Wounds
Conditions
Keywords
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
Brief summary
The main purpose of this phase III clinical trial was to show safety and efficacy of Oleogel-S10 in accelerating the wound healing of Split-Thickness Skin Graft (STSG) donor sites.
Detailed description
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 blinded to the treatment of the wound halves.
Interventions
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
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
Sponsors
Birken AG
Study design
Allocation
RANDOMIZED
Intervention model
SINGLE_GROUP
Primary purpose
TREATMENT
Masking
SINGLE (Outcomes Assessor)
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
* Participants at least 18 years old who have provided written informed consent * Presenting a split-thickness skin graft donor site wound with a minimum size of 15 cm2 and with a minimum width of 3 cm. * Participant was able to understand the Informed Consent Form (ICF) provided and was 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 were closed (but no longer than 28 days after surgery). * Willing to perform all necessary wound dressing changes at the trial site. Also the participant needed to agree to return to site for 3 and 12 months follow-up visits. * Women of childbearing potential who were in the period between menarche and menopause needed to apply a 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). Birth control method needed to have been applied for at least 1 monthly cycle prior to first administration of study drug, be maintained during the study treatment phase and continued for at least 30 days after the last administration of study drug. Sexually active, non-vasectomized men needed to use a barrier method (condoms) during the treatment phase of this clinical trial.
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 was chronic or currently active and which the Investigator considered would adversely affect the healing of the acute wounds or involved 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 were 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 ICF 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.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Intra-individual Difference in Time to Wound Closure | 2 to 4 weeks | 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. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Severity of Adverse Events | Day 0 (start of treatment) until end of treatment (Day 28 or earlier if full wound closure was achieved earlier). | 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). |
| Time From Surgery Until Wound Closure is Achieved | 2 to 4 weeks | 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 110 participants with missing values replaced by a value of 0, for outcome measure 2 missing values were not replaced. For 2 of the 110 wounds data were missing, thus the reported values are calculated from 108 STSG donor site wound halves by intervention (Oleogel-S10 and non-adhesive wound dressing vs. non-adhesive wound dressing only). |
| Percentage of Participants With Earlier Healing | 2 to 4 weeks | 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 |
| Percentage of Participants With Wound Closure at Different Time Points | 2 to 4 weeks | 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. |
| Percentage of Wound Epithelialization at Different Time Points as Assessed by the Investigator | 2 to 4 weeks | 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. |
| Frequency of Adverse Events | Day 0 (start of treatment) until end of treatment (Day 28 or earlier if full wound closure was achieved earlier). | — |
| Cosmetic Outcome at 3 and 12 Months After Surgery, Respectively | 3 months and 12 months | Blinded photographic evaluation which wound half resembles more closely the surrounding skin with regard to texture, redness, growth of hair, and pigmentation. |
| Likert Scale Rating of Tolerability | 2 to 4 weeks | 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, non-adhesive wound dressing only is better tolerated, non-adhesive wound dressing only is much better tolerated). |
| Pharmacokinetic (PK) Data (Number of Plasma Samples With Measurable Betulin Concentration) | up to 4 weeks | 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. |
| Pharmacokinetic (PK) Data (Plasma Betulin Concentration) | up to 4 weeks | 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 |
| Adverse Events by Relationship to Study Medication | Day 0 (start of treatment) until end of treatment (Day 28 or earlier if full wound closure was achieved earlier). | 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'. |
| Likert Scale Rating of Efficacy | 2 to 4 weeks | 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). |
Countries
France, Greece, Latvia, Spain
Participant flow
Recruitment details
Participants were enrolled from 04 Apr 2013 to 04 Sep 2013 in 14 clinical centers in 4 countries: Spain (6 centers), Greece (3 centers), Latvia (2 centers), and France (3 centers).
Pre-assignment details
113 participants were screened and wound halves of 112 participants were randomized and treated. For one participant, wound halves were neither randomized nor treated because the split-thickness skin graft surgery was cancelled. Overall, 112 wounds in 112 participants were treated.
