PROSPERO International prospective register of systematic reviews
Individual patient data meta-analysis of randomised controlled trials of vitamin D supplementation to prevent acute respiratory infection and acute exacerbations of asthma and COPD
Adrian Martineau, David Jolliffe, Richard Hooper, Khalid Khan, Christopher Griffiths, Carlos Camargo
Adrian Martineau, David Jolliffe, Richard Hooper, Khalid Khan, Christopher Griffiths, Carlos Camargo. Individual patient data meta-analysis of randomised controlled trials of vitamin D supplementation to prevent acute respiratory infection and acute exacerbations of asthma and COPD.
Available from http://www.crd.york.ac.uk/PROSPERO/display_record.asp?ID=CRD42014013953
The primary objective of this IPD meta-analysis is to determine whether there are differential effects of vitamin D supplementation on incidence of acute respiratory infection and acute exacerbations of asthma and Chronic Obstructive Pulmonary Disease (COPD) in participant sub-groups categorised by baseline vitamin D status, age, sex, race/ethnic origin, body mass index, presence or absence of respiratory comorbidity, pneumococcal / influenza vaccine status, vitamin D dose administered, type of vitamin D administered, frequency of vitamin D administration, duration of supplementation, attained vitamin D status at end of trial, vitamin D-related genotype, degree of compliance with protocol and severity of asthma / COPD (where applicable).
MEDLINE, EMBASE, BIOSIS, LILACS, Pascal, Science Citation Index, Cochrane Database of Systematic Reviews (CDSR), Cochrane Central Register of Controlled Trials (CENTRAL), Database of Abstracts of Reviews of Effects (DARE) and the Health Technology Assessment Database (HTA). There will be no restrictions according to language or publication period.
Types of study to be included
Only randomised controlled trials will be eligible to be included in the review.
Condition or domain being studied
Acute respiratory infection, asthma, COPD
Studies will be eligible to contribute primary data to this meta-analysis if they are:
• Randomised controlled trials of vitamin D supplementation in which data relating to incidence of ARI, incidence of exacerbation of asthma / COPD have been prospectively collected using directed, closed questions routinely directed at all participants
• Approved by a research ethics committee
Supplementation with vitamin D (either vitamin D3 [cholecalciferol] or vitamin D2 [ergocalciferol]) administered at any dose with any frequency via any route.
Placebo or vitamin D administered at a dose different to that given in the intervention arm of the trial
Trials conducted in any setting, in males and females of any age and any race/ethnic origin with and without vitamin D deficiency at baseline will all be potentially eligible for inclusion.
Incidence of acute respiratory infection
Incidence of acute asthma exacerbation
Incidence of acute COPD exacerbation
a) Hospital attendance, defined as Emergency Department attendance / hospital admission for ARI
b) Use of antimicrobials for treatment of ARI
c) Work / school absence due to ARI
d) Adverse events including hypercalcaemia, renal stones, drop-out/withdrawal rates, serious adverse events (both ARI-related and total) and mortality (both ARI-related and total)
e) Hospital attendance for acute asthma exacerbation, defined as Emergency Department attendance / hospital admission for acute exacerbation
f) Medication use, including requirement for systemic corticosteroids for treatment of acute exacerbation of asthma
g) Asthma-related mortality
h) Hospital attendance for acute exacerbation of COPD, defined as Emergency Department attendance / hospital admission for acute exacerbation
i) Medication use, including requirement for systemic corticosteroids and / or antibiotics for treatment of acute exacerbation of COPD
j) COPD-related mortality
Data extraction, (selection and coding)
Studies will be selected following literature search (as detailed in section 16) on the basis of eligibility criteria detailed above under 'Participants/population'.
Data will be extracted by Principal Investigators, in discussion with the Chief Investigator, the study statistician and the project data manager.
Final details of data to be extracted will be uploaded subsequently (protocol still in development)
Risk of bias (quality) assessment
We will use the Risk of Bias tool developed by the Cochrane Collaboration to score the quality of each study. In subsequent meta-analysis, sensitivity analyses will be used to examine the robustness of statistical and clinical conclusions to the inclusion/exclusion of trials deemed at high risk of bias.
Strategy for data synthesis
Individual level patient data (IPD) will be used. A quantitative synthesis is planned: we will perform both a one-step and a two-step IPD meta-analysis to obtain the pooled intervention effect.
Analysis of subgroups or subsets
We will perform pre-specified sub-group analyses according to:
i) Baseline vitamin D status;
iii) Race/ethnic origin;
iv) Body mass index;
v) Presence or absence of respiratory comorbidity;
vi) Influenza vaccine status;
vii) Dose of vitamin D administered;
viii) Type of vitamin D administered;
ix) Frequency of vitamin D administration;
x) Attained vitamin D status at end of trial;
xi) Severity of asthma/COPD (where applicable).
We will present our findings at one or more international scientific conferences and publish them for publication in medical journals. We will disseminate our findings to the general public by the publication of press releases linked to publications.
Contact details for further information
Centre for Primary Care and Public Health, Barts and The London School of Medicine and Dentistry, Queen Mary University of London, 58 Turner St, London E1 2AB
Organisational affiliation of the review
Centre for Primary Care and Public Health, Barts and The London School of Medicine and Dentistry, Queen Mary University of London
Professor Adrian Martineau, QMUL Mr David Jolliffe, QMUL Dr Richard Hooper, QMUL Professor Khalid Khan, QMUL Professor Christopher Griffiths, QMUL Professor Carlos Camargo, Harvard Medical School
Professor John Aloia, Winthrop University Hospital, New York, USA Dr Peter Bergman, Karolinska Institute, Stockholm, Sweden Professor Susanna Esposito, Università degli Studi di Milano, Milan, Italy Dr Cameron Grant, University of Auckland, New Zealand Professor Wim Janssens, Universitair ziekenhuis Leuven, Leuven, Belgium Dr Ilkka Laaksi, University of Tampere, Tampere, Finland Dr Semira Manseki-Holland, University of Birmingham, Birmingham, UK Dr Hidetoshi Mezawa, Jikei University School of Medicine, Tokyo, Japan Professor David Murdoch, University of Otago, Christchurch, New Zealand Professor Rachel Neale, QIMR Berghofer Medical Research Institute, Queensland, Australia Dr Judy Rees, Dartmouth-Hitchcock Medical Center, New hampshire, USA Professor Iwona Stelmach, Medical University of Lodz, Lodz, Poland Dr Geeta Trilok Kumar, Delhi University, New Delhi, India Professor Mitsuyoshi Urashima, Jikei University School of Medicine, Tokyo, Japan
Anticipated or actual start date
03 November 2014
Anticipated completion date
25 April 2016
NIHR Health Technology Assessment Programme (HTA), ref 13/03/25
Martineau AR, Jolliffe DA, Hooper RL, Greenberg L, Aloia JF, Bergman P, et al. Vitamin D supplementation to prevent acute respiratory tract infections: systematic review and meta-analysis of individual participant data. BMJ. 2017;356:i6583. http://www.bmj.com/content/356/bmj.i6583
Stage of review at time of this submission
Piloting of the study selection process
Formal screening of search results against eligibility criteria
Risk of bias (quality) assessment
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