Gilenya in Amyotrophic Lateral Sclerosis (ALS)

The purpose of this study is to determine whether Gilenya, also known as fingolimod, is safe and tolerable in patients with Amyotrophic Lateral Sclerosis (ALS).

The primary objective of the study is to determine the acute safety and tolerability of oral administration of Gilenya (fingolimod) 0.5mg daily vs. matched oral placebo administered daily.

The primary outcome measure will be safety and tolerability; safety will be assessed by the occurrence of adverse events and clinically meaningful changes in vital signs, ophthalmologic examination, physical examination, electrocardiogram and standard clinical laboratory blood tests, and tolerability will be defined as the ability of subjects to complete the entire 4-week study.

The secondary outcome measure will be the measured effect of the treatment on circulating lymphocyte populations in patients with ALS.

Exploratory outcome measures will include the rate of decline of the ALS Functional Rating Scale (Revised) (ALSFRS-R) and Slow Vital Capacity (VC) during the course of treatment.

This study will be conducted in subjects who meet the El Escorial criteria of possible, laboratory-supported probable, probable, or definite criteria for a diagnosis of ALS. At screening, eligible subjects must be at least 18 years old, must have an SVC ≥ 65% of predicted capacity for age, height and gender, and must provide written informed consent prior to screening. Subjects on a stable dose of riluzole and those not taking riluzole, and women of child-bearing age at screening are eligible for inclusion as long as they meet specific protocol requirements.

Subjects will remain on randomized, placebo-controlled, double-blind treatment until the Week 4 visit. Each randomized subject will also have a Week 8 Follow-up Telephone Interview to assess for adverse events (AEs), changes in concomitant medications and to administer the ALSFRS-R.

Eligibility Criteria:
Inclusion Criteria:

1. Age 18 years or older.
2. Sporadic or familial ALS diagnosed as possible, laboratory-supported probable, probable, or definite as defined by revised El Escorial criteria (Appendix 1).
3. Onset of weakness or spasticity due to ALS ≤ 2 years (24 months) prior to Baseline Visit.
4. Slow vital capacity (SVC) measure ≥65% of predicted for gender, height, and age at the screening visit.
5. Subjects must not have taken riluzole for at least 30 days, or be on a stable dose of riluzole for at least 30 days, prior to randomization (riluzole-naïve subjects are permitted in the study).
6. Subjects must be able to swallow oral medication at the Screening Visit and expected to be able to swallow the capsule throughout the course of the study.
7. Capable of providing informed consent and following trial procedures.
8. Geographically accessible to the site.
9. Women must not be able to become pregnant (e.g. post menopausal, surgically sterile, or using adequate birth control methods) for the duration of the study and three months after study completion. Adequate contraception includes: abstinence, hormonal contraception (oral contraception, implanted contraception, injected contraception or other hormonal (patch or contraceptive ring, for example) contraception), intrauterine device (IUD) in place for ≥ 3 months, barrier method in conjunction with spermicide, or another adequate method.
10. Subjects must agree not to take live attenuated vaccines (including seasonal flu vaccine) 30 days before randomization, throughout the duration of the trial and for 60 days following the trial.

Exclusion Criteria:

1. Prior use of fingolimod (Gilenya®).
2. History or presence of cardiac conditions including:

   1. Cardiovascular or cerebrovascular disease in the previous 6 months (eg. myocardial infarction, unstable angina, or stroke)
   2. Congestive heart failure
   3. First, second- or third-degree atrioventricular block, sick sinus syndrome, or other serious cardiac rhythm disturbances
   4. Any history of Torsades de Pointes
3. Treatment with a prohibited medication within 30 days of the Baseline Visit:

   a. Class Ia or III antiarrhythmic medications: i.e., Quinidine, Sotalol Includes Nuedexta b. QT interval prolonging medications c. Ketoconazole d. Beta-blockers e. Calcium channel blockers f. Immunosuppressant medication g. Chemotherapeutic (anti-neoplastic) medications
4. Evidence on examination or ECG of bradycardia (\<55 bpm), QTc \>450ms for women or \>430 msec for men, or 1st degree or higher conduction block.
5. History of unexplained syncope or cardiac syncope.
6. Serum AST and ALT value \>2.0 times the upper normal limit.
7. Active infection (acute or chronic).
8. History of diabetes.
9. History of macular edema or uveitis.
10. History of lymphopenia.
11. History of acquired or inherited immune deficiency syndrome, including leukopenia.
12. History of severe untreated chronic obstructive sleep apnea.
13. Exposure to any other agent currently under investigation for the treatment of patients with ALS (off-label use or investigational) within 30 days of the Baseline Visit.
14. Presence of tracheostomy.
15. Use of non-invasive ventilation for hypoventilation due to ALS (such as BiPAP).
16. Presence of feeding tube.
17. Presence of diaphragmatic pacing system.
18. The presence of unstable psychiatric disease, cognitive impairment, or dementia that would impair ability of the subject to provide informed consent, according to PI judgment, or a history of active substance abuse within the prior year.
19. Clinically significant history of unstable or severe cardiac, oncologic, hepatic, or renal disease, or other medically significant illness.
20. Pregnant women or women currently breastfeeding.