A Study of AZD8233 in Participants With Dyslipidemia

Sponsor

AstraZeneca (Industry)

Overall Status

Completed

CT.gov ID

NCT04641299

Collaborator

(none)

119

Enrollment

Locations

Arms

8.7

Actual Duration (Months)

6.3

Patients Per Site

0.7

Patients Per Site Per Month

Study Details

Study Description

Brief Summary

AZD8233 is a PCSK9-targeted ASO for the reduction of circulating levels of LDL-C. This study aims to evaluate the dose-dependent reduction in LDL-C after SC administration of multiple doses of AZD8233 as well as the associated adverse effects profile. The data generated will be used to guide choice of doses, dosing regimens, and sample sizes, as well as safety and PD monitoring in the further clinical development program.

Condition or Disease	Intervention/Treatment	Phase
Dyslipidaemia	Drug: AZD8233 Drug: Placebo	Phase 2

Detailed Description

This is a randomized parallel, double-blind, placebo-controlled, dose-ranging Phase 2b study in approximately 108 participants with dyslipidemia. The primary objective of the study is to investigate the effect of AZD8233 on LDL-C across different dose levels. The study will be conducted at up to 25 sites in up to 4 countries.

The screening period starts up to 42 days before the randomization visit and ends on Day -1. Eligible participants will attend 7 visits during the treatment period and 7 additional visits during the safety follow up period. Eligible participants are randomized across four different treatment arms in a 1:1:1:1 ratio for a 12-week treatment period. The planned treatment arms are AZD8233 low dose, AZD8233 medium dose, AZD8233 high dose, and Placebo. Participants will be dosed SC on Days 1, 8, 29, and 57.

Study Design

Study Type:

Interventional

Actual Enrollment :

119 participants

Allocation:

Randomized

Intervention Model:

Parallel Assignment

Masking:

Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)

Primary Purpose:

Treatment

Official Title:

A Randomized, Parallel, Double-blind, Placebo-controlled, Dose-ranging, Phase 2b Study to Evaluate the Efficacy, Safety and Tolerability of AZD8233 Treatment in Participants With Dyslipidemia

Actual Study Start Date :

Oct 28, 2020

Actual Primary Completion Date :

Jul 20, 2021

Actual Study Completion Date :

Jul 20, 2021

Arms and Interventions

Arm	Intervention/Treatment
Placebo Comparator: Placebo Placebo solution for subcutaneous injection.	Drug: Placebo Placebo solution
Experimental: AZD8233 high dose AZD8233 high dose for subcutaneous injection.	Drug: AZD8233 PCSK9-targeted ASO for the reduction of circulating levels of LDL-C.
Experimental: AZD8233 medium dose AZD8233 medium dose for subcutaneous injection.	Drug: AZD8233 PCSK9-targeted ASO for the reduction of circulating levels of LDL-C.
Experimental: AZD8233 low dose AZD8233 low does for subcutaneous injection.	Drug: AZD8233 PCSK9-targeted ASO for the reduction of circulating levels of LDL-C.

Outcome Measures

Primary Outcome Measures

Percentage change from baseline in geometric mean of LDL-C concentration in plasma at week 12. [Measurement at week 12]

Secondary Outcome Measures

Percentage change from baseline in geometric mean of PCSK9 concentration in plasma at weeks 1, 3, 4, 6, 8, 10, 12, 14, 16, 18, 20, 22 and 24. [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]
Percentage change from baseline in concentration 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]
Plasma concentration of AZD8233 [Measurement at week 1, week 4, week 6, week 8, week 10, week 12, week 16, week 20, week 24]
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]
Percentage change from baseline in levels of LDL-C 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]

Other Outcome Measures

Number of subjects with adverse events (AEs) [Measurement at 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]
Vital sign: Systolic blood pressure (SBP) [Measurement at 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]
Vital sign: Diastolic blood pressure (DBP) [Measurement at 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]
Vital sign: Pulse rate [Measurement at 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]
Vital sign: Oral body temperature [Measurement at 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]
Number of subjects with an ECG determined to be abnormal and clinically significant [Measurement at 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]
Number of subjects with clinically significant changes in haematology and or clinical chemistry parameters [Measurement at 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]

Eligibility Criteria

Criteria

Ages Eligible for Study:

18 Years to 75 Years

Sexes Eligible for Study:

All

Accepts Healthy Volunteers:

Key Inclusion Criteria:

Male or female.
Participant must be 18 to 75 years of age.
Body mass index between 19 and 40 kg/m2.
Participants who have a fasting LDL-C ≥ 70 mg/dL but < 190 mg/dL.
Have fasting triglycerides < 400 mg/dL.
Should be receiving moderate- or high-intensity statin therapy.
Should be on stable medication for ≥ 3 months prior to screening with no planned medication or dose change during study participation. The exception to this restriction is for fenofibrate; if the participant is receiving fenofibrate, the therapy must be stable for at least 6 weeks prior to randomization at a dose that is appropriate for the duration of the study in the judgement of the Investigator. Other fibrate therapy (and derivatives) are prohibited.

Key Exclusion Criteria:

Estimated glomerular filtration rate < 40 mL/min/1.73m2 CKD-EPI.
Any uncontrolled or serious disease, or any medical dysfunction or surgical condition that, in the opinion of the Investigator, may either interfere with participation in the clinical study and/or put the participant at significant risk.
Poorly controlled type 2 diabetes mellitus, defined as 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 as judged by the Investigator.
Malignancy (except non-melanoma skin cancers, cervical in-situ carcinoma, breast ductal
Carcinoma in-situ, or Stage 1 prostate carcinoma) within the last 10 years.
LDL or plasma apheresis within 12 months prior to randomization.
Uncontrolled hypertension defined as average supine SBP > 160 mmHg or DBP > 90 mmHg at Visit 1 or Visit 3.
Heart rate after 10 minutes supine rest < 50 bpm or > 100 bpm.
Any laboratory values with the following deviations at Screening:
Positive result on screening for hepatitis B, hepatitis C or HIV.
ALT > 1.5 × ULN.
AST > 1.5 × ULN.
TBL > ULN.
ALP > 1.5 × ULN.
WBC < LLN.
Haemoglobin < 12 g/dL in men or < 11 g/dL in women.
Platelet count ≤ LLN.
aPTT > ULN and PT > ULN.
UACR > 11.3 mg/mmol (100 mg/g).
UPCR > 300 mg/g.
Any clinically important abnormalities in rhythm, conduction or morphology of the resting ECG and any clinically important abnormalities in the 12-lead ECG as judged by the Investigator.
Mipomersen, or lomitapide within 12 months prior to randomization.
Previous administration of AZD8233/AZD6615.
Previous administration of PCSK9 inhibition treatment.
Participation in another clinical study with a study intervention administered in the last 3 months prior to randomization or 5 half-lives from last dose to first administration of study intervention, whichever is the longest.

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	Research Site	Roseville	California	United States	95661
2	Research Site	Inverness	Florida	United States	34452
3	Research Site	Jacksonville	Florida	United States	32216
4	Research Site	Pembroke Pines	Florida	United States	33024
5	Research Site	Meridian	Idaho	United States	83646
6	Research Site	Indianapolis	Indiana	United States	46260
7	Research Site	New Windsor	New York	United States	12553
8	Research Site	Greensboro	North Carolina	United States	27408
9	Research Site	Fargo	North Dakota	United States	58104
10	Research Site	Cincinnati	Ohio	United States	45219
11	Research Site	Aarhus N		Denmark	8200
12	Research Site	Frederiksberg		Denmark	2000
13	Research Site	Herlev		Denmark	2730
14	Research Site	Roskilde		Denmark	4000
15	Research Site	Viborg		Denmark	8800
16	Research Site	Bratislava		Slovakia	831 03
17	Research Site	Bratislava		Slovakia	85101
18	Research Site	Rožňava		Slovakia	048 01
19	Research Site	Trebišov		Slovakia	7501