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

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ClinicalTrials.gov Identifier: NCT03913143
Recruitment Status : Active, not recruiting
First Posted : April 12, 2019
Last Update Posted : January 11, 2021
Sponsor:
Information provided by (Responsible Party):
ProQR Therapeutics

Study Description
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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

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: sepofarsen 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 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 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
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Study Type : Interventional  (Clinical Trial)
Actual Enrollment : 36 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 2021
Estimated Study Completion Date : December 2021

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Arms and Interventions
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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 Name: 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 Name: QR-110
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
Sham intravitreal injection (no experimental drug administered)


Outcome Measures
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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
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Information from the National Library of Medicine

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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 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:

  • 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
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Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT03913143


Locations
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Sponsors and Collaborators
ProQR Therapeutics
Investigators
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Study Director: ProQR Medical Monitor ProQR Therapeutics
More Information
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Additional Information:

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Responsible Party: ProQR Therapeutics
ClinicalTrials.gov Identifier: NCT03913143    
Other Study ID Numbers: PQ-110-003
2018-003501-25 ( EudraCT Number )
First Posted: April 12, 2019    Key Record Dates
Last Update Posted: January 11, 2021
Last Verified: December 2020
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD: No

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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
QR-110
sepofarsen
Additional relevant MeSH terms:
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Blindness
Neurologic Manifestations
Vision Disorders
Sensation Disorders
Eye Diseases
Retinal Diseases
Leber Congenital Amaurosis
 Eye Diseases, Hereditary
Eye Abnormalities
Genetic Diseases, Inborn
Disease
Pathologic Processes
Nervous System Diseases
Congenital Abnormalities