Evaluation of the Efficacy and Safety of ADL5945 for the Treatment of Opioid-induced Constipation in Adults Taking Opioid Therapy for Chronic Noncancer Pain

Study Overview
=================
Brief Summary
-----------------
Morphine and related opioid analgesics are known to slow gastrointestinal (GI) motility and reduce intestinal secretion through their binding to μ opioid receptors (MORs) within the GI tract. The most common symptoms associated with the effects of opioids are constipation and nausea and/or vomiting. Moreover, constipation is a common and distressing side effect of long-term opioid therapy. The primary objective of this study was to compare ADL5945, a MOR antagonist, with placebo in the treatment of opioid-induced constipation (OIC) in adults taking long-term opioid therapy for chronic noncancer pain.

Official Title
-----------------
A Randomized, Double-blind, Placebo-controlled, Phase 2 Study to Evaluate the Efficacy and Safety of ADL5945 for the Treatment of Opioid-induced Constipation in Adults Taking Opioid Therapy for Chronic Noncancer Pain

Conditions
-----------------
Opioid Induced Constipation

Intervention / Treatment
-----------------
* Drug: Placebo
* Drug: ADL5945 0.1 mg
* Drug: ADL5945 0.25 mg


Participation Criteria
=================
Eligibility Criteria
-----------------
Key Inclusion Criteria be a man or woman aged 18 to 75 years, inclusive, at the time of screening have a body weight ≥45 kilograms (kg) and a body mass index (BMI) ≤40 kilograms per square meter (kg/m^2) be taking a stable daily dose of opioids of ≥30-milligrams (mg) morphine-equivalent total -daily dose for chronic noncancer pain for ≥30 days before screening have opioid-induced constipation (OIC) by history. Additionally, based on the data collected during the 1-week screening period, participants must have <3 spontaneous bowel movements (SBMs) per week and have experienced ≥1 other bowel movement (BM) symptom (that is, straining to pass a stool, lumpy hard stools or small pellets, or sense of incomplete evacuation after passing a stool) for ≥25% of the total BMs be willing to discontinue use of all laxatives and stool softeners during the study period except as allowed by the protocol Key Exclusion Criteria be pregnant, lactating, or planning to become pregnant during the study have aspartate aminotransferase (AST), alanine aminotransferase (ALT), blood urea nitrogen, or serum creatinine results ≥ 2 times the upper limit of normal have a recent history of myocardial infarction (MI) or unstable angina have an active malignancy of any type be taking opioids primarily for fibromyalgia be taking methadone as a maintenance medication (participants taking methadone for pain may be enrolled) be taking intrathecal opioids for the management of pain be taking tramadol, tapentadol, or any mixed agonist/antagonist opioid analgesics as the sole opioid for analgesia be taking any μ-opioid receptors (MOR) antagonist, including opioids in combination with naloxone, naltrexone, or methylnaltrexone bromide be taking medical marijuana for pain have gastrointestinal (GI) or pelvic disorders known to affect bowel transit, produce GI obstruction, or contribute to bowel dysfunction have taken antispasmodics, antidiarrheals, or prokinetics within 7 days before the start of the screening week be taking nonopioid medications known to cause constipation be taking antidiarrheals and have an incidence or a history of intermittent diarrhea or loose stools be unwilling to abstain from grapefruit and grapefruit-containing products have a history of alcoholism or illicit drug dependence or abuse within 5 years before screening have positive results on a urine drug screen (excluding opioids) that indicate illicit drug use

Ages Eligible for Study
-----------------
Minimum Age: 18 Years
Maximum Age: 75 Years

Sexes Eligible for Study
-----------------
All

Accepts Healthy Volunteers
-----------------
No

Study Plan
=================
How is the study designed?
-----------------

Design Details

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


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Placebo Comparator: Placebo<br>Each participant received 1 placebo capsule orally twice daily (BID) during the Run-in Placebo Period (1 week), the Double-blind Treatment Period (4 weeks), and the Run-out Placebo Period (1 week). | Drug: Placebo<br> <br> |
| Experimental: ADL5945 0.1 mg<br>During the Run-in Placebo Period, each participant received 1 placebo capsule orally BID for 1 week. Then during the Double-blind Treatment Period, each participant received one 0.1-milligrams (mg) ADL5945 capsule orally BID for 4 weeks. Then during the Run-out Placebo Period, each participant received 1 placebo capsule orally BID for 1 week. | Drug: Placebo<br> <br> Drug: ADL5945 0.1 mg<br> <br> |
| Experimental: ADL5945 0.25 mg<br>During the Run-in Placebo Period, each participant received 1 placebo capsule orally BID for 1 week. Then during the Double-blind Treatment Period, each participant received one 0.25-mg ADL5945 capsule orally BID for 4 weeks. Then during the Run-out Placebo Period, each participant received 1 placebo capsule orally BID for 1 week. | Drug: Placebo<br> <br> Drug: ADL5945 0.25 mg<br> <br> |

What is the study measuring?
-----------------
Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change From Baseline in the Weekly Average of Spontaneous Bowel Movements (SBMs) During Treatment | An SBM was defined as a bowel movement (BM) with no laxative use in the previous 24 hours. Each weekly SBM average was calculated as follows: (7 × number of SBMs) / (number of days with nonmissing data). The overall SBM rate for the 4-week double-blind treatment period was calculated as follows: (the average of the first week + the average of the second week + the average of the third week + the average of the fourth week) / 4. | Baseline, Weeks 1 through 4 of treatment | 

 Terms related to the study
=================
Keywords Provided by Centre Hospitalier Valida
-----------------
opioid therapy, constipation, chronic noncancer pain, mu opioid receptor antagonist, ADL5945