PK Effects of SHR4640 on Repaglinide and Midazolam, and the Impact of SHR4640 on QT Interval

NCT06196580 | Completed Phase 1

• 1 other identifier: SHR4640-113
• Study Type: interventional
• Target: 24
• Locations: 1 country
• Sites: 1

Brief Summary

The purpose of this study is to evaluate the PK effects of SHR4640 tablets on repaglinide and midazolam, as well as the effects of SHR4640 tablets on the QT interval in healthy subjects.

Conditions

Gout and Hyperuricemia

Outcome Measures

Primary Outcomes (4)

• The plasma PK parameters of repaglinide, midazolam, and SHR4640 in combination: Cmax

  Day 1 to Day 24

• The plasma PK parameters of repaglinide, midazolam, and SHR4640 in combination: AUC0-t

  Day 1 to Day 24

• The plasma PK parameters of repaglinide, midazolam, and SHR4640 in combination: AUC0-inf

  Day 1 to Day 24

• QTcF corrected for baseline and placebo after oral administration of SHR4640 tablets（ ΔΔ QTcF）

  Day 1 to Day 24

Secondary Outcomes (8)

• The plasma PK parameters of repaglinide, midazolam, and SHR4640 in combination: Tmax

  Day 1 to Day 24

• The plasma PK parameters of repaglinide, midazolam, and SHR4640 in combination: t1/2

  Day 1 to Day 24

• The plasma PK parameters of repaglinide, midazolam, and SHR4640 in combination: CL/F

  Day 1 to Day 24

• The plasma PK parameters of repaglinide, midazolam, and SHR4640 in combination: Vz/F

  Day 1 to Day 24

• PK parameters for oral SHR4640 tablets: Cmax

  Day 1 to Day 24

Study Arms (3)

SHR4640 group A

EXPERIMENTAL

Drug: repaglinide; midazolam; SHR4640

SHR4640 group B

EXPERIMENTAL

Drug: repaglinide; midazolam; SHR4640; SHR4640 placebo

SHR4640 Placebo

PLACEBO COMPARATOR

Drug: repaglinide; midazolam; SHR4640 placebo

Interventions

repaglinide; midazolam; SHR4640 DRUG

repaglinide; midazolam; SHR4640

SHR4640 group A

repaglinide; midazolam; SHR4640; SHR4640 placebo DRUG

repaglinide; midazolam; SHR4640; SHR4640 placebo

SHR4640 group B

repaglinide; midazolam; SHR4640 placebo DRUG

repaglinide; midazolam; SHR4640 placebo

SHR4640 Placebo

Eligibility Criteria

• Age: 18 Years - 45 Years
• Sex: all
• Healthy Volunteers: Yes
• Age Groups: Adult (18-64)

You may qualify if:

• Voluntarily sign the informed consent form before the start of the trial-related activities, and be able to understand the procedures and methods of the trial, and are willing to strictly comply with the clinical trial protocol to complete the trial;
• Aged 18 to 45 years old (both ends included, subject to the time of signing the informed consent form), male or female;
• Male weight ≥ 50 kg, female weight ≥ 45 kg, and body mass index (BMI): 19-26 kg/m2 (both ends included);
• No fertility plan and agree to take non-drug high-efficiency contraceptive measures (see appendix 1 for details) within 28 days from signing the informed consent form to the last administration of the trial drug, and no plans for sperm donation or egg donation.

You may not qualify if:

• Individuals who have a history of smoking within the 3 months before signing the informed consent form (average daily smoking\>5 cigarettes) or who cannot stop using any tobacco products during the study period;
• The average daily intake of alcohol in the three months before signing the informed consent is more than 7 g for women (about 200 ml beer, 70 ml wine or 22 ml low-alcohol liquor) and 14 g for men (about 400 ml beer, 140 ml wine or 45 ml low-alcohol liquor); Those who cannot abstain from alcohol during the trial;
• Within the first 7 days of randomization, consumed any beverage or food containing grapefruit; Or have eaten any beverages or foods containing methylxanthines, such as coffee, tea, cola, chocolate, etc., within the previous 2 days at random;
• Allergic constitution, or allergic or suspected allergic to SHR4640 tablets, repaglinide or midazolam;
• Drug abusers, or those who have positive urinary abuse during screening;
• any history of severe clinical disease or conditions that the researcher believes may affect the results of the trial, including but not limited to the history of circulatory, endocrine, nervous, digestive, urinary, or blood, immune, psychiatric, and metabolic diseases;
• Patients with contraindication of repaglinide (type 1 diabetes, C-peptide negative diabetes patients, diabetes ketoacidosis patients with or without coma);
• Patients with contraindications to midazolam (acute angle closure glaucoma, severe respiratory insufficiency, sleep apnea syndrome, myasthenia gravis, schizophrenia, and severe depressive state);
• During screening, vital signs, physical examinations, laboratory tests, cardiac ultrasound, abdominal ultrasound, or chest imaging examinations indicate the presence of abnormalities that are clinically significant according to the judgment of the investigator;
• When screening, ultrasound examination of the urinary system indicates the presence of stones or crystals in the urinary system;
• Individuals with acute kidney injury before screening or random ;
• Individuals with serum uric acid higher than 420 μmol/L at screening, , or a history of hyperuricemia and/or gout disease;
• Individuals with QTcF\>450 ms, PR interval\>200 ms, QRS complex time limit\>120 ms, or HR\>100 bpm, or other abnormalities that were clinically significant as determined by the researcher;
• Individuals with risk factors for torsade de pointe ventricular tachycardia, such as heart failure, hypokalemia, short QT syndrome, long QT syndrome, or a first-degree relatives family history of unexplained sudden death, drowning, or sudden infant death syndrome in young adulthood (≤ 40 years old);
• Individuals with positive hepatitis B surface antigen (HBsAg), or anti-hepatitis C virus (HCV) antibodies, or human immunodeficiency virus (HIV) antibodies, or syphilis antibodies during screening;

Sponsors & Collaborators

• Jiangsu HengRui Medicine Co., Ltd.: lead

Study Sites (1)

The Second Hospital of Anhui Medical University

Hefei, Anhui, 300041, China

Location

Related Publications (1)

• Cheng Y, Hu X, Pei Z, Zhang Z, Lin H, Feng S, Gao Z, Ma Y, Cao Z, Zhang Q, Zheng L, Zhang W, Shen K, Hu W. Evaluating the drug-drug interactions of SHR4640 on repaglinide and midazolam in healthy subjects. Expert Opin Drug Metab Toxicol. 2025 Jan-Feb;21(2):217-224. doi: 10.1080/17425255.2024.2428367. Epub 2024 Nov 14.

  PMID: 39530130 DERIVED

MeSH Terms

Conditions

Gout; Hyperuricemia

Interventions

repaglinide; Midazolam; ruzinurad

Condition Hierarchy (Ancestors)

Arthritis; Joint Diseases; Musculoskeletal Diseases; Crystal Arthropathies; Rheumatic Diseases; Purine-Pyrimidine Metabolism, Inborn Errors; Metabolism, Inborn Errors; Genetic Diseases, Inborn; Congenital, Hereditary, and Neonatal Diseases and Abnormalities; Metabolic Diseases; Nutritional and Metabolic Diseases; Pathologic Processes; Pathological Conditions, Signs and Symptoms

Intervention Hierarchy (Ancestors)

Benzodiazepines; Benzazepines; Heterocyclic Compounds, 2-Ring; Heterocyclic Compounds, Fused-Ring; Heterocyclic Compounds

Study Design

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

Model Details: This study is a single-center, randomized, double blind, three-period, and three-group parallel design trial, consisting of three groups (group A、 group B and placebo group).

Study Record Dates

• First Submitted: December 24, 2023
• First Posted: January 9, 2024
• Study Start: January 4, 2024
• Primary Completion: February 16, 2024
• Study Completion: February 16, 2024
• Last Updated: March 6, 2024

Record last verified: 2024-03

Locations

CN (1)