Tolerability, Efficacy, and PK of ZSP1601 in Patients With Non-Alcoholic Steatohepatitis (NASH)

Study Overview
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Brief Summary
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Double-blind, randomized, placebo-controlled study to explore the safety, tolerability PK characteristics and early efficacy of ZSP1601 tablets in patients with non-alcoholic steatohepatitis (NASH).

Official Title
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A Multi-center, Randomized, Double-blind, Dose-increasing, Placebo-controlled，Multi-dose, 28-day Continuous Administration Phase Ib/IIa Clinical Trial to Evaluate the Tolerability, Efficacy, and PK of ZSP1601 in Patients With Nonalcoholic Steatohepatitis

Conditions
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Non-Alcoholic Steatohepatitis (NASH)

Intervention / Treatment
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* Drug: ZSP1601
* Drug: ZSP1601 Placebo


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Subjects are required to meet the following criteria in order to be included in the trial: Signature signed informed consent before the trial, and fully understood the content, process and possible adverse reactions. Subjects must be willing and able to adhere to the visit schedule and protocol requirements and be available to complete the study. Subjects(including partners)have no gestation plans and must use reliable methods of contraception during the study and until 6 months following the last dose of investigational product. Male and female subjects aged 18-65 (including 18 and 65). B ultrasound confirmed fatty liver. NASH diagnosis or NASH phenotypic diagnosis. Liver fat ≥10% at baseline (MRI-PDFF) Exclusion Criteria: Eligible subjects must not meet any of the following exclusion criteria: Excessive drinking for 3 consecutive months within 1 year before screening. Allergic constitution. Subjects who donated blood or bleeding profusely(> 400 mL)in the 3 months preceding study screening. Subjects having a history of bariatric surgery or preparing for bariatric surgery recently. Subjects having a history of liver transplantation or plans for liver transplantation Any diseases that increase the risk of bleeding, such as hemorrhoids, acute gastritis or gastric and duodenal ulcers. Liver biopsy indicates cirrhosis or previous clinical diagnosis of cirrhosis. Type 1 diabetes mellitus. Uncontrolled type 2 diabetes mellitus (HbA1c≥8.0%)。 Any clinically significant abnormality upon physical examination or in the clinical laboratory tests, history or presence of other causes of liver disease,but not limited to above disorders: hepatitis b or hepatitis c virus (HCV) infection and chronic alcoholic liver disease, drug-induced liver disease, autoimmune hepatitis, primary biliary cirrhosis, primary sclerosing cholangitis, Wilson 's disease, alpha 1 - antitrypsin deficiency, liver, obvious abnormal liver function (ALT and AST acuity 5 x ULN or TBIL acuity 1.5 x ULN), etc. Dysphagia or any medical history in gastrointestinal that interferes with the absorption of drugs. History of having any special food(including dragon fruit,mango,grapefruit,etc.),strenuous exercises,or other factors may interfere with the absorption, distribution, metabolism, or excretion of drug within 2 weeks prior to screening. Participated in another clinical research study and received any investigational products within 3 months prior to dosing. Presence of clinically significant abnormalities in ECG or QTcB>450ms in males,or QTcB>470ms in females. HIV positive. Clinically significant nephropathy or renal dysfunction, blood creatinine >1.5×ULN, eGFR< 60 mL/min/1.73m2 [calculation formula: Ccr:(140-age)× weight (kg) /0.818×Scr(mumol /L), female ×0.85]. Platelet count <100×109/L. Antinuclear antibody (ANA) confirmed positive and clinically significant. Abnormal TSH with clinical significance. Female during pregnancy and lactation or positive serum pregnancy test. Patients with contraindication of MRI scan. Take any product contains alcohol within 24 hours prior to dosing. Have chocolate, any food or beverage that contains caffeine or xanthine within 24 hours prior to dosing. Positive for urine drug screening or history of substance abuse for a period of 5 consecutive years before screening. Any acute illness or concomitant medication from screening to first dosing. As judged by the researcher, it is not suitable to join the clinical researcher.

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: Parallel Assignment
Masking: Quadruple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: ZSP1601-Dose 1<br>ZSP1601-50mg once daily | Drug: ZSP1601<br>* ZSP1601 tablets be taken orally for 28 days.<br>Drug: ZSP1601 Placebo<br>* Subjects will receive matching placebo of ZSP1601<br>|
| Experimental: ZSP1601-Dose 2<br>ZSP1601-50mg twice daily | Drug: ZSP1601<br>* ZSP1601 tablets be taken orally for 28 days.<br>Drug: ZSP1601 Placebo<br>* Subjects will receive matching placebo of ZSP1601<br>|
| Experimental: ZSP1601-Dose 3<br>ZSP1601-100mg once daily | Drug: ZSP1601<br>* ZSP1601 tablets be taken orally for 28 days.<br>Drug: ZSP1601 Placebo<br>* Subjects will receive matching placebo of ZSP1601<br>|
| Placebo Comparator: Placebo<br>Placebo | Drug: ZSP1601 Placebo<br>* Subjects will receive matching placebo of ZSP1601<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Number and severity of treatment-emergent adverse events (TEAEs) and Serious Adverse Events(SAE) following oral doses of ZSP1601 and placebo. | severity of treatment-emergent adverse events (TEAEs) and Serious Adverse Events(SAE) | Initiation of study treatment (Day 1) up to 2 weeks post-treatment. | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| MRI-PDFF | liver fat content with Magnetic resonance imaging proton density fat fraction (MRI-PDFF) | Baseline and Day 28. | 
| TNF-α | Tumor necrosis factor alpha level in serum | Baseline and Day 28. | 
| ALT | serum Alanine Aminotransferase | Baseline and Day 28. | 
| AST | serum Aspartate Aminotransferase | Baseline and Day 28. | 
| Tmax | The time after dosing when Cmax occurs (Tmax) | Day1 and day 14 | 
| Cmax | Maximum Contentration | Day1 and day 14 | 
| t1/2z | t1/2z is defined as the time to decline half of the drug concentration in plasma. | Day1 and day 14 | 
| Rac of Cmax | Rac of ZSP1601 Peak Plasma Concentration at steady state | Day1 and day 14 | 
| DF of ZSP1601 at steady status | Multiple-dose plasma PK parameter: DF of ZSP1601 at steady status | Day1 and day 14 | 
| AUClast（AUC0-t） | AUClast is defined as the concentration of drug from time zero to the last quantifiable concentration. | Baseline (0h) and day 14 | 
| Rac of AUC | RAC of ZSP1601 Area under the plasma concentration versus time curve at steady state | Day1 and day 14 |