RECOVERY Trial - Communications to Participants DSA

**** Version 1 of this agreement is an amendment for internal technical upgrade and no changes to the purpose section have been made***

BACKGROUND:

The RECOVERY trial, coordinated by Oxford University, is a national clinical trial aimed at identifying treatments that may be beneficial for people hospitalised with suspected or confirmed COVID-19 (Corona Virus).

In 2019 a novel coronavirus-induced disease (COVID-19) emerged in Wuhan, China. A month later the Chinese Center for Disease Control and Prevention identified a new betacoronavirus (SARS [Severe Acute Respiratory Syndrome] coronavirus 2, or SARS-CoV-2) as the aetiological (causing or contributing to the development of a disease or condition) agent. The clinical manifestations of COVID-19 range from asymptomatic infection or mild, transient symptoms to severe viral pneumonia with respiratory failure. As many patients do not progress to severe disease the overall case fatality rate per infected individual is low, but hospitals in areas with significant community transmission experienced a major increase in the number of hospitalized pneumonia patients, and the frequency of severe disease in hospitalised patients was recorded as high as 30%. The progression from prodrome (an early symptom indicating the onset of a disease or illness - in this case usually fever, fatigue and cough) to severe pneumonia requiring oxygen support or mechanical ventilation often takes one to two weeks after the onset of symptoms. The kinetics of viral replication in the respiratory tract are not well characterized, but this relatively slow progression provides a potential time window in which antiviral therapies could influence the course of disease. The RECOVERY Trial aims to compare several different treatments that may be useful for patients with COVID-19. These treatments have been recommended by the expert panel that advises the Chief Medical Officer (CMO) in England.

TRANSPARENCY/PARTICIPANTS:

The Health Research Authority (HRA) details in their Research Transparency Strategy that ‘Informing Participants’ is one of the four elements of research transparency, stating that it is a good practice requirement that people who have taken part in a research project are thanked for their contribution and told about what it helped the researchers to find out, where appropriate. Furthermore, the UK Policy Framework for Health and Social Care Research says: “Information about the findings of the research [should be] available, in a suitable format and timely manner, to those who took part in it, unless otherwise justified.” This approach is also supported by the National Institute of Health Research (NIHR) and United Kingdom Research and Innovation (UKRI) who are funders of the RECOVERY trial.

There has been recurring feedback from patient panels that people would like to hear about the results of the trials in which they participated. Such feedback has been received from members of panels that are coordinated by the Nuffield Department of Population Health at Oxford University.

To this end, the RECOVERY trial team are looking to send a series of updates to participants to make them aware of the trial results to which they have contributed. An agreement is therefore being put in place with NHS England to facilitate this (the subject of this agreement)

Traditionally, the trials units within the University of Oxford’s Nuffield Department of Population Health have collected patient contact details including addresses and would therefore have been able to communicate directly with trial participants. However, due to the requirement to recruit people into the trial quickly whilst minimising impact on frontline workers, participant addresses have not been captured in this instance. Given the short duration of the study intervention for RECOVERY (10 day treatment period), direct to participant communications systems have not been established, in contrast to the department’s longer-term cardiovascular trials where the treatment period can be as long as 5 years. Consequently, the RECOVERY trial team are looking for support from NHS England through the NHS DigiTrials service to determine the addresses of trial participants using the cohort details provided by Oxford University, and contact participants, by letter, on their behalf.

Whilst there has been considerable media coverage of the results of the trial, the RECOVERY team would like to thank participants directly for their contribution and ensure that they are aware of the trial results, as well as inviting participants to support future public engagement and involvement by becoming part of a RECOVERY-specific participant panel. This panel will provide feedback on future communications and ensure that the trial team are aware of the needs and concerns of existing and future participants. The letters will also provide an opportunity to remind participants that information about how their data are handled is available on the trial website.

RECOVERY wishes to inform its surviving participants (or parents/guardians of child participants) of the results to date from the RECOVERY trial. This is considered best practice and Nuffield Department of Public Health has always done this at the end of its trials before. Because RECOVERY has generated results already (but the trial is still ongoing) the team wish to inform participants throughout the course of the trial. The RECOVERY team would also like to take the opportunity to give participants the opportunity to opt out of such communications in the future, or to receive them electronically (rather than by mail). The team also keen to involve participants in the development of RECOVERY and other trials, so would allow participants to volunteer for this if they are interested, as well as thanking them for their participation in the trial.

The RECOVERY database has a unique participant ID for each participant, linked to their NHS number.

This linkage has been validated already as it is used to collect outcome data from NHS England for the trial, so NHS England can also link from participant ID to NHS Number.

