Evaluation of the Tolerability of Switching Subjects on Chronic ATC Opioid Therapy to Buprenorphine HCl Buccal Film

An Evaluation of the Tolerability of Switching Subjects on Chronic Around-the-Clock (ATC) Opioid Therapy to Buprenorphine HCl Buccal Film

The primary aim of this study is to determine if chronic pain subjects on around-the-clock opioids who are receiving 100 to 220 mg oral morphine sulfate equivalent (MSE) can be safely transitioned on to buprenorphine hydrochloride (HCl) buccal film at 50% of their MSE dose without inducing opioid withdrawal or reversing analgesic effects.

Study Overview

• Status: Completed
• Conditions: Pain
• Intervention / Treatment: Drug: Buprenorphine; Drug: Placebo film; Drug: Oxycodone; Drug: Morphine sulfate; Drug: Placebo capsule

• Study Type: Interventional
• Enrollment (Actual): 39
• Phase: Phase 2

Contacts and Locations

Study Locations

• United States
  • Kansas
    • Overland Park, Kansas, United States, 66212
      • Vince and Associates Clinical Research, Inc.
  • Pennsylvania
    • Philadelphia, Pennsylvania, United States, 19139
      • CRI Lifetree
  • Utah
    • Salt Lake, Utah, United States, 84106
      • CRI Lifetree (Lifetree Clinical Research)

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years to 60 years (Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

Inclusion Criteria:

1. Written informed consent obtained prior to any study-related procedure being performed
2. Male or non-lactating female subjects 18 to 60 years of age at time of consent
3. Female subjects who are non-pregnant on the basis of screening serum pregnancy test and who are practicing abstinence or using a medically acceptable form of contraception (eg, intrauterine device, hormonal birth control, or double barrier method) or have been post-menopausal, biologically sterile, or surgically sterile (ie, hysterectomy, bilateral oophorectomy, or tubal ligation) for more than 1 year
4. Male subjects who are practicing abstinence, surgically sterile or are using a medically acceptable form of contraception
5. Subjects with a ≥6 months history of chronic pain (including peripheral neuropathic pain) requiring ATC opioid therapy with ≥80 mg but ≤220 mg MSE per day for at least 28 days
6. Receiving one of the following opioids ATC for ≥28 days: (i) Morphine Sulfate; (ii) Oxycodone hydrochloride
7. Displays signs and symptoms of withdrawal (ie, COWS score ≥5) within 5 minutes following naloxone challenge
8. Able to understand the study procedures, complete the assessment scales, and communicate meaningfully with study personnel
9. Stable health, as determined by the Principal Investigator, on the basis of medical history, physical examination, and screening laboratory results

Exclusion Criteria:

1. Inability to meet study participation requirements, including two 2-night stays with pharmacokinetic sampling
2. A history or current evidence of clinically significant pulmonary (eg, asthma, chronic obstructive pulmonary disease, cor pulmonale or severe bronchial asthma ), gastrointestinal, hepatic, renal, hematologic, immunologic, endocrine, neurologic, oncologic or psychiatric disorder or any other condition, including evidence of abnormalities on physical examination, abnormal vital signs, electrocardiogram (ECG), or clinical laboratory values which in the opinion of the Investigator, would jeopardize the safety of the subject or impact the validity of the study results
3. Supine systolic blood pressure >180 mm Hg or <90 mm Hg or diastolic blood pressure > 105 mm Hg or <50 mm Hg at screening (may be repeated once)
4. COWS score greater than 4 prior to the screening naloxone challenge
5. Aspartate aminotransferase or alanine aminotransferase >3 times the upper limits of normal or serum creatinine >1.9 mg/dL at Screening, or any laboratory abnormality which, in the opinion of the Investigator, would contraindicate study participation
6. Use of monoamine oxidase inhibitors within 14 days of screening or during the study
7. Use of any medication, nutraceutical or herbal product with cytochrome P450 3A4 inhibition or induction properties within the past 30 days
8. Donation of 450 mL or more of blood within 30 days prior to screening or a hemoglobin value <11.0 g/dL at screening
9. Documented history of alcohol and/or substance abuse (excluding nicotine and/or caffeine) within 5 years prior to screening, and/or is currently in treatment or is seeking treatment for alcohol and/or substance abuse, as assessed by the Diagnostic and Statistical Manual of Mental Disorders (DSM-IV-TR) criteria
10. Positive alcohol breath test at screening
11. Positive urine toxicology screen for drugs of abuse at screening
12. History of hypersensitivity, allergy, or contraindication to any opioid or clinically significant intolerance to buprenorphine or naloxone
13. History of seizures, convulsions, or increased intra-cranial pressure (history of pediatric febrile seizures is permitted)
14. History of significant head injury within 6 months of screening
15. Any clinically significant abnormality of the buccal mucosa which could impact drug absorption
16. Participation in the treatment phase of a clinical research study involving any investigational drug within 28 days (or 5 elimination half-lives, whichever is longer) of screening
17. Previous participation in this clinical study or any other clinical study involving BEMA buprenorphine (buprenorphine HCl buccal film)
18. In the Investigator's opinion at significant risk for suicidal behavior based on the Columbia Suicide Severity Rating Scale (C-SSRS)
19. Hypokalemia or clinically unstable cardiac disease, including unstable atrial fibrillation, symptomatic bradycardia, unstable congestive heart failure, or active myocardial ischemia
20. History of myocardial infarction
21. Corrected QT interval (QTcF) of ≥450 milliseconds on the 12-lead ECG
22. History of long QT syndrome or a family member with this condition
23. Use of class IA antiarrhythmic medications or class III antiarrhythmic medications within 14 days of screening
24. Current use of α2 agonist antihypertensives (eg, clonidine), 5-HT3 antagonists (eg, ondansetron), benzodiazepines, or other medications that would be anticipated to confound detection of signs and symptoms of opioid withdrawal
25. Involvement in the planning and/or conduct of the study (applies to both sponsor or designee staff and staff at the study sites)

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Supportive Care
• Allocation: Randomized
• Interventional Model: Crossover Assignment
• Masking: Quadruple

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: MSE Dose Group 1; Morning and evening dose of buprenorphine HCl buccal film (300 μg) + placebo capsule in one period, and then placebo film + over-encapsulated ATC opioid (morphine sulfate or oxycodone) at 50% MSE daily dose in the alternate period	Drug: Buprenorphine; Other Names: BEMA Buprenorphine; BELBUCA; Buprenorphine HCl buccal film; Buprenorphine buccal film; EN3409; Drug: Placebo film; Matching placebo buccal film; Other Names: Placebo buccal film; BEMA placebo; Drug: Oxycodone; Oxycodone extended-release (ER) or immediate-release (IR) 5, 10, 15, 20, and 30 mg over-encapsulated oral tablets; Other Names: OxyContin; Oxycodone tablets; Oxycodone IR; Drug: Morphine sulfate; Morphine sulfate 15, 30, and 60 mg ER or 15 and 30 mg IR over-encapsulated oral tablets; Other Names: MS Contin; Morphine sulfate tablets; Morphine sulfate IR; Drug: Placebo capsule; Oral placebo capsules matching the over-encapsulated morphine sulfate and oxycodone tablets; Other Names: Matching placebo capsules
Experimental: MSE Dose Group 2; Morning and evening dose of buprenorphine HCl buccal film (450 μg) + placebo capsule in one period, and then placebo film + over-encapsulated ATC opioid (morphine sulfate or oxycodone) at 50% MSE daily dose in the alternate period	Drug: Buprenorphine; Other Names: BEMA Buprenorphine; BELBUCA; Buprenorphine HCl buccal film; Buprenorphine buccal film; EN3409; Drug: Placebo film; Matching placebo buccal film; Other Names: Placebo buccal film; BEMA placebo; Drug: Oxycodone; Oxycodone extended-release (ER) or immediate-release (IR) 5, 10, 15, 20, and 30 mg over-encapsulated oral tablets; Other Names: OxyContin; Oxycodone tablets; Oxycodone IR; Drug: Morphine sulfate; Morphine sulfate 15, 30, and 60 mg ER or 15 and 30 mg IR over-encapsulated oral tablets; Other Names: MS Contin; Morphine sulfate tablets; Morphine sulfate IR; Drug: Placebo capsule; Oral placebo capsules matching the over-encapsulated morphine sulfate and oxycodone tablets; Other Names: Matching placebo capsules

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Number of Responders	A responder is defined as a subject whose maximum (across all time points) clinical opiate withdrawal scale (COWS) total score is ≥13. COWS scores range 0 to 4 or 5 on 11 items related to opiate withdrawal signs or symptoms; total score range 0 to 48 where 0-4 = no withdrawal and 5-12 = mild, 13-24 = moderate, 25-36 = moderately severe, more than 36 = severe withdrawal.	Pre-dose (-0.5), 0.5, 1, 1.5, 2, 2.5, 3, 3.5, 4, 6, 9, 12, 12.5, 13, 13.5, 14, 16, and 24 (or end of study visit) hours post 1st study drug dose on each day of administration (period 1 [day 1] and period 2 [day 2]) in each treatment sequence
Maximum COWS Total Score	Investigator-rated COWS scores range 0 to 4 or 5 on 11 items related to opiate withdrawal signs or symptoms; total score range 0 to 48 where 0-4 = no withdrawal and 5-12 = mild, 13-24 = moderate, 25-36 = moderately severe, more than 36 = severe withdrawal. The maximum COWs total score is defined as the maximum COWs total score across all time points during the corresponding treatment period after study drug administration for each subject.	Pre-dose (-0.5), 0.5, 1, 1.5, 2, 2.5, 3, 3.5, 4, 6, 9, 12, 12.5, 13, 13.5, 14, 16, and 24 (or end of study visit) hours post 1st study drug dose on each day of administration (period 1 [day 1] and period 2 [day 2]) in each treatment sequence
Change From Baseline in Maximum COWS Total Score	Investigator-rated COWS scores range 0 to 4 or 5 on 11 items related to opiate withdrawal signs or symptoms; total score range 0 to 48 where 0-4 = no withdrawal and 5-12 = mild, 13-24 = moderate, 25-36 = moderately severe, more than 36 = severe withdrawal. The change from baseline in maximum COWS total score is determined as the difference between the maximum COWs total score and the baseline COWs total score.	Pre-dose (-0.5; baseline), 0.5, 1, 1.5, 2, 2.5, 3, 3.5, 4, 6, 9, 12, 12.5, 13, 13.5, 14, 16, and 24 (or end of study visit) hours post 1st study drug dose on each day of administration (period 1 [day 1] and period 2 [day 2]) in each treatment sequence

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Change From Baseline in COWS Total Score Over Time	Investigator-rated COWS scores range 0 to 4 or 5 on 11 items related to opiate withdrawal signs or symptoms; total score range 0 to 48 where 0-4 = no withdrawal and 5-12 = mild, 13-24 = moderate, 25-36 = moderately severe, more than 36 = severe withdrawal.	Pre-dose (-0.5; baseline), 0.5, 1, 1.5, 2, 2.5, 3, 3.5, 4, 6, 9, 12, 12.5, 13, 13.5, 14, 16, and 24 (or end of study visit) hours post 1st study drug dose on each day of administration (period 1 [day 1] and period 2 [day 2]) in each treatment sequence
Change From Baseline in "Pain Now" Over Time Using NRS	Subject rating of pain intensity using 11-point numerical rating scale (NRS) where 0=no pain and 10=pain as bad as you can imagine.	Pre-dose (-0.5; baseline), 0.5, 1, 2, 4, 9, 12, 12.5, 13, 14, 16, and 24 (or end of study visit) hours post 1st study drug dose on each day of administration (period 1 [day 1] and period 2 [day 2]) in each treatment sequence

Collaborators and Investigators

• Sponsor: BioDelivery Sciences International
• Investigators: Study Director: Todd Kirby, PhD, Endo Pharmaceuticals

Study record dates

Study Major Dates

• Study Start: June 1, 2013
• Primary Completion (Actual): July 1, 2014
• Study Completion (Actual): July 1, 2014

Study Registration Dates

• First Submitted: June 4, 2013
• First Submitted That Met QC Criteria: June 4, 2013
• First Posted (Estimate): June 6, 2013

Study Record Updates

• Last Update Posted (Actual): February 27, 2017
• Last Update Submitted That Met QC Criteria: January 12, 2017
• Last Verified: January 1, 2017

More Information

Terms related to this study

• Keywords: ATC, Opioid, withdrawal, switch
• Additional Relevant MeSH Terms: Physiological Effects of Drugs; Central Nervous System Depressants; Peripheral Nervous System Agents; Analgesics; Sensory System Agents; Analgesics, Opioid; Narcotics; Narcotic Antagonists; Buprenorphine; Morphine; Oxycodone
• Other Study ID Numbers: EN3409-204