TuberculosisPhase 1/2NCT00396084

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

A Phase 1/2 study testing Gatifloxacin, Isoniazid and Levofloxacin in people with Tuberculosis, run by National Institute of Allergy and Infectious Diseases (NIAID) at 2 sites in 2 countries.

Completed

Finished. The study has ended and is not enrolling. Results may be posted on the official record.

Official record

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Trial summary

Who is it for?: Ages 18 to 65 years
Conditions the study is for: Tuberculosis
What is being tested?: Gatifloxacin, Isoniazid and Levofloxacin
Type of treatment: Pill or oral medicine
Could I receive a placebo?: No, everyone receives an active treatment
How many people: 70 participants
Where: 2 sitesin 2 countries
Study dates: 10 Feb 2004to 28 Dec 2007
Phase: Phase 1/2
Are there results?: Yes, posted in the registrySummary in the doctors' view

Key requirements

Who can take part, as listed by the sponsor. Only the study team can confirm whether you are eligible, so take this list to your doctor.

Ages 18 to 65 years
All sexes
No healthy volunteers
Adult, Older adult

Who may be able to join

-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.

Who cannot join

-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.

Trial locations and contacts

2 sites in 2 countries.

Country

City, postcode or hospital

2 sites in 2 countries

United States1 site

San Francisco General Hospital - Pulmonary and Critical Care Medicine
San Francisco, California, 94110-3518

Other trials in United States

Brazil1 site

Universidade Federal do Espirito Santo - Duke Hubert-Yeargan Center
Vitória, Espírito Santo, 29040-091

Other trials in Brazil

About this study

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 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.

Read the 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.

Conditions: Tuberculosis
Being tested: Gatifloxacin, Isoniazid, Levofloxacin, Linezolid, Moxifloxacin
Keywords: Brazil, gatifloxacin, isoniazid, levofloxacin, linezolid, moxifloxacin, tuberculosis
Medical subject headings: Tuberculosis

What participants receive

What participants receive. In a randomised study each person is assigned to one group by chance.

GatifloxacinDrug
Gatifloxacin 400 mg/day x 7 days.
IsoniazidDrug
Isoniazid 300 mg/day x 7 days.
LevofloxacinDrug
Levofloxacin 1000 mg/day x 7 days.
LinezolidDrug
Linezolid 600 mg/day x 7 days; Linezolid 600 mg every 12 hours x 7 days.
MoxifloxacinDrug
Moxifloxacin 400 mg/day x 7 days.

Study groups in NCT00396084
Study group	Role	What they receive
Gatifloxacin	Experimental	10 subjects to receive gatifloxacin 400 mg orally once daily for 7 days. Receives: Drug: Gatifloxacin
Isoniazid	Active comparator	20 subjects to receive isoniazid 300 mg orally once daily for 7days. Receives: Drug: Isoniazid
Levofloxacin	Experimental	10 subjects to receive levofloxacin 1000 mg orally once daily for 7days. Receives: Drug: Levofloxacin
Linezolid every 12 hours	Experimental	10 subjects to receive linezolid 600 mg orally every 12 hours daily for 7 days. Receives: Drug: Linezolid
Linezolid once daily	Experimental	10 subjects to receive linezolid 600 mg orally once daily for 7days. Receives: Drug: Linezolid
Moxifloxacin	Experimental	10 subjects to receive moxifloxacin 400 mg orally once daily for 7 days. Receives: Drug: Moxifloxacin

What is being measured

The primary outcome is the main question the study is designed to answer.

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.
Measured: 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.
Measured: 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.
Measured: 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.
Measured: 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.
Measured: 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.
Measured: Day 2 to Day 7 Monotherapy

Secondary outcomes (14)

Sputum mRNA Clearance Rate - Results Are Pending.
Measured: Study drug administration duration
Sputum Cytokine Proteins - Results Are Pending.
Measured: Study drug administration duration
Maximum Plasma Drug Concentration (Cmax)
Maximum plasma concentration, given sampling scheme
Measured: Day 5 (7 time points)
Time to Maximum Plasma Drug Concentration (Tmax) and Half-life
Measured: Day 5 (7 time points)
Maximum Plasma Drug Concentration/Minimum Inhibitory Concentration (Cmax/MIC)
Measured: 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.
Measured: 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.
Measured: Day 5 (7 time points)
Maximum Plasma Drug Concentration (Cmax)
Maximum Plasma Drug Concentration (Cmax), given sampling scheme
Measured: 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
Measured: 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
Measured: Day 5 (7 time points)
Maximum Plasma Drug Concentration/Minimum Inhibitory Concentration (Cmax/MIC) Adjusted for Free Drug Concentrations
Measured: 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
Measured: 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
Measured: 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.
Measured: Day 5 (7 time points)

Timeline

From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.

10 Feb 200428 Dec 2007

First posted6 Nov 2006 (estimated)
Study start10 Feb 2004
Primary completion23 Nov 2007
Study completion28 Dec 2007

Resources

Official record on ClinicalTrials.govThe registry entry this page is built from, with its full change history.
Posted resultsParticipant flow, outcome measures and adverse events reported by the sponsor.
Publications (6)Papers the sponsor has linked to this study.
Other trials for TuberculosisStudies of the same condition, open and under way.
More trials run by National Institute of Allergy and Infectious Diseases (NIAID)The sponsor's other registered studies.
What the trial phases meanHow a treatment moves from first tests in people to approval.

More details

For doctors and researchers: how the study is designed, who runs it, and its registry IDs.

Study design

Study type: Interventional
Phase: Phase 1/2
Primary purpose: Treatment
Allocation: Randomised
Intervention model: Parallel groups
Masking: None (open label)
Enrolment: 70 participants (actual)

IDs, dates and publications

ClinicalTrials.gov ID: NCT00396084
Sponsor's protocol ID: 01-553
Status last verified: 10 Mar 2010
First submitted: 3 Nov 2006
Last updated: 8 Nov 2018
Results posted: Yes, on ClinicalTrials.gov
FDA-regulated drug: Yes
FDA-regulated device: No

Publications

Johnson JL, Hadad DJ, Boom WH, Daley CL, Peloquin CA, Eisenach KD, Jankus DD, Debanne SM, Charlebois ED, Maciel E, Palaci M, Dietze R. Early and extended early bactericidal activity of levofloxacin, gatifloxacin and moxifloxacin in pulmonary tuberculosis. Int J Tuberc Lung Dis. 2006 Jun;10(6):605-12.
PubMed 16776446
Dietze R, Hadad DJ, McGee B, Molino LP, Maciel EL, Peloquin CA, Johnson DF, Debanne SM, Eisenach K, Boom WH, Palaci M, Johnson JL. Early and extended early bactericidal activity of linezolid in pulmonary tuberculosis. Am J Respir Crit Care Med. 2008 Dec 1;178(11):1180-5. doi: 10.1164/rccm.200806-892OC. Epub 2008 Sep 11.
PubMed 18787216
Millard J, Pertinez H, Bonnett L, Hodel EM, Dartois V, Johnson JL, Caws M, Tiberi S, Bolhuis M, Alffenaar JC, Davies G, Sloan DJ. Linezolid pharmacokinetics in MDR-TB: a systematic review, meta-analysis and Monte Carlo simulation. J Antimicrob Chemother. 2018 Jul 1;73(7):1755-1762. doi: 10.1093/jac/dky096.
PubMed 29584861
Peloquin CA, Hadad DJ, Molino LP, Palaci M, Boom WH, Dietze R, Johnson JL. Population pharmacokinetics of levofloxacin, gatifloxacin, and moxifloxacin in adults with pulmonary tuberculosis. Antimicrob Agents Chemother. 2008 Mar;52(3):852-7. doi: 10.1128/AAC.01036-07. Epub 2007 Dec 10.
PubMed 18070980
McGee B, Dietze R, Hadad DJ, Molino LP, Maciel EL, Boom WH, Palaci M, Johnson JL, Peloquin CA. Population pharmacokinetics of linezolid in adults with pulmonary tuberculosis. Antimicrob Agents Chemother. 2009 Sep;53(9):3981-4. doi: 10.1128/AAC.01378-08. Epub 2009 Jun 29.
PubMed 19564361
Li L, Mahan CS, Palaci M, Horter L, Loeffelholz L, Johnson JL, Dietze R, Debanne SM, Joloba ML, Okwera A, Boom WH, Eisenach KD. Sputum Mycobacterium tuberculosis mRNA as a marker of bacteriologic clearance in response to antituberculosis therapy. J Clin Microbiol. 2010 Jan;48(1):46-51. doi: 10.1128/JCM.01526-09. Epub 2009 Nov 18.
PubMed 19923475

Want to know more?

The sponsor has not listed a contact. The official record may have more details.

Talk to your doctor first and take this page with you. Only the study team can confirm whether you can join.

Questions to ask the study team

What is the study trying to find out?
What would I need to do, and how often would I visit?
Could I receive a placebo instead of the treatment?
What are the possible risks and benefits for me?
Will it cost me anything? Are travel or time paid for?
Can I keep seeing my own doctor during the study?
What happens when the study ends?

See locations

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All Tuberculosis trials

Study at a glance

From the registry record, last updated by the sponsor on 8 Nov 2018. Recruitment status is as the sponsor reported it: confirm with the study team.

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
ClinicalTrials.gov ID: NCT00396084
Acronym / sponsor ID: 01-553
Conditions: Tuberculosis
Keywords: Brazil, gatifloxacin, isoniazid, levofloxacin, linezolid, moxifloxacin, tuberculosis
Phase: Phase 1/2
Study type: Interventional
Recruitment status: Completed
Enrolment: 70 participants (actual)
Lead sponsor: National Institute of Allergy and Infectious Diseases (NIAID)US National Institutes of Health
Study start: 10 Feb 2004 (actual)
Primary completion: 23 Nov 2007 (actual)
Study completion: 28 Dec 2007 (actual)
First posted: 6 Nov 2006 (estimated)
Results: Posted 25 Jun 2009

Clinical summary

The research question as the sponsor registered it. This describes what the study plans to test, not what it found.

Detailed description

Study design

Primary purpose: Treatment
Allocation: Randomised
Intervention model: Parallel groups
Masking: None (open label)
Number of arms: 6

Arm	Type	Receives
Gatifloxacin	Experimental	Drug: Gatifloxacin10 subjects to receive gatifloxacin 400 mg orally once daily for 7 days.
Isoniazid	Active comparator	Drug: Isoniazid20 subjects to receive isoniazid 300 mg orally once daily for 7days.
Levofloxacin	Experimental	Drug: Levofloxacin10 subjects to receive levofloxacin 1000 mg orally once daily for 7days.
Linezolid every 12 hours	Experimental	Drug: Linezolid10 subjects to receive linezolid 600 mg orally every 12 hours daily for 7 days.
Linezolid once daily	Experimental	Drug: Linezolid10 subjects to receive linezolid 600 mg orally once daily for 7days.
Moxifloxacin	Experimental	Drug: Moxifloxacin10 subjects to receive moxifloxacin 400 mg orally once daily for 7 days.

Who may qualify

Ages: 18 to 65 years
Sex: All
Healthy volunteers: Not accepted
Age groups: Adult, Older adult

Key inclusion criteria (1 listed)

-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.

Key exclusion criteria (1 listed)

-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.

Eligibility is decided by the study team after screening; this overview does not establish that a patient qualifies. Full inclusion and exclusion criteria.

Interventions

Intervention	Type	Arms
GatifloxacinGatifloxacin 400 mg/day x 7 days.	Drug	Gatifloxacin
IsoniazidIsoniazid 300 mg/day x 7 days.	Drug	Isoniazid
LevofloxacinLevofloxacin 1000 mg/day x 7 days.	Drug	Levofloxacin
LinezolidLinezolid 600 mg/day x 7 days; Linezolid 600 mg every 12 hours x 7 days.	Drug	Linezolid every 12 hours, Linezolid once daily
MoxifloxacinMoxifloxacin 400 mg/day x 7 days.	Drug	Moxifloxacin

Primary outcome

Sputum Bacillary Loads: Adjusted Area Under the Curve (aAUC)
Time frame: Study drug administration duration - 7 days monotherapy
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
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
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
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
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
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.

14 secondary outcomes

Sputum mRNA Clearance Rate - Results Are Pending.
Time frame: Study drug administration duration
Sputum Cytokine Proteins - Results Are Pending.
Time frame: Study drug administration duration
Maximum Plasma Drug Concentration (Cmax)
Time frame: Day 5 (7 time points)
Time to Maximum Plasma Drug Concentration (Tmax) and Half-life
Time frame: Day 5 (7 time points)
Maximum Plasma Drug Concentration/Minimum Inhibitory Concentration (Cmax/MIC)
Time frame: Day 5 (7 time points)
Pharmacokinetic Parameters: Area Under the Curve (AUC) During First 12 and 24 Hours
Time frame: Day 5 (7 time points)
Area Under the Curve During First 12 or 24 Hours / Minimum Inhibitory Concentration (AUC/MIC)
Time frame: Day 5 (7 time points)
Maximum Plasma Drug Concentration (Cmax)
Time frame: Day 5 (7 time points)
Pharmacokinetic Parameters: Area Under the Curve During First 12 and 24 Hours
Time frame: Day 5 (7 time points)
Maximum Plasma Drug Concentrations (Cmax), Adjusted for Free Drug Concentration
Time frame: Day 5 (7 time points)
Maximum Plasma Drug Concentration/Minimum Inhibitory Concentration (Cmax/MIC) Adjusted for Free Drug Concentrations
Time frame: Day 5 (7 time points)
Area Under the Curve (AUC) During First 12 and 24 Hours Adjusted for Free Drug Concentrations
Time frame: Day 5 (7 time points)
Area Under the Curve (AUC) Adjusted for Free Drug Concentrations/Minimum Inhibitory Concentration (MIC)
Time frame: Day 5 (7 time points)
Percent Dosing Interval Above Minimum Inhibitory Concentration (MIC)
Time frame: Day 5 (7 time points)

Results and safety

Results posted to the registry on 25 Jun 2009, as reported by the sponsor. Figures are copied from the record, not re-analysed. Full results on ClinicalTrials.gov.

Participant flow

Group	Started	Completed
Gatifloxacin 400 mg/Day	10	10
Levofloxacin 1000 mg/Day	10	10
Linezolid 600 mg / Once Daily	10	10
Linezolid 600 mg / Twice Daily	10	9
Moxifloxacin 400 mg/Day	10	9
Isoniazid (INH) 300 mg/Day	20	18

Primary outcome: Sputum Bacillary Loads: Adjusted Area Under the Curve (aAUC)

Time frame: Study drug administration duration - 7 days monotherapy. Mean (Standard Deviation). Unit: Percentage

Measure	Gatifloxacin 400 mg/Day n = 10	Levofloxacin 1000 mg/Day n = 10	Moxifloxacin 400 mg/Day n = 10	Isoniazid (INH) 300 mg/Day n = 10
Day 1	0.98 (0.03)	0.98 (0.03)	0.96 (0.04)	0.95 (0.03)
Day 2	0.96 (0.03)	0.95 (0.05)	0.94 (0.06)	0.90 (0.04)
Day 3	0.92 (0.05)	0.91 (0.07)	0.91 (0.08)	0.87 (0.04)
Day 4	0.89 (0.07)	0.88 (0.08)	0.89 (0.09)	0.84 (0.04)
Day 5	0.87 (0.08)	0.85 (0.09)	0.87 (0.10)	0.81 (0.05)
Day 6	0.85 (0.08)	0.83 (0.10)	0.85 (0.10)	0.80 (0.06)
Day 7	0.82 (0.09)	0.81 (0.10)	0.83 (0.10)	0.80 (0.06)

Gatifloxacin 400 mg/Day vs Levofloxacin 1000 mg/Day vs Moxifloxacin 400 mg/Day vs Isoniazid (INH) 300 mg/Day: p <0.001, ANOVA
Gatifloxacin 400 mg/Day vs Levofloxacin 1000 mg/Day vs Moxifloxacin 400 mg/Day vs Isoniazid (INH) 300 mg/Day: p = 0.041, Wilcoxon (Mann-Whitney)
Gatifloxacin 400 mg/Day vs Levofloxacin 1000 mg/Day vs Moxifloxacin 400 mg/Day vs Isoniazid (INH) 300 mg/Day: p = 0.008, Wilcoxon (Mann-Whitney)

Population analysed: The aAUC was calculated for 10 subjects per treatment arm (n=40).

Primary outcome: 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. Mean (Standard Deviation). Unit: log10 cfu/ml/day

Measure	Gatifloxacin 400 mg/Day n = 10	Levofloxacin 1000 mg/Day n = 10	Moxifloxacin 400 mg/Day n = 10	Isoniazid (INH) 300 mg/Day n = 10
Value	0.35 (0.27)	0.45 (0.35)	0.33 (0.39)	0.67 (0.17)

Gatifloxacin 400 mg/Day vs Levofloxacin 1000 mg/Day vs Moxifloxacin 400 mg/Day vs Isoniazid (INH) 300 mg/Day: p = 0.05, ANOVA
Gatifloxacin 400 mg/Day vs Isoniazid (INH) 300 mg/Day: p = 0.01, Wilcoxon (Mann-Whitney)
Moxifloxacin 400 mg/Day vs Isoniazid (INH) 300 mg/Day: p = 0.02, Wilcoxon (Mann-Whitney)

Population analysed: Early bactericidal activity (EBA 0-2) was calculated for 10 subjects per treatment arm (n=40).

Primary outcome: Extended Early Bactericidal Activity (EBA) From Days 2 to 7; Fluoroquinolones/Isoniazid (INH) Comparison

Time frame: Day 2 to Day 7 Monotherapy. Mean (Standard Deviation). Unit: log10 cfu/ml/day

Measure	Gatifloxacin 400 mg/Day n = 10	Levofloxacin 1000 mg/Day n = 10	Moxifloxacin 400 mg/Day n = 9	Isoniazid (INH) 300 mg/Day n = 9
Value	0.17 (0.13)	0.18 (0.13)	0.17 (0.09)	0.08 (0.09)

Gatifloxacin 400 mg/Day vs Levofloxacin 1000 mg/Day vs Moxifloxacin 400 mg/Day vs Isoniazid (INH) 300 mg/Day: p = 0.51, ANOVA
Gatifloxacin 400 mg/Day vs Levofloxacin 1000 mg/Day vs Moxifloxacin 400 mg/Day vs Isoniazid (INH) 300 mg/Day: p = 0.16, ANOVA
Gatifloxacin 400 mg/Day vs Levofloxacin 1000 mg/Day vs Moxifloxacin 400 mg/Day vs Isoniazid (INH) 300 mg/Day: p = 0.036, Wilcoxon (Mann-Whitney)

Population analysed: A total of 38 patients were analyzed for Early Bactericidal Activity (EBA) Days 2-7. One patient in the moxifloxacin arm discontinued the study drug after 4 days. One patient in the INH arm discontinued the study drug after 6 days.

Primary outcome: Sputum Bacillary Loads: Adjusted Area Under the Curve (aAUC)

Time frame: Study drug administration duration - 7 days monotherapy. Mean (Standard Deviation). Unit: Percentage

Measure	Isoniazid 300 mg/Day n = 10	Linezolid 600 mg/Once Daily n = 10	Linezolid 600 mg/Twice Daily n = 9
Day 1	0.94 (0.06)	0.98 (0.04)	0.98 (0.04)
Day 2	0.89 (0.08)	0.97 (0.07)	0.96 (0.07)
Day 3	0.89 (0.03)	0.96 (0.07)	0.95 (0.08)
Day 4	0.85 (0.09)	0.96 (0.07)	0.94 (0.08)
Day 5	0.83 (0.10)	0.95 (0.07)	0.94 (0.08)
Day 6	0.81 (0.12)	0.95 (0.07)	0.93 (0.07)
Day 7	0.83 (0.07)	0.95 (0.07)	0.93 (0.07)

Isoniazid 300 mg/Day vs Linezolid 600 mg/Once Daily vs Linezolid 600 mg/Twice Daily: p <0.001, ANOVA
Isoniazid 300 mg/Day vs Linezolid 600 mg/Once Daily vs Linezolid 600 mg/Twice Daily: p = 0.023, Wilcoxon (Mann-Whitney)
Isoniazid 300 mg/Day vs Linezolid 600 mg/Once Daily vs Linezolid 600 mg/Twice Daily: p = 0.018, Wilcoxon (Mann-Whitney)

Population analysed: The aAUC was calculated for 29 patients. One patient in the linezolid twice daily arm withdrew after randomization before receiving any doses of study drug.

15 secondary outcomes are reported in the full results.

Adverse events

Time frame: Adverse event data were collected from February 2004 through October 2007.. Other adverse events reported at 5% frequency or more

Group	Serious adverse events	Other adverse events	Deaths
Gatifloxacin 400 mg/Day	0 of 10 (0%)	8 of 10 (80%)	Not reported
Levofloxacin 1000 mg/Day	0 of 10 (0%)	7 of 10 (70%)	Not reported
Linezolid 600 mg / Once Daily	0 of 10 (0%)	8 of 10 (80%)	Not reported
Linezolid 600 mg / Twice Daily	0 of 10 (0%)	5 of 10 (50%)	Not reported
Moxifloxacin 400 mg/Day	0 of 10 (0%)	7 of 10 (70%)	Not reported
Isoniazid (INH) 300 mg/Day	0 of 20 (0%)	7 of 20 (35%)	Not reported

Limitations and caveats (from the sponsor): The small sample size had limited power to detect small differences in EBA between study arms even though we enrolled patients with smear-positive TB and high sputum bacillary burden to improve chances of detecting differences between treatment arms.

Loading the posted results from ClinicalTrials.gov…

Research links

Official record on ClinicalTrials.govLast updated by the sponsor 8 Nov 2018.
Posted resultsParticipant flow, baseline, all outcome measures and adverse events.
Results publication: PubMed 16776446Johnson JL, Hadad DJ, Boom WH, Daley CL, Peloquin CA, Eisenach KD, Jankus DD, Debanne SM, Charlebois ED, Maciel E, Palaci M, Dietze R. Early and extended early bactericidal activity of levofloxacin, gatifloxacin and moxifloxacin in pulmonary tuberculosis. Int J Tuberc Lung Dis. 2006 Jun;10(6):605-12.
Results publication: PubMed 18787216Dietze R, Hadad DJ, McGee B, Molino LP, Maciel EL, Peloquin CA, Johnson DF, Debanne SM, Eisenach K, Boom WH, Palaci M, Johnson JL. Early and extended early bactericidal activity of linezolid in pulmonary tuberculosis. Am J Respir Crit Care Med. 2008 Dec 1;178(11):1180-5. doi: 10.1164/rccm.200806-892OC. Epub 2008 Sep 11.
Results publication: PubMed 29584861Millard J, Pertinez H, Bonnett L, Hodel EM, Dartois V, Johnson JL, Caws M, Tiberi S, Bolhuis M, Alffenaar JC, Davies G, Sloan DJ. Linezolid pharmacokinetics in MDR-TB: a systematic review, meta-analysis and Monte Carlo simulation. J Antimicrob Chemother. 2018 Jul 1;73(7):1755-1762. doi: 10.1093/jac/dky096.
Results publication: PubMed 18070980Peloquin CA, Hadad DJ, Molino LP, Palaci M, Boom WH, Dietze R, Johnson JL. Population pharmacokinetics of levofloxacin, gatifloxacin, and moxifloxacin in adults with pulmonary tuberculosis. Antimicrob Agents Chemother. 2008 Mar;52(3):852-7. doi: 10.1128/AAC.01036-07. Epub 2007 Dec 10.
Results publication: PubMed 19564361McGee B, Dietze R, Hadad DJ, Molino LP, Maciel EL, Boom WH, Palaci M, Johnson JL, Peloquin CA. Population pharmacokinetics of linezolid in adults with pulmonary tuberculosis. Antimicrob Agents Chemother. 2009 Sep;53(9):3981-4. doi: 10.1128/AAC.01378-08. Epub 2009 Jun 29.
Results publication: PubMed 19923475Li L, Mahan CS, Palaci M, Horter L, Loeffelholz L, Johnson JL, Dietze R, Debanne SM, Joloba ML, Okwera A, Boom WH, Eisenach KD. Sputum Mycobacterium tuberculosis mRNA as a marker of bacteriologic clearance in response to antituberculosis therapy. J Clin Microbiol. 2010 Jan;48(1):46-51. doi: 10.1128/JCM.01526-09. Epub 2009 Nov 18.

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Referral and contact

AzTrials does not enrol participants or take referrals. Contact the study team or a site listed below; they decide who can take part. This study is not recruiting at the moment.

The record lists no contact. Use the official record to reach the sponsor.

2 sites in 2 countries: see every site and its status.

Questions about this trial

What is this clinical trial studying?

A Phase 1/2 study testing Gatifloxacin, Isoniazid and Levofloxacin in people with Tuberculosis, run by National Institute of Allergy and Infectious Diseases (NIAID) at 2 sites in 2 countries.

The full registered description is in the About this study section and the official record.

Who may be eligible to take part?

The sponsor lists 1 inclusion and 1 exclusion criteria. Eligibility is decided by the study team after screening, so read the full criteria and contact a listed site.

Is this clinical trial currently recruiting?

The record says: finished, as of the sponsor's last update on 8 Nov 2018. Status can change between updates, so confirm with the study contact before making plans.

Where is the study taking place?

The record lists 2 sites in United States, Brazil. Whether a site is taking part right now should be confirmed with that site. See every site.

What are the possible benefits and risks?

They depend on the study and the treatment, and no study can promise a benefit. The study team explains the known risks during informed consent, before anyone joins; the record itself does not list them.

What does this combined phase mean?

Phase 1 studies test a treatment in a small group of people for the first time or in a new way, mainly to check safety and find the right dose.

Phase 2 studies give the treatment to a larger group to see whether it has the intended effect and to keep checking safety.

Not every study follows the same path, and some studies (observational studies, device studies) have no phase.

Are results available for this study?

Yes. Results are posted in the registry (first posted 25 Jun 2009). A summary is in the For doctors view, and the full results are on ClinicalTrials.gov.

How can a doctor refer a patient or contact the research team?

The record lists no contact. The official record names the sponsor, who can be asked directly. AzTrials does not enrol participants or take referrals.

What does the primary outcome measure?

Sputum Bacillary Loads: Adjusted Area Under the Curve (aAUC) (time frame: Study drug administration duration - 7 days monotherapy). The study lists 6 primary outcomes in all. It is what the study was designed to measure, not a finding.

Where can I read the original study information?

On the ClinicalTrials.gov record for NCT00396084, which also lists 6 linked publications.

Does a listing mean the treatment is approved or proven to work?

No. A listing means the study is registered. It does not show that the treatment is safe, works, or is approved by a regulator.

How often is this information updated?

AzTrials copies changed records from ClinicalTrials.gov every night and reloads the whole registry every week. The sponsor last updated this record on 8 Nov 2018.