This Was an Open-label, Single-arm Extension Study (CFTY720D2306E1) to a Double-blind, Randomized Multicenter, Placebo-controlled, Parallel-group Core Study (CFTY720D2306) in PPMS.

Study Overview
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Brief Summary
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The purpose of this study is to evaluate whether FTY720 is effective in delaying MS disability progression compared to placebo in patients with PPMS. This was an open-label, single-arm extension study to a double-blind, randomized multicenter, placebo-controlled, parallel-group core study. The core study completed and eligible patients enrolled into the extension study at the next scheduled or unscheduled core study visit. All patients, regardless of their treatment in the core study, received fingolimod 0.5 mg in the extension study. The extension study was terminated early after the results of the core study became available showing that the study did not meet its primary endpoint which was defined as confirmed disability progression in this population

Official Title
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A Double-blind, Randomized, Multicenter, Placebo-controlled, Parallel-group Study Comparing the Efficacy and Safety of 0.5mg Fingolimod Administered Orally Once Daily Versus Placebo in Patients With Primary Progressive Multiple Sclerosis and An Open-label, Single-arm Extension Study to the Double-blind, Randomized, Multicenter, Placebo-controlled, Parallel-group Study Comparing the Efficacy and Safety of0.5 mg FTY720 Administered Orally Once Daily Versus Placebo in Patients With Primary Progressive Multiple Sclerosis

Conditions
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Primary Progressive Multiple Sclerosis

Intervention / Treatment
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* Drug: FTY720
* Drug: Placebo


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: General sign written informed consent prior to participating in the study 25 through 65 years of age inclusive females of childbearing potential must: have a negative pregnancy test at Baseline (prior to randomization) and use simultaneously two forms of effective contraception during the treatment and 3-months after discontinuation of study medication Primary Progressive Multiple sclerosis. diagnosis of primary progressive multiple sclerosis (according to the 2005 Revised McDonald criteria): time since first reported symptoms between 2 and 10 years evidence of clinical disability progression in the 2 years prior to Screening disability status at Screening EDSS score of 3.5-6.0 inclusive pyramidal functional system score of 2 or more 25'TWT less than 30 seconds Extension study Inclusion criteria Patients initially randomized to fingolimod 1.25 mg or placebo as part of the first study cohort, were to have completed at least 3 years on study drug treatment at the time of extension study initiation. Patients initially randomized to fingolimod 0.5 mg or placebo as part of the second study cohort, were to have continued on study drug treatment until such time as the last ongoing patient enrolled in the study had reached 3 years in study Exclusion Criteria: PPMS specific: History of relapses/attacks Progressive neurological disorder other than PPMS Pure cerebellar syndrome or pure visual progressive syndrome or pure cognitive progressive syndrome Presence of spinal cord compression at screening MRI Relevant history of vitamin B12 deficit Evidence of syphilis or borreliosis at Screening Cardiovascular conditions: Myocardial infarction within the past 6 months or current unstable ischemic heart disease History of angina pectoris due to coronary spasm or history of Raynaud's phenomenon Severe cardiac failure or cardiac arrest History of symptomatic bradycardia Resting pulse <55 bpm pre-dose History of sick sinus syndrome or sino-atrial heart block History or presence of second and third degree AV block or an increase QT interval (QTc>440 ms) Arrythmia requiring treatment with class III antiarrythmic drugs History of positive tilt test from workout of vasovagal syncope Hypertension, not controlled with medication Pulmonary: Severe respiratory disease or pulmonary fibrosis TB Abnormal X-ray, suggestive of active pulmonary disease Abnormal PFT: <70% of predicted for FEV1 and FVC; <60% for DLCO Patients receiving chronic (daily) therapies for asthma Hepatic: Known history of alcohol abuse, chronic liver or biliary disease Total or conjugated Brb >ULN, unless in context of Gilbert's syndrome AP >1.5xULN; ALT/AST >2xULN; GGT>3xULN Other: History of chronic disease of the immune system other than MS Malignancy (other than successfully treated SCC or BCC) Diabetes Mellitus Macular Edema present at screening HIV, Hepatitis C or B, other active infection History of total lymphoid irradiation or bone marrow transplantation Serum creatinine >1.7 mg/dl WBC <3500 cells/mm3 Lymphocyte count <800 cells/mm3 History of substance abuse or any other factor that may interfere with subject ability to cooperate and comply with the study procedures Unable to undergo MRI scans Participation in any therapeutical clinical research study in the 6 months prior to randomization Pregnant or lactating women Drugs requiring wash-out period: 3 months: Systemic corticosteroids or ACTH INF-beta 6 months: Immunosuppressive medication Immunoglobulins Monoclonal antibodies Drugs that exclude participation in the study: Cladribine Cyclophosphamide Mitoxantrone (except: patients who received a cumulative dose of no more than 60mg/m2 more than 5 years ago could enter the study) Extension study Exclusion criteria -Patients were not eligible for enrollment in the extension study if they had any of the following key exclusion criteria at the extension study Baseline visit: active chronic immune system disease other than MS (or stable disease treated with immune therapy); known immunodeficiency syndrome; active infection; uncontrolled diabetes mellitus; macularedema; treatment with Class Ia or III antiarrhythmic drugs; any of the specified cardiac, pulmonary, or hepatic conditions; or any medically unstable condition

Ages Eligible for Study
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Minimum Age: 25 Years
Maximum Age: 65 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Quadruple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: FTY720D 0.5 mg<br>Cohort 2: The 0.5 mg group consists of patients who were directly randomized to fingolimod 0.5 mg (i.e. AFTER the amendment | Drug: FTY720<br>* Fingolimod capsules at doses of 1.25 mg (prior to implementation of Amendment 5) and 0.5 mg (after Amendment 5) were administered orally once daily<br>|
| Placebo Comparator: Placebo<br>Cohort 1 and 2: Patients randomized to placebo continued on placebo after re-randomization | Drug: Placebo<br>* Matching placebo capsules were administered orally once daily<br>|
| Experimental: FTY720D 1.25 mg switch to 0.5 mg<br>Cohort 1: fingolimod 1.25 group consists of patients who were initially randomized to fingolimod 1.25 mg and switched to fingolimod 0.5 mg after amendment on Nov 2009 | Drug: FTY720<br>* Fingolimod capsules at doses of 1.25 mg (prior to implementation of Amendment 5) and 0.5 mg (after Amendment 5) were administered orally once daily<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Kaplan-Meier Estimate of the Risk of 3-month Confirmed Disability Progression Based on Composite Endpoint | 3-month sustained increase from Baseline in EDSS (at least 1 point increase from Baseline for patients with a Baseline value of 5 or less or at least 0.5 point increase from Baseline for patients with a Baseline value of 5.5 or more) or 3-month sustained increase of at least 20% from BL in the time taken to complete the timed 25-foot walk test (25' TWT); or 3-month sustained increase of at least 20% from BL in the time taken to complete the 9-HPT. The 25' TWT is a quantitative measure of lower extremity function. The EDSS is a scale assessing neurologic impairment, including a series of scores in each of 8 functional systems: Visual, Brain Stem, Pyramidal, Cerebellar, Sensory, Bowel and Bladder, Cerebral and Other functions. The score ranges from 0 (normal) to 10 (death due to MS)). The 9-hole peg test (9-HPT) is a quantitative measure of upper extremity (arm and hand) function. | up to 36 months after the last patient was randomized | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Kaplan-Meier Estimate of the Risk of 3- Month Confirmed Disability Progression Based on Expanded Disability Status Scale (EDSS) | The Expanded Disability Status Scale (EDSS) is a scale for assessing neurologic impairment in MS (Kurtzke 1983) and includes a series of scores in each of 8 functional systems and 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. Fatigue is not included in the Cerebral score of the EDSS. The score ranges from 0 (normal) to 10 (death due to MS) | up to 36 months after the last patient was randomized | 
| Percent Change From Baseline in Brain Volume at Month 36 | The percent change from Baseline in brain volume was analyzed using a random coefficients model. The model included: 1) fixed effects: treatment and region and 2) continuous covariates: time, number of Gd enhancing lesions at Baseline, Baseline T2 volume, and normalized brain volume at Baseline. Time as a continuous covariate allowed for the estimation of different slopes and intercepts among treatment groups. | Baseline to month 36 | 
| Kaplan Meier Estimate -Percentage of Participants With 3- Month Confirmed Disability Progression Based on 9-HPT. | The 9-HPT is a quantitative measure of upper extremity (arm and hand) function designed and validated for evaluation of MS patients. N= Total number of patients included in the analysis | up to 36 months after the last patient was randomized | 
| Kaplan Meier Estimate -Percentage of Participants With 3- Month Confirmed Disability Progression Based on 25' TWT. | The 25' TWT is a quantitative measure of lower extremity function designed and validated for evaluation of MS patients. N= Total number of patients included in the analysis | up to 36 months after the last patient was randomized | 
| Number of New/Enlarging T2 Lesions Per Year Measured From Baseline to Month 36 | Inflammatory disease, as measured by number of new or newly-enlarging T2 lesions, was assessed by Magnetic resonance Imaging (MRI) scanning of the brain and full spinal cord. N= Total number of patients included in the analysis | Baseline to 36 months | 
| Number of Gd-enhancing Lesions at Month 36 | Inflammatory disease, as measured by number of T1 Gd-enhancing lesions, was assessed by MRI scanning of the brain and full spinal cord. N= Total number of patients included in the analysis | Baseline to 36 months | 
