Clinical trial NCT06274853: GS-441524 for COVID-19 SAD, FE, and MAD Study in Healthy Subjects
Official title: 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
Study type: INTERVENTIONAL
Overall status: WITHDRAWN
Phase: PHASE1
Conditions: COVID-19
Lead sponsor: National Institute of Allergy and Infectious Diseases (NIAID)
Sponsor class: NIH
Collaborators: name: Leidos Biomedical Research, Inc.
name: ICON Government and Public Health Solutions, Inc
First posted: 2024-02-23
Enrollment: 0
Sex: ALL
Minimum age (years): 18
Maximum age (years): 55
Standard ages: ADULT
Accepts healthy volunteers: yes
Allocation: RANDOMIZED
Intervention model: SEQUENTIAL
Primary purpose: TREATMENT

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.

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:

  1. Do not have a uterus, or
  2. Are surgically sterile (for example: has undergone complete hysterectomy, bilateral oophorectomy, or tubal ligation; should be verified by medical documentation), or
  3. Have permanent cessation of ovarian function due to ovarian failure or surgical removal of the ovaries, or
  4. 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:

  1. Combined (estrogen- and progestogen-containing) hormonal contraception associated with inhibition of ovulation (oral, intravaginal, or transdermal)
  2. Progestogen-only hormonal contraception (oral, injectable/implantable, or intrauterine hormone-releasing system)
  3. Implantable intrauterine device
  4. Surgical sterilization (for example, vasectomy or bilateral tubal ligation; should be verified by medical documentation)
  5. 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).

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:

  1. Uncontrolled arrhythmias
  2. History of congestive heart failure
  3. Corrected QT value with Fridericia's formula (QTcF) \>450 msec for males and \>470 msec for females or history of prolonged QT syndrome
  4. 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.

Primary outcomes:
measure: Treatment-emergent adverse events (TEAEs)
timeFrame: 10 days
measure: Blood Pressure in mm/Hg
timeFrame: 10 days
measure: Pulse in beats/min
timeFrame: 10 days
measure: Respiratory Rate in breaths per minute
timeFrame: 10 days
measure: Body Temperature in degrees
timeFrame: 10 days
measure: Electrocardiogram (ECG) as measured by PR interval
timeFrame: 10 days
measure: Electrocardiogram (ECG) as measured by QT interval
timeFrame: 10 days
measure: Electrocardiogram (ECG) as measured by QT corrected (Fridericia's)
timeFrame: 10 days
Secondary outcomes:
measure: Plasma PK Parameter C-Max
timeFrame: 10 days
measure: Plasma PK Parameter t-max
timeFrame: 10 days
measure: Plasma PK Parameter t-lag
timeFrame: 10 days
measure: Plasma PK Parameter AUC 0-last
timeFrame: 6 days
measure: Plasma PK Parameter AUC 0-inf
timeFrame: 6 days
measure: Plasma PK Parameter t 1/2
timeFrame: 10 days
measure: Plasma PK Parameter CL/F
timeFrame: 10 days
measure: Plasma PK Parameter Vz/F
timeFrame: 10 days
measure: Urine PK Parameter Ae urine
timeFrame: 10 days
measure: Urine PK Parameter Fe urine
timeFrame: 10 days
measure: Urine PK Parameter CL R
timeFrame: 10 days
measure: Plasma PK Parameter C trough
timeFrame: 10 days
measure: Plasma PK Parameter AUC 0-tau
timeFrame: 10 days
measure: Plasma PK Parameter CL/F ss
timeFrame: 10 days
measure: Plasma PK Parameter Vz/F ss
timeFrame: 10 days
measure: Plasma PK Parameter R ac
timeFrame: 10 days
Other outcomes:
Locations:
Study officials:
affiliation: NCATS
name: Philip E Sanderson, PhD
role: STUDY_DIRECTOR
References: