidence Interval	(2-Sided) 80%; -58.39 to -16.87
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 15.60
	Estimation Comments

Statistical Analysis 25

Statistical Analysis Overview	Comparison Group Selection	KPL-716: CIU Cohort, Placebo: CIU Cohort
	Comments	Change at Week 7
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.1672
	Comments	Calculated from an ANCOVA model including treatment as factor and baseline values as covariate.
	Method	ANCOVA
	Comments
Method of Estimation	Estimation Parameter	LS Mean Difference
	Estimated Value	-79.5
	Confidence Interval	(2-Sided) 80%; -151.20 to -7.75
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 43.79
	Estimation Comments

Statistical Analysis 26

Statistical Analysis Overview	Comparison Group Selection	KPL-716: CIP Cohort, Placebo: CIP Cohort
	Comments	Change at Week 7
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.3518
	Comments	Calculated from an ANCOVA model including treatment as factor and baseline values as covariate.
	Method	ANCOVA
	Comments
Method of Estimation	Estimation Parameter	LS Mean Difference
	Estimated Value	43.7
	Confidence Interval	(2-Sided) 80%; -17.09 to 104.55
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 45.81
	Estimation Comments

Statistical Analysis 27

Statistical Analysis Overview	Comparison Group Selection	KPL-716: LSC Cohort, Placebo: LSC Cohort
	Comments	Change at Week 7
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.2974
	Comments	Calculated from an ANCOVA model including treatment as factor and baseline values as covariate.
	Method	ANCOVA
	Comments
Method of Estimation	Estimation Parameter	LS Mean Difference
	Estimated Value	-68.7
	Confidence Interval	(2-Sided) 80%; -161.52 to 24.09
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 49.22
	Estimation Comments

Statistical Analysis 28

Statistical Analysis Overview	Comparison Group Selection	KPL-716: PPs Cohort, Placebo: PPs Cohort
	Comments	Change at Week 7
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.0555
	Comments	Calculated from an ANCOVA model including treatment as factor and baseline values as covariate.
	Method	ANCOVA
	Comments
Method of Estimation	Estimation Parameter	LS Mean Difference
	Estimated Value	-38.1
	Confidence Interval	(2-Sided) 80%; -62.83 to -13.33
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 18.60
	Estimation Comments

Statistical Analysis 29

Statistical Analysis Overview	Comparison Group Selection	KPL-716: CIU Cohort, Placebo: CIU Cohort
	Comments	Change at Week 8
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.2614
	Comments	Calculated from an ANCOVA model including treatment as factor and baseline values as covariate.
	Method	ANCOVA
	Comments
Method of Estimation	Estimation Parameter	LS Mean Difference
	Estimated Value	-78.3
	Confidence Interval	(2-Sided) 80%; -171.17 to 14.62
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 56.72
	Estimation Comments

Statistical Analysis 30

Statistical Analysis Overview	Comparison Group Selection	KPL-716: CIP Cohort, Placebo: CIP Cohort
	Comments	Change at Week 8
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.4134
	Comments	Calculated from an ANCOVA model including treatment as factor and baseline values as covariate.
	Method	ANCOVA
	Comments
Method of Estimation	Estimation Parameter	LS Mean Difference
	Estimated Value	31.7
	Confidence Interval	(2-Sided) 80%; -18.62 to 81.98
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 37.89
	Estimation Comments

Statistical Analysis 31

Statistical Analysis Overview	Comparison Group Selection	KPL-716: LSC Cohort, Placebo: LSC Cohort
	Comments	Change at Week 8
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.2620
	Comments	Calculated from an ANCOVA model including treatment as factor and baseline values as covariate.
	Method	ANCOVA
	Comments
Method of Estimation	Estimation Parameter	LS Mean Difference
	Estimated Value	-69.6
	Confidence Interval	(2-Sided) 80%; -154.44 to 15.24
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 44.99
	Estimation Comments

Statistical Analysis 32

Statistical Analysis Overview	Comparison Group Selection	KPL-716: PPs Cohort, Placebo: PPs Cohort
	Comments	Change at Week 8
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.0269
	Comments	Calculated from an ANCOVA model including treatment as factor and baseline values as covariate.
	Method	ANCOVA
	Comments
Method of Estimation	Estimation Parameter	LS Mean Difference
	Estimated Value	-40.2
	Confidence Interval	(2-Sided) 80%; -62.46 to -18.02
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 16.70
	Estimation Comments

Statistical Analysis 33

Statistical Analysis Overview	Comparison Group Selection	KPL-716: CIU Cohort, Placebo: CIU Cohort
	Comments	Change at Week 10
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.1709
	Comments	Calculated from an ANCOVA model including treatment as factor and baseline values as covariate.
	Method	ANCOVA
	Comments
Method of Estimation	Estimation Parameter	LS Mean Difference
	Estimated Value	-81.2
	Confidence Interval	(2-Sided) 80%; -155.46 to -7.02
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 45.32
	Estimation Comments

Statistical Analysis 34

Statistical Analysis Overview	Comparison Group Selection	KPL-716: CIP Cohort, Placebo: CIP Cohort
	Comments	Change at Week 10
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.0042
	Comments	Calculated from an ANCOVA model including treatment as factor and baseline values as covariate.
	Method	ANCOVA
	Comments
Method of Estimation	Estimation Parameter	LS Mean Difference
	Estimated Value	42.9
	Confidence Interval	(2-Sided) 80%; 25.61 to 60.22
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 12.98
	Estimation Comments

Statistical Analysis 35

Statistical Analysis Overview	Comparison Group Selection	KPL-716: LSC Cohort, Placebo: LSC Cohort
	Comments	Change at Week 10
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.3772
	Comments	Calculated from an ANCOVA model including treatment as factor and baseline values as covariate.
	Method	ANCOVA
	Comments
Method of Estimation	Estimation Parameter	LS Mean Difference
	Estimated Value	-53.2
	Confidence Interval	(2-Sided) 80%; -142.19 to 35.88
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 47.22
	Estimation Comments

Statistical Analysis 36

Statistical Analysis Overview	Comparison Group Selection	KPL-716: PPs Cohort, Placebo: PPs Cohort
	Comments	Change at Week 10
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.0857
	Comments	Calculated from an ANCOVA model including treatment as factor and baseline values as covariate.
	Method	ANCOVA
	Comments
Method of Estimation	Estimation Parameter	LS Mean Difference
	Estimated Value	-28.3
	Confidence Interval	(2-Sided) 80%; -49.06 to -7.63
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 15.54
	Estimation Comments

Statistical Analysis 37

Statistical Analysis Overview	Comparison Group Selection	KPL-716: CIU Cohort, Placebo: CIU Cohort
	Comments	Change at Week 12
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.0607
	Comments	Calculated from an ANCOVA model including treatment as factor and baseline values as covariate.
	Method	ANCOVA
	Comments
Method of Estimation	Estimation Parameter	LS Mean Difference
	Estimated Value	-77.3
	Confidence Interval	(2-Sided) 80%; -120.48 to -34.20
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 26.34
	Estimation Comments

Statistical Analysis 38

Statistical Analysis Overview	Comparison Group Selection	KPL-716: CIP Cohort, Placebo: CIP Cohort
	Comments	Change at Week 12
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.4862
	Comments	Calculated from an ANCOVA model including treatment as factor and baseline values as covariate.
	Method	ANCOVA
	Comments
Method of Estimation	Estimation Parameter	LS Mean Difference
	Estimated Value	88.8
	Confidence Interval	(2-Sided) 80%; -77.57 to 255.22
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 124.79
	Estimation Comments

Statistical Analysis 39

Statistical Analysis Overview	Comparison Group Selection	KPL-716: LSC Cohort, Placebo: LSC Cohort
	Comments	Change at Week 12
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.3968
	Comments	Calculated from an ANCOVA model including treatment as factor and baseline values as covariate.
	Method	ANCOVA
	Comments
Method of Estimation	Estimation Parameter	LS Mean Difference
	Estimated Value	-53.2
	Confidence Interval	(2-Sided) 80%; -146.96 to 40.58
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 49.73
	Estimation Comments

Statistical Analysis 40

Statistical Analysis Overview	Comparison Group Selection	KPL-716: PPs Cohort, Placebo: PPs Cohort
	Comments	Change at Week 12
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.1624
	Comments	Calculated from an ANCOVA model including treatment as factor and baseline values as covariate.
	Method	ANCOVA
	Comments
Method of Estimation	Estimation Parameter	LS Mean Difference
	Estimated Value	-24.2
	Confidence Interval	(2-Sided) 80%; -46.31 to -2.11
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 16.57
	Estimation Comments

Statistical Analysis 41

Statistical Analysis Overview	Comparison Group Selection	KPL-716: CIU Cohort, Placebo: CIU Cohort
	Comments	Change at Week 14
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.1349
	Comments	Calculated from an ANCOVA model including treatment as factor and baseline values as covariate.
	Method	ANCOVA
	Comments
Method of Estimation	Estimation Parameter	LS Mean Difference
	Estimated Value	-76.8
	Confidence Interval	(2-Sided) 80%; -138.58 to -14.93
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 37.75
	Estimation Comments

Statistical Analysis 42

Statistical Analysis Overview	Comparison Group Selection	KPL-716: CIP Cohort, Placebo: CIP Cohort
	Comments	Change at Week 14
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.0525
	Comments	Calculated from an ANCOVA model including treatment as factor and baseline values as covariate.
	Method	ANCOVA
	Comments
Method of Estimation	Estimation Parameter	LS Mean Difference
	Estimated Value	45.5
	Confidence Interval	(2-Sided) 80%; 16.38 to 74.56
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 21.81
	Estimation Comments

Statistical Analysis 43

Statistical Analysis Overview	Comparison Group Selection	KPL-716: LSC Cohort, Placebo: LSC Cohort
	Comments	Change at Week 14
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.2719
	Comments	Calculated from an ANCOVA model including treatment as factor and baseline values as covariate.
	Method	ANCOVA
	Comments
Method of Estimation	Estimation Parameter	LS Mean Difference
	Estimated Value	-76.6
	Confidence Interval	(2-Sided) 80%; -172.71 to 19.55
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 50.98
	Estimation Comments

Statistical Analysis 44

Statistical Analysis Overview	Comparison Group Selection	KPL-716: PPs Cohort, Placebo: PPs Cohort
	Comments	Change at Week 14
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.0957
	Comments	Calculated from an ANCOVA model including treatment as factor and baseline values as covariate.
	Method	ANCOVA
	Comments
Method of Estimation	Estimation Parameter	LS Mean Difference
	Estimated Value	-30.7
	Confidence Interval	(2-Sided) 80%; -53.86 to -7.49
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 17.39
	Estimation Comments

Statistical Analysis 45

Statistical Analysis Overview	Comparison Group Selection	KPL-716: CIU Cohort, Placebo: CIU Cohort
	Comments	Change at Week 16
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.0942
	Comments	Calculated from an ANCOVA model including treatment as factor and baseline values as covariate.
	Method	ANCOVA
	Comments
Method of Estimation	Estimation Parameter	LS Mean Difference
	Estimated Value	-79.8
	Confidence Interval	(2-Sided) 80%; -133.83 to -25.78
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 32.98
	Estimation Comments

Statistical Analysis 46

Statistical Analysis Overview	Comparison Group Selection	KPL-716: CIP Cohort, Placebo: CIP Cohort
	Comments	Change at Week 16
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.1606
	Comments	Calculated from an ANCOVA model including treatment as factor and baseline values as covariate.
	Method	ANCOVA
	Comments
Method of Estimation	Estimation Parameter	LS Mean Difference
	Estimated Value	34.6
	Confidence Interval	(2-Sided) 80%; 3.16 to 66.09
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 23.60
	Estimation Comments

Statistical Analysis 47

Statistical Analysis Overview	Comparison Group Selection	KPL-716: LSC Cohort, Placebo: LSC Cohort
	Comments	Change at Week 16
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.2096
	Comments	Calculated from an ANCOVA model including treatment as factor and baseline values as covariate.
	Method	ANCOVA
	Comments
Method of Estimation	Estimation Parameter	LS Mean Difference
	Estimated Value	-77.0
	Confidence Interval	(2-Sided) 80%; -156.58 to 2.58
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 42.20
	Estimation Comments

Statistical Analysis 48

Statistical Analysis Overview	Comparison Group Selection	KPL-716: PPs Cohort, Placebo: PPs Cohort
	Comments	Change at Week 16
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.1279
	Comments	Calculated from an ANCOVA model including treatment as factor and baseline values as covariate.
	Method	ANCOVA
	Comments
Method of Estimation	Estimation Parameter	LS Mean Difference
	Estimated Value	-29.3
	Confidence Interval	(2-Sided) 80%; -53.74 to -4.89
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 18.32
	Estimation Comments

Statistical Analysis 49

Statistical Analysis Overview	Comparison Group Selection	KPL-716: CIU Cohort, Placebo: CIU Cohort
	Comments	Change at Week 18
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.0479
	Comments	Calculated from an ANCOVA model including treatment as factor and baseline values as covariate.
	Method	ANCOVA
	Comments
Method of Estimation	Estimation Parameter	LS Mean Difference
	Estimated Value	-75.0
	Confidence Interval	(2-Sided) 80%; -112.96 to -37.08
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 23.17
	Estimation Comments

Statistical Analysis 50

Statistical Analysis Overview	Comparison Group Selection	KPL-716: CIP Cohort, Placebo: CIP Cohort
	Comments	Change at Week 18
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.1700
	Comments	Calculated from an ANCOVA model including treatment as factor and baseline values as covariate.
	Method	ANCOVA
	Comments
Method of Estimation	Estimation Parameter	LS Mean Difference
	Estimated Value	32.8
	Confidence Interval	(2-Sided) 80%; 2.28 to 63.37
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 22.91
	Estimation Comments

Statistical Analysis 51

Statistical Analysis Overview	Comparison Group Selection	KPL-716: LSC Cohort, Placebo: LSC Cohort
	Comments	Change at Week 18
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.1142
	Comments	Calculated from an ANCOVA model including treatment as factor and baseline values as covariate.
	Method	ANCOVA
	Comments
Method of Estimation	Estimation Parameter	LS Mean Difference
	Estimated Value	-80.1
	Confidence Interval	(2-Sided) 80%; -136.03 to -24.15
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 29.67
	Estimation Comments

Statistical Analysis 52

Statistical Analysis Overview	Comparison Group Selection	KPL-716: PPs Cohort, Placebo: PPs Cohort
	Comments	Change at Week 18
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.3980
	Comments	Calculated from an ANCOVA model including treatment as factor and baseline values as covariate.
	Method	ANCOVA
	Comments
Method of Estimation	Estimation Parameter	LS Mean Difference
	Estimated Value	-18.0
	Confidence Interval	(2-Sided) 80%; -45.80 to 9.71
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 20.82
	Estimation Comments

13. Secondary Outcome

Title	Change From Baseline in Weekly Average of Difficulty Falling Asleep Numerical Rating Scale (NRS) Over Time
Description	Participants were asked daily to assign a numerical score to the intensity of their difficulty falling asleep last night due to itch using a scale from 0 to 10, with 0 indicating not difficult at all and 10 indicating extremely difficult.
Time Frame	Baseline, Weeks 1-18

Outcome Measure Data

Analysis Population Description

Modified intent to treat (mITT) set: all randomized participants who received at least 1 dose of KPL-716 or placebo and had at least 1 post-baseline efficacy assessment in the double-blind treatment period. Missing data were imputed using the last observation carried forward (LOCF) method. Once a participant started treatment period (through Week 8), missing data in treatment period were imputed. Once a participant started the follow up (FU) period, missing data in FU period were imputed.

Arm/Group Title	KPL-716: CIU Cohort	Placebo: CIU Cohort	KPL-716: CIP Cohort	Placebo: CIP Cohort	KPL-716: LP Cohort	Placebo: LP Cohort	KPL-716: LSC Cohort	Placebo: LSC Cohort	KPL-716: PPs Cohort	Placebo: PPs Cohort
Arm/Group Description	Participants with CIU received KPL-716 weekly for 8 weeks	Participants with CIU received placebo weekly for 8 weeks	Participants with CIP received KPL-716 weekly for 8 weeks	Participants with CIP received placebo weekly for 8 weeks	Participants with LP received KPL-716 weekly for 8 weeks	Participants with LP received placebo weekly for 8 weeks	Participants with LSC received KPL-716 weekly for 8 weeks	Participants with LSC received placebo weekly for 8 weeks	Participants with PPs received KPL-716 weekly for 8 weeks	Participants with PPs received placebo weekly for 8 weeks
Measure Participants	4	2	14	9	3	0	4	1	14	7
Change at Week 1	-2.1 (0.67)	-0.3 (0.29)	-0.6 (0.44)	-1.7 (0.40)	-0.3 (0.08)	-3.0 (1.31)	-1.0 (NA)	-0.7 (0.16)	0.0 (0.24)
Change at Week 2	-3.3 (0.78)	-0.4 (0.43)	-2.0 (0.52)	-3.1 (0.57)	-0.9 (0.30)	-4.3 (1.96)	-1.0 (NA)	-1.3 (0.26)	-0.6 (0.35)
Change at Week 3	-4.2 (1.21)	-0.5 (0.50)	-2.6 (0.59)	-2.9 (0.70)	-1.6 (0.87)	-4.6 (2.10)	-1.6 (NA)	-2.4 (0.56)	-0.8 (0.42)
Change at Week 4	-4.5 (1.35)	0.0 (0.00)	-2.7 (0.72)	-2.9 (0.82)	-2.5 (1.57)	-4.8 (1.91)	-2.1 (NA)	-3.1 (0.55)	-1.0 (0.70)
Change at Week 5	-5.0 (1.57)	-0.4 (0.43)	-3.0 (0.76)	-3.0 (0.71)	-2.9 (1.64)	-5.2 (1.95)	-2.0 (NA)	-4.1 (0.72)	-1.5 (0.89)
Change at Week 6	-5.0 (1.45)	-0.5 (0.50)	-3.0 (0.69)	-3.8 (0.71)	-3.1 (1.61)	-5.5 (1.82)	-2.6 (NA)	-4.4 (0.69)	-1.4 (0.90)
Change at Week 7	-4.5 (1.56)	-0.2 (0.21)	-3.0 (0.65)	-3.7 (0.75)	-3.6 (1.65)	-5.6 (1.76)	-2.6 (NA)	-4.8 (0.72)	-1.8 (1.08)
Change at Week 8	-3.8 (1.66)	-0.3 (0.29)	-3.2 (0.64)	-2.9 (0.81)	-3.6 (1.65)	-5.4 (1.94)	-3.3 (NA)	-5.2 (0.70)	-2.1 (1.21)
Change at Week 9	-4.4 (1.46)	0.7 (0.71)	-2.9 (0.69)	-3.7 (0.65)	-5.1 (0.86)	-5.4 (1.88)	-3.4 (NA)	-5.3 (0.70)	-2.4 (1.27)
Change at Week 10	-4.4 (1.64)	-0.5 (0.50)	-2.6 (0.65)	-4.5 (0.55)	-5.1 (0.86)	-5.6 (1.69)	-3.0 (NA)	-5.2 (0.77)	-2.4 (1.21)
Change at Week 11	-4.7 (1.78)	-0.5 (0.50)	-2.6 (0.76)	-4.6 (0.69)	-5.1 (0.86)	-5.7 (1.61)	-3.1 (NA)	-5.0 (0.77)	-2.4 (1.20)
Change at Week 12	-4.7 (1.73)	-0.5 (0.50)	-2.5 (0.73)	-4.1 (0.71)	-5.1 (0.86)	-5.9 (1.50)	-2.6 (NA)	-4.9 (0.78)	-2.5 (1.17)
Change at Week 13	-4.1 (1.90)	-0.5 (0.50)	-2.5 (0.65)	-4.3 (0.73)	-5.6 (0.43)	-5.9 (1.53)	-1.9 (NA)	-5.0 (0.80)	-2.5 (1.18)
Change at Week 14	-3.6 (1.92)	-0.5 (0.50)	-2.8 (0.65)	-4.3 (0.78)	-5.6 (0.36)	-5.8 (1.58)	-2.1 (NA)	-5.1 (0.78)	-2.6 (1.20)
Change at Week 15	-4.4 (1.77)	-0.5 (0.50)	-2.6 (0.61)	-4.1 (0.73)	-5.6 (0.36)	-6.0 (1.45)	-2.4 (NA)	-5.0 (0.83)	-2.8 (1.35)
Change at Week 16	-4.1 (1.86)	-0.5 (0.50)	-2.8 (0.68)	-3.8 (0.91)	-5.6 (0.36)	-6.0 (1.43)	-1.9 (NA)	-4.9 (0.81)	-2.7 (1.32)
Change at Week 17	-4.2 (1.91)	-0.5 (0.50)	-2.7 (0.64)	-3.5 (0.85)	-5.6 (0.36)	-6.2 (1.32)	-1.4 (NA)	-4.6 (0.97)	-3.0 (1.37)
Change at Week 18	-4.4 (1.79)	-0.5 (0.50)	-2.8 (0.72)	-3.6 (0.92)	-5.7 (0.43)	-6.2 (1.32)	-1.3 (NA)	-4.6 (0.98)	-3.0 (1.36)

14. Secondary Outcome

Title	Percent Change From Baseline in Weekly Average of Difficulty Falling Asleep NRS Over Time
Description	Participants were asked daily to assign a numerical score to the intensity of their difficulty falling asleep last night due to itch using a scale from 0 to 10, with 0 indicating not difficult at all and 10 indicating extremely difficult.
Time Frame	Baseline, Weeks 1-18

Outcome Measure Data

Analysis Population Description

Modified intent to treat (mITT) set: all randomized participants who received at least 1 dose of KPL-716 or placebo and had at least 1 post-baseline efficacy assessment in the double-blind treatment period. Missing data were imputed using the last observation carried forward (LOCF) method. Once a participant started treatment period (through Week 8), missing data in treatment period were imputed. Once a participant started the follow up (FU) period, missing data in FU period were imputed.

Arm/Group Title	KPL-716: CIU Cohort	Placebo: CIU Cohort	KPL-716: CIP Cohort	Placebo: CIP Cohort	KPL-716: LP Cohort	Placebo: LP Cohort	KPL-716: LSC Cohort	Placebo: LSC Cohort	KPL-716: PPs Cohort	Placebo: PPs Cohort
Arm/Group Description	Participants with CIU received KPL-716 weekly for 8 weeks	Participants with CIU received placebo weekly for 8 weeks	Participants with CIP received KPL-716 weekly for 8 weeks	Participants with CIP received placebo weekly for 8 weeks	Participants with LP received KPL-716 weekly for 8 weeks	Participants with LP received placebo weekly for 8 weeks	Participants with LSC received KPL-716 weekly for 8 weeks	Participants with LSC received placebo weekly for 8 weeks	Participants with PPs received KPL-716 weekly for 8 weeks	Participants with PPs received placebo weekly for 8 weeks
Measure Participants	4	2	14	9	3	0	4	1	14	7
Change at Week 1	-35.3 (9.68)	-22.2 (13.83)	-4.9 (8.21)	-26.6 (9.88)	-3.6 (1.17)	-42.9 (17.69)	-7.4 (36.83)	-9.3 (2.32)	1.2 (3.33)
Change at Week 2	-51.1 (13.32)	-34.9 (19.03)	-31.2 (7.80)	-48.7 (9.38)	-10.9 (5.13)	-59.3 (23.10)	-0.5 (48.09)	-15.0 (3.50)	-9.3 (5.03)
Change at Week 3	-63.9 (20.16)	-40.9 (28.80)	-42.1 (8.81)	-48.7 (10.60)	-20.0 (15.28)	-64.8 (24.87)	-6.2 (51.77)	-27.6 (6.38)	-11.2 (9.16)
Change at Week 4	-61.0 (15.91)	-1.4 (22.72)	-43.3 (10.71)	-50.3 (12.88)	-31.4 (27.58)	-67.6 (21.14)	-14.2 (44.00)	-36.3 (6.64)	-12.2 (9.53)
Change at Week 5	-71.7 (22.82)	-36.4 (32.59)	-46.0 (11.47)	-50.4 (13.80)	-37.2 (28.02)	-73.1 (23.65)	-15.4 (49.24)	-48.4 (7.51)	-20.8 (10.78)
Change at Week 6	-73.1 (21.37)	-42.1 (30.52)	-47.5 (9.49)	-60.6 (11.42)	-39.8 (26.65)	-79.0 (25.98)	-30.3 (54.08)	-52.7 (7.40)	-19.0 (10.63)
Change at Week 7	-62.2 (19.51)	-19.4 (27.88)	-50.5 (8.27)	-61.5 (9.95)	-46.3 (23.22)	-80.0 (24.71)	-30.3 (51.45)	-57.2 (8.21)	-24.5 (11.79)
Change at Week 8	-51.9 (21.00)	-25.8 (30.00)	-54.1 (8.75)	-47.9 (10.52)	-46.3 (23.22)	-77.0 (28.52)	-38.6 (59.36)	-63.2 (8.55)	-27.5 (12.29)
Change at Week 9	-52.4 (10.60)	55.9 (15.15)	-50.6 (8.32)	-60.6 (9.20)	-66.9 (0.00)	-78.0 (27.25)	-40.3 (56.72)	-64.3 (8.48)	-32.3 (12.17)
Change at Week 10	-62.3 (22.58)	-43.1 (32.26)	-45.5 (7.86)	-69.4 (8.70)	-66.9 (0.00)	-80.6 (23.28)	-35.5 (48.46)	-62.0 (8.70)	-31.5 (12.50)
Change at Week 11	-66.4 (24.89)	-43.1 (35.55)	-43.2 (9.82)	-69.8 (10.86)	-66.9 (0.00)	-82.1 (21.38)	-37.1 (44.50)	-58.9 (8.47)	-33.2 (12.17)
Change at Week 12	-66.4 (23.94)	-43.1 (34.20)	-43.4 (10.02)	-64.0 (11.08)	-66.9 (0.00)	-85.2 (18.38)	-30.2 (38.26)	-58.5 (8.78)	-33.7 (12.60)
Change at Week 13	-55.7 (26.31)	-43.7 (37.59)	-43.5 (9.52)	-68.2 (10.53)	-72.8 (0.00)	-84.6 (19.01)	-21.9 (39.57)	-60.6 (9.18)	-34.1 (13.19)
Change at Week 14	-48.5 (25.78)	-44.0 (36.83)	-49.4 (9.01)	-68.9 (9.97)	-73.8 (0.00)	-83.6 (20.28)	-25.2 (42.21)	-61.7 (9.25)	-34.1 (13.28)
Change at Week 15	-62.3 (24.47)	-43.3 (34.96)	-44.1 (8.74)	-67.0 (9.67)	-73.8 (0.00)	-86.2 (17.11)	-28.5 (35.62)	-60.2 (9.90)	-38.3 (14.22)
Change at Week 16	-56.4 (25.57)	-43.7 (36.52)	-47.8 (10.02)	-64.3 (11.08)	-73.8 (0.00)	-86.7 (16.48)	-21.8 (34.30)	-58.9 (9.71)	-37.0 (13.95)
Change at Week 17	-58.5 (26.89)	-43.6 (38.41)	-45.1 (9.46)	-60.3 (10.47)	-73.8 (0.00)	-89.3 (13.31)	-16.8 (27.70)	-53.7 (11.52)	-41.2 (16.54)
Change at Week 18	-61.1 (24.70)	-43.4 (35.29)	-48.1 (10.22)	-61.9 (11.30)	-74.7 (0.00)	-89.3 (13.31)	-15.1 (27.70)	-53.4 (11.61)	-41.8 (16.68)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	KPL-716: CIU Cohort, Placebo: CIU Cohort
	Comments	Change at Week 1
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.4979
	Comments	Calculated from an ANCOVA model including treatment as factor and baseline values as covariate.
	Method	ANCOVA
	Comments
Method of Estimation	Estimation Parameter	LS mean difference
	Estimated Value	-13.2
	Confidence Interval	(2-Sided) 80%; -41.17 to 14.86
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 17.11
	Estimation Comments

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	KPL-716: CIP Cohort, Placebo: CIP Cohort
	Comments	Change at Week 1
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.1079
	Comments	Calculated from an ANCOVA model including treatment as factor and baseline values as covariate.
	Method	ANCOVA
	Comments
Method of Estimation	Estimation Parameter	LS mean difference
	Estimated Value	21.7
	Confidence Interval	(2-Sided) 80%; 4.63 to 38.83
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 12.88
	Estimation Comments

Statistical Analysis 3

Statistical Analysis Overview	Comparison Group Selection	KPL-716: LSC Cohort, Placebo: LSC Cohort
	Comments	Change at Week 1
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.4837
	Comments	Calculated from an ANCOVA model including treatment as factor and baseline values as covariate.
	Method	ANCOVA
	Comments
Method of Estimation	Estimation Parameter	LS mean difference
	Estimated Value	-35.6
	Confidence Interval	(2-Sided) 80%; -114.19 to 43.07
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 41.70
	Estimation Comments

Statistical Analysis 4

Statistical Analysis Overview	Comparison Group Selection	KPL-716: PPs Cohort, Placebo: PPs Cohort
	Comments	Change at Week 1
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.0208
	Comments	Calculated from an ANCOVA model including treatment as factor and baseline values as covariate.
	Method	ANCOVA
	Comments
Method of Estimation	Estimation Parameter	LS mean difference
	Estimated Value	-10.5
	Confidence Interval	(2-Sided) 80%; -15.99 to -4.98
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 4.14
	Estimation Comments

Statistical Analysis 5

Statistical Analysis Overview	Comparison Group Selection	KPL-716: CIU Cohort, Placebo: CIU Cohort
	Comments	Change at Week 2
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.5413
	Comments	Calculated from an ANCOVA model including treatment as factor and baseline values as covariate.
	Method	ANCOVA
	Comments
Method of Estimation	Estimation Parameter	LS mean difference
	Estimated Value	-16.2
	Confidence Interval	(2-Sided) 80%; -54.74 to 22.38
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 23.54
	Estimation Comments

Statistical Analysis 6

Statistical Analysis Overview	Comparison Group Selection	KPL-716: CIP Cohort, Placebo: CIP Cohort
	Comments	Change at Week 2
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.1683
	Comments	Calculated from an ANCOVA model including treatment as factor and baseline values as covariate.
	Method	ANCOVA
	Comments
Method of Estimation	Estimation Parameter	LS mean difference
	Estimated Value	17.5
	Confidence Interval	(2-Sided) 80%; 1.28 to 33.74
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 12.22
	Estimation Comments

Statistical Analysis 7

Statistical Analysis Overview	Comparison Group Selection	KPL-716: LSC Cohort, Placebo: LSC Cohort
	Comments	Change at Week 2
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.3933
	Comments	Calculated from an ANCOVA model including treatment as factor and baseline values as covariate.
	Method	ANCOVA
	Comments
Method of Estimation	Estimation Parameter	LS mean difference
	Estimated Value	-58.8
	Confidence Interval	(2-Sided) 80%; -161.43 to 43.89
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 54.45
	Estimation Comments

Statistical Analysis 8

Statistical Analysis Overview	Comparison Group Selection	KPL-716: PPs Cohort, Placebo: PPs Cohort
	Comments	Change at Week 2
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.3705
	Comments	Calculated from an ANCOVA model including treatment as factor and baseline values as covariate.
	Method	ANCOVA
	Comments
Method of Estimation	Estimation Parameter	LS mean difference
	Estimated Value	-5.7
	Confidence Interval	(2-Sided) 80%; -14.06 to 2.58
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 6.25
	Estimation Comments

Statistical Analysis 9

Statistical Analysis Overview	Comparison Group Selection	KPL-716: CIU Cohort, Placebo: CIU Cohort
	Comments	Change at Week 3
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.5644
	Comments	Calculated from an ANCOVA model including treatment as factor and baseline values as covariate.
	Method	ANCOVA
	Comments
Method of Estimation	Estimation Parameter	LS mean difference
	Estimated Value	-23.0
	Confidence Interval	(2-Sided) 80%; -81.36 to 35.34
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 35.63
	Estimation Comments

Statistical Analysis 10

Statistical Analysis Overview	Comparison Group Selection	KPL-716: CIP Cohort, Placebo: CIP Cohort
	Comments	Change at Week 3
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.6384
	Comments	Calculated from an ANCOVA model including treatment as factor and baseline values as covariate.
	Method	ANCOVA
	Comments
Method of Estimation	Estimation Parameter	LS mean difference
	Estimated Value	6.6
	Confidence Interval	(2-Sided) 80%; -11.75 to 24.94
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 13.82
	Estimation Comments

Statistical Analysis 11

Statistical Analysis Overview	Comparison Group Selection	KPL-716: LSC Cohort, Placebo: LSC Cohort
	Comments	Change at Week 3
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.4229
	Comments	Calculated from an ANCOVA model including treatment as factor and baseline values as covariate.
	Method	ANCOVA
	Comments
Method of Estimation	Estimation Parameter	LS mean difference
	Estimated Value	-58.6
	Confidence Interval	(2-Sided) 80%; -169.13 to 51.95
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 58.62
	Estimation Comments

Statistical Analysis 12

Statistical Analysis Overview	Comparison Group Selection	KPL-716: PPs Cohort, Placebo: PPs Cohort
	Comments	Change at Week 3
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.1688
	Comments	Calculated from an ANCOVA model including treatment as factor and baseline values as covariate.
	Method	ANCOVA
	Comments
Method of Estimation	Estimation Parameter	LS mean difference
	Estimated Value	-16.3
	Confidence Interval	(2-Sided) 80%; -31.47 to -1.18
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 11.38
	Estimation Comments

Statistical Analysis 13

Statistical Analysis Overview	Comparison Group Selection	KPL-716: CIU Cohort, Placebo: CIU Cohort
	Comments	Change at Week 4
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.1243
	Comments	Calculated from an ANCOVA model including treatment as factor and baseline values as covariate.
	Method	ANCOVA
	Comments
Method of Estimation	Estimation Parameter	LS mean difference
	Estimated Value	-59.6
	Confidence Interval	(2-Sided) 80%; -105.59 to -13.53
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 28.11
	Estimation Comments

Statistical Analysis 14

Statistical Analysis Overview	Comparison Group Selection	KPL-716: CIP Cohort, Placebo: CIP Cohort
	Comments	Change at Week 4
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.6841
	Comments	Calculated from an ANCOVA model including treatment as factor and baseline values as covariate.
	Method	ANCOVA
	Comments
Method of Estimation	Estimation Parameter	LS mean difference
	Estimated Value	6.9
	Confidence Interval	(2-Sided) 80%; -15.35 to 29.22
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 16.79
	Estimation Comments

Statistical Analysis 15

Statistical Analysis Overview	Comparison Group Selection	KPL-716: LSC Cohort, Placebo: LSC Cohort
	Comments	Change at Week 4
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.3963
	Comments	Calculated from an ANCOVA model including treatment as factor and baseline values as covariate.
	Method	ANCOVA
	Comments
Method of Estimation	Estimation Parameter	LS mean difference
	Estimated Value	-53.4
	Confidence Interval	(2-Sided) 80%; -147.31 to 40.59
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 49.83
	Estimation Comments

Statistical Analysis 16

Statistical Analysis Overview	Comparison Group Selection	KPL-716: PPs Cohort, Placebo: PPs Cohort
	Comments	Change at Week 4
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.0571
	Comments	Calculated from an ANCOVA model including treatment as factor and baseline values as covariate.
	Method	ANCOVA
	Comments
Method of Estimation	Estimation Parameter	LS mean difference
	Estimated Value	-24.1
	Confidence Interval	(2-Sided) 80%; -39.85 to -8.32
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 11.85
	Estimation Comments

Statistical Analysis 17

Statistical Analysis Overview	Comparison Group Selection	KPL-716: CIU Cohort, Placebo: CIU Cohort
	Comments	Change at Week 5
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.4457
	Comments	Calculated from an ANCOVA model including treatment as factor and baseline values as covariate.
	Method	ANCOVA
	Comments
Method of Estimation	Estimation Parameter	LS mean difference
	Estimated Value	-35.3
	Confidence Interval	(2-Sided) 80%; -101.32 to 30.73
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 40.32
	Estimation Comments

Statistical Analysis 18

Statistical Analysis Overview	Comparison Group Selection	KPL-716: CIP Cohort, Placebo: CIP Cohort
	Comments	Change at Week 5
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.8075
	Comments	Calculated from an ANCOVA model including treatment as factor and baseline values as covariate.
	Method	ANCOVA
	Comments
Method of Estimation	Estimation Parameter	LS mean difference
	Estimated Value	4.4
	Confidence Interval	(2-Sided) 80%; -19.44 to 28.32
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 17.99
	Estimation Comments

Statistical Analysis 19

Statistical Analysis Overview	Comparison Group Selection	KPL-716: LSC Cohort, Placebo: LSC Cohort
	Comments	Change at Week 5
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.4093
	Comments	Calculated from an ANCOVA model including treatment as factor and baseline values as covariate.
	Method	ANCOVA
	Comments
Method of Estimation	Estimation Parameter	LS mean difference
	Estimated Value	-57.7
	Confidence Interval	(2-Sided) 80%; -162.84 to 47.40
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 55.75
	Estimation Comments

Statistical Analysis 20

Statistical Analysis Overview	Comparison Group Selection	KPL-716: PPs Cohort, Placebo: PPs Cohort
	Comments	Change at Week 5
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.0543
	Comments	Calculated from an ANCOVA model including treatment as factor and baseline values as covariate.
	Method	ANCOVA
	Comments
Method of Estimation	Estimation Parameter	LS mean difference
	Estimated Value	-27.6
	Confidence Interval	(2-Sided) 80%; -45.42 to -9.76
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 13.40
	Estimation Comments

Statistical Analysis 21

Statistical Analysis Overview	Comparison Group Selection	KPL-716: CIU Cohort, Placebo: CIU Cohort
	Comments	Change at Week 6
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.4711
	Comments	Calculated from an ANCOVA model including treatment as factor and baseline values as covariate.
	Method	ANCOVA
	Comments
Method of Estimation	Estimation Parameter	LS mean difference
	Estimated Value	-31.0
	Confidence Interval	(2-Sided) 80%; -92.88 to 30.78
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 37.75
	Estimation Comments

Statistical Analysis 22

Statistical Analysis Overview	Comparison Group Selection	KPL-716: CIP Cohort, Placebo: CIP Cohort
	Comments	Change at Week 6
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.3925
	Comments	Calculated from an ANCOVA model including treatment as factor and baseline values as covariate.
	Method	ANCOVA
	Comments
Method of Estimation	Estimation Parameter	LS mean difference
	Estimated Value	13.0
	Confidence Interval	(2-Sided) 80%; -6.74 to 32.79
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 14.89
	Estimation Comments

Statistical Analysis 23

Statistical Analysis Overview	Comparison Group Selection	KPL-716: LSC Cohort, Placebo: LSC Cohort
	Comments	Change at Week 6
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.5095
	Comments	Calculated from an ANCOVA model including treatment as factor and baseline values as covariate.
	Method	ANCOVA
	Comments
Method of Estimation	Estimation Parameter	LS mean difference
	Estimated Value	-48.7
	Confidence Interval	(2-Sided) 80%; -164.22 to 66.72
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 61.24
	Estimation Comments

Statistical Analysis 24

Statistical Analysis Overview	Comparison Group Selection	KPL-716: PPs Cohort, Placebo: PPs Cohort
	Comments	Change at Week 6
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.0199
	Comments	Calculated from an ANCOVA model including treatment as factor and baseline values as covariate.
	Method	ANCOVA
	Comments
Method of Estimation	Estimation Parameter	LS mean difference
	Estimated Value	-33.8
	Confidence Interval	(2-Sided) 80%; -51.35 to -16.18
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 13.22
	Estimation Comments

Statistical Analysis 25

Statistical Analysis Overview	Comparison Group Selection	KPL-716: CIU Cohort, Placebo: CIU Cohort
	Comments	Change at Week 7
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.3029
	Comments	Calculated from an ANCOVA model including treatment as factor and baseline values as covariate.
	Method	ANCOVA
	Comments
Method of Estimation	Estimation Parameter	LS mean difference
	Estimated Value	-42.8
	Confidence Interval	(2-Sided) 80%; -99.26 to 13.69
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 34.48
	Estimation Comments

Statistical Analysis 26

Statistical Analysis Overview	Comparison Group Selection	KPL-716: CIP Cohort, Placebo: CIP Cohort
	Comments	Change at Week 7
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.4094
	Comments	Calculated from an ANCOVA model including treatment as factor and baseline values as covariate.
	Method	ANCOVA
	Comments
Method of Estimation	Estimation Parameter	LS mean difference
	Estimated Value	10.9
	Confidence Interval	(2-Sided) 80%; -6.28 to 28.16
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 12.97
	Estimation Comments

Statistical Analysis 27

Statistical Analysis Overview	Comparison Group Selection	KPL-716: LSC Cohort, Placebo: LSC Cohort
	Comments	Change at Week 7
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.4828
	Comments	Calculated from an ANCOVA model including treatment as factor and baseline values as covariate.
	Method	ANCOVA
	Comments
Method of Estimation	Estimation Parameter	LS mean difference
	Estimated Value	-49.8
	Confidence Interval	(2-Sided) 80%; -159.63 to 60.05
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 58.25
	Estimation Comments

Statistical Analysis 28

Statistical Analysis Overview	Comparison Group Selection	KPL-716: PPs Cohort, Placebo: PPs Cohort
	Comments	Change at Week 7
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.0383
	Comments	Calculated from an ANCOVA model including treatment as factor and baseline values as covariate.
	Method	ANCOVA
	Comments
Method of Estimation	Estimation Parameter	LS mean difference
	Estimated Value	-32.8
	Confidence Interval	(2-Sided) 80%; -52.26 to -13.26
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 14.66
	Estimation Comments

Statistical Analysis 29

Statistical Analysis Overview	Comparison Group Selection	KPL-716: CIU Cohort, Placebo: CIU Cohort
	Comments	Change at Week 8
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.5322
	Comments	Calculated from an ANCOVA model including treatment as factor and baseline values as covariate.
	Method	ANCOVA
	Comments
Method of Estimation	Estimation Parameter	LS mean difference
	Estimated Value	-26.1
	Confidence Interval	(2-Sided) 80%; -86.66 to 34.65
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 37.10
	Estimation Comments

Statistical Analysis 30

Statistical Analysis Overview	Comparison Group Selection	KPL-716: CIP Cohort, Placebo: CIP Cohort
	Comments	Change at Week 8
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.6577
	Comments	Calculated from an ANCOVA model including treatment as factor and baseline values as covariate.
	Method	ANCOVA
	Comments
Method of Estimation	Estimation Parameter	LS mean difference
	Estimated Value	-6.2
	Confidence Interval	(2-Sided) 80%; -24.38 to 12.03
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 13.71
	Estimation Comments

Statistical Analysis 31

Statistical Analysis Overview	Comparison Group Selection	KPL-716: LSC Cohort, Placebo: LSC Cohort
	Comments	Change at Week 8
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.6259
	Comments	Calculated from an ANCOVA model including treatment as factor and baseline values as covariate.
	Method	ANCOVA
	Comments
Method of Estimation	Estimation Parameter	LS mean difference
	Estimated Value	-38.3
	Confidence Interval	(2-Sided) 80%; -165.08 to 88.40
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 67.21
	Estimation Comments

Statistical Analysis 32

Statistical Analysis Overview	Comparison Group Selection	KPL-716: PPs Cohort, Placebo: PPs Cohort
	Comments	Change at Week 8
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.0312
	Comments	Calculated from an ANCOVA model including treatment as factor and baseline values as covariate.
	Method	ANCOVA
	Comments
Method of Estimation	Estimation Parameter	LS mean difference
	Estimated Value	-35.7
	Confidence Interval	(2-Sided) 80%; -56.01 to -15.38
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 15.27
	Estimation Comments

Statistical Analysis 33

Statistical Analysis Overview	Comparison Group Selection	KPL-716: CIU Cohort, Placebo: CIU Cohort
	Comments	Change at Week 9
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.0103
	Comments	Calculated from an ANCOVA model including treatment as factor and baseline values as covariate.
	Method	ANCOVA
	Comments
Method of Estimation	Estimation Parameter	LS mean difference
	Estimated Value	-108.3
	Confidence Interval	(2-Sided) 80%; -138.97 to -77.61
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 18.73
	Estimation Comments

Statistical Analysis 34

Statistical Analysis Overview	Comparison Group Selection	KPL-716: CIP Cohort, Placebo: CIP Cohort
	Comments	Change at Week 9
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.4330
	Comments	Calculated from an ANCOVA model including treatment as factor and baseline values as covariate.
	Method	ANCOVA
	Comments
Method of Estimation	Estimation Parameter	LS mean difference
	Estimated Value	10.0
	Confidence Interval	(2-Sided) 80%; -6.59 to 26.56
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 12.43
	Estimation Comments

Statistical Analysis 35

Statistical Analysis Overview	Comparison Group Selection	KPL-716: LSC Cohort, Placebo: LSC Cohort
	Comments	Change at Week 9
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.6165
	Comments	Calculated from an ANCOVA model including treatment as factor and baseline values as covariate.
	Method	ANCOVA
	Comments
Method of Estimation	Estimation Parameter	LS mean difference
	Estimated Value	-37.7
	Confidence Interval	(2-Sided) 80%; -158.82 to 83.39
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 64.23
	Estimation Comments

Statistical Analysis 36

Statistical Analysis Overview	Comparison Group Selection	KPL-716: PPs Cohort, Placebo: PPs Cohort
	Comments	Change at Week 9
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.0488
	Comments	Calculated from an ANCOVA model including treatment as factor and baseline values as covariate.
	Method	ANCOVA
	Comments
Method of Estimation	Estimation Parameter	LS mean difference
	Estimated Value	-32.0
	Confidence Interval	(2-Sided) 80%; -52.11 to -11.84
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 15.13
	Estimation Comments

Statistical Analysis 37

Statistical Analysis Overview	Comparison Group Selection	KPL-716: CIU Cohort, Placebo: CIU Cohort
	Comments	Change at Week 10
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.6636
	Comments	Calculated from an ANCOVA model including treatment as factor and baseline values as covariate.
	Method	ANCOVA
	Comments
Method of Estimation	Estimation Parameter	LS mean difference
	Estimated Value	-19.2
	Confidence Interval	(2-Sided) 80%; -84.53 to 46.16
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 39.90
	Estimation Comments

Statistical Analysis 38

Statistical Analysis Overview	Comparison Group Selection	KPL-716: CIP Cohort, Placebo: CIP Cohort
	Comments	Change at Week 10
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.0583
	Comments	Calculated from an ANCOVA model including treatment as factor and baseline values as covariate.
	Method	ANCOVA
	Comments
Method of Estimation	Estimation Parameter	LS mean difference
	Estimated Value	23.9
	Confidence Interval	(2-Sided) 80%; 8.18 to 39.52
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 11.75
	Estimation Comments

Statistical Analysis 39

Statistical Analysis Overview	Comparison Group Selection	KPL-716: LSC Cohort, Placebo: LSC Cohort
	Comments	Change at Week 10
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.4975
	Comments	Calculated from an ANCOVA model including treatment as factor and baseline values as covariate.
	Method	ANCOVA
	Comments
Method of Estimation	Estimation Parameter	LS mean difference
	Estimated Value	-45.1
	Confidence Interval	(2-Sided) 80%; -148.55 to 58.36
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 54.87
	Estimation Comments

Statistical Analysis 40

Statistical Analysis Overview	Comparison Group Selection	KPL-716: PPs Cohort, Placebo: PPs Cohort
	Comments	Change at Week 10
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.0653
	Comments	Calculated from an ANCOVA model including treatment as factor and baseline values as covariate.
	Method	ANCOVA
	Comments
Method of Estimation	Estimation Parameter	LS mean difference
	Estimated Value	-30.5
	Confidence Interval	(2-Sided) 80%; -51.17 to -9.82
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 15.54
	Estimation Comments

Statistical Analysis 41

Statistical Analysis Overview	Comparison Group Selection	KPL-716: CIU Cohort, Placebo: CIU Cohort
	Comments	Change at Week 11
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.6316
	Comments	Calculated from an ANCOVA model including treatment as factor and baseline values as covariate.
	Method	ANCOVA
	Comments
Method of Estimation	Estimation Parameter	LS mean difference
	Estimated Value	-23.4
	Confidence Interval	(2-Sided) 80%; -95.42 to 48.62
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 43.98
	Estimation Comments

Statistical Analysis 42

Statistical Analysis Overview	Comparison Group Selection	KPL-716: CIP Cohort, Placebo: CIP Cohort
	Comments	Change at Week 11
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.0874
	Comments	Calculated from an ANCOVA model including treatment as factor and baseline values as covariate.
	Method	ANCOVA
	Comments
Method of Estimation	Estimation Parameter	LS mean difference
	Estimated Value	26.6
	Confidence Interval	(2-Sided) 80%; 7.05 to 46.18
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 14.68
	Estimation Comments

Statistical Analysis 43

Statistical Analysis Overview	Comparison Group Selection	KPL-716: LSC Cohort, Placebo: LSC Cohort
	Comments	Change at Week 11
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.4662
	Comments	Calculated from an ANCOVA model including treatment as factor and baseline values as covariate.
	Method	ANCOVA
	Comments
Method of Estimation	Estimation Parameter	LS mean difference
	Estimated Value	-45.0
	Confidence Interval	(2-Sided) 80%; -139.99 to 50.03
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 50.39
	Estimation Comments

Statistical Analysis 44

Statistical Analysis Overview	Comparison Group Selection	KPL-716: PPs Cohort, Placebo: PPs Cohort
	Comments	Change at Week 11
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.1073
	Comments	Calculated from an ANCOVA model including treatment as factor and baseline values as covariate.
	Method	ANCOVA
	Comments
Method of Estimation	Estimation Parameter	LS mean difference
	Estimated Value	-25.6
	Confidence Interval	(2-Sided) 80%; -45.76 to -5.51
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 15.12
	Estimation Comments

Statistical Analysis 45

Statistical Analysis Overview	Comparison Group Selection	KPL-716: CIU Cohort, Placebo: CIU Cohort
	Comments	Change at Week 12
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.6197
	Comments	Calculated from an ANCOVA model including treatment as factor and baseline values as covariate.
	Method	ANCOVA
	Comments
Method of Estimation	Estimation Parameter	LS mean difference
	Estimated Value	-23.3
	Confidence Interval	(2-Sided) 80%; -92.62 to 45.96
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 42.31
	Estimation Comments

Statistical Analysis 46

Statistical Analysis Overview	Comparison Group Selection	KPL-716: CIP Cohort, Placebo: CIP Cohort
	Comments	Change at Week 12
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.1868
	Comments	Calculated from an ANCOVA model including treatment as factor and baseline values as covariate.
	Method	ANCOVA
	Comments
Method of Estimation	Estimation Parameter	LS mean difference
	Estimated Value	20.6
	Confidence Interval	(2-Sided) 80%; 0.63 to 40.55
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 14.97
	Estimation Comments

Statistical Analysis 47

Statistical Analysis Overview	Comparison Group Selection	KPL-716: LSC Cohort, Placebo: LSC Cohort
	Comments	Change at Week 12
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.3321
	Comments	Calculated from an ANCOVA model including treatment as factor and baseline values as covariate.
	Method	ANCOVA
	Comments
Method of Estimation	Estimation Parameter	LS mean difference
	Estimated Value	-55.0
	Confidence Interval	(2-Sided) 80%; -136.65 to 26.71
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 43.32
	Estimation Comments

Statistical Analysis 48

Statistical Analysis Overview	Comparison Group Selection	KPL-716: PPs Cohort, Placebo: PPs Cohort
	Comments	Change at Week 12
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.1310
	Comments	Calculated from an ANCOVA model including treatment as factor and baseline values as covariate.
	Method	ANCOVA
	Comments
Method of Estimation	Estimation Parameter	LS mean difference
	Estimated Value	-24.8
	Confidence Interval	(2-Sided) 80%; -45.64 to -3.95
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 15.67
	Estimation Comments

Statistical Analysis 49

Statistical Analysis Overview	Comparison Group Selection	KPL-716: CIU Cohort, Placebo: CIU Cohort
	Comments	Change at Week 13
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.8128
	Comments	Calculated from an ANCOVA model including treatment as factor and baseline values as covariate.
	Method	ANCOVA
	Comments
Method of Estimation	Estimation Parameter	LS mean difference
	Estimated Value	-12.0
	Confidence Interval	(2-Sided) 80%; -88.15 to 64.13
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 46.49
	Estimation Comments

Statistical Analysis 50

Statistical Analysis Overview	Comparison Group Selection	KPL-716: CIP Cohort, Placebo: CIP Cohort
	Comments	Change at Week 13
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.1004
	Comments	Calculated from an ANCOVA model including treatment as factor and baseline values as covariate.
	Method	ANCOVA
	Comments
Method of Estimation	Estimation Parameter	LS mean difference
	Estimated Value	24.7
	Confidence Interval	(2-Sided) 80%; 5.75 to 43.69
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 14.23
	Estimation Comments

Statistical Analysis 51

Statistical Analysis Overview	Comparison Group Selection	KPL-716: LSC Cohort, Placebo: LSC Cohort
	Comments	Change at Week 13
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.2962
	Comments	Calculated from an ANCOVA model including treatment as factor and baseline values as covariate.
	Method	ANCOVA
	Comments
Method of Estimation	Estimation Parameter	LS mean difference
	Estimated Value	-62.8
	Confidence Interval	(2-Sided) 80%; -147.28 to 21.71
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 44.81
	Estimation Comments

Statistical Analysis 52

Statistical Analysis Overview	Comparison Group Selection	KPL-716: PPs Cohort, Placebo: PPs Cohort
	Comments	Change at Week 13
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.1236
	Comments	Calculated from an ANCOVA model including treatment as factor and baseline values as covariate.
	Method	ANCOVA
	Comments
Method of Estimation	Estimation Parameter	LS mean difference
	Estimated Value	-26.5
	Confidence Interval	(2-Sided) 80%; -48.31 to -4.67
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 16.40
	Estimation Comments

Statistical Analysis 53

Statistical Analysis Overview	Comparison Group Selection	KPL-716: CIU Cohort, Placebo: CIU Cohort
	Comments	Change at Week 14
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.9276
	Comments	Calculated from an ANCOVA model including treatment as factor and baseline values as covariate.
	Method	ANCOVA
	Comments
Method of Estimation	Estimation Parameter	LS mean difference
	Estimated Value	-4.5
	Confidence Interval	(2-Sided) 80%; -79.10 to 70.11
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 45.55
	Estimation Comments

Statistical Analysis 54

Statistical Analysis Overview	Comparison Group Selection	KPL-716: CIP Cohort, Placebo: CIP Cohort
	Comments	Change at Week 14
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.1657
	Comments	Calculated from an ANCOVA model including treatment as factor and baseline values as covariate.
	Method	ANCOVA
	Comments
Method of Estimation	Estimation Parameter	LS mean difference
	Estimated Value	19.5
	Confidence Interval	(2-Sided) 80%; 1.55 to 37.45
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 13.46
	Estimation Comments

Statistical Analysis 55

Statistical Analysis Overview	Comparison Group Selection	KPL-716: LSC Cohort, Placebo: LSC Cohort
	Comments	Change at Week 14
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.3461
	Comments	Calculated from an ANCOVA model including treatment as factor and baseline values as covariate.
	Method	ANCOVA
	Comments
Method of Estimation	Estimation Parameter	LS mean difference
	Estimated Value	-58.4
	Confidence Interval	(2-Sided) 80%; -148.54 to 31.71
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 47.80
	Estimation Comments

Statistical Analysis 56

Statistical Analysis Overview	Comparison Group Selection	KPL-716: PPs Cohort, Placebo: PPs Cohort
	Comments	Change at Week 14
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.1118
	Comments	Calculated from an ANCOVA model including treatment as factor and baseline values as covariate.
	Method	ANCOVA
	Comments
Method of Estimation	Estimation Parameter	LS mean difference
	Estimated Value	-27.6
	Confidence Interval	(2-Sided) 80%; -49.58 to -5.64
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 16.51
	Estimation Comments

Statistical Analysis 57

Statistical Analysis Overview	Comparison Group Selection	KPL-716: CIU Cohort, Placebo: CIU Cohort
	Comments	Change at Week 15
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.6912
	Comments	Calculated from an ANCOVA model including treatment as factor and baseline values as covariate.
	Method	ANCOVA
	Comments
Method of Estimation	Estimation Parameter	LS mean difference
	Estimated Value	-18.9
	Confidence Interval	(2-Sided) 80%; -89.75 to 51.89
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 43.24
	Estimation Comments

Statistical Analysis 58

Statistical Analysis Overview	Comparison Group Selection	KPL-716: CIP Cohort, Placebo: CIP Cohort
	Comments	Change at Week 15
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.0973
	Comments	Calculated from an ANCOVA model including treatment as factor and baseline values as covariate.
	Method	ANCOVA
	Comments
Method of Estimation	Estimation Parameter	LS mean difference
	Estimated Value	22.9
	Confidence Interval	(2-Sided) 80%; 5.50 to 40.35
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 13.07
	Estimation Comments

Statistical Analysis 59

Statistical Analysis Overview	Comparison Group Selection	KPL-716: LSC Cohort, Placebo: LSC Cohort
	Comments	Change at Week 15
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.2890
	Comments	Calculated from an ANCOVA model including treatment as factor and baseline values as covariate.
	Method	ANCOVA
	Comments
Method of Estimation	Estimation Parameter	LS mean difference
	Estimated Value	-57.7
	Confidence Interval	(2-Sided) 80%; -133.72 to 18.37
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 40.33
	Estimation Comments

Statistical Analysis 60

Statistical Analysis Overview	Comparison Group Selection	KPL-716: PPs Cohort, Placebo: PPs Cohort
	Comments	Change at Week 15
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.2310
	Comments	Calculated from an ANCOVA model including treatment as factor and baseline values as covariate.
	Method	ANCOVA
	Comments
Method of Estimation	Estimation Parameter	LS mean difference
	Estimated Value	-21.9
	Confidence Interval	(2-Sided) 80%; -45.43 to 1.60
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 17.68
	Estimation Comments

Statistical Analysis 61

Statistical Analysis Overview	Comparison Group Selection	KPL-716: CIU Cohort, Placebo: CIU Cohort
	Comments	Change at Week 16
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.7967
	Comments	Calculated from an ANCOVA model including treatment as factor and baseline values as covariate.
	Method	ANCOVA
	Comments
Method of Estimation	Estimation Parameter	LS mean difference
	Estimated Value	-12.7
	Confidence Interval	(2-Sided) 80%; -86.69 to 61.28
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 45.17
	Estimation Comments

