Trial Outcomes & Findings for Phase III, Randomized, Double-Blind, Placebo-Controlled, Trial of Linaclotide Administered to Patients With Chronic Constipation (NCT NCT00765882)

NCT ID: NCT00765882

Last Updated: 2013-01-30

Results Overview

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.

• Recruitment status: COMPLETED
• Study phase: PHASE3
• Target enrollment: 633 participants
• Primary outcome timeframe: Change from Baseline to Week 12
• Results posted on: 2013-01-30

Participant Flow

Patient Recruitment occurred from October 2008 to March 2009 at 103 study centers (95 in the United States and 8 in Canada).

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).

Participant milestones

Measure	Placebo Dose matched placebo, oral administration, once per day.	Linaclotide 145µg Linaclotide, 145µg dose, oral administration, once per day	Linaclotide 290µg Linaclotide, 290µg dose, oral administration, once per day
Overall Study STARTED	215	213	205
Overall Study COMPLETED	191	173	169
Overall Study NOT COMPLETED	24	40	36

Reasons for withdrawal

Measure	Placebo Dose matched placebo, oral administration, once per day.	Linaclotide 145µg Linaclotide, 145µg dose, oral administration, once per day	Linaclotide 290µg Linaclotide, 290µg dose, oral administration, once per day
Overall Study Adverse Event	10	21	20
Overall Study Lack of Efficacy	4	0	1
Overall Study Protocol Violation	4	3	1
Overall Study Withdrawal by Subject	2	6	6
Overall Study Lost to Follow-up	1	9	6
Overall Study Other Reason	3	1	2

Baseline Characteristics

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

Baseline characteristics by cohort

Measure	Placebo n=215 Participants Dose matched placebo, oral administration, once per day.	Linaclotide 145µg n=213 Participants Linaclotide, 145µg dose, oral administration, once per day	Linaclotide 290µg n=205 Participants Linaclotide, 290µg dose, oral administration, once per day	Total n=633 Participants Total of all reporting groups
Age Continuous	47.0 years STANDARD_DEVIATION 13.5 • n=5 Participants	48.5 years STANDARD_DEVIATION 12.3 • n=7 Participants	47.3 years STANDARD_DEVIATION 13.3 • n=5 Participants	47.6 years STANDARD_DEVIATION 13.0 • n=4 Participants
Age, Customized 18 years to 64 years	188 participants n=5 Participants	189 participants n=7 Participants	183 participants n=5 Participants	560 participants n=4 Participants
Age, Customized 65 years and older	27 participants n=5 Participants	24 participants n=7 Participants	22 participants n=5 Participants	73 participants n=4 Participants
Sex: Female, Male Female	196 Participants n=5 Participants	195 Participants n=7 Participants	181 Participants n=5 Participants	572 Participants n=4 Participants
Sex: Female, Male Male	19 Participants n=5 Participants	18 Participants n=7 Participants	24 Participants n=5 Participants	61 Participants n=4 Participants
Region of Enrollment United States	208 participants n=5 Participants	208 participants n=7 Participants	198 participants n=5 Participants	614 participants n=4 Participants
Region of Enrollment Canada	7 participants n=5 Participants	5 participants n=7 Participants	7 participants n=5 Participants	19 participants n=4 Participants

PRIMARY outcome

Timeframe: Change from Baseline to Week 12

Population: 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.

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.

Outcome measures

Measure	Placebo n=215 Participants Dose matched placebo, oral administration, once per day.	Linaclotide 145µg n=213 Participants Linaclotide, 145µg dose, oral administration, once per day	Linaclotide 290µg n=202 Participants Linaclotide, 290µg dose, oral administration, once per day
Complete Spontaneous Bowel Movement (CSBM) Overall Responder Responder	13 participants	34 participants	43 participants
Complete Spontaneous Bowel Movement (CSBM) Overall Responder Nonresponder	202 participants	179 participants	159 participants

SECONDARY outcome

Timeframe: Change from Baseline to Week 12

Population: 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.

