Table 2, Review protocol for review question 2 - Evidence reviews for the use of vitamin D supplementation as prevention and treatment of COVID-19

Field	Content
PROSPERO registration number	Not registered
Review title	Vitamin D supplementation for preventing SARS CoV 2 infection (and subsequent COVID-19)
Review question	What is the clinical effectiveness and safety of vitamin D supplementation for the prevention of SARS CoV2 infection (and subsequent COVID-19) in adults, young people and children?
Objective	To investigate the clinical efficacy, effectiveness and safety of vitamin D supplementation to prevent SARS CoV2 infection (and subsequent COVID-19).
Searches	The following databases will be searched: Cochrane Central Register of Controlled Trials (CENTRAL) Cochrane Database of Systematic Reviews (CDSR) Embase MEDLINE Searches will be restricted by: From year 2002 onwards English language only Human studies only Other searches: WHO databases of global research ClinicalTrials.gov medRxiv and bioRxiv There will be no re-run of searches. The full search strategies for MEDLINE, Embase and CENTRAL database will be published in the final review.
Condition or domain being studied	COVID-19
Population	Inclusion: Adults, young people and children who are not infected with SARS CoV2 (or SAR CoV1 and MERS). Notes: Studies on specific sub-populations such as those identified as ‘vulnerable’, ‘extremely vulnerable’ or other comorbidities will be included. Subgroups will be explored, see (section 17). Exclusion: Adults, young people and children who already have contracted SARS CoV2 at the point of study entry.
Intervention	Vitamin D supplementation (all dosages, formulations and routes of administration). Note: Vitamin D supplementation as a combination preventative strategy with other preventative interventions will be included if other preventative interventions are balanced out in the control arm.
Comparator	Placebo or no preventative intervention Note: for vitamin D supplementation as a combination preventative strategy with other preventative interventions, the comparator will be the index preventative intervention(s). For example: Vitamin D + Preventative treatment X versus Preventative treatment X.
Types of study to be included	Inclusion: Systematic review of RCTs RCTs (including open-label) Controlled Clinical Trials If there is insufficient RCT and CCT, prospective and retrospective cohort studies with control arm will be included. Exclusion: Case-control studies Cross section studies Case series and case reports Qualitative studies
Other exclusion criteria	Conference abstracts will be excluded. Preprints will be excluded. However, references of preprints that meet the inclusion criteria will be made available as an appendix to the evidence review. Rationales for exclusion: Unknown authenticity of, Study design Analytical methods Outcomes data being reported Conclusion being drawn Ethical approval Conflict of interests Decisions based on data from unknown authenticity may be harmful to patients.
Context	It has been hypothesised that vitamin D may have a role in the body’s immune response to respiratory viruses. The 2 major forms of vitamin D, vitamin D3 (colecalciferol) and vitamin D2 (ergocalciferol), are licensed for the prevention and treatment of vitamin D deficiency. Vitamin D supplements are not specifically licensed for preventing or treating any infection, including the novel coronavirus infection that causes COVID-19.
Primary outcomes (critical outcomes)	Incidence of SARS CoV2 infection (laboratory/virologically confirmed) SARS CoV2 infection rate (laboratory/virologically confirmed) Number of people who developed COVID-19 (laboratory/virologically confirmed) Severity of COVID-19
Secondary outcomes (important outcomes)	Mortality Morbidity Adverse effects and safety Poor outcomes (for example, long COVID) Tolerability Adherence
Data extraction (selection and coding)	All references identified by the searches and from other sources will be uploaded into EPPI reviewer and de-duplicated. 10% of the abstracts will be reviewed by two reviewers, with any disagreements resolved by discussion or, if necessary, a third independent reviewer. The full text of potentially eligible studies will be retrieved and will be assessed in line with the criteria outlined above. A standardised form will be used to extract data (for example, baseline vitamin D status, dosage) from studies (see Developing NICE guidelines: the manual, Appendix L).
Risk of bias (quality) assessment	Risk of bias will be assessed using the appropriate checklist as described in Developing NICE guidelines: the manual. For systematic review, ROBIS will be used For RCT and CCT, Cochrane RoB 2 tool will be used For prospective and retrospective cohort study, Cochrane ROBINS-I will be used.
Strategy for data synthesis	Where appropriate, pairwise meta-analysis will be conducted based on Cochrane Handbook for Systematic Reviews of Interventions (version 6.1, 2020) Heterogeneity will be assessed by visual inspection of 95%CIs, I squared and Chi squared. Where data points are sufficient, sensitivity analysis will be conducted for studies with high risk of bias GRADE will be used to present the evidence. Where data points are sufficient, funnel plot will be used to assess publication bias.
Analysis of sub-groups	Subgroup effects will be explored for: Age Gender Ethnicity Comorbidities Body mass index Use of immune suppressing treatments Socioeconomic status Baseline vitamin D status Other supplement use Timing of vitamin D measurements (for example, historical, on entry to hospital / intensive care unit) Shielding status Living in care homes
Type and method of review	Intervention
Language	English
Country	Review conducted by NICE, England
Anticipated or actual start date	26/10/2020
Anticipated completion date	23/11/2020
Named contact	5a. Named contact Toni Tan Catrin Austin 5b. Organisational affiliation of the review National Institute for Health and Care Excellence (NICE) and Public Health England (PHE)
Review team members	From NICE: Toni Tan Catrin Austin Thomas Hudson
Funding sources/sponsor	This systematic review is being completed by NICE which receives funding from DH&SC, NHSE and PHE.
Conflicts of interest	All guideline committee members and anyone who has direct input into NICE guidelines (including the evidence review team and expert witnesses) must declare any potential conflicts of interest in line with NICE’s code of practice for declaring and dealing with conflicts of interest. Any relevant interests, or changes to interests, will also be declared publicly at the start of each guideline committee meeting. Before each meeting, any potential conflicts of interest will be considered by the guideline committee Chair and a senior member of the development team. Any decisions to exclude a person from all or part of a meeting will be documented. Any changes to a member’s declaration of interests will be recorded in the minutes of the meeting. Declarations of interests will be published with the final guideline.
Collaborators	Development of this systematic review will be overseen by an advisory committee who will use the review to inform the development of evidence-based recommendations in line with section 3 of appendix L of Developing NICE guidelines: the manual. Members of the guideline committee are available on the NICE website.
Other registration details	N/A
Reference/URL for published protocol	N/A
Dissemination plans	NICE may use a range of different methods to raise awareness of the guideline. These include standard approaches such as: notifying registered stakeholders of publication publicising the guideline through NICE’s newsletter and alerts issuing a press release or briefing as appropriate, posting news articles on the NICE website, using social media channels, and publicising the guideline within NICE.
Keywords	Vitamin D, COVID-19.
Details of existing review of same topic by same authors	N/A
Additional information	None
Details of final publication	www.nice.org.uk

Field

Content

PROSPERO registration number

Not registered

Review title

Vitamin D supplementation for preventing SARS CoV 2 infection (and subsequent COVID-19)

Review question

What is the clinical effectiveness and safety of vitamin D supplementation for the prevention of SARS CoV2 infection (and subsequent COVID-19) in adults, young people and children?

Objective

To investigate the clinical efficacy, effectiveness and safety of vitamin D supplementation to prevent SARS CoV2 infection (and subsequent COVID-19).

Searches

The following databases will be searched:

Cochrane Central Register of Controlled Trials (CENTRAL)
Cochrane Database of Systematic Reviews (CDSR)
Embase
MEDLINE

Searches will be restricted by:

From year 2002 onwards
English language only
Human studies only

Other searches:

WHO databases of global research
ClinicalTrials.gov
medRxiv and bioRxiv

There will be no re-run of searches.

The full search strategies for MEDLINE, Embase and CENTRAL database will be published in the final review.

Condition or domain being studied

COVID-19

Population

Inclusion:

Adults, young people and children who are not infected with SARS CoV2 (or SAR CoV1 and MERS).

Notes: Studies on specific sub-populations such as those identified as ‘vulnerable’, ‘extremely vulnerable’ or other comorbidities will be included.

Subgroups will be explored, see (section 17).

Exclusion:

Adults, young people and children who already have contracted SARS CoV2 at the point of study entry.

Intervention

Vitamin D supplementation (all dosages, formulations and routes of administration).

Note: Vitamin D supplementation as a combination preventative strategy with other preventative interventions will be included if other preventative interventions are balanced out in the control arm.

Comparator

Placebo or no preventative intervention

Note: for vitamin D supplementation as a combination preventative strategy with other preventative interventions, the comparator will be the index preventative intervention(s). For example: Vitamin D + Preventative treatment X versus Preventative treatment X.

Types of study to be included

Inclusion:

Systematic review of RCTs
RCTs (including open-label)
Controlled Clinical Trials

If there is insufficient RCT and CCT, prospective and retrospective cohort studies with control arm will be included.

Exclusion:

Case-control studies
Cross section studies
Case series and case reports
Qualitative studies

Other exclusion criteria

Conference abstracts will be excluded.
Preprints will be excluded. However, references of preprints that meet the inclusion criteria will be made available as an appendix to the evidence review. Rationales for exclusion: Unknown authenticity of,
- Study design
- Analytical methods
- Outcomes data being reported
- Conclusion being drawn
- Ethical approval
- Conflict of interests

Decisions based on data from unknown authenticity may be harmful to patients.

