A Phase 2 interventional study of AZD5847 and Ethambutol, isoniazid, pyrazinamide, rifampin in Tuberculosis, sponsored by National Institute of Allergy and Infectious Diseases (NIAID). Completed at 1 site in South Africa. Open to participants aged 18 Years to 65 Years. Per ClinicalTrials.gov, last updated 2018-10-15.
Sponsored by National Institute of Allergy and Infectious Diseases (NIAID) · Phase 2, Interventional, and Treatment
The purpose of this study is to assess the early bacterial activity (EBA) from day 0 to day 14 of Astra Zeneca Drug (AZD5847) at four different doses and schedules (500 mg once daily, 500 mg twice daily, 1200 mg once daily, and 800 mg twice daily) in subjects with newly-diagnosed sputum smear positive pulmonary TB. A total of 75 subjects will be enrolled, with 15 randomized to each AZD5847 study arm or standard treatment with Rifafour. Duration of drug treatment is 14 days.
This is a study of early bactericidal activity (EBA) in treatment-naïve patients with active pulmonary tuberculosis. This prospective, randomized, open-label study that will compare the effect of monotherapy with each of four dose levels of AZD5847 to that of an active control (Rifafour administered orally once daily) on the concentration of Mycobacterium tuberculosis (M. tb) in expectorated sputum (colony-forming units per mL of sputum). Daily quantitative sputum cultures will be performed during treatment and analyzed by investigators who will be blinded to the assigned treatment. The duration of therapy will be 14 days in order to support an assessment of early bactericidal activity (days 0-2) and sterilizing activity (days 3-14). Because of the risk of emergence of drug resistance in TB patients treated with a single active drug, regulatory and ethical requirements restrict monotherapy to a maximum duration of 14 days (EMEA Draft TB Guidance 2008). The study will utilize a standard design and will thus support comparison with other marketed and investigational antimycobacterial agents (Donald and Diacon 2008). The primary aim of the study is to assess the EBA 0-14 of AZD5847 at four different doses and schedules (500 mg once daily, 500 mg twice daily, 1200 mg once daily, and 800 mg twice daily) in subjects with newly-diagnosed sputum smear positive pulmonary TB. The secondary aim is to assess the EBA 0-2 and EBA 2-14 of AZD5847 at the above doses.
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This study's enrollment of 75 is below the median of 150 across 952 interventional studies indexed under Tuberculosis.
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Exclusion Criteria:
AZD5847 500 mg orally once daily given to 15 male and female subjects aged 18 to 65 years with newly diagnosed sputum smear positive pulmonary tuberculosis
Drug: AZD5847
AZD5847 500 mg orally twice daily given to 15 male and female subjects aged 18 to 65 years with newly diagnosed sputum smear positive pulmonary tuberculosis
Drug: AZD5847
AZD5847 1200 mg orally once daily given to 15 male and female subjects aged 18 to 65 years with newly diagnosed sputum smear positive pulmonary tuberculosis
Drug: AZD5847
AZD5847 800 mg orally twice daily given to 15 male and female subjects aged 18 to 65 years with newly diagnosed sputum smear positive pulmonary tuberculosis
Drug: AZD5847
Rifafour e-275 mg tablets given to 15 male and female subjects aged 18 to 65 years with newly diagnosed sputum smear positive pulmonary tuberculosis
Drug: Ethambutol, isoniazid, pyrazinamide, rifampin
Eligible subjects will be randomly assigned to receive monotherapy with one of four doses of oral AZD5847 for 14 days: 500 mg orally once daily, 500 mg orally twice daily, 1200 mg orally once daily, or 800 mg orally twice daily.
Eligible subjects will be randomly assigned to receive treatment with standard 4 drug anti-tuberculosis regimen: Rifafour e-275 mg tablets (75 mg isoniazid/150 mg Rifampin/275 mg Ethambutol/400 mg Pyrazinamide) orally, dosed by body weight for 14 days.
Early Bactericidal Activity: Rate of change in sputum colony forming unit (CFU) counts (bactericidal activity) during the entire 14 days of study drug administration (EBA0-14)
Time frame: Day 0 to Day 14
Adverse event collection: Complete blood count, coagulation panels, liver function tests, Creatine phosphokinase, urinalysis and 12-lead electrocardiograms as well as unsolicited events (adverse events, serious adverse events).
Time frame: Day 0 to Day 28
Change in Mycobacterium tuberculosis (MTB) mRNA in sputum by RT-PCR for fbpB, hspX, icl1, rrnA-p1 and other specific mycobacterial mRNA targets of interest over the periods (baseline and Days 2, 4, 8, 14)
Time frame: Baseline and Days 2, 4, 8, 14
Change in urine, sputum, and serum metabolomic biomarkers over the periods (baseline and Days 8, 14)
Time frame: Baseline and Days 8, 14
Pharmacokinetic and pharmacodynamic parameters Tmax, Cmax, half life, AUC, AUC/MIC, Cmax, Cmax/MIC, time > MIC using non-compartmental analysis, compartmental and population models
Time frame: Day 1, 3, 5, 10 and 14
Rate of change in sputum CFU counts (bactericidal activity) during the first 2 days of study drug administration (traditional EBA; EBA0-2)
Time frame: Day 0 to Day 2
Rate of change in sputum CFU counts (bactericidal activity) during the first 2 to 14 days of study drug administration (traditional EBA; EBA2-14)
Time frame: Day 2 to Day 14
The change in time after inoculation until culture detection (time to detection; TTD) in MGIT enriched liquid culture media over the period Day 0 to Day 2
Time frame: Day 0 to Day 2
The change in time after inoculation until culture detection (time to detection; TTD) in MGIT enriched liquid culture media over the period Day 2 to Day 14
Time frame: Day 2 to Day 14
The change in time after inoculation until culture detection (time to detection; TTD) in Mycobacterial Growth Indicator Tube (MGIT) enriched liquid culture media over the period Day 0 to Day 14
Time frame: Day 0 to Day 14
This study is completed, as verified in Mar 2014. You cannot join it, but the record below documents what was studied.
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National Institute of Allergy and Infectious Diseases (NIAID)