NHS Digital Data Release Register - reformatted

University of Glasgow

Project 1 — DARS-NIC-72180-R2L5Y

Opt outs honoured: Yes - patient objections upheld (Section 251)

Sensitive: Sensitive, and Non Sensitive

When: 2018/10 — 2018/12.

Repeats: One-Off, Ongoing

Legal basis: Health and Social Care Act 2012 – s261(7)

Categories: Identifiable

Datasets:

  • MRIS - Flagging Current Status Report
  • MRIS - Cause of Death Report
  • Hospital Episode Statistics Admitted Patient Care

Objectives:

Initial phase III clinical trials of febuxostat suggested that it may be associated with increased cardiovascular risk. Subsequent studies have not supported this risk and a definitive study to confirm or refute this safety concern is still required. The European Union (EU) Risk Management Plan (RMP) for febuxostat (Version 2.0; 19 February 2008) indicates that a post marketing study to evaluate cardiovascular effects of febuxostat is to be conducted as part of the Pharmacovigilance Plan. An outline synopsis of this study was presented as Annex 5 of the RMP. The FAST study is intended to fulfil this objective. It is a large safety study of febuxostat versus standard urate lowering therapy with allopurinol for chronic symptomatic hyperuricaemia. This study compares the relative cardiovascular safety of the two treatment strategies, and recruitment began in December 2011. Febuxostat is an effective treatment for gout. Aside from meeting the European Medicines Agency regulatory commitments, establishing that this drug is safe in patients who are at risk of cardiovascular disease is of clear benefit, offering an important alternative for managing this condition in a group of patients who are at risk of gout. Other aspects of drug safety are also assessed in the course of this trial by reporting of Serious Adverse Events through the pharmacovigilance process. Record linkage to national datasets of hospital admissions, deaths and cancer diagnoses is the primary method of identifying Serious Adverse Events and potential cardiovascular endpoints in the FAST study. Identification of all hospitalisations, deaths and diagnoses of cancer allows assessment of the safety of the study interventions, febuxostat and allopurinol. Record linkage output will only be used to identify Serious Adverse Events and study endpoints. The data will not be used for commercial purposes as this is an academic study involving university research groups. Record level data will only be received by the Robertson Centre for Biostatistics, University of Glasgow. Potential Serious Adverse Events will be identified there, and an anonymised report of these will be sent to the Medicines Monitoring Unit, University of Dundee, where they will be clinically reviewed by medical staff to identify potential endpoints and confirm Serious Adverse Events. This report will not include patient identifiable information, with participants only identified by study number. The study team at the University of Glasgow request further information about potential endpoint events from the healthcare services involved with the episode of care. This additional clinical information (which does not contain data from NHS Digital) is anonymised by the study team and submitted to a blinded endpoint committee for adjudication, allowing the robust identification of primary and secondary endpoints. Analysis of this data will determine the output of this study. The results of the FAST study will be disseminated through peer reviewed journals and scientific meetings. Other collaborating academic institutions will not be given access to record level data, but may be given aggregate data (with small numbers suppressed in line with the HES Analysis Guide) for further analysis. All study participants have given written informed consent for the study sponsor to access their electronic or other medical records. The study has been approved by Research Ethics Committee, the MHRA, The European Medicines Agency and local NHS R+D offices.

Expected Benefits:

This research will establish whether febuxostat is as safe as allopurinol with respect to cardiovascular outcomes (stroke, myocardial infarction and cardiovascular death). This study could result in changes to treatment guidelines in the way patients with gout are treated. The results will also inform regulators about the safety of different gout medications. Gout is the most common inflammatory arthritis, affecting around 2.5% of UK patients. It causes significant morbidity and impaired quality of life in patients. Benefits to patients Patients with gout often have reduced quality of life due to symptoms including pain and limitation of activities. Gout is a longterm condition and it is important to know which medications are safest for prevention of acute attacks of gout in patients. Benefits to the NHS Gout causes a significant cost burden on the NHS and costs are likely to increase further as the population ages. Results of the FAST study are expected to be available in 2020.

