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Trial of Linaclotide in Patients With Irritable Bowel Syndrome With Constipation (IBS-C)

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ClinicalTrials.gov Identifier: NCT00938717
Recruitment Status : Completed
First Posted : July 14, 2009
Results First Posted : January 30, 2013
Last Update Posted : November 5, 2013
Sponsor:
Collaborator:
Forest Laboratories
Information provided by (Responsible Party):
Ironwood Pharmaceuticals, Inc.

Study Type Interventional
Study Design Allocation: Randomized;   Intervention Model: Parallel Assignment;   Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor);   Primary Purpose: Treatment
Condition Irritable Bowel Syndrome With Constipation
Intervention Drug: Linaclotide or Matching Placebo
Enrollment 805
Recruitment Details Patient recruitment occurred over a fifteen month period from July 2009 to September 2010 at 111 US study sites.
Pre-assignment Details Patients went through a 14 to 21 day Pretreatment Period during which the patients provided qualifying bowel habit and symptoms, and rescue medicine usage information through an interactive voice response system (IVRS). All randomized patients needed an abdominal pain score ≥ 3.
Arm/Group Title Placebo Linaclotide
Hide Arm/Group Description Dose-matched placebo, oral administration, once per day. Linaclotide 290μg, oral administration, once per day.
Period Title: Overall Study
Started 403 402
Completed 305 294
Not Completed 98 108
Reason Not Completed
Adverse Event             10             41
Protocol Violation             11             8
Withdrawal by Subject             26             24
Lost to Follow-up             13             18
Lack of Efficacy             33             15
Other reason             5             2
Arm/Group Title Placebo Linaclotide Total
Hide Arm/Group Description Dose-matched placebo, oral administration, once per day. Linaclotide 290μg, oral administration, once per day. Total of all reporting groups
Overall Number of Baseline Participants 403 402 805
Hide Baseline Analysis Population Description
[Not Specified]
Age Continuous  
Mean (Standard Deviation)
Unit of measure:  Years
Number Analyzed 403 participants 402 participants 805 participants
44.0  (13.4) 44.7  (13.1) 44.3  (13.3)
Age, Customized  
Measure Type: Number
Unit of measure:  Participants
Number Analyzed 403 participants 402 participants 805 participants
18 years 64 years 386 379 765
65 years and older 17 23 40
Sex: Female, Male  
Measure Type: Count of Participants
Unit of measure:  Participants
Number Analyzed 403 participants 402 participants 805 participants
Female
352
  87.3%
369
  91.8%
721
  89.6%
Male
51
  12.7%
33
   8.2%
84
  10.4%
Region of Enrollment  
Measure Type: Number
Unit of measure:  Participants
United States Number Analyzed 403 participants 402 participants 805 participants
403 402 805
1.Primary Outcome
Title Abdominal Pain and Complete Spontaneous Bowel Movement (APC) Responder, 9 Out of 12 Weeks
Hide Description

A patient is considered to be a 9 out of 12 week APC responder if, for at least 9 out of the first 12 weeks of the treatment period, the patient had at least 3 CSBMs, had an increase of at least 1 CSBM from baseline, and had a decrease of at least 30 percent in their Abdominal Pain (AP) score from baseline during a particular week.

The AP score assesses patient's worst AP in the past 24 hours using an 11-point scale (from 0-10), where 0 represents no AP and 10 represents very severe AP.

SBM is defined as a bowel movement that occurs in the absence of laxative, enema, or suppository use on either the calendar day of the bowel movement or the calendar day before the bowel movement. CSBM is defined as an SBM associated with a sense of complete evacuation.

