Olorinab in Irritable Bowel Syndrome With Predominant Constipation (IBS-C) and Irritable Bowel Syndrome With Predominant Diarrhea (IBS-D)

Study Overview
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Brief Summary
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The purpose of this study is to determine whether olorinab is a safe and effective treatment for abdominal pain in participants with irritable bowel syndrome (IBS).

Official Title
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A Phase 2, Multi-Center, Randomized, Double-Blind, Placebo-Controlled Parallel-Group Study to Evaluate the Safety, Tolerability, and Efficacy of Olorinab in Subjects With Irritable Bowel Syndrome Experiencing Abdominal Pain

Conditions
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Irritable Bowel Syndrome

Intervention / Treatment
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* Drug: Olorinab
* Drug: Olorinab
* Drug: Olorinab
* Drug: Placebo
* Drug: Olorinab
* Drug: Olorinab


Participation Criteria
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Eligibility Criteria
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Main Study Inclusion Criteria: Diagnosis of irritable bowel syndrome (IBS) with predominant constipation (IBS-C) or predominant diarrhea (IBS-D) according to Rome IV criteria at Visit 1 (Screening) Per the Rome IV diagnostic algorithm for IBS, participants 50 years of age and over are to have had one of the following with a result that rules out causes of abdominal pain other than IBS: Colonoscopy (within 10 years of Visit 1 [Screening]) Flexible sigmoidoscopy and double contrast barium enema (within 5 years of Visit 1 [Screening]) Computed tomography colonography (within 5 years of Visit 1 [Screening]) Main Study Exclusion Criteria: Diagnosis of IBS with mixed bowel habits (IBS-M) or unsubtyped IBS (IBS-U) Clinically relevant changes in dietary, lifestyle, or exercise regimen within 30 days prior to Visit 1 (Screening) that may confound efficacy assessments in the clinical judgment of the Investigator (or designee) Any colonic or major abdominal surgery (eg, bariatric surgery [including gastric banding], stomach surgery, small/large bowel surgery, or abdominal large vessel surgery). History of cholecystectomy is exclusionary for participants with IBS-D. For participants with IBS-C, a history of cholecystectomy more than 6 months prior to Visit 1 (Screening) is allowed. Procedures such as appendectomy, hysterectomy, caesarean section, or polypectomy are allowed as long as they have occurred at least 3 months prior to Visit 1 (Screening). Long-Term Extension Inclusion Criteria: •All participants must have completed the Main Study (including both Visit 8 [Week 12] and Visit 9 [Week 14]) Long-Term Extension Exclusion Criteria: Participant meets any exclusion criteria from the Main Study at the time of assessing eligibility for the LTE, unless approved by the Sponsor in advance. Participant had less than 75% overall compliance with eDiary entries during the Main Study. Participant deviated from the prescribed dosage regimen during the Main Study (ie, overall study treatment compliance less than 85% or more than 115%), unless approved by the Sponsor in advance.

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 70 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Quadruple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Olorinab low dose (Main Study)<br> | Drug: Olorinab<br>* Olorinab Dose 1 capsule or tablet by mouth, 3 times per day up to 12 weeks<br>* Other names: APD371;|
| Experimental: Olorinab medium dose (Main Study)<br> | Drug: Olorinab<br>* Olorinab Dose 2 capsule or tablet by mouth, 3 times per day up to 12 weeks<br>* Other names: APD371;|
| Experimental: Olorinab high dose (Main Study)<br> | Drug: Olorinab<br>* Olorinab Dose 3 capsule or tablet by mouth, 3 times per day up to 12 weeks<br>* Other names: APD371;|
| Placebo Comparator: Placebo (Main Study)<br> | Drug: Placebo<br>* Olorinab matching placebo capsule or tablet by mouth, 3 times per day up to 12 weeks<br>|
| Experimental: Olorinab (Long-Term Extension)<br>Participants will receive olorinab based on their treatment assignment in the Main Study. | Drug: Olorinab<br>* Olorinab Dose 2 capsule or tablet by mouth, 3 times per day up to 52 weeks<br>* Other names: APD371;Drug: Olorinab<br>* Olorinab Dose 3 capsule or tablet by mouth, 3 times per day up to 52 weeks<br>* Other names: APD371;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Main Study: Change From Baseline in Average Abdominal Pain Score (AAPS) at Week 12 | The APS is a single question, 11-point numeric rating scale in which 0 represents no abdominal pain and 10 represents the worst possible abdominal pain. The change in AAPS from Baseline at Week 12 was analyzed using a mixed-effects model repeated measures (MMRM) analysis with treatment, stratification factors, week, and treatment-by-week interaction as factors and Baseline AAPS as a covariate. An unstructured variance-covariance matrix was used for the MMRM analysis. | Baseline and Week 12 | 
| Main Study: Number of Participants With Treatment-Emergent Adverse Events (TEAEs) and Serious Adverse Events (SAEs) | An adverse event (AE) was any untoward medical occurrence in a participant administered a medicinal product without regard to possibility of causal relationship. An SAE was an AE resulting in any of the following outcomes or deemed significant for any other reason: death; initial or prolonged inpatient hospitalization; life-threatening experience (immediate risk of dying); persistent or significant disability/incapacity; congenital anomaly. TEAEs were defined as any AE that started or worsened in severity on or after the first dose of study treatment. | Up to 14 Weeks | 
| LTE Period: Number of Participants With TEAEs and SAEs | An AE was any untoward medical occurrence in a participant administered a medicinal product without regard to possibility of causal relationship. An SAE was an AE resulting in any of the following outcomes or deemed significant for any other reason: death; initial or prolonged inpatient hospitalization; life-threatening experience (immediate risk of dying); persistent or significant disability/incapacity; congenital anomaly. TEAEs were defined as any AE that started or worsened in severity on or after the first dose of study treatment. | Up to 54 Weeks | 
| Main Study: Number of Participants With Clinically Significant Abnormal Laboratory Parameters | Blood samples were collected for the analysis of laboratory parameters including serum chemistry, hematology, coagulation, and urinalysis. The investigator was responsible for reviewing laboratory results for clinically significant abnormalities. | Baseline to Week 14 | 
| LTE Study: Number of Participants With Clinically Significant Abnormal Laboratory Parameters | Blood samples were collected for the analysis of laboratory parameters including serum chemistry, hematology, coagulation, and urinalysis. The investigator was responsible for reviewing laboratory results for clinically significant abnormalities. | Baseline to Week 54 (of LTE) | 
| Main Study: Number of Participants With Clinically Significant Abnormal Vital Signs | Parameters assessed for vital signs included blood pressure (systolic and diastolic blood pressure), heart rate (HR), body temperature, and respiratory rate. The investigator was responsible for reviewing vital signs for clinically significant abnormalities. | Baseline to Week 14 | 
| LTE Study: Number of Participants With Clinically Significant Abnormal Vital Signs | Parameters assessed for vital signs included blood pressure (systolic and diastolic blood pressure), HR, body temperature, and respiratory rate. The investigator was responsible for reviewing vital signs for clinically significant abnormalities. | Baseline to Week 54 (of LTE) | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Main Study: Percentage of Participants Achieving a Greater Than or Equal to (>=) 30% Improvement in AAPS at Week 12 | The percentage of participants achieving a >= 30% improvement in AAPS from Baseline at Week 12 was analyzed using a Cochran-Mantel-Haenszel (CMH) test stratified by the stratification factors. Missing post-baseline AAPS data was imputed using multiple imputation (MI) under the missing at random (MAR) assumption. Participants who were randomized but did not have at least 1 post-Baseline observation were considered non-responders. A >= 30% improvement in AAPS was a reduction in AAPS of 30% or more when compared to Baseline AAPS. | Baseline and Week 12 | 
| Main Study: Percentage of Participants Achieving a >= 30% Improvement in AAPS From Baseline for at Least 6 of the 12 Weeks | The percentage of participants achieving a >= 30% improvement in AAPS from Baseline for at least 6 of the 12 weeks during the Treatment Period were analyzed using a CMH test stratified by the stratification factors. A >= 30% improvement in AAPS is a reduction in AAPS of 30% or more when compared to Baseline AAPS. Missing post-baseline AAPS data was imputed using MI under the MAR assumption. | Baseline and Week 12 | 
| Main Study: Percent Change From Baseline in AAPS at Week 12 | The percent change in AAPS from Baseline at Week 12 was analyzed using an MMRM analysis with treatment, stratification factors, week, and treatment-by-week interaction as factors and Baseline AAPS as a covariate. Baseline is the last non-missing measurement collected prior to the first dose of study treatment at Day 1. | Baseline and Week 12 | 
| Main Study: Change From Baseline in Number of Pain-Free Days at Week 12 | The change from Baseline at Week 12 in number of pain-free days per week was analyzed using a MMRM analysis with treatment, stratification factors, week, and treatment-by-week interaction as factors and Baseline pain free days as a covariate. Pain-free days were defined as days with a pain score of zero (0). Baseline is the last non-missing measurement collected prior to the first dose of study treatment at Day 1. | Baseline and Week 12 | 
| Main Study: Maximum Concentration (Cmax) of Olorinab | Blood samples were collected from participants at indicated timepoints after the administration of study treatment to investigate Cmax of Olorinab. Pharmacokinetic (PK) analysis was conducted using standard non-compartmental methods. | On Day 1: Pre-dose and 0.5, 1, 2, 4, and 8 hours post dose and Week 4: Pre-dose and 0.5, 1 and 2 hours post dose | 
| Main Study: Time of Maximum Concentration After Drug Administration (Tmax) of Olorinab | Blood samples were collected from participants at indicated timepoints after the administration of study treatment to investigate Tmax of Olorinab. PK analysis was conducted using standard non-compartmental methods. | On Day 1: Pre-dose and 0.5, 1, 2, 4, and 8 hours post dose and Week 4: Pre-dose and 0.5, 1 and 2 hours post dose | 
| Main Study: Plasma Trough Concentrations (Ctrough) of Olorinab | Blood samples were collected from participants at indicated time frames after the administration of study treatment to investigate Ctrough of Olorinab. PK analysis was conducted using standard non-compartmental methods. | Pre dose on Day 1, Day 2 and Weeks 2, 4, 8, 10 and 12 | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Abdominal pain, IBS-C (IBS with predominant constipation), IBS-D (IBS with predominant diarrhea), Olorinab, APD371, Irritable bowel syndrome (IBS)