Clinical trial NCT04823611: A Study of AZD8233 in Participants With Dyslipidemia.
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
Overall status: COMPLETED
Phase: PHASE1
PHASE2
Conditions: Dyslipidemia
Keywords: AZD8233
Efficacy
PK
PD
Immunogenicity
Safety
Tolerability
Lead sponsor: AstraZeneca
Sponsor class: INDUSTRY
First posted: 2021-04-01
Enrollment: 87
Sex: ALL
Minimum age (years): 20
Maximum age (years): 75
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Intervention model description: Parallel Assignment
Primary purpose: TREATMENT

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.

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

Primary outcomes:
measure: Part B: Change in LDL-C in Serum at Week 12
timeFrame: Baseline to week 12
Secondary outcomes:
measure: Part B: Percentage Change From Baseline in LDL-C in Serum at Week 12
timeFrame: Measurement at baseline and week 12
measure: Part B: Change in PCSK9 in Plasma at Week 12
timeFrame: Baseline to week 12
measure: Part B: Percentage Change From Baseline in PCSK9 in Plasma at Week 12
timeFrame: Measurement at baseline and week 12
measure: Part A & Part C: AUC (0-24) of AZD8233
timeFrame: Day 1 and Day 57
measure: Part A & Part C: Cmax of AZD8233
timeFrame: Day 1 and Day 57
measure: Part A & Part C: t1/2 of AZD8233
timeFrame: Day 1 and Day 57
measure: Part A & Part C: CL/F (L/h) of AZD8233
timeFrame: Day 1 and Day 57
measure: Part A & Part C: Vz/F (L)
timeFrame: Day 1 and Day 57
Other outcomes:
Locations:
city: Chiyoda-ku
country: Japan
facility: Research Site
city: Chuo-ku
country: Japan
facility: Research Site
city: Chuo-ku
country: Japan
facility: Research Site
city: Chuo-ku
country: Japan
facility: Research Site
city: Osaka-shi
country: Japan
facility: Research Site
city: Shinjuku-ku
country: Japan
facility: Research Site
city: Suita-shi
country: Japan
facility: Research Site
Study officials:
References: