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

December 20, 2022 updated by: AstraZeneca

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

Status

Indicates the current recruitment status or the expanded access status.
Terminated

Conditions

Conditions

The disease, disorder, syndrome, illness, or injury that is being studied. On ClinicalTrials.gov, conditions may also include other health-related issues, such as lifespan, quality of life, and health risks.

Intervention / Treatment

Intervention / Treatment

A process or action that is the focus of a clinical study. Interventions include drugs, medical devices, procedures, vaccines, and other products that are either investigational or already available. Interventions can also include noninvasive approaches, such as education or modifying diet and exercise.

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

Study Type

Describes the nature of a clinical study. Study types include interventional studies (also called clinical trials), observational studies (including patient registries), and expanded access.
Interventional

Enrollment (Actual)

Enrollment

The number of participants in a clinical study. The "anticipated" enrollment is the target number of participants that the researchers need for the study.
3

Phase

Phase

The stage of a clinical trial studying a drug or biological product, based on definitions developed by the U.S. Food and Drug Administration (FDA). The phase is based on the study's objective, the number of participants, and other characteristics. There are five phases: Early Phase 1 (formerly listed as Phase 0), Phase 1, Phase 2, Phase 3, and Phase 4. Not Applicable is used to describe trials without FDA-defined phases, including trials of devices or behavioral interventions.
  • Phase 1

Contacts and Locations

This section provides the contact details for those conducting the study, and information on where this study is being conducted.

Study Locations

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

Participation Criteria

Researchers look for people who fit a certain description, called eligibility criteria. Some examples of these criteria are a person's general health condition or prior treatments.

Eligibility Criteria

Eligibility Criteria

The key requirements that people who want to participate in a clinical study must meet or the characteristics they must have. Eligibility criteria consist of both inclusion criteria (which are required for a person to participate in the study) and exclusion criteria (which prevent a person from participating). Types of eligibility criteria include whether a study accepts healthy volunteers, has age or age group requirements, or is limited by sex.

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

This section provides details of the study plan, including how the study is designed and what the study is measuring.

How is the study designed?

Design Details

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

Arms and Interventions

Participant Group / Arm

Participant Group / Arm

A group or subgroup of participants in a clinical trial that receives a specific intervention/treatment, or no intervention, according to the trial's protocol.
Intervention / Treatment

Intervention / Treatment

A process or action that is the focus of a clinical study. Interventions include drugs, medical devices, procedures, vaccines, and other products that are either investigational or already available. Interventions can also include noninvasive approaches, such as education or modifying diet and exercise.
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

Primary Outcome Measures

In a clinical study's protocol, the planned outcome measure that is the most important for evaluating the effect of an intervention/treatment. Most clinical studies have one primary outcome measure, but some have more than one.
Outcome Measure
Measure Description
Time Frame
Observed maximum plasma concentration (Cmax)
Time Frame: Baseline, 24 hour post-dose, Day 3, 7, 14, 28, 42, 56 and 90
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)
Time Frame: Baseline, 24 hour post-dose, Day 3, 7, 14, 28, 42, 56 and 90
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)
Time Frame: Baseline, 24 hour post-dose, Day 3, 7, 14, 28, 42, 56 and 90
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)
Time Frame: Baseline, 24 hour post-dose
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)
Time Frame: Post-dose (0-8 hour and 8-24 hour) at Day 1
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)
Time Frame: Post-dose (0-8 hour and 8-24 hour) at Day 1
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)
Time Frame: Post-dose (0-8 hour and 8-24 hour) at Day 1
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)
Time Frame: Day 1 to Day 90
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

Secondary Outcome Measures

In a clinical study's protocol, a planned outcome measure that is not as important as the primary outcome measure for evaluating the effect of an intervention but is still of interest. Most clinical studies have more than one secondary outcome measure.
Outcome Measure
Measure Description
Time Frame
Percentage reduction in proprotein convertase subtilisin/kexin type 9 (PCSK9) plasma levels from baseline
Time Frame: Baseline, 24 hour post-dose, Day 3, 7, 14, 28, 42, 56 and 90
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

This is where you will find people and organizations involved with this study.

