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

• Sponsor: Birken AG (Industry)
• Overall Status: Completed
• CT.gov ID: NCT01657305
• Collaborator: (none)
• Enrollment: 107
• Locations: 24
• Arms: 2
• Duration (Months): 25
• Patients Per Site: 4.5
• Patients Per Site Per Month: 0.2

Study Details

Study Description

Brief Summary

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.

Condition or Disease	Intervention/Treatment	Phase
Wounds	Drug: Oleogel-S10, non-adhesive wound dressing; Device: Non-adhesive wound dressing only	Phase 3

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 blind to the treatment of the wound halves.

Study Design

• Study Type: Interventional
• Actual Enrollment: 107 participants
• Allocation: Randomized
• Intervention Model: Single Group Assignment
• Masking: Single (Outcomes Assessor)
• Primary Purpose: Treatment
• Official Title: 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
• Study Start Date: Aug 1, 2012
• Actual Primary Completion Date: Aug 1, 2013
• Actual Study Completion Date: Sep 1, 2014

Arms and Interventions

Arm	Intervention/Treatment
Experimental: Oleogel-S10, non-adhesive wound dressing 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; 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.; Other Names: Episalvan®
Other: Non-adhesive wound dressing only 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; 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.; Other Names: Mepilex®

Outcome Measures

Primary Outcome Measures

1. Intra-individual Difference in Time to Wound Closure [up 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 Outcome Measures

1. Time From Surgery Until Wound Closure is Achieved [up 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 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).

2. Percentage of Participants With Earlier Healing [up 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

3. Percentage of Participants With Wound Closure at Different Time Points [up 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.

4. Percentage of Wound Epithelialization at Different Time Points as Assessed by the Investigator [up 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.

5. Likert Scale Rating of Efficacy [up 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).

6. 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.

7. Likert Scale Rating of Tolerability [up 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, standard of care is better tolerated, standard of care is much better tolerated).

8. 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.

9. 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

10. Frequency of Adverse Events [Day 0 (start of treatment) until end of treatment (Day 28 or earlier if full wound closure was achieved earlier).]

11. 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).

12. 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'.

Eligibility Criteria

Criteria

• Ages Eligible for Study: 18 Years and Older
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

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.

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	Medical University of Graz	Graz		Austria
2	Landesklinik für Dermatologie	Salzburg		Austria
3	Medical University Vienna	Vienna		Austria
4	University Multiprofile Hospital for Active Treatment-"Dr. Georgi Stranski" EAD	Pleven		Bulgaria
5	University Multiprofile Hospital for Active Treatment "Saint George"	Plovdiv		Bulgaria
6	Multiprofile Hospital for Active Treatment- Ruse	Ruse		Bulgaria
7	University Multiprofile Hospital for Active Treatment and Emergency Medicine "N.I.Pirogov"	Sofia		Bulgaria
8	University Multiprofile Hospital for Active Treatment-Varna at MMA-Sofia	Varna		Bulgaria
9	Universtity Hospital Brno	Brno		Czechia
10	University Hospital Olomouc	Olomouc		Czechia
11	Päijät-Hämeen keskussairaala	Lahti		Finland
12	Satakunnan keskussairaala	Pori		Finland
13	Trauma Hospital	Berlin		Germany
14	University Hospital	Düsseldorf		Germany
15	Essen University Hospital	Essen		Germany
16	University Hospital	Frankfurt		Germany
17	University Medical Center	Freiburg		Germany
18	University Medicine Greifswald	Greifswald		Germany
19	HELIOS Clinic	Krefeld		Germany
20	University Medical Center	Mainz		Germany
21	Klinikum rechts der Isar	München		Germany
22	Klinikum Offenbach am Main	Offenbach		Germany
23	Univesity Hospital Gdansk	Gdansk		Poland
24	Samodzelny Publiczny Szpital Kliniczny Nr. 1	Lublin		Poland

Sponsors and Collaborators

• Birken AG

Investigators

• Principal Investigator: Hans Robert Metelmann, Prof, Universitätsmedizin Greifswald MKG-Chirurgie/Plastische Operationen

Study Documents (Full-Text)

None provided.

More Information

Publications

None provided.

• Responsible Party: Birken AG
• ClinicalTrials.gov Identifier: NCT01657305
• Other Study ID Numbers: BSH-12; 2012-000777-23
• First Posted: Aug 6, 2012
• Last Update Posted: Jan 23, 2018
• Last Verified: May 1, 2017

• Individual Participant Data (IPD) Sharing Statement: No
• Plan to Share IPD: No
• Keywords provided by Birken AG: 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
• Additional relevant MeSH terms: Wounds and Injuries

Study Results

Participant Flow

Recruitment Details	Study participants were enrolled from 03 Aug 2012 to 01 Aug 2013 in 18 clinical centers in 6 countries: Germany (8 centers), Czech Republic (2 centers), Poland (1 center), Finland (1 center), Austria (2 centers), and Bulgaria (4 centers).
Pre-assignment Detail	111 participants were screened and wound halves of 107 participants were randomized and treated. For four screened participants, wound halves were neither randomized nor treated with study medication for the following reasons: not randomized by mistake, violation of inclusion criteria, surgery cancelled, and withdrawal of consent.

Arm/Group Title	Entire Study Population
Arm/Group Description	Intraindividual comparison: A split-thickness skin graft (STSG) donor site wound ≥15 cm² in size was divided in 2 halves. One wound half was randomized to Oleogel-S10 treatment and non-adhesive wound dressing, the other half to non-adhesive wound dressing (intra-individual comparison). Non-adhesive wound dressings such as 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 approximately 1 mm or 0.04 inches. Treatment was repeated and wound dressings were changed at least every 3 to 4 days until wound closure (at least 95% epithelialisation) was achieved or the end of treatment was reached at Day 28.
Period Title: Overall Study
STARTED	107
COMPLETED	82
NOT COMPLETED	25

Baseline Characteristics

Arm/Group Title	Entire Study Population
Arm/Group Description	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.
Overall Participants	107
Age (Count of Participants)
<=18 years	2 1.9%
Between 18 and 65 years	65 60.7%
>=65 years	40 37.4%
Age (years) [Median (Full Range) ]
Median (Full Range) [years]	56
Sex: Female, Male (Count of Participants)
Female	39 36.4%
Male	68 63.6%
Region of Enrollment (participants) [Number]
Czech Republic	40 37.4%
Austria	4 3.7%
Finland	3 2.8%
Poland	2 1.9%
Bulgaria	24 22.4%
Germany	34 31.8%

Outcome Measures

1. Primary Outcome

Title	Intra-individual Difference in Time to Wound Closure
Description	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	up to 4 weeks

Outcome Measure Data

Analysis Population Description

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.

Arm/Group Title	Entire Study Population
Arm/Group Description	All patients treated with Oleogel-S10 plus non-adhesive wound dressing and with non-adhesive wound dressing only.
Measure Participants	107
Mean (95% Confidence Interval) [days]	-1.4

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Entire Study Population
	Comments	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. Negative values for the intra-individual time difference indicate faster healing of the Oleogel-S10-treated wound half. For right-censored observations (no wound closure observed in blinded photo evaluation), wound closure was conservatively calculated as +1 day after the last photo.
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	<0.0001
	Comments	2-sided, significance level = 0.05
	Method	t-test, 2 sided
	Comments

2. Secondary Outcome

Title	Time From Surgery Until Wound Closure is Achieved
Description	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).
Time Frame	up to 4 weeks

Outcome Measure Data

Analysis Population Description

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 5 of the 107 wounds, data were missing, thus the reported values are calculated from 102 STSG donor site wound halves by intervention

Arm/Group Title	Oleogel-S10, Non-adhesive Wound Dressing	Non-adhesive Wound Dressing Only
Arm/Group Description	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 inches) every 3 to 4 days until 95% epithelialization of the wound or end of treatment at Day 28. Oleogel-S10, non-adhesive wound dressing: 1 cm or 100 mg Oleogel-S10 per cm2 wound area (corresponds to thickness of approximately 1 mm or 0.04 inches) every 3 to 4 days until 95% epithelialization of the wound or end of treatment at Day 28.	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. Non-adhesive wound dressing only: 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.
Measure Participants	107	107
Measure Number of STSG wound (halves) analyzed	102	102
Mean (95% Confidence Interval) [Days from surgery until wound closure]	15.5	17.1

3. Secondary Outcome

Title	Percentage of Participants With Earlier Healing
Description	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	up to 4 weeks

Outcome Measure Data

Analysis Population Description

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/Group Title	Oleogel-S10, Non-adhesive Wound Dressing	Non-adhesive Wound Dressing Only
Arm/Group Description	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 inches) every 3 to 4 days until 95% epithelialization of the wound or end of treatment at Day 28. Oleogel-S10, non-adhesive wound dressing: 1 cm or 100 mg Oleogel-S10 per cm2 wound area (corresponds to thickness of approximately 1 mm or 0.04 inches) every 3 to 4 days until 95% epithelialization of the wound or end of treatment at Day 28.	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. Non-adhesive wound dressing only: 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.
Measure Participants	107	107
Number (95% Confidence Interval) [Percentage with earlier healing]	61.7	7.5

4. Secondary Outcome

Title	Percentage of Participants With Wound Closure at Different Time Points
Description	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	up to 4 weeks

Outcome Measure Data

Analysis Population Description

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=5 participants at all time points.

Arm/Group Title	Oleogel-S10, Non-adhesive Wound Dressing	Non-adhesive Wound Dressing Only
Arm/Group Description	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 inches) every 3 to 4 days until 95% epithelialization of the wound or end of treatment at Day 28. Oleogel-S10, non-adhesive wound dressing: 1 cm or 100 mg Oleogel-S10 per cm2 wound area (corresponds to thickness of approximately 1 mm or 0.04 inches) every 3 to 4 days until 95% epithelialization of the wound or end of treatment at Day 28.	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. Non-adhesive wound dressing only: 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.
Measure Participants	102	102
Day 7	2.0	1.0
Day 10	25.5	15.7
Day 14	49.0	37.3
Day 18	70.6	61.8
Day 21	77.5	71.6
Day 28	94.1	90.2

5. Secondary Outcome

Title	Percentage of Wound Epithelialization at Different Time Points as Assessed by the Investigator
Description	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	up to 4 weeks

Outcome Measure Data

Analysis Population Description

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=1 participant at all time points.

Arm/Group Title	Oleogel-S10, Non-adhesive Wound Dressing	Non-adhesive Wound Dressing Only
Arm/Group Description	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 inches) every 3 to 4 days until 95% epithelialization of the wound or end of treatment at Day 28. Oleogel-S10, non-adhesive wound dressing: 1 cm or 100 mg Oleogel-S10 per cm2 wound area (corresponds to thickness of approximately 1 mm or 0.04 inches) every 3 to 4 days until 95% epithelialization of the wound or end of treatment at Day 28.	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. Non-adhesive wound dressing only: 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.
Measure Participants	107	107
Day 7	36.7	28.1
Day 10	60.0	49.9
Day 14	82.2	74.3
Day 18	89.7	82.3
Day 21	92.2	85.8
Day 28	93.9	90.0

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Entire Study Population, Non-adhesive Wound Dressing Only
	Comments
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	<0.0001
	Comments	Day 7
	Method	t-test, 2 sided
	Comments
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	8.6
	Confidence Interval	(2-Sided) 95%; 6.0 to 11.2
	Parameter Dispersion	Type: Standard Deviation; Value: 13.4
	Estimation Comments	Difference in degree of epithelialization [%] (Oleogel-S10 minus standard of care)

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Entire Study Population, Non-adhesive Wound Dressing Only
	Comments
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	<0.0001
	Comments	Day 10
	Method	t-test, 2 sided
	Comments
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	10.1
	Confidence Interval	(2-Sided) 95%; 6.9 to 13.4
	Parameter Dispersion	Type: Standard Deviation; Value: 17.0
	Estimation Comments	Difference in degree of epithelialization [%] (Oleogel-S10 minus standard of care)

Statistical Analysis 3

Statistical Analysis Overview	Comparison Group Selection	Entire Study Population, Non-adhesive Wound Dressing Only
	Comments
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	<0.0001
	Comments	Day 14
	Method	t-test, 2 sided
	Comments
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	7.9
	Confidence Interval	(2-Sided) 95%; 4.6 to 11.1
	Parameter Dispersion	Type: Standard Deviation; Value: 17.0
	Estimation Comments	Difference in degree of epithelialization [%] (Oleogel-S10 minus standard of care)

