Trial Outcomes & Findings for 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) (NCT NCT01880424)
NCT ID: NCT01880424
Last Updated: 2016-09-27
Results Overview
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.
COMPLETED
PHASE3
1722 participants
Baseline and Weeks 1-12 during the Treatment Period
2016-09-27
Participant Flow
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).
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.
Participant milestones
| Measure |
Linaclotide Arm
Linaclotide 290 ug capsules, oral, once daily
|
Placebo Arm
matching placebo capsules, oral, once daily
|
|---|---|---|
|
Overall Study
STARTED
|
417
|
422
|
|
Overall Study
COMPLETED
|
384
|
367
|
|
Overall Study
NOT COMPLETED
|
33
|
55
|
Reasons for withdrawal
| Measure |
Linaclotide Arm
Linaclotide 290 ug capsules, oral, once daily
|
Placebo Arm
matching placebo capsules, oral, once daily
|
|---|---|---|
|
Overall Study
Adverse Event
|
7
|
6
|
|
Overall Study
Lack of Efficacy
|
1
|
4
|
|
Overall Study
Lost to Follow-up
|
3
|
2
|
|
Overall Study
Protocol Violation
|
11
|
13
|
|
Overall Study
Withdrawal by Subject
|
10
|
30
|
|
Overall Study
Other
|
1
|
0
|
Baseline Characteristics
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)
Baseline characteristics by cohort
| Measure |
Linaclotide Arm
n=417 Participants
Linaclotide 290 ug capsules, oral, once daily
|
Placebo Arm
n=422 Participants
matching placebo capsules, oral, once daily
|
Total
n=839 Participants
Total of all reporting groups
|
|---|---|---|---|
|
Age, Continuous
|
41.0 years
STANDARD_DEVIATION 13.1 • n=5 Participants
|
41.3 years
STANDARD_DEVIATION 13.5 • n=7 Participants
|
41.1 years
STANDARD_DEVIATION 13.3 • n=5 Participants
|
|
Age, Customized
between 18 to 65 years
|
400 participants
n=5 Participants
|
405 participants
n=7 Participants
|
805 participants
n=5 Participants
|
|
Age, Customized
>= 65 years
|
17 participants
n=5 Participants
|
17 participants
n=7 Participants
|
34 participants
n=5 Participants
|
|
Sex: Female, Male
Female
|
333 Participants
n=5 Participants
|
355 Participants
n=7 Participants
|
688 Participants
n=5 Participants
|
|
Sex: Female, Male
Male
|
84 Participants
n=5 Participants
|
67 Participants
n=7 Participants
|
151 Participants
n=5 Participants
|
|
countries
China
|
327 Participants
n=5 Participants
|
332 Participants
n=7 Participants
|
659 Participants
n=5 Participants
|
|
countries
Canada
|
3 Participants
n=5 Participants
|
3 Participants
n=7 Participants
|
6 Participants
n=5 Participants
|
|
countries
Australia
|
19 Participants
n=5 Participants
|
14 Participants
n=7 Participants
|
33 Participants
n=5 Participants
|
|
countries
New Zealand
|
4 Participants
n=5 Participants
|
4 Participants
n=7 Participants
|
8 Participants
n=5 Participants
|
|
countries
United States
|
64 Participants
n=5 Participants
|
69 Participants
n=7 Participants
|
133 Participants
n=5 Participants
|
PRIMARY outcome
Timeframe: Baseline and Weeks 1-12 during the Treatment PeriodPopulation: 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.
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.
Outcome measures
| Measure |
Linaclotide Arm
n=417 Participants
Linaclotide 290 ug capsules, oral, once daily
|
Placebo Arm
n=422 Participants
matching placebo capsules, oral, once daily
|
|---|---|---|
|
12-week Abdominal Pain/Abdominal Discomfort Weekly Responder
|
250 Participants
|
206 Participants
|
PRIMARY outcome
Timeframe: Baseline and Weeks 1-12 during the Treatment PeriodPopulation: 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.
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.
Outcome measures
| Measure |
Linaclotide Arm
n=417 Participants
Linaclotide 290 ug capsules, oral, once daily
|
Placebo Arm
n=422 Participants
matching placebo capsules, oral, once daily
|
|---|---|---|
|
12-week Irritable Bowel Syndrome (IBS) Degree of Relief Responder
|
132 Participants
|
65 Participants
|
SECONDARY outcome
Timeframe: Baseline and 12-week Treatment PeriodPopulation: 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).
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.
Outcome measures
| Measure |
Linaclotide Arm
n=417 Participants
Linaclotide 290 ug capsules, oral, once daily
|
Placebo Arm
n=422 Participants
matching placebo capsules, oral, once daily
|
|---|---|---|
|
Change From Baseline in 12-week Complete Spontaneous Bowel Movement Frequency Rate
|
1.94 CSBMs per Week
Standard Error 0.15
|
0.97 CSBMs per Week
Standard Error 0.15
|
SECONDARY outcome
Timeframe: Baseline and 12-week Treatment PeriodPopulation: 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).
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.
Outcome measures
| Measure |
Linaclotide Arm
n=417 Participants
Linaclotide 290 ug capsules, oral, once daily
|
Placebo Arm
n=422 Participants
matching placebo capsules, oral, once daily
|
|---|---|---|
|
Change From Baseline in 12-week Spontaneous Bowel Movement Frequency Rate
|
2.96 SBMs per Week
Standard Error 0.17
|
1.51 SBMs per Week
Standard Error 0.17
|
SECONDARY outcome
Timeframe: Baseline and 12-week Treatment PeriodPopulation: 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).
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 \[entirely liquid\]).
Outcome measures
| Measure |
Linaclotide Arm
n=371 Participants
Linaclotide 290 ug capsules, oral, once daily
|
Placebo Arm
n=360 Participants
matching placebo capsules, oral, once daily
|
|---|---|---|
|
Change From Baseline in 12-week Stool Consistency
|
1.51 Units on a Scale (BSFS)
Standard Error 0.07
|
0.82 Units on a Scale (BSFS)
Standard Error 0.07
|
SECONDARY outcome
Timeframe: Baseline and 12-week Treatment PeriodPopulation: 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).
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).
Outcome measures
| Measure |
Linaclotide Arm
n=371 Participants
Linaclotide 290 ug capsules, oral, once daily
|
Placebo Arm
n=360 Participants
matching placebo capsules, oral, once daily
|
|---|---|---|
|
Change From Baseline in 12-week Severity of Straining
|
-1.02 Units on a Scale
Standard Error 0.05
|
-0.69 Units on a Scale
Standard Error 0.05
|
SECONDARY outcome
Timeframe: Baseline and 12-week Treatment PeriodPopulation: 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).
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.
Outcome measures
| Measure |
Linaclotide Arm
n=417 Participants
Linaclotide 290 ug capsules, oral, once daily
|
Placebo Arm
n=419 Participants
matching placebo capsules, oral, once daily
|
|---|---|---|
|
Change From Baseline in 12-week Abdominal Bloating
|
-1.50 Units on a Scale
Standard Error 0.12
|
-0.94 Units on a Scale
Standard Error 0.12
|
SECONDARY outcome
Timeframe: Baseline and 12-week Treatment PeriodPopulation: 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).
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.
Outcome measures
| Measure |
Linaclotide Arm
n=417 Participants
Linaclotide 290 ug capsules, oral, once daily
|
Placebo Arm
n=419 Participants
matching placebo capsules, oral, once daily
|
|---|---|---|
|
Change From Baseline in 12-week Abdominal Pain
|
-1.56 Units on a Scale
Standard Error 0.12
|
-1.07 Units on a Scale
Standard Error 0.12
|
SECONDARY outcome
Timeframe: Baseline and 12-week Treatment PeriodPopulation: 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).
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.
Outcome measures
| Measure |
Linaclotide Arm
n=417 Participants
Linaclotide 290 ug capsules, oral, once daily
|
Placebo Arm
n=419 Participants
matching placebo capsules, oral, once daily
|
|---|---|---|
|
Change From Baseline in 12-week Abdominal Discomfort
|
-1.46 Units on a Scale
Standard Error 0.12
|
-0.98 Units on a Scale
Standard Error 0.12
|
Adverse Events
Linaclotide Arm
Placebo Arm
Serious adverse events
| Measure |
Linaclotide Arm
n=416 participants at risk
Linaclotide 290 ug capsules, oral, once daily
|
Placebo Arm
n=419 participants at risk
matching placebo capsules, oral, once daily
|
|---|---|---|
|
Gastrointestinal disorders
Colitis
|
0.00%
0/416 • 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.
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.
|
0.24%
1/419 • Number of events 1 • 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.
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.
|
|
General disorders
Non-cardiac chest pain
|
0.00%
0/416 • 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.
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.
|
0.24%
1/419 • Number of events 1 • 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.
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.
|
|
Infections and infestations
Pericoronitis
|
0.24%
1/416 • Number of events 1 • 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.
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.
|
0.00%
0/419 • 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.
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.
|
|
Neoplasms benign, malignant and unspecified (incl cysts and polyps)
Uterine leiomyoma
|
0.00%
0/416 • 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.
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.
|
0.24%
1/419 • Number of events 1 • 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.
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.
|
|
Nervous system disorders
Multiple system atrophy
|
0.00%
0/416 • 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.
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.
|
0.24%
1/419 • Number of events 1 • 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.
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.
|
|
Pregnancy, puerperium and perinatal conditions
Abortion spontaneous
|
0.00%
0/416 • 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.
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.
|
0.24%
1/419 • Number of events 1 • 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.
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.
|
|
Pregnancy, puerperium and perinatal conditions
Ectopic pregnancy
|
0.24%
1/416 • Number of events 1 • 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.
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.
|
0.00%
0/419 • 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.
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.
|
|
Renal and urinary disorders
Bladder outlet obstruction
|
0.00%
0/416 • 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.
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.
|
0.24%
1/419 • Number of events 1 • 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.
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.
|
|
Respiratory, thoracic and mediastinal disorders
Chronic obstructive pulmonary disease
|
0.24%
1/416 • Number of events 1 • 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.
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.
|
0.00%
0/419 • 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.
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.
|
|
Surgical and medical procedures
Abortion induced
|
0.24%
1/416 • Number of events 1 • 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.
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.
|
0.95%
4/419 • Number of events 4 • 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.
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.
|
Other adverse events
| Measure |
Linaclotide Arm
n=416 participants at risk
Linaclotide 290 ug capsules, oral, once daily
|
Placebo Arm
n=419 participants at risk
matching placebo capsules, oral, once daily
|
|---|---|---|
|
Gastrointestinal disorders
Diarrhea
|
9.4%
39/416 • Number of events 39 • 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.
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.
|
1.2%
5/419 • Number of events 5 • 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.
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.
|
|
Infections and infestations
Upper respiratory tract infection
|
4.3%
18/416 • Number of events 18 • 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.
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.
|
5.0%
21/419 • Number of events 21 • 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.
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.
|
Additional Information
Results disclosure agreements
- Principal investigator is a sponsor employee 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.
- Publication restrictions are in place
Restriction type: OTHER