A Study to Assess the Safety, Efficacy and Tolerability of AZD8233 Treatment in Participants With Hyperlipidaemia

Study Overview
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Brief Summary
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AZD8233 is a PCSK9-targeted ASO for the reduction of circulating levels of LDL-C. This study aims to evaluate safety, efficacy and tolerability of AZD8233.

Detailed Description
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This is a randomized parallel, double-blind, placebo-controlled Phase 2b study in approximately 376 participants with hyperlipidaemia. The primary objective of the study is to assess the safety and tolerability of AZD8233 as compared with placebo, and the effect of AZD8233 versus placebo on relative change in LDL-C. The study will be conducted at up to 100 sites in up to 8 countries. The screening period starts up to 28 days before the randomization visit and ends on Day -1. Eligible participants will attend 1 enrollment visit and 15 visits during the treatment period and 2 additional visits during the safety follow up period.

Official Title
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A Randomised, Parallel, Double-Blind, Placebo-Controlled Phase 2b Study to Assess the Safety, Tolerability and Efficacy of AZD8233 Treatment in Participants With Hyperlipidaemia

Conditions
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Hyperlipidaemia

Intervention / Treatment
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* Drug: AZD8233
* Drug: Placebo


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Participant must be 18 to 75 years of age, inclusive, at the time of signing the informed consent Participants who have a fasting LDL-C ≥ 70 mg/dL (1.8 mmol/L) but < 190 mg/dL (4.9 mmol/L) at screening Participants who have fasting triglycerides < 400 mg/dL (< 4.52 mmol/L) at screening Participants are receiving a stable dose (≥ 3 months) of maximally tolerated statin and/or ezetimibe therapy Male or female of non-childbearing potential Signed and dated written informed consent prior to any mandatory study specific procedures, sampling, and analyses Exclusion Criteria: eGFR < 40 mL/min/1.73m2 using the CKD-EPI History or presence of gastrointestinal, hepatic or renal disease or any other conditions known to interfere with absorption, distribution, metabolism or excretion of drugs Any uncontrolled or serious disease, or any medical (eg,. known major active infection or major haematological, renal, metabolic, gastrointestinal or endocrine dysfunction) or surgical condition that, in the opinion of the investigator, may either interfere with participation in the clinical study and/or put the participant at significant risk (according to the investigator's judgment) if he/she participates in the clinical study Poorly controlled T2DM, defined as HbA1c > 10% Acute ischaemic cardiovascular events including stroke within 30 days, or heart failure with New York Heart Association (NYHA) Class III to IV Blood dyscrasias with increased risk of bleeding including idiopathic thrombocytopenic purpura and thrombotic thrombocytopenic purpura or symptoms of increased risk of bleeding (frequent bleeding gums or nose bleeds) High-risk of bleeding diathesis or anti-platelet therapy other than low dose aspirin (≤100mg/day). Malignancy within the last 10 years Recipient of any major organ transplant LDL or plasma apheresis within 12 months prior to randomisation Uncontrolled hypertension defined as average supine SBP > 160 mmHg or DBP > 90 mmHg Heart rate after 10 minutes supine rest < 50 or > 100 bpm Any laboratory values with the following deviations at the Screening Visit; test may be repeated at the discretion of the investigator if abnormal: Any positive result on screening for serum hepatitis B surface antigen, hepatitis C antibody, and human immunodeficiency virus (HIV) ALT > 1.5 × ULN AST > 1.5 × ULN TBL > ULN ALP > 1.5 × ULN WBC < lower limit of normal (LLN). Haemoglobin < 12 g/dL in males or < 11 g/dL in females Platelet count ≤ LLN aPTT > ULN or Prothrombin Time > ULN UACR > 11 mg/mmol (100 mg/g) UPCR > 300 mg/g Any clinically important abnormalities in rhythm, conduction or morphology of the resting ECG and any clinically important abnormalities in the 12-lead ECG QTcF > 470 ms; high degree atrioventricular (AV)-block grade II-III and sinus node dysfunction with significant sinus pause untreated with pacemaker; and cardiac tachyarrhythmias History of drug and/or alcohol abuse or a positive screen for drugs of abuse Use of warfarin, direct or indirect thrombin inhibitors or factor Xa inhibitors Mipomersen, or lomitapide within 12 months prior to randomisation Any fibrate therapy other than fenofibrate; if the participant is on fenofibrate therapy, the dose should be stable for at least 6 weeks prior to randomisation Previous administration of AZD8233/AZD6615) or inclisiran (LEQVIO ® Novartis) Use of evolocumab (REPATHA® Amgen) and alirocumab (PRALUENT® Regeneron) within 3 months of screening

