Primary: To evaluate the efficacy of QR-110 administered by intravitreal (IVT) injection.Secondary:1. To evaluate the safety and tolerability of QR-110 administered via IVT injection.2. To evaluate changes in patient-reported outcome (PRO) measures…
ID
Source
Brief title
Condition
- Eye disorders congenital
- Congenital eye disorders (excl glaucoma)
Synonym
Research involving
Sponsors and support
Intervention
Outcome measures
Primary outcome
The change from baseline in BCVA (based on ETDRS and/or BRVT) at 12 months of
treatment versus sham-procedure
Secondary outcome
Key secondary endpoint: Change from baseline in mobility course score at 12
months of treatment versus sham, as assessed by a masked central reader
Secondary endpoints:
• Change from baseline in BCVA:
- By >= 3 lines (or >= 0.3 logMAR change) in subjects with BCVA equal to
or better than 1.7 logMAR at baseline
- By a clinically meaningful improvement in subjects with BCVA worse
than 1.7 logMAR at baseline
• Change from baseline in mobility course score
• Change from baseline in BCVA based on Freiburg Visual Acuity and contrast
Test (FrACT)
• Change from baseline in light sensitivity to FST (white, red, and blue)
• Change from baseline in ellipsoid zone (EZ) width/area assessed by spectral
domain optical coherence tomography SD-OCT
• Change from baseline in low luminance visual acuity (LLVA)
• Change from baseline in oculomotor instability
• Change from baseline as determined by fundus autofluorescence (FAF) imaging
• Change from baseline as determined by microperimetry
• Change from baseline in PRO measures, as measured by:
- The Visual Function Questionnaire-25 (VFQ-25) score (adult subjects)
- The Cardiff Visual Ability Questionnaire for Children (CVAQC)
(pediatric subjects)
- The Patient Global Impressions of Severity (PGI S)
- The Patient Global Impressions of Change (PGI C)
• Systemic exposure to QR-110
• Ocular and non-ocular AEs
Background summary
Leber*s congenital amaurosis (LCA) is a severe inherited retinal degenerative
disease resulting in blindness, often in early childhood. In subjects with LCA
due to the p.Cys998X mutation in the CEP290 gene (subsequently referred to as
CEP290 p.Cys998X mutation), visual symptoms are usually detectable before 1
year of age and further deterioration over time has also been reported.
Subjects show severe vision disturbances from an early age and slow progressive
loss of remaining vision. There are currently no approved therapies for the
treatment of LCA due to the CEP290 p.Cys998X mutation and a large unmet medical
need exists.
The primary goal of the development plan for QR-110 is to provide a treatment
to overcome the genetic defect in subjects with at least 1 CEP290 allele
containing the CEP290 p.Cys998X mutation, resulting in functional vision
restoration or preservation. The intended route of administration is
intravitreal injection
Study objective
Primary: To evaluate the efficacy of QR-110 administered by intravitreal (IVT)
injection.
Secondary:
1. To evaluate the safety and tolerability of QR-110 administered via IVT
injection.
2. To evaluate changes in patient-reported outcome (PRO) measures in subjects
treated with QR-110
3. To evaluate the systemic exposure of QR-110 administered by IVT injection.
Study design
The study is a double-masked, randomized, controlled, multiple-dose study to
evaluate the efficacy, safety, tolerability and systemic exposure of QR 110
administered via IVT injection in subjects with LCA due to the CEP290 p.Cys998X
mutation.
At study start subjects will be randomized to one of the following treatment
groups:
1) Group 1: QR-110 (160 µg loading dose administered on Day 1, 80 µg
maintenance dose administered at Month 3 and every 6 months thereafter [160/80
µg]; n = 10)
2) Group 2: QR-110 (80 µg loading dose administered on Day 1, 40 µg maintenance
dose administered at Month 3 and every 6 months thereafter [80/40 µg]; n = 10)
3) Group 3: Sham-pr ocedure (administered on Day 1, Month 3 and every 6 months
thereafter; n = 10)
Once at least 6 subjects per treatment group have been treated for at least 3
months, an interim analysis (IA) will be performed. Based on observed treatment
effect size at the IA time point a sample-size re-estimation will be performed
according to predefined criteria (see under Statistical Methodology).
