Chronic Idiopathic Constipation, Irritable Bowel Syndrome With Constipation
Conditions
Keywords
Immunogenicity, Irritable Bowel Syndrome with Constipation, Chronic Idiopathic Constipation, Linaclotide, Linzess
Brief summary
The primary objective of this study is to assess the potential of LINZESS® (linaclotide) treatment to induce the development of anti-drug antibodies (ADAs). The secondary objectives are to provide additional evidence supporting the long-term safety and efficacy of linaclotide in adult irritable bowel syndrome with constipation (IBS-C) and chronic idiopathic constipation (CIC) participants and to evaluate lower doses of linaclotide.
Detailed description
This study includes up to a 3-week Screening Period, followed by a 52-week treatment period. Participants with CIC meeting the entry criteria received linaclotide 145 μg capsules, orally, once daily and participants with IBS-C meeting the entry criteria received linaclotide 290 μg capsules, orally, once daily. Participants with intolerable Adverse Events (AEs), following resolution of the AEs, could be randomized to receive 290 μg, 145 μg, or the lower dose of 72 μg linaclotide oral capsules for IBS-C; and 145 μg or 72 μg for CIC. Participants who experienced further intolerable AEs after the randomization could be transitioned to open-label 72 μg linaclotide.
Interventions
DRUGLinaclotide
Linaclotide capsules, orally, once daily.
Sponsors
Ironwood Pharmaceuticals, Inc.
Forest Laboratories
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
* Participants meet the Rome III criteria for IBS-C or CIC: * IBS-C Criteria: the participant must meet the following 2 criteria (A and B). A. IBS Criteria: The participant must have abdominal pain or discomfort at least 3 days per month in the 3 months before diagnosis (with symptom onset at least 6 months before diagnosis) associated with 2 or more of the following: 1. Improvement with defecation. 2. Onset associated with a change in frequency of stool. 3. Onset associated with a change in form (appearance) of stool. B. Stool Consistency Requirement: During the 3 months before diagnosis in the absence of laxative or enema use, the patient has hard or lumpy stools (Bristol Stool Form Scale \[BSFS\] score 1 or 2) with at least 25% of bowel movements (BMs) and has loose or mushy stools (BSFS 5 or 6) with \<25% of BMs. * CIC Criteria: the participant must meet the following 3 criteria (A, B, and C): A. Participant meets 2 or more of the following criteria for 3 months before the diagnosis with symptom onset at least 6 months before diagnosis: 1. Straining during at least 25% of defecations. 2. Lumpy or hard stools in at least 25% of defecations. 3. Sensation of incomplete evacuation for at least 25% of defecations. 4. Sensation of anorectal obstruction/blockage for at least 25% of defecations. 5. Manual maneuvers to facilitate at least 25% of defecations (e.g., digital evacuation, support of the pelvic floor). 6. Fewer than 3 defecations per week. B. Loose stools are rarely present without the use of laxatives. C. Insufficient criteria for irritable bowel syndrome. (The criteria for IBS are provided in Point A under IBS Criteria, above). * Participant meets the colonoscopy requirements, which are modified from the Summary of the US-Multi-Society Task Force on Colorectal Cancer and other Colonoscopy Requirements. * Participant has successfully completed protocol procedures (with no clinically significant findings).
Exclusion criteria
* At Day 1 visit, the participant reports having 6 or more spontaneous bowel movements (SBMs) in the week prior to screening. * At Day 1 visit, the participant reports having any SBMs that were watery (BSFS=7) or more than 1 SBM that was mushy (BSFS=6) in the week prior to screening. * Participant has a structural abnormality of the gastrointestinal (GI) tract or a disease or condition that can affect GI motility. * Participant 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. * Participant has ever received linaclotide as a treatment (including commercially-available product) or has been randomized into any clinical study in which linaclotide was a treatment. (participant who enrolled into linaclotide clinical studies conducted prior or during this study but failed to be randomized are eligible for the current study). * Participant has ever received plecanatide, SP-333, or has participated in a plecanatide clinical study.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Number of Participants With Positive Treatment-Related Anti-Drug Antibodies (ADA) in Serum | Baseline (Day 1) up to 52 weeks or 8 months post last dose if ADA positive at Week 52 (approximately 84 weeks) | 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. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Change From Baseline in Participant Assessment of Irritable Bowel Syndrome (IBS) Symptom Severity for Participants With Irritable Bowel Syndrome With Constipation (IBS-C) | Baseline (Day 1) to Week 2, 4, 12, 26, 40 and 52 (Open Label Treatment 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. |
| Change From Baseline in Degree of Relief of IBS Symptoms for Participants With IBS-C | Baseline (Day 1) to Weeks 2, 4, 12, 26, 40 and 52 (Open Label Treatment 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. |
| IBS Treatment Satisfaction Assessment Postbaseline for Participants With IBS-C | Weeks 2, 4, 12, 26, 40 and 52 (Open Label Treatment Period) | 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. |
| Constipation Treatment Satisfaction Assessment Postbaseline for Participants With Chronic Idiopathic Constipation (CIC) | Weeks 2, 4, 12, 26, 40 and 52 (Open Label Treatment Period) | 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. |
| Change From Baseline in Participant's Assessment of Constipation Severity | Baseline (Day 1) to Weeks 2, 4, 12, 26, 40 and 52 (Open Label Treatment 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. |
| Number of Participants With Recurrence of Intolerable Diarrhea | 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. |
| Percentage of Participants With Treatment Emergent Adverse Events (TEAE) | From first dose of study treatment up to Week 52 | 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. |
| Time to First Recurrence of Diarrhea | 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. |
| Time to First Recurrence of Intolerable Diarrhea | 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. |
| Number of Participants With Recurrence of Diarrhea | From first dose in the Double-blind Treatment Period to Week 52 | Participant reporting any instance of diarrhea during the Double-blind Treatment Period. |
Countries
United States
Participant flow
Recruitment details
828 participants were enrolled, 2 participants were enrolled but did not receive study treatment and were not included in any analysis populations.
Pre-assignment details
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.
Participants by arm
| Arm | Count |
|---|---|
| LINZESS® 145 μg (CIC, Open Label) 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. | 508 |
| 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. | 318 |
| Total | 826 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 | FG002 | FG003 | FG004 | FG005 | FG006 | FG007 | FG008 |
|---|---|---|---|---|---|---|---|---|---|---|
| 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 | Lost to Follow-up | 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 |
| Dose-reduced Open Label Treatment Period | Protocol Violation | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 1 |
| Dose-reduced Open Label Treatment Period | Withdrawal of Consent | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 3 | 1 |
| 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 | 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 |
| Double-blind Treatment Period | Withdrawal of Consent | 0 | 0 | 1 | 3 | 3 | 1 | 1 | 0 | 0 |
| 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 | Lost to Follow-up | 51 | 29 | 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 |
| Open-label Treatment Period | Protocol Violation | 10 | 4 | 0 | 0 | 0 | 0 | 0 | 0 | 0 |
| Open-label Treatment Period | Withdrawal of Consent | 43 | 28 | 0 | 0 | 0 | 0 | 0 | 0 | 0 |
Baseline characteristics
| Characteristic | LINZESS® 145 μg (CIC, Open Label) | LINZESS® 290 μg (IBS-C, Open Label) | Total |
|---|---|---|---|
| Age, Continuous | 49.6 years STANDARD_DEVIATION 15.3 | 45.2 years STANDARD_DEVIATION 13.9 | 47.9 years STANDARD_DEVIATION 14.9 |
| Age, Customized >=40 to <65 years | 274 Participants | 170 Participants | 444 Participants |
| Age, Customized <40 years | 140 Participants | 120 Participants | 260 Participants |
| Age, Customized >=65 years | 94 Participants | 28 Participants | 122 Participants |
| Race/Ethnicity, Customized American Indian or Alaska Native | 1 Participants | 2 Participants | 3 Participants |
| Race/Ethnicity, Customized Asian | 19 Participants | 17 Participants | 36 Participants |
| Race/Ethnicity, Customized Black or African American | 135 Participants | 68 Participants | 203 Participants |
| Race/Ethnicity, Customized Hispanic or Latino | 124 Participants | 76 Participants | 200 Participants |
| Race/Ethnicity, Customized Multiple Races | 4 Participants | 3 Participants | 7 Participants |
| Race/Ethnicity, Customized Native Hawaiian or Other Pacific Islander | 1 Participants | 1 Participants | 2 Participants |
| Race/Ethnicity, Customized Not Hispanic or Latino | 384 Participants | 242 Participants | 626 Participants |
| Race/Ethnicity, Customized White | 348 Participants | 227 Participants | 575 Participants |
| Sex: Female, Male Female | 410 Participants | 259 Participants | 669 Participants |
| Sex: Female, Male Male | 98 Participants | 59 Participants | 157 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | 1 / 508 | 0 / 318 |
| other Total, other adverse events | 133 / 508 | 122 / 318 |
| serious Total, serious adverse events | 16 / 508 | 6 / 318 |
Outcome results
Primary
Number of Participants With Positive Treatment-Related Anti-Drug Antibodies (ADA) in Serum
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.
