Trials on the horizon by Professor Michael Reade

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

The problem with clinical trials in trauma
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

The problem with clinical trials in trauma
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)

Alternatives to 28-day mortality
• 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

Trials on the horizon
• Viscoelastic-guided protocols
• Lyophilised plasma
• Tranexamic acid
• Fibrinogen concentrate & cryoprecipitate
• Cryopreserved platelets
• Cold-stored platelets
• Erythropoietin as an immunomodulator in trauma

iTACTIC

Plasma
First ever trial demonstration that
prehospital plasma reduces mortality

RePHILL

RePHILL
LyoPlas (Germany). Single donor. ABO-specific. Up to 15-month
shelf-life. In production since 2007 (1990-2006 had been a
pooled product)

RePHILL: progress
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

French Lyophilised Plasma
FLyP reduced the requirement for massive transfusion

French Lyophilised Plasma
Will FLyP affect survival?

PATCH-Trauma
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

PATCH-Trauma

PATCH-Trauma
• 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

Fibrinogen in trauma
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

FI in TIC
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

FiiRST
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

FEISTY
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

FEISTY
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

FEISTY
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.

CRYOSTAT
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
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

CRYOSTAT-2
UK (Curry, Davenport, Stanworth)
CRYOSTAT - 2
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)

CLIP
• US Navy 1970s technology
• 2 year shelf life at -80°C
• Resuspended in plasma
• No requirement to remove
residual DMSO

CLIP
• 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.

Cold-stored platelets

EPO-TRAUMA
• 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

Trials on the horizon by Professor Michael Reade

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