Protect-CH: Prophylactic Therapy in Care Homes Trial

The COVID-19 pandemic has had a devastating effect in care homes. COVID-19 causes illness and death in care home residents and staff. Measures to reduce viral spread into care homes, such as limiting family visits, impact on residents’ health and wellbeing. Beyond public health measures to prevent infection, treatments are urgently needed to minimise these impacts on residents. Many potential treatments have been proposed that might prevent COVID-19 but none have been tested in care homes.

A large clinical trial platform will be set up to test several treatments intended to reduce the spread of COVID-19 within care homes and reduce the risks of hospitalisation and death. A trial platform allows multiple treatments to be tested in parallel, with results analysed regularly. As soon as a treatment is shown to be effective or ineffective, it is removed from the platform. This makes space for new treatments, tested and chosen by government advisors, to be added and rapidly evaluated.

PROTECT-CH will test one or more treatments with the aim of reducing the risk of care home residents catching the virus that causes COVID-19 and of developing severe disease. The results of the study will rapidly be made available to ensure that treatments can be introduced without delay and COVID-19 guidelines quickly updated. The aim of this trial is to set in place a research and governance infrastructure for the efficient delivery of a suite of randomised comparisons to prevent COVID-19 infection and reduce severity/transmission and death in residents in care homes. This trial has been commissioned by the National Institute of Health Research, (NIHR133443) and is badged as an Urgent Public Health (UPH) initiative (trial), under the Data & Connectivity banner.

More than 400 care homes will be recruited from across the UK and approximately 12,000 residents. Care homes will be allocated to a treatment or standard care (no additional treatment). Most of the treatments are expected to be given for two months before assessing whether they have worked, and whether the treatments are cost-effective. Training materials will be developed including videos and audio descriptions for care home staff. For residents, (or legal representatives who will make decisions on their behalf if they do not have capacity) information on the study and the treatments will be provided to help them make an informed decision on whether to take part.

The University of Nottingham has considered the legal basis for processing data under the following articles:

Article 6(1)(e) - processing is necessary for the performance of a task carried out in the public interest or in the exercise of official authority vested in the controller.

Providing treatments to care home residents during an outbreak will reduce the risk of catching the virus that causes COVID-19 and of developing severe disease. The effectiveness and the cost effectiveness of each intervention are unknown; therefore, this research needs to be carried out in the public interest.

The University of Nottingham has identified the legal basis for processing special category data (ethnicity) under GDPR as Article 9(2)(j) - processing is necessary for archiving purposes in the public interest, scientific or historical research purposes or statistical purposes in accordance with Article 89(1) based on Union or Member State law which shall be proportionate to the aim pursued, respect the essence of the right to data protection and provide for suitable and specific measures to safeguard the fundamental rights and the interests of the data subject.

All the relevant variables needed to perform the trial analysis have been identified in each requested dataset and will be extracted by NHS Digital for each participant in the trial. Minimally identifiable data (such as NHS number, date of birth, gender and full postcode) will be used to link all the relevant datasets involved in the analysis including the electronic case report form (eCRF) collected in site by the trial team. The data will then be pseudonymised and identifiable data removed before releasing the dataset for the statistical and economic analysis. The requested NHS Digital data will be used to build the final dataset for the analysis containing all the primary and secondary outcomes and baseline characteristics of each participant. This linked data will be used to carry out the analyses necessary to answer the research questions for this project in order to achieve the identified aim.

Data will be collected from care homes based in England, Scotland, Northern Ireland and Wales and therefore similar data will be requested from the devolved nation equivalents of NHS Digital. Data will be stored and processed in the Trusted Research Environment (TRE) located at University of Dundee (UoD) and managed by the HIC Team (Health Informatics Centre).

The main clinical analysis will be carried out by statisticians at the Nottingham Clinical Trials Unit, University of Nottingham and the economic analysis will be performed by health economists based at the University of Surrey. Other process analyses will be carried out by University of Cambridge. All the analysts will be granted with a secure access to the TRE in Dundee to perform the data management and analyses.

Data will be requested in multiple extracts as participants will be recruited to the study over a period of months. Participants are each followed up for 120 days, and there will be interim analyses conducted, therefore the data flow will be continuous for the duration of the study.

Study participants residing in the same care home will all receive the same study treatment, or usual care. Each treatment under analysis will be compared with the standard care. Each comparison of an active treatment with standard care requires 200 care homes with a 1:1 randomisation (i.e. 100 care homes for each arm) i.e. in the region of 6,400 residents per comparison assuming an average of 32 residents per home taking part in the trial. Justification of these estimates can be found in the protocol section “Power calculation”. The trial design uses a platform structure that allows multiple treatments to be evaluated simultaneously. Randomisation will use equal probability between all active treatments in the platform at the time and a single standard care arm (i.e. allocation ratio 1:1:1:1 if three experimental treatments are in the trial concurrently). To ensure that the platform delivers answers on whether treatments are effective in prevention in a timely manner, the number of active treatments will be limited to three at most at any point. Therefore at least 400 care homes need to be included in the study to compare 3 active treatments to standard care, corresponding to around 13,000 residents.

Care Home criteria:

Inclusions:

· Location: UK care homes for older people, with and without nursing.

· Size: >20 residents in the care home in total.

Exclusions:

· Care Quality Commission quality: Inadequate, or equivalent in devolved administrations.

· Current or recent (within 4 weeks) positive Polymerase Chain Reaction (PCR) or lateral flow test (or equivalent) for SARS-CoV-2 in any resident and/or staff.

Resident criteria:

Inclusions:

· Resident in a Care Home.

· Age >65 years

· Able to give informed consent for participation or has identified a personal legal representative who can give consent, if resident lacks capacity.

Exclusions:

· Currently taking all trial interventions.

· Contraindication to all trial interventions.

· In another COVID-19 prevention or treatment trial.

· Identified by care home staff to have entered end-stage palliative care.

· Resident in care home for short-term respite care.

· Resident’s general practitioner is unable to support their involvement in the trial.

A total of 13 datasets that have been requested as part of this application:

- GPES Data for Pandemic Planning and Research (GDPPR)

- Hospital Episode Statistics (HES) Admitted Patient Care, HES Outpatients, HES Critical Care

- Civil Registration of Deaths

- COVID-19 Vaccination Status

- Demographics

- COVID-19 UK Non-hospital antigen testing results (Pillar 2)

- Second Generation Surveillance System (SGSS)

- Emergency Care Dataset (ECDS)

- Secondary User Service (SUS) Payment By Results (PBR) Accident & Emergency, SUS PBR Outpatients, SUS PBR Spells

These datasets are requested in order to assess the primary and secondary outcomes for the trial analysis, to describe the baseline characteristics of the participants in the trial and to carry out the economic analyses.

1. Baseline characteristics (Age, sex, ethnicity, comorbidities, smoking, previous COVID test, COVID vaccination and frailty index). For this analysis the following datasets are needed: GDPPR, COVID tests (SGSS and COVID-19 UK Non-hospital antigen testing results (Pillar 2)), COVID-19 Vaccination Status.

2. Primary outcome (COVID infection, hospital admission or death). For these outcomes the following datasets are needed: COVID tests, HES APC, Civil Registration of Deaths and Demographics.

3. Secondary outcomes during the 60 days post-randomisation (healthcare contacts for COVID-19 (111,999, outpatients appointments, remote consultations, GP visits etc.), COVID infection with or without symptoms, hospital admission, cause of hospital admission, length of stay, death, cause of death, frailty index). For these outcomes the following datasets are needed: GDPPR, HES Outpatients, ECDS, HES APC, COVID tests, Civil Registration of Deaths, Demographics.

4. Economic evaluation (EQ-5D-5L utilities and EQ-VAS at 60 days, Quality Adjusted Life Years, Healthcare resource use and costs (including A&E attendance, outpatients, hospital admission and critical care hospital stay), Incremental cost-per QALY and Net Monetary Benefit). For these outcomes the following datasets are needed: SUS (A&E, Spells and Outpatients), GDPPR, HES (Outpatients, APC, CC), ECDS.

Some of this information will be collected by care home staff through the eCRF but the plan is to minimise such data collection to reduce burden on care homes, and obtain as much data as possible from routine sources.

Identifiers will be requested to be able to link the data to the eCRF data collected on site. Consent to collect identifiable patient data will be obtained.

The trial is composed of 2 stages:

• Set up stage – 4 months

• Trial data collection/analysis – 20 months

This initial application is to request an 18 months Data Sharing Agreement (DSA) with the possibility to extend depending on progression of the pandemic and ongoing results from the trial.

The requested information could only be obtained from automatically collected routine data. Individually collected data would impose a substantial burden on care homes and would not be an efficient use of public funding, when the required data can be obtained from linkage of national, routine datasets.

Only minimal health data needs to be collected for the purpose of the analysis therefore only relevant variables from specific datasets have been selected and only residents who consented the access to their data will be included in the trial. The time window of data collection is also strictly reduced to the time window relevant for the analyses.

- University of Nottingham is the sole Data Controller and a Data Processor.

- University of Dundee is a data processor and the location where the data will be stored.

- University of Surrey and University of Cambridge are data processors and will be granted access to the TRE managed by the University of Dundee.

The following organisations are involved in the wider project (but are not processing the data):

The University of Edinburgh – Scottish Care Homes leader

The University of Warwick – Hospital at Care home Services expert

The University College London -Care home research expert

The Queen's University of Belfast – NI care home lead

The University of Cardiff – Wales care home lead

This project is funded by the National Institute for Health Research (NIHR) which does not have any role in the research being carried out.

The University of Nottingham will send to the HIC TRE recurring batches of data obtained from the eCRF for trial participants. These will be sent as soon as the data has been collected on site and when the end of the follow-up period has been reached for each participant / care home. University of Nottingham will also send lists of identifiers (NHS number, Date of Birth, Gender, Postcode) for residents who have consented to take part in the study on to the HIC TRE at University of Dundee, who in turn will send it securely to NHS Digital.

This information will be used by NHS Digital to extract the selected variables from the requested data sources for these specific care home residents in England. NHS Digital will securely send the requested data with the supplied identifiers removed and the Study ID attached at the agreed frequency to the HIC TRE in Dundee, where data managers will perform the linkage between the various datasets and will anonymise the final dataset. These data managers will also pre-process the data to store it securely in the TRE and will perform maintenance work to make sure the data protection requirements are met and the data continue to be securely stored and backed up. They will create an automated procedure to receive multiple batches of data at regular intervals.

Data flows will be recurrent, as care homes are expected to be randomised over a period of weeks or months. Data analyses will be carried out regularly for the Data Monitoring Committee. Fortnightly releases of data are requested to make sure analyses can be carried out in real time and results can be used to inform clinical practice in a timely manner.

At each stage data from all requested datasets extracted for all trial participants will be needed. The first data collection date is expected to be soon after the 1st of May 2021, as soon as participants’ consent forms are received. Prospective data is required for all datasets from the participants’ consent date. Additionally, for the GDPPR dataset retrospective data is also required. This dataset has been collected under a specific COVID-19 related direction, and as such can only be used for COVID-19 research related purposes.

A data manager from the University of Nottingham will remotely access all the data stored on the HIC TRE to perform cleaning and further processing for each batch of data received, with the final aim to create the completed dataset for the analysis. In order to create the final dataset the information collected through the eCRF will be linked with the routine data obtained from NHS Digital and the devolved nation equivalents of NHS Digital. The data manager will also manage and pre-process the data to be used by the Universities of Surrey and Cambridge for the respective analyses. The data will be pseudonymised and will not be used for purposes other than those outlined in the original application. Data analysts from the Universities of Nottingham, Surrey and Cambridge will remotely access the TRE to work on the pseudonymised datasets to perform the clinical and economic analyses.

Personal identifiable data from routine data will not be retained beyond the period of coverage of the data sharing agreement with the routine data providers. Linkage and removal of personal identifiable data e.g. NHS number will be undertaken following receipt of each batch of routine data from the providers. Each participant will be flagged with a pseudonymised ID and only the minimal and necessary variables from different external linked datasets will be retained in the final datasets in order to perform the analyses. All data retained for the purposes of the trial in an anonymised form will be held securely in the HIC TRE and only authorised users who previously received appropriate training will be granted access to the data.

The University of Nottingham will maintain the confidentiality of all participants’ data and will not disclose information by which participants may be identified to any third party where consent has not been gained for this disclosure.

Access to identifiable data will be restricted only to the data manager and HIC support team. The data analysts will carry out analyses only using pseudonymised datasets. Data processing is only carried out by substantive employees of the data processor(s) and or data controller(s) who have been appropriately trained in data protection and confidentiality.

As a result of the data processing, the following will be produced:

• NIHR funder Reports

• Submissions to peer reviewed journals such as “The new England Journal of Medicine” or “The Lancet.

• Presentations at various National and international Conferences, COVID related.

In the outputs only aggregated data will be included. Descriptive, outcome and economic data will be reported at the level of the randomised allocation and not at the level of the care home. Moreover, appropriate disclosure rules will be followed for each dataset used in the analysis in any publication of the final results.

The results of the principal comparisons will be reported first to the trial collaborators. The main reports will be drafted by members of the PROTECT-CH writing committee, and the final version will be agreed by the Platform Steering Committee before submission for publication, on behalf of the collaboration. The trial will be reported in accordance with the relevant Consolidated Standards of Reporting Trials (CONSORT) guidelines. Findings will be disseminated through publication in academic journals and presentations at academic conferences. Dissemination of findings will be prioritised to trial participants (residents/care home staff) who will receive regular newsletter updates. Oral/poster presentations and workshops at sponsor hosted events, community meetings and professional/stake holder/user conferences will be targeted.

The trial team will seek to disseminate in a way to support best practice. They will liaise with the Enabling Research in Care Homes (EnRICH) network to identify potential research users, other researchers, policy makers, commissioners, clinicians, care home managers and staff, care home residents and relatives. Dissemination outputs will be tailored towards each group including peer reviewed journal articles, evidence summaries, briefing papers and video clips. Media coverage will be sought in the form of local newspapers, television and radio outlets and social media. This will be enabled further via connecting with the university’s specialist experts in information technology and communication departments. Requests will be sent to relevant agencies to feature the research project in their newsletters and websites.

The target dates for the achievement of final outcome is not predictable due to unknown progress of the pandemic. It is possible that the process of testing treatments and then replacing them with new ones could go on for many months or years. However, analyses will be carried out in real time and therefore any successful treatment will be identified in a timely manner, and will promptly replace the usual care to reduce the risk of infection in the care home residents. This will follow rapid publication of results. The same will apply for treatments that are shown to be ineffective and therefore promptly removed from the trial to be replaced with any new approved experimental prophylaxis. From a Covid-19 outbreak occurring within the Care Home, the consenting residents in the trial will be monitored for a period of 60 days for the primary outcome and 120 days for secondary outcomes, during which time the various datasets will be sent to the TRE and subsequently analysed by the Data Processing team. Therefore, if numbers allow, the first results could be potentially gathered within the next few months and published before the end of 2021.

The COVID-19 pandemic has had a catastrophic effect in care homes with direct effects through causing illness and death, and indirect impact from policies to reduce viral spread into care homes, e.g. by limiting family visits.

One treatment, dexamethasone, reduced COVID-19 deaths in hospitalised patients with severe disease and need oxygen therapy; as such, it is not relevant to most people in care homes. Vaccination against SARS-CoV-2 has commenced in care homes but its efficacy in older people with multiple comorbidities and immunosenescence remains poorly defined. This proposal to set up a large platform cluster-randomised trial will test several treatments intended to reduce the spread of COVID-19 within care homes, and reduce the risks of hospitalisations that have had a substantial burden on the provision of the health care to the whole population, triggering in turn lockdowns and further restrictions.

New treatments will be identified to reduce the risk of contracting the severe end of spectrum of COVID19 infection therefore preventing hospitalisation, death and long-term disability in care home residents, with consequent benefits for the whole population and national health services.

Results from this trial are expected to inform decisions whether to change current clinical practice in the UK, in terms of offering prophylactic treatment to home care residents exposed to an immediate COVID outbreak in their care home. The results of this trial will provide benefit to the NHS by reducing hospital admissions and further specialised health care for short and long term COVID effects, with consequent reduction of burden on the health care force and costs. Results can be applied to care home residents in similar types of settings internationally. It is hoped that guidelines and health policies will benefit from these results in real time as soon as the evidence is published, expected to happen in the coming months.

Yielded Benefits is not a requirement for new applications.