Irritable Bowel Syndrome
Conditions
Keywords
Irritable Bowel Syndrome, Irritable Bowel Syndrome with predominantly diarrhea (IBS-D), Irritable Bowel Syndrome with mixed episodes of diarrhea and constipation (IBS-M), Vibegron, Beta-3 adrenergic receptor (β3-AR), Pain
Brief summary
This study will evaluate the efficacy and safety of vibegron, a beta-3 adrenergic receptor (β3-AR) agonist, in the treatment of pain associated with irritable bowel syndrome (IBS) due to IBS with predominant diarrhea (IBS-D) or mixed episodes of diarrhea and constipation (IBS-M).
Interventions
DRUGVibegron
oral administration
DRUGPlacebo
oral administration
Sponsors
Urovant Sciences GmbH
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
TRIPLE (Subject, Investigator, Outcomes Assessor)
Eligibility
Sex/Gender
FEMALE
Age
18 Years to 70 Years
Healthy volunteers
No
Inclusion criteria
* Diagnosis of irritable bowel syndrome (IBS) with predominantly diarrhea (IBS-D) or IBS with mixed episodes of diarrhea and constipation (IBS-M) according to the Rome IV criteria * Has completed a colonoscopy according to the American Gastroenterological Association criteria, with no clinically significant findings in the last 5 years * Has no clinically significant findings on a physical examination or clinical laboratory tests that could interfere with study participation or confound study assessments, in the opinion of the Investigator. Serum tissue transglutaminase antibody (IgA) must be negative. Fecal calprotectin testing is optional and should only be considered if there is a strong suspicion that the participant has inflammatory bowel disease (IBD) (eg, family history in a 1st degree relative, other genetic factors, etc.) or other organic disease, according to the clinical judgement of the investigator.
Exclusion criteria
* Diagnosis of IBS-C or IBS-U per Rome IV criteria * History of chronic idiopathic constipation or functional constipation * Structural abnormality of the gastrointestinal tract or a disease (e.g., known small intestine bacterial overgrowth) or condition that can affect gastrointestinal motility * History of a gastrointestinal motility disorder other than IBS (e.g., gastroparesis, intestinal pseudo-obstruction, achalasia, Parkinsons disease, multiple sclerosis, spinal cord injury) * Prior history of a gastrointestinal malignancy, inflammatory bowel disease, celiac disease * Planned gastrointestinal or abdominal surgery within the next 6 months * Co-existing gastroesophageal reflux disease or functional dyspepsia with symptoms predominant to IBS symptoms * Symptoms or diagnosis of a medical condition other than IBS that may contribute to abdominal pain (e.g., interstitial cystitis; fibromyalgia currently being treated with pregabalin or gabapentin; and endometriosis with uncontrolled abdominal pain)
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Number of Irritable Bowel Syndrome (IBS) With Predominantly Diarrhea (IBS-D) Participants Who Were Abdominal Pain Intensity (API) Weekly Responders at Week 12 | Baseline; Week 12 | An API Weekly Responder was defined as a participant who experienced a decrease in the weekly average of worst abdominal pain in the past 24 hours scores of at least 30% compared with the Baseline weekly average. A participant was considered a responder over Weeks 1 to 12 if they met the criteria for at least 50% of the weeks assessed (i.e., ≥6 weeks). |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Number of IBS-D Participants Who Were API Weekly Responders With ≥ 40% Improvement Over 12 Weeks | Baseline; 12 weeks | An API Weekly Responder was defined as a participant who experienced a decrease in the weekly average of worst abdominal pain in the past 24 hours scores of at least 40% compared with the Baseline weekly average. A participant was considered a responder over Weeks 1 to 12 if they met the criteria for at least 50% of the weeks assessed (i.e., ≥6 weeks). |
| Number of IBS-D Participants Who Were API Weekly Responders With ≥ 50% Improvement Over 12 Weeks | Baseline; 12 weeks | An API Weekly Responder was defined as a participant who experienced a decrease in the weekly average of worst abdominal pain in the past 24 hours scores of at least 50% compared with the Baseline weekly average. A participant was considered a responder over Weeks 1 to 12 if they met the criteria for at least 50% of the weeks assessed (i.e., ≥6 weeks). |
| Number of Global Improvement Scale (GIS) Responders at Week 12 for All IBS Participants, Including IBS-D and IBS-M Participants | Week 12 | Global improvement assessment asks participants to evaluate their current IBS status by asking the following question: How would you rate your IBS signs or symptoms overall over the past 7 days?: (1) significantly relieved; (2) moderately relieved; (3) slightly relieved; (4) unchanged; (5) slightly worse; (6) moderately worse; (7) significantly worse. A responder was defined as a participant who answered that their symptoms were either moderately relieved or significantly relieved. A participant with a missing GIS response was considered to be a non-responder. |
| Number of Participants With Clinically Meaningful Changes From Baseline in Clinical Laboratory Values at Week 12 | Baseline; Week 12 | The investigator determined whether a change was clinically meaningful. |
| Number of Participants With Clinically Relevant Changes From Baseline in Vital Sign Values at Week 12 | Baseline; Week 12 | Clinical relevance was determined by the investigator. |
| Number of Participants With Any Treatment-emergent Adverse Event (TEAE) | from the time the participant provided informed consent to participate in the study at the Screening Visit until completion of the Safety Follow-up Call (up to Day 113 or Early Withdrawal plus 28 days) | TEAEs are defined as events that began or worsened in severity after the first dose of the double-blind study treatment through 14 days after the last dose of study treatment. |
Countries
United States
Participant flow
Pre-assignment details
Of 806 participants screened for this study, 222 were randomized (after a 2-week, single-blind placebo Run-in Period), and 222 received 1 dose of double-blind study drug in the Treatment Period (Safety Set: placebo, N = 111; vibegron, N = 111).
Participants by arm
| Arm | Count |
|---|---|
| Placebo Participants received matching placebo, orally, once daily for 12 weeks. Participants were stratified by Baseline abdominal pain intensity (API) score (\< 6 versus ≥ 6 on a 0- to 10-point numeric rating scale) and irritable bowel syndrome (IBS) subtype (IBS with predominant diarrhea \[IBS-D\] versus IBS with mixed episodes of diarrhea and constipation \[IBS-M\]). | 108 |
| Vibegron 75 mg Participants received vibegron 75 milligrams (mg), orally, once daily for 12 weeks. Participants were stratified by Baseline API score (\< 6 versus ≥ 6 on a 0- to 10-point numeric rating scale) and IBS subtype (IBS-D versus IBS-M). | 111 |
| Total | 219 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Overall Study | Adverse Event | 3 | 0 |
| Overall Study | Could Not Come Due to Covid | 1 | 0 |
| Overall Study | Covid 19 Concern; Possible Site Closure | 0 | 1 |
| Overall Study | Covid 19 Restrictions | 2 | 0 |
| Overall Study | Lost to Follow-up | 5 | 1 |
| Overall Study | Physician Decision | 1 | 1 |
| Overall Study | Pregnancy | 0 | 1 |
| Overall Study | Prescribed Exclusionary Medication (Med) | 1 | 0 |
| Overall Study | Protocol Violation | 3 | 1 |
| Overall Study | Ran Out of Study Meds (Covid Quarantine) | 1 | 0 |
| Overall Study | Unable to Complete Procedures | 0 | 1 |
| Overall Study | Withdrawal by Subject | 4 | 5 |
| Overall Study | Withdrawn Due to Work/School Schedule | 0 | 1 |
Baseline characteristics
| Characteristic | Placebo | Total | Vibegron 75 mg |
|---|---|---|---|
| Abdominal Pain Intensity Score (Stratified Strata) < 6 | 77 Participants | 155 Participants | 78 Participants |
| Abdominal Pain Intensity Score (Stratified Strata) ≥ 6 | 31 Participants | 64 Participants | 33 Participants |
| Age, Continuous | 39.6 years STANDARD_DEVIATION 13.1 | 40.1 years STANDARD_DEVIATION 13.48 | 40.5 years STANDARD_DEVIATION 13.88 |
| IBS Subtype (Stratified Strata) IBS-D | 63 Participants | 129 Participants | 66 Participants |
| IBS Subtype (Stratified Strata) IBS-M | 45 Participants | 90 Participants | 45 Participants |
| Race/Ethnicity, Customized American Indian or Alaska Native | 1 Participants | 2 Participants | 1 Participants |
| Race/Ethnicity, Customized Asian | 0 Participants | 1 Participants | 1 Participants |
| Race/Ethnicity, Customized Black or African American | 24 Participants | 49 Participants | 25 Participants |
| Race/Ethnicity, Customized Captured as Other | 1 Participants | 4 Participants | 3 Participants |
| Race/Ethnicity, Customized Native Hawaiian or Other Pacific Islander | 0 Participants | 1 Participants | 1 Participants |
| Race/Ethnicity, Customized White | 82 Participants | 162 Participants | 80 Participants |
