Trial Outcomes & Findings for Trial of Linaclotide in Patients With Irritable Bowel Syndrome With Constipation (IBS-C) (NCT NCT00938717)
NCT ID: NCT00938717
Last Updated: 2013-11-05
Results Overview
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.
COMPLETED
PHASE3
805 participants
Change from Baseline to Week 12
2013-11-05
Participant Flow
Patient recruitment occurred over a fifteen month period from July 2009 to September 2010 at 111 US study sites.
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.
Participant milestones
| Measure |
Placebo
Dose-matched placebo, oral administration, once per day.
|
Linaclotide
Linaclotide 290μg, oral administration, once per day.
|
|---|---|---|
|
Overall Study
STARTED
|
403
|
402
|
|
Overall Study
COMPLETED
|
305
|
294
|
|
Overall Study
NOT COMPLETED
|
98
|
108
|
Reasons for withdrawal
| Measure |
Placebo
Dose-matched placebo, oral administration, once per day.
|
Linaclotide
Linaclotide 290μg, oral administration, once per day.
|
|---|---|---|
|
Overall Study
Adverse Event
|
10
|
41
|
|
Overall Study
Protocol Violation
|
11
|
8
|
|
Overall Study
Withdrawal by Subject
|
26
|
24
|
|
Overall Study
Lost to Follow-up
|
13
|
18
|
|
Overall Study
Lack of Efficacy
|
33
|
15
|
|
Overall Study
Other reason
|
5
|
2
|
Baseline Characteristics
Trial of Linaclotide in Patients With Irritable Bowel Syndrome With Constipation (IBS-C)
Baseline characteristics by cohort
| Measure |
Placebo
n=403 Participants
Dose-matched placebo, oral administration, once per day.
|
Linaclotide
n=402 Participants
Linaclotide 290μg, oral administration, once per day.
|
Total
n=805 Participants
Total of all reporting groups
|
|---|---|---|---|
|
Age Continuous
|
44.0 years
STANDARD_DEVIATION 13.4 • n=93 Participants
|
44.7 years
STANDARD_DEVIATION 13.1 • n=4 Participants
|
44.3 years
STANDARD_DEVIATION 13.3 • n=27 Participants
|
|
Age, Customized
18 years 64 years
|
386 Participants
n=93 Participants
|
379 Participants
n=4 Participants
|
765 Participants
n=27 Participants
|
|
Age, Customized
65 years and older
|
17 Participants
n=93 Participants
|
23 Participants
n=4 Participants
|
40 Participants
n=27 Participants
|
|
Sex: Female, Male
Female
|
352 Participants
n=93 Participants
|
369 Participants
n=4 Participants
|
721 Participants
n=27 Participants
|
|
Sex: Female, Male
Male
|
51 Participants
n=93 Participants
|
33 Participants
n=4 Participants
|
84 Participants
n=27 Participants
|
|
Region of Enrollment
United States
|
403 participants
n=93 Participants
|
402 participants
n=4 Participants
|
805 participants
n=27 Participants
|
PRIMARY outcome
Timeframe: Change from Baseline to Week 12Population: 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.
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.
Outcome measures
| Measure |
Placebo
n=403 Participants
Dose-matched placebo, oral administration, once per day.
|
Linaclotide
n=401 Participants
Linaclotide 290μg, oral administration, once per day.
|
|---|---|---|
|
Abdominal Pain and Complete Spontaneous Bowel Movement (APC) Responder, 9 Out of 12 Weeks
|
12 participants
|
51 participants
|
PRIMARY outcome
Timeframe: Change from Baseline to Week 12Population: 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.
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.
Outcome measures
| Measure |
Placebo
n=403 Participants
Dose-matched placebo, oral administration, once per day.
|
Linaclotide
n=401 Participants
Linaclotide 290μg, oral administration, once per day.
|
|---|---|---|
|
Complete Spontaneous Bowel Movement (CSBM) 3+1 Responder, 9 Out of 12 Weeks
|
20 participants
|
72 participants
|
PRIMARY outcome
Timeframe: Change from Baseline to Week 12Population: 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.
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.
Outcome measures
| Measure |
Placebo
n=403 Participants
Dose-matched placebo, oral administration, once per day.
|
Linaclotide
n=401 Participants
Linaclotide 290μg, oral administration, once per day.
|
|---|---|---|
|
Abdominal Pain Responder, 9 Out of 12 Weeks
|
79 participants
|
156 participants
|
PRIMARY outcome
Timeframe: Change from Baseline to Week 12Population: 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.
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.
Outcome measures
| Measure |
Placebo
n=403 Participants
Dose-matched placebo, oral administration, once per day.
|
Linaclotide
n=401 Participants
Linaclotide 290μg, oral administration, once per day.
|
|---|---|---|
|
Abdominal Pain and Complete Spontaneous Bowel Movement (APC) Responder, 6 Out of 12 Weeks
|
56 participants
|
135 participants
|
SECONDARY outcome
Timeframe: Change from Baseline to Week 12Population: 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.
The change from baseline in 12-week CSBM frequency (i.e., weekly CSBM frequency over the first 12 weeks of the Treatment Period).
Outcome measures
| Measure |
Placebo
n=403 Participants
Dose-matched placebo, oral administration, once per day.
|
Linaclotide
n=401 Participants
Linaclotide 290μg, oral administration, once per day.
|
|---|---|---|
|
12-Week Complete Spontaneous Bowel Movement (CSBM) Frequency
|
0.70 CSBMs per Week
Standard Error 0.12
|
2.24 CSBMs per Week
Standard Error 0.12
|
SECONDARY outcome
Timeframe: Change from Baseline to Week 12Population: 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.
The change from baseline in 12-week SBM frequency (i.e., weekly SBM frequency over the first 12 weeks of the Treatment Period).
Outcome measures
| Measure |
Placebo
n=403 Participants
Dose-matched placebo, oral administration, once per day.
|
Linaclotide
n=401 Participants
Linaclotide 290μg, oral administration, once per day.
|
|---|---|---|
|
12-Week Spontaneous Bowl Movement (SBM) Frequency
|
1.31 SBMs per Week
Standard Error 0.18
|
4.02 SBMs per Week
Standard Error 0.18
|
SECONDARY outcome
Timeframe: Change from Baseline to Week 12Population: 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.
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 \[entirely liquid\]).
Outcome measures
| Measure |
Placebo
n=332 Participants
Dose-matched placebo, oral administration, once per day.
|
Linaclotide
n=338 Participants
Linaclotide 290μg, oral administration, once per day.
|
|---|---|---|
|
12-Week Change in Stool Consistency
|
0.61 Units on a scale
Standard Error 0.06
|
1.91 Units on a scale
Standard Error 0.06
|
SECONDARY outcome
Timeframe: Change from Baseline to Week 12Population: 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.
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=332 Participants
Dose-matched placebo, oral administration, once per day.
|
Linaclotide
n=338 Participants
Linaclotide 290μg, oral administration, once per day.
|
|---|---|---|
|
12-Week Change in Severity of Straining
|
-0.66 Units on a scale
Standard Error 0.05
|
-1.24 Units on a scale
Standard Error 0.04
|
SECONDARY outcome
Timeframe: Change from Baseline to Week 12Population: 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.
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.
Outcome measures
| Measure |
Placebo
n=403 Participants
Dose-matched placebo, oral administration, once per day.
|
Linaclotide
n=401 Participants
Linaclotide 290μg, oral administration, once per day.
|
|---|---|---|
|
12-Week Change in Abdominal Pain Score
|
-1.07 Units on a scale
Standard Error 0.09
|
-1.85 Units on a scale
Standard Error 0.09
|
SECONDARY outcome
Timeframe: Change from Baseline to Week 12Population: 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.
Abdominal discomfort was assessed on an 11-point scale where a value of 0 is "none" and a value of 10 is "very severe".
Outcome measures
| Measure |
Placebo
n=403 Participants
Dose-matched placebo, oral administration, once per day.
|
Linaclotide
n=401 Participants
Linaclotide 290μg, oral administration, once per day.
|
|---|---|---|
|
12-Week Change in Abdominal Discomfort
|
-1.10 Units on a scale
Standard Error 0.09
|
-1.94 Units on a scale
Standard Error 0.09
|
SECONDARY outcome
Timeframe: Change from Baseline to Week 12Population: 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.
Bloating was assessed on an 11-point scale where a value of 0 is "none" and a value of 10 is "very severe".
Outcome measures
| Measure |
Placebo
n=403 Participants
Dose-matched placebo, oral administration, once per day.
|
Linaclotide
n=401 Participants
Linaclotide 290μg, oral administration, once per day.
|
|---|---|---|
|
12-Week Change in Bloating
|
-1.03 Units on a scale
Standard Error 0.10
|
-1.91 Units on a scale
Standard Error 0.09
|
SECONDARY outcome
Timeframe: Change from Baseline to Week 12Population: 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.
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.
Outcome measures
| Measure |
Placebo
n=403 Participants
Dose-matched placebo, oral administration, once per day.
|
Linaclotide
n=401 Participants
Linaclotide 290μg, oral administration, once per day.
|
|---|---|---|
|
Complete Spontaneous Bowl Movement (CSBM) Responder for 6 Weeks Out of 12 Weeks of Treatment
|
91 participants
Interval 2.29 to 4.21
|
191 participants
|
SECONDARY outcome
Timeframe: Change from Baseline to Week 12Population: 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.
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.
Outcome measures
| Measure |
Placebo
n=403 Participants
Dose-matched placebo, oral administration, once per day.
|
Linaclotide
n=401 Participants
Linaclotide 290μg, oral administration, once per day.
|
|---|---|---|
|
Abdominal Pain Responder for 6 Out of 12 Weeks
|
139 participants
|
196 participants
|
SECONDARY outcome
Timeframe: Change from Baseline to Week 12Population: 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.
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.
Outcome measures
| Measure |
Placebo
n=403 Participants
Dose-matched placebo, oral administration, once per day.
|
Linaclotide
n=401 Participants
Linaclotide 290μg, oral administration, once per day.
|
|---|---|---|
|
12-Week Percent of Abdominal Pain-free Days
|
4.83 Percent of Pain-free Days
Standard Deviation 16.64
|
10.49 Percent of Pain-free Days
Standard Deviation 23.42
|
Adverse Events
Placebo
Linaclotide
Serious adverse events
| Measure |
Placebo
n=403 participants at risk
Dose-matched placebo, oral administration, once per day.
|
Linaclotide
n=402 participants at risk
Linaclotide 290μg, oral administration, once per day.
|
|---|---|---|
|
Nervous system disorders
Transient ischemic attack
|
0.25%
1/403 • Number of events 1 • Adverse event data were collected from July of 2009 to September of 2010 (26 weeks of safety data were collected)
|
0.00%
0/402 • Adverse event data were collected from July of 2009 to September of 2010 (26 weeks of safety data were collected)
|
|
Neoplasms benign, malignant and unspecified (incl cysts and polyps)
Uterine leiomyoma
|
0.25%
1/403 • Number of events 1 • Adverse event data were collected from July of 2009 to September of 2010 (26 weeks of safety data were collected)
|
0.00%
0/402 • Adverse event data were collected from July of 2009 to September of 2010 (26 weeks of safety data were collected)
|
|
Skin and subcutaneous tissue disorders
Angioedema
|
0.25%
1/403 • Number of events 1 • Adverse event data were collected from July of 2009 to September of 2010 (26 weeks of safety data were collected)
|
0.00%
0/402 • Adverse event data were collected from July of 2009 to September of 2010 (26 weeks of safety data were collected)
|
|
Infections and infestations
Bronchitis
|
0.25%
1/403 • Number of events 1 • Adverse event data were collected from July of 2009 to September of 2010 (26 weeks of safety data were collected)
|
0.00%
0/402 • Adverse event data were collected from July of 2009 to September of 2010 (26 weeks of safety data were collected)
|
|
Infections and infestations
Pneumonia viral
|
0.25%
1/403 • Number of events 1 • Adverse event data were collected from July of 2009 to September of 2010 (26 weeks of safety data were collected)
|
0.00%
0/402 • Adverse event data were collected from July of 2009 to September of 2010 (26 weeks of safety data were collected)
|
|
Ear and labyrinth disorders
Vertigo
|
0.25%
1/403 • Number of events 1 • Adverse event data were collected from July of 2009 to September of 2010 (26 weeks of safety data were collected)
|
0.00%
0/402 • Adverse event data were collected from July of 2009 to September of 2010 (26 weeks of safety data were collected)
|
|
Gastrointestinal disorders
Abdominal pain lower
|
0.25%
1/403 • Number of events 1 • Adverse event data were collected from July of 2009 to September of 2010 (26 weeks of safety data were collected)
|
0.00%
0/402 • Adverse event data were collected from July of 2009 to September of 2010 (26 weeks of safety data were collected)
|
|
Neoplasms benign, malignant and unspecified (incl cysts and polyps)
Rectal cancer stage IV
|
0.25%
1/403 • Number of events 1 • Adverse event data were collected from July of 2009 to September of 2010 (26 weeks of safety data were collected)
|
0.00%
0/402 • Adverse event data were collected from July of 2009 to September of 2010 (26 weeks of safety data were collected)
|
|
Musculoskeletal and connective tissue disorders
Rotator cuff syndrome
|
0.00%
0/403 • Adverse event data were collected from July of 2009 to September of 2010 (26 weeks of safety data were collected)
|
0.25%
1/402 • Number of events 1 • Adverse event data were collected from July of 2009 to September of 2010 (26 weeks of safety data were collected)
|
|
Infections and infestations
Appendicitis
|
0.00%
0/403 • Adverse event data were collected from July of 2009 to September of 2010 (26 weeks of safety data were collected)
|
0.25%
1/402 • Number of events 1 • Adverse event data were collected from July of 2009 to September of 2010 (26 weeks of safety data were collected)
|
|
Surgical and medical procedures
Cystopexy
|
0.00%
0/403 • Adverse event data were collected from July of 2009 to September of 2010 (26 weeks of safety data were collected)
|
0.25%
1/402 • Number of events 1 • Adverse event data were collected from July of 2009 to September of 2010 (26 weeks of safety data were collected)
|
|
Neoplasms benign, malignant and unspecified (incl cysts and polyps)
Hodgkin's disease nodular sclerosis stage IVa
|
0.00%
0/403 • Adverse event data were collected from July of 2009 to September of 2010 (26 weeks of safety data were collected)
|
0.25%
1/402 • Number of events 1 • Adverse event data were collected from July of 2009 to September of 2010 (26 weeks of safety data were collected)
|
Other adverse events
| Measure |
Placebo
n=403 participants at risk
Dose-matched placebo, oral administration, once per day.
|
Linaclotide
n=402 participants at risk
Linaclotide 290μg, oral administration, once per day.
|
|---|---|---|
|
Gastrointestinal disorders
Diarrhea
|
2.5%
10/403 • Adverse event data were collected from July of 2009 to September of 2010 (26 weeks of safety data were collected)
|
19.7%
79/402 • Adverse event data were collected from July of 2009 to September of 2010 (26 weeks of safety data were collected)
|
|
Gastrointestinal disorders
Nausea
|
6.0%
24/403 • Adverse event data were collected from July of 2009 to September of 2010 (26 weeks of safety data were collected)
|
5.7%
23/402 • Adverse event data were collected from July of 2009 to September of 2010 (26 weeks of safety data were collected)
|
|
Infections and infestations
Sinusitis
|
6.9%
28/403 • Adverse event data were collected from July of 2009 to September of 2010 (26 weeks of safety data were collected)
|
5.7%
23/402 • Adverse event data were collected from July of 2009 to September of 2010 (26 weeks of safety data were collected)
|
|
Infections and infestations
Upper respiratory tract infection
|
5.5%
22/403 • Adverse event data were collected from July of 2009 to September of 2010 (26 weeks of safety data were collected)
|
5.5%
22/402 • Adverse event data were collected from July of 2009 to September of 2010 (26 weeks of safety data were collected)
|
|
Infections and infestations
Urinary tract infection
|
5.5%
22/403 • Adverse event data were collected from July of 2009 to September of 2010 (26 weeks of safety data were collected)
|
4.2%
17/402 • Adverse event data were collected from July of 2009 to September of 2010 (26 weeks of safety data were collected)
|
Additional Information
Results disclosure agreements
- Principal investigator is a sponsor employee 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.
- Publication restrictions are in place
Restriction type: OTHER