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

• Sponsor: Cubist Pharmaceuticals LLC (Industry)
• Overall Status: Terminated
• CT.gov ID: NCT01901341
• Collaborator: (none)
• Enrollment: 44
• Arms: 2
• Actual Duration (Months): 7.4

Study Details

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.

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 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 Design

• Study Type: Interventional
• Actual Enrollment: 44 participants
• Allocation: Randomized
• Intervention Model: Parallel Assignment
• Masking: Triple (Participant, Investigator, Outcomes Assessor)
• Primary Purpose: Treatment
• Official Title: A 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
• Actual Study Start Date: Jul 2, 2013
• Actual Primary Completion Date: Feb 13, 2014
• Actual Study Completion Date: Feb 13, 2014

Arms and Interventions

Arm	Intervention/Treatment
Experimental: CB-5945 0.25 milligrams (mg) CB-5945 administered orally twice daily (BID) for a 12-week treatment period	Drug: CB-5945; Other Names: Bevenopran ADL5945
Placebo Comparator: Placebo Placebo administered orally BID for a 12-week treatment period	Drug: Placebo

Outcome Measures

Primary Outcome Measures

1. Overall Spontaneous Bowel Movement (SBM) Responder Rates at the 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 Outcome Measures

1. 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").

2. 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 Outcome Measures

1. 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.

Eligibility Criteria

Criteria

• Ages Eligible for Study: 18 Years to 80 Years
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

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)

Contacts and Locations

Locations

No locations specified.

Sponsors and Collaborators

• Cubist Pharmaceuticals LLC

Investigators

None specified.

Study Documents (Full-Text)

None provided.

More Information

Publications

None provided.

• Responsible Party: Cubist Pharmaceuticals LLC
• ClinicalTrials.gov Identifier: NCT01901341
• Other Study ID Numbers: 2402-005; 5945-OIC-12-04
• First Posted: Jul 17, 2013
• Last Update Posted: Nov 15, 2018
• Last Verified: Oct 1, 2018

• Individual Participant Data (IPD) Sharing Statement: Yes
• Plan to Share IPD: Yes
• Keywords provided by Cubist Pharmaceuticals LLC: Opioid; Constipation; Chronic; Pain
• Additional relevant MeSH terms: Constipation; Opioid-Induced Constipation

Study Results

Participant Flow

Recruitment Details	Due to difficulties with enrollment, this study was terminated early.

Arm/Group Title	CB-5945	Placebo
Arm/Group Description	0.25 mg CB-5945 administered orally BID for a 12-week treatment period	Placebo administered orally BID for a 12-week treatment period
Period Title: Overall Study
STARTED	22	22
Received at Least 1 Dose of Study Drug	22	22
COMPLETED	2	1
NOT COMPLETED	20	21

Baseline Characteristics

Arm/Group Title	CB-5945	Placebo	Total
Arm/Group Description	0.25 mg CB-5945 administered orally BID for a 12-week treatment period	Placebo administered orally BID for a 12-week treatment period	Total of all reporting groups
Overall Participants	22	22	44
Age (Count of Participants)
LTE18	0 0%	0 0%	0 0%
BTWN	20 90.9%	22 100%	42 95.5%
GTE65	2 9.1%	0 0%	2 4.5%
Sex: Female, Male (Count of Participants)
Female	13 59.1%	16 72.7%	29 65.9%
Male	9 40.9%	6 27.3%	15 34.1%

Outcome Measures

1. Primary Outcome

Title	Overall Spontaneous Bowel Movement (SBM) Responder Rates at the 12-weeks
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

Outcome Measure Data

Analysis Population Description

Zero participants were analyzed, and no data was collected for this measure. Due to lack of enrollment, the study was terminated early.

Arm/Group Title	CB-5945	Placebo
Arm/Group Description	0.25 mg CB-5945 administered orally BID for a 12-week treatment period	Placebo administered orally BID for a12-week treatment period
Measure Participants	0	0

2. Secondary Outcome

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

Outcome Measure Data

Analysis Population Description

Zero participants were analyzed, and no data was collected for this measure. Due to lack of enrollment, the study was terminated early.

Arm/Group Title	CB-5945	Placebo
Arm/Group Description	0.25 mg CB-5945 administered orally BID for a 12-week treatment period	Placebo administered orally BID for a 12-week treatment period
Measure Participants	0	0

3. Secondary Outcome

Title	Overall Complete Spontaneous Bowel Movement (CSBM) Responder Rates at 12 Weeks
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

Outcome Measure Data

Analysis Population Description

Zero participants were analyzed, and no data was collected for this measure. Due to lack of enrollment, the study was terminated early.

Arm/Group Title	CB-5945	Placebo
Arm/Group Description	0.25 mg CB-5945 administered orally BID for a 12-week treatment period	Placebo administered orally BID for a 12-week treatment period
Measure Participants	0	0

4. Other Pre-specified Outcome

Title	Cardiovascular, Gastrointestinal and Central Opioid Withdrawal Events
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

Outcome Measure Data

Analysis Population Description

All participants randomized to treatment who received ≥ 1 dose of double-blind study medication.

Arm/Group Title	CB-5945	Placebo
Arm/Group Description	0.25 mg CB-5945 administered orally BID for a 12-week treatment period	Placebo administered orally BID for a 12-week treatment period
Measure Participants	22	22
Subjects with at Least One Confirmed CV Event	0 0%	0 0%
Subjects with at Least One Confirmed GI Event	0 0%	0 0%
Subjects with at Least One Confirmed OW Event	0 0%	0 0%

Adverse Events

Time Frame	Baseline through 16 weeks
Adverse Event Reporting Description	SAEs that occurred before the first dose of double-blind study medication were only included in the safety database.
Arm/Group Title	CB-5945		Placebo
Arm/Group Description	0.25 mg CB-5945 administered orally BID for a 12-week treatment period		Placebo administered orally BID for a 12-week treatment period
All Cause Mortality
	CB-5945		Placebo
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	/ (NaN)		/ (NaN)
Serious Adverse Events
	CB-5945		Placebo
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	1/22 (4.5%)		1/22 (4.5%)
Neoplasms benign, malignant and unspecified (incl cysts and polyps)
Colon cancer	1/22 (4.5%)	1	0/22 (0%)	0
Vascular disorders
Hypotension	0/22 (0%)	0	1/22 (4.5%)	1
Other (Not Including Serious) Adverse Events
	CB-5945		Placebo
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	14/22 (63.6%)		10/22 (45.5%)
Blood and lymphatic system disorders
Anaemia	0/22 (0%)	0	1/22 (4.5%)	1
Endocrine disorders
Adrenal insufficiency	0/22 (0%)	0	1/22 (4.5%)	1
Eye disorders
Blepharospasm	1/22 (4.5%)	1	0/22 (0%)	0
Lacrimation increased	1/22 (4.5%)	1	0/22 (0%)	0
Conjunctivitis	1/22 (4.5%)	1	1/22 (4.5%)	1
Foreign body sensation in eyes	1/22 (4.5%)	1	0/22 (0%)	0
Gastrointestinal disorders
Abdominal pain	3/22 (13.6%)	3	0/22 (0%)	0
Abdominal pain lower	0/22 (0%)	0	1/22 (4.5%)	1
Constipation	1/22 (4.5%)	1	0/22 (0%)	0
Diarrhoea	5/22 (22.7%)	5	0/22 (0%)	0
Nausea	0/22 (0%)	0	2/22 (9.1%)	2
Proctalgia	1/22 (4.5%)	1	0/22 (0%)	0
Vomiting	1/22 (4.5%)	1	1/22 (4.5%)	1
Abdominal distension	1/22 (4.5%)	1	1/22 (4.5%)	1
General disorders
Chest discomfort	1/22 (4.5%)	1	0/22 (0%)	0
Chills	1/22 (4.5%)	1	0/22 (0%)	0
Fatigue	1/22 (4.5%)	1	0/22 (0%)	0
Pain	1/22 (4.5%)	1	0/22 (0%)	0
Pyrexia	0/22 (0%)	0	1/22 (4.5%)	1
Infections and infestations
Bronchitis	1/22 (4.5%)	1	1/22 (4.5%)	1
Gastroenteritis viral	1/22 (4.5%)	1	0/22 (0%)	0
Upper respiratory tract infection	1/22 (4.5%)	2	3/22 (13.6%)	3
Urinary tract infection	0/22 (0%)	0	2/22 (9.1%)	2
Injury, poisoning and procedural complications
Foot fracture	0/22 (0%)	0	1/22 (4.5%)	1
Investigations
Hepatic enzyme increased	1/22 (4.5%)	1	0/22 (0%)	0
Weight decreased	1/22 (4.5%)	1	0/22 (0%)	0
Weight increased	0/22 (0%)	0	1/22 (4.5%)	1
Musculoskeletal and connective tissue disorders
Back pain	1/22 (4.5%)	1	0/22 (0%)	0
Muscle twitching	1/22 (4.5%)	1	0/22 (0%)	0
Nervous system disorders
Headache	2/22 (9.1%)	2	0/22 (0%)	0
Hypoaesthesia	1/22 (4.5%)	1	0/22 (0%)	0
Migraine	1/22 (4.5%)	1	0/22 (0%)	0
Neuropathy peripheral	1/22 (4.5%)	1	0/22 (0%)	0
Somnolence	1/22 (4.5%)	1	0/22 (0%)	0
Tremor	2/22 (9.1%)	2	0/22 (0%)	0
Psychiatric disorders
Depression	1/22 (4.5%)	1	0/22 (0%)	0
Renal and urinary disorders
Pollakiuria	1/22 (4.5%)	1	0/22 (0%)	0
Urinary incontinence	1/22 (4.5%)	1	0/22 (0%)	0
Respiratory, thoracic and mediastinal disorders
Rhinorrhoea	1/22 (4.5%)	1	0/22 (0%)	0
Nasal congestion	0/22 (0%)	0	1/22 (4.5%)	1
Skin and subcutaneous tissue disorders
Hyperhidrosis	2/22 (9.1%)	2	0/22 (0%)	0
Night sweats	1/22 (4.5%)	1	0/22 (0%)	0
Rash pruritic	0/22 (0%)	0	1/22 (4.5%)	1
Skin reaction	1/22 (4.5%)	1	0/22 (0%)	0
Rash	1/22 (4.5%)	1	0/22 (0%)	0

Limitations/Caveats

Due to difficulties with enrollment, the study was terminated early.

More Information

Certain Agreements

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