A Trial of Linaclotide 290 μg in Patients With Irritable... | NCT03573908

Name	Class
Allergan Sales, LLC	INDUSTRY

Label	Type	Description	Intervention Names
Linaclotide 290 µg	Experimental	Participants receive linaclotide 290 µg orally once daily for 12 weeks during the Treatment Period. At Week 12 participants are rerandomized to receive either linaclotide 290 µg or placebo for 4 weeks in the Randomized Withdrawal Period.	Drug: Linaclotide Drug: Placebo
Placebo	Placebo Comparator	Participants receive placebo to linaclotide orally once daily for 12 weeks during the Treatment Period. At Week 12 participants are switched to receive linaclotide 290 µg for 4 weeks during the Randomized Withdrawal Period.	Drug: Linaclotide Drug: Placebo

Name	Type	Description	Arm Group Labels	Other Names
Linaclotide	Drug	Oral capsule	Linaclotide 290 µg Placebo

Outcomes Module

Primary Outcomes

Measure	Description	Time Frame
Overall Change From Baseline in Abdominal Score (Abdominal Bloating, Abdominal Discomfort, and Abdominal Pain) Throughout the Treatment Period	A participant's daily abdominal score was calculated as the average of daily e-diary abdominal pain, abdominal bloating and abdominal discomfort scores, each based on an 11-point scale of 0 (none) and 10 (worst possible). Baseline abdominal score was derived from the eDiary data collected daily in the Pretreatment Period, specifically the period of time from 14 days before randomization up to the time of randomization. The participant's abdominal score was averaged on a weekly basis, and each weekly change from baseline was calculated for the treatment period and used as the dependent variable in the mixed model with repeated measures (MMRM) model. MMRM results are based on a model with treatment, analysis week, region and treatment-by-week interaction as fixed effects and baseline as a covariate. An unstructured covariance structure was used to model intra-subject correlation with subjects as a random effect.	Baseline (14 days before randomization up to the time of randomization), Treatment Period (Weeks 1-12)

Secondary Outcomes

Measure	Description	Time Frame
Cumulative Distribution of Change From Baseline in 12-Week Abdominal Score	A participant's daily abdominal score was calculated as the average of daily e-diary abdominal pain, abdominal bloating and abdominal discomfort scores, each based on an 11-point scale of 0 (none) and 10 (worst possible). Baseline abdominal score was derived from the eDiary data collected daily in the Pretreatment Period, specifically the period of time from 14 days before randomization up to the time of randomization. The 12-week abdominal score was the average of the non-missing abdominal scores reported over the course of the treatment period. Change from baseline (BL) was calculated as the 12-week score minus the baseline score. The table presents the percentage of participants whose 12-week change from baseline was less than or equal to the threshold value of the score change (cumulative distribution of change).

Eligibility Module

Name	Affiliation	Role
Wilmin Bartolini, PhD	Ironwood Pharmaceuticals, Inc.	Study Chair

Facility	Status	City	State	ZIP	Country	Contacts
Clinical Research Associates		Huntsville	Alabama	35801	United States
Elite Clinical Studies

PubMed Identifier	Type	Citation	Retractions
36227782	Derived	Brenner DM, Lacy BE, Ford AC, Bartolini W, Wu J, Shea EP, Bochenek W, Boinpally R, Almansa C. Linaclotide Reduced Response Time for Irritable Bowel Syndrome With Constipation Symptoms: Analysis of 4 Randomized Controlled Trials. Am J Gastroenterol. 2023 May 1;118(5):872-879. doi: 10.14309/ajg.0000000000002064. Epub 2022 Oct 12.
34465695

ID	Title	Description
FG000	Placebo	Participants were randomized to receive placebo to linaclotide orally once daily for 12 weeks during the Treatment Period.
FG001	Linaclotide 290 µg	Participants were randomized to receive linaclotide 290 µg orally once daily for 12 weeks during the Treatment Period.

Type	Includes Protocol	Includes SAP	Includes ICF	Document Label	Document Date	Document Uploaded Date	Document File Name
Prot	Yes	No	No	Study Protocol	Mar 26, 2018	Oct 19, 2020

Type

Title

Description

Population Description

Reporting Status

Anticipated Posting Date

Parameter Type

Dispersion Type

Unit of Measure

Calculate Percentage

Time Frame

Units Analyzed

Denominator Units Selected

Arm/Group Information

Denominators

Classes

Analyses

Primary

Overall Change From Baseline in Abdominal Score (Abdominal Bloating, Abdominal Discomfort, and Abdominal Pain) Throughout the Treatment Period

A participant's daily abdominal score was calculated as the average of daily e-diary abdominal pain, abdominal bloating and abdominal discomfort scores, each based on an 11-point scale of 0 (none) and 10 (worst possible). Baseline abdominal score was derived from the eDiary data collected daily in the Pretreatment Period, specifically the period of time from 14 days before randomization up to the time of randomization. The participant's abdominal score was averaged on a weekly basis, and each weekly change from baseline was calculated for the treatment period and used as the dependent variable in the mixed model with repeated measures (MMRM) model. MMRM results are based on a model with treatment, analysis week, region and treatment-by-week interaction as fixed effects and baseline as a covariate. An unstructured covariance structure was used to model intra-subject correlation with subjects as a random effect.

Intent to Treat Population: all randomized participants. Two participants were excluded from the analysis due to missing scores.

Posted

Least Squares Mean

Standard Error

score on a scale

Baseline (14 days before randomization up to the time of randomization), Treatment Period (Weeks 1-12)

ID	Title	Description
OG000	Placebo	Participants randomized to receive placebo to linaclotide orally once daily for 12 weeks during the Treatment Period.
OG001	Linaclotide 290 µg	Participants randomized to receive linaclotide 290 µg orally once daily for 12 weeks during the Treatment Period.

Units	Counts
Participants	OG000306 OG001306

Title

Denominators

Categories

Title	Measurements
	OG000-1.182± 0.109 OG001-1.898± 0.111

Group IDs	Group Description	Statistical Method	Statistical Comment	P-Value	P-Value Comment	Parameter Type	Parameter Value	Dispersion Type	Dispersion Value	Confidence Interval Sides	Confidence Interval %	CI Lower Limit	CI Upper Limit	CI Lower Limit Comment	CI Upper Limit Comment	Estimate Comment	Tested Non-Inferiority	Non-Inferiority Type	Non-Inferiority Comment	Other Analysis Description
OG000 OG001	The overall family-wise Type I error rate for the primary and secondary outcome measures were controlled at the α=0.05 level by employing a fixed-sequence testing procedure. Outcome measures were tested using 10 hypotheses, each comparing linaclotide versus placebo, in the sequence of presentation of statistical analyses in this record. If the hypothesis comparing the 2 groups was statistically significant (α=0.05), then the next hypothesis was to be tested; otherwise, testing would stop.	MMRM		< 0.0001		Least squares (LS) mean difference	-0.715			2-Sided	95	-0.998	-0.433			Least squares (LS) mean difference (linaclotide - placebo)

Secondary

Cumulative Distribution of Change From Baseline in 12-Week Abdominal Score

A participant's daily abdominal score was calculated as the average of daily e-diary abdominal pain, abdominal bloating and abdominal discomfort scores, each based on an 11-point scale of 0 (none) and 10 (worst possible). Baseline abdominal score was derived from the eDiary data collected daily in the Pretreatment Period, specifically the period of time from 14 days before randomization up to the time of randomization. The 12-week abdominal score was the average of the non-missing abdominal scores reported over the course of the treatment period. Change from baseline (BL) was calculated as the 12-week score minus the baseline score. The table presents the percentage of participants whose 12-week change from baseline was less than or equal to the threshold value of the score change (cumulative distribution of change).

Intent to Treat Population: all randomized participants. Participants with available 12-week abdominal score.

Posted

Number

percentage of participants

Baseline (14 days before randomization up to the time of randomization), Treatment Period (Weeks 1-12)

ID	Title	Description
OG000	Placebo	Participants randomized to receive placebo to linaclotide orally once daily for 12 weeks during the Treatment Period.
OG001	Linaclotide 290 µg	Participants randomized to receive linaclotide 290 µg orally once daily for 12 weeks during the Treatment Period.

Secondary

Percentage of 6/12 Week Abdominal Score Responders (Responder Rate)

A 6/12 week abdominal score responder is a participant who meets the weekly abdominal score responder criteria for at least 6 out of the 12 weeks of the Treatment Period. For each week in the Treatment Period, a weekly abdominal score responder is a participant who has an improvement from baseline of at least 2 points (ie, a -2 point change from baseline) in the respective weekly abdominal score. If a participant did not have at least 4 completed eDiary entries for a particular Treatment Period week, the participant was not considered a responder for that week.

A participant's daily abdominal score was calculated as the average of daily e-diary abdominal pain, abdominal bloating and abdominal discomfort scores, each based on an 11-point scale of 0 (none) and 10 (worst possible). The participant's abdominal score was averaged on a weekly basis, and each weekly change from baseline was calculated for the treatment period.

Intent to Treat Population: all randomized participants.

Posted

Number

95% Confidence Interval

percentage of participants

Baseline (14 days before randomization up to the time of randomization), Treatment Period (Weeks 1-12)

ID	Title	Description
OG000	Placebo	Participants randomized to receive placebo to linaclotide orally once daily for 12 weeks during the Treatment Period.
OG001	Linaclotide 290 µg	Participants randomized to receive linaclotide 290 µg orally once daily for 12 weeks during the Treatment Period.

Secondary

Overall Change From Baseline in Abdominal Score (Abdominal Bloating, Abdominal Discomfort, and Abdominal Pain) Over Time in the Treatment Period

Intent to Treat Population: all randomized participants. Participants with an assessment at given time point.

Posted

Least Squares Mean

Standard Error

score on a scale

Baseline (14 days before randomization up to the time of randomization), Weeks 1-12

ID	Title	Description
OG000	Placebo	Participants randomized to receive placebo to linaclotide orally once daily for 12 weeks during the Treatment Period.
OG001	Linaclotide 290 µg

