Safety and Efficacy of Linaclotide in Patients With Chronic Constipation and Prominent Abdominal Bloating

Phase 3b, Randomized, Double-Blind, Placebo-Controlled, Parallel-Group Trial of Linaclotide Administered Orally for 12 Weeks to Patients With Chronic Constipation and Prominent Abdominal Bloating at Baseline

The purpose of this study is to evaluate the efficacy and safety of linaclotide compared with placebo in patients with chronic constipation (CC) and prominent abdominal bloating. This study includes an up to 3-week screening period and a 2-3 week pretreatment period. Patients who are eligible will be randomized to one of two doses of linaclotide or placebo for 12 weeks. This 12-week study will assess the effects of linaclotide on bowel movement frequency, as well as other abdominal and bowel symptoms of CC.

Study Overview

• Status: Completed
• Conditions: Constipation; Chronic Constipation
• Intervention / Treatment: Drug: Linaclotide 290 micrograms; Drug: Linaclotide 145 micrograms; Drug: Matching placebo

• Study Type: Interventional
• Enrollment (Actual): 487
• Phase: Phase 3

Contacts and Locations

Study Locations

• Canada
  • Ontario
    • Sarnia, Ontario, Canada, N7T 4X3
      • Forest Investigative Site 059
    • Sudbury, Ontario, Canada, P3E 1H5
      • Forest Investigative Site 054
    • Toronto, Ontario, Canada, M4S 1Y2
      • Forest Investigative Site 086
    • Toronto, Ontario, Canada, M9W 4L6
      • Forest Investigative Site 147
    • Vaughan, Ontario, Canada, L4L 4Y7
      • Forest Investigative Site 152
• United States
  • Arizona
    • Chandler, Arizona, United States, 85224
      • Forest Investigative Site 020
    • Chandler, Arizona, United States, 85224
      • Forest Investigative Site 102
    • Glendale, Arizona, United States, 85308
      • Forest Investigative Site 149
    • Goodyear, Arizona, United States, 85395
      • Forest Investigative Site 126
    • Phoenix, Arizona, United States, 85018
      • Forest Investigative Site 018
    • Phoenix, Arizona, United States, 85020
      • Forest Investigative Site 061
    • Scottsdale, Arizona, United States, 85251
      • Forest Investigative Site 022
    • Tucson, Arizona, United States, 85704
      • Forest Investigative Site 079
    • Tucson, Arizona, United States, 85712
      • Forest Investigative Site 071
  • Arkansas
    • North Little Rock, Arkansas, United States, 72117
      • Forest Investigative Site 135
  • California
    • Anaheim, California, United States, 92801
      • Forest Investigative Site 106
    • Laguna Hills, California, United States, 92653
      • Forest Investigative Site 104
    • Mission Hills, California, United States, 91345
      • Forest Investigative Site 066
    • San Carlos, California, United States, 94070
      • Forest Investigative Site 095
    • San Diego, California, United States, 92108
      • Forest Investigative Site 009
    • Santa Monica, California, United States, 90404
      • Forest Investigative Site 151
    • Westlake Village, California, United States, 91361
      • Forest Investigative Site 010
  • Colorado
    • Boulder, Colorado, United States, 80304
      • Forest Investigative Site 012
    • Colorado Springs, Colorado, United States, 80904
      • Forest Investigative Site 041
    • Colorado Springs, Colorado, United States, 80907
      • Forest Investigative Site 045
    • Longmont, Colorado, United States, 80501
      • Forest Investigative Site 060
  • Connecticut
    • Bristol, Connecticut, United States, 06010
      • Forest Investigative Site 007
    • Waterbury, Connecticut, United States, 06708
      • Forest Investigative Site 153
  • Florida
    • Boynton Beach, Florida, United States, 33426
      • Forest Investigative Site 091
    • Bradenton, Florida, United States, 34208
      • Forest Investigative Site 047
    • Brooksville, Florida, United States, 34601
      • Forest Investigative Site 042
    • Coral Gables, Florida, United States, 33134
      • Forest Investigative Site 133
    • DeLand, Florida, United States, 32720
      • Forest Investigative Site 131
    • Ft. Myers, Florida, United States, 33916
      • Forest Investigative Site 051
    • Inverness, Florida, United States, 34452
      • Forest Investigative Site 137
    • Jacksonville, Florida, United States, 32205
      • Forest Investigative Site 114
    • Jupiter, Florida, United States, 33458
      • Forest Investigative Site 004
    • Kissimmee, Florida, United States, 34741
      • Forest Investigative Site 016
    • Lauderdale Lakes, Florida, United States, 33319
      • Forest Investigative Site 097
    • Miami, Florida, United States, 33143
      • Forest Investigative Site 003
    • Miami, Florida, United States, 33183
      • Forest Investigative Site 002
    • New Smyrna Beach, Florida, United States, 32168
      • Forest Investigative Site 130
    • Ocala, Florida, United States, 34471
      • Forest Investigative Site 040
    • Orlando, Florida, United States, 32806
      • Forest Investigative Site 083
    • Oviedo, Florida, United States, 32765
      • Forest Investigative Site 150
    • Port Orange, Florida, United States, 32129
      • Forest Investigative Site 132
    • Seminole, Florida, United States, 33777
      • Forest Investigative Site 127
    • St. Petersburg, Florida, United States, 33709
      • Forest Investigative Site 087
    • Tampa, Florida, United States, 33606
      • Forest Investigative Site 064
    • Zephyrhills, Florida, United States, 33542
      • Forest Investigative Site 115
  • Georgia
    • Marietta, Georgia, United States, 30060
      • Forest Investigative Site 021
    • Marietta, Georgia, United States, 30067
      • Forest Investigative Site 011
    • Sandy Springs, Georgia, United States, 30328
      • Forest Investigative Site 109
    • Stockbridge, Georgia, United States, 30281
      • Forest Investigative Site 037
    • Woodstock, Georgia, United States, 30189
      • Forest Investigative Site 023
  • Idaho
    • Idaho Falls, Idaho, United States, 83404
      • Forest Investigative Site 015
  • Illinois
    • Peoria, Illinois, United States, 61602
      • Forest Investigative Site 122
    • Rockford, Illinois, United States, 61107
      • Forest Investigative Site 043
  • Indiana
    • Anderson, Indiana, United States, 46011
      • Forest Investigative Site 107
  • Iowa
    • Clive, Iowa, United States, 50325
      • Forest Investigative Site 117
    • Clive, Iowa, United States, 50325
      • Forest Investigative Site 146
    • Davenport, Iowa, United States, 52807
      • Forest Investigative Site 143
    • Iowa City, Iowa, United States, 52242
      • Forest Investigative Site 055
  • Kansas
    • Newton, Kansas, United States, 67114
      • Forest Investigative Site 028
    • Overland Park, Kansas, United States, 66215
      • Forest Investigative Site 112
    • Wichita, Kansas, United States, 67205
      • Forest Investigative Site 034
    • Wichita, Kansas, United States, 67207
      • Forest Investigative Site 032
  • Kentucky
    • Lexington, Kentucky, United States, 40509
      • Forest Investigative Site 128
    • Madisonville, Kentucky, United States, 42431
      • Forest Investigative Site 134
  • Louisiana
    • Baton Rouge, Louisiana, United States, 70809
      • Forest Investigative Site 121
    • Metairie, Louisiana, United States, 70006
      • Forest Investigative Site 124
    • Monroe, Louisiana, United States, 71201
      • Forest Investigative Site 101
    • Shreveport, Louisiana, United States, 71101
      • Forest Investigative Site 058
    • Shreveport, Louisiana, United States, 71103
      • Forest Investigative Site 099
  • Maryland
    • Baltimore, Maryland, United States, 21215
      • Forest Investigative Site 062
    • Chevy Chase, Maryland, United States, 20815
      • Forest Investigative Site 008
    • Hagerstown, Maryland, United States, 21742
      • Forest Investigative Site 014
    • Towson, Maryland, United States, 21286
      • Forest Investigative Site 024
  • Massachusetts
    • Boston, Massachusetts, United States, 02135
      • Forest Investigative Site 006
  • Michigan
    • Chesterfield, Michigan, United States, 48047
      • Forest Investigative Site 070
    • Traverse City, Michigan, United States, 49684
      • Forest Investigative Site 145
  • Mississippi
    • Jackson, Mississippi, United States, 39202
      • Forest Investigative Site 141
  • Nebraska
    • Fremont, Nebraska, United States, 68025
      • Forest Investigative Site 077
    • Omaha, Nebraska, United States, 68134
      • Forest Investigative Site 048
  • Nevada
    • Henderson, Nevada, United States, 89014
      • Forest Investigative Site 052
    • Las Vegas, Nevada, United States, 89121
      • Forest Investigative Site 080
  • New Jersey
    • Clifton, New Jersey, United States, 07012
      • Forest Investigative Site 036
    • Marlton, New Jersey, United States, 08053
      • Forest Investigative Site 088
    • Vineland, New Jersey, United States, 08360
      • Forest Investigative Site 033
  • New Mexico
    • Albuquerque, New Mexico, United States, 87106
      • Forest Investigative Site 063
    • Albuquerque, New Mexico, United States, 87108
      • Forest Investigative Site 093
  • New York
    • Brooklyn, New York, United States, 11206
      • Forest Investigative Site 044
    • Great Neck, New York, United States, 11021
      • Forest Investigative Site 017
  • North Carolina
    • Asheboro, North Carolina, United States, 27203
      • Forest Investigative Site 142
    • Asheville, North Carolina, United States, 28801
      • Forest Investigative Site 094
    • Boone, North Carolina, United States, 28607
      • Forest Investigative Site 075
    • Chapel Hill, North Carolina, United States, 27599-7080
      • Forest Investigative Site 123
    • Davidson, North Carolina, United States, 28036
      • Forest Investigative Site 140
    • Fayetteville, North Carolina, United States, 28304
      • Forest Investigative Site 039
    • Greensboro, North Carolina, United States, 27403
      • Forest Investigative Site 031
    • Greensboro, North Carolina, United States, 27408
      • Forest Investigative Site 029
    • Greensboro, North Carolina, United States, 27408
      • Forest Investigative Site 078
    • Harrisburg, North Carolina, United States, 28075
      • Forest Investigative Site 084
    • Hickory, North Carolina, United States, 28601
      • Forest Investigative Site 073
    • Hickory, North Carolina, United States, 28602
      • Forest Investigative Site 050
    • High Point, North Carolina, United States, 27262
      • Forest Investigative Site 139
    • Raleigh, North Carolina, United States, 27612
      • Forest Investigative Site 027
    • Statesville, North Carolina, United States, 28625
      • Forest Investigative Site 119
    • Wilmington, North Carolina, United States, 28401
      • Forest Investigative Site 089
    • Winston-Salem, North Carolina, United States, 27103
      • Forest Investigative Site 074
  • Ohio
    • Cincinnati, Ohio, United States, 45242
      • Forest Investigative Site 025
    • Cincinnati, Ohio, United States, 45249
      • Forest Investigative Site 120
    • Cleveland, Ohio, United States, 44122
      • Forest Investigative Site 056
    • Columbus, Ohio, United States, 43215
      • Forest Investigative Site 026
    • Dayton, Ohio, United States, 45415
      • Forest Investigative Site 098
    • Dayton, Ohio, United States, 45432
      • Forest Investigative Site 090
    • Mentor, Ohio, United States, 44060
      • Forest Investigative Site 085
    • Wadsworth, Ohio, United States, 44281
      • Forest Investigative Site 068
  • Oklahoma
    • Oklahoma City, Oklahoma, United States, 73104
      • Forest Investigative Site 118
  • Pennsylvania
    • Levittown, Pennsylvania, United States, 19056
      • Forest Investigative Site 081
    • Pittsburgh, Pennsylvania, United States, 15206
      • Forest Investigative Site 001
    • Reading, Pennsylvania, United States, 19606
      • Forest Investigative Site 110
  • South Carolina
    • Greer, South Carolina, United States, 29650
      • Forest Investigative Site 116
    • Simpsonville, South Carolina, United States, 29681
      • Forest Investigative Site 046
  • South Dakota
    • Dakota Dunes, South Dakota, United States, 57049
      • Forest Investigative Site 092
  • Tennessee
    • Chattanooga, Tennessee, United States, 37421
      • Forest Investigative Site 129
    • Kingsport, Tennessee, United States, 37660
      • Forest Investigative Site 138
  • Texas
    • Austin, Texas, United States, 78756
      • Forest Investigative Site 125
    • Dallas, Texas, United States, 75231
      • Forest Investigative Site 035
    • Dallas, Texas, United States, 75234
      • Forest Investigative Site 005
    • Fort Worth, Texas, United States, 76135
      • Forest Investigative Site 111
    • Houston, Texas, United States, 77034
      • Forest Investigative Site 100
    • Katy, Texas, United States, 77450
      • Forest Investigative Site 067
    • Pasadena, Texas, United States, 77505
      • Forest Investigative Site 049
    • San Antonio, Texas, United States, 78229
      • Forest Investigative Site 076
    • San Antonio, Texas, United States, 78209
      • Forest Investigative Site 030
    • Sugarland, Texas, United States, 77479
      • Forest Investigative Site 065
  • Utah
    • Ogden, Utah, United States, 84405
      • Forest Investigative Site 019
    • Salt Lake City, Utah, United States, 84107
      • Forest Investigative Site 105
    • Sandy, Utah, United States, 84094
      • Forest Investigative Site 113
  • Virginia
    • Charlottesville, Virginia, United States, 22911
      • Forest Investigative Site 053
    • Chesapeake, Virginia, United States, 23320
      • Forest Investigative Site 108
    • Chesapeake, Virginia, United States, 23320
      • Forest Investigative Site 136
    • Christiansburg, Virginia, United States, 24073
      • Forest Investigative Site 148
    • Lynchburg, Virginia, United States, 24502
      • Forest Investigative Site 072
    • Newport News, Virginia, United States, 23606
      • Forest Investigative Site 069
    • Norfolk, Virginia, United States, 23502
      • Forest Investigative Site 013
    • Richmond, Virginia, United States, 23294
      • Forest Investigative Site 038
  • Washington
    • Spokane, Washington, United States, 99208
      • Forest Investigative Site 103
  • Wisconsin
    • La Crosse, Wisconsin, United States, 54601
      • Forest Investigative Site 082
    • Milwaukee, Wisconsin, United States, 53215
      • Forest Investigative Site 096

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: Yes
• Genders Eligible for Study: All

Description

Inclusion Criteria:

• Patient has completed a colonoscopy according to the American Gastroenterological Association criteria with no clinically significant findings
• Patient has successfully completed protocol procedures (with no clinically significant findings)

• Patient meets protocol criteria for Chronic Constipation(CC): < 3 bowel movements per week and reports one or more of the following symptoms for at least 12 weeks:

  1. Straining during more than 25% of BMs
  2. Lumpy or hard stools during more than 25% of BMs
  3. Sensation of incomplete evacuation during more than 25% of BMs
• Patient demonstrates continued chronic constipation and bloating through Pretreatment Period
• Patient is compliant with Interactive voice response System (IVRS)

Exclusion Criteria:

• Patient has a history of loose or watery stools
• Patient has symptoms of or been diagnosed with Irritable Bowel Syndrome (IBS)
• Patient has a structural abnormality of the gastrointestinal (GI) tract or a disease or condition that can affect GI motility
• Patient has any protocol-excluded or clinically significant medical or surgical history that would limit the patient's ability to complete or participate in this clinical trial or could confound the study assessments

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Quadruple

Number of Arms

3

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Placebo Comparator: Placebo; Matching placebo	Drug: Matching placebo; oral capsule, taken once daily each morning at least 30 minutes before breakfast
Experimental: Linaclotide 290 micrograms	Drug: Linaclotide 290 micrograms; oral capsule, taken once daily each morning at least 30 minutes before breakfast
Experimental: Linaclotide 145 Micrograms; Linaclotide 145 micrograms	Drug: Linaclotide 145 micrograms; oral capsule, taken once daily each morning at least 30 minutes before breakfast

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
9/12 Week Complete Spontaneous Bowel Movement (CSBM) 3+1 Responder	A 9/12 Week CSBM 3+1 Responder is a patient who is a CSBM 3+1 Weekly Responder for at least 9 out of the 12 weeks of the Treatment Period. A CSBM 3+1 Weekly Responder is a patient who had a CSBM Weekly Frequency Rate that was 3 or greater and increased by 1 or more from baseline.	12-week treatment period

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
9/12 Week Complete Spontaneous Bowel Movement (CSBM) 3+1 Responder	A 9/12 Week CSBM 3+1 Responder is a patient who is a CSBM 3+1 Weekly Responder for at least 9 out of the 12 weeks of the Treatment Period. A CSBM 3+1 Weekly Responder is a patient who had a CSBM Weekly Frequency Rate that was 3 or greater and increased by 1 or more from baseline.	12-week treatment period
Change From Baseline in 12-Week Abdominal Bloating	Abdominal Bloating was measured daily using an 11-point Numerical Rating Scale (NRS) where a value of 0 represents no abdominal bloating and a value of 10 represents very severe abdominal bloating. The abdominal bloating score from Baseline is derived from the Interactive Voice Response System (IVRS) daily diary data collected in the Pretreatment Period, specifically the period of time from 14 days before randomization up to the time of randomization (Visit 3, Day 1). The change from baseline in 12-Week Abdominal Bloating score is the difference between the average nonmissing daily patient assessments of abdominal bloating scores during the 14 day Baseline period, and the average of the nonmissing daily patient assessments of abdominal bloating scores reported during the 12 week Treatment Period.	Baseline and 12-week treatment period
Percent Change From Baseline in 12-week Abdominal Bloating	Abdominal Bloating was measured daily using an 11-point Numerical Rating Scale (NRS) where a value of 0 represents no abdominal bloating and a value of 10 represents very severe abdominal bloating. The abdominal bloating score from Baseline is derived from the Interactive Voice Response System (IVRS) daily diary data collected in the Pretreatment Period, specifically the period of time from 14 days before randomization, up to the time of randomization (Visit 3, Day 1). The percent change from baseline in 12-Week Abdominal Bloating score is the percentage difference between the average nonmissing daily patient assessments score of abdominal bloating scores during the 14 day Baseline period, and the average of the nonmissing daily patient assessments of abdominal bloating scores reported during the 12 week Treatment Period.	Baseline and 12-week treatment period
Percent Change From Baseline in Abdominal Bloating at Week 12	Abdominal bloating was measured daily using an 11-point Numerical Rating Scale (NRS) where a value of 0 represents no abdominal bloating and a value of 10 represents very severe abdominal bloating. The abdominal bloating score from Baseline is derived from the Interactive Voice Response System (IVRS) daily diary data collected in the Pretreatment Period, specifically the period of time from 14 days before randomization, up to the time of randomization (Visit 3, Day 1). The percent change from baseline at Week 12 in Abdominal Bloating score is the percentage difference between the average nonmissing daily patient assessments of abdominal bloating scores during the 14 day Baseline period, and the average of the nonmissing daily patient assessments of abdominal bloating scores reported during Week 12.	Baseline and Week 12
6/12 Week Abdominal Bloating 30% Responder	A patient was a 6/12 week abdominal bloating 30% responder if, for at least 6 weeks of the 12-week treatment period, that patient's improvement from baseline in the weekly abdominal bloating score was ≥ 30% from baseline.	12-week treatment period
Change From Baseline in 12-week CSBM Frequency Rate	A patient's 12-week CSBM frequency rate from Baseline is derived from the Interactive Voice Response System (IVRS) daily diary data collected in the Pretreatment Period, specifically the period of time from 14 days before randomization, up to the time of randomization (Visit 3, Day 1). A patient's 12-week CSBM frequency rate was the CSBM rate (CSBMs/week) calculated over the 12 weeks of the treatment period. Only the Placebo versus Linaclotide 145 micrograms arm comparison is a secondary measure type for this outcome measure. The additional data for the Linaclotide 290 micrograms arm (a pre-specified additional outcome measure) is presented here for ease of comparison.	Baseline and 12-week treatment period
Change From Baseline in CSBM Frequency Rate at Week 1.	A patient's CSBM frequency rate from Baseline is derived from the Interactive Voice Response System (IVRS) daily diary data collected in the Pretreatment Period, specifically the period of time from 14 days before randomization, up to the time of randomization (Visit 3, Day 1). A patient's CSBM frequency rate at week 1 was the CSBM rate (CSBMs/week) calculated over that week. Only the Placebo versus Linaclotide 145 micrograms arm comparison is a secondary measure type for this outcome measure. The additional data for the Linaclotide 290 micrograms arm (a pre-specified additional outcome measure) is presented here for ease of comparison.	Baseline and Week 1
Change From Baseline in CSBM Frequency Rate at Week 4.	A patient's CSBM frequency rate from Baseline is derived from the Interactive Voice Response System (IVRS) daily diary data collected in the Pretreatment Period, specifically the period of time from 14 days before randomization, up to the time of randomization (Visit 3, Day 1). A patient's CSBM frequency rate at week 4 was the CSBM rate (CSBMs/week) calculated over that week. Only the Placebo versus Linaclotide 145 micrograms arm comparison is a secondary measure type for this outcome measure. The additional data for the Linaclotide 290 micrograms arm (a pre-specified additional outcome measure) is presented here for ease of comparison.	Baseline and Week 4
Change From Baseline in CSBM Frequency Rate at Week 8	A patient's CSBM frequency rate from Baseline is derived from the Interactive Voice Response System (IVRS) daily diary data collected in the Pretreatment Period, specifically the period of time from 14 days before randomization, up to the time of randomization (Visit 3, Day 1). A patient's CSBM frequency rate at week 8 was the CSBM rate (CSBMs/week) calculated over that week. Only the Placebo versus Linaclotide 145 micrograms arm comparison is a secondary measure type for this outcome measure. The additional data for the Linaclotide 290 micrograms arm (a pre-specified additional outcome measure) is presented here for ease of comparison.	Baseline and Week 8
Change From Baseline in CSBM Frequency Rate at Week 12	A patient's CSBM frequency rate from Baseline is derived from the Interactive Voice Response System (IVRS) daily diary data collected in the Pretreatment Period, specifically the period of time from 14 days before randomization, up to the time of randomization (Visit 3, Day 1). A patient's CSBM frequency rate at week 12 was the CSBM rate (CSBMs/week) calculated over that week. Only the Placebo versus Linaclotide 145 micrograms arm comparison is a secondary measure type for this outcome measure. The additional data for the Linaclotide 290 micrograms arm (a pre-specified additional outcome measure) is presented here for ease of comparison.	Baseline and Week 12
Change From Baseline in 12-Week SBM Frequency Rate	A patient's Baseline SBM frequency rate is derived from the Interactive Voice Response System (IVRS) daily diary data collected in the Pretreatment Period, specifically the period of time from 14 days before randomization, up to the time of randomization (Visit 3, Day 1). A patient's 12-week SBM frequency rate was the SBM rate (SBMs/week) calculated over the 12 weeks of the treatment period. Only the Placebo versus Linaclotide 145 micrograms arm comparison is a secondary measure type for this outcome measure. The additional data for the Linaclotide 290 micrograms arm (a pre-specified additional outcome measure) is presented here for ease of comparison.	12-week treatment period
Change From Baseline in SBM Frequency Rate at Week 1	A patient's baseline SBM frequency rate is derived from the Interactive Voice Response System (IVRS) daily diary data collected in the Pretreatment Period, specifically the period of time from 14 days before randomization, up to the time of randomization (Visit 3, Day 1). A patient's SBM frequency rate at week 1 was the SBM rate (SBMs/week) calculated over that week. Only the Placebo versus Linaclotide 145 micrograms arm comparison is a secondary measure type for this outcome measure. The additional data for the Linaclotide 290 micrograms arm (a pre-specified additional outcome measure) is presented here for ease of comparison.	Baseline and Week 1
Change From Baseline in SBM Frequency Rate at Week 4	A patient's baseline SBM frequency rate is derived from the Interactive Voice Response System (IVRS) daily diary data collected in the Pretreatment Period, specifically the period of time from 14 days before randomization, up to the time of randomization (Visit 3, Day 1). A patient's SBM frequency rate at Week 4 was the SBM rate (SBMs/week) calculated over that week. Only the Placebo versus Linaclotide 145 micrograms arm comparison is a secondary measure type for this outcome measure. The additional data for the Linaclotide 290 micrograms arm (a pre-specified additional outcome measure) is presented here for ease of comparison.	Baseline and Week 4
Change From Baseline in SBM Frequency Rate at Week 8	A patient's baseline SBM frequency rate is derived from the Interactive Voice Response System (IVRS) daily diary data collected in the Pretreatment Period, specifically the period of time from 14 days before randomization, up to the time of randomization (Visit 3, Day 1). A patient's SBM frequency rate at Week 8 was the SBM rate (SBMs/week) calculated over that week. Only the Placebo versus Linaclotide 145 micrograms arm comparison is a secondary measure type for this outcome measure. The additional data for the Linaclotide 290 micrograms arm (a pre-specified additional outcome measure) is presented here for ease of comparison.	Baseline and Week 8
Change From Baseline in SBM Frequency Rate at Week 12	A patient's baseline SBM frequency rate is derived from the Interactive Voice Response System (IVRS) daily diary data collected in the Pretreatment Period, specifically the period of time from 14 days before randomization, up to the time of randomization (Visit 3, Day 1). A patient's SBM frequency rate at week 12 was the SBM rate (SBMs/week) calculated over that week. Only the Placebo versus Linaclotide 145 micrograms arm comparison is a secondary measure type for this outcome measure. The additional data for the Linaclotide 290 micrograms arm (a pre-specified additional outcome measure) is presented here for ease of comparison.	Baseline and Week 12
Change From Baseline in the Number of Days With a Spontaneous Bowel Movement (SBM)	A patient's baseline number of days with a Spontaneous Bowel Movement (SBM) was calculated as the number of days with at least 1 Spontaneous Bowel Movement (SBM), derived from the Interactive Voice Response System (IVRS) daily diary data collected in the Pretreatment Period, specifically the period of time from 14 days before randomization, up to the time of randomization (Visit 3, Day 1). A patient's number of days with a SBM during the Treatment Period was calculated as the number of days with at least 1 Spontaneous Bowel Movement (SBM), divided by treatment duration (in days), and multiplied by 7. Only the Placebo versus Linaclotide 145 micrograms arm comparison is a secondary measure type for this outcome measure. The additional data for the Linaclotide 290 micrograms arm (a pre-specified additional outcome measure) is presented here for ease of comparison.	Baseline and 12-week treatment period
SBM Within 24 Hours After the First Dose of Investigational Product	The proportion of patients with a SBM within 24 hours of first taking investigational product in each linaclotide dose group was compared with the proportion in the placebo group using the Cochran-Mantel-Haenszel (CMH) test controlling for geographic region. Only the Placebo versus Linaclotide 145 micrograms arm comparison is a secondary measure type for this outcome measure. The additional data for the Linaclotide 290 micrograms arm (a pre-specified additional outcome measure) is presented here for ease of comparison.	24 hours from first dose of investigational product (Day 1)
Time to Spontaneous Bowel Movement (SBM) After the First Dose of Investigational Product	Time to first SBM after the first dose of investigation product was defined as the number of hours between the time of the first dose of investigational product to the occurrence of the first SBM. Patients who did not achieve an SBM were considered censored, with time to censoring defined as the number of hours elapsing from the time of the first dose of investigational product was taken to the end of the day of the last dose, at 12:00 AM (24:00 military time). Only the Placebo versus Linaclotide 145 micrograms arm comparison is a secondary measure type for this outcome measure. The additional data for the Linaclotide 290 micrograms arm (a pre-specified additional outcome measure) is presented here for ease of comparison.	12-week treatment period
Change From Baseline in 12-week Stool Consistency	Stool consistency was measured using the 7-point Bristol Stool Form Scale (BSFS): = separate hard lumps like nuts [difficult to pass]; = sausage shaped but lumpy; = like a sausage but with cracks on surface; = like a sausage or snake, smooth and soft; = soft blobs with clear-cut edges [passed easily]; = fluffy pieces with ragged edges, a mushy stool; = watery, no solid pieces [entirely liquid] A patient's BSFS score for the baseline period (14 days before randomization, up to the time of randomization) and for the 12-week treatment period, was the average of the nonmissing BSFS scores from the SBMs reported by the patient during the respective baseline and treatment periods. Only the Placebo versus Linaclotide 145 micrograms arm comparison is a secondary measure type for this outcome measure. The additional data for the Linaclotide 290 micrograms arm (a pre-specified additional outcome measure) is presented here for ease of comparison.	Baseline and 12-week treatment period
Change From Baseline in Stool Consistency at Week 12	Stool consistency was measured using the 7-point Bristol Stool Form Scale (BSFS): = separate hard lumps like nuts [difficult to pass]; = sausage shaped but lumpy; = like a sausage but with cracks on surface; = like a sausage or snake, smooth and soft; = soft blobs with clear-cut edges [passed easily]; = fluffy pieces with ragged edges, a mushy stool; = watery, no solid pieces [entirely liquid] A patient's BSFS score for the baseline period (14 days before randomization, up to the time of randomization) and at week 12, was the average of the nonmissing BSFS scores from the SBMs reported by the patient during the respective baseline period and during Week 12. Only the Placebo versus Linaclotide 145 micrograms arm comparison is a secondary measure type for this outcome measure. The additional data for the Linaclotide 290 micrograms arm (a pre-specified additional outcome measure) is presented here for ease of comparison.	Baseline and Week 12
Change From Baseline in 12-week Severity of Straining	Severity of straining was measured using a 5-point ordinal scale, where of value of 1 is "not at all" and a value of 5 is "an extreme amount." A patient's straining score for baseline was derived from the Interactive Voice Response System (IVRS) daily diary data collected in the Pretreatment Period, specifically the period of time from 14 days before randomization, up to the time of randomization (Visit 3, Day 1). A patient's straining score for the treatment period was the average of the nonmissing straining scores from the SBMs reported by the patient during the 12-week treatment period. Only the Placebo versus Linaclotide 145 micrograms arm comparison is a secondary measure type for this outcome measure. The additional data for the Linaclotide 290 micrograms arm (a pre-specified additional outcome measure) is presented here for ease of comparison.	Baseline and 12-week treatment period
Change From Baseline in Severity of Straining at Week 12	Severity of straining was measured using a 5-point ordinal scale, where of value of 1 is "not at all" and a value of 5 is "an extreme amount." A patient's straining score for baseline was derived from the Interactive Voice Response System (IVRS) daily diary data collected in the Pretreatment Period, specifically the period of time from 14 days before randomization, up to the time of randomization (Visit 3, Day 1). A patient's straining score at Week 12 was the average of the nonmissing straining scores from the SBMs reported by that patient during analysis Week 12. Only the Placebo versus Linaclotide 145 micrograms arm comparison is a secondary measure type for this outcome measure. The additional data for the Linaclotide 290 micrograms arm (a pre-specified additional outcome measure) is presented here for ease of comparison.	Baseline and Week 12
9/12 Week Mild Straining and Diarrhea-free Responder	A patient was a 9/12 week mild straining and diarrhea-free responder if that patient met the weekly criterion for at least 9 weeks of the 12-week treatment period. A patient was considered to have met the weekly criterion in a given week if that patient had a nonmissing average straining score ≤ 2 (where a value of 1 represents no straining, an a value of 5 represents an extreme amount of straining), and the patient had no diarrhea adverse event (AE) reported for that week. Only the Placebo versus Linaclotide 145 micrograms arm comparison is a secondary measure type for this outcome measure. The additional data for the Linaclotide 290 micrograms arm (a pre-specified additional outcome measure) is presented here for ease of comparison.	12-week treatment period

Collaborators and Investigators

• Sponsor: Forest Laboratories
• Collaborators: Ironwood Pharmaceuticals, Inc.
• Investigators: Study Director: Steven Shiff, MD, Forest Laboratories

Publications and helpful links

General Publications

• Lacy BE, Shea EP, Manuel M, Abel JL, Jiang H, Taylor DCA. Lessons learned: Chronic idiopathic constipation patient experiences with over-the-counter medications. PLoS One. 2021 Jan 11;16(1):e0243318. doi: 10.1371/journal.pone.0243318. eCollection 2021.
• Lacy BE, Schey R, Shiff SJ, Lavins BJ, Fox SM, Jia XD, Blakesley RE, Hao X, Cronin JA, Currie MG, Kurtz CB, Johnston JM, Lembo AJ. Linaclotide in Chronic Idiopathic Constipation Patients with Moderate to Severe Abdominal Bloating: A Randomized, Controlled Trial. PLoS One. 2015 Jul 29;10(7):e0134349. doi: 10.1371/journal.pone.0134349. eCollection 2015.

Study record dates

Study Major Dates

• Study Start: August 1, 2012
• Primary Completion (Actual): May 1, 2013
• Study Completion (Actual): August 1, 2013

Study Registration Dates

• First Submitted: July 13, 2012
• First Submitted That Met QC Criteria: July 13, 2012
• First Posted (Estimate): July 17, 2012

Study Record Updates

• Last Update Posted (Estimate): April 26, 2016
• Last Update Submitted That Met QC Criteria: March 24, 2016
• Last Verified: March 1, 2016

More Information

Terms related to this study

• Keywords: Chronic Constipation; Linaclotide; Abdominal Bloating
• Additional Relevant MeSH Terms: Signs and Symptoms, Digestive; Constipation; Molecular Mechanisms of Pharmacological Action; Gastrointestinal Agents; Guanylyl Cyclase C Agonists; Enzyme Activators; Linaclotide
• Other Study ID Numbers: LIN-MD-04