The BASIL-2 trial: comparing the clinical and cost-effectiveness of revascularisation strategies for severe limb ischaemia

The aim of the BASIL-2 (Bypass vs. Angioplasty in Severe Ischaemia of the Leg) trial is to determine whether a ‘vein bypass (VB) first’ or a ‘best endovascular treatment (BET) first’ revascularisation strategy represents the most clinically and cost-effective treatment for severe limb ischaemia (SLI) due to below the knee (infra-geniculate) arterial disease. The original BASIL trial, on which BASIL-2 builds, was carried out in 2000-2005 involving a separate cohort of 452 patients across 27 UK hospitals.

The data requested for BASIL-2 trial is crucially important in order to answer the study research question since the primary outcome of the trial is amputation free survival, defined as the time to major limb (above ankle) amputation of the index (trial) leg or death from any cause.

BASIL-2 is an individually randomised, multi-centre, pragmatic, two-arm, open trial of two alternative revascularisation strategies (VB first vs. BET first) for the management of SLI due to infra-popliteal (with or without inflow) disease. Patients are allocated to two intervention arms: part of patients will receive BET and another part receive VB surgery.

Patients affected by SLI due to below-the-knee disease, and who are suitable for both bypass surgery and endovascular treatment, are invited to be randomly allocated to one or other of the treatments.

The consent signed by participants and the BASIL 2 Trial application to NIHR’s Health Technology Assessment Programme (HTA Ref: 12-35-45) allows linkage to patient data available in the NHS routine clinical datasets, including mortality data from the Office of National Statistics (now referred to as Civil Registration (Deaths) data) through the Health and Social Care Information Centre (now NHS Digital) and other central UK NHS bodies. The linkage will allow University of Birmingham to double-check the main outcomes against routine data sources and extend the follow up of patients in the trial. It will also allow timely collection of accurate, long term outcome and health resource usage data without needing further contact with the study participants. This is important as it will link a trial of treatments that may become a clinical standard of care to long term outcomes that are routinely collected in clinical trial data but which will not be collected from participants during follow up period of the trial.

The GDPR lawful basis for University of Birmingham to process this data is Article 6(1)(e) and Article 9(2)(j). The study is in the interest of public health and advances of vascular science.

Processing is permitted under common law as all participants have consented; the consent form, participant information material and the original application (HTA Ref: 12-35-45) have been approved by the NRES Committee West Midlands - Coventry & Warwickshire (REC ref: 14/WM/0057).

The University of Birmingham are the Data Controller who will also process the data.

As well as the BASIL-2 trial sites in the UK, there are four trial sites located in Denmark and Sweden. No data provided under this agreement would be shared outside England and Wales; rather, the Danish and Swedish trial sites may provide their outcome information to the UK trial sites for comparison purposes, but not for any record level linkage.

The study Trial Steering Committee acts in an advisory capacity but does not have any decision making power over the purposes for which data will be processed, or the manner in which data shared under this agreement will be processed; therefore University of Birmingham are considered to be the sole data controller and the only organisation that will process data.

The trial was awarded NIHR funding in 2014 and this funding award is still active.

The trial has gone through a rigorous scientific peer review and undertaken a structured methodology which is set out in the study protocol and approved by the above Research Ethics Committee.

Regular newsletters are sent to participants, the latest one being Summer 2019, these provide participants with a regular update on the trial.

The study commenced in 2014 and as at June 2020 has recruited 329 participants from all sites. The revised target recruitment to the study is 389 participants in total. While four trial centres are based in Denmark and Sweden, the rest of the 50 trial hospital sites are located in the UK. The dataset will be requested for patients from England and Wales only, since the NHS Digital data does not cover Scotland. No NHS Digital data will be shared with Denmark and Sweden.

Since the primary outcome of the study is amputation-free survival or death, as described in the previous section, University of Birmingham require the following variables:

i. Date of death;

ii. Cause of death;

iii. Major amputation (amputation of leg above ankle)

iv. Leg (left or right)

v. Date of amputation

vi. Hospital where amputation was carried out.

The requested data will be used for primary outcomes as well as cost-effectiveness analysis.

The data requested will be a patient level information and have the intention to answer a specific research question- the primary objective of the study. The data provided to NHS Digital will be linked using the NHS number and patient's date of birth (date of birth will be needed as a second identifier for confirmation). The research is undertaken using a structured methodology, set out in the protocol and approved by both an appropriate ethics and scientific approval committee. The study is being conducted in compliance with Good Clinical Practice, Data Protection Act and General Data Protection Regulation. The risk of re-identification of participants outside of trial management team is minimised by removing the participants identifiable information prior to entering their trial data on the database. Participants are allocated a unique trial number which will be used for data linkage and overall data management.

The information will be stored on a hard drive which is maintained and backed up by the University IT service. The data will only be processed on the Birmingham University campus computers, locally, in the Birmingham Clinical Trials Unit building. The access to the computers will be user restricted and only trial members who are all substantive employees of University of Birmingham will have access to it. The data retrieved from NHS digital will be transferred on the secure trial database to enable statistical analysis. The study data will not be shared with any other organisation except in the form of aggregate outputs with small numbers suppressed in line with the HES Analysis Guide.

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 i.e.: employees, agents and contractors of the Data Recipient who may have access to that data).

As a result of data processing final results will be disseminated to The Vascular Society for Great Britain and Ireland, trial stakeholders and most importantly to the trial participants and public. The results will be communicated via publications, conferences, various media channels, the trial website and to the wider society. University of Birmingham aim to disseminate the final output after April 2022, which is an expected end of trial date. It is important to emphasise that the outputs will only include the aggregate, small number suppressed data (in line with the HES Analysis Guide), and no individual data will be published.

In line with HRA guidelines the results will be made available to the trial participants, and to other interested groups of communities if appropriate, in the form of newsletters, leaflets or pamphlets. The trial participants will be provided feedback on the outcome of research towards which they contributed. Output material will include a summary of the findings and information/links where to find more comprehensive results.

The BASIL-2 trial is registered with the International Standard Randomised Controlled Trial Number (ISRCTN) registry, thus adheres to the recent guidelines of World health Organisation (WHO) International Clinical registry Platform (ICTRP) and International Committee of Medical Journal Editors (ICMJE) on improving the publicly available information about clinical trials. The registration ensures free public domain access and use all the trial metadata generated during the process of registration, updating and reporting.

At the end of the study a full account of the research will be available on another public domain, NIHR Journals Library. This will contain comprehensive accounts on the trial. Other, smaller publication formats may also be considered. All publications in journals will go through a rigorous scientific peer review.

To improve the awareness of clinicians, and The Vascular Society in general, the final results will be presented at conferences. The BASIL-2 trial has a yearly representation at the Vascular Society for Great Britain and Ireland (at the STARS – St Thomas' Advanced Revascularisation Symposium – conference), to which nationally and internationally recognised figures in the field of lower limb revascularisation are invited. The updates will be delivered via lectures, case demonstrations or open discussions. New developments in the field of lower limb revascularisation will be discussed and shared.

The benefit of the study and of this particular exercise will be in the interest of public health and advances of vascular science.

Severe Limb Ischaemia (SLI) is the most severe form of lower limb peripheral arterial disease and is a seriously disabling, life and limb threatening condition. It is associated with a marked reduction in individual’s quality of life and has a poor prognosis. The current treatment options for SLI are vein bypass, endovascular intervention (angioplasty, stenting), amputation and end-of-life care. The SLI population covers one in every 1000-2000 diagnoses in the UK each year. Moreover, the incidence of SLI is rising primarily as a result of ageing population, increased incidences of diabetes and high rates of smoking. If the blood supply to the leg is not restored without delay, a patient is likely to lose their limb or die within 12 months.

At the societal level, caring for patients with SLI is extremely costly to NHS and social care services. This is mainly due to the often-prolonged recovery time from surgery and endovascular intervention. For example, in the BASIL-2 trial, patients on average spend 5-6 weeks in hospital during the first year after intervention, and 2-3 weeks per year thereafter. SLI patients are frequently discharged to nursing and residential homes and those that return home often require significant support in the community as well as costly adaptations to their houses.

It is clear that SLI presents a significant burden at both levels: at the society and personal level. For this reason it is important to determine which treatment (venous bypass or best endovascular treatment) is best at preventing amputation and death, avoiding ulcers and gangrene and relieving pain due to the blocked infra popliteal arteries.

It is also crucially important to study the relative costs of the two revascularisation strategies to see which method offers “the best value for money” for NHS and social care. This will only be achieved with robust data collection during the study.

University of Birmingham will process the personal data needed to establish the primary outcome (Amputation Free Survival – AFS) under GDPR Article 6(1)(e) 'task in the public interest' and Article 9(2)(j) 'scientific research'.

Differences in the primary outcome (AFS) between the trial arms will be assessed by comparing time from randomisation to major limb amputation or death from any cause between randomised groups, assessed up until the end of the follow up period up to 92 months. The trial will address the question of the choice of the first revascularisation strategy at the point of clinical equipoise. This will be answered by the planned Intention to Treat analysis for the primary outcome, where participants are analysed according to the first intervention they were allocated to, regardless of subsequent interventions received, or whether they actually receive the allocated intervention (a small proportion may not receive their allocated intervention).

The University of Birmingham aim to recruit a total 389 participants to the study (across all study sites) to randomise to two trial arms. Individual trial participants will not directly benefit from the study, but University of Birmingham will apply the generalisability of the results obtained from the chosen sample size to the population at large. The outputs of the study will be presented at conferences and vascular societies and the results drawn should inform policy makers to implement the guidelines and/or recommend further trials.

No data has been disseminated under the previous agreement so no yielded benefits have been achieved to date.