Efficacy and Safety Study of CB-5945 for the Treatment of Opioid-Induced Constipation

ID: NCT01901328
Status: Terminated
Phase: Phase 3
Start Date: August 01, 2013
First Submitted: July 09, 2013
Last Updated: January 05, 2016
Results: Available
Success Rate: 12%
Sponsors & Collaborators: Cubist Pharmaceuticals LLC
Location: Canada, United States
Conditions: Opioid-Induced Constipation
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Study Description

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).
Condition or disease Intervention/treatment Phase

Opioid-Induced Constipation

Drug: CB-5945
Other Names
Bevenopran ADL5945
Drug: Placebo
Other Names
Phase 3

Tracking Information

First Submitted DateJuly 09, 2013
Last Update Posted DateJanuary 05, 2016
Start DateAugust 01, 2013
Actual Completion DateApril 01, 2014
Primary Completion DateFebruary 01, 2014
Results First Submitted DateApril 19, 2015
Received Results Disposit DateN/A

Current Primary Outcome Measures

  • Overall Spontaneous Bowel Movement (SBM) Responder Rates at 12-weeks [Time Frame: 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).

Original Primary Outcome Measures

  • 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).

Current Secondary Outcome Measures

  • Change From Baseline of Chronic Opioid-Related Gastrointestinal Symptom Scale (CORGISS) Scores at 12 Weeks [Time Frame: 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 [Time Frame: 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).

Original Secondary Outcome Measures

  • 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).

  • 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”).

Study Design

Brief TitleEfficacy and Safety Study of CB-5945 for the Treatment of Opioid-Induced Constipation
Official TitleA Multicenter, Randomized, Double-Blind, Placebo-Controlled, Phase 3 Study to Evaluate the Efficacy and Safety of CB-5945 for the Treatment of Opioid-Induced Constipation in Adults Taking Opioid Therapy for Chronic Non-Cancer 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).

Study TypeInterventional
Study PhasePhase 3
Estimated Enrollment
49
Allocation
Randomized
Interventional Model
Parallel Assignment
Masking
Triple
Primary Purpose
Treatment
Conditions
Opioid-Induced Constipation
Target Follow-Up Duration N/A
Biospecimen:
N/A
Sampling MethodN/A
Study PopulationN/A
Intervention
Drug: CB-5945

Other Names
Bevenopran
ADL5945
Drug: Placebo

Other Names
Study Groups/Cohorts
CB-5945
0.25 milligrams (mg) CB-5945 administered orally twice dailly (BID) for a 12-week treatment period

Placebo
Placebo administered orally BID for a 12-week treatment period

Study Arms
Experimental CB-5945
0.25 milligrams (mg) CB-5945 administered orally twice dailly (BID) for a 12-week treatment period
Drug : CB-5945

Placebo Comparator Placebo
Placebo administered orally BID for a 12-week treatment period
Drug : Placebo

Arm Intervention/Treatment
Experimental CB-5945
0.25 milligrams (mg) CB-5945 administered orally twice dailly (BID) for a 12-week treatment period
Drug : CB-5945
Placebo Comparator Placebo
Placebo administered orally BID for a 12-week treatment period
Drug : Placebo

Recruitment Information

Recruitment Status:Terminated
Enrollment49
Completion DateApril 01, 2014
Eligibility 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)
GenderAll
Age18 Years to 80 Years
Accepts Healthy VolunteersNo
Contacts
Not Available
Listed Location Countries
Canada
United States

Administrative Information

NCT Number:NCT01901328
Other Study ID Numbers
2402-004
5945-OIC-12-03
Has Data Monitoring CommitteeYes
U.S. FDA-regulated Product Studies a U.S. FDA-regulated Drug Product: No
Studies a U.S. FDA-regulated Device Product: No
Device Product Not Approved or Cleared by U.S. FDA: No
IPD Sharing Statement
Not Available
Responsible Party,
Study Sponsor
Cubist Pharmaceuticals LLC
Collaborators
Not Available
Investigators
Not Available

Participant Flow

Recruitment Details

Key information relevant to the recruitment process for the overall study, such as dates of the recruitment period and locations
Due to difficulties with enrollment, this study was terminated early.

Pre-Assignment Details

Significant events and approaches for the overall study following participant enrollment, but prior to group assignment
Not Available

Reporting Groups

TitleDescription
CB-5945
0.25 milligrams (mg) CB-5945 administered orally twice dailly (BID) for a 12-week treatment period
Placebo
Placebo administered orally BID for a 12-week treatment period

Participant Flow: Overall

CB-5945Placebo
2623
Started2623
Completed42
Not Completed2221
Lack of Efficacy01
Lost to Follow-up10
Physician Decision01
Protocol Violation11
Study Terminated by Sponsor1916
Withdrawal by Subject12

Baseline Characteristics

Population Description

Explanation of how the number of participants for analysis was determined. Includes whether analysis was per protocol, intention to treat, or another method. Also provides relevant details such as imputation technique, as appropriate.
All participants randomized to treatment who received ≥ 1 dose of double-blind study medication.

Reporting Groups

TitleDescription
CB-5945
0.25 mg CB-5945 administered orally BID for a 12-week treatment period
Placebo
Placebo administered orally BID for a 12-week treatment period
Total
Total of all reporting groups

Baseline Measures

CB-5945PlaceboTotal
Overall Participants Analyzed
Units: Participants
Participants Analyzed
262349
262349
Age
Units: participants - Number
Participants Analyzed
262349
<=18 years000
>=65 years112
Between 18 and 65 years252247
Gender
Units: participants - Number
Participants Analyzed
262349
Female191837
Male7512

Outcome Measures

1. Primary: Overall Spontaneous Bowel Movement (SBM) Responder Rates at 12-weeks

Measure Type
Primary
Measure Title
Overall Spontaneous Bowel Movement (SBM) Responder Rates at 12-weeks
Measure Description
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 Description

Explanation of how the number of participants for analysis was determined. Includes whether analysis was per protocol, intention to treat, or another method. Also provides relevant details such as imputation technique, as appropriate.
Zero participants were analyzed, and no data was collected for this measure. Due to lack of enrollment, the study was terminated early.

Reporting Groups

TitleDescription
CB-5945
0.25 mg CB-5945 administered orally BID for a 12-week treatment period
Placebo
Placebo administered orally BID for a 12-week treatment period

Outcome Measures

CB-5945Placebo
Participants Analyzed
Units: Participants
00

2. Secondary: Change From Baseline of Chronic Opioid-Related Gastrointestinal Symptom Scale (CORGISS) Scores at 12 Weeks

Measure Type
Secondary
Measure Title
Change From Baseline of Chronic Opioid-Related Gastrointestinal Symptom Scale (CORGISS) Scores at 12 Weeks
Measure Description
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 Description

Explanation of how the number of participants for analysis was determined. Includes whether analysis was per protocol, intention to treat, or another method. Also provides relevant details such as imputation technique, as appropriate.
Zero participants were analyzed, and no data was collected for this measure. Due to lack of enrollment, the study was terminated early.

Reporting Groups

TitleDescription
CB-5945
0.25 mg CB-5945 administered orally BID for a 12-week treatment period
Placebo
Placebo administered orally BID for a 12-week treatment period

Outcome Measures

CB-5945Placebo
Participants Analyzed
Units: Participants
00

3. Secondary: Overall Complete Spontaneous Bowel Movement (CSBM) Responder Rates at 12 Weeks

Measure Type
Secondary
Measure Title
Overall Complete Spontaneous Bowel Movement (CSBM) Responder Rates at 12 Weeks
Measure Description
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 Description

Explanation of how the number of participants for analysis was determined. Includes whether analysis was per protocol, intention to treat, or another method. Also provides relevant details such as imputation technique, as appropriate.
Zero participants were analyzed, and no data was collected for this measure. Due to lack of enrollment, the study was terminated early.

Reporting Groups

TitleDescription
CB-5945
0.25 mg CB-5945 administered orally BID for a 12-week treatment period
Placebo
Placebo administered orally BID for a 12-week treatment period

Outcome Measures

CB-5945Placebo
Participants Analyzed
Units: Participants
00

4. Other Pre-specified: Adjudicated Cardiovascular, Gastrointestinal and Central Opioid Withdrawal Events

Measure Type
Other Pre-specified
Measure Title
Adjudicated Cardiovascular, Gastrointestinal and Central Opioid Withdrawal Events
Measure Description
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

Population Description

Explanation of how the number of participants for analysis was determined. Includes whether analysis was per protocol, intention to treat, or another method. Also provides relevant details such as imputation technique, as appropriate.
Not Available

Reporting Groups

TitleDescription
CB-5945
0.25 milligrams CB-5945 administered orally BID for a 12-week treatment period
Placebo
Placebo administered orally BID for a 12-week treatment period

Outcome Measures

CB-5945Placebo
Participants Analyzed
Units: Participants
2623
Adjudicated Cardiovascular, Gastrointestinal and Central Opioid Withdrawal Events
Units: participants - Number
Subjects with at Least One Confirmed CV Event00
Subjects with at Least One Confirmed GI Event00
Subjects with at Least One Confirmed OW Event00

Serious Adverse Events

Time Frame
Baseline through 16 weeks
Additional Description
SAEs that occurred before the first dose of double-blind study medication were only included in the safety database.
Frequency Threshold0% (Threshold above which other adverse events are reported)

Reporting Groups

TitleDescription
CB-5945
0.25 mg CB-5945 administered orally BID for a 12-week treatment period
Placebo
Placebo administered orally BID for a 12-week treatment period

Serious Adverse Events

CB-5945Placebo
Total, serious adverse events
No. of participants affected / at risk0/26 (0.00%)0/23 (0.00%)

Other Adverse Events

Time Frame
Baseline through 16 weeks
Additional Description
SAEs that occurred before the first dose of double-blind study medication were only included in the safety database.
Frequency Threshold0% (Threshold above which other adverse events are reported)

Reporting Groups

TitleDescription
CB-5945
0.25 mg CB-5945 administered orally BID for a 12-week treatment period
Placebo
Placebo administered orally BID for a 12-week treatment period

Other Adverse Events

CB-5945Placebo
Total, other adverse events
No. of participants affected / at risk10/26 (0.00%)4/23 (0.00%)
Abdominal pain
No. of participants affected / at risk3/26 (0.00%)0/23 (0.00%)
Diarrhoea
No. of participants affected / at risk1/26 (0.00%)1/23 (0.00%)
Gastrooesophageal reflux disease
No. of participants affected / at risk1/26 (0.00%)0/23 (0.00%)
Nausea
No. of participants affected / at risk1/26 (0.00%)1/23 (0.00%)
Drug withdrawal syndrome
No. of participants affected / at risk1/26 (0.00%)0/23 (0.00%)
Fall
No. of participants affected / at risk1/26 (0.00%)1/23 (0.00%)
Acute sinusitis
No. of participants affected / at risk1/26 (0.00%)0/23 (0.00%)
Bronchitis
No. of participants affected / at risk1/26 (0.00%)0/23 (0.00%)
Nasopharyngitis
No. of participants affected / at risk0/26 (0.00%)1/23 (0.00%)
Oral candidiasis
No. of participants affected / at risk1/26 (0.00%)0/23 (0.00%)
Upper respiratory tract infection
No. of participants affected / at risk0/26 (0.00%)1/23 (0.00%)
Urinary tract infection
No. of participants affected / at risk1/26 (0.00%)1/23 (0.00%)
Rash erythematous
No. of participants affected / at risk1/26 (0.00%)1/23 (0.00%)
Flatulence
No. of participants affected / at risk1/26 (0.00%)1/23 (0.00%)
Type 2 diabetes mellitus
No. of participants affected / at risk0/26 (0.00%)1/23 (0.00%)
Back pain
No. of participants affected / at risk1/26 (0.00%)0/23 (0.00%)
Myalgia
No. of participants affected / at risk0/26 (0.00%)1/23 (0.00%)
Pain in extremity
No. of participants affected / at risk1/26 (0.00%)0/23 (0.00%)
Headache
No. of participants affected / at risk1/26 (0.00%)0/23 (0.00%)
Sensory loss
No. of participants affected / at risk1/26 (0.00%)0/23 (0.00%)

More Information

Certain Agreements

Principal Investigators are NOT employed by the organization sponsoring the study.

Results Point of Contact

Name/TitleOrganizationPhoneEmail
Vice President, Clinical Research
Cubist Pharmaceuticals
(781) 860-8660