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

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.

Time frame: Baseline and 0 to 48 hours after Time 0

Population: All randomized participants from the Intent-to-Treat (ITT) Population who did not have missing SPID-48 values. Missing SPID-48 data were not imputed.

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.

Time frame: Baseline and 4, 8, 24 and 48 hours after Time 0

Population: All randomized participants from the ITT Population with data available at each timepoint.

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.

Time frame: 4, 8, 24 and 48 hours after Time 0

Population: All randomized participants from the ITT Population with data available at each timepoint.

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.

Time frame: Baseline and 0 to 4, 0 to 8 and 0 to 24 hours after Time 0

Population: All randomized participants from the Intent-to-Treat (ITT) Population who did not have missing SPID values.

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.

Time frame: End of treatment (Day 3) or early termination

Population: All randomized participants from the ITT Population.

The percentage of participants who needed to take an alternate medication for pain relief during the treatment period.

Time frame: From Time 0 (first dose of study drug) up to 48 hours

Population: All randomized participants from the ITT Population.

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.

Time frame: From Time 0 (first dose of study drug) up to 48 hours

Population: All randomized participants from the ITT Population

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.

Time frame: 4, 8, 24 and 48 hours after Time 0 (first dose of study drug)

Population: All randomized participants from the ITT Population

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.

Time frame: From Time 0 (first dose of study drug) to time of first perceptible pain relief (up to 83 minutes)

Population: All randomized participants from the ITT Population.

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.

Time frame: From Time 0 to time of first use of rescue medication (up to 280 minutes)

Population: All randomized participants from the ITT Population.

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.

Time frame: From Time 0 (first dose of study drug) to time of meaningful pain relief (up to 227 minutes)

Population: All randomized participants from the ITT Population.

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.

Time frame: From Time 0 (first dose of study drug) to time of confirmed meaningful pain relief (up to 64 minutes)

Population: All randomized participants from the ITT Population.

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.

Time frame: From Time 0 (first dose of study drug) to time of peak pain relief (up to 1437 minutes)

Population: All randomized participants from the ITT Population

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.

Time frame: 4, 8, 24 and 48 hours after Time 0

Population: All randomized participants from the ITT Population with data available at each timepoint.

Total use of rescue medication is defined as the number of times a participant took rescue medication.

Time frame: Over 24 and 48 hours after Time 0 (first dose of study drug)

Population: All randomized participants from the ITT Population who used rescue medication during the specified time intervals.