VASO (Vitamin D and Arthroplasty Surgery Outcomes) study - supplementation of vitamin D deficiency to improve outcomes after total hip or knee replacement: study protocol for a randomised controlled feasibility trial
Morrison et al. Trials
VASO (Vitamin D and Arthroplasty Surgery Outcomes) study - supplementation of vitamin D deficiency to improve outcomes after total hip or knee replacement: study protocol for a randomised controlled feasibility trial
Rory J. M. Morrison 0 1
Deborah Bunn 2
William K. Gray 2
Paul N. Baker 4 5
Craig White 5
Amar Rangan 3 4 5
Kenneth S. Rankin 0
Mike R. Reed 0 1 4
0 University of Newcastle , Newcastle upon Tyne NE1 7RU , UK
1 Department of Orthopaedics, Northumbria Healthcare NHS Foundation Trust , Woodhorn Lane, Ashington, Northumberland NE63 9JJ , UK
2 Research and Development, Northumbria Healthcare NHS Foundation Trust , Rake Lane, North Shields NE29 8NH , UK
3 Faculty of Medical Sciences & NDORMS, University of Oxford , Oxford OX3 7LD , UK
4 Department of Health Sciences, University of York , Heslington, York YO10 5DD , UK
5 Department of Orthopaedics, South Tees Hospitals NHS Foundation Trust , Marton Lane, Middlesbrough TS4 3BW , UK
Background: Vitamin D deficiency has been linked to poor outcomes after total hip replacement (THR) or total knee replacement (TKR), including lower patient-reported outcome measures (PROMs), peri-prosthetic infection and longer hospital stay. We present a randomised feasibility trial protocol designed to prospectively investigate the influence of vitamin D testing, and subsequent supplementation for deficiency, prior to THR/TKR. Methods/design: One hundred adult patients undergoing primary THR/TKR for osteoarthritis at two NHS hospital trusts in North East England will be recruited. Exclusion criteria include lack of mental capacity, revision surgery, participants already taking vitamin D/calcium supplements, or a known contraindication to vitamin D treatment. Participants will be ineligible for the trial if they have an estimated glomerular filtration rate < 30 ml/minute. We will measure patients' vitamin D levels at baseline, and those identified as deficient (vitamin D < 50 nmol/L) will be randomised to receive either vitamin D supplementation or no supplementation prior to, and for 6 months following, surgery. Patients with a normal vitamin D level (≥50 nmol/L) will receive no supplementation. Vitamin D levels will be rechecked on the day of surgery and again at 6 months. Patients will also complete a lifestyle questionnaire, as well as the Oxford hip or knee and EQ-5D-3 L PROM questionnaires, at baseline and at 6 months following surgery. The aims are to determine the feasibility of the methodology and to gather data to inform the conduct of a future, larger trial to investigate if supplementation with vitamin D, in those who are deficient, prior to THR/TKR improves outcomes as measured by PROM scores. Discussion: Previous reports have measured vitamin D levels and correlated this to outcome, but we can find no randomised trial in which researchers investigated the effect of supplementation. The aim of this trial is to determine if vitamin D deficiency is a modifiable risk factor for poor outcome after THR/TKR. Trial registration: ISRCTN Registry, ISRCTN14533082. Registered on 3 April 2017.
Vitamin D; Cholecalciferol; Deficiency; PROMs; Arthroplasty; THR; TKR; Hip; Knee; Replacement
The extra-skeletal effects of vitamin D are well
documented, affecting almost every cell type through the
vitamin D receptor, and deficiency has been linked to a
myriad of conditions, including cancer, auto-immune
disease, cardio-respiratory disease and depression [
The vitamin is synthesised in the skin in response to
sunlight; however, for at least 6 months of the year, the
United Kingdom is located above the latitude where this
can be achieved [
]. Consequently, insufficient levels
during the winter and spring months are reported in > 50% of
adults over 65 years of age [
Vitamin D deficiency has been linked to poorer
patient-reported outcome measures (PROMs) following
total hip replacement (THR) and total knee replacement
(TKR). In 2010, researchers in a study comprising 62
patients reported that those with vitamin D deficiency
(25-hydroxyvitamin D [25-OH vitamin D] < 40 nmol/L)
had lower Harris Hip Scores before and after surgery
than those with a sufficient level (25-OH vitamin D >
40 nmol/L) [
]. A similar result was found in patients
undergoing TKR [
]. Shin et al. reported a statistically
significant lower Knee Society score, as well as a longer 6-m
walk time, following TKR surgery in patients with vitamin
D deficiency than in those with a normal level [
Lee et al. [
] suggested a link between vitamin D
deficiency and post-operative pain. The authors found that,
at 3 months following TKR surgery, 13.8% of those
patients with pre-operative deficiency were more likely to
report ongoing moderate to severe pain than those with
sufficient levels (5.9%; p = 0.05), and the role of vitamin
D in the modulation of anti-inflammatory cytokines was
suggested as a possible reason for this.
In a German study of over 1000 arthroplasty patients,
vitamin D deficiency was associated with a significantly
longer stay following surgery, by 4.3 days (mean 15.6 vs.
11.3 days), even when adjusting for confounders in
multivariable analysis [
]. The same authors reported a
significantly greater prevalence of vitamin D deficiency in
patients presenting at their unit for revision surgery due
to peri-prosthetic joint infection, compared with those
presenting with aseptic loosening or for primary surgery
]. Their conclusion, like that of others, is
recommendation of a randomised trial to investigate the effect of
vitamin D supplementation prior to THR/TKR in a bid
to improve outcomes. To date, to our knowledge, no
such trial has been performed or registered.
On the basis of National Joint Registry data, 190,000
primary THR/TKR procedures were carried out in
England, Wales and Northern Ireland in 2016 [
patients remain unhappy following joint replacement
surgery, with up to 20% of TKR patients reporting
], and the origin of a negative
outcome may be multi-factorial. PROM scores are
measured in the NHS prior to and at 6 months following
surgery to assess outcomes following THR/TKR, with
financial implications for NHS trusts if they are a negative
outlier, defined as 3 SD below the mean PROM
improvement. NHS PROMs are currently assessed using
the Oxford hip or knee score, as well as the EQ-5D-3 L,
a generic measure of health status.
The aim of this prospective, randomised controlled trial
is to determine the feasibility of the methodology and to
gather data to inform the conduct of a future, larger trial
to investigate if supplementation with vitamin D, in
those who are deficient, prior to THR/TKR improves
outcomes as measured by PROM scores.
Ethics, consent and permissions
Northumbria Healthcare NHS Foundation Trust is the
trial sponsor. The trial will be conducted in accordance
with the Declaration of Helsinki. The trial has received a
favourable ethical opinion from the Yorkshire and the
Humber – Bradford Leeds Research Ethics Committee
(17/YH/0067) and has Health Research Authority
approval (Integrated Research Application Service 216934).
It has National Institute for Health Research portfolio
status (Central Portfolio Management System identifier
33969) and was prospectively registered on 3 April 2017
with the International Standard Registered Clinical/soCial
sTudy Number (ISRCTN) database (ISRCTN14533082).
The current protocol is version 1, dated 31 January 2017,
and any changes to the protocol will be communicated to
all relevant parties, including patients. We have received
charitable funding from Orthopaedic Research UK to
support this study.
In this feasibility trial, we will recruit a total of 100
participants from 2 NHS hospital trusts in North East
England: Northumbria Healthcare NHS Foundation Trust
and South Tees Hospitals NHS Foundation Trust.
Participant recruitment was expected to commence by May
2017, and the trial is due to last 20 months. This
assumes 2 months for patient recruitment, up to 3 months
between recruitment and surgery, 6 months to complete
post-operative PROM scores, 6 months for data retrieval
and analysis, and 3 months to write the study report.
Figure 1 displays the trial schedule, and a Standard
Protocol Items: Recommendations for Interventional
Trials (SPIRIT) checklist is included as Additional file 1.
Participants will be older than 18 years of age and be
scheduled for primary THR/TKR performed for a
Day 1 to
Body Mass Index
Routine and 25-OH Vitamin D Blood
Vitamin D supplementation if
randomised to intervention group
Oxford Hip or Knee Score
Hospital Episode Statistics
diagnosis of osteoarthritis. Exclusion criteria include
participants who lack the mental capacity to comply
with study procedures, participants undergoing revision
surgery, participants already taking vitamin D
supplements, participants with a known contraindication to
vitamin D treatment (such as a previous diagnosis of
sarcoidosis or hyperparathyroidism), and participants with
an allergy to vitamin D. Participants will be ineligible for
the trial if they have renal impairment with an estimated
glomerular filtration rate (eGFR) < 30 ml/minute.
Eligible participants will be identified in the outpatient
clinic of their treating surgeon once they have been
added to the waiting list for surgery. The research team
will inform potential participants about the trial and
provide them with a patient information sheet. Willing
participants will be screened for eligibility by good
clinical practice (GCP)-trained research staff, and have the
opportunity to ask any questions they may have about
the trial, before giving written informed consent for
participation (Additional file 2). Patients will be given up to
1 week to make a decision regarding their involvement
in the trial; if they are happy to give consent straight
away, then this will be allowed. Patients will be free to
withdraw from the study at any time without having to
give a reason. They will not be eligible to participate in
other clinical trials during the study period.
Participants will have routine baseline blood tests
performed, including full blood count, urea and electrolytes,
eGFR, liver function tests, calcium and albumin, as well
as having their serum 25-OH vitamin D level measured.
These tests will be analysed pragmatically using the
routine laboratory methods available at each NHS Trust
hospital. Northumbria use the cobas e 601 Total 25-OH
vitamin D immunochemiluminescence assay (Roche
Diagnostics International Ltd., Rotkreuz, Switzerland), which
has a detection range of 7.5–175 nmol/L and a
laboratory-quoted coefficient of variation of 7.7%. At
South Tees, the IDS-iSYS 25-Hydroxy Vitamin Ds
immunoassay (Immuno Diagnostic Systems [IDS], Boldon,
UK) is used, which has a detection range of 18–313 nmol/
L and a quoted coefficient of variation up to 11.6%.
Patients will also be asked if they give their consent for
an extra sample of blood to be taken and stored
anonymously at Newcastle University for research purposes only,
including in future research trials. Participants will provide
basic demographic data and complete a questionnaire
regarding diet and lifestyle to assess their exposure to
environmental and dietary vitamin D. Whilst we could not
find a validated questionnaire to assess diet and
lifestyle influences, the questions we will ask are similar
to those reported by Lee et al. [
]. Answers will be
recorded in the case report form (CRF), and patients
will be allocated a trial identifier that does not
contain any patient-identifiable data.
As part of their routine care, participants complete
baseline PROMs, which are either the Oxford hip or
knee score, and the EQ-5D-3 L questionnaires
(Appendix 1). These are routine measures collected
by the NHS to assess the quality of care experienced
by patients undergoing THR/TKR. These
questionnaires, which are used to gather routinely collected
data, will be obtained for this trial.
Those participants with vitamin D deficiency (< 50 nmol/
L) will be randomised to receive either vitamin D
supplementation or no supplementation. Research nurses
recruiting participants into the trial will call the research
and development (R&D) department at the sponsor site
by telephone to obtain the participant’s randomised group
allocation. The central R&D administrator will provide
this information from a randomisation log generated by
the website www.randomization.com. Randomisation will
be stratified by study site, and patients will be allocated to
either vitamin D supplementation or no supplementation
using a 1:1 ratio at both sites. The R&D administrator will
provide written confirmation of group allocation using
secure nhs.net email.
Those patients who are randomised to receive treatment
will receive oral cholecalciferol according to their
vitamin D level. Patients with insufficiency (25–49 nmol/L)
will receive 1600 IU/day oral cholecalciferol until
6 months following surgery. Patients with deficiency (<
25 nmol/L) will receive 20,000 IU of oral cholecalciferol
twice per week for 8 weeks, then receive 1600 IU/day
oral cholecalciferol until 6 months following surgery.
