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Trials on the horizon by Professor Michael Reade

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Professor Michael Reade: Trials on the horizon.
From CICM ASM PROGRAM 2019.

Published in: Health & Medicine
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Trials on the horizon by Professor Michael Reade

  1. 1. Trauma trials on the horizon Michael Reade MBBS MPH DPhil DMedSc AFRACMA FCCM FANZCA FCICM Anaesthetist & Intensive Care Physician ADF Professor of Military Medicine & Surgery Brigadier. Assistant Surgeon General – Australian Army Joint Capabilities Group │ Joint Health Command │ Defence Professor of Military Medicine and Surgery
  2. 2. The problem with clinical trials in trauma Joint Capabilities Group │ Joint Health Command │ Defence Professor of Military Medicine and Surgery Heterogeneity of patients, trauma mechanism and physiological effect – none of which can be well characterised at time of inclusion (combined with a desire to enrol only those with ‘preventable’ mortality risk) Landmark mortality is a dichotomous outcome – resulting in less study power Expecting a brief intervention to be ‘seen’ 28 days later is ambitious, especially given the reduction in the third peak of the trimodal distribution of death Post-immediate care Some populations are systematically different; group imbalances can ruin trial May interact with intercurrent care
  3. 3. The problem with clinical trials in trauma Joint Capabilities Group │ Joint Health Command │ Defence Professor of Military Medicine and Surgery Needs: - A very big mountain (effect size) - Watching for a very long time (sample size) - Other effects of the mountain e.g. a shadow (surrogate outcomes)
  4. 4. Alternatives to 28-day mortality Joint Capabilities Group │ Joint Health Command │ Defence Professor of Military Medicine and Surgery • 24-hour mortality • Long-term functional outcome • Cause-specific mortality (e.g. death due to bleeding) • Biological surrogates (e.g. inflammatory mediators) • Health system efficiency outcomes (e.g. transfusion requirement) • Organ-support free days • Length of stay • Composites e.g. mortality OR transfusion >10 units EQ-5D
  5. 5. Trials on the horizon Joint Capabilities Group │ Joint Health Command │ Defence Professor of Military Medicine and Surgery • Viscoelastic-guided protocols • Lyophilised plasma • Tranexamic acid • Fibrinogen concentrate & cryoprecipitate • Cryopreserved platelets • Cold-stored platelets • Erythropoietin as an immunomodulator in trauma
  6. 6. iTACTIC Joint Capabilities Group │ Joint Health Command │ Defence Professor of Military Medicine and Surgery
  7. 7. iTACTIC Joint Capabilities Group │ Joint Health Command │ Defence Professor of Military Medicine and Surgery
  8. 8. Plasma Joint Capabilities Group │ Joint Health Command │ Defence Professor of Military Medicine and Surgery First ever trial demonstration that prehospital plasma reduces mortality
  9. 9. RePHILL Joint Capabilities Group │ Joint Health Command │ Defence Professor of Military Medicine and Surgery
  10. 10. RePHILL Joint Capabilities Group │ Joint Health Command │ Defence Professor of Military Medicine and Surgery LyoPlas (Germany). Single donor. ABO-specific. Up to 15-month shelf-life. In production since 2007 (1990-2006 had been a pooled product)
  11. 11. RePHILL: progress Joint Capabilities Group │ Joint Health Command │ Defence Professor of Military Medicine and Surgery RePHILL trial investigators meeting. Study of prehospital transfusion now halfway - 200th patient recruited Christmas Day! @RePHILL_trial Emergency Care = Research 24/7. @Magpas_Charity @EastAngliAirAmb 29 Jan 2019 Jan 2019: >200/490 patients
  12. 12. French Lyophilised Plasma Joint Capabilities Group │ Joint Health Command │ Defence Professor of Military Medicine and Surgery FLyP reduced the requirement for massive transfusion
  13. 13. French Lyophilised Plasma Joint Capabilities Group │ Joint Health Command │ Defence Professor of Military Medicine and Surgery Will FLyP affect survival?
