TBTC Study 28: Moxifloxacin Versus Isoniazid for TB Treatment

• To compare the safety and tolerability of the moxifloxacin regimen to that of the isoniazid regimen [ Time Frame: 8 weeks ] [ Designated as safety issue: Yes ]
• 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 ] [ Designated as safety issue: No ]
• To compare the proportion of patients with any Grade 3 or 4 adverse reactions [ Time Frame: 8 weeks ] [ Designated as safety issue: Yes ]
• To compare adverse events and 2-month culture conversion rates among HIV-infected patients vs. HIV-uninfected patients [ Time Frame: 8 weeks ] [ Designated as safety issue: Yes ]
• To compare the rates of treatment failure of the moxifloxacin regimen and the isoniazid regimen [ Time Frame: 6 months ] [ Designated as safety issue: No ]
• 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 ] [ Designated as safety issue: Yes ]

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

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.

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.

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

• Active Comparator: HRZE
  isoniazid, rifampin, pyrazinamide, ethambutol, moxifloxacin-placebo
  Intervention: Drug: isoniazid
• Experimental: MRZE
  moxifloxacin, rifampin, pyrazinamide, ethambutol, isoniazid-placebo
  Intervention: Drug: Moxifloxacin (with rifampin, pyrazinamide, and ethambutol)

• 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. Epub 2009 Apr 30.
• 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.

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

• Global Alliance for TB Drug Development
• Bayer