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A Study of AZD8233 in Participants With Dyslipidemia. (HAYATE)

Primary Purpose

Dyslipidemia

Status

Completed

Phase

Phase 1

Locations

Japan

Study Type

Interventional

Intervention

Part A:Placebo

Part A:AZD8233

Part B:Placebo

Part B:AZD8233

Part C: Placebo

Part C: AZD8233

About this trial

This is an interventional treatment trial for Dyslipidemia focused on measuring AZD8233, Efficacy, PK, PD, Immunogenicity, Safety, Tolerability

Eligibility Criteria

20 Years - 75 Years (Adult, Older Adult)All SexesDoes not accept healthy volunteers

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

Sites / Locations

Research Site
Research Site
Research Site
Research Site
Research Site
Research Site
Research Site

Arms of the Study

Arm 1

Arm 2

Arm 3

Arm 4

Arm 5

Arm 6

Arm 7

Arm Type

Placebo Comparator

Experimental

Placebo Comparator

Experimental

Placebo Comparator

Experimental

Arm Label

Part A:Placebo

Part A:AZD8233

Part B:Placebo

Part B:AZD8233 medium dose

Part B:AZD8233 low dose

Part C: Placebo

Part C: AZD8233 medium dose

Arm Description

Placebo solution for subcutaneous injection.

AZD8233 for subcutaneous injection.

Placebo solution for subcutaneous injection.

AZD8233 medium dose for subcutaneous injection.

AZD8233 low dose for subcutaneous injection.

Placebo solution for subcutaneous injection.

AZD8233 medium dose for subcutaneous injection.

Outcomes

Primary Outcome Measures

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.

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.

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.

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.

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).

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.

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.

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.

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.

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.

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.

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.

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.

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.

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.

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.

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.

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.

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.

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.

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.

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.

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.

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.

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.

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.

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.

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.

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.

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.

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.

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.

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.

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.

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.

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.

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.

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.

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.

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.

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.

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.

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.

Part C: Vital sign: Systolic blood pressure (SBP)

Part C: Vital sign: Pulse rate

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.

Part C: Number of patients with abnormal findings in resting 12-lead Electrocariogram (ECG) .

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.

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.

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.

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.

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.

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.

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.

Part C: Laboratory assessments: Hematology - Differential WBC count

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.

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.

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.

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.

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.

Part C: Vital sign: Diastolic blood pressure (DBP)

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.

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.

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.

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.

Part C: Laboratory assessments: Serum clinical chemistry - Liver enzymes

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.

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.

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.

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.

Part C: Laboratory assessments - Coagulation

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.

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.

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.

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.

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.

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.

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.

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.

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.

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.

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.

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.

Secondary Outcome Measures

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.

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.

Part A:Plasma PK analysis: Observed maximum plasma concentration (Cmax)

To characterize the PK of AZD8233 following SC administration of multiple doses.

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.

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.

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.

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.

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.

Part A:Plasma PK analysis: Observed trough plasma drug concentration (Ctrough).

To characterize the PK of AZD8233 following SC administration of multiple doses.

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.

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.

Part A:Plasma PK analysis: Half-life associated with the terminal slope (λz) of a semi-logarithmic concentration-time curve (t1/2).

To characterize the PK of AZD8233 following SC administration of multiple doses.

Part A:Plasma PK analysis: Mean Residence Time (MRT).

To characterize the PK of AZD8233 following SC administration of multiple doses.

Part A:Urine PK analysis: Amount excreted in urine (Ae).

To characterize the PK of AZD8233 following SC administration of multiple doses.

Part A:Urine PK analysis: Fraction excreted unchanged in urine (Fe).

To characterize the PK of AZD8233 following SC administration of multiple doses.

Part A:Urine PK analysis: Renal clearance (CLR).

To characterize the PK of AZD8233 following SC administration of multiple doses.

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.

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.

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.

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.

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.

Part B: Plasma concentration of AZD8233

Part B:Anti-drug antibodies (ADAs) during the treatment period and follow-up period.

To evaluate the immunogenicity of AZD8233.

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.

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.

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.

Part C:Plasma PK analysis: Observed maximum plasma concentration (Cmax)

To characterize the PK of AZD8233 following SC administration of multiple doses.

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.

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.

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.

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.

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.

Part C:Plasma PK analysis: Observed trough plasma drug concentration (Ctrough).

To characterize the PK of AZD8233 following SC administration of multiple doses.

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.

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.

Part C:Plasma PK analysis: Half-life associated with the terminal slope (λz) of a semi-logarithmic concentration-time curve (t1/2).

To characterize the PK of AZD8233 following SC administration of multiple doses.

Part C:Plasma PK analysis: Mean Residence Time (MRT).

To characterize the PK of AZD8233 following SC administration of multiple doses.

Part C:Urine PK analysis: Amount excreted in urine (Ae).

To characterize the PK of AZD8233 following SC administration of multiple doses.

Part C:Urine PK analysis: Fraction excreted unchanged in urine (Fe).

To characterize the PK of AZD8233 following SC administration of multiple doses.

Part C:Urine PK analysis: Renal clearance (CLR).

To characterize the PK of AZD8233 following SC administration of multiple doses.

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.

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.

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.

Full Information

NCT ID

NCT04823611

First Posted

February 1, 2021

Last Updated

October 3, 2022

Sponsor

AstraZeneca

1. Study Identification

Unique Protocol Identification Number

NCT04823611

Brief Title

A Study of AZD8233 in Participants With Dyslipidemia.

Acronym

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

Study Type

Interventional

2. Study Status

Record Verification Date

September 2022

Overall Recruitment Status

Completed

Study Start Date

January 20, 2021 (Actual)

Primary Completion Date

September 10, 2022 (Actual)

Study Completion Date

September 10, 2022 (Actual)

3. Sponsor/Collaborators

Responsible Party, by Official Title

Sponsor

Name of the Sponsor

AstraZeneca

4. Oversight

Studies a U.S. FDA-regulated Drug Product

Yes

Studies a U.S. FDA-regulated Device Product

Product Manufactured in and Exported from the U.S.

Yes

Data Monitoring Committee

5. Study Description

Brief 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.

Detailed 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.

6. Conditions and Keywords

Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study

Dyslipidemia

Keywords

AZD8233, Efficacy, PK, PD, Immunogenicity, Safety, Tolerability

7. Study Design

Primary Purpose

Treatment

Study Phase

Phase 1, Phase 2

Interventional Study Model

Parallel Assignment

Model Description

Parallel Assignment

Masking

ParticipantCare ProviderInvestigator

Masking Description

Part A: Single blind Part B: Double blind Part C: Single blind

Allocation

Randomized

Enrollment

87 (Actual)

8. Arms, Groups, and Interventions

Arm Title

Part A:Placebo

Arm Type

Placebo Comparator

Arm Description

Placebo solution for subcutaneous injection.

Arm Title

Part A:AZD8233

Arm Type

Experimental

Arm Description

AZD8233 for subcutaneous injection.

Arm Title

Part B:Placebo

Arm Type

Placebo Comparator

Arm Description

Placebo solution for subcutaneous injection.

Arm Title

Part B:AZD8233 medium dose

Arm Type

Experimental

Arm Description

AZD8233 medium dose for subcutaneous injection.

Arm Title

Part B:AZD8233 low dose

Arm Type

Experimental

Arm Description

AZD8233 low dose for subcutaneous injection.

Arm Title

Part C: Placebo

Arm Type

Placebo Comparator

Arm Description

Placebo solution for subcutaneous injection.

Arm Title

Part C: AZD8233 medium dose

Arm Type

Experimental

Arm Description

AZD8233 medium dose for subcutaneous injection.

Intervention Type

Drug

Intervention Name(s)

Part A:Placebo

Intervention Description

Placebo solution

Intervention Type

Drug

Intervention Name(s)

Part A:AZD8233

Intervention Description

PCSK9-targeted ASO for the reduction of circulating levels of LDL-C.

Intervention Type

Drug

Intervention Name(s)

Part B:Placebo

Intervention Description

Placebo solution

Intervention Type

Drug

Intervention Name(s)

Part B:AZD8233

Intervention Description

PCSK9-targeted ASO for the reduction of circulating levels of LDL-C.

Intervention Type

Drug

Intervention Name(s)

Part C: Placebo

Intervention Description

Placebo solution

Intervention Type

Drug

Intervention Name(s)

Part C: AZD8233

Intervention Description

PCSK9-targeted ASO for the reduction of circulating levels of LDL-C.

Primary Outcome Measure Information:

Title

Part A: Number of subjects with adverse events (AEs) due to AZD8233 SC multiple dose treatment.

Description

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.

Time Frame

From randomization to final Follow-up Visit (Week 16 post last dose).

Title

Part A: Vital sign: Systolic blood pressure (SBP)

Description

Time Frame

From Day1(pre-dose) to final Follow-up Visit (Week 16 post last dose).

Title

Part A: Vital sign: Pulse rate

Description

Time Frame

From Day1(pre-dose) to final Follow-up Visit (Week 16 post last dose)

Title

Part A: Vital sign: Body temperature

Description

To assess the oral body temperature as a variable of safety and tolerability of AZD8233 following SC administration of multiple doses.

Time Frame

From Day 1(pre-dose) to final Follow-up Visit (Week 16 post last dose).

Title

Part A: Number of patients with abnormal findings in resting 12-lead Electrocariogram (ECG) .

Description

Time Frame

From Day1(pre-dose) to final Follow-up Visit (Week 16 post last dose).

Title

Part A: Number of subject with abnormal findings in cardiac telemetry

Description

To assess cardiac telemetry as a variable of safety and tolerability of AZD8233 following SC administration of multiple doses.

Time Frame

At Day -1, Days 1 to 3 (pre-dose to 24 hours post-dose), and Day 57 (pre-dose to 24 hours post-dose).

Title

Part A: Laboratory assessments: Hematology - Blood cells count

Description

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.

Time Frame

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.

Title

Part A: Laboratory assessments: Hematology - Hemoglobin (Hb)

Description

To assess Hb as a variable of safety and tolerability of AZD8233 following SC administration of multiple doses.

Time Frame

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.

Title

Part A: Laboratory assessments: Hematology - Hematocrit (HCT)

Description

To assess HCT as a variable of safety and tolerability of AZD8233 following SC administration of multiple doses.

Time Frame

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

Title

Part A: Laboratory assessments: Hematology - Mean corpuscular volume (MCV)

Description

To assess MCV as a variable of safety and tolerability of AZD8233 following SC administration of multiple doses.

Time Frame

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

Title

Part A: Laboratory assessments: Hematology - Mean corpuscular hemoglobin (MCH)

Description

To assess MCH as a variable of safety and tolerability of AZD8233 following SC administration of multiple doses.

Time Frame

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.

Title

Part A: Laboratory assessments: Hematology - Mean corpuscular hemoglobin concentration (MCHC)

Description

To assess MCHC as a variable of safety and tolerability of AZD8233 following SC administration of multiple doses.

Time Frame

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.

Title

Part A: Laboratory assessments: Hematology - Differential WBC count

Description

Time Frame

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.

Title

Part A: Laboratory assessments: Hematology - Platelet count and platelet function assessment.

Description

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.

Time Frame

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.

Title

Part A: Laboratory assessments: Hematology - Reticulocytes absolute count

Description

To assess Reticulocytes absolute count as a variable of safety and tolerability of AZD8233 following SC administration of multiple doses.

Time Frame

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.

Title

Part A: Laboratory assessments: Serum clinical chemistry - Electrolytes

Description

To assess serum level of sodium, potassium, calcium as a variable of safety and tolerability of AZD8233 following SC administration of multiple doses.

Time Frame

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.

Title

Part A: Laboratory assessments: Serum clinical chemistry - Blood urea nitrogen (BUN)

Description

To assess serum level of BUN as a variable of safety and tolerability of AZD8233 following SC administration of multiple doses.

Time Frame

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.

Title

Part A: To assess serum level of BUN as a variable of safety and tolerability of AZD8233 following SC administration of multiple ascending doses.

Description

To assess serum level of creatinine as a variable of safety and tolerability of AZD8233 following SC administration of multiple doses.

Time Frame

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.

Title

Part A: Laboratory assessments: Serum clinical chemistry - Glucose (fasting)

Description

To assess serum fasting glucose level as a variable of safety and tolerability of AZD8233 following SC administration of multiple doses.

Time Frame

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.

Title

Part A: Laboratory assessments: Serum clinical chemistry - Creatine kinase

Description

To assess the level of serum creatine kinase as a variable of safety and tolerability of AZD8233 following SC administration of multiple doses.

Time Frame

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.

Title

Part A: Laboratory assessments: Serum clinical chemistry - Direct bilirubin

Description

To assess the level of serum bilirubin (direct) as a variable of safety and tolerability of AZD8233 following SC administration of multiple doses.

Time Frame

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.

Title

Part A: Laboratory assessments: Serum clinical chemistry - Hemoglobin A1c (HbA1c)

Description

To assess the level of HbA1c as a variable of safety and tolerability of AZD8233 following SC administration of multiple doses.

Time Frame

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.

Title

Part A: Laboratory assessments: Serum clinical chemistry - Liver enzymes

Description

Time Frame

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.

Title

Part A: Laboratory assessments: Serum clinical chemistry - Total bilirubin

Description

To assess the level of serum bilirubin (total) as a variable of safety and tolerability of AZD8233 following SC administration of multiple doses.

Time Frame

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.

Title

Part A: Laboratory assessments: Serum clinical chemistry - Cell enzymes

Description

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.

Time Frame

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.

Title

Part A: Laboratory assessments: Serum clinical chemistry - Bicarbonate

Description

To assess the level of bicarbonate as a variable of safety and tolerability of AZD8233 following SC administration of multiple doses.

Time Frame

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.

Title

Part A: Laboratory assessments: Serum clinical chemistry - Uric acid

Description

To assess the level of uric acid as a variable of safety and tolerability of AZD8233 following SC administration of multiple doses.

Time Frame

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.

Title

Part A: Laboratory assessments - Coagulation

Description

Time Frame

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.

Title

Part A: Renal safety biomarkers - Urine clusterin

Description

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.

Time Frame

Day 1 (pre-dose, 24 hours and 48 hours post-dose), Days 8 and 29 (pre-dose), and Day 57 (pre-dose).

Title

Part A: Renal safety biomarkers - Urine cystatin-C

Description

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.

Time Frame

Day 1 (pre-dose, 24 hours and 48 hours post-dose), Days 8 and 29 (pre-dose), and Day 57 (pre-dose).

Title

Part A: Renal safety biomarkers - Urine N-acetyl-beta-D-glucosaminidase (NAG)

Description

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.

Time Frame

Day 1 (pre-dose, 24 hours and 48 hours post-dose), Days 8 and 29 (pre-dose), and Day 57 (pre-dose).

Title

Part A: Renal safety biomarkers - Urine albumin

Description

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.

Time Frame

Day 1 (pre-dose, 24 hours and 48 hours post-dose), Days 8 and 29 (pre-dose), and Day 57 (pre-dose).

Title

Part A: Renal safety biomarkers - Urine creatinine

Description

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.

Time Frame

Day 1 (pre-dose, 24 hours and 48 hours post-dose), Days 8 and 29 (pre-dose), and Day 57 (pre-dose).

Title

Part A: Renal safety biomarkers - Urine Kidney injury molecule1 (KIM-1)

Description

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.

Time Frame

Day 1 (pre-dose, 24 hours and 48 hours post-dose), Days 8 and 29 (pre-dose), and Day 57 (pre-dose).

Title

Part A: Renal safety biomarkers - Urine Neutrophil gelatinase-associated lipocalin (NGAL)

Description

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.

Time Frame

Day 1 (pre-dose, 24 hours and 48 hours post-dose), Days 8 and 29 (pre-dose), and Day 57 (pre-dose).

Title

Part A: Renal safety biomarkers - Urine Osteopontin

Description

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.

Time Frame

Day 1 (pre-dose, 24 hours and 48 hours post-dose), Days 8 and 29 (pre-dose), and Day 57 (pre-dose).

Title

Part A: Renal safety biomarkers - Urine total protein

Description

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.

Time Frame

Day 1 (pre-dose, 24 hours and 48 hours post-dose), Days 8 and 29 (pre-dose), and Day 57 (pre-dose).

Title

Part A: Immune Activation Response - High-sensitivity C-reactive protein (hs-CRP)

Description

To assess hs-CRP level as a variable of safety and tolerability of AZD8233 following SC administration of multiple doses.

Time Frame

From screening to final Follow-up Visit (Week 16 post last dose).

Title

Part A: Complement Activation panel

Description

To assess chemotactic factor (C3a, Bb, and C5a) levels as a variable of safety and tolerability of AZD8233 following SC administration of multiple doses.

Time Frame

Days 1 and 57 (pre-dose, 1, 2, and 4 hours post-dose).

Title

Part A: Laboratory assessments - Sampling for dipstick urinalysis for hematuria

Description

To assess dipstick urinalysis for hematuria as a variable of safety and tolerability of AZD8233 following SC administration of multiple doses.

Time Frame

Day1 to Day3 (pre-dose and then 24 and 48 h post -dose), Day8 (pre-dose), Day29 (pre-dose) and Day57 (pre-dose).

Title

Part B:Absolute change from baseline in long-transformed LDL-C in serum at week12.

Description

Absolute change from baseline in long-transformed LDL-C in serum.

Time Frame

Measurement at week 12

Title

Part A: Vital sign: Diastolic blood pressure (DBP)

Description

Time Frame

From Day1(pre-dose) to final Follow-up Visit (Week 16 post last dose).

Title

Part C: Number of subjects with adverse events (AEs) due to AZD8233 SC multiple dose treatment.

Description

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.

Time Frame

From randomization to final Follow-up Visit (Week 16 post last dose).

Title

Part C: Vital sign: Systolic blood pressure (SBP)

Description

Time Frame

From Day1(pre-dose) to final Follow-up Visit (Week 16 post last dose).

Title

Part C: Vital sign: Pulse rate

Description

Time Frame

From Day1(pre-dose) to final Follow-up Visit (Week 16 post last dose)

Title

Part C: Vital sign: Body temperature

Description

To assess the oral body temperature as a variable of safety and tolerability of AZD8233 following SC administration of multiple doses.

Time Frame

From Day 1(pre-dose) to final Follow-up Visit (Week 16 post last dose).

Title

Part C: Number of patients with abnormal findings in resting 12-lead Electrocariogram (ECG) .

Description

Time Frame

From Day1(pre-dose) to final Follow-up Visit (Week 16 post last dose).

Title

Part C: Number of subject with abnormal findings in cardiac telemetry

Description

To assess cardiac telemetry as a variable of safety and tolerability of AZD8233 following SC administration of multiple doses.

Time Frame

At Day -1, Days 1 to 3 (pre-dose to 24 hours post-dose), and Day 57 (pre-dose to 24 hours post-dose).

Title

Part C: Laboratory assessments: Hematology - Hemoglobin (Hb)

Description

To assess Hb as a variable of safety and tolerability of AZD8233 following SC administration of multiple doses.

Time Frame

Day-1, Day1 ( 24 hours post- dose), Day8 , Day29 (pre-dose), Day57 (pre-dose), Week 2,4,8,12 and 16 post last dose.

Title

Part C: Laboratory assessments: Hematology - Blood cells count

Description

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.

Time Frame

Day-1, Day1 ( 24 hours post- dose), Day8 , Day29 (pre-dose), Day57 (pre-dose), Week 2,4,8,12 and 16 post last dose.

Title

Part C: Laboratory assessments: Hematology - Hematocrit (HCT)

Description

To assess HCT as a variable of safety and tolerability of AZD8233 following SC administration of multiple doses.

Time Frame

Day-1, Day1 ( 24 hours post- dose), Day8, Day29 (pre-dose), Day57 (pre-dose), Week 2,4,8,12 and 16 post last dose

Title

Part C: Laboratory assessments: Hematology - Mean corpuscular volume (MCV)

Description

To assess MCV as a variable of safety and tolerability of AZD8233 following SC administration of multiple doses.

Time Frame

Day-1, Day1 ( 24 hours post- dose), Day8 , Day29 (pre-dose), Day57 (pre-dose), Week 2,4,8,12 and 16 post last dose

Title

Part C: Laboratory assessments: Hematology - Mean corpuscular hemoglobin (MCH)

Description

To assess MCH as a variable of safety and tolerability of AZD8233 following SC administration of multiple doses.

Time Frame

Day-1, Day1 ( 24 hours post- dose), Day8, Day29 (pre-dose), Day57 (pre-dose), Week 2,4,8,12 and 16 post last dose.

Title

Part C: Laboratory assessments: Hematology - Mean corpuscular hemoglobin concentration (MCHC)

Description

To assess MCHC as a variable of safety and tolerability of AZD8233 following SC administration of multiple doses.

Time Frame

Day-1, Day1 ( 24 hours post- dose), Day8, Day29 (pre-dose), Day57 (pre-dose), Week 2,4,8,12 and 16 post last dose.

Title

Part C: Laboratory assessments: Hematology - Differential WBC count

Description

Time Frame

Day-1, Day1 ( 24 hours post- dose), Day8 , Day29 (pre-dose), Day57 (pre-dose), Week 2,4,8,12 and 16 post last dose.

Title

Part C: Laboratory assessments: Hematology - Platelet count and platelet function assessment.

Description

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.

Time Frame

Day-1, Day1 ( 24 hours post- dose), Day8, Day29 (pre-dose), Day57 (pre-dose), Week 2,4,8,12 and 16 post last dose.

Title

Part C: Laboratory assessments: Hematology - Reticulocytes absolute count

Description

To assess Reticulocytes absolute count as a variable of safety and tolerability of AZD8233 following SC administration of multiple doses.

Time Frame

Day-1, Day1 ( 24 hours post- dose), Day8 , Day29 (pre-dose), Day57 (pre-dose), Week 2,4,8,12 and 16 post last dose.

Title

Part C: Laboratory assessments: Serum clinical chemistry - Electrolytes

Description

To assess serum level of sodium, potassium, calcium as a variable of safety and tolerability of AZD8233 following SC administration of multiple doses.

Time Frame

Day-1, Day1 ( 24 hours post- dose), Day8, Day29 (pre-dose), Day57 (pre-dose), Week 2,4,8,12 and 16 post last dose.

Title

Part C: Laboratory assessments: Serum clinical chemistry - Blood urea nitrogen (BUN)

Description

To assess serum level of BUN as a variable of safety and tolerability of AZD8233 following SC administration of multiple doses.

Time Frame

Day-1, Day1 ( 24 hours post- dose), Day8 , Day29 (pre-dose), Day57 (pre-dose), Week 2,4,8,12 and 16 post last dose.

Title

Part C: To assess serum level of BUN as a variable of safety and tolerability of AZD8233 following SC administration of multiple ascending doses.

Description

To assess serum level of creatinine as a variable of safety and tolerability of AZD8233 following SC administration of multiple doses.

Time Frame

Day-1, Day1 ( 24 hours post- dose), Day8 , Day29 (pre-dose), Day57 (pre-dose), Week 2,4,8,12 and 16 post last dose.

Title

Part C: Vital sign: Diastolic blood pressure (DBP)

Description

Time Frame

From Day1(pre-dose) to final Follow-up Visit (Week 16 post last dose).

Title

Part C: Laboratory assessments: Serum clinical chemistry - Glucose (fasting)

Description

To assess serum fasting glucose level as a variable of safety and tolerability of AZD8233 following SC administration of multiple doses.

Time Frame

Day-1, Day1 ( 24 hours post- dose), Day8, Day29 (pre-dose), Day57 (pre-dose), Week 2,4,8,12 and 16 post last dose.

Title

Part C: Laboratory assessments: Serum clinical chemistry - Creatine kinase

Description

To assess the level of serum creatine kinase as a variable of safety and tolerability of AZD8233 following SC administration of multiple doses.

Time Frame

Day-1, Day1 ( 24 hours post- dose), Day8, Day29 (pre-dose), Day57 (pre-dose), Week 2,4,8,12 and 16 post last dose.

Title

Part C: Laboratory assessments: Serum clinical chemistry - Direct bilirubin

Description

To assess the level of serum bilirubin (direct) as a variable of safety and tolerability of AZD8233 following SC administration of multiple doses.

Time Frame

Day-1, Day1 ( 24 hours post- dose), Day8, Day29 (pre-dose), Day57 (pre-dose), Week 2,4,8,12 and 16 post last dose.

Title

Part C: Laboratory assessments: Serum clinical chemistry - Hemoglobin A1c (HbA1c)

Description

To assess the level of HbA1c as a variable of safety and tolerability of AZD8233 following SC administration of multiple doses.

Time Frame

Day-1, Day1 ( 24 hours post- dose), Day8, Day29 (pre-dose), Day57 (pre-dose), Week 2,4,8,12 and 16 post last dose.

Title

Part C: Laboratory assessments: Serum clinical chemistry - Liver enzymes

Description

Time Frame

Day-1, Day1 ( 24 hours post- dose), Day8, Day29 (pre-dose), Day57 (pre-dose), Week 2,4,8,12 and 16 post last dose.

Title

Part C: Laboratory assessments: Serum clinical chemistry - Total bilirubin

Description

To assess the level of serum bilirubin (total) as a variable of safety and tolerability of AZD8233 following SC administration of multiple doses.

Time Frame

Day-1, Day1 ( 24 hours post- dose), Day8 , Day29 (pre-dose), Day57 (pre-dose), Week 2,4,8,12 and 16 post last dose.

Title

Part C: Laboratory assessments: Serum clinical chemistry - Cell enzymes

Description

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.

Time Frame

Day-1, Day1 ( 24 hours post- dose), Day8, Day29 (pre-dose), Day57 (pre-dose), Week 2,4,8,12 and 16 post last dose.

Title

Part C: Laboratory assessments: Serum clinical chemistry - Bicarbonate

Description

To assess the level of bicarbonate as a variable of safety and tolerability of AZD8233 following SC administration of multiple doses.

Time Frame

Day-1, Day1 ( 24 hours post- dose), Day8, Day29 (pre-dose), Day57 (pre-dose), Week 2,4,8,12 and 16 post last dose.

Title

Part C: Laboratory assessments: Serum clinical chemistry - Uric acid

Description

To assess the level of uric acid as a variable of safety and tolerability of AZD8233 following SC administration of multiple doses.

Time Frame

Day-1, Day1 ( 24 hours post- dose), Day8, Day29 (pre-dose), Day57 (pre-dose), Week 2,4,8,12 and 16 post last dose.

Title

Part C: Laboratory assessments - Coagulation

Description

Time Frame

Day-1, Day1 ( 24 hours post- dose), Day8, Day29 (pre-dose), Day57 (pre-dose), Week 2,4,8,12 and 16 post last dose.

Title

Part C: Renal safety biomarkers - Urine clusterin

Description

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.

Time Frame

Day 1 (pre-dose, 24 hours and 48 hours post-dose), Day 8, Day 29 (pre-dose), and Day 57 (pre-dose).

Title

Part C: Renal safety biomarkers - Urine cystatin-C

Description

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.

Time Frame

Day 1 (pre-dose, 24 hours and 48 hours post-dose), Day 8, Day 29 (pre-dose), and Day 57 (pre-dose).

Title

Part C: Renal safety biomarkers - Urine N-acetyl-beta-D-glucosaminidase (NAG)

Description

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.

Time Frame

Day 1 (pre-dose, 24 hours and 48 hours post-dose), Day 8 , Day 29 (pre-dose), and Day 57 (pre-dose).

Title

Part C: Renal safety biomarkers - Urine albumin

Description

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.

Time Frame

Day 1 (pre-dose, 24 hours and 48 hours post-dose), Day 8 , Day 29 (pre-dose), and Day 57 (pre-dose).

Title

Part C: Renal safety biomarkers - Urine creatinine

Description

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.

Time Frame

Day 1 (pre-dose, 24 hours and 48 hours post-dose), Day 8, Day 29 (pre-dose), and Day 57 (pre-dose).

Title

Part C: Renal safety biomarkers - Urine Neutrophil gelatinase-associated lipocalin (NGAL)

Description

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.

Time Frame

Day 1 (pre-dose, 24 hours and 48 hours post-dose), Day 8, Day 29 (pre-dose), and Day 57 (pre-dose).

Title

Part C: Renal safety biomarkers - Urine Osteopontin

Description

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.

Time Frame

Day 1 (pre-dose, 24 hours and 48 hours post-dose), Day 8 , Day 29 (pre-dose), and Day 57 (pre-dose).

Title

Part C: Renal safety biomarkers - Urine total protein

Description

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.

Time Frame

Day 1 (pre-dose, 24 hours and 48 hours post-dose), Day 8 , Day 29 (pre-dose), and Day 57 (pre-dose).

Title

Part C: Immune Activation Response - High-sensitivity C-reactive protein (hs-CRP)

Description

To assess hs-CRP level as a variable of safety and tolerability of AZD8233 following SC administration of multiple doses.

Time Frame

From screening to final Follow-up Visit (Week 16 post last dose).

Title

Part C: Complement Activation panel

Description

To assess chemotactic factor (Bb, and C5a) levels as a variable of safety and tolerability of AZD8233 following SC administration of multiple doses.

Time Frame

Days 1 and 57 (pre-dose, 1, 2, and 4 hours post-dose).

Title

Part C: Laboratory assessments - Sampling for dipstick urinalysis for hematuria

Description

To assess dipstick urinalysis for hematuria as a variable of safety and tolerability of AZD8233 following SC administration of multiple doses.

Time Frame

Day1 to Day3 (pre-dose and then 24 and 48 h post -dose), Day8 , Day29 (pre-dose) and Day57 (pre-dose).

Title

Part C: Renal safety biomarkers - Urine Kidney injury molecule1 (KIM-1)

Description

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.

Time Frame

Day 1 (pre-dose, 24 hours and 48 hours post-dose), Day 8 , Day29 (pre-dose), and Day 57 (pre-dose).

Secondary Outcome Measure Information:

Title

Part A:Plasma PK analysis. Time delay between drug administration and the first observed concentration in plasma (tlag).

Description

To characterize the PK of AZD8233 following SC administration of multiple doses.

Time Frame

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.

Title

Part A:Plasma PK analysis: Time to reach peak or maximum observed concentration or response following drug administration (tmax).

Description

To characterize the PK of AZD8233 following SC administration of multiple doses.

Time Frame

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.

Title

Part A:Plasma PK analysis: Observed maximum plasma concentration (Cmax)

Description

To characterize the PK of AZD8233 following SC administration of multiple doses.

Time Frame

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.

Title

Part A:Area under the plasma concentration-curve from time zero to time last value above the limit of quantification (AUC[0-last]

Description

To characterize the PK of AZD8233 following SC administration of multiple doses.

Time Frame

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.

Title

Part A:Plasma PK analysis: Area under the concentration-time curve from time zero to 24 hours post-dose (AUC[0-24])

Description

To characterize the PK of AZD8233 following SC administration of multiple doses.

Time Frame

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).

Title

Part A:Plasma PK analysis: Area under the concentration-time curve from time zero to 48 hours post-dose (AUC[0-48])

Description

To characterize the PK of AZD8233 following SC administration of multiple doses.

Time Frame

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).

Title

Part A:Plasma PK analysis: Area under the concentration-time curve from time zero extrapolated to infinity (AUC).

Description

To characterize the PK of AZD8233 following SC administration of multiple doses.

Time Frame

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.

Title

Part A:Plasma PK analysis: Area under the plasma concentration-time curve from time during the dosing interval (AUCt).

Description

To characterize the PK of AZD8233 following SC administration of multiple doses.

Time Frame

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.

Title

Part A:Plasma PK analysis: Observed trough plasma drug concentration (Ctrough).

Description

To characterize the PK of AZD8233 following SC administration of multiple doses.

Time Frame

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.

Title

Part A:Plasma PK analysis: Apparent total body clearance of drug from plasma after extravascular administration (CL/F).

Description

To characterize the PK of AZD8233 following SC administration of multiple doses.

Time Frame

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.

Title

Part A:Plasma PK analysis: Apparent volume of distribution for parent drug at terminal phase (extravascular administration) (Vz/F).

Description

To characterize the PK of AZD8233 following SC administration of multiple doses.

Time Frame

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.

Title

Part A:Plasma PK analysis: Half-life associated with the terminal slope (λz) of a semi-logarithmic concentration-time curve (t1/2).

Description

To characterize the PK of AZD8233 following SC administration of multiple doses.

Time Frame

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.

Title

Part A:Plasma PK analysis: Mean Residence Time (MRT).

Description

To characterize the PK of AZD8233 following SC administration of multiple doses.

Time Frame

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.

Title

Part A:Urine PK analysis: Amount excreted in urine (Ae).

Description

To characterize the PK of AZD8233 following SC administration of multiple doses.

Time Frame

Treatment Days 1 to 3 (Pre-dose and intervals 0-6, 6-12 hours and 12-24 hours post-dose).

Title

Part A:Urine PK analysis: Fraction excreted unchanged in urine (Fe).

Description

To characterize the PK of AZD8233 following SC administration of multiple doses.

Time Frame

Treatment Days 1 to 3 (Pre-dose and intervals 0-6, 6-12 hours and 12-24 hours post-dose).

Title

Part A:Urine PK analysis: Renal clearance (CLR).

Description

To characterize the PK of AZD8233 following SC administration of multiple doses.

Time Frame

Treatment Days 1 to 3 (Pre-dose and intervals 0-6, 6-12 hours and 12-24 hours post-dose).

Title

Part A:Absolute change from baseline in log-transformed PCSK9 in plasma and Percent change from baseline in PCSK9 in plasma.

Description

To assess the effect of AZD8233 on levels of PCSK9 following SC administration of multiple doses.

Time Frame

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.

Title

Part A:Percentage change from baseline in levels of LDL-C in serum.

Description

To assess the effect of AZD8233 on levels of LDL-C following SC administration of multiple doses.

Time Frame

Title

Part B:Absolute change from baseline in log-transformed PCSK9 in plasma and Percent change from baseline in PCSK9 in plasma.

Description

To assess the effect of different doses of AZD8233 on PCSK9 versus placebo.

Time Frame

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.

Title

Part B:Percentage change from baseline in levels of LDL-C in serum.

Description

To assess the effect of different doses of AZD8233 on LDL-C versus placebo.

Time Frame

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.

Title

Part B:Levels of other lipid parameters of TC, HDL-C, Non-HDL-C, VLDL-C, ApoA1, ApoB, Lp(a) , Triglycerides, Remnants cholesterol.

Description

To assess the effect of AZD8233 on other lipid parameters versus placebo.

Time Frame

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.

Title

Part B: Plasma concentration of AZD8233

Time Frame

Measurement at week 1, week 4, week 6, week 8, week 10, week 12, week 16, week 20, week 24.

Title

Part B:Anti-drug antibodies (ADAs) during the treatment period and follow-up period.

Description

To evaluate the immunogenicity of AZD8233.

Time Frame

Measurement at week 0, week 1, week 4, week 8, week 12, week 16, week 20, week 24.

Title

Part A:Levels of other lipid parameters of TC, HDL-C, Non-HDL-C, VLDL-C, ApoA1, ApoB, Lp(a) , Triglycerides.

Description

To assess the effect of AZD8233 on other lipid parameters versus placebo.

Time Frame

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.

Title

Part C:Plasma PK analysis. Time delay between drug administration and the first observed concentration in plasma (tlag).

Description

To characterize the PK of AZD8233 following SC administration of multiple doses.

Time Frame

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.

Title

Part C:Plasma PK analysis: Time to reach peak or maximum observed concentration or response following drug administration (tmax).

Description

To characterize the PK of AZD8233 following SC administration of multiple doses.

Time Frame

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.

Title

Part C:Plasma PK analysis: Observed maximum plasma concentration (Cmax)

Description

To characterize the PK of AZD8233 following SC administration of multiple doses.

Time Frame

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.

Title

Part C:Area under the plasma concentration-curve from time zero to time last value above the limit of quantification (AUC[0-last]

Description

To characterize the PK of AZD8233 following SC administration of multiple doses.

Time Frame

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.

Title

Part C:Plasma PK analysis: Area under the concentration-time curve from time zero to 24 hours post-dose (AUC[0-24])

Description

To characterize the PK of AZD8233 following SC administration of multiple doses.

Time Frame

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).

Title

Part C:Plasma PK analysis: Area under the concentration-time curve from time zero to 48 hours post-dose (AUC[0-48])

Description

To characterize the PK of AZD8233 following SC administration of multiple doses.

Time Frame

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).

Title

Part C:Plasma PK analysis: Area under the concentration-time curve from time zero extrapolated to infinity (AUC).

Description

To characterize the PK of AZD8233 following SC administration of multiple doses.

Time Frame

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.

Title

Part C:Plasma PK analysis: Area under the plasma concentration-time curve from time during the dosing interval (AUCt).

Description

To characterize the PK of AZD8233 following SC administration of multiple doses.

Time Frame

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.

Title

Part C:Plasma PK analysis: Observed trough plasma drug concentration (Ctrough).

Description

To characterize the PK of AZD8233 following SC administration of multiple doses.

Time Frame

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.

Title

Part C:Plasma PK analysis: Apparent total body clearance of drug from plasma after extravascular administration (CL/F).

Description

To characterize the PK of AZD8233 following SC administration of multiple doses.

Time Frame

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.

Title

Part C:Plasma PK analysis: Apparent volume of distribution for parent drug at terminal phase (extravascular administration) (Vz/F).

Description

To characterize the PK of AZD8233 following SC administration of multiple doses.

Time Frame

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.

Title

Part C:Plasma PK analysis: Half-life associated with the terminal slope (λz) of a semi-logarithmic concentration-time curve (t1/2).

Description

To characterize the PK of AZD8233 following SC administration of multiple doses.

Time Frame

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.

Title

Part C:Plasma PK analysis: Mean Residence Time (MRT).

Description

To characterize the PK of AZD8233 following SC administration of multiple doses.

Time Frame

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.

Title

Part C:Urine PK analysis: Amount excreted in urine (Ae).

Description

To characterize the PK of AZD8233 following SC administration of multiple doses.

Time Frame

Treatment Days 1 to 3 (Pre-dose and intervals 0-6, 6-12 hours and 12-24 hours post-dose).

Title

Part C:Urine PK analysis: Fraction excreted unchanged in urine (Fe).

Description

To characterize the PK of AZD8233 following SC administration of multiple doses.

Time Frame

Treatment Days 1 to 3 (Pre-dose and intervals 0-6, 6-12 hours and 12-24 hours post-dose).

Title

Part C:Urine PK analysis: Renal clearance (CLR).

Description

To characterize the PK of AZD8233 following SC administration of multiple doses.

Time Frame

Treatment Days 1 to 3 (Pre-dose and intervals 0-6, 6-12 hours and 12-24 hours post-dose).

Title

Part C:Absolute change from baseline in log-transformed PCSK9 in plasma and Percent change from baseline in PCSK9 in plasma.

Description

To assess the effect of AZD8233 on levels of PCSK9 following SC administration of multiple doses.

Time Frame

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.

Title

Part C:Percentage change from baseline in levels of LDL-C in serum.

Description

To assess the effect of AZD8233 on levels of LDL-C following SC administration of multiple doses.

Time Frame

Title

Part C:Levels of other lipid parameters of TC, HDL-C, Non-HDL-C, VLDL-C, ApoA1, ApoB, Lp(a) , Triglycerides.

Description

To assess the effect of AZD8233 on other lipid parameters versus placebo.

Time Frame

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.

10. Eligibility

Sex

All

Minimum Age & Unit of Time

20 Years

Maximum Age & Unit of Time

75 Years

Accepts Healthy Volunteers

Eligibility Criteria

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

Facility Information:

Facility Name

Research Site

City

Chiyoda-ku

ZIP/Postal Code

1010041

Country

Japan

Facility Name

Research Site

City

Chuo-ku

ZIP/Postal Code

103-0027

Country

Japan

Facility Name

Research Site

City

Chuo-ku

ZIP/Postal Code

104-0031

Country

Japan

Facility Name

Research Site

City

Chuo-ku

ZIP/Postal Code

1040031

Country

Japan

Facility Name

Research Site

City

Osaka-shi

ZIP/Postal Code

530-0001

Country

Japan

Facility Name

Research Site

City

Shinjuku-ku

ZIP/Postal Code

160-0008

Country

Japan

Facility Name

Research Site

City

Suita-shi

ZIP/Postal Code

565-0853

Country

Japan

12. IPD Sharing Statement

Plan to Share IPD

Learn more about this trial

A Study of AZD8233 in Participants With Dyslipidemia.

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