Clinical trial NCT04964557: A Study to Assess the Safety, Efficacy and Tolerability of AZD8233 Treatment in Participants With Hyperlipidaemia
Official title: A Randomised, Parallel, Double-Blind, Placebo-Controlled Phase 2b Study to Assess the Safety, Tolerability and Efficacy of AZD8233 Treatment in Participants With Hyperlipidaemia
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE2
Conditions: Hyperlipidaemia
Keywords: AZD8233
Efficacy
PK
PD
Safety
Tolerability
Lead sponsor: AstraZeneca
Sponsor class: INDUSTRY
First posted: 2021-07-16
Enrollment: 411
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 safety, efficacy and tolerability of AZD8233.

Detailed description: This is a randomized parallel, double-blind, placebo-controlled Phase 2b study in approximately 376 participants with hyperlipidaemia. The primary objective of the study is to assess the safety and tolerability of AZD8233 as compared with placebo, and the effect of AZD8233 versus placebo on relative change in LDL-C. The study will be conducted at up to 100 sites in up to 8 countries.

The screening period starts up to 28 days before the randomization visit and ends on Day -1. Eligible participants will attend 1 enrollment visit and 15 visits during the treatment period and 2 additional visits during the safety follow up period.

Eligibility criteria: Inclusion Criteria:

* Participant must be 18 to 75 years of age, inclusive, at the time of signing the informed consent
* Participants who have a fasting LDL-C ≥ 70 mg/dL (1.8 mmol/L) but \< 190 mg/dL (4.9 mmol/L) at screening
* Participants who have fasting triglycerides \< 400 mg/dL (\< 4.52 mmol/L) at screening
* Participants are receiving a stable dose (≥ 3 months) of maximally tolerated statin and/or ezetimibe therapy
* Male or female of non-childbearing potential
* Signed and dated written informed consent prior to any mandatory study specific procedures, sampling, and analyses

Exclusion Criteria:

* eGFR \< 40 mL/min/1.73m2 using the CKD-EPI
* History or presence of gastrointestinal, hepatic or renal disease or any other conditions known to interfere with absorption, distribution, metabolism or excretion of drugs
* Any uncontrolled or serious disease, or any medical (eg,. known major active infection or major haematological, renal, metabolic, gastrointestinal or endocrine 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 (according to the investigator's judgment) if he/she participates in the clinical study
* Poorly controlled T2DM, defined as HbA1c \> 10%
* Acute ischaemic cardiovascular events including stroke within 30 days, or heart failure with New York Heart Association (NYHA) Class III to IV
* Blood dyscrasias with increased risk of bleeding including idiopathic thrombocytopenic purpura and thrombotic thrombocytopenic purpura or symptoms of increased risk of bleeding (frequent bleeding gums or nose bleeds)
* High-risk of bleeding diathesis or anti-platelet therapy other than low dose aspirin (≤100mg/day).
* Malignancy within the last 10 years
* Recipient of any major organ transplant
* LDL or plasma apheresis within 12 months prior to randomisation
* Uncontrolled hypertension defined as average supine SBP \> 160 mmHg or DBP \> 90 mmHg
* Heart rate after 10 minutes supine rest \< 50 or \> 100 bpm
* Any laboratory values with the following deviations at the Screening Visit; test may be repeated at the discretion of the investigator if abnormal:

  * Any positive result on screening for serum hepatitis B surface antigen, hepatitis C antibody, and human immunodeficiency virus (HIV)
  * ALT \> 1.5 × ULN
  * AST \> 1.5 × ULN
  * TBL \> ULN
  * ALP \> 1.5 × ULN
  * WBC \< lower limit of normal (LLN).
  * Haemoglobin \< 12 g/dL in males or \< 11 g/dL in females
  * Platelet count ≤ LLN
  * aPTT \> ULN or Prothrombin Time \> ULN
  * UACR \> 11 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
* QTcF \> 470 ms; high degree atrioventricular (AV)-block grade II-III and sinus node dysfunction with significant sinus pause untreated with pacemaker; and cardiac tachyarrhythmias
* History of drug and/or alcohol abuse or a positive screen for drugs of abuse
* Use of warfarin, direct or indirect thrombin inhibitors or factor Xa inhibitors
* Mipomersen, or lomitapide within 12 months prior to randomisation
* Any fibrate therapy other than fenofibrate; if the participant is on fenofibrate therapy, the dose should be stable for at least 6 weeks prior to randomisation
* Previous administration of AZD8233/AZD6615) or inclisiran (LEQVIO ® Novartis)
* Use of evolocumab (REPATHA® Amgen) and alirocumab (PRALUENT® Regeneron) within 3 months of screening

Primary outcomes:
measure: Percentage Change From Baseline on Serum LDL-C
timeFrame: From baseline to Day 197
measure: Number of Subjects With Adverse Events (AEs)
timeFrame: On-study includes adverse events with an onset date on or after the date of first dose of IP through study competition, planned visit date Day 281.
measure: Vital Signs - Temperature
timeFrame: Baseline, Days 15, 29, 57, 85, 113, 141, 169, 197, 225, and 281.
measure: Vital Sign - Weight
timeFrame: Baseline and Day 281.
measure: Number of Participants With an ECG Determined to be Abnormal and Clinically Significant
timeFrame: Baseline, Days 85, 169, 225, and 281.
measure: Vital Sign - Systolic Blood Pressure
timeFrame: Baseline, Days 15, 29, 57, 85, 113, 141, 169, 197, 225, and 281.
measure: Vital Sign - Diastolic Blood Pressure
timeFrame: Baseline, Days 15, 29, 57, 85, 113, 141, 169, 197, 225, and 281.
measure: Vital Sign - Pulse Rate
timeFrame: Baseline, Days 15, 29, 57, 85, 113, 141, 169, 197, 225, and 281.
measure: Treatment Emergent Platelet Count Abnormalities
timeFrame: Treatment emergent includes results after the first dose of IP through study competition, planned visit date Day 281.
Secondary outcomes:
measure: Percentage Change From Baseline on Serum PCSK9
timeFrame: From baseline to Day 197
measure: Plasma Concentration of AZD8233
timeFrame: Pre-dose of Day 29, Day 85, Day 141, Day 183, Day 197
measure: Anti-drug Antibodies (ADAs) During the Treatment Period and Follow-up Period
timeFrame: Pre-dose of Day 1, Day 29, Day 57, Day 85, Day 113, Day 141, Day 169, Day 197, Day 281
Other outcomes:
Locations:
city: Huntsville
country: United States
facility: Research Site
state: Alabama
city: Canoga Park
country: United States
facility: Research Site
state: California
city: Lincoln
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: Cincinnati
country: United States
facility: Research Site
state: Ohio
city: Stow
country: United States
facility: Research Site
state: Ohio
city: Mount Pleasant
country: United States
facility: Research Site
state: South Carolina
city: Suffolk
country: United States
facility: Research Site
state: Virginia
city: Benesov
country: Czechia
facility: Research Site
city: Brandys nad Labem
country: Czechia
facility: Research Site
city: Brno
country: Czechia
facility: Research Site
city: Jaromer
country: Czechia
facility: Research Site
city: Liberec 2
country: Czechia
facility: Research Site
city: Louny
country: Czechia
facility: Research Site
city: Ostrava-Dubina
country: Czechia
facility: Research Site
city: Pribram
country: Czechia
facility: Research Site
city: Teplice
country: Czechia
facility: Research Site
city: Uherske Hradiste
country: Czechia
facility: Research Site
city: Aarhus N
country: Denmark
facility: Research Site
city: Herlev
country: Denmark
facility: Research Site
city: Herning
country: Denmark
facility: Research Site
city: Hvidovre
country: Denmark
facility: Research Site
city: København NV
country: Denmark
facility: Research Site
city: Roskilde
country: Denmark
facility: Research Site
city: Svendborg
country: Denmark
facility: Research Site
city: Viborg
country: Denmark
facility: Research Site
city: Balatonfüred
country: Hungary
facility: Research Site
city: Békéscsaba
country: Hungary
facility: Research Site
city: Debrecen
country: Hungary
facility: Research Site
city: Orosháza
country: Hungary
facility: Research Site
city: Amsterdam
country: Netherlands
facility: Research Site
city: Doetinchem
country: Netherlands
facility: Research Site
city: Ede
country: Netherlands
facility: Research Site
city: Gouda
country: Netherlands
facility: Research Site
city: Harderwijk
country: Netherlands
facility: Research Site
city: Rotterdam
country: Netherlands
facility: Research Site
city: Bydgoszcz
country: Poland
facility: Research Site
city: Chrzanów
country: Poland
facility: Research Site
city: Kraków
country: Poland
facility: Research Site
city: Puławy
country: Poland
facility: Research Site
city: Ruda Śląska
country: Poland
facility: Research Site
city: Tychy
country: Poland
facility: Research Site
city: Wierzchosławice
country: Poland
facility: Research Site
city: Łódź
country: Poland
facility: Research Site
city: Bratislava
country: Slovakia
facility: Research Site
city: Brezno
country: Slovakia
facility: Research Site
city: Lucenec
country: Slovakia
facility: Research Site
city: Presov
country: Slovakia
facility: Research Site
city: Roznava
country: Slovakia
facility: Research Site
city: Svidnik
country: Slovakia
facility: Research Site
city: Trebišov
country: Slovakia
facility: Research Site
city: Ferrol
country: Spain
facility: Research Site
city: L'Hospitalet de Llobregat
country: Spain
facility: Research Site
city: La Coruña
country: Spain
facility: Research Site
city: Santiago de Compostela
country: Spain
facility: Research Site
city: Sevilla
country: Spain
facility: Research Site
city: Sevilla
country: Spain
facility: Research Site
city: Zaragoza
country: Spain
facility: Research Site
Study officials:
References: