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

• Sponsor: Birken AG (Industry)
• Overall Status: Completed
• CT.gov ID: NCT01807650
• Collaborator: (none)
• Enrollment: 112
• Locations: 14
• Arms: 2
• Duration (Months): 18
• Patients Per Site: 8
• Patients Per Site Per Month: 0.4

Study Details

Study Description

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.

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 blinded to the treatment of the wound halves.

Study Design

• Study Type: Interventional
• Actual Enrollment: 112 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: Mar 1, 2013
• Actual Primary Completion Date: Sep 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.	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 [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 Outcome Measures

1. 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).

2. 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

3. 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.

4. 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.

5. 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).

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 [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).

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:

• 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.

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	CHU de Bordeaux	Bordeaux		France
2	Hôpital de la Conception	Marseille		France
3	CHU de Nantes	Nantes		France
4	KAT General Hospital of Attica	Athens		Greece
5	National University, "Andreas Syggros" Skin & Venereal Diseases Hospital	Athens		Greece
6	Aristotle University General Hospital	Thessaloniki		Greece
7	Riga East University Hospital, Microsurgery Center	Riga		Latvia
8	Riga East University Hospital, State Burn Center	Riga		Latvia
9	Hospital de la Santa Creu i Sant Pau	Barcelona		Spain
10	Hospital Universitari Vall d'Hebron	Barcelona		Spain
11	Hospital Universitario de Getafe	Madrid		Spain
12	Hopital Universitari i Politecnic La Fe	Valencia		Spain
13	Hospital Universitario Rio Ortega	Valladolid		Spain
14	Hospital Miguel Servet	Zaragoza		Spain

Sponsors and Collaborators

• Birken AG

Investigators

• Principal Investigator: Juan Pedro Barret Nerin, MD, Hospital Universitari Vall d´Hebron, Barcelona, Spain

Study Documents (Full-Text)

None provided.

More Information

Publications

• Barret JP, Podmelle F, Lipový B, Rennekampff HO, Schumann H, Schwieger-Briel A, Zahn TR, Metelmann HR; BSH-12 and BSG-12 study groups. Accelerated re-epithelialization of partial-thickness skin wounds by a topical betulin gel: Results of a randomized phase III clinical trials program. Burns. 2017 Sep;43(6):1284-1294. doi: 10.1016/j.burns.2017.03.005. Epub 2017 Apr 8.

• Responsible Party: Birken AG
• ClinicalTrials.gov Identifier: NCT01807650
• Other Study ID Numbers: BSG-12; 2012-003390-26
• First Posted: Mar 8, 2013
• Last Update Posted: Jul 19, 2018
• Last Verified: Jul 1, 2018

• 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	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 Detail	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.

Arm/Group Title	Entire Study Population
Arm/Group Description	A split-thickness skin graft (STSG) donor site wound >15cm2 in size was divided in 2 halves. One half of the STSG wound was randomized to Oleogel-S10 treatment plus non-adhesive wound dressing. The other wound half was covered with a non-adhesive wound dressing only as control (intra-individual comparison)
Period Title: Overall Study
STARTED	112
COMPLETED	92
NOT COMPLETED	20

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	112
Age (Count of Participants)
<=18 years	0 0%
Between 18 and 65 years	89 79.5%
>=65 years	23 20.5%
Age (years) [Median (Full Range) ]
Median (Full Range) [years]	49
Sex: Female, Male (Count of Participants)
Female	39 34.8%
Male	73 65.2%
Region of Enrollment (participants) [Number]
Greece	14 12.5%
Latvia	31 27.7%
France	11 9.8%
Spain	56 50%

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	2 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	Entire Study Population
Arm/Group Description	All participants treated with Oleogel-S10 plus non-adhesive wound dressing and with non-adhesive wound dressing only
Measure Participants	110
Mean (95% Confidence Interval) [days]	-0.8

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.
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	=0.0232
	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 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

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 2 of the 110 wounds, data were missing, thus the reported values are calculated from 108 STSG donor site wound halves by intervention

Arm/Group Title	Oleogel-S10 and 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 of the STSG wound was randomized to Oleogel-S10 treatment plus non-adhesive wound dressing.	A split-thickness skin graft (STSG) donor site wound >15cm2 in size was divided in 2 halves. One half of the STSG wound was randomized to coverage with non-adhesive wound dressing only.
Measure Participants	110	110
Measure STSG Wound (Halves)	108	108
Mean (95% Confidence Interval) [Days from surgery until wound closure]	15.1	16.0

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	2 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 and 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 of the STSG wound was randomized to Oleogel-S10 treatment plus non-adhesive wound dressing.	A split-thickness skin graft (STSG) donor site wound >15cm2 in size was divided in 2 halves. One half of the STSG wound was randomized to coverage with non-adhesive wound dressing only.
Measure Participants	110	110
Number (95% Confidence Interval) [Percentage with earlier healing]	45.5	30.0

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	2 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=2 participants at all time points.

Arm/Group Title	Oleogel-S10 and 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 of the STSG wound was randomized to Oleogel-S10 treatment plus non-adhesive wound dressing.	A split-thickness skin graft (STSG) donor site wound >15cm2 in size was divided in 2 halves. One half of the STSG wound was randomized to coverage with non-adhesive wound dressing only.
Measure Participants	110	110
Day 7	2.8	3.7
Day 10	14.8	8.3
Day 14	48.1	48.1
Day 18	79.6	71.3
Day 21	86.1	80.6
Day 28	96.3	91.7

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	2 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 and 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 of the STSG wound was randomized to Oleogel-S10 treatment plus non-adhesive wound dressing.	A split-thickness skin graft (STSG) donor site wound >15cm2 in size was divided in 2 halves. One half of the STSG wound was randomized to coverage with non-adhesive wound dressing only.
Measure Participants	110	110
Day 7	27.4	21.3
Day 10	48.6	42.5
Day 14	80.6	74.9
Day 18	90.9	85.0
Day 21	94.0	88.5
Day 28	96.4	92.8

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	=0.0005
	Comments	Day 7
	Method	t-test, 2 sided
	Comments
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	6.1
	Confidence Interval	(2-Sided) 95%; 2.7 to 9.4
	Parameter Dispersion	Type: Standard Deviation; Value: 17.8
	Estimation Comments	Mean difference in degree of epithelialization [%] (Oleogel-S10 and non-adhesive wound dressing minus non-adhesive wound dressing only)

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	=0.0002
	Comments	Day 10
	Method	t-test, 2 sided
	Comments
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	6.2
	Confidence Interval	(2-Sided) 95%; 3.0 to 9.4
	Parameter Dispersion	Type: Standard Deviation; Value: 16.9
	Estimation Comments	Mean difference in degree of epithelialization [%] (Oleogel-S10 and non-adhesive wound dressing minus non-adhesive wound dressing only)

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	=0.0028
	Comments	Day 14
	Method	t-test, 2 sided
	Comments
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	5.6
	Confidence Interval	(2-Sided) 95%; 2.0 to 9.3
	Parameter Dispersion	Type: Standard Deviation; Value: 19.3
	Estimation Comments	Mean difference in degree of epithelialization [%] (Oleogel-S10 and non-adhesive wound dressing minus non-adhesive wound dressing only)

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	=0.0009
	Comments	Day 18
	Method	t-test, 2 sided
	Comments
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	5.9
	Confidence Interval	(2-Sided) 95%; 2.5 to 9.3
	Parameter Dispersion	Type: Standard Deviation; Value: 18.0
	Estimation Comments	Mean difference in degree of epithelialization [%] (Oleogel-S10 and non-adhesive wound dressing minus non-adhesive wound dressing only)

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	=0.0003
	Comments	Day 21
	Method	t-test, 2 sided
	Comments
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	5.6
	Confidence Interval	(2-Sided) 95%; 2.6 to 8.6
	Parameter Dispersion	Type: Standard Deviation; Value: 15.8
	Estimation Comments	Mean difference in degree of epithelialization [%] (Oleogel-S10 and non-adhesive wound dressing minus non-adhesive wound dressing only)

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	=0.0145
	Comments	Day 28
	Method	t-test, 2 sided
	Comments
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	3.6
	Confidence Interval	(2-Sided) 95%; 0.7 to 6.4
	Parameter Dispersion	Type: Standard Deviation; Value: 15.1
	Estimation Comments	Mean difference in degree of epithelialization [%] (Oleogel-S10 and non-adhesive wound dressing minus non-adhesive wound dressing only)

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	2 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	107	103	101	101	105	110	100	99	98	102
Oleogel-S10 much more effective	4.7	13.6	16.8	17.8	17.1	7.7	15.0	16.2	15.3	14.7
Oleogel-S10 more effective	44.9	35.0	36.6	33.7	35.2	31.7	36.0	35.4	35.7	36.3
Both treatments same efficacy	40.2	40.8	36.6	37.6	37.1	53.8	38.0	39.4	38.8	39.2
Standard of care (SOC) more effective	9.3	10.7	9.9	9.9	9.5	6.7	11.0	8.1	8.2	7.8
SOC much more effective	0.9	0.0	0.0	1.0	1.0	0.0	0.0	1.0	2.0	2.0

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 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/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	95	95	95	95	65	65	65	65
Wound half treated with Oleogel-S10	18.9	1.1	32.6	25.3	13.8	0.0	27.7	15.4
Wound half treated with wound dressing only	8.4	0.0	13.7	14.7	3.1	0.0	9.2	4.6
Both equal	71.6	98.9	50.5	56.8	83.1	100.0	60.0	80.0

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, non-adhesive wound dressing only is better tolerated, non-adhesive wound dressing only is much better tolerated).
Time Frame	2 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	112	112	112	112	112	112	112	112	112	112
Oleogeogel-S10 much better tolerated	5.4 4.8%	8.9 NaN	11.6 NaN	12.5 NaN	13.4 NaN	8.0 NaN	13.4 NaN	16.1 NaN	15.2 NaN	16.1 NaN
Oleogel-S10 better tolerated	30.4 27.1%	33.9 NaN	28.6 NaN	26.8 NaN	28.9 NaN	23.2 NaN	29.5 NaN	26.8 NaN	25.9 NaN	27.7 NaN
Both treatments equally well tolerated	58.9 52.6%	44.6 NaN	46.4 NaN	48.2 NaN	49.1 NaN	58.0 NaN	37.5 NaN	37.5 NaN	40.2 NaN	41.1 NaN
SOC better tolerated	2.7 2.4%	5.4 NaN	3.6 NaN	3.6 NaN	3.6 NaN	3.6 NaN	8.9 NaN	7.1 NaN	5.4 NaN	5.4 NaN
SOC much better tolerated	0.0 0%	0.0 NaN	0.9 NaN	0.0 NaN	0.0 NaN	0.0 NaN	0.0 NaN	0.9 NaN	0.9 NaN	0.9 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	112	112
Measure Plasma Samples	112	290
Samples below LLOQ (<1 ng/mL)	110	271
Samples above LLOQ	2	13
Samples without 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 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/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	112	112
Measure Samples above LLOQ	2	13
Mean (Full Range) [Betulin (ng/mL)]	24.0	10.4

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	112
Adverse events (AEs)	53.6 47.9%
Serious adverse events	4.5 4%
AEs leading to discontinuation	3.6 3.2%
Related AEs	14.3 12.8%
Application site reactions	24.1 21.5%
Non treatment-emergent AEs	7.1 6.3%

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	112
Mild (CTCAE Grade 1)	40.2 35.9%
Moderate (CTCAE Grade 2)	27.7 24.7%
Severe (CTCAE Grade 3)	7.1 6.3%
Life-Threatening (CTCAE Grade 4)	2.7 2.4%
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	112
'Unlikely' related	2.7 2.4%
'Possibly' related	5.4 4.8%
'Probably' related	8.0 7.1%
Unknown relationship	1.8 1.6%
No relationship	47.3 42.2%

