To assess the safety and tolerability of AZD8233 as compared with placebo in participants with hyperlipidaemia receiving maximally tolerated statin and/or ezetimibe therapy as defined by the investigator.
ID
Source
Brief title
Condition
- Cardiac disorders, signs and symptoms NEC
- Lipid metabolism disorders
- Arteriosclerosis, stenosis, vascular insufficiency and necrosis
Synonym
Research involving
Sponsors and support
Intervention
Outcome measures
Primary outcome
- Primary safety and tolerability will be evaluated in terms of AEs, vital
signs, ECG, and clinical laboratory evaluations, including platelet count.
- Primary efficacy will be evaluated in terms of the relative change in serum
LDL-C from baseline to the end of Week 28.
Secondary outcome
- Secondary efficacy will be evaluated in terms of the relative change in PCSK9
from baseline to the end of Week 28.
- Secondary PK: Model population PK parameters to be reported in a separate
report
- Secondary immunogenicity: Development of ADA (anti-drug antibodies) and titre
(if participants are ADA positive) during treatment and follow-up
Background summary
Elevated plasma LDL-C, is a main risk factor for cardiovascular disease and is
typically caused by a combination of environmental and genetic factors. Statin
therapy is the standard lipid lowering medication for both primary and
secondary prevention of cardiovascular disease. Reduction of LDL-C by statins
leads to a significant reduction in cardiovascular events. Statins reduce LDL-C
by inhibiting HMG CoA reductase, the rate limiting enzyme of hepatic
cholesterol synthesis. However, despite the substantial benefits of statin
therapy, many patients do not reach LDL-C target goals.
Genetic studies have identified PCSK9 as an important HMG-CoA-independent
circulating regulator of LDL-C. Circulating PCSK9 is derived mainly from the
liver and increases LDL-C by promoting degradation of hepatic LDL receptors.
Gain of function mutations in PCSK9 cause familial dominant
hypercholesterolemia; loss of function is associated with low circulating
levels of LDL-C and a reduced risk of major vascular events.
Based on the significant clinical benefit of PCSK9 inhibition, AstraZeneca is
developing a human PCSK9-targeted, GalNAc conjugated ASO that specifically
inhibits PCSK9 expression in the liver. Severe, reversible thrombocytopenia has
been observed in some ASO programs in clinical trials, but it is not known
whether all members of the class have this characteristic (Crooke et al 2017).
This study will evaluate platelet count, over time, in AZD8233-treated
participants with hyperlipidaemia, receiving maximally tolerated statin and/or
ezetimibe therapy, compared with placebo. The aim of the study is to see if any
thrombocytopenia signal is observed, and whether it is feasible to reduce
platelet monitoring frequency and maintain patient safety. AZD8233 may provide
novel treatment options for patients with hyperlipidaemia.
Study objective
To assess the safety and tolerability of AZD8233 as compared with placebo in
participants with hyperlipidaemia receiving maximally tolerated statin and/or
ezetimibe therapy as defined by the investigator.
Study design
This is a randomised parallel, double blind, placebo controlled Phase 2b study
to evaluate the safety and tolerability of AZD8233 as compared with placebo.
The study is planned to be carried out across approximately 100 clinical sites
in around 8 countries. Approximately 376 participants with hyperlipidaemia will
be randomly assigned to AZD8233 60 mg or matching placebo in a 1:1 ratio.
Participants will be treated with AZD8233 or placebo SC, Q4W for 28 weeks, to
provide data to guide platelet monitoring for future programs. The aim is that,
of the participants randomised to AZD8233 doses, at least 150 should complete
the 28 weeks of planned treatment. The effect of AZD8233 60 mg, administered
SC, Q4W for 28 weeks, on concentrations of LDL-C in serum will also be
evaluated.
There will be an initial screening period starting up to 28 days before and
ending on the day before the randomisation visit (ie, Day -1). The study is
divided into a planned treatment period of 28 weeks followed by a safety
follow-up of 12 weeks. Overall, this makes a total study participation time of
40 weeks once participants are randomly assigned into the trial.
Intervention
The intervention group receives AZD8233 60 mg, administered SC, Q4W for 28
weeks. The placebo group receives placebo, administered SC, Q4W for 28 weeks.
Study burden and risks
Potential risks of AZD8233 are as follows: (please refer to Clinical Study
Protocol Table 2 for complete overview and mitigation strategy)
- Thrombocytopenia
- Kidney injury
- Liver Toxicity - Transaminase Elevations
- Anti-drug Antibodies
- Injection Site Reactions
- Complement Activation
- Inhibition of Intrinsic Coagulation Pathway
- Hypersensitivity and Anaphylactic Reaction
- Flu-like Reactions
- Pain near SC injection site
AZD8233 is expected to lower circulating PCSK9 in this study in all
AZD8233-treated participants (see Protocol Section 4.3). Pharmacologic
inhibition of PCSK9 is known to increase catabolism of LDL-C and reduce
circulating LDL-C. Low levels of LDL-C are associated with a lower risk of
incident atherosclerotic CVD events, providing an important clinical benefit to
individuals with hyperlipidaemia. A detailed description of the chemistry,
pharmacology, efficacy, and safety of AZD8233 is provided in the IB.
Taking into account the measures taken to minimize risk to participants
participating in this study, the potential risks identified in association with
AZD8233 are justified by the anticipated benefits that may be afforded to
participants with hyperlipidaemia. Furthermore, findings from this study may
serve to ameliorate the perception of risk potentially associated with AZD8233
around thrombocytopenia and guide recommendations for monitoring.
Prinses Beatrixlaan 582
Den Haag 2595BM
NL
Prinses Beatrixlaan 582
Den Haag 2595BM
NL
Listed location countries
Age
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 at screening
- 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
Design
Recruitment
Followed up by the following (possibly more current) registration
No registrations found.
Other (possibly less up-to-date) registrations in this register
No registrations found.
In other registers
| Register | ID |
|---|---|
| EudraCT | EUCTR2020-005845-18-NL |
| CCMO | NL77542.000.21 |