Chronic Kidney Disease
Conditions
Keywords
Type 2 Diabetes, Diabetic Kidney Disease, Multiple Ascending Dose, Single Ascending Dose, Creatinine, Food Effect, Pharmacokinetics, Safety
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.
Interventions
DRUGAZD4248
AZD4248 will be administered orally.
DRUGPlacebo
Placebo will be administered orally.
Sponsors
AstraZeneca
Parexel
Study design
Allocation
RANDOMIZED
Intervention model
SEQUENTIAL
Primary purpose
TREATMENT
Masking
DOUBLE (Subject, Caregiver)
Eligibility
Sex/Gender
ALL
Age
18 Years to 75 Years
Healthy volunteers
Yes
Inclusion 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 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. 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.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Parts A, B, and C: Number of Participants with Adverse Events (AEs) and Serious Adverse Events (SAEs) | From Day 1 to Follow Up visit (Part A: up to 12 days; Part B and C: up to 19 days) | To assess the safety and tolerability of AZD4248 following single oral ascending doses or single IV administration to healthy participants and multiple oral ascending doses to healthy participants and participants with CKD and T2D (DKD). |
| Part D: Intra- and inter-participant variability of estimated glomerular filtration rate (eGFR) derived from home self-testing device measurements | Day 1 to Day 169 | To assess intra- and inter-participant variability of twice weekly home-based serum creatinine measurements. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Area under concentration-time curve from time 0 to infinity (AUCinf) | Part A1 and A2: Days 1-7, Part A3: Days 1-3, Part B: Days 1-17. Part C: Days 1-17 | To characterize the PK of AZD4248 following oral administration of single and multiple doses or a single IV administration of AZD4248. To assess the impact of food on the PK of AZD4248 following a single oral administration. |
| Area under concentration-curve from time 0 to the last quantifiable concentration (AUClast) | Part A1 and A2: Days 1-7, Part A3: Days 1-3, Part B: Days 1-17. Part C: Days 1-17 | To characterize the PK of AZD4248 following oral administration of single and multiple doses or a single IV administration of AZD4248. To assess the impact of food on the PK of AZD4248 following a single oral administration. |
| Dose normalized AUClast (AUClast/D) | Part A1 and A2: Days 1-7, Part A3: Days 1-3, Part B: Days 1-17. Part C: Days 1-17 | To characterize the PK of AZD4248 following oral administration of single and multiple doses or a single IV administration of AZD4248. |
| Dose normalized AUCinf (AUCinf/D) | Part A1 and A2: Days 1-7, Part A3: Days 1-3, Part B: Days 1-17. Part C: Days 1-17 | To characterize the PK of AZD4248 following oral administration of single and multiple doses or a single IV administration of AZD4248. |
| Apparent total body clearance (CL/F) | Part A1 and A2: Days 1-7, Part A3: Days 1-3, Part B: Days 1-17. Part C: Days 1-17 | To characterize the PK of AZD4248 following oral administration of single and multiple doses or a single IV administration of AZD4248. |
| Maximum observed drug concentration (Cmax) | Part A1 and A2: Days 1-7, Part A3: Days 1-3, Part B: Days 1-17. Part C: Days 1-17 | To characterize the PK of AZD4248 following oral administration of single and multiple doses or a single IV administration of AZD4248. To assess the impact of food on the PK of AZD4248 following a single oral administration |
| Dose normalized Cmax (Cmax/D) | Part A1 and A2: Days 1-7, Part A3: Days 1-3, Part B: Days 1-17. Part C: Days 1-17 | To characterize the PK of AZD4248 following oral administration of single and multiple doses or a single IV administration of AZD4248. |
| Terminal elimination half-life (t½λz) | Part A1 and A2: Days 1-7, Part A3: Days 1-3, Part B: Days 1-17. Part C: Days 1-17 | To characterize the PK of AZD4248 following oral administration of single and multiple doses or a single IV administration of AZD4248. |
| Terminal rate constant (λz) | Part A1 and A2: Days 1-7, Part A3: Days 1-3, Part B: Days 1-17. Part C: Days 1-17 | To characterize the PK of AZD4248 following oral administration of single and multiple doses or a single IV administration of AZD4248. |
| Time delay between drug administration and the first observed concentration (tlag) | Part A1 and A2: Days 1-7, Part A3: Days 1-3. | To characterize the PK of AZD4248 following oral administration of single and multiple doses or a single IV administration of AZD4248. |
| Time of last quantifiable concentration (tlast) | Part A1 and A2: Days 1-7, Part A3: Days 1-3, Part B: Days 1-17. Part C: Days 1-17 | To characterize the PK of AZD4248 following oral administration of single and multiple doses or a single IV administration of AZD4248. |
| Time to reach maximum observed concentration (tmax) | Part A1 and A2: Days 1-7, Part A3: Days 1-3, Part B: Days 1-17. Part C: Days 1-17 | To characterize the PK of AZD4248 following oral administration of single and multiple doses or a single IV administration of AZD4248. To assess the impact of food on the PK of AZD4248 following a single oral administration |
| Apparent volume of distribution based on the terminal phase (Vz/F) | Part A1 and A2: Days 1-7, Part A3: Days 1-3, Part B: Days 1-17. Part C: Days 1-17 | To characterize the PK of AZD4248 following oral administration of single and multiple doses or a single IV administration of AZD4248. |
| Absolute bioavailability (F) | Part A1 and A2: Days 1-7, Part A3: Days 1-3. | To characterize the PK of AZD4248 following oral administration of single and multiple doses or a single IV administration of AZD4248. |
| Total body clearance (CL) | Part A1 and A2: Days 1-7, Part A3: Days 1-3, Part B: Days 1-17. Part C: Days 1-17 | To characterize the PK of AZD4248 following oral administration of single and multiple doses or a single IV administration of AZD4248. |
| Volume of distribution at steady state (Vss) | Part A1 and A2: Days 1-7, Part A3: Days 1-3. | To characterize the PK of AZD4248 following oral administration of single and multiple doses or a single IV administration of AZD4248. |
| Area under concentration-time curve in the dose interval (AUCtau) | Part B: Days 1-17. Part C: Days 1-17 | To characterize the PK of AZD4248 following oral administration of single and multiple doses or a single IV administration of AZD4248. |
| Dose normalized AUCtau (AUCtau/D) | Part B: Days 1-17. Part C: Days 1-17 | To characterize the PK of AZD4248 following oral administration of single and multiple doses or a single IV administration of AZD4248. |
| Accumulation ratio for AUC (Rac AUC) | Part B: Days 1-17. Part C: Days 1-17 | To characterize the PK of AZD4248 following oral administration of single and multiple doses or a single IV adnminstration of AZD4248. |
| Accumulation ratio for Cmax (Rac Cmax) | Part B: Days 1-17. Part C: Days 1-17 | To characterize the PK of AZD4248 following oral administration of single and multiple doses or a single IV administration of AZD4248. |
| Temporal change parameter (TCP) | Part B: Days 1-17. Part C: Days 1-17 | To characterize the PK of AZD4248 following oral administration of single and multiple doses or a single IV administration of AZD4248. |
| Individual and cumulative amount of unchanged drug excreted into urine from time t1 to time t2 [Ae(t1-t2)] | Part A: Days 1-2. Part B: Days 1-4 and 11-14. Part C: Days 1-4 and 11-14 | To characterize the PK of AZD4248 following oral administration of single and multiple doses or a single IV administration of AZD4248 |
| Individual and cumulative percentage of dose excreted unchanged in urine from time t1 to time t2 [fe(t1-t2)] | Part A: Days 1-2. Part B: Days 1-4 and 11-14. Part C: Days 1-4 and 11-14 | To characterize the PK of AZD4248 following oral administration of single and multiple doses or a single IV administration of AZD4248 |
| Renal clearance (CLR) | Part A: Days 1-2. Part B: Days 1-4 and 11-14. Part C: Days 1-4 and 11-14 | To characterize the PK of AZD4248 following oral administration of single and multiple doses or a single IV administration of AZD4248 |
| Percentage change from baseline in plasma target engagement marker | Part A: Days 1-5. Part B: Days 1-4 and 11-14. Part C: Days 1-4 and 11-14 | To evaluate the TE of AZD4248 by assessing reduction in plasma target engagement marker following single (oral or IV) and multiple oral dosing of AZD4248. |
| Part D: Intra- and inter-participant variability of eGFR derived from laboratory measurements | Day 1 to Day 169 | To assess the intra- and inter-participant variability of monthly laboratory-based creatinine measurements. |
| Part D: Changes over longitudinal follow-up in participant-reported experience questionnaire on collective participant satisfaction, usability and device acceptability data | Day 1 to Day 169 | To evaluate the usability, user satisfaction, and feasibility of delivering a home self-testing device and its accompanying smartphone application. |
| Part D: Summary of qualitative insights from optional individual in-depth interview samples | Day 30 to Day 84 | To evaluate the usability, user satisfaction, and feasibility of delivering a self-testing, home self-testing device and its accompanying smartphone application. |
| Part D: Changes over longitudinal follow-up in site-based staff reported PTSFQ | Day 1 to Day 169 | To assess clinical site staff-reported usability and satisfaction of delivering and management of the home self-testing device and software. |
| Part D: Estimated glomerular filtration rate (eGFR) | Day 1 to Day 169 | To compare home-based serum creatinine measurements against the standard laboratory measurements. |
| Part D: Proportion of completed creatinine tests, with completed assessments | Day 1 to Day 169 | To assess the rates of missing data due to missed tests or test errors. |
Countries
United States
Contacts
CONTACTAstraZeneca Clinical Study Information Center
Outcome results
None listed