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Content may be subject to copyright.
The effects of high dose vitamin D
supplementation as a nutritional
intervention strategy on biochemical
and inflammatory factors in adults with
COVID-19: Study protocol for a
randomized controlled trial
Zahra Khorasanchi
1,2,*
, Ali Jafazadeh Esfehani
3,*
, Payam Sharifan
1,*
,
Elahe Hasanzadeh
4
, Mohammad Reza Shadmand Foumani Moghadam
5
,
Omid Ahmadi
6
, Reyhaneh Ebrahimi
4
, Seyede Zahra Lotfi
7
,
Nasrin Milani
8
, Mahnaz Mozdourian
9
, Reza Rezvani
1
,
Hasan Vatanparast
10
, Reza Assaran Darban
11
, Gordon Ferns
12
and Majid Ghayour Mobarhan
4,*
Abstract
Introduction: Low serum vitamin D has been shown to be a risk factor for Coronavirus 2019 (COVID-19). The aim of this
study was to assess the effects of high dose vitamin D supplementation on hs-CRP, ESR and clinical outcomes, including duration
of hospitalization, quality of life and New York Heart Association (NYHA) Functional Classification, in adults with COVID-19.
Methods: This double-blind, randomized control trial will be conducted on patients with RT-PCR and/or chest CT scan diagnosis
of COVID-19 admitted in Imam Reza Hospital, Mashhad, Iran. Participants will be randomized into control and intervention
groups based on randomization sampling. The intervention group will receive soft gel containing 50,000 IU vitamin D on the
first day followed by 10,000 IU/day through a supplement drop daily for 29 days. The control group will receive 1000 IU vitamin
D daily through supplement drop and a placebo soft gel. All participants will undergo laboratory assessment including inflamma-
tory markers, serum 25)OH)D, complete blood count (CBC), liver and renal profile, lipid profile and erythrocyte sedimentation
rate (ESR) at baseline and at day 30. The mortality rate will be recorded in both groups. Results: Data will be presented using
descriptive statistics. Comparison of changes in study parameters over the study period will be performed using analysis of covari-
ance adjusting for possible confounders. Conclusions: The findings of this will provide evidence on the effects of high dose vita-
min D supplementation on inflammatory markers in hospitalized COVID-19 patients.
1
Department of Nutrition, School of Medicine, Mashhad University of Medical Sciences, Mashhad, Iran
2
Student Research Committee, Faculty of Medicine, Mashhad University of Medical Sciences, Mashhad, Iran
3
Metabolic Syndrome Research Center, Mashhad University of Medical Sciences, Mashhad, Iran
4
International UNESCO center for Health Related Basic Sciences and Human Nutrition, Department of Nutrition, Faculty of Medicine, Mashhad
University of Medical Sciences, Mashhad, Iran
5
Varastegan Institute for Medical Sciences, Mashhad, Iran
6
Department of Parasitology and Mycology, Torbat Jam Faculty of Medical Sciences, Torbat Jam, Iran
7
Kidney Transplantation Complication Research Center, Mashhad University of Medical Sciences, Mashhad, Iran
8
Department of Internal Medicine, Faculty of Medicine, Mashhad University of Medical Sciences, Mashhad, Iran
9
Lung Diseases Research Center, Mashhad University of Medical Sciences, Mashhad, Iran
10
College of Pharmacy and Nutrition, University of Saskatchewan, Health Sciences E-Wing, Saskatoon, Saskatchewan, Canada
11
Department of Biology, Faculty of Sciences, Mashhad Branch, Islamic Azad University, Mashhad, Iran
12
Division of Medical Education, Brighton and Sussex Medical School, Brighton, UK
*
Equally contributed as first authors.
Corresponding author:
Majid Ghayour-Mobarhan, International UNESCO center for Health Related Basic Sciences and Human Nutrition, Department of Nutrition, Faculty of
Medicine, Mashhad University of Medical Sciences, Mashhad, 99199-91766, Iran.
Email: ghayourm@mums.ac.ir
Protocol
Nutrition and Health
1–7
© The Author(s) 2022
Article reuse guidelines:
sagepub.com/journals-permissions
DOI: 10.1177/02601060221082384
journals.sagepub.com/home/nah
Keywords
COVID-19, vitamin d, inflammation
Introduction
Since the novel coronavirus disease (COVID-19) has
become pandemic, several strategies for the prevention
and treatment of this fatal disease have been proposed.
These strategies have become more important by the emer-
gence of new variants of this virus, such as the delta variant.
