A Study to Assess the Safety, Efficacy and Tolerability of AZD8233 Treatment in Participants With Hyperlipidaemia
Condition: Hyperlipidaemia
MeSH terms: Hyperlipidemias; Hyperlipoproteinemias
Intervention: AZD8233; Placebo
Intervention description: PCSK9-targeted ASO for the reduction of circulating levels of LDL-C.; Placebo solution
Phase: Phase 2
Study type: Interventional
Primary purpose: Treatment
Allocation: Randomized
Intervention model: Parallel Assignment
Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
Enrollment: 411.0
Sex: All
Minimum age: 18 Years
Maximum age: 75 Years
Healthy volunteers: No
Keywords: AZD8233; Efficacy; PK; PD; Safety; Tolerability

Summary:

      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.
    

Eligibility criteria:

        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