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Trial registered on ANZCTR


Registration number
ACTRN12620001166965p
Ethics application status
Submitted, not yet approved
Date submitted
9/09/2020
Date registered
6/11/2020
Date last updated
6/11/2020
Date data sharing statement initially provided
6/11/2020
Type of registration
Prospectively registered

Titles & IDs
Public title
Do stAtins faVourably modify atherosclerotIc plaque in patients with differeNt levels of polygenic Cardiovascular (CV) rIsk?
Scientific title
Do stAtins faVourably modify atherosclerotIc plaque in patients with differeNt levels of polygenic Cardiovascular (CV) rIsk?
Secondary ID [1] 301762 0
None
Universal Trial Number (UTN)
U111-1255-2472
Trial acronym
DA VINCI
Linked study record

Health condition
Health condition(s) or problem(s) studied:
Cardiovascular disease 318221 0
Coronary atherosclerosis 318222 0
Polygenic risk 318223 0
Condition category
Condition code
Cardiovascular 316234 316234 0 0
Coronary heart disease

Intervention/exposure
Study type
Interventional
Description of intervention(s) / exposure
Participants with established cardiovascular disease, determined through a clinically indicated CT coronary angiogram (CTCA) will be enrolled into the study to evaluate the impact of statin therapy on changes in plaque burden and composition in participants with different polygenic risk scores.
Participants will be randomised to receive atorvastatin 40mg or placebo tablet to be taken orally, once daily for 18months. Participants will be asked to return unused tablets to monitor adherence to the intervention.
They will undergo a second CTCA to determine changes to coronary plaque burden at 18 months.
Intervention code [1] 318057 0
Treatment: Drugs
Comparator / control treatment
Participants randomised to the placebo arm of the trial will receive 40mg equivalent study drug for 18 months. The placebo contains inactive ingredients: calcium carbonate, microcrystalline cellulose, lactose, croscarmellose sodium, polysorbate 80, hydroxypropylcellulose, magnesium stearate, opadry white YS-1-7040 and antifoam emulsion. Tablets do not contain gluten, sucrose or glucose.
Control group
Placebo

Outcomes
Primary outcome [1] 324424 0
The change in non-calcified plaque volume, with Bonferroni correction assessed on changes between baseline and follow up CT coronary angiogram imaging.
Timepoint [1] 324424 0
The outcome will be assessed at 18 months from the baseline CT coronary angiogram.
Secondary outcome [1] 384594 0
Changes in total atheroma volume assessed on CT coronary angiogram.

Timepoint [1] 384594 0
Assessed at 18 months, end of study.
Secondary outcome [2] 387657 0
Changes in calcified plaque volume assessed on CT coronary angiogram.
Timepoint [2] 387657 0
Assessed at 18months, end of study.
Secondary outcome [3] 387658 0
Changes in percent atheroma volume assessed on CT coronary angiogram.
Timepoint [3] 387658 0
Assessed at 18months, at end of study
Secondary outcome [4] 387659 0
Changes in maximum lumen stenosis assessed on CT coronary angiogram.
Timepoint [4] 387659 0
Assessed at 18 months, end of study.
Secondary outcome [5] 387660 0
Changes in Leaman score assessed on CT coronary angiogram.
Timepoint [5] 387660 0
Assessed at 18 months, end of study.
Secondary outcome [6] 387661 0
Changes in fat attenuation index assessed on CT coronary angiogram.
Timepoint [6] 387661 0
Assessed at 18 months, end of study.

Eligibility
Key inclusion criteria
1. Capable of providing written informed consent and willing to adhere to all protocol requirements
2. Male or female 18 years and over
3. Established coronary atherosclerosis on a clinically indicated Computed Tomography Coronary Angiogram (CTCA)
a. Stenosis diameter 20 – 50% in a major epicardial artery
b. Quality of imaging acceptable to imaging core laboratory
4. Low density lipoprotein cholesterol (LDL-C) >1.8mmol/L
5. Able to have a polygenic risk score (PRS) calculated
6. Female participants must not be pregnant, breastfeeding or plan to become pregnant during the study. Female participants of childbearing potential must have a negative urine pregnancy test at the Screening Visit
7. Investigator believes that the participant is willing to adhere to all protocol requirements, including returning for follow up CTCA.
Minimum age
18 Years
Maximum age
No limit
Gender
Both males and females
Can healthy volunteers participate?
No
Key exclusion criteria
1. Unable to provide written informed consent;
2. Unable or unwilling to adhere to all protocol requirements;
3. Requirement for lipid lowering therapy;
4. Hepatic or gall bladder disease;
5. Body mass index >40kg/m2;
6. Known contraindication to statin therapy;
7. Estimated glomerular filtration rate of <60 mL/min calculated using the Chronic Kidney Disease Epidemiology Collaboration equation;
8. Anaemia, defined as haemoglobin concentration <11 g/dL for males and haemoglobin concentration <9 g/dL for females;
9. History of malignancy within the past 5 years, with the exception of non-melanoma skin cancers;
10. Evidence of any other clinically significant non-cardiac disease or condition that, in the opinion of the Investigator, would preclude participation in the study;
11. Already participating in another trial involving the use of a study drug

Study design
Purpose of the study
Treatment
Allocation to intervention
Randomised controlled trial
Procedure for enrolling a subject and allocating the treatment (allocation concealment procedures)
Central randomisation via electronic data capture system.
Methods used to generate the sequence in which subjects will be randomised (sequence generation)
Participants will be grouped into 3 tertiles, low, medium and high based on their polygenic risk score. Randomisation 1:1 will take place within each of these groups.
Masking / blinding
Blinded (masking used)
Who is / are masked / blinded?
The people receiving the treatment/s
The people administering the treatment/s
The people assessing the outcomes
Intervention assignment
Parallel
Other design features
Phase
Phase 2 / Phase 3
Type of endpoint(s)
Efficacy
Statistical methods / analysis
The sample size is based on the primary objective to compare progression rates between participants randomized to atorvastatin or placebo within each PRS stratum, with a Bonferroni adjustment to account for testing in the three PRS strata. Within each PRS strata, we require 86 patients per treatment group to undergo serial, evaluable imaging to provide 80% power to detect a difference in progression of noncalcified plaque volume between groups of 15 mm3, assuming a standard deviation of 30mm3. Assuming 14% of participants will be lost to follow up, 200 patients will be recruited within each PRS stratum (600 patients total).

Baseline characteristics will be summarised descriptively with comparisons between PRS categories and imaging parameters using a t-test (or Mann-Whitney’s U test if not normally distributed). The relationship between PRS and measures of coronary atherosclerosis, pericoronary and epicardial fat will be determined in all patients studied at baseline (n=1000) and for serial progression of these parameters in the combined placebo groups (n=300) using mixed effects regression models. Within each PRS strata, changes in volumetric plaque measures, lumen stenosis and fat attenuation index will be compared between the two treatment groups using analysis of covariance (ANCOVA) with baseline levels as a covariate:

Recruitment
Recruitment status
Not yet 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)
NSW,QLD,SA,WA,VIC
Recruitment hospital [1] 17068 0
Monash Medical Centre - Clayton campus - Clayton
Recruitment hospital [2] 17069 0
Flinders Medical Centre - Bedford Park
Recruitment hospital [3] 17070 0
Royal North Shore Hospital - St Leonards
Recruitment hospital [4] 17071 0
Royal Perth Hospital - Perth
Recruitment hospital [5] 17072 0
Greenslopes Private Hospital - Greenslopes
Recruitment hospital [6] 17073 0
The Wesley Hospital - Auchenflower
Recruitment postcode(s) [1] 30741 0
3168 - Clayton
Recruitment postcode(s) [2] 30742 0
5042 - Bedford Park
Recruitment postcode(s) [3] 30743 0
2065 - St Leonards
Recruitment postcode(s) [4] 30744 0
6000 - Perth
Recruitment postcode(s) [5] 30745 0
4120 - Greenslopes
Recruitment postcode(s) [6] 30746 0
4066 - Auchenflower

Funding & Sponsors
Funding source category [1] 306192 0
Government body
Name [1] 306192 0
Department of Health, Medical Research Future Fund
Address [1] 306192 0
Department of Health
GPO Box 1421
Canberra ACT 2601
Country [1] 306192 0
Australia
Primary sponsor type
University
Name
Monash University
Address
Wellington Road
CLAYTON VIC 3800
Country
Australia
Secondary sponsor category [1] 306667 0
None
Name [1] 306667 0
Address [1] 306667 0
Country [1] 306667 0

Ethics approval
Ethics application status
Submitted, not yet approved
Ethics committee name [1] 306404 0
Monash Health HREC
Ethics committee address [1] 306404 0
246 Clayton Road,
Clayton VIC 3168
Ethics committee country [1] 306404 0
Australia
Date submitted for ethics approval [1] 306404 0
21/10/2020
Approval date [1] 306404 0
Ethics approval number [1] 306404 0

Summary
Brief summary
This study will be a placebo-controlled, double-blind, randomised Phase 2b/3 study in participants with established cardiovascular disease to evaluate the impact of statin therapy on changes in plaque burden and composition in participants with different polygenic risk scores using CT coronary angiogram. The study will take place at ten sites in Australia.
Trial website
Trial related presentations / publications
Public notes

Contacts
Principal investigator
Name 103766 0
Prof Stephen Nicholls
Address 103766 0
C/- Monash University
Wellington Road
CLAYTON VIC 3800
Country 103766 0
Australia
Phone 103766 0
+61 3 9594 2726
Fax 103766 0
Email 103766 0
stephen.nicholls@monash.edu
Contact person for public queries
Name 103767 0
Ms Julie Butters
Address 103767 0
C/- Monash University
Wellington Road
CLAYTON VIC 3800
Country 103767 0
Australia
Phone 103767 0
+61 3 9594 2726
Fax 103767 0
Email 103767 0
julie.butters@monash.edu
Contact person for scientific queries
Name 103768 0
Prof Stephen Nicholls
Address 103768 0
C/- Monash University
Wellington Road
CLAYTON VIC 3800
Country 103768 0
Australia
Phone 103768 0
+61 3 9594 2726
Fax 103768 0
Email 103768 0
stephen.nicholls@monash.edu

Data sharing statement
Will individual participant data (IPD) for this trial be available (including data dictionaries)?
No
No/undecided IPD sharing reason/comment
What supporting documents are/will be available?
No other documents available
Summary results
No Results