Tranexamic Acid to Reduce Delirium After Gastrointestinal Surgery: the TRIGS-D Trial (TRIGS-D)

Tranexamic Acid to Reduce Delirium After Gastrointestinal Surgery: the TRIGS-D Trial (a Substudy of the TRIGS Trial)

Prophylactic TxA administration in patients undergoing major gastrointestinal surgery reduces the incidence of delirium after surgery when compared with placebo. The unifying hypothesis is that systemic and neuro-inflammation lead to neuronal injury and resultant postoperative delirium.

Study Overview

• Status: Recruiting
• Conditions: Dementia; Surgical Site Infection; Cognition
• Intervention / Treatment: Drug: Placebo; Drug: Tranexamic Acid 100Mg/ml Inj Vial 10ml

Detailed Description

Delirium is a devastating complication of medical and perioperative care, associated with increased morbidity and mortality, dementia and impaired long-term cognition, and loss of independence. Delirium is also associated with neuronal injury placing patients at risk for long-term changes in cognition. There are no proven therapies for postoperative delirium, mainly due to the lack of adequately powered, biologically plausible trials.

There is growing evidence that tranexamic acid (TxA) may reduce inflammatory pathways in the central nervous system and protect the blood-brain barrier in trauma, and surgery.

This sub-study of the TRIGS trial (www.trigs.com.au) is evaluating the potential impact of TxA on the incidence and severity of delirium after surgery.

TRIGS-D Study Aims: In a subset of 826 patients enrolled in the TRIGS randomized trial data will be collected to identify delirium incidence and severity. The specific aims are to investigate whether TxA:

Aim 1: Reduces the incidence of postoperative delirium diagnosed with the 3D-CAM.

Aim 2: Reduces the severity of delirium diagnosed with the 3D-CAM-Severity (3D-CAM-S).

Aim 3: Modulates inflammatory (plasma cytokines, innate cell immune profile) and neurophysiological (EEG) responses in concert with any alteration in the incidence or severity of delirium.

Aim 4: Reduces longer-term impairment of quality of life and improves disability-free survival.

Primary hypothesis: Prophylactic TxA administration in patients undergoing major gastrointestinal surgery reduces the incidence of delirium after surgery when compared with placebo. The unifying hypothesis is that systemic and neuro-inflammation lead to neuronal injury and resultant postoperative delirium.

Study Design: Multicentre, randomized, triple-blind, placebo-controlled, clinical trial (a sub-study of the TRIGS trial). Patients are randomly assigned to either TxA or matched placebo. The incidence of postoperative delirium will be assessed daily using the 3D-CAM or CAM-ICU and medical record review for the first 3 days after surgery. In addition, follow up assessments will be done at 30 days and 12 months.

• Study Type: Interventional
• Enrollment (Anticipated): 826
• Phase: Phase 3

Contacts and Locations

• Study Contact: Name: Paul S Myles, DSci; Phone Number: +61390763176; Email: p.myles@alfred.org.au
• Study Contact Backup: Name: Sophie KA Wallace; Phone Number: +61390762651; Email: s.wallace@alfred.org.au

Study Locations

• Australia
  • Victoria
    • Melbourne, Victoria, Australia, 3181
      • Recruiting
      • Alfred Health
      • Contact: Paul S Myles, DSc; Phone Number: 3176 0390762000; Email: p.myles@alfred.org.au
      • Contact: Sophie Wallace, MPH; Phone Number: 0390762651; Email: s.wallace@alfred.org.au

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years to 100 years (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

Inclusion criteria

• Adult patients scheduled for elective gastrointestinal (oesophageal, gastric, hepatobiliary, colorectal) surgery
• with 2 or more risk factors for complications:
• age ≥70 years,
• American Society of Anesthesiologists (ASA) physical status 3 or 4,
• heart failure, diabetes,
• chronic respiratory disease,
• obesity (BMI ≥30 kg/m2),
• vascular disease,
• preoperative haemoglobin <100 g/L,
• renal impairment (se. creatinine ≥150 micromol/L), or low albumin (<30 g/L).
• Written informed consent will be obtained. Exclusion criteria
• Poor spoken and/or written language comprehension,
• laparoscopic and other minor (eg. closure of stoma) surgery,
• pre-existing infection/sepsis,
• history of spontaneous pulmonary embolism or arterial thrombosis,
• current arterial or venous thrombosis,
• familial thrombophilia (e.g. Lupus anticoagulant, protein C deficiency, factor V Leiden),
• contraindication to TxA.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Prevention
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Quadruple

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Active Comparator: Tranexamic Acid; 12 mg/kg, before surgical incision, and then an infusion of 3 mg/kg/h until the end of surgery.	Drug: Tranexamic Acid 100Mg/ml Inj Vial 10ml; Intervention is from the Tranexamic acid to Reduce Infection after Gastrointestinal Surgery: the TRIGS Trial. A multicentre, pragmatic, double-blind, randomised clinical trial will compare the incidence of surgical site infection and red cell transfusion requirements after IV tranexamic acid and placebo in patients undergoing gastrointestinal surgery; Other Names: Cyklokapron
Placebo Comparator: Placebo; 12 mg/kg, before surgical incision, and then an infusion of 3 mg/kg/h until the end of surgery.	Drug: Placebo; Normal saline; Other Names: Normal Saline

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
incidence of delirium in the first 3 days postoperatively	3D-Confusion Assessment Method (3D-CAM) or CAM-ICU if the Used to measure delirium. Assessments will be conducted twice daily A classification of delirium will be made if both features 1 and 2 are present	post surgical incision to day 3 (at anytime)obtaining information from the patient, family and staff, and thorough chart review

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Delirium severity	3D-CAM-S	post surgical incision to day 3 (inclusive)
Quality of Life Intergroup differences	using the Short form survey 12 - Quality of Life Intergroup differences in long-term (12 month) in perioperative cognitive decline	12 months post surgical incision
Disability	World Health Organization disability assessment schedule. Intergroup differences in long-term (12 month) in perioperative cognitive decline	12 months post surgical incision
perioperative neurocognitive disorders (NCDs)	NCD will be defined as any of: (i) subjective complaint, (ii) a 4-point reduction in TICS-B, (iii) SF or VF, and (iv) functional deficit defined as a reduction in WHODAS score of 5% or more from baseline (before surgery).	12 months post surgical incision
Days at home up to 30 days after surgery (DAH30)	DAH30 is patient-centred and reflects the patient's primary aim of a healthy recovery, reduced hospital costs and serious complications, and avoiding re-admission (often due to postoperative delirium).	30 days post surgical incision post surgical incision
cytokine levels	Blood tests measured in 92 key inflammatory/immune markers using technology	preoperative, postoperative day 1 and 3 post surgical incision
neuronal injury biomarker	used to evaluate temporal changes in the innate cellular immune and inflammatory profile, and for changes in fibrinolysis	preoperative, postoperative day 1 and 3 post surgical incision

Collaborators and Investigators

• Sponsor: Bayside Health
• Collaborators: Monash University
• Investigators: Study Chair: Paul S Myles, DSci, Monash University

Study record dates

Study Major Dates

• Study Start (Actual): November 1, 2022
• Primary Completion (Anticipated): December 30, 2025
• Study Completion (Anticipated): December 31, 2025

Study Registration Dates

• First Submitted: July 5, 2022
• First Submitted That Met QC Criteria: July 20, 2022
• First Posted (Actual): July 22, 2022

Study Record Updates

• Last Update Posted (Estimate): January 11, 2023
• Last Update Submitted That Met QC Criteria: January 9, 2023
• Last Verified: July 1, 2022

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Mental Disorders; Pathologic Processes; Nervous System Diseases; Infections; Postoperative Complications; Neurologic Manifestations; Confusion; Neurobehavioral Manifestations; Neurocognitive Disorders; Wound Infection; Delirium; Surgical Wound Infection; Molecular Mechanisms of Pharmacological Action; Fibrin Modulating Agents; Antifibrinolytic Agents; Hemostatics; Coagulants; Tranexamic Acid
• Other Study ID Numbers: 58/20

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: Yes
• IPD Plan Description: Following written request and review by the steering committee
• IPD Sharing Time Frame: Following analysis for the publication
• IPD Sharing Access Criteria: Written request
• IPD Sharing Supporting Information Type: Study Protocol; Statistical Analysis Plan (SAP)

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No
• product manufactured in and exported from the U.S.: No