iTACTIC – implementing Treatment Algorithms for the Correction of Trauma-Induced Coagulopathy: study protocol for a multicentre, randomised controlled trial
Baksaas-Aasen et al. Trials
iTACTIC - implementing Treatment Algorithms for the Correction of Trauma- Induced Coagulopathy: study protocol for a multicentre, randomised controlled trial
Kjersti Baksaas-Aasen 0
Lewis Gall 2
Simon Eaglestone 2
Claire Rourke 2
Nicole. P. Juffermans 1
J. Carel Goslings 6
Paal Aksel Naess 0
Susan van Dieren 6
Sisse Rye Ostrowski 7
Jakob Stensballe 7
Marc Maegele 5
Simon J. Stanworth 3 4
Christine Gaarder 0
Karim Brohi 2
Per I. Johansson 7
0 Department of Traumatology, Oslo University Hospital , Oslo , Norway
1 Department of Intensive Care Medicine, Academic Medical Center , Amsterdam , The Netherlands
2 Centre for Trauma Sciences, Blizard Institute, Queen Mary University of London , London , UK
3 Radcliffe Department of Medicine, University of Oxford , Oxford , UK
4 NHS Blood and Transplant/Oxford University Hospital NHS Trust, John Radcliffe Hospital , Oxford , UK
5 Department for Traumatology and Orthopedic Surgery, Cologne-Merheim Medical Centre, University of Witten/Herdecke , Cologne , Germany
6 Trauma Unit, Department of Surgery, Academic Medical Center , Amsterdam , The Netherlands
7 Section for Transfusion Medicine, Capital Region Blood Bank, Copenhagen University Hospital , Rigshospitalet, Copenhagen , Denmark
Background: Traumatic injury is the fourth leading cause of death globally. Half of all trauma deaths are due to bleeding and most of these will occur within 6 h of injury. Haemorrhagic shock following injury has been shown to induce a clotting dysfunction within minutes, and this early trauma-induced coagulopathy (TIC) may exacerbate bleeding and is associated with higher mortality and morbidity. In spite of improved resuscitation strategies over the last decade, current transfusion therapy still fails to correct TIC during ongoing haemorrhage and evidence for the optimal management of bleeding trauma patients is lacking. Recent publications describe increasing the use of Viscoelastic Haemostatic Assays (VHAs) in trauma haemorrhage; however, there is insufficient evidence to support their superiority to conventional coagulation tests (CCTs). Methods/design: This multicentre, randomised controlled study will compare the haemostatic effect of an evidence-based VHA-guided versus an optimised CCT-guided transfusion algorithm in haemorrhaging trauma patients. A total of 392 adult trauma patients will be enrolled at major trauma centres. Participants will be eligible if they present with clinical signs of haemorrhagic shock, activate the local massive haemorrhage protocol and initiate first blood transfusion. Enrolled patients will be block randomised per centre to either VHA-guided or CCT-guided transfusion therapy in addition to that therapy delivered as part of standard care, until haemostasis is achieved. Patients will be followed until discharge or 28 days. The primary endpoint is the proportion of subjects alive and free of massive transfusion (less than 10 units of red blood cells) at 24 h. Secondary outcomes include the effect of CCT- versus VHA-guided therapy on organ failure, total hospital and intensive care lengths of stay, health care resources needed and mortality. Surviving patients will be asked to complete a quality of life questionnaire (EuroQol EQ-5DTM) at day 90. Discussion: CCTs have traditionally been used to detect TIC and monitor response to treatment in traumatic major haemorrhage. The use of VHAs is increasing, but limited evidence exists to support the superiority of these technologies (or comparatively) for patient-centred outcomes. This knowledge gap will be addressed by this trial.
Trial registration: ClinicalTrials.gov, ID: NCT02593877. Registered on 15 October 2015.
Queen Mary University of London
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The contact person of the above sponsor organisation is: Dr. Sally Burtles, Director of Research Services and
Business Development, Joint Research Management Office, QM Innovation Building, 5 Walden Street, London E1
2EF; phone: 020 7882 7260; Email:
Academic Medical Centre, Amsterdam, The Netherlands
Kliniken der Stadt Köln gGmbH, Cologne, Germany
Rigshospitalet (Copenhagen University Hospital), Copenhagen, Denmark
John Radcliff Hospital, Oxford, United Kingdom
Oslo University Hospital, Oslo, Norway
The Royal London Hospital, London, United Kingdom
Centre for Trauma Sciences, Blizard Institute, Queen Mary University of London, London, United Kingdom
Health Economics Research Centre, Nuffield Department of Population Health, University of Oxford, Oxford, United
Sites that are planning to start recruitment in mid/late 2017
Nottingham University Hospitals, Queen’s Medical Centre, Nottingham, United Kingdom
University of Kansas Hospital (UKH), Kansas City, MO, USA
Protocol version: 3.0/14.03.2017 (Additional file 1)
Traumatic injury is responsible for a large and increasing
proportion of the world’s burden of disease and is the
fourth leading cause of death globally [
]. Half of all trauma
deaths are due to bleeding and most of these will occur
within 6 h from injury [
]. Haemorrhagic shock following
injury has been shown to induce a clotting dysfunction (i.e.
coagulopathy) within minutes [
]. Such early
traumainduced coagulopathy (TIC) may exacerbate bleeding and
is associated with higher mortality and morbidity [
4, 6, 7
Many more injured patients will go on to develop different
types of coagulopathy at different times during the course
of their treatment, either as a result of their body’s ongoing
response to trauma or as a consequence of their clinical
care. Coagulopathic, haemorrhaging trauma patients have
increased blood transfusion requirements, increased
mortality and more adverse outcomes [
improvements in surgical techniques, resuscitation strategies and
intensive care treatments, outcomes for critically injured
patients remain poor [
]. Within the last decade research
focussing on TIC has led to improved resuscitation
strategies, resulting in the early and more aggressive use of
blood products and coagulation factors for the
management of massively bleeding patients.
In spite of improved resuscitation strategies, current
transfusion therapy still fails to correct coagulopathy
during ongoing haemorrhage [
]. The mechanisms
and genesis of TIC have yet to be fully elucidated, and
there are many questions about how to optimally
diagnose, resuscitate and monitor the critically bleeding
trauma patient. It is important to detect TIC as early as
possible. Conventional coagulation tests (CCT), such as
prothrombin time/international normalised ratio (PT/
INR), activated partial thromboplastin time (APTT),
fibrinogen concentration and PLT, have traditionally been
used. However, there is a striking lack of evidence to
support the use of these CCTs to monitor resuscitation,
although threshold triggers for intervention based on
CCTs have been suggested . Recent published
evidence describes an increasing recognition for the
potential of the two current market-leading Viscoelastic
Haemostatic Assays (VHAs) namely
thromboelastography (TEG®; Haemonetics Incorporation) and rotational
thromboelastometry (ROTEM®; TEM Innovation
GmbH). Both platforms use similar test modes to rapidly
and accurately determine the functional coagulation
status of patient whole blood. However, the evidence
base supporting a role for these VHA devices is
limited, and less attention has been directed to
understanding their cost-effectiveness. Cost-effectiveness
may be particularly relevant both in the context of
additional therapeutic interventions required, but also
in potential savings, if fewer treatments are required
based on delivery of individualised assessments of
The relative contribution of blood components, such
as fibrinogen and platelets, to clot strength can be
evaluated through the use of specific inhibitors or agonists
]. The viscoelastic properties of blood samples are
recorded under low shear conditions, thereby providing a
comprehensive visual profile of clot formation and
Unlike laboratory-based CCTs which might take more
than 60 min for the results to be available to clinicians
], VHA is a point-of-care device which might provide
clinically relevant results within even 5–10 min and thus
may be repeated in a massive bleeding situation to
identify patient-specific needs for transfusion components in
a timelier manner. Furthermore, VHAs provide the
potential to detect hyperfibrinolysis, and possibly
hypercoagulability. However, VHA assays and testing have costs,
require training and additional oversight, and may not
provide insight into other potentially important
haemostatic derangements at the endothelial or platelet level.
In addition, other publications attest to how changes in
the process and pathways for the delivery of CCTs can
be modified and accelerated [
Whilst VHA has been used for many years in liver
transplant and cardio-pulmonary surgery, robust data
supporting its universal uptake in the context of trauma
are lacking. Whilst some publications have attempted to
identify VHA patterns and thresholds characterizing
TIC and the need for massive transfusion in trauma
patients, definitive evidence proving its superiority over
CCTs in the diagnosis and management of coagulopathy
in the acute setting is not available [
Although considered a preventable major cause of
death, the management of coagulopathic bleeding in
trauma patients remains primarily based upon
retrospective registry studies of survival and extrapolating the
results of transfusion practice performed in the elective,
non-acute surgical setting. Treatment is diverse
comprising the empiric transfusion of red blood cells (RBC)
and clotting product supplements to patients, blind to
the type and severity of TIC they may have – or indeed
even if they do not have coagulopathy. It is well
established that blood transfusion carries significant health
risks both related to transmission of pathogens and to
the development of transfusion reactions. Published in
2015, the results of the Pragmatic, Randomised Optimal
Platelet and Plasma Ratios (PROPPR) trial [
the best evidence to date for optimal trauma
haemorrhage resuscitation. PROPPR demonstrated that an
empiric massive transfusion protocol (MTP) aiming at a
ratio of 1:1:1 of blood components (RBC 1: plasma 1:
platelets 1) administered from the early phase of care
and during ongoing haemorrhage was associated with
fewer exsanguinations in the initial 24 h (p = 0.03) and a
tendency towards improved 24-h survival (p = 0.12) than
a 1:1:2 ratio.
The present prospective randomised controlled trial (RCT)
will employ evidence-based treatment algorithms to compare
outcomes of VHA-guided resuscitation versus CCT
resuscitation support in haemorrhaging trauma patients.
The hypothesis for this comparative study is that
VHA-directed therapy will enhance early haemostatic
control by the targeted correction of TIC, whilst also
reducing the total amount of blood products and
procoagulants administered to all bleeding trauma patients,
including those not having TIC. This would significantly
reduce both the number of patients receiving blood
transfusion and the number of transfused blood
products per transfused patient, thereby improving both
patient safety and resource utilisation.
This is an investigator-initiated, multi-centred,
superiority, parallel-group, randomised controlled trial
performed at eight major trauma centres. The trial sites
include: Rigshospitalet (Copenhagen, Denmark),
Academic Medical Centre (Amsterdam, The Netherlands),
Oslo University Hospital (Oslo, Norway), Kliniken der
Stadt Köln gGmbH Cologne, Germany), The Royal
London Hospital (London, UK), John Radcliffe Hospital
(Oxford, UK). Nottingham University Hospitals, Queen’s
Medical Centre (Nottingham, United Kingdom) and
University of Kansas Hospital (UKH) (Kansas City, MO,
USA) are planning to start recruitment in 2017.
This protocol (Additional file 1) conforms to the
Consolidated Standard of Reporting Trials (CONSORT)
guidelines. Figure 1 shows the Standard Protocol Items:
Recommendation for Interventional Trials (SPIRIT)
schedule of enrolment, interventions and assessments.
The SPIRIT Checklist is given in the Additional file 2.
An overview of the study process is provided in Fig. 2
Adult trauma patients (according to local definitions)
will be enrolled if they present with clinical signs of
haemorrhagic shock, according to the responsible
trauma team leader, activate the local massive
haemorrhage protocol, according to the participating
institutions’ specific routines, and initiate first transfusion.
Participants must be randomised within 3 h of injury
and 1 h of admission to the ED of the participating study
site. Agreement is provided on behalf of incapacitated
patients by a personal consultee (PC) or a nominated
There are no exclusion criteria.
The primary objective is to compare the haemostatic
effect of VHA assay-guided transfusion strategy versus
optimised CCT-guided transfusion strategy in
haemorrhaging trauma patients.
The secondary objectives of the study are to determine
the effects of VHA-led versus optimised CCT-guided
resuscitation on organ failure, hospital length of stay (LOS),
intensive care unit (ICU) stay, duration of mechanical
ventilation, health care resource needs and mortality.
