A Multicenter, Open-label, Randomized, Active-controlled Clinical Study to Compare the Efficacy and Safety of Different Combination Regimens of JDB0131 Benzenesulfonate Tablets With Delamanid in Patients With Rifampin-resistant Tuberculosis (JD-RISE)
试验速览
- 阶段
- 2 期
- 状态
- 招募中
- 入组人数
- 60
- 试验地点
- 7
- 主要终点
- Percentage of Patients with Sputum Culture Conversion (SCC)
研究概览
简要总结
This is a multicenter, randomized, open-label, active-controlled clinical study designed to evaluate the efficacy, safety, and pharmacokinetic characteristics of different doses of JDB0131 benzenesulfonate tablets compared with delamanid in combination with bedaquiline, linezolid, levofloxacin (moxifloxacin)/clofazimine, etc. in the treatment of patients with drug-resistant (including rifampicin-resistant) tuberculosis for 8 weeks.
研究设计
- 研究类型
- Interventional
- 分配方式
- Randomized
- 干预模型
- Parallel
- 主要目的
- Treatment
- 盲法
- None
入排标准
- 年龄范围
- 14 Years 至 —（Child, Adult, Older Adult）
- 性别
- All
- 接受健康志愿者
- 否
入选标准
- •Age: 14 years through 65 years of age, male or female
- •Weight: 40kg ≤ weight ≤ 90kg
- •Patients with clinically confirmed pulmonary tuberculosis, Drug Susceptibility Testing (DST) results confirmed to be at least rifampicin-resistant, molecular or phenotypic DST results within 3 months before enrollment can be received
- •Sputum acid-fast bacilli smear is positive (≥2+ once or 1+ twice at least)
- •Patients who are currently taking anti-tuberculosis treatment or using drugs with anti-tuberculosis effects agree to stop all anti-tuberculosis drug treatment and complete a 7-day washout period
- •Women of reproductive age must agree to use highly effective contraceptive measures throughout the study and for at least 6 months after discontinuation of the drug. Male participants whose partners are women of reproductive age must agree to use appropriate contraceptive methods throughout the study and for at least 6 months after discontinuation of the drug (see protocol Appendix 1)
- •Fully understand the purpose and requirements of this trial, voluntarily sign the written informed consent and agree to abide by the relevant provisions of the informed consent
排除标准
- •Those who cannot take delamanid, bedaquiline, or linezolid for various reasons
- •Take delamanid, bedaquiline, or linezolid for more than 1 month (can be enrolled if evidence of no resistance to the above drugs is provided)
- •Hematogenously disseminated pulmonary tuberculosis or severe extrapulmonary tuberculosis as determined by the investigator; or patients with pulmonary tuberculosis who are assessed by the investigator to be likely to require surgical treatment within 8 weeks
- •History of torsades de pointes or risk factors, including a personal or family history of long QT syndrome (LQTS), persistent hypothyroidism, or bradycardia
- •Anyone with any of the following cardiovascular diseases or other conditions within 6 months before enrollment:
- •Myocardial infarction;
- •Heart surgery or coronary revascularization (coronary artery bypass grafting/percutaneous transluminal coronary angioplasty);
- •Unstable angina;
- •Congestive heart failure (New York Heart Association functional class III or IV);
- •Transient ischemic attack or severe cerebrovascular disease.
- •Peripheral neuropathy CTCAE grade 3 or 4; Grade 1 or 2 peripheral neuropathy that the investigator judges may progress/worsen during the study; Patients with optic neuritis
- •History of gastrointestinal surgery or resection that may affect the absorption and/or excretion of oral medications
- •Patients who are considered by the investigator to be unsuitable for this trial due to unstable or severe cardiovascular, renal, hepatic, blood, tumor, endocrine metabolic, psychiatric or rheumatic diseases
- •History of alcohol dependence or drug abuse within 6 months before screening, the investigator believes that it may affect the safety of the participants and affect the trial compliance
- •Patients who have used other clinical trial investigational drugs within 3 months before administration
- •Concomitant take drugs that cause bone marrow suppression
- •Concomitant take serotonin reuptake inhibitors, tricyclic antidepressants, serotonin, serotonin receptor agonists, and other drugs
- •Concomitant take drugs that prolong the QT interval, such as quinidine, procainamide, amiodarone, sotalol, etc.
- •Chronic systemic corticosteroid therapy, cumulative take for more than 4 weeks within 3 months before enrollment
- •Allergic to any investigational drug or related substance as confirmed by the researcher's clinical judgment
- •Women who have a positive pregnancy test during screening or are breastfeeding
- •Patients with hepatitis B virus (HBV) positive results (HBsAg, HBeAg, and HBcAb); positive hepatitis C virus (HCV) antibodies and aspartate aminotransferase (AST) or alanine aminotransferase (ALT) levels >3 times the upper limit of normal; positive Human Immunodeficiency Virus (HIV) antibody test; positive syphilis antibody test and active syphilis
- •Laboratory tests show any of the following:
- •Hemoglobin < 80 g/L;
- •platelets < 75 ✕ 109 /L;
- •Aspartate aminotransferase (AST) > 3 times the upper limit of normal;
- •Alanine aminotransferase (ALT) > 3 times the upper limit of normal;
- •Serum total bilirubin (TBIL) > 2 times the upper limit of normal;
- •Serum creatinine (Cr) > 1.5 times the upper limit of normal;
- •Serum amylase > 2 times the upper limit of normal.
- •The following abnormalities were found in the electrocardiogram (ECG):
- •At least twice QTcF intervals > 450 ms (male) or > 470 ms (female);
- •Pathological Q waves (defined as >40 ms or deep >0.4-0.5mV);
- •ECG suggests preexcitation syndrome;
- •ECG suggests left bundle branch block or right bundle branch block; or second or third degree heart block;
- •Intraventricular conduction delay with QRS duration >120ms;
- •Bradycardia with a sinus rate < 50 bpm.
- •In the investigator's judgment, any condition that affects the subject's compliance with the study protocol, or any serious medical or psychological condition that may affect the interpretation of efficacy and safety data, or any condition that may affect the subject's safety when participating in the trial
研究组 & 干预措施
Group A: BJLLfx(M)/C
Bedaquiline (B) and JDB0131 (J) and Linezolid (L) and Levofloxacin (Lfx) or (Moxifloxacin (M)) / Clofazimine (C)
Patients will take medications for 8 consecutive weeks.
Patients will be randomized based on fluoroquinolone resistance. If fluoroquinolone-susceptible, patients in group A will receive Levofloxacin (Lfx) or Moxifloxacin (M). If fluoroquinolone-resistant, patients in group A will receive Clofazimine （C）.
干预措施: JDB0131 100mg (Drug)
Group B: BJLLfx(M)/C
Bedaquiline (B) and JDB0131 (J) and Linezolid (L) and Levofloxacin (Lfx) or (Moxifloxacin (M)) / Clofazimine (C).
Patients will take medications for 8 consecutive weeks.
Patients will be randomized based on fluoroquinolone resistance. If fluoroquinolone-susceptible, patients in group A will receive Levofloxacin (Lfx) or Moxifloxacin (M). If fluoroquinolone-resistant, patients in group A will receive Clofazimine （C）.
干预措施: JDB0131 200mg (Drug)
Group C: BDLLfx/C
Bedaquiline (B) and Delamanid (D) and Linezolid (L) and Levofloxacin (Lfx) / Clofazimine (C).
Patients will take medications for 8 consecutive weeks.
Patients will be randomized based on fluoroquinolone resistance. If fluoroquinolone-susceptible, patients in group C will receive Levofloxacin (Lfx). If fluoroquinolone-resistant, patients in group C will receive Clofazimine (C).
干预措施: Delamanid (D) (Drug)
结局指标
主要结局
Percentage of Patients with Sputum Culture Conversion (SCC)
时间窗: During the 8-week treatment period and after treatment
SCC was defined as a patient without SCC at baseline who subsequently met the definition of SCC. A patient was classified as having achieved SCC if he/she achieved 2 consecutive sputum cultures negative for growth of mycobacterium tuberculosis (MTB) at least 7 days apart and had no further sputum cultures that were positive for growth within the specified time frame. Patients who have sputum cultures that were positive during treatment but only converted to negative at the end of treatment were also counted as negative.
次要结局
- Time to Sputum Culture Conversion (SCC)(During the 8-week treatment period and after treatment)
- Time to positivity (TTP)(During the 8-week treatment period and after treatment)
- Number of Participants With Clinically Significant Abnormality in Vital Signs(During the 8-week treatment period)
- Number of Participants With Clinically Significant Abnormalities in Electrocardiogram (ECG) Values(During the 8-week treatment period)
- Number of Participants With Clinical Significant Abnormality in Laboratory Test(During the 8-week treatment period)
- Number of Patients With Adverse Events (AEs) and at least one Treatment-emergent Adverse Events (TEAEs)(During the 8-week treatment period)
- Number of Patients With Serious Adverse Events (SAEs)(During the 8-week treatment period)
- Number of Participants With Any Concomitant Medication Usage(During the 8-week treatment period)
- Time to peak (Tmax)(During the 8-week treatment period (specified in protocol))
- Peak concentration (Cmax)(During the 8-week treatment period (specified in protocol))
- Area under the plasma concentration-time curve from the first medication to 12 hours (AUC0-12)(During the 8-week treatment period (specified in protocol))
- Time to peak at steady state (Tss,max)(During the 8-week treatment period (specified in protocol))
- Peak concentration at steady state (Css,max)(During the 8-week treatment period (specified in protocol))
- Trough concentration at steady state (Css,min)(During the 8-week treatment period (specified in protocol))
- Average steady-state plasma concentration (Css,avg)(During the 8-week treatment period (specified in protocol))
- Elimination half-life (t1/2,ss)(During the 8-week treatment period (specified in protocol))
- Area under the plasma concentration-time curve from the last dose to 12 hours (AUC0-12,ss)(During the 8-week treatment period (specified in protocol))
- Area under the plasma concentration-time curve from the last dose to the last measurable concentration time t (AUC0-t,ss)(During the 8-week treatment period (specified in protocol))
- Area under the plasma concentration-time curve from the last dose extrapolated to infinity (AUC0-∞,ss)(During the 8-week treatment period (specified in protocol))
- Apparent volume of distribution (Vd,ss/F)(During the 8-week treatment period (specified in protocol))
- Oral clearance (CLss/F)(During the 8-week treatment period (specified in protocol))
- Accumulation ratio: Rac(Cmax) = Cmax,ss on day 56 / Cmax on day 1(During the 8-week treatment period (specified in protocol))
- Rac (AUC) = AUC0-12,ss on day 56 / AUC0-12 on day 1(During the 8-week treatment period (specified in protocol))
- Fluctuation coefficient: fluctuation percentage at steady state = 100 * (Css,max - Css,min) / Css,avg(During the 8-week treatment period (specified in protocol))