An Open-Label Extension Study to Evaluate Safety & Tolerability of QR-421a in Subjects With Retinitis Pigmentosa

Study Overview
=================
Brief Summary
-----------------
PQ-421a-002 (Helia) is an open-label, extension study to evaluate the safety, tolerability and efficacy of QR 421a (ultevursen) administered via intravitreal (IVT) injection in one or both eyes, in subjects ≥ 12 years of age with RP due to mutations in exon 13 of the USH2A gene, for an anticipated period of 24 months, or until provision of continued treatment by other means is available, provided the subject's benefit-risk determination remains positive.

Detailed Description
-----------------
PQ-421a-002 is an open-label, extension study to evaluate the safety, tolerability and efficacy of QR-421a (ultevursen) in subjects with RP due to mutations in exon 13 of the USH2A gene. Subjects that have participated in QR-421a clinical studies, i.e. PQ-421a-001 (Stellar), PQ-421a-003 (Sirius) and PQ-421a-004 (Celeste), will be given the opportunity to enroll into this extension study for continued dosing, provided the subject's benefit-risk assessment is positive, or for additional follow up. The Investigator, in consultation and agreement with the Medical Monitor, will decide on subject's enrollment upon assessment of subject's benefit-risk. QR-421a will be first administered to the Contralateral Eye (CE or fellow eye), as defined in the preceding study, and will be repeated every 6 months. Administration of QR-421a to the Treatment Eye (TE or study eye), as defined in the preceding study, can commence 3 months (9 months for subjects from study PQ-421a-001) after the treatment of the contralateral eye has been initiated and will be repeated every 6 months as well. The Investigator, in consultation and agreement with the Medical Monitor, will decide on dosing of both eyes. Continued subject treatment in this study will be pursued provided that the benefit-risk balance is positive for the individual subject, as discussed and agreed upon with the Medical Monitor. The same safety monitoring protocol and efficacy assessments will apply to both eyes. Baseline functional and structural measurements for the treatment eye will be those from the preceding QR-421a study. Baseline functional and structural measurements for the contralateral eye will be those from the Screening /Day 1 visit of the current study.

Official Title
-----------------
An Open-Label Extension Study to Evaluate the Safety and Tolerability of QR 421a in Subjects With Retinitis Pigmentosa (RP) Due to Mutations in Exon 13 of the USH2A Gene (Helia)

Conditions
-----------------
Retinitis Pigmentosa, Usher Syndrome Type 2

Intervention / Treatment
-----------------
* Drug: RNA antisense oligonucleotide for intravitreal injection


Participation Criteria
=================
Eligibility Criteria
-----------------
Principal Inclusion Criteria: Subjects who have participated in a preceding QR-421a study and who may derive benefit from continued treatment with QR 421a, and/or continued follow up, as assessed by the Investigator, in consultation and agreement with the Medical Monitor An adult (≥ 18 years) willing and able to provide informed consent for participation prior to performing any study related procedures, and suitable verbal, auditory, written and/or tactile sign language communication as to allow informed consent to be obtained, in the opinion of the Investigator. OR A minor (12 to < 18 years) able to provide age-appropriate assent for study participation, and with a parent or legal guardian willing and able to provide written permission for the subject's participation prior to performing any study related procedures. Principal Exclusion Criteria: Presence of any significant ocular or non-ocular disease/disorder (or medication and/or laboratory test abnormalities) which, in the opinion of the Investigator and with concurrence of the Medical Monitor, may either put the subject at risk because of participation in the study, may influence the results of the study, or the subject's ability to participate in the study. This includes but is not limited to a subject who has uncontrolled cystoid macular edema (CME) in the treatment eye. CME is permissible if stable for 3 months (with or without treatment). Past CME is permissible if resolved for more than 1 month. Receipt within 3 months prior to Screening of any intraocular or periocular surgery (including refractive surgery), or an IVT injection or planned intraocular surgery or procedure during the course of the study. Safety issue during preceding QR-421a study that may compromise subject safety when continued dosing, as determined by the Investigator, and in consultation with the Medical Monitor.

Ages Eligible for Study
-----------------
Minimum Age: 12 Years

Sexes Eligible for Study
-----------------
All

Accepts Healthy Volunteers
-----------------
No

Study Plan
=================
How is the study designed?
-----------------

Design Details

Primary Purpose: Treatment
Intervention Model: Single Group Assignment
Interventional Model Description: Eligible participants from previous QR-421a study can be enrolled into this extension study to receive continuous dosing of QR-421a for 24 months or until treatment becomes available (whichever is longer). Subject who receive follow up only, will be in this study for 12 months.
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Other: QR421a RNA antisense oligonucleotide for intravitreal injection<br>There is only one treatment arm in the PQ-421a-002 study; All participants that are eligible to be dosed will receive QR-421a in an open label fashion. | Drug: RNA antisense oligonucleotide for intravitreal injection<br>* QR-421a will be first administered to the fellow eye (as defined in the preceding study), and will be repeated every 6 months. Treatment of the study eye (as defined in the preceding study) can commence 3 months (9 months for subjects from study PQ-421a-001) after the treatment of the fellow eye has been initiated and will be repeated every 6 months as well. Continued subject treatment in this study will be pursued provided that the benefit-risk balance is positive for the individual subject.<br>|

What is the study measuring?
-----------------
Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Ocular Adverse Events (AEs) | Number of subjects with ocular treatment emergent adverse events (TEAEs) in the contralateral eye (CE) is presented. Frequency of individual TEAEs by system organ class and preferred term is presented in the safety section and clinical trial summary report. Time frame of reporting is the maximum followup period from first subject first visit to last end of study visit. | 1 year, 1 month | 
| Non-ocular Adverse Events (AEs) | Number of subjects with non-ocular treatment emergent adverse events (TEAEs) is presented. Frequency of individual TEAEs by system organ class and preferred term is presented in the safety section and clinical trial summary report. Time frame of reporting is the maximum follow up period from first subject first visit to last end of study visit. | 1 year, 1 month | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Best Corrected Visual Acuity (BCVA) | Change from baseline | 24 months | 
| Low Luminance Visual Acuity (LLVA) | Change from baseline | 24 months | 
| Ellipsoid Zone (EZ) Area/Width by Spectral Domain Optical Coherence Tomography (SD-OCT) | Change from baseline | 24 months | 
| Static Perimetry | Change from baseline | 24 months | 
| Microperimetry | Change from baseline | 24 months | 
| Exposure of QR-421a in Serum | Exposure of QR-421a in serum | 12 months | 

 Terms related to the study
=================
Keywords Provided by Centre Hospitalier Valida
-----------------
QR-421a, Retinitis Pigmentosa, Usher Syndrome, Exon 13 Mutation, USH2A gene, Night Blindness, Usherin protein, Deaf Blind, Retinal Disease, Eye Disease, Vision Disorders, Congenital, Familial and Genetic Disorders, PQ-421a-002