E.1 Medical condition or disease under investigation |
E.1.1 | Medical condition(s) being investigated |
chronic visual loss related to optic neuritis in multiple sclerosis |
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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] - Nervous System Diseases [C10] |
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 | 10028245 |
E.1.2 | Term | Multiple sclerosis |
E.1.2 | System Organ Class | 10029205 - Nervous system disorders |
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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 | 10030942 |
E.1.2 | Term | Optic neuritis |
E.1.2 | System Organ Class | 10029205 - Nervous system 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 demonstrate the superiority of biotin 300 mg/day over placebo in the visual improvement of patients suffering from chronic visual loss after optic neuritis related to multiple sclerosis |
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E.2.2 | Secondary objectives of the trial |
To evaluate the safety of high doses of Biotin |
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E.2.3 | Trial contains a sub-study | No |
E.3 | Principal inclusion criteria |
1. Signed and dated written inform consent form in accordance with local regulations: having freely given their written informed consent to participate in the study. 2. Diagnosis criteria of MS fulfilling the actualised Mc Donald criteria (2010) 3. Uni-or bilateral optic neuropathy with worst eye VA≤ 5/10 confirmed at 6 months 4. Worsening of visual acuity during the last three years (at least 1/10 point) 5. Patient aged 18-75 years 6. Likely to be able to participate in all scheduled evaluations and complete all required study procedures. 7. In the opinion of the investigator, the patient will be compliant and have a high probability of completing the study. |
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E.4 | Principal exclusion criteria |
1. Optic neuritis relapse within the three months before inclusion 2. Presence of other ocular pathology (glaucoma, cataract, retinopathy, anterior uveitis, myopia>7 d, intraocular pressure>20 mm Hg, amblyopia, retinal or optic head abnormalities (drusen, dysversion…) 3. Bilateral visual acuity <1/20 4. Visual impairment caused by ocular flutter or nystagmus 5. Patients with uncontrolled hepatic disorder, renal or cardiovascular disease, or cancer 6. Patients with hypersensitivity to biotin or MD1003’s excipients 7. Patients treated with any new medication for MS (immunomodulators, immunosuppressive) but fampridine, initiated less than 3 months prior to inclusion 8. Treatment with fampridine initiated less than 1 month prior to inclusion 9. Laboratory tests out of normal range according to the reference laboratory values. Deviations may be accepted if considered clinically insignificant for the conduct of study by the investigator, 10. Patients with history or presence of alcohol abuse or drug addiction, 11. Pregnant or breast-feeding women, 12. Women of childbearing age without effective contraception (oral pill or IUCD), 13. Patients likely to be non-compliant to the study procedures or for whom a long-term follow-up seems to be difficult to achieve. 14. Normal RNFL at OCT |
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E.5 End points |
E.5.1 | Primary end point(s) |
The primary endpoint is the mean change in best corrected visual acuity (logMAR) at 100% contrast between baseline and month 6 of the diseased eye (where the diseased eye is defined as the eye with the worst visual acuity (<5/10) at baseline and with evidence of worsening during the past three years). |
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E.5.1.1 | Timepoint(s) of evaluation of this end point |
The primary and secondary endpoints will be assessed both at the end of the placebo-controlled period (M6) and at the end of the extension phase (M12, M24, M36 and M48). During long term extension phase of 18 months, the visual acuity (ETDRS) will be assessed every 6 months. |
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E.5.2 | Secondary end point(s) |
1. Proportion of patients with improvement of VA of the diseased eye of at least 0.3 logMAR 2. Proportion of patients with improvement of bilateral AV from <5 (70 visual acuity score) to ≥5/10 (70) at 100% contrast 3. Proportion of eyes with reappearance of P100 waves or improvement of P100 latencies≥10 ms at M6 (or M12 for the extension phase) 4. Clinical global impression of change(CGI) at M6 and M12 evaluated by the clinician (CGI) and by the patient (SGI) 5. Mean change in NEIFVQ-25 (functional vision questionnaire) between baseline and M6 (or M12 for the extension phase) 6. Mean change in SF36 subscores between baseline and M6 (or M12 for the extension phase). In addition, the following endpoints will be used as exploratory endpoints to provide additional support to study results: - Proportion of patients with improvement of VA of the selected eye of at least 0.1 and 0.2 logMAR at 100% contrast at M6 (and M12 and then every 6 months until M24) - Mean change in visual acuity of the non-selected eye at 100% contrast between baseline and M6 (M12 for the extension phase and then every 6 months until M24) - Mean change in visual acuity of all eyes at 100% contrast between baseline and M6 (M12 for the extension phase and then every 6 months until M24) - Mean change in bilateral visual acuity at 100% contrast between baseline and M6 (M12 for the extension phase and then every 6 months until M24) - Mean change in visual acuity of the selected eye at 5% contrast between baseline and M6 (M12 for the extension phase and then every 6 months until M24) - Mean change in visual acuity of all eyes at 5% contrast between baseline and M6 - Proportion of patients with at least one eye improved by at least 0.1, 0.2 and 0.3 logMAR at 5% contrast at M6 - Mean change in the mean deviation visual field defect of the selected eye between baseline and M6 (or M12 for the extension phase) - Mean change in the mean deviation visual field defect of all eyes between baseline and M6 (or M12 for the extension phase) - Mean change in the Pattern Standard Deviation of the selected eye between baseline and M6 (or M12 for the extension phase) - Mean change in the Pattern Standard Deviation of all eyes between baseline and M6 (or M12 for the extension phase) Mean change in Retinal Nerve Fiber Layer (RNFL) of all eyes |
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E.5.2.1 | Timepoint(s) of evaluation of this end point |
The primary and secondary endpoints will be assessed both at the end of the placebo-controlled period (M6) and at the end of the extension phase (M12, M24, M36 and M48). During long term extension phase of 18 months, the visual acuity (ETDRS) will be assessed every 6 months. |
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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 | No |
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 | 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 | 20 |
E.8.6 Trial involving sites outside the EEA |
E.8.6.1 | Trial being conducted both within and outside the EEA | No |
E.8.6.2 | Trial being conducted completely outside of the EEA | No |
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 | 3 |
E.8.9.1 | In the Member State concerned months | |
E.8.9.1 | In the Member State concerned days | |
E.8.9.2 | In all countries concerned by the trial years | 3 |