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

Cubist Pharmaceuticals LLC, a subsidiary of Merck & Co., Inc. (Rahway, New Jersey USA)

Status and phase: Completed; Phase 2

Conditions: Opioid Induced Constipation

Treatments: Drug: Placebo; Drug: ADL5945 0.25 mg; Drug: ADL5945 0.1 mg

Study type: Interventional

Funder types: Industry

Identifiers

NCT01207427

2402-001

45CL242 (Other Identifier)

Details and patient eligibility

About

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.

Enrollment: 131 patients

Sex: All

Ages: 18 to 75 years old

Volunteers: No Healthy Volunteers

Inclusion and exclusion 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

Trial design

Primary purpose: Treatment

Allocation: Randomized

Interventional model: Parallel Assignment

Masking: Quadruple Blind

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131 participants in 3 patient groups, including a placebo group

Placebo

Placebo Comparator group

Description:

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).

Treatment:

Drug: Placebo

ADL5945 0.1 mg

Experimental group

Description:

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.

Treatment:

Drug: Placebo

Drug: ADL5945 0.1 mg

ADL5945 0.25 mg

Experimental group

Description:

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.

Treatment:

Drug: Placebo

Drug: ADL5945 0.25 mg