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 NCT00765999)

Last Updated: 2019-02-15

Results Overview

An AE is any untoward medical occurrence in a clinical study participant administered study drug. An AE could, therefore, be any unfavorable and unintended sign (including an abnormal laboratory finding), symptom, or disease temporally associated with the use of the study drug, whether or not related to the medicinal product. An AE that occurred during the treatment period was defined as a TEAE if the AE was either not present at, or before, the day of the first dose of open-label study medication in this study or was present at, or before, the day of the first dose of open-label study medication in this study and increased in severity during the treatment period. AEs included abnormal clinically significant findings for clinical laboratory tests, physical examination findings, vital sign measurements and electrocardiograms (ECGs).

Recruitment status

COMPLETED

Study phase

PHASE3

Target enrollment

1559 participants

Primary outcome timeframe

Up to 78 weeks for AEs; within 30 days of last dose of study drug (up to 82 weeks) for serious AEs.

Results posted on

2019-02-15

Participant Flow

Of the 1559 enrolled participants, all but 5 also received study drug, leading to an overall safety population of 1554 participants.

Participant milestones

Participant milestones
Measure	Linaclotide Linaclotide 290 μg/day capsules, administered orally once daily for up to 78 weeks in participants with either CC or IBS-C. Dose reduction to 145 μg/day was permitted at the discretion of the Investigator if a participant experienced adverse events (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	1554
Overall Study COMPLETED	770
Overall Study NOT COMPLETED	784

Reasons for withdrawal

Reasons for withdrawal
Measure	Linaclotide Linaclotide 290 μg/day capsules, administered orally once daily for up to 78 weeks in participants with either CC or IBS-C. Dose reduction to 145 μg/day was permitted at the discretion of the Investigator if a participant experienced adverse events (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 Adverse Event	203
Overall Study Insufficient Therapeutic Response	100
Overall Study Protocol Violation	95
Overall Study Consent Withdrawn	202
Overall Study Lost to Follow-up	131
Overall Study Study Terminated by Sponsor	2
Overall Study Other Miscellaneous Reasons	51

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	Linaclotide n=1554 Participants Linaclotide 290 μg/day capsules, administered orally once daily for up to 78 weeks in participants with either CC or IBS-C. Dose reduction to 145 μg/day was permitted at the discretion of the Investigator if a participant experienced adverse events (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	46.0 years STANDARD_DEVIATION 13.2 • n=5 Participants
Sex: Female, Male Female	1414 Participants n=5 Participants
Sex: Female, Male Male	140 Participants n=5 Participants
Race/Ethnicity, Customized White	1197 Participants n=5 Participants
Race/Ethnicity, Customized African American	312 Participants n=5 Participants
Race/Ethnicity, Customized Other	45 Participants n=5 Participants
Race/Ethnicity, Customized Hispanic	192 Participants n=5 Participants
Race/Ethnicity, Customized Non-Hispanic	1362 Participants n=5 Participants
Weight	76.02 kilogram (kg) STANDARD_DEVIATION 17.85 • n=5 Participants
Height	164.59 centimeters (cm) STANDARD_DEVIATION 8.05 • n=5 Participants
Body Mass Index (BMI)	28.03 kg/m^2 STANDARD_DEVIATION 6.14 • n=5 Participants

PRIMARY outcome

Timeframe: Up to 78 weeks for AEs; within 30 days of last dose of study drug (up to 82 weeks) for serious AEs.

Population: The analysis population consisted of participants in the Enrolled Population who received at least 1 dose of the open-label investigational product. It was identified that 1 participant enrolled twice in the study under 2 ID numbers; this participant is included in both the IBS-C and CC Safety Populations, leading to an analyzed population of 1555.

