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Intravenous Gentamicin Therapy for Recessive Dystrophic Epidermolysis Bullosa (RDEB)

Primary Purpose

Recessive Dystrophic Epidermolysis Bullosa

Status

Recruiting

Phase

Phase 1

Locations

United States

Study Type

Interventional

Intervention

Gentamicin

About this trial

This is an interventional treatment trial for Recessive Dystrophic Epidermolysis Bullosa focused on measuring Nonsense Mutations

Eligibility Criteria

7 Years - undefined (Child, Adult, Older Adult)All SexesDoes not accept healthy volunteers

Inclusion Criteria:

Provision of signed and dated informed consent form
Stated willingness to comply with all study procedures and availability for the duration of the study
Male or female, aged 7 and up can participate in the 14 day IV gentamicin trial. Male or female, aged 18 and up can participate in the 3 month IV gentamicin trial.
Been diagnosed with recessive dystrophic epidermolysis bullosa (RDEB) and with a nonsense mutation in the COL7A1 gene.
Immunofluorescence evaluation of skin biopsies reveals absence or decreased intensity of C7 expression at their DEJ (dermal epidermal junction) compared with normal human skin biopsies.
Cultured fibroblasts from patient skin synthesize and secrete full-length, 290kDa C7 alpha chains in the presence of supplemented gentamicin (400 μg/ml in culture).
Ability to sit or lie down for over 30 minutes for IV infusions. For those in the 3 month trial, to be willing to continue treatment at home under the supervision of licensed and trained infusion nurses.

Exclusion Criteria:

Recent exposure to gentamicin within the past 6 weeks.
Pre-existing known auditory impairment.
Pre-existing known renal impairment.
Pre-existing known allergies to aminoglycosides or sulfate compounds.
Pregnancy or lactation
Current use of medications with known ototoxicity or nephrotoxicity.
Current enrollment in another experimental clinical trial involving systemic treatment with C7 or C7 producing products for the treatment of RDEB.

Sites / Locations

University of Southern CaliforniaRecruiting

Arms of the Study

Arm 1

Arm Type

Experimental

Arm Label

Intravenous Gentamicin

Arm Description

Intravenous gentamicin (7.5 mgs/kg) daily for for either 14 days and then stopped or twice weekly for three months and then stopped.

Outcomes

Primary Outcome Measures

Full-length type VII collagen expression

Increased expression of full-length type VII collagen as assessed by immunofluorescence

Generation of anchoring fibrils

Generation of new anchoring fibrils as assessed by immuno-electron microscopy

Absence of gentamicin side effects

Absence of gentamicin side effects, especially the detection of any ototoxicity or nephrotoxicity

Secondary Outcome Measures

Improved Disease Activity scores

Improved epidermolysis bullosa Disease Activity scores

Improved Quality of Life score

Full Information

NCT ID

NCT03392909

First Posted

January 2, 2018

Last Updated

November 1, 2022

Sponsor

University of Southern California

1. Study Identification

Unique Protocol Identification Number

NCT03392909

Brief Title

Intravenous Gentamicin Therapy for Recessive Dystrophic Epidermolysis Bullosa (RDEB)

Official Title

Restoration of Full-Length Type VII Collagen in RDEB Patients With Nonsense Mutations After Intravenous Gentamicin Treatment

Study Type

Interventional

2. Study Status

Record Verification Date

November 2022

Overall Recruitment Status

Recruiting

Study Start Date

July 5, 2018 (Actual)

Primary Completion Date

December 1, 2023 (Anticipated)

Study Completion Date

December 1, 2023 (Anticipated)

3. Sponsor/Collaborators

Responsible Party, by Official Title

Principal Investigator

Name of the Sponsor

University of Southern California

4. Oversight

Studies a U.S. FDA-regulated Drug Product

Yes

Studies a U.S. FDA-regulated Device Product

Product Manufactured in and Exported from the U.S.

Data Monitoring Committee

Yes

5. Study Description

Brief Summary

Recessive dystrophic epidermolysis bullosa (RDEB) is an incurable, devastating, inherited skin disease caused by mutations in the COL7A1 gene that encodes for type VII collagen (C7), the major component of anchoring fibrils (AFs), structures that mediate epidermal-dermal adherence. Thirty percent of RDEB patients have nonsense mutations. The investigators recently demonstrated in 5 such patients that intradermal and topical gentamicin induced "read-through" of their nonsense mutations and created robust and sustained new C7 and AFs at the dermal-epidermal junction (DEJ) of their skin and also stimulated wound closure and reduced new blister formation. No untoward side effects occurred. Herein, the investigators propose evaluating the safety and efficacy of intravenous gentamicin in these patients. In theory, this intravenous administration has the possibility of treating simultaneously all of the patients' skin wounds. The milestones will be increased C7 and AFs in the patients' DEJ, improved EB Disease Activity Scores, and absence of gentamicin side effects.

6. Conditions and Keywords

Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study

Recessive Dystrophic Epidermolysis Bullosa

Keywords

Nonsense Mutations

7. Study Design

Primary Purpose

Treatment

Study Phase

Phase 1, Phase 2

Interventional Study Model

Single Group Assignment

Masking

None (Open Label)

Allocation

N/A

Enrollment

9 (Anticipated)

8. Arms, Groups, and Interventions

Arm Title

Intravenous Gentamicin

Arm Type

Experimental

Arm Description

Intravenous gentamicin (7.5 mgs/kg) daily for for either 14 days and then stopped or twice weekly for three months and then stopped.

Intervention Type

Drug

Intervention Name(s)

Gentamicin

Other Intervention Name(s)

Gentamicin Sulfate

Intervention Description

Short-term intravenous gentamicin therapy should have the advantage of treating all of the patient's multiple skin wounds simultaneously. Six patients (three adults and 3 children) will receive intravenous gentamicin (7.5 mgs/kg) daily for 14 days and then stopped. Three adult patients will receive intravenous gentamicin (7.5mg/kg) biweekly for three months and then stopped.

Primary Outcome Measure Information:

Title

Full-length type VII collagen expression

Description

Increased expression of full-length type VII collagen as assessed by immunofluorescence

Time Frame

6 months

Title

Generation of anchoring fibrils

Description

Generation of new anchoring fibrils as assessed by immuno-electron microscopy

Time Frame

6 months

Title

Absence of gentamicin side effects

Description

Absence of gentamicin side effects, especially the detection of any ototoxicity or nephrotoxicity

Time Frame

6 months

Secondary Outcome Measure Information:

Title

Improved Disease Activity scores

Description

Improved epidermolysis bullosa Disease Activity scores

Time Frame

6 months

Title

Improved Quality of Life score

Description

Improved Quality of Life score

Time Frame

6 months

10. Eligibility

Sex

All

Minimum Age & Unit of Time

7 Years

Accepts Healthy Volunteers

Eligibility Criteria

Inclusion Criteria: Provision of signed and dated informed consent form Stated willingness to comply with all study procedures and availability for the duration of the study Male or female, aged 7 and up can participate in the 14 day IV gentamicin trial. Male or female, aged 18 and up can participate in the 3 month IV gentamicin trial. Been diagnosed with recessive dystrophic epidermolysis bullosa (RDEB) and with a nonsense mutation in the COL7A1 gene. Immunofluorescence evaluation of skin biopsies reveals absence or decreased intensity of C7 expression at their DEJ (dermal epidermal junction) compared with normal human skin biopsies. Cultured fibroblasts from patient skin synthesize and secrete full-length, 290kDa C7 alpha chains in the presence of supplemented gentamicin (400 μg/ml in culture). Ability to sit or lie down for over 30 minutes for IV infusions. For those in the 3 month trial, to be willing to continue treatment at home under the supervision of licensed and trained infusion nurses. Exclusion Criteria: Recent exposure to gentamicin within the past 6 weeks. Pre-existing known auditory impairment. Pre-existing known renal impairment. Pre-existing known allergies to aminoglycosides or sulfate compounds. Pregnancy or lactation Current use of medications with known ototoxicity or nephrotoxicity. Current enrollment in another experimental clinical trial involving systemic treatment with C7 or C7 producing products for the treatment of RDEB.

Central Contact Person:

First Name & Middle Initial & Last Name or Official Title & Degree

David T Woodley, MD

Phone

626-533-6028

dwoodley@usc.edu

First Name & Middle Initial & Last Name or Official Title & Degree

Mei Chen, Ph.D

Phone

323-865-0621

chenm@usc.edu

Overall Study Officials:

First Name & Middle Initial & Last Name & Degree

David T. Woodley, MD

Organizational Affiliation

Professor, University of Southern California

Official's Role

Principal Investigator

First Name & Middle Initial & Last Name & Degree

Mei Chen, Ph.D

Organizational Affiliation

Professor, University of Southern California

Official's Role

Principal Investigator

Facility Information:

Facility Name

University of Southern California

City

Los Angeles

State/Province

California

ZIP/Postal Code

90033

Country

United States

Individual Site Status

Recruiting

Facility Contact:

First Name & Middle Initial & Last Name & Degree

David Woodley, MD

Phone

323-865-0956

dwoodley@usc.edu

First Name & Middle Initial & Last Name & Degree

Mei Chen, Ph.D

Phone

323-865-0621

chenm@usc.edu

12. IPD Sharing Statement

Plan to Share IPD

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Intravenous Gentamicin Therapy for Recessive Dystrophic Epidermolysis Bullosa (RDEB)

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