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.
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.
Study Type
INTERVENTIONAL
Allocation
RANDOMIZED
Purpose
TREATMENT
Masking
DOUBLE
Enrollment
36
Administration orally.
Administration orally.
The First Hospital of Jilin University
Changchun, Jilin, China
Safety of TNP-2092 by Assessment of the Number of Participants With Adverse Events (AEs)
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.
Time frame: Up to 17 days after the first dosing.
Maximum Observed Plasma Concentration (Cmax) of TNP-2092 Capsules in Liver Cirrhosis Patients With Hyperammonemia on Day 1.
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 frame: 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
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.
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 frame: 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
Area Under the Plasma Concentration-time Curve From the Time of Administration Extrapolated to Infinity (AUC0-∞) on Day 15
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 frame: 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
This platform is for informational purposes only and does not constitute medical advice. Always consult a qualified healthcare professional.
Time to Reach the Maximum Observed Plasma Concentration (Tmax) on Day 1
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 frame: 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
Maximum Observed Plasma Concentration (Cmax) of TNP-2092 Capsules in Liver Cirrhosis Patients With Hyperammonemia on Day 15.
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 frame: 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
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.
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 frame: 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
Time to Reach the Maximum Observed Plasma Concentration (Tmax) Day 15
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 frame: 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
Area Under the Plasma Concentration-time Curve From the Time of Administration Extrapolated to Infinity (AUC0-∞) Day 1
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 frame: 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
Half Life (t1/2) of TNP-2092 Capsules on Day 1
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 frame: 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
Half Life (t1/2) of TNP-2092 Capsules on Day 15
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 frame: 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
Area Under the Plasma Concentration-time Curve Within a Dosing Interval (AUC0-tau) on Day 1
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 frame: 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
Area Under the Plasma Concentration-time Curve Within a Dosing Interval (AUC0-tau) on Day 15
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 frame: 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
Accumulation Index Rac(Cmax) of TNP-2092 Capsules in Liver Cirrhosis Patients With Hyperammonemia
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)
Time frame: 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.
Accumulation Index Rac(AUC) of TNP-2092 Capsules in Liver Cirrhosis Patients With Hyperammonemia
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).
Time frame: 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.
Changes in the Fasting Venous Blood Ammonia Concentration From Baseline (Mean Pre-treatment Measured)
The changes in the fasting venous blood ammonia concentration from baseline will be compared with the placebo to evaluate the preliminary efficacy of TNP-2092 Capsules in liver cirrhosis patients with hyperammonemia.
Time frame: Baseline and Day 15
Proportion of Participants With Positive Result of Number Connection Test A (NCT-A)
Evaluation of NCT-A is based on the time required to complete the test. The results will be positive according to following criteria: 1) the time is over 34.3 seconds while the age is less than 35 years; 2) the time is over 45.7 seconds while the age is between 35 to 44 years; 3) the time is over 52.8 seconds while age is between 45 to 54 years; 4) the time is over 61.9 seconds while the age is between 55 to 64 years. The positive result means a worse outcome.
Time frame: Baseline, Day 7 and Day 15
Proportion of Participants With Positive Result of Digital Symbol Test (DST)
Evaluation of Digital symbol test (DST) is based on the score gained within 90 seconds, and the results are positive according to following criteria: 1) the score is less than 40.5 while the age is less than 35 years; 2) the score is less than 35.0 while the age is between 35 to 44 years; 3) the score is less than 28.5 while the age is between 45 to 54 years; 4) the score is less than 26.0 while the age is between 55 to 64 years. The positive result means a worse outcome.
Time frame: Baseline, Day 7 and Day 15
Changes in the Total Scores of Quality of Life (QOL) From Baseline
Changes in the total scores of QOL from baseline will be compared with the placebo to evaluate the preliminary efficacy of TNP-2092 Capsules in liver cirrhosis patients with hyperammonemia. The range of QOL scores is 30 \~ 150. Patients with lower scores means a better outcome.
Time frame: Baseline, Day 7 and Day 15
Proportion of Participants Whose Asterixis is Elicited
Asterixis is a physical exam finding that can be elicited by asking the participant to extend the arms, flex the wrists, and spread the fingers wide. Clinically, asterixis produces flapping tremors. In a flapping tremor, an participant will flap their wrists like a bird flapping its wings. Asterixis elicited means a worse outcome.
Time frame: Baseline, Day 7 and Day 15
Clinical Grade of Hepatic Encephalopathy
Grade 0 of HE (without HE) is nomal, Grade 0 of HE (MHE) is alterations of brain function in neuropsychological or neurophysiological measures without clinical signs of HE, Grade 1 of HE is mild lack of awareness, Grade 2 of HE is lethargic, Grade 3 of HE is somnolent, and Grade 4 of HE is coma. Higher score means worse outcome.
Time frame: Baseline, Day 7 and Day 15
Areas Under the Blood Ammonia Concentration-time Curve
Plasma concentrations of Blood Ammonia were measured by a specific and validated assay. Changes in the Fasting Venous Blood Ammonia Concentration From Baseline were used to measure AUC.
Time frame: Baseline to Day 15