Ipmsc milan meeting_february2013_booklet

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  • 1. International Progressive Multiple Sclerosis Collaborative First Scientific Conference February 6-8, 2013 San Raffaele Congress Centre, Milan, Italy1
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  • 3. February 2013 Dear Participants, Welcome to Milan and thank you for joining us for two days to explore together how to strategically boost the foundations for research into treatment for progressive MS. Presidents Emeriti The MS Societies from Canada, Italy, the Netherlands, the Sarah Phillips (UK) Peter W. Schmidt (USA) United Kingdom, and the USA first explained ambitious plans to Peter A. Schweitzer (USA) James D. Wolfensohn (USA) form an international collaborative for research into progressive MS. Immediately the Board of the MS International Federation President and Chairman Weyman T Johnson (USA) (MSIF) responded with enthusiasm. People with progressive Treasurer MS long for the day that there will be some treatment. People Robert Hubbard (Australia) with relapsing remitting MS equally wonder when they will enter Founder Sylvia Lawry (USA) this phase and whether by that time that treatment will exist. Board Members Mario Battaglia (Italy) This event and your participation in it therefore raise hope for all Pedro Carrascal-Rueda (Spain) Sophie Galland-Froger (France) people with and affected by MS. Our efforts together resonate Simon Gillespie (UK) John Golding (Norway) with all MS organisations, whether members of MSIF or not. Ed Kangas (USA) Peter Kauffeldt (Denmark) Daniel Larouche (Canada) Antonella Moretti (Italy) Of course, this is not work for the short term – and our members Dorothea Pitschnau-Michel (Germany) know this. We trust that your collective insight and expertise will Chris Polman (Netherlands) Dorinda Roos (Netherlands) help refine and consolidate the plans for this crucial research. Eli Rubenstein (USA) Yves Savoie (Canada) MSIF, its five members that stood at the root of this effort, and Mai Sharawy (Egypt) Martin Stevens (UK) all its member organisations are resolved to build on that to Ramkrishna Subbaraman (India) Alan Thompson (UK) design the fundraising campaigns to contribute to this Charles van der Straten Waillet (Belgium) enterprise. María José Wuille-Bille (Argentina) Cynthia Zagieboylo (USA) Honorary Life Board Members We thank the Italian and US MS Societies for hosting this Leon Cligman (France) Alistair M Fraser (Canada) conference, we thank you for participating, and we wish you all Jürg Kesselring (Switzerland) Sarah Phillips (UK) much success. David L Torrey (Canada) MSIF is an NGO in official relations with the World Health Organization (WHO) Registered Charity 1105321 On behalf of A charity and company limited by guarantee, registered in England and Wales. Registered office: (as above) Company No.: 05088553 Peer Baneke, CEO and Weyman Johnson, Chairman3
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  • 5. Dear Colleagues, It is our great pleasure to welcome you to this, the first meeting of the International Progressive Multiple Sclerosis Collaborative. There can be few more challenging areas for people with MS, those involved in providing treatment and the research community, than the Progressive forms of MS. They raise fundamental questions which are still to be answered; relating to our understanding of the mechanisms underlying progression and how best to evaluate potential treatments, focussing on remyelination/repair and neuroprotection. As a consequence, there are few if any therapeutic options available to those with Progressive MS. Moreover, because of the failure of all the recent clinical trials in these MS patients, the interest of pharmaceutical companies for this area is quite low. This is all the more stark, given the ever-increasing number of treatments for the earlier relapsing/remitting form of the condition. This collaborative was, quite appropriately, instigated by five MS Societies together with the MS International Federation. The purpose is to raise the profile of Progressive MS, encourage ever greater international collaboration towards achieving the ultimate vision of bringing new treatments to people with progressive MS. The first stage in this process was to identify the key blocks to such a vision and to form working groups to consider how to address and overcome them. The outcome of their deliberations is being incorporated into this meeting, alongside the views of other experts both from within and outside the field. This international initiative seeks to complement and align with the considerable research and trials activity currently underway in the progressive MS arena and this has also been incorporated into the meeting’s agenda. This meeting has been designed to be interactive but also focusses on specific, critically important areas. Addressing the challenge of progressive MS will require a truly concerted effort across all groups - researchers, clinicians, colleagues in industry, people affected by the condition. The key to the success of this meeting will be your engagement as an audience of carefully chosen experts. Together we need to further define the key objectives for the next stage so that we can provide our fund-raisers with a coherent strategy on which they can base their campaign which will, in turn support this international effort to accelerate the delivery of new treatments for Progressive MS. We have been delighted to have had such a positive response to our invitation and look forward to a truly productive and ‘game-changing’ meeting. Alan Thompson Giancarlo Comi5
  • 6. International Progressive MS Collaborative Aim of the meetingDespite significant progress in the development of therapies for relapsing MS, progressive MSremains comparatively disappointing. This situation is unacceptable for patients, clinicians andcaregivers, and it is the responsibility of the global MS community to facilitate the developmentof treatment options for people with progressive MS.The International Progressive MS Collaborative was created in 2011 by the MS Societies ofUnited States, Canada, Italy, United Kingdom, Netherlands and the MS International Federationto expedite the development of therapies for effective disease modification and symptommanagement in progressive MS, giving hope to people living with progressive MS worldwide.The creation of the IPMSC will address the glaring need for effective treatments for progressiveMS and demonstrates the international community’s commitment to creating a world free of allMS. The IPMSC aims to enable cross border and cross discipline collaboration. These activitieswill be carefully coordinated with IPMSC member societies and future potential partner societiesand other supporting parties.Since its creation, the IPMSC has been engaging the global community and begun to frame aresearch and funding strategy.The IPMSC will employ a multi-faceted research strategy to achieve its mission. This strategy willbe implemented through short, medium, and long-term funding commitments for the followingfive priority areas:1. Experimental Models2. Identification and Validation of Targets and Repurposing of existing therapeutic agents3. Proof-of-Concept Clinical Trial Strategies (Phase II Trials)4. Clinical Outcome Measures (Phase III Trials)5. Symptom Management and Rehabilitation 6
  • 7. These areas represent opportunities where concerted research efforts would provide significant impact in overcoming the current barriers in developing effective treatments for progressive MS and provide a clear roadmap for the future. During the initial consultations in 2012, scientific working groups convened by the IMPSC have been tasked with developing short, medium and long term research goals in the five priority areas. The scientific working groups convened by the IPMSC presented their reports during a meeting held in November 2012. In organizing the First International Scientific meeting, the IPMSC is aiming to: • Stimulate an open and inclusive discussion with partners engaged in expediting the development of effective therapies for progressive forms of multiple sclerosis • Identify research priorities in therapies development for progressive forms of multiple sclerosis focusing on five priority research areas and building on IPMSC working group reports • Present learning lessons from other initiatives/operative models that could benefit all partners in therapies development for progressive forms of multiple sclerosis • Stimulate collaborations for research • Stimulate MS Societies, non-profit, pharmaceutical industry and academic partnerships By the time the meeting closed, the IPMSC hopes to have identified opportunities to expedite the development of effective therapies for progressive MS.7
  • 8. This conference is organized by: Multiple Sclerosis International Federation Dutch Multiple Sclerosis Research Foundation Italian Multiple Sclerosis Society Multiple Sclerosis Society of Canada National Multiple Sclerosis Society UK Multiple Sclerosis SocietyFunding for this meeting provided in part through the support of Genzyme, a Sanofi Company Novartis Pharmaceuticals 8
  • 9. IPMSC Steering Committee Scientific Planning Committee Ceri Angood Timothy Coetzee Multiple Sclerosis International Federation National Multiple Sclerosis Society Peer Baneke Giancarlo Comi Multiple Sclerosis International Federation Scientific Institute San Raffaele Bruce Bebo Anne Cross National Multiple Sclerosis Society Washington University Sch Medicine Dhia Chandraratna Paul O’Connor Multiple Sclerosis International Federation St. Michael’s Hospital Alan Thompson Timothy Coetzee University College London National Multiple Sclerosis Society Wolfgang Bruck Giancarlo Comi University Medical Center Göttingen University Vita-Salute San Raffaele Paola Zaratin Anthony Feinstein Italian Multiple Sclerosis Society University of Toronto Ed Holloway UK MS Society Raj Kapoor University College London Hospitals Meeting Logistics Karen Lee Multiple Sclerosis Society of Canada Chiara Damico Marco Salvetti Italian Multiple Sclerosis Society Universita di Roma Linda Isella Alan Thompson San Raffaele Congress Centre University College London Eileen Madray Paola Zaratin National Multiple Sclerosis Society Italian Multiple Sclerosis Society Steven Wilson Kim Zuidwijk Steven W. Events Dutch Multiple Sclerosis ResearchFoundation9
  • 10. Working Groups of the International MS Collaborative Experimental Models for Improved Preclinical Evaluation of Novel TherapiesDavid Baker Jeroen GuertsQueen Mary University of London VU Medical Centre AmsterdamDhia Chandraratna Karen LeeMultiple Sclerosis International Federation Multiple Sclerosis Society of CanadaElga de Vries Malcolm MacleodVU Medical Centre Amsterdam University of EdinburghCharles ffrench Constant Ken SmithUniversity of Edinburgh University College LondonRoberto Furlan Peter Stys (Chair)San Raffaele Scientific Institute University of CalgarySusan GoelzELAN Pharmaceuticals 10
  • 11. Target Identification and Validation Pathways for Repurposing of Existing Therapeutic Agents Sergio Baranzini Rogier Hintzen University of California Erasmus Medical Centre Diego Centonze Catherine Lubetzki University Tor Vergata - Rome University Pierre & Marie Curie Siddharthan Chandran Marco Salvetti University of Edinburgh University of Rome Francesco Cucca Stephen Sawcer University of Sassari University of Cambridge Ranjan Dutta Paola Zaratin Cleveland Clinic Italian Multiple Sclerosis Society Peter Goodfellow (Chair) GlaxoSmithKline11
  • 12. Proof-of-Concept and Clinical Trial StrategiesFred Barkhof Xavier MontalbanVU Medical Centre Amsterdam Hospital Universitari Vall d’HebronJeremy Chataway John PetkauNational Hospital for Neurology & Neurosurgery University of British ColumbiaTimothy Coetzee Chris PolmanNational Multiple Sclerosis Society VU Medical Centre AmsterdamGordon Francis Nancy RichertNovartis Pharmaceuticals Biogen IdecRaj Kapoor Tony TraboulseeNational Hospital for Neurology & Neurosurgery University of British ColumbiaFred Lubin (Chair) Jerry WolinskyMount Sinai School of Medicine University 12
  • 13. Clinical Outcome Measures & Trial Design David Andrich Paul O’Connor University of Western Australia Unversity of Toronto Andy Blight Michael Panzara Acorda Therapeutics, Inc. Genzyme Corporation Stefan Cano Donald Patrick University of Plymouth University of Washington Stephen Coons Jack Stenner The Critical Path Institute Lexile Robert Fox Luigi Tesio Cleveland Clinic University of Milan Jeremy Hobart (Chair) Bernard Uitdehaag Plymouth Hospital VU Medical Centre Amsterdam Ludwig Kappos John Zajicek University of Basel Plymouth University Jason Lundy The Critical Path Institute13
  • 14. Symptom Management & Rehabilitation StrategiesMaria Pia Amato Chris HeesenUniversity of Florence United Medical CenterUlrik Dalgas Albert LoAarhus University Brown UniversityJohn DeLuca Alan ThompsonNew Jersey Medical School University College LondonAnthony Feinstein Lesley WhiteUniversity of Toronto University of GeorgiaPeter Feys (Chair) Kim ZuidwijkHasselt University Dutch Multiple Sclerosis SocietyJenny FreemanPlymouth University 14
  • 15. IPMSC First Scientific Conference Daily Program February 6th 2013 19:30 Welcome dinner at the NH Milano 2 Hotel February 7th 2013 Meeting Venue: San Raffaele Congress Centre - Caravella Santa Maria Room 8.15 & 8.30 Hostess to walk attendees from the Walking direction and map NH Milano 2 Hotel to the San available at hotel front desk Raffaele Congress Centre 8.00 – 9.00 Shuttle bus from NH Milano 2 Hotel to San Raffaele Congress Centre 8.00 – 9.00 REGISTRATION 9.00 – 9.10 Welcome from Italian MS Society Mario A. Battaglia 9.10 – 9.30 ‘A call for Action’ John Golding Timothy Coetzee 9.30 – 9.45 Welcome, introduction and aims Alan Thompson of the meeting 9.45 - 10.00 Ongoing initiatives in progressive MS Giancarlo Comi Session I Chairperson: Wolfgang Bruck 10.00 - 10.15 Target identification and Wolfgang Bruck repurposing in progressive MS15
  • 16. 10.15 – 10.45 1st Keynote speaker Genetic profile Stephen Sawcer Discussant Sergio Baranzini10.45 – 11.15 2st Keynote speaker Immunologic aspects of progressive MS Scott Zamvil Discussant Marco Salvetti11.15 - 11.30 Coffee break11.30 – 11.50 Study group II report Peter Goodfellow11.50 – 12.20 General Discussion12.20 – 12.30 Sum up of the Session I Wolfgang Bruck12.30 – 13.30 Lunch Session II Chairperson: Anne Cross13.30 - 13.35 Experimental models for improved Anne Cross understanding of progressive MS and preclinical evaluation of novel therapies 13.35 - 14.25 1st Keynote speakers Clues from degenerative aspects Bruce Trapp of progressive MS pathology Clues from inflammatory aspects of Hans Lassmann progressive MS pathology14.25 - 14.35 Discussion of pathology and patho- physiology of progression 14.35 - 15.05 2st Keynote speaker Pitfalls and problems with animal models David Baker Discussant Marco Prinz 16
  • 17. 15.05 - 15.15 Discussion of the animal models 15.15 - 15.25 Study group I report Peter Stys 15.25 - 15.35 General discussion 15.35 - 15.45 Sum up of the Session II Anne Cross 15.45 - 16.00 Coffee break Session III Chairperson: Giancarlo Comi 16.00 - 16.15 Proof-of-concept clinical trial strategies Giancarlo Comi 16.15 - 16.45 1st Keynote speaker Study design and biomarkers for disease Gavin Giovannoni modifying treatment phase II clinical trials Discussant Massimo Filippi 16.45 - 17.15 2st Keynote speaker Phase II trial design: including single-arm Jeremy Chataway multi-arm, adaptive Discussant Jerry Wolinsky 17.15 - 17.35 Study Group III report Raj Kapoor 17.35 - 18.05 General Discussion 18.05 - 18.15 Sum up of the Session III Giancarlo Comi 18.00 – 18.30 Shuttle bus from San Raffaele Congress Centre to NH Milano 2 Hotel 19.30 – 20.15 Shuttle bus from NH Milano 2 Hotel to Ciborio Hall Walking instructions and map available at hotel front desk 20.00 Gala Dinner at Ciborio Hall – OSR DIBIT 2 22.00 - 23.00 Shuttle bus from Ciborio Hall to NH Milano 2 Hotel17
  • 18. February 8th 2013 Meeting Venue: San Raffaele Congress Centre - Caravella Santa Maria Room8.15 & 8.30 Hostess to walk attendees from the Walking direction and map NH Milano 2 Hotel to the San available at hotel front desk Raffaele Congress Centre8.00 – 9.00 Shuttle bus from NH Milano 2 Hotel to San Raffaele Congress Centre Session IV Chairperson: Chris Polman9.00 - 9.15 Clinical outcome measures Chris Polman and phase III trial designs9.15 - 9.45 1st Keynote speaker Phase III trials of DMTs in progressive MS: Jeffrey Cohen endpoints and other aspects of trial design Discussant Ludwig Kappos9.45 - 10.15 2st Keynote speaker Phase III trials in progressive MS: Per Solberg Sorensen biomarkers of information, axonal damage demyelination and remyelination Discussant Robert Fox10.15 - 10.35 Study group IV report Jeremy Hobart10.35 - 10.45 General discussion10.45 - 10.55 Sum up of the Session IV Chris Polman10.55 - 11.10 Coffee break 18
  • 19. Session V Chairperson: Alan Thompson 11.10 - 11.25 Symptom management therapies Alan Thompson and rehabilitation strategies 11.25 – 11.55 1st Keynote speaker Congnitive rehabilitation John De Luca and progressive MS Discussant Maria Pia Amato 11.55 - 12.25 2st Keynote speaker Exercise therapy and multiple sclerosis Ulrik Dalgas Discussant Chris Heesen 12.25 - 12.55 Study group V report Peter Feys 12.45 - 13.15 General discussion 13.15 - 13.25 Sum up of the Session V Alan Thompson 13.25 - 14.30 Lunch Session VI Chairperson: Monica Di Luca 14.30 - 15.45 Challenges that together we can Steve Buchsbaum address to bring new medicines Sarah Tabrizi to patients: non-profit, Paul Matthews academia and pharma views 15.45 - 16.15 Panel discussion Moderated by Heather Brown Steve Buchsbaum Sarah Tabrizi Paul Matthews 16.15 – 16.30 Coffee break19
  • 20. Session VII Moderator: Timothy Coetzee ‘Facing progressive MS’16.30 – 17.00 Collaborative Progressive MS Research Alan Thompson Program: IPMSC proposal and Antonella Moretti next key actions 17.00 – 17.30 Open Forum with IPMSC Giancarlo Comi Scientific Leadership Anthony Feinstein Bob Fox Raj Kapoor Marco Salvetti Alan Thompson17.30 – 17.45 Conclusion and perspective Weyman Johnson17.45 – 18.15 Shuttle bus from San Raffaele Congress Centre to NH Milano 2 Hotel 20
  • 21. Abstracts of keynote speakers21
  • 22. Phase II Trial design: including single-arm, multi-arm, adaptive Jeremy Chataway Queen Square MS Centre, National Hospital for Neurology and Neurosurgery, LondonUsing standard parallel arm control/active arm trial design in SPMS/PPMS, can take 10 yearsfrom a phase 2 trial inception to phase 3 trial finish. Over the last 2 decades, over 4500 SPMSpatients have completed major phase 3 trials, with trial durations of 2-3 years.The overwhelming conclusion is that these have been negative, with the few positive signalsdue to co-enrollment of a more transitional RRMS/SPMS population or considering a sub-set of the major outcome. The current consensus is that SPMS is most likely to respond to aneuroprotective strategy, and indeed there are a number of promising candidate drugs to test.The clear challenge is to test multiple drugs simultaneously in a timely and efficient manner,whilst preserving trial integrity. This talk will look two recent classically designed single-armphase II trials (Lamotrigine and MS-STAT), before moving onto multi-arm paradigms (eg MS-SMART) including adaptive trial design. 22
  • 23. Phase III: trials of DMTs in progressive MS: endpoints and other aspects of trial design Jeffrey A. Cohen Experimental Therapeutics of Mellen MS Center, Cleveland Clinic, Cleveland, OH USA This presentation is intended to provide a conceptual framework for discussion of the design of pivotal trials to test potential therapies for progressive multiple sclerosis (MS). I will attempt to provide an overview of available outcome measures, an update of ongoing efforts to refine those measures and develop new ones, and identify continued areas of need. Different methods to measure efficacy are required at different stages of the treatment development process. Highly sensitive measures are needed for early-phase exploratory and proof-of-concept studies. Clinically meaningful (though less sensitive) measures are needed for pivotal trials. The hallmark of progressive MS is gradual worsening of impairment/disability. Thus, the primary outcome of pivotal trials in progressive MS will focus on this domain. Historically, the most widely used clinician-assessed measure of neurologic impairment/disability in MS clinical trials has been the Expanded Disability Status Scale (EDSS). Currently, the EDSS is the only impairment/disability measure accepted by regulators for registration studies of MS therapies. The advantages and shortcomings of the EDSS have been widely discussed and recently reviewed.1 Recommendations for refinements to the EDSS include development of a standard script for examining clinicians measuring the EDSS in trials to improve reliability and lessen the risk of unblinding, simplification of the scoring rules, determination of the optimal duration of time over which to confirm EDSS worsening, and attempts to determine whether the scale could be simplified by eliminating non-informative functional systems. The MS Functional Composite (MSFC) was originally proposed as an alternative to address some of the perceived shortcomings of the EDSS. Despite documentation of some advantages, the MSFC in its original form also has several shortcomings and has not been accepted by regulators. Identified issues with the MSFC include floor and ceiling effects for the component tests in some patient populations, lack of a vision test,23
  • 24. issues related to the cognitive test (the Paced Auditory Serial Addition Test), and difficulty withinterpretation of the dimensionless composite summary score (an average of the Z-scores ofthe component tests).1 The National MS Society Task Force on Clinical Disability Measurescurrently is working with the Critical Path Institute to address these issues with the goal ofsecuring formal approval by the US Food and Drug Administration of the MSFC approachas a measure of impairment/disability for use in MS clinical trials.2 The Critical Path Instituteis private-public partnership intended to bring together representatives of industry, academicleaders, regulators, and patient advocacy groups to facilitate the drug discovery and approvalprocess, including development of more informative and effective outcome measures.Patient reported outcomes (PROs) are an alternative method for capturing neurologicimpairment/disability from the patient’s perspective.In addition being more sensitive to some important aspects of MS such as pain or fatigue, PROscan provide an indication of the clinical meaningfulness of clinician assessments and nonclinicalmeasures. It is widely presumed that central nervous system tissue damage in early stagesof MS is caused primarily by an abnormal “outside-in” inflammatory process, reflected mostdirectly by acute relapses and MRI lesion activity (new or enlarging T2-hyperintense lesions andgadolinium-enhancing T1 lesions). Relapses may continue to occur as patients transition fromrelapsing-remitting (RR) MS to secondary progressive (SP) disease and also rarely occur inpatients whose disease was progressive from onset. Some agents approved to reduce relapsesin RRMS, also were effective in reducing relapses in SPMS, e.g. interferon-beta 1a in the IMPACTtrial.3 However, relapses should be included as only a tertiary endpoint in trials focused ontreating the “degenerative” process presumed to cause gradual progression. Similarly, standardMRI lesion analyses also will be of lesser importance in trials of progressive MS.Several so-called “advanced” MRI measures that have the potential to assess tissue integrity aremore likely to be informative in progressive MS, including atrophy (whole brain, regional, cortical, 24
  • 25. spinal cord), diffusion tensor imaging (whole brain, lesion, tractography), and magnetization transfer imaging (whole brain, lesion, cortical, spinal cord). All of these MRI endpoints represent varying trade-offs of practical issues (feasibility of implementation in multicenter trials), reliability, sensitivity to change over time and treatment effects, and validity. Some, e.g. whole brain atrophy, are appropriate for inclusion as a key secondary endpoint now in pivotal trials. Others are under consideration as endpoints in proof of concept studies but in pivotal trials would be more appropriate as tertiary outcomes at this time. Nevertheless, much work is needed to validate MRI measures as surrogates of disability. There also has been substantial interest in optical coherence tomography (OCT) as an additional method to quantify retinal pathology relevant to MS, most notably retinal nerve fiber layer thickness, macular volume, and segmented ganglion cell layer thickness. Like some of the advanced MRI measures, OCT-related endpoints have been proposed as endpoints in proof of concept studies but in pivotal trials are more appropriate as tertiary outcomes. Other endpoints to consider as exploratory endpoints in pivotal trials include electrophysiological tests of pathway functional integrity and laboratory biomarkers to monitor myelin and axonal structural integrity. Although a large number of potential biomarkers have been proposed, none has been fully validated. 4 Neurofilament concentration in cerebrospinal fluid shows promise as a way to monitor axonal damage. It will be useful to include novel exploratory endpoints in pivotal trials to corroborate results on the primary and secondary endpoints, for additional analyses e.g. kinetics of the response, subgroups, etc., and, perhaps most important, to validate the exploratory endpoints. References 1. Cohen JA, Reingold SC, Polman CH et al. Disability outcome measures in multiple sclerosis trials: current status and future prospects. Lancet Neurology 2012;11:467-476. 2. Ontaneda D, LaRocca N, Coetzee T, Rudick RA. Revisiting the Multiple Sclerosis Functional Composite: proceedings from the National Multiple Sclerosis Society (NMSS) Task Force on Clinical Disability Outcomes. Mult Scler J 2012;18:1074-1080. 3. Cohen JA, Cutter GR, Fischer JS et al. Benefit of interferon β-1a on MSFC progression in secondary progressive MS. Neurology 2002;59:679-687. 4. Graber JJ, Dhib-Jalbut S. Biomarkers of disease activity in multiple sclerosis. J Neurol Sci 2011;305:1-10.25
  • 26. Exercise therapy and multiple sclerosis Ulrik Dalgas Department of Public Health, Section of Sport Science, Aarhus University, DenmarkMultiple Sclerosis (MS) patients are characterised by impaired muscle strength, maximaloxygen consumption and functional capacity. Furthermore, fatigue, depression and increasedcardiovascular disease risk are frequent symptoms in MS patients. This reflects probably boththe effects of the disease per se and the reversible effects of an inactive lifestyle(1). Nonetheless,MS patients were advised not to participate in exercise because it was reported to lead toworsening of symptoms or fatigue. During recent years, it has been increasingly acknowledgedthat exercise benefits MS patients. However, the effects of exercise have mainly been studiedin mild to moderately impaired MS patients with an EDSS score of less than 5. Different typesof exercise have been evaluated in studies generally characterised by small sample sizes andwith most focus put on basic physical exercise modalities such as endurance training andresistance training(2-4). Furthermore, only few studies(5-7) have included follow up periods inthe study design and only few studies have looked at interventions that are integrated in thecommunity(8). However, the existing exercise recommendations(2;9;10) are based on studiesapplying either relapsing-remitting MS (RRMS) or minor groups of patients with mixed diseasecourses. Several reviews(2-4) only identified one study(11) exclusively applying secondaryprogressive MS (SPMS) patients, whereas no studies have focused on primary progressive MS(PPMS). Consequently, exercise studies in the progressive subgroups seem important due tolimited number of treatment options and the more frequent number and severity of symptoms.A further shortcoming of the literature is the lack of exercise studies in severely disabled MSpatients (EDSS≥6.5). Preliminary (non-controlled) data have started to emerge in a studyevaluating the effects of resistance training in advanced MS (EDSS 6.5-8) showing beneficialeffects(12). However, much work remains to be done in this group of patients. 26
  • 27. Recently, studies have tried to link exercise therapy/physical activity to MS disease progression(13). Some studies do indicate a slowing of the disease process in physical active MS patients but still convincing data is lacking, leaving a very important question unanswered. Approaches to this problem would also include studies evaluating possible effects of exercise on neurobiological processes known to be associated to the disease process. Finally, future studies should look into therapies combining exercise therapy with other behavioural treatments, which seems to be promising areas to pursue given that a behavioural change of the patient is needed for engagement in exercise while living in the community. Reference List (1) Karpatkin H. Multiple Sclerosis and Exercise – A review of the evidence. Int J MS Care 2006;7:36-41. (2) Dalgas U, Stenager E, Ingemann-Hansen T. Multiple sclerosis and physical exercise: recommendations for the application of resistance-, endurance- and combined training. Mult Scler 2008 Jan;14(1):35-53. (3) Heesen C, Romberg A, Gold S, Schulz KH. Physical exercise in multiple sclerosis: supportive care or a putative disease-modifying treatment. Expert Rev Neurother 2006 Mar;6(3):347-55. (4) White LJ, Dressendorfer RH. Exercise and multiple sclerosis. Sports Med 2004;34(15):1077-100. (5) Garrett M, Hogan N, Larkin A, Saunders J, Jakeman P, Coote S. Exercise in the community for people with multiple sclerosis -- a follow-up of people with minimal gait impairment. Mult Scler 2012 Nov 6. (6) Dodd K, Taylor N, Shields N, Prasad D, McDonald E, Gillon A. Progressive resistance training did not improve walking but can improve muscle performance, quality of life and fatigue in adults with multiple sclerosis: a randomized controlled trial. Mult Scler 2011 Nov;17(11):1362-74. (7) Dalgas U, Stenager E, Jakobsen J, Petersen T, Hansen H, Knudsen C, et al. Resistance training improves muscle strength and functional capacity in multiple sclerosis. Neurology 2009 Dec 12;73:1478-84. (8) Garrett M, Hogan N, Larkin A, Saunders J, Jakeman P, Coote S. Exercise in the community for people with minimal gait impairment due to MS: an assessor-blind randomized controlled trial. Mult Scler 2012 Nov 5. (9) Dalgas U, Ingemann-Hansen T, Stenager E. Physical Exercise and MS Recommendations. Int MS J 2009 Apr;16(1):5-11. (10) Petajan JH, White AT. Recommendations for physical activity in patients with multiple sclerosis. Sports Med 1999 Mar;27(3):179-91. (11) Ayan PC, Martin S, V, De Souza TF, De Paz Fernandez JA. Effects of a resistance training program in multiple sclerosis Spanish patients: a pilot study. J Sport Rehabil 2007 May;16(2):143-53. (12) Filipi ML, Kucera DL, Filipi EO, Ridpath AC, Leuschen MP. Improvement in strength following resistance training in MS patients despite varied disability levels. NeuroRehabilitation 2011 Jan 1;28(4):373-82. (13) Dalgas U, Stenager E. Exercise and disease progression in multiple sclerosis: can exercise slow down the progression of multiple sclerosis? Ther Adv Neurol Disord 2012 Mar;5(2):81-95.27
  • 28. Cognitive Rehabilitation and Progressive MS John DeLuca Kessler Foundation–Departments Physical Medicine Rehabilitation and Neurology and Neurosciences UMDNJ -New Jersey Medical School Anthony Feinstein Department of Psychiatry, Sunnybrook Health Sciences Centre ,Toronto Maria Pia Amato Department of NEUROFARBA, University of FlorenceIt is now well established that up to 70% of persons with multiple sclerosis (MS) suffer from cognitiveimpairment (Chiaravalloti & DeLuca, 2008). It is generally accepted, although not absolute, thatcognitive impairment is more severe and encompasses a greater range of cognitive involvementin progressive MS (especially secondary progressive MS, SP) than relapsing-remitting MS (RR).Despite the dearth of longitudinal studies exploring the influence of disease course on cognition,there is evidence of cognitive decline may be associated with increasing EDSS and diseaseduration. However, it is also well known that cognitive impairment does occur at all stages of thedisease. MRI parameters show a modest correlation with cognition, and are significantly moderatedby environmental enrichment (Sumowski, 2010, 2012). Recent evidence suggests that grey matterparameters are particularly sensitive to cognitive dysfunction, including those with SP and primaryprogressive (PP) MS. In all, given the frequency and degree of cognitive involvement in personswith MS, the need for cognitive rehabilitation therapies and programs is clear. Compared to studiesin stroke and traumatic brain injury, relatively few studies of cognitive rehabilitation exist in personswith MS (O’Brien, 2008). Typically, inclusion criteria for behavioral studies are based on the presenceand/or degree of cognitive impairment, not disease course. Approximately half the studies containSP and/or PP subjects as part of the subject pool, while the other half either excludes these patientsor the sample composition is not clearly specified. The percentage of progressive patients in thesamples ranges from about 10% to 50%, but typically accounts for about 20-40% of the sample. Farfewer PP than SP subjects are included.Two recent Cochrane reviews on cognitive rehabilitation (Rosti-Otajavi & Hamalainen, 2011; das 28
  • 29. Nair et al, 2012), yielded mixed conclusions. Rosti-Otajavi & Hamalainen concluded that “12 of 14 studies showed some evidence of positive effects of neuropsychological rehabilitation” However, . das Nair (2012), which only included RCT’s limited to memory rehabilitation, found only 4 studies and concluded that there was no support memory rehabilitation. Both have concluded that there is a low level of evidence to support such rehabilitation at this time in persons with MS, primarily because of the low number of studies and several methodological problems in design. It should be recognized however that while Cochrane reviews have an important role, they also have important limitations. For instance, strict criteria are used for study inclusion (e.g., only including RCT’s), often resulting in the exclusion of important and often well-designed studies because they do not fit into the Cochrane model. For example, well designed case-control studies are often not included yet they provide the basis for designing future RCT’s. There is a growing literature clearly showing that targeted interventions designed to improve the strength of encoding can significantly improve learning and memory (DeLuca & Chiaravalloti, 2011). A second limitation is that strict Cochrane criteria often downgrade evidence for “technical” reasons, often diminishing the results of a study due to “minor” challenges in the design (e.g., randomized but using odd-even criteria). For example, while within-group designs are considered among the strongest control techniques available, they are not considered strong according to Cochrane criteria. Beyond the Cochrane approach, there is modest support that behavioral cognitive rehabilitation can significantly improve targeted cognitive processes, especially learning and memory, with some support for executive functions (Sumowski et al, 2010, Goverover et al, 2011, Leavitt et al, 2012). There are no studies on processing speed. When SP and/or PP subjects are included in a cognitive rehabilitation study, a separate analysis by disease course is typically not conducted. As such, any conclusions based on disease course cannot be made with confidence. Of interest is a recent study which specifically examined cognitive reserve in SP and showed that protective effect of intellectual enrichment on cognitive decline may be greater in more advanced disease (i.e., SP) than earlier (RR) (Sumowski et al., 2012).29
  • 30. There is preliminary evidence that physical activity (e.g., aerobic fitness, exercise training) may beassociated with improved cognition in MS. One small study showed that cardiovascular fitness wasassociated with improved processing speed, sustained attention and working memory (Prakash etal, 2007). Another small study showed that such fitness was greater white and grey matter integrityand processing speed (Prakash et al, 2010). However, yet another RCT showed no effect (Okenet al., 2004). Nonetheless, the notion that physical activity may improve cognition in MS deservesfurther research.With respect to pharmacological approaches, disease-modifying therapies showlittle to no effect in improving cognition (Langdon, 2011). This should not be too surprising sincecognition is not a primary outcome on any of these trials. In addition sine the vast majority of suchtrials are on RR patients, little to nothing is known about its impact in SP and PP MS. Targetedpharmacological approaches have yielded mixed results at best with approximately half showingsome effect on improving cognitive performance and the other half no effect (Patti et al, 2011). Therehas been no consistent effect on improving cognition in any class of medication. While most of thetargeted approaches do include progressive patients along with RR, subset analysis is rare or non-existent.Taken together, the published research on various approaches to improve cognitive impairmentin progressive MS is embarrassingly poor. Little if anything can be said about any such approachto address one of the most significant and disabling symptoms of MS, namely cognition. Becausecognitive impairment affects so many aspects of a person’s life (e.g., vocational, familial, social,emotional, cultural), what is required is a concerted effort to examine approaches, techniques andprograms designed to improve cognitive impairment in MS. 30
  • 31. Study design and biomarkers for disease modifying treatments for phase II clinical trials Gavin Giovannoni Blizard Institute Barts and The London School of Medicine and Dentistry, London Before addressing the aims of my talk I have an attempt to deconstructed the title to make sure I address the topic at hand. Definitions: Study (1) design and (2) biomarkers for (3) disease modifying treatments for (4) phase II clinical trials 1. Design: a. To conceive or fashion in the mind; invent b. To formulate a plan for; devise. c. To plan out in systematic, usually graphic form. d. To create or contrive for a particular purpose or effect. e. To have as a goal or purpose; intend. f. To create or execute in an artistic or highly skilled manner 2. Biomarkers: a. Biological Marker (Biomarker) -A characteristic that is objectively measured and evaluated as an indicator of normal biologic processes, pathogenic processes, or pharmacologic responses to a therapeutic intervention. b. Clinical Endpoint -A characteristic or variable that reflects how a patient feels, functions or survives. c. Surrogate Endpoint -A biomarker intended to substitute for a clinical endpoint. A surrogate endpoint is expected to predict clinical benefit (or harm, or lack of benefit or harm) based on epidemiologic, therapeutic, pathophysiologic or other scientific evidence. NIH Biomarker Definitions Working Group - 199831
  • 32. 3.Disease modifying treatments Disease modifying treatments or DMTs is a class of therapeutics or interventions that modify the course of multiple sclerosis. DMTs usually imply a positive or an improved outcome. However, a broader definition of a DMT could imply any intervention or biological process that worsens the disease course.4. Phase II clinical trials Phase II clinical trials are non-registration trials and are done to assess dosing requirements and efficacy. Safety and toxicity is also an important outcome in phase II trials. Phase II trials are very important in that the results are often used as go-no-go signals for further drug development. It is important that Phase II trials are robust and designed to give an answer relatively quickly.All trial designs should be underpinned by a working pathogenic model. In the case ofprogressive multiple sclerosis the current dogma states that MS is an autoimmune inflammatoryneurodegenerative disease of the central nervous system characterised by demyelination andvariable degrees of axonal loss and gliosis. Inflammation is believed to be primary driver ofdemyelination and is also responsible for acute axonal damage. Axonal transection is prominentin acute lesions and is followed by both Wallerian, or distal, degeneration and by a dying back,or proximal, axonopathy. Both the distal and proximal degeneration of axons occurs overa time course of weeks to months, which has implication for biomarker-based studies. Forexample, when measuring neurofilaments, which are released into the cerebrospinal fluid afteraxonal transection, as an outcome measure of neuroprotection the time course of the axonaldegeneration is important; the duration of the study must be long enough to encompass theduration of this degenerative process. 32
  • 33. What about those axons that survive and recover from acute, focal inflammatory events? Demyelinated axons that are not transected can remyelinate or undergo a process of axonal plasticity in which the synthesis and redistribution of sodium channels across demyelinated axonal segments results in the restoration of conduction. Animal studies suggest that remyelinated axons are protected from delayed neurodegeneration. In comparison, axons that remain demyelinated are believed to be rendered vulnerable to delayed neurodegeneration. Other less well studied features of recovery included central adaptation from lateral axonal sprouting; in other words surviving neurones restore function by taking on additional connections. Axonal sprouting places an increased metabolic burden on surviving neurones and as a result may contribute to delayed neurodegeneration analogous to that what occurs to the anterior horn cell in the post-polio syndrome. Another emerging factor that has been hypothesised to occur is the non-specific damage that inflammation causes to the functional proteome and genome that leads to premature senescence. In other words inflammation brings forward normal age-related neurodegeneration. All of these processes will result in the gradual and delayed drop-out of axons and neurones which can occur independently of on-going autoimmune driven acute inflammation. This may explain the secondary progression that occurs despite suppression of focal autoimmune inflammation with potent anti-inflammatory strategies, such mitoxantrone, alemtuzumab or bone marrow transplantation. Although the latter agents are effective in suppressing inflammation driven by adaptive immunity there is evidence of on- going inflammation in the form of innate immune activation mainly due to microglia, which remain activated. These hot microglia are susceptible to further activation in response to peripheral inflammatory stimuli and are hypothesised to underlie the acute deterioration in neurological function that is seen in response to systemic infections. Pathological studies have clearly demonstrated that in MSers dying in the non-relapsing secondary progressive phase of the disease active autoimmune driven focal33
  • 34. inflammation is still present. Therefore it makes little sense to use neuroprotective therapieswithout suppressing this ongoing inflammation. The logical triumvirate strategy would thereforebe anti-inflammatory therapies, combined with neuroprotective drugs followed by strategies topromote remyelination.Pathological studies of MS demonstrate that it is a multifocal disease affecting the wholeneuraxis. Therefore neurodegeneration is partly a length-dependent process and more likelyto affect the systems served by the longest neuronal pathways; this explains why progressivespastic paraparesis with sphincter involvement is the predominant clinical syndrome that isseen with progressive MS. The implication of this is that any effective therapy that works inprogressive MS should have an effect that is first seen on the functioning of the neuronalpathways with the longest central axons;hence the focus on mobility in the EDSS and other outcome measures. Unfortunately, changesin mobility occur too slowly, on average, to be used in pragmatic phase II studies and hence theshift towards biomarkers in new exploratory trial designs.To try and address both the acute neurodegeneration from focal inflammatory lesions andthe delayed neurodegeneration that is seen in the post-autoimmune inflammatory secondaryprogression we have developed two novel trial designs. Both these designs have been developedfrom insights from animal models.Trial 1: acute optic neuritis as a model of neurodegeneration as a result of focal lesion in MSIn optic neuritis loss of vision typically develops over days and recovers over several weeks.Despite the majority of subjects making a good recovery from optic neuritis approximately10-15% of subjects the recovery is poor. The acute inflammatory lesion in the optic nerveresembles MS plaques found elsewhere in the CNS, and because its characteristics can bestudied using a combination of clinical, electrophysiological and imaging methods, it presents 34
  • 35. an ideal lesion to assess the effects of treatments acute neurodegeneration. In addition, the present treatment using corticosteroids has little or no impact on the extent to which vision finally recovers after an attack of optic neuritis. Therefore, in the absence of an effective acute treatment, prevention of residual disability from an attack of optic neuritis represents an unmet need in MS. Until recently, it was thought that visual loss in optic neuritis occurred primarily because axons which become demyelinated cannot conduct action potentials reliably. However imaging of the retinal nerve fibre layer (RNFL) using optical coherence tomography (OCT), and of the optic nerve using magnetic resonance imaging, both demonstrate that acute optic neuritis is associated with significant volume loss, and that this correlates with impaired visual function. These findings raise the possibility that neuroprotection could be achieved in acute optic neuritis and hence by inference in other exacerbations of MS. We have shown in our animal model that there is a window in which neuroprotective agent can be given to improve the outcome from acute inflammatory lesions; we have referred to this window the inflammatory penumbra, which is analogous to the ischaemic penumbra that occurs in stroke. In our EAE model the inflammatory penumbra is between 3 and 4 days and corresponds to the period of blood-brain-barrier breakdown. We therefore propose that in optic neuritis and other focal lesions that a similar penumbra exists and that for any acute neuroprotective agent to have an effect it needs to be given as soon as possible as within a window in which the blood-brain- barrier is compromised. Based on gadolinium studies this penumbra is likely to be less than 3 weeks. In our phenytoin optic neuritis neuroprotection study we have proposed that the window is less than 14 days. The following is a flowchart of the trial and a brief synopsis of the study. An exploratory phase IIa study to evaluate phenytoin as neuroprotective strategy in acute optic neuritis35
  • 36. An exploratory phase IIa study to evaluate phenytoin as neuroprotective strategy in acute optic neuritis Acute unilateral optic neuritis 1. <14 days since symptom onset 2. Visual acuity worse than or equal to 6/9 in affected eye 3. No prior history of optic neuritis or disease in the contralateral unaffected eye; corrected VA better than or equal to 6/6 4. If patients has MS EDSS 5.5 or less Informed consent Patients can be offered at the discretion of the treating physician treatment with a short course of steroids PHENYTOIN Randomised acutely (<14 days) to phenytoin* or placebo *acute oral loading dose (15mg/kg rounded up to nearest 100mg) followed by maintenance dose 4mg/kg or maximum 300mg/day for 24 weeks Further investigations and baseline MRI brain within 28 days of symptom yes Not part of ITT Alternative diagnosis cohort no Primary outcome at 48 weeks Retinal nerve fibre thickness in affected eye relative to healthy / unaffected eye Secondary outcomes at 48 weeks Low contrast visual acuity Visual evoked potential latency and amplitude MRI outcomes, Etc.Estimated power calculations assuming half of all patients are treated with steroids 36
  • 37. yes Not part of ITT Alternative diagnosis cohort no Primary outcome at 48 weeks Retinal nerve fibre thickness in affected eye relative to healthy / unaffected eye Secondary outcomes at 48 weeks Low contrast visual acuity Visual evoked potential latency and amplitude MRI outcomes, Etc. Estimated power calculations assuming half of all patients are treated with steroids Trial 1 Synopsis Title: A phase II double-blind, randomised, placebo-controlled trial of neuroprotection with phenytoin in acute optic neuritis Giovannoni, page 4 of 8. Short title: Neuroprotection with phenytoin in optic neuritis Trial medication: Phenytoin vs placebo Phase of trial: Phase II Objectives: The primary aim is to assess whether immediate and sustained sodium channel blockade with phenytoin has a neuroprotective effect on axonal degeneration after an attack of acute demyelinating optic neuritis. Secondary aims are to assess whether phenytoin improves visual outcome, whether phenytoin promotes remyelination of the optic nerve, and to assess a range of biomarkers. Type of trial: Phase II, double-blind, randomised, parallel group, multi-site trial in people with acute demyelinating optic neuritis, with or without a history of relapsing remitting multiple sclerosis. Trial design and methods: 90 people with acute optic neuritis will be recruited into a double blind parallel group controlled trial in which random allocation will be made to receive treatment with either phenytoin or placebo for 3 months. Recruitment, follow-up and trial management will be achieved through a collaborative network of sites in England. The primary endpoint will be the effect of treatment on thinning of the retinal nerve fibre layer, whose thickness can be measured noninvasively, reliably and sensitively using Optical Coherence Tomography (OCT). The trial is powered to detect a 50% beneficial effect on the primary outcome measure. Outcome will be measured at entry and after 6 months. Trial duration per 6 months participant: Estimated total trial 24 months duration: Planned trial sites: UCL Institute of Neurology and the National Hospital for Neurology and37 Neurosurgery, London, and Royal Hallamshire Hospital, Sheffield
  • 38. Type of trial: Phase II, double-blind, randomised, parallel group, multi-site trial in people with acute demyelinating optic neuritis, with or without a history of relapsing remitting multiple sclerosis.Trial design and methods: 90 people with acute optic neuritis will be recruited into a double blind parallel group controlled trial in which random allocation will be made to receive treatment with either phenytoin or placebo for 3 months. Recruitment, follow-up and trial management will be achieved through a collaborative network of sites in England. The primary endpoint will be the effect of treatment on thinning of the retinal nerve fibre layer, whose thickness can be measured noninvasively, reliably and sensitively using Optical Coherence Tomography (OCT). The trial is powered to detect a 50% beneficial effect on the primary outcome measure. Outcome will be measured at entry and after 6 months.Trial duration per 6 monthsparticipant:Estimated total trial 24 monthsduration:Planned trial sites: UCL Institute of Neurology and the National Hospital for Neurology and Neurosurgery, London, and Royal Hallamshire Hospital, SheffieldTotal number of participants 90planned:Main inclusion criteria: Acute optic neuritis, within 14 days of onset of visual loss, visual acuity in affected eye < 6/12Statistical methodology and The primary comparison will estimate the active vs placebo difference inanalysis: the mean thickness of the retinal nerve fibre layer in the affected eye at six months, adjusted for the corresponding baseline measurement in the unaffected eye. The trial is powered to detect a 50% reduction of loss of the retinal nerve fibre layer with treatment compared to placebo. Trial 2: Changes in cerebrospinal fluid neurofilament levels as outcome to address non-relapsing secondary progressive MS CSF neurofilament is a biomarker of neurodegeneration in MS and is responsive to disease modulation. Six to 12 month of treatment of natalizumab, in relapsing MS, reduced NFL levels 5 of 8. Giovannoni, page from a mean value of 1.3 (SD=2.2) to 0.4 (SD=0.27) ng/ml (p < 0.001) (Gunnarsson et al., 2011); levels of CSF NF did not return to normal in patients with SPMS. We therefore propose performing a study using CSF neurofilament levels as a surrogate outcome in neuroprotective MS trials. An effective neuroprotective agent should prevent or reduce ongoing neurodegeneration in progressive MS and reduce the levels of neurofilament levels in the spinal fluid. The introduction of atraumatic needles and the possible use of ultrasound guidance make CSF sampling more MSer-friendly and appears to be an acceptable to MSers (Gafson and Giovannoni, 2012). Power calculations for our proposed study that will evaluate oxcarbazepine (OxCBZ) as a neuroprotective agent in progressive MS uses and enrichment design. Only MSers with a CSF NF-light level above normal (≥0.690ng/ml), which is found in approximately 75% of subjects with progressive MS, will be eligible for the study. To detect a treatment effect that will reduce the level of CSF NF-light level by 50%, compared to placebo, and allowing for 30% decrease due to regression to the mean, with a power of 84%, will require 27 subjects/arm. Allowing for a 10% drop-out rate from the CSF NF-light sub-study will require 30 subjects per arm. Gafson AR, Giovannoni G. Towards the incorporation of lumbar puncture into clinical trials for multiple sclerosis. Mult Scler. 2012 Oct;18(10):1509-11. 38 Giovannoni G. Cerebrospinal fluid neurofilament: the biomarker that will resuscitate the Spinal Tap.
  • 39. and enrichment design. Only MSers with a CSF NF-light level above normal (≥0.690ng/ml), which is found in approximately 75% of subjects with progressive MS, will be eligible for the study. To detect a treatment effect that will reduce the level of CSF NF-light level by 50%, compared to placebo, and allowing for 30% decrease due to regression to the mean, with a power of 84%, will require 27 subjects/arm. Allowing for a 10% drop-out rate from the CSF NF-light sub-study will require 30 subjects per arm. Gafson AR, Giovannoni G. Towards the incorporation of lumbar puncture into clinical trials for multiple sclerosis. Mult Scler. 2012 Oct;18(10):1509-11. Giovannoni G. Cerebrospinal fluid neurofilament: the biomarker that will resuscitate the Spinal Tap. Mult Scler. 2010 Mar;16(3):285-6. Giovannoni G, Nath A. After the storm: neurofilament levels as a surrogate endpoint for neuroaxonal damage. Neurology. 2011 Apr 5;76(14):1200-1. Gunnarsson M, Malmeström C, Axelsson M, Sundström P, Dahle C, Vrethem M, Olsson T, Piehl F, Norgren N, Rosengren L, Svenningsson A, Lycke J. Axonal damage in relapsing multiple sclerosis is markedly reduced by natalizumab. Ann Neurol. 2011 Jan;69(1):83-9. A phase II double-blind, randomised, placebo-controlled trial of neuroprotection with oxcarbazepine in early non-relapsing secondary progressive multiple sclerosis Early SPMS 1. A diagnosis of definite multiple sclerosis 2. Treatment with interferon beta or glatiramer acetate for at least 12 months 3. EDSS score between 3.5 and 5.5 4. No history of relapses in the preceding 6 months 5. A history of slow progression of disability over a period of at least 6 months 6. Age 18-55 years Informed consent / bloods / CSF (week -4) No Excluded as they Raised CSF NFL would be non- Giovannoni, page 6 of 8. informative Yes Repeat CSF analysis (week – 1) Randomised to oxcarbazepine or placebo (week 0) Repeat CSF analysis (week 24) Primary outcome at 24 weeks Relative reduction in CSF NFL levels Secondary outcomes at 24 weeks EDSS, timed 25-foot walk, 9-hole peg test and the MSIS-29 Safety profile Tertiary outcomes at 24 weeks exploratory CSF biomarkers that including NCAM, GAP43, NFH and GFAP39
  • 40. Trial 2 SynopsisTitle: A phase II double-blind, randomised, placebo-controlled trial of neuroprotection with oxcarbazepine in early non-relapsing secondary progressive multiple sclerosisShort title: PROXIMUS STUDY - PRotective role of OXcarbazepine in MUltiple SclerosisTrial medication: Oxcarabzepine vs placeboPhase of trial: Phase IIObjectives: The primary aim is to assess whether sodium channel blockade with oxcarbazepine has a neuroprotective effect on axonal degeneration in early secondary progressive multiple sclerosis (SPMS). Secondary aims are to assess whether oxcarbazepine improves clinical and MRI outcomes.Type of trial: Phase II, double-blind, randomised, parallel group, in people with early secondary progressive multiple sclerosis (SPMS).Trial design and methods: 60 people with early SPMS, who are already on licensed disease- modifying therapies (interferon-beta or glatiramer acetate) will be recruited into a double blind parallel group controlled trial in which random allocation will be made to receive treatment with either oxcarbazepine or placebo for 12 months. Only trial subjects with a raised CSF neurofilament light level with randomized; i.e. this trial will be enriched for subject most likely to progress over the next 12 months. Recruitment, follow-up and trial management will be achieved through a collaborative network of sites at UCLP (UCL Partners). The primary endpoint will be the effect of treatment on CSF NFL light levels at 12 months. The trial is powered to detect a 50% beneficial effect on the primary outcome measure compared to placebo. The outcome will be measured at entry, and 6 and 12 months.Trial duration per 12 monthsparticipant:Estimated total trial 36 monthsduration:Planned trial sites: Royal London Hospital and the National Hospital for Neurology and Neurosurgery, London.Total number of participants 90planned:Main inclusion criteria: 6 month history of sustained progression despite being interferon-beta or glatiramer acetate without a relapse in the last 12 months.Statistical methodology and The primary comparison will estimate the active vs placebo difference in 40analysis: the change In CSF NFL levels at 12 months, adjusted for the corresponding baseline measurement. The trial is powered to detect a
  • 41. raised CSF neurofilament light level with randomized; i.e. this trial will be enriched for subject most likely to progress over the next 12 months. Recruitment, follow-up and trial management will be achieved through a collaborative network of sites at UCLP (UCL Partners). The primary endpoint will be the effect of treatment on CSF NFL light levels at 12 months. The trial is powered to detect a 50% beneficial effect on the primary outcome measure compared to placebo. The outcome will be measured at entry, and 6 and 12 months. Trial duration per 12 months participant: Estimated total trial 36 months duration: Planned trial sites: Royal London Hospital and the National Hospital for Neurology and Neurosurgery, London. Total number of participants 90 planned: Main inclusion criteria: 6 month history of sustained progression despite being interferon-beta or glatiramer acetate without a relapse in the last 12 months. Statistical methodology and The primary comparison will estimate the active vs placebo difference in analysis: the change In CSF NFL levels at 12 months, adjusted for the corresponding baseline measurement. The trial is powered to detect a 50% reduction in CSF NFL level with treatment compared to placebo. Giovannoni, page 8 of 8.41
  • 42. Clues from Inflammatory Aspects of Progressive MS Pathology Hans Lassmann Center for Brain Research, Medical University of Vienna, AustriaAbsence of contrast-enhancing lesions and lack of efficacy of anti-inflammatory treatments inprogressive multiple sclerosis (MS) has been regarded as evidence that inflammation, mediatedby adaptive immunity, plays no major role in propagation of tissue injury in this stage of thedisease. This view is not supported by neuropathological observations. Overall, inflammationin the MS brain decreases with age and disease duration. However, active demyelination andaxonal or neuronal injury in the progressive stage of the disease is invariably associated byT-cell and B-cell infiltration of the lesions. When inflammation in the MS brain at late diseasestages declines to levels seen in age matched controls also active demyelination and axonaldamage declines to levels seen in the respective controls. T- and B-cell infiltrates within thetissue in active progressive MS are in part located in areas without blood brain barrier proteinleakage. Furthermore, the exact nature of the inflammatory reaction, their activation state withinthe lesions and their potential response to current anti-inflammatory treatments are currentlynot defined.The type of tissue injury, characterized by plaque like primary demyelination associated withaxonal and neuronal degeneration, is specific for MS and is not seen in comparable form inany other chronic inflammatory disease of the human central nervous system. It is also only inpart reproduced in currently available experimental models. Specific primary demyelination inexperimental models can be induced by specific adaptive immune reactions, involving cytotoxicT-cells or auto-antibodies. Evidence that these mechanisms are involved in active MS lesions 42
  • 43. in progressive MS is currently sparse. Analysis of mechanisms of tissue injury in active lesions or progressive MS suggests that oxidative injury and mitochondrial damage may play a key role. Current experimental models of inflammatory demyelination, driven by Class I or Class II restricted T-cells, by auto-antibodies or by innate immunity do not reflect the extent of oxidative injury, seen in direct comparison with active MS lesions from the progressive stage of the disease. The current data suggest that oxidative burst driven by inflammation is important in propagating tissue injury in MS, but that this mechanism is amplified by an increased susceptibility of the tissue to this type of tissue damage. Possible mechanism of this increased susceptibility are age related changes in the CNS tissue, progressive age-dependent accumulation of iron within the human brain as well as chronic microglia activation and mitochondrial damage, due to the accumulation of previous tissue injury in the MS brain. In addition, age dependent neurodegeneration may have further deleterious clinical consequences in a damaged brain, which has passed the threshold of functional compensation.43
  • 44. Genetic Profile Stephen Sawcer Department of Clinical Neuroscience, Addenbrooke’s Hospital, University of Cambridge, Cambridge, UKGenome Wide Association Studies have the potential to reveal novel unbiased insights into complex heritable traits by enabling hypothesis free screening of common variation. Theapproach has revolutionised the genetics of susceptibility but has yet to provide any insightinto the genetic factors underlying critically important clinical features of the disease suchcourse and severity. Given that the most recent GWAS involved almost 10,000 patients thisdisappointing result is surprising and immediately raises several questions. First are thesephenotypes heritable? Intuitively it seems inconceivable that matters such as the extent ofrelapse activity and the rate of accumulation of disability might not be influenced by geneticvariation. However beyond this intuition there is surprisingly little evidence supporting the roleof genetic factors. In their assessment of over 1,000 multiplex families Hensiek et al. foundonly marginally significant evidence for correlation in clinical course amongst affected relatives,and no convincing evidence for such correlation in severity. Although the absence of evidenceshould not be confused with evidence of absence these disappointing data could indicatethat the genetic factors of relevance in shaping the phenotype of multiple sclerosis exert onlyvery modest effects. Second are these phenotypes measured well enough? Here one mightspeculate lays the greatest weakness in the previous GWAS looking at clinical phenotypes inmultiple sclerosis. Like all association based studies GWAS are critically dependent upon thecorrelation between the variables tested (the genotypes) and the phenotype measured. If themeasured phenotype (e.g. EDSS or MSSS) is only poorly correlated with the clinically relevantvariable (rate of accumulation of disability) then one can expect that power will be substantiallimited. Since course is usually dichotomised into those with and those without a history ofclinically evident relapse it seems inevitable that the correlation between this dichotomy andany SNP genuinely influencing relapse activity will be modest, even if that SNP had a relatively 44
  • 45. large effect on relapse activity. This dichotomisation essentially throws away all the information contained in the variation in relapse activity that exists between affected individuals. It seems likely that a GWAS based on a more robust (better correlated) biomarker of relapse activity that reflects both clinically evident and sub-clinical relapse activity would likely be much better powered. The negative results of the GWAS studies completed so far seem to indicate that traditional measures of severity such as the EDSS and the MSSS are likely to be inadequately correlated with the primary determinants of neurodegeneration, and that dogmatic views about heterogeneity around primary progressive disease need to be abandoned so that relapse activity can be tested as a quantitative aspect of the disease. There seems to be no reason why GWAS can’t help to unravel the nature of progression IF such biomarkers can be found and utilised in sufficient numbers of individuals. On a positive note GWAS have already revealed convincing evidence that age at onset (a poorly measured variable that is usually just a reflection of a patients recall) is likely determined by the burden of susceptibility alleles an individual carries. However it is worth stating that this does not necessarily means that the alleles relevant to susceptibility will also be relevant to progression or other aspects of the phenotype.45
  • 46. Phase III trials in progressive MS: biomarkers of inflammation, axonal damage, demyelination and remyelination Per Soelberg Sørensen Danish Multiple Sclerosis Center, Rigshospitalet, Copenhagen University Hospital, DenmarkWhereas biomarkers may be of considerable value in phase II proof-of-concept trials, clinical outcomes,in particular disability progression, are the hallmark in phase III clinical trials of progressive multiplesclerosis (MS).Outcome measures of biomarkers of inflammation, axonal damage, demyelination and remyelinationin progressive MS include imaging measures and biomarkers in blood and CSF. A major issue is theproblem of feasibility and standardisation across many different sites participating in pivotal phase IIItrials in progressive MS. Especially many new promising MRI techniques for measuring structural andfunctional changes are not suitable for multi-centre trials.Among the conventional MRI measures, gadolinium enhancing lesions are the most appropriatemeasure for focal inflammatory sites with blood-brain barrier disruption. However, in progressive MSthese are of less importance because of the compartmentalization of the inflammation in primary andsecondary progressive MS.Hyperintensive T2 lesions are very unspecific and may reflect several different pathologies includingoedema inflammation, demyelination and axonal loss.T1 hypointensive lesions, black holes, correlate with axonal loss, but are more suitable for trials inrelapsing-remitting MS where lesions are discrete.Atrophy measures are probably most appropriate for measuring axonal damage in phase III trials inprogressive MS. One of the best evaluated measures to assess brain atrophy is the brain parenchymalfraction that, however, only correlates moderately with clinical disability. Pseudo atrophy in the first yearof anti-inflammatory therapies make measurements during the first 6-12 months after treatment startunreliable.Grey matter atrophy studied by doubled inversion recovery imaging is currently used as a primary andsecondary endpoint in phase II trials and may be important in phase III trials of progressive MS.Measurements of spinal cord atrophy correlates with clinical disability in primary and secondary 46
  • 47. progressive MS but has not yet been established as outcome in phase III trials of progressive MS. Among the new MRI techniques, magnetization transfer ratio (MTR) may be the most promising. Lesional MTR decreases during the acute phase of demyelination and subsequently recovers depending on the degree of remyelination, in the absence of axonal loss. MTR is a rather unspecific marker of demyelination and axonal damage, but decreased MTR has a predictive value for deterioration of clinical disability and should be evaluated as an endpoint in phase III trials in progressive MS as it is possible to standardize MTR across different trial centres. Diffusion tensor imaging is an interesting MRI technique for measuring tract-specific abnormalities but is still an experimental technique and not feasible for multi-centre studies due to lack of standardization of measurements. Proton MR spectroscopic imaging is a sensitive technique, in which NAA is a marker of neuronal and axonal integrity whereas choline measures demyelination and repair. It is possible to measure whole- brain NAA that may correlate with disability and cognitive function, but the technique has no place in phase III trials of progressive MS as it lacks standardization. Functional MRI and the use of positron emission tomography (PET) tracers are still only for experimental use, although modern PET tracers bind to the translocator protein 18KDa (TSPO), which is up-regulated in activated microglia. These PET tracers could be of interest as markers of areas of microglia activation in the normal appearing white and gray matter in future trials in progressive MS. Measurements of retinal nerve fibre layer (RNFL) thickness with optical coherence tomography (OCT) may provide a candidate biomarker for brain atrophy in MS patients. This interesting technique is under validation in ongoing phase II and phase III randomized controlled trials as secondary or tertiary endpoints. Regarding biomarkers in body fluids, CSF is the compartment closest to the central nervous system pathology, but multiple lumbar punctures may be used in small phase II clinical trials but are less suitable for large scale phase III trials. Nevertheless, the concentration of47
  • 48. neurofilament (both light and heavy chain) is increased in patients with progressive MS and correlateswith CNS inflammation and axonal loss. Hence, neurofilament in CSF might be the most promisingmeasure of permanent of neurological disabilities in trials of progressive MS.Glial fibrillary acidic protein (GFAP) is associated with astrocytosis and irreversible brain tissue damageat late stage MS. However, the value as biomarker for atrophy has still to be demonstrated in largecohorts of patients in standardized controlled studies. Other molecules that are potential biomarkers inCSF for axonal damage are NAA and S100 protein. Proteomics may also be of value. Markers of diseaseactivity are neurofilament, CXCL13, IL10 and osteopontin.There are no established biomarkers in blood for measurement of atrophy or inflammation anddemyelination. Neurofilament, light and heavy, in plasma is less suitable compared to CSF measurements.Auto-antibodies against myelin have been studied but none of them have convincingly been shownto identify inflammation or axonal damage. A number of molecules are under investigation includingadhesion molecules, matrix metalloproteinase, and osteopontin, T-cell activation and transcriptionfactors, KIR4.1 antibodies, and GFAP.In conclusion, atrophy measures, in particular grey matter atrophy, and magnetization transfer ratio mightbe candidates for biomarkers of atrophy and neurodegeneration in phase III clinical trials of progressiveMS. Neurofilament is the most promising biomarker in body fluids, more predictive in CSF than in blood,although it does probably not distinguish between inflammation, demyelination and axonal damage.Several other candidates have shown promising potential to reflect inflammation and demyelinationor neurodegeneration and axonal loss, but none of them have convincingly been validated in phaseIII randomized clinical trials in progressive MS. However, phase III studies in progressive MS usingbiomarkers as endpoints are encouraged, as surrogate endpoints are urgently needed in clinical trialsthat test the efficacy of drugs with potential, neuroprotective or reparative properties. 48
  • 49. Immunologic Aspects of Progressive Multiple Sclerosis Scott S. Zamvil Department Neurology, University of California, San Francisco Multiple sclerosis (MS) is a central nervous system (CNS) inflammatory demyelinating disease that is considered to have an autoimmune etiology. The initial relapsing-remitting (RR) phase of MS is associated with substantial lymphocytic inflammation, which is thought to be directed by an adaptive immune response to myelin autoantigens. The secondary progressive (SP) phase of MS is associated with more prominent neurodegeneration. In contrast with the lymphocytic inflammation in RRMS, cells of innate immunity may have a more prominent role in SPMS. In this presentation, I will summarize data and concepts regarding adaptive and innate immune responses in MS progression. Many immunologic studies related to early MS have focused on T cell immune responses to candidate oligodendrocyte-derived proteins antigens, MBP PLP and MOG. As for EAE, a majority of studies , concentrate on antigen-specific CD4+ T cells. However, it is recognized that CD8+ T cells may also contribute to different phases of MS. Data from peripheral blood and CNS pathology in MS indicate that IFN-γ-secreting (Th1) and IL-17-producing (Th17) memory T cells drive the initial inflammatory response in MS. These proinflammatory cells are controlled by various regulatory T cell subsets, which may contain defects in MS. Genetic studies have not identified mutations in genes encoding myelin or other CNS autoantigens that account for CNS autoreactivity. However, genome wide association studies (GWAS) have demonstrated association of MS susceptibility with polymorphisms, not only within MHC, but also certain genes involved in T cell regulation and expansion. Whether genes that influence disease progression (“disease modifiers”) exist and contribute to possible changes in immune reactivity is not clear. Although limited and not necessarily convincing, several different functional observations suggest that adaptive immune responses could participate in MS progression. Some data suggest that there could be phenotypic changes in expression of T cell polarizing cytokines or genes controlling their transcription. Diversification of T cell responses from one determinant to49
  • 50. another determinant of the same myelin protein (intramolecular epitope spreading), from one myelinprotein to another or to a neuronal antigen (intermolecular spreading) may occur. Evidence indicatesthat antibody reactivity to autoantigens also changes during progression from RRMS to SPMS. Therole of adaptive B cell immunity in progression is also supported by the identification of B cell follicleswith germinal center formation in the meninges in SPMS. A better understanding how each of thesepotential mechanisms contributes to progression is needed. In this regard, it could be advantageous tocombine different immunologic techniques (e.g. CFSE, ICS, MHC tetramers...) to identify and evaluatethe phenotype of rare lymphocyte populations that may participate in disease progression.Evidence from studies of CNS pathology and the peripheral immune system suggest innate immunitycontributes to MS progression. Separate from focal areas of CNS inflammation, activated microglia aredetected in regions of normal appearing white matter in progressive MS. It has been observed that myeloidcells (dendritic cells (DC) and monocytes) in SPMS express higher levels of certain proinflammatoryT cell-polarizing cytokines and costimulatory molecules than in RRMS. This proinflammatory “type I”(or M1 for monocytes/macrophages) shift is particularly important in communication between innateand adaptive immunity, as it has been observed that when serving as APC, these cells can promoteproinflammatory T cell differentiation. The relationship between innate and adaptive immunity is importantfor understanding the mechanism of action of some established MS therapies, and for certain agents indevelopment. Glatiramer acetate (GA) is a polypeptide-based therapy approved for RRMS and is knownto induce T cell immune modulation in MS patients. It is recognized that GA induces anti-inflammatory“type II” (M2) myeloid cells, and it is these cells that promote the development of regulatory T cells. Data inhumans and in experimental animals indicate that BG-12 and laquinimod, two therapies in developmentfor RRMS exert a primary effect on innate immune cells and promote development of type II DC andmonocytes. Agents that inhibit pathways participating in proinflammatory myeloid cell differentiation maybe attractive candidates for treatment of progressive MS. 50
  • 51. International progressive IPMSC Collaborative Additional documents51
  • 52. 52
  • 53. 4581692012 MSJ181110.1177/1352458512458169Multiple Sclerosis JournalFox et al. MULTIPLE SCLEROSIS MSJ New Perspectives JOURNAL Multiple Sclerosis Journal Setting a research agenda for 18(11) 1534–1540 © The Author(s) 2012 Reprints and permissions: progressive multiple sclerosis: sagepub.co.uk/journalsPermissions.nav DOI: 10.1177/1352458512458169 The International Collaborative msj.sagepub.com on Progressive MS Robert J Fox1, Alan Thompson2, David Baker3, Peer Baneke4, Doug Brown5, Paul Browne4, Dhia Chandraratna4, Olga Ciccarelli2, Timothy Coetzee6, Giancarlo Comi7, Anthony Feinstein8, Raj Kapoor9, Karen Lee10, Marco Salvetti11, Kersten Sharrock12, Ahmed Toosy2, Paola Zaratin13 and Kim Zuidwijk14 Abstract Despite significant progress in the development of therapies for relapsing MS, progressive MS remains comparatively disappointing. Our objective, in this paper, is to review the current challenges in developing therapies for progressive MS and identify key priority areas for research. A collaborative was convened by volunteer and staff leaders from several MS societies with the mission to expedite the development of effective disease-modifying and symptom management therapies for progressive forms of multiple sclerosis.Through a series of scientific and strategic planning meetings, the collaborative identified and developed new perspectives on five key priority areas for research: experimental models, identification and validation of targets and repurposing opportunities, proof-of-concept clinical trial strategies, clinical outcome measures, and symptom management and rehabilitation. Our conclusions, tackling the impediments in developing therapies for progressive MS will require an integrated, multi-disciplinary approach to enable effective translation of research into therapies for progressive MS. Engagement of the MS research community through an international effort is needed to address and fund these research priorities with the ultimate goal of expediting the development of disease-modifying and symptom-relief treatments for progressive MS. Keywords multiple sclerosis, progressive multiple sclerosis, neuroprotection, rehabilitation, research agenda Date received: 29th June 2011; revised: 18th July 2012; accepted: 22nd July 2012 The last two decades have seen dramatic progress in relaps- models have provided insights into the pathophysiology of ing–remitting multiple sclerosis (RRMS). Experimental central nervous system inflammation and demyelination. autoimmune encephalomyelitis (EAE) and other animal Clinical diagnostic criteria have been refined, and 1Mellen 9National Hospital for Neurology and Neurosurgery, London, UK. Center for Multiple Sclerosis, Neurological Institute, and Lerner 10MS Society of Canada, Toronto, ON, Canada. College of Medicine, Cleveland Clinic, Cleveland, OH, USA. 2Department of Brain Repair and Rehabilitation, University College 11Center for Neurology and Experimental Therapies, Sapienza London Institute of Neurology, Faculty of Brain Sciences, London, University, Rome, Italy. 12Fast Forward, LLC, New York, NY, USA. UK. 3Centre for Neuroscience and Trauma, Blizard Institute, Barts and The 13Italian MS Society, Genoa, Italy. 14MS Research Foundation, Voorschoten, The Netherlands. London School of Medicine and Dentistry, Queen Mary University of London, UK. 4Multiple Sclerosis International Federation, London, UK. Corresponding author: 5Multiple Sclerosis Society, London, UK. Robert J. Fox, Mellen Center for Multiple Sclerosis, Neurological 6National MS Society, New York, NY, USA. Institute, and Lerner College of Medicine, Cleveland Clinic, 9500 Euclid 7Department of Neurology, Scientific Institute San Raffaele, Milan, Italy. Ave, U-10, Cleveland Clinic, Cleveland, OH, 44122 USA. 8Department of Psychiatry, University of Toronto, Canada. Email: foxr@ccf.org Downloaded from msj.sagepub.com at Università degli studi di Pavia on January 17, 2013 53
