Use of a tumor necrosis factor antagonist for preventing or reducing post-operative delirium

Abstract

This invention provides a method of preventing or reducing post-operative delirium in a subject following a surgery or operation on said subject, the method comprising administering a therapeutically effective amount of a Tumour Necrosis Factor alpha (TNF) antagonist to said subject within three hours of said surgery or operation.

Description

Our Docket 92249-PCT (00456-0035)METHODS FOR PREVENTING OR REDUCING POST OPERATIVE DELIRIUM

[0001] This application claims the benefit of U.S. Provisional Application No. 63 / 751,000, filed January 29, 2025, the contents of which are hereby incorporated by reference.

[0002] Throughout this application, various publications are referenced, including referenced in parenthesis. The disclosures of all publications mentioned in this application in their entireties are hereby incorporated by reference into this application in order to provide additional description of the art to which this invention pertains and of the features in the art which can be employed with this invention.TECHNICAL FIELD

[0003] This disclosure relates to methods of preventing or reducing cognitive decline following surgery, including preventing or reducing post-operative delirium.BACKGROUND OF THE INVENTION

[0004] A broken hip (hip fracture) is a very serious injury that requires surgery to repair or replace the broken bone followed by a 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. Worldwide there are 1.3 million hip fractures each year, with more than 70,000 in the UK. Around a quarter of patients who have a hip fracture 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.SUMMARY OF THE INVENTION

[0005] This invention provides a method of preventing or reducing post-operative delirium in a subject following a surgery or operation on said subject, the method comprising administering a therapeutically effective amount of a Tumour Necrosis Factor (TNF) antagonist to said subject within three hours of said surgery or operation.BRIEF DESCRIPTION OF THE DRAWINGS

[0007] Fig. 1 shows a flow chart for a clinical trial protocol for determining if patients who have operations for hip fractures are less likely to have delirium when treating with infliximab during the operation.

[0008] Inclusion Criteria:

[0009] 1. Patient’s age 60 years old and over.

[0010] 2. Patient is diagnosed with a hip fracture that in the opinion of the treating surgeon may benefit from surgical treatment.

[0011] Exclusion Criteria:

[0012] 1. The patient has severely impaired renal function eGFR <30 ml.min-1.

[0013] 2. The patient has severely impaired hepatic function.

[0014] 3. The patient is currently taking any anti-TNF drug.

[0015] 4. The patient has a contra-indication to anti TNF injection.

[0016] 5. The patient has a known hypersensitivity to any anti-TNF agent or any of the excipients.

[0017] 6. The patient has known active tuberculosis (TB) or history of TB or at risk of developing TB e.g., through the use of immunosuppressants.

[0018] 7. The patient has another known active infection (chronic or localised) or known history of recurring infections or condition which may predispose patients to infection, including the use of concomitant immunosuppressive medications.

[0019] 8. The participant has known lung fibrosis.

[0020] 9. The patient had systemic inflammatory disorder such as rheumatoid arthritis or inflammatory bowel disease.

[0021] 10. The patient has known moderate to severe heart failure (NYHA class III / IV).

[0022] 11. The patient has HIV, Hepatitis B or C (based on medical history).

[0023] 12. The patient is at risk of Hepatitis B or HIV infections, including intravenous drug use.

[0024] 13. The patient has been diagnosed with Multiple Sclerosis (MS) or other central or peripheral nervous system demyelinating disorders.

[0025] 14. History of malignancy within five years prior to screening or any evidence of persistent malignancy, except basal cell or squamous cell carcinomas of the skin, or cervical carcinoma in situ which has been treated or excised in a curative procedure.

[0026] 15. The patient has had a live vaccination 4 weeks prior to study entry or will require one within 12 weeks after the study intervention.

[0027] 16. The patient takes biologies or DMARDS.

[0028] 17. The patient is or has been participant in a clinical trial of a medicinal product in the last 12 weeks.

[0029] 18. Previous participation in the same randomized comparison.

[0030] 19. A second hip fracture (other side) while the patient is still enrolled in the Platform following their first hip fracture.DETAILED DESCRIPTION

[0032] The following embodiments and examples (including details thereof) are set forth to aid in an understanding of the subject matter of this disclosure but are not intended to, and should not be construed to, limit in any way the invention that is claimed.

[0033] This invention provides a method of preventing or reducing post-operative delirium in a subject following a surgery or operation on said subject, the method comprising administering a therapeutically effective amount of a Tumour Necrosis Factor (TNF) antagonist to said patient within three hours of said surgery or operation.

[0034] In some embodiments, the surgery or operation is an orthopedic surgery or operation.

[0035] In some embodiments, the surgery or operation is to repair a hip fracture or is a hip replacement surgery.

[0036] In some embodiments, the surgery or operation is to repair a knee fracture or is a knee replacement surgery.

[0037] In some embodiments, the surgery or operation is a cardiac surgery, preferably a cardiac bypass grafting surgery.

[0038] In some embodiments, the subj ect has a chest infection and / or a urinary tract infection (UTI).

[0039] In some embodiments, the subject is administered the TNF antagonist after the chest infection and / or a UTI is detected.

[0040] In some embodiments, the TNF antagonist is an anti-TNF antibody, antibody-like molecule, antibody fragment or fusion thereof, aptamer, siRNA molecule, an antisense oligonucleotide, a ribozyme, or a small chemical inhibitor.

[0041] In some embodiments, the TNF antagonist is infliximab, adalimumab, or etanercept.

[0042] In some embodiments, the TNF antagonist is infliximab.

[0043] In some embodiments, the administering is intravenous administering. In some embodiments, the administering is subcutaneous administering.

[0044] In some embodiments, the administering occurs up to thirty minutes before the surgery or operation.

[0045] In some embodiments, the administering begins before the surgery or operation, and continues for up to 1.5 hours during the course of surgery or operation.

[0046] In some embodiments, the subject is intravenously administered a single infusion of infliximab at 5mg / kg body weight, diluted in 250ml of 0.9% saline.

[0047] In some embodiments, the TNF antagonist is a TNF receptor antagonist, preferably an anti-TNF receptor antibody, antibody-like molecule, antibody fragment or fusion thereof, aptamer, siRNA molecule, an antisense oligonucleotide, a ribozyme, or a small chemical inhibitor.

[0048] In some embodiments, the TNF antagonist is administered after the subject is anesthetized but before commencement of surgical cutting.

[0049] In some embodiments, the TNF antagonist is administered during the surgery or operation, preferably continuing during the total duration of the surgery or operation.

[0050] In some embodiments, the duration of the surgery or operation is less than two hours, preferably about one hour or less.

[0051] In some embodiments, the subject does not display symptoms of delirium in the five days following the operation or surgery.

[0052] In some embodiments, the subject’s cognitive impairment score, mobility, and / or mortality risk is unchanged or improved at 4 to 12 months after the operation or surgery relative to their cognitive impairment score, mobility, and / or mortality risk at the time of the surgery or operation.

[0053] In some embodiments, the subject’s Memorial Delirium Assessment Score (MDAS) score within five days following the operation or surgery is less than 10, preferably less than 5, more preferably less than 2.

[0054] In some embodiments, the subject’s Telephone Interview for Cognitive Status (TICS) and / or Euroquol-5D-5L (EQ-5D-5L) score is unchanged or improved at 4 to 12 months after the operation or surgery relative to the subject’s TICS or EQ-5D-5L score at the time of the surgery or operation.

[0055] In some embodiments, the subject does not develop a surgical complication, preferably a surgical complication of grade 3 or above, during or after the surgery or procedure. In an non-limiting example, the subject does not develop a surgical complication of grade 3 or above within a month to a year after the surgery or procedure.

[0056] In some embodiments, the subject is at risk of developing post-operative delirium, preferably wherein the subject is age 60 or older and / or has a pre-existing cognitive impairment.

[0057] By “preventing cognitive decline following surgery” we include the meaning that the method, use or agent of the invention is considered to reduce the likelihood of the occurrence of cognitive decline in a patient who has undergone a surgical procedure. Thus, the invention may be used, or be for use, prophylactically before any sign of cognitive decline following surgery develops in the patient. While it is preferred that cognitive decline is prevented from occurring in the patient, it is understood that some incidence of cognitive decline following surgery may still remain but it is envisaged that the use of the present invention will reduce the symptoms of, and / or reduce the persistence of, that cognitive decline. Thus, by “reducing cognitive decline following surgery” we include the meaning that the duration and or severity of post-operative delirium is lessened and the symptoms are reduced thus improving the cognition of the patient while perhaps not entirely preventing the onset of the cognitive decline. This can be established by a battery of neuropsychological tests.

[0058] By “cognitive decline” we include the meaning of any condition that manifests in impaired cognitive function in a patient. Such disorders may arise in patients of any age. The symptoms of such disorders may include drowsiness, fatigue, concentration impairment, vertigo, confusion, memory impairment, memory loss, delirium, loss of motor neuronal control and other such symptoms as would be understood by a person of skill in the art.

[0059] Delirium is a symptom, or group of symptoms, but is also a syndrome, which is caused by a disturbance in the normal functioning of the brain. Thus, it is envisaged that while delirium may be a symptom of the cognitive disorder, where another disorder is present, it may also be the only cognitive disorder that has presented in the patient and thus the present invention may be beneficial where no other cognitive disorder has yet been characterized but the patient is exhibiting signs of delirium.

[0060] By “cognitive decline following surgery”, we include the deterioration of intellectual function reflected as memory and concentration impairment presenting in a patient after that patient has undergone a surgical procedure. Such deterioration of intellectual function may take many forms and as such this definition includes any form of cognitive decline presenting post-operatively. The present invention is considered to be particularly useful when administered before, during or immediately following surgery. In general, cognitive dysfunctions followingsurgery are common and effective immediately following recovery. Delirium is commonly seen after surgery, usually soon after surgery (hours to days) and fluctuating over time.

[0061] It is envisaged that the symptoms of cognitive decline following surgery may include memory loss, memory impairment, concentration impairment, delirium, dementia, and / or sickness behavior.

[0062] By “delirium” is included an acute and debilitating decline in attention, focus, perception, and cognition that produces an altered form of semi-consciousness. Delirium is a syndrome, or group of symptoms, caused by a disturbance in the normal functioning of the brain. The delirious patient has a reduced awareness of and responsiveness to the environment, which may be manifested as disorientation, incoherence, and memory disturbance.

