A Safety and Efficacy Study of a Range of Linaclotide Doses Administered Orally to Children Ages 6-17 Years Who Fulfill Modified Rome III Criteria for Child/Adolescent Functional Constipation (FC)

• Sponsor: Forest Laboratories (Industry)
• Overall Status: Completed
• CT.gov ID: NCT02559570
• Collaborator: Ironwood Pharmaceuticals, Inc. (Industry)
• Enrollment: 173
• Locations: 62
• Arms: 5
• Actual Duration (Months): 30.8
• Patients Per Site: 2.8
• Patients Per Site Per Month: 0.1

Study Details

Study Description

Brief Summary

The purpose of this study was to evaluate dose response of the safety and efficacy of linaclotide for the treatment of functional constipation (FC), in children age 6-17 years. This study includes up to a 4-week Screening Period, and a 2 to 3-week Pretreatment Period. Participants age 6-11 years will receive oral liquid formulation and participants 12-17 years will receive solid oral capsule or liquid oral solution.

Children ages 6-11 years meeting the entry criteria will be randomized to 1 of 3 doses of linaclotide or placebo for 4 weeks. Children ages 12-17 years meeting the entry criteria will be randomized to 1 of 4 doses of linaclotide or placebo for 4 weeks.

This 4-week study will assess the effects of linaclotide on bowel movement frequency, as well as other bowel symptoms of FC.

Condition or Disease	Intervention/Treatment	Phase
Functional Constipation in Children Ages 6-17 Years	Drug: Placebo; Drug: LIN Dose A; Drug: LIN Dose B; Drug: LIN Dose C; Drug: LIN 145 µg	Phase 2

Study Design

• Study Type: Interventional
• Actual Enrollment: 173 participants
• Allocation: Randomized
• Intervention Model: Parallel Assignment
• Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
• Primary Purpose: Treatment
• Official Title: A Multicenter, Randomized, Double-blind, Placebo-controlled, Parallel-group, Safety and Efficacy Study of a Range of Linaclotide Doses Administered Orally to Children, Ages 6 to 17 Years, Who Fulfill Modified Rome III Criteria for Child/Adolescent Functional Constipation (FC)
• Actual Study Start Date: Nov 3, 2015
• Actual Primary Completion Date: Apr 20, 2018
• Actual Study Completion Date: May 29, 2018

Arms and Interventions

Arm	Intervention/Treatment
Placebo Comparator: Placebo Participants aged 6 to 11 or 12 to 17 years received matching placebo linaclotide (LIN), 30 minutes before evening meal, once daily for 4 weeks. Administered as liquid oral solution for participants 6 to 11 years of age and solid oral capsule or liquid oral solution for participants 12 to 17 years of age.	Drug: Placebo; Participants received matching placebo LIN liquid solution or solid capsules, orally, 30 minutes before evening meal, once daily for 4 weeks.
Experimental: LIN Dose A (9 ug or 18 ug) Participants aged 6 to 11 years with weight 18 to <35 kg received LIN 9 ug, oral solution, 30 minutes before evening meal, once daily for 4 weeks. Participants aged 6 to 11 years with weight ≥35 kg received LIN 18 ug, oral solution, 30 minutes before evening meal, once daily for 4 weeks. Participants aged 12 to 17 years received LIN 18 ug, oral solution or solid capsules, 30 minutes before evening meal, once daily for 4 weeks.	Drug: LIN Dose A; Participants received LIN 9 or 18 ug liquid solution or solid capsules, orally, 30 minutes before evening meal, once daily for 4 weeks.; Other Names: LINZESS
Experimental: LIN Dose B (18 ug or 36 ug) Participants aged 6 to 11 years with weight 18 to <35 kg received LIN 18 ug, oral solution, 30 minutes before evening meal, once daily for 4 weeks. Participants aged 6 to 11 years with weight ≥35 kg received LIN 36 ug, oral solution, 30 minutes before evening meal, once daily for 4 weeks. Participants aged 12 to 17 years received LIN 36 ug, oral solution or solid capsules, 30 minutes before evening meal, once daily for 4 weeks.	Drug: LIN Dose B; Participants received LIN 18 or 36 ug liquid solution or solid capsules, orally, 30 minutes before evening meal, once daily for 4 weeks.; Other Names: LINZESS
Experimental: LIN Dose C (36 ug or 72 ug) Participants aged 6 to 11 years with weight 18 to <35 kg received LIN 36 ug, oral solution, 30 minutes before evening meal, once daily for 4 weeks. Participants aged 6 to 11 years with weight ≥35 kg received LIN 72 ug, oral solution, 30 minutes before evening meal, once daily for 4 weeks. Participants aged 12 to 17 years received LIN 72 ug, oral solution or solid capsules, 30 minutes before evening meal, once daily for 4 weeks.	Drug: LIN Dose C; Participants received LIN 36 or 72 ug liquid solution or solid capsules, orally, 30 minutes before evening meal, once daily for 4 weeks.; Other Names: LINZESS
Experimental: LIN 145 µg Participants aged 12 to 17 years received LIN 145 ug, oral solution or solid capsules, 30 minutes before evening meal, once daily for 4 weeks.	Drug: LIN 145 µg; Participants received LIN 145 µg, liquid solution or solid capsules, 30 minutes before evening meal, once daily for 4 weeks.; Other Names: LINZESS

Outcome Measures

Primary Outcome Measures

1. Change From Baseline (CFB) in 4-week Overall Spontaneous Bowel Movement (SBM) Frequency Rate During the Treatment Period [Baseline (14-day prior to randomization and up to randomization) to Week 4]

   SBM was defined as a BM that occurred in the absence of laxative, suppository, or enema use on the calendar day of the BM or the calendar day before the BM. SBM rate was defined as SBMs/week during the 4-week Treatment period. Participants recorded the occurrence of BMs and use of rescue medication, morning and evening, daily in an eDiary since pretreatment period. The SBM frequency rate (SBMs/week) during the analysis period for each participant were calculated as [(total number of SBMs in the analysis period/number of days in the analysis period)*7]. Baseline value was based on values collected 14 days before randomization up to randomization. Change from Baseline was calculated as the SBM frequency rate during the 4-week treatment period - SBM frequency rate at baseline. A positive change from Baseline indicates improvement. Least squares mean (LSM) and standard error (SE) were calculated using analysis of covariance (ANCOVA) method.

Secondary Outcome Measures

1. Change From Baseline (CFB) in 4-week Daytime Abdominal Pain [Baseline (14-day prior to randomization) to Week 4]

   The abdominal pain score was measured using 5-point scale. Participants answered the questions, How much did your tummy hurt as: 0=none, 1=a tiny bit, 2=a little, 3=some, and 4=a lot. The 4-week daytime abdominal pain was calculated as the average of nonmissing scores in evening eDiary during the Treatment Period with higher value indicating greater symptom severity. Baseline value was the average of non-missing values collected 14 days before randomization. Change from Baseline was calculated as the daytime abdominal pain score during the 4-week treatment period (i.e. average of non-missing daytime scores during 4-week treatment period) - daytime abdominal pain score at baseline. A negative change from Baseline indicates improvement. LSM and SE were calculated using ANCOVA method.

2. Change From Baseline (CFB) in 4-week Stool Consistency [Baseline (14-day prior to randomization and up to randomization) to Week 4]

   Participants used 7-point pediatric Bristol Stool Form (p-BSFS) scale to rate stool consistency for each BM in morning and evening eDiary where 1=small hard lumps or balls like pebbles,2=fat sausage shape but lumpy and hard,3=a sausage but with cracks on it,4=sausage or snake, smooth and soft,5=chicken nuggets, soft smooth blobs,6=oatmeal, fluffy mushy pieces,7=milkshake, watery. Scores in 4-week treatment period were calculated by 2 approaches-1) following derivation similar in earlier adult studies, mean of participants non-missing, SBM associated p-BSFS scores during 4-week treatment period (adult derivation),2) observed weighted average of daily p-BSFS scores during that period. Daily p-BSFS score was average of non-missing morning and/or evening assessments of p-BSFS score from SBMs reported by participants on that specific day. Baseline value was based on values collected 14 days before randomization up to randomization. LSM and SE were calculated using ANCOVA method.

3. Change From Baseline (CFB) in 4-week of Severity of Straining [Baseline (14-day prior to randomization and up to randomization) to Week 4]

   Severity of straining was scored on 5-point scale for question-When you pooped, how hard did you push? The score ranges from 0= not hard at all,1= I pushed a tiny bit hard,2= I pushed a little hard,3= I pushed hard,4= I pushed very hard with higher scores indicating more severe straining. Participants recorded degree of straining for each BM in morning and evening eDiary. Data was derived as adult derivation and weighted average. Scores during 4-week treatment period were calculated following two approaches - (1) following derivation similar in earlier adult studies, as mean of participant's non-missing, SBM associated straining scores during 4-week treatment period (adult derivation) and (2) as observed weighted average of daily straining scores during that period. Daily straining score was the average of non-missing morning and/or evening assessments of straining score from the SBMs reported by the participants on that specific day. LSM and SE were calculated using ANCOVA method.

