Download Projet INCO-DEV / CE 2001

Ethical Issues
in the development and
implementation of a multicentre
Randomised Controlled Trial of a 4
month Gatifloxacin-containing
regimen for the treatment of
Pulmonary Tuberculosis
Christian Lienhardt - IRD
TB control
• Objective:
– to break the cycle of transmission of TB by interrupting
inter-human transmission of infection and protecting
individuals against the disease.
• Means :
– early detection of smear-positive TB cases
– rapid treatment of smear-positive TB cases, using shortcourse chemotherapy (6 to 8 months)
– full case-holding through DOTS strategy
– chemoprophylaxis
– vaccines
However,
- despite a treatment of proven efficacy, TB rates
continue to increase in resource-poor countries
- operational efficacy of DOT,S not proven
- persistence of high treatment default rates
- spread of multi-drug resistances
How to improve TB control ?
 increase early detection of smear +
TB cases
 improve delivery of treatment
 decrease duration of treatment
 new drugs ?
 new combinations of drugs ?
Fluoroquinolones
• bactericidal activity in vitro against M.
tuberculosis (Garcia–Rodrigues 1993,
Yew 1994)
• confirmed in animal models
• rapidly absorbed
• high concentrations in respiratory cells,
secretions and macrophages
• long curative capacity after oral intake
Ofloxacine
• Proven bactericidal activity against M.
tuberculosis (Gillespie 1998)
• Low cost
• Included in the WHO essential drug list
• Several clinical trials (Tsukamura 1986, Hong
Kong Chest Service/MRC 1992, TRC
Chennai 2001):
– sputum smear conversion in 90 to 95%
patients after 2 months
– relapse rate after treatment 3 to 12% (6
months)
Gatifloxacin (1)
• active against Gram + and Gram - organisms
• plasma concentrations higher than MIC
obtained with other fluoroquinolones
• in vitro and in vivo experiments:
– more active than ofloxacin against
susceptible and resistant TB isolates
– anti-TB activity similar to moxifloxacin
(Tomioka 2002; Alvirez-Freites 2002)
7
6.5
Log cfu / ml
6
5.5
ciprofloxacin
ofloxacin
levofloxacin
moxifloxacin
gatifloxacin
5
4.5
4
0
10
20
30
40
50
60
Quinolone concentration (mg/L)
70
80
90
100
3
ciprofloxacin
ofloxacin
levofloxacin
moxifloxacin
gatifloxacin
2.5
Log cfu / ml
2
1.5
1
0.5
0
0
10
20
30
40
Quinolone concentration (mg/L)
50
60
Gatifloxacin (2)
• approved by FDA for the treatment of
community acquired pneumonia, acute
bronchitis, acute sinusitis, uncomplicated skin
infections, UTIs and gonococcal infections
• approved doses range from single 400 mg
oral dose to 400 mg (600 mg) oral or
intravenous followed by oral doses for 3 to 14
days
Gatifloxacin (3)
• Relatively benign toxicity profile, with
significant adverse effects occurring rarely
• seems to be free of many of the class effects
of quinolone antibiotics (eg. photo-toxicity)
• potential cardiotoxicity (QT enlargement),
although of a minor degree compared to
many other compounds
• reported effect on glucose homeostasis
(hypo-, hyperglycemia)
However,
• gatifloxacin not been used so far in the treatment
of tuberculosis
• not been used for periods of treatment > 14 days
in humans
 additional investigations needed
 proposed workplan
Data from preclinical studies (ICH Guideline M3):
• pre-clinical toxicology profile supports its use as
daily therapy in humans for four months (6 month
chronic toxicity studies in animals + life-time
carcinogenicity studies)
• adverse effect profile will not limit its use in
humans when used for four months as part of a
multi-drug anti-TB regimen
Proposed workplan
1.
Further Pre-Clinical Toxicology studies
2. Phase I Pharmacokinetic study
3. Phase II Trials
4. Phase III RCT
5. Get Regulatory Authority Approval
1. Pre-Clinical Toxicology
studies
• comparative toxicity study in three arms:
G vs. HRZ vs. GHRZ (28-day study in dogs)
• In vitro mouse lymphoma assay and in vivo
micronucleus test with gatifloxacin and HRZ
to determine the mutagenicity/genotoxicity
potential of the combination
2. Pre-Clinical PK study
• Phase I single-dose healthy normal volunteer
drug-drug cross-over bioavailability/
equivalence study of gatifloxacin alone vs
gatifloxacin combined with HRZ vs HRZ
under fasted conditions
3. Phase II Trials
• Early Bactericidal Activity (EBA) 7-day study
of gatifloxacin and other FQs in patients with
newly diagnosed pulmonary tuberculosis
• Serial Sputum Colony Counts (SSCC) study
to assess the sterilising activity of a
gatifloxacin-containing regimen compared
with other FQ-containing regimens in patients
with pulmonary TB
4. Phase III RCT
Phase III Multicentre Open-label
Randomised Controlled Trial of
Gatifloxacin-containing Short-course
Regimen vs Standard 6-month Regimen for the
Treatment of Pulmonary
Tuberculosis
EC-funded Project N° ICA - 2001 - 10126
Regulatory authority
• Needed ?
• Which one ?
• Competent ?
Question to the MHRA
Based on the background documentation
and the proposed workplan, is it justified
to conduct a pivotal Phase III clinical trial
comparing a four-month daily gatifloxacincontaining regimen with a standard six
month short course regimen for the treatment of
pulmonary TB ?
Response from MHRA (1)
1. Bridging toxicity study of three months duration
considered sufficient for supporting the non-clinical
safety of the proposed 4-drug combination
2. since extensive human experience exists as regard
to the drugs being tested, the non-clinical
investigations would not be a progress-limiting factor
3. the timing of the clinical trials would not depend on
the conduct and results of the non-clinical studies
Response from MHRA (2)
4. Open label design of the phase III study
considered acceptable, provided that the
investigator assessing the patients and the
laboratories conducting the sputum analyses
are blind to the treatment received by the
patient
Response from MHRA (3)
In conclusion
- as enough safeguards are built into the
clinical trials with respect to safety, the clinical
development plan was considered to be
complete and sufficient
- it was also considered unnecessary to wait
for the completion of the non-clinical studies
before starting the clinical trials
Objectives of the Phase III RCT
• To evaluate the efficacy and safety of a gatifloxacincontaining four month regimen in the treatment of
pulmonary tuberculosis in comparison with a
standard 6-month regimen
• To compare the sterilising activities of these 2
regimens during the intensive phase
• To develop research capacities in order to conduct
clinical trials in developing countries, through
appropriate training and transfer of technologies
Methods
• Open-label Randomised Controlled Trial
• Non-inferiority trial
• Sample size: 1035 patients/arm
• Treatments :
- test: 2 months GHRZ / 2 months GHR
- control: 2 months EHRZ / 4 months RH
• Investigation sites: Benin, Guinee, Kenya,
Senegal, South Africa
Randomisation
•
•
•
•
randomisation lists, stratified per centre/site
individual codes in sealed envelopes
treatment unblind
microbiologists blind to the origin of sputa
Inclusion
Male and female patients, aged 18 to 65 years,
with a recently microscopically diagnosed
pulmonary tuberculosis and giving informed
consent to participate in the trial
Exclusion
- History of TB within the last 3 years
- Pregnant women
- Concomitant infection requiring additional
anti-infectious treatment (especially antiretroviral therapy)
- HIV infected patients at WHO stage 3 and
stage 4
Initial Examination
• Complete clinical examination
• Pre-screening of MDR-TB (MGIT)
• Sputum samples collected for smears, culture
and sensitivity testing
• Chest X-Ray
• Blood samples (biology)
• ECG
Follow-up during treatment
• Initial phase (2 months): daily treatment (DOT)
• Continuation phase: treatment given every 2
weeks
• Monthly follow-up :
- observance
- tolerance, adverse effets
- clinical examination
- blood samples
- sputum collection for smear, culture and
sensitivity testing
Follow-up after treatment
• patients seen at 1, 2, 4, 6, 9, 12, 15 and
18 months after treatment
