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A Phase 3, International, Multicenter, Randomized, Double-blind, Placebo-controlled, Parallel-group Efficacy and Safety Trial of Linaclotide Administered Orally for 12 Weeks to Patients With Irritable Bowel Syndrome With Constipation (IBS-C) (D5630C00001)

The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been evaluated by the U.S. Federal Government. Read our disclaimer for details.
 
ClinicalTrials.gov Identifier: NCT01880424
Recruitment Status : Completed
First Posted : June 19, 2013
Results First Posted : September 27, 2016
Last Update Posted : September 27, 2016
Sponsor:
Collaborator:
Ironwood Pharmaceuticals, Inc.
Information provided by (Responsible Party):
AstraZeneca

Study Type Interventional
Study Design Allocation: Randomized;   Intervention Model: Parallel Assignment;   Masking: Double (Participant, Investigator);   Primary Purpose: Treatment
Condition Irritable Bowel Syndrome With Constipation (IBS-C)
Interventions Drug: Placebo
Drug: Linaclotide
Enrollment 1722
Recruitment Details Patient recruitment occurred over an 18-month period from July 2013 to January 2015 at 98 study centers (40 in China, 42 in the US, 10 in Australia, 5 in New Zealand, and 1 in Canada).
Pre-assignment Details Patients went through a 14 to 21-day Pretreatment Period during which they provided qualifying bowel habit and symptom severity assessments and rescue medicine usage through an electronic diary (eDiary). 1722 patients provided consents with 839 qualified to join th study.
Arm/Group Title Linaclotide Arm Placebo Arm
Hide Arm/Group Description Linaclotide 290 ug capsules, oral, once daily matching placebo capsules, oral, once daily
Period Title: Overall Study
Started 417 422
Completed 384 367
Not Completed 33 55
Reason Not Completed
Adverse Event             7             6
Lack of Efficacy             1             4
Lost to Follow-up             3             2
Protocol Violation             11             13
Withdrawal by Subject             10             30
Other             1             0
Arm/Group Title Linaclotide Arm Placebo Arm Total
Hide Arm/Group Description Linaclotide 290 ug capsules, oral, once daily matching placebo capsules, oral, once daily Total of all reporting groups
Overall Number of Baseline Participants 417 422 839
Hide Baseline Analysis Population Description
Intent to Treat (ITT) Population (all 839 randomized patients)
Age, Continuous  
Mean (Standard Deviation)
Unit of measure:  Years
Number Analyzed 417 participants 422 participants 839 participants
41.0  (13.1) 41.3  (13.5) 41.1  (13.3)
Age, Customized  
Measure Type: Number
Unit of measure:  Participants
Number Analyzed 417 participants 422 participants 839 participants
between 18 to 65 years 400 405 805
>= 65 years 17 17 34
Sex: Female, Male  
Measure Type: Count of Participants
Unit of measure:  Participants
Number Analyzed 417 participants 422 participants 839 participants
Female
333
  79.9%
355
  84.1%
688
  82.0%
Male
84
  20.1%
67
  15.9%
151
  18.0%
countries  
Measure Type: Number
Unit of measure:  Participants
Number Analyzed 417 participants 422 participants 839 participants
China 327 332 659
Canada 3 3 6
Australia 19 14 33
New Zealand 4 4 8
United States 64 69 133
1.Primary Outcome
Title 12-week Abdominal Pain/Abdominal Discomfort Weekly Responder
Hide Description

A 12-week Abdominal Pain/Abdominal Discomfort Responder is a patient who meets the Abdominal Pain/Abdominal Discomfort Weekly Responder criteria (i.e., an improvement of ≥30% from baseline in either the mean abdominal pain score or mean abdominal discomfort score for that week, with neither score worsening from baseline for that week) for at least 6 out of the 12 weeks of the Treatment Period.

Abdominal pain at its worst (in the last 24 hours) was assessed daily by patients on an 11-point numerical rating scale (NRS) where 0 represents no abdominal pain and 10 represents very severe abdominal pain.

Abdominal discomfort (in the last 24 hours) was assessed daily by patients on an 11-point NRS where 0 represents no abdominal discomfort and 10 represents very severe abdominal discomfort.

Time Frame Baseline and Weeks 1-12 during the Treatment Period
Hide Outcome Measure Data
Hide Analysis Population Description
Intent to Treat (ITT) Population (all 839 randomized patients). If a patient did not have an abdominal pain score or abdominal discomfort score for a particular Treatment Period week, the patient was not considered a responder for that week.
Arm/Group Title Linaclotide Arm Placebo Arm
Hide Arm/Group Description:
Linaclotide 290 ug capsules, oral, once daily
matching placebo capsules, oral, once daily
Overall Number of Participants Analyzed 417 422
Measure Type: Number
Unit of Measure: Participants
250 206
Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection Linaclotide Arm, Placebo Arm
Comments Null Hypothesis: There is no difference between the linaclotide dose and placebo in the proportion of 12-week Abdominal Pain/Abdominal Discomfort Responders or there is no difference in the proportion of 12-week IBS Degree of Relief Responders. With 800 planned patients, the statistical power was expected to be approximately 95%, with an overall type I error rate controlled at the 0.05 level (2-sided), based on assumptions from NCT00948818 (LIN-MD-31) study data.
Type of Statistical Test Superiority or Other
Comments [Not Specified]
Statistical Test of Hypothesis P-Value 0.0010
Comments Statistical significance (p<0.05) was required in both co-primary efficacy parameters to meet the primary efficacy objective; both p-values met this criterion.
Method Cochran-Mantel-Haenszel
Comments Cochran-Mantel-Haenszel test controlling for geographic region
Method of Estimation Estimation Parameter Odds Ratio (OR)
Estimated Value 1.59
Confidence Interval 95%
1.21 to 2.09
Estimation Comments Odds ratio for response rate (linaclotide : placebo)
2.Primary Outcome
Title 12-week Irritable Bowel Syndrome (IBS) Degree of Relief Responder
Hide Description

A 12-week IBS Degree of Relief Responder is a patient who meets the IBS Degree of Relief Weekly Responder criteria (i.e., response to the degree of relief of IBS symptoms question for that week was "Considerably relieved" or "Completely relieved") for at least 6 out of the 12 weeks of the Treatment Period.

Degree of relief of IBS symptoms (in the last 7 days) was assessed weekly by patients on a 7-point balanced ordinal scale where 1 = Completely relieved, 4 = Unchanged, and 7 = As bad as I can imagine.

Time Frame Baseline and Weeks 1-12 during the Treatment Period
Hide Outcome Measure Data
Hide Analysis Population Description
Intent to Treat (ITT) Population (all 839 randomized patients). If a patient did not have an IBS degree of relief score for a particular Treatment Period week, the patient was not considered a responder for that week.
Arm/Group Title Linaclotide Arm Placebo Arm
Hide Arm/Group Description:
Linaclotide 290 ug capsules, oral, once daily
matching placebo capsules, oral, once daily
Overall Number of Participants Analyzed 417 422
Measure Type: Number
Unit of Measure: Participants
132 65
Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection Linaclotide Arm, Placebo Arm
Comments Null Hypothesis: There is no difference between the linaclotide dose and placebo in the proportion of 12-week Abdominal Pain/Abdominal Discomfort Responders or there is no difference in the proportion of 12-week IBS Degree of Relief Responders. With 800 planned patients, the statistical power was expected to be approximately 95%, with an overall type I error rate controlled at the 0.05 level (2-sided), based on assumptions from NCT00948818 (LIN-MD-31) study data.
Type of Statistical Test Superiority or Other
Comments [Not Specified]
Statistical Test of Hypothesis P-Value <0.0001
Comments Statistical significance (p<0.05) was required in both co-primary efficacy parameters to meet the primary efficacy objective; both p-values met this criterion.
Method Cochran-Mantel-Haenszel
Comments Cochran-Mantel-Haenszel test controlling for geographic region
Method of Estimation Estimation Parameter Odds Ratio (OR)
Estimated Value 2.56
Confidence Interval 95%
1.83 to 3.58
Estimation Comments Odds ratio for response rate (linaclotide : placebo)
3.Secondary Outcome
Title Change From Baseline in 12-week Complete Spontaneous Bowel Movement Frequency Rate
Hide Description

The change from baseline in 12-week CSBM frequency (i.e., average weekly CSBM frequency over the 12 weeks of the Treatment Period).

