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

NCT06135675 | Completed Phase 1 Results

• 1 other identifier: TNP-2092-06
• Study Type: interventional
• Target: 36
• Locations: 1 country
• Sites: 1

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.

Conditions

Hyperammonemia

Outcome Measures

Primary Outcomes (15)

• 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.

  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.

  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.

  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.

  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) 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.

  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.

  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.

  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.

  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.

  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.

  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.

  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.

  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.

  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)

  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).

  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.

Secondary Outcomes (7)

• Changes in the Fasting Venous Blood Ammonia Concentration From Baseline (Mean Pre-treatment Measured)

  Baseline and Day 15

• Proportion of Participants With Positive Result of Number Connection Test A (NCT-A)

  Baseline, Day 7 and Day 15

• Proportion of Participants With Positive Result of Digital Symbol Test (DST)

  Baseline, Day 7 and Day 15

• Changes in the Total Scores of Quality of Life (QOL) From Baseline

  Baseline, Day 7 and Day 15

• Proportion of Participants Whose Asterixis is Elicited

  Baseline, Day 7 and Day 15

Study Arms (4)

TNP-2092 capsules 100mg Twice daily(BID)

EXPERIMENTAL

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.

Drug: TNP-2092 capsules

TNP-2092 capsules 300mg BID

EXPERIMENTAL

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.

Drug: TNP-2092 capsules

TNP-2092 capsules 600mg BID

EXPERIMENTAL

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.

Drug: TNP-2092 capsules

Placebo

PLACEBO COMPARATOR

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.

Drug: Placebo

Interventions

TNP-2092 capsules DRUG

Administration orally.

Also known as: Rifaquizinone capsules

TNP-2092 capsules 100mg Twice daily(BID); TNP-2092 capsules 300mg BID; TNP-2092 capsules 600mg BID

Placebo DRUG

Administration orally.

Also known as: TNP-2092 placebo capsules

Placebo

Eligibility Criteria

• Age: 18 Years - 65 Years
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• (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.

You may not qualify if:

• 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.

Sponsors & Collaborators

• TenNor Therapeutics (Suzhou) Limited: lead
• The First Hospital of Jilin University: collaborator

Study Sites (1)

The First Hospital of Jilin University

Changchun, Jilin, China

Location

MeSH Terms

Conditions

Hyperammonemia

Interventions

TNP-2092

Condition Hierarchy (Ancestors)

Pathologic Processes; Pathological Conditions, Signs and Symptoms

Results Point of Contact

• Title: TenNor
• Organization: TenNor Therapeutics (Suzhou) Limited.

info@tennorx.com

0512-86861990

Study Officials

• Yanhua Ding, MD

  The First Hospital of Jilin University

  PRINCIPAL INVESTIGATOR

Publication Agreements

• PI is Sponsor Employee: No
• Restrictive Agreement: No

Study Design

• Study Type: interventional
• Phase: phase 1
• Allocation: RANDOMIZED
• Masking: DOUBLE
• Who Masked: PARTICIPANT, INVESTIGATOR
• Purpose: TREATMENT
• Intervention Model: SEQUENTIAL
• Sponsor Type: INDUSTRY
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: November 13, 2023
• First Posted: November 18, 2023
• Study Start: August 27, 2020
• Primary Completion: June 16, 2021
• Study Completion: June 16, 2021
• Last Updated: April 25, 2025
• Results First Posted: May 10, 2024

Record last verified: 2025-04

Data Sharing

• IPD Sharing: Will not share

Locations

CN (1)