Statistical Analysis 62

Statistical Analysis Overview	Comparison Group Selection	KPL-716: CIP Cohort, Placebo: CIP Cohort
	Comments	Change at Week 16
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.2868
	Comments	Calculated from an ANCOVA model including treatment as factor and baseline values as covariate.
	Method	ANCOVA
	Comments
Method of Estimation	Estimation Parameter	LS mean difference
	Estimated Value	16.5
	Confidence Interval	(2-Sided) 80%; -3.50 to 36.44
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 14.98
	Estimation Comments

Statistical Analysis 63

Statistical Analysis Overview	Comparison Group Selection	KPL-716: LSC Cohort, Placebo: LSC Cohort
	Comments	Change at Week 16
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.2369
	Comments	Calculated from an ANCOVA model including treatment as factor and baseline values as covariate.
	Method	ANCOVA
	Comments
Method of Estimation	Estimation Parameter	LS mean difference
	Estimated Value	-64.9
	Confidence Interval	(2-Sided) 80%; -138.08 to 8.37
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 38.83
	Estimation Comments

Statistical Analysis 64

Statistical Analysis Overview	Comparison Group Selection	KPL-716: PPs Cohort, Placebo: PPs Cohort
	Comments	Change at Week 16
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.2228
	Comments	Calculated from an ANCOVA model including treatment as factor and baseline values as covariate.
	Method	ANCOVA
	Comments
Method of Estimation	Estimation Parameter	LS mean difference
	Estimated Value	-21.9
	Confidence Interval	(2-Sided) 80%; -44.97 to 1.17
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 17.34
	Estimation Comments

Statistical Analysis 65

Statistical Analysis Overview	Comparison Group Selection	KPL-716: CIU Cohort, Placebo: CIU Cohort
	Comments	Change at Week 17
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.7740
	Comments	Calculated from an ANCOVA model including treatment as factor and baseline values as covariate.
	Method	ANCOVA
	Comments
Method of Estimation	Estimation Parameter	LS mean difference
	Estimated Value	-14.9
	Confidence Interval	(2-Sided) 80%; -92.74 to 62.89
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 47.51
	Estimation Comments

Statistical Analysis 66

Statistical Analysis Overview	Comparison Group Selection	KPL-716: CIP Cohort, Placebo: CIP Cohort
	Comments	Change at Week 17
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.3000
	Comments	Calculated from an ANCOVA model including treatment as factor and baseline values as covariate.
	Method	ANCOVA
	Comments
Method of Estimation	Estimation Parameter	LS mean difference
	Estimated Value	15.1
	Confidence Interval	(2-Sided) 80%; -3.74 to 33.98
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 14.14
	Estimation Comments

Statistical Analysis 67

Statistical Analysis Overview	Comparison Group Selection	KPL-716: LSC Cohort, Placebo: LSC Cohort
	Comments	Change at Week 17
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.1472
	Comments	Calculated from an ANCOVA model including treatment as factor and baseline values as covariate.
	Method	ANCOVA
	Comments
Method of Estimation	Estimation Parameter	LS mean difference
	Estimated Value	-72.4
	Confidence Interval	(2-Sided) 80%; -131.59 to -13.30
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 31.37
	Estimation Comments

Statistical Analysis 68

Statistical Analysis Overview	Comparison Group Selection	KPL-716: PPs Cohort, Placebo: PPs Cohort
	Comments	Change at Week 17
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.5536
	Comments	Calculated from an ANCOVA model including treatment as factor and baseline values as covariate.
	Method	ANCOVA
	Comments
Method of Estimation	Estimation Parameter	LS mean difference
	Estimated Value	-12.4
	Confidence Interval	(2-Sided) 80%; -39.77 to 14.94
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 20.56
	Estimation Comments

Statistical Analysis 69

Statistical Analysis Overview	Comparison Group Selection	KPL-716: CIU Cohort, Placebo: CIU Cohort
	Comments	Change at Week 18
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.7131
	Comments	Calculated from an ANCOVA model including treatment as factor and baseline values as covariate.
	Method	ANCOVA
	Comments
Method of Estimation	Estimation Parameter	LS mean difference
	Estimated Value	-17.6
	Confidence Interval	(2-Sided) 80%; -89.13 to 53.84
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 43.65
	Estimation Comments

Statistical Analysis 70

Statistical Analysis Overview	Comparison Group Selection	KPL-716: CIP Cohort, Placebo: CIP Cohort
	Comments	Change at Week 18
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.3762
	Comments	Calculated from an ANCOVA model including treatment as factor and baseline values as covariate.
	Method	ANCOVA
	Comments
Method of Estimation	Estimation Parameter	LS mean difference
	Estimated Value	13.9
	Confidence Interval	(2-Sided) 80%; -6.49 to 34.24
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 15.27
	Estimation Comments

Statistical Analysis 71

Statistical Analysis Overview	Comparison Group Selection	KPL-716: LSC Cohort, Placebo: LSC Cohort
	Comments	Change at Week 18
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.1419
	Comments	Calculated from an ANCOVA model including treatment as factor and baseline values as covariate.
	Method	ANCOVA
	Comments
Method of Estimation	Estimation Parameter	LS mean difference
	Estimated Value	-74.1
	Confidence Interval	(2-Sided) 80%; -133.26 to -14.97
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 31.37
	Estimation Comments

Statistical Analysis 72

Statistical Analysis Overview	Comparison Group Selection	KPL-716: PPs Cohort, Placebo: PPs Cohort
	Comments	Change at Week 18
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.5817
	Comments	Calculated from an ANCOVA model including treatment as factor and baseline values as covariate.
	Method	ANCOVA
	Comments
Method of Estimation	Estimation Parameter	LS mean difference
	Estimated Value	-11.6
	Confidence Interval	(2-Sided) 80%; -39.22 to 15.95
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 20.74
	Estimation Comments

15. Secondary Outcome

Title	Change From Baseline in Weekly Average of Sleep Quality NRS Over Time
Description	Participants were asked daily to assign a numerical score to the quality of their sleep in the previous night using a scale from 0 to 10, with 0 indicating best possible sleep and 10 indicating worst possible sleep.
Time Frame	Baseline, Weeks 1-18

Outcome Measure Data

Analysis Population Description

Modified intent to treat (mITT) set: all randomized participants who received at least 1 dose of KPL-716 or placebo and had at least 1 post-baseline efficacy assessment in the double-blind treatment period. Missing data were imputed using the last observation carried forward (LOCF) method. Once a participant started treatment period (through Week 8), missing data in treatment period were imputed. Once a participant started the follow up (FU) period, missing data in FU period were imputed.

Arm/Group Title	KPL-716: CIU Cohort	Placebo: CIU Cohort	KPL-716: CIP Cohort	Placebo: CIP Cohort	KPL-716: LP Cohort	Placebo: LP Cohort	KPL-716: LSC Cohort	Placebo: LSC Cohort	KPL-716: PPs Cohort	Placebo: PPs Cohort
Arm/Group Description	Participants with CIU received KPL-716 weekly for 8 weeks	Participants with CIU received placebo weekly for 8 weeks	Participants with CIP received KPL-716 weekly for 8 weeks	Participants with CIP received placebo weekly for 8 weeks	Participants with LP received KPL-716 weekly for 8 weeks	Participants with LP received placebo weekly for 8 weeks	Participants with LSC received KPL-716 weekly for 8 weeks	Participants with LSC received placebo weekly for 8 weeks	Participants with PPs received KPL-716 weekly for 8 weeks	Participants with PPs received placebo weekly for 8 weeks
Measure Participants	4	2	14	9	3	0	4	1	14	7
Change at Week 1	-0.8 (1.32)	-0.3 (0.29)	-0.2 (0.33)	-1.6 (0.43)	-0.2 (0.17)	-2.6 (1.26)	-1.0 (NA)	-0.6 (0.20)	-0.3 (0.19)
Change at Week 2	-2.0 (1.63)	-0.4 (0.43)	-1.7 (0.56)	-2.7 (0.60)	-0.7 (0.41)	-3.7 (1.75)	-0.7 (NA)	-1.1 (0.30)	-0.4 (0.29)
Change at Week 3	-1.9 (1.86)	-0.5 (0.50)	-1.9 (0.54)	-2.7 (0.62)	-1.5 (1.02)	-4.2 (1.98)	-1.0 (NA)	-2.0 (0.52)	-0.5 (0.42)
Change at Week 4	-2.6 (2.12)	0.0 (0.00)	-2.0 (0.65)	-2.7 (0.93)	-2.3 (1.67)	-4.4 (1.78)	-2.0 (NA)	-2.8 (0.59)	-0.9 (0.64)
Change at Week 5	-2.8 (2.35)	-0.4 (0.43)	-2.3 (0.68)	-2.8 (0.73)	-2.8 (1.75)	-4.4 (1.61)	-1.9 (NA)	-3.5 (0.75)	-1.2 (0.91)
Change at Week 6	-2.6 (2.45)	-0.5 (0.50)	-2.4 (0.69)	-3.7 (0.64)	-3.0 (1.73)	-5.2 (1.53)	-2.4 (NA)	-3.8 (0.70)	-1.1 (0.95)
Change at Week 7	-2.6 (2.31)	-0.2 (0.21)	-2.4 (0.65)	-3.6 (0.79)	-3.4 (1.78)	-5.3 (1.43)	-2.0 (NA)	-4.2 (0.71)	-1.5 (1.10)
Change at Week 8	-2.5 (2.38)	-0.3 (0.29)	-2.5 (0.67)	-3.6 (0.89)	-3.4 (1.78)	-5.6 (1.24)	-3.0 (NA)	-4.7 (0.72)	-1.8 (1.23)
Change at Week 9	-2.9 (2.12)	0.7 (0.71)	-2.3 (0.69)	-4.1 (0.78)	-5.1 (0.86)	-5.6 (1.28)	-3.0 (NA)	-5.0 (0.70)	-2.0 (1.35)
Change at Week 10	-2.5 (2.23)	-0.5 (0.50)	-1.9 (0.65)	-4.9 (0.71)	-5.1 (0.86)	-5.7 (1.21)	-2.6 (NA)	-5.2 (0.74)	-1.9 (1.29)
Change at Week 11	-2.5 (1.93)	-0.5 (0.50)	-2.0 (0.72)	-4.9 (0.77)	-5.1 (0.86)	-5.7 (1.21)	-2.9 (NA)	-4.9 (0.78)	-2.0 (1.25)
Change at Week 12	-2.7 (2.04)	-0.5 (0.50)	-1.6 (0.80)	-4.4 (0.83)	-5.1 (0.86)	-5.7 (1.21)	-2.7 (NA)	-4.8 (0.80)	-2.0 (1.24)
Change at Week 13	-2.4 (2.11)	-0.5 (0.50)	-1.9 (0.72)	-4.6 (0.85)	-5.6 (0.43)	-5.6 (1.24)	-1.7 (NA)	-5.0 (0.80)	-2.1 (1.24)
Change at Week 14	-2.5 (2.43)	-0.5 (0.50)	-2.0 (0.62)	-4.3 (0.94)	-5.6 (0.36)	-5.5 (1.30)	-1.9 (NA)	-5.0 (0.77)	-5.0 (0.81)
Change at Week 15	-2.6 (2.31)	-0.5 (0.50)	-2.1 (0.62)	-4.1 (0.89)	-5.6 (0.36)	-5.7 (1.22)	-2.1 (NA)	-5.0 (0.81)	-2.3 (1.27)
Change at Week 16	-3.0 (2.23)	-0.5 (0.50)	-2.5 (0.70)	-3.6 (1.01)	-5.6 (0.36)	-5.8 (1.19)	-1.4 (NA)	-4.9 (0.80)	-2.2 (1.25)
Change at Week 17	-3.5 (2.03)	-0.5 (0.50)	-2.3 (0.66)	-3.7 (0.98)	-5.6 (0.36)	-5.7 (1.21)	-1.4 (NA)	-4.6 (0.95)	-2.5 (1.29)
Change at Week 18	-3.3 (2.12)	-0.5 (0.50)	-2.3 (0.74)	-3.6 (1.00)	-5.7 (0.43)	-5.7 (1.21)	-1.3 (NA)	-4.6 (0.96)	-2.5 (1.29)

16. Secondary Outcome

Title	Percent Change From Baseline in Weekly Average of Sleep Quality NRS Over Time
Description	Participants were asked daily to assign a numerical score to the quality of their sleep in the previous night using a scale from 0 to 10, with 0 indicating best possible sleep and 10 indicating worst possible sleep.
Time Frame	Baseline, Weeks 1-18

Outcome Measure Data

Analysis Population Description

Modified intent to treat (mITT) set: all randomized participants who received at least 1 dose of KPL-716 or placebo and had at least 1 post-baseline efficacy assessment in the double-blind treatment period. Missing data were imputed using the last observation carried forward (LOCF) method. Once a participant started treatment period (through Week 8), missing data in treatment period were imputed. Once a participant started the follow up (FU) period, missing data in FU period were imputed.

Arm/Group Title	KPL-716: CIU Cohort	Placebo: CIU Cohort	KPL-716: CIP Cohort	Placebo: CIP Cohort	KPL-716: LP Cohort	Placebo: LP Cohort	KPL-716: LSC Cohort	Placebo: LSC Cohort	KPL-716: PPs Cohort	Placebo: PPs Cohort
Arm/Group Description	Participants with CIU received KPL-716 weekly for 8 weeks	Participants with CIU received placebo weekly for 8 weeks	Participants with CIP received KPL-716 weekly for 8 weeks	Participants with CIP received placebo weekly for 8 weeks	Participants with LP received KPL-716 weekly for 8 weeks	Participants with LP received placebo weekly for 8 weeks	Participants with LSC received KPL-716 weekly for 8 weeks	Participants with LSC received placebo weekly for 8 weeks	Participants with PPs received KPL-716 weekly for 8 weeks	Participants with PPs received placebo weekly for 8 weeks
Measure Participants	4	2	14	9	3	0	4	1	14	7
Change at Week 1	-1.0 (32.15)	-28.7 (45.50)	-2.6 (5.75)	-26.3 (7.18)	-3.0 (2.92)	-40.7 (17.63)	-1.4 (38.74)	-6.7 (2.75)	-4.9 (3.91)
Change at Week 2	-20.2 (34.79)	-42.6 (49.24)	-28.7 (8.26)	-45.6 (10.32)	-9.2 (7.29)	-56.7 (24.07)	6.8 (52.89)	-12.4 (3.67)	-6.0 (5.22)
Change at Week 3	-15.5 (39.26)	-49.7 (55.57)	-33.4 (7.94)	-47.2 (9.92)	-18.9 (17.50)	-64.4 (26.92)	6.3 (59.14)	-22.7 (6.03)	-7.1 (8.58)
Change at Week 4	-25.0 (31.15)	-2.2 (44.09)	-34.6 (10.18)	-47.9 (12.72)	-29.8 (28.43)	-67.2 (22.95)	-6.6 (50.42)	-34.4 (6.75)	-11.7 (9.60)
Change at Week 5	-25.7 (42.76)	-43.4 (60.51)	-38.4 (9.11)	-50.7 (11.38)	-35.5 (30.62)	-67.3 (23.31)	-16.9 (51.21)	-43.0 (7.95)	-15.9 (11.31)
Change at Week 6	-20.9 (47.36)	-50.4 (67.03)	-40.9 (8.43)	-62.7 (10.54)	-38.1 (30.62)	-80.2 (22.99)	-32.7 (50.51)	-46.7 (7.82)	-13.0 (11.12)
Change at Week 7	-23.2 (37.03)	-22.9 (52.41)	-42.4 (8.45)	-61.6 (10.55)	-44.6 (30.62)	-82.4 (20.44)	-27.3 (44.90)	-52.0 (8.41)	-19.4 (11.96)
Change at Week 8	-19.5 (40.74)	-29.9 (57.65)	-43.4 (8.98)	-60.7 (11.22)	-44.6 (30.62)	-87.3 (14.69)	-37.0 (32.27)	-59.5 (8.96)	-23.1 (12.75)
Change at Week 9	-28.7 (15.95)	66.0 (22.57)	-42.2 (8.76)	-66.6 (10.13)	-66.9 (0.00)	-86.2 (15.97)	-37.3 (35.08)	-63.6 (9.13)	-25.5 (12.99)
Change at Week 10	-21.5 (41.87)	-50.1 (59.26)	-37.4 (8.65)	-76.4 (10.00)	-66.9 (0.00)	-88.4 (13.41)	-31.9 (29.47)	-65.9 (9.22)	-25.1 (13.11)
Change at Week 11	-29.0 (31.17)	-49.4 (44.11)	-37.1 (9.54)	-76.5 (11.03)	-66.9 (0.00)	-88.4 (13.41)	-35.1 (29.47)	-61.1 (9.12)	-26.1 (12.97)
Change at Week 12	-29.3 (34.97)	-49.7 (49.49)	-30.9 (11.35)	-70.1 (13.12)	-66.9 (0.00)	-88.4 (13.41)	-33.5 (29.47)	-60.2 (9.58)	-27.0 (13.63)
Change at Week 13	-24.0 (35.58)	-49.7 (50.36)	-35.9 (10.59)	-74.7 (12.24)	-72.8 (0.00)	-87.3 (14.69)	-22.7 (32.27)	-63.9 (9.92)	-28.4 (14.11)
Change at Week 14	-20.4 (42.00)	-50.3 (59.44)	-38.2 (9.62)	-71.9 (11.12)	-73.8 (0.00)	-85.7 (16.60)	-24.8 (36.48)	-64.9 (9.77)	-29.3 (13.90)
Change at Week 15	-25.9 (37.20)	-49.9 (52.64)	-38.6 (9.08)	-69.7 (10.50)	-73.8 (0.00)	-87.9 (14.05)	-27.3 (30.87)	-63.9 (10.34)	-31.3 (14.70)
Change at Week 16	-33.5 (35.42)	-49.7 (50.13)	-44.1 (10.40)	-64.0 (12.02)	-73.8 (0.00)	-89.0 (12.77)	-19.1 (28.06)	-63.6 (10.16)	-29.4 (14.45)
Change at Week 17	-48.6 (28.92)	-49.0 (40.94)	-41.3 (9.88)	-65.1 (11.42)	-73.8 (0.00)	-88.4 (13.41)	-19.2 (29.47)	-58.7 (12.22)	-34.8 (17.38)
Change at Week 18	-41.8 (31.93)	-49.4 (45.20)	-42.8 (10.42)	-64.7 (12.04)	-74.7 (0.00)	-88.4 (13.41)	-17.6 (29.47)	-58.7 (12.25)	-34.7 (17.43)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	KPL-716: CIU Cohort, Placebo: CIU Cohort
	Comments	Change at Week 1
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.6532
	Comments	Calculated from an ANCOVA model including treatment as factor and baseline values as covariate.
	Method	ANCOVA
	Comments
Method of Estimation	Estimation Parameter	LS mean difference
	Estimated Value	27.7
	Confidence Interval	(2-Sided) 80%; -63.60 to 119.06
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 55.77
	Estimation Comments

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	KPL-716: CIP Cohort, Placebo: CIP Cohort
	Comments	Change at Week 1
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.0187
	Comments	Calculated from an ANCOVA model including treatment as factor and baseline values as covariate.
	Method	ANCOVA
	Comments
Method of Estimation	Estimation Parameter	LS mean difference
	Estimated Value	23.6
	Confidence Interval	(2-Sided) 80%; 11.38 to 35.85
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 9.23
	Estimation Comments

Statistical Analysis 3

Statistical Analysis Overview	Comparison Group Selection	KPL-716: LSC Cohort, Placebo: LSC Cohort
	Comments	Change at Week 1
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.4707
	Comments	Calculated from an ANCOVA model including treatment as factor and baseline values as covariate.
	Method	ANCOVA
	Comments
Method of Estimation	Estimation Parameter	LS mean difference
	Estimated Value	-39.3
	Confidence Interval	(2-Sided) 80%; -123.27 to 44.68
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 44.53
	Estimation Comments

