Trial Outcomes & Findings for An Open-Label, Long-term Study to Assess the Immunogenicity of LINZESS® (Linaclotide) Administered Orally to Adult Participants With Irritable Bowel Syndrome With Constipation or Chronic Idiopathic Constipation (NCT NCT02590432)

Last Updated: 2019-08-22

Results Overview

Participants who met either of the following criteria: 1) treatment-induced ADA-positive (≥ 1 postbaseline ADA-positive sample) for baseline ADA negative or ADA-undetermined participants or 2) treatment-boosted ADA-positive (≥ 1 postbaseline ADA-positive sample with titer values ≥ 4-fold the baseline titer value) for baseline ADA-positive participants were reported as a ADA positive responder.

Recruitment status

COMPLETED

Study phase

PHASE4

Target enrollment

828 participants

Primary outcome timeframe

Baseline (Day 1) up to 52 weeks or 8 months post last dose if ADA positive at Week 52 (approximately 84 weeks)

Results posted on

2019-08-22

Participant Flow

828 participants were enrolled, 2 participants were enrolled but did not receive study treatment and were not included in any analysis populations.

826 participants received LINZESS® 145μg \[CIC\] and 290μg \[IBS-C\] in the Open Label Treatment Period. Out of 826, 114 participants were randomized in the Double-blind Treatment Period and 57 out of 114 participants received 72 μg in the Dose-reduced Open Label Treatment Period due to intolerable AEs.

Participant milestones

Participant milestones
Measure	LINZESS® 145 μg (CIC, Open Label) LINZESS® 145 μg capsules, orally, once daily for up to 52 weeks for participants with chronic idiopathic constipation (CIC). If an intolerable adverse event (AE) occurred participants could be randomized to the Double-blind Treatment Period.	LINZESS® 290 μg (IBS-C, Open Label) LINZESS® 290 μg capsules, orally, once daily for up to 52 weeks for participants with irritable bowel syndrome with constipation (IBS-C). If an intolerable AE occurred participants could be randomized to the Double-blind Treatment Period.	LINZESS® 290 μg (IBS-C, Double Blind) Following participation in the Open Label Treatment Period, LINZESS® 290 μg capsules, orally, once daily from double-blind randomization up to Week 52 for participants with IBS-C. If an intolerable AE occurred, dose was reduced to Open Label 72 μg, if applicable.	LINZESS® 145 μg (IBS-C, Double Blind) Following participation in the Open Label Treatment Period, LINZESS® 145 μg capsules, orally, once daily from double-blind randomization up to Week 52 for participants with IBS-C. If an intolerable AE occurred, dose was reduced to Open Label 72 μg, if applicable.	LINZESS® 72 μg (IBS-C, Double Blind) Following participation in the Open Label Treatment Period, LINZESS® 72 μg capsules, orally, once daily from double-blind randomization up to Week 52 for participants with IBS-C. If an intolerable AE occurred, dose was maintained at Open Label 72 μg, if applicable.	LINZESS® 145 μg (CIC, Double Blind) Following participation in the Open Label Treatment Period, LINZESS® 145 μg capsules, orally, once daily from double-blind randomization up to Week 52 for participants with CIC. If an intolerable AE occurred, dose was reduced to 72 μg, if applicable.	LINZESS® 72 μg (CIC, Double Blind) Following participation in the Open Label Treatment Period, LINZESS® 72 μg capsules, orally, once daily from double-blind randomization up to Week 52 for participants with CIC. If an intolerable AE occurred, dose was maintained at Open Label 72 μg, if applicable.	LINZESS® 72 μg (CIC, Dose-reduced Open Label) Following participation in the Double-blind Treatment Period, if an intolerable AE occurred, LINZESS® 72 μg capsules, orally, once daily up to Week 52 for participants with CIC.	LINZESS® 72 μg (IBS-C, Dose-reduced Open Label) Following participation in the Double-blind Treatment Period, if an intolerable AE occurred, LINZESS® 72 μg capsules, orally, once daily up to Week 52 for participants with IBS-C.
Open-label Treatment Period STARTED	508	318	0	0	0	0	0	0	0
Open-label Treatment Period COMPLETED	276	166	0	0	0	0	0	0	0
Open-label Treatment Period NOT COMPLETED	232	152	0	0	0	0	0	0	0
Double-blind Treatment Period STARTED	0	0	18	18	16	32	30	0	0
Double-blind Treatment Period COMPLETED	0	0	1	3	7	6	9	0	0
Double-blind Treatment Period NOT COMPLETED	0	0	17	15	9	26	21	0	0
Dose-reduced Open Label Treatment Period STARTED	0	0	0	0	0	0	0	31	26
Dose-reduced Open Label Treatment Period COMPLETED	0	0	0	0	0	0	0	13	8
Dose-reduced Open Label Treatment Period NOT COMPLETED	0	0	0	0	0	0	0	18	18

Reasons for withdrawal

Reasons for withdrawal
Measure	LINZESS® 145 μg (CIC, Open Label) LINZESS® 145 μg capsules, orally, once daily for up to 52 weeks for participants with chronic idiopathic constipation (CIC). If an intolerable adverse event (AE) occurred participants could be randomized to the Double-blind Treatment Period.	LINZESS® 290 μg (IBS-C, Open Label) LINZESS® 290 μg capsules, orally, once daily for up to 52 weeks for participants with irritable bowel syndrome with constipation (IBS-C). If an intolerable AE occurred participants could be randomized to the Double-blind Treatment Period.	LINZESS® 290 μg (IBS-C, Double Blind) Following participation in the Open Label Treatment Period, LINZESS® 290 μg capsules, orally, once daily from double-blind randomization up to Week 52 for participants with IBS-C. If an intolerable AE occurred, dose was reduced to Open Label 72 μg, if applicable.	LINZESS® 145 μg (IBS-C, Double Blind) Following participation in the Open Label Treatment Period, LINZESS® 145 μg capsules, orally, once daily from double-blind randomization up to Week 52 for participants with IBS-C. If an intolerable AE occurred, dose was reduced to Open Label 72 μg, if applicable.	LINZESS® 72 μg (IBS-C, Double Blind) Following participation in the Open Label Treatment Period, LINZESS® 72 μg capsules, orally, once daily from double-blind randomization up to Week 52 for participants with IBS-C. If an intolerable AE occurred, dose was maintained at Open Label 72 μg, if applicable.	LINZESS® 145 μg (CIC, Double Blind) Following participation in the Open Label Treatment Period, LINZESS® 145 μg capsules, orally, once daily from double-blind randomization up to Week 52 for participants with CIC. If an intolerable AE occurred, dose was reduced to 72 μg, if applicable.	LINZESS® 72 μg (CIC, Double Blind) Following participation in the Open Label Treatment Period, LINZESS® 72 μg capsules, orally, once daily from double-blind randomization up to Week 52 for participants with CIC. If an intolerable AE occurred, dose was maintained at Open Label 72 μg, if applicable.	LINZESS® 72 μg (CIC, Dose-reduced Open Label) Following participation in the Double-blind Treatment Period, if an intolerable AE occurred, LINZESS® 72 μg capsules, orally, once daily up to Week 52 for participants with CIC.	LINZESS® 72 μg (IBS-C, Dose-reduced Open Label) Following participation in the Double-blind Treatment Period, if an intolerable AE occurred, LINZESS® 72 μg capsules, orally, once daily up to Week 52 for participants with IBS-C.
Open-label Treatment Period Adverse Event	97	79	0	0	0	0	0	0	0
Open-label Treatment Period Lack of Efficacy	14	5	0	0	0	0	0	0	0
Open-label Treatment Period Withdrawal of Consent	43	28	0	0	0	0	0	0	0
Open-label Treatment Period Lost to Follow-up	51	29	0	0	0	0	0	0	0
Open-label Treatment Period Protocol Violation	10	4	0	0	0	0	0	0	0
Open-label Treatment Period Non-compliance with Study Drug	7	1	0	0	0	0	0	0	0
Open-label Treatment Period Other Miscellaneous Reasons	10	6	0	0	0	0	0	0	0
Double-blind Treatment Period Adverse Event	0	0	14	12	6	22	20	0	0
Double-blind Treatment Period Lack of Efficacy	0	0	1	0	0	0	0	0	0
Double-blind Treatment Period Withdrawal of Consent	0	0	1	3	3	1	1	0	0
Double-blind Treatment Period Lost to Follow-up	0	0	1	0	0	2	0	0	0
Double-blind Treatment Period Non-compliance with Study Drug	0	0	0	0	0	1	0	0	0
Dose-reduced Open Label Treatment Period Adverse Event	0	0	0	0	0	0	0	12	15
Dose-reduced Open Label Treatment Period Lack of Efficacy	0	0	0	0	0	0	0	1	0
Dose-reduced Open Label Treatment Period Withdrawal of Consent	0	0	0	0	0	0	0	3	1
Dose-reduced Open Label Treatment Period Lost to Follow-up	0	0	0	0	0	0	0	0	1
Dose-reduced Open Label Treatment Period Protocol Violation	0	0	0	0	0	0	0	0	1
Dose-reduced Open Label Treatment Period Non-compliance with Study Drug	0	0	0	0	0	0	0	1	0
Dose-reduced Open Label Treatment Period Other Miscellaneous Reasons	0	0	0	0	0	0	0	1	0

Baseline Characteristics

An Open-Label, Long-term Study to Assess the Immunogenicity of LINZESS® (Linaclotide) Administered Orally to Adult Participants With Irritable Bowel Syndrome With Constipation or Chronic Idiopathic Constipation

Baseline characteristics by cohort

Baseline characteristics by cohort
Measure	LINZESS® 145 μg (CIC, Open Label) n=508 Participants LINZESS® 145 μg capsules, orally, once daily for up to 52 weeks for participants with CIC. If an intolerable AE occurred participants could be randomized to the Double-blind Treatment Period.	LINZESS® 290 μg (IBS-C, Open Label) n=318 Participants LINZESS® 290 μg capsules, orally, once daily for up to 52 weeks for participants with IBS-C. If an intolerable AE occurred participants could be randomized to the Double-blind Treatment Period.	Total n=826 Participants Total of all reporting groups
Age, Continuous	49.6 years STANDARD_DEVIATION 15.3 • n=5 Participants	45.2 years STANDARD_DEVIATION 13.9 • n=7 Participants	47.9 years STANDARD_DEVIATION 14.9 • n=5 Participants
Age, Customized <40 years	140 Participants n=5 Participants	120 Participants n=7 Participants	260 Participants n=5 Participants
Age, Customized >=40 to <65 years	274 Participants n=5 Participants	170 Participants n=7 Participants	444 Participants n=5 Participants
Age, Customized >=65 years	94 Participants n=5 Participants	28 Participants n=7 Participants	122 Participants n=5 Participants
Sex: Female, Male Female	410 Participants n=5 Participants	259 Participants n=7 Participants	669 Participants n=5 Participants
Sex: Female, Male Male	98 Participants n=5 Participants	59 Participants n=7 Participants	157 Participants n=5 Participants
Race/Ethnicity, Customized White	348 Participants n=5 Participants	227 Participants n=7 Participants	575 Participants n=5 Participants
Race/Ethnicity, Customized Black or African American	135 Participants n=5 Participants	68 Participants n=7 Participants	203 Participants n=5 Participants
Race/Ethnicity, Customized Asian	19 Participants n=5 Participants	17 Participants n=7 Participants	36 Participants n=5 Participants
Race/Ethnicity, Customized American Indian or Alaska Native	1 Participants n=5 Participants	2 Participants n=7 Participants	3 Participants n=5 Participants
Race/Ethnicity, Customized Native Hawaiian or Other Pacific Islander	1 Participants n=5 Participants	1 Participants n=7 Participants	2 Participants n=5 Participants
Race/Ethnicity, Customized Multiple Races	4 Participants n=5 Participants	3 Participants n=7 Participants	7 Participants n=5 Participants
Race/Ethnicity, Customized Hispanic or Latino	124 Participants n=5 Participants	76 Participants n=7 Participants	200 Participants n=5 Participants
Race/Ethnicity, Customized Not Hispanic or Latino	384 Participants n=5 Participants	242 Participants n=7 Participants	626 Participants n=5 Participants

PRIMARY outcome

Timeframe: Baseline (Day 1) up to 52 weeks or 8 months post last dose if ADA positive at Week 52 (approximately 84 weeks)

Population: Safety population included all participants in the screened population (all participants who had signed an informed consent form (ICF) for the study and received a patient identification number) who received ≥ 1 administration of study treatment. Participants with ≥ 1 assessable postbaseline sample were analyzed (ADA-undetermined excluded).

Outcome measures

Outcome measures
Measure	LINZESS® 145 μg (CIC, Open Label) n=498 Participants LINZESS® 145 μg capsules, orally, once daily for up to 52 weeks for participants with CIC. If an intolerable AE occurred participants could be randomized to the Double-blind Treatment Period.	LINZESS® 290 μg (IBS-C, Open Label) n=309 Participants LINZESS® 290 μg capsules, orally, once daily for up to 52 weeks for participants with IBS-C. If an intolerable AE occurred participants could be randomized to the Double-blind Treatment Period.	LINZESS® 72 μg (IBS-C, Double Blind) Following participation in the Open Label Treatment Period, LINZESS® 72 μg capsules, orally, once daily from double-blind randomization up to Week 52 for participants with IBS-C. If an intolerable AE occurred, dose was maintained at Open Label 72 μg, if applicable.	LINZESS® 145 μg (CIC, Double Blind) Following participation in the Open Label Treatment Period, LINZESS® 145 μg capsules, orally, once daily from double-blind randomization up to Week 52 for participants with CIC. If an intolerable AE occurred, dose was reduced to 72 μg, if applicable.	LINZESS® 72 μg (CIC, Double Blind) Following participation in the Open Label Treatment Period, LINZESS® 72 μg capsules, orally, once daily from double-blind randomization up to Week 52 for participants with CIC. If an intolerable AE occurred, dose was maintained at Open Label 72 μg, if applicable.
Number of Participants With Positive Treatment-Related Anti-Drug Antibodies (ADA) in Serum	3 Participants	1 Participants	—	—	—

SECONDARY outcome

Timeframe: Baseline (Day 1) to Weeks 2, 4, 12, 26, 40 and 52 (Open Label Treatment Period)

Population: Intent to Treat (ITT) population included all participants in the safety population who had ≥ 1 postbaseline assessment for any efficacy or health outcomes parameter. Number analyzed were the participants with analysis values at both baseline and postbaseline during the specified time period.

Participants rated constipation severity during the previous 7 days on a 5-point ordinal scale where, 1=None, 2=Mild, 3=Moderate, 4=Severe and 5=Very Severe. Higher scores indicate greater severity. A negative change from Baseline indicates improvement.

Outcome measures

Outcome measures
Measure	LINZESS® 145 μg (CIC, Open Label) n=503 Participants LINZESS® 145 μg capsules, orally, once daily for up to 52 weeks for participants with CIC. If an intolerable AE occurred participants could be randomized to the Double-blind Treatment Period.	LINZESS® 290 μg (IBS-C, Open Label) n=311 Participants LINZESS® 290 μg capsules, orally, once daily for up to 52 weeks for participants with IBS-C. If an intolerable AE occurred participants could be randomized to the Double-blind Treatment Period.	LINZESS® 72 μg (IBS-C, Double Blind) Following participation in the Open Label Treatment Period, LINZESS® 72 μg capsules, orally, once daily from double-blind randomization up to Week 52 for participants with IBS-C. If an intolerable AE occurred, dose was maintained at Open Label 72 μg, if applicable.	LINZESS® 145 μg (CIC, Double Blind) Following participation in the Open Label Treatment Period, LINZESS® 145 μg capsules, orally, once daily from double-blind randomization up to Week 52 for participants with CIC. If an intolerable AE occurred, dose was reduced to 72 μg, if applicable.	LINZESS® 72 μg (CIC, Double Blind) Following participation in the Open Label Treatment Period, LINZESS® 72 μg capsules, orally, once daily from double-blind randomization up to Week 52 for participants with CIC. If an intolerable AE occurred, dose was maintained at Open Label 72 μg, if applicable.
Change From Baseline in Participant's Assessment of Constipation Severity Change from Baseline at Week 12	-1.4 score on a scale Standard Deviation 1.1	-1.3 score on a scale Standard Deviation 1.2	—	—	—
Change From Baseline in Participant's Assessment of Constipation Severity Baseline	3.5 score on a scale Standard Deviation 0.8	3.4 score on a scale Standard Deviation 0.8	—	—	—
Change From Baseline in Participant's Assessment of Constipation Severity Change from Baseline at Week 2	-1.1 score on a scale Standard Deviation 1.1	-1.2 score on a scale Standard Deviation 1.1	—	—	—
Change From Baseline in Participant's Assessment of Constipation Severity Change from Baseline at Week 4	-1.3 score on a scale Standard Deviation 1.1	-1.3 score on a scale Standard Deviation 1.1	—	—	—
Change From Baseline in Participant's Assessment of Constipation Severity Change from Baseline at Week 26	-1.4 score on a scale Standard Deviation 1.1	-1.3 score on a scale Standard Deviation 1.1	—	—	—
Change From Baseline in Participant's Assessment of Constipation Severity Change from Baseline at Week 40	-1.6 score on a scale Standard Deviation 1.1	-1.3 score on a scale Standard Deviation 1.0	—	—	—
Change From Baseline in Participant's Assessment of Constipation Severity Change from Baseline at Week 52	-1.6 score on a scale Standard Deviation 1.1	-1.5 score on a scale Standard Deviation 1.1	—	—	—

SECONDARY outcome

Timeframe: Baseline (Day 1) to Week 2, 4, 12, 26, 40 and 52 (Open Label Treatment Period)

Population: ITT population consisted of all participants in the safety population who had ≥ 1 postbaseline assessment for any efficacy or health outcomes parameter. Number analyzed were the participants with analysis values at both baseline and postbaseline during the specified time period.

Participants rated IBS symptoms severity during the previous 7 days on a 5-point ordinal scale where, 1=None, 2=Mild, 3=Moderate, 4=Severe and 5=Very severe. Higher scores indicate greater severity. A negative change from Baseline indicates improvement.

Outcome measures

Outcome measures
Measure	LINZESS® 145 μg (CIC, Open Label) n=311 Participants LINZESS® 145 μg capsules, orally, once daily for up to 52 weeks for participants with CIC. If an intolerable AE occurred participants could be randomized to the Double-blind Treatment Period.	LINZESS® 290 μg (IBS-C, Open Label) LINZESS® 290 μg capsules, orally, once daily for up to 52 weeks for participants with IBS-C. If an intolerable AE occurred participants could be randomized to the Double-blind Treatment Period.	LINZESS® 72 μg (IBS-C, Double Blind) Following participation in the Open Label Treatment Period, LINZESS® 72 μg capsules, orally, once daily from double-blind randomization up to Week 52 for participants with IBS-C. If an intolerable AE occurred, dose was maintained at Open Label 72 μg, if applicable.	LINZESS® 145 μg (CIC, Double Blind) Following participation in the Open Label Treatment Period, LINZESS® 145 μg capsules, orally, once daily from double-blind randomization up to Week 52 for participants with CIC. If an intolerable AE occurred, dose was reduced to 72 μg, if applicable.	LINZESS® 72 μg (CIC, Double Blind) Following participation in the Open Label Treatment Period, LINZESS® 72 μg capsules, orally, once daily from double-blind randomization up to Week 52 for participants with CIC. If an intolerable AE occurred, dose was maintained at Open Label 72 μg, if applicable.
Change From Baseline in Participant Assessment of Irritable Bowel Syndrome (IBS) Symptom Severity for Participants With Irritable Bowel Syndrome With Constipation (IBS-C) Baseline	3.4 score on a scale Standard Deviation 0.7	—	—	—	—
Change From Baseline in Participant Assessment of Irritable Bowel Syndrome (IBS) Symptom Severity for Participants With Irritable Bowel Syndrome With Constipation (IBS-C) Change from Baseline at Week 2	-1.0 score on a scale Standard Deviation 1.1	—	—	—	—
Change From Baseline in Participant Assessment of Irritable Bowel Syndrome (IBS) Symptom Severity for Participants With Irritable Bowel Syndrome With Constipation (IBS-C) Change from Baseline at Week 4	-1.1 score on a scale Standard Deviation 1.0	—	—	—	—
Change From Baseline in Participant Assessment of Irritable Bowel Syndrome (IBS) Symptom Severity for Participants With Irritable Bowel Syndrome With Constipation (IBS-C) Change from Baseline at Week 12	-1.2 score on a scale Standard Deviation 1.1	—	—	—	—
Change From Baseline in Participant Assessment of Irritable Bowel Syndrome (IBS) Symptom Severity for Participants With Irritable Bowel Syndrome With Constipation (IBS-C) Change from Baseline at Week 26	-1.2 score on a scale Standard Deviation 1.0	—	—	—	—
Change From Baseline in Participant Assessment of Irritable Bowel Syndrome (IBS) Symptom Severity for Participants With Irritable Bowel Syndrome With Constipation (IBS-C) Change from Baseline at Week 40	-1.2 score on a scale Standard Deviation 1.0	—	—	—	—
Change From Baseline in Participant Assessment of Irritable Bowel Syndrome (IBS) Symptom Severity for Participants With Irritable Bowel Syndrome With Constipation (IBS-C) Change from Baseline at Week 52	-1.3 score on a scale Standard Deviation 1.0	—	—	—	—

SECONDARY outcome

Timeframe: Baseline (Day 1) to Weeks 2, 4, 12, 26, 40 and 52 (Open Label Treatment Period)

Population: Intent-to-treat (ITT) population included all participants in the safety population who had ≥ 1 postbaseline assessment for any efficacy or health outcomes parameter. Number analyzed were the participants with analysis values at both baseline and postbaseline during the specified time period.

Participants rated degree of relief of IBS symptoms during previous 7 days on a 7-point balanced ordinal scale where, 1=completely relieved, 2=considerably relieved, 3=somewhat relieved, 4=unchanged, 5=somewhat worse, 6=considerably worse and 7=as bad as I can imagine. Lower scores indicate greater relief. A negative change from Baseline indicates improvement.

Outcome measures

Outcome measures
Measure	LINZESS® 145 μg (CIC, Open Label) n=311 Participants LINZESS® 145 μg capsules, orally, once daily for up to 52 weeks for participants with CIC. If an intolerable AE occurred participants could be randomized to the Double-blind Treatment Period.	LINZESS® 290 μg (IBS-C, Open Label) LINZESS® 290 μg capsules, orally, once daily for up to 52 weeks for participants with IBS-C. If an intolerable AE occurred participants could be randomized to the Double-blind Treatment Period.	LINZESS® 72 μg (IBS-C, Double Blind) Following participation in the Open Label Treatment Period, LINZESS® 72 μg capsules, orally, once daily from double-blind randomization up to Week 52 for participants with IBS-C. If an intolerable AE occurred, dose was maintained at Open Label 72 μg, if applicable.	LINZESS® 145 μg (CIC, Double Blind) Following participation in the Open Label Treatment Period, LINZESS® 145 μg capsules, orally, once daily from double-blind randomization up to Week 52 for participants with CIC. If an intolerable AE occurred, dose was reduced to 72 μg, if applicable.	LINZESS® 72 μg (CIC, Double Blind) Following participation in the Open Label Treatment Period, LINZESS® 72 μg capsules, orally, once daily from double-blind randomization up to Week 52 for participants with CIC. If an intolerable AE occurred, dose was maintained at Open Label 72 μg, if applicable.
Change From Baseline in Degree of Relief of IBS Symptoms for Participants With IBS-C Baseline	4.2 score on a scale Standard Deviation 0.8	—	—	—	—
Change From Baseline in Degree of Relief of IBS Symptoms for Participants With IBS-C Change from Baseline at Week 2	-1.4 score on a scale Standard Deviation 1.3	—	—	—	—
Change From Baseline in Degree of Relief of IBS Symptoms for Participants With IBS-C Change from Baseline at Week 4	-1.6 score on a scale Standard Deviation 1.3	—	—	—	—
Change From Baseline in Degree of Relief of IBS Symptoms for Participants With IBS-C Change from Baseline at Week 12	-1.8 score on a scale Standard Deviation 1.3	—	—	—	—
Change From Baseline in Degree of Relief of IBS Symptoms for Participants With IBS-C Change from Baseline at Week 26	-1.8 score on a scale Standard Deviation 1.3	—	—	—	—
Change From Baseline in Degree of Relief of IBS Symptoms for Participants With IBS-C Change from Baseline at Week 40	-1.9 score on a scale Standard Deviation 1.3	—	—	—	—
Change From Baseline in Degree of Relief of IBS Symptoms for Participants With IBS-C Change from Baseline at Week 52	-1.8 score on a scale Standard Deviation 1.3	—	—	—	—

SECONDARY outcome

Timeframe: Weeks 2, 4, 12, 26, 40 and 52 (Open Label Treatment Period)

Population: ITT population included all participants in the safety population who had ≥ 1 postbaseline assessment for any efficacy or health outcomes parameter. Number analyzed is the number of participants with data available for analysis at the given time-point.

Participants rated degree of satisfaction with the LINZESS®'s ability to relieve IBS symptoms on a 5-point ordinal scale where, 1=Not at all satisfied, 2=A little satisfied, 3=Moderately satisfied, 4=Quite satisfied and 5=Very satisfied. Higher scores indicate greater satisfaction.

Outcome measures

Outcome measures
Measure	LINZESS® 145 μg (CIC, Open Label) n=311 Participants LINZESS® 145 μg capsules, orally, once daily for up to 52 weeks for participants with CIC. If an intolerable AE occurred participants could be randomized to the Double-blind Treatment Period.	LINZESS® 290 μg (IBS-C, Open Label) LINZESS® 290 μg capsules, orally, once daily for up to 52 weeks for participants with IBS-C. If an intolerable AE occurred participants could be randomized to the Double-blind Treatment Period.	LINZESS® 72 μg (IBS-C, Double Blind) Following participation in the Open Label Treatment Period, LINZESS® 72 μg capsules, orally, once daily from double-blind randomization up to Week 52 for participants with IBS-C. If an intolerable AE occurred, dose was maintained at Open Label 72 μg, if applicable.	LINZESS® 145 μg (CIC, Double Blind) Following participation in the Open Label Treatment Period, LINZESS® 145 μg capsules, orally, once daily from double-blind randomization up to Week 52 for participants with CIC. If an intolerable AE occurred, dose was reduced to 72 μg, if applicable.	LINZESS® 72 μg (CIC, Double Blind) Following participation in the Open Label Treatment Period, LINZESS® 72 μg capsules, orally, once daily from double-blind randomization up to Week 52 for participants with CIC. If an intolerable AE occurred, dose was maintained at Open Label 72 μg, if applicable.
IBS Treatment Satisfaction Assessment Postbaseline for Participants With IBS-C Week 2	3.3 score on a scale Standard Deviation 1.2	—	—	—	—
IBS Treatment Satisfaction Assessment Postbaseline for Participants With IBS-C Week 4	3.6 score on a scale Standard Deviation 1.1	—	—	—	—
IBS Treatment Satisfaction Assessment Postbaseline for Participants With IBS-C Week 12	3.7 score on a scale Standard Deviation 1.1	—	—	—	—
IBS Treatment Satisfaction Assessment Postbaseline for Participants With IBS-C Week 26	3.7 score on a scale Standard Deviation 1.1	—	—	—	—
IBS Treatment Satisfaction Assessment Postbaseline for Participants With IBS-C Week 40	3.7 score on a scale Standard Deviation 1.1	—	—	—	—
IBS Treatment Satisfaction Assessment Postbaseline for Participants With IBS-C Week 52	3.8 score on a scale Standard Deviation 1.1	—	—	—	—

SECONDARY outcome

Timeframe: Weeks 2, 4, 12, 26, 40 and 52 (Open Label Treatment Period)

Population: ITT population consisted of all participants in the safety population who had ≥ 1 postbaseline assessment for any efficacy or health outcomes parameter. Number analyzed is the number of participants with data available for analysis at the given time-point.

Participants rated degree of satisfaction with LINZESS®'s ability to relieve constipation symptoms on a 5-point ordinal scale where 1=Not at all satisfied, 2=A little satisfied, 3=Moderately satisfied, 4=Quite satisfied and 5=Very satisfied. Higher scores indicate greater satisfaction.

Outcome measures

Outcome measures
Measure	LINZESS® 145 μg (CIC, Open Label) n=503 Participants LINZESS® 145 μg capsules, orally, once daily for up to 52 weeks for participants with CIC. If an intolerable AE occurred participants could be randomized to the Double-blind Treatment Period.	LINZESS® 290 μg (IBS-C, Open Label) LINZESS® 290 μg capsules, orally, once daily for up to 52 weeks for participants with IBS-C. If an intolerable AE occurred participants could be randomized to the Double-blind Treatment Period.	LINZESS® 72 μg (IBS-C, Double Blind) Following participation in the Open Label Treatment Period, LINZESS® 72 μg capsules, orally, once daily from double-blind randomization up to Week 52 for participants with IBS-C. If an intolerable AE occurred, dose was maintained at Open Label 72 μg, if applicable.	LINZESS® 145 μg (CIC, Double Blind) Following participation in the Open Label Treatment Period, LINZESS® 145 μg capsules, orally, once daily from double-blind randomization up to Week 52 for participants with CIC. If an intolerable AE occurred, dose was reduced to 72 μg, if applicable.	LINZESS® 72 μg (CIC, Double Blind) Following participation in the Open Label Treatment Period, LINZESS® 72 μg capsules, orally, once daily from double-blind randomization up to Week 52 for participants with CIC. If an intolerable AE occurred, dose was maintained at Open Label 72 μg, if applicable.
Constipation Treatment Satisfaction Assessment Postbaseline for Participants With Chronic Idiopathic Constipation (CIC) Week 2	3.4 score on a scale Standard Deviation 1.2	—	—	—	—
Constipation Treatment Satisfaction Assessment Postbaseline for Participants With Chronic Idiopathic Constipation (CIC) Week 4	3.5 score on a scale Standard Deviation 1.2	—	—	—	—
Constipation Treatment Satisfaction Assessment Postbaseline for Participants With Chronic Idiopathic Constipation (CIC) Week 12	3.7 score on a scale Standard Deviation 1.1	—	—	—	—
Constipation Treatment Satisfaction Assessment Postbaseline for Participants With Chronic Idiopathic Constipation (CIC) Week 26	3.8 score on a scale Standard Deviation 1.1	—	—	—	—
Constipation Treatment Satisfaction Assessment Postbaseline for Participants With Chronic Idiopathic Constipation (CIC) Week 40	3.9 score on a scale Standard Deviation 1.1	—	—	—	—
Constipation Treatment Satisfaction Assessment Postbaseline for Participants With Chronic Idiopathic Constipation (CIC) Week 52	4.0 score on a scale Standard Deviation 1.1	—	—	—	—

SECONDARY outcome

Timeframe: From first dose in the Double-blind Treatment Period to Week 52

Population: Double-blind safety population consisted of all participants in the randomized population who received ≥ 1 dose of study treatment during the Double-blind Treatment Period. Number of Participants Analyzed were the participants reporting intolerable diarrhea during the Open-label Treatment Period.

Participant reporting any instance of diarrhea during the Double-blind Treatment Period.

Outcome measures

Outcome measures
Measure	LINZESS® 145 μg (CIC, Open Label) n=17 Participants LINZESS® 145 μg capsules, orally, once daily for up to 52 weeks for participants with CIC. If an intolerable AE occurred participants could be randomized to the Double-blind Treatment Period.	LINZESS® 290 μg (IBS-C, Open Label) n=17 Participants LINZESS® 290 μg capsules, orally, once daily for up to 52 weeks for participants with IBS-C. If an intolerable AE occurred participants could be randomized to the Double-blind Treatment Period.	LINZESS® 72 μg (IBS-C, Double Blind) n=16 Participants Following participation in the Open Label Treatment Period, LINZESS® 72 μg capsules, orally, once daily from double-blind randomization up to Week 52 for participants with IBS-C. If an intolerable AE occurred, dose was maintained at Open Label 72 μg, if applicable.	LINZESS® 145 μg (CIC, Double Blind) n=29 Participants Following participation in the Open Label Treatment Period, LINZESS® 145 μg capsules, orally, once daily from double-blind randomization up to Week 52 for participants with CIC. If an intolerable AE occurred, dose was reduced to 72 μg, if applicable.	LINZESS® 72 μg (CIC, Double Blind) n=29 Participants Following participation in the Open Label Treatment Period, LINZESS® 72 μg capsules, orally, once daily from double-blind randomization up to Week 52 for participants with CIC. If an intolerable AE occurred, dose was maintained at Open Label 72 μg, if applicable.
Number of Participants With Recurrence of Diarrhea	11 Participants	12 Participants	5 Participants	19 Participants	18 Participants

SECONDARY outcome

Timeframe: From first dose in the Double-blind Treatment Period to Week 52

Participants reporting any instance of intolerable diarrhea during the Double-blind Treatment Period (Non-responder otherwise). Only includes participants reporting intolerable diarrhea during the Open-label Treatment Period.

Outcome measures

Outcome measures
Measure	LINZESS® 145 μg (CIC, Open Label) n=17 Participants LINZESS® 145 μg capsules, orally, once daily for up to 52 weeks for participants with CIC. If an intolerable AE occurred participants could be randomized to the Double-blind Treatment Period.	LINZESS® 290 μg (IBS-C, Open Label) n=17 Participants LINZESS® 290 μg capsules, orally, once daily for up to 52 weeks for participants with IBS-C. If an intolerable AE occurred participants could be randomized to the Double-blind Treatment Period.	LINZESS® 72 μg (IBS-C, Double Blind) n=16 Participants Following participation in the Open Label Treatment Period, LINZESS® 72 μg capsules, orally, once daily from double-blind randomization up to Week 52 for participants with IBS-C. If an intolerable AE occurred, dose was maintained at Open Label 72 μg, if applicable.	LINZESS® 145 μg (CIC, Double Blind) n=29 Participants Following participation in the Open Label Treatment Period, LINZESS® 145 μg capsules, orally, once daily from double-blind randomization up to Week 52 for participants with CIC. If an intolerable AE occurred, dose was reduced to 72 μg, if applicable.	LINZESS® 72 μg (CIC, Double Blind) n=29 Participants Following participation in the Open Label Treatment Period, LINZESS® 72 μg capsules, orally, once daily from double-blind randomization up to Week 52 for participants with CIC. If an intolerable AE occurred, dose was maintained at Open Label 72 μg, if applicable.
Number of Participants With Recurrence of Intolerable Diarrhea	10 Participants	11 Participants	4 Participants	19 Participants	17 Participants

SECONDARY outcome

Timeframe: From first dose of study treatment up to Week 52

Population: Safety population included all participants in the screened population who received ≥ 1 administration of study treatment.

An adverse event is any untoward medical occurrence in a patient or clinical investigation participant administered a pharmaceutical product and which does not necessarily have a causal relationship with this treatment. An adverse event can therefore be any unfavorable and unintended sign (including an abnormal laboratory finding), symptom, or disease temporally associated with the use of a medicinal (investigational) product, whether or not related to the medicinal (investigational) product. A TEAE is an AE that occurred after receiving the first dose of investigational product or an AE present prior to first dose but increased in severity during the Treatment Period.

Outcome measures

Outcome measures
Measure	LINZESS® 145 μg (CIC, Open Label) n=508 Participants LINZESS® 145 μg capsules, orally, once daily for up to 52 weeks for participants with CIC. If an intolerable AE occurred participants could be randomized to the Double-blind Treatment Period.	LINZESS® 290 μg (IBS-C, Open Label) n=318 Participants LINZESS® 290 μg capsules, orally, once daily for up to 52 weeks for participants with IBS-C. If an intolerable AE occurred participants could be randomized to the Double-blind Treatment Period.	LINZESS® 72 μg (IBS-C, Double Blind) Following participation in the Open Label Treatment Period, LINZESS® 72 μg capsules, orally, once daily from double-blind randomization up to Week 52 for participants with IBS-C. If an intolerable AE occurred, dose was maintained at Open Label 72 μg, if applicable.	LINZESS® 145 μg (CIC, Double Blind) Following participation in the Open Label Treatment Period, LINZESS® 145 μg capsules, orally, once daily from double-blind randomization up to Week 52 for participants with CIC. If an intolerable AE occurred, dose was reduced to 72 μg, if applicable.	LINZESS® 72 μg (CIC, Double Blind) Following participation in the Open Label Treatment Period, LINZESS® 72 μg capsules, orally, once daily from double-blind randomization up to Week 52 for participants with CIC. If an intolerable AE occurred, dose was maintained at Open Label 72 μg, if applicable.
Percentage of Participants With Treatment Emergent Adverse Events (TEAE)	62.6 percentage of participants	66.0 percentage of participants	—	—	—

SECONDARY outcome

Timeframe: From first dose in the Double-blind Treatment Period to Week 52

Time to first recurrence of diarrhea was defined as event/censored date - double-blind start date + 1, where event date (responders) = first recurrence of diarrhea date during the double-blind treatment period; censoring date (non-responders) = double-blind end date. Only includes participants reporting intolerable diarrhea during the open-label treatment period.

Outcome measures

Outcome measures
Measure	LINZESS® 145 μg (CIC, Open Label) n=17 Participants LINZESS® 145 μg capsules, orally, once daily for up to 52 weeks for participants with CIC. If an intolerable AE occurred participants could be randomized to the Double-blind Treatment Period.	LINZESS® 290 μg (IBS-C, Open Label) n=17 Participants LINZESS® 290 μg capsules, orally, once daily for up to 52 weeks for participants with IBS-C. If an intolerable AE occurred participants could be randomized to the Double-blind Treatment Period.	LINZESS® 72 μg (IBS-C, Double Blind) n=16 Participants Following participation in the Open Label Treatment Period, LINZESS® 72 μg capsules, orally, once daily from double-blind randomization up to Week 52 for participants with IBS-C. If an intolerable AE occurred, dose was maintained at Open Label 72 μg, if applicable.	LINZESS® 145 μg (CIC, Double Blind) n=29 Participants Following participation in the Open Label Treatment Period, LINZESS® 145 μg capsules, orally, once daily from double-blind randomization up to Week 52 for participants with CIC. If an intolerable AE occurred, dose was reduced to 72 μg, if applicable.	LINZESS® 72 μg (CIC, Double Blind) n=29 Participants Following participation in the Open Label Treatment Period, LINZESS® 72 μg capsules, orally, once daily from double-blind randomization up to Week 52 for participants with CIC. If an intolerable AE occurred, dose was maintained at Open Label 72 μg, if applicable.
Time to First Recurrence of Diarrhea	19.0 days Interval 2.0 to 64.0	15.0 days Interval 2.0 to 96.0	NA days Interval 21.0 to Median and upper limit of CI was not reached due to low number of participants with events.	4.0 days Interval 1.0 to Upper limit of CI was not reached due to low number of participants with events.	9.0 days Interval 3.0 to Upper limit of CI was not reached due to low number of participants with events.

SECONDARY outcome

Timeframe: From first dose in the Double-blind Treatment Period to Week 52

Time to first recurrence of intolerable diarrhea was defined as event/censored date - double-blind start date + 1, where event date (responders) = first recurrence of intolerable diarrhea date during the double-blind treatment period; censoring date (non-responders) = double-blind end date. Only includes participants reporting intolerable diarrhea during the open-label treatment period.

Outcome measures

Outcome measures
Measure	LINZESS® 145 μg (CIC, Open Label) n=17 Participants LINZESS® 145 μg capsules, orally, once daily for up to 52 weeks for participants with CIC. If an intolerable AE occurred participants could be randomized to the Double-blind Treatment Period.	LINZESS® 290 μg (IBS-C, Open Label) n=17 Participants LINZESS® 290 μg capsules, orally, once daily for up to 52 weeks for participants with IBS-C. If an intolerable AE occurred participants could be randomized to the Double-blind Treatment Period.	LINZESS® 72 μg (IBS-C, Double Blind) n=16 Participants Following participation in the Open Label Treatment Period, LINZESS® 72 μg capsules, orally, once daily from double-blind randomization up to Week 52 for participants with IBS-C. If an intolerable AE occurred, dose was maintained at Open Label 72 μg, if applicable.	LINZESS® 145 μg (CIC, Double Blind) n=29 Participants Following participation in the Open Label Treatment Period, LINZESS® 145 μg capsules, orally, once daily from double-blind randomization up to Week 52 for participants with CIC. If an intolerable AE occurred, dose was reduced to 72 μg, if applicable.	LINZESS® 72 μg (CIC, Double Blind) n=29 Participants Following participation in the Open Label Treatment Period, LINZESS® 72 μg capsules, orally, once daily from double-blind randomization up to Week 52 for participants with CIC. If an intolerable AE occurred, dose was maintained at Open Label 72 μg, if applicable.
Time to First Recurrence of Intolerable Diarrhea	19.0 days Interval 2.0 to Upper limit of CI was not reached due to low number of participants with events.	18.0 days Interval 2.0 to Upper limit of CI was not reached due to low number of participants with events.	NA days Interval 55.0 to Median and upper limit of CI was not reached due to low number of participants with events.	8.0 days Interval 1.0 to 254.0	9.0 days Interval 3.0 to Upper limit of CI was not reached due to low number of participants with events.

Adverse Events

LINZESS® 145 μg (CIC)

Serious events: 16 serious events

Other events: 133 other events

Deaths: 1 deaths

LINZESS® 290 μg (IBS-C)

Serious events: 6 serious events

Other events: 122 other events

Deaths: 0 deaths

Serious adverse events

Other adverse events

Other adverse events
Measure	LINZESS® 145 μg (CIC) n=508 participants at risk LINZESS® 145 μg capsules, orally, once daily for up to 52 weeks for participants with CIC. If an Intolerable AE occurred participants could be randomized to the Double-blind Treatment Period (145 μg or 72 μg) or entered the Dose-reduced 72 μg Open Label Period.	LINZESS® 290 μg (IBS-C) n=318 participants at risk LINZESS® 290 μg capsules, orally, once daily for up to 52 weeks for participants with IBS-C. If an intolerable AE occurred participants could be randomized to the Double-blind Treatment Period (290 μg, 145 μg or 72 μg) or entered the Dose-reduced 72 μg Open Label Period.
Gastrointestinal disorders Diarrhoea	25.6% 130/508 • From first dose of study treatment up to 1 day post last dose for non-serious adverse events and up to 30 days post last dose of study treatment for serious adverse events (Up to 56 Weeks) Adverse Events were monitored/assessed according to indication (CIC and IBS-C), irrespective of the dose level, and cannot be reported for each dose separately.	36.5% 116/318 • From first dose of study treatment up to 1 day post last dose for non-serious adverse events and up to 30 days post last dose of study treatment for serious adverse events (Up to 56 Weeks) Adverse Events were monitored/assessed according to indication (CIC and IBS-C), irrespective of the dose level, and cannot be reported for each dose separately.
Gastrointestinal disorders Flatulence	2.2% 11/508 • From first dose of study treatment up to 1 day post last dose for non-serious adverse events and up to 30 days post last dose of study treatment for serious adverse events (Up to 56 Weeks) Adverse Events were monitored/assessed according to indication (CIC and IBS-C), irrespective of the dose level, and cannot be reported for each dose separately.	5.7% 18/318 • From first dose of study treatment up to 1 day post last dose for non-serious adverse events and up to 30 days post last dose of study treatment for serious adverse events (Up to 56 Weeks) Adverse Events were monitored/assessed according to indication (CIC and IBS-C), irrespective of the dose level, and cannot be reported for each dose separately.

Additional Information

Therapeutic Area, Head

Allergan

Phone: 714-246-4500

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 cannot require changes to the communication and cannot extend the embargo.
Publication restrictions are in place

Restriction type: OTHER