To Assess the Pharmacokinetics, Safety, and Tolerability of AZD8233 in Participants With Chronic Kidney Disease (CKD), End Stage Renal Disease (ESRD) and Healthy Participants.

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

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.

Study Overview

• Status: Terminated
• Conditions: End Stage Renal Disease
• Intervention / Treatment: Drug: AZD8233

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.

• Study Type: Interventional
• Enrollment (Actual): 3
• Phase: Phase 1

Contacts and Locations

Study Locations

• Poland
  • Gdańsk, Poland, 80-952
    • Research Site

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years to 80 years (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

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).

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Non-Randomized
• Interventional Model: Parallel Assignment
• Masking: None (Open Label)

Number of Arms

3

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Cohort 1; Participants with severe renal impairment will receive a single dose of AZD8233 on Day 1.	Drug: AZD8233; Participants will receive a single subcutaneous (SC) dose of AZD8233 into the region of the abdomen.
Experimental: Cohort 2; Participants who are healthy will receive a single dose of AZD8233 on Day 1.	Drug: AZD8233; Participants will receive a single subcutaneous (SC) dose of AZD8233 into the region of the abdomen.
Experimental: Cohort 3; Participants with ESRD on dialysis will receive a single dose of AZD8233 on Day 1.	Drug: AZD8233; Participants will receive a single subcutaneous (SC) dose of AZD8233 into the region of the abdomen.

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Observed maximum plasma concentration (Cmax)	The pharmacokinetics (PK) parameter of AZD8233 full-length antisense oligonucleotide (ASOs) in participants with severe renal impairment and ESRD compared to matched healthy control participants will be assessed using plasma concentrations. Cmax is defined as observed maximum plasma concentration of AZD8233.	Baseline, 24 hour post-dose, Day 3, 7, 14, 28, 42, 56 and 90
Area under the plasma concentration-time curve from time zero extrapolated to infinity (AUCinf)	The PK of AZD8233 full-length ASOs in participants with severe renal impairment and ESRD compared to matched healthy control participants will be assessed using plasma concentrations. AUCinf is defined as area under the plasma concentration-time curve from time zero extrapolated to infinity of AZD8233. AUCinf is estimated by AUClast + Clast/λz where Clast is the observed last quantifiable drug concentration.	Baseline, 24 hour post-dose, Day 3, 7, 14, 28, 42, 56 and 90
Area under the plasma concentration-curve from time zero to time of last quantifiable concentration (AUClast)	The PK of AZD8233 full-length ASOs in participants with severe renal impairment and ESRD compared to matched healthy control participants will be assessed using plasma concentrations. AUClast is defined as area under the plasma concentration-curve from time zero to time of last quantifiable concentration of AZD8233.	Baseline, 24 hour post-dose, Day 3, 7, 14, 28, 42, 56 and 90
Area under the concentration-time curve from time zero to 24 hours after dosing (AUC0-24)	The PK of AZD8233 full-length ASOs in participants with severe renal impairment and ESRD compared to matched healthy control participants will be assessed using plasma concentrations. AUC0-24 is defined as area under the concentration-time curve from time zero to 24 hours after dosing of AZD8233.	Baseline, 24 hour post-dose
Renal clearance (CLR)	The PK of AZD8233 full-length ASOs in participants with severe renal impairment and ESRD compared to matched healthy control participants will be assessed using urine concentrations. CLR is defined as renal clearance of AZD8233 from plasma.	Post-dose (0-8 hour and 8-24 hour) at Day 1
Amount excreted in urine (Ae)	The PK of AZD8233 full-length ASOs in participants with severe renal impairment and ESRD compared to matched healthy control participants will be assessed using urine concentrations. The PK urine parameters for AZD8233 full-length ASOs will be derived from Ae. Ae(0-last) is defined as cumulative amount of analyte excreted unchanged in urine at the last sampling interval of AZD8233.	Post-dose (0-8 hour and 8-24 hour) at Day 1
Fraction unbound in plasma (fe)	The PK of AZD8233 full-length ASOs in participants with severe renal impairment and ESRD compared to matched healthy control participants will be assessed using urine concentrations. The PK urine parameters for AZD8233 full-length ASOs will be derived from fe. fe(0-last) is defined as percentage of dose excreted unchanged in urine from time zero to the last measured time-point for an analyte of AZD8233.	Post-dose (0-8 hour and 8-24 hour) at Day 1
Number of participants with adverse events (AEs)	To assess safety and tolerability of AZD8233 in participants with severe renal impairment, ESRD and their healthy matched controls.	Day 1 to Day 90

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Percentage reduction in proprotein convertase subtilisin/kexin type 9 (PCSK9) plasma levels from baseline	To asses the percentage change from baseline in PCSK9 plasma levels over-time in participants with severe renal impairment and ESRD compared to their healthy matched controls.	Baseline, 24 hour post-dose, Day 3, 7, 14, 28, 42, 56 and 90

Collaborators and Investigators

• Sponsor: AstraZeneca
• Collaborators: Parexel

Study record dates

Study Major Dates

• Study Start (Actual): August 10, 2022
• Primary Completion (Actual): November 23, 2022
• Study Completion (Actual): November 23, 2022

Study Registration Dates

• First Submitted: September 23, 2021
• First Submitted That Met QC Criteria: September 23, 2021
• First Posted (Actual): October 4, 2021

Study Record Updates

• Last Update Posted (Actual): December 22, 2022
• Last Update Submitted That Met QC Criteria: December 20, 2022
• Last Verified: December 1, 2022

More Information

Terms related to this study

• Keywords: Renal Impairment; Pharmacokinetic; Pharmacodynamic; End Stage Renal Disease (ESRD)
• Additional Relevant MeSH Terms: Urologic Diseases; Renal Insufficiency; Renal Insufficiency, Chronic; Kidney Diseases; Kidney Failure, Chronic
• Other Study ID Numbers: D7990C00007; 2021-003044-24 (EudraCT Number)

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: Yes

IPD Plan Description

Qualified researchers can request access to anonymized individual patient-level data from AstraZeneca group of companies sponsored clinical trials via the requests portal. All requests will be evaluated as per the AZ disclosure commitment: https://astrazenecagrouptrials.pharmacm.com/ST/Submission/Disclosure.

Yes, indicates that AZ are accepting requests for IPD, but this does not mean all requests will be shared.

• IPD Sharing Time Frame: AstraZeneca will meet or exceed data availability as per the commitments made to the EFPIA Pharma Data Sharing Principles. For details of our timelines, please rerefer to our disclosure commitment at https://astrazenecagrouptrials.pharmacm.com/ST/Submission/Disclosure.
• IPD Sharing Access Criteria: When a request has been approved AstraZeneca will provide access to the de-identified individual patient-level data in an approved sponsored tool. Signed Data Sharing Agreement (non-negotiable contract for data accessors) must be in place before accessing requested information. Additionally, all users will need to accept the terms and conditions of the SAS MSE to gain access. For additional details, please review the Disclosure Statements at https://astrazenecagrouptrials.pharmacm.com/ST/Submission/Disclosure.

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: Yes
• Studies a U.S. FDA-regulated device product: No