Evaluation of Patient Retention of Fingolimod vs. Currently Approved Disease Modifying Therapy in Patients With Relapsing Remitting Multiple Sclerosis.

A 12-month, Prospective, Randomized, Active-controlled, Open-label Study to Evaluate the Patient Retention of Fingolimod vs. Approved First-line Disease Modifying Therapies in Adults With Relapsing Remitting Multiple Sclerosis (PREFERMS)

A 12 month study where 852 patients with relapsing remitting MS will be randomized 1:1 to fingolimod or approved disease modifying therapy. Patients will be be treatment naive or have only been treated with one class of DMT (Interferon beta preparation or glatiramer acetate) . Patients will be able to switch to different treatment for safety, efficacy, tolerability or convenience during the study.

Primary objective is to evaluate efficacy of fingolimod by assessing patients retention on treatment. Secondary objectives are to compare reasons for discontinuation, adverse events, cognitive impairment, medication satisfaction and change in brain volume measured by MRI.

852 Patients with relapsing remitting MS will be randomized 1:1 to fingolimod or approved first line DMTs. Patients must be either treatment naive or have received treatment with only one class of treatment (interferon beta preparation or glatiramer acetate) . Patients previously treated with DMT and randomized to the DMT arm may not remain on the same treatment for the study and will have to switch to a different class (i.e., previously treated with glatiramer acetate will switch to interferon beta preparaption, previously treated with interferon beta preparation will swtich to glatiramer acetate).

Entry criteria at screening include but are not limited to, age 18-65, diagnosis with RRMS, EDSS < or equal to 6, not pregnant or planning pregnancy and women of childbearing potential willing to use contraception throughout the study.

Exclusion criteria include but are not limited to - prior exposure to fingolimod, history of malignancy within 5 years, other than RRMS types of MS, other diseases of the immune system, active macular edema, systemic bacterial, viral or fungal infections, patients without vaccine against varicella zoster, receipt of live or attentuated vaccines within a month of screening, history of various cardiac conditions, presence of certain ECG abnormalities, resting heart rate < 45 bpm, symptomatic bradycardia, recurrent syncope, severe untreated sleep apnea, severe pulmonary conditions, various hepatic conditions, certain neurologic disorders, pregnancy.

Patients may switch treatment before 3 months for safety reasons only, after 3 months for safety, efficacy, tolerability or convenience. Treatment switch during the study may be to any of study approved treatments irrespective of prior treatment.

Patients randomized to fingolimod will need to have 6 hours of observation for signs and symptoms of bradycardia following administration of the first dose. Extended observation or overnight observation may be necessary under certain circumstances. Primary objective is to evaluate efficacy of fingolimod by assessing patients retention on treatment. Secondary objectives are to compare reasons for discontinuation, adverse events, cognitive impairment, medication satisfaction and change in brain volume measured by MRI. Exploratory objectives include annualized relapse rate, OCT, MRI evaluations, biomarkers and patient reported outcome measures.

Inclusion Criteria:

1. written informed consent must be obtained prior to any assessment being performed.

2. Male and female patients aged 18-65 years inclusive.

3. Patients diagnosed with relapsing remitting MS, defined by the 2010 revised McDonald criteria (Pollman et al, 2011) (Appendix 1).

4. EDSS score of less than or equal to 6.

5. Patients naive to treatment or who have been treated with no more than one class of DMT previously (interferon β preparation or glatiramer acetate), and who, per investigator judgment, may benefit from a change of treatment class.

6. Patients who have been treated with DMF for less than 2 months total exposure and who have a normal lymphocyte count at screening.

7. Women of childbearing potential must have a negative urine and serum β-human chorionic gonadotropin (β-hCG) pregnancy test at screening and at baseline.

8. Before entry women must be:

   • Post menopausal for at least 1 year, or
   • Surgically sterile (have had a hysterectomy or bilateral oophorectomy, tubal ligation or otherwise incapable of pregnancy, or
   • Practicing a highly effective method of birth control if sexually active, including hormonal prescription oral contraceptives, contraceptive injections, contraceptive patch, intrauterine device, double barrier method (e.g., condoms, diaphragm or cervical cap with spermicidal foam, cream or gel), or male partner sterilization consistent with local regulations regarding use of birth control methods for patients participating in clinical trials, for the duration of their participation in the study, or
   • Not heterosexually active (patients who are not heterosexually active at screening must agree to utilize a highly effective method of birth control if they become heterosexually active during their participation in the study) 4.2 Exclusion criteria

1. Use of other investigational drugs within 30 days of screening.

2. History of hypersensitivity to any of the study drugs or to drugs of similar chemical classes.

3. Prior exposure to fingolimod or any other S1P receptor modulating compounds.

4. History or presence of malignancy of any organ system (other than successfully treated basal or squamous cell carcinoma of the skin or stage 0 carcinoma of the cervix), treated or untreated, within the past 5 years, regardless of whether there is evidence of local recurrence or metastases.

