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

This study has been completed.
Sponsor:
Information provided by:
National Institute of Allergy and Infectious Diseases (NIAID)
ClinicalTrials.gov Identifier:
NCT00396084
First received: November 3, 2006
Last updated: June 9, 2011
Last verified: March 2010
  Purpose

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.


Condition Intervention Phase
TB Multi-drug Resistant
Drug: Gatifloxacin
Drug: Levofloxacin
Drug: Moxifloxacin
Drug: Isoniazid
Drug: Linezolid
Phase 1
Phase 2

Study Type: Interventional
Study Design: Allocation: Randomized
Endpoint Classification: Safety/Efficacy Study
Intervention Model: Parallel Assignment
Masking: Open Label
Primary Purpose: Treatment
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

Resource links provided by NLM:


Further study details as provided by National Institute of Allergy and Infectious Diseases (NIAID):

Primary Outcome Measures:
  • Sputum Bacillary Loads: Adjusted Area Under the Curve (aAUC) [ Time Frame: Study drug administration duration - 7 days monotherapy ] [ Designated as safety issue: No ]
    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.

  • Difference in Sputum Bacillary Loads: Early Bactericidal Activity (EBA) Days 0 to 2; Fluoroquinolones/Isoniazid (INH) Comparison [ Time Frame: Day 0 to Day 2 Monotherapy ] [ Designated as safety issue: No ]
    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.

  • Extended Early Bactericidal Activity (EBA) From Days 2 to 7; Fluoroquinolones/Isoniazid (INH) Comparison [ Time Frame: Day 2 to Day 7 Monotherapy ] [ Designated as safety issue: No ]
    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.

  • Sputum Bacillary Loads: Adjusted Area Under the Curve (aAUC) [ Time Frame: Study drug administration duration - 7 days monotherapy ] [ Designated as safety issue: No ]
    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.

  • Difference in Sputum Bacillary Loads: Early Bactericidal Activity (EBA) Days 0 to 2; Linezolid Once Daily/Linezolid Twice Daily/Isoniazid (INH) Comparison [ Time Frame: Day 0 to Day 2 Monotherapy ] [ Designated as safety issue: No ]
    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.

  • Difference in Sputum Bacillary Loads: Extended Early Bactericidal Activity (EBA) From Days 2 to 7; Linezolid Once Daily/Linezolid Twice Daily/INH Comparison [ Time Frame: Day 2 to Day 7 Monotherapy ] [ Designated as safety issue: No ]
    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.


Secondary Outcome Measures:
  • Sputum mRNA Clearance Rate - Results Are Pending. [ Time Frame: Study drug administration duration ] [ Designated as safety issue: No ]
  • Sputum Cytokine Proteins - Results Are Pending. [ Time Frame: Study drug administration duration ] [ Designated as safety issue: No ]
  • Maximum Plasma Drug Concentration (Cmax) [ Time Frame: Day 5 (7 time points) ] [ Designated as safety issue: No ]
    Maximum plasma concentration, given sampling scheme

  • Time to Maximum Plasma Drug Concentration (Tmax) and Half-life [ Time Frame: Day 5 (7 time points) ] [ Designated as safety issue: No ]
  • Maximum Plasma Drug Concentration/Minimum Inhibitory Concentration (Cmax/MIC) [ Time Frame: Day 5 (7 time points) ] [ Designated as safety issue: No ]
  • Pharmacokinetic Parameters: Area Under the Curve (AUC) During First 12 and 24 Hours [ Time Frame: Day 5 (7 time points) ] [ Designated as safety issue: No ]
    Area under the curve (AUC), from time 0-12 hours for INH or 0-24 hours for gatifloxacin, levofloxacin, and moxifloxacin.

  • Area Under the Curve During First 12 or 24 Hours / Minimum Inhibitory Concentration (AUC/MIC) [ Time Frame: Day 5 (7 time points) ] [ Designated as safety issue: No ]
    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.

  • Maximum Plasma Drug Concentration (Cmax) [ Time Frame: Day 5 (7 time points) ] [ Designated as safety issue: No ]
    Maximum Plasma Drug Concentration (Cmax), given sampling scheme

  • Pharmacokinetic Parameters: Area Under the Curve During First 12 and 24 Hours [ Time Frame: Day 5 (7 time points) ] [ Designated as safety issue: No ]
    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

  • Maximum Plasma Drug Concentrations (Cmax), Adjusted for Free Drug Concentration [ Time Frame: Day 5 (7 time points) ] [ Designated as safety issue: No ]
    Cmax adjusted for free drug concentrations after 5 days of monotherapy with study drugs

  • Maximum Plasma Drug Concentration/Minimum Inhibitory Concentration (Cmax/MIC) Adjusted for Free Drug Concentrations [ Time Frame: Day 5 (7 time points) ] [ Designated as safety issue: No ]
  • Area Under the Curve (AUC) During First 12 and 24 Hours Adjusted for Free Drug Concentrations [ Time Frame: Day 5 (7 time points) ] [ Designated as safety issue: No ]
    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

  • Area Under the Curve (AUC) Adjusted for Free Drug Concentrations/Minimum Inhibitory Concentration (MIC) [ Time Frame: Day 5 (7 time points) ] [ Designated as safety issue: No ]
    Area Under the Curve 0-12 (AUC 0-12) Adjusted for Free Drug Concentrations/Minimum Inhibitory Concentration (MIC) and AUC 0-24/MIC

  • Percent Dosing Interval Above Minimum Inhibitory Concentration (MIC) [ Time Frame: Day 5 (7 time points) ] [ Designated as safety issue: No ]
    Determined by linear extrapolation of concentration-versus-time curve to intersection with MIC.


Enrollment: 70
Study Start Date: February 2004
Study Completion Date: December 2007
Primary Completion Date: November 2007 (Final data collection date for primary outcome measure)
Arms Assigned Interventions
Experimental: Linezolid once daily
10 subjects to receive linezolid 600 mg orally once daily for 7days.
Drug: Linezolid
Linezolid 600 mg/day x 7 days; Linezolid 600 mg every 12 hours x 7 days.
Experimental: Levofloxacin
10 subjects to receive levofloxacin 1000 mg orally once daily for 7days.
Drug: Levofloxacin
Levofloxacin 1000 mg/day x 7 days.
Experimental: Moxifloxacin
10 subjects to receive moxifloxacin 400 mg orally once daily for 7 days.
Drug: Moxifloxacin
Moxifloxacin 400 mg/day x 7 days.
Experimental: Linezolid every 12 hours
10 subjects to receive linezolid 600 mg orally every 12 hours daily for 7 days.
Drug: Linezolid
Linezolid 600 mg/day x 7 days; Linezolid 600 mg every 12 hours x 7 days.
Active Comparator: Isoniazid
20 subjects to receive isoniazid 300 mg orally once daily for 7days.
Drug: Isoniazid
Isoniazid 300 mg/day x 7 days.
Experimental: Gatifloxacin
10 subjects to receive gatifloxacin 400 mg orally once daily for 7 days.
Drug: Gatifloxacin
Gatifloxacin 400 mg/day x 7 days.

Detailed Description:

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.

  Eligibility

Ages Eligible for Study:   18 Years to 65 Years
Genders Eligible for Study:   Both
Accepts Healthy Volunteers:   No
Criteria

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.
  Contacts and Locations
Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the Contacts provided below. For general information, see Learn About Clinical Studies.

Please refer to this study by its ClinicalTrials.gov identifier: NCT00396084

Locations
United States, California
San Francisco General Hospital
San Francisco, California, United States, 94110
Brazil
Universidade Federal do Espirito Santo/HUCAM
Vitoria, Brazil, 29040-091
Sponsors and Collaborators
  More Information

Publications:
Responsible Party: Director, ORA, HHS/NIAID/DMID
ClinicalTrials.gov Identifier: NCT00396084     History of Changes
Other Study ID Numbers: 01-553, TBRU 10
Study First Received: November 3, 2006
Results First Received: November 19, 2008
Last Updated: June 9, 2011
Health Authority: Brazil: National Committee of Ethics in Research
United States: Federal Government
United States: Institutional Review Board
United States: Food and Drug Administration

Keywords provided by National Institute of Allergy and Infectious Diseases (NIAID):
tuberculosis, linezolid, gatifloxacin, levofloxacin, isoniazid, moxifloxacin, Brazil

Additional relevant MeSH terms:
Tuberculosis
Tuberculosis, Pulmonary
Actinomycetales Infections
Bacterial Infections
Gram-Positive Bacterial Infections
Lung Diseases
Mycobacterium Infections
Respiratory Tract Diseases
Respiratory Tract Infections
Fluoroquinolones
Gatifloxacin
Isoniazid
Levofloxacin
Linezolid
Moxifloxacin
Norgestimate, ethinyl estradiol drug combination
Ofloxacin
Anti-Bacterial Agents
Anti-Infective Agents
Anti-Infective Agents, Urinary
Antimetabolites
Antineoplastic Agents
Antitubercular Agents
Contraceptive Agents
Contraceptive Agents, Female
Contraceptives, Oral
Contraceptives, Oral, Combined
Enzyme Inhibitors
Fatty Acid Synthesis Inhibitors
Hypolipidemic Agents

ClinicalTrials.gov processed this record on October 21, 2014