Multicentre randomised controlled trial to compare the clinical and cost-effectiveness of a ‘vein bypass first’ with an ‘endovascular first’ revascularisation strategy for severe limb ischaemia due to infrageniculate arterial disease (Bypass v Angioplasty in Severe Ischaemia of the Leg, BASIL-2)

DESIGN: An individually randomised multi-centre pragmatic two-arm open trial of two alternative revascularisation strategies (vein bypass first vs. best endovascular first) for the management of severe limb ischaemia (SLI) due to below the knee (BTK) infra-geniculate (IG), with or without at or above the knee (AATK) femoro-popliteal (FP) disease, incorporating an internal pilot phase and within-trial health economic analysis. SETTING: Eleven UK regions comprising networks of vascular and endovascular surgical services located within NHS Hospital Trusts. TARGET POPULATION: Patients admitted to hospital with SLI due to BTK (IG), with or without AATK (FP), disease and who in the opinion of the responsible clinicians (vascular surgeons, interventional radiologists, diabetologists) require early BTK (IG) +/- AATK (FP) revascularisation in addition to evidence-based best medical therapy (BMT) and foot and wound care. HEALTH TECHNOLOGIES BEING ASSESSED: Participants will be allocated to either a ‘vein bypass first’ or a ‘best endovascular first’ (angioplasty +/- stent) revascularisation strategy. All patients will receive treatment to BTK (IG) arteries and, where clinically indicated, also to (FP) disease AATK. MEASUREMENT OF COSTS AND OUTCOMES: As recommended by NICE (CG 147) the primary outcome will be amputation free survival (AFS), defined as the time to major limb (above the ankle) amputation of the index (trial) limb or death from any cause. Follow-up will be between 2 and 5 years post intervention (median 3.3 years). Secondary end-points will include: • Overall survival (OS) • In-hospital and 30-day procedure related morbidity and mortality • Major adverse limb events (MALE) • Major cardiovascular events (SLI affecting the contralateral limb, acute coronary syndrome (ACS), stroke) • Relief of ischaemic pain (VAS, medication usage) • Psychological morbidity (HADS) • QoL assessed using generic (EQ-5D-5L, SF-12, ICECAP-O) and disease specific (VascuQoL) tools. • Re- and cross-over intervention rates • Healing of tissue loss (ulcers, gangrene) using SINBAD and PEDIS (International Working Group on the Diabetic Foot) classifications and the 2012 Infectious Diseases Society of America Clinical Practice Guideline for the Diagnosis and Treatment of Diabetic Foot Infections • Extent and healing of minor (toe and forefoot) amputations • Haemodynamic changes; absolute ankle and toe pressures as well as ankle and toe to brachial indices (ABI, TBI). Costs incurred to the NHS will be derived by measuring and valuing health care resource use. Relevant resource use will include using patient case notes and hospital record systems to obtain details of initial and subsequent procedures (bypass and/or interventional revascularisation) provided to patients; inpatient stay, length of hospital stay and use of resources during the stay. Information on consultations with general practitioners and practice-based nurses will be collected through patient-reported questionnaires. Cost to the individual patients and carers, due to out-of-pocket payments and travel expenses, will be collected through patient reported questionnaires. As in BASIL-1, outcomes will be measured by dedicated research nurses at baseline and months 1, 3, 6, 9, 12, 18, 24, 30 and 36 after randomisation. The primary AFS outcome will also be assessed at the end of the study follow-up period. SAMPLE SIZE: The trial will have a sample size of 600, equally randomised between the two groups, providing 90% power to detect a hazard ratio of 0.66 for the primary outcome of AFS at the 5% significance (equivalent to a difference in AFS at 3 years of 12% between 53% and 65%). The sample size calculation is based on a time-to-event analysis across the duration of trial, conservatively allowing for 10% loss-to-follow up (it was less than 1% in BASIL-1). PROJECT TIMETABLE INCLUDING RECRUITMENT RATES: Study duration of 69 months: 0-6: setup; 7-18 recruitment commences in all sites (internal pilot); 19-42: complete recruitment; 43-66: complete follow-up; 67-69: analysis and reporting. The internal pilot study will comprise the first year of recruitment and assess whether recruitment rates are adequate for the full study to be judged feasible. The trial will recruit in 11 regions across the UK (South and South West, South London, North London, Oxford, West Midlands, East Midlands, Hull and East of England, Leeds and West Yorkshire, Sheffield, North East, East and West Scotland). Some centres comprise a single large unit (e.g. Sheffield) while others represent a network of vascular units across several NHS Trusts (e.g. West Midlands, North and South London, Scotland). The PIs in each centre have reviewed the proposal; analysed their clinical activity; and have attested to the fact that they believe the proposed recruitment target of 2 patients per region per month is feasible and achievable (letters of support appended). Many of the PIs successfully recruited patients into BASIL-1. ECONOMIC EVALUATION: A within-trial economic evaluation will be carried out from the perspective of NHS and personal social services (PSS), based on the prospective collection of resource use and effectiveness data. The analysis will be based on a number of outcomes including cost per year AFS and QoL measures. In addition, a cost-utility analysis will be undertaken to calculate the cost per additional quality-adjusted life year (QALY) gained.