Patients’ calcium levels will be re-checked to monitor for
hypercalcaemia, and vitamin D treatment will be
stopped if this is noted. Patients will not be blinded to
their treatment allocation.
Those participants with a normal vitamin D level (≥
50 nmol/L) will be eligible for inclusion in the trial, but
not for randomisation. Along with those patients with
vitamin D deficiency who are randomised to receive no
supplementation, they will act as control subjects. The
control patients will be blinded to their vitamin D status
for the duration of the trial and asked not to start taking
any supplements containing vitamin D for the duration
of their participation in the trial. There are therefore
three groups in this trial; patients with vitamin D
deficiency who do not receive supplementation, patients
with vitamin D deficiency who receive supplementation,
and patients with sufficient vitamin D levels. Not
providing vitamin D supplementation is current standard
practice in the participating NHS trusts, so the control
group will, in effect, receive standard care.
All participants will have blood tests, including
remeasurement of 25-OH vitamin D on the day of surgery,
prior to the start of the operation. Patients receiving
vitamin D supplementation will also have their calcium
level re-checked to monitor for hypercalcaemia. They
will undergo primary THR/TKR under the care of their
consultant orthopaedic surgeon, and no specific
guidance is given with regard to choice of implant, surgical
approach, closure, peri-operative care, rehabilitation or
clinical follow-up; the approach is pragmatic and should
be routine care for that unit.
For the purposes of the trial, all participants will be seen
again at 6 months following surgery to repeat the diet
and lifestyle questionnaire and to re-measure their
25OH vitamin D level. They will also be reminded about
completion of the routine 6-month post-operative
PROM scores sent by the NHS. Those participants who
were randomised to receive treatment will also be asked
to complete an adherence to supplementation
questionnaire and return their vitamin D supplement packets.
The overall aim of this study is to determine if it is
feasible to run a large, multi-centre clinical trial to
investigate the effect of vitamin D supplementation on
outcome following THR/TKR. We will analyse the trial
processes, which are key to the future study. We will
record the number of eligible patients per site as well as
recruitment, retention and refusal rates. The proportion
of patients undergoing primary THR/TKR who did not
meet the eligibility criteria will also be calculated to
ensure that this is not too limiting.
The primary clinical outcome measurement for the
trial is the effect of vitamin D on health gain following
THR/TKR. Health gain is calculated as the difference
between pre-operative and post-operative PROM scores.
Condition-specific health gain is measured using either
the Oxford hip or knee scores, whilst generic health is
measured using the EQ-5D-3 L. We will obtain the
routine patient-level PROM data that is supplied to NHS
trusts to determine these outcomes.
Secondary outcomes include length of hospital stay,
readmission rate and complications. To determine these
outcomes, we will interrogate data routinely held in
patient records and hospital databases at the study sites.
These databases will allow the research team to collect
demographic data, co-morbidities, hospital episode
statistical data (including length of stay, readmission within
30 days of surgery, return to theatre within 30 days of
surgery, requirement for critical care during admission),
and complication data to include 30-day medical
complications, 60-day thromboembolic complications,
90-day mortality and any superficial or deep infections
within the study period. Any expected or unexpected
adverse events will be recorded on a trial adverse events
form and reported to the sponsor. Any serious adverse
events, including death, those prolonging or requiring
hospitalisation, causing permanent or significant
disability/incapacity, or a life-threatening condition, will be
reported to the sponsor and the research ethics
committee. The relationship to the study will also be
determined. The sponsor has usual NHS indemnity.
A secure Excel database (Microsoft Inc., Redmond, WA,
USA) will be used to record data. Statistical analysis will
be performed using IBM SPSS software (IBM, Armonk,
NY, USA). We will compare health gain between groups
at baseline and at 6 months, as well as mean
preoperative and post-operative PROM scores between
groups. Significance will be denoted at p < 0.05, and we
will report 95% CIs as appropriate. The statistical test
chosen to compare groups will depend on the data
distribution and the level of the data (nominal, ordinal or
interval/ratio). For parametric data comparing two
groups, Student’s t test for independent samples will be
used. The Welch correction will be used if variances are
unequal. If the distributions are not normal or the data
ordinal, the Mann-Whitney U test will be used. The
chisquare test or Fisher’s exact test, depending on observed
frequencies, will be used for non-parametric data. Paired
tests will be used to compare data within participants
pre- and post-surgery as appropriate, with tests (e.g.,
paired t test, Wilcoxon signed-rank test) selected
depending on the level and distribution of the data as
described above. We recognise that outcomes are likely to
be confounded with baseline characteristics (e.g., low
physical activity levels, age), type of surgery (TKR/THR)
and hospital site, and we will investigate the influence of
these baseline confounders on outcomes using
multivariable modelling (e.g., logistic regression, analysis of
covariance). However, given that this is a feasibility study,
and it is therefore not fully powered, such multivariable
techniques will be used sparingly and only where
justified (e.g., sufficient variable-to-participant ratio). The
main aim of inferential analysis of clinical outcomes will
be to inform a future fully powered study, rather than to
draw direct inferences regarding outcomes.
Using the observed mean and SD of the PROM scores
collected from this preliminary data, as well as the
reported minimal clinically important difference for the
Oxford hip and knee scores and EQ-5D-3 L, a sample
size calculation can be performed to inform a larger,
future trial. The retention rate derived from these
feasibility data will be incorporated into the final sample size to
allow for possible attrition. The recruitment rate and
resource allocation can also be applied to the final sample
size required to plan the future trial requirements. The
two NHS trusts involved in this trial carried out almost
4500 hip or knee replacements in 2016. We have chosen
to recruit 100 patients for this feasibility trial on the
basis of an expected recruitment rate at the two NHS
trusts over 2 months.
Each site will hold data according to the Data Protection
Act 1998, and data will be collated in CRFs identified by
a unique identification number (i.e., the trial number)
only. A trial enrolment log at the sites will list the
identification numbers. All data recorded electronically will be
held on password-protected NHS trust information
technology systems with permission for access as
detailed in the delegation log. All study files will be stored
in accordance with GCP guidelines. Trial data will be
sent to the sponsor via secure nhs.net email and
accessed only by the study team. Study documents held
by the sponsor will be retained in a secure, locked
location for the duration of the trial. All essential
documents, including source documents, will be retained for
a minimum period of 5 years after study completion. All
work will be conducted following NHS trust data
The trial management group is the executive
decisionmaking body and is responsible for the day-to-day
running and management of the feasibility study. Led by the
chief investigator, it will consist of the lead investigator,
research nurses, and statistician. The team will meet on
a monthly basis by teleconference and face-to-face at
least once per year. It will monitor adherence to the trial
protocols at the trial sites. Quality assurance checks will
be undertaken to ensure the integrity of randomisation,
study entry procedures and data collection. Safety and
efficacy will be assessed using adverse event data
collection. This will be analysed 6 months from the study
opening to recruitment and again at 12 months.
The flow of participants in the trial is displayed in Fig. 2.
A number of studies have suggested a link between
vitamin D deficiency and poor outcomes after joint
replacement surgery [
]. However, these studies have
only measured vitamin D levels and have not
prospectively observed the effect of supplementation. We can
find no randomised interventional trial in the published
literature to investigate if vitamin D deficiency is a
modifiable risk factor and whether supplementation
prior to surgery improves outcomes; this trial would
therefore be the first.
For this feasibility trial, we will not delay the date of
surgery until vitamin D levels have normalised. One of
the questions to answer in this feasibility study is if
surgery should be delayed until vitamin D levels are
normalised in a definitive trial. Currently we have no good
evidence that surgery should be delayed.
The design of this trial has been discussed with the
Total Hip User Group, a local expert patient group
consisting of patients who have undergone, despite their
name, both THR and TKR. They have also had input
with regard to the wording of the patient information
sheet and informed consent form.
There are a number of limitations to the present
feasibility study. Firstly, there are two different methods for
measurement of vitamin D used between the two
centres, although this is pragmatic, and patients will get
repeated measurements at the same hospital with the
same analyser. The trial is being conducted in only one
region, and therefore geographical influences on vitamin
D levels will not be accounted for. The trial period is
only recruiting over a short time period, rather than 1
whole year, so seasonal variations in vitamin D level
cannot be accounted for. We are not measuring other
markers of bone status such as parathyroid hormone,
and we are not measuring vitamin D binding protein.