[0063] By “reducing cognitive decline” we include the meaning that the progression of the symptoms of the cognitive disorder over time is slowed and those symptoms are lessened and potentially reversed by the use of the invention. The invention may be used to improve cognitive function by reducing the onset of cognitive decline. Such an improvement may provide patients with greater independence and a greater quality of life.

[0064] In an embodiment of any aspect of the present invention a TNF antagonist may be administered systemically. Such systemic administration may, for example, be by intravenous (i.v.) administration in an appropriate formulation. It is envisaged that i.v. administration will lead to a rapid and more efficacious effect. An example of an embodiment where systemic administration may be appropriate includes administration to patients who are undergoing one or more multiple surgical procedures, or where the surgical procedure results in major trauma to the body.

[0065] The dose may be between 0.01 to 500 mg / kg body weight; 1 to 400 mg / kg body weight; 2 to 200 mg / kg body weight; 3 to 100 mg / kg body weight or 4 to 50 mg / kg (or any combination of these upper and lower limits, as would be appreciated by the skilled person). The dose used may in practice be limited by the solubility of the compound. Examples of possible doses are 0.01, 0.05, 0.075, 0.1, 0.2, 0.5, 0.7, 1, 2, 5, 10, 12, 15, 20, 25, 30, 35, 40, 45, 50 or 100 mg per kg body weight up to, for example 500 mg / kg body weight, or any value in between. It is envisaged that preferred doses of TNF antagonist would be adjusted according to relative potency.

[0066] In embodiments of the invention relating to preventing or reducing cognitive decline following a planned inflammatory trigger, the TNF antagonist may be administered, or may befor administration, before, during or after the surgery or operation. For example, the TNF antagonist may be administered before the commencement of a surgical procedure on said patient. Such administration may be immediately before surgery or several seconds, minutes or even hours before surgery. Alternatively, the TNF antagonist may be administered during a surgical procedure on said patient.

[0067] In yet another alternative, the TNF antagonist may be administered, or may be for administration, after completion of a surgical procedure on said patient. In this embodiment, it is envisaged that the TNF antagonist may be administered, or may be for administration, up to 3 hours, preferably within 1 hour, after completion of said surgical procedure. Alternatively, the TNF antagonist may be administered, or may be for administration, between 0 seconds (i.e. immediately after completion of the surgical procedure) up to 1 day after completion of the surgical procedure. Thus this may be between 5 seconds and 10 hours after completion of the surgical procedure. Preferably, this may be between 30 seconds and 1 hour, for example 30 minutes, after completion of the surgical procedure. Such administration (or administration in any other aspect of the invention) may comprise a single administration of a single dose, or may comprise multiple administrations of the same, increasing, or decreasing doses, as appropriate. Thus, the administration may be over a course of time as prescribed by the physician.

[0068] By “TNF antagonist” we include the meaning that the antagonist is any compound that antagonizes, thus decreases or ablates, the effects of TNF. Thus the antagonist may be a compound that targets TNF itself, a compound that targets any upstream effector of TNF or a compound that targets any downstream effector of TNF. By “targeting TNF itself’ we mean blocking or reducing the transcription, translation, post-translational modification of precursors, or release of TNF from cells where it is synthesized, as would be understood by a person of skill in the art. By “targets any upstream effector of TNF” we mean any signal or molecule that triggers the synthesis and / or release of TNF. By “targets any downstream effector of TNF” we mean any receptor or other compound that interacts with TNF to bring about its effects in vivo.

[0069] Thus, in any aspect of the invention, the TNF antagonist may be a TNF receptor antagonist.

[0070] The TNF antagonist may be an antibody, an antibody fragment or fusion thereof. Thus, the TNF antagonist may be an anti-TNF antibody or fragment or fusion thereof. Suchantibodies may be polyclonal or monoclonal. Non-human antibodies may be humanized, for use in human patients. The antibodies may alternatively be chimeric, as would be understood by a person of skill in the art. The antibody fragment may be a Fab, Fv, ScFv or dAb, as would be understood by those skilled in the art. By “ScFv molecules” we mean molecules wherein the VH and VL partner domains of the antibody are linked via a flexible oligopeptide.

[0071] The advantages of using antibody fragments, rather than whole antibodies, are several-fold. The smaller size of the fragments may lead to improved pharmacological properties, such as better penetration of solid tissue. Effector functions of whole antibodies, such as complement binding, are removed. Fab, Fv, ScFv and dAb antibody fragments can all be expressed in and secreted from E. colt, thus allowing the facile production of large amounts of the said fragments. Whole antibodies, and F(ab')2 fragments are “bivalent”. By “bivalent” we mean that the said antibodies and F(ab')2 fragments have two antigen combining sites. In contrast, Fab, Fv, ScFv and dAb fragments are monovalent, having only one antigen combining site.

[0072] Many available TNF antagonists may be useful in the context of the present invention. Agents which bind TNF and block its action include anti human TNF monoclonal antibodies, marketed examples include infliximab (Remicade®), adalimumab (Humira®), human TNF-R fusion protein such as etanercept (Enbrel®) or other agents which resemble antibodies which bind TNF.

[0073] Inhibitors of TNF receptor include antibodies or antibody-like molecules (fragments, chains, dAbs etc) which bind to TNF receptors, more are marketed at present.

[0074] Inhibitors of TNF signaling, and signaling pathways, include inhibitors of NFKB. MAP kinases etc. could also be used.

[0075] Alternatively, the TNF antagonist may be a small chemical entity. Such chemical entities may be identified through high-throughput screening of compound libraries, or they may be designed in silico to interact with their intended target, such as receptors for TNF.

[0076] In an alternative embodiment, the TNF antagonist may be an aptamer, siRNA molecule, an antisense oligonucleotide, or a ribozyme. In some embodiments, an aptamer is administered in the same manner as an antibody (e.g., intravenously or subcutaneously). Thus, such antagonists may inhibit the transcription and / or translation of TNF, as appropriate. Antisense oligonucleotides are single-stranded nucleic acids, which can specifically bind to a complementary nucleic acid sequence. By binding to the appropriate target sequence, an RNA-RNA, a DNA-DNA, or RNA-DNA duplex is formed. These nucleic acids are often termed “antisense” because they are complementary to the sense or coding strand of the gene. Formation of a triple helix has proven possible where the oligonucleotide is bound to a DNA duplex. It was found that oligonucleotides could recognize sequences in the major groove of the DNA double helix. A triple helix was formed thereby. This suggests that it is possible to synthesize sequence-specific molecules which specifically bind double-stranded DNA via recognition of major groove hydrogen binding sites.

[0077] By binding to the target nucleic acid, the above oligonucleotides can inhibit the function of the target nucleic acid. This could, for example, be a result of blocking the transcription, processing, poly(A)addition, replication, translation, or promoting inhibitory mechanisms of the cells, such as promoting RNA degradations.

[0078] Antisense oligonucleotides are prepared in the laboratory and then introduced into cells, for example by microinjection or uptake from the cell culture medium into the cells, or they are expressed in cells after transfection with plasmids or retroviruses or other vectors carrying an antisense gene.

[0079] Typically, antisense oligonucleotides are 15 to 35 bases in length. For example, 20-mer oligonucleotides have been shown to inhibit the expression of the epidermal growth factor receptor mRNA (Witters et al, Breast Cancer Res Treat 53:41-50 (1999)) and 25-mer oligonucleotides have been shown to decrease the expression of adrenocorticotropic hormone by greater than 90% (Frankel et al, J Neurosurg 91:261-7 (1999)). However, it is appreciated that it may be desirable to use oligonucleotides with lengths outside this range, for example 10, 11, 12, 13, or 14 bases, or 36, 37, 38, 39 or 40 bases.

[0080] It is envisaged that the surgical procedure or operation may be carried out under general anesthesia, regional anesthesia, local anesthesia, sedation or a combination thereof. By “general anesthesia” is meant anesthesia where the patient is “asleep”, i.e. not conscious, during the surgical procedure. There are three phases of general anesthesia: induction (getting off to sleep); maintenance (keeping asleep while having the surgical procedure); and emergence (waking up after the operation). Different drugs are utilized at these different stages. It is envisaged that the present invention may be suitable for application during all three phases. It is envisaged that the antagonists of the present invention may be combined with other drugs, such as anesthetic drugs, for ease of administration during the different phases of anesthesia, if appropriate, as would be directed by the physician.

[0081] Regional anesthesia involves an infusion or single injection of local anesthetic sometimes with additives (opiods, clonidine, etc) at a site away from the operative field. For example, spinal (intrathecal) anesthesia (caesareans, prostate surgery, knee surgery), epidural anesthesia, caudal anesthesia, regional nerve blocks (Bier’s block for the arm). The present invention may also be useful for application in surgical procedures carried out under regional anesthesia. Antagonists of the present invention may be combined with anesthetic formulations for ease of administration, if appropriate.

[0082] Local anesthesia involves injection of local anesthetic drugs close to the area where the procedure is to be carried out.

[0083] As used herein, “about” in the context of a numerical value or range means ±10% of the numerical value or range recited.

[0084] As used herein, an “amount” of a compound as measured in milligrams refers to the milligrams of compound present in a preparation, regardless of the form of the preparation. An “amount of compound which is 80 mg” means the amount of the compound in a preparation is 80 mg, regardless of the form of the preparation. Thus, when in the form with a carrier, the weight of the carrier necessary to provide a dose of 80 mg compound would be greater than 80 mg due to the presence of the carrier.

[0085] As used herein, to “treat” or "treating" encompasses, but is not limited to inducing inhibition, regression, or stasis of the disorder and / or disease. As used herein, “inhibition” of disease progression, disease symptoms or disease complications in a subject means preventing, reducing or reversing the disease progression, disease symptoms and / or disease complications in the subject.

[0086] It is understood that where a parameter range is provided, all integers within that range, and tenths thereof, are also provided by the invention. For example, “20-40 mg” includes 20.0 mg, 20.1 mg, 20.2 mg, 20.3 mg, etc. up to 40.0 mg.

[0087] For the foregoing embodiments, each embodiment disclosed herein is contemplated as being applicable to each of the other disclosed embodiments.EXAMPLESExample 1 - World Hip Trauma Evaluation - Delirium and Cognitive Impairment

[0088] A broken hip (hip fracture) is a very serious injury that requires surgery to repair or replace the broken bone followed by a period in hospital to recover. Around a quarter ofpatients with hip fracture die within a year and those that survive have a permanent loss of quality of life. Worldwide there are 1.3 million hip fractures each year, with more than 70,000 in the UK. Around a quarter of patients who have a hip fracture 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 they are treated with infliximab during the operation.

[0089] This study is open to all patients aged over 60 years with a hip fracture, apart from the very small number of patients who do not have an operation on their hip. 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. Patients at approximately 8 hospitals in the UK will be approached to take part in the study. 564 participants will take part, with half being allocated by chance to receiving infliximab, and half to receiving a placebo containing no infliximab. Neither the patients nor their doctors will know which treatment they had to make the study fair. All other elements of the patients’ treatment will follow the normal care pathway for all hip fracture patients at the hospital.

[0090] A simple questionnaire is used to measure symptoms of delirium in the first five days after surgery. The patients’ mobility, quality of life and complications, including the risk of infection and of developing dementia in the 12 months after surgery is assessed. Some participants may also consent to have their brain waves monitored during surgery and to have small blood samples taken before and in the days after surgery to measure the level of inflammation in the blood.

[0091] Table 1: Synopsis

[0092] Table 2: Abbreviations

[0093] BACKGROUND AND RATIONALE

[0094] What is the clinical problem being addressed?

[0095] Delirium is a common neuropsychiatric syndrome defined as disturbance of attention, awareness and cognition which develops over a short period of time, represents a change from baseline and tends to fluctuate during the course of the day.1Older patients with hip fracture are at particularly high risk of developing post-operative delirium due to the physiological stress and inflammation from the injury, pain and associated analgesia, and the surgery required to treat the broken bone. UK national audit data for 2018 showed that 25% of all patients with hip fracture suffered with post-operative delirium.2As well as being distressing for patientsand their families, post-operative delirium is associated with poor functional outcomes, reduced quality of life, longer hospital stays and increased mortality.3,4People with hip fracture admitted from their own home who develop delirium are twice as likely to die while in hospital, and nearly four times more likely to need placement in a nursing home, compared to those who do not develop delirium in the post-operative period. Furthermore, post-operative delirium is also closely associated with long-term cognitive impairment.5,6

[0096] In this trial we will investigate if an infusion of the anti-TNF agent infliximab during surgery, has an effect on delirium symptoms in the immediate post-operative period and on the development of cognitive impairment, quality of life and mortality in the following year.

[0097] How does the existing literature support this proposal?

[0098] The inflammatory response following surgery is associated with the development of delirium and long-term cognitive impairment. The cytokines released in the periphery as a result of the surgical trauma lead to increased permeability of the blood brain barrier,7ingress of activated monocytes and activation of the microglia, which lead to neuronal injury and delirium.3Although a wide variety of inflammatory mediators have been implicated in the development of delirium, there is compelling evidence that many of the effects are mediated by TNF.8In patients undergoing coronary artery bypass grafting, post-operative TNF levels were found to be raised in the group who developed delirium,9and in a series of 148 patients, including 75 cases with fractures, surgery was associated with increased levels of circulating TNF, with a positive correlation of TNF and IL-6 levels and the development of delirium.10A study of cytokines in the systemic circulation and the CSF in patients aged >55yr undergoing knee surgery found no change in TNF levels at 3 hours and beyond post-surgery, although IL-6 was increased in both blood and CSF.11However, TNF is released within a few minutes of commencement of surgery and has a relatively short half-life of approximately 30 min in the circulation. Therefore, timing of blood sampling is crucial. In a group of 124 patients aged >70years undergoing hip arthroplasty under epidural anesthesia, there was an increase in plasma TNF levels 30 min after anesthesia.12

[0099] Raised levels of TNF are also associated with impaired cognitive function in non-surgical patients. In a series of 300 patients with mild to severe Alzheimer’s disease, raised serum TNF levels were associated with increased neuropsychiatric symptoms characteristic of sickness behavior, independent of delirium.13Furthermore, acute systemic inflammatory events in patients with Alzheimer’s disease were associated with higher circulating TNF levelsand increase in cognitive decline.14Higher levels of TNF and IL-6 were associated with smaller hippocampal volume on magnetic resonance imaging scan in 28 older adults.15

[0100] Various strategies have been used in an attempt to reduce post-operative cognitive dysfunction16and act, at least in part, by reducing TNF levels. They include modification of anesthetic agents17as well as ancillary treatments that also have been shown to result in diminished pro-inflammatory cytokine levels, including TNF. Whilst the use of regional anesthesia is not associated with lower levels of circulating proinflammatory cytokines compared to general anesthesia,18volatile anesthetic agents such as sevoflurane have been associated with elevated serum TNF and IL-6 and a higher incidence of delirium in elderly patients undergoing surgery.19In a cohort of older patients undergoing laparoscopic cholecystectomy, use of isoflurane or sevoflurane resulted in higher levels of circulating TNF, IL-ip and IL6, and an increased incidence of delirium.20Low dose dexmedetomidine, which is licensed for use as a sedative, resulted in reduced incidence of delirium and lower circulating TNF levels in older patients undergoing hip arthroplasty,21and a meta-analysis of 15 randomized control trials confirmed that administration of dexmedetomidine resulted in reduction of circulating TNF, IL-ipand IL-6.22A recent review highlighted the evidence for dexmedetomidine reducing levels of TNF in patients with delirium.8Administration of hypertonic saline resulted in a reduction in the risk of development of post-operative delirium and was associated with a significant reduction in circulating TNF levels in patients undergoing surgery for fractured neck of femur.23A trial comparing parecoxib, a selective COX-2 inhibitor, with placebo found reduced incidence of delirium in elderly patients undergoing knee arthroplasty and was associated with reduced levels of TNF, IL-6 and IL-p in the circulation.24Similar results were reported in atrial of celecoxib.25

[0101] Whilst there have been no trials to assess the efficacy of anti -TNF in reducing delirium and cognitive impairment in patients undergoing surgery, there are data showing improvement in cognitive function, mood, pain and sleep in patients with systemic inflammatory disorders receiving anti-TNF. Patients with rheumatoid arthritis treated with adalimumab showed improvement in cognitive function26and infliximab treatment in patients with rheumatoid arthritis resulted in improvement in sleep and alertness disturbance, which were unrelated to amelioration of joint tenderness, swelling and morning stiffness.27A study of patients with sarcoidosis found cognitive impairment in 35% of patients compared to 14% of controls, and treatment with infliximab or adalimumab resulted in significant improvement in cognitive function compared to those treated with steroid with or without methotrexate.28Aphase 3 trial of 618 patients with mild to moderate psoriasis found significant improvement in depression in the group treated with etanercept.29Importantly, this was unrelated to indices of disease activity, including clearance of skin lesions or joint pain. A nested case-controlled study of 8.5 million insured adults in the USA found that there was an increased risk of development of Alzheimer’s disease in patients with rheumatoid arthritis that was significantly reduced in patients treated with etanercept. A trial of infliximab found improvement in depression in patients with high baseline levels of inflammatory cytokines, including circulating TNF.30A trial of adalimumab showed improvement in pain and depression in patients with moderate to severe hi dradenitis suppuritiva.31Sleep disturbances have also been shown to improve following anti-TNF. A randomized trial of etanercept showed improvement in sleep pattern in patients with alcohol dependence.32Similarly, in patients with high baseline inflammation and treatment resistant depression, infliximab led to improved sleep continuity.33

[0102] Based on the above evidence, our hypothesis is that TNF released by immune cells recruited to the site of surgery crosses the blood-brain barrier to activate resident microglia. It also increases permeability of the blood-brain barrier to allow ingress of circulating activated monocytes. This leads to neuronal damage, which is manifest as delirium.

[0103] Need for this comparison

[0104] Avoiding post-operative delirium is a priority for the NHS; reducing delirium is a ‘Key Performance Indicator’ for the UK NHFD and is linked to Best Practice Tariff payments in England. Delirium is a devastating acute neuropsychiatric syndrome, common in people with hip fracture, and associated with adverse outcomes. Despite this, there are no treatments to prevent or ameliorate delirium, in part due to our poor understanding of the underlying biology.

[0105] A recent NIHR James Find Alliance Research Priority Setting Partnership, identified: “What are the best treatments to prevent and treat confusion and delirium after surgery in adults with a fragility fracture of the lower limb?” as a key research priority. It also addresses a key research question in the forthcoming Association of Anesthetists’ guidance on perioperative management of hip fracture: “What are the best anesthetic interventions to prevent and treat confusion and delirium after surgery for hip fracture?”

[0106] The overarching aim of the WHiTE Platform Study is to improve the care of patients with a fracture of their hip. Delirium delays patients’ recovery and puts them at greater risk of complications so reducing the severity of delirium is an important component of the platform.

[0107] OJECTIVES AND OUTCOME MEASURES

[0108] Primary Objective:

[0109] To compare peak delirium in the 5 days following hip fracture surgery between the treatment groups.

[0110] Secondary Objective:

[0111] 1. To compare cognitive impairment scores at 4 and 12 months post-diagnosis of a hip fracture between the treatment groups.

[0112] 2. To compare health-related quality of life at 4* and 12 months post-diagnosis of a hip fracture between the treatment groups.

[0113] 3. To compare mortality risk within the first 12 months post-diagnosis of a hip fracture between the treatment groups.

[0114] 4. To compare mobility at 4* and 12 months post-diagnosis between the treatment groups.

[0115] 5. To compare residential status at 4* and 12 months post-diagnosis of a hip fracture between the treatment groups.

[0116] 6. To compare the risk and pattern of complications at any point within the first 12 months post-diagnosis of a hip fracture between the treatment groups.

[0117] * Objectives at these timepoints are collected as part of the overarching Platform.

[0118] Exploratory mechanistic objectives

[0119] The following objectives will be investigated through analysis of blood samples and analysis of EEG recordings.

[0120] i) To investigate the role of TNF in the development of delirium and explore the effect of treatment with anti-TNF through blood sample analysis.

[0121] ii) Explore which EEG patterns are associated with neuronal inflammation as measured on blood biomarkers, and whether this association with neuronal inflammation is attenuated by the administration of anti-TNF during surgery.

[0122] iii) Explore whether EEG patterns that correlate with inflammation are predictive of the development and severity of delirium.

[0123] Blood sample collection and the collection of EEG recordings will only be conducted in a subset of recruitment centers based on research team capacity and availability of relevantequipment. The collection of data for the exploratory objectives will take part during the internal pilot phase (defined as the recruitment of the first 120 patients). Consent to provide blood samples and / or EEG recordings for the exploratory mechanistic objectives will be optional for participants.

[0124] Outcome measures

[0125] The common outcome data described in the Platform Master Protocol will be collected and augmented with additional data collection during the first five days during and after hip fracture surgery and at 4- and 12-months post-diagnosis of a hip fracture. Additional outcomes specific for this randomized comparison are:

[0126] Post-operative delirium

[0127] Peak post-operative delirium will be measured by the MDAS. Participants will be assessed once daily after the surgical repair of the hip fracture using the MDAS34from day 1 to day 5. The MDAS is a validated scale which quantifies the severity of delirium based on 10 features which integrates behavioral observations with objective cognitive testing. MDAS generates a scale from 0 to 30 (30 is most severe) and can be completed by trained research staff in 5 minutes or less4. The peak MDAS score will be the maximum recorded score reflecting the worst and most delirious state of the participants in the first five days after surgery.

[0128] In addition to the expertise and experience within the research team, we sought advice from several external sources with regard to the choice of primary outcome measure in this trial. While several other assessment tools were considered, MDAS has been used widely in previous trials, including large trials in the hip fracture population. The peak MDAS recorded in the 5 days following surgery provides a comprehensive assessment of the severity of delirium, integrating behavioral observations with objective cognitive testing.35Furthermore, MDAS is based upon the diagnostic criteria for delirium in the Diagnostic and Statistical Manual of Mental Disorders; the 10 MDAS features being: reduced level of consciousness / awareness, disorientation, short-term memory impairment, impaired digit span, reduced ability to maintain and shift attention, disorganized thinking, perceptual disturbance, delusions, decreased or increased psychomotor activity, and sleep-wake cycle disturbance. Another key consideration was the feasibility of training staff to use the delirium assessment tool in the context of a large-scale trial. We believe that the peak MDAS in the first five daysfollowing surgery will provide a comprehensive assessment of delirium, without requiring extensive training and / or specialist staff to administer it.

[0129] The Minimal Clinically Important Difference for the MDAS is 2.5 on the 0-30 point scale. Prior estimates of the of the peak MDAS in the post-operative period in patients with hip fracture was 7.04. However, in an recent NIHR-funded feasibility comparison nested within the WHiTE platform, the standard deviation of peak MDAS was estimated to be 8.4. The decision to adopt a Minimal Clinically Important Difference (MCID) of 2.5 using the full scale of the MDAS tool (c.f. a cut-off score) was made based upon a review of the literature and direct discussions with experts in the field.

[0130] Cognitive impairment

[0131] Patients will complete the TICS UK English 2014 questionnaire to assess Cognitive Impairment at 4- and 12-months post-diagnosis of a hip fracture. Since most people treated for a hip fracture in the UK are not followed-up in person after being discharged from hospital, TICS questionnaire is the best tool in this setting. A 3-point difference in TICS score (score=0-41, with lower scores indicating cognitive impairment) is considered clinically significant.

[0132] Complications

[0133] The expected complications for the comparison are detailed in this protocol. To facilitate collection of complications as per the Platform Master Protocol, medical records for all participants will be reviewed by appropriately trained staff for indicators of wound infection at discharge. In addition to the Platform follow-up time points, at 12 months post-diagnosis of a hip fracture, the participants will self-report (via telephone interview, electronic media or postal questionnaire) on signs of infections. For those participants lacking capacity, an appropriate proxy will be asked to provide this information. In rare cases, where participants or carers cannot be contacted, information with regards symptoms / treatment for infection will be obtained from the participant’s GP and / or recruitment center.

[0134] Upon indication of potential signs of infection in the participant report at 4 months, the recruitment center / GP will be contacted and asked to review the participant’s medical records to provide additional information. Due to its severity, diagnosis of a ‘deep infection’ will always be documented in the participant’s medical records.

[0135] The following outcome measures will only be collected in a subset of recruitment centers and where patients have consented to their collection:

[0136] Blood samples

[0137] 10ml blood samples will be collected at baseline, 30 minutes following the start of surgery, 24, 48 hours and 5 days post-surgery. The blood will be centrifuged and serum aliquots stored locally at recruitment centers until shipment to the University of Oxford for analysis.

[0138] EEG recordings

[0139] A frontal montage monitoring strip will be applied to the participant’ s forehead before the start of surgery and intraoperative EEG recordings will be taken. EEG data will be collected as raw waveform, with the processed scalar value based on power spectral analysis and the burst suppression ratio.

[0140] DESIGN

[0141] Concept

[0142] This is a multi-center, two-arm placebo-controlled randomized comparison embedded within the overarching WHiTE Platform testing clinical superiority between the treatment groups with embedded exploratory mechanistic outcomes.

[0143] This will be a two-phased comparison. Phase 1 (internal pilot) will confirm the expected rate of recruitment and acceptability of procedures in 4 UK hospitals. Phase 2 (main phase) will extend the randomized comparison for a total of approximately 8 hospitals.

[0144] Internal Pilot

[0145] The internal pilot phase is defined as the period during which the first 120 consecutive participants are consented into the study. It is anticipated that the internal pilot will take place over a period of 6 months. Screening logs will be kept at each recruitment center to determine the number of patients assessed for eligibility and reasons for any exclusion. The number of eligible and recruited patients, and the number of patients who decline consent or withdraw will be recorded. The DSMC and POC will closely monitor recruitment in order to make a recommendation regarding continued progress of the comparison against the specified stop / go criteria. If the comparison is stopped due to feasibility not being shown, then all participants will be followed up per protocol. If the comparison continues into the main phase, participants from the internal pilot will be included in the final analysis.

[0146] Data collection for the exploratory mechanistic outcomes will be conducted during the internal pilot phase only.

[0147] Main phase

[0148] During the main comparison phase, the remainder of the target 564 participants will be recruited. Participants will be allocated on a 1 : 1 basis to either placebo or infliximab infusion treatments.

[0149] Assessments will include all those described in the Platform Master Protocol, augmented with additional data relevant to this specific randomized comparison. In summary:

[0150] Routine pre-operative cognitive assessment will be made using the delirium screening tool 4AT; these scores are used throughout the UK as part of routine admission clinical practice. Further baseline demographic data including pre-injury mobility and residential status will be collected. Participants or their proxies will also be asked to complete the EQ-5D-5L to indicate their typical pre-injury quality of life status.

[0151] The primary outcome is post-operative delirium recorded using the peak MDAS which will be recorded each day during the first five days after surgery.

[0152] At 4- and 12-months post-diagnosis of a hip fracture, cognitive impairment using TICS, EQ-5D-5L, residential and mobility status, complications and participant-completed resource use questionnaires will be collected by the central research team at the University of Oxford. We will adopt the techniques used in the previously conducted WHiTE Cohort study to collect self-reported or proxy-reported information.

[0153] STUDY PROCEDURES

[0154] A study flow chart is provided in Fig. 1.

[0155] PARTICIPANT IDENTIFICATION

[0156] Comparison participants

[0157] A subset of participants in the overarching WHiTE platform will be eligible for this randomized comparison.

[0158] Inclusion criteria

[0159] As per the overarching Platform Master Protocol; all adults aged 60 years or over diagnosed with a hip fracture that in the opinion of the treating surgeon may benefit from surgical treatment.

[0160] Exclusion criteria

[0161] In addition to the exclusion criteria stated in the overarching platform protocol, a patient is not eligible if ANY of the following apply:

[0162] 1. The patient has severely impaired renal function eGFR <30 ml.min-1

[0163] 2. The patient has severely impaired hepatic function

[0164] 3. The patient is currently taking any anti-TNF drug

[0165] 4. The patient has a contra-indication to anti-TNF injection

[0166] 5. The patient has a known hypersensitivity to any anti-TNF agent or any of the excipients

[0167] 6. The patient has known active tuberculosis (TB) or history of TB or at risk of developing TB e.g. through the use of immunosuppressants

[0168] 7. The patient has another known active infection (chronic or localized) or known history of recurring infections or condition which may predispose patients to infection, including the use of concomitant immunosuppressive medications

[0169] 8. The patient has known lung fibrosis

[0170] 9. The patient had systemic inflammatory disorder such as rheumatoid arthritis or inflammatory bowel disease

[0171] 10. The patient has known moderate to severe heart failure (NYHA class III / IV)

[0172] 11. The patient has HIV, Hepatitis B or C (based on medical history)

[0173] 12. The patient is at risk ofHepatitis B or HIV infections, including intravenous drug use

[0174] 13. The patient has been diagnosed with Multiple Sclerosis (MS) or other central or peripheral nervous system demyelinating disorders

[0175] 14. The patient has history of malignancy within five years prior to screening or any evidence of persistent malignancy, except basal cell or squamous cell carcinomas of the skin, or cervical carcinoma in situ which has been treated or excised in a curative procedure.

[0176] 15. The patient has had a live vaccination 4 weeks prior to study entry or will require one within 12 weeks after the study intervention

[0177] 16. The patient takes biologies including anakinra or abatacept or DMARDS

[0178] 17. The patient is or has been a participant in a clinical trial of a medicinal product in the last 12 weeks

[0179] Pre-operative radiographs of the chest are routine in this patient group. Participants with a history of TB or signs of TB on the chest radiograph will be excluded from enrolment in the study. This is in line with UK guidelines that a chest radiograph is used for screening patients who are to be commenced on regular anti-TNF therapy.36

[0180] Eligibility for entry into the comparison will be confirmed by a medically qualified person.

[0181] Consent

[0182] Patients will be presumed to have capacity unless established otherwise and the default will be to seek prospective individual consent from every patient. Where patients do not have capacity, those procedures laid down in the Platform Master Protocol will apply.

[0183] Where participants are recruited in a recruitment center that is taking part in the collection of the exploratory mechanistic outcomes, they will be provided with the option to consent to having their EEG recordings and blood samples being collected.

[0184] For participants who do not have capacity at the time of consent, the Legal Representative will be given the option to consent for the EEG recordings and blood sample collection. Should the participant regain full capacity during the first 5 days post-surgery, they will be provided with information about the collection of blood samples. Written consent for this optional part of the protocol will then be sought from the participant. A copy of the consent form will be stored in the participant’s medical notes. If the participant does not wish for any further blood samples to be collected, a note will be made in the participants’ medical record and study record that no further samples will be collected.

[0185] With regard to these provisions, the randomized comparison described in this appendix is a CTIMP.

[0186] Randomization

[0187] Randomization will be as per the Platform Master Protocol. Randomization will be on a 1:1 basis to infliximab or placebo, stratified by recruitment center and the presence / absence of cognitive impairment at presentation. The allocation sequence will be generated by the trial statistician using variable block sizes and stored securely in a web-basedencrypted system provided by OCTRU. Full details will be stored in a separate randomization and blinding plan stored in the confidential statistics section of the trial master file.

[0188] Randomization will be performed as close to the time of induction of anesthesia as possible to avoid the risk of postponement of surgery or moving to a different theatre list.

[0189] Blinding and code-breaking

[0190] This is a double-blinded comparison, whereby the participant and the local research team members involved in the delirium assessment and data collection process will be blinded to the allocated treatment. An appropriately qualified anesthetist will prepare the comparison medications following randomization.

[0191] Unless specifically requested, participants in this comparison will not be informed which of the two treatments they have received. No formal assessment of the success or otherwise of the blinding will be made. Participants who request information with regards the treatment they received, will be informed at the end of the follow-up period or at the point of withdrawal from this randomized comparison.

[0192] A 24-hour emergency unblinding function will be available via the secure online Randomization system to reveal which treatment a participant has been allocated to, should this be required. However, the emergency scenario will always be managed using the applicable local and national policy and guidelines, which will not require staff to carry out unblinding first.

[0193] Unblinded information will be provided if one or more of the following criteria is satisfied:

[0194] 1. Emergency circumstances

[0195] 2. Other reason (non-emergency)

[0196] No Cl’s approval is required if the reason for unblinding is 1 above. If the reason for unblinding is 2, Cl’s approval will be required first.

[0197] As all emergency cases would not require immediate unblinding, no out of hours contact is appointed.

[0198] The members of the central trial team who are authorized to unblind participants will be listed in a Trial Specific Instructions Unblinding Annex document. Request for unblinding from the research teams or PI will be forwarded to an authorized member of the central trialteam. If the person requiring the unblinding is not the PI then that health care professional will notify the Investigating team that an unblinding is required for a trial participant and an assessment to unblind should be made in consultation with the clinical and research teams. The authorized members of the team will follow the randomization system user guide for unblinding as detailed in relevant OCTRU SOP.

[0199] On receipt of the treatment allocation details the PI or treating health care professional will continue to deal with the participant’s medical emergency as appropriate. The PI will document the breaking of the code and the reasons for doing so in the investigator site fde and medical notes. It will also be documented at the end of the comparison in any final comparison report and / or statistical report. The unblinded information and any related correspondence will be stored in a password protected subfolder in the eTMF in the patient’s subfolder accessible only to authorized member of the central trial team.

[0200] The CI will notify the Sponsor in writing as soon as possible following the code break detailing the necessity of the code break. The CI will also notify the relevant authorities. The written information will be disseminated to the DSMC for review in accordance with the DSMC Charter.

[0201] Assessments

[0202] Schedule of assessments

[0203] The overall schedule of assessments, including the common outcome set and the additional outcomes measured for this comparison, and methods for data collection are described in the table below:

[0204] Table 3: Assessment schedule, instruments and means of collection&&

[0205] Key:ABaseline information will be collected before surgery where possible, otherwise it will be collected as soon as possible after. * indicates measurement timepoint or data collected is in addition to the Platform Common Dataset specified in the Platform Master Protocol **indicates samples to be collected only by those centers participating in the mechanistic outcomes on participants where consent for this optional data collection has been obtained. Italicized sections indicate data collected as part of the overarching Platform.

[0206] Visits and Contacts

[0207] Contact 1 : Pre-operatively, 4AT and AMTS will be collected on the hospital ward to determine baseline cognitive function and the presence or absence of delirium.

[0208] A 10 ml blood sample will also be collected from consented participants in those centers participating in the exploratory mechanistic part of the protocol.

[0209] Contact 2: Baseline data collection as per Platform Master Protocol.

[0210] Contact 3: During surgery: EEG recordings will be taken throughout surgery from consented participants in those centers participating in the exploratory mechanistic part of the protocol. For patients whose EEG recording will be recorded, a list of the anesthetic drugs received intraoperatively will also be collected. A 10 ml blood sample will be collected from consented participants in those centers participating in the exploratory mechanistic part of the protocol at 30 mins after start of surgery.

[0211] Contacts 4-8: Days 1-5 after the day of surgery, delirium assessments will be made on the hospital ward by trained staff using the MDAS. Opioid use will also be collected. Ten ml blood samples will be collected from consented participants in those centers participating in the exploratory mechanistic part of the protocol at 24 and 48 hours and on day 5 post-surgery.

[0212] Contact 9: Follow-up at 4 months post-diagnosis of a hip fracture as per Platform Master Protocol with the addition of TICS.

[0213] Contact 10: Follow-up at 12 months post-diagnosis of a hip fracture, will be completed directly with the participant or a proxy either via telephone interviews by a member of the central research team, or through electronic means (electronic questionnaire / survey) depending on choice expressed by the participant or proxy at the time of consent.

[0214] Mechanistic Outcomes Analysis

[0215] Blood samples

[0216] The main objective of the mechanistic work will be to investigate the mechanisms leading to the development of delirium, specifically the levels of proinflammatory cytokines released by the innate immune cells, the chemokines which recruit these cells to the site of surgery and the efficacy of infliximab in blocking these pathways. Markers of monocyte / macrophage activation, blood-brain barrier permeability and the degree of neuronal damage will be measured, as well as the effect of infliximab on all these processes.

[0217] Only a select number of recruitment centers will take part in the mechanistic data collection. Blood samples for the analyses will be collected and serum aliquots stored by the centers at 5 timepoints during the first 5 days of surgery:

[0218] o Pre-surgery

[0219] o At 30 minutes following start of surgery (+ / - 15 minute window)

[0220] o 24 hours post-surgery (+ / - 12 hour window)

[0221] o 48 hours post-surgery (+ / - 12 hour window)

[0222] o Day 5 post-surgery (+ / - 36 hour window)

[0223] The hypothesis is that circulating TNF released by inflammatory cells, including neutrophils and pro-inflammatory macrophages, recruited to the site of surgical ‘injury’, increases the permeability of the blood brain and promotes the ingress into the brain of activated monocytes and activation of resident microglia. This in turn leads to neuronal damage,37,38post-operative delirium and cognitive impairment. It will be tested whether this pathway can be inhibited by perioperative administration of infliximab, which binds and inactivates the TNF. TNF is released immediately on commencement of surgery and has a short half-life of 30 min in the circulation, being detectable only within 1 hour of the surgery but not at 3 hours or later. Therefore, the infusion of infliximab in the anesthetic room will commence before surgery and will continue for the total duration of the surgery. The duration of the surgery is on average 1 hour, and very rarely more than two. Infliximab has a half-life of 8 days. Therefore, the proposed dosage regimen will permit full target engagement.

[0224] Blood Sample handling for comparison purposes

[0225] At each sample collection time-point, 10ml of blood will be drawn into a vacutainer and subsequently centrifuged. The serum will be divided into aliquots and frozen immediately at <-20° C at the recruitment center. Once the storage box is filled to capacity these will be couriered to Kennedy Institute at the University of Oxford along with the sample tracking form. Details of the assays, documentation and sample analysis will be provided in the relevant laboratory SOP. For the purposes of analysis to determine the mechanistic outcomes, the samples will be analyzed within the duration of the ethical approval for this comparison.

[0226] Samples will be pseudo-anonymized using a coded label containing a constant reference ID, a partial randomization number, and reference numbers to the timepoints and aliquots collected.

[0227] Blood Sample handling for long-term storage

[0228] Participants for whom samples will be collected, will be asked to provide (or a legal representative) informed consent approving long-term storage, and future use of tissue and blood. As new mechanisms of action, safety and efficacy may evolve during or following the comparison, which are unknown at present.

[0229] Any remaining biospecimens from participants who have not consented to long-term storage will be destroyed at the end of the comparison as per Kennedy Institute at the University of Oxford SOPs.

[0230] Biospecimens, for which consent to long-term storage has been provided, will be anonymized and stored for a maximum of 15 years from the end of comparison at the Kennedy Institute at the University of Oxford, along with a blank copy of the comparison consent form and a letter from the Chief Investigator affirming that consent had been obtained appropriately using the form provided for these purposes. Any remaining biospecimens will be destroyed at the end of the long-term storage period.

[0231] EEG recordings

[0232] The first aim of this mechanistic work would be to quantify the occurrence of EEG patterns of cerebral vulnerability which correlate with the severity of postoperative delirium. The second aim will be to correlate the EEG patterns with measurement of neuroinflammation using blood biomarkers in the early postoperative period. By establishing the link between markers of neuronal inflammation and the pattern of the brains electrical activity at the time of surgery the aim is to demonstrate to what extent the occurrence and severity of delirium can be predicted at the time of surgery (‘intraoperatively’).

[0233] The recording of raw EEG data will be made on routinely available anesthetic monitors that are available in clinical practice for the monitoring of depth of anesthesia. The recording will be continuous frontal montage raw EEG, to commence at the start of anesthesia until the end of surgery with analysis retrospectively. The recordings will be downloaded from the EEG monitor at the recruitment center after the operation according to relevant recruitment center SOPs or policies. The download of the digital recording will be sent to the University of Oxford via a secure server that each recruitment center participating in the mechanistic work will be given upload access to. The recordings will be stored on secure servers at the University of Oxford. Analysis of the patterns of EEG will take place at the University of Oxford with the comparison identification number as the identifier.

[0234] The anesthetist caring for the participant will not be required to make any interpretation of the raw EEG during surgery - this data will be analyzed retrospectively when paired with the markers of neuronal inflammation.

[0235] Definition of End of Comparison

[0236] The end of the comparison is the point at which the follow-up of the last participant has been completed, all the data has been entered and all queries have been resolved. The last direct data collection will be at one year post-diagnosis of a hip fracture of the last participant. The Sponsor, MHRA and main REC will be notified in writing if the comparison has been concluded or terminated early.

