Trial Outcomes & Findings for Dose-range-finding, Phase 2 Trial of Oral Linaclotide Acetate Administered to Patients With Chronic Constipation (NCT NCT00402337)
NCT ID: NCT00402337
Last Updated: 2013-03-05
Results Overview
Change in SBM frequency during Weeks 1 through 4 of the treatment period from the weekly SBM rate obtained during the pretreatment period.
COMPLETED
PHASE2
310 participants
Change from Baseline to Week 4
2013-03-05
Participant Flow
Patient recruitment occurred over a 13 month period from November 2006 to December 2007 at 57 US study sites.
Patients went through a 14 to 17 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 |
Linaclotide, 72μg
Linaclotide, 72μg dose, 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
|
Linaclotide, 579μg
Linaclotide, 579μg dose, oral administration, once per day
|
Placebo
Dose-matched placebo, oral administration, once per day.
|
|---|---|---|---|---|---|
|
Overall Study
STARTED
|
59
|
57
|
62
|
63
|
69
|
|
Overall Study
COMPLETED
|
54
|
51
|
58
|
51
|
61
|
|
Overall Study
NOT COMPLETED
|
5
|
6
|
4
|
12
|
8
|
Reasons for withdrawal
| Measure |
Linaclotide, 72μg
Linaclotide, 72μg dose, 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
|
Linaclotide, 579μg
Linaclotide, 579μg dose, oral administration, once per day
|
Placebo
Dose-matched placebo, oral administration, once per day.
|
|---|---|---|---|---|---|
|
Overall Study
Adverse Event
|
0
|
2
|
2
|
3
|
2
|
|
Overall Study
Noncompliance
|
0
|
0
|
0
|
0
|
2
|
|
Overall Study
Withdrawal by Subject
|
5
|
3
|
1
|
6
|
4
|
|
Overall Study
Lost to Follow-up
|
0
|
0
|
1
|
2
|
0
|
|
Overall Study
Physician Decision
|
0
|
0
|
0
|
1
|
0
|
|
Overall Study
Other Reason
|
0
|
1
|
0
|
0
|
0
|
Baseline Characteristics
Dose-range-finding, Phase 2 Trial of Oral Linaclotide Acetate Administered to Patients With Chronic Constipation
Baseline characteristics by cohort
| Measure |
Linaclotide, 72μg
n=59 Participants
Linaclotide, 72μg dose, oral administration, once per day
|
Linaclotide, 145μg
n=56 Participants
Linaclotide, 145μg dose, oral administration, once per day. One patient was randomized into the study but did not receive ≥ 1 dose of study drug, thus was not included in the Safety Population.
|
Linaclotide, 290μg
n=62 Participants
Linaclotide, 290μg dose, oral administration, once per day
|
Linaclotide, 579μg
n=63 Participants
Linaclotide, 579μg dose, oral administration, once per day
|
Placebo
n=69 Participants
Dose-matched placebo, oral administration, once per day.
|
Total
n=309 Participants
Total of all reporting groups
|
|---|---|---|---|---|---|---|
|
Age Continuous
|
45.9 years
STANDARD_DEVIATION 14.1 • n=5 Participants
|
46.4 years
STANDARD_DEVIATION 11.7 • n=7 Participants
|
48.4 years
STANDARD_DEVIATION 12.7 • n=5 Participants
|
49.2 years
STANDARD_DEVIATION 14.0 • n=4 Participants
|
46.1 years
STANDARD_DEVIATION 15.5 • n=21 Participants
|
47.2 years
STANDARD_DEVIATION 13.7 • n=8 Participants
|
|
Age, Customized
18 years to 65 years
|
52 Participants
n=5 Participants
|
53 Participants
n=7 Participants
|
57 Participants
n=5 Participants
|
57 Participants
n=4 Participants
|
64 Participants
n=21 Participants
|
283 Participants
n=8 Participants
|
|
Age, Customized
Older than 65 years
|
7 Participants
n=5 Participants
|
3 Participants
n=7 Participants
|
5 Participants
n=5 Participants
|
6 Participants
n=4 Participants
|
5 Participants
n=21 Participants
|
26 Participants
n=8 Participants
|
|
Sex: Female, Male
Female
|
55 Participants
n=5 Participants
|
54 Participants
n=7 Participants
|
58 Participants
n=5 Participants
|
56 Participants
n=4 Participants
|
61 Participants
n=21 Participants
|
284 Participants
n=8 Participants
|
|
Sex: Female, Male
Male
|
4 Participants
n=5 Participants
|
2 Participants
n=7 Participants
|
4 Participants
n=5 Participants
|
7 Participants
n=4 Participants
|
8 Participants
n=21 Participants
|
25 Participants
n=8 Participants
|
|
Region of Enrollment
United States
|
59 participants
n=5 Participants
|
56 participants
n=7 Participants
|
62 participants
n=5 Participants
|
63 participants
n=4 Participants
|
69 participants
n=21 Participants
|
309 participants
n=8 Participants
|
PRIMARY outcome
Timeframe: Change from Baseline to Week 4Population: 307 patients who received ≥ 1 capsule of study drug and had ≥ 1 post-baseline response to the IVRS Treatment Period Question #12 "How many bowel movements did you have today or yesterday since your last call?" were included in the intent-to-treat (ITT) Population.
