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

Phase 3

Completed

Conditions: Pulmonary Tuberculosis

Interventions: Drug: Moxifloxacin, Ethambutol, Isoniazid, Pyrazinamide & Rifampicin

Registration Number: NCT00864383

Lead Sponsor: Global Alliance for TB Drug Development

Brief Summary: 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.

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).

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).

Recruitment & Eligibility

Status: COMPLETED

Sex: All

Target Recruitment: 1931

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 smear microscopy at least one of which must be processed and positive at the study laboratory.
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) and alanine transaminase (ALT) 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 e.g. diabetes, liver or kidney disease, blood disorders,peripheral neuritis, chronic diarrhoeal disease in which the current clinical condition of the patient is likely to prejudice the response to, or assessment of treatment.
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 (i.e. resistant to rifampicin and isoniazid) or monoresistant to rifampicin, or resistant to any fluoroquinolone)
Weight less than 35kg
HIV infection with CD4 count less than 250 cells/µL.
End stage liver failure (class Child-Pugh C).

Study & Design

Study Type: INTERVENTIONAL

Study Design: PARALLEL

Arm && Interventions

Group	Intervention	Description
Regimen 3 - 2EMRZ/2MR	Moxifloxacin, Ethambutol, Isoniazid, Pyrazinamide & Rifampicin	* 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
Regimen 2 - 2MHRZ/2MHR	Moxifloxacin, Ethambutol, Isoniazid, Pyrazinamide & Rifampicin	* 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.
Regimen 1 - 2EHRZ/4HR (control regimen)	Moxifloxacin, Ethambutol, Isoniazid, Pyrazinamide & Rifampicin	* 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.

Primary Outcome Measures

Name	Time	Method
Combined Failure of Bacteriological Cure and Relapse Within One Year of Completion of Therapy as Defined by Culture Using Solid Media (Lowenstein-Jensen - LJ).	18 months (within one year of completion of therapy)	The primary efficacy outcome was the proportion of patients who had bacteriologically or clinically defined failure or relapse within 18 months after randomization (a composite unfavorable outcome). Culture-negative status was defined as two negative-culture results at different visits without an intervening positive result. The date of culture-negative status was defined as the date of the first negative-culture result. This status continued until there were two positive cultures, without an intervening negative culture, or until there was a single positive culture that was not followed by two negative cultures. Relapse strains were those shown to be identical on 24-locus Mycobacterial interspersed repetitive units (MIRU) analysis. For the final 18 month study visit when both L-J samples were contaminated or missing, if the subject could not be brought back, liquid medium culture results were used in place of solid medium culture results.
Number of Patients With Grade 3 or 4 Adverse Events (Using a Modified Division of Acquired Immunodeficiency Syndrome National Institute of Allergy and Infectious Diseases [DAIDS] Scale of Adverse Event Reporting)	18 months (within one year of completion of therapy)	The number of participants includes all patients who had at least one grade 3 or 4 adverse event.

Secondary Outcome Measures

Name	Time	Method
Combined Failure of Bacteriological Cure and Relapse as Defined by Culture Using Liquid Media (Mycobacteria Growth Indicator Tube-MGIT).	18 months (within one year of completion of therapy)	The secondary analysis of efficacy outcome was the proportion of patients who had bacteriologically or clinically defined failure or relapse within 18 months after randomization (a composite unfavorable outcome) based on MGIT. Culture-negative status was defined as two negative-culture results at different visits without an intervening positive result. The date of culture-negative status was defined as the date of the first negative-culture result. This status continued until there were two positive cultures, without an intervening negative culture, or until there was a single positive culture that was not followed by two negative cultures. Relapse strains were those shown to be identical on 24-locus Mycobacterial interspersed repetitive units (MIRU) analysis.
Number of Patients Who Are Culture Negative (Solid LJ Culture)	8 weeks	Number of patients who are TB LJ culture negative at 8 weeks.
Number of Patients Who Are Culture Negative (Liquid MGIT Culture)	8 weeks	Number of patients who are TB MGIT culture negative at 8 weeks.
Time to First Culture Negative Sputum Sample (LJ Solid Media)	18 months	Culture negative for TB using LJ cultures.
Time to First Culture Negative Sputum Sample (MGIT Liquid Media)	18 months
Sensitivity Analysis Assuming All Losses to Follow-up and Non-tuberculous Deaths Have an Unfavorable Outcome Using Solid (L-J) Media.	18 months	Sensitivity Analysis of Primary Efficacy Results of All Randomized Subjects Imputing Unfavorable for Missing Outcomes. Analysis is the number of subjects with an unfavorable outcome. Favorable outcome is defined as the number of subjects with a negative TB culture status at 18 months (at or after 72 weeks), who had not already been classified as having an unfavorable outcome, and whose last positive TB culture result ("isolated positive culture") was followed by at least two negative culture results.
Sensitivity Analyses Assuming All Losses to Follow-up and Non-tuberculous Deaths Have a Favourable Outcome Using Solid (L-J) Media.	18 months	Sensitivity Analysis of Primary Efficacy Results of All Randomized Subjects Imputing Favorable for Missing Outcomes. Analysis is the number of subjects with an unfavorable outcome. Favorable outcome is defined as the number of subjects with a negative TB culture status at 18 months (at or after 72 weeks), who had not already been classified as having an unfavorable outcome, and whose last positive TB culture result ("isolated positive culture") was followed by at least two negative culture results.

