NCT00396084

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

Completed Phase 1, PHASE2 Results posted Last updated 8 November 2018

What this trial tests

Phase 1, PHASE2 trial testing Gatifloxacin in Tuberculosis in 70 participants. Completed in 28 December 2007.

Timeline

10 February 2004

Primary endpoint
23 November 2007

28 December 2007

Quick facts

Lead sponsor	National Institute of Allergy and Infectious Diseases (NIAID)
Phase	Phase 1, PHASE2
Status	Completed
Study type	INTERVENTIONAL
Allocation	randomized
Design	parallel
Masking	none
Primary purpose	treatment
Enrollment	70
Start date	10 February 2004
Primary completion	23 November 2007
Estimated completion	28 December 2007
Sites	2 locations across United States, Brazil

Drugs / interventions tested

• Gatifloxacin (GATIFLOXACIN) — full drug profile →
• Isoniazid (ISONIAZID) — full drug profile →
• Levofloxacin (Levofloxacin) — full drug profile →
• Linezolid — full drug profile →
• Moxifloxacin (moxifloxacin) — full drug profile →

Conditions studied

• Tuberculosis — all drugs for Tuberculosis →

Sponsor

National Institute of Allergy and Infectious Diseases (NIAID)

Who can join

Adults 18 to 65, any sex, with Tuberculosis. Patients with the condition only — healthy volunteers not accepted.

Results — posted to ClinicalTrials.gov

Per-arm endpoint measurements with 95% confidence intervals where reported. Source: trial results section.

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

Day 1

Group	Value	95% CI
Gatifloxacin 400 mg/Day	0.98	± 0.03
Levofloxacin 1000 mg/Day	0.98	± 0.03
Moxifloxacin 400 mg/Day	0.96	± 0.04
Isoniazid (INH) 300 mg/Day	0.95	± 0.03

Day 2

Group	Value	95% CI
Gatifloxacin 400 mg/Day	0.96	± 0.03
Levofloxacin 1000 mg/Day	0.95	± 0.05
Moxifloxacin 400 mg/Day	0.94	± 0.06
Isoniazid (INH) 300 mg/Day	0.90	± 0.04

Day 3

Group	Value	95% CI
Gatifloxacin 400 mg/Day	0.92	± 0.05
Levofloxacin 1000 mg/Day	0.91	± 0.07
Moxifloxacin 400 mg/Day	0.91	± 0.08
Isoniazid (INH) 300 mg/Day	0.87	± 0.04

Day 4

Group	Value	95% CI
Gatifloxacin 400 mg/Day	0.89	± 0.07
Levofloxacin 1000 mg/Day	0.88	± 0.08
Moxifloxacin 400 mg/Day	0.89	± 0.09
Isoniazid (INH) 300 mg/Day	0.84	± 0.04

Day 5

Group	Value	95% CI
Gatifloxacin 400 mg/Day	0.87	± 0.08
Levofloxacin 1000 mg/Day	0.85	± 0.09
Moxifloxacin 400 mg/Day	0.87	± 0.10
Isoniazid (INH) 300 mg/Day	0.81	± 0.05

Day 6

Group	Value	95% CI
Gatifloxacin 400 mg/Day	0.85	± 0.08
Levofloxacin 1000 mg/Day	0.83	± 0.10
Moxifloxacin 400 mg/Day	0.85	± 0.10
Isoniazid (INH) 300 mg/Day	0.80	± 0.06

Day 7

Group	Value	95% CI
Gatifloxacin 400 mg/Day	0.82	± 0.09
Levofloxacin 1000 mg/Day	0.81	± 0.10
Moxifloxacin 400 mg/Day	0.83	± 0.10
Isoniazid (INH) 300 mg/Day	0.80	± 0.06

Maximum Plasma Drug Concentration (Cmax) Secondary · Day 5 (7 time points)

Maximum plasma concentration, given sampling scheme

Group	Value	95% CI
Gatifloxacin 400 mg/Day	4.8	3.8 – 6.4
Levofloxacin 1000 mg/Day	15.6	8.6 – 43.0
Moxifloxacin 400 mg/Day	6.1	4.5 – 9.0
Isoniazid (INH) 300 mg/Day	3.6	2.5 – 6.1

Difference in Sputum Bacillary Loads: Early Bactericidal Activity (EBA) Days 0 to 2; Fluoroquinolones/Isoniazid (INH) Comparison Primary · 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.

