Safety, Tolerability, Extended Early Bactericidal Activity and PK of Higher Doses Rifampicin in Adults With Pulmonary TB (HR1)

This is an interventional treatment trial for Pulmonary Tuberculosis (TB) focused on measuring Dose Ranging, Extended Early Bactericidal Activity, Maximum tolerable dose, Pharmacokinetics, Pulmonary Tuberculosis, Rifampicin, Rifafour, Safety, Tolerability, Max Tolerable Dose Read More

Inclusion Criteria:

1. The patient is able and willing to provide written, informed consent prior to all trial-related procedures including HIV testing.
2. The patient is aged between 18 and 65 years, inclusive.
3. The patient has a body weight (in light clothing and with no shoes) between 40 and 85 kg, inclusive.
4. The patient is a newly diagnosed, previously untreated, uncomplicated, sputum smear-positive, pulmonary TB patient.
5. The patient has a normal chest X-ray or a picture which in the opinion of the Investigator is compatible with TB.
6. The patient is sputum positive on direct microscopy for acid-fast bacilli (at least 1+ on the IUATLD/WHO scale (Appendix 4)).
7. The patient is able to produce an adequate volume of sputum as estimated from a spot assessment (estimated 10 ml or more overnight production).
8. The patient has a negative serum pregnancy test (female subjects of childbearing potential only)
9. The patient agrees to use a highly effective method of birth control (i.e. two of the following precautions: tubal ligation, vaginal diaphragm, intrauterine device, condom, oral contraceptives, contraceptive implant, combined hormonal patch, combined injectable contraceptive or depot-medroxyprogesterone acetate, partner(s) has/have had a vasectomy) throughout the participation in the trial and for 1 week after last dose, unless she and her partner(s) are sterile (that is, women who have had a bilateral oophorectomy and/or hysterectomy or have been postmenopausal for at least 12 consecutive months; men who have had bilateral orchidectomy).
10. A Karnofsky score of at least 60 (requires occasional assistance but is able to care for most of his/her needs).

Exclusion Criteria:

1. The patient is in poor general condition where any delay in treatment cannot be tolerated per discretion of the Investigator.
2. Rifampicin-resistant bacteria have been detected in the patient's sputum specimen collected within the Pre-Treatment Period and tested at the study laboratory.
3. The patient has received treatment with any drug active against MTB within the 3 months prior to Visit 1: isoniazid, ethambutol, amikacin, cycloserine, rifabutin, rifampicin, streptomycin, kanamycin, para-aminosalicylic acid, rifapentine, pyrazinamide, thioacetazone, capreomycin, quinolones, thioamides.
4. The patient has a history of allergy to isoniazid, ethambutol, rifampicin and pyrazinamide,
5. The patient has a history of previous TB.
6. The patient has Hepatitis B.
7. The patient had Hepatitis C.
8. The patient is infected with HIV and has a CD4 count < 350 cells/uL (Visit 1).
9. The patient is receiving antiretroviral therapy (ART).
10. The patient has been taking rifampicin within 30 days prior to Visit 1.
11. The patient is a diabetic using insulin.
12. The patient is pregnant or breast-feeding (female patients only).
13. The patient has a history and/or presence (or evidence) of neuropathy or epilepsy.

14. The patient has a history of or current clinically relevant cardiovascular disorder such as:

    1. heart failure, coronary heart disease, hypertension, arrhythmia, tachyarrhythmia or status after myocardial infarction.
    2. family history of sudden death of unknown or cardiac-related cause, or of prolonged QTc interval.
15. Concomitant use of any drug known to prolong QTc interval (including amiodarone, bepridil chloroquine, chlorpromazine, cisapride, clarithromycin, disopyramide dofetilide, domperidone, droperidol, erythromycin, halofantrine, haloperidol, ibutilide, levomethadyl, mesoridazine, methadone, pentamidine, pimozide, procainamide, quinidine, sotalol, sparfloxacin, thioridazine).
16. The patient has any disease or condition in which the use of the standard TB drugs or any of their components is contra-indicated, including but not limited to allergy to any TB drug or their components.
17. There is clinically significant evidence of extrathoracic TB (miliary TB, abdominal TB, urogenital TB, osteoarthritic TB, TB meningitis), as judged by the Investigator.
18. Evidence of serious lung conditions other than TB or uncontrolled obstructive bronchial disease.
19. The patient has clinically relevant changes in the ECG such as atrioventricular (AV) block, prolongation of the QRS complex over 120 milliseconds, or of either the QTcF or QTcB interval over 450 milliseconds on the screening ECG.
20. There is any evidence showing that the patient has renal impairment, including but not limited to serum creatinine levels above the upper limit of the laboratory reference range.
21. The patient has abnormal alanine aminotransferase (ALT) and/or aspertate transferase (AST) levels > 1 times the upper limit of the laboratory reference range (at Visit 1).
22. There is evidence showing the patient has clinically significant metabolic, gastrointestinal, neurological, psychiatric or endocrine diseases, malignancy, or other abnormalities (other than the indication being studied).
23. The patient has any disease or condition in which any of the medicinal products listed in the section pertaining to prohibited medication is used.
24. The patient has a known or suspected, current or history of drug or amphetamine abuse, within the past 2 years, that is, in the opinion of the Investigator, sufficient to compromise the safety or cooperation of the patient.
25. The patient has a known or suspected current history of significant alcohol consumption, i.e. more than 20 units/week, within the past 2 years.
26. The patient used any drugs or substances known to be strong inhibitors or inducers of cytochrome P450 enzymes within 30 days prior to Visit 4 (including xenobiotics, quinidine, tyramine, ketoconazole, testosterone, quinine, gestodene, metyrapone, phenelzine, doxorubicin, troleandomycin, cyclobenzaprine, erythromycin, cocaine, furafylline, cimetidine, dextromethorphan). Exceptions may be made for patients who have received 3 days or less of one of these drugs or substances, if there has been a wash-out period prior to Visit 4 equivalent to at least 5 half-lives of that drug or substance.
27. The patient used any therapeutic agents known to alter any major organ function (e.g., barbiturates, phenothiazines, cimetidine) within 14 days prior to Visit 4.