Controlled Comparison of Two Moxifloxacin Containing Treatment Shortening Regimens in Pulmonary Tuberculosis

Condition(s) targeted: Pulmonary Tuberculosis

Intervention: Moxifloxacin,Ethambutol,Isoniazid,Pyrazinamide & Rifampicin (Drug)

Phase: Phase 3

Status: Recruiting

Sponsored by: University College, London

Official(s) and/or principal investigator(s):
Stephen H Gillespie, MB BCh BAO MD DSc, Study Director, Affiliation: Centre for Medical Microbiology, Royal Free & University College Medical School
Andrew Nunn, BSc MSc, Principal Investigator, Affiliation: MRC Clinical Trials Unit
Sarah K Meredith, MB BS MSc, Principal Investigator, Affiliation: MRC Clinical Trials Unit
Timothy D McHugh, BSc PhD CSi, Principal Investigator, Affiliation: Centre for Medical Microbiology, Royal Free and University College Medical School
Ali Zumla, BSc MBChB MSc PhD, Principal Investigator, Affiliation: Centre for International Health, Royal Free and University College Medical School
Alexander Pym, MB BMRCP PhD, Principal Investigator, Affiliation: Unit for Clinical & Biomedical TB Research, MRC Durban
Peter Mwaba, MB ChB MMed PhD, Principal Investigator, Affiliation: University Teaching Hospital
Noel Sam, MMed MD, Principal Investigator, Affiliation: Kilimanjaro Christian Medical Centre
Andreas Diacon, BM MD, Principal Investigator, Affiliation: Tiervlei Trial Center and University of Stellenbosch
Rodney Dawson, MB ChB FCP, Principal Investigator, Affiliation: Centre for TB Research and Innovation, UCT Lung Institute
Evans Amukoye, MD, Principal Investigator, Affiliation: Centre for Respiratory Disease Research at KEMRI
Klaus Reither, MD, MScIH, Principal Investigator, Affiliation: NIMR Mbeya Medical Research Programme

Overall contact:
Stephen H Gillespie, Phone: +44 (0) 20 7794 0500, Ext: 33539, Email: s.gillespie@medsch.ucl.ac.uk

REMoxTB is a study for the "Rapid Evaluation of Moxifloxacin in the treatment of sputum smear positive tuberculosis". REMoxTB aims to find and evaluate new drugs and regimens that shorten the duration of tuberculosis therapy.

The purpose of REMoxTB is to evaluate the efficacy, safety and acceptability of two moxifloxacin-containing treatment combinations to determine whether substituting ethambutol with moxifloxacin in one combination, and/or substituting isoniazid with moxifloxacin in another combination, makes it possible to reduce the duration of treatment for TB.

Official title: A Randomised Placebo - Controlled Double Blind Trial Comparing 1) a Two Month Intensive Phase of Ethambutol, Moxifloxacin, Rifampicin, Pyrazinamide Versus the Standard Regimen (Ethambutol, Isoniazid, Rifampicin, Pyrazinamide) and 2) a Treatment Shortening Regimen Comparing Two Months Moxifloxacin, Isoniazid, Rifampicin, Pyrazinamide Followed by Two Months Moxifloxacin, Isoniazid, Rifampicin Versus the Standard Regimen (Two Months Ethambutol, Isoniazid, Rifampicin, Pyrazinamide Followed by Four Months Isoniazid and Rifampicin) for the Treatment of Adults With Pulmonary Tuberculosis

Study design: Treatment, Randomized, Double Blind (Subject, Caregiver, Investigator, Outcomes Assessor), Placebo Control, Parallel Assignment, Safety/Efficacy Study

Primary outcome:

Combined failure of bacteriological cure and relapse as defined by culture using solid media.

Proportion of patients with grade 3 or 4 adverse events (using a modified DAIDS scale of adverse event reporting)

Secondary outcome:

Combined failure of bacteriological cure and relapse as defined by culture using liquid media

Proportion of patients who are culture negative (solid and liquid media)

Time to first culture negative sputum sample (solid and liquid media)

Speed of decline of sputum viable count by culture using solid or liquid media

Detailed description: The current recommended treatments for tuberculosis (TB) require a patient to take multiple drugs for six to eight months. Because the course of therapy is long, many patients do not adhere to treatment and as a consequence they have a poor outcome. In these cases either the sputum is not cleared of the bacteria causing tuberculosis, or the disease returns again (called relapse). Response to medication can be monitored during treatment by collecting regular sputum samples and examining these samples by culture, for the organisms that cause tuberculosis.

The commonly used drugs to treat tuberculosis are rifampicin, isoniazid, ethambutol and pyrazinamide. Previous studies in animals and in humans suggest that a new drug called moxifloxacin may also be an effective treatment in tuberculosis. Moreover, promising laboratory studies on mice suggest that moxifloxacin may enable the total duration of chemotherapy to be reduced to four months, which would be a significant improvement for patients taking medication for tuberculosis.

This study will involve comparisons that are designed to assess whether substituting moxifloxacin for individual drugs in existing treatment combinations will enable tuberculosis treatment to be shortened. Patients selected for the study will be allocated to one of three treatment groups. The first group will be given six months standard treatment. A second group will receive moxifloxacin substituted for ethambutol, as part of a four month regimen, to see whether the shorter treatment is not inferior to the standard six month treatment. The third group will receive moxifloxacin substituted for isoniazid, as part of a four month regimen, to see whether the shorter treatment is not inferior to the standard six month treatment.

Hypotheses:

1. In treatment-naïve adults with active pulmonary TB treated with eight weeks of moxifloxacin (M), isoniazid (H), rifampicin (R) and pyrazinamide (Z) (i. e. a standard regimen where moxifloxacin is substituted for ethambutol (E)), followed by nine weeks of moxifloxacin, isoniazid and rifampicin, followed by nine weeks of placebo, the proportion of patients who experience treatment failure or disease relapse in the twelve months following treatment completion will not be inferior to that observed in patients who are treated with a standard regimen (eight weeks of ethambutol, isoniazid, rifampicin and pyrazinamide followed by eighteen weeks of isoniazid plus rifampicin) (Comparison 1). See Fig. 1 REMox Trial Design.

2. In treatment-naïve adults with active pulmonary TB treated with eight weeks of ethambutol, moxifloxacin, rifampicin and pyrazinamide (i. e. a standard regimen where moxifloxacin is substituted for isoniazid), followed by nine weeks of moxifloxacin and rifampicin followed by nine weeks of placebo, the proportion of patients who experience treatment failure or disease relapse in the twelve months following treatment completion will not be inferior to that observed in patients who are treated with a standard regimen (eight weeks of ethambutol, isoniazid, rifampicin and pyrazinamide followed by eighteen weeks of isoniazid plus rifampicin) (Comparison 2).

Minimum age: 18 Years. Maximum age: N/A. Gender(s): Both.

Criteria:

Inclusion Criteria:

- Signed written consent or witnessed oral consent in the case of illiteracy, before

undertaking any trial related activity.

- Two sputum specimens positive for tubercle bacilli on direct smear microscopy at the

local laboratory and confirmed at the study laboratory on a sample taken at screening.

- Aged 18 years or over.

- No previous anti-tuberculosis chemotherapy.

- A firm home address that is readily accessible for visiting and willingness to inform

the study team of any change of address during the treatment and follow-up period.

- Agreement to participate in the study and to give a sample of blood for HIV testing

(see appendices 1 & 2).

- Pre-menopausal women must be using a barrier form of contraception or be surgically

sterilised or have an IUCD in place.

- Laboratory parameters performed up to 14 days before enrolment. (Serum aspartate

transaminase (AST) activity less than 3 times the upper limit of normal. Serum total bilirubin level less than 2. 5 times upper limit of normal. Creatinine clearance (CrCl) level greater than 30 mls/min. Haemoglobin level of at least 7. 0 g/dL. Platelet count of at least 50x109cells/L. Serum potassium greater than 3. 5 mmol/L.)

- Negative pregnancy test (women of childbearing potential).

Exclusion Criteria:

- Unable to take oral medication.

- Previously enrolled in this study.

- Received any investigational drug in the past 3 months.

- Received an antibiotic active against M. tuberculosis in the last 14 days

(fluoroquinolones, macrolides, standard anti-tuberculosis drugs).

- Any condition that may prove fatal during the first two months of the study period.

- TB meningitis or other forms of severe tuberculosis with high risk of a poor outcome

- Pre-existing non-tuberculosis disease likely to prejudice the response to, or

assessment of, treatment e. g. insulin-dependent diabetes, liver or kidney disease, blood disorders, peripheral neuritis, chronic diarrhoeal disease.

- Pregnant or breast feeding.

- Suffering from a condition likely to lead to uncooperative behaviour e. g. psychiatric

illness or alcoholism.

- Contraindications to any medications in the study regimens.

- Known to have congenital or sporadic syndromes of QTc prolongation or receiving

concomitant medication reported to increase the QTc interval (e. g. amiodarone, sotalol, disopyramide, quinidine, procainamide, terfenadine).

- Known allergy to any fluoroquinolone antibiotic or history of tendinopathy associated

with quinolones.

- Patients already receiving anti-retroviral therapy.

- Patients whose initial isolate is shown to be multiple drug resistant.

- Weight less than 35kg

- HIV infection with CD4 count less than 250 cells/µL.

- End stage liver failure (class Child-Pugh C).

Stephen H Gillespie, Phone: +44 (0) 20 7794 0500, Ext: 33539, Email: s.gillespie@medsch.ucl.ac.uk

Centre for Respiratory Disease Research at KEMRI, Nairobi, Kenya; Not yet recruiting
Evans Amukoye, Phone: +254202722541, Email: crdr@todays.co.ke
Evans Amukoye, Principal Investigator

Unit for Clinical & Biomedical TB Research, MRC Durban, Durban, South Africa; Active, not recruiting

Tiervlei Trial Center and University of Stellenbosch, Cape Town, South Africa; Recruiting
Andreas Diacon, Phone: +27 21 9497751, Email: ahd@sun.ac.za
Andreas Diacon, Principal Investigator

Centre for TB Research and Innovation, UCT Lung Institute, Cape Town, South Africa; Recruiting
Rodney Dawspon, Phone: +27214066863/4, Email: Rodney.Dawson@uct.ac.za
Rodney Dawson, Principal Investigator

Kilimanjaro Christian Medical Centre, Moshi, Tanzania; Not yet recruiting
Ndekya Oriyo, Phone: +255-27-2754377, Ext: 348, Email: ndekya@kcmc.ac.tz
Noel Sam, Principal Investigator

NIMR Mbeya Medical Research Programme, Mbeya, Tanzania; Recruiting
Klaus Reither, Phone: +255-25-250 2239, Email: kreither@mmrp.org
Klaus Reither, Principal Investigator

University Teaching Hospital, Lusaka, Zambia; Recruiting
Shabir Lakhi, Phone: +2602 11 255 224, Email: lakhisr@coppernet.zm
Peter Mwaba, Principal Investigator

REMoxTB website

Starting date: January 2008
Ending date: January 2011
Last updated: March 17, 2009