| Percent Change in Total T2 Lesion Volume From Baseline to Month 36 | Inflammatory disease as measured by percent change in total T2 lesion volume (mm3) was assessed by MRI. N= Total number of patients included in the analysis | Baseline to month 36 | 
| Change From Baseline in the Patient Reported Indices in Multiple Sclerosis (PRIMUS-QoL Score) | The quality of life scale contains 22 items. Each item will be given a score of 1 or 0. A score of 1 (or 0) indicates the presence (or absence) of the symptom or adverse quality of life. All 22 item scores will be summed to obtain a total score ranging from 0 (good) to 22 (poor), which is the PRIMUS QoL scale score | Baseline, 36 months | 
| Change From Baseline in PRIMUS-Activities | The activities subscale of PRIMUS contains 15 items and each item is given a score of 0 (able to do on own without difficulties), 1 (able to do on own with difficulties), or 2 (unable to do on own). All 15 items were summed to obtain a total score ranging from 0 (good) to 30 (poor). | Baseline, 36 months | 
| Change From Baseline in Unidimensional Fatigue Impact (U-FIS) Score | Unidimensional Fatigue Impact Scale (U-FIS), contains 22 patient-reported items that assess the impact of fatigue on cognitive, physical, and psychosocial functioning. Responses formed a single unidimensional scale measuring fatigue impact. The U-FIS was calculated and analyzed according to the U-FIS scoring manual. The U-FIS scale contains 22 items with 5 possible outcomes for each item. Two response categories (about half the time and a lot of the time) were combined into 1 category to obtain 4 possible outcomes: 0 (never), 1 (a little of the time), 2 (about half the time/a lot of the time), and 3 (all the time). The 22 condensed item scores were summed to obtain a total score ranging from 0 (no fatigue) to 66 (severe fatigue impact). | Baseline, 36 months | 
| Change From Baseline in European Quality of Life - 5 Dimensions (EQ-5D Score) | EQ-5D: participant rated questionnaire to assess health-related quality of life in terms of a single utility score. Health State Profile component assesses level of current health for 5 domains: mobility, self care, usual activities, pain and discomfort, and anxiety and depression; 1 indicates better health state (no problems); 3 indicates worst health state (confined to bed). Scoring formula developed by EuroQoL Group assigns a utility value for each domain in the profile. Score is transformed and results in a total score range -0.594 to 1.000; higher score indicates a better health state. | Baseline, 36 months | 
| Change From Baseline in Multiple Sclerosis Walking Scale (MSWS-12 Score) | The Multiple Sclerosis Walking Scaleis a patient reported measure of walking quality (Hobart et al 2003), consisting of 12 items asking patients to rate the impact of MS upon their walking ability. Responses were captured on a 3-point scale ranging from 1 (Not at all) to 3 (A lot) for items 1 to 3 and on a 5-point scale ranging from 1 (not limited) to 5 (extremely) for items 4 to 12. All 12 item scores were summed to obtain a total score ranging from 12 (good) to 54 (poor) which is the MSWS-12 scale score. The total score was transformed to a 0 to 100 scale score. The MSWS-12 scale score will be transformed to a 0-100 scale score before any summaries or statistical analyses are performed. The transformed score is obtained by subtracting 12 and divided by 42 and multiplying by 100 (i.e., transformed scale score = (raw scale score- 12)/42*100). | Baseline, 36 months | 
| Blood Concentrations of Fingolimod and Fingolimod-phosphate | Concentrations of fingolimod and fingolimod-phosphate in whole blood were determined by validated liquid chromatography methods with tandem mass spectrometry. The lower limits of quantification were 0.08 ng/ml for fingolimod and 0.1 ng/ml for fingolimod-phosphate. Venous blood samples were collected for the analysis. | Month 3 up to 36 months | 
| Change in MSFC Z-score and Subscale Scores From Baseline to Month 36 | The Multiple Sclerosis Functional Composite (MSFC) is a multidimensional clinical outcome measure that includes quantitative tests of leg function/ambulation (Timed 25-Foot Walk), arm function (9-Hole Peg Test), and cognitive function (Paced Auditory Serial Addition Test). The overall MSFC z-score as an average of the three standardized scores derived using baseline data pooled over each treatment arm as reference population. Higher scores reflect better neurological function and a positive change from Baseline indicates improvement. | Baseline to Month 36 | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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FTY720, primary progressive multiple sclerosis,PPMS