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PDE6A Gene Therapy for Retinitis Pigmentosa (Pigment)

Primary Purpose

Retinitis Pigmentosa

Status

Active

Phase

Phase 1

Locations

Germany

Study Type

Interventional

Intervention

subretinal injection of rAAV.hPDE6A

About this trial

This is an interventional treatment trial for Retinitis Pigmentosa

Eligibility Criteria

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

Inclusion Criteria:

clinical diagnosis of retinitis pigmentosa
confirmed mutation in PDE6A gene
≥ 18 years of age
visual acuity ≥ 20/400
no infection with Human Immundeficiency Virus (HIV)
negative pregnancy test in women with childbearing potential (a woman who is two years post-menopausal or surgically sterile is not considered to be of childbearing potential)
Male patients must agree to use condoms during the first 6 months post treatment.
Female patients of childbearing potential must agree to use an effective method of birth control during the first 6 months post treatment.
ability to understand and willingness to consent to study protocol

Exclusion Criteria:

Ocular (study eye & fellow eye)

additional interfering ocular conditions with impact on study results (e.g. ocular opacity and advanced cataract, uveitis, amblyopia)
recent (6 months) ocular surgery, intravitreal or subretinal implantation of a medical device
disease causing mutations in another known retinitis pigmentosa gene
ocular infection with herpes simplex virus in medical history
history of ocular malignancies
disorders of the internal retina (e.g. retinal detachment in the patients history)
glaucoma defined as damage of the optic nerve
vascular retinal occlusion
diabetic patients suffering from retinopathy and/or macula edema
any other retinopathy due to other diseases e.g. (but not limited to) arterial hypertension, trauma or acquired inflammatory diseases (uveitis serology), contraindication to pharmacological mydriasis (e.g. history of angle block glaucoma)
absence of visual function on the contralateral eye Systemic
systemic conditions (e.g. coronary heart disease, autoimmune disorders) which may affect study participation or outcome measures
History of poorly controlled Diabetes Mellitus type 1 or type 2
systemic illness or medically relevant abnormal laboratory values in blood analysis including renal and hepatic functions at inclusion
patients treated with oral corticoids within 14 days prior inclusion
current or recent participation in other study/or administration of biologic agent within the last three months
known sensitivity to any compound used in the study
contraindications to systemic immunosuppression
contraindications in view of the planned surgery (e.g. but not limited to anaemia Hb<10g/dl, coagulopathy with PT/PTT >1,5 fold upper limit, hypertension with values above 180 mmHg systolic and 110 mmHg diastolic) including intolerance and contraindications to general anaesthesia
intolerance to contrast agents used for diagnostic methods like angiography with fluoresceine or indocyanine green (e.g. but not limited to hyperthyroidism, hepatic insufficiency)
subject/partner of childbearing potential unwilling to use adequate contraception for four months
nursing or pregnant women
any other cause that, in the investigator's opinion, renders potential subjects not suitable for the study

Sites / Locations

Universitätsklinikum Tübingen, Department für Augenheilkunde

Arms of the Study

Arm 1

Arm Type

Experimental

Arm Label

Subretinal injection of rAAV.hPDE6A

Arm Description

Single subretinal injection of rAAV.hPDE6A

Outcomes

Primary Outcome Measures

Slit lamp examination

to determine possibly occurring ocular inflammation and to observe if there are any treatment effects

Fundus biomicroscopy to determine possibly occurring ocular inflammation and to observe if there are any treatment effects

To determine possibly occurring ocular inflammation and to observe if there are any treatment effects

Angiography

To determine possibly occurring ocular inflammation and to observe if there are any treatment effects

Secondary Outcome Measures

Visual acuity

To determine any therapy effects concerning visual acuity

Contrast sensitivity

To determine any therapy effects concerning the contrast sensitivity

Visual field

To determine any therapy effects concerning the visual field

Colour vision

To determine any therapy effects concerning colour vision

Pupillography

To determine any therapy effects concerning pupil reaction

Electrophysiology

To determine any therapy effects concerning the electrophysiology

Full Information

NCT ID

NCT04611503

First Posted

May 20, 2020

Last Updated

December 7, 2022

Sponsor

STZ eyetrial

1. Study Identification

Unique Protocol Identification Number

NCT04611503

Brief Title

PDE6A Gene Therapy for Retinitis Pigmentosa

Acronym

Pigment

Official Title

PIGMENT - PDE6A Gene Therapy for Retinitis Pigmentosa

Study Type

Interventional

2. Study Status

Record Verification Date

December 2022

Overall Recruitment Status

Active, not recruiting

Study Start Date

September 24, 2019 (Actual)

Primary Completion Date

July 2023 (Anticipated)

Study Completion Date

July 2027 (Anticipated)

3. Sponsor/Collaborators

Responsible Party, by Official Title

Sponsor

Name of the Sponsor

STZ eyetrial

4. Oversight

Studies a U.S. FDA-regulated Drug Product

Studies a U.S. FDA-regulated Device Product

Data Monitoring Committee

Yes

5. Study Description

Brief Summary

The PDE6A gene encodes a subunit of the rod phosphodiesterase. The loss of this enzyme function leads to a chronically elevated cGMP level which causes an increased calcium inflow into the cell and thereby the hyperactivation of cell death pathways. The goal of the PIGMENT study is to develop, produce and investigate a recombinant adeno-associated viral (AAV) gene transfer vector for the curative therapy of PDE6A-linked retinitis pigmentosa in patients, in order to counteract their disease progression and to stop further impairment of visual function. The vector is given with a single subretinal injection.

Detailed Description

"PIGMENT - Subretinal PDE6A gene therapy for retinitis pigmentosa" is an open mono-center, phase I/IIa trial with fellow-eye comparison. The study begins with a detailed preliminary examination (Screening), comprises a total of 13 visits and ends after one year. In between, after the gene therapy injection (injection of the vector under the retina with one of four doses), regular controls are carried out at the Center for Ophthalmology Tübingen. Monitoring will be contimued after the first year, once a year two, three, four and five years after the injection. The study will take place exclusively at the Center for Ophthalmology in Tübingen and involves nine patients. All patients participating in this study receive treatment, i.e. there is no placebo or sham treatment group. A 30-day safety distance is maintained between each patient and each group. An independent committee will decide, after each injection of three patients, which dose the following three patients will receive. Patients can benefit from the treatment by slowing or stopping the loss of the rods and allowing them to function to a certain extent. Therefore, a possible benefit for patients may be that the vision problems will be improved by gene therapy. Such improvements could improve the overall quality of life and well-being. However, as no experience with gene therapy for retinitis pigmentosa in humans has yet been gained, we cannot promise any improvement. Within the scope of this study, patients will be given particularly intensive care and psychological support will also be offered in order to do everything for the patient's well-being and health during the study. Time Schedule: Start of trial Q3/2019 (FPFV), end of recruitment Q3/2020, end of trial Q4/2025 (LPLV), duration of trial per patient: one year with four years of follow-up. The final study report will be prepared after completion of the four year follow-up period (5 years after treatment).

6. Conditions and Keywords

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

Retinitis Pigmentosa

7. Study Design

Primary Purpose

Treatment

Study Phase

Phase 1, Phase 2

Interventional Study Model

Sequential Assignment

Masking

None (Open Label)

Allocation

N/A

Enrollment

9 (Actual)

8. Arms, Groups, and Interventions

Arm Title

Subretinal injection of rAAV.hPDE6A

Arm Type

Experimental

Arm Description

Single subretinal injection of rAAV.hPDE6A

Intervention Type

Drug

Intervention Name(s)

subretinal injection of rAAV.hPDE6A

Other Intervention Name(s)

Gene therapy

Intervention Description

The first 3 patients (C1) will receive the intermediate dose 1x1010 vg. After injection of the 3rd patient of C1, the DMC will give a go/no go decision. If 'nogo', a lower dose (5x109 vg) will be given to the next group of 3 patients (C2). The DMC will give a go/no go decision. In case of a "go" decision, 3 further patients (C3) will be treated with the same dose. In the case of a no-go decision, the next dose will be the minimal dose 1x109 vg. In case of a 'go' decision of the DMC after the third patient, the next 3 patients will receive a subretinal injection of vector at the highest dose 5x1010 vg. The DMC will give a go/no go decision after review of all safety data available at D30 of cohort 2. If safety data is considered favourably by the DMC, then 3further patients (cohort 3) will be treated with the same dose (5x1010 vg). Should any safety concerns arise, the last three patients (cohort 3) will receive the intermediate dose (1x1010 vg).

Primary Outcome Measure Information:

Title

Slit lamp examination

Description

to determine possibly occurring ocular inflammation and to observe if there are any treatment effects

Time Frame

1 year + 4 years follow-up

Title

Fundus biomicroscopy to determine possibly occurring ocular inflammation and to observe if there are any treatment effects

Description

To determine possibly occurring ocular inflammation and to observe if there are any treatment effects

Time Frame

1 year + 4 years follow-up

Title

Angiography

Description

To determine possibly occurring ocular inflammation and to observe if there are any treatment effects

Time Frame

1 year + 4 years follow-up

Secondary Outcome Measure Information:

Title

Visual acuity

Description

To determine any therapy effects concerning visual acuity

Time Frame

1 year + 4 years follow-up

Title

Contrast sensitivity

Description

To determine any therapy effects concerning the contrast sensitivity

Time Frame

1 year + 4 years follow-up

Title

Visual field

Description

To determine any therapy effects concerning the visual field

Time Frame

1 year + 4 years follow-up

Title

Colour vision

Description

To determine any therapy effects concerning colour vision

Time Frame

1 year + 4 years follow-up

Title

Pupillography

Description

To determine any therapy effects concerning pupil reaction

Time Frame

1 year + 4 years follow-up

Title

Electrophysiology

Description

To determine any therapy effects concerning the electrophysiology

Time Frame

1 year + 4 years follow-up

10. Eligibility

Sex

All

Minimum Age & Unit of Time

18 Years

Accepts Healthy Volunteers

Eligibility Criteria

Inclusion Criteria: clinical diagnosis of retinitis pigmentosa confirmed mutation in PDE6A gene ≥ 18 years of age visual acuity ≥ 20/400 no infection with Human Immundeficiency Virus (HIV) negative pregnancy test in women with childbearing potential (a woman who is two years post-menopausal or surgically sterile is not considered to be of childbearing potential) Male patients must agree to use condoms during the first 6 months post treatment. Female patients of childbearing potential must agree to use an effective method of birth control during the first 6 months post treatment. ability to understand and willingness to consent to study protocol Exclusion Criteria: Ocular (study eye & fellow eye) additional interfering ocular conditions with impact on study results (e.g. ocular opacity and advanced cataract, uveitis, amblyopia) recent (6 months) ocular surgery, intravitreal or subretinal implantation of a medical device disease causing mutations in another known retinitis pigmentosa gene ocular infection with herpes simplex virus in medical history history of ocular malignancies disorders of the internal retina (e.g. retinal detachment in the patients history) glaucoma defined as damage of the optic nerve vascular retinal occlusion diabetic patients suffering from retinopathy and/or macula edema any other retinopathy due to other diseases e.g. (but not limited to) arterial hypertension, trauma or acquired inflammatory diseases (uveitis serology), contraindication to pharmacological mydriasis (e.g. history of angle block glaucoma) absence of visual function on the contralateral eye Systemic systemic conditions (e.g. coronary heart disease, autoimmune disorders) which may affect study participation or outcome measures History of poorly controlled Diabetes Mellitus type 1 or type 2 systemic illness or medically relevant abnormal laboratory values in blood analysis including renal and hepatic functions at inclusion patients treated with oral corticoids within 14 days prior inclusion current or recent participation in other study/or administration of biologic agent within the last three months known sensitivity to any compound used in the study contraindications to systemic immunosuppression contraindications in view of the planned surgery (e.g. but not limited to anaemia Hb<10g/dl, coagulopathy with PT/PTT >1,5 fold upper limit, hypertension with values above 180 mmHg systolic and 110 mmHg diastolic) including intolerance and contraindications to general anaesthesia intolerance to contrast agents used for diagnostic methods like angiography with fluoresceine or indocyanine green (e.g. but not limited to hyperthyroidism, hepatic insufficiency) subject/partner of childbearing potential unwilling to use adequate contraception for four months nursing or pregnant women any other cause that, in the investigator's opinion, renders potential subjects not suitable for the study

Overall Study Officials:

First Name & Middle Initial & Last Name & Degree

Dominik Fischer, Prof.

Organizational Affiliation

University Hospital Tuebingen

Official's Role

Principal Investigator

Facility Information:

Facility Name

Universitätsklinikum Tübingen, Department für Augenheilkunde

City

Tuebingen

ZIP/Postal Code

72076

Country

Germany

12. IPD Sharing Statement

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PDE6A Gene Therapy for Retinitis Pigmentosa

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