An Open-label, Dose Escalation and Double-masked, Randomized, Controlled Trial Evaluating Safety and Tolerability of Sepofarsen in Children (<8 Years of Age) With LCA10 Caused by Mutations in the CEP290 Gene.

Study Overview
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Brief Summary
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PQ-110-005 (BRIGHTEN) is an open-label, dose escalation and double-masked, randomized, controlled study evaluating safety and tolerability of sepofarsen administered via intravitreal (IVT) injection in pediatric subjects (<8 years of age) with LCA10 due to the c.2991+1655A>G mutation over 24 months of treatment.

Detailed Description
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This is an open-label, dose escalation and double-masked, randomized, controlled study evaluating safety and tolerability of sepofarsen administered via intravitreal (IVT) injection in pediatric subjects (<8 years of age) with LCA10 due to the c.2991+1655A>G mutation. The study consists of two parts: an open-label dose escalation part, followed by a double-masked randomized part. In the open label part; subjects will be assigned to one of 3 planned dose groups using a staggered dose escalation design. After at least 1 patient is dosed in each group; the Data Monitoring Committee (DMC) will review at least 4 weeks of safety data post dosing; and may recommend initiation of the next dose group. The DMC may recommend initiation of the double-masked randomized part of the study after completion of the last dose group in the dose escalation part of the study. In the double-masked, randomized, controlled part of the study; subjects will be randomized to one of 2 planned dose groups . Subjects will receive a unilateral IVT injection of sepofarsen on Day 1. Thereafter a 6-monthly dosing schedule is planned. After each dosing subjects will be assessed for safety and tolerability at follow up visits.

Official Title
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An Open-Label, Dose Escalation and Double-Masked, Randomized, Controlled Study to Evaluate the Safety and Tolerability of Sepofarsen in Pediatric Subjects <8 Years of Age With Leber Congenital Amaurosis Type 10 (LCA10) Due to the c.2991 +1655A>G (p.Cys998X) Mutation.

Conditions
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Sensation Disorders, Leber Congenital Amaurosis 10, Blindness, Leber Congenital Amaurosis, Vision Disorders, Neurologic Manifestations, Eye Diseases, Eye Disorders Congenital, Retinal Disease, Retinal Degeneration, Retinal Dystrophies

Intervention / Treatment
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* Drug: sepofarsen


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Male or female child, <8 years of age at Screening with a clinical diagnosis of LCA and a molecular diagnosis of homozygosity or compound heterozygosity for the CEP290 p.Cys998X mutation, based on genotyping analysis at Screening. A historic genotyping report from a certified laboratory are acceptable with Sponsor approval. BCVA equal to or better than Logarithm of the Minimum Angle of Resolution (logMAR) + 4.0 (Light Perception), and equal to or worse than logMAR + 0.4 in the treatment eye. Detectable outer nuclear layer (ONL) in the area of the macula. Exclusion Criteria: Presence of any significant ocular or non-ocular disease/disorder which may put the subject at risk because of participation in the trial' may influence the results of the trial, or the subject's ability to participate in the trial. Receipt within 1 month 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 trial. Current treatment or treatment within the past 12 months with therapies known to influence the immune system (including but not limited to cytostatics, interferons, TNF-binding proteins, drugs acting on immunophilins, or antibodies with known impact on the immune system). Current treatment or treatment within the past 3 months or planned treatment with drugs known to be toxic to the lens, retina, or the optic nerve. Use of any investigational drug or device within 3 months or 5 half-lives of Day 1, whichever is longer, or plans to participate in another study of a drug or device during the trial period. Any prior receipt of genetic or stem-cell therapy for ocular or non-ocular disease.

Ages Eligible for Study
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Minimum Age: 0 Years
Maximum Age: 7 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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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Sequential Assignment
Interventional Model Description: The study consists of two parts: an open-label dose escalation part, followed by a double-masked randomized part.
Masking: Triple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Group 1 - open label<br> | Drug: sepofarsen<br>* RNA antisense oligonucleotide for intravitreal injection<br>* Other names: QR-110;|
| Experimental: Group 2 - open label<br> | Drug: sepofarsen<br>* RNA antisense oligonucleotide for intravitreal injection<br>* Other names: QR-110;|
| Experimental: Group 3: open label<br> | Drug: sepofarsen<br>* RNA antisense oligonucleotide for intravitreal injection<br>* Other names: QR-110;|
| Experimental: Group 4: double-masked, randomized to one of 2 dose cohorts<br> | Drug: sepofarsen<br>* RNA antisense oligonucleotide for intravitreal injection<br>* Other names: QR-110;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Incidence and severity of ocular adverse events (AEs) | Incidence and severity of ocular adverse events (AEs) | 24 months | 
| Incidence and severity of non-ocular adverse events (AEs) | Incidence and severity of non-ocular adverse events (AEs) | 24 months | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change from baseline to Month 12 in Best-corrected visual acuity (BCVA) | Mean change in BCVA relative to baseline after 12 months of treatment | 12 months | 
| Change from baseline to Month 12 in retinal sensitivity measured by Full-field stimulus testing (FST) | Mean change in retinal sensitivity measured by FST relative to baseline after 12 months of treatment | 12 months | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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LCA10, CEP290, p.Cys998X, c.2991+1655A>G, Leber Congenital Amaurosis, Antisense oligonucleotide, RNA therapy, QR-110, sepofarsen, pediatric, children