Participants by arm
| Arm | Count |
|---|---|
| Entire Study Population Intra-individual comparison: A split-thickness skin graft (STSG) donor site wound ≥15 cm² in size was divided in 2 halves. One half was randomized to Oleogel-S10 treatment and non-adhesive wound dressing, the other half to non-adhesive wound dressing only. Non-adhesive wound dressings, specifically soft silicone faced polyurethane foam dressings (e.g., Mepilex®), represent standard of care (SOC) in the treatment of STSG donor site wounds. Oleogel-S10 was administered at a thickness of 1 mm (0.04 inches) and wound dressings were changed at least every 3 to 4 days. Study treatment continued until both wound halves were closed (at least 95% epithelialised) or ended at Day 28. | 112 |
| Total | 112 |
Withdrawals & dropouts
| Period | Reason | FG000 |
|---|---|---|
| Overall Study | Adverse Event | 5 |
| Overall Study | Lack of Full Wound Closure at Day 28 | 13 |
| Overall Study | Other | 2 |
Baseline characteristics
| Characteristic | Entire Study Population |
|---|---|
| Age, Categorical <=18 years | 0 Participants |
| Age, Categorical >=65 years | 23 Participants |
| Age, Categorical Between 18 and 65 years | 89 Participants |
| Age, Continuous | 49 years |
| Region of Enrollment France | 11 participants |
| Region of Enrollment Greece | 14 participants |
| Region of Enrollment Latvia | 31 participants |
| Region of Enrollment Spain | 56 participants |
| Sex: Female, Male Female | 39 Participants |
| Sex: Female, Male Male | 73 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk | EG003 affected / at risk | EG004 affected / at risk |
|---|---|---|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — | — / — | — / — | — / — |
| other Total, other adverse events | 30 / 112 | 2 / 112 | 4 / 112 | 9 / 112 | 40 / 112 |
| serious Total, serious adverse events | 4 / 112 | 0 / 112 | 0 / 112 | 1 / 112 | 5 / 112 |
Outcome results
Primary
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.
Time frame: 2 to 4 weeks
Population: The intent-to-treat (ITT) analysis population included all participants who were treated at least once with study medication, i.e. who received any dose of Oleogel-S10 and who had signed an informed consent form.
| Arm | Measure | Value (MEAN) |
|---|---|---|
| Entire Study Population | Intra-individual Difference in Time to Wound Closure | -0.8 days |
Comparison: All participants received both treatments and treatments were intra-individually compared.~Hypotheses tested: H0: δ = 0 and H1: δ ≠ 0 with δ being the difference in time to wound closure between treatments.p-value: =0.0232t-test, 2 sided
Secondary
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'.
Time frame: Day 0 (start of treatment) until end of treatment (Day 28 or earlier if full wound closure was achieved earlier).
Population: The safety analysis population included all participants who received treatment at least once, i.e. who received any dose of Oleogel-S10 or standard of care (SOC). If the application of any treatment was uncertain, the participant was included in the SAF.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Entire Study Population | Adverse Events by Relationship to Study Medication | 'Unlikely' related | 2.7 Participants with adverse events (%) |
| Entire Study Population | Adverse Events by Relationship to Study Medication | 'Possibly' related | 5.4 Participants with adverse events (%) |
| Entire Study Population | Adverse Events by Relationship to Study Medication | 'Probably' related | 8.0 Participants with adverse events (%) |
| Entire Study Population | Adverse Events by Relationship to Study Medication | Unknown relationship | 1.8 Participants with adverse events (%) |
| Entire Study Population | Adverse Events by Relationship to Study Medication | No relationship | 47.3 Participants with adverse events (%) |
Secondary
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.
Time frame: 3 months and 12 months
Population: The intent-to-treat (ITT) analysis population included 96 participants for the 3-months follow-up and 65 participants for the 12-months follow-up.~\*Note: The assessment for one patient was missing as no photo was not taken at the Month 3 follow-up visit, therefore this outcome measure is based on 95 patients
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Entire Study Population | Cosmetic Outcome at 3 and 12 Months After Surgery, Respectively | Wound half treated with Oleogel-S10 | 18.9 Percentage of wounds |
| Entire Study Population | Cosmetic Outcome at 3 and 12 Months After Surgery, Respectively | Both equal | 71.6 Percentage of wounds |
| Entire Study Population | Cosmetic Outcome at 3 and 12 Months After Surgery, Respectively | Wound half treated with wound dressing only | 8.4 Percentage of wounds |
| Non-adhesive Wound Dressing Only | Cosmetic Outcome at 3 and 12 Months After Surgery, Respectively | Both equal | 98.9 Percentage of wounds |
| Non-adhesive Wound Dressing Only | Cosmetic Outcome at 3 and 12 Months After Surgery, Respectively | Wound half treated with wound dressing only | 0.0 Percentage of wounds |
| Non-adhesive Wound Dressing Only | Cosmetic Outcome at 3 and 12 Months After Surgery, Respectively | Wound half treated with Oleogel-S10 | 1.1 Percentage of wounds |
| Investigator Assessment Day 21 | Cosmetic Outcome at 3 and 12 Months After Surgery, Respectively | Both equal | 50.5 Percentage of wounds |
| Investigator Assessment Day 21 | Cosmetic Outcome at 3 and 12 Months After Surgery, Respectively | Wound half treated with Oleogel-S10 | 32.6 Percentage of wounds |
| Investigator Assessment Day 21 | Cosmetic Outcome at 3 and 12 Months After Surgery, Respectively | Wound half treated with wound dressing only | 13.7 Percentage of wounds |
| Investigator Assessment Day 28 | Cosmetic Outcome at 3 and 12 Months After Surgery, Respectively | Wound half treated with Oleogel-S10 | 25.3 Percentage of wounds |
| Investigator Assessment Day 28 | Cosmetic Outcome at 3 and 12 Months After Surgery, Respectively | Wound half treated with wound dressing only | 14.7 Percentage of wounds |
| Investigator Assessment Day 28 | Cosmetic Outcome at 3 and 12 Months After Surgery, Respectively | Both equal | 56.8 Percentage of wounds |
| Investigator Assessment End of Treatment | Cosmetic Outcome at 3 and 12 Months After Surgery, Respectively | Wound half treated with wound dressing only | 3.1 Percentage of wounds |
| Investigator Assessment End of Treatment | Cosmetic Outcome at 3 and 12 Months After Surgery, Respectively | Wound half treated with Oleogel-S10 | 13.8 Percentage of wounds |
| Investigator Assessment End of Treatment | Cosmetic Outcome at 3 and 12 Months After Surgery, Respectively | Both equal | 83.1 Percentage of wounds |
| Participant Assessment Day 7 | Cosmetic Outcome at 3 and 12 Months After Surgery, Respectively | Wound half treated with wound dressing only | 0.0 Percentage of wounds |
| Participant Assessment Day 7 | Cosmetic Outcome at 3 and 12 Months After Surgery, Respectively | Wound half treated with Oleogel-S10 | 0.0 Percentage of wounds |
| Participant Assessment Day 7 | Cosmetic Outcome at 3 and 12 Months After Surgery, Respectively | Both equal | 100.0 Percentage of wounds |
| Participant Assessment Day 14 | Cosmetic Outcome at 3 and 12 Months After Surgery, Respectively | Wound half treated with wound dressing only | 9.2 Percentage of wounds |
| Participant Assessment Day 14 | Cosmetic Outcome at 3 and 12 Months After Surgery, Respectively | Wound half treated with Oleogel-S10 | 27.7 Percentage of wounds |
| Participant Assessment Day 14 | Cosmetic Outcome at 3 and 12 Months After Surgery, Respectively | Both equal | 60.0 Percentage of wounds |
| Participant Assessment Day 21 | Cosmetic Outcome at 3 and 12 Months After Surgery, Respectively | Wound half treated with Oleogel-S10 | 15.4 Percentage of wounds |
| Participant Assessment Day 21 | Cosmetic Outcome at 3 and 12 Months After Surgery, Respectively | Wound half treated with wound dressing only | 4.6 Percentage of wounds |
| Participant Assessment Day 21 | Cosmetic Outcome at 3 and 12 Months After Surgery, Respectively | Both equal | 80.0 Percentage of wounds |
Secondary
Frequency of Adverse Events
Time frame: Day 0 (start of treatment) until end of treatment (Day 28 or earlier if full wound closure was achieved earlier).
Population: The safety analysis population included all participants who received treatment at least once, i.e. who received any dose of Oleogel-S10 or standard of care (SOC). If the application of any treatment was uncertain, the participant was included in the SAF.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Entire Study Population | Frequency of Adverse Events | Adverse events (AEs) | 53.6 Participants with adverse events (%) |
| Entire Study Population | Frequency of Adverse Events | Serious adverse events | 4.5 Participants with adverse events (%) |
| Entire Study Population | Frequency of Adverse Events | AEs leading to discontinuation | 3.6 Participants with adverse events (%) |
| Entire Study Population | Frequency of Adverse Events | Related AEs | 14.3 Participants with adverse events (%) |
| Entire Study Population | Frequency of Adverse Events | Application site reactions | 24.1 Participants with adverse events (%) |
| Entire Study Population | Frequency of Adverse Events | Non treatment-emergent AEs | 7.1 Participants with adverse events (%) |
Secondary
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).
Time frame: 2 to 4 weeks
Population: The intent-to-treat (ITT) analysis population included all participants who were treated at least once with study medication, i.e. who received any dose of Oleogel-S10 and who had signed an informed consent form.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Entire Study Population | Likert Scale Rating of Efficacy | Oleogel-S10 more effective | 44.9 Percentage of efficacy assessments |
| Entire Study Population | Likert Scale Rating of Efficacy | Oleogel-S10 much more effective | 4.7 Percentage of efficacy assessments |
| Entire Study Population | Likert Scale Rating of Efficacy | Standard of care (SOC) more effective | 9.3 Percentage of efficacy assessments |
| Entire Study Population | Likert Scale Rating of Efficacy | Both treatments same efficacy | 40.2 Percentage of efficacy assessments |
| Entire Study Population | Likert Scale Rating of Efficacy | SOC much more effective | 0.9 Percentage of efficacy assessments |
| Non-adhesive Wound Dressing Only | Likert Scale Rating of Efficacy | SOC much more effective | 0.0 Percentage of efficacy assessments |
| Non-adhesive Wound Dressing Only | Likert Scale Rating of Efficacy | Oleogel-S10 more effective | 35.0 Percentage of efficacy assessments |
| Non-adhesive Wound Dressing Only | Likert Scale Rating of Efficacy | Both treatments same efficacy | 40.8 Percentage of efficacy assessments |
| Non-adhesive Wound Dressing Only | Likert Scale Rating of Efficacy | Standard of care (SOC) more effective | 10.7 Percentage of efficacy assessments |
| Non-adhesive Wound Dressing Only | Likert Scale Rating of Efficacy | Oleogel-S10 much more effective | 13.6 Percentage of efficacy assessments |
| Investigator Assessment Day 21 | Likert Scale Rating of Efficacy | Both treatments same efficacy | 36.6 Percentage of efficacy assessments |
| Investigator Assessment Day 21 | Likert Scale Rating of Efficacy | SOC much more effective | 0.0 Percentage of efficacy assessments |
| Investigator Assessment Day 21 | Likert Scale Rating of Efficacy | Oleogel-S10 more effective | 36.6 Percentage of efficacy assessments |
| Investigator Assessment Day 21 | Likert Scale Rating of Efficacy | Oleogel-S10 much more effective | 16.8 Percentage of efficacy assessments |
| Investigator Assessment Day 21 | Likert Scale Rating of Efficacy | Standard of care (SOC) more effective | 9.9 Percentage of efficacy assessments |
| Investigator Assessment Day 28 | Likert Scale Rating of Efficacy | Both treatments same efficacy | 37.6 Percentage of efficacy assessments |
| Investigator Assessment Day 28 | Likert Scale Rating of Efficacy | Standard of care (SOC) more effective | 9.9 Percentage of efficacy assessments |
| Investigator Assessment Day 28 | Likert Scale Rating of Efficacy | SOC much more effective | 1.0 Percentage of efficacy assessments |
| Investigator Assessment Day 28 | Likert Scale Rating of Efficacy | Oleogel-S10 more effective | 33.7 Percentage of efficacy assessments |
| Investigator Assessment Day 28 | Likert Scale Rating of Efficacy | Oleogel-S10 much more effective | 17.8 Percentage of efficacy assessments |
| Investigator Assessment End of Treatment | Likert Scale Rating of Efficacy | Both treatments same efficacy | 37.1 Percentage of efficacy assessments |
| Investigator Assessment End of Treatment | Likert Scale Rating of Efficacy | Oleogel-S10 much more effective | 17.1 Percentage of efficacy assessments |
| Investigator Assessment End of Treatment | Likert Scale Rating of Efficacy | Oleogel-S10 more effective | 35.2 Percentage of efficacy assessments |
| Investigator Assessment End of Treatment | Likert Scale Rating of Efficacy | Standard of care (SOC) more effective | 9.5 Percentage of efficacy assessments |
| Investigator Assessment End of Treatment | Likert Scale Rating of Efficacy | SOC much more effective | 1.0 Percentage of efficacy assessments |
| Participant Assessment Day 7 | Likert Scale Rating of Efficacy | Oleogel-S10 much more effective | 7.7 Percentage of efficacy assessments |
| Participant Assessment Day 7 | Likert Scale Rating of Efficacy | Standard of care (SOC) more effective | 6.7 Percentage of efficacy assessments |
| Participant Assessment Day 7 | Likert Scale Rating of Efficacy | Both treatments same efficacy | 53.8 Percentage of efficacy assessments |
| Participant Assessment Day 7 | Likert Scale Rating of Efficacy | SOC much more effective | 0.0 Percentage of efficacy assessments |
| Participant Assessment Day 7 | Likert Scale Rating of Efficacy | Oleogel-S10 more effective | 31.7 Percentage of efficacy assessments |
| Participant Assessment Day 14 | Likert Scale Rating of Efficacy | Oleogel-S10 much more effective | 15.0 Percentage of efficacy assessments |
| Participant Assessment Day 14 | Likert Scale Rating of Efficacy | Both treatments same efficacy | 38.0 Percentage of efficacy assessments |
| Participant Assessment Day 14 | Likert Scale Rating of Efficacy | Standard of care (SOC) more effective | 11.0 Percentage of efficacy assessments |
| Participant Assessment Day 14 | Likert Scale Rating of Efficacy | Oleogel-S10 more effective | 36.0 Percentage of efficacy assessments |
| Participant Assessment Day 14 | Likert Scale Rating of Efficacy | SOC much more effective | 0.0 Percentage of efficacy assessments |
| Participant Assessment Day 21 | Likert Scale Rating of Efficacy | Standard of care (SOC) more effective | 8.1 Percentage of efficacy assessments |
| Participant Assessment Day 21 | Likert Scale Rating of Efficacy | Both treatments same efficacy | 39.4 Percentage of efficacy assessments |
| Participant Assessment Day 21 | Likert Scale Rating of Efficacy | Oleogel-S10 more effective | 35.4 Percentage of efficacy assessments |
| Participant Assessment Day 21 | Likert Scale Rating of Efficacy | Oleogel-S10 much more effective | 16.2 Percentage of efficacy assessments |
| Participant Assessment Day 21 | Likert Scale Rating of Efficacy | SOC much more effective | 1.0 Percentage of efficacy assessments |
| Participant Assessment Day 28 | Likert Scale Rating of Efficacy | SOC much more effective | 2.0 Percentage of efficacy assessments |
| Participant Assessment Day 28 | Likert Scale Rating of Efficacy | Both treatments same efficacy | 38.8 Percentage of efficacy assessments |
| Participant Assessment Day 28 | Likert Scale Rating of Efficacy | Oleogel-S10 more effective | 35.7 Percentage of efficacy assessments |
| Participant Assessment Day 28 | Likert Scale Rating of Efficacy | Standard of care (SOC) more effective | 8.2 Percentage of efficacy assessments |
| Participant Assessment Day 28 | Likert Scale Rating of Efficacy | Oleogel-S10 much more effective | 15.3 Percentage of efficacy assessments |
| Participant Assessment EoT | Likert Scale Rating of Efficacy | Standard of care (SOC) more effective | 7.8 Percentage of efficacy assessments |
| Participant Assessment EoT | Likert Scale Rating of Efficacy | Oleogel-S10 more effective | 36.3 Percentage of efficacy assessments |
| Participant Assessment EoT | Likert Scale Rating of Efficacy | Oleogel-S10 much more effective | 14.7 Percentage of efficacy assessments |
| Participant Assessment EoT | Likert Scale Rating of Efficacy | SOC much more effective | 2.0 Percentage of efficacy assessments |
| Participant Assessment EoT | Likert Scale Rating of Efficacy | Both treatments same efficacy | 39.2 Percentage of efficacy assessments |
Secondary
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, non-adhesive wound dressing only is better tolerated, non-adhesive wound dressing only is much better tolerated).
Time frame: 2 to 4 weeks
Population: The safety analysis population (SAF) included all participants who received treatment at least once, i.e. who received any dose of Oleogel-S10 or standard of care (SOC). If the application of any treatment was uncertain, the participant was included in the SAF.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Entire Study Population | Likert Scale Rating of Tolerability | Oleogeogel-S10 much better tolerated | 5.4 Percentage of participants |
| Entire Study Population | Likert Scale Rating of Tolerability | Both treatments equally well tolerated | 58.9 Percentage of participants |
| Entire Study Population | Likert Scale Rating of Tolerability | SOC much better tolerated | 0.0 Percentage of participants |
| Entire Study Population | Likert Scale Rating of Tolerability | SOC better tolerated | 2.7 Percentage of participants |
| Entire Study Population | Likert Scale Rating of Tolerability | Oleogel-S10 better tolerated | 30.4 Percentage of participants |
| Non-adhesive Wound Dressing Only | Likert Scale Rating of Tolerability | Oleogeogel-S10 much better tolerated | 8.9 Percentage of participants |
| Non-adhesive Wound Dressing Only | Likert Scale Rating of Tolerability | SOC better tolerated | 5.4 Percentage of participants |
| Non-adhesive Wound Dressing Only | Likert Scale Rating of Tolerability | Both treatments equally well tolerated | 44.6 Percentage of participants |
| Non-adhesive Wound Dressing Only | Likert Scale Rating of Tolerability | SOC much better tolerated | 0.0 Percentage of participants |
| Non-adhesive Wound Dressing Only | Likert Scale Rating of Tolerability | Oleogel-S10 better tolerated | 33.9 Percentage of participants |
| Investigator Assessment Day 21 | Likert Scale Rating of Tolerability | Oleogeogel-S10 much better tolerated | 11.6 Percentage of participants |
| Investigator Assessment Day 21 | Likert Scale Rating of Tolerability | Both treatments equally well tolerated | 46.4 Percentage of participants |
| Investigator Assessment Day 21 | Likert Scale Rating of Tolerability | SOC better tolerated | 3.6 Percentage of participants |
| Investigator Assessment Day 21 | Likert Scale Rating of Tolerability | Oleogel-S10 better tolerated | 28.6 Percentage of participants |
| Investigator Assessment Day 21 | Likert Scale Rating of Tolerability | SOC much better tolerated | 0.9 Percentage of participants |
| Investigator Assessment Day 28 | Likert Scale Rating of Tolerability | Both treatments equally well tolerated | 48.2 Percentage of participants |
| Investigator Assessment Day 28 | Likert Scale Rating of Tolerability | Oleogeogel-S10 much better tolerated | 12.5 Percentage of participants |
| Investigator Assessment Day 28 | Likert Scale Rating of Tolerability | SOC much better tolerated | 0.0 Percentage of participants |
| Investigator Assessment Day 28 | Likert Scale Rating of Tolerability | SOC better tolerated | 3.6 Percentage of participants |
| Investigator Assessment Day 28 | Likert Scale Rating of Tolerability | Oleogel-S10 better tolerated | 26.8 Percentage of participants |
| Investigator Assessment End of Treatment | Likert Scale Rating of Tolerability | Both treatments equally well tolerated | 49.1 Percentage of participants |
| Investigator Assessment End of Treatment | Likert Scale Rating of Tolerability | Oleogeogel-S10 much better tolerated | 13.4 Percentage of participants |
| Investigator Assessment End of Treatment | Likert Scale Rating of Tolerability | Oleogel-S10 better tolerated | 28.9 Percentage of participants |
| Investigator Assessment End of Treatment | Likert Scale Rating of Tolerability | SOC better tolerated | 3.6 Percentage of participants |
| Investigator Assessment End of Treatment | Likert Scale Rating of Tolerability | SOC much better tolerated | 0.0 Percentage of participants |
| Participant Assessment Day 7 | Likert Scale Rating of Tolerability | SOC better tolerated | 3.6 Percentage of participants |
| Participant Assessment Day 7 | Likert Scale Rating of Tolerability | Both treatments equally well tolerated | 58.0 Percentage of participants |
| Participant Assessment Day 7 | Likert Scale Rating of Tolerability | SOC much better tolerated | 0.0 Percentage of participants |
| Participant Assessment Day 7 | Likert Scale Rating of Tolerability | Oleogel-S10 better tolerated | 23.2 Percentage of participants |
| Participant Assessment Day 7 | Likert Scale Rating of Tolerability | Oleogeogel-S10 much better tolerated | 8.0 Percentage of participants |
| Participant Assessment Day 14 | Likert Scale Rating of Tolerability | Oleogeogel-S10 much better tolerated | 13.4 Percentage of participants |
| Participant Assessment Day 14 | Likert Scale Rating of Tolerability | SOC better tolerated | 8.9 Percentage of participants |
| Participant Assessment Day 14 | Likert Scale Rating of Tolerability | Both treatments equally well tolerated | 37.5 Percentage of participants |
| Participant Assessment Day 14 | Likert Scale Rating of Tolerability | Oleogel-S10 better tolerated | 29.5 Percentage of participants |
| Participant Assessment Day 14 | Likert Scale Rating of Tolerability | SOC much better tolerated | 0.0 Percentage of participants |
| Participant Assessment Day 21 | Likert Scale Rating of Tolerability | Oleogel-S10 better tolerated | 26.8 Percentage of participants |
| Participant Assessment Day 21 | Likert Scale Rating of Tolerability | Both treatments equally well tolerated | 37.5 Percentage of participants |
| Participant Assessment Day 21 | Likert Scale Rating of Tolerability | SOC better tolerated | 7.1 Percentage of participants |
| Participant Assessment Day 21 | Likert Scale Rating of Tolerability | Oleogeogel-S10 much better tolerated | 16.1 Percentage of participants |
| Participant Assessment Day 21 | Likert Scale Rating of Tolerability | SOC much better tolerated | 0.9 Percentage of participants |
| Participant Assessment Day 28 | Likert Scale Rating of Tolerability | SOC much better tolerated | 0.9 Percentage of participants |
| Participant Assessment Day 28 | Likert Scale Rating of Tolerability | Both treatments equally well tolerated | 40.2 Percentage of participants |
| Participant Assessment Day 28 | Likert Scale Rating of Tolerability | Oleogel-S10 better tolerated | 25.9 Percentage of participants |
| Participant Assessment Day 28 | Likert Scale Rating of Tolerability | SOC better tolerated | 5.4 Percentage of participants |
| Participant Assessment Day 28 | Likert Scale Rating of Tolerability | Oleogeogel-S10 much better tolerated | 15.2 Percentage of participants |
| Participant Assessment EoT | Likert Scale Rating of Tolerability | SOC better tolerated | 5.4 Percentage of participants |
| Participant Assessment EoT | Likert Scale Rating of Tolerability | Oleogel-S10 better tolerated | 27.7 Percentage of participants |
| Participant Assessment EoT | Likert Scale Rating of Tolerability | Oleogeogel-S10 much better tolerated | 16.1 Percentage of participants |
| Participant Assessment EoT | Likert Scale Rating of Tolerability | SOC much better tolerated | 0.9 Percentage of participants |
| Participant Assessment EoT | Likert Scale Rating of Tolerability | Both treatments equally well tolerated | 41.1 Percentage of participants |
Secondary
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
Time frame: 2 to 4 weeks
Population: The intent-to-treat (ITT) analysis population included all participants who were treated at least once with study medication, i.e. who received any dose of Oleogel-S10 and who had signed an informed consent form.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Entire Study Population | Percentage of Participants With Earlier Healing | 45.5 Percentage with earlier healing |
| Non-adhesive Wound Dressing Only | Percentage of Participants With Earlier Healing | 30.0 Percentage with earlier healing |
Secondary
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.
Time frame: 2 to 4 weeks
Population: The intent-to-treat (ITT) analysis population included all participants who were treated at least once with study medication, i.e. who received any dose of Oleogel-S10 and who had signed an informed consent form. Data were missing for n=2 participants at all time points.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Entire Study Population | Percentage of Participants With Wound Closure at Different Time Points | Day 7 | 2.8 Percentage with wound closure |
| Entire Study Population | Percentage of Participants With Wound Closure at Different Time Points | Day 10 | 14.8 Percentage with wound closure |
| Entire Study Population | Percentage of Participants With Wound Closure at Different Time Points | Day 14 | 48.1 Percentage with wound closure |
| Entire Study Population | Percentage of Participants With Wound Closure at Different Time Points | Day 18 | 79.6 Percentage with wound closure |
| Entire Study Population | Percentage of Participants With Wound Closure at Different Time Points | Day 21 | 86.1 Percentage with wound closure |
| Entire Study Population | Percentage of Participants With Wound Closure at Different Time Points | Day 28 | 96.3 Percentage with wound closure |
| Non-adhesive Wound Dressing Only | Percentage of Participants With Wound Closure at Different Time Points | Day 21 | 80.6 Percentage with wound closure |
| Non-adhesive Wound Dressing Only | Percentage of Participants With Wound Closure at Different Time Points | Day 7 | 3.7 Percentage with wound closure |
| Non-adhesive Wound Dressing Only | Percentage of Participants With Wound Closure at Different Time Points | Day 18 | 71.3 Percentage with wound closure |
| Non-adhesive Wound Dressing Only | Percentage of Participants With Wound Closure at Different Time Points | Day 10 | 8.3 Percentage with wound closure |
| Non-adhesive Wound Dressing Only | Percentage of Participants With Wound Closure at Different Time Points | Day 28 | 91.7 Percentage with wound closure |
| Non-adhesive Wound Dressing Only | Percentage of Participants With Wound Closure at Different Time Points | Day 14 | 48.1 Percentage with wound closure |
Secondary
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.
Time frame: 2 to 4 weeks
Population: The intent-to-treat (ITT) analysis population included all participants who were treated at least once with study medication, i.e. who received any dose of Oleogel-S10 and who had signed an informed consent form.
| Arm | Measure | Group | Value (MEAN) |
|---|---|---|---|
| Entire Study Population | Percentage of Wound Epithelialization at Different Time Points as Assessed by the Investigator | Day 10 | 48.6 Area Percent of initial wound size |
| Entire Study Population | Percentage of Wound Epithelialization at Different Time Points as Assessed by the Investigator | Day 18 | 90.9 Area Percent of initial wound size |
| Entire Study Population | Percentage of Wound Epithelialization at Different Time Points as Assessed by the Investigator | Day 7 | 27.4 Area Percent of initial wound size |
| Entire Study Population | Percentage of Wound Epithelialization at Different Time Points as Assessed by the Investigator | Day 21 | 94.0 Area Percent of initial wound size |
| Entire Study Population | Percentage of Wound Epithelialization at Different Time Points as Assessed by the Investigator | Day 14 | 80.6 Area Percent of initial wound size |
| Entire Study Population | Percentage of Wound Epithelialization at Different Time Points as Assessed by the Investigator | Day 28 | 96.4 Area Percent of initial wound size |
| Non-adhesive Wound Dressing Only | Percentage of Wound Epithelialization at Different Time Points as Assessed by the Investigator | Day 28 | 92.8 Area Percent of initial wound size |
| Non-adhesive Wound Dressing Only | Percentage of Wound Epithelialization at Different Time Points as Assessed by the Investigator | Day 7 | 21.3 Area Percent of initial wound size |
| Non-adhesive Wound Dressing Only | Percentage of Wound Epithelialization at Different Time Points as Assessed by the Investigator | Day 10 | 42.5 Area Percent of initial wound size |
| Non-adhesive Wound Dressing Only | Percentage of Wound Epithelialization at Different Time Points as Assessed by the Investigator | Day 14 | 74.9 Area Percent of initial wound size |
| Non-adhesive Wound Dressing Only | Percentage of Wound Epithelialization at Different Time Points as Assessed by the Investigator | Day 18 | 85.0 Area Percent of initial wound size |
| Non-adhesive Wound Dressing Only | Percentage of Wound Epithelialization at Different Time Points as Assessed by the Investigator | Day 21 | 88.5 Area Percent of initial wound size |
p-value: =0.000595% CI: [2.7, 9.4]t-test, 2 sided
p-value: =0.000295% CI: [3, 9.4]t-test, 2 sided
p-value: =0.002895% CI: [2, 9.3]t-test, 2 sided
p-value: =0.000995% CI: [2.5, 9.3]t-test, 2 sided
p-value: =0.000395% CI: [2.6, 8.6]t-test, 2 sided
p-value: =0.014595% CI: [0.7, 6.4]t-test, 2 sided
Secondary
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.
Time frame: up to 4 weeks
Population: The safety analysis population included all participants who received treatment at least once, i.e. who received any dose of Oleogel-S10 or standard of care (SOC). If the application of any treatment was uncertain, the participant was included in the SAF.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Entire Study Population | Pharmacokinetic (PK) Data (Number of Plasma Samples With Measurable Betulin Concentration) | Samples below LLOQ (<1 ng/mL) | 110 Plasma Samples |
| Entire Study Population | Pharmacokinetic (PK) Data (Number of Plasma Samples With Measurable Betulin Concentration) | Samples above LLOQ | 2 Plasma Samples |
| Entire Study Population | Pharmacokinetic (PK) Data (Number of Plasma Samples With Measurable Betulin Concentration) | Samples without valid result | 0 Plasma Samples |
| Non-adhesive Wound Dressing Only | Pharmacokinetic (PK) Data (Number of Plasma Samples With Measurable Betulin Concentration) | Samples below LLOQ (<1 ng/mL) | 271 Plasma Samples |
| Non-adhesive Wound Dressing Only | Pharmacokinetic (PK) Data (Number of Plasma Samples With Measurable Betulin Concentration) | Samples above LLOQ | 13 Plasma Samples |
| Non-adhesive Wound Dressing Only | Pharmacokinetic (PK) Data (Number of Plasma Samples With Measurable Betulin Concentration) | Samples without valid result | 6 Plasma Samples |
Secondary
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
Time frame: up to 4 weeks
Population: A total of 13 participants had a total of 15 samples with betulin concentrations above the LLOQ (1 ng/mL), 2 participants with 2 samples each above LLOQ
| Arm | Measure | Value (MEAN) |
|---|---|---|
| Entire Study Population | Pharmacokinetic (PK) Data (Plasma Betulin Concentration) | 24.0 Betulin (ng/mL) |
| Non-adhesive Wound Dressing Only | Pharmacokinetic (PK) Data (Plasma Betulin Concentration) | 10.4 Betulin (ng/mL) |
Secondary
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).
Time frame: Day 0 (start of treatment) until end of treatment (Day 28 or earlier if full wound closure was achieved earlier).
Population: The safety analysis population included all participants who received treatment at least once, i.e. who received any dose of Oleogel-S10 or standard of care (SOC). If the application of any treatment was uncertain, the participant was included in the SAF.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Entire Study Population | Severity of Adverse Events | Mild (CTCAE Grade 1) | 40.2 Participants with adverse events (%) |
| Entire Study Population | Severity of Adverse Events | Moderate (CTCAE Grade 2) | 27.7 Participants with adverse events (%) |
| Entire Study Population | Severity of Adverse Events | Severe (CTCAE Grade 3) | 7.1 Participants with adverse events (%) |
| Entire Study Population | Severity of Adverse Events | Life-Threatening (CTCAE Grade 4) | 2.7 Participants with adverse events (%) |
| Entire Study Population | Severity of Adverse Events | Death (CTCAE Grade 5) | 0.0 Participants with adverse events (%) |
Secondary
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 110 participants with missing values replaced by a value of 0, for outcome measure 2 missing values were not replaced. For 2 of the 110 wounds data were missing, thus the reported values are calculated from 108 STSG donor site wound halves by intervention (Oleogel-S10 and non-adhesive wound dressing vs. non-adhesive wound dressing only).
Time frame: 2 to 4 weeks
Population: The intent-to-treat (ITT) analysis population included all participants who were treated at least once with study medication, i.e. who received any dose of Oleogel-S10 and who had signed an informed consent form. For 2 of the 110 wounds, data were missing, thus the reported values are calculated from 108 STSG donor site wound halves by intervention
| Arm | Measure | Value (MEAN) |
|---|---|---|
| Entire Study Population | Time From Surgery Until Wound Closure is Achieved | 15.1 Days from surgery until wound closure |
| Non-adhesive Wound Dressing Only | Time From Surgery Until Wound Closure is Achieved | 16.0 Days from surgery until wound closure |