The Need for International Clinical Trials for Patients with HTLV-1

associated myelopathy A Neglected Disease!

Dr. Fabiola MartinUniversity of York

UK

HTLV-1 Fighters

Centre for Immunology and Infection

Overview

Part AEvidence based TreatmentPart BPlanned multicentre international HAM/TSP trial

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

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

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.

HAM/TSPCLINICAL TRIAL STUDY GROUPJUNE 2011

Brazil

UK

Japan USA

HAM/TSP Clinical Trial

001

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.

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

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

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)

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

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

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

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

International Trials

Which HAM/TSP patients?Which drug?Which outcome?

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

Which Drug?

NothingCorticosteroidsInterferon-alphaCiclosporin-AMonocloncal-ABSodium ValproateRaltegravir

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)

HAM/TSP Multicentre Exploratory Trial-Prednisolone

Study flow sheet

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

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

Outcome measuresPrimary endpoints

10m TW

Secondary endpoints Many!

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

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

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

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

Thank you.

Yoshi YamanoEriko AotaniEisuke IouneBernardo Galvao-CastroFernanda GrassiRamon KruschewskyMarcus TT SilvaAbelardo Araujo

Steve JacobsonIrene CorteseRaya MassoudGraham TaylorMartin Bland

University of YorkSantander

Centre for Immunology and Infection