Face masks for the prevention of COVID-19 - Rationale and design of the randomised controlled trial DANMASK-19
Authors: Christian Torp-Pedersen
Natasja Schytte
Tobias Todsen
Henning Bundgaard
Romona Trebbien
Anton Friis Mariager
Kerstin Skovgaard
Johan Skov Bundgaard
Thomas Benfield
Daniel Emil Tadeusz Raaschou-Pedersen
Mikkel Porsborg Andersen
Christian von Buchwald
Kasper Iversen
Henrik Ullum
Journal: Danish medical journal (2020)
Discipline: CLINICAL MEDICINE
Keywords: COVID-19; face masks; SARS-CoV-2; randomized controlled trial; infection risk
Affiliations: .

Abstract:  Introduction: The coronavirus disease 19 (COVID-19) pandemic, caused by Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2), progresses globally, and means to reduce the transmission are needed. In the community, the use of face masks is increasing world-wide, but documentation for the efficacy of this remedy is lacking. This trial investigates whether the use of face masks in the community will reduce wearers' risk of SARS-CoV-2 infection. Methods: This study will be a two-arm, unblinded, randomised controlled trial. We will include adults (&gt;18 years of age) without prior confirmed COVID-19 or symptoms suggestive of COVID-19, who spend more than three hours per day outside the home with exposure to other people. A total of 6,000 participants are randomly assigned 1:1 to use face masks or not for a 30-day period during the pandemic. Participants will perform self-testing; quick test for SARS-CoV-2 antibodies (immunoglobulin M (IgM) and immunoglobulin G (IgG)) (the Livzon lateral flow test) and oropharyngeal/nasal swabs for viral detection using polymerase chain reaction (PCR). The primary endpoint following the 30-day study period is the difference in the number of SARS-CoV-2-infected individuals between the two study groups as assessed by a positive nasopharyngeal swap, a positive antibody test or a hospital-based diagnosis of SARS-CoV-2 infection. Conclusions: We will study whether a face mask protects the wearer of the mask against SARS-CoV-2 infection. The findings are expected to apply to the present pandemic and to future viral outbreaks and to provide evidence for authority recommendations across the world. Funding: This study was funded by Salling Fondene. Trial registration: ClinicalTrials.gov Identifier: NCT04337541. 

Retracted: No

PubPeer comments:
 The following letter has been submitted as a Letter to the Editor (with additional footnotes and details) to DMJ, and appears here to ensure that this comment appears before final publication of the trial results. Letter of concern regarding u201cReduction in COVID-19 Infection Using Surgical Facial Masks Outside the Healthcare Systemu201d Noah A Haber, Sarah Wieten, Emily R. Smith Noah A Haber, ScD (corresponding author) Postdoctoral Fellow Meta-Research Innovation Center at Stanford University (METRICS) Stanford University noahhaber@stanford.edu Sarah Wieten, PhD Postdoctoral Fellow Meta-Research Innovation Center at Stanford University (METRICS) Stanford University Emily R. Smith, ScD, MPH Assistant Professor Departments of Global Health and of Exercise and Nutrition Sciences Milken Institute School of Public Health The George Washington University We are concerned about the design and interpretation of u201cReduction in COVID-19 Infection Using Surgical Facial Masks Outside the Healthcare System,u201d (1) a randomized controlled trial in Denmark regarding utility of mask-wearing. At this time, a trial registration and protocol paper have been posted, and the resultsu2014which we have not seenu2014are expected to be published shortly. According to the authors, their goal is to: u201cstudy whether a face mask protects the wearer of the mask against SARS-CoV-2 infection. The findings are expected to apply to the present pandemic and to future viral outbreaks and to provide evidence for authority recommendations across the world,u201d (1). We believe that the design of this study is inappropriate to achieve these stated objectives. What follows is a description of some of the study design elements which limit what the study can tell us about mask wearing and COVID-19. The authors misleadingly frame their study as u201cinvestigat[ing] whether the use of face masks in the community will reduce wearers risk of SARS-CoV-2 infectionu201d. The protocol paper suggests the two study arms are u201cmasks must be carried outside the homeu2026u201d vs u201cmasks are not to be used,u201d (1), and the clinical trial registration suggests they are  randomiz[ing participants] to either wear facial masks or not,u201d (2). However, this trial is better described as examining whether a delivery of 50 surgical masks plus weekly messages induce mask-wearing behavior. A secondary question is whether that messaging reduces the risk of SARS-CoV-2 infection. It is essential to distinguish between stated objectives and the actual intervention because we anticipate compliance problems with mask wearing or non-mask wearing. Participants in the non-mask non-message arm are likely to have worn masks during the study and vice versa. Non-compliance in both study arms will dilute the effect of interest and bias it toward the null with respect to the stated objectives. The trial is also severely underpowered based on the effect size assumption in the protocol, exacerbated by the low incidence of COVID-19 in Denmark. The sample size calculation assumes at least a 50% relative risk reduction; this is unreasonably high given that it is the product of both compliance behavior and mask protective effects. The combined effect size would surely be smaller than that found in three observational studies collectively showing that actually wearing masks (i.e. ignoring the impact of non-compliance) outside the healthcare setting reduced the risk of SARS infection by less than 50% [pooled risk ratio 0u00b756 (0u00b740u20130u00b779)] (3). Further, Denmark almost certainly experienced a much lower than the predicted 2% incidence over the course of this trial (4,5), although data on this are limited. Issues around outcome measurement further reduce the effective power of this study. Firstly, participants were only followed for 30 days post randomization. However, based on the natural history of disease, this is not long enough to actually capture all infections in the study period. While about half of people infected with COVID-19 will report symptoms within 5 days, it may be two weeks or more until some people develop symptoms or achieve a viral load above the limit of detection (6). The substantial lag makes detecting casesu2014and thus the effects of masksu2014far less likely during this trial: Participants are assigned to their arm; then change their behaviors; then their infection probabilities change; then, if exposed, the virus has a latency period when infection is not detectable; and then finally testing occurs. That leaves, at most, only two to three weeks of effective measurement time to pick up cases. Secondly, properties of the test itself (e.g. probability of false negatives or positive) increases the variance estimate, as well as potential error associated with self-testing procedures. Measurement error in the dependent variable generally inflates standard errors, further reducing power. In sum, this study has a number of critical design limitations which lead it to being biased toward the null and underpowered to answer the question of interest as stated by the investigators. Statistical insignificance and or too-small effect measured are the most likely outcome as an artifact of the studyu2019s design, regardless of the true effect of masks. Additionally, the trial only measures protective effects to the wearer, not transmission effects to other individuals (source control). Source control is hypothesized to be the primary way masks work to reduce the spread of SARS-CoV-2 (7). This study poses a serious risk of mistranslation, in part due to misleading statements about what the study actually measures in the protocol paper and trial registration. To most decision-makers, null or too-small effects will be misinterpreted to mean that masks are ineffective. However, the more accurate translation is that this study is uninformative regarding the benefits (or lack thereof) of wearing masks outside of the healthcare setting. As such, we caution decision-makers and the media from interpreting the results of this trial as being anything other than artifacts of weak design. Works cited 1. tBundgaard H, Bundgaard JS, Raaschou-Pedersen DET, Mariager AF, Schytte N, von Buchwald C, et al. Face masks for the prevention of COVID-19 - Rationale and design of the randomised controlled trial DANMASK-19. Dan Med J. 2020 Aug 18;67(9). 2. tBundgaard H. Reduction in COVID-19 Infection Using Surgical Facial Masks Outside the Healthcare System - Full Text View - ClinicalTrials.gov [Internet]. ClinicalTrials.gov. 2020 [cited 2020 Sep 7]. Available from: https: clinicaltrials.gov ct2 show NCT04337541 3. tChu DK, Akl EA, Duda S, Solo K, Yaacoub S, Schu00fcnemann HJ, et al. Physical distancing, face masks, and eye protection to prevent person-to-person transmission of SARS-CoV-2 and COVID-19: a systematic review and meta-analysis. The Lancet. 2020 Jun;395(10242):1973u201387. 4. tIversen K, Bundgaard H, Hasselbalch RB, Kristensen JH, Nielsen PB, Pries-Heje M, et al. Risk of COVID-19 in health-care workers in Denmark: an observational cohort study. The Lancet Infectious Diseases. 2020 Aug;S1473309920305892. 5. tEuropean Centre for Disease Prevention and Control. Download the daily number of new reported cases of COVID-19 by country worldwide [Internet]. Download the daily number of new reported cases of COVID-19 by country worldwide. [cited 2020 Sep 7]. Available from: https: www.ecdc.europa.eu en publications-data download-todays-data-geographic-distribution-covid-19-cases-worldwide 6. tLauer SA, Grantz KH, Bi Q, Jones FK, Zheng Q, Meredith HR, et al. The Incubation Period of Coronavirus Disease 2019 (COVID-19) From Publicly Reported Confirmed Cases: Estimation and Application. Annals of Internal Medicine. 2020 May 5;172(9):577u201382. 7. tWorld Health Organization. Advice on the use of masks in the context of COVID-19: interim guidance, 5 June 2020 [Internet]. Geneva: World Health Organization; 2020. Available from: https: apps.who.int iris handle 10665 332293 ,