Vitamin K therapy to improve vascular health in patients with chronic kidney disease

Plain English Summary

Background and study aims
Chronic kidney disease is a long-term medical condition where the kidneys do work properly. It is a common disease, and particularly so in older people. Kidney problems affect the kidney, and also the health of blood vessels and the heart, leading to an increased risk of heart disease or strokes. Kidney problems lead to blood vessels becoming stiffer than usual, due to a build-up of calcium in the wall of the blood vessel. So finding ways to stop or reverse this stiffening of the blood vessels is really important, and we don’t have good treatments for this problem at the moment. Some recent research suggests that vitamin K—a vitamin present in vegetables and dairy foods—might be able to slow down or stop this build-up of calcium in blood vessels. Before we can recommend this as a treatment though, it is important that giving extra vitamin K is tested properly in controlled trials such as this one.

Who can participate?
Patients with chronic kidney disease (stages 3b and 4 - so does not include those on dialysis)

What does the study involve?
Participants are randomly allocated into one of two groups. One group takes 400mcg of vitamin K once a day. The other group takes a placebo once a day. Each participant is asked to go to their study centre first for a screening visit, to see whether they are suitable for the study. They then visit the centre a further three times – at the start of the study, 6 months later and, finally, 12 months later. They undergo a number of tests during these visits including blood pressure measurements when lying down and when stood up, walking speed, strength and balance tests and an x-ray of their abdomen. Investigators also take samples of blood and ask participants to provide a urine sample. A small pencil-like device is also placed over the blood vessel of each participant to measure their pulse to test how stiff their blood vessels are. The electrical activity of their heart is also monitored with a heart tracing. At the end of each visit, participants are asked to take home a diary to record any falls they might have over the next six months. They are also given a blood pressure cuff to wear for the next 24 hours and a supply of the study medication they have been allocated to receive.

What are the possible benefits and risks of participating?
This dose of vitamin K has been used before and is known to be safe but as with all medications there is a small possibility of side effects. These can include sickness, diarrhoea and dizziness. Having blood taken can cause some bruising. The blood pressure cuff causes mild discomfort to some people. We allow participants to have plenty of rest in between the walking and strength tests so that they are not made overly tired by the tests.

Where is the study run from?
University of Dundee and the University of Glasgow, Scotland (UK)

When is the study starting and how long is it expected to run for?
June 2015 to August 2017

Who is funding the study?
The British Heart Foundation (UK)

Who is the main contact?
Dr Miles Witham
m.witham@dundee.ac.uk

Trial website

Type

Public

Primary contact

Dr Miles Witham

ORCID ID

Contact details

Ninewells Hospital and Medical School
Ageing and Health Division of Medicine and Therapeutics
Ninewells Avenue
Dundee
DD1 9SY
United Kingdom
01382 383086
Miles.Witham@newcastle.ac.uk

Type

Scientific

Additional contact

Dr Miles Witham

ORCID ID

Contact details

Ninewells Hospital and Medical School
Ageing and Health Division of Medicine and Therapeutics
Ninewells Avenue
Dundee
DD1 9SY
United Kingdom

EudraCT number

ClinicalTrials.gov number

Protocol/serial number

2014CV03

Scientific title

Vitamin K therapy to improve vascular health in patients with chronic kidney disease: a randomised controlled trial

Acronym

K4Kidneys

Study hypothesis

That 1 year of vitamin K2 supplementation (400mcg per day) improves pulse wave velocity compared to placebo in patients with CKD stages 3b and 4

Ethics approval

East of Scotland Research Ethics Committee, 16/06/2015, approval number: 15/ES/0085

Study design

Two-centre parallel-group placebo-controlled randomised trial

Primary study design

Interventional

Secondary study design

Randomised controlled trial

Trial setting

Other

Trial type

Treatment

Patient information sheet

Not available in web format; please use contact details to request a patient information sheet

Condition

Chronic kidney disease stages 3b and 4

Intervention

400 mcg once daily oral vitamin K2 (MK7 subtype) vs matching placebo

Intervention type

Supplement

Phase

Drug names

Primary outcome measure

Between-group difference in carotid-femoral pulse wave velocity (PWV) at 12 months using the Sphygmocor system

Secondary outcome measures

All measured at 0,6 and 12 months except for aortic radiography:

1. Vascular health:
1.1. Office and 24 hour blood pressure
1.2. B-type natriuretic peptide
1.3. Central systolic blood pressure and augmentation index derived from applanation tonometry at the radial artery using the Sphygmocor system.
1.4. Pulse wave velocity at 6 months (in addition to the primary outcome measured at 12 months)
2. Insulin and glucose levels to calculate insulin resistance using HOMA-IR
3. Marker of effect of vitamin K: dp-ucMGP levels.
4. Calcium and bone metabolism and turnover:
4.1. Osteocalcin
4.2. Tartrate resistant acid phosphatase-5b
4.3. Parathyroid hormone
4.4. Fetuin
4.5. Fibroblast growth factor-23
4.6. 25-hydroxyvitamin D
4.7. 1,25-hydroxyvitamin D
5. Renal function: We will measure serum creatinine, and urinary protein/creatinine ratio on a spot urine sample at each timepoint
6. Radiological calcification: We will perform lateral abdominal radiography at baseline and 12 months to assess aortic calcification.
7. Physical function:
7.1. Short physical performance battery
7.2 Grip strength at each timepoint
7.3. Monthly falls diary to prospectively record falls

Overall trial start date

01/06/2015

Overall trial end date

31/03/2019

Reason abandoned (if study stopped)

Participant inclusion criteria

1. Age >18 years
2. CKD stages 3b or 4 (eGFR of >15 ml/min and <45 ml/min by MDRD4 equation)

Participant type

Patient

Age group

Adult

Gender

Both

Target number of participants

166

Total final enrolment

159

Participant exclusion criteria

1. Atrial fibrillation
2. Taking warfarin (which antagonises vitamin K) or other coumadin derivatives.
3. Taking vitamin K
4. Unable to give written informed consent
5. Currently enrolled in another trial, or within 30 days of completing another trial
6. Pregnant or (if female and pre-menopausal) not using reliable contraception

Recruitment start date

01/06/2015

Recruitment end date

31/05/2016

Countries of recruitment

United Kingdom

Trial participating centre

Ninewells Hospital and Medical School
Ageing and Health Division of Medicine and Therapeutics Ninewells Avenue
Dundee
DD1 9SY
United Kingdom

Trial participating centre

University of Glasgow
Institute of Cardiovascular and Medical Sciences
Glasgow
G12 8TA
United Kingdom

Organisation

Tayside Academic Science Centre (NHS Tayside and University of Dundee)

Sponsor details

TASC
Level 3
Ninewells Hospital
Dundee
DD1 9SY
United Kingdom
01382 383900
tasctayside@nhs.net

Sponsor type

University/education

Website

http://www.ahspartnership.org.uk/

Funder type

Research organisation

Funder name

British Heart Foundation

Alternative name(s)

BHF

Funding Body Type

unknown

Funding Body Subtype

Location

Publication and dissemination plan

To be confirmed at a later date

IPD sharing statement:
The datasets generated during and/or analysed during the current study are available from the corresponding author on reasonable request. Anonymised, individual-participant data from the current study will be available to bona-fide researchers upon request from Professor Miles Witham (Miles.Witham@newcastle.ac.uk), subject to submission of a data access request outlining the planned analysis, purpose of the analysis, data required and publication plan, and subject to approval by the Sponsor

Intention to publish date

30/09/2019

Participant level data

Available on request

Basic results (scientific)

See additional file ISRCTN21444964_BasicResults_27Sep19.pdf

Publication list

2020 results in https://pubmed.ncbi.nlm.nih.gov/32817311/ (added 24/08/2020)

Publication citations

• ISRCTN21444964_BasicResults_27Sep19.pdf Uploaded 27/09/2019

24/08/2020: Publication reference and total final enrolment number added. 30/09/2019: The IPD sharing statement was added to the publication and dissemination plan. 27/09/2019: The basic results of this trial have been uploaded as an additional file. 17/06/2019: An intention to publish date has been added. 10/06/2019: Dr Miles Witham's email address has been updated. 03/09/2018: The overall trial end date was updated from 31/08/2017 to 31/03/2019. 05/04/2016: Ethics approval information added.