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

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ClinicalTrials.gov Identifier: NCT01871285
Recruitment Status : Completed
First Posted : June 6, 2013
Results First Posted : February 3, 2016
Last Update Posted : February 27, 2017
Sponsor:
Information provided by (Responsible Party):
BioDelivery Sciences International

Brief Summary:
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.

Condition or disease Intervention/treatment Phase
Pain Drug: Buprenorphine Drug: Placebo film Drug: Oxycodone Drug: Morphine sulfate Drug: Placebo capsule Phase 2

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Study Type : Interventional  (Clinical Trial)
Actual Enrollment : 39 participants
Allocation: Randomized
Intervention Model: Crossover Assignment
Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
Primary Purpose: Supportive Care
Official Title: An Evaluation of the Tolerability of Switching Subjects on Chronic Around-the-Clock (ATC) Opioid Therapy to Buprenorphine HCl Buccal Film
Study Start Date : June 2013
Actual Primary Completion Date : July 2014
Actual Study Completion Date : July 2014

Resource links provided by the National Library of Medicine


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:
  • Buprenorphine buccal film
  • Buprenorphine HCl buccal film
  • EN3409
  • BEMA Buprenorphine
  • BELBUCA

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:
  • Oxycodone tablets
  • OxyContin
  • 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:
  • Morphine sulfate tablets
  • MS Contin
  • Morphine sulfate IR

Drug: Placebo capsule
Oral placebo capsules matching the over-encapsulated morphine sulfate and oxycodone tablets
Other Name: 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:
  • Buprenorphine buccal film
  • Buprenorphine HCl buccal film
  • EN3409
  • BEMA Buprenorphine
  • BELBUCA

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:
  • Oxycodone tablets
  • OxyContin
  • 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:
  • Morphine sulfate tablets
  • MS Contin
  • Morphine sulfate IR

Drug: Placebo capsule
Oral placebo capsules matching the over-encapsulated morphine sulfate and oxycodone tablets
Other Name: Matching placebo capsules




Primary Outcome Measures :
  1. Number of Responders [ Time Frame: 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 ]
    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.

  2. Maximum COWS Total Score [ Time Frame: 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 ]
    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.

  3. Change From Baseline in Maximum COWS Total Score [ Time Frame: 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 ]
    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.


Secondary Outcome Measures :
  1. Change From Baseline in COWS Total Score Over Time [ Time Frame: 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 ]
    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.

  2. Change From Baseline in "Pain Now" Over Time Using NRS [ Time Frame: 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 ]
    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.



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Ages Eligible for Study:   18 Years to 60 Years   (Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
Criteria

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)

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 ClinicalTrials.gov identifier (NCT number): NCT01871285


Locations
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United States, Kansas
Vince and Associates Clinical Research, Inc.
Overland Park, Kansas, United States, 66212
United States, Pennsylvania
CRI Lifetree
Philadelphia, Pennsylvania, United States, 19139
United States, Utah
CRI Lifetree (Lifetree Clinical Research)
Salt Lake, Utah, United States, 84106
Sponsors and Collaborators
BioDelivery Sciences International
Investigators
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Study Director: Todd Kirby, PhD Endo Pharmaceuticals

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Responsible Party: BioDelivery Sciences International
ClinicalTrials.gov Identifier: NCT01871285     History of Changes
Other Study ID Numbers: EN3409-204
First Posted: June 6, 2013    Key Record Dates
Results First Posted: February 3, 2016
Last Update Posted: February 27, 2017
Last Verified: January 2017

Keywords provided by BioDelivery Sciences International:
ATC, Opioid, withdrawal, switch

Additional relevant MeSH terms:
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Analgesics, Opioid
Morphine
Buprenorphine
Oxycodone
Narcotics
Central Nervous System Depressants
Physiological Effects of Drugs
Analgesics
Sensory System Agents
Peripheral Nervous System Agents
Narcotic Antagonists