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

The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been evaluated by the U.S. Federal Government. Read our disclaimer for details. Identifier: NCT01696643
Recruitment Status : Terminated (A review of blinded data indicates that the number of participant exposures needed to reach ICH standards has been met)
First Posted : October 1, 2012
Results First Posted : September 28, 2015
Last Update Posted : February 3, 2016
Information provided by (Responsible Party):
Cubist Pharmaceuticals LLC

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.

Condition or disease Intervention/treatment Phase
Opioid-Induced Constipation Drug: CB-5945 Drug: Placebo Phase 3

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.

Study Type : Interventional  (Clinical Trial)
Actual Enrollment : 1407 participants
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Triple (Participant, Investigator, Outcomes Assessor)
Primary Purpose: Treatment
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 Start Date : October 2012
Actual Primary Completion Date : June 2014
Actual Study Completion Date : October 2014

Resource links provided by the National Library of Medicine

MedlinePlus related topics: Constipation

Arm Intervention/treatment
Experimental: CB-5945
0.25 milligrams (mg) CB-5945, administered orally, twice daily (BID) for 52 weeks
Drug: CB-5945
Other Name: Bevenopran

Placebo Comparator: Placebo
Placebo, administered orally, BID for 52 weeks
Drug: Placebo

Primary Outcome Measures :
  1. Percentage of Participants With Treatment-Emergent Adverse Events (TEAEs) [ Time Frame: Baseline through Week 56 ]
    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 :
  1. Change From Baseline in Mean Daily Opioid Dose at Weeks 49-52 [ Time Frame: Baseline, 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.

  2. Change From Baseline in Patient Assessment of Constipation-Quality of Life (PAC-QOL) Questionnaire at Week 52 [ Time Frame: Baseline, 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.

  3. Change From Baseline in Patient-Reported Constipation Severity Assessment (PCSA) at Week 52 [ Time Frame: Baseline, 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.

  4. Plasma Trough Concentrations of CB-5945 [ Time Frame: Weeks 4, 12, 24, 36, and 52 ]
    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.

Other Outcome Measures:
  1. Number of Participants With Adjudicated Cardiovascular, Gastrointestinal, or Central Opioid Withdrawal Events [ Time Frame: Baseline through Week 56 ]

    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.

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Ages Eligible for Study:   18 Years to 80 Years   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No

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)

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its identifier (NCT number): NCT01696643

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Sponsors and Collaborators
Cubist Pharmaceuticals LLC
Study Director: Medical Monitor Cubist Pharmaceuticals LLC

Responsible Party: Cubist Pharmaceuticals LLC Identifier: NCT01696643     History of Changes
Other Study ID Numbers: 2402-006
5945-SOIC-12-05 ( Other Identifier: Cubist Study Number )
First Posted: October 1, 2012    Key Record Dates
Results First Posted: September 28, 2015
Last Update Posted: February 3, 2016
Last Verified: January 2016

Keywords provided by Cubist Pharmaceuticals LLC:

Additional relevant MeSH terms:
Signs and Symptoms, Digestive
Signs and Symptoms
Analgesics, Opioid
Central Nervous System Depressants
Physiological Effects of Drugs
Sensory System Agents
Peripheral Nervous System Agents