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The Need for International Clinical Trials for Patients with HTLV-1
associated myelopathy A Neglected Disease!
Dr. Fabiola MartinUniversity of York
UK
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HTLV-1 Fighters
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Centre for Immunology and Infection
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Overview
Part AEvidence based TreatmentPart BPlanned multicentre international HAM/TSP trial
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TreatmentGroups Drug N Stage Length Outcome
Antiretovirals Lamivudine 5 any 10m Transient, sig: 1/5
Zidovudine 21 any 2w- 6m None- transient
Lamivudine + Zidovudine
16 any 12m none
Tenofovir 6 any 3m-12m none
Raltegravir 5 any 12m No clinical benefittransient reduction of pVL
Steroids Prednisolone/Methylprednisolone/ Danazol
201 any 1m-2y Almost always transient
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TreatmentGroups Drug N Stage Length Outcome
Steroid sparing
Interferon α or β1a 291 any 1m-6m Transient at 3MUReduction in pVL
Azathioprine 9 any 1-3m Some
Pentoxyfylline 15 >3years 1m Transient
Dacluzimab (humanised anti-Tac)
9 Any 14 w Some clinical improvement Reduction in pVL
Ciclosporine-A 7 < 2years 12m Some clinical improvement Reduction in CSF viral load
HDAC inhibitors
Sodium valproate 16 >2y 3m-2y Transient worseningReduction in viral load
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Urgently Needed
International collaborations are needed to test drugs prospectively in a controlled trials and make head to
head comparisons of different treatment strategies depending on
HAM/TSP staging.
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HAM/TSPCLINICAL TRIAL STUDY GROUPJUNE 2011
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Brazil
UK
Japan USA
HAM/TSP Clinical Trial
001
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Benefits/Objectives
Pool Know HowPool RecoursesClinical Data BaseLaboratory Data Base
Collect evidence of efficacy of treatment regimes for different HAM/TSP subgroups.
INCREASE OUR CHANCE TO ATTRACT GRANTS.
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Salvador
• Prof Dr Bernardo Galvao-Castro• Dr Fernanda GrassiHTLV Reference CentreEscola Bahiana de Medicina e Saude PublicaFundacao Oswaldo Cruz/Fiocruz
1070 HTLV-1 positive patients registered50% regularly followed up
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Rio
• Dr Marcus T Silva• Prof Abelardo AraujoInstituto de Pesquisa Clinica Evandro ChagasLaboratorio de Pesquisa Clinica em NeuroinfeccaoFundacao Oswaldo Cruz/Fiocruz
1000 HTLV positive patients registered
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Japan
• Dr Yoshi YamanoSt Mariana University School of MedicineInstitute of Medical ScienceDepartment of Rare Diseases ResearchMinistry of Health, Labour and Welfare
100 patients with definite HAM/TSPAdditional 300 patients (12 hospital)
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Japan• Dr Erinko Atoni• Dr Eisuke IouneClinical Trial Coordinating Centre Kitasato University of Research Centre of Clinical
PharmacologyGovernment funded
– Trial management– Patients registration/minimisatin– Data management– Central monitoring– Statistical analysis
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NIH/USA
• Prof Steven Jacobson• Dr Irene C.M CorteseNational Institutes of Health, Viral Immunology Section,
Neuroimmunology Branch
200 HTLV-1 positive patients registered10 HAM/TSP patientsLargest cohort in the USA
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UK
• Dr Graham P TaylorNational Centre for Human RetrovirologyImperial College Healthcare NHS TrustNon-endemic, Afro-Caribbean
350 HTLV positive patients registered85 HAM/TSP patients Largest cohort in Europe
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York
• Dr Fabiola MartinCentre for Immunology and InfectionHull and York Medical SchoolUniversity of York
Chief investigator Coordinator of the HAM/TSP Clinical Trial Study-Group
• Prof Martin BlandClinical Trial statistician
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International Trials
Which HAM/TSP patients?Which drug?Which outcome?
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Which Patients?
Rapidly progressive (1)
Chronic progressive (active, 2a)
Chronic mild (3)
10 20( years)
severe
mild
Chronic progressive (inactive, 2b)
Clinicalseverity
Y.Yamano et al June 2011, modified
Slow progressor
Non-progressor
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Which Drug?
NothingCorticosteroidsInterferon-alphaCiclosporin-AMonocloncal-ABSodium ValproateRaltegravir
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Which Outcome?
10m Timed Walk deteriorates by a mean 2 second/ yearOver 6 months:Mean intra-patient variability 8.31 seconds (95% CI: 7.09 to 9.74)Mean inter-patients variability 19.9 seconds (95% CI: 16.7 to 23.7)
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HAM/TSP Multicentre Exploratory Trial-Prednisolone
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Study flow sheet
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ALL HAM patients Able to walk 10m
po Steroid
Placebo
Non
Rapid
iv/po Steroid
Minimisation
Slow DB RCT
Observation
Off treatment
Off treatment
Off treatment
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ObjectivesPrimary objectives:Efficacy
Secondary objectives:
1. Safety & Tolerance
2. Biomarkers of subgroup characterisation, progression and treatment response of HAM/TSP
3. Strengthen of the international HAM CTG consortium
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Outcome measuresPrimary endpoints
10m TW
Secondary endpoints Many!
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Management
Sponsors/Auditors/Monitoring
Clinical Trial Coordination Centre
Trial Management Group: Locally, 12 x/year
Trial Steering Group: Internationally, 4x/year
Data Safety & Monitoring Board: Independent, 2x year
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HAMLET-P CTCC(Kitasato Uni)
Study ManagementRegistration/MinimisationData managementHandling of safety informationData monitoring and on-site monitoring in JapanDrug distributionStatistical analysis
NOPRO Pharma
NOPRO Pharma
Study agents
Tokyo Women’s Medical Univ.
Tokyo Women’s Medical Univ.
Key controllerStores & Ships study agents
NIPPON EXPRESS
NIPPON EXPRESS
Delivery
Study agentsTo each
site
Participating sites:Brazil/Japan/ UK/USA
Independent monitoring
IDMCAudit
IDMCAudit
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Needs
FUNDING:Clinical trial in JAPAN & NIH = OKCTCC: financed by JapanApplication to Medical Research Council-UK to
fund Brazil & UK was rejected 19 Sept 2012 feedback awaitedBrazil is applying to Fiocruz
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Future
Progress in Biomarker studies PhD/PostDoc and physician exchange programs between UoY and FiocruzHAMLET-PC: Prednisolone vs Ciclosporin-A HAMLET-?INF: winner against InterferonHAMLET-? Physio: winner+/-intense PhysiotherapyCNS brain volume studies with NIHHAM/TSP proviral DNA threshold study:
Dr F Grassi/ Prof Bernardo Galvao-CastroActive patient and public involvement
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Thank you.
Yoshi YamanoEriko AotaniEisuke IouneBernardo Galvao-CastroFernanda GrassiRamon KruschewskyMarcus TT SilvaAbelardo Araujo
Steve JacobsonIrene CorteseRaya MassoudGraham TaylorMartin Bland
University of YorkSantander
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Centre for Immunology and Infection