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

AstraZeneca

Status and phase: Not yet enrolling; Phase 1

Conditions: Chronic Kidney Disease

Treatments: Drug: Placebo; Drug: AZD4248

Study type: Interventional

Funder types: Industry

Identifiers

NCT07024823

D8380C00001

Details and patient eligibility

About

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).

Full description

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.

Enrollment: 164 estimated patients

Sex: All

Ages: 18 to 75 years old

Volunteers: Accepts Healthy Volunteers

Inclusion and exclusion criteria

Key Inclusion Criteria:

• 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 35 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.

Key Exclusion Criteria:

• 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.

Trial design

Primary purpose: Treatment

Allocation: Randomized

Interventional model: Sequential Assignment

Masking: Double Blind

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164 participants in 7 patient groups

Part A1 SAD

Experimental group

Description:

Participants will receive single ascending oral dose of AZD4248 or placebo.

Treatment:

Drug: Placebo

Drug: AZD4248

Drug: Placebo

Drug: AZD4248

Part A2 SAD Chinese Cohort

Experimental group

Description:

Participants will receive single oral dose of AZD4248 or placebo.

Treatment:

Drug: Placebo

Drug: AZD4248

Drug: Placebo

Drug: AZD4248

Part A3 SAD IV Cohort

Experimental group

Description:

Participants will receive single IV infusion of AZD4248 or placebo.

Treatment:

Drug: Placebo

Drug: AZD4248

Drug: Placebo

Drug: AZD4248

Part B1 MAD

Experimental group

Description:

Participants will receive multiple ascending oral doses of AZD4248 or placebo.

Treatment:

Drug: Placebo

Drug: AZD4248

Drug: Placebo

Drug: AZD4248

Part B2 MAD Japanese

Experimental group

Description:

Participants will receive multiple ascending oral doses of AZD4248 or placebo.

Treatment:

Drug: Placebo

Drug: AZD4248

Drug: Placebo

Drug: AZD4248

Part C Multiple Dosing DKD

Experimental group

Description:

Participants will receive multiple oral doses of AZD4248 or placebo.

Treatment:

Drug: Placebo

Drug: AZD4248

Drug: Placebo

Drug: AZD4248

Part D Observational Cohort

No Intervention group

Description:

Participants will participate in home-based creatinine self-measurement.