Clinical trial NCT06135675: PK Profile and Preliminary Efficacy of TNP-2092 Capsules in Liver Cirrhosis Patients With Hyperammonemia
Official title: 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
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE1
PHASE2
Conditions: Hyperammonemia
Lead sponsor: TenNor Therapeutics Inc.
Sponsor class: INDUSTRY
Collaborators: name: The First Hospital of Jilin University
First posted: 2023-11-18
Enrollment: 36
Sex: ALL
Minimum age (years): 18
Maximum age (years): 65
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: SEQUENTIAL
Primary purpose: TREATMENT

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.

Eligibility criteria: 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.

Primary outcomes:
measure: Safety of TNP-2092 by Assessment of the Number of Participants With Adverse Events (AEs)
timeFrame: Up to 17 days after the first dosing.
measure: Maximum Observed Plasma Concentration (Cmax) of TNP-2092 Capsules in Liver Cirrhosis Patients With Hyperammonemia on Day 1.
timeFrame: 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
measure: 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.
timeFrame: 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
measure: Area Under the Plasma Concentration-time Curve From the Time of Administration Extrapolated to Infinity (AUC0-∞) on Day 15
timeFrame: 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
measure: Time to Reach the Maximum Observed Plasma Concentration (Tmax) on Day 1
timeFrame: 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
measure: Maximum Observed Plasma Concentration (Cmax) of TNP-2092 Capsules in Liver Cirrhosis Patients With Hyperammonemia on Day 15.
timeFrame: 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
measure: 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.
timeFrame: 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
measure: Time to Reach the Maximum Observed Plasma Concentration (Tmax) Day 15
timeFrame: 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
measure: Area Under the Plasma Concentration-time Curve From the Time of Administration Extrapolated to Infinity (AUC0-∞) Day 1
timeFrame: 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
measure: Half Life (t1/2) of TNP-2092 Capsules on Day 1
timeFrame: 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
measure: Half Life (t1/2) of TNP-2092 Capsules on Day 15
timeFrame: 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
measure: Area Under the Plasma Concentration-time Curve Within a Dosing Interval (AUC0-tau) on Day 1
timeFrame: 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
measure: Area Under the Plasma Concentration-time Curve Within a Dosing Interval (AUC0-tau) on Day 15
timeFrame: 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
measure: Accumulation Index Rac(Cmax) of TNP-2092 Capsules in Liver Cirrhosis Patients With Hyperammonemia
timeFrame: 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.
measure: Accumulation Index Rac(AUC) of TNP-2092 Capsules in Liver Cirrhosis Patients With Hyperammonemia
timeFrame: 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:
measure: Changes in the Fasting Venous Blood Ammonia Concentration From Baseline (Mean Pre-treatment Measured)
timeFrame: Baseline and Day 15
measure: Proportion of Participants With Positive Result of Number Connection Test A (NCT-A)
timeFrame: Baseline, Day 7 and Day 15
measure: Proportion of Participants With Positive Result of Digital Symbol Test (DST)
timeFrame: Baseline, Day 7 and Day 15
measure: Changes in the Total Scores of Quality of Life (QOL) From Baseline
timeFrame: Baseline, Day 7 and Day 15
measure: Proportion of Participants Whose Asterixis is Elicited
timeFrame: Baseline, Day 7 and Day 15
measure: Clinical Grade of Hepatic Encephalopathy
timeFrame: Baseline, Day 7 and Day 15
measure: Areas Under the Blood Ammonia Concentration-time Curve
timeFrame: Baseline to Day 15
Other outcomes:
Locations:
city: Changchun
country: China
facility: The First Hospital of Jilin University
state: Jilin
Study officials:
affiliation: The First Hospital of Jilin University
name: Yanhua Ding, MD
role: PRINCIPAL_INVESTIGATOR
References: