A Study to Evaluate Efficacy, Safety, Tolerability and Exposure After a Repeat-dose of Sepofarsen (QR-110) in LCA10 (ILLUMINATE) (ILLUMINATE)

Double-masked, Randomized, Controlled, Multiple-dose Study to Evaluate Efficacy, Safety, Tolerability and Syst. Exposure of QR-110 in Leber's Congenital Amaurosis (LCA) Due to c.2991+1655A>G Mutation (p.Cys998X) in the CEP290 Gene

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

Study Overview

• Status: Active, not recruiting
• Conditions: Eye Diseases; Neurologic Manifestations; Eye Diseases, Hereditary; Sensation Disorders; Vision Disorders; Blindness; Leber Congenital Amaurosis; Leber Congenital Amaurosis 10; Retinal Disease; Eye Disorders Congenital
• Intervention / Treatment: Drug: sepofarsen; Other: Sham

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.

• Study Type: Interventional
• Enrollment (Actual): 36
• Phase: Phase 2; Phase 3

Contacts and Locations

Study Locations

• Belgium
  • Ghent, Belgium
    • Universitair Ziekenhuis Gent (UZ)
• Brazil
  • MG
    • Belo Horizonte, MG, Brazil, 30150270
      • INRET Clínica/ Santa Casa de Misericórdia de Belo Horizonte
  • SP
    • São Paulo, SP, Brazil, 04023-062
      • Federal University of São Paulo - Hospital São Paulo (UNIFESP-HSP)
• Canada
  • Ontario
    • Toronto, Ontario, Canada, M5G 2L3
      • The Hospital for Sick Children - Sickkids
  • Quebec
    • Montréal, Quebec, Canada, H4A 3J1
      • McGill University Health Centre - Centre for Innovative Medicine
• France
  • Paris, France, 75012
    • Centre de maladies rares CHNO des Quinze Vingt
  • Strasbourg, France, 67091
    • Hospital Civil de Strasbourg
• Germany
  • Gießen, Germany, 35392
    • Justus-Liebig Universität - Department of Ophthalmology
  • Tuebingen, Germany, 72076
    • University of Tuebingen - Inst. for Ophthalmic Research
• Italy
  • Naples, Italy, 80131
    • Eye Clinic University of Campania Luigi Vanvitelli
• Netherlands
  • Amsterdam, Netherlands, 1105 AZ
    • Amsterdam University Medica Center - Locatie AMC
  • Rotterdam, Netherlands, 3011 BH
    • Het Oogziekenhuis Rotterdam
• United Kingdom
  • London, United Kingdom, EC1V 2PD
    • Moorfields Eye Hospital - NHS Foundation Trust
• United States
  • Iowa
    • Iowa City, Iowa, United States, 52242
      • University of Iowa

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 8 years and older (Child, Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

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 Exclusion Criteria Relating to Treatment Initiation Contralateral Eye:

• Presence of any significant ocular or non-ocular disease/disorder (including medication and laboratory test abnormalities).
• History or presence of ocular herpetic diseases.
• Presence of any active ocular infection in either eye.
• Presence of any lens opacities which are clinically significant, would adequately prevent clinical and photographic evaluation of the retina.
• A planned IVT injection or intraocular or periocular surgery/procedure (including refractive surgery) during the course of the study.
• A history of glaucoma or an IOP greater than 24 mmHg that is not controlled with medication.
• History of amblyopia.
• Plans to participate in another study of a drug or device during the study period.
• Pregnant and breastfeeding subjects.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Quadruple

Number of Arms

3

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Group 1: Dose 1 sepofarsen (QR-110); Initial loading dose, followed by maintenance doses at month 3 and every 6 months there after, administered by intravitreal injection (24 months duration of treatment). After 12 months treatment of the contralateral eye may be initiated	Drug: sepofarsen; RNA antisense oligonucleotide for intravitreal injection; Other Names: QR-110
Active Comparator: Group 2: Dose 2 sepofarsen (QR-110); Initial loading dose, followed by maintenance doses at month 3 and every 6 months there after, administered by intravitreal injection (24 months duration of treatment). After 12 months treatment of the contralateral eye may be initiated	Drug: sepofarsen; RNA antisense oligonucleotide for intravitreal injection; Other Names: QR-110
Sham Comparator: Group 3: Sham; Sham procedure (no experimental drug administered), Day 1, month 3 and every six months there after. After 12 months cross over to active study drug may be initiated	Other: Sham; Sham-Procedure (no experimental drug administered)

