Long-term Safety and Tolerability of 0.5 mg Fingolimod in Patients With Relapsing Forms of Multiple Sclerosis

Phase 3

Completed

Conditions: Relapsing Forms of Multiple Sclerosis

Interventions: Drug: Fingolimod

Registration Number: NCT01201356

Lead Sponsor: Novartis Pharmaceuticals

Brief Summary: The purpose of this study was to collect long-term safety and tolerability, long-term efficacy, and health outcome data in all patients currently ongoing in the fingolimod multiple sclerosis clinical development program. This study combined all currently ongoing Phase II and III fingolimod extension studies as well as ongoing and newly planned studies into one single long-term extension protocol that provided patients with continuous treatment until fingolimod was registered, commercially available, and reimbursed in the respective countries.

Detailed Description: This study had two parts:

* Part 1, collecting long-term safety, tolerability, efficacy and health outcomes data through approximately 30-Jun-2016 until all end of study (EOS) visits of Part 1 and last follow-up visit through Jan-2017 and

* Part 2, collecting limited safety and tolerability data until approximately 30 Jun 2018, in a subset of patients who participated in Part 1, and other eligible patients from ongoing fingolimod trials.

Recruitment & Eligibility

Status: COMPLETED

Sex: All

Target Recruitment: 4125

Inclusion Criteria

Patients who have completed selected ongoing or planned trials with FTY720.

Key

Exclusion Criteria

Premature permanent discontinuation of a previous fingolimod study.
Pregnant or nursing (lactating) women.
Women of child-bearing potential, UNLESS they are using two birth control methods, at least 1 of which must be hormonal contraception, tubal sterilization, partner's vasectomy or intrauterine device.
Chronic disease of the immune system, other than multiple sclerosis, which may require immunosuppressive treatment.
Diabetic patients with moderate or severe non-proliferative diabetic retinopathy or proliferative diabetic retinopathy and uncontrolled diabetic patients with HbA1c > 8%.
Active systemic bacterial, viral or fungal infections, or known to have AIDS, Hepatitis B, Hepatitis C infection or have positive HIV antibody, Hepatitis B surface antigen or Hepatitis C antibody tests.
Previous treatment with cladribine, cyclophosphamide or mitoxantrone.
Treatment with immunoglobulins and/or monoclonal antibodies (including Natalizumab) in the past 3 months during the previous fingolimod study:
Any of the following cardiovascular conditions that have developed during the previous fingolimod study:
- Myocardial infarction within the past 6 months prior to entry in the extension study or with current unstable ischemic heart disease;
- Cardiac failure (Class III, according to New York Heart Association Classification) or any severe cardiac disease as determined by the investigator;
- Arrhythmia requiring current treatment with Class III antiarrhythmic drugs (e.g., amiodarone, bretylium, sotalol, ibutilide, azimilide, dofetilide)
- History or presence of a third degree AV block
- Proven history of sick sinus syndrome or sino-atrial heart block
- Known history of angina pectoris due to coronary spasm or Raynaud's phenomenon
Any of the following pulmonary conditions during the previous fingolimod study:
- Severe respiratory disease or pulmonary fibrosis diagnosed (during the previous fingolimod study)
- Active tuberculosis
Alcohol abuse, chronic liver disease during the previous fingolimod study.

The patient must have participated in a previous fingolimod trial to be eligible to participate in this trial.

Study & Design

Study Type: INTERVENTIONAL

Study Design: SINGLE_GROUP

Arm && Interventions

Group	Intervention	Description
Fingolimod 0.5 mg/day	Fingolimod	Open-label fingolimod 0.5 mg, taken orally once daily

Primary Outcome Measures

Name	Time	Method
Parts I and II: Number of Participants With Adverse Events, Serious Adverse Event, and Death	Baseline (Part I) to Month 6 Follow-up (Part II), up to 8 years	Analysis of absolute and relative frequencies for Adverse Event (AE), Serious Adverse Event (SAE) and Deaths by primary System Organ Class (SOC) to demonstrate that Fingolimod 0.5 mg/day is safe in patients with relapsing forms of Multiple Sclerosis (MS) through the monitoring of relevant clinical and laboratory safety parameters. Only descriptive analysis performed.

