Phase III Efficacy and Safety Study of Oleogel-S10 in Epidermolysis Bullosa (EASE)

Double-blind, Randomised, Vehicle-controlled, Phase III, Efficacy and Safety Study With 24-month Open-label Follow-up of Oleogel-S10 in Patients With Inherited Epidermolysis Bullosa

This was a Phase III, Efficacy and Safety Study of Oleogel-S10 in Participants with Inherited Epidermolysis Bullosa (EB).

EB is a rare group of genetic skin fragility disorders characterised by blistering of the skin in response to minor injury. In most cases, onset of EB is at birth or shortly after. All participants affected by any type of EB share the main characteristic of repeatedly developing painful wounds that take days to months to heal. Current treatment of EB is primarily preventative and supportive including protection from mechanical forces by avoiding rubbing, early treatment of wounds to prevent infections, and protection of the wound with adequate non-adhesive dressings to enable healing.

The active pharmaceutical ingredient in Oleogel-S10 is a refined birch bark extract, quantified to 72 to 88% betulin.

This clinical study of Oleogel-S10 in patients with inherited EB has been carried out to investigate whether Oleogel-S10 is effective for treatment of EB wounds and safe for long-term use.

Oleogel-S10 was compared to a control gel. The control gel matched Oleogel-S10 in terms of texture and visual appearance to allow for double-blinding. The packaging for Oleogel-S10 gel and the control gel were identical. The participant received either Oleogel-S10 or control gel for a double-blind study phase of 90 days. The probability that the participant received Oleogel-S10 was 50%, which means that they had a 1 in 2 chance of receiving Oleogel-S10. However, in the follow-up phase of the study all participants were treated with Oleogel-S10 for a period of 24 months.

This clinical study was performed at 49 study sites in 26 countries (Argentina, Australia, Austria, Brazil, Chile, Colombia, Czech Republic, Denmark, France, Georgia, Germany, Greece, Hong Kong [China], Hungary, Ireland, Israel, Italy, Romania, Russia, Serbia, Singapore, Spain, Switzerland, Ukraine, United Kingdom, and the United States); 223 participants participated in total.

Study Overview

• Status: Completed
• Conditions: Epidermolysis Bullosa
• Intervention / Treatment: Drug: Oleogel-S10; Drug: Control gel

• Study Type: Interventional
• Enrollment (Actual): 223
• Phase: Phase 3

Contacts and Locations

Study Locations

• Argentina
  • Buenos Aires, Argentina, 1425
    • Consutorios Medicos (Instituto de Neumonologia y Dermatologia)
  • Buenos Aires, Argentina, 1426
    • Centro Médico Dra. De Salvo
  • Buenos Aires, Argentina, C1056ABJ
    • Centro de investigaciones Metabolicas, CINME
• Australia
  • New South Wales
    • Sydney, New South Wales, Australia, 2031
      • Sydney Children's Hospital
    • Sydney, New South Wales, Australia, 2217
      • Premier Specialists
  • Victoria
    • Parkville, Victoria, Australia, 3050
      • The Royal Melbourne Hospital
    • Parkville, Victoria, Australia, 3502
      • Murdoch Childrens Research Institute Royal Children's Hospital
• Austria
  • Salzburg, Austria, 5020
    • Universitaetsklinik fuer Dermatologie
• Brazil
  • São Paulo, Brazil, 05403.000
    • Instituto Da Crianca HCFMUSP
  • Pernanbuco
    • Recife, Pernanbuco, Brazil, 50070550
      • IMIP
  • Santa Catarina
    • Blumenau, Santa Catarina, Brazil, 89020400
      • Universidade Regional de Blumenau
• Chile
  • Santiago, Chile, 7760099
    • Fundacion Debra Chile
• Colombia
  • DC
    • Bogotá, DC, Colombia
      • Hospital De San Jose
• Czechia
  • Brno, Czechia, 61500
    • University Hospital Brno, Children´s Hospital
• Denmark
  • Aarhus, Denmark, 8000
    • Aarhus University Hospital
• France
  • Paris, France, 75015
    • Hôpital Necker-Enfants Malades
  • Toulouse, France, 31059
    • CHU Toulouse - Hospital Larrey
• Georgia
  • Tbilisi, Georgia, 159
    • S/R National Center of Dermatology and Venerology
• Germany
  • Freiburg im Breisgau, Germany, 79104
    • Medical Center University Freiburg
  • Hannover, Germany, 30173
    • Kinder- und Jugendkrankenhaus Auf der Bult
• Greece
  • Attiki
    • Athens, Attiki, Greece, 16121
      • Hospital of Skin and Veneral Diseases "A. Syggros"
• Hong Kong
  • Hong Kong, Hong Kong
    • Prince of Wales Hospital, The Chinese University of Hong Kong
• Hungary
  • Budapest, Hungary, 1085
    • Semmelweis University, Faculty of Medicine
• Ireland
  • Dublin, Ireland
    • Our Ladys Childrens Hospital
• Israel
  • Tel Aviv, Israel, 64239
    • Tel Aviv Sourasky Medical Center
• Italy
  • Milan, Italy, 20122
    • Fondazione IRCCS Ca' Granda Ospedale Maggiore Policlinico
  • Roma, Italy, 00165
    • Bambino Gesu Children Hospital
  • Roma, Italy, 00167
    • Istituto Dermopatico dell'Immacolata IDI-IRCCS
• Romania
  • Bucharest, Romania, 011025
    • Centrul Medical Sanador
• Russian Federation
  • Moscow, Russian Federation, 107076
    • State Scientific Center for Dermatovenerology and Cosmetology
  • Moscow, Russian Federation, 119991
    • Scientific Center of Children's Health
• Serbia
  • Belgrade, Serbia, 11000
    • University of Belgrade, School of Medicine
• Singapore
  • Singapore, Singapore, 229899
    • Kandang Kerbau (KK) Women's and Children's Hospital
• Spain
  • Barcelona, Spain, 08950
    • Hospital Sant Joan de Déu
  • Barcelona, Spain, 8035
    • Hospital Universitari de la Vall d'Hebron
  • Madrid, Spain, 28046
    • Hospital Universitario La Paz
  • Sevilla, Spain, 41014
    • Hospital Viamed Santa Angela De la Cruz
• Switzerland
  • Bern, Switzerland, 3010
    • Bern University Hospital
• Ukraine
  • Kyiv, Ukraine, 01135
    • National Children Specialized Hospital "Ohmatdyt" of Ministry of Health of Ukraine
• United Kingdom
  • Birmingham, United Kingdom
    • Birmingham Children's Hospital NHS Trust
  • London, United Kingdom, WC1N3JH
    • Great Ormond Street Hospital
• United States
  • Arizona
    • Phoenix, Arizona, United States, 85016
      • Phoenix Children's Hospital
  • Colorado
    • Aurora, Colorado, United States, 80045
      • Children's Hospital Colorado
  • Florida
    • Miami, Florida, United States, 33144
      • Amjad Plastic Research
  • Minnesota
    • Minneapolis, Minnesota, United States, 55455
      • University of Minnesota
  • New York
    • Stony Brook, New York, United States, 11790
      • Stony Brook University Hospital
  • Ohio
    • Cincinnati, Ohio, United States, 45229
      • Cincinnati Children's Hospital Medical Center
  • Pennsylvania
    • Philadelphia, Pennsylvania, United States, 19104
      • The Children's Hospital of Philadelphia
    • Philadelphia, Pennsylvania, United States, 19107
      • Thomas Jefferson University Hospital
  • South Carolina
    • Charleston, South Carolina, United States, 29425
      • Medical University of South Carolina
  • Texas
    • San Antonio, Texas, United States, 78218
      • Texas Dermatology and Laser Specialists

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 3 weeks and older (Child, Adult, Older Adult)
• Accepts Healthy Volunteers: No

Description

Inclusion Criteria:

• Male and female patients with the following subtypes of inherited EB: junctional EB (JEB), dystrophic EB (DEB), and Kindler EB aged ≥21 days
• Patients with an EB target wound (i.e., EB partial thickness wound of 10 cm² to 50 cm² in size aged ≥21 days and <9 months)
• Patient and/or his/her legal representative has/have been informed, has/have read and understood the patient information/informed consent form, and has/have given written informed consent
• Patient and/or his/her legal representative must be able and willing to follow study procedures and instructions

Exclusion Criteria:

• Patient has EB simplex
• EB target wound that is ≥9 months old or has clinical signs of local infection
• Use of systemic antibiotics for wound-related infections within 7 days prior to enrolment
• Administration of systemic or topical steroids (except for inhaled, ophthalmic or topical applications, such as budesonide suspension for oesophageal strictures [e.g., Pulmicort respules® 0.25 mg/2 mL or 0.5 mg/2 mL]) within 30 days before enrolment
• Immunosuppressive therapy or cytotoxic chemotherapy within 60 days prior to enrolment
• Patient has undergone stem cell transplant or gene therapy for the treatment of inherited EB
• Current and/or former malignancy including basal cell carcinomas and squamous cell carcinomas
• Enrolment in any interventional study or treated with any investigational drug for any disease within 4 weeks prior to study entry
• Factors present in the patient and/or his/her legal representative that could interfere with study compliance such as inability to attend scheduled study visits or compliance with home dressing changes
• Pregnant or nursing women and women of childbearing potential including postmenarchal female adolescents not willing to use an effective form of birth control with failure rates <1% per year (e.g., implant, injectable, combined oral contraceptive, intrauterine contraceptive device, sexual abstinence, vasectomised partner) during participation in the study (and at least 3 months thereafter)
• Patient is a member of the investigational team or his/her immediate family
• Patient lives in the same household as a study participant

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Triple

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Oleogel-S10	Drug: Oleogel-S10; 10% birch bark extract in 90% sunflower oil; Other Names: Episalvan; Filsuvez
Placebo Comparator: Control Gel	Drug: Control gel; Sunflower oil, Cera flava/yellow wax, and Carnauba wax (matched Oleogel-S10 in terms of texture and visual appearance); Other Names: Vehicle gel

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Proportion of Patients With First Complete Closure of the EB Target Wound Within 45 Days of Treatment	Proportion of subjects with first complete closure of the EB target wound (defined as EB partial-thickness wound of 10 cm2 to 50 cm2 in size and ≥21 days to <9 months in age) in subjects with inherited EB (subtypes DEB, JEB, or Kindler EB) within 45 days of treatment with Oleogel-S10 compared to control gel based on clinical assessment by the investigator (the wound was rated as "closed" at first appearance of complete re-epithelialization without drainage).	45±7 days

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Time to First Complete Closure of the EB Target Wound as Evidenced by Clinical Assessment Until Day 90 (D90) or End of Double-blind Phase (EDBP)	The first key secondary endpoint was time to first complete closure of the EB target wound as evidenced by clinical assessment within 90 days or by EDBP, using a nonstratified log-rank test. If the primary analysis of the primary efficacy endpoint showed superiority at the 5% significance level, hierarchical confirmatory testing of the 6 key secondary endpoints was to be performed.	90±7 days
Proportion of Patients With First Complete Closure of the EB Target Wound at D90 or EDBP Based on Clinical Assessment by the Investigator Until D90 or EDBP	The second key secondary endpoint was the proportion of subjects with first complete closure of the EB target wound within 90 days of treatment or by EDBP based on clinical assessment by the investigator.	90±7 days
The Incidence of EB Target Wound Infection Between Baseline (DBP D0) and D90 or EDBP as Evidenced by Adverse Events (AEs) and/or Use of Topical and/or Systemic Antibiotics (Related to Wound Infection)	The incidence of EB target wound infections between Baseline (DBP D0) and D90 or EDBP was assessed based on the total number of patients with an EB target wound infection, as evidenced by AEs and/or the use of topical and/or systemic antibiotics, and the total number of patients	90±7 days
The Maximum Severity of EB Target Wound Infection Between Baseline (DBP D0) and D90 or EDBP as Evidenced by AEs	Target wound infections between baseline (DBP D0) and D90 or EDBP were assessed for maximum severity (maximum severity was evaluated if a subject had a wound infection event evidenced by AEs). [Note: Here, 1 event less is recorded in the control gel group as for the previous secondary outcome measure, because only wound infections that were reported as AEs could be assessed for severity and were included in this analysis.]	90±7 days
Change From Baseline (DBP D0) in Total Body Wound Burden as Evidenced by Clinical Assessment Using Section I (Assessment of the Skin Except for the Anogenital Region) of the 'EB Disease Activity and Scarring Index' (EBDASI), at D90 or EDBP	The evaluation of total body wound burden (TBWB) was based on clinical assessment using Section I (Skin) of the Epidermolysis Bullosa Disease Activity and Scarring Index (EBDASI). The EBDASI skin activity (blistering/erosions/crusting) was scored from 0 to 10 for each of 10 anatomical locations (excluding the anogenital and buttocks regions). Therefore, the total skin activity score (i.e., TBWB) could range from 0 to 100, with lower scores indicative of less wound burden. The change in TBWB was assessed from baseline (DBP D0) to D90 or EDBP.	90±7 days
Change From Baseline (DBP D0) in Itching Using the 'Itch Man Scale' in Patients ≥ 4 Years and up to 13 Years of Age Before Wound Dressing Changes at D90 or EDBP	Change from Baseline at D90 or EDBP on the Itch Man Scale in patients 4-13 years of age. The scale runs from 0 (comfortable, no itch) to 4 (itches most terribly, impossible to sit still, concentrate).	90±7 days
Change From Baseline (DBP D0) in Itching Using the 'Leuven Itch Scale' in Patients ≥ 14 Years of Age Before Wound Dressing Changes at D90 or End of Double Blind Phase (EDBP)	Change in Leuven Itch Scale (patients ≥ 14 years of age) scores taken from two time points, Baseline and Day 90±7 [End of Double Blind Phase (EDBP)]. The Leuven Itch Scale measures six dimensions of the itch experience: Frequency Subscore (0 = Never to 100 = Always); Duration Subscore (0 = Between 0 and 30 minutes to 100 = More than 2 hours); Severity Subscore (0 = No itch to 100 = Worst possible itch); Consequences Subscore [0 = Never to 100 = Always (lower score indicates less negative consequences from the itch)]; Distress Subscore (0 = Not distressing at all to 100 = Very distressing); Surface Area Subscore (0-100, high values indicate more parts of the body are itching)	90±7 days

Collaborators and Investigators

• Sponsor: Amryt Research Limited
• Investigators: Principal Investigator: Johannes S Kern, MD PhD, Melbourne Health

Study record dates

Study Major Dates

• Study Start (Actual): March 29, 2017
• Primary Completion (Actual): June 11, 2020
• Study Completion (Actual): May 27, 2022

Study Registration Dates

• First Submitted: February 27, 2017
• First Submitted That Met QC Criteria: February 27, 2017
• First Posted (Actual): March 3, 2017

Study Record Updates

• Last Update Posted (Actual): July 20, 2023
• Last Update Submitted That Met QC Criteria: July 3, 2023
• Last Verified: July 1, 2023

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Skin Diseases; Congenital Abnormalities; Genetic Diseases, Inborn; Skin Diseases, Genetic; Skin Diseases, Vesiculobullous; Skin Abnormalities; Epidermolysis Bullosa
• Other Study ID Numbers: BEB-13; 2016-002066-32 (EudraCT Number)

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: NO

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: Yes
• Studies a U.S. FDA-regulated device product: No