A Study to Investigate Safety, Tolerability, Pharmacokinetics, and Pharmacodynamics of AZD4248 in Healthy Participants and Participants With Chronic Kidney Disease and Type 2 Diabetes and to Assess Home Measurements of Creatinine in a Non Interventional Cohort

Официальное название

A Phase I Randomized, Single-Blind, Placebo-Controlled Study to Assess the Safety, Tolerability, Pharmacokinetics, and Pharmacodynamics of AZD4248 Following Single and Multiple Ascending Dose Administration in Healthy Participants and Participants With Chronic Kidney Disease and Type 2 Diabetes and to Assess Home Measurements of Creatinine in a Prospective, Non-interventional Cohort Study

Обзор

This study will evaluate safety, tolerability, pharmacokinetics (PK), and pharmacodynamics (PD) of single ascending doses (SAD) and multiple ascending doses (MAD) of AZD4248 administered as an oral solution and intravenous (IV) infusion. Additionally, the study investigates the non-interventional feasibility of home measurement of serum creatinine in participants with diabetic kidney disease (DKD).

Подробное описание

This is a Phase I, first in human (FIH), randomized, single-blind, placebo-controlled study of AZD4248 involving healthy participants (Parts A and B) and participants with DKD (Part C) and to assess home measurements of creatinine in a prospective, non-interventional cohort in participants with DKD (Part D).

The study consists of 4 parts:

* Part A: SAD. Part A will consist of Parts A1 (single ascending doses in healthy participants), A2 (single dose in healthy Chinese participants), and A3 (IV infusion in healthy participants). * Part B: MAD. Part B will consist of Parts B1 (multiple ascending doses in healthy participants) and B2 (multiple ascending doses in healthy participants of Japanese descent). * Part C: Multiple dosing in participants with DKD. * Part D: Multi-site, non-interventional, prospective cohort evaluation of home-based creatinine self-measurement in participants with DKD.

Вмешательства

• Препарат AZD4248
  AZD4248 will be administered orally.
• Препарат Placebo
  Placebo will be administered orally.
• Препарат AZD4248
  AZD4248 will be administered via IV infusion.
• Препарат Placebo
  Placebo will be administered via IV infusion.

Первичные конечные точки

• Parts A, B, and C: Number of Participants with Adverse Events (AEs) and Serious Adverse Events (SAEs) [Срок оценки: From Day 1 to Follow Up visit (Part A: up to 12 days; Part B and C: up to 19 days)]
• Part D: Intra- and inter-participant variability of estimated glomerular filtration rate (eGFR) derived from home self-testing device measurements [Срок оценки: Day 1 to Day 169]

Вторичные конечные точки (12)

• Area under concentration-time curve from time 0 to infinity (AUCinf) [Срок оценки: Part A1 and A2: Days 1-7, Part A3: Days 1-3, Part B: Days 1-17. Part C: Days 1-17]
• Area under concentration-curve from time 0 to the last quantifiable concentration (AUClast) [Срок оценки: Part A1 and A2: Days 1-7, Part A3: Days 1-3, Part B: Days 1-17. Part C: Days 1-17]
• Dose normalized AUClast (AUClast/D) [Срок оценки: Part A1 and A2: Days 1-7, Part A3: Days 1-3, Part B: Days 1-17. Part C: Days 1-17]
• Dose normalized AUCinf (AUCinf/D) [Срок оценки: Part A1 and A2: Days 1-7, Part A3: Days 1-3, Part B: Days 1-17. Part C: Days 1-17]
• Apparent total body clearance (CL/F) [Срок оценки: Part A1 and A2: Days 1-7, Part A3: Days 1-3, Part B: Days 1-17. Part C: Days 1-17]
• Maximum observed drug concentration (Cmax) [Срок оценки: Part A1 and A2: Days 1-7, Part A3: Days 1-3, Part B: Days 1-17. Part C: Days 1-17]
• Dose normalized Cmax (Cmax/D) [Срок оценки: Part A1 and A2: Days 1-7, Part A3: Days 1-3, Part B: Days 1-17. Part C: Days 1-17]
• Terminal elimination half-life (t½λz) [Срок оценки: Part A1 and A2: Days 1-7, Part A3: Days 1-3, Part B: Days 1-17. Part C: Days 1-17]
• Terminal rate constant (λz) [Срок оценки: Part A1 and A2: Days 1-7, Part A3: Days 1-3, Part B: Days 1-17. Part C: Days 1-17]
• Time delay between drug administration and the first observed concentration (tlag) [Срок оценки: Part A1 and A2: Days 1-7, Part A3: Days 1-3.]
• Time of last quantifiable concentration (tlast) [Срок оценки: Part A1 and A2: Days 1-7, Part A3: Days 1-3, Part B: Days 1-17. Part C: Days 1-17]
• Time to reach maximum observed concentration (tmax) [Срок оценки: Part A1 and A2: Days 1-7, Part A3: Days 1-3, Part B: Days 1-17. Part C: Days 1-17]

Критерии участия

Критерии включения

\- Healthy participants with suitable veins for cannulation or repeated venipuncture.

Parts A and B:

• Have a body mass index (BMI) between 18 and 30 kilograms per millimeter (kg/m2), inclusive.
• For Chinese participants (Part A2): participants are to be Chinese, defined as having both parents and 4 grandparents who are Chinese. This includes second and third generation participants of Chinese descent whose parents or grandparents are living in a country other than China.
• For Japanese participants (Part B2): participants are to be Japanese, defined as having both parents and 4 grandparents who are Japanese. This includes second and third generation participants of Japanese descent whose parents or grandparents are living in a country other than Japan.

Part C:

• Have a BMI between 20 and 40 kg/m2, inclusive.
• Have a diagnosis of diabetic kidney disease (DKD).
• Hemoglobin A1C (HbA1c) of ≤ 10.5%.
• Participants are required to be on a stable dose of angiotensin converting enzyme inhibitor (ACEi) or angiotensin receptor blocker (ARB) for at least 6 weeks prior to Visit 1 and throughout the Screening Period. In addition, participants should be on stable doses of all other medication for ≥ 6 weeks before Screening.

Part D:

• Have a BMI between 20 and 35 kg/m2, inclusive.
• Have a diagnosis of DKD as defined by a) diagnosis of type 2 diabetes (T2D) b) eGFR values and c) urine albumin to creatinine ratio (UACR) values.
• HbA1c of ≤ 10.5%.
• Participants are required to be on a stable dose of ACEi or ARB for at least 6 weeks prior to Visit 1 and throughout the Screening Period. In addition, participants should be on stable doses of all other medication for ≥ 6 weeks before Screening.
• Participants must be able and motivated to use the home creatinine device and smartphone independently by successfully performing the test without assistance from site staff.
• Participants must be able to read and understand English sufficient to participate in site visits and home testing.

Критерии исключения

• History of any clinically important disease or disorder which may put the participant at risk because of participation in the study or influence the results.
• Any positive result on Screening for serum hepatitis B surface antigen (HBsAg), hepatitis B core antibody (HBcAb), or human immunodeficiency virus (HIV).

Parts A and B:

• History or presence of gastrointestinal, hepatic, or renal disease.
• Any clinically important illness, medical/surgical procedure, or trauma within 4 weeks of the first administration of study intervention.
• History of severe allergy/hypersensitivity or ongoing clinically important allergy/hypersensitivity, or history of hypersensitivity to drugs with a similar chemical structure or class to AZD4248.
• Participants who have previously received AZD4248.

Part C:

• History or presence of gastrointestinal, hepatic, or renal disease.
• Any clinically important illness, medical/surgical procedure, or trauma within 4 weeks of the first administration of study intervention.
• History of severe allergy/hypersensitivity or ongoing clinically important allergy/hypersensitivity, or history of hypersensitivity to drugs with a similar chemical structure or class to AZD4248.
• Use of drugs that are strong or moderate CYP3A4 inhibitors/inducers or P-gp inhibitors from within 3 weeks before Screening until the end of the last sample collection.
• Participants who have previously received AZD4248.
• Participants on serum creatinine-altering drugs should be on long-term treatment at a stable dose prior to study entry.
• Expected change of dosing regimen during the study.
• History of clinically significant heart or vascular disease.
• New York Heart Association Class 2, 3, or 4 or history of hospitalization for heart failure within 6 months of screening.
• Ventricular arrhythmias requiring treatment.
• Amputation due to peripheral artery disease.
• Severe chronic obstructive pulmonary disease as judged by the Investigator or hospitalization for exacerbation in the last 6 months.

Part D:

• Participants on serum creatinine-altering drugs should be on long-term treatment at a stable dose prior to study entry.
• Expected change of dosing regimen during the study.

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

Здоровые добровольцы: Да

Дизайн исследования

Распределение

Рандомизированное

Модель

Последовательный дизайн

Маскирование

Двойное слепое

Основная цель

Лечение

Центры проведения

США · 5 центров

• Research Site — Glendale
• Research Site — Chicago
• Research Site — Ann Arbor
• Research Site — Saint Paul
• Research Site — San Antonio

Идентификаторы

NCT: NCT07024823 · D8380C00001

Первоисточники (государственные реестры)

• ClinicalTrials.gov (NIH, США)

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