Clinical trial NCT00144417: TBTC Study 28: Moxifloxacin Versus Isoniazid for TB Treatment
Official title: TBTC Study 28: Evaluation of a Moxifloxacin-based, Isoniazid-sparing Regimen for Tuberculosis Treatment
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE2
Conditions: Tuberculosis
Keywords: tuberculosis
TB
treatment
efficacy
safety
Lead sponsor: Centers for Disease Control and Prevention
Sponsor class: FED
Collaborators: name: Global Alliance for TB Drug Development
name: Bayer
First posted: 2005-09-05
Enrollment: 433
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

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.

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

Primary outcomes:
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
timeFrame: 8 weeks
Secondary outcomes:
measure: To compare the safety and tolerability of the moxifloxacin regimen to that of the isoniazid regimen
timeFrame: 8 weeks
measure: 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
timeFrame: 8 weeks
measure: To compare the proportion of patients with any Grade 3 or 4 adverse reactions
timeFrame: 8 weeks
measure: To compare adverse events and 2-month culture conversion rates among HIV-infected patients vs. HIV-uninfected patients
timeFrame: 8 weeks
measure: To compare the rates of treatment failure of the moxifloxacin regimen and the isoniazid regimen
timeFrame: 6 months
measure: To determine whether there is delayed toxicity attributable to moxifloxacin (toxicity that becomes evident after the 8 weeks of moxifloxacin therapy)
timeFrame: 6 months
Other outcomes:
Locations:
city: Little Rock
country: United States
facility: Veterans Administration Medical Center of Arkansas
state: Arkansas
city: Los Angeles
country: United States
facility: University of Southern California Medical Center
state: California
city: San Diego
country: United States
facility: University of California at San Diego
state: California
city: San Francisco
country: United States
facility: University of California, San Francincisco
state: California
city: Denver
country: United States
facility: Denver Public Health Department
state: Colorado
city: Washington DC
country: United States
facility: Washington DC Veterans Administration Medical Center
state: District of Columbia
city: Atlanta
country: United States
facility: Emory University School of Medicine
state: Georgia
city: Chicago
country: United States
facility: Northwestern University
state: Illinois
city: Hines
country: United States
facility: Hines Veterans Administration Medical Center
state: Illinois
city: Baltimore
country: United States
facility: Johns Hopkins University School of Medicine
state: Maryland
city: Boston
country: United States
facility: Boston University Medical Center
state: Massachusetts
city: Newark
country: United States
facility: New Jersey School of Medicine
state: New Jersey
city: New York
country: United States
facility: Columbia University
state: New York
city: New York
country: United States
facility: Harlem Hospital, Columbia University
state: New York
city: Durham
country: United States
facility: Duke University Medical Center
state: North Carolina
city: Nashville
country: United States
facility: Veterans Administration Tennessee Valley Health Care System
state: Tennessee
city: Fort Worth
country: United States
facility: University of North Texas Health Science Center
state: Texas
city: Houston
country: United States
facility: Houston Veterans Administration Medical Center
state: Texas
city: San Antonio
country: United States
facility: Audie L Murphy Memorial Veterans Administration Medical Center
state: Texas
city: Seattle
country: United States
facility: Seattle-King County Health Department
state: Washington
city: Rio de Janeiro
country: Brazil
facility: Hopital Universitario Clementino Fraga Filho
city: Winnepeg
country: Canada
facility: University of Manitoba
state: Manitoba
city: Montreal
country: Canada
facility: Montreal Chest Institute
state: Quebec
city: Durban
country: South Africa
facility: Nelson R. Mandela School of Medicine
state: KwaZulu Natal
city: Barcelona
country: Spain
facility: Agencia de Salut Publica
city: Kampala
country: Uganda
facility: Makerere University Medical School
Study officials:
affiliation: Johns Hopkins University
name: Richard E Chaisson, MD
role: STUDY_CHAIR
affiliation: Johns Hopkins University
name: Susan E Dorman, MD
role: PRINCIPAL_INVESTIGATOR
affiliation: Case Western Reserve University
name: John L Johnson, MD
role: PRINCIPAL_INVESTIGATOR
References:
citation: 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.
citation: 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.
citation: 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.