Status and phase
Conditions
Treatments
About
The trial will evaluate the extended bactericidal activity of 14 consecutive days of oral administration of TMC207 alone, TMC207 with pyrazinamide, TMC207 with PA-824, PA-824 with pyrazinamide and PA-824 with moxifloxacin and pyrazinamide, as determined by the rate of change of log CFU in sputum over the time period Day 0-14 in participants with smear positive pulmonary tuberculosis (TB). A control group will receive standard treatment.
Enrollment
Sex
Ages
Volunteers
Inclusion and exclusion criteria
Inclusion Criteria:
Provide written, informed consent prior to all trial-related procedures including HIV testing.
Male or female, aged between 18 and 65 years inclusive.
Body weight (in light clothing and with no shoes) between 40 and 90 kg, inclusive.
Newly diagnosed, previously untreated, sputum smear-positive pulmonary TB.
A chest X-ray picture which in the opinion of the Investigator is compatible with TB.
Sputum positive on direct microscopy for acid-fast bacilli (at least 1+ on the IUATLD/WHO scale).
Ability to produce an adequate volume of sputum as estimated from a spot assessment (estimated 10 ml or more overnight production).
Females may participate if they are: 1) of non-childbearing potential (have had a bilateral oophorectomy and/or hysterectomy or have been postmenopausal for at least 12 consecutive months), 2) if they are using effective birth control methods and are willing to continue practicing birth control methods throughout treatment or 3) be non-heterosexually active, practice sexual abstinence or have a vasectomized partner (confirmed sterile). Therefore to be eligible for this study women of childbearing potential should either: 1) use a double barrier method to prevent pregnancy (i.e. use a condom with either diaphragm or cervical cap) or 2) use hormonal based contraceptives in combination with a barrier contraceptive, or 3) use an intrauterine device in combination with a barrier contraceptive. They must also be willing to continue these contraceptive measures until 6 months after the last dose of study medication or 6 months after discontinuation from study medication in case of premature discontinuation. (Note: Hormone-based contraception alone may not be reliable when taking IMP; therefore, hormone-based contraceptives alone cannot be used by female participants to prevent pregnancy).
Male participants who are having heterosexual intercourse with females of child-bearing potential are required to use one of the following birth control methods during their participation in the trial and for 12 weeks after their last dose of study medication to prevent pregnancy:
The use of the above mentioned birth control method does not apply if the male participant has been vasectomised or has had a bilateral orchidectomy minimally one month prior to screening, or is not heterosexually active, or practice sexual abstinence or if the female sexual partner has had a bilateral oophorectomy and/or hysterectomy or has been postmenopausal for at least 12 consecutive months.
Exclusion Criteria
Medical History
Evidence of clinically significant (as judged by the investigator), metabolic, gastrointestinal, cardiovascular, musculoskeletal, ophthalmological, pulmonary, neurological, psychiatric or endocrine diseases, malignancy, or other abnormalities (other than the indication being studied).
Poor general condition where any delay in treatment cannot be tolerated per discretion of the Investigator.
A history of previous TB.
Clinically significant evidence of extrathoracic TB (miliary TB, abdominal TB, urogenital TB, osteoarthritic TB, TB meningitis), as judged by the Investigator.
History of allergy to the IMP or related substances, including a known allergy to any fluoroquinolone antibiotic, history of tendinopathy associated with quinolones or suspected hypersensitivity to any rifamycin antibiotics.
Isoniazid-resistant and Rifampicin-resistant bacteria detected with a sputum specimen collected within the pre-treatment period and tested at the study laboratory.
Known or suspected, current or history of within the past 2 years, alcohol or drug abuse, that is, in the opinion of the Investigator, sufficient to compromise the safety or cooperation of the participant.
HIV infected participants:
Having participated in other clinical studies with investigational agents within 8 weeks prior to trial start.
Significant cardiac arrhythmia requiring medication.
Participants with the following at screening:
Females who are pregnant, breast-feeding, or planning to conceive a child within 6 months of cessation of treatment.
Males planning to conceive a child within twelve weeks of cessation of treatment.
History and/or presence (or evidence) of neuropathy or epilepsy.
Diabetes Mellitus requiring insulin.
History of lens opacity or evidence of lens opacity on slit lamp ophthalmologic examination.
For males, any evidence or history of a clinically significant abnormality in the reproductive system, including but not limited to the following: serum testosterone, luteinizing hormone (LH), and/or follicle-stimulating hormone (FSH) levels outside the laboratory reference range. An evaluation resulting in an isolated abnormal value (i.e., only 1 of the 3 hormones is abnormal) may be repeated using a morning (ideally, 8am) serum specimen. If the laboratory value on the repeat specimen is outside the laboratory reference range, unless the result is deemed not clinically significant by the Investigator in consultation with the Sponsor Medical Monitor, the participant should be excluded.
Specific Treatments
Previously received treatment with TMC207 or PA-824 as part of a clinical trial.
Treatment received with any drug active against MTB within the 3 months prior to Visit 1 (e.g. isoniazid, ethambutol, amikacin, cycloserine, rifabutin, rifampicin, streptomycin, kanamycin, para-aminosalicylic acid, rifapentine, pyrazinamide, thioacetazone, capreomycin, fluoroquinolones, thioamides, metronidazole).
Any diseases or conditions 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, their component or to the IMP.
Any disease or conditions in which any of the medicinal products listed in the section pertaining to prohibited medications is used.
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). The exception is moxifloxacin which is one of the drugs being evaluated in this study, with extensive ECG monitoring to help ensure patient safety.
Use of any drugs or substances within 30 days prior to dosing known to be strong inhibitors or inducers of cytochrome P450 enzymes (such as quinidine, tyramine, ketoconazole, testosterone, quinine, gestodene, metyrapone, phenelzine, doxorubicin, troleandomycin, cyclobenzaprine, erythromycin, cocaine, furafylline, cimetidine, dextromethorphan). Exceptions may be made for participants that have received 3 days or less of one of these drugs or substances, if there has been a wash-out period before administration of IMP equivalent to at least 5 half-lives of that drug or substance.
Use of any therapeutic agents known to alter any major organ function (e.g., barbiturates, opiates, phenothiazines, cimetidine) within 30 days prior to dosing.
Use of systemic glucocorticoids within one year prior to dosing.
Based on Laboratory Abnormalities
Participants with the following toxicities at screening as defined by the enhanced Division of Microbiology and Infectious Disease (DMID) adult toxicity table (November 2007):
Primary purpose
Allocation
Interventional model
Masking
85 participants in 6 patient groups
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Data sourced from clinicaltrials.gov
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