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Safety and Efficacy Study in Patients With Retinitis Pigmentosa Due to Mutations in PDE6B Gene

Primary Purpose

Retinitis Pigmentosa

Status

Recruiting

Phase

Phase 1

Locations

France

Study Type

Interventional

Intervention

AAV2/5-hPDE6B

About this trial

This is an interventional treatment trial for Retinitis Pigmentosa focused on measuring Adeno-associated virus, AAV, Retinitis Pigmentosa, PDE6B, Gene Therapy, Gene Transfer, Retinal Dystrophy, Eye Diseases, Vision Disorders, Eye Diseases, Hereditary, Retinal Diseases, Retinal Degeneration

Eligibility Criteria

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

Key Inclusion Criteria:

Clinical and molecular diagnosis of retinitis pigmentosa caused by defect in PDE6B gene without other syndromic manifestations
Aged 18 years or older
Ability to give informed consent

Key Exclusion Criteria:

Previous ocular surgery or thermal laser within 6 months before the surgery
Lens opacities or obscured ocular media upon recruitment such reliable evaluation or grading of the posterior segment cannot be performed
Known serious allergies to the fluorescein dye used in angiography, to the mydriatic, steroidal and non-steroidal eye drops
Participation in another clinical trial with an investigational agent
Enrolled or being enrolled in another gene therapy clinical trial
Active, extraocular infection requiring the prolonged or chronic use of antimicrobial agents
Chronic medical conditions, cancer
Abnormal laboratory values
On immunosuppressive therapy

Sites / Locations

Clinique Ophtalmologique, CHU de NantesRecruiting

Arms of the Study

Arm 1

Arm 2

Arm 3

Arm 4

Arm 5

Arm Type

Experimental

Arm Label

Cohort 1 - Low Dose

Cohort 2a - Medium Dose

Cohort 2b - High Dose

Cohort 3 - High Dose (confirmatory cohort)

Cohort 4 - High Dose - 13 years old or older population

Arm Description

Biological: AAV2/5-hPDE6B Unilateral (one eye), subretinal, administration of the lowest dose. Dose-escalation will be performed after DSMC assessment.

Biological: AAV2/5-hPDE6B Unilateral (one eye), subretinal, administration of the medium dose. Confirmatory dose will be determined after DSMC assessment.

Biological: AAV2/5-hPDE6B Unilateral (one eye), subretinal, administration of the highest dose. Confirmatory dose will be determined after DSMC assessment.

Biological: AAV2/5-hPDE6B Unilateral (one eye), subretinal, administration of the confirmatory dose.

Outcomes

Primary Outcome Measures

Incidence of ocular and non-ocular adverse events

Secondary Outcome Measures

Improvement in visual function

Improvement in visual function as assessed by mobility test

Improvement in visual fields

Improvement in visual fields as assessed by visual fields measurements

Improvement in visual function

Improvement in visual function as assessed by reading speed

Improvement in Quality of Life

Quality of life will be measured by Quality of Life questionnaire National Eye Institute Visual Function Questionnaire (NEI VFQ-25)

Full Information

NCT ID

NCT03328130

First Posted

October 5, 2017

Last Updated

September 11, 2023

Sponsor

Coave Therapeutics

1. Study Identification

Unique Protocol Identification Number

NCT03328130

Brief Title

Safety and Efficacy Study in Patients With Retinitis Pigmentosa Due to Mutations in PDE6B Gene

Official Title

Safety and Efficacy of a Unilateral Subretinal Administration of HORA-PDE6B in Patients With Retinitis Pigmentosa Harbouring Mutations in the PDE6B Gene Leading to a Defect in PDE6ß Expression

Study Type

Interventional

2. Study Status

Record Verification Date

September 2023

Overall Recruitment Status

Recruiting

Study Start Date

November 6, 2017 (Actual)

Primary Completion Date

December 2029 (Anticipated)

Study Completion Date

December 2029 (Anticipated)

3. Sponsor/Collaborators

Responsible Party, by Official Title

Sponsor

Name of the Sponsor

Coave Therapeutics

4. Oversight

Studies a U.S. FDA-regulated Drug Product

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

The study is a Phase I/II, monocentric, open-label, dose-ranging safety and efficacy gene therapy intervention by subretinal administration of AAV2/5-hPDE6B. At least twelve patients 18 years of age or older, within four consecutive cohorts of patients, will be recruited. Then at least four patients 13 years of age or older, within a fifth cohort, will be recruited.

Detailed Description

Retinitis pigmentosa (RP) is a disease where part of the eye (the retina) is degenerating over time. Patients initially present with night blindness, and later in life experience loss of central vision which leads to blindness. RP is a highly variable disorder with some patients developing symptomatic visual loss in childhood whereas others remain asymptomatic until mid-adulthood. There are no treatments available. This study focuses on the form of RP caused by mutations (modifications) in the genetic information necessary to make the protein called rod cGMP phosphodiesterase 6 β subunit (or PDE6β). Clinical diagnosis is made by function tests of the eye and confirmed using a specific method called molecular testing to verify that the PDE6B gene is not correct. This study uses a gene therapy vector inspired from an adeno-associated virus (AAV) called AAV2/5-hPDE6B. This vector intends to supply to the target cells the PDE6B therapeutic gene that is not functioning properly in the cell. The AAV parts of the gene therapy vector work as a vehicle to deliver the normal human PDE6B gene into the cells of the retina.

6. Conditions and Keywords

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

Retinitis Pigmentosa

Keywords

Adeno-associated virus, AAV, Retinitis Pigmentosa, PDE6B, Gene Therapy, Gene Transfer, Retinal Dystrophy, Eye Diseases, Vision Disorders, Eye Diseases, Hereditary, Retinal Diseases, Retinal Degeneration

7. Study Design

Primary Purpose

Treatment

Study Phase

Phase 1, Phase 2

Interventional Study Model

Sequential Assignment

Model Description

Five successive cohorts separated by DSMC assessments

Masking

None (Open Label)

Allocation

Non-Randomized

Enrollment

23 (Anticipated)

8. Arms, Groups, and Interventions

Arm Title

Cohort 1 - Low Dose

Arm Type

Experimental

Arm Description

Biological: AAV2/5-hPDE6B Unilateral (one eye), subretinal, administration of the lowest dose. Dose-escalation will be performed after DSMC assessment.

Arm Title

Cohort 2a - Medium Dose

Arm Type

Experimental

Arm Description

Biological: AAV2/5-hPDE6B Unilateral (one eye), subretinal, administration of the medium dose. Confirmatory dose will be determined after DSMC assessment.

Arm Title

Cohort 2b - High Dose

Arm Type

Experimental

Arm Description

Biological: AAV2/5-hPDE6B Unilateral (one eye), subretinal, administration of the highest dose. Confirmatory dose will be determined after DSMC assessment.

Arm Title

Cohort 3 - High Dose (confirmatory cohort)

Arm Type

Experimental

Arm Description

Biological: AAV2/5-hPDE6B Unilateral (one eye), subretinal, administration of the confirmatory dose.

Arm Title

Cohort 4 - High Dose - 13 years old or older population

Arm Type

Experimental

Arm Description

Biological: AAV2/5-hPDE6B Unilateral (one eye), subretinal, administration of the confirmatory dose.

Intervention Type

Biological

Intervention Name(s)

AAV2/5-hPDE6B

Intervention Description

Subretinal administration in one eye

Primary Outcome Measure Information:

Title

Incidence of ocular and non-ocular adverse events

Time Frame

1 year + 4 years follow-up

Secondary Outcome Measure Information:

Title

Improvement in visual function

Description

Improvement in visual function as assessed by mobility test

Time Frame

1 year + 4 years follow-up

Title

Improvement in visual fields

Description

Improvement in visual fields as assessed by visual fields measurements

Time Frame

1 year + 4 years follow-up

Title

Improvement in visual function

Description

Improvement in visual function as assessed by reading speed

Time Frame

1 year + 4 years follow-up

Title

Improvement in Quality of Life

Description

Quality of life will be measured by Quality of Life questionnaire National Eye Institute Visual Function Questionnaire (NEI VFQ-25)

Time Frame

1 year + 4 years follow-up

10. Eligibility

Sex

All

Minimum Age & Unit of Time

13 Years

Accepts Healthy Volunteers

Eligibility Criteria

Key Inclusion Criteria: Clinical and molecular diagnosis of retinitis pigmentosa caused by defect in PDE6B gene without other syndromic manifestations Aged above 13 years Ability to give informed consent Key Exclusion Criteria: Previous ocular surgery or thermal laser within 6 months before the surgery Lens opacities or obscured ocular media upon recruitment such reliable evaluation or grading of the posterior segment cannot be performed Known serious allergies to the fluorescein dye used in angiography, to the mydriatic, steroidal and non-steroidal eye drops Participation in another clinical trial with an investigational agent Enrolled or being enrolled in another gene therapy clinical trial Active, extraocular infection requiring the prolonged or chronic use of antimicrobial agents Chronic medical conditions, cancer Abnormal laboratory values On immunosuppressive therapy

Central Contact Person:

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

Medical Director / Chief Development Officer, MD

Phone

01 81 69 87 70

contact@coavetx.com

Facility Information:

Facility Name

Clinique Ophtalmologique, CHU de Nantes

City

Nantes

ZIP/Postal Code

44093

Country

France

Individual Site Status

Recruiting

Facility Contact:

First Name & Middle Initial & Last Name & Degree

Pierre Lebranchu

pierre.lebranchu@chu-nantes.fr

12. IPD Sharing Statement

Plan to Share IPD

Citations:

PubMed Identifier

22828504

Citation

Petit L, Lheriteau E, Weber M, Le Meur G, Deschamps JY, Provost N, Mendes-Madeira A, Libeau L, Guihal C, Colle MA, Moullier P, Rolling F. Restoration of vision in the pde6beta-deficient dog, a large animal model of rod-cone dystrophy. Mol Ther. 2012 Nov;20(11):2019-30. doi: 10.1038/mt.2012.134. Epub 2012 Jul 24.

Results Reference

result

PubMed Identifier

26857842

Citation

Pichard V, Provost N, Mendes-Madeira A, Libeau L, Hulin P, Tshilenge KT, Biget M, Ameline B, Deschamps JY, Weber M, Le Meur G, Colle MA, Moullier P, Rolling F. AAV-mediated Gene Therapy Halts Retinal Degeneration in PDE6beta-deficient Dogs. Mol Ther. 2016 May;24(5):867-76. doi: 10.1038/mt.2016.37. Epub 2016 Feb 9.

Results Reference

result

PubMed Identifier

30646425

Citation

Palmowski-Wolfe A, Stingl K, Habibi I, Schorderet D, Tran HV. Novel PDE6B Mutation Presenting with Retinitis Pigmentosa - A Case Series of Three Patients. Klin Monbl Augenheilkd. 2019 Apr;236(4):562-567. doi: 10.1055/a-0811-5480. Epub 2019 Jan 15.

Results Reference

derived

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Safety and Efficacy Study in Patients With Retinitis Pigmentosa Due to Mutations in PDE6B Gene

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