Clinical trial NCT05065463: To Assess the Pharmacokinetics, Safety, and Tolerability of AZD8233 in Participants With Chronic Kidney Disease (CKD), End Stage Renal Disease (ESRD) and Healthy Participants.
Official title: A Single Dose, Non-randomised, Open-label, Parallel Group Study to Assess the Pharmacokinetics, PCSK9 Reduction, Safety, and Tolerability of AZD8233 in Participants With Severe Renal Impairment, End Stage Renal Disease and Healthy Participants as Controls
Study type: INTERVENTIONAL
Overall status: TERMINATED
Phase: PHASE1
Conditions: End Stage Renal Disease
Keywords: End Stage Renal Disease (ESRD)
Renal Impairment
Pharmacokinetic
Pharmacodynamic
Lead sponsor: AstraZeneca
Sponsor class: INDUSTRY
Collaborators: name: Parexel
First posted: 2021-10-04
Enrollment: 3
Sex: ALL
Minimum age (years): 18
Maximum age (years): 80
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: yes
Allocation: NON_RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

Brief summary: The study is intended to assess the pharmacokinetics (PK), proprotein convertase subtilisin/kexin type 9 (PCSK9) reduction, safety and tolerability of AZD8233 in male and female participants with severe renal impairment and participants with ESRD compared to matched healthy control participants.

Detailed description: This is an open-label, single dose, non-randomised, parallel group study. Participant will be enrolled in 3 cohorts.

* Cohort 1 will include 8 participants with severe renal impairment (estimated glomerular filtration rate \[eGFR\] of ≥15 to \< 30 mL/min/1.73 m\^2).
* Cohort 2 will include 8 healthy participants with normal renal function (eGFR of ≥ 90 mL/min/1.73 m\^2) that will serve as matched controls for Cohort 1 and Cohort 3. Matching will account for age, Body mass index (BMI), and gender.
* Cohort 3 will include 8 participants with ESRD on dialysis (eGFR of \< 15 mL/min/1.73 m\^2).

  * Participants in Cohort 3 will receive a single dose of AZD8233 the day after haemodialysis.

Participant will receive the study drug on Day 1, discharged on Day 2 followed by out-patient follow-up visits on Day 3, 7, 14, 28, 42, 56, and 90.

Eligibility criteria: Inclusion Criteria:

1. For Cohort 1 and 3 (CKD/ESRD): Participants that are on statins, ACEi/ARB, beta-blocker, diuretic or on any other cardio-renal relevant treatment, the dose should be stable at least 4 weeks prior to Screening (Visit 1) (no dose adjustments within 4 weeks prior to Screening \[Visit 1\]).
2. For Cohort 2 (HV): Participants who are overtly healthy as determined by medical evaluation including medical history, physical examination, laboratory tests, and cardiac monitoring. (a) Have an eGFR of ≥ 90 mL/min/1.73 m\^2 as determined at Screening (Visit 1) via the CKD-EPI formula.
3. For Cohort 1 (CKD): Participants who are severely renally impaired.

   (a) Have an eGFR of ≥15 to \< 30 mL/min/1.73 m\^2 as determined at Screening (Visit 1) via the CKD-EPI formula.
4. For Cohort 3 (ESRD): Participants with ESRD on dialysis.

   1. Have an eGFR of \< 15 mL/min/1.73 m\^2.
   2. Have been on stable intermittent haemodialysis for at least 3 months prior to Screening (Visit 1).
5. Body weight of at least 50 kg and BMI within the range ≥ 18 to ≤ 35 kg/m\^2 (inclusive).
6. Female of non-childbearing potential or male. Contraceptive use by men should be consistent with local regulations regarding the methods of contraception for those participating in clinical studies.

Exclusion Criteria:

1. Participant has a positive SARS-CoV-2 test result within 2 weeks before screening (Visit 1) or between screening and admission to study centre (Day -22 to Day - 2).
2. Clinical signs and symptoms consistent with COVID-19 (eg, fever, dry cough, dyspnoea, sore throat, fatigue) 2 weeks before screening (Visit 1) or between screening and admission to study centre (Visit 2).
3. Participant has been previously hospitalised with COVID-19 infection within the last 3 months prior to Screening (Visit 1).
4. Known or suspected history of substance dependence or a positive screen for drugs or alcohol abuse at the Screening Visit.
5. Any laboratory values with the following deviations at the Screening Visit (Visit 1); test may be repeated at the discretion of the Investigator if abnormal:

   (a) Any positive result on screening for serum hepatitis B surface antigen, hepatitis C antibody, and HIV. (b) Alanine aminotransferase \> 1.5 × ULN (c) Aspartate aminotransferase \> 1.5 × ULN (d) Total bilirubin \> ULN (e) Haemoglobin \< 9 g/dL (f) Platelet count ≤ LLN
6. Previous allogeneic bone marrow transplant.
7. Non-leukocyte depleted whole blood transfusion within 120 days of genetic sample collection.

9. Participants with a known hypersensitivity to AZD8233 or any of the excipients of the product.

10. For Cohort 2: Any clinically significant disease or disorder (eg, cardiovascular, pulmonary, gastrointestinal, liver, renal, neurological, musculoskeletal including bone fractures, endocrine including adrenal insufficiency, metabolic, malignant, psychiatric, major physical impairment,), skin disorder, history of, or ongoing clinically significant allergy/hypersensitivity.

11. Cohort 1 \& 3: Presence of unstable medical (e.g., diabetes) or psychological conditions and renal transplant patients.

12. Previous administration of AZD8233/AZD6615 or inclisiran (LEQVIO®, Novartis).

13. Current or previous treatment with drugs for reduction of PCSK9 (for example evolocumab, alirocumab or inclisiran).

Primary outcomes:
measure: Observed maximum plasma concentration (Cmax)
timeFrame: Baseline, 24 hour post-dose, Day 3, 7, 14, 28, 42, 56 and 90
measure: Area under the plasma concentration-time curve from time zero extrapolated to infinity (AUCinf)
timeFrame: Baseline, 24 hour post-dose, Day 3, 7, 14, 28, 42, 56 and 90
measure: Area under the plasma concentration-curve from time zero to time of last quantifiable concentration (AUClast)
timeFrame: Baseline, 24 hour post-dose, Day 3, 7, 14, 28, 42, 56 and 90
measure: Area under the concentration-time curve from time zero to 24 hours after dosing (AUC0-24)
timeFrame: Baseline, 24 hour post-dose
measure: Renal clearance (CLR)
timeFrame: Post-dose (0-8 hour and 8-24 hour) at Day 1
measure: Amount excreted in urine (Ae)
timeFrame: Post-dose (0-8 hour and 8-24 hour) at Day 1
measure: Fraction unbound in plasma (fe)
timeFrame: Post-dose (0-8 hour and 8-24 hour) at Day 1
measure: Number of participants with adverse events (AEs)
timeFrame: Day 1 to Day 90
Secondary outcomes:
measure: Percentage reduction in proprotein convertase subtilisin/kexin type 9 (PCSK9) plasma levels from baseline
timeFrame: Baseline, 24 hour post-dose, Day 3, 7, 14, 28, 42, 56 and 90
Other outcomes:
Locations:
city: Gdańsk
country: Poland
facility: Research Site
Study officials:
References: