Pain
Conditions
Keywords
ATC, Opioid, withdrawal, switch
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.
Interventions
DRUGBuprenorphine
DRUGPlacebo film
Matching placebo buccal film
DRUGOxycodone
Oxycodone extended-release (ER) or immediate-release (IR) 5, 10, 15, 20, and 30 mg over-encapsulated oral tablets
DRUGMorphine sulfate
Morphine sulfate 15, 30, and 60 mg ER or 15 and 30 mg IR over-encapsulated oral tablets
DRUGPlacebo capsule
Oral placebo capsules matching the over-encapsulated morphine sulfate and oxycodone tablets
Sponsors
BioDelivery Sciences International
Study design
Allocation
RANDOMIZED
Intervention model
CROSSOVER
Primary purpose
SUPPORTIVE_CARE
Masking
QUADRUPLE (Subject, Caregiver, Investigator, Outcomes Assessor)
Eligibility
Sex/Gender
ALL
Age
18 Years to 60 Years
Healthy volunteers
No
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)
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Number of Responders | 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. |
| Maximum COWS Total Score | 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. |
| Change From Baseline in Maximum 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 | 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
| Measure | Time frame | Description |
|---|---|---|
| Change From Baseline in COWS Total Score Over Time | 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. |
| Change From Baseline in Pain Now Over Time Using NRS | 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. |
Countries
United States
Participant flow
Recruitment details
Subjects with at least 6 months history of chronic pain requiring around-the-clock (ATC) opioid therapy with 80 to 220 mg morphine sulfate equivalent (MSE) per day for at least 28 days
Pre-assignment details
Subjects were enrolled and entered a screening period (73). Those meeting criteria for study entry including positive precipitated withdrawal during naloxone challenge (39) were randomized and stratified to 2 dose groups (subjects requiring 80-160 mg MSE/day ATC to MSE Dose Group 1 and subjects requiring 161-220 mg MSE/day ATC to MSE Dose Group 2).
Participants by arm
| Arm | Count |
|---|---|
| MSE Dose Group 1 Morning and evening dose of buprenorphine HCl buccal film (300 μg) + placebo capsule in one period, and then placebo buccal film + over-encapsulated ATC opioid at 50% MSE daily dose in the alternate period | 33 |
| MSE Dose Group 2 Morning and evening dose of buprenorphine HCl buccal film (450 μg) + placebo capsule in one period, and then placebo buccal film + over-encapsulated ATC opioid at 50% MSE daily dose in the alternate period | 6 |
| Total | 39 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 | FG002 | FG003 |
|---|---|---|---|---|---|
| First Intervention (1 Day) | Adverse Event | 1 | 0 | 0 | 0 |
| First Intervention (1 Day) | Lost to Follow-up | 0 | 1 | 1 | 0 |
Baseline characteristics
| Characteristic | MSE Dose Group 1 | MSE Dose Group 2 | Total |
|---|---|---|---|
| Age, Categorical <=18 years | 0 Participants | 0 Participants | 0 Participants |
| Age, Categorical >=65 years | 0 Participants | 0 Participants | 0 Participants |
| Age, Categorical Between 18 and 65 years | 33 Participants | 6 Participants | 39 Participants |
| Age, Continuous | 43.0 years | 44.0 years | 43.0 years |
| Gender Female | 17 Participants | 4 Participants | 21 Participants |
| Gender Male | 16 Participants | 2 Participants | 18 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk | EG003 affected / at risk |
|---|---|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — | — / — | — / — |
| other Total, other adverse events | 18 / 32 | 13 / 32 | 1 / 6 | 0 / 5 |
| serious Total, serious adverse events | 1 / 32 | 0 / 32 | 0 / 6 | 0 / 5 |
Outcome results
Primary
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.
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
Population: Analysis based on Per-protocol population (all randomized subjects who did not have major protocol deviations that might have confounded interpretation of the COWS \[eg, received erroneous treatment\], completed both crossover periods, and provided at least the first 4 hours of COWS data for each of 2 treatment periods); 4 subjects were excluded.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| MSE Dose Group 1 - Buprenorphine | Change From Baseline in Maximum COWS Total Score | 4.0 score | Standard Deviation 2.92 |
| MSE Dose Group 1 - ATC Opioid | Change From Baseline in Maximum COWS Total Score | 3.9 score | Standard Deviation 4.11 |
| MSE Dose Group 2 - Buprenorphine | Change From Baseline in Maximum COWS Total Score | 4.5 score | Standard Deviation 1.73 |
| MSE Dose Group 2 - ATC Opioid | Change From Baseline in Maximum COWS Total Score | 4.3 score | Standard Deviation 1.89 |
p-value: 0.794295% CI: [-1.6, 1.24]Mixed Models Analysis
p-value: 0.615595% CI: [-11.89, 13.25]Mixed Models Analysis
Primary
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.
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
Population: Analysis based on Per-protocol population (all randomized subjects who did not have major protocol deviations that might have confounded interpretation of the COWS \[eg, received erroneous treatment\], completed both crossover periods, and provided at least the first 4 hours of COWS data for each of 2 periods); 4 subjects were excluded.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| MSE Dose Group 1 - Buprenorphine | Maximum COWS Total Score | 4.6 score | Standard Deviation 3.15 |
| MSE Dose Group 1 - ATC Opioid | Maximum COWS Total Score | 5.3 score | Standard Deviation 4.42 |
| MSE Dose Group 2 - Buprenorphine | Maximum COWS Total Score | 5.5 score | Standard Deviation 1.91 |
| MSE Dose Group 2 - ATC Opioid | Maximum COWS Total Score | 6.3 score | Standard Deviation 2.5 |
p-value: 0.794295% CI: [-1.6, 1.24]Mixed Models Analysis
p-value: 0.615595% CI: [-11.89, 13.25]Mixed Models Analysis
Primary
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.
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
Population: Analysis based on Per-protocol population (all randomized subjects who did not have major protocol deviations that might have confounded interpretation of the COWS \[eg, received erroneous treatment\], completed both crossover periods, and provided at least the first 4 hours of COWS data for each of the 2 treatment periods); 4 subjects were excluded.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| MSE Dose Group 1 - Buprenorphine | Number of Responders | 1 participants |
| MSE Dose Group 1 - ATC Opioid | Number of Responders | 2 participants |
| MSE Dose Group 2 - Buprenorphine | Number of Responders | 0 participants |
| MSE Dose Group 2 - ATC Opioid | Number of Responders | 0 participants |
Secondary
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.
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
Population: Analysis based on Per-protocol population (all randomized subjects who did not have major protocol deviations that might have confounded interpretation of the COWS \[eg, received erroneous treatment\], completed both crossover periods, and provided at least the first 4 hours of COWS data for each of 2 treatment periods); 4 subjects were excluded.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| MSE Dose Group 1 - Buprenorphine | Change From Baseline in COWS Total Score Over Time | Hour 0.5 | 0.1 score | Standard Deviation 0.67 |
| MSE Dose Group 1 - Buprenorphine | Change From Baseline in COWS Total Score Over Time | Hour 13 | 0.9 score | Standard Deviation 1.26 |
| MSE Dose Group 1 - Buprenorphine | Change From Baseline in COWS Total Score Over Time | Hour 12.5 | 1.0 score | Standard Deviation 1.32 |
| MSE Dose Group 1 - Buprenorphine | Change From Baseline in COWS Total Score Over Time | Hour 3 | 0.6 score | Standard Deviation 1.72 |
| MSE Dose Group 1 - Buprenorphine | Change From Baseline in COWS Total Score Over Time | Hour 12 | 2.1 score | Standard Deviation 2.38 |
| MSE Dose Group 1 - Buprenorphine | Change From Baseline in COWS Total Score Over Time | Hour 2 | 0.3 score | Standard Deviation 0.9 |
| MSE Dose Group 1 - Buprenorphine | Change From Baseline in COWS Total Score Over Time | Hour 14 | 0.7 score | Standard Deviation 1.33 |
| MSE Dose Group 1 - Buprenorphine | Change From Baseline in COWS Total Score Over Time | Hour 3.5 | 0.9 score | Standard Deviation 1.81 |
| MSE Dose Group 1 - Buprenorphine | Change From Baseline in COWS Total Score Over Time | Hour 9 | 0.9 score | Standard Deviation 1.47 |
| MSE Dose Group 1 - Buprenorphine | Change From Baseline in COWS Total Score Over Time | Hour 24 | 1.8 score | Standard Deviation 3.13 |
| MSE Dose Group 1 - Buprenorphine | Change From Baseline in COWS Total Score Over Time | Hour 1 | 0.3 score | Standard Deviation 1.04 |
| MSE Dose Group 1 - Buprenorphine | Change From Baseline in COWS Total Score Over Time | Hour 4 | 0.8 score | Standard Deviation 1.54 |
| MSE Dose Group 1 - Buprenorphine | Change From Baseline in COWS Total Score Over Time | Hour 16 | 0.5 score | Standard Deviation 1.55 |
| MSE Dose Group 1 - Buprenorphine | Change From Baseline in COWS Total Score Over Time | Hour 1.5 | 0.4 score | Standard Deviation 1.31 |
| MSE Dose Group 1 - Buprenorphine | Change From Baseline in COWS Total Score Over Time | Hour 13.5 | 1.0 score | Standard Deviation 1.76 |
| MSE Dose Group 1 - Buprenorphine | Change From Baseline in COWS Total Score Over Time | Hour 6 | 0.6 score | Standard Deviation 1.58 |
| MSE Dose Group 1 - Buprenorphine | Change From Baseline in COWS Total Score Over Time | Hour 2.5 | 0.6 score | Standard Deviation 1.41 |
| MSE Dose Group 1 - ATC Opioid | Change From Baseline in COWS Total Score Over Time | Hour 6 | 0.6 score | Standard Deviation 2.76 |
| MSE Dose Group 1 - ATC Opioid | Change From Baseline in COWS Total Score Over Time | Hour 13 | 0.5 score | Standard Deviation 1.72 |
| MSE Dose Group 1 - ATC Opioid | Change From Baseline in COWS Total Score Over Time | Hour 9 | 1.4 score | Standard Deviation 3.64 |
| MSE Dose Group 1 - ATC Opioid | Change From Baseline in COWS Total Score Over Time | Hour 24 | 0.7 score | Standard Deviation 3.12 |
| MSE Dose Group 1 - ATC Opioid | Change From Baseline in COWS Total Score Over Time | Hour 12 | 1.5 score | Standard Deviation 3.43 |
| MSE Dose Group 1 - ATC Opioid | Change From Baseline in COWS Total Score Over Time | Hour 12.5 | 0.5 score | Standard Deviation 2.01 |
| MSE Dose Group 1 - ATC Opioid | Change From Baseline in COWS Total Score Over Time | Hour 16 | -0.1 score | Standard Deviation 1.88 |
| MSE Dose Group 1 - ATC Opioid | Change From Baseline in COWS Total Score Over Time | Hour 2 | 0.2 score | Standard Deviation 2.48 |
| MSE Dose Group 1 - ATC Opioid | Change From Baseline in COWS Total Score Over Time | Hour 2.5 | 0.3 score | Standard Deviation 2.32 |
| MSE Dose Group 1 - ATC Opioid | Change From Baseline in COWS Total Score Over Time | Hour 1 | 0.0 score | Standard Deviation 1.94 |
| MSE Dose Group 1 - ATC Opioid | Change From Baseline in COWS Total Score Over Time | Hour 14 | 0.2 score | Standard Deviation 2.06 |
| MSE Dose Group 1 - ATC Opioid | Change From Baseline in COWS Total Score Over Time | Hour 3 | 0.2 score | Standard Deviation 2.49 |
| MSE Dose Group 1 - ATC Opioid | Change From Baseline in COWS Total Score Over Time | Hour 0.5 | -0.3 score | Standard Deviation 1.47 |
| MSE Dose Group 1 - ATC Opioid | Change From Baseline in COWS Total Score Over Time | Hour 3.5 | 0.3 score | Standard Deviation 2.17 |
| MSE Dose Group 1 - ATC Opioid | Change From Baseline in COWS Total Score Over Time | Hour 13.5 | 0.4 score | Standard Deviation 1.8 |
| MSE Dose Group 1 - ATC Opioid | Change From Baseline in COWS Total Score Over Time | Hour 4 | 0.4 score | Standard Deviation 2.48 |
| MSE Dose Group 1 - ATC Opioid | Change From Baseline in COWS Total Score Over Time | Hour 1.5 | 0.2 score | Standard Deviation 2.5 |
| MSE Dose Group 2 - Buprenorphine | Change From Baseline in COWS Total Score Over Time | Hour 12 | 3.3 score | Standard Deviation 2.5 |
| MSE Dose Group 2 - Buprenorphine | Change From Baseline in COWS Total Score Over Time | Hour 0.5 | 0.0 score | Standard Deviation 0.82 |
| MSE Dose Group 2 - Buprenorphine | Change From Baseline in COWS Total Score Over Time | Hour 1 | 0.8 score | Standard Deviation 1.5 |
| MSE Dose Group 2 - Buprenorphine | Change From Baseline in COWS Total Score Over Time | Hour 1.5 | 0.5 score | Standard Deviation 1.29 |
| MSE Dose Group 2 - Buprenorphine | Change From Baseline in COWS Total Score Over Time | Hour 2 | 1.8 score | Standard Deviation 1.5 |
| MSE Dose Group 2 - Buprenorphine | Change From Baseline in COWS Total Score Over Time | Hour 2.5 | 1.3 score | Standard Deviation 1.26 |
| MSE Dose Group 2 - Buprenorphine | Change From Baseline in COWS Total Score Over Time | Hour 3 | 0.3 score | Standard Deviation 0.96 |
| MSE Dose Group 2 - Buprenorphine | Change From Baseline in COWS Total Score Over Time | Hour 3.5 | 1.5 score | Standard Deviation 1.73 |
| MSE Dose Group 2 - Buprenorphine | Change From Baseline in COWS Total Score Over Time | Hour 4 | 1.0 score | Standard Deviation 1.15 |
| MSE Dose Group 2 - Buprenorphine | Change From Baseline in COWS Total Score Over Time | Hour 6 | 1.0 score | Standard Deviation 1.15 |
| MSE Dose Group 2 - Buprenorphine | Change From Baseline in COWS Total Score Over Time | Hour 9 | 1.3 score | Standard Deviation 1.26 |
| MSE Dose Group 2 - Buprenorphine | Change From Baseline in COWS Total Score Over Time | Hour 12.5 | 3.0 score | Standard Deviation 3.56 |
| MSE Dose Group 2 - Buprenorphine | Change From Baseline in COWS Total Score Over Time | Hour 13 | 3.3 score | Standard Deviation 3.77 |
| MSE Dose Group 2 - Buprenorphine | Change From Baseline in COWS Total Score Over Time | Hour 13.5 | 1.8 score | Standard Deviation 2.63 |
| MSE Dose Group 2 - Buprenorphine | Change From Baseline in COWS Total Score Over Time | Hour 14 | 3.3 score | Standard Deviation 3.1 |
| MSE Dose Group 2 - Buprenorphine | Change From Baseline in COWS Total Score Over Time | Hour 16 | 1.8 score | Standard Deviation 2.06 |
| MSE Dose Group 2 - Buprenorphine | Change From Baseline in COWS Total Score Over Time | Hour 24 | 2.0 score | Standard Deviation 2.58 |
| MSE Dose Group 2 - ATC Opioid | Change From Baseline in COWS Total Score Over Time | Hour 13 | 0.0 score | Standard Deviation 3.83 |
| MSE Dose Group 2 - ATC Opioid | Change From Baseline in COWS Total Score Over Time | Hour 4 | -1.0 score | Standard Deviation 1.83 |
| MSE Dose Group 2 - ATC Opioid | Change From Baseline in COWS Total Score Over Time | Hour 3.5 | -0.8 score | Standard Deviation 1.71 |
| MSE Dose Group 2 - ATC Opioid | Change From Baseline in COWS Total Score Over Time | Hour 1 | -1.0 score | Standard Deviation 1.41 |
| MSE Dose Group 2 - ATC Opioid | Change From Baseline in COWS Total Score Over Time | Hour 13.5 | -0.3 score | Standard Deviation 3.4 |
| MSE Dose Group 2 - ATC Opioid | Change From Baseline in COWS Total Score Over Time | Hour 3 | -1.0 score | Standard Deviation 1.63 |
| MSE Dose Group 2 - ATC Opioid | Change From Baseline in COWS Total Score Over Time | Hour 2.5 | -1.0 score | Standard Deviation 0.82 |
| MSE Dose Group 2 - ATC Opioid | Change From Baseline in COWS Total Score Over Time | Hour 0.5 | -1.3 score | Standard Deviation 0.96 |
| MSE Dose Group 2 - ATC Opioid | Change From Baseline in COWS Total Score Over Time | Hour 14 | -0.3 score | Standard Deviation 3.1 |
| MSE Dose Group 2 - ATC Opioid | Change From Baseline in COWS Total Score Over Time | Hour 2 | -1.0 score | Standard Deviation 0.82 |
| MSE Dose Group 2 - ATC Opioid | Change From Baseline in COWS Total Score Over Time | Hour 1.5 | -1.0 score | Standard Deviation 1.41 |
| MSE Dose Group 2 - ATC Opioid | Change From Baseline in COWS Total Score Over Time | Hour 12 | 0.3 score | Standard Deviation 3.77 |
| MSE Dose Group 2 - ATC Opioid | Change From Baseline in COWS Total Score Over Time | Hour 24 | 2.8 score | Standard Deviation 2.63 |
| MSE Dose Group 2 - ATC Opioid | Change From Baseline in COWS Total Score Over Time | Hour 12.5 | 1.3 score | Standard Deviation 4.27 |
| MSE Dose Group 2 - ATC Opioid | Change From Baseline in COWS Total Score Over Time | Hour 9 | 1.0 score | Standard Deviation 1.15 |
| MSE Dose Group 2 - ATC Opioid | Change From Baseline in COWS Total Score Over Time | Hour 6 | 0.0 score | Standard Deviation 2.58 |
| MSE Dose Group 2 - ATC Opioid | Change From Baseline in COWS Total Score Over Time | Hour 16 | -0.3 score | Standard Deviation 3.1 |
Secondary
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.
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
Population: Analysis based on Per-protocol population (all randomized subjects who did not have major protocol deviations that might have confounded interpretation of the COWS \[eg, received erroneous treatment\], completed both crossover periods, and provided at least the first 4 hours of COWS data for each of the 2 treatment periods); 4 subjects excluded.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| MSE Dose Group 1 - Buprenorphine | Change From Baseline in Pain Now Over Time Using NRS | Hour 14 | -0.7 units on a scale | Standard Deviation 2.24 |
| MSE Dose Group 1 - Buprenorphine | Change From Baseline in Pain Now Over Time Using NRS | Hour 0.5 | -0.3 units on a scale | Standard Deviation 1.24 |
| MSE Dose Group 1 - Buprenorphine | Change From Baseline in Pain Now Over Time Using NRS | Hour 1 | -0.5 units on a scale | Standard Deviation 1.43 |
| MSE Dose Group 1 - Buprenorphine | Change From Baseline in Pain Now Over Time Using NRS | Hour 13 | -0.4 units on a scale | Standard Deviation 2.4 |
| MSE Dose Group 1 - Buprenorphine | Change From Baseline in Pain Now Over Time Using NRS | Hour 2 | -0.7 units on a scale | Standard Deviation 1.37 |
| MSE Dose Group 1 - Buprenorphine | Change From Baseline in Pain Now Over Time Using NRS | Hour 12 | 0.5 units on a scale | Standard Deviation 2.13 |
| MSE Dose Group 1 - Buprenorphine | Change From Baseline in Pain Now Over Time Using NRS | Hour 9 | -0.5 units on a scale | Standard Deviation 2.29 |
| MSE Dose Group 1 - Buprenorphine | Change From Baseline in Pain Now Over Time Using NRS | Hour 12.5 | 0.0 units on a scale | Standard Deviation 2.29 |
| MSE Dose Group 1 - Buprenorphine | Change From Baseline in Pain Now Over Time Using NRS | Hour 16 | -0.9 units on a scale | Standard Deviation 2.37 |
| MSE Dose Group 1 - Buprenorphine | Change From Baseline in Pain Now Over Time Using NRS | Hour 4 | -0.9 units on a scale | Standard Deviation 1.97 |
| MSE Dose Group 1 - Buprenorphine | Change From Baseline in Pain Now Over Time Using NRS | Hour 24 | -0.2 units on a scale | Standard Deviation 2.45 |
| MSE Dose Group 1 - ATC Opioid | Change From Baseline in Pain Now Over Time Using NRS | Hour 12.5 | -0.4 units on a scale | Standard Deviation 2.01 |
| MSE Dose Group 1 - ATC Opioid | Change From Baseline in Pain Now Over Time Using NRS | Hour 14 | -1.2 units on a scale | Standard Deviation 2.02 |
| MSE Dose Group 1 - ATC Opioid | Change From Baseline in Pain Now Over Time Using NRS | Hour 0.5 | -0.6 units on a scale | Standard Deviation 0.92 |
| MSE Dose Group 1 - ATC Opioid | Change From Baseline in Pain Now Over Time Using NRS | Hour 9 | -0.1 units on a scale | Standard Deviation 1.97 |
| MSE Dose Group 1 - ATC Opioid | Change From Baseline in Pain Now Over Time Using NRS | Hour 2 | -1.2 units on a scale | Standard Deviation 1.49 |
| MSE Dose Group 1 - ATC Opioid | Change From Baseline in Pain Now Over Time Using NRS | Hour 24 | -0.2 units on a scale | Standard Deviation 2.12 |
| MSE Dose Group 1 - ATC Opioid | Change From Baseline in Pain Now Over Time Using NRS | Hour 1 | -1.1 units on a scale | Standard Deviation 1.3 |
| MSE Dose Group 1 - ATC Opioid | Change From Baseline in Pain Now Over Time Using NRS | Hour 4 | -1.0 units on a scale | Standard Deviation 1.8 |
| MSE Dose Group 1 - ATC Opioid | Change From Baseline in Pain Now Over Time Using NRS | Hour 12 | 0.3 units on a scale | Standard Deviation 2.01 |
| MSE Dose Group 1 - ATC Opioid | Change From Baseline in Pain Now Over Time Using NRS | Hour 13 | -0.7 units on a scale | Standard Deviation 2.07 |
| MSE Dose Group 1 - ATC Opioid | Change From Baseline in Pain Now Over Time Using NRS | Hour 16 | -1.4 units on a scale | Standard Deviation 2.03 |
| MSE Dose Group 2 - Buprenorphine | Change From Baseline in Pain Now Over Time Using NRS | Hour 2 | 0.8 units on a scale | Standard Deviation 0.96 |
| MSE Dose Group 2 - Buprenorphine | Change From Baseline in Pain Now Over Time Using NRS | Hour 12 | 1.5 units on a scale | Standard Deviation 1.91 |
| MSE Dose Group 2 - Buprenorphine | Change From Baseline in Pain Now Over Time Using NRS | Hour 12.5 | 1.0 units on a scale | Standard Deviation 2.16 |
| MSE Dose Group 2 - Buprenorphine | Change From Baseline in Pain Now Over Time Using NRS | Hour 13 | 0.8 units on a scale | Standard Deviation 1.89 |
| MSE Dose Group 2 - Buprenorphine | Change From Baseline in Pain Now Over Time Using NRS | Hour 14 | 1.0 units on a scale | Standard Deviation 2.16 |
| MSE Dose Group 2 - Buprenorphine | Change From Baseline in Pain Now Over Time Using NRS | Hour 16 | 0.3 units on a scale | Standard Deviation 2.22 |
| MSE Dose Group 2 - Buprenorphine | Change From Baseline in Pain Now Over Time Using NRS | Hour 24 | 0.8 units on a scale | Standard Deviation 2.99 |
| MSE Dose Group 2 - Buprenorphine | Change From Baseline in Pain Now Over Time Using NRS | Hour 0.5 | -0.5 units on a scale | Standard Deviation 1.73 |
| MSE Dose Group 2 - Buprenorphine | Change From Baseline in Pain Now Over Time Using NRS | Hour 1 | 0.3 units on a scale | Standard Deviation 1.26 |
| MSE Dose Group 2 - Buprenorphine | Change From Baseline in Pain Now Over Time Using NRS | Hour 4 | 0.5 units on a scale | Standard Deviation 1.73 |
| MSE Dose Group 2 - Buprenorphine | Change From Baseline in Pain Now Over Time Using NRS | Hour 9 | 1.0 units on a scale | Standard Deviation 1.41 |
| MSE Dose Group 2 - ATC Opioid | Change From Baseline in Pain Now Over Time Using NRS | Hour 24 | 0.0 units on a scale | Standard Deviation 2.94 |
| MSE Dose Group 2 - ATC Opioid | Change From Baseline in Pain Now Over Time Using NRS | Hour 2 | -1.3 units on a scale | Standard Deviation 1.5 |
| MSE Dose Group 2 - ATC Opioid | Change From Baseline in Pain Now Over Time Using NRS | Hour 16 | -1.3 units on a scale | Standard Deviation 3.3 |
| MSE Dose Group 2 - ATC Opioid | Change From Baseline in Pain Now Over Time Using NRS | Hour 14 | -1.0 units on a scale | Standard Deviation 3.37 |
| MSE Dose Group 2 - ATC Opioid | Change From Baseline in Pain Now Over Time Using NRS | Hour 9 | -0.8 units on a scale | Standard Deviation 2.06 |
| MSE Dose Group 2 - ATC Opioid | Change From Baseline in Pain Now Over Time Using NRS | Hour 4 | -1.8 units on a scale | Standard Deviation 2.06 |
| MSE Dose Group 2 - ATC Opioid | Change From Baseline in Pain Now Over Time Using NRS | Hour 13 | -0.8 units on a scale | Standard Deviation 2.99 |
| MSE Dose Group 2 - ATC Opioid | Change From Baseline in Pain Now Over Time Using NRS | Hour 12.5 | -0.3 units on a scale | Standard Deviation 2.99 |
| MSE Dose Group 2 - ATC Opioid | Change From Baseline in Pain Now Over Time Using NRS | Hour 12 | -0.3 units on a scale | Standard Deviation 2.63 |
| MSE Dose Group 2 - ATC Opioid | Change From Baseline in Pain Now Over Time Using NRS | Hour 1 | -1.5 units on a scale | Standard Deviation 1 |
| MSE Dose Group 2 - ATC Opioid | Change From Baseline in Pain Now Over Time Using NRS | Hour 0.5 | -1.3 units on a scale | Standard Deviation 0.5 |