Title: WHiTE-DECI: World Hip Trauma Evaluation – Delirium and Cognitive Impairment; a randomised feasibility trial comparing severity of delirium symptomatology between hip fracture patients 60 years and over treated with a peri-operative infusion of anti-TNF or placebo.
Funder: Department of Health and Social Care

Abstract: Background Older patients with a hip fracture are at a particularly high risk of developing post-operative delirium due to the injury, pain, analgesia and the surgery required to treat the broken bone. National audit data in England, Wales and Northern Ireland for 2018 showed that 25% of patients with hip fracture suffered with post-operative delirium.Post-operative delirium is associated with reduced quality-of-life, longer hospital stays and increased mortality, as well as long-term cognitive impairment. This proposal seeks to investigate an intervention that could prevent or reduce the severity of post-operative delirium in patients with hip fracture. Aim The aim of this feasibility trial is to inform the design of a pragmatic multi-centre randomised controlled trial of anti-Tumour Necrosis Factor (TNF) vs placebo during hip fracture surgery with regard the severity of delirium symptomatology. Design A multi-centre, two-arm randomised placebo-controlled feasibility trial Participants All patients aged 60 years and over with a hip fracture are potentially eligible to participate in this study. Patients who lack capacity may be entered into the trial under a pre-specified consultee agreement process. Patients with contra-indications to anti-TNF and those treated non-operatively will be excluded. Intervention One hundred and twenty participants (60 per group) from a minimum of 4 UK hospitals will be randomly allocated to a single infusion of anti-TNF or placebo at the start of anaesthesia and continued during surgery. All other components of the hip fracture surgery and subsequent care will be at the discretion of the clinical team as per normal clinical practice. The trial will employ 1:1 random allocation, stratified by centre and the presence or absence of cognitive impairment before surgery. Outcomes The main outcome for this feasibility trial will be to establish the rate of recruitment in the context of a multi-centre feasibility pragmatic Clinical Trial of a Medicinal Product and to optimise trial processes, including intervention delivery and data collection. Outcomes for a potential definitive trial will also be assessed including the peak Memorial Delirium Assessment Scale on day 1-5 post-surgery and the health-related quality of life score EQ-5D-5L, development of cognitive impairment, mobility and residential status 4 months after hip fracture diagnosis. PPI input A recent NIHR James Lind Alliance Patient and Public Research Priority Setting Partnership, identified: &ldquo;What are the best treatments to prevent and treat confusion and delirium after surgery in adults with a fragility fracture of the lower limb?&rdquo; as a key research priority. The UK Musculoskeletal Trauma PPI group has been instrumental in the development of this application with specific input into i) the confirmation of the appropriateness of the proposed definitive study outcome instrument to measure effectiveness in this clinical setting, ii) the writing and editing of the plain English summary and iii) the proposed dissemination strategy. Continued PPI input will be provided by the PPI group under leadership from Lay co-applicant GRANT.

Lay abstract: This study has been designed following a James Lind Alliance Patient and Public Research Priority Setting Partnership, which identified the following question as a key research priority: &ldquo;What are the best treatments to prevent and treat confusion and delirium after surgery in adults with a broken bone in the leg?&rdquo; The study has been co-produced with the UK Musculoskeletal Trauma Patient and Public Involvement Group. A broken hip (hip fracture) is a very serious injury that requires surgery to repair or replace the broken bone followed by a long period in hospital to recover. Around a quarter of patients with hip fracture die within a year and those that survive have a permanent loss of quality of life. In the UK more than 70,000 people break their hip. Around a quarter of hip fracture patients have an episode of delirium around the time of their surgery. Delirium is a condition where the patient loses awareness of themselves and their environment, and has difficulty thinking clearly. For relatives and friends, as well as the patient, delirium is very disturbing. The symptoms of delirium are similar to those of patients with dementia but develop over a short period and tend to vary over time. In the short-term, delirium leads to longer stays in hospital and an increased risk of complications including death. In the longer-term, delirium is closely linked with an increased risk of developing dementia. Delirium is thought to be caused by inflammation in the brain. The inflammation is triggered by the injury and thought to get worse during surgery. This study will investigate a drug called infliximab which is given during surgery. Infliximab is a powerful anti-inflammatory drug. The aim of this study is to decide if patients who have operations on broken hips are less likely to have delirium, if we treat them with infliximab during the operation. This study is a small study which help decide if a larger study is feasible. Eligible patients will be approached for recruitment before their treatment where possible. Patients who are unable to consent for themselves may take part in the trial with the agreement of their relatives or an independent doctor. 120 participants from 4 hospitals will take part. Half will be allocated by chance to the study drug, and half to a placebo containing no infliximab. All other elements of the patients treatment will follow the normal care pathway for all hip fracture patients at the hospital. We will use a simple questionnaire to measure symptoms of delirium in the first five days after surgery. We will also assess the patients mobility, quality of life and complications, including the risk of infection and of developing dementia.

Research activity codes: 6.1 PHARMACEUTICALS
Health categories: INJURIES AND ACCIDENTS;MENTAL HEALTH