Trial Locations

Locations (47): Mahatma Gandhi Medical College& Hospital
🇮🇳
Jaipur, Rajsthan, India
A-One Hospital
🇮🇳
Delhi, India
Centre for advanced lung and sleep disorders
🇮🇳
New Delhi, India
Rajavithi Hospital, Division Of Pulmonary Medicine
🇹🇭
Bangkok, Phayathai, Thailand
Jigyasa Medical Center
🇮🇳
Moradabad, Uttar Pradesh, India
Hospital General de Occidente de la secretaria
🇲🇽
Guadalajara, Seattle, Mexico
Varshneya Chest Clinic & Eye Care Centre
🇮🇳
Aligarh, Uttar Pradesh, India
Surya Kant Clinic
🇮🇳
Lucknow, Uttar Pradesh, India
Ish Medical Centre and Respiratory Lab,
🇮🇳
New Delhi, India
Centre for Respiratory Disease Research at KEMRI
🇰🇪
Nairobi, Kenya
NIMR Mbeya Medical Research Programme
🇹🇿
Mbeya, Tanzania
University Teaching Hospital
🇿🇲
Lusaka, Zambia
Dr. S. K. Katiyar, Swaroop Nagar,
🇮🇳
Kanpur, Uttar Pradesh, India
Dr. D.K. Chauhan
🇮🇳
New Delhi, India
Kilimanjaro Christian Medical Centre
🇹🇿
Moshi, Tanzania
Dr. Neeraj Gupta Clinic
🇮🇳
Firozabad, Uttar Pradesh, India
Arya Chest Clinic, UP,India
🇮🇳
Meerut, Uttar Pradesh, India
Sri Ram Plaza
🇮🇳
Meerut, Uttar Pradesh, India
Srinagarind Hospital, Division of Pulmonary Medicine, Khon Kaen University
🇹🇭
Khon Kaen, Mueang, Thailand
Chest Disease Institute (CDI), Ministry of Public,
🇹🇭
Nonthaburi, Mueang, Thailand
Ram-Tej Hospital,
🇮🇳
Agra, Uttar Pradesh, India
Shanghai Pulmonary Hospital
🇨🇳
Shanghai, China
Beijing Tuberculosis and Thoracic Tumor Research Institute
🇨🇳
Beijing, China
TB Institute
🇨🇳
Tianjin, China
Nirmal Kumar Jain
🇮🇳
Jaipur, Rajasthan, India
Siddharth Nursing Home,
🇮🇳
Agra, Uttar pradesh, India
Rajul Nursing Home
🇮🇳
Aligarh, Uttar Pradesh, India
S.P.S Chauhan Clinic
🇮🇳
Firozabad, Uttar Pradesh, India
Indra Nursing Home and Maternity Centre
🇮🇳
Ghaziabad, Uttar Pradesh, India
Dr. AK Singh Clinic
🇮🇳
Kanpur, Uttar Pradesh, India
Dr. R. K. Garg's Clinic,
🇮🇳
Gaziabad, Uttar Pradesh, India
Saanvi MultiSpeciality Clinic,
🇮🇳
Moradabad, Uttar Pradesh, India
Dr. Mittal's clinic
🇮🇳
New Delhi, India
Diligent Hospital
🇮🇳
New Delhi, India
Smt Prakash Devi Memorial Medical Centre,
🇮🇳
New Delhi, India
Institute of Respiratory Medicine (IPR) Jalan Pahang
🇲🇾
Kuala Lumpur, Malaysia
Clinical HIV Research Unit (CHRU)
🇿🇦
Johannesburg, Westdene, South Africa
Tiervlei Trial Center and University of Stellenbosch
🇿🇦
Cape Town, South Africa
New City Hospital and Trauma Centre,
🇮🇳
Lucknow, Uttar Pradesh, India
Madibeng centre for Research, 40 Pienaar Street,
🇿🇦
Madibeng, Brits, South Africa
Centre for TB Research and Innovation, University of Cape Town Lung Institute
🇿🇦
Cape Town, South Africa
Unit for Clinical & Biomedical TB Research, MRC Durban
🇿🇦
Durban, South Africa
Guru Tej Bahadur Hospital
🇮🇳
Kanpur, Uttar Pradesh, India
Dr. Komal Gupta
🇮🇳
Lucknow, Uttar Pradesh, India
Surya Chest Foundation,
🇮🇳
Lucknow, Uttar Pradesh, India
Dr. Mahip Saluja Clinic, U.P.
🇮🇳
Meerut,, Uttar Pradesh, India
Dr. S. P. Sondhi Clinic,
🇮🇳
Meerut, Uttar Pradesh, India