Trial Outcomes & Findings for Efficacy Study to Evaluate Buprenorphine HCl Buccal Film in Opioid-Experienced Subjects (NCT NCT01675167)

Last Updated: 2017-02-27

Results Overview

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).

Recruitment status

COMPLETED

Study phase

PHASE3

Target enrollment

815 participants

Primary outcome timeframe

Baseline, week 12

Results posted on

2017-02-27

Participant Flow

Of 1656 subjects screened, 938 subjects entered an analgesic taper phase and 1 subject was eligible to bypass the analgesic taper phase; a total of 815 subjects progressed to the open-label (OL) titration phase. Subjects who completed the open-label titration phase (511) were eligible for randomization in the double-blind (DB) treatment phase.

Participant milestones

Participant milestones
Measure	OL Buprenorphine HCl Buccal Film Buprenorphine hydrochloride (HCl) buccal film, 150, 300, 450, 600, 750, or 900 μg, applied to the buccal mucosa every 12 hours for up to 8 weeks in the open-label titration period	DB Buprenorphine HCl Buccal Film Buprenorphine HCl buccal film, 150, 300, 450, 600, 750, or 900 μg, applied to the buccal mucosa every 12 hours for 12 weeks in the double-blind treatment period	DB Placebo Film Placebo buccal film applied to the buccal mucosa every 12 hours for 12 weeks in the double-blind treatment period
Open-label Titration Phase STARTED	815	0	0
Open-label Titration Phase COMPLETED	511	0	0
Open-label Titration Phase NOT COMPLETED	304	0	0
Double-blind Treatment Phase STARTED	0	254	257
Double-blind Treatment Phase COMPLETED	0	206	147
Double-blind Treatment Phase NOT COMPLETED	0	48	110

Reasons for withdrawal

Reasons for withdrawal
Measure	OL Buprenorphine HCl Buccal Film Buprenorphine hydrochloride (HCl) buccal film, 150, 300, 450, 600, 750, or 900 μg, applied to the buccal mucosa every 12 hours for up to 8 weeks in the open-label titration period	DB Buprenorphine HCl Buccal Film Buprenorphine HCl buccal film, 150, 300, 450, 600, 750, or 900 μg, applied to the buccal mucosa every 12 hours for 12 weeks in the double-blind treatment period	DB Placebo Film Placebo buccal film applied to the buccal mucosa every 12 hours for 12 weeks in the double-blind treatment period
Open-label Titration Phase Adverse Event	81	0	0
Open-label Titration Phase Lack of Efficacy	63	0	0
Open-label Titration Phase Withdrawal by Subject	46	0	0
Open-label Titration Phase Protocol Violation	43	0	0
Open-label Titration Phase Lost to Follow-up	15	0	0
Open-label Titration Phase Withdrawal due to opioid withdrawal	1	0	0
Open-label Titration Phase Other	55	0	0
Double-blind Treatment Phase Lack of Efficacy	0	19	61
Double-blind Treatment Phase Withdrawal by Subject	0	11	6
Double-blind Treatment Phase Adverse Event	0	5	13
Double-blind Treatment Phase Protocol Violation	0	4	11
Double-blind Treatment Phase Lost to Follow-up	0	1	5
Double-blind Treatment Phase Withdrawal due to opioid withdrawal	0	1	9
Double-blind Treatment Phase Other	0	7	5

Baseline Characteristics

Efficacy Study to Evaluate Buprenorphine HCl Buccal Film in Opioid-Experienced Subjects

Baseline characteristics by cohort

Baseline characteristics by cohort
Measure	DB Buprenorphine HCl Buccal Film n=243 Participants Buprenorphine HCl buccal film, 150, 300, 450, 600, 750, or 900 μg, applied to the buccal mucosa every 12 hours for 12 weeks in the double-blind treatment period	DB Placebo Film n=248 Participants Placebo buccal film applied to the buccal mucosa every 12 hours for 12 weeks in the double-blind treatment period	Total n=491 Participants Total of all reporting groups
Age, Categorical <=18 years	0 Participants n=5 Participants	0 Participants n=7 Participants	0 Participants n=5 Participants
Age, Categorical Between 18 and 65 years	211 Participants n=5 Participants	206 Participants n=7 Participants	417 Participants n=5 Participants
Age, Categorical >=65 years	32 Participants n=5 Participants	42 Participants n=7 Participants	74 Participants n=5 Participants
Age, Continuous	53.0 years n=5 Participants	55.0 years n=7 Participants	54.0 years n=5 Participants
Gender Female	130 Participants n=5 Participants	136 Participants n=7 Participants	266 Participants n=5 Participants
Gender Male	113 Participants n=5 Participants	112 Participants n=7 Participants	225 Participants n=5 Participants
Region of Enrollment United States	243 participants n=5 Participants	248 participants n=7 Participants	491 participants n=5 Participants

PRIMARY outcome

Timeframe: 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 19 subjects from 1 site were excluded from the population.

Outcome measures

Outcome measures
Measure	DB Buprenorphine HCl Buccal Film n=243 Participants Buprenorphine HCl buccal film, 150, 300, 450, 600, 750, or 900 μg, applied to the buccal mucosa every 12 hours for 12 weeks in the double-blind treatment period	DB Placebo Film n=248 Participants Placebo buccal film applied to the buccal mucosa every 12 hours for 12 weeks in the double-blind treatment period
Change From Baseline to Week 12 in Average Daily Pain Intensity Scores	0.88 units on a scale Standard Deviation 1.785	1.92 units on a scale Standard Deviation 1.867

SECONDARY outcome

Timeframe: 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 numeric rating scale (NRS) ranging from 0 (no pain) to 10 (worst pain imaginable).

Outcome measures

Outcome measures
Measure	DB Buprenorphine HCl Buccal Film n=243 Participants Buprenorphine HCl buccal film, 150, 300, 450, 600, 750, or 900 μg, applied to the buccal mucosa every 12 hours for 12 weeks in the double-blind treatment period	DB Placebo Film n=248 Participants Placebo buccal film applied to the buccal mucosa every 12 hours for 12 weeks in the double-blind treatment period
Number of Participants With Response to Treatment (Responder) Using NRS Scale Responders with ≥30% pain reduction	156 participants	76 participants
Number of Participants With Response to Treatment (Responder) Using NRS Scale Responders with ≥50% pain reduction	96 participants	42 participants

SECONDARY outcome

Timeframe: Week 1 to Week 12

Use of analgesic rescue medication recorded in subject diary

Outcome measures

Outcome measures
Measure	DB Buprenorphine HCl Buccal Film n=243 Participants Buprenorphine HCl buccal film, 150, 300, 450, 600, 750, or 900 μg, applied to the buccal mucosa every 12 hours for 12 weeks in the double-blind treatment period	DB Placebo Film n=248 Participants Placebo buccal film applied to the buccal mucosa every 12 hours for 12 weeks in the double-blind treatment period
Number of Subjects With Opioid Rescue Medication Use Week 1 (n=242, 246)	215 participants	228 participants
Number of Subjects With Opioid Rescue Medication Use Week 2 (n=234, 204)	202 participants	185 participants
Number of Subjects With Opioid Rescue Medication Use Week 3 (n=229, 189)	197 participants	172 participants
Number of Subjects With Opioid Rescue Medication Use Week 4 (n=229, 179)	191 participants	164 participants
Number of Subjects With Opioid Rescue Medication Use Week 5 (n=222, 162)	186 participants	147 participants
Number of Subjects With Opioid Rescue Medication Use Week 6 (n=219, 161)	185 participants	146 participants
Number of Subjects With Opioid Rescue Medication Use Week 7 (n=213, 154)	178 participants	140 participants
Number of Subjects With Opioid Rescue Medication Use Week 8 (n=210, 152)	177 participants	137 participants
Number of Subjects With Opioid Rescue Medication Use Week 9 (n=207, 146)	173 participants	129 participants
Number of Subjects With Opioid Rescue Medication Use Week 10 (n=205, 145)	172 participants	130 participants
Number of Subjects With Opioid Rescue Medication Use Week 11 (n=203, 144)	172 participants	130 participants
Number of Subjects With Opioid Rescue Medication Use Week 12 (n=201, 141)	166 participants	128 participants

SECONDARY outcome

Timeframe: 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

Overall time to reach the "optimum" dose of study medication required to progress to double-blind treatment

Outcome measures

Outcome measures
Measure	DB Buprenorphine HCl Buccal Film n=511 Participants Buprenorphine HCl buccal film, 150, 300, 450, 600, 750, or 900 μg, applied to the buccal mucosa every 12 hours for 12 weeks in the double-blind treatment period	DB Placebo Film Placebo buccal film applied to the buccal mucosa every 12 hours for 12 weeks in the double-blind treatment period
Time to Optimal Dose of Open-label Study Medication	24.5 days Standard Deviation 11.70	—

SECONDARY outcome

Timeframe: 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.

Outcome measures

Outcome measures
Measure	DB Buprenorphine HCl Buccal Film n=243 Participants Buprenorphine HCl buccal film, 150, 300, 450, 600, 750, or 900 μg, applied to the buccal mucosa every 12 hours for 12 weeks in the double-blind treatment period	DB Placebo Film n=248 Participants Placebo buccal film applied to the buccal mucosa every 12 hours for 12 weeks in the double-blind treatment period
Percentage of Participants With Treatment Failure in the Double-blind Treatment Phase (up to 12 Weeks)	9.9 percentage of participants	29.4 percentage of participants

SECONDARY outcome

Timeframe: 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 (19). Includes only participants with PGIC assessment at week 12 (n=231 buprenorphine and n=230 placebo).

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)

Outcome measures

Outcome measures
Measure	DB Buprenorphine HCl Buccal Film n=231 Participants Buprenorphine HCl buccal film, 150, 300, 450, 600, 750, or 900 μg, applied to the buccal mucosa every 12 hours for 12 weeks in the double-blind treatment period	DB Placebo Film n=230 Participants Placebo buccal film applied to the buccal mucosa every 12 hours for 12 weeks in the double-blind treatment period
Patient Global Impression of Change	4.5 units on a scale Standard Deviation 1.86	3.2 units on a scale Standard Deviation 1.98

SECONDARY outcome

Timeframe: 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 (19). Includes only participants with RMDQ assessment at week 12 (n=225 buprenorphine and n=231 placebo).

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.

Outcome measures

Outcome measures
Measure	DB Buprenorphine HCl Buccal Film n=225 Participants Buprenorphine HCl buccal film, 150, 300, 450, 600, 750, or 900 μg, applied to the buccal mucosa every 12 hours for 12 weeks in the double-blind treatment period	DB Placebo Film n=231 Participants Placebo buccal film applied to the buccal mucosa every 12 hours for 12 weeks in the double-blind treatment period
Change From Baseline to Week 12 in Roland Morris Disability Questionnaire	0.5 units on a scale Standard Deviation 5.03	1.6 units on a scale Standard Deviation 5.63

SECONDARY outcome

Timeframe: 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 (19). Includes only participants with MOS assessment at week 12 (n=231 buprenorphine and n=230 placebo).

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).

Outcome measures

Outcome measures
Measure	DB Buprenorphine HCl Buccal Film n=231 Participants Buprenorphine HCl buccal film, 150, 300, 450, 600, 750, or 900 μg, applied to the buccal mucosa every 12 hours for 12 weeks in the double-blind treatment period	DB Placebo Film n=230 Participants Placebo buccal film applied to the buccal mucosa every 12 hours for 12 weeks in the double-blind treatment period
Change From Baseline to Week 12 in Medical Outcome Score Sleep Subscale Sleep problems index	-0.36 units on a scale Standard Deviation 7.857	-1.37 units on a scale Standard Deviation 8.359
Change From Baseline to Week 12 in Medical Outcome Score Sleep Subscale Sleep disturbance	-0.93 units on a scale Standard Deviation 10.739	-3.54 units on a scale Standard Deviation 12.038
Change From Baseline to Week 12 in Medical Outcome Score Sleep Subscale Somnolence	0.20 units on a scale Standard Deviation 12.927	-0.38 units on a scale Standard Deviation 15.301
Change From Baseline to Week 12 in Medical Outcome Score Sleep Subscale Sleep adequacy	0.13 units on a scale Standard Deviation 17.924	3.61 units on a scale Standard Deviation 18.326
Change From Baseline to Week 12 in Medical Outcome Score Sleep Subscale Snoring	0.87 units on a scale Standard Deviation 18.630	-2.78 units on a scale Standard Deviation 15.945
Change From Baseline to Week 12 in Medical Outcome Score Sleep Subscale Awaken short of breath or headache	0.52 units on a scale Standard Deviation 17.288	-4.26 units on a scale Standard Deviation 19.628

SECONDARY outcome

Timeframe: 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 (19). Includes only participants with MOS assessment at week 12 (n=231 buprenorphine and n=230 placebo).

