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Trial registered on ANZCTR


Registration number
ACTRN12617000401358
Ethics application status
Approved
Date submitted
13/03/2017
Date registered
17/03/2017
Date last updated
28/06/2018
Type of registration
Retrospectively registered

Titles & IDs
Public title
Effect of Alirocumab on Lipoprotein(a) (Lp(a)) Metabolism in Subjects with Moderate to High Risk of Heart Disease
Scientific title
Mechanism of the Effect of Alirocumab on Lipoprotein(a) Metabolism in Subjects with Inherited Elevation in Lipoprotein(a)
Secondary ID [1] 291436 0
LPS14508
Universal Trial Number (UTN)
Nil
Trial acronym
LIPAMAB
Linked study record
Nil

Health condition
Health condition(s) or problem(s) studied:
Cardiovascular Disease (CVD) 302465 0
Condition category
Condition code
Cardiovascular 302029 302029 0 0
Coronary heart disease

Intervention/exposure
Study type
Interventional
Description of intervention(s) / exposure
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.
Intervention code [1] 297480 0
Treatment: Drugs
Comparator / control treatment
Not applicable
Control group
Uncontrolled

Outcomes
Primary outcome [1] 301453 0
Lp(a) plasma levels will be assessed in patients with moderate-to-high risk of CVD

Timepoint [1] 301453 0
Lp(a) levels will be assessed at baseline and at week 18 after intervention commencement

Secondary outcome [1] 332709 0
Very-low density lipoprotein (VLDL) in plasma will be assessed

Timepoint [1] 332709 0
Baseline and at week 18 after intervention commencement

Secondary outcome [2] 332781 0
Intermediate-density lipoprotein (IDL) will be assessed in plasma
Timepoint [2] 332781 0
Baseline and at week 18 (visits 14 & 18) after intervention

Clarification:
After intervention, during week 18, participants visit clinic 5 days in a row (visit 14, 15, 16, 17, and 18). This time point occurs after intervention, during week 18 on visit numbers 14 and 18 (not weeks).
Secondary outcome [3] 332782 0
Low-density lipoprotein (LDL) will be assessed in plasma
Timepoint [3] 332782 0
Baseline and at week 18 (visits 14 & 18) after intervention

Clarification:
After intervention, during week 18, participants visit clinic 5 days in a row (visit 14, 15, 16, 17, and 18). This time point occurs after intervention, during week 18 on visit numbers 14 and 18 (not weeks).
Secondary outcome [4] 332783 0
ApoB-100 concentrations will be assessed in plasma
Timepoint [4] 332783 0
Baseline and at week 18 (visits 14 & 18) after intervention

Clarification:
After intervention, during week 18, participants visit clinic 5 days in a row (visit 14, 15, 16, 17, and 18). This time point occurs after intervention, during week 18 on visit numbers 14 and 18 (not weeks).
Secondary outcome [5] 332784 0
High-density lipoprotein (HDL) will be assessed in plasma
Timepoint [5] 332784 0
Baseline and at week 18 (visits 14 & 18) after intervention

Clarification:
After intervention, during week 18, participants visit clinic 5 days in a row (visit 14, 15, 16, 17, and 18). This time point occurs after intervention, during week 18 on visit numbers 14 and 18 (not weeks).
Secondary outcome [6] 332785 0
Indices of biodiversity of gut microbiota in stool samples will be assessed
Timepoint [6] 332785 0
Baseline and at week 18 (once only on any visit including 15, 16, 17 or 18) after intervention

Clarification:
This time point can occur anytime during week 18, but after visit 14, So, participant would attend clinic 4 days in a row for study visits 15, 16, 17 and 18 after intervention and participants would bring stool sample on one of these visits (not weeks).
Secondary outcome [7] 348668 0
An assessment of the plasma lipid and lipoprotein profile, including Lp(a) and apo(a), 3 – 8 months after the cessation of the intervention trial has been added.
Timepoint [7] 348668 0
Addition of follow-up visit 3 – 8 months after cessation of the intervention trial

Eligibility
Key inclusion criteria
1. Caucasian and non-caucasian
2. Aged 18-75 years inclusive, male or female
3. 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
4. Participants will be of stable weight and maintaining a guideline recommended heart healthy diet (lower saturated fat, higher complex carbohydrate and lower salt content)
5. 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
Minimum age
18 Years
Maximum age
75 Years
Gender
Both males and females
Can healthy volunteers participate?
No
Key exclusion criteria
1. Cardiovascular events in the past 6-months
2. History of venous thromboembolism and/or pulmonary embolism
3. Low-density lipoprotein cholesterol equal to or less than 1.0 mmol/L
4. Participation in another clinical trial involving a PCSK9 monoclonal antibody
5. Type 1 Diabetes Mellitus
6. Type 2 Diabetes Mellitus
7. Secondary hyperlipidaemia
8. Renal disease (creatinine >130 micro mol/L, including proteinuria, nephrotic syndrome)
9. Hepatic dysfunction (AST or ALT > 5x ULN)
10. Current anaemia or past history of significant anaemia e.g. haemolytic anaemia (Hb must be >125 g/L to be eligible)
11. Haematological disorders
12. Recent history of haemorrhage or donation of blood within the 3 months prior to screening
13. Women who are on hormone replacement therapy
14. Positive laboratory screening result for HIV, Hepatitis B or C
15. Current smoker
16. Psychiatric illness (participants who are stable on treatment for depression or anxiety are eligible)
17. Alcohol excess (>30 g/day)
18. Hypersensitivity or contraindicating co-morbidities to Aspirin
19. 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)
20. Active auto-immune or vasculitic disorders
21. Likelihood of not completing the study as per judgement of investigator
22. Of Japanese and South East Asian decent
23. Women who are pregnant and / or not using a highly effective method of contraception
24. People highly dependent on medical care (i.e. unstable clinical status requiring frequent ambulatory or inpatient care)
25. People with a cognitive impairment, an intellectual disability or a mental illness
26. People whose primary language is other than English (LOTE) who will not be able to provide informed consent
27. Known hypersensitivity to monoclonal antibody or any component of the drug product
28. Donated blood within 3 months prior to Day 1


