Tuberculosis Clinical Trial
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
Verified date | March 10, 2010 |
Source | National Institute of Allergy and Infectious Diseases (NIAID) |
Contact | n/a |
Is FDA regulated | No |
Health authority | |
Study type | Interventional |
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.
Status | Completed |
Enrollment | 70 |
Est. completion date | December 28, 2007 |
Est. primary completion date | November 23, 2007 |
Accepts healthy volunteers | No |
Gender | All |
Age group | 18 Years to 65 Years |
Eligibility |
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. |
Country | Name | City | State |
---|---|---|---|
Brazil | Universidade Federal do Espirito Santo - Duke Hubert-Yeargan Center | Vitória | Espírito Santo |
United States | San Francisco General Hospital - Pulmonary and Critical Care Medicine | San Francisco | California |
Lead Sponsor | Collaborator |
---|---|
National Institute of Allergy and Infectious Diseases (NIAID) |
United States, Brazil,
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 — View Citation
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. — View Citation
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 M — View Citation
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. E — View Citation
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. — View Citation
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. Epub 2007 Dec — View Citation
Type | Measure | Description | Time frame | Safety issue |
---|---|---|---|---|
Primary | 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 | |
Primary | 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 | |
Primary | 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 | |
Primary | 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 | |
Primary | 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 | |
Primary | 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 | Sputum mRNA Clearance Rate - Results Are Pending. | Study drug administration duration | ||
Secondary | Sputum Cytokine Proteins - Results Are Pending. | Study drug administration duration | ||
Secondary | Maximum Plasma Drug Concentration (Cmax) | Maximum plasma concentration, given sampling scheme | Day 5 (7 time points) | |
Secondary | Time to Maximum Plasma Drug Concentration (Tmax) and Half-life | Day 5 (7 time points) | ||
Secondary | Maximum Plasma Drug Concentration/Minimum Inhibitory Concentration (Cmax/MIC) | Day 5 (7 time points) | ||
Secondary | 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) | |
Secondary | 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) | |
Secondary | Maximum Plasma Drug Concentration (Cmax) | Maximum Plasma Drug Concentration (Cmax), given sampling scheme | Day 5 (7 time points) | |
Secondary | 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) | |
Secondary | 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) | |
Secondary | Maximum Plasma Drug Concentration/Minimum Inhibitory Concentration (Cmax/MIC) Adjusted for Free Drug Concentrations | Day 5 (7 time points) | ||
Secondary | 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) | |
Secondary | 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) | |
Secondary | 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) |
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