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

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

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

European and Developing Countries Clinical Trials Partnership (EDCTP), University College, London, Bayer Healthcare Pharmaceuticals, Inc./Bayer Schering Pharma, Sanofi

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.

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). 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).

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.

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.

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

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.

Combined Failure of Bacteriological Cure and Relapse Within One Year of Completion of Therapy as Defined by Culture Using Solid Media (Lowenstein-Jensen - LJ).

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)

Combined Failure of Bacteriological Cure and Relapse as Defined by Culture Using Liquid Media (Mycobacteria Growth Indicator Tube-MGIT).

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.

Sensitivity Analysis Assuming All Losses to Follow-up and Non-tuberculous Deaths Have an Unfavorable Outcome Using Solid (L-J) Media.

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.

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.

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).

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