Safety and Tolerability of ZE74-0282 in Healthy Volunteers

Официальное название

A Double-Blind, Placebo-Controlled, First-in-Human Study of the Safety, Tolerability, and Pharmacokinetics of ZE74-0282 in Healthy Volunteers

Обзор

This first-in-human, randomized, double-blind, placebo-controlled Phase 1 study evaluates the safety, tolerability, and pharmacokinetics of single, split, and multiple oral doses of ZE74-0282 under fasted or fed conditions in healthy adult volunteers.

Подробное описание

This is a double-blind, randomized, placebo-controlled, first-in-human Phase 1 study evaluating the safety, tolerability, and pharmacokinetics of ZE74-0282 in healthy adult volunteers. A total of up to 64 participants are planned: 48 participants in Part A and 16 participants in Part B. Each cohort will enroll 8 participants, with 6 randomized to ZE74-0282 and 2 randomized to matching placebo. Dose levels and cohort progression will be reviewed sequentially by the Safety Review Committee based on blinded safety and available pharmacokinetic data.

Part A comprises Cohorts 1, 2, 2a, 3, 4, and 5. It evaluates single ascending doses and, where selected by the Safety Review Committee, split or twice-daily dosing on Day 1. Cohort 2a evaluates 75 mg twice daily, administered 12 hours (+/- 30 minutes) apart on Day 1, for a total daily dose of 150 mg. Dosing in each Part A cohort begins with 2 sentinel participants before dosing the remaining participants. Part A participants are confined from Day -1 through Day 4 and complete the end-of-study visit on Day 8 (+/- 1 day).

Part B comprises Cohorts 6 and 7 and evaluates multiple ascending doses for 7 days. Cohort 6 receives 75 mg twice daily and Cohort 7 receives 150 mg twice daily. Doses are administered approximately 12 hours (+/- 30 minutes) apart on Days 1 through 6, with a morning dose only on Day 7, for a total of 13 doses. Part B participants are confined from Day -1 through Day 8, have a follow-up telephone call on Day 11, and complete the end-of-study visit on Day 18 (+/- 1 day).

Вмешательства

• Препарат ZE74-0282-0001 or placebo
  The participant will receive ZE74-0282-0001 or placebo

Первичные конечные точки

• Incidence of AEs/SAEs [Срок оценки: Baseline to Day 8]
• Change from Baseline in body weight [Срок оценки: Baseline to Day 8]
• Change from Baseline in blood pressure [Срок оценки: Baseline to Day 8]
• Change from Baseline in electrocardiogram (ECG) QT interval [Срок оценки: Baseline to Day 8]
• Change from Baseline in haematology parameters [Срок оценки: Baseline to Day 8]
• Change from Baseline in pulse rate [Срок оценки: Baseline to Day 8]
• Change from Baseline in respiratory rate [Срок оценки: Baseline to Day 8]
• Change from Baseline in temperature [Срок оценки: Baseline to Day 8]
• Change from Baseline in clinical chemistry parameters [Срок оценки: Baseline to Day 8]
• Change from baseline in coagulation parameters [Срок оценки: Baseline to Day 8]

Вторичные конечные точки (12)

• Maximum observed plasma concentration [Срок оценки: PK samples will be collected from Day 1 to Day 4 and on Day 8]
• Time to Cmax [Срок оценки: PK samples will be collected from Day 1 to Day 4 and on Day 8]
• Area under the concentration-time curve from 0 to time of last quantifiable concentration [Срок оценки: PK samples will be collected from Day 1 to Day 4 and on Day 8]
• Area under the concentration-time curve from 0 to 24 hours [Срок оценки: PK samples will be collected from Day 1 to Day 4 and on Day 8]
• Area under the concentration-time curve from 0 to infinity [Срок оценки: PK samples will be collected from Day 1 to Day 4 and on Day 8]
• Apparent terminal elimination half-life [Срок оценки: PK samples will be collected from Day 1 to Day 4 and on Day 8]
• Terminal elimination rate constant [Срок оценки: PK samples will be collected from Day 1 to Day 4 and on Day 8]
• Total apparent body clearance following oral administration [Срок оценки: PK samples will be collected from Day 1 to Day 4 and on Day 8]
• Apparent volume of distribution following oral administration [Срок оценки: PK samples will be collected from Day 1 to Day 4 and on Day 8]
• Trough plasma concentration (Ctrough) - Part B [Срок оценки: Predose on Day 1 through 264 hours after the Day 7 morning dose (Day 18).]
• Apparent steady-state clearance - Part B [Срок оценки: Predose on Day 1 through 264 hours after the Day 7 morning dose (Day 18).]
• Apparent steady-state volume of distribution (Vss/F) - Part B [Срок оценки: Predose on Day 1 through 264 hours after the Day 7 morning dose (Day 18).]

Критерии участия

Критерии включения

• Healthy volunteers will be included in the study if they satisfy all of the following criteria:

• Must have given written informed consent before any study-related activities are carried out and must be able to understand the full nature and purpose of the trial, including possible risks and adverse effects.
• Adult males and females, 18 to 55 years of age (inclusive) at Screening.
• Body mass index (BMI) ≥18.0 and ≤32.0 kg/m2, with a body weight ≤100 kg at Screening.
• Medically healthy (in the opinion of the PI or delegate), as determined by pre-study medical history, and without CS abnormalities including the following:

• Physical examination without any clinically relevant findings;
• Systolic blood pressure in the range of 90 to 160 mmHg and diastolic blood pressure in the range of 50 to 95 mmHg after resting for 5 minutes in a semi-supine or supine position.
• Pulse rate in the range of 45 to 100 beats per minute after 5 minutes resting in a semi-supine or supine position.
• Body temperature (tympanic), between 35.5°C and 37.7°C.
• Electrocardiogram without CS abnormalities including QTcF <450 msec.
• Female volunteers:

• Must be of non childbearing potential i.e., surgically sterilised (hysterectomy, bilateral salpingectomy, bilateral oophorectomy) at least 6 weeks before the screening visit or postmenopausal (where postmenopausal is defined as no menses for 12 months without an alternative medical cause and a follicle stimulating hormone \[FSH\] level consistent with postmenopausal status, per local laboratory guidelines), or
• If of childbearing potential, must:

i. Have a negative pregnancy test at the screening visit and on admission to the study site on Day -1.

ii. Agree not to attempt to become pregnant or donate ova from signing the ICF until at least 30 days after the last dose of study drug.

iii. Agree to use adequate contraception (defined as use of a condom by the male partner combined with use of a highly effective method of contraception \[Section 10.4.3\]) from the time of consent/screening until at least 30 days after the last dose of study drug, if not exclusively in a same-sex relationship or abstinent as a committed lifestyle.

• Male volunteers:

• Must agree not to donate sperm from signing the ICF until at least 90 days after the last dose of study drug.
• If engaging in sexual intercourse with a female partner who could become pregnant, must agree to use adequate contraception (defined as use of a condom combined with use of a highly effective method of contraception) from signing the ICF until at least 90 days after the last dose of study drug.
• If engaging in sexual intercourse with a female partner who is not of childbearing potential or a same-sex partner, must agree to use a condom from signing the ICF until at least 5 days after the last dose of study drug.
• Have suitable venous access for blood sampling.
• Willing and able to comply with all study assessments and adhere to the protocol schedule and restrictions.

Критерии исключения

• Healthy volunteers will be excluded from the study if there is evidence of any of the following at the screening visit or prior to dosing at the timepoint in the SoA:

• History of anaphylaxis or other significant allergy which, in the opinion of the PI (or delegate), would interfere with the volunteer's ability to participate in the study.
• History or presence of CS cardiovascular, pulmonary, hepatic, renal, haematological, gastrointestinal, endocrine, immunologic, dermatologic, psychiatric, or neurological disease/disorder, including any acute illness, within the past 3 months determined by the PI (or delegate) to be clinically relevant.
• History of surgery or hospitalisation within 3 months prior to screening, or surgery planned during the study.
• Any history of malignant disease in the last 10 years (excludes surgically resected skin squamous cell or basal cell carcinoma with histopathologically-confirmed clear margins).
• Presence of clinically relevant immunosuppression from, but not limited to, immunodeficiency conditions such as common variable hypogammaglobulinemia.
• History of risk factors for torsade de pointes (including a family history of long QT syndrome or sudden cardiac death) or a known arrythmia.
• Presence or having sequelae of gastrointestinal, liver (including Gilbert's syndrome), kidney, or other conditions known to interfere with the absorption, distribution, metabolism, or excretion of drugs.
• Liver function test results elevated more than 1.5 fold above the ULN for gamma glutamyl transferase, bilirubin (total, conjugated and unconjugated), ALP, AST or ALT. Volunteers with ALP and/or ALT/AST above the limits specified may be included, at the discretion of the PI (or delegate), if the levels are unaccompanied by clinical signs and are determined to be normal variants.
• Estimated creatinine clearance <60 mL/min using the Cockcroft-Gault formula or serum creatinine >1.5 fold above the ULN.
• A history of or positive test results for human immunodeficiency virus (HIV), hepatitis B surface antigen (HBsAg), or hepatitis C virus (HCV) antibodies at the screening visit.
• Positive drugs of abuse test or alcohol breath test results at the screening visit and/or on admission to the study site on Day 1. Note that positive carbon monoxide test at Screening is not exclusionary.
• Regular consumption of more than 10 standard alcoholic drinks/week and/or more than 4 standard alcoholic drinks on any one day, where 1 standard drink is 10 g of pure alcohol and is equivalent to 285 mL beer \[4.9% Alc/Vol\], 100 mL wine \[12% Alc/Vol\], or 30 mL spirit \[40% Alc/Vol\]).
• Participants must be nonsmokers (including tobacco, nicotine replacement therapy, e-cigarettes and marijuana) for at least 3 months prior to the dose of study drug, have a negative carbon monoxide test at Screening and check-in (Day -1) to the clinical facility and refrain from smoking for the duration of the study. Note that positive carbon monoxide test at Screening is not exclusionary.
• Females who are breastfeeding or are planning to breastfeed from screening until 3 months after the dose of study drug (or 5 × half-lives, whichever is longer).
• Unable to swallow oral medication
• Use of any prescription or over-the-counter medication (including oral contraceptives herbal products, nutritional supplements, diet aids, vitamin supplements, minerals and hormone supplements) within 7 days or 5 half-lives of the medication (whichever is longer) prior to the dose of study drug, except the use of paracetamol doses of 500 mg up to every 6 hours or 2 g per day maximum for no more than 3 consecutive days in one week.
• Current infection that requires systemically absorbed antibiotic, antifungal, antiparasitic or antiviral medication within 10 days prior to dose of study drug.
• Use of inactivated vaccines within 14 days or live vaccines within 30 days prior to the study drug administration and during the study.
• Participants must not take systemic immunosuppressive (e.g., corticosteroids, methotrexate, azathioprine, cyclosporine) or immunomodulating medications (e.g., interferon) within 28 days or 5 half-lives of any relevant agent(s) (whichever is longer) prior to dosing and during the study.
• Donation of blood or plasma within 30 days prior to dosing of study drug, or loss of whole blood of more than 500 mL within 30 days prior to first dose of study drug, or receipt of a blood transfusion within 1 year of the first dose of study drug.
• Participation in a clinical study of an investigational drug or investigational device within 30 days or 5 half-lives of the investigational drug (whichever is longer) prior to screening.
• Any other condition or prior therapy that in the opinion of the PI (or delegate) would make the volunteer unsuitable for this study, including inability to cooperate fully with the requirements of the study protocol or likelihood of noncompliance with any study requirements.

Критерии приведены из реестра в оригинале (на английском). Окончательную оценку соответствия проводит исследовательский центр.

Здоровые добровольцы: Да

Дизайн исследования

Распределение

Рандомизированное

Модель

Параллельные группы

Маскирование

Двойное слепое

Основная цель

Другое

Центры проведения

Австралия · 1 центр

• Scientia Clinical Research Ltd. — Randwick

Идентификаторы

NCT: NCT07527221 · ZE74-0282-0001

Первоисточники (государственные реестры)

• ClinicalTrials.gov (NIH, США)

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