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.

Phase 3TerminatedNCT00731692

Novartis Pharmaceuticals970 enrolled

Overview

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

Study Type

INTERVENTIONAL

Allocation

RANDOMIZED

Purpose

TREATMENT

Masking

QUADRUPLE

Enrollment

970

Conditions

Primary Progressive Multiple Sclerosis

Interventions

Eligibility

Sex: ALLMin age: 25 YearsMax age: 65 Years

Medical Language ↔ Plain English

Inclusion Criteria: General 1. sign written informed consent prior to participating in the study 2. 25 through 65 years of age inclusive 3. 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. 1. diagnosis of primary progressive multiple sclerosis (according to the 2005 Revised McDonald criteria): 2. time since first reported symptoms between 2 and 10 years 3. evidence of clinical disability progression in the 2 years prior to Screening 4. 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

Locations (157)

Novartis Investigative Site

Newport Beach, California, United States

Novartis Investigative Site

Sacramento, California, United States

Novartis Investigative Site

Aurora, Colorado, United States

Novartis Investigative Site

Pompano Beach, Florida, United States

Novartis Investigative Site

Tampa, Florida, United States

Outcomes

Primary Outcomes

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.

Time frame: up to 36 months after the last patient was randomized

Secondary Outcomes

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)

Time frame: 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.

Time frame: 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

Time frame: 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

Time frame: 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

Time frame: 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

Time frame: 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

Time frame: 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