Trial Outcomes & Findings for An Open-label, Long-term Safety Study of Linaclotide in Patients With Chronic Constipation or Irritable Bowel Syndrome With Constipation (NCT NCT00730171)

Last Updated: 2018-02-19

Results Overview

For RI and Phase 2 RO participants, an AE that occurred during the study was considered a TEAE if it was not present before the day of the first dose of open-label study drug, or was present before the day of the first dose of open-label study drug but increased in severity on or after that day. For Phase 3 RO participants, an AE that occurred during the study was considered a TEAE if it was not present before the day of the first dose of double-blind study drug in trial MCP-103-302 or MCP-103-303, or was present before the day of the first dose of double-blind study drug in those trials but increased in severity on or after that day. Deaths and serious AEs (SAEs) are those that occurred on or after the date of the first dose of open-label study drug, and within 30 days of the date of last dose of open-label study drug.

Recruitment status

COMPLETED

Study phase

PHASE3

Target enrollment

1743 participants

Primary outcome timeframe

From first dose of open-label study drug up to 78 weeks

Results posted on

2018-02-19

Participant Flow

Participants were categorized as either randomization-ineligible (RI) from the lead-in double-blind trials MCP-103-302 or MCP-103-303, or rollover (RO) from lead-in double-blind trials MCP-103-302, MCP-103-303, and from Phase 2 double-blind studies MCP-103-004, MCP-103-005, and MCP-103-201, or MCP-103-202 (See Detailed Description for NCT numbers).

A total of 1743 participants were enrolled in the study; 1725 received ≥1 dose of open-label linaclotide (included in the Overall Safety Population). One participant enrolled twice in the study under 2 ID numbers and is included as an RI participant in the CC Safety Population, and as an RO participant in the IBS-C and Overall Safety Populations.

Participant milestones

Participant milestones
Measure	Overal Safey Population: Total All RI and RO participants who received linaclotide 290 μg/day capsules, administered orally once daily for up to 78 weeks. Dose reduction to 145 μg/day was permitted at the discretion of the Investigator if a participant experienced AEs intolerable enough to prompt consideration of study withdrawal. After a temporary suspension of dosing, participants may have received either 145 μg/day or 290 μg/day of linaclotide, at the discretion of the Investigator. Subsequent dose adjustments (increases or decreases between 290 μg/day and 145 μg/day) were permitted also at the Investigator's discretion.
Overall Study STARTED	1725
Overall Study CC Safety Population	607
Overall Study IBS-C Safety Population	1119
Overall Study COMPLETED	954
Overall Study NOT COMPLETED	771

Reasons for withdrawal

Reasons for withdrawal
Measure	Overal Safey Population: Total All RI and RO participants who received linaclotide 290 μg/day capsules, administered orally once daily for up to 78 weeks. Dose reduction to 145 μg/day was permitted at the discretion of the Investigator if a participant experienced AEs intolerable enough to prompt consideration of study withdrawal. After a temporary suspension of dosing, participants may have received either 145 μg/day or 290 μg/day of linaclotide, at the discretion of the Investigator. Subsequent dose adjustments (increases or decreases between 290 μg/day and 145 μg/day) were permitted also at the Investigator's discretion.
Overall Study Didn't Meet Inclusion/Exclusion Criteria	5
Overall Study Adverse Event	193
Overall Study Protocol Violation	48
Overall Study Withdrawal by Subject	202
Overall Study Lost to Follow-up	121
Overall Study Insufficient Therapeutic Response	141
Overall Study Other	61

Baseline Characteristics

An Open-label, Long-term Safety Study of Linaclotide in Patients With Chronic Constipation or Irritable Bowel Syndrome With Constipation

Baseline characteristics by cohort

Baseline characteristics by cohort
Measure	Overall Safety Population n=1725 Participants All RI and RO participants who received linaclotide 290 μg/day capsules, administered orally once daily for up to 78 weeks. Dose reduction to 145 μg/day was permitted at the discretion of the Investigator if a participant experienced AEs intolerable enough to prompt consideration of study withdrawal. After a temporary suspension of dosing, participants may have received either 145 μg/day or 290 μg/day of linaclotide, at the discretion of the Investigator. Subsequent dose adjustments (increases or decreases between 290 μg/day and 145 μg/day) were permitted also at the Investigator's discretion.
Age, Continuous	47.1 years STANDARD_DEVIATION 13.5 • n=93 Participants
Sex: Female, Male Female	1532 Participants n=93 Participants
Sex: Female, Male Male	193 Participants n=93 Participants

