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

Hyperammonemia Clinical Trial

Official title:

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

Clinical Trial Details — Status: Completed

Administrative data

• NCT number: NCT06135675
• Other study ID #: TNP-2092-06
• Status: Completed
• Phase: Phase 1/Phase 2
• Start date: August 27, 2020
• Est. completion date: June 12, 2021

Study information

• Verified date: December 2023
• Source: TenNor Therapeutics Inc.
• Contact: n/a
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial 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.

Recruitment information / eligibility

• Status: Completed
• Enrollment: 36
• Est. completion date: June 12, 2021
• Est. primary completion date: June 12, 2021
• Accepts healthy volunteers: No
• Gender: All
• Age group: 18 Years to 65 Years

Eligibility

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.

Related Conditions & MeSH terms

• Hyperammonemia
• Liver Cirrhosis

Intervention

Drug:
• TNP-2092 capsules
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.
• TNP-2092 capsules Placebo
TNP-2092 capsules Placebo 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.

Locations

Country	Name	City	State
China	The First Hospital of Jilin University	Changchun	Jilin

Sponsors (1)

Lead Sponsor	Collaborator
TenNor Therapeutics (Suzhou) Limited

Country where clinical trial is conducted

China, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	Maximum Observed Plasma Concentration (Cmax) of TNP-2092 Capsules in Liver Cirrhosis Patients With Hyperammonemia on 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
Primary	Area Under the Plasma Concentration-time Curve From the First Administration to the Last Measurable Plasma Concentration (AUC0-last) on 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
Primary	Area Under the Plasma Concentration-time Curve From the First Administration Extrapolated to Infinity (AUC0-8) 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
Primary	Time to Reach the Maximum Observed Plasma Concentration (Tmax) 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
Primary	Maximum Observed Plasma Concentration (Cmax) of TNP-2092 Capsules in Liver Cirrhosis Patients With Hyperammonemia on 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
Primary	Area Under the Plasma Concentration-time Curve From the First Administration to the Last Measurable Plasma Concentration (AUC0-last) on 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
Primary	Time to Reach the Maximum Observed Plasma Concentration (Tmax) 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
Primary	Area Under the Plasma Concentration-time Curve From the First Administration Extrapolated to Infinity (AUC0-8) 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
Secondary	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