Gyrate Atrophy Ocular and Systemic Study

Gyrate Atrophy Clinical Trial

— GYROS  

Official title:

Gyrate Atrophy Ocular and Systemic Study

Clinical Trial Details — Status: Recruiting

Administrative data

• NCT number: NCT05312736
• Other study ID #: GYROS
• Status: Recruiting
• Start date: November 21, 2023
• Est. completion date: January 31, 2028

Study information

• Verified date: August 2023
• Source: Jaeb Center for Health Research
• Contact: Coordinating Center
• Phone: 8139758690
• Email: ffb[@]jaeb.org
• Is FDA regulated: No
• Study type: Observational

Clinical Trial Summary

The Gyrate Atrophy Ocular and Systemic Study characterizes the natural history of ornithine levels and retinal degeneration (RD) associated with disease-causing OAT variants in the presence of standard care dietary treatment regimens over 4 years. The research goal is to understand the impact of OAT mutations on plasma ornithine levels and retinal degeneration.

Description:

Gyrate atrophy is a rare inherited chorioretinal degeneration that is associated with hyperornithinemia, an inborn error of metabolism caused by autosomal recessive mutations in the ornithine aminotransferase (OAT) gene. Gyrate atrophy is characterized by childhood-onset nyctalopia and sharply demarcated areas of chorioretinal atrophy that initially involve the midperipheral fundus. The atrophic areas typically coalesce and enlarge towards the posterior pole in the second and third decades of life, leading to severe visual field constriction and vision loss if left untreated. The current standard care treatment of gyrate atrophy is an arginine restricted diet that is implemented in practice using dietary protein restriction with essential amino acid supplementation. However, dietary treatment is highly burdensome on patients and negatively impacts quality of life such that only about ~20% of patients are able to comply. Strict adherence to dietary protein restriction (particularly through adolescence), essential amino acid supplementation, and nutritional management of body weight especially during intercurrent illness and pregnancy are among the challenges of treatment. Periods of suboptimal dietary control led to plasma ornithine elevation and progressive chorioretinal degeneration.

Investigators are developing gene therapy as a potential one-time treatment that could arrest disease progression while avoiding or reducing the need for dietary treatment. To facilitate a future interventional gene therapy clinical trial, there is a need to evaluate natural history of and the relationship between potential clinical trial outcome measures.

The objectives of the OAT gene natural history study are as follows:

1. Natural History

1. Characterize the natural history of retinal degeneration associated with disease-causing OAT variants in the presence of standard care dietary treatment regimens over four (4) years, using functional, structural, and patient-reported outcome measures.

2. Characterize the natural history of ornithine levels associated with disease-causing OAT variants in the presence of standard care dietary treatment regimens over four (4) years.

3. Determine within-patient variability of ornithine levels associated with disease-causing OAT variants in the presence of standard care dietary treatment regimens over four (4) years.

4. Evaluate inter-eye correlation on ocular measures.

2. Metabolic-Structure-Function Relationships

1. Explore relationship of structural outcomes with functional outcomes in individuals with disease-causing OAT variants.

2. Explore relationship of plasma ornithine levels with structural and functional outcomes in individuals with disease-causing OAT variants.

3. Identify Rapid Progressors

1. Explore possible risk factors (genotype, phenotype, environmental, comorbidities, and dietary therapy/supplements) for progression of the functional, structural, and patient-reported outcome measures over four (4) years in individuals with disease-causing OAT variants.

2. Explore possible risk factors (genotype, phenotype, environmental, comorbidities, and dietary therapy/supplements) for ornithine levels over four (4) years in individuals with disease-causing OAT variants.

The expected impact of the OAT gene natural history study is to inform a future interventional clinical trial design and implementation, including the following:

1. Determine within-patient variability of ornithine levels.

2. Develop quantitative measures of progression of the area of preserved retina and establish its reproducibility, sensitivity to change, and relationship with other measures.

3. Establish rates of progression of retinal degeneration on all functional, structural, and patient-reported outcome measures, and determine which measures are most sensitive to change.

4. Determine primary time points and duration for a planned future treatment trial.

5. Use variability and inter-eye correlation of outcomes for trial sample size calculations.

6. Identify candidates for the future trial, including eligibility criteria based on risk factors and cut points for severity of disease most likely to benefit from treatment.

7. Establish study procedures and workflows for practical implementation of the same testing procedures in a future trial.

Recruitment information / eligibility

• Status: Recruiting
• Enrollment: 45
• Est. completion date: January 31, 2028
• Est. primary completion date: August 31, 2027
• Accepts healthy volunteers: No
• Gender: All
• Age group: 12 Years and older

Eligibility

Inclusion Criteria:

• Participants must meet all the following inclusion criteria at the Screening Visit in order to be eligible to enroll into the genetic screening phase.

• Willing to participate in the study and able to communicate consent during the consent process.

• Willing and able to complete all study visit assessments at each visit over the forty-eight (48) month study period. Age = 12 years.

Must meet one (1) of the Genetic Screening Criteria below:

• At least 2 disease-causing variants in the OAT gene which are homozygous or heterozygous in trans, based on a report from a clinically certified lab, or a report from a research lab that has been pre-approved by the study Genetics Committee.

• At least 2 disease-causing variants in the OAT gene with unknown phase, based on a report from a clinically certified lab, or a report from a research lab that has been pre-approved by the study Genetics Committee, AND must meet both of the following phenotype criteria: .Classic fundus appearance of gyrate atrophy (based on investigator discretion) AND Elevated ornithine levels >300 µmol/L (documented on any prior lab report).

Note: if a participant has a variant(s) of unknown significance, they will still qualify if they meet the Genetic Screening Criteria above. Ocular Inclusion Criteria Participant must meet the following criteria at the Screening Visit to enroll into the genetic screening phase.

Both eyes must have a clinical diagnosis of retinal dystrophy. Both eyes must permit good quality photographic imaging (e.g., but not limited to, clear ocular media, adequate pupil dilation, stable fixation).

Exclusion Criteria:

• Participants must not meet any of the following exclusion criteria at the Screening Visit in order to be eligible to enroll into the genetic screening phase.

• Single pathogenic or likely pathogenic genetic variants known to be associated with autosomal dominant retinitis pigmentosa/retinal dystrophy (AD, heterozygous), X-374 linked retinitis pigmentosa/retinal dystrophy (XL, hemizygous), or mitochondrial inheritance.

• Expected to enter experimental treatment trial at any time during this study. History of more than 1 year of cumulative treatment, at any time, with an agent associated with pigmentary retinopathy, including hydroxychloroquine, chloroquine, thioridazine, and deferoxamine. Note: Since this is a Natural History Study collecting data on the progression of Gyrate Atrophy, pregnant women will not be specifically excluded from participation.

Ocular Exclusion Criteria:

• If either eye has any of the following ocular exclusion criteria at the Screening Visit, then the participant is not eligible to enroll into the genetic screening phase.

• Current vitreous hemorrhage.

• Current or any history of tractional or rhegmatogenous retinal detachment.

• Current or any history of (for example, but not limited to prior to cataract or refractive surgery) spherical equivalent of the refractive error worse than -8 Diopters of myopia. • • • History of intraocular surgery (for example, but not limited to cataract surgery, vitrectomy, penetrating keratoplasty, or LASIK) within the last 3 months.

• Current or any history of confirmed diagnosis of glaucoma (for example, but not limited to glaucomatous VF changes or nerve changes, or history of glaucoma filtering surgery). e. Current or any history of retinal vascular occlusion or proliferative diabetic retinopathy.

• History or current evidence of ocular disease that, in the opinion of the investigator, may confound assessment of visual function.

• The following medications and treatments are prohibited as they can affect progression of retinal pigmentosa. The participant must not have received or planning to receive the following treatments.

• Any use of ocular stem cell or gene therapy.

• Any treatment with ocriplasmin.

• Treatment with Ozurdex (dexamethasone), Iluvien or Yutiq (fluocinolone 404 acetonide) intravitreal implant.

The following medications and treatments are excluded within the specified timeframe:

• Treatment with an ophthalmic oligonucleotide within the last 9 months (last treatment date is less than 9 months prior to Screening Visit date).

• Treatment with any other product within five times the expected half-life of the product (time from last treatment date to Screening Visit date is at least 4115 times the half-life of the given product).

• Treatment that can alter visual acuity between Screening and Baseline (e.g., periorbital injections.)

Related Conditions & MeSH terms

• Atrophy
• Gyrate Atrophy

Locations

Country	Name	City	State
Brazil	INRET Clínica e Centro de Pesquisa	Belo Horizonte	Minas Gerais
Canada	University of Toronto, Hospital for Sick Children	Toronto	Ontario
Finland	Helsinki University Hospital	Helsinki
France	Centre Hospitalier National d'Ophtalmologie des Quinze-Vingts, INSERM-DGOS CIC1423	Paris
Germany	University of Tuebingen, Centre for Ophthalmology	Tübingen
United Kingdom	Moorfields Eye Hospital	London
United States	Johns Hopkins University, Wilmer Eye Institute	Baltimore	Maryland
United States	Harvard Univ., Massachusetts Eye and Ear Infirmary	Boston	Massachusetts
United States	Center for Advanced Retinal and Ocular Therapeutics	Philadelphia	Pennsylvania
United States	University of California San Francisco	San Francisco	California

Sponsors (4)

Lead Sponsor	Collaborator
Jaeb Center for Health Research	Conquering Gyrate Atrophy Foundation, Department of Health and Human Services, Food and Drug Administration (FDA)

Countries where clinical trial is conducted

United States,  Brazil,  Canada,  Finland,  France,  Germany,  United Kingdom, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Other	Patient Reported Outcomes Adults 18 years or older	Measured by Michigan Retinal Degeneration Questionnaire (MRDQ) Visual Symptom and Impact Outcomes Patient Reported Outcome (ViSIO-PRO) Patient-Reported Outcomes Measurement Information System (PROMIS®-29)	Baseline and every two years until study completion (4 years)
Other	Patient Reported Outcomes Adolescents 12-17 years	Measured by Visual Symptom and Impact Outcomes Patient Reported Outcome (ViSIO-PRO) L. V. Prasad-Functional Vision Questionnaire (LVP-FVQ II)	Baseline and every two years until study completion (4 years)
Primary	Structural Outcome: Characterize Change using Quantitative Measures of Progression of the Area of Preserved Retina	Measured by Wide Field Fundus Autofluorescence (FAF)	Baseline and every year until study completion (4 years)
Primary	Structural Outcome: Characterize Change using Quantitative Measures of Progression of the Area of Preserved Retina (Use with FAF for assessments)	Measured by wide field color photography	Baseline and every year until study completion (4 years)
Primary	Metabolic Outcome: Characterize Change in Plasma Ornithine Level	Obtained by fasting plasma amino acids panel and evaluated by a central lab	Baseline and every year until study completion (4 years)
Primary	Metabolic Outcome: Characterize Change in Blood Spot Ornithine Level	Obtained by fasting blood spot test amino acids panel and evaluated by a central lab	Baseline and every 4 months until study completion (4 years)
Secondary	Structural Outcome: Ellipsoid zone (EZ) area	Measured by Spectral Domain Optical Coherence Tomography (SD-OCT)	Baseline and every year until study completion (4 years)
Secondary	Structural Outcome: Area of Post Subcapsular Cataract	Measured by Red Reflex Photography	Baseline and every year until study completion (4 years)
Secondary	Structural Outcome: Foveal Avascular Zone (FAZ) Area and Macular Vessel Density	Measured by OCTA Ancillary Test at Subset of Sites	Baseline and every year until study completion (4 years)
Secondary	Functional Outcome: Visual Field Sensitivity Measured with Quantitative Topographic Analysis (Hill of Vision)	Measured by Octopus 900 Pro	Screening visit and every year until study completion (4 years) with the exception of baseline.
Secondary	Functional Outcome: Early Treatment of Diabetic Retinopathy Study (ETDRS) Best Corrected Visual Acuity (BCVA) letter score	Measured on the Electronic Visual Acuity (EVA) system or ETDRS charts.	Screening visit and every year until study completion (4 years) with the exception of baseline.
Secondary	Functional Outcome: Low Visual Acuity Test - for participants unable to see ETDRS letters	Measured on the Berkeley Rudimentary Vision Test (BRVT)	Screening visit and every year until study completion (4 years) with the exception of baseline.
Secondary	Functional Outcome: ETDRS Best Corrected Low Luminance Visual Acuity Letter Score	Measured on the Electronic Visual Acuity (EVA) system or ETDRS charts.	Screening visit and every year until study completion (4 years) with the exception of baseline.
Secondary	Functional Outcome: Change in Mean Retinal Sensitivity	Measured by Fundus-Guided Microperimetry (MP)	Baseline and every year until study completion (4 years)
Secondary	Functional Outcome: Change in Full-Field Retinal Sensitivity	Measured by full-field stimulus threshold (FST) testing to blue, white, and red stimuli	Baseline and every year until study completion (4 years)
Secondary	Functional Outcome: Change in Retinal Function	Measured by full-field electroretinogram (ERG) amplitudes and timing in response to rod- and cone-specific stimuli.	Baseline and every year until study completion (4 years)
Secondary	Metabolic Outcome: Proline, lysine, glutamine, glutamate, arginine, and related metabolite: creatine and its precursor guanidinoacetate	Obtained by fasting plasma amino acids panel and evaluated by a central lab	Two (2) fasting plasma samples collected on two (2) different days, within ten (10) days of Baseline Visit date and every year until study completion (4 years)
Secondary	Metabolic Outcome: Level of dietary protein control	Obtained from serum albumin sample evaluated by a central lab	Baseline and every year until study completion (4 years)

External Links

•   Foundation Fighting Blindness Public Website