4. Change From Baseline (CFB) in 4-week Abdominal Bloating Daytime Symptoms Based on Evening Assessment [Baseline (14-day prior to randomization) to Week 4]

   Participants recorded their assessment of abdominal bloating in the evening eDiary. Participants answered the question: How big and full did your tummy feel? on a scale, where: 0=none, 1=a tiny bit, 2=a little, 3=medium or 4=very, with a higher score indicating more severe bloating. Baseline value was the average of values collected 14 days before randomization. The 4-week daytime abdominal bloating symptoms were calculated as the average of non-missing scores reported in the evening eDiary during the treatment period. Change from Baseline was calculated as the 4-week daytime abdominal bloating score during the treatment period - daytime abdominal bloating score at baseline. A negative change from Baseline indicates improvement. LSM and SE were calculated using ANCOVA method.

5. Change From Baseline (CFB) in 4-week Overall Complete Spontaneous Bowel Movement Frequency Rate (CSBM/Week) During the Treatment Period [Baseline (14-day prior to randomization and up to randomization) to Week 4]

   SBM was defined as a BM that occurred in the absence of laxative, suppository, or enema use on the calendar day of the BM or the calendar day before the BM. A CSBM was an SBM that was associated with a sense of complete evacuation. Participants recorded their assessment of the sensation of incomplete evacuation for each BM in the morning and evening eDiary. The 4-week overall CSBM frequency rate was calculated as [total number of CSBMs in the analysis period/number of days in the analysis period]*7). Baseline value was based on values collected 14 days before randomization and up to randomization. Change from Baseline was calculated as the CSBM frequency rate during the 4-week treatment period - CSBM frequency rate at baseline. A positive change from Baseline indicates improvement. LSM and SE were calculated using ANCOVA method.

6. Change From Baseline in 4-week Fecal Incontinence Daytime Symptoms Based on Evening Assessment [Baseline (14-day prior to randomization) to Week 4]

   Participants recorded the presence of incontinence episodes in daytime daily since pre-treatment period (14-day prior to randomization) in the evening eDiary for participants randomized following protocol amendment #3. The 4-week daytime fecal incontinence was calculated as the mean of non-missing participant scores reported in the evening eDiary during the Treatment Period. Baseline value was the average of values collected 14 days before randomization. Change from Baseline was calculated as the 4-week fecal incontinence daytime symptoms during the treatment period - fecal incontinence daytime symptoms at baseline. A negative change from Baseline indicates improvement. No data is reported for LIN 145 μg as it was an exploratory arm group.

Eligibility Criteria

Criteria

• Ages Eligible for Study: 6 Years to 17 Years
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

Inclusion Criteria:

• Participant weighs at least 18 kg (kilograms) (39.7 lbs)

• Participant meets modified Rome III criteria for child/adolescent FC: For at least 2 months before the Screening Visit, the participant has had 2 or fewer defecations (with each defecation occurring in the absence of any laxative, suppository, or enema use during the preceding 24 hours) in the toilet per week. In addition, at least once per week, patient meets 1 or more of the following:

• 1. History of retentive posturing or excessive volitional stool retention
• 1. History of painful or hard bowel movements (BMs)
• 1. Presence of a large faecal mass in the rectum
• 1. History of large diameter stools that may obstruct the toilet
• 1. At least one episode of fecal incontinence per week

• Participant is willing to discontinue any laxatives used before the Pretreatment Visit in favor of the protocol-permitted rescue medicine

• Participant has an average of fewer than 3 spontaneous BMs (SBMs) per week during the 14 days before the randomization day and up to the randomization. An SBM is defined as a BM that occurs in the absence of laxative, enema, or suppository use on the calendar day of the BM or the calendar day before the BM

• Participant or participant/guardian/legally authorized representative (LAR) or caregiver is compliant with electronic diary (eDiary) by completing both the morning and evening assessments for 10 out of the 14 days immediately preceding the Randomization Visit

Exclusion Criteria:

• Participant meets Rome III criteria for Child/Adolescent irritable bowel syndrome (IBS): At least once per week for at least 2 months before the Screening Visit, the participant has experienced abdominal discomfort (an uncomfortable sensation not described as pain) or pain associated with 2 or more of the following at least 25% of the time:

• 1. Improvement with defecation
• 1. Onset associated with a change in frequency of stool
• 1. Onset associated with a change in form (appearance) of stool

• Participant reports having more than 1 loose, mushy stool (eDiary-recorded stool consistency of 6 on the Pediatric Bristol Stool Form Scale [p-BSFS]) or any watery stool (eDiary-recorded stool consistency of 7 on the p-BSFS) with any SBM that occurred in the absence of laxative use on the calendar day of the BM or the calendar day before the BM during the 14 days before the randomization day and up to the randomization

• Select medical history or conditions that may be related to other causes of constipation or may interfere with safety and efficacy analyses

• Participant has required manual or hospital-based disimpassion any time prior to randomization

• Participant is unable to tolerate the placebo during the Screening Period

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	HealthStar Research, LLC	Hot Springs	Arkansas	United States	71913
2	Applied Research Center of Arkansas	Little Rock	Arkansas	United States	72212
3	Advanced Research Center	Anaheim	California	United States	92805
4	Kindred Medical Institute for Clinical Trials, LLC	Corona	California	United States	92879
5	WCCT Global, LLC	Costa Mesa	California	United States	92626
6	Ark Clinical Research	Long Beach	California	United States	90806
7	ACTCA, Inc	Los Angeles	California	United States	90017
8	Children's Hospital Los Angeles	Los Angeles	California	United States	90017
9	Orange County Research Institute	Ontario	California	United States	91762
10	Center for Clinical Trials, LLC	Paramount	California	United States	90723
11	UCSD Rady Children's Hospital	San Diego	California	United States	92123
12	University of California at San Francisco	San Francisco	California	United States	94143
13	Ventura Clinical Trials	Ventura	California	United States	93003
14	Colorado Springs Health Partners, HCP-Clinical Research, LLC	Colorado Springs	Colorado	United States	80922
15	Nova Southeastern University	Fort Lauderdale	Florida	United States	33314
16	Homestead Research Institute	Homestead	Florida	United States	33030
17	RM Medical Research	Homestead	Florida	United States	33030
18	Advanced Medical Research Center	Miami	Florida	United States	33135
19	SCORE Physician Alliance, LLC	Saint Petersburg	Florida	United States	33710
20	Children's Center for Digestive Health Care LLC	Atlanta	Georgia	United States	30342
21	Sleepcare Clinical Research Institute	Stockbridge	Georgia	United States	30281
22	Riley Hospital for Children at Indiana University Health	Indianapolis	Indiana	United States	46202
23	Heartland Research Associates, LLC	Wichita	Kansas	United States	67205
24	Kentucky Pediatric/ Adult Research	Bardstown	Kentucky	United States	40004
25	Kosair Children's Hospital - Pediatric Clinical Research Unit	Louisville	Kentucky	United States	40202
26	Michael W. Simon, MD, PSC	Nicholasville	Kentucky	United States	40356
27	Willis-Knighton Physician Network	Shreveport	Louisiana	United States	71118
28	University of Maryland Children's Hospital	Baltimore	Maryland	United States	21201
29	Massachusetts General Hospital	Boston	Massachusetts	United States	02114
30	University Of Minnesota	Minneapolis	Minnesota	United States	55455
31	GI Associates and Endoscopy Center	Jackson	Mississippi	United States	39232
32	Craig A. Speigel, MD	Bridgeton	Missouri	United States	63044
33	Midwest Children Health Research Institute	Lincoln	Nebraska	United States	68505
34	Midwest Children Health Research Institute	Lincoln	Nebraska	United States	68516
35	Goryeb Children's Hospital	Morristown	New Jersey	United States	07962
36	Columbia University Medical Center and Morgan Stanley	New York	New York	United States	10032
37	Asheboro Research Associates	Asheboro	North Carolina	United States	27203
38	University of North Carolina at Chapel Hill	Chapel Hill	North Carolina	United States	27599
39	Capital Pediatrics and Adolescent Center PLLC	Raleigh	North Carolina	United States	27609
40	Ohio Pediatric Research Association	Dayton	Ohio	United States	45414
41	IPS Research Company	Oklahoma City	Oklahoma	United States	73103
42	Pediatric Care Specialists	Johnstown	Pennsylvania	United States	15904
43	St. Christopher's Hospital for Children	Philadelphia	Pennsylvania	United States	19134
44	Children's Hospital of Pittsburgh of UPMC	Pittsburgh	Pennsylvania	United States	15224
45	Preferred Primary Care Physicians, Inc.	Pittsburgh	Pennsylvania	United States	15236
46	Frontier Clinical Research, LLC	Scottdale	Pennsylvania	United States	15683
47	Montgomery Medical Inc.	Smithfield	Pennsylvania	United States	15478
48	Rhode Island Hospital	Providence	Rhode Island	United States	02903
49	Coastal Pediatric Research	Charleston	South Carolina	United States	29414
50	Coastal Pediatrics Associates	Mount Pleasant	South Carolina	United States	29464
51	Cook Children's Medical Center	Fort Worth	Texas	United States	76104
52	Texas Children's Hospital/Baylor College Medicine	Houston	Texas	United States	77030
53	Houston Clinical Research Associates	Houston	Texas	United States	77090
54	Sun Research Institute	San Antonio	Texas	United States	78215
55	Southwest Children's Research Associates, P.A.	San Antonio	Texas	United States	78229
56	ClinPoint Trials	Waxahachie	Texas	United States	75165
57	Foothill Family Clinic South / J. Lewis Research, Inc.	Salt Lake City	Utah	United States	84121
58	Pediatric Specialists of Virginia	Fairfax	Virginia	United States	22031
59	Virginia Tech Carilion School of Medicine Pediatric	Roanoke	Virginia	United States	24013
60	Seattle Children's Hospital	Seattle	Washington	United States	98105
61	Stollery Children's Hospital	Edmonton	Alberta	Canada	T6G 2B7
62	Children's Hospital of Western Ontario	London	Ontario	Canada	N6A 4G5

