A Randomized, Double-blind, Placebo-controlled Phase I/II Clinical Study to Evaluate the Safety, Tolerability, Pharmacokinetics Characteristics and Primary Efficacy of HS-10517 in Chinese Adult Participants
试验速览
- 阶段
- 1 期
- 状态
- 招募中
- 发起方
- 入组人数
- 340
- 试验地点
- 1
- 主要终点
- The incidence and severity of adverse events (AE), serious adverse events (SAE) and adverse events leading to withdrawal from the trial and the correlation with the investigational drug in single ascending dose (SAD)
研究概览
简要总结
A Phase I/II, randomized, double-blind, placebo-controlled study to evaluate safety, tolerability, pharmacokinetics and primary efficacy of HS-10517 in Chinese adult participants.
研究设计
- 研究类型
- Interventional
- 分配方式
- Randomized
- 干预模型
- Parallel
- 主要目的
- Other
- 盲法
- Double (Participant, Investigator)
入排标准
- 年龄范围
- 18 Years 至 45 Years（Adult）
- 性别
- All
- 接受健康志愿者
- 是
入选标准
- •Inclusion Criteria for SAD, MAD and SE：
- •Subjects should fully understand the content, process and possible adverse reactions of the study, and voluntarily sign the informed consent form;
- •The age at the time of signing the informed consent is between 18 and 45 years old (including the critical value)
- •Subjects with negative COVID-19 nucleic acid detection in screening period;
- •The body mass index (BMI=body weight [kg]/height2 [m2]) at screening is 19~27kg/m2 (including the critical value), and the weight of men is ≥ 50kg, and that of women is ≥ 40kg;
- •The blood pregnancy test of female subjects in the screening period and the baseline period is negative;
- •Female subjects must agree to take effective contraceptive measures from the date of signing the informed consent form to 30 days after the last administration:
- •Those with fertility: from the date of signing the informed consent form to 30 days after the last administration, ① avoid pregnancy, ② if having sex with the opposite sex, agree to continue to use one or more forms of effective contraception (such as verified intrauterine devices, bilateral tubal ligation or correct use of condoms, excluding any form of hormonal contraceptives). If the male partner has undergone an effective sterilization operation, additional effective contraception measures should be taken when the sperm is uncertain);
- •Non-fertility: ① Postmenopausal (spontaneous amenorrhea ≥ 12 months, or spontaneous amenorrhea ≥ 6 months and FSH>40 IU/L, without other obvious pathological or physiological reasons) before screening; Or ② documented surgical sterilization (such as hysterectomy, bilateral salpingectomy or bilateral oophorectomy, etc.);
- •Male subjects (including their female partners) must agree to take effective contraceptive measures from the date of signing the informed consent form to 30 days after the last administration:
- •Those who are fertile must agree to use condoms correctly. If their female partners are women of child-bearing age and have fertility (have not undergone hysterectomy, bilateral salpingectomy or bilateral oophorectomy and have no medical proven ovarian failure), their female partners must take effective contraceptive measures (such as oral/injection/vaginal or implantable hormone contraceptives, or other physical barrier, surgery and other female contraceptive methods) within 30 days after the last administration;
- •Those who are infertile, such as those who have undergone effective sterilization operations, take additional effective contraceptive measures when they are not sure whether they have sperm);
- •Male subjects agree to avoid donating sperm within 30 days from the initiation of drug administration until the last administration.
- •Inclusion Criteria for Phase II dose exploration:
- •Subjects should fully understand the content, process and possible adverse reactions of the study, and voluntarily sign the informed consent form;
- •The age at the time of signing the informed consent is ≥ 18 years old;
- •In the first 2 days (48 hours) before randomization, COVID-19 nucleic acid detected by RT-PCR is positive;
- •During the screening period, the subject is assessed by the research doctor as a patient with mild to moderate COVID-19 infection;
- •During the screening period, the subject is assessed by the research doctor and show symptoms/signs of COVID-19 infection for the first time within 2 days before randomization;
- •At least one of targeted COVID-19 symptoms exists within the first 24 hours of randomization and meets the corresponding severity;
- •Female subjects must agree to take the drug from the date of signing the informed consent form to 30 days after the last administration; Effective contraceptive measures:
- •Those with fertility: from the date of signing the informed consent form to 30 days after the last administration, ① avoid pregnancy, ② if having sex with the opposite sex, agree to continue to use one or more forms of effective contraception (such as verified intrauterine devices, bilateral tubal ligation or correct use of condoms, excluding any form of hormonal contraceptives). If the male partner has undergone an effective sterilization operation, additional effective contraception measures should be taken when the sperm is uncertain);
- •Male subjects (including their female partners) agree to take effective contraceptive measures from the date of signing the informed consent form to 30 days after the last administration:
- •Those who are fertile must agree to use condoms correctly. If their female partners are women of child-bearing age and have fertility (have not undergone hysterectomy, bilateral salpingectomy or bilateral oophorectomy and have no medical proven ovarian failure), their female partners must take effective contraceptive measures (such as oral/injection/vaginal or implantable hormone contraceptives, or other physical barrier, surgery and other female contraceptive methods) within 30 days after the last administration
- •Those who are infertile, such as those who have undergone effective sterilization, take additional effective contraceptive measures when they are not sure whether they have sperm).
- •The pregnancy test of female subjects in the screening period and the baseline period is negative;
- •Male subjects agree to avoid donating sperm within 30 days from the start of administration until the last administration
- •Exclusion Criteria of SAD, MAD and SE:
- •According to the judgment of the principal investigator, the participant is accompanied with suspected COVID-19 related clinical symptoms/signs;
- •During screening, those who are judged to be clinically significant by the principal investigator through medical history inquiry, physical examination, vital signs, blood oxygen saturation (SpO2), laboratory examination, 12-lead electrocardiogram (ECG), abdominal ultrasound, chest X-ray examination, etc;
- •Participants with clinically significant diseases (such as neuropsychiatric system, cardiovascular system, urinary system, digestive system, respiratory system, skeletal muscle system, endocrine and metabolic system, blood system, skin disease, immune system, tumor, etc.) are evaluated by the researcher as not suitable for this study;
- •Previous major surgery, or according to the judgment of the principal investigator, there is any physiological or disease or condition that may affect the absorption of the study drug (such as gastrectomy, cholecystectomy, enterotomy, etc.);
- •According to the judgment of the principal investigator, there is any physical or psychological disease or condition that may increase the risk of the test, affect the compliance of the subject with the other case, or affect the subject's completion of the test;
- •Within 2 weeks or 5 half-life (whichever is longer) before screening, and during the whole study period, it is expected to take any medicine and health care products, including prescription drugs, over-the-counter drugs and Chinese herbal medicine (including oral contraceptives, external spermicide, drugs with systemic therapeutic effects through percutaneous absorption and St. John's wort);
- •Participants have participated in any clinical study or taken study drugs within 3 months before screening;
- •Have a history of vaccination within 30 days before screening, or plan to have a vaccination throughout the study period;
- •Difficult in blood sample collection, unable to tolerate multiple venous blood collection and any contraindication of blood sample collection;
- •Large amount of blood loss or donation (more than 250mL) within 3 months before screening;
- •At screening, 12-lead ECG is abnormal and had clinical significance according to the judgment of the researcher, such as the QT interval (QTcB) corrected by Bazett (formula QT/RR0.5), the absolute value of QTcB in males is more than 450ms, and the absolute value of QTcB in females is more than 470ms;
- •When screening, endogenous creatinine clearance rate is less than 80mL/min, according to Cockcroft-Gault formula: endogenous creatinine clearance rate (mL/min)=(140 - age) × body weight (kg) 72 × serum creatinine concentration (mg/dL) (female × 0.85);
- •During the screening period and/or the baseline period, the blood pressure and pulse are within the following range: systolic blood pressure <90 mmHg or ≥ 140 mmHg, diastolic blood pressure <60 mmHg or ≥ 90 mmHg, pulse <55 bpm or >100 bpm;
- •Have a history of drug dependence or drug abuse in the past, or have a positive urine drug test during screening;
- •Those who have a history of severe allergy to drugs, food and articles (including allergy to latex, dust mites, pollen, etc.), or are known to be allergic to the test drug ingredients;
- •Within 2 weeks before screening, dieting or receiving dietary treatment for whatever reason, or major changes in dietary habits;
- •Have a history of alcoholism in the past (drinking more than 14 units of alcohol per week on average), or drink more than 14 units of alcohol per time in the past two weeks (1 unit=285mL of beer, 25mL of spirits, 125mL of wine), or cannot stop drinking alcohol products during the test; Or positive alcohol breath test during screening;
- •Those who smoke more than 5 cigarettes per day on average in the three months before screening, or who cannot stop using any tobacco products during the test;
- •Within 2 weeks before screening, subjects ingested foods that may affect drug metabolism, such as grapefruit juice;
- •The average daily intake of coffee, tea, cola or other caffeinated drinks exceeds 6 cups (about 250mL per cup) within 3 months before screening;
- •Those who have difficulty swallowing solid preparations such as tablets;
- •Female subjects are in pregnancy or lactation at the time of screening;
- 另有 14 项未显示
排除标准
- 未提供
研究组 & 干预措施
HS-10517 Dose 4
Dose level 1 of HS-10517 Tablets，Dose 4
干预措施: HS-10517 Dose 4 (Drug)
HS-10517 Dose 1
Dose level 1 of HS-10517 Tablets，Dose 1
干预措施: HS-10517 Dose 1 (Drug)
HS-10517 Dose 2
Dose level 1 of HS-10517 Tablets，Dose 2
干预措施: HS-10517 Dose 2 (Drug)
HS-10517 Dose 3
Dose level 1 of HS-10517 Tablets，Dose 3
干预措施: HS-10517 Dose 3 (Drug)
Placebo Comparator
Dose level A of placebo
干预措施: Placebo (Drug)
结局指标
主要结局
The incidence and severity of adverse events (AE), serious adverse events (SAE) and adverse events leading to withdrawal from the trial and the correlation with the investigational drug in single ascending dose (SAD)
时间窗: Day 1 to Day 5
The definition of adverse event \[AE\] is any untoward medical occurrence in a patient or clinical study participant, temporally associated with the use of study intervention, whether or not considered related to the study intervention. The definition of serious adverse event \[SAE\] is any untoward medical occurrence at any dose that results in death; is life threatening; requires inpatient hospitalization or prolongation of existing hospitalization; results in persistent disability/incapacity; results in congenital anomaly/birth defect.
Number of participants with clinically significant change from baseline in vital signs in SAD
时间窗: Day 1 to Day 5
Number of participants with clinically significant change from baseline in 12-lead electrocardiogram (ECG) findings in SAD
时间窗: Day 1 to Day 5
Criteria for clinically significant changes in 12-lead ECG are defined as: a postdose QTc interval increase by ≥30 msec from the baseline and is \>450 msec; or an absolute QTc value is ≥500 msec for any scheduled 12-lead ECG.
Number of participants with clinically significant abnormalities in laboratory examination in SAD
时间窗: Day 1 to Day 5
Number of participants with clinically significant abnormalities in physical examination in SAD
时间窗: Day 1 to Day 5
The incidence and severity of adverse events (AE), serious adverse events (SAE) and adverse events leading to withdrawal from the trial and the correlation with the investigational drug in multiple ascending dose (MAD)
时间窗: Day 1 to Day 14
The definition of adverse event \[AE\] is any untoward medical occurrence in a patient or clinical study participant, temporally associated with the use of study intervention, whether or not considered related to the study intervention. The definition of serious adverse event \[SAE\] is any untoward medical occurrence at any dose that results in death; is life threatening; requires inpatient hospitalization or prolongation of existing hospitalization; results in persistent disability/incapacity; results in congenital anomaly/birth defect.
Number of participants with clinically significant change from baseline in vital signs in MAD
时间窗: Day 1 to Day 14
Number of participants with clinically significant change from baseline in 12-lead electrocardiogram (ECG) findings in MAD
时间窗: Day 1 to Day 14
Criteria for clinically significant changes in 12-lead ECG are defined as: a postdose QTc interval increase by ≥30 msec from the baseline and is \>450 msec; or an absolute QTc value is ≥500 msec for any scheduled 12-lead ECG.
Number of participants with clinically significant abnormalities in laboratory examination in MAD
时间窗: Day 1 to Day 14
Number of participants with clinically significant abnormalities in physical examination in MAD
时间窗: Day 1 to Day 14
The incidence and severity of adverse events (AE), serious adverse events (SAE) and adverse events leading to withdrawal from the trial and the correlation with the investigational drug in supratherapeutic exposure (SE)
时间窗: Day 1 to Day 13
The definition of adverse event \[AE\] is any untoward medical occurrence in a patient or clinical study participant, temporally associated with the use of study intervention, whether or not considered related to the study intervention. The definition of serious adverse event \[SAE\] is any untoward medical occurrence at any dose that results in death; is life threatening; requires inpatient hospitalization or prolongation of existing hospitalization; results in persistent disability/incapacity; results in congenital anomaly/birth defect.
Number of participants with clinically significant change from baseline in vital signs in SE
时间窗: Day 1 to Day 13
Number of participants with clinically significant change from baseline in 12-lead electrocardiogram (ECG) findings in SE
时间窗: Day 1 to Day 13
Criteria for clinically significant changes in 12-lead ECG are defined as: a postdose QTc interval increase by ≥30 msec from the baseline and is \>450 msec; or an absolute QTc value is ≥500 msec for any scheduled 12-lead ECG.
Number of participants with clinically significant abnormalities in laboratory examination in SE
时间窗: Day 1 to Day 13
Number of participants with clinically significant abnormalities in physical examination in SE
时间窗: Day 1 to Day 13
Percentage of participants with a negative RT-PCR test through day 5-modified intent-to-treat (mITT) population.
时间窗: Day 1 to Day 5
次要结局
- Apparent clearance at steady state (CLss/F) in last dose of MAD(Day 1 to Day 14)
- Area under the concentration time profile in one dosing interval at steady state (AUCss) in last dose of MAD(Day 1 to Day 14)
- Maximum plasma concentration (Cmax) in SAD(Day 1 to Day 5)
- Time for Cmax (tmax) in SAD(Day 1 to Day 5)
- Area under the concentration time profile from time 0 to the time of last quantifiable plasma concentration (AUC0-last) in SAD(Day 1 to Day 5)
- Area under the concentration time profile from time 0 to infinity (AUC0-inf) in SAD(Day 1 to Day 5)
- Terminal rate constant (λz) in SAD(Day 1 to Day 5)
- Terminal half-life (t1/2) in SAD(Day 1 to Day 5)
- Apparent clearance (CL/F) in SAD(Day 1 to Day 5)
- Apparent volume of distribution (Vd/F) in SAD(Day 1 to Day 5)
- Mean residence time (MRT) in SAD symptoms to the sustained clinical resolution within 28 days（Phase II）(Day 1 to Day 5)
- Maximum plasma concentration (Cmax) in first dose of MAD(Day 1 to Day 14)
- Time for Cmax (tmax) in first dose of MAD(Day 1 to Day 14)
- Area under the concentration time profile from time 0 to 24 hours in first dose of MAD(Day 1 to Day 14)
- Area under the concentration time profile from time 0 to 12 hours in first dose of MAD(Day 1 to Day 14)
- Maximum plasma concentration at steady state (Css,max) in last dose of MAD(Day 1 to Day 14)
- Time for Cmax at steady state (tss,max) in last dose of MAD(Day 1 to Day 14)
- Minimum plasma concentration at steady state (Css,min) in last dose of MAD(Day 1 to Day 14)
- Degree of accumulation after multiple doses (RAC, including RAUC and RCmax) in last dose of MAD(Day 1 to Day 14)
- Maximum plasma concentration (Cmax) in SE(Day 1 to Day 13)
- Time for Cmax (tmax) in SE(Day 1 to Day 13)
- Area under the concentration time profile from time 0 to the time of last quantifiable plasma concentration (AUC0-last) in SE(Day 1 to Day 13)
- Area under the concentration time profile from time 0 to infinity (AUC0-inf) in SE(Day 1 to Day 13)
- Terminal rate constant (λz) in SE(Day 1 to Day 13)
- Terminal half-life (t1/2) in SE(Day 1 to Day 13)
- Apparent clearance (CL/F) in SE(Day 1 to Day 13)
- Apparent volume of distribution (Vd/F) in SE(Day 1 to Day 13)
- Mean residence time (MRT) in SE(Day 1 to Day 13)
- Time to sustained resolution of 11 COVID-19 symptoms within 28 days(Day 1 to Day 28)
- Change of viral load over time compared to baseline(Day 1 to Day 28)
- Time to the first negative RT-PCR test(Day 1 to Day 28)
- Virological response at each time point after randomization(Day 1 to Day 28)
- Time to sustained alleviation of 11 targeted COVID-19 signs/symptoms within 28 days(Day 1 to Day 28)
- Time to sustained resolution of each targeted COVID-19 symptom(Day 1 to Day 28)
- Change of the score of each COVID-19 symptom(Day 1 to Day 28)
- Proportion of severe cases within 28 days(Day 1 to Day 28)
- The plasma concentration of HS-10517 in COVID-19 patients in phase II study(Day 1 to Day 7)
- Population apparent clearance (CL/F) of COVID-19 patients in phase II study(Day 1 to Day 7)
- Population apparent volume of distribution (Vd/F) of COVID-19 patients in phase II study(Day 1 to Day 7)