A Phase 1b/2a Study to Evaluate the Safety, Tolerability, PK Profile and Preliminary Efficacy of Multiple Doses of TNP-2092 Capsules in Liver Cirrhosis Patients With Hyperammonemia
试验速览
- 阶段
- 1 期
- 状态
- 已完成
- 发起方
- 入组人数
- 36
- 试验地点
- 1
- 主要终点
- Time to Reach the Maximum Observed Plasma Concentration (Tmax) Day 15
研究概览
简要总结
The aim of this study was to evaluate the safety, tolerability, and pharmacokinetic characteristics of TNP-2092 Capsules in liver cirrhosis patients with hyperammonemia; and to preliminarily observe the effects of the study drug on blood ammonia and hepatic encephalopathy related clinical symptoms and signs, neuropsychological indicators, and quality of life in liver cirrhosis patients with hyperammonemia.
详细描述
The aim of this study was to evaluate the safety, tolerability, and pharmacokinetic characteristics of TNP-2092 Capsules in liver cirrhosis patients with hyperammonemia; and to preliminarily observe the effects of the study drug on blood ammonia and hepatic encephalopathy related clinical symptoms and signs, neuropsychological indicators, and quality of life in liver cirrhosis patients with hyperammonemia.
A total of 3 dose groups will be set up, i.e., 100 mg BID, 300 mg BID and 600 mg BID groups. Drugs will be orally administered 30 min after breakfast and dinner for 14 consecutive days, and last dose will be administered 30 min after breakfast on the morning of D15. Each dose group will include a study drug TNP-2092 capsule arm and a placebo control arm. Subjects will exit upon completion of the safety and tolerability evaluation on D17.
Twelve liver cirrhosis patients with hyperammonemia are planned to be enrolled in each dose group. The 12 patients will be assigned in a ratio of 2:1 to the TNP-2092 capsule arm and the placebo arm, with 8 patients receiving TNP-2092 Capsules and 4 receiving placebos.
Enrollment for the second dose group may start only after the previous dose group has fully completed the treatment period and passed the safety and tolerability evaluation.
研究设计
- 研究类型
- Interventional
- 分配方式
- Randomized
- 干预模型
- Sequential
- 主要目的
- Treatment
- 盲法
- Double (Participant, Investigator)
入排标准
- 年龄范围
- 18 Years 至 65 Years（Adult, Older Adult）
- 性别
- All
- 接受健康志愿者
- 否
入选标准
- •18-65 (inclusive) years of age, male or female.
- •Clinically diagnosed with liver cirrhosis.
- •Fasting venous blood ammonia above upper limit of normal (ULN).
- •Organ functions must meet the following criteria:
- •Peripheral blood: absolute neutrophil count ≥ 0.5*109/L, platelet ≥20*109/L, hemoglobin ≥ 8 g/dL.
- •Liver: aspartate aminotransferase (AST) and alanine aminotransferase (ALT) ≤ 5 × ULN; serum total bilirubin (TBL) ≤ 5 × ULN.
- •Kidney: creatinine clearance ≥ 60 mL/min.
- •No malabsorption or other gastrointestinal disorders that affect drug absorption.
- •Weight ≥ 45 kg and body mass index [BMI = weight (kg)/height 2 (m2) ] between 18 and 34 (inclusive) kg/m
- •Subjects (including their partners) will have no pregnancy plan and voluntarily take effective contraceptive measures within 6 months after drug withdrawal. Refer to Appendix 9 for specific contraceptive measures.
- •Subjects or their legal representatives sign the Informed Consent Form and fully understand the content, procedures, and potential adverse reactions prior to the initiation of the study.
- •Able to complete the study per the requirements in the study protocol.
排除标准
- •Subjects who are allergic to rifamycin or quinolone antibacterial agents or those with an allergic constitution.
- •Pregnant or lactating women, or women of childbearing age with a positive pregnancy test from the screening period to initiation of the study treatment.
- •Subjects with serious nervous or mental disorders.
- •Subjects with Child-Pugh class C liver cirrhosis.
- •Subjects with Grade 2 or above hepatic encephalopathy.
