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

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

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.

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.