A Safety and Efficacy Study of a Range of Linaclotide Doses Administered Orally to Children Ages 7-17 Years, With Irritable Bowel Syndrome With Constipation

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, A Multicenter, Randomized, Double-blind, Placebo-controlled Safety and Efficacy Study of a Range of Linaclotide Doses Administered Orally to Children Ages 7-17 Years, With Irritable Bowel Syndrome With Constipation (IBS-C) (ie, Fulfill Rome III Criteria for Child/Adolescent IBS and Fulfill Modified Rome III Criteria for Child/Adolescent Functional Constipation

Status

Terminated

Phases

Phase 2

Study type

Interventional

Source

ClinicalTrials.gov

Registry ID

NCT02559817

Acronym

LIN-MD-63

Enrollment

101

Registered

2015-09-24

Start date

2015-11-01

Completion date

2019-08-30

Last updated

2020-12-28

For informational purposes only — not medical advice. Sourced from public registries and may not reflect the latest updates. Terms

Conditions

Irritable Bowel Syndrome With Constipation

Keywords

Irritable Bowel Syndrome with Constipation in children, Linzess

Brief summary

The purpose of this study is to evaluate the safety and efficacy of linaclotide for the treatment of Irritable Bowel syndrome with Constipation (IBS-C), in children age 7-17 years. This study includes up to a 4-week Screening Period, and a 2 to 3-week Pretreatment Period. Patients age 7-11 will receive oral liquid or oral solid capsule and patients 12-17 will receive solid oral capsule formulation. Children ages 7-11 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 IBS-C.

Interventions

DRUGLinaclotide Dose A

DRUGLinaclotide Dose B

DRUGLinaclotide Dose C

DRUGLinaclotide Approved Adult Dose

DRUGMatching Placebo

Study design

Allocation

RANDOMIZED

Intervention model

PARALLEL

Primary purpose

TREATMENT

Masking

QUADRUPLE (Subject, Caregiver, Investigator, Outcomes Assessor)

Eligibility

Sex/Gender

ALL

Age

7 Years to 17 Years

Healthy volunteers

Inclusion criteria

* Patient weighs at least 18 kg (39.7 lbs) * Patient meets Rome III criteria for child/adolescent IBS: at least once per week for at least 2 months before Screening Visit, the patient 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: * a) Improvement with defecation * b) Onset associated with a change in frequency of stool * c) Onset associated with a change in form (appearance) of stool * Patient meets modified Rome III criteria for child/adolescent Functional Constipation (FC): For at least 2 months before the Screening Visit, the patient 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: * a) History of retentive posturing or excessive volitional stool retention * b) History of painful or hard bowel movements (BMs) * c) Presence of a large fecal mass in the rectum * d) History of large diameter stools that may obstruct the toilet * Patient is willing to discontinue any laxatives used before the Pretreatment Visit in favor of the protocol-permitted rescue medicine * Patient 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 * Patient or parent/guardian/LAR or caregiver is compliant with eDiary by completing both the morning and evening assessments for 10 out of the 14 days immediately preceding the Randomization Visit

Exclusion criteria

* Patient 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 * Patient has required manual disimpaction anytime prior to randomization or disimpaction during in-patient hospitalization within one year prior to randomization * Patient is unable to tolerate the placebo during rhe Screening Period

Design outcomes

Primary

Measure	Time frame	Description
Change From Baseline in 4-week Overall Spontaneous Bowel Movement (SBM) Frequency Rate (SBMs/Week) During the Treatment Period	Baseline (14 days 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.

Secondary

Measure	Time frame	Description
Change From Baseline in 4-week Abdominal Pain Daytime Symptoms Based on Evening Assessment of Abdominal Pain Symptoms	Baseline (14 days 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.
Change From Baseline in 4-week Stool Consistency	Baseline (14 days 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 as mean of participants non-missing, SBM associated p-BSFS scores during 4-week treatment period. Baseline value was based on values collected 14 days before randomization up to randomization.
Change From Baseline in 4-week Severity of Straining	Baseline (14 days 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. Scores during 4-week treatment period were calculated as mean of participant's non-missing, SBM associated straining scores during 4-week treatment period.
Change From Baseline in 4-week Abdominal Bloating Daytime Symptoms Based on Evening Assessment	Baseline (14 days 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.
Change From Baseline in 4-week Overall Complete Spontaneous Bowel Movement (CSBM) Frequency Rate (CSBMs Per Week)	Baseline (14 days 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.

Countries

Canada, United States

Participant flow

Pre-assignment details

There was a screening period of 14 to 28 days, followed by a Pretreatment period of 14 to 21 days, prior to randomization of study participants.

