Back to resultsTo Assess the Pharmacokinetics, Safety, and Tolerability of AZD8233 in Participants With Chronic Kidney Disease (CKD), End Stage Renal Disease (ESRD) and Healthy Participants.
Primary Purpose
End Stage Renal Disease
Status
Terminated
Phase
Phase 1
Locations
Poland
Study Type
Interventional
Intervention
AZD8233
Sponsored by
About this trial
This is an interventional treatment trial for End Stage Renal Disease focused on measuring End Stage Renal Disease (ESRD), Renal Impairment, Pharmacokinetic, Pharmacodynamic
Eligibility Criteria
Inclusion Criteria:
- 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]).
- 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.
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.
For Cohort 3 (ESRD): Participants with ESRD on dialysis.
- Have an eGFR of < 15 mL/min/1.73 m^2.
- Have been on stable intermittent haemodialysis for at least 3 months prior to Screening (Visit 1).
- Body weight of at least 50 kg and BMI within the range ≥ 18 to ≤ 35 kg/m^2 (inclusive).
- 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:
- 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).
- 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).
- Participant has been previously hospitalised with COVID-19 infection within the last 3 months prior to Screening (Visit 1).
- Known or suspected history of substance dependence or a positive screen for drugs or alcohol abuse at the Screening Visit.
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
- Previous allogeneic bone marrow transplant.
- 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).
Sites / Locations
- Research Site
Arms of the Study
Arm 1
Arm 2
Arm 3
Arm Type
Experimental
Experimental
Experimental
Arm Label
Cohort 1
Cohort 2
Cohort 3
Arm Description
Participants with severe renal impairment will receive a single dose of AZD8233 on Day 1.
Participants who are healthy will receive a single dose of AZD8233 on Day 1.
Participants with ESRD on dialysis will receive a single dose of AZD8233 on Day 1.
Outcomes
Primary Outcome Measures
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.
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.
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.
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.
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.
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.
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.
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.
Secondary Outcome Measures
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.
Full Information
NCT ID
NCT05065463
First Posted
September 23, 2021
Last Updated
December 20, 2022
Sponsor
AstraZeneca
Collaborators
Parexel
1. Study Identification
Unique Protocol Identification Number
NCT05065463
Brief Title
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
2. Study Status
Record Verification Date
December 2022
Overall Recruitment Status
Terminated
Why Stopped
A decision has been taken to discontinue the development of AZD8233 (PCSK9-ASO for sc administration) due to low likelihood of demonstrating a benefit significantly above the current standard of care for patients with high-risk hypercholesterolemia.
Study Start Date
August 10, 2022 (Actual)
Primary Completion Date
November 23, 2022 (Actual)
Study Completion Date
November 23, 2022 (Actual)
3. Sponsor/Collaborators
Responsible Party, by Official Title
Sponsor
Name of the Sponsor
AstraZeneca
Collaborators
Parexel
4. Oversight
Studies a U.S. FDA-regulated Drug Product
Yes
Studies a U.S. FDA-regulated Device Product
No
Data Monitoring Committee
No
5. Study Description
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.
6. Conditions and Keywords
Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study
End Stage Renal Disease
Keywords
End Stage Renal Disease (ESRD), Renal Impairment, Pharmacokinetic, Pharmacodynamic
7. Study Design
Primary Purpose
Treatment
Study Phase
Phase 1
Interventional Study Model
Parallel Assignment
Masking
None (Open Label)
Allocation
Non-Randomized
Enrollment
3 (Actual)
8. Arms, Groups, and Interventions
Arm Title
Cohort 1
Arm Type
Experimental
Arm Description
Participants with severe renal impairment will receive a single dose of AZD8233 on Day 1.
Arm Title
Cohort 2
Arm Type
Experimental
Arm Description
Participants who are healthy will receive a single dose of AZD8233 on Day 1.
Arm Title
Cohort 3
Arm Type
Experimental
Arm Description
Participants with ESRD on dialysis will receive a single dose of AZD8233 on Day 1.
Intervention Type
Drug
Intervention Name(s)
AZD8233
Intervention Description
Participants will receive a single subcutaneous (SC) dose of AZD8233 into the region of the abdomen.
Primary Outcome Measure Information:
Title
Observed maximum plasma concentration (Cmax)
Description
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.
Time Frame
Baseline, 24 hour post-dose, Day 3, 7, 14, 28, 42, 56 and 90
Title
Area under the plasma concentration-time curve from time zero extrapolated to infinity (AUCinf)
Description
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.
Time Frame
Baseline, 24 hour post-dose, Day 3, 7, 14, 28, 42, 56 and 90
Title
Area under the plasma concentration-curve from time zero to time of last quantifiable concentration (AUClast)
Description
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.
Time Frame
Baseline, 24 hour post-dose, Day 3, 7, 14, 28, 42, 56 and 90
Title
Area under the concentration-time curve from time zero to 24 hours after dosing (AUC0-24)
Description
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.
Time Frame
Baseline, 24 hour post-dose
Title
Renal clearance (CLR)
Description
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.
Time Frame
Post-dose (0-8 hour and 8-24 hour) at Day 1
Title
Amount excreted in urine (Ae)
Description
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.
Time Frame
Post-dose (0-8 hour and 8-24 hour) at Day 1
Title
Fraction unbound in plasma (fe)
Description
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.
Time Frame
Post-dose (0-8 hour and 8-24 hour) at Day 1
Title
Number of participants with adverse events (AEs)
Description
To assess safety and tolerability of AZD8233 in participants with severe renal impairment, ESRD and their healthy matched controls.
Time Frame
Day 1 to Day 90
Secondary Outcome Measure Information:
Title
Percentage reduction in proprotein convertase subtilisin/kexin type 9 (PCSK9) plasma levels from baseline
Description
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.
Time Frame
Baseline, 24 hour post-dose, Day 3, 7, 14, 28, 42, 56 and 90
10. Eligibility
Sex
All
Minimum Age & Unit of Time
18 Years
Maximum Age & Unit of Time
80 Years
Accepts Healthy Volunteers
Accepts Healthy Volunteers
Eligibility Criteria
Inclusion Criteria:
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]).
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.
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.
For Cohort 3 (ESRD): Participants with ESRD on dialysis.
Have an eGFR of < 15 mL/min/1.73 m^2.
Have been on stable intermittent haemodialysis for at least 3 months prior to Screening (Visit 1).
Body weight of at least 50 kg and BMI within the range ≥ 18 to ≤ 35 kg/m^2 (inclusive).
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:
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).
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).
Participant has been previously hospitalised with COVID-19 infection within the last 3 months prior to Screening (Visit 1).
Known or suspected history of substance dependence or a positive screen for drugs or alcohol abuse at the Screening Visit.
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
Previous allogeneic bone marrow transplant.
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).
Facility Information:
Facility Name
Research Site
City
Gdańsk
ZIP/Postal Code
80-952
Country
Poland
12. IPD Sharing Statement
Plan to Share IPD
Yes
IPD Sharing 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.
IPD Sharing URL
https://astrazenecagroup-dt.pharmacm.com/DT/Home
Learn more about this trial
To Assess the Pharmacokinetics, Safety, and Tolerability of AZD8233 in Participants With Chronic Kidney Disease (CKD), End Stage Renal Disease (ESRD) and Healthy Participants.
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