Initially the worse eye (defined by visual acuity at Screening) will be treated
and will be called the treatment eye hereafter. If both eyes have the same
visual acuity, the Investigator should determine the eye with the worse visual
function as the treatment eye, according to other measures of ophthalmic
function (eg. Full-field Stimulus Testing [FST] or mobility course score). If
the visual function is the same per the Investigator*s assessment, then the
treatment eye will be determined at the Investigator*s discretion.
After th e first eye has been treated for at least 12 months, treatment of the
contralateral eye and cross-over of the subjects assigned to sham may be
initiated in eligible eyes, based on assessment of benefit/risk, and with
concurrence of the Medical Monitor.
Frequent study visits and safety monitoring by the investigator will be in
place, together with oversight by the Medical Monitor and the Data Monitoring
Committee (DMC). The Investigator or the Medical Monitor (in consultation with
the DMC) may decide to hold (delay or skip) or discontinue study treatment for
an individual subject. Stopping criteria are described in Section 4.2.2.
Subjects who discontinue study treatment will continue to be followed for
safety and efficacy.
For subjects completing the study and deriving therapeutic benefit, the Sponsor
plans on providing continued access to the study drug until drug registration,
as long as the benefit/risk continues to be positive.
Study Plan
The study includes a 28 day screening period.
During the screening period, subjects will be assessed according to the
eligibility criteria. Historic genotyping results from a certified genetic
laboratory are acceptable with Sponsor approval. For subjects without a
historic genotyping result, genotyping and gene sequencing analysis to
determine the presence of the CEP290 p.Cys998X mutation will be performed. It
is recommended that screening will be conducted in a stepwise manner, so that
eligibility is confirmed first with less intensive assessments and more
intensive assessments are conducted after eligibility by all other criteria
have been confirmed.
Subjects who meet all eligibility criteria will be enrolled into the study and
will receive their first study treatment on Day 1. QR-110 will be administered
via IVT injection in accordance with the procedures outlined by the American
Academy of Ophthalmology and as outlined in the Study Reference Manual.
Subjects in the sham-procedure group will undergo a procedure that will closely
mimic the active injection, but there will be no penetration of the globe.
Administration of study treatment , as well as clinical monitoring of the
subject during and right after administration of study treatment, will be
performed by an unmasked physician, but clinical assessments (including
efficacy and safety assessments) will be performed by a separate, masked
physician where possible. After each administration of study treatment,
subjects will be monitored for safety, including intraocular pressure (IOP) and
signs of inflammation.
Efficacy and safety assessments, including best-corrected visual acuity (BCVA),
mobility course score, retinal imaging, functional assessments of vision and
patient-reported outcome (PRO) measures, will be performed at selected study
visits. All assessments will be performed on both eyes. The primary endpoint
will be assessed at 12 months of treatment. Analysis of all other efficacy and
safety parameters will also be reported at that time point. All efficacy and
safety parameters will continue to be followed during the 24-month treatment
period. Collection of serum samples for evaluation of systemic exposure will
take place as outlined in the Schedule of Events (SOE) (Appendix 1 of the
protocol).
Intervention
The current study will evaluate 2 dose levels (see also the study schematic in
the protocol):
• Loading dose of 160 microgram followed by an 80 microgram maintenance dose at
Month 3 and subsequent maintenance doses at a 6 monthly interval
• Loading dose of 80 microgram, followed by a 40 microgram maintenance dose at
Month 3 and subsequent maintenance doses at a 6 monthly interval
In addition, treatment of the contralateral eye (to occur in the second year)
will involve only a 6-monthly dosing interval.
Study burden and risks
In the first 12 months: a maximum of 3 treatments for the eye with the least
eyesight.
After 12 months: if the second eye is eligible for treatment a maximum of 2
treatments in the second eye. If both eyes are treated: a different eye will
receive treatment every 3 months. In total there are 25 visits. There will be
18 visits to the research center and 7 telephone calls. The study drug will
be administered via intravitreal injection. In addition to the administration
of the study drug, various tests are performed. Please see the ICF for a
detailed description of the various tests.
