IMAGINE-II: An Extension Study to Evaluate the Long-Term Safety and Durability of Effect of LUM001 in the Treatment of Cholestatic Liver Disease in Pediatric Subjects With Alagille Syndrome

• Sponsor: Mirum Pharmaceuticals, Inc. (Industry)
• Overall Status: Completed
• CT.gov ID: NCT02117713
• Collaborator: Lumena Pharmaceuticals, Inc. (Industry), Childhood Liver Disease Research and Education Network (Other)
• Enrollment: 34
• Locations: 11
• Arm: 1
• Actual Duration (Months): 62.6
• Patients Per Site: 3.1
• Patients Per Site Per Month: 0

Study Details

Study Description

Brief Summary

This is a multicentre, extension study of LUM001 in children diagnosed with Alagille Syndrome who have completed participation in a core LUM001 treatment protocol. The primary objective is to evaluate long-term safety and tolerability of LUM001. Efficacy will be assessed by evaluating the effect of LUM001 on the biochemical markers and pruritus associated with Alagille Syndrome.

Condition or Disease	Intervention/Treatment	Phase
Alagille Syndrome	Drug: LUM001 (Maralixibat)	Phase 2

Study Design

• Study Type: Interventional
• Actual Enrollment: 34 participants
• Allocation: N/A
• Intervention Model: Single Group Assignment
• Masking: Double (Participant, Investigator)
• Primary Purpose: Treatment
• Official Title: A Multicenter Extension Study to Evaluate the Long-Term Safety and Durability of the Therapeutic Effect of LUM001, an Apical Sodium-Dependent Bile Acid Transporter Inhibitor (ASBTi), in the Treatment of Cholestatic Liver Disease in Pediatric Subjects With Alagille Syndrome
• Actual Study Start Date: Mar 16, 2015
• Actual Primary Completion Date: Jun 1, 2020
• Actual Study Completion Date: Jun 1, 2020

Arms and Interventions

Arm	Intervention/Treatment
Experimental: LUM001 (Maralixibat) Participant will receive LUM001 also known as Maralixibat (MRX) administered orally once per day.	Drug: LUM001 (Maralixibat); Dosing of LUM001 also known as Maralixibat (MRX) with the objective of achieving optimal control of pruritus at a dose level that is tolerated by the participant and up to a maximum daily dose of 280 micrograms per kilogram (mcg/kg).

Outcome Measures

Primary Outcome Measures

1. Change From MRX Baseline to Week 48 in Fasting Serum Bile Acid (sBA) [Baseline to Week 48]

   This primacy efficacy endpoint is the mean change from MRX baseline to week 48 in fasting sBA levels.

Secondary Outcome Measures

1. Change From MRX Baseline to Week 216 in Fasting Serum Bile Acid (sBA) [Baseline to week 216]

   The secondary endpoint of this study was the mean change from MRX baseline to week 216 fasting in sBA levels.

2. Change From Baseline to Week 218 in Pruritus [Baseline to Week 218]

   This secondary efficacy endpoint is the mean change from MRX baseline over time to week 218 in pruritus as measured by ItchRO(Obs) weekly average morning severity score. ItchRO scores range from 0 to 4; the higher score indicates increasing itch severity (0 = none; 4 = very severe). Results reported here are the long-term results.

3. Change From Baseline to Week 216 in Alanine Aminotransferase [Baseline to week 216]

   This secondary efficacy endpoint is the mean change from MRX baseline to week 216 in ALT levels.

4. Change From Baseline to End of Treatment in Alkaline Phosphatase [Baseline to Week 216]

   This secondary efficacy endpoint is the mean change from MRX baseline to week 216 in ALP levels.

5. Change From MRX Baseline to Week 216 in Aspartate Aminotransferase [Baseline to week 216]

   This secondary efficacy endpoint is the mean change from MRX baseline to week 216 in AST levels.

6. Change From MRX Baseline to Week 216 in Clinician Xanthoma Severity Score [Baseline to week 216]

   This secondary efficacy endpoint is the mean change from MRX baseline to week 216 in clinician xanthoma severity scores. It is based on a 0-4 scale to rate the number of lesions present and the degree to which the lesions interfere or limit activities. Clinician xanthoma severity scores range from 0 to 4, with a score of zero representing no evidence of xanthomatosis and a score of 4 representing xanthoma so severe that it is disabling.

7. Change From Baseline to Week 216/LOFC Clinician Scratch Scale (CSS) Score [Baseline to Week 216]

   This secondary efficacy endpoint is the mean change from MRX baseline over time to week 216/LOCF in pruritus as measured by the Clinician Scratch Scale (CSS). The Clinician Scratch Scale uses a 5-point scale, where 0 = none; 1 = rubbing or mild scratching when undistracted; 2 = active scratching without evident skin abrasions; 3 = abrasion evident; 4 = cutaneous mutilation, haemorrhage and scarring evident.

8. Change From MRX Baseline to Week 216 in Gamma Glutamyltransferase [Baseline to Week 216]

   This secondary efficacy endpoint is the mean change from MRX baseline to week 216 in GGT.

9. Mean Change From MRX Baseline to Week 216 in Total Bilirubin [Baseline to week 216]

   This secondary efficacy endpoint is the mean change from MRX baseline to week 216 in total bilirubin.

10. Mean Change From MRX Baseline to Week 216 in Direct Bilirubin [Baseline to week 216]

    This secondary efficacy endpoint is the mean change from MRX baseline to week 216 in direct bilirubin.

Eligibility Criteria

Criteria

• Ages Eligible for Study: 1 Year to 18 Years
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

Inclusion Criteria:

1. Male or female, 12 months to 18 years of age.

2. Competent to provide informed consent and assent (per institutional review board/Ethics Committee [IRB/EC]), as appropriate.

3. Completed participation in the LUM001-301 protocol.

4. Females of childbearing potential must have a negative urine pregnancy test [beta human chorionic gonadotropin (beta-hCG)] at the Baseline Visit.

5. Sexually active females must be prepared to use an effective method of contraception during the trial.

Effective methods of contraception are considered to be:

1. Hormonal (for example, contraceptive pill, patch, intramuscular implant or injection); or

2. Barrier method, for example, (a) condom with spermicide, or (b) diaphragm, with spermicide; or

3. Intrauterine device (IUD).

4. Participants above the age of assent and caregivers and children must be able to read and understand English or Spanish.

5. Caregivers (and age appropriate participants) must have access to phone for scheduled calls from study site.

6. Caregivers (and age appropriate participants) must be willing and able to complete a daily electronic diary (ItchRO) during the first consecutive 12 weeks of the study and then for 4 consecutive weeks following the Week 24 and Week 44 visits.

7. Caregivers (and age appropriate participants) must digitally accept the licensing agreement in the ItchRO electronic diary software at the outset of the study.

8. Eligible participants must be able to adhere to local Ethics Committee or Institutional Review Board (IRB) blood volume limits for laboratory testing.

9. The participant has completed the protocol either through Week 144, or the End of Trial visit, or has received permission from the sponsor and the Premier Medical monitor to re-enter the study in the long-term, optional follow-up treatment period 2.

10. Females of child-bearing potential must have a negative urine or serum pregnancy test (beta-HCG]) at the time of entry into the long-term optional follow-up treatment period 2.

11. Male and female participants of child-bearing potential who are sexually active, or are not currently sexually active, but become sexually active during the study or for 30 days following the last dose of study drug, must agree to use acceptable contraception during the study.

12. Informed consent and assent (per IRB/EC) as appropriate.

13. Caregivers (and age appropriate participants) must have access to phone for scheduled calls from study site.

14. Caregivers (and age appropriate participants) must be willing to follow the rules of eDiary completion.

Exclusion Criteria:

1. Experienced an adverse event or serious adverse event (SAE) related to the study drug during the LUM001-301 protocol that led to the discontinuation of the participant from the core study.

2. Any conditions or abnormalities (including laboratory abnormalities) which in the opinion of the Investigator, Medical Monitor or ChiLDReN Protocol Chair, may compromise the safety of the participant, or interfere with the participant participating in or completing the study.

3. History or known presence of gallstones or kidney stones.

4. History of non-adherence during the participant's participation in the LUM001-301 protocol. Non-adherence is defined by dosing compliance (dosing compliance is calculated by [the total number of doses that were actually taken by the participant] divided by [the total number of doses that should have been taken by the participant] multiplied by 100) of less than 80% in the LUM001-301 protocol.

5. Unlikely to comply with the study protocol, or unsuitable for any other reason, as judged by the investigator.

6. All above exclusion criteria will apply upon re-entry into the long-term, optional follow-up treatment period 2.

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	Children's Hospital Los Angeles	Los Angeles	California	United States	90027
2	University of California at San Francisco Children's Hospital	San Francisco	California	United States	94143
3	Children's Hospital Colorado	Aurora	Colorado	United States	80045
4	Riley Hospital for Children	Indianapolis	Indiana	United States	46202
5	Cincinnati Children's Hospital Medical Center	Cincinnati	Ohio	United States	45229
6	The Children's Hospital of Philadelphia	Philadelphia	Pennsylvania	United States	19147
7	Children's Hospital of Pittsburgh of UPMC	Pittsburgh	Pennsylvania	United States	15224
8	Baylor College of Medicine/Texas Children's Hospital	Houston	Texas	United States	77030
9	University of Utah	Salt Lake City	Utah	United States	84113
10	Seattle Children's Hospital	Seattle	Washington	United States	98105
11	The Hospital for Sick Children	Toronto	Ontario	Canada	M5G 1X8

Sponsors and Collaborators

• Mirum Pharmaceuticals, Inc.
• Lumena Pharmaceuticals, Inc.
• Childhood Liver Disease Research and Education Network

Investigators

• Study Director: Study Director, Mirum

Study Documents (Full-Text)

• Study Protocol - May 13, 2019
• Statistical Analysis Plan - Apr 9, 2020

More Information

Publications

None provided.

• Responsible Party: Mirum Pharmaceuticals, Inc.
• ClinicalTrials.gov Identifier: NCT02117713
• Other Study ID Numbers: LUM001-305; SHP625-305
• First Posted: Apr 21, 2014
• Last Update Posted: Jul 1, 2021
• Last Verified: Jun 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
• Additional relevant MeSH terms: Liver Diseases; Alagille Syndrome; Syndrome

Study Results

Participant Flow

Arm/Group Title	LUM001 (Maralixibat)
Arm/Group Description	Participant received LUM001 also known as Maralixibat (MRX) administered orally once per day for up to 216 weeks.
Period Title: Week 48
STARTED	34
COMPLETED	26
NOT COMPLETED	8
Period Title: Week 48
STARTED	26
COMPLETED	20
NOT COMPLETED	6

Baseline Characteristics

Arm/Group Title	Core Study Period
Arm/Group Description	Participant received LUM001 also known as Maralixibat (MRX) administered orally once per day.
Overall Participants	34
Age (years of age) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [years of age]	7 (4.55)
Sex: Female, Male (Count of Participants)
Female	14 41.2%
Male	20 58.8%
Race (NIH/OMB) (Count of Participants)
American Indian or Alaska Native	0 0%
Asian	1 2.9%
Native Hawaiian or Other Pacific Islander	0 0%
Black or African American	4 11.8%
White	27 79.4%
More than one race	1 2.9%
Unknown or Not Reported	1 2.9%
Region of Enrollment (participants) [Number]
Canada	4 11.8%
United States	30 88.2%

Outcome Measures

1. Primary Outcome

Title	Change From MRX Baseline to Week 48 in Fasting Serum Bile Acid (sBA)
Description	This primacy efficacy endpoint is the mean change from MRX baseline to week 48 in fasting sBA levels.
Time Frame	Baseline to Week 48

Outcome Measure Data

Analysis Population Description

Since most participants escalated to MRX 280 ug/kg/day, the summary is presented as a single arm.

Arm/Group Title	MRX Baseline Value	Maralixibat Week 48 Values
Arm/Group Description	These are the MRX baseline values for participants	Week 48 values for participants.
Measure Participants	34	26
Mean (Standard Deviation) [μmol/L]	223.62 (205.041)	157.35 (178.538)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	MRX Baseline Value, Maralixibat Week 48 Values
	Comments
	Type of Statistical Test	Equivalence
	Comments	Student's t-test used to test if mean change is statistically significant; null hypothesis is that the mean change from baseline is equal to zero.
Statistical Test of Hypothesis	p-Value	0.1157
	Comments
	Method	Student's t-test
	Comments
Method of Estimation	Estimation Parameter	Mean Difference (Net)
	Estimated Value	-28.59
	Confidence Interval	(2-Sided) 95%; -64.72 to 7.54
	Parameter Dispersion	Type: Standard Deviation; Value: 89.456
	Estimation Comments	Difference is only calculated in participants who had baseline and week 48 values for n= 26

2. Secondary Outcome

Title	Change From MRX Baseline to Week 216 in Fasting Serum Bile Acid (sBA)
Description	The secondary endpoint of this study was the mean change from MRX baseline to week 216 fasting in sBA levels.
Time Frame	Baseline to week 216

Outcome Measure Data

Analysis Population Description

Since most participants escalated to MRX 280 ug/kg/day, the summary is presented as a single arm.

Arm/Group Title	Maralixibat Baseline Values	Week 216
Arm/Group Description	These are the MRX baseline values for participants.	These are the week 216 values of participants
Measure Participants	34	10
Mean (Standard Deviation) [μmol/L]	223.62 (205.041)	118.81 (126.878)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	MRX Baseline Value, Maralixibat Week 48 Values
	Comments
	Type of Statistical Test	Equivalence
	Comments	Student's t-test used to test if mean change is statistically significant; null hypothesis is that the mean change from baseline is equal to zero.
Statistical Test of Hypothesis	p-Value	0.1469
	Comments
	Method	Student's t-test
	Comments
Method of Estimation	Estimation Parameter	Mean Difference (Net)
	Estimated Value	-45.15
	Confidence Interval	(2-Sided) 95%; -109.48 to 19.19
	Parameter Dispersion	Type: Standard Deviation; Value: 89.934
	Estimation Comments
Other Statistical Analysis		Difference is only calculated in participants who had baseline and week 216 values for n=10

3. Secondary Outcome

Title	Change From Baseline to Week 218 in Pruritus
Description	This secondary efficacy endpoint is the mean change from MRX baseline over time to week 218 in pruritus as measured by ItchRO(Obs) weekly average morning severity score. ItchRO scores range from 0 to 4; the higher score indicates increasing itch severity (0 = none; 4 = very severe). Results reported here are the long-term results.
Time Frame	Baseline to Week 218

Outcome Measure Data

Analysis Population Description

Since most participants escalated to MRX 280 ug/kg/day, the summary is presented as a single arm.

Arm/Group Title	Maralixibat Baseline Values	Week 218
Arm/Group Description	These are the MRX baseline values for participants.	These are values from Week 218.
Measure Participants	34	6
Mean (Standard Deviation) [score on a scale]	2.533 (0.8423)	0.429 (0.8571)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	MRX Baseline Value, Maralixibat Week 48 Values
	Comments
	Type of Statistical Test	Equivalence
	Comments	Student's t-test was used to test if mean change was statistically significant (null hypothesis is that the mean change from baseline is equal to zero).
Statistical Test of Hypothesis	p-Value	0.005
	Comments
	Method	Student's t-test
	Comments
Method of Estimation	Estimation Parameter	Mean Difference (Net)
	Estimated Value	-2.353
	Confidence Interval	(2-Sided) 95%; -3.101 to -1.606
	Parameter Dispersion	Type: Standard Deviation; Value: 0.7124
	Estimation Comments	Difference is only calculated in participants who had baseline and week 218 values for n=6

4. Secondary Outcome

Title	Change From Baseline to Week 216 in Alanine Aminotransferase
Description	This secondary efficacy endpoint is the mean change from MRX baseline to week 216 in ALT levels.
Time Frame	Baseline to week 216

Outcome Measure Data

Analysis Population Description

Since most participants escalated to MRX 280 ug/kg/day, the summary is presented as a single arm.

Arm/Group Title	MRX Baseline Value	Week 216 Values
Arm/Group Description	These are the MRX baseline values for participants	These are the week 216 values for participants.
Measure Participants	34	7
Mean (Standard Deviation) [U/L]	152.9 (82.26)	222.4 (126.53)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	MRX Baseline Value, Maralixibat Week 48 Values
	Comments
	Type of Statistical Test	Equivalence
	Comments	Student's t-test was used to test if mean change was statistically significant (null hypothesis is that the mean change from baseline is equal to zero).
Statistical Test of Hypothesis	p-Value	0.2607
	Comments
	Method	Student's t-test
	Comments
Method of Estimation	Estimation Parameter	Mean Difference (Net)
	Estimated Value	56.0
	Confidence Interval	(2-Sided) 95%; -54.4 to 166.4
	Parameter Dispersion	Type: Standard Deviation; Value: 119.32
	Estimation Comments	Difference is only calculated in participants who had baseline and week 216 values for n=7

5. Secondary Outcome

Title	Change From Baseline to End of Treatment in Alkaline Phosphatase
Description	This secondary efficacy endpoint is the mean change from MRX baseline to week 216 in ALP levels.
Time Frame	Baseline to Week 216

Outcome Measure Data

Analysis Population Description

Since most participants escalated to MRX 280 ug/kg/day, the summary is presented as a single arm.

Arm/Group Title	MRX Baseline Value	Week 216 Values
Arm/Group Description	These are the MRX baseline values for participants	These are the 2616 values for participants.
Measure Participants	34	7
Mean (Standard Deviation) [U/L]	598.8 (199.89)	528.3 (221.93)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	MRX Baseline Value, Maralixibat Week 48 Values
	Comments
	Type of Statistical Test	Equivalence
	Comments	Student's t-test was used to test if mean change was statistically significant (null hypothesis is that the mean change from baseline is equal to zero).
Statistical Test of Hypothesis	p-Value	0.1340
	Comments
	Method	Student's t-test
	Comments
Method of Estimation	Estimation Parameter	Mean Difference (Net)
	Estimated Value	-141.6
	Confidence Interval	(2-Sided) 95%; -341.6 to 58.4
	Parameter Dispersion	Type: Standard Deviation; Value: 216.25
	Estimation Comments	Difference is only calculated in participants who had baseline and week 216 values for n=7

6. Secondary Outcome

Title	Change From MRX Baseline to Week 216 in Aspartate Aminotransferase
Description	This secondary efficacy endpoint is the mean change from MRX baseline to week 216 in AST levels.
Time Frame	Baseline to week 216

Outcome Measure Data

Analysis Population Description

Since most participants escalated to MRX 280 ug/kg/day, the summary is presented as a single arm.

Arm/Group Title	MRX Baseline Value	Week 216
Arm/Group Description	These are the MRX baseline values for participants	These are the week 216 values for participants.
Measure Participants	34	7
Mean (Standard Deviation) [U/L]	149.7 (88.27)	231.4 (122.26)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	MRX Baseline Value, Maralixibat Week 48 Values
	Comments
	Type of Statistical Test	Equivalence
	Comments	Student's t-test was used to test if mean change was statistically significant (null hypothesis is that the mean change from baseline is equal to zero).
Statistical Test of Hypothesis	p-Value	0.1474
	Comments
	Method	Student's t-test
	Comments
Method of Estimation	Estimation Parameter	Mean Difference (Net)
	Estimated Value	47.6
	Confidence Interval	(2-Sided) 95%; -22.4 to 117.6
	Parameter Dispersion	Type: Standard Deviation; Value: 75.68
	Estimation Comments	Difference is only calculated in participants who had baseline and week 216 values for n=7

