A Study of AZD8233 in Participants With Dyslipidemia.

Dyslipidemia Clinical Trial

— HAYATE  

Official title:

A Phase 1 and 2 Study to Evaluate the Safety, Tolerability, Efficacy, Pharmacokinetics and Pharmacodynamics of AZD8233 Following a Multiple Subcutaneous Dose Administration in Japanese Participants With Dyslipidemia

Clinical Trial Details — Status: Completed

Administrative data

• NCT number: NCT04823611
• Other study ID #: D7990C00006
• Status: Completed
• Phase: Phase 1/Phase 2
• Start date: January 20, 2021
• Est. completion date: September 10, 2022

Study information

• Verified date: September 2022
• Source: AstraZeneca
• Contact: n/a
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial Summary

A Phase 1 and 2 Study of AZD8233 in Participants with Dyslipidemia and this study consists of Part A , Part B and Part C. Part A is designed as a randomized, single-blind (blinding of participants and sites), placebo-controlled, multiple dose, phase 1 study. Part B is designed as a randomized, double-blind, placebo-controlled, dose-ranging, phase 2 study. Part C is designed as a randomized , single-blind (blinding of participants and sites), placebo-controlled, multiple dose, phase 1 study.

Description:

Part A: This is designed as a randomized, single-blind (blinding of participants and sites), placebo-controlled, multiple dose, phase 1 study. Approximately 11 Japanese participants will be randomized in an 8:3 ratio into 1 of the 2 single-blinded treatment arms; AZD8233 high dose or placebo. Participants will be dosed SC on Days 1, 8, 29, and 57. Part B:This is designed as a randomized, double-blind, placebo-controlled, dose-ranging, phase 2 study. Approximately 60 Japanese participants will be randomized in a 1:1:1 ratio into 1 of the 4 double-blinded treatment arms; AZD8233 low dose, AZD8233 medium dose, or placebo. Participants will be dosed SC on Days 1, 29, and 57. Part C:This is designed as a randomized, single-blind (blinding of participants and sites), placebo-controlled, multiple dose, phase 1 study. Approximately 11 Japanese participants will be randomized in an 8:3 ratio into 1 of the 2 single-blinded treatment arms; AZD8233 medium dose or placebo. Participants will be dosed SC on Days 1, 29, and 57.

Recruitment information / eligibility

• Status: Completed
• Enrollment: 87
• Est. completion date: September 10, 2022
• Est. primary completion date: September 10, 2022
• Accepts healthy volunteers: No
• Gender: All
• Age group: 20 Years to 75 Years

Eligibility

Key Inclusion Criteria:

Part A

• Participants must be 20 to 60 years of age inclusive, at the time of signing the informed consent
• Participants who have a fasting LDL-C = 70 mg/dL but < 140 mg/dL at screening
• Participants who have fasting triglycerides < 400 mg/dL at screening
• Participants who should be receiving statin therapy
• Participants who should be on stable medication for a certain time period prior to randomization
• Body mass index (BMI) between 19 and 40 kg/m2
• Females must not be pregnant and must have a negative pregnancy test at screening and randomisation, must not be lactating , and must be of nonchild-bearing potential Part B
• Participants must be 20 to 75 years of age inclusive, at the time of signing the informed consent
• Have a fasting LDL-C = 70 mg/dL but < 190 mg/dL at screening (Visit 2)
• Have fasting triglycerides < 400 mg/dL at screening (Visit 2)
• Should be receiving statin therapy
• LDL-lowering medications should be on stable dosing for = 3 months prior to screening with no planned medication or dose change during study participation
• BMI between 19 and 40 kg/m2
• Female participants must not be pregnant and must have a negative pregnancy test at screening and randomisation, must not be lactating, and must not be of childbearing potential Part C
• Participants must be 20 to 60 years of age inclusive, at the time of signing the informed consent
• Participants who have a fasting LDL-C = 70 mg/dL but < 140 mg/dL at screening
• Participants who have fasting triglycerides < 400 mg/dL at screening
• Participants who should be receiving statin therapy
• Participants who should be on stable medication for a certain time period prior to randomization
• Body mass index (BMI) between 19 and 40 kg/m2
• Females must not be pregnant and must have a negative pregnancy test at screening and randomisation, must not be lactating , and must be of nonchild-bearing potential Key Exclusion Criteria: Part A
• eGFR < 60 mL/min/1.73m2 using the Japanese equation
• Blood dyscrasias with increased risk of bleeding including idiopathic thrombocytopenic purpura and thrombotic thrombocytopenic purpura or symptoms of increased risk of bleeding. Or participants receiving anti-coagulation therapy
• History of major bleed or high-risk of bleeding diathesis
• Subjects with a high 10-year risk of coronary heart disease as calculated using the Suita score
• Heart rate after 10 minutes of sitting rest < 50 or > 100 beats per minute
• Uncontrolled hypertension defined as sitting SBP > 140 mmHg or DBP > 90 mmHg Part B
• eGFR < 40 mL/min/1.73m2 using the Japanese equation at Visit 1
• Poorly controlled type 2 diabetes mellitus (T2DM), defined as Haemoglobin A1c (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 diathesis as judged by the Investigator
• Uncontrolled hypertension defined as sitting SBP > 160 mmHg or DBP > 90 mmHg at Visit 1 or Visit 3
• Heart rate after 10 minutes sitting rest < 50 bpm or > 100 bpm at Visit 1 or Visit 3 Part C
• eGFR < 60 mL/min/1.73m2 using the Japanese equation
• Blood dyscrasias with increased risk of bleeding including idiopathic thrombocytopenic purpura and thrombotic thrombocytopenic purpura or symptoms of increased risk of bleeding. Or participants receiving anti-coagulation therapy
• History of major bleed or high-risk of bleeding diathesis
• Subjects with a high 10-year risk of coronary heart disease as calculated using the Suita score
• Heart rate after 10 minutes of sitting rest < 50 or > 100 beats per minute
• Uncontrolled hypertension defined as sitting SBP > 140 mmHg or DBP > 90 mmHg

Related Conditions & MeSH terms

• Dyslipidemia
• Dyslipidemias

Intervention

Drug:
• Part A:Placebo
Placebo solution
• Part A:AZD8233
PCSK9-targeted ASO for the reduction of circulating levels of LDL-C.
• Part B:Placebo
Placebo solution
• Part B:AZD8233
PCSK9-targeted ASO for the reduction of circulating levels of LDL-C.
• Part C: Placebo
Placebo solution
• Part C: AZD8233
PCSK9-targeted ASO for the reduction of circulating levels of LDL-C.

Locations

Country	Name	City	State
Japan	Research Site	Chiyoda-ku
Japan	Research Site	Chuo-ku
Japan	Research Site	Chuo-ku
Japan	Research Site	Chuo-ku
Japan	Research Site	Osaka-shi
Japan	Research Site	Shinjuku-ku
Japan	Research Site	Suita-shi

Sponsors (1)

Lead Sponsor	Collaborator
AstraZeneca

Country where clinical trial is conducted

Japan, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	Part A: Number of subjects with adverse events (AEs) due to AZD8233 SC multiple dose treatment.	To assess AEs as a variable of safety and tolerability of AZD8233 following SC administration of multiple doses. Serious AEs will be recorded from the time of informed consent.	From randomization to final Follow-up Visit (Week 16 post last dose).
Primary	Part A: Vital sign: Systolic blood pressure (SBP)	To assess SBP as a variable of safety and tolerability of AZD8233 following SC administration of multiple doses. BP will be collected after the subject has rested in the supine position for at least 5 minutes.	From Day1(pre-dose) to final Follow-up Visit (Week 16 post last dose).
Primary	Part A: Vital sign: Pulse rate	To assess supine position pulse as a variable of safety and tolerability of AZD8233 following SC administration of multiple doses. Pulse rate will be collected after the subject has rested in the supine position for at least 5 minutes.	From Day1(pre-dose) to final Follow-up Visit (Week 16 post last dose)
Primary	Part A: Vital sign: Body temperature	To assess the oral body temperature as a variable of safety and tolerability of AZD8233 following SC administration of multiple doses.	From Day 1(pre-dose) to final Follow-up Visit (Week 16 post last dose).
Primary	Part A: Number of patients with abnormal findings in resting 12-lead Electrocariogram (ECG) .	To assess the clinically significant abnormalities in the cardiovascular system functioning using a 12-lead ECG ( RR, PR, QRS, QT, QTcF, and heart rate )as a variable of safety and tolerability of AZD8233 following SC administration of multiple doses. ECG evaluations will be recorded after approximately 10 min resting in supine position. During treatment period, ECG will be done on Days 1 and 57 (pre-dose and at 0.5, 1, 2, 3, 4, 6, 8, 12 and 24, 36 and 48 hours post-dose), and Days 8 and 29 (pre-dose).	From Day1(pre-dose) to final Follow-up Visit (Week 16 post last dose).
Primary	Part A: Number of subject with abnormal findings in cardiac telemetry	To assess cardiac telemetry as a variable of safety and tolerability of AZD8233 following SC administration of multiple doses.	At Day -1, Days 1 to 3 (pre-dose to 24 hours post-dose), and Day 57 (pre-dose to 24 hours post-dose).
Primary	Part A: Laboratory assessments: Hematology - Blood cells count	To assess red blood cells (RBC) and white blood cells (WBC) as a variable of safety and tolerability of AZD8233 following SC administration of multiple doses.	Day-1, Day1 ( 24 hours post- dose), Day8 ( pre-dose), Day29 (pre-dose), Day57 (pre-dose), Week 2,4,8,12 and 16 post last dose.
Primary	Part A: Laboratory assessments: Hematology - Hemoglobin (Hb)	To assess Hb as a variable of safety and tolerability of AZD8233 following SC administration of multiple doses.	Day-1, Day1 ( 24 hours post- dose), Day8 ( pre-dose), Day29 (pre-dose), Day57 (pre-dose), Week 2,4,8,12 and 16 post last dose.
Primary	Part A: Laboratory assessments: Hematology - Hematocrit (HCT)	To assess HCT as a variable of safety and tolerability of AZD8233 following SC administration of multiple doses.	Day-1, Day1 ( 24 hours post- dose), Day8 ( pre-dose), Day29 (pre-dose), Day57 (pre-dose), Week 2,4,8,12 and 16 post last dose
Primary	Part A: Laboratory assessments: Hematology - Mean corpuscular volume (MCV)	To assess MCV as a variable of safety and tolerability of AZD8233 following SC administration of multiple doses.	Day-1, Day1 ( 24 hours post- dose), Day8 ( pre-dose), Day29 (pre-dose), Day57 (pre-dose), Week 2,4,8,12 and 16 post last dose
Primary	Part A: Laboratory assessments: Hematology - Mean corpuscular hemoglobin (MCH)	To assess MCH as a variable of safety and tolerability of AZD8233 following SC administration of multiple doses.	Day-1, Day1 ( 24 hours post- dose), Day8 ( pre-dose), Day29 (pre-dose), Day57 (pre-dose), Week 2,4,8,12 and 16 post last dose.
Primary	Part A: Laboratory assessments: Hematology - Mean corpuscular hemoglobin concentration (MCHC)	To assess MCHC as a variable of safety and tolerability of AZD8233 following SC administration of multiple doses.	Day-1, Day1 ( 24 hours post- dose), Day8 ( pre-dose), Day29 (pre-dose), Day57 (pre-dose), Week 2,4,8,12 and 16 post last dose.
Primary	Part A: Laboratory assessments: Hematology - Differential WBC count	To assess differential WBC count absolute count of neutrophils, lymphocytes, monocytes, eosinophils and basophils as a variable of safety and tolerability of AZD8233 following SC administration of multiple doses.	Day-1, Day1 ( 24 hours post- dose), Day8 ( pre-dose), Day29 (pre-dose), Day57 (pre-dose), Week 2,4,8,12 and 16 post last dose.
Primary	Part A: Laboratory assessments: Hematology - Platelet count and platelet function assessment.	To assess platelet count in platelet rich plasma (PRP) using Light Transmission Aggregometry (LTA) as a variable of safety and tolerability of AZD8233 following SC administration of multiple doses.	Day-1, Day1 ( 24 hours post- dose), Day8 ( pre-dose), Day29 (pre-dose), Day57 (pre-dose), Week 2,4,8,12 and 16 post last dose.
Primary	Part A: Laboratory assessments: Hematology - Reticulocytes absolute count	To assess Reticulocytes absolute count as a variable of safety and tolerability of AZD8233 following SC administration of multiple doses.	Day-1, Day1 ( 24 hours post- dose), Day8 ( pre-dose), Day29 (pre-dose), Day57 (pre-dose), Week 2,4,8,12 and 16 post last dose.
Primary	Part A: Laboratory assessments: Serum clinical chemistry - Electrolytes	To assess serum level of sodium, potassium, calcium as a variable of safety and tolerability of AZD8233 following SC administration of multiple doses.	Day-1, Day1 ( 24 hours post- dose), Day8 ( pre-dose), Day29 (pre-dose), Day57 (pre-dose), Week 2,4,8,12 and 16 post last dose.
Primary	Part A: Laboratory assessments: Serum clinical chemistry - Blood urea nitrogen (BUN)	To assess serum level of BUN as a variable of safety and tolerability of AZD8233 following SC administration of multiple doses.	Day-1, Day1 ( 24 hours post- dose), Day8 ( pre-dose), Day29 (pre-dose), Day57 (pre-dose), Week 2,4,8,12 and 16 post last dose.
Primary	Part A: To assess serum level of BUN as a variable of safety and tolerability of AZD8233 following SC administration of multiple ascending doses.	To assess serum level of creatinine as a variable of safety and tolerability of AZD8233 following SC administration of multiple doses.	Day-1, Day1 ( 24 hours post- dose), Day8 ( pre-dose), Day29 (pre-dose), Day57 (pre-dose), Week 2,4,8,12 and 16 post last dose.
Primary	Part A: Laboratory assessments: Serum clinical chemistry - Glucose (fasting)	To assess serum fasting glucose level as a variable of safety and tolerability of AZD8233 following SC administration of multiple doses.	Day-1, Day1 ( 24 hours post- dose), Day8 ( pre-dose), Day29 (pre-dose), Day57 (pre-dose), Week 2,4,8,12 and 16 post last dose.
Primary	Part A: Laboratory assessments: Serum clinical chemistry - Creatine kinase	To assess the level of serum creatine kinase as a variable of safety and tolerability of AZD8233 following SC administration of multiple doses.	Day-1, Day1 ( 24 hours post- dose), Day8 ( pre-dose), Day29 (pre-dose), Day57 (pre-dose), Week 2,4,8,12 and 16 post last dose.
Primary	Part A: Laboratory assessments: Serum clinical chemistry - Direct bilirubin	To assess the level of serum bilirubin (direct) as a variable of safety and tolerability of AZD8233 following SC administration of multiple doses.	Day-1, Day1 ( 24 hours post- dose), Day8 ( pre-dose), Day29 (pre-dose), Day57 (pre-dose), Week 2,4,8,12 and 16 post last dose.
Primary	Part A: Laboratory assessments: Serum clinical chemistry - Hemoglobin A1c (HbA1c)	To assess the level of HbA1c as a variable of safety and tolerability of AZD8233 following SC administration of multiple doses.	Day-1, Day1 ( 24 hours post- dose), Day8 ( pre-dose), Day29 (pre-dose), Day57 (pre-dose), Week 2,4,8,12 and 16 post last dose.
Primary	Part A: Laboratory assessments: Serum clinical chemistry - Liver enzymes	To assess the level of Alkaline phosphatase (ALP), Alanine aminotransferase (ALT), Aspartate aminotransferase (AST), and Gamma glutamyl transpeptidase (GGT) as a variable of safety and tolerability of AZD8233 following SC administration of multiple doses.	Day-1, Day1 ( 24 hours post- dose), Day8 ( pre-dose), Day29 (pre-dose), Day57 (pre-dose), Week 2,4,8,12 and 16 post last dose.
Primary	Part A: Laboratory assessments: Serum clinical chemistry - Total bilirubin	To assess the level of serum bilirubin (total) as a variable of safety and tolerability of AZD8233 following SC administration of multiple doses.	Day-1, Day1 ( 24 hours post- dose), Day8 ( pre-dose), Day29 (pre-dose), Day57 (pre-dose), Week 2,4,8,12 and 16 post last dose.
Primary	Part A: Laboratory assessments: Serum clinical chemistry - Cell enzymes	To assess the level of serum glutamate dehydrogenase (GLDH) and lactate dehydrogenase (LDH) as a variable of safety and tolerability of AZD8233 following SC administration of multiple doses.	Day-1, Day1 ( 24 hours post- dose), Day8 ( pre-dose), Day29 (pre-dose), Day57 (pre-dose), Week 2,4,8,12 and 16 post last dose.
Primary	Part A: Laboratory assessments: Serum clinical chemistry - Bicarbonate	To assess the level of bicarbonate as a variable of safety and tolerability of AZD8233 following SC administration of multiple doses.	Day-1, Day1 ( 24 hours post- dose), Day8 ( pre-dose), Day29 (pre-dose), Day57 (pre-dose), Week 2,4,8,12 and 16 post last dose.
Primary	Part A: Laboratory assessments: Serum clinical chemistry - Uric acid	To assess the level of uric acid as a variable of safety and tolerability of AZD8233 following SC administration of multiple doses.	Day-1, Day1 ( 24 hours post- dose), Day8 ( pre-dose), Day29 (pre-dose), Day57 (pre-dose), Week 2,4,8,12 and 16 post last dose.
Primary	Part A: Laboratory assessments - Coagulation	To assess activated partial thrombin time (aPTT), prothrombin time (PT), and International normalized ratio (INR) as a variable of safety and tolerability of AZD8233 following SC administration of multiple doses.	Day-1, Day1 ( 24 hours post- dose), Day8 ( pre-dose), Day29 (pre-dose), Day57 (pre-dose), Week 2,4,8,12 and 16 post last dose.
Primary	Part A: Renal safety biomarkers - Urine clusterin	To assess renal biomarker by evaluation of urine clusterin level as a variable of safety and tolerability of AZD8233 following SC administration of multiple doses.	Day 1 (pre-dose, 24 hours and 48 hours post-dose), Days 8 and 29 (pre-dose), and Day 57 (pre-dose).
Primary	Part A: Renal safety biomarkers - Urine cystatin-C	To assess renal biomarker by evaluation of urine cystatin-C level as a variable of safety and tolerability of AZD8233 following SC administration of multiple doses.	Day 1 (pre-dose, 24 hours and 48 hours post-dose), Days 8 and 29 (pre-dose), and Day 57 (pre-dose).
Primary	Part A: Renal safety biomarkers - Urine N-acetyl-beta-D-glucosaminidase (NAG)	To assess renal biomarker by evaluation of urine NAG level as a variable of safety and tolerability of AZD8233 following SC administration of multiple doses.	Day 1 (pre-dose, 24 hours and 48 hours post-dose), Days 8 and 29 (pre-dose), and Day 57 (pre-dose).
Primary	Part A: Renal safety biomarkers - Urine albumin	To assess renal biomarker by evaluation of urine albumin level as a variable of safety and tolerability of AZD8233 following SC administration of multiple doses.	Day 1 (pre-dose, 24 hours and 48 hours post-dose), Days 8 and 29 (pre-dose), and Day 57 (pre-dose).
Primary	Part A: Renal safety biomarkers - Urine creatinine	To assess renal biomarker by evaluation of urine creatinine level as a variable of safety and tolerability of AZD8233 following SC administration of multiple doses.	Day 1 (pre-dose, 24 hours and 48 hours post-dose), Days 8 and 29 (pre-dose), and Day 57 (pre-dose).
Primary	Part A: Renal safety biomarkers - Urine Kidney injury molecule1 (KIM-1)	To assess renal biomarker by evaluation of urine KIM-1 level as a variable of safety and tolerability of AZD8233 following SC administration of multiple doses.	Day 1 (pre-dose, 24 hours and 48 hours post-dose), Days 8 and 29 (pre-dose), and Day 57 (pre-dose).
