TBTC Study 28: Moxifloxacin Versus Isoniazid for TB Treatment

Tuberculosis Clinical Trial

Official title:

TBTC Study 28: Evaluation of a Moxifloxacin-based, Isoniazid-sparing Regimen for Tuberculosis Treatment

Clinical Trial Details — Status: Completed

Administrative data

• NCT number: NCT00144417
• Other study ID #: CDC-NCHSTP-4448
• Status: Completed
• Phase: Phase 2
• First received: September 1, 2005
• Last updated: August 2, 2011
• Start date: February 2006
• Est. completion date: December 2007

Study information

• Verified date: June 2011
• Source: Centers for Disease Control and Prevention
• Contact: n/a
• Is FDA regulated: No
• Health authority: United States: Food and Drug Administration
• Study type: Interventional

Clinical Trial 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.

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.

Recruitment information / eligibility

• Status: Completed
• Enrollment: 433
• Est. completion date: December 2007
• Est. primary completion date: June 2007
• Accepts healthy volunteers: No
• Gender: Both
• Age group: 18 Years and older

Eligibility

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

Study Design

Allocation: Randomized, Endpoint Classification: Safety/Efficacy Study, Intervention Model: Parallel Assignment, Masking: Double Blind (Subject, Caregiver, Investigator), Primary Purpose: Treatment

Related Conditions & MeSH terms

• Tuberculosis

Intervention

Drug:
• Moxifloxacin (with rifampin, pyrazinamide, and ethambutol)
Moxifloxacin 400mg daily, 8 weeks
• isoniazid
isoniazid, oral, 300 mg, daily, 8 weeks

Locations

Country	Name	City	State
Brazil	Hopital Universitario Clementino Fraga Filho	Rio de Janeiro
Canada	Montreal Chest Institute	Montreal	Quebec
Canada	University of Manitoba	Winnepeg	Manitoba
South Africa	Nelson R. Mandela School of Medicine	Durban	KwaZulu Natal
Spain	Agencia de Salut Publica	Barcelona
Uganda	Makerere University Medical School	Kampala
United States	Emory University School of Medicine	Atlanta	Georgia
United States	Johns Hopkins University School of Medicine	Baltimore	Maryland
United States	Boston University Medical Center	Boston	Massachusetts
United States	Northwestern University	Chicago	Illinois
United States	Denver Public Health Department	Denver	Colorado
United States	Duke University Medical Center	Durham	North Carolina
United States	University of North Texas Health Science Center	Fort Worth	Texas
United States	Hines Veterans Administration Medical Center	Hines	Illinois
United States	Houston Veterans Administration Medical Center	Houston	Texas
United States	Veterans Administration Medical Center of Arkansas	Little Rock	Arkansas
United States	University of Southern California Medical Center	Los Angeles	California
United States	Veterans Administration Tennessee Valley Health Care System	Nashville	Tennessee
United States	Columbia University	New York	New York
United States	Harlem Hospital, Columbia University	New York	New York
United States	New Jersey School of Medicine	Newark	New Jersey
United States	Audie L Murphy Memorial Veterans Administration Medical Center	San Antonio	Texas
United States	University of California at San Diego	San Diego	California
United States	University of California, San Francincisco	San Francisco	California
United States	Seattle-King County Health Department	Seattle	Washington
United States	Washington DC Veterans Administration Medical Center	Washington DC	District of Columbia

Sponsors (3)

Lead Sponsor	Collaborator
Centers for Disease Control and Prevention	Bayer, Global Alliance for TB Drug Development

Countries where clinical trial is conducted

United States,  Brazil,  Canada,  South Africa,  Spain,  Uganda, 

References & Publications (1)

Dorman SE, Johnson JL, Goldberg S, Muzanye G, Padayatchi N, Bozeman L, Heilig CM, Bernardo J, Choudhri S, Grosset JH, Guy E, Guyadeen P, Leus MC, Maltas G, Menzies D, Nuermberger EL, Villarino M, Vernon A, Chaisson RE; Tuberculosis Trials Consortium. Subs — View Citation

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	• 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	No
Secondary	To compare the safety and tolerability of the moxifloxacin regimen to that of the isoniazid regimen		8 weeks	Yes
Secondary	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	No
Secondary	To compare the proportion of patients with any Grade 3 or 4 adverse reactions		8 weeks	Yes
Secondary	To compare adverse events and 2-month culture conversion rates among HIV-infected patients vs. HIV-uninfected patients		8 weeks	Yes
Secondary	To compare the rates of treatment failure of the moxifloxacin regimen and the isoniazid regimen		6 months	No
Secondary	To determine whether there is delayed toxicity attributable to moxifloxacin (toxicity that becomes evident after the 8 weeks of moxifloxacin therapy)		6 months	Yes