Ipmsc milan meeting_february2013_booklet

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International ProgressiveMultiple SclerosisCollaborativeFirst Scientific Conference

February 6-8, 2013San Raffaele Congress Centre, Milan, Italy

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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. The MS Societies from Canada, Italy, the Netherlands, the United Kingdom, and the USA first explained ambitious plans to form an international collaborative for research into progressive MS. Immediately the Board of the MS International Federation (MSIF) responded with enthusiasm. People with progressive MS long for the day that there will be some treatment. People with relapsing remitting MS equally wonder when they will enter this phase and whether by that time that treatment will exist. This event and your participation in it therefore raise hope for all people with and affected by MS. Our efforts together resonate with all MS organisations, whether members of MSIF or not. Of course, this is not work for the short term – and our members know this. We trust that your collective insight and expertise will help refine and consolidate the plans for this crucial research. MSIF, its five members that stood at the root of this effort, and all its member organisations are resolved to build on that to design the fundraising campaigns to contribute to this enterprise. We thank the Italian and US MS Societies for hosting this conference, we thank you for participating, and we wish you all much success. On behalf of Peer Baneke, CEO and Weyman Johnson, Chairman

Presidents Emeriti

Sarah Phillips (UK)

Peter W. Schmidt (USA) Peter A. Schweitzer (USA)

James D. Wolfensohn (USA)

President and Chairman

Weyman T Johnson (USA)

Treasurer

Robert Hubbard (Australia)

Founder

Sylvia Lawry (USA)

Board Members

Mario Battaglia (Italy)

Pedro Carrascal-Rueda (Spain) Sophie Galland-Froger (France)

Simon Gillespie (UK)

John Golding (Norway) Ed Kangas (USA)

Peter Kauffeldt (Denmark)

Daniel Larouche (Canada) Antonella Moretti (Italy)

Dorothea Pitschnau-Michel (Germany)

Chris Polman (Netherlands) Dorinda Roos (Netherlands)

Eli Rubenstein (USA)

Yves Savoie (Canada) Mai Sharawy (Egypt)

Martin Stevens (UK)

Ramkrishna Subbaraman (India) Alan Thompson (UK)

Charles van der Straten Waillet (Belgium)

María José Wuille-Bille (Argentina) Cynthia Zagieboylo (USA)

Honorary Life Board Members Leon Cligman (France)

Alistair M Fraser (Canada)

Jürg Kesselring (Switzerland) Sarah Phillips (UK)

David L Torrey (Canada)

MSIF is an NGO in official relations with the World

Health Organization (WHO)

Registered Charity 1105321

A charity and company limited by guarantee,

registered in England and Wales. Registered office: (as above)

Company No.: 05088553

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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 Comi

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International Progressive MS CollaborativeAim of the meeting

Despite significant progress in the development of therapies for relapsing MS, progressive MS

remains comparatively disappointing. This situation is unacceptable for patients, clinicians and

caregivers, and it is the responsibility of the global MS community to facilitate the development

of treatment options for people with progressive MS.

The International Progressive MS Collaborative was created in 2011 by the MS Societies of

United States, Canada, Italy, United Kingdom, Netherlands and the MS International Federation

to expedite the development of therapies for effective disease modification and symptom

management 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 progressive

MS and demonstrates the international community’s commitment to creating a world free of all

MS. The IPMSC aims to enable cross border and cross discipline collaboration. These activities

will be carefully coordinated with IPMSC member societies and future potential partner societies

and other supporting parties.

Since its creation, the IPMSC has been engaging the global community and begun to frame a

research and funding strategy.

The IPMSC will employ a multi-faceted research strategy to achieve its mission. This strategy will

be implemented through short, medium, and long-term funding commitments for the following

five priority areas:

1. Experimental Models

2. Identification and Validation of Targets and Repurposing of existing therapeutic agents

3. Proof-of-Concept Clinical Trial Strategies (Phase II Trials)

4. Clinical Outcome Measures (Phase III Trials)

5. Symptom Management and Rehabilitation

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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.

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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 Society

Funding for this meeting provided in part through the support of

Genzyme, a Sanofi Company

Novartis Pharmaceuticals

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Scientific Planning Committee

Timothy Coetzee National Multiple Sclerosis Society

Giancarlo Comi Scientific Institute San Raffaele

Anne Cross Washington University Sch Medicine

Paul O’Connor St. Michael’s Hospital

Alan ThompsonUniversity College London

Wolfgang Bruck University Medical Center Göttingen

Paola Zaratin Italian Multiple Sclerosis Society

Meeting Logistics

Chiara Damico Italian Multiple Sclerosis Society

Linda Isella San Raffaele Congress Centre

Eileen Madray National Multiple Sclerosis Society

Steven WilsonSteven W. Events

IPMSC Steering Committee

Ceri AngoodMultiple Sclerosis International Federation

Peer BanekeMultiple Sclerosis International Federation

Bruce BeboNational Multiple Sclerosis Society

Dhia ChandraratnaMultiple Sclerosis International Federation

Timothy CoetzeeNational Multiple Sclerosis Society

Giancarlo ComiUniversity Vita-Salute San Raffaele

Anthony FeinsteinUniversity of Toronto

Ed HollowayUK MS Society

Raj KapoorUniversity College London Hospitals

Karen LeeMultiple Sclerosis Society of Canada

Marco SalvettiUniversita di Roma


Paola ZaratinItalian Multiple Sclerosis Society

Kim ZuidwijkDutch Multiple SclerosisResearchFoundation

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 Society

Funding for this meeting provided in part through the support of

Genzyme, a Sanofi Company

Novartis Pharmaceuticals

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Working Groups of theInternational MS Collaborative

Jeroen GuertsVU Medical Centre Amsterdam

Karen LeeMultiple Sclerosis Society of Canada

Malcolm MacleodUniversity of Edinburgh

Ken SmithUniversity College London

Peter Stys (Chair)University of Calgary

David BakerQueen Mary University of London

Dhia ChandraratnaMultiple Sclerosis International Federation

Elga de VriesVU Medical Centre Amsterdam

Charles ffrench ConstantUniversity of Edinburgh

Roberto FurlanSan Raffaele Scientific Institute Susan GoelzELAN Pharmaceuticals

Experimental Models for ImprovedPreclinical Evaluation of Novel Therapies

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Rogier HintzenErasmus Medical Centre

Catherine LubetzkiUniversity Pierre & Marie Curie

Marco SalvettiUniversity of Rome

Stephen Sawcer University of Cambridge

Paola ZaratinItalian Multiple Sclerosis Society

Sergio BaranziniUniversity of California

Diego CentonzeUniversity Tor Vergata - Rome

Siddharthan ChandranUniversity of Edinburgh

Francesco CuccaUniversity of Sassari

Ranjan DuttaCleveland Clinic

Peter Goodfellow (Chair)GlaxoSmithKline

Target Identification and Validation Pathwaysfor Repurposing of Existing Therapeutic Agents

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Xavier MontalbanHospital Universitari Vall d’Hebron

John PetkauUniversity of British Columbia

Chris PolmanVU Medical Centre Amsterdam

Nancy RichertBiogen Idec

Tony TraboulseeUniversity of British Columbia

Jerry WolinskyUniversity

Fred BarkhofVU Medical Centre Amsterdam

Jeremy ChatawayNational Hospital for Neurology & Neurosurgery

Timothy CoetzeeNational Multiple Sclerosis Society

Gordon FrancisNovartis Pharmaceuticals

Raj KapoorNational Hospital for Neurology & Neurosurgery

Fred Lubin (Chair)Mount Sinai School of Medicine

Proof-of-Concept and Clinical Trial Strategies

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Clinical Outcome Measures & Trial Design

Paul O’ConnorUnversity of Toronto

Michael PanzaraGenzyme Corporation

Donald PatrickUniversity of Washington

Jack StennerLexile

Luigi TesioUniversity of Milan

Bernard UitdehaagVU Medical Centre Amsterdam

John ZajicekPlymouth University

David AndrichUniversity of Western Australia

Andy BlightAcorda Therapeutics, Inc.

Stefan CanoUniversity of Plymouth

Stephen CoonsThe Critical Path Institute

Robert FoxCleveland Clinic

Jeremy Hobart (Chair)Plymouth Hospital

Ludwig KapposUniversity of Basel

Jason LundyThe Critical Path Institute

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Chris HeesenUnited Medical Center

Albert LoBrown University


Lesley WhiteUniversity of Georgia

Kim ZuidwijkDutch Multiple Sclerosis Society

Maria Pia AmatoUniversity of Florence

Ulrik DalgasAarhus University

John DeLucaNew Jersey Medical School

Anthony FeinsteinUniversity of Toronto

Peter Feys (Chair)Hasselt University

Jenny FreemanPlymouth University

Symptom Management & Rehabilitation Strategies

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IPMSC First Scientific ConferenceDaily Program

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 IChairperson: Wolfgang Bruck

10.00 - 10.15 Target identification and Wolfgang Bruck repurposing in progressive MS

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

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SESSION IIChairperson: Anne Cross

10.15 – 10.45 1st Keynote speaker Genetic profile Stephen Sawcer Discussant Sergio Baranzini

10.45 – 11.15 2st Keynote speaker Immunologic aspects of progressive MS Scott Zamvil

Discussant Marco Salvetti

11.15 - 11.30 Coffee break

11.30 – 11.50 Study group II report Peter Goodfellow

11.50 – 12.20 General Discussion

12.20 – 12.30 Sum up of the Session I Wolfgang Bruck

12.30 – 13.30 Lunch

13.30 - 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 pathology

14.25 - 14.35 Discussion of pathology and pathophysiology of progression 14.35 - 15.05 2st Keynote speaker Pitfalls and problems with animal models David Baker

Discussant Marco Prinz

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SESSION IIIChairperson: Giancarlo Comi

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


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 Hotel

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SESSION IV Chairperson: Chris Polman

February 8th 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

9.00 - 9.15 Clinical outcome measures Chris Polman and phase III trial designs

9.15 - 9.45 1st Keynote speaker Phase III trials of DMTs in progressive MS: Jeffrey Cohen endpoints and other aspects of trial design

Discussant Ludwig Kappos

9.45 - 10.15 2st Keynote speaker Phase III trials in progressive MS: Per Solberg Sorensen biomarkers of information, axonal damage demyelination and remyelination

Discussant Robert Fox

10.15 - 10.35 Study group IV report Jeremy Hobart


10.45 - 10.55 Sum up of the Session IV Chris Polman


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SESSION VChairperson: 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


13.15 - 13.25 Sum up of the Session V Alan Thompson

13.25 - 14.30 Lunch

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 break

SESSION VIChairperson: Monica Di Luca

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‘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 Thompson

17.30 – 17.45 Conclusion and perspective Weyman Johnson

17.45 – 18.15 Shuttle bus from San Raffaele Congress Centre to NH Milano 2 Hotel

SESSION VIIModerator: Timothy Coetzee

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Abstracts of keynote speakers

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Jeremy Chataway

Phase II Trial design:including single-arm, multi-arm, adaptive

Queen Square MS Centre, National Hospital for Neurology and Neurosurgery, London

Using standard parallel arm control/active arm trial design in SPMS/PPMS, can take 10 years

from a phase 2 trial inception to phase 3 trial finish. Over the last 2 decades, over 4500 SPMS

patients 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 signals

due 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 a

neuroprotective 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-arm

phase II trials (Lamotrigine and MS-STAT), before moving onto multi-arm paradigms (eg MS-

SMART) including adaptive trial design.

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Phase III: trials of DMTs in progressive MS:endpoints and other aspects of trial design

Jeffrey A. CohenExperimental 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,

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issues related to the cognitive test (the Paced Auditory Serial Addition Test), and difficulty with

interpretation of the dimensionless composite summary score (an average of the Z-scores of

the component tests).1 The National MS Society Task Force on Clinical Disability Measures

currently is working with the Critical Path Institute to address these issues with the goal of

securing formal approval by the US Food and Drug Administration of the MSFC approach

as a measure of impairment/disability for use in MS clinical trials.2 The Critical Path Institute

is private-public partnership intended to bring together representatives of industry, academic

leaders, regulators, and patient advocacy groups to facilitate the drug discovery and approval

process, including development of more informative and effective outcome measures.

Patient reported outcomes (PROs) are an alternative method for capturing neurologic

impairment/disability from the patient’s perspective.

In addition being more sensitive to some important aspects of MS such as pain or fatigue, PROs

can provide an indication of the clinical meaningfulness of clinician assessments and nonclinical

measures. It is widely presumed that central nervous system tissue damage in early stages

of MS is caused primarily by an abnormal “outside-in” inflammatory process, reflected most

directly by acute relapses and MRI lesion activity (new or enlarging T2-hyperintense lesions and

gadolinium-enhancing T1 lesions). Relapses may continue to occur as patients transition from

relapsing-remitting (RR) MS to secondary progressive (SP) disease and also rarely occur in

patients whose disease was progressive from onset. Some agents approved to reduce relapses

in RRMS, also were effective in reducing relapses in SPMS, e.g. interferon-beta 1a in the IMPACT

trial.3 However, relapses should be included as only a tertiary endpoint in trials focused on

treating the “degenerative” process presumed to cause gradual progression. Similarly, standard

MRI 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 are

more likely to be informative in progressive MS, including atrophy (whole brain, regional, cortical,

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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.

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Ulrik Dalgas

Exercise therapy and multiple sclerosis

Department of Public Health, Section of Sport Science, Aarhus University, Denmark

Multiple Sclerosis (MS) patients are characterised by impaired muscle strength, maximal

oxygen consumption and functional capacity. Furthermore, fatigue, depression and increased

cardiovascular disease risk are frequent symptoms in MS patients. This reflects probably both

the 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 to

worsening of symptoms or fatigue. During recent years, it has been increasingly acknowledged

that exercise benefits MS patients. However, the effects of exercise have mainly been studied

in mild to moderately impaired MS patients with an EDSS score of less than 5. Different types

of exercise have been evaluated in studies generally characterised by small sample sizes and

with most focus put on basic physical exercise modalities such as endurance training and

resistance training(2-4). Furthermore, only few studies(5-7) have included follow up periods in

the study design and only few studies have looked at interventions that are integrated in the

community(8). However, the existing exercise recommendations(2;9;10) are based on studies

applying either relapsing-remitting MS (RRMS) or minor groups of patients with mixed disease

courses. Several reviews(2-4) only identified one study(11) exclusively applying secondary

progressive MS (SPMS) patients, whereas no studies have focused on primary progressive MS

(PPMS). Consequently, exercise studies in the progressive subgroups seem important due to

limited 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 MS

patients (EDSS≥6.5). Preliminary (non-controlled) data have started to emerge in a study

evaluating the effects of resistance training in advanced MS (EDSS 6.5-8) showing beneficial

effects(12). However, much work remains to be done in this group of patients.

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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.

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Cognitive Rehabilitation and Progressive MS

John DeLucaKessler 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 AmatoDepartment of NEUROFARBA, University of Florence

It is now well established that up to 70% of persons with multiple sclerosis (MS) suffer from cognitive

impairment (Chiaravalloti & DeLuca, 2008). It is generally accepted, although not absolute, that

cognitive impairment is more severe and encompasses a greater range of cognitive involvement

in 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 disease

duration. However, it is also well known that cognitive impairment does occur at all stages of the

disease. MRI parameters show a modest correlation with cognition, and are significantly moderated

by environmental enrichment (Sumowski, 2010, 2012). Recent evidence suggests that grey matter

parameters are particularly sensitive to cognitive dysfunction, including those with SP and primary

progressive (PP) MS. In all, given the frequency and degree of cognitive involvement in persons

with MS, the need for cognitive rehabilitation therapies and programs is clear. Compared to studies

in stroke and traumatic brain injury, relatively few studies of cognitive rehabilitation exist in persons

with MS (O’Brien, 2008). Typically, inclusion criteria for behavioral studies are based on the presence

and/or degree of cognitive impairment, not disease course. Approximately half the studies contain

SP and/or PP subjects as part of the subject pool, while the other half either excludes these patients

or the sample composition is not clearly specified. The percentage of progressive patients in the

samples ranges from about 10% to 50%, but typically accounts for about 20-40% of the sample. Far

fewer 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).

30

There is preliminary evidence that physical activity (e.g., aerobic fitness, exercise training) may be

associated with improved cognition in MS. One small study showed that cardiovascular fitness was

associated with improved processing speed, sustained attention and working memory (Prakash et

al, 2007). Another small study showed that such fitness was greater white and grey matter integrity

and processing speed (Prakash et al, 2010). However, yet another RCT showed no effect (Oken

et al., 2004). Nonetheless, the notion that physical activity may improve cognition in MS deserves

further research.With respect to pharmacological approaches, disease-modifying therapies show

little to no effect in improving cognition (Langdon, 2011). This should not be too surprising since

cognition is not a primary outcome on any of these trials. In addition sine the vast majority of such

trials are on RR patients, little to nothing is known about its impact in SP and PP MS. Targeted

pharmacological approaches have yielded mixed results at best with approximately half showing

some effect on improving cognitive performance and the other half no effect (Patti et al, 2011). There

has been no consistent effect on improving cognition in any class of medication. While most of the

targeted 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 impairment

in progressive MS is embarrassingly poor. Little if anything can be said about any such approach

to address one of the most significant and disabling symptoms of MS, namely cognition. Because

cognitive 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 and

programs designed to improve cognitive impairment in MS.

30 31

Study design and biomarkers for disease modifyingtreatments 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 - 1998

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 of

progressive multiple sclerosis the current dogma states that MS is an autoimmune inflammatory

neurodegenerative disease of the central nervous system characterised by demyelination and

variable degrees of axonal loss and gliosis. Inflammation is believed to be primary driver of

demyelination and is also responsible for acute axonal damage. Axonal transection is prominent

in 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 over

a time course of weeks to months, which has implication for biomarker-based studies. For

example, when measuring neurofilaments, which are released into the cerebrospinal fluid after

axonal transection, as an outcome measure of neuroprotection the time course of the axonal

degeneration is important; the duration of the study must be long enough to encompass the

duration 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 focal

34

inflammation is still present. Therefore it makes little sense to use neuroprotective therapies

without suppressing this ongoing inflammation. The logical triumvirate strategy would therefore

be anti-inflammatory therapies, combined with neuroprotective drugs followed by strategies to

promote remyelination.

Pathological studies of MS demonstrate that it is a multifocal disease affecting the whole

neuraxis. Therefore neurodegeneration is partly a length-dependent process and more likely

to affect the systems served by the longest neuronal pathways; this explains why progressive

spastic paraparesis with sphincter involvement is the predominant clinical syndrome that is

seen with progressive MS. The implication of this is that any effective therapy that works in

progressive MS should have an effect that is first seen on the functioning of the neuronal

pathways with the longest central axons;

hence the focus on mobility in the EDSS and other outcome measures. Unfortunately, changes

in mobility occur too slowly, on average, to be used in pragmatic phase II studies and hence the

shift towards biomarkers in new exploratory trial designs.

To try and address both the acute neurodegeneration from focal inflammatory lesions and

the delayed neurodegeneration that is seen in the post-autoimmune inflammatory secondary

progression we have developed two novel trial designs. Both these designs have been developed

from insights from animal models.

Trial 1: acute optic neuritis as a model of neurodegeneration as a result of focal lesion in MS

In 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 approximately

10-15% of subjects the recovery is poor. The acute inflammatory lesion in the optic nerve

resembles MS plaques found elsewhere in the CNS, and because its characteristics can be

studied 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 neuritis

36

Giovannoni, page 4 of 8.

An exploratory phase IIa study to evaluate phenytoin as neuroprotective strategy in acute optic neuritis

Informed consent

Acute unilateral optic neuritis1. <14 days since symptom onset2. Visual acuity worse than or equal to 6/9 in affected eye3. No prior history of optic neuritis or disease in the contralateral unaffected eye; corrected VA better

than or equal to 6/64. If patients has MS EDSS 5.5 or less

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

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.

Alternative diagnosisNot part of ITT

cohort yes

no

Estimated power calculations assuming half of all patients are treated with steroids

36 37


An exploratory phase IIa study to evaluate phenytoin as neuroprotective strategy in acute optic neuritis

Informed consent

Acute unilateral optic neuritis1. <14 days since symptom onset2. Visual acuity worse than or equal to 6/9 in affected eye3. No prior history of optic neuritis or disease in the contralateral unaffected eye; corrected VA better

than or equal to 6/64. If patients has MS EDSS 5.5 or less

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

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.

Alternative diagnosisNot part of ITT

cohort yes

no

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

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 participant:

6 months

Estimated total trial duration:

24 months

Planned trial sites: UCL Institute of Neurology and the National Hospital for Neurology and Neurosurgery, London, and Royal Hallamshire Hospital, Sheffield

Total number of participants planned:

90

Main inclusion criteria: Acute optic neuritis, within 14 days of onset of visual loss, visual acuity in affected eye < 6/12

Statistical methodology and analysis:

The primary comparison will estimate the active vs placebo difference in 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.

38


Trial 1 Synopsis

Title: A phase II double-blind, randomised, placebo-controlled trial of neuroprotection with phenytoin in acute optic neuritis

Short title: Neuroprotection with phenytoin in optic neuritis

Trial medication: Phenytoin vs placebo


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.


6 months


24 months

Planned trial sites: UCL Institute of Neurology and the National Hospital for Neurology and Neurosurgery, London, and Royal Hallamshire Hospital, Sheffield


90

Main inclusion criteria: Acute optic neuritis, within 14 days of onset of visual loss, visual acuity in affected eye < 6/12


The primary comparison will estimate the active vs placebo difference in 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 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.

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.

38 39


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 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.

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 SPMS1. A diagnosis of definite multiple sclerosis2. Treatment with interferon beta or glatiramer acetate for at least 12 months3. EDSS score between 3.5 and 5.54. No history of relapses in the preceding 6 months5. A history of slow progression of disability over a period of at least 6 months6. Age 18-55 years

Informed consent / bloods / CSF (week -4)

Repeat CSF analysis (week – 1)

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 GFAP

Raised CSF NFLExcluded as they

would be non- informative

No

Yes

Randomised to oxcarbazepine or placebo (week 0)

Repeat CSF analysis (week 24)

40


Trial 2 Synopsis

Title: A phase II double-blind, randomised, placebo-controlled trial of neuroprotection with oxcarbazepine in early non-relapsing secondary progressive multiple sclerosis

Short title: PROXIMUS STUDY - PRotective role of OXcarbazepine in MUltiple Sclerosis

Trial medication: Oxcarabzepine vs placebo


Objectives: 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.


12 months


36 months

Planned trial sites: Royal London Hospital and the National Hospital for Neurology and Neurosurgery, London.


90

Main inclusion criteria: 6 month history of sustained progression despite being interferon-beta or glatiramer acetate without a relapse in the last 12 months.


The primary comparison will estimate the active vs placebo difference in 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.

40 41


Trial 2 Synopsis

Title: A phase II double-blind, randomised, placebo-controlled trial of neuroprotection with oxcarbazepine in early non-relapsing secondary progressive multiple sclerosis

Short title: PROXIMUS STUDY - PRotective role of OXcarbazepine in MUltiple Sclerosis

Trial medication: Oxcarabzepine vs placebo


Objectives: 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.


12 months


36 months

Planned trial sites: Royal London Hospital and the National Hospital for Neurology and Neurosurgery, London.


90

Main inclusion criteria: 6 month history of sustained progression despite being interferon-beta or glatiramer acetate without a relapse in the last 12 months.


The primary comparison will estimate the active vs placebo difference in 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.

42

Clues from Inflammatory Aspectsof Progressive MS Pathology

Hans Lassmann Center for Brain Research, Medical University of Vienna, Austria

Absence of contrast-enhancing lesions and lack of efficacy of anti-inflammatory treatments in

progressive multiple sclerosis (MS) has been regarded as evidence that inflammation, mediated

by adaptive immunity, plays no major role in propagation of tissue injury in this stage of the

disease. This view is not supported by neuropathological observations. Overall, inflammation

in the MS brain decreases with age and disease duration. However, active demyelination and

axonal or neuronal injury in the progressive stage of the disease is invariably associated by

T-cell and B-cell infiltration of the lesions. When inflammation in the MS brain at late disease

stages declines to levels seen in age matched controls also active demyelination and axonal

damage declines to levels seen in the respective controls. T- and B-cell infiltrates within the

tissue in active progressive MS are in part located in areas without blood brain barrier protein

leakage. Furthermore, the exact nature of the inflammatory reaction, their activation state within

the lesions and their potential response to current anti-inflammatory treatments are currently

not defined.

The type of tissue injury, characterized by plaque like primary demyelination associated with

axonal and neuronal degeneration, is specific for MS and is not seen in comparable form in

any other chronic inflammatory disease of the human central nervous system. It is also only in

part reproduced in currently available experimental models. Specific primary demyelination in

experimental models can be induced by specific adaptive immune reactions, involving cytotoxic

T-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.

44

Stephen Sawcer

Genetic Profile

Genome Wide Association Studies have the potential to reveal novel unbiased insights in

to complex heritable traits by enabling hypothesis free screening of common variation. The

approach has revolutionised the genetics of susceptibility but has yet to provide any insight

into the genetic factors underlying critically important clinical features of the disease such

course and severity. Given that the most recent GWAS involved almost 10,000 patients this

disappointing result is surprising and immediately raises several questions. First are these

phenotypes heritable? Intuitively it seems inconceivable that matters such as the extent of

relapse activity and the rate of accumulation of disability might not be influenced by genetic

variation. However beyond this intuition there is surprisingly little evidence supporting the role

of genetic factors. In their assessment of over 1,000 multiplex families Hensiek et al. found

only marginally significant evidence for correlation in clinical course amongst affected relatives,

and no convincing evidence for such correlation in severity. Although the absence of evidence

should not be confused with evidence of absence these disappointing data could indicate

that the genetic factors of relevance in shaping the phenotype of multiple sclerosis exert only

very modest effects. Second are these phenotypes measured well enough? Here one might

speculate lays the greatest weakness in the previous GWAS looking at clinical phenotypes in

multiple sclerosis. Like all association based studies GWAS are critically dependent upon the

correlation between the variables tested (the genotypes) and the phenotype measured. If the

measured phenotype (e.g. EDSS or MSSS) is only poorly correlated with the clinically relevant

variable (rate of accumulation of disability) then one can expect that power will be substantial

limited. Since course is usually dichotomised into those with and those without a history of

clinically evident relapse it seems inevitable that the correlation between this dichotomy and

any SNP genuinely influencing relapse activity will be modest, even if that SNP had a relatively

Department of Clinical Neuroscience, Addenbrooke’s Hospital, University of Cambridge, Cambridge, UK

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.

46

Phase III trials in progressive MS: biomarkers of inflammation,axonal damage, demyelination and remyelination

Per Soelberg SørensenDanish Multiple Sclerosis Center, Rigshospitalet, Copenhagen University Hospital, Denmark

Whereas 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 multiple

sclerosis (MS).

Outcome measures of biomarkers of inflammation, axonal damage, demyelination and remyelination

in progressive MS include imaging measures and biomarkers in blood and CSF. A major issue is the

problem of feasibility and standardisation across many different sites participating in pivotal phase III

trials in progressive MS. Especially many new promising MRI techniques for measuring structural and

functional changes are not suitable for multi-centre trials.

Among the conventional MRI measures, gadolinium enhancing lesions are the most appropriate

measure for focal inflammatory sites with blood-brain barrier disruption. However, in progressive MS

these are of less importance because of the compartmentalization of the inflammation in primary and

secondary progressive MS.

Hyperintensive T2 lesions are very unspecific and may reflect several different pathologies including

oedema inflammation, demyelination and axonal loss.

T1 hypointensive lesions, black holes, correlate with axonal loss, but are more suitable for trials in

relapsing-remitting MS where lesions are discrete.

Atrophy measures are probably most appropriate for measuring axonal damage in phase III trials in

progressive MS. One of the best evaluated measures to assess brain atrophy is the brain parenchymal

fraction that, however, only correlates moderately with clinical disability. Pseudo atrophy in the first year

of anti-inflammatory therapies make measurements during the first 6-12 months after treatment start

unreliable.

Grey matter atrophy studied by doubled inversion recovery imaging is currently used as a primary and

secondary 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 of

48

neurofilament (both light and heavy chain) is increased in patients with progressive MS and correlates

with CNS inflammation and axonal loss. Hence, neurofilament in CSF might be the most promising

measure of permanent of neurological disabilities in trials of progressive MS.

Glial fibrillary acidic protein (GFAP) is associated with astrocytosis and irreversible brain tissue damage

at late stage MS. However, the value as biomarker for atrophy has still to be demonstrated in large

cohorts of patients in standardized controlled studies. Other molecules that are potential biomarkers in

CSF for axonal damage are NAA and S100 protein. Proteomics may also be of value. Markers of disease

activity are neurofilament, CXCL13, IL10 and osteopontin.

There are no established biomarkers in blood for measurement of atrophy or inflammation and

demyelination. 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 shown

to identify inflammation or axonal damage. A number of molecules are under investigation including

adhesion molecules, matrix metalloproteinase, and osteopontin, T-cell activation and transcription

factors, KIR4.1 antibodies, and GFAP.

In conclusion, atrophy measures, in particular grey matter atrophy, and magnetization transfer ratio might

be candidates for biomarkers of atrophy and neurodegeneration in phase III clinical trials of progressive

MS. 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 demyelination

or neurodegeneration and axonal loss, but none of them have convincingly been validated in phase

III randomized clinical trials in progressive MS. However, phase III studies in progressive MS using

biomarkers as endpoints are encouraged, as surrogate endpoints are urgently needed in clinical trials

that test the efficacy of drugs with potential, neuroprotective or reparative properties.

48 49

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 to

Scott S. ZamvilDepartment Neurology, University of California, San Francisco

Immunologic Aspects of Progressive Multiple Sclerosis

50

another determinant of the same myelin protein (intramolecular epitope spreading), from one myelin

protein to another or to a neuronal antigen (intermolecular spreading) may occur. Evidence indicates

that antibody reactivity to autoantigens also changes during progression from RRMS to SPMS. The

role of adaptive B cell immunity in progression is also supported by the identification of B cell follicles

with germinal center formation in the meninges in SPMS. A better understanding how each of these

potential mechanisms contributes to progression is needed. In this regard, it could be advantageous to

combine different immunologic techniques (e.g. CFSE, ICS, MHC tetramers...) to identify and evaluate

the phenotype of rare lymphocyte populations that may participate in disease progression.

Evidence from studies of CNS pathology and the peripheral immune system suggest innate immunity

contributes to MS progression. Separate from focal areas of CNS inflammation, activated microglia are

detected in regions of normal appearing white matter in progressive MS. It has been observed that myeloid

cells (dendritic cells (DC) and monocytes) in SPMS express higher levels of certain proinflammatory

T 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 innate

and adaptive immunity, as it has been observed that when serving as APC, these cells can promote

proinflammatory T cell differentiation. The relationship between innate and adaptive immunity is important

for understanding the mechanism of action of some established MS therapies, and for certain agents in

development. Glatiramer acetate (GA) is a polypeptide-based therapy approved for RRMS and is known

to 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 in

humans and in experimental animals indicate that BG-12 and laquinimod, two therapies in development

for RRMS exert a primary effect on innate immune cells and promote development of type II DC and

monocytes. Agents that inhibit pathways participating in proinflammatory myeloid cell differentiation may

be attractive candidates for treatment of progressive MS.

50 51

International progressive IPMSC CollaborativeAdditional documents

52

52 53

Multiple Sclerosis Journal18(11) 1534 –1540© The Author(s) 2012Reprints and permissions: sagepub.co.uk/journalsPermissions.navDOI: 10.1177/1352458512458169msj.sagepub.com

MULTIPLESCLEROSIS MSJJOURNAL

The last two decades have seen dramatic progress in relaps-ing–remitting multiple sclerosis (RRMS). Experimental autoimmune encephalomyelitis (EAE) and other animal

models have provided insights into the pathophysiology of central nervous system inflammation and demyelination. Clinical diagnostic criteria have been refined, and

Setting a research agenda for progressive multiple sclerosis: The International Collaborative 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

AbstractDespite 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.

Keywordsmultiple sclerosis, progressive multiple sclerosis, neuroprotection, rehabilitation, research agenda

Date received: 29th June 2011; revised: 18th July 2012; accepted: 22nd July 2012

1Mellen Center for Multiple Sclerosis, Neurological Institute, and Lerner College of Medicine, Cleveland Clinic, Cleveland, OH, USA. 2 Department of Brain Repair and Rehabilitation, University College London Institute of Neurology, Faculty of Brain Sciences, London, UK.

3 Centre for Neuroscience and Trauma, Blizard Institute, Barts and The London School of Medicine and Dentistry, Queen Mary University of London, UK.

4Multiple Sclerosis International Federation, London, UK. 5Multiple Sclerosis Society, London, UK. 6National MS Society, New York, NY, USA.7Department of Neurology, Scientific Institute San Raffaele, Milan, Italy. 8Department of Psychiatry, University of Toronto, Canada.

458169 MSJ181110.1177/1352458512458169Multiple Sclerosis JournalFox et al.2012

New Perspectives

9National Hospital for Neurology and Neurosurgery, London, UK.10MS Society of Canada, Toronto, ON, Canada. 11 Center for Neurology and Experimental Therapies, Sapienza

University, Rome, Italy.12Fast Forward, LLC, New York, NY, USA. 13Italian MS Society, Genoa, Italy. 14MS Research Foundation, Voorschoten, The Netherlands.

Corresponding author:Robert J. Fox, Mellen Center for Multiple Sclerosis, Neurological Institute, and Lerner College of Medicine, Cleveland Clinic, 9500 Euclid Ave, U-10, Cleveland Clinic, Cleveland, OH, 44122 USA. Email: [email protected]

at Università degli studi di Pavia on January 17, 2013msj.sagepub.comDownloaded from

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Fox et al. 1535

biomarkers are being developed that predict future disease activity and disability. A clear pathway has emerged for developing RRMS therapies: studies in experimental mod-els, Phase I safety studies, Phase II trials with active MRI lesions as the primary outcome, and finally Phase III trials using relapses and sustained progression of disability as primary outcome. Eight disease-modifying therapies have received regulatory approval for RRMS and several more are in late-stage clinical development and could receive regulatory approval shortly.

For all the success in developing treatments for RRMS, the story in progressive MS is comparatively disappointing and more challenging. Even the definition of progressive MS has been elusive. At the clinical level, progressive MS is defined as the gradual progression of clinical disability in a patient either with a preceding relapsing course (sec-ondary progressive MS, SPMS) or without a preceding relapsing course (primary progressive MS, PPMS).1 There may be superimposed evidence of overt inflammation, but frequent relapses and many new lesions on MRI are more suggestive of RRMS. At the imaging level, progressive MS is the gradual accumulation of imaging abnormalities. At the pathology level, progressive MS is the abnormal pro-cesses present in neurons or glial cells that lead to irrevers-ible injury that causes clinical disability progression. An inherent difficulty in studying progressive MS is the indis-tinct overlap with RRMS, with the pathologic origins of progressive MS probably developing much earlier than its clinical manifestations. Here, PPMS and SPMS are grouped together, since they share many similarities – clinically, pathologically, and particularly as revealed by imaging technology.2

Animal models such as EAE provide only limited insight into the pathophysiology of progressive MS. New MRI lesions are only occasionally seen in progressive MS, resulting in uncertainty as to which imaging or other bio-marker should be employed in Phase II proof-of-concept clinical trials. The clinical metrics used in RRMS have unclear sensitivity in progressive MS, limiting their utility. Mechanisms for identifying candidate therapies among existing therapies are not well defined.

Clinical trials of anti-inflammatory therapies in progres-sive MS have been generally negative or inconsistent. Immunosuppressive and immunomodulating drugs such as cladribine, azathioprine, and cyclophosphamide have shown no evidence for efficacy in SPMS and PPMS. Only mitoxantrone has been approved for SPMS in some coun-tries, and this treatment has a serious adverse effect profile. Finally, early attempts to approach progressive MS with putative neuroprotective therapies have failed, as seen in the recent trial of lamotrigine.3

Given the challenges presented by progressive MS, a collaborative was convened by volunteer and staff leaders from several MS societies ‘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 meet-ings, five key priority areas for research were identified (Table 1). These areas represent opportunities where con-certed 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.

Experimental models

Experimental models for MS have provided important insights into disease pathogenesis and potential therapies.4 Neurotoxicity models inform neuroprotection strategies that may prevent neurodegeneration in MS.4 The three most commonly studied animal models in MS are: EAE, virally induced demyelinating disease models and toxin-induced models of demyelination.5 Despite their extensive use, the clinical course, immunology and neuropathology of these models reflect only part of the pathophysiological spectrum of human MS.4,6 Therefore, direct extrapolation of results obtained in these models to MS is often tenuous, and the effect of therapeutic interventions in animals must be interpreted with care.7 In addition, most of the current models follow a monophasic episode of inflammation and therefore predominantly mirror only the impact of acute inflammation and neuronal injury seen in RRMS.4,6

Several animal models claim to represent human pro-gressive MS,8 but few offer compelling evidence.6 The chronicity of these models is usually short and the compo-sition of lesions different from MS.6 Furthermore, most of these models do not reflect the irreversible deficits charac-terizing progressive MS.9

Therefore, there is an urgent need for better animal mod-els that reproduce the key clinical and pathological features of SPMS and PPMS. Such models should include the role of CD8-positive T cells and notably macrophages, which com-prise a major component in progressive MS lesions. Ectopic B cell follicles should be studied as an alternative disease-related mechanism. Additional models are also needed that demonstrate robust chronic demyelination and neurode-generation, such as an autoimmune-independent, inflam-matory glial cell-associated neurodegeneration, which more accurately reflects progressive MS. In addition to animal models, brain-slice cultures that demonstrate demyelination and neurodegeneration may be informative,

Table 1. Five key research priorities for progressive MS.

- Experimental Models- Identification and Validation of Targets and Repurposing

Opportunities- Proof-of-Concept Clinical Trial Strategies- Clinical Outcome Measures- Symptom Management and Rehabilitation


54 55

1536 Multiple Sclerosis Journal 18(11)

especially if they can be adapted to use human post-mor-tem tissue where MS pathology can be directly examined.

Identification and validation of targets and repurposing opportunities

While our understanding of the pathophysiology of pro-gressive MS is yielding knowledge which can be applied to the development of new treatments, identifying and validat-ing targets for use in drug discovery for progressive MS remains a significant challenge. Helpful insights may come from genome-wide association studies (GWAS). Since the first non-MHC susceptibility locus (IL2RA) was identi-fied,10 the list of MS risk loci is growing, with around 50 loci identified to date.11 However, no individual gene vari-ant has been identified as the ideal therapeutic target and, even when considering all disease-associated variants together, risk loci explain only a modest fraction of disease heritability.12 Notwithstanding these limitations, the avail-able results may suffice for computational and systems biology analyses to provide novel insights into biological pathways involved in disease pathogenesis. Indeed, compu-tational biology is shifting from diagrammatic representa-tion of pathways to mathematical models. These techniques hold promise to provide the tools for interpreting genetic data across different knowledge domains.13 Furthermore, systematic assessments of the functional consequences of the associated variants are underway. Together, the results of these studies could help prioritize putative therapeutic targets and steer the development of new compounds.

In addition, methods have recently been developed to select old drugs for new targets. Historically, repositioning of a compound for a new indication has been a chance occurrence, driven by observations of unforeseen favorable effects. Now there is intense research on how to systemati-cally infer new therapeutic targets for drugs that have already been registered for human use. Side-effect or chem-ical similarities between drugs and ligand sets are examples of this new strategy.14,15 These data may be further refined through screenings of registered drugs on cellular and ani-mal models of MS.

Superimposing biologically relevant pathways identi-fied through GWAS studies to ‘catalogues’ of pheno-typic effects of registered drugs may shorten the process of identifying therapies with potential efficacy in progressive MS. This strategy is safe for patients, since repurposed drugs usually come with years of post-marketing experience in other diseases. This strategy is also cost-effective, since it streamlines preclinical and early-stage clinical studies. Indeed, the latest GWAS data did not show substantial differences at susceptibil-ity loci between relapsing and primary progressive forms of MS, suggesting relevance of GWAS results to pro-gressive MS.11

The therapeutic opportunities that come from GWAS, computational biology and systematic reassessment of the effects of pharmaceutical compounds need further develop-ment to achieve their potential application to progressive MS. Intellectual property and the possibility of re-evaluat-ing compounds that have not made it through the approval process are among the issues that, if properly addressed, may help accelerate the development of effective therapies for progressive MS.16

Proof-of-concept clinical trial strategies

Agents for which there is promising preclinical data need to be developed through early phase clinical trials for evi-dence of safety and therapeutic benefit. Phase II trials gen-erally rely on biomarkers that are more sensitive to therapeutic effects than clinical measures. Biomarker out-comes enable Phase II trials to be shorter and have a smaller sample size than Phase III trials.

Valid surrogate biomarkers need to predict clinical out-comes. Phase II trials in RRMS have advanced because lesion activity on MRI is an accepted biomarker of clinical relapse rate.17 In contrast, no comparable measure has been identified in progressive MS. There are no agreed imaging markers of neurodegenerative processes such as energy failure, ionic imbalances and loss of neuronal integrity. The problem is compounded by limitations of clinical measures of disease progression against which any biomarker might be validated.

At present, promising imaging metrics include cerebral and spinal cord atrophy, lesion T1 hypointensity, magneti-zation transfer ratio to assess lesion microstructure, and optical coherence tomography to measure axonal degenera-tion in the retina.18 There is enough longitudinal data to enable sample sizes to be calculated for most of these tech-niques for proof-of-concept trials, but their sensitivity to change and responsiveness to treatment is not well under-stood. Newer techniques that assess tissue microstructure are also candidate metrics, including diffusion tensor imag-ing19 in addition to methods that can derive axonal density and radius. Techniques that examine earlier events in the injury pathway include sodium imaging20 and measure-ments of metabolic markers, including the neuronal/mito-chondrial marker N-acetylaspartate.21 These techniques could be complemented and extended by positron emission tomography (PET).22 Little is known about the sensitivity, responsiveness and predictive power of most of these imag-ing techniques and their limited availability may restrict their widespread use.

