TBTC Study 28: Moxifloxacin Versus Isoniazid for TB Treatment - Full Text View

Sponsors and Collaborators:	Centers for Disease Control and Prevention Global Alliance for TB Drug Development Bayer
Information provided by:	Centers for Disease Control and Prevention
ClinicalTrials.gov Identifier:	NCT00144417

Purpose

This double-blind, randomized controlled trial evaluates moxifloxacin versus isoniazid in daily treatment during the first two months of treatment with rifampin, pyrazinamide and ethambutol for sputum smear-positive pulmonary tuberculosis.

Condition	Intervention	Phase
Tuberculosis	Drug: Moxifloxacin (with rifampin, pyrazinamide, and ethambutol) Drug: moxifloxacin	Phase II

MedlinePlus related topics: Tuberculosis

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

U.S. FDA Resources

Study Type:	Interventional
Study Design:	Treatment, Randomized, Double Blind (Subject, Caregiver, Investigator), Active Control, Parallel Assignment, Safety/Efficacy Study
Official Title:	TBTC Study 28: Evaluation of a Moxifloxacin-Based, Isoniazid-Sparing Regimen for Tuberculosis Treatment

Further study details as provided by Centers for Disease Control and Prevention:

Primary Outcome Measures:

• To compare the culture-conversion rate at the end of the intensive phase of therapy of the moxifloxacin regimen vs. that of the isoniazid regimen

Secondary Outcome Measures:

To compare the safety and tolerability of the moxifloxacin regimen to that of the isoniazid regimen
To determine the time to culture-conversion of the moxifloxacin regimen and the isoniazid regimen using data from 2-, 4-, 6-, and 8-week cultures
To compare the proportion of patients with any Grade 3 or 4 adverse reactions
To compare adverse events and 2-month culture conversion rates among HIV-infected patients vs. HIV-uninfected patients
To compare the rates of treatment failure of the moxifloxacin regimen and the isoniazid regimen
To determine whether there is delayed toxicity attributable to moxifloxacin (toxicity that becomes evident after the 8 weeks of moxifloxacin therapy)

Enrollment:	433
Study Start Date:	February 2006
Estimated Study Completion Date:	December 2007

Arms	Assigned Interventions
HRZE: Active Comparator isoniazid, rifampin, pyrazinamide, ethambutol, moxifloxacin-placebo	Drug: moxifloxacin moxifloxacin, oral, 400 mg, daily, 8 weeks
MRZE: Experimental moxifloxacin, rifampin, pyrazinamide, ethambutol, isoniazid-placebo	Drug: Moxifloxacin (with rifampin, pyrazinamide, and ethambutol) Drug: moxifloxacin moxifloxacin, oral, 400 mg, daily, 8 weeks

Detailed Description:

The primary objective of this Phase 2 clinical trial is to compare the safety and antimicrobial activity of a moxifloxacin-containing regimen (moxifloxacin, rifampin, pyrazinamide, ethambutol [MRZE]) in which moxifloxacin has been substituted for isoniazid, to the standard control regimen (isoniazid, rifampin, pyrazinamide, ethambutol [HRZE]) in the first two months of treatment of sputum smear-positive pulmonary tuberculosis. The assessment of antimicrobial activity will be sputum culture-conversion. Higher rates of sputum culture conversion after 2 months of treatment with a moxifloxacin-containing regimen would support Phase 3 clinical trials of moxifloxacin in treatment regimens of less than the current 6 month standard regimens.

Rationale - Current treatment of smear positive pulmonary tuberculosis requires a minimum of 6 months, a treatment duration that is challenging for patients and tuberculosis control programs. Therefore, a high priority in tuberculosis research is the identification of agents that can shorten treatment. Several fluoroquinolone antibiotics have potent activity against Mycobacterium tuberculosis (M. tuberculosis) in preclinical testing. Of the currently available fluoroquinolones, moxifloxacin has excellent activity in vitro and in animal models of tuberculosis, a favorable pharmacokinetic profile (serum half-life of 10-12 hours), lack of problematic drug-drug interactions, no need for dosage adjustment for renal and hepatic insufficiency, and an excellent safety profile. In addition, in the murine model of tuberculosis, the substitution of moxifloxacin for isoniazid resulted in significant reductions in the time to culture conversion and the time to sterilization when compared to the standard combination rifampin, isoniazid and pyrazinamide. However, moxifloxacin has not been fully evaluated in humans for tuberculosis treatment. There is a need to assess not only the anti-tuberculosis activity of moxifloxacin-containing regimens, but also the safety of more prolonged therapy with moxifloxacin.

Two-month culture conversion rates are a well-accepted surrogate marker for the sterilizing activity of anti-tuberculosis drugs. Rifampin and pyrazinamide, the key drugs in current 6-month regimens, markedly increase 2-month culture-conversion rates. Therefore, this study will use 2-month culture conversion rate as the measure of antimicrobial activity of moxifloxacin.

Eligibility

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

Criteria

Inclusion Criteria:

Suspected pulmonary tuberculosis with acid-fast bacilli in a stained smear of expectorated or induced sputum. Patients whose sputum cultures do not grow M. tuberculosis and those having an M. tuberculosis isolate resistant to (one or more) isoniazid, rifampin, fluoroquinolones, will be discontinued from the study, but followed for 14 days to detect late toxicities from study therapy. Patients having extra-pulmonary manifestations of tuberculosis, in addition to smear-positive pulmonary disease, are eligible for enrollment. Sputum must be expectorated or induced; smear results from respiratory secretions obtained by bronchoalveolar lavage or bronchial wash may not be used for assessment of study eligibility.
Willingness to have HIV testing performed, if HIV serostatus is not known or if the last documented negative HIV test was more than 6 months prior to enrollment. HIV testing does not need to be repeated if there is written documentation of a positive test (positive ELISA and Western Blot or a plasma HIV-RNA level greater than 5000 copies/ml) at any time in the past.
7 (seven) or fewer days of multidrug therapy for tuberculosis disease in the 6 months preceding enrollment.
7 (seven) or fewer days of fluoroquinolone therapy in the 3 months preceding enrollment.
Age > 18 years
Karnofsky score of at least 60 (requires occasional assistance but is able to care for most of his/her needs; see Appendix B).
Signed informed consent
Women with child-bearing potential must agree to practice an adequate (barrier) method of birth control or to abstain from heterosexual intercourse during study therapy.
Laboratory parameters done at, or  14 days prior to, screening:
Serum amino aspartate transferase (AST) activity ≤ 3 times the upper limit of normal
Serum total bilirubin level ≤ 2.5 times the upper limit of normal
Serum creatinine level ≤ 2 times the upper limit of normal
Complete blood count with hemoglobin level of at least 7.0 g/dL
Complete blood count with platelet count of at least 50,000/mm3
Serum potassium > 3.5 meq/L
Negative pregnancy test (women of childbearing potential)

Exclusion Criteria:

Breast-feeding
Known intolerance to any of the study drugs
Known allergy to any fluoroquinolone antibiotic
Concomitant disorders or conditions for which moxifloxacin (MXF), isoniazid (INH), rifampin (RIF), pyrazinamide (PZA), or ethambutol (EMB) are contraindicated. These include severe hepatic damage, acute liver disease of any cause, and acute uncontrolled gouty arthritis.
Current or planned therapy during the intensive phase of therapy using drugs having unacceptable interactions with rifampin (rifabutin can be substituted for rifampin during the continuation phase of therapy).
Current or planned antiretroviral therapy during the intensive phase of therapy.
History of prolonged QT syndrome or current or planned therapy with quinidine, procainamide, amiodarone, sotalol, disopyramide, ziprasidone, or terfenadine during the intensive phase of therapy.
Pulmonary silicosis
Central nervous system TB

Contacts and Locations

Please refer to this study by its ClinicalTrials.gov identifier: NCT00144417

Show 26 Study Locations

Sponsors and Collaborators

Centers for Disease Control and Prevention

Global Alliance for TB Drug Development

Bayer

Investigators

Study Chair:	Richard E Chaisson, MD	Johns Hopkins University
Principal Investigator:	Susan E Dorman, MD	Johns Hopkins University
Principal Investigator:	John L Johnson, MD	Case Western Reserve University

More Information

Study ID Numbers:	CDC-NCHSTP-4448
Study First Received:	September 1, 2005
Last Updated:	September 20, 2007
ClinicalTrials.gov Identifier:	NCT00144417
Health Authority:	United States: Food and Drug Administration

Keywords provided by Centers for Disease Control and Prevention:

tuberculosis
TB
treatment
efficacy
safety

Study placed in the following topic categories:

Bacterial Infections
Rifampin
Gram-Positive Bacterial Infections
Moxifloxacin
Mycobacterium Infections

Ethambutol
Tuberculosis
Pyrazinamide
Isoniazid

Additional relevant MeSH terms:

Anti-Infective Agents
Anti-Bacterial Agents
Therapeutic Uses

Antitubercular Agents
Pharmacologic Actions
Actinomycetales Infections

ClinicalTrials.gov processed this record on January 16, 2009