Oleogel-S10 in Wound Healing of Split-Thickness Skin Graft Donor Sites (BSH-12)

Study Overview
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Brief Summary
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The main purpose of this phase III clinical trial was to compare intra-individually the efficacy, safety and tolerability of Oleogel-S10 and non-adhesive wound dressing versus non-adhesive wound dressing only in accelerating the wound healing of Split-Thickness Skin Graft (STSG) donor sites.

Detailed Description
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Oleogel-S10 has shown efficacy and was well tolerated in previous clinical trials in participants with skin lesions. Especially the results in a previous study with STSG donor sites suggested that Oleogel-S10 should be efficacious and safe in the treatment of superficial wounds. The present phase III clinical trial in STSG donor sites was initiated to demonstrate wound healing progress, i.e., the time to healing and the grade of epithelialization of the wound. In this study, STSG donor sites were separated into 2 wound halves. Randomly assigned, 1 wound half was treated with Oleogel-S10 and non-adhesive wound dressing, the other wound half with non-adhesive wound dressing only (standard of care). Wound healing progress was documented by photos which were assessed by expert reviewers blind to the treatment of the wound halves.

Official Title
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Open, Blindly Evaluated, Prospective, Controlled, Randomized, Multicenter Phase III Clinical Trial to Compare Intra-individually the Efficacy and Tolerance of Oleogel-S10 Versus Standard of Care in Accelerating the Wound Healing of Split-Thickness Skin Graft Donor Sites

Conditions
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Wounds

Intervention / Treatment
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* Drug: Oleogel-S10, non-adhesive wound dressing
* Device: Non-adhesive wound dressing only


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Presenting a split-thickness skin graft donor site wound with a minimum size of 15 cm2 and with a minimum width of 3 cm. Patient is able to understand the Informed Consent Form (ICF) provided and is prepared to comply with all study requirements, including the following: Visiting the trial site for wound dressing change and photo documentation every third or fourth day until both wound halves are closed (but no longer than 28 days after surgery). Willing to perform all necessary wound dressing changes at the trial site. Also the patient needs to agree to return to site for 3 and 12 months follow-up visits. Women of childbearing potential must apply highly effective method of birth control (failure rate less than 1% per year when used consistently and correctly (e.g., implants, injectables, combined oral contraceptives, some intrauterine contraceptive devices (IUDs), sexual abstinence, or a vasectomized partner)). Exclusion Criteria: Diseases or conditions that could, in the opinion of the Investigator, interfere with the assessment of safety or efficacy. A skin disorder that is chronic or currently active and which the Investigator considers will adversely affect the healing of the acute wounds or involves the areas to be examined in this trial. A history of clinically significant hypersensitivity to any of the drugs, surgical dressings or excipients to be used in this trial. Known multiple allergic disorders. Taking, or have taken, any investigational drugs within 3 months prior to the screening visit. Pregnant or breast feeding women are not allowed to participate in the study. Inappropriate to participate in the study, for any reason, in the opinion of the investigator. Mental incapacity or language barriers precluding adequate understanding the Informed consent form or co-operation or willingness to follow study procedures. Previous participation in this study. Employee at the investigational site, relative or spouse of the investigator.

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: Single Group Assignment
Masking: Single


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Oleogel-S10, non-adhesive wound dressing<br>A split-thickness skin graft (STSG) donor site wound >15cm2 in size was divided in 2 halves. One half was randomized to Oleogel-S10 treatment and non-adhesive wound dressing (intra-individual comparison). Oleogel-S10 was administered (1 cm or 100 mg per cm2 wound area corresponding to thickness of about 1 mm or 0.04 inch) every 3 to 4 days until 95% epithelialization of the wound or end of treatment at Day 28. | Drug: Oleogel-S10, non-adhesive wound dressing<br>* 1 cm or 100 mg Oleogel-S10 per cm2 wound area (corresponds to thickness of approximately 1 mm or 0.04 inch) every 3 to 4 days until 95% epithelialization of the wound or end of treatment at Day 28.<br>* Other names: Episalvan®;|
| Other: Non-adhesive wound dressing only<br>A STSG donor site wound >15cm2 in size was divided in 2 halves. One half was randomized to treatment with non-adhesive wound dressing only (intra-individual comparison). Non-adhesive wound dressings are standard of care (SOC) in the treatment of STSG donor sites. Wound dressings were changed every 3 to 4 days until 95% epithelialization of the wound or end of treatment at Day 28. | Device: Non-adhesive wound dressing only<br>* Soft silicone faced polyurethane foam dressing such as Mepilex® only every 3 to 4 days until 95% epithelialization of the wound or end of treatment at Day 28.<br>* Other names: Mepilex®;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Intra-individual Difference in Time to Wound Closure | Intra-individual difference in time to wound closure between wound halves, either treated with Oleogel-S10 and non-adhesive wound dressing or treated with non-adhesive wound dressing only. Independent experts were blind to treatment and assessed efficacy based on chronological series of cropped and coded photographs by wound half that were taken before start of treatment, during wound dressing changes and at the end of treatment. Difference in time to wound closure was calculated for every individual participant as [time taken for wound half treated with Oleogel-S10 to close] - [time taken for wound half treated with non-adhesive wound dressing to close], i.e., results below 0 indicate earlier wound closure of Oleogel-S10 treatment. The overall mean difference in time to wound closure was calculated based on all mean differences in time to wound closure of individual participants. Hence, primary outcome data derived from mean difference in time to wound closure by participant. | up to 4 weeks | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Time From Surgery Until Wound Closure is Achieved | Time from surgery until wound closure is achieved, separately for wound halves treated with Oleogel-S10 and non-adhesive wound dressing vs. non-adhesive wound dressing only. While outcome measure 1 (intra-individual difference in time to wound closure) was calculated based on mean intra-individual difference in time to wound closure in 107 participants with missing values replaced by a value of 0, for outcome measure 2 missing values were not replaced. For 5 of the 107 wounds data were missing, thus the reported values are calculated from 102 STSG donor site wound halves by intervention (Oleogel-S10 and non-adhesive wound dressing vs. non-adhesive wound dressing only). | up to 4 weeks | 
| Percentage of Participants With Earlier Healing | Percentage of participants with earlier healing of wound area treated with Oleogel-S10 and non-adhesive wound dressing compared to non-adhesive wound dressing only | up to 4 weeks | 
| Percentage of Participants With Wound Closure at Different Time Points | For separate time points (Day 7, Day 10, Day 14, Day 18, Day 21, and Day 28), the frequencies of wound areas which have reached wound closure were calculated. | up to 4 weeks | 
| Percentage of Wound Epithelialization at Different Time Points as Assessed by the Investigator | A study team member assessed the progress of wound healing by treatment regimen and noted the degree of epithelialization (expressed in percent of the original wound size) at wound dressing changes on Day 7, Day 10, Day 14, Day 18, Day 21, and Day 28. | up to 4 weeks | 
| Likert Scale Rating of Efficacy | Participants and investigators were asked to grade the efficacy of Oleogel-S10 and non-adhesive wound dressing versus non-adhesive wound dressing only on a 5-point Likert scale (treatment with Oleogel-S10 is much more effective, treatment with Oleogel-S10 is more effective, both treatments have the same efficacy, non-adhesive wound dressing only is more effective, non-adhesive wound dressing only is much more effective). | up to 4 weeks | 
| Cosmetic Outcome at 3 and 12 Months After Surgery, Respectively | Blinded photographic evaluation which wound half resembles more closely the surrounding skin with regard to texture, redness, growth of hair, and pigmentation. | 3 months and 12 months | 
| Likert Scale Rating of Tolerability | Participants and investigators were asked to evaluate the tolerability of Oleogel-S10 and non-adhesive wound dressing versus non-adhesive wound dressing only (standard of care) on a 5-point Likert scale (treatment with Oleogel-S10 is much better tolerated, treatment with Oleogel-S10 is better tolerated, both treatments are equally well tolerated, standard of care is better tolerated, standard of care is much better tolerated). | up to 4 weeks | 
| Pharmacokinetic (PK) Data (Number of Plasma Samples With Measurable Betulin Concentration) | Systemic presence/concentration of betulin in blood plasma samples. Plasma samples were collected in weekly intervals and at the end of treatment (when wound closure was achieved or at Day 28). Samples were analysed in a central laboratory with a validated LC-MS/MS method with a lower limit of quantification (LLOQ) of 1 ng/mL. | up to 4 weeks | 
| Pharmacokinetic (PK) Data (Plasma Betulin Concentration) | Systemic presence/concentration of betulin in blood plasma samples - values for the number of samples with measurable values in samples above the lower limit of quantification (LLOQ) of 1 ng/mL | up to 4 weeks | 
| Frequency of Adverse Events |  | Day 0 (start of treatment) until end of treatment (Day 28 or earlier if full wound closure was achieved earlier). | 
| Severity of Adverse Events | Adverse Events were graded according to the National Cancer Institute (NCI) Common Toxicity Criteria for Adverse Events (CTCAE) as being mild (NCI CTCAE Grade 1), moderate (NCI CTCAE Grade 2), severe (NCI CTCAE Grade 3), life-threatening (NCI CTCAE Grade 4) or death (NCI CTCAE Grade 5). | Day 0 (start of treatment) until end of treatment (Day 28 or earlier if full wound closure was achieved earlier). | 
| Adverse Events by Relationship to Study Medication | Adverse events were assessed as being 'unlikely', 'possibly' or 'probably' related to study medication, 'not related' to study medication or the relationship to study medication was rated as 'unknown'. | Day 0 (start of treatment) until end of treatment (Day 28 or earlier if full wound closure was achieved earlier). | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Split-Thickness Skin Graft (STSG) donor site, Split-thickness skin graft, STSG, Wound healing, Skin grafting, Superficial wound, Partial-thickness wound, Time to wound closure