Transcript HAM/TSP CLINICAL TRIAL STUDY GROUP JUNE 2011 Brazil 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
Planned multicentre international HAM/TSP trial
Treatment
Groups
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 benefit
transient reduction of
pVL
1m-2y
Almost always
transient
Steroids
Prednisolone/
201 any
Methylprednisolone
/ Danazol
Treatment
Groups
Drug
N
Steroid
sparing
Interferon α or β1a
HDAC
inhibitors
Stage
Length
Outcome
291 any
1m-6m
Transient at 3MU
Reduction in pVL
Azathioprine
9
any
1-3m
Some
Pentoxyfylline
15
>3years
1m
Transient
Dacluzimab
(humanised antiTac)
9
Any
14 w
Some clinical
improvement
Reduction in pVL
Ciclosporine-A
7
< 2years 12m
Some clinical
improvement
Reduction in CSF
viral load
Sodium valproate
16
>2y
Transient worsening
Reduction in viral
load
3m-2y
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/TSP
CLINICAL TRIAL STUDY GROUP
JUNE 2011
UK
Japan
USA
Brazil
HAM/TSP
Clinical Trial
001
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.
Salvador
• Prof Dr Bernardo Galvao-Castro
• Dr Fernanda Grassi
HTLV Reference Centre
Escola Bahiana de Medicina e Saude Publica
Fundacao Oswaldo Cruz/Fiocruz
1070 HTLV-1 positive patients registered
50% regularly followed up
Rio
• Dr Marcus T Silva
• Prof Abelardo Araujo
Instituto de Pesquisa Clinica Evandro Chagas
Laboratorio de Pesquisa Clinica em Neuroinfeccao
Fundacao Oswaldo Cruz/Fiocruz
1000 HTLV positive patients registered
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)
Japan
• Dr Erinko Atoni
• Dr Eisuke Ioune
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
NIH/USA
• Prof Steven Jacobson
• Dr Irene C.M Cortese
National Institutes of Health, Viral Immunology Section,
Neuroimmunology Branch
200 HTLV-1 positive patients registered
10 HAM/TSP patients
Largest cohort in the USA
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
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
International Trials
Which HAM/TSP patients?
Which drug?
Which outcome?
Which Patients?
Rapidly progressive (1)
severe
Chronic progressive (active, 2a)
Clinical
severity
Slow progressor
Chronic progressive (inactive, 2b)
Non-progressor
Chronic mild (3)
mild
10
20（years）
Y.Yamano et al June 2011, modified
Which Drug?
Nothing
Corticosteroids
Interferon-alpha
Ciclosporin-A
Monocloncal-AB
Sodium Valproate
Raltegravir
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)
A LE HAM/TSP Multicentre Exploratory TrialPrednisolone
Study flow sheet
HAM/TSP
ambulant
Group A:
Group B:
Group C:
Rapid n= 12
Slow n= 66
Non n= 12
Corticosteroids
Corticosteroids
Placebo
n= 33
n= 33
Observe
Recruitment
Screening
Consent
Assessment
Treatment
Follow up
(12 weeks)
(24 weeks)
(24 weeks)
ALL HAM
patients
iv/po Steroid
Able to walk 10m
Off treatment
Minimisation
Slow
po Steroid
Off treatment
Placebo
Off treatment
DB RCT
Non
Observation
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
Outcome measures
Primary 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
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
NIPPON
EXPRESS
Delivery
Tokyo Women’s
Medical Univ.
Key controller
Stores & Ships
study agents
NOPRO
Pharma
IDMC
Audit
Study
agents
Independent monitoring
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
Future
Progress in Biomarker studies
PhD/PostDoc and physician exchange programs
between UoY and Fiocruz
HAMLET-PC: Prednisolone vs Ciclosporin-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
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
Centre for Immunology and Infection