Blindness, Eye Diseases, Eye Diseases, Hereditary, Eye Disorders Congenital, Leber Congenital Amaurosis, Leber Congenital Amaurosis 10, Neurologic Manifestations, Retinal Disease, Sensation Disorders, Vision Disorders
Conditions
Keywords
LCA10, CEP290, p.Cys998X, c.2991+1655A>G, Leber's Congenital Amaurosis, Antisense oligonucleotide, RNA therapy, QR-110, sepofarsen
Brief summary
The purpose of this double-masked, randomized, controlled, multiple-dose study is to evaluate the efficacy, safety, tolerability and systemic exposure of sepofarsen (QR-110) administered via intravitreal injection in subjects with Leber's Congenital Amaurosis (LCA) due to the CEP290 p.Cys998X mutation after 24 months of treatment
Detailed description
The purpose of this double-masked, randomized, controlled, multiple-dose study is to evaluate the efficacy, safety, tolerability and systemic exposure of sepofarsen (QR-110) administered via intravitreal injection in subjects with Leber's Congenital Amaurosis (LCA) due to the CEP290 p.Cys998X mutation after 24 months of treatment. At study start subjects will be randomized to one of 3 treatment groups with either active study drug or sham treatment. Sepofarsen (QR-110) will be administered via intravitreal (IVT) injection into the subject's treatment eye (the subject's worse eye). Subjects in the sham-procedure group will undergo a procedure that will closely mimic the active injection. After each dosing subjects will be assessed for safety and tolerability at follow up visits. After the first eye has been treated for at least 12 months, treatment of the contralateral eye and cross-over of subjects assigned to sham procedure may be initiated in eligible eyes (in a masked manner) based on assessment of benefit/risk (including review of data from all clinical trials), and with concurrence of the Medical Monitor.
Interventions
DRUGsepofarsen
RNA antisense oligonucleotide for intravitreal injection
OTHERSham
Sham-Procedure (no experimental drug administered)
Sponsors
ProQR Therapeutics
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
QUADRUPLE (Subject, Caregiver, Investigator, Outcomes Assessor)
Eligibility
Sex/Gender
ALL
Age
8 Years to No maximum
Healthy volunteers
No
Inclusion criteria
Main Inclusion Criteria Relating to Study Initiation: * Male or female, ≥ 8 years of age at Screening with a clinical diagnosis of LCA10 and a molecular diagnosis of homozygosity or compound heterozygosity for the c.2991+1655A\>G mutation, based on genotyping analysis at Screening. A historic genotyping report from a certified laboratory is acceptable with Sponsor approval. * BCVA better or equal to Logarithm of the Minimum Angle of Resolution (LogMAR) +3.0 (Hand Motion), and equal to or worse than LogMAR +0.4 in the treatment eye. * Detectable outer nuclear layer (ONL) in the area of the macula. * An electroretinogram (ERG) result consistent with LCA. A historic ERG result may be acceptable for eligibility. Main
Exclusion criteria
Relating to Study Initiation: * Presence of any significant ocular or non-ocular disease/disorder (including medication and laboratory test abnormalities). * Prior receipt of intraocular surgery, periocular surgery, or IVT injection within 1 month prior to study start or planned intraocular surgery or procedure during the course of the study.Subjects who received an intraocular or periocular surgery between 1 to 3 months prior Screening, may only be considered for inclusion if there are no clinically significant complications of surgery present, and following approval by the Medical Monitor. * History or presence of ocular herpetic diseases. * Presence of any active ocular infection in the either eye. * Presence of lens opacities/cataracts in the treatment eye. * Current treatment or treatment within the past 12 months with therapies known to influence the immune system. * History of glaucoma, or an IOP greater than 24 mmHg, at is not controlled with medication. * History of amblyopia * Use of any investigational drug or device within 90 days or 5 half-lives of Day 1, whichever is longer, or plans to participate in another study of a drug or device during the PQ-110-003 study period. * Any prior receipt of genetic or stem-cell therapy. * Known hypersensitivity to antisense oligonucleotides or any constituents of the injection. * Pregnant and breastfeeding subjects. Main Inclusion Criteria Relating to Treatment Initiation Contralateral Eye: * BCVA equal to or better than LP (logMAR +4), using the best BCVA reading at Month 12 and based on ETDRS or BRVT. * Detectable outer nuclear layer (ONL) in the area of the macula. * Clear ocular media and adequate pupillary dilation to permit good quality retinal imaging. Main
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Change in BCVA | 12 months | Change in Best-corrected visual acuity (BCVA) relative to baseline after 12 months of treatment versus sham-procedure |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Clinical meaningful improvement in subjects with BCVA ≤ 1.7 LogMAR | 12 and 24 months | Change from baseline in BCVA by a clinically meaningful improvement in subjects with BCVA equal to or worse than 1.7 LogMAR at baseline. |
| Change in BCVA based on FrACT | 12 and 24 months | Change from baseline in BCVA based on Freiburg visual acuity and contrast test (FrACT) |
| Change in mobility course score | 12 and 24 months | Change from baseline in mobility course score |
| Change in ellipsoid zone (EZ) width/area assessed by SD-OCT | 12 and 24 months | Change from baseline in ellipsoid zone (EZ) width/area assessed by SD-OCT |
| Change in oculomotor instability (OCI) | 12 and 24 months | Change in oculomotor instability from baseline |
| Change in FST light sensitivity | 12 and 24 months | Change from baseline in light sensitivity Full-field light sensitivity threshold (FST) testing (white, red, blue) |
| Change in LLVA | 12 and 24 months | Change from baseline in low luminance visual acuity (LLVA) |
| Change from baseline in BCVA ≤ -0.3 LogMAR | 12 and 24 months | Change from baseline in BCVA in subjects with BCVA better than 1.7 Logarithm of the minimum angle of resolution (LogMAR) at baseline |
| Change in patient reported visual function via CVAQC (pediatrics) | 12 and 24 months | Change in patient reported visual function, as measured by the Cardiff Visual Ability Questionnaire for Children (CVAQC) for pediatric subjects relative to baseline |
| Change in the Patient Global Impressions of Severity (PGI-S) | 12 and 24 months | Change in the patient-reported outcome (PRO) Patient Global Impressions of Severity (PGI-S) |
| Change in the Patient Global Impressions of Change (PGI-C) | 12 and 24 months | Change in the PRO Patient Global Impressions of Change (PGI-C) |
| Change in FAF | 12 and 24 months | Change from baseline as determined by fundus autofluorescence (FAF) imaging |
| Changes in microperimetry | 12 and 24 months | Change from baseline as determined by microperimetry |
| Systemic exposure to QR-110 | 12 and 24 months | Systemic exposure to QR-110 |
| Ocular and non-ocular AEs | 12 and 24 months | Frequency and severity of ocular and non-ocular AEs |
| Change in patient reported visual function via VFQ-25 (adults) | 12 and 24 months | Change in patient reported visual function, as measured by the Visual Function Questionnaire-25 (VFQ-25) score for adult subjects relative to baseline |
Countries
Belgium, Brazil, Canada, France, Germany, Italy, Netherlands, United Kingdom, United States
Outcome results
None listed