A spontaneous bowel movement (SBM) is defined as a bowel movement without laxative use in the preceding 24 hours. A CSBM is defined as an SBM that is associated with a sense of complete evacuation.

Time Frame Baseline and 12-week Treatment Period
Hide Outcome Measure Data
Hide Analysis Population Description
Intent to Treat (ITT) Population (all 839 randomized patients); analysis includes patients with analysis values at both baseline and during the Treatment Period. An observed cases approach to missing post-baseline data was applied (i.e., no imputation for missing values).
Arm/Group Title Linaclotide Arm Placebo Arm
Hide Arm/Group Description:
Linaclotide 290 ug capsules, oral, once daily
matching placebo capsules, oral, once daily
Overall Number of Participants Analyzed 417 422
Least Squares Mean (Standard Error)
Unit of Measure: CSBMs per Week
1.94  (0.15) 0.97  (0.15)
4.Secondary Outcome
Title Change From Baseline in 12-week Spontaneous Bowel Movement Frequency Rate
Hide Description

The change from baseline in 12-week SBM frequency (i.e., average weekly SBM frequency over the 12 weeks of the Treatment Period).

SBM is defined as a bowel movement without laxative use in the preceding 24 hours.

Time Frame Baseline and 12-week Treatment Period
Hide Outcome Measure Data
Hide Analysis Population Description
Intent to Treat (ITT) Population (all 839 randomized patients); analysis includes patients with analysis values at both baseline and during the Treatment Period. An observed cases approach to missing post-baseline data was applied (i.e., no imputation for missing values).
Arm/Group Title Linaclotide Arm Placebo Arm
Hide Arm/Group Description:
Linaclotide 290 ug capsules, oral, once daily
matching placebo capsules, oral, once daily
Overall Number of Participants Analyzed 417 422
Least Squares Mean (Standard Error)
Unit of Measure: SBMs per Week
2.96  (0.17) 1.51  (0.17)
5.Secondary Outcome
Title Change From Baseline in 12-week Stool Consistency
Hide Description

The change from baseline in 12-week stool consistency (i.e., the average of the non-missing Bristol Stool Form Scale [BSFS] score from the SBMs occurring during the 12-week Treatment Period).

Consistency of each bowel movement was assessed daily by patients using the 7-point BSFS (1=Separate hard lumps like nuts [difficult to pass] to 7=Watery, no solid pieces [entirely liquid]).

Time Frame Baseline and 12-week Treatment Period
Hide Outcome Measure Data
Hide Analysis Population Description
Intent to Treat (ITT) Population (all 839 randomized patients); analysis includes patients with analysis values at both baseline and during the Treatment Period. An observed cases approach to missing post-baseline data was applied (i.e., no imputation for missing values).
Arm/Group Title Linaclotide Arm Placebo Arm
Hide Arm/Group Description:
Linaclotide 290 ug capsules, oral, once daily
matching placebo capsules, oral, once daily
Overall Number of Participants Analyzed 371 360
Least Squares Mean (Standard Error)
Unit of Measure: Units on a Scale (BSFS)
1.51  (0.07) 0.82  (0.07)
6.Secondary Outcome
Title Change From Baseline in 12-week Severity of Straining
Hide Description

The change from baseline in 12-week severity of straining (i.e., the average of the non-missing straining scores from the SBMs occurring during the 12-week Treatment Period).

Severity of straining was assessed daily by patients on a 5-point ordinal scale (1=Not at all to 5=An extreme amount).

