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
Overview
- Phase
- Phase 1
- Intervention
- GS-441524
- Conditions
- COVID-19
- Sponsor
- National Center for Advancing Translational Sciences (NCATS)
- Enrollment
- 70
- Primary Endpoint
- Blood Pressure in mm/Hg
- Status
- Withdrawn
- Last Updated
- last year
Overview
Brief Summary
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.
Detailed Description
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.
Investigators
Eligibility Criteria
Inclusion Criteria
- •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.
Exclusion Criteria
- •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.
Arms & Interventions
SAD Cohort 1
A single oral dose of 100 mg GS-441524 under fasted conditions
Intervention: GS-441524
SAD Placebo
Matching Placebo under fasted conditions
Intervention: Placebo
SAD Cohort 2
A single oral dose of 300 mg GS-441524
Intervention: GS-441524
SAD Cohort 3
A single oral dose of 600 mg GS-441524
Intervention: GS-441524
SAD Cohort 4
A single oral dose of 1000 mg GS-441524
Intervention: GS-441524
SAD Cohort 5
Optional Cohort - dose TBD
Intervention: GS-441524
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
Intervention: GS-441524
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
Intervention: GS-441524
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
Intervention: GS-441524
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
Intervention: GS-441524
MAD Placebo
Matching Placebo under fasted or fed conditions
Intervention: Placebo
Outcomes
Primary Outcomes
Blood Pressure in mm/Hg
Time Frame: 10 days
Changes from baseline
Respiratory Rate in breaths per minute
Time Frame: 10 days
Changes from baseline
Pulse in beats/min
Time Frame: 10 days
Changes from baseline
Body Temperature in degrees
Time Frame: 10 days
Changes from baseline
Treatment-emergent adverse events (TEAEs)
Time Frame: 10 days
Number of incidences
Electrocardiogram (ECG) as measured by PR interval
Time Frame: 10 days
Changes from baseline
Electrocardiogram (ECG) as measured by QT interval
Time Frame: 10 days
Changes from baseline
Electrocardiogram (ECG) as measured by QT corrected (Fridericia's)
Time Frame: 10 days
Changes from baseline
Secondary Outcomes
- 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)