Statistical Analysis 4

Statistical Analysis Overview	Comparison Group Selection	Entire Study Population, Non-adhesive Wound Dressing Only
	Comments
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	<0.0001
	Comments	Day 18
	Method	t-test, 2 sided
	Comments
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	7.4
	Confidence Interval	(2-Sided) 95%; 3.9 to 10.9
	Parameter Dispersion	Type: Standard Deviation; Value: 18.3
	Estimation Comments	Difference in degree of epithelialization [%] (Oleogel-S10 minus standard of care)

Statistical Analysis 5

Statistical Analysis Overview	Comparison Group Selection	Entire Study Population, Non-adhesive Wound Dressing Only
	Comments
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	<0.0001
	Comments	Day 21
	Method	t-test, 2 sided
	Comments
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	6.4
	Confidence Interval	(2-Sided) 95%; 3.7 to 9.1
	Parameter Dispersion	Type: Standard Deviation; Value: 14.1
	Estimation Comments	Difference in degree of epithelialization [%] (Oleogel-S10 minus standard of care)

Statistical Analysis 6

Statistical Analysis Overview	Comparison Group Selection	Entire Study Population, Non-adhesive Wound Dressing Only
	Comments
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	=0.0021
	Comments	Day 28
	Method	t-test, 2 sided
	Comments
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	3.9
	Confidence Interval	(2-Sided) 95%; 1.5 to 6.4
	Parameter Dispersion	Type: Standard Deviation; Value: 12.9
	Estimation Comments	Difference in degree of epithelialization [%] (Oleogel-S10 minus standard of care)

6. Secondary Outcome

Title	Likert Scale Rating of Efficacy
Description	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	up to 4 weeks

Outcome Measure Data

Analysis Population Description

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/Group Title	Investigator Asssessment Day 7	Investigator Assessment Day 14	Investigator Assessment Day 21	Investigator Assessment Day 28	Investigator Assessment End of Treatment	Participant Assessment Day 7	Participant Assessment Day 14	Participant Assessment Day 21	Participant Assessment Day 28	Participant Assessment EoT
Arm/Group Description	Efficacy as assessed by investigator at Day 7	Efficacy as assessed by investigator at Day 14	Efficacy as assessed by investigator at Day 21	Efficacy as assessed by investigator at Day 28	Efficacy as assessed by investigator at End of Treatment (EoT)	Efficacy as assessed by participant at Day 7	Efficacy as assessed by participant at Day 14	Efficacy as assessed by participant at Day 21	Efficacy as assessed by participant at Day 28	Efficacy as assessed by participant at EoT
Measure Participants	100	101	97	95	104	100	101	97	95	104
Oleogel-S10 much more effective	15.0	20.8	19.6	15.8	16.3	18.0	15.8	21.6	20.0	21.2
Oleogel-S10 more effective	46.0	49.5	51.5	52.6	51.9	44.0	46.5	42.3	42.1	41.3
Both treatments same efficacy	31.0	24.8	25.8	29.5	28.8	33.0	31.7	32.0	34.7	34.6
Standard of care (SOC) more effective	8.0	3.0	1.0	1.1	1.9	5.0	4.0	3.1	3.2	2.9
SOC much more effective	0.0	2.0	2.1	1.1	1.0	0.0	2.0	1.0	0.0	0.0

7. Secondary Outcome

Title	Cosmetic Outcome at 3 and 12 Months After Surgery, Respectively
Description	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

Outcome Measure Data

Analysis Population Description

The intent-to-treat (ITT) analysis population included 87 participants for the 3-months follow-up and 83 participants for the 12-months follow-up.

Arm/Group Title	Texture at 3 Months Follow-up	Hair Growth at 3 Months Follow-up	Pigmentation at 3 Months Follow-up	Redness at 3 Months Follow-up	Texture at 12 Months Follow-up	Hair Growth at 12 Months Follow-up	Pigmentation at 12 Months Follow-up	Redness at 12 Months Follow-up
Arm/Group Description	Evaluation of cosmetic outcome with regard to texture at 3 months follow-up	Evaluation of cosmetic outcome with regard to hair growth at 3 months follow-up	Evaluation of cosmetic outcome with regard to pigmentation at 3 months follow-up	Evaluation of cosmetic outcome with regard to redness at 3 months follow-up	Evaluation of cosmetic outcome with regard to texture at 12 months follow-up	Evaluation of cosmetic outcome with regard to hair growth at 12 months follow-up	Evaluation of cosmetic outcome with regard to pigmentation at 12 months follow-up	Evaluation of cosmetic outcome with regard to redness at 12 months follow-up
Measure Participants	87	87	87	87	83	83	83	83
Wound half treated with Oleogel-S10	36.8	1.1	41.4	31.0	13.3	2.4	20.5	10.8
Wound half treated with wound dressing only	5.7	0.0	6.9	5.7	2.4	1.2	8.4	3.6
Both equal	51.7	97.7	47.1	58.6	84.3	96.4	68.7	85.5

8. Secondary Outcome

Title	Likert Scale Rating of Tolerability
Description	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).
Time Frame	up to 4 weeks

Outcome Measure Data

Analysis Population Description

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/Group Title	Investigator Asssessment Day 7	Investigator Assessment Day 14	Investigator Assessment Day 21	Investigator Assessment Day 28	Investigator Assessment End of Treatment	Participant Assessment Day 7	Participant Assessment Day 14	Participant Assessment Day 21	Participant Assessment Day 28	Participant Assessment EoT
Arm/Group Description	Tolerability as assessed by investigator at Day 7	Tolerability as assessed by investigator at Day 14	Tolerability as assessed by investigator at Day 21	Tolerability as assessed by investigator at Day 28	Tolerability as assessed by investigator at End of Treatment (EoT)	Tolerability as assessed by participant at Day 7	Tolerability as assessed by participant at Day 14	Tolerability as assessed by participant at Day 21	Tolerability as assessed by participant at Day 28	Tolerability as assessed by participant at EoT
Measure Participants	107	107	107	107	107	107	107	107	107	107
Oleogeogel-S10 much better tolerated	6.0 5.6%	9.9 NaN	14.4 NaN	11.6 NaN	11.5 NaN	10.0 NaN	7.9 NaN	16.5 NaN	12.6 NaN	13.5 NaN
Oleogel-S10 better tolerated	38.0 35.5%	40.6 NaN	32.0 NaN	32.6 NaN	33.7 NaN	34.0 NaN	37.6 NaN	29.9 NaN	31.6 NaN	30.8 NaN
Both treatments equally well tolerated	52.0 48.6%	49.5 NaN	51.5 NaN	55.8 NaN	54.8 NaN	53.0 NaN	50.5 NaN	51.5 NaN	54.7 NaN	54.8 NaN
SOC better tolerated	4.0 3.7%	0.0 NaN	2.1 NaN	0.0 NaN	0.0 NaN	3.0 NaN	4.0 NaN	2.1 NaN	1.1 NaN	1.0 NaN
SOC much better tolerated	0.0 0%	0.0 NaN	0.0 NaN	0.0 NaN	0.0 NaN	0.0 NaN	0.0 NaN	0.0 NaN	0.0 NaN	0.0 NaN

9. Secondary Outcome

Title	Pharmacokinetic (PK) Data (Number of Plasma Samples With Measurable Betulin Concentration)
Description	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

Outcome Measure Data

Analysis Population Description

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/Group Title	Day 0 (Pre-dose)	Treatment Period
Arm/Group Description	Plasma samples collected at the day of STSG surgery prior to first treatment with study medication	Plasma samples collected at Day 7, Day 14, Day 21 or at end of treatment (day of wound closure or Day 28)
Measure Participants	107	106
Measure Plasma Samples	107	281
Samples below LLOQ (<1 ng/mL)	105	272
Samples above LLOQ (range in ng/mL)	2	3
Samples with no valid result	0	6

10. Secondary Outcome

Title	Pharmacokinetic (PK) Data (Plasma Betulin Concentration)
Description	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

Outcome Measure Data

Analysis Population Description

A total of 5 participants had a total of 5 samples with betulin concentrations above the LLOQ (1 ng/mL)

Arm/Group Title	Day 0 (Pre-dose)	Treatment Period
Arm/Group Description	Plasma samples collected at the day of STSG surgery prior to first treatment with study medication	Plasma samples collected at Day 7, Day 14, Day 21 or at end of treatment (day of wound closure or Day 28)
Measure Participants	107	106
Measure Samples above LLOQ	2	3
Mean (Full Range) [Betulin (ng/mL)]	2.1	2.4

11. Secondary Outcome

Title	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).

