Early Bactericidal Activity of Linezolid, Gatifloxacin, Levofloxacin, Isoniazid (INH) and Moxifloxacin in HIV Negative Adults With Initial Episodes of Sputum Smear-Positive Pulmonary Tuberculosis
| Status: | Completed |
|---|---|
| Conditions: | Infectious Disease, Infectious Disease |
| Therapuetic Areas: | Immunology / Infectious Diseases |
| Healthy: | No |
| Age Range: | 18 - 65 |
| Updated: | 11/10/2018 |
| Start Date: | February 10, 2004 |
| End Date: | December 28, 2007 |
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.
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.
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.
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.
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.
We found this trial at
2
sites
San Francisco, California 94110
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