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Multiple Sclerosis: HELP
Articles from Ontario
Based on 469 articles published since 2009
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These are the 469 published articles about Multiple Sclerosis that originated from Ontario during 2009-2019.
 
+ Citations + Abstracts
Pages: 1 · 2 · 3 · 4 · 5 · 6 · 7 · 8 · 9 · 10 · 11 · 12 · 13 · 14 · 15 · 16 · 17 · 18 · 19
101 Review Oral versus intravenous steroids for treatment of relapses in multiple sclerosis. 2009

Burton, Jodie M / O'Connor, Paul W / Hohol, Marika / Beyene, Joseph. ·Division of Neurology, St. Michael's Hospital, 30 Bond Street, Toronto, Ontario, Canada, M5B 1W8. ·Cochrane Database Syst Rev · Pubmed #19588409.

ABSTRACT: BACKGROUND: Multiple Sclerosis (MS), a chronic inflammatory and neurodegenerative disease of the central nervous system (CNS), is characterized by recurrent relapses of CNS inflammation ranging from mild to severely disabling. Relapses have long been treated with steroids to reduce inflammation and hasten recovery. However, the commonly used intravenous methylprednisolone requires repeated infusions with the added costs of homecare or hospitalization, and may interfere with daily responsibilities. Oral steroids have been used in place of intravenous steroids, with lower direct and indirect costs. OBJECTIVES: The primary objective was to compare efficacy of oral versus intravenous steroids for MS relapses <= 6 weeks. Secondary comparisons included subsequent relapse rate, disability, ambulation, hospitalization, immunological markers, radiological markers, and quality of life. SEARCH STRATEGY: A literature search was performed using Cochrane MS Group Trials Register (July 2008), Cochrane Central Register of Controlled Trials (CENTRAL) "The Cochrane Library 2008, issue 3, MEDLINE (PubMed) (1966-July 2008), EMBASE (1980-July 2008), abstracts from meetings of the American Academy of Neurology (2002-2008), the European Federation of Neurological Sciences (2002-2008), the European Committee for Treatment and Research in Multiple Sclerosis and American Committee for Treatment and Research in Multiple Sclerosis (2002-2008) handsearching. No language restrictions were applied. SELECTION CRITERIA: Randomized or quasi-randomized trials comparing oral and intravenous steroids for acute relapses (<=30 days) in clinically definite MS patients over age 16 were eligible. DATA COLLECTION AND ANALYSIS: Methodological was assessed using trial publications and personal communication. Elevant data was extracted, and effect size was reported as mean difference (MD),weighted mean difference (WMD), odds ratio (OR) and absolute risk difference (ARD). MAIN RESULTS: Eligible studies (167 patients) were identified. Only one outcome, the proportion of patients with EDSS improvement at 4 weeks, was common to three trials. Otherwise outcomes were too heterogeneous to pool. Only one trial employed an equivalence design, but all reported no statistically significant difference in outcomes between groups. Namely, there was no significant difference in the degree of recovery 4 weeks following treatment. No difference was found in subsequent relapse rate, disability, hospitalization, ambulation, bioavailability, or in magnetic resonance imaging (MRI). Due to methodological limitations, heterogeneous treatment regimens and limited data, formal conclusions about equivalence of oral and intravenous steroidscannot be made. Oral Megadose Corticosteroid Therapy of Acute Exacerbations of Multiple Sclerosis (OMEGA) trial, designed to address such limitations, is currently underway. AUTHORS' CONCLUSIONS: The trials reviewed support the hypothesis that no significant differences in clinical, radiological or pharmacological outcomes oral and intravenous steroids for MS relapses exist. However, with the small number of patients and methodological limitations, conclusions of equivalence are premature.

102 Review Associations between chronic disease, age and physical and mental health status. 2009

Hopman, W M / Harrison, M B / Coo, H / Friedberg, E / Buchanan, M / VanDenKerkhof, E G. ·Clinical Research Centre, Kingston General Hospital, ON, Canada. hopmanw@kgh.kari.net ·Chronic Dis Can · Pubmed #19527569.

ABSTRACT: This paper examines the associations between chronic disease, age, and physical and mental health-related quality of life (HRQOL), using data collected in 10 studies representing five chronic conditions. HRQOL was measured using the SF-36 or the shorter subset, SF-12. Physical Component Summary (PCS) and Mental Component Summary (MCS) scores were graphed by condition in age increments of 10 years, and compared to age- and sex-adjusted normative data. Linear regression models for the PCS and MCS were controlled for available confounders. The sample size of 2418 participants included 129 with renal failure, 366 with osteoarthritis (OA), 487 with heart failure, 1160 with chronic wound (leg ulcer) and 276 with multiple sclerosis (MS). For the PCS, there were large differences between the normative data and the mean scores of those with chronic diseases, but small differences for the MCS. Female gender and comorbid conditions were associated with poorer HRQOL; increased age was associated with poorer PCS and better MCS. This study provided additional evidence that, while physical function could be severely and negatively affected by both chronic disease and advanced age, mental health remained relatively high and stable.

103 Review Differential diagnosis of dizziness. 2009

Chan, Yvonne. ·Department of Otolaryngology-Head and Neck Surgery, University of Toronto, Toronto, Canada. y.chan@utoronto.ca ·Curr Opin Otolaryngol Head Neck Surg · Pubmed #19365263.

ABSTRACT: PURPOSE OF REVIEW: Dizziness is one of the most common complaints among patients presenting to primary care physicians, neurologists, and otolaryngologists. This symptom is nonspecific and includes a broad differential diagnosis. The current review aims to present a general overview of the approach to dizziness as well as to discuss the more common causes in detail. RECENT FINDINGS: The term dizziness encompasses a large spectrum of symptomatology. Understanding how to differentiate between vestibular disorders and other types of dizziness is the key to the evaluation and management of dizzy patients. The distinction between central and peripheral vertigo will be emphasized and the various causes of each type of vertigo will be presented. SUMMARY: Dizziness is a common medical condition that impacts significantly on patients' activities of daily living. This review outlines the clinical approach to dizziness to facilitate timely diagnosis and management of this complex symptom.

104 Review Epstein-Barr virus and multiple sclerosis. 2009

Pohl, Daniela. ·Faculty of Medicine, University of Ottawa, Canada. dpohl@cheo.on.ca ·J Neurol Sci · Pubmed #19361810.

ABSTRACT: Epstein-Barr virus (EBV) is a human DNA herpesvirus infecting more than 90% of the world's population. EBV is the etiological agent of infectious mononucleosis (Pfeiffer's disease). Furthermore, diverse malignancies such as Burkitt and Hodgkin lymphoma have been associated with EBV. More recently, a possible role for EBV has been suggested in chronic inflammatory/autoimmune diseases like rheumatoid arthritis and systemic lupus erythematosus as well as in multiple sclerosis (MS). MS is currently regarded as a disease with multifactorial etiology, EBV being one possible factor in MS manifestation: Infectious mononucleosis has been shown to increase the risk of developing MS later in life. EBV seroprevalence rates are higher in MS as compared to controls, in adult as well as in pediatric MS patients. Moreover, EBV antibody titres and EBV specific T-cells are increased in MS patients as compared to healthy individuals. Recently, CNS B-cells of MS patients have been reported to harbour EBV. However, there is still controversy whether EBV could be a causative agent as opposed to an innocent bystander in the pathogenesis of MS. This review summarizes current knowledge on the association of EBV and MS including a critical discussion of equivocal findings.

105 Guideline Evidence-based guideline: assessment and management of psychiatric disorders in individuals with MS: report of the Guideline Development Subcommittee of the American Academy of Neurology. 2014

Minden, Sarah L / Feinstein, Anthony / Kalb, Rosalind C / Miller, Deborah / Mohr, David C / Patten, Scott B / Bever, Christopher / Schiffer, Randolph B / Gronseth, Gary S / Narayanaswami, Pushpa / Anonymous1150780. ·From the Department of Psychiatry, Brigham and Women's Hospital (S.L.M.), and Department of Neurology, Beth Israel Deaconess Medical Center (P.N.), Harvard Medical School, Boston, MA · Department of Psychiatry (A.F.), University of Toronto, Canada · National Multiple Sclerosis Society (R.C.K.), New York · Mellen Center (D.M.), Cleveland Clinic, OH · Department of Preventive Medicine (D.C.M.), Northwestern University, Evanston, IL · Department of Community Health Sciences & Hotchkiss Brain Institute (S.B.P.), University of Calgary, Canada · VA Maryland Health Care System (C.B.), Baltimore, MD · Santa Fe, NM (R.B.S.) · and Department of Neurology (G.S.G.), University of Kansas Medical Center, Kansas City. ·Neurology · Pubmed #24376275.

ABSTRACT: OBJECTIVE: To make evidence-based recommendations for screening, diagnosing, and treating psychiatric disorders in individuals with multiple sclerosis (MS). METHODS: We reviewed the literature (1950 to August 2011) and evaluated the available evidence. RESULTS AND RECOMMENDATIONS: Clinicians may consider using the Center for Neurologic Study Emotional Lability Scale to screen for pseudobulbar affect (Level C). Clinicians may consider the Beck Depression Inventory and a 2-question tool to screen for depressive disorders and the General Health Questionnaire to screen for broadly defined emotional disturbances (Level C). Evidence is insufficient to support/refute the use of other screening tools, the possibility that somatic/neurovegetative symptoms affect these tools' accuracy, or the use of diagnostic instruments or clinical evaluation procedures for identifying psychiatric disorders in MS (Level U). Clinicians may consider a telephone-administered cognitive behavioral therapy program for treating depressive symptoms (Level C). Although pharmacologic and nonpharmacologic therapies are widely used to treat depressive and anxiety disorders in individuals with MS, evidence is insufficient to support/refute the use of the antidepressants and individual and group therapies reviewed herein (Level U). For pseudobulbar affect, a combination of dextromethorphan and quinidine may be considered (Level C). Evidence is insufficient to determine the psychiatric effects in individuals with MS of disease-modifying and symptomatic therapies and corticosteroids; risk factors for suicide; and treatment of psychotic disorders (Level U). Research is needed on the effectiveness in individuals with MS of pharmacologic and nonpharmacologic treatments frequently used in the non-MS population.

106 Clinical Trial Placebo-Controlled Trial of an Oral BTK Inhibitor in Multiple Sclerosis. 2019

Montalban, Xavier / Arnold, Douglas L / Weber, Martin S / Staikov, Ivan / Piasecka-Stryczynska, Karolina / Willmer, Jonathan / Martin, Emily C / Dangond, Fernando / Syed, Sana / Wolinsky, Jerry S / Anonymous1881289. ·From Vall d'Hebron University Hospital, Barcelona (X.M.) · St. Michael's Hospital, University of Toronto, Toronto (X.M.), and Montreal Neurological Institute and NeuroRx Research, Montreal (D.L.A.) - both in Canada · the Institute of Neuropathology and the Department of Neurology, University Medical Center, Göttingen, Germany (M.S.W.) · the Department of Neurology, Acibadem City Clinic Tokuda Hospital, Sofia, Bulgaria (I.S.) · the Department of Histology and Embryology, Poznan University of Medical Science, Poznan, Poland (K.P.-S.) · the Global Clinical Development Center, EMD Serono Research and Development Institute, Billerica, MA (J.W., E.M., F.D., S.S.) · and McGovern Medical School, University of Texas Health Science Center at Houston, Houston (J.S.W.). ·N Engl J Med · Pubmed #31075187.

ABSTRACT: BACKGROUND: Bruton's tyrosine kinase (BTK) regulates the functions of B cells and myeloid cells that are implicated in the pathogenesis of multiple sclerosis. Evobrutinib is a selective oral BTK inhibitor that has been shown to inhibit B-cell activation both in vitro and in vivo. METHODS: In this double-blind, randomized, phase 2 trial, we assigned patients with relapsing multiple sclerosis to one of five groups: placebo, evobrutinib (at a dose of 25 mg once daily, 75 mg once daily, or 75 mg twice daily), or open-label dimethyl fumarate (DMF) as a reference. The primary end point was the total (cumulative) number of gadolinium-enhancing lesions identified on T RESULTS: A total of 267 patients were randomly assigned to a trial group. The mean (±SD) total number of gadolinium-enhancing lesions during weeks 12 through 24 was 3.85±5.44 in the placebo group, 4.06±8.02 in the evobrutinib 25-mg group, 1.69±4.69 in the evobrutinib 75-mg once-daily group, 1.15±3.70 in the evobrutinib 75-mg twice-daily group, and 4.78±22.05 in the DMF group. The baseline adjusted rate ratios for the total number of lesions over time as compared with placebo were 1.45 in the evobrutinib 25-mg group (P = 0.32), 0.30 in the evobrutinib 75-mg once-daily group (P = 0.005), and 0.44 in the evobrutinib 75-mg twice-daily group (P = 0.06). The unadjusted annualized relapse rate at week 24 was 0.37 in the placebo group, 0.57 in the evobrutinib 25-mg group, 0.13 in the evobrutinib 75-mg once-daily group, 0.08 in the evobrutinib 75-mg twice-daily group, and 0.20 in the DMF group. There was no significant effect of trial group on the change from baseline in the EDSS score. Elevations in liver aminotransferase values were observed with evobrutinib. CONCLUSIONS: Patients with relapsing multiple sclerosis who received 75 mg of evobrutinib once daily had significantly fewer enhancing lesions during weeks 12 through 24 than those who received placebo. There was no significant difference with placebo for either the 25-mg once-daily or 75-mg twice-daily dose of evobrutinib, nor in the annualized relapse rate or disability progression at any dose. Longer and larger trials are required to determine the effect and risks of evobrutinib in patients with multiple sclerosis. (Funded by EMD Serono; ClinicalTrials.gov number, NCT02975349.).

107 Clinical Trial Efficacy and safety of teriflunomide in Asian patients with relapsing forms of multiple sclerosis: A subgroup analysis of the phase 3 TOWER study. 2019

Miller, Aaron E / Xu, Xianhao / Macdonell, Richard / Vucic, Steve / Truffinet, Philippe / Benamor, Myriam / Thangavelu, Karthinathan / Freedman, Mark S. ·Department of Neurology, Icahn School of Medicine at Mount Sinai, New York, NY, United States. Electronic address: aaron.miller@mssm.edu. · Department of Neurology, Beijing Hospital, Beijing, China. Electronic address: xuxianhao99@163.com. · Department of Neurology, Austin Health, Heidelberg, Australia. Electronic address: richard.macdonell@austin.org.au. · Faculty of Medicine, University of Sydney, Sydney, Australia. Electronic address: s.vucic@neura.edu.au. · R&D, Sanofi, Chilly-Mazarin, France. Electronic address: Philippe.Truffinet@sanofi.com. · Global Pharmacovigilance & Epidemiology, Sanofi, Chilly-Mazarin, France. Electronic address: Myriam.Benamor@sanofi.com. · Biostatistics, Sanofi, Cambridge, MA, United States. Electronic address: Karthinathan.Thangavelu@sanofi.com. · Multiple Sclerosis Research Unit, Department of Neurology, University of Ottawa and the Ottawa Hospital Research Institute, Ottawa, ON, Canada. Electronic address: mfreedman@toh.ca. ·J Clin Neurosci · Pubmed #30348586.

ABSTRACT: In the phase 3 TOWER (NCT00751881) study, teriflunomide 14 mg significantly reduced annualized relapse rate (ARR) and risk of 12-week confirmed disability worsening (12-w CDW) vs placebo in patients with relapsing forms of MS (RMS). The TOWER population included an appreciable proportion of Asian patients. Reductions in ARR and 12-w CDW associated with teriflunomide 14 mg were comparable between the Asian and overall populations, as were the rates for adverse events and serious adverse events, with no new or unexpected safety findings. These observations provide further evidence to support the clinical benefits and safety profile of teriflunomide in a broad range of patients with RMS.

108 Clinical Trial Natural Killer Cells Regulate Th17 Cells After Autologous Hematopoietic Stem Cell Transplantation for Relapsing Remitting Multiple Sclerosis. 2018

Darlington, Peter J / Stopnicki, Brandon / Touil, Tarik / Doucet, Jean-Sebastien / Fawaz, Lama / Roberts, Morgan E / Boivin, Marie-Noëlle / Arbour, Nathalie / Freedman, Mark S / Atkins, Harold L / Bar-Or, Amit. ·Departments of Exercise Science and Biology, PERFORM Centre, Concordia University, Montreal, QC, Canada. · Neuroimmunology Unit, McGill University and Montreal Neurological Institute, Montreal, QC, Canada. · Clinical Biological Imaging and Genetic Repository, McGill University, Montreal, QC, Canada. · Department of Neurosciences, Université de Montréal, Centre de Recherche du Centre Hospitalier de l'Université de Montréal (CRCHUM), Montréal, QC, Canada. · Department of Medicine, Ottawa Hospital Research Institute, University of Ottawa, Ottawa, ON, Canada. · Blood and Marrow Transplant Program, Ottawa General Hospital, Ottawa, ON, Canada. · Center for Neuroinflammation and Experimental Therapeutics and Department of Neurology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, United States. ·Front Immunol · Pubmed #29867923.

ABSTRACT: In autoimmunity, the balance of different helper T (Th) cell subsets can influence the tissue damage caused by autoreactive T cells. Pro-inflammatory Th1 and Th17 T cells are implicated as mediators of several human autoimmune conditions such as multiple sclerosis (MS). Autologous hematopoietic stem cell transplantation (aHSCT) has been tested in phase 2 clinical trials for MS patients with aggressive disease. Abrogation of new clinical relapses and brain lesions can be seen after ablative aHSCT, accompanied by significant reductions in Th17, but not Th1, cell populations and activity. The cause of this selective decrease in Th17 cell responses following ablative aHSCT is not completely understood. We identified an increase in the kinetics of natural killer (NK) cell reconstitution, relative to CD4

109 Clinical Trial Effect of natalizumab on disease progression in secondary progressive multiple sclerosis (ASCEND): a phase 3, randomised, double-blind, placebo-controlled trial with an open-label extension. 2018

Kapoor, Raju / Ho, Pei-Ran / Campbell, Nolan / Chang, Ih / Deykin, Aaron / Forrestal, Fiona / Lucas, Nisha / Yu, Bei / Arnold, Douglas L / Freedman, Mark S / Goldman, Myla D / Hartung, Hans-Peter / Havrdová, Eva Kubala / Jeffery, Douglas / Miller, Aaron / Sellebjerg, Finn / Cadavid, Diego / Mikol, Dan / Steiner, Deborah / Anonymous621123. ·National Hospital for Neurology and Neurosurgery, University College London Hospitals NHS Foundation Trust, London, UK. Electronic address: r.kapoor@nhs.net. · Biogen, Cambridge, MA, USA. · Montreal Neurological Institute, Montreal, QC, Canada; NeuroRx Research, Montreal, QC, Canada. · University of Ottawa, Ottawa Hospital Research Institute, Ottawa, ON, Canada. · University of Virginia, Charlottesville, VA, USA. · Department of Neurology, Medical Faculty, Heinrich-Heine University, Düsseldorf, Germany. · First Faculty of Medicine and General University Hospital, Charles University, Prague, Czech Republic. · Piedmont HealthCare, Mooresville, NC, USA. · Icahn School of Medicine at Mount Sinai, New York, NY, USA. · Danish Multiple Sclerosis Center, Rigshospitalet, University of Copenhagen, Copenhagen, Denmark. ·Lancet Neurol · Pubmed #29545067.

ABSTRACT: BACKGROUND: Although several disease-modifying treatments are available for relapsing multiple sclerosis, treatment effects have been more modest in progressive multiple sclerosis and have been observed particularly in actively relapsing subgroups or those with lesion activity on imaging. We sought to assess whether natalizumab slows disease progression in secondary progressive multiple sclerosis, independent of relapses. METHODS: ASCEND was a phase 3, randomised, double-blind, placebo-controlled trial (part 1) with an optional 2 year open-label extension (part 2). Enrolled patients aged 18-58 years were natalizumab-naive and had secondary progressive multiple sclerosis for 2 years or more, disability progression unrelated to relapses in the previous year, and Expanded Disability Status Scale (EDSS) scores of 3·0-6·5. In part 1, patients from 163 sites in 17 countries were randomly assigned (1:1) to receive 300 mg intravenous natalizumab or placebo every 4 weeks for 2 years. Patients were stratified by site and by EDSS score (3·0-5·5 vs 6·0-6·5). Patients completing part 1 could enrol in part 2, in which all patients received natalizumab every 4 weeks until the end of the study. Throughout both parts, patients and staff were masked to the treatment received in part 1. The primary outcome in part 1 was the proportion of patients with sustained disability progression, assessed by one or more of three measures: the EDSS, Timed 25-Foot Walk (T25FW), and 9-Hole Peg Test (9HPT). The primary outcome in part 2 was the incidence of adverse events and serious adverse events. Efficacy and safety analyses were done in the intention-to-treat population. This trial is registered with ClinicalTrials.gov, number NCT01416181. FINDINGS: Between Sept 13, 2011, and July 16, 2015, 889 patients were randomly assigned (n=440 to the natalizumab group, n=449 to the placebo group). In part 1, 195 (44%) of 439 natalizumab-treated patients and 214 (48%) of 448 placebo-treated patients had confirmed disability progression (odds ratio [OR] 0·86; 95% CI 0·66-1·13; p=0·287). No treatment effect was observed on the EDSS (OR 1·06, 95% CI 0·74-1·53; nominal p=0·753) or the T25FW (0·98, 0·74-1·30; nominal p=0·914) components of the primary outcome. However, natalizumab treatment reduced 9HPT progression (OR 0·56, 95% CI 0·40-0·80; nominal p=0·001). In part 1, 100 (22%) placebo-treated and 90 (20%) natalizumab-treated patients had serious adverse events. In part 2, 291 natalizumab-continuing patients and 274 natalizumab-naive patients received natalizumab (median follow-up 160 weeks [range 108-221]). Serious adverse events occurred in 39 (13%) patients continuing natalizumab and in 24 (9%) patients initiating natalizumab. Two deaths occurred in part 1, neither of which was considered related to study treatment. No progressive multifocal leukoencephalopathy occurred. INTERPRETATION: Natalizumab treatment for secondary progressive multiple sclerosis did not reduce progression on the primary multicomponent disability endpoint in part 1, but it did reduce progression on its upper-limb component. Longer-term trials are needed to assess whether treatment of secondary progressive multiple sclerosis might produce benefits on additional disability components. FUNDING: Biogen.

110 Clinical Trial Subcutaneous interferon β-1a in the treatment of clinically isolated syndromes: 3-year and 5-year results of the phase III dosing frequency-blind multicentre REFLEXION study. 2017

Comi, Giancarlo / De Stefano, Nicola / Freedman, Mark S / Barkhof, Frederik / Uitdehaag, Bernard M J / de Vos, Marlieke / Marhardt, Kurt / Chen, Liang / Issard, Delphine / Kappos, Ludwig. ·Department of Neurology, Scientific Institute H.S. Raffaele, Milan, Italy. · Department of Medicine, Surgery and Neuroscience, University of Siena, Siena, Italy. · Department of Medicine (Neurology), University of Ottawa, Ottawa Hospital Research Institute, Ottawa, Ontario, Canada. · Department of Diagnostic Radiology, VU University Medical Center, Amsterdam, The Netherlands. · The Institutes of Neurology and Healthcare Engineering, UCL, London, UK. · Department of Neurology, VU University Medical Center, Amsterdam, The Netherlands. · Department of Radiology and Nuclear Medicine, VU University Medical Center, Amsterdam, The Netherlands. · Global Medical Affairs, Merck GmbH, Vienna, Austria. · Global Biostatistics, EMD Serono Inc., Billerica, Massachusetts, USA. · Department of Biostatistics, Cytel Inc., Geneva, Switzerland. · Departments of Medicine, Clinical Research, Biomedicine, and Biomedical Engineering, University Hospital Basel, Basel, Switzerland. ·J Neurol Neurosurg Psychiatry · Pubmed #28039317.

ABSTRACT: OBJECTIVE: Early treatment following a first clinical demyelinating event (FCDE) delays further disease activity in patients with multiple sclerosis (MS). This study determined the effects of early versus delayed treatment (DT) with subcutaneous interferon (sc IFN) β-1a 44 μg in patients with an FCDE up to 60 months postrandomisation. METHODS: Patients who completed the 24-month double-blind REFLEX (REbif FLEXible dosing in early MS) study entered an extension (REFLEXION, REbif FLEXible dosing in early MS extensION): patients initially randomised to sc IFN β-1a and not reaching clinically definite MS (clinically definite MS, CDMS (second attack or sustained Expanded Disability Status Scale (EDSS) score increase)) continued original treatment (three times weekly (tiw) or once weekly (qw)); placebo patients switched to tiw (DT); patients with CDMS switched to tiw. Clinical, MRI and adverse event data up to month 60 are reported. RESULTS: 402/517 (77.8%) REFLEX patients entered REFLEXION (DT, n=133; tiw, n=127; qw, n=142). At month 60, cumulative probability of CDMS was: DT 44.6%; qw 40.7% (nominal p=0.084 vs DT); tiw 39.2% (nominal p=0.032 vs DT). Cumulative probability of McDonald MS conversion (CDMS or new MRI activity) at month 60 was also reduced for tiw versus DT (nominal p<0.001). At month 60, mean cumulative numbers of new T2, gadolinium-enhancing and T1 hypointense lesions were lower with sc IFN β-1a qw (nominal p<0.05) and tiw versus DT (nominal p<0.001); T2 and T1 hypointense lesion volume change was lower for sc IFN β-1a tiw versus DT (nominal p<0.01). Treatment was well tolerated; fewer patients receiving tiw versus qw were positive for neutralising or binding antibodies. CONCLUSIONS: Over 5 years in patients presenting with an FCDE, early sc IFN β-1a tiw administration versus DT prolonged time to CDMS and McDonald MS, and reduced overall MRI activity. TRIAL REGISTRATION NUMBER: NCT00813709; Results.

111 Clinical Trial Comparing outcomes from clinical studies of oral disease-modifying therapies (dimethyl fumarate, fingolimod, and teriflunomide) in relapsing MS: Assessing absolute differences using a number needed to treat analysis. 2016

Freedman, Mark S / Montalban, Xavier / Miller, Aaron E / Dive-Pouletty, Catherine / Hass, Steven / Thangavelu, Karthinathan / Leist, Thomas P. ·University of Ottawa and the Ottawa Hospital Research Institute, The Ottawa Hospital - General Campus, 501 Smyth Road, Ottawa, ON, Canada, K1H 8L6. Electronic address: mfreedman@toh.ca. · Department of Neurology-Neuroimmunology, Cemcat, Vall d'Hebron University Hospital, P. de la Vall d'Hebron, 119-129, Barcelona 08035, Spain. · Icahn School of Medicine at Mount Sinai, The Corinne Goldsmith Dickinson Center for Multiple Sclerosis, 5 East 98th Street, New York 10029, USA. · Sanofi Genzyme, 1 Avenue Pierre Brossolette, Chilly-Mazarin 91385, France. · Sanofi Genzyme, 500 Kendall Street, Cambridge, MA 02142, USA. · Comprehensive Multiple Sclerosis Center, Thomas Jefferson University Hospital, 900 Walnut Street, Ste. 200, Philadelphia, PA 19107, USA. ·Mult Scler Relat Disord · Pubmed #27919491.

ABSTRACT: Dimethyl fumarate (DMF), fingolimod, and teriflunomide are oral disease-modifying therapies (DMTs) indicated for the treatment of relapsing-remitting multiple sclerosis. Despite well-established limitations of cross-trial comparisons, DMTs are still frequently compared in terms of relative reductions in specific endpoints, most commonly annualized relapse rate. Consideration of absolute risk reduction and number needed to treat (NNT) provides an alternative approach to assess the magnitude of treatment effect and can provide valuable additional information on therapeutic gain. Using data from pivotal studies of DMF (DEFINE, NCT00420212; CONFIRM, NCT00451451), fingolimod (FREEDOMS, NCT00289978; FREEDOMS II, NCT00355134), and teriflunomide (TEMSO, NCT00134563; TOWER, NCT00751881), we calculated NNTs to prevent any relapse, more severe relapses (such as those leading to hospitalization or requiring intravenous corticosteroids), and disability worsening. Higher relative reductions were reported for DMF and fingolimod vs placebo on overall relapse and relapses requiring intravenous corticosteroids in both individual and pooled studies (pooled data unavailable for fingolimod). However, NNTs for each outcome were similar for DMF and teriflunomide, with marginally lower NNTs observed with fingolimod. By contrast, for relapses requiring hospitalization, relative reductions were higher and NNTs were substantially lower for teriflunomide compared with DMF. For fingolimod, there were inconsistent outcomes between the two studies for relapses requiring hospitalization; thus, comparative conclusions against DMF or teriflunomide cannot be clearly established. The risk of disability worsening was significantly reduced in both teriflunomide studies, but only in a single study for DMF (DEFINE) and fingolimod (FREEDOMS). NNTs to prevent one patient from experiencing disability worsening were similar in DEFINE, FREEDOMS, and TEMSO and TOWER but were higher in CONFIRM and FREEDOMS II. This NNT analysis demonstrates broadly comparable effects for DMF, fingolimod, and teriflunomide across key clinical outcomes. These observations are clinically relevant and may help to inform treatment decisions by providing additional information on therapeutic gain beyond informal assessments of relative reductions alone.

112 Clinical Trial Comparison of Quantitative Cerebral Blood Flow Measurements Performed by Bookend Dynamic Susceptibility Contrast and Arterial Spin-Labeling MRI in Relapsing-Remitting Multiple Sclerosis. 2016

D'Ortenzio, R M / Hojjat, S P / Vitorino, R / Cantrell, C G / Lee, L / Feinstein, A / O'Connor, P / Carroll, T J / Aviv, R I. ·University of Toronto (R.M.D., P.O.C., L.L., A.F., R.I.A.), Toronto, Ontario, Canada. · Medical Imaging (S.P.H., R.V., R.I.A.), Sunnybrook Health Sciences Centre, Toronto, Ontario, Canada r.dortenzio@mail.utoronto.ca. · Medical Imaging (S.P.H., R.V., R.I.A.), Sunnybrook Health Sciences Centre, Toronto, Ontario, Canada. · Departments of Biomedical Engineering (C.G.C., T.J.C.). · Neurology (L.L.). · From the Departments of Psychiatry (A.F.). · Radiology (T.J.C.), Northwestern University, Chicago, Illinois. ·AJNR Am J Neuroradiol · Pubmed #27686489.

