| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
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| E.1.1.1 | Medical condition in easily understood language |
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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 | 20.1 |
| E.1.2 | Level | PT |
| E.1.2 | Classification code | 10062766 |
| E.1.2 | Term | Stargardt's disease |
| 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 |
| To determine if emixustat hydrochloride (emixustat) reduces the rate of progression of macular atrophy (MA) compared to placebo in subjects with Stargardt disease (STGD) |
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| E.2.2 | Secondary objectives of the trial |
1. To evaluate the safety and tolerability of emixustat compared to placebo
2. To assess changes in retinal sensitivity as determined by photopic microperimetry with emixustat compared to placebo
3. To assess changes in contrast sensitivity with emixustat compared to placebo
4. To assess changes in reading speed with emixustat compared to placebo
5. To assess changes in best-corrected visual acuity (BCVA) letter score with emixustat compared to placebo
6. To assess changes in total area of decreased autofluorescence (definitely decreased plus questionably decreased) with emixustat compared to placebo
7. To assess changes in total area of ellipsoid zone (EZ) loss with emixustat compared to placebo
8. To assess changes in mean outer nuclear layer (ONL) thickness with emixustat compared to placebo
9. To assess changes in quality-of-life instruments (QOLs) with emixustat compared to placebo |
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| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal inclusion criteria |
Subjects who meet all of the following criteria at Screening and Baseline (unless otherwise indicated) may be eligible for inclusion in the study:
1. Males or females, age ≥ 16 years.
2. Clinical diagnosis of MA secondary to STGD in one or both eyes as determined by the Investigator.
3. The subject must have 1 or more pathogenic mutation(s) of the ABCA4 (ATP binding cassette subfamily A member 4) gene. If only one ABCA4 pathogenic mutation is identified or if two ABCA4 pathogenic mutations that typically occur on the same allele (ie, “in cis”) are identified, the subject must have a typical STGD phenotype (at least one eye has flecks at the level of the retinal pigmented epithelium [RPE] typically seen in STGD) and be approved by the Sponsor. If 2 or more pathogenic mutations that do not typically occur on the same allele are identified, a typical STGD phenotype and separate Sponsor approval are not required. Segregation analysis is not required. The pathogenicity of all mutations will be determined by the Sponsor working with experts in ophthalmic genetics.
4. The study eye must meet the following criteria as determined by the central reading center’s assessment of FAF imaging at Screening:
a. Total area of DDAF
i. If the lesion is unifocal: ≥ 3.0 – 22.0 mm2 (~1.2 – 8.7 disc areas) in size.
ii. If the lesion is multifocal: ≥ 1.0 – 22.0 mm2 (~0.4 – 8.7 disc areas) in size.
b. The entire lesion must be completely visualized on the macula-centered image (Field 2 – Macula Image). The DDAF lesion must be able to be imaged in its entirety, and all lesion borders must be ≥ 300 microns from all image edges.
5. Early Treatment Diabetic Retinopathy Study (ETDRS) BCVA letter score of ≥ 25 letters (approximately ≥ 20/320 Snellen) in the study eye at Screening.
6. Adequate clarity of ocular media and adequate pupillary dilation to permit good quality imaging of macular atrophy in the study eye as determined by the Investigator.
7. Able to reliably administer oral medication by self or with available assistance.
8. Able and willing to provide written informed consent/assent
a. For subjects ≥ 18 years of age: able and willing to provide written informed consent before undergoing any study-related procedures.
b. For subjects ≥ 16 and < 18 years of age: able and willing to provide written informed assent, and has a parent or legal guardian able and willing to provide written informed consent for the minor before the subject undergoes any study-related procedures. Where required by local regulations, both parents must consent to the subject's participation in the study, if both have legal custody. |
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| E.4 | Principal exclusion criteria |
Subjects will be excluded from participation in the study if they meet any of the following criteria at Screening or Baseline (unless otherwise indicated):
1. Macular atrophy associated with a condition other than STGD in either eye
2. DDAF with contiguous area of peripapillary atrophy in the study eye, as determined by the reading center
3. Mutation(s) in any of the following genes – elongation of very long chain fatty acids-like 4 (ELOVL4), prominin 1 (PROM1), or peripherin 2 (PRPH2)/retinal degeneration slow (RDS) – determined by the Sponsor working with experts in ophthalmic genetics to likely be disease-causing
4. If tested, any mutation(s):
a. In a gene(s) encoding a visual cycle protein [e.g., retinal pigment epithelium 65 (RPE65), lecithin:retinol acyltransferase (LRAT), retinol dehydrogenase 12 (RDH12), RDH5, and retinaldehyde binding protein 1 (RLBP1)], confirmed by the Sponsor working with experts in ophthalmic genetics to likely be disease-causing. Testing for these mutations is not required.
b. Associated with a non-STGD retinal dystrophy/degeneration, confirmed by the Sponsor working with experts in ophthalmic genetics to likely be disease-causing. Testing is not required
5. Presence in either eye of an active ocular disease that in the opinion of the Investigator compromises or confounds visual function, including, but not limited to, choroidal neovascularization, diabetic retinopathy, uveitis, other macular diseases, or uncontrolled glaucoma/ocular hypertension
6. History of any intraocular or ocular surface surgery in either eye ≤ 3 months prior to Screening.
7. Current or previous participation in an interventional study to treat STGD using gene therapy or stem cell therapy.
8. Current or previous participation in a study to treat STGD using a vitamin A derivative ≤ 6 months prior to Screening.
9. Current or previous participation in a study to treat STGD using a complement inhibitor ≤ 6 months prior to Screening.
10. Known hypersensitivity to emixustat or any of the excipients in emixustat tablets (ie, silicified microcrystalline cellulose, pregelatinized starch, colloidal silicon dioxide, and stearic acid).
11. Prohibited medications: Please refer to the protocol.
12. Any of the following laboratory abnormalities at Screening: Please refer to the protocol
13. Participation in any study using an investigational drug within 30 days or 5 half-lives (of the investigational drug) of Screening.
14. Participation in any study of an interventional, investigational device within 60 days of Screening.
15. Anticipated participation during the study period in any study using an investigational drug or an interventional, investigational device.
16. Presence of other medical or ophthalmic disease, physical examination finding, or clinical laboratory finding that in the opinion of the Investigator contraindicates the use of an investigational drug, places the subject at risk by participating in the study, might interfere with the evaluation of the efficacy or safety of emixustat, negatively impacts subject compliance with the protocol, confounds the ability to interpret data from the study, or jeopardizes the subject’s ability to complete the protocol.
17. Current or history of cancer (except for adequately treated basal cell or squamous cell carcinoma of the skin) within 1 year of Screening.
18. History of myocardial infarction, stroke, unstable ischemic heart disease, uncontrolled cardiac arrhythmia, or hospitalization for congestive heart failure within 6 months of Screening.
19. Abnormal electrocardiogram (ECG) results that are considered by the Investigator to be clinically significant at Screening.
20. Female subjects who are pregnant or lactating.
21. Female subjects of childbearing potential [ie not postmenopausal (without menses for 12months without an alternative medical cause) and not surgically sterile via hysterectomy, bilateral salpingectomy, or
bilateral oophorectomy] who are not willing to practice a medically accepted method of birth control with their non-surgically sterile male sexual partner from Screening through 30days following the completion
of the study. Medically accepted methods of birth control include true abstinence, estrogen+progestogen hormonal contraceptives, progestogen-only hormonal contraceptives, nonhormonal or hormonal intrauterine contraceptive device, bilateral tubal occlusion, male or female condom, contraceptive sponge with spermicide, diaphragm with spermicide, or cervical cap with spermicide. True abstinence is when abstinence from heterosexual intercourse is in line with the preferred
and usual lifestyle of the subject and is not just limited to the duration of this study
22. Male subjects who are not surgically sterile and are not willing to practice a medically accepted method of birth control with their female partner of childbearing potential (as listed above) from Screening through 30 days after completion of the study |
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| E.5 End points |
| E.5.1 | Primary end point(s) |
| The primary efficacy endpoint will be the mean rate of change from baseline in the total area of the MA lesion(s) in the study eye (in mm2 per year), defined as the area of definitely decreased autofluorescence as imaged by reduced-illuminance FAF. |
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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) |
Secondary efficacy endpoints will include:
1. Mean change from baseline in retinal sensitivity as assessed by photopic microperimetry
2. Mean change from baseline in contrast sensitivity.
3. Mean change from baseline in reading speed.
4. Mean change from baseline in ETDRS BCVA letter score.
5. Mean rate of change from baseline in the total area of decreased autofluorescence (definitely decreased plus questionably decreased), as imaged by reduced-illuminance FAF.
6. Mean rate of change from baseline in the total area of EZ loss, as imaged on SD-OCT
7. Mean change from baseline in mean ONL thickness, as imaged on SD-OCT
8. Mean change from baseline in QOL instruments. |
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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 | No |
| E.6.10 | Pharmacogenetic | No |
| E.6.11 | Pharmacogenomic | No |
| E.6.12 | Pharmacoeconomic | No |
| E.6.13 | Others | No |
| 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) | No |
| 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 | Yes |
| E.8.2.3 | Other | No |
| E.8.2.4 | Number of treatment arms in the trial | 2 |
| 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 |
| Denmark |
| France |
| Germany |
| Italy |
| Netherlands |
| South Africa |
| Spain |
| United Kingdom |
| 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
|
|
| E.8.9 Initial estimate of the duration of the trial |
| E.8.9.1 | In the Member State concerned years | 3 |
| E.8.9.1 | In the Member State concerned months | 5 |
| E.8.9.1 | In the Member State concerned days | 0 |
| E.8.9.2 | In all countries concerned by the trial years | 3 |
| E.8.9.2 | In all countries concerned by the trial months | 8 |
| E.8.9.2 | In all countries concerned by the trial days | 0 |
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