Early Bactericidal Activity of Linezolid, Gatifloxacin, Levofloxacin, Isoniazid (INH) and Moxifloxacin in HIV Negative Adults With Initial Episodes of Sputum Smear-Positive Pulmonary Tuberculosis

Study Overview
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Brief Summary
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This study will evaluate the ability of 4 antibiotics to kill the bacteria that cause tuberculosis (TB). The antibiotics to be studied are linezolid, gatifloxacin, levofloxacin, and moxifloxacin. All are approved by the Brazilian health authorities to treat infections caused by germs other than TB. Seventy human immunodeficiency virus (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, Isoniazid, which has been used around the world as a standard of care treatment for TB. Volunteers will stay in the hospital for 10 days and be given a study antibiotic 7 of those days. Blood and saliva 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.

Detailed Description
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Multi-drug resistant tuberculosis now affects all regions of the world and is a significant concern for national tuberculosis (TB) control programs. The development and testing of new drugs and new classes of drugs and immunotherapeutic agents are vital elements in the global response to this challenge. The fluoroquinolones and oxazolidinones represent two promising classes of drugs that show activity against Mycobacterium tuberculosis (MTB). This study is a randomized, open label, multiple dose phase I clinical trial to evaluate the early bactericidal activity (EBA) of gatifloxacin, levofloxacin, moxifloxacin, and linezolid compared with an isoniazid (INH) control arm in patients with newly-diagnosed sputum smear-positive pulmonary tuberculosis (TB). Secondary study objectives are to: compare results of sputum MTB messenger ribonucleic acid (mRNA) clearance with results of a standard EBA study [change in sputum viable counts [colony forming units (CFU)]; compare the rate of clearance of sputum cytokine proteins with results of a standard EBA assay CFU; determine the pharmacokinetics (PK) of the study drugs in patients with smear-positive pulmonary TB; and demonstrate that lack of EBA activity is not due to low serum drug concentrations. Seventy human immunodeficiency virus (HIV) negative adults, aged 18-65 years, who have been newly diagnosed with pulmonary TB, 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 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 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 this possibility 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.

Official Title
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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

Conditions
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Tuberculosis

Intervention / Treatment
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* Drug: Gatifloxacin
* Drug: Isoniazid
* Drug: Levofloxacin
* Drug: Linezolid
* Drug: Moxifloxacin


Participation Criteria
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Eligibility Criteria
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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 acid fast bacilli (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 aspartate aminotransferase (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: -Human immunodeficiency virus (HIV) infection. -Weight less than 75 percent 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 disseminated 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, sertraline, 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 electrocardiogram (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/mm^3. -Platelet count less than 150,000/mm^3. -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.

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 65 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Gatifloxacin<br>10 subjects to receive gatifloxacin 400 mg orally once daily for 7 days. | Drug: Gatifloxacin<br>* Gatifloxacin 400 mg/day x 7 days.<br>|
| Active Comparator: Isoniazid<br>20 subjects to receive isoniazid 300 mg orally once daily for 7days. | Drug: Isoniazid<br>* Isoniazid 300 mg/day x 7 days.<br>|
| Experimental: Levofloxacin<br>10 subjects to receive levofloxacin 1000 mg orally once daily for 7days. | Drug: Levofloxacin<br>* Levofloxacin 1000 mg/day x 7 days.<br>|
| Experimental: Linezolid every 12 hours<br>10 subjects to receive linezolid 600 mg orally every 12 hours daily for 7 days. | Drug: Linezolid<br>* Linezolid 600 mg/day x 7 days; Linezolid 600 mg every 12 hours x 7 days.<br>|
| Experimental: Linezolid once daily<br>10 subjects to receive linezolid 600 mg orally once daily for 7days. | Drug: Linezolid<br>* Linezolid 600 mg/day x 7 days; Linezolid 600 mg every 12 hours x 7 days.<br>|
| Experimental: Moxifloxacin<br>10 subjects to receive moxifloxacin 400 mg orally once daily for 7 days. | Drug: Moxifloxacin<br>* Moxifloxacin 400 mg/day x 7 days.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Sputum Bacillary Loads: Adjusted Area Under the Curve (aAUC) | The adjusted area under the curve (aAUC) for sputum colony forming units (cfu) for each day on treatment was calculated. The aAUC represents the percentage of the expected AUC given no change in log cfu in response to study drug administration. | Study drug administration duration - 7 days monotherapy | 
| Difference in Sputum Bacillary Loads: Early Bactericidal Activity (EBA) Days 0 to 2; Fluoroquinolones/Isoniazid (INH) Comparison | Early bactericidal activity (EBA 0-2) was calculated as the rate of fall in sputum colony forming units (cfu) (expressed in log10 units) during the first 2 days of monotherapy. | Day 0 to Day 2 Monotherapy | 
| Extended Early Bactericidal Activity (EBA) From Days 2 to 7; Fluoroquinolones/Isoniazid (INH) Comparison | The rate of fall in sputum cfu between day 2 and day 7 of monotherapy was estimated by the slope of the linear regression obtained by fitting the 6 sputum cfu values corresponding to Days 2 through 7. | Day 2 to Day 7 Monotherapy | 
| Sputum Bacillary Loads: Adjusted Area Under the Curve (aAUC) | The adjusted area under the curve (aAUC) for sputum colony forming unit (cfu) for each day on treatment was calculated for patients in the INH arm and those in the Linezolid once daily and Linezolid twice daily arms. The aAUC represents the percentage of the expected AUC given no change in log cfu in response to study drug administration. | Study drug administration duration - 7 days monotherapy | 
| Difference in Sputum Bacillary Loads: Early Bactericidal Activity (EBA) Days 0 to 2; Linezolid Once Daily/Linezolid Twice Daily/Isoniazid (INH) Comparison | Early bactericidal activity (EBA 0-2) was calculated as the rate of fall in sputum cfu (expressed in log10 units) during the first 2 days of monotherapy. Mean values for the 3 treatment groups were compared. | Day 0 to Day 2 Monotherapy | 
| Difference in Sputum Bacillary Loads: Extended Early Bactericidal Activity (EBA) From Days 2 to 7; Linezolid Once Daily/Linezolid Twice Daily/INH Comparison | The rate of fall in sputum cfu between day 2 and day 7 of monotherapy was estimated by the slope of the linear regression obtained by fitting the 6 sputum cfu values corresponding to Days 2 through 7. | Day 2 to Day 7 Monotherapy | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Sputum mRNA Clearance Rate - Results Are Pending. |  | Study drug administration duration | 
| Sputum Cytokine Proteins - Results Are Pending. |  | Study drug administration duration | 
| Maximum Plasma Drug Concentration (Cmax) | Maximum plasma concentration, given sampling scheme | Day 5 (7 time points) | 
| Time to Maximum Plasma Drug Concentration (Tmax) and Half-life |  | Day 5 (7 time points) | 
| Maximum Plasma Drug Concentration/Minimum Inhibitory Concentration (Cmax/MIC) |  | Day 5 (7 time points) | 
| Pharmacokinetic Parameters: Area Under the Curve (AUC) During First 12 and 24 Hours | Area under the curve (AUC), from time 0-12 hours for INH or 0-24 hours for gatifloxacin, levofloxacin, and moxifloxacin. | Day 5 (7 time points) | 
| Area Under the Curve During First 12 or 24 Hours / Minimum Inhibitory Concentration (AUC/MIC) | Area Under the Curve (AUC) During First 12 or 24 Hours /Minimum Inhibitory Concentration. AUC reflects total drug (bound and unbound). MIC values were determined using protein-containing media. | Day 5 (7 time points) | 
| Maximum Plasma Drug Concentration (Cmax) | Maximum Plasma Drug Concentration (Cmax), given sampling scheme | Day 5 (7 time points) | 
| Pharmacokinetic Parameters: Area Under the Curve During First 12 and 24 Hours | Median pharmacokinetic parameters (range). AUC 0-12 and AUC 0-24 = area under the curve during the first 12 and 24 hours after dosing, respectively | Day 5 (7 time points) | 
| Maximum Plasma Drug Concentrations (Cmax), Adjusted for Free Drug Concentration | Cmax adjusted for free drug concentrations after 5 days of monotherapy with study drugs | Day 5 (7 time points) | 
| Maximum Plasma Drug Concentration/Minimum Inhibitory Concentration (Cmax/MIC) Adjusted for Free Drug Concentrations |  | Day 5 (7 time points) | 
| Area Under the Curve (AUC) During First 12 and 24 Hours Adjusted for Free Drug Concentrations | Median pharmacodynamic parameters (range) adjusted for free drug concentrations. AUC 0-12 and AUC 0-24 = area under the curve during the first 12 and 24 hours after dosing, respectively | Day 5 (7 time points) | 
| Area Under the Curve (AUC) Adjusted for Free Drug Concentrations/Minimum Inhibitory Concentration (MIC) | Area Under the Curve 0-12 (AUC 0-12) Adjusted for Free Drug Concentrations/Minimum Inhibitory Concentration (MIC) and AUC 0-24/MIC | Day 5 (7 time points) | 
| Percent Dosing Interval Above Minimum Inhibitory Concentration (MIC) | Determined by linear extrapolation of concentration-versus-time curve to intersection with MIC. | Day 5 (7 time points) | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Brazil, gatifloxacin, isoniazid, levofloxacin, linezolid, moxifloxacin, tuberculosis