Pulmonary Tuberculosis
Conditions
Keywords
Tuberculosis, Drug-Sensitive Tuberculosis, Linezolid, HRZE (isoniazid, rifampicin, pyrazinamide, ethambutol), Pulmonary Tuberculosis, TB
Brief summary
The purpose of this study is to evaluate the mycobactericidal activity, safety, tolerability, and pharmacokinetics of 6 doses of linezolid: 300 mg once per day, 300 mg twice per day, 600 mg once per day, 600 mg twice per day and 1200 mg once per day administered orally for 14 consecutive days or 1200 mg administered three times per week for two weeks in adult subjects with newly diagnosed drug-sensitive, smear-positive pulmonary tuberculosis.
Interventions
DRUGLinezolid
DRUGHRZE (isoniazid rifampicin,pyrazinamide,ethambutol)
isoniazid (H) 75 mg plus rifampicin (R) 150 mg plus pyrazinamide (Z) 400 mg plus ethambutol (E) 275 mg
Sponsors
Global Alliance for TB Drug Development
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to 75 Years
Healthy volunteers
No
Inclusion criteria
Subjects are required to meet all of the following inclusion criteria in order to be randomized. 1. Provide written, informed consent prior to all trial-related procedures. 2. Male or female, aged between 18 and 75 years inclusive. 3. Body weight (in light clothing and with no shoes) between 35 and 100 kg, inclusive. 4. Drug-sensitive pulmonary Tuberculosis (TB) determined by testing at the trial appointed laboratory: M.tb positive and rifampicin sensitive on molecular test (e.g. GeneXpert or Hain) and sputum smear-positive pulmonary TB on direct microscopy for acid-fast bacilli (at least 1+ on the IUATLD/WHO scale). 1. either newly diagnosed OR 2. untreated for at least 3 years after cure from a previous episode (Subject can give a history of cure and previous treatment); AND 3. Previous TB treatment must be discontinued as per
Exclusion criteria
17. 5. A chest X-Ray which in the opinion of the Investigator is consistent with TB. 6. Ability to produce an adequate volume of sputum as estimated from a screening Coached Spot Sputum Sample assessment (estimated 10 ml or more overnight production). 7. Be of non-childbearing potential or using effective methods of birth control, as defined below: Non-childbearing potential: 1. Subject - not heterosexually active or practices sexual abstinence; OR 2. Female Subject/sexual partner - bilateral oophorectomy, bilateral tubal ligation and/or hysterectomy or has been postmenopausal with a history of no menses for at least 12 consecutive months; OR 3. Male Subject/sexual partner - vasectomised or has had a bilateral orchidectomy minimally three months prior to screening; Effective birth control methods: A double contraceptive method should be used as follows: 1. Double barrier method which can include any 2 of the following: a male condom, diaphragm, cervical cap, or female condom (male and female condoms should not be used together); OR 2. Barrier method (one of the above) combined with hormone-based contraceptives or an intra-uterine device for the female Subject/partner; AND 3. Are willing to continue practicing one of the above mentioned birth control methods throughout treatment and for 1 month (both male and female Subjects) after the last dose of study medication or discontinuation from study medication in case of premature discontinuation.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Bactericidal Activity (Time to Positivity) Days 0 - 14 [BA(TTP)] | Days -2, -1, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14 | \[BA(TTP)\] will be determined by the rate of change in time to sputum culture positivity (TTP) over 14 days of treatment in the Mycobacterial Growth Indicator Tube system, represented by the model-fitted log(TTP) results as calculated by the regression of the observed log(TTP) results over time. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| The Bactericidal Activity Colony Forming Unit (BACFU)(0-14), BACFU(0-2) and BACFU(7-14) | Day 1, 2, 3, 4, 5, 6, 7, 8, 8, 9, 10, 11, 12, 13, 14 | \[BACFU\] will be determined by the rate of change in colony forming unit (CFU) counts, over 14 days of treatment represented by the model-fitted log(CFU) counts as calculated by the regression of the observed log (CFU) counts over time. |
| Incidence of Treatment Emergent Adverse Events (TEAEs) presented by severity (DMID Grade), relatedness, and seriousness, leading to early withdrawal and leading to death. | Screening (-9 to -3, -2, -1), Day 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, and Follow-Up (Day 21) | — |
| Pharmacokinetic parameters for subjects (except in the HRZE treatment arm): Cmax, T1/2, AUC 0 - 12 | Day 12 (pre-dose, 0.5, 1, 2, 4, 8, 12 and 24 hours post-dose) for 1200 3X per week, Day 14 (pre-dose, 0.5, 1, 2, 4, 8, 12, and 24 hours post-dose) for 600 mg QD (B), and Day 14 (pre-dose, 0.5, 1, 2, 4, 8, and 12 hours post-dose) for other arms | Cmax: Maximum observed plasma drug concentration. T1/2: Half-life of elimination of the profile. AUC0-12: Area under the concentration time (t) curve from zero to 12 hours. Before calculation of AUC0-12, the 12 hour post-dose concentration will be interpolated using T1/2, if not available |
| The Bactericidal Activity (Time to Positivity) Days 0 - 2 [BA(TTP)](0-2), and Bactericidal Activity (Time to Positivity) Days 7 - 14 [BA(TTP)](7-14) | Day -2, -1, 1, 2, 7, 8, 9, 10, 11, 12, 13, 14 | \[BA(TTP)\] will be determined by the rate of change in TTP represented by the model-fitted log(TTP) as calculated by the regression of the observed log(CFU) counts over time. |
| Time over concentration that inhibits 50% of mitochondrial protein synthesis (MPS IC50) | Day 12 (1200 mg three times per week), Day 14 (all other experimental arms) | calculated for each subject in the linezolid arms individually and for each of the linezolid arms as a group, based on the established MPS IC50 for linezolid (8.0 ug/ml). |
| Correlation between AUC0-12 and AUC0-inf, Cmax and time over minimum inhibitory concentration and BA (0-2, 0-14 and 7-14) will be determined using both time to positivity and colony forming unit results, for all subjects combined. | Days -2, -1, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14 | — |
| Time over minimum inhibitory concentration (MIC) will be calculated for each subject in the linezolid arms individually and for each of the linezolid arms as a group, based on the MIC determined at baseline. | Baseline (Day -2 to -1), Day 12 (1200 mg three times per week), Day 14 (all other experimental arms) | — |
Countries
South Africa
Outcome results
None listed