Primary	Part A: Renal safety biomarkers - Urine Neutrophil gelatinase-associated lipocalin (NGAL)	To assess renal biomarker by evaluation of urine NAG level as a variable of safety and tolerability of AZD8233 following SC administration of multiple doses.	Day 1 (pre-dose, 24 hours and 48 hours post-dose), Days 8 and 29 (pre-dose), and Day 57 (pre-dose).
Primary	Part A: Renal safety biomarkers - Urine Osteopontin	To assess renal biomarker by evaluation of urine osteopontin level as a variable of safety and tolerability of AZD8233 following SC administration of multiple doses.	Day 1 (pre-dose, 24 hours and 48 hours post-dose), Days 8 and 29 (pre-dose), and Day 57 (pre-dose).
Primary	Part A: Renal safety biomarkers - Urine total protein	To assess renal biomarker by evaluation of urine protein (total) level as a variable of safety and tolerability of AZD8233 following SC administration of multiple doses.	Day 1 (pre-dose, 24 hours and 48 hours post-dose), Days 8 and 29 (pre-dose), and Day 57 (pre-dose).
Primary	Part A: Immune Activation Response - High-sensitivity C-reactive protein (hs-CRP)	To assess hs-CRP level as a variable of safety and tolerability of AZD8233 following SC administration of multiple doses.	From screening to final Follow-up Visit (Week 16 post last dose).
Primary	Part A: Complement Activation panel	To assess chemotactic factor (C3a, Bb, and C5a) levels as a variable of safety and tolerability of AZD8233 following SC administration of multiple doses.	Days 1 and 57 (pre-dose, 1, 2, and 4 hours post-dose).
Primary	Part A: Laboratory assessments - Sampling for dipstick urinalysis for hematuria	To assess dipstick urinalysis for hematuria as a variable of safety and tolerability of AZD8233 following SC administration of multiple doses.	Day1 to Day3 (pre-dose and then 24 and 48 h post -dose), Day8 (pre-dose), Day29 (pre-dose) and Day57 (pre-dose).
Primary	Part B:Absolute change from baseline in long-transformed LDL-C in serum at week12.	Absolute change from baseline in long-transformed LDL-C in serum.	Measurement at week 12
Primary	Part A: Vital sign: Diastolic blood pressure (DBP)	To assess DBP as a variable of safety and tolerability of AZD8233 following SC administration of multiple doses. BP will be collected after the subject has rested in the supine position for at least 5 minutes.	From Day1(pre-dose) to final Follow-up Visit (Week 16 post last dose).
Primary	Part C: Number of subjects with adverse events (AEs) due to AZD8233 SC multiple dose treatment.	To assess AEs as a variable of safety and tolerability of AZD8233 following SC administration of multiple doses. Serious AEs will be recorded from the time of informed consent.	From randomization to final Follow-up Visit (Week 16 post last dose).
Primary	Part C: Vital sign: Systolic blood pressure (SBP)	To assess SBP as a variable of safety and tolerability of AZD8233 following SC administration of multiple doses. BP will be collected after the subject has rested in the supine position for at least 5 minutes.	From Day1(pre-dose) to final Follow-up Visit (Week 16 post last dose).
Primary	Part C: Vital sign: Pulse rate	To assess supine position pulse as a variable of safety and tolerability of AZD8233 following SC administration of multiple doses. Pulse rate will be collected after the subject has rested in the supine position for at least 5 minutes.	From Day1(pre-dose) to final Follow-up Visit (Week 16 post last dose)
Primary	Part C: Vital sign: Body temperature	To assess the oral body temperature as a variable of safety and tolerability of AZD8233 following SC administration of multiple doses.	From Day 1(pre-dose) to final Follow-up Visit (Week 16 post last dose).
Primary	Part C: Number of patients with abnormal findings in resting 12-lead Electrocariogram (ECG) .	To assess the clinically significant abnormalities in the cardiovascular system functioning using a 12-lead ECG ( RR, PR, QRS, QT, QTcF, and heart rate )as a variable of safety and tolerability of AZD8233 following SC administration of multiple doses. ECG evaluations will be recorded after approximately 10 min resting in supine position. During treatment period, ECG will be done on Days 1 and 57 (pre-dose and at 0.5, 1, 2, 3, 4, 6, 8, 12 and 24, 36 and 48 hours post-dose), and Days 8 and 29 (pre-dose).	From Day1(pre-dose) to final Follow-up Visit (Week 16 post last dose).
Primary	Part C: Number of subject with abnormal findings in cardiac telemetry	To assess cardiac telemetry as a variable of safety and tolerability of AZD8233 following SC administration of multiple doses.	At Day -1, Days 1 to 3 (pre-dose to 24 hours post-dose), and Day 57 (pre-dose to 24 hours post-dose).
Primary	Part C: Laboratory assessments: Hematology - Hemoglobin (Hb)	To assess Hb as a variable of safety and tolerability of AZD8233 following SC administration of multiple doses.	Day-1, Day1 ( 24 hours post- dose), Day8 , Day29 (pre-dose), Day57 (pre-dose), Week 2,4,8,12 and 16 post last dose.
Primary	Part C: Laboratory assessments: Hematology - Blood cells count	To assess red blood cells (RBC) and white blood cells (WBC) as a variable of safety and tolerability of AZD8233 following SC administration of multiple doses.	Day-1, Day1 ( 24 hours post- dose), Day8 , Day29 (pre-dose), Day57 (pre-dose), Week 2,4,8,12 and 16 post last dose.
Primary	Part C: Laboratory assessments: Hematology - Hematocrit (HCT)	To assess HCT as a variable of safety and tolerability of AZD8233 following SC administration of multiple doses.	Day-1, Day1 ( 24 hours post- dose), Day8, Day29 (pre-dose), Day57 (pre-dose), Week 2,4,8,12 and 16 post last dose
Primary	Part C: Laboratory assessments: Hematology - Mean corpuscular volume (MCV)	To assess MCV as a variable of safety and tolerability of AZD8233 following SC administration of multiple doses.	Day-1, Day1 ( 24 hours post- dose), Day8 , Day29 (pre-dose), Day57 (pre-dose), Week 2,4,8,12 and 16 post last dose
