Natural History of PRPF31 Mutation-Associated Retinal Dystrophy

Retinitis Pigmentosa Clinical Trial

Official title:

A Natural History and Outcome Measure Discovery Study of PRPF31 Mutation-Associated Retinal Dystrophy

Clinical Trial Details — Status: Recruiting

Administrative data

• NCT number: NCT05573984
• Other study ID #: VP001-CL001
• Status: Recruiting
• Start date: July 7, 2022
• Est. completion date: April 30, 2027

Study information

• Verified date: March 2023
• Source: PYC Therapeutics
• Contact: Lexitas Pharma Services, Inc.
• Phone: 1-510-423-2680
• Email: quokka[@]lexitas.com
• Is FDA regulated: No
• Study type: Observational

Clinical Trial 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.

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).

Recruitment information / eligibility

• Status: Recruiting
• Enrollment: 50
• Est. completion date: April 30, 2027
• Est. primary completion date: December 31, 2026
• Accepts healthy volunteers: No
• Gender: All
• Age group: 10 Years and older

Eligibility

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.

Related Conditions & MeSH terms

• Eye Diseases
• Eye Diseases, Hereditary
• Genetic Diseases, Inborn
• Retinal Dystrophies
• Retinitis
• Retinitis Pigmentosa

Locations

Country	Name	City	State
Australia	Centre For Eye Research Australia (CERA) - Retinal Gene Therapy Unit	East Melbourne
Australia	Lions Eye Institute	Nedlands	Western Australia
United States	University of Michigan Kellogg Eye Center	Ann Arbor	Michigan
United States	Retina Foundation of the Southwest	Dallas	Texas
United States	University of Florida Health	Jacksonville	Florida
United States	Oregon Health and Science University - Casey Eye Institute	Portland	Oregon
United States	University of California San Francisco	San Francisco	California

Sponsors (1)

Lead Sponsor	Collaborator
PYC Therapeutics

Countries where clinical trial is conducted

United States,  Australia, 

References & Publications (8)

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. — View 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

Hartong DT, Berson EL, Dryja TP. Retinitis pigmentosa. Lancet. 2006 Nov 18;368(9549):1795-809. doi: 10.1016/S0140-6736(06)69740-7. — View 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. — View 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. — View 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. — View 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. — View 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. — View Citation

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	Change from Baseline in Best Corrected Visual Acuity (BCVA)	BCVA letter score utilizing ETDRS (Early Treatment Diabetic Retinopathy Study) or BRVT (Berkeley Rudimentary Vision Test) for patients not able to see letters	Baseline through Year 4
Primary	Change in Best Corrected Low Luminance Visual Acuity (LLVA)	Best corrected LLVA letter score measured using the ETDRS charts and a special light filter lens	Baseline through Year 4
Primary	Change from Baseline in Retinal Thickness	Retinal thickness is measured using spectral domain optical coherence tomography (SD-OCT), as measured by the central reading center	Baseline through Year 4
Primary	Change from Baseline in 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 4
Primary	Change from Baseline in 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 4
Primary	Change from Baseline in Visual Field Sensitivity	Visual field sensitivity measured by static perimetry with topographic analysis-Hill of Vision conducted by the central reading center	Baseline through Year 4
Primary	Change from Baseline in Mean Macular Sensitivity	Mean macular sensitivity measured on guided microperimetry	Baseline through Year 4
Primary	Change from Baseline in Fixation Stability	Fixation stability as measured by Macular Integrity Assessment (MAIA) microperimeter	Baseline through Year 4
Primary	Change from Baseline in Full Field Retinal Sensitivity	Dark-adapted visual sensitivity via full-field stimulus threshold (FST) measurement	Baseline through Year 4
Primary	Change from Baseline in Electrical response	Electrical response measured using Full-field electroretinogram (ERG) with specific stimuli	Baseline through Year 4
Primary	Characterization of Changes of the Retina with Fundus Photography	Abnormalities captured by fundus photography	Baseline through Year 4
Primary	Change from Baseline in Area of Fundus Autofluorescence (FAF)	Area of hypo-autofluorescence captured by fundus autofluorescence (FAF)	Baseline through Year 4
Primary	Change from Baseline in Functional Vision	Functional vision is measured with a functional mobility course (Ora-VNC™) score	3 times prior to Month 4
Primary	Change in Patient Reported Outcome Measures using Michigan Retinal Degeneration Questionnaire (MRDQ)	Responses on the MRDQ, a validated patient reported outcomes measure designed in accordance with U.S. FDA guidelines, specifically for conditions of inherited retinal degeneration (IRDs)	Baseline through Year 4
Primary	Change in Patient Reported Outcome Measures using Patient Global Impression of Severity (PGI-S) scale	Responses on the PGI-S to assess severity of the patient's condition	Baseline through Year 4
Primary	Change in Patient Reported Outcome Measures using Patient Global Impression of Change (PGI-C) scale	Responses on the PGI-C to assess change of the patient's condition	Baseline through Year 4
Primary	Genomic Analysis for Study Eligibility	Whole exome genomic analysis	Screening
Primary	Ocular Adverse Events (AEs)	Frequency of ocular adverse events (AEs)	Screening through Year 4