5. Patients diagnosed with Secondary Progressive Multiple Sclerosis (SPMS) or Primary Progressive MS (PPMS).

6. Patients with a history of chronic disease of the immune system other than MS or a known immunodeficiency syndrome.

7. Patients who have been treated with:

   • Natalizumab, mitoxantrone, cladribine, rituximab, alemtuzumab, ofatumumab, ocrelizumab at any time before randomization

   • Immunoglobulins, or pulse of corticosteroids with more than 6 months cumulative exposure

   • Immunosuppressive/chemotherapeutic medications (e.g., methotrexate, azathioprine, cyclophosphamide, cellcept, Cytoxan, IVIG) with more than 6 months of cumulative exposure and within 6 months prior to randomization

   • Corticosteroids or adrenocorticotropic hormones in the past 30 days before randomization. Patients that require corticosteroids for a relapse during the screening period may be rescreened 30 days after the last dose.

8. History of treatment with both classes of approved first line DMT (interferon β preparation and glatiramer acetate) or DMF exposure of 2 months or longer.

9. Patients with uncontrolled diabetes mellitus (HbA1c > 7%).

10. Diagnosis of macular edema during the screening phase. Patients with a history of macular edema will be allowed to enter the study provided that they do not have macular edema at the screening visit.

11. Patients with active systemic bacterial, viral or fungal infections, or known to have AIDS, Hepatitis B, Hepatitis C infection or positive HIV antibody, Hepatitis B surface antigen or Hepatitis C antibody tests.

12. Patients without history of chickenpox or without vaccination against varicella-zoster virus at screening (patients may be vaccinated and rescreened one month or longer after vaccination).

13. Patients who have received any live or live attenuated vaccines (including for varicella-zoster or measles) within 1 month prior to baseline.

14. Patients with any medically unstable condition as assessed by the investigator.

15. Patients with a history of the following cardiovascular conditions:

    • Cardiac arrest.

    • myocardial infarction, unstable angina, stroke, transient ischemic attack, decompensated heart failure requiring hospitalization, or Class III/IV heart failure (Appendix 3).

    • Congestive heart failure.

    • Hypertension that is not controlled with prescribed medications. These patients may be rescreened if blood pressure is stabilized with treatment.

    • Cerebrovascular disease.

    • History or presence of Mobitz Type II 2nd degree or 3rd degree AV block or sick sinus syndrome, unless patient has a pacemaker.

    • Patients at higher risk of symptomatic bradycardia or heart block because of a coexisting medical condition or certain concomitant medications.

    • Patients randomized to the fingolimod arm with prolonged QTc interval at screening (corrected QT interval > 450 ms in males and > 470 ms in females); for patients randomized to the fingolimod treatment arm before dosing (baseline) or during the 6-hour observation period; and those patients at additional risk for QT prolongation (e.g., hypokalemia, hypomagnesemia, congenital long-QT syndrome), or on a concomitant therapy with QT prolonging drugs with a known risk of Torsades de pointes (e.g., citalopram, chlorpromazine, haloperidol, methadone, erythromycin).

    • Patients receiving class Ia or Class III antiarrhythmic drugs (Appendix 6)
    • Patients receiving concurrent therapy with drugs that slow the heart rate or atrioventricular conduction (e.g., beta blockers, digoxin, or heart-rate slowing calcium channel blockers such as diltiazem, verapamil or digoxin). The possibility to switch to drugs that do not slow the heart rate or atrioventricular conduction should be evaluated by the physician prescribing these drugs before initiating fingolimod treatment.
    • History of sick sinus syndrome or sinoatrial heart block.
    • Resting heart rate of < 45 bpm or symptomatic bradycardia
    • Recurrent syncope
    • Severe untreated sleep apnea

16. Patients with severe pulmonary conditions (including severe respiratory disease, pulmonary fibrosis, active tuberculosis, severe or poorly controlled asthma).

17. Patients with any of the following hepatic conditions:

    • Chronic liver or biliary disease

    • Total bilirubin greater than upper limit of normal (ULN) at screening unless in the context of Gilbert's syndrome
    • Conjugated bilirubin greater than the ULN at screening
    • AST (SGOT), ALT (SGPT) greater than 3 times ULN at screening
    • Alkaline phosphatase (AP) greater than 1.5 times the ULN at screening

18. Serum creatinine greater than 2.0 mg/dL (176.5 µmol/L) at screening.

19. Patients with the following neurological/psychiatric disorders:

    • History of substance abuse (drug or alcohol) in the past five years as determined by the investigator
    • Progressive neurological disorder other than MS which may affect study participation as determined by the investigator
    • Any serious psychiatric condition that may interfere with the patient's ability to cooperate and comply with the study procedures as determined by the investigator

20. Women who are pregnant or nursing (lactating) or planning to become pregnant.

21. Any condition that in the opinion of the investigator, would compromise the well-being of the patient or the conduct of the study, or prevent the patient from meeting or performing study requirements.

22. Pre-planned surgery or medical procedure that would interfere with the conduct of the study.

23. Employee of the sponsor, investigator or study center, with direct involvement in the proposed study or other studies under the direction of that investigator or study center, as well as family members of the employees or the investigator.