Low Back Pain
Conditions
Keywords
CLBP, Chronic Low Back Pain, Chronic Pain, Back Pain
Brief summary
The purpose of this study is to determine if buprenorphine hydrochloride (HCl) buccal film is effective in treating opioid-naive subjects, with moderate to severe chronic low back pain (CLBP), who require continuous around-the-clock (ATC) pain relief for an extended period of time.
Interventions
DRUGBuprenorphine
Buprenorphine HCl Buccal Film at doses ranging from 75-600 mcg twice daily
DRUGPlacebo
Matching Placebo Buccal Film twice daily
Sponsors
BioDelivery Sciences International
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
* Diagnosis of moderate to severe low back pain for ≥6 months * Treating CLBP with a stable daily maintenance dose of non-opioid analgesic medication up to 10 mg morphine sulfate equivalents (MSE) per day for ≥4 weeks. (Additional as needed \[PRN\] non-opioid analgesic medications permitted on top of the stable daily maintenance dose of non-opioid analgesic) * Stable health, as determined by Principal Investigator * Are female who are practicing abstinence or using a medically acceptable form of contraception or have been post-menopausal, biologically sterile, or surgically sterile for more than 1 year * Willing and able to comply with all protocol required visits and assessments
Exclusion criteria
* Current cancer related pain or received chemotherapy with 6 months of screening * Receiving opioid analgesic medication \>10 mg MSE per day within 28 days of screening * Subjects with a history of other chronic painful conditions * Reflex sympathetic dystrophy or causalgia, acute spinal cord compression, cauda equina compression, acute nerve root compression, meningitis, or discitis * Allergy or contraindications to any opioid or acetaminophen * Surgical procedure for relief of pain with 6 months * Hypokalemia or clinically unstable cardiac disease, including: unstable atrial fibrillation, symptomatic bradycardia, unstable congestive heart failure, or active myocardial ischemia * QT interval corrected using Fridericia's formula (QTcF) of ≥450 milliseconds on the 12-lead electrocardiogram (ECG) * History of long QT syndrome or a family member with this condition * Moderate to severe hepatic impairment * Moderate to severe renal impairment * Current or past history of alcohol abuse * Positive urine toxicology screen for drug of abuse * History or abnormalities on physical exam, vital signs, electrocardiogram, or laboratory values
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Change From Baseline to Week 12 in Average Daily Pain Intensity Scores | Baseline, Week 12 | Change in pain intensity = average of daily pain scores from the last 7 days prior to Week 12 visit - average of daily pain scores for the last 7 days prior to randomization. Average pain intensity over the last 24 hours was rated on an 11-point numeric rating scale (NRS) ranging from 0 (no pain) to 10 (worst pain imaginable). |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Number of Subjects With Rescue Medication Use | Week 1 to Week 12 in double-blind treatment | Use of analgesic rescue medication recorded in subject diary. |
| Time to Optimal Dose of Open-label Study Medication | Up to 8 weeks in open-label titration | Overall time to reach the optimal dose of study medication required to progress to double-blind treatment. |
| Percentage of Participants With Treatment Failure in the Double-blind Treatment Phase (up to 12 Weeks) | Baseline to treatment failure or end of double-blind treatment phase (up to 12 weeks) | Treatment failure is defined as study discontinuation due to lack of efficacy or discontinuation due to adverse events in the double-blind treatment phase. |
| Number of Participants With Response to Treatment (Responder) Using NRS Scale | Prior to open-label titration to Week 12 in double-blind treatment | Responders are subjects who achieve a relative reduction in pain intensity from the start of open-label titration to Week 12 in double-blind treatment. Average pain intensity over the last 24 hours was rated on an 11-point NRS ranging from 0 (no pain) to 10 (worst pain imaginable). |
| Change From Baseline to Week 12 in Roland Morris Disability Questionnaire | Baseline, Week 12 | Subjects assess disability due to back pain using the Roland Morris Disability Questionnaire (RMDQ) consisting of 24 statements of disability. The score of the RMDQ is the total number of items checked, ranging from 0 to 24 with higher scores indicating greater disability. |
| Change From Baseline to Week 12 in Medical Outcomes Score Sleep Subscale | Baseline, Week 12 | Medical Outcomes Score (MOS) Sleep Scale uses 12 items to measure 6 dimensions of sleep (sleep disturbance, somnolence, sleep adequacy, snoring, awaken short of breath or headache, and quantity of sleep/optimal sleep) and an overall sleep problems index score. The scores of the dimensions (except quantity of sleep/optimal sleep) and of the sleep problem index range on a 0 to 100 scale, with higher scores reflecting more of the attribute implied by the name (eg, greater sleep disturbance, greater adequacy of sleep). |
| Patient Global Impression of Change | Week 12 | Subjects assessed their change in activity limitations as they relate to their painful condition since beginning treatment using the Patient Global Impression of Change (PGIC) questionnaire, a 7-point scale ranging from 1 (no change \[or condition has got worse\]) to 7 (a great deal better, and a considerable improvement that made all the difference) |
Countries
United States
Participant flow
Pre-assignment details
Of 1633 subjects screened, a total of 752 subjects were enrolled into the open-label (OL) titration phase. Subjects who completed the OL titration phase (462) were eligible for randomization in the double-blind (DB) treatment phase.
Participants by arm
| Arm | Count |
|---|---|
| DB Buprenorphine HCl Buccal Film Buprenorphine HCl buccal film, 150, 300, or 450 µg, applied to the buccal mucosa every 12 hours for 12 weeks in the double-blind treatment phase | 209 |
| DB Placebo Film Placebo buccal film applied to the buccal mucosa every 12 hours for 12 weeks in the double-blind treatment phase | 211 |
| Total | 420 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 | FG002 |
|---|---|---|---|---|
| Double-blind Treatment Phase | Adverse Event | 0 | 13 | 7 |
| Double-blind Treatment Phase | Lack of Efficacy | 0 | 8 | 23 |
| Double-blind Treatment Phase | Lost to Follow-up | 0 | 4 | 9 |
| Double-blind Treatment Phase | Not exposed to DB study medication | 0 | 1 | 0 |
| Double-blind Treatment Phase | Other | 0 | 7 | 0 |
| Double-blind Treatment Phase | Protocol Violation | 0 | 7 | 10 |
| Double-blind Treatment Phase | Withdrawal by Subject | 0 | 11 | 8 |
| Double-blind Treatment Phase | Withdrawal due to opioid withdrawal | 0 | 3 | 1 |
| Open-label Titration Phase | Adverse Event | 109 | 0 | 0 |
| Open-label Titration Phase | Lack of Efficacy | 33 | 0 | 0 |
| Open-label Titration Phase | Lost to Follow-up | 22 | 0 | 0 |
| Open-label Titration Phase | Other | 68 | 0 | 0 |
| Open-label Titration Phase | Protocol Violation | 24 | 0 | 0 |
| Open-label Titration Phase | Withdrawal by Subject | 34 | 0 | 0 |
Baseline characteristics
| Characteristic | DB Placebo Film | Total | DB Buprenorphine HCl Buccal Film |
|---|---|---|---|
| Age, Categorical <=18 years | 0 Participants | 0 Participants | 0 Participants |
| Age, Categorical >=65 years | 25 Participants | 54 Participants | 29 Participants |
| Age, Categorical Between 18 and 65 years | 186 Participants | 366 Participants | 180 Participants |
| Age, Continuous | 49.0 years | 51.0 years | 52.0 years |
| Gender Female | 124 Participants | 231 Participants | 107 Participants |
| Gender Male | 87 Participants | 189 Participants | 102 Participants |
| Region of Enrollment United States | 211 participants | 420 participants | 209 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 | 443 / 749 | 43 / 229 | 31 / 232 |
| serious Total, serious adverse events | 4 / 749 | 3 / 229 | 1 / 232 |
Outcome results
Primary
Change From Baseline to Week 12 in Average Daily Pain Intensity Scores
Change in pain intensity = average of daily pain scores from the last 7 days prior to Week 12 visit - average of daily pain scores for the last 7 days prior to randomization. Average pain intensity over the last 24 hours was rated on an 11-point numeric rating scale (NRS) ranging from 0 (no pain) to 10 (worst pain imaginable).
Time frame: Baseline, Week 12
Population: Analysis based on ITT population; all randomized subjects who received at least 1 dose of double-blind study medication. One (1) subject did not receive double-blind study medication and an additional 41 subjects from 1 site were excluded from the population.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| DB Buprenorphine HCl Buccal Film | Change From Baseline to Week 12 in Average Daily Pain Intensity Scores | 0.94 units on a scale | Standard Deviation 1.846 |
| DB Placebo Film | Change From Baseline to Week 12 in Average Daily Pain Intensity Scores | 1.59 units on a scale | Standard Deviation 2.04 |
p-value: 0.001295% CI: [-1.07, -0.26]ANCOVA
Secondary
Change From Baseline to Week 12 in Medical Outcomes Score Sleep Subscale
Medical Outcomes Score (MOS) Sleep Scale uses 12 items to measure 6 dimensions of sleep (sleep disturbance, somnolence, sleep adequacy, snoring, awaken short of breath or headache, and quantity of sleep/optimal sleep) and an overall sleep problems index score. The scores of the dimensions (except quantity of sleep/optimal sleep) and of the sleep problem index range on a 0 to 100 scale, with higher scores reflecting more of the attribute implied by the name (eg, greater sleep disturbance, greater adequacy of sleep).
Time frame: Baseline, Week 12
Population: Analysis based on PRO population; randomized subjects who received at least 1 dose of double-blind study medication and had at least 1 post-dose assessment on PRO measures. Subjects from 1 site are excluded from the population (41). Includes only participants with MOS assessment at week 12 (n=199 buprenorphine and n=194 placebo).
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| DB Buprenorphine HCl Buccal Film | Change From Baseline to Week 12 in Medical Outcomes Score Sleep Subscale | Sleep problems index | -0.23 units on a scale | Standard Deviation 8.274 |
| DB Buprenorphine HCl Buccal Film | Change From Baseline to Week 12 in Medical Outcomes Score Sleep Subscale | Sleep disturbance | -1.43 units on a scale | Standard Deviation 12.405 |
| DB Buprenorphine HCl Buccal Film | Change From Baseline to Week 12 in Medical Outcomes Score Sleep Subscale | Somnolence | 0.90 units on a scale | Standard Deviation 15.823 |
| DB Buprenorphine HCl Buccal Film | Change From Baseline to Week 12 in Medical Outcomes Score Sleep Subscale | Sleep adequacy | 1.71 units on a scale | Standard Deviation 19.204 |
| DB Placebo Film | Change From Baseline to Week 12 in Medical Outcomes Score Sleep Subscale | Sleep adequacy | 6.19 units on a scale | Standard Deviation 19.285 |
| DB Placebo Film | Change From Baseline to Week 12 in Medical Outcomes Score Sleep Subscale | Sleep problems index | 0.10 units on a scale | Standard Deviation 8.48 |
| DB Placebo Film | Change From Baseline to Week 12 in Medical Outcomes Score Sleep Subscale | Somnolence | 0.14 units on a scale | Standard Deviation 17.381 |
| DB Placebo Film | Change From Baseline to Week 12 in Medical Outcomes Score Sleep Subscale | Sleep disturbance | -1.68 units on a scale | Standard Deviation 12.515 |
Secondary
Change From Baseline to Week 12 in Roland Morris Disability Questionnaire
Subjects assess disability due to back pain using the Roland Morris Disability Questionnaire (RMDQ) consisting of 24 statements of disability. The score of the RMDQ is the total number of items checked, ranging from 0 to 24 with higher scores indicating greater disability.
