| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
| Leber’s Congenital Amaurosis (LCA) due to c.2991+1655A>G Mutation (p.Cys998X) in the CEP290 Gene |
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| E.1.1.1 | Medical condition in easily understood language |
| LCA due to the p.Cys998X mutation in the CEP290 gene (LCA10) |
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| E.1.1.2 | Therapeutic area | Diseases [C] - Eye Diseases [C11] |
| MedDRA Classification |
| E.1.2 Medical condition or disease under investigation |
| E.1.2 | Version | 20.0 |
| E.1.2 | Level | PT |
| E.1.2 | Classification code | 10070667 |
| E.1.2 | Term | Leber's congenital amaurosis |
| E.1.2 | System Organ Class | 10010331 - Congenital, familial and genetic disorders |
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| E.1.3 | Condition being studied is a rare disease | Yes |
| E.2 Objective of the trial |
| E.2.1 | Main objective of the trial |
The primary objective is to evaluate the efficacy of QR-110 administered by intravitreal (IVT) injection in subjects with LCA due to the CEP290 p.Cys998X mutation
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| E.2.2 | Secondary objectives of the trial |
The secondary objectives are to evaluate:
- The safety and tolerability of QR-110 administered via IVT injection in subjects with LCA due to the CEP290 p.Cys998X mutation
- Changes in quality of life in subjects with LCA due to the CEP290 p.Cys998X mutation treated with QR-110
- The systemic exposure of QR-110 administered by IVT injection in subjects with LCA due to the CEP290 p.Cys998X mutation
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| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal inclusion criteria |
Relating to Study Initiation: The subject is eligible for the study and thus eligible to receive QR-110 or sham-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 CEP290 p.Cys998X mutation, based on genotyping analysis at Screening. Historic genotyping results from a certified laboratory are 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 (see Section 8.1) 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 (see Section 8.1).
6. Clear ocular media and adequate pupillary dilation to permit good quality retinal imaging, as assessed by the Investigator.
7. An adult willing to comply with the protocol, follow study instructions, attend study visits as required and willing and able to complete all study assessments, in the opinion of the Investigator -OR- a minor able to complete all study assessments and comply with the protocol and has a parent or caregiver willing and able to follow study instructions and attend study visits with the subject as required, in the opinion of the Investigator.
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. |
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| E.4 | Principal 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. 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 treatment eye.
2. History or presence of ocular herpetic diseases (including herpes simplex virus, varicella zoster or cytomegalovirus) in the treatment eye.
3. Presence of any active ocular infection in either eye.
4. Receipt within 3 months 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.
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,
5. Presence of any of the following lens opacities in the treatment eye: cortical opacity ≥ +2, posterior subcapsular opacity ≥ +2, or a nuclear sclerosis ≥ +2, and which are: 1) clinically significant in the opinion of the Investigator, 2) would adequately prevent clinical and photographic evaluation of the retina.
6. Receipt within 3 months 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.
7. Current treatment or treatment within the past 12 months with therapies known to influence the immune system (including but not limited to cytostatics, interferons, TNF-binding proteins, drugs acting on immunophilins, or antibodies with known impact on the immune system). Subjects that have been treated with systemic steroids within the past 12 months or that require intermittent use of topical steroids may be considered for inclusion following approval by the Medical Monitor.
8. A history of glaucoma or an IOP greater than 24 mmHg in the treatment eye that is not controlled with medication at the time of informed consent.
9. History of amblyopia in the treatment eye.
10. 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.
11. Any prior receipt of genetic or stem-cell therapy for ocular or non-ocular disease.
12. History of malignancy within 5 years prior to screening, except adequately treated squamous or basal cell carcinoma of the skin or carcinoma in situ of the cervix that has been successfully treated.
13. Known hypersensitivity to antisense oligonucleotides or any constituents of the injection.
14. Pregnant and breastfeeding subjects. |
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| E.5 End points |
| E.5.1 | Primary end point(s) |
| The primary endpoint is mean change from baseline in BCVA (based on ETDRS and/or BRVT) at 12 months of treatment versus sham. |
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| E.5.1.1 | Timepoint(s) of evaluation of this end point |
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| E.5.2 | Secondary end point(s) |
Key secondary: 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:
o By ≥ 3 lines (or ≥ -0.3 logMAR change) in subjects with BCVA equal to or better than 1.7 logMAR at baseline
o 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 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 in retina as determined by fundus autofluorescence (FAF) imaging
- Change from baseline in PRO measures, as measured by:
o The Visual Function Questionnaire-25 (VFQ-25) score (adult subjects)
o The Cardiff Visual Ability Questionnaire for Children (CVAQC) (pediatric subjects)
o the Patient Global Impressions of Severity (PGI-S)
o the Patient Global Impressions of Change (PGI-C)
- Systemic exposure to QR-110
- Ocular and non-ocular AEs |
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| E.5.2.1 | Timepoint(s) of evaluation of this end point |
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| E.6 and E.7 Scope of the trial |
| E.6 | Scope of the trial |
| E.6.1 | Diagnosis | No |
| E.6.2 | Prophylaxis | No |
| E.6.3 | Therapy | Yes |
| E.6.4 | Safety | Yes |
| E.6.5 | Efficacy | Yes |
| E.6.6 | Pharmacokinetic | Yes |
| E.6.7 | Pharmacodynamic | No |
| E.6.8 | Bioequivalence | No |
| E.6.9 | Dose response | Yes |
| E.6.10 | Pharmacogenetic | No |
| E.6.11 | Pharmacogenomic | No |
| E.6.12 | Pharmacoeconomic | No |
| E.6.13 | Others | Yes |
| E.6.13.1 | Other scope of the trial description |
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| E.7 | Trial type and phase |
| E.7.1 | Human pharmacology (Phase I) | No |
| E.7.1.1 | First administration to humans | No |
| E.7.1.2 | Bioequivalence study | No |
| E.7.1.3 | Other | No |
| E.7.1.3.1 | Other trial type description | |
| E.7.2 | Therapeutic exploratory (Phase II) | Yes |
| E.7.3 | Therapeutic confirmatory (Phase III) | Yes |
| E.7.4 | Therapeutic use (Phase IV) | No |
| E.8 Design of the trial |
| E.8.1 | Controlled | Yes |
| E.8.1.1 | Randomised | Yes |
| E.8.1.2 | Open | No |
| E.8.1.3 | Single blind | No |
| E.8.1.4 | Double blind | Yes |
| E.8.1.5 | Parallel group | Yes |
| E.8.1.6 | Cross over | No |
| E.8.1.7 | Other | No |
| E.8.2 | Comparator of controlled trial |
| E.8.2.1 | Other medicinal product(s) | No |
| E.8.2.2 | Placebo | No |
| E.8.2.3 | Other | Yes |
| E.8.2.3.1 | Comparator description |
| Comparator 1: dose level 2 IMP; Comparator 2: Sham IVT injection (no IMP administration) |
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| E.8.2.4 | Number of treatment arms in the trial | 3 |
| E.8.3 |
The trial involves single site in the Member State concerned
| Yes |
| E.8.4 | The trial involves multiple sites in the Member State concerned | No |
| E.8.5 | The trial involves multiple Member States | Yes |
| E.8.5.1 | Number of sites anticipated in the EEA | 14 |
| E.8.6 Trial involving sites outside the EEA |
| E.8.6.1 | Trial being conducted both within and outside the EEA | Yes |
| E.8.6.2 | Trial being conducted completely outside of the EEA | No |
| E.8.6.3 | If E.8.6.1 or E.8.6.2 are Yes, specify the regions in which trial sites are planned |
| Brazil |
| Canada |
| European Union |
| United States |
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| E.8.7 | Trial has a data monitoring committee | Yes |
| E.8.8 |
Definition of the end of the trial and justification where it is not the last
visit of the last subject undergoing the trial
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| E.8.9 Initial estimate of the duration of the trial |
| E.8.9.1 | In the Member State concerned years | 2 |
| E.8.9.1 | In the Member State concerned months | 10 |
| E.8.9.1 | In the Member State concerned days | 0 |
| E.8.9.2 | In all countries concerned by the trial years | 2 |
| E.8.9.2 | In all countries concerned by the trial months | 10 |
| E.8.9.2 | In all countries concerned by the trial days | 0 |
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