Drug-resistant Tuberculosis
Conditions
Brief summary
A randomized, open, drug controlled design of experiments was used to evaluate the early bactericidal activity, safety, tolerance and pharmacokinetic characteristics of JDB0131 benzenesulfonate tablet taken orally by drug sensitive pulmonary tuberculosis patients. Five groups are proposed to be set up in this test (JDB0131 benzenesulfonate 100mg BID, JDB0131 benzenesulfonate 200mg QD, JDB0131 benzenesulfonate 200mg BID, anti tuberculosis drug fixed dose composite dosage QD is determined according to the weight of the study participants, and delamanid 100mg BID)
Interventions
DRUGJDB0131
JDB0131 benzenesulfonate is a new anti tuberculosis compound based on delamanid. According to the existing results of pre clinical in vitro activity, in vivo efficacy, pharmacokinetics and safety in human body, JDB0131 benzenesulfonate has the same in vivo efficacy, better lung tissue distribution and better safety as delamanid. In December 2016, JDB0131 obtained the drug clinical approval issued by the CFDA, and were approved the clinical stage research that development of drug-resistant tuberculosis adaptation.
DRUGDelamanid
Delamanid is a new drug developed by Otsuka Pharmaceutical Co., Ltd. in Japan to treat multidrug resistant tuberculosis. In 2014, Delamanid was conditionally approved for marketing by the European Medicines Agency and recommended for use in adult MDR-TB patients who cannot form an effective regimen due to drug resistance or tolerance reasons. In the same year, WHO recommended that Delamanid be conditionally used for long-term treatment of adult MDR-TB. In 2016, the WHO recommended widening the age range for Delamanid to 6-17 years old. In March 2018, Delamanid was listed in China.
DRUGEthylpyrazine rifampicide (II)
Ethylpyrazine rifampicide (II) is suitable for the first two months of intensive treatment of pulmonary tuberculosis with short-term therapy. This product is a compound preparation, consisting of 0.15g of rifampicin (C43H58N4O12), 0.075g of isoniazid (C6H7N3O), 0.4g of pyrazinamide (C5H5N3O), and 0.275g of ethambutol hydrochloride (C10H24N2O2 · 2HCl) per tablet.
Sponsors
West China Hospital
Wuhan Pulmonary Hospital
Beijing Chest Hospital
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to 65 Years
Healthy volunteers
No
Inclusion criteria
* (Those who must meet all the selection criteria can enter the group) 1. Age of study participants: 18 years old≤ age ≤ 65 years old, male or female; 2. Study participant weight: 40kg≤ body weight≤90kg 3. Patients with clinically confirmed pulmonary tuberculosis, and have not received anti-tuberculosis therapy within 2 years, at least one positive sputum acid-fast bacilli smear (AFB at least 1+); 4. Be willing to provide a blood sample for HIV testing; 5. Non-lactating and non-pregnant women who agree to use highly effective contraception throughout the study period, and male study participants must agree to use appropriate contraceptive methods throughout the study period; 6. The study participants fully understand the purpose, nature, methods and possible adverse reactions of the trial, voluntarily act as research participants, and sign informed consent; 7. Those who are willing to complete the test according to the requirements of the program.
Exclusion criteria
* (Meet any of the following criteria will be excluded) 1. Rifampicin resistance; 2. Positive for human immunodeficiency virus (HIV) antibodies; positive for hepatitis B surface antigen (HBsAg); positive for hepatitis C virus (HCV) antibodies; positive for treponemal antibodies; 3. Clear hepatobiliary disease, including but not limited to chronic active hepatitis and/or severe hepatic insufficiency; Aspartate aminotransferase (AST) or alanine aminotransferase (ALT) \> 3 times the upper limit of normal; Total serum bilirub (TBIL) \> 2 times the upper limit of normal; 4. Have a history of kidney disease or manifestations related to renal disease: 1) history of unstable or rapidly progressive kidney disease; 2) Moderate/severe renal impairment or end-stage renal disease (eGFR\<60mL/min/1.73m2); 3) Serum creatinine (Cr) ≥ 133 μmol/L (1.5 mg/mL) in men, Cr ≥ 124 μmol/L (1.4 mg/mL) in women; 5. Have a family history of QT prolongation syndrome or are taking drugs that cause QT interval prolongation, such as: quinidine, procainamide, amiodarone, sotalol, etc.; 6. ECG showed the following abnormalities: 1) QTcF\>450 ms (corrected by Fridericia formula); 2) pathological Q wave (defined as \>40ms or depth \>0.4-0.5mV); 3) ECG suggests pre-excitation syndrome; 4) ECG suggests left bundle branch block or right bundle branch block; 5) ECG shows second- or third-degree heart block; 6) QRS duration \> 120ms indoor conduction delay; 7) Sinus heart rate \< bradycardia of 50bpm; 7. Those who have any of the following cardiovascular diseases or other conditions within 6 months before enrollment: 1) myocardial infarction; 2) Cardiac surgery or coronary revascularization (coronary artery bypass grafting/percutaneous transluminal coronary angioplasty); 3) unstable angina; 4) congestive heart failure (New York Cardiology Society Cardiac Function Class III or IV); 5) transient ischemic attack or severe cerebrovascular disease; 8. Anyone who is unable to comply with the uniform diet due to allergies or special dietary requirements; 9. Those with a history of gastrointestinal surgery or resection that may affect the absorption and/or excretion of oral medications; 10. Those who have abnormal ophthalmic examination during the screening period and are judged by the investigator to be unsuitable for participating in this trial; 11. Depression: those with a score higher than 7 on the Hamilton Depression Scale (17 items, see Appendix 2); 12. Those who are judged to have any unstable or severe cardiovascular, renal, liver, hematology, tumor, endocrine metabolism, psychiatric or rheumatic diseases and therefore consider them unsuitable to participate in this trial; 13. Those who cannot control the consumption of alcohol or alcohol-containing products from 48 h before administration to the completion of the last pharmacokinetic blood sample collection, and do not consume any food or beverage containing or metabolizing caffeine or xanthines (such as coffee, strong tea, cola, chocolate); 14. Patients who have used other clinical trial study drugs within 3 months prior to administration; 15. Patients with a history of alcohol dependence or substance abuse within 6 months prior to screening, which the investigator believes may affect the safety of study participants and affect trial adherence; 16. Use of psychotropic drugs such as barbiturates, opioids, and phenothiazines within 30 days; 17. Chronic systemic corticosteroid therapy, defined as any dose of systemic corticosteroid therapy, cumulative use for more than 4 weeks in the 3 months prior to enrollment; 18. Those who are allergic to any investigational drug or related substances confirmed by the clinical judgment of the investigator; 19. Strong inducers or inhibitors of cytochrome P450 enzyme (e.g., carbamazepine, phenytoin, rifampicin, clarithromycin, ritonavir, ketoconazole, itraconazole, etc.) within 30 days before treatment; 20. Women with a positive pregnancy test or breastfeeding during screening; 21. Those who received live attenuated vaccine within 4 weeks before the study drug (except inactivated influenza vaccine such as seasonal influenza vaccine for injection); 22. Any condition that, in the judgment of the investigator, affects the study participant's adherence to the study protocol, or incorporates any serious medical or psychological condition that may affect the interpretation of efficacy and safety data, or that the study participant's participation in the trial may affect his or her own safety.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| EBA | he change of TB bacterium burden in sputum from Day 0 to Day 2 and/or Day 14 | Early bactericidal activity (EBA), counted by daily log (CFU) change |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Fluctuation coefficient | Day 0 to Day 21 | Percent fluctuation at steady state = 100 \* (Css, max - Css, min) / Css, avg. |
| Percentage of Participants With Adverse Events (AEs) | average of 6 month | An AE was defined as any new medical problem, or exacerbation of an existing problem, experienced by a participant while enrolled in the trial, whether or not it was considered drug-related by the investigator. |
| Percentage of Participants With Immediately Reportable Events (IREs) | average of 6 month | An AE was considered serious if it was fatal; life-threatening; persistently or significantly disabling or incapacitating; required in-participant hospitalization or prolonged hospitalization; a congenital anomaly/birth defect; or other medically significant event that, based upon appropriate medical judgment, may have jeopardized the participant and may have required medical or surgical intervention to prevent one of the outcomes listed above. The following were considered as IREs- serious adverse events (SAEs), pregnancies in trial participants or their partners, and all events involving overdose, misuse and abuse.problem, experienced by a participant while enrolled in the trial, whether or not it was considered drug-related by the investigator. |
| ECG | an average of 6 month | ECG QT Interval |
| Safe tolerance | through study completion, an average of 6 month | laboratory tests |
| Tmax | Day 0 to Day 21 | Time to Reach Maximal Peak Plasma Concentration for JDB0131 |
| Cmax | Day 0 to Day 21 | Maximal Peak Plasma Concentration for JDB0131 |
| AUC0-24h | Day 0 to Day 21 | Area under plasma concentration time curve from initial administration to 12 hours for JDB0131 |
| T Tss,max | Day 0 to Day 21 | Steady state peak time for JDB0131 |
| Rac（AUC） | Day 0 to Day 21 | AUC0-12,ss at day 14 compared to AUC0-12 at day 1 |
| Css,min | Day 0 to Day 21 | Steady-state valley concentration for JDB0131 |
| Css,avg | Day 0 to Day 21 | Mean steady-state blood drug concentration for JDB0131 |
| t1/2,ss | Day 0 to Day 21 | Elimination half life for JDB0131 |
| AUC0-12,ss | Day 0 to Day 21 | Area under the plasma concentration time curve from the last administration to 12 hours for JDB0131 |
| AUC0-t,ss | Day 0 to Day 21 | Area under the plasma concentration-time curve from the last dose to the last measurable concentration time t for JDB0131 |
| AUC0-∞,ss | Day 0 to Day 21 | Area under the plasma concentration-time curve from the last dose extrapolated to infinity for JDB0131 |
| Vd,ss | Day 0 to Day 21 | Apparent volume of distribution for JDB0131 |
| CL,ss | Day 0 to Day 21 | Oral clearance for JDB0131 |
| Rac（Cmax） | Day 0 to Day 21 | Ratio of Cmax,ss at day 14 to Cmax at day 1 |
| Css,max | Day 0 to Day 21 | Steady state peak concentration for JDB0131 |
Countries
China
Contacts
Primary ContactNaihui Chu, Dr.
Backup ContactMailing Huang, Dr.
Outcome results
None listed