Time frame: 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).
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| LINZESS® 145 μg (CIC, Open Label) | Number of Participants With Positive Treatment-Related Anti-Drug Antibodies (ADA) in Serum | 3 Participants |
| LINZESS® 290 μg (IBS-C, Open Label) | Number of Participants With Positive Treatment-Related Anti-Drug Antibodies (ADA) in Serum | 1 Participants |
Secondary
Change From Baseline in Degree of Relief of IBS Symptoms for Participants With IBS-C
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.
Time frame: 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.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| LINZESS® 145 μg (CIC, Open Label) | 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 |
| LINZESS® 145 μg (CIC, Open Label) | 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 |
| LINZESS® 145 μg (CIC, Open Label) | 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 |
| LINZESS® 145 μg (CIC, Open Label) | 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 |
| LINZESS® 145 μg (CIC, Open Label) | 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 |
| LINZESS® 145 μg (CIC, Open Label) | 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 |
| LINZESS® 145 μg (CIC, Open Label) | 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
Change From Baseline in Participant Assessment of Irritable Bowel Syndrome (IBS) Symptom Severity for Participants With Irritable Bowel Syndrome With Constipation (IBS-C)
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.
Time frame: 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.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| LINZESS® 145 μg (CIC, Open Label) | 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 |
| LINZESS® 145 μg (CIC, Open Label) | 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 |
| LINZESS® 145 μg (CIC, Open Label) | 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 |
| LINZESS® 145 μg (CIC, Open Label) | 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 |
| LINZESS® 145 μg (CIC, Open Label) | 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 |
| LINZESS® 145 μg (CIC, Open Label) | 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 |
| LINZESS® 145 μg (CIC, Open Label) | 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 |
Secondary
Change From Baseline in Participant's Assessment of Constipation Severity
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.
Time frame: 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.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| LINZESS® 145 μg (CIC, Open Label) | 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 |
| LINZESS® 145 μg (CIC, Open Label) | 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 |
| LINZESS® 145 μg (CIC, Open Label) | 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 |
| LINZESS® 145 μg (CIC, Open Label) | 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 |
| LINZESS® 145 μg (CIC, Open Label) | 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 |
| LINZESS® 145 μg (CIC, Open Label) | 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 |
| LINZESS® 145 μg (CIC, Open Label) | Change From Baseline in Participant's Assessment of Constipation Severity | Baseline | 3.5 score on a scale | Standard Deviation 0.8 |
| LINZESS® 290 μg (IBS-C, Open Label) | Change From Baseline in Participant's Assessment of Constipation Severity | Change from Baseline at Week 52 | -1.5 score on a scale | Standard Deviation 1.1 |
| LINZESS® 290 μg (IBS-C, Open Label) | Change From Baseline in Participant's Assessment of Constipation Severity | Baseline | 3.4 score on a scale | Standard Deviation 0.8 |
| LINZESS® 290 μg (IBS-C, Open Label) | Change From Baseline in Participant's Assessment of Constipation Severity | Change from Baseline at Week 2 | -1.2 score on a scale | Standard Deviation 1.1 |
| LINZESS® 290 μg (IBS-C, Open Label) | 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 |
| LINZESS® 290 μg (IBS-C, Open Label) | Change From Baseline in Participant's Assessment of Constipation Severity | Change from Baseline at Week 12 | -1.3 score on a scale | Standard Deviation 1.2 |
| LINZESS® 290 μg (IBS-C, Open Label) | Change From Baseline in Participant's Assessment of Constipation Severity | Change from Baseline at Week 26 | -1.3 score on a scale | Standard Deviation 1.1 |
| LINZESS® 290 μg (IBS-C, Open Label) | Change From Baseline in Participant's Assessment of Constipation Severity | Change from Baseline at Week 40 | -1.3 score on a scale | Standard Deviation 1 |
Secondary
Constipation Treatment Satisfaction Assessment Postbaseline for Participants With Chronic Idiopathic Constipation (CIC)
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.
Time frame: 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.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| LINZESS® 145 μg (CIC, Open Label) | Constipation Treatment Satisfaction Assessment Postbaseline for Participants With Chronic Idiopathic Constipation (CIC) | Week 2 | 3.4 score on a scale | Standard Deviation 1.2 |
| LINZESS® 145 μg (CIC, Open Label) | Constipation Treatment Satisfaction Assessment Postbaseline for Participants With Chronic Idiopathic Constipation (CIC) | Week 4 | 3.5 score on a scale | Standard Deviation 1.2 |
| LINZESS® 145 μg (CIC, Open Label) | Constipation Treatment Satisfaction Assessment Postbaseline for Participants With Chronic Idiopathic Constipation (CIC) | Week 12 | 3.7 score on a scale | Standard Deviation 1.1 |
| LINZESS® 145 μg (CIC, Open Label) | Constipation Treatment Satisfaction Assessment Postbaseline for Participants With Chronic Idiopathic Constipation (CIC) | Week 26 | 3.8 score on a scale | Standard Deviation 1.1 |
| LINZESS® 145 μg (CIC, Open Label) | Constipation Treatment Satisfaction Assessment Postbaseline for Participants With Chronic Idiopathic Constipation (CIC) | Week 40 | 3.9 score on a scale | Standard Deviation 1.1 |
| LINZESS® 145 μg (CIC, Open Label) | 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
IBS Treatment Satisfaction Assessment Postbaseline for Participants With IBS-C
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.
Time frame: 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.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| LINZESS® 145 μg (CIC, Open Label) | IBS Treatment Satisfaction Assessment Postbaseline for Participants With IBS-C | Week 2 | 3.3 score on a scale | Standard Deviation 1.2 |
| LINZESS® 145 μg (CIC, Open Label) | IBS Treatment Satisfaction Assessment Postbaseline for Participants With IBS-C | Week 4 | 3.6 score on a scale | Standard Deviation 1.1 |
| LINZESS® 145 μg (CIC, Open Label) | IBS Treatment Satisfaction Assessment Postbaseline for Participants With IBS-C | Week 12 | 3.7 score on a scale | Standard Deviation 1.1 |
| LINZESS® 145 μg (CIC, Open Label) | IBS Treatment Satisfaction Assessment Postbaseline for Participants With IBS-C | Week 26 | 3.7 score on a scale | Standard Deviation 1.1 |
| LINZESS® 145 μg (CIC, Open Label) | IBS Treatment Satisfaction Assessment Postbaseline for Participants With IBS-C | Week 40 | 3.7 score on a scale | Standard Deviation 1.1 |
| LINZESS® 145 μg (CIC, Open Label) | IBS Treatment Satisfaction Assessment Postbaseline for Participants With IBS-C | Week 52 | 3.8 score on a scale | Standard Deviation 1.1 |
Secondary
Number of Participants With Recurrence of Diarrhea
Participant reporting any instance of diarrhea during the Double-blind Treatment Period.
Time frame: 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.
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| LINZESS® 145 μg (CIC, Open Label) | Number of Participants With Recurrence of Diarrhea | 11 Participants |
| LINZESS® 290 μg (IBS-C, Open Label) | Number of Participants With Recurrence of Diarrhea | 12 Participants |
| LINZESS® 72 μg (IBS-C, Double Blind) | Number of Participants With Recurrence of Diarrhea | 5 Participants |
| LINZESS® 145 μg (CIC, Double Blind) | Number of Participants With Recurrence of Diarrhea | 19 Participants |
| LINZESS® 72 μg (CIC, Double Blind) | Number of Participants With Recurrence of Diarrhea | 18 Participants |
Comparison: LINZESS® 145 μg versus (vs) LINZESS® 290 μgp-value: 195% CI: [0.3, 5.5]Fisher's Exact Test
Comparison: LINZESS® 72 μg vs LINZESS® 290 μgp-value: 0.084495% CI: [0.1, 1.1]Fisher's Exact Test
Comparison: LINZESS® 72 μg vs LINZESS® 145 μgp-value: 195% CI: [0.3, 2.5]Fisher's Exact Test
Secondary
Number of Participants With Recurrence of Intolerable Diarrhea
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.