Group	Value	95% CI
Gatifloxacin 400 mg/Day	0.35	± 0.27
Levofloxacin 1000 mg/Day	0.45	± 0.35
Moxifloxacin 400 mg/Day	0.33	± 0.39
Isoniazid (INH) 300 mg/Day	0.67	± 0.17

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

Group	Value	95% CI
Gatifloxacin 400 mg/Day	0.17	± 0.13
Levofloxacin 1000 mg/Day	0.18	± 0.13
Moxifloxacin 400 mg/Day	0.17	± 0.09
Isoniazid (INH) 300 mg/Day	0.08	± 0.09

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

Day 1

Group	Value	95% CI
Isoniazid 300 mg/Day	0.94	± 0.06
Linezolid 600 mg/Once Daily	0.98	± 0.04
Linezolid 600 mg/Twice Daily	0.98	± 0.04

Day 2

Group	Value	95% CI
Isoniazid 300 mg/Day	0.89	± 0.08
Linezolid 600 mg/Once Daily	0.97	± 0.07
Linezolid 600 mg/Twice Daily	0.96	± 0.07

Day 3

Group	Value	95% CI
Isoniazid 300 mg/Day	0.89	± 0.03
Linezolid 600 mg/Once Daily	0.96	± 0.07
Linezolid 600 mg/Twice Daily	0.95	± 0.08

Day 4

Group	Value	95% CI
Isoniazid 300 mg/Day	0.85	± 0.09
Linezolid 600 mg/Once Daily	0.96	± 0.07
Linezolid 600 mg/Twice Daily	0.94	± 0.08

Day 5

Group	Value	95% CI
Isoniazid 300 mg/Day	0.83	± 0.10
Linezolid 600 mg/Once Daily	0.95	± 0.07
Linezolid 600 mg/Twice Daily	0.94	± 0.08

Day 6

Group	Value	95% CI
Isoniazid 300 mg/Day	0.81	± 0.12
Linezolid 600 mg/Once Daily	0.95	± 0.07
Linezolid 600 mg/Twice Daily	0.93	± 0.07

Day 7

Group	Value	95% CI
Isoniazid 300 mg/Day	0.83	± 0.07
Linezolid 600 mg/Once Daily	0.95	± 0.07
Linezolid 600 mg/Twice Daily	0.93	± 0.07

Difference in Sputum Bacillary Loads: Early Bactericidal Activity (EBA) Days 0 to 2; Linezolid Once Daily/Linezolid Twice Daily/Isoniazid (INH) Comparison Primary · 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.

Group	Value	95% CI
Isoniazid 300 mg/Day	0.67	± 0.35
Linezolid 600 mg/Once Daily	0.18	± 0.27
Linezolid 600 mg/Twice Daily	0.26	± 0.42

Time to Maximum Plasma Drug Concentration (Tmax) and Half-life Secondary · Day 5 (7 time points)

Tmax

Group	Value	95% CI
Gatifloxacin 400 mg/Day	1.5	1.0 – 8.0
Levofloxacin 1000 mg/Day	1.0	1.0 – 4.0
Moxifloxacin 400 mg/Day	1.0	1.0 – 2.0
Isoniazid (INH) 300 mg/Day	1	1.0 – 2.0

Half-life

Group	Value	95% CI
Gatifloxacin 400 mg/Day	6.0	5.2 – 9.3
Levofloxacin 1000 mg/Day	7.6	4.4 – 19.1
Moxifloxacin 400 mg/Day	8.1	5.1 – 9.9
Isoniazid (INH) 300 mg/Day	2.5	1.5 – 4.9

Maximum Plasma Drug Concentration/Minimum Inhibitory Concentration (Cmax/MIC) Secondary · Day 5 (7 time points)

Group	Value	95% CI
Gatifloxacin 400 mg/Day	9.5	8.4 – 11.3
Levofloxacin 1000 mg/Day	15.6	12.2 – 16.6
Moxifloxacin 400 mg/Day	12.3	9.6 – 13.4
Isoniazid (INH) 300 mg/Day	70.6	64.0 – 76.2

Difference in Sputum Bacillary Loads: Extended Early Bactericidal Activity (EBA) From Days 2 to 7; Linezolid Once Daily/Linezolid Twice Daily/INH Comparison Primary · 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.

Group	Value	95% CI
Isoniazid 300 mg/Day	0.16	± 0.11
Linezolid 600 mg/Once Daily	0.09	± 0.17
Linezolid 600 mg/Twice Daily	0.04	± 0.11

Pharmacokinetic Parameters: Area Under the Curve (AUC) During First 12 and 24 Hours Secondary · Day 5 (7 time points)

Area under the curve (AUC), from time 0-12 hours for INH or 0-24 hours for gatifloxacin, levofloxacin, and moxifloxacin.

Group	Value	95% CI
Gatifloxacin 400 mg/Day	42.8	31.7 – 51.0
Levofloxacin 1000 mg/Day	129.1	103.4 – 358.3
Moxifloxacin 400 mg/Day	55.3	36.0 – 79.1
Isoniazid (INH) 300 mg/Day	11.9	7.1 – 37.4

Area Under the Curve During First 12 or 24 Hours / Minimum Inhibitory Concentration (AUC/MIC) Secondary · Day 5 (7 time points)

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.

