A Study of AZD8233 in Participants With Dyslipidemia.

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

Status

Completed

Phases

Phase 1Phase 2

Study type

Interventional

Source

ClinicalTrials.gov

Registry ID

NCT04823611

Acronym

HAYATE

Enrollment

Registered

2021-04-01

Start date

2021-01-20

Completion date

2022-09-10

Last updated

2024-12-24

For informational purposes only — not medical advice. Sourced from public registries and may not reflect the latest updates. Terms

Conditions

Dyslipidemia

Keywords

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

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.

Interventions

DRUGPart A:Placebo

Placebo solution

DRUGPart A:AZD8233

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

DRUGPart B:Placebo

Placebo solution

DRUGPart B:AZD8233

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

DRUGPart C: Placebo

Placebo solution

DRUGPart C: AZD8233

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

Study design

Allocation

RANDOMIZED

Intervention model

PARALLEL

Primary purpose

TREATMENT

Masking

TRIPLE (Subject, Caregiver, Investigator)

Masking description

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

Intervention model description

Parallel Assignment

Eligibility

Sex/Gender

ALL

Age

20 Years to 75 Years

Healthy volunteers

Inclusion 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

Design outcomes

Primary

Measure	Time frame	Description
Part B: Change in LDL-C in Serum at Week 12	Baseline to week 12	Part B: Change from baseline in LDL-C at week 12. Results are based on Mixed Model Repeated Measures (MMRM) analysis on the log-transformed change from baseline. Log-transformed change from baseline is calculated as the visit value in log minus the baseline value in log. The results from the model are then back transformed. Note: log(week 12 data) - log(baseline data) = log(week12/baseline), which is a ratio

Secondary

Measure	Time frame	Description
Part B: Change in PCSK9 in Plasma at Week 12	Baseline to week 12	Part B: Change from baseline in PCSK9 in plasma at week 12. Results are based on Mixed Model Repeated Measures (MMRM) analysis on the log-transformed change from baseline. Log-transformed change from baseline is calculated as the visit value in log minus the baseline value in log. The results from the model are then back transformed. Note: log(week 12 data) - log(baseline data) = log(week12/baseline), which is a ratio
Part B: Percentage Change From Baseline in PCSK9 in Plasma at Week 12	Measurement at baseline and week 12	Percentage change from baseline to week 12 in proprotein convertase subtilisin/kexin type-9 (PCSK9) in plasma
Part A & Part C: AUC (0-24) of AZD8233	Day 1 and Day 57	Area Under the plasma concentration time curve from time 0 to time 24 hours
Part B: Percentage Change From Baseline in LDL-C in Serum at Week 12	Measurement at baseline and week 12	Percentage change from baseline to week 12 in Low-density Lipoprotein Cholesterol (LDL-C) in serum
Part A & Part C: t1/2 of AZD8233	Day 1 and Day 57	Terminal half-life
Part A & Part C: CL/F (L/h) of AZD8233	Day 1 and Day 57	Apparent plasma clearance
Part A & Part C: Vz/F (L)	Day 1 and Day 57	Apparent Volume of distribution during the terminal phase
Part A & Part C: Cmax of AZD8233	Day 1 and Day 57	Maximum plasma concentration

Countries

Japan

Participant flow

Participants by arm

Arm	Count
Part A:AZD8233 90mg AZD8233 for subcutaneous injection.	8
Part A:Placebo Placebo solution for subcutaneous injection.	3
Part B:AZD8233 50mg AZD8233 medium dose for subcutaneous injection.	22
Part B:AZD8233 15mg AZD8233 low dose for subcutaneous injection.	22
Part B:Placebo Placebo solution for subcutaneous injection.	21
Part C: AZD8233 60mg AZD8233 medium dose for subcutaneous injection.	8
Part C: Placebo Placebo solution for subcutaneous injection.	3
Total	87

Withdrawals & dropouts

Period	Reason	FG000	FG001	FG002	FG003	FG004	FG005	FG006
Overall Study	Adverse Event	2	0	1	0	0	0	0

Baseline characteristics

Characteristic	Part A:AZD8233 90mg	Part A:Placebo	Part B:AZD8233 50mg	Part B:AZD8233 15mg	Part B:Placebo	Part C: AZD8233 60mg	Part C: Placebo	Total
Age, Continuous	53.1 Years STANDARD_DEVIATION 5.38	47.0 Years STANDARD_DEVIATION 11.36	60.6 Years STANDARD_DEVIATION 6.29	64.4 Years STANDARD_DEVIATION 5.5	61.9 Years STANDARD_DEVIATION 7.04	52.0 Years STANDARD_DEVIATION 6.37	52.0 Years STANDARD_DEVIATION 3.61	59.6 Years STANDARD_DEVIATION 7.86
Race/Ethnicity, Customized Not Hispanic or Latino	8 Participants	3 Participants	22 Participants	22 Participants	21 Participants	8 Participants	3 Participants	87 Participants
Sex: Female, Male Female	2 Participants	1 Participants	12 Participants	7 Participants	9 Participants	2 Participants	0 Participants	33 Participants
Sex: Female, Male Male	6 Participants	2 Participants	10 Participants	15 Participants	12 Participants	6 Participants	3 Participants	54 Participants

Adverse events

Event type	EG000 affected / at risk	EG001 affected / at risk	EG002 affected / at risk	EG003 affected / at risk	EG004 affected / at risk	EG005 affected / at risk	EG006 affected / at risk
deaths Total, all-cause mortality	0 / 8	0 / 3	0 / 22	0 / 22	0 / 21	0 / 8	0 / 3
other Total, other adverse events	6 / 8	2 / 3	5 / 22	6 / 22	7 / 21	2 / 8	1 / 3
serious Total, serious adverse events	0 / 8	0 / 3	0 / 22	0 / 22	0 / 21	0 / 8	0 / 3

Outcome results

Primary

Part B: Change in LDL-C in Serum at Week 12

Part B: Change from baseline in LDL-C at week 12. Results are based on Mixed Model Repeated Measures (MMRM) analysis on the log-transformed change from baseline. Log-transformed change from baseline is calculated as the visit value in log minus the baseline value in log. The results from the model are then back transformed. Note: log(week 12 data) - log(baseline data) = log(week12/baseline), which is a ratio

Time frame: Baseline to week 12

Population: Full Analysis Set (Part B only). These data were not pre-specified for parts A and C

Arm	Measure	Value (GEOMETRIC_LEAST_SQUARES_MEAN)
Part B:AZD8233 50mg	Part B: Change in LDL-C in Serum at Week 12	0.198 Ratio
Part B:AZD8233 15mg	Part B: Change in LDL-C in Serum at Week 12	0.458 Ratio
Part B:Placebo	Part B: Change in LDL-C in Serum at Week 12	0.953 Ratio

Secondary