Controlled Comparison of Two Moxifloxacin Containing Treatment Shortening Regimens in Pulmonary Tuberculosis - Full Text View

Sponsor:	University College, London
Collaborators:	Medical Research Council Kilimanjaro Christian Medical Centre, Tanzania University of Zambia Medical Research Council, South Africa University of Stellenbosch University of Cape Town Kenya Medical Research Institute European and Developing Countries Clinical Trials Partnership (EDCTP) Global Alliance for TB Drug Development Bayer Healthcare Pharmaceuticals, Inc./Bayer Schering Pharma Sanofi-Aventis
Information provided by:	University College, London
ClinicalTrials.gov Identifier:	NCT00864383

Purpose

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.

Condition	Intervention	Phase
Pulmonary Tuberculosis	Drug: Moxifloxacin,Ethambutol,Isoniazid,Pyrazinamide & Rifampicin	Phase III

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

Resource links provided by NLM:

MedlinePlus related topics: Tuberculosis

Drug Information available for: Isoniazid Rifampin Ethambutol Pyrazinamide Moxifloxacin Moxifloxacin hydrochloride Ftivazide Ethambutol hydrochloride

U.S. FDA Resources

Further study details as provided by University College, London:

Primary Outcome Measures:

Combined failure of bacteriological cure and relapse as defined by culture using solid media. [ Time Frame: 18 months (within one year of completion of therapy) ] [ Designated as safety issue: No ]
Proportion of patients with grade 3 or 4 adverse events (using a modified DAIDS scale of adverse event reporting) [ Time Frame: 18 months (within one year of completion of therapy) ] [ Designated as safety issue: Yes ]

Secondary Outcome Measures:

Combined failure of bacteriological cure and relapse as defined by culture using liquid media [ Time Frame: 18 months (within one year of completion of therapy) ] [ Designated as safety issue: No ]
Proportion of patients who are culture negative (solid and liquid media) [ Time Frame: 8 weeks ] [ Designated as safety issue: No ]
Time to first culture negative sputum sample (solid and liquid media) [ Time Frame: Estimated 3 to 6 months ] [ Designated as safety issue: No ]
Speed of decline of sputum viable count by culture using solid or liquid media [ Time Frame: 6 months ] [ Designated as safety issue: No ]

Estimated Enrollment:	2400
Study Start Date:	January 2008
Estimated Study Completion Date:	January 2011
Estimated Primary Completion Date:	January 2011 (Final data collection date for primary outcome measure)

Arms	Assigned Interventions
1: Placebo Comparator 2EHRZ/4HR (Regimen 1 - the control regimen) Eight weeks of chemotherapy with ethambutol, isoniazid, rifampicin and pyrazinamide plus the moxifloxacin placebo, followed by Nine weeks of isoniazid and rifampicin plus the moxifloxacin placebo, followed by Nine weeks of isoniazid and rifampicin only.	Drug: Moxifloxacin,Ethambutol,Isoniazid,Pyrazinamide & Rifampicin Moxifloxacin 400 mg Rifampicin < 45 kg 450 mg > 45 kg 600 mg Isoniazid 300 mg Pyrazinamide < 40 kg 25 mg/kg rounded to nearest 500 mg* 40-55 kg 1000 mg > 55 kg - 75 kg 1500 mg > 75 kg 2000 mg Ethambutol < 40 kg 15 mg/kg rounded to nearest 100 mg 40-55 kg 800 mg > 55 kg - 75 kg 1200 mg > 75 kg 1600 mg *For pyrazinamide dosing in patients < 40 kg, 1000 mg used instead of 500 mg All treatment is taken daily, for a duration of up to 26 weeks depending on treatment arm.
2: Experimental 2MHRZ/2MHR (Regimen 2) Eight weeks of chemotherapy with moxifloxacin, isoniazid, rifampicin and pyrazinamide plus the ethambutol placebo, followed by Nine weeks of moxifloxacin, isoniazid and rifampicin, followed by Nine weeks of the isoniazid placebo and the rifampicin placebo.	Drug: Moxifloxacin,Ethambutol,Isoniazid,Pyrazinamide & Rifampicin Moxifloxacin 400 mg Rifampicin < 45 kg 450 mg > 45 kg 600 mg Isoniazid 300 mg Pyrazinamide < 40 kg 25 mg/kg rounded to nearest 500 mg* 40-55 kg 1000 mg > 55 kg - 75 kg 1500 mg > 75 kg 2000 mg Ethambutol < 40 kg 15 mg/kg rounded to nearest 100 mg 40-55 kg 800 mg > 55 kg - 75 kg 1200 mg > 75 kg 1600 mg *For pyrazinamide dosing in patients < 40 kg, 1000 mg used instead of 500 mg All treatment is taken daily, for a duration of up to 26 weeks depending on treatment arm.
3: Experimental 2EMRZ/2MR (Regimen 3) Eight weeks of chemotherapy with ethambutol, moxifloxacin, rifampicin and pyrazinamide plus the isoniazid placebo, followed by Nine weeks of moxifloxacin and rifampicin plus the isoniazid placebo, followed by Nine weeks of the isoniazid placebo and the rifampicin placebo	Drug: Moxifloxacin,Ethambutol,Isoniazid,Pyrazinamide & Rifampicin Moxifloxacin 400 mg Rifampicin < 45 kg 450 mg > 45 kg 600 mg Isoniazid 300 mg Pyrazinamide < 40 kg 25 mg/kg rounded to nearest 500 mg* 40-55 kg 1000 mg > 55 kg - 75 kg 1500 mg > 75 kg 2000 mg Ethambutol < 40 kg 15 mg/kg rounded to nearest 100 mg 40-55 kg 800 mg > 55 kg - 75 kg 1200 mg > 75 kg 1600 mg *For pyrazinamide dosing in patients < 40 kg, 1000 mg used instead of 500 mg All treatment is taken daily, for a duration of up to 26 weeks depending on treatment arm.

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:

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.
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).

Eligibility

Ages Eligible for Study:	18 Years and older
Genders Eligible for Study:	Both
Accepts Healthy Volunteers:	No

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).

Contacts and Locations

Please refer to this study by its ClinicalTrials.gov identifier: NCT00864383

Contacts

Contact: Stephen H Gillespie

+44 (0) 20 7794 0500 ext 33539

s.gillespie@medsch.ucl.ac.uk

Locations

Kenya
Centre for Respiratory Disease Research at KEMRI	Not yet recruiting
Nairobi, Kenya
Contact: Evans Amukoye +254202722541 crdr@todays.co.ke
Principal Investigator: Evans Amukoye
South Africa
Unit for Clinical & Biomedical TB Research, MRC Durban	Active, not recruiting
Durban, South Africa
Tiervlei Trial Center and University of Stellenbosch	Recruiting
Cape Town, South Africa
Contact: Andreas Diacon +27 21 9497751 ahd@sun.ac.za
Principal Investigator: Andreas Diacon
Centre for TB Research and Innovation, UCT Lung Institute	Recruiting
Cape Town, South Africa
Contact: Rodney Dawspon +27214066863/4 Rodney.Dawson@uct.ac.za
Principal Investigator: Rodney Dawson
Tanzania
Kilimanjaro Christian Medical Centre	Not yet recruiting
Moshi, Tanzania
Contact: Ndekya Oriyo +255-27-2754377 ext 348 ndekya@kcmc.ac.tz
Principal Investigator: Noel Sam
NIMR Mbeya Medical Research Programme	Recruiting
Mbeya, Tanzania
Contact: Klaus Reither +255-25-250 2239 kreither@mmrp.org
Principal Investigator: Klaus Reither
Zambia
University Teaching Hospital	Recruiting
Lusaka, Zambia
Contact: Shabir Lakhi +2602 11 255 224 lakhisr@coppernet.zm
Principal Investigator: Peter Mwaba

Sponsors and Collaborators

University College, London

Medical Research Council

Kilimanjaro Christian Medical Centre, Tanzania

University of Zambia

Medical Research Council, South Africa

University of Stellenbosch

University of Cape Town

Kenya Medical Research Institute

European and Developing Countries Clinical Trials Partnership (EDCTP)

Global Alliance for TB Drug Development

Bayer Healthcare Pharmaceuticals, Inc./Bayer Schering Pharma

Sanofi-Aventis

Investigators

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

More Information

Additional Information:

REMoxTB website This link exits the ClinicalTrials.gov site

No publications provided

Responsible Party:	University College London ( Professor Stephen H. Gillespie )
Study ID Numbers:	REMoxTB, ISRCTN85595810
Study First Received:	March 17, 2009
Last Updated:	March 17, 2009
ClinicalTrials.gov Identifier:	NCT00864383 History of Changes
Health Authority:	South Africa: Medicines Control Council; Zambia: Pharmaceutical Regulatory Authority; Tanzania: Food & Drug Administration

Additional relevant MeSH terms:

Bacterial Infections
Antimetabolites
Anti-Infective Agents
Molecular Mechanisms of Pharmacological Action
Rifampin
Anti-Bacterial Agents
Gram-Positive Bacterial Infections
Respiratory Tract Infections
Respiratory Tract Diseases
Moxifloxacin
Therapeutic Uses
Tuberculosis
Nucleic Acid Synthesis Inhibitors
Isoniazid

Antilipemic Agents
Enzyme Inhibitors
Pyrazinamide
Actinomycetales Infections
Pharmacologic Actions
Antibiotics, Antitubercular
Lung Diseases
Tuberculosis, Pulmonary
Mycobacterium Infections
Ethambutol
Antitubercular Agents
Fatty Acid Synthesis Inhibitors
Leprostatic Agents

ClinicalTrials.gov processed this record on February 08, 2010