• regular clinical examination
• sputum samples collected for smear,
culture and DST if culture positive
End-points (1)
Efficacy:
- Primary outcome :
- Time to relapse, defined from the date of
treatment cure to date of relapse
- Percent relapses at 24 months
- Secondary outcomes :
- Percent smear conversion at 8 weeks
- Percent patients cured in each arm
End-points (2)
Safety:
• Primary outcome: percent adverse events in
each arm
• Secondary outcome: distribution of type and
grading of adverse events
Risks associated with the study
1. Drug resistance
•
•
•
“amplifier effect”
if resistance to gatifloxacin, patient treated
based on results of DST
patients with R resistant result considered
as MDR-TB
 stop treatment + hospitalisation + second
line treatment
Risks associated with the study
2. Adverse effets
- digestive troubles (nausea, diarrhoea),
- skin rash, photo-toxicity
- muscle pain, joint pain, tendinitis
- change in glucose tolerance, pancreatitis
- neurological symptoms (convulsions,
mental confusion, headache),
- increase in liver enzymes (hepatitis)
- increase in creatinin (renal insufficiency)
Trial Management
Trial Steering Committee (TSC):
• Trial coordinator + medical statistician + PIs
of all sites
• reviews the trial process
• takes decisions on salient issues related to
the conduct of the trial
• checks production of expected deliverables
and reports
• evaluates the final results of the trial
• meets once a year
Trial Monitoring
Data and Safety Monitoring Committee
(DSMC) :
• fully independent committee
• provides advice to the trial coordinator on all
aspects of the trial
• recommends and supervises interim analysis
• makes specific recommendations to the TSC
on the continuation of the trial, particularly on
ethical and safety issues
• meets at least three times during the course
of the trial
Ethical Aspects
1. Ethical reviews
2. Informed Consent
3. HIV infection
1. Ethical Reviews
• Ethical aspects of the project fully evaluated
by EC before funding  Ethical Report on
Grant proposal
• Overarching protocol submitted to the
competent body for independent examination
of the scientific merits and ethical
acceptability in each partner country
• Also submitted
committee
to
the
WHO/SCHRIS
1. Ethical Reviews
• It is expected that the research will contribute to significant
improvement in the treatment of tuberculosis.
• According to present knowledge on the various drug used,
patients included in the study are exposed to minimal risks
and burdens.
• Hence, this clinical trial meets the conditions that the risk
are not disproportionate to the potential benefits.
• The organisation and modalities for the conduct of the RCT
appear in agreement with the regulations of the Helsinki
Declaration
2. Informed Consent
• Informed consent to participate in the study sought
from every TB patient eligible for inclusion in the
study
• Fully appropriate information as to the purpose and
nature of intervention given at start
• Risks and benefits clearly explained in the language
of the patient
• The person may freely withdraw consent at any time.
• Patients who will not consent to participate in the
study will be managed as recommended by the
National TB control programmes.
3. HIV infection
• HIV test offered to all diagnosed TB cases but
no obligation to be tested
• people free to decide to know their result or
not
• pre-counselling procedures
• national recommendations for HIV testing and
related procedures will be followed
Expected Results
• The bactericidal activity of the tested regimen
is at least equivalent to the bactericidal
activity of the control regimen
• The tested regimen is at least as good as the
control regimen in terms of cure rates and
relapse rates
• Scientific capacities to conduct further clinical
trials on TB are developed in South partner
countries
Partners
• North
– IRD, Paris, France (Coordination)
– Service de Maladies Infectieuses et Tropicales,
Hopital Raymond Poincaré, Garches, France
– Mycobacteriology Unit, Tropical Medicine
Institute, Antwerpen, Belgium
– Microbiology Unit, St George’s Hospital Medical
School, London, UK
– London School of Hygiene and Tropical
Medicine, London, UK
Partners
• South :
– Programme
National
de
Lutte
antiTuberculeuse, Dakar, Sénégal
– Programme
National
de
Lutte
antiTuberculeuse, Cotonou, Bénin
– Hopital Ignace Deen, Service de Pneumophtisiologie, Conakry, Guinée
– MRC, South Africa
– Kenya Medical Research Institute, Nairobi,
Kenya