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.
试验速览
- 阶段
- 1 期
- 状态
- 尚未招募
- 发起方
- 入组人数
- 64
- 试验地点
- 1
- 主要终点
- Parts 1 (SAD) and 2 (MAD): Safety and tolerability of HL40626S
研究概览
简要总结
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.
详细描述
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.
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)
盲法说明
The study will be double-blinded. The participants and the clinical personnel involved in the collection, monitoring, revision, or evaluation of AEs, or personnel who could have an impact on the outcome of the study will be blinded with respect to the participant's treatment assignment (HL40626S or placebo).
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
- •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).
排除标准
- •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
- •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
- •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
- •Exception: hormonal contraceptives, acetaminophen ≤ 1 gram/day or ibuprofen ≤ 800 mg/day may be administered at Investigator's discretion.
研究组 & 干预措施
Part 1(SAD): HL40626S
Healthy participants receive single fasting oral HL40626S tablets in five sequential dose-escalation cohorts. Sentinel safety evaluation is required before full cohort dosing.
干预措施: HL40626S tablets (Drug)
Part 1(SAD): Placebo
Healthy participants receive single fasting oral placebo tablets matching HL40626S, one dose per participant.
干预措施: HL40626S placebo (Drug)
Part 2 (MAD) : Placebo
Healthy participants receive once-daily oral matching placebo tablets for 14 days.
干预措施: HL40626S placebo (Drug)
Part 2 (MAD): HL40626S
Healthy participants receive once-daily fasting oral HL40626S tablets for 14 consecutive days across three sequential cohorts.
干预措施: HL40626S tablets (Drug)
结局指标
主要结局
Parts 1 (SAD) and 2 (MAD): Safety and tolerability of HL40626S
时间窗: From signed informed consent through Day 15 for SAD and Day 29 for MAD.
Assess incidence, severity, causality and clinical outcome of treatment-emergent adverse events (TEAEs) and serious adverse events (SAEs) graded per CTCAE Version 6.0. Clinically significant abnormal results from physical examinations, vital sign tests, clinical laboratory tests and 12-lead ECG assessments are evaluated against baseline.
Parts 1 (SAD) and 2 (MAD): Incidence of Treatment-Emergent Adverse Events [Safety and Tolerability]
时间窗: From signed informed consent through Day 15 for SAD and Day 29 for MAD.
Assess incidence, severity, causality and clinical outcome of treatment-emergent adverse events (TEAEs) graded per CTCAE Version 6.0 to characterize the safety and tolerability of HL40626S in Part 1 (SAD) and Part 2 (MAD).
Parts 1 (SAD) and 2 (MAD): Incidence of serious adverse events (SAEs) [Safety and Tolerability]
时间窗: From signed informed consent through Day 15 for SAD and Day 29 for MAD.
Assess Incidence, severity, causality, and clinical outcome of serious adverse events (SAEs) graded per CTCAE Version 6.0 to characterize the safety and tolerability of HL40626S in Part 1 (SAD) and Part 2 (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]
时间窗: From signed informed consent through Day 15 for SAD and Day 29 for MAD.
Abnormal findings from physical examinations, vital sign measurements, laboratory analyses and 12-lead ECG tracings are compared against each participant's baseline values to support the overall safety and tolerability assessment of HL40626S in Part 1 (SAD) and Part 2 (MAD).
次要结局
- Part 1 (SAD): Maximum observed plasma concentration (Cmax)(Predose up to 96 hours (Day 5) post single dose.)
- Part 1 (SAD): Time to maximum observed plasma concentration (Tmax)(Predose up to 96 hours (Day 5) post single dose.)
- Part 1 (SAD): Area under the plasma concentration-time curve from time zero to last measurable concentration (AUClast)(Predose up to 96 hours (Day 5) post single dose.)
- Part 1 (SAD): Area under the plasma concentration-time curve extrapolated to infinite time (AUCinf)(Predose up to 96 hours (Day 5) post single dose.)
- Part 1 (SAD): Terminal elimination rate constant (Kel)(Predose up to 96 hours (Day 5) post single dose.)
- Part 1 (SAD): Terminal half-life (t1/2)(Predose up to 96 hours (Day 5) post single dose.)
- Part 1 (SAD): Apparent clearance (CL/F)(Predose up to 96 hours (Day 5) post single dose.)
- Part 1 (SAD): Apparent volume of distribution during terminal phase (Vd/F)(Predose up to 96 hours (Day 5) post single dose.)
- Part 2 (MAD): Maximum plasma concentration at steady state (Css,max)(Predose Day 1 to 96 hours after the final Day 14 dose, up to Day 18.)
- Part 2 (MAD): Minimum plasma concentration at steady state (Css, min)(Predose Day 1 to 96 hours after the final Day 14 dose, up to Day 18.)
- Part 2 (MAD): Area under the curve at steady state from time zero to time t (AUC0-τ,ss)(Predose Day 1 to 96 hours after the final Day 14 dose, up to Day 18.)
- Part 2 (MAD): Apparent clearance at steady-state (CLss/F)(Predose Day 1 to 96 hours after the final Day 14 dose, up to Day 18.)
- Part 2 (MAD): Average plasma concentration at steady state (Css,av)(Predose Day 1 to 96 hours after the final Day 14 dose, up to Day 18.)
- Part 2 (MAD): Apparent volume of distribution during terminal phase at steady state (Vss/F)(Predose Day 1 to 96 hours after the final Day 14 dose, up to Day 18.)
- Part 2 (MAD): Accumulation ratio based on peak concentration (Rac,Cmax)(Predose Day 1 to 96 hours after the final Day 14 dose, up to Day 18.)
- Part 2 (MAD): Accumulation ratio based on dosing interval AUC (Rac,AUCτ)(Predose Day 1 to 96 hours after the final Day 14 dose, up to Day 18.)
- Parts 1 and 2: Plasma IFNγ concentration(Baseline up to 24 hours post single dose (Day 2) for SAD, and up to 24 hours after the Day 14 last dose (Day 15) for MAD.)
- Part 2 (MAD): Incidence and titre of anti-drug antibodies (ADA) against HL40626S(Baseline Day 1 predose, Day 7 predose, Day 14 predose, and Day 29 EOS visit)
- Part 1 (SAD): Area under the plasma concentration-time curve extrapolated to infinite time (AUCinf)(Predose up to 5 days post single dose.)
- Part 1 (SAD): Maximum observed plasma concentration (Cmax)(Predose up to 5 days post single dose.)
- Part 1 (SAD): Time to maximum observed plasma concentration (Tmax)(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)(Predose up to 5 days post single dose.)
- Part 1 (SAD): Terminal elimination rate constant (Kel)(Predose up to 5 days post single dose.)