Nutritional supplementations such as vitamin D have been
considered as a potentially effective method, along with
antiviral agents, in treatment and reducing the severity of
the Severe Acute Respiratory Syndrome Coronavirus 2
(SARS-CoV-2) infection.
SARS-CoV-2 enters respiratory cells through angiotensin-
converting enzyme 2 (ACE2) receptor. The hypothesis for the
importance of treating hypovitaminosis D in COVID-19
patients has been originated from the observations that
vitamin D down-regulated ACE-2 receptors (Arboleda and
Urcuqui-Inchima, 2020; Hoffmann et al., 2020). From the
clinical point of view, hypovitaminosis D is related to the
poor prognosis in COVID-19 patients (Munshi et al., 2021).
Observational studies have shown a greater risk of mortality
due to COVID-19 in vitamin D deficient patients (Baktash
et al., 2021; Mariani et al., 2021; Radujkovic et al., 2020).
Although studies have shown the effectiveness of
vitamin D supplementation on COVID-19 outcomes,
results from randomized clinical trials are inconsistent. A
recent meta-analysis on the randomized controlled trials
revealed that there might be an association between
vitamin D supplementation and improvement of clinical
outcomes such as hospital length of stay and mortality.
However there is a lack of evidence regarding the optimal
dose and duration of vitamin D supplementation, particu-
larly in hospitalized patients (Pal et al., 2021).
The inconsistent results of existing studies justify the
need for a well-designed intervention where factors such
as the duration of treatment, dosage and delivery of
vitamin D, as well as biomarkers and clinical outcomes
are chosen and measured in the light of recent findings.
Hence, we aimed to design and perform a randomized clin-
ical trial to evaluate the effect of high dose vitamin D sup-
plementation on selected biomarkers and clinical outcomes
of patients infected with COVID-19.
Methods/design
Trial design
This RCT protocol was written according to the CONSORT
SPIRIT 2013 guidelines. In the present double-blind, rando-
mized, placebo-controlled parallel single center, intent-to-treat
clinical trial study we will include 140 patients with the
diagnosis of COVID-19. Figure 1 https://link.springer.com/
article/10.1186/s13063-020-04928-5 - Figure 1 shows the
trial design. Participants will be selected from patients with
the diagnosis of COVID-19 admitted in Imam Reza hospital
related to Mashhad University of Medical Sciences
(MUMS) from January 2021.
Eligibility criteria
Eligibility criteria for covid-19 patients will be done as
follows. Individuals will be allocated into two groups by
block randomization.
Inclusion criteria
Hospitalized patients are eligible to participate if they are at
least 30 years old, have a confirmed SARS-CoV-2 infection
by RT-PCR and/or chest CT scan within the preceding three
days, and willingness to participate in the study by signing
an informed consent form (or informed consent form
obtained from the trusted person, or emergency inclusion
procedure in the context of lockdown, as appropriate).
Exclusion criteria
The following exclusion criteria are considered: Cancer,
renal failure, history of calcium lithiasis, contraindications
for consumption of vitamin D supplements, including
active granulomatosis (sarcoidosis, tuberculosis, lymph-
oma), receiving treatment with vitamin D or vitamin D sup-
plementation during the preceding month (with the
exception of supplements providing 800 IU or less
vitamin D per day), known hypervitaminosis D or hypercal-
cemia, known intolerance to vitamin D, enrolment in
another clinical trial simultaneously.
Baseline assessment
Summarizes the study timeline is presented in Table 1. The
baseline assessment related clinical status (severity of
disease) will be performed by internist, then the research diet-
itian, who will collect demographic details, medical history,
New York Heart Association (NYHA) functional class and
short-form 36 Health Status Questionnaire (SF-36).
Randomization and interventions
Eligibility of patients will be determined at the first screen-
ing visit. Block randomization method will be used for this
trial study. Participants will be allocated randomly (1:1) to
2Nutrition and Health 0(0)
control and intervention groups based on random block pro-
cedure consisting of two subjects per block. Blocking will
be complemented according to patient’s baseline character-
istics such as severity of disease (mild or moderate) and
type of intervention.
The intervention group will receive high-dose vitamin D3
supplement in a single bolus dose of 50,000 IU as a soft gel
(ZAHRAVI, Iran) on the day of inclusion followed by a
daily dose of 10,000 IU for 29 days in the form of oral drop
(Prepared in the Department of Pharmacology, Mashhad
University of Medical Sciences) from the second day of
admission. Cholecalciferol is packaged in a drop containing
10,000 IU/mL. Thus, participants in the intervention group
take 1 mL of vitamin D drop daily. The control group will
receive gelatin soft gels as placebo, along with 1000 IU
vitamin D3 supplement in the form of oral drop (one mL of
oral drops containing 1000 IU) daily for 30 days from the
day of inclusion Soft gel and supplement drops are prepared
in the Department of Pharmacology, Mashhad University of
Medical Sciences.
Ethics approval
The study has been approved by the ethics committee of
Mashhad university of Medical Sciences (Ethic number:
IR.MUMS.REC.1399.237) and was registered in the
Iranian Registry of Clinical Trials website (IRCT ID:
IRCT20110726007117N11).
Safety consideration
The intervention will be stopped in cases such as any
intervention-related side effects and upon the request of par-
ticipants due to deterioration in their disease condition. Also
Follow up will be done one month after the end of the study
to evaluate complications. Also study participants will be
asked to contact the investigators regarding observation of
toxicity symptoms within 2 years of the study. In order to
prevent matrix calcification, we will consider vitamin K2
100 microgram/day (RDA dose of vitamin K). The Ethics
committee of Mashhad University of Medical Sciences
(MUMS) will decide for the referred cases. All subjects
will be informed of their laboratory test results as the
study will be completed.
Power calculation and sample size estimates
The sample size was calculated with respect to the desired
power (80%) and effect size (0.52) for this study (Munro,
2005). Considering a potential dropout rate of 10%, the
Figure 1. Study flow chart.
Khorasanchi et al. 3
sample size was calculated as 140 participants (70 partici-
pants in each group).
n=
2z1−α
2+z1−β
2
f2=2(1 /96 +0/84)2
(0 /5)2=63 ≃70
Blinding
This study is double-blind and both the investigators and
the participants will be blinded regarding the supplementa-
tion dose. Both drops (High dose and low dose vitamin D)
will be labelled as A and B by the Department of
Pharmacology, respectively. In addition, both drops will
be similar in taste, colour, size and identical manufacturing
department (Department of Pharmacology, Mashhad
University of Medical Sciences, Mashhad, Iran).
Applied tests during the study
Clinical outcome measurement. We will assess clinical
outcome indicators such as quality of life (SF-36 question-
naire) and the New York Heart Association (NYHA) func-
tional classification (Eskandari et al., 2015; Montazeri et al.,
2005) at baseline and after one month of intervention.
Moreover duration of hospital stay were recorded.
Laboratory assessment
Primary outcome tests such as Hs-CRP and ESR will be
measured Pars Azmun test kits in BT-3000 auto-analyzer
Biotechnical, Rome, Italy and Westergren method
respectively.
All blood samples will be taken in the morning and after
12 h of midnight fasting by taking 10 mL of intravenous
blood, which will be stored in two tubes, including a tube
containing EDTA for complete blood count (CBC) test
and a gel tube for biochemical and hormonal tests. The
samples will then be centrifuged at 3500 rpm for 15 min
at 4 °C to separate serum and aliquots of serum and will
then be stored at −80 °C for analysis. A sample will be ana-
lysed for CBC, and the rest of the samples will be stored
immediately at −80 °C.
Hematologic measurements include CBC using blood
control (R&D SYSTEMS, Minnesota, USA) in Sysmex
KX21 (Sysmex, Japan). Biochemical measurements
include fasting blood glucose (FBG), alanine aminotrans-
ferase (ALT), aspartate aminotransferase (AST), alkaline
phosphatase (ALP), gamma-glutamyl transferase (GGT),
Lactate Dehydrogenase (LDH), urea, creatinine, calcium,
phosphate, and albumin. For FBG, ALT, AST, ALP,
GGT, Creatinine, and BUN, LDL-c, HDL-c, Triglycerides
(TG), total cholesterol (Pars Azmun test kits in BT-3000
auto-analyzer Biotechnical, Rome, Italy).
Serum 25(OH)D concentrations will be measured using
commercial ELISA kits (Pishgaman Sanjesh- Iran), using
an Awareness/Stat Fax 2100 analyzer.
Statistical methods
All analyses will be based on the intention-to-treat (ITT)
approach. Data will be analyzed by using the SPSS
Table 1. Timeline and applied tests.
Time Point weeks
024
Enrolment ✓
Eligibility screening ✓
Informed consent ✓
Randomization ✓
Allocation ✓
Intervention Treatment: 50.000 IU soft gel (single dose) and 10.000 IU daily
drop daily
✓
Control: placebo soft gel (single dose) +1000 IU drop daily
Compliance and side effect
Laboratory assessment ✓✓
Inflammatory markers (hs-CRP, ESR, RDW, NLR, PLR) ✓✓
Renal function tests (Cr, Urea) ✓✓
Liver function tests (LDH,AST,ALT,GGT) ✓✓
Lipid profile (LDL-c, HDL-c,TG, Total cholesterol) ✓✓
Fasting blood glucose ✓✓
Ca, P, Albumin, 25(OH)D ✓✓
SF-36 and NYHA questionnaire ✓✓
Fasting blood glucose (FBG), alanine aminotransferase (ALT), aspartate aminotransferase (AST), alkaline phosphatase (ALP), gamma-glutamyl transferase
(GGT), Lactate Dehydrogenase (LDH), Creatinine (Cr), calcium (Ca), phosphate (P), High sensitive C-Reactive Protein (hs-CRP), Erythrocyte
sedimentation rate (ESR), Red Cell Distribution Width (RDW), Neutrophil-to-lymphocyte ratio (NLR), Platelet-to-lymphocyte ratio (PLR), Low-density
lipoprotein cholestrol (LDL-c), High-density lipoprotein cholesterol (HDL-c), Triglycerides (TG).
4Nutrition and Health 0(0)
software, version 16 (IBM Inc, Chicago, IL, USA).
Continuous and categorical data will be demonstrated as
mean ±standard deviation (SD), frequency of distribution
in different categories (%), respectively. The normality of
data will be assessed by Kolmogorov-Smirnov test
Comparison of continuous data between intervention and
control groups at baseline will be performed using the inde-
pendent t-test or Mann-Whitney test Paired t-test or
Wilcoxon test will be conducted for before and after inter-
vention comparisons. Comparison of the distribution
pattern of categorical data will be performed using the chi-
square or Fisher exact tests. The mixed model analysis will
be applied to identify any differences between two treat-
ment groups after adjusting for confounding variables con-
sidering the random effects of confounders. In addition, the
chi-square test or exact Fischer test will be performed to
compare mortality rates between study groups. In this
study the considered value of alpha will less than 0.05.
Outcome measures
The primary objective is to compare the effect of high dose
consists of a bolus initial dose and a continuous dose oral
vitamin D3 administration on hs-CRP, ESR and clinical
outcomes, including duration of hospital stay, quality of
life (SF-36 questionnaire) and the New York Heart
Association (NYHA) Functional Classification, in hospita-
lized adults infected with severe acute respiratory syndrome
coronavirus-2 (SARS-CoV-2).
Secondary outcomes include
To compare the effect of high dose with low dose oral
vitamin D3 administration on
•Inflammatory markers, including NLR, PLR, RDW.
•Renal function tests, including creatinine and urea.
•Liver function tests, including AST, ALT, ALP, LDH
and GGT.
•Lipid profile, including low density lipoprotein-
cholesterol (LDL-c), high density lipoprotein-
cholesterol (HDL-c), Triglyceride, total cholesterol,
and fasting plasma glucose.
•To compare the effect of high dose with low dose oral
vitamin D3 administration on 28-day all-cause mor-
tality rate in hospitalized adults infected with
SARS-CoV-2.
Discussion
The emerging rapid dissemination and increasing mortality
of COVID-19 have resulted in the administration of various
empirical medications and supplements without solid evi-
dence for their effectiveness (Huttner et al., 2020; Shin,
2020; Vijayvargiya et al., 2020). However, considerable
numbers of the studied medications were not effective
against COVID-19 till preparing this protocol.
Theoretically, an agent that has the potential to prevent
virus replication and cytokine storm at the same time can
be considered as the most effective treatment in this
disease (Clark, 2020; Hirawat et al., 2021). Based on previ-
ous studies, vitamin D has the potential to be effective in
both pathways (Arboleda and Urcuqui-Inchima, 2020;
Farid et al., 2021; Gilani et al., 2021; Jakovac, 2020;
Khan et al., 2021). Furthermore, vitamin D has immunomo-
dulatory effects that can hypothetically prevent or reduce
the cytokine storm in the process of COVID-19 through
augmentation of the innate immune response and reducing
the acquired immune system response to COVID-19
(Gasmi et al., 2020; TurrubIATes-HernánDez et al., 2021;
Yaqinuddin et al., 2021). Cross-sectional studies showed
a relationship between serum vitamin D levels and
COVID-19 severity and outcome (Katz et al., 2021;
Kazemi et al., 2021; Luo et al., 2021; Yadav et al., 2021).
