Safety and Efficacy of rAAV.hCNGA3 Gene Therapy in Patients With CNGA3-linked Achromatopsia (Colourbridge)

Safety and Efficacy of a Bilateral Single Subretinal Injection of rAAV.hCNGA3 in Adult and Minor Patients With CNGA3-linked Achromatopsia Investigated in a Randomized, Wait List Controlled, Observer-masked Trial

The purpose of this study is to proof the safety and efficacy of a single bilateral subretinal injection of rAAV.hCNGA3 in adult and minor patients with CNGA3-linked achromatopsia.

Study Overview

• Status: Recruiting
• Conditions: Achromatopsia
• Intervention / Treatment: Drug: rAAV.hCNGA3

Detailed Description

Title: Safety and efficacy of a bilateral single subretinal injection of rAAV.hCNGA3 in adult and minor patients with CNGA3-linked achromatopsia investigated in a randomized, wait list controlled, observer-masked trial

Phase: I/II

Indication: CNGA3-linked achromatopsia

Aim: to proof the safety and efficacy of a single bilateral subretinal injection of rAAV.hCNGA3 in adult and minor patients with CNGA3-linked achromatopsia.

Study design: open, mono-center, randomized, wait list controlled, observer-masked trial

Study Population:

Inclusion Criteria (Both Eyes)

• clinical diagnosis of achromatopsia
• 6-12 years of age
• ≥ 18 years of age
• confirmed mutation in CNGA3
• BCVA ≥ 20/400
• a minimal outer nuclear layer thickness of 10µm at 3° eccentricity (normal = 38±6µm)
• ability to understand and willingness to consent to study protocol
• no infection with Human Immundeficiency Virus (HIV)
• 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.
• 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)

Exclusion Criteria

• • any other retinopathy due to other diseases e.g. (but not limited to) arterial hypertension, trauma or acquired inflammatory diseases (uveitis serology) , retinopathy of the premature
• systemic conditions (e.g. coronary heart disease, congenital/genetic conditions, autoimmune disorders) which may affect study participation or outcome measures
• current or recent participation in other study or administration of biologic agent within the last three months
• recent (6 months) ocular surgery, intravitreal or subretinal implantation of a medical device
• known sensitivity to any compound used in the study
• contraindications to systemic immunosuppression
• subject/partner of childbearing potential unwilling to use adequate contraception for six months after dosing
• nursing or pregnant female subject women
• any other cause that, in the investigator's opinion, renders potential subjects not suitable for the study
• mutations in another achromatopsia gene
• contraindications in view of the planned surgery (e.g. anaemia Hb<8g/dl, severe coagulopathy, severe blood pressure fluctuations) including intolerance and contraindications to general anaesthesia
• ocular opacity and mature cataract
• 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
• history of poorly controlled (HbA1c > 7%) Diabetes Mellitus type 1 or type 2
• patients treated with systemic corticoids within 14 days prior inclusion
• systemic illness or medically significant abnormal laboratory values >3 UNL in blood analysis including renal and hepatic functions at inclusion
• absence of vision on the other contralateral eye
• contraindication to pharmacological mydriasis (e.g. history of angle block glaucoma)

Patient Number: 3 Strata: Cohort A n = 4, ≥ 18 years of age and previous participation in phaseI/II, Cohort B n = 4, ≥ 18 years of age, Cohort C n= 6, 6-12 years of age

Treatment:

Each cohort will receive a single subretinal injection of 1x10e11 vector genome particles of rAAV.hCNGA3 in each eye at different time-points. Cohort A, in whom the first eye has received treatment under protocol version 5.0, will only receive one injection in the second eye.

After standard three-port 23G pars plana vitrectomy, balanced salt solution will be used to induce a localized primary retinal detachment in a controlled fashion. Vector solution will be applied using disposable 41G extendible subretinal injection needles within a standard 23G body to fit the port system.

Primary Endpoint:

Primary endpoint safety: Safety assessment 12 months after treatment, descriptively Primary endpoint efficacy: Contrast sensitivity (Pelli Robson 3 m) 6 months after treatment

Key secondary endpoints efficacy 12 months after treatment:

• Contrast sensitivity (Pelli Robson 3 m)
• BCVA assessed using the ETDRS visual acuity protocol
• Microperimetry (MAIA) (20°)
• Chromatic Pupil Campimetry
• Patient reported outcomes (VFQ25/CVFQ, A3-PRO) Safety as the primary endpoint will be assessed by clinical examination of ocular inflammation (slit lamp, fundus biomicroscopy, fundus photography. Systemic safety will be assessed by vital signs, routine clinical chemistry testing (including CRP, ESR) and full/differential blood counts. Immunopathology essays will include specific enzyme-linked immunosorbent assays for humoral antibodies against rAAV8 capsid protein. Biodistribution will be monitored by polymerase chain reaction studies on rAAV8 genome in blood, urine, saliva and tear fluid.

Statistical Methods:

Efficacy: The analysis of the primary endpoint (contrast sensitivity after 6 months) will be done using a pre / post comparison for the entire sample including both eyes for cohort B and C (n=10) and only one eye for cohort A (n=4) with GEE correction for the dependency of left and right eye. In the waiting group the second (therapeutic) phase will be used. The dependency appears for cohorts B and C which contribute both eyes but not for cohort A which contributes only one eye to the efficacy analysis. The study is powered for this analysis. We will use the specific type of IEE (Independence Estimating Equations) which reveals correct standard errors and a robust estimate for model parameters.

Additionally, we will compare the Intervention group vs. control group (waiting group) (n=7 vs. 7), using baseline adjusted analysis of covariance and between subject comparisons. This analysis will use GEEs as described for the primary analysis including both eyes of cohort B and C and only the newly treated eye in cohort A. This analysis will be descriptive and provide evidence for the planning of a randomized Phase III trial.

The primary analysis population will be the ITT in which only patients with baseline measurements will be included. For patients providing baseline measurements in one eye, only this eye will be included. Multiple imputation will be done with sampling unit "eye" if only baseline, but not follow up data are available. Descriptive parameters will be given for the full cohort (n=14) and for the sub-strata (n=4, 4, 6 pooled), additionally, correlation analysis descriptively for the comparison of subjective and objective measurements will be done.

Safety (ITT): AEs and SAEs will be documented using line listings and tabulations (MedDRA code will be applied). Frequency tabulations of certain classes of events will be given including two-sided 95% confidence intervals.

The aim of analysis (1) is to gain evidence for a sample size estimation for a phase III trial with similar design, where analysis (2) will be confirmatory and powered according to a sample size estimation.

Time Schedule: of trial November 2015 end of recruitment 04/2022, end of trial 04/2027, 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).

• Study Type: Interventional
• Enrollment (Anticipated): 14
• Phase: Phase 2; Phase 1

Contacts and Locations

• Study Contact: Name: Barbara J Wilhelm, Prof.; Phone Number: +49 7071 2984898; Email: Barbara.Wilhelm@stz-eyetrial.de
• Study Contact Backup: Name: Dominik Fischer, Prof.; Phone Number: +49 7071 298 37 21; Email: dominik.fischer@uni-tuebingen.de

Study Locations

• Germany
  • Tuebingen, Germany, 72076
    • Recruiting
    • University Hospital Tuebingen, Center for Ophthalmology
    • Contact: Manuel D Fischer, MD, PhD; Phone Number: ++40 7071 29 84894; Email: dominik.fischer@med.uni-tuebingen.de
    • Contact: Barbara J Wilhelm, MD, PhD; Phone Number: ++40 7071 29 84898; Email: barbara.wilhelm@stz-eyetrial.de

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 6 years and older (Child, Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

Inclusion Criteria (Both Eyes)

• clinical diagnosis of achromatopsia
• 6-12 years of age
• ≥ 18 years of age
• confirmed mutation in CNGA3
• BCVA ≥ 20/400
• a minimal outer nuclear layer thickness of 10µm at 3° eccentricity (normal = 38±6µm)
• ability to understand and willingness to consent to study protocol
• no infection with Human Immundeficiency Virus (HIV)
• 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.
• 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)

Exclusion Criteria

• any other retinopathy due to other diseases e.g. (but not limited to) arterial hypertension, trauma or acquired inflammatory diseases (uveitis serology) , retinopathy of the premature
• systemic conditions (e.g. coronary heart disease, congenital/genetic conditions, autoimmune disorders) which may affect study participation or outcome measures
• current or recent participation in other study or administration of biologic agent within the last three months
• recent (6 months) ocular surgery, intravitreal or subretinal implantation of a medical device
• known sensitivity to any compound used in the study
• contraindications to systemic immunosuppression
• subject/partner of childbearing potential unwilling to use adequate contraception for six months after dosing
• nursing or pregnant female subject women
• any other cause that, in the investigator's opinion, renders potential subjects not suitable for the study
• mutations in another achromatopsia gene
• contraindications in view of the planned surgery (e.g. anaemia Hb<8g/dl, severe coagulopathy, severe blood pressure fluctuations) including intolerance and contraindications to general anaesthesia
• ocular opacity and mature cataract
• 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
• history of poorly controlled (HbA1c > 7%) Diabetes Mellitus type 1 or type 2
• patients treated with systemic corticoids within 14 days prior inclusion
• systemic illness or medically significant abnormal laboratory values >3 UNL in blood analysis including renal and hepatic functions at inclusion
• absence of vision on the other contralateral eye
• contraindication to pharmacological mydriasis (e.g. history of angle block glaucoma)

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Sequential Assignment
• Masking: None (Open Label)

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Other: Treatment arm; single subretinal injection of 1x10e11 vector genome particles of rAAV.hCNGA3 in each eye at different time-points	Drug: rAAV.hCNGA3; Single subretinal injection of rAAV.hCNGA3
Other: Waiting group Arm; Waiting group will serve as comparator group first and will receive the treatment at a later timepoint.	Drug: rAAV.hCNGA3; Single subretinal injection of rAAV.hCNGA3

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Safety (AE). Number of Participants With Abnormal Laboratory Values and/or Adverse Events That Are Related to Treatment	Safety as the primary endpoint will be assessed by clinical examination of ocular inflammation (slit lamp, fundus biomicroscopy, fundus photography. Systemic safety will be assessed by vital signs, routine clinical chemistry testing (including CRP, ESR) and full/differential blood counts. Immunopathology essays will include specific enzyme-linked immunosorbent assays for humoral antibodies against rAAV8 capsid protein. Biodistribution will be monitored by polymerase chain reaction studies on rAAV8 genome in blood, urine, saliva and tear fluid.	Day 0 - Day 365

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Efficacy measures. Number of Participants With improved Visual Function.	The investigation of treatment effects as reflected by patient/parent reported outcomes and the efficacy of the intervention on visual function, as well as the evaluation of retinal imaging (safety) are secondary aims of the trial.	Day 14 - Day 365

Collaborators and Investigators

• Sponsor: STZ eyetrial
• Collaborators: Ludwig-Maximilians - University of Munich; University Hospital Tuebingen
• Investigators: Principal Investigator: Dominik Fischer, Prof., University Hospital Tuebingen, Center for Ophthalmology

Publications and helpful links

General Publications

• Reichel FF, Michalakis S, Wilhelm B, Zobor D, Muehlfriedel R, Kohl S, Weisschuh N, Sothilingam V, Kuehlewein L, Kahle N, Seitz I, Paquet-Durand F, Tsang SH, Martus P, Peters T, Seeliger M, Bartz-Schmidt KU, Ueffing M, Zrenner E, Biel M, Wissinger B, Fischer D. Three-year results of phase I retinal gene therapy trial for CNGA3-mutated achromatopsia: results of a non randomised controlled trial. Br J Ophthalmol. 2022 Nov;106(11):1567-1572. doi: 10.1136/bjophthalmol-2021-319067. Epub 2021 May 18.
• Fischer MD, Michalakis S, Wilhelm B, Zobor D, Muehlfriedel R, Kohl S, Weisschuh N, Ochakovski GA, Klein R, Schoen C, Sothilingam V, Garcia-Garrido M, Kuehlewein L, Kahle N, Werner A, Dauletbekov D, Paquet-Durand F, Tsang S, Martus P, Peters T, Seeliger M, Bartz-Schmidt KU, Ueffing M, Zrenner E, Biel M, Wissinger B. Safety and Vision Outcomes of Subretinal Gene Therapy Targeting Cone Photoreceptors in Achromatopsia: A Nonrandomized Controlled Trial. JAMA Ophthalmol. 2020 Jun 1;138(6):643-651. doi: 10.1001/jamaophthalmol.2020.1032.

Study record dates

Study Major Dates

• Study Start (Actual): November 1, 2015
• Primary Completion (Anticipated): April 1, 2023
• Study Completion (Anticipated): April 1, 2027

Study Registration Dates

• First Submitted: September 18, 2015
• First Submitted That Met QC Criteria: November 18, 2015
• First Posted (Estimate): November 20, 2015

Study Record Updates

• Last Update Posted (Estimate): December 8, 2022
• Last Update Submitted That Met QC Criteria: December 7, 2022
• Last Verified: December 1, 2022

More Information

Terms related to this study

• Keywords: CNGA3-linked
• Additional Relevant MeSH Terms: Nervous System Diseases; Eye Diseases; Neurologic Manifestations; Eye Diseases, Hereditary; Sensation Disorders; Vision Disorders; Cone Dystrophy; Color Vision Defects
• Other Study ID Numbers: RDC-CNGA3-01; 2014-001874-32 (EudraCT Number); 096/2015 AMG1 (Other Identifier: Ethics Committee Tübingen)

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: No