Ipmsc milan meeting_february2013_booklet

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Ipmsc milan meeting_february2013_booklet

  1. 1. International Progressive Multiple Sclerosis Collaborative First Scientific Conference February 6-8, 2013 San Raffaele Congress Centre, Milan, Italy1
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  3. 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. 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. 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. 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. 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. 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. 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. 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. 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. 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. 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. 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. 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. 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. 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. 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. 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. 21. Abstracts of keynote speakers21
  22. 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. 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. 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. 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. 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. 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. 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. 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. 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. 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. 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. 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. 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. 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. 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. 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. 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. 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. 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. 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. 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. 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. 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. 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. 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. 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. 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. 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

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