Influence of JY09 on Pharmacokinetics of Metformin , Rosuvastatin , and Digoxin and the QT Interval Study in Overweight Chinese Subjects

Evaluation of the Effects of Exendin-4 Fc Fusion Protein (JY09) Injection on the Pharmacokinetic Profiles of Metformin Hydrochloride Tablets, Rosuvastatin Calcium Tablets, and Digoxin Tablets and on the QT Interval in Overweight Chinese Subjects

This trial is conducted in china. The aim of the trial is as follows:

• To assess the effect of multiple subcutaneous injections of JY09 injection on the pharmacokinetic (PK) profile of multiple oral doses of metformin hydrochloride tablets, a single oral dose of Rosuvastatin calcium tablets, or digoxin tablets in overweight Chinese subjects;
• To assess the effect of multiple subcutaneous injections of JY09 injection on QT interval in overweight Chinese subjects.

Study Overview

• Status: Active, not recruiting
• Conditions: Diabetes Mellitus, Type 2; Overweight
• Intervention / Treatment: Drug: Exendin-4 Fc fusion protein (JY09) injection; Drug: Metformin Hydrochloride tablet; Drug: Rosuvastatin calcium tablets; Drug: Digoxin tablet

• Study Type: Interventional
• Enrollment (Actual): 28
• Phase: Phase 1

Contacts and Locations

Study Locations

• China
  • Beijing
    • Beijing, Beijing, China
      • Peking University Third Hospital drug clinical trial Institute

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: Adult
• Accepts Healthy Volunteers: Yes

Description

Inclusion Criteria:

1. Age: Overweight subjects with full capacity for civil behavior who are ≥ 18 years old and ≤ 45 years old (the ratio of the number of subjects of either sex is not less than 1/3).
2. Body weight: men ≥ 50.0 kg, women ≥ 45.0 kg, body mass index (BMI) ≥ 24.0 kg/m2 and ≤ 28.0 kg/m2 , BMI = weight (kg)/height (m2 ).
3. Those who do not plan to have children in the last 6 months, do not plan to donate sperm/eggs, and are willing to use effective contraception for 6 months after the end of dosing.
4. Fully understand the trial and possible adverse effects, have the ability to communicate normally with the investigator, as well as comply with study requirements, follow protocol procedures and limitations, and be able to visit on time.
5. Understand the content of the informed consent form, agree to participate in this trial and voluntarily sign the consent form.

Exclusion Criteria:

1. A clear history of central nervous system, cardiovascular system, renal, hepatic, pulmonary, metabolic, and musculoskeletal disorders or other notable diseases.
2. Individuals with gastrointestinal disorders, such as history of hepatobiliary disease, history of gastrointestinal disease, history of gastrointestinal surgery (except appendectomy) or history of chronic pancreatitis or idiopathic acute pancreatitis, and those with habitual diarrhea.
3. Previous tip-twisting ventricular tachycardia or other risk factors that can lead to malignant arrhythmias, or a family history of first-degree relatives (i.e., biological parents, siblings, or children) with short QT syndrome, long QT syndrome, unexplained sudden death, drowning, or sudden infant death syndrome in young adulthood (less than/equal to 40 years of age), or cardiac conduction block.
4. Have disorders of electrolyte metabolism such as hyperkalemia, hypokalemia, hypomagnesemia, hypomagnesemia, hypercalcemia or hypocalcemia.
5. If the results of vital signs (blood pressure, pulse, respiration, temperature) are abnormal and clinically significant, a retest is allowed to confirm the results if they are abnormal, and the abnormal values of each vital sign.
6. Physical examination, laboratory tests, 12-lead electrocardiogram (ECG), abdominal ultrasound, calcitonin and chest radiographs (orthopantomograms) suggesting the presence of abnormalities judged by the investigator to be clinically significant (retesting was allowed once).
7. Smokers who smoked an average of more than 5 cigarettes per day in the 3 months prior to screening or who could not give up smoking during their participation in the trial or who had a positive smoke test.
8. Those who have participated in other clinical trials as a subject within 3 months prior to screening.
9. Those who donated blood or blood products ≥400 mL within 3 months prior to screening.
10. Those who cannot tolerate venipuncture and have a history of needle and blood sickness.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Non-Randomized
• Interventional Model: Crossover Assignment
• Masking: None (Open Label)

Number of Arms

1

Arms and Interventions

Participant Group / Arm

Intervention / Treatment

Experimental: Exendin-4 Fc fusion protein (JY09) injection; D22 received a single subcutaneous abdominal injection of 1.2 mg of JY09 injection after completion of PK blood sampling; D29 to D78 received continuous subcutaneous abdominal injections of 2.4 mg of JY09 injection in the morning, once weekly (total of 8 administrations). All doses were to be administered within 3 min.

Drug: Exendin-4 Fc fusion protein (JY09) injection; D22 received a single subcutaneous abdominal injection of 1.2 mg of JY09 injection after completion of PK blood sampling; D29, D36, D43, D50, D57, D64, D71, and D78 subjects returned to the study center to receive a subcutaneous abdominal injection of 2.4 mg of JY09 injection(total of 8 administrations).All doses were to be administered within 3 min.; Other Names: JY09; Drug: Metformin Hydrochloride tablet; D1 to D4 continuous oral administration of 0.5 g metformin hydrochloride tablets twice daily (D4 was administered only in the morning, with a total of 7 administrations) for a washout period of 96 h;0.5 g metformin hydrochloride tablets orally twice a day continuously from D85 to D88 (D88 was given only in the morning, for a total of 7 doses).; Other Names: Metformin; Drug: Rosuvastatin calcium tablets; D8 received a single oral administration of 10 mg of Rosuvastatin calcium tablets in the morning, with a washout period of 168 h,and 10 mg Rosuvastatin calcium tablets orally at 72 h ± 0.5 h (D95) after JY09 administration.; Other Names: Rosuvastatin; Drug: Digoxin tablet; D15 received a single oral administration of 0.25 mg digoxin tablets in the morning, with a washout period of 168 h,oral 0.25 mg digoxin tablets 72 h±0.5 h after JY09 administration (D102); Other Names: digoxin

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
The Metformin Peak Concentration (Cmax )	The peak concentration(Cmax） is the highest level of plasma concentration that occurs after administration.This parameter is an important index to reflect the absorption rate and degree of drug in vivo.	During a dosing interval (0-36 hours) after the last of 7 repeated doses of metformin without JY09 exposure (Day 4) and at JY09 steady state (Day 88)
Area under the Metformin blood concentration-time curve	AUC refers to the area under the drug time curve, which is the area surrounded by the pharmacokinetic blood concentration curve to the time axis. This parameter is an important index to evaluate the degree of drug absorption, reflecting the exposure characteristics of drugs in vivo.	During a dosing interval (0-36 hours) after the last of 7 repeated doses of metformin without JY09 exposure (Day 4) and at JY09 steady state (Day 88)
The Rosuvastatin Peak Concentration (Cmax )	The peak concentration(Cmax） is the highest level of plasma concentration that occurs after administration.This parameter is an important index to reflect the absorption rate and degree of drug in vivo.	From time 0 to 96 hours after a single dose of Rosuvastatin without JY09 exposure (Day 8) and at JY09 steady state (Day 95)
Area under the Rosuvastatin blood concentration-time curve	Area under curve(AUC) refers to the area under the drug time curve, which is the area surrounded by the pharmacokinetic blood concentration curve to the time axis. This parameter is an important index to evaluate the degree of drug absorption, reflecting the exposure characteristics of drugs in vivo.	From time 0 to 96 hours after a single dose of Rosuvastatin without JY09 exposure (Day 8) and at JY09 steady state (Day 95)
The Digoxin Peak Concentration (Cmax )	The peak concentration(Cmax） is the highest level of plasma concentration that occurs after administration.This parameter is an important index to reflect the absorption rate and degree of drug in vivo.	From time 0 to 168 hours after a single dose of Digoxin without JY09 exposure (Day 15) and at JY09 steady state (Day 102)
Baseline-corrected difference of Corrected QT interval after multiple subcutaneous injections of JY09 injection	Corrected QT interval is a QT interval adjusted by heart rate, which is an index of cardiac depolarization and repolarization	From time 0 to 72 hours after a single dose of JY09 (Day 22) and at JY09 steady state (Day 92)

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Safety endpoint-Adverse events	All adverse medical events occurring after the subject receives the experimental drug, which may be manifested as symptoms, signs, diseases, or abnormalities in laboratory tests, but may not necessarily have a causal relationship with the experimental drug.	From baseline (Day -1) to follow-up (Day 123)
Vital signs-Blood pressure	Blood pressure includes systolic and diastolic blood pressure.	From baseline (Day -1) to follow-up (Day 123)
Vital signs-Pulse	Pulse refers to the pulsation formed in the arteries when the heart contracts, due to the flow of blood from the heart into the arteries. Pulse is one of the vital signs of human body, and it is an important index to measure heart rate and blood pressure.	From baseline (Day -1) to follow-up (Day 123)
Vital signs-Respiration	Respiration refers to the process of gas exchange between the body and the outside world.	From baseline (Day -1) to follow-up (Day 123)
Physical examination	Include general condition, skin, neck (including thyroid), head (including eyes, ears, nose, throat), chest, abdomen, back, lymph nodes, limbs, and nervous system.	From baseline (Day -1) to follow-up (Day 123)
Laboratory tests-Routine blood	Blood routine refers to the examination of blood conditions and diseases by observing the changes in the number and morphological distribution of blood cells.	From baseline (Day -1) to follow-up (Day 123)
Laboratory tests-Blood biochemistry	Blood biochemical examination can determine the content of sugars, lipids, hormones, ions and other substances in the blood, and provide help for the diagnosis and treatment of diseases.	From baseline (Day -1) to follow-up (Day 123)
Laboratory tests-Urine routine	Urine routine is of great significance not only for the observation of the curative effect of the diagnosis of urinary system diseases, but also for the diagnosis and prognosis of other system diseases.	From baseline (Day -1) to follow-up (Day 123)
Laboratory tests-coagulation function	The coagulation function test is mainly to find out whether the clotting factors in the patient's body are abnormal.	From baseline (Day -1) to follow-up (Day 123)
12-lead electrocardiogram (ECG)	Electrocardiogram (ECG) is an objective index of the occurrence, propagation and recovery of cardiac excitation. It is used for the examination of various arrhythmias, ventricular and atrial hypertrophy, myocardial infarction, arrhythmia, myocardial ischemia and other diseases.	From baseline (Day -1) to follow-up (Day 123)
Immunogenicity	Immunogenicity refers to the performance that can cause an immune response, that is, the antigen can stimulate specific immune cells, so that immune cells activation, proliferation, differentiation, and eventually produce immune effecting substances antibodies and sensitized lymphocytes.	From baseline (Day -1) to follow-up (Day 123)

