Chronic Non-malignant Pain
Conditions
Keywords
Chronic pain, opioid, transdermal, Butrans™ [BTDS]
Brief summary
The objective of this study is to demonstrate the effectiveness and tolerability of the buprenorphine transdermal system (5, 10 and 20) in comparison to matching placebo transdermal system in subjects with chronic nonmalignant pain syndromes currently controlled by oral opioids. The double-blind treatment intervention duration is 2 weeks during which time supplemental analgesic medication (acetaminophen) 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 situations for the relief of moderate to severe pain.
Interventions
Buprenorphine transdermal patch 5, 10 or 20 mcg/h applied for 7-day wear.
DRUGPlacebo to match BTDS
Placebo to match buprenorphine transdermal patch applied for 7-day wear.
Sponsors
Napp Pharmaceuticals Limited
Purdue Pharma LP
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
DOUBLE (Subject, Investigator)
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
* At least 2 month's history of nonmalignant pain, currently in stable pain control on opioid therapy. * Good, very good or excellent pain control on current opioid therapy. * Willing and able to use a telephone interactive voice response service.
Exclusion criteria
* Currently receiving daily morphine or oxycodone monotherapy. * Scheduled for surgery of the disease site (eg, major joint replacement surgery), or any other major surgery, which would fall within the study period. Other protocol-specific exclusion/inclusion criteria may apply.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| The Number of Subjects With Ineffective Treatment During the Double-blind Evaluation Phase. | Double-blind phase (14 days) | Ineffective treatment was defined as: * Subject took \>1 gram of acetaminophen in a 24-hour period, or * Subject required a change in transdermal patch (TDS) dose, or * Subject had difficulty in keeping the TDS on, or * Subject discontinued due to ineffective treatment (but did not meet any of the above criteria). Note: some subjects may have had multiple reasons for ineffective treatment and are counted under each category. Therefore the sum of subjects across all criteria for ineffective treatment is greater than the total number of subjects with ineffective treatment. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Time (Days) From the Initial Dose of Study Drug in the Double-blind Evaluation Phase to Ineffective Treatment | 14 days | The time of ineffective treatment was calculated as the earliest of the following: * The date the subject first took \>1 gram of acetaminophen, * The visit date when ineffective treatment was first determined, or * The date the last patch was removed. |
| The Number of Subjects Who Had Ineffective Treatment or Who Discontinued Due to Reasons Other Than Ineffective Treatment in the Double-blind Phase | 14 days | Note: The total numbers of Subjects w/ineffective treatment or who discont'd for placebo and BTDS are 1 less because there were reasons other than lack of efficacy that made up this total: adverse event, death, lost to follow- up, protocol violation, and other. Example for placebo 89+5=94; however, 93 is indicated for the total because there is 1 subject in the placebo group who was counted under ineffective treatment and discontinued due to reasons other than lack of efficacy. The same is true for 1 subject in BTDS. |
| The Amount of Rescue Medication Used for Pain (Average Daily Number of Acetaminophen Tablets). | 14 days | The average daily acetaminophen (Panadol) use (1 tablet = 500 mg) during the double-blind phase was compared between the treatment groups using ANCOVA methodology with terms for country and treatment. The average escape medication used in the last 4 days prior to randomization was included as a covariate. |
Countries
United Kingdom, United States
Participant flow
Recruitment details
(First patient first visit) 19-Mar-2001 to (last patient last visit) 22-Jul-2001 at 42 centers: 21 in the UK and 21 in the US.
Pre-assignment details
The Run-in period (N = 588 subjects started) consisted of titration from buprenorphine transdermal patch (BTDS) 5 to BTDS 10, or 20 mcg/h for tolerability. If BTDS was not tolerated or pain increased, the subject was discontinued. N = 267 subjects were randomized.
Participants by arm
| Arm | Count |
|---|---|
| Double-blind Placebo Patch Reference drug - Placebo transdermal patch to match BTDS 5, 10, or 20 mcg/h applied for 7-day wear. | 138 |
| Double-blind BTDS Test drug - buprenorphine transdermal patch (BTDS) 5, 10, or 20 mcg/h applied for 7-day wear. | 129 |
| Total | 267 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Overall Study | Adverse Event | 4 | 6 |
| Overall Study | Lost to Follow-up | 1 | 0 |
| Overall Study | Protocol Violation | 1 | 0 |
Baseline characteristics
| Characteristic | Double-blind Placebo Patch | Double-blind BTDS | Total |
|---|---|---|---|
| Age Continuous | 59.2 years STANDARD_DEVIATION 11.48 | 56.2 years STANDARD_DEVIATION 13.34 | 57.7 years STANDARD_DEVIATION 12.48 |
| Region of Enrollment United Kingdom | 92 participants | 87 participants | 179 participants |
| Region of Enrollment United States | 46 participants | 42 participants | 88 participants |
| Sex: Female, Male Female | 88 Participants | 79 Participants | 167 Participants |
| Sex: Female, Male Male | 50 Participants | 50 Participants | 100 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 | 21 / 138 | 25 / 129 | 245 / 588 |
| serious Total, serious adverse events | 0 / 138 | 0 / 129 | 7 / 588 |
Outcome results
Primary
The Number of Subjects With Ineffective Treatment During the Double-blind Evaluation Phase.
Ineffective treatment was defined as: * Subject took \>1 gram of acetaminophen in a 24-hour period, or * Subject required a change in transdermal patch (TDS) dose, or * Subject had difficulty in keeping the TDS on, or * Subject discontinued due to ineffective treatment (but did not meet any of the above criteria). Note: some subjects may have had multiple reasons for ineffective treatment and are counted under each category. Therefore the sum of subjects across all criteria for ineffective treatment is greater than the total number of subjects with ineffective treatment.
Time frame: Double-blind phase (14 days)
Population: The Full Analysis Population (N = 266) for efficacy analyses included all subjects who were randomized and provided at least 1 efficacy assessment in the double-blind phase.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Double-blind Placebo Patch | The Number of Subjects With Ineffective Treatment During the Double-blind Evaluation Phase. | Reason: discontinued due to ineffective treatment | 2 participants |
| Double-blind Placebo Patch | The Number of Subjects With Ineffective Treatment During the Double-blind Evaluation Phase. | Reason: difficulty keeping patch on | 6 participants |
| Double-blind Placebo Patch | The Number of Subjects With Ineffective Treatment During the Double-blind Evaluation Phase. | Reason: took more than 1 gram of acetaminophen/day | 81 participants |
| Double-blind Placebo Patch | The Number of Subjects With Ineffective Treatment During the Double-blind Evaluation Phase. | Reason: required a change in TDS dose | 34 participants |
| Double-blind Placebo Patch | The Number of Subjects With Ineffective Treatment During the Double-blind Evaluation Phase. | Subjects With Ineffective Treatment | 89 participants |
| Double-blind BTDS | The Number of Subjects With Ineffective Treatment During the Double-blind Evaluation Phase. | Reason: difficulty keeping patch on | 1 participants |
| Double-blind BTDS | The Number of Subjects With Ineffective Treatment During the Double-blind Evaluation Phase. | Reason: took more than 1 gram of acetaminophen/day | 59 participants |
| Double-blind BTDS | The Number of Subjects With Ineffective Treatment During the Double-blind Evaluation Phase. | Reason: required a change in TDS dose | 25 participants |
| Double-blind BTDS | The Number of Subjects With Ineffective Treatment During the Double-blind Evaluation Phase. | Reason: discontinued due to ineffective treatment | 3 participants |
| Double-blind BTDS | The Number of Subjects With Ineffective Treatment During the Double-blind Evaluation Phase. | Subjects With Ineffective Treatment | 66 participants |
| Total | The Number of Subjects With Ineffective Treatment During the Double-blind Evaluation Phase. | Subjects With Ineffective Treatment | 155 participants |
| Total | The Number of Subjects With Ineffective Treatment During the Double-blind Evaluation Phase. | Reason: discontinued due to ineffective treatment | 5 participants |
| Total | The Number of Subjects With Ineffective Treatment During the Double-blind Evaluation Phase. | Reason: took more than 1 gram of acetaminophen/day | 140 participants |
| Total | The Number of Subjects With Ineffective Treatment During the Double-blind Evaluation Phase. | Reason: difficulty keeping patch on | 7 participants |
| Total | The Number of Subjects With Ineffective Treatment During the Double-blind Evaluation Phase. | Reason: required a change in TDS dose | 59 participants |
Comparison: H0: the odds of ineffective treatment is the same for subjects receiving placebo as for those receiving BTDS versus the alternative H1: the odds of ineffective treatment is different for subjects receiving placebo from those receiving BTDS.p-value: 0.021795% CI: [1.09, 2.95]Regression, Logistic
Secondary
The Amount of Rescue Medication Used for Pain (Average Daily Number of Acetaminophen Tablets).
The average daily acetaminophen (Panadol) use (1 tablet = 500 mg) during the double-blind phase was compared between the treatment groups using ANCOVA methodology with terms for country and treatment. The average escape medication used in the last 4 days prior to randomization was included as a covariate.
Time frame: 14 days
Population: Full Analysis (N = 266) consisted of subjects who were randomized into the double-blind evaluation phase, were exposed to study drug, and provided at least 1 efficacy assessment during the double-blind evaluation phase.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| Double-blind Placebo Patch | The Amount of Rescue Medication Used for Pain (Average Daily Number of Acetaminophen Tablets). | 2.2 Tablets | Standard Error 0.15 |
| Double-blind BTDS | The Amount of Rescue Medication Used for Pain (Average Daily Number of Acetaminophen Tablets). | 1.8 Tablets | Standard Error 0.14 |
Secondary
The Number of Subjects Who Had Ineffective Treatment or Who Discontinued Due to Reasons Other Than Ineffective Treatment in the Double-blind Phase
Note: The total numbers of Subjects w/ineffective treatment or who discont'd for placebo and BTDS are 1 less because there were reasons other than lack of efficacy that made up this total: adverse event, death, lost to follow- up, protocol violation, and other. Example for placebo 89+5=94; however, 93 is indicated for the total because there is 1 subject in the placebo group who was counted under ineffective treatment and discontinued due to reasons other than lack of efficacy. The same is true for 1 subject in BTDS.
Time frame: 14 days
Population: Full Analysis (N = 266) consisted of subjects who were randomized into the double-blind evaluation phase, were exposed to study drug, and provided at least 1 efficacy assessment during the double-blind evaluation phase.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Double-blind Placebo Patch | The Number of Subjects Who Had Ineffective Treatment or Who Discontinued Due to Reasons Other Than Ineffective Treatment in the Double-blind Phase | Subjects w/ineffective treatment or who discont'd | 93 participants |
| Double-blind Placebo Patch | The Number of Subjects Who Had Ineffective Treatment or Who Discontinued Due to Reasons Other Than Ineffective Treatment in the Double-blind Phase | Ineffective Treatment | 89 participants |
| Double-blind Placebo Patch | The Number of Subjects Who Had Ineffective Treatment or Who Discontinued Due to Reasons Other Than Ineffective Treatment in the Double-blind Phase | Discontinued due to other reasons | 5 participants |
| Double-blind BTDS | The Number of Subjects Who Had Ineffective Treatment or Who Discontinued Due to Reasons Other Than Ineffective Treatment in the Double-blind Phase | Subjects w/ineffective treatment or who discont'd | 71 participants |
| Double-blind BTDS | The Number of Subjects Who Had Ineffective Treatment or Who Discontinued Due to Reasons Other Than Ineffective Treatment in the Double-blind Phase | Ineffective Treatment | 66 participants |
| Double-blind BTDS | The Number of Subjects Who Had Ineffective Treatment or Who Discontinued Due to Reasons Other Than Ineffective Treatment in the Double-blind Phase | Discontinued due to other reasons | 6 participants |
Secondary
Time (Days) From the Initial Dose of Study Drug in the Double-blind Evaluation Phase to Ineffective Treatment
The time of ineffective treatment was calculated as the earliest of the following: * The date the subject first took \>1 gram of acetaminophen, * The visit date when ineffective treatment was first determined, or * The date the last patch was removed.
Time frame: 14 days
Population: Full Analysis (N = 266) consisted of subjects who were randomized into the double-blind evaluation phase, were exposed to study drug, and provided at least 1 efficacy assessment during the double-blind evaluation phase.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Double-blind Placebo Patch | Time (Days) From the Initial Dose of Study Drug in the Double-blind Evaluation Phase to Ineffective Treatment | 5.6 Days | Standard Error 0.44 |
| Double-blind BTDS | Time (Days) From the Initial Dose of Study Drug in the Double-blind Evaluation Phase to Ineffective Treatment | 7.4 Days | Standard Error 0.45 |