Randomized trials in cardiovascular and metabolic diseases

Lead Research Organisation: University of Oxford

Abstract

The aim of this programme is to demonstrate reliably any benefits of treatments that can be widely used in common diseases such as heart disease, diabetes, stroke and cancer. Even quite modest improvements in outcome in common conditions can lead to important benefits for patients. In order to be sure that treatments really work, large numbers of people usually need to be given the treatment and compared with similar people not given the treatment. The most reliable way to do this is using randomisation, a method whereby who gets given a treatment is determined by chance (like tossing a coin). These randomised trials also often involve masking (or blinding) the treatment so that neither the participants nor their doctors or nurses know if they are taking an active or dummy treatment, this helps with making the study reliable. Over the past several years, we have pioneered ways of running randomised trials involving thousands of people efficiently and cost-effectively to gain reliable information. We have developed a wide experience of using IT and centrally held health records to streamline the running of large trials. Partly why statin treatments are so widely used is as a result of studies that we have run. Ongoing studies include testing aspirin in people with diabetes and a new lipid changing drug added to statin therapy in people at high risk of heart problems.

Technical Summary

The aim of this programme is to generate reliable evidence about interventions with the potential for significant public health benefit. Treatments with even modest effects in common diseases (such as cancer, cardiovascular disease, diabetes, chronic kidney disease or osteoporosis) may make significant contributions to reducing morbidity and mortality globally. Building on epidemiological evidence generated in PHRU and elsewhere for associations between various biomarkers or risk factors (e.g. lipid markers, 25(OH) vitamin D), we aim to deliver large-scale randomised evidence to determine whether such associations are causal and reversible. Along with smoking and blood pressure, blood lipids are a major cause of cardiovascular disease, a major cause of morbidity and mortality worldwide. Higher levels of LDL cholesterol and lower levels of HDL cholesterol are associated with higher risks of coronary heart disease. Partly as a result of a series of large randomised trials (HPS, SEARCH and SHARP run by PHRU) and meta-analyses (also conducted by PHRU), statins, which effectively lower LDL cholesterol, are now very widely used for the primary and secondary prevention of cardiovascular disease. However, although widely used, available and highly cost-effective some patients remain at high risk despite statin use, thus additional safe treatments to modify risk are needed. Attention is now turning to newer drugs which modulate lipids by other mechanisms. The effects of such additional treatments on top of statins are likely to be modest, so large-scale randomised evidence are required to assess their effects reliably, hence the REVEAL trial of a cholesterol ester transfer protein inhibitor (CETPI) anacetrapib has randomized 30,000 people worldwide at risk of cardiovascular disease.
Over the last several years, PHRU has developed streamlined methods to recruit large numbers of patients and conduct trials efficiently (e.g. REVEAL) as well as cost-effectively (e.g. ASCEND), including using factorial designs to address more than one question at a time and using record linkage to facilitate follow-up, both during the trials (e.g. ASCEND, 3C, LENS) and in the longer-term (e.g. HPS, SEARCH). In addition, PHRU has piloted trials of non-commercial questions (e.g. high-dose vitamin D in older people) and of a combination of angiotensin receptor blocker and neprolysin inhibitor (ARNI) in chronic kidney disease with a view to securing funding for larger trials aiming to generate reliable evidence.
Dementia and other neurodegenerative diseases are also major causes of public health problems, and incur huge costs for families and health and social services, but they have been relatively poorly researched. Collaborating with other researchers, MADE and Schizophrenia ATLAS in neurodegenerative diseases will help answer important clinical questions and help build collaborations for the future.

Publications

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3C Study Collaborative Group (2018) Campath, calcineurin inhibitor reduction, and chronic allograft nephropathy (the 3C Study) - results of a randomized controlled clinical trial. in American journal of transplantation : official journal of the American Society of Transplantation and the American Society of Transplant Surgeons

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3C Study Collaborative Group (2018) Campath, calcineurin inhibitor reduction, and chronic allograft nephropathy (the 3C Study) - results of a randomized controlled clinical trial. in American journal of transplantation : official journal of the American Society of Transplantation and the American Society of Transplant Surgeons

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ASCEND Study Collaborative Group (2018) Effects of Aspirin for Primary Prevention in Persons with Diabetes Mellitus. in The New England journal of medicine

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ASCEND Study Collaborative Group (2018) Effects of Aspirin for Primary Prevention in Persons with Diabetes Mellitus. in The New England journal of medicine

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ASCEND Study Collaborative Group (2018) Effects of n-3 Fatty Acid Supplements in Diabetes Mellitus. in The New England journal of medicine

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Baigent C (2018) Should We Increase GFR with Bardoxolone in Alport Syndrome? in Journal of the American Society of Nephrology : JASN

 
Description BHF CRE Infrastructure Award Research grant: A comparison of the risk of cardiovascular events and cancer in the ASCEND study population with a similar population of people with diabetes identified using electronic primary care records.
Amount £30,000 (GBP)
Organisation British Heart Foundation (BHF) 
Sector Charity/Non Profit
Country United Kingdom
Start 01/2019 
End 03/2019
 
Description BHF grant for ASCEND
Amount £1,078,553 (GBP)
Funding ID SP/14/331114 
Organisation British Heart Foundation (BHF) 
Sector Charity/Non Profit
Country United Kingdom
Start 01/2015 
End 12/2018
 
Description National Institute for Health Research (NIHR) Infrastructure Visiting Speaker Award.
Amount £244 (GBP)
Organisation National Institute for Health Research 
Sector Public
Country United Kingdom
Start 01/2018 
End 01/2018
 
Description ASCEND-Eye 
Organisation Birmingham Heartlands Hospital
Country United Kingdom 
Sector Hospitals 
PI Contribution Each partnering Diabetic Eye Screening Programme is facilitating the data linkage by identifying appropriate staff to run a query on their local database. All collaborations commenced in November-December 2018 and are ongoing This project is in the early stages of finalising data sharing agreements before data extractions can begin.
Collaborator Contribution Each partnering Diabetic Eye Screening Programme is facilitating the data linkage by identifying appropriate staff to run a query on their local database. All collaborations commenced in November-December 2018 and are ongoing This project is in the early stages of finalising data sharing agreements before data extractions can begin.
Impact tbc
Start Year 2018
 
Description ASCEND-Eye 
Organisation Doncaster and Bassetlaw Hospitals NHS Foundation Trust
Department Doncaster Royal Infirmary
Country United Kingdom 
Sector Hospitals 
PI Contribution Each partnering Diabetic Eye Screening Programme is facilitating the data linkage by identifying appropriate staff to run a query on their local database. All collaborations commenced in November-December 2018 and are ongoing This project is in the early stages of finalising data sharing agreements before data extractions can begin.
Collaborator Contribution Each partnering Diabetic Eye Screening Programme is facilitating the data linkage by identifying appropriate staff to run a query on their local database. All collaborations commenced in November-December 2018 and are ongoing This project is in the early stages of finalising data sharing agreements before data extractions can begin.
Impact tbc
Start Year 2018
 
Description ASCEND-Eye 
Organisation East Sussex Healthcare NHS Trust
Country United Kingdom 
Sector Public 
PI Contribution Each partnering Diabetic Eye Screening Programme is facilitating the data linkage by identifying appropriate staff to run a query on their local database. All collaborations commenced in November-December 2018 and are ongoing This project is in the early stages of finalising data sharing agreements before data extractions can begin.
Collaborator Contribution Each partnering Diabetic Eye Screening Programme is facilitating the data linkage by identifying appropriate staff to run a query on their local database. All collaborations commenced in November-December 2018 and are ongoing This project is in the early stages of finalising data sharing agreements before data extractions can begin.
Impact tbc
Start Year 2018
 
Description ASCEND-Eye 
Organisation Farnham Hospital
PI Contribution Each partnering Diabetic Eye Screening Programme is facilitating the data linkage by identifying appropriate staff to run a query on their local database. All collaborations commenced in November-December 2018 and are ongoing This project is in the early stages of finalising data sharing agreements before data extractions can begin.
Collaborator Contribution Each partnering Diabetic Eye Screening Programme is facilitating the data linkage by identifying appropriate staff to run a query on their local database. All collaborations commenced in November-December 2018 and are ongoing This project is in the early stages of finalising data sharing agreements before data extractions can begin.
Impact tbc
Start Year 2018
 
Description ASCEND-Eye 
Organisation Hertford County Hospital
Country United Kingdom 
Sector Hospitals 
PI Contribution Each partnering Diabetic Eye Screening Programme is facilitating the data linkage by identifying appropriate staff to run a query on their local database. All collaborations commenced in November-December 2018 and are ongoing This project is in the early stages of finalising data sharing agreements before data extractions can begin.
Collaborator Contribution Each partnering Diabetic Eye Screening Programme is facilitating the data linkage by identifying appropriate staff to run a query on their local database. All collaborations commenced in November-December 2018 and are ongoing This project is in the early stages of finalising data sharing agreements before data extractions can begin.
Impact tbc
Start Year 2018
 
Description ASCEND-Eye 
Organisation Homerton University Hospital
PI Contribution Each partnering Diabetic Eye Screening Programme is facilitating the data linkage by identifying appropriate staff to run a query on their local database. All collaborations commenced in November-December 2018 and are ongoing This project is in the early stages of finalising data sharing agreements before data extractions can begin.
Collaborator Contribution Each partnering Diabetic Eye Screening Programme is facilitating the data linkage by identifying appropriate staff to run a query on their local database. All collaborations commenced in November-December 2018 and are ongoing This project is in the early stages of finalising data sharing agreements before data extractions can begin.
Impact tbc
Start Year 2018
 
Description ASCEND-Eye 
Organisation Hull Royal Infirmary
Country United Kingdom 
Sector Hospitals 
PI Contribution Each partnering Diabetic Eye Screening Programme is facilitating the data linkage by identifying appropriate staff to run a query on their local database. All collaborations commenced in November-December 2018 and are ongoing This project is in the early stages of finalising data sharing agreements before data extractions can begin.
Collaborator Contribution Each partnering Diabetic Eye Screening Programme is facilitating the data linkage by identifying appropriate staff to run a query on their local database. All collaborations commenced in November-December 2018 and are ongoing This project is in the early stages of finalising data sharing agreements before data extractions can begin.
Impact tbc
Start Year 2018
 
Description ASCEND-Eye 
Organisation John Radcliffe Hospital
Country United Kingdom 
Sector Hospitals 
PI Contribution Each partnering Diabetic Eye Screening Programme is facilitating the data linkage by identifying appropriate staff to run a query on their local database. All collaborations commenced in November-December 2018 and are ongoing This project is in the early stages of finalising data sharing agreements before data extractions can begin.
Collaborator Contribution Each partnering Diabetic Eye Screening Programme is facilitating the data linkage by identifying appropriate staff to run a query on their local database. All collaborations commenced in November-December 2018 and are ongoing This project is in the early stages of finalising data sharing agreements before data extractions can begin.
Impact tbc
Start Year 2018
 
Description ASCEND-Eye 
Organisation King's Mill Hospital
Country United Kingdom 
Sector Hospitals 
PI Contribution Each partnering Diabetic Eye Screening Programme is facilitating the data linkage by identifying appropriate staff to run a query on their local database. All collaborations commenced in November-December 2018 and are ongoing This project is in the early stages of finalising data sharing agreements before data extractions can begin.
Collaborator Contribution Each partnering Diabetic Eye Screening Programme is facilitating the data linkage by identifying appropriate staff to run a query on their local database. All collaborations commenced in November-December 2018 and are ongoing This project is in the early stages of finalising data sharing agreements before data extractions can begin.
Impact tbc
Start Year 2018
 
Description ASCEND-Eye 
Organisation Mid Yorkshire Hospitals NHS Trust
Country United Kingdom 
Sector Public 
PI Contribution Each partnering Diabetic Eye Screening Programme is facilitating the data linkage by identifying appropriate staff to run a query on their local database. All collaborations commenced in November-December 2018 and are ongoing This project is in the early stages of finalising data sharing agreements before data extractions can begin.
Collaborator Contribution Each partnering Diabetic Eye Screening Programme is facilitating the data linkage by identifying appropriate staff to run a query on their local database. All collaborations commenced in November-December 2018 and are ongoing This project is in the early stages of finalising data sharing agreements before data extractions can begin.
Impact tbc
Start Year 2018
 
Description ASCEND-Eye 
Organisation Norfolk and Norwich University Hospitals NHS Foundation Trust
Country United Kingdom 
Sector Public 
PI Contribution Each partnering Diabetic Eye Screening Programme is facilitating the data linkage by identifying appropriate staff to run a query on their local database. All collaborations commenced in November-December 2018 and are ongoing This project is in the early stages of finalising data sharing agreements before data extractions can begin.
Collaborator Contribution Each partnering Diabetic Eye Screening Programme is facilitating the data linkage by identifying appropriate staff to run a query on their local database. All collaborations commenced in November-December 2018 and are ongoing This project is in the early stages of finalising data sharing agreements before data extractions can begin.
Impact tbc
Start Year 2018
 
Description ASCEND-Eye 
Organisation Public Health Wales NHS Trust
Country United Kingdom 
Sector Public 
PI Contribution Each partnering Diabetic Eye Screening Programme is facilitating the data linkage by identifying appropriate staff to run a query on their local database. All collaborations commenced in November-December 2018 and are ongoing This project is in the early stages of finalising data sharing agreements before data extractions can begin.
Collaborator Contribution Each partnering Diabetic Eye Screening Programme is facilitating the data linkage by identifying appropriate staff to run a query on their local database. All collaborations commenced in November-December 2018 and are ongoing This project is in the early stages of finalising data sharing agreements before data extractions can begin.
Impact tbc
Start Year 2018
 
Description BEST-D collaboration Nuffield Department of Clinical and Laboratory Sciences 
Organisation University of Oxford
Department Nuffield Division of Clinical Laboratory Sciences
Country United Kingdom 
Sector Academic/University 
PI Contribution BEST-D study leads
Collaborator Contribution Shared blood samples for the BEST-D study. Undertaken study of impact of vitamin D on TRegulatory cells.
Impact Results are being written up
Start Year 2017
 
Description ORION-4 
Organisation The Medicines Company
Country Global 
Sector Private 
PI Contribution New trial HPS-4/TIMI 65/ORION-4, collaboration with The Medicines Company on a large scale outcomes study of inclisiran. Funding agreed December 2017 from the Medicines Company to the University of Oxford. Further collaboration with TIMI study group and Harvard University to coordinate the trial.
Collaborator Contribution Funding for the study
Impact n/a
Start Year 2017
 
Description University of South Dakota 
Organisation University of South Dakota
Country United States 
Sector Academic/University 
PI Contribution knowledge sharing
Collaborator Contribution knowledge sharing
Impact n/a
Start Year 2018
 
Description Adolescent Type 1 Diabetes Cardio-Renal Intervention Trialn (AdDIT) steering committee member 
Form Of Engagement Activity A formal working group, expert panel or dialogue
Part Of Official Scheme? No
Geographic Reach International
Primary Audience Professional Practitioners
Results and Impact Renal and Cardiovascular Risk According to Tertiles of Urinary Albumin-to-Creatinine Ratio: The Adolescent Type 1 Diabetes Cardio-Renal Intervention Trial (AdDIT). Marcovecchio ML, Chiesa ST, Armitage J, Daneman D, Donaghue KC, Jones TW, Mahmud FH, Marshall SM, Neil HAW, Dalton RN, Deanfield J, Dunger DB; Adolescent Type 1 Diabetes Cardio-Renal Intervention Trial (AdDIT) Study Group. Diabetes Care 2018; 41(9) 1963-1969
Year(s) Of Engagement Activity 2018
 
Description CTAP Clinical Trial Advisory Panel member for Alzheimer's Research UK ESC Research Committee 
Form Of Engagement Activity A formal working group, expert panel or dialogue
Part Of Official Scheme? No
Geographic Reach International
Primary Audience Professional Practitioners
Results and Impact CTAP Clinical Trial Advisory Panel member for Alzheimer's Research UK
ESC Research Committee
Year(s) Of Engagement Activity 2018
 
Description Can PPI improve recruitment and retention in clinical trials? 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Geographic Reach National
Primary Audience Professional Practitioners
Results and Impact 'Can PPI improve recruitment and retention in clinical trials?' NIHR Evaluation, Trials and Studies Coordinating Centre, Southampton (2018).
Year(s) Of Engagement Activity 2018
 
Description Co-chair of Global risk-based monitoring 
Form Of Engagement Activity A formal working group, expert panel or dialogue
Part Of Official Scheme? No
Geographic Reach International
Primary Audience Industry/Business
Results and Impact Sept 2018, Carol Knott invited as speaker and co-chair of 2 day conference: Global Risk-based Monitoring. Run in London for 60 attendees: Pharmaceutical Industry Quality Assurance Directors from across Europe. Outcome was sharing of methods of providing trial oversight without huge expenditure on routine on-site visits.
Year(s) Of Engagement Activity 2018
 
Description INTERVAL steering committee 
Form Of Engagement Activity A formal working group, expert panel or dialogue
Part Of Official Scheme? No
Geographic Reach International
Primary Audience Professional Practitioners
Results and Impact haired the steering Committee for the INTERVAL trial:
Di Angelantonio E, Thompson SG, Kaptoge S, Moore C, Walker M, Armitage J, Ouwehand WH, Roberts DJ, Danesh J; INTERVAL Trial Group. Efficiency and safety of varying the frequency of whole blood donation (INTERVAL): a randomised trial of 45 000 donors. Lancet 2017;390:2360-2371
Year(s) Of Engagement Activity 2018
 
Description Media interviews at ESC 2018 
Form Of Engagement Activity A press release, press conference or response to a media enquiry/interview
Part Of Official Scheme? No
Geographic Reach International
Primary Audience Media (as a channel to the public)
Results and Impact Series of media interviews undertaken by Martin Landray and Louise Bowman as a result of the publication of results of the ASCEND Trial. The results were announced at ESC Congress, August 2017 in Barcelona. Interviews with a wide variety of media organisations from around the globe.
Year(s) Of Engagement Activity 2018
 
Description Media interviews at ESC congress 2017 
Form Of Engagement Activity A press release, press conference or response to a media enquiry/interview
Part Of Official Scheme? No
Geographic Reach International
Primary Audience Media (as a channel to the public)
Results and Impact Series of media interviews undertaken by Martin Landray and Louise Bowman as a result of the publication of results of the REVEAL Trial. The results were announced at ESC Congress, August 2017 in Barcelona. Interviews with a wide variety of media organisations from around the globe.
Year(s) Of Engagement Activity 2017
 
Description PIRRIST: A patient and public involvement (PPI) intervention to enhance recruitment and retention in surgical trials 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Geographic Reach National
Primary Audience Professional Practitioners
Results and Impact 'PIRRIST: A patient and public involvement (PPI) intervention to enhance recruitment and retention in surgical trials.' Department of Health Sciences, University of York (2019).
Year(s) Of Engagement Activity 2019
 
Description PIRRIST: A patient and public involvement (PPI) intervention to enhance recruitment and retention in surgical trials 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Geographic Reach International
Primary Audience Professional Practitioners
Results and Impact Crocker JC, Rees S, Locock L, Petit-Zeman S, Chant A, Treweek S, Cook JA, Farrar N, Woolfall K, Bostock J, Harmston R, Ferrey A, Bulbulia R. PIRRIST: A patient and public involvement (PPI) intervention to enhance recruitment and retention in surgical trials. Oral presentation at IDEAL Conference, Bristol, 2018. Published in International Journal of Surgery 2018; 59, Supplement 1: S-S2, #3.
Year(s) Of Engagement Activity 2018
 
Description Workshop - Effective Monitoring in Clinical Trials 
Form Of Engagement Activity A formal working group, expert panel or dialogue
Part Of Official Scheme? No
Geographic Reach National
Primary Audience Professional Practitioners
Results and Impact May 2018, Carol Knott Invited by University of Oslo to run a day long workshop: Effective Monitoring in Clinical Trials for 30 Monitors and Quality Assurance Managers from across Norway. The focus was on performing a trial risk assessment and implementing 'risk-based monitoring'. Follow-up advice also provided about identifying 'trigger factors' for making on-site visits.
Year(s) Of Engagement Activity 2018
 
Description Workshop - Engaging tricky sites: hints and tips 
Form Of Engagement Activity A formal working group, expert panel or dialogue
Part Of Official Scheme? No
Geographic Reach National
Primary Audience Professional Practitioners
Results and Impact May 2018, Carol Knott Invited to run an In-Conference workshop at Society for Clinical Trials (SCT 2018) Portland, Oregon, US: Engaging tricky sites: hints and tips. The focus was on managing research sites through the trial life-cycle, to maximize efficiency of recruitment and maintaining compliance. Worked with international panel self, plus 3 others to deliver workshop for 80 attendees. Follow-up advice has been sought and provided to 3 workshop attendees from US Universities developing monitoring plans
Year(s) Of Engagement Activity 2018