Fentanyl Sublingual Spray for the Treatment of Moderate to Severe Post-Operative 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 Fentanyl Sublingual Spray compared with placebo in participants with postoperative pain after a bunionectomy.

Official Title
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A Phase 2 Multicenter, Randomized, Double-Blind, Multiple-Dose, Parallel-Group, Placebo-Controlled Study of Fentanyl Sublingual Spray for the Treatment of Moderate to Severe Post-Operative Pain

Conditions
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Pain

Intervention / Treatment
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* Drug: Fentanyl
* 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 to 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: Lower Dose Fentanyl<br>Lower dose Fentanyl delivered via sublingual spray every 4 hours. | Drug: Fentanyl<br>* Fentanyl delivered via sublingual spray<br>|
| Experimental: Higher Dose Fentanyl Sublingual Spray<br>Higher dose Fentanyl delivered via sublingual spray every 4 hours. | Drug: Fentanyl<br>* Fentanyl delivered via sublingual spray<br>|
| Placebo Comparator: Placebo<br>Placebo (matching Fentanyl) delivered via sublingual spray every 4 hours. | Drug: Placebo<br>* Matching placebo delivered via sublingual 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 (NRS SPID-48) 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 [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. | Over 0 to 48 hours after Time 0 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| NRS Pain Intensity Difference (NRS PID) at Each Categorical Time Point 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 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 time point 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. NRS PID is reported as the least squares mean difference. | Baseline, 1, 16, and 24 hours | 
| NRS Pain Intensity Score at Each Scheduled Time Point 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 after Time 0 (time of administration of the first dose of study drug). A lower value indicates improvement in pain. | Baseline, 1, 16, and 24 hours | 
| NRS SPID 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 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 timepoint], and negative numbers indicate an increase in pain [minimum(min)=-10 at each timepoint]. 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. | Over 0 to 4 hours (NRS SPID-4), over 0 to 8 hours (NRS SPID-8), and over 0 to 24 hours (NRS SPID-24) | 
| Total Pain Relief (TOTPAR) 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. | Over 0 to 4 hours (TOTPAR-4), over 0 to 8 hours (TOTPAR-8), over 0 to 24 hours (TOTPAR-24), and over 0 to 48 hours (TOTPAR-48) | 
| Time to Onset of Analgesia | Measured as time to perceptible pain relief confirmed by meaningful pain relief using the 2-stopwatch method (2 stopwatches will be started as soon as the first dose of study drug is administered. Each participant will be instructed to stop the first stopwatch when he or she experiences any perceptible pain relief and the second stopwatch when he or she experiences pain relief that is meaningful to them.) | Within 48 hours | 
| Pain Relief at Each Scheduled Time Point After Time 0 (First Dose of Study Medication) | Pain relief is determined on a 5-point categorical scale where 0=none, 1=a little, 2=some, 3=a lot, 4=complete. | 2.5, 5, 15, 30, and 45 minutes, and 1, 1.5, 2, 3, 4, 5, 6, 7, 8, 12, 16, 20, 24, 32, 40, and 48 hours, as well as immediately before each use of rescue analgesia | 
| Peak Pain Relief From Time 0 (First Dose of Study Medication) | The highest level of pain relief achieved on a 5-point categorical scale where 0=none, 1=a little, 2=some, 3=a lot, 4=complete. | Within 48 hours after Time 0 | 
| Time (Minutes) to Peak Pain Relief From Time 0 (First Dose of Study Medication) |  | Within 48 hours after Time 0 | 
| Time (Minutes) to First Perceptible Pain Relief From Time 0 (First Dose of Study Medication) | Time to perceptible and meaningful pain relief will be evaluated using the 2-stopwatch method (after the first dose only) (2 stopwatches will be started as soon as the first dose of study drug is administered. Each participant will be instructed to stop the first stopwatch when he or she experiences any perceptible pain relief and the second stopwatch when he or she experiences pain relief that is meaningful to them.) | Within 48 hours after Time 0 | 
| Time (Minutes) to Meaningful Pain Relief From Time 0 (First Dose of Study Medication) | Time to perceptible and meaningful pain relief will be evaluated using the 2-stopwatch method (after the first dose only) (2 stopwatches will be started as soon as the first dose of study drug is administered. Each participant will be instructed to stop the first stopwatch when he or she experiences any perceptible pain relief and the second stopwatch when he or she experiences pain relief that is meaningful to them.) | Within 48 hours after Time 0 | 
| Number of Participants Using Rescue Medication |  | Within 48 hours | 
| Time (Minutes) to First Use of Rescue Medication (Duration of Analgesia) Following Each Dose of the Investigational Product (IP) |  | Within 48 hours | 
| Number of Participants Using Rescue Analgesia Over 0 to 24 Hours and Over 0 to 48 Hours |  | Over 0 to 24 hours; Over 0 to 48 hours | 
| Participant Global Evaluation of Study Drug | Participants provide a global evaluation of study drug on a 5-point categorical scale where 0=poor, 1=fair, 2=good, 3=very good, and 4=excellent. | Within 48 hours |