Primary	Part C: Laboratory assessments: Hematology - Mean corpuscular hemoglobin (MCH)	To assess MCH as a variable of safety and tolerability of AZD8233 following SC administration of multiple doses.	Day-1, Day1 ( 24 hours post- dose), Day8, Day29 (pre-dose), Day57 (pre-dose), Week 2,4,8,12 and 16 post last dose.
Primary	Part C: Laboratory assessments: Hematology - Mean corpuscular hemoglobin concentration (MCHC)	To assess MCHC as a variable of safety and tolerability of AZD8233 following SC administration of multiple doses.	Day-1, Day1 ( 24 hours post- dose), Day8, Day29 (pre-dose), Day57 (pre-dose), Week 2,4,8,12 and 16 post last dose.
Primary	Part C: Laboratory assessments: Hematology - Differential WBC count	To assess differential WBC count absolute count of neutrophils, lymphocytes, monocytes, eosinophils and basophils as a variable of safety and tolerability of AZD8233 following SC administration of multiple doses.	Day-1, Day1 ( 24 hours post- dose), Day8 , Day29 (pre-dose), Day57 (pre-dose), Week 2,4,8,12 and 16 post last dose.
Primary	Part C: Laboratory assessments: Hematology - Platelet count and platelet function assessment.	To assess platelet count in platelet rich plasma (PRP) using Light Transmission Aggregometry (LTA) as a variable of safety and tolerability of AZD8233 following SC administration of multiple doses.	Day-1, Day1 ( 24 hours post- dose), Day8, Day29 (pre-dose), Day57 (pre-dose), Week 2,4,8,12 and 16 post last dose.
Primary	Part C: Laboratory assessments: Hematology - Reticulocytes absolute count	To assess Reticulocytes absolute count as a variable of safety and tolerability of AZD8233 following SC administration of multiple doses.	Day-1, Day1 ( 24 hours post- dose), Day8 , Day29 (pre-dose), Day57 (pre-dose), Week 2,4,8,12 and 16 post last dose.
Primary	Part C: Laboratory assessments: Serum clinical chemistry - Electrolytes	To assess serum level of sodium, potassium, calcium as a variable of safety and tolerability of AZD8233 following SC administration of multiple doses.	Day-1, Day1 ( 24 hours post- dose), Day8, Day29 (pre-dose), Day57 (pre-dose), Week 2,4,8,12 and 16 post last dose.
Primary	Part C: Laboratory assessments: Serum clinical chemistry - Blood urea nitrogen (BUN)	To assess serum level of BUN as a variable of safety and tolerability of AZD8233 following SC administration of multiple doses.	Day-1, Day1 ( 24 hours post- dose), Day8 , Day29 (pre-dose), Day57 (pre-dose), Week 2,4,8,12 and 16 post last dose.
Primary	Part C: To assess serum level of BUN as a variable of safety and tolerability of AZD8233 following SC administration of multiple ascending doses.	To assess serum level of creatinine as a variable of safety and tolerability of AZD8233 following SC administration of multiple doses.	Day-1, Day1 ( 24 hours post- dose), Day8 , Day29 (pre-dose), Day57 (pre-dose), Week 2,4,8,12 and 16 post last dose.
Primary	Part C: Vital sign: Diastolic blood pressure (DBP)	To assess DBP as a variable of safety and tolerability of AZD8233 following SC administration of multiple doses. BP will be collected after the subject has rested in the supine position for at least 5 minutes.	From Day1(pre-dose) to final Follow-up Visit (Week 16 post last dose).
Primary	Part C: Laboratory assessments: Serum clinical chemistry - Glucose (fasting)	To assess serum fasting glucose level as a variable of safety and tolerability of AZD8233 following SC administration of multiple doses.	Day-1, Day1 ( 24 hours post- dose), Day8, Day29 (pre-dose), Day57 (pre-dose), Week 2,4,8,12 and 16 post last dose.
Primary	Part C: Laboratory assessments: Serum clinical chemistry - Creatine kinase	To assess the level of serum creatine kinase as a variable of safety and tolerability of AZD8233 following SC administration of multiple doses.	Day-1, Day1 ( 24 hours post- dose), Day8, Day29 (pre-dose), Day57 (pre-dose), Week 2,4,8,12 and 16 post last dose.
Primary	Part C: Laboratory assessments: Serum clinical chemistry - Direct bilirubin	To assess the level of serum bilirubin (direct) as a variable of safety and tolerability of AZD8233 following SC administration of multiple doses.	Day-1, Day1 ( 24 hours post- dose), Day8, Day29 (pre-dose), Day57 (pre-dose), Week 2,4,8,12 and 16 post last dose.
Primary	Part C: Laboratory assessments: Serum clinical chemistry - Hemoglobin A1c (HbA1c)	To assess the level of HbA1c as a variable of safety and tolerability of AZD8233 following SC administration of multiple doses.	Day-1, Day1 ( 24 hours post- dose), Day8, Day29 (pre-dose), Day57 (pre-dose), Week 2,4,8,12 and 16 post last dose.
Primary	Part C: Laboratory assessments: Serum clinical chemistry - Liver enzymes	To assess the level of Alkaline phosphatase (ALP), Alanine aminotransferase (ALT), Aspartate aminotransferase (AST), and Gamma glutamyl transpeptidase (GGT) as a variable of safety and tolerability of AZD8233 following SC administration of multiple doses.	Day-1, Day1 ( 24 hours post- dose), Day8, Day29 (pre-dose), Day57 (pre-dose), Week 2,4,8,12 and 16 post last dose.
Primary	Part C: Laboratory assessments: Serum clinical chemistry - Total bilirubin	To assess the level of serum bilirubin (total) as a variable of safety and tolerability of AZD8233 following SC administration of multiple doses.	Day-1, Day1 ( 24 hours post- dose), Day8 , Day29 (pre-dose), Day57 (pre-dose), Week 2,4,8,12 and 16 post last dose.
Primary	Part C: Laboratory assessments: Serum clinical chemistry - Cell enzymes	To assess the level of serum glutamate dehydrogenase (GLDH) and lactate dehydrogenase (LDH) as a variable of safety and tolerability of AZD8233 following SC administration of multiple doses.	Day-1, Day1 ( 24 hours post- dose), Day8, Day29 (pre-dose), Day57 (pre-dose), Week 2,4,8,12 and 16 post last dose.
Primary	Part C: Laboratory assessments: Serum clinical chemistry - Bicarbonate	To assess the level of bicarbonate as a variable of safety and tolerability of AZD8233 following SC administration of multiple doses.	Day-1, Day1 ( 24 hours post- dose), Day8, Day29 (pre-dose), Day57 (pre-dose), Week 2,4,8,12 and 16 post last dose.
Primary	Part C: Laboratory assessments: Serum clinical chemistry - Uric acid	To assess the level of uric acid as a variable of safety and tolerability of AZD8233 following SC administration of multiple doses.	Day-1, Day1 ( 24 hours post- dose), Day8, Day29 (pre-dose), Day57 (pre-dose), Week 2,4,8,12 and 16 post last dose.
Primary	Part C: Laboratory assessments - Coagulation	To assess activated partial thrombin time (aPTT), prothrombin time (PT), and International normalized ratio (INR) as a variable of safety and tolerability of AZD8233 following SC administration of multiple doses.	Day-1, Day1 ( 24 hours post- dose), Day8, Day29 (pre-dose), Day57 (pre-dose), Week 2,4,8,12 and 16 post last dose.
Primary	Part C: Renal safety biomarkers - Urine clusterin	To assess renal biomarker by evaluation of urine clusterin level as a variable of safety and tolerability of AZD8233 following SC administration of multiple doses.	Day 1 (pre-dose, 24 hours and 48 hours post-dose), Day 8, Day 29 (pre-dose), and Day 57 (pre-dose).
Primary	Part C: Renal safety biomarkers - Urine cystatin-C	To assess renal biomarker by evaluation of urine cystatin-C level as a variable of safety and tolerability of AZD8233 following SC administration of multiple doses.	Day 1 (pre-dose, 24 hours and 48 hours post-dose), Day 8, Day 29 (pre-dose), and Day 57 (pre-dose).
Primary	Part C: Renal safety biomarkers - Urine N-acetyl-beta-D-glucosaminidase (NAG)	To assess renal biomarker by evaluation of urine NAG level as a variable of safety and tolerability of AZD8233 following SC administration of multiple doses.	Day 1 (pre-dose, 24 hours and 48 hours post-dose), Day 8 , Day 29 (pre-dose), and Day 57 (pre-dose).
Primary	Part C: Renal safety biomarkers - Urine albumin	To assess renal biomarker by evaluation of urine albumin level as a variable of safety and tolerability of AZD8233 following SC administration of multiple doses.	Day 1 (pre-dose, 24 hours and 48 hours post-dose), Day 8 , Day 29 (pre-dose), and Day 57 (pre-dose).
Primary	Part C: Renal safety biomarkers - Urine creatinine	To assess renal biomarker by evaluation of urine creatinine level as a variable of safety and tolerability of AZD8233 following SC administration of multiple doses.	Day 1 (pre-dose, 24 hours and 48 hours post-dose), Day 8, Day 29 (pre-dose), and Day 57 (pre-dose).
Primary	Part C: Renal safety biomarkers - Urine Neutrophil gelatinase-associated lipocalin (NGAL)	To assess renal biomarker by evaluation of urine NAG level as a variable of safety and tolerability of AZD8233 following SC administration of multiple doses.	Day 1 (pre-dose, 24 hours and 48 hours post-dose), Day 8, Day 29 (pre-dose), and Day 57 (pre-dose).
Primary	Part C: Renal safety biomarkers - Urine Osteopontin	To assess renal biomarker by evaluation of urine osteopontin level as a variable of safety and tolerability of AZD8233 following SC administration of multiple doses.	Day 1 (pre-dose, 24 hours and 48 hours post-dose), Day 8 , Day 29 (pre-dose), and Day 57 (pre-dose).
Primary	Part C: Renal safety biomarkers - Urine total protein	To assess renal biomarker by evaluation of urine protein (total) level as a variable of safety and tolerability of AZD8233 following SC administration of multiple doses.	Day 1 (pre-dose, 24 hours and 48 hours post-dose), Day 8 , Day 29 (pre-dose), and Day 57 (pre-dose).
Primary	Part C: Immune Activation Response - High-sensitivity C-reactive protein (hs-CRP)	To assess hs-CRP level as a variable of safety and tolerability of AZD8233 following SC administration of multiple doses.	From screening to final Follow-up Visit (Week 16 post last dose).
Primary	Part C: Complement Activation panel	To assess chemotactic factor (Bb, and C5a) levels as a variable of safety and tolerability of AZD8233 following SC administration of multiple doses.	Days 1 and 57 (pre-dose, 1, 2, and 4 hours post-dose).
Primary	Part C: Laboratory assessments - Sampling for dipstick urinalysis for hematuria	To assess dipstick urinalysis for hematuria as a variable of safety and tolerability of AZD8233 following SC administration of multiple doses.	Day1 to Day3 (pre-dose and then 24 and 48 h post -dose), Day8 , Day29 (pre-dose) and Day57 (pre-dose).
Primary	Part C: Renal safety biomarkers - Urine Kidney injury molecule1 (KIM-1)	To assess renal biomarker by evaluation of urine KIM-1 level as a variable of safety and tolerability of AZD8233 following SC administration of multiple doses.	Day 1 (pre-dose, 24 hours and 48 hours post-dose), Day 8 , Day29 (pre-dose), and Day 57 (pre-dose).
Secondary	Part A:Plasma PK analysis. Time delay between drug administration and the first observed concentration in plasma (tlag).	To characterize the PK of AZD8233 following SC administration of multiple doses.	Days 1 and 57 (Pre-dose, 0.5, 1, 1.5, 2, 2.5, 3, 4, 5, 6, 8, 10, 12, 24, 36, 48 hours post-dose); Day 8 (pre-dose), Days 15, 22, 29 (pre-dose), Days 36 and 44.
Secondary	Part A:Plasma PK analysis: Time to reach peak or maximum observed concentration or response following drug administration (tmax).	To characterize the PK of AZD8233 following SC administration of multiple doses.	Days 1 and 57 (Pre-dose, 0.5, 1, 1.5, 2, 2.5, 3, 4, 5, 6, 8, 10, 12, 24, 36, 48 hours post-dose); Day 8 (pre-dose), Days 15, 22, 29 (pre-dose), Days 36 and 44.
Secondary	Part A:Plasma PK analysis: Observed maximum plasma concentration (Cmax)	To characterize the PK of AZD8233 following SC administration of multiple doses.	Days 1 and 57 (Pre-dose, 0.5, 1, 1.5, 2, 2.5, 3, 4, 5, 6, 8, 10, 12, 24, 36, 48 hours post-dose); Day 8 (pre-dose), Days 15, 22, 29 (pre-dose), Days 36 and 44.
Secondary	Part A:Area under the plasma concentration-curve from time zero to time last value above the limit of quantification (AUC[0-last]	To characterize the PK of AZD8233 following SC administration of multiple doses.	Days 1 and 57 (Pre-dose, 0.5, 1, 1.5, 2, 2.5, 3, 4, 5, 6, 8, 10, 12, 24, 36, 48 hours post-dose); Day 8 (pre-dose), Days 15, 22, 29 (pre-dose), Days 36 and 44.
Secondary	Part A:Plasma PK analysis: Area under the concentration-time curve from time zero to 24 hours post-dose (AUC[0-24])	To characterize the PK of AZD8233 following SC administration of multiple doses.	Days 1 and 57 (Pre-dose, 0.5, 1, 1.5, 2, 2.5, 3, 4, 5, 6, 8, 10, 12, 24 hours post-dose).
Secondary	Part A:Plasma PK analysis: Area under the concentration-time curve from time zero to 48 hours post-dose (AUC[0-48])	To characterize the PK of AZD8233 following SC administration of multiple doses.	Days 1 and 57 (Pre-dose, 0.5, 1, 1.5, 2, 2.5, 3, 4, 5, 6, 8, 10, 12, 24, 36, 48 hours post-dose).
Secondary	Part A:Plasma PK analysis: Area under the concentration-time curve from time zero extrapolated to infinity (AUC).	To characterize the PK of AZD8233 following SC administration of multiple doses.	Days 1 and 57 (Pre-dose, 0.5, 1, 1.5, 2, 2.5, 3, 4, 5, 6, 8, 10, 12, 24, 36, 48 hours post-dose); Day 8 (pre-dose), Days 15, 22, 29 (pre-dose), Days 36 and 44.
Secondary	Part A:Plasma PK analysis: Area under the plasma concentration-time curve from time during the dosing interval (AUCt).	To characterize the PK of AZD8233 following SC administration of multiple doses.	Days 1 and 57 (Pre-dose, 0.5, 1, 1.5, 2, 2.5, 3, 4, 5, 6, 8, 10, 12, 24, 36, 48 hours post-dose); Day 8 (pre-dose), Days 15, 22, 29 (pre-dose), Days 36 and 44.
Secondary	Part A:Plasma PK analysis: Observed trough plasma drug concentration (Ctrough).	To characterize the PK of AZD8233 following SC administration of multiple doses.	Days 1 and 57 (Pre-dose, 0.5, 1, 1.5, 2, 2.5, 3, 4, 5, 6, 8, 10, 12, 24, 36, 48 hours post-dose); Day 8 (pre-dose), Days 15, 22, 29 (pre-dose), Days 36 and 44.
Secondary	Part A:Plasma PK analysis: Apparent total body clearance of drug from plasma after extravascular administration (CL/F).	To characterize the PK of AZD8233 following SC administration of multiple doses.	Days 1 and 57 (Pre-dose, 0.5, 1, 1.5, 2, 2.5, 3, 4, 5, 6, 8, 10, 12, 24, 36, 48 hours post-dose); Day 8 (pre-dose), Days 15, 22, 29 (pre-dose), Days 36 and 44.
Secondary	Part A:Plasma PK analysis: Apparent volume of distribution for parent drug at terminal phase (extravascular administration) (Vz/F).	To characterize the PK of AZD8233 following SC administration of multiple doses.	Days 1 and 57 (Pre-dose, 0.5, 1, 1.5, 2, 2.5, 3, 4, 5, 6, 8, 10, 12, 24, 36, 48 hours post-dose); Day 8 (pre-dose), Days 15, 22, 29 (pre-dose), Days 36 and 44.
Secondary	Part A:Plasma PK analysis: Half-life associated with the terminal slope (?z) of a semi-logarithmic concentration-time curve (t1/2).	To characterize the PK of AZD8233 following SC administration of multiple doses.	Days 1 and 57 (Pre-dose, 0.5, 1, 1.5, 2, 2.5, 3, 4, 5, 6, 8, 10, 12, 24, 36, 48 hours post-dose); Day 8 (pre-dose), Days 15, 22, 29 (pre-dose), Days 36 and 44.
Secondary	Part A:Plasma PK analysis: Mean Residence Time (MRT).	To characterize the PK of AZD8233 following SC administration of multiple doses.	Days 1 and 57 (Pre-dose, 0.5, 1, 1.5, 2, 2.5, 3, 4, 5, 6, 8, 10, 12, 24, 36, 48 hours post-dose); Day 8 (pre-dose), Days 15, 22, 29 (pre-dose), Days 36 and 44.
Secondary	Part A:Urine PK analysis: Amount excreted in urine (Ae).	To characterize the PK of AZD8233 following SC administration of multiple doses.	Treatment Days 1 to 3 (Pre-dose and intervals 0-6, 6-12 hours and 12-24 hours post-dose).
Secondary	Part A:Urine PK analysis: Fraction excreted unchanged in urine (Fe).	To characterize the PK of AZD8233 following SC administration of multiple doses.	Treatment Days 1 to 3 (Pre-dose and intervals 0-6, 6-12 hours and 12-24 hours post-dose).
Secondary	Part A:Urine PK analysis: Renal clearance (CLR).	To characterize the PK of AZD8233 following SC administration of multiple doses.	Treatment Days 1 to 3 (Pre-dose and intervals 0-6, 6-12 hours and 12-24 hours post-dose).
Secondary	Part A:Absolute change from baseline in log-transformed PCSK9 in plasma and Percent change from baseline in PCSK9 in plasma.	To assess the effect of AZD8233 on levels of PCSK9 following SC administration of multiple doses.	At screening, Day -1, Days 1 to 3 and Days 57 to 58 (pre-dose and 48 hours post-dose), Day 8 (pre-dose), Days 15, 22, Day 29 (pre-dose), Days 36, 44, Day 56, week 2 to 14 (at 2, 4, 6, 8, 10, 12, and 14 weeks) and week 16 post-dose.
Secondary	Part A:Percentage change from baseline in levels of LDL-C in serum.	To assess the effect of AZD8233 on levels of LDL-C following SC administration of multiple doses.	At screening, Day -1, Days 1 to 3 and Days 57 to 58 (pre-dose and 48 hours post-dose), Day 8 (pre-dose), Days 15, 22, Day 29 (pre-dose), Days 36, 44, Day 56, week 2 to 14 (at 2, 4, 6, 8, 10, 12, and 14 weeks) and week 16 post-dose.
Secondary	Part B:Absolute change from baseline in log-transformed PCSK9 in plasma and Percent change from baseline in PCSK9 in plasma.	To assess the effect of different doses of AZD8233 on PCSK9 versus placebo.	Measurement at screening, week 0, week 1, week 3, week 4, week 6, week 8, week 10, week 12, week 14, week 16, week 18, week 20, week 22, week 24.
Secondary	Part B:Percentage change from baseline in levels of LDL-C in serum.	To assess the effect of different doses of AZD8233 on LDL-C versus placebo.	Measurement at screening, week 0, week 1, week 3, week 4, week 6, week 8, week 10, week 12, week 14, week 16, week 18, week 20, week 22, week 24.
Secondary	Part B:Levels of other lipid parameters of TC, HDL-C, Non-HDL-C, VLDL-C, ApoA1, ApoB, Lp(a) , Triglycerides, Remnants cholesterol.	To assess the effect of AZD8233 on other lipid parameters versus placebo.	Measurement at screening, week 0, week 1, week 3, week 4, week 6, week 8, week 10, week 12, week 14, week 16, week 18, week 20, week 22, week 24.
Secondary	Part B: Plasma concentration of AZD8233		Measurement at week 1, week 4, week 6, week 8, week 10, week 12, week 16, week 20, week 24.
Secondary	Part B:Anti-drug antibodies (ADAs) during the treatment period and follow-up period.	To evaluate the immunogenicity of AZD8233.	Measurement at week 0, week 1, week 4, week 8, week 12, week 16, week 20, week 24.
Secondary	Part A:Levels of other lipid parameters of TC, HDL-C, Non-HDL-C, VLDL-C, ApoA1, ApoB, Lp(a) , Triglycerides.	To assess the effect of AZD8233 on other lipid parameters versus placebo.	Measurement at screening, Day -1, Days 1 to 3 and Days 57 to 58 (pre-dose and 48 hours post-dose), Day 8 (pre-dose), Days 15, 22, Day 29 (pre-dose), Days 36, 44, Day 56, week 2 to 14 (at 2, 4, 6, 8, 10, 12, and 14 weeks) and week 16 post-dose.
Secondary	Part C:Plasma PK analysis. Time delay between drug administration and the first observed concentration in plasma (tlag).	To characterize the PK of AZD8233 following SC administration of multiple doses.	Days 1 and 57 (Pre-dose, 0.5, 1, 1.5, 2, 2.5, 3, 4, 5, 6, 8, 10, 12, 24, 36, 48 hours post-dose); Day 8, Days 15, 22, 29 (pre-dose), Days 36 and 44.
