E.1 Medical condition or disease under investigation |
E.1.1 | Medical condition(s) being investigated |
acute demyelinating optic neuritis |
|
E.1.1.1 | Medical condition in easily understood language |
Acute demeylinating optic neuritis (ADON), is an inflammation of the optic nerve causing blurring, graying, or loss of vision, often with accompanying pain. |
|
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 | 15.1 |
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 |
|
E.1.3 | Condition being studied is a rare disease | No |
E.2 Objective of the trial |
E.2.1 | Main objective of the trial |
To assess if fingolimod will reduce the mean retinal nerve fiber layer (RNFL) thinning (measured as the OCT-determined difference between the RNFLT of the affected eye after 18 weeks of treatment and the baseline RNFLT of the fellow eye) relative to placebo in patients with suspected ADON, all of whom will receive standard steroid treatment. |
|
E.2.2 | Secondary objectives of the trial |
• To compare the impact of immediate treatment with fingolimod 0.5 mg/daily (48 weeks of continuous treatment) versus delayed treatment with fingolimod 0.5 mg/daily (18 weeks of placebo then 30 weeks of fingolimod) in patients with suspected ADON who are receiving standard treatment with steroids on the following outcomes:
• Low-contrast visual acuity of the affected eye assessed by low-contrast Sloan letter charts at 1.25 and 2.5% contrast levels at 48 weeks.
• Vision-based quality of life (QoL) as assessed by the QoL
questionnaire NEI-VFQ-25 at weeks 18 and 48.
• The proportion of patients converting to 2010 McDonald MS (Polman et al. 2011) between the assessment at the screening visit and weeks 18 and 48.
• To evaluate the tolerability and safety of fingolimod in patients with ADON |
|
E.2.3 | Trial contains a sub-study | No |
E.3 | Principal inclusion criteria |
• Written informed consent must be obtained before any assessment is performed.
• Male and female patients aged between 18 and 50 years, inclusive.
• Clinical signs and symptoms of unilateral ADON (loss of vision, pain on movement, impairment of color vision) starting within the 14 days prior to intended randomization.
• The qualifying ADON must be the first clinical episode of a probable demyelinating disease.
• Able to undergo treatment with intravenous methylprednisolone (IVMP).
• Received first IVMP dose prior to Visit 2. |
|
E.4 | Principal exclusion criteria |
• History of any unexplained eye or neurological symptomatology lasting longer than 48 hours and indicative of a demyelinating disorder.
• Bilateral optic neuritis.
• Functionally or clinically relevant comorbidity of either eye such as glaucoma, optic nerve hypoplasia, macular full or partial thickness macular hole, macular edema, vitreomacular traction, epiretinal membrane, uveitis, or other diseases of the optic nerve or a history thereof.
• High clinical likelihood of a form of optic neuritis other than ADON (e.g., severe optic disk edema, atrophic optic disk, retinal exudates, or hemorrhages).
• Total average RNFL thickness of less than or equal to 80 μm in the fellow eye (unaffected eye)
• Patients meeting any of the following cardiovascular conditions at Screening:
a. history of cardiac arrest;
b. severe untreated sleep apnea;
c. history of myocardial infarction; congestive heart failure;
d. ischemic heart disease;
e. cerebrovascular disease;
f. patients receiving current treatment with Class Ia or III
antiarrhythmic drugs (e.g., quinidine, disopyramide, amiodarone, bretylium, sotalol, ibulitide, azimilide, dofelitide, ajmaline, procainamide).
g. patients with relevant risk factors for QT prolongation, for
example, hypokalaemia, hypomagnesemia or congenital QT prolongation;
h. history or presence of a second-degree AV block Type II or
third-degree AV block or corrected QTc inverval >450 msec in males and >470 msec in females corrected using Fridericia’s formula (based on screening ECG report from central reader);
i. history of sick sinus syndrome or sino-atrial heart block;
j. uncontrolled hypertension despite prescribed medications;
k. resting heart rate <45 bpm;
• Patients receiving current treatment (at randomization) beta blockers, heart-rate slowing calcium channel blockers (e.g. ivadrabine, verapamil, or diltiazem), or other substances which may decrease heart rate such as digoxin, anticholinesteratic agents or pilocarpine.
Advice from a cardiologist should be sought regarding the switch to non-heart-rate lowering medicinal products (for more details, please refer to Appendix 3)
• Pregnant or nursing (lactating) women, where pregnancy is defined as the state of a female after conception and until the termination of gestation, confirmed by a positive hCG laboratory test.
• Women of child-bearing potential, defined as all women physiologically capable of becoming pregnant, unless they are using highly effective contraception during the study and for 2 months after stopping treatment. ” Highly effective contraception ” is defined as contraception that results in less than 1% unwanted pregnancies when used properly according to the label. |
|
E.5 End points |
E.5.1 | Primary end point(s) |
RNFL thinning, to evaluate whether immediate treatment with fingolimod can reduce the axonal loss of retinal neurons following an episode of ADON |
|
E.5.1.1 | Timepoint(s) of evaluation of this end point |
after 18 weeks of treatment |
|
E.5.2 | Secondary end point(s) |
assessment of whether immediate treatment with fingolimod can reduce the loss of visual acuity following an episode of ADON |
|
E.5.2.1 | Timepoint(s) of evaluation of this end point |
when full stabilization of the visual function |
|
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 | No |
E.6.10 | Pharmacogenetic | Yes |
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) | Yes |
E.7.3 | Therapeutic confirmatory (Phase III) | No |
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
| No |
E.8.4 | The trial involves multiple sites in the Member State concerned | Yes |
E.8.4.1 | Number of sites anticipated in Member State concerned | 6 |
E.8.5 | The trial involves multiple Member States | Yes |
E.8.5.1 | Number of sites anticipated in the EEA | 22 |
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 |
Germany |
Italy |
Spain |
United Kingdom |
United States |
|
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 | 2 |
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 | 2 |
E.8.9.2 | In all countries concerned by the trial days | 0 |