Study of Buprenorphine Sublingual Spray for the Treatment of Moderate to Severe Pain

Study Overview
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Brief Summary
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The primary objective of this trial is to evaluate analgesic efficacy of Buprenorphine Sublingual (under the tongue) Spray compared with placebo in participants with postoperative pain after bunionectomy.

Official Title
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A Phase 3, Randomized, Double Blind, Multiple Dose, Parallel Group, Placebo Controlled Study of Buprenorphine Sublingual Spray (0.5 mg TID, 0.25 mg TID, and 0.125 mg TID) for the Treatment of Moderate to Severe Pain

Conditions
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Pain

Intervention / Treatment
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* Drug: Buprenorphine
* Drug: Placebo


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Meets protocol-specified criteria for qualification and contraception Willing and able to remain confined in the study unit for the entire duration of each treatment period and comply with restrictions related food, drink and medications Voluntarily consents to participate and provides written informed consent prior to any protocol-specific procedures Exclusion Criteria: History or current use of over-the-counter medications, dietary supplements, or drugs (including nicotine and alcohol) outside protocol-specified parameters Signs, symptoms or history of any condition that, per protocol or in the opinion of the investigator, might compromise: the safety or well-being of the participant or study staff; the safety or well-being of the participant's offspring (such as through pregnancy or breast-feeding); the analysis of results

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 65 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Double


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Buprenorphine 0.5 mg TID<br>Participants received buprenorphine 0.5 mg sublingual (under the tongue) spray three times daily (TID) for two days. | Drug: Buprenorphine<br>* Buprenorphine sublingual spray delivered via single 100 μL spray<br>|
| Experimental: Buprenorphine 0.25 mg TID<br>Participants received buprenorphine 0.25 mg sublingual spray TID for two days. | Drug: Buprenorphine<br>* Buprenorphine sublingual spray delivered via single 100 μL spray<br>|
| Experimental: Buprenorphine 0.125 mg TID<br>Participants received buprenorphine 0.125 mg sublingual spray TID for two days. | Drug: Buprenorphine<br>* Buprenorphine sublingual spray delivered via single 100 μL spray<br>|
| Placebo Comparator: Placebo<br>Participants received placebo-matching buprenorphine sublingual spray TID for two days. | Drug: Placebo<br>* Placebo-matching buprenorphine sublingual spray delivered via single 100 μL spray<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Numeric Rating Scale (NRS) Summed Pain Intensity Difference (SPID) Over 0 to 48 Hours After Time 0 (NRS SPID-48) | Pain intensity was assessed by the participant using an 11-point NRS from 0=no pain to 10=worst possible pain. Pain intensity scores were collected at Baseline (prior to study drug) and at multiple time points up to 48 hours after Time 0 (administration of first dose of study drug). Pain intensity difference is calculated by subtracting the pain intensity at each time point from the pain intensity at Time 0. The SPID scores are the sum of the differences at each time point multiplied by the duration in hours since the previous time point. Positive numbers indicate a reduction in pain [maximum(max)=10 at each time point], and negative numbers indicate an increase in pain [minimum(min)=-10 at each time point]. The overall min and max are -10 and 10 times the number of hours specified; SPID-48 range is -480 to 480. The NRS SPID-48 was analyzed using an analysis of covariance (ANCOVA) model, which included treatment and site as main effects and Baseline pain intensity as the covariate. | Baseline and 0 to 48 hours after Time 0 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| NRS Mean Pain Intensity Difference (PID) at 4, 8, 24 and 48 Hours After Time 0 | Pain intensity was assessed by the participant using an 11-point NRS from 0=no pain to 10=worst possible pain. Pain intensity scores were collected at Baseline (prior to study drug administration) and at multiple time points up to 48 hours after Time 0 (time of administration of the first dose of study drug). NRS PID is defined as the difference in pain at each scheduled timepoint relative to Baseline (PID=pain intensity at baseline - pain intensity at time point). A higher value of NRS PID score indicates a higher decrease in pain from Baseline. | Baseline and 4, 8, 24 and 48 hours after Time 0 | 
| NRS Mean Pain Intensity Score at 4, 8, 24 and 48 Hours After Time 0 | Pain intensity was assessed by the participant using an 11-point NRS from 0=no pain to 10=worst possible pain. Pain intensity scores were collected at Baseline (prior to study drug administration) and at multiple time points up to 48 hours after Time 0 (time of administration of the first dose of study drug). A lower value indicates improvement in pain. | 4, 8, 24 and 48 hours after Time 0 | 
| NRS SPID Over 4 Hours (SPID-4), 8 Hours (SPID-8) and 24 Hours (SPID-24) After Time 0 | Pain intensity was assessed by the participant using an 11-point NRS from 0=no pain to 10=worst possible pain. Pain intensity scores were collected at Baseline (prior to study drug) and at multiple time points up to 48 hours after Time 0 (administration of first dose of study drug). Pain intensity difference is calculated by subtracting the pain intensity at each time point from the pain intensity at Time 0. The SPID scores are the sum of the differences at each time point multiplied by the duration in hours since the previous time point. Positive numbers indicate a reduction in pain [max=10 at each time point] and negative numbers indicate an increase in pain [min=-10 at each time point]. The overall min and max are -10 and 10 times the number of hours specified: SPID-4=(-40 to 40), SPID-8=(-80 to 80) and SPID-24=(-240 to 240). The NRS SPID-4, 8 and 24 were analyzed using an ANCOVA model which included treatment and site as main effects and Baseline pain intensity as the covariate. | Baseline and 0 to 4, 0 to 8 and 0 to 24 hours after Time 0 | 
| Total Pain Relief (TOTPAR) Over 4, 8, 24 and 48 Hours After Time 0 | TOTPAR was assessed by the participant using a 5-point NRS (0=no relief, 1=a little, 2=some, 3=a lot, 4=complete relief). TOTPAR scores were collected at Baseline (prior to study drug) and at multiple time points up to 48 hours after Time 0 (first dose of study drug). The TOTPAR scores are the sum of the pain relief at each time point multiplied by the duration in hours since the previous time point. Larger positive numbers indicate more pain relief (maximum=4 at each time point) and smaller positive numbers indicate less pain relief (minimum=0 at each time point). The overall minimum is 0 for each variable and the overall maximum is 4 times the number of hours specified for the variable: TOTPAR-4=(0 to 16), TOTPAR-8=(0 to 32), TOTPAR-24=(0 to 96) and TOTPAR-48=(0 to 192). TOTPAR-4, TOTPAR-8, TOTPAR-24 and TOTPAR-48 were analyzed using an ANCOVA model with factors for treatment, site and baseline pain intensity. | 4, 8, 24 and 48 hours after Time 0 | 
| Time to Onset of Analgesia | Time to onset of analgesia was measured as time to first perceptible pain relief confirmed by meaningful pain relief using the 2-stopwatch method. The study staff started 2 stopwatches as soon as the first dose of study drug was administered. Each participant was instructed to stop the first stopwatch when he or she experienced any perceptible pain relief and the second stopwatch when he or she experienced pain relief that was meaningful to them. If the second stopwatch was not stopped, time was censored at the time of the second dose of study drug or the use of rescue medication, whichever came first. If both stopwatches were not stopped time was censored at the time of the second dose of study drug or the use of rescue medication whichever came first. Time to onset of analgesia was defined as the time when the first stopwatch was stopped given that the second stopwatch is stopped. | From Time 0 (first dose of study drug) to time of confirmed meaningful pain relief (up to 64 minutes) | 
| Percentage of Participants With Scores in Each Pain Relief Category at 4, 8, 24 and 48 Hours After Time 0 | Pain relief was assessed by the participant using a 5-point NRS (0=no relief, 1=a little, 2=some, 3=a lot, 4=complete relief). The percentage of participants with scores in each pain relief category are reported. Missing values were imputed. | 4, 8, 24 and 48 hours after Time 0 (first dose of study drug) | 
| Percentage of Participants With Peak Scores in Each Pain Relief Category | Peak pain relief is the highest value of pain relief experienced during the study. Pain relief was assessed by the participant using a 5-point NRS (0=no relief, 1=a little, 2=some, 3=a lot, 4=complete relief). The percentage of participants with peak scores in each pain relief category are reported. | From Time 0 (first dose of study drug) up to 48 hours | 
| Time to Peak Pain Relief | Time to peak pain relief is the time to the highest value of pain relief experienced during the study. Pain relief was assessed by the participant using a 5-point NRS (0=no relief, 1=a little, 2=some, 3=a lot, 4=complete relief). If no pain relief was observed, then the time was censored at the time of the last pain assessment. | From Time 0 (first dose of study drug) to time of peak pain relief (up to 1437 minutes) | 
| Time to First Perceptible Pain Relief | Time to first perceptible pain relief was evaluated using the 2 stopwatch method and is defined as the time when the participant stops the first stopwatch. If it was not stopped time was censored at the time that the second stopwatch was stopped or the time of the second dose or the time that rescue medication was used whichever came first. | From Time 0 (first dose of study drug) to time of first perceptible pain relief (up to 83 minutes) | 
| Time to Meaningful Pain Relief | Time to meaningful pain relief was evaluated using the 2 stopwatch method and is defined as the time when the participant stops the second stopwatch. If it was not stopped time was censored at the time that the second stopwatch was stopped or the time of the second dose or the time that rescue medication was used whichever came first. | From Time 0 (first dose of study drug) to time of meaningful pain relief (up to 227 minutes) | 
| Percentage of Participants Using Rescue Medication for Pain | The percentage of participants who needed to take an alternate medication for pain relief during the treatment period. | From Time 0 (first dose of study drug) up to 48 hours | 
| Time to First Use of Rescue Medication for Pain | Time to first use of rescue medication is the time from Time 0 (time of administration of the first dose of study drug) to the first use of rescue medication. If rescue medication was not taken the time was censored at the time of the last pain assessment. | From Time 0 to time of first use of rescue medication (up to 280 minutes) | 
| Total Use of Rescue Medication Over 0 to 24 Hours and 0 to 48 Hours | Total use of rescue medication is defined as the number of times a participant took rescue medication. | Over 24 and 48 hours after Time 0 (first dose of study drug) | 
| Participant's Global Evaluation of Study Drug | Global evaluation of study drug was completed at the end of treatment (Day 3) or before early termination if a participant discontinued early. Participants were asked to provide an overall rating of their study medication in controlling pain on a 5-point NRS, where 0=poor, 1=fair, 2=good, 3=very good, and 4=excellent. The percentage of participants with scores in each pain relief category are reported. | End of treatment (Day 3) or early termination | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Post-Surgical Pain, Bunionectomy