Rifapentine Plus Moxifloxacin for Treatment of Pulmonary Tuberculosis - Full Text View

Sponsor:	Johns Hopkins University
Collaborator:	Federal University of Rio de Janeiro
Information provided by (Responsible Party):	Susan E. Dorman, Johns Hopkins University
ClinicalTrials.gov Identifier:	NCT00728507

Purpose

Although effective therapy for tuberculosis is available, TB continues to cause significant problems worldwide, and rates of multi-drug resistant (MDR) TB cases are on the rise. A major obstacle to the control of TB is poor adherence with lengthy (usually 6 months) and complicated treatment regimens. Incomplete TB treatment can lead to serious consequences such as increased severity of illness and death, prolonged infectiousness and transmission in the community, and the development of drug resistance. The development of new treatment strategies with more stronger drugs could lead to shorter and simpler regimens. A TB treatment regimen that allowed treatment duration to be meaningfully decreased would have important public health implications.

This trial will compare the effect and safety of a new oral regimen to that of the standard regimen for the first phase of treatment for pulmonary tuberculosis.

The experimental regimen will consist of the following:

Two months of isoniazid, rifapentine, pyrazinamide and moxifloxacin (HPZM) administered once daily. Pyridoxine (vitamin B6) will be given with each dose of isoniazid.

The standard control intensive phase regimen will consist of the following:

Two months of isoniazid, rifampin, pyrazinamide, and ethambutol (HRZE) administered once daily. Pyridoxine (vitamin B6) will be given with each dose of isoniazid.

Following intensive phase therapy (the study phase), all patients will be treated with a non-experimental continuation phase regimen.

In mice, the combination of Moxifloxacin and Rifapentine have cured the animals significantly faster than the standard regimen and this study will be the first step to see if the potential is also there in humans.

Condition	Intervention	Phase
Tuberculosis	Drug: Rifapentine, Moxifloxacin, Pyrazinamide, Isoniazid Drug: Isoniazid, Rifampin, Pyrazinamide, Ethambutol	Phase II

Study Type:	Interventional
Study Design:	Allocation: Randomized Endpoint Classification: Safety/Efficacy Study Intervention Model: Parallel Assignment Masking: Open Label Primary Purpose: Treatment
Official Title:	A Phase II Randomized, Open-label Trial of a Rifapentine Plus Moxifloxacin-Based Regimen for Intensive Phase Treatment of Smear-Positive Pulmonary Tuberculosis

Resource links provided by NLM:

MedlinePlus related topics: B Vitamins Tuberculosis

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

U.S. FDA Resources

Further study details as provided by Johns Hopkins University:

Primary Outcome Measures:

To compare, by treatment group, the proportions of patients with a negative sputum culture at the end of intensive phase therapy. [ Time Frame: Week 8 ] [ Designated as safety issue: No ]
To compare the safety and tolerability of the 2 intensive phase regimens. [ Time Frame: Weekly or more frequent ] [ Designated as safety issue: Yes ]

Secondary Outcome Measures:

To compare the time to respiratory culture conversion of the 2 intensive phase regimens, using data from weekly cultures. [ Time Frame: Weekly ] [ Designated as safety issue: No ]
To compare, by treatment group, the proportions of subjects who experience treatment failure. [ Time Frame: Month 6 ] [ Designated as safety issue: No ]
To compare, by HIV serostatus, a) the safety of the 2 intensive phase regimens, b) the proportions of patients with negative sputum cultures at the end of intensive phase therapy, and c) the time to culture conversion using data from weekly cultures. [ Time Frame: Weekly or more frequent ] [ Designated as safety issue: Yes ]
To compare, in subjects with versus without cavitation on baseline chest x-ray, the proportions of patients with negative sputum cultures at the end of intensive phase therapy. [ Time Frame: Week 8 ] [ Designated as safety issue: No ]
To store serum for future assessment of hypersensitivity to study drugs, should it occur; to store plasma for future assessment of drug concentrations [ Time Frame: Future ] [ Designated as safety issue: Yes ]

Estimated Enrollment:	216
Study Start Date:	November 2009
Estimated Study Completion Date:	June 2013
Estimated Primary Completion Date:	December 2012 (Final data collection date for primary outcome measure)

Arms	Assigned Interventions
Experimental: 1 Two months of isoniazid, rifapentine, pyrazinamide and moxifloxacin (HPZM) administered once daily. Pyridoxine (vitamin B6) will be given with each dose of isoniazid.	Drug: Rifapentine, Moxifloxacin, Pyrazinamide, Isoniazid Rifapentine:150mg tablets, dose = 300mg for subjects <= 45kg and 450mg for those >45kg by mouth once a day for 8 weeks; Moxifloxacin 400mg tablet by mouth once a day for 8 weeks, Isoniazid and Pyrazinamide per standard of care for TB treatment. Other Name: Priftin, Avelox
Active Comparator: 2 Two months of isoniazid, rifampin, pyrazinamide, and ethambutol (HRZE) administered once daily. Pyridoxine (vitamin B6) will be given with each dose of isoniazid.	Drug: Isoniazid, Rifampin, Pyrazinamide, Ethambutol Administered per standard of care for TB treatment

Eligibility

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

Criteria

Inclusion Criteria:

Presumptive diagnosis of sputum smear-positive pulmonary TB.
Age: ≥18 years
Seven (7) or fewer days of multidrug therapy for TB disease in the preceding 6 months.
Seven (7) or fewer days of fluoroquinolone therapy in the preceding 3 months.
Documentation of HIV infection status.
For HIV seropositive individuals, a CD4 T lymphocyte count of greater than or equal to 200 cells/mm3.
Documentation of study baseline laboratory parameters done at, or ≤ 14 days prior to screening:
- AST less than or equal to 2.5 times upper limit of normal.
- Total bilirubin level less than 2.5 times upper limit of normal.
- Creatinine level less than 2 times upper limit of normal.
- Hemoglobin level of at least 8.0 g/dl.
- Platelet count of at least 75,000 mm3.
- Potassium level of at least 3.5.
- Negative pregnancy test (women of childbearing potential).
Karnofsky score of at least 60 (requires occasional assistance but is able to care for most of his/her needs).
Male or nonpregnant, nonnursing female.
Provision of informed consent.

Exclusion Criteria:

CD4 count < 200 cells/cu mm.
Presence of active AIDS-related opportunistic infection (other than TB) or active AIDS-related malignancy.
Known intolerance to any of the study drugs.
Concomitant disorders or conditions for which any of the study drugs is contraindicated. These include severe hepatic damage, acute liver disease of any cause, and acute uncontrolled gouty arthritis.
Inability to take oral medication.
Central nervous system TB.
Pulmonary silicosis.
Current or planned therapy, during study phase (intensive phase of TB treatment), with any one or more of the following drugs: quinidine, procainamide, amiodarone, sotalol, disopyramide, terfenadine, cisapride, erythromycin, clarithromycin, phenothiazines, haloperidol, olanzapine, ziprasidone, tricyclic antidepressants, chronic corticosteroids administered either orally or intravenously, chronic fluconazole,chronic itraconazole, chronic ketoconazole, oral or intravenous tacrolimus, oral or intravenous cyclosporine, HIV protease inhibitor, HIV non-nucleoside reverse transcriptase inhibitor.
Concurrent severe and/or uncontrolled medical or psychiatric condition that, in the opinion of the investigator, could cause unacceptable safety risks or compromise compliance with the protocol.
Unable or unwilling to receive directly observed therapy and/or adhere with follow-up (e.g. due to residence remote from the study site).
Refusal of consent.

Contacts and Locations

Please refer to this study by its ClinicalTrials.gov identifier: NCT00728507

Contacts

Contact: Susan Dorman, MD	410-955-1755	dsusan1@jhmi.edu
Contact: Anne R Efron, MSN, MPH	410-502-2803	aefron@jhmi.edu

Locations

Brazil
Hospital Universitario Clementio Fraga Filho	Recruiting
Rio de Janeiro, Brazil
Contact: Marcus Conde, MD, PhD +55(21)2562 2426 marcusconde@hucff.ufrj.br
Contact: Carla Loredo, RN +55(21)2562 2426 carla.loredo@gmail.com
Principal Investigator: Marcus Conde, MD, PhD

Sponsors and Collaborators

Johns Hopkins University

Federal University of Rio de Janeiro

Investigators

Principal Investigator:

Susan Dorman, MD

Johns Hopkins University

More Information

Publications:

Rosenthal IM, Williams K, Tyagi S, Peloquin CA, Vernon AA, Bishai WR, Grosset JH, Nuermberger EL. Potent twice-weekly rifapentine-containing regimens in murine tuberculosis. Am J Respir Crit Care Med. 2006 Jul 1;174(1):94-101. Epub 2006 Mar 30.

Nuermberger EL, Yoshimatsu T, Tyagi S, O'Brien RJ, Vernon AN, Chaisson RE, Bishai WR, Grosset JH. Moxifloxacin-containing regimen greatly reduces time to culture conversion in murine tuberculosis. Am J Respir Crit Care Med. 2004 Feb 1;169(3):421-6. Epub 2003 Oct 24.

Nuermberger EL, Yoshimatsu T, Tyagi S, Williams K, Rosenthal I, O'Brien RJ, Vernon AA, Chaisson RE, Bishai WR, Grosset JH. Moxifloxacin-containing regimens of reduced duration produce a stable cure in murine tuberculosis. Am J Respir Crit Care Med. 2004 Nov 15;170(10):1131-4. Epub 2004 Aug 11.

Responsible Party:	Susan E. Dorman, Associate Professor of Medicine, Johns Hopkins University
ClinicalTrials.gov Identifier:	NCT00728507 History of Changes
Other Study ID Numbers:	06-0018
Study First Received:	July 30, 2008
Last Updated:	August 23, 2011
Health Authority:	United States: Food and Drug Administration; Brazil: National Committee of Ethics in Research; Brazil: Ethics Committee

Keywords provided by Johns Hopkins University:

Tuberculosis
Moxifloxacin
Rifapentine

Additional relevant MeSH terms:

Tuberculosis
Tuberculosis, Pulmonary
Mycobacterium Infections
Actinomycetales Infections
Gram-Positive Bacterial Infections
Bacterial Infections
Lung Diseases
Respiratory Tract Diseases
Respiratory Tract Infections
Ethambutol
Isoniazid
Pyrazinamide
Rifampin
Rifapentine
Moxifloxacin

Norgestimate, ethinyl estradiol drug combination
Antitubercular Agents
Anti-Bacterial Agents
Anti-Infective Agents
Therapeutic Uses
Pharmacologic Actions
Fatty Acid Synthesis Inhibitors
Hypolipidemic Agents
Antimetabolites
Molecular Mechanisms of Pharmacological Action
Lipid Regulating Agents
Antibiotics, Antitubercular
Enzyme Inhibitors
Leprostatic Agents
Nucleic Acid Synthesis Inhibitors

ClinicalTrials.gov processed this record on February 09, 2012