7. Secondary Outcome

Title	Change From MRX Baseline to Week 216 in Clinician Xanthoma Severity Score
Description	This secondary efficacy endpoint is the mean change from MRX baseline to week 216 in clinician xanthoma severity scores. It is based on a 0-4 scale to rate the number of lesions present and the degree to which the lesions interfere or limit activities. Clinician xanthoma severity scores range from 0 to 4, with a score of zero representing no evidence of xanthomatosis and a score of 4 representing xanthoma so severe that it is disabling.
Time Frame	Baseline to week 216

Outcome Measure Data

Analysis Population Description

Since most participants escalated to MRX 280 ug/kg/day, the summary is presented as a single arm.

Arm/Group Title	MRX Baseline Value	Week 216
Arm/Group Description	These are the MRX baseline values for participants	These are the week 216 values for participants.
Measure Participants	34	7
Mean (Standard Deviation) [Points]	0.9 (1.33)	1.1 (1.68)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	MRX Baseline Value, Maralixibat Week 48 Values
	Comments
	Type of Statistical Test	Equivalence
	Comments	Student's t-test was used to test if mean change was statistically significant (null hypothesis is that the mean change from baseline is equal to zero).
Statistical Test of Hypothesis	p-Value	1.00
	Comments
	Method	Student's t-test
	Comments
Method of Estimation	Estimation Parameter	Mean Difference (Net)
	Estimated Value	0
	Confidence Interval	(2-Sided) 95%; -0.5 to 0.5
	Parameter Dispersion	Type: Standard Deviation; Value: 0.58
	Estimation Comments	Difference is only calculated in participants who had baseline and week 216 values for n=7

8. Secondary Outcome

Title	Change From Baseline to Week 216/LOFC Clinician Scratch Scale (CSS) Score
Description	This secondary efficacy endpoint is the mean change from MRX baseline over time to week 216/LOCF in pruritus as measured by the Clinician Scratch Scale (CSS). The Clinician Scratch Scale uses a 5-point scale, where 0 = none; 1 = rubbing or mild scratching when undistracted; 2 = active scratching without evident skin abrasions; 3 = abrasion evident; 4 = cutaneous mutilation, haemorrhage and scarring evident.
Time Frame	Baseline to Week 216

Outcome Measure Data

Analysis Population Description

Since most participants escalated to MRX 280 ug/kg/day, the summary is presented as a single arm.

Arm/Group Title	MRX Baseline Value	Week 216
Arm/Group Description	These are the MRX baseline values for participants	These are the week 216 values for participants.
Measure Participants	34	7
Mean (Standard Deviation) [Points]	2.9 (1.08)	1.1 (1.07)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	MRX Baseline Value, Maralixibat Week 48 Values
	Comments
	Type of Statistical Test	Equivalence
	Comments	Student's t-test used to test if mean change is statistically significant (null hypothesis is that the mean change from baseline is equal to zero).
Statistical Test of Hypothesis	p-Value	0.0167
	Comments
	Method	Student's t-test
	Comments
Method of Estimation	Estimation Parameter	Mean Difference (Net)
	Estimated Value	-1.7
	Confidence Interval	(2-Sided) 95%; -3 to -0.4
	Parameter Dispersion	Type: Standard Deviation; Value: 1.38
	Estimation Comments	Difference is only calculated in participants who had baseline and week 216 values for n=7

9. Secondary Outcome

Title	Change From MRX Baseline to Week 216 in Gamma Glutamyltransferase
Description	This secondary efficacy endpoint is the mean change from MRX baseline to week 216 in GGT.
Time Frame	Baseline to Week 216

Outcome Measure Data

Analysis Population Description

Since most participants escalated to MRX 280 ug/kg/day, the summary is presented as a single arm.

Arm/Group Title	MRX Baseline Value	Week 216 Values
Arm/Group Description	These are the MRX baseline values for participants	These are the week 216 values of the participants.
Measure Participants	34	7
Mean (Standard Deviation) [U/L]	493.5 (380.29)	431 (235.35)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	MRX Baseline Value, Maralixibat Week 48 Values
	Comments
	Type of Statistical Test	Equivalence
	Comments	Student's t-test was used to test if mean change was statistically significant (null hypothesis is that the mean change from baseline is equal to zero).
Statistical Test of Hypothesis	p-Value	0.9108
	Comments
	Method	Student's t-test
	Comments
Method of Estimation	Estimation Parameter	Mean Difference (Net)
	Estimated Value	10.9
	Confidence Interval	(2-Sided) 95%; -216.6 to 238.3
	Parameter Dispersion	Type: Standard Deviation; Value: 245.92
	Estimation Comments	Difference is only calculated in participants who had baseline and week 216 values for n=7

10. Secondary Outcome

Title	Mean Change From MRX Baseline to Week 216 in Total Bilirubin
Description	This secondary efficacy endpoint is the mean change from MRX baseline to week 216 in total bilirubin.
Time Frame	Baseline to week 216

Outcome Measure Data

Analysis Population Description

Since most participants escalated to MRX 280 ug/kg/day, the summary is presented as a single arm.

Arm/Group Title	MRX Baseline Value	Week 216
Arm/Group Description	These are the MRX baseline values for participants	These are the week 216 values for participants.
Measure Participants	34	7
Mean (Standard Deviation) [mg/dL]	5.62 (6.420)	5.39 (5.181)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	MRX Baseline Value, Maralixibat Week 48 Values
	Comments
	Type of Statistical Test	Equivalence
	Comments	Student's t-test was used to test if mean change was statistically significant(null hypothesis is that the mean change from baseline is equal to zero).
Statistical Test of Hypothesis	p-Value	0.1207
	Comments
	Method	Student's t-test
	Comments
Method of Estimation	Estimation Parameter	Mean Difference (Net)
	Estimated Value	0.1207
	Confidence Interval	(2-Sided) 95%; -3.03 to 0.45
	Parameter Dispersion	Type: Standard Deviation; Value: 1.882
	Estimation Comments	Difference is only calculated in participants who had baseline and week 216 values for n=7

11. Secondary Outcome

Title	Mean Change From MRX Baseline to Week 216 in Direct Bilirubin
Description	This secondary efficacy endpoint is the mean change from MRX baseline to week 216 in direct bilirubin.
Time Frame	Baseline to week 216

Outcome Measure Data

Analysis Population Description

Since most participants escalated to MRX 280 ug/kg/day, the summary is presented as a single arm.

Arm/Group Title	MRX Baseline Value	Week 216 Values
Arm/Group Description	These are the MRX baseline values for participants	These are the week 216 values of the participants.
Measure Participants	34	7
Mean (Standard Deviation) [mg/dL]	3.541 (3.6433)	3.714 (3.8369)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	MRX Baseline Value, Maralixibat Week 48 Values
	Comments
	Type of Statistical Test	Equivalence
	Comments	Student's t-test was used to test if mean change was statistically significant (null hypothesis is that the mean change from baseline is equal to zero).
Statistical Test of Hypothesis	p-Value	0.0927
	Comments
	Method	Student's t-test
	Comments
Method of Estimation	Estimation Parameter	Mean Difference (Net)
	Estimated Value	-0.943
	Confidence Interval	(2-Sided) 95%; -2.098 to 0.212
	Parameter Dispersion	Type: Standard Deviation; Value: 1.2488
	Estimation Comments	Difference is only calculated in participants who had baseline and week 216 values for n=7

