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Phase III, Randomized, Double-Blind, Placebo-Controlled, Trial of Linaclotide Administered to Patients With Chronic Constipation

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ClinicalTrials.gov Identifier: NCT00765882
Recruitment Status : Completed
First Posted : October 3, 2008
Results First Posted : January 30, 2013
Last Update Posted : January 30, 2013
Sponsor:
Collaborator:
Ironwood Pharmaceuticals, Inc.
Information provided by (Responsible Party):
Forest Laboratories

Study Type Interventional
Study Design Allocation: Randomized;   Intervention Model: Parallel Assignment;   Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor);   Primary Purpose: Treatment
Condition Chronic Constipation
Interventions Drug: Linaclotide 290 micrograms
Drug: Linaclotide 145 micrograms
Drug: Placebo
Enrollment 633
Recruitment Details Patient Recruitment occurred from October 2008 to March 2009 at 103 study centers (95 in the United States and 8 in Canada).
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).
Arm/Group Title Placebo Linaclotide 145µg Linaclotide 290µg
Hide Arm/Group Description Dose matched placebo, oral administration, once per day. Linaclotide, 145µg dose, oral administration, once per day Linaclotide, 290µg dose, oral administration, once per day
Period Title: Overall Study
Started 215 213 205
Completed 191 173 169
Not Completed 24 40 36
Reason Not Completed
Adverse Event             10             21             20
Lack of Efficacy             4             0             1
Protocol Violation             4             3             1
Withdrawal by Subject             2             6             6
Lost to Follow-up             1             9             6
Other Reason             3             1             2
Arm/Group Title Placebo Linaclotide 145µg Linaclotide 290µg Total
Hide Arm/Group Description Dose matched placebo, oral administration, once per day. Linaclotide, 145µg dose, oral administration, once per day Linaclotide, 290µg dose, oral administration, once per day Total of all reporting groups
Overall Number of Baseline Participants 215 213 205 633
Hide Baseline Analysis Population Description
[Not Specified]
Age Continuous  
Mean (Standard Deviation)
Unit of measure:  Years
Number Analyzed 215 participants 213 participants 205 participants 633 participants
47.0  (13.5) 48.5  (12.3) 47.3  (13.3) 47.6  (13.0)
Age, Customized  
Measure Type: Number
Unit of measure:  Participants
Number Analyzed 215 participants 213 participants 205 participants 633 participants
18 years to 64 years 188 189 183 560
65 years and older 27 24 22 73
Sex: Female, Male  
Measure Type: Count of Participants
Unit of measure:  Participants
Number Analyzed 215 participants 213 participants 205 participants 633 participants
Female
196
  91.2%
195
  91.5%
181
  88.3%
572
  90.4%
Male
19
   8.8%
18
   8.5%
24
  11.7%
61
   9.6%
Region of Enrollment  
Measure Type: Number
Unit of measure:  Participants
Number Analyzed 215 participants 213 participants 205 participants 633 participants
United States 208 208 198 614
Canada 7 5 7 19
1.Primary Outcome
Title Complete Spontaneous Bowel Movement (CSBM) Overall Responder
Hide Description

A 12-week CSBM overall responders was defined as a patient who for at least 9 of the 12 weeks of the treatment period had a CSBM weekly frequency rate that was 3 or greater and increased by 1 or more from baseline.

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
A total of 633 patients were randomized to treatment and received at least 1 dose of study drug. 630 patients were included in the Intent to Treat (ITT) Population. An observed-cases approach to missing postbaseline data was applied.
Arm/Group Title Placebo Linaclotide 145µg Linaclotide 290µg
Hide Arm/Group Description:
Dose matched placebo, oral administration, once per day.
Linaclotide, 145µg dose, oral administration, once per day
Linaclotide, 290µg dose, oral administration, once per day
Overall Number of Participants Analyzed 215 213 202
Measure Type: Number
Unit of Measure: participants
Responder 13 34 43
Nonresponder 202 179 159
Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection Placebo, Linaclotide 145µg
Comments

Null hypothesis: There is no difference in the proportion of 12-week CSBM overall responders between patients taking the 145-μg dose and those taking placebo.

The power, adjusted for multiplicity, was expected to be 90% based on study NCT00402337 (MCP-103-201) data.

Type of Statistical Test Superiority or Other
Comments [Not Specified]
Statistical Test of Hypothesis P-Value 0.0012
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 2.93
Confidence Interval (2-Sided) 95%
1.50 to 5.72
Estimation Comments [Not Specified]
Hide Statistical Analysis 2
Statistical Analysis Overview Comparison Group Selection Placebo, Linaclotide 290µg
Comments

Null hypothesis: There is no difference in the proportion of 12-week CSBM overall responders between patients taking the 290-μg dose and those taking placebo.

The power, adjusted for multiplicity, was expected to be 96% based on study NCT00460811 (MCP-103-202) 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 4.22
Confidence Interval (2-Sided) 95%
2.20 to 8.10
Estimation Comments [Not Specified]
2.Secondary Outcome
Title 12-week Complete Spontaneous Bowel Movement (CSBM) Frequency Rate
Hide Description The number of CSBMs per week.
Time Frame Change from Baseline to Week 12
Hide Outcome Measure Data
Hide Analysis Population Description
A total of 633 patients were randomized to treatment and received at least 1 dose of study drug. 630 patients were included in the Intent to Treat (ITT) Population. An observed-cases approach to missing postbaseline data was applied.
Arm/Group Title Placebo Linaclotide 145µg Linaclotide 290µg
Hide Arm/Group Description:
Dose matched placebo, oral administration, once per day.
Linaclotide, 145µg dose, oral administration, once per day
Linaclotide, 290µg dose, oral administration, once per day
Overall Number of Participants Analyzed 215 213 202
Least Squares Mean (Standard Error)
Unit of Measure: CSBM per week
0.614  (0.209) 2.011  (0.215) 2.653  (0.217)
3.Secondary Outcome
Title 12-Week Spontaneous Bowel Movement (SBM) Frequency Rate
Hide Description A patient's 12-week spontaneous bowel movement (SBM) frequency rate was the number of SBMs per week calculated over the 12-weeks of the treatment period.
Time Frame Change from Baseline to Week 12
Hide Outcome Measure Data
Hide Analysis Population Description
A total of 633 patients were randomized to treatment and received at least 1 dose of study drug. 630 patients were included in the Intent to Treat (ITT) Population. An observed-cases approach to missing postbaseline data was applied.
Arm/Group Title Placebo Linaclotide 145µg Linaclotide 290µg
Hide Arm/Group Description:
Dose matched placebo, oral administration, once per day.
Linaclotide, 145µg dose, oral administration, once per day
Linaclotide, 290µg dose, oral administration, once per day
Overall Number of Participants Analyzed 215 213 202
Least Squares Mean (Standard Error)
Unit of Measure: SBM per week
1.113  (0.265) 3.466  (0.272) 3.675  (0.275)
4.Secondary Outcome
Title 12-Week Stool Consistency
Hide Description

The consistency of each BM was assessed using the 7-point Bristol Stool Form Scale:

