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HAYATE: A Study of AZD8233 in Participants With Dyslipidemia.

Sponsor
AstraZeneca (Industry)
Overall Status
Active, not recruiting
CT.gov ID
NCT04823611
Collaborator
(none)
87
Enrollment
7
Locations
7
Arms
19.7
Anticipated Duration (Months)
12.4
Patients Per Site
0.6
Patients Per Site Per Month

Study Details

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.

Condition or Disease Intervention/Treatment Phase
  • Drug: Part A:Placebo
  • Drug: Part A:AZD8233
  • Drug: Part B:Placebo
  • Drug: Part B:AZD8233
  • Drug: Part C: Placebo
  • Drug: Part C: AZD8233
 Phase 1/Phase 2

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.

Study Design

Study Type:
Interventional
Actual Enrollment :
87 participants
Allocation:
Randomized
Intervention Model:
Parallel Assignment
Intervention Model Description:
Parallel AssignmentParallel Assignment
Masking:
Triple (Participant, Care Provider, Investigator)
Masking Description:
Part A: Single blind Part B: Double blind Part C: Single blind
Primary Purpose:
Treatment
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
Actual Study Start Date :
Jan 20, 2021
Anticipated Primary Completion Date :
Sep 12, 2022
Anticipated Study Completion Date :
Sep 12, 2022

Arms and Interventions

Arm Intervention/Treatment
Placebo Comparator: Part A:Placebo

Placebo solution for subcutaneous injection.

Drug: Part A:Placebo
Placebo solution
Experimental: Part A:AZD8233

AZD8233 for subcutaneous injection.

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

Placebo solution for subcutaneous injection.

Drug: Part B:Placebo
Placebo solution
Experimental: Part B:AZD8233 medium dose

AZD8233 medium dose for subcutaneous injection.

Drug: Part B:AZD8233
PCSK9-targeted ASO for the reduction of circulating levels of LDL-C.
Experimental: Part B:AZD8233 low dose

AZD8233 low dose for subcutaneous injection.

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

Placebo solution for subcutaneous injection.

Drug: Part C: Placebo
Placebo solution
Experimental: Part C: AZD8233 medium dose

AZD8233 medium dose for subcutaneous injection.

Drug: Part C: AZD8233
PCSK9-targeted ASO for the reduction of circulating levels of LDL-C.

Outcome Measures

Primary Outcome Measures

  1. Part A: Number of subjects with adverse events (AEs) due to AZD8233 SC multiple dose treatment. [From randomization to final Follow-up Visit (Week 16 post last dose).]

    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.

  2. Part A: Vital sign: Systolic blood pressure (SBP) [From Day1(pre-dose) to final Follow-up Visit (Week 16 post last dose).]

    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.

  3. Part A: Vital sign: Pulse rate [From Day1(pre-dose) to final Follow-up Visit (Week 16 post last dose)]

    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.

  4. Part A: Vital sign: Body temperature [From Day 1(pre-dose) to final Follow-up Visit (Week 16 post last dose).]

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

  5. Part A: Number of patients with abnormal findings in resting 12-lead Electrocariogram (ECG) . [From Day1(pre-dose) to final Follow-up Visit (Week 16 post last dose).]

    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).

  6. Part A: Number of subject with abnormal findings in cardiac telemetry [At Day -1, Days 1 to 3 (pre-dose to 24 hours post-dose), and Day 57 (pre-dose to 24 hours post-dose).]

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

  7. Part A: Laboratory assessments: Hematology - Blood cells count [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.]

    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.

  8. Part A: Laboratory assessments: Hematology - Hemoglobin (Hb) [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.]

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

  9. Part A: Laboratory assessments: Hematology - Hematocrit (HCT) [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]

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

  10. Part A: Laboratory assessments: Hematology - Mean corpuscular volume (MCV) [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]

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

  11. Part A: Laboratory assessments: Hematology - Mean corpuscular hemoglobin (MCH) [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.]

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

  12. Part A: Laboratory assessments: Hematology - Mean corpuscular hemoglobin concentration (MCHC) [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.]

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

  13. Part A: Laboratory assessments: Hematology - Differential WBC count [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.]

    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.

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

    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.

  15. Part A: Laboratory assessments: Hematology - Reticulocytes absolute count [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.]

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

  16. Part A: Laboratory assessments: Serum clinical chemistry - Electrolytes [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.]

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

  17. Part A: Laboratory assessments: Serum clinical chemistry - Blood urea nitrogen (BUN) [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.]

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

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

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

  19. Part A: Laboratory assessments: Serum clinical chemistry - Glucose (fasting) [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.]

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

  20. Part A: Laboratory assessments: Serum clinical chemistry - Creatine kinase [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.]

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

  21. Part A: Laboratory assessments: Serum clinical chemistry - Direct bilirubin [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.]

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

  22. Part A: Laboratory assessments: Serum clinical chemistry - Hemoglobin A1c (HbA1c) [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.]

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

  23. Part A: Laboratory assessments: Serum clinical chemistry - Liver enzymes [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.]

    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.

  24. Part A: Laboratory assessments: Serum clinical chemistry - Total bilirubin [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.]

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

  25. Part A: Laboratory assessments: Serum clinical chemistry - Cell enzymes [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.]

    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.

  26. Part A: Laboratory assessments: Serum clinical chemistry - Bicarbonate [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.]

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

  27. Part A: Laboratory assessments: Serum clinical chemistry - Uric acid [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.]

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

  28. Part A: Laboratory assessments - Coagulation [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.]

    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.

  29. Part A: Renal safety biomarkers - Urine clusterin [Day 1 (pre-dose, 24 hours and 48 hours post-dose), Days 8 and 29 (pre-dose), and Day 57 (pre-dose).]

    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.

  30. Part A: Renal safety biomarkers - Urine cystatin-C [Day 1 (pre-dose, 24 hours and 48 hours post-dose), Days 8 and 29 (pre-dose), and Day 57 (pre-dose).]

    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.

  31. Part A: Renal safety biomarkers - Urine N-acetyl-beta-D-glucosaminidase (NAG) [Day 1 (pre-dose, 24 hours and 48 hours post-dose), Days 8 and 29 (pre-dose), and Day 57 (pre-dose).]

    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.

  32. Part A: Renal safety biomarkers - Urine albumin [Day 1 (pre-dose, 24 hours and 48 hours post-dose), Days 8 and 29 (pre-dose), and Day 57 (pre-dose).]

    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.

  33. Part A: Renal safety biomarkers - Urine creatinine [Day 1 (pre-dose, 24 hours and 48 hours post-dose), Days 8 and 29 (pre-dose), and Day 57 (pre-dose).]

    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.

  34. Part A: Renal safety biomarkers - Urine Kidney injury molecule1 (KIM-1) [Day 1 (pre-dose, 24 hours and 48 hours post-dose), Days 8 and 29 (pre-dose), and Day 57 (pre-dose).]

    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.

  35. Part A: Renal safety biomarkers - Urine Neutrophil gelatinase-associated lipocalin (NGAL) [Day 1 (pre-dose, 24 hours and 48 hours post-dose), Days 8 and 29 (pre-dose), and Day 57 (pre-dose).]

    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.

  36. Part A: Renal safety biomarkers - Urine Osteopontin [Day 1 (pre-dose, 24 hours and 48 hours post-dose), Days 8 and 29 (pre-dose), and Day 57 (pre-dose).]

    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.

  37. Part A: Renal safety biomarkers - Urine total protein [Day 1 (pre-dose, 24 hours and 48 hours post-dose), Days 8 and 29 (pre-dose), and Day 57 (pre-dose).]

    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.

  38. Part A: Immune Activation Response - High-sensitivity C-reactive protein (hs-CRP) [From screening to final Follow-up Visit (Week 16 post last dose).]

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

  39. Part A: Complement Activation panel [Days 1 and 57 (pre-dose, 1, 2, and 4 hours post-dose).]

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

  40. Part A: Laboratory assessments - Sampling for dipstick urinalysis for hematuria [Day1 to Day3 (pre-dose and then 24 and 48 h post -dose), Day8 (pre-dose), Day29 (pre-dose) and Day57 (pre-dose).]

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

  41. Part B:Absolute change from baseline in long-transformed LDL-C in serum at week12. [Measurement at week 12]

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

  42. Part A: Vital sign: Diastolic blood pressure (DBP) [From Day1(pre-dose) to final Follow-up Visit (Week 16 post last dose).]

    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.

  43. Part C: Number of subjects with adverse events (AEs) due to AZD8233 SC multiple dose treatment. [From randomization to final Follow-up Visit (Week 16 post last dose).]

    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.

  44. Part C: Vital sign: Systolic blood pressure (SBP) [From Day1(pre-dose) to final Follow-up Visit (Week 16 post last dose).]

    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.

  45. Part C: Vital sign: Pulse rate [From Day1(pre-dose) to final Follow-up Visit (Week 16 post last dose)]

    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.

  46. Part C: Vital sign: Body temperature [From Day 1(pre-dose) to final Follow-up Visit (Week 16 post last dose).]

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

  47. Part C: Number of patients with abnormal findings in resting 12-lead Electrocariogram (ECG) . [From Day1(pre-dose) to final Follow-up Visit (Week 16 post last dose).]

    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).

  48. Part C: Number of subject with abnormal findings in cardiac telemetry [At Day -1, Days 1 to 3 (pre-dose to 24 hours post-dose), and Day 57 (pre-dose to 24 hours post-dose).]

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

  49. Part C: Laboratory assessments: Hematology - Hemoglobin (Hb) [Day-1, Day1 ( 24 hours post- dose), Day8 , Day29 (pre-dose), Day57 (pre-dose), Week 2,4,8,12 and 16 post last dose.]

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

  50. Part C: Laboratory assessments: Hematology - Blood cells count [Day-1, Day1 ( 24 hours post- dose), Day8 , Day29 (pre-dose), Day57 (pre-dose), Week 2,4,8,12 and 16 post last dose.]

    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.

  51. Part C: Laboratory assessments: Hematology - Hematocrit (HCT) [Day-1, Day1 ( 24 hours post- dose), Day8, Day29 (pre-dose), Day57 (pre-dose), Week 2,4,8,12 and 16 post last dose]

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

  52. Part C: Laboratory assessments: Hematology - Mean corpuscular volume (MCV) [Day-1, Day1 ( 24 hours post- dose), Day8 , Day29 (pre-dose), Day57 (pre-dose), Week 2,4,8,12 and 16 post last dose]

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

  53. Part C: Laboratory assessments: Hematology - Mean corpuscular hemoglobin (MCH) [Day-1, Day1 ( 24 hours post- dose), Day8, Day29 (pre-dose), Day57 (pre-dose), Week 2,4,8,12 and 16 post last dose.]

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

  54. Part C: Laboratory assessments: Hematology - Mean corpuscular hemoglobin concentration (MCHC) [Day-1, Day1 ( 24 hours post- dose), Day8, Day29 (pre-dose), Day57 (pre-dose), Week 2,4,8,12 and 16 post last dose.]

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

  55. Part C: Laboratory assessments: Hematology - Differential WBC count [Day-1, Day1 ( 24 hours post- dose), Day8 , Day29 (pre-dose), Day57 (pre-dose), Week 2,4,8,12 and 16 post last dose.]

    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.

  56. Part C: Laboratory assessments: Hematology - Platelet count and platelet function assessment. [Day-1, Day1 ( 24 hours post- dose), Day8, Day29 (pre-dose), Day57 (pre-dose), Week 2,4,8,12 and 16 post last dose.]

    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.

  57. Part C: Laboratory assessments: Hematology - Reticulocytes absolute count [Day-1, Day1 ( 24 hours post- dose), Day8 , Day29 (pre-dose), Day57 (pre-dose), Week 2,4,8,12 and 16 post last dose.]

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

  58. Part C: Laboratory assessments: Serum clinical chemistry - Electrolytes [Day-1, Day1 ( 24 hours post- dose), Day8, Day29 (pre-dose), Day57 (pre-dose), Week 2,4,8,12 and 16 post last dose.]

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

  59. Part C: Laboratory assessments: Serum clinical chemistry - Blood urea nitrogen (BUN) [Day-1, Day1 ( 24 hours post- dose), Day8 , Day29 (pre-dose), Day57 (pre-dose), Week 2,4,8,12 and 16 post last dose.]

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

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

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

  61. Part C: Vital sign: Diastolic blood pressure (DBP) [From Day1(pre-dose) to final Follow-up Visit (Week 16 post last dose).]

    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.

  62. Part C: Laboratory assessments: Serum clinical chemistry - Glucose (fasting) [Day-1, Day1 ( 24 hours post- dose), Day8, Day29 (pre-dose), Day57 (pre-dose), Week 2,4,8,12 and 16 post last dose.]

