Safety, Tolerability, Pharmacokinetic Characteristics and Preliminary Efficacy of TNP-2092 Capsules in Liver Cirrhosis Patients With Hyperammonemia

Study Overview
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Brief Summary
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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.

Official Title
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A Phase 1b/2a, Single-center, Randomized, Double-blind, Placebo-controlled Study to Evaluate the Safety, Tolerability, Pharmacokinetic Characteristics and Preliminary Efficacy of Multiple Ascending Doses of TNP-2092 Capsules in Liver Cirrhosis Patients With Hyperammonemia

Conditions
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Hyperammonemia

Intervention / Treatment
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* Drug: TNP-2092 placebo capsules
* Drug: TNP-2092 capsules


Participation Criteria
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Eligibility Criteria
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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.

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 65 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Sequential Assignment
Masking: Double


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: TNP-2092 capsules 100mg Twice daily(BID)<br> | Drug: TNP-2092 capsules<br>* TNP-2092 capsules 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.<br>|
| Experimental: TNP-2092 capsules 300mg BID<br> | Drug: TNP-2092 capsules<br>* TNP-2092 capsules 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.<br>|
| Experimental: TNP-2092 capsules 600mg BID<br> | Drug: TNP-2092 capsules<br>* TNP-2092 capsules 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.<br>|
| Placebo Comparator: TNP-2092 placebo capsules<br> | Drug: TNP-2092 placebo capsules<br>* TNP-2092 placebo capsules 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.<br>* Other names: rifaquizinone;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Maximum observed plasma concentration (Cmax) of TNP-2092 capsules in liver cirrhosis patients with hyperammonemia on Day 1 and 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 and 12 h post-dose | 
| Area under the plasma concentration-time curve from the first administration to the last measurable plasma concentration (AUC0-last) on Day 1 and 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 and 12 h post-dose | 
| Area under the plasma concentration-time curve from the first administration extrapolated to infinity (AUC0-∞) Day 1 and 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 and 12 h post-dose | 
| Time to reach the maximum observed plasma concentration (Tmax) Day 1 and 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 and 12 h post-dose | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| 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. | Day 15 |