  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
A total of 633 patients were randomized to treatment and received at least 1 dose of study drug. 630 patients were included in the ITT Population; 97 patients with no pretreatment spontaneous bowel movements were excluded from the 12-Week Stool Consistency analysis. An observed-cases approach to missing postbaseline data was applied.
Arm/Group Title Placebo Linaclotide 145µg Linaclotide 290µg
Hide Arm/Group Description:
Dose matched placebo, oral administration, once per day.
Linaclotide, 145µg dose, oral administration, once per day
Linaclotide, 290µg dose, oral administration, once per day
Overall Number of Participants Analyzed 183 182 168
Least Squares Mean (Standard Error)
Unit of Measure: units on a scale
0.572  (0.098) 1.823  (0.100) 2.009  (0.103)
5.Secondary Outcome
Title 12-Week 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
A total of 633 patients were randomized to treatment and received at least 1 dose of study drug. 630 patients were included in the ITT Population; 97 Patients with no pretreatment spontaneous bowel movements were excluded from the 12-Week Severity of Straining analysis. An observed-cases approach to missing postbaseline data was applied.
Arm/Group Title Placebo Linaclotide 145µg Linaclotide 290µg
Hide Arm/Group Description:
Dose matched placebo, oral administration, once per day.
Linaclotide, 145µg dose, oral administration, once per day
Linaclotide, 290µg dose, oral administration, once per day
Overall Number of Participants Analyzed 183 182 168
Least Squares Mean (Standard Error)
Unit of Measure: units on a scale
-0.554  (0.060) -1.141  (0.061) -1.208  (0.063)
6.Secondary Outcome
Title 12-Week Abdominal Discomfort
Hide Description Abdominal discomfort is based on a 5-point scale where a value of l is "none" and a value of 5 is "very severe."
Time Frame Change from Baseline to Week 12
Hide Outcome Measure Data
Hide Analysis Population Description
A total of 633 patients were randomized to treatment and received at least 1 dose of study drug. 630 patients were included in the Intent to Treat (ITT) Population. 1 additional patient without a baseline Abdominal Discomfort score was excluded from analysis in this endpoint. An observed-cases approach to missing postbaseline data was applied.
Arm/Group Title Placebo Linaclotide 145µg Linaclotide 290µg
Hide Arm/Group Description:
Dose matched placebo, oral administration, once per day.
Linaclotide, 145µg dose, oral administration, once per day
Linaclotide, 290µg dose, oral administration, once per day
Overall Number of Participants Analyzed 215 213 201
Least Squares Mean (Standard Error)
Unit of Measure: units on a scale
-0.271  (0.043) -0.455  (0.044) -0.485  (0.045)
7.Secondary Outcome
Title 12-Week Bloating
Hide Description Bloating was based on a 5-point scale where a value of l is "none" and a value of 5 is "very severe".
Time Frame Change from Baseline to Week 12
Hide Outcome Measure Data
Hide Analysis Population Description
A total of 633 patients were randomized to treatment and received at least 1 dose of study drug. 630 patients were included in the ITT population; 1 additional patient without a baseline Bloating score was excluded from analysis in this endpoint. An observed-cases approach to missing postbaseline data was applied.
Arm/Group Title Placebo Linaclotide 145µg Linaclotide 290µg
Hide Arm/Group Description:
Dose matched placebo, oral administration, once per day.
Linaclotide, 145µg dose, oral administration, once per day
Linaclotide, 290µg dose, oral administration, once per day
Overall Number of Participants Analyzed 215 213 201
Least Squares Mean (Standard Error)
Unit of Measure: units on a scale
-0.244  (0.048) -0.432  (0.049) -0.485  (0.049)
8.Secondary Outcome
Title 12-Week Constipation Severity
Hide Description Constipation severity was based on a 5-point ordinal scale where a value of l is "none" and a value of 5 is "very severe".
Time Frame Change from Baseline to Week 12
Hide Outcome Measure Data
Hide Analysis Population Description
A total of 633 patients were randomized to treatment and received at least 1 dose of study drug. 630 patients were included in the ITT population; 11 additional patients who dropped out prior to finishing 1 week of the trial were excluded from the Constipation Severity endpoint. An observed-cases approach to missing postbaseline data was applied.
Arm/Group Title Placebo Linaclotide 145µg Linaclotide 290µg
Hide Arm/Group Description:
Dose matched placebo, oral administration, once per day.
Linaclotide, 145µg dose, oral administration, once per day
Linaclotide, 290µg dose, oral administration, once per day
Overall Number of Participants Analyzed 212 209 198
Least Squares Mean (Standard Error)
Unit of Measure: units on a scale
-0.306  (0.062) -0.908  (0.063) -0.954  (0.064)
Time Frame Adverse Event reporting occurred from October 2008 through August 2009.
Adverse Event Reporting Description [Not Specified]
 