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 quantity of sleep dimension is the average number of hours of sleep per night reported and optimal sleep is when the number of hours of sleep is ≥7.

Outcome measures

Outcome measures
Measure	DB Buprenorphine HCl Buccal Film n=231 Participants Buprenorphine HCl buccal film, 150, 300, 450, 600, 750, or 900 μg, applied to the buccal mucosa every 12 hours for 12 weeks in the double-blind treatment period	DB Placebo Film n=230 Participants Placebo buccal film applied to the buccal mucosa every 12 hours for 12 weeks in the double-blind treatment period
Medical Outcomes Score Sleep Subscale - Quantity of Sleep/Optimal Sleep Quantity of Sleep/Optimal Sleep ≥7	75 participants	81 participants
Medical Outcomes Score Sleep Subscale - Quantity of Sleep/Optimal Sleep Quantity of Sleep/Optimal Sleep <7	156 participants	149 participants

Adverse Events

OL Buprenorphine HCl Buccal Film

Serious events: 14 serious events

Other events: 268 other events

Deaths: 0 deaths

DB Buprenorphine HCl Buccal Film

Serious events: 4 serious events

Other events: 42 other events

Deaths: 0 deaths

DB Placebo Film

Serious events: 4 serious events

Other events: 49 other events

Deaths: 0 deaths

Serious adverse events

Other adverse events

Other adverse events
Measure	OL Buprenorphine HCl Buccal Film n=810 participants at risk Buprenorphine HCl buccal film, 150, 300, 450, 600, 750, or 900 µg, applied to the buccal mucosa every 12 hours for up to 8 weeks in the open-label titration period	DB Buprenorphine HCl Buccal Film n=254 participants at risk Buprenorphine HCl buccal film, 150, 300, 450, 600, 750, or 900 µg, applied to the buccal mucosa every 12 hours for 12 weeks in the double-blind titration period	DB Placebo Film n=256 participants at risk Placebo buccal film, 150, 300, 450, 600, 750, or 900 µg, applied to the buccal mucosa every 12 hours for 12 weeks in the double-blind titration period
Gastrointestinal disorders Constipation	8.3% 67/810 • Number of events 73 • From informed consent at screening through 14 days after last dose in the double-blind treatment phase (up to 26 weeks) Analysis based on Safety population; all enrolled subjects who received at least 1 dose of study drug in the respective period (open-label titration and double-blind treatment)	2.8% 7/254 • Number of events 8 • From informed consent at screening through 14 days after last dose in the double-blind treatment phase (up to 26 weeks) Analysis based on Safety population; all enrolled subjects who received at least 1 dose of study drug in the respective period (open-label titration and double-blind treatment)	0.78% 2/256 • Number of events 2 • From informed consent at screening through 14 days after last dose in the double-blind treatment phase (up to 26 weeks) Analysis based on Safety population; all enrolled subjects who received at least 1 dose of study drug in the respective period (open-label titration and double-blind treatment)
Gastrointestinal disorders Nausea	16.8% 136/810 • Number of events 167 • From informed consent at screening through 14 days after last dose in the double-blind treatment phase (up to 26 weeks) Analysis based on Safety population; all enrolled subjects who received at least 1 dose of study drug in the respective period (open-label titration and double-blind treatment)	7.5% 19/254 • Number of events 19 • From informed consent at screening through 14 days after last dose in the double-blind treatment phase (up to 26 weeks) Analysis based on Safety population; all enrolled subjects who received at least 1 dose of study drug in the respective period (open-label titration and double-blind treatment)	7.4% 19/256 • Number of events 19 • From informed consent at screening through 14 days after last dose in the double-blind treatment phase (up to 26 weeks) Analysis based on Safety population; all enrolled subjects who received at least 1 dose of study drug in the respective period (open-label titration and double-blind treatment)
Gastrointestinal disorders Vomiting	6.7% 54/810 • Number of events 63 • From informed consent at screening through 14 days after last dose in the double-blind treatment phase (up to 26 weeks) Analysis based on Safety population; all enrolled subjects who received at least 1 dose of study drug in the respective period (open-label titration and double-blind treatment)	5.5% 14/254 • Number of events 15 • From informed consent at screening through 14 days after last dose in the double-blind treatment phase (up to 26 weeks) Analysis based on Safety population; all enrolled subjects who received at least 1 dose of study drug in the respective period (open-label titration and double-blind treatment)	2.3% 6/256 • Number of events 6 • From informed consent at screening through 14 days after last dose in the double-blind treatment phase (up to 26 weeks) Analysis based on Safety population; all enrolled subjects who received at least 1 dose of study drug in the respective period (open-label titration and double-blind treatment)
General disorders Drug withdrawal syndrome	1.2% 10/810 • Number of events 10 • From informed consent at screening through 14 days after last dose in the double-blind treatment phase (up to 26 weeks) Analysis based on Safety population; all enrolled subjects who received at least 1 dose of study drug in the respective period (open-label titration and double-blind treatment)	3.5% 9/254 • Number of events 9 • From informed consent at screening through 14 days after last dose in the double-blind treatment phase (up to 26 weeks) Analysis based on Safety population; all enrolled subjects who received at least 1 dose of study drug in the respective period (open-label titration and double-blind treatment)	9.8% 25/256 • Number of events 25 • From informed consent at screening through 14 days after last dose in the double-blind treatment phase (up to 26 weeks) Analysis based on Safety population; all enrolled subjects who received at least 1 dose of study drug in the respective period (open-label titration and double-blind treatment)
Nervous system disorders Dizziness	5.2% 42/810 • Number of events 47 • From informed consent at screening through 14 days after last dose in the double-blind treatment phase (up to 26 weeks) Analysis based on Safety population; all enrolled subjects who received at least 1 dose of study drug in the respective period (open-label titration and double-blind treatment)	0.79% 2/254 • Number of events 2 • From informed consent at screening through 14 days after last dose in the double-blind treatment phase (up to 26 weeks) Analysis based on Safety population; all enrolled subjects who received at least 1 dose of study drug in the respective period (open-label titration and double-blind treatment)	0.78% 2/256 • Number of events 2 • From informed consent at screening through 14 days after last dose in the double-blind treatment phase (up to 26 weeks) Analysis based on Safety population; all enrolled subjects who received at least 1 dose of study drug in the respective period (open-label titration and double-blind treatment)
Nervous system disorders Headache	6.7% 54/810 • Number of events 61 • From informed consent at screening through 14 days after last dose in the double-blind treatment phase (up to 26 weeks) Analysis based on Safety population; all enrolled subjects who received at least 1 dose of study drug in the respective period (open-label titration and double-blind treatment)	2.4% 6/254 • Number of events 6 • From informed consent at screening through 14 days after last dose in the double-blind treatment phase (up to 26 weeks) Analysis based on Safety population; all enrolled subjects who received at least 1 dose of study drug in the respective period (open-label titration and double-blind treatment)	3.1% 8/256 • Number of events 8 • From informed consent at screening through 14 days after last dose in the double-blind treatment phase (up to 26 weeks) Analysis based on Safety population; all enrolled subjects who received at least 1 dose of study drug in the respective period (open-label titration and double-blind treatment)
Nervous system disorders Somnolence	5.1% 41/810 • Number of events 54 • From informed consent at screening through 14 days after last dose in the double-blind treatment phase (up to 26 weeks) Analysis based on Safety population; all enrolled subjects who received at least 1 dose of study drug in the respective period (open-label titration and double-blind treatment)	0.00% 0/254 • From informed consent at screening through 14 days after last dose in the double-blind treatment phase (up to 26 weeks) Analysis based on Safety population; all enrolled subjects who received at least 1 dose of study drug in the respective period (open-label titration and double-blind treatment)	0.00% 0/256 • From informed consent at screening through 14 days after last dose in the double-blind treatment phase (up to 26 weeks) Analysis based on Safety population; all enrolled subjects who received at least 1 dose of study drug in the respective period (open-label titration and double-blind treatment)

Additional Information

Clinical Trial Coordinator

Endo Pharmaceuticals Inc.

Email: [email protected]

Results disclosure agreements

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