Participants by arm

Arm	Count
Matching Placebo Taken once daily each evening, at least 30 minutes before their evening meal, with the exception of the first Treatment Period dose which will be taken at the study center, after at least a 2-hour fast Placebo liquid oral solution or placebo solid oral capsule in children 7-11 years of age Placebo solid oral capsule in children 12-17 years of age	19
Linaclotide Dose A Taken once daily each evening, at least 30 minutes before their evening meal, with the exception of the first Treatment Period dose which will be taken at the study center, after at least a 2-hour fast. Dose A: 18 micrograms liquid oral solution or solid oral capsule in children 7-11 years of age with weight 18 to \<35 kg Dose A: 36 micrograms liquid oral solution or solid oral capsule in children 7-11 years of age with weight ≥ 35 kg Dose A: 36 micrograms solid oral capsule in children 12-17 years of age	29
Linaclotide Dose B Taken once daily each evening, at least 30 minutes before their evening meal, with the exception of the first Treatment Period dose which will be taken at the study center, after at least a 2-hour fast. Dose B: 36 micrograms liquid oral solution or solid oral capsule in children 7-11 years of age with weight 18 to \<35 kg Dose B: 72 micrograms liquid oral solution or solid oral capsule in children 7-11 years of age with weight ≥ 35 kg Dose B: 72 micrograms solid oral capsule in children 12-17 years of age	21
Linaclotide Dose C Taken once daily each evening, at least 30 minutes before their evening meal,, with the exception of the first Treatment Period dose which will be taken at the study center, after at least a 2-hour fast. Dose C: 72 micrograms liquid oral solution or solid oral capsule in children 7-11 years of age with weight 18 to \<35 kg Dose C: 145 micrograms liquid oral solution or solid oral capsule in children 7-11 years of age with weight ≥ 35 kg Dose C: 145 micrograms solid oral capsule in children 12-17 years of age	24
Linaclotide Approved Adult Dose Taken once daily each evening, at least 30 minutes before their evening meal, with the exception of the first Treatment Period dose which will be taken at the study center, after at least a 2-hour fast. Approved Adult Dose: 290 micrograms solid oral capsule in children 12-17 years of age	8
Total	101

Withdrawals & dropouts

Period	Reason	FG000	FG001	FG002	FG003
Treatment Period	Adverse Event	1	0	1	0
Treatment Period	Lack of Efficacy	0	1	0	0
Treatment Period	Lost to Follow-up	0	1	0	1
Treatment Period	Non-Compliance With Study Drug	0	0	1	0
Treatment Period	Protocol Violation	0	0	0	1

Baseline characteristics

Characteristic	Matching Placebo	Linaclotide Dose A	Linaclotide Dose B	Linaclotide Dose C	Linaclotide Approved Adult Dose	Total
Age, Continuous	11.9 Years STANDARD_DEVIATION 2.61	11.9 Years STANDARD_DEVIATION 2.95	12.7 Years STANDARD_DEVIATION 3.51	12.4 Years STANDARD_DEVIATION 3.26	13.5 Years STANDARD_DEVIATION 1.77	12.3 Years STANDARD_DEVIATION 3
Age, Customized Age 12 years through 17 years	11 Participants	16 Participants	12 Participants	13 Participants	8 Participants	60 Participants
Age, Customized Age 7 years through 11 years	8 Participants	13 Participants	9 Participants	11 Participants	0 Participants	41 Participants
Body Mass Index (BMI)	21.29 kg/m^2 STANDARD_DEVIATION 3.266	23.56 kg/m^2 STANDARD_DEVIATION 5.322	24.85 kg/m^2 STANDARD_DEVIATION 6.304	24.57 kg/m^2 STANDARD_DEVIATION 8.517	23.92 kg/m^2 STANDARD_DEVIATION 5.955	23.67 kg/m^2 STANDARD_DEVIATION 6.208
Race/Ethnicity, Customized Hispanic or Latino	4 Participants	7 Participants	5 Participants	7 Participants	3 Participants	26 Participants
Race/Ethnicity, Customized Not Hispanic or Latino	15 Participants	22 Participants	16 Participants	17 Participants	5 Participants	75 Participants
Race/Ethnicity, Customized Black or African American	7 Participants	10 Participants	6 Participants	7 Participants	1 Participants	31 Participants
Race/Ethnicity, Customized Multiple	0 Participants	2 Participants	0 Participants	1 Participants	1 Participants	4 Participants
Race/Ethnicity, Customized White	12 Participants	17 Participants	15 Participants	16 Participants	6 Participants	66 Participants
Sex: Female, Male Female	13 Participants	19 Participants	15 Participants	16 Participants	5 Participants	68 Participants
Sex: Female, Male Male	6 Participants	10 Participants	6 Participants	8 Participants	3 Participants	33 Participants
Weight	49.87 kg STANDARD_DEVIATION 14.387	55.22 kg STANDARD_DEVIATION 19.339	60.13 kg STANDARD_DEVIATION 22.67	56.80 kg STANDARD_DEVIATION 20.943	61.93 kg STANDARD_DEVIATION 17.586	56.14 kg STANDARD_DEVIATION 19.523

Adverse events

Event type	EG000 affected / at risk	EG001 affected / at risk	EG002 affected / at risk	EG003 affected / at risk	EG004 affected / at risk
deaths Total, all-cause mortality	0 / 19	0 / 29	0 / 21	0 / 24	0 / 8
other Total, other adverse events	3 / 19	6 / 29	5 / 21	3 / 24	1 / 8
serious Total, serious adverse events	1 / 19	1 / 29	0 / 21	0 / 24	0 / 8

Outcome results

Primary

Change From Baseline in 4-week Overall Spontaneous Bowel Movement (SBM) Frequency Rate (SBMs/Week) During the Treatment Period

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.

Time frame: Baseline (14 days prior to randomization and up to randomization) to week 4