The primary endpoint is the proportion of subjects alive
and free of massive transfusion (less than 10 units of
RBC transfused) at 24 h post admission.
The secondary endpoints listed below will be analysed in
order to provide a sensitive and comprehensive
description of outcomes and health care resource demands for
the VHA and CCT arm subjects:
All-cause mortality at 6 and 24 h and 28 and 90 days post admission
Duration and severity of coagulopathy until
haemostasis, as defined by the area under the time
multiplied by Prothrombin Ratio (PTr) curve, with
coagulopathy defined as PTr > 1.2. Patients who die
will have their time of haemostasis set at 24 h, and
last PTr extrapolated to this time point
Proportion of patients who have corrected coagulopathy, defined as PTr < 1.2, after first 8 units of RBC
Time to haemostasis (defined as having occurred at the end of the first hour free of red cell transfusions and the treating clinicians believe primary haemostasis has been achieved)
Time spent in coagulopathic condition, defined as
PTr ≥ 1.2, until haemostasis, defined as the point 1 h
from the last administration of RBC and the treating
clinician believes that primary haemostasis has been
Blood products administered (RBC, plasma, platelets
alone and in total) within first 6 and 24 h after
28-day ventilator-free and ICU-free days (patients
who die in hospital during the 28-day study period
will be considered to have zero hospital-free days)
Total hospital length of stay
28-day symptomatic thromboembolic events defined
as: deep venous thrombosis (DVT) diagnosed by
compression ultrasound or venography, pulmonary
embolism diagnosed by computed tomography (CT)
pulmonary angiogram or ventilation-perfusion scan
or myocardial infarction and/or stroke identified by
standard clinical diagnostic investigation(s)
Incidence of transfusion-related complications
Incidence of organ dysfunction, defined by
Sequential Organ Failure Assessment (SOFA) score
Health care resource, productivity costs and HRQoL (EuroQol EQ-5DTM at discharge or day 28, and at day 90)
Lifetime health economic cost-effectiveness of perso
nalised VHA-guided haemorrhagic treatment versus
MTP-based on best practice and CCTs
Local investigators will identify eligible adult trauma
patients with haemorrhagic shock and ongoing bleeding as
soon as possible after the patient has arrived in the
emergency department (ED), using local transfusion
triggers. If patients are deemed to be eligible, consent for
entry into the trial will be sought. A screening log will
be completed once a week, which will record all patients
considered for eligibility to the trial by the
investigator(s). The log will include age, gender,
inclusion/exclusion criteria and other reasons for non-enrolment. The
screening log data will be reviewed at regular intervals.
Enrolled patients will be block randomised per centre to
either the CCT or the VHA study arm within 3 h of injury
and within 1 h of admission. The trial will be un-blinded
for clinical staff and site investigators. Once a patient is
determined eligible for the study and informed consent or
agreement has been obtained, each subject will be enrolled
as soon as possible and will be assigned a unique
alphanumeric study identifier. Randomisation will be performed
by the site investigator opening a sealed envelope
containing the randomised treatment group, to allow for
immediate allocation of subjects. An independent party,
appointed by the sponsor, will generate the randomisation
sequence and site envelopes centrally.
Schedule of intervention
All participating centres will initiate the management of
the study population according to standard local
protocols regardless of enrolment in the trial. Following
randomisation, study participants will undergo
interventions at set time points as outlined in Fig. 1
(Standard Protocol Items: Recommendations for
Interventional Trials (SPIRIT) schedule of enrolment,
interventions and assessments) and be followed up for
90 days after enrolment.
All participating centres currently manage critically
bleeding trauma patients according to a standardised
MTP aiming at a ratio of RBC 1: plasma 1: platelets 1
(1:1:1), typically administering plasma from the start of
resuscitation and platelets immediately as they become
available. Tranexamic acid (TXA) will be administered
to all patients as an intravenous bolus of 1 g over
10 min (either pre-hospital or in the ED) followed by an
intravenous infusion of 1 g over 8 h, providing that the
patient is less than 3 h post injury.
Current use of additional diagnostics and therapy,
such as systematic approach according to Advanced
Trauma Life Support (ATLS®) principles, early imaging
(e.g. X-rays, Focussed Assessment with Sonography for
Trauma (FAST), computer tomography (CT)), activation
criteria for MTP, surgical approach applying damage
control principles when indicated, the availability and
use of interventional radiology, will not be affected in
either of the study groups. An optimised initial MTP
based on a 1:1:1 balanced transfusion will be
implemented in all centres for approximately 2 months prior
to initiation of the RCT and standardised as far as local
routines and blood product availability allow.
Initiation of study care
Corresponding and optimised algorithms based on VHA
trigger parameters for the VHA arm and CCT results
for the CCT arm, respectively, have been developed and
will be applied in the enrolled subjects (Fig. 3a, b, c).
During active haemorrhage, samples will be taken for
CCT/VHA analysis at baseline and after every 4 units of
RBC until haemostasis. The results from each blood
sample will be acted upon as soon as they are available.
For the VHA arm, this implies acting upon the
parameters as they are appearing, not waiting until the VHA
trace is completed.
If a planned study intervention has not yet been
administered, the sample will be taken and analysed (where
resources allow) but will not be used to guide study
intervention. The first sample taken after a study
intervention is actually administered will be the next sample used to
guide study intervention based upon the respective protocol.
The same blood products and procoagulants will be
employed in both study arms, with existing standard
practice in all participating centres being closely aligned
to that of the CCT arm. Trial products will be given as
an addition to the 1:1:1 baseline MTP and TXA. The
procoagulants included in the algorithms are fibrinogen
concentrate or cryoprecipitate and additional platelets,
plasma and TXA.
Enrolled patients will be block randomised per centre
to either study arm:
CCT: haemostatic resuscitation (standard care),
based on a MTP aiming at ratio 1:1:1 of blood
components (RBC 1: plasma 1: platelets 1) and
TXA, and CCTs to guide further resuscitation with
blood products and procoagulant factors
VHA: haemostatic resuscitation (standard care),
based on a MTP aiming at ratio 1:1:1 of blood
components (RBC 1: plasma 1: platelets 1) and
TXA, and VHA-guiding further resuscitation with blood products and procoagulant factors
Randomised study care – VHA arm
VHA will be conducted for all subjects in the VHA arm
at each time point up to 24 h. During active
haemorrhage, samples will be taken for VHA analysis
at baseline and after every 4 units of RBC until
haemostasis. The clinical course of subjects
randomised to the VHA arm will follow a treatment
algorithm utilizing VHA results (Fig. 3a and b). The
subject will be treated with standard haemostatic
resuscitation based on a MTP aiming for 1:1:1 ratio of
blood components and initial TXA. In addition,
according to threshold values in the algorithms, the
subjects will be given fibrinogen concentrate or
cryoprecipitate and/or additional platelets, plasma and
TXA depending on the VHA results.
Fibrinogen concentrate or cryoprecipitate will be
administrated when FIBTEM Clot Amplitude at 5 min
(CA5) is below 10 mm or functional fibrinogen (FF)
TEG® Maximum Amplitude (MA) is below 20 mm.
Additional platelets are indicated when the subtracted
amplitude of FIBTEM CA5 from EXTEM CA5 is below
30 mm, or the subtracted amplitude of FF TEG® MA
from rapid TEG® MA is below 45 mm. Additional
plasma is indicated when the results show a normal
EXTEM CA5, defined as above 40 mm, but still a
prolonged EXTEM clotting time (CT), defined as above
80 s, or normal rapid TEG® MA, defined as above
65 mm, but still a prolonged rapid TEG® activated
clotting time (ACT), defined as above 120 s. Additional
TXA is indicated when the EXTEM Lysis Index at
30 min (LI30) is below 85% or rapid TEG® clot lysis at
30 min (Ly30) is above 10%.
This VHA treatment algorithm is based upon analysis
of more than 2200 trauma subjects enrolled to a
prospective observational study conducted at the
participating study sites, entitled Activation of Coagulation and
Inflammation in Trauma (ACIT). Analysis of the ACIT
dataset has enabled the definition of clinically relevant
VHA thresholds and patterns by which it is possible to
rapidly identify coagulopathic patients and anticipate the
need for massive transfusion. These threshold
parameters have been applied to the generation of an
evidencebased targeted treatment algorithm.
According to pre-designation, each study centre will
only conduct VHA using either thromboelastography
(TEG®) or rotational thromboelastometry (ROTEM®) to
determine the following parameters:
TEG®: RapidTEG® ACT, MA and Ly30; functional fibrinogen TEG® MA
ROTEM®: EXTEM CT, CA5 and Li30; FIBTEM CA5
Randomised study care – CCT arm
CCTs will be conducted for all subjects in the CCT arm
at each time point up to 24 h. The tests will comprise
platelet counts (PLT), activated partial thromboplastin
time (aPTT), prothrombin time – international
normalised ratio (PT/INR) and Clauss fibrinogen assay. PTr
and Clauss fibrinogen will be measured for all study
subjects at each time point.
The clinical course of subjects randomised to the CCT
arm will follow a treatment algorithm utilizing CCT
results (Fig. 3c) and based upon current published
evidence and empiric best practice according to the
PROPPR and CRASH-2 trials data (i.e. a 1:1:1 product
ratio, with the anti-fibrinolytic TXA) [
subject will be treated with standard haemostatic
resuscitation based on a MTP aiming for a 1:1:1 ratio of blood
components and initial TXA. In addition, the subjects
will be given fibrinogen concentrate or cryoprecipitate
and/or additional platelets and plasma depending on the
Fibrinogen concentrate or cryoprecipitate will be
indicated when fibrinogen values are below 2.0 g/L.
Additional platelets will be indicated with PLT below
100 × 109/L and additional plasma will be
administrated when the INR is above 1.2 despite normal
fibrinogen, defined as 2.0 g/L or above. There are no
generally accepted indications for additional
antifibrinolytic therapy using CCTs.
Detail of outcome measures collected
SOFA score (Additional file 3)
SOFA score will be registered until discharge from ICU.
Blood products and procoagulants
Timings, total number (and doses if appropriate) of
different blood products and procoagulants administered
both pre-hospital and after admission to the study
centre, during resuscitation and after 6 and 24 h will be
RBC, fresh frozen plasma (FFP)/Octaplas,
cryoprecipitate, platelets, whole blood and/or
autologous RBC from cell salvage
Coagulation factor concentrates (prothrombin complex concentrate (PCC), fibrinogen, activated recombinant factor VII (rFVIIa)) TXA
Timings (during first 24 h only) and total volume of
different fluids administered both pre-hospital and after
admission to the study centre until 24 h will be recorded
including crystalloids, colloids and hypertonic saline.
Type of medication administered, timings, dose and
indication will be recorded daily until day 28 with
particular attention to duration of treatment (stop date).
Qualifying episodes will be defined by radiological
evidence, like contrast extravasation on CT scan, and/or
clinical suspicion, like haemodynamic instability,
combined with transfusion requirement after initial
haemostasis (defined as the point 1 h from the last
administration of RBC and the treating clinician believes
primary haemostasis has been achieved).
Calculated by the subtracting the number of days spent
on mechanical ventilation from 28. Death before day 28,
recorded as 28.
Calculated as the total number of days spent on
inotropic drugs, including for instance noradrenaline,
Renal replacement therapy days
Calculated as the number of days spent on
haemodialysis or haemofiltration.
The total length of stay in the ICU. If the patient is in
the ICU at any time point during a calendar day, this
day will be considered an ICU day.
Length of stay
Length of stay will be recorded in days, for the total
number spent in ICU and in hospital. If the patient is in
the hospital at any time point during a day, this day will
be considered a hospital day.
Description, timing, duration and reasons for all surgical
episodes will be recorded. This includes interventional
radiology and bedside surgical interventions in addition
to major surgical procedures.
Symptomatic venous thromboembolic events will be
recorded, as confirmed by either compression ultrasound/
venography (DVT or by CT – pulmonary angiogram/
ventilation – perfusion scan (pulmonary embolism (PE)).
Other thromboembolic events, such as myocardial
infarction and/or stroke, will be identified by standard
clinical diagnostic investigations(s).
First destination after discharge and disposition at
90 days post admission will be recorded as either
home, rehabilitation facility, nursing home, other
hospital or other.
Quality of life (Qol)
Subject quality of life will be assessed using the EuroQoL
EQ-5D™ questionnaire, a standardised instrument for use as
a measure of health outcome. Quality of life assessment will
be conducted in the study centre upon discharge of the
subject from hospital and at 90 days post admission.
The in-hospital (i.e. discharge) questionnaire will be
conducted by research investigators with the patient
where possible, but may also be completed with patient’s
PC if necessary. The questionnaire can be completed in
less than 5 min. Where the subject has already left
hospital, the questionnaire will be posted out with a return
stamped addressed envelope.
Patients who have not returned the questionnaire
within 2 weeks of the initial request will be telephoned
as a reminder to complete the questionnaire and may be
asked to complete it over the telephone if necessary.
A further EuroQoL EQ-5DTM questionnaire will be
provided to assess subject quality of life at 90 ± 5 days
post admission. Confirmation with the local (i.e. hospital
care record system) and regional resources (i.e. NHS
Health and Social Care Information Centre Spine
Services) will ensure that only surviving patients receive a
Cessation of study care (haemostasis)
For the purposes of this comparative study, haemostasis
(end of study care) will be defined as the point 1 h from
the last administration of RBC and the treating clinician
believes that primary haemostasis has been achieved.
Procedure for data collection
Study subject data will be captured locally using a paper
Case Report Form (CRF), following local data security
routines. CRF data are transferred and uploaded to a
centralised study database whereupon study data
integrity is reviewed weekly by the Trial Coordinating Centre.
Adverse event reporting
Patients included in this trial have a high risk of
morbidity and mortality, with either treatment being
administered during a phase of critical bleeding and circulatory
failure. Therefore, patients have a very high risk of
experiencing several adverse events (AEs) and serious
adverse events (SAEs). All SAEs, expected or not, will be
recorded on a SAE form. Any SAE, death or
thromboembolic or ischaemic events (myocardial infarction,
stroke, pulmonary embolus, DVT) that are considered
to be ‘related’ and unexpected are to be reported to the
sponsor within 24 h, and to the Main Research Ethics
Committee (MREC) within 15 days in line with the
Urgent safety measures
The chief investigator (CI) will take urgent safety
measures to ensure the safety and protection of the clinical
trial subjects from any immediate hazard to their health
and safety. The measures should be taken immediately.
In this instance, the approval of the Ethics Committee
prior to implementing these safety measures is not
required. However, it is the responsibility of the CI to
inform the sponsor and the Main Research Ethics
Committee (MREC) (via telephone) of this event
The CI has an obligation to inform both the MREC in
writing within 3 days, in the form of a substantial
amendment. The sponsor (Joint Research Management
Office (JRMO)) must be sent a copy of the
correspondence with regards to this matter.
Annual safety reporting
The CI will send the Annual Progress Report to the
MREC using the NRES template (the anniversary date is
the date on the MREC ‘favourable opinion’ letter from
the MREC) and to the sponsor.
Every reasonable effort will be made to maintain
protocol compliance and to retain patient participation in the
study, consistent with the provisions of informed
consent and good clinical practice. The following are
potential reasons why a patient may be withdrawn from the
1. Withdrawal of consent/agreement
2. Retrospective exclusion: if a patient is deemed to not
meet one or more of the inclusion/exclusion criteria
in retrospect they will be withdrawn from the study
3. Major protocol deviation from the study design by
the subject, observed or suspected by the
4. Administrative: the sponsor or monitoring
committees decide to terminate or discontinue the
5. The subject’s health would be jeopardised by
continued participation and hence will be withdrawn
at the discretion of the investigator
The study withdrawal form will be completed for these
patients and a reason for withdrawal captured. All
subject’s withdrawn from the study will be managed in
accordance with the hospital’s standard procedures.
Data collection and follow-up for withdrawn subjects
Patients who withdraw from the study after
randomisation will be followed for safety by conducting safety
assessments through to the end of day 28. If a patient who
withdraws has an ongoing SAE every effort must be
made to follow up such events until satisfactory
resolution is obtained or until further follow-up is no longer
Subjects who withdraw from the study will be replaced.
End of study definition
The study will be considered closed when all surviving
subjects complete in-hospital safety and outcome
monitoring. This includes: safety measures of SAE rate within
28 days, total hospital stay, total critical care stays,
28day ventilator-free days and 28-day mortality
Based upon legacy registry data from the partners,
approximately 28% of patients will need massive
transfusion or die. It is expected that this figure will decrease to
an overall proportion of 15% in the VHA group (i.e.
using VHA-guided strategy). In order to detect a
difference from 28% to 15% with a power of 80% and a
twosided alpha of 0.05, 170 patients per group are required.
One hundred and ninety-six patients per study arm
allows a 13% dropout rate, with an allocation ratio of 1.
The planned sample size for this study is 392 patients
for which MTP is activated and transfusions initiated,
196 in each study arm.
Method of analysis
All primary and secondary outcomes will be analysed as
intention-to-treat, and will include all randomised
patients for whom the primary outcome of ‘alive’ and ‘free
of massive transfusion’ at 24 h is recorded. The primary
endpoint of patients who are alive and free of massive
transfusion at 24 h will be assessed by difference in
proportion with 95% confidence intervals. The chi-square
test or Fischer’s exact test will be used were appropriate.
Absolute risk reduction and relative risk reduction by
VHA-guided therapy will be calculated.
Kaplan-Meier mortality estimates between the two
arms for all-cause mortality at 6 and 24 h, as well as 28
and 90 days post admission, will be estimated for the
secondary endpoint of death.
A per-protocol analysis and a sensitivity analysis will
be performed for the primary endpoint. The following
patients will be excluded from the per-protocol analysis:
Patients who do not have at least one ROTEM®/
TEG®/CCT test performed and
Who die within 60 min after baseline blood sampling or
Who achieve haemostasis within 60 min of baseline sampling
Both ROTEM®-guided and TEG®-guided therapy
together (i.e. the VHA arm) will be compared with the
CCT arm. Separate analyses will be performed for
ROTEM®-guided and TEG®-guided therapy alone for
primary endpoints and correction of coagulopathy.
All applied tests will be two-sided and p values of 0.05
will be accepted as statistically significant. We will report
p values with and without correction for multiple
The following patient categories will be included in all
primary and secondary analyses but will also be analysed
separately as subgroup analyses:
Patients with known pre-existing coagulopathy
Oral anticoagulant therapy (except for aspirin)
Excluding patients with severe traumatic brain injury (AIS brain 4,5 or 6)
Patients who arriving in a coagulopathic state (PTr > 1.2)
Patients who received a massive transfusion (10 or more RBC units in the first 24 h)
Missing data are not expected for the primary outcome.
Sensitivity analysis for secondary outcomes will be
assessed using 100 multiple imputations for missing
data. Rubin rules will be used to summarise the results
of the multiple imputations.
Integrated cost-effectiveness analysis
A cost-effectiveness analysis will be conducted to assess
the costs and effects of VHA-guided therapy versus
those of optimised empiric treatment. A model will be
developed which will be structured around the key
clinical time points and events in the early management
pathway of bleeding trauma patients.
The two treatment policies will be compared in terms
of their estimated costs and effects (quality-adjusted life
years (QALYs): calculated by combining survival and
HRQoL data) and incremental analyses will be
performed. If VHA-guided therapy is more effective but
also more costly than empirical treatment, then the
incremental cost-effectiveness ratio (ICER) will be
calculated. The ICER is calculated by dividing the difference
in costs between VHA and empirically guided therapy
by the difference in effects (QALYs) and gives the
additional cost of generating one additional unit of outcome
(here, a QALY).
So as to account for the uncertainty in the model
input data, parameters will be entered as distributions
rather than point estimates. Probabilistic sensitivity
analysis will be used to take repeated random draws
from all distributions simultaneously, