A Study Of The Effectiveness Of Wafermine Alone And In Combination With Opioids In Subjects Undergoing Bunionectomy

Study Overview
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Brief Summary
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To evaluate the safety and effectiveness of Wafermine administered with and without an opioid medication for acute pain following bunionectomy surgery.

Detailed Description
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This is a Phase 2, randomised, double-blind, double-dummy, placebo-controlled evaluation of the analgesic efficacy and safety of WafermineTM alone and in combination with low-dose oxycodone in adult subjects who experience post-operative pain after undergoing primary unilateral bunionectomy. The study will randomise sufficient subjects to have 72 completed subjects at 1 site. Study subjects will receive multiple doses of study medication over a 14 hour period and will be asked to complete pain and relief assessments as well as tolerability questionnaires over a 24 hour period.

Official Title
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A Pilot Study Of The Efficacy Of WafermineTM Alone And In Combination With Opioids In Subjects Undergoing Bunionectomy

Conditions
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Acute Pain

Intervention / Treatment
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* Drug: Wafermine
* Drug: Oxycodone
* Drug: Placebo


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Scheduled for a bunionectomy (with no additional procedures). Healthy, ambulatory subjects able to understand and willing to comply with study procedures, study restrictions and requirements. Body mass index (BMI) ≥19 to ≤33 kg/m2. Females: Not pregnant, not lactating, and not planning to become pregnant during the study. Females: Be abstinent, surgically sterile, at least two years post-menopausal; or medically acceptable contraception. Able to read and understand English. Able to swallow oral capsules whole. Exclusion Criteria: Allergy, intolerance, or contraindication to ketamine, oxycodone, morphine, ibuprofen or surgical medications. Clinically significant medical condition. History of illicit drug use or alcohol abuse and not in full remission. Positive test for human immunodeficiency virus (HIV), hepatitis B virus (HBV), or hepatitis C virus (HCV) at the screening visit. Clinically significant 12 lead ECG abnormalities at screening. Smokers who are unwilling to abstain during the inpatient stay.

Ages Eligible for Study
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Minimum Age: 18 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: Quadruple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Placebo Comparator: Group A<br>Placebo wafers given every 2 hours Placebo capsule given every 4 hours Placebo wafers top-up dose given at hour 1 | Drug: Placebo<br>* Placebo capsule or placebo wafer<br>|
| Active Comparator: Group B<br>Placebo wafers given every 2 hours Oxycodone given every 4 hours Placebo wafers top-up dose given at hour 1 | Drug: Oxycodone<br>* 5 mg oxycodone capsule<br>|
| Experimental: Group C<br>Wafermine™ 35 mg wafer + placebo wafer given every 2 hours Placebo capsule given every 4 hours Wafermine™ 35 mg wafer + placebo wafer top-up dose at hour 1 | Drug: Wafermine<br>* 35 or 70 mg ketamine in a sublingual wafer<br>* Other names: Sublingual ketamine;|
| Experimental: Group D<br>Wafermine™ 35 mg wafer + placebo wafer given every 2 hours Oxycodone 5 mg capsule every 4 hours Wafermine™ 35 mg wafer + placebo wafer top-up dose at hour 1 | Drug: Wafermine<br>* 35 or 70 mg ketamine in a sublingual wafer<br>* Other names: Sublingual ketamine;Drug: Oxycodone<br>* 5 mg oxycodone capsule<br>|
| Experimental: Group E<br>Wafermine™ 35 mg + placebo wafer given every 4 hours Placebo wafers given every 2 hours Placebo capsule given every 4 hours Wafermine™ 35 mg wafer + placebo wafer top-up dose at hour 1 | Drug: Wafermine<br>* 35 or 70 mg ketamine in a sublingual wafer<br>* Other names: Sublingual ketamine;|
| Experimental: Group F<br>Wafermine™ 35 mg + placebo wafer given every 4 hours Placebo wafers given every 2 hours Oxycodone 5 mg given every 4 hours Wafermine™ 35 mg wafer + placebo wafer top-up dose at hour 1 | Drug: Wafermine<br>* 35 or 70 mg ketamine in a sublingual wafer<br>* Other names: Sublingual ketamine;Drug: Oxycodone<br>* 5 mg oxycodone capsule<br>|
| Experimental: Group G<br>Wafermine™ 70 mg given every 4 hours Placebo wafer given every 2 hours Placebo capsule given every 4 hours 2 Placebo wafers top-up dose at hour 1 | Drug: Wafermine<br>* 35 or 70 mg ketamine in a sublingual wafer<br>* Other names: Sublingual ketamine;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Total Pain Relief (TOTPAR) | Subjects will use an 11 point numerical pain rating scale (NPRS) where 0=No Pain and 10= Worst Possible pain to rate their pain at 0.5, 1, 1.5, 2, 2.5, 3, 3.5, 4, 4.5, 5, 5.5, 6, 6.5, 7, 7.5, 8, 8.5, 9, 9.5, 10, 10.5, 11, 11.5, 12, 12.5, 13, 13.5, 14, 14.5, 15, 15.5, 16 and 24 hours. TOTPAR is computed as follows at the specified time points: TOTPAR-t = ∑ [T(i) - T(i-1) * [(PR(i-1) + PR(i))/2] | 24 hours | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Percent with maximum Pain Relief | The percent of maximum pain relief is defined as the proportion of subjects reporting Complete Relief (score of 4) on a 4 point categorical scale (no relief, a little relief, some relief, a lot of relief and complete relief) at each time point over the sampling interval. | 24 hours | 
| Proportion of Subjects requiring Rescue Medication | Calculation of the proportion of subjects requiring Rescue Medication at each time point over the sampling interval. | 24 hours | 
| Time to onset of perceptible and meaningful pain relief | Calculated using the double stopwatch technique. Subjects stop the first stopwatch when they experience perceptible relief and the second stopwatch when they experience meaningful relief. | 24 hours | 
| Time to onset of complete pain relief (Peak Relief) | Measurement of the time it takes subjects to report their maximum pain relief on a 5 point categorical relief scale (0=no relief, 1=a little relief, 2=some relief, 3=a lot of relief, 4=complete relief) | 24 hours | 
| Time to maximum reduction in pain intensity | Measurement of the time it takes subjects to reach their maximum reduction in pain on the 11 point NPRS where 0=No pain and 10=Worst Possible pain. | 24 hours | 
| Time for pain intensity to return to baseline | Measurement of the time for pain intensity to return to baseline using scores from the NPRS assessments where 0=No pain and 10=Worst possible pain. | 24 hours | 
| Time to rescue medication | Measurement of the time elapsed from initial dose of study medication to time of first dose of rescue medication. | 24 hours | 
| Percentage of Maximum Total Pain Relief (TOTPAR) | Subjects will use an 11 point numerical pain rating scale (NPRS) where 0=No Pain and 10= Worst Possible pain to rate their pain at 0.5, 1, 1.5, 2, 2.5, 3, 3.5, 4, 4.5, 5, 5.5, 6, 6.5, 7, 7.5, 8, 8.5, 9, 9.5, 10, 10.5, 11, 11.5, 12, 12.5, 13, 13.5, 14, 14.5, 15, 15.5, 16 and 24 hours. Percentage of Maximum Total Pain Relief is computed at each time-point using: %maxTOTPAR= 〖TOTPAR〗_t/〖maxTOTPAR〗_t x100 | 24 hours | 
| Sum of Pain Intensity Differences (SPID) | Subjects will use an 11 point numerical pain rating scale (NPRS) where 0-No Pain and 10= Worst Possible pain to rate their pain at 0.5, 1, 1.5, 2, 2.5, 3, 3.5, 4, 4.5, 5, 5.5, 6, 6.5, 7, 7.5, 8, 8.5, 9, 9.5, 10, 10.5, 11, 11.5, 12, 12.5, 13, 13.5, 14, 14.5, 15, 15.5, 16 and 24 hours. Sum of Pain Intensity Differences is computed at 0.5, 1, 1.5, 2, 2.5, 3, 3.5, 4, 4.5, 5, 5.5, 6, 6.5, 7, 7.5, 8, 8.5, 9, 9.5, 10, 10.5, 11, 11.5, 12, 12.5, 13, 13.5, 14, 14.5, 15, 15.5, 16 and 24 hours. SPIDx is a time weighted sum of pain intensity difference score from baseline over the time interval in hours. | 24 hours | 
| Responder Rates (30% and 50%) | The responder rate is defined as the proportion of subjects with a value of percentage change greater than or equal to 30% (and 50%) from baseline in pain intensity (using scores from the 11 point NPRS where 0=no pain and 10=worst possible pain) at each time point over the sampling interval. | 24 hours | 
| Safety (treatment emergent adverse events, significant changes in physical examination findings as well as vital sign measurements) | Measurement of treatment emergent adverse events reported during the study. Measurement of significant changes in physical examination findings as well as vital sign measurements (heart rate, blood pressure, breathing rate and pulse oximetry readings). | 24 hours | 
| Tolerability (judged by subject answers on oral symptoms questionnaire) | Measurement of tolerability as judged by subject answers on oral symptoms questionnaire measuring irritation, burning and bitterness, as well as physical examination of oral cavity. Also measuring the number of subjects who discontinue the study due to intolerable side effects. | 24 hours | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Bunion, Bunionectomy