Safety and Pharmacokinetics/Pharmacodynamics of HSK3486 in Patients With Hepatic Impairment

NCT ID: NCT04145596

Last Updated: 2020-12-17

Basic Information

• Recruitment Status: COMPLETED
• Clinical Phase: PHASE1
• Total Enrollment: 24 participants
• Study Classification: INTERVENTIONAL
• Study Start Date: 2019-11-14
• Study Completion Date: 2020-07-13

Brief Summary

Comparison of the pharmacokinetics/Pharmacodynamics of the HSK3486 in Patients With Mild and Moderate Hepatic Impairment Compared with Healthy Volunteers

Detailed Description

This is a single-center, open-label, non-randomized, parallel-controlled Phase I clinical study carried out in patients with compensated chronic liver disease (Child-Pugh A), patients with decompensated chronic liver disease (Child-Pugh B), and age-, weight-, and gender-matched subjects with normal liver functions.

Conditions

Hepatic Impairment

Study Design

• Allocation Method: NON_RANDOMIZED
• Intervention Model: PARALLEL
• Primary Study Purpose: DIAGNOSTIC
• Blinding Strategy: NONE

Study Groups

Compensated Chronic Liver Disease (Child-Pugh A)

Group Type: ACTIVE_COMPARATOR

HSK3486

Intervention Type: DRUG

HSK3486，Initially 0.4 mg/kg was administered as a 1 minute bolus, followed immediately by a constant infusion dose of 0.4 mg/kg/h administered as a 30 minute infusion via infusion pump.

Decompensated Chronic Liver Disease (Child-Pugh B)

Group Type: ACTIVE_COMPARATOR

HSK3486

Intervention Type: DRUG

HSK3486，Initially 0.4 mg/kg was administered as a 1 minute bolus, followed immediately by a constant infusion dose of 0.4 mg/kg/h administered as a 30 minute infusion via infusion pump.

healthy volunteers（Normal liver functions）

Group Type: ACTIVE_COMPARATOR

HSK3486

Intervention Type: DRUG

HSK3486，Initially 0.4 mg/kg was administered as a 1 minute bolus, followed immediately by a constant infusion dose of 0.4 mg/kg/h administered as a 30 minute infusion via infusion pump.

Interventions

HSK3486

HSK3486，Initially 0.4 mg/kg was administered as a 1 minute bolus, followed immediately by a constant infusion dose of 0.4 mg/kg/h administered as a 30 minute infusion via infusion pump.

Intervention Type: DRUG

Eligibility Criteria

Inclusion Criteria

1. Sign the informed consent form and fully understand the content, procedure and possible adverse effects before the trial starts；

2. Able to complete the study in compliance with the requirements of the clinical trial protocol;

3. Subjects (including their partners) are willing to voluntarily adopt an effective measure of contraception starting from screening to 6 months after the last dose of the investigational drug.

4. Male or female subjects aged 18-64 years old (including 18 and 64 years old);

5. Male subjects weighing ≥ 50 kg, female subjects weighing ≥ 45 kg;Body mass index (BMI) = weight (kg)/height2 (m2); BMI of ≥ 18 and ≤ 30 kg/m2 (inclusive);

6. Blood pressure between 90-149/60-94 mmHg (inclusive); heart rate between 55-100 bpm (inclusive); body temperature between 35.9-37.6°C (inclusive); respiratory rate between 12-20 breaths per min (inclusive); SpO2 when inhaling ≥ 95%;

7. Normal physical examination results or abnormal physical examination results with no clinical significance;

8. For subjects with normal liver functions, their clinical laboratory tests (blood routine, blood biochemistry, urine routine, and coagulation function) should be normal or abnormal without clinical significance;

9. No potential difficult airway (modified Mallampati score of Grade I to II);

10. For subjects with normal liver functions, they should have no history of primary diseases in major organs, including but not limited to gastrointestinal, respiratory, renal, hepatic, neurological, hematological, , endocrine, oncological, immunological, psychiatric or cardiovascular and cerebrovascular diseases;

11. Child-Pugh grade A or B hepatic insufficiency caused by previous primary liver diseases: including non-alcoholic steatohepatitis and viral hepatitis (hepatitis B, hepatitis C);

12. The liver function is determined by the investigators as stable within 14 days before drug administration;

13. Have not used any drug or dosing regimen within 4 weeks before screening that can stabilize the primary liver disease.

Exclusion Criteria

1. Have not used any drug or dosing regimen within 4 weeks before screening that can stabilize the primary liver disease;

2. Patient having contraindications to deep sedation/general anesthesia or a history of past sedation/anesthesia accidents;

3. Known sensitivity to excipients in HSK3486 injectable emulsion (soybean oil, glycerin, triglyceride, egg lecithin, sodium oleate and sodium hydroxide); or with allergic constitution (including history of drug allergies and allergic diseases);

4. History of alcohol abuse (> 2 units of alcohol consumed per day: 1 unit = 285 mL of beer, or 25 mL of liquor, or 100 mL of wine) within 3 months prior to screening;

5. History of drug abuse within 3 months prior to screening, or a history of long-term use of benzodiazepines;

6. Blood/plasma donation or blood loss of ≥ 200 mL, or plasma exchange within 30 days prior to screening;

7. In receipt of prescription drugs, Chinese herbal medicines, over-the-counter drugs or food supplements (such as vitamins and calcium supplements) other than contraceptives, paracetamol, non-steroidal anti-inflammatory drugs, topical over-the-counter preparations, within 2 weeks prior to screening (patients with hepatic insufficiency can also use drugs for treating primary liver diseases);

8. Participated in other drug/medical device trials within 3 month prior to screening;

9. Patients with clinically significant abnormalities in ECG (such as tachycardia/bradycardia requiring medication, II-III degree atrioventricular block or QTcF interval ≥ 450 ms (Fridericia's correction formula), or other clinically significant abnormalities determined by the clinician);

10. Female subjects in lactation or having positive serum pregnancy test results during the screening period or the trial;

11. Positive screening result of any indicators of hepatitis B surface antigen, hepatitis C antibody or hepatitis C core antigen, HIV antibody, or syphilis antibody (hepatitis B surface antigen, hepatitis C antibody or hepatitis C core antigen may be positive for patients with hepatic insufficiency);

12. Subjects with serious or clinically significant infections (such as infections of the respiratory tract or central nervous system), trauma, or major surgery within 4 weeks prior to screening;

13. Subjects expected to have surgery or hospitalization during the trial;

14. Subjects who have consumed any beverages or foods containing alcohol (or positive alcohol breath test results), grapefruit juice or methylxanthine (such as coffee, tea, cola, chocolate, and functional drinks), participated in strenuous physical activities, and with other factors that may affect drug absorption, distribution, metabolism, and excretion within 1 day prior to dose administration;

15. Subjects with positive urine drug screening results (morphine, methamphetamine, ketamine, marijuana, ecstasy pills);

16. Subjects unsuitable for arterial blood collection, such as subjects who have positive Allen's test results;

17. Subjects who are unable to fast for 8 hrs before dose administration;

18. Subjects who have used propofol, other sedatives/anesthetics, and/or opioid analgesics or compounds containing analgesics within 72 hrs prior to dose administration;

19. Subjects judged by the investigator to be unsuitable for participating in this trial for any reason.

20. Clinical laboratory abnormalities with clinical significance, or other clinical findings showing the following illnesses with clinically significance, including but not limited to gastrointestinal, respiratory, renal, neural, hematological, endocrine, neoplastic, immunological, psychiatric or cardiovascular and cerebrovascular diseases other than primary liver diseases;

21. Patients with liver failure, or with cirrhotic combined with hepatic encephalopathy, hepatocellular carcinoma, and esophageal and gastric variceal bleeding and other complications considered by the investigator as unsuitable for the clinical study;

22. History of liver transplantation.

• Minimum Eligible Age: 18 Years
• Maximum Eligible Age: 64 Years
• Eligible Sex: ALL
• Accepts Healthy Volunteers: Yes

Sponsors

The First Hospital of Jilin University

OTHER

Sponsor Role: collaborator

Sichuan Haisco Pharmaceutical Group Co., Ltd

INDUSTRY

Sponsor Role: lead

Responsible Party

Responsibility Role: SPONSOR

Principal Investigators

Yan-hua Ding, PhD

Role: STUDY_DIRECTOR

Phase I Clinical Trial Laboratory，The First Hospital of Jilin University

Locations

Phase I Clinical Trial Laboratory, The First Hospital of Jilin University

Changchun, Jilin, China

Countries

China

References

Qin L, Ren L, Wan S, Liu G, Luo X, Liu Z, Li F, Yu Y, Liu J, Wei Y. Design, Synthesis, and Evaluation of Novel 2,6-Disubstituted Phenol Derivatives as General Anesthetics. J Med Chem. 2017 May 11;60(9):3606-3617. doi: 10.1021/acs.jmedchem.7b00254. Epub 2017 Apr 28.

Reference Type: RESULT

PMID: 28430430 (View on PubMed)

Hu Y, Li X, Liu J, Chen H, Zheng W, Zhang H, Wu M, Li C, Zhu X, Lou J, Yan P, Wu N, Liu X, Ma S, Wang X, Ding Y, Xuan C. Safety, pharmacokinetics and pharmacodynamics of a novel gamma-aminobutyric acid (GABA) receptor potentiator, HSK3486, in Chinese patients with hepatic impairment. Ann Med. 2022 Dec;54(1):2769-2780. doi: 10.1080/07853890.2022.2129433.

Reference Type: DERIVED

PMID: 36217101 (View on PubMed)

Other Identifiers

HSK3486-105

Identifier Type: -

Identifier Source: org_study_id