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Change in BCVA	Change in Best-corrected visual acuity (BCVA) relative to baseline after 12 months of treatment versus sham-procedure	12 months

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Change from baseline in BCVA ≤ -0.3 LogMAR	Change from baseline in BCVA in subjects with BCVA better than 1.7 Logarithm of the minimum angle of resolution (LogMAR) at baseline	12 and 24 months
Clinical meaningful improvement in subjects with BCVA ≤ 1.7 LogMAR	Change from baseline in BCVA by a clinically meaningful improvement in subjects with BCVA equal to or worse than 1.7 LogMAR at baseline.	12 and 24 months
Change in BCVA based on FrACT	Change from baseline in BCVA based on Freiburg visual acuity and contrast test (FrACT)	12 and 24 months
Change in mobility course score	Change from baseline in mobility course score	12 and 24 months
Change in ellipsoid zone (EZ) width/area assessed by SD-OCT	Change from baseline in ellipsoid zone (EZ) width/area assessed by SD-OCT	12 and 24 months
Change in oculomotor instability (OCI)	Change in oculomotor instability from baseline	12 and 24 months
Change in FST light sensitivity	Change from baseline in light sensitivity Full-field light sensitivity threshold (FST) testing (white, red, blue)	12 and 24 months
Change in LLVA	Change from baseline in low luminance visual acuity (LLVA)	12 and 24 months
Change in patient reported visual function via VFQ-25 (adults)	Change in patient reported visual function, as measured by the Visual Function Questionnaire-25 (VFQ-25) score for adult subjects relative to baseline	12 and 24 months
Change in patient reported visual function via CVAQC (pediatrics)	Change in patient reported visual function, as measured by the Cardiff Visual Ability Questionnaire for Children (CVAQC) for pediatric subjects relative to baseline	12 and 24 months
Change in the Patient Global Impressions of Severity (PGI-S)	Change in the patient-reported outcome (PRO) Patient Global Impressions of Severity (PGI-S)	12 and 24 months
Change in the Patient Global Impressions of Change (PGI-C)	Change in the PRO Patient Global Impressions of Change (PGI-C)	12 and 24 months
Change in FAF	Change from baseline as determined by fundus autofluorescence (FAF) imaging	12 and 24 months
Changes in microperimetry	Change from baseline as determined by microperimetry	12 and 24 months
Systemic exposure to QR-110	Systemic exposure to QR-110	12 and 24 months
Ocular and non-ocular AEs	Frequency and severity of ocular and non-ocular AEs	12 and 24 months

Collaborators and Investigators

• Sponsor: ProQR Therapeutics
• Investigators: Study Director: ProQR Medical Monitor, ProQR Therapeutics

Publications and helpful links

Helpful Links

• Sponsor website

Study record dates

Study Major Dates

• Study Start (Actual): April 4, 2019
• Primary Completion (Actual): January 31, 2022
• Study Completion (Anticipated): March 1, 2023

Study Registration Dates

• First Submitted: February 21, 2019
• First Submitted That Met QC Criteria: April 11, 2019
• First Posted (Actual): April 12, 2019

Study Record Updates

• Last Update Posted (Actual): March 17, 2022
• Last Update Submitted That Met QC Criteria: March 2, 2022
• Last Verified: February 1, 2022

More Information

Terms related to this study

• Keywords: Antisense oligonucleotide; CEP290; LCA10; p.Cys998X; c.2991+1655A>G; Leber's Congenital Amaurosis; RNA therapy; QR-110; sepofarsen
• Additional Relevant MeSH Terms: Pathologic Processes; Nervous System Diseases; Congenital Abnormalities; Disease; Retinal Diseases; Eye Diseases; Sensation Disorders; Genetic Diseases, Inborn; Blindness; Vision Disorders; Neurologic Manifestations; Leber Congenital Amaurosis; Eye Diseases, Hereditary; Eye Abnormalities
• Other Study ID Numbers: PQ-110-003; 2018-003501-25 (EudraCT Number)

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: No

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: Yes
• Studies a U.S. FDA-regulated device product: No