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

Overview

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.

Full Title of Study: “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 Type

  • Study Type: Interventional
  • Study Design
    • Allocation: Randomized
    • Intervention Model: Parallel Assignment
    • Primary Purpose: Treatment
    • Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
  • Study Primary Completion Date: October 2013

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).

Interventions

  • 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.

Arms, Groups and Cohorts

  • Placebo Comparator: Regimen 1 – 2EHRZ/4HR (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.
  • Experimental: Regimen 2 – 2MHRZ/2MHR
    • 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.
  • Experimental: Regimen 3 – 2EMRZ/2MR
    • 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

Clinical Trial Outcome Measures

Primary Measures

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

  • Combined Failure of Bacteriological Cure and Relapse as Defined by Culture Using Liquid Media (Mycobacteria Growth Indicator Tube-MGIT).
    • Time Frame: 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)
    • Time Frame: 8 weeks
    • Number of patients who are TB LJ culture negative at 8 weeks.
  • Number of Patients Who Are Culture Negative (Liquid MGIT Culture)
    • Time Frame: 8 weeks
    • Number of patients who are TB MGIT culture negative at 8 weeks.
  • Time to First Culture Negative Sputum Sample (LJ Solid Media)
    • Time Frame: 18 months
    • Culture negative for TB using LJ cultures.
  • Time to First Culture Negative Sputum Sample (MGIT Liquid Media)
    • Time Frame: 18 months
  • Sensitivity Analysis Assuming All Losses to Follow-up and Non-tuberculous Deaths Have an Unfavorable Outcome Using Solid (L-J) Media.
    • Time Frame: 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.
    • Time Frame: 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.

Participating in This Clinical Trial

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).

Gender Eligibility: All

Minimum Age: 18 Years

Maximum Age: N/A

Are Healthy Volunteers Accepted: No

Investigator Details

  • Lead Sponsor
    • Global Alliance for TB Drug Development
  • Collaborator
    • European and Developing Countries Clinical Trials Partnership (EDCTP)
  • Provider of Information About this Clinical Study
    • Sponsor
  • Overall Official(s)
    • Stephen H Gillespie, MB BCh BAO MD DSc, Study Director, University of St Andrews
    • Andrew Nunn, BSc MSc, Principal Investigator, MRC Clinical Trials Unit
    • Sarah K Meredith, MB BS MSc, Principal Investigator, MRC Clinical Trials Unit
    • Timothy D McHugh, BSc PhD CSi, Principal Investigator, Centre for Medical Microbiology, Royal Free and University College Medical School
    • Ali Zumla, BSc MBChB MSc PhD, Principal Investigator, Centre for International Health, Royal Free and University College Medical School
    • Alexander Pym, MB BMRCP PhD, Principal Investigator, Unit for Clinical & Biomedical TB Research, MRC Durban
    • Peter Mwaba, MB ChB MMed PhD, Principal Investigator, University Teaching Hospital
    • Noel Sam, MMed MD, Principal Investigator, Kilimanjaro Christian Medical Centre
    • Andreas Diacon, BM MD, Principal Investigator, Tiervlei Trial Center and University of Stellenbosch
    • Rodney Dawson, MB ChB FCP, Principal Investigator, Centre for TB Research and Innovation, UCT Lung Institute
    • Evans Amukoye, MBChB. Mmed (Paediatric), Principal Investigator, Centre for Respiratory Disease Research at KEMRI
    • Leonard Maboko, MD MSc PhD, Principal Investigator, NIMR – Mbeya Medical Research Programme
    • Ian Sanne, MBBCH FCP(SA), Principal Investigator, Clinical HIV Research Unit (CHRU), Westdene
    • Cheryl Louw, MBChB, Principal Investigator, Madibeng Centre For Research, Brits
    • Mengqui Gao, MD, Principal Investigator, Beijing Tuberculosis and Thoracic Tumor Research Institute
    • Qing Zhang, MD, Principal Investigator, Shanghai Pulmonary Hospital, Shanghai, China
    • Xiexiu Wang, MD, Principal Investigator, TB Institute, Tianjin
    • Aziah Mahayiddin, MD, Principal Investigator, Institute of Respiratory Medicine (IPR) Jalan Pahang, Malaysia
    • Watchara Boonsawat, MD PhD, Principal Investigator, Srinagarind Hospital, Division of Pulmonary Medicine, Khon Kaen University
    • Charoen Chuchottaworn, MD, Principal Investigator, Chest Disease Institute (CDI), Ministry of Public Health, Nonthaburi
    • Pairaj Kateruttanakul, MD, Principal Investigator, Rajavithi Hospital, Division of Pulmonary, Department of Medicine, Bangkok
    • Gerardo Amaya-Tapia, MD, Principal Investigator, Hospital General de occidente de la secretaria, Seattle, Mexico
    • Stephen Murray, M.D, PhD, Principal Investigator, Global Alliance for TB Drug Development
    • Michael Brown, BA, BM, BCh, MRCP, PhD, DTM&H, Principal Investigator, London School of Hygiene and Tropical Medicine
    • Rakesh Lal, MD, Principal Investigator, Centre for Advanced Lung and Sleep Disorders, New Delhi, India
    • Rakesh Mittal, MBBS MD, Principal Investigator, Dr. Mittal’s Clinic, Balaji Medical Store, New Delhi, India
    • A K Jain, MBBS FICA, Principal Investigator, Diligent Hospital, New Delhi, India
    • Mahesh Kapoor, MBBS DTCD, Principal Investigator, A One Hospital, New Delhi, India
    • D K Chauhan, MBBS, Principal Investigator, Dr D.K. Chauhan, New Delhi, India
    • Mahip Saluja, M.D, Principal Investigator, Dr. Mahip Saluja Clinic, Meerut, U.P. India
    • Neeraj Gupta, MD, Principal Investigator, Dr. Neeraj Gupta, Firozabad ,U.P, India
    • Subodh Katiyar, MD, Principal Investigator, Dr Subodh, Swaroop Nagar,Kanpur, India
    • Nirmal K Jain, MD, Principal Investigator, Dr.Nirmal Kumar Jain, Jaipur, India
    • Komal Gupta, M.D, Principal Investigator, Kilkari , Lucknow , India
    • Fahad Khan, MD, Principal Investigator, New City Hospital and Trauma Centre, Lucknow, India
    • Vaibhav Gupta, MD, Principal Investigator, Saanvi MultiSpeciality Clinic, Moradabad, UP, India,
    • Suraj P Sondhi, MD, Principal Investigator, Dr. S. P. Sondhi Clinic , Meerut U.P India
    • Siddharth Agarwal, MD, Principal Investigator, Siddharth Nursing Home, Agra, U.P India
    • Sanjay Teotia, M.D, Principal Investigator, Dr. Sanjay Teotia Clinic, Meerut, U.P , India
    • S PS Chauhan, MD, Principal Investigator, Dr. SPS Chauhan, Firozabad, U.P-India,
    • Mahesh Mishra, MD, Principal Investigator, Mahatma Gandhi Medical College& Hospital , Jaipur, India
    • Ashish Rohatgi, DTCD, Principal Investigator, Ish Medical Centre and Respiratory Lab, New Delhi- India
    • Om P Rai, MD, Principal Investigator, Guru Tej Bahadur Hospital, Kanpur India
    • Pawan Varshneya, MD, Principal Investigator, Varshneya Chest Clinic & Eye Care Centre, Aligarh, UP India
    • R K Garg, MD, Principal Investigator, Dr. R. K. Garg’s Clinic, U.P, India
    • Vinod K Karhana, M.D, Principal Investigator, Prakash Devi Memorial Medical Centre,New Delhi, India
    • Vijay K Khurana, M.D, Principal Investigator, Ram-Tej Hospital, Agra, India
    • Surya Kant, MD, FCCP, FNCP, FCAI, Principal Investigator, Dr.Surya Kant, Lucknow, India
    • Shalini Arya, MD, Principal Investigator, Arya Chest Clinic, Meerut, UP,India
    • Ashok K Singh, MD, FCCP, FCCS, Principal Investigator, Pulmonary Care and Sleep Clinic, Kanpur, India
    • Bhanu P Singh, MD, FCCP, Principal Investigator, Surya Chest Foundation, Lucknow India
    • Chandra P Singh, MD, Principal Investigator, Jigyasa Medical Center,Uttar Pradesh, India
    • Arun Aggarwal, MD, Principal Investigator, Indra Nursing Home and Maternity Centre, Uttar Pradesh, India
    • Anjula Bhargava, MS, Principal Investigator, Rajul Nursing Home, Sasni Gate, Aligarh, UP India
    • Angela Crook, Principal Investigator, MRC Clinical Trials Unit
    • Salome Charalambous, Principal Investigator, The Aurum Institute, Tembisa Hospital, South Africa
    • Lerato Mohapi, Principal Investigator, Soweto Perinatal HIV Research Unit, Johannesburg, South Africa
    • Nesri Padayatchi, Principal Investigator, Caprisa eThakwini Research Facility, Durban, South Africa
    • Sandy Pillay, Principal Investigator, International Clinical Trials Unit, Durban, South Africa

References

Bryant JM, Harris SR, Parkhill J, Dawson R, Diacon AH, van Helden P, Pym A, Mahayiddin AA, Chuchottaworn C, Sanne IM, Louw C, Boeree MJ, Hoelscher M, McHugh TD, Bateson AL, Hunt RD, Mwaigwisya S, Wright L, Gillespie SH, Bentley SD. Whole-genome sequencing to establish relapse or re-infection with Mycobacterium tuberculosis: a retrospective observational study. Lancet Respir Med. 2013 Dec;1(10):786-92. doi: 10.1016/S2213-2600(13)70231-5. Epub 2013 Nov 21.

Friedrich SO, Rachow A, Saathoff E, Singh K, Mangu CD, Dawson R, Phillips PP, Venter A, Bateson A, Boehme CC, Heinrich N, Hunt RD, Boeree MJ, Zumla A, McHugh TD, Gillespie SH, Diacon AH, Hoelscher M; Pan African Consortium for the Evaluation of Anti-tuberculosis Antibiotics (PanACEA). Assessment of the sensitivity and specificity of Xpert MTB/RIF assay as an early sputum biomarker of response to tuberculosis treatment. Lancet Respir Med. 2013 Aug;1(6):462-70. doi: 10.1016/S2213-2600(13)70119-X. Epub 2013 Jul 1.

Citations Reporting on Results

Gillespie SH, Crook AM, McHugh TD, Mendel CM, Meredith SK, Murray SR, Pappas F, Phillips PP, Nunn AJ; REMoxTB Consortium. Four-month moxifloxacin-based regimens for drug-sensitive tuberculosis. N Engl J Med. 2014 Oct 23;371(17):1577-87. doi: 10.1056/NEJMoa1407426. Epub 2014 Sep 7.

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