We are also giving those patients randomised to
treatment standard doses based on their category of
insufficiency, rather than treating them individually to a target.
Finally, there is no placebo used for the control groups.
The results of this trial will be presented at scientific
meetings and submitted for publication in relevant
peerreviewed journals. Results will also be disseminated to
patients and staff involved in the trial. Published results
will not contain any patient-identifiable data and will be
presented for the whole group rather than for individual
participants. The results of this trial will be used to
inform the design of a definitive, large-scale, multi-centre
randomised controlled trial.
The current protocol is version 1, dated 31 January
2017. Recruitment began on 4 May 2017, and the trial
was still open at the time of this protocol submission.
The trial is expected to run until December 2018.
Patient-reported outcome measures used in the trial
1. Oxford hip or knee score: The Oxford hip [
] scores are validated 12-item questionnaires
used to assess function and pain with 5 response
options per question. The overall score is from 0 to
48, with the highest score indicating the best
2. EQ-5D-3 L: The EQ-5D-3 L [
] assesses five
domains of health—mobility, self-care, usual
activities, pain/discomfort and anxiety/depression.
There are three levels of responses for each: no
problems, some problems and extreme problems/
unable to carry out. Patients are also asked to
complete a visual analogue scale ranging from 0
(worst) to 100 (best) with reference to their own
health state. Responses are converted to an ‘index’
score which can be compared with population norms.
Additional file 1: SPIRIT 2013 checklist: recommended items to address
in a clinical trial protocol and related documents. (DOC 122 kb)
Additional file 2: Consent form for the VASO trial. (TIFF 489 kb)
25-OH Vitamin D: 25-Hydroxyvitamin D; CRF: Case report form;
eGFR: Estimated glomerular filtration rate; GCP: Good clinical practice;
HRA: Health Research Authority; IRAS: Integrated Research Application
Service; ISRCTN: International Standard Registered Clinical/soCial sTudy
Number; PROM: Patient-reported outcome measure; R&D: Research and
development; SPIRIT: Standard Protocol Items: Recommendations for
Interventional Trials; THR: Total hip replacement; TKR: Total knee replacement;
VASO: Vitamin D and Arthroplasty Surgery Outcomes
We are grateful to all of the research nurses at Northumbria and South Tees
Hospitals NHS Trust who recruit patients into the trial, and to all of the
patients who agree to take part in the trial. We are grateful to the laboratory
and pharmacy staff at both sites for helping to run the trial, and to the
Central Biobank staff at Newcastle University for the storage of research
The trial has received funding from Orthopaedic Research UK after peer review
of a grant application. Orthopaedic Research UK had no influence on the
design of the study and will have no influence on the collection, analysis or
interpretation of data. RJMM is also supported by a 1-year research fellowship
from the Royal College of Surgeons of England.
Availability of data and materials
The datasets generated and/or analysed during the present study are not
publicly available, because the trial has only started recruiting patients, but
future anonymised data may be available from the corresponding author on
reasonable request, at the chief investigator’s discretion.
RJMM and MRR designed the trial and wrote and edited the manuscript.
WKG contributed to the statistical design and edited the manuscript. DB,
KSR, AR, PNB and CW contributed to the design of the trial and edited the
manuscript. All authors read and approved the final manuscript.
Ethics approval and consent to participate
The trial has a favourable ethical opinion from the Yorkshire & the Humber –
Bradford Leeds Research Ethics Committee (17/YH/0067) and has Health
Research Authority (HRA) approval (IRAS 216934). Willing participants will be
screened for eligibility by good clinical practice (GCP)-trained research staff
and will have the opportunity to ask any questions they may have about the
trial before giving written informed consent for participation. Patients will be
given up to 1 week to make a decision regarding their involvement in the
trial; if they are happy to give consent straight away, then this will be
allowed. Patients will be free to withdraw from the study at any time
without having to give a reason.
Consent for publication
The authors declare that they have no competing interests.
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