[0237] INTERVENTIONS

[0238] Description of the randomized treatments

[0239] Participants will be randomly allocated to one of the treatment arms:

[0240] - Intervention: Single infusion of infliximab at 5mg / kg body weight, diluted in 250 mL of 0.9% saline and administered intravenously over a 2-hour period

[0241] - Placebo control: Identical volumes of 0.9% saline

[0242] Both infliximab and saline have marketing authorization and infliximab is approved for use at the dose that will be administered in accordance with this protocol appendix, but outside its licensed indication. They will both be prepared prior to administration.

[0243] All recruitment centers will be required to use infliximab 100 mg powder concentrate for reconstitution in solution for infusion. It will be supplied by the manufacturer or their agents to the recruitment centers.

[0244] Labelling, Storage and Administration of the IMP

[0245] A bulk batch of the IMP will be ring-fenced for the comparison and stored in the operating theatre in accordance with the requirements as described in the approved SmPC. This box will be labelled by pharmacy with a comparison-specific annex 13 compliant clinical trial label on its outer packaging (label A).

[0246] A comparison-specific prescription will be prepared by a delegated member of staff. An appropriately trained clinician not involved in the assessment of any comparison outcomes will carry out the online treatment allocation reveal process. The medication will be prepared following local processes for the reconstitution of monoclonal antibodies.

[0247] The infusion will be prepared in an area away from any blinded members of the clinical team so as not to reveal the treatment allocation to potential blinded assessors. The infusion bag will be labelled as per routine clinical practice in the operating theatre, indicating the bag contains either the IMP or placebo (Label B). The IMP and placebo are clear colorless solutions, indistinguishable to the human eye. No members of the blinded assessment staff will be present in the operating theatre.

[0248] The medication will then be administered by the attending anesthetist within 24 hours of reconstitution.

[0249] The name of the person administering the trial treatment will be recorded on the treatment CRF. The attending anesthetist will give the intravenous intervention or placebo over a 2-hour period. It is standard practice for anesthetists to follow instructions on how to draw up and administer drugs during surgery. In addition, it is standard UK practice to affix preprinted labels to drugs used by anesthetists. The label that will be affixed to the infusion bag is not classed as a trial specific labelling, simply a standard of care.

[0250] Accountability of the Comparison Treatment

[0251] As this is a pragmatic comparison involving a one-off administration of the intervention, a risk adapted approach has been employed to ensure the appropriate level of documentation is kept to record IMP accountability as per standard local practice. For clarity -pharmacy involvement is limited to taking receipt of the IMP from the supplier and the initial labelling of the bulk batch. Drug accountability logs will be kept with the IMP and completed by a trained and unblinded (i.e. not involved in the assessment of any comparison outcomes) member of staff as per the delegation log. Number of packs stored in the operating theatre and batch numbers for each box will be recorded. Participants’ weight will also be documented here to ensure that the correct amount of drug is prepared.

[0252] Anesthetic technique

[0253] A regional or general anesthesia technique will be used for each participant as per routine clinical care. Intra-operative analgesia may be achieved by combining a local anesthetic nerve block, plus paracetamol 1g and opioid analgesia as clinically indicated. Surgery to fix or replace the broken part of the hip will take place using the preferred technique and implants of the operating surgeons as per routine clinical practice. Relevant details of the treatment pathway will be recorded.

[0254] Safety of the IMPAnti-TNF agents act by binding to circulating TNF released by the trauma associated with injury and surgery and the complexes are rapidly cleared by the mononuclear phagocyte system. Infliximab is the only anti-TNF approved for IV administration (infusion over 2 hours). This method of delivery will ensure that peak levels are present in the circulation for the entire duration of the surgery and in the immediate post-operative period. More than 20 million patients have been treated with the anti-TNFs and over 3 million with infliximab. The drug has an exceptional safety record. An early Cochrane review39found no increase in adverse events in patients with rheumatoid arthritis treated with infliximab compared to placebo. A more recent systematic review of elderly patients with psoriasis identified increased infusion related reactions, reactivation of TB and chest infections.40A meta-analysis of adverse events in patients with rheumatoid arthritis treated with infliximab confirmed that there were more infusion related reactions but no significant risk of infection compared to placebo.41However, the Food and Drug Administration report of increased respiratory and genito-urinary infections has been noted, as well as reactivation of latent TB. It is important to note that all these data pertain to patients receiving regular anti-TNF over a period of many years whilst this protocol appendix only calls for administering a single dose. Early trials of infliximab for inflammatory bowel disease in patients receiving repeated doses had uncertainty regarding an association with lifetime risk of malignancy. However, in this study we will only be administering infliximab on a single occasion and large scale registry data demonstrated infliximab is not related to increased risk of malignancy. Lichtenstein GR, Feagan BG, Cohen RD, et al. Serious infection and mortality in patients with Crohn's disease: more than 5 years of follow-up in the TREAT registry. Am J Gastroenterol 2012; 107: 1409-22.

[0255] SAFETY REPORTING

[0256] Safety reporting for each participant will begin from the time of consent and will end when the participant has reached their final follow up time point, at 1 year post-diagnosis of a hip fracture. As the safety profile of Infliximab is very well known, only SAEs will be reported for this comparison. Investigators should follow up serious adverse events until resolved or until stabilization or resolution.

[0257] All SUSARs are to be reported according to the guidelines relevant to CTIMPs specified in the Platform Master Protocol.

[0258] Related and expected Serious Adverse Events

[0259] See Platform Master Protocol for details of SAEs that are expected and related to the fracture and surgical procedure. Additional expected and related SAEs, which in line with the Platform Master Protocol are reported using a complications form, for this comparison are:

[0260] - Reactivation of TB is an expected event that is associated with the IMP, including a positive result from the peri -operative ELISpot tests.

[0261] Expectedness

[0262] See Platform Master Protocol for detail on the assessment of expectedness. For SAEs that require reporting, expectedness of SARs will be determined according to the relevant RSI section of the Summary of Product Characteristics. The RSI used (within the SmPC) will be the current Sponsor and MHRA approved version at the time of the event occurrence. All SARs which are more specific or more severe in nature or present as a life-threatening event will be reported as SUSARs.

[0263] STATISTICS & ANALYSES

[0264] Sample Size Determination

[0265] The proposed sample size for this study is 564 participants. The Minimal Clinically Important Difference for the MDAS is 2.5 on the 0-30 point scale. Prior estimates of the Standard Deviation of the peak MDAS in the post-operative period in patients with hip fracture was 7.04. However in an recent NIHR-funded feasibility comparison nested within the WHiTE platform, the standard deviation of peak MDAS was estimated to be 8.4. This equates to a small to moderate effect size of 0.30. A sample size of 478 participants (239 per arm) will enable the detection of an effect size of 0.30 based on a null hypothesis of no difference with 90% power and 5% (2-sided) significance. Allowing for 15% loss to follow-up, this is inflated to 564 patients (282 per arm). Although we do not anticipate this level of attrition for the primary outcome measure, this inflation of the sample size calculation will allow us to collect high-quality secondary outcome data.

[0266] It is anticipated that the DSMC will review the sample size assumptions. In particular, the standard deviation and the distribution of the peak MDAS, will be reviewed at the end of the internal pilot phase of the comparison and again when approximately half of the participants have reached their primary outcome time-point.

[0267] Due to the exploratory nature of the mechanistic objectives, no sample size calculation has been conducted. Data will be collected during the internal pilot phase. Analysiswill be performed on all available samples and will provide important data to allow for further grant funding to be obtained.

[0268] Analysis Populations

[0269] The primary analysis population will be ITT; that is all participants will be analyzed as randomized. Sensitivity analyses will be undertaken on the per-protocol population for the primary outcome and key secondary outcomes.

[0270] The ITT population includes all randomized participants including:

[0271] 1. Participants who are randomized but do not undergo surgery (such as those who died or were found to be ineligible after randomization but before surgery).

[0272] 2. Participants who are randomized and found to be ineligible during or after surgery.

[0273] Note: participants who withdraw from the comparison between randomization and 1 year post-diagnosis of a hip fracture will provide data up to the point of withdrawal.

[0274] The ‘PP’ population will be the ITT population excluding participants as described in 1 and 2 above and other major deviations from the protocol which will be fully described in the Statistical Analysis Plan.

[0275] The Level of Statistical Significance

[0276] The statistical significance will be assessed at 5% for two-sided tests. All p-values will be reported to 3 decimal places. 95% confidence intervals will be reported throughout.

[0277] 12.4 Decision Points

[0278] We will exploit the efficiencies available from nesting this comparison within the Platform. This Platform has been built based upon the experiences of the WHiTE cohort study which has successfully delivered six

[0279] hip fracture trials. The comparison processes are streamlined and harmonized with those of the Platform so that we should be able to achieve 65% recruitment of eligible patients and 90% follow-up of available participants (those alive and not withdrawn) at the primary outcome time-point.

[0280] During the internal pilot phase, we expect to recruit 120 patients from 4 pilot recruitment centers. The DSMC and POC will closely monitor recruitment during the feasibility phase and make a recommendation with regards continued progress of the comparison. If recruitment is below 70 participants, we will consider stopping the comparisonfor feasibility reasons. If between 70 and 100 participants, we will review the recruitment processes and implement the committees’ recommendations. If recruitment is more than 100 participants, we will progress with the main phase of the study.

[0281] A total of 564 participants will be randomized across approximately 8 recruitment centers. In the event that recruitment in each of the centers is lower than anticipated we have a network of 120 hospitals in addition to the proposed 8 centers that have previously worked with us on multicenter trials.

[0282] Analysis

[0283] A full, detailed SAP will be drafted early in the comparison, and will be finalized prior to the primary analysis data lock. Any subsequent changes to the SAP will be fully justified in the final report. Stata (StataCorp LO) or other appropriate validated statistical software will be used for analysis.

[0284] If the trial stops early, due to being non-feasible or for any other reason, the study will be analyzed and reported as an external pilot / feasibility study.

[0285] Otherwise, patients from the internal pilot / feasibility stage will be included in the final analysis and the study reported as per the CONSORT statement and any relevant extensions. Baseline demographic data will be summarized by treatment groups to assess comparability between treatment arms. Binary and categorical data will be summarized as frequencies and percentages, normally distributed continuous data will be summarized as means and standard deviations, and non-normally distributed continuous data as medians and interquartile ranges. Primary and secondary outcomes will be explored graphically.