Statistical Analysis 4

Statistical Analysis Overview	Comparison Group Selection	KPL-716: PPs Cohort, Placebo: PPs Cohort
	Comments	Change at Week 1
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.7108
	Comments	Calculated from an ANCOVA model including treatment as factor and baseline values as covariate.
	Method	ANCOVA
	Comments
Method of Estimation	Estimation Parameter	LS mean difference
	Estimated Value	-1.8
	Confidence Interval	(2-Sided) 80%; -8.22 to 4.59
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 4.81
	Estimation Comments

Statistical Analysis 5

Statistical Analysis Overview	Comparison Group Selection	KPL-716: CIU Cohort, Placebo: CIU Cohort
	Comments	Change at Week 2
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.7355
	Comments	Calculated from an ANCOVA model including treatment as factor and baseline values as covariate.
	Method	ANCOVA
	Comments
Method of Estimation	Estimation Parameter	LS mean difference
	Estimated Value	22.4
	Confidence Interval	(2-Sided) 80%; -76.47 to 121.23
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 60.36
	Estimation Comments

Statistical Analysis 6

Statistical Analysis Overview	Comparison Group Selection	KPL-716: CIP Cohort, Placebo: CIP Cohort
	Comments	Change at Week 2
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.2167
	Comments	Calculated from an ANCOVA model including treatment as factor and baseline values as covariate.
	Method	ANCOVA
	Comments
Method of Estimation	Estimation Parameter	LS mean difference
	Estimated Value	16.9
	Confidence Interval	(2-Sided) 80%; -0.66 to 34.52
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 13.27
	Estimation Comments

Statistical Analysis 7

Statistical Analysis Overview	Comparison Group Selection	KPL-716: LSC Cohort, Placebo: LSC Cohort
	Comments	Change at Week 2
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.4058
	Comments	Calculated from an ANCOVA model including treatment as factor and baseline values as covariate.
	Method	ANCOVA
	Comments
Method of Estimation	Estimation Parameter	LS mean difference
	Estimated Value	-63.5
	Confidence Interval	(2-Sided) 80%; -178.16 to 51.13
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 60.80
	Estimation Comments

Statistical Analysis 8

Statistical Analysis Overview	Comparison Group Selection	KPL-716: PPs Cohort, Placebo: PPs Cohort
	Comments	Change at Week 2
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.3323
	Comments	Calculated from an ANCOVA model including treatment as factor and baseline values as covariate.
	Method	ANCOVA
	Comments
Method of Estimation	Estimation Parameter	LS mean difference
	Estimated Value	-6.4
	Confidence Interval	(2-Sided) 80%; -14.95 to 2.15
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 6.43
	Estimation Comments

Statistical Analysis 9

Statistical Analysis Overview	Comparison Group Selection	KPL-716: CIU Cohort, Placebo: CIU Cohort
	Comments	Change at Week 3
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.6496
	Comments	Calculated from an ANCOVA model including treatment as factor and baseline values as covariate.
	Method	ANCOVA
	Comments
Method of Estimation	Estimation Parameter	LS mean difference
	Estimated Value	34.3
	Confidence Interval	(2-Sided) 80%; -77.29 to 145.80
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 68.11
	Estimation Comments

Statistical Analysis 10

Statistical Analysis Overview	Comparison Group Selection	KPL-716: CIP Cohort, Placebo: CIP Cohort
	Comments	Change at Week 3
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.2925
	Comments	Calculated from an ANCOVA model including treatment as factor and baseline values as covariate.
	Method	ANCOVA
	Comments
Method of Estimation	Estimation Parameter	LS mean difference
	Estimated Value	13.8
	Confidence Interval	(2-Sided) 80%; -3.12 to 30.70
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 12.76
	Estimation Comments

Statistical Analysis 11

Statistical Analysis Overview	Comparison Group Selection	KPL-716: LSC Cohort, Placebo: LSC Cohort
	Comments	Change at Week 3
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.4074
	Comments	Calculated from an ANCOVA model including treatment as factor and baseline values as covariate.
	Method	ANCOVA
	Comments
Method of Estimation	Estimation Parameter	LS mean difference
	Estimated Value	-70.7
	Confidence Interval	(2-Sided) 80%; -198.92 to 57.46
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 67.98
	Estimation Comments

Statistical Analysis 12

Statistical Analysis Overview	Comparison Group Selection	KPL-716: PPs Cohort, Placebo: PPs Cohort
	Comments	Change at Week 3
	Type of Statistical Test	Other
	Comments
Statistical Test of Hypothesis	p-Value	0.1584
	Comments	Calculated from an ANCOVA model including treatment as factor and baseline values as covariate.
	Method	ANCOVA
	Comments
Method of Estimation	Estimation Parameter	LS mean difference
	Estimated Value	-15.5
	Confidence Interval	(2-Sided) 80%; -29.60 to -1.49
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 10.56
	Estimation Comments

Statistical Analysis 13

Statistical Analysis Overview	Comparison Group Selection	KPL-716: CIU Cohort, Placebo: CIU Cohort
	Comments	Change at Week 4
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.7013
	Comments	Calculated from an ANCOVA model including treatment as factor and baseline values as covariate.
	Method	ANCOVA
	Comments
Method of Estimation	Estimation Parameter	LS mean difference
	Estimated Value	-22.8
	Confidence Interval	(2-Sided) 80%; -111.31 to 65.69
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 54.04
	Estimation Comments

Statistical Analysis 14

Statistical Analysis Overview	Comparison Group Selection	KPL-716: CIP Cohort, Placebo: CIP Cohort
	Comments	Change at Week 4
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.4230
	Comments	Calculated from an ANCOVA model including treatment as factor and baseline values as covariate.
	Method	ANCOVA
	Comments
Method of Estimation	Estimation Parameter	LS mean difference
	Estimated Value	13.4
	Confidence Interval	(2-Sided) 80%; -8.30 to 35.05
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 16.35
	Estimation Comments

Statistical Analysis 15

Statistical Analysis Overview	Comparison Group Selection	KPL-716: LSC Cohort, Placebo: LSC Cohort
	Comments	Change at Week 4
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.4055
	Comments	Calculated from an ANCOVA model including treatment as factor and baseline values as covariate.
	Method	ANCOVA
	Comments
Method of Estimation	Estimation Parameter	LS mean difference
	Estimated Value	-60.6
	Confidence Interval	(2-Sided) 80%; -169.90 to 48.69
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 57.96
	Estimation Comments

Statistical Analysis 16

Statistical Analysis Overview	Comparison Group Selection	KPL-716: PPs Cohort, Placebo: PPs Cohort
	Comments	Change at Week 4
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.0709
	Comments	Calculated from an ANCOVA model including treatment as factor and baseline values as covariate.
	Method	ANCOVA
	Comments
Method of Estimation	Estimation Parameter	LS mean difference
	Estimated Value	-22.7
	Confidence Interval	(2-Sided) 80%; -38.41 to -6.96
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 11.82
	Estimation Comments

Statistical Analysis 17

Statistical Analysis Overview	Comparison Group Selection	KPL-716: CIU Cohort, Placebo: CIU Cohort
	Comments	Change at Week 5
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.8268
	Comments	Calculated from an ANCOVA model including treatment as factor and baseline values as covariate.
	Method	ANCOVA
	Comments
Method of Estimation	Estimation Parameter	LS mean difference
	Estimated Value	17.7
	Confidence Interval	(2-Sided) 80%; -103.77 to 139.17
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 74.17
	Estimation Comments

Statistical Analysis 18

Statistical Analysis Overview	Comparison Group Selection	KPL-716: CIP Cohort, Placebo: CIP Cohort
	Comments	Change at Week 5
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.4082
	Comments	Calculated from an ANCOVA model including treatment as factor and baseline values as covariate.
	Method	ANCOVA
	Comments
Method of Estimation	Estimation Parameter	LS mean difference
	Estimated Value	12.4
	Confidence Interval	(2-Sided) 80%; -7.03 to 31.75
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 14.63
	Estimation Comments

Statistical Analysis 19

Statistical Analysis Overview	Comparison Group Selection	KPL-716: LSC Cohort, Placebo: LSC Cohort
	Comments	Change at Week 5
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.4818
	Comments	Calculated from an ANCOVA model including treatment as factor and baseline values as covariate.
	Method	ANCOVA
	Comments
Method of Estimation	Estimation Parameter	LS mean difference
	Estimated Value	-50.4
	Confidence Interval	(2-Sided) 80%; -161.43 to 60.56
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 58.86
	Estimation Comments

Statistical Analysis 20

Statistical Analysis Overview	Comparison Group Selection	KPL-716: PPs Cohort, Placebo: PPs Cohort
	Comments	Change at Week 5
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.0673
	Comments	Calculated from an ANCOVA model including treatment as factor and baseline values as covariate.
	Method	ANCOVA
	Comments
Method of Estimation	Estimation Parameter	LS mean difference
	Estimated Value	-27.1
	Confidence Interval	(2-Sided) 80%; -45.64 to -8.58
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 13.93
	Estimation Comments

Statistical Analysis 21

Statistical Analysis Overview	Comparison Group Selection	KPL-716: CIU Cohort, Placebo: CIU Cohort
	Comments	Change at Week 6
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.7429
	Comments	Calculated from an ANCOVA model including treatment as factor and baseline values as covariate.
	Method	ANCOVA
	Comments
Method of Estimation	Estimation Parameter	LS mean difference
	Estimated Value	29.6
	Confidence Interval	(2-Sided) 80%; -105.00 to 164.10
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 82.15
	Estimation Comments

Statistical Analysis 22

Statistical Analysis Overview	Comparison Group Selection	KPL-716: CIP Cohort, Placebo: CIP Cohort
	Comments	Change at Week 6
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.1227
	Comments	Calculated from an ANCOVA model including treatment as factor and baseline values as covariate.
	Method	ANCOVA
	Comments
Method of Estimation	Estimation Parameter	LS mean difference
	Estimated Value	21.8
	Confidence Interval	(2-Sided) 80%; 3.88 to 39.79
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 13.55
	Estimation Comments

Statistical Analysis 23

Statistical Analysis Overview	Comparison Group Selection	KPL-716: LSC Cohort, Placebo: LSC Cohort
	Comments	Change at Week 6
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.4996
	Comments	Calculated from an ANCOVA model including treatment as factor and baseline values as covariate.
	Method	ANCOVA
	Comments
Method of Estimation	Estimation Parameter	LS mean difference
	Estimated Value	-47.5
	Confidence Interval	(2-Sided) 80%; -156.95 to 62.02
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 58.06
	Estimation Comments

Statistical Analysis 24

Statistical Analysis Overview	Comparison Group Selection	KPL-716: PPs Cohort, Placebo: PPs Cohort
	Comments	Change at Week 6
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.0244
	Comments	Calculated from an ANCOVA model including treatment as factor and baseline values as covariate.
	Method	ANCOVA
	Comments
Method of Estimation	Estimation Parameter	LS mean difference
	Estimated Value	-33.6
	Confidence Interval	(2-Sided) 80%; -51.87 to -15.43
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 13.69
	Estimation Comments

Statistical Analysis 25

Statistical Analysis Overview	Comparison Group Selection	KPL-716: CIU Cohort, Placebo: CIU Cohort
	Comments	Change at Week 7
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.9967
	Comments	Calculated from an ANCOVA model including treatment as factor and baseline values as covariate.
	Method	ANCOVA
	Comments
Method of Estimation	Estimation Parameter	LS mean difference
	Estimated Value	-0.3
	Confidence Interval	(2-Sided) 80%; -105.50 to 104.92
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 64.24
	Estimation Comments

Statistical Analysis 26

Statistical Analysis Overview	Comparison Group Selection	KPL-716: CIP Cohort, Placebo: CIP Cohort
	Comments	Change at Week 7
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.1739
	Comments	Calculated from an ANCOVA model including treatment as factor and baseline values as covariate.
	Method	ANCOVA
	Comments
Method of Estimation	Estimation Parameter	LS mean difference
	Estimated Value	19.1
	Confidence Interval	(2-Sided) 80%; 1.15 to 37.12
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 13.57
	Estimation Comments

Statistical Analysis 27

Statistical Analysis Overview	Comparison Group Selection	KPL-716: LSC Cohort, Placebo: LSC Cohort
	Comments	Change at Week 7
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.3978
	Comments	Calculated from an ANCOVA model including treatment as factor and baseline values as covariate.
	Method	ANCOVA
	Comments
Method of Estimation	Estimation Parameter	LS mean difference
	Estimated Value	-55.1
	Confidence Interval	(2-Sided) 80%; -152.39 to 42.26
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 51.61
	Estimation Comments

Statistical Analysis 28

Statistical Analysis Overview	Comparison Group Selection	KPL-716: PPs Cohort, Placebo: PPs Cohort
	Comments	Change at Week 7
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.0397
	Comments	Calculated from an ANCOVA model including treatment as factor and baseline values as covariate.
	Method	ANCOVA
	Comments
Method of Estimation	Estimation Parameter	LS mean difference
	Estimated Value	-32.7
	Confidence Interval	(2-Sided) 80%; -52.26 to -13.07
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 14.73
	Estimation Comments

Statistical Analysis 29

Statistical Analysis Overview	Comparison Group Selection	KPL-716: CIU Cohort, Placebo: CIU Cohort
	Comments	Change at Week 8
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.8922
	Comments	Calculated from an ANCOVA model including treatment as factor and baseline values as covariate.
	Method	ANCOVA
	Comments
Method of Estimation	Estimation Parameter	LS mean difference
	Estimated Value	10.4
	Confidence Interval	(2-Sided) 80%; -105.32 to 126.14
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 70.66
	Estimation Comments

Statistical Analysis 30

Statistical Analysis Overview	Comparison Group Selection	KPL-716: CIP Cohort, Placebo: CIP Cohort
	Comments	Change at Week 8
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.2439
	Comments	Calculated from an ANCOVA model including treatment as factor and baseline values as covariate.
	Method	ANCOVA
	Comments
Method of Estimation	Estimation Parameter	LS mean difference
	Estimated Value	17.3
	Confidence Interval	(2-Sided) 80%; -1.80 to 36.45
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 14.43
	Estimation Comments

Statistical Analysis 31

Statistical Analysis Overview	Comparison Group Selection	KPL-716: LSC Cohort, Placebo: LSC Cohort
	Comments	Change at Week 8
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.3076
	Comments	Calculated from an ANCOVA model including treatment as factor and baseline values as covariate.
	Method	ANCOVA
	Comments
Method of Estimation	Estimation Parameter	LS mean difference
	Estimated Value	-50.3
	Confidence Interval	(2-Sided) 80%; -120.29 to 19.61
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 37.10
	Estimation Comments

Statistical Analysis 32

Statistical Analysis Overview	Comparison Group Selection	KPL-716: PPs Cohort, Placebo: PPs Cohort
	Comments	Change at Week 8
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.0322
	Comments	Calculated from an ANCOVA model including treatment as factor and baseline values as covariate.
	Method	ANCOVA
	Comments
Method of Estimation	Estimation Parameter	LS mean difference
	Estimated Value	-36.4
	Confidence Interval	(2-Sided) 80%; -57.32 to -15.55
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 15.70
	Estimation Comments

Statistical Analysis 33

Statistical Analysis Overview	Comparison Group Selection	KPL-716: CIU Cohort, Placebo: CIU Cohort
	Comments	Change at Week 9
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.0418
	Comments	Calculated from an ANCOVA model including treatment as factor and baseline values as covariate.
	Method	ANCOVA
	Comments
Method of Estimation	Estimation Parameter	LS mean difference
	Estimated Value	-94.7
	Confidence Interval	(2-Sided) 80%; -139.98 to -49.36
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 27.67
	Estimation Comments

Statistical Analysis 34

Statistical Analysis Overview	Comparison Group Selection	KPL-716: CIP Cohort, Placebo: CIP Cohort
	Comments	Change at Week 9
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.0865
	Comments	Calculated from an ANCOVA model including treatment as factor and baseline values as covariate.
	Method	ANCOVA
	Comments
Method of Estimation	Estimation Parameter	LS mean difference
	Estimated Value	24.4
	Confidence Interval	(2-Sided) 80%; 6.49 to 42.26
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 13.44
	Estimation Comments

Statistical Analysis 35

Statistical Analysis Overview	Comparison Group Selection	KPL-716: LSC Cohort, Placebo: LSC Cohort
	Comments	Change at Week 9
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.3489
	Comments	Calculated from an ANCOVA model including treatment as factor and baseline values as covariate.
	Method	ANCOVA
	Comments
Method of Estimation	Estimation Parameter	LS mean difference
	Estimated Value	-48.9
	Confidence Interval	(2-Sided) 80%; -124.96 to 27.11
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 40.32
	Estimation Comments

Statistical Analysis 36

Statistical Analysis Overview	Comparison Group Selection	KPL-716: PPs Cohort, Placebo: PPs Cohort
	Comments	Change at Week 9
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.0286
	Comments	Calculated from an ANCOVA model including treatment as factor and baseline values as covariate.
	Method	ANCOVA
	Comments
Method of Estimation	Estimation Parameter	LS mean difference
	Estimated Value	-38.1
	Confidence Interval	(2-Sided) 80%; -59.34 to -16.79
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 15.99
	Estimation Comments

Statistical Analysis 37

Statistical Analysis Overview	Comparison Group Selection	KPL-716: CIU Cohort, Placebo: CIU Cohort
	Comments	Change at Week 10
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.7198
	Comments	Calculated from an ANCOVA model including treatment as factor and baseline values as covariate.
	Method	ANCOVA
	Comments
Method of Estimation	Estimation Parameter	LS mean difference
	Estimated Value	28.6
	Confidence Interval	(2-Sided) 80%; -90.32 to 147.59
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 72.63
	Estimation Comments

Statistical Analysis 38

Statistical Analysis Overview	Comparison Group Selection	KPL-716: CIP Cohort, Placebo: CIP Cohort
	Comments	Change at Week 10
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.0088
	Comments	Calculated from an ANCOVA model including treatment as factor and baseline values as covariate.
	Method	ANCOVA
	Comments
Method of Estimation	Estimation Parameter	LS mean difference
	Estimated Value	39.0
	Confidence Interval	(2-Sided) 80%; 21.32 to 56.63
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 13.27
	Estimation Comments

Statistical Analysis 39

Statistical Analysis Overview	Comparison Group Selection	KPL-716: LSC Cohort, Placebo: LSC Cohort
	Comments	Change at Week 10
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.2371
	Comments	Calculated from an ANCOVA model including treatment as factor and baseline values as covariate.
	Method	ANCOVA
	Comments
Method of Estimation	Estimation Parameter	LS mean difference
	Estimated Value	-56.5
	Confidence Interval	(2-Sided) 80%; -120.39 to 7.34
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 33.87
	Estimation Comments

Statistical Analysis 40

Statistical Analysis Overview	Comparison Group Selection	KPL-716: PPs Cohort, Placebo: PPs Cohort
	Comments	Change at Week 10
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.0210
	Comments	Calculated from an ANCOVA model including treatment as factor and baseline values as covariate.
	Method	ANCOVA
	Comments
Method of Estimation	Estimation Parameter	LS mean difference
	Estimated Value	-40.8
	Confidence Interval	(2-Sided) 80%; -62.30 to -19.35
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 16.14
	Estimation Comments

Statistical Analysis 41

Statistical Analysis Overview	Comparison Group Selection	KPL-716: CIU Cohort, Placebo: CIU Cohort
	Comments	Change at Week 11
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.7312
	Comments	Calculated from an ANCOVA model including treatment as factor and baseline values as covariate.
	Method	ANCOVA
	Comments
Method of Estimation	Estimation Parameter	LS mean difference
	Estimated Value	20.4
	Confidence Interval	(2-Sided) 80%; -68.17 to 108.94
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 54.07
	Estimation Comments

Statistical Analysis 42

Statistical Analysis Overview	Comparison Group Selection	KPL-716: CIP Cohort, Placebo: CIP Cohort
	Comments	Change at Week 11
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.0150
	Comments	Calculated from an ANCOVA model including treatment as factor and baseline values as covariate.
	Method	ANCOVA
	Comments
Method of Estimation	Estimation Parameter	LS mean difference
	Estimated Value	39.4
	Confidence Interval	(2-Sided) 80%; 19.88 to 58.83
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 14.64
	Estimation Comments

Statistical Analysis 43

Statistical Analysis Overview	Comparison Group Selection	KPL-716: LSC Cohort, Placebo: LSC Cohort
	Comments	Change at Week 11
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.2559
	Comments	Calculated from an ANCOVA model including treatment as factor and baseline values as covariate.
	Method	ANCOVA
	Comments
Method of Estimation	Estimation Parameter	LS mean difference
	Estimated Value	-53.3
	Confidence Interval	(2-Sided) 80%; -117.22 to 10.52
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 33.87
	Estimation Comments

Statistical Analysis 44

Statistical Analysis Overview	Comparison Group Selection	KPL-716: PPs Cohort, Placebo: PPs Cohort
	Comments	Change at Week 11
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.0419
	Comments	Calculated from an ANCOVA model including treatment as factor and baseline values as covariate.
	Method	ANCOVA
	Comments
Method of Estimation	Estimation Parameter	LS mean difference
	Estimated Value	-35.0
	Confidence Interval	(2-Sided) 80%; -56.21 to -13.72
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 15.97
	Estimation Comments

Statistical Analysis 45

Statistical Analysis Overview	Comparison Group Selection	KPL-716: CIU Cohort, Placebo: CIU Cohort
	Comments	Change at Week 12
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.7589
	Comments	Calculated from an ANCOVA model including treatment as factor and baseline values as covariate.
	Method	ANCOVA
	Comments
Method of Estimation	Estimation Parameter	LS mean difference
	Estimated Value	20.4
	Confidence Interval	(2-Sided) 80%; -78.95 to 119.74
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 60.66
	Estimation Comments

Statistical Analysis 46

Statistical Analysis Overview	Comparison Group Selection	KPL-716: CIP Cohort, Placebo: CIP Cohort
	Comments	Change at Week 12
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.0374
	Comments	Calculated from an ANCOVA model including treatment as factor and baseline values as covariate.
	Method	ANCOVA
	Comments
Method of Estimation	Estimation Parameter	LS mean difference
	Estimated Value	39.1
	Confidence Interval	(2-Sided) 80%; 15.97 to 62.31
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 17.42
	Estimation Comments

Statistical Analysis 47

Statistical Analysis Overview	Comparison Group Selection	KPL-716: LSC Cohort, Placebo: LSC Cohort
	Comments	Change at Week 12
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.2463
	Comments	Calculated from an ANCOVA model including treatment as factor and baseline values as covariate.
	Method	ANCOVA
	Comments
Method of Estimation	Estimation Parameter	LS mean difference
	Estimated Value	-54.9
	Confidence Interval	(2-Sided) 80%; -118.80 to 8.93
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 33.87
	Estimation Comments

Statistical Analysis 48

Statistical Analysis Overview	Comparison Group Selection	KPL-716: PPs Cohort, Placebo: PPs Cohort
	Comments	Change at Week 12
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.0632
	Comments	Calculated from an ANCOVA model including treatment as factor and baseline values as covariate.
	Method	ANCOVA
	Comments
Method of Estimation	Estimation Parameter	LS mean difference
	Estimated Value	-33.2
	Confidence Interval	(2-Sided) 80%; -55.56 to -10.90
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 16.78
	Estimation Comments

Statistical Analysis 49

Statistical Analysis Overview	Comparison Group Selection	KPL-716: CIU Cohort, Placebo: CIU Cohort
	Comments	Change at Week 13
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.7053
	Comments	Calculated from an ANCOVA model including treatment as factor and baseline values as covariate.
	Method	ANCOVA
	Comments
Method of Estimation	Estimation Parameter	LS mean difference
	Estimated Value	25.7
	Confidence Interval	(2-Sided) 80%; -75.41 to 126.78
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 61.73
	Estimation Comments

Statistical Analysis 50

Statistical Analysis Overview	Comparison Group Selection	KPL-716: CIP Cohort, Placebo: CIP Cohort
	Comments	Change at Week 13
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.0285
	Comments	Calculated from an ANCOVA model including treatment as factor and baseline values as covariate.
	Method	ANCOVA
	Comments
Method of Estimation	Estimation Parameter	LS mean difference
	Estimated Value	38.7
	Confidence Interval	(2-Sided) 80%; 17.09 to 60.34
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 16.25
	Estimation Comments

Statistical Analysis 51

Statistical Analysis Overview	Comparison Group Selection	KPL-716: LSC Cohort, Placebo: LSC Cohort
	Comments	Change at Week 13
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.2236
	Comments	Calculated from an ANCOVA model including treatment as factor and baseline values as covariate.
	Method	ANCOVA
	Comments
Method of Estimation	Estimation Parameter	LS mean difference
	Estimated Value	-64.6
	Confidence Interval	(2-Sided) 80%; -134.58 to 5.32
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 37.10
	Estimation Comments

Statistical Analysis 52

Statistical Analysis Overview	Comparison Group Selection	KPL-716: PPs Cohort, Placebo: PPs Cohort
	Comments	Change at Week 13
	Type of Statistical Test	Other
	Comments
Statistical Test of Hypothesis	p-Value	0.0558
	Comments	Calculated from an ANCOVA model including treatment as factor and baseline values as covariate.
	Method	ANCOVA
	Comments
Method of Estimation	Estimation Parameter	LS mean difference
	Estimated Value	-35.5
	Confidence Interval	(2-Sided) 80%; -58.65 to -12.41
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 17.38
	Estimation Comments

Statistical Analysis 53

Statistical Analysis Overview	Comparison Group Selection	KPL-716: CIU Cohort, Placebo: CIU Cohort
	Comments	Change at Week 14
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.7089
	Comments	Calculated from an ANCOVA model including treatment as factor and baseline values as covariate.
	Method	ANCOVA
	Comments
Method of Estimation	Estimation Parameter	LS mean difference
	Estimated Value	29.9
	Confidence Interval	(2-Sided) 80%; -89.41 to 149.24
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 72.86
	Estimation Comments

Statistical Analysis 54

Statistical Analysis Overview	Comparison Group Selection	KPL-716: CIP Cohort, Placebo: CIP Cohort
	Comments	Change at Week 14
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.0347
	Comments	Calculated from an ANCOVA model including treatment as factor and baseline values as covariate.
	Method	ANCOVA
	Comments
Method of Estimation	Estimation Parameter	LS mean difference
	Estimated Value	33.7
	Confidence Interval	(2-Sided) 80%; 14.08 to 53.35
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 14.76
	Estimation Comments

Statistical Analysis 55

Statistical Analysis Overview	Comparison Group Selection	KPL-716: LSC Cohort, Placebo: LSC Cohort
	Comments	Change at Week 14
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.2835
	Comments	Calculated from an ANCOVA model including treatment as factor and baseline values as covariate.
	Method	ANCOVA
	Comments
Method of Estimation	Estimation Parameter	LS mean difference
	Estimated Value	-60.9
	Confidence Interval	(2-Sided) 80%; -139.99 to 18.16
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 41.94
	Estimation Comments

Statistical Analysis 56

Statistical Analysis Overview	Comparison Group Selection	KPL-716: PPs Cohort, Placebo: PPs Cohort
	Comments	Change at Week 14
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.0525
	Comments	Calculated from an ANCOVA model including treatment as factor and baseline values as covariate.
	Method	ANCOVA
	Comments
Method of Estimation	Estimation Parameter	LS mean difference
	Estimated Value	-35.5
	Confidence Interval	(2-Sided) 80%; -58.31 to -12.77
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 17.11
	Estimation Comments

Statistical Analysis 57

Statistical Analysis Overview	Comparison Group Selection	KPL-716: CIU Cohort, Placebo: CIU Cohort
	Comments	Change at Week 15
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.7347
	Comments	Calculated from an ANCOVA model including treatment as factor and baseline values as covariate.
	Method	ANCOVA
	Comments
Method of Estimation	Estimation Parameter	LS mean difference
	Estimated Value	24.0
	Confidence Interval	(2-Sided) 80%; -81.68 to 129.66
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 64.52
	Estimation Comments

Statistical Analysis 58

Statistical Analysis Overview	Comparison Group Selection	KPL-716: CIP Cohort, Placebo: CIP Cohort
	Comments	Change at Week 15
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.0390
	Comments	Calculated from an ANCOVA model including treatment as factor and baseline values as covariate.
	Method	ANCOVA
	Comments
Method of Estimation	Estimation Parameter	LS mean difference
	Estimated Value	31.0
	Confidence Interval	(2-Sided) 80%; 12.50 to 49.60
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 13.94
	Estimation Comments

Statistical Analysis 59

Statistical Analysis Overview	Comparison Group Selection	KPL-716: LSC Cohort, Placebo: LSC Cohort
	Comments	Change at Week 15
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.2299
	Comments	Calculated from an ANCOVA model including treatment as factor and baseline values as covariate.
	Method	ANCOVA
	Comments
Method of Estimation	Estimation Parameter	LS mean difference
	Estimated Value	-60.6
	Confidence Interval	(2-Sided) 80%; -127.49 to 6.33
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 35.48
	Estimation Comments

Statistical Analysis 60

Statistical Analysis Overview	Comparison Group Selection	KPL-716: PPs Cohort, Placebo: PPs Cohort
	Comments	Change at Week 15
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.0884
	Comments	Calculated from an ANCOVA model including treatment as factor and baseline values as covariate.
	Method	ANCOVA
	Comments
Method of Estimation	Estimation Parameter	LS mean difference
	Estimated Value	-32.6
	Confidence Interval	(2-Sided) 80%; -56.70 to -8.53
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 18.11
	Estimation Comments

Statistical Analysis 61

Statistical Analysis Overview	Comparison Group Selection	KPL-716: CIU Cohort, Placebo: CIU Cohort
	Comments	Change at Week 16
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.8085
	Comments	Calculated from an ANCOVA model including treatment as factor and baseline values as covariate.
	Method	ANCOVA
	Comments
Method of Estimation	Estimation Parameter	LS mean difference
	Estimated Value	16.3
	Confidence Interval	(2-Sided) 80%; -84.37 to 116.87
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 61.44
	Estimation Comments

Statistical Analysis 62

Statistical Analysis Overview	Comparison Group Selection	KPL-716: CIP Cohort, Placebo: CIP Cohort
	Comments	Change at Week 16
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.2283
	Comments	Calculated from an ANCOVA model including treatment as factor and baseline values as covariate.
	Method	ANCOVA
	Comments
Method of Estimation	Estimation Parameter	LS mean difference
	Estimated Value	19.9
	Confidence Interval	(2-Sided) 80%; -1.33 to 41.14
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 15.96
	Estimation Comments

Statistical Analysis 63

Statistical Analysis Overview	Comparison Group Selection	KPL-716: LSC Cohort, Placebo: LSC Cohort
	Comments	Change at Week 16
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.1625
	Comments	Calculated from an ANCOVA model including treatment as factor and baseline values as covariate.
	Method	ANCOVA
	Comments
Method of Estimation	Estimation Parameter	LS mean difference
	Estimated Value	-69.9
	Confidence Interval	(2-Sided) 80%; -130.76 to -9.11
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 32.26
	Estimation Comments

Statistical Analysis 64

Statistical Analysis Overview	Comparison Group Selection	KPL-716: PPs Cohort, Placebo: PPs Cohort
	Comments	Change at Week 16
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.0707
	Comments	Calculated from an ANCOVA model including treatment as factor and baseline values as covariate.
	Method	ANCOVA
	Comments
Method of Estimation	Estimation Parameter	LS mean difference
	Estimated Value	-34.2
	Confidence Interval	(2-Sided) 80%; -57.87 to -10.52
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 17.80
	Estimation Comments

Statistical Analysis 65

Statistical Analysis Overview	Comparison Group Selection	KPL-716: CIU Cohort, Placebo: CIU Cohort
	Comments	Change at Week 17
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.9944
	Comments	Calculated from an ANCOVA model including treatment as factor and baseline values as covariate.
	Method	ANCOVA
	Comments
Method of Estimation	Estimation Parameter	LS mean difference
	Estimated Value	0.4
	Confidence Interval	(2-Sided) 80%; -81.79 to 82.55
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 50.17
	Estimation Comments

Statistical Analysis 66

Statistical Analysis Overview	Comparison Group Selection	KPL-716: CIP Cohort, Placebo: CIP Cohort
	Comments	Change at Week 17
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.1327
	Comments	Calculated from an ANCOVA model including treatment as factor and baseline values as covariate.
	Method	ANCOVA
	Comments
Method of Estimation	Estimation Parameter	LS mean difference
	Estimated Value	23.9
	Confidence Interval	(2-Sided) 80%; 3.71 to 44.05
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 15.16
	Estimation Comments

Statistical Analysis 67

Statistical Analysis Overview	Comparison Group Selection	KPL-716: LSC Cohort, Placebo: LSC Cohort
	Comments	Change at Week 17
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.1777
	Comments	Calculated from an ANCOVA model including treatment as factor and baseline values as covariate.
	Method	ANCOVA
	Comments
Method of Estimation	Estimation Parameter	LS mean difference
	Estimated Value	-69.2
	Confidence Interval	(2-Sided) 80%; -133.09 to -5.35
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 33.87
	Estimation Comments

Statistical Analysis 68

Statistical Analysis Overview	Comparison Group Selection	KPL-716: PPs Cohort, Placebo: PPs Cohort
	Comments	Change at Week 17
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.2796
	Comments	Calculated from an ANCOVA model including treatment as factor and baseline values as covariate.
	Method	ANCOVA
	Comments
Method of Estimation	Estimation Parameter	LS mean difference
	Estimated Value	-23.9
	Confidence Interval	(2-Sided) 80%; -52.34 to 4.61
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 21.40
	Estimation Comments

Statistical Analysis 69

Statistical Analysis Overview	Comparison Group Selection	KPL-716: CIU Cohort, Placebo: CIU Cohort
	Comments	Change at Week 18
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.8999
	Comments	Calculated from an ANCOVA model including treatment as factor and baseline values as covariate.
	Method	ANCOVA
	Comments
Method of Estimation	Estimation Parameter	LS mean difference
	Estimated Value	7.6
	Confidence Interval	(2-Sided) 80%; -83.15 to 98.30
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 55.40
	Estimation Comments

Statistical Analysis 70

Statistical Analysis Overview	Comparison Group Selection	KPL-716: CIP Cohort, Placebo: CIP Cohort
	Comments	Change at Week 18
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.1867
	Comments	Calculated from an ANCOVA model including treatment as factor and baseline values as covariate.
	Method	ANCOVA
	Comments
Method of Estimation	Estimation Parameter	LS mean difference
	Estimated Value	22.0
	Confidence Interval	(2-Sided) 80%; 0.68 to 43.23
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 15.99
	Estimation Comments

Statistical Analysis 71

Statistical Analysis Overview	Comparison Group Selection	KPL-716: LSC Cohort, Placebo: LSC Cohort
	Comments	Change at Week 18
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.1717
	Comments	Calculated from an ANCOVA model including treatment as factor and baseline values as covariate.
	Method	ANCOVA
	Comments
Method of Estimation	Estimation Parameter	LS mean difference
	Estimated Value	-70.8
	Confidence Interval	(2-Sided) 80%; -134.68 to -6.94
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 33.87
	Estimation Comments

Statistical Analysis 72

Statistical Analysis Overview	Comparison Group Selection	KPL-716: PPs Cohort, Placebo: PPs Cohort
	Comments	Change at Week 18
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.2792
	Comments	Calculated from an ANCOVA model including treatment as factor and baseline values as covariate.
	Method	ANCOVA
	Comments
Method of Estimation	Estimation Parameter	LS mean difference
	Estimated Value	-23.9
	Confidence Interval	(2-Sided) 80%; -52.50 to 4.61
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 21.46
	Estimation Comments

17. Secondary Outcome

Title	Change From Baseline in Dermatology Life Quality Index (DLQI) Total Score Over Time
Description	The DLQI is a 10-question questionnaire that considers symptoms and feelings, daily activities, leisure, school, personal relationships, and treatment. Each question, except question 7, is answered on a scale of 0 to 3 (0 for not at all, 1 for a little, 2 for a lot, and 3 for very much), taking into account the previous week. For question 7: participants were asked "Over the last week, has your skin prevented you from working or studying?" If answered yes, score=3; If no, a second question will be asked: "Over the last week how much has your skin been a problem at work or studying?" If further answered a lot, score=2; if a little, score=1; if not at all or not relevant, score=0. The DLQI total score is defined as the sum of all 10-question scores with minimum of 0 meaning no effect on quality of life and 30 meaning extremely large effect.
Time Frame	Baseline, Weeks 4, 8, 12, 16, 18

Outcome Measure Data

Analysis Population Description

Modified intent to treat (mITT) set: all randomized participants who received at least 1 dose of KPL-716 or placebo and had at least 1 post-baseline efficacy assessment in the double-blind treatment period. Missing data were imputed using the last observation carried forward (LOCF) method. Once a participant started treatment period (through Week 8), missing data in treatment period were imputed. Once a participant started the follow up (FU) period, missing data in FU period were imputed.

Arm/Group Title	KPL-716: CIU Cohort	Placebo: CIU Cohort	KPL-716: CIP Cohort	Placebo: CIP Cohort	KPL-716: LP Cohort	Placebo: LP Cohort	KPL-716: LSC Cohort	Placebo: LSC Cohort	KPL-716: PPs Cohort	Placebo: PPs Cohort
Arm/Group Description	Participants with CIU received KPL-716 weekly for 8 weeks	Participants with CIU received placebo weekly for 8 weeks	Participants with CIP received KPL-716 weekly for 8 weeks	Participants with CIP received placebo weekly for 8 weeks	Participants with LP received KPL-716 weekly for 8 weeks	Participants with LP received placebo weekly for 8 weeks	Participants with LSC received KPL-716 weekly for 8 weeks	Participants with LSC received placebo weekly for 8 weeks	Participants with PPs received KPL-716 weekly for 8 weeks	Participants with PPs received placebo weekly for 8 weeks
Measure Participants	4	2	14	9	3	0	4	1	14	7
Change at Week 4	-5.8 (1.49)	0.0 (0.00)	-3.4 (0.86)	-8.0 (1.96)	-4.7 (2.60)	-4.5 (2.99)	0.0 (NA)	-10.0 (1.83)	-0.6 (3.12)
Change at Week 8	-6.5 (1.04)	0.0 (0.00)	-3.6 (1.37)	-8.3 (2.01)	-4.7 (2.60)	-3.0 (4.55)	-12.0 (NA)	-11.2 (1.75)	-1.4 (3.33)
Change at Week 12	-6.5 (1.04)	0.0 (0.00)	-4.3 (1.53)	-8.3 (2.01)	-7.0 (2.00)	-3.0 (4.55)	-12.0 (NA)	-10.7 (1.69)	-1.5 (3.76)
Change at Week 16	-7.3 (1.55)	0.0 (0.00)	-4.8 (1.83)	-7.9 (2.25)	-10.0 (1.00)	-6.3 (2.29)	-5.0 (NA)	-10.0 (1.82)	-9.5 (2.46)
Change at Week 18	-6.0 (1.73)	0.0 (0.00)	-4.4 (2.02)	-8.7 (2.28)	-17.5 (5.50)	-6.5 (2.18)	-8.0 (NA)	-9.9 (2.01)	-9.2 (2.04)

18. Secondary Outcome

Title	Percent Change From Baseline in DLQI Total Score Over Time
Description	The DLQI is a 10-question questionnaire that considers symptoms and feelings, daily activities, leisure, school, personal relationships, and treatment. Each question, except question 7, is answered on a scale of 0 to 3 (0 for not at all, 1 for a little, 2 for a lot, and 3 for very much), taking into account the previous week. For question 7: participants were asked "Over the last week, has your skin prevented you from working or studying?" If answered yes, score=3; If no, a second question will be asked: "Over the last week how much has your skin been a problem at work or studying?" If further answered a lot, score=2; if a little, score=1; if not at all or not relevant, score=0. The DLQI total score is defined as the sum of all 10-question scores with minimum of 0 meaning no effect on quality of life and 30 meaning extremely large effect.
Time Frame	Baseline, Weeks 4, 8, 12, 16, 18

Outcome Measure Data

Analysis Population Description

Modified intent to treat (mITT) set: all randomized participants who received at least 1 dose of KPL-716 or placebo and had at least 1 post-baseline efficacy assessment in the double-blind treatment period. Missing data were imputed using the last observation carried forward (LOCF) method. Once a participant started treatment period (through Week 8), missing data in treatment period were imputed. Once a participant started the follow up (FU) period, missing data in FU period were imputed.

Arm/Group Title	KPL-716: CIU Cohort	Placebo: CIU Cohort	KPL-716: CIP Cohort	Placebo: CIP Cohort	KPL-716: LP Cohort	Placebo: LP Cohort	KPL-716: LSC Cohort	Placebo: LSC Cohort	KPL-716: PPs Cohort	Placebo: PPs Cohort
Arm/Group Description	Participants with CIU received KPL-716 weekly for 8 weeks	Participants with CIU received placebo weekly for 8 weeks	Participants with CIP received KPL-716 weekly for 8 weeks	Participants with CIP received placebo weekly for 8 weeks	Participants with LP received KPL-716 weekly for 8 weeks	Participants with LP received placebo weekly for 8 weeks	Participants with LSC received KPL-716 weekly for 8 weeks	Participants with LSC received placebo weekly for 8 weeks	Participants with PPs received KPL-716 weekly for 8 weeks	Participants with PPs received placebo weekly for 8 weeks
Measure Participants	4	2	14	9	3	0	4	1	14	7
Change at Week 4	-51.0 (17.71)	-3.7 (25.35)	-32.8 (8.77)	-52.4 (10.95)	-24.2 (17.01)	-53.5 (33.55)	6.1 (94.72)	-68.2 (11.77)	4.1 (16.65)
Change at Week 8	-54.5 (12.95)	-2.4 (18.53)	-41.1 (13.32)	-56.0 (16.63)	-24.2 (17.01)	-32.5 (64.55)	-85.7 (182.21)	-72.2 (10.71)	-2.3 (15.15)
Change at Week 12	-54.5 (12.95)	-2.4 (18.53)	-48.1 (14.36)	-55.7 (16.59)	-36.4 (0.00)	-32.5 (64.55)	-85.7 (182.21)	-72.9 (11.58)	-5.4 (17.75)
Change at Week 16	-60.5 (15.08)	-2.5 (21.57)	-51.0 (11.94)	-54.0 (13.79)	-61.4 (0.00)	-71.9 (23.07)	-41.5 (65.13)	-69.6 (8.18)	-60.7 (12.54)
Change at Week 18	-52.5 (18.16)	-3.4 (25.99)	-44.0 (12.37)	-61.3 (14.29)	-89.7 (0.00)	-75.0 (19.53)	-52.4 (55.14)	-68.7 (9.18)	-62.6 (14.08)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	KPL-716: CIU Cohort, Placebo: CIU Cohort
	Comments	Change at Week 4
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.2289
	Comments	Calculated from an ANCOVA model including treatment as factor and baseline values as covariate.
	Method	ANCOVA
	Comments
Method of Estimation	Estimation Parameter	LS Mean Difference
	Estimated Value	-47.3
	Confidence Interval	(2-Sided) 80%; -98.77 to 4.10
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 31.41
	Estimation Comments

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	KPL-716: CIP Cohort, Placebo: CIP Cohort
	Comments	Change at Week 4
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.1788
	Comments	Calculated from an ANCOVA model including treatment as factor and baseline values as covariate.
	Method	ANCOVA
	Comments
Method of Estimation	Estimation Parameter	LS Mean Difference
	Estimated Value	19.6
	Confidence Interval	(2-Sided) 80%; 0.96 to 38.27
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 14.08
	Estimation Comments

Statistical Analysis 3

Statistical Analysis Overview	Comparison Group Selection	KPL-716: LSC Cohort, Placebo: LSC Cohort
	Comments	Change at Week 4
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.6544
	Comments	Calculated from an ANCOVA model including treatment as factor and baseline values as covariate.
	Method	ANCOVA
	Comments
Method of Estimation	Estimation Parameter	LS Mean Difference
	Estimated Value	-59.6
	Confidence Interval	(2-Sided) 80%; -275.19 to 156.06
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 114.35
	Estimation Comments

Statistical Analysis 4

Statistical Analysis Overview	Comparison Group Selection	KPL-716: PPs Cohort, Placebo: PPs Cohort
	Comments	Change at Week 4
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.0023
	Comments	Calculated from an ANCOVA model including treatment as factor and baseline values as covariate.
	Method	ANCOVA
	Comments
Method of Estimation	Estimation Parameter	LS Mean Difference
	Estimated Value	-72.2
	Confidence Interval	(2-Sided) 80%; -99.39 to -45.09
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 20.40
	Estimation Comments

Statistical Analysis 5

Statistical Analysis Overview	Comparison Group Selection	KPL-716: CIU Cohort, Placebo: CIU Cohort
	Comments	Change at Week 8
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.1081
	Comments	Calculated from an ANCOVA model including treatment as factor and baseline values as covariate.
	Method	ANCOVA
	Comments
Method of Estimation	Estimation Parameter	LS Mean Difference
	Estimated Value	-52.1
	Confidence Interval	(2-Sided) 80%; -89.68 to -14.47
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 22.96
	Estimation Comments

Statistical Analysis 6

Statistical Analysis Overview	Comparison Group Selection	KPL-716: CIP Cohort, Placebo: CIP Cohort
	Comments	Change at Week 8
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.4926
	Comments	Calculated from an ANCOVA model including treatment as factor and baseline values as covariate.
	Method	ANCOVA
	Comments
Method of Estimation	Estimation Parameter	LS Mean Difference
	Estimated Value	14.9
	Confidence Interval	(2-Sided) 80%; -13.39 to 43.26
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 21.37
	Estimation Comments

Statistical Analysis 7

Statistical Analysis Overview	Comparison Group Selection	KPL-716: LSC Cohort, Placebo: LSC Cohort
	Comments	Change at Week 8
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.8315
	Comments	Calculated from an ANCOVA model including treatment as factor and baseline values as covariate.
	Method	ANCOVA
	Comments
Method of Estimation	Estimation Parameter	LS Mean Difference
	Estimated Value	53.2
	Confidence Interval	(2-Sided) 80%; -361.63 to 467.98
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 219.98
	Estimation Comments

Statistical Analysis 8

Statistical Analysis Overview	Comparison Group Selection	KPL-716: PPs Cohort, Placebo: PPs Cohort
	Comments	Change at Week 8
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.0014
	Comments	Calculated from an ANCOVA model including treatment as factor and baseline values as covariate.
	Method	ANCOVA
	Comments
Method of Estimation	Estimation Parameter	LS Mean Difference
	Estimated Value	-69.9
	Confidence Interval	(2-Sided) 80%; -94.61 to -45.22
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 18.56
	Estimation Comments

Statistical Analysis 9

Statistical Analysis Overview	Comparison Group Selection	KPL-716: CIU Cohort, Placebo: CIU Cohort
	Comments	Change at Week 12
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.1081
	Comments	Calculated from an ANCOVA model including treatment as factor and baseline values as covariate.
	Method	ANCOVA
	Comments
Method of Estimation	Estimation Parameter	LS Mean Difference
	Estimated Value	-52.1
	Confidence Interval	(2-Sided) 80%; -89.68 to -14.47
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 22.96
	Estimation Comments

Statistical Analysis 10

Statistical Analysis Overview	Comparison Group Selection	KPL-716: CIP Cohort, Placebo: CIP Cohort
	Comments	Change at Week 12
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.7339
	Comments	Calculated from an ANCOVA model including treatment as factor and baseline values as covariate.
	Method	ANCOVA
	Comments
Method of Estimation	Estimation Parameter	LS Mean Difference
	Estimated Value	7.6
	Confidence Interval	(2-Sided) 80%; -21.65 to 36.82
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 21.97
	Estimation Comments

Statistical Analysis 11

Statistical Analysis Overview	Comparison Group Selection	Placebo: LSC Cohort, KPL-716: PPs Cohort
	Comments	Change at Week 12
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.8315
	Comments	Calculated from an ANCOVA model including treatment as factor and baseline values as covariate.
	Method	ANCOVA
	Comments
Method of Estimation	Estimation Parameter	LS Mean Difference
	Estimated Value	53.2
	Confidence Interval	(2-Sided) 80%; -361.63 to 467.98
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 219.98
	Estimation Comments

Statistical Analysis 12

Statistical Analysis Overview	Comparison Group Selection	KPL-716: PPs Cohort, Placebo: PPs Cohort
	Comments	Change at Week 12
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.0055
	Comments	Calculated from an ANCOVA model including treatment as factor and baseline values as covariate.
	Method	ANCOVA
	Comments
Method of Estimation	Estimation Parameter	LS Mean Difference
	Estimated Value	-67.6
	Confidence Interval	(2-Sided) 80%; -95.92 to -39.22
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 21.26
	Estimation Comments

Statistical Analysis 13

Statistical Analysis Overview	Comparison Group Selection	KPL-716: CIU Cohort, Placebo: CIU Cohort
	Comments	Change at Week 16
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.1188
	Comments	Calculated from an ANCOVA model including treatment as factor and baseline values as covariate.
	Method	ANCOVA
	Comments
Method of Estimation	Estimation Parameter	LS Mean Difference
	Estimated Value	-57.9
	Confidence Interval	(2-Sided) 80%; -101.70 to -14.15
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 26.73
	Estimation Comments

Statistical Analysis 14

Statistical Analysis Overview	Comparison Group Selection	KPL-716: CIP Cohort, Placebo: CIP Cohort
	Comments	Change at Week 16
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.8697
	Comments	Calculated from an ANCOVA model including treatment as factor and baseline values as covariate.
	Method	ANCOVA
	Comments
Method of Estimation	Estimation Parameter	LS Mean Difference
	Estimated Value	3.0
	Confidence Interval	(2-Sided) 80%; -21.26 to 27.35
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 18.27
	Estimation Comments

Statistical Analysis 15

Statistical Analysis Overview	Comparison Group Selection	KPL-716: LSC Cohort, Placebo: LSC Cohort
	Comments	Change at Week 16
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.7368
	Comments	Calculated from an ANCOVA model including treatment as factor and baseline values as covariate.
	Method	ANCOVA
	Comments
Method of Estimation	Estimation Parameter	LS Mean Difference
	Estimated Value	-30.3
	Confidence Interval	(2-Sided) 80%; -178.62 to 117.94
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 78.64
	Estimation Comments

Statistical Analysis 16

Statistical Analysis Overview	Comparison Group Selection	KPL-716: PPs Cohort, Placebo: PPs Cohort
	Comments	Change at Week 16
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.5571
	Comments	Calculated from an ANCOVA model including treatment as factor and baseline values as covariate.
	Method	ANCOVA
	Comments
Method of Estimation	Estimation Parameter	LS Mean Difference
	Estimated Value	-9.0
	Confidence Interval	(2-Sided) 80%; -29.03 to 11.03
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 15.02
	Estimation Comments

Statistical Analysis 17

Statistical Analysis Overview	Comparison Group Selection	KPL-716: CIU Cohort, Placebo: CIU Cohort
	Comments	Change at Week 18
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.2251
	Comments	Calculated from an ANCOVA model including treatment as factor and baseline values as covariate.
	Method	ANCOVA
	Comments
Method of Estimation	Estimation Parameter	LS Mean Difference
	Estimated Value	-49.1
	Confidence Interval	(2-Sided) 80%; -101.80 to 3.69
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 32.21
	Estimation Comments

Statistical Analysis 18

Statistical Analysis Overview	Comparison Group Selection	KPL-716: CIP Cohort, Placebo: CIP Cohort
	Comments	Change at Week 18
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.3733
	Comments	Calculated from an ANCOVA model including treatment as factor and baseline values as covariate.
	Method	ANCOVA
	Comments
Method of Estimation	Estimation Parameter	LS Mean Difference
	Estimated Value	17.3
	Confidence Interval	(2-Sided) 80%; -7.90 to 42.48
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 18.93
	Estimation Comments

Statistical Analysis 19

Statistical Analysis Overview	Comparison Group Selection	KPL-716: LSC Cohort, Placebo: LSC Cohort
	Comments	Change at Week 18
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.7662
	Comments	Calculated from an ANCOVA model including treatment as factor and baseline values as covariate.
	Method	ANCOVA
	Comments
Method of Estimation	Estimation Parameter	LS Mean Difference
	Estimated Value	-22.6
	Confidence Interval	(2-Sided) 80%; -148.16 to 102.89
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 66.57
	Estimation Comments

Statistical Analysis 20

Statistical Analysis Overview	Comparison Group Selection	KPL-716: PPs Cohort, Placebo: PPs Cohort
	Comments	Change at Week 18
	Type of Statistical Test	Other
	Comments
Statistical Test of Hypothesis	p-Value	0.7241
	Comments	Calculated from an ANCOVA model including treatment as factor and baseline values as covariate.
	Method	ANCOVA
	Comments
Method of Estimation	Estimation Parameter	LS Mean Difference
	Estimated Value	-6.1
	Confidence Interval	(2-Sided) 80%; -28.54 to 16.44
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 16.87
	Estimation Comments

19. Secondary Outcome

Title	Change From Baseline in ItchyQoL Total Score Over Time
Description	ItchyQoL focuses on impact of pruritus on daily activities and on the level of psychological stress. It contains 22 items. The frequency items are scored using a 5-point Likert scale ranging from "never" to "all the time". The bother items are scored from 1 (not bothered) to 5 (severely bothered). The recall period in ItchyQoL is the past week. The ItchyQoL total score is defined as the sum of all 22-items scores. Total scores can be classified as little (0-30), mild (31-50), moderate (51-80), and severe (81-110).
Time Frame	Baseline, Weeks 4, 8, 12, 16, 18

Outcome Measure Data

Analysis Population Description

Modified intent to treat (mITT) set: all randomized participants who received at least 1 dose of KPL-716 or placebo and had at least 1 post-baseline efficacy assessment in the double-blind treatment period. Missing data were imputed using the last observation carried forward (LOCF) method. Once a participant started treatment period (through Week 8), missing data in treatment period were imputed. Once a participant started the follow up (FU) period, missing data in FU period were imputed.

Arm/Group Title	KPL-716: CIU Cohort	Placebo: CIU Cohort	KPL-716: CIP Cohort	Placebo: CIP Cohort	KPL-716: LP Cohort	Placebo: LP Cohort	KPL-716: LSC Cohort	Placebo: LSC Cohort	KPL-716: PPs Cohort	Placebo: PPs Cohort
Arm/Group Description	Participants with CIU received KPL-716 weekly for 8 weeks	Participants with CIU received placebo weekly for 8 weeks	Participants with CIP received KPL-716 weekly for 8 weeks	Participants with CIP received placebo weekly for 8 weeks	Participants with LP received KPL-716 weekly for 8 weeks	Participants with LP received placebo weekly for 8 weeks	Participants with LSC received KPL-716 weekly for 8 weeks	Participants with LSC received placebo weekly for 8 weeks	Participants with PPs received KPL-716 weekly for 8 weeks	Participants with PPs received placebo weekly for 8 weeks
Measure Participants	4	2	14	9	3	0	4	1	14	7
Change at Week 4	-17.0 (13.07)	0.0 (0.00)	-10.9 (3.63)	-18.9 (6.25)	-27.3 (15.32)	-31.5 (13.91)	0.0 (NA)	-29.0 (5.61)	-16.9 (7.04)
Change at Week 8	-23.3 (9.08)	-0.5 (0.50)	-17.8 (4.61)	-20.8 (8.66)	-27.3 (15.32)	-38.8 (15.84)	-10.0 (NA)	-35.8 (5.88)	-23.1 (7.31)
Change at Week 12	-22.8 (11.74)	0.0 (0.00)	-22.0 (5.96)	-19.2 (5.78)	-47.0 (6.00)	-41.5 (11.99)	-18.0 (NA)	-35.5 (6.54)	-27.3 (4.62)
Change at Week 16	-33.3 (11.46)	0.0 (0.00)	-19.9 (5.18)	-18.1 (6.93)	-50.0 (3.00)	-41.5 (11.89)	-18.0 (NA)	-38.1 (5.66)	-29.2 (8.15)
Change at Week 18	-29.3 (9.68)	0.0 (0.00)	-25.1 (7.18)	-21.4 (6.82)	-64.5 (14.50)	-46.8 (8.62)	-15.0 (NA)	-32.9 (6.40)	-31.8 (8.46)

20. Secondary Outcome

Title	Percent Change From Baseline in ItchyQoL Total Score Over Time
Description	ItchyQoL focuses on impact of pruritus on daily activities and on the level of psychological stress. It contains 22 items. The frequency items are scored using a 5-point Likert scale ranging from "never" to "all the time". The bother items are scored from 1 (not bothered) to 5 (severely bothered). The recall period in ItchyQoL is the past week. The ItchyQoL total score is defined as the sum of all 22-items scores. Total scores can be classified as little (0-30), mild (31-50), moderate (51-80), and severe (81-110).
Time Frame	Baseline, Weeks 4, 8, 12, 16, 18

Outcome Measure Data

Analysis Population Description

Modified intent to treat (mITT) set: all randomized participants who received at least 1 dose of KPL-716 or placebo and had at least 1 post-baseline efficacy assessment in the double-blind treatment period. Missing data were imputed using the last observation carried forward (LOCF) method. Once a participant started treatment period (through Week 8), missing data in treatment period were imputed. Once a participant started the follow up (FU) period, missing data in FU period were imputed.

Arm/Group Title	KPL-716: CIU Cohort	Placebo: CIU Cohort	KPL-716: CIP Cohort	Placebo: CIP Cohort	KPL-716: LP Cohort	Placebo: LP Cohort	KPL-716: LSC Cohort	Placebo: LSC Cohort	KPL-716: PPs Cohort	Placebo: PPs Cohort
Arm/Group Description	Participants with CIU received KPL-716 weekly for 8 weeks	Participants with CIU received placebo weekly for 8 weeks	Participants with CIP received KPL-716 weekly for 8 weeks	Participants with CIP received placebo weekly for 8 weeks	Participants with LP received KPL-716 weekly for 8 weeks	Participants with LP received placebo weekly for 8 weeks	Participants with LSC received KPL-716 weekly for 8 weeks	Participants with LSC received placebo weekly for 8 weeks	Participants with PPs received KPL-716 weekly for 8 weeks	Participants with PPs received placebo weekly for 8 weeks
Measure Participants	4	2	14	9	3	0	4	1	14	7
Change at Week 4	-21.4 (16.56)	-0.2 (23.57)	-13.0 (5.15)	-24.3 (6.43)	-29.1 (7.02)	-47.8 (17.37)	39.7 (46.22)	-34.8 (5.84)	-14.6 (8.32)
Change at Week 8	-29.2 (11.47)	-0.6 (16.32)	-23.7 (7.21)	-26.0 (9.01)	-29.1 (7.02)	-56.3 (23.23)	27.3 (61.79)	-42.7 (6.29)	-21.9 (8.97)
Change at Week 12	-28.3 (14.70)	0.2 (20.91)	-29.4 (6.30)	-25.0 (7.29)	-50.9 (0.00)	-58.2 (15.85)	12.0 (42.18)	-42.7 (6.58)	-26.0 (10.25)
Change at Week 16	-41.7 (14.66)	-0.2 (20.86)	-26.5 (6.61)	-23.2 (7.65)	-54.6 (0.00)	-59.8 (12.34)	19.8 (32.82)	-45.8 (6.06)	-29.4 (9.44)
Change at Week 18	-36.6 (12.16)	0.0 (17.30)	-32.5 (7.93)	-27.6 (9.17)	-69.2 (0.00)	-63.8 (7.49)	10.2 (19.94)	-39.6 (7.06)	-31.7 (11.00)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	KPL-716: CIU Cohort, Placebo: CIU Cohort
	Comments	Change at Week 4
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.5195
	Comments	Calculated from an ANCOVA model including treatment as factor and baseline values as covariate.
	Method	ANCOVA
	Comments
Method of Estimation	Estimation Parameter	LS Mean Difference
	Estimated Value	-21.1
	Confidence Interval	(2-Sided) 80%; -68.69 to 26.43
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 29.04
	Estimation Comments

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	KPL-716: CIP Cohort, Placebo: CIP Cohort
	Comments	Change at Week 4
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.1869
	Comments	Calculated from an ANCOVA model including treatment as factor and baseline values as covariate.
	Method	ANCOVA
	Comments
Method of Estimation	Estimation Parameter	LS Mean Difference
	Estimated Value	11.3
	Confidence Interval	(2-Sided) 80%; 0.34 to 22.26
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 8.27
	Estimation Comments

Statistical Analysis 3

Statistical Analysis Overview	Comparison Group Selection	KPL-716: LSC Cohort, Placebo: LSC Cohort
	Comments	Change at Week 4
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.2545
	Comments	Calculated from an ANCOVA model including treatment as factor and baseline values as covariate.
	Method	ANCOVA
	Comments
Method of Estimation	Estimation Parameter	LS Mean Difference
	Estimated Value	-87.5
	Confidence Interval	(2-Sided) 80%; -191.75 to 16.79
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 55.30
	Estimation Comments

Statistical Analysis 4

Statistical Analysis Overview	Comparison Group Selection	KPL-716: PPs Cohort, Placebo: PPs Cohort
	Comments	Change at Week 4
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.0643
	Comments	Calculated from an ANCOVA model including treatment as factor and baseline values as covariate.
	Method	ANCOVA
	Comments
Method of Estimation	Estimation Parameter	LS Mean Difference
	Estimated Value	-20.2
	Confidence Interval	(2-Sided) 80%; -33.88 to -6.57
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 10.26
	Estimation Comments

Statistical Analysis 5

Statistical Analysis Overview	Comparison Group Selection	KPL-716: CIU Cohort, Placebo: CIU Cohort
	Comments	Change at Week 8
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.2503
	Comments	Calculated from an ANCOVA model including treatment as factor and baseline values as covariate.
	Method	ANCOVA
	Comments
Method of Estimation	Estimation Parameter	LS Mean Difference
	Estimated Value	-28.6
	Confidence Interval	(2-Sided) 80%; -61.52 to 4.35
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 20.11
	Estimation Comments

Statistical Analysis 6

Statistical Analysis Overview	Comparison Group Selection	KPL-716: CIP Cohort, Placebo: CIP Cohort
	Comments	Change at Week 8
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.8468
	Comments	Calculated from an ANCOVA model including treatment as factor and baseline values as covariate.
	Method	ANCOVA
	Comments
Method of Estimation	Estimation Parameter	LS Mean Difference
	Estimated Value	2.3
	Confidence Interval	(2-Sided) 80%; -13.08 to 17.62
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 11.58
	Estimation Comments

Statistical Analysis 7

Statistical Analysis Overview	Comparison Group Selection	KPL-716: LSC Cohort, Placebo: LSC Cohort
	Comments	Change at Week 8
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.3755
	Comments	Calculated from an ANCOVA model including treatment as factor and baseline values as covariate.
	Method	ANCOVA
	Comments
Method of Estimation	Estimation Parameter	LS Mean Difference
	Estimated Value	-83.6
	Confidence Interval	(2-Sided) 80%; -222.98 to 55.18
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 73.93
	Estimation Comments

Statistical Analysis 8

Statistical Analysis Overview	Comparison Group Selection	KPL-716: PPs Cohort, Placebo: PPs Cohort
	Comments	Change at Week 8
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.0755
	Comments	Calculated from an ANCOVA model including treatment as factor and baseline values as covariate.
	Method	ANCOVA
	Comments
Method of Estimation	Estimation Parameter	LS Mean Difference
	Estimated Value	-20.9
	Confidence Interval	(2-Sided) 80%; -35.58 to -6.15
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 11.06
	Estimation Comments

Statistical Analysis 9

Statistical Analysis Overview	Comparison Group Selection	KPL-716: CIU Cohort, Placebo: CIU Cohort
	Comments	Change at Week 12
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.3486
	Comments	Calculated from an ANCOVA model including treatment as factor and baseline values as covariate.
	Method	ANCOVA
	Comments
Method of Estimation	Estimation Parameter	LS Mean Difference
	Estimated Value	-28.6
	Confidence Interval	(2-Sided) 80%; -70.76 to 13.65
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 25.77
	Estimation Comments

Statistical Analysis 10

Statistical Analysis Overview	Comparison Group Selection	KPL-716: CIP Cohort, Placebo: CIP Cohort
	Comments	Change at Week 12
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.6559
	Comments	Calculated from an ANCOVA model including treatment as factor and baseline values as covariate.
	Method	ANCOVA
	Comments
Method of Estimation	Estimation Parameter	LS Mean Difference
	Estimated Value	-4.4
	Confidence Interval	(2-Sided) 80%; -17.28 to 8.50
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 9.69
	Estimation Comments

Statistical Analysis 11

Statistical Analysis Overview	Comparison Group Selection	KPL-716: LSC Cohort, Placebo: LSC Cohort
	Comments	Change at Week 12
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.2987
	Comments	Calculated from an ANCOVA model including treatment as factor and baseline values as covariate.
	Method	ANCOVA
	Comments
Method of Estimation	Estimation Parameter	LS Mean Difference
	Estimated Value	-70.2
	Confidence Interval	(2-Sided) 80%; -165.35 to 24.94
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 50.46
	Estimation Comments

Statistical Analysis 12

Statistical Analysis Overview	Comparison Group Selection	KPL-716: PPs Cohort, Placebo: PPs Cohort
	Comments	Change at Week 12
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.1966
	Comments	Calculated from an ANCOVA model including treatment as factor and baseline values as covariate.
	Method	ANCOVA
	Comments
Method of Estimation	Estimation Parameter	LS Mean Difference
	Estimated Value	-16.7
	Confidence Interval	(2-Sided) 80%; -33.29 to -0.13
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 12.43
	Estimation Comments

Statistical Analysis 13

Statistical Analysis Overview	Comparison Group Selection	KPL-716: CIU Cohort, Placebo: CIU Cohort
	Comments	Change at Week 16
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.2051
	Comments	Calculated from an ANCOVA model including treatment as factor and baseline values as covariate.
	Method	ANCOVA
	Comments
Method of Estimation	Estimation Parameter	LS Mean Difference
	Estimated Value	-41.5
	Confidence Interval	(2-Sided) 80%; -83.56 to 0.62
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 25.70
	Estimation Comments

Statistical Analysis 14

Statistical Analysis Overview	Comparison Group Selection	KPL-716: CIP Cohort, Placebo: CIP Cohort
	Comments	Change at Week 16
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.7511
	Comments	Calculated from an ANCOVA model including treatment as factor and baseline values as covariate.
	Method	ANCOVA
	Comments
Method of Estimation	Estimation Parameter	LS Mean Difference
	Estimated Value	-3.3
	Confidence Interval	(2-Sided) 80%; -16.79 to 10.25
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 10.16
	Estimation Comments

Statistical Analysis 15

Statistical Analysis Overview	Comparison Group Selection	KPL-716: LSC Cohort, Placebo: LSC Cohort
	Comments	Change at Week 16
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.1797
	Comments	Calculated from an ANCOVA model including treatment as factor and baseline values as covariate.
	Method	ANCOVA
	Comments
Method of Estimation	Estimation Parameter	LS Mean Difference
	Estimated Value	-79.6
	Confidence Interval	(2-Sided) 80%; -153.68 to -5.59
	Parameter Dispersion	Type: Standard Deviation; Value: 39.27
	Estimation Comments

Statistical Analysis 16

Statistical Analysis Overview	Comparison Group Selection	KPL-716: PPs Cohort, Placebo: PPs Cohort
	Comments	Change at Week 16
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.1715
	Comments	Calculated from an ANCOVA model including treatment as factor and baseline values as covariate.
	Method	ANCOVA
	Comments
Method of Estimation	Estimation Parameter	LS Mean Difference
	Estimated Value	-16.3
	Confidence Interval	(2-Sided) 80%; -31.61 to -1.08
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 11.45
	Estimation Comments

Statistical Analysis 17

Statistical Analysis Overview	Comparison Group Selection	KPL-716: CIU Cohort, Placebo: CIU Cohort
	Comments	Change at Week 18
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.1850
	Comments	Calculated from an ANCOVA model including treatment as factor and baseline values as covariate.
	Method	ANCOVA
	Comments
Method of Estimation	Estimation Parameter	LS Mean Difference
	Estimated Value	-36.5
	Confidence Interval	(2-Sided) 80%; -71.47 to -1.63
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 21.32
	Estimation Comments

Statistical Analysis 18

Statistical Analysis Overview	Comparison Group Selection	KPL-716: CIP Cohort, Placebo: CIP Cohort
	Comments	Change at Week 18
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.6907
	Comments	Calculated from an ANCOVA model including treatment as factor and baseline values as covariate.
	Method	ANCOVA
	Comments
Method of Estimation	Estimation Parameter	LS Mean Difference
	Estimated Value	-4.9
	Confidence Interval	(2-Sided) 80%; -21.15 to 11.29
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 12.19
	Estimation Comments

Statistical Analysis 19

Statistical Analysis Overview	Comparison Group Selection	KPL-716: LSC Cohort, Placebo: LSC Cohort
	Comments	Change at Week 18
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.0901
	Comments	Calculated from an ANCOVA model including treatment as factor and baseline values as covariate.
	Method	ANCOVA
	Comments
Method of Estimation	Estimation Parameter	LS Mean Difference
	Estimated Value	-74.0
	Confidence Interval	(2-Sided) 80%; -118.97 to -29.02
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 23.85
	Estimation Comments

Statistical Analysis 20

Statistical Analysis Overview	Comparison Group Selection	KPL-716: PPs Cohort, Placebo: PPs Cohort
	Comments	Change at Week 18
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.5640
	Comments	Calculated from an ANCOVA model including treatment as factor and baseline values as covariate.
	Method	ANCOVA
	Comments
Method of Estimation	Estimation Parameter	LS Mean Difference
	Estimated Value	-7.8
	Confidence Interval	(2-Sided) 80%; -25.64 to 9.94
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 13.34
	Estimation Comments

21. Primary Outcome

Title	Percent Change From Baseline in Weekly Average WI-NRS at Week 8
Description	WI-NRS score: Participants were asked daily to assign a numerical score to the intensity of their most severe (worst) pruritus in the past 24 hours using a scale from 0 to 10, with 0 indicating no pruritus and 10 indicating the worst imaginable pruritus. Daily scores were averaged for a weekly score. A negative change from Baseline indicates improvement.
Time Frame	Baseline, Week 8

Outcome Measure Data

Analysis Population Description

Modified intent to treat (mITT) set: all randomized participants who received at least 1 dose of KPL-716 or placebo and had at least 1 post-baseline efficacy assessment in the double-blind treatment period. Missing data were imputed using the last observation carried forward (LOCF) method.

Arm/Group Title	KPL-716: CIU Cohort	Placebo: CIU Cohort	KPL-716: CIP Cohort	Placebo: CIP Cohort	KPL-716: LP Cohort	Placebo: LP Cohort	KPL-716: LSC Cohort	Placebo: LSC Cohort	KPL-716: PPs Cohort	Placebo: PPs Cohort
Arm/Group Description	Participants with CIU received KPL-716 weekly for 8 weeks	Participants with CIU received placebo weekly for 8 weeks	Participants with CIP received KPL-716 weekly for 8 weeks	Participants with CIP received placebo weekly for 8 weeks	Participants with LP received KPL-716 weekly for 8 weeks	Participants with LP received placebo weekly for 8 weeks	Participants with LSC received KPL-716 weekly for 8 weeks	Participants with LSC received placebo weekly for 8 weeks	Participants with PPs received KPL-716 weekly for 8 weeks	Participants with PPs received placebo weekly for 8 weeks
Measure Participants	4	2	14	9	3	0	4	1	14	7
Least Squares Mean (Standard Error) [percent change]	-50.7 (21.56)	-19.0 (31.07)	-52.4 (9.32)	-48.8 (11.63)	-39.4 (10.21)	-85.0 (11.76)	7.0 (26.80)	-66.5 (7.78)	-29.0 (11.00)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	KPL-716: CIU Cohort, Placebo: CIU Cohort
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.4734
	Comments	Calculated from an ANCOVA model including treatment as factor and baseline values as covariate.
	Method	ANCOVA
	Comments
Method of Estimation	Estimation Parameter	LS mean difference
	Estimated Value	-31.7
	Confidence Interval	(2-Sided) 80%; -95.11 to 31.76
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 38.73
	Estimation Comments

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	KPL-716: CIP Cohort, Placebo: CIP Cohort
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.8130
	Comments	Calculated from an ANCOVA model including treatment as factor and baseline values as covariate.
	Method	ANCOVA
	Comments
Method of Estimation	Estimation Parameter	LS mean difference
	Estimated Value	-3.6
	Confidence Interval	(2-Sided) 80%; -23.33 to 16.18
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 14.91
	Estimation Comments

Statistical Analysis 3

Statistical Analysis Overview	Comparison Group Selection	KPL-716: LSC Cohort, Placebo: LSC Cohort
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.0979
	Comments	Calculated from an ANCOVA model including treatment as factor and baseline values as covariate.
	Method	ANCOVA
	Comments
Method of Estimation	Estimation Parameter	LS mean difference
	Estimated Value	-92.0
	Confidence Interval	(2-Sided) 80%; -150.60 to -33.32
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 31.10
	Estimation Comments

Statistical Analysis 4

Statistical Analysis Overview	Comparison Group Selection	KPL-716: PPs Cohort, Placebo: PPs Cohort
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.0122
	Comments	Calculated from an ANCOVA model including treatment as factor and baseline values as covariate.
	Method	ANCOVA
	Comments
Method of Estimation	Estimation Parameter	LS mean difference
	Estimated Value	-37.5
	Confidence Interval	(2-Sided) 80%; -55.48 to -19.61
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 13.48
	Estimation Comments

Adverse Events

Time Frame	From first dose of study treatment through the end-of-study visit (Week 18).
Adverse Event Reporting Description	The adverse event data are presented by combined cohorts for public reporting purposes because the low numbers of participants in the individual disease-specific cohorts may cause re-identification concerns if presented separately.
Arm/Group Title	KPL-716		Placebo
Arm/Group Description	KPL-716 weekly for 8 weeks		Placebo weekly for 8 weeks
All Cause Mortality
	KPL-716		Placebo
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	0/39 (0%)		0/19 (0%)
Serious Adverse Events
	KPL-716		Placebo
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	1/39 (2.6%)		0/19 (0%)
Skin and subcutaneous tissue disorders
Angioedema	1/39 (2.6%)		0/19 (0%)
Other (Not Including Serious) Adverse Events
	KPL-716		Placebo
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	15/39 (38.5%)		11/19 (57.9%)
Eye disorders
Chalazion	1/39 (2.6%)		0/19 (0%)
Gastrointestinal disorders
Nausea	1/39 (2.6%)		0/19 (0%)
General disorders
Fatigue	0/39 (0%)		2/19 (10.5%)
Chest pain	0/39 (0%)		1/19 (5.3%)
Infections and infestations
Upper respiratory tract infection	2/39 (5.1%)		1/19 (5.3%)
Influenza	1/39 (2.6%)		1/19 (5.3%)
Sinusitis	1/39 (2.6%)		1/19 (5.3%)
Urinary tract infection	1/39 (2.6%)		1/19 (5.3%)
Conjunctivitis	1/39 (2.6%)		0/19 (0%)
Lower respiratory tract infection	1/39 (2.6%)		0/19 (0%)
Lymphangitis	1/39 (2.6%)		0/19 (0%)
Nasopharyngitis	1/39 (2.6%)		0/19 (0%)
Pharyngitis streptococcal	0/39 (0%)		1/19 (5.3%)
Streptococcal infection	0/39 (0%)		1/19 (5.3%)
Injury, poisoning and procedural complications
Contusion	1/39 (2.6%)		0/19 (0%)
Fall	1/39 (2.6%)		0/19 (0%)
Muscle contusion	1/39 (2.6%)		0/19 (0%)
Muscle strain	1/39 (2.6%)		0/19 (0%)
Investigations
Haemoglobin decreased	0/39 (0%)		2/19 (10.5%)
Cardiac murmur	1/39 (2.6%)		0/19 (0%)
Platelet count decreased	1/39 (2.6%)		0/19 (0%)
Electrocardioagram T wave abnormal	0/39 (0%)		1/19 (5.3%)
Metabolism and nutrition disorders
Hypokalemia	1/39 (2.6%)		0/19 (0%)
Type 2 diabetes mellitus	1/39 (2.6%)		0/19 (0%)
Vitamin B12 deficiency	0/39 (0%)		1/19 (5.3%)
Musculoskeletal and connective tissue disorders
Back pain	1/39 (2.6%)		1/19 (5.3%)
Arthritis	1/39 (2.6%)		0/19 (0%)
Myalgia	1/39 (2.6%)		0/19 (0%)
Pain in extremity	1/39 (2.6%)		0/19 (0%)
Rotator cuff syndrome	1/39 (2.6%)		0/19 (0%)
Nervous system disorders
Dizziness	0/39 (0%)		1/19 (5.3%)
Headache	0/39 (0%)		1/19 (5.3%)
Pregnancy, puerperium and perinatal conditions
Pregnancy	1/39 (2.6%)		0/19 (0%)
Renal and urinary disorders
Renal colic	1/39 (2.6%)		0/19 (0%)
Haematuria	0/39 (0%)		1/19 (5.3%)
Respiratory, thoracic and mediastinal disorders
Cough	1/39 (2.6%)		1/19 (5.3%)
Oropharyngeal pain	1/39 (2.6%)		0/19 (0%)
Sinus congestion	1/39 (2.6%)		0/19 (0%)
Nasal congestion	0/39 (0%)		1/19 (5.3%)
Skin and subcutaneous tissue disorders
Pruritus	2/39 (5.1%)		0/19 (0%)
Dermatitis contact	1/39 (2.6%)		1/19 (5.3%)
Dermatitis	1/39 (2.6%)		0/19 (0%)
Pityriasis rosea	1/39 (2.6%)		0/19 (0%)
Psoriasis	1/39 (2.6%)		0/19 (0%)

Limitations/Caveats

[Not Specified]

More Information

Certain Agreements

Principal Investigators are NOT employed by the organization sponsoring the study.

Sponsor has the first right to publish study results. PI may publish study results after Sponsor publishes the study results or 18 months after study completion at all participating sites, whichever comes first, provided that Sponsor may embargo such publication for up to 60 days for purposes of identifying confidential information that must be removed and up to an additional 60 days to prepare a patent application if there is patentable subject matter in the PI's proposed publication.