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 short-course 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)

4

4.5

5

5.5

6

6.5

7

0 10 20 30 40 50 60 70 80 90 100

Quinolone concentration (mg/L)

Lo

g c

fu /

ml

ciprofloxacin

ofloxacin

levofloxacin

moxifloxacin

gatifloxacin

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 study3. Phase II Trials4. 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 documentationand the proposed workplan, is it justifiedto conduct a pivotal Phase III clinical trialcomparing a four-month daily gatifloxacin-

containing regimen with a standard sixmonth 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 gatifloxacin-containing 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 anti-retroviral 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 to the WHO/SCHRIS committee

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 anti-

Tuberculeuse, Dakar, Sénégal– Programme National de Lutte anti-

Tuberculeuse, Cotonou, Bénin – Hopital Ignace Deen, Service de Pneumo-

phtisiologie, Conakry, Guinée – MRC, South Africa– Kenya Medical Research Institute, Nairobi,

Kenya