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Dr. Fabiola Martin University of York UK

The Need for International Clinical Trials for Patients with HTLV-1 associated myelopathy A Neglected Disease!. Dr. Fabiola Martin University of York UK. HTLV-1 Fighters. Centre for Immunology and Infection. Overview. Part A Evidence based Treatment Part B

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Dr. Fabiola Martin University of York UK

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  1. The Need for International Clinical Trials for Patients with HTLV-1 associated myelopathy A Neglected Disease! Dr. Fabiola MartinUniversity of York UK

  2. HTLV-1 Fighters

  3. Centre for Immunology and Infection

  4. Overview Part A Evidence based Treatment Part B Planned multicentre international HAM/TSP trial

  5. Treatment

  6. Treatment

  7. 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.

  8. HAM/TSPClinical Trial STUDY groupJune 2011

  9. UK USA Japan Brazil HAM/TSP Clinical Trial 001

  10. Benefits/Objectives Pool Know How Pool Recourses Clinical Data Base Laboratory Data Base Collect evidence of efficacy of treatment regimes for different HAM/TSP subgroups. INCREASE OUR CHANCE TO ATTRACT GRANTS.

  11. Salvador • Prof Dr Bernardo Galvao-Castro • Dr Fernanda Grassi HTLV Reference Centre EscolaBahiana de Medicina e SaudePublica FundacaoOswaldo Cruz/Fiocruz 1070 HTLV-1 positive patients registered 50% regularly followed up

  12. Rio • Dr Marcus T Silva • Prof AbelardoAraujo Instituto de PesquisaClinicaEvandroChagas Laboratorio de PesquisaClinicaemNeuroinfeccao FundacaoOswaldo Cruz/Fiocruz 1000 HTLV positive patients registered

  13. Japan • Dr Yoshi Yamano St Mariana University School of Medicine Institute of Medical Science Department of Rare Diseases Research Ministry of Health, Labour and Welfare 100 patients with definite HAM/TSP Additional 300 patients (12 hospital)

  14. Japan • DrErinkoAtoni • DrEisukeIoune Clinical Trial Coordinating Centre Kitasato University of Research Centre of Clinical Pharmacology Government funded • Trial management • Patients registration/minimisatin • Data management • Central monitoring • Statistical analysis

  15. NIH/USA • Prof Steven Jacobson • Dr Irene C.M Cortese National Institutes of Health, Viral Immunology Section, NeuroimmunologyBranch 200 HTLV-1 positive patients registered 10 HAM/TSP patients Largest cohort in the USA

  16. UK • Dr Graham P Taylor National Centre for Human Retrovirology Imperial College Healthcare NHS Trust Non-endemic, Afro-Caribbean 350 HTLV positive patients registered 85 HAM/TSP patients Largest cohort in Europe

  17. York • Dr Fabiola Martin Centre for Immunology and Infection Hull and York Medical School University of York Chief investigator Coordinator of the HAM/TSP Clinical Trial Study-Group • Prof Martin Bland Clinical Trial statistician

  18. International Trials Which HAM/TSP patients? Which drug? Which outcome?

  19. Which Patients? Rapidly progressive (1) severe Chronic progressive (active, 2a) Slow progressor Clinical severity Chronic progressive (inactive, 2b) Non-progressor Chronic mild (3) mild （years） 10 20 Y.Yamano et al June 2011, modified

  20. Which Drug? Nothing Corticosteroids Interferon-alpha Ciclosporin-A Monocloncal-AB Sodium Valproate Raltegravir

  21. Which Outcome? 10m Timed Walk deteriorates by a mean 2 second/ year Over 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)

  22. HAMLET-P HAM/TSP Multicentre Exploratory Trial-Prednisolone

  23. Study flow sheet

  24. ALL HAM patients Able to walk 10m iv/po Steroid Off treatment Minimisation Rapid po Steroid Off treatment Slow DB RCT Placebo Off treatment Non Observation

  25. Objectives Primary 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

  26. Outcome measures Primary endpoints 10m TW Secondary endpoints Many!

  27. 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

  28. Participating sites: Brazil/Japan/ UK/USA HAMLET-P CTCC (Kitasato Uni) Study Management Registration/Minimisation Data management Handling of safety information Data monitoring and on-site monitoring in Japan Drug distribution Statistical analysis Study agents To each site Tokyo Women’s Medical Univ. NOPRO Pharma NIPPON EXPRESS IDMC Audit Key controller Stores & Ships study agents Delivery Study agents Independent monitoring

  29. Needs FUNDING: Clinical trial in JAPAN & NIH = OK CTCC: financed by Japan Application to Medical Research Council-UK to fund Brazil & UK was rejected 19 Sept 2012 feedback awaited Brazil is applying to Fiocruz

  30. Future Progress in Biomarker studies PhD/PostDocand physician exchange programs between UoY and Fiocruz HAMLET-PC: Prednisolone vsCiclosporin-A HAMLET-?INF: winner against Interferon HAMLET-? Physio: winner+/-intense Physiotherapy CNS brain volume studies with NIH HAM/TSP proviral DNA threshold study: Dr F Grassi/ Prof Bernardo Galvao-Castro Active patient and public involvement

  31. Thank you. Yoshi Yamano Eriko Aotani Eisuke Ioune Bernardo Galvao-Castro Fernanda Grassi Ramon Kruschewsky Marcus TT Silva Abelardo Araujo Steve Jacobson Irene Cortese Raya Massoud Graham Taylor Martin Bland University of York Santander

  32. Centre for Immunology and Infection

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