Chronic Pain, Osteoarthritis of the Knee
Conditions
Keywords
Chronic pain,, OA of the knee,, opioid,, transdermal
Brief summary
The objective of this study is to determine the analgesic efficacy and safety of Buprenorphine Transdermal System (BTDS) 10 and 20 compared to placebo in opioid-naïve subjects with moderate to severe chronic pain due to osteoarthritis (OA) of the knee. The double-blind treatment intervention duration is 12 weeks, during which time supplemental analgesic medication (immediate-release oxycodone for the first 6 days postrandomization and acetaminophen or ibuprofen for the remainder of the double-blind phase) will be provided to all subjects in addition to study drug.
Detailed description
Buprenorphine is a synthetic opioid analgesic with over 25 years of international clinical experience indicating it to be safe and effective in a variety of therapeutic settings for the relief of moderate to severe pain. BTDS is a transdermal system formulation that is designed to deliver a consistent and a steady dose of buprenorphine over a 7-day period with limited blood concentration fluctuation.
Interventions
DRUGBuprenorphine
transdermal system 10 and 20 applied for 7-day wear
DRUGPlacebo
transdermal system (placebo) applied for 7-day wear
Sponsors
Purdue Pharma LP
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
DOUBLE (Subject, Investigator)
Eligibility
Sex/Gender
ALL
Age
40 Years to No maximum
Healthy volunteers
No
Inclusion criteria
* subjects with moderate to severe chronic osteoarthritis (OA) pain of the knee (lasting several hours daily) as their predominant pain condition, * clinical diagnosis of OA of the knee 1 year or longer, * subjects treated within the 14 days prior to screening with nonopioid therapy only, or with therapy including opioids at a dose of \< 5 mg oxycodone (or equivalent) per day, * subjects whose OA knee pain is not adequately controlled with nonopioid analgesic medication and who the investigator feels are appropriate candidates for around-the-clock opioid therapy.
Exclusion criteria
* subjects who have had arthroscopy on either knee or hip within 6 months of entering the study or open surgery on either knee or hip within 9 months of entering the study, * subjects who are allergic to buprenorphine or who have a history of allergies to other opioids, * subjects who have allergies or other contraindications to transdermal delivery systems or patch adhesives. Other protocol-specific inclusion/
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Average Pain Over the Last 24 Hours Score of the Study Knee at Week 12 of the Double Blind Phase. | 24 hours (week 12) | Average pain over the last 24 hours scores of the study knee at week 12 was evaluated on an 11-point scale: 0 = no pain, 10 = worst pain imaginable, recorded daily. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Mean Daily Number of Tablets of Nonopioid Supplemental Analgesic Used From Week 2 to 12 of the Double-blind Phase. | 10 weeks | Subjects were permitted to take sponsor-provided supplemental analgesic medication after week 1 of the double-blind treatment (acetaminophen or ibuprofen). |
| Sleep Disturbance Subscale of the MOS-Sleep Scale at Weeks 4, 8, and 12 of the Double-blind Phase. | Weeks 4, 8, and 12 of the double-bind phase | The MOS Sleep Scale consists of 12 individual items (4 sleep disturbance, 2 sleep adequacy, 1 quantity of sleep and optimal sleep, 3 somnolence, 1 snoring, and 1 shortness of breath) and takes 5 to 10 minutes to complete. Question 1 is scored on a scale of 1 to 5 ( 1 = 0-15 min to more than 60 min) and Questions 2 to 12 are scored on a scale of 1 to 6 (1 = all of the time to 6 = none of the time. The Sleep Disturbance Subscale score is derived from the scores to Questions 1, 3, 7, and 8 and ranges from 0 to 100, where higher scores indicate greater sleep disturbance. |
Countries
United States
Participant flow
Recruitment details
27-Sep-2007 (first patient first visit) to 28-Apr-2009 (last patient last visit) at 83 medical/research sites in US
Pre-assignment details
Open-label run-in period designed to select those subjects who both tolerated and responded to treatment with BTDS 10 or BTDS 20 (an enriched design). N = 1151 entered the run-in period, and N = 571 completed. One subject was not dosed, therefore N = 570 randomized. N = 3 subjects did not have safety data, therefore N = 567 had double-blind data.
