Opioid-Induced Constipation
Conditions
Keywords
Opioid, Constipation, Chronic, Pain
Brief summary
The purpose of this study is to evaluate the safety and efficacy of CB-5945 for the treatment of opioid-induced constipation (OIC)in adults taking opioid therapy for chronic non-cancer pain.
Detailed description
This is a multicenter, double-blind, placebo-controlled, parallel-group study in participants with OIC taking opioid therapy for chronic non-cancer pain. Approximately 600 participants (300 participants per treatment group) with OIC will be randomized at approximately 75 study centers to receive either oral 0.25 mg CB-5945 BID or oral matching placebo BID for the 12-week double-blind treatment period, followed by a 4-week follow-up period. All randomized participants will be evaluated for clinical response for duration of their study participation. All participants will be followed for safety for 4 weeks after last dose of the study medication, regardless of when they discontinue study medication. The clinical study report for this study includes pooled results for studies 5945-OIC-12-02 (NCT01901302) 5945-OIC-12-03 (NCT01901328), and 5945-OIC-12-04 (NCT01901341).
Interventions
DRUGCB-5945
DRUGPlacebo
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
TRIPLE (Subject, Investigator, Outcomes Assessor)
Eligibility
Sex/Gender
ALL
Age
18 Years to 80 Years
Healthy volunteers
No
Inclusion criteria
Key Inclusion Criteria: * Is taking a stable daily dose of opioids of ≥30 mg morphine equivalent total daily dose (METDD) for chronic non-cancer pain * Has constipation that is caused by the chronic use of opioids * Is willing to use only the study provided laxative(s) and to discontinue use of all other laxatives, enemas, stool softeners, and other medications to treat constipation (e.g., lubiprostone) from Screening until the last study assessment Key
Exclusion criteria
* Has gastrointestinal (GI) or pelvic disorders known to affect bowel transit (for example \[e.g.\], obstruction) or contribute to bowel dysfunction * Has evidence of intestinal obstruction * Has a history of rectal bleeding not due to hemorrhoids or fissures within 6 months of screening * Has an active malignancy of any type (participants with a history of successfully treated malignancy \>5 years before the scheduled administration of study medication and participants with treated basal or squamous cell cancer may be enrolled) * Is taking antispasmodics (e.g., dicyclomine), antidiarrheals (e.g., loperamide), prokinetics (e.g., metoclopramide), or locally acting chloride channel activators (e.g., lubiprostone) * Is taking non-opioid medications known to cause constipation (e.g., iron sulfate therapy, tricyclic antidepressants)
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Overall Spontaneous Bowel Movement (SBM) Responder Rates at 12-weeks | 12 weeks | A Spontaneous Bowel Movement (SBM) Weekly Responder (calculated for each week of the 12-week double-blind treatment period) is a participant who has ≥ 3 SBMs for the week and an increase from baseline of ≥1 SBM for the specified week, based on at least 4 Available Data Days (ADDs) during the week. For the definition of the primary efficacy endpoint, Overall SBM Responder is a participant who is a Weekly SBM Responder for 9 of the 12 weeks of the double-blind treatment period, including 3 of the last 4 weeks (Weeks 9, 10, 11 and 12). |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Change From Baseline of Chronic Opioid-Related Gastrointestinal Symptom Scale (CORGISS) Scores at 12 Weeks | Baseline, 12 weeks | The CORGISS is designed to assess GI symptoms related to opioid use in patients with chronic non-cancer pain. The CORGISS asks participants to rate the severity of GI symptoms over the previous 24 hours, with answers ranging from 0 (did not experience) to 4 (very severe). |
| Overall Complete Spontaneous Bowel Movement (CSBM) Responder Rates at 12 Weeks | 12 weeks | A CSBM Weekly Responder is a subject who has ≥ 3 CSBMs for the specified week and an increase from baseline of ≥1 CSBM for the week. An Overall CSBM Responder is a subject who is a Weekly CSBM Responder for 9 of the 12 weeks of the double-blind treatment period, including 3 of the last 4 weeks (Weeks 9, 10, 11 and 12). |
Other
| Measure | Time frame | Description |
|---|---|---|
| Adjudicated Cardiovascular, Gastrointestinal and Central Opioid Withdrawal Events | Baseline through 16 weeks | Cardiovascular (CV) events of interested included myocardial infarction, unstable angina, cardiovascular accident, congestive heart failure, serious arrhythmia, resuscitated cardiac arrest, and death. Gastrointestinal (GI) events of interest included emergency department visits for SAEs of gastroenteritis, hepatitis, pancreatitis, nausea, vomiting, diarrhea, and abdominal pain or cramping. Central opioid withdrawal events of interest included opioid withdrawal syndrome. |
Participant flow
Recruitment details
Due to difficulties with enrollment, this study was terminated early.
Participants by arm
| Arm | Count |
|---|---|
| CB-5945 0.25 mg CB-5945 administered orally BID for a 12-week treatment period | 26 |
| Placebo Placebo administered orally BID for a 12-week treatment period | 23 |
| Total | 49 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Overall Study | Lack of Efficacy | 0 | 1 |
| Overall Study | Lost to Follow-up | 1 | 0 |
| Overall Study | Physician Decision | 0 | 1 |
| Overall Study | Protocol Violation | 1 | 1 |
| Overall Study | Study Terminated by Sponsor | 19 | 16 |
| Overall Study | Withdrawal by Subject | 1 | 2 |
Baseline characteristics
| Characteristic | CB-5945 | Placebo | Total |
|---|---|---|---|
| Age, Categorical BTWN | 25 Participants | 22 Participants | 47 Participants |
| Age, Categorical GTE65 | 1 Participants | 1 Participants | 2 Participants |
| Age, Categorical LTE18 | 0 Participants | 0 Participants | 0 Participants |
| Sex: Female, Male Female | 19 Participants | 18 Participants | 37 Participants |
| Sex: Female, Male Male | 7 Participants | 5 Participants | 12 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — |
| other Total, other adverse events | 10 / 26 | 4 / 23 |
| serious Total, serious adverse events | 0 / 26 | 0 / 23 |
Outcome results
Primary
Overall Spontaneous Bowel Movement (SBM) Responder Rates at 12-weeks
A Spontaneous Bowel Movement (SBM) Weekly Responder (calculated for each week of the 12-week double-blind treatment period) is a participant who has ≥ 3 SBMs for the week and an increase from baseline of ≥1 SBM for the specified week, based on at least 4 Available Data Days (ADDs) during the week. For the definition of the primary efficacy endpoint, Overall SBM Responder is a participant who is a Weekly SBM Responder for 9 of the 12 weeks of the double-blind treatment period, including 3 of the last 4 weeks (Weeks 9, 10, 11 and 12).
Time frame: 12 weeks
Population: Zero participants were analyzed, and no data was collected for this measure. Due to lack of enrollment, the study was terminated early.
Secondary
Change From Baseline of Chronic Opioid-Related Gastrointestinal Symptom Scale (CORGISS) Scores at 12 Weeks
The CORGISS is designed to assess GI symptoms related to opioid use in patients with chronic non-cancer pain. The CORGISS asks participants to rate the severity of GI symptoms over the previous 24 hours, with answers ranging from 0 (did not experience) to 4 (very severe).
Time frame: Baseline, 12 weeks
Population: Zero participants were analyzed, and no data was collected for this measure. Due to lack of enrollment, the study was terminated early.
Secondary
Overall Complete Spontaneous Bowel Movement (CSBM) Responder Rates at 12 Weeks
A CSBM Weekly Responder is a subject who has ≥ 3 CSBMs for the specified week and an increase from baseline of ≥1 CSBM for the week. An Overall CSBM Responder is a subject who is a Weekly CSBM Responder for 9 of the 12 weeks of the double-blind treatment period, including 3 of the last 4 weeks (Weeks 9, 10, 11 and 12).
Time frame: 12 weeks
Population: Zero participants were analyzed, and no data was collected for this measure. Due to lack of enrollment, the study was terminated early.
Other Pre-specified
Adjudicated Cardiovascular, Gastrointestinal and Central Opioid Withdrawal Events
Cardiovascular (CV) events of interested included myocardial infarction, unstable angina, cardiovascular accident, congestive heart failure, serious arrhythmia, resuscitated cardiac arrest, and death. Gastrointestinal (GI) events of interest included emergency department visits for SAEs of gastroenteritis, hepatitis, pancreatitis, nausea, vomiting, diarrhea, and abdominal pain or cramping. Central opioid withdrawal events of interest included opioid withdrawal syndrome.
Time frame: Baseline through 16 weeks
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| CB-5945 | Adjudicated Cardiovascular, Gastrointestinal and Central Opioid Withdrawal Events | Subjects with at Least One Confirmed CV Event | 0 participants |
| CB-5945 | Adjudicated Cardiovascular, Gastrointestinal and Central Opioid Withdrawal Events | Subjects with at Least One Confirmed GI Event | 0 participants |
| CB-5945 | Adjudicated Cardiovascular, Gastrointestinal and Central Opioid Withdrawal Events | Subjects with at Least One Confirmed OW Event | 0 participants |
| Placebo | Adjudicated Cardiovascular, Gastrointestinal and Central Opioid Withdrawal Events | Subjects with at Least One Confirmed CV Event | 0 participants |
| Placebo | Adjudicated Cardiovascular, Gastrointestinal and Central Opioid Withdrawal Events | Subjects with at Least One Confirmed GI Event | 0 participants |
| Placebo | Adjudicated Cardiovascular, Gastrointestinal and Central Opioid Withdrawal Events | Subjects with at Least One Confirmed OW Event | 0 participants |