- •Subjects who have been diagnosed with Clostridium difficile-induced pseudomembranous enteritis within 3 months.
- •Subjects who have had systemic infection or gastrointestinal bleeding within 7 days prior to screening.
- •Subjects with clinically significant abnormal clinical laboratory tests or other clinical findings indicative of clinically significant disorders that, in the opinion of the investigator, make them not eligible for this clinical study.
- •Subjects who have used sedatives, probiotics, cathartics or antibacterial agents within 7 days prior to screening.
- •Subjects who have used other study drugs or participated in other drug clinical trials within 1 month prior to screening.
- •Subjects need to use the following concomitant drugs during the study treatment period: cathartics and drugs for ammonia reduction listed in 5.2.1 in the Guidelines on the Management of Hepatic Encephalopathy in Liver Cirrhosis 2018 (e.g., lactulose, lactitol, L-ornithine L-aspartate(LOLA), rifaximin, other antibacterial agents, etc.) ; HIV protease inhibitors (e.g., ritonavir boosted or non-boosted saquinavir, atazanavir, darunavir, fosamprenavir, tipranavir, etc.) ; praziquantel; halothane; class IA and III antiarrhythmics (disopyramide, procainamide, quinidine, amiodarone, dofetilide, dronedarone, ibutilide, sotalol, etc.) ; strong inhibitors and inducers of liver metabolic enzymes;
- •Positive HIV antigen/antibody screen; positive Treponema pallidum antibody screen requires the investigator's judgment with the consideration of Rapid plasma regain（RPR） results.
- •Positive urine drug screen or history of drug abuse within the past 5 years.
- •Positive alcohol breath test.
- •Acute diseases or concomitant medications from screening to study medication.
- •Other circumstances deemed by the investigator to be unsuitable for enrollment in this study.
研究组 & 干预措施
TNP-2092 capsules 100mg Twice daily(BID)
Subjects received TNP-2092 capsules orally twice daily at the dose of 100 mg in the fed state for consecutive 14 days and received the last dose in the fed state on the morning of Day 15.
干预措施: TNP-2092 capsules (Drug)
TNP-2092 capsules 300mg BID
Subjects received TNP-2092 capsules orally twice daily at the dose of 300 mg in the fed state for consecutive 14 days and received the last dose in the fed state on the morning of Day 15.
干预措施: TNP-2092 capsules (Drug)
TNP-2092 capsules 600mg BID
Subjects received TNP-2092 capsules orally twice daily at the dose of 600 mg in the fed state for consecutive 14 days and received the last dose in the fed state on the morning of Day 15.
干预措施: TNP-2092 capsules (Drug)
Placebo
Subjects received TNP-2092 placebo capsules orally twice daily in the fed state for consecutive 14 days and received the last dose in the fed state on the morning of Day 15.
干预措施: Placebo (Drug)
结局指标
主要结局
Time to Reach the Maximum Observed Plasma Concentration (Tmax) Day 15
时间窗: Day 15: 30-60 min prior to the first dose, and 0.5 h, 1 h, 2 h, 3 h, 4 h, 5 h, 6 h, 8 h, 10 h, 12 h, 24 h and 36 h post-dose
Plasma concentrations of TNP-2092 were measured by a specific and validated assay. Plasma PK parameters of TNP-2092 were read directly from the plasma concentration versus time profiles or calculated by using standard non-compartmental methods.
Safety of TNP-2092 by Assessment of the Number of Participants With Adverse Events (AEs)
时间窗: Up to 17 days after the first dosing.
To investigate the safety and tolerability of TNP-2092 by assessment of the number of participants with AEs following administration of TNP-2092 capsules. An Adverse Event (AE) was defined as any untoward medical occurrence in a clinical investigation participant administered a drug; it does not necessarily have to have a causal relationship with this treatment.
Maximum Observed Plasma Concentration (Cmax) of TNP-2092 Capsules in Liver Cirrhosis Patients With Hyperammonemia on Day 1.
时间窗: Day 1: 30-60 min prior to the first dose, and 0.5 h, 1 h, 2 h, 3 h, 4 h, 5 h, 6 h, 8 h, 10 h and 12 h post-dose
Plasma concentrations of TNP-2092 were measured by a specific and validated assay. Plasma PK parameters of TNP-2092 were read directly from the plasma concentration versus time profiles or calculated by using standard non-compartmental methods.
Area Under the Plasma Concentration-time Curve From the Time of Administration to the Time of the Last Measurable Plasma Concentration (AUC0-last) on Day 1.
时间窗: Day 1: 30-60 min prior to the first dose, and 0.5 h, 1 h, 2 h, 3 h, 4 h, 5 h, 6 h, 8 h, 10 h and 12 h post-dose
Plasma concentrations of TNP-2092 were measured by a specific and validated assay. Plasma PK parameters of TNP-2092 were read directly from the plasma concentration versus time profiles or calculated by using standard non-compartmental methods.
Area Under the Plasma Concentration-time Curve From the Time of Administration Extrapolated to Infinity (AUC0-∞) on Day 15
时间窗: Day 15: 30-60 min prior to the first dose, and 0.5 h, 1 h, 2 h, 3 h, 4 h, 5 h, 6 h, 8 h, 10 h, 12 h, 24 h and 36 h post-dose
Plasma concentrations of TNP-2092 were measured by a specific and validated assay. Plasma PK parameters of TNP-2092 were read directly from the plasma concentration versus time profiles or calculated by using standard non-compartmental methods.
Time to Reach the Maximum Observed Plasma Concentration (Tmax) on Day 1
时间窗: Day 1: 30-60 min prior to the first dose, and 0.5 h, 1 h, 2 h, 3 h, 4 h, 5 h, 6 h, 8 h, 10 h and 12 h post-dose
Plasma concentrations of TNP-2092 were measured by a specific and validated assay. Plasma PK parameters of TNP-2092 were read directly from the plasma concentration versus time profiles or calculated by using standard non-compartmental methods.
Maximum Observed Plasma Concentration (Cmax) of TNP-2092 Capsules in Liver Cirrhosis Patients With Hyperammonemia on Day 15.
时间窗: Day 15: 30-60 min prior to the first dose, and 0.5 h, 1 h, 2 h, 3 h, 4 h, 5 h, 6 h, 8 h, 10 h, 12 h, 24 h and 36 h post-dose
Plasma concentrations of TNP-2092 were measured by a specific and validated assay. Plasma PK parameters of TNP-2092 were read directly from the plasma concentration versus time profiles or calculated by using standard non-compartmental methods.
Area Under the Plasma Concentration-time Curve From the Time of Administration to the Time of the Last Measurable Plasma Concentration (AUC0-last) on Day 15.
时间窗: Day 15: 30-60 min prior to the first dose, and 0.5 h, 1 h, 2 h, 3 h, 4 h, 5 h, 6 h, 8 h, 10 h, 12 h, 24 h and 36 h post-dose
Plasma concentrations of TNP-2092 were measured by a specific and validated assay. Plasma PK parameters of TNP-2092 were read directly from the plasma concentration versus time profiles or calculated by using standard non-compartmental methods.
Area Under the Plasma Concentration-time Curve From the Time of Administration Extrapolated to Infinity (AUC0-∞) Day 1
时间窗: Day 1: 30-60 min prior to the first dose, and 0.5 h, 1 h, 2 h, 3 h, 4 h, 5 h, 6 h, 8 h, 10 h and 12 h post-dose
Plasma concentrations of TNP-2092 were measured by a specific and validated assay. Plasma PK parameters of TNP-2092 were read directly from the plasma concentration versus time profiles or calculated by using standard non-compartmental methods.
Half Life (t1/2) of TNP-2092 Capsules on Day 1
时间窗: Day 1: 30-60 min prior to the first dose, and 0.5 h, 1 h, 2 h, 3 h, 4 h, 5 h, 6 h, 8 h, 10 h and 12 h post-dose
Plasma concentrations of TNP-2092 were measured by a specific and validated assay. Plasma PK parameters of TNP-2092 were read directly from the plasma concentration versus time profiles or calculated by using standard non-compartmental methods.
Half Life (t1/2) of TNP-2092 Capsules on Day 15
时间窗: Day 15: 30-60 min prior to the first dose, and 0.5 h, 1 h, 2 h, 3 h, 4 h, 5 h, 6 h, 8 h, 10 h, 12 h, 24 h and 36 h post-dose
Plasma concentrations of TNP-2092 were measured by a specific and validated assay. Plasma PK parameters of TNP-2092 were read directly from the plasma concentration versus time profiles or calculated by using standard non-compartmental methods.
Area Under the Plasma Concentration-time Curve Within a Dosing Interval (AUC0-tau) on Day 1
时间窗: Day 1: 30-60 min prior to the first dose, and 0.5 h, 1 h, 2 h, 3 h, 4 h, 5 h, 6 h, 8 h, 10 h and 12 h post-dose
Plasma concentrations of TNP-2092 were measured by a specific and validated assay. Plasma PK parameters of TNP-2092 were read directly from the plasma concentration versus time profiles or calculated by using standard non-compartmental methods.
Area Under the Plasma Concentration-time Curve Within a Dosing Interval (AUC0-tau) on Day 15
时间窗: Day 15: 30-60 min prior to the first dose, and 0.5 h, 1 h, 2 h, 3 h, 4 h, 5 h, 6 h, 8 h, 10 h, 12 h, 24 h and 36 h post-dose
Plasma concentrations of TNP-2092 were measured by a specific and validated assay. Plasma PK parameters of TNP-2092 were read directly from the plasma concentration versus time profiles or calculated by using standard non-compartmental methods.
Accumulation Index Rac(Cmax) of TNP-2092 Capsules in Liver Cirrhosis Patients With Hyperammonemia
时间窗: Day 1: 30-60 min prior to first dose, and 0.5 h, 1 h, 2 h, 3 h, 4 h, 5 h, 6 h, 8 h, 10 h, and 12 h post-dose (prior to next dose). Day 15: 30-60 min pre-dose, and 0.5 h, 1 h, 2 h, 3 h, 4 h, 5 h, 6 h, 8 h, 10 h, 12 h, 24 h and 36 h post-dose.
Plasma concentrations of TNP-2092 were measured by a specific and validated assay. Plasma PK parameters of TNP-2092 were read directly from the plasma concentration versus time profiles or calculated by using standard non-compartmental methods. Rac (Cmax) was calculated from the ratio of Cmax (Day 15) to Cmax (Day 1)
Accumulation Index Rac(AUC) of TNP-2092 Capsules in Liver Cirrhosis Patients With Hyperammonemia
时间窗: Day 1: 30-60 min prior to first dose, and 0.5 h, 1 h, 2 h, 3 h, 4 h, 5 h, 6 h, 8 h, 10 h, and 12 h post-dose (prior to next dose). Day 15: 30-60 min pre-dose, and 0.5 h, 1 h, 2 h, 3 h, 4 h, 5 h, 6 h, 8 h, 10 h, 12 h, 24 h and 36 h post-dose.
Plasma concentrations of TNP-2092 were measured by a specific and validated assay. Plasma PK parameters of TNP-2092 were read directly from the plasma concentration versus time profiles or calculated by using standard non-compartmental methods. Rac (AUC) was calculated from the ratio of AUC0-tau (Day 15) to AUC0-tau(Day 1).
次要结局
- Changes in the Fasting Venous Blood Ammonia Concentration From Baseline (Mean Pre-treatment Measured)(Baseline and Day 15)
- Proportion of Participants With Positive Result of Number Connection Test A (NCT-A)(Baseline, Day 7 and Day 15)
- Proportion of Participants With Positive Result of Digital Symbol Test (DST)(Baseline, Day 7 and Day 15)
- Changes in the Total Scores of Quality of Life (QOL) From Baseline(Baseline, Day 7 and Day 15)
- Proportion of Participants Whose Asterixis is Elicited(Baseline, Day 7 and Day 15)
- Clinical Grade of Hepatic Encephalopathy(Baseline, Day 7 and Day 15)
- Areas Under the Blood Ammonia Concentration-time Curve(Baseline to Day 15)