Official Title: “Randomized, Open Label, Multiple Dose Phase I Study of the Early Bactericidal Activity of Linezolid, Gatifloxacin, Levofloxacin, and Moxifloxacin in HIV-Non-Infected Adults With Initial Episodes of Sputum Smear-Positive Pulmonary Tuberculosis”

This study will look at the ability of 4 antibiotics to kill the bacteria that cause tuberculosis (TB). The antibiotics to be studied are linezolid, gatifloxacin, levofloxacin, and moxifloxacin. They are all approved by the Brazilian health authorities to treat infections caused by other germs but are not approved to treat TB in Brazil or anywhere else.

Seventy HIV-negative adults, aged 18-65 years, who have been newly diagnosed with pulmonary (lung) TB, will participate in this study. Study volunteers will be given one of the 4 study drugs or a comparison antibiotic, isozianid. Isoniazid has been used around the world to treat tuberculosis and is being given in this study as a standard drug. Volunteers will stay in the hospital for 10 days and be given a study antibiotic 7 of those days. Blood and spit samples will be taken. Six weeks later, volunteers will return for a final health check. All volunteers will receive 6 months of standard tuberculosis treatment outside of the hospital.

Study Type: Interventional

Study Design: Treatment, Randomized, Open Label, Active Control, Parallel Assignment, Safety/Efficacy Study

Study Primary Completion Date: November 2007

The primary objective of this randomized, open label, multiple dose, phase I clinical trial is to evaluate and compare the early bactericidal activity (EBA) of the new fluoroquinolone antibiotics moxifloxacin, levofloxacin, and gatifloxacin, as well as once and twice daily 600 mg doses of linezolid, a new oxazolidinone antibiotic, compared with an isoniazid (INH) control arm in patients with newly-diagnosed sputum smear-positive pulmonary tuberculosis (TB). Secondary study objectives are to: compare the results of sputum Mycobacterium tuberculosis (MTB) mRNA clearance with results of a standard EBA study [change in sputum viable counts (CFU)]; compare the rate of clearance of sputum cytokine proteins with results of a standard EBA assay (CFU) [change in sputum viable counts (CFU)]; determine the pharmacokinetics (PK) of the study drugs (moxifloxacin, levofloxacin, gatifloxacin, linezolid, and isoniazid) in patients with smear-positive pulmonary TB; and demonstrate that lack of EBA activity is not due to low serum drug concentrations. The primary study endpoint is the projected net proportionate difference in sputum bacillary load [quantitative colony forming units (CFU) on solid media] as measured by area under the curve while receiving a single study drug. Secondary study endpoints are: rate of clearance of sputum MTB mRNA and proteins, such as 85 B alpha antigen and alpha crystalline; rate of clearance of sputum cytokine proteins; and plasma drug concentration for determination of PK profile of each study drug. Seventy HIV-negative adults, aged 18-65 years, who have been newly diagnosed with pulmonary TB, will participate in this study. They will be enrolled and admitted to the Centro de Pesquisa (Clinical Research Ward) at the Hospital Universitario Cassiano Antonio de Moraes of the Universidade Federal do Espírito Santo in Vitória. The study subjects will be randomized to receive gatifloxacin, levofloxacin, moxifloxacin, or INH (control), and after these arms are enrolled, they will be randomized to receive either linezolid (600 mg once daily) or linezolid (600 mg twice daily) or INH (control). During the inpatient stay, study drugs will be given for 7 days following a 2-day drug-free period when baseline sputum bacillary counts will be measured. The 7-day duration of the study drug phase of the study will allow measurement of sputum bactericidal activity both during the first 2 days of study drug administration and between days 2 and 7 of study drug administration to gain additional information on the possible sterilizing activity of the drugs. The extended nature of these EBA studies will allow assessment of the possibility of sterilizing activity in the study drugs that would be missed if a shorter EBA study was performed. Sputum specimens will be collected for 2 days prior to initiation of study drug in order to establish a baseline quantitative culture result and then specimens will be collected daily thereafter. Sputum specimens will be processed to evaluate changes in mycobacterial mRNA/proteins and cytokine proteins. PK studies will be performed after 5 days of study drug administration (Day 5).

Safety evaluations including clinical examination, complete blood counts, and serum total bilirubin, aspartate aminotransferase (AST), creatinine, and urinalysis will be followed to monitor for drug toxicity. Drug susceptibility testing will be performed on an initial sputum isolate and will be repeated after completion of 7 days of study drugs, and on isolates from patients with positive sputum cultures at the day 42 study visit to assess for the development of acquired drug resistance. Isolates will be tested against INH, rifampicin, pyrazinamide, ethambutol and the subject's assigned study drug. Patients who are found to be resistant to their assigned study drug at baseline will not be analyzable. After the initial treatment, all subjects will receive 6 months of standard TB treatment outside of the hospital.

Intervention(s) in this Clinical Trial

• Drug: Gatifloxacin
  • Gatifloxacin 400 mg/day x 7 days
• Drug: Levofloxacin
  • Levofloxacin 1000 mg/day x 7days
• Drug: Moxifloxacin
  • Moxifloxacin 400 mg/day x 7 days
• Drug: Linezolid
  • Linezolid 600 mg/day x 7days; Linezolid 600 mg q12h x 7 days
• Drug: Isoniazid
  • INH 300 mg/day x 7days

Arms, Groups and Cohorts in this Clinical Trial

• Experimental: 3
  • Gatifloxacin 400 mg/day x 7 days
• Experimental: 1
  • Levofloxacin 1000 mg/day x 7days
• Experimental: 2
  • Moxifloxacin 400 mg/day x 7 days
• Experimental: 6
  • Linezolid 600 mg q12h x 7 days
• Experimental: 5
  • Linezolid 600 mg/day x 7days
• Active Comparator: 4
  • INH 300 mg/day x 7days

Primary Measures

• Difference in sputum bacillary loads
  • Time Frame: Study drug administration duration
    Safety Issue?: No

Secondary Measures

• Sputum mRNA clearance rate
  • Time Frame: Study drug administration duration
    Safety Issue?: No
• Sputum cytokine proteins
  • Time Frame: Study drug administration duration
    Safety Issue?: No
• Plasma drug concentrations
  • Time Frame: Study drug administration duration
    Safety Issue?: No

Inclusion Criteria:

• Adults, male or female, age 18 to 65 years.
• Women with child-bearing potential (not surgically sterilized or postmenopausal for less than 1 year) must be using or agree to use an adequate method of birth control
• [condom: intravaginal spermicide (foams, jellies, sponge) and diaphragm: cervical cap or intrauterine device] during study drug treatment.
• Newly diagnosed sputum smear-positive pulmonary tuberculosis as confirmed by sputum
• AFB smear and chest X-ray findings consistent with pulmonary tuberculosis.
• Willing and able to provide informed consent.
• Reasonably normal hemoglobin (greater than or equal to 8 gm/dL), renal function (serum creatinine less than 2 mg/dL), hepatic function (serum AST less than 1.5 times the upper limit of normal for the testing laboratory and total bilirubin less than 1.3 mg/dL), and random blood glucose less than 150 mg/dL.

Exclusion Criteria:

• HIV infection.
• Weight less than 75% of ideal body weight.
• Presence of significant hemoptysis. Patients who cough up frank blood (more than blood streaked sputum) will not be eligible for enrollment.
• Pregnant or breastfeeding women and those who are not practicing birth control.
• Significant respiratory impairment (respiratory rate greater than 35/minute).
• Clinical suspicion of dissemated tuberculosis or tuberculosis meningitis.
• Presence of serious underlying medical illness, such as liver failure, renal failure, diabetes mellitus, chronic alcoholism, decompensated heart failure, hematologic malignancy or patients receiving myelosuppressive chemotherapy.
• Patients receiving any of the following medications - monoamine oxidase inhibitors (phenelzine, tranylcypromine), adrenergic/serotonergic agonists such as pseudoephedrine and phenylpropanolamine (frequently found in cold and cough remedies), tricyclic antidepressants (amitriptyline, nortriptyline, protriptyline, doxepin, amoxapine, etc), antipsychotics such as chlorpromazine and buspirone, serotonin re-uptake inhibitors (fluoxetine, paroxetine, sertaline, etc.), buproprion, agents known to prolong the QTc interval [erythromycin, clarithromycin, astemizole, type Ia (quinidine, procainamide, disopyramide) and III (amiodarone, sotalol) anti-arrhythmics, carbamazepine, insulin, sulfonylureas, and meperidine.
• Presence of QTc prolongation (greater than 450 msec) on baseline EKG.
• Allergy or contraindication to use of study drugs.
• Treatment with antituberculosis medications or other antibiotics with known activity against M. tuberculosis during the preceding 6 months.
• Inability to provide informed consent.
• Total white blood cell count less than 3000/mm3.
• Platelet count less than 150,000/mm3. Patients with suspected drug resistant tuberculosis (e.g., contact to source patient with drug resistant tuberculosis, patients who have relapsed after previous treatment for tuberculosis).
• Patients likely, in the opinion of the local investigator, to be unable to comply with the requirements of the study protocol.

Gender Eligibility for this Clinical Trial: Both

Minimum Age for this Clinical Trial: 18 Years

Maximum Age for this Clinical Trial: 65 Years

Are Healthy Volunteers Accepted for this Clinical Trial?: No

Lead Sponsor: National Institute of Allergy and Infectious Diseases (NIAID)

Information obtained from ClinicalTrials.gov on October 07, 2008

Link to the current ClinicalTrials.gov record. http://clinicaltrials.gov/show/NCT00396084

Study ID Number: 01-553

ClinicalTrials.gov Identifier: NCT00396084

Health Authority: Brazil: National Committee of Ethics in Research