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Age
Inclusion criteria
Relating to Study Initiation : The subject is eligible for the study and thus
eligible to receive QR-110 or fake-procedure in the treatment eye (ie, the
first eye to be treated) if all the following inclusion criteria apply at
Screening/Day 1:
1. An adult (>= 18 years) willing and able to provide informed consent for
participation -OR- a minor (8 to < 18 years) with a parent or legal guardian
willing and able to provide written permission for the subject*s participation
prior to performing any study related procedures and pediatric subjects able to
provide age appropriate assent for study participation.
2. 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 c.2991+1655A>G mutation, based on genotyping analysis at Screening.
Historic genotyping report from a certified laboratory is acceptable with
Sponsor approval.
3. BCVA better or equal to Logarithm of the Minimum Angle of Resolution
(logMAR) +3.0 (Hand Motion), and equal or worse than logMAR + 0.4 (approximate
Snellen equivalent 20/50) in the treatment eye, using the best BCVA reading at
Screening and based on the Early Treatment Diabetic Retinopathy Study (ETDRS)
or the Berkeley rudimentary vision test (BRVT).
4. Detectable outer nuclear layer (ONL) in the area of the macula as determined
by the Investigator at Screening.
5. An electroretinogram (ERG) result consistent with LCA, as determined by the
Investigator. A historic ERG result may be acceptable for eligibility.
6. Clear ocular media and adequate pupillary dilation to permit good quality
retinal imaging, as assessed by the Investigator.
7. Non-pregnant and non-breastfeeding subjects.
Relating to Treatment Initiation Contralateral Eye:
1. BCVA better or equal to Logarithm of the Minimum Angle of Resolution
(logMAR) +3.0 (Hand Motion), and equal or worse than logMAR + 0.4 (approximate
Snellen equivalent 20/50) in the contralateral eye, using the best BCVA reading
at Month 12 (see Section 8.1) and based on the
Early Treatment Diabetic Retinopathy Study (ETDRS) or the Berkeley Rudimentary
Vision Test (BRVT).
2. Detectable outer nuclear layer (ONL) in the area of the macula of the
contralateral eye as determined by the Investigator.
3. Clear ocular media and adequate pupillary dilation to permit good quality
retinal imaging in the contralateral eye, as assessed by the Investigator.
4. Non-pregnant and non-breastfeeding subjects.
Exclusion criteria
Relating to Study Initiation : The subject is ineligible for the study if any
of the following criteria apply at Screening/Day 1:
1. Presence of any significant ocular or non-ocular disease/disorder (including
medication and laboratory test abnormalities) which, in the opinion of the
Investigator and with concurrence of the Medical Monitor, may either put the
subject at risk because of participation in the study, may influence the
results of the study, or the subject*s ability to participate in the study.
2. 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 study period.
3. Any prior receipt of genetic or stem-cell therapy for ocular or non-ocular
disease.
4. 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 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.
5. Known hypersensitivity to antisense oligonucleotides or any constituents of
the injection.
6. Pregnant and breastfeeding subjects.
Relating to Treatment Initiation Contralateral Eye:
1. Presence of any significant ocular or non-ocular disease/disorder (including
medication and laboratory test abnormalities) which, in the opinion of the
Investigator and with concurrence of the Medical Monitor, may either put the
subject at risk because of participation in the study, may influence the
results of the study, or the subject's ability to participate in the study.
This includes but is not limited a subject who: 1)
is not an appropriate candidate for antisense oligonucleotide treatment,
2) has concurrent cystoid macular edema (CME) in the contralateral eye.
2. A planned IVT injection or intraocular or periocular
surgery/procedure (including refractive surgery) in the contralateral eye
during the course of the study.
3. Plans to participate in another study of a drug or device during the
study period.
4. Pregnant and breastfeeding subjects.
Design
Recruitment
Followed up by the following (possibly more current) registration
No registrations found.
Other (possibly less up-to-date) registrations in this register
No registrations found.
In other registers
| Register | ID |
|---|---|
| EudraCT | EUCTR2018-003501-25-NL |
| ClinicalTrials.gov | NCT03913143 |
| CCMO | NL68298.000.18 |