Clinical Trials Register

Summary
EudraCT Number:	2020-002337-15
Sponsor's Protocol Code Number:	99625945
National Competent Authority:	Norway - NOMA
Clinical Trial Type:	EEA CTA
Trial Status:	Completed
Date on which this record was first entered in the EudraCT database:	2020-06-29
Trial 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

Norway - NOMA

A.2

EudraCT number

2020-002337-15

A.3

Full title of the trial

TOPICAL GENTAMICIN TREATMENT OF PATIENTS WITH EPIDERMOLYSIS BULLOSA DUE TO NONSENSE MUTATIONS (THE GENTELBULL STUDY)

A.3.1

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

TOPICAL GENTAMICIN TREATMENT OF PATIENTS WITH EPIDERMOLYSIS BULLOSA

A.3.2

Name or abbreviated title of the trial where available

GENTELBULL

A.4.1

Sponsor's protocol code number

99625945

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	Oslo University Hospital
B.1.3.4	Country	Norway
B.3.1 and B.3.2	Status of the sponsor	Non-Commercial
B.4 Source(s) of Monetary or Material Support for the clinical trial:
B.4.1	Name of organisation providing support	Oslo University Hospital
B.4.2	Country	Norway
B.5 Contact point designated by the sponsor for further information on the trial
B.5.1	Name of organisation	Section of dermatology, Oslo University Hospital
B.5.2	Functional name of contact point	Øystein Sandanger
B.5.3	Address:
B.5.3.1	Street Address	Sognsvannveien 20
B.5.3.2	Town/ city	Oslo
B.5.3.3	Post code	0372
B.5.3.4	Country	Norway
B.5.6	E-mail	oystein.sandanger@rr-research.no

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	Infectogenta
D.2.1.1.2	Name of the Marketing Authorisation holder	Infectopharm
D.2.1.2	Country which granted the Marketing Authorisation	Germany
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	Gentamicin sulfate 0.1% ointment
D.3.4	Pharmaceutical form
D.3.4.1	Specific paediatric formulation	No
D.3.7	Routes of administration for this IMP	Topical use (Noncurrent)
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	No
D.3.11.12	Homeopathic medicinal product	No
D.3.11.13	Another type of medicinal product	No

D.8 Information on Placebo

E. General Information on the Trial

E.1 Medical condition or disease under investigation

E.1.1

Medical condition(s) being investigated

Epidermolysis bullosa caused by nonsense mutations or splice site mutations

E.1.1.1

Medical condition in easily understood language

Epidermolysis bullosa, a hereditary genetic skin disease with fragile skin an frequent wounding.

E.1.1.2

Therapeutic area

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

MedDRA Classification

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 overall purpose of this study is to address whether topical gentamicin therapy is an effective and feasible treatment. Specifically, we will investigate the effect of non-intensive treatment (once daily or every other day) on skin protein expression, as well as quantify the effect on wound healing in patients with EB caused by PSC (part A). Furthermore, we will address in vitro whether gentamicin restores protein expression of genes affected by SSM in fibroblasts derived from skin biopsies obtained from patients with EB caused by SSM (part B). If these in vitro experiments yield positive results, the patients donating the cells will be offered to enter part A of this study. The main objective is to investigate whether non-intensive topical gentamicin therapy reduces total wound area after 6 weeks treatment.

E.2.2

Secondary objectives of the trial

Whether non-intensive topical gentamicin therapy for 6 weeks reduces wound relapse the following 12 weeks.
Whether non-intensive topical gentamicin therapy improves the affected protein translation at week 6. And if so, whether expression of the affected protein is maintained 12 weeks after the treatment has ended.
Whether the topical gentamicin treatment results in measurable systemic levels of gentamicin
Whether gentamicin (500 ug/mL) rescues the affected protein translation in dermal fibroblasts carrying EB-causing splice site mutations in vitro
Whether gentamicin increases mRNA expression of the affected protein in dermal fibroblasts in vitro

E.2.3

Trial contains a sub-study

E.3

Principal inclusion criteria

Part A 1. The patient has EB caused by nonsense mutation 2. The patient has a symmetrical distribution of wounds which allows for wounds on one side of the body to serve as control wounds, while study therapy is applied to the other side. 3. The patient (if an adult) or parent(s)/guardian(s) is capable of giving signed informed consent as described in Appendix 1 which includes compliance with the requirements and restrictions listed in the informed consent form (ICF) and in this protocol
Part B 1. The patient has EB caused by splice site mutations 2. The patient (if an adult) or parent(s)/guardian(s) is capable of giving signed informed consent as described in Appendix 1 which includes compliance with the requirements and restrictions listed in the informed consent form (ICF) and in this protocol.

E.4

Principal exclusion criteria

Part A 1. Known contact allergy against gentamicin sulfate or other ingredients in the ointment 2. Known intolerance to gentamicin sulfate of any sort 3. Moderate or severely reduced kidney function (eGFR <30) 4. Use other experimental therapy against EB 5. Receiving systemic aminoglycosides during the last 3 months
Part B 1. The patient also carries a nonsense mutation that can be the cause of EB

E.5 End points

E.5.1

Primary end point(s)

Part A • Mean of ratios for wound areas (measured in cm2) at week 6 to that of week 0 of gentamicin-treated wounds, compared to the corresponding mean of ratios for standard care-treated wounds. The observed effect is considered significant if p<0.05 (unpaired t-test). Of note, each patient may or may not reach the primary end point independent of the other participants
Part B • Protein expression in treated cells, untreated cells (negative control) and cells from one healthy control (positive control), quantified with western blot analysis and immune fluorescence analysis.

E.5.1.1

Timepoint(s) of evaluation of this end point

Part A: week 6 Part B: after 5 days of in vitro stimulation with gentamici

E.5.2

Secondary end point(s)

Part A • Mean of ratios for single wound areas (measured in cm2) at week 18 to that of week 6 of gentamicin-treated wounds, compared to the corresponding mean of ratios for standard care-treated wounds. The

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observed effect is considered significant if p<0.05 (unpaired t-test). Of note, each patient may or may not reach the primary end point independent of the other participants
• Immune histochemistry analysis of skin biopsy obtained from healed treated wound area at week 6 and 18 compared to skin biopsy from nontreated non-affected skin obtained at baseline (negative control) and non-affected skin from one healthy control (positive control)
• Trough levels gentamicin in serum day 1 and week 6. If detectable day 1, levels will be monitored more frequently (see section 8.3.3)
Part B • mRNA expression in treated cells, untreated cells (negative control) and cells from one healthy control (positive control) quantified with polymerase chain reaction (qPCR)

E.5.2.1

Timepoint(s) of evaluation of this end point

Part A Week 6 or 18 as indicated
Part B after 5 days of in vitro stimulation with gentamicin

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

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)

Yes

E.7.3

Therapeutic confirmatory (Phase III)

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

Yes

E.8.1.3

Single blind

E.8.1.4

Double blind

E.8.1.5

Parallel group

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

E.8.2.3

Other

Yes

E.8.2.3.1

Comparator description

Each patient serves as their own control: half their body is treated and the other half is control

E.8.2.4

Number of treatment arms in the trial

E.8.3

The trial involves single site in the Member State concerned

Yes

E.8.4

The trial involves multiple sites in the Member State concerned

E.8.5

The trial involves multiple Member States

E.8.6 Trial involving sites outside the EEA

E.8.6.1

Trial being conducted both within and outside the EEA

E.8.6.2

Trial being conducted completely outside of the EEA

E.8.7

Trial has a data monitoring committee

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

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

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.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

Yes

F.3.3.6.1

Details of subjects incapable of giving consent

Young age

F.3.3.7

Others

Yes

F.3.3.7.1

Details of other specific vulnerable populations

They all have epidermolysis bullosa

F.4 Planned number of subjects to be included

F.4.1

In the member state

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)

Individual patients who benefit from the treatment as specified in the protocol will be offered continued treatment.

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

2020-09-16

Ethics Committee Opinion of the trial application

Favourable

Ethics Committee Opinion: Reason(s) for unfavourable opinion

Date of Ethics Committee Opinion

2020-06-16

P. End of Trial
P.	End of Trial Status	Completed
P.	Date of the global end of the trial	2022-05-01

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