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

  63. Part C: Laboratory assessments: Serum clinical chemistry - Creatine kinase [Day-1, Day1 ( 24 hours post- dose), Day8, Day29 (pre-dose), Day57 (pre-dose), Week 2,4,8,12 and 16 post last dose.]

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

  64. Part C: Laboratory assessments: Serum clinical chemistry - Direct bilirubin [Day-1, Day1 ( 24 hours post- dose), Day8, Day29 (pre-dose), Day57 (pre-dose), Week 2,4,8,12 and 16 post last dose.]

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

  65. Part C: Laboratory assessments: Serum clinical chemistry - Hemoglobin A1c (HbA1c) [Day-1, Day1 ( 24 hours post- dose), Day8, Day29 (pre-dose), Day57 (pre-dose), Week 2,4,8,12 and 16 post last dose.]

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

  66. Part C: Laboratory assessments: Serum clinical chemistry - Liver enzymes [Day-1, Day1 ( 24 hours post- dose), Day8, Day29 (pre-dose), Day57 (pre-dose), Week 2,4,8,12 and 16 post last dose.]

    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.

  67. Part C: Laboratory assessments: Serum clinical chemistry - Total bilirubin [Day-1, Day1 ( 24 hours post- dose), Day8 , Day29 (pre-dose), Day57 (pre-dose), Week 2,4,8,12 and 16 post last dose.]

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

  68. Part C: Laboratory assessments: Serum clinical chemistry - Cell enzymes [Day-1, Day1 ( 24 hours post- dose), Day8, Day29 (pre-dose), Day57 (pre-dose), Week 2,4,8,12 and 16 post last dose.]

    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.

  69. Part C: Laboratory assessments: Serum clinical chemistry - Bicarbonate [Day-1, Day1 ( 24 hours post- dose), Day8, Day29 (pre-dose), Day57 (pre-dose), Week 2,4,8,12 and 16 post last dose.]

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

  70. Part C: Laboratory assessments: Serum clinical chemistry - Uric acid [Day-1, Day1 ( 24 hours post- dose), Day8, Day29 (pre-dose), Day57 (pre-dose), Week 2,4,8,12 and 16 post last dose.]

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

  71. Part C: Laboratory assessments - Coagulation [Day-1, Day1 ( 24 hours post- dose), Day8, Day29 (pre-dose), Day57 (pre-dose), Week 2,4,8,12 and 16 post last dose.]

    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.

  72. Part C: Renal safety biomarkers - Urine clusterin [Day 1 (pre-dose, 24 hours and 48 hours post-dose), Day 8, Day 29 (pre-dose), and Day 57 (pre-dose).]

    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.

  73. Part C: Renal safety biomarkers - Urine cystatin-C [Day 1 (pre-dose, 24 hours and 48 hours post-dose), Day 8, Day 29 (pre-dose), and Day 57 (pre-dose).]

    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.

  74. Part C: Renal safety biomarkers - Urine N-acetyl-beta-D-glucosaminidase (NAG) [Day 1 (pre-dose, 24 hours and 48 hours post-dose), Day 8 , Day 29 (pre-dose), and Day 57 (pre-dose).]

    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.

  75. Part C: Renal safety biomarkers - Urine albumin [Day 1 (pre-dose, 24 hours and 48 hours post-dose), Day 8 , Day 29 (pre-dose), and Day 57 (pre-dose).]

    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.

  76. Part C: Renal safety biomarkers - Urine creatinine [Day 1 (pre-dose, 24 hours and 48 hours post-dose), Day 8, Day 29 (pre-dose), and Day 57 (pre-dose).]

    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.

  77. Part C: Renal safety biomarkers - Urine Neutrophil gelatinase-associated lipocalin (NGAL) [Day 1 (pre-dose, 24 hours and 48 hours post-dose), Day 8, Day 29 (pre-dose), and Day 57 (pre-dose).]

    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.

  78. Part C: Renal safety biomarkers - Urine Osteopontin [Day 1 (pre-dose, 24 hours and 48 hours post-dose), Day 8 , Day 29 (pre-dose), and Day 57 (pre-dose).]

    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.

  79. Part C: Renal safety biomarkers - Urine total protein [Day 1 (pre-dose, 24 hours and 48 hours post-dose), Day 8 , Day 29 (pre-dose), and Day 57 (pre-dose).]

