Randomised trials in cardiovascular and metabolic disease

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 and kidney disease. 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 the decision about who receives a treatment is determined by chance (like tossing a coin). In order to help provide reliable results, 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. 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. Ongoing studies include testing a cholesterol-lowering drug added to statin therapy in people at high risk of heart problems, a new treatment for kidney disease and testing an established medication to investigate whether it can slow the worsening of eye disease in people with diabetes.

Technical Summary

This programme aims to generate reliable evidence about interventions with potential for significant public health benefit. Treatments with even modest effects in common diseases (such as vascular disease, diabetes or chronic kidney disease) may make significant contributions to reducing morbidity and mortality globally. Building on epidemiological evidence and other data generated in PHRU, CTSU and elsewhere, we aim to deliver large-scale randomised evidence to determine the efficacy and safety of treatments in cardiovascular and metabolic disease. 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 our large randomised trials (HPS, SEARCH and SHARP) and meta-analyses, statins, which effectively lower LDL cholesterol, are now very widely used for both primary and secondary prevention of cardiovascular disease. However 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 treatments on top of statins are likely to be modest, so large-scale randomised evidence is required to assess their effects reliably, hence the ORION-4 trial of a silencing RNA to PCSK9 (inclisiran) will recruit 15,000 people at high risk of cardiovascular disease. Participants will receive 6-monthly injections of inclisiran or placebo and be followed for at least 5 years at large streamlined clinics based in the UK and USA. Recent trials of sodium glucose co-transporter 2 inhibitors (SGLT2i) have shown they reduce the risk of cardiovascular disease (in particular heart failure) and progression of kidney disease among patients with diabetes. The mechanism by which SGLT2i affect kidney function does not require the presence of diabetes, so an important question in nephrology is whether SGLT2i also reduce the risk of cardiovascular disease and progression of kidney disease among patients with established chronic kidney disease, regardless of whether they have diabetes or not. The EMPA-KIDNEY trial will recruit at least 5000 participants with chronic kidney disease (at least a third with and a third without diabetes) and compare the effect of empagliflozin 10 mg daily versus placebo on a cardiorenal primary outcome. The LENS trial is also comparing an established treatment (fenofibrate) among participants with diabetic eye disease to test the hypothesis (raised by other trials) that fenofibrate may delay the progression of retinopathy.
Over the last several years, PHRU has developed streamlined methods to recruit large numbers of patients and conduct trials efficiently as well as cost-effectively (e.g. ASCEND), including 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). Such efforts will continue in the next quinquennium (including using the ongoing trials as laboratories for such methodological development) so that the outputs from this programme will not only be reliable answers to important questions in the treatment of cardiovascular and metabolic disease, but also rapidly transferable information on how to conduct such trials for use by the wider trials community.

Publications

10 25 50
 
Description ASCEND-Eye Diabetic Eye Screening Programme 
Organisation Bexhill Hospital
Country United Kingdom 
Sector Hospitals 
PI Contribution The ASCEND-Eye study will use linked data from the NHS Diabetic Eye Screening Programme (DESP) to determine whether aspirin or omega-3 fatty acids alter the course of diabetic retinopathy or diabetic maculopathy. Each partnering DESP is facilitating the data linkage by identifying appropriate staff to run a query on their local database, or to facilitate the software provider to extract data on their behalf.
Collaborator Contribution academic collaboration
Impact n/a
Start Year 2019
 
Description ASCEND-Eye Diabetic Eye Screening Programme 
Organisation Birmingham Heartlands Hospital
Country United Kingdom 
Sector Hospitals 
PI Contribution The ASCEND-Eye study will use linked data from the NHS Diabetic Eye Screening Programme (DESP) to determine whether aspirin or omega-3 fatty acids alter the course of diabetic retinopathy or diabetic maculopathy. Each partnering DESP is facilitating the data linkage by identifying appropriate staff to run a query on their local database, or to facilitate the software provider to extract data on their behalf.
Collaborator Contribution academic collaboration
Impact n/a
Start Year 2019
 
Description ASCEND-Eye Diabetic Eye Screening Programme 
Organisation Farnham Hospital
Country United Kingdom 
Sector Hospitals 
PI Contribution The ASCEND-Eye study will use linked data from the NHS Diabetic Eye Screening Programme (DESP) to determine whether aspirin or omega-3 fatty acids alter the course of diabetic retinopathy or diabetic maculopathy. Each partnering DESP is facilitating the data linkage by identifying appropriate staff to run a query on their local database, or to facilitate the software provider to extract data on their behalf.
Collaborator Contribution academic collaboration
Impact n/a
Start Year 2019
 
Description ASCEND-Eye Diabetic Eye Screening Programme 
Organisation Glenfield Hospital
Country United Kingdom 
Sector Hospitals 
PI Contribution The ASCEND-Eye study will use linked data from the NHS Diabetic Eye Screening Programme (DESP) to determine whether aspirin or omega-3 fatty acids alter the course of diabetic retinopathy or diabetic maculopathy. Each partnering DESP is facilitating the data linkage by identifying appropriate staff to run a query on their local database, or to facilitate the software provider to extract data on their behalf.
Collaborator Contribution academic collaboration
Impact n/a
Start Year 2019
 
Description ASCEND-Eye Diabetic Eye Screening Programme 
Organisation Gloucestershire Royal Hospital
Country United Kingdom 
Sector Hospitals 
PI Contribution The ASCEND-Eye study will use linked data from the NHS Diabetic Eye Screening Programme (DESP) to determine whether aspirin or omega-3 fatty acids alter the course of diabetic retinopathy or diabetic maculopathy. Each partnering DESP is facilitating the data linkage by identifying appropriate staff to run a query on their local database, or to facilitate the software provider to extract data on their behalf.
Collaborator Contribution academic collaboration
Impact n/a
Start Year 2019
 
Description ASCEND-Eye Diabetic Eye Screening Programme 
Organisation Hertford County Hospital
Country United Kingdom 
Sector Hospitals 
PI Contribution The ASCEND-Eye study will use linked data from the NHS Diabetic Eye Screening Programme (DESP) to determine whether aspirin or omega-3 fatty acids alter the course of diabetic retinopathy or diabetic maculopathy. Each partnering DESP is facilitating the data linkage by identifying appropriate staff to run a query on their local database, or to facilitate the software provider to extract data on their behalf.
Collaborator Contribution academic collaboration
Impact n/a
Start Year 2019
 
Description ASCEND-Eye Diabetic Eye Screening Programme 
Organisation Homerton University Hospital
Country United Kingdom 
Sector Hospitals 
PI Contribution The ASCEND-Eye study will use linked data from the NHS Diabetic Eye Screening Programme (DESP) to determine whether aspirin or omega-3 fatty acids alter the course of diabetic retinopathy or diabetic maculopathy. Each partnering DESP is facilitating the data linkage by identifying appropriate staff to run a query on their local database, or to facilitate the software provider to extract data on their behalf.
Collaborator Contribution academic collaboration
Impact n/a
Start Year 2019
 
Description ASCEND-Eye Diabetic Eye Screening Programme 
Organisation Hull Royal Infirmary
Country United Kingdom 
Sector Hospitals 
PI Contribution The ASCEND-Eye study will use linked data from the NHS Diabetic Eye Screening Programme (DESP) to determine whether aspirin or omega-3 fatty acids alter the course of diabetic retinopathy or diabetic maculopathy. Each partnering DESP is facilitating the data linkage by identifying appropriate staff to run a query on their local database, or to facilitate the software provider to extract data on their behalf.
Collaborator Contribution academic collaboration
Impact n/a
Start Year 2019
 
Description ASCEND-Eye Diabetic Eye Screening Programme 
Organisation John Radcliffe Hospital
Country United Kingdom 
Sector Hospitals 
PI Contribution The ASCEND-Eye study will use linked data from the NHS Diabetic Eye Screening Programme (DESP) to determine whether aspirin or omega-3 fatty acids alter the course of diabetic retinopathy or diabetic maculopathy. Each partnering DESP is facilitating the data linkage by identifying appropriate staff to run a query on their local database, or to facilitate the software provider to extract data on their behalf.
Collaborator Contribution academic collaboration
Impact n/a
Start Year 2019
 
Description ASCEND-Eye Diabetic Eye Screening Programme 
Organisation King's Mill Hospital
Country United Kingdom 
Sector Hospitals 
PI Contribution The ASCEND-Eye study will use linked data from the NHS Diabetic Eye Screening Programme (DESP) to determine whether aspirin or omega-3 fatty acids alter the course of diabetic retinopathy or diabetic maculopathy. Each partnering DESP is facilitating the data linkage by identifying appropriate staff to run a query on their local database, or to facilitate the software provider to extract data on their behalf.
Collaborator Contribution academic collaboration
Impact n/a
Start Year 2019
 
Description ASCEND-Eye Diabetic Eye Screening Programme 
Organisation Mid Yorkshire Hospitals NHS Trust
Country United Kingdom 
Sector Public 
PI Contribution The ASCEND-Eye study will use linked data from the NHS Diabetic Eye Screening Programme (DESP) to determine whether aspirin or omega-3 fatty acids alter the course of diabetic retinopathy or diabetic maculopathy. Each partnering DESP is facilitating the data linkage by identifying appropriate staff to run a query on their local database, or to facilitate the software provider to extract data on their behalf.
Collaborator Contribution academic collaboration
Impact n/a
Start Year 2019
 
Description ASCEND-Eye Diabetic Eye Screening Programme 
Organisation Moorfields Eye Hospital
Country United Kingdom 
Sector Hospitals 
PI Contribution The ASCEND-Eye study will use linked data from the NHS Diabetic Eye Screening Programme (DESP) to determine whether aspirin or omega-3 fatty acids alter the course of diabetic retinopathy or diabetic maculopathy. Each partnering DESP is facilitating the data linkage by identifying appropriate staff to run a query on their local database, or to facilitate the software provider to extract data on their behalf.
Collaborator Contribution academic collaboration
Impact n/a
Start Year 2019
 
Description ASCEND-Eye Diabetic Eye Screening Programme 
Organisation NHS England
Country United Kingdom 
Sector Public 
PI Contribution The ASCEND-Eye study will use linked data from the NHS Diabetic Eye Screening Programme (DESP) to determine whether aspirin or omega-3 fatty acids alter the course of diabetic retinopathy or diabetic maculopathy. Each partnering DESP is facilitating the data linkage by identifying appropriate staff to run a query on their local database, or to facilitate the software provider to extract data on their behalf.
Collaborator Contribution academic collaboration
Impact n/a
Start Year 2019
 
Description ASCEND-Eye Diabetic Eye Screening Programme 
Organisation Norfolk and Norwich University Hospitals NHS Foundation Trust
Country United Kingdom 
Sector Public 
PI Contribution The ASCEND-Eye study will use linked data from the NHS Diabetic Eye Screening Programme (DESP) to determine whether aspirin or omega-3 fatty acids alter the course of diabetic retinopathy or diabetic maculopathy. Each partnering DESP is facilitating the data linkage by identifying appropriate staff to run a query on their local database, or to facilitate the software provider to extract data on their behalf.
Collaborator Contribution academic collaboration
Impact n/a
Start Year 2019
 
Description ASCEND-Eye Diabetic Eye Screening Programme 
Organisation Public Health Wales NHS Trust
Country United Kingdom 
Sector Public 
PI Contribution The ASCEND-Eye study will use linked data from the NHS Diabetic Eye Screening Programme (DESP) to determine whether aspirin or omega-3 fatty acids alter the course of diabetic retinopathy or diabetic maculopathy. Each partnering DESP is facilitating the data linkage by identifying appropriate staff to run a query on their local database, or to facilitate the software provider to extract data on their behalf.
Collaborator Contribution academic collaboration
Impact n/a
Start Year 2019
 
Description EMPA Kidney regional coordinating centres 
Organisation Duke University
Department Duke Clinical Research Institute
Country United States 
Sector Academic/University 
PI Contribution 1. Duke Clinical Research Institute, Durham USA: DCRI is the US Regional Coordinating Centre for EMPA-KIDNEY paid by a grant from University of Oxford to DCRI. DCRI coordinates all activities for the trial in the US including management of 55 clinical centres and recruitment of 1250 participants. This collaboration began in 2018 and is ongoing. 2. University of British Columbia, Vancouver Canada. UBC is the US Regional Coordinating Centre for EMPA-KIDNEY paid by a grant from University of Oxford to UBC. UBC coordinates all activities for the trial in the US including management of 20 clinical centres and recruitment of 500 participants. This collaboration began in 2018 and is ongoing. 3. University of Wurzburg, Wurzburg Germany. UW is the German Regional Coordinating Centre for EMPA-KIDNEY paid by a grant from University of Oxford to UW. UW coordinates all activities for the trial in Germany including management of 35 clinical centres and recruitment of 1250 participants. This collaboration began in 2018 and is ongoing. 4. National Centre for CKD Research, Nanjing China. Nanjing is part of the China Regional Coordinating Centre for EMPA-KIDNEY paid by a grant from University of Oxford to Nanjing. Nanjing coordinates all activities for the trial in China including management of 25 clinical centres and recruitment of 1000 participants. This collaboration began in 2018 and is ongoing.
Collaborator Contribution research collaboration
Impact 2020-recruitment phase
Start Year 2019
 
Description EMPA Kidney regional coordinating centres 
Organisation University of British Columbia
Country Canada 
Sector Academic/University 
PI Contribution 1. Duke Clinical Research Institute, Durham USA: DCRI is the US Regional Coordinating Centre for EMPA-KIDNEY paid by a grant from University of Oxford to DCRI. DCRI coordinates all activities for the trial in the US including management of 55 clinical centres and recruitment of 1250 participants. This collaboration began in 2018 and is ongoing. 2. University of British Columbia, Vancouver Canada. UBC is the US Regional Coordinating Centre for EMPA-KIDNEY paid by a grant from University of Oxford to UBC. UBC coordinates all activities for the trial in the US including management of 20 clinical centres and recruitment of 500 participants. This collaboration began in 2018 and is ongoing. 3. University of Wurzburg, Wurzburg Germany. UW is the German Regional Coordinating Centre for EMPA-KIDNEY paid by a grant from University of Oxford to UW. UW coordinates all activities for the trial in Germany including management of 35 clinical centres and recruitment of 1250 participants. This collaboration began in 2018 and is ongoing. 4. National Centre for CKD Research, Nanjing China. Nanjing is part of the China Regional Coordinating Centre for EMPA-KIDNEY paid by a grant from University of Oxford to Nanjing. Nanjing coordinates all activities for the trial in China including management of 25 clinical centres and recruitment of 1000 participants. This collaboration began in 2018 and is ongoing.
Collaborator Contribution research collaboration
Impact 2020-recruitment phase
Start Year 2019
 
Description EMPA Kidney regional coordinating centres 
Organisation University of Wurzburg
Country Germany 
Sector Academic/University 
PI Contribution 1. Duke Clinical Research Institute, Durham USA: DCRI is the US Regional Coordinating Centre for EMPA-KIDNEY paid by a grant from University of Oxford to DCRI. DCRI coordinates all activities for the trial in the US including management of 55 clinical centres and recruitment of 1250 participants. This collaboration began in 2018 and is ongoing. 2. University of British Columbia, Vancouver Canada. UBC is the US Regional Coordinating Centre for EMPA-KIDNEY paid by a grant from University of Oxford to UBC. UBC coordinates all activities for the trial in the US including management of 20 clinical centres and recruitment of 500 participants. This collaboration began in 2018 and is ongoing. 3. University of Wurzburg, Wurzburg Germany. UW is the German Regional Coordinating Centre for EMPA-KIDNEY paid by a grant from University of Oxford to UW. UW coordinates all activities for the trial in Germany including management of 35 clinical centres and recruitment of 1250 participants. This collaboration began in 2018 and is ongoing. 4. National Centre for CKD Research, Nanjing China. Nanjing is part of the China Regional Coordinating Centre for EMPA-KIDNEY paid by a grant from University of Oxford to Nanjing. Nanjing coordinates all activities for the trial in China including management of 25 clinical centres and recruitment of 1000 participants. This collaboration began in 2018 and is ongoing.
Collaborator Contribution research collaboration
Impact 2020-recruitment phase
Start Year 2019
 
Description ORION-4 press announcement 
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 Public/other audiences
Results and Impact I was involved in some of the press activity around the announcement of the ORION-17 trial, including answering questions for the BHF and the Sun
Year(s) Of Engagement Activity 2019