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 Adverse Event (AE)		Non-adhesive Wound Dressing Localized AE		Localized AE Both Wound Halves		Entire Study Population -Systemic and Localized AEs
Arm/Group Description	All participants treated with Oleogel-S10 and 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 and 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 and 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 with non-adhesive wound dressing only are reported in this arm.		All participants treated with Oleogel-S10 and non-adhesive wound dressing and 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 participant are reported in this arm.		All participants treated with Oleogel-S10 and non-adhesive wound dressing and/or non-adhesive wound dressing only. Local and systemic AEs are reported in this arm.
All Cause Mortality
	Entire Study Population - Systemic Adverse Events (AE)		Oleogel-S10 Localized Adverse Event (AE)		Non-adhesive Wound Dressing Localized AE		Localized AE Both Wound Halves		Entire Study Population -Systemic and Localized AEs
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	/ (NaN)		/ (NaN)		/ (NaN)		/ (NaN)		/ (NaN)
Serious Adverse Events
	Entire Study Population - Systemic Adverse Events (AE)		Oleogel-S10 Localized Adverse Event (AE)		Non-adhesive Wound Dressing Localized AE		Localized AE Both Wound Halves		Entire Study Population -Systemic and Localized AEs
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	4/112 (3.6%)		0/112 (0%)		0/112 (0%)		1/112 (0.9%)		5/112 (4.5%)
Infections and infestations
Wound infection	0/112 (0%)	0	0/112 (0%)	0	0/112 (0%)	0	1/112 (0.9%)	1	1/112 (0.9%)	1
Sepsis	1/112 (0.9%)	1	0/112 (0%)	0	0/112 (0%)	0	0/112 (0%)	0	1/112 (0.9%)	1
Bacteremia	1/112 (0.9%)	1	0/112 (0%)	0	0/112 (0%)	0	0/112 (0%)	0	1/112 (0.9%)	1
Injury, poisoning and procedural complications
Postoperative wound complication	1/112 (0.9%)	1	0/112 (0%)	0	0/112 (0%)	0	0/112 (0%)	0	1/112 (0.9%)	1
Psychiatric disorders
Mania	1/112 (0.9%)	1	0/112 (0%)	0	0/112 (0%)	0	0/112 (0%)	0	1/112 (0.9%)	1
Respiratory, thoracic and mediastinal disorders
Bronchospasm	1/112 (0.9%)	1	0/112 (0%)	0	0/112 (0%)	0	0/112 (0%)	0	1/112 (0.9%)	1
Other (Not Including Serious) Adverse Events
	Entire Study Population - Systemic Adverse Events (AE)		Oleogel-S10 Localized Adverse Event (AE)		Non-adhesive Wound Dressing Localized AE		Localized AE Both Wound Halves		Entire Study Population -Systemic and Localized AEs
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	30/112 (26.8%)		2/112 (1.8%)		4/112 (3.6%)		9/112 (8%)		40/112 (35.7%)
Blood and lymphatic system disorders
Anemia	6/112 (5.4%)	6	0/112 (0%)	0	0/112 (0%)	0	0/112 (0%)	0	6/112 (5.4%)	6
Gastrointestinal disorders
Constipation	8/112 (7.1%)	8	0/112 (0%)	0	0/112 (0%)	0	0/112 (0%)	0	8/112 (7.1%)	8
General disorders
Pain	6/112 (5.4%)	6	0/112 (0%)	0	0/112 (0%)	0	0/112 (0%)	0	6/112 (5.4%)	6
Pyrexia	12/112 (10.7%)	13	0/112 (0%)	0	0/112 (0%)	0	0/112 (0%)	0	12/112 (10.7%)	13
Infections and infestations
Skin infection	2/112 (1.8%)	2	1/112 (0.9%)	1	2/112 (1.8%)	2	4/112 (3.6%)	4	9/112 (8%)	9
Skin and subcutaneous tissue disorders
Pain of skin	4/112 (3.6%)	4	0/112 (0%)	0	2/112 (1.8%)	2	4/112 (3.6%)	4	10/112 (8.9%)	10
Pruritus	5/112 (4.5%)	5	1/112 (0.9%)	1	0/112 (0%)	0	3/112 (2.7%)	3	9/112 (8%)	9

Limitations/Caveats

[Not Specified]

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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.