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. (INFORMS)

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

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 Overview

• Status: Terminated
• Conditions: Primary Progressive Multiple Sclerosis
• Intervention / Treatment: Drug: FTY720; Drug: Placebo

• Study Type: Interventional
• Enrollment (Actual): 970
• Phase: Phase 3

Contacts and Locations

Study Locations

• Australia
  • New South Wales
    • Camperdown, New South Wales, Australia, 2050
      • Novartis Investigative Site
    • Liverpool, New South Wales, Australia, 2170
      • Novartis Investigative Site
  • Tasmania
    • Hobart, Tasmania, Australia, 7000
      • Novartis Investigative Site
  • Victoria
    • Box Hill, Victoria, Australia, 3128
      • Novartis Investigative Site
    • Heidelberg, Victoria, Australia, 3084
      • Novartis Investigative Site
    • Parkville, Victoria, Australia, 3050
      • Novartis Investigative Site
• Belgium
  • Charleroi, Belgium, 6000
    • Novartis Investigative Site
  • Edegem, Belgium, 2650
    • Novartis Investigative Site
  • Leuven, Belgium, 3000
    • Novartis Investigative Site
  • Liege, Belgium, 4000
    • Novartis Investigative Site
  • Melsbroek, Belgium, 1820
    • Novartis Investigative Site
  • Sint-Truiden, Belgium, 3800
    • Novartis Investigative Site
• Canada
  • Alberta
    • Calgary, Alberta, Canada, T2N 2T9
      • Novartis Investigative Site
    • Edmonton, Alberta, Canada, T6R 2B7
      • Novartis Investigative Site
  • British Columbia
    • Burnaby, British Columbia, Canada, V5G 2X6
      • Novartis Investigative Site
    • Vancouver, British Columbia, Canada, V6T 2B5
      • Novartis Investigative Site
  • Nova Scotia
    • Halifax, Nova Scotia, Canada, B3H 4K4
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  • Ontario
    • Ottawa, Ontario, Canada, K1H 8L6
      • Novartis Investigative Site
    • Toronto, Ontario, Canada, M4N 3M5
      • Novartis Investigative Site
    • Toronto, Ontario, Canada, M5B 1W8
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  • Quebec
    • Gatineau, Quebec, Canada, J9J 0A5
      • Novartis Investigative Site
    • Greenfield Park, Quebec, Canada, J4V 2J2
      • Novartis Investigative Site
    • Montreal, Quebec, Canada, H2L 4M1
      • Novartis Investigative Site
    • Montreal, Quebec, Canada, H3A 2B4
      • Novartis Investigative Site
  • Saskatchewan
    • Regina, Saskatchewan, Canada, S4T 1A5
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• Czechia
  • Ostrava-Poruba, Czechia, 708 00
    • Novartis Investigative Site
  • Plzen, Czechia, 301 00
    • Novartis Investigative Site
  • Praha 2, Czechia, 128 08
    • Novartis Investigative Site
  • Teplice, Czechia, 415 29
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  • CZE
    • Olomouc, CZE, Czechia, 775 20
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  • Czech Republic
    • Brno, Czech Republic, Czechia, 656 91
      • Novartis Investigative Site
    • Rychnov nad Kneznou, Czech Republic, Czechia, 516 01
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• Denmark
  • Aarhus, Denmark, 8000 C
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  • Sønderborg, Denmark, 6400
    • Novartis Investigative Site
• Finland
  • Helsinki, Finland, 00930
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  • Tampere, Finland, 33100
    • Novartis Investigative Site
  • Turku, Finland, 20520
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• France
  • Bordeaux Cedex, France, F-33076
    • Novartis Investigative Site
  • Lille Cedex, France, 59037
    • Novartis Investigative Site
  • Marseille cedex 05, France, 13385
    • Novartis Investigative Site
  • Montpellier, France, 34295
    • Novartis Investigative Site
  • Nantes Cedex 1, France, 44093
    • Novartis Investigative Site
  • Paris Cedex 13, France, 75651
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  • Rennes, France, 35043
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  • Strasbourg, France, 67091
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• Germany
  • Berlin, Germany, 10713
    • Novartis Investigative Site
  • Berlin, Germany, 13347
    • Novartis Investigative Site
  • Bochum, Germany, 44791
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  • Dresden, Germany, 01307
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  • Duesseldorf, Germany, D-40225
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  • Erlangen, Germany, 91054
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  • Essen, Germany, 45147
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  • Freiburg, Germany, 79106
    • Novartis Investigative Site
  • Hannover, Germany, 30625
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  • Hennigsdorf, Germany, 16761
    • Novartis Investigative Site
  • Magdeburg, Germany, 39120
    • Novartis Investigative Site
  • Muenchen, Germany, 81675
    • Novartis Investigative Site
  • Muenster, Germany, 48149
    • Novartis Investigative Site
  • Munchen, Germany, 81377
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  • Teupitz, Germany, 15755
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  • Trier, Germany, 54292
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  • Würzburg, Germany, 97080
    • Novartis Investigative Site
• Hungary
  • Budapest, Hungary, 1145
    • Novartis Investigative Site
  • Budapest, Hungary, 1076
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  • Debrecen, Hungary, 4032
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  • Gyor, Hungary, 9024
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  • Miskolc, Hungary, 3526
    • Novartis Investigative Site
  • Veszprem, Hungary, H-8200
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• Italy
  • BA
    • Bari, BA, Italy, 70124
      • Novartis Investigative Site
  • BS
    • Montichiari, BS, Italy, 25018
      • Novartis Investigative Site
  • CH
    • Chieti, CH, Italy, 66100
      • Novartis Investigative Site
  • CT
    • Catania, CT, Italy, 95123
      • Novartis Investigative Site
  • GE
    • Genova, GE, Italy, 16132
      • Novartis Investigative Site
  • MI
    • Milano, MI, Italy, 20132
      • Novartis Investigative Site
    • Milano, MI, Italy, 20122
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  • PA
    • Cefalù, PA, Italy, 90015
      • Novartis Investigative Site
  • PD
    • Padova, PD, Italy, 35128
      • Novartis Investigative Site
  • RM
    • Roma, RM, Italy, 00133
      • Novartis Investigative Site
    • Roma, RM, Italy, 00189
      • Novartis Investigative Site
  • TO
    • Orbassano, TO, Italy, 10043
      • Novartis Investigative Site
  • VA
    • Gallarate, VA, Italy, 21013
      • Novartis Investigative Site
• Netherlands
  • Amsterdam, Netherlands, 1105 AZ
    • Novartis Investigative Site
  • Eindhoven, Netherlands, 5623 EJ
    • Novartis Investigative Site
  • Nieuwegein, Netherlands, 3435 CM
    • Novartis Investigative Site
  • Nijmegen, Netherlands, 6525 GC
    • Novartis Investigative Site
  • Sittard-Geleen, Netherlands, 6162 BG
    • Novartis Investigative Site
  • CK
    • Breda, CK, Netherlands, 4818
      • Novartis Investigative Site
• Poland
  • Lodz, Poland, 90-153
    • Novartis Investigative Site
  • Lublin, Poland, 20-954
    • Novartis Investigative Site
  • Warszawa, Poland, 02-097
    • Novartis Investigative Site
  • Warszawa, Poland, 02-957
    • Novartis Investigative Site
• Spain
  • Madrid, Spain, 28046
    • Novartis Investigative Site
  • Madrid, Spain, 28040
    • Novartis Investigative Site
  • Andalucia
    • Sevilla, Andalucia, Spain, 41009
      • Novartis Investigative Site
  • Catalunya
    • Badalona, Catalunya, Spain, 08916
      • Novartis Investigative Site
    • Barcelona, Catalunya, Spain, 08035
      • Novartis Investigative Site
    • Barcelona, Catalunya, Spain, 08036
      • Novartis Investigative Site
    • Girona, Catalunya, Spain, 17007
      • Novartis Investigative Site
    • L'Hospitalet de Llobregat, Catalunya, Spain, 08907
      • Novartis Investigative Site
    • Lleida, Catalunya, Spain, 25198
      • Novartis Investigative Site
  • Comunidad Valenciana
    • Valencia, Comunidad Valenciana, Spain, 46026
      • Novartis Investigative Site
  • Madrid
    • Majadahonda, Madrid, Spain, 28222
      • Novartis Investigative Site
  • Pais Vasco
    • Bilbao, Pais Vasco, Spain, 48013
      • Novartis Investigative Site
• Sweden
  • Goeteborg, Sweden, 413 45
    • Novartis Investigative Site
  • Stockholm, Sweden, 17176
    • Novartis Investigative Site
• Switzerland
  • Basel, Switzerland, 4031
    • Novartis Investigative Site
  • Bern, Switzerland, 3010
