ADDITION: Anglo-Dutch-Danish study of Intensive Treatment In peOple with screeN-detected diabetes (MR798)

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Objective for processing

Data controller & processor [1 paragraph unchanged] (a) a) The ADDITION study is led by the MRC Epidemiology Unit, a department within the University of Cambridge. (b) b) ADDITION Cambridge is part of a wider ADDITION-Europe collaboration with centres in Denmark (Aarhus University), the Netherlands (University Medical Centre, Utrecht) and another UK site (University of Leicester). (c) c) Only the University of Cambridge will have access to the record level data supplied by NHS digital. England. Rationale Aims: The MRC Epidemiology Unit, University of Cambridge applied for and secured funding from the Medical Research Council to undertake this work. a) The original aims of the ADDITION study were to assess the effectiveness and cost effectiveness of screening for type-2 diabetes and the effectiveness and cost-effectiveness of intensive treatment of multiple risk factors among people with screen-detected type 2 diabetes. Data concerning the effectiveness of multifactorial intensive treatment have been reported for 5 and 10 year follow-up, and data concerning the effects of screening have been reported for 10 year follow-up. The results demonstrate some ongoing uncertainty due to the limited number of observed outcomes during the existing follow-up period. Aims b) This study aims to collect follow up information for the full screened population in Cambridge (approximately 39,000 participants) to ascertain long term outcomes of screening and intensive such as death. a) The aim of the ADDITION study is to assess the effectiveness and cost effectiveness of screening for type-2 diabetes. c) University of Cambridge aims to continue to efficiently follow-up participants using registers in order to assess the long-term effects of screening on all-cause mortality and of early intensive multifactorial treatment among screen-detected patients on CVD risk and mortality. In doing so University of Cambridge will describe any observed legacy effects of improved control of risk factors early in the disease trajectory. In addition, the higher number of events over 15 years of follow-up will increase the power of cohort analyses quantifying the associations between changes in behaviour and weight and risk of events. b) The study aims to collect follow up information for the full screened population in Cambridge (approximately 39,000 participants) to ascertain long term outcomes such as death. Background: Background a) ADDITION first began recruiting participants in 2002. Since this time, it has continued to follow participants up to ascertain their long-term outcomes, in particular mortality data. a) ADDITION first began recruiting participants in 2002. Since this time it has continued to follow participants up to ascertain their long-term outcomes, namely mortality data. b) ADDITION is a complex study including several levels of randomisation and sub-studies. From the original screened cohort of ~39,000, (the "ADDITION screening cohort"), 867 were diagnosed with diabetes and were subsequently randomised to either usual care or an intensive multi-factorial intervention (the ADDITION Cambridge main cohort). 239 of the participants from the ADDITION-Cambridge main cohort were included in a sub-study called ADDITION-plus. 239 extra, new participants were also recruited for ADDITION-plus. These 478 participants form the ADDITION-plus cohort. b) ADDITION is a complex study. From the original screened cohort of ~39,000, (the "ADDITION screening cohort"), 867 were diagnosed with diabetes and were subsequently randomised to either usual care or an intensive multi-factorial intervention (the ADDITION Cambridge main cohort). 239 of the participants from the ADDITION-Cambridge main cohort were included in a sub-study called ADDITION-plus. 239 extra, new participants were also recruited for ADDITION-plus. These 478 participants form the ADDITION-plus cohort. For clarity, this agreement covers ONLY the "ADDITION screening cohort" of ~39,000 For clarity, this Application covers ONLY the "ADDITION screening cohort" of ~39,000 [2 paragraphs unchanged] "ADDITION screening cohort" – MR798 mortality data (this Application) agreement) [2 paragraphs unchanged] In this Agreement, the data received from NHS Digital is mortality data for the full "ADDITION screening cohort" of ~39,000 to identify the current status of those originally screened as part of the ADDITION study. This will allow the research team to establish if early screening for type 2 diabetes provides ongoing benefits and inform NHS policy decisions concerning whether population-based diabetes screening programmes should be established in Europe and worldwide. University of Cambridge is the controller as the organisation responsible for ensuring that the Data will only be processed for the purpose described above. Rationale: The MRC Epidemiology Unit, University of Cambridge applied for and secured funding from the Medical Research Council to undertake this work. Data Minimisation: In this agreement, the data received from NHS England is mortality data for the full "ADDITION screening cohort" of ~39,000 to identify the current status of those originally screened as part of the ADDITION study. This will allow the research team to establish if screening for type 2 diabetes provides ongoing benefits and inform NHS policy decisions concerning whether population-based diabetes screening programmes should be established in Europe and worldwide. Previous mortality releases to University of Cambridge have included the entire text of civil death registration (likely due to data standards at the time of the initial application, 2006). However, University of Cambridge only require the following fields for processing: STUDY_ID as originally provided by us, Date of Death, Cause of Death text A, Cause of Death text B, Cause of Death text C, Cause of Death text D, Cause of Death text E, ICD10 Underlying Cause, ICD10 Multiple Cause Code 1, ICD10 Multiple Cause Code 2, ICD10 Multiple Cause Code 3, ICD10 Multiple Cause Code 4, ICD10 Multiple Cause Code 5, ICD10 Multiple Cause Code 6, ICD10 Multiple Cause Code 7, ICD10 Multiple Cause Code 8, ICD10 Multiple Cause Code 9, ICD10 Multiple Cause Code 10, ICD10 Multiple Cause Code 11, ICD10 Multiple Cause Code 12, ICD10 Multiple Cause Code 13, ICD10 Multiple Cause Code 14, ICD10 Multiple Cause Code 15, These fields are required in order to ascertain fact of death, date of death, and to classify cause of death into one of six broad categories (see details of processing below). After processing we will delete original files received from NHS England and retain only date of death and derived variables as described in section 5b. The lawful basis for processing personal data under the UK GDPR is: 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. The lawful basis for processing special category data under the UK GDPR is: 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. This processing is in the public interest because it adheres to the UK Policy Framework for Health and Social Care Research, which protects and promotes the interests of patients, service users and the public, and aims to produce generalisable and publicly available information to inform future decisions over patients’ treatments or care.

Processing activities

Data Flow & What data is provided Data Provided: a) NHS Digital England already hold a file from the University of Cambridge containing identifiers of participants (less any that object to data linkage) recruited in Cambridge. This includes: [6 paragraphs unchanged] b) The University of Cambridge will use used the Study ID to link the data previously disseminated (i.e. (i.e., data the University of Cambridge holds). By means of this re-identification, the mortality data to be disseminated is therefore considered Identifiable. c) The data will be was downloaded at the University of Cambridge MRC Epidemiology Unit and transferred immediately to an independent, physically-separated physically separated network that is isolated from public network systems and can only be [19 words unchanged] the Unit premises but is known as the private network where all of the Unit's patient data is stored. It is not connected to the [39 words unchanged] study team members accessing the data have a contract with the Unit. Pseudonymised data may be released from the Unit’s physically separate server onto the Unit's main network, and may be accessed on site or by remote access. Pseudonymised data may be released from the Unit’s physically separate server onto the Unit's main network and may be accessed on site or by remote access. [1 paragraph unchanged] Mortality data sets are were previously requested in under this application. agreement. Previously received quarterly update of mortality data since 2006 (previously from ONS). Data is requested going forward for the duration of the Data Sharing Agreement. [2 paragraphs unchanged] The Data will not leave England/Wales at any time. Derived variables are generated as follows: - University of Cambridge to remove all directly identifying information not needed for death classification (names, addresses, NHS number, date of birth, location of death, occupation, details of persons reporting and certifying death). - Remaining data (date of death, cause of death text fields, ICD codings) is reviewed by a clinical professional who is (a) independent of the ADDITION study (b) an ONS Accredited Researcher (c) employed by the University of Cambridge. - The clinical professional classifies each death record as one of the following: 1 = CVD death 2 = cancer death 3 = accident / trauma / suicide 4 = other (excluding COVID) 5 = unknown / unascertainable 6 = COVID and also notes whether diabetes was mentioned on the death certificate. University of Cambridge also record fact of deaths for participants in the study's contact database so that they are sent no further correspondence.

Expected output

[1 paragraph unchanged] - The ADDITION Europe study has so far led to the publication of 76 more than 80 papers in peer-reviewed scientific journals, with a further 4 under review or in press. journals. Data from ADDITION has also contributed to 12 PhD theses and 52 oral presentations or posters at international conferences. The primary analysis of 5 year 5-year outcomes was published in the Lancet (Griffin et al. (2011). Lancet, 378 (9786), 156167). - Participant dissemination events have continued throughout the past 10 years, including public meetings and annual newsletters. - The results of the 10 year analysis of the ADDITION-Europe trial of multifactorial intensive treatment among people with screen-detected type 2 diabetes were published in 2019 (Lancet Diabetes Endocrinol 2019;7:925-937). As well as the results of the 10-year follow-up of the main trial, we have described the patient reported outcomes (Diabet Med 2020;37:1509-1518) and reported a number of cohorts analyses. The following outputs will be produced: (Diabetes Obes Metab 2021;23:730-741, Diabet Med. 2021 ;38:e14646, Diabetologia 2019;62:1391-1402 and Cardiovasc Diabetol 2019;18:98. All publications are open access, in line with the University of Cambridge open-access policy, and can be accessed by clinicians, academics, policy makers and interested members of the public. - The results of the 10 year analysis will be submitted to this or a similar leading medical journal by December 2018 (subject to the completion of the processing activities described above). Findings were presented at the annual meeting of the European Association for the Study of Diabetes (EASD) in September 2016. Throughout 2018, secondary analyses including cost-utility analysis and mechanistic analyses will be published in leading medical or disease-specific peer-reviewed journals such as the Lancet, BMJ, Diabetalogia, Diabetes Care, and International Journal of Obesity. All publications will be open access, in line with the University of Cambridge open-access policy, and can be accessed by clinicians, academics, policy makers and interested members of the public. - A simplified version of the main findings has been issued to participants and GP practices that took part as part of the annual newsletter. Lay-summary findings are also published on the organisation’s website. - A simplified version of the findings will be issued to participants and GP practices that took part as part of the annual newsletter. Lay-summary findings are also published on the organisation’s website. Participant dissemination events have continued throughout the past 10 years, including public meetings and annual newsletters. [2 paragraphs unchanged] University of Cambridge will report the effect of a single round of screening for T2D on all-cause mortality over 20 years of follow-up in Spring 2024. University of Cambridge will report the effect of early intensive multifactorial treatment among screen-detected patients on CVD risk and mortality over 15 years of follow-up by the end of 2024. University of Cambridge will report the associations between changes in behaviour and weight and risk of premature mortality over 15 in Spring 2025.

Expected measurable benefits

a) Type 2 diabetes is frequently asymptomatic, with the true onset occurring [20 words unchanged] and when patients are diagnosed, around 20-30% have evidence of diabetic complications. Due to the lower than expected incidence of cardiovascular events and premature mortality, there remains some uncertainty about the effects of earlier detection of type 2 diabetes through population screening and of intensive treatment of multiple risk factors following detection by screening. Long-term follow-up of the ADDITION study will reduce this uncertainty and inform the management of newly diagnosed patients and to establish by more precisely establishing the size and nature of the long-term benefits of detecting and treating diabetes earlier. NHS digital England data will inform the long term follow up and allow study of [28 words unchanged] clinician decisions nationally on the best way to care for this population. The data will also be used to inform the cost-utility analysis. Completeness of information on the health outcomes, including death, is crucial to enable a true cost to the NHS to be determined and hence influence implementation decisions on the course of treatment for the population. This could lead to reductions in NHS spending on treatments without proven effectiveness or to invest in treatments that will generate savings in the future through reduced NHS service use. b) ADDITION-Cambridge investigators will continue to contribute to the organisation and delivery of diabetes care both locally and nationally (e.g. guideline development, managed care networks, expert review group for diabetes QOF indicators, National Screening Committee Advisory Group, UK Department of Health Vascular screening programme) and therefore will continue to establish mechanisms for influencing policy and practice in these and related fields. b) ADDITION-Cambridge has existing responsibility for organisation and delivery of diabetes care both locally and nationally (e.g. guideline development, managed care networks, expert review group for diabetes QOF indicators, National Screening Committee Advisory Group, UK Department of Health Vascular screening programme) and therefore have established mechanisms for influencing policy and practice in these and related fields. c) Results from this study will help to inform care early in the course of the disease and will provide further information on whether people in middle-age should be offered screening for diabetes in the UK and worldwide. c) Results from this study will help inform care early in the course of the disease and will provide information on whether people in middle-age should be offered screening for diabetes in the UK and worldwide . The study findings will be disseminated to key stakeholders, charities, and the public via reports in journals, conferences, and all University of Cambridge's social media channels. University of Cambridge's communications team regularly disseminates the study findings via all channels. d) It is estimated that 1 in 16 UK adults has (diagnosed or undiagnosed) type 2 diabetes, and this creates a substantial burden of suffering and health service use. Treatment of type 2 diabetes and related complications (cardiovascular disease, amputation, blindness, kidney failure) accounts for 10% of the NHS budget. This is expected to rise as the number of people in the UK who have type 2 diabetes is estimated to rise to 6.25 million by 2035. It is hoped that through publication of findings in appropriate media, the findings of this research will add to the body of evidence that is considered by the bodies, organisations and individual care practitioners charged with making policy decisions for or within the NHS or treatment decisions in relation to specific patients. Type 2 diabetes is frequently asymptomatic, with the true onset occurring several years before diagnosis.

Benefits reported

[4 paragraphs unchanged] There have been more than 35 40 publications from the UK alone feeding into the academic discourse on the treatment of diabetes: the full list can be seen here, http://addition.au.dk/publications/. diabetes. The ADDITION-Europe trial demonstrated that sustained reductions in glycaemia and related CVD risk factors over ten years among people with screen-detected T2D managed in primary care are achievable and safe. People with screen detected T2D demonstrated high levels of potentially modifiable CVD risk factors. Relatively small between-group differences in treatment of these risk factors in the first five years after diagnosis were associated with reductions in rates of CVD events and mortality over ten years of 13% and 10%, respectively. However, due to the smaller than expected number of events there was residual uncertainty around these estimates. ADDITION has contributed the majority of original data concerning screening for type 2 diabetes referred to in international guidelines (UK National Screening Committee and US Preventive Service Task Force). As a consequence, in most high-income country health systems population screening for T2D is not recommended but rather a stratified approach to testing among those at increased risk. [1 paragraph unchanged]

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Objective for processing

[19 paragraphs unchanged] In this application, Agreement, the data required received from NHS Digital is mortality data for the full "ADDITION screening cohort" [41 words unchanged] whether population-based diabetes screening programmes should be established in Europe and worldwide.

Expected output

[1 paragraph unchanged] - The ADDITION Europe study has so far led to the publication of [42 words unchanged] published in the Lancet (Griffin et al. (2011). Lancet, 378 (9786), 156167). - Participant dissemination events have continued throughout the past 10 years, including public meetings and annual newsletters. [1 paragraph unchanged] - The results of the 10 year analysis will be submitted to this [90 words unchanged] accessed by clinicians, academics, policy makers and interested members of the public. - A simplified version of the findings will be issued to participants and GP practices that took part as part of our the annual newsletter. Lay-summary findings are also published on the organisation’s website. [2 paragraphs unchanged]

Benefits reported

[4 paragraphs unchanged] There have been more than 35 publications from the UK alone feeding into the academic discourse on the treatment of diabetes: the full list can be seen here, http://addition.au.dk/publications/, but some example papers are: http://addition.au.dk/publications/. Patient-centred care, health behaviours and cardiovascular risk factor levels in people with recently diagnosed type 2 diabetes: 5 year follow-up of the ADDITION-plus trial cohort. Dambha-Miller H, Cooper AJM, Simmons RK, Kinmonth AL, Griffin SJ. BMJ Open 2016;6(1):e008931. Medication burden in the first 5 years following diagnosis of type 2 diabetes: findings from the ADDITION-UK trial cohort. Black JA, Simmons RK. BMJ Open Diabetes Res Care. 2015 Oct 1;3(1):e000075. doi: 10.1136/bmjdrc-2014-000075. eCollection 2015 Cardiovascular risk reduction following diagnosis of diabetes by screening: one-year results from the ADDITION-Cambridge trial cohort. Charles M, Simmons RK, Williams KM, Roglic G, Sharp SJ, Kinmonth AL, Wareham NJ, Griffin SJ. Brit J Gen Pract 2012;62:294-295. Are people with negative screening tests falsely reassured? A parallel group cohort study embedded in the ADDITION (Cambridge) randomised controlled trial. Paddison CAM, Eborall HC, Sutton S, French DP, Vasconcelos J, Prevost AT, Kinmonth AL, Griffin SJ. BMJ 2009;339:b4535. Patients’ experiences of screening for type 2 diabetes: prospective qualitative study embedded in the ADDITION (Cambridge) randomised controlled trial. Eborall HC, Davies R, Kinmonth AL, Griffin S, Lawton J. BMJ 2007;335:490-493. [1 paragraph unchanged]

Unchanged: Processing activities, Expected measurable benefits.

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Datasets: + Civil Registrations of Death; + Demographics

Unchanged: Objective for processing, Processing activities, Expected output, Expected measurable benefits, Benefits reported.