Group	Value	95% CI
Gatifloxacin 400 mg/Day	85.6	70.7 – 89.7
Levofloxacin 1000 mg/Day	129.1	121.0 – 145.0
Moxifloxacin 400 mg/Day	110.5	98.9 – 121.6
Isoniazid (INH) 300 mg/Day	215.2	177.4 – 329.6

Maximum Plasma Drug Concentration (Cmax) Secondary · Day 5 (7 time points)

Maximum Plasma Drug Concentration (Cmax), given sampling scheme

Group	Value	95% CI
Isoniazid 300 mg/Day	3.3	2.5 – 5.3
Linezolid 600 mg/Once Daily	15.0	11.9 – 21.3
Linezolid 600 mg/Twice Daily	19.4	11.8 – 24.9

Adverse events — posted to ClinicalTrials.gov

Time frame: Adverse event data were collected from February 2004 through October 2007.. Reporting threshold: 5%. Adverse-event reports describe events observed during the trial — not all are caused by the drug.

Gatifloxacin 400 mg/Day

Serious: 0/10 (0%)

Deaths: —

Levofloxacin 1000 mg/Day

Serious: 0/10 (0%)

Deaths: —

Linezolid 600 mg / Once Daily

Serious: 0/10 (0%)

Deaths: —

Linezolid 600 mg / Twice Daily

Serious: 0/10 (0%)

Deaths: —

Moxifloxacin 400 mg/Day

Serious: 0/10 (0%)

Deaths: —

Isoniazid (INH) 300 mg/Day

Serious: 0/20 (0%)

Deaths: —

Other adverse events (17 terms — click to expand)

Reaction	System	Gatifloxacin 400 mg/Day	Levofloxacin 1000 mg/Day	Linezolid 600 mg / Once Da…	Linezolid 600 mg / Twice D…	Moxifloxacin 400 mg/Day	Isoniazid (INH) 300 mg/Day
Rales (or Crackles)	Respiratory, thoracic and mediastinal disorders	—	—	—	—	—	—
Acne	Skin and subcutaneous tissue disorders	—	—	—	—	—	—
Diarrhea	Gastrointestinal disorders	—	—	—	—	—	—
Hemoglobin Decreased	Blood and lymphatic system disorders	—	—	—	—	—	—
Chest Pain	Respiratory, thoracic and mediastinal disorders	—	—	—	—	—	—
Elevated Monocytes	Blood and lymphatic system disorders	—	—	—	—	—	—
Fever	General disorders	—	—	—	—	—	—
Hematocrit Decreased	Blood and lymphatic system disorders	—	—	—	—	—	—
Intestinal Ancyclostomiasis	Gastrointestinal disorders	—	—	—	—	—	—
Intestinal Strongyloidiasis	Gastrointestinal disorders	—	—	—	—	—	—
Joint Pain	Musculoskeletal and connective tissue disorders	—	—	—	—	—	—
Ronchi	Respiratory, thoracic and mediastinal disorders	—	—	—	—	—	—
Sweating	General disorders	—	—	—	—	—	—
Wheezing	Respiratory, thoracic and mediastinal disorders	—	—	—	—	—	—
Intestinal Constipation	Gastrointestinal disorders	—	—	—	—	—	—
Lumbar Pain	Musculoskeletal and connective tissue disorders	—	—	—	—	—	—
Pain in Both Shoulders	Musculoskeletal and connective tissue disorders	—	—	—	—	—	—

Data from ClinicalTrials.gov NCT00396084 adverse events section.

Sponsor's own description

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.

Publications & conference data

6 peer-reviewed publications reference this trial (live from Europe PMC):

1. Early and extended early bactericidal activity of linezolid in pulmonary tuberculosis.
   Dietze R, Hadad DJ, McGee B, Molino LP, et al · · 2008 · cited 105× · PMID 18787216 · DOI 10.1164/rccm.200806-892oc
2. Sputum Mycobacterium tuberculosis mRNA as a marker of bacteriologic clearance in response to antituberculosis therapy.
   Li L, Mahan CS, Palaci M, Horter L, et al · · 2010 · cited 42× · PMID 19923475 · DOI 10.1128/jcm.01526-09
3. Potential Repurposed Drug Candidates for Tuberculosis Treatment: Progress and Update of Drugs Identified in Over a Decade.
   Sharma K, Ahmed F, Sharma T, Grover A, et al · · 2023 · cited 30× · PMID 37251185 · DOI 10.1021/acsomega.2c05511
4. Limited sampling strategy and target attainment analysis for levofloxacin in patients with tuberculosis.
   Alsultan A, An G, Peloquin CA. · · 2015 · cited 27× · PMID 25870068 · DOI 10.1128/aac.00341-15
5. Fluoroquinolones for treating tuberculosis (presumed drug-sensitive).
   Ziganshina LE, Titarenko AF, Davies GR. · · 2013 · cited 19× · PMID 23744519 · DOI 10.1002/14651858.cd004795.pub4
6. Dose optimization of TBI-223 for enhanced therapeutic benefit compared to linezolid in antituberculosis regimen.
   Strydom N, Ernest JP, Imperial M, Solans BP, et al · · 2024 · cited 11× · PMID 39181887 · DOI 10.1038/s41467-024-50781-4