ABSTRACT: BACKGROUND AND PURPOSE: Quantitative CBF usage as a biomarker for cognitive impairment and disease progression in MS is potentially a powerful tool for longitudinal patient monitoring. Dynamic susceptibility contrast perfusion with bookend T1-calibration (bookend technique) and pseudocontinuous arterial spin-labeling have recently been used for CBF quantification in relapsing-remitting MS. The noninvasive nature of pseudocontinuous arterial spin-labeling is advantageous over gadolinium-based techniques, but correlation between the techniques is not well-established in the context of MS. MATERIALS AND METHODS: We compared pseudocontinuous arterial spin-labeling CBF with the bookend technique in a prospective cohort of 19 healthy controls, 19 subjects with relapsing-remitting MS without cognitive impairment, and 20 subjects with relapsing-remitting MS with cognitive impairment on a voxelwise and Brodmann region basis. The linear Pearson correlation, SNR, and coefficient of variation were quantified. RESULTS: Voxelwise paired t tests revealed no significant CBF differences between techniques after normalization of global mean intensities. The highest Pearson correlations were observed in deep GM structures (average r = 0.71 for the basal ganglia and r = 0.65 for the thalamus) but remained robust for cortical GM, WM, and white matter lesions (average r = 0.51, 0.53, 0.54, respectively). Lower Pearson correlations were observed for cortical lesions (average r = 0.23). Brodmann region correlations were significant for all groups. All correlations were maintained in healthy controls and in patients with relapsing-remitting multiple sclerosis. The highest SNR was present in bookend perfusion, while the highest coefficient of variation was present in white matter lesions. CONCLUSIONS: Agreement between pseudocontinuous arterial spin-labeling and bookend technique CBF measurements is demonstrated in healthy controls and patients with relapsing-remitting MS.

113 Clinical Trial Safety and Efficacy of Siponimod (BAF312) in Patients With Relapsing-Remitting Multiple Sclerosis: Dose-Blinded, Randomized Extension of the Phase 2 BOLD Study. 2016

Kappos, Ludwig / Li, David K B / Stüve, Olaf / Hartung, Hans-Peter / Freedman, Mark S / Hemmer, Bernhard / Rieckmann, Peter / Montalban, Xavier / Ziemssen, Tjalf / Hunter, Brian / Arnould, Sophie / Wallström, Erik / Selmaj, Krzysztof. ·Neurologic Clinic and Policlinic, Department of Medicine, University Hospital Basel, Basel, Switzerland2Department of Clinical Research, University Hospital Basel, Basel, Switzerland3Department of Biomedicine and Biomedical Engineering, University Hospital Basel, Basel, Switzerland. · Department of Radiology, University of British Columbia, Vancouver, British Columbia, Canada5Department of Medicine (Neurology), University of British Columbia, Vancouver, British Columbia, Canada. · University of Texas Southwestern Medical Center, Dallas. · Department of Neurology, Medical Faculty, Heinrich Heine University, Düsseldorf, Germany. · The Ottawa Hospital Research Institute, University of Ottawa, Ottawa, Ontario, Canada. · Technical University of Munich, Munich, Germany. · Sozialstiftung Bamberg Hospital, Bamberg, Germany. · MS Centre of Catalonia, Vall d´Hebron University Hospital, Barcelona, Spain. · Center of Clinical Neuroscience, University of Technology Dresden, Dresden, Germany. · Novartis Pharma AG, Basel, Switzerland. · Department of Neurology, Medical University of Lodz, Lodz, Poland. ·JAMA Neurol · Pubmed #27380540.

ABSTRACT: IMPORTANCE: This dose-blinded extension of the phase 2 BOLD (BAF312 on MRI Lesion Given Once Daily) Study in relapsing-remitting multiple sclerosis provides evidence on disease activity and safety of a range of siponimod doses for up to 24 months. OBJECTIVE: To assess the safety and efficacy of siponimod for up to 24 months during the dose-blinded extension of the BOLD Study. DESIGN, SETTING, AND PARTICIPANTS: At extension baseline in a randomized clinical trial, patients taking siponimod continued at the originally assigned dose and patients taking placebo were rerandomized to the 5 siponimod doses. Initial treatment was titrated over 10 days. A total of 252 eligible patients were treated at specialized multiple sclerosis centers for this study conducted from August 30, 2010, through June 3, 2013. INTERVENTIONS: Siponimod at 10-mg, 2-mg, 1.25-mg, 0.5-mg, and 0.25-mg doses. MAIN OUTCOMES AND MEASURES: Safety assessment included blood tests, documentation of adverse events at regular scheduled visits and Holter monitoring; key efficacy measures were annualized relapse rate and magnetic resonance imaging lesion activity. RESULTS: Among the 252 eligible patients, the mean (SD) ages were 37.2 (8.4) years, 35.2 (9.1) years, 34.0 (7.6) years, 35.1 (9.2) years, and 36.8 (9.1) years in the 0.25-mg, 0.5-mg, 1.25-mg, 2-mg, and 10-mg groups. Of the 252 patients, 184 (73%) entered the extension and received siponimod (10 mg: n = 33; 2 mg: n = 29; 1.25 mg: n = 43; 0.5 mg: n = 29; and 0.25 mg: n = 50); 159 (86.4%) completed the dose-blinded extension. The incidence of adverse events was similar across treatment groups (10 mg: 87.9%; 2 mg: 89.7%; 1.25 mg: 88.4%; 0.5 mg: 96.6%; and 0.25 mg: 84.0%). Nine patients reported serious adverse events (2 mg: 3/29 [10.3%], 1.25 mg: 1/43 [2.3%], 0.5 mg: 4/29 [13.8%], and 0.25 mg: 1/50 [2.0%]; no serious adverse event was reported for more than 1 patient and no new safety signals occurred compared with the BOLD Study. Dose titration mitigated symptomatic bradycardic events. Reductions in mean (95% CI) gadolinium-enhancing T1 lesion counts from the last BOLD assessment were sustained in the 10-mg, 2-mg, 1.25-mg, and 0.5-mg dose groups (0 [0-0], 0.1 [0-1.9], 0.1 [0-2.6], and 0.1 [0-2.8] at month 24, respectively). At the 3 highest vs 2 lowest doses, the estimated new/newly enlarging T2 lesion counts (95% CIs) were lower during months 6 to 12 (0.5 [0.2-1.3], 0.4 [0.2-1.1], and 0.2 [0.1-0.6] vs 1.3 [0.6-2.8] and 1.4 [0.7-2.7]), months 12 to 18 (0.4 [0.1-1.1], 0.4 [0.1-1.3], and 0.4 [0.2-1.0] vs 1.0 [0.4-2.6] and 3.6 [1.7-7.6]), and months 18 to 24 (0 [0-not estimable], 0.9 [0.1-7.6], and 0.1 [0-1.7] vs 1.6 [0.3-7.7] and 2.0 [0.4-9.5]). Annualized relapse rates (95% CIs) up to month 24 were similarly lower for the 3 highest doses: 0.22 (0.12-0.40) for 10 mg, 0.20 (0.10-0.38) for 2 mg, and 0.14 (0.08-0.26) for 1.25 mg vs 0.33 (0.19-0.56) for 0.5 mg and 0.33 (0.21-0.50) for 0.25 mg. CONCLUSIONS AND RELEVANCE: For up to 24 months of siponimod treatment, multiple sclerosis disease activity was low and there were no new safety signals; investigation in phase 3 trials is encouraged. TRIAL REGISTRATION: clinicaltrials.gov Identifier: NCT01185821.

114 Clinical Trial Immunoablation and autologous haemopoietic stem-cell transplantation for aggressive multiple sclerosis: a multicentre single-group phase 2 trial. 2016

Atkins, Harold L / Bowman, Marjorie / Allan, David / Anstee, Grizel / Arnold, Douglas L / Bar-Or, Amit / Bence-Bruckler, Isabelle / Birch, Paul / Bredeson, Christopher / Chen, Jacqueline / Fergusson, Dean / Halpenny, Mike / Hamelin, Linda / Huebsch, Lothar / Hutton, Brian / Laneuville, Pierre / Lapierre, Yves / Lee, Hyunwoo / Martin, Lisa / McDiarmid, Sheryl / O'Connor, Paul / Ramsay, Timothy / Sabloff, Mitchell / Walker, Lisa / Freedman, Mark S. ·Ottawa Hospital Research Institute, Ottawa, ON, Canada; The Ottawa Hospital Blood and Marrow Transplant Program, Ottawa, ON, Canada; Department of Medicine, University of Ottawa, Ottawa, ON, Canada. Electronic address: hatkins@ohri.ca. · Ottawa Hospital Research Institute, Ottawa, ON, Canada; The Ottawa Hospital MS Clinic, Ottawa, ON, Canada. · Ottawa Hospital Research Institute, Ottawa, ON, Canada; The Ottawa Hospital Blood and Marrow Transplant Program, Ottawa, ON, Canada; Department of Medicine, University of Ottawa, Ottawa, ON, Canada. · The Ottawa Hospital Blood and Marrow Transplant Program, Ottawa, ON, Canada. · Department of Neurology and Neurosurgery, Montreal Neurological Institute and Hospital, McGill University, Montréal, QC, Canada; NeuroRx Research, Montreal, QC, Canada. · Department of Neurology and Neurosurgery, Montreal Neurological Institute and Hospital, McGill University, Montréal, QC, Canada; Neuroimmunology Unit, Montreal Neurological Institute and Hospital, McGill University, Montréal, QC, Canada. · The Ottawa Hospital Blood and Marrow Transplant Program, Ottawa, ON, Canada; Department of Medicine, University of Ottawa, Ottawa, ON, Canada. · Ottawa Stem Cell Program, Canadian Blood Services, Ottawa, ON, Canada. · Department of Neurology and Neurosurgery, Montreal Neurological Institute and Hospital, McGill University, Montréal, QC, Canada; Department of Neurosciences, Cleveland Clinic, Cleveland, OH, USA. · Ottawa Hospital Research Institute, Ottawa, ON, Canada; Department of Medicine, University of Ottawa, Ottawa, ON, Canada. · Ottawa Hospital Research Institute, Ottawa, ON, Canada. · McGill University Health Center, Montreal, QC, Canada; Division of Oncology, Department of Medicine, McGill University, Montreal, QC, Canada. · Department of Neurology and Neurosurgery, Montreal Neurological Institute and Hospital, McGill University, Montréal, QC, Canada. · Division of Neurology, St Michael's Hospital, University of Toronto, Toronto, ON, Canada. · School of Psychology, University of Ottawa, Ottawa, ON, Canada; The Ottawa Hospital MS Clinic, Ottawa, ON, Canada. · Ottawa Hospital Research Institute, Ottawa, ON, Canada; Department of Medicine, University of Ottawa, Ottawa, ON, Canada; The Ottawa Hospital MS Clinic, Ottawa, ON, Canada. ·Lancet · Pubmed #27291994.

ABSTRACT: BACKGROUND: Strong immunosuppression, including chemotherapy and immune-depleting antibodies followed by autologous haemopoietic stem-cell transplantation (aHSCT), has been used to treat patients with multiple sclerosis, improving control of relapsing disease. We addressed whether near-complete immunoablation followed by immune cell depleted aHSCT would result in long-term control of multiple sclerosis. METHODS: We did this phase 2 single-arm trial at three hospitals in Canada. We enrolled patients with multiple sclerosis, aged 18-50 years with poor prognosis, ongoing disease activity, and an Expanded Disability Status Scale of 3.0-6.0. Autologous CD34 selected haemopoietic stem-cell grafts were collected after mobilisation with cyclophosphamide and filgrastim. Immunoablation with busulfan, cyclophosphamide, and rabbit anti-thymocyte globulin was followed by aHSCT. The primary outcome was multiple sclerosis activity-free survival (events were clinical relapse, appearance of a new or Gd-enhancing lesion on MRI, and sustained progression of Expanded Disability Status Scale score). This study was registered at ClinicalTrials.gov, NCT01099930. FINDINGS: Between diagnosis and aHSCT, 24 patients had 167 clinical relapses over 140 patient-years with 188 Gd-enhancing lesions on 48 pre-aHSCT MRI scans. Median follow-up was 6.7 years (range 3.9-12.7). The primary outcome, multiple sclerosis activity-free survival at 3 years after transplantation was 69.6% (95% CI 46.6-84.2). With up to 13 years of follow-up after aHSCT, no relapses occurred and no Gd enhancing lesions or new T2 lesions were seen on 314 MRI sequential scans. The rate of brain atrophy decreased to that expected for healthy controls. One of 24 patients died of transplantation-related complications. 35% of patients had a sustained improvement in their Expanded Disability Status Scale score. INTERPRETATION: We describe the first treatment to fully halt all detectable CNS inflammatory activity in patients with multiple sclerosis for a prolonged period in the absence of any ongoing disease-modifying drugs. Furthermore, many of the patients had substantial recovery of neurological function despite their disease's aggressive nature. FUNDING: Multiple Sclerosis Scientific Research Foundation.

115 Clinical Trial Multiple sclerosis relapses are associated with increased fatigue and reduced health-related quality of life - A post hoc analysis of the TEMSO and TOWER studies. 2016

Mäurer, Mathias / Comi, Giancarlo / Freedman, Mark S / Kappos, Ludwig / Olsson, Tomas P / Wolinsky, Jerry S / Miller, Aaron E / Dive-Pouletty, Catherine / Bozzi, Sylvie / O'Connor, Paul W. ·Klinik für Neurologie, Caritas Krankenhaus Bad Mergentheim, Uhlandstraße 7, 97980 Bad Mergentheim, Germany. Electronic address: mathias.maeurer@ckbm.de. · Department of Neurology and Institute of Experimental Neurology, University Vita-Salute San Raffaele, Via Olgettina 60, 20132 Milan, Italy. Electronic address: comi.giancarlo@hsr.it. · University of Ottawa and the Ottawa Hospital Research Institute, The Ottawa Hospital - General Campus, 501 Smyth Road, Ottawa, ON, Canada K1H 8L6. Electronic address: mfreedman@toh.on.ca. · Neurology, Departments of Medicine, Clinical Research and Biomedicine, University Hospital Basel, Petersgraben 4, CH-4031 Basel, Switzerland. Electronic address: lkappos@uhbs.ch. · Neuroimmunology Unit, Department of Clinical Neurosciences, Karolinska Hospital, CMM L8:04, 17176 Stockholm, Sweden. Electronic address: tomas.olsson@ki.se. · Department of Diagnostic and Interventional Imaging, University of Texas Health Science Center at Houston, 6431 Fannin Street, Houston, TX 77030, USA. Electronic address: jerry.s.wolinsky@uth.tmc.edu. · Corinne Goldsmith Dickinson Center for MS, Icahn School of Medicine at Mount Sinai, 5 East 98th Street, Box 1138, New York, NY 10029, USA. Electronic address: aaron.miller@mssm.edu. · Health Economics/Outcomes Research, Sanofi Genzyme, 1 Avenue Pierre Brossolette, 91385 Chilly-Mazarin, France. Electronic address: catherine.dive-pouletty@sanofi.com. · Health Economics/Outcomes Research, Sanofi Genzyme, 1 Avenue Pierre Brossolette, 91385 Chilly-Mazarin, France. Electronic address: sylvie.bozzi@sanofi.com. · St Michael's Hospital, Division of Neurology, 30 Bond Street, Toronto, ON, Canada M5B 1W8. Electronic address: oconnorp@smh.ca. ·Mult Scler Relat Disord · Pubmed #27237754.

ABSTRACT: BACKGROUND: Two pivotal phase 3 teriflunomide studies provided data on relapses, fatigue, and health-related quality of life (HRQoL) in patients with relapsing forms of multiple sclerosis (MS). OBJECTIVES: Using pooled data from the TEMSO (NCT00134563) and TOWER (NCT00751881) studies, we investigated the association between relapse severity, and changes from baseline to Week 108 in fatigue and HRQoL outcomes. METHODS: Four definitions of relapse severity were applied in this analysis: sequelae post-relapse; relapse leading to hospitalization; relapse requiring intravenous corticosteroids; and intense relapse. We assessed the association between relapse severity and changes in Fatigue Impact Scale score (n=959), physical and mental health component summary scores from the Short Form (SF)-36 questionnaire (n=904), and SF-6D utility index scores (n=820). RESULTS: Irrespective of the definition of relapse severity applied, in patients experiencing severe relapse(s), fatigue was increased and HRQoL was decreased; these changes were statistically significant (p<0.0001), and were also clinically significant in many cases. The greatest worsening in fatigue and HRQoL was observed in patients with relapses leading to hospitalization. CONCLUSIONS: Given that severe relapses adversely affect patient-reported fatigue and HRQoL, prevention of severe relapses should be an important therapeutic aim in the treatment of patients with MS.

116 Clinical Trial Adherence to interferon β-1a therapy using an electronic self-injector in multiple sclerosis: a multicentre, single-arm, observational, phase IV study. 2016

Devonshire, Virginia A / Feinstein, Anthony / Moriarty, Patrick. ·Department of Neurology, University of British Columbia, Vancouver, Canada. vdev@shaw.ca. · Department of Psychiatry, Sunnybrook Health Sciences Centre, University of Toronto, Toronto, Canada. antfeinstein@aol.com. · A division of EMD Inc., EMD Serono, 2695 North Sheridan Way, Suite 200, Mississauga, ON, L5K 2N6, Canada. Patrick.moriarty@emdserono.com. ·BMC Res Notes · Pubmed #26951043.

ABSTRACT: BACKGROUND: In a multicentre, single-arm, observational, phase IV study, we evaluated 24-week treatment adherence of relapsing multiple sclerosis (RMS) patients using an electronic auto-injection device (RebiSmart(®)) for subcutaneous injection of interferon (IFN) β-1a. METHODS: A total of 162 adult participants with RMS were enrolled into the study to use RebiSmart(®) to self-administer IFN β-1a 44 μg three times weekly for a maximum of 96 weeks. The number of administered injections was recorded in the electronic device log. Adherence to treatment was defined as the administration of ≥80% of expected injections. Cognitive impairment and injection anxiety were assessed via questionnaires. RESULTS: Overall, 91.8 and 82.9% of participants were adherent to treatment at weeks 12 and 24, respectively. By weeks 12 and 24, 8.2 and 13.9% of participants had discontinued treatment. There were no statistically significant differences in adherence rates at weeks 12 and 24 according to cognitive impairment status or injection anxiety. By week 24, 69.9% of participants were less fearful of injection than when they started the study. According to participant evaluations, the absence of a visible needle, comfort settings, and the calendar for tracking the injection schedule were all important features of the RebiSmart(®) injection system. At week 24, 99.3% of participants reported that they would like to continue using RebiSmart(®) as their injector. CONCLUSIONS: RebiSmart(®) use is associated with high treatment adherence, as objectively assessed using electronic injection logs. Future research should examine if RebiSmart(®) use improves long-term treatment outcomes in RMS. This study was registered with ClinicalTrials.gov as NCT01128075, on May 20, 2010.

117 Clinical Trial Long-term safety and efficacy of teriflunomide: Nine-year follow-up of the randomized TEMSO study. 2016

O'Connor, Paul / Comi, Giancarlo / Freedman, Mark S / Miller, Aaron E / Kappos, Ludwig / Bouchard, Jean-Pierre / Lebrun-Frenay, Christine / Mares, Jan / Benamor, Myriam / Thangavelu, Karthinathan / Liang, Jinjun / Truffinet, Philippe / Lawson, Victoria J / Wolinsky, Jerry S / Anonymous510858. ·From the University of Toronto (P.O.), Ontario, Canada · University Vita-Salute San Raffaele (G.C.), Milan, Italy · University of Ottawa and the Ottawa Hospital Research Institute (M.S.F.), Ontario, Canada · Icahn School of Medicine at Mount Sinai (A.E.M.), New York, NY · University Hospital Basel (L.K.), Switzerland · Laval University, Centre Hospitalier Universitaire de Québec (J.-P.B.), Québec, Canada · Hôpital Pasteur (C.L.-F.), Nice, France · Fakultni Nemocnice Olomouc (J.M.), Olomouc, Czech Republic · Sanofi Genzyme (M.B., P.T.), Chilly-Mazarin, France · Sanofi Genzyme (K.T.), Cambridge, MA · Sanofi (J.L.), Bridgewater, NJ · Fishawack Communications Ltd. (V.J.L.), Abingdon, UK · and University of Texas Health Science Center at Houston (J.S.W.). ·Neurology · Pubmed #26865517.

ABSTRACT: OBJECTIVE: To report safety and efficacy outcomes from up to 9 years of treatment with teriflunomide in an extension (NCT00803049) of the pivotal phase 3 Teriflunomide Multiple Sclerosis Oral (TEMSO) trial (NCT00134563). METHODS: A total of 742 patients entered the extension. Teriflunomide-treated patients continued the original dose; those previously receiving placebo were randomized 1:1 to teriflunomide 14 mg or 7 mg. RESULTS: By June 2013, median (maximum) teriflunomide exposure exceeded 190 (325) weeks per patient; 468 patients (63%) remained on treatment. Teriflunomide was well-tolerated with continued exposure. The most common adverse events (AEs) matched those in the core study. In extension year 1, first AEs of transient liver enzyme increases or reversible hair thinning were generally attributable to patients switching from placebo to teriflunomide. Approximately 11% of patients discontinued treatment owing to AEs. Twenty percent of patients experienced serious AEs. There were 3 deaths unrelated to teriflunomide. Soon after the extension started, annualized relapse rates and gadolinium-enhancing T1 lesion counts fell in patients switching from placebo to teriflunomide, remaining low thereafter. Disability remained stable in all treatment groups (median Expanded Disability Status Scale score ≤2.5; probability of 12-week disability progression ≤0.48). CONCLUSIONS: In the TEMSO extension, safety observations were consistent with the core trial, with no new or unexpected AEs in patients receiving teriflunomide for up to 9 years. Disease activity decreased in patients switching from placebo and remained low in patients continuing on teriflunomide. CLASSIFICATION OF EVIDENCE: This study provides Class III evidence that long-term treatment with teriflunomide is well-tolerated and efficacy of teriflunomide is maintained long-term.

118 Clinical Trial Oral fingolimod in primary progressive multiple sclerosis (INFORMS): a phase 3, randomised, double-blind, placebo-controlled trial. 2016

Lublin, Fred / Miller, David H / Freedman, Mark S / Cree, Bruce A C / Wolinsky, Jerry S / Weiner, Howard / Lubetzki, Catherine / Hartung, Hans-Peter / Montalban, Xavier / Uitdehaag, Bernard M J / Merschhemke, Martin / Li, Bingbing / Putzki, Norman / Liu, Fonda C / Häring, Dieter A / Kappos, Ludwig / Anonymous6320856. ·The Corinne Goldsmith Dickinson Center for Multiple Sclerosis, Icahn School of Medicine at Mount Sinai, New York, NY, USA. Electronic address: fred.lublin@mssm.edu. · Queen Square MS Centre, UCL Institute of Neurology, London, UK. · The Ottawa Hospital Research Institute, University of Ottawa, Ottawa, ON, Canada. · Multiple Sclerosis Center, University of California San Francisco, CA, USA. · University of Texas Health Science Center at Houston, Houston, TX, USA. · Brigham and Women's Hospital, Harvard Medical School, Boston, MA, USA. · University Paris 6, Salpêtrière Hospital APHP, Center of Clinical Investigation, Paris, France. · Department of Neurology, Medical Faculty, Heinrich-Heine University, Düsseldorf, Germany. · Hospital Universitari Vall d'Hebron, Barcelona, Spain. · VU University Medical Center, Amsterdam, Netherlands. · Novartis Pharma AG, Basel, Switzerland. · Novartis Pharmaceuticals Corporation, East Hanover, NJ, USA. · Departments of Medicine, Clinical Research, Biomedicine and Biomedical Engineering, University Hospital, University of Basel, Switzerland. ·Lancet · Pubmed #26827074.

ABSTRACT: BACKGROUND: No treatments have been approved for primary progressive multiple sclerosis. Fingolimod, an oral sphingosine 1-phosphate receptor modulator, is effective in relapse-onset multiple sclerosis, but has not been assessed in primary progressive multiple sclerosis. We assessed the safety and efficacy of fingolimod in patients with primary progressive multiple sclerosis. METHODS: In INFORMS, a multicentre, double-blind, placebo-controlled parallel-group study, patients with primary progressive multiple sclerosis recruited across 148 centres in 18 countries were randomly allocated (1:1) with computer-generated blocks to receive oral fingolimod or placebo for at least 36 months and a maximum of 5 years. Patients were initially assigned to fingolimod 1·25 mg per day or placebo (cohort 1); however, after a protocol amendment on Nov 19, 2009, patients were switched in a masked manner to fingolimod 0·5 mg, whereas those on placebo continued on matching placebo. From then onwards, patients were assigned to receive fingolimod 0·5 mg/day or placebo (cohort 2). Key inclusion criteria were age 25-65 years, clinical diagnosis of primary progressive multiple sclerosis, 1 year or more of disease progression, and two of the following criteria: positive brain MRI; positive spinal cord MRI; or positive cerebrospinal fluid. Additional eligibility criteria included disease duration of 2-10 years and objective evidence of disability progression in the previous 2 years. Patients and study investigators were masked to group assignment. We used a novel primary composite endpoint based on change from baseline in Expanded Disability Status Scale (EDSS), 25' Timed-Walk Test, or Nine-Hole Peg Test to assess time to 3-month confirmed disability progression in study participants treated for at least 3 years. All randomised patients took at least one dose of study drug. The primary efficacy analysis included all patients in cohort 2 and those assigned to placebo in cohort 1. The safety analysis included all patients in cohorts 1 and 2. This study is registered with ClinicalTrials.gov, number NCT00731692. The study is now closed. FINDINGS: 970 patients were randomly assigned between Sept 3, 2008, and Aug 30, 2011 (147 to fingolimod 1·25 mg and 133 to placebo in cohort 1; 336 to fingolimod 0·5 mg and 354 to placebo in cohort 2). The efficacy analysis set (n=823) consisted of 336 patients randomly allocated to fingolimod 0·5 mg and 487 to placebo. Baseline characteristics were similar across groups and representative of a primary progressive multiple sclerosis population (48% women, mean age 48·5 years [SD 8·4], mean EDSS 4·67 [SD 1·03], 87% free of gadolinium-enhancing lesions). By end of study, 3-month confirmed disability progression had occurred in 232 and 338 patients in the fingolimod and placebo groups, respectively, resulting in Kaplan-Meier estimates of 77·2% (95% CI 71·87-82·51) of patients in the fingolimod group versus 80·3% (73·31-87·25) of patients in the placebo group (risk reduction 5·05%; hazard ratio 0·95, 95% CI 0·80-1·12; p=0·544). Safety results were generally consistent with those of studies of fingolimod in patients with relapse-onset multiple sclerosis. Lymphopenia occurred in 19 (6%) patients in the fingolimod group versus none in the placebo group, bradycardia in five (1%) versus one (<1%), and first-degree atrioventricular block in three (1%) versus six (1%). Serious adverse events occurred in 84 (25%) patients in the fingolimod group and 117 (24%) in the placebo group, including macular oedema in six (2%) versus six (1%), and basal-cell carcinoma in 14 (4%) versus nine (2%). INTERPRETATION: The anti-inflammatory effects of fingolimod did not slow disease progression in primary progressive multiple sclerosis. Therapeutic strategies for primary progressive multiple sclerosis might need different approaches to those used for relapse-onset multiple sclerosis. FUNDING: Novartis Pharma AG.

119 Clinical Trial Long-term results from a phase 2 extension study of fingolimod at high and approved dose in relapsing multiple sclerosis. 2015

Montalban, Xavier / Comi, Giancarlo / Antel, Jack / O'Connor, Paul / de Vera, Ana / Cremer, Malika / Sfikas, Nikolaos / von Rosenstiel, Philipp / Kappos, Ludwig. ·Neurology-Neuroimmunology Department & Neurorehabilitation Unit, Edif. Cemcat, Vall d'Hebron University Hospital, 119-129, 08035, Barcelona, Spain. xavier.montalban@cem-cat.org. · Department of Neurology, Vita-Salute San Raffaele, University, Milan, Italy. · Department of Neurology and Neurosurgery, Montreal Neurological Institute University, 3801, Room 111, Montreal, Canada. · St. Michael's Hospital, 30 Bond St, Toronto, ON, M5B 1W8, Canada. · Novartis Pharma AG, Basel, Switzerland. · Departments of Medicine, Clinical Research, Biomedicine and Biomedical Engineering, University Hospital, Basel, Switzerland. ·J Neurol · Pubmed #26338810.

ABSTRACT: Fingolimod safety and efficacy data in relapsing-remitting multiple sclerosis (RRMS) are available up to 5 years, from an extension of a randomized, placebo-controlled, double-blind, phase 2 study, at a dose higher (5.0/1.25 mg) than the approved dose of 0.5 mg. The objective of the study is to present the end-of-study data (>7 years) from the open-label extension of the phase 2 study. In the core phase (6 months), patients (N = 281) were randomized to placebo or fingolimod 1.25/5 mg. In the extension, placebo patients were randomized to fingolimod 1.25/5 mg. All patients received open-label 1.25 mg fingolimod after month 24 and 0.5 mg after month 60. Clinical visits were performed every 3 months, expanded disability status scale (EDSS) every 6 months and magnetic resonance imaging (MRI) annually. 122 (48.8%) patients completed the extension study; overall fingolimod exposure was 1230.7 patient-years. The most common (>10%) reasons for study discontinuation were adverse events (19.6%) and consent withdrawal (16.4%). Fingolimod treatment for >7 years was associated with sustained low clinical and MRI disease activity. Over 60% of patients remained relapse free and about 80% were free from any MRI activity. Overall annualized relapse rate was 0.18. Long-term fingolimod treatment was not associated with new safety concerns. Long-term fingolimod was well tolerated and associated with a sustained low level of disease activity.

120 Clinical Trial Two Multiple Sclerosis Quality-of-Life Measures: Comparison in a National Sample. 2015

Moore, Fraser / Vickrey, Barbara / Fortin, Kathy / Lee, Liesly. ·1Department of Neurology,Jewish General Hospital,McGill University,Montreal. · 2Department of Neurology,University of California,Los Angeles,California,USA. · 3Department of Medical Affairs,Boisbriand,Quebec. · 4Division of Neurology,Sunnybrook Health Science Center,Toronto,Ontario,Canada. ·Can J Neurol Sci · Pubmed #25586701.

ABSTRACT: BACKGROUND: Multiple sclerosis (MS) has a profound impact on patients' health-related quality of life (HRQoL). It is unclear how HRQoL can be best assessed for different purposes. This study aimed to compare two HRQoL questionnaires of differing lengths for feasibility of administration, patient perceptions and psychometric properties. METHODS: This was an open-label, 24-month study in 334 patients with relapsing MS treated with subcutaneous interferon β-1a. At baseline and months 6, 12, 18 and 24, patients completed the Multiple Sclerosis International Quality of Life (MusiQoL) and Multiple Sclerosis Quality of Life-54 (MSQOL-54) questionnaires and compared them using an evaluation questionnaire. HRQoL scores over time and psychometric properties (correlations with clinical disease measures, relative validity and responsiveness to change) of the questionnaires were assessed. RESULTS: A minority of patients had missing items on either HRQoL measure. Completion time was significantly shorter for MusiQoL versus MSQOL-54 (p<0.0001). Patients felt that MusiQoL was easier to use than MSQOL-54 but preferred MSQOL-54 in terms of thoroughness. Mean HRQoL scores increased significantly from baseline to 24 months; correlations of both measures were stronger with an anxiety and depression measure than with disability or recent relapse occurrence. Relative validity and responsiveness to change were similar for both instruments. CONCLUSION: The shorter MusiQoL is suitable for evaluating HRQoL in patients with MS and may be more practical to administer than the more thorough MSQOL-54.

121 Clinical Trial Ten-year follow-up of the 'minimal MRI lesion' subgroup from the original CHAMPS Multiple Sclerosis Prevention Trial. 2015

Simon, J H / Kinkel, R P / Kollman, C / O'Connor, P / Fisher, E / You, X / Hyde, R / Anonymous1750810. ·Portland VA Medical Center, VA Medical Center and Oregon Health Science Center, USA jack.simon1@me.com. · Department of Neurosciences, University of California San Diego, USA. · Department of Biostatistics, Jaeb Center for Health Research, Tampa, FL, USA. · Multiple Sclerosis Clinic, St. Michael's Hospital, Toronto, ON, Canada. · Department of Biomedical Engineering, Cleveland Clinic, Cleveland, OH, USA. · Departments of Biostatistics, Biogen Idec Inc, Cambridge, MA, USA. · Global Medical Affairs, Biogen Idec Inc, Cambridge, MA, USA. ·Mult Scler · Pubmed #25344370.

ABSTRACT: BACKGROUND: Patients with clinically isolated syndrome (CIS) and characteristic magnetic resonance imaging (MRI) lesions are at high risk for multiple sclerosis (MS). However, patients with a minimal MRI lesion burden (a low T2-hyperintense [low T2] lesion count) may have borderline formal diagnostic criteria, presenting a clinical management challenge. OBJECTIVE: Compare the 10-year disease progression of patients with low and higher T2 lesion counts treated over most intervals. METHODS: CIS patients from the original CHAMPS MS trial were retrospectively assigned to low-T2 (first quartile; 2-8 lesions) or higher-T2 (second through fourth quartiles; ≥ 9 lesions) groups using baseline T2 lesion counts. The 5- and 10-year open-label extension of CHAMPS (CHAMPIONS) evaluated conversion to clinically definite MS (CDMS), MRI activity, relapses, and disability. RESULTS: The vast majority of patients showed new disease activity by MRI and/or clinical criteria at 10 years (low-T2 86%; higher-T2 98%). Fewer low-T2 than higher-T2 patients developed CDMS (40% vs. 63%; p = 0.013); low-T2 patients also had fewer new brain lesions, less brain volume loss, and less disability progression. CONCLUSION: CIS patients with low T2 lesion counts show continued disease activity. However, all assessments of disease progression over 10 years indicated a significantly less severe disease course for low-T2 patients.

122 Clinical Trial First-dose effects of fingolimod: Pooled safety data from three phase 3 studies. 2014

DiMarco, John P / O'Connor, Paul / Cohen, Jeffrey A / Reder, Anthony T / Zhang-Auberson, Lixin / Tang, Dejun / Collins, William / Kappos, Ludwig. ·Division of Cardiovascular Medicine, University of Virginia Health System, P.O. Box 800158, Charlottesville, VA 22908-0466, USA. Electronic address: jdimarco1@live.com. · St Michael׳s Hospital, 30 Bond Street, University of Toronto, Toronto, ON, Canada M5B 1W8. Electronic address: oconnorp@smh.toronto.on.ca. · Cleveland Clinic, 9500 Euclid Avenue, Cleveland, OH 44195, USA. Electronic address: cohenj@ccf.org. · University of Chicago Medical Center, 5841 S. Maryland Ave, Chicago, IL 60637-1403, USA. Electronic address: areder@neurology.bsd.uchicago.edu. · Novartis Pharma AG, CH-4056 Basel, Switzerland. Electronic address: lixin.zhang_auberson@novartis.com. · Novartis Pharmaceuticals Corporation, One Health Plaza, East Hanover, NJ 07936-1080, USA. Electronic address: dejun.tang@novartis.com. · Novartis Pharma AG, CH-4056 Basel, Switzerland. Electronic address: william.collins@novartis.com. · Neurology, Departments of Medicine, Clinical Research and Biomedicine, University Hospital, Petersgraben 4, CH-4031 Basel, Switzerland. Electronic address: ludwig.kappos@usb.ch. ·Mult Scler Relat Disord · Pubmed #26265275.

ABSTRACT: Fingolimod treatment initiation is associated with a transient slowing of heart rate and atrioventricular conduction. This report presents first-dose fingolimod effects (0.5mg or 1.25mg) on cardiac parameters using phase 3 FREEDOMS, FREEDOMS II and TRANSFORMS pooled study data (n=3635 patients). Vital signs were recorded hourly for ≥6h; 12-lead electrocardiogram (ECG) was obtained at baseline and at 6h post-dose. Clinical events were graded at the first-dose administrator׳s discretion. At screening, on day 1 and at month 3, 1073 patients underwent 24-h ambulatory electrocardiogram monitoring. A transient decrease in mean measured heart rate occurred 4-5h after the first dose, with a maximum reduction of 8 (fingolimod 0.5mg) and 11 beats per minute (fingolimod 1.25mg) below baseline. Symptomatic bradycardia at treatment initiation was reported in 0.6% (fingolimod 0.5mg) and 2.1% (fingolimod 1.25mg) of patients; events were typically mild or moderate in severity, and most resolved spontaneously. Atrioventricular (AV) conduction delays were observed in a few patients (Wenckebach (Mobitz type I) second-degree AV block, fingolimod 0.5mg, 0.2%; 1.25mg, 1%: 2:1 AV block fingolimod, 0.5mg, 0%; 1.25mg, 0.2% on ECG 6-h post-dose). These were usually well tolerated and first occurred within 6h of dosing. Consistent with its effects on atrial myocytes, fingolimod treatment initiation induced a transient slowing of heart rate and AV conduction. However, symptomatic bradycardia and second-degree AV block were uncommon and did not require intervention.

123 Clinical Trial First-dose effects of fingolimod after switching from injectable therapies in the randomized, open-label, multicenter, Evaluate Patient OutComes (EPOC) study in relapsing multiple sclerosis. 2014

Hughes, Bruce / Cascione, Mark / Freedman, Mark S / Agius, Mark / Kantor, Daniel / Gudesblatt, Mark / Goldstick, Lawrence P / Agashivala, Neetu / Schofield, Lesley / McCague, Kevin / Hashmonay, Ron / Barbato, Luigi / Anonymous1740839. ·Mercy Ruan Neuroscience Center, Des Moines, IA, USA. Electronic address: brucehughes@mac.com. · Tampa Neurology Associates, Tampa, FL, USA. Electronic address: me@markcascione.com. · University of Ottawa and the Ottawa Hospital Research Institute, Ottawa, ON, Canada. Electronic address: MFREEDMAN@Ottawahospital.on.ca. · University of California Davis, Veterans Affairs Northern California Health Care System (VANCHCS), CA, USA. Electronic address: markaagius@hotmail.com. · Neurologique Foundation, Inc., Jacksonville, FL, USA. Electronic address: dkantor@neurologique.org. · Multiple Sclerosis Comprehensive Care Center, St Islip, NY, USA. Electronic address: mgudesbl@southshoreneurologic.com. · Neurology Specialists Inc, Dayton, OH, USA. Electronic address: lgoldstick@hotmail.com. · Novartis Pharmaceuticals Corporation, East Hanover, NJ, USA. Electronic address: neetu.agashivala@novartis.com. · Novartis Pharmaceuticals Corporation, East Hanover, NJ, USA. Electronic address: lesley.schofield@novartis.com. · Novartis Pharmaceuticals Corporation, East Hanover, NJ, USA. Electronic address: kevin.mccague@novartis.com. · Novartis Pharmaceuticals Corporation, East Hanover, NJ, USA. Electronic address: ronny.hashmonay@novartis.com. · Novartis Pharmaceuticals Corporation, East Hanover, NJ, USA. Electronic address: lou.barbato@novartis.com. ·Mult Scler Relat Disord · Pubmed #26265274.

ABSTRACT: BACKGROUND: In pivotal phase 3 studies, fingolimod treatment initiation was associated with a transient reduction in heart rate (HR). Atrioventricular (AV) conduction delays, which were typically asymptomatic, were detected in a small minority of patients. OBJECTIVE: We report the first-dose effects of fingolimod in patients who switched from injectable therapies during the Evaluate Patient OutComes (EPOC) study (ClinicalTrials.gov Identifier: NCT01216072). METHODS: This was a phase 4, 6-month, randomized, active-comparator, open-label, multicenter study. It included over 900 fingolimod-treated patients with relapsing multiple sclerosis, with subgroups of individuals who were receiving common concomitant HR-lowering medications or had pre-existing cardiac conditions (PCCs). Vital signs were recorded hourly for 6h post-dose. A 12-lead electrocardiogram was obtained at baseline and at 6h post-dose. RESULTS: A transient decrease in mean HR and blood pressure occurred within 6h of the first fingolimod dose. The incidence of symptomatic bradycardia was low (1%); eight patients reported dizziness and there was one case each of fatigue, palpitations, dyspnea, cardiac discomfort, and gait disturbance. These symptomatic events were typically mild or moderate in severity and all resolved spontaneously, without intervention or fingolimod discontinuation. CONCLUSION: First-dose effects in patients with PCCs and in those receiving concomitant HR-lowering medications were consistent with effects observed in the overall study population and with results from previous clinical trials. The EPOC study provides additional data demonstrating the transient and generally benign nature of fingolimod first-dose effects on HR and AV conduction in a large population that is more representative of patients encountered in routine clinical practice than in the pivotal trials.