Time Frame Change from Baseline to Week 12
Hide Outcome Measure Data
Hide Analysis Population Description
805 patients were randomized to treatment. 804 patients had at least 1 postrandomization entry of the primary efficacy assessment and were included in the Intent to Treat (ITT) Population. An observed-cases approach to missing postbaseline data was applied.
Arm/Group Title Placebo Linaclotide
Hide Arm/Group Description:
Dose-matched placebo, oral administration, once per day.
Linaclotide 290μg, oral administration, once per day.
Overall Number of Participants Analyzed 403 401
Measure Type: Number
Unit of Measure: participants
12 51
Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection Placebo, Linaclotide
Comments Null Hypothesis: There is no difference between the 290 μg dose and placebo groups in the proportion of 9/12 Week APC 3 + 1 Responders. The power, adjusted for multiplicity, was expected to be 93% based on NCT00460811 (MCP-103-202) study data.
Type of Statistical Test Superiority or Other
Comments [Not Specified]
Statistical Test of Hypothesis P-Value <0.0001
Comments The p-value is still less than 0.05 after adjusting multiplicity using a serial gatekeeping multiple comparison procedure.
Method Cochran-Mantel-Haenszel
Comments [Not Specified]
Method of Estimation Estimation Parameter Odds Ratio (OR)
Estimated Value 4.65
Confidence Interval (2-Sided) 95%
2.44 to 8.84
Estimation Comments [Not Specified]
2.Primary Outcome
Title Complete Spontaneous Bowel Movement (CSBM) 3+1 Responder, 9 Out of 12 Weeks
Hide Description

A patient is considered to be a CSBM 3+1 responder if, for at least 9 out of the 12 weeks of the treatment period, the patient had at least 3 CSBMs and experienced an increase of at least 1 CSBM from baseline during a particular week.

A CSBM was defined as a Spontaneous Bowel Movement (SBM) that was associated with a sense of complete evacuation.

An SBM was 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.

Time Frame Change from Baseline to Week 12
Hide Outcome Measure Data
Hide Analysis Population Description
805 patients were randomized to treatment. 804 patients had at least 1 postrandomization entry of the primary efficacy assessment and were included in the ITT Population. An observed-cases approach to missing postbaseline data was applied.
Arm/Group Title Placebo Linaclotide
Hide Arm/Group Description:
Dose-matched placebo, oral administration, once per day.
Linaclotide 290μg, oral administration, once per day.
Overall Number of Participants Analyzed 403 401
Measure Type: Number
Unit of Measure: participants
20 72
Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection Placebo, Linaclotide
Comments Null Hypothesis: There is no difference between the 290 μg dose and placebo groups in the proportion of 9/12 Week CSBM 3 + 1 Responders. The power, adjusted for multiplicity, was expected to be 93% based on NCT00460811 (MCP-103-202) study data.
Type of Statistical Test Superiority or Other
Comments [Not Specified]
Statistical Test of Hypothesis P-Value <0.0001
Comments The p-value is still less than 0.05 after adjusting multiplicity using a serial gatekeeping multiple comparison procedure.
Method Cochran-Mantel-Haenszel
Comments [Not Specified]
Method of Estimation Estimation Parameter Odds Ratio (OR)
Estimated Value 4.19
Confidence Interval (2-Sided) 95%
2.50 to 7.03
Estimation Comments [Not Specified]
3.Primary Outcome
Title Abdominal Pain Responder, 9 Out of 12 Weeks
Hide Description

A patient is considered to be an abdominal pain responder if, for at least 9 out of the 12 weeks of the treatment period, they experienced a decrease of at least 30 percent in the mean abdominal pain score from baseline during a particular week.

The Abdominal Pain score assesses patient's worst abdominal pain in the past 24 hours using an 11-point scale (from 0-10), where 0 represents no abdominal pain and 10 represents very severe abdominal pain.

Time Frame Change from Baseline to Week 12
Hide Outcome Measure Data
Hide Analysis Population Description
805 patients were randomized to treatment. 804 patients had at least 1 postrandomization entry of the primary efficacy assessment and were included in the ITT Population. An observed-cases approach to missing postbaseline data was applied.
Arm/Group Title Placebo Linaclotide
Hide Arm/Group Description:
Dose-matched placebo, oral administration, once per day.
Linaclotide 290μg, oral administration, once per day.
Overall Number of Participants Analyzed 403 401
Measure Type: Number
Unit of Measure: participants
79 156
Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection Placebo, Linaclotide
Comments Null Hypothesis: There is no difference between the 290 μg dose and placebo groups in the proportion of 9/12 Week Abdominal Pain Responders. The power, adjusted for multiplicity, was expected to be 93% based on NCT00460811 (MCP-103-202) study data.
Type of Statistical Test Superiority or Other
Comments [Not Specified]
Statistical Test of Hypothesis P-Value <0.0001
Comments The p-value is still less than 0.05 after adjusting multiplicity using a serial gatekeeping multiple comparison procedure.
Method Cochran-Mantel-Haenszel
Comments [Not Specified]
Method of Estimation Estimation Parameter Odds Ratio (OR)
Estimated Value 2.62
Confidence Interval (2-Sided) 95%
1.91 to 3.60
Estimation Comments [Not Specified]
4.Primary Outcome
Title Abdominal Pain and Complete Spontaneous Bowel Movement (APC) Responder, 6 Out of 12 Weeks
Hide Description

A patient is considered to be a 6 out of 12 week APC responder if, for at least 6 out of the first 12 weeks of the treatment period, the patient had an increase of at least 1 CSBM from baseline, and had a decrease of at least 30 percent in their Abdominal Pain (AP) score from baseline during a particular week.

The AP score assesses patient's worst AP in the past 24 hours using an 11-point scale (from 0-10), where 0 represents no AP and 10 represents very severe AP.

SBM is defined as a bowel movement that occurs in the absence of laxative, enema, or suppository use on either the calendar day of the bowel movement or the calendar day before the bowel movement. CSBM is defined as an SBM associated with a sense of complete evacuation.

Time Frame Change from Baseline to Week 12
Hide Outcome Measure Data
Hide Analysis Population Description
805 patients were randomized to treatment. 804 patients had at least 1 postrandomization entry of the primary efficacy assessment and were included in the ITT Population. An observed-cases approach to missing postbaseline data was applied.
Arm/Group Title Placebo Linaclotide
Hide Arm/Group Description:
Dose-matched placebo, oral administration, once per day.
Linaclotide 290μg, oral administration, once per day.
Overall Number of Participants Analyzed 403 401
Measure Type: Number
Unit of Measure: participants
56 135
Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection Placebo, Linaclotide
Comments

Null Hypothesis: There is no difference between the 290 μg dose and placebo groups in the proportion of 6/12 Week APC + 1 Responders.

The power, adjusted for multiplicity, was expected to be 86% based on NCT00460811 (MCP-103-202) study data.

Type of Statistical Test Superiority or Other
Comments [Not Specified]
Statistical Test of Hypothesis P-Value <0.0001
Comments The p-value is still less than 0.05 after adjusting multiplicity using a serial gatekeeping multiple comparison procedure.
Method Cochran-Mantel-Haenszel
Comments [Not Specified]
Method of Estimation Estimation Parameter Odds Ratio (OR)
Estimated Value 3.16
Confidence Interval (2-Sided) 95%
2.22 to 4.49
Estimation Comments [Not Specified]
5.Secondary Outcome
Title 12-Week Complete Spontaneous Bowel Movement (CSBM) Frequency
Hide Description The change from baseline in 12-week CSBM frequency (i.e., weekly CSBM frequency over the first 12 weeks of the Treatment Period).
Time Frame Change from Baseline to Week 12
Hide Outcome Measure Data
Hide Analysis Population Description
805 patients were randomized to treatment. 804 patients had at least 1 postrandomization entry of the primary efficacy assessment and were included in the ITT Population. An observed-cases approach to missing postbaseline data was applied.
Arm/Group Title Placebo Linaclotide
Hide Arm/Group Description:
Dose-matched placebo, oral administration, once per day.
Linaclotide 290μg, oral administration, once per day.
Overall Number of Participants Analyzed 403 401
Least Squares Mean (Standard Error)
Unit of Measure: CSBMs per Week
0.70  (0.12) 2.24  (0.12)
6.Secondary Outcome
Title 12-Week Spontaneous Bowl Movement (SBM) Frequency
Hide Description The change from baseline in 12-week SBM frequency (i.e., weekly SBM frequency over the first 12 weeks of the Treatment Period).
Time Frame Change from Baseline to Week 12
Hide Outcome Measure Data
Hide Analysis Population Description
805 patients were randomized to treatment. 804 patients had at least 1 postrandomization entry of the primary efficacy assessment and were included in the ITT Population. An observed-cases approach to missing postbaseline data was applied.
Arm/Group Title Placebo Linaclotide
Hide Arm/Group Description:
Dose-matched placebo, oral administration, once per day.
Linaclotide 290μg, oral administration, once per day.
Overall Number of Participants Analyzed 403 401
Least Squares Mean (Standard Error)
Unit of Measure: SBMs per Week
1.31  (0.18) 4.02  (0.18)
7.Secondary Outcome
Title 12-Week Change in Stool Consistency
Hide Description

The consistency of each BM was assessed by patients using the 7-point Bristol Stool Form Scale (BSFS) from 1 to 7.

  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]).
Time Frame Change from Baseline to Week 12
Hide Outcome Measure Data
Hide Analysis Population Description
805 patients were randomized to treatment; 804 patients had at least 1 postrandomization entry of the primary efficacy assessment and included in the ITT Population; 134 patients with no pretreatment spontaneous bowel movements were excluded from the Stool Consistency analysis. An observed-cases approach to missing postbaseline data was applied.
Arm/Group Title Placebo Linaclotide
Hide Arm/Group Description:
Dose-matched placebo, oral administration, once per day.
Linaclotide 290μg, oral administration, once per day.
Overall Number of Participants Analyzed 332 338
Least Squares Mean (Standard Error)
Unit of Measure: Units on a scale
0.61  (0.06) 1.91  (0.06)
8.Secondary Outcome
Title 12-Week Change in Severity of Straining
Hide Description Straining is measured on a 5-point scale where a value of 1 is "not at all" and a value of 5 is "an extreme amount".
Time Frame Change from Baseline to Week 12
Hide Outcome Measure Data
Hide Analysis Population Description
805 patients were randomized to treatment; 804 patients had at least 1 postrandomization entry of the primary efficacy assessment and included in the ITT Population; 134 patients with no pretreatment spontaneous bowel movements were excluded from the Straining analysis. An observed-cases approach to missing postbaseline data was applied.
Arm/Group Title Placebo Linaclotide
Hide Arm/Group Description:
Dose-matched placebo, oral administration, once per day.
Linaclotide 290μg, oral administration, once per day.
Overall Number of Participants Analyzed 332 338
Least Squares Mean (Standard Error)
Unit of Measure: Units on a scale
-0.66  (0.05) -1.24  (0.04)
9.Secondary Outcome
Title 12-Week Change in Abdominal Pain Score
Hide Description Abdominal Pain at its worst (in the last 24 hours) is based on an 11-point scale where 0 represents no abdominal pain and 10 represents very severe abdominal pain.
Time Frame Change from Baseline to Week 12
Hide Outcome Measure Data
Hide Analysis Population Description
805 patients were randomized to treatment. 804 patients had at least 1 postrandomization entry of the primary efficacy assessment and were included in the ITT Population. An observed-cases approach to missing postbaseline data was applied.
Arm/Group Title Placebo Linaclotide
Hide Arm/Group Description:
Dose-matched placebo, oral administration, once per day.
Linaclotide 290μg, oral administration, once per day.
Overall Number of Participants Analyzed 403 401
Least Squares Mean (Standard Error)
Unit of Measure: Units on a scale
-1.07  (0.09) -1.85  (0.09)
10.Secondary Outcome
Title 12-Week Change in Abdominal Discomfort
Hide Description Abdominal discomfort was assessed on an 11-point scale where a value of 0 is "none" and a value of 10 is "very severe".
Time Frame Change from Baseline to Week 12
Hide Outcome Measure Data
Hide Analysis Population Description
805 patients were randomized to treatment. 804 patients had at least 1 postrandomization entry of the primary efficacy assessment and were included in the ITT Population. An observed-cases approach to missing postbaseline data was applied.