A number of tissue fluid biomarkers have been studied, mostly to assess immunological activity. Markers of spe-cific injury mechanisms are also emerging, including chemokines associated with intrathecal B lymphocyte activity that might drive cortical injury,23 nitric oxide


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Fox et al. 1537

metabolites,24 and neurofilaments released by damaged axons.25 A significant drawback to widespread application of these biomarkers is their typical measurement from cer-ebrospinal fluid, which is not easily accessible. Nonetheless, cerebrospinal fluid is increasingly incorporated into designs of progressive MS trials, and efforts to identify biomarkers in plasma and serum are underway.

Better biomarkers would power smaller and shorter tri-als. More flexible trial designs are also being examined to achieve the same aim. These include modified entry criteria to enrich trials for patients more likely to progress. Adaptive designs such as those used in cancer trials could make use of prognostic biomarkers to stratify an outcome analysis that is sensitive to subpopulation treatment effects,26 and could employ an interim futility analysis to exclude non-effective agents.27

These considerations suggest that proof-of-concept clin-ical trial strategies are likely to evolve significantly if (1) biomarkers can be identified and validated that measure important events in the neuronal injury pathway, are relia-ble, easily implemented, dynamic over time, and correlate with disability, and (2) if trial designs can be developed which further minimize trial size and duration. Importantly, these innovations will need sufficient community consen-sus to be accepted by regulatory authorities.

Clinical outcome measures

A critical aspect in the development of therapies is a meas-urement tool of therapeutic efficacy. The ideal measure-ment tool is precise, reproducible, broad-based in its assessment, sensitive to change over time, and predictive of future change. The evaluation of MS therapies in RRMS was greatly assisted by clear definitions and objective measurement of clinical relapses. Establishing outcome measures for progressive MS has been more difficult. This difficulty arises from the varied manifestations of progres-sive MS (motor, sensory, coordination, cognitive, etc.), their slow rate of evolution, and difficulties in their quanti-tative measurement. There are two main pathways to solv-ing this challenge: refinement of existing outcome measures and development of new outcome measures.

Of the existing measures, The Kurtzke Expanded Disability Status Scale (EDSS)28 is the most common dis-ability measure in MS trials. However, EDSS is an inher-ently subjective assessment by a neurologist, has poor intra- and inter-rater reliability,29 and has poor precision. Refinements to the EDSS would likely improve its perfor-mance, although many of its shortcomings are inherent to the tool and so are insurmountable.

The Multiple Sclerosis Functional Composite (MSFC) is the outcome of an international panel charged with replacing the EDSS.30 Advantages to the MSFC include its dynamic assessment of different functions relevant to MS (ambulation, arm function, and cognition) and improved

statistical performance. Since the introduction of the MSFC, many validation studies have shown its clinical cor-relations and predictive capacity. Despite these apparent advantages, the MSFC has not always been more sensitive than the EDSS in clinical trials. Equally important, the MSFC has not yet been accepted by regulators as an alter-native to EDSS. As with EDSS, further refinement of the MSFC may improve its sensitivity, reliability, and respon-siveness, although some shortcomings cannot be overcome.31

Important goals of MS therapies are to reduce symptom severity, improve function, and enhance quality of life. These are best evaluated through patient-reported outcome measures (PROMs), including global assessments of daily function and health-related quality of life (HRQL) meas-ures.32 Regulatory interest in PROMs is growing, with guidelines emerging regarding the integration of PROMs into clinical trials.33 Efforts to improve clinical disability assessment in MS are already underway.31

Symptom management and rehabilitation

MS results in a diversity of symptoms, bringing increasing physical, psychological and emotional burden, particularly in the progressive stage of the condition. In spite of the introduction of effective disease-modifying treatments, symptom management and rehabilitation remain essential components of MS therapy, helping to alleviate the impact of disability and improve quality of life. Surprisingly, the rationale for specific pharmacological treatments for symp-toms is frequently based on few trials with small patient numbers, often underpowered and unblinded.34 Recently, these shortcomings have begun to be addressed with a few well conducted studies, such as using cannabinoids35 and fampridine36 for motor symptoms. While cognitive deficits can now be clearly defined, fatigue remains more difficult to evaluate in trials because (a) less is known about the pathophysiology and (b) it may be influenced by psychiat-ric factors, making quantitative characterization problem-atic and often confounded. Depression and anxiety may respond well to either pharmacologic or cognitive behavio-ral treatment.37–39 Symptom management in MS can be advanced in a number of ways. First, there should be tar-geted research to improve our understanding of the patho-logical mechanisms leading to symptom-related disability. This knowledge will allow more focused translational steps towards developing symptomatic therapies. Secondly, potential treatments should be assessed in rigorous, well designed trials that are sufficiently powered to establish beneficial effects, the optimum dosage, and short- and long-term side effects. Potential symptom interactions and confounding factors should be accounted for in the trial design. Ideally, studies should incorporate PROMs, surro-gate pathological markers related to the particular symptom


56 57


under study and an assessment of cost-effectiveness. Third, further development of reproducible and responsive meas-ures for different symptoms is needed.

Symptomatic treatment is normally part of a multidis-ciplinary patient-centered approach that may involve rehabilitation. The relationship between neuroplasticity and rehabilitation is a critically important area for further research. Functional brain reorganization is well described in MS, showing increasing activation extent and the recruitment of additional areas, and hinting at the prospect of compensatory strategies.40,41 Some motor net-works may be altered by training42 but there is a need to investigate if enhancing network plasticity may improve the outcomes of rehabilitation. Combining functional and structural imaging with cognitive rehabilitation may help develop treatments for cognitive impairment.43 Finally, applying brain–computer interface technology in patients with advanced MS may allow greater motor independ-ence, communication and environmental control.44

Conclusions and future directions

Despite great progress in relapsing MS, much work is needed to achieve similar successes for progressive MS. There are a number of key areas of unmet need which are blocking treatment development in progressive MS. Although the international scientific community has made progress in some of these areas (Table 2), there have not been commensurate gains in progressive MS treatments. Tackling these issues will require an integrated, multi-dis-ciplinary approach to enable effective translation of research into therapies. To this end, the International Progressive MS Collaborative is committed to engaging the MS research community through an international effort to fund a spectrum of research activities relevant to progressive MS with the ultimate goal of expediting the development of disease-modifying and symptom-relief treatments for progressive MS.

To address these five challenging areas, which currently impede the treatment of progressive MS, the International Progressive MS Collaborative commissioned five working groups, comprised of international experts, to identify

specific strategies and potential lines of research that would overcome the barriers and realize the opportunities within each area. Following an international meeting in early 2013, we anticipate that a call will be issued to address these opportunities. Potential sources of funding for this call include the existing research funding mechanisms of the member organizations of the International Progressive MS Collaborative as well as other partners (e.g., govern-ment, industry). In addition, there will be an international fundraising effort led by the Multiple Sclerosis International Federation and financial support will be solicited from diverse channels around the world, including foundations, government, corporate, and private funding organizations.

Fostering global collaboration by the MS research com-munity is a bold ambition, and potentially fraught with many challenges. Fortunately, the opportunities have never been as favorable as they are today, with unprecedented data on disease etiology, pathophysiology, and disease course. Furthermore, we can look to other diseases for inspiration. Collaborative efforts like the Forum for Collaborative HIV Research, the Alzheimer’s Disease Neuroimaging Initiative, and the Innovative Medicines Initiative, provide powerful examples of how collaboration can accelerate research among a diverse group of stake-holders. While the collaborative efforts in progressive MS will almost certainly differ from those in other fields, the time is right for concerted action.

Acknowledgments

The meetings of the International Collaborative on Progressive Multiple Sclerosis were funded by the Italian Multiple Sclerosis Foundation (FISM), MS Society of Canada, MS International Federation, MS Research Foundation (The Netherlands), UK MS Society, and the National MS Society (USA).

Funding

This activity received no specific grant from any funding agency in the public, commercial, or not-for-profit sectors.

Conflict of interest

Robert J. Fox received personal compensation for activities with Avanir, Biogen Idec, Novartis, and Questcor, and research support

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


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Fox et al. 1539

from the National MS Society (USA) and National Institutes of Health (USA).

David Baker is a founder of Canbex and has received personal compensation for activities with UCB and Biogen Idec.

Peer Baneke, none.Doug Brown, none.Paul Browne, none.Olga Ciccarelli is on the editorial board of Neurology and is a

clinical editor for CML Multiple Sclerosis. She has received research funding from the Wellcome Trust, MS Society of Great Britain and Northern Ireland, UCL Biomedical Research Centre, and Engineering and Physical Sciences Research Council. She has received speaker honoraria from Bayer-Schering and GE Healthcare.

Dhia Chandraratna, none.Timothy Coetzee, none.Giancarlo Comi has received personal compensation for activ-

ities with Novartis, TEVA Pharmaceutical Ind. Ltd, Sanofi-Aventis, Merck Serono, Bayer Schering, Actelion.

Anthony Feinstein has received grant support from the Multiple Sclerosis Society of Canada and honoraria from Merck-Serono, Teva, BayerSchering and Biogen.

Raj Kapoor has received personal compensation for activities with Bayer Schering, Biogen Idec, Genzyme, Merck Serono, MS Therapeutics, Novartis, and TEVA, and research support from Novartis, the MS Society of GB & NI and the National MS Society (USA).

Karen Lee, none.Marco Salvetti received lecture fees from Biogen-Dompé,

research support from Bayer-Schering, Biogen-Dompé, Merck-Serono, Sanofi-Aventis.

Kersten Sharrock, none.Alan Thompson has received honoraria/support for travel for

consulting from BTG International, Biogen Idec, Merck Serono, Eisai Ltd, Novartis, and honoraria and support for travel for teach-ing from Serono Symposia International Foundation.

Ahmed Toosy, none.Paola Zaratin, none.Kim Zuidwijk, none.

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60

60 61

Working Groups Reportspresented at the

International Progressive MS Collaborative meeting

“Research strategy and prioritization discussioninvolving the Steering Committee

and Working Group representatives”

held in November 1-2, 2012At SOFITEL London Heathrow

62

Main Goal of the Initiative: “To expedite the development of effective disease modifying and symptom

management 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 progression

c) 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 progMS

d) in contrast, innate immunity (e.g. microglia, or yet to be identified subsets of leukocytes) may play a

very significant role

e) the approach will be initially focused on PPMS: we think it best represents the neurodegenerative

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 progression

f) 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

Experimental models for improved preclinicalevaluation of novel therapies

Working Group 1 - Report

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 rodents

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 degeneration

B) In vivo models: given that mechanistic information is severely lacking, a reasonable initial approach

will 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 TBA

Comments:

- 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.K. Stys

On behalf of the Experimental models for improved preclinical evaluation of novel therapies Working

Group

66

Target identification and repurposingWorking Group 2 - Report

1. Unmet needs in the Working Group area of interest (avoid duplications; include a confrontation

with our catalogues of existing spend on progressive MS; confront with other initiatives in the

field).

Patients with progressive forms of MS have few treatment options. New therapies can be developed by

careful elucidation of disease mechanism and identification of appropriate targets for intervention. This

approach may take many years and has failed, so far, to yield success. Continuation of this approach is

likely (and may continue) under existing funding mechanisms.

Given the objective of the IPMSC, a different approach should be run in parallel: it would be possible

consider more active management of the portfolios of the MS organizations. This ‘managed’ portfolio

approach is counter cultural in academic research. However, it may also free resources for the new

approaches.

In summary, we propose to add to the “canonical” long-term strategy, based on more traditional

approaches for the identification of mechanisms susceptible to therapeutic intervention, and

funded under the traditional calls, a short/medium term one, based on pragmatic approaches

and areas of research that have been ignored. Only the latter should be the one under the

auspices 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 of

research that have been ignored or underfunded.

Proposal 2.

An alternative approach to finding new treatments is to test existing drugs – the extreme version of this

approach 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 availability

of 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?

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 respect

to 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 informed

groups 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 effects

or 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 be

transferred 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 believed

that new ideas are needed, one approach to is the ‘Grand Challenge Exploration Grants’ used by the

Bill 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 new

research ideas from the community.

MS Progressive Disease Challenge. Twenty, one year, grants for €50,000. Applications – 2,000 words

with 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.

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 outcomes

b. Imaging outcomes

c. Fluid Biomarkers

d. Patient selection criteria

3. 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 DesignWorking 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?

72

3. Which international collaborative efforts should be undertaken that justify global funding

A. 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 profiles

B. Maximising recruitment and retention:

• Targeted literature searches

• Liaison/networking with other disease group groups

• Primary research

C. 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.

74

Symptom management and Rehabilitation strategiesWorking Group 5 - Report

The 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 of

symptomatic treatment. However, synergies with research on symptomatic treatment that is in line with

the 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) interventions

have so far focused on persons with mild and moderate disability while only in recent years, rehabilitation

trials 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 MS

and that overall greater disability is seen with increasing disease duration (SP and PP). In the cognitive

domain, patients with SPMS appear to be the most impaired especially in processing speed and working

memory.(1) .Preliminary evidence suggests that depression appears least often in PPMS (ref).

Unmet needs

The WG decided to focus on persons with moderate to severe disability, which is mostly associated

with SP MS and advanced PP MS. Walking, visual function, cognition and mood were valued as most

important 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 physical

capacities impacts on health indicators (physical fitness) and quality of life (depression, anxiety). In the

physical 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 higher

EDSS levels is sparse.(3; 4) The same is true for cognitive rehabilitation, which has tended to target

memory. 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.

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.

78

Reference List

(1) Langdon DW. Cognition in multiple sclerosis. Curr Opin Neurol 2011 Jun;24(3):244-9.

(2) Heesen C, Bohm J, Reich C, Kasper J, Goebel M, Gold SM. Patient perception of bodily functions in

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

Participants

80

Maria AbbracchioUniversity of MilanVia Balzaretti 9Milan, 20133ITALYEmail: [email protected]

Roberta AmadeoCommittee of People with MS (Chair)Italian MS Societyvia Operai 40Genova, 16149ITALYEmail: [email protected]

Jack AntelMcGill University3801 University 111Montreal, QC H3A 2B4CANADAEmail: [email protected]

Peer BanekeMS International Federation (CEO)SkylineHhouse200 Union StreetLondon, HP6 5HDUNITED KINGDOMEmail: [email protected]

Francesca AloisiIstituto Superiore di SanitàViale Regina Elena 299Rome, 00161ITALYEmail: [email protected]

Maria Pia AmatoDept. of Neurology University of FlorenceViale Morgagni 85Florence, 50134ITALYEmail: [email protected]

David BakerQueen Mary University of LondonBlizard InstituteLondon, N22 6JGUNITED KINGDOMEmail: [email protected]

Brenda BanwellThe Children’s Hospital of Philadelphia34th St. & Civic Center Blvd.Philadelphia, PA 19104UNITED STATESEmail: [email protected]

80 81

Sergio BaranziniUniversity of California San Francisco513 Parnassus AveRoom S-256San Francisco, CA 94143UNITED STATESEmail: [email protected]

Mario Alberto BattagliaItalian MS Foundation (Chair)Via Operai, 40Genova, 16149ITALYEmail: [email protected]

Bruce Bebo National MS SocietyResearch Programs Department5958 Bryant RdLake Oswego, OR 97035UNITED STATESEmail: [email protected]

Andrew BlightAcorda Therapeutics, Inc.420 Saw Mill River RoadArdsley, NY 10502UNITED STATESEmail: [email protected]

Frederik BarkhofVu University Medical CenterDe Boelelaan 1117Amsterdam, 1081 HVTHE NETHERLANDS Email: [email protected]

Luca Battistini Fondazione Santa LuciaVia del Fosso di Fiorano 63-65Via Ardeatina 306Rome, 00143ITALYEmail: [email protected]

Matthew BellizziUniversity of Rochester601 Elmwood Ave Box 645Rochester, NY 14642UNITED STATESEmail:[email protected]

Dennis BourdetteOregon Health & Science UniversityDepatment of Neurology L2263181 SW Sam Jackson Park RoadPortland, OR 97239UNITED STATESEmail: [email protected]

82

Amy BowenMS TrustSpirella BuildingBridge RoadLetchworth, Hertfordshire SG6 4ETUNITED KINGDOMEmail: [email protected]

Heather BrownThe Lancet Neurology32 Jamestown RoadCamden, London NW1 7BYUNITED KINGDOMEmail: [email protected]

Steven BuchsbaumBill and Melinda Gates Foundation500 Fifth Ave NorthSeattle, WA 98119UNITED STATESEmail: [email protected]

Cathy CarlsonNational MS SocietyResearch Information733 Third Avenue 3rd FloorNew York, NY 10017UNITED STATESEmail: [email protected]

Giampaolo BrichettoItalian MS SocietyResearch DepartmetVia Operai, 40Genova, 16149ITALYEmail: [email protected]

Wolfgang BrückUniversity Medical Center Göttingen, Department of NeuropathologyRobert-Koch-Str. 40Göttingen, Lower Saxony 37075GERMANYEmail: [email protected]

Peter CalabresiJohns HopkinsPathology 627600 N. Wolfe St.Baltimore, MD 21287UNITED STATESEmail: [email protected]

William Carroll Department of NeurologySir Charles Gairdner Hospital NedlandsWESTERN AUSTRALIA Email: [email protected]

82 83

Niamh CawleyUniversity College LondonUCL Institute Of NeurologyDept Brain Repair & rehabilitationQueen Square, LondonLondon, WC1N 3BGUNITED KINGDOMEmail: [email protected]

Siddharthan ChandranThe University of EdinburghCentre for Clinical Brain SciencesChancellor’s Building, 49 Little France Crescent,Edinburgh, Midlothian EH16 4SBUNITED KINGDOMEmail: [email protected]

Dhia ChandraratnaResearch DepartmentMS International Federation200 Union StreetLondon, SA70 7PUUNITED KINGDOMEmail: [email protected]

Olga CiccarelliUniversity College LondonInstitute of NeurologyQueen SquareLondon, WC1N 3BGUNITED KINGDOMEmail: [email protected]

Diego CentonzeTor Vergata UniversityViale Oxford 81Roma, Lazio 00133ITALYEmail: [email protected]

Jeremy ChatawayNational Hospital for Neurology and NeurosurgeryQueen SquareLondon, WC1N 3BGUNITED KINGDOMEmail: [email protected]

Peter Chin Novartis1 Health PlazaEast Hanover, NJ 07936UNITED STATESEmail: [email protected]

Timothy CoetzeeResearch Preograms DepartmentNational MS Society733 Third AvenueNew York, NY 10017UNITED STATESEmail: [email protected]

84

Jeffrey CohenCleveland ClinicMellen Center9500 Euclid AveCleveland, OH 44195UNITED STATES Email: [email protected]

Giancarlo ComiScientific Institute San RaffaeleVia Olgettina, 48Milan, 20132ITALYEmail: [email protected]

Jorge CorrealeRaul Carrea Institute for Neurological Research FLENIMontañeses 2325Buenos Aires, 1426ARGENTINAEmail: [email protected]

Anne CrossWashington University Sch MedicineCampus Box 8111; 660 S. Euclid AvenueDepartment of NeurologySt. Louis, MO 63110UNITED STATESEmail: [email protected]: [email protected]

Bruce CohenDepartment of Neurology Northwestern University, 710 North Lake Shore DriveAbbott Hall 1121 Chicago, IL 60611UNITED STATESEmail: [email protected]

Stephen Joel CoonsCritical Path Institute1730 E River RoadTucson, AZ 85718UNITED STATES Email: [email protected]

Matt CranerUniversity of OxfordMS Clinical Trials UnitJohn Radcliffe HospitalOxford, OX3 9DUUNITED KINGDOMEmail: [email protected]

Francesco CuccaConsiglio Nazionale delle RicercheIstituto di Ricerca Genetica e BiomedicaCittadella UniversitariaMonserrato, 09042ITALYEmail: [email protected]

84 85

Gary CutterUniversity of Alabama at Birmingham1665 University BlvdRyals Public Health Building 414Birmingham, AL 35243UNITED STATES

Ulrik DalgasAarhus UniversityDalgas Avenue 4Aarhus, Jylland 8000DENMARKEmail: [email protected]

Gabriele DatiItalian MS SocietyResearch DepartmentVia Operai 40Genoa, 16149ITALY Email: [email protected]

Brigit De JongUniversity Nijmegen Medical CentreSt RadboudUbbergseveldweg 85Nijmegen, Gelderland 6522 HDTHE NETHERLANDSEmail: [email protected]

Sandra D’AlfonsoA Avogadro UniversityVia Solaroli 17Novara, 28100ITALYEmail: [email protected]

Chiara DamicoItalian MS SocietyResearch DepartmentVia Operai 40Genoa, 16149ITALYEmail: [email protected]

Philip De JagerBrigham and Women’s Hospital77 Ave Louis Pasteur, NRB168Boston, MA 02115UNITED STATESEmail: [email protected]

Nicola De Stefano University of SienaViale Bracci 2Siena, Tuscany 53100ITALY Email: [email protected]

86

Elga De VriesDept. of Molecular Cell Biology and ImmunologyP.O.Box 7057Amsterdam, 1007MVTHE NETHERLANDSEmail: [email protected]

Nicoletta Di GiambattistaItalian MS SocietyFund Raising DepartmentVia Operai 40Genoa, 16149ITALYEmail: [email protected]

Monica DiLucaEuropean Brain CouncilFondation UniversitaireUniversity of Milanovia Balzaretti, 9Milano, 20133ITALYEmail: [email protected]

Ranjan DuttaCleveland Clinic9500 Euclid Avenue, NC-30Cleveland, OH 44118UNITED STATESEmail: [email protected]

John DeLucaKessler Foundation1199 Pleasant Valley WayWest Orange, NJ 07052UNITED STATESEmail: [email protected]

Ricarda DiemUniversity Clinic HeidelbergDep. of NeurooncologyIm Neuenheimer Feld 400Heidelberg, Baden-Württemberg 66120GERMANYEmail: [email protected]

Giulio DisantoUniversity of OxfordLe Gros Clark BuildingSouth Parks RoadOxford, OX1 3QXUNITED KINGDOM Email: [email protected]

Barbara ErbaItalian MS SocietyCommunication DepartmentVia Operai 40Genoa, 16149ITALYEmail: [email protected]

86 87

Nikolaos EvangelouNottingham University3 Castle GroveThe ParkNottingham, NG8 1DNUNITED KINGDOMEmail: [email protected]

Chiara FenoglioUniversity of Milan, IRCCS Cà Granda Foundation Ospedale Maggiore Policlinicovia F. Sforza 35Milan, 20122ITALYEmail: [email protected]

Charles Ffrench-ConstantMRC Centre for Regenerative Medicine University of EdinburghEdinburgh boQuarter5 Little France DriveEdinburgh, Midlothian EH164UUUNITED KINGDOMEmail: [email protected]

Elizabeth FisherCleveland ClinicDepartment of Biomedical Eng’g ND209500 Euclid AvenueCleveland, OH 44121UNITED STATESEmail: [email protected]

Anthony FeinsteinUniversity of TorontoSunnybrook Health Sciences CentreDepartment of PsychiatryToronto, ON M4N3M5CANADAEmail: [email protected]

Peter FeysHasselt UniversityAgoralaan Gebouw ADiepenbeek, 3590BELGIUMEmail: [email protected]

Massimo FilippiSan Raffaele Scientific Institute and Vita-Salute San Raffaele UniversityVia Olgettina, 60Milan, 20132ITALYEmail: [email protected]

Matteo FlorisConsiglio Nazionale delle RicercheCRS4Parco PolarisLoc. PixinamannaPula, Sardinia 09077ITALYEmail: [email protected]

88

Robert FoxCleveland Clinic9500 Euclid Ave, U-10Cleveland, OH 44195UNITED STATESEmail: [email protected]

Gordon FrancisNovartis1451 Montgomery St #1San Francisco, CA 94133UNITED STATESEmail: [email protected]

Lars FuggerUniversity of OxfordWeatherall Institute of Molecular MedicineJohn Radcliffe HospitalOxford, OX3 9DSUNITED KINGDOMEmail: [email protected]

Giuseppe GazzolaItalian MS SocietyCommunication DepartmentVia Operai 40Genoa, 16149ITALYEmail: [email protected]

Jennifer FreemanPlymouth UniversityPeninsula Allied Health CentreDerriford RdPlymouth, Devon PL6 8BHUNITED KINGDOMEmail: [email protected]

Marta FumagalliUniversità degli Studi di MilanoBalzaretti 9Milan, 20133ITALYEmail: [email protected]

Roberto FurlanOspedale San RaffaeleVia Olgettina, 60Milano, 20132ITALYEmail: [email protected]

Daniela GalimbertiUniversity of Milan, Ospedale Policlinicovia F. Sforza 35Milan, 20122ITALYEmail: [email protected]

88 89

Gavin GiovannoniQueen Mary University of LondonThe Royal London HospitalWhite ChapelLondon, E1 1BBUNITED KINGDOMEmail: [email protected]

Susan GoelzMS Society6900 SE 35th AvePortland, OR 97202UNITED STATESEmail: [email protected]

John GoldingEuropean MS PlatformGroenliveien 21Fredrikstad, 1605NORWAYEmail: [email protected]

Roberta GuglielminoItalian MS SocietyResearch DepartmentVia Operai 40Genoa, 16149ITALYEmail: [email protected]

Jeroen Geurts,VU University Medical CenterVan der Boechorststraat 7Amsterdam, 1082 MSTHE NETHERLANDSEmail: [email protected]

Peter Goodfellow14 Parliament HillLondon, NW3 2SYUNITED KINGDOMEmail: [email protected]

Andrew Goodman. University of Rochester601 Elmwood AvenueRochester, NY 14618UNITED STATESEmail: [email protected]

Päivi HämäläinenMasku Neurological Rehabilitation CentreVaihemäentie 10Masku, 21250FINLANDEmail: [email protected]

90

Hans-Peter HartungHeinrich-Heine-UniversityMoorenstr. 5Dept. of NeurologyDuesseldorf, NRW 40225GERMANYEmail:[email protected]

Christoph HeesenUniversity Medical Center HamburgMartinistrasse 52Hamburg, 20246GERMANYEmail: [email protected]

Jeremy HobartPlymouth University Peninsula Schools of Medicine & DentistryRoom N13, ITTC Building,1 Davy RoadTamar Science ParkPlymouth, Devon PL6 8BXUNITED KINGDOMEmail: [email protected]

Lynn HudsonCritical Path Institute1730 E River RoadTucson, AZ 85718UNITED STATESEmail: [email protected]

Liat HayardenyTeva Pharmaceuticals37 Yehuda Hanasie stTel Aviv, 69391ISRAELEmail: [email protected]

Thomas Henze Reha-Zentrum NittenauEichendorffstr. 21Nittenau, Bavaria 93149GERMANY Email: [email protected]

Rogier HintzenErasmus MCsgavendijkwal 230Rotterdam, 3015GDTHE NETHERLANDSEmail: [email protected]

Edward HollowayUK MS SocietyResearch DepartmentMS National Centre372 Edgware RoadLondon, NW2 6NDUNITED KINGDOMEmail: [email protected]

90 91

Matilde IngleseMount Sinai School of MedicineOne Gustave L. Levy Place Box 1137New York, NY 10029UNITED STATESEmail: [email protected]

Timm Jessen Bionamics plcGottorfstrasse 3Schleswig, 24837GERMANY Email: [email protected]

Raj KapoorNational Hospital for NeurologyQueen SquareLondon, WC1N 3BGUNITED KINGDOMEmail: [email protected]

Bernd KieseierHeinrich-Heine-UniversityMoorenstrasse 5Düsseldorf, NRW 40225GERMANYEmail: [email protected]

Weyman JohnsonMS International Federation (Chair)249 Crooked Creek LaneAthens, GA 30607UNITED STATESEmail: [email protected]

Ludwig KapposUniversity Hospital BaselPetersgraben 4Basel, 4031SWITZERLANDEmail: [email protected]

Hans LassmannMedical University of ViennaSpitalgasse 4Wien, A-1090AUSTRIAEmail: [email protected]

Karen LeeMS Society of CanadaResearch Department175 Bloor Street EastNorth Tower, Suite 700Toronto, ON M4W 3R8CANADAEmail: [email protected]

92

Letizia LeocaniSan Raffaele Scientific InstituteVia Olgettina n. 60Milan, 20132ITALY Email: [email protected]

David LeppertF. Hoffmann-La Roche AGGrenzacherstrasse 124Basel, 4070SWITZERLANDEmail: [email protected]

Albert LoBrown-VA255 Promenade StreetUnit 630Providence, RI 02908UNITED STATESEmail: [email protected]

Claudia LucchinettiMayo Clinic200 First Street SWRochester, MN 55905UNITED STATESEmail: [email protected]

John LincolnUniversity of Texas, UT Health6310 Almeda RoadApt. 1219Houston, TX 77021UNITED STATESEmail: [email protected]

Catherine LubetzkiUniversity Pierre and Marie CurieSalpetriere Hospital47 Bd de l’Hopital,Paris, 75013,FRANCEEmail: [email protected]

Paola LustroItalian MS SocietyCommunication DepartmentVia Operai 40Genoa, 16149ITALYEmail: [email protected]

Malcolm MacleodUniversity of EdinburghWestern General HospitalCrewe RoadEdinburgh, EH4 2XUUNITED KINGDOMEmail: [email protected]

92 93

Giovanni MancardiUniversity of GenoaLargo P. Daneo,3 - 16132 Genoa, 16132ITALYEmail: [email protected]

Enrica MarcenaroItalian MS SocietyCommunication DepartmentVia Operai 40Genoa, 16149ITALYEmail: [email protected]

Gianvito MartinoSan Raffaele HospitalVia Olgettina, 58Milan, 20132ITALYEmail: [email protected]

Victoria MatthewsRehabilitation in MS - RIMS28 Riverside GardensRomsey, SO51 8HNUNITED KINGDOMEmail: [email protected]

Filippo Martinelli BoneschiScientific Institute San RaffaeleVia Olgettina 48Milan, 20132ITALYEmail: [email protected]

Donna MastermanRocheGrenzacherstrasse 183Bay 074/3W.306BBasel, 4070SWITZERLANDEmail: [email protected]

Paul MatthewsImperial College/GlaxoSmithKlineHammersmith Hospital, Burlingdon DanesDuCane RoadLondon, W12 0NNUNITED KINGDOMEmail: [email protected]

Graham McReynoldsNational MS Society2003 SE Larch Ave.Portland, OR 97214UNITED STATESEmail: [email protected]

94

Jan MeilofDpt Neurology, University Medical Center MS-Centre Northern NetherlandsGroningenPO Box 30001Groningen, 9700RBTHE NETHERLANDSEmail: [email protected]

Mary MilgromNational MS Society900 South BroadwayDenver, CO 80209UNITED STATESEmail: [email protected]

Xavier MontalbanCemcat - Vall d’Hebron University HospitalEdifici Cemcat - Vall d’Hebron University HospitalPg. Vall d’Hebron, 119-129Barcelona, 08035SPAINEmail: [email protected]

Francesco MoriUniversità Tor Vergataviale Oxford 81Roma, 00133ITALYEmail: [email protected]

David MillerUniversity College London UCL Institute of NeurologyNMR Research UnitQueen SquareLondon, WC1N 3BGUNITED KINGDOMEmail: [email protected]

Antonella MorettiItalian MS Society (CEO)Via Operai 40Genoa, 16149ITALYEmail: [email protected]

Robert MotlUniversity of Illinois at Urbana-Champaign906 S. Goodwin AveUrbana, IL 61801UNITED STATES Email: [email protected]

Paolo MuraroImperial College LondonBurlington Danes Buiding, Imperial CollegeDu Cane RoadLondon, W12 0NNUNITED KINGDOMEmail: [email protected]

94 95

Ceri NapierMS International Federation3rd Floor, Skyline House200 Union StreetLondon, SE1 0LXUNITED KINGDOM Email: [email protected]

Jiwon OhJohns Hopkins University600 N. Wolfe St.Pathology Building, Room 627Baltimore, MD 21287UNITED STATESEmail: [email protected]

Michael PanzaraGenzyme500 Kendall StCambridge, MA 02142UNITED STATESEmail: [email protected]

John PetkauUniversity of British ColumbiaDepartment of Statistics3182 Earth Sciences Building2207 Main MallVancouver, BC V6T 1Z4CANADAEmail: [email protected]

Lucia PalmisanoIstituto Superiore di SanitàViale Regina Elena 299Rome, 00161ITALYEmail: [email protected]

Graziano PesoleUniversity of Bari and IBBE-CNRvia Amendola 165/ABari, 70125ITALYEmail: [email protected]

Laura PiccioWashington University in St Louis660 South Euclid, Campus box 8111St Louis, MO 63110UNITED STATESEmail: [email protected]

Chris PolmanVU Medical CentreBoelelaan 1117Amsterdam, 1081HVTHE NETHERLANDSEmail: [email protected]

96

Michela PonzioItalian MS Society Research Department Via Operai 40Genoa, 16149ITALYEmail: [email protected]

Carlo PozzilliSapienza University of RomeViale dell’Universita’ 30Roma, 00185ITALYEmail: [email protected]

Maura PugliattiUniversity of SassariViale San Pietro 10Sassari, 07100ITALYEmail: [email protected]

Daniel ReichNational Institutes of Health10 Center Drive MSC 1400Building 10 Room 5C103Bethesda, MD 20012UNITED STATESEmail: [email protected]

Marco PrinzUniversity of FreiburgBreisacherstr. 64Freiburg, D-79100GERMANYEmail: [email protected]

Sreeram RamagopalanQueen Mary University of LondonBlizard institute4 Newark StreetLondon, E1 2ATUNITED KINGDOMEmail: [email protected]

Stephen ReingoldScientific & Clinical Review Associates, LLCPO Box 34239 Brinton Hill RoadSalisbury, CT 06068-0342UNITED STATESEmail: [email protected]

Richard ReynoldsImperial College LondonDivision of Brain SciencesHammersmith HospitalLondon, W12 0NNUNITED KINGDOMEmail: [email protected]

96 97

Nancy RichertBiogenIdecBio6-614 Cambridge CtrCambridge, MA 02142UNITED STATESEmail: [email protected]

Nick RijkeUK MS SocietyResearch DepartmentMS National Centre372 Edgware RoadLondon, NW2 6NDUNITED KINGDOMEmail: [email protected]

Maria RoccaOspedale San Raffaelevia Olgettina 60Milan, 20132ITALYEmail: [email protected]

Marco SalvettiSapienza University - FISMS. Andrea Hospital, 1035 via di GrottarossaRome, 00189ITALYEmail: [email protected]

Bruce RobertsGenzyme49 New York AvenueFramingham, MA 01701UNITED STATESEmail: [email protected]

Richard RudickCleveland Clinic9500 Euclid Ave., JJ36Cleveland, OH 44195UNITED STATESEmail: [email protected]

Yves SavoieMS Society of Canada (CEO)175 Bloor St E, Suite 700North TowerToronto, ON M4W3R8CANADAEmail: [email protected]

Stephen SawcerUniversity of CambridgeAddenbrooke’s Hospital, BOX 165Hills RoadCambridge, CB2 0QQUNITED KINGDOMEmail: [email protected]

98

Antonio ScalfariImperial CollegeDu Cane roadHammersmith HospitalLondon, W12 0NNUNITED KINGDOMEmail: [email protected]

Elio ScarpiniUniversity of Milan, Ospedale Policlinicovia F. Sforza, 35Milan, 20122ITALYEmail: [email protected]

Kenneth SmithUniversity College LondonUCL Institute of NeurologyQueen SquareLondon, WC1N 3BGUNITED KINGDOMEmail: [email protected]

Alessandra SolariFoundation Neurological InstituteC. BestaVia Celoria 11Milan, 20133ITALYEmail: [email protected]

Finn SellebjergDanish Multiple Sclerosis CenterCopenhagen University Hospital RigshospitaletBlegdamsvej 9Copenhagen, 2100DENMARKEmail: [email protected]

Kathryn SmithFast Forward (NMSS)154 Hamburg RoadLyme, CT 06371UNITED STATESEmail: [email protected]

Per Soelberg SorensenRigshospitalet, Copenhagen University HospitalBlegdamsvej 9Copenhagen, DK-2100DENMARKEmail: [email protected]

Maria Pia SormaniUniversity of GenoaVia Pastore 1Genoa, 16132ITALYEmail: [email protected]

98 99

Christine Stadelmann-NesslerUniversity Medical Center,NeuropathologyRobert-Koch-Str. 40Göttingen, 37099GERMANYEmail: [email protected]

Olaf Stuve University of Texas SouthwesternMedical CenterDepartment of Neurology5223 Harry Hines Boulevard, #J3.118Dallas, TX 75390UNITED STATESEmail: [email protected]

Peter StysUniversity of Calgary3330 Hospital Dr.Calgary, AB T2N 4N1CANADAEmail: [email protected]

Carla TaveggiaSan Raffaele Scientific Institutevia Olgettina 58Milan, 20132ITALYEmail: [email protected]

Anthony TraboulseeUniversity of British ColumbiaUBC Hospital2211 Wesbrook Mall, room s199Vancovuer, BC V6T 2B5CANADAEmail: [email protected]

Sarah TabriziUniversitity College LondonUCL Dept of Neurodegenerative DiseaseUCL Institute of NeurologyQueen SquareLondon, WC1N 3BGUNITED KINGDOMEmail: [email protected]

Luigi TesioRehabilitation MedicineUniversità degli Studivia Giuseppe Mercalli 32Milan, 20122ITALYEmail: [email protected]

Alan ThompsonUniversity College LondonUCL Institute of Neurology, box 9Queen SquareLondon, WC1N 3BGUNITED KINGDOMEmail: [email protected]

100

Jean-Louis ThonnardUCLouvain53 avenue MounierBrussels, 1200BELGIUMEmail: [email protected]

Maria TrojanoUniversity of BariDepartment of Neurological & Psychiatric SciencesPoliclinico Piazza G. Cesare,11Bari, 70121ITALYEmail: [email protected]

Antonio UccelliUniversity of GenoaLargo P. Daneo 3Genoa, 16132ITALYEmail: [email protected]

Renato UmetonCytoSolve Inc.701 Concord AvenueCambridge, MA 02138UNITED STATESEmail: [email protected]

Bruce TrappCleveland Clinic9500 Euclid AveNC30Cleveland, OH 44195UNITED STATESEmail: [email protected]

Philippe TruffuinetSanofi1 Avenue Pierre BrossoletteChilly-Mazarin, 91385FRANCEEmail: [email protected]

Bernard UitdehaagVU University Medical CenterP.O. Box 7057Amsterdam, 1007 MBTHE NETHERLANDSEmail: [email protected]

Steven Van de PavertUniversity College LondonQueen SquareLondon, WC1N 3BGUNITED KINGDOMEmail: [email protected]

100 101

Emmanuelle WaubantUniversity of CaliforniaSan Francisco675 Nelson Rising Lane, room 221San Francisco, CA 94158UNITED STATESEmail: [email protected]

Howard WeinerBrigham and Women’s Hospital77 Avenue Louis PasteurHIM Bldg Room 730Boston, MA 02115UNITED STATESEmail: [email protected]

Jonathan WillmerEMD Serono45A Middlesex TurnpikeBillerica, MA 01821UNITED STATESEmail: [email protected]

Cynthia ZagieboyloNational MS Society6353 North Avon RoadHoneoye Falls, NY 14472UNITED STATESEmail: [email protected]

Martin WeberUniversitätsmedizin GöttingenRobert-Koch Strasse 40Göttingen, Niedersachsen 37075GERMANYEmail: [email protected]

Lesley WhiteUniversity of Georgia500 lacenbark Dr.Athens, GA 30605UNITED STATESEmail: [email protected]

Jerry WolinskyUniversity of Texas Health Science Center at Houston6431 Fannin StreetHouston, TX 77030UNITED STATESEmail: [email protected]

Scott ZamvilUniversity of CaliforniaSan Francisco675 Nelson Rising Lane, NS-215ASan Francisco, CA 94158UNITED STATESEmail: [email protected]

102

Paola ZaratinItalian MS SocietyResearch Department Via Operai 40Genoa, 16149ITALYEmail: [email protected]

Tjalf ZiemssenUniversity Clinic, DresdenFetscherstr. 74Dresden, Sachsen 01307GERMANYEmail: [email protected]

102 103

Expense Reimbursement Guidelines & Voucher

104

IF REQUESTED, reimbursement will be made to meeting participants for travel expenses incurred for

travel to the First Scientific Conference of the International Progressive MS Collaborative. Expense

vouchers 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 meeting

Questions relating to reimbursement should be addressed to [email protected]

Revised 2/6/2013

EXPENSE REIMBURSEMENT GUIDELINES

104 105

Payee:

Mail my Check to:

EXPENSE VOUCHER

(Volunteers and Others)

Name & Date of Meeting

International Progressive MS CollaborativeFIRST SCIENTIFIC CONFERENCE

FEBRUARY 6-8, 2013

Itinerary - From: (City)

To: MILAN, ITALY

I certify that this statement is correct and that expenses were incurred by me in performance of this meeting.

Leave Blank:$_____________

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 Paid

Airfare

Train/Bus

Mileage: ____@ 56.5 cents

Parking/Tolls

Taxi/Airport Bus/Tips

Hotel

Meals

Other: Explain on reverse

Totals Amount Claimed

Date2/5/2013US$

Date2/6/2013US$

Date2/7/2013US$

Date2/8/2013US$

Date Date TOTALUS $

Dept & Program

AP 4201

Instructions for Completion

1. List expenses by day.2. Attach original receipts for all

expenses claimed3. Total columns across and at

bottom of each column.4. Make a copy for your records5. Sign voucher and submit original

with attachments to:

Eileen MadrayResearch Programs Department, NMSS

733 Third Avenue, 3rd FlrNew York, NY 10017-3288

By: MARCH 15, 2013

106

Sunday (Insert Date)

Monday

Tuesday

Wednesday

Thursday

Friday

Saturday

International Progressive MS CollaborativeFirst Scientific Conference

February 6-8, 2013, Milan ItalyExpense Reimbursement Form (Page 2 of 2)

Explanations

International Progressive MS CollaborativeFirst Scientific Conference

February 6-8, 2013, Milan ItalyExpense Reimbursement Form (Page 2 of 2)

Explanations

106 107

Edited by Chiara Damico - Italian MS Society

Ipmsc milan meeting_february2013_booklet

Health & Medicine

critical path

optical coherence

ms international

phase ii trials

multiple sclerosis

existing therapeutic

acute optic

secondary