Adverse Events

Time Frame	Baseline to End of Treatment (Week 216)
Arm/Group Title	LUM001 (Maralixibat)
Arm/Group Description	Participant received LUM001 (also known as Maralixibat or MRX) as oral solution once daily based on participant's weight. The dose was escalated from 14, 35, 70, 140 and 280 microgram per kilogram per day (mcg/kg/day) for 4-week dose escalation period. During 8-weeks of dose optimization period, drug was adjusted in titrated manner and dosing was continued to complete the stable dosing and safety monitoring periods for up to 96 weeks of cumulative LUM001 exposure in this study. Dosing during long-term optional follow-up treatment periods 1 and 2 was maintained at the same dose levels as at weeks 96 and 144 for participants rolling over into these treatment periods respectively.
All Cause Mortality
	LUM001 (Maralixibat)
	Affected / at Risk (%)	# Events
Total	0/34 (0%)
Serious Adverse Events
	LUM001 (Maralixibat)
	Affected / at Risk (%)	# Events
Total	6/34 (17.6%)
Blood and lymphatic system disorders
Anaemia	1/34 (2.9%)	1
Gastrointestinal disorders
Haematemesis	1/34 (2.9%)	1
Haematochezia	1/34 (2.9%)	1
Hepatobiliary disorders
Autoimmune hepatitis	1/34 (2.9%)	1
Chronic hepatic failure	1/34 (2.9%)	1
Infections and infestations
Fungal infection	1/34 (2.9%)	1
Metabolism and nutrition disorders
Malnutrition	1/34 (2.9%)	1
Respiratory, thoracic and mediastinal disorders
Epistaxis	1/34 (2.9%)	1
Other (Not Including Serious) Adverse Events
	LUM001 (Maralixibat)
	Affected / at Risk (%)	# Events
Total	34/34 (100%)
Blood and lymphatic system disorders
Lymphadenopathy	2/34 (5.9%)	2
Splenic infarction	1/34 (2.9%)	1
Congenital, familial and genetic disorders
Bicuspid aortic valve	1/34 (2.9%)	1
Non-compaction cardiomyopathy	1/34 (2.9%)	1
Ear and labyrinth disorders
Ear pain	3/34 (8.8%)	5
Eustachian tube dysfunction	1/34 (2.9%)	2
Excessive cerumen production	1/34 (2.9%)	1
Tympanic membrane perforation	1/34 (2.9%)	1
Vertigo	1/34 (2.9%)	1
Eye disorders
Asthenopia	1/34 (2.9%)	1
Eye pruritus	1/34 (2.9%)	1
Vision blurred	1/34 (2.9%)	1
Gastrointestinal disorders
Abdominal discomfort	3/34 (8.8%)	4
Abdominal distension	1/34 (2.9%)	1
Abdominal pain	6/34 (17.6%)	39
Abdominal pain lower	1/34 (2.9%)	1
Abdominal pain upper	6/34 (17.6%)	18
Aphthous ulcer	1/34 (2.9%)	1
Dental caries	1/34 (2.9%)	1
Diarrhoea	13/34 (38.2%)	37
Dry mouth	1/34 (2.9%)	1
Eosinophilic oesophagitis	1/34 (2.9%)	1
Faecaloma	1/34 (2.9%)	1
Gastrooesophageal reflux disease	4/34 (11.8%)	4
Haematochezia	2/34 (5.9%)	2
Inguinal hernia	1/34 (2.9%)	1
Nausea	3/34 (8.8%)	4
Post-tussive vomiting	2/34 (5.9%)	2
Toothache	1/34 (2.9%)	1
Vomiting	10/34 (29.4%)	17
General disorders
Asthenia	1/34 (2.9%)	1
Catheter site haemorrhage	1/34 (2.9%)	1
Catheter site pain	1/34 (2.9%)	1
Chest pain	2/34 (5.9%)	3
Fatigue	1/34 (2.9%)	1
Influenza like illness	6/34 (17.6%)	22
Medical device pain	2/34 (5.9%)	2
Peripheral swelling	1/34 (2.9%)	1
Pyrexia	15/34 (44.1%)	39
Hepatobiliary disorders
Hepatobiliary disease	1/34 (2.9%)	1
Hepatosplenomegaly	1/34 (2.9%)	1
Jaundice	1/34 (2.9%)	1
Immune system disorders
Seasonal allergy	2/34 (5.9%)	2
Infections and infestations
Adenovirus infection	2/34 (5.9%)	2
Anorectal infection	1/34 (2.9%)	1
Bacterial infection	1/34 (2.9%)	1
Bronchitis	1/34 (2.9%)	1
Conjunctivitis	1/34 (2.9%)	1
Conjunctivitis viral	1/34 (2.9%)	1
Ear infection	7/34 (20.6%)	15
Ear infection bacterial	1/34 (2.9%)	1
Eye infection	1/34 (2.9%)	1
Fungal skin infection	1/34 (2.9%)	1
Gastroenteritis	1/34 (2.9%)	1
Gastroenteritis viral	4/34 (11.8%)	5
Gastrointestinal viral infection	1/34 (2.9%)	1
Gingivitis	1/34 (2.9%)	1
Hand-foot-and-mouth disease	1/34 (2.9%)	2
Herpes simplex	1/34 (2.9%)	5
Influenza	1/34 (2.9%)	1
Kidney infection	1/34 (2.9%)	1
Localised infection	1/34 (2.9%)	1
Nasopharyngitis	10/34 (29.4%)	24
Oral herpes	1/34 (2.9%)	2
Otitis media	1/34 (2.9%)	3
Parainfluenzae virus infection	1/34 (2.9%)	1
Pharyngitis streptococcal	5/34 (14.7%)	10
Pneumonia	2/34 (5.9%)	2
Pneumonia bacterial	1/34 (2.9%)	1
Respiratory tract infection viral	1/34 (2.9%)	1
Sinusitis	6/34 (17.6%)	11
Staphylococcal skin infection	1/34 (2.9%)	1
Tinea capitis	1/34 (2.9%)	1
