Clinical trial NCT04641299: A Study of AZD8233 in Participants With Dyslipidemia
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
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE2
Conditions: Dyslipidaemia
Keywords: Dose Range Finding
AZD8233
Efficacy
PK
PD
Immunogenicity
Safety
Tolerability
Lead sponsor: AstraZeneca
Sponsor class: INDUSTRY
First posted: 2020-11-23
Enrollment: 119
Sex: ALL
Minimum age (years): 18
Maximum age (years): 75
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

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.

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.

Eligibility 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.

Primary outcomes:
measure: Change in Low-density Lipoprotein Cholesterol (LDL-C) at Week 12.
timeFrame: Baseline to week 12
Secondary outcomes:
measure: Relative Change From Baseline in PCSK9 Concentration in Plasma at Week 12.
timeFrame: Baseline to week 12
measure: Percentage Change From Baseline in Concentration of TC, HDL-C, Non-HDL-C, VLDL-C, ApoA1, ApoB, Lp(a), Triglycerides, Remnants Cholesterol
timeFrame: Baseline to week 12
measure: Plasma Concentration of AZD8233
timeFrame: Measurement at week 1, week 4, week 6, week 8, week 10, week 12, week 16, week 20, week 24 after first dose administration.
measure: Anti-drug Antibodies (ADAs) During the Treatment Period and Follow-up Period
timeFrame: Measurement at week 0, week 1, week 4, week 8, week 12, week 16, week 20, week 24
measure: Percentage Change From Baseline in Levels of LDL-C in Plasma
timeFrame: Baseline to week 12
Other outcomes:
measure: Number of Subjects With an ECG Determined to be Abnormal and Clinically Significant
timeFrame: Baseline to Week 24
Locations:
city: Roseville
country: United States
facility: Research Site
state: California
city: Inverness
country: United States
facility: Research Site
state: Florida
city: Jacksonville
country: United States
facility: Research Site
state: Florida
city: Pembroke Pines
country: United States
facility: Research Site
state: Florida
city: Meridian
country: United States
facility: Research Site
state: Idaho
city: Indianapolis
country: United States
facility: Research Site
state: Indiana
city: New Windsor
country: United States
facility: Research Site
state: New York
city: Greensboro
country: United States
facility: Research Site
state: North Carolina
city: Fargo
country: United States
facility: Research Site
state: North Dakota
city: Cincinnati
country: United States
facility: Research Site
state: Ohio
city: Aarhus N
country: Denmark
facility: Research Site
city: Frederiksberg
country: Denmark
facility: Research Site
city: Herlev
country: Denmark
facility: Research Site
city: Roskilde
country: Denmark
facility: Research Site
city: Viborg
country: Denmark
facility: Research Site
city: Bratislava
country: Slovakia
facility: Research Site
city: Bratislava
country: Slovakia
facility: Research Site
city: Rožňava
country: Slovakia
facility: Research Site
city: Trebišov
country: Slovakia
facility: Research Site
Study officials:
References: