A Phase 1, Double-Blind, Placebo-Controlled, Randomized, Single Ascending Dose, Multiple Ascending Dose, and Food Effect Study to Assess the Safety, Tolerability, and Pharmacokinetics of GS-441524 in Healthy Subjects
试验速览
- 阶段
- 1 期
- 状态
- 撤回
- 发起方
- 入组人数
- 70
- 主要终点
- Blood Pressure in mm/Hg
研究概览
简要总结
The goal of this clinical trial is to evaluate the safety, tolerability, and pharmacokinetics of GS-441524 in healthy subjects. The main questions to answer are: 1) What dosage of GS-441524 is required for adequate therapeutic plasma levels? 2) Does fed or fasted state produce variability in plasma levels? 3) How is GS-441524 eliminated from the body.
Participants will receive varying levels of GS-441524 or placebo to evaluate AEs and plasma levels.
详细描述
This study will consist of 3 parts: an a single ascending dose (SAD) part, an food effect (FE) part, and an multiple ascending dose (MAD) part.
- SAD Part This will be a randomized, double-blind, placebo-controlled single-dose study part of GS-441524 in healthy human subjects. The SAD part will consist of at least 4 cohorts and up to 5 cohorts. Subjects will be randomized into one dose cohort and receive either active drug or placebo. Within each cohort, 6 subjects will receive GS-441524 and 2 subjects will receive placebo. The proposed doses are: 100 mg, 300 mg, 600 mg, and 1000 mg.
A sentinel group of 2 subjects will be randomized to active drug or placebo (1 active; 1 placebo) and will be dosed ahead of the rest of each cohort. There will be a minimum of 48 hours between dosing of the 2 sentinel subjects and the remainder of the cohort. A review of sentinel group safety data after dosing will be completed before dose administration will continue in the remaining 6 subjects (5 active; 1 placebo) of each cohort. An optional fifth dose level may be added based on safety and PK data from the first 4 cohorts.
- FE Part This will be a randomized, balanced, single-dose, two-treatment (fed vs fasting), two-period, two sequence crossover study part in healthy human subjects using a clinically relevant dose of GS-441524 (a dose that may achieve an anticipated efficacious exposure of 2 µM3). The dose will be selected from the SAD part and will be given once under fasting conditions and once under fed conditions (after completion of a standard FDA defined high-fat breakfast) in 1 cohort of 6 subjects.
- MAD Part This will be a randomized, double-blind, placebo-controlled, repeat-dose study part of GS-441524 in healthy human subjects. There will be up to 3 dose cohorts. Subjects will be randomized into one dose cohort to receive either active drug or placebo. Within each cohort, 6 subjects will receive GS-441524 and 2 subjects will receive placebo. Subjects will be administered GS-441524 or placebo twice daily for 5 days (Days 1 to 5) and only a morning dose on Day 6.
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 55 Years（Adult）
- 性别
- All
- 接受健康志愿者
- 是
入选标准
- •Must be able to verbalize understanding of the consent form, able to provide written informed consent, and verbalize willingness to complete study procedures, be able to comply with protocol requirements, rules and regulations of study site, and be likely to complete all the study interventions.
- •Must be considered a healthy male or healthy female of nonchildbearing potential.
- •Women of nonchildbearing potential are considered women who:
- •Do not have a uterus, or
- •Are surgically sterile (for example: has undergone complete hysterectomy, bilateral oophorectomy, or tubal ligation; should be verified by medical documentation), or
- •Have permanent cessation of ovarian function due to ovarian failure or surgical removal of the ovaries, or
- •Are postmenopausal as defined by 12 months or more of spontaneous amenorrhea as confirmed by a follicle-stimulating hormone (FSH) level >30 mIU/mL.
- •Between 18 and 55 years of age, inclusive.
- •Body mass index (BMI) within 18.0 to 32.0 kg/m2, inclusive.
- •Minimum weight of at least 50.0 kg at screening.
- •Male subjects who are sexually active with female partners of childbearing potential must use, with their partner, a condom plus an approved method of effective contraception from the time of screening until 90 days after the last dose of investigational medicinal product (IMP). Additionally, male subjects must agree to not donate sperm during the study and for at least 90 days from the last dose of IMP. Effective methods of contraception are:
- •Combined (estrogen- and progestogen-containing) hormonal contraception associated with inhibition of ovulation (oral, intravaginal, or transdermal)
- •Progestogen-only hormonal contraception (oral, injectable/implantable, or intrauterine hormone-releasing system)
- •Implantable intrauterine device
- •Surgical sterilization (for example, vasectomy or bilateral tubal ligation; should be verified by medical documentation)
- •Male condom with spermicidal gel/foam or with female cap or diaphragm (double barrier)
- •Must have normal renal function (estimated glomerular filtration rate [eGFR] >75 mL/min/1.73 m2, as calculated by the CKD-EPI 2021 creatinine formula).
排除标准
- •Have a medical history of clinically significant neurological, cardiovascular, renal, hepatic, chronic respiratory or gastrointestinal disease, or psychiatric disorder as judged by an Investigator.
- •Have clinically significant abnormal biochemistry, hematology, or urinalysis results as judged by an Investigator.
- •Have disorders that may interfere with drug absorption, distribution, metabolism, and excretion processes.
- •Positive test results for human immunodeficiency virus (HIV)-1/HIV-2 antibodies, hepatitis B surface antigen (HBsAg), or hepatitis C virus (HCV) antibody.
- •Serious cardiac illness or other medical condition including, but not limited to:
- •Uncontrolled arrhythmias
- •History of congestive heart failure
- •Corrected QT value with Fridericia's formula (QTcF) >450 msec for males and >470 msec for females or history of prolonged QT syndrome
- •Have a blood pressure reading outside of the following range: systolic blood pressure <86 mmHg or >149 mmHg and diastolic blood pressure <50 mmHg or >94 mmHg
- •History of pancreatitis and history of hepatic or biliary disease, including those with known history/diagnosis of Gilbert's syndrome. Subjects with gall bladder removal <90 days prior to screening.
- •Regular alcohol consumption in males >21 units per week and females >14 units per week (1 unit=12 ounces of beer, 1.5 ounces of spirit, or 5 ounces of wine) within 12 months prior to screening.
- •Positive test result for alcohol and/or drugs of abuse at screening or prior to the first IMP administration.
- •Current smokers and those who have smoked within 90 days prior to the first IMP administration. Current users of e cigarettes and nicotine replacement products, and those who have used these products within 90 days prior to the first IMP administration.
- •Concurrent treatment or treatment with an investigational drug within 30 days prior to the first dose of IMP.
- •Blood donation of approximately 500 mL within 56 days or plasma donation within 7 days of screening.
- •Subjects who are taking, or have taken, any prescribed or over-the-counter drugs (other than a maximum of 2 g per day of acetaminophen, hormone replacement therapy, hormonal contraception) or herbal remedies in the 14 days before randomization. Exceptions may apply on a case-by-case basis if considered not to interfere with the objectives of the study, as agreed by the Investigator and Sponsor's Medical Monitor.
- •Known allergy or intolerance to remdesivir.
- •Any condition that, in the opinion of an Investigator, would interfere with evaluation or interpretation of subject safety or study results.
- •Affiliated with, or a family member of, site staff directly involved in the study, or anyone with a financial interest in the outcome of the study.
- •Subjects who are unable, in the opinion of an Investigator, to comply fully with the study requirements.
研究组 & 干预措施
SAD Cohort 1
A single oral dose of 100 mg GS-441524 under fasted conditions
干预措施: GS-441524 (Drug)
SAD Placebo
Matching Placebo under fasted conditions
干预措施: Placebo (Drug)
SAD Cohort 2
A single oral dose of 300 mg GS-441524
干预措施: GS-441524 (Drug)
SAD Cohort 3
A single oral dose of 600 mg GS-441524
干预措施: GS-441524 (Drug)
SAD Cohort 4
A single oral dose of 1000 mg GS-441524
干预措施: GS-441524 (Drug)
SAD Cohort 5
Optional Cohort - dose TBD
干预措施: GS-441524 (Drug)
Food Effect
Randomized, balanced, single-dose, two-treatment (fed vs fasting), two-period, two sequence crossover study part in healthy human subjects Treatment A: a single oral dose of TBD mg GS-441524 under fasted conditions Treatment B: a single oral dose of TBD mg GS-441524 under fed conditions
干预措施: GS-441524 (Drug)
MAD Cohort 1
Multiple oral doses of TBD mg GS-441524under fasted or fed conditions twice daily for 5 days (Days 1 to 5) and only a morning dose on Day 6
干预措施: GS-441524 (Drug)
MAD Cohort 2
Multiple oral doses of TBD mg GS-441524under fasted or fed conditions twice daily for 5 days (Days 1 to 5) and only a morning dose on Day 6
干预措施: GS-441524 (Drug)
MAD Cohort 3
Multiple oral doses of TBD mg GS-441524under fasted or fed conditions twice daily for 5 days (Days 1 to 5) and only a morning dose on Day 6
干预措施: GS-441524 (Drug)
MAD Placebo
Matching Placebo under fasted or fed conditions
干预措施: Placebo (Drug)
结局指标
主要结局
Blood Pressure in mm/Hg
时间窗: 10 days
Changes from baseline
Respiratory Rate in breaths per minute
时间窗: 10 days
Changes from baseline
Pulse in beats/min
时间窗: 10 days
Changes from baseline
Body Temperature in degrees
时间窗: 10 days
Changes from baseline
Treatment-emergent adverse events (TEAEs)
时间窗: 10 days
Number of incidences
Electrocardiogram (ECG) as measured by PR interval
时间窗: 10 days
Changes from baseline
Electrocardiogram (ECG) as measured by QT interval
时间窗: 10 days
Changes from baseline
Electrocardiogram (ECG) as measured by QT corrected (Fridericia's)
时间窗: 10 days
Changes from baseline
次要结局
- Plasma PK Parameter AUC 0-last(6 days)
- Plasma PK Parameter AUC 0-inf(6 days)
- Plasma PK Parameter t 1/2(10 days)
- Plasma PK Parameter CL/F(10 days)
- Plasma PK Parameter C-Max(10 days)
- Plasma PK Parameter t-lag(10 days)
- Plasma PK Parameter t-max(10 days)
- Plasma PK Parameter Vz/F(10 days)
- Urine PK Parameter Ae urine(10 days)
- Plasma PK Parameter C trough(10 days)
- Plasma PK Parameter AUC 0-tau(10 days)
- Plasma PK Parameter CL/F ss(10 days)
- Urine PK Parameter Fe urine(10 days)
- Urine PK Parameter CL R(10 days)
- Plasma PK Parameter Vz/F ss(10 days)
- Plasma PK Parameter R ac(10 days)