Natural History of Autosomal Dominant Optic Atrophy (ADOA), Caused by OPA1 Mutation

Study Overview
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Brief Summary
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The purpose of this study is to characterize the disease progression of confirmed OPA1 mutation-associated autosomal dominant optic atrophy (ADOA) by evaluating the changes in ocular structural and functional outcomes.

Detailed Description
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This is a multi-center, longitudinal, prospective, observational natural history study of patients with confirmed OPA1 mutation (haploinsufficiency) associated ADOA. The study will be conducted at up to 10 sites across the United States, Australia and Europe. Each participant's medical record will be reviewed for historical information, and clinical data will be recorded in a secure database. Natural history data will be collected prospectively and will include ophthalmic exams, imaging studies and electrophysiological testing. Assessments will be conducted as described in this protocol approximately every 3 months in the first year and every 6 months in the second year of the study after each participant's baseline visit

Official Title
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A Natural History Study in Patients With Genetically Confirmed Diagnosis of Autosomal Dominant Optic Atrophy (ADOA), Caused by OPA1 Mutation

Conditions
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Autosomal Dominant Optic Atrophy, Optic Atrophy, Autosomal Dominant, Optic Atrophies, Hereditary, Kjer Optic Atrophy

Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Participants and/or their parent(s)/guardian(s) must have given written informed consent before any study-related activities are carried out and must be able to understand the full nature and purpose of the trial, including possible risks and adverse effects. Assent, where appropriate, will be obtained according to institutional guidelines. Males and females, 8 years of age and above. Have a clinical diagnosis of OPA1 mutation (haploinsufficiency) associated ADOA. No other ocular pathology. Patients with best-corrected visual acuity (BCVA) of between 20/40 (70 Early Treatment of Diabetic Retinopathy Study [ETDRS] letters) and 20/160 (39-43 ETDRS letters) Willing and able to comply with all study assessments and adhere to the protocol schedule and restrictions. For sites performing the Detection of apoptosis in retinal cells (DARC) procedure, and in volunteers ≥ 12 years only: Female volunteers must: I. Be of non-child-bearing potential at least 6 weeks before the screening visit or postmenopausal (where postmenopausal is defined as no menses for 12 months without an alternative medical cause), or II. If of childbearing potential, must: Have a negative pregnancy test at the screening visit and prior to each administration of ANX776, and Agree not to attempt to become pregnant or donate ova from signing the consent form until at least 30 days after the last dose of ANX776, and Agree to use adequate contraception (defined as the use of a condom by the male partner combined with the use of a highly effective method of contraception from one month prior to screening until at least 30 days after the last dose of ANX776, if not exclusively in a same-sex relationship or abstinent as a committed lifestyle. Male volunteers must: Agree not to donate sperm from signing the consent form until at least 90 days after the last dose of ANX776, and If engaging in sexual intercourse with a female partner who could become pregnant, agree to use adequate contraception (defined as the use of a condom combined with the use of a highly effective method of contraception) from signing the consent form until at least 90 days after the last dose of study drug. Exclusion Criteria: Participant has a known allergy to ANX776 or any of its excipients. Have any uncontrolled systemic disease that, in the opinion of the Investigator, would preclude participation in the study, which includes but is not limited to, infection, uncontrolled elevated blood pressure, cardiovascular disease, or glycemic control issues, or any other medical condition that may put the participant at risk due to study procedures. Note: comorbidities relevant to the pathogenesis of OPA1 associated ADOA (including hearing loss, peripheral neuropathy, myopathy, and ataxia) are acceptable. Have mutations in genes that cause ADOA, other than OPA1 (for example in case of dominant negative ADOA) and ADOA Plus. Within 3 months prior to Baseline (Visit 2), have undergone any vitreoretinal surgery (scleral buckle, pars plana vitrectomy, retrieval of a dropped nucleus or intraocular lens, radial optic neurotomy, sheathotomy, cyclodestructive procedures or multiple filtration surgeries [2 or more]) or any other ocular surgery. Have ocular media opacity or poor pupillary dilation prohibiting quality ophthalmic evaluation or photography, as assessed by the Investigator. Have used any investigational drug or device within 90 days or 5 estimated half-lives of Visit 2, whichever is longer, or plan to participate in another study of a drug or device during the study period. Participation in observational trials is allowable based on Investigator discretion and consultation with the Medical Monitor. It is assumed that the observational trial evaluations would not interfere with participation in this study. Have received any prior cell or gene therapy for a retinal condition. Have a recent history (<6 months) of or current excessive recreational drug or alcohol use, in the opinion of the Investigator. Note: excessive alcohol use is defined as regular consumption of > 10 standard drinks per week or > 4 standard drinks per day, where 1 standard drink is defined as 10 grams of pure alcohol. Any other condition or prior therapy that in the opinion of the Investigator would make the volunteer unsuitable for this study, including inability to cooperate fully with the requirements of the study protocol or likelihood of noncompliance with any study requirements.

Ages Eligible for Study
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Minimum Age: 8 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Best-corrected High Contrast Visual Acuity (HCVA) | Best-corrected high contrast visual acuity (HCVA) for both distance and near will be evaluated using the ETDRS electronic visual acuity charts and the MNRead acuity chart | Baseline through Year 2 | 
| Low Contrast Visual Acuity (LCVA) | Low contrast visual acuity (LCVA) for both distance and near will be evaluated using the low contrast ETDRS letter chart | Screening through Year 2 | 
| Contrast Sensitivity | Contrast sensitivity recorded using the Pelli-Robson chart | Baseline through Year 2 | 
| Color Vision | Color vision tested using the Hardy Rand Rittler test | Baseline through Year 2 | 
| Retinal Thickness | Change retinal thickness is measured using spectral domain optical coherence tomography (SD-OCT), as measured by the central reading center (SD-OCT), as measured by the central reading center | Baseline through Year 2 | 
| Ellipsoid Zone (EZ) Volume | Change in EZ volume measured using spectral domain optical coherence tomography (SD-OCT), as measured by the central reading center | Baseline through Year 2 | 
| Ellipsoid Zone (EZ) Area | Change in EZ area measured using spectral domain optical coherence tomography (SD-OCT), as measured by the central reading center | Baseline through Year 2 | 
| Visual Field Sensitivity | Visual field sensitivity measured by automated static perimetry | Baseline through Year 2 | 
| Multifocal Visual Evoked Potential (mfVEP) | The waveform of the evoked responses, the latency, and amplitude are analyzed. | Baseline through Year 2 | 
| Pregnancy Test | A urine human chorionic gonadotropin (hCG) pregnancy conducted in all women of childbearing potential (WOCBP) > 12 years of age at baseline. If a urine test is positive, the DARC procedure will not be performed. | Baseline | 
| DARC (Detection of Apoptosing Retinal Cells) | The DARC test is conducted using an IV injection of fluorescently labelled Annexin V (called ANX776). Individual stressed and apoptotic retinal cells are visible as white spots on the image for DARC count, which are quantified using a confocal scanning laser ophthalmoscope using the indocyanine green angiography (ICGA) settings. | Baseline through Year 2 | 
| Flavoprotein Fluorescence (FPF) | Functional imaging of mitochondria using Flavoprotein Fluorescence. | Baseline through Year 2 | 
| Retinal Abnormalities | Ultrawide fundus photography is conducted OU to assess retinal abnormalities | Baseline through Year 2 | 
| Adverse Events (AEs) | Frequency of ocular adverse events (AEs) | Screening through Year 2 | 
| Genomic Analysis for Study Eligibility | OPA1 genetic testing at screening visit | Screening | 
| Vital signs | Vital signs assessments (pulse rate, body temperature, systolic and diastolic blood pressure, and respiratory rate) performed in participants undergoing the DARC assessment only. | Baseline through Year 2 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| To determine the outcome measures that are associated with ADOA disease progression. | To understand the disease progression in participants with confirmed OPA1 mutation-associated ADOA determined by changes in structural and functional markers from the primary outcome within the study period. | Baseline through Year 2 |