Outcome measures

Outcome measures
Measure	Linaclotide (CC) n=523 Participants Linaclotide 290 μg/day capsules, administered orally once daily for up to 78 weeks in participants with CC. 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, paticipants 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.	Linaclotide (IBS-C) n=1032 Participants Linaclotide 290 μg/day capsules, administered orally once daily for up to 78 weeks in participants with IBS-C. 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.
Number of Participants With at Least One Treatment-Emergent Adverse Events (TEAEs)	399 Participants	748 Participants

Adverse Events

Linaclotide (CC)

Serious events: 31 serious events

Other events: 267 other events

Deaths: 0 deaths

Linaclotide (IBS-C)

Serious events: 57 serious events

Other events: 510 other events

Deaths: 0 deaths

Serious adverse events

Other adverse events

Other adverse events
Measure	Linaclotide (CC) n=523 participants at risk Linaclotide 290 μg/day capsules, administered orally once daily for up to 78 weeks in participants with CC. 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.	Linaclotide (IBS-C) n=1032 participants at risk Linaclotide 290 μg/day capsules, administered orally once daily for up to 78 weeks in participants with IBS-C. 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.
Gastrointestinal disorders Diarrhoea	34.2% 179/523 • Up to 78 weeks for AEs; within 30 days of last dose of study drug (up to 82 weeks) for serious AEs. The safety population consisted of all participants in the Enrolled Population who received at least 1 dose of the open-label investigational product. It was identified that 1 participant enrolled twice in the study under 2 ID numbers; this participant is included in both the IBS-C and CC Safety Populations, leading to an analyzed population of 1555.	33.4% 345/1032 • Up to 78 weeks for AEs; within 30 days of last dose of study drug (up to 82 weeks) for serious AEs. The safety population consisted of all participants in the Enrolled Population who received at least 1 dose of the open-label investigational product. It was identified that 1 participant enrolled twice in the study under 2 ID numbers; this participant is included in both the IBS-C and CC Safety Populations, leading to an analyzed population of 1555.
Gastrointestinal disorders Abdominal pain	6.5% 34/523 • Up to 78 weeks for AEs; within 30 days of last dose of study drug (up to 82 weeks) for serious AEs. The safety population consisted of all participants in the Enrolled Population who received at least 1 dose of the open-label investigational product. It was identified that 1 participant enrolled twice in the study under 2 ID numbers; this participant is included in both the IBS-C and CC Safety Populations, leading to an analyzed population of 1555.	6.7% 69/1032 • Up to 78 weeks for AEs; within 30 days of last dose of study drug (up to 82 weeks) for serious AEs. The safety population consisted of all participants in the Enrolled Population who received at least 1 dose of the open-label investigational product. It was identified that 1 participant enrolled twice in the study under 2 ID numbers; this participant is included in both the IBS-C and CC Safety Populations, leading to an analyzed population of 1555.
Gastrointestinal disorders Nausea	5.5% 29/523 • Up to 78 weeks for AEs; within 30 days of last dose of study drug (up to 82 weeks) for serious AEs. The safety population consisted of all participants in the Enrolled Population who received at least 1 dose of the open-label investigational product. It was identified that 1 participant enrolled twice in the study under 2 ID numbers; this participant is included in both the IBS-C and CC Safety Populations, leading to an analyzed population of 1555.	4.9% 51/1032 • Up to 78 weeks for AEs; within 30 days of last dose of study drug (up to 82 weeks) for serious AEs. The safety population consisted of all participants in the Enrolled Population who received at least 1 dose of the open-label investigational product. It was identified that 1 participant enrolled twice in the study under 2 ID numbers; this participant is included in both the IBS-C and CC Safety Populations, leading to an analyzed population of 1555.
Gastrointestinal disorders Abdominal distension	5.4% 28/523 • Up to 78 weeks for AEs; within 30 days of last dose of study drug (up to 82 weeks) for serious AEs. The safety population consisted of all participants in the Enrolled Population who received at least 1 dose of the open-label investigational product. It was identified that 1 participant enrolled twice in the study under 2 ID numbers; this participant is included in both the IBS-C and CC Safety Populations, leading to an analyzed population of 1555.	3.4% 35/1032 • Up to 78 weeks for AEs; within 30 days of last dose of study drug (up to 82 weeks) for serious AEs. The safety population consisted of all participants in the Enrolled Population who received at least 1 dose of the open-label investigational product. It was identified that 1 participant enrolled twice in the study under 2 ID numbers; this participant is included in both the IBS-C and CC Safety Populations, leading to an analyzed population of 1555.
