Clinical trial NCT07024823: 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
Official title: 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
Study type: INTERVENTIONAL
Overall status: NOT_YET_RECRUITING
Phase: PHASE1
Conditions: Chronic Kidney Disease
Keywords: Type 2 Diabetes
Diabetic Kidney Disease
Multiple Ascending Dose
Single Ascending Dose
Creatinine
Food Effect
Pharmacokinetics
Safety
Lead sponsor: AstraZeneca
Sponsor class: INDUSTRY
Collaborators: name: Parexel
First posted: 2025-06-17
Enrollment: 164
Sex: ALL
Minimum age (years): 18
Maximum age (years): 75
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: yes
Allocation: RANDOMIZED
Intervention model: SEQUENTIAL
Primary purpose: TREATMENT

Brief summary: 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).

Detailed 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.

Eligibility 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.

Primary outcomes:
measure: Parts A, B, and C: Number of Participants with Adverse Events (AEs) and Serious Adverse Events (SAEs)
timeFrame: From Day 1 to Follow Up visit (Part A: up to 12 days; Part B and C: up to 19 days)
measure: Part D: Intra- and inter-participant variability of estimated glomerular filtration rate (eGFR) derived from home device measurements
timeFrame: Day 1 to Day 169
Secondary outcomes:
measure: Area under concentration-time curve from time 0 to infinity (AUCinf)
timeFrame: Part A1 and A2: Days 1-7, Part A3: Days 1-3, Part B: Days 1-17. Part C: Days 1-17
measure: Area under concentration-curve from time 0 to the last quantifiable concentration (AUClast)
timeFrame: Part A1 and A2: Days 1-7, Part A3: Days 1-3, Part B: Days 1-17. Part C: Days 1-17
measure: Dose normalized AUClast (AUClast/D)
timeFrame: Part A1 and A2: Days 1-7, Part A3: Days 1-3, Part B: Days 1-17. Part C: Days 1-17
measure: Dose normalized AUCinf (AUCinf/D)
timeFrame: Part A1 and A2: Days 1-7, Part A3: Days 1-3, Part B: Days 1-17. Part C: Days 1-17
measure: Apparent total body clearance (CL/F)
timeFrame: Part A1 and A2: Days 1-7, Part A3: Days 1-3, Part B: Days 1-17. Part C: Days 1-17
measure: Maximum observed drug concentration (Cmax)
timeFrame: Part A1 and A2: Days 1-7, Part A3: Days 1-3, Part B: Days 1-17. Part C: Days 1-17
measure: Dose normalized Cmax (Cmax/D)
timeFrame: Part A1 and A2: Days 1-7, Part A3: Days 1-3, Part B: Days 1-17. Part C: Days 1-17
measure: Terminal elimination half-life (t½λz)
timeFrame: Part A1 and A2: Days 1-7, Part A3: Days 1-3, Part B: Days 1-17. Part C: Days 1-17
measure: Terminal rate constant (λz)
timeFrame: Part A1 and A2: Days 1-7, Part A3: Days 1-3, Part B: Days 1-17. Part C: Days 1-17
measure: Time delay between drug administration and the first observed concentration (tlag)
timeFrame: Part A1 and A2: Days 1-7, Part A3: Days 1-3.
measure: Time of last quantifiable concentration (tlast)
timeFrame: Part A1 and A2: Days 1-7, Part A3: Days 1-3, Part B: Days 1-17. Part C: Days 1-17
measure: Time to reach maximum observed concentration (tmax)
timeFrame: Part A1 and A2: Days 1-7, Part A3: Days 1-3, Part B: Days 1-17. Part C: Days 1-17
measure: Apparent volume of distribution based on the terminal phase (Vz/F)
timeFrame: Part A1 and A2: Days 1-7, Part A3: Days 1-3, Part B: Days 1-17. Part C: Days 1-17
measure: Absolute bioavailability (F)
timeFrame: Part A1 and A2: Days 1-7, Part A3: Days 1-3.
measure: Total body clearance (CL)
timeFrame: Part A1 and A2: Days 1-7, Part A3: Days 1-3, Part B: Days 1-17. Part C: Days 1-17
measure: Volume of distribution at steady state (Vss)
timeFrame: Part A1 and A2: Days 1-7, Part A3: Days 1-3.
measure: Area under concentration-time curve in the dose interval (AUCtau)
timeFrame: Part B: Days 1-17. Part C: Days 1-17
measure: Dose normalized AUCtau (AUCtau/D)
timeFrame: Part B: Days 1-17. Part C: Days 1-17
measure: Accumulation ratio for AUC (Rac AUC)
timeFrame: Part B: Days 1-17. Part C: Days 1-17
measure: Accumulation ratio for Cmax (Rac Cmax)
timeFrame: Part B: Days 1-17. Part C: Days 1-17
measure: Temporal change parameter (TCP)
timeFrame: Part B: Days 1-17. Part C: Days 1-17
measure: Individual and cumulative amount of unchanged drug excreted into urine from time t1 to time t2 [Ae(t1-t2)]
timeFrame: Part A: Days 1-2. Part B: Days 1-4 and 11-14. Part C: Days 1-4 and 11-14
measure: Individual and cumulative percentage of dose excreted unchanged in urine from time t1 to time t2 [fe(t1-t2)]
timeFrame: Part A: Days 1-2. Part B: Days 1-4 and 11-14. Part C: Days 1-4 and 11-14
measure: Renal clearance (CLR)
timeFrame: Part A: Days 1-2. Part B: Days 1-4 and 11-14. Part C: Days 1-4 and 11-14
measure: Percentage change from baseline in plasma target engagement marker
timeFrame: Part A: Days 1-5. Part B: Days 1-4 and 11-14. Part C: Days 1-4 and 11-14
measure: Part D: Intra- and inter-participant variability of eGFR derived from laboratory measurements
timeFrame: Day 1 to Day 169
measure: Part D: Changes over longitudinal follow-up in participant-reported experience questionnaire, qualitative insights
timeFrame: Day 1 to Day 169
measure: Part D: Changes over longitudinal follow-up in participant-reported UMUX-Lite survey, qualitative insights
timeFrame: Day 1 to Day 169
measure: Part D: Changes over longitudinal follow-up in site-based staff reported PTSFQ qualitative insights
timeFrame: Day 1 to Day 169
measure: Part D: Estimated glomerular filtration rate (eGFR)
timeFrame: Day 1 to Day 169
measure: Part D: Proportion of completed creatinine tests, with completed assessments
timeFrame: Day 1 to Day 169
Other outcomes:
Locations:
city: Glendale
country: United States
facility: Research Site
state: California
Study officials:
References: