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
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.
Active, not recruiting | Multiple Sclerosis | Multisite
Pilot Study for Evaluation of Glatiramer Acetate in RRMS Patients With Comorbid Autoimmune Conditions
Multiple Sclerosis (MS) is an auto-immune neurodegenerative disease that affects more than
400,000 individuals in the United States, and 2.5 million worldwide
(www.nationalmssociety.org). The main pathogenic mechanism in MS involves an inflammatory
condition that damages the myelin of the central nervous system (CNS), resulting in axonal
damage and neurological impairment, often leading to severe disability. MS is one of the
most common causes of neurological disability in young and middle-aged adult individuals,
and as such has a tremendous physical, psychological and social impact on patients' lives.
MS is a complex disease diagnosed by McDonald criteria with different clinical and
pathological phenotypes. Several forms of MS have been described: Relapsing-Remitting
(RRMS), Secondary-Progressive MS (SPMS), Progressive-Relapsing MS (PRMS), and
Primary-Progressive MS (PPMS).
Glatiramer Acetate (GA) and Beta-Interferons (β-IFNs) are well established first-line
immunomodulating treatment options for relapsing remitting multiple sclerosis (RRMS) with
excellent safety profiles. The mechanisms of action of GA and IFNs are different. It is well
known that in general Disease-Modifying Treatments (DMTs) reduce relapse rate in more than
half of the multiple sclerosis (MS) patients who receive DMT, while having little if any
effect on the rest. It has been speculated that the response to beta-interferons or GA may
have genetic basis. As Axtell RC et al. indicated the experimental autoimmune
encephalomyeilits (EAE) in mouse caused by TH1 cells generally respond well to
interferon-beta, while EAE caused by TH17 cells get worse with interferon-beta.
Autoimmune disease is an extreme situation where the autoimmune response overshoots and goes
out of control. The other extreme is a degenerative disorder, where the autoimmune response
is not strong enough for effective protection, and degeneration therefore continues. GA
being an immunomodulator may provide both properly regulated immune suppression (in the case
of autoimmune disease) and properly regulated immune activation (in the case of the
Autoimmune conditions cluster in families with high risk for multiple sclerosis than in
general population which suggests that the disease might arise on a background of a
generalized susceptibility to autoimmunity. Occurrence of psoriasis, autoimmune thyroiditis,
vasculitis, rheumatoid arthritis, scleroderma, lupus are seen more commonly in MS patients.
Many of these patients initially get started on beta-IFNs, and usually do not do well on
them. According to Investigator's and the USC MS Comprehensive Care Center experience,
autoimmune co-morbidity associated with MS can serve as a biological marker predicting good
response to GA and unfavorable response to the IFNs.
A Non-randomized, Exploratory, Study to Assess Clinical Response to Gilenya® (Fingolimod) in a Cohort of Relapsing Remitting Hispanic MS Forms
The primary objective of this study is to determine the success of Gilenya® (fingolimod)
treatment in patients with MS of Hispanic descent relative to their ancestral background.
Therapeutic success will be determined by annualized relapse rate (ARR; defined as the
number of relapses divided by the person years followed) after initiation of treatment with
Gilenya® (fingolimod)in comparison to the relapse rate in the previous 12 months. This will
be determined based on medical chart extraction, in-person assessment and regular clinical
A secondary objective of this study is to investigate whether the efficacy of Gilenya®
(fingolimod) is superior or equal in HW which have higher loads of Amerindian versus
Caucasian background with opticospinal MS (OSMS-NMO neg) versus classical MS (CMS) in the
first 12 months using radiological and clinical parameters. The following measures will be
1. Number of relapse-free patients over the investigational period
2. Site of relapse defined as brain or spinal cord.
3. Sustained Disability progression will be defined as a one point (1) increase from
baseline in patients with baseline EDSS score from 0 to 5.0; or half a point (0.5)
increase in patients with baseline EDSS score of 5-5.5 or above after 3 months.
4. MRI changes as described as number of new T2 lesions and number of Gd-enhancing lesions
after 12 months from baseline.
Unknown status | Multiple Sclerosis | Not Multisite
A Multicenter, Observational, Open-Label, Single-Arm Study of Tysabri in Early Relapsing-Remitting Multiple Sclerosis in Anti-JCV Antibody Negative Patients
Multiple studies have demonstrated the positive effect of early therapy on patients who were in the earliest stages of relapsing-remitting multiple sclerosis (RRMS; having 1 clinical event clinically isolated syndrome [CIS] and magnetic resonance images [MRIs] suggestive of MS). These studies involved partially effective medications, all with approximately a 30% reduction in relapse rate.Tysabri is a monoclonal antibody that binds and interferes with the action of 41 integrin which results in reducing certain cells of the immune system transmigration across the blood brain barrier.In the recently presented Tysabri Observational Program (TOP) data, early treatment was most effective in treatment-nave patients and patients with lower Expanded Disability Status Scale (EDSS) scores. Thus, use of an effective agent (Tysabri) in the early stages of MS (when immune cell collections have not yet developed behind the blood-brain barrier [BBB]) may be beneficial, and has not been systematically studied.Study population includes RRMS patients diagnosed with Mc Donald's Criteria, Age 18 to 45 years old, Anti-JCV antibody negative test within 6 months of Screening Visit or negative test for anti-JCV antibody at Baseline Visit.Methodology:This is a Phase 4, single-country, multicenter, open-label, prospective, observational study.The primary objective of the study is to determine which baseline and yearly response factors (clinical and para clinical) predict overall disease-free status at Month 12 and Month 24, and clinical disease-free status in subsequent Months 36 and 48. The response factors include clinical assessments of sustained EDSS progression, relapse status, and MRI measures, and patient reported outcomes (PROs) of cognition, capacity to work, quality of life (QoL), and visual function assessments.In general, continuous variables will be presented with summary statistics (mean, standard deviation, median, range), and categorical variables will be presented with frequency distributions. All analyses will be conducted using 2-sided tests at the type I error rate (alpha level) of 0.05 unless otherwise stated.There will be up to 10 clinic visits included in this protocol. A patients participation in the study will last up to 48 months.
Mechanistic Studies of Phase III Trial With BAF312 in Secondary Progressive Multiple Sclerosis (AMS04)
This study is complementary to a multi-center, randomized, double-blind,parallel-group,
placebo-controlled, variable treatment duration study comparing the efficacy and safety of
BAF312 to placebo in patients with SPMS (NCT01665144). Investigators will explore both
immunological and neuroprotective mechanisms of BAF312 (siponimod), a novel agent in the
setting of a SPMS clinical trial.
This study is part of a multi-center study, with the University of Michigan serving as the