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

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.

• Drug: Placebo
  twice daily
• Drug: ADL5945 0.1 mg
  twice daily
• Drug: ADL5945 0.25 mg
  twice daily

• Placebo Comparator: Placebo
  Intervention: Drug: Placebo
• Experimental: ADL5945 0.1 mg
  Intervention: Drug: ADL5945 0.1 mg
• Experimental: ADL5945 0.25 mg
  Intervention: Drug: ADL5945 0.25 mg

Key Inclusion Criteria

• be a man or woman aged 18 to 75 years, inclusive, at the time of screening
• have a body weight ≥ 45 kg and a body mass index (BMI) ≤ 40 kg/m2
• be taking a stable daily dose of opioids of ≥ 30-mg morphine-equivalent total daily dose for chronic noncancer pain for ≥ 30 days before screening
• have OIC by history and based on the data collected during the 1-week screening period: subjects must have < 3 SBMs per week and have experienced ≥ 1 other BM symptom (ie, 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 (subjects 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 MOR antagonist, including opioids in combination with naloxone, naltrexone, or methylnaltrexone bromide
• be taking medical marijuana for pain
• have 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, 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