A Study of AZD8233 in Participants With Dyslipidemia

• ClinicalTrials.gov Identifier: NCT04641299
• Recruitment Status: Completed
• First Posted: November 23, 2020
• Results First Posted: November 18, 2022
• Last Update Posted: November 18, 2022
• Sponsor: AstraZeneca
• Information provided by (Responsible Party): AstraZeneca

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 (Clinical Trial)
• 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: October 28, 2020
• Actual Primary Completion Date: July 20, 2021
• Actual Study Completion Date: July 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 :

1. Change in Low-density Lipoprotein Cholesterol (LDL-C) at Week 12. [ Time Frame: Baseline to week 12 ]
   Change from baseline in low-density lipoprotein cholesterol (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.

Secondary Outcome Measures :

1. Relative Change From Baseline in PCSK9 Concentration in Plasma at Week 12. [ Time Frame: Baseline to week 12 ]
   Relative change from baseline in PCSK9 concentration in plasma at week 12.
2. Percentage Change From Baseline in Concentration of TC, HDL-C, Non-HDL-C, VLDL-C, ApoA1, ApoB, Lp(a), Triglycerides, Remnants Cholesterol [ Time Frame: Baseline to week 12 ]
   Percentage change from baseline in concentration of TC, HDL-C, Non-HDL-C, VLDL-C, ApoA1, ApoB, Lp(a), Triglycerides, Remnants cholesterol at week 12
3. 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 after first dose administration. ]
   Plasma concentration of AZD8233 after first dose administration
4. Anti-drug Antibodies (ADAs) During the Treatment Period and Follow-up Period [ Time Frame: Measurement at week 0, week 1, week 4, week 8, week 12, week 16, week 20, week 24 ]
   ADA titre results for subjects with positive ADA during the treatment period and follow-up period.
5. Percentage Change From Baseline in Levels of LDL-C in Plasma [ Time Frame: Baseline to week 12 ]
   Percentage change from baseline in levels of LDL-C in plasma from baseline to week 12.

Other Outcome Measures:

1. Number of Subjects With an ECG Determined to be Abnormal and Clinically Significant [ Time Frame: Baseline to Week 24 ]
   Number of subjects with an ECG determined to be abnormal and clinically significant at baseline and end of treatment.

Eligibility Criteria

• Ages Eligible for Study: 18 Years to 75 Years (Adult, Older Adult)
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

Criteria

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

United States, California

Research Site

Roseville, California, United States, 95661

United States, Florida

Research Site

Inverness, Florida, United States, 34452

Research Site

Jacksonville, Florida, United States, 32216

Research Site

Pembroke Pines, Florida, United States, 33024

United States, Idaho

Research Site

Meridian, Idaho, United States, 83646

United States, Indiana

Research Site

Indianapolis, Indiana, United States, 46260

United States, New York

Research Site

New Windsor, New York, United States, 12553

United States, North Carolina

Research Site

Greensboro, North Carolina, United States, 27408

United States, North Dakota

Research Site

Fargo, North Dakota, United States, 58104

United States, Ohio

Research Site

Cincinnati, Ohio, United States, 45219

Denmark

Research Site

Aarhus N, Denmark, 8200

Research Site

Frederiksberg, Denmark, 2000

Research Site

Herlev, Denmark, 2730

Research Site

Roskilde, Denmark, 4000

Research Site

Viborg, Denmark, 8800

Slovakia

Research Site

Bratislava, Slovakia, 831 03

Research Site

Bratislava, Slovakia, 85101

Research Site

Rožňava, Slovakia, 048 01

Research Site

Trebišov, Slovakia, 7501

Sponsors and Collaborators

AstraZeneca

  Study Documents (Full-Text)

Documents provided by AstraZeneca:

Study Protocol  [PDF] December 16, 2020

Statistical Analysis Plan  [PDF] August 11, 2021

More Information

Additional Information:

Redacted Protocol 

redacted Statistical Analysis Plan 

Redacted Clinical Study Report Synopsis 

• Responsible Party: AstraZeneca
• ClinicalTrials.gov Identifier: NCT04641299
• Other Study ID Numbers: D7990C00003
• First Posted: November 23, 2020
• Results First Posted: November 18, 2022
• Last Update Posted: November 18, 2022
• Last Verified: October 2022

• Studies a U.S. FDA-regulated Drug Product: Yes
• Studies a U.S. FDA-regulated Device Product: No

Keywords provided by AstraZeneca:

Dose Range Finding; AZD8233; Efficacy; PK; PD; Immunogenicity; Safety; Tolerability

Additional relevant MeSH terms:

Dyslipidemias; Lipid Metabolism Disorders; Metabolic Diseases