Outputs:

Results will be reported in a peer-reviewed journal and at major scientific and clinical meetings. The timescale for this is expected to be around 2020. The research team believe that the results of this study would be of interest to a high impact factor journal such as the Lancet or New England Journal of Medicine. The research team will organise press releases to coincide with the publication to promote knowledge mobilisation of the study results. The research team will also present the findings at major cardiovascular and rheumatology scientific and clinical meetings. Target date around 2020 as above. The research team will also send copies of the results to guideline groups such as NICE (National Institute for Health and Care Excellence) and SIGN (Scottish Intercollegiate Guidelines Network) and ask that they are considered and incorporated appropriately into revisions of guidelines. Target date 2020 as above. The research team will produce a non-technical summary of the results which the research team will send to patients who participated in the trial, patient groups and gout charities and the research team will work to generate media coverage of the study results and communicate these to the wider public. Target date 2020 as above. In this case, an additional output will be the determination of adjudicated endpoints/adverse events, which will mean the study can report to the EMA. Outputs will also be shared with funders, but ownership and control of the outputs rests with the University of Dundee.

Processing:

All organisations party to this agreement must comply with the Data Sharing Framework Contract requirements, including those regarding the use (and purposes of that use) by “Personnel” (as defined within the Data Sharing Framework Contract ie: employees, agents and contractors of the Data Recipient who may have access to that data). There will be no linkage of data provided by NHS Digital to any data, other than as described in this document. Any data shared outside of the University of Glasgow will contain only data that is aggregated (with small numbers suppressed in line with the HES Analysis Guide). Summary reports of serious adverse events and suspected unexpected serious adverse reaction reports are made to the Medicines and Healthcare products Regulatory Agency (MHRA) in line with clinical trials requirements. The Robertson Centre for Biostatics (part of the University of Glasgow, acting as Data Processor) will provide: - Data management (including e-CRF design, database setup and management, data validation) - Statistical analysis and reporting (final report, Independent Data Monitoring Committee reports) - Data management and statistical support to record linkage - provision of support for issues relating to data quality and use of endpoint adjudication system - project management and quality assurance - health economic analysis and reporting Sample size 456 positively adjudicated events will be required to show non-inferiority between the two study treatment arms with 80% statistical power, an upper limit of non-inferiority hazard ratio of 1.3 and a one-sided alpha of 0.025. It is estimated that 6142 randomised participants, followed up for an average of 3 years will be sufficient to accrue the required 456 positively adjudicated events, allowing for a 20% drop out from the per protocol population. Data will be received from NHS Digital and linked to trial data, and potential endpoints will be investigated further by obtaining information from medical records. Endpoint packages will be adjudicated by an endpoint committee blinded to treatment allocation. Data analysis will be carried out according to a pre-determined data analysis plan. The primary outcome and its individual components (CV death, non-fatal stroke and hospitalisation for non-fatal myocardial infarction/biomarker positive ACS) will be analysed using Cox proportional hazards models including the randomised treatment group and strata (previous cardiovascular events) as covariates. Statistical significance for treatment effects will be based on the Wald statistic and 95% confidence intervals of for the estimated hazard ratio comparing febuxostat to allopurinol. The primary analysis will be a non-inferiority analysis of the primary outcome based on the per-protocol (on randomised therapy) population. A supporting non-inferiority analysis will then be performed on the intention-to-treat (ITT) population. If non-inferiority is demonstrated, a superiority analysis will be carried out based on the ITT population. A prospective sensitivity analysis will also be carried out for both primary and secondary outcomes by censoring participant follow-up at 90 days beyond per-protocol period to ascertain if withdrawal is a presage of disease. The possibility of differential drop out in the per-protocol analysis will be adjusted for by in a further analysis adjusting for age, sex, cholesterol levels, systolic blood pressure, smoking status and past medical history of diabetes, hypertension and cardiovascular disease.