Trial Outcomes & Findings for Randomized, Double-blind, Dose-range-finding, Phase 2 Study of Linaclotide Administered to Patients With Irritable Bowel Syndrome With Constipation (IBS-C) (NCT NCT00460811)

NCT ID: NCT00460811

Last Updated: 2013-02-04

Results Overview

The change in the weekly normalized CSBM Rate during Weeks 1 through 12 of the Treatment Period from the weekly normalized CSBM Rate obtained during the Pretreatment Period. The CSBM rate was normalized based on the number of CSBMs occurring in that week, adjusting for differences in the duration of the week and black-out periods (time not covered due to a missed IVRS call) versus 7x24 hours.

• Recruitment status: COMPLETED
• Study phase: PHASE2
• Target enrollment: 420 participants
• Primary outcome timeframe: Change from Baseline to Week 12
• Results posted on: 2013-02-04

Participant Flow

Patient recruitment occurred over a 12 month period from March 2007 to February 2008 at 92 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	72 μg Linaclotide Acetate Linaclotide, 72μg dose, oral administration, once per day	145 μg Linaclotide Acetate Linaclotide, 145μg dose, oral administration, once per day	290 μg Linaclotide Acetate Linaclotide, 290μg dose, oral administration, once per day	579 μg Linaclotide Acetate Linaclotide, 579μg dose, oral administration, once per day	Matching Placebo Dose-matched placebo, oral administration, once per day
Overall Study STARTED	79	82	85	89	85
Overall Study COMPLETED	63	67	71	71	65
Overall Study NOT COMPLETED	16	15	14	18	20

Reasons for withdrawal

Measure	72 μg Linaclotide Acetate Linaclotide, 72μg dose, oral administration, once per day	145 μg Linaclotide Acetate Linaclotide, 145μg dose, oral administration, once per day	290 μg Linaclotide Acetate Linaclotide, 290μg dose, oral administration, once per day	579 μg Linaclotide Acetate Linaclotide, 579μg dose, oral administration, once per day	Matching Placebo Dose-matched placebo, oral administration, once per day
Overall Study Adverse Event	4	6	3	10	2
Overall Study Noncompliance	1	0	0	2	1
Overall Study Withdrawal by Subject	7	7	6	3	11
Overall Study Physician Decision	1	0	0	0	0
Overall Study Lost to Follow-up	3	2	5	3	6

Baseline Characteristics

Randomized, Double-blind, Dose-range-finding, Phase 2 Study of Linaclotide Administered to Patients With Irritable Bowel Syndrome With Constipation (IBS-C)

Baseline characteristics by cohort

Measure	72 µg Linaclotide Acetate n=79 Participants Linaclotide, 72μg dose, oral administration, once per day	145 µg Linaclotide Acetate n=82 Participants Linaclotide, 145μg dose, oral administration, once per day	290 µg Linaclotide Acetate n=85 Participants Linaclotide, 290μg dose, oral administration, once per day	579 µg Linaclotide Acetate n=89 Participants Linaclotide, 579μg dose, oral administration, once per day	Matching Placebo n=85 Participants Dose-matched placebo, oral administration, once per day	Total n=420 Participants Total of all reporting groups
Age Continuous	42.3 years STANDARD_DEVIATION 12.5 • n=5 Participants	45.6 years STANDARD_DEVIATION 10.8 • n=7 Participants	45.8 years STANDARD_DEVIATION 11.4 • n=5 Participants	43.7 years STANDARD_DEVIATION 11.4 • n=4 Participants	44.3 years STANDARD_DEVIATION 11.3 • n=21 Participants	44.4 years STANDARD_DEVIATION 11.5 • n=10 Participants
Age, Customized 18 years to 65 years	77 Participants n=5 Participants	79 Participants n=7 Participants	81 Participants n=5 Participants	86 Participants n=4 Participants	85 Participants n=21 Participants	408 Participants n=10 Participants
Age, Customized Older than 65 years	2 Participants n=5 Participants	3 Participants n=7 Participants	4 Participants n=5 Participants	3 Participants n=4 Participants	0 Participants n=21 Participants	12 Participants n=10 Participants
Sex: Female, Male Female	74 Participants n=5 Participants	78 Participants n=7 Participants	78 Participants n=5 Participants	79 Participants n=4 Participants	78 Participants n=21 Participants	387 Participants n=10 Participants
Sex: Female, Male Male	5 Participants n=5 Participants	4 Participants n=7 Participants	7 Participants n=5 Participants	10 Participants n=4 Participants	7 Participants n=21 Participants	33 Participants n=10 Participants
Region of Enrollment United States	75 participants n=5 Participants	79 participants n=7 Participants	80 participants n=5 Participants	86 participants n=4 Participants	81 participants n=21 Participants	401 participants n=10 Participants
Region of Enrollment Canada	4 participants n=5 Participants	3 participants n=7 Participants	5 participants n=5 Participants	3 participants n=4 Participants	4 participants n=21 Participants	19 participants n=10 Participants

