A Study to Investigate Safety, Tolerability, Pharmacokinetics, and Pharmacodynamics of AZD4954 in Healthy Adult Participants With or Without Elevated Lipoprotein (a) (Lp[a]) Levels, and Participants With Dyslipidemia

Официальное название

A Phase I, Randomized, Single-blind, Placebo-controlled Study to Assess the Safety, Tolerability, Pharmacokinetics and Pharmacodynamics of AZD4954 Following Single and Multiple Ascending Dose Administration to Healthy Participants With or Without Elevated Lp(a) Levels, and Participants With Dyslipidemia

Обзор

The purpose of the study is to evaluate the safety, tolerability, pharmacokinetics (PK), and pharmacodynamics (PD) of single and multiple ascending doses of AZD4954 in healthy participants with or without elevated Lipoprotein(a) (Lp\[a\]) levels and participants with dyslipidemia.

Подробное описание

This is a first time in human, placebo-controlled, single and multiple ascending dose (SAD and MAD) study in healthy male and female participants (Part A) or healthy participants with elevated Lp(a) levels (≥ 30 mg/dL) and participants with dyslipidemia with elevated Lp(a) levels (≥ 70 mg/dL) and low-density lipoprotein cholesterol (LDL-C) ≥ 70 mg/dL and \< 190 mg/dL (Part B).

The study consists of 2 parts: Part A (SAD) and Part B (MAD).

Part A of the study will consist of Part A1 and Part A2, comprising:

* A Screening Period of maximum 28 days. * Admission to study site (Day -1). * A Treatment Period (Day 1 to Day 15 at the study site) with a single dose of AZD4954 or placebo on Day 1. * A Follow-up Visit within 26 to 30 days after the study intervention dose for all cohorts (Day 29 ±2 days).

Part B has 3 types of MAD cohorts - global cohorts with healthy participants, global cohort with participants with dyslipidemia, and a Japanese cohort. The global MAD cohorts (healthy participants) and Japanese MAD cohort will comprise:

* A Screening Period of maximum 28 days. * Admission to study site (Day -1). * A Treatment Period during which participants will receive either AZD4954 or placebo once daily for 21 days (Day 1 to 21). * A Follow-up Visit within 26 to 30 days after the last study intervention dose (Day 49 ±2 days).

The global MAD cohort (participants with dyslipidemia) will comprise:

* A Screening Period of maximum 28 days. * Residential study site visits from Day -1 to Day 2 and Day 21 to Day 22. * Non-residential study site visits on Day 8 and Day 15. * A Treatment Period during which participants will receive either AZD4954 or placebo once daily for 21 days (Day 1 to 21). * A Follow-up Visit within 26 to 30 days after the last study intervention dose (Day 49 ± 2 days).

Вмешательства

• Препарат AZD4954
  AZD4954 will be administered orally.
• Препарат Placebo
  Placebo will be administered orally.

Первичные конечные точки

• Part A: Number of participants with Adverse Events (AEs) and Serious Adverse Events (SAEs) [Срок оценки: From Screening (Day -28 to Day -2) to Follow-up visit (Up to Day 29±2 days)]
• Part B: Number of participants with AEs and SAEs [Срок оценки: From Screening (Day -28 to Day -2) to Follow-up visit (Up to Day 49±2 days)]

Вторичные конечные точки (12)

• Part A: Area under concentration-time curve from time 0 to infinity (AUCinf) [Срок оценки: Up to Day 29±2 days]
• Area under concentration-curve from time 0 to the last quantifiable concentration (AUClast) [Срок оценки: Part A: Up to Day 29±2 days; Part B: Up to Day 49±2 days]
• Part B: Area under concentration-time curve in the dosing interval (AUCtau) [Срок оценки: Up to Day 49±2 days]
• Dose normalized AUClast (AUClast/D) [Срок оценки: Part A: Up to Day 29±2 days; Part B: Up to Day 49±2 days]
• Dose normalized AUCinf (AUCinf/D) [Срок оценки: Part A: Up to Day 29±2 days; Part B: Up to Day 49±2 days]
• Part B: Dose normalized AUCtau (AUCtau/D) [Срок оценки: Up to Day 49±2 days]
• Apparent total body clearance (CL/F) [Срок оценки: Part A: Up to Day 29±2 days; Part B: Up to Day 49±2 days]
• Maximum observed drug concentration (Cmax) [Срок оценки: Part A: Up to Day 29±2 days; Part B: Up to Day 49±2 days]
• Dose normalized Cmax (Cmax/D) [Срок оценки: Part A: Up to Day 29±2 days; Part B: Up to Day 49±2 days]
• Terminal elimination half-life (t1/2λz) [Срок оценки: Part A: Up to Day 29±2 days; Part B: Up to Day 49±2 days]
• Time of last quantifiable concentration (tlast) [Срок оценки: Part A: Up to Day 29±2 days; Part B: Up to Day 49±2 days]
• Time to reach maximum observed concentration (tmax) [Срок оценки: Part A: Up to Day 29±2 days; Part B: Up to Day 49±2 days]

Критерии участия

Критерии включения

All Parts:

• Participants with plasminogen level (concentration) within normal range at the Screening Visit.
• All females must have a negative pregnancy test at the Screening Visit and on admission to the study site.
• Females of childbearing potential must not be lactating and if heterosexually active must agree to use an approved method of highly effective contraception.
• Females of non-childbearing potential must be confirmed at the Screening Visit.
• Sexually active fertile male participants with partners of childbearing potential must adhere to the study specific contraception methods from the time of first administration of study intervention until 3 months after the study Follow-up Visit.

Parts A and B (Healthy Participants):

• Male and female participants aged 18 to 65 years with suitable veins for cannulation or repeated venipuncture.
• Have a body mass index (BMI) between 18 and 35 kg/m² inclusive.
• For Japanese and Chinese participants (Parts A and B):

• A Japanese participant is defined as having both parents and 4 grandparents who are ethnically Japanese. This includes second and third generation Japanese whose parents or grandparents are living in a country other than Japan.
• A Chinese participant is defined as having both parents and 4 grandparents who are ethnically Chinese. This includes second and third generation Chinese whose parents or grandparents are living in a country other than China.

Part B (Healthy Participants):

• Participants must have elevated Lp(a) ≥ 30 mg/dL at the Screening Visit.

Part B (Participants with Dyslipidemia):

• Male and female participants aged 18 to 70 years with suitable veins for cannulation or repeated venipuncture.
• Have a BMI > 18 kg/m².
• Participants must have elevated Lp(a) ≥ 70 mg/dL at the Screening Visit.
• Participants with a fasting LDL-C ≥ 70 mg/dL and < 190 mg/L at the Screening Visit.
• Participants should be receiving moderate or high-intensity statin therapy for ≥ 2 months prior to the Screening Visit, according to the American College of Cardiology/American Heart Association guidelines on blood cholesterol management.
• Participants with documented coronary artery disease, stroke, or peripheral artery disease or at moderate or high risk for an atherosclerotic cardiovascular disease event.
• There should be no planned medication or dose change during study participation.

Критерии исключения

All Parts:

• History of any clinically important disease or disorder.
• History or presence of gastrointestinal, hepatic, or renal disease or any other condition known to interfere with absorption, distribution, metabolism, or excretion of drugs.
• Any clinically important illness, medical/surgical procedure, or trauma within 4 weeks of the first administration of study intervention.
• Participants with known bleeding or coagulation disorders.
• Participants who have an elevated high-sensitivity C-reactive protein (> 3 mg/L) or have a prothrombin time/international normalized ratio (PT/INR) or activated partial thromboplastin time (aPTT) > 1.25 times × upper limit normal (ULN).
• Any clinically important abnormalities in hematology, coagulation, clinical chemistry, urinalysis, abnormal vital signs or abnormal laboratory values.
• Any positive result on Screening for serum hepatitis B surface antigen (HBsAg), hepatitis B core antibody (HBcAb), hepatitis C virus (HCV) or human immunodeficiency virus (HIV).
• Any clinically important abnormalities in rhythm, conduction, or morphology of the resting 12-lead electrocardiogram (ECG) at Screening.
• Use of drugs with enzyme inducing properties such as St John's Wort within 3 weeks prior to the first administration of study intervention.

Parts A and B (Healthy Participants):

• Use of any prescribed or nonprescribed medication including antacids, analgesics (other than paracetamol/acetaminophen), herbal remedies, intake of > 3 × daily recommended levels of vitamins and minerals during the 2 weeks prior to the first administration of study intervention or longer if the medication has a long half-life.
• Current smokers or those who have smoked or used nicotine products.

Part B (Participants with Dyslipidemia):

• Acute ischemic cardiovascular event in the last 12 months prior to randomization.
• Poorly controlled diabetes.
• Previous administration of Lp(a) inhibitor.
• Have uncontrolled hypertension.
• Abnormal vital heart rate.

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

Здоровые добровольцы: Нет

Дизайн исследования

Распределение

Рандомизированное

Модель

Последовательный дизайн

Маскирование

Тройное слепое

Основная цель

Лечение

Центры проведения

США · 6 центров

• Research Site — Glendale
• Research Site — Inverness
• Research Site — Jacksonville
• Research Site — Port Orange
• Research Site — Brooklyn
• Research Site — San Antonio

Идентификаторы

NCT: NCT06980428 · D7300C00001

Первоисточники (государственные реестры)

• ClinicalTrials.gov (NIH, США)

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