TBTC Study 28: Moxifloxacin Versus Isoniazid for TB Treatment

NCT ID: NCT00144417

Last Updated: 2011-08-03

Basic Information

• Recruitment Status: COMPLETED
• Clinical Phase: PHASE2
• Total Enrollment: 433 participants
• Study Classification: INTERVENTIONAL
• Study Start Date: 2006-02-28
• Study Completion Date: 2007-12-31

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.

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.

Conditions

Tuberculosis

Study Design

• Allocation Method: RANDOMIZED
• Intervention Model: PARALLEL
• Primary Study Purpose: TREATMENT
• Blinding Strategy: TRIPLE

Study Groups

HRZE

isoniazid, rifampin, pyrazinamide, ethambutol, moxifloxacin-placebo

Group Type: ACTIVE_COMPARATOR

isoniazid

Intervention Type: DRUG

isoniazid, oral, 300 mg, daily, 8 weeks

MRZE

moxifloxacin, rifampin, pyrazinamide, ethambutol, isoniazid-placebo

Group Type: EXPERIMENTAL

Moxifloxacin (with rifampin, pyrazinamide, and ethambutol)

Intervention Type: DRUG

Moxifloxacin 400mg daily, 8 weeks

Interventions

Moxifloxacin (with rifampin, pyrazinamide, and ethambutol)

Moxifloxacin 400mg daily, 8 weeks

Intervention Type: DRUG

isoniazid

isoniazid, oral, 300 mg, daily, 8 weeks

Intervention Type: DRUG

Eligibility 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

• Minimum Eligible Age: 18 Years
• Eligible Sex: ALL
• Accepts Healthy Volunteers: No

Sponsors

Global Alliance for TB Drug Development

OTHER

Sponsor Role: collaborator

Bayer

INDUSTRY

Sponsor Role: collaborator

Centers for Disease Control and Prevention

FED

Sponsor Role: lead

Responsible Party

CHSRB/DTBE/NCHHSTP/CDC

Principal Investigators

Richard E Chaisson, MD

Role: STUDY_CHAIR

Johns Hopkins University

Susan E Dorman, MD

Role: PRINCIPAL_INVESTIGATOR

Johns Hopkins University

John L Johnson, MD

Role: PRINCIPAL_INVESTIGATOR

Case Western Reserve University

Locations

Veterans Administration Medical Center of Arkansas

Little Rock, Arkansas, United States

University of Southern California Medical Center

Los Angeles, California, United States

University of California at San Diego

San Diego, California, United States

University of California, San Francincisco

San Francisco, California, United States

Denver Public Health Department

Denver, Colorado, United States

Washington DC Veterans Administration Medical Center

Washington D.C., District of Columbia, United States

Emory University School of Medicine

Atlanta, Georgia, United States

Northwestern University

Chicago, Illinois, United States

Hines Veterans Administration Medical Center

Hines, Illinois, United States

Johns Hopkins University School of Medicine

Baltimore, Maryland, United States

Boston University Medical Center

Boston, Massachusetts, United States

New Jersey School of Medicine

Newark, New Jersey, United States

Columbia University

New York, New York, United States

Harlem Hospital, Columbia University

New York, New York, United States

Duke University Medical Center

Durham, North Carolina, United States

Veterans Administration Tennessee Valley Health Care System

Nashville, Tennessee, United States

University of North Texas Health Science Center

Fort Worth, Texas, United States

Houston Veterans Administration Medical Center

Houston, Texas, United States

Audie L Murphy Memorial Veterans Administration Medical Center

San Antonio, Texas, United States

Seattle-King County Health Department

Seattle, Washington, United States

Hopital Universitario Clementino Fraga Filho

Rio de Janeiro, Rio de Janeiro, Brazil

University of Manitoba

Winnepeg, Manitoba, Canada

Montreal Chest Institute

Montreal, Quebec, Canada

Nelson R. Mandela School of Medicine

Durban, KwaZulu-Natal, South Africa

Agencia de Salut Publica

Barcelona, , Spain

Makerere University Medical School

Kampala, , Uganda

Countries

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

References

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. Substitution of moxifloxacin for isoniazid during intensive phase treatment of pulmonary tuberculosis. Am J Respir Crit Care Med. 2009 Aug 1;180(3):273-80. doi: 10.1164/rccm.200901-0078OC. Epub 2009 Apr 30.

Reference Type: RESULT

PMID: 19406981 (View on PubMed)

Zhang N, Savic RM, Boeree MJ, Peloquin CA, Weiner M, Heinrich N, Bliven-Sizemore E, Phillips PPJ, Hoelscher M, Whitworth W, Morlock G, Posey J, Stout JE, Mac Kenzie W, Aarnoutse R, Dooley KE; Tuberculosis Trials Consortium (TBTC) and Pan African Consortium for the Evaluation of Antituberculosis Antibiotics (PanACEA) Networks. Optimising pyrazinamide for the treatment of tuberculosis. Eur Respir J. 2021 Jul 20;58(1):2002013. doi: 10.1183/13993003.02013-2020. Print 2021 Jul.

Reference Type: DERIVED

PMID: 33542052 (View on PubMed)

Mac Kenzie WR, Heilig CM, Bozeman L, Johnson JL, Muzanye G, Dunbar D, Jost KC Jr, Diem L, Metchock B, Eisenach K, Dorman S, Goldberg S. Geographic differences in time to culture conversion in liquid media: Tuberculosis Trials Consortium study 28. Culture conversion is delayed in Africa. PLoS One. 2011 Apr 11;6(4):e18358. doi: 10.1371/journal.pone.0018358.

Reference Type: DERIVED

PMID: 21494548 (View on PubMed)

Other Identifiers

CDC-NCHSTP-4448

Identifier Type: -

Identifier Source: org_study_id