Early Bactericidal Activity Safety Pulmonary Tuberculosis Pyrifazimine (TBI-166)
Early Bactericidal Activity Safety Pulmonary Tuberculosis Pyrifazimine (TBI-166)
The new drug pyrifazimine (previous name: TBI-166) developed by the Institute of Materia
 Medica of the Chinese Academy of Medical Sciences which is Beijing Union Pharmaceutical
 Second Factory relied on is obtained by retaining the key skeleton of the lead drug
 clofazimine which can exert its efficacy and modification by introducing moderate polar
 groups structural. While the drug has strong activity against tuberculosis-sensitive bacteria
 and drug-resistant bacteria in vivo and in vitro, its pharmacokinetic properties and skin
 staining side effects have been significantly improved compared with the lead drugs, so that
 the drug can achieve the goal that reducing fat solubility, accelerating metabolism in the
 body, reducing skin staining and reducing side effects. In addition, pyrifazimine has a weak
 effect on liver drug enzymes, and is suitable for combined use in the clinical treatment of
 tuberculosis. The development of the drug is expected to provide a new method for the
 clinical treatment of drug-resistant tuberculosis, benefit patients, and produce good social
 benefits.

 In November 2016, the new anti-drug-resistant tuberculosis drug pyrifazimine and its tablets
 (formerly chemical drug registration classification 1.1) obtained the drug clinical approval
 issued by the CFDA (batch number: 2016L10025/2016L09987), and were approved the clinical
 stage research that development of drug-resistant tuberculosis adaptation.

 In accordance with relevant requirements of drug registration regulations, technical
 guidelines, etc., this project has completed the safety, tolerability, and pharmacokinetic
 clinical trials of a single dose of pyrifazimine tablets in healthy subjects, i.e. Phase Ia
 clinical trials test.
Inclusion Criteria:

 -  (Those who must meet all the selection criteria can enter the group)

 1. People who volunteer to participate in this trial and sign an informed consent
 form;

 2. The range of the age is from 18 to 65 years old, regardless of gender;

 3. The weight range of the patient who wear lightweight clothing and no shoes is
 from 40 to 90 Kg;

 4. The patient is diagnosed with (initial treatment) tuberculosis, and the untreated
 sputum smear is 2+ or 2 times 1+ or more;

 5. Chest x-ray examination results are consistent with tuberculosis;

 6. Molecular tests show positive for Mycobacterium tuberculosis (e.g. GeneXpert or
 Hain) or positive for sputum culture;

 7. Women in the reproductive period have a negative urine pregnancy test and agree
 to use high-efficiency contraception during the study period;

 8. Male patients must agree to use appropriate contraceptive methods.

 Exclusion Criteria:

 -  (Meet any of the following criteria will be excluded)

 1. Those who cannot tolerate treatment delay;

 2. Those who have used any drugs that are effective against Mycobacterium
 tuberculosis within 3 months before screening;

 3. History of allergy to clofazimine, rifamycin and its derivatives, isoniazid,
 pyrazinamide or ethambutol;

 4. Use any drugs or substances known to be strong inhibitors or inducers of
 cytochrome P450 enzymes within 30 days before administration (Including but not
 limited to quinidine, tyramine, ketoconazole, fluconazole, testosterone, quinine,
 progesterone, Methitione, phenpromazine, doxorubicin, trilithomycin,
 erythromycin, cocaine, furanilide, cimetidine, dextromethorphan);

 5. Resistance to isoniazid and rifampicin;

 6. Any disease or symptom that contradicts the use of rifampicin, isoniazid,
 pyrazinamide or ethambutol;

 7. Severe extrapulmonary tuberculosis (blood disseminated tuberculosis, digestive
 system tuberculosis, genitourinary tuberculosis, bone and joint tuberculosis,
 tuberculosis meningitis, etc.);

 8. There is evidence of silicosis, pulmonary fibrosis or other lung diseases
 considered by researchers to be serious (except tuberculosis);

 9. The patient has chronic obstructive pulmonary disease or asthma;

 10. Any clinically relevant concomitant circumstances or renal impairment
 characterized by serum creatinine level ≥1.5xULN, or liver damage with ALT and/or
 AST level ≥3×ULN and/or GGT level ≥3×ULN within the laboratory reference range;

 11. History of alcohol abuse [weekly alcohol intake is greater than 21 units/week
 (male) and 14 units/week (female) (1 unit=360mL beer; or 150mL glucose wine; or
 45mL white wine)], or the subject is unwilling to stop drinking from 24 hours
 before the start of the study to the end of the study, or had a positive alcohol
 breath test at the time of enrollment;

 12. Subjects with liver, kidney, metabolism, autoimmune diseases, neurological,
 mental, blood system diseases, malignant tumors, long-term immunosuppressive
 agents;

 13. People with a history of drug abuse or a positive urine drug screening;

 14. Screening positive for hepatitis B, HIV, HCV virus and Treponema pallidum
 antibody;

 15. Those who have a history of fainting needles and are judged to be clinically
 significant by the investigator;

 16. Participated in clinical research of other drugs or devices three months before
 the start of the trial;

 17. The subject has the following characteristics at the time of screening (according
 to the measurement and reading of the central electrocardiogram):

 1. The QT/QTc interval is significantly prolonged, for example, the QTcF (Fridericia
 correction) or QTcB (Bazett correction) interval is confirmed to be >450 ms
 during screening;

 2. Has a history of Ventricular tachycardia torsades de pointes, such as heart
 failure, hypokalemia, long QT syndrome, etc.;

 3. Uses any drug known to extend the QTc interval 30 doses before the medication.
 (Not limited to amiodarone, bepridil, chloroquine, chlorpromazine, cisapride,
 cyclobenzaprine, clarithromycin, dipyrazine, doperidol, erythromycin, fluorine
 alcohol, Haloperidol, ibutilide, levamisole, methadone, mesalamide, pimozine,
 procaine, quinine, sotalol, sparfloxacin, thiazide);

 4. The investigator judges that any ECG abnormalities of clinical significance.