TBTC Study 28: Moxifloxacin Versus Isoniazid for TB Treatment

Sponsor

Centers for Disease Control and Prevention (U.S. Fed)

Overall Status

Completed

CT.gov ID

NCT00144417

Collaborator

Global Alliance for TB Drug Development (Other), Bayer (Industry)

433

Enrollment

Locations

Arms

21.9

Duration (Months)

16.7

Patients Per Site

0.8

Patients Per Site Per Month

Study Details

Study Description

Brief 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.

Condition or Disease	Intervention/Treatment	Phase
Tuberculosis	Drug: Moxifloxacin (with rifampin, pyrazinamide, and ethambutol) Drug: isoniazid	Phase 2

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.

Study Design

Study Type:

Interventional

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 :

Feb 1, 2006

Actual Primary Completion Date :

Jun 1, 2007

Actual Study Completion Date :

Dec 1, 2007

Arms and Interventions

Arm	Intervention/Treatment
Active Comparator: HRZE isoniazid, rifampin, pyrazinamide, ethambutol, moxifloxacin-placebo	Drug: isoniazid isoniazid, oral, 300 mg, daily, 8 weeks
Experimental: MRZE moxifloxacin, rifampin, pyrazinamide, ethambutol, isoniazid-placebo	Drug: Moxifloxacin (with rifampin, pyrazinamide, and ethambutol) Moxifloxacin 400mg daily, 8 weeks

Arm

Intervention/Treatment

Active Comparator: HRZE

isoniazid, rifampin, pyrazinamide, ethambutol, moxifloxacin-placebo

Drug: isoniazid

isoniazid, oral, 300 mg, daily, 8 weeks

Experimental: MRZE

moxifloxacin, rifampin, pyrazinamide, ethambutol, isoniazid-placebo

Drug: Moxifloxacin (with rifampin, pyrazinamide, and ethambutol)

Moxifloxacin 400mg daily, 8 weeks

Outcome Measures

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 [8 weeks]

Secondary Outcome Measures

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

Eligibility Criteria

Criteria

Ages Eligible for Study:

18 Years and Older

Sexes Eligible for Study:

All

Accepts Healthy Volunteers:

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

Locations

	Site	City	State	Country	Postal Code
1	Veterans Administration Medical Center of Arkansas	Little Rock	Arkansas	United States	72205
2	University of Southern California Medical Center	Los Angeles	California	United States	90033
3	University of California at San Diego	San Diego	California	United States	92103
4	University of California, San Francincisco	San Francisco	California	United States	94110
5	Denver Public Health Department	Denver	Colorado	United States	80204
6	Washington DC Veterans Administration Medical Center	Washington DC	District of Columbia	United States	20422
7	Emory University School of Medicine	Atlanta	Georgia	United States	30303
8	Northwestern University	Chicago	Illinois	United States	60611
9	Hines Veterans Administration Medical Center	Hines	Illinois	United States	60141
10	Johns Hopkins University School of Medicine	Baltimore	Maryland	United States	21231
11	Boston University Medical Center	Boston	Massachusetts	United States	02118
12	New Jersey School of Medicine	Newark	New Jersey	United States	07103
13	Columbia University	New York	New York	United States	10032
14	Harlem Hospital, Columbia University	New York	New York	United States	10037
15	Duke University Medical Center	Durham	North Carolina	United States	27710
16	Veterans Administration Tennessee Valley Health Care System	Nashville	Tennessee	United States	37232
17	University of North Texas Health Science Center	Fort Worth	Texas	United States	76104
18	Houston Veterans Administration Medical Center	Houston	Texas	United States	77030
19	Audie L Murphy Memorial Veterans Administration Medical Center	San Antonio	Texas	United States	78284
20	Seattle-King County Health Department	Seattle	Washington	United States	98104
21	Hopital Universitario Clementino Fraga Filho	Rio de Janeiro		Brazil	2194.590
22	University of Manitoba	Winnepeg	Manitoba	Canada	R3A 1R8
23	Montreal Chest Institute	Montreal	Quebec	Canada	H2X 2P4
24	Nelson R. Mandela School of Medicine	Durban	KwaZulu Natal	South Africa
25	Agencia de Salut Publica	Barcelona		Spain	08023
26	Makerere University Medical School	Kampala		Uganda