Other Outcome Measures

Outcome Measure	Measure Description	Time Frame
Area Under the Effect Curve from time 0 to the last measurable concentration (AUEC0-t )	AUEC0-t is a Pharmacodynamics -related endpoint for glucose, C-peptide and insulin in the Oral glucose tolerance test (OGTT),which reflects the amount of exposure to the effect.	From time 0 to 240 minutes after Oral glucose(Day21) and Oral glucose(Day84).
The Peak Effect Concentration(ECmax）	ECmax is a Pharmacodynamics -related endpoint for glucose, C-peptide and insulin in the Oral glucose tolerance test (OGTT),which reflects the maximum effective concentration.	From time 0 to 240 minutes after Oral glucose(Day21) and Oral glucose(Day84).
Maximum Effect Time(ETmax )	ETmax is a Pharmacodynamics -related endpoint for glucose, C-peptide and insulin in the Oral glucose tolerance test (OGTT),which reflects the time of the first maximum effect.	From time 0 to 240 minutes after Oral glucose(Day21) and Oral glucose(Day84).
(AUEC0-t after JY09 administration - AUEC0-t before JY09 administration)/AUEClast before JY09 administration ×100%(Δ%AUEC0-t)	Δ%AUEC0-t is a Pharmacodynamics -related endpoint for glucose, C-peptide and insulin in the Oral glucose tolerance test (OGTT), which reflects changes in the amount of effect exposure before and after administration.	From time 0 to 240 minutes after Oral glucose(Day21) and Oral glucose(Day84).
(post-administration Maximum Effect(Emax)- pre-administration Maximum Effect(Emax))/pre-administration Maximum Effect(Emax)×100%(Δ%Emax )	Δ%Emax is a Pharmacodynamics -related endpoint for glucose, C-peptide and insulin in the Oral glucose tolerance test (OGTT), which reflects changes in maximum effects before and after administration.	From time 0 to 240 minutes after Oral glucose(Day21) and Oral glucose(Day84).
Body fat mass	Body fat mass refers to the amount of fat in a person's body.	Day19 or Day20,Day103 or Day104.
Body fat percentage	Body fat percentage refers to fat content as a percentage of total body weight.	Day19 or Day20,Day103 or Day104.
Fat-free weight	Fat-free weight refers to the body weight after the removal of fat, also known as lean body weight, is the weight of other body components other than fat.	Day19 or Day20,Day103 or Day104.
Skeletal muscle mass	Skeletal muscle mass is the percentage of skeletal muscle in the body, and can be used to determine health status.	Day19 or Day20,Day103 or Day104.
Waist-to-hip ratio	Waist-to-hip ratio is the ratio between waist and hip circumference and is an important indicator of central obesity.	Day19 or Day20,Day103 or Day104.
Visceral fat area	Visceral fat area is an indicator used to assess the degree of abdominal obesity in an individual, and it can be measured in a number of ways, such as CT (computed tomography) or MRI (magnetic resonance imaging). This area of adipose tissue around the abdomen is associated with the risk of a number of chronic diseases such as heart disease and diabetes.	Day19 or Day20,Day103 or Day104.
Pharmacodynamically relevant plasma endogenous markers（If necessary）	The investigator will use JY09 PK residual or backup plasma samples from this trial to assay efficacy-related endogenous marker concentrations to support individualized dosing of JY09.	From time 0 to 72 hours after a single dose of JY09 (Day 22) and at JY09 steady state (Day 92) and Day21，Day29，Day43，Day83
Pharmacodynamically relevant plasma metabolomics(if necessary)	The investigator will use JY09 PK residual or backup plasma samples from this trial to assay efficacy-related metabolomics to support individualized dosing of JY09.	From time 0 to 72 hours after a single dose of JY09 (Day 22) and at JY09 steady state (Day 92) and Day21，Day29，Day43，Day83
Blood Cell Genotype Characterization (if necessary)	Blood cell samples after centrifugation at each time point of the immunogenicity assay were retained for each subject so that they could be used for genotypic testing at a later stage, if necessary, to support individualized dosing of JY09.	Day21，Day29，Day43，Day83
Bacteria genus	Species of bacteria in intestinal flora.	Day21 or Day22,Day84 or Day85
Relative abundance	Relative abundance of genera and strains of bacteria	Day21 or Day22,Day84 or Day85

Collaborators and Investigators

• Sponsor: Beijing Dongfang Biotech Co., Ltd.

Study record dates

Study Major Dates

• Study Start (Actual): October 19, 2023
• Primary Completion (Estimated): April 7, 2024
• Study Completion (Estimated): April 7, 2024

Study Registration Dates

• First Submitted: January 22, 2024
• First Submitted That Met QC Criteria: January 30, 2024
• First Posted (Actual): February 8, 2024

Study Record Updates

• Last Update Posted (Actual): February 8, 2024
• Last Update Submitted That Met QC Criteria: January 30, 2024
• Last Verified: January 1, 2024

More Information

Terms related to this study

• Keywords: QT Interval; JY09
• Additional Relevant MeSH Terms: Glucose Metabolism Disorders; Metabolic Diseases; Endocrine System Diseases; Diabetes Mellitus; Overnutrition; Nutrition Disorders; Body Weight; Diabetes Mellitus, Type 2; Overweight; Hypoglycemic Agents; Physiological Effects of Drugs; Molecular Mechanisms of Pharmacological Action; Anti-Arrhythmia Agents; Enzyme Inhibitors; Antimetabolites; Hormones; Hormones, Hormone Substitutes, and Hormone Antagonists; Protective Agents; Cardiotonic Agents; Anticholesteremic Agents; Hypolipidemic Agents; Lipid Regulating Agents; Hydroxymethylglutaryl-CoA Reductase Inhibitors; Calcium-Regulating Hormones and Agents; Anti-Obesity Agents; Incretins; Digoxin; Rosuvastatin Calcium; Calcium; Metformin; Exenatide
• Other Study ID Numbers: dfbt-jy09-ow-2023-101

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: NO

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No