| Sex: Female, Male Female | 108 Participants | 219 Participants | 111 Participants |
| Sex: Female, Male Male | 0 Participants | 0 Participants | 0 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | 0 / 111 | 0 / 111 |
| other Total, other adverse events | 19 / 111 | 13 / 111 |
| serious Total, serious adverse events | 1 / 111 | 2 / 111 |
Outcome results
Primary
Number of Irritable Bowel Syndrome (IBS) With Predominantly Diarrhea (IBS-D) Participants Who Were Abdominal Pain Intensity (API) Weekly Responders at Week 12
An API Weekly Responder was defined as a participant who experienced a decrease in the weekly average of worst abdominal pain in the past 24 hours scores of at least 30% compared with the Baseline weekly average. A participant was considered a responder over Weeks 1 to 12 if they met the criteria for at least 50% of the weeks assessed (i.e., ≥6 weeks).
Time frame: Baseline; Week 12
Population: Full Analysis Set for IBS-D participants: all randomized participants with IBS-D who who took at least one dose of double-blind study medication and had at least one evaluable post-randomization weekly API score (i.e., where evaluable was considered a minimum of 5 diary entries in a week)
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Placebo | Number of Irritable Bowel Syndrome (IBS) With Predominantly Diarrhea (IBS-D) Participants Who Were Abdominal Pain Intensity (API) Weekly Responders at Week 12 | 27 Participants |
| Vibegron 75 mg | Number of Irritable Bowel Syndrome (IBS) With Predominantly Diarrhea (IBS-D) Participants Who Were Abdominal Pain Intensity (API) Weekly Responders at Week 12 | 27 Participants |
90% CI: [-16.1, 12.3]
Secondary
Number of Global Improvement Scale (GIS) Responders at Week 12 for All IBS Participants, Including IBS-D and IBS-M Participants
Global improvement assessment asks participants to evaluate their current IBS status by asking the following question: How would you rate your IBS signs or symptoms overall over the past 7 days?: (1) significantly relieved; (2) moderately relieved; (3) slightly relieved; (4) unchanged; (5) slightly worse; (6) moderately worse; (7) significantly worse. A responder was defined as a participant who answered that their symptoms were either moderately relieved or significantly relieved. A participant with a missing GIS response was considered to be a non-responder.
Time frame: Week 12
Population: Full Analysis Set: all randomized participants who took at least one dose of double-blind study medication and had at least one evaluable post-randomization weekly API score (i.e., where evaluable was considered a minimum of 5 diary entries in a week)
| Arm | Measure | Group | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| Placebo | Number of Global Improvement Scale (GIS) Responders at Week 12 for All IBS Participants, Including IBS-D and IBS-M Participants | IBS-D Participants | 21 Participants |
| Placebo | Number of Global Improvement Scale (GIS) Responders at Week 12 for All IBS Participants, Including IBS-D and IBS-M Participants | IBS-M Participants | 16 Participants |
| Placebo | Number of Global Improvement Scale (GIS) Responders at Week 12 for All IBS Participants, Including IBS-D and IBS-M Participants | All Participants | 37 Participants |
| Vibegron 75 mg | Number of Global Improvement Scale (GIS) Responders at Week 12 for All IBS Participants, Including IBS-D and IBS-M Participants | IBS-D Participants | 28 Participants |
| Vibegron 75 mg | Number of Global Improvement Scale (GIS) Responders at Week 12 for All IBS Participants, Including IBS-D and IBS-M Participants | IBS-M Participants | 16 Participants |
| Vibegron 75 mg | Number of Global Improvement Scale (GIS) Responders at Week 12 for All IBS Participants, Including IBS-D and IBS-M Participants | All Participants | 44 Participants |
Comparison: IBS-D Participants90% CI: [-4.8, 22.9]
Comparison: IBS-M Participants90% CI: [-16.7, 16.4]
Comparison: All Participants90% CI: [-5.4, 15.9]
Secondary
Number of IBS-D Participants Who Were API Weekly Responders With ≥ 40% Improvement Over 12 Weeks
An API Weekly Responder was defined as a participant who experienced a decrease in the weekly average of worst abdominal pain in the past 24 hours scores of at least 40% compared with the Baseline weekly average. A participant was considered a responder over Weeks 1 to 12 if they met the criteria for at least 50% of the weeks assessed (i.e., ≥6 weeks).
Time frame: Baseline; 12 weeks
Population: Full Analysis Set for IBS-D participants
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Placebo | Number of IBS-D Participants Who Were API Weekly Responders With ≥ 40% Improvement Over 12 Weeks | 20 Participants |
| Vibegron 75 mg | Number of IBS-D Participants Who Were API Weekly Responders With ≥ 40% Improvement Over 12 Weeks | 22 Participants |
90% CI: [-11.7, 14.9]
Secondary
Number of IBS-D Participants Who Were API Weekly Responders With ≥ 50% Improvement Over 12 Weeks
An API Weekly Responder was defined as a participant who experienced a decrease in the weekly average of worst abdominal pain in the past 24 hours scores of at least 50% compared with the Baseline weekly average. A participant was considered a responder over Weeks 1 to 12 if they met the criteria for at least 50% of the weeks assessed (i.e., ≥6 weeks).
Time frame: Baseline; 12 weeks
Population: Full Analysis Set for IBS-D participants
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Placebo | Number of IBS-D Participants Who Were API Weekly Responders With ≥ 50% Improvement Over 12 Weeks | 13 Participants |
| Vibegron 75 mg | Number of IBS-D Participants Who Were API Weekly Responders With ≥ 50% Improvement Over 12 Weeks | 18 Participants |
90% CI: [-5.5, 18.8]
Secondary
Number of Participants With Any Treatment-emergent Adverse Event (TEAE)
TEAEs are defined as events that began or worsened in severity after the first dose of the double-blind study treatment through 14 days after the last dose of study treatment.
Time frame: from the time the participant provided informed consent to participate in the study at the Screening Visit until completion of the Safety Follow-up Call (up to Day 113 or Early Withdrawal plus 28 days)
Population: Safety Analysis Set: all participants who received at least 1 dose of study treatment. Participants were included in the treatment group corresponding to the study treatment they actually received for the analysis of safety data.
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Placebo | Number of Participants With Any Treatment-emergent Adverse Event (TEAE) | 37 Participants |
| Vibegron 75 mg | Number of Participants With Any Treatment-emergent Adverse Event (TEAE) | 37 Participants |
Secondary
Number of Participants With Clinically Meaningful Changes From Baseline in Clinical Laboratory Values at Week 12
The investigator determined whether a change was clinically meaningful.
Time frame: Baseline; Week 12
Population: Safety Analysis Set
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Placebo | Number of Participants With Clinically Meaningful Changes From Baseline in Clinical Laboratory Values at Week 12 | 0 Participants |
| Vibegron 75 mg | Number of Participants With Clinically Meaningful Changes From Baseline in Clinical Laboratory Values at Week 12 | 0 Participants |
Secondary
Number of Participants With Clinically Relevant Changes From Baseline in Vital Sign Values at Week 12
Clinical relevance was determined by the investigator.
Time frame: Baseline; Week 12
Population: Safety Analysis Set
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Placebo | Number of Participants With Clinically Relevant Changes From Baseline in Vital Sign Values at Week 12 | 0 Participants |
| Vibegron 75 mg | Number of Participants With Clinically Relevant Changes From Baseline in Vital Sign Values at Week 12 | 0 Participants |