Sponsor

Sponsor

The organization or person who initiates the study and who has authority and control over the study.
AstraZeneca

Collaborators

Collaborators

An organization other than the sponsor that provides support for a clinical study. This support may include activities related to funding, design, implementation, data analysis, or reporting.
Parexel

Study record dates

These dates track the progress of study record and summary results submissions to ClinicalTrials.gov. Study records and reported results are reviewed by the National Library of Medicine (NLM) to make sure they meet specific quality control standards before being posted on the public website.

Study Major Dates

Study Start (Actual)

Study Start

The actual date on which the first participant was enrolled in a clinical study. The "anticipated" study start date is the date that the researchers think will be the study start date.
August 10, 2022

Primary Completion (Actual)

Primary Completion

The date on which the last participant in a clinical study was examined or received an intervention to collect final data for the primary outcome measure. Whether the clinical study ended according to the protocol or was terminated does not affect this date. For clinical studies with more than one primary outcome measure with different completion dates, this term refers to the date on which data collection is completed for all the primary outcome measures. The "anticipated" primary completion date is the date that the researchers think will be the primary completion date for the study.
November 23, 2022

Study Completion (Actual)

Study Completion

The date on which the last participant in a clinical study was examined or received an intervention/treatment to collect final data for the primary outcome measures, secondary outcome measures, and adverse events (that is, the last participant's last visit). The "anticipated" study completion date is the date that the researchers think will be the study completion date.
November 23, 2022

Study Registration Dates

First Submitted

First Submitted

The date on which the study sponsor or investigator first submitted a study record to ClinicalTrials.gov. There is typically a delay of a few days between the first submitted date and the record's availability on ClinicalTrials.gov (the first posted date).
September 23, 2021

First Submitted That Met QC Criteria

First Submitted That Met QC Criteria

The date on which the study sponsor or investigator first submits a study record that is consistent with National Library of Medicine (NLM) quality control (QC) review criteria. The sponsor or investigator may need to revise and submit a study record one or more times before NLM's QC review criteria are met. It is the responsibility of the sponsor or investigator to ensure that the study record is consistent with the NLM QC review criteria.
September 23, 2021

First Posted (Actual)

First Posted

The date on which the study record was first available on ClinicalTrials.gov after National Library of Medicine (NLM) quality control (QC) review has concluded. There is typically a delay of a few days between the date the study sponsor or investigator submitted the study record and the first posted date.
October 4, 2021

Study Record Updates

Last Update Posted (Actual)

Last Update Posted

The most recent date on which changes to a study record were made available on ClinicalTrials.gov. There may be a delay between when the changes were submitted to ClinicalTrials.gov by the study's sponsor or investigator (the last update submitted date) and the last update posted date.
December 22, 2022

Last Update Submitted That Met QC Criteria

Last Update Submitted That Met QC Criteria

The most recent date on which the study sponsor or investigator submitted changes to a study record that are consistent with National Library of Medicine (NLM) quality control (QC) review criteria. It is the responsibility of the sponsor or investigator to ensure that the study record is consistent with the NLM QC review criteria.
December 20, 2022

Last Verified

Last Verified

The most recent date on which the study sponsor or investigator confirmed the information about a clinical study on ClinicalTrials.gov as accurate and current. If a study with a recruitment status of recruiting; not yet recruiting; or active, not recruiting has not been confirmed within the past 2 years, the study's recruitment status is shown as unknown.
December 1, 2022

More Information

Terms related to this study

Keywords

Additional Relevant MeSH Terms

Other Study ID Numbers

Other Study ID Numbers

Identifiers or ID numbers other than the NCT number that are assigned to a clinical study by the study's sponsor, funders, or others. These numbers may include unique identifiers from other trial registries and National Institutes of Health grant 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

This information was retrieved directly from the website clinicaltrials.gov without any changes. If you have any requests to change, remove or update your study details, please contact register@clinicaltrials.gov. As soon as a change is implemented on clinicaltrials.gov, this will be updated automatically on our website as well.

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