TBTC Study 28: Moxifloxacin Versus Isoniazid for TB Treatment

This study has been completed.
Sponsor:
Collaborators:
Global Alliance for TB Drug Development
Bayer
Information provided by:
Centers for Disease Control and Prevention
ClinicalTrials.gov Identifier:
NCT00144417
First received: September 1, 2005
Last updated: August 2, 2011
Last verified: June 2011

September 1, 2005
August 2, 2011
February 2006
June 2007   (final data collection date for primary outcome measure)
• 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 [ Time Frame: 8 weeks ] [ Designated as safety issue: No ]
• 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
Complete list of historical versions of study NCT00144417 on ClinicalTrials.gov Archive Site
  • To compare the safety and tolerability of the moxifloxacin regimen to that of the isoniazid regimen [ Time Frame: 8 weeks ] [ Designated as safety issue: Yes ]
  • 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 [ Time Frame: 8 weeks ] [ Designated as safety issue: No ]
  • To compare the proportion of patients with any Grade 3 or 4 adverse reactions [ Time Frame: 8 weeks ] [ Designated as safety issue: Yes ]
  • To compare adverse events and 2-month culture conversion rates among HIV-infected patients vs. HIV-uninfected patients [ Time Frame: 8 weeks ] [ Designated as safety issue: Yes ]
  • To compare the rates of treatment failure of the moxifloxacin regimen and the isoniazid regimen [ Time Frame: 6 months ] [ Designated as safety issue: No ]
  • To determine whether there is delayed toxicity attributable to moxifloxacin (toxicity that becomes evident after the 8 weeks of moxifloxacin therapy) [ Time Frame: 6 months ] [ Designated as safety issue: Yes ]
  • • 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)
Not Provided
Not Provided
 
TBTC Study 28: Moxifloxacin Versus Isoniazid for TB Treatment
TBTC Study 28: Evaluation of a Moxifloxacin-based, Isoniazid-sparing Regimen for Tuberculosis Treatment

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.

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.

Interventional
Phase 2
Allocation: Randomized
Endpoint Classification: Safety/Efficacy Study
Intervention Model: Parallel Assignment
Masking: Double Blind (Subject, Caregiver, Investigator)
Primary Purpose: Treatment
Tuberculosis
  • Drug: Moxifloxacin (with rifampin, pyrazinamide, and ethambutol)
    Moxifloxacin 400mg daily, 8 weeks
  • Drug: isoniazid
    isoniazid, oral, 300 mg, daily, 8 weeks
  • Active Comparator: HRZE
    isoniazid, rifampin, pyrazinamide, ethambutol, moxifloxacin-placebo
    Intervention: Drug: isoniazid
  • Experimental: MRZE
    moxifloxacin, rifampin, pyrazinamide, ethambutol, isoniazid-placebo
    Intervention: Drug: Moxifloxacin (with rifampin, pyrazinamide, and ethambutol)

*   Includes publications given by the data provider as well as publications identified by ClinicalTrials.gov Identifier (NCT Number) in Medline.
 
Completed
433
December 2007
June 2007   (final data collection date for primary outcome measure)

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
Both
18 Years and older
No
Contact information is only displayed when the study is recruiting subjects
United States,   Brazil,   Canada,   South Africa,   Spain,   Uganda
 
NCT00144417
CDC-NCHSTP-4448
Yes
Dr. Stefan Goldberg, CHSRB/DTBE/NCHHSTP/CDC
Centers for Disease Control and Prevention
  • Global Alliance for TB Drug Development
  • Bayer
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
Centers for Disease Control and Prevention
June 2011

ICMJE     Data element required by the International Committee of Medical Journal Editors and the World Health Organization ICTRP