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 75 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Quadruple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: AZD8233<br>AZD8233 for subcutaneous use | Drug: AZD8233<br>* PCSK9-targeted ASO for the reduction of circulating levels of LDL-C.<br>|
| Placebo Comparator: Placebo<br>Placebo solution for subcutaneous injection | Drug: Placebo<br>* Placebo solution<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Percentage Change From Baseline on Serum LDL-C | Percentage change in Low-density Lipoprotein Cholesterol (LDL-C) from baseline to Day 197. | From baseline to Day 197 | 
| Number of Subjects With Adverse Events (AEs) | Please refer to the adverse event module for specifics. | On-study includes adverse events with an onset date on or after the date of first dose of IP through study competition, planned visit date Day 281. | 
| Vital Signs - Temperature | Mean and standard deviation of Temperature at each scheduled visit by treatment. | Baseline, Days 15, 29, 57, 85, 113, 141, 169, 197, 225, and 281. | 
| Vital Sign - Weight | Mean and standard deviation of Weight at each scheduled visit by treatment. | Baseline and Day 281. | 
| Number of Participants With an ECG Determined to be Abnormal and Clinically Significant | Number of participants With an ECG Determined to be Abnormal and Clinically Significant at each scheduled visit by treatment | Baseline, Days 85, 169, 225, and 281. | 
| Vital Sign - Systolic Blood Pressure | Mean and standard deviation of Systolic Blood Pressure at each scheduled visit by treatment. | Baseline, Days 15, 29, 57, 85, 113, 141, 169, 197, 225, and 281. | 
| Vital Sign - Diastolic Blood Pressure | Mean and standard deviation of Diastolic Blood Pressure at each scheduled visit by treatment. | Baseline, Days 15, 29, 57, 85, 113, 141, 169, 197, 225, and 281. | 
| Vital Sign - Pulse Rate | Mean and standard deviation of Pulse rate at each scheduled visit by treatment. | Baseline, Days 15, 29, 57, 85, 113, 141, 169, 197, 225, and 281. | 
| Treatment Emergent Platelet Count Abnormalities | Treatment emergent platelet count abnormalities by pre-specified criteria by treatment. | Treatment emergent includes results after the first dose of IP through study competition, planned visit date Day 281. | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Percentage Change From Baseline on Serum PCSK9 | Percentage change in Proprotein convertase subtilisin/kexin type-9 (PCSK9) from baseline to Day 197. | From baseline to Day 197 | 
| Plasma Concentration of AZD8233 | AZD8233 full length ASO concentrations in plasma were summarised by descriptive statistics by sampling time point and listed on individual level based on the PK analysis set. | Pre-dose of Day 29, Day 85, Day 141, Day 183, Day 197 | 
| Anti-drug Antibodies (ADAs) During the Treatment Period and Follow-up Period | Number of ADA positive subjects at each time point during the treatment period and follow-up period. | Pre-dose of Day 1, Day 29, Day 57, Day 85, Day 113, Day 141, Day 169, Day 197, Day 281 | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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AZD8233, Efficacy, PK, PD, Safety, Tolerability