A Study of AZD8233 in Participants With Dyslipidemia
Condition: Dyslipidaemia
MeSH terms: Dyslipidemias
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: 119.0
Sex: All
Minimum age: 18 Years
Maximum age: 75 Years
Healthy volunteers: No
Keywords: Dose Range Finding; AZD8233; Efficacy; PK; PD; Immunogenicity; Safety; Tolerability

Summary:

      AZD8233 is a PCSK9-targeted ASO for the reduction of circulating levels of LDL-C. This study
      aims to evaluate the dose-dependent reduction in LDL-C after SC administration of multiple
      doses of AZD8233 as well as the associated adverse effects profile. The data generated will
      be used to guide choice of doses, dosing regimens, and sample sizes, as well as safety and PD
      monitoring in the further clinical development program.
    

Eligibility criteria:

        Key Inclusion Criteria:

          -  Male or female.

          -  Participant must be 18 to 75 years of age.

          -  Body mass index between 19 and 40 kg/m2.

          -  Participants who have a fasting LDL-C ≥ 70 mg/dL but < 190 mg/dL.

          -  Have fasting triglycerides < 400 mg/dL.

          -  Should be receiving moderate- or high-intensity statin therapy.

          -  Should be on stable medication for ≥ 3 months prior to screening with no planned
             medication or dose change during study participation. The exception to this
             restriction is for fenofibrate; if the participant is receiving fenofibrate, the
             therapy must be stable for at least 6 weeks prior to randomization at a dose that is
             appropriate for the duration of the study in the judgement of the Investigator. Other
             fibrate therapy (and derivatives) are prohibited.

        Key Exclusion Criteria:

          -  Estimated glomerular filtration rate < 40 mL/min/1.73m2 CKD-EPI.

          -  Any uncontrolled or serious disease, or any medical 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.

          -  Poorly controlled type 2 diabetes mellitus, defined as HbA1c > 10% at Visit 1.

          -  Acute ischaemic cardiovascular event in the last 12 months prior to randomization.

          -  Heart failure with New York Heart Association (NYHA) Class III-IV.

          -  High-risk of bleeding as judged by the Investigator.

          -  Malignancy (except non-melanoma skin cancers, cervical in-situ carcinoma, breast
             ductal

          -  Carcinoma in-situ, or Stage 1 prostate carcinoma) within the last 10 years.

          -  LDL or plasma apheresis within 12 months prior to randomization.

          -  Uncontrolled hypertension defined as average supine SBP > 160 mmHg or DBP > 90 mmHg at
             Visit 1 or Visit 3.

          -  Heart rate after 10 minutes supine rest < 50 bpm or > 100 bpm.

          -  Any laboratory values with the following deviations at Screening:

               -  Positive result on screening for hepatitis B, hepatitis C or HIV.

               -  ALT > 1.5 × ULN.

               -  AST > 1.5 × ULN.

               -  TBL > ULN.

               -  ALP > 1.5 × ULN.

               -  WBC < LLN.

               -  Haemoglobin < 12 g/dL in men or < 11 g/dL in women.

               -  Platelet count ≤ LLN.

               -  aPTT > ULN and PT > ULN.

               -  UACR > 11.3 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 as judged by
             the Investigator.

          -  Mipomersen, or lomitapide within 12 months prior to randomization.

          -  Previous administration of AZD8233/AZD6615.

          -  Previous administration of PCSK9 inhibition treatment.

          -  Participation in another clinical study with a study intervention administered in the
             last 3 months prior to randomization or 5 half-lives from last dose to first
             administration of study intervention, whichever is the longest.