CompletedPhase 2ACTRN12617000401358

Effect of Alirocumab on Lipoprotein(a) (Lp(a)) Metabolism in Subjects with Moderate to High Risk of Heart Disease

Mechanism of the Effect of Alirocumab on Lipoprotein(a) Metabolism in Subjects with Inherited Elevation in Lipoprotein(a)

Sponsor

Linear Clinical Research Ltd.

Enrollment

21 participants

Start Date

Jan 11, 2017

Study Type

Interventional

Conditions

Cardiovascular Disease (CVD)

Summary

Primary Objective: To describe and determine the mechanism by which a proprotein convertase subtilisin/kexin type 9 (PCSK9) inhibitor alters the kinetics of Lp(a) and its protein components, as well as the concentrations and kinetics of apoB-100 containing lipoproteins in statin-treated patients with inherited high plasma Lp(a) who are at moderate-to-high risk of cardiovascular disease (CVD). Hypothesis: Inhibition of PCSK9 increases apoB-100 catabolism and decreases hepatic secretion of apoB-100, and hence, the pool of apoB-100 available for binding to apo(a), resulting in a decrease in the production and plasma concentrations of Lp(a). Study Design: A 12-week (treatment period) single-arm, open-label, pre- and post-designed pilot study of the effect of Alirocumab (two-weekly subcutaneously injected dose of 150 mg) on plasma Lp(a) concentration and metabolism in 21 patients with inherited high plasma Lp(a). The CVD risk (low or moderate-to-high) of participants will be determined based on the Australian National Vascular Disease Prevention Alliance (NVDPA) Guidelines for management of absolute cardiovascular disease risk. Participant Numbers: N=21 participants to complete the study

Eligibility

Sex: Both males and femalesMin Age: 18 YearssMax Age: 75 Yearss

Inclusion Criteria6

Caucasian and non-caucasian
Aged 18-75 years inclusive, male or female
Men and women on maximally tolerated high potency stains with elevated plasma Lp(a) concentrations [equal or more than 0.6 g/L] who have moderate-to-high cardiovascular disease (CVD) risk based on the Australian National Vascular Disease Prevention Alliance (NVDPA) Guidelines for management of absolute cardiovascular disease risk (including documented and/or family history of CVD or CVD risk equivalent including documented history of other clinical atherosclerotic disease(s) i.e. peripheral artery disease, clinically significant carotid artery disease, abdominal aortic aneurysm)
For the purposes of this project, documented CVD includes: documentation of a history of myocardial infarction [MI], coronary artery bypass graft surgery, percutaneous transluminal coronary angioplasty, or alternative revascularization procedure [e.g. atherectomy/stent], coronary artery disease documented by exercise or non-exercise stress test and/or clinically significant carotid artery disease documented by angiography, carotid ultrasonography, or any other accepted cardiac computed imaging technique
Participants will be of stable weight and maintaining a guideline recommended heart healthy diet (lower saturated fat, higher complex carbohydrate and lower salt content)
Participants will be on concurrent aspirin therapy, 75 mg – 300 mg orally once daily, for at least one week prior to Day 1 and continue for the duration of the study

Exclusion Criteria28

Cardiovascular events in the past 6-months
History of venous thromboembolism and/or pulmonary embolism
Low-density lipoprotein cholesterol equal to or less than 1.0 mmol/L
Participation in another clinical trial involving a PCSK9 monoclonal antibody
Type 1 Diabetes Mellitus
Type 2 Diabetes Mellitus
Secondary hyperlipidaemia
Renal disease (creatinine >130 micro mol/L, including proteinuria, nephrotic syndrome)
Hepatic dysfunction (AST or ALT > 5x ULN)
Current anaemia or past history of significant anaemia e.g. haemolytic anaemia (Hb must be >125 g/L to be eligible)
Haematological disorders
Recent history of haemorrhage or donation of blood within the 3 months prior to screening
Women who are on hormone replacement therapy
Positive laboratory screening result for HIV, Hepatitis B or C
Current smoker
Psychiatric illness (participants who are stable on treatment for depression or anxiety are eligible)
Alcohol excess (>30 g/day)
Hypersensitivity or contraindicating co-morbidities to Aspirin
Lipid-lowering therapies that are known to have major effects on plasma Lp(a) levels e.g. niacin, high dose fish oils (equal or more than 4 g/day)
Active auto-immune or vasculitic disorders
Likelihood of not completing the study as per judgement of investigator
Of Japanese and South East Asian decent
Women who are pregnant and / or not using a highly effective method of contraception
People highly dependent on medical care (i.e. unstable clinical status requiring frequent ambulatory or inpatient care)
People with a cognitive impairment, an intellectual disability or a mental illness
People whose primary language is other than English (LOTE) who will not be able to provide informed consent
Known hypersensitivity to monoclonal antibody or any component of the drug product
Donated blood within 3 months prior to Day 1

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Interventions

A 12-week (treatment period) single-arm, open-label, pre- and post-designed pilot study of the effect of Alirocumab (two-weekly subcutaneously injected dose of 150 mg for a total of 6 doses) on plasma Lp(a) concentration and metabolism in 21 patients with inherited high plasma Lp(a). The CVD risk (low or moderate-to-high) of participants will be determined based on the Australian National Vascular Disease Prevention Alliance (NVDPA) Guidelines for management of absolute cardiovascular disease risk.