PRIMARY outcome

Timeframe: From first dose of open-label study drug up to 78 weeks

Population: Enrolled participants who received at least 1 dose of open-label study drug. It was identified that 1 participant enrolled twice in the study under 2 ID numbers; this participant is included as an RI participant in the CC Safety Population, and as an RO participant in both the IBS-C and Overall Safety Populations.

Outcome measures

Outcome measures
Measure	CC Safety Population: Total n=607 Participants RI and RO participants who met the Rome II criteria for CC and who received linaclotide 290 μg/day capsules, administered orally once daily for up to 78 weeks. Dose reduction to 145 μg/day was permitted at the discretion of the Investigator.	IBS-C Safety Population: Total n=1119 Participants RI and RO participants who met the Rome II criteria for IBS-C and who received linaclotide 290 μg/day capsules, administered orally once daily for up to 78 weeks. Dose reduction to 145 μg/day was permitted at the discretion of the Investigator.	Overall Safety Population: Total n=1725 Participants All RI and RO participants who received linaclotide 290 μg/day capsules, administered orally once daily for up to 78 weeks. Dose reduction to 145 μg/day was permitted at the discretion of the Investigator.
Number of Participants With at Least One Treatment-Emergent Adverse Event (TEAE)	65 Participants	389 Participants	454 Participants

Adverse Events

CC Safety Population: Total

Serious events: 41 serious events

Other events: 283 other events

Deaths: 2 deaths

IBS-C Safety Population: Total

Serious events: 56 serious events

Other events: 572 other events

Deaths: 2 deaths

Overall Safety Population: Total

Serious events: 97 serious events

Other events: 855 other events

Deaths: 4 deaths

Serious adverse events

Other adverse events

Other adverse events
Measure	CC Safety Population: Total n=607 participants at risk RI and RO participants who met the modified Rome II criteria for CC and who received linaclotide 290 μg/day capsules, administered orally once daily for up to 78 weeks. Dose reduction to 145 μg/day was permitted at the discretion of the Investigator.	IBS-C Safety Population: Total n=1119 participants at risk RI and RO participants who met the modified Rome II criteria for IBS-C and who received linaclotide 290 μg/day capsules, administered orally once daily for up to 78 weeks. Dose reduction to 145 μg/day was permitted at the discretion of the Investigator.	Overall Safety Population: Total n=1725 participants at risk All RI and RO participants who received linaclotide 290 μg/day capsules, administered orally once daily for up to 78 weeks. Dose reduction to 145 μg/day was permitted at the discretion of the Investigator.
Gastrointestinal disorders Diarrhoea	29.5% 179/607 • From first dose of open-label study drug up to 78 weeks for adverse events (AEs) and within 30 days of last dose of study drug (up to 82 weeks) for serious AEs. It was identified that 1 participant enrolled twice in the study under 2 ID numbers; this participant is included as an RI participant in the CC Safety Population, and as an RO participant in both the IBS-C and Overall Safety Populations.	32.0% 358/1119 • From first dose of open-label study drug up to 78 weeks for adverse events (AEs) and within 30 days of last dose of study drug (up to 82 weeks) for serious AEs. It was identified that 1 participant enrolled twice in the study under 2 ID numbers; this participant is included as an RI participant in the CC Safety Population, and as an RO participant in both the IBS-C and Overall Safety Populations.	31.1% 537/1725 • From first dose of open-label study drug up to 78 weeks for adverse events (AEs) and within 30 days of last dose of study drug (up to 82 weeks) for serious AEs. It was identified that 1 participant enrolled twice in the study under 2 ID numbers; this participant is included as an RI participant in the CC Safety Population, and as an RO participant in both the IBS-C and Overall Safety Populations.
Gastrointestinal disorders Abdominal pain	3.8% 23/607 • From first dose of open-label study drug up to 78 weeks for adverse events (AEs) and within 30 days of last dose of study drug (up to 82 weeks) for serious AEs. It was identified that 1 participant enrolled twice in the study under 2 ID numbers; this participant is included as an RI participant in the CC Safety Population, and as an RO participant in both the IBS-C and Overall Safety Populations.	6.6% 74/1119 • From first dose of open-label study drug up to 78 weeks for adverse events (AEs) and within 30 days of last dose of study drug (up to 82 weeks) for serious AEs. It was identified that 1 participant enrolled twice in the study under 2 ID numbers; this participant is included as an RI participant in the CC Safety Population, and as an RO participant in both the IBS-C and Overall Safety Populations.	5.6% 97/1725 • From first dose of open-label study drug up to 78 weeks for adverse events (AEs) and within 30 days of last dose of study drug (up to 82 weeks) for serious AEs. It was identified that 1 participant enrolled twice in the study under 2 ID numbers; this participant is included as an RI participant in the CC Safety Population, and as an RO participant in both the IBS-C and Overall Safety Populations.
Gastrointestinal disorders Nausea	5.9% 36/607 • From first dose of open-label study drug up to 78 weeks for adverse events (AEs) and within 30 days of last dose of study drug (up to 82 weeks) for serious AEs. It was identified that 1 participant enrolled twice in the study under 2 ID numbers; this participant is included as an RI participant in the CC Safety Population, and as an RO participant in both the IBS-C and Overall Safety Populations.	5.3% 59/1119 • From first dose of open-label study drug up to 78 weeks for adverse events (AEs) and within 30 days of last dose of study drug (up to 82 weeks) for serious AEs. It was identified that 1 participant enrolled twice in the study under 2 ID numbers; this participant is included as an RI participant in the CC Safety Population, and as an RO participant in both the IBS-C and Overall Safety Populations.	5.5% 95/1725 • From first dose of open-label study drug up to 78 weeks for adverse events (AEs) and within 30 days of last dose of study drug (up to 82 weeks) for serious AEs. It was identified that 1 participant enrolled twice in the study under 2 ID numbers; this participant is included as an RI participant in the CC Safety Population, and as an RO participant in both the IBS-C and Overall Safety Populations.
Gastrointestinal disorders Constipation	2.6% 16/607 • From first dose of open-label study drug up to 78 weeks for adverse events (AEs) and within 30 days of last dose of study drug (up to 82 weeks) for serious AEs. It was identified that 1 participant enrolled twice in the study under 2 ID numbers; this participant is included as an RI participant in the CC Safety Population, and as an RO participant in both the IBS-C and Overall Safety Populations.	5.8% 65/1119 • From first dose of open-label study drug up to 78 weeks for adverse events (AEs) and within 30 days of last dose of study drug (up to 82 weeks) for serious AEs. It was identified that 1 participant enrolled twice in the study under 2 ID numbers; this participant is included as an RI participant in the CC Safety Population, and as an RO participant in both the IBS-C and Overall Safety Populations.	4.7% 81/1725 • From first dose of open-label study drug up to 78 weeks for adverse events (AEs) and within 30 days of last dose of study drug (up to 82 weeks) for serious AEs. It was identified that 1 participant enrolled twice in the study under 2 ID numbers; this participant is included as an RI participant in the CC Safety Population, and as an RO participant in both the IBS-C and Overall Safety Populations.
Gastrointestinal disorders Flatulence	5.6% 34/607 • From first dose of open-label study drug up to 78 weeks for adverse events (AEs) and within 30 days of last dose of study drug (up to 82 weeks) for serious AEs. It was identified that 1 participant enrolled twice in the study under 2 ID numbers; this participant is included as an RI participant in the CC Safety Population, and as an RO participant in both the IBS-C and Overall Safety Populations.	3.2% 36/1119 • From first dose of open-label study drug up to 78 weeks for adverse events (AEs) and within 30 days of last dose of study drug (up to 82 weeks) for serious AEs. It was identified that 1 participant enrolled twice in the study under 2 ID numbers; this participant is included as an RI participant in the CC Safety Population, and as an RO participant in both the IBS-C and Overall Safety Populations.	4.1% 70/1725 • From first dose of open-label study drug up to 78 weeks for adverse events (AEs) and within 30 days of last dose of study drug (up to 82 weeks) for serious AEs. It was identified that 1 participant enrolled twice in the study under 2 ID numbers; this participant is included as an RI participant in the CC Safety Population, and as an RO participant in both the IBS-C and Overall Safety Populations.
Infections and infestations Urinary tract infection	7.2% 44/607 • From first dose of open-label study drug up to 78 weeks for adverse events (AEs) and within 30 days of last dose of study drug (up to 82 weeks) for serious AEs. It was identified that 1 participant enrolled twice in the study under 2 ID numbers; this participant is included as an RI participant in the CC Safety Population, and as an RO participant in both the IBS-C and Overall Safety Populations.	7.6% 85/1119 • From first dose of open-label study drug up to 78 weeks for adverse events (AEs) and within 30 days of last dose of study drug (up to 82 weeks) for serious AEs. It was identified that 1 participant enrolled twice in the study under 2 ID numbers; this participant is included as an RI participant in the CC Safety Population, and as an RO participant in both the IBS-C and Overall Safety Populations.	7.5% 129/1725 • From first dose of open-label study drug up to 78 weeks for adverse events (AEs) and within 30 days of last dose of study drug (up to 82 weeks) for serious AEs. It was identified that 1 participant enrolled twice in the study under 2 ID numbers; this participant is included as an RI participant in the CC Safety Population, and as an RO participant in both the IBS-C and Overall Safety Populations.
Infections and infestations Sinusitis	6.6% 40/607 • From first dose of open-label study drug up to 78 weeks for adverse events (AEs) and within 30 days of last dose of study drug (up to 82 weeks) for serious AEs. It was identified that 1 participant enrolled twice in the study under 2 ID numbers; this participant is included as an RI participant in the CC Safety Population, and as an RO participant in both the IBS-C and Overall Safety Populations.	7.4% 83/1119 • From first dose of open-label study drug up to 78 weeks for adverse events (AEs) and within 30 days of last dose of study drug (up to 82 weeks) for serious AEs. It was identified that 1 participant enrolled twice in the study under 2 ID numbers; this participant is included as an RI participant in the CC Safety Population, and as an RO participant in both the IBS-C and Overall Safety Populations.	7.1% 123/1725 • From first dose of open-label study drug up to 78 weeks for adverse events (AEs) and within 30 days of last dose of study drug (up to 82 weeks) for serious AEs. It was identified that 1 participant enrolled twice in the study under 2 ID numbers; this participant is included as an RI participant in the CC Safety Population, and as an RO participant in both the IBS-C and Overall Safety Populations.
Infections and infestations Upper respiratory tract infection	4.4% 27/607 • From first dose of open-label study drug up to 78 weeks for adverse events (AEs) and within 30 days of last dose of study drug (up to 82 weeks) for serious AEs. It was identified that 1 participant enrolled twice in the study under 2 ID numbers; this participant is included as an RI participant in the CC Safety Population, and as an RO participant in both the IBS-C and Overall Safety Populations.	5.5% 61/1119 • From first dose of open-label study drug up to 78 weeks for adverse events (AEs) and within 30 days of last dose of study drug (up to 82 weeks) for serious AEs. It was identified that 1 participant enrolled twice in the study under 2 ID numbers; this participant is included as an RI participant in the CC Safety Population, and as an RO participant in both the IBS-C and Overall Safety Populations.	5.1% 88/1725 • From first dose of open-label study drug up to 78 weeks for adverse events (AEs) and within 30 days of last dose of study drug (up to 82 weeks) for serious AEs. It was identified that 1 participant enrolled twice in the study under 2 ID numbers; this participant is included as an RI participant in the CC Safety Population, and as an RO participant in both the IBS-C and Overall Safety Populations.

Additional Information

Michael Hall, MD

Ironwood Pharmaceuticals, Inc.

Phone: (617) 621-7722

Results disclosure agreements

Principal investigator is a sponsor employee PI may publish or disclose the results of the study 24 months after final data lock provided that sponsor can review the publication prior to public release, sponsor can request removal of confidential information of sponsor (not including results of trial), and sponsor can request a publication delay in order to protect potentially patentable information. Furthermore, if a publication committee is developing an initial publication, PI is to delay disclosure until that publication is published
Publication restrictions are in place

Restriction type: OTHER