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

NCT00396084 | Completed Phase 1 Results FDA Drug

• 1 other identifier: 01-553
• Study Type: interventional
• Target: 70
• Locations: 2 countries
• Sites: 2

Brief Summary

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.

Conditions

Tuberculosis

Keywords

Brazil; gatifloxacin; isoniazid; levofloxacin; linezolid; moxifloxacin; tuberculosis

Outcome Measures

Primary Outcomes (6)

• 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 Outcomes (14)

• 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)

  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)

Study Arms (6)

Gatifloxacin

EXPERIMENTAL

10 subjects to receive gatifloxacin 400 mg orally once daily for 7 days.

Drug: Gatifloxacin

Isoniazid

ACTIVE COMPARATOR

20 subjects to receive isoniazid 300 mg orally once daily for 7days.

Drug: Isoniazid

Levofloxacin

EXPERIMENTAL

10 subjects to receive levofloxacin 1000 mg orally once daily for 7days.

Drug: Levofloxacin

Linezolid every 12 hours

EXPERIMENTAL

10 subjects to receive linezolid 600 mg orally every 12 hours daily for 7 days.

Drug: Linezolid

Linezolid once daily

EXPERIMENTAL

10 subjects to receive linezolid 600 mg orally once daily for 7days.

Drug: Linezolid

Moxifloxacin

EXPERIMENTAL

10 subjects to receive moxifloxacin 400 mg orally once daily for 7 days.

Drug: Moxifloxacin

Interventions

Gatifloxacin DRUG

Gatifloxacin 400 mg/day x 7 days.

Gatifloxacin

Isoniazid DRUG

Isoniazid 300 mg/day x 7 days.

Isoniazid

Levofloxacin DRUG

Levofloxacin 1000 mg/day x 7 days.

Levofloxacin

Linezolid DRUG

Linezolid 600 mg/day x 7 days; Linezolid 600 mg every 12 hours x 7 days.

Linezolid every 12 hours; Linezolid once daily

Moxifloxacin DRUG

Moxifloxacin 400 mg/day x 7 days.

Moxifloxacin

Eligibility Criteria

• Age: 18 Years - 65 Years
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• 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.

You may not qualify if:

• 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.

Sponsors & Collaborators

• National Institute of Allergy and Infectious Diseases (NIAID): lead

Study Sites (2)

San Francisco General Hospital - Pulmonary and Critical Care Medicine

San Francisco, California, 94110-3518, United States

Location

Universidade Federal do Espirito Santo - Duke Hubert-Yeargan Center

Vitória, Espírito Santo, 29040-091, Brazil

Location

Related Publications (6)

• 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.

  PMID: 16776446 RESULT

• 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.

  PMID: 18787216 RESULT

• 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.

  PMID: 29584861 RESULT

• 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.

  PMID: 18070980 RESULT

• 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.

  PMID: 19564361 RESULT

• 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.

  PMID: 19923475 RESULT

MeSH Terms

Conditions

Tuberculosis

Interventions

Gatifloxacin; Isoniazid; Levofloxacin; Linezolid; Moxifloxacin

Condition Hierarchy (Ancestors)

Mycobacterium Infections; Actinomycetales Infections; Gram-Positive Bacterial Infections; Bacterial Infections; Bacterial Infections and Mycoses; Infections

Intervention Hierarchy (Ancestors)

Fluoroquinolones; 4-Quinolones; Quinolones; Quinolines; Heterocyclic Compounds, 2-Ring; Heterocyclic Compounds, Fused-Ring; Heterocyclic Compounds; Hydrazines; Organic Chemicals; Isonicotinic Acids; Acids, Heterocyclic; Pyridines; Heterocyclic Compounds, 1-Ring; Ofloxacin; Acetamides; Amides; Acetates; Acids, Acyclic; Carboxylic Acids; Oxazolidinones; Oxazoles; Azoles

Limitations and Caveats

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.

Results Point of Contact

• Title: John L. Johnson, M.D.
• Organization: Case Western Reserve University, Tuberculosis Research Unit

jlj@case.edu

(216) 368-1949

Publication Agreements

• PI is Sponsor Employee: No
• Restrictive Agreement: No

Study Design

• Study Type: interventional
• Phase: phase 1
• Allocation: RANDOMIZED
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: PARALLEL
• Sponsor Type: NIH

Study Record Dates

• First Submitted: November 3, 2006
• First Posted: November 6, 2006
• Study Start: February 10, 2004
• Primary Completion: November 23, 2007
• Study Completion: December 28, 2007
• Last Updated: November 8, 2018
• Results First Posted: June 25, 2009

Record last verified: 2010-03-10

Locations

US (1); BR (1)