The number of CSBMs per week.

Outcome measures

Measure	Placebo n=215 Participants Dose matched placebo, oral administration, once per day.	Linaclotide 145µg n=213 Participants Linaclotide, 145µg dose, oral administration, once per day	Linaclotide 290µg n=202 Participants Linaclotide, 290µg dose, oral administration, once per day
12-week Complete Spontaneous Bowel Movement (CSBM) Frequency Rate	0.614 CSBM per week Standard Error 0.209	2.011 CSBM per week Standard Error 0.215	2.653 CSBM per week Standard Error 0.217

SECONDARY outcome

Timeframe: Change from Baseline to Week 12

Population: 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.

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.

Outcome measures

Measure	Placebo n=215 Participants Dose matched placebo, oral administration, once per day.	Linaclotide 145µg n=213 Participants Linaclotide, 145µg dose, oral administration, once per day	Linaclotide 290µg n=202 Participants Linaclotide, 290µg dose, oral administration, once per day
12-Week Spontaneous Bowel Movement (SBM) Frequency Rate	1.113 SBM per week Standard Error 0.265	3.466 SBM per week Standard Error 0.272	3.675 SBM per week Standard Error 0.275

SECONDARY outcome

Timeframe: Change from Baseline to Week 12

Population: 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.

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]

Outcome measures

Measure	Placebo n=183 Participants Dose matched placebo, oral administration, once per day.	Linaclotide 145µg n=182 Participants Linaclotide, 145µg dose, oral administration, once per day	Linaclotide 290µg n=168 Participants Linaclotide, 290µg dose, oral administration, once per day
12-Week Stool Consistency	0.572 units on a scale Standard Error 0.098	1.823 units on a scale Standard Error 0.100	2.009 units on a scale Standard Error 0.103

SECONDARY outcome

Timeframe: Change from Baseline to Week 12

Population: 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.

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.

Outcome measures

Measure	Placebo n=183 Participants Dose matched placebo, oral administration, once per day.	Linaclotide 145µg n=182 Participants Linaclotide, 145µg dose, oral administration, once per day	Linaclotide 290µg n=168 Participants Linaclotide, 290µg dose, oral administration, once per day
12-Week Severity of Straining	-0.554 units on a scale Standard Error 0.060	-1.141 units on a scale Standard Error 0.061	-1.208 units on a scale Standard Error 0.063

SECONDARY outcome

Timeframe: Change from Baseline to Week 12

Population: 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.

Abdominal discomfort is based on a 5-point scale where a value of l is "none" and a value of 5 is "very severe."

Outcome measures

Measure	Placebo n=215 Participants Dose matched placebo, oral administration, once per day.	Linaclotide 145µg n=213 Participants Linaclotide, 145µg dose, oral administration, once per day	Linaclotide 290µg n=201 Participants Linaclotide, 290µg dose, oral administration, once per day
12-Week Abdominal Discomfort	-0.271 units on a scale Standard Error 0.043	-0.455 units on a scale Standard Error 0.044	-0.485 units on a scale Standard Error 0.045

SECONDARY outcome

Timeframe: Change from Baseline to Week 12

Population: 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.

Bloating was based on a 5-point scale where a value of l is "none" and a value of 5 is "very severe".

Outcome measures

Measure	Placebo n=215 Participants Dose matched placebo, oral administration, once per day.	Linaclotide 145µg n=213 Participants Linaclotide, 145µg dose, oral administration, once per day	Linaclotide 290µg n=201 Participants Linaclotide, 290µg dose, oral administration, once per day
12-Week Bloating	-0.244 units on a scale Standard Error 0.048	-0.432 units on a scale Standard Error 0.049	-0.485 units on a scale Standard Error 0.049

SECONDARY outcome

Timeframe: Change from Baseline to Week 12

Population: 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.

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".

Outcome measures

Measure	Placebo n=212 Participants Dose matched placebo, oral administration, once per day.	Linaclotide 145µg n=209 Participants Linaclotide, 145µg dose, oral administration, once per day	Linaclotide 290µg n=198 Participants Linaclotide, 290µg dose, oral administration, once per day
12-Week Constipation Severity	-0.306 units on a scale Standard Error 0.062	-0.908 units on a scale Standard Error 0.063	-0.954 units on a scale Standard Error 0.064

Adverse Events

Placebo

Serious events: 4 serious events

Other events: 35 other events

Deaths: 0 deaths

Linaclotide 145µg

Serious events: 3 serious events

Other events: 70 other events

Deaths: 0 deaths

Linaclotide 290µg

Serious events: 7 serious events

Other events: 49 other events

Deaths: 0 deaths

Serious adverse events

Measure	Placebo n=215 participants at risk Dose matched placebo, oral administration, once per day.	Linaclotide 145µg n=213 participants at risk Linaclotide, 145µg dose, oral administration, once per day	Linaclotide 290µg n=205 participants at risk Linaclotide, 290µg dose, oral administration, once per day
Respiratory, thoracic and mediastinal disorders Bronchitis	0.00% 0/215 • Adverse Event reporting occurred from October 2008 through August 2009.	0.47% 1/213 • Adverse Event reporting occurred from October 2008 through August 2009.	0.00% 0/205 • Adverse Event reporting occurred from October 2008 through August 2009.
Hepatobiliary disorders Cholecystitis	0.00% 0/215 • Adverse Event reporting occurred from October 2008 through August 2009.	0.00% 0/213 • Adverse Event reporting occurred from October 2008 through August 2009.	0.49% 1/205 • Adverse Event reporting occurred from October 2008 through August 2009.
Metabolism and nutrition disorders Dehydration	0.00% 0/215 • Adverse Event reporting occurred from October 2008 through August 2009.	0.00% 0/213 • Adverse Event reporting occurred from October 2008 through August 2009.	0.49% 1/205 • Adverse Event reporting occurred from October 2008 through August 2009.
Gastrointestinal disorders Diverticulitis	0.00% 0/215 • Adverse Event reporting occurred from October 2008 through August 2009.	0.00% 0/213 • Adverse Event reporting occurred from October 2008 through August 2009.	0.49% 1/205 • Adverse Event reporting occurred from October 2008 through August 2009.
Injury, poisoning and procedural complications Drug toxicity	0.00% 0/215 • Adverse Event reporting occurred from October 2008 through August 2009.	0.47% 1/213 • Adverse Event reporting occurred from October 2008 through August 2009.	0.00% 0/205 • Adverse Event reporting occurred from October 2008 through August 2009.
Reproductive system and breast disorders Endometriosis	0.00% 0/215 • Adverse Event reporting occurred from October 2008 through August 2009.	0.00% 0/213 • Adverse Event reporting occurred from October 2008 through August 2009.	0.49% 1/205 • Adverse Event reporting occurred from October 2008 through August 2009.
Blood and lymphatic system disorders Lymphoma	0.00% 0/215 • Adverse Event reporting occurred from October 2008 through August 2009.	0.00% 0/213 • Adverse Event reporting occurred from October 2008 through August 2009.	0.49% 1/205 • Adverse Event reporting occurred from October 2008 through August 2009.
Vascular disorders Orthostatic hypotension	0.00% 0/215 • Adverse Event reporting occurred from October 2008 through August 2009.	0.00% 0/213 • Adverse Event reporting occurred from October 2008 through August 2009.	0.49% 1/205 • Adverse Event reporting occurred from October 2008 through August 2009.
Neoplasms benign, malignant and unspecified (incl cysts and polyps) Pancreatic carcinoma	0.00% 0/215 • Adverse Event reporting occurred from October 2008 through August 2009.	0.00% 0/213 • Adverse Event reporting occurred from October 2008 through August 2009.	0.49% 1/205 • Adverse Event reporting occurred from October 2008 through August 2009.
Injury, poisoning and procedural complications Postoperative wound infection	0.00% 0/215 • Adverse Event reporting occurred from October 2008 through August 2009.	0.00% 0/213 • Adverse Event reporting occurred from October 2008 through August 2009.	0.49% 1/205 • Adverse Event reporting occurred from October 2008 through August 2009.
Gastrointestinal disorders Small intestinal obstruction	0.00% 0/215 • Adverse Event reporting occurred from October 2008 through August 2009.	0.47% 1/213 • Adverse Event reporting occurred from October 2008 through August 2009.	0.00% 0/205 • Adverse Event reporting occurred from October 2008 through August 2009.
Cardiac disorders Angina pectoris	0.47% 1/215 • Adverse Event reporting occurred from October 2008 through August 2009.	0.00% 0/213 • Adverse Event reporting occurred from October 2008 through August 2009.	0.00% 0/205 • Adverse Event reporting occurred from October 2008 through August 2009.
Respiratory, thoracic and mediastinal disorders Cellulitis	0.47% 1/215 • Adverse Event reporting occurred from October 2008 through August 2009.	0.00% 0/213 • Adverse Event reporting occurred from October 2008 through August 2009.	0.00% 0/205 • Adverse Event reporting occurred from October 2008 through August 2009.
Hepatobiliary disorders Cholelithiasis	0.47% 1/215 • Adverse Event reporting occurred from October 2008 through August 2009.	0.00% 0/213 • Adverse Event reporting occurred from October 2008 through August 2009.	0.00% 0/205 • Adverse Event reporting occurred from October 2008 through August 2009.
Endocrine disorders Goitre	0.47% 1/215 • Adverse Event reporting occurred from October 2008 through August 2009.	0.00% 0/213 • Adverse Event reporting occurred from October 2008 through August 2009.	0.00% 0/205 • Adverse Event reporting occurred from October 2008 through August 2009.