Infections and infestations Upper respiratory tract infection	5.9% 31/523 • Up to 78 weeks for AEs; within 30 days of last dose of study drug (up to 82 weeks) for serious AEs. The safety population consisted of all participants in the Enrolled Population who received at least 1 dose of the open-label investigational product. It was identified that 1 participant enrolled twice in the study under 2 ID numbers; this participant is included in both the IBS-C and CC Safety Populations, leading to an analyzed population of 1555.	6.3% 65/1032 • Up to 78 weeks for AEs; within 30 days of last dose of study drug (up to 82 weeks) for serious AEs. The safety population consisted of all participants in the Enrolled Population who received at least 1 dose of the open-label investigational product. It was identified that 1 participant enrolled twice in the study under 2 ID numbers; this participant is included in both the IBS-C and CC Safety Populations, leading to an analyzed population of 1555.
Infections and infestations Sinusitis	6.1% 32/523 • Up to 78 weeks for AEs; within 30 days of last dose of study drug (up to 82 weeks) for serious AEs. The safety population consisted of all participants in the Enrolled Population who received at least 1 dose of the open-label investigational product. It was identified that 1 participant enrolled twice in the study under 2 ID numbers; this participant is included in both the IBS-C and CC Safety Populations, leading to an analyzed population of 1555.	5.9% 61/1032 • Up to 78 weeks for AEs; within 30 days of last dose of study drug (up to 82 weeks) for serious AEs. The safety population consisted of all participants in the Enrolled Population who received at least 1 dose of the open-label investigational product. It was identified that 1 participant enrolled twice in the study under 2 ID numbers; this participant is included in both the IBS-C and CC Safety Populations, leading to an analyzed population of 1555.
Infections and infestations Urinary tract infection	5.7% 30/523 • Up to 78 weeks for AEs; within 30 days of last dose of study drug (up to 82 weeks) for serious AEs. The safety population consisted of all participants in the Enrolled Population who received at least 1 dose of the open-label investigational product. It was identified that 1 participant enrolled twice in the study under 2 ID numbers; this participant is included in both the IBS-C and CC Safety Populations, leading to an analyzed population of 1555.	5.6% 58/1032 • Up to 78 weeks for AEs; within 30 days of last dose of study drug (up to 82 weeks) for serious AEs. The safety population consisted of all participants in the Enrolled Population who received at least 1 dose of the open-label investigational product. It was identified that 1 participant enrolled twice in the study under 2 ID numbers; this participant is included in both the IBS-C and CC Safety Populations, leading to an analyzed population of 1555.
Nervous system disorders Headache	6.5% 34/523 • Up to 78 weeks for AEs; within 30 days of last dose of study drug (up to 82 weeks) for serious AEs. The safety population consisted of all participants in the Enrolled Population who received at least 1 dose of the open-label investigational product. It was identified that 1 participant enrolled twice in the study under 2 ID numbers; this participant is included in both the IBS-C and CC Safety Populations, leading to an analyzed population of 1555.	4.1% 42/1032 • Up to 78 weeks for AEs; within 30 days of last dose of study drug (up to 82 weeks) for serious AEs. The safety population consisted of all participants in the Enrolled Population who received at least 1 dose of the open-label investigational product. It was identified that 1 participant enrolled twice in the study under 2 ID numbers; this participant is included in both the IBS-C and CC Safety Populations, leading to an analyzed population of 1555.

Additional Information

Vice President, Clinical Development, Gastrointestinal

Allergan, Inc.

Phone: 1-862-261-7000

Email: [email protected]

Results disclosure agreements

Principal investigator is a sponsor employee A disclosure restriction on the PI is that the sponsor can review results communications prior to public release and can embargo communications regarding trial results for a period that is less than or equal to 90 days from the time submitted to the sponsor for review. The sponsor may request the PI delay submission for any publication while the sponsor files applications for patents or other registrations of intellectual property rights.
Publication restrictions are in place

Restriction type: OTHER