Time frame: Baseline, Week 12
Population: Analysis based on PRO population; randomized subjects who received at least 1 dose of double-blind study medication and had at least 1 post-dose assessment on PRO measures. Subjects from 1 site are excluded from the population (41). Includes only participants with RMDQ assessment at week 12 (n=193 buprenorphine and n=189 placebo).
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| DB Buprenorphine HCl Buccal Film | Change From Baseline to Week 12 in Roland Morris Disability Questionnaire | 0.6 units on a scale | Standard Deviation 5.37 |
| DB Placebo Film | Change From Baseline to Week 12 in Roland Morris Disability Questionnaire | 1.2 units on a scale | Standard Deviation 5.75 |
Secondary
Number of Participants With Response to Treatment (Responder) Using NRS Scale
Responders are subjects who achieve a relative reduction in pain intensity from the start of open-label titration to Week 12 in double-blind treatment. Average pain intensity over the last 24 hours was rated on an 11-point NRS ranging from 0 (no pain) to 10 (worst pain imaginable).
Time frame: Prior to open-label titration to Week 12 in double-blind treatment
Population: Analysis based on ITT population; all randomized subjects who received at least 1 dose of double-blind study medication. One (1) subject did not receive double-blind study medication and an additional 41 subjects from 1 site were excluded from the population.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| DB Buprenorphine HCl Buccal Film | Number of Participants With Response to Treatment (Responder) Using NRS Scale | Responders with ≥30% pain reduction | 131 participants |
| DB Buprenorphine HCl Buccal Film | Number of Participants With Response to Treatment (Responder) Using NRS Scale | Responders with ≥50% pain reduction | 86 participants |
| DB Placebo Film | Number of Participants With Response to Treatment (Responder) Using NRS Scale | Responders with ≥30% pain reduction | 99 participants |
| DB Placebo Film | Number of Participants With Response to Treatment (Responder) Using NRS Scale | Responders with ≥50% pain reduction | 69 participants |
Comparison: Responders with ≥50% pain reductionp-value: 0.0754Cochran-Mantel-Haenszel
Comparison: Responders with ≥30% pain reductionp-value: 0.0012Cochran-Mantel-Haenszel
Secondary
Number of Subjects With Rescue Medication Use
Use of analgesic rescue medication recorded in subject diary.
Time frame: Week 1 to Week 12 in double-blind treatment
Population: Analysis based on ITT population; all randomized subjects who received at least 1 dose of double-blind study medication. One (1) subject did not receive double-blind study medication and an additional 41 subjects from 1 site were excluded from the population.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| DB Buprenorphine HCl Buccal Film | Number of Subjects With Rescue Medication Use | Week 1 | 123 participants |
| DB Buprenorphine HCl Buccal Film | Number of Subjects With Rescue Medication Use | Week 2 | 112 participants |
| DB Buprenorphine HCl Buccal Film | Number of Subjects With Rescue Medication Use | Week 3 | 85 participants |
| DB Buprenorphine HCl Buccal Film | Number of Subjects With Rescue Medication Use | Week 4 | 81 participants |
| DB Buprenorphine HCl Buccal Film | Number of Subjects With Rescue Medication Use | Week 5 | 76 participants |
| DB Buprenorphine HCl Buccal Film | Number of Subjects With Rescue Medication Use | Week 6 | 74 participants |
| DB Buprenorphine HCl Buccal Film | Number of Subjects With Rescue Medication Use | Week 7 | 73 participants |
| DB Buprenorphine HCl Buccal Film | Number of Subjects With Rescue Medication Use | Week 8 | 64 participants |
| DB Buprenorphine HCl Buccal Film | Number of Subjects With Rescue Medication Use | Week 9 | 67 participants |
| DB Buprenorphine HCl Buccal Film | Number of Subjects With Rescue Medication Use | Week 10 | 60 participants |
| DB Buprenorphine HCl Buccal Film | Number of Subjects With Rescue Medication Use | Week 11 | 62 participants |
| DB Buprenorphine HCl Buccal Film | Number of Subjects With Rescue Medication Use | Week 12 | 56 participants |
| DB Placebo Film | Number of Subjects With Rescue Medication Use | Week 11 | 72 participants |
| DB Placebo Film | Number of Subjects With Rescue Medication Use | Week 1 | 140 participants |
| DB Placebo Film | Number of Subjects With Rescue Medication Use | Week 7 | 85 participants |
| DB Placebo Film | Number of Subjects With Rescue Medication Use | Week 2 | 132 participants |
| DB Placebo Film | Number of Subjects With Rescue Medication Use | Week 10 | 81 participants |
| DB Placebo Film | Number of Subjects With Rescue Medication Use | Week 3 | 107 participants |
| DB Placebo Film | Number of Subjects With Rescue Medication Use | Week 8 | 85 participants |
| DB Placebo Film | Number of Subjects With Rescue Medication Use | Week 4 | 98 participants |
| DB Placebo Film | Number of Subjects With Rescue Medication Use | Week 12 | 72 participants |
| DB Placebo Film | Number of Subjects With Rescue Medication Use | Week 5 | 92 participants |
| DB Placebo Film | Number of Subjects With Rescue Medication Use | Week 9 | 82 participants |
| DB Placebo Film | Number of Subjects With Rescue Medication Use | Week 6 | 94 participants |
Secondary
Patient Global Impression of Change
Subjects assessed their change in activity limitations as they relate to their painful condition since beginning treatment using the Patient Global Impression of Change (PGIC) questionnaire, a 7-point scale ranging from 1 (no change \[or condition has got worse\]) to 7 (a great deal better, and a considerable improvement that made all the difference)
Time frame: Week 12
Population: Analysis based on Patient-Reported Outcomes (PRO) population; randomized subjects who received at least 1 dose of double-blind medication and had at least 1 post-dose assessment on PRO measures. Subjects from 1 site excluded from population (41). Includes only participants with PGIC assessment at week 12 (n=198 buprenorphine and n=194 placebo).
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| DB Buprenorphine HCl Buccal Film | Patient Global Impression of Change | 4.5 units on a scale | Standard Deviation 1.75 |
| DB Placebo Film | Patient Global Impression of Change | 3.9 units on a scale | Standard Deviation 1.99 |
Secondary
Percentage of Participants With Treatment Failure in the Double-blind Treatment Phase (up to 12 Weeks)
Treatment failure is defined as study discontinuation due to lack of efficacy or discontinuation due to adverse events in the double-blind treatment phase.
Time frame: Baseline to treatment failure or end of double-blind treatment phase (up to 12 weeks)
Population: Analysis based on ITT population; all randomized subjects who received at least 1 dose of double-blind study medication. One (1) subject did not receive double-blind study medication and an additional 41 subjects from 1 site were excluded from the population.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| DB Buprenorphine HCl Buccal Film | Percentage of Participants With Treatment Failure in the Double-blind Treatment Phase (up to 12 Weeks) | 9.6 percentage of participants |
| DB Placebo Film | Percentage of Participants With Treatment Failure in the Double-blind Treatment Phase (up to 12 Weeks) | 14.2 percentage of participants |
Secondary
Time to Optimal Dose of Open-label Study Medication
Overall time to reach the optimal dose of study medication required to progress to double-blind treatment.
Time frame: Up to 8 weeks in open-label titration
Population: Analysis based on randomized subjects in the Safety population; all subjects who received at least 1 dose of study medication and were randomized into double-blind treatment.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| DB Buprenorphine HCl Buccal Film | Time to Optimal Dose of Open-label Study Medication | 17.1 days | Standard Deviation 7.77 |