Time frame: 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.
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| LINZESS® 145 μg (CIC, Open Label) | Number of Participants With Recurrence of Intolerable Diarrhea | 10 Participants |
| LINZESS® 290 μg (IBS-C, Open Label) | Number of Participants With Recurrence of Intolerable Diarrhea | 11 Participants |
| LINZESS® 72 μg (IBS-C, Double Blind) | Number of Participants With Recurrence of Intolerable Diarrhea | 4 Participants |
| LINZESS® 145 μg (CIC, Double Blind) | Number of Participants With Recurrence of Intolerable Diarrhea | 19 Participants |
| LINZESS® 72 μg (CIC, Double Blind) | Number of Participants With Recurrence of Intolerable Diarrhea | 17 Participants |
Comparison: LINZESS® 145 μg vs LINZESS® 290 μgp-value: 195% CI: [0.3, 5.1]Fisher's Exact Test
Comparison: LINZESS® 72 μg vs LINZESS® 290 μgp-value: 0.079995% CI: [0.1, 1]Fisher's Exact Test
Comparison: LINZESS® 72 μg vs LINZESS® 145 μgp-value: 0.787195% CI: [0.3, 2.2]Fisher's Exact Test
Secondary
Percentage of Participants With Treatment Emergent Adverse Events (TEAE)
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.
Time frame: 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.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| LINZESS® 145 μg (CIC, Open Label) | Percentage of Participants With Treatment Emergent Adverse Events (TEAE) | 62.6 percentage of participants |
| LINZESS® 290 μg (IBS-C, Open Label) | Percentage of Participants With Treatment Emergent Adverse Events (TEAE) | 66.0 percentage of participants |
Secondary
Time to First Recurrence of Diarrhea
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.
Time frame: 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.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| LINZESS® 145 μg (CIC, Open Label) | Time to First Recurrence of Diarrhea | 19.0 days |
| LINZESS® 290 μg (IBS-C, Open Label) | Time to First Recurrence of Diarrhea | 15.0 days |
| LINZESS® 72 μg (IBS-C, Double Blind) | Time to First Recurrence of Diarrhea | NA days |
| LINZESS® 145 μg (CIC, Double Blind) | Time to First Recurrence of Diarrhea | 4.0 days |
| LINZESS® 72 μg (CIC, Double Blind) | Time to First Recurrence of Diarrhea | 9.0 days |
Comparison: LINZESS® 145 μg vs LINZESS® 290 μgp-value: 0.99395% CI: [0.42, 2.19]Log-Rank Test
Comparison: LINZESS® 72 μg vs LINZESS® 290 μgp-value: 0.024795% CI: [0.11, 0.89]Log-Rank Test
Comparison: LINZESS® 72 μg vs LINZESS® 145 μgp-value: 0.514995% CI: [0.41, 1.5]Log-Rank Test
Secondary
Time to First Recurrence of Intolerable Diarrhea
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.
Time frame: 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.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| LINZESS® 145 μg (CIC, Open Label) | Time to First Recurrence of Intolerable Diarrhea | 19.0 days |
| LINZESS® 290 μg (IBS-C, Open Label) | Time to First Recurrence of Intolerable Diarrhea | 18.0 days |
| LINZESS® 72 μg (IBS-C, Double Blind) | Time to First Recurrence of Intolerable Diarrhea | NA days |
| LINZESS® 145 μg (CIC, Double Blind) | Time to First Recurrence of Intolerable Diarrhea | 8.0 days |
| LINZESS® 72 μg (CIC, Double Blind) | Time to First Recurrence of Intolerable Diarrhea | 9.0 days |
Comparison: LINZESS® 145 μg vs LINZESS® 290 μgp-value: 0.951995% CI: [0.39, 2.18]Log-Rank Test
Comparison: LINZESS® 72 μg vs LINZESS® 290 μgp-value: 0.023495% CI: [0.08, 0.87]Log-Rank Test
Comparison: LINZESS® 72 μg vs LINZESS® 145 μgp-value: 0.451895% CI: [0.39, 1.47]Log-Rank Test