Sponsors and Collaborators

• Forest Laboratories
• Ironwood Pharmaceuticals, Inc.

Investigators

• Study Director: Taryn Weissman, Allergan, LLC

Study Documents (Full-Text)

• Study Protocol - May 16, 2017
• Statistical Analysis Plan - Jun 28, 2018

More Information

Publications

None provided.

• Responsible Party: Forest Laboratories
• ClinicalTrials.gov Identifier: NCT02559570
• Other Study ID Numbers: LIN-MD-62
• First Posted: Sep 24, 2015
• Last Update Posted: Jun 19, 2019
• Last Verified: Jun 1, 2019

• Studies a U.S. FDA-regulated Drug Product: Yes
• Studies a U.S. FDA-regulated Device Product: No
• Keywords provided by Forest Laboratories: Functional constipation in children; LINZESS
• Additional relevant MeSH terms: Constipation; Linaclotide

Study Results

Participant Flow

Pre-assignment Detail	Pediatric participants aged 6 to 11 years were dosed using a weight-based approach. For participants who weighed <35 kg, the doses administered corresponded to about 0.25 to 0.5, 0.5 to 1, or 1 to 2 µg/kg. For participants who weighed ≥35 kg, the doses were not to exceed 0.5, 1, or 2 µg/kg.

Arm/Group Title	Placebo	LIN Dose A (9 ug or 18 ug)	LIN Dose B (18 ug or 36 ug)	LIN Dose C (36 ug or 72 ug)	LIN 145 µg
Arm/Group Description	Participants aged 6 to 11 or 12 to 17 years received matching placebo linaclotide (LIN), 30 minutes before evening meal, once daily for 4 weeks. Administered as liquid oral solution for participants 6 to 11 years of age and solid oral capsule or liquid oral solution for participants 12 to 17 years of age.	Participants aged 6 to 11 years with weight 18 to <35 kg received LIN 9 ug, oral solution, 30 minutes before evening meal, once daily for 4 weeks. Participants aged 6 to 11 years with weight ≥35 kg received LIN 18 ug, oral solution, 30 minutes before evening meal, once daily for 4 weeks. Participants aged 12 to 17 years received LIN 18 ug, oral solution or solid capsules, 30 minutes before evening meal, once daily for 4 weeks	Participants aged 6 to 11 years with weight 18 to <35 kg received LIN 18 ug, oral solution, 30 minutes before evening meal, once daily for 4 weeks. Participants aged 6 to 11 years with weight ≥35 kg received LIN 36 ug, oral solution, 30 minutes before evening meal, once daily for 4 weeks. Participants aged 12 to 17 years received LIN 36 ug, oral solution or solid capsules, 30 minutes before evening meal, once daily for 4 weeks.	Participants aged 6 to 11 years with weight 18 to <35 kg received LIN 36 ug, oral solution, 30 minutes before evening meal, once daily for 4 weeks. Participants aged 6 to 11 years with weight ≥35 kg received LIN 72 ug, oral solution, 30 minutes before evening meal, once daily for 4 weeks. Participants aged 12 to 17 years received LIN 72 ug, oral solution or solid capsules, 30 minutes before evening meal, once daily for 4 weeks.	Participants aged 12 to 17 years received LIN 145 ug, oral solution or solid capsules, 30 minutes before evening meal, once daily for 4 weeks.
Period Title: Overall Study
STARTED	41	36	41	39	16
COMPLETED	39	34	39	36	14
NOT COMPLETED	2	2	2	3	2

Baseline Characteristics

Arm/Group Title	Placebo	LIN Dose A (9 ug or 18 ug)	LIN Dose B (18 ug or 36 ug)	LIN Dose C (36 ug or 72 ug)	LIN 145 µg	Total
Arm/Group Description	Participants aged 6 to 11 or 12 to 17 years received matching placebo linaclotide (LIN), 30 minutes before evening meal, once daily for 4 weeks. Administered as liquid oral solution for participants 6 to 11 years of age and solid oral capsule or liquid oral solution for participants 12 to 17 years of age.	Participants aged 6 to 11 years with weight 18 to <35 kg received LIN 9 ug, oral solution, 30 minutes before evening meal, once daily for 4 weeks. Participants aged 6 to 11 years with weight ≥35 kg received LIN 18 ug, oral solution, 30 minutes before evening meal, once daily for 4 weeks. Participants aged 12 to 17 years received LIN 18 ug, oral solution or solid capsules, 30 minutes before evening meal, once daily for 4 weeks	Participants aged 6 to 11 years with weight 18 to <35 kg received LIN 18 ug, oral solution, 30 minutes before evening meal, once daily for 4 weeks. Participants aged 6 to 11 years with weight ≥35 kg received LIN 36 ug, oral solution, 30 minutes before evening meal, once daily for 4 weeks. Participants aged 12 to 17 years received LIN 36 ug, oral solution or solid capsules, 30 minutes before evening meal, once daily for 4 weeks.	Participants aged 6 to 11 years with weight 18 to <35 kg received LIN 36 ug, oral solution, 30 minutes before evening meal, once daily for 4 weeks. Participants aged 6 to 11 years with weight ≥35 kg received LIN 72 ug, oral solution, 30 minutes before evening meal, once daily for 4 weeks. Participants aged 12 to 17 years received LIN 72 ug, oral solution or solid capsules, 30 minutes before evening meal, once daily for 4 weeks.	Participants aged 12 to 17 years received LIN 145 ug, oral solution or solid capsules, 30 minutes before evening meal, once daily for 4 weeks.	Total of all reporting groups
Overall Participants	41	36	41	39	16	173
Age (years) [Mean (Full Range) ]
Mean (Full Range) [years]	10.7	10.9	11.0	11.3	14.7	11.3
Sex: Female, Male (Count of Participants)
Female	20 48.8%	17 47.2%	25 61%	23 59%	8 50%	93 53.8%
Male	21 51.2%	19 52.8%	16 39%	16 41%	8 50%	80 46.2%
Race/Ethnicity, Customized (Count of Participants)
White	30 73.2%	29 80.6%	32 78%	29 74.4%	11 68.8%	131 75.7%
Black or African American	10 24.4%	7 19.4%	9 22%	8 20.5%	4 25%	38 22%
Asian	0 0%	0 0%	0 0%	0 0%	1 6.3%	1 0.6%
American Indian or Alaska Native	0 0%	0 0%	0 0%	1 2.6%	0 0%	1 0.6%
Multiple	1 2.4%	0 0%	0 0%	1 2.6%	0 0%	2 1.2%
Race/Ethnicity, Customized (Count of Participants)
Hispanic or Latino	8 19.5%	7 19.4%	12 29.3%	9 23.1%	4 25%	40 23.1%
Not Hispanic or Latino	33 80.5%	29 80.6%	29 70.7%	30 76.9%	12 75%	133 76.9%
Spontaneous Bowel Movement (SBM) Frequency Rate (SBMs/week) [Mean (Full Range) ]
Mean (Full Range) [SBMs/week]	1.248	1.462	1.307	1.324	1.810	1.376

Outcome Measures

1. Secondary Outcome

Title	Change From Baseline (CFB) in 4-week Daytime Abdominal Pain
Description	The abdominal pain score was measured using 5-point scale. Participants answered the questions, How much did your tummy hurt as: 0=none, 1=a tiny bit, 2=a little, 3=some, and 4=a lot. The 4-week daytime abdominal pain was calculated as the average of nonmissing scores in evening eDiary during the Treatment Period with higher value indicating greater symptom severity. Baseline value was the average of non-missing values collected 14 days before randomization. Change from Baseline was calculated as the daytime abdominal pain score during the 4-week treatment period (i.e. average of non-missing daytime scores during 4-week treatment period) - daytime abdominal pain score at baseline. A negative change from Baseline indicates improvement. LSM and SE were calculated using ANCOVA method.
Time Frame	Baseline (14-day prior to randomization) to Week 4

Outcome Measure Data

Analysis Population Description

ITT population, all participants who had at least 1 postbaseline entry on BM characteristic assessments that determined occurrences of SBMs (i.e. BM frequency and rescue medication use). No data is reported for LIN 145 μg as it was an exploratory arm group. An observed-cases approach to missing postbaseline data was applied.

Arm/Group Title	Placebo	LIN Dose A (9 ug or 18 ug)	LIN Dose B (18 ug or 36 ug)	LIN Dose C (36 ug or 72 ug)
Arm/Group Description	Participants aged 6 to 11 or 12 to 17 years received matching placebo linaclotide (LIN), 30 minutes before evening meal, once daily for 4 weeks. Administered as liquid oral solution for participants 6 to 11 years of age and solid oral capsule or liquid oral solution for participants 12 to 17 years of age.	Participants aged 6 to 11 years with weight 18 to <35 kg received LIN 9 ug, oral solution, 30 minutes before evening meal, once daily for 4 weeks. Participants aged 6 to 11 years with weight ≥35 kg received LIN 18 ug, oral solution, 30 minutes before evening meal, once daily for 4 weeks. Participants aged 12 to 17 years received LIN 18 ug, oral solution or solid capsules, 30 minutes before evening meal, once daily for 4 weeks	Participants aged 6 to 11 years with weight 18 to <35 kg received LIN 18 ug, oral solution, 30 minutes before evening meal, once daily for 4 weeks. Participants aged 6 to 11 years with weight ≥35 kg received LIN 36 ug, oral solution, 30 minutes before evening meal, once daily for 4 weeks. Participants aged 12 to 17 years received LIN 36 ug, oral solution or solid capsules, 30 minutes before evening meal, once daily for 4 weeks.	Participants aged 6 to 11 years with weight 18 to <35 kg received LIN 36 ug, oral solution, 30 minutes before evening meal, once daily for 4 weeks. Participants aged 6 to 11 years with weight ≥35 kg received LIN 72 ug, oral solution, 30 minutes before evening meal, once daily for 4 weeks. Participants aged 12 to 17 years received LIN 72 ug, oral solution or solid capsules, 30 minutes before evening meal, once daily for 4 weeks.
Measure Participants	41	36	41	39
Least Squares Mean (Standard Error) [score on a scale]	-0.291 (0.102)	-0.333 (0.108)	-0.289 (0.102)	-0.171 (0.103)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Placebo, LIN Dose A (9 ug or 18 ug)
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.7789
	Comments
	Method	ANCOVA
	Comments	ANCOVA model estimates/t-tests comparing specified treatment groups, controlling for age group and baseline value.
Method of Estimation	Estimation Parameter	Least Squares Mean Difference
	Estimated Value	-0.042
	Confidence Interval	(2-Sided) 95%; -0.335 to 0.252
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 0.149
	Estimation Comments	ANCOVA model was applied with treatment arm groups (linaclotide doses A, B, and C, and placebo) and age group (6 to 11 years of age and 12 to 17 years of age) as factors and baseline value as covariate.

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Placebo, LIN Dose B (18 ug or 36 ug)
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.9930
	Comments
	Method	ANCOVA
	Comments	ANCOVA model estimates/t-tests comparing specified treatment groups, controlling for age group and baseline value.
Method of Estimation	Estimation Parameter	Least Squares Mean Difference
	Estimated Value	0.001
	Confidence Interval	(2-Sided) 95%; -0.282 to 0.284
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 0.143
	Estimation Comments	ANCOVA model was applied with treatment arm groups (linaclotide doses A, B, and C, and placebo) and age group (6 to 11 years of age and 12 to 17 years of age) as factors and baseline value as covariate.

Statistical Analysis 3

Statistical Analysis Overview	Comparison Group Selection	Placebo, LIN Dose C (36 ug or 72 ug)
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.4107
	Comments
	Method	ANCOVA
	Comments	ANCOVA model estimates/t-tests comparing specified treatment groups, controlling for age group and baseline value.
Method of Estimation	Estimation Parameter	Least Squares Mean Difference
	Estimated Value	0.120
	Confidence Interval	(2-Sided) 95%; -0.167 to 0.408
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 0.146
	Estimation Comments	ANCOVA model was applied with treatment arm groups (linaclotide doses A, B, and C, and placebo) and age group (6 to 11 years of age and 12 to 17 years of age) as factors and baseline value as covariate.

2. Primary Outcome

Title	Change From Baseline (CFB) in 4-week Overall Spontaneous Bowel Movement (SBM) Frequency Rate During the Treatment Period
Description	SBM was defined as a BM that occurred in the absence of laxative, suppository, or enema use on the calendar day of the BM or the calendar day before the BM. SBM rate was defined as SBMs/week during the 4-week Treatment period. Participants recorded the occurrence of BMs and use of rescue medication, morning and evening, daily in an eDiary since pretreatment period. The SBM frequency rate (SBMs/week) during the analysis period for each participant were calculated as [(total number of SBMs in the analysis period/number of days in the analysis period)*7]. Baseline value was based on values collected 14 days before randomization up to randomization. Change from Baseline was calculated as the SBM frequency rate during the 4-week treatment period - SBM frequency rate at baseline. A positive change from Baseline indicates improvement. Least squares mean (LSM) and standard error (SE) were calculated using analysis of covariance (ANCOVA) method.
Time Frame	Baseline (14-day prior to randomization and up to randomization) to Week 4

Outcome Measure Data

Analysis Population Description

ITT population, all participants who had at least 1 postbaseline entry on BM characteristic assessments that determined occurrences of SBMs (i.e. BM frequency and rescue medication use). No data is reported for LIN 145 μg as it was an exploratory arm group. An observed-cases approach to missing postbaseline data was applied.

Arm/Group Title	Placebo	LIN Dose A (9 ug or 18 ug)	LIN Dose B (18 ug or 36 ug)	LIN Dose C (36 ug or 72 ug)
Arm/Group Description	Participants aged 6 to 11 or 12 to 17 years received matching placebo linaclotide (LIN), 30 minutes before evening meal, once daily for 4 weeks. Administered as liquid oral solution for participants 6 to 11 years of age and solid oral capsule or liquid oral solution for participants 12 to 17 years of age.	Participants aged 6 to 11 years with weight 18 to <35 kg received LIN 9 ug, oral solution, 30 minutes before evening meal, once daily for 4 weeks. Participants aged 6 to 11 years with weight ≥35 kg received LIN 18 ug, oral solution, 30 minutes before evening meal, once daily for 4 weeks. Participants aged 12 to 17 years received LIN 18 ug, oral solution or solid capsules, 30 minutes before evening meal, once daily for 4 weeks	Participants aged 6 to 11 years with weight 18 to <35 kg received LIN 18 ug, oral solution, 30 minutes before evening meal, once daily for 4 weeks. Participants aged 6 to 11 years with weight ≥35 kg received LIN 36 ug, oral solution, 30 minutes before evening meal, once daily for 4 weeks. Participants aged 12 to 17 years received LIN 36 ug, oral solution or solid capsules, 30 minutes before evening meal, once daily for 4 weeks.	Participants aged 6 to 11 years with weight 18 to <35 kg received LIN 36 ug, oral solution, 30 minutes before evening meal, once daily for 4 weeks. Participants aged 6 to 11 years with weight ≥35 kg received LIN 72 ug, oral solution, 30 minutes before evening meal, once daily for 4 weeks. Participants aged 12 to 17 years received LIN 72 ug, oral solution or solid capsules, 30 minutes before evening meal, once daily for 4 weeks.
Measure Participants	41	36	41	39
Least Squares Mean (Standard Error) [SBMs/week]	2.000 (0.394)	1.412 (0.422)	1.814 (0.397)	2.364 (0.403)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Placebo, LIN Dose A (9 ug or 18 ug)
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.3097
	Comments
	Method	ANCOVA
	Comments	ANCOVA model estimates/t-tests comparing specified treatment groups, controlling for age group and baseline value.
Method of Estimation	Estimation Parameter	Least Squares Mean Difference
	Estimated Value	-0.588
	Confidence Interval	(2-Sided) 95%; -1.729 to 0.552
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 0.577
	Estimation Comments	ANCOVA model was applied with treatment arm groups (linaclotide doses A, B, and C, and placebo) and age group (6 to 11 years of age and 12 to 17 years of age) as factors and baseline value as covariate.

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Placebo, LIN Dose B (18 ug or 36 ug)
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.7384
	Comments
	Method	ANCOVA
	Comments	ANCOVA model estimates/t-tests comparing specified treatment groups, controlling for age group and baseline value.
Method of Estimation	Estimation Parameter	Least Squares Mean Difference
	Estimated Value	-0.186
	Confidence Interval	(2-Sided) 95%; -1.286 to 0.913
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 0.557
	Estimation Comments	ANCOVA model was applied with treatment arm groups (linaclotide doses A, B, and C, and placebo) and age group (6 to 11 years of age and 12 to 17 years of age) as factors and baseline value as covariate.

Statistical Analysis 3

Statistical Analysis Overview	Comparison Group Selection	Placebo, LIN Dose C (36 ug or 72 ug)
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.5188
	Comments
	Method	ANCOVA
	Comments	ANCOVA model estimates/t-tests comparing specified treatment groups, controlling for age group and baseline value.
Method of Estimation	Estimation Parameter	Least Squares Mean Difference
	Estimated Value	0.364
	Confidence Interval	(2-Sided) 95%; -0.748 to 1.477
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 0.563
	Estimation Comments	ANCOVA model was applied with treatment arm groups (linaclotide doses A, B, and C, and placebo) and age group (6 to 11 years of age and 12 to 17 years of age) as factors and baseline value as covariate.

3. Secondary Outcome

Title	Change From Baseline (CFB) in 4-week Stool Consistency
Description	Participants used 7-point pediatric Bristol Stool Form (p-BSFS) scale to rate stool consistency for each BM in morning and evening eDiary where 1=small hard lumps or balls like pebbles,2=fat sausage shape but lumpy and hard,3=a sausage but with cracks on it,4=sausage or snake, smooth and soft,5=chicken nuggets, soft smooth blobs,6=oatmeal, fluffy mushy pieces,7=milkshake, watery. Scores in 4-week treatment period were calculated by 2 approaches-1) following derivation similar in earlier adult studies, mean of participants non-missing, SBM associated p-BSFS scores during 4-week treatment period (adult derivation),2) observed weighted average of daily p-BSFS scores during that period. Daily p-BSFS score was average of non-missing morning and/or evening assessments of p-BSFS score from SBMs reported by participants on that specific day. Baseline value was based on values collected 14 days before randomization up to randomization. LSM and SE were calculated using ANCOVA method.
Time Frame	Baseline (14-day prior to randomization and up to randomization) to Week 4

Outcome Measure Data

Analysis Population Description

ITT population-participants who had at least 1 postbaseline entry on BM characteristic that determined occurrences of SBMs (BM frequency and rescue medication use). No data is reported for LIN 145 μg as it was exploratory arm group. Observed-cases approach used. Overall number of participants analyzed = who had data at Baseline and post-baseline.

Arm/Group Title	Placebo	LIN Dose A (9 ug or 18 ug)	LIN Dose B (18 ug or 36 ug)	LIN Dose C (36 ug or 72 ug)
Arm/Group Description	Participants aged 6 to 11 or 12 to 17 years received matching placebo linaclotide (LIN), 30 minutes before evening meal, once daily for 4 weeks. Administered as liquid oral solution for participants 6 to 11 years of age and solid oral capsule or liquid oral solution for participants 12 to 17 years of age.	Participants aged 6 to 11 years with weight 18 to <35 kg received LIN 9 ug, oral solution, 30 minutes before evening meal, once daily for 4 weeks. Participants aged 6 to 11 years with weight ≥35 kg received LIN 18 ug, oral solution, 30 minutes before evening meal, once daily for 4 weeks. Participants aged 12 to 17 years received LIN 18 ug, oral solution or solid capsules, 30 minutes before evening meal, once daily for 4 weeks	Participants aged 6 to 11 years with weight 18 to <35 kg received LIN 18 ug, oral solution, 30 minutes before evening meal, once daily for 4 weeks. Participants aged 6 to 11 years with weight ≥35 kg received LIN 36 ug, oral solution, 30 minutes before evening meal, once daily for 4 weeks. Participants aged 12 to 17 years received LIN 36 ug, oral solution or solid capsules, 30 minutes before evening meal, once daily for 4 weeks.	Participants aged 6 to 11 years with weight 18 to <35 kg received LIN 36 ug, oral solution, 30 minutes before evening meal, once daily for 4 weeks. Participants aged 6 to 11 years with weight ≥35 kg received LIN 72 ug, oral solution, 30 minutes before evening meal, once daily for 4 weeks. Participants aged 12 to 17 years received LIN 72 ug, oral solution or solid capsules, 30 minutes before evening meal, once daily for 4 weeks.
Measure Participants	34	32	34	34
CFB at Week 4 (Adult derivation)	0.690 (0.174)	0.641 (0.177)	0.652 (0.174)	1.046 (0.172)
CFB at Week 4 (Weighted average)	0.668 (0.167)	0.606 (0.170)	0.594 (0.166)	0.930 (0.165)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Placebo, LIN Dose A (9 ug or 18 ug)
	Comments	Adult derivation
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.8426
	Comments
	Method	ANCOVA
	Comments	ANCOVA model estimates/t-tests comparing specified treatment groups, controlling for age group and baseline value.
Method of Estimation	Estimation Parameter	Least Squares Mean Difference
	Estimated Value	-0.050
	Confidence Interval	(2-Sided) 95%; -0.543 to 0.444
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 0.249
	Estimation Comments	ANCOVA model was applied with treatment arm groups (linaclotide doses A, B, and C, and placebo) and age group (6 to 11 years of age and 12 to 17 years of age) as factors and baseline value as covariate.

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Placebo, LIN Dose B (18 ug or 36 ug)
	Comments	Adult derivation
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.8770
	Comments
	Method	ANCOVA
	Comments	ANCOVA model estimates/t-tests comparing specified treatment groups, controlling for age group and baseline value.
Method of Estimation	Estimation Parameter	Least Squares Mean Difference
	Estimated Value	-0.038
	Confidence Interval	(2-Sided) 95%; -0.525 to 0.448
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 0.246
	Estimation Comments	ANCOVA model was applied with treatment arm groups (linaclotide doses A, B, and C, and placebo) and age group (6 to 11 years of age and 12 to 17 years of age) as factors and baseline value as covariate.

Statistical Analysis 3

Statistical Analysis Overview	Comparison Group Selection	Placebo, LIN Dose C (36 ug or 72 ug)
	Comments	Adult derivation
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.1502
	Comments
	Method	ANCOVA
	Comments	ANCOVA model estimates/t-tests comparing specified treatment groups, controlling for age group and baseline value.
Method of Estimation	Estimation Parameter	Least Squares Mean Difference
	Estimated Value	0.356
	Confidence Interval	(2-Sided) 95%; -0.131 to 0.842
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 0.246
	Estimation Comments	ANCOVA model was applied with treatment arm groups (linaclotide doses A, B, and C, and placebo) and age group (6 to 11 years of age and 12 to 17 years of age) as factors and baseline value as covariate.

Statistical Analysis 4

Statistical Analysis Overview	Comparison Group Selection	Placebo, LIN Dose A (9 ug or 18 ug)
	Comments	Weighted average
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.7949
	Comments
	Method	ANCOVA
	Comments	ANCOVA model estimates/t-tests comparing specified treatment groups, controlling for age group and baseline value.
Method of Estimation	Estimation Parameter	Least Squares Mean Difference
	Estimated Value	-0.062
	Confidence Interval	(2-Sided) 95%; -0.535 to 0.410
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 0.239
	Estimation Comments	ANCOVA model was applied with treatment arm groups (linaclotide doses A, B, and C, and placebo) and age group (6 to 11 years of age and 12 to 17 years of age) as factors and baseline value as covariate.

Statistical Analysis 5

Statistical Analysis Overview	Comparison Group Selection	Placebo, LIN Dose B (18 ug or 36 ug)
	Comments	Weighted average
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.7543
	Comments
	Method	ANCOVA
	Comments	ANCOVA model estimates/t-tests comparing specified treatment groups, controlling for age group and baseline value.
Method of Estimation	Estimation Parameter	Least Squares Mean Difference
	Estimated Value	-0.074
	Confidence Interval	(2-Sided) 95%; -0.540 to 0.392
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 0.235
	Estimation Comments	ANCOVA model was applied with treatment arm groups (linaclotide doses A, B, and C, and placebo) and age group (6 to 11 years of age and 12 to 17 years of age) as factors and baseline value as covariate.

Statistical Analysis 6

Statistical Analysis Overview	Comparison Group Selection	Placebo, LIN Dose C (36 ug or 72 ug)
	Comments	Weighted average
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.2676
	Comments
	Method	ANCOVA
	Comments	ANCOVA model estimates/t-tests comparing specified treatment groups, controlling for age group and baseline value.
Method of Estimation	Estimation Parameter	Least Squares Mean Difference
	Estimated Value	0.262
	Confidence Interval	(2-Sided) 95%; -0.204 to 0.728
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 0.235
	Estimation Comments	ANCOVA model was applied with treatment arm groups (linaclotide doses A, B, and C, and placebo) and age group (6 to 11 years of age and 12 to 17 years of age) as factors and baseline value as covariate.