Participants by arm
| Arm | Count |
|---|---|
| Double-blind BTDS 10 or 20 Buprenorphine transdermal patches (BTDS) 10 or 20 mcg/h applied for 7-day wear | 282 |
| Double-blind Placebo Placebo patches to match the BTDS patches applied for 7-day wear | 285 |
| Total | 567 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Overall Study | Administrative | 4 | 9 |
| Overall Study | Adverse Event | 44 | 30 |
| Overall Study | Lack of Efficacy | 14 | 39 |
| Overall Study | Lost to Follow-up | 4 | 3 |
| Overall Study | Withdrawal by Subject | 7 | 13 |
Baseline characteristics
| Characteristic | Double-blind BTDS 10 or 20 | Double-blind Placebo | Total |
|---|---|---|---|
| Age Continuous | 59.1 years STANDARD_DEVIATION 9.75 | 59.1 years STANDARD_DEVIATION 9.77 | 59.1 years STANDARD_DEVIATION 9.75 |
| Sex: Female, Male Female | 175 Participants | 181 Participants | 356 Participants |
| Sex: Female, Male Male | 107 Participants | 104 Participants | 211 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk |
|---|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — | — / — |
| other Total, other adverse events | 108 / 282 | 53 / 285 | 520 / 1,151 |
| serious Total, serious adverse events | 13 / 282 | 3 / 285 | 5 / 1,151 |
Outcome results
Primary
Average Pain Over the Last 24 Hours Score of the Study Knee at Week 12 of the Double Blind Phase.
Average pain over the last 24 hours scores of the study knee at week 12 was evaluated on an 11-point scale: 0 = no pain, 10 = worst pain imaginable, recorded daily.
Time frame: 24 hours (week 12)
Population: The full analysis population is the group of subjects who were randomized and received at least 1 dose of double-blind study drug
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Double-blind BTDS 10 or 20 | Average Pain Over the Last 24 Hours Score of the Study Knee at Week 12 of the Double Blind Phase. | Screening (Visit 2) | 7.16 units on a scale | Standard Deviation 1.34 |
| Double-blind BTDS 10 or 20 | Average Pain Over the Last 24 Hours Score of the Study Knee at Week 12 of the Double Blind Phase. | Prerandomization (Visit 3) | 2.63 units on a scale | Standard Deviation 1.292 |
| Double-blind BTDS 10 or 20 | Average Pain Over the Last 24 Hours Score of the Study Knee at Week 12 of the Double Blind Phase. | Double-blind Week 12 (Visit 8) | 3.82 units on a scale | Standard Deviation 2.644 |
| Double-blind Placebo | Average Pain Over the Last 24 Hours Score of the Study Knee at Week 12 of the Double Blind Phase. | Screening (Visit 2) | 7.06 units on a scale | Standard Deviation 1.3 |
| Double-blind Placebo | Average Pain Over the Last 24 Hours Score of the Study Knee at Week 12 of the Double Blind Phase. | Prerandomization (Visit 3) | 2.74 units on a scale | Standard Deviation 1.186 |
| Double-blind Placebo | Average Pain Over the Last 24 Hours Score of the Study Knee at Week 12 of the Double Blind Phase. | Double-blind Week 12 (Visit 8) | 4.22 units on a scale | Standard Deviation 2.644 |
Comparison: \[Week 12 analysis\] The null hypothesis was no group differences. The alternative hypothesis was that BTDS arm was superior to the placebo arm.~Pain scale is 11 points (0 = no pain to 10 = pain as bad as you can imagine).p-value: 0.085395% CI: [-0.8, 0.05]Mixed Models Analysis
Secondary
Mean Daily Number of Tablets of Nonopioid Supplemental Analgesic Used From Week 2 to 12 of the Double-blind Phase.
Subjects were permitted to take sponsor-provided supplemental analgesic medication after week 1 of the double-blind treatment (acetaminophen or ibuprofen).
Time frame: 10 weeks
Population: Subjects in the full analysis population who took at least 1 dose of supplemental analgesic medication.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Double-blind BTDS 10 or 20 | Mean Daily Number of Tablets of Nonopioid Supplemental Analgesic Used From Week 2 to 12 of the Double-blind Phase. | 0.701 tablets | Standard Deviation 0.8139 |
| Double-blind Placebo | Mean Daily Number of Tablets of Nonopioid Supplemental Analgesic Used From Week 2 to 12 of the Double-blind Phase. | 0.740 tablets | Standard Deviation 0.8566 |
Comparison: Categorical analysis P value is based on a Fisher's exact test. Mean daily number of tablets for subjects who took \<=1 dose of supplemental analgesiap-value: 0.709895% CI: [-0.233, 0.159]ANCOVA
Secondary
Sleep Disturbance Subscale of the MOS-Sleep Scale at Weeks 4, 8, and 12 of the Double-blind Phase.
The MOS Sleep Scale consists of 12 individual items (4 sleep disturbance, 2 sleep adequacy, 1 quantity of sleep and optimal sleep, 3 somnolence, 1 snoring, and 1 shortness of breath) and takes 5 to 10 minutes to complete. Question 1 is scored on a scale of 1 to 5 ( 1 = 0-15 min to more than 60 min) and Questions 2 to 12 are scored on a scale of 1 to 6 (1 = all of the time to 6 = none of the time. The Sleep Disturbance Subscale score is derived from the scores to Questions 1, 3, 7, and 8 and ranges from 0 to 100, where higher scores indicate greater sleep disturbance.
Time frame: Weeks 4, 8, and 12 of the double-bind phase
Population: Full Analysis Population (N = 570) consisted of subjects who were randomized and received at least 1 dose of double-blind study drug.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Double-blind BTDS 10 or 20 | Sleep Disturbance Subscale of the MOS-Sleep Scale at Weeks 4, 8, and 12 of the Double-blind Phase. | Prerandomization | 23.23 units on a scale | Standard Deviation 19.583 |
| Double-blind BTDS 10 or 20 | Sleep Disturbance Subscale of the MOS-Sleep Scale at Weeks 4, 8, and 12 of the Double-blind Phase. | Week 8 | 27.46 units on a scale | Standard Deviation 23.795 |
| Double-blind BTDS 10 or 20 | Sleep Disturbance Subscale of the MOS-Sleep Scale at Weeks 4, 8, and 12 of the Double-blind Phase. | Week 4 | 27.22 units on a scale | Standard Deviation 23.086 |
| Double-blind BTDS 10 or 20 | Sleep Disturbance Subscale of the MOS-Sleep Scale at Weeks 4, 8, and 12 of the Double-blind Phase. | Week 12 | 29.60 units on a scale | Standard Deviation 25.177 |
| Double-blind BTDS 10 or 20 | Sleep Disturbance Subscale of the MOS-Sleep Scale at Weeks 4, 8, and 12 of the Double-blind Phase. | Screening | 49.51 units on a scale | Standard Deviation 24.79 |
| Double-blind Placebo | Sleep Disturbance Subscale of the MOS-Sleep Scale at Weeks 4, 8, and 12 of the Double-blind Phase. | Week 12 | 33.63 units on a scale | Standard Deviation 25.606 |
| Double-blind Placebo | Sleep Disturbance Subscale of the MOS-Sleep Scale at Weeks 4, 8, and 12 of the Double-blind Phase. | Screening | 51.23 units on a scale | Standard Deviation 25.945 |
| Double-blind Placebo | Sleep Disturbance Subscale of the MOS-Sleep Scale at Weeks 4, 8, and 12 of the Double-blind Phase. | Prerandomization | 26.04 units on a scale | Standard Deviation 20.822 |
| Double-blind Placebo | Sleep Disturbance Subscale of the MOS-Sleep Scale at Weeks 4, 8, and 12 of the Double-blind Phase. | Week 4 | 35.08 units on a scale | Standard Deviation 25.565 |
| Double-blind Placebo | Sleep Disturbance Subscale of the MOS-Sleep Scale at Weeks 4, 8, and 12 of the Double-blind Phase. | Week 8 | 34.78 units on a scale | Standard Deviation 24.715 |
Comparison: Weeks 4, 8, 12 analysis The sleep disturbance subscale was analyzed using the mixed effect linear model with fixed effects for treatment (BTDS or placebo) and time (weeks 1, 2, 4, 8, 12) as categorical, screening mean and prerandomization mean value as covariates, and subject as a random effect.p-value: 0.003495% CI: [-7.44, -1.48]Mixed Models Analysis