A Multicenter Efficacy Study of a Diclofenac+Menthol Gel in Subjects With Ankle Sprain

Study Overview
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Brief Summary
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This Phase III pivotal efficacy study will assess efficacy and onset of pain relief of MFC51123 gel vs. placebo and MFC51123 gel vs. 1% diclofenac gel and 3% menthol gel in participants with an ankle sprain to support topical MFC51123 gel registration.

Detailed Description
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This is a multi-center, randomized, double-blind, repeat-dose, placebo-controlled, parallel-group trial in participants with ankle sprain. Eligible participants will be randomly assigned to one of four treatment groups (1% diclofenac plus 3% menthol gel, 1% diclofenac plus 0.09% menthol gel, 3% menthol gel or placebo gel with 0.09% menthol). Treatment will be self-administered by participants four times daily on an out-patient basis. Participants will rate pain intensity score (NRS) at rest and on movement, pain relief score (PRS) and cooling and soothing sensations. After leaving the clinic, participants will continue to complete scheduled pain intensity and pain relief assessments and answer questions about cooling sensation by answering questions in a paper diary card. The investigator (or designee) will measure the ankle swelling via the 'figure-of-eight' method on treatment Days 1 (at Baseline), 3, 7 and 10. Participants will continue treatment until they are pain free or for up to 10 days, whichever occurs first. At the end of the treatment, participants will be assessed for function of the injured joint by the investigator. In addition, the participants will evaluate treatment satisfaction, sensory features of the gel and provide a global assessment of the treatment by using a questionnaire.

Official Title
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A Clinical Study to Assess the Efficacy and Onset of Pain Relief of Topical MFC51123 Diclofenac-Menthol Gel Versus Controls in Ankle Sprain

Conditions
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Pain

Intervention / Treatment
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* Drug: 1% diclofenac sodium plus 3% menthol
* Drug: 1% diclofenac sodium plus 0.09% menthol
* Drug: 3% menthol
* Drug: Placebo with 0.09% menthol gel


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Age: 16-65 years Good general and mental health Grade I or Grade II acute sprain of the lateral ankle within 24 hours of Visit 1, a pain intensity score of the ankle sprain that is ≥ 5 as measured on an 11-point numerical rating scale, and a peri-malleolar edema (sub-malleolar perimeter difference of ≥ 20mm between injured and uninjured ankle Females of child-bearing age practicing a reliable method of contraception Exclusion Criteria: Pregnant or breast-feeding females If participant has treated the ankle sprain with treatment such as oral or other topical pain relief medications, massage or physical therapy since experiencing the ankle sprain Acute or chronic pain disorders, which may confound the study pain evaluations Participant has has injury to both ankles or to both medial and lateral ligaments of the same ankle Known or suspected hypersensitivity, allergy, intolerance or contraindication to the use of any of the study medications Participant has a medical history of renal or hepatic disease, a current active peptic ulcer or a history of upper gastrointestinal bleeding or perforation related to previous NSAID therapy

Ages Eligible for Study
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Minimum Age: 16 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: 1% diclofenac sodium plus 3% menthol<br>1% diclofenac sodium plus 3% menthol gel supplied in 30 gram (g) tubes sufficient for each subject to apply 4g of gel to the injured ankle region four times daily for up to 10 days. | Drug: 1% diclofenac sodium plus 3% menthol<br>* To be applied four times daily for 10 days.<br>|
| Experimental: 1% diclofenac sodium plus 0.09% menthol<br>1% diclofenac sodium plus 0.09% menthol gel supplied in 30g tubes sufficient for each subject to apply 4g of gel to the injured ankle region four times daily for up to 10 days. | Drug: 1% diclofenac sodium plus 0.09% menthol<br>* To be applied four times daily for 10 days.<br>|
| Experimental: 3% menthol<br>3% menthol gel supplied in 30g tubes sufficient for each subject to apply 4g of gel to the injured ankle region four times daily for up to 10 days. | Drug: 3% menthol<br>* To be applied four times daily for 10 days.<br>|
| Placebo Comparator: Placebo with 0.09% menthol gel<br>Placebo with 0.09% menthol gel supplied in 30g tubes sufficient for each subject to apply 4g of gel to the injured ankle region four times daily for up to 10 days. | Drug: Placebo with 0.09% menthol gel<br>* To be applied four times daily for 10 days.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Area Under the Curve From Day 1 to Day 3 (AUC1-3 Days) of Pain Intensity(PI) on Movement for Diclofenac/Methanol Gel and Placebo Gel | AUC of PI on movement was measured by a numerical rating scale (NRS) during the 48 hour time interval from Day 1 to 3. AUC1-3 day was calculated based on trapezoidal method. Pain intensity was measured in NRS scale from 0 (no pain) to 10 (extreme pain). Participants assessed the severity of ankle pain using the NRS scale at baseline (prior to treatment) and at 10, 30 minutes and 1, 4, 6, 12, 18 and 24 hours after the first dose of treatment and twice daily after dosing. | up to 72 hours | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| AUC1-3 Days of PI on Movement for Diclofenac Sodium + Methanol, Diclofenac, Methanol and Placebo | AUC of PI on movement was measured by a numerical rating scale (NRS) during the 48 hour time interval from Day 1 to 3. AUC1-3 day was calculated based on trapezoidal method. Pain intensity was measured in NRS scale from 0 (no pain) to 10 (extreme pain). Participants assessed the severity of ankle pain using the NRS scale at baseline (prior to treatment) and at 10, 30 minutes and 1, 4, 6, 12, 18 and 24 hours after the first dose of treatment and twice daily after dosing. | up to 72 hours | 
| Pain Intensity Difference (PID) on Movement | PID on movement, calculated as PI at a given time 't' (after walking 5 steps on a flat surface) subtracted by the PI at baseline. Participants assessed the severity of ankle pain (PI) using the NRS scale from 0 (no pain) to 10 (extreme pain). PI was measured at baseline (prior to treatment) and at 10, 30 minutes (min.) and 1, 4, 6, 12, 18 and 24 hours after the first dose of treatment and twice daily after dosing. | Baseline to 10 days | 
| PID at Rest | PID at rest was calculated as PI at a given time point't' (at rest) subtracted by the PI at baseline. Participants assessed the severity of ankle pain (PI) using the NRS scale from 0 (no pain) to 10 (extreme pain). PI was measured at baseline (prior to treatment) and at 10, 30 minutes and 1, 4, 6, 12, 18 and 24 hours after the first dose of treatment and twice daily after dosing. | Baseline to 10 days | 
| Pain Relief Score (PRS) | Pain relief was measured at each time point using a 5-point Pain Relief Scale ranging from 0-4 while at rest (Where: 0- No pain relief; 1- A little or perceptible pain relief; 2- Meaningful pain relief; 3- A lot of relief; 4- Complete relief). Participants assessed the degree of ankle pain relief using the PRS scores at 10, 30 minutes and 1, 4, 6, 12, 18 and 24 hours after the first dose of treatment and twice daily after the first day of treatment. | Day 1 to Day 7 | 
| Sum of Pain Intensity Difference (SPID) | SPID was calculated as the time weighted sum of pain intensity differences (PID) from 0 to 7 Days. PID was calculated as PI at a given time point 't' subtracted by the PI at baseline. PI was measured on NRS scale from 0 (no pain) to 10 (extreme pain). The possible range of SPID for 0-6 hours was from -60 to 60, for 0-12 hours was from -120 to 120, for 0-1 day was from -240 to 240, for 0-3 days was from -720 to 720, for 0-7 days was from -1680 to 1680. A higher value of SPID indicates greater pain relief. | Baseline to Day 7 | 
| Time of Onset of Pain Relief (TOPR) | TOPR was measured by time when participants reported PRS ≥ 1, i.e. a little or perceptible pain relief'. | Baseline to 10 days (end of study) | 
| Time of Onset of Meaningful Pain Relief (TOMR) | TOMR was measured by time when participants reported PRS ≥ 2, i.e. some or meaningful pain relief | up to 10 days (end of study) | 
| Time of Onset of Cooling Sensation (TOCS) | Time of onset of cooling sensation measured by time when subjects reported to have a 'cooling effect as an enhancement of pain relief'. To assess this endpoint, participants were asked at 10, 30 minutes and at 1, 4, 6 hours post first dose Do you feel a cooling sensation at the injured ankle from the study gel? | up to 6 hours | 
| Total Pain Relief (TOTPAR) | TOTPAR was calculated as sum of the products of PRS with time interval from one time point to the other. PRS was measured at each time point on a scale: 0= No pain relief, 1= A little or perceptible pain relief, 2= Meaningful pain relief, 3= A lot of relief, 4= Complete relief. The possible range of TOTPAR for 0-6 hours was from 0 to 24, for 0-12 hours was from 0 to 48, for 0-24 hours was from 0 to 96, for 0-72 hours was from 0 to 288, for 24-72 hours was from 0 to 192 and for 0-168 hours was from 0 to 672. | Baseline to 168 hours | 
| Skin Temperature | Skin temperature was measured by thermal imaging. | At 10, 30, 60 minutes, 4 and 6 hours | 
| Ankle Swelling | Ankle swelling measured by figure of eight method of injured ankle. | Day 1 (baseline), 3, and 7 | 
| Time to Complete Recovery | Time to complete recovery measured as the day with complete relief of ankle pain (Participant-rated NRS scores were 0 for pain intensity at rest and pain) and swelling (Participants did not have any apparent swelling nor experience any pain or limitation of movement of the injured ankle as determined by the Principal Investigator or designee during the course of an ankle exam). | up to 240 hours | 
| Patient's Global Assessment in Response to Treatment (PGART) | PGART was measured at the end of study in a scale from 0-4 (Where: 0- Poor; 1- Fair; 2- Good; 3- Very Good; 4- Excellent) | up to Day 10 |