Clinical Trials Register

Summary
EudraCT Number:	2016-002066-32
Sponsor's Protocol Code Number:	BEB-13
National Competent Authority:	Italy - Italian Medicines Agency
Clinical Trial Type:	EEA CTA
Trial Status:	Completed
Date on which this record was first entered in the EudraCT database:	2018-01-30
Trial results	View results

Index
A. PROTOCOL INFORMATION
B. SPONSOR INFORMATION
C. APPLICANT IDENTIFICATION
D. IMP IDENTIFICATION
D.8 INFORMATION ON PLACEBO
E. GENERAL INFORMATION ON THE TRIAL
F. POPULATION OF TRIAL SUBJECTS
G. INVESTIGATOR NETWORKS TO BE INVOLVED IN THE TRIAL
N. REVIEW BY THE COMPETENT AUTHORITY OR ETHICS COMMITTEE IN THE COUNTRY CONCERNED
P. END OF TRIAL

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A. Protocol Information

A.1

Member State Concerned

Italy - Italian Medicines Agency

A.2

EudraCT number

2016-002066-32

A.3

Full title of the trial

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

A.3.1

Title of the trial for lay people, in easily understood, i.e. non-technical, language

A Clinical Trial which compare the safety and efficacy of a wound gel, the study treatment, or a sunflower oil-based vehicle gel in patients with Inherited Epidermolysis Bullosa (EB)

A.3.2

Name or abbreviated title of the trial where available

EASE study

A.4.1

Sponsor's protocol code number

BEB-13

A.7

Trial is part of a Paediatric Investigation Plan

A.8

EMA Decision number of Paediatric Investigation Plan

B. Sponsor Information
B.Sponsor: 1
B.1.1	Name of Sponsor	Amryt Research Limited
B.1.3.4	Country	Ireland
B.3.1 and B.3.2	Status of the sponsor	Commercial
B.4 Source(s) of Monetary or Material Support for the clinical trial:
B.4.1	Name of organisation providing support	Amryt Research Limited
B.4.2	Country	Ireland
B.5 Contact point designated by the sponsor for further information on the trial
B.5.1	Name of organisation	Amryt Research Limited
B.5.2	Functional name of contact point	Tobias Zahn
B.5.3	Address:
B.5.3.1	Street Address	Fitzwilliam Hall, Fitzwilliam Place
B.5.3.2	Town/ city	Dublin 2
B.5.3.4	Country	Ireland
B.5.4	Telephone number	4972339749 208
B.5.6	E-mail	tobias.zahn@amrytpharma.com

D. IMP Identification
D.IMP: 1
D.1.2 and D.1.3	IMP Role	Test
D.2	Status of the IMP to be used in the clinical trial
D.2.1	IMP to be used in the trial has a marketing authorisation	Yes
D.2.1.1.1	Trade name	Episalvan gel
D.2.1.1.2	Name of the Marketing Authorisation holder	Birken AG
D.2.1.2	Country which granted the Marketing Authorisation	European Union
D.2.5	The IMP has been designated in this indication as an orphan drug in the Community	No
D.2.5.1	Orphan drug designation number
D.3 Description of the IMP
D.3.1	Product name	Oleogel-S10
D.3.4	Pharmaceutical form	Gel
D.3.4.1	Specific paediatric formulation	No
D.3.7	Routes of administration for this IMP	Cutaneous use
D.3.8 to D.3.10 IMP Identification Details (Active Substances)
D.3.8	INN - Proposed INN	Birch bark extract
D.3.9.1	CAS number	1640971-03-4
D.3.9.2	Current sponsor code	Dry extract from betulae cortex
D.3.9.3	Other descriptive name	BIRCH BARK EXTRACT
D.3.9.4	EV Substance Code	SUB180085
D.3.10	Strength
D.3.10.1	Concentration unit	% (W/W) percent weight/weight
D.3.10.2	Concentration type	equal
D.3.10.3	Concentration number	10
D.3.11 The IMP contains an:
D.3.11.1	Active substance of chemical origin	Yes
D.3.11.2	Active substance of biological/ biotechnological origin (other than Advanced Therapy IMP (ATIMP)	No
	The IMP is a:
D.3.11.3	Advanced Therapy IMP (ATIMP)	No
D.3.11.3.1	Somatic cell therapy medicinal product	No
D.3.11.3.2	Gene therapy medical product	No
D.3.11.3.3	Tissue Engineered Product	No
D.3.11.3.4	Combination ATIMP (i.e. one involving a medical device)	No
D.3.11.3.5	Committee on Advanced therapies (CAT) has issued a classification for this product	No
D.3.11.4	Combination product that includes a device, but does not involve an Advanced Therapy	No
D.3.11.5	Radiopharmaceutical medicinal product	No
D.3.11.6	Immunological medicinal product (such as vaccine, allergen, immune serum)	No
D.3.11.7	Plasma derived medicinal product	No
D.3.11.8	Extractive medicinal product	No
D.3.11.9	Recombinant medicinal product	No
D.3.11.10	Medicinal product containing genetically modified organisms	No
D.3.11.11	Herbal medicinal product	Yes
D.3.11.12	Homeopathic medicinal product	No
D.3.11.13	Another type of medicinal product	No

D.8 Information on Placebo
D.8 Placebo: 1
D.8.1	Is a Placebo used in this Trial?	Yes
D.8.3	Pharmaceutical form of the placebo	Gel
D.8.4	Route of administration of the placebo	Cutaneous use

E. General Information on the Trial

E.1 Medical condition or disease under investigation

E.1.1

Medical condition(s) being investigated

Inherited Epidermolysis Bullosa

E.1.1.1

Medical condition in easily understood language

Illness called Epidermolysis bullosa (EB) that makes skin blister and have open sores and wounds

E.1.1.2

Therapeutic area

Diseases [C] - Skin and Connective Tissue Diseases [C17]

MedDRA Classification

E.1.2 Medical condition or disease under investigation

E.1.2	Version	20.0
E.1.2	Level	PT
E.1.2	Classification code	10014989
E.1.2	Term	Epidermolysis bullosa
E.1.2	System Organ Class	10010331 - Congenital, familial and genetic disorders

E.1.3

Condition being studied is a rare disease

Yes

E.2 Objective of the trial

E.2.1

Main objective of the trial

The primary objective of the double-blind phase is to compare the efficacy of Oleogel-S10 (treatment arm A) with vehicle (treatment arm B) in the promotion of healing of EB partial thickness wounds. This will be assessed as evidenced by the incidence of the first complete closure of the EB target wound (defined as EB partial thickness wound of 10 cm2 to 50 cm2 in size aged ≥21 days in any subtype of inherited EB) within 45±7 days of treatment).

E.2.2

Secondary objectives of the trial

1/ Compare the efficacy of IMP with placebo as evidenced by several criteria described in the protocol
2/ Compare the safety of IMP with placebo as evidenced by the incidence, severity, and relatedness of AEs and based on laboratory assessments
3/ Compare the tolerability of IMP with placebo
4/ Assess betulin exposure

E.2.3

Trial contains a sub-study

E.3

Principal inclusion criteria

A patient will be eligible for study participation only if all of the following criteria apply:
1. Male and female patients with any subtype of inherited EB including EBS, JEB, DEB, and Kindler syndrome age ≥4 years [Note: Children <4 years of age may be included only after confirmation by the Independent Data Monitoring Committee (IDMC) upon review of the safety and bioanalytical data at the interim safety review stage].
2. Patients with an EB target wound (i.e., EB partial thickness wound of 10 cm2 to 50 cm2 in size aged ≥21 days)
3. 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
4. Patient and/or his/her legal representative must be able and willing to follow study procedures and instructions

E.4

Principal exclusion criteria

A patient will not be eligible to participate in this study if any of the following criteria apply:
1. EB target wound with clinical signs of local infection
2. Use of systemic antibiotics for wound-related infections within 7 days prior to enrolment
3. 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
4. Immunosuppressive therapy or cytotoxic chemotherapy within 60 days prior to enrolment
5. Patient has undergone stem cell transplant or gene therapy for the treatment of inherited EB
6. Current and/or former malignancy including basal cell carcinomas and squamous cell carcinomas
7. Enrolment in any interventional study or treated with any investigational drug for any disease within 4 weeks prior to study entry
8. 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
9. 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)
10.Patient is a member of the investigational team or his/her immediate family
11.Patient lives in the same household as a study participant.

E.5 End points

E.5.1

Primary end point(s)

Proportion of patients with first complete closure of the EB target wound (defined as EB partial thickness wound of 10 cm2 to 50 cm2 in size aged ≥21 days in any subtype of inherited EB) within 45±7 days of treatment with Oleogel-S10 compared to vehicle based on clinical assessment by the investigator (the wound will be rated as “closed” at first appearance of complete reepithelialisation without drainage confirmed by a second observation within the following week)

E.5.1.1

Timepoint(s) of evaluation of this end point

See section E.5.1

E.5.2

Secondary end point(s)

Secondary efficacy endpoints
• Time to first complete closure of the EB target wound as evidenced by clinical assessment until D90±7.
• Proportion of patients with first complete closure of the EB target wound within D14±5, D30±7, D60±7, and D90±7 based on clinical assessment by the investigator
• Proportion of patients with first complete closure of the EB target wound within at D7±5, D14±5, D30±7, D45±7, D60±7, and D90±7 based on patient assessment
• Proportion of patients with first complete closure of the EB target wound at D7±5, D14±5, D30±7, D45±7, D60±7, and D90±7 based on blinded evaluation of photographs
• Percentage change from baseline (D0) in EB target wound size as evidenced by blinded evaluation of photographs taken at D7±5, D14±5, D30±7, D45±7, D60±7, and D90±7
• Change from baseline (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 D30±7, D60±7, and D90±7
• Change from baseline (D0) in body surface area percentage (BSAP) of TBSA affected by EB partial thickness wounds as evidenced by clinical assessment based on the ‘Lund and Browder’ chart at D30±7, D60±7, and D90±7
• The incidence and maximum severity of wound infection between baseline (D0) and D90±7 as evidenced by AEs and/or use of topical and/or systemic antibiotics (related to wound infection)
• Change from baseline (D0) in ‘background’ pain using the ‘Face, Legs, Activity, Cry, Consolability’ (FLACC) scale in patients <4 years of age and the ‘Wong-Baker FACES® Pain Rating Scale’ in patients ≥4 years of age before wound dressing changes at D7±5, D14±5, D30±7, D45±7, D60±7, and D90±7
• Change from baseline (D0) in ‘procedural’ pain using the FLACC scale in patients <4 years of age and the ‘Wong-Baker FACES® Pain Rating Scale’ in patients ≥4 years of age after wound dressing changes at D7±5, D14±5, D30±7, D45±7, D60±7, and D90±7 Change from baseline (D0) in itching using the ‘Itch Man Scale’ in patients ≥4 years and up to 13 years of age and the ‘Leuven Itch Scale’ in patients ≥14 years of age before wound dressing changes at D7±5, D30±7, D60±7, and D90±7
• Change from baseline in impact of wounds on sleep (in patients ≥14 years of age) as measured by differences in 11-point Likert scales at D7±5, D30±7, D60±7, and D90±7
• The number of days missed from school or from work due to EB as reported by patients at D0, D14±5, D30±7, D45±7, D60±7, and D90±7
• Evaluation of the treatment response (in patients ≥14 years of age) using the Treatment Satisfaction Questionnaire for Medication (TSQM), Version 9 at D7±5, D30±7, D60±7, and D90±7
Safety endpoints
• Incidence, severity, and relatedness of AEs
• Local tolerability as judged by the investigator
• Safety laboratory data
• Systemic exposure to betulin, if consent provided

E.5.2.1

Timepoint(s) of evaluation of this end point

See section E.5.2

E.6 and E.7 Scope of the trial

E.6

Scope of the trial

E.6.1

Diagnosis

E.6.2

Prophylaxis

E.6.3

Therapy

Yes

E.6.4

Safety

Yes

E.6.5

Efficacy

Yes

E.6.6

Pharmacokinetic

Yes

E.6.7

Pharmacodynamic

E.6.8

Bioequivalence

E.6.9

Dose response

E.6.10

Pharmacogenetic

E.6.11

Pharmacogenomic

E.6.12

Pharmacoeconomic

E.6.13

Others

E.7

Trial type and phase

E.7.1

Human pharmacology (Phase I)

E.7.1.1

First administration to humans

E.7.1.2

Bioequivalence study

E.7.1.3

Other

E.7.1.3.1

Other trial type description

E.7.2

Therapeutic exploratory (Phase II)

E.7.3

Therapeutic confirmatory (Phase III)

Yes

E.7.4

Therapeutic use (Phase IV)

E.8 Design of the trial

E.8.1

Controlled

Yes

E.8.1.1

Randomised

Yes

E.8.1.2

Open

E.8.1.3

Single blind

E.8.1.4

Double blind

Yes

E.8.1.5

Parallel group

Yes

E.8.1.6

Cross over

E.8.1.7

Other

E.8.2

Comparator of controlled trial

E.8.2.1

Other medicinal product(s)

E.8.2.2

Placebo

Yes

E.8.2.3

Other

E.8.2.4

Number of treatment arms in the trial

E.8.3

The trial involves single site in the Member State concerned

E.8.4

The trial involves multiple sites in the Member State concerned

Yes

E.8.4.1

Number of sites anticipated in Member State concerned

E.8.5

The trial involves multiple Member States

Yes

E.8.5.1

Number of sites anticipated in the EEA

E.8.6 Trial involving sites outside the EEA

E.8.6.1

Trial being conducted both within and outside the EEA

Yes

E.8.6.2

Trial being conducted completely outside of the EEA

E.8.6.3

If E.8.6.1 or E.8.6.2 are Yes, specify the regions in which trial sites are planned

Australia

Austria

Croatia

France

Germany

Greece

Ireland

Israel

Italy

Mexico

Spain

Switzerland

Turkey

United Kingdom

United States

E.8.7

Trial has a data monitoring committee

Yes

E.8.8

Definition of the end of the trial and justification where it is not the last visit of the last subject undergoing the trial

LVLS estimated in June 2020

E.8.9 Initial estimate of the duration of the trial

E.8.9.1

In the Member State concerned years

E.8.9.1

In the Member State concerned months

E.8.9.1

In the Member State concerned days

E.8.9.2

In all countries concerned by the trial years

E.8.9.2

In all countries concerned by the trial months

E.8.9.2

In all countries concerned by the trial days

F. Population of Trial Subjects

F.1 Age Range

F.1.1

Trial has subjects under 18

Yes

F.1.1

Number of subjects for this age range:

F.1.1.1

In Utero

F.1.1.2

Preterm newborn infants (up to gestational age < 37 weeks)

F.1.1.3

Newborns (0-27 days)

F.1.1.4

Infants and toddlers (28 days-23 months)

F.1.1.5

Children (2-11years)

Yes

F.1.1.5.1

Number of subjects for this age range:

F.1.1.6

Adolescents (12-17 years)

Yes

F.1.1.6.1

Number of subjects for this age range:

F.1.2

Adults (18-64 years)

Yes

F.1.2.1

Number of subjects for this age range:

F.1.3

Elderly (>=65 years)

F.1.3.1

Number of subjects for this age range:

F.2 Gender

F.2.1

Female

Yes

F.2.2

Male

Yes

F.3 Group of trial subjects

F.3.1

Healthy volunteers

F.3.2

Patients

Yes

F.3.3

Specific vulnerable populations

Yes

F.3.3.1

Women of childbearing potential not using contraception

F.3.3.2

Women of child-bearing potential using contraception

Yes

F.3.3.3

Pregnant women

F.3.3.4

Nursing women

F.3.3.5

Emergency situation

F.3.3.6

Subjects incapable of giving consent personally

F.3.3.7

Others

F.4 Planned number of subjects to be included

F.4.1

In the member state

164

F.4.2

For a multinational trial

F.4.2.1

In the EEA

110

F.4.2.2

In the whole clinical trial

164

F.5

Plans for treatment or care after the subject has ended the participation in the trial (if it is different from the expected normal treatment of that condition)

None

G. Investigator Networks to be involved in the Trial

N. Review by the Competent Authority or Ethics Committee in the country concerned

Competent Authority Decision

Authorised

Date of Competent Authority Decision

2017-10-18

Ethics Committee Opinion of the trial application

Favourable

Ethics Committee Opinion: Reason(s) for unfavourable opinion

Date of Ethics Committee Opinion

2017-04-12

P. End of Trial
P.	End of Trial Status	Completed

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