The GLasses Against transmission of SARS-CoV-2 in the communitY (GLASSY) trial: A pragmatic randomized trial (study protocol)
Version 11.01.2022. (DRAFT)
Atle Fretheim (project lead), Lars G. Hemkens, Arnfinn Helleve, Ingeborg Hess Elgersma, Petter Elstrøm, Oliver Kacelnik
Abstract
Background: A systematic review of observational studies indicated that eye protection may be an effective measure to prevent SARS-CoV-2 infections. Randomized trials are needed to assess whether the observed associations are caused by protection of the eye or confounding factors such as other systematic differences between users and non-users of eye protection, co-interventions, or changes in COVID-19 incidence when comparison were done over time.
Methods: Pragmatic, virtual, parallel group, 1:1 randomized, unblinded, superiority trial. We will recruit and randomize participants via an online portal. The trial will be fully remote and virtual without any personal interaction between investigators and participants. All members of the public are eligible who confirm that they are at least 18 years of age, do not require or regularly wear glasses, use public transport at least around 3 days per week, and are willing to be randomized to wear, or not wear glasses when using public transport, for a 2-week period. Persons who are dependent on visual aids but typically use contact lenses are eligible. The participants will be randomized (1:1) to receive advice to wear glasses (sunglasses or other types of glasses) while using public transport, or to the control group. The control group will not be advised to wear glasses, and knowing that they are in the control group, we will encourage them only to use glasses as they normally would. The intervention and follow-up will last for 2 weeks for each participant. All data collection will take place anonymously, online when the trial period is over. The primary outcome is self-report of having had a positive COVID-19 test result (antigen or PCR-test). We aim to include about 25000 participants to have a statistical power of 80% to detect a relative risk reduction of 25% for the primary outcome.
Discussion: Many have easy access to sunglasses or other glasses.. Wearing glasses may provide eye protection and repurposing sunglasses for infection control could be a simple, readily available, environmentally friendly, safe, and sustainable infection prevention measure.
Keywords
COVID-19; non-pharmaceutical intervention; prevention; glasses; pragmatic trial; randomized trial
Introduction
Background and rationale
The potential effectiveness of eye protective gear for infection control was pointed out over 100 years ago [1], but this simple intervention has received limited attention during the ongoing pandemic, except as part of personal protection equipment (PPE) for health care workers.
A recent systematic review of studies estimating the impact of eye protection on transmission of SARS-CoV-2 identified 5 observational studies: 1 case-control study, 1 retrospective cohort study, and 3 before-after comparisons [2]. All were conducted among health workers in various settings. With one exception, all studies reported substantial associations between use of eye protection and reduced infection risk, with odds ratios ranging from 0.04 (95% CI 0.00 to 0.69) to 0.6 (0.44 to 0.81).
The systematic review authors also identified three cross sectional studies examining the use of glasses in the community, all of which found a substantially lower proportions of people wearing glasses among COVID-19 patients compared to the corresponding proportion for the public in general. A case-control study from Norway, not included in the systematic review, also reported a substantially lower proportion of wearers of eyeglasses among the COVID-19 than in the control group, though the difference was reduced and not statistically significant (p>0.05) after multivariate adjustment [3].
In summary, the current best evidence indicates that eye protection may be an effective measure for reducing transmission risk, but randomized trials are needed to assess whether the observed associations are caused by protection of the eye or confounding factors such as other systematic differences between users and non-users of eye protection, co-interventions, or changes in COVID-19 incidence when comparison were done over time.
Many have easy access to sunglasses, and it requires little effort to use them in everyday life - after all, some of them are worn just for fashion. Repurposing sunglasses for infection control could be a simple, readily available, environmentally friendly, safe, and sustainable infection prevention measure. Those who regularly use contact lenses could forego using lenses for infection control reasons and wear the eyeglasses they typically have, instead. Again, this could be a very simple measure to prevent infections
We therefore plan to carry out a randomized trial in the community, to assess whether wearing glasses reduces the risk of SARS-CoV-2 infection.
Objectives
Our objective is to assess whether encouraging people to wear glasses impacts on their risk of SARS-CoV-2 infection.
Trial design
Pragmatic, parallel group, 1:1 randomized, unblinded, superiority trial.
Methods: Participants, interventions and outcomes
Study setting
Community. We will recruit participants via an online portal that will be distributed as widely as possible to the Norwegian public, and hopefully also in other countries. The trial will be fully remote and virtual without any personal interaction between investigators and participants, aiming for maximal anonymity.
Eligibility criteria
All members of the public can take part as long as they confirm that they
a) are at least 18 years of age
b) do not require or regularly wear glasses
c) use public transport at least around 3 days per week, on average
d) are willing to be randomized to wear, or not wear glasses when using public transport,
for a 2-week period.
e) provide informed consent
Persons who are dependent on visual aids but typically use contact lenses are eligible.
Who will take informed consent?
Informed consent will be collected online, on the same web-page where people can sign up to participate.
Interventions
Explanation for the choice of comparators
This study aims to determine the impact advising people to use glasses, in real life circumstances. Hence, the control group will receive no specific advice, and will not be encouraged to change their behavior. The intervention is to advise participants to wear sunglasses or other types of glasses while using public transport. The control group will not be advised to wear glasses, and knowing that they are in the control group, we will encourage them only to use glasses as they normally would.
Intervention description
The intervention group will be advised to wear sunglasses (or other types of glasses) while using public transport. They will also be encouraged to use glasses in other settings as well.
Criteria for discontinuing or modifying allocated interventions
None. The trial period is only 14 days for each participant, and we do not plan to define specific criteria for discontinuing or modifying allocated interventions.
Strategies to improve adherence to interventions
None. We do not plan to maintain any form of contact with the participants between trial enrollment and data collects two weeks later.
Relevant concomitant care permitted or prohibited during the trial
We will not give any advice about concomitant care or interventions.
Outcomes
The primary outcome is
- positive COVID-19 test result (antigen or PCR-test)
Secondary outcomes are
- symptoms of respiratory symptoms
- need for medical care (all-cause)
- need for medical care (related to respiratory symptoms)
- need for medical care (due to injuries)
All outcomes are defined as events occurring during the follow-up (randomization to 14 days).
All outcomes are remotely and anonymously collected via self-reporting.
Participant timeline
Participants will be enrolled continuously during the winter and spring of 2022. The trial period for each participant is 14 days.
Table 1: Participant timeline
Enrolment/ Allocation
Post-allocation
follow-up visits
D0
14 days
Recruitment & Baseline assessment
Eligibility criteria
X
Informed consent
X
Randomization
Interventional: Advise to wear glasses
X
Control: Routine life
X
Outcome measures (online)
Positive COVID-19 test result
X
Symptoms of respiratory symptoms
X
Need for medical care (all-cause)
X
Need for medical care (related to respiratory symptoms)
X
Need for medical care (due to injuries)
X
Participant characteristics (online)
Demographics and risk factors
X
All data will be collected remotely and anonymously (online).
Sample size
Assuming no loss to follow-up and that wearing of glasses leads to a relative risk reduction of 25% for the primary outcome, we will need around 22,000 participants self-reporting on the primary outcome to detect a statistically significant effect (p<0.05) with 80% power. This is based on an expected event rate for the primary outcome in the control group (real life) of 2% (corresponding to a 14-day incidence of 1000/100,000).
We acknowledge that due to the biology of the virus, it willl take some time for the intervention to have an impact on infection numbers (assuming an estimated incubation period for the Omicron variant of about 3 days). We are also aware that the last days of the intervention are not captured by the follow-up. For feasibility and to keep a study of this scale as pragmatic as possible, we decided to accept this dilution of the effect size, as it does not lead to differential bias. Of note, the basis for the sample size calculation is a relative risk reduction of 25%, which is smaller than the large effects reported in observational studies.
Recruitment
We will recruit participants via an online portal that will be distributed as widely as possible to the Norwegian public, an hopefully also in other countries. We will collaborate with Norwegian State Television (NRK) and other media outlets to generate public interest in the trial.
Assignment of interventions: allocation
Sequence generation
We will use a simple 1:1 randomisation by means of computer-generated random numbers.
Concealment mechanism
The allocation will be concealed as the participant themselves will be directly informed of their allocation as soon as they have agreed to take part in the trial and have completed the online consent form.
Implementation
Generation of allocation sequence, enrolment of participants and assignment of participants will all be handled by the trial web-page.
Assignment of interventions: Blinding
Who will be blinded?
Only data analysts will be kept blind to allocation group.
Data collection and management
Plans for assessment and collection of outcomes
All outcome data will be collected by self-report, with all participants completing a fully anonymous online form at the end of their trial period.
We will collect the following anonymous data on participant characteristics:
- Regular use of contact lenses?
- Age
- Country (if the trial recruits outside Norway)
- Number of days on public transport during the study period
- Use of glasses on public transport during study period (all the time; most of the time; some of the time; never)
Plans to promote participant retention and complete follow-up
As all data collection will be anonymous, we will not be aware of which participants have or have not completed and submitted the online questionnaire.
Data management
The participants will enter data directly to an online survey form themselves. Participants in each group (intervention, control) will receive the same link to the data form, which will not contain any person data, thus all data will be fully anonymous. Data will be collected and stored through the Nettskjema-system (University of Oslo).
If we can recruit participants abroad, they will be informed that the data will be stored at out server in Norway. We do not plan to transfer any other data across country borders, however the dataset resulting from the study will only consist of anonymous data and will thus be sharable with any interested party.
Confidentiality
The only person data we will collect are the names of each participant for the consent forms, and their e-mail addresses, which will be used to send them the link to the data collection form. There will be limited access to the list of names and e-mail-addresses of the participants, and this will be store on a secure server with access control.
Ethics
All participants will have to register and consent to participation through an online portal with information about the goal of the trial and eligibility criteria. The consent form will be stored and will not be anonymous. After completing the consent form the participants will be randomized and will receive information about which study arm they have been allocated to, and they will be advised accordingly, i.e. to wear or not to wear glasses. After two weeks the participants will receive an e-mail with a link to an online data collection form. There will be one link for the intervention group, and a different link for the control group, to enable us to differentiate between participants in the two groups. Thus, the data will be completely anonymous – there will be no way, neither in theory or in practice to track the data back to an identifiable individual.
Participation in the trial entails negligible risk and it may yield important findings that can inform decision about infection control measures in the ongoing and future epidemics. This our assessment is that the risk-benefit of the trial is highly favorable.
We have the study protocol to the Regional Ethics Committee for ethical review.
Statistical methods
Statistical methods for primary and secondary outcomes
We will conduct conventional unadjusted analyses to estimate the relative risk for the prespecified outcomes, with 95% confidence intervals. The primary analysis will follow the intention-to-treat (ITT) principle (patients will be analyzed according to their group allocation).
Methods for additional analyses (e.g. subgroup analyses)
We will conduct a subgroup analysis for participants that use contact lenses. We hypothesize that the effect may be smaller for this group, since one possible mechanism for viral transmission is that the viruses attach to ACE-2 receptors in the cornea, which we assume are protected by contact lenses (2).
Methods in analysis to handle protocol non-adherence and any statistical methods to handle missing data
We will include all data collected, and it will be analysed by the intention to treat principle. We do not plan to use any methods for handling missing data.
Plans to give access to the full protocol, participant level-data and statistical code
We intend to give full access to the full protocol, participant-level dataset, and statistical code, to anyone who is interested. If any free text data is collected, we intend to delete this from the publicly available dataset.
Oversight
Adverse event reporting and harm
We will ask the participants whether they needed any medical attention during the trial period, and specifically ask for injuries.
Plans for communicating important protocol amendments to relevant parties (e.g. trial participants, ethical committees)
We will report important protocol modifications (e.g., changes to eligibility criteria, outcomes, analyses) to the Regional Ethics Committee.
Dissemination plans
We plan to communicate trial results to the public, and other relevant groups via publication in peer-reviewed biomedical journals, via social media and through the sponsor website.
Trial status
Conception; 11 January 2022; Version 1.0
Declarations
Authors’ contributions {31b}
AF is the Chief Investigator and led the protocol development. LGH had the original idea for the study and contributed to study design and to development of the protocol. AH is responsible for the data collection platform and contributed to study design and to development of the protocol. IHE, PE and OK contributed to study design and to development of the protocol.
Funding
All running costs are covered by the Norwegian Institute of Public Health.
Availability of data and materials
The final trial dataset will be freely available to the public, except for free text.
Competing interests
The authors declare that they have no competing interests.
References
1. MAXCY, K.F. THE TRANSMISSION OF INFECTION THROUGH THE EYE. Journal of the American Medical Association 1919, 72, 636-639, doi:10.1001/jama.1919.02610090020005.
2. Byambasuren, O.; Beller, E.; Clark, J.; Collignon, P.; Glasziou, P. The effect of eye protection on SARS-CoV-2 transmission: a systematic review. Antimicrob Resist Infect Control 2021, 10, 156, doi:10.1186/s13756-021-01025-3.
3. Stålcrantz J, M.E., Madsen C, Sørreime B, Stefanoff P. . "Kartlegging av smittesteder for covid-19 i Oslo - resultater fra en kasus-kontroll-undersøkelse". [Mapping of community exposures for covid-19 in Oslo – results of a case-control investigation] Norwegian Institute of Public Health: Oslo, 2021.