A Phase 1, First-in-human, Randomized, Placebo Controlled, Double Blind, Single Ascending Dose (SAD) Study to Evaluate the Safety, Tolerability, Pharmacokinetics, Pharmacodynamics and Immunogenicity of AV-380 in Healthy Subjects
试验速览
- 阶段
- 1 期
- 状态
- 已完成
- 入组人数
- 51
- 试验地点
- 1
- 主要终点
- Clinical laboratory measurements - Blood chemistry - calcium
研究概览
简要总结
This double-blinded, placebo-controlled, single ascending dose (SAD) study is designed to evaluate the safety, pharmacokinetics (PK), pharmacodynamics (PD), and immunogenicity in healthy subjects of a single dose of AV-380. AV-380 is an immunoglobulin (Ig) G1 monoclonal antibody (mAb) intended to bind circulating human growth differentiation factor 15 (GDF-15), a cytokine involved in cancer-induced cachexia.
研究设计
- 研究类型
- Interventional
- 分配方式
- Randomized
- 干预模型
- Sequential
- 主要目的
- Treatment
- 盲法
- Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
入排标准
- 年龄范围
- 18 Years 至 50 Years（Adult）
- 性别
- All
- 接受健康志愿者
- 是
入选标准
- •Healthy male and female volunteers, 18 to 50 years of age, inclusive.
- •A body mass index (BMI) between 18 and 30 kg/m2 and weight between 60 and 90 kg.
- •Healthy as indicated by a comprehensive clinical assessment (detailed medical history and complete physical examination). Supine blood pressure (BP), heart rate (HR), electrocardiogram (ECG) intervals and routine laboratory tests within the normal range of the study center (see Appendix 4) or considered not clinically significant by the Investigator. Alanine aminotransferase (ALT), aspartate aminotransferase (AST), and total bilirubin must be < 1.5 times the upper limit of the normal range (ULN). Total bilirubin, if above 1.5 x ULN, is only acceptable with a history of Gilbert's Syndrome.
- •Non-smoker or ex-smoker for longer than 6 months.
- •Sexually active pre-menopausal female subjects and female partners of male subjects must use adequate contraceptive measures, while on study and for at least 100 days after the IMP administration. Sexually active male subjects must use adequate contraceptive measures, while on study and for at least 160 days after the last dose of IMP. All fertile male and female subjects and their partners must agree to use a highly effective method of contraception. Effective birth control includes hormonal contraception (oral, intravaginal, transdermal, injectable or implantable), intrauterine device (IUD) plus one barrier method; or 2 barrier methods. Effective barrier methods are male or female condoms, diaphragms, and spermicides (creams or gels that contain a chemical to kill sperm). Vasectomy (at least 3 months before IMP administration) and vasectomized partner (provided that the partner is the sole sexual partner of the trial participant and that the absence of sperm in the ejaculate has been confirmed) are acceptable methods of contraception, as well as post-menopausal female for at least 1 year (confirmed with serum follicle stimulating hormone [FSH] > 25.8 IU/L at screening), or surgically sterilized female subjects. Abstinence is not an acceptable contraception method. Female subjects who are of non-childbearing potential due to a surgical procedure or medical condition must provide documentation, and vasectomized male subjects must bring in the surgical report of the procedure.
- •Able to sign and understand an ICF and able to comply with study restrictions prior to selection.
排除标准
- •Presence or history of any disorder that may prevent the successful completion of the study.
- •Clinically significant abnormalities in laboratory test results (including hepatic and renal panels, complete blood count, chemistry panel and urinalysis), such as:
- •White blood cell count < 3.0x109/L.
- •Neutrophils < 1.5x109/L or clinically abnormal according to the subject's ethnic group (must be > 1.0x109/L for subjects of African descent).
- •Hemoglobin < 10 g/dL.
- •Platelet count < 125x109/L or > 450x109/L.
- •ALT > 1.5 ULN.
- •AST > 1.5 ULN.
- •Total bilirubin > 1.5 ULN (except in the presence of Gilbert's syndrome).
- •Creatinine > 1.2 ULN.
- •Sodium < 132 mmol/L or > 147 mmol/L.
- •Potassium < 3.2 mmol/L or > 5.5 mmol/L.
- •Chloride < 93 mmol/L or > 111 mmol/L.
- •Calcium < 8.3 mmol/L or > 10.7 mmol/L. Clinically significant abnormal values for all other laboratory parameters are at the investigator's discretion.
- •Any surgical or medical condition that may interfere with the absorption, distribution, metabolism, or excretion of the investigational medicine product.
- •Any history of drug related hypersensitivity reaction.
- •Prior treatment with a monoclonal antibody.
- •Intercurrent illness as evidenced by, e.g., nausea, vomiting, fever, or diarrhea) within 7 days before D
- •History of drug abuse (habitual taking of addictive or illegal drugs) within 1 year before D
- •Consumption of any caffeine-containing products (e.g., coffee, tea, chocolate, or soda) or grapefruit-containing products or alcoholic beverages within 48 hours before D1 and until D
- •Any condition or disease detected during the medical interview / physical examination that would render the subject unsuitable for the study, place the subject at undue risk or interfere with the ability of the subject to complete the study in the opinion of the Investigator or his designee.
- •Frequent headaches and/or migraine, recurrent nausea and / or vomiting.
- •Female subjects who are pregnant, or breastfeeding.
- •Positive screen for drugs of abuse (amphetamines, barbiturates, benzodiazepines, cannabinoids, cocaine, opiates, phencyclidine [PCP]) and breath alcohol test at screening or D-
- •Positive serology for hepatitis B or hepatitis C or human immunodeficiency viruses (HIV).
- •Positive SARS-CoV-2 RT-PCR.
- •Any condition detected at screening that may interfere with or bias the physical examinations to be performed during the study.
- •Any prescribed or over-the-counter medication or herbal products taken within 1 week prior to start of administration of IMP (D1) or within 6 times the elimination half-life of the medication prior to start of IMP intake (whichever is longer), except birth control as described in inclusion criterion number 5 in Section 6.
- •Vitamin/mineral supplements and occasional use of acetaminophen is allowed up until 24 hours before dosing.
- •Participation in a clinical trial or use of an investigational drug within 30 days before randomization.
- •Any vaccination within 30 days before signature of informed consent.
研究组 & 干预措施
AV-380 IV 8 mg/kg
IV infusion of AV-380 at dose level 8 mg/kg
干预措施: AV-380 (Drug)
AV-380 IV 4 mg/kg
IV infusion of AV-380 at dose level 4 mg/kg
干预措施: AV-380 (Drug)
AV-380 IV 13 mg/kg
IV infusion of AV-380 at dose level 13 mg/kg
干预措施: AV-380 (Drug)
AV-380 IV 20 mg/kg
IV infusion of AV-380 at dose level 20 mg/kg
干预措施: AV-380 (Drug)
AV-380 SC 4 mg/kg
Subcutaneous injection of AV-380 at dose level 4 mg/kg
干预措施: AV-380 (Drug)
AV-380 SC 2 mg/kg
Subcutaneous injection of AV-380 at dose level 2 mg/kg
干预措施: AV-380 (Drug)
AV-380 SC 1 mg/kg
Subcutaneous injection of AV-380 at dose level 1 mg/kg
干预措施: AV-380 (Drug)
Placebo
干预措施: Placebo (Drug)
结局指标
主要结局
Clinical laboratory measurements - Blood chemistry - calcium
时间窗: Visits Day 1 through Day 60
Calcium (mg/dL)
Assessment of adverse events (AEs) and treatment emergent adverse events (TEAEs)
时间窗: Through study completion, an average of 60 days
Injection site safety and tolerability assessment
时间窗: Visit Day 1
Site injection tolerability will be assessed by the Investigator using a 4-level score (none, mild, moderate, severe) after IV infusion and SC injection.
Clinical laboratory measurements - Hematology - erythrocytes
时间窗: Visits Day 1 through Day 60
Erythrocytes
Clinical laboratory measurements - Hematology - hematocrit
时间窗: Visits Day 1 through Day 60
Hematocrit (%)
Clinical laboratory measurements - Hematology - white blood cell count
时间窗: Visits Day 1 through Day 60
White blood cell count with differential (neutrophils, basophils, eosinophils, lymphocytes, monocytes and platelets) (X10(3)/UL)
Clinical laboratory measurements - Blood chemistry - blood urea nitrogen
时间窗: Visits Day 1 through Day 60
Blood urea nitrogen (mg/dl)
Clinical laboratory measurements - Blood chemistry - glucose
时间窗: Visits Day 1 through Day 60
Glucose (mg/dL)
Clinical laboratory measurements - Blood chemistry - sodium
时间窗: Visits Day 1 through Day 60
Sodium (mmol/L)
Clinical laboratory measurements - Blood chemistry - chloride
时间窗: Visits Day 1 through Day 60
Chloride (mmol/L)
Clinical laboratory measurements - Hematology - hemoglobin
时间窗: Visits Day 1 through Day 60
Hemoglobin (g/dL)
Clinical laboratory measurements - Blood chemistry - potassium
时间窗: Visits Day 1 through Day 60
Potassium (mmol/L)
Clinical laboratory measurements - Blood chemistry - CO2
时间窗: Visits Day 1 through Day 60
CO2 (mmol/L)
Clinical laboratory measurements - Blood chemistry - creatinine
时间窗: Visits Day 1 through Day 60
creatinine (mg/dL), glucose, total proteins, triglycerides, total cholesterol, AST, ALT, gamma-glutamyltransferase, creatinine phosphokinase, albumin, alkaline phosphatase, and total bilirubin
Clinical laboratory measurements - Blood chemistry - total proteins
时间窗: Visits Day 1 through Day 60
Total proteins (g/dL), triglycerides, total cholesterol, AST, ALT, gamma-glutamyltransferase, creatinine phosphokinase, albumin, alkaline phosphatase, and total bilirubin
Clinical laboratory measurements - Blood chemistry - alkaline phosphatase
时间窗: Visits Day 1 through Day 60
Alkaline phosphatase (U/L)
Clinical laboratory measurements - Blood chemistry - total bilirubin
时间窗: Visits Day 1 through Day 60
Total bilirubin (mg/dl)
Clinical laboratory measurements - Coagulation - International normalized ratio
时间窗: Visits Day 1 through Day 60
International normalized ratio
Clinical laboratory measurements - Hormonology
时间窗: Visits Day 1 through Day 90
Measured parameters: Hormonology (TSH, FSH (for post-menopausal women); β-HCG (for women of childbearing potential))
Clinical laboratory measurements - Urinalysis - protein
时间窗: Visits Day 1 through Day 60
Protein (negative/positive)
Clinical laboratory measurements - Urinalysis - glucose
时间窗: Visits Day 1 through Day 60
Glucose (negative/positive)
Clinical laboratory measurements - Blood chemistry - triglycerides
时间窗: Visits Day 1 through Day 60
Triglycerides (mg/dL)
Clinical laboratory measurements - Blood chemistry - AST
时间窗: Visits Day 1 through Day 60
AST (U/L)
Clinical laboratory measurements - Blood chemistry - ALT
时间窗: Visits Day 1 through Day 60
ALT (U/L)
Clinical laboratory measurements - Blood chemistry - Gamma-glutamyltransferase
时间窗: Visits Day 1 through Day 60
Gamma-glutamyltransferase (U/L)
Clinical laboratory measurements - Coagulation - partial thromboplastin time
时间窗: Visits Day 1 through Day 60
Activated partial thromboplastin time (secs)
Clinical laboratory measurements - Coagulation - prothrombin time
时间窗: Visits Day 1 through Day 60
Prothrombin time (sec)
Clinical laboratory measurements - Urinalysis - nitrites
时间窗: Visits Day 1 through Day 60
Nitrites (negative/positive)
Clinical laboratory measurements - Blood chemistry - total cholesterol
时间窗: Visits Day 1 through Day 60
Total cholesterol (mg/dL)
Clinical laboratory measurements - Blood chemistry - Creatinine phosphokinase
时间窗: Visits Day 1 through Day 60
Creatinine phosphokinase (mg/dL)
Clinical laboratory measurements - Hormonology - FSH
时间窗: Visits Day 1 through Day 90
FSH (mIU/mL)
Clinical laboratory measurements - Urinalysis - pH
时间窗: Visits Day 1 through Day 60
pH
Clinical laboratory measurements - Blood chemistry - albumin
时间窗: Visits Day 1 through Day 60
Albumin (g/dL)
Vital signs measurements - Blood pressure
时间窗: Visits Day 1 through Day 90
Supine and standing systolic and diastolic blood pressure (mmHg)
Vital signs measurements - Heart rate
时间窗: Visits Day 1 through Day 90
Heart rate (beats/min)
Clinical laboratory measurements - Hormonology - TSH
时间窗: Visits Day 1 through Day 90
TSH (mIU/mL)
Clinical laboratory measurements - Urinalysis - leukocytes
时间窗: Visits Day 1 through Day 60
Leukocytes (negative/positive)
Clinical laboratory measurements - Urinalysis - ketones
时间窗: Visits Day 1 through Day 60
Ketones (negative/positive)
Clinical laboratory measurements - Urinalysis - blood
时间窗: Visits Day 1 through Day 60
Blood (negative/positive)
Vital signs measurements - Body temperature
时间窗: Visits Day 1 through Day 90
Body temperature (degrees Celsius)
Electrocardiogram (ECG) measurements - Mean heart rate
时间窗: Visits Day 1 through Day 90
ECG mean heart rate (beats/min)
Electrocardiogram (ECG) measurements - QTcF interval
时间窗: Visits Day 1 through Day 90
QTcF interval, aggregate (msec)
Electrocardiogram (ECG) measurements - PR interval
时间窗: Visits Day 1 through Day 90
PR interval, aggregate (msec)
Vital signs measurements - Respiratory rate
时间窗: Visits Day 1 through Day 90
Respiratory rate (breaths/min)
Electrocardiogram (ECG) measurements - QRS axis
时间窗: Visits Day 1 through Day 90
QRS axis (deg)
次要结局
- Serum PK of single dose AV-380 via intravenous infusion and subcutaneous injection(Visits Day 1 through Day 90)
- AV-380 immunogenicity in healthy subjects - anti-AV-380 antibodies (human anti-human antibodies [HAHA]) levels in serum.(Visits Day 1 through Day 180)
- To correlate the serum level of GDF-15 with the dose and serum level of AV-380(Visits Day 1 through Day 90)
- AV-380 immunogenicity in healthy subjects - Monocyte chemoattractant protein 1 (MCP-1) levels in serum.(Visits Day 1 and Day 2)