Change in SBM frequency during Weeks 1 through 4 of the treatment period from the weekly SBM rate obtained during the pretreatment period.
Outcome measures
| Measure |
Linaclotide, 72μg
n=59 Participants
Linaclotide, 72μg dose, oral administration, once per day
|
Linaclotide, 145μg
n=56 Participants
Linaclotide, 145μg dose, oral administration, once per day
|
Linaclotide, 290μg
n=62 Participants
Linaclotide, 290μg dose, oral administration, once per day
|
Linaclotide, 579μg
n=62 Participants
Linaclotide, 579μg dose, oral administration, once per day
|
Placebo
n=68 Participants
Dose-matched placebo, oral administration, once per day.
|
|---|---|---|---|---|---|
|
Change From Pretreatment in Weekly Normalized Spontaneous Bowel Movement (SBM) Frequency
|
2.59 SBMs per week
Standard Error 0.407
|
3.25 SBMs per week
Standard Error 0.412
|
3.57 SBMs per week
Standard Error 0.391
|
4.29 SBMs per week
Standard Error 0.394
|
1.45 SBMs per week
Standard Error 0.383
|
SECONDARY outcome
Timeframe: Change from Baseline to Week 4Population: 307 patients who received ≥ 1 capsule of study drug and had ≥ 1 post-baseline response to the IVRS Treatment Period Question #12 "How many bowel movements did you have today or yesterday since your last call?" were included in the ITT Population.
A patient was an SBM 75% Responder if the patient was an SBM Responder for ≥3 of the 4 treatment period weeks. For each week of the treatment and postreatment periods, a patient was considered an SBM Responder if for that week the patient 1) completed ≥4 days of IVRS questions,2) had an SBM rate of ≥ 3 for the week, and 3) had an increase in SBM rate of ≥ 1 from their baseline weekly SBM rate.
Outcome measures
| Measure |
Linaclotide, 72μg
n=59 Participants
Linaclotide, 72μg dose, oral administration, once per day
|
Linaclotide, 145μg
n=56 Participants
Linaclotide, 145μg dose, oral administration, once per day
|
Linaclotide, 290μg
n=62 Participants
Linaclotide, 290μg dose, oral administration, once per day
|
Linaclotide, 579μg
n=62 Participants
Linaclotide, 579μg dose, oral administration, once per day
|
Placebo
n=68 Participants
Dose-matched placebo, oral administration, once per day.
|
|---|---|---|---|---|---|
|
SBM 75% Responder for the Treatment Period (Based on the Normalized Rate)
|
35 participants
|
31 participants
|
38 participants
|
42 participants
|
22 participants
|
SECONDARY outcome
Timeframe: Change from Baseline to Week 4Population: 307 patients who received ≥ 1 capsule of study drug and had ≥ 1 post-baseline response to the IVRS Treatment Period Question #12 "How many bowel movements did you have today or yesterday since your last call?" were included in the ITT Population.
A patient was a complete spontaneous bowel movement (CSBM) 75% Responder if the patient was a CSBM Responder for ≥3 of the 4 treatment period weeks. For each week of the treatment and postreatment periods, a patient was considered a CSBM Responder if for that week the patient 1) completed ≥4 days of IVRS questions,2) had a CSBM rate of ≥ 3 for the week, and 3) had an increase in CSBM rate of ≥ 1 from their baseline weekly CSBM rate.
Outcome measures
| Measure |
Linaclotide, 72μg
n=59 Participants
Linaclotide, 72μg dose, oral administration, once per day
|
Linaclotide, 145μg
n=56 Participants
Linaclotide, 145μg dose, oral administration, once per day
|
Linaclotide, 290μg
n=62 Participants
Linaclotide, 290μg dose, oral administration, once per day
|
Linaclotide, 579μg
n=62 Participants
Linaclotide, 579μg dose, oral administration, once per day
|
Placebo
n=68 Participants
Dose-matched placebo, oral administration, once per day.
|
|---|---|---|---|---|---|
|
CSBM 75% Responder for the Treatment Period (Based on the Normalized Rate)
|
11 participants
|
15 participants
|
20 participants
|
18 participants
|
5 participants
|
SECONDARY outcome
Timeframe: Change from Baseline to Week 4Population: 307 patients who received ≥ 1 capsule of study drug and had ≥ 1 post-baseline response to the IVRS Treatment Period Question #12 "How many bowel movements did you have today or yesterday since your last call?" were included in the ITT Population.
CSBMs measured daily during the treatment period. During each daily phone call into the IVRS, patients were asked: How many bowel movements did you have today or yesterday after your last call?
Outcome measures
| Measure |
Linaclotide, 72μg
n=59 Participants
Linaclotide, 72μg dose, oral administration, once per day
|
Linaclotide, 145μg
n=56 Participants
Linaclotide, 145μg dose, oral administration, once per day
|
Linaclotide, 290μg
n=62 Participants
Linaclotide, 290μg dose, oral administration, once per day
|
Linaclotide, 579μg
n=62 Participants
Linaclotide, 579μg dose, oral administration, once per day
|
Placebo
n=68 Participants
Dose-matched placebo, oral administration, once per day.
|
|---|---|---|---|---|---|
|
Change From Baseline in the Weekly Normalized CSBM Rate for the Treatment Period
|
1.47 CSBMs per week
Standard Error 0.295
|
1.59 CSBMs per week
Standard Error 0.298
|
1.75 CSBMs per week
Standard Error 0.283
|
2.26 CSBMs per week
Standard Error 0.285
|
0.45 CSBMs per week
Standard Error 0.279
|
SECONDARY outcome
Timeframe: Change from Baseline to Week 4Population: 307 patients who received ≥ 1 capsule of study drug and had ≥ 1 post-baseline response to the IVRS Treatment Period Question #12 "How many bowel movements did you have today or yesterday since your last call?" were included in the ITT. 29 patients with no pretreatment spontaneous bowel movements were excluded from the Stool Consistency analysis.
Stool consistency analyses were performed using the 7-point BSFS, whereby a score of 1 = 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; and 7 = entirely liquid.
Outcome measures
| Measure |
Linaclotide, 72μg
n=53 Participants
Linaclotide, 72μg dose, oral administration, once per day
|
Linaclotide, 145μg
n=53 Participants
Linaclotide, 145μg dose, oral administration, once per day
|
Linaclotide, 290μg
n=55 Participants
Linaclotide, 290μg dose, oral administration, once per day
|
Linaclotide, 579μg
n=57 Participants
Linaclotide, 579μg dose, oral administration, once per day
|
Placebo
n=60 Participants
Dose-matched placebo, oral administration, once per day.
|
|---|---|---|---|---|---|
|
Change From Baseline in Stool Consistency (BSFS) Score for the Treatment Period
|
1.35 units on a scale
Standard Error 0.182
|
1.57 units on a scale
Standard Error 0.177
|
1.68 units on a scale
Standard Error 0.175
|
2.00 units on a scale
Standard Error 0.171
|
0.50 units on a scale
Standard Error 0.170
|
SECONDARY outcome
Timeframe: Change from Baseline to Week 4Population: 307 patients who received ≥ 1 capsule of study drug and had ≥ 1 post-baseline response to the IVRS Treatment Period Question #12 "How many bowel movements did you have today or yesterday since your last call?" were included in the ITT Population. 29 patients with no pretreatment spontaneous bowel movements were excluded from the Straining analysis.
Straining was assessed using a 5-point ordinal scale, whereby a score of 1 = not at all, 2 = a little bit, 3 = a moderate amount, 4 = a great deal, and 5 = an extreme amount.
Outcome measures
| Measure |
Linaclotide, 72μg
n=53 Participants
Linaclotide, 72μg dose, oral administration, once per day
|
Linaclotide, 145μg
n=53 Participants
Linaclotide, 145μg dose, oral administration, once per day
|
Linaclotide, 290μg
n=55 Participants
Linaclotide, 290μg dose, oral administration, once per day
|
Linaclotide, 579μg
n=57 Participants
Linaclotide, 579μg dose, oral administration, once per day
|
Placebo
n=60 Participants
Dose-matched placebo, oral administration, once per day.
|
|---|---|---|---|---|---|
|
Change From Baseline in Straining Score for the Treatment Period
|
-0.71 units on a scale
Standard Error 0.102
|
-0.97 units on a scale
Standard Error 0.098
|
-1.11 units on a scale
Standard Error 0.097
|
-1.14 units on a scale
Standard Error 0.095
|
-0.52 units on a scale
Standard Error 0.094
|
Adverse Events
Linaclotide, 72μg
Linaclotide, 145μg
Linaclotide, 290μg
Linaclotide, 579μg
Placebo
Serious adverse events
| Measure |
Linaclotide, 72μg
n=59 participants at risk
Linaclotide, 72μg dose, oral administration, once per day
|
Linaclotide, 145μg
n=56 participants at risk
Linaclotide, 145μg dose, oral administration, once per day
|
Linaclotide, 290μg
n=62 participants at risk
Linaclotide, 290μg dose, oral administration, once per day
|
Linaclotide, 579μg
n=63 participants at risk
Linaclotide, 579μg dose, oral administration, once per day
|
Placebo
n=69 participants at risk
Dose-matched placebo, oral administration, once per day.
|
|---|---|---|---|---|---|
|
Musculoskeletal and connective tissue disorders
Humerus fracture
|
0.00%
0/59 • Adverse event data were collected from November of 2006 to February of 2008.
|
0.00%
0/56 • Adverse event data were collected from November of 2006 to February of 2008.
|
0.00%
0/62 • Adverse event data were collected from November of 2006 to February of 2008.
|
0.00%
0/63 • Adverse event data were collected from November of 2006 to February of 2008.
|
1.4%
1/69 • Adverse event data were collected from November of 2006 to February of 2008.
|
|
Cardiac disorders
Atrial fibrillation
|
0.00%
0/59 • Adverse event data were collected from November of 2006 to February of 2008.
|
0.00%
0/56 • Adverse event data were collected from November of 2006 to February of 2008.
|
0.00%
0/62 • Adverse event data were collected from November of 2006 to February of 2008.
|
0.00%
0/63 • Adverse event data were collected from November of 2006 to February of 2008.
|
1.4%
1/69 • Adverse event data were collected from November of 2006 to February of 2008.
|
|
Infections and infestations
Pneumonia
|
0.00%
0/59 • Adverse event data were collected from November of 2006 to February of 2008.
|
0.00%
0/56 • Adverse event data were collected from November of 2006 to February of 2008.
|
0.00%
0/62 • Adverse event data were collected from November of 2006 to February of 2008.
|
0.00%
0/63 • Adverse event data were collected from November of 2006 to February of 2008.
|
1.4%
1/69 • Adverse event data were collected from November of 2006 to February of 2008.
|
Other adverse events
| Measure |
Linaclotide, 72μg
n=59 participants at risk
Linaclotide, 72μg dose, oral administration, once per day
|
Linaclotide, 145μg
n=56 participants at risk
Linaclotide, 145μg dose, oral administration, once per day
|
Linaclotide, 290μg
n=62 participants at risk
Linaclotide, 290μg dose, oral administration, once per day
|
Linaclotide, 579μg
n=63 participants at risk
Linaclotide, 579μg dose, oral administration, once per day
|
Placebo
n=69 participants at risk
Dose-matched placebo, oral administration, once per day.
|
|---|---|---|---|---|---|
|
Gastrointestinal disorders
Flatulence
|
3.4%
2/59 • Adverse event data were collected from November of 2006 to February of 2008.
|
5.4%
3/56 • Adverse event data were collected from November of 2006 to February of 2008.
|
3.2%
2/62 • Adverse event data were collected from November of 2006 to February of 2008.
|
3.2%
2/63 • Adverse event data were collected from November of 2006 to February of 2008.
|
5.8%
4/69 • Adverse event data were collected from November of 2006 to February of 2008.
|
|
Gastrointestinal disorders
Abdominal pain
|
3.4%
2/59 • Adverse event data were collected from November of 2006 to February of 2008.
|
8.9%
5/56 • Adverse event data were collected from November of 2006 to February of 2008.
|
3.2%
2/62 • Adverse event data were collected from November of 2006 to February of 2008.
|
3.2%
2/63 • Adverse event data were collected from November of 2006 to February of 2008.
|
4.3%
3/69 • Adverse event data were collected from November of 2006 to February of 2008.
|
|
Gastrointestinal disorders
Diarrhea
|
5.1%
3/59 • Adverse event data were collected from November of 2006 to February of 2008.
|
8.9%
5/56 • Adverse event data were collected from November of 2006 to February of 2008.
|
4.8%
3/62 • Adverse event data were collected from November of 2006 to February of 2008.
|
14.3%
9/63 • Adverse event data were collected from November of 2006 to February of 2008.
|
2.9%
2/69 • Adverse event data were collected from November of 2006 to February of 2008.
|
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