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)

Novartis

Status and phase: Terminated; Phase 3

Conditions: Primary Progressive Multiple Sclerosis

Treatments: Drug: FTY720; Drug: Placebo

Study type: Interventional

Funder types: Industry

Identifiers

NCT00731692

2007-002627-32 (EudraCT Number)

CFTY720D2306

Details and patient eligibility

About

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

Enrollment: 970 patients

Sex: All

Ages: 25 to 65 years old

Volunteers: No Healthy Volunteers

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

Trial design

Primary purpose: Treatment

Allocation: Randomized

Interventional model: Parallel Assignment

Masking: Quadruple Blind

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970 participants in 3 patient groups, including a placebo group

FTY720D 0.5 mg

Experimental group

Description:

Cohort 2: The 0.5 mg group consists of patients who were directly randomized to fingolimod 0.5 mg (i.e. AFTER the amendment

Treatment:

Drug: FTY720

Placebo

Placebo Comparator group

Description:

Cohort 1 and 2: Patients randomized to placebo continued on placebo after re-randomization

Treatment:

Drug: Placebo

FTY720D 1.25 mg switch to 0.5 mg

Experimental group

Description:

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

Treatment:

Drug: FTY720