Outcome Measure Data

Analysis Population Description

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/Group Title	Entire Study Population
Arm/Group Description	All participants who were randomized and treated with Oleogel-S10 and non-adhesive wound dressing and/or non-adhesive wound dressing only.
Measure Participants	107
Adverse events (AEs)	17.8 16.6%
Serious adverse events	1.9 1.8%
AEs leading to discontinuation	1.9 1.8%
Related AEs	2.8 2.6%
Application site reactions	8.4 7.9%

12. Secondary Outcome

Title	Severity of Adverse Events
Description	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).

Outcome Measure Data

Analysis Population Description

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/Group Title	Entire Study Population
Arm/Group Description	All participants who were randomized and treated with Oleogel-S10 and non-adhesive wound dressing and/or non-adhesive wound dressing only.
Measure Participants	107
Mild (CTCAE Grade 1)	10.3 9.6%
Moderate (CTCAE Grade 2)	4.7 4.4%
Severe (CTCAE Grade 3)	4.7 4.4%
Life-Threatening (CTCAE Grade 4)	0.0 0%
Death (CTCAE Grade 5)	0.0 0%

13. Secondary Outcome

Title	Adverse Events by Relationship to Study Medication
Description	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).

Outcome Measure Data

Analysis Population Description

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/Group Title	Entire Study Population
Arm/Group Description	All participants who were randomized and treated with Oleogel-S10 and non-adhesive wound dressing and/or non-adhesive wound dressing only.
Measure Participants	107
'Unlikely' related	0.0 0%
'Possibly' related	2.8 2.6%
'Probably' related	0.0 0%
Unknown relationship	0.0 0%
No relationship	15.9 14.9%

Adverse Events

Time Frame	Day 0 (start of treatment) until end of treatment (Day 28 or earlier if full wound closure was achieved earlier).
Arm/Group Title	Entire Study Population - Systemic Adverse Events (AE)		Oleogel-S10 Localized AE		Non-adhesive Wound Wound Dressing Localized AE		Localized AE Both Wound Halves
Arm/Group Description	All participants treated with Oleogel-S10 plus non-adhesive wound dressing and/or non-adhesive wound dressing only. AEs not localized to any wound application site by the investigator are reported in this arm.		All participants treated with Oleogel-S10 plus non-adhesive wound dressing and/or non-adhesive wound dressing only. Application site reactions as judged by the investigator which occurred only at the Oleogel-S10 wound half are reported in this arm.		All participants treated with Oleogel-S10 plus non-adhesive wound dressing and/or non-adhesive wound dressing only. Application site reactions as judged by the investigator which occurred only at the wound half treated only with non-adhesive wound dressing are reported in this arm.		All participants treated with Oleogel-S10 plus non-adhesive wound dressing and/or non-adhesive wound dressing only. Application site reactions as judged by the investigator which occurred at both the Oleogel-S10 wound half and the non-adhesive wound dressing only half in one patient are reported in this arm.
All Cause Mortality
	Entire Study Population - Systemic Adverse Events (AE)		Oleogel-S10 Localized AE		Non-adhesive Wound Wound Dressing Localized AE		Localized AE Both Wound Halves
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	/ (NaN)		/ (NaN)		/ (NaN)		/ (NaN)
Serious Adverse Events
	Entire Study Population - Systemic Adverse Events (AE)		Oleogel-S10 Localized AE		Non-adhesive Wound Wound Dressing Localized AE		Localized AE Both Wound Halves
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	1/107 (0.9%)		0/107 (0%)		0/107 (0%)		1/107 (0.9%)
Infections and infestations
Wound infection	0/107 (0%)	0	0/107 (0%)	0	0/107 (0%)	0	1/107 (0.9%)	1
Skin and subcutaneous tissue disorders
Diabetic foot	1/107 (0.9%)	1	0/107 (0%)	0	0/107 (0%)	0	0/107 (0%)	0
Other (Not Including Serious) Adverse Events
	Entire Study Population - Systemic Adverse Events (AE)		Oleogel-S10 Localized AE		Non-adhesive Wound Wound Dressing Localized AE		Localized AE Both Wound Halves
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	0/107 (0%)		0/107 (0%)		0/107 (0%)		0/107 (0%)

Limitations/Caveats

[Not Specified]

More Information

Certain Agreements

Principal Investigators are NOT employed by the organization sponsoring the study.

Publication requires approval of the sponsor without specification of an embargo time period.