  • 54. Fox et al. 1535biomarkers are being developed that predict future disease Table 1. Five key research priorities for progressive MS.activity and disability. A clear pathway has emerged for - Experimental Modelsdeveloping RRMS therapies: studies in experimental mod- - Identification and Validation of Targets and Repurposingels, Phase I safety studies, Phase II trials with active MRI Opportunitieslesions as the primary outcome, and finally Phase III trials - Proof-of-Concept Clinical Trial Strategiesusing relapses and sustained progression of disability as - Clinical Outcome Measuresprimary outcome. Eight disease-modifying therapies have - Symptom Management and Rehabilitationreceived regulatory approval for RRMS and several moreare in late-stage clinical development and could receiveregulatory approval shortly. therapies for progressive forms of multiple sclerosis’. For all the success in developing treatments for RRMS, Through a series of scientific and strategic planning meet-the story in progressive MS is comparatively disappointing ings, five key priority areas for research were identifiedand more challenging. Even the definition of progressive (Table 1). These areas represent opportunities where con-MS has been elusive. At the clinical level, progressive MS certed research efforts would provide significant impact inis defined as the gradual progression of clinical disability overcoming the current barriers in developing effectivein a patient either with a preceding relapsing course (sec- treatments for progressive MS and provide a clear roadmapondary progressive MS, SPMS) or without a preceding for the future.relapsing course (primary progressive MS, PPMS).1 Theremay be superimposed evidence of overt inflammation, but Experimental modelsfrequent relapses and many new lesions on MRI are moresuggestive of RRMS. At the imaging level, progressive MS Experimental models for MS have provided importantis the gradual accumulation of imaging abnormalities. At insights into disease pathogenesis and potential therapies.4the pathology level, progressive MS is the abnormal pro- Neurotoxicity models inform neuroprotection strategiescesses present in neurons or glial cells that lead to irrevers- that may prevent neurodegeneration in MS.4 The threeible injury that causes clinical disability progression. An most commonly studied animal models in MS are: EAE,inherent difficulty in studying progressive MS is the indis- virally induced demyelinating disease models and toxin-tinct overlap with RRMS, with the pathologic origins of induced models of demyelination.5 Despite their extensiveprogressive MS probably developing much earlier than its use, the clinical course, immunology and neuropathologyclinical manifestations. Here, PPMS and SPMS are grouped of these models reflect only part of the pathophysiologicaltogether, since they share many similarities – clinically, spectrum of human MS.4,6 Therefore, direct extrapolationpathologically, and particularly as revealed by imaging of results obtained in these models to MS is often tenuous,technology.2 and the effect of therapeutic interventions in animals must Animal models such as EAE provide only limited insight be interpreted with care.7 In addition, most of the currentinto the pathophysiology of progressive MS. New MRI models follow a monophasic episode of inflammation andlesions are only occasionally seen in progressive MS, therefore predominantly mirror only the impact of acuteresulting in uncertainty as to which imaging or other bio- inflammation and neuronal injury seen in RRMS.4,6marker should be employed in Phase II proof-of-concept Several animal models claim to represent human pro-clinical trials. The clinical metrics used in RRMS have gressive MS,8 but few offer compelling evidence.6 Theunclear sensitivity in progressive MS, limiting their utility. chronicity of these models is usually short and the compo-Mechanisms for identifying candidate therapies among sition of lesions different from MS.6 Furthermore, most ofexisting therapies are not well defined. these models do not reflect the irreversible deficits charac- Clinical trials of anti-inflammatory therapies in progres- terizing progressive MS.9sive MS have been generally negative or inconsistent. Therefore, there is an urgent need for better animal mod-Immunosuppressive and immunomodulating drugs such as els that reproduce the key clinical and pathological featurescladribine, azathioprine, and cyclophosphamide have of SPMS and PPMS. Such models should include the role ofshown no evidence for efficacy in SPMS and PPMS. Only CD8-positive T cells and notably macrophages, which com-mitoxantrone has been approved for SPMS in some coun- prise a major component in progressive MS lesions. Ectopictries, and this treatment has a serious adverse effect profile. B cell follicles should be studied as an alternative disease-Finally, early attempts to approach progressive MS with related mechanism. Additional models are also needed thatputative neuroprotective therapies have failed, as seen in demonstrate robust chronic demyelination and neurode-the recent trial of lamotrigine.3 generation, such as an autoimmune-independent, inflam- Given the challenges presented by progressive MS, a matory glial cell-associated neurodegeneration, whichcollaborative was convened by volunteer and staff leaders more accurately reflects progressive MS. In addition tofrom several MS societies ‘to expedite the development of animal models, brain-slice cultures that demonstrateeffective disease-modifying and symptom management demyelination and neurodegeneration may be informative, Downloaded from msj.sagepub.com at Università degli studi di Pavia on January 17, 2013 54
  • 55. 1536 Multiple Sclerosis Journal 18(11) especially if they can be adapted to use human post-mor- The therapeutic opportunities that come from GWAS, tem tissue where MS pathology can be directly examined. computational biology and systematic reassessment of the effects of pharmaceutical compounds need further develop- ment to achieve their potential application to progressive Identification and validation of targets MS. Intellectual property and the possibility of re-evaluat- and repurposing opportunities ing compounds that have not made it through the approval process are among the issues that, if properly addressed, While our understanding of the pathophysiology of pro- may help accelerate the development of effective therapies gressive MS is yielding knowledge which can be applied to for progressive MS.16 the development of new treatments, identifying and validat- ing targets for use in drug discovery for progressive MS Proof-of-concept clinical trial remains a significant challenge. Helpful insights may come from genome-wide association studies (GWAS). Since the strategies first non-MHC susceptibility locus (IL2RA) was identi- Agents for which there is promising preclinical data need to fied,10 the list of MS risk loci is growing, with around 50 be developed through early phase clinical trials for evi- loci identified to date.11 However, no individual gene vari- dence of safety and therapeutic benefit. Phase II trials gen- ant has been identified as the ideal therapeutic target and, erally rely on biomarkers that are more sensitive to even when considering all disease-associated variants therapeutic effects than clinical measures. Biomarker out- together, risk loci explain only a modest fraction of disease comes enable Phase II trials to be shorter and have a smaller heritability.12 Notwithstanding these limitations, the avail- sample size than Phase III trials. able results may suffice for computational and systems Valid surrogate biomarkers need to predict clinical out- biology analyses to provide novel insights into biological comes. Phase II trials in RRMS have advanced because pathways involved in disease pathogenesis. Indeed, compu- lesion activity on MRI is an accepted biomarker of clinical tational biology is shifting from diagrammatic representa- relapse rate.17 In contrast, no comparable measure has been tion of pathways to mathematical models. These techniques identified in progressive MS. There are no agreed imaging hold promise to provide the tools for interpreting genetic markers of neurodegenerative processes such as energy data across different knowledge domains.13 Furthermore, failure, ionic imbalances and loss of neuronal integrity. The systematic assessments of the functional consequences of problem is compounded by limitations of clinical measures the associated variants are underway. Together, the results of disease progression against which any biomarker might of these studies could help prioritize putative therapeutic be validated. targets and steer the development of new compounds. At present, promising imaging metrics include cerebral In addition, methods have recently been developed to and spinal cord atrophy, lesion T1 hypointensity, magneti- select old drugs for new targets. Historically, repositioning zation transfer ratio to assess lesion microstructure, and of a compound for a new indication has been a chance optical coherence tomography to measure axonal degenera- occurrence, driven by observations of unforeseen favorable tion in the retina.18 There is enough longitudinal data to effects. Now there is intense research on how to systemati- enable sample sizes to be calculated for most of these tech- cally infer new therapeutic targets for drugs that have niques for proof-of-concept trials, but their sensitivity to already been registered for human use. Side-effect or chem- change and responsiveness to treatment is not well under- ical similarities between drugs and ligand sets are examples stood. Newer techniques that assess tissue microstructure of this new strategy.14,15 These data may be further refined are also candidate metrics, including diffusion tensor imag- through screenings of registered drugs on cellular and ani- ing19 in addition to methods that can derive axonal density mal models of MS. and radius. Techniques that examine earlier events in the Superimposing biologically relevant pathways identi- injury pathway include sodium imaging20 and measure- fied through GWAS studies to ‘catalogues’ of pheno- ments of metabolic markers, including the neuronal/mito- typic effects of registered drugs may shorten the process chondrial marker N-acetylaspartate.21 These techniques of identifying therapies with potential efficacy in could be complemented and extended by positron emission progressive MS. This strategy is safe for patients, tomography (PET).22 Little is known about the sensitivity, since repurposed drugs usually come with years of post- responsiveness and predictive power of most of these imag- marketing experience in other diseases. This strategy is ing techniques and their limited availability may restrict also cost-effective, since it streamlines preclinical and their widespread use. early-stage clinical studies. Indeed, the latest GWAS A number of tissue fluid biomarkers have been studied, data did not show substantial differences at susceptibil- mostly to assess immunological activity. Markers of spe- ity loci between relapsing and primary progressive forms cific injury mechanisms are also emerging, including of MS, suggesting relevance of GWAS results to pro- chemokines associated with intrathecal B lymphocyte gressive MS.11 activity that might drive cortical injury,23 nitric oxide Downloaded from msj.sagepub.com at Università degli studi di Pavia on January 17, 201355
  • 56. Fox et al. 1537metabolites,24 and neurofilaments released by damaged statistical performance. Since the introduction of theaxons.25 A significant drawback to widespread application MSFC, many validation studies have shown its clinical cor-of these biomarkers is their typical measurement from cer- relations and predictive capacity. Despite these apparentebrospinal fluid, which is not easily accessible. Nonetheless, advantages, the MSFC has not always been more sensitivecerebrospinal fluid is increasingly incorporated into designs than the EDSS in clinical trials. Equally important, theof progressive MS trials, and efforts to identify biomarkers MSFC has not yet been accepted by regulators as an alter-in plasma and serum are underway. native to EDSS. As with EDSS, further refinement of the Better biomarkers would power smaller and shorter tri- MSFC may improve its sensitivity, reliability, and respon-als. More flexible trial designs are also being examined to siveness, although some shortcomings cannot beachieve the same aim. These include modified entry criteria overcome.31to enrich trials for patients more likely to progress. Adaptive Important goals of MS therapies are to reduce symptomdesigns such as those used in cancer trials could make use severity, improve function, and enhance quality of life.of prognostic biomarkers to stratify an outcome analysis These are best evaluated through patient-reported outcomethat is sensitive to subpopulation treatment effects,26 and measures (PROMs), including global assessments of dailycould employ an interim futility analysis to exclude non- function and health-related quality of life (HRQL) meas-effective agents.27 ures.32 Regulatory interest in PROMs is growing, with These considerations suggest that proof-of-concept clin- guidelines emerging regarding the integration of PROMsical trial strategies are likely to evolve significantly if (1) into clinical trials.33 Efforts to improve clinical disabilitybiomarkers can be identified and validated that measure assessment in MS are already underway.31important events in the neuronal injury pathway, are relia-ble, easily implemented, dynamic over time, and correlatewith disability, and (2) if trial designs can be developed Symptom management andwhich further minimize trial size and duration. Importantly, rehabilitationthese innovations will need sufficient community consen- MS results in a diversity of symptoms, bringing increasingsus to be accepted by regulatory authorities. physical, psychological and emotional burden, particularly in the progressive stage of the condition. In spite of the introduction of effective disease-modifying treatments,Clinical outcome measures symptom management and rehabilitation remain essentialA critical aspect in the development of therapies is a meas- components of MS therapy, helping to alleviate the impacturement tool of therapeutic efficacy. The ideal measure- of disability and improve quality of life. Surprisingly, thement tool is precise, reproducible, broad-based in its rationale for specific pharmacological treatments for symp-assessment, sensitive to change over time, and predictive of toms is frequently based on few trials with small patientfuture change. The evaluation of MS therapies in RRMS numbers, often underpowered and unblinded.34 Recently,was greatly assisted by clear definitions and objective these shortcomings have begun to be addressed with a fewmeasurement of clinical relapses. Establishing outcome well conducted studies, such as using cannabinoids35 andmeasures for progressive MS has been more difficult. This fampridine36 for motor symptoms. While cognitive deficitsdifficulty arises from the varied manifestations of progres- can now be clearly defined, fatigue remains more difficultsive MS (motor, sensory, coordination, cognitive, etc.), to evaluate in trials because (a) less is known about thetheir slow rate of evolution, and difficulties in their quanti- pathophysiology and (b) it may be influenced by psychiat-tative measurement. There are two main pathways to solv- ric factors, making quantitative characterization problem-ing this challenge: refinement of existing outcome measures atic and often confounded. Depression and anxiety mayand development of new outcome measures. respond well to either pharmacologic or cognitive behavio- Of the existing measures, The Kurtzke Expanded ral treatment.37–39 Symptom management in MS can beDisability Status Scale (EDSS)28 is the most common dis- advanced in a number of ways. First, there should be tar-ability measure in MS trials. However, EDSS is an inher- geted research to improve our understanding of the patho-ently subjective assessment by a neurologist, has poor logical mechanisms leading to symptom-related disability.intra- and inter-rater reliability,29 and has poor precision. This knowledge will allow more focused translational stepsRefinements to the EDSS would likely improve its perfor- towards developing symptomatic therapies. Secondly,mance, although many of its shortcomings are inherent to potential treatments should be assessed in rigorous, wellthe tool and so are insurmountable. designed trials that are sufficiently powered to establish The Multiple Sclerosis Functional Composite (MSFC) beneficial effects, the optimum dosage, and short- andis the outcome of an international panel charged with long-term side effects. Potential symptom interactions andreplacing the EDSS.30 Advantages to the MSFC include its confounding factors should be accounted for in the trialdynamic assessment of different functions relevant to MS design. Ideally, studies should incorporate PROMs, surro-(ambulation, arm function, and cognition) and improved gate pathological markers related to the particular symptom Downloaded from msj.sagepub.com at Università degli studi di Pavia on January 17, 2013 56
  • 57. 1538 Multiple Sclerosis Journal 18(11) Table 2. Examples of ongoing projects in progressive MS. - Clinical trials, including Phase II and Phase III trials  fingolimod, rituximab, several stem cell studies, and other potential disease-modifying therapies  phenytoin, amiloride, cannabinoids, and other symptomatic therapies - MS phenotypic project (NMSS/ECTRIMS Clinical Trials Committee) - Multiple Sclerosis Functional Composite Study Group - Risk Factors for MS Progression Project - Pathobiology of MS: complex interplay between degeneration and inflammation (Multiple Sclerosis Scientific Research Foundation Multi-Center Collaborative Grant) - UK MS Clinical Trials Network - Multiple Sclerosis Functional Composite Task Force, National MS Society under study and an assessment of cost-effectiveness. Third, specific strategies and potential lines of research that would further development of reproducible and responsive meas- overcome the barriers and realize the opportunities within ures for different symptoms is needed. each area. Following an international meeting in early Symptomatic treatment is normally part of a multidis- 2013, we anticipate that a call will be issued to address ciplinary patient-centered approach that may involve these opportunities. Potential sources of funding for this rehabilitation. The relationship between neuroplasticity call include the existing research funding mechanisms of and rehabilitation is a critically important area for further the member organizations of the International Progressive research. Functional brain reorganization is well MS Collaborative as well as other partners (e.g., govern- described in MS, showing increasing activation extent ment, industry). In addition, there will be an international and the recruitment of additional areas, and hinting at the fundraising effort led by the Multiple Sclerosis International prospect of compensatory strategies.40,41 Some motor net- Federation and financial support will be solicited from works may be altered by training42 but there is a need to diverse channels around the world, including foundations, investigate if enhancing network plasticity may improve government, corporate, and private funding organizations. the outcomes of rehabilitation. Combining functional and Fostering global collaboration by the MS research com- structural imaging with cognitive rehabilitation may help munity is a bold ambition, and potentially fraught with develop treatments for cognitive impairment.43 Finally, many challenges. Fortunately, the opportunities have never applying brain–computer interface technology in patients been as favorable as they are today, with unprecedented with advanced MS may allow greater motor independ- data on disease etiology, pathophysiology, and disease ence, communication and environmental control.44 course. Furthermore, we can look to other diseases for inspiration. Collaborative efforts like the Forum for Collaborative HIV Research, the Alzheimer’s Disease Conclusions and future directions Neuroimaging Initiative, and the Innovative Medicines Despite great progress in relapsing MS, much work is Initiative, provide powerful examples of how collaboration needed to achieve similar successes for progressive MS. can accelerate research among a diverse group of stake- There are a number of key areas of unmet need which are holders. While the collaborative efforts in progressive MS blocking treatment development in progressive MS. will almost certainly differ from those in other fields, the Although the international scientific community has made time is right for concerted action. progress in some of these areas (Table 2), there have not been commensurate gains in progressive MS treatments. Acknowledgments Tackling these issues will require an integrated, multi-dis- The meetings of the International Collaborative on Progressive ciplinary approach to enable effective translation of Multiple Sclerosis were funded by the Italian Multiple Sclerosis research into therapies. To this end, the International Foundation (FISM), MS Society of Canada, MS International Progressive MS Collaborative is committed to engaging Federation, MS Research Foundation (The Netherlands), UK MS the MS research community through an international effort Society, and the National MS Society (USA). to fund a spectrum of research activities relevant to progressive MS with the ultimate goal of expediting the Funding development of disease-modifying and symptom-relief This activity received no specific grant from any funding agency treatments for progressive MS. in the public, commercial, or not-for-profit sectors. To address these five challenging areas, which currently impede the treatment of progressive MS, the International Conflict of interest Progressive MS Collaborative commissioned five working Robert J. Fox received personal compensation for activities with groups, comprised of international experts, to identify Avanir, Biogen Idec, Novartis, and Questcor, and research support Downloaded from msj.sagepub.com at Università degli studi di Pavia on January 17, 201357
  • 58. Fox et al. 1539from the National MS Society (USA) and National Institutes of 7. Fitzner D and Simons M. Chronic progressive multiple sclero-Health (USA). sis – pathogenesis of neurodegeneration and therapeutic strat- David Baker is a founder of Canbex and has received personal egies. Curr Neuropharmacol 2010; 8: 305–315.compensation for activities with UCB and Biogen Idec. 8. Pryce G, O’Neill JK, Croxford JL, et al. Autoimmune toler- Peer Baneke, none. ance eliminates relapses but fails to halt progression in a model Doug Brown, none. of multiple sclerosis. J Neuroimmunol 2005; 165: 41–52. Paul Browne, none. 9. Linker RA and Lee DH. Models of autoimmune demyelin- Olga Ciccarelli is on the editorial board of Neurology and is a ation in the central nervous system: on the way to translationalclinical editor for CML Multiple Sclerosis. She has received medicine. Exp Transl Stroke Med 2009; 1: 5.research funding from the Wellcome Trust, MS Society of Great 10. Hafler DA, Compston A, Sawcer S, et al. Risk alleles for mul-Britain and Northern Ireland, UCL Biomedical Research Centre, tiple sclerosis identified by a genomewide study. N Engl Jand Engineering and Physical Sciences Research Council. She has Med 2007; 357: 851–862.received speaker honoraria from Bayer-Schering and GE 11. Sawcer S, Hellenthal G, Pirinen M, et al. Genetic risk and aHealthcare. primary role for cell-mediated immune mechanisms in mul- Dhia Chandraratna, none. tiple sclerosis. Nature 2011; 476: 214–219. Timothy Coetzee, none. 12. Bush WS, Sawcer SJ, de Jager PL, et al. Evidence for poly- Giancarlo Comi has received personal compensation for activ- genic susceptibility to multiple sclerosis – the shape of thingsities with Novartis, TEVA Pharmaceutical Ind. Ltd, Sanofi- to come. Am J Hum Genet 2010; 86: 621–625.Aventis, Merck Serono, Bayer Schering, Actelion. 13. Ayyadurai VA and Dewey CF. CytoSolve: A scalable compu- Anthony Feinstein has received grant support from the tational method for dynamic integration of multiple molecularMultiple Sclerosis Society of Canada and honoraria from Merck- pathway models. Cell Mol Bioeng 2011; 4: 28–45.Serono, Teva, BayerSchering and Biogen. 14. Campillos M, Kuhn M, Gavin AC, Jensen LJ and Bork P. Raj Kapoor has received personal compensation for activities Drug target identification using side-effect similarity. Sciencewith Bayer Schering, Biogen Idec, Genzyme, Merck Serono, MS 2008; 321: 263–266.Therapeutics, Novartis, and TEVA, and research support from 15. Keiser MJ, Setola V, Irwin JJ, et al. Predicting new molecularNovartis, the MS Society of GB & NI and the National MS targets for known drugs. Nature 2009; 462: 175–181.Society (USA). 16. Dolgin E. Nonprofit disease groups earmark grants for drug Karen Lee, none. repositioning. Nat Med 2011; 17: 1027. Marco Salvetti received lecture fees from Biogen-Dompé, 17. Sormani MP, Bonzano L, Roccatagliata L, Cutter GR, Man-research support from Bayer-Schering, Biogen-Dompé, Merck- cardi GL and Bruzzi P. Magnetic resonance imaging as aSerono, Sanofi-Aventis. potential surrogate for relapses in multiple sclerosis: a meta- Kersten Sharrock, none. analytic approach. Ann Neurol 2009; 65: 268–275. Alan Thompson has received honoraria/support for travel for 18. Barkhof F, Calabresi PA, Miller DH and Reingold SC.consulting from BTG International, Biogen Idec, Merck Serono, Imaging outcomes for neuroprotection and repair in multipleEisai Ltd, Novartis, and honoraria and support for travel for teach- sclerosis trials. Nat Rev Neurol 2009; 5: 256–266.ing from Serono Symposia International Foundation. 19. Fox RJ, Cronin T, Lin J, et al. Measuring myelin repair and Ahmed Toosy, none. axonal loss with diffusion tensor imaging. Am J Neuroradiol Paola Zaratin, none. 2011; 32: 85–91. Kim Zuidwijk, none. 20. Inglese M, Madelin G, Oesingmann N, et al. Brain tissue sodium concentration in multiple sclerosis: a sodium imagingReferences study at 3 tesla. Brain 2010; 133: 847–857. 1. Lublin FD and Reingold SC. Defining the clinical course of 21. Paling D, Golay X, Wheeler-Kingshott C, Kapoor R and multiple sclerosis: results of an international survey. Neurology Miller D. Energy failure in multiple sclerosis and its investi- 1996; 46: 907–911. gation using MR techniques. J Neurol 2011; 258: 2113–2127. 2. Antel J, Antel S, Caramanos Z, Arnold D and Kuhlmann T. 22. Owen DR, Piccini P and Matthews PM. Towards molecular Primary progressive multiple sclerosis: part of the MS disease imaging of multiple sclerosis. Mult Scler 2011; 17: 262–272. spectrum or separate disease entity? Acta Neuropathol (Berl) 23. Sellebjerg F, Bornsen L, Khademi M, et al. Increased cere- 2012; (Epub ahead of print). brospinal fluid concentrations of the chemokine CXCL13 in 3. Kapoor R, Furby J, Hayton T, et al. Lamotrigine for neuro- active MS. Neurology 2009; 73: 2003–2010. protection in secondary progressive multiple sclerosis: a ran- 24. Rejdak K, Eikelenboom MJ, Petzold A, et al. CSF nitric oxide domised, double-blind, placebo-controlled, parallel-group metabolites are associated with activity and progression of trial. Lancet Neurol 2010; 9: 681–688. multiple sclerosis. Neurology 2004; 63: 1439–1445. 4. Kipp M, van der Star B, Vogel D, et al. Experimental in vivo 25. Gunnarsson M, Malmestrom C, Axelsson M, et al. Axonal and in vitro models of multiple sclerosis: EAE and beyond. damage in relapsing multiple sclerosis is markedly reduced by Multiple Sclerosis and Related Disorders 2012; 1: 15–28. natalizumab. Ann Neurol 2011; 69: 83–89. 5. Pachner AR. Experimental models of multiple sclerosis. 26. Riddell C, Zhao Y and Petkau A. An adaptive clinical trial Curr Opin Neurol 2011; 24: 291–299. design for a sensitive subgroup examined in the multiple 6. 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  • 59. 1540 Multiple Sclerosis Journal 18(11) secondary progressive multiple sclerosis. Mult Scler 2011; 17: (CAMS study): multicentre randomised placebo-controlled 81–88. trial. Lancet 2003; 362: 1517–1526. 28. Kurtzke JF. Rating neurologic impairment in multiple scle- 36. Goodman AD, Brown TR, Krupp LB, et al. Sustained-release rosis: An expanded disability status scale (EDSS). Neurology oral fampridine in multiple sclerosis: a randomised, double- 1983; 33: 1444–1452. blind, controlled trial. Lancet 2009; 373: 732–738. 29. Noseworthy JH, Vandervoort MK, Wong CJ, Ebers GC and 37. Ehde DM, Kraft GH, Chwastiak L, et al. Efficacy of parox- the Canadian Cooperative MS Study Group. Interrater vari- etine in treating major depressive disorder in persons with ability with the expanded disability status scale (EDSS) and multiple sclerosis. Gen Hosp Psychiatry 2008; 30: 40–48. functional systems (FS) in a multiple sclerosis clinical trial. 38. Mohr DC, Boudewyn AC, Goodkin DE, Bostrom A and Neurology 1990; 40: 971–975. Epstein L. Comparative outcomes for individual cognitive- 30. Rudick R, Antel J, Confavreux C, et al. Recommendations behavior therapy, supportive-expressive group psychother- from the National Multiple Sclerosis Society clinical out- apy, and sertraline for the treatment of depression in multiple comes assessment task force. Ann Neurol 1997; 42: 379–382. sclerosis. J Consult Clin Psychol 2001; 69: 942–949. 31. Cohen J, Reingold S, Polman C and Wolinsky J. Trials 39. Korostil M and Feinstein A. Anxiety disorders and their clini- obotIACoC and Sclerosis iM. Disability outcome measures cal correlates in multiple sclerosis patients. Mult Scler 2007; in multiple sclerosis clinical trials: current status and future 13: 67–72. prospects. Lancet Neurol 2012; (in press). 40. Pantano P, Mainero C and Caramia F. Functional brain reor- 32. Miller DM and Allen R. Quality of life in multiple sclerosis: ganization in multiple sclerosis: evidence from fMRI studies. determinants, measurement, and use in clinical practice. Current J Neuroimaging 2006; 16: 104–114. Neurology & Neuroscience Reports 2010; 10: 397–406. 41. Rocca MA, Colombo B, Falini A, et al. Cortical adaptation in 33. U.S. Food and Drug Administration. Guidance for industry patients with MS: a cross-sectional functional MRI study of patient-reported outcome measures: Use in medical prod- disease phenotypes. Lancet Neurol 2005; 4: 618–26. uct development to support labeling claims. http://www.fda. 42. Morgen K, Kadom N, Sawaki L, et al. Training-dependent gov/Drugs/GuidanceComplianceRegulatoryInformation/ plasticity in patients with multiple sclerosis. Brain 2004; 127: Guidances/default.htm. Silver Spring, MD: Office of Com- 2506–2517. munications, Division of Drug Information, Food and Drug 43. Penner I, Opwis K and Kappos L. Relation between functional Administration, 2009. brain imaging, cognitive impairment and cognitive rehabilitation 34. Thompson AJ, Toosy AT and Ciccarelli O. Pharmacologi- in patients with multiple sclerosis. J Neurol 2007; 254, Suppl 2: cal management of symptoms in multiple sclerosis: current 1153–1157. approaches and future directions. Lancet Neurol 2010; 9: 44. Kim SP, Simeral JD, Hochberg LR, Donoghue JP, Friehs GM 1182–1199. and Black MJ. Point-and-click cursor control with an intracor- 35. Zajicek J, Fox P, Sanders H, et al. Cannabinoids for treatment tical neural interface system by humans with tetraplegia. IEEE of spasticity and other symptoms related to multiple sclerosis Trans Neural Syst Rehabil Eng 2011; 19: 193–203. Downloaded from msj.sagepub.com at Università degli studi di Pavia on January 17, 201359
  • 60. 60
  • 61. Working Groups Reports presented at the International Progressive MS Collaborative meeting “Research strategy and prioritization discussion involving the Steering Committee and Working Group representatives” held in November 1-2, 2012 At SOFITEL London Heathrow61
  • 62. Experimental models for improved preclinical evaluation of novel therapies Working Group 1 - ReportMain Goal of the Initiative: “To expedite the development of effective disease modifying and symptommanagement therapies for progressive forms of multiple sclerosis”Goal of our working group: “To devise models for improved preclinical evaluation of novel therapies”Definitions:• progMS: “progressive MS” for the purposes of this exercise, we are lumping SPMS and PPMS into , a single group reflecting the progressive, minimally inflammatory stage of MS. The assumption is that both forms are pathophysiologically similar, and the resulting models will be used to reflect both types. This assumption remains to be proven.Premises:a) in contrast to the vast accumulated knowledge of immunobiology of RRMS, very little is known of mechanisms of progMS.b) current MS therapeutics, all aimed at immune modulation/anti-inflammation appear to be ineffective in non-inflammatory progMS, and have limited effect on long term progressionc) primary adaptive immune systems (T-& B-cells) should not be the focus of our approach: we assume that this biology plays a very limited role in progMSd) in contrast, innate immunity (e.g. microglia, or yet to be identified subsets of leukocytes) may play a very significant rolee) approach will be initially focused on PPMS: we think it best represents the neurodegenerative the component of MS without the additional (and perhaps confounding) influence of overt peripheral inflammation, current or historical. SPMS vs. PPMS comparisons may be instructive. Additional initial focus will be on primary degenerative mechanisms, rather than failure of repair, recognizing that the balance of both is important for clinical progressionf) we recognize that previous animal modeling in the neurosciences (including in EAE) has suffered from limited internal validity and limited generalizability; however, it is unclear how to mitigate such limitations in this effort 62
  • 63. g) embarking on drug testing (whether re-purposing or de novo) prematurely for progMS is ill-advised given the paucity of mechanistic understanding/rational drug targets. However, we recognize that clinical testing cannot await elucidation of all mechanistic details of progMS: moving to clinical trials therefore needs to be carefully considered vis-à-vis the expected growth in basic knowledge about progMS, and good trial design followed. Preferred initial hypotheses (not in order of importance, not mutually exclusive): 1) mitochondrial abnormalities underlie progressive disease 2) primary myelin abnormalities underlie progressive disease 3) microglial abnormalities drive progressive disease 4) oligos/myelin are the primary initial target of the underlying degenerative “influence” Given the above, we agreed on a plan involving three directions to pursue (some in parallel, some sequential stemming from prior insights) in order to achieve our working group goal: A) Human pathology: which aspects of human pathology in progMS require more study to gain further insight? • review relevant and unique aspects of human progMS pathology, in consultation with expert neuropathologists • are there differences between slow vs. rapid progressors? • human microarray, proteomics, lipidomics, metabolomics in vulnerable pathways: unique aspects? • gray matter lesions/atrophy: primary or secondary to WM disease? Particular attention to neuronal/ synaptic pathology in progMS GM. Unique aspects? • particular attention to: free radical/oxidative damage, mitochondrial pathology • in relation to the specific hypotheses above: 1) mitochondrial pathology: fusion/fission, swelling, number, distribution 2) myelin abnormalities in progMS: examine myelin in PPMS (pathology, proteomics, mass spec, 2D gels, advanced microscopy, human MR/MRS. If abnormalities are found, use this material to induce pathology in vitro/in rodents63
  • 64. 3) microglial abnormalities: are there unique aspects of microglial activation in progMS vis-à-vis synaptic stripping? Myelin abnormalities/phagocytosis? Excitotoxic component?4) examine in greater detail the pathological aspects of oligo/myelin pathology in progMS to try to prove (or disprove) that these elements are primary targets of degenerationB) In vivo models: given that mechanistic information is severely lacking, a reasonable initial approachwill be to examine existing in vivo models, comparing and contrasting with human progMS pathology(not in order of preference/importance).- acute EAE, but studied long-term: what are the late effects of prior inflammation?- chronic EAE (assumes inflammation drives chronic degeneration; guinea pigs)- cuprizone, including aged C57BL/6- lysolecithin- intraspinal LPS demyelination (Felts et al., 2005): “hypoxia-like demyelination”- virus e.g.Theiler’s- genetic models e.g.: • TCR-transgenic (e.g. Goverman et al., 1993): 1° autoimmune • PLP overexpressor (e.g. Ip et al., 2006): 1° biochemical/degenerative • innate inflammation reporter mice (that can be imaged) • inducible restricted demyelinator mice • novel emerging models from labs of some workgroup members TBAComments:- meta-analysis of existing data from studies reporting more than one outcome may help understand the differences between different models and different outcome measures. A formal prospective exercise pooling unpublished data may help validate assertions about the characteristics of existing models in relation to progressive MS- these models should be designed, conducted and reported so as to minimize the risk that findings might be confounded by bias (randomization, blinding, sample size calculation, inclusion and exclusion 64
  • 65. criteria, available study protocol); and consideration might be given to a registration system to get around the problem of publication bias - models should test drugs under clinically relevant circumstances (both sexes, established disease, oral or s.c. administration) - where effect sizes are small (and clinically relevant effect sizes are likely to be small) and where there are concerns about the generalizability of results, we should consider multi-centre Phase 3 animal studies prior to embarking on a clinical trial C) In vitro/cell-based models: to enable mechanistic understanding of progMS, and facilitate molecular dissection of putative disease mechanisms, ex vivo assays may be instructive. - progMS tissue or extracts, applied to cultured cells (neurons, glia, myelinating cultures) - microglial/neuronal ± myelinating co-cultures: examine free radical biology, phagocytosis, stripping, clustering, RNA, miRNA - acute ex vivo slices e.g. dorsal column, optic nerve, examined with ephys, microscopy, to study various degenerative pathways e.g. glutamate receptors, Cu deregulation, axonal Ca stores, free radicals - cultures of neurons, oligos, myelinating co-cultures: cuprizone or equivalent Cu deregulation conditions - spinal cord degenerating slice cultures (from EAE animals) - human post-mortem cultures? Comments: - advantages: more amenable to mechanistic dissection - limitations include inability to model long term processes which are likely most relevant in progMS - a combined approach of studying samples ex vivo taken from chronic in vivo models may partially mitigate such limitations Respectfully submitted by P Stys .K. On behalf of the Experimental models for improved preclinical evaluation of novel therapies Working Group65
  • 66. Target identification and repurposing Working Group 2 - Report1. Unmet needs in the Working Group area of interest (avoid duplications; include a confrontationwith our catalogues of existing spend on progressive MS; confront with other initiatives in thefield).Patients with progressive forms of MS have few treatment options. New therapies can be developed bycareful elucidation of disease mechanism and identification of appropriate targets for intervention. Thisapproach may take many years and has failed, so far, to yield success. Continuation of this approach islikely (and may continue) under existing funding mechanisms.Given the objective of the IPMSC, a different approach should be run in parallel: it would be possibleconsider more active management of the portfolios of the MS organizations. This ‘managed’ portfolioapproach is counter cultural in academic research. However, it may also free resources for the newapproaches.In summary, we propose to add to the “canonical” long-term strategy, based on more traditionalapproaches for the identification of mechanisms susceptible to therapeutic intervention, andfunded under the traditional calls, a short/medium term one, based on pragmatic approachesand areas of research that have been ignored. Only the latter should be the one under theauspices of the IPMSC.Proposal 1.It would be helpful for the MS organizations to make an international catalogue of all existing funding.Such a catalogue could be used by the IPMSC to set international priorities and to highlight areas ofresearch that have been ignored or underfunded.Proposal 2.An alternative approach to finding new treatments is to test existing drugs – the extreme version of thisapproach is to test all drugs without reference to either their current indications or targets. This ‘pragmatic’or ‘serendipitous’ approach has the advantage of speed – any positive result can lead to rapid availabilityof a new treatment. Given the difficulty in making drugs and the importance of safety data, it could be 66
  • 67. argued that this is an important method for finding new therapies. The ‘pragmatic’ approach can be modified by consideration of existing information, for example, new immunomodulating therapies could be tested in MS patients. Since the majority of these trials will fail, it would be important to accompany these attempts with a strategy that allows to store and “recycle” key biological information that may be collected during these trials (at least part of these data should be methodologically standardized and collected on a balanced panel of pathways and molecules that are considered key for neurodegeneration and neuroinflammation). Alternative routes of administration (i.e. CNS delivery technologies), best synergies and timing are all additional and complex aspects that reinforce the need of a coordinated effort. Proposal 3. Develop a strategy for testing as many existing drugs as possible for use in progressive disease. Current attempts to do this are limited by access to patients, costs of clinical trials and expense of on-patent drugs. Start attempts to get, from industry, access to existing drugs and negotiate access to data and samples (if available) that failed in phase 2-3. In addition, start attempts to get access to available “genetic” data and in vitro screening data of registered drugs that are coming from academia and not necessarily only from industry. Ideally, this data integration should extend also to other neurodegenerative or immune- mediated diseases. 2. How other Working Groups may help fill the existing gaps in the Working Group area of interest (i.e. “questions for other Working Groups”). General questions: 1. Do we have the political will to work together for patient benefit? 2. Do we wish to manage the research portfolio? 3. Are we prepared to work with industry if it furthers our aims? Specific questions: 1. Do we have access to appropriate patient groups? 2. Do we have patient registries with patients who are informed and likely to consent to joining trials of experimental therapies?67
  • 68. 3. What is an appropriate clinical design to test multiple drugs?4. What end points should be used?5. Is there any point in testing in existing animal models of disease or should we go straight to man?3. Which international collaborative efforts should be undertaken that justify global funding: a)where money should be spent (research areas, technologies, etc) and why (expected return); b)suggestions for funding models.a) Before taking decisions we need to have a description of the existing portfolio. However, with respectto the above proposals “2” and “3” money may be spent on a cross-national network of centres, devoted ,to develop and perform, in a coordinated way, POC trials on repurposed drugs. A registry of informedgroups of patients may be a complementary initiative.Efforts to identify the best compounds and the best targets must integrate and cross-fertilize each other.An effective way to achieve this result is to gather the growing information on the off-the-shelf effectsor chemical similarities of existing drugs and superimpose it on data/information on plausible targets.A coordinated effort to collect and in-silico elaborate high-quality pathogenetic data (warehouse) to betransferred to in-vitro validation (openness to data sharing increases the chance of favorable evaluation).b) Before describing funding models we need to define what we are trying to do. However, If it is believedthat new ideas are needed, one approach to is the ‘Grand Challenge Exploration Grants’ used by theBill and Melinda Gates Foundation., consideration could be given to stimulating ‘new ideas’ for research.Almost by definition, this means research with higher risk. This is an efficient way of scanning for newresearch ideas from the community.MS Progressive Disease Challenge. Twenty, one year, grants for €50,000. Applications – 2,000 wordswith anonymised review (reviewers unaware of applicant identity). 68
  • 69. IPSMC-WG3: Proof of Concept and Clinical trials Strategies Working Group 3 - Report 1. Unmet needs in the Working Group area of interest WG3 stipulates that patients with progressive forms of MS have few treatment options and that greater focus on developing new disease modifying treatments for progressive forms of MS is need. WG3 has identified three key unmet needs for Proof of Concept (PoC) trials of new agents for progressive MS. These include: 1 What would be the progressive MS equivalent to the 6 month gadolinium-enhancing lesion trials currently used for RRMS POC trials? 2 What metrics might be available for progressive POC and what needs to be developed? 3 What biomarkers need to be developed to aid POC trials? A survey of over 60 key opinion leaders determined that there was a lack of consensus between clinical and imaging outcomes. This likely reflects an insufficient body of data to support use of either clinical or imaging modalities as primary endpoints in PoC trials. 2. How other Working Groups may help fill the existing gaps in the Working Group area of interest 1 How will the activities of WG3 and WG4 be coordinated with other international activities (i.e. NMSS- ECTRIMS International Advisory Committee on Clinical Trials)? 2 How do we incorporate the perspectives of regulatory authorities in development of PoC strategies? 3 How will this activity be influenced by ongoing initiatives such as the review of the Lublin-Reingold clinical course descriptors? 4 How should we incorporate the findings of ongoing PoC trials in SP and PPMS into the planning by WG3? 3. Which international collaborative efforts should be undertaken that justify global funding: a) where money should be spent and why; b) suggestions for funding models.69
  • 70. As a potential next step the group proposes the following strategies:1. Organize an international scientific workshop that would conduct an in-depth exploration of key issues and develop a consensus statement for consideration by the research community.2. Commission a series of opinion/perspectives papers by KOLs to address key issues relevant to PoC clinical trials. Areas to be explored could include:a. Clinical outcomesb. Imaging outcomesc. Fluid Biomarkersd. Patient selection criteria3. Develop an RFP to fund one or more collaborative projects that would:a. Collect data sets that include rate of change in whole brain volume.b. Collect data sets that measure rate of change in grey matter volume.c. Evaluate the utility of these imaging modalities as an outcome measure in proof of concept clinical trials. 70
  • 71. Clinical Outcome measures & Trial Design Working Group 4 - Report 1. Unmet needs A. The selection, and development, of outcome measures for progressive MS relies on clarity of the key clinical variables that are progressing. Work group 3 identified that the field needs a better understanding of exactly what progresses in progressive MS. Specifically, there was felt to be a need to identify, define, and clarify the variables for measurement in clinical trials of progressive MS. B. Successful clinical trials of progressive MS rely on the recruitment and retention of participants. Work group 3 recognized the importance of these issues and the need for research to maximize recruitment and retention. Also, the group recognized that clinical trials would be assisted by the early identification of the progressive phase, and the identification of people with faster progression C. There are many potential clinical trials designs. The group recognized that the field ought to have a full understanding of the pros, cons and implications of the different clinical trial study designs that were available. The group recognized Jeremy Chataway’s work in this area but recommended this was extended, unless it is considered complete. D. It was felt that more could be learned from previous trials in progressive MS 2. How other working groups may help fill the existing gaps/ questions for other groups • The group acknowledged the existing efforts to advance the EDSS and MSFC, were supportive of that work, and recognized this appeared planned and funded. Do others agree? • Pros, cons, and implications of seamless adaptive trial design?71
  • 72. 3. Which international collaborative efforts should be undertaken that justify global fundingA. Clarifying key clinical outcome variables:• Targeted literature reviews• Examination of existing databases • Natural history studies (e.g. London Ontario, Lyon) • NARCOMS • SWIMS • MS UK register • Clinical trials (e.g. lamotrigine, CUPID, simvastatin) • De Novo research aimed at: • Identify, define and clarify key variables for measurement • Determining, for the key variables, their within-and between-person variability, and their progression and trajectories over time. • Research to understand whether to measure single variables of profilesB. Maximising recruitment and retention:• Targeted literature searches• Liaison/networking with other disease group groups• Primary researchC. Clinical trial designs:• Production of a review(s) of all clinical trials designs, pros, cons, and implications in the context of clinical trials of progressive MS• International scientific workshop to explore all possibilities and present a consensus on pros and cons of various designs considered appropriate for progressive MS 72
  • 73. D. Lessons to be learned from trials of progressive MS • Production of a review(s) of all previously conducted clinical trials; pros, cons, and implications for future trials of progressive MS. 4. Funding opportunities There was a concern that standard models of research funding had limitations in relation to the speed at which this work is achievable, and the nature and quality of the work undertaken. The group explored the research funding model established thought the Critical Path Institute, and the formation of consortia to oversee and conduct some aspects of the work proposed. Whilst there is a clear advantage in this approach, there were some concerns that this might not enable open competition.73
  • 74. Symptom management and Rehabilitation strategies Working Group 5 - ReportThe workgroup has chosen to focus on rehabilitation given that needs for collaborative and multi-disciplinary research to improve life of persons with progressive MS seem greater than in the domain ofsymptomatic treatment. However, synergies with research on symptomatic treatment that is in line withthe identified priorities for action, is welcomed.What is known and unknown on progressive MS versus RR?The degree to which the prevalence and severity of symptoms differ between the various types of MS,or whether treatment effects are determined by type of MS is not clear. Most (rehabilitation) interventionshave so far focused on persons with mild and moderate disability while only in recent years, rehabilitationtrials have included larger samples and begun to differentiate effects according to type of MS.It is assumed that, overall, motor and cognitive dysfunction, manifest similarly in different types of MSand that overall greater disability is seen with increasing disease duration (SP and PP). In the cognitivedomain, patients with SPMS appear to be the most impaired especially in processing speed and workingmemory.(1) .Preliminary evidence suggests that depression appears least often in PPMS (ref).Unmet needsThe WG decided to focus on persons with moderate to severe disability, which is mostly associatedwith SP MS and advanced PP MS. Walking, visual function, cognition and mood were valued as mostimportant functions by persons with MS with a disease course longer than 15 years.(2)Ambulatory function is a valuable bodily function, needed ‘to move around effectively in one’s environment’(definition of Mobility, see WHO).Arm function is crucial for effective performance of activities of daily life (ADL). Restriction in physicalcapacities impacts on health indicators (physical fitness) and quality of life (depression, anxiety). In thephysical domain, exercise therapy has been shown to be effective at different levels of the ICF model(International Classification of Functioning) in low EDSS ranges (EDSS≤4,5), while research in higherEDSS levels is sparse.(3; 4) The same is true for cognitive rehabilitation, which has tended to targetmemory. This treatment should be distinguished from cognitive behavioral therapy (CBT) which focuses 74
  • 75. on depression. Here, studies have again recruited patients with RRMS and lesser degrees of disability. On the other hand, tentative evidence suggests antidepressant medication may be effective irrespective of disease course. (5) Investigating the interaction effects between physical training, cognitive function and mood/behavior is an additional challenge to optimize effects at different ICF levels. Another challenge relates to optimal treatment modalities. As not all patients have equal access to specialized treatment, it is also important to develop programs that can be effective in persons with MS living in the community. Note. One may argue that fatigue, as well as tremor and ataxia are overall most disabling symptoms without effective treatment so far. However, we have chosen to focus on unmet clinical needs that can be addressed with a relative high chance on success with collaborative efforts. However, progress in these domains is also possible (e.g. tremor and ataxia, when augmenting the standard of rigorous and valid assessment including functionality). What is recommended and what are the actions? Based on the above, we propose actions of collaborative research in the domain of physical and behavioral rehabilitation for persons with a more advanced stage of the disease (i.e. EDSS ≥ 5). The following questions will be addressed: • Can improvement in physical function, cognition and mood be achieved given accumulating degeneration of the nervous system in this patient group? Is there still restorative function, and can responders be identified (cognitive, behavioral and neurophysiological)? • Can effects of physical and behavioral management be reached at all levels of the ICF (international classification of functioning)? In other words, are changes exceeding function and activity level, and clinical meaningful for the person in his home and community setting? • Does exercise impact on fatigue, mood and cognitive function? Can mood and cognitive function at baseline predict which patients will respond optimally to the exercise treatment.75
  • 76. • What do pwMS in more advanced stage of the disease see as a useful goal, and what is the optimal treatment regime and delivery mode of training to achieve this? o At what point can effects be reached, and how can it be maintained? o Are there treatment modalities that are more appropriate for this population? This includes the investigation of innovative rehabilitation technology both for gait and arm function. o Can physical training also be harmful if too intensive?The following links with other working groups should ne considered: • WG1. Research in EAE can also include studies on exercise therapy, and different dosages of therapy, duration and delivery modes. The EAE model can facilitate exploration of the effects of exercise therapy on the CNS and potentially disease progression. This information may then be mirrored to some degree by studies in human subjects. • WG 2. Exercise trials may benefit from updated guidelines on clinical trials, that may be partly implemented in rehabilitation research. • WG 3. There is a need for a better understanding of the psychometric properties of mobility outcome measures in more advanced MS, and the clinical relevance of these measures. Guidance on methodology on responder analyses as well as handling of drop-out data would also be beneficial. • The research on the restorative potential of training could be addressed by neurophysiological research, to identify responders. • Exploring the relationship between behavioral changes and neural plasticity will be an important element of the program. Can structural and functional brain imaging provide clues as to which patients may benefit from intensive cognitive rehabilitation and cognitive behavioral therapy? • Does antidepressant medication confer benefits beyond improving mood? Preliminary data suggests the use of SSRI medication may improve diffusion tensor indices of brain pathology. 76
  • 77. PART 3.Which international collaborative efforts should be undertaken that justify global funding: a) where money should be spent (research areas, technologies, etc.) and why (expected return) We have identified priorities for collaborative research in part 1, section ‘actions’ . b) suggestions for funding models. • Collaborative funding models: Funding for meetings between researchers to o Identify existing research databases on the recommended topics and how to undertake efforts to merge them with focus on meta-analyses to be performed taking type of MS into account. o Develop experimental designs to be conducted in a multi-disciplinary (and multi-center) approach (depending on the expertise already present in the groups) in preparation of research grant applications (see below) • Research funding models Funding to conduct multiple (multi-center) studies in different countries and settings • Develop a framework for industry-generated research in the identified area of interest. One can stimulate industry to integrate rehabilitation interventions in their experimental designs (additional effects of rehabilitation or symptomatic treatment). • Network organizations as RIMS and CMSC may be contacted for o Dissemination of the priorities put forward by the MS collaborative o Identify core researchers and practitioners that may be consulted o Direct their funding programs, albeit limited, to the recommendations of the progressive collaborative.77
  • 78. Reference List(1) Langdon DW. Cognition in multiple sclerosis. Curr Opin Neurol 2011 Jun;24(3):244-9.(2) eesen C, Bohm J, Reich C, Kasper J, Goebel M, Gold SM. Patient perception of bodily functions in H multiple sclerosis: gait and visual function are the most valuable. Mult Scler 2008 Aug;14(7):988-91.(3) Snook EM, Motl RW. Effect of exercise training on walking mobility in multiple sclerosis: a meta¬analysis. Neurorehabil Neural Repair 2009 Feb;23(2):108-16.(4) Dalgas U, Stenager E, Ingemann-Hansen T.Multiple sclerosis and physical exercise: recommendations for the application of resistance-, endurance-and combined training. Mult Scler 2008;14(1):35-53.(5) Feinstein A. Multiple sclerosis and depression. Mult Scler 2011 Nov;17(11):1276-81. 78
  • 79. Participants79
  • 80. Maria Abbracchio Francesca AloisiUniversity of Milan Istituto Superiore di SanitàVia Balzaretti 9 Viale Regina Elena 299Milan, 20133 Rome, 00161ITALY ITALYEmail: mariapia.abbracchio@unimi.it Email: fos4@iss.itRoberta Amadeo Maria Pia AmatoCommittee of People with MS (Chair) Dept. of Neurology University ofItalian MS Society Florencevia Operai 40 Viale Morgagni 85Genova, 16149 Florence, 50134ITALY ITALYEmail: r.amadeo@aism.it Email: mariapia.amato@unifi.itJack Antel David BakerMcGill University Queen Mary University of London3801 University 111 Blizard InstituteMontreal, QC H3A 2B4 London, N22 6JGCANADA UNITED KINGDOMEmail: jack.antel@mcgill.ca Email: david.baker@qmul.ac.ukPeer Baneke Brenda BanwellMS International Federation (CEO) The Children’s Hospital of PhiladelphiaSkylineHhouse 34th St. & Civic Center Blvd.200 Union Street Philadelphia, PA 19104London, HP6 5HD UNITED STATESUNITED KINGDOM Email: banwellb@email.chop.eduEmail: pbaneke@msif.org 80
  • 81. Sergio Baranzini Frederik Barkhof University of California San Francisco Vu University Medical Center 513 Parnassus Ave De Boelelaan 1117 Room S-256 Amsterdam, 1081 HV San Francisco, CA 94143 THE NETHERLANDS UNITED STATES Email: f.barkhof@vumc.nl Email: sebaran@cgl.ucsf.edu Mario Alberto Battaglia Luca Battistini Italian MS Foundation (Chair) Fondazione Santa Lucia Via Operai, 40 Via del Fosso di Fiorano 63-65 Genova, 16149 Via Ardeatina 306 ITALY Rome, 00143 Email: presidenza@aism.it ITALY Email: l.battistini@hsantalucia.it Bruce Bebo Matthew Bellizzi National MS Society University of Rochester Research Programs Department 601 Elmwood Ave Box 645 5958 Bryant Rd Rochester, NY 14642 Lake Oswego, OR 97035 UNITED STATES UNITED STATES Email: Email: bruce.bebo@nmss.org matthew_bellizzi@urmc.rochester.edu Andrew Blight Dennis Bourdette Acorda Therapeutics, Inc. Oregon Health & Science University 420 Saw Mill River Road Depatment of Neurology L226 Ardsley, NY 10502 3181 SW Sam Jackson Park Road UNITED STATES Portland, OR 97239 Email: ablight@acorda.com UNITED STATES Email: bourdett@ohsu.edu81
  • 82. Amy Bowen Giampaolo BrichettoMS Trust Italian MS SocietySpirella Building Research DepartmetBridge Road Via Operai, 40Letchworth, Hertfordshire SG6 4ET Genova, 16149UNITED KINGDOM ITALYEmail: amy.bowen@mstrust.org.uk Email: giampaolo.brichetto@aism.itHeather Brown Wolfgang BrückThe Lancet Neurology University Medical Center Göttingen,32 Jamestown Road Department of NeuropathologyCamden, London NW1 7BY Robert-Koch-Str. 40UNITED KINGDOM Göttingen, Lower Saxony 37075Email: heather.brown@lancet.com GERMANY Email: wbrueck@med.uni-goettingen.deSteven Buchsbaum Peter CalabresiBill and Melinda Gates Foundation Johns Hopkins500 Fifth Ave North Pathology 627Seattle, WA 98119 600 N. Wolfe St.UNITED STATES Baltimore, MD 21287Email: UNITED STATESSteven.Buchsbaum@gatesfoundation.org Email: calabresi@jhmi.eduCathy Carlson William CarrollNational MS Society Department of NeurologyResearch Information Sir Charles Gairdner Hospital Nedlands733 Third Avenue 3rd Floor Western AustraliaNew York, NY 10017 Email: wm.carroll@me.comUNITED STATESEmail: cathy.carlson@nmss.org 82
  • 83. Niamh Cawley Diego Centonze University College London Tor Vergata University UCL Institute Of Neurology Viale Oxford 81 Dept Brain Repair & rehabilitation Roma, Lazio 00133 Queen Square, London ITALY London, WC1N 3BG Email: centonze@uniroma2.it UNITED KINGDOM Email: n.cawley@ucl.ac.uk Siddharthan Chandran Jeremy Chataway The University of Edinburgh National Hospital for Neurology and Centre for Clinical Brain Sciences Neurosurgery Chancellor’s Building, Queen Square 49 Little France Crescent, London, WC1N 3BG Edinburgh, Midlothian EH16 4SB UNITED KINGDOM UNITED KINGDOM Email: jeremychataway@gmail.com Email: siddharthan.chandran@ed.ac.uk Dhia Chandraratna Peter Chin Research Department Novartis MS International Federation 1 Health Plaza 200 Union Street East Hanover, NJ 07936 London, SA70 7PU UNITED STATES UNITED KINGDOM Email: peter.chin@novartis.com Email: dhia@msif.org Olga Ciccarelli Timothy Coetzee University College London Research Preograms Department Institute of Neurology National MS Society Queen Square 733 Third Avenue London, WC1N 3BG New York, NY 10017 UNITED KINGDOM UNITED STATES Email: o.ciccarelli@ucl.ac.uk Email: timothy.coetzee@nmss.org83
  • 84. Jeffrey Cohen Bruce CohenCleveland Clinic Department of NeurologyMellen Center Northwestern University,9500 Euclid Ave 710 North Lake Shore DriveCleveland, OH 44195 Abbott Hall 1121 Chicago, IL 60611UNITED STATES UNITED STATESEmail: cohenj@ccf.org Email: bac106@northwestern.eduGiancarlo Comi Stephen Joel CoonsScientific Institute San Raffaele Critical Path InstituteVia Olgettina, 48 1730 E River RoadMilan, 20132 Tucson, AZ 85718ITALY UNITED STATESEmail: comi.giancarlo@hsr.it Email: sjcoons@c-path.orgJorge Correale Matt CranerRaul Carrea Institute for Neurological University of OxfordResearch FLENI MS Clinical Trials UnitMontañeses 2325 John Radcliffe HospitalBuenos Aires, 1426 Oxford, OX3 9DUARGENTINA UNITED KINGDOMEmail: jcorreale@fleni.org.ar Email: matthew.craner@ndcn.ox.ac.ukAnne Cross Francesco CuccaWashington University Sch Medicine Consiglio Nazionale delle RicercheCampus Box 8111; 660 S. Euclid Istituto di Ricerca Genetica e BiomedicaAvenue Cittadella UniversitariaDepartment of Neurology Monserrato, 09042St. Louis, MO 63110 ITALYUNITED STATES Email: foddisimona73@gmail.comEmail: crossa@neuro.wustl.eduEmail: cutterg@prodigy.net 84
  • 85. Gary Cutter Sandra D’ lfonso A University of Alabama at Birmingham A Avogadro University 1665 University Blvd Via Solaroli 17 Ryals Public Health Building 414 Novara, 28100 Birmingham, AL 35243 ITALY UNITED STATES Email: dalfonso@med.unipmn.it Ulrik Dalgas Chiara Damico Aarhus University Italian MS Society Dalgas Avenue 4 Research Department Aarhus, Jylland 8000 Via Operai 40 DENMARK Genoa, 16149 Email: dalgas@sport.au.dk ITALY Email: chiara.damico@aism.it Gabriele Dati Philip De Jager Italian MS Society Brigham and Women’s Hospital Research Department 77 Ave Louis Pasteur, NRB168 Via Operai 40 Boston, MA 02115 Genoa, 16149 UNITED STATES ITALY Email: pdejager@rics.bwh.harvard.edu Email: gabriele.dati@aism.it Brigit De Jong Nicola De Stefano University Nijmegen Medical Centre University of Siena St Radboud Viale Bracci 2 Ubbergseveldweg 85 Siena, Tuscany 53100 Nijmegen, Gelderland 6522 HD ITALY THE NETHERLANDS Email: destefano@unisi.it Email: b.jong@neuro.umcn.nl85
  • 86. Elga De Vries John DeLucaDept. of Molecular Cell Biology and Kessler FoundationImmunology 1199 Pleasant Valley WayP.O.Box 7057 West Orange, NJ 07052Amsterdam, 1007MV UNITED STATESTHE NETHERLANDS Email: jdeluca@kesslerfoundation.orgEmail: he.devries@vumc.nlNicoletta Di Giambattista Ricarda DiemItalian MS Society University Clinic HeidelbergFund Raising Department Dep. of NeurooncologyVia Operai 40 Im Neuenheimer Feld 400Genoa, 16149 Heidelberg, Baden-Württemberg 66120ITALY GERMANYEmail: nicoletta.digiambattista@aism.it Email: ricarda.diem@med.uni-heidelberg.deMonica DiLucaEuropean Brain Council Giulio DisantoFondation Universitaire University of OxfordUniversity of Milano Le Gros Clark Buildingvia Balzaretti, 9 South Parks RoadMilano, 20133 Oxford, OX1 3QXITALY UNITED KINGDOMEmail: monica.diluca@unimi.it Email: giulio.dis@gmail.comRanjan Dutta Barbara ErbaCleveland Clinic Italian MS Society9500 Euclid Avenue, NC-30 Communication DepartmentCleveland, OH 44118 Via Operai 40UNITED STATES Genoa, 16149Email: duttar@ccf.org ITALY Email: barbaraerba@gmail.com 86
  • 87. Nikolaos Evangelou Anthony Feinstein Nottingham University University of Toronto 3 Castle Grove Sunnybrook Health Sciences Centre The Park Department of Psychiatry Nottingham, NG8 1DN Toronto, ON M4N3M5 UNITED KINGDOM CANADA Email: nikos.evangelou@nottingham.ac.uk Email: ant.feinstein@utoronto.ca Chiara Fenoglio Peter Feys University of Milan, IRCCS Cà Granda Hasselt University Foundation Ospedale Maggiore Policlinico Agoralaan Gebouw A via F. Sforza 35 Diepenbeek, 3590 Milan, 20122 BELGIUM ITALY Email: Peter.Feys@uhasselt.be Email: chiara.fenoglio@unimi.it Charles Ffrench-Constant Massimo Filippi MRC Centre for Regenerative Medicine San Raffaele Scientific Institute and University of Edinburgh Vita-Salute San Raffaele University Edinburgh boQuarter Via Olgettina, 60 5 Little France Drive Milan, 20132 Edinburgh, Midlothian EH164UU ITALY UNITED KINGDOM Email: filippi.massimo@hsr.it Email: cffc@ed.ac.uk Elizabeth Fisher Matteo Floris Cleveland Clinic Consiglio Nazionale delle Ricerche Department of Biomedical Eng’g ND20 CRS4 9500 Euclid Avenue Parco Polaris Cleveland, OH 44121 Loc. Pixinamanna UNITED STATES Pula, Sardinia 09077 Email: fishere@ccf.org ITALY Email: floris@crs4.it87
  • 88. Robert Fox Jennifer FreemanCleveland Clinic Plymouth University9500 Euclid Ave, U-10 Peninsula Allied Health CentreCleveland, OH 44195 Derriford RdUNITED STATES Plymouth, Devon PL6 8BHEmail: foxr@ccf.org UNITED KINGDOM Email: jenny.freeman@plymouth.ac.ukGordon Francis Marta FumagalliNovartis Università degli Studi di Milano1451 Montgomery St #1 Balzaretti 9San Francisco, CA 94133 Milan, 20133UNITED STATES ITALYEmail: gordon.francis@novartis.com Email: marta.fumagalli@unimi.itLars Fugger Roberto FurlanUniversity of Oxford Ospedale San RaffaeleWeatherall Institute of Molecular Via Olgettina, 60Medicine Milano, 20132John Radcliffe Hospital ITALYOxford, OX3 9DS Email: furlan.roberto@hsr.itUNITED KINGDOMEmail: lars.fugger@imm.ox.ac.ukGiuseppe Gazzola Daniela GalimbertiItalian MS Society University of Milan, Ospedale PoliclinicoCommunication Department via F. Sforza 35Via Operai 40 Milan, 20122Genoa, 16149 ITALYITALY Email: daniela.galimberti@unimi.itEmail: giuseppe.gazzola@aism.it 88
  • 89. Gavin Giovannoni Jeroen Geurts, Queen Mary University of London VU University Medical Center The Royal London Hospital Van der Boechorststraat 7 White Chapel Amsterdam, 1082 MS London, E1 1BB THE NETHERLANDS UNITED KINGDOM Email: j.geurts@vumc.nl Email: g.giovannoni@qmul.ac.uk Susan Goelz Peter Goodfellow MS Society 14 Parliament Hill 6900 SE 35th Ave London, NW3 2SY Portland, OR 97202 UNITED KINGDOM UNITED STATES Email: pngoodfellow@yahoo.co.uk Email: susanegoelz@gmail.com John Golding Andrew Goodman. European MS Platform University of Rochester Groenliveien 21 601 Elmwood Avenue Fredrikstad, 1605 Rochester, NY 14618 NORWAY UNITED STATES Email: john@golding.no Email: andrew_goodman@urmc. rochester.edu Roberta Guglielmino Päivi Hämäläinen Italian MS Society Masku Neurological Rehabilitation Research Department Centre Via Operai 40 Vaihemäentie 10 Genoa, 16149 Masku, 21250 ITALY FINLAND Email: roberta.guglielmino@aism.it Email: paivi.hamalainen@ms-liitto.fi89
  • 90. Hans-Peter Hartung Liat HayardenyHeinrich-Heine-University Teva PharmaceuticalsMoorenstr. 5 37 Yehuda Hanasie stDept. of Neurology Tel Aviv, 69391Duesseldorf, NRW 40225 ISRAELGERMANY Email: liat.hayardeny@teva.co.ilEmail:hans-peter.hartung@uni-duesseldorf.deChristoph Heesen Thomas HenzeUniversity Medical Center Hamburg Reha-Zentrum NittenauMartinistrasse 52 Eichendorffstr. 21Hamburg, 20246 Nittenau, Bavaria 93149GERMANY GERMANYEmail: heesen@uke.uni-hamburg.de Email: t.henze@online.deJeremy Hobart Rogier HintzenPlymouth University Peninsula Schools of Erasmus MCMedicine & Dentistry sgavendijkwal 230Room N13, ITTC Building, Rotterdam, 3015GD1 Davy Road THE NETHERLANDSTamar Science Park Email: r.hintzen@erasmusmc.nlPlymouth, Devon PL6 8BXUNITED KINGDOMEmail: jeremy.hobart@pms.ac.ukLynn Hudson Edward HollowayCritical Path Institute UK MS Society1730 E River Road Research DepartmentTucson, AZ 85718 MS National CentreUNITED STATES 372 Edgware RoadEmail: lhudson@c-path.org London, NW2 6ND UNITED KINGDOM Email: nhenry@mssociety.org.uk 90
  • 91. Matilde Inglese Weyman Johnson Mount Sinai School of Medicine MS International Federation (Chair) One Gustave L. Levy Place Box 1137 249 Crooked Creek Lane New York, NY 10029 Athens, GA 30607 UNITED STATES UNITED STATES Email: matilde.inglese@mssm.edu Email: weymanjohnson@paulhastings.com Timm Jessen Ludwig Kappos Bionamics plc University Hospital Basel Gottorfstrasse 3 Petersgraben 4 Schleswig, 24837 Basel, 4031 GERMANY SWITZERLAND Email: jessen@bionamics.de Email: lkappos@uhbs.ch Raj Kapoor Hans Lassmann National Hospital for Neurology Medical University of Vienna Queen Square Spitalgasse 4 London, WC1N 3BG Wien, A-1090 UNITED KINGDOM AUSTRIA Email: r.kapoor@nhs.net Email: hans.lassmann@meduniwien.ac.at Bernd Kieseier Heinrich-Heine-University Karen Lee Moorenstrasse 5 MS Society of Canada Düsseldorf, NRW 40225 Research Department GERMANY 175 Bloor Street East Email: Bernd.kieseier@uni-duesseldorf.de North Tower, Suite 700 Toronto, ON M4W 3R8 CANADA Email: karen.lee@mssociety.ca91
  • 92. Letizia Leocani John LincolnSan Raffaele Scientific Institute University of Texas, UT HealthVia Olgettina n. 60 6310 Almeda RoadMilan, 20132 Apt. 1219ITALY Houston, TX 77021Email: leocani.letizia@hsr.it UNITED STATES Email: John.A.Lincoln@uth.tmc.eduDavid Leppert Catherine LubetzkiF. Hoffmann-La Roche AG University Pierre and Marie CurieGrenzacherstrasse 124 Salpetriere HospitalBasel, 4070 47 Bd de l’Hopital,SWITZERLAND Paris, 75013,Email: david.leppert@roche.com FRANCE Email: catherine.lubetzki@upmc.frAlbert Lo Paola LustroBrown-VA Italian MS Society255 Promenade Street Communication DepartmentUnit 630 Via Operai 40Providence, RI 02908 Genoa, 16149UNITED STATES ITALYEmail: Albert_Lo@brown.edu Email: paola.lustro@aism.itClaudia Lucchinetti Malcolm MacleodMayo Clinic University of Edinburgh200 First Street SW Western General HospitalRochester, MN 55905 Crewe RoadUNITED STATES Edinburgh, EH4 2XUEmail: clucchinetti@mayo.edu UNITED KINGDOM Email: malcolm.macleod@ed.ac.uk 92
  • 93. Giovanni Mancardi Filippo Martinelli Boneschi University of Genoa Scientific Institute San Raffaele Largo P Daneo,3 - 16132 . Via Olgettina 48 Genoa, 16132 Milan, 20132 ITALY ITALY Email: glmancardi@neurologia.unige.it Email: martinelli.filippo@hsr.it Enrica Marcenaro Donna Masterman Italian MS Society Roche Communication Department Grenzacherstrasse 183 Via Operai 40 Bay 074/3W.306B Genoa, 16149 Basel, 4070 ITALY SWITZERLAND Email: enrica.marcenaro@aism.it Email: donna.masterman@roche.com Gianvito Martino Paul Matthews San Raffaele Hospital Imperial College/GlaxoSmithKline Via Olgettina, 58 Hammersmith Hospital, Burlingdon Danes Milan, 20132 DuCane Road ITALY London, W12 0NN Email: martino.gianvito@hsr.it UNITED KINGDOM Email: p.matthews@imperial.ac.uk Victoria Matthews Graham McReynolds Rehabilitation in MS - RIMS National MS Society 28 Riverside Gardens 2003 SE Larch Ave. Romsey, SO51 8HN Portland, OR 97214 UNITED KINGDOM UNITED STATES Email: vickimatthews28@gmail.com Email: graham.mcreynolds@nmss.org93
  • 94. Jan Meilof David MillerDpt Neurology, University Medical University College LondonCenter UCL Institute of NeurologyMS-Centre Northern Netherlands NMR Research UnitGroningen Queen SquarePO Box 30001 London, WC1N 3BGGroningen, 9700RB UNITED KINGDOMTHE NETHERLANDS Email: david.h.miller@ucl.ac.ukEmail: meilofjf@mzh.nlMary Milgrom Antonella MorettiNational MS Society Italian MS Society (CEO)900 South Broadway Via Operai 40Denver, CO 80209 Genoa, 16149UNITED STATES ITALYEmail: mary.milgrom@nmss.org Email: relest@aism.itXavier Montalban Robert MotlCemcat - Vall d’Hebron University University of Illinois at Urbana-ChampaignHospital 906 S. Goodwin AveEdifici Cemcat - Vall d’Hebron Urbana, IL 61801University Hospital UNITED STATESPg. Vall d’Hebron, 119-129 Email: robmotl@illinois.eduBarcelona, 08035SPAINEmail: xavier.montalban@cem-cat.orgFrancesco Mori Paolo MuraroUniversità Tor Vergata Imperial College Londonviale Oxford 81 Burlington Danes Buiding, Imperial CollegeRoma, 00133 Du Cane RoadITALY London, W12 0NNEmail: francesco808@virgilio.it UNITED KINGDOM Email: p.muraro@imperial.ac.uk 94
  • 95. Ceri Napier Lucia Palmisano MS International Federation Istituto Superiore di Sanità 3rd Floor, Skyline House Viale Regina Elena 299 200 Union Street Rome, 00161 London, SE1 0LX ITALY UNITED KINGDOM Email: l.palmisano@iss.it Email: ceri@msif.org Jiwon Oh Graziano Pesole Johns Hopkins University University of Bari and IBBE-CNR 600 N. Wolfe St. via Amendola 165/A Pathology Building, Room 627 Bari, 70125 Baltimore, MD 21287 ITALY UNITED STATES Email: graziano.pesole@uniba.it Email: jioh@jhsph.edu Michael Panzara Laura Piccio Genzyme Washington University in St Louis 500 Kendall St 660 South Euclid, Campus box 8111 Cambridge, MA 02142 St Louis, MO 63110 UNITED STATES UNITED STATES Email: michael.panzara@genzyme.com Email: picciol@neuro.wustl.edu John Petkau University of British Columbia Chris Polman Department of Statistics VU Medical Centre 3182 Earth Sciences Building Boelelaan 1117 2207 Main Mall Amsterdam, 1081HV Vancouver, BC V6T 1Z4 THE NETHERLANDS CANADA Email: ch.polman@vumc.nl Email: john@stat.ubc.ca95
  • 96. Michela Ponzio Marco PrinzItalian MS Society University of FreiburgResearch Department Breisacherstr. 64Via Operai 40 Freiburg, D-79100Genoa, 16149 GERMANYITALY Email: marco.prinz@uniklinik-freiburg.deEmail: michela.ponzio@aism.itCarlo Pozzilli Sreeram RamagopalanSapienza University of Rome Queen Mary University of LondonViale dell’Universita’ 30 Blizard instituteRoma, 00185 4 Newark StreetITALY London, E1 2ATEmail: carlo.pozzilli@uniroma1.it UNITED KINGDOM Email: sreeram@ramagopalan.netMaura Pugliatti Stephen ReingoldUniversity of Sassari Scientific & Clinical Review Associates, LLCViale San Pietro 10 PO Box 342Sassari, 07100 39 Brinton Hill RoadITALY Salisbury, CT 06068-0342Email: mpugliatti@yahoo.com UNITED STATES Email: scra.llc@earthlink.netDaniel Reich Richard ReynoldsNational Institutes of Health Imperial College London10 Center Drive MSC 1400 Division of Brain SciencesBuilding 10 Room 5C103 Hammersmith HospitalBethesda, MD 20012 London, W12 0NNUNITED STATES UNITED KINGDOMEmail: daniel.reich@nih.gov Email: r.reynolds@imperial.ac.uk 96
  • 97. Nancy Richert Bruce Roberts BiogenIdec Genzyme Bio6-6 49 New York Avenue 14 Cambridge Ctr Framingham, MA 01701 Cambridge, MA 02142 UNITED STATES UNITED STATES Email: bruce.roberts@genzyme.com Email: nancy.richert@biogenidec.com Nick Rijke Richard Rudick UK MS Society Cleveland Clinic Research Department 9500 Euclid Ave., JJ36 MS National Centre Cleveland, OH 44195 372 Edgware Road UNITED STATES London, NW2 6ND Email: rudickr@ccf.org UNITED KINGDOM Email: nhenry@mssociety.org.uk Maria Rocca Yves Savoie Ospedale San Raffaele MS Society of Canada (CEO) via Olgettina 60 175 Bloor St E, Suite 700 Milan, 20132 North Tower ITALY Toronto, ON M4W3R8 Email: rocca.mara@hsr.it CANADA Email: yves.savoie@mssociety.ca Marco Salvetti Stephen Sawcer Sapienza University - FISM University of Cambridge S. Andrea Hospital, 1035 via di Addenbrooke’s Hospital, BOX 165 Grottarossa Hills Road Rome, 00189 Cambridge, CB2 0QQ ITALY UNITED KINGDOM Email: marco.salvetti@uniroma1.it Email: sjs1016@mole.bio.cam.ac.uk97
  • 98. Antonio Scalfari Finn SellebjergImperial College Danish Multiple Sclerosis CenterDu Cane road Copenhagen University HospitalHammersmith Hospital RigshospitaletLondon, W12 0NN Blegdamsvej 9UNITED KINGDOM Copenhagen, 2100Email: a.scalfari@imperial.ac.uk DENMARK Email: sellebjerg@dadlnet.dkElio Scarpini Kathryn SmithUniversity of Milan, Ospedale Policlinico Fast Forward (NMSS)via F. Sforza, 35 154 Hamburg RoadMilan, 20122 Lyme, CT 06371ITALY UNITED STATESEmail: elio.scarpini@unimi.it Email: kathryn.ellen.smith@gmail.comKenneth Smith Per Soelberg SorensenUniversity College London Rigshospitalet, Copenhagen UniversityUCL Institute of Neurology HospitalQueen Square Blegdamsvej 9London, WC1N 3BG Copenhagen, DK-2100UNITED KINGDOM DENMARKEmail: k.smith@ion.ucl.ac.uk Email: pss@rh.dkAlessandra Solari Maria Pia SormaniFoundation Neurological Institute University of GenoaC. Besta Via Pastore 1Via Celoria 11 Genoa, 16132Milan, 20133 ITALYITALY Email: mariapia.sormani@unige.itEmail: solari@istituto-besta.it 98
  • 99. Christine Stadelmann-Nessler Anthony Traboulsee University Medical Center, University of British Columbia Neuropathology UBC Hospital Robert-Koch-Str. 40 2211 Wesbrook Mall, room s199 Göttingen, 37099 Vancovuer, BC V6T 2B5 GERMANY CANADA Email: Email: t.traboulsee@ubc.ca cstadelmann@med.uni-goettingen.de Olaf Stuve Sarah Tabrizi University of Texas Southwestern Universitity College London Medical Center UCL Dept of Neurodegenerative Disease Department of Neurology UCL Institute of Neurology 5223 Harry Hines Boulevard, #J3.118 Queen Square Dallas, TX 75390 London, WC1N 3BG UNITED STATES UNITED KINGDOM Email: olaf.suve@utsouthwestern.edu Email: sarah.tabrizi@prion.ucl.ac.uk Peter Stys Luigi Tesio University of Calgary Rehabilitation Medicine 3330 Hospital Dr. Università degli Studi Calgary, AB T2N 4N1 via Giuseppe Mercalli 32 CANADA Milan, 20122 Email: pstys@ucalgary.ca ITALY Email: luigi.tesio@unimi.it Carla Taveggia Alan Thompson San Raffaele Scientific Institute University College London via Olgettina 58 UCL Institute of Neurology, box 9 Milan, 20132 Queen Square ITALY London, WC1N 3BG Email: taveggia.carla@hsr.it UNITED KINGDOM Email: alan.thompson@ucl.ac.uk99
  • 100. Jean-Louis Thonnard Bruce TrappUCLouvain Cleveland Clinic53 avenue Mounier 9500 Euclid AveBrussels, 1200 NC30BELGIUM Cleveland, OH 44195Email: jean-louis.thonnard@uclouvain.be UNITED STATES Email: trappb@ccf.orgMaria Trojano Philippe TruffuinetUniversity of Bari SanofiDepartment of Neurological & Psychiatric 1 Avenue Pierre BrossoletteSciences Chilly-Mazarin, 91385Policlinico Piazza G. Cesare,11 FRANCEBari, 70121 Email: philippe.truffinet@sanofi.comITALYEmail: maria.trojano@uniba.itAntonio Uccelli Bernard UitdehaagUniversity of Genoa VU University Medical CenterLargo P Daneo 3 . P Box 7057 .O.Genoa, 16132 Amsterdam, 1007 MBITALY THE NETHERLANDSEmail: auccelli@neurologia.unige.it Email: bmj.uitdehaag@vumc.nlRenato Umeton Steven Van de PavertCytoSolve Inc. University College London701 Concord Avenue Queen SquareCambridge, MA 02138 London, WC1N 3BGUNITED STATES UNITED KINGDOMEmail: umeton@mit.edu Email: stevenvandepavert@gmail.com 100
  • 101. Emmanuelle Waubant Martin Weber University of California Universitätsmedizin Göttingen San Francisco Robert-Koch Strasse 40 675 Nelson Rising Lane, room 221 Göttingen, Niedersachsen 37075 San Francisco, CA 94158 GERMANY UNITED STATES Email: martin.weber@med.uni-goettingen. Email: emmanuelle.waubant@ucsf.edu de Howard Weiner Lesley White Brigham and Women’s Hospital University of Georgia 77 Avenue Louis Pasteur 500 lacenbark Dr. HIM Bldg Room 730 Athens, GA 30605 Boston, MA 02115 UNITED STATES UNITED STATES Email: ljwhite.home@gmail.com Email: hweiner@rics.bwh.harvard.edu Jonathan Willmer Jerry Wolinsky EMD Serono University of Texas 45A Middlesex Turnpike Health Science Center at Houston Billerica, MA 01821 6431 Fannin Street UNITED STATES Houston, TX 77030 Email: jonathan.willmer@emdserono.com UNITED STATES Email: jerry.s.wolinsky@uth.tmc.edu Cynthia Zagieboylo Scott Zamvil National MS Society University of California 6353 North Avon Road San Francisco Honeoye Falls, NY 14472 675 Nelson Rising Lane, NS-215A UNITED STATES San Francisco, CA 94158 Email: cynthia.zagieboylo@nmss.org UNITED STATES Email: zamvil@ucsf.neuroimmunol.org101
  • 102. Paola Zaratin Tjalf ZiemssenItalian MS Society University Clinic, DresdenResearch Department Via Operai 40 Fetscherstr. 74Genoa, 16149 Dresden, Sachsen 01307ITALY GERMANYEmail: paola.zaratin@aism.it Email: Ziemssen@web.de 102
  • 103. Expense Reimbursement Guidelines & Voucher103
  • 104. EXPENSE REIMBURSEMENT GUIDELINES Revised 2/6/2013IF REQUESTED, reimbursement will be made to meeting participants for travel expenses incurred fortravel to the First Scientific Conference of the International Progressive MS Collaborative. Expensevouchers must be submitted to the National MS Society no later than March 15, 2013.• Boarding passes must be attached to all expense vouchers, regardless of whether you used the Society travel agency. If you need your boarding passes to claim airline miles, a photocopy will suffice.• Receipts are required for all expenses.• Reimbursement will be made in US Dollars only; convert all foreign currency to US$.• We are not set up to accommodate wire transfers/direct deposit, you will receive reimbursement in the form of a US$ check.• If you wish your check to be mailed to your home address, please indicate on the reimbursement form.Allowable Expenses:• Private Automobile: Use of POV is reimbursed at 56.5 cents per mile, plus tolls and parking fees. This amount covers fuel, and other costs associated with the vehicle. Rental car IS NOT authorized for this meeting.• Airfare: Tickets purchased from sources other than our designated agent, ProtravelInc will be reimbursed at the lowest possible rate. Airline tickets must be purchased at least 7 days in advance. Proof of payment and boarding passes are required for reimbursement.• Taxi Fares and Public Transportation will be reimbursed at actual cost plus approximately a 15% tip. Receipts are required for reimbursement. It is expected that care will be taken to travel in the most cost efficient way. Personal transportation e.g. to the theatre or dinner, WILL NOT be reimbursed.• Railroad Fare will be reimbursed at the lowest available rate• Lodgings: The cost of your room and tax will be master billed.• Meals: It is expected that you will use your discretion when purchasing meals not provided during the meetingQuestions relating to reimbursement should be addressed to eileen.madray@nmss.org 104
  • 105. Expense Voucher (Volunteers and Others) Payee: Instructions for Completion Mail my Check to: 1. List expenses by day. 2. Attach original receipts for all expenses claimed 3. Total columns across and at bottom of each column. Name & Date of Meeting 4. Make a copy for your records 5. Sign voucher and submit original International Progressive MS Collaborative with attachments to: FIRST SCIENTIFIC CONFERENCE FEBRUARY 6-8, 2013 Eileen Madray Research Programs Department, NMSS 733 Third Avenue, 3rd Flr Itinerary - From: (City) New York, NY 10017-3288 To: MILAN, ITALY By: MARCH 15, 2013 Dept & Program Date Date Date Date Date Date TOTAL AP 4201 2/5/2013 2/6/2013 2/7/2013 2/8/2013 US $ US$ US$ US$ US$ Airfare Train/Bus Mileage: ____@ 56.5 cents Parking/Tolls Taxi/Airport Bus/Tips Hotel Meals Other: Explain on reverse Totals Amount Claimed I certify that this statement is correct and that expenses Leave Blank: were incurred by me in performance of this meeting. $_____________ Payment Due Payee $_____________ Signature Date For NMSS Use Only Approval: __________________ Research Programs Department Date: _____________ Vendor # ______________________________ Entry Date ______________________ A/P Processing Acct: _____________________ Total $ ________________________ Due Date ___________ Acct. ______________ Check $______________________ Voucher# ___________ Acct. ______________ Date Paid105
  • 106. International Progressive MS Collaborative First Scientific Conference February 6-8, 2013, Milan Italy Expense Reimbursement Form (Page 2 of 2) ExplanationsSunday (Insert Date)MondayTuesdayWednesdayThursdayFridaySaturday 106
  • 107. Edited by Chiara Damico - Italian MS Society107