Trial Review

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Trial registered on ANZCTR


Registration number
ACTRN12622000447752
Ethics application status
Approved
Date submitted
11/03/2022
Date registered
21/03/2022
Date last updated
10/05/2024
Date data sharing statement initially provided
21/03/2022
Type of registration
Prospectively registered

Titles & IDs
Public title
Evaluating the effects of Vitamin K supplements on Aortic Stenosis
Scientific title
A randomised trial evaluating the effect of phylloquinone on the progression of mild to moderate aortic stenosis
Secondary ID [1] 306060 0
Nil
Universal Trial Number (UTN)
Trial acronym
PASSPORT
Linked study record

Health condition
Health condition(s) or problem(s) studied:
Calcific Aortic Stenosis 324708 0
Condition category
Condition code
Cardiovascular 322156 322156 0 0
Other cardiovascular diseases
Cardiovascular 323008 323008 0 0
Diseases of the vasculature and circulation including the lymphatic system

Intervention/exposure
Study type
Interventional
Description of intervention(s) / exposure
Vitamin-K1 10 mg oral capsules, daily for minimum 12 months (last in) and up to 21 months (first in) with median duration 16 months.

Participants will receive their randomised treatments in 3-month allocations. Every 3 months existing treatments will be returned. Adherence will be assessed by pill counts and completion of the Morisky scale.
Intervention code [1] 322468 0
Prevention
Intervention code [2] 322469 0
Treatment: Other
Comparator / control treatment
Matched placebo capsules (micro-cellulose, Optima Ovest Ltd), taken orally, daily for minimum 12 months (last in) and up to 21 months (first in) with median duration 16 months.
Control group
Placebo

Outcomes
Primary outcome [1] 329924 0
Difference in aortic valve calcification volume measured on CT-calcium score scans at baseline and final follow-up visit.
Timepoint [1] 329924 0
Final follow-up visit will be between 12-21 months (median 16 months) post baseline.
Secondary outcome [1] 404307 0
Change in aortic valve peak flow velocity measured by transthoracic echocardiography.
Timepoint [1] 404307 0
Final follow-up visit will be between 12-21 months (median 16 months) post baseline.
Secondary outcome [2] 407501 0
Change in aortic valve mean flow velocity measured by transthoracic echocardiography.
Timepoint [2] 407501 0
Final follow-up visit will be between 12-21 months (median 16 months) post baseline.
Secondary outcome [3] 407502 0
Change in aortic valve peak gradient measured by transthoracic echocardiography.
Timepoint [3] 407502 0
Final follow-up visit will be between 12-21 months (median 16 months) post baseline.
Secondary outcome [4] 407503 0
Change in aortic valve mean gradient measured by transthoracic echocardiography.
Timepoint [4] 407503 0
Final follow-up visit will be between 12-21 months (median 16 months) post baseline.
Secondary outcome [5] 407504 0
Change in aortic valve area measured by transthoracic echocardiography.
Timepoint [5] 407504 0
Final follow-up visit will be between 12-21 months (median 16 months) post baseline.
Secondary outcome [6] 407505 0
Change in aortic valve dimensionless index measured by transthoracic echocardiography.
Timepoint [6] 407505 0
Final follow-up visit will be between 12-21 months (median 16 months) post baseline.
Secondary outcome [7] 407506 0
Change in left ventricular mass as measured by transthoracic echocardiography.
Timepoint [7] 407506 0
Final follow-up visit will be between 12-21 months (median 16 months) post baseline.

Eligibility
Key inclusion criteria
1) Aged 18+ years
2) Mild to moderate calcific aortic stenosis (peak flow velocity greater than 2.5m/s and less than 4m/s)
3) Valve area greater than 1 cm2
4) At least mild aortic valve calcification (Rosenhek category=1) on echocardiography.
Minimum age
18 Years
Maximum age
No limit
Sex
Both males and females
Can healthy volunteers participate?
No
Key exclusion criteria
1) Planned procedure to unblock heart arteries
2) Clinically important disease of any heart valve
3) Kidney disease (eGFR<40ml/min)
4) Intolerance to Vitamin-K
5) Prescribed a Vitamin-K blocker or supplement
6) Heart rhythm disturbance preventing a good quality CT-calcium score scan
7) Pregnancy
8) Unlikely to complete the 12 months follow-up.

Study design
Purpose of the study
Prevention
Allocation to intervention
Randomised controlled trial
Procedure for enrolling a subject and allocating the treatment (allocation concealment procedures)
Allocation will be concealed and randomised allocation will be via central computer interface.

Subjects, referring physicians and study personnel assessing outcomes will be blinded to treatment allocation.
Methods used to generate the sequence in which subjects will be randomised (sequence generation)
Computer generated random allocation to one of two groups in a 1:1 ratio. Randomisation will incorporate block sizes of 2 or 4 and will be stratified by stenosis grade (mild vs moderate).
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
The people analysing the results/data
Intervention assignment
Parallel
Other design features
Phase
Not Applicable
Type of endpoint/s
Efficacy
Statistical methods / analysis
Fifty-four subjects per study arm (total 108) will have 90% power to detect a 57% difference between progression in AVC of 181µL in controls vs 78µL for active treatment with a common standard deviation of 165; 80% power to detect a 49% difference; and 70% power to detect a 40% difference, at a significance level of 5%.
Power will be augmented by 1) increasing follow up duration to median of 16 months: Each subject will receive the final CT-scan after minimum 12 months and within the final 3 months of year-2 (range from 12 to 21 months); and 2) by excluding patients with aortic sclerosis (35% of the Brandenburg study population) who have a very low rate of progression to CAS.

Allowance for a dropout of up to 25% would retain 80% power. The study will also be able to detect a 10% difference in peak flow velocity with an alpha of 0.05 and beta of 0.80.

The primary intention to treat analysis will compare the change in aortic valve calcification (AVC) from baseline to study end using a repeated measures general linear model with final AVC as outcome and baseline AVC as covariate (last measurement carried forward for missing values). Sensitivity analyses will include subjects who completed follow up.

Recruitment
Recruitment status
Recruiting
Date of first participant enrolment
Anticipated
1/07/2022
Actual
1/07/2023
Date of last participant enrolment
Anticipated
1/07/2024
Actual
Date of last data collection
Anticipated
30/06/2025
Actual
Sample size
Target
108
Accrual to date
83
Final
Recruitment in Australia
Recruitment state(s)
WA
Recruitment hospital [1] 21347 0
Royal Perth Hospital - Perth
Recruitment postcode(s) [1] 36238 0
6000 - Perth

Funding & Sponsors
Funding source category [1] 310397 0
Charities/Societies/Foundations
Name [1] 310397 0
National Heart Foundation
Country [1] 310397 0
Australia
Primary sponsor type
University
Name
University of Western Australia
Address
35 Stirling Highway
Crawley WA 6009
Country
Australia
Secondary sponsor category [1] 311546 0
None
Name [1] 311546 0
Address [1] 311546 0
Country [1] 311546 0

Ethics approval
Ethics application status
Approved
Ethics committee name [1] 310045 0
Royal Perth Hospital Human Research Ethics Committee
Ethics committee address [1] 310045 0
East Metropolitan Health Service Executive
Level 2, Kirkman House
198 Wellington Street
Perth Western Australia 6000
Ethics committee country [1] 310045 0
Australia
Date submitted for ethics approval [1] 310045 0
17/11/2021
Approval date [1] 310045 0
30/12/2021
Ethics approval number [1] 310045 0
RGS0000005161

Summary
Brief summary
Calcific aortic stenosis is a condition in which build-up of calcium on the aortic valve, located at the outflow of the heart, progressively blocks blood flow to the organs and can cause debilitating symptoms and very poor survival. Timely replacement of the valve can be lifesaving but comes with significant risks and at high cost. The incidence is increasing in Australia. Until now there have been no treatments that can prevent the progressive obstruction of the aortic valve. Our pilot study showed that supplementation of Vitamin-K, 10mg per day is safe and can prevent all early types of calcification in the arteries. The double-blind, randomised, placebo-controlled PASSPORT trial will test whether Vitamin-K can slow or prevent the calcium build-up and obstruction of the aortic valve. 108 subjects with mild or moderate aortic stenosis on echocardiography will be randomised to Vitamin K1 10mg per day or matching placebo for a median duration of 16 months (range 12-21 months). All subjects will receive an echocardiogram and non-contrast CT-calcium score at baseline and at the end of the trial. The primary end point will be progression in aortic valve calcium score on CT scans and secondary outcomes will be progression of flow obstruction parameters as assessed by echocardiography.
Trial website
Trial related presentations / publications
Public notes

Contacts
Principal investigator
Name 116298 0
Prof Carl Schultz
Address 116298 0
Department of Cardiology
Level 4, South Block
Royal Perth Hospital
197 Wellington Street
Perth, WA, 6000
Country 116298 0
Australia
Phone 116298 0
+61 08 92242244
Fax 116298 0
Email 116298 0
carl.schultz@health.wa.gov.au
Contact person for public queries
Name 116299 0
Prof Carl Schultz
Address 116299 0
Department of Cardiology
Level 4, South Block
Royal Perth Hospital
197 Wellington Street
Perth, WA, 6000
Country 116299 0
Australia
Phone 116299 0
+61 08 92242244
Fax 116299 0
Email 116299 0
carl.schultz@health.wa.gov.au
Contact person for scientific queries
Name 116300 0
Prof Carl Schultz
Address 116300 0
Department of Cardiology
Level 4, South Block
Royal Perth Hospital
197 Wellington Street
Perth, WA, 6000
Country 116300 0
Australia
Phone 116300 0
+61 08 92242244
Fax 116300 0
Email 116300 0
carl.schultz@health.wa.gov.au

Data sharing statement
Will individual participant data (IPD) for this trial be available (including data dictionaries)?
No
No/undecided IPD sharing reason/comment
No decision has been made


What supporting documents are/will be available?

No Supporting Document Provided



Results publications and other study-related documents

Documents added manually
No documents have been uploaded by study researchers.

Documents added automatically
No additional documents have been identified.