Therefore, vitamin D administration was considered in
some COVID-19 treatment protocols without confirmed
evidence. On the other hand, the findings of currently pub-
lished RCTs on the effects of vitamin D administration on
severity and disease outcome in COVID-19 patients are
controversial (Butler-Laporte et al., 2021; Murai et al.,
2021; Shah et al., 2021). The dose of vitamin D required
to protect our body against COVID-19 infections still not
clear. Following medical evidence, serum vitamin D con-
centrations of 50 to 60 ng /mL seem to be suitable
(Chakhtoura et al., 2020). In this respect, the first stage con-
sists of a high initial dose followed by a lower maintenance
dose. Studies reported that to attain the above serum con-
centration needed 4000 IU vitamin D/day (for over 12
weeks) or 11,000 IU /day (for 4 weeks) in vitamin D defi-
cient people. Recently, a study recommended that doses
ranging from 4000 IU to 10,000 IU (for bone action and
non-calcemic effects, respectively) are effective and safe
to attain the beneficial effects of vitamin D (Ferder et al.,
2020).
The findings of this RCT might provide evidence about
accepting or rejecting the hypothesis that daily dose of
10,000 IU vitamin D in the form of drop for 29 days admi-
nistered to COVID-19 patients is effective in reducing
admission duration, disease severity and mortality. Due to
the adequate sample size, this RCT can produce reliable
findings that will help clinicians and researchers in decision
making to whether include vitamin D administration in the
treatment protocol of COVID-19 patients or perform the
administration with caution till further studies provide
more evidence in this regard.
Conclusion
We describe the protocol for a clinical trial design investi-
gating the effects of high dose vitamin D supplementation
as a nutritional intervention strategy on biochemical and
inflammatory factors in adults with COVID-19. Our
hypothesis is that oral supplementation of 10,000 IU of
vitamin D for one month, will decrease the inflammation
Khorasanchi et al. 5
and improve clinical outcomes in the covid-19 patients.
Finding of the current study, negative or positive, could
provide a step change in the evidence guiding current and
future policies regarding the validity, dosage and duration
of vitamin D administration as complementary treatment
in COVID-19 patients.
Abbreviation
Hs-CRP High sensitive C - reactive protein
NLR Neutrophil-to-lymphocyte ratio
ALP Alkaline phosphatase
ALT Alanine aminotransferase
AST Aspartate aminotransferase
Ca calcium
Cr Creatinine
ESR Erythrocyte sedimentation rate
FBG Fasting blood glucose
GGT Gamma-glutamyl transferase
HDL-c High-density lipoprotein cholesterol
LDH Lactate Dehydrogenase
LDL-c Low-density lipoprotein cholesterol
P Phosphate
PLR Platelet-to-lymphocyte ratio
RDW Red Cell Distribution Width
TG Triglycerides
Acknowledgements
We sincerely thank all patients participating in this study in
advance, because this study would not be possible without their
cooperation. We also express our appreciation to those who
helped us in in this study.
This study is funded by Mashhad University of Medical
Sciences (grant nu: 981873).
Availability of data and materials
The datasets collected and/or analyzed during the present study are
not publicly accessible due to ethical concerns but corresponding
author may provide datasets upon reasonable request.
Authors’contributions
MGH, HV, RR, ZL, NM, MM initially conceptualized and
designed the study. PSH, ZKH and AJ upgraded the protocol
design. MGH contributed to obtaining the initial funding. The
manuscript was written by ZKH, PSH and AJ and was reviewed
by all members. AJ was responsible for the design optimizing
and statistical analysis. EH, MSH, OA and RE contribute sam-
pling. GF performed English editing. All authors read and
approved the final manuscript.
Consent for publication and ethical approval
to the paper
Ethical approval was obtained from ethics committee of MUMS.
The ethical approval code is IR.MUMS.REC.1399.237. The
informed consent will be obtained from all study participants or
their legal guardian.
ORCID iDs
Reza Rezvani https://orcid.org/0000-0003-3585-9854
Hasan Vatanparast https://orcid.org/0000-0003-2621-8385
Majid Ghayour Mobarhan https://orcid.org/0000-0002-1081-
6754
Trial registration
This trial is registered at clinicaltrials.gov (ID: IRCT20110726007
117N11) on July 6, 2020.
Trial status
The trial enrollment started on 22 January 2021 and currently is
collecting data. Collection labour data of patients expected to
take about 4 months.
Declaration of conflicting interests
The author(s) declared no potential conflicts of interest with respect to
the research, authorship, and/or publication of this article.
Funding
The author(s) disclosed receipt of the following financial support
for the research, authorship, and/or publication of this article:
This work was supported by the Mashhad University of Medical
Sciences, (grant number 981873).
Supplemental Material
Supplemental material for this article is available online.
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