Safety Study of CB-5945 for the Treatment of Opioid-Induced Constipation
Primary Purpose
Opioid-Induced Constipation
Status
Terminated
Phase
Phase 3
Locations
Study Type
Interventional
Intervention
CB-5945
Placebo
Sponsored by
About this trial
This is an interventional treatment trial for Opioid-Induced Constipation focused on measuring Opioid, Constipation, Chronic, Pain
Eligibility Criteria
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 (for example, lubiprostone) during the study period (from Screening until the last study assessment).
- Is able and willing to refrain from facilitating defecation via manual maneuvers (for example, digital evacuation or support of the pelvic floor) during the study period (from Screening to the last study assessment)
Exclusion Criteria:
- Has gastrointestinal (GI) or pelvic disorders known to affect bowel transit (for example, obstruction) or contribute to bowel dysfunction
- Has evidence of intestinal obstruction
- Has a history of rectal bleeding not due to hemorrhoids or fissures
- 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 (for example, dicyclomine), antidiarrheals (for example, loperamide), prokinetics (for example, metoclopramide), or locally acting chloride channel activators (for example, lubiprostone)
- Is taking non-opioid medications known to cause constipation (for example, iron sulfate therapy or tricyclic antidepressants)
Sites / Locations
Arms of the Study
Arm 1
Arm 2
Arm Type
Experimental
Placebo Comparator
Arm Label
CB-5945
Placebo
Arm Description
0.25 milligrams (mg) CB-5945, administered orally, twice daily (BID) for 52 weeks
Placebo, administered orally, BID for 52 weeks
Outcomes
Primary Outcome Measures
Percentage of Participants With Treatment-Emergent Adverse Events (TEAEs)
A TEAE was defined as any adverse event (AE) that occurred from the time of first dose of the study drug through the last study evaluation or pre-existing AEs that were aggravated in severity or frequency during the dosing period. The percentages of participants with at least 1 TEAE, with at least 1 drug-related TEAE (drug-related included "possibly related" or "related" as deemed by the Investigator; it also included events if causality was missing), and who discontinued from treatment due to a TEAE are presented. A summary of serious and other non-serious AEs regardless of causality is located in the Reported Adverse Events module.
Secondary Outcome Measures
Change From Baseline in Mean Daily Opioid Dose at Weeks 49-52
Throughout the study, participants were asked to record changes in maintenance opioid consumption and use of opioid analgesics for breakthrough or exacerbation of pain in a paper diary. Opioid consumption (including rescue opioids) of each participant was converted to an oral morphine-equivalent total daily dose (METDD). Opioid consumption (in milligrams of METDD) was summarized in 4-week intervals. The change from baseline to Weeks 49-52 is summarized.
Change From Baseline in Patient Assessment of Constipation-Quality of Life (PAC-QOL) Questionnaire at Week 52
The PAC-QOL questionnaire contains a total of 28 items, each rated within 4 subscales: physical discomfort, psychosocial discomfort, worries and concerns, and satisfaction. Each item was rated on a 5-point Likert scale with the following score definitions, depending on the question: 0 = not at all (or none of the time), 1 = a little bit (or a little of the time), 2 = moderately (or some of the time), 3 = quite a bit (or most of the time), and 4 = extremely (or all of the time). The total score is the mean of all non-missing items. The range of the total score is 0 (response is 'not at all' for each item) to 4 (response is 'extremely' for each item). Negative change from baseline values indicate improvement in constipation quality of life. Each participant completed the PAC-QOL at Baseline and Week 52 using a 2-week recall period.
Change From Baseline in Patient-Reported Constipation Severity Assessment (PCSA) at Week 52
The PCSA asked participants to rate the severity of their overall constipation during the 24 hours prior to the assessment, using a scale of 0 to 10, where 0 is no constipation and 10 is the worst constipation imaginable.
Plasma Trough Concentrations of CB-5945
Blood samples for trough concentrations of CB-5945 were collected before the participant's morning dose of study drug at Weeks 4, 12, 24, 36, and 52. Overall concentration was based on the mean trough level for each participant across all weeks.
Full Information
NCT ID
NCT01696643
First Posted
September 21, 2012
Last Updated
October 17, 2018
Sponsor
Cubist Pharmaceuticals LLC
1. Study Identification
Unique Protocol Identification Number
NCT01696643
Brief Title
Safety Study of CB-5945 for the Treatment of Opioid-Induced Constipation
Official Title
Phase 3 Study to Evaluate the Long-Term Safety and Tolerability of CB-5945 for the Treatment of Opioid-Induced Constipation in Adults Taking Opioid Therapy for Chronic Non-Cancer Pain
Study Type
Interventional
2. Study Status
Record Verification Date
October 2018
Overall Recruitment Status
Terminated
Why Stopped
A review of blinded data indicates that the number of participant exposures needed to reach ICH standards has been met
Study Start Date
October 12, 2012 (Actual)
Primary Completion Date
July 21, 2014 (Actual)
Study Completion Date
July 21, 2014 (Actual)
3. Sponsor/Collaborators
Responsible Party, by Official Title
Sponsor
Name of the Sponsor
Cubist Pharmaceuticals LLC
4. Oversight
5. Study Description
Brief Summary
The purpose of this study is to evaluate the long-term safety and tolerability 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 1,400 participants (approximately 700 participants per treatment group) with OIC will be randomized at approximately 225 study centers to receive either 0.25 milligrams (mg) CB-5945 twice daily (BID) or a matching placebo BID for the 52-week double-blind treatment period, followed by a 4-week follow-up period. All randomized participants will be evaluated for safety, tolerability, and quality of life from the first dose of study drug through Week 56.
6. Conditions and Keywords
Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study
Opioid-Induced Constipation
Keywords
Opioid, Constipation, Chronic, Pain
7. Study Design
Primary Purpose
Treatment
Study Phase
Phase 3
Interventional Study Model
Parallel Assignment
Masking
ParticipantInvestigatorOutcomes Assessor
Allocation
Randomized
Enrollment
1407 (Actual)
8. Arms, Groups, and Interventions
Arm Title
CB-5945
Arm Type
Experimental
Arm Description
0.25 milligrams (mg) CB-5945, administered orally, twice daily (BID) for 52 weeks
Arm Title
Placebo
Arm Type
Placebo Comparator
Arm Description
Placebo, administered orally, BID for 52 weeks
Intervention Type
Drug
Intervention Name(s)
CB-5945
Other Intervention Name(s)
Bevenopran
Intervention Type
Drug
Intervention Name(s)
Placebo
Primary Outcome Measure Information:
Title
Percentage of Participants With Treatment-Emergent Adverse Events (TEAEs)
Description
A TEAE was defined as any adverse event (AE) that occurred from the time of first dose of the study drug through the last study evaluation or pre-existing AEs that were aggravated in severity or frequency during the dosing period. The percentages of participants with at least 1 TEAE, with at least 1 drug-related TEAE (drug-related included "possibly related" or "related" as deemed by the Investigator; it also included events if causality was missing), and who discontinued from treatment due to a TEAE are presented. A summary of serious and other non-serious AEs regardless of causality is located in the Reported Adverse Events module.
Time Frame
Baseline through Week 56
Secondary Outcome Measure Information:
Title
Change From Baseline in Mean Daily Opioid Dose at Weeks 49-52
Description
Throughout the study, participants were asked to record changes in maintenance opioid consumption and use of opioid analgesics for breakthrough or exacerbation of pain in a paper diary. Opioid consumption (including rescue opioids) of each participant was converted to an oral morphine-equivalent total daily dose (METDD). Opioid consumption (in milligrams of METDD) was summarized in 4-week intervals. The change from baseline to Weeks 49-52 is summarized.
Time Frame
Baseline, Weeks 49-52
Title
Change From Baseline in Patient Assessment of Constipation-Quality of Life (PAC-QOL) Questionnaire at Week 52
Description
The PAC-QOL questionnaire contains a total of 28 items, each rated within 4 subscales: physical discomfort, psychosocial discomfort, worries and concerns, and satisfaction. Each item was rated on a 5-point Likert scale with the following score definitions, depending on the question: 0 = not at all (or none of the time), 1 = a little bit (or a little of the time), 2 = moderately (or some of the time), 3 = quite a bit (or most of the time), and 4 = extremely (or all of the time). The total score is the mean of all non-missing items. The range of the total score is 0 (response is 'not at all' for each item) to 4 (response is 'extremely' for each item). Negative change from baseline values indicate improvement in constipation quality of life. Each participant completed the PAC-QOL at Baseline and Week 52 using a 2-week recall period.
Time Frame
Baseline, Week 52
Title
Change From Baseline in Patient-Reported Constipation Severity Assessment (PCSA) at Week 52
Description
The PCSA asked participants to rate the severity of their overall constipation during the 24 hours prior to the assessment, using a scale of 0 to 10, where 0 is no constipation and 10 is the worst constipation imaginable.
Time Frame
Baseline, Week 52
Title
Plasma Trough Concentrations of CB-5945
Description
Blood samples for trough concentrations of CB-5945 were collected before the participant's morning dose of study drug at Weeks 4, 12, 24, 36, and 52. Overall concentration was based on the mean trough level for each participant across all weeks.
Time Frame
Weeks 4, 12, 24, 36, and 52
Other Pre-specified Outcome Measures:
Title
Number of Participants With Adjudicated Cardiovascular, Gastrointestinal, or Central Opioid Withdrawal Events
Description
Cardiovascular (CV) events of interested included mycardial infarction, unstable angina, CV accident, congestive heart failure, serious arrhythmia, resuscitated cardiac arrest, and death.
Gastrointestinal (GI) events of interest included emergency department visits for the serious adverse events of gastroenteritis, hepatitis, pancreatitis, nausea, vomiting, diarrhea, and abdominal pain or cramping.
Central opioid withdrawal (OW) events of interest included opioid withdrawal syndrome. The adverse events that indicated central OW included, but were not limited to, hyperhidrosis, tremor, dysphoria, and myalgia.
The number of participants with at least 1 confirmed CV, GI, or Central OW event is presented.
Time Frame
Baseline through Week 56
10. Eligibility
Sex
All
Minimum Age & Unit of Time
18 Years
Maximum Age & Unit of Time
80 Years
Accepts Healthy Volunteers
No
Eligibility Criteria
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 (for example, lubiprostone) during the study period (from Screening until the last study assessment).
Is able and willing to refrain from facilitating defecation via manual maneuvers (for example, digital evacuation or support of the pelvic floor) during the study period (from Screening to the last study assessment)
Exclusion Criteria:
Has gastrointestinal (GI) or pelvic disorders known to affect bowel transit (for example, obstruction) or contribute to bowel dysfunction
Has evidence of intestinal obstruction
Has a history of rectal bleeding not due to hemorrhoids or fissures
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 (for example, dicyclomine), antidiarrheals (for example, loperamide), prokinetics (for example, metoclopramide), or locally acting chloride channel activators (for example, lubiprostone)
Is taking non-opioid medications known to cause constipation (for example, iron sulfate therapy or tricyclic antidepressants)
Overall Study Officials:
First Name & Middle Initial & Last Name & Degree
Medical Monitor
Organizational Affiliation
Cubist Pharmaceuticals LLC
Official's Role
Study Director
12. IPD Sharing Statement
Plan to Share IPD
Yes
IPD Sharing Plan Description
https://www.merck.com/clinical-trials/pdf/ProcedureAccessClinicalTrialData.pdf
IPD Sharing URL
http://engagezone.msd.com/ds_documentation.php
Learn more about this trial
Safety Study of CB-5945 for the Treatment of Opioid-Induced Constipation
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