PRIMARY outcome

Timeframe: Change from Baseline to Week 12

Population: The Intent-to-treat (ITT) Population included 419 patients of the Safety Population who also had ≥ 1 post-dose evaluation of the primary efficacy assessment (i.e., CSBM Frequency)

The change in the weekly normalized CSBM Rate during Weeks 1 through 12 of the Treatment Period from the weekly normalized CSBM Rate obtained during the Pretreatment Period.

The CSBM rate was normalized based on the number of CSBMs occurring in that week, adjusting for differences in the duration of the week and black-out periods (time not covered due to a missed IVRS call) versus 7x24 hours.

Outcome measures

Measure	72 ug Linaclotide Acetate n=79 Participants Linaclotide, 72μg dose, oral administration, once per day	145 ug Linaclotide Acetate n=82 Participants Linaclotide, 145μg dose, oral administration, once per day	290 ug Linaclotide Acetate n=84 Participants Linaclotide, 290μg dose, oral administration, once per day	579 ug Linaclotide Acetate n=89 Participants Linaclotide, 579μg dose, oral administration, once per day	Matching Placebo n=85 Participants Dose-matched placebo, oral administration, once per day.
Change From Baseline in the Weekly Normalized Complete Spontaneous Bowel Movement (CSBM) Rate During Weeks 1 Through 12 of the Treatment Period	2.90 CSBMs per week Standard Error 0.385	2.49 CSBMs per week Standard Error 0.380	3.61 CSBMs per week Standard Error 0.372	2.68 CSBMs per week Standard Error 0.369	1.01 CSBMs per week Standard Error 0.372

SECONDARY outcome

Timeframe: Change from Baseline to Week 12

Population: The ITT Population included 419 patients of the Safety Population who also had ≥ 1 post-dose evaluation of the primary efficacy assessment (i.e., CSBM Frequency).

For each week of the Treatment and Posttreatment 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 the baseline weekly CSBM rate.

Outcome measures

Measure	72 ug Linaclotide Acetate n=79 Participants Linaclotide, 72μg dose, oral administration, once per day	145 ug Linaclotide Acetate n=82 Participants Linaclotide, 145μg dose, oral administration, once per day	290 ug Linaclotide Acetate n=84 Participants Linaclotide, 290μg dose, oral administration, once per day	579 ug Linaclotide Acetate n=89 Participants Linaclotide, 579μg dose, oral administration, once per day	Matching Placebo n=85 Participants Dose-matched placebo, oral administration, once per day.
CSBM 75% Responder for the Treatment Period (Based on the Normalized Rate)	20 participants	16 participants	27 participants	21 participants	10 participants

SECONDARY outcome

Timeframe: Change from Baseline to Week 12

Population: The ITT Population included 419 patients of the Safety Population who also had ≥ 1 post-dose evaluation of the primary efficacy assessment (i.e., CSBM Frequency).

SBMs were measured daily during the treatment period by patient calls to the IVRS.

Outcome measures

Measure	72 ug Linaclotide Acetate n=79 Participants Linaclotide, 72μg dose, oral administration, once per day	145 ug Linaclotide Acetate n=82 Participants Linaclotide, 145μg dose, oral administration, once per day	290 ug Linaclotide Acetate n=84 Participants Linaclotide, 290μg dose, oral administration, once per day	579 ug Linaclotide Acetate n=89 Participants Linaclotide, 579μg dose, oral administration, once per day	Matching Placebo n=85 Participants Dose-matched placebo, oral administration, once per day.
Change From Baseline in the Weekly Normalized SBM Rate for the Treatment Period	4.62 SBMs per week Standard Error 0.457	4.36 SBMs per week Standard Error 0.453	4.97 SBMs per week Standard Error 0.442	5.64 SBMs per week Standard Error 0.439	1.68 SBMs per week Standard Error 0.442

SECONDARY outcome

Timeframe: Change from Baseline to Week 12

Population: The ITT Population included 419 patients of the Safety Population who also had ≥ 1 post-dose evaluation of the primary efficacy assessment (i.e., CSBM Frequency). 15 patients with no pretreatment spontaneous bowel movements were excluded from the Stool Consistency analysis.

Stool consistency analyses were performed using the 7-point Bristol Stool Form Scale (BSFS), whereby a score of 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; and 7 = watery, no solid pieces (entirely liquid).

Outcome measures

Measure	72 ug Linaclotide Acetate n=76 Participants Linaclotide, 72μg dose, oral administration, once per day	145 ug Linaclotide Acetate n=78 Participants Linaclotide, 145μg dose, oral administration, once per day	290 ug Linaclotide Acetate n=82 Participants Linaclotide, 290μg dose, oral administration, once per day	579 ug Linaclotide Acetate n=85 Participants Linaclotide, 579μg dose, oral administration, once per day	Matching Placebo n=83 Participants Dose-matched placebo, oral administration, once per day.
Change From Baseline in Stool Consistency (7-point Ordinal BSFS) for the Treatment Period	1.91 units on a scale Standard Error 0.133	1.80 units on a scale Standard Error 0.131	2.28 units on a scale Standard Error 0.127	2.20 units on a scale Standard Error 0.127	0.56 units on a scale Standard Error 0.127

SECONDARY outcome

Timeframe: Change from Baseline to Week 12

Population: The ITT Population included 419 patients of the Safety Population who also had ≥ 1 post-dose evaluation of the primary efficacy assessment (i.e., CSBM Frequency). 15 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	72 ug Linaclotide Acetate n=76 Participants Linaclotide, 72μg dose, oral administration, once per day	145 ug Linaclotide Acetate n=78 Participants Linaclotide, 145μg dose, oral administration, once per day	290 ug Linaclotide Acetate n=82 Participants Linaclotide, 290μg dose, oral administration, once per day	579 ug Linaclotide Acetate n=85 Participants Linaclotide, 579μg dose, oral administration, once per day	Matching Placebo n=83 Participants Dose-matched placebo, oral administration, once per day.
Change From Baseline in Straining (5-point Ordinal Scale) for the Treatment Period	-1.23 units on a scale Standard Error 0.081	-1.20 units on a scale Standard Error 0.080	-1.48 units on a scale Standard Error 0.077	-1.35 units on a scale Standard Error 0.078	-0.71 units on a scale Standard Error 0.078

SECONDARY outcome

Timeframe: Change from Baseline to Week 12

Population: The ITT Population included 419 patients of the Safety Population who also had ≥ 1 post-dose evaluation of the primary efficacy assessment (i.e., CSBM Frequency). 13 patients who dropped out prior to finishing 1 week of the trial have missing data.

Patients provided a weekly assessment of Degree of Relief of IBS Symptoms using a 7-point balanced scale (1=completely relieved, 2=considerably relieved, 3=somewhat relieved, 4=unchanged, 5=somewhat worse, 6=considerably worse, 7=as bad as I can imagine).

Outcome measures

Measure	72 ug Linaclotide Acetate n=77 Participants Linaclotide, 72μg dose, oral administration, once per day	145 ug Linaclotide Acetate n=79 Participants Linaclotide, 145μg dose, oral administration, once per day	290 ug Linaclotide Acetate n=81 Participants Linaclotide, 290μg dose, oral administration, once per day	579 ug Linaclotide Acetate n=87 Participants Linaclotide, 579μg dose, oral administration, once per day	Matching Placebo n=82 Participants Dose-matched placebo, oral administration, once per day.
Change From Baseline in Degree of Relief of Irritable Bowel Syndrome (IBS) Symptoms (7-point Balanced Scale) for the Treatment Period	-1.33 units on a scale Standard Error 0.108	-1.37 units on a scale Standard Error 0.107	-1.66 units on a scale Standard Error 0.105	-1.49 units on a scale Standard Error 0.104	-0.81 units on a scale Standard Error 0.105

SECONDARY outcome

Timeframe: Change from Baseline to Week 12

Population: The ITT Population included 419 patients of the Safety Population who also had ≥ 1 post-dose evaluation of the primary efficacy assessment (i.e., CSBM Frequency).

During the study, patients provided their self assessment of abdominal pain using a 5-point ordinal scale (1=none, 2=mild, 3=moderate, 4=severe, 5=very severe

Outcome measures

Measure	72 ug Linaclotide Acetate n=79 Participants Linaclotide, 72μg dose, oral administration, once per day	145 ug Linaclotide Acetate n=82 Participants Linaclotide, 145μg dose, oral administration, once per day	290 ug Linaclotide Acetate n=84 Participants Linaclotide, 290μg dose, oral administration, once per day	579 ug Linaclotide Acetate n=89 Participants Linaclotide, 579μg dose, oral administration, once per day	Matching Placebo n=85 Participants Dose-matched placebo, oral administration, once per day.
Change From Baseline in Abdominal Pain (5-point Ordinal Scale) for the Treatment Period	-0.71 units on a scale Standard Error 0.075	-0.71 units on a scale Standard Error 0.074	-0.90 units on a scale Standard Error 0.073	-0.86 units on a scale Standard Error 0.072	-0.49 units on a scale Standard Error 0.073

Adverse Events

72 µg Linaclotide Acetate

Serious events: 0 serious events

Other events: 21 other events

Deaths: 0 deaths

145 µg Linaclotide Acetate

Serious events: 0 serious events

Other events: 23 other events

Deaths: 0 deaths

290 µg Linaclotide Acetate

Serious events: 1 serious events

Other events: 26 other events

Deaths: 0 deaths

579 µg Linaclotide Acetate

Serious events: 0 serious events

Other events: 30 other events

Deaths: 0 deaths

Matching Placebo

Serious events: 0 serious events

Other events: 17 other events

Deaths: 0 deaths

Serious adverse events

Measure	72 µg Linaclotide Acetate n=79 participants at risk Linaclotide, 72μg dose, oral administration, once per day	145 µg Linaclotide Acetate n=82 participants at risk Linaclotide, 145μg dose, oral administration, once per day	290 µg Linaclotide Acetate n=85 participants at risk Linaclotide, 290μg dose, oral administration, once per day	579 µg Linaclotide Acetate n=89 participants at risk Linaclotide, 579μg dose, oral administration, once per day	Matching Placebo n=85 participants at risk Dose-matched placebo, oral administration, once per day
Gastrointestinal disorders Faecaloma	0.00% 0/79 • Adverse event data were collected from March of 2007 to April 2008.	0.00% 0/82 • Adverse event data were collected from March of 2007 to April 2008.	1.2% 1/85 • Adverse event data were collected from March of 2007 to April 2008.	0.00% 0/89 • Adverse event data were collected from March of 2007 to April 2008.	0.00% 0/85 • Adverse event data were collected from March of 2007 to April 2008.

Other adverse events

Measure	72 µg Linaclotide Acetate n=79 participants at risk Linaclotide, 72μg dose, oral administration, once per day	145 µg Linaclotide Acetate n=82 participants at risk Linaclotide, 145μg dose, oral administration, once per day	290 µg Linaclotide Acetate n=85 participants at risk Linaclotide, 290μg dose, oral administration, once per day	579 µg Linaclotide Acetate n=89 participants at risk Linaclotide, 579μg dose, oral administration, once per day	Matching Placebo n=85 participants at risk Dose-matched placebo, oral administration, once per day
Gastrointestinal disorders Abdominal distension	1.3% 1/79 • Adverse event data were collected from March of 2007 to April 2008.	3.7% 3/82 • Adverse event data were collected from March of 2007 to April 2008.	1.2% 1/85 • Adverse event data were collected from March of 2007 to April 2008.	4.5% 4/89 • Adverse event data were collected from March of 2007 to April 2008.	5.9% 5/85 • Adverse event data were collected from March of 2007 to April 2008.
Gastrointestinal disorders Abdominal pain	5.1% 4/79 • Adverse event data were collected from March of 2007 to April 2008.	3.7% 3/82 • Adverse event data were collected from March of 2007 to April 2008.	4.7% 4/85 • Adverse event data were collected from March of 2007 to April 2008.	7.9% 7/89 • Adverse event data were collected from March of 2007 to April 2008.	3.5% 3/85 • Adverse event data were collected from March of 2007 to April 2008.
Gastrointestinal disorders Diarrhea	11.4% 9/79 • Adverse event data were collected from March of 2007 to April 2008.	12.2% 10/82 • Adverse event data were collected from March of 2007 to April 2008.	16.5% 14/85 • Adverse event data were collected from March of 2007 to April 2008.	18.0% 16/89 • Adverse event data were collected from March of 2007 to April 2008.	1.2% 1/85 • Adverse event data were collected from March of 2007 to April 2008.
Nervous system disorders Headache	1.3% 1/79 • Adverse event data were collected from March of 2007 to April 2008.	3.7% 3/82 • Adverse event data were collected from March of 2007 to April 2008.	5.9% 5/85 • Adverse event data were collected from March of 2007 to April 2008.	2.2% 2/89 • Adverse event data were collected from March of 2007 to April 2008.	7.1% 6/85 • Adverse event data were collected from March of 2007 to April 2008.
Infections and infestations Nasopharyngitis	3.8% 3/79 • Adverse event data were collected from March of 2007 to April 2008.	8.5% 7/82 • Adverse event data were collected from March of 2007 to April 2008.	1.2% 1/85 • Adverse event data were collected from March of 2007 to April 2008.	1.1% 1/89 • Adverse event data were collected from March of 2007 to April 2008.	5.9% 5/85 • Adverse event data were collected from March of 2007 to April 2008.
Gastrointestinal disorders Nausea	1.3% 1/79 • Adverse event data were collected from March of 2007 to April 2008.	9.8% 8/82 • Adverse event data were collected from March of 2007 to April 2008.	1.2% 1/85 • Adverse event data were collected from March of 2007 to April 2008.	3.4% 3/89 • Adverse event data were collected from March of 2007 to April 2008.	5.9% 5/85 • Adverse event data were collected from March of 2007 to April 2008.
Infections and infestations Upper respiratory tract infection	0.00% 0/79 • Adverse event data were collected from March of 2007 to April 2008.	2.4% 2/82 • Adverse event data were collected from March of 2007 to April 2008.	4.7% 4/85 • Adverse event data were collected from March of 2007 to April 2008.	5.6% 5/89 • Adverse event data were collected from March of 2007 to April 2008.	3.5% 3/85 • Adverse event data were collected from March of 2007 to April 2008.
Infections and infestations Urinary tract infection	8.9% 7/79 • Adverse event data were collected from March of 2007 to April 2008.	1.2% 1/82 • Adverse event data were collected from March of 2007 to April 2008.	5.9% 5/85 • Adverse event data were collected from March of 2007 to April 2008.	1.1% 1/89 • Adverse event data were collected from March of 2007 to April 2008.	2.4% 2/85 • Adverse event data were collected from March of 2007 to April 2008.

Additional Information

Doug Levine, MD

Ironwood Pharmaceuticals

Phone: 617.374.3906

Email: dlevine@ironwoodpharma.com

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