Arm/Group Title Placebo Linaclotide
Hide Arm/Group Description:
Dose-matched placebo, oral administration, once per day.
Linaclotide 290μg, oral administration, once per day.
Overall Number of Participants Analyzed 403 401
Least Squares Mean (Standard Error)
Unit of Measure: Units on a scale
-1.10  (0.09) -1.94  (0.09)
11.Secondary Outcome
Title 12-Week Change in Bloating
Hide Description Bloating was assessed on an 11-point scale where a value of 0 is "none" and a value of 10 is "very severe".
Time Frame Change from Baseline to Week 12
Hide Outcome Measure Data
Hide Analysis Population Description
805 patients were randomized to treatment. 804 patients had at least 1 postrandomization entry of the primary efficacy assessment and were included in the ITT Population. An observed-cases approach to missing postbaseline data was applied.
Arm/Group Title Placebo Linaclotide
Hide Arm/Group Description:
Dose-matched placebo, oral administration, once per day.
Linaclotide 290μg, oral administration, once per day.
Overall Number of Participants Analyzed 403 401
Least Squares Mean (Standard Error)
Unit of Measure: Units on a scale
-1.03  (0.10) -1.91  (0.09)
12.Secondary Outcome
Title Complete Spontaneous Bowl Movement (CSBM) Responder for 6 Weeks Out of 12 Weeks of Treatment
Hide Description A patient is considered to be a CSBM responder if, for at least 6 out of the 12 weeks of the treatment period, an increase of at least 1 CSBM per week from baseline was experienced.
Time Frame Change from Baseline to Week 12
Hide Outcome Measure Data
Hide Analysis Population Description
805 patients were randomized to treatment. 804 patients had at least 1 postrandomization entry of the primary efficacy assessment and were included in the ITT Population. An observed-cases approach to missing postbaseline data was applied.
Arm/Group Title Placebo Linaclotide
Hide Arm/Group Description:
Dose-matched placebo, oral administration, once per day.
Linaclotide 290μg, oral administration, once per day.
Overall Number of Participants Analyzed 403 401
Measure Type: Number
Unit of Measure: participants
91 191
13.Secondary Outcome
Title Abdominal Pain Responder for 6 Out of 12 Weeks
Hide Description A patient is considered to be an AP responder if, for at least 6 out of the first 12 weeks of the treatment period, the patient had a decrease of at least 30 percent in their Abdominal Pain score from baseline during a particular week.
Time Frame Change from Baseline to Week 12
Hide Outcome Measure Data
Hide Analysis Population Description
805 patients were randomized to treatment. 804 patients had at least 1 postrandomization entry of the primary efficacy assessment and were included in the ITT Population. An observed-cases approach to missing postbaseline data was applied.
Arm/Group Title Placebo Linaclotide
Hide Arm/Group Description:
Dose-matched placebo, oral administration, once per day.
Linaclotide 290μg, oral administration, once per day.
Overall Number of Participants Analyzed 403 401
Measure Type: Number
Unit of Measure: participants
139 196
14.Secondary Outcome
Title 12-Week Percent of Abdominal Pain-free Days
Hide Description

Abdominal pain free (APF) days are those days where the patient reported a score of '0' for abdominal pain at its worst.

Abdominal Pain at its worst (in the last 24 hours) is based on an 11-point scale where 0 represents no abdominal pain and 10 represents very severe abdominal pain.

Time Frame Change from Baseline to Week 12
Hide Outcome Measure Data
Hide Analysis Population Description
805 patients were randomized to treatment. 804 patients had at least 1 postrandomization entry of the primary efficacy assessment and were included in the ITT Population. An observed-cases approach to missing postbaseline data was applied.
Arm/Group Title Placebo Linaclotide
Hide Arm/Group Description:
Dose-matched placebo, oral administration, once per day.
Linaclotide 290μg, oral administration, once per day.
Overall Number of Participants Analyzed 403 401
Mean (Standard Deviation)
Unit of Measure: Percent of Pain-free Days
4.83  (16.64) 10.49  (23.42)
Time Frame Adverse event data were collected from July of 2009 to September of 2010 (26 weeks of safety data were collected)
Adverse Event Reporting Description [Not Specified]
 
Arm/Group Title Placebo Linaclotide
Hide Arm/Group Description Dose-matched placebo, oral administration, once per day. Linaclotide 290μg, oral administration, once per day.
All-Cause Mortality
Placebo Linaclotide
Affected / at Risk (%) Affected / at Risk (%)
Total   --/--      --/--    
Hide Serious Adverse Events
Placebo Linaclotide
Affected / at Risk (%) # Events Affected / at Risk (%) # Events
Total   7/403 (1.74%)      4/402 (1.00%)    
Ear and labyrinth disorders     
Vertigo   1/403 (0.25%)  1 0/402 (0.00%)  0
Gastrointestinal disorders     
Abdominal pain lower   1/403 (0.25%)  1 0/402 (0.00%)  0
Infections and infestations     
Bronchitis   1/403 (0.25%)  1 0/402 (0.00%)  0
Pneumonia viral   1/403 (0.25%)  1 0/402 (0.00%)  0
Appendicitis   0/403 (0.00%)  0 1/402 (0.25%)  1
Musculoskeletal and connective tissue disorders     
Rotator cuff syndrome   0/403 (0.00%)  0 1/402 (0.25%)  1
Neoplasms benign, malignant and unspecified (incl cysts and polyps)     
Uterine leiomyoma   1/403 (0.25%)  1 0/402 (0.00%)  0
Rectal cancer stage IV   1/403 (0.25%)  1 0/402 (0.00%)  0
Hodgkin's disease nodular sclerosis stage IVa   0/403 (0.00%)  0 1/402 (0.25%)  1
Nervous system disorders     
Transient ischemic attack   1/403 (0.25%)  1 0/402 (0.00%)  0
Skin and subcutaneous tissue disorders     
Angioedema   1/403 (0.25%)  1 0/402 (0.00%)  0
Surgical and medical procedures     
Cystopexy   0/403 (0.00%)  0 1/402 (0.25%)  1
Indicates events were collected by systematic assessment
Hide Other (Not Including Serious) Adverse Events
Frequency Threshold for Reporting Other Adverse Events 5%
Placebo Linaclotide
Affected / at Risk (%) # Events Affected / at Risk (%) # Events
Total   86/403 (21.34%)      137/402 (34.08%)    
Gastrointestinal disorders     
Diarrhea   10/403 (2.48%)  79/402 (19.65%) 
Nausea   24/403 (5.96%)  23/402 (5.72%) 
Infections and infestations     
Sinusitis   28/403 (6.95%)  23/402 (5.72%) 
Upper respiratory tract infection   22/403 (5.46%)  22/402 (5.47%) 
Urinary tract infection   22/403 (5.46%)  17/402 (4.23%) 
Indicates events were collected by systematic assessment
Certain Agreements
Principal Investigators are NOT employed by the organization sponsoring the study.
There IS an agreement between Principal Investigators and the Sponsor (or its agents) that restricts the PI's rights to discuss or publish trial results after the trial is completed.
The disclosure restriction on the PI is that publication cannot be made for 24 months from the date of final data lock of the study, the sponsor can review the publication prior to public release, sponsor requires a minimum 60 day review period for each publication, sponsor can request removal of confidential information of sponsor (not including results of trial), and sponsor can request an additional delay period of 60 days in order to protect potentially patentable information.
Results Point of Contact
Layout table for Results Point of Contact information
Name/Title: Doug Levine, MD
Organization: Ironwood Pharmaceuticals
Phone: 617.374.3906
EMail: dlevine@ironwoodpharma.com
Layout table for additonal information
Responsible Party: Ironwood Pharmaceuticals, Inc.
ClinicalTrials.gov Identifier: NCT00938717    
Other Study ID Numbers: MCP-103-302
First Submitted: July 12, 2009
First Posted: July 14, 2009
Results First Submitted: September 28, 2012
Results First Posted: January 30, 2013
Last Update Posted: November 5, 2013