Multi-dose Study for Efficacy, Safety, Tolerability, Exposure of QR-110 in LCA10 (ILLUMINATE)

• ClinicalTrials.gov Identifier: NCT03913143
• Recruitment Status: Recruiting
• First Posted: April 12, 2019
• Last Update Posted: September 25, 2019
• Sponsor: ProQR Therapeutics
• Information provided by (Responsible Party): ProQR Therapeutics

Study Description

Brief Summary:

The purpose of this double-masked, randomized, controlled, multiple-dose study is to evaluate the efficacy, safety, tolerability and systemic exposure of 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

Condition or disease	Intervention/treatment	Phase
Leber Congenital Amaurosis 10; Blindness; Leber Congenital Amaurosis; Vision Disorders; Sensation Disorders; Neurologic Manifestations; Eye Diseases; Eye Diseases, Hereditary; Eye Disorders Congenital; Retinal Disease	Drug: QR-110; Other: Sham	Phase 2; Phase 3

Detailed Description:

The purpose of this double-masked, randomized, controlled, multiple-dose study is to evaluate the efficacy, safety, tolerability and systemic exposure of 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.

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 may be initiated based on assessment of benefit/risk (including review of data from all clinical trials), and with concurrence of the Medical Monitor.

Study Design

• Study Type: Interventional (Clinical Trial)
• Estimated Enrollment: 30 participants
• Allocation: Randomized
• Intervention Model: Parallel Assignment
• Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
• Primary Purpose: Treatment
• Official Title: 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
• Actual Study Start Date: April 4, 2019
• Estimated Primary Completion Date: December 2020
• Estimated Study Completion Date: December 2021

Arms and Interventions

Arm	Intervention/treatment
Experimental: Group 1: Dose 1 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: QR-110; RNA antisense oligonucleotide for intravitreal injection
Active Comparator: Group 2: Dose 2 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: QR-110; RNA antisense oligonucleotide for intravitreal injection
Sham Comparator: Group 3: Sham; Sham Intravitreal Injection (no experimental drug administered), at month 0, month 3 and every six months there after. After 12 months cross over to active study drug may be initiated	Other: Sham; Shame intravitreal injection (no experimental drug administered)

Outcome Measures

Primary Outcome Measures :

1. Mean change in BCVA after 12 months [ Time Frame: 12 months ]
   Mean change in Best-corrected visual acuity (BCVA) relative to baseline after 12 months of treatment versus sham

Secondary Outcome Measures :

1. Percentage of subjects ≥-0.3 LogMAR change in BCVA vs sham [ Time Frame: 12 and 24 months ]
   Percentage of subjects with baseline BCVA ≥ 1.7 Logarithm of the minimum angle of resolution (LogMAR) with ≥ 0.3 LogMAR change in BCVA in treated versus sham
2. Percentage of subjects <1.7 Logmar with clinical meaningful improvement in mobility course score [ Time Frame: 12 and 24 months ]
   Percentage of subjects with baseline BCVA < 1.7 LogMAR with a clinically meaningful improvement in mobility course score in treated versus sham
3. Change in BCVA between two QR-110 dose groups [ Time Frame: 12 and 24 months ]
   Change in BCVA relative to baseline in the Dose 1 QR-110 dose group versus the dose 2 QR-110 dose group
4. Change in BCVA to baseline in pooled QR-110 subjects [ Time Frame: 12 and 24 months ]
   Change in BCVA in both QR-110 dose groups pooled relative to baseline
5. Change in mobility course score [ Time Frame: 12 and 24 months ]
   Change in mobility course score relative to baseline in the treatment eye versus sham
6. Change in mobility course score binocular vision [ Time Frame: 12 and 24 months ]
   Change in mobility course score binocular vision versus baseline versus sham
7. Rate of change in oculomotor instability from baseline [ Time Frame: 12 and 24 months ]
   Rate of change in oculomotor instability from baseline
8. Full-field light sensitivity threshold (FST) testing for white light from baseline [ Time Frame: 12 and 24 months ]
   Full-field light sensitivity threshold (FST) testing for white light from baseline
9. Full-field light sensitivity threshold (FST) testing for red light from baseline [ Time Frame: 12 and 24 months ]
   Full-field light sensitivity threshold (FST) testing for red light from baseline
10. Full-field light sensitivity threshold (FST) testing for blue light from baseline [ Time Frame: 12 and 24 months ]
    Full-field light sensitivity threshold (FST) testing for blue light from baseline
11. Change in photoreceptor inner/outer segment by OCT [ Time Frame: 12 and 24 months ]
    Change in photoreceptor inner segment/outer segment (inner segment [IS]/outer segment [OS]; ellipsoid zone [EZ] line) assessed by OCT relative to baseline
12. Change in patient reported visual function via VFQ-25 (adults) [ Time Frame: 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
13. Change in patient reported visual function via CVAQC (pediatrics) [ Time Frame: 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
14. Change in the Patient Global Impressions of Severity (PGI-S) [ Time Frame: 12 and 24 months ]
    Change in the patient-reported outcome (PRO) Patient Global Impressions of Severity (PGI-S)
15. Change in the Patient Global Impressions of Change (PGI-C) [ Time Frame: 12 and 24 months ]
    Change in the PRO Patient Global Impressions of Change (PGI-C)
16. Change in ERG [ Time Frame: 12 months ]
    Change in Electroretinogram (ERG) via International Society for Clinical Electrophysiology of Vision [ISCEV] standard for full-field clinical ERG) relative to baseline
17. Changes in ophthalmic examination findings [ Time Frame: 12 and 24 months ]
    Changes in ophthalmic examination findings
18. Severity of ocular AEs [ Time Frame: 12 and 24 months ]
    Severity of ocular AEs
19. Frequency of non-ocular AEs [ Time Frame: 12 and 24 months ]
    Frequency of non-ocular AEs

Eligibility Criteria

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

Criteria

Main Inclusion Criteria:

• Male or female, ≥ 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. Historic genotyping results from a certified laboratory are acceptable with Sponsor approval.
• BCVA greater or equal to Logarithm of the Minimum Angle of Resolution (LogMAR) +3.0, and equal or worse than LogMAR + 0.4 in both eyes.
• Detectable outer nuclear layer (ONL) in the area of the macula as determined by the reading center at Screening.
• An electroretinogram (ERG) result consistent with LCA, as determined by the reading center. A historic ERG result may be acceptable for eligibility.

Main Exclusion Criteria:

• Any contraindication to IVT injection according to the Investigator's clinical judgment and international guidelines (Avery 2014).
• Any ocular and/or general disease or condition that could compromise subject's safety or interfere with assessment of efficacy and safety, as determined by the Investigator.
• Prior receipt of intraocular surgery or IVT injection within 3 months prior to study start or planned intraocular surgery or procedure during the course of the study.
• 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 therapy for LCA.

Contacts and Locations

Contacts

Contact: Clinical Trials Manager; +31 (0)88 1667000; clinical@proqr.com

Locations

United States, Florida

University of Miami - Bascom Palmer Eye Institute; Not yet recruiting

Miami, Florida, United States, 33156

Principal Investigator: Byron Lam

United States, Iowa

University of Iowa; Not yet recruiting

Iowa City, Iowa, United States, 52242

Principal Investigator: Stephen Russell

United States, New York

Columbia University Medical Center; Not yet recruiting

New York, New York, United States, 10032

Principal Investigator: Steven Brooks

United States, Oregon

Casey Eye Institute - Oregon Health & Science University; Not yet recruiting

Portland, Oregon, United States, 97239-4197

Principal Investigator: Paul Yang

United States, Pennsylvania

University of Pennsylvania - Center for Advanced Retinal & Ocular Therapeutics; Not yet recruiting

Philadelphia, Pennsylvania, United States, 19104

Principal Investigator: Tomas Aleman

United States, Texas

Baylor College of Medicine; Recruiting

Houston, Texas, United States, 77030

Contact: Annika Joshi 713-798-8419 Annika.joshi@bcm.edu

Principal Investigator: Tahira Scholle, MD

Belgium

Universitair Ziekenhuis Gent (UZ); Not yet recruiting

Ghent, Belgium

Principal Investigator: Bart Leroy

Canada, Ontario

The Hospital for Sick Children - SickKids; Not yet recruiting

Toronto, Ontario, Canada, M5G 2L3

Principal Investigator: Elise Heon

Canada, Quebec

McGill University Health Centre - Centre for Innovative Medicine; Not yet recruiting

Montréal, Quebec, Canada, H4A 3J1

Principal Investigator: Robert Koenekoop

France

Centre de maladies rares CHNO des Quinze Vingt; Not yet recruiting

Paris, France, 75012

Principal Investigator: Isabelle Audo

Hospital Civil de Strasbourg; Not yet recruiting

Strasbourg, France, 67091

Principal Investigator: Helene Dollfus

Germany

University of Tuebingen - Inst. for Ophthalmic Research; Recruiting

Tuebingen, Germany, 72076

Contact: Nadine Kahle

Principal Investigator: Katarina Stingl, MD

Netherlands

Amsterdam University Medica Center - Locatie AMC; Not yet recruiting

Amsterdam, Netherlands, 1105 AZ

Principal Investigator: Camiel Boon

Radboud Universitair Medisch Centrum; Not yet recruiting

Nijmegen, Netherlands, 6525 GA

Principal Investigator: Carel Hoyng

Het Oogziekenhuis Rotterdam; Not yet recruiting

Rotterdam, Netherlands, 3011 BH

Principal Investigator: L. Ingeborgh van den Born

United Kingdom

Moorfields Eye Hospital - NHS Foundation Trust; Not yet recruiting

London, United Kingdom, EC1V 2PD

Principal Investigator: Michel Michaelides

Sponsors and Collaborators

ProQR Therapeutics

Investigators

• Study Director: Lisa Grillone; ProQR Medical Monitor

More Information

Additional Information:

Sponsor website 

• Responsible Party: ProQR Therapeutics
• ClinicalTrials.gov Identifier: NCT03913143 History of Changes
• Other Study ID Numbers: PQ-110-003; 2018-003501-25 ( EudraCT Number )
• First Posted: April 12, 2019
• Last Update Posted: September 25, 2019
• Last Verified: September 2019

Individual Participant Data (IPD) Sharing Statement:

• Plan to Share IPD: No

• Studies a U.S. FDA-regulated Drug Product: Yes
• Studies a U.S. FDA-regulated Device Product: No

Keywords provided by ProQR Therapeutics:

LCA10; CEP290; p.Cys998X; c.2991+1655A>G; Leber's Congenital Amaurosis; Antisense oligonucleotide; RNA therapy

Additional relevant MeSH terms:

Blindness; Neurologic Manifestations; Vision Disorders; Sensation Disorders; Retinal Diseases; Leber Congenital Amaurosis; Eye Diseases, Hereditary; Eye Abnormalities; Genetic Diseases, Inborn; Disease; Eye Diseases; Pathologic Processes; Nervous System Diseases; Signs and Symptoms; Congenital Abnormalities