  14. 14. PATCH-Trauma Joint Capabilities Group │ Joint Health Command │ Defence Professor of Military Medicine and Surgery Screen at scene of injury Randomise 1g TXA Bolus dose placebo Blood test 1g TXA placebo8 hr infusion STOP Blood test +24h + + DVT Ultrasound Day 5-7 n = 579 n = 579 6 months Telephone interview Pre-hospitalHospital Blood test 73% Recruitment Currently 860 Target 1184 Remaining 324 As of 1-Mar-2019
  15. 15. PATCH-Trauma Joint Capabilities Group │ Joint Health Command │ Defence Professor of Military Medicine and Surgery
  16. 16. PATCH-Trauma Joint Capabilities Group │ Joint Health Command │ Defence Professor of Military Medicine and Surgery • 4 Western Pennsylvania Prehospital Systems • Opt-out consent • Within 2 hrs of injury, SBP<90mmHg, HR>110 • Excludes: cardiac arrest > 5 mins, penetrating TBI • 1g bolus prehospital; bolus or infusion in hospital • Primary outcome: 30 day mortality • Coagulation / inflammation substudies • 994 patients over 3 years • Adult trauma patients requiring at least 1 unit of blood transfusion and/or immediate operating room • Excludes: MI, stroke, DVT/PE, seizure disorder • Primary outcome: Differences in the proportion of activated monocytes among the 3 treatment arms • 2 dosing groups (2 g, 4 g) and placebo • Completed 150 patient enrolment DEC 18
  17. 17. Fibrinogen in trauma Joint Capabilities Group │ Joint Health Command │ Defence Professor of Military Medicine and Surgery Possible problems with fibrinogen concentrate: • Unlike plasma, does not replace volume – which presumably must be replaced with crystalloid. This might be detrimental … • Studies showing improved viscoelastic results with fibrinogen administration may misrepresent in vivo coagulopathy & not reflect patient outcome benefit
  18. 18. FI in TIC Joint Capabilities Group │ Joint Health Command │ Defence Professor of Military Medicine and Surgery Austria (Fries et al): FI in TIC Inclusion Adult trauma patients with “significant signs of internal bleeding” prehospital Intervention Approx. 50mg/kg fibrinogen concentrate or placebo Blinding Double-blind Outcome Primary outcome - FIBTEM MCF Secondary outcomes - transfusion requirement/blood loss, thromboembolic complications, morbidity and length of ICU and hospital stay Progress 67 patients randomised; completed Dec 2015. Not yet presented or published
  19. 19. FiiRST Joint Capabilities Group │ Joint Health Command │ Defence Professor of Military Medicine and Surgery Canada (Callum et al) - FiiRST Injured patient at risk of bleeding: SBP <100mmHg at any time from injury until 30 min post admission AND RBC transfusion ordered 6g Fg Concentrate within 60 min vs. placebo FgC prepared in blood bank Feasibility (96% received in <1hr); FC concentration achieved was higher than placebo Completed recruitment 50 patients
  20. 20. FEISTY Joint Capabilities Group │ Joint Health Command │ Defence Professor of Military Medicine and Surgery Fibrinogen Early In Severe Trauma study (FEISTY) pilot trial • Queensland, Australia 40-hospital pilot trial • Inclusion: major trauma, FIBTEM A5<10mm • Fibrinogen concentrate vs. cryoprecipitate, with doses determined by FIBTEM A5 • Outcomes: feasibility, speed of administration, fibrinogen concentration Endorsed by ANZICS CTG March 2016 Target 100 patients enrolment completed March 2018 Courtesy Dr James Winearls, Gold Coast University Hospital Australia
  21. 21. FEISTY Joint Capabilities Group │ Joint Health Command │ Defence Professor of Military Medicine and Surgery Courtesy Dr James Winearls, Gold Coast University Hospital Australia Secondary outcomes: • No difference in PRBC transfused prehospital, at 24hr, or total • Higher mortality in FC group (12 vs 3 patients); likely a spurious result
  22. 22. FEISTY Joint Capabilities Group │ Joint Health Command │ Defence Professor of Military Medicine and Surgery Courtesy Dr James Winearls, Gold Coast University Hospital Australia FEISTY-II (Winearls et al.) Inclusion Adults, ABC score>=2 OR “significant haemorrhage”, activation of MTP, FIBTEM A5 <=10mm Intervention 3-6g fibrinogen concentrate (as determined by the FIBTEM A5) vs. 10-20U cryoprecipitate (as determined by the FIBTEM A5) Blinding Unblinded Outcome Still under discussion. ? NON-INFERIORITY IN: PRBC (units) in 1st 24hr Functional outcome at 6 months Progress Would require 2000 patients for 1U PRBC non-inferiority In-principle provision of FC by CSL-Behring not yet agreed Funded for lead-in phase by NBA and EMF 1. Avoids giving FC or cryoprecipitate to patients who do not need it 2. Uses an outcome with economic relevance 3. Avoids seeking differences in mortality in a population likely to have a low preventable death rate 4. Asks the most relevant question to clinicians & blood policy-makers in Australia (&?worldwide) i.e. is the increasing use of FC, driven by the increasing use of ROTEM/TEG, something that at least is not inferior (in both clinical outcomes and resource utilisation) to standard care.
  23. 23. CRYOSTAT Joint Capabilities Group │ Joint Health Command │ Defence Professor of Military Medicine and Surgery UK (Curry, Stanworth, Brohi) CRYOSTAT-1 Inclusion Adult trauma patients Active bleeding with shock Activation of MTP and/or transfusion emergency (Group O) RBC <3hrs from injury Intervention 2 pools of cryoprecipitate within 90min – vs. standard care Blinding Unblinded Outcome Feasibility Progress Completed recruitment 43 patients. 85% received cryo. within 90 minutes. Cryo. concentration achieved was higher in the cryo. Group. Trend to reduced mortality (10 vs 27%, p=0.14) UK (Curry, Stanworth, Brohi) E-Fit 1 Inclusion Adult trauma patients Active bleeding with shock Activation of MTP and/or transfusion emergency (Group O) RBC Intervention 6g Fg Concentrate within 45min – vs. placebo Blinding Prepared study packs in ED. Empty blinded bottles – use black syringe Outcome Feasibility Progress Completed recruitment 48 patients
  24. 24. CRYOSTAT-2 Joint Capabilities Group │ Joint Health Command │ Defence Professor of Military Medicine and Surgery UK (Curry, Davenport, Stanworth) CRYOSTAT - 2 Inclusion Adult trauma patients MTP activated Has received at least one unit of a blood component Intervention Early 3 pools (15U) cryoprecipitate (approx. 6g fibrinogen) (within 90 min) vs. standard transfusion therapy (i.e. MTP with no cryo.) Blinding Not blinded Outcome 28 day mortality 6 month functional outcome 90% power to detect 7% reduction in mortality from baseline of 26% Progress 1568 pts; commenced enrolment JUL17. 559 recruited to date (MAY 19)
  25. 25. CLIP Joint Capabilities Group │ Joint Health Command │ Defence Professor of Military Medicine and Surgery • US Navy 1970s technology • 2 year shelf life at -80°C • Resuspended in plasma • No requirement to remove residual DMSO
  26. 26. CLIP Joint Capabilities Group │ Joint Health Command │ Defence Professor of Military Medicine and Surgery • Hypothesis: cryopreserved platelets will be at least as effective, cost-effective and safe as conventional liquid-stored platelets • Blinded randomised phase III clinical non-inferiority trial in approximately 12 Australian (and New Zealand?) hospitals. • Eligibility: Adult cardiac surgical patients with a high risk of platelet transfusion by the Adult Cardiac Surgery Platelet Transfusion (ACSePT) score. • Primary Endpoint: Volume of post-surgical bleeding in the first 24 hours from the time the patient arrives in the ICU • Major Secondary Endpoints: • BARC composite bleeding endpoint (≥2L bleeding in 24hr, ≥5U PRBC in 48hr, or reoperation due to bleeding); requirement for blood products; volume of postoperative fluid resuscitation; adverse effects, especially local or systemic infection, fever, venous thromboembolism, arterial occlusion, need for surgical intervention, and ARDS.
  27. 27. Cold-stored platelets Joint Capabilities Group │ Joint Health Command │ Defence Professor of Military Medicine and Surgery
  28. 28. Cold-stored platelets Joint Capabilities Group │ Joint Health Command │ Defence Professor of Military Medicine and Surgery
  29. 29. Cold-stored platelets Joint Capabilities Group │ Joint Health Command │ Defence Professor of Military Medicine and Surgery
  30. 30. EPO-TRAUMA Joint Capabilities Group │ Joint Health Command │ Defence Professor of Military Medicine and Surgery • Critically ill trauma patients requiring mechanical ventilation admitted to participating centres. • Exclusions: history of DVT, PE or other thromboembolic event; chronic hypercoagulable disorder, including known malignancy; • 40,000 Units EPO subcutaneously administered as soon as possible (maximum 24 hours) after the estimated time of traumatic injury with a second dose on study day 8 vs. placebo • Primary outcome: Combined mortality and severe disability (defined as a WHODAS 2.0 score ≥ 24) at six months • 2403 patients
  31. 31. Joint Capabilities Group │ Joint Health Command │ Defence Professor of Military Medicine and Surgery

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