Upper respiratory tract infection	16/34 (47.1%)	63
Urinary tract infection	3/34 (8.8%)	5
Viral infection	4/34 (11.8%)	5
Viral upper respiratory tract infection	2/34 (5.9%)	2
Injury, poisoning and procedural complications
Arterial injury	1/34 (2.9%)	1
Arthropod sting	1/34 (2.9%)	1
Concussion	3/34 (8.8%)	3
Contusion	1/34 (2.9%)	1
Hand fracture	1/34 (2.9%)	1
Head injury	2/34 (5.9%)	2
Joint injury	1/34 (2.9%)	1
Ligament sprain	1/34 (2.9%)	1
Limb injury	1/34 (2.9%)	1
Muscle injury	1/34 (2.9%)	1
Procedural anxiety	1/34 (2.9%)	1
Procedural haemorrhage	1/34 (2.9%)	1
Procedural pain	4/34 (11.8%)	8
Rib fracture	1/34 (2.9%)	1
Skin abrasion	2/34 (5.9%)	2
Skin laceration	2/34 (5.9%)	2
Sports injury	1/34 (2.9%)	1
Sunburn	1/34 (2.9%)	1
Tibia fracture	1/34 (2.9%)	1
Investigations
Alanine aminotransferase abnormal	1/34 (2.9%)	1
Alanine aminotransferase increased	10/34 (29.4%)	14
Aspartate aminotransferase abnormal	1/34 (2.9%)	1
Aspartate aminotransferase increased	8/34 (23.5%)	8
Blood albumin increased	1/34 (2.9%)	1
Blood alkaline phosphatase increased	2/34 (5.9%)	2
Blood bicarbonate decreased	1/34 (2.9%)	2
Blood bilirubin increased	2/34 (5.9%)	3
Gamma-glutamyltransferase abnormal	1/34 (2.9%)	1
Gamma-glutamyltransferase increased	2/34 (5.9%)	2
Heart rate irregular	1/34 (2.9%)	1
International normalised ratio abnormal	1/34 (2.9%)	1
International normalised ratio increased	7/34 (20.6%)	9
Neutrophil count decreased	1/34 (2.9%)	1
Platelet count decreased	1/34 (2.9%)	1
Ultrasound liver abnormal	1/34 (2.9%)	1
Vitamin D decreased	2/34 (5.9%)	3
White blood cell count increased	1/34 (2.9%)	1
Metabolism and nutrition disorders
Decreased appetite	2/34 (5.9%)	2
Hypertriglyceridaemia	1/34 (2.9%)	1
Vitamin D deficiency	5/34 (14.7%)	6
Vitamin E deficiency	1/34 (2.9%)	1
Vitamin K deficiency	2/34 (5.9%)	2
Musculoskeletal and connective tissue disorders
Arthralgia	3/34 (8.8%)	3
Back pain	5/34 (14.7%)	7
Growth retardation	1/34 (2.9%)	1
Muscle spasms	1/34 (2.9%)	1
Musculoskeletal chest pain	1/34 (2.9%)	1
Musculoskeletal pain	2/34 (5.9%)	2
Myalgia	1/34 (2.9%)	1
Neck pain	1/34 (2.9%)	1
Pain in extremity	4/34 (11.8%)	9
Neoplasms benign, malignant and unspecified (incl cysts and polyps)
Hepatic adenoma	1/34 (2.9%)	1
Neoplasm skin	1/34 (2.9%)	1
Skin papilloma	2/34 (5.9%)	2
Nervous system disorders
Carotid artery stenosis	1/34 (2.9%)	1
Dizziness	1/34 (2.9%)	1
Febrile convulsion	1/34 (2.9%)	1
Headache	12/34 (35.3%)	16
Migraine	1/34 (2.9%)	1
Peripheral sensory neuropathy	1/34 (2.9%)	1
Restless legs syndrome	1/34 (2.9%)	1
Seizure	1/34 (2.9%)	1
Somnolence	1/34 (2.9%)	1
Psychiatric disorders
Anxiety	2/34 (5.9%)	2
Depression	1/34 (2.9%)	1
Insomnia	2/34 (5.9%)	2
Renal and urinary disorders
Chromaturia	1/34 (2.9%)	1
Dysuria	2/34 (5.9%)	2
Haematuria	1/34 (2.9%)	1
Proteinuria	2/34 (5.9%)	2
Renal tubular acidosis	1/34 (2.9%)	1
Respiratory, thoracic and mediastinal disorders
Adenoidal disorder	1/34 (2.9%)	1
Cough	13/34 (38.2%)	18
Dyspnoea	1/34 (2.9%)	1
Epistaxis	7/34 (20.6%)	84
Nasal congestion	6/34 (17.6%)	9
Oropharyngeal pain	9/34 (26.5%)	12
Pulmonary artery stenosis	1/34 (2.9%)	1
Respiratory disorder	1/34 (2.9%)	1
Rhinitis allergic	1/34 (2.9%)	1
Rhinorrhoea	7/34 (20.6%)	9
Sleep apnoea syndrome	1/34 (2.9%)	1
Sneezing	1/34 (2.9%)	1
Throat irritation	1/34 (2.9%)	1
Skin and subcutaneous tissue disorders
Acne	1/34 (2.9%)	1
Alopecia areata	1/34 (2.9%)	1
Erythema	2/34 (5.9%)	2
Exfoliative rash	1/34 (2.9%)	1
Ingrowing nail	1/34 (2.9%)	1
Miliaria	1/34 (2.9%)	1
Papule	1/34 (2.9%)	1
Pruritus	8/34 (23.5%)	11
Rash	7/34 (20.6%)	10
Rash erythematous	1/34 (2.9%)	1
Skin hypertrophy	1/34 (2.9%)	1
Skin hypopigmentation	1/34 (2.9%)	1
Xanthoma	1/34 (2.9%)	2
Vascular disorders
Flushing	1/34 (2.9%)	1
Hypertension	1/34 (2.9%)	1

Limitations/Caveats

Limitations of the trial such as small numbers of subjects analysed or technical problems leading to unreliable data.

More Information

Certain Agreements

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

There IS an agreement between Principal Investigators and the Sponsor (or its agents) that restricts the PI's rights to discuss or publish trial results after the trial is completed.