Time Frame Baseline and 12-week Treatment Period
Hide Outcome Measure Data
Hide Analysis Population Description
Intent to Treat (ITT) Population (all 839 randomized patients); analysis includes patients with analysis values at both baseline and during the Treatment Period. An observed cases approach to missing post-baseline data was applied (i.e., no imputation for missing values).
Arm/Group Title Linaclotide Arm Placebo Arm
Hide Arm/Group Description:
Linaclotide 290 ug capsules, oral, once daily
matching placebo capsules, oral, once daily
Overall Number of Participants Analyzed 371 360
Least Squares Mean (Standard Error)
Unit of Measure: Units on a Scale
-1.02  (0.05) -0.69  (0.05)
7.Secondary Outcome
Title Change From Baseline in 12-week Abdominal Bloating
Hide Description

The change from baseline in 12-week abdominal bloating (i.e., the average of the non-missing daily abdominal bloating scores reported during the 12-week Treatment Period).

Abdominal bloating (in the last 24 hours) was assessed daily by patients on an 11-point NRS where 0 represents no abdominal bloating and 10 represents very severe abdominal bloating.

Time Frame Baseline and 12-week Treatment Period
Hide Outcome Measure Data
Hide Analysis Population Description
Intent to Treat (ITT) Population (all 839 randomized patients); analysis includes patients with analysis values at both baseline and during the Treatment Period. An observed cases approach to missing post-baseline data was applied (i.e., no imputation for missing values).
Arm/Group Title Linaclotide Arm Placebo Arm
Hide Arm/Group Description:
Linaclotide 290 ug capsules, oral, once daily
matching placebo capsules, oral, once daily
Overall Number of Participants Analyzed 417 419
Least Squares Mean (Standard Error)
Unit of Measure: Units on a Scale
-1.50  (0.12) -0.94  (0.12)
8.Secondary Outcome
Title Change From Baseline in 12-week Abdominal Pain
Hide Description

The change from baseline in 12-week abdominal pain (i.e., the average of the non-missing daily abdominal pain scores reported during the 12-week Treatment Period).

Abdominal pain at its worst (in the last 24 hours) was assessed daily by patients on an 11-point NRS where 0 represents no abdominal pain and 10 represents very severe abdominal pain.

Time Frame Baseline and 12-week Treatment Period
Hide Outcome Measure Data
Hide Analysis Population Description
Intent to Treat (ITT) Population (all 839 randomized patients); analysis includes patients with analysis values at both baseline and during the Treatment Period. An observed cases approach to missing post-baseline data was applied (i.e., no imputation for missing values).
Arm/Group Title Linaclotide Arm Placebo Arm
Hide Arm/Group Description:
Linaclotide 290 ug capsules, oral, once daily
matching placebo capsules, oral, once daily
Overall Number of Participants Analyzed 417 419
Least Squares Mean (Standard Error)
Unit of Measure: Units on a Scale
-1.56  (0.12) -1.07  (0.12)
9.Secondary Outcome
Title Change From Baseline in 12-week Abdominal Discomfort
Hide Description

The change from baseline in 12-week abdominal discomfort (i.e., the average of the non-missing daily abdominal discomfort scores reported during the 12-week Treatment Period).

Abdominal discomfort (in the last 24 hours) was assessed daily by patients on an 11-point NRS where 0 represents no abdominal discomfort and 10 represents very severe abdominal discomfort.

Time Frame Baseline and 12-week Treatment Period
Hide Outcome Measure Data
Hide Analysis Population Description
Intent to Treat (ITT) Population (all 839 randomized patients); analysis includes patients with analysis values at both baseline and during the Treatment Period. An observed cases approach to missing post-baseline data was applied (i.e., no imputation for missing values).
Arm/Group Title Linaclotide Arm Placebo Arm
Hide Arm/Group Description:
Linaclotide 290 ug capsules, oral, once daily
matching placebo capsules, oral, once daily
Overall Number of Participants Analyzed 417 419
Least Squares Mean (Standard Error)
Unit of Measure: Units on a Scale
-1.46  (0.12) -0.98  (0.12)
Time Frame Adverse event data were collected from July 2013 to May 2015 (12 weeks of safety data were collected). Includes serious adverse events that occurred on or after the date of the first dose of study drug and within 30 days of the last dose of study drug.
Adverse Event Reporting Description Of the 839 randomized patients, a total of 835 patients received at least one dose of double-blind study drug and were included in the Safety Population.
 
Arm/Group Title Linaclotide Arm Placebo Arm
Hide Arm/Group Description Linaclotide 290 ug capsules, oral, once daily matching placebo capsules, oral, once daily
All-Cause Mortality
Linaclotide Arm Placebo Arm
Affected / at Risk (%) Affected / at Risk (%)
Total   --/--      --/--    
Hide Serious Adverse Events
Linaclotide Arm Placebo Arm
Affected / at Risk (%) # Events Affected / at Risk (%) # Events
Total   4/416 (0.96%)      10/419 (2.39%)    
Gastrointestinal disorders     
Colitis  1  0/416 (0.00%)  0 1/419 (0.24%)  1
General disorders     
Non-cardiac chest pain  1  0/416 (0.00%)  0 1/419 (0.24%)  1
Infections and infestations     
Pericoronitis  1  1/416 (0.24%)  1 0/419 (0.00%)  0
Neoplasms benign, malignant and unspecified (incl cysts and polyps)     
Uterine leiomyoma  1  0/416 (0.00%)  0 1/419 (0.24%)  1
Nervous system disorders     
Multiple system atrophy  1  0/416 (0.00%)  0 1/419 (0.24%)  1
Pregnancy, puerperium and perinatal conditions     
Abortion spontaneous  1  0/416 (0.00%)  0 1/419 (0.24%)  1
Ectopic pregnancy  1  1/416 (0.24%)  1 0/419 (0.00%)  0
Renal and urinary disorders     
Bladder outlet obstruction  1  0/416 (0.00%)  0 1/419 (0.24%)  1
Respiratory, thoracic and mediastinal disorders     
Chronic obstructive pulmonary disease  1  1/416 (0.24%)  1 0/419 (0.00%)  0
Surgical and medical procedures     
Abortion induced  1  1/416 (0.24%)  1 4/419 (0.95%)  4
Indicates events were collected by systematic assessment
1
Term from vocabulary, MedDRA Version 16.0
Hide Other (Not Including Serious) Adverse Events
Frequency Threshold for Reporting Other Adverse Events 0.03%
Linaclotide Arm Placebo Arm
Affected / at Risk (%) # Events Affected / at Risk (%) # Events
Total   56/416 (13.46%)      26/419 (6.21%)    
Gastrointestinal disorders     
Diarrhea  1  39/416 (9.38%)  39 5/419 (1.19%)  5
Infections and infestations     
Upper respiratory tract infection  1  18/416 (4.33%)  18 21/419 (5.01%)  21
Indicates events were collected by systematic assessment
1
Term from vocabulary, MedDRA Version 16.0
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.
All data generated in this trial will be the property of AstraZeneca and Ironwood Pharmaceuticals, Inc. An integrated clinical and statistical report will be prepared at the completion of the trial. Publication of the results by the Investigator will be subject to mutual agreement between the Investigator, AstraZeneca, and Ironwood Pharmaceuticals, Inc.
Results Point of Contact
Layout table for Results Point of Contact information
Name/Title: Peter Zeng
Organization: AstraZeneca
Phone: +86 21 6030 1867
EMail: peter.zeng@astrazeneca.com
Layout table for additonal information
Responsible Party: AstraZeneca
ClinicalTrials.gov Identifier: NCT01880424    
Other Study ID Numbers: ICP-103-307
First Submitted: June 12, 2013
First Posted: June 19, 2013
Results First Submitted: April 28, 2016
Results First Posted: September 27, 2016
Last Update Posted: September 27, 2016