RECOVERY would create a list of participant IDs (excluding anyone RECOVERY knows to have withdrawn consent for all forms of follow-up) and provide this securely to NHS England using existing secure data transfer methods. This list would indicate whether the participant should receive the adult letter, or whether the parent/guardian letter should be sent to their parent or guardian.

This list of Participant ID's will be compared against the existing cohort that NHS England receives for the main RECOVERY Trial Data Sharing Agreement on a weekly basis (under DARS-NIC-365354-R3M0Q).

NHS England would perform a vital status check and remove any additional participants known to have died (whom RECOVERY may not have been aware of due to the intermittent nature of the vital status update that RECOVERY receives).

NHS England would then retrieve the address for the remaining participants and provide this to APS Group - a marketing service group that is a recognized and trusted provider of NHS Services. They are used frequently to co-ordinate mail outs for NHS Bodies.

APS Group would have the template letters and would merge address details onto the letter prior to mailing it out.

NHS England would also return the final list of participant IDs who will be mailed a newsletter to the RECOVERY team.

NHS England would store the final list of recipients, but would not use it for any future mailings which would begin with RECOVERY providing a new list of participant IDs.

Each mailing would include information for participants who wish to opt out of future mailings. This information will also be on the trial website and included in the privacy notice. Participants will be able to write, telephone or e-mail their intention to the RECOVERY team who would flag their record accordingly in the database.

Any such participants would be removed from the list of participant IDs that RECOVERY send to NHS England for any subsequent mailing (along with those who have died, withdrawn consent for follow-up or elected to receive communications electronically).

Ethical approval of these communications will be handled directly by the RECOVERY trial, who have engaged with the Chair of the Cambridge East Research Ethics Committee (REC) (trial ref 20/EE/0101). The outcome of this engagement was that it would be sufficient for the ethics committee to approve a template and/or the 'boundaries' within which the communication would work. After that, each letter does not need to be approved, though the RECOVERY trial will send a copy for their records. The RECOVERY trial team will seek feedback from the existing Nuffield Department of Population Health and NHS DigiTrials public panels to ensure that the communications are appropriate to lay audiences, prior to review by the research ethics committee. These panels have already been involved in reviewing other RECOVERY-related materials.

The University of Oxford relies on the General Data Protection Regulation (GDPR) Article 6 (1) (e), to carry out its public task and for processing special categories of data (including health information); and GDPR Article 9.2(j), for archiving, research and statistics.

**** Version 1 of this agreement is an amendment for internal technical upgrade and no changes to the purpose section have been made***

The key immediate output will be a file of participant IDs, names and addresses which would be passed to APS to generate the mailings.

APS are an approved mailing house with the relevant NHS England approvals.

The ultimate output of this data processing will be participants being mailed a letter to inform them about the results to date from the RECOVERY trial. This data processing is for this single element of the much larger RECOVERY trial so other outputs such as results presentations and publications would not be expected as a result of this specific process.

The RECOVERY trial has a separate DSA for other data that are being processed that would generate these more traditional outputs. However, the process of securely sending the study results to trial participants described in this application will be an exemplar of good practice, which will encourage other researchers to provide similar information to their trial participants.

**** Version 1 of this agreement is an amendment for internal technical upgrade and no changes to the purpose section have been made***

By the end of July 2020, the RECOVERY trial had successfully established over 175 sites across the UK and recruited over 11,000 participants treated in hospital for COVID-19. The data linkage already established to received SUS+ and other data is providing important information to the Data Monitoring Committee on a weekly basis about patients' recovery (i.e. discharge from hospital), in-hospital death and procedures required. Provision of complete and reliable data to the DMC through May and early June 2020 is critical to allow robust assessment of the effects of the the trial treatments with a major contribution to these data expected from analysis of the routine health care data requested under this agreement.

On Thursday 4 June, in response to a request from the UK Medicines and Healthcare Products Regulatory Agency (MHRA), the independent Data Monitoring Committee conducted a further review of the data. The DMC recommended the chief investigators review the unblinded data on the hydroxychloroquine arm of the trial. The results included a total of 1542 patients randomised to hydroxychloroquine compared with 3132 patients randomised to usual care alone. There was no significant difference in the primary endpoint of 28-day mortality (25.7% hydroxychloroquine vs. 23.5% usual care; hazard ratio 1.11 [95% confidence interval 0.98-1.26]; p=0.10). There was also no evidence of beneficial effects on hospital stay duration or other outcomes. These results were released to the public and on the 15 July 2020, the U.S. Food and Drug Administration (FDA) revoked the emergency use authorization (EUA) that allowed for chloroquine phosphate and hydroxychloroquine sulfate donated to the Strategic National Stockpile to be used to treat certain hospitalized patients with COVID-19 when a clinical trial was unavailable, or participation in a clinical trial was not feasible. This result has major implications for countries around the world who were planning to scale manufacturing of these drugs in order to treat COVID patients.

On 8 June 2020, recruitment to the dexamethasone arm was halted since, in the view of the trial Steering Committee, sufficient patients had been enrolled to establish whether or not the drug had a meaningful benefit. On 16 June 2020, preliminary results were released. A total of 2104 patients were randomised to receive dexamethasone 6 mg once per day (either by mouth or by intravenous injection) for ten days and were compared with 4321 patients randomised to usual care alone. Among the patients who received usual care alone, 28-day mortality was highest in those who required ventilation (41%), intermediate in those patients who required oxygen only (25%), and lowest among those who did not require any respiratory intervention (13%). Dexamethasone reduced deaths by one-third in ventilated patients (rate ratio 0.65 [95% confidence interval 0.48 to 0.88]; p=0.0003) and by one fifth in other patients receiving oxygen only (0.80 [0.67 to 0.96]; p=0.0021). There was no benefit among those patients who did not require respiratory support (1.22 [0.86 to 1.75]; p=0.14). Based on these results, 1 death would be prevented by treatment of around 8 ventilated patients or around 25 patients requiring oxygen alone.

On the 16 June 2020, on the basis of these results, the MHRA issued an alert to health care providers in the UK recommending the use of dexamethasone in hospitalised patients with COVID who require oxygen or ventilation. In addition dexamethasone has also been added to the government’s parallel export list, which bans companies from buying medicines meant for UK patients and selling them on for a higher price in another country.

A recent analysis estimates that treatment with Dexamethasone may save between 4,000 and 27,000 lives in the UK by January 20201 (depending on the number of COVID-19 cases during Q3-4 2020) and potentially over half a million lives worldwide (https://www.medrxiv.org/content/10.1101/2020.07.29.20164269v1). Without the results from RECOVERY the effectiveness of this treatment would not be known.

A paper was recently published in the New England Journal of Medicine entitled "Dexamethasone in Hospitalized Patients with Covid-19 — Preliminary Report" (17/07/2020) detailing the results.

The above demonstrates that the RECOVERY Trial is a fast paced moving trial with plenty to communicate to participants about updates and ongoing work.

BACKGROUND:

The RECOVERY trial, coordinated by Oxford University, is a national clinical trial aimed at identifying treatments that may be beneficial for people hospitalised with suspected or confirmed COVID-19 (Corona Virus).

In 2019 a novel coronavirus-induced disease (COVID-19) emerged in Wuhan, China. A month later the Chinese Center for Disease Control and Prevention identified a new betacoronavirus (SARS [Severe Acute Respiratory Syndrome] coronavirus 2, or SARS-CoV-2) as the aetiological (causing or contributing to the development of a disease or condition) agent. The clinical manifestations of COVID-19 range from asymptomatic infection or mild, transient symptoms to severe viral pneumonia with respiratory failure. As many patients do not progress to severe disease the overall case fatality rate per infected individual is low, but hospitals in areas with significant community transmission experienced a major increase in the number of hospitalized pneumonia patients, and the frequency of severe disease in hospitalised patients was recorded as high as 30%. The progression from prodrome (an early symptom indicating the onset of a disease or illness - in this case usually fever, fatigue and cough) to severe pneumonia requiring oxygen support or mechanical ventilation often takes one to two weeks after the onset of symptoms. The kinetics of viral replication in the respiratory tract are not well characterized, but this relatively slow progression provides a potential time window in which antiviral therapies could influence the course of disease. The RECOVERY Trial aims to compare several different treatments that may be useful for patients with COVID-19. These treatments have been recommended by the expert panel that advises the Chief Medical Officer (CMO) in England.

TRANSPARENCY/PARTICIPANTS:

The Health Research Authority (HRA) details in their Research Transparency Strategy that ‘Informing Participants’ is one of the four elements of research transparency, stating that it is a good practice requirement that people who have taken part in a research project are thanked for their contribution and told about what it helped the researchers to find out, where appropriate. Furthermore, the UK Policy Framework for Health and Social Care Research says: “Information about the findings of the research [should be] available, in a suitable format and timely manner, to those who took part in it, unless otherwise justified.” This approach is also supported by the National Institute of Health Research (NIHR) and United Kingdom Research and Innovation (UKRI) who are funders of the RECOVERY trial.

There has been recurring feedback from patient panels that people would like to hear about the results of the trials in which they participated. Such feedback has been received from members of panels that are coordinated by the Nuffield Department of Population Health at Oxford University.

To this end, the RECOVERY trial team are looking to send a series of updates to participants to make them aware of the trial results to which they have contributed. An agreement is therefore being put in place with NHS Digital to facilitate this (the subject of this agreement)

Traditionally, the trials units within the University of Oxford’s Nuffield Department of Population Health have collected patient contact details including addresses and would therefore have been able to communicate directly with trial participants. However, due to the requirement to recruit people into the trial quickly whilst minimising impact on frontline workers, participant addresses have not been captured in this instance. Given the short duration of the study intervention for RECOVERY (10 day treatment period), direct to participant communications systems have not been established, in contrast to the department’s longer-term cardiovascular trials where the treatment period can be as long as 5 years. Consequently, the RECOVERY trial team are looking for support from NHS Digital through the NHS DigiTrials service to determine the addresses of trial participants using the cohort details provided by Oxford University, and contact participants, by letter, on their behalf.

Whilst there has been considerable media coverage of the results of the trial, the RECOVERY team would like to thank participants directly for their contribution and ensure that they are aware of the trial results, as well as inviting participants to support future public engagement and involvement by becoming part of a RECOVERY-specific participant panel. This panel will provide feedback on future communications and ensure that the trial team are aware of the needs and concerns of existing and future participants. The letters will also provide an opportunity to remind participants that information about how their data are handled is available on the trial website.

RECOVERY wishes to inform its surviving participants (or parents/guardians of child participants) of the results to date from the RECOVERY trial. This is considered best practice and Nuffield Department of Public Health has always done this at the end of its trials before. Because RECOVERY has generated results already (but the trial is still ongoing) the team wish to inform participants throughout the course of the trial. The RECOVERY team would also like to take the opportunity to give participants the opportunity to opt out of such communications in the future, or to receive them electronically (rather than by mail). The team also keen to involve participants in the development of RECOVERY and other trials, so would allow participants to volunteer for this if they are interested, as well as thanking them for their participation in the trial.

The RECOVERY database has a unique participant ID for each participant, linked to their NHS number.

This linkage has been validated already as it is used to collect outcome data from NHS Digital for the trial, so NHS Digital can also link from participant ID to NHS number.

RECOVERY would create a list of participant IDs (excluding anyone RECOVERY knows to have withdrawn consent for all forms of follow-up) and provide this securely to NHS Digital using existing secure data transfer methods. This list would indicate whether the participant should receive the adult letter, or whether the parent/guardian letter should be sent to their parent or guardian.

This list of Participant ID's will be compared against the existing cohort that NHS Digital receives for the main RECOVERY Trial Data Sharing Agreement on a weekly basis (under DARS-NIC-365354).

NHS Digital would perform a vital status check and remove any additional participants known to have died (whom RECOVERY may not have been aware of due to the intermittent nature of the vital status update that RECOVERY receives).

NHS Digital would then retrieve the address for the remaining participants and provide this to APS Group - a marketing service group that is a recognized and trusted provider of NHS Services. They are used frequently to co-ordinate mail outs for NHS Bodies.

APS Group would have the template letters and would merge address details onto the letter prior to mailing it out.

NHS Digital would also return the final list of participant IDs who will be mailed a newsletter to the RECOVERY team.

NHS Digital would store the final list of recipients, but would not use it for any future mailings which would begin with RECOVERY providing a new list of participant IDs.

Each mailing would include information for participants who wish to opt out of future mailings. This information will also be on the trial website and included in the privacy notice. Participants will be able to write, telephone or e-mail their intention to the RECOVERY team who would flag their record accordingly in the database.

Any such participants would be removed from the list of participant IDs that RECOVERY send to NHS Digital for any subsequent mailing (along with those who have died, withdrawn consent for follow-up or elected to receive communications electronically).

Ethical approval of these communications will be handled directly by the RECOVERY trial, who have engaged with the Chair of the Cambridge East Research Ethics Committee (REC) (trial ref 20/EE/0101). The outcome of this engagement was that it would be sufficient for the ethics committee to approve a template and/or the 'boundaries' within which the communication would work. After that, each letter does not need to be approved, though the RECOVERY trial will send a copy for their records.The RECOVERY trial team will seek feedback from the existing Nuffield Department of Population Health and NHS DigiTrials public panels to ensure that the communications are appropriate to lay audiences, prior to review by the research ethics committee. These panels have already been involved in reviewing other RECOVERY-related materials.

The University of Oxford relies on the General Data Protection Regulation (GDPR) Article 6 (1) (e), to carry out its public task and for processing special categories of data (including health information); and GDPR Article 9.2(j), for archiving, research and statistics.

The key immediate output will be a file of participant IDs, names and addresses which would be passed to APS to generate the mailings.

APS are an approved mailing house with the relevant NHS Digital approvals.

The ultimate output of this data processing will be participants being mailed a letter to inform them about the results to date from the RECOVERY trial. This data processing is for this single element of the much larger RECOVERY trial so other outputs such as results presentations and publications would not be expected as a result of this specific process.

The RECOVERY trial has a separate DSA for other data that are being processed that would generate these more traditional outputs. However, the process of securely sending the study results to trial participants described in this application will be an exemplar of good practice, which will encourage other researchers to provide similar information to their trial participants.

By the end of July 2020, the RECOVERY trial had successfully established over 175 sites across the UK and recruited over 11,000 participants treated in hospital for COVID-19. The data linkage already established to received SUS+ and other data is providing important information to the Data Monitoring Committee on a weekly basis about patients' recovery (i.e. discharge from hospital), in-hospital death and procedures required. Provision of complete and reliable data to the DMC through May and early June 2020 is critical to allow robust assessment of the effects of the the trial treatments with a major contribution to these data expected from analysis of the routine health care data requested under this agreement.

On Thursday 4 June, in response to a request from the UK Medicines and Healthcare Products Regulatory Agency (MHRA), the independent Data Monitoring Committee conducted a further review of the data. The DMC recommended the chief investigators review the unblinded data on the hydroxychloroquine arm of the trial. The results included a total of 1542 patients randomised to hydroxychloroquine compared with 3132 patients randomised to usual care alone. There was no significant difference in the primary endpoint of 28-day mortality (25.7% hydroxychloroquine vs. 23.5% usual care; hazard ratio 1.11 [95% confidence interval 0.98-1.26]; p=0.10). There was also no evidence of beneficial effects on hospital stay duration or other outcomes. These results were released to the public and on the 15 July 2020, the U.S. Food and Drug Administration (FDA) revoked the emergency use authorization (EUA) that allowed for chloroquine phosphate and hydroxychloroquine sulfate donated to the Strategic National Stockpile to be used to treat certain hospitalized patients with COVID-19 when a clinical trial was unavailable, or participation in a clinical trial was not feasible. This result has major implications for countries around the world who were planning to scale manufacturing of these drugs in order to treat COVID patients.

On 8 June 2020, recruitment to the dexamethasone arm was halted since, in the view of the trial Steering Committee, sufficient patients had been enrolled to establish whether or not the drug had a meaningful benefit. On 16 June 2020, preliminary results were released. A total of 2104 patients were randomised to receive dexamethasone 6 mg once per day (either by mouth or by intravenous injection) for ten days and were compared with 4321 patients randomised to usual care alone. Among the patients who received usual care alone, 28-day mortality was highest in those who required ventilation (41%), intermediate in those patients who required oxygen only (25%), and lowest among those who did not require any respiratory intervention (13%). Dexamethasone reduced deaths by one-third in ventilated patients (rate ratio 0.65 [95% confidence interval 0.48 to 0.88]; p=0.0003) and by one fifth in other patients receiving oxygen only (0.80 [0.67 to 0.96]; p=0.0021). There was no benefit among those patients who did not require respiratory support (1.22 [0.86 to 1.75]; p=0.14). Based on these results, 1 death would be prevented by treatment of around 8 ventilated patients or around 25 patients requiring oxygen alone.

On the 16 June 2020, on the basis of these results, the MHRA issued an alert to health care providers in the UK recommending the use of dexamethasone in hospitalised patients with COVID who require oxygen or ventilation. In addition dexamethasone has also been added to the government’s parallel export list, which bans companies from buying medicines meant for UK patients and selling them on for a higher price in another country.

A recent analysis estimates that treatment with Dexamethasone may save between 4,000 and 27,000 lives in the UK by January 20201 (depending on the number of COVID-19 cases during Q3-4 2020) and potentially over half a million lives worldwide (https://www.medrxiv.org/content/10.1101/2020.07.29.20164269v1). Without the results from RECOVERY the effectiveness of this treatment would not be known.

A paper was recently published in the New England Journal of Medicine entitled "Dexamethasone in Hospitalized Patients with Covid-19 — Preliminary Report" (17/07/2020) detailing the results.

The above demonstrates that the RECOVERY Trial is a fast paced moving trial with plenty to communicate to participants about updates and ongoing work.