Study design
Purpose of the study
Treatment
Allocation to intervention
Non-randomised trial
Procedure for enrolling a subject and allocating the treatment (allocation concealment procedures)
Not applicable
Methods used to generate the sequence in which subjects will be randomised (sequence generation)
Not applicable
Masking / blinding
Open (masking not used)
Who is / are masked / blinded?



Intervention assignment
Single group
Other design features
Not applicable
Phase
Phase 2
Type of endpoint(s)
Pharmacodynamics
Statistical methods / analysis
Data at the end of the treatment period will be compared using paired t-tests. Between-group comparisons will be performed using independent t-tests. Associations between kinetics of Lp(a) and its protein components, apo(a) and apoB-100, and lipoproteins (e.g. VLDL, IDL and LDL), and other metabolic parameters will be examined using simple and multiple linear regression methods employing causal models based on a priori hypothesis and variables that are significant at p<0.05 in univariate analysis. Statistical significance will be defined at the 5% level using a 2-tailed test.

Sample Size:
Sample size calculations are based on the effect of Alirocumab on Lp(a)-apoB-100 PR. We assume that the reduction in Lp(a)-apoB-100 concentrations is chiefly reflected by the corresponding decrease in Lp(a)-apoB-100 PR. Data from Stein et al (Lancet 2012; 380:29) suggest that a sample size of 15 will give the study 95% power to detect a significant decrease in the PR of Lp(a)-apoB-100 with Alirocumab (n=15 23.2%, SD 20%). We will, however, recruit 21 patients to take into account a potential dropout of 20%. Of note, the investigators have a large database of subjects with a wide-range of plasma Lp(a) concentrations. Participants will be replaced to maintain a sample size of 15.

Statistical significance will be defined at the 5% level using a 2-tailed test.

Recruitment
Recruitment status
Recruiting
Date of first participant enrolment
Anticipated
Actual
Date of last participant enrolment
Anticipated
Actual
Date of last data collection
Anticipated
Actual
Sample size
Target
Accrual to date
Final
Recruitment in Australia
Recruitment state(s)
WA
Recruitment hospital [1] 7660 0
Linear Clinical Research - Nedlands
Recruitment postcode(s) [1] 15579 0
6009 - Nedlands

Funding & Sponsors
Funding source category [1] 295904 0
Commercial sector/Industry
Name [1] 295904 0
Regeneron Pharmaceuticals Inc
Address [1] 295904 0
777 Old Saw River Rd
Tarrytown
NY 10591
Country [1] 295904 0
United States of America
Primary sponsor type
Commercial sector/Industry
Name
Linear Clinical Research Ltd.
Address
Level 1, B Block
Hospital Avenue
Nedlands, WA 6009
Country
Australia
Secondary sponsor category [1] 294777 0
None
Name [1] 294777 0
None
Address [1] 294777 0
Not applicable
Country [1] 294777 0

Ethics approval
Ethics application status
Approved
Ethics committee name [1] 297185 0
Bellberry Human Research Ethics Comittee
Ethics committee address [1] 297185 0
129 Glen Osmond Road
Eastwood
SA 5063
Ethics committee country [1] 297185 0
Australia
Date submitted for ethics approval [1] 297185 0
10/08/2016
Approval date [1] 297185 0
11/10/2016
Ethics approval number [1] 297185 0
2016-08-622

Summary
Brief 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
Trial website
None
Trial related presentations / publications
None
Public notes
None

Contacts
Principal investigator
Name 73262 0
Prof Gerald Watts
Address 73262 0
Work Organisation Address:
School of Medicine and Pharmacology Royal Perth Hospital Unit
The University of Western Australia (M570)
35 Stirling Highway
CRAWLEY WA 6009
AUSTRALIA
Country 73262 0
Australia
Phone 73262 0
+61 8 9224 0248
Fax 73262 0
+61 8 9224 0246
Email 73262 0
gerald.watts@uwa.edu.au
Contact person for public queries
Name 73263 0
Prof Gerald Watts
Address 73263 0
Work Organisation Address:
School of Medicine and Pharmacology Royal Perth Hospital Unit
The University of Western Australia (M570)
35 Stirling Highway
CRAWLEY WA 6009
AUSTRALIA
Country 73263 0
Australia
Phone 73263 0
+61 8 63825100
Fax 73263 0
+61 8 9381 2578
Email 73263 0
gerald.watts@uwa.edu.au
Contact person for scientific queries
Name 73264 0
Prof Gerald Watts
Address 73264 0
Work Organisation Address:
School of Medicine and Pharmacology Royal Perth Hospital Unit
The University of Western Australia (M570)
35 Stirling Highway
CRAWLEY WA 6009
AUSTRALIA
Country 73264 0
Australia
Phone 73264 0
+61 8 63825100
Fax 73264 0
+61 8 9381 2578
Email 73264 0
gerald.watts@uwa.edu.au

No data has been provided for results reporting
Summary results
Not applicable