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A 12-month, randomized, rater- and dose-blinded study to compare the efficacy and safety of fingolimod 0.25 mg and 0.5 mg administered orally once daily with glatiramer acetate 20 mg administered subcutaneously once daily in patients with relapsing-remitting multiple sclerosis - ASSESS

Description

Fingolimod (FTY720) Gilenya is an oral, once-daily immunomodulatory drug that has been approved for the treatment of relapsing MS in the United States, Europe, and other countries. Fingolimod causes a reversible sequestration of a proportion of CD4+ and CD8+ positive T cells and B cells from blood and spleen into lymph nodes and Peyers patches, apparently without affecting many of the functional properties of these cells. Under normal circumstances, T cells selectively require S1P1 activation for emigration from the thymus, and both T and B cells require this receptor for egress from peripheral lymphoid organs. Fingolimod-P acts as a super-agonist of the S1P1 receptor on lymphocytes, inducing its uncoupling/internalization and intracellular lysosomal degradation. The internalization and degradation of S1P1 renders these cells unresponsive to S1P, depriving them of the obligatory signal to egress from lymphoid organs and recirculate to peripheral inflammatory tissues.The purpose of this study is to compare 2 doses (0.25 mg and 0.50 mg) of fingolimod to glatiramer acetate (20 mg) and to evaluate the efficacy and safety of fingolimod 0.25 mg for the treatment of patients with relapsing-remitting MS (RRMS) as part of a post-approval commitment for the FDA.The primary objective is to demonstrate that at least 1 dose (0.5 mg or 0.25 mg) of fingolimod is superior to glatiramer acetate 20 mg SC in reducing the ARR up to 12 months in patients with relapsing-remitting MS. This is a multicenter, randomized, rater- and dose-blinded study to compare the efficacy and safety of 0.25 mg and 0.5 mg of fingolimod with glatiramer acetate 20 mg s.c. in patients with RRMS. Approximately 1990 patients with RRMS will be randomly assigned to treatment at study sites in the US, with the possible addition of other countries. All patient will received study medication free of charge.The study population will consist of adult male and female patients with RRMS who meet all of the inclusion criteria and none of the exclusion criteria. Treatment-nave patients and patients previously treated with disease modifying therapies for MS, with the exception of S1P modulator therapy, are eligible to participate in the study. Patients being treated with first-line DMDs at the screening visit can continue drug intake up to the day before Day 1 of this study (i.e., there is no need for a washout period).This study will consist of 3 periods: Screening Period: up to 1 month for all patients Treatment Period: 12 months of glatiramer acetate 20 mg, fingolimod 0.25 mg, orfingolimod 0.5 mg Follow-up period will occur 3 months (12 weeks) after the last dose of study drug for all PatientsAfter signing the informed consent, patients will enter the Screening Period to determine eligibility for the study. After inclusion/exclusion criteria are reviewed again and after study assessments are conducted, patients will enter the Treatment Period and will be randomly assigned into 1 of 3 groups in a 3:2:1 ratio: Group 1 will receive fingolimod 0.25 mg orally once a day for up to 12 months Group 2 will receive fingolimod 0.5 mg orally once a day for up to 12 months Group 3 will receive glatiramer acetate 20 mg subcutaneously once a day for up to12 months, respectively. Multiple sclerosis relapses will be defined using protocol specific definitions. The Expanded Disability Status Scale (EDSS) is a scale for assessing neurologic impairment in MS and will be used to confirm an MS relapse.Data analysis will include the following sets: Randomized set: consists of all patients who are assigned randomization numbers. The patients in this set are called randomized patients. This set will be used to summarize patient disposition, demographic and baseline characteristics, and protocol deviation information. Full-analysis set: Consists of all patients who are randomly assigned and take at least 1 dose of study drug. Following the intent-to-treat principle, patients will be grouped according to the assigned treatment at randomization. Efficacy analyses will be performed on the full-analysis set unless otherwise notified. Per-protocol set: Consists of all patients in the full-analysis set who do not have any major protocol deviations that could confound the interpretation of analyses conducted on the full-analysis set. The per-protocol set will only be used for the supportive analyses of the primary efficacy variable. Safety set: Consists of all patients in the full-analysis set who take at least 1 dose of study drug. Patients will be analyzed according to the treatment they have actually taken. Safety and tolerability analyses will be performed on the safety set unless otherwise notified. Follow-up set: The follow-up set consists of all patients in the safety set who have followup visit data or who have at least 1 safety assessment (AEs, laboratory test, vital sign measurement, or ophthalmology assessments) 46 days or more than 46 days after study drug discontinuation. Only the safety follow-up data analysis will be performed on the follow-up set.For each of the 2 fingolimod doses, the null hypothesis is that there is no difference in the ARRs between patients treated with fingolimod and those treated with glatiramer acetate versus the alternative hypothesis that there is a difference between the 2 treatment groups. The null hypothesis will be rejected if the observed P value for the between-treatment comparison is less than the significance level as specified in the multiplicity adjustment procedure described later in this section.No formal hypothesis will be tested between the 2 fingolimod doses because the study is not powered to detect a difference in treatment effect between these doses.

Phase

Phase 3/4

Inclusion and Exclusion Criteria

  • Written informed consent must be obtained before any assessment is performed
  • Male and female patients 18 to 65 years of age, inclusive.
  • Patients with RRMS, as defined by 2010 revised McDonald criteria.
  • Patients must be neurologically stable with no onset of relapse or any steroid use within 30 days of randomization
  • Patients with at least 1 documented relapse during the previous year or 2 documented relapses during the previous 2 years before randomization.
  • Patients with an EDSS score of 0 to 6 inclusive at Screening. A score of 6.0 indicates unilateral assistance (cane or crutch) required to walk at least 100 meters with or without resting.
  • Patients treated with interferon beta or glatimer acetate can continue their treatment until randomization

  • Patients with a history of malignancy of any organ system (other than cutaneous basal cell carcinoma)
  • Patients with an active chronic disease (or stable but treated with immune therapy) of the immune system other than MS (e.g., rheumatoid arthritis, scleroderma, Sjogren's syndrome, Crohn's disease, ulcerative colitis) or with a known immunodeficiency syndrome (HIV-antibody positive, AIDS, hereditary immune deficiency, drug-induced immune deficiency).
  • Patients who have been treated with:
  • High-dose intravenous (IV) immunoglobulin (Ig) within 2 months before randomization
  • Immunosuppressive/chemotherapeutic medications (e.g., azathioprine, cyclophosphamide, methotrexate) within 6 months before randomization
  • Monoclonal antibodies (including natalizumab) within 6 months before randomization
  • Rituximab, alemtuzumab, ofatumumab, ocrelizumab, mitoxantrone or cladribine at any time before randomization
  • Patients who have been treated with corticosteroids or adrenocorticotropic hormones in the past 30 days before the screening visit
  • Patients with uncontrolled diabetes mellitus (HbA1c >7%)
  • Patients with a diagnosis of macular edema during Screening (patients with a history of macular edema will be allowed to enter the study provided that they do not have macular edema at Screening)
  • Positive screening for serological markers for hepatitis A, B, C, and E indicating acute or chronic infection:
  • Patients who are negative for varicella zoster virus IgG antibodies at Screening
  • Patients who have received any live or live attenuated vaccines (including for varicella zoster virus, herpes simplex, or measles) within 1 month before randomization
  • Patients who have received total lymphoid irradiation or bone marrow transplantation
  • Patients with any unstable medical/psychiatric condition, as assessed by the primary treating physician at each site

Sites

  • California

    • Novartis Investigative Site, Torrance, California, 90509
    • Novartis Investigative Site, Los Alamitos, California, 90720
    • Novartis Investigative Site, Oceanside, California, 92056
    • Novartis Investigative Site, La Jolla, California, 92037
    • Novartis Investigative Site, Fresno, California, 93710
    • Novartis Investigative Site, Berkeley, California, 94705
    • Novartis Investigative Site, San Francisco, California, 94117
    • Novartis Investigative Site, Sacramento, California, 95817
  • Nevada

    • Novartis Investigative Site, Las Vegas, Nevada, 89106
  • Arizona

    • Novartis Investigative Site, Sun City, Arizona, 85351
    • Novartis Investigative Site, Phoenix, Arizona, 85013
    • Novartis Investigative Site, Phoenix, Arizona, 85004
    • Novartis Investigative Site, Phoenix, Arizona, 85018
    • Novartis Investigative Site, Gilbert, Arizona, 85234
    • Novartis Investigative Site, Tucson, Arizona, 85741
  • Utah

    • Novartis Investigative Site, Salt Lake City, Utah, 84103
  • New Mexico

    • Novartis Investigative Site, Albuquerque, New Mexico, 87131
  • Colorado

    • Novartis Investigative Site, Colorado Springs, Colorado, 80920
    • Novartis Investigative Site, Boulder, Colorado, 80304
    • Novartis Investigative Site, Denver, Colorado, 80218
    • Novartis Investigative Site, Denver, Colorado, 80220
    • Novartis Investigative Site, Aurora, Colorado, 80045
    • Novartis Investigative Site, Fort Collins, Colorado, 80525
    • Novartis Investigative Site, Fort Collins, Colorado, 80528
  • Oregon

    • Novartis Investigative Site, Portloand, Oregon, 97225
  • Washington

    • Novartis Investigative Site, Issaquah, Washington, 98029
    • Novartis Investigative Site, Seattle, Washington, 98101
  • Montana

    • Novartis Investigative Site, Great Falls, Montana, 59405
    • Novartis Investigative Site, Great Falls, Montana, 59405
  • Oklahoma

    • Novartis Investigative Site, Oklahoma City, Oklahoma, 73112
    • Novartis Investigative Site, Oklahoma City, Oklahoma, 73104
    • Novartis Investigative Site, Oklahoma City, Oklahoma, 73104
    • Novartis Investigative Site, Tulsa, Oklahoma, 74137
  • Texas

    • Novartis Investigative Site, San Antonio, Texas, 78229
    • Novartis Investigative Site, San Antonio, Texas, 78231
    • Novartis Investigative Site, San Antonio, Texas, 78258
    • Novartis Investigative Site, Round Rock, Texas, 78681
    • Novartis Investigative Site, Sherman, Texas, 75092
    • Novartis Investigative Site, Dallas, Texas, 75246
    • Novartis Investigative Site, Dallas, Texas, 75390
    • Novartis Investigative Site, Dallas, Texas, 75214
    • Novartis Investigative Site, Houston, Texas, 77076
    • Novartis Investigative Site, Houston, Texas, 77030
  • Kansas

    • Novartis Investigative Site, Kansas City, Kansas, 66160
    • Novartis Investigative Site, Lenexa, Kansas, 66212
  • Missouri

    • Novartis Investigative Site, Kansas City, Missouri, 64111
    • Novartis Investigative Site, Saint Louis, Missouri, 63141
    • Novartis Investigative Site, St. Louis, Missouri, 63131
    • Novartis Investigative Site, St. Louis, Missouri, 63104
  • Iowa

    • Novartis Investigative Site, West Des Moines, Iowa, 50314
  • Arkansas

    • Novartis Investigative Site, Little Rock, Arkansas, 72205
  • Minnesota

    • Novartis Investigative Site, Golden Valley, Minnesota, 55422
  • Tennessee

    • Novartis Investigative Site, Cordova, Tennessee, 38018
    • Novartis Investigative Site, Nashville, Tennessee, 37205
    • Novartis Investigative Site, Nashville, Tennessee, 37204
  • Louisiana

    • Novartis Investigative Site, Hammond, Louisiana, 70403
    • Novartis Investigative Site, New Orleans, Louisiana, 70121
  • Illinois

    • Novartis Investigative Site, Elk Grove Village, Illinois, 60007
    • Novartis Investigative Site, Elk Grove Village, Illinois, 60007
    • Novartis Investigative Site, Palos Heights, Illinois, 60463
    • Novartis Investigative Site, Northbrook, Illinois, 60062
    • Novartis Investigative Site, Flossmoor, Illinois, 60422
    • Novartis Investigative Site, Chicago, Illinois, 60612
    • Novartis Investigative Site, Evanston, Illinois, 60201
  • Mississippi

    • Novartis Investigative Site, Ocean Springs, Mississippi, 39564
  • Wisconsin

    • Novartis Investigative Site, Milwaukee, Wisconsin, 53215
  • Alabama

    • Novartis Investigative Site, Cullman, Alabama, 35058
    • Novartis Investigative Site, Huntsville, Alabama, 35801
  • Indiana

    • Novartis Investigative Site, Indianapolis, Indiana, 46202
    • Novartis Investigative Site, Indianapolis, Indiana, 46256
  • Kentucky

    • Novartis Investigative Site, Louisville, Kentucky, 40207
    • Novartis Investigative Site, Lexington, Kentucky, 40536
  • Michigan

    • Novartis Investigative Site, Grand Rapids, Michigan, 49503
  • Ohio

    • Novartis Investigative Site, Cincinnati, Ohio, 45219
    • Novartis Investigative Site, Dayton, Ohio, 45408
    • Novartis Investigative Site, Dayton, Ohio, 45408
  • Georgia

    • Novartis Investigative Site, Douglasville, Georgia, 30134
    • Novartis Investigative Site, Douglasville, Georgia, 30134
    • Novartis Investigative Site, Atlanta, Georgia, 30327
  • Mexico

    • Novartis Investigative Site, Culiacan, 80020
  • San Luis Potosí

    • Novartis Investigative Site, San Luis Potosi, San Luis Potosí, 78240
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