Secondary	Part C:Plasma PK analysis: Time to reach peak or maximum observed concentration or response following drug administration (tmax).	To characterize the PK of AZD8233 following SC administration of multiple doses.	Days 1 and 57 (Pre-dose, 0.5, 1, 1.5, 2, 2.5, 3, 4, 5, 6, 8, 10, 12, 24, 36, 48 hours post-dose); Day 8, Days 15, 22, 29 (pre-dose), Days 36 and 44.
Secondary	Part C:Plasma PK analysis: Observed maximum plasma concentration (Cmax)	To characterize the PK of AZD8233 following SC administration of multiple doses.	Days 1 and 57 (Pre-dose, 0.5, 1, 1.5, 2, 2.5, 3, 4, 5, 6, 8, 10, 12, 24, 36, 48 hours post-dose); Day 8, Days 15, 22, 29 (pre-dose), Days 36 and 44.
Secondary	Part C:Area under the plasma concentration-curve from time zero to time last value above the limit of quantification (AUC[0-last]	To characterize the PK of AZD8233 following SC administration of multiple doses.	Days 1 and 57 (Pre-dose, 0.5, 1, 1.5, 2, 2.5, 3, 4, 5, 6, 8, 10, 12, 24, 36, 48 hours post-dose); Day 8, Days 15, 22, 29 (pre-dose), Days 36 and 44.
Secondary	Part C:Plasma PK analysis: Area under the concentration-time curve from time zero to 24 hours post-dose (AUC[0-24])	To characterize the PK of AZD8233 following SC administration of multiple doses.	Days 1 and 57 (Pre-dose, 0.5, 1, 1.5, 2, 2.5, 3, 4, 5, 6, 8, 10, 12, 24 hours post-dose).
Secondary	Part C:Plasma PK analysis: Area under the concentration-time curve from time zero to 48 hours post-dose (AUC[0-48])	To characterize the PK of AZD8233 following SC administration of multiple doses.	Days 1 and 57 (Pre-dose, 0.5, 1, 1.5, 2, 2.5, 3, 4, 5, 6, 8, 10, 12, 24, 36, 48 hours post-dose).
Secondary	Part C:Plasma PK analysis: Area under the concentration-time curve from time zero extrapolated to infinity (AUC).	To characterize the PK of AZD8233 following SC administration of multiple doses.	Days 1 and 57 (Pre-dose, 0.5, 1, 1.5, 2, 2.5, 3, 4, 5, 6, 8, 10, 12, 24, 36, 48 hours post-dose); Day 8, Days 15, 22, 29 (pre-dose), Days 36 and 44.
Secondary	Part C:Plasma PK analysis: Area under the plasma concentration-time curve from time during the dosing interval (AUCt).	To characterize the PK of AZD8233 following SC administration of multiple doses.	Days 1 and 57 (Pre-dose, 0.5, 1, 1.5, 2, 2.5, 3, 4, 5, 6, 8, 10, 12, 24, 36, 48 hours post-dose); Day 8, Days 15, 22, 29 (pre-dose), Days 36 and 44.
Secondary	Part C:Plasma PK analysis: Observed trough plasma drug concentration (Ctrough).	To characterize the PK of AZD8233 following SC administration of multiple doses.	Days 1 and 57 (Pre-dose, 0.5, 1, 1.5, 2, 2.5, 3, 4, 5, 6, 8, 10, 12, 24, 36, 48 hours post-dose); Day 8, Days 15, 22, 29 (pre-dose), Days 36 and 44.
Secondary	Part C:Plasma PK analysis: Apparent total body clearance of drug from plasma after extravascular administration (CL/F).	To characterize the PK of AZD8233 following SC administration of multiple doses.	Days 1 and 57 (Pre-dose, 0.5, 1, 1.5, 2, 2.5, 3, 4, 5, 6, 8, 10, 12, 24, 36, 48 hours post-dose); Day 8, Days 15, 22, 29 (pre-dose), Days 36 and 44.
Secondary	Part C:Plasma PK analysis: Apparent volume of distribution for parent drug at terminal phase (extravascular administration) (Vz/F).	To characterize the PK of AZD8233 following SC administration of multiple doses.	Days 1 and 57 (Pre-dose, 0.5, 1, 1.5, 2, 2.5, 3, 4, 5, 6, 8, 10, 12, 24, 36, 48 hours post-dose); Day 8, Days 15, 22, 29 (pre-dose), Days 36 and 44.
Secondary	Part C:Plasma PK analysis: Half-life associated with the terminal slope (?z) of a semi-logarithmic concentration-time curve (t1/2).	To characterize the PK of AZD8233 following SC administration of multiple doses.	Days 1 and 57 (Pre-dose, 0.5, 1, 1.5, 2, 2.5, 3, 4, 5, 6, 8, 10, 12, 24, 36, 48 hours post-dose); Day 8, Days 15, 22, 29 (pre-dose), Days 36 and 44.
Secondary	Part C:Plasma PK analysis: Mean Residence Time (MRT).	To characterize the PK of AZD8233 following SC administration of multiple doses.	Days 1 and 57 (Pre-dose, 0.5, 1, 1.5, 2, 2.5, 3, 4, 5, 6, 8, 10, 12, 24, 36, 48 hours post-dose); Day 8, Days 15, 22, 29 (pre-dose), Days 36 and 44.
Secondary	Part C:Urine PK analysis: Amount excreted in urine (Ae).	To characterize the PK of AZD8233 following SC administration of multiple doses.	Treatment Days 1 to 3 (Pre-dose and intervals 0-6, 6-12 hours and 12-24 hours post-dose).
Secondary	Part C:Urine PK analysis: Fraction excreted unchanged in urine (Fe).	To characterize the PK of AZD8233 following SC administration of multiple doses.	Treatment Days 1 to 3 (Pre-dose and intervals 0-6, 6-12 hours and 12-24 hours post-dose).
Secondary	Part C:Urine PK analysis: Renal clearance (CLR).	To characterize the PK of AZD8233 following SC administration of multiple doses.	Treatment Days 1 to 3 (Pre-dose and intervals 0-6, 6-12 hours and 12-24 hours post-dose).
Secondary	Part C:Absolute change from baseline in log-transformed PCSK9 in plasma and Percent change from baseline in PCSK9 in plasma.	To assess the effect of AZD8233 on levels of PCSK9 following SC administration of multiple doses.	At screening, Day -1, Days 1 to 3 and Days 57 to 58 (pre-dose and 48 hours post-dose), Day 8, Days 15, 22, Day 29 (pre-dose), Days 36, 44, Day 56, week 2 to 14 (at 2, 4, 6, 8, 10, 12, and 14 weeks) and week 16 post-dose.
Secondary	Part C:Percentage change from baseline in levels of LDL-C in serum.	To assess the effect of AZD8233 on levels of LDL-C following SC administration of multiple doses.	At screening, Day -1, Days 1 to 3 and Days 57 to 58 (pre-dose and 48 hours post-dose), Day 8, Days 15, 22, Day 29 (pre-dose), Days 36, 44, Day 56, week 2 to 14 (at 2, 4, 6, 8, 10, 12, and 14 weeks) and week 16 post-dose.
Secondary	Part C:Levels of other lipid parameters of TC, HDL-C, Non-HDL-C, VLDL-C, ApoA1, ApoB, Lp(a) , Triglycerides.	To assess the effect of AZD8233 on other lipid parameters versus placebo.	Measurement at screening, Day -1, Days 1 to 3 and Days 57 to 58 (pre-dose and 48 hours post-dose), Day 8, Days 15, 22, Day 29 (pre-dose), Days 36, 44, Day 56, week 2 to 14 (at 2, 4, 6, 8, 10, 12, and 14 weeks) and week 16 post-dose.