4. Secondary Outcome

Title	Change From Baseline (CFB) in 4-week of Severity of Straining
Description	Severity of straining was scored on 5-point scale for question-When you pooped, how hard did you push? The score ranges from 0= not hard at all,1= I pushed a tiny bit hard,2= I pushed a little hard,3= I pushed hard,4= I pushed very hard with higher scores indicating more severe straining. Participants recorded degree of straining for each BM in morning and evening eDiary. Data was derived as adult derivation and weighted average. Scores during 4-week treatment period were calculated following two approaches - (1) following derivation similar in earlier adult studies, as mean of participant's non-missing, SBM associated straining scores during 4-week treatment period (adult derivation) and (2) as observed weighted average of daily straining scores during that period. Daily straining score was the average of non-missing morning and/or evening assessments of straining score from the SBMs reported by the participants on that specific day. LSM and SE were calculated using ANCOVA method.
Time Frame	Baseline (14-day prior to randomization and up to randomization) to Week 4

Outcome Measure Data

Analysis Population Description

ITT population-participants who had at least 1 postbaseline entry on BM characteristic that determined occurrences of SBMs (BM frequency and rescue medication use). No data is reported for LIN 145 μg as it was exploratory arm group. Observed-cases approach used. Overall number of participants analyzed = who had data at Baseline and post-baseline.

Arm/Group Title	Placebo	LIN Dose A (9 ug or 18 ug)	LIN Dose B (18 ug or 36 ug)	LIN Dose C (36 ug or 72 ug)
Arm/Group Description	Participants aged 6 to 11 or 12 to 17 years received matching placebo linaclotide (LIN), 30 minutes before evening meal, once daily for 4 weeks. Administered as liquid oral solution for participants 6 to 11 years of age and solid oral capsule or liquid oral solution for participants 12 to 17 years of age.	Participants aged 6 to 11 years with weight 18 to <35 kg received LIN 9 ug, oral solution, 30 minutes before evening meal, once daily for 4 weeks. Participants aged 6 to 11 years with weight ≥35 kg received LIN 18 ug, oral solution, 30 minutes before evening meal, once daily for 4 weeks. Participants aged 12 to 17 years received LIN 18 ug, oral solution or solid capsules, 30 minutes before evening meal, once daily for 4 weeks	Participants aged 6 to 11 years with weight 18 to <35 kg received LIN 18 ug, oral solution, 30 minutes before evening meal, once daily for 4 weeks. Participants aged 6 to 11 years with weight ≥35 kg received LIN 36 ug, oral solution, 30 minutes before evening meal, once daily for 4 weeks. Participants aged 12 to 17 years received LIN 36 ug, oral solution or solid capsules, 30 minutes before evening meal, once daily for 4 weeks.	Participants aged 6 to 11 years with weight 18 to <35 kg received LIN 36 ug, oral solution, 30 minutes before evening meal, once daily for 4 weeks. Participants aged 6 to 11 years with weight ≥35 kg received LIN 72 ug, oral solution, 30 minutes before evening meal, once daily for 4 weeks. Participants aged 12 to 17 years received LIN 72 ug, oral solution or solid capsules, 30 minutes before evening meal, once daily for 4 weeks.
Measure Participants	34	32	34	34
CFB at Week 4 (Adult derivation)	-0.657 (0.145)	-0.710 (0.150)	-0.778 (0.147)	-0.893 (0.145)
CFB at Week 4 (Weighted average)	-0.656 (0.143)	-0.710 (0.149)	-0.769 (0.145)	-0.855 (0.143)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Placebo, LIN Dose A (9 ug or 18 ug)
	Comments	Adult derivation
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.7997
	Comments
	Method	ANCOVA
	Comments	ANCOVA model estimates/t-tests comparing specified treatment groups, controlling for age group and baseline value.
Method of Estimation	Estimation Parameter	Least Squares Mean Difference
	Estimated Value	-0.053
	Confidence Interval	(2-Sided) 95%; -0.465 to 0.359
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 0.208
	Estimation Comments	ANCOVA model was applied with treatment arm groups (linaclotide doses A, B, and C, and placebo) and age group (6 to 11 years of age and 12 to 17 years of age) as factors and baseline value as covariate.

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Placebo, LIN Dose B (18 ug or 36 ug)
	Comments	Adult derivation
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.5602
	Comments
	Method	ANCOVA
	Comments	ANCOVA model estimates/t-tests comparing specified treatment groups, controlling for age group and baseline value.
Method of Estimation	Estimation Parameter	Least Squares Mean Difference
	Estimated Value	-0.121
	Confidence Interval	(2-Sided) 95%; -0.530 to 0.288
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 0.207
	Estimation Comments	ANCOVA model was applied with treatment arm groups (linaclotide doses A, B, and C, and placebo) and age group (6 to 11 years of age and 12 to 17 years of age) as factors and baseline value as covariate.

Statistical Analysis 3

Statistical Analysis Overview	Comparison Group Selection	Placebo, LIN Dose C (36 ug or 72 ug)
	Comments	Adult derivation
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.2529
	Comments
	Method	ANCOVA
	Comments	ANCOVA model estimates/t-tests comparing specified treatment groups, controlling for age group and baseline value.
Method of Estimation	Estimation Parameter	Least Squares Mean Difference
	Estimated Value	-0.236
	Confidence Interval	(2-Sided) 95%; -0.641 to 0.170
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 0.205
	Estimation Comments	ANCOVA model was applied with treatment arm groups (linaclotide doses A, B, and C, and placebo) and age group (6 to 11 years of age and 12 to 17 years of age) as factors and baseline value as covariate.

Statistical Analysis 4

Statistical Analysis Overview	Comparison Group Selection	Placebo, LIN Dose A (9 ug or 18 ug)
	Comments	Weighted average
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.7923
	Comments
	Method	ANCOVA
	Comments	ANCOVA model estimates/t-tests comparing specified treatment groups, controlling for age group and baseline value.
Method of Estimation	Estimation Parameter	Least Squares Mean Difference
	Estimated Value	-0.054
	Confidence Interval	(2-Sided) 95%; -0.461 to 0.352
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 0.206
	Estimation Comments	ANCOVA model was applied with treatment arm groups (linaclotide doses A, B, and C, and placebo) and age group (6 to 11 years of age and 12 to 17 years of age) as factors and baseline value as covariate.

Statistical Analysis 5

Statistical Analysis Overview	Comparison Group Selection	Placebo, LIN Dose B (18 ug or 36 ug)
	Comments	Weighted average
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.5802
	Comments
	Method	ANCOVA
	Comments	ANCOVA model estimates/t-tests comparing specified treatment groups, controlling for age group and baseline value.
Method of Estimation	Estimation Parameter	Least Squares Mean Difference
	Estimated Value	-0.113
	Confidence Interval	(2-Sided) 95%; -0.517 to 0.290
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 0.204
	Estimation Comments	ANCOVA model was applied with treatment arm groups (linaclotide doses A, B, and C, and placebo) and age group (6 to 11 years of age and 12 to 17 years of age) as factors and baseline value as covariate.

Statistical Analysis 6

Statistical Analysis Overview	Comparison Group Selection	Placebo, LIN Dose C (36 ug or 72 ug)
	Comments	Weighted average
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.3263
	Comments
	Method	ANCOVA
	Comments	ANCOVA model estimates/t-tests comparing specified treatment groups, controlling for age group and baseline value.
Method of Estimation	Estimation Parameter	Least Squares Mean Difference
	Estimated Value	-0.199
	Confidence Interval	(2-Sided) 95%; -0.600 to 0.201
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 0.202
	Estimation Comments	ANCOVA model was applied with treatment arm groups (linaclotide doses A, B, and C, and placebo) and age group (6 to 11 years of age and 12 to 17 years of age) as factors and baseline value as covariate.

5. Secondary Outcome

Title	Change From Baseline (CFB) in 4-week Abdominal Bloating Daytime Symptoms Based on Evening Assessment
Description	Participants recorded their assessment of abdominal bloating in the evening eDiary. Participants answered the question: How big and full did your tummy feel? on a scale, where: 0=none, 1=a tiny bit, 2=a little, 3=medium or 4=very, with a higher score indicating more severe bloating. Baseline value was the average of values collected 14 days before randomization. The 4-week daytime abdominal bloating symptoms were calculated as the average of non-missing scores reported in the evening eDiary during the treatment period. Change from Baseline was calculated as the 4-week daytime abdominal bloating score during the treatment period - daytime abdominal bloating score at baseline. A negative change from Baseline indicates improvement. LSM and SE were calculated using ANCOVA method.
Time Frame	Baseline (14-day prior to randomization) to Week 4

Outcome Measure Data

Analysis Population Description

ITT population, all participants who had at least 1 postbaseline entry on BM characteristic assessments that determined occurrences of SBMs (i.e. BM frequency and rescue medication use). No data is reported for LIN 145 μg as it was an exploratory arm group. An observed-cases approach to missing postbaseline data was applied.

Arm/Group Title	Placebo	LIN Dose A (9 ug or 18 ug)	LIN Dose B (18 ug or 36 ug)	LIN Dose C (36 ug or 72 ug)
Arm/Group Description	Participants aged 6 to 11 or 12 to 17 years received matching placebo linaclotide (LIN), 30 minutes before evening meal, once daily for 4 weeks. Administered as liquid oral solution for participants 6 to 11 years of age and solid oral capsule or liquid oral solution for participants 12 to 17 years of age.	Participants aged 6 to 11 years with weight 18 to <35 kg received LIN 9 ug, oral solution, 30 minutes before evening meal, once daily for 4 weeks. Participants aged 6 to 11 years with weight ≥35 kg received LIN 18 ug, oral solution, 30 minutes before evening meal, once daily for 4 weeks. Participants aged 12 to 17 years received LIN 18 ug, oral solution or solid capsules, 30 minutes before evening meal, once daily for 4 weeks	Participants aged 6 to 11 years with weight 18 to <35 kg received LIN 18 ug, oral solution, 30 minutes before evening meal, once daily for 4 weeks. Participants aged 6 to 11 years with weight ≥35 kg received LIN 36 ug, oral solution, 30 minutes before evening meal, once daily for 4 weeks. Participants aged 12 to 17 years received LIN 36 ug, oral solution or solid capsules, 30 minutes before evening meal, once daily for 4 weeks.	Participants aged 6 to 11 years with weight 18 to <35 kg received LIN 36 ug, oral solution, 30 minutes before evening meal, once daily for 4 weeks. Participants aged 6 to 11 years with weight ≥35 kg received LIN 72 ug, oral solution, 30 minutes before evening meal, once daily for 4 weeks. Participants aged 12 to 17 years received LIN 72 ug, oral solution or solid capsules, 30 minutes before evening meal, once daily for 4 weeks.
Measure Participants	41	36	41	39
Least Squares Mean (Standard Error) [score on a scale]	-0.314 (0.104)	-0.266 (0.110)	-0.287 (0.104)	-0.275 (0.105)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Placebo, LIN Dose A (9 ug or 18 ug)
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.7507
	Comments
	Method	ANCOVA
	Comments	ANCOVA model estimates/t-tests comparing specified treatment groups, controlling for age group and baseline value.
Method of Estimation	Estimation Parameter	Least Squares Mean Difference
	Estimated Value	0.048
	Confidence Interval	(2-Sided) 95%; -0.252 to 0.349
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 0.152
	Estimation Comments	ANCOVA model was applied with treatment arm groups (linaclotide doses A, B, and C, and placebo) and age group (6 to 11 years of age and 12 to 17 years of age) as factors and baseline value as covariate.

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Placebo, LIN Dose B (18 ug or 36 ug)
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.8505
	Comments
	Method	ANCOVA
	Comments	ANCOVA model estimates/t-tests comparing specified treatment groups, controlling for age group and baseline value.
Method of Estimation	Estimation Parameter	Least Squares Mean Difference
	Estimated Value	0.028
	Confidence Interval	(2-Sided) 95%; -0.262 to 0.317
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 0.146
	Estimation Comments	ANCOVA model was applied with treatment arm groups (linaclotide doses A, B, and C, and placebo) and age group (6 to 11 years of age and 12 to 17 years of age) as factors and baseline value as covariate.

Statistical Analysis 3

Statistical Analysis Overview	Comparison Group Selection	Placebo, LIN Dose C (36 ug or 72 ug)
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.7933
	Comments
	Method	ANCOVA
	Comments	ANCOVA model estimates/t-tests comparing specified treatment groups, controlling for age group and baseline value.
Method of Estimation	Estimation Parameter	Least Squares Mean Difference
	Estimated Value	0.039
	Confidence Interval	(2-Sided) 95%; -0.254 to 0.332
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 0.149
	Estimation Comments	ANCOVA model was applied with treatment arm groups (linaclotide doses A, B, and C, and placebo) and age group (6 to 11 years of age and 12 to 17 years of age) as factors and baseline value as covariate.

6. Secondary Outcome

Title	Change From Baseline (CFB) in 4-week Overall Complete Spontaneous Bowel Movement Frequency Rate (CSBM/Week) During the Treatment Period
Description	SBM was defined as a BM that occurred in the absence of laxative, suppository, or enema use on the calendar day of the BM or the calendar day before the BM. A CSBM was an SBM that was associated with a sense of complete evacuation. Participants recorded their assessment of the sensation of incomplete evacuation for each BM in the morning and evening eDiary. The 4-week overall CSBM frequency rate was calculated as [total number of CSBMs in the analysis period/number of days in the analysis period]*7). Baseline value was based on values collected 14 days before randomization and up to randomization. Change from Baseline was calculated as the CSBM frequency rate during the 4-week treatment period - CSBM frequency rate at baseline. A positive change from Baseline indicates improvement. LSM and SE were calculated using ANCOVA method.
Time Frame	Baseline (14-day prior to randomization and up to randomization) to Week 4

Outcome Measure Data

Analysis Population Description

ITT population, all participants who had at least 1 postbaseline entry on BM characteristic assessments that determined occurrences of SBMs (i.e. BM frequency and rescue medication use). No data is reported for LIN 145 μg as it was an exploratory arm group. An observed-cases approach to missing postbaseline data was applied.

Arm/Group Title	Placebo	LIN Dose A (9 ug or 18 ug)	LIN Dose B (18 ug or 36 ug)	LIN Dose C (36 ug or 72 ug)
Arm/Group Description	Participants aged 6 to 11 or 12 to 17 years received matching placebo linaclotide (LIN), 30 minutes before evening meal, once daily for 4 weeks. Administered as liquid oral solution for participants 6 to 11 years of age and solid oral capsule or liquid oral solution for participants 12 to 17 years of age.	Participants aged 6 to 11 years with weight 18 to <35 kg received LIN 9 ug, oral solution, 30 minutes before evening meal, once daily for 4 weeks. Participants aged 6 to 11 years with weight ≥35 kg received LIN 18 ug, oral solution, 30 minutes before evening meal, once daily for 4 weeks. Participants aged 12 to 17 years received LIN 18 ug, oral solution or solid capsules, 30 minutes before evening meal, once daily for 4 weeks	Participants aged 6 to 11 years with weight 18 to <35 kg received LIN 18 ug, oral solution, 30 minutes before evening meal, once daily for 4 weeks. Participants aged 6 to 11 years with weight ≥35 kg received LIN 36 ug, oral solution, 30 minutes before evening meal, once daily for 4 weeks. Participants aged 12 to 17 years received LIN 36 ug, oral solution or solid capsules, 30 minutes before evening meal, once daily for 4 weeks.	Participants aged 6 to 11 years with weight 18 to <35 kg received LIN 36 ug, oral solution, 30 minutes before evening meal, once daily for 4 weeks. Participants aged 6 to 11 years with weight ≥35 kg received LIN 72 ug, oral solution, 30 minutes before evening meal, once daily for 4 weeks. Participants aged 12 to 17 years received LIN 72 ug, oral solution or solid capsules, 30 minutes before evening meal, once daily for 4 weeks.
Measure Participants	41	36	41	39
Least Squares Mean (Standard Error) [CSBMs/week]	1.240 (0.308)	0.815 (0.328)	1.005 (0.309)	1.320 (0.314)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Placebo, LIN Dose A (9 ug or 18 ug)
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.3461
	Comments
	Method	ANCOVA
	Comments	ANCOVA model estimates/t-tests comparing specified treatment groups, controlling for age group and baseline value.
Method of Estimation	Estimation Parameter	Least Squares Mean Difference
	Estimated Value	-0.425
	Confidence Interval	(2-Sided) 95%; -1.313 to 0.463
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 0.450
	Estimation Comments	ANCOVA model was applied with treatment arm groups (linaclotide doses A, B, and C, and placebo) and age group (6 to 11 years of age and 12 to 17 years of age) as factors and baseline value as covariate.

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Placebo, LIN Dose B (18 ug or 36 ug)
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.5892
	Comments
	Method	ANCOVA
	Comments	ANCOVA model estimates/t-tests comparing specified treatment groups, controlling for age group and baseline value.
Method of Estimation	Estimation Parameter	Least Squares Mean Difference
	Estimated Value	-0.235
	Confidence Interval	(2-Sided) 95%; -1.095 to 0.624
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 0.435
	Estimation Comments	ANCOVA model was applied with treatment arm groups (linaclotide doses A, B, and C, and placebo) and age group (6 to 11 years of age and 12 to 17 years of age) as factors and baseline value as covariate.

Statistical Analysis 3

Statistical Analysis Overview	Comparison Group Selection	Placebo, LIN Dose C (36 ug or 72 ug)
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.8560
	Comments
	Method	ANCOVA
	Comments	ANCOVA model estimates/t-tests comparing specified treatment groups, controlling for age group and baseline value.
Method of Estimation	Estimation Parameter	Least Squares Mean Difference
	Estimated Value	0.080
	Confidence Interval	(2-Sided) 95%; -0.789 to 0.949
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 0.440
	Estimation Comments	ANCOVA model was applied with treatment arm groups (linaclotide doses A, B, and C, and placebo) and age group (6 to 11 years of age and 12 to 17 years of age) as factors and baseline value as covariate.

7. Secondary Outcome

Title	Change From Baseline in 4-week Fecal Incontinence Daytime Symptoms Based on Evening Assessment
Description	Participants recorded the presence of incontinence episodes in daytime daily since pre-treatment period (14-day prior to randomization) in the evening eDiary for participants randomized following protocol amendment #3. The 4-week daytime fecal incontinence was calculated as the mean of non-missing participant scores reported in the evening eDiary during the Treatment Period. Baseline value was the average of values collected 14 days before randomization. Change from Baseline was calculated as the 4-week fecal incontinence daytime symptoms during the treatment period - fecal incontinence daytime symptoms at baseline. A negative change from Baseline indicates improvement. No data is reported for LIN 145 μg as it was an exploratory arm group.
Time Frame	Baseline (14-day prior to randomization) to Week 4

Outcome Measure Data

Analysis Population Description

Participants from ITT population included all participants who had at least 1 postbaseline entry on BM characteristic assessments that determined occurrences of SBMs (i.e. BM frequency and rescue medication use) who were randomized following the implementation of fecal incontinence assessment in the protocol (amendment #3).

Arm/Group Title	Placebo	LIN Dose A (9 ug or 18 ug)	LIN Dose B (18 ug or 36 ug)	LIN Dose C (36 ug or 72 ug)
Arm/Group Description	Participants aged 6 to 11 or 12 to 17 years received matching placebo linaclotide (LIN), 30 minutes before evening meal, once daily for 4 weeks. Administered as liquid oral solution for participants 6 to 11 years of age and solid oral capsule or liquid oral solution for participants 12 to 17 years of age.	Participants aged 6 to 11 years with weight 18 to <35 kg received LIN 9 ug, oral solution, 30 minutes before evening meal, once daily for 4 weeks. Participants aged 6 to 11 years with weight ≥35 kg received LIN 18 ug, oral solution, 30 minutes before evening meal, once daily for 4 weeks. Participants aged 12 to 17 years received LIN 18 ug, oral solution or solid capsules, 30 minutes before evening meal, once daily for 4 weeks	Participants aged 6 to 11 years with weight 18 to <35 kg received LIN 18 ug, oral solution, 30 minutes before evening meal, once daily for 4 weeks. Participants aged 6 to 11 years with weight ≥35 kg received LIN 36 ug, oral solution, 30 minutes before evening meal, once daily for 4 weeks. Participants aged 12 to 17 years received LIN 36 ug, oral solution or solid capsules, 30 minutes before evening meal, once daily for 4 weeks.	Participants aged 6 to 11 years with weight 18 to <35 kg received LIN 36 ug, oral solution, 30 minutes before evening meal, once daily for 4 weeks. Participants aged 6 to 11 years with weight ≥35 kg received LIN 72 ug, oral solution, 30 minutes before evening meal, once daily for 4 weeks. Participants aged 12 to 17 years received LIN 72 ug, oral solution or solid capsules, 30 minutes before evening meal, once daily for 4 weeks.
Measure Participants	11	9	13	10
Mean (Standard Deviation) [incontinence episodes]	-0.028 (0.081)	-0.025 (0.083)	-0.009 (0.067)	0.170 (0.298)

Adverse Events

Time Frame	From first dose of study treatment up to Day 30 after the last dose for serious adverse events (SAEs) and from first dose up to Day 1 after the last dose for other adverse events
Adverse Event Reporting Description	Safety population included all participants in the randomized population who took at least 1 dose of double-blind study treatment.
Arm/Group Title	Placebo		LIN Dose A (9 ug or 18 ug)		LIN Dose B (18 ug or 36 ug)		LIN Dose C (36 ug or 72 ug)		LIN 145 µg
Arm/Group Description	Participants aged 6 to 11 or 12 to 17 years received matching placebo linaclotide (LIN), 30 minutes before evening meal, once daily for 4 weeks. Administered as liquid oral solution for participants 6 to 11 years of age and solid oral capsule or liquid oral solution for participants 12 to 17 years of age.		Participants aged 6 to 11 years with weight 18 to <35 kg received LIN 9 ug, oral solution, 30 minutes before evening meal, once daily for 4 weeks. Participants aged 6 to 11 years with weight ≥35 kg received LIN 18 ug, oral solution, 30 minutes before evening meal, once daily for 4 weeks. Participants aged 12 to 17 years received LIN 18 ug, oral solution or solid capsules, 30 minutes before evening meal, once daily for 4 weeks		Participants aged 6 to 11 years with weight 18 to <35 kg received LIN 18 ug, oral solution, 30 minutes before evening meal, once daily for 4 weeks. Participants aged 6 to 11 years with weight ≥35 kg received LIN 36 ug, oral solution, 30 minutes before evening meal, once daily for 4 weeks. Participants aged 12 to 17 years received LIN 36 ug, oral solution or solid capsules, 30 minutes before evening meal, once daily for 4 weeks.		Participants aged 6 to 11 years with weight 18 to <35 kg received LIN 36 ug, oral solution, 30 minutes before evening meal, once daily for 4 weeks. Participants aged 6 to 11 years with weight ≥35 kg received LIN 72 ug, oral solution, 30 minutes before evening meal, once daily for 4 weeks. Participants aged 12 to 17 years received LIN 72 ug, oral solution or solid capsules, 30 minutes before evening meal, once daily for 4 weeks.		Participants aged 12 to 17 years received LIN 145 ug, oral solution or solid capsules, 30 minutes before evening meal, once daily for 4 weeks.
All Cause Mortality
	Placebo		LIN Dose A (9 ug or 18 ug)		LIN Dose B (18 ug or 36 ug)		LIN Dose C (36 ug or 72 ug)		LIN 145 µg
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	0/41 (0%)		0/36 (0%)		0/41 (0%)		0/39 (0%)		0/16 (0%)
Serious Adverse Events
	Placebo		LIN Dose A (9 ug or 18 ug)		LIN Dose B (18 ug or 36 ug)		LIN Dose C (36 ug or 72 ug)		LIN 145 µg
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	0/41 (0%)		1/36 (2.8%)		0/41 (0%)		0/39 (0%)		1/16 (6.3%)
Gastrointestinal disorders
Vomiting	0/41 (0%)		0/36 (0%)		0/41 (0%)		0/39 (0%)		1/16 (6.3%)
Psychiatric disorders
Suicidal ideation	0/41 (0%)		1/36 (2.8%)		0/41 (0%)		0/39 (0%)		0/16 (0%)
Other (Not Including Serious) Adverse Events
	Placebo		LIN Dose A (9 ug or 18 ug)		LIN Dose B (18 ug or 36 ug)		LIN Dose C (36 ug or 72 ug)		LIN 145 µg
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	3/41 (7.3%)		1/36 (2.8%)		3/41 (7.3%)		10/39 (25.6%)		4/16 (25%)
Gastrointestinal disorders
Diarrhoea	0/41 (0%)		1/36 (2.8%)		3/41 (7.3%)		4/39 (10.3%)		2/16 (12.5%)
Faecaloma	0/41 (0%)		0/36 (0%)		0/41 (0%)		2/39 (5.1%)		0/16 (0%)
Vomiting	1/41 (2.4%)		1/36 (2.8%)		0/41 (0%)		0/39 (0%)		1/16 (6.3%)
Infections and infestations
Viral sinusitis	0/41 (0%)		0/36 (0%)		0/41 (0%)		0/39 (0%)		1/16 (6.3%)
Investigations
Alanine aminotransferase increased	1/41 (2.4%)		0/36 (0%)		0/41 (0%)		0/39 (0%)		1/16 (6.3%)
Aspartate aminotransferase increased	1/41 (2.4%)		0/36 (0%)		0/41 (0%)		0/39 (0%)		1/16 (6.3%)
Nervous system disorders
Headache	1/41 (2.4%)		1/36 (2.8%)		0/41 (0%)		4/39 (10.3%)		0/16 (0%)

Limitations/Caveats

[Not Specified]

More Information

Certain Agreements

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

A disclosure restriction on the PI is that the sponsor can review results communications prior to public release and can embargo communications regarding trial results for a period that is less than or equal to 90 days from the time submitted to the sponsor for review. The sponsor cannot require changes to the communication and cannot extend the embargo.