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| Name | Class |
|---|---|
| The First Hospital of Jilin University | OTHER |
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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.
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.
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| Label | Type | Description | Intervention Names |
|---|---|---|---|
| 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. |
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| 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. |
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| 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. |
|
| 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. |
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| Name | Type | Description | Arm Group Labels | Other Names |
|---|---|---|---|---|
| TNP-2092 capsules | Drug | Administration orally. |
|
| Measure | Description | Time Frame |
|---|---|---|
| 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 |
| 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. | Baseline and Day 15 |
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Inclusion Criteria:
Exclusion Criteria:
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| Name | Affiliation | Role |
|---|---|---|
| Yanhua Ding, MD | The First Hospital of Jilin University | Principal Investigator |
| Facility | Status | City | State | ZIP | Country | Contacts |
|---|---|---|---|---|---|---|
| The First Hospital of Jilin University | Changchun | Jilin | China |
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| ID | Title | Description |
|---|---|---|
| FG000 | TNP-2092 Capsules 100mg Twice Daily(BID) | 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. |
| FG001 | TNP-2092 Capsules 300mg BID | 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. |
| FG002 | TNP-2092 Capsules 600mg BID | 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. |
| FG003 | TNP-2092 Capsules Placebo | 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. |
| Title | Milestones | Reasons Not Completed | ||||||||||||
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| Overall Study |
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| ID | Title | Description |
|---|---|---|
| BG000 | TNP-2092 Capsules 100mg Twice Daily(BID) | 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. |
| BG001 | TNP-2092 Capsules 300mg BID |
| Units | Counts |
|---|---|
| Participants |
|
| Title | Description | Population Description | Parameter Type | Dispersion Type | Unit of Measure | Calculate Percentage | Denominator Units Selected | Denominators | Classes |
|---|---|---|---|---|---|---|---|---|---|
| Age, Categorical | Count of Participants |
| Type | Title | Description | Population Description | Reporting Status | Anticipated Posting Date | Parameter Type | Dispersion Type | Unit of Measure | Calculate Percentage | Time Frame | Units Analyzed | Denominator Units Selected | Arm/Group Information | Denominators | Classes | Analyses | |||
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| Primary | 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. | All subjects who have received at least one dose of study drug. | Posted | Number | participants | Up to 17 days after the first dosing. |
|
17 days after the first dose
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| ID | Title | Description | Deaths (Affected) | Deaths (At Risk) | Serious Events (Affected) | Serious Events (At Risk) | Other Events (Affected) | Other Events (At Risk) |
|---|---|---|---|---|---|---|---|---|
| EG000 | TNP-2092 Capsules 100mg Twice Daily(BID) | 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. |
| Term | Organ System | Source Vocabulary | Assessment Type | Notes | Statistical Information |
|---|---|---|---|---|---|
| Gastrointestinal haemorrhage | Gastrointestinal disorders | Systematic Assessment |
| Term | Organ System | Source Vocabulary | Assessment Type | Notes | Statistical Information |
|---|---|---|---|---|---|
| neutrophil count decreased | Investigations | Systematic Assessment |
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| Title | Organization | Phone | Extension | |
|---|---|---|---|---|
| TenNor | TenNor Therapeutics (Suzhou) Limited. | 0512-86861990 | info@tennorx.com |
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| Type | Includes Protocol | Includes SAP | Includes ICF | Document Label | Document Date | Document Uploaded Date | Document File Name |
|---|---|---|---|---|---|---|---|
| Prot_SAP | Yes | Yes | No | Study Protocol and Statistical Analysis Plan | Aug 17, 2021 | Dec 4, 2023 | Prot_SAP_000.pdf |
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| ID | Term |
|---|---|
| D022124 | Hyperammonemia |
| ID | Term |
|---|---|
| D010335 | Pathologic Processes |
| D013568 | Pathological Conditions, Signs and Symptoms |
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| ID | Term |
|---|---|
| C000619733 | TNP-2092 |
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| Placebo | Drug | Administration orally. |
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| 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. |
| Proportion of Participants With Positive Result of Number Connection Test A (NCT-A) |
Evaluation of NCT-A is based on the time required to complete the test. The results will be positive according to following criteria: 1) the time is over 34.3 seconds while the age is less than 35 years; 2) the time is over 45.7 seconds while the age is between 35 to 44 years; 3) the time is over 52.8 seconds while age is between 45 to 54 years; 4) the time is over 61.9 seconds while the age is between 55 to 64 years. The positive result means a worse outcome. |
| Baseline, Day 7 and Day 15 |
| Proportion of Participants With Positive Result of Digital Symbol Test (DST) | Evaluation of Digital symbol test (DST) is based on the score gained within 90 seconds, and the results are positive according to following criteria: 1) the score is less than 40.5 while the age is less than 35 years; 2) the score is less than 35.0 while the age is between 35 to 44 years; 3) the score is less than 28.5 while the age is between 45 to 54 years; 4) the score is less than 26.0 while the age is between 55 to 64 years. The positive result means a worse outcome. | Baseline, Day 7 and Day 15 |
| Changes in the Total Scores of Quality of Life (QOL) From Baseline | Changes in the total scores of QOL from baseline will be compared with the placebo to evaluate the preliminary efficacy of TNP-2092 Capsules in liver cirrhosis patients with hyperammonemia. The range of QOL scores is 30 ~ 150. Patients with lower scores means a better outcome. | Baseline, Day 7 and Day 15 |
| Proportion of Participants Whose Asterixis is Elicited | Asterixis is a physical exam finding that can be elicited by asking the participant to extend the arms, flex the wrists, and spread the fingers wide. Clinically, asterixis produces flapping tremors. In a flapping tremor, an participant will flap their wrists like a bird flapping its wings. Asterixis elicited means a worse outcome. | Baseline, Day 7 and Day 15 |
| Clinical Grade of Hepatic Encephalopathy | Grade 0 of HE (without HE) is nomal, Grade 0 of HE (MHE) is alterations of brain function in neuropsychological or neurophysiological measures without clinical signs of HE, Grade 1 of HE is mild lack of awareness, Grade 2 of HE is lethargic, Grade 3 of HE is somnolent, and Grade 4 of HE is coma. Higher score means worse outcome. | Baseline, Day 7 and Day 15 |
| Areas Under the Blood Ammonia Concentration-time Curve | Plasma concentrations of Blood Ammonia were measured by a specific and validated assay. Changes in the Fasting Venous Blood Ammonia Concentration From Baseline were used to measure AUC. | Baseline to Day 15 |
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. |
| BG002 | TNP-2092 Capsules 600mg BID | 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. |
| BG003 | TNP-2092 Capsules Placebo | 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. |
| BG004 | Total | Total of all reporting groups |
| Participants |
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| Age, Continuous | Mean | Standard Deviation | years |
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| Sex: Female, Male | Count of Participants | Participants |
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| Race (NIH/OMB) | Count of Participants | Participants |
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| Fasting Venous Blood Ammonia Concentration | Fasting venous blood ammonia concentration before first dosing. | Mean | Standard Deviation | μmol/L |
|
| OG001 | TNP-2092 Capsules 300mg BID | 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. |
| OG002 | TNP-2092 Capsules 600mg BID | 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. |
| OG003 | Placebo | 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. |
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| Primary | 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. | All subjects who have been randomized into groups, have received at least one dose of study drug, and have at least one evaluable pharmacokinetic parameter. | Posted | Mean | Standard Deviation | ng/ml | 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 |
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| Primary | 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. | All subjects who have been randomized into groups, have received at least one dose of study drug, and have at least one evaluable pharmacokinetic parameter. | Posted | Mean | Standard Deviation | h*ng/ml | 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 |
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| Primary | 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. | All subjects who have been randomized into groups, have received at least one dose of study drug, and have at least one evaluable pharmacokinetic parameter. | Posted | Mean | Standard Deviation | h*ng/ml | 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 |
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| Primary | 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. | All subjects who have been randomized into groups, have received at least one dose of study drug, and have at least one evaluable pharmacokinetic parameter. | Posted | Mean | Standard Deviation | h | 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 |
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| Primary | 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. | All subjects who have been randomized into groups, have received at least one dose of study drug, and have at least one evaluable pharmacokinetic parameter. | Posted | Mean | Standard Deviation | ng/ml | 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 |
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| Primary | 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. | All subjects who have been randomized into groups, have received at least one dose of study drug, and have at least one evaluable pharmacokinetic parameter. | Posted | Mean | Standard Deviation | h*ng/ml | 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 |
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| Primary | 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. | All subjects who have been randomized into groups, have received at least one dose of study drug, and have at least one evaluable pharmacokinetic parameter. | Posted | Mean | Standard Deviation | h | 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 |
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| Primary | 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. | All subjects who have been randomized into groups, have received at least one dose of study drug, and have at least one evaluable pharmacokinetic parameter. | Posted | Mean | Standard Deviation | h*ng/ml | 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 |
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| Primary | 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. | All subjects who have been randomized into groups, have received at least one dose of study drug, and have at least one evaluable pharmacokinetic parameter. | Posted | Mean | Standard Deviation | h | 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 |
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| Primary | 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. | All subjects who have been randomized into groups, have received at least one dose of study drug, and have at least one evaluable pharmacokinetic parameter. | Posted | Mean | Standard Deviation | h | 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 |
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| Primary | 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. | All subjects who have been randomized into groups, have received at least one dose of study drug, and have at least one evaluable pharmacokinetic parameter. | Posted | Mean | Standard Deviation | h*ng/mL | 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 |
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| Primary | 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. | All subjects who have been randomized into groups, have received at least one dose of study drug, and have at least one evaluable pharmacokinetic parameter. | Posted | Mean | Standard Deviation | h*ng/mL | 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 |
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| Primary | 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) | All subjects who have been randomized into groups, have received at least one dose of study drug, and have at least one evaluable pharmacokinetic parameter. | Posted | Mean | Standard Deviation | ratio | 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. |
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| Primary | 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). | All subjects who have been randomized into groups, have received at least one dose of study drug, and have at least one evaluable pharmacokinetic parameter. | Posted | Mean | Standard Deviation | ratio | 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. |
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| 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. | All the subjects who were randomized into groups | Posted | Mean | Standard Deviation | μmol/L | Baseline and Day 15 |
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| Secondary | Proportion of Participants With Positive Result of Number Connection Test A (NCT-A) | Evaluation of NCT-A is based on the time required to complete the test. The results will be positive according to following criteria: 1) the time is over 34.3 seconds while the age is less than 35 years; 2) the time is over 45.7 seconds while the age is between 35 to 44 years; 3) the time is over 52.8 seconds while age is between 45 to 54 years; 4) the time is over 61.9 seconds while the age is between 55 to 64 years. The positive result means a worse outcome. | All the subjects who were randomized into groups | Posted | Count of Participants | Participants | Baseline, Day 7 and Day 15 |
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| Secondary | Proportion of Participants With Positive Result of Digital Symbol Test (DST) | Evaluation of Digital symbol test (DST) is based on the score gained within 90 seconds, and the results are positive according to following criteria: 1) the score is less than 40.5 while the age is less than 35 years; 2) the score is less than 35.0 while the age is between 35 to 44 years; 3) the score is less than 28.5 while the age is between 45 to 54 years; 4) the score is less than 26.0 while the age is between 55 to 64 years. The positive result means a worse outcome. | All the subjects who were randomized into groups | Posted | Count of Participants | Participants | Baseline, Day 7 and Day 15 |
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| Secondary | Changes in the Total Scores of Quality of Life (QOL) From Baseline | Changes in the total scores of QOL from baseline will be compared with the placebo to evaluate the preliminary efficacy of TNP-2092 Capsules in liver cirrhosis patients with hyperammonemia. The range of QOL scores is 30 ~ 150. Patients with lower scores means a better outcome. | All the subjects who were randomized into groups | Posted | Mean | Standard Deviation | score on a scale | Baseline, Day 7 and Day 15 |
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| Secondary | Proportion of Participants Whose Asterixis is Elicited | Asterixis is a physical exam finding that can be elicited by asking the participant to extend the arms, flex the wrists, and spread the fingers wide. Clinically, asterixis produces flapping tremors. In a flapping tremor, an participant will flap their wrists like a bird flapping its wings. Asterixis elicited means a worse outcome. | All the subjects who were randomized into groups | Posted | Count of Participants | Participants | Baseline, Day 7 and Day 15 |
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| Secondary | Clinical Grade of Hepatic Encephalopathy | Grade 0 of HE (without HE) is nomal, Grade 0 of HE (MHE) is alterations of brain function in neuropsychological or neurophysiological measures without clinical signs of HE, Grade 1 of HE is mild lack of awareness, Grade 2 of HE is lethargic, Grade 3 of HE is somnolent, and Grade 4 of HE is coma. Higher score means worse outcome. | All the subjects who were randomized into groups | Posted | Count of Participants | Participants | Baseline, Day 7 and Day 15 |
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| Secondary | Areas Under the Blood Ammonia Concentration-time Curve | Plasma concentrations of Blood Ammonia were measured by a specific and validated assay. Changes in the Fasting Venous Blood Ammonia Concentration From Baseline were used to measure AUC. | All the subjects who were randomized into groups | Posted | Mean | Standard Deviation | h*μmol/L | Baseline to Day 15 |
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| 0 |
| 8 |
| 0 |
| 8 |
| 6 |
| 8 |
| EG001 | TNP-2092 Capsules 300mg BID | 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. | 0 | 8 | 0 | 8 | 6 | 8 |
| EG002 | TNP-2092 Capsules 600mg BID | 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. | 0 | 8 | 0 | 8 | 7 | 8 |
| EG003 | Placebo | 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. | 0 | 12 | 1 | 12 | 8 | 12 |
| white blood cell count decreased | Investigations | Systematic Assessment |
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| Lymphocyte count decreased | Investigations | Systematic Assessment |
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| Hypoalbuminaemia | Metabolism and nutrition disorders | Systematic Assessment |
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| Platelet count decreased | Investigations | Systematic Assessment |
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| Lipase increased | Investigations | Systematic Assessment |
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| Alanine aminotransferase increased | Investigations | Systematic Assessment |
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| Aspartate aminotransferase increased | Investigations | Systematic Assessment |
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| Blood bilirubin increased | Investigations | Systematic Assessment |
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| Blood fibrinogen decreased | Investigations | Systematic Assessment |
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| Abdominal distention | Gastrointestinal disorders | Systematic Assessment |
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| Anaemia | Blood and lymphatic system disorders | Systematic Assessment |
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Not provided
Not provided
| Day 7 |
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| Day 15 |
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| Day 7 |
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| Day 15 |
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| Day 15 |
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| No |
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| Whether asterixis is elicited on Day 7 |
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| Whether asterixis is elicited on Day 15 |
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| Grade 0 of HE (MHE) |
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| Grade 1 of HE |
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| Grade 2 of HE |
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| Grade 3 of HE |
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| Grade 4 of HE |
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| Day 7 |
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| Day 15 |
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| Day 1-Day 15 |
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