PK Profile and Preliminary Efficacy of TNP-2092 Capsules in Liver Cirrhosis Patients With Hyperammonemia

Phase 1

Completed

Conditions: Hyperammonemia

Interventions: Drug: TNP-2092 capsules
Drug: Placebo

Registration Number: NCT06135675

Lead Sponsor: TenNor Therapeutics (Suzhou) Limited

Brief Summary: 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.

Detailed Description: 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.

Recruitment & Eligibility

Status: COMPLETED

Sex: All

Target Recruitment: 36

Inclusion Criteria

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/m2.
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.

Exclusion Criteria

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.

Study & Design

Study Type: INTERVENTIONAL

Study Design: SEQUENTIAL

Arm && Interventions

Group	Intervention	Description
TNP-2092 capsules 100mg Twice daily(BID)	TNP-2092 capsules	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.
TNP-2092 capsules 300mg BID	TNP-2092 capsules	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.
TNP-2092 capsules 600mg BID	TNP-2092 capsules	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.
Placebo	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.

Primary Outcome Measures

Name	Time	Method
Safety of TNP-2092 by Assessment of the Number of Participants With Adverse Events (AEs)	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.	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.	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	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	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.	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.	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) Day 15	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	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	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	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	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	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	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	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).

Secondary Outcome Measures

Name	Time	Method
Changes in the Fasting Venous Blood Ammonia Concentration From Baseline (Mean Pre-treatment Measured)	Baseline and Day 15	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.
Proportion of Participants With Positive Result of Number Connection Test A (NCT-A)	Baseline, Day 7 and Day 15	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.
Proportion of Participants With Positive Result of Digital Symbol Test (DST)	Baseline, Day 7 and Day 15	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.
Changes in the Total Scores of Quality of Life (QOL) From Baseline	Baseline, Day 7 and Day 15	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.
Proportion of Participants Whose Asterixis is Elicited	Baseline, Day 7 and Day 15	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.
Clinical Grade of Hepatic Encephalopathy	Baseline, Day 7 and Day 15	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.
Areas Under the Blood Ammonia Concentration-time Curve	Baseline to Day 15	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.