Context

It has been hypothesised that vitamin D may have a role in the body’s immune response to respiratory viruses. The 2 major forms of vitamin D, vitamin D3 (colecalciferol) and vitamin D2 (ergocalciferol), are licensed for the prevention and treatment of vitamin D deficiency. Vitamin D supplements are not specifically licensed for preventing or treating any infection, including the novel coronavirus infection that causes COVID-19.

Primary outcomes (critical outcomes)

Incidence of SARS CoV2 infection (laboratory/virologically confirmed)
SARS CoV2 infection rate (laboratory/virologically confirmed)
Number of people who developed COVID-19 (laboratory/virologically confirmed)
Severity of COVID-19

Secondary outcomes (important outcomes)

Mortality
Morbidity
Adverse effects and safety
Poor outcomes (for example, long COVID)
Tolerability
Adherence

Data extraction (selection and coding)

All references identified by the searches and from other sources will be uploaded into EPPI reviewer and de-duplicated. 10% of the abstracts will be reviewed by two reviewers, with any disagreements resolved by discussion or, if necessary, a third independent reviewer.

The full text of potentially eligible studies will be retrieved and will be assessed in line with the criteria outlined above. A standardised form will be used to extract data (for example, baseline vitamin D status, dosage) from studies (see Developing NICE guidelines: the manual, Appendix L).

Risk of bias (quality) assessment

Risk of bias will be assessed using the appropriate checklist as described in Developing NICE guidelines: the manual.

For systematic review, ROBIS will be used

For RCT and CCT, Cochrane RoB 2 tool will be used

For prospective and retrospective cohort study, Cochrane ROBINS-I will be used.

Strategy for data synthesis

Where appropriate, pairwise meta-analysis will be conducted based on Cochrane Handbook for Systematic Reviews of Interventions (version 6.1, 2020)

Heterogeneity will be assessed by visual inspection of 95%CIs, I squared and Chi squared.
Where data points are sufficient, sensitivity analysis will be conducted for studies with high risk of bias
GRADE will be used to present the evidence.
Where data points are sufficient, funnel plot will be used to assess publication bias.

Analysis of sub-groups

Subgroup effects will be explored for:

Age
Gender
Ethnicity
Comorbidities
Body mass index
Use of immune suppressing treatments
Socioeconomic status
Baseline vitamin D status
Other supplement use
Timing of vitamin D measurements (for example, historical, on entry to hospital / intensive care unit)
Shielding status
Living in care homes

Type and method of review

Intervention

Language

English

Country

Review conducted by NICE, England

Anticipated or actual start date

26/10/2020

Anticipated completion date

23/11/2020

Named contact

5a. Named contact

Toni Tan

Catrin Austin

5b. Organisational affiliation of the review

National Institute for Health and Care Excellence (NICE) and Public Health England (PHE)

Review team members

From NICE:

Toni Tan
Catrin Austin
Thomas Hudson

Funding sources/sponsor

This systematic review is being completed by NICE which receives funding from DH&SC, NHSE and PHE.

Conflicts of interest

All guideline committee members and anyone who has direct input into NICE guidelines (including the evidence review team and expert witnesses) must declare any potential conflicts of interest in line with NICE’s code of practice for declaring and dealing with conflicts of interest. Any relevant interests, or changes to interests, will also be declared publicly at the start of each guideline committee meeting. Before each meeting, any potential conflicts of interest will be considered by the guideline committee Chair and a senior member of the development team. Any decisions to exclude a person from all or part of a meeting will be documented. Any changes to a member’s declaration of interests will be recorded in the minutes of the meeting. Declarations of interests will be published with the final guideline.

Collaborators

Development of this systematic review will be overseen by an advisory committee who will use the review to inform the development of evidence-based recommendations in line with section 3 of appendix L of Developing NICE guidelines: the manual. Members of the guideline committee are available on the NICE website.

Other registration details

N/A

Reference/URL for published protocol

N/A

Dissemination plans

NICE may use a range of different methods to raise awareness of the guideline. These include standard approaches such as:

notifying registered stakeholders of publication
publicising the guideline through NICE’s newsletter and alerts
issuing a press release or briefing as appropriate, posting news articles on the NICE website, using social media channels, and publicising the guideline within NICE.

Keywords

Vitamin D, COVID-19.

Details of existing review of same topic by same authors

N/A

Additional information

None

Details of final publication

www.nice.org.uk

From: Evidence reviews for the use of vitamin D supplementation as prevention and treatment of COVID-19

Cover of Evidence reviews for the use of vitamin D supplementation as prevention and treatment of COVID-19

Evidence reviews for the use of vitamin D supplementation as prevention and treatment of COVID-19: Vitamin D for COVID-19: Evidence review A.

NICE Guideline, No. 187.

London: National Institute for Health and Care Excellence (NICE); 2020 Dec.

NCBI Bookshelf. A service of the National Library of Medicine, National Institutes of Health.

Table 2Review protocol for review question 2