A Study of HL40626S Tablets in Healthy Adults

Official title

A Randomized, Double-Blind, Placebo-Controlled, Sequential Group, 2-Part, Phase Ι Study to Evaluate the Safety, Tolerability, Pharmacokinetics and Pharmacodynamics of HL40626S Tablets Following Oral Administration of Single and Multiple Ascending Doses to Healthy Adult Participants.

Overview

This is a single-centre, randomized, double-blind, placebo-controlled Phase 1 study to assess safety, tolerability, pharmacokinetics (PK), pharmacodynamics (PD), and immunogenicity of HL40626S tablets following single and multiple ascending oral doses to healthy adult participants aged 18-55 years.

Detailed description

In Part 1 (Single Ascending Dose, SAD), healthy participants are randomized to receive a single fasting oral dose of HL40626S tablets or matching placebo across five sequential ascending dose cohorts. Each cohort enrolls 8 participants. Sentinel dosing is implemented for every cohort to monitor initial safety before full cohort enrolment.

In Part 2 (Multiple Ascending Dose, MAD), healthy participants are randomized to receive once-daily fasting oral doses of HL40626S tablets or matching placebo for 14 consecutive days across three sequential ascending dose cohorts. Each cohort enrolls 8 participants. All decisions to escalate to the next dose cohort were reviewed and approved by an independent Safety Review Committee (SRC) following complete data review of the preceding cohort.

Interventions

• Drug HL40626S tablets
  Oral study tablets administered in a dose-escalation design
• Drug HL40626S placebo
  Inactive oral placebo tablets matching the active drug dose-escalation scheme

Primary outcome measures

• Parts 1 (SAD) and 2 (MAD): Incidence of Treatment-Emergent Adverse Events [Safety and Tolerability] [Time frame: From signed informed consent through Day 15 for SAD and Day 29 for MAD.]
• Parts 1 (SAD) and 2 (MAD): Incidence of serious adverse events (SAEs) [Safety and Tolerability] [Time frame: From signed informed consent through Day 15 for SAD and Day 29 for MAD.]
• Parts 1 (SAD) and 2 (MAD): Proportion of participants with clinically significant abnormal findings in physical examinations, vital signs, clinical laboratory tests, and 12-lead ECG assessments relative to baseline [Safety and Tolerability] [Time frame: From signed informed consent through Day 15 for SAD and Day 29 for MAD.]

Secondary outcome measures (5)

• Part 1 (SAD): Maximum observed plasma concentration (Cmax) [Time frame: Predose up to 5 days post single dose.]
• Part 1 (SAD): Time to maximum observed plasma concentration (Tmax) [Time frame: Predose up to 5 days post single dose.]
• Part 1 (SAD): Area under the plasma concentration-time curve from time zero to last measurable concentration (AUClast) [Time frame: Predose up to 5 days post single dose.]
• Part 1 (SAD): Area under the plasma concentration-time curve extrapolated to infinite time (AUCinf) [Time frame: Predose up to 5 days post single dose.]
• Part 1 (SAD): Terminal elimination rate constant (Kel) [Time frame: Predose up to 5 days post single dose.]

Eligibility criteria

Inclusion criteria

• Capable of understanding the written informed consent document; willingly provides valid, signed written informed consent; willing and able to comply with the schedule, requirements and restrictions of the study.
• Between the ages of 18.0 and 55.0 years (inclusive) at the time of Screening.
• BMI between 18.0 and 32.0 kg/m2 (inclusive) at the time of Screening, with a body weight ≥ 50 kg.
• In good general health, as determined by the Investigator.
• Female participants must be non-pregnant and non-lactating.
• Female participants must be of non-childbearing potential, or agree to use dual contraception methods (female participants exclusively in same-sex relationships are exempt from the above contraception requirements), and abstain from ova (egg) donation throughout the entire duration of the study and for at least 90 days after the last dose, and have negative pregnancy test results at Screening (serum) and Day -1 (urine). (Note: As this is a first-in-human \[FIH\] study, the applicable t₁/₂ and corresponding restriction period may be adjusted based on emerging PK data).
• Male participants with female partners of reproductive potential must agree to practice complete abstinence or to use a condom (male participant) plus an additional highly effective method (female partner) of contraception for the duration of the study and for at least 90 days after last dosing (Male participants exclusively in same-sex relationships are exempt from the above contraception requirements); all male participants must also agree to refrain from sperm donation for at least 90 days after the last dose. (Note: As this is a FIH study, the applicable t₁/₂ and corresponding restriction period will be adjusted based on real-time PK data).

Exclusion criteria

• Clinically significant abnormal medical history, such as gastrointestinal, cardiovascular, musculoskeletal, endocrine, hematologic, psychiatric, renal, hepatic, bronchopulmonary, neurologic, immunologic, lipid metabolism disorders, drug hypersensitivity, as determined by the Investigator, any abnormal findings on physical examination, VS measurements, ECG or laboratory tests at Screening, Admission or pre dose on Day 1 that, in the opinion of the Investigator, could jeopardize achieving the study objectives and/or compromise the participant's safety.
• Any of the following ECG findings at Screening, Admission and/or pre dose on Day 1:

• Any out-of-range ECG parameter(s) or abnormal finding(s) considered clinically significant by the Investigator.
• Any ECG finding that, in the opinion of the Investigator, may compromise interpretation of ECG for cardiac safety assessments and/or complicate interpretation of events that may occur post dose (e.g., QT not accurately measurable, conduction abnormalities).
• Participants with QTcF >450 msec (if male) or >470 msec (if female) will be excluded.
• Resting HR < 40 bpm or >100 bpm when vital signs are measured at Screening
• SARS-CoV-2 positive by PCR at Admission regardless of symptoms.
• Unstable cardiovascular disease, including recent (within 6 months of screening) myocardial infarction or cardiac arrhythmia.
• Ongoing liver disease or unexplained liver function test (LFT) elevations, defined as ALT, AST, gamma glutamyltransferase (GGT), alkaline phosphatase (ALP) or total/direct bilirubin > upper limit of the reference range (ULRR) at Screening or Admission. Participants with confirmed Gilbert's syndrome will not be permitted to enroll in the study.
• Indications of pre-metabolic syndrome and/or systemic inflammation, as suggested by high-sensitivity C-reactive protein (hsCRP) of > 3 mg/L, elevated erythrocyte sedimentation rate (Male ≥ 15 mm/hr, Female ≥ 20 mm/hr) or Hemoglobin A1c (HbA1c) >5.3% at Screening.
• History of cancer (malignancy) with the exception of basal or squamous cell carcinoma of the skin.
• Respiratory tract infection (upper and/or lower) treated with antibiotics within 12 weeks of Screening.
• Clinically significant infection or known inflammatory condition or history of clinically significant infection within 28 days prior to study drug administration on Day 1 that, in the opinion of the Investigator, would affect the participant's ability to participate in the trial.
• History of drug or alcohol abuse (as defined by DSM-V) within 12 months prior to Screening.
• Positive test result for alcohol (breath) or drugs of abuse (urine) at Screening or Admission.
• Positive serology result for hepatitis B surface antigen (HBsAg), hepatitis C antibody (HCV Ab) or human immunodeficiency virus antibody (HIV Ab) at Screening.
• Active or recent herpes simplex or herpes zoster infection, if considered clinically relevant as per investigator discretion.
• Venous access considered inadequate for PK sample collection; history of evidence of adverse symptoms associated with phlebotomy or blood donation.
• Participation in a study of any investigational drug, device, biologic or other agent within 30 days (or 5 half-lives, whichever is longer \[as applicable\]) prior to Day 1.
• Loss or donation of blood >500 mL (within 30 days prior to Screening); donation of bone marrow or peripheral stem cells (within 90 days prior to Day 1); or donation of plasma (within 7 days prior to Screening).
• No more than 10 standard drinks per week per NHMRC alcohol guidelines within 90 days prior to screening.
• Use of alcohol within 72 hours prior to study drug administration on Day 1.
• Use of prescription drugs within 14 days (or 5 half-lives, whichever is longer), or non-prescription drugs and/or herbal supplements within 7 days (or 5 half-lives, whichever is longer) prior to study drug administration on Day 1. Exception: hormonal contraceptives, acetaminophen ≤ 1 gram/day or ibuprofen ≤ 800 mg/day may be administered at Investigator's discretion.

Criteria are shown verbatim from the registry (in English). Final eligibility is always assessed by the study center.

Healthy volunteers: Yes

Study design

Allocation

Randomized

Model

Sequential

Masking

Quadruple blind

Primary purpose

Treatment

Study locations

Australia · 1 center

• Nucleus Network Pty Ltd — Melbourne

Identifiers

NCT: NCT07736586 · HLD25011-P1-1

Primary sources (government registries)

• ClinicalTrials.gov (US NIH)

View this study on ClinicalTrials.gov ↗