Arm/Group Title Placebo Linaclotide 145µg Linaclotide 290µg
Hide Arm/Group Description Dose matched placebo, oral administration, once per day. Linaclotide, 145µg dose, oral administration, once per day Linaclotide, 290µg dose, oral administration, once per day
All-Cause Mortality
Placebo Linaclotide 145µg Linaclotide 290µg
Affected / at Risk (%) Affected / at Risk (%) Affected / at Risk (%)
Total   --/--   --/--   --/-- 
Hide Serious Adverse Events
Placebo Linaclotide 145µg Linaclotide 290µg
Affected / at Risk (%) Affected / at Risk (%) Affected / at Risk (%)
Total   4/215 (1.86%)   3/213 (1.41%)   7/205 (3.41%) 
Blood and lymphatic system disorders       
Lymphoma  1  0/215 (0.00%)  0/213 (0.00%)  1/205 (0.49%) 
Cardiac disorders       
Angina pectoris  1  1/215 (0.47%)  0/213 (0.00%)  0/205 (0.00%) 
Endocrine disorders       
Goitre  1  1/215 (0.47%)  0/213 (0.00%)  0/205 (0.00%) 
Gastrointestinal disorders       
Diverticulitis  1  0/215 (0.00%)  0/213 (0.00%)  1/205 (0.49%) 
Small intestinal obstruction  1  0/215 (0.00%)  1/213 (0.47%)  0/205 (0.00%) 
Hepatobiliary disorders       
Cholecystitis  1  0/215 (0.00%)  0/213 (0.00%)  1/205 (0.49%) 
Cholelithiasis  1  1/215 (0.47%)  0/213 (0.00%)  0/205 (0.00%) 
Injury, poisoning and procedural complications       
Drug toxicity  1  0/215 (0.00%)  1/213 (0.47%)  0/205 (0.00%) 
Postoperative wound infection  1  0/215 (0.00%)  0/213 (0.00%)  1/205 (0.49%) 
Metabolism and nutrition disorders       
Dehydration  1  0/215 (0.00%)  0/213 (0.00%)  1/205 (0.49%) 
Neoplasms benign, malignant and unspecified (incl cysts and polyps)       
Pancreatic carcinoma  1  0/215 (0.00%)  0/213 (0.00%)  1/205 (0.49%) 
Reproductive system and breast disorders       
Endometriosis  1  0/215 (0.00%)  0/213 (0.00%)  1/205 (0.49%) 
Respiratory, thoracic and mediastinal disorders       
Bronchitis  1  0/215 (0.00%)  1/213 (0.47%)  0/205 (0.00%) 
Cellulitis  1  1/215 (0.47%)  0/213 (0.00%)  0/205 (0.00%) 
Vascular disorders       
Orthostatic hypotension  1  0/215 (0.00%)  0/213 (0.00%)  1/205 (0.49%) 
Indicates events were collected by systematic assessment
1
Term from vocabulary, MedDRA 13.0
Hide Other (Not Including Serious) Adverse Events
Frequency Threshold for Reporting Other Adverse Events 5%
Placebo Linaclotide 145µg Linaclotide 290µg
Affected / at Risk (%) Affected / at Risk (%) Affected / at Risk (%)
Total   35/215 (16.28%)   70/213 (32.86%)   49/205 (23.90%) 
Gastrointestinal disorders       
Diarrhea  1  6/215 (2.79%)  42/213 (19.72%)  30/205 (14.63%) 
Flatulence  1  13/215 (6.05%)  16/213 (7.51%)  13/205 (6.34%) 
Abdominal pain  1  5/215 (2.33%)  11/213 (5.16%)  11/205 (5.37%) 
Infections and infestations       
Upper respiratory tract infection  1  14/215 (6.51%)  16/213 (7.51%)  9/205 (4.39%) 
Indicates events were collected by systematic assessment
1
Term from vocabulary, MedDRA
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 study will be the property of Forest Research Institute. 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 and Forest Research Institute
Results Point of Contact
Layout table for Results Point of Contact information
Name/Title: Paul F.C. Eng, PhD. Director, Clinical Development
Organization: Forest Research Institute
Phone: 201-427-8071
EMail: Paul.Eng@frx.com
Layout table for additonal information
Responsible Party: Forest Laboratories
ClinicalTrials.gov Identifier: NCT00765882    
Other Study ID Numbers: LIN-MD-01
First Submitted: October 1, 2008
First Posted: October 3, 2008
Results First Submitted: September 28, 2012
Results First Posted: January 30, 2013
Last Update Posted: January 30, 2013