Opioid Induced Constipation
Conditions
Keywords
opioid therapy, constipation, chronic noncancer pain, mu opioid receptor antagonist, ADL5945
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.
Interventions
Sponsors
Cubist Pharmaceuticals LLC, a subsidiary of Merck & Co., Inc. (Rahway, New Jersey USA)
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
QUADRUPLE (Subject, Caregiver, Investigator, Outcomes Assessor)
Eligibility
Sex/Gender
ALL
Age
18 Years to 75 Years
Healthy volunteers
No
Inclusion 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
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Change From Baseline in the Weekly Average of Spontaneous Bowel Movements (SBMs) During Treatment | Baseline, Weeks 1 through 4 of 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. |
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| ADL5945 0.1 mg 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 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. | 43 |
| ADL5945 0.25 mg 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. | 45 |
| Placebo 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). | 43 |
| Total | 131 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 | FG002 |
|---|---|---|---|---|
| Double-blind Treatment Period | Adverse Event | 0 | 1 | 0 |
| Double-blind Treatment Period | Lost to Follow-up | 0 | 0 | 1 |
| Double-blind Treatment Period | Protocol Violation | 2 | 1 | 1 |
| Double-blind Treatment Period | Withdrawal by Subject | 1 | 0 | 0 |
Baseline characteristics
| Characteristic | Total | ADL5945 0.1 mg | ADL5945 0.25 mg | Placebo |
|---|---|---|---|---|
| Age, Categorical BTWN | 124 Participants | 40 Participants | 44 Participants | 40 Participants |
| Age, Categorical GTE65 | 7 Participants | 3 Participants | 1 Participants | 3 Participants |
| Age, Categorical LTE18 | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Sex: Female, Male Female | 63 Participants | 20 Participants | 20 Participants | 23 Participants |
| Sex: Female, Male Male | 68 Participants | 23 Participants | 25 Participants | 20 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk |
|---|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — | — / — |
| other Total, other adverse events | 14 / 43 | 19 / 45 | 15 / 43 |
| serious Total, serious adverse events | 0 / 43 | 2 / 45 | 0 / 43 |
Outcome results
Primary
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.
Time frame: Baseline, Weeks 1 through 4 of treatment
Population: All participants who were randomized to study treatment and had at least 1 evaluable SBM post-dose measurement during the Double-blind Period. Last-observation-carried-forward (LOCF) was used to impute missing postbaseline values.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| ADL5945 0.1 mg | Change From Baseline in the Weekly Average of Spontaneous Bowel Movements (SBMs) During Treatment | 1.96 Number of SBMs/week | Standard Error 0.35 |
| ADL5945 0.25 mg | Change From Baseline in the Weekly Average of Spontaneous Bowel Movements (SBMs) During Treatment | 3.42 Number of SBMs/week | Standard Error 0.49 |
| Placebo | Change From Baseline in the Weekly Average of Spontaneous Bowel Movements (SBMs) During Treatment | 1.44 Number of SBMs/week | Standard Error 0.27 |