[0286] The main analysis will investigate differences in the primary outcome measure, the peak (maximum) MDAS scores during the first five days post-operatively. The principal analyses will be conducted on the ITT population using a mixed-effects linear regression model adjusting for stratification factors. Center will be included as a random effect to allow for any heterogeneity in response between centers, and the presence or absence of permanent cognitive impairment pre-surgery included as a fixed effect. Models will also adjust for important baseline covariates to maximize precision, which will include age as a continuous variable, sex, type of surgery as either fixation or total hip replacement, and type of anesthesia as either general anesthetic or spinal anesthetic. The treatment difference will be based on the estimate of adjusted means and 95% confidence intervals, with a 2-sided significance level of 5% being used for comparative tests. The sensitivity of the primary outcome data to the underlyingpopulation will be assessed using the PP population; the definitions of this population are described and will be fully defined in the SAP.

[0287] The analysis of secondary clinical outcomes will use multi-level mixed effects regression models and will include all time-points, where appropriate. Continuous outcomes will be analyzed using linear mixed effects regression, and binary outcomes will be analyzed using logistic mixed effects regression.

[0288] Missing data will be minimized through careful data management. Missing data will be described with reasons given where available; the number and percentage of individuals in the missing data category will be presented by treatment groups. The nature and mechanism for missing variables and outcomes will be investigated and sensitivity analyses will be undertaken to assess the underlying missing data assumptions, in particular whether it can be treated as missing completely at random. Missing data may be imputed in sensitivity analyses if considered beneficial to the interpretation of the main findings. Any imputation methods used for scores and other derived variables will be carefully considered and justified. Reasons for ineligibility, non-compliance, withdrawal or other protocol violations will be stated and any missing data patterns summarized.

[0289] Serious adverse events will be explored to assess if they differ between groups. Example 2 - WHiTE13-DECl - An investigation of people 60 years and over with a broken hip to determine whether they are less likely to have delirium after hip surgery treated with infliximab during the operation.

[0290] 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: “What are the best treatments to prevent and treat confusion and delirium after surgery in adults with a broken bone in the leg?” 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 period in hospital to recover. Around a quarter of patients with hip fractures die within a year and those that survive have a permanent loss of quality of life. Worldwide there are 1.3 million hip fractures each year, with more than 70,000 in the UK. Around a quarter of patients who have a hip fracture 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, and 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 is 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. This study aims 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.

[0291] Who can participate?

[0292] Patients aged over 60 years with a hip fracture, apart from the very small number of patients who do not have an operation on their hip.

[0293] What does this study involve?

[0294] Patients at approximately 8 hospitals in the UK will be approached to take part in the study. 564 participants will take part, with half being allocated by chance to receiving infliximab, and half to receiving a placebo containing no infliximab. Neither the patients nor their doctors will know which treatment they had to make the study fair. All other elements of the patient’s treatment will follow the normal care pathway for all hip fracture patients at the hospital. Baseline information including pre-injury mobility and residential status will be collected. Participants or their proxies will also be asked to complete the EQ-5D-5L questionnaire to indicate their typical pre-injury quality of life status. A simple questionnaire called the Memorial Delirium Assessment Scale (MDAS) will be used to measure symptoms of delirium in the first five days after surgery. Participants’ mobility, quality of life and complications, including the risk of infection and developing dementia in the 12 months after surgery will also be measured. Some of the study participants may be asked to consent to have their brain waves monitored during surgery and to have small blood samples taken before and in the days after surgery to measure the level of inflammation in the blood.

[0295] What are the possible benefits and risks of participating?

[0296] Infliximab is already used very widely in the NHS as a treatment for a range of diseases, but it has not been tested to see if it could help prevent delirium after surgery. Hip fracture surgery carries some risk, including infection in the surgical wound, blood clots, chest or urine infection. These risks are the same for people who are not part of this research project.

[0297] There is a small risk of undesirable reactions to the injection of infliximab such as headache, nausea and throat or sinus infections. Very rarely, some people can develop an allergic reaction to infliximab. Patients will have continuous monitoring whilst the infliximab is being given, so if this were to happen during surgery, the anesthetist would treat the reaction as per normal clinical care.

[0298] There is a very small risk that the infliximab may cause old infections of tuberculosis and hepatitis to come back again. Long-term repeated use of infliximab affects the immune system so can make you more likely to develop infections but in this case, as it will only be administered once, it is very unlikely that this will occur.

[0299] Study information

[0300] Scientific Title: A feasibility study for a randomized controlled comparison on the effect of infusion of anti-TNF or placebo during surgery on delirium symptoms between hip fracture patients over 60 years of age.

[0301] Acronym: WHiTE13-DECI

[0302] Study hypothesis: To investigate if an infusion of the anti-TNF agent infliximab during surgery has an effect on delirium symptoms in the immediate post-operative period and on the development of cognitive impairment, quality of life and mortality in the following year.

[0303] Study design: Multicenter two-arm randomized placebo-controlled superiority comparison with embedded exploratory mechanistic outcome study.

[0304] Primary study design: Interventional

[0305] Secondary study design: Randomized controlled trial

[0306] Study setting(s): Hospital, Intemet / virtual, Telephone

[0307] Study type(s): Prevention

[0308] Condition: Hip fracture

[0309] Interventions: WHiTE 13 DECI is a randomized comparison appended to the World Hip Trauma Evaluation (WHiTE) Platform. WHiTE is a platform trial designed to efficiently deliver multiple randomized comparisons of interventions for patients aged 60 years and over with a hip fracture. The Platform and its appended randomized comparisons are governed by one single set of ethical and regulatory approvals and an explicit legal basis and processingpurpose for the use of patient-level data. The Platform affords a common core dataset and documentation.

[0310] Individual randomized comparisons are not dependent on each other and each will have unique start and stop dates and publication of results without compromising the integrity of the Platform.

[0311] Specifically for WHiTE 13-DECI: Participants will be allocated on a 1: 1 basis to either placebo or infliximab infusion treatments.

[0312] - Intervention: Single infusion of infliximab at 5mg / kg body weight, diluted in 250ml of 0.9% saline and administered intravenously over 2 hours

[0313] - Placebo control: Identical volumes of 0.9% saline

[0314] Intervention Type: Drug - Infliximab

[0315] Primary outcome measure: Peak postoperative delirium measured using the Memorial Delirium Assessment Scale (MDAS) on days 1-5 after surgery.

[0316] Secondary outcome measures:

[0317] 1. Cognitive impairment measured using the Telephone Interview for Cognitive Status (TICS) at 4 and 12 months post-diagnosis of a hip fracture;

[0318] 2. Health-related quality of life measured using the Euroqol-5D-5L pre-injury, at 4 and 12 months post-diagnosis of a hip fracture;

[0319] 3. Mortality risk measured using death notification up to 12 months post-diagnosis of a hip fracture;

[0320] 4. Subjective mobility status measured using the UK National Hip Fracture Database Mobility Scale at 4 and 12 months post-diagnosis of a hip fracture;

[0321] 5. Residential status measured using the UK National Hip Fracture Database Residential Status at 4 and 12 months post-diagnosis of a hip fracture; and

[0322] 6. Risk and pattern of complications measured using bespoke reporting forms up to 12 months post-diagnosis of a hip fracture.

[0323] Participant inclusion criteria: Adults aged 60 years or over diagnosed with a hip fracture that in the opinion of the treating surgeon may benefit from surgical treatment.

[0324] Participant type (s): Patient

[0325] Age group: Mixed

[0326] Lower age limit: 60 Years

[0327] Sex: Both

[0328] Target number of participants: Planned Sample Size: 564; UK Sample Size: 564

[0329] Participant exclusion criteria:

[0330] 1. The patient has severely impaired renal function eGFR <30 ml.min-1;

[0331] 2. The patient has severely impaired hepatic function;

[0332] 3. The patient is currently taking any anti-TNF drug;

[0333] 4. The patient has a contra-indication to anti-TNF injection;

[0334] 5. The patient has a known hypersensitivity to any anti-TNF agent or any of the excipients;

[0335] 6. The patient has known active tuberculosis (TB) or a history of TB or is at risk of developing TB; e.g. through the use of immunosuppressants;

[0336] 7. The patient has another known active infection (chronic or localized) or known history of recurring infections or conditions which may predispose patients to infection, including the use of concomitant immunosuppressive medications;

[0337] 8. The patient has known lung fibrosis;

[0338] 9. The patient had systemic inflammatory disorder such as rheumatoid arthritis or inflammatory bowel disease;

[0339] 10. The patient has known moderate to severe heart failure (NYHA class III / IV);

[0340] 11. The patient has HIV, Hepatitis B or C (based on medical history);

[0341] 12. The patient is at risk of Hepatitis B or HIV infections, including intravenous drug use;

[0342] 13. The patient has been diagnosed with Multiple Sclerosis (MS) or other central or peripheral nervous system demyelinating disorders;

[0343] 14. The patient has a history malignancy within five years prior to screening or any evidence of persistent malignancy, except basal cell or squamous cell carcinomas of the skin, or cervical carcinoma in situ which has been treated or excised in a curative procedure

[0344] 15. The patient has had a live vaccination 4 weeks prior to study entry or will require one within 12 weeks after the study intervention;

[0345] 16. The patient takes biologies including anakinra or abatacept or DMARDS; and

[0346] 17. The patient is or has been a participant in a clinical trial of a medicinal product in the last 12 weeks.Example 3 - Outcomes for WHiTE-DeCl study

[0347] 1. The participants receiving infliximab perioperatively have significantly lower prevalence and severity of post operative delirium compared to those receiving placebo as exemplified by a lower peak Memorial Delirium Assessment Score (MDAS). MDAS includes 10 items to assess the subject’s level of consciousness (awareness), orientation, short term memory, digit span (counting 3 - 5 number backwards and forwards), ability to maintain and shift attention, disorganised thinking, perceptual disturbance, delusions, decreased or increased psychomotor activity, sleep-wake cycle disturbance).

[0348] 2. The participants receiving infliximab perioperatively have better cognition compared to those receiving placebo at 4 and 12 months after hip fracture as measured using the Telephone Interview for Cognitive Status (TICS). TICS includes domains of orientation, concentration, short-term memory, language, praxis and mathematical skills.

[0349] 3. The participants receiving infliximab perioperatively have better cognition compared to those receiving placebo have higher health-related quality of life measured using Euroquol-5D-5L, which assess domains of mobility, self-care, usual activities, pain / discomfort, anxiety / depression.

[0350] 4. The participants receiving infliximab perioperatively are less likely to be residing in a care home compared to those receiving placebo at 4 and 12 months after hip fracture.

[0351] 5. The participants receiving infliximab perioperatively are no more likely than those treated with placebo to develop grade 3 or above complications.REFERENCES1. American Psychiatric Association. Diagnostic and Statistical Manual of Mental Disorders (DSM-5). 4th ed. American Psychiatric Association, 2000.2. NHFD 2018 annual report. https: / / www.nhfd.co.uk / 20 / hipfractureR.nsf / docs / reports2018 (accessed Feb 15, 2021).3. Alam A, Hana Z, Jin Z, Suen KC, Ma D. Surgery, neuroinflammation and cognitive impairment. EBioMedicine. 2018; 37: 547-56.4. Marcantonio E, Ta T, Duthie E, Resnick NM. Delirium severity and psychomotor types: Their relationship with outcomes after hip fracture repair. J Am Geriatr Soc 2002; 50: 850-7.5. Krogseth M, Watne LO, Juliebo V, et al. Delirium is a risk factor for further cognitive decline in cognitively impaired hip fracture patients. Arch Gerontol Geriatr 2016; 64: 38-44.6. Witlox J, Slor CJ, Jansen RWMM, et al. The neuropsychological sequelae of delirium in elderly patients with hip fracture three months after hospital discharge. Int Psychogeriatrics 2013; 25: 1521-31.7. Rochfort KD, Cummins PM. The blood-brain barrier endothelium: A target for pro-inflammatory cytokines. Biochem Soc Trans 2015; 43: 702-6.8. Clark IA, Vissel B. The inflammatory nature of post-surgical delirium predicts benefit of agents with anti-TNF effects, such as dexmedetomidine. Front Neurosci 2018; 12. DOI: 10.3389 / fhins.2018.00257.9. Kazmierski J, Banys A, Latek J, Bourke J, Jaszewski R. Raised IL-2 and TNF-a concentrations are associated with postoperative delirium in patients undergoing coronaryartery bypass graft surgery. Int Psychogeriatrics 2014; 26: 845-55.10. Chen W, Liu B, Zhang F, Xue P, Cui R, Lei W. The effects of dexmedetomidine on postoperative cognitive dysfunction and inflammatory factors in senile patients. Int J Clin Exp Med 2015; 8: 4601-5.11. Hirsch J, Vacas S, Terrando N, et al. Perioperative cerebrospinal fluid and plasma inflammatory markers after orthopedic surgery. J Neuroinflammation 2016; 13: 1-12.12. Sun D, Yang L, Wu Y, Liu R, Han J, Wang L. Effect of intravenous infusion of dobutamine hydrochloride on the development of early postoperative cognitive dysfunction in elderly patients via inhibiting the release of tumor necrosis factor-a. Eur J Pharmacol 2014; 741: 150— 5.13. Holmes C, Cunningham C, Zotova E, Culliford D, Perry VH. Proinflammatory cytokines, sickness behavior, and Alzheimer disease. Neurology 2011; 77: 212-8.14. Holmes C, Cunningham C, Zotova E, et al. Systemic inflammation and disease progression in alzheimer disease. Neurology 2009; 73: 768-74.15. Sudheimer D. KD, O’Hara R, Spiegel D, et al. Cortisol, cytokines, and hippocampal volume interactions in the elderly. Front Aging Neurosci 2014; 6. D01:10.3389 / fiiagi.2014.00153.16. KotekarN, Shenkar A, Nagaraj R. Postoperative cognitive dysfunction - current preventive strategies. Clin. 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Protective effect of celecoxib on early postoperative cognitive dysfunction in geriatric patients. Front Neurol 2018; 9. DOI: 10.3389 / fheur.2018.00633. 26. Raftery G, He J, Pearce R, et al. Disease activity and cognition in rheumatoid arthritis: An open label pilot study. Arthritis Res Ther 2012; 14. DOI: 10.1186 / ar4108.27. Zamarron C, Maceiras F, Mera A, Gomez-Reino JJ. Effect of the first infliximab infusion on sleep and alertness in patients with active rheumatoid arthritis. Ann Rheum Dis 2004; 63: 88-90.28. Elfferich MD, Nelemans PJ, Ponds RW, De Vries J, Wijnen PA, Drent M. Everyday cognitive failure in sarcoidosis: The prevalence and the effect of anti-TNF-a treatment. Respiration 2010; 80: 212-9.29. Tyring S, Gottlieb A, Papp K, et al. Etanercept and clinical outcomes, fatigue, and depression in psoriasis: Double-blind placebo-controlled randomized phase III trial. Lancet 2006; 367: 29-35.30. Raison CL, Rutherford RE, Woolwine BJ, et al. A randomized controlled trial of the tumor necrosis factor antagonist infliximab for treatment-resistant depression: The role of baseline inflammatory biomarkers. JAMA Psychiatry 2013; 70: 31-41.31. Scheinfeld N, Sundaram M, Teixeira H, Gu Y, Okun M. Reduction in pain scores and improvement in depressive symptoms in patients with hidradenitis suppurativa treated with adalimumab in a phase 2, randomized, placebo-controlled trial. Dermatol Online J 2016; 22. DOI: 10.5070 / d3223030360.32. Irwin MR, Olmstead R, Valladares EM, Breen EC, Ehlers CL. Tumor Necrosis Factor Antagonism Normalizes Rapid Eye Movement Sleep in Alcohol Dependence. Biol Psychiatry 2009; 66: 191-5.33. Weinberger JF, Raison CL, Rye DB, et al. Inhibition of tumor necrosis factor improves sleep continuity in patients with treatment resistant depression and high inflammation. Brain Behav Immun 2015; 47: 193-200.34. Breitbart W, Rosenfeld B, Roth A, Smith MJ, Cohen K, Passik S. The memorial delirium assessment scale. J Pain Symptom Manage 1997; 13: 128-37.35. Kluger MT, Skarin M, Collier J, et al. Steroids to reduce the impact on delirium (STRIDE): a double-blind, randomized, placebo-controlled feasibility trial of pre-operative dexamethasone in people with hip fracture. Anesthesia 2021. DOI: 10.1111 / anae.15465. 36. British Thoracic Society Standards of Care Committee. BTS recommendations for assessing risk and for managing Mycobacterium tuberculosis infection and disease in patients due to start anti-TNF-alpha treatment. Thorax 2005; 60: 800-5.37. Halaas NB, Blennow K, Idland AV, et al. Neurofdament light in serum and cerebrospinal fluid of hip fracture patients with delirium. Dement Geriatr Cogn Disord 2019; 46: 346-57.38 Casey CP, Lindroth H, Mohanty R, et al. Postoperative delirium is associated with increased plasma neurofdament light. Brain 2020; 143: 47-54.39. Blumenauer BB, Judd M, Wells GA, et al. Infliximab for the treatment of rheumatoid arthritis. 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Claims

CLAIMSWhat is claimed is:

1. A method of preventing or reducing post-operative delirium in a subject following a surgery or operation on said subject, the method comprising administering a therapeutically effective amount of a Tumour Necrosis Factor (TNF) antagonist to said subject within three hours of said surgery or operation.

2. The method of claim 1, wherein the surgery or operation is an orthopedic surgery or operation.

3. The method of claim 1 or 2, wherein the surgery or operation is to repair a hip fracture or is a hip replacement surgery.

4. The method of claim 1 or 2, wherein the surgery or operation is to repair a knee fracture or is a knee replacement surgery.

5. The method of claim 1, wherein the surgery or operation is a cardiac surgery, preferably a cardiac bypass grafting surgery.

6. The method of any one of claims 1-5, wherein the subject has a chest infection and / or a urinary tract infection (UTI).

7. The method of claim 6, wherein the subject is administered the TNF antagonist after the chest infection and / or a UTI is detected.

8. The method of any one of claims 1-7, wherein the TNF antagonist is an anti -TNF antibody, antibody-like molecule, antibody fragment or fusion thereof, aptamer, siRNA molecule, an antisense oligonucleotide, a ribozyme, or a small chemical inhibitor.

9. The method of any one of claims 1-8, wherein the TNF antagonist is infliximab, adalimumab, or etanercept.

10. The method of any one of claims 1-9, wherein the TNF antagonist is infliximab.

11. The method of any one of claims 1-10, wherein the subject is intravenously administered a single infusion of infliximab at 5mg / kg body weight, diluted in 250ml of 0.9% saline.

12. The method of any one of claims 1-11, wherein the TNF antagonist is a TNF receptor antagonist, preferably an anti -TNF receptor antibody, antibody-like molecule, antibody fragment or fusion thereof, aptamer, siRNA molecule, an antisense oligonucleotide, a ribozyme, or a small chemical inhibitor.

13. The method of any one of claims 1-12, wherein the TNF antagonist is administered after the subject is anesthetized but before commencement of surgical cutting.

14. The method of any one of claims 1-13, wherein the TNF antagonist is administered during the surgery or operation, preferably continuing during the total duration of the surgery or operation.

15. The method of any one of claims 1-14, wherein the duration of the surgery or operation is less than two hours, preferably about one hour or less.

16. The method of any one of claims 1-15, wherein the subject does not display symptoms of delirium in the five days following the operation or surgery.

17. The method of any one of claims 1-16, wherein the subject’s cognitive impairment score, mobility, and / or mortality risk is unchanged or improved at 4 to 12 months after the operation or surgery relative to their cognitive impairment score, mobility, and / or mortality risk at the time of the surgery or operation.

18. The method of any one of claims 1-17, wherein the subject’s Memorial Delirium Assessment Score (MDAS) score within five days following the operation or surgery is less than 10, preferably less than 5, more preferably less than 2.

19. The method of any one of claims 1-18, wherein the subject’s Telephone Interview for Cognitive Status (TICS) and / or Euroquol-5D-5L (EQ-5D-5L) score is unchanged or improved at 4 to 12 months after the operation or surgery relative to the subject’s TICS or EQ-5D-5L score at the time of the surgery or operation.

20. The method of any one of claims 1-19, wherein the subject does not develop a surgical complication, preferably a surgical complication of grade 3 or above, during or after the surgery or procedure.

21. The method of any one of claims 1-20, wherein the subject is at risk of developing postoperative delirium, preferably wherein the subject is age 60 or older and / or has a preexisting cognitive impairment.

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