Clinical trial NCT05573984: Natural History of PRPF31 Mutation-Associated Retinal Dystrophy
Official title: A Natural History and Outcome Measure Discovery Study of PRPF31 Mutation-Associated Retinal Dystrophy
Study type: OBSERVATIONAL
Overall status: ACTIVE_NOT_RECRUITING
Conditions: Retinitis Pigmentosa
Eye Diseases, Hereditary
Retinal Dystrophies
Retinal Dystrophy Rod
Retinal Dystrophy Rod Progressive
Keywords: Retinitis Pigmentosa
Retinitis Pigmentosa Type 11
RP11
PRPF31
Retinal Dystrophy
PRPF31 Mutation-Associated Retinal Dystrophy
Lead sponsor: PYC Therapeutics
Sponsor class: INDUSTRY
First posted: 2022-10-10
Enrollment: 50
Sex: ALL
Minimum age (years): 10
Standard ages: CHILD
ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Observational model: COHORT
Time perspective: PROSPECTIVE
Sampling method: NON_PROBABILITY_SAMPLE
Study population: The study population will consist of approximately 50 participants (100 eyes) with a genetically confirmed PRPF31 mutation.

Brief summary: The purpose of this study is to characterize the natural history through temporal systemic evaluation of subjects identified with PRPF31 mutation-associated retinal dystrophy, also called retinitis pigmentosa type 11, or RP11.

Assessments will be completed to measure and evaluate structural and functional visual changes including those impacting patient quality of life associated with this inherited retinal condition and observing how these changes evolve over time.

Detailed description: This is a multi-center, longitudinal, prospective observational natural history study of participants with a molecularly confirmed mutation in PRPF31. Approximately 50 participants (100 eyes) at approximately 5 sites will be enrolled into a uniform protocol for follow-up and evaluations. 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, electrophysiological testing, functional mobility evaluations, and questionnaires. Assessments will be conducted in a standardized protocol every 16 weeks ± 4 weeks for the first year and then every 24 weeks ± 4 weeks for up to approximately 4 years after each participant's baseline visit (Visit 2).

Eligibility criteria: Inclusion Criteria:

Participants must meet all of the following in order to be enrolled into the study:

1. Male or female, ≥ 10 years of age at baseline (Visit 2).
2. Have a clinical and molecular diagnosis of PRPF31 mutation-associated retinal dystrophy.
3. If ≥ 18 years of age, understand the language of the informed consent and are willing and able to provide written informed consent prior to any study procedures. If \< 18 years of age, are willing to assent to study participation in writing and have a legally authorized representative provide written informed consent on your behalf.
4. Are willing to comply with the instructions and attend all scheduled study visits.

Exclusion Criteria:

Participants or, in the case of ocular-specific criteria, individual eyes with any of the following will not be allowed to participate in this study:

1. Have any uncontrolled systemic disease that, in the opinion of the Investigator, would preclude participation in the study (e.g., infection, uncontrolled elevated blood pressure, cardiovascular disease, or glycemic control issues) or put the participant at risk due to study procedures.
2. Have mutations in genes that cause autosomal dominant retinitis pigmentosa (adRP), X-linked retinitis pigmentosa (XLRP), or presence of biallelic mutations in autosomal recessive RP/retinal dystrophy genes other than PRPF31 mutations.
3. Have used anti-vascular endothelial growth factor (VEGF) agents or corticosteroid injections or implants.
4. Have had Ozurdex® implants placed within 3 months or Retisert® or Iluvien® implants placed within 3 years prior to Visit 2.
5. Within 3 months prior to 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 \[2 or more\], etc.) or any other ocular surgery.
6. Have ocular media opacity or poor pupillary dilation that prohibits quality ophthalmic evaluation or photography.
7. 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 drug or device during the study period.
8. Have received any prior cell or gene therapy for a retinal condition.
9. Have a history of illicit drug use or alcohol dependency.

Primary outcomes:
measure: Change from Baseline in Best Corrected Visual Acuity (BCVA)
timeFrame: Baseline through Year 4
measure: Change in Best Corrected Low Luminance Visual Acuity (LLVA)
timeFrame: Baseline through Year 4
measure: Change from Baseline in Retinal Thickness
timeFrame: Baseline through Year 4
measure: Change from Baseline in Ellipsoid Zone (EZ) Area
timeFrame: Baseline through Year 4
measure: Change from Baseline in Ellipsoid Zone (EZ) Volume
timeFrame: Baseline through Year 4
measure: Change from Baseline in Visual Field Sensitivity
timeFrame: Baseline through Year 4
measure: Change from Baseline in Mean Macular Sensitivity
timeFrame: Baseline through Year 4
measure: Change from Baseline in Fixation Stability
timeFrame: Baseline through Year 4
measure: Change from Baseline in Full Field Retinal Sensitivity
timeFrame: Baseline through Year 4
measure: Change from Baseline in Electrical response
timeFrame: Baseline through Year 4
measure: Characterization of Changes of the Retina with Fundus Photography
timeFrame: Baseline through Year 4
measure: Change from Baseline in Area of Fundus Autofluorescence (FAF)
timeFrame: Baseline through Year 4
measure: Change from Baseline in Functional Vision
timeFrame: 3 times prior to Month 4
measure: Change in Patient Reported Outcome Measures using Michigan Retinal Degeneration Questionnaire (MRDQ)
timeFrame: Baseline through Year 4
measure: Change in Patient Reported Outcome Measures using Patient Global Impression of Severity (PGI-S) scale
timeFrame: Baseline through Year 4
measure: Change in Patient Reported Outcome Measures using Patient Global Impression of Change (PGI-C) scale
timeFrame: Baseline through Year 4
measure: Genomic Analysis for Study Eligibility
timeFrame: Screening
measure: Ocular Adverse Events (AEs)
timeFrame: Screening through Year 4
Secondary outcomes:
Other outcomes:
Locations:
city: San Francisco
country: United States
facility: University of California San Francisco
state: California
city: Jacksonville
country: United States
facility: University of Florida Health
state: Florida
city: Ann Arbor
country: United States
facility: University of Michigan Kellogg Eye Center
state: Michigan
city: Portland
country: United States
facility: Oregon Health and Science University - Casey Eye Institute
state: Oregon
city: Dallas
country: United States
facility: Retina Foundation of the Southwest
state: Texas
city: Nedlands
country: Australia
facility: Lions Eye Institute
state: Western Australia
city: East Melbourne
country: Australia
facility: Centre For Eye Research Australia (CERA) - Retinal Gene Therapy Unit
Study officials:
affiliation: PYC Therapeutics
name: Sreenivasu Mudumba, PhD
role: STUDY_CHAIR
References:
citation: Hartong DT, Berson EL, Dryja TP. Retinitis pigmentosa. Lancet. 2006 Nov 18;368(9549):1795-809. doi: 10.1016/S0140-6736(06)69740-7.
citation: Ferrari S, Di Iorio E, Barbaro V, Ponzin D, Sorrentino FS, Parmeggiani F. Retinitis pigmentosa: genes and disease mechanisms. Curr Genomics. 2011 Jun;12(4):238-49. doi: 10.2174/138920211795860107.
citation: Rio Frio T, Wade NM, Ransijn A, Berson EL, Beckmann JS, Rivolta C. Premature termination codons in PRPF31 cause retinitis pigmentosa via haploinsufficiency due to nonsense-mediated mRNA decay. J Clin Invest. 2008 Apr;118(4):1519-31. doi: 10.1172/JCI34211.
citation: Sullivan LS, Bowne SJ, Seaman CR, Blanton SH, Lewis RA, Heckenlively JR, Birch DG, Hughbanks-Wheaton D, Daiger SP. Genomic rearrangements of the PRPF31 gene account for 2.5% of autosomal dominant retinitis pigmentosa. Invest Ophthalmol Vis Sci. 2006 Oct;47(10):4579-88. doi: 10.1167/iovs.06-0440.
citation: Venturini G, Rose AM, Shah AZ, Bhattacharya SS, Rivolta C. CNOT3 is a modifier of PRPF31 mutations in retinitis pigmentosa with incomplete penetrance. PLoS Genet. 2012;8(11):e1003040. doi: 10.1371/journal.pgen.1003040. Epub 2012 Nov 8.
citation: Vithana EN, Abu-Safieh L, Allen MJ, Carey A, Papaioannou M, Chakarova C, Al-Maghtheh M, Ebenezer ND, Willis C, Moore AT, Bird AC, Hunt DM, Bhattacharya SS. A human homolog of yeast pre-mRNA splicing gene, PRP31, underlies autosomal dominant retinitis pigmentosa on chromosome 19q13.4 (RP11). Mol Cell. 2001 Aug;8(2):375-81. doi: 10.1016/s1097-2765(01)00305-7.
citation: Wheway G, Douglas A, Baralle D, Guillot E. Mutation spectrum of PRPF31, genotype-phenotype correlation in retinitis pigmentosa, and opportunities for therapy. Exp Eye Res. 2020 Mar;192:107950. doi: 10.1016/j.exer.2020.107950. Epub 2020 Jan 31.
citation: Food and Drug Administration. Rare Diseases: Natural History Studies for Drug Development. Draft Guidance for Industry 2019. https://www.fda.gov/media/122425/download