TBTC Study 28: Moxifloxacin Versus Isoniazid for TB Treatment
Information source: Centers for Disease Control and Prevention
ClinicalTrials.gov processed this data on August 23, 2015 Link to the current ClinicalTrials.gov record.
Condition(s) targeted: Tuberculosis
Intervention: Moxifloxacin (with rifampin, pyrazinamide, and ethambutol) (Drug); isoniazid (Drug)
Phase: Phase 2
Status: Completed
Sponsored by: Centers for Disease Control and Prevention Official(s) and/or principal investigator(s): Richard E Chaisson, MD, Study Chair, Affiliation: Johns Hopkins University Susan E Dorman, MD, Principal Investigator, Affiliation: Johns Hopkins University John L Johnson, MD, Principal Investigator, Affiliation: Case Western Reserve University
Summary
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.
Clinical Details
Official title: TBTC Study 28: Evaluation of a Moxifloxacin-based, Isoniazid-sparing Regimen for Tuberculosis Treatment
Study design: Allocation: Randomized, Endpoint Classification: Safety/Efficacy Study, Intervention Model: Parallel Assignment, Masking: Double Blind (Subject, Caregiver, Investigator), Primary Purpose: Treatment
Primary outcome: • 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: To compare the safety and tolerability of the moxifloxacin regimen to that of the isoniazid regimenTo 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)
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
Minimum age: 18 Years.
Maximum age: N/A.
Gender(s): Both.
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
Locations and Contacts
Hopital Universitario Clementino Fraga Filho, Rio de Janeiro 2194.590, Brazil
Agencia de Salut Publica, Barcelona 08023, Spain
Makerere University Medical School, Kampala, Uganda
Veterans Administration Medical Center of Arkansas, Little Rock, Arkansas 72205, United States
University of Southern California Medical Center, Los Angeles, California 90033, United States
University of California at San Diego, San Diego, California 92103, United States
University of California, San Francincisco, San Francisco, California 94110, United States
Denver Public Health Department, Denver, Colorado 80204, United States
Washington DC Veterans Administration Medical Center, Washington DC, District of Columbia 20422, United States
Emory University School of Medicine, Atlanta, Georgia 30303, United States
Northwestern University, Chicago, Illinois 60611, United States
Hines Veterans Administration Medical Center, Hines, Illinois 60141, United States
Nelson R. Mandela School of Medicine, Durban, KwaZulu Natal, South Africa
University of Manitoba, Winnepeg, Manitoba R3A 1R8, Canada
Johns Hopkins University School of Medicine, Baltimore, Maryland 21231, United States
Boston University Medical Center, Boston, Massachusetts 02118, United States
New Jersey School of Medicine, Newark, New Jersey 07103, United States
Columbia University, New York, New York 10032, United States
Harlem Hospital, Columbia University, New York, New York 10037, United States
Duke University Medical Center, Durham, North Carolina 27710, United States
Montreal Chest Institute, Montreal, Quebec H2X 2P4, Canada
Veterans Administration Tennessee Valley Health Care System, Nashville, Tennessee 37232, United States
University of North Texas Health Science Center, Fort Worth, Texas 76104, United States
Houston Veterans Administration Medical Center, Houston, Texas 77030, United States
Audie L Murphy Memorial Veterans Administration Medical Center, San Antonio, Texas 78284, United States
Seattle-King County Health Department, Seattle, Washington 98104, United States
Additional Information
Starting date: February 2006
Last updated: August 2, 2011
|