    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.

  80. Part C: Immune Activation Response - High-sensitivity C-reactive protein (hs-CRP) [From screening to final Follow-up Visit (Week 16 post last dose).]

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

  81. Part C: Complement Activation panel [Days 1 and 57 (pre-dose, 1, 2, and 4 hours post-dose).]

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

  82. Part C: Laboratory assessments - Sampling for dipstick urinalysis for hematuria [Day1 to Day3 (pre-dose and then 24 and 48 h post -dose), Day8 , Day29 (pre-dose) and Day57 (pre-dose).]

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

  83. Part C: Renal safety biomarkers - Urine Kidney injury molecule1 (KIM-1) [Day 1 (pre-dose, 24 hours and 48 hours post-dose), Day 8 , Day29 (pre-dose), and Day 57 (pre-dose).]

    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

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

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

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

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

  3. Part A:Plasma PK analysis: Observed maximum plasma concentration (Cmax) [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.]

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

  14. Part A:Urine PK analysis: Amount excreted in urine (Ae). [Treatment Days 1 to 3 (Pre-dose and intervals 0-6, 6-12 hours and 12-24 hours post-dose).]

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

  15. Part A:Urine PK analysis: Fraction excreted unchanged in urine (Fe). [Treatment Days 1 to 3 (Pre-dose and intervals 0-6, 6-12 hours and 12-24 hours post-dose).]

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

  16. Part A:Urine PK analysis: Renal clearance (CLR). [Treatment Days 1 to 3 (Pre-dose and intervals 0-6, 6-12 hours and 12-24 hours post-dose).]

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

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

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

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

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

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

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

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

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

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

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

  22. 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.]

  23. Part B:Anti-drug antibodies (ADAs) during the treatment period and follow-up period. [Measurement at week 0, week 1, week 4, week 8, week 12, week 16, week 20, week 24.]

    To evaluate the immunogenicity of AZD8233.

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

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

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

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

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

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

  27. Part C:Plasma PK analysis: Observed maximum plasma concentration (Cmax) [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.]

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

  38. Part C:Urine PK analysis: Amount excreted in urine (Ae). [Treatment Days 1 to 3 (Pre-dose and intervals 0-6, 6-12 hours and 12-24 hours post-dose).]

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

  39. Part C:Urine PK analysis: Fraction excreted unchanged in urine (Fe). [Treatment Days 1 to 3 (Pre-dose and intervals 0-6, 6-12 hours and 12-24 hours post-dose).]

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

  40. Part C:Urine PK analysis: Renal clearance (CLR). [Treatment Days 1 to 3 (Pre-dose and intervals 0-6, 6-12 hours and 12-24 hours post-dose).]

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

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

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

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

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

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

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

Eligibility Criteria

Criteria

Ages Eligible for Study:
20 Years to 75 Years
Sexes Eligible for Study:
All
Accepts Healthy Volunteers:
No
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

Contacts and Locations

Locations

Site City State Country Postal Code
1 Research Site Chiyoda-ku Japan 1010041
2 Research Site Chuo-ku Japan 103-0027
3 Research Site Chuo-ku Japan 104-0031
4 Research Site Chuo-ku Japan 1040031
5 Research Site Osaka-shi Japan 530-0001
6 Research Site Shinjuku-ku Japan 160-0008
7 Research Site Suita-shi Japan 565-0853

Sponsors and Collaborators

  • AstraZeneca

Investigators

None specified.

Study Documents (Full-Text)

None provided.

More Information

Publications

None provided.
Responsible Party:
AstraZeneca
ClinicalTrials.gov Identifier:
NCT04823611
Other Study ID Numbers:
  • D7990C00006
First Posted:
Apr 1, 2021
Last Update Posted:
Jun 8, 2022
Last Verified:
May 1, 2022
Individual Participant Data (IPD) Sharing Statement:
No
Plan to Share IPD:
No
Studies a U.S. FDA-regulated Drug Product:
Yes
Studies a U.S. FDA-regulated Device Product:
No
Product Manufactured in and Exported from the U.S.:
Yes
Keywords provided by AstraZeneca
AZD8233
Efficacy
PK
PD
Immunogenicity
Safety
Tolerability
Additional relevant MeSH terms:
Dyslipidemias

Study Results

No Results Posted as of Jun 8, 2022