Secondary Outcome Measures

Name	Time	Method
Part I: Percent Brain Volume Change (PBVC) Relative to First Dose of Fingolimod	Month 3 to Month 156	Descriptive statistics on percent brain volume change from first dose of fingolimod baseline were presented by visit. A negative change from baseline indicates improvement.
Part I: Number of Participants With Confirmed 6-month Disability Progression After First Dose of Fingolimod	Month 12 to Month 156	Disability progression was defined based on an increase in the EDSS score by 1.5 point for patients with a first dose of fingolimod (FDF) baseline EDSS score of 0, 1 point for patients with FDF baseline EDSS of \>=1 and \<=5.5, and by 0.5 points for patients with an FDF baseline EDSS\>5.5, confirmed after 6 months and all intermediate EDSS assessments. A 6-month confirmed disability progression was defined as a 6-month sustained increase from the reference (potential onset of progression) value in the EDSS scores. i.e., every EDSS score (scheduled or unscheduled) within a 6-month duration after the first progression should meet the progression criteria as specified above. The confirmation could only happen at a scheduled visit and in the absence of a relapse. Only descriptive analysis performed.
Part I: Annualized Rates of New or Newly Enlarging T2 Lesions (ARneT2) Compared With First Dose of Fingolimod	Month 0 (Core Baseline) to End of Study (an average of Month 156)	Annualized rate of new/newly enlarging T2 lesions (ARneT2) is defined as the number of new or newly enlarging T2 lesions experienced during a specific period of time adjusted to a one-year period. ARneT2 was calculated as follows: (total number of new/newly enlarging T2 lesions) / (total number of days in the study for all patients for that specific period of time) x 365.25.Month 0 is the first dose of fingolimod study drug among all studies in which patient participated. Only descriptive analysis performed.
Part I: Change From First Dose of Fingolimod in Total T1 Hypointense Lesions Volume	Month 3 to End of Study (Study Completion Visit)	T1 hypointense lesion (black hole) volume was summarized by presenting descriptive statistics for change from first dose of fingolimod baseline values by visit.
Part I: Annualized Rate of Brain Atrophy (ARBA) Relative to First Dose of Fingolimod	Month 3 to Month 156	The annualized rate of brain volume change is an "averaged annual percentage change" in brain volume. ARBA was calculated as: ARBA = \[(SIENA/100+1) \^ (365.25/#days)-1\]\100 where SIENA=(Vk/V0-1)\100 and Vk is the brain volume at time k, V0 is the brain volume at time 0 and k is the total number of days in the study for all patients for that specific period of time) × 365.25. Only descriptive analysis performed.
Part I: Aggregate Annualized Relapse Rates (ARR) From First Dose of Fingolimod	Month 0 (Core Baseline) to End of Follow-up Visit (an average of 162 months)	Annualized relapse rate (ARR) is defined as the number of all relapses (including both confirmed and unconfirmed relapses) experienced during a specific period of time adjusted to a one-year period. ARR is calculated as follows: (total number of all relapses) / (total number of days in the study for all patients for that specific period of time) x 365.25. Month 0 is the first dose of fingolimod study drug among all studies in which patient participated. Only descriptive analysis performed.
Part I: Number of Participants With Relapses (Confirmed and Unconfirmed) From First Dose of Fingolimod	Month 0 (Core Baseline) to End of Follow-up Visit (an average of 162 months)	A relapse is defined as the appearance of a new neurological abnormality or worsening of previously stable or improving pre-existing neurological abnormality, separated by at least 30 days from onset of a preceding clinical demyelinating event. The abnormality must be present for at least 24 hours and occur in the absence of fever (\<37.5°C) or infection. In Study Part One, a relapse must be confirmed by an Expanded Disability Status Scale (EDSS) certified Physician within 7 days of the onset of symptoms. A relapse is confirmed when it is accompanied by an increase of at least half a step (0.5) on the EDSS or an increase of 1 point on two different Functional Systems (FS) of the EDSS or 2 points on one of the FS (excluding Bowel/Bladder or Cerebral FS). Month 0 is the first dose of fingolimod study drug among all studies in which patient participated. Only descriptive analysis performed.
Part I: Change From First Dose of Fingolimod in Total T2 Lesions Volume	Month 3 to End of Study (Study Completion Visit)	Total volume of T2 lesions was summarized by presenting descriptive statistics for change from first dose of fingolimod baseline values by visit.
Part I: Number of Participants With Categorized Change From First Dose of Fingolimod in Expanded Disability Status Scale (EDSS) Overall Score	Month 3 to Month 6 Follow-up	The EDSS is a scale for assessing neurological impairment in MS (Kurtzke 1983) including (1) a series of scores in each of eight functional systems, and (2) the EDSS steps (ranging from 0 (normal) to 10 (death due to MS). The functional systems are Visual, Brain Stem, Pyramidal, Cerebellar, Sensory, Bowel and Bladder, Cerebral and Other functions. Based on the assessment of each FS, the participant's overall score is categorized as Improvement, Stable or Deterioration. If baseline EDSS score is \<=5, improvement is indicated by an EDSS score change of \<= -1, stable is indicated by an EDSS score change of \> -1 and \<= 0.5, deterioration is indicated by an EDSS score change of \> 0.5; if baseline EDSS score is \> 5, improvement is indicated by an EDSS score change of \<= -0.5, stable is indicated by an EDSS score change of \> -0.5 and \<= 0, deterioration is indicated by an EDSS score change of \> 0. Only descriptive analysis performed.
Part I: Change From First Dose of Fingolimod in Expanded Disability Status Scale (EDSS)	Month 0 (Core Baseline) to End of Follow-up Visit (an average of 162 months)	The EDSS is a scale for assessing neurological impairment in MS (Kurtzke 1983) including (1) a series of scores in each of eight functional systems, and (2) the EDSS steps (ranging from 0 (normal) to 10 (death due to MS). The functional systems are Visual, Brain Stem, Pyramidal, Cerebellar, Sensory, Bowel and Bladder, Cerebral and Other functions. Based on the assessment of each FS, the participant's overall score is determined between 0 to 10. A negative change from baseline indicates improvement. Only descriptive analysis performed.