    • Novartis Investigative Site
  • Lausanne, Switzerland, 1011
    • Novartis Investigative Site
  • Lugano, Switzerland, 6900
    • Novartis Investigative Site
  • Zuerich, Switzerland, 8091
    • Novartis Investigative Site
• Turkey
  • Ankara, Turkey, 06100
    • Novartis Investigative Site
  • Atakum / Samsun, Turkey, 55139
    • Novartis Investigative Site
  • Balcova / Izmir, Turkey, 35340
    • Novartis Investigative Site
  • Istanbul, Turkey, 34093
    • Novartis Investigative Site
  • Yenisehir / Izmir, Turkey
    • Novartis Investigative Site
• United Kingdom
  • Bristol, United Kingdom, BS10 5NB
    • Novartis Investigative Site
  • London, United Kingdom, EC1A 7BE
    • Novartis Investigative Site
  • London, United Kingdom, SE5 9RS
    • Novartis Investigative Site
  • London, United Kingdom, NW1 2BU
    • Novartis Investigative Site
  • London, United Kingdom, W8 6RF
    • Novartis Investigative Site
  • Newcastle Upon Tyne, United Kingdom, NE1 4LP
    • Novartis Investigative Site
  • Norwich, United Kingdom, NR4 7UY
    • Novartis Investigative Site
  • Manchester
    • Salford, Manchester, United Kingdom, M6 8HD
      • Novartis Investigative Site
  • South Yorkshire
    • Sheffield, South Yorkshire, United Kingdom, S10 2JF
      • Novartis Investigative Site
• United States
  • California
    • Newport Beach, California, United States, 92660
      • Novartis Investigative Site
    • Sacramento, California, United States, 95817
      • Novartis Investigative Site
  • Colorado
    • Aurora, Colorado, United States, 80045
      • Novartis Investigative Site
  • Florida
    • Pompano Beach, Florida, United States, 33060
      • Novartis Investigative Site
    • Tampa, Florida, United States, 33609
      • Novartis Investigative Site
  • Georgia
    • Atlanta, Georgia, United States, 30302
      • Novartis Investigative Site
  • Illinois
    • Chicago, Illinois, United States, 60611
      • Novartis Investigative Site
    • Chicago, Illinois, United States, 60637
      • Novartis Investigative Site
  • Kansas
    • Kansas City, Kansas, United States, 66160
      • Novartis Investigative Site
  • Maryland
    • Baltimore, Maryland, United States, 21287
      • Novartis Investigative Site
  • Massachusetts
    • Boston, Massachusetts, United States, 02135
      • Novartis Investigative Site
    • Brookline, Massachusetts, United States, 02445
      • Novartis Investigative Site
  • Michigan
    • Detroit, Michigan, United States, 48201
      • Novartis Investigative Site
  • Missouri
    • Saint Louis, Missouri, United States, 63110
      • Novartis Investigative Site
  • New Jersey
    • Teaneck, New Jersey, United States, 07666
      • Novartis Investigative Site
  • New York
    • Buffalo, New York, United States, 14203
      • Novartis Investigative Site
    • New York, New York, United States, 10029
      • Novartis Investigative Site
    • Rochester, New York, United States, 14642
      • Novartis Investigative Site
    • Stony Brook, New York, United States, 11794
      • Novartis Investigative Site
  • North Carolina
    • Charlotte, North Carolina, United States, 28207
      • Novartis Investigative Site
    • Durham, North Carolina, United States, 27705
      • Novartis Investigative Site
  • Ohio
    • Cleveland, Ohio, United States, 44195
      • Novartis Investigative Site
    • Columbus, Ohio, United States, 43221
      • Novartis Investigative Site
  • Pennsylvania
    • Pittsburgh, Pennsylvania, United States, 15213
      • Novartis Investigative Site
  • Tennessee
    • Knoxville, Tennessee, United States, 37934
      • Novartis Investigative Site
    • Nashville, Tennessee, United States, 37212
      • Novartis Investigative Site
  • Texas
    • Dallas, Texas, United States, 75390-9034
      • Novartis Investigative Site
    • Houston, Texas, United States, 77030
      • Novartis Investigative Site
    • San Antonio, Texas, United States, 78229
      • Novartis Investigative Site
  • Vermont
    • Burlington, Vermont, United States, 05401
      • Novartis Investigative Site
  • Virginia
    • Charlottesville, Virginia, United States, 22904
      • Novartis Investigative Site
  • Washington
    • Seattle, Washington, United States, 98122
      • Novartis Investigative Site
  • Wisconsin
    • Madison, Wisconsin, United States, 53792
      • Novartis Investigative Site

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 25 years to 65 years (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

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

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Quadruple

Number of Arms

3

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: FTY720D 0.5 mg; 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; 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
Placebo Comparator: Placebo; Cohort 1 and 2: Patients randomized to placebo continued on placebo after re-randomization	Drug: Placebo; Matching placebo capsules were administered orally once daily
Experimental: FTY720D 1.25 mg switch to 0.5 mg; 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; 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

What is the study measuring?

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

Collaborators and Investigators

• Sponsor: Novartis Pharmaceuticals

Publications and helpful links

General Publications

• Leppert D, Kropshofer H, Haring DA, Dahlke F, Patil A, Meinert R, Tomic D, Kappos L, Kuhle J. Blood Neurofilament Light in Progressive Multiple Sclerosis: Post Hoc Analysis of 2 Randomized Controlled Trials. Neurology. 2022 May 24;98(21):e2120-e2131. doi: 10.1212/WNL.0000000000200258. Epub 2022 Apr 4.
• Koch MW, Mostert J, Repovic P, Bowen JD, Strijbis E, Uitdehaag B, Cutter G. Smoking, obesity, and disability worsening in PPMS: an analysis of the INFORMS original trial dataset. J Neurol. 2022 Mar;269(3):1663-1669. doi: 10.1007/s00415-021-10750-z. Epub 2021 Aug 15.
• Koch MW, Mostert J, Zhang Y, Wolinsky JS, Lublin FD, Strijbis E, Cutter G. Association of Age With Contrast-Enhancing Lesions Across the Multiple Sclerosis Disease Spectrum. Neurology. 2021 Sep 28;97(13):e1334-e1342. doi: 10.1212/WNL.0000000000012603. Epub 2021 Aug 10.
• Miller DH, Lublin FD, Sormani MP, Kappos L, Yaldizli O, Freedman MS, Cree BAC, Weiner HL, Lubetzki C, Hartung HP, Montalban X, Uitdehaag BMJ, MacManus DG, Yousry TA, Gandini Wheeler-Kingshott CAM, Li B, Putzki N, Merschhemke M, Haring DA, Wolinsky JS. Brain atrophy and disability worsening in primary progressive multiple sclerosis: insights from the INFORMS study. Ann Clin Transl Neurol. 2018 Jan 30;5(3):346-356. doi: 10.1002/acn3.534. eCollection 2018 Mar.
• Lublin F, Miller DH, Freedman MS, Cree BAC, Wolinsky JS, Weiner H, Lubetzki C, Hartung HP, Montalban X, Uitdehaag BMJ, Merschhemke M, Li B, Putzki N, Liu FC, Haring DA, Kappos L; INFORMS study investigators. Oral fingolimod in primary progressive multiple sclerosis (INFORMS): a phase 3, randomised, double-blind, placebo-controlled trial. Lancet. 2016 Mar 12;387(10023):1075-1084. doi: 10.1016/S0140-6736(15)01314-8. Epub 2016 Jan 28. Erratum In: Lancet. 2017 Jan 21;389(10066):254.
• Hartung HP, Aktas O. Bleak prospects for primary progressive multiple sclerosis therapy: downs and downs, but a glimmer of hope. Ann Neurol. 2009 Oct;66(4):429-32. doi: 10.1002/ana.21880. No abstract available.

Study record dates

Study Major Dates

• Study Start (Actual): July 28, 2008
• Primary Completion (Actual): June 22, 2015
• Study Completion (Actual): June 22, 2015

Study Registration Dates

• First Submitted: August 7, 2008
• First Submitted That Met QC Criteria: August 7, 2008
• First Posted (Estimate): August 11, 2008

Study Record Updates

• Last Update Posted (Actual): June 14, 2017
• Last Update Submitted That Met QC Criteria: May 9, 2017
• Last Verified: May 1, 2017

More Information

Terms related to this study

• Keywords: FTY720, primary progressive multiple sclerosis,PPMS
• Additional Relevant MeSH Terms: Pathologic Processes; Nervous System Diseases; Immune System Diseases; Demyelinating Autoimmune Diseases, CNS; Autoimmune Diseases of the Nervous System; Demyelinating Diseases; Autoimmune Diseases; Multiple Sclerosis; Multiple Sclerosis, Chronic Progressive; Sclerosis; Physiological Effects of Drugs; Molecular Mechanisms of Pharmacological Action; Immunosuppressive Agents; Immunologic Factors; Sphingosine 1 Phosphate Receptor Modulators; Fingolimod Hydrochloride
• Other Study ID Numbers: CFTY720D2306; 2007-002627-32 (EudraCT Number)

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: Undecided

IPD Plan Description

Novartis is committed to sharing with qualified external researchers, access to patient-level data and supporting clinical documents from eligible studies. These requests are reviewed and approved by an independent review panel on the basis of scientific merit. All data provided is anonymized to respect the privacy of patients who have participated in the trial in line with applicable laws and regulations.

This trial data availability is according to the criteria and process described on www.clinicalstudydatarequest.com

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: Yes
• Studies a U.S. FDA-regulated device product: No