TBTC Study 28: Moxifloxacin Versus Isoniazid for TB Treatment
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| ClinicalTrials.gov Identifier: NCT00144417 |
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Recruitment Status :
Completed
First Posted : September 5, 2005
Last Update Posted : August 3, 2011
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| Condition or disease | Intervention/treatment | Phase |
|---|---|---|
| Tuberculosis | Drug: Moxifloxacin (with rifampin, pyrazinamide, and ethambutol) Drug: isoniazid | Phase 2 |
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.
| Study Type : | Interventional (Clinical Trial) |
| Actual Enrollment : | 433 participants |
| Allocation: | Randomized |
| Intervention Model: | Parallel Assignment |
| Masking: | Triple (Participant, Care Provider, Investigator) |
| Primary Purpose: | Treatment |
| Official Title: | TBTC Study 28: Evaluation of a Moxifloxacin-based, Isoniazid-sparing Regimen for Tuberculosis Treatment |
| Study Start Date : | February 2006 |
| Actual Primary Completion Date : | June 2007 |
| Actual Study Completion Date : | December 2007 |
| Arm | Intervention/treatment |
|---|---|
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Active Comparator: HRZE
isoniazid, rifampin, pyrazinamide, ethambutol, moxifloxacin-placebo
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Drug: isoniazid
isoniazid, oral, 300 mg, daily, 8 weeks |
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Experimental: MRZE
moxifloxacin, rifampin, pyrazinamide, ethambutol, isoniazid-placebo
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Drug: Moxifloxacin (with rifampin, pyrazinamide, and ethambutol)
Moxifloxacin 400mg daily, 8 weeks |
- • 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 ]
- To compare the safety and tolerability of the moxifloxacin regimen to that of the isoniazid regimen [ Time Frame: 8 weeks ]
- 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 ]
- To compare the proportion of patients with any Grade 3 or 4 adverse reactions [ Time Frame: 8 weeks ]
- To compare adverse events and 2-month culture conversion rates among HIV-infected patients vs. HIV-uninfected patients [ Time Frame: 8 weeks ]
- To compare the rates of treatment failure of the moxifloxacin regimen and the isoniazid regimen [ Time Frame: 6 months ]
- 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 ]
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| Ages Eligible for Study: | 18 Years and older (Adult, Older Adult) |
| Sexes Eligible for Study: | All |
| Accepts Healthy Volunteers: | No |
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
To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.
Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT00144417
Show 26 study locations
| 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 |
Publications automatically indexed to this study by ClinicalTrials.gov Identifier (NCT Number):
| Responsible Party: | Dr. Stefan Goldberg, CHSRB/DTBE/NCHHSTP/CDC |
| ClinicalTrials.gov Identifier: | NCT00144417 |
| Other Study ID Numbers: |
CDC-NCHSTP-4448 |
| First Posted: | September 5, 2005 Key Record Dates |
| Last Update Posted: | August 3, 2011 |
| Last Verified: | June 2011 |
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tuberculosis TB treatment efficacy safety |
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Tuberculosis Mycobacterium Infections Actinomycetales Infections Gram-Positive Bacterial Infections Bacterial Infections Bacterial Infections and Mycoses Infections Moxifloxacin Rifampin Isoniazid Pyrazinamide Ethambutol Anti-Bacterial Agents Anti-Infective Agents Topoisomerase II Inhibitors |
Topoisomerase Inhibitors Enzyme Inhibitors Molecular Mechanisms of Pharmacological Action Antineoplastic Agents Antibiotics, Antitubercular Antitubercular Agents Leprostatic Agents Nucleic Acid Synthesis Inhibitors Cytochrome P-450 CYP2B6 Inducers Cytochrome P-450 Enzyme Inducers Cytochrome P-450 CYP2C8 Inducers Cytochrome P-450 CYP2C19 Inducers Cytochrome P-450 CYP2C9 Inducers Cytochrome P-450 CYP3A Inducers Fatty Acid Synthesis Inhibitors |