Trial of Linaclotide in Patients With Chronic Idiopathic Constipation

Study Overview
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Brief Summary
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The objective of this trial was to determine the efficacy and safety of linaclotide 72 ug administered once daily to patients with chronic idiopathic constipation (CIC). The primary efficacy parameter is the percentage of participants in each dosing group that meet the protocol definition for complete spontaneous bowel movement (CSBM) Overall Responder.

Detailed Description
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The trial also included a 145 ug linaclotide treatment arm (an FDA-approved dose for CIC) as an established positive control to validate the study design.

Official Title
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A Phase 3, Randomized, Double-blind, Placebo-controlled, Parallel-group Trial of Linaclotide (72 ug or 145 ug) Administered Orally for 12 Weeks to Patients With Chronic Idiopathic Constipation

Conditions
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Chronic Idiopathic Constipation

Intervention / Treatment
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* Drug: Linaclotide
* Drug: Matching Placebo


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Patient has completed a colonoscopy if one is needed according to the American Gastroenterological Association (AGA) criteria, with no clinically significant findings Patient has no clinically significant findings on a physical examination and clinical laboratory tests Patient meets protocol criteria for CIC: reports < 3 bowel movements (BMs) per week and reports one or more of the following during ≥ 25% of BMs: straining, lumpy or hard stools, sensation of incomplete evacuation during the 3 months before the diagnosis with the onset at least 6 months before the diagnosis Patient is compliant with daily interactive voice response system (IVRS) calls Patient reports an average of < 3 complete spontaneous BMs (CSBMs) and ≤ 6 SBMs per week by the IVRS over the 14 calendar days before the Randomization Visit and the calendar day of Randomization. Exclusion Criteria: Patient has history of loose or watery stools Patient has symptoms of or been diagnosed with irritable bowel syndrome (IBS) Patient has a structural abnormality of the gastrointestinal (GI) tract or a disease or condition that can affect GI motility Patient has any protocol-excluded or clinically significant medical or surgical history that could confound the study assessments Patient has Bristol Stool Form Scale score of 7 during Pretreatment period.

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Quadruple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: 72 μg linaclotide<br>72 μg oral linaclotide, once daily for 12 weeks | Drug: Linaclotide<br> <br> * Other names: Constella;|
| Experimental: 145 μg linaclotide<br>145 μg oral linaclotide, once daily for 12 weeks | Drug: Linaclotide<br> <br> * Other names: Constella;|
| Placebo Comparator: Placebo<br>matching placebo, once daily for 12 weeks | Drug: Matching Placebo<br> <br> |

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Percentage of 12-Week CSBM Overall Responders | A 12-week CSBM Overall Responder is a participant who was a CSBM Weekly Responder for at least 9 of the 12 weeks of the Treatment Period. A CSBM Weekly Responder is a participant who had a CSBM weekly frequency rate that was 3 or greater and increased by 1 or more from baseline, and completed ≥ 4 IVRS calls for the specified week. A CSBM is defined as an SBM that is associated with a sense of complete evacuation. An SBM is defined as a bowel movement BM that occurred in the absence of laxative, enema, or suppository use on either the calendar day of the BM or the calendar day before the BM. | Week 12 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change From Baseline in 12-Week CSBM Frequency Rate | A participant's 12-week CSBM Frequency Rate is the CSBM rate (CSBMs/week) calculated over the 12 weeks of the Treatment Period. A CSBM is defined as an SBM that is associated with a sense of complete evacuation. An SBM is defined as a BM that occurred in the absence of laxative, enema, or suppository use on either the calendar day of the BM or the calendar day before the BM. | Baseline, Week 1 to Week 12 | 
| Change From Baseline in 12-Week SBM Frequency Rate | A participant's 12-week SBM Frequency Rate is the SBM rate (SBMs/week) calculated over the 12-weeks of the Treatment Period. An SBM is defined as a BM that occurred in the absence of laxative, enema, or suppository use on either the calendar day of the BM or the calendar day before the BM. | Baseline, Week 1 to Week 12 | 
| Change From Baseline in 12-Week Stool Consistency Score | Stool consistency was measured daily using the 7-point ordinal Bristol Stool Form Scale (BSFS; 1 = separate hard lumps like nuts [difficult to pass]; 2 = sausage shaped but lumpy; 3 = like a sausage but with cracks on surface; 4 = like a sausage or snake, smooth and soft; 5 = soft blobs with clear-cut edges [passed easily]; 6 = fluffy pieces with ragged edges, a mushy stool; 7 = watery, no solid pieces [entirely liquid]). The participant's BSFS score for the Treatment Period is the average of the non-missing BSFS scores from the SBMs reported by the participant during the 12-week Treatment Period. | Baseline, Week 1 to Week 12 | 
| Change From Baseline in 12-Week Straining Score | Straining was measured daily using a 5-point ordinal scale (1 = not at all; 2 = a little bit; 3 = a moderate amount; 4 = a great deal; 5 = an extreme amount). The participant's straining score for the Treatment Period is the average of the non-missing straining scores from the SBMs reported by the participant during the 12-week Treatment Period. | Baseline, Week 1 to Week 12 | 
| Percentage of 12-Week CSBM Overall Responders (>1 SBM/Week Subpopulation) | A 12-week CSBM Overall Responder is a participant who was a CSBM Weekly Responder for at least 9 of the 12 weeks of the Treatment Period. A CSBM Weekly Responder is a participant who had a CSBM weekly frequency rate that was 3 or greater and increased by 1 or more from baseline, and completed ≥4 IVRS calls for the specified week. A CSBM is defined as an SBM that is associated with a sense of complete evacuation. An SBM is defined as a BM that occurred in the absence of laxative, enema, or suppository use on either the calendar day of the BM or the calendar day before the BM. | Week 12 | 
| Percentage of Month 1 CSBM Responders | A Month 1 CSBM Responder is a participant who is a CSBM weekly responder for at least 3 of the 4 weeks of Month 1 of the Treatment Period. A CSBM weekly responder is a participant who had a CSBM weekly frequency rate that was 3 or greater and increased by 1 or more from baseline based on a minimum of 4 complete IVRS calls for that week. A CSBM is defined as an SBM that is associated with a sense of complete evacuation. An SBM is defined as a BM that occurred in the absence of laxative, enema, or suppository use on either the calendar day of the BM or the calendar day before the BM. | Month 1 | 
| Percentage of Month 2 CSBM Responders | A Month 2 CSBM Responder is a participant who is a CSBM weekly responder for at least 3 of the 4 weeks of Month 2 of the Treatment Period. A CSBM weekly responder is a participant who had a CSBM weekly frequency rate that was 3 or greater and increased by 1 or more from baseline based on a minimum of 4 complete IVRS calls for that week. A CSBM is defined as an SBM that is associated with a sense of complete evacuation. An SBM is defined as a BM that occurred in the absence of laxative, enema, or suppository use on either the calendar day of the BM or the calendar day before the BM. | Month 2 | 
| Percentage of Month 3 CSBM Responders | A Month 3 CSBM Responder is a participant who is a CSBM weekly responder for at least 3 of the 4 weeks of Month 3 of the Treatment Period. A CSBM weekly responder is a participant who had a CSBM weekly frequency rate that was 3 or greater and increased by 1 or more from baseline based on a minimum of 4 complete IVRS calls for that week. A CSBM is defined as an SBM that is associated with a sense of complete evacuation. An SBM is defined as a BM that occurred in the absence of laxative, enema, or suppository use on either the calendar day of the BM or the calendar day before the BM. | Month 3 | 
| Change From Baseline in 12-Week Abdominal Bloating | Abdominal bloating was measured daily using an 11-point NRS (0 = none; 10 = very severe). The participant's abdominal bloating score for the Treatment Period is the average of the non-missing daily participant assessments of abdominal bloating scores reported during the 12-week Treatment Period. | Baseline, Week 1 to Week 12 | 
| Change From Baseline in 12-Week Abdominal Discomfort | Abdominal discomfort was measured daily using an 11-point NRS (0 = none; 10 = very severe). The participant's abdominal discomfort score for the Treatment Period is the average of the non-missing daily participant assessments of abdominal discomfort scores reported during the 12-week Treatment Period. | Baseline, Week 1 to Week 12 |