124 Clinical Trial Human placenta-derived cells (PDA-001) for the treatment of adults with multiple sclerosis: a randomized, placebo-controlled, multiple-dose study. 2014

Lublin, Fred D / Bowen, James D / Huddlestone, John / Kremenchutzky, Marcelo / Carpenter, Adam / Corboy, John R / Freedman, Mark S / Krupp, Lauren / Paulo, Corri / Hariri, Robert J / Fischkoff, Steven A. ·Icahn School of Medicine at Mount Sinai, 5 East 98th Street, Box 1138, New York, NY 10029, United States. Electronic address: fred.lublin@mssm.edu. · Swedish Neuroscience Institute, 1600 East Jefferson, Suite 205, Seattle, WA 98122, United States. Electronic address: James.Bowen@swedish.org. · MultiCare Health System-Neuroscience Center of Washington, 915 6th Avenue, Suite 101 and 200, Tacoma, WA 98405, United States. Electronic address: John.Huddlestone@multicare.org. · London Health Sciences Centre, University Hospital, Multiple Sclerosis Clinic, 7th Floor, 339 Windermere Road, PO Box 5339, London, ON, Canada N6A 5A5. Electronic address: Marcelo.Kremenchutzky@lhsc.on.ca. · University of Minnesota, Clinical Neuroscience Research Unit, 717 Delaware Street SE, Suite 246, Minneapolis, MN 55414, United States. Electronic address: carpe004@umn.edu. · University of Colorado Denver, 12631 E. 17th Avenue, Mail Stop B185, Room 5506, Aurora, CO 80045, United States. Electronic address: John.Corboy@ucdenver.edu. · The Ottawa Hospital Multiple Sclerosis Clinic, 501 Smyth Road, Box 607, Ottawa, Ontario, Canada K1H 8L6. Electronic address: mfreedman@ottawahospital.on.ca. · MS Comprehensive Care Center, MSC T12-020 SUNY, Stony Brook, NY 11794, United States. Electronic address: Lauren.Krupp@stonybrook.edu. · Celgene Cellular Therapeutics, 7 Powderhorn Road, Warren, NJ 07059, United States. Electronic address: cpaulo@celgene.com. · Celgene Cellular Therapeutics, 7 Powderhorn Road, Warren, NJ 07059, United States. Electronic address: rhariri@celgene.com. · Celgene Cellular Therapeutics, 7 Powderhorn Road, Warren, NJ 07059, United States. Electronic address: sfischkoff@celgene.com. ·Mult Scler Relat Disord · Pubmed #25891548.

ABSTRACT: BACKGROUND: Infusion of PDA-001, a preparation of mesenchymal-like cells derived from full-term human placenta, is a new approach in the treatment of patients with multiple sclerosis. OBJECTIVE: This safety study aimed to rule out the possibility of paradoxical exacerbation of disease activity by PDA-001 in patients with multiple sclerosis. METHODS: This was a phase 1b, multicenter, randomized, double-blind, placebo-controlled, 2-dose ranging study including patients with relapsing-remitting multiple sclerosis or secondary progressive multiple sclerosis. The study was conducted at 6 sites in the United States and 2 sites in Canada. Patients were randomized 3:1 to receive 2 low-dose infusions of PDA-001 (150×10(6) cells) or placebo, given 1 week apart. After completing this cohort, subsequent patients received high-dose PDA-001 (600×10(6) cells) or placebo. Monthly brain magnetic resonance imaging scans were performed. The primary end point was ruling out the possibility of paradoxical worsening of MS disease activity. This was monitored using Cutter׳s rule (≥5 new gadolinium lesions on 2 consecutive scans) by brain magnetic resonance imaging on a monthly basis for six months and also the frequency of multiple sclerosis relapse. RESULTS: Ten patients with relapsing-remitting multiple sclerosis and 6 with secondary progressive multiple sclerosis were randomly assigned to treatment: 6 to low-dose PDA-001, 6 to high-dose PDA-001, and 4 to placebo. No patient met Cutter׳s rule. One patient receiving high-dose PDA-001 had an increase in T2 and gadolinium lesions and in Expanded Disability Status Scale score during a multiple sclerosis flare 5 months after receiving PDA-001. No other patient had an increase in Expanded Disability Status Scale score>0.5, and most had stable or decreasing Expanded Disability Status Scale scores. With high-dose PDA-001, 1 patient experienced a grade 1 anaphylactoid reaction and 1 had grade 2 superficial thrombophlebitis. Other adverse events were mild to moderate and included headache, fatigue, infusion site reactions, and urinary tract infection. CONCLUSION: PDA-001 infusions were safe and well tolerated in relapsing-remitting multiple sclerosis and secondary progressive multiple sclerosis patients. No paradoxical worsening of lesion counts was noted with either dose.

125 Clinical Trial Oral teriflunomide for patients with a first clinical episode suggestive of multiple sclerosis (TOPIC): a randomised, double-blind, placebo-controlled, phase 3 trial. 2014

Miller, Aaron E / Wolinsky, Jerry S / Kappos, Ludwig / Comi, Giancarlo / Freedman, Mark S / Olsson, Tomas P / Bauer, Deborah / Benamor, Myriam / Truffinet, Philippe / O'Connor, Paul W / Anonymous4710805. ·Icahn School of Medicine at Mount Sinai, New York, NY, USA. Electronic address: aaron.miller@mssm.edu. · University of Texas Health Science Center at Houston, Houston, TX, USA. · University Hospital of Basel, Basel, Switzerland. · University Vita-Salute San Raffaele, Milan, Italy. · University of Ottawa and Ottawa Hospital Research Institute, Ottawa, ON, Canada. · Karolinska Institute, Stockholm, Sweden. · Sanofi, Bridgewater, NJ, USA. · Genzyme, a Sanofi company, Chilly-Mazarin, France. · University of Toronto, Toronto, ON, Canada. ·Lancet Neurol · Pubmed #25192851.

ABSTRACT: BACKGROUND: Teriflunomide is a once-daily oral immunomodulator approved for the treatment of relapsing-remitting multiple sclerosis. We aimed to assess the efficacy and safety of teriflunomide in patients with a first clinical episode suggestive of multiple sclerosis. METHODS: In this randomised, double-blind, placebo-controlled, parallel-group study, we enrolled patients aged 18-55 years with clinically isolated syndrome (defined as a neurological event consistent with demyelination, starting within 90 days of randomisation, and two or more T2-weighted MRI lesions ≥3 mm in diameter) from 112 centres (mostly hospitals) in 20 countries. Participants were randomly assigned (1:1:1) in a double-blind manner (by an interactive voice response system) to once-daily oral teriflunomide 14 mg, teriflunomide 7 mg, or placebo, for up to 108 weeks. Patients, staff administering the interventions, and outcome assessors were masked to treatment assignment. The primary endpoint was time to relapse (a new neurological abnormality separated by ≥30 days from a preceding clinical event, present for ≥24 h in the absence of fever or known infection), which defined conversion to clinically definite multiple sclerosis. The key secondary endpoint was time to relapse or new gadolinium-enhancing or T2 lesions on MRI, whichever occurred first. The primary outcome was analysed for the modified intention-to-treat population; safety analyses included all randomised patients who were exposed to the study drug, as treated. This trial is registered with ClinicalTrials.gov, number NCT00622700. FINDINGS: Between Feb 13, 2008, and Aug 22, 2012, 618 patients were enrolled and randomly assigned to teriflunomide 14 mg (n=216), teriflunomide 7 mg (n=205), or placebo (n=197). Two patients in each of the teriflunomide groups did not receive the study drug, so the modified intention-to-treat population comprised 214 patients in the teriflunomide 14 mg group, 203 in the teriflunomide 7 mg group, and 197 in the placebo group. Compared with placebo, teriflunomide significantly reduced the risk of relapse defining clinically definite multiple sclerosis at the 14 mg dose (hazard ratio [HR] 0·574 [95% CI 0·379-0·869]; p=0·0087) and at the 7 mg dose (0·628 [0·416-0·949]; p=0·0271). Teriflunomide reduced the risk of relapse or a new MRI lesion compared with placebo at the 14 mg dose (HR 0·651 [95% CI 0·515-0·822]; p=0·0003) and at the 7 mg dose (0·686 [0·540-0·871]; p=0·0020). During the study, six patients who were randomly assigned to placebo accidently also received teriflunomide at some point: four received 7 mg and two received 14 mg. Therefore, the safety population comprised 216 patients on teriflunomide 14 mg, 207 on teriflunomide 7 mg, and 191 on placebo. Adverse events that occurred in at least 10% of patients in either teriflunomide group and with an incidence that was at least 2% higher than that with placebo were increased alanine aminotransferase (40 [19%] of 216 patients in the 14 mg group, 36 [17%] of 207 in the 7 mg group vs 27 [14%] of 191 in the placebo group), hair thinning (25 [12%] and 12 [6%] vs 15 [8%]), diarrhoea (23 [11%] and 28 [14%] vs 12 [6%]), paraesthesia (22 [10%] and 11 [5%] vs 10 [5%]), and upper respiratory tract infection (20 [9%] and 23 [11%] vs 14 [7%]). The most common serious adverse event was an increase in alanine aminotransferase (four [2%] and five [2%] vs three [2%]). INTERPRETATION: TOPIC is to our knowledge the first study to report benefits of an available oral disease-modifying therapy in patients with early multiple sclerosis. These results extend the stages of multiple sclerosis in which teriflunomide shows a beneficial effect. FUNDING: Genzyme, a Sanofi company.

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