Phase 2a EBA Trial of AZD5847
Phase 2a EBA Trial of AZD5847
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.
Inclusion Criteria:

 - Adults, male or female, age 18 to 65 years - Post-menopausal women under the age of 65
 years will be included in the study. Women of childbearing potential must be using or agree
 to use an adequate method of birth control through the end of study follow up. These
 methods include: total sexual abstinence; a single male partner who has been vasectomized
 combined with use of a condom; a combination of two effective birth control methods from
 the following list: a. an intrauterine device plus a condom; b. a tubal ligation (tubes
 tied) plus a condom; c. Depo-provera injections plus a condom; d. Intravaginal ring plus a
 condom - Newly diagnosed sputum smear-positive pulmonary tuberculosis as confirmed by at
 least one sputum AFB + smear (at least grade 1+ using the WHO/IUATLD grading scale) -
 Willing and able to provide informed consent - Hemoglobin >/= 8 gm/dL - Serum creatinine <
 2 mg/dL (<176.8 umol/L) - Serum AST < 3.0 times the upper limit of normal for the testing
 laboratory and total bilirubin < 1.3 mg/dL - Random blood glucose < 150 mg/dL (< 8.32
 mmol/L) - If HIV-positive, not currently on ART, CD4 count> 350 muL^-1 and/or no need to
 start ART in the opinion of the local investigator - Cough productive of at least 10 ml
 (two teaspoons) of sputum daily per patient report over the week prior to enrollment. -
 Chest radiograph compatible with pulmonary TB. - Negative sputum Xpert™ MTB/RIF test for
 rifampin resistance. - Negative urine pregnancy test

 Exclusion Criteria:

 - HIV infection with CD4 count of </=350muL^-1 and/or the need to start ART in the opinion
 of the local investigator. - Weight less than 40 kg or greater than 90 kg - Presence of
 hemoptysis. Subjects who cough up frank blood (more than blood streaked sputum) will not be
 eligible for enrollment. - Subjects with rifampin resistance as determined by the Xpert
 test as screening. - Pregnant or breastfeeding women - Presence of pneumothorax on
 pretreatment chest radiograph - Clinical suspicion of disseminated tuberculosis or
 tuberculous meningitis or pulmonary TB requiring immediate start of standard chemotherapy
 in the opinion of the local investigator - Presence of serious underlying medical illness,
 such as liver failure, renal failure,any diabetes mellitus, chronic alcoholism (> 3
 alcoholic drinks per day), decompensated heart failure, cardiac arrhythmias, hematologic
 malignancy or subjects receiving myelosuppressive chemotherapy. - Allergy or
 contraindication to study drugs - Prior treatment for TB with antituberculous medications
 (isoniazid, rifampin, pyrazinamide, ethambutol or streptomycin or those treated with other
 antibiotics with known activity against MTB during the preceding 6 months (for example
 aminoglycosides, fluoroquinolones, carbapenems and linezolid) - Subjects taking monoamine
 oxidase (MAO) inhibitors or selective serotonin release inhibitor (SSRI) medications -
 Total white blood cell count less than 3000/mm^3 - Platelet count less than 150,000/mm^3 -
 Subjects with QTcF> 450 msec, QTcF < 340 msec, and/or family history of long QT syndrome -
 Subjects unlikely in the opinion of the local investigator to be able to comply with the
 requirements of the study protocol - Subjects whose urine tests positive for INH
 metabolites, indicating they are already receiving anti-TB treatment. - History of
 tuberculosis less than 5 years ago, history of more than one episode of tuberculosis,
 history of drug resistant tuberculosis, or household contact with an individual who has
 confirmed drug-resistant tuberculosis. - Known arrhythmias or other cardiac conditions -
 Active severe dermatologic disease (Grade 3 or Grade 4 per DMID Adult Toxicity Table) -
 Immunosuppressive conditions or receiving immunosuppressive medications - A history of
 optic neuritis. - Subjects on antiretroviral therapy for HIV (including AZT, 3TC, FTC, D4T,
 ddI, ddC, tenofovir, abacavir, nevirapine, efavirenz, ritonavir, lopinavir, atazanavir,
 saquinavir, darunavir, indinavir, raltegravir) - Subjects taking drugs capable of
 prolonging the QTc interval, such as type Ia and III anti-arrhythmics - Random urine
 toxicology screen positive for cocaine or methamphetamines.