Group IDs	Group Description	Statistical Method	P-Value	P-Value Comment	Parameter Type	Parameter Value	Confidence Interval Sides	Confidence Interval %	CI Lower Limit	CI Upper Limit	Non-Inferiority Type
OG000 OG001	Week 12. The overall family-wise Type I error rate for primary and secondary outcome measures were controlled at the α=0.05 level by employing a fixed-sequence testing procedure. Outcome measures were tested using 10 hypotheses, each comparing linaclotide versus placebo, in the sequence of presentation of statistical analyses in this record. If the hypothesis comparing the 2 groups was statistically significant (α=0.05), then the next hypothesis was to be tested; otherwise, testing would stop.	MMRM	< 0.0001	LS mean difference and p-value were obtained based on an MMRM with treatment, analysis week, geographic region, and treatment-by-week interactions as fixed effects, and baseline score as a covariate.	LS mean difference	-0.867	2-Sided	95	-1.219	-0.515	Superiority
OG000 OG001	Week 10. The overall family-wise Type I error rate for primary and secondary outcome measures were controlled at the α=0.05 level by employing a fixed-sequence testing procedure. Outcome measures were tested using 10 hypotheses, each comparing linaclotide versus placebo, in the sequence of presentation of statistical analyses in this record. If the hypothesis comparing the 2 groups was statistically significant (α=0.05), then the next hypothesis was to be tested; otherwise, testing would stop.	MMRM	< 0.0001	LS mean difference and p-value were obtained based on an MMRM with treatment, analysis week, geographic region, and treatment-by-week interactions as fixed effects, and baseline score as a covariate.	LS mean difference	-0.719	2-Sided	95	-1.062	-0.376	Superiority
OG000 OG001	Week 8. The overall family-wise Type I error rate for primary and secondary outcome measures were controlled at the α=0.05 level by employing a fixed-sequence testing procedure. Outcome measures were tested using 10 hypotheses, each comparing linaclotide versus placebo, in the sequence of presentation of statistical analyses in this record. If the hypothesis comparing the 2 groups was statistically significant (α=0.05), then the next hypothesis was to be tested; otherwise, testing would stop.	MMRM	0.0002	LS mean difference and p-value were obtained based on an MMRM with treatment, analysis week, geographic region, and treatment-by-week interactions as fixed effects, and baseline score as a covariate.	LS mean difference	-0.665	2-Sided	95	-1.007	-0.322	Superiority
OG000 OG001	Week 6. The overall family-wise Type I error rate for primary and secondary outcome measures were controlled at the α=0.05 level by employing a fixed-sequence testing procedure. Outcome measures were tested using 10 hypotheses, each comparing linaclotide versus placebo, in the sequence of presentation of statistical analyses in this record. If the hypothesis comparing the 2 groups was statistically significant (α=0.05), then the next hypothesis was to be tested; otherwise, testing would stop.	MMRM	< 0.0001	LS mean difference and p-value were obtained based on an MMRM with treatment, analysis week, geographic region, and treatment-by-week interactions as fixed effects, and baseline score as a covariate.	LS mean difference	-0.831	2-Sided	95	-1.151	-0.511	Superiority
OG000 OG001	Week 4. The overall family-wise Type I error rate for primary and secondary outcome measures were controlled at the α=0.05 level by employing a fixed-sequence testing procedure. Outcome measures were tested using 10 hypotheses, each comparing linaclotide versus placebo, in the sequence of presentation of statistical analyses in this record. If the hypothesis comparing the 2 groups was statistically significant (α=0.05), then the next hypothesis was to be tested; otherwise, testing would stop.	MMRM	< 0.0001	LS mean difference and p-value were obtained based on an MMRM with treatment, analysis week, geographic region, and treatment-by-week interactions as fixed effects, and baseline score as a covariate.	LS mean difference	-0.683	2-Sided	95	-0.982	-0.383	Superiority
OG000 OG001	Week 2. The overall family-wise Type I error rate for primary and secondary outcome measures were controlled at the α=0.05 level by employing a fixed-sequence testing procedure. Outcome measures were tested using 10 hypotheses, each comparing linaclotide versus placebo, in the sequence of presentation of statistical analyses in this record. If the hypothesis comparing the 2 groups was statistically significant (α=0.05), then the next hypothesis was to be tested; otherwise, testing would stop.	MMRM	< 0.0001	LS mean difference and p-value were obtained based on an MMRM with treatment, analysis week, geographic region, and treatment-by-week interactions as fixed effects, and baseline score as a covariate.	LS mean difference	-0.628	2-Sided	95	-0.888	-0.368	Superiority
OG000 OG001	Week 1. The overall family-wise Type I error rate for primary and secondary outcome measures were controlled at the α=0.05 level by employing a fixed-sequence testing procedure. Outcome measures were tested using 10 hypotheses, each comparing linaclotide versus placebo, in the sequence of presentation of statistical analyses in this record. If the hypothesis comparing the 2 groups was statistically significant (α=0.05), then the next hypothesis was to be tested; otherwise, testing would stop.	MMRM	< 0.0001	LS mean difference and p-value were obtained based on an MMRM with treatment, analysis week, geographic region, and treatment-by-week interactions as fixed effects, and baseline score as a covariate.	LS mean difference	-0.435	2-Sided	95	-0.641	-0.228	Superiority
OG000 OG001	Week 3. Not part of the fixed-sequence testing procedure.	MMRM	< 0.0001	LS mean difference and p-value were obtained based on an MMRM with treatment, analysis week, geographic region, and treatment-by-week interactions as fixed effects, and baseline score as a covariate.	LS mean difference	-0.683	2-Sided	95	-0.969	-0.398	Superiority
OG000 OG001	Week 5. Not part of the fixed-sequence testing procedure.	MMRM	< 0.0001	LS mean difference and p-value were obtained based on an MMRM with treatment, analysis week, geographic region, and treatment-by-week interactions as fixed effects, and baseline score as a covariate.	LS mean difference	-0.768	2-Sided	95	-1.076	-0.460	Superiority
OG000 OG001	Week 7. Not part of the fixed-sequence testing procedure.	MMRM	< 0.0001	LS mean difference and p-value were obtained based on an MMRM with treatment, analysis week, geographic region, and treatment-by-week interactions as fixed effects, and baseline score as a covariate.	LS mean difference	-0.758	2-Sided	95	-1.086	-0.431	Superiority
OG000 OG001	Week 9. Not part of the fixed-sequence testing procedure.	MMRM	< 0.0001	LS mean difference and p-value were obtained based on an MMRM with treatment, analysis week, geographic region, and treatment-by-week interactions as fixed effects, and baseline score as a covariate.	LS mean difference	-0.703	2-Sided	95	-1.043	-0.363	Superiority
OG000 OG001	Week 11. Not part of the fixed-sequence testing procedure.	MMRM	< 0.0001	LS mean difference and p-value were obtained based on an MMRM with treatment, analysis week, geographic region, and treatment-by-week interactions as fixed effects, and baseline score as a covariate.	LS mean difference	-0.844	2-Sided	95	-1.189	-0.498	Superiority

ID	Title	Description	Deaths (At Risk)	Serious Events (Affected)	Serious Events (At Risk)	Other Events (Affected)	Other Events (At Risk)
EG000	Placebo	Participants randomized to receive placebo to linaclotide orally once daily for 12 weeks during the Treatment Period.	308	2	308	15	308
EG001	Linaclotide 290 µg	Participants randomized to receive linaclotide 290 µg orally once daily for 12 weeks during the Treatment Period.	306	4	306	26	306
EG002	Linaclotide 290 µg -> Linaclotide 290 µg	Participants who received linaclotide 290 µg orally once daily for 12 weeks during the Treatment Period were rerandomized to continue linaclotide 290 µg for 4 weeks in the Randomized Withdrawal Period.	138	1	138	5	138
EG003	Linaclotide 290 µg -> Placebo	Participants who received linaclotide 290 µg orally once daily for 12 weeks during the Treatment Period were rerandomized to receive placebo for 4 weeks in the Randomized Withdrawal Period.	137	0	137	4	137
EG004	Placebo -> Linaclotide 290 µg	Participants who received placebo orally once daily for 12 weeks during the Treatment Period were switched to receive linaclotide 290 µg for 4 weeks during the Randomized Withdrawal Period.	279	1	279	21	279

Term	Organ System	Source Vocabulary	Assessment Type	Statistical Information
Bipolar disorder	Psychiatric disorders	MedDRA 21.0	Systematic Assessment	EG0000 affected308 at risk EG0011 affected306 at risk EG0020 affected138 at risk EG0030 affected137 at risk EG0040 affected279 at risk
Breast cancer	Neoplasms benign, malignant and unspecified (incl cysts and polyps)	MedDRA 21.0	Systematic Assessment	EG0001 affected308 at risk EG0010 affected306 at risk EG0020 affected138 at risk EG003
Cerebral infarction	Nervous system disorders	MedDRA 21.0	Systematic Assessment	EG0001 affected308 at risk EG0010 affected306 at risk EG0020 affected138 at risk EG003
Hemiparaesthesia	Nervous system disorders	MedDRA 21.0	Systematic Assessment	EG0000 affected308 at risk EG0011 affected306 at risk EG0020 affected138 at risk EG003
Nephrolithiasis	Renal and urinary disorders	MedDRA 21.0	Systematic Assessment	EG0000 affected308 at risk EG0011 affected306 at risk EG0020 affected138 at risk EG003
Uterine leiomyoma	Neoplasms benign, malignant and unspecified (incl cysts and polyps)	MedDRA 21.0	Systematic Assessment	EG0000 affected308 at risk EG0011 affected306 at risk EG0020 affected138 at risk EG003
Anaemia	Blood and lymphatic system disorders	MedDRA 21.0	Systematic Assessment	EG0000 affected308 at risk EG0010 affected306 at risk EG0021 affected138 at risk EG003
Vomiting	Gastrointestinal disorders	MedDRA 21.0	Systematic Assessment	EG0000 affected308 at risk EG0010 affected306 at risk EG0020 affected138 at risk EG003

Term	Organ System	Source Vocabulary	Assessment Type	Statistical Information
Diarrhoea	Gastrointestinal disorders	MedDRA 21.0	Systematic Assessment	EG0005 affected308 at risk EG00114 affected306 at risk EG0023 affected138 at risk EG0032 affected137 at risk EG00416 affected279 at risk
Nasopharyngitis	Infections and infestations	MedDRA 21.0	Systematic Assessment	EG0009 affected308 at risk EG0015 affected306 at risk EG0022 affected138 at risk EG003
Headache	Nervous system disorders	MedDRA 21.0	Systematic Assessment	EG0003 affected308 at risk EG0018 affected306 at risk EG0020 affected138 at risk EG003

ID	Title	Description
BG000	Placebo	Participants randomized to receive placebo to linaclotide orally once daily for 12 weeks during the Treatment Period.
BG001	Linaclotide 290 µg	Participants randomized to receive linaclotide 290 µg orally once daily for 12 weeks during the Treatment Period.
BG002	Total	Total of all reporting groups