Other adverse events

Measure	Placebo n=215 participants at risk Dose matched placebo, oral administration, once per day.	Linaclotide 145µg n=213 participants at risk Linaclotide, 145µg dose, oral administration, once per day	Linaclotide 290µg n=205 participants at risk Linaclotide, 290µg dose, oral administration, once per day
Gastrointestinal disorders Diarrhea	2.8% 6/215 • Adverse Event reporting occurred from October 2008 through August 2009.	19.7% 42/213 • Adverse Event reporting occurred from October 2008 through August 2009.	14.6% 30/205 • Adverse Event reporting occurred from October 2008 through August 2009.
Gastrointestinal disorders Flatulence	6.0% 13/215 • Adverse Event reporting occurred from October 2008 through August 2009.	7.5% 16/213 • Adverse Event reporting occurred from October 2008 through August 2009.	6.3% 13/205 • Adverse Event reporting occurred from October 2008 through August 2009.
Infections and infestations Upper respiratory tract infection	6.5% 14/215 • Adverse Event reporting occurred from October 2008 through August 2009.	7.5% 16/213 • Adverse Event reporting occurred from October 2008 through August 2009.	4.4% 9/205 • Adverse Event reporting occurred from October 2008 through August 2009.
Gastrointestinal disorders Abdominal pain	2.3% 5/215 • Adverse Event reporting occurred from October 2008 through August 2009.	5.2% 11/213 • Adverse Event reporting occurred from October 2008 through August 2009.	5.4% 11/205 • Adverse Event reporting occurred from October 2008 through August 2009.

Additional Information

Paul F.C. Eng, PhD. Director, Clinical Development

Forest Research Institute

Phone: 201-427-8071

Email: Paul.Eng@frx.com

Results disclosure agreements

• Principal investigator is a sponsor employee 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
• Publication restrictions are in place

Restriction type: OTHER