A Phase I/IIa Trial to Evaluate the Safety, Tolerability, PK, and Preliminary Efficacy of Single and Multiple Ascending Doses of YN001 in Healthy Subjects and Multiple Ascending Doses of YN001 in Patient With Coronary Atherosclerosis
试验速览
- 阶段
- 1 期
- 状态
- 已完成
- 入组人数
- 144
- 试验地点
- 6
- 主要终点
- Part I: The safety and tolerability of YN001 in healthy subjects.
研究概览
简要总结
This study consists of two parts. The SAD and MAD of part I are a randomized, double-blind, placebo-controlled, single and multiple ascending dose study in healthy adult subjects. The MAD expansion cohort of part I is single arm and multipal ascending dose in heallthy subjects. Part II (phase Ib/IIa) is a multicenter, randomized, controlled, open label, multiple ascending dose study in patients with coronary atherosclerosis.
详细描述
Part I (phase Ia) is consists of 2 sections. The sections 1 is designed to evaluate the safety, tolerability, and pharmacokinetics of single and multiple ascending doses of intravenously administered YN001, and to evaluate the effect of SAD of intravenously administered YN001 on the QT/QTc interval, and the immunogenicity of MAD of intravenously administered YN001 in healthy subjects. Besides, the section 2 is designed to evaluate the safety and tolerability of multiple intravenous administration of YN001 without pre-medication or with different pre-medication regimens in Chinese healthy subjects.
Part II (phase Ib/IIa) is designed to evaluate the safety, tolerability, pharmacokinetics, preliminary efficacy, immunogenicity, and the effect on cytokine changes of MAD of intravenously administered YN001 in patients with coronary atherosclerosis.
研究设计
- 研究类型
- Interventional
- 分配方式
- Randomized
- 干预模型
- Parallel
- 主要目的
- Treatment
- 盲法
- Triple (Participant, Investigator, Outcomes Assessor)
入排标准
- 年龄范围
- 18 Years 至 75 Years（Adult, Older Adult）
- 性别
- All
- 接受健康志愿者
- 是
入选标准
- •Part I (Phase Ia)-Inclusion criteria:
- •Fully understand the purposes, features, and methods of the study and the possible adverse reactions, voluntarily participate in the study as a subject, and sign the ICF before performing any assessment.
- •Chinese healthy male or female subjects between 18 and 55 years.
- •A Body Mass Index (BMI) of 18-28 kg/m2 (inclusive), with a body weight of at least 50 kg for males and 45 kg for females.
- •Be in good general health at discretion of the investigator based on the results (be normal or abnormal without clinical significance) of medical history, physical examination, vital signs,12-lead ECG, laboratory tests (Hematology; Blood chemistry; Urinalysis, Coagulation and CRP) and viral serology.
- •Female subjects must be non-pregnant and non-lactating, and women of childbearing potential (including the male subject's female companion) must agree to use effective method of contraception from the screening period to 3 months after receiving their last dose of the investigational drug.
- •Willing and able to comply with the requirements of protocol.
- •Part I (Phase Ia)-
排除标准
- •Prior treatment with other investigational drug(s) within 3 months or 5 half-lives, whichever is longer, prior to the first dosing.
- •Prior treatment with any prescription drugs, herbal supplements, over the counter (OTC) medication, dietary supplements (vitamins included), or any type of vaccination within 2 weeks prior to the first dosing.
- •Presenting with history of severe food allergy (e.g., anaphylactic reaction). Mild (e.g., non-anaphylactic, hypersensitivity) food allergies such as lactose intolerance/ glucose intolerance are permitted.
- •Allergy to multiple kinds of drugs or presenting with history of allergic reactions to any components of the study drug.
- •Known any clinically abnormal diseases or factors, including but not limited to neurological, cardiovascular, hematological, hepatic, renal, gastrointestinal, respiratory, metabolic, endocrine, immunological, skeletal system diseases, or other reasons that, in the opinion of the investigator, makes the subject inappropriate for inclusion in this study.
- •Presenting with history of myopathy/ myalgia, or susceptible to myopathy/ rhabdomyolysis.
- •Presence of hypothyroidism.
- •Presenting and/or relapse history (within the last 3 years) of acute or chronic bronchospastic disease (including asthma and chronic obstructive pulmonary disease, treated, or not treated) or cardiac dysfunction or myocardial infarction.
- •Known inflammatory bowel disease, ulcers, gastrointestinal or rectal bleeding within 6 months prior to the first dosing.
- •Presenting with history of pancreatic injury or pancreatitis within 6 months prior to the first dosing.
- •Presence of symptoms of urinary obstruction or difficulty in voiding.
- •Presenting and/ or relapse history (within the last 3 years) of autonomic dysfunction (e.g., recurrent episodes of fainting, palpitations, etc.).
- •Evidence of major diseases that not recovered within 2 weeks prior to the first dosing, or major surgery is expected during the study.
- •Presenting with history of impaired renal function defined by clinically significantly abnormal creatinine or BUN and/ or urea values, or abnormal urinary constituents (e.g., albuminuria).
- •Presence of liver disease or liver injury, defined by abnormal liver function tests.
- •Fasting triglyceride > 3.4 mmol/L.
- •Presenting with history of clinically significant ECG abnormalities, or any of the following abnormalities at screening or baseline. QTcF>470 msec for male, QTcF>480 msec for female.
- •Hemoglobin levels are below 120 g/L for males and 110 g/L for females at screening.
- •Donation or blood loss is more than 400 mL within 3 months prior to screening.
- •Use more than 10 cigarettes per day or habitual use of nicotine-containing products within 3 months prior to screening.
- •Presenting with history of drug abuse within 12 months prior to screening, or use of any drugs within 3 months prior to screening, or a positive result of drug abuse screen at screening.
- •Consumption of more than 14 standard drinks of alcohol per week within 3 months prior to screening, or consumption of alcohol-containing products 48 hours prior to the first dosing or having positive alcohol breath test at baseline.
- •Positive for HBsAg, HCV, HIV, TP-Ab.
- •Presence of any other diseases or conditions that, in the opinion of the investigator, would make it unsuitable for the subject to participate in this study.
- •Part II (Phase Ib/IIa)-Inclusion criteria:
- •Fully understand the purposes, features, and methods of the study and the possible adverse reactions, voluntarily participate in the study as a subject, and sign the ICF before performing any assessment.
- •Chinese male or female subjects between 18 and 75 years.
- •Patients diagnosed with confirmed coronary atherosclerosis and 25-75% stenosis determined by coronary angiography.
- •Suspicion of vulnerable plaque based on clinical practice and determined by OCT examination.
- •Measurable targeted segment by estimation must be at least 40 mm in length.
- •Female subjects must be non-pregnant and non-lactating, and women of childbearing potential (including the male subject's female companion) must agree to use effective method of contraception from the screening period to 3 months after receiving their last dose of the investigational drug.
- •Willing and able to comply with the requirements of protocol.
- •Part II (Phase Ib/IIa)-Exclusion criteria:
- •Prior treatment with other investigational drug(s) within 30 days or 5 half-lives, whichever is longer, prior to the first dosing.
- •Any type of vaccination within 4 weeks prior to the first dosing.
- •Presence of moderate or heavily calcification lesion in target segment determined by coronary angiography.
- •Known familial hypercholesterolemia.
- •Relapse and highly symptomatic arrhythmia uncontrolled by drugs within the past 3 months, such as ventricular tachycardia, atrial fibrillation with rapid ventricular rate and paroxysmal supraventricular tachycardia.
- •Presenting with history of any type of stroke (cerebral lacunar infarction excluded).
- •Presenting with history of myopathy/ myalgia, or susceptible to myopathy/ rhabdomyolysis.
- •Known inflammatory bowel disease, ulcers, gastrointestinal or rectal bleeding within 6 months prior to the first dosing.
- •Presenting with history of pancreatic injury or pancreatitis within 6 months prior to the first dosing.
- •Evidence of major diseases that not recovered within 2 weeks prior to the first dosing, or major surgery is expected during the study.
- •Any surgical operation is planned during the study.
- •Presenting with history of malignancy.
- •Presence of any type of autoimmune disease.
- •Allergy to multiple food or drugs or presenting with history of allergic reactions to any components of the study drug.
- •Prior treatment with CABG, PCI, heart transplantation, SAVR/TAVR, etc., or CABG, PCI, heart transplantation, SAVR/TAVR, etc., is planned during the study.
- •Life expectancy is less than 1 year.
- •Left ventricular ejection fraction (LVEF) <40%.
- 另有 8 项未显示
研究组 & 干预措施
Part I-Matching placebo for YN001
Matching placebo for YN001 will be administrated intravenous.
干预措施: Placebo for YN001 (Drug)
YN001
YN001 will be administrated intravenous by single ascending dose, multiple ascending doses weekly or twice a week.
干预措施: YN001 (Drug)
Part II-Rosuvastatin calcium tablets
Rosuvastatin calcium tablets will be given by orally.
干预措施: rosuvastatin calcium tablets (Drug)
结局指标
主要结局
Part I: The safety and tolerability of YN001 in healthy subjects.
时间窗: Up to 29 days
To evaluate the incidence of Adverse Events as Assessed by CTCAE v5.0, Clinically Significant Laboratory Abnormalities, Clinically Significant Electrocardiogram Abnormalities, Clinically Significant Vital Signs Abnormalities, Clinically Significant Physical Examination Abnormalities.
Part I: Maximum plasma concentration(Cmax) of YN001
时间窗: Up to 168 hours of post initiation of last dose
To evaluate the pharmacokinetics (PK) characteristics of of intravenously administered YN001 in healthy subjects
Part I: Time of maximum concentration (Tmax) of YN001
时间窗: Up to 168 hours of post initiation of last dose
To evaluate the pharmacokinetics (PK) characteristics of of intravenously administered YN001 in healthy subjects.
Part I: Elimination half-life (t1/2) of YN001
时间窗: Up to 168 hours of post initiation of last dose
To evaluate the pharmacokinetics (PK) characteristics of of intravenously administered YN001 in healthy subjects.
Part I: Area under the plasma concentration-time curve from time 0 to the collection time point of the last measurable concentration (AUC0-t) of YN001
时间窗: Up to 168 hours of post initiation of last dose
To evaluate the pharmacokinetics (PK) characteristics of of intravenously administered YN001 in healthy subjects.
Part II: The safety and tolerability of intravenously administered YN001 in patients with coronary atherosclerosis.
时间窗: Up to 29 days
To evaluate the incidence of Adverse Events as Assessed by CTCAE v5.0, Clinically Significant Laboratory Abnormalities, Clinically Significant Electrocardiogram Abnormalities, Clinically Significant Vital Signs Abnormalities, Clinically Significant Physical Examination Abnormalities, Clinically Significant Echocardiogram Abnormalities.
次要结局
- Part II: Area under the plasma concentration-time curve from time 0 to the collection time point of the last measurable concentration (AUC0-t) of YN001(Up to 96 hours of post initiation of last dose)
- Part II: Change in percent atheroma volume (PAV) of coronary plaque comparing to baseline(Up to 91 days or EOT)
- Part I: C-QTc analysis(Pre-dose and up to 48 hours post initiation of infusion)
- Part I: Pharmacodynamic evaluation(Up to 96 hours of post initiation of last dose)
- Part II: Elimination half-life (t1/2) of YN001(Up to 96 hours of post initiation of last dose)
- Part I: Immunogenicity analysis(Up to 96 hours of post initiation of last dose)
- Part II: Maximum plasma concentration(Cmax) of YN001(Up to 96 hours of post initiation of last dose)
- Part II: Time of maximum concentration (Tmax) of YN001(Up to 96 hours of post initiation of last dose)
- Part II: Change in total atheroma volume (TAV) of coronary plaque comparing to baseline(Up to 91 days or EOT)
- Part II: Change in detection rate of macrophage cluster within coronary plaque comparing to baseline(Up to 91 days or EOT)
- Part II: Change in atherosclerosis plaque located at other arteries(Up to 91 days or EOT)
- Part II: Immunogenicity analysis(Up to 91 days or EOT)
- Part II： Pharmacodynamic analysis(Up to 91 days or EOT)
- Part II: Change in minimum fibrous cap thickness (FCT) of coronary plaque comparing to baseline(Up to 91 days or EOT)
- Part II: Change in maximum IMT and plaque thickness(Up to 91 days or EOT)
- Part II: Change in coronary minimal lumen area (MLA) comparing to baseline(Up to 91 days or EOT)
- Part II: Change in maximum lipid arc and lipid core length of coronary plaque comparing to baseline(Up to 91 days or EOT)
- Part II: Cytokines analysis(Up to 91 days or EOT)