Efficacy and Safety of Levofloxacin for the Treatment of MDR-TB
Condition: Tuberculosis, Multidrug-Resistant
MeSH terms: Tuberculosis; Tuberculosis, Multidrug-Resistant
Intervention: Levofloxacin; Optimized background regimen (OBR)
Intervention description: Levofloxacin is a quinolone antibiotic used to treat lung, sinus, skin, and urinary tract infections caused by bacteria. The chemical name is (-)-(S)-9fluoro-2,3-dihydro-3-methyl-10-(4-methyl-1-piperazinyl)-7-oxo-7H-pyrido[1,2,3-de]-1,4benzoxazine-6-carboxylic acid hemihydrate.; For this study "OBR" will mean optimized background regimen, not including a quinolone. OBR will be selected at the discretion of the study investigator to conform with standards of care and local site guidelines. In general, the OBR regimen should include at least 3 drugs (other than levofloxacin) to which the patient's isolate is not expected to be resistant, with one of these being an injectable agent, at the usual recommended doses.
Intervention MeSH terms: Levofloxacin
Phase: Phase 2
Study type: Interventional
Primary purpose: Treatment
Allocation: Randomized
Intervention model: Parallel Assignment
Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
Enrollment: 111.0
Sex: All
Minimum age: 18 Years
Healthy volunteers: No
Keywords: Levofloxacin; Optimized background regimen

Summary:

      Multi-drug-resistant tuberculosis (MDR-TB) affects nearly 600,000 persons each year around
      the world. This type of tuberculosis is very difficult to treat, and many patients die from
      it. Drugs of the fluoroquinolone class are very important for treating MDR-TB, but the best
      dose of one of the most effective fluoroquinolones, levofloxacin, is not known. This
      application proposes a study to determine the best dose of levofloxacin to use in treating
      MDR-TB. 120 patients will receive their usual treatment, plus levofloxacin at one of four
      doses. The study will be performed in Peru and in South Africa, where MDR-TB is common.
    

Eligibility criteria:

        Inclusion Criteria:

          1. Patients with smear-positive, culture positive* pulmonary TB

          2. Sputum contains isoniazid* and rifampin-resistant, Ofloxacin-susceptible MTB, all by
             MTBDR-sl

          3. Previously treated or newly diagnosed with tuberculosis

          4. Willingness to have HIV testing performed, if HIV serostatus is not known or if the
             last documented negative HIV test was more than 3 months prior to enrollment.

          5. Age ≥ 18 years.

          6. Weight > 40 Kg

          7. Karnofsky score of > 60 (see section 18.1)

          8. Willingness by the patient to attend scheduled follow-up visits and undergo study
             assessments.

          9. Women with child-bearing potential must agree to use birth control if you are having
             sex with men while participating in this study and for three months afterward.

         10. Laboratory parameters (performed within 14 days prior to enrollment):

               -  Estimated Serum creatinine clearance should be <50, using nomogram78

               -  Hemoglobin concentration ≥ 9.0 g/dL

               -  Platelet count of ≥ 80,000/mm3

               -  Absolute neutrophil count (ANC) > 1000/ mm3

               -  Negative pregnancy test (for women of childbearing potential) within 14 days of
                  enrollment

               -  HIV viral load and CD4 count if HIV infected (within 3 months)

               -  Serum ALT and total bilirubin <3 times upper limit of normal

         11. Able to provide informed consent

        Note: *Subjects may be enrolled on the basis of a presumption that they will be culture
        positive at either screening or baseline if they are smear-positive, but they will be
        excluded from the analysis if cultures are subsequently negative. This will not be deemed a
        protocol violation. Similarly, subjects with rifampin susceptibility on a DNA-based test
        may be enrolled on the basis of a presumption that they will also be INH-resistant, but
        they will be excluded from the analysis if the isolate is subsequently shown to be
        INH-susceptible. This will also not be deemed a protocol violation.

        Exclusion Criteria:

          1. Currently breast-feeding or pregnant.

          2. Known allergy or intolerance to or toxicity from fluoroquinolones or other medications
             utilized in this study.

          3. In the judgment of the physician the patient is not expected to survive for 6 months

          4. Anticipated surgical intervention for the treatment of pulmonary tuberculosis

          5. Participation in another investigational drug trial within the past 30 days

          6. Concurrent use of known QT-prolonging drugs: a list of such medications can be found
             at http://www.azcert.org/medical-pros/drug-lists/printable-drug-list.cfm

          7. Poorly controlled diabetes

          8. Known g-6-phosphate dehydrogenase deficiency

          9. Use of quinolone for 7 days within past 30 days

         10. QTc interval greater than 450 msec for men or greater than 470 msec for women