Evaluation of Patient Retention of Fingolimod vs. Currently Approved Disease Modifying Therapy in Patients With Relapsing Remitting Multiple Sclerosis.
Condition: Relapsing Remitting Multiple Sclerosis
MeSH terms: Multiple Sclerosis; Multiple Sclerosis, Relapsing-Remitting; Sclerosis
Intervention: Fingolimod; Disease Modifying therapy
Intervention MeSH terms: Fingolimod Hydrochloride
Phase: Phase 4
Study type: Interventional
Primary purpose: Treatment
Allocation: Randomized
Intervention model: Parallel Assignment
Masking: None (Open Label)
Enrollment: 881.0
Sex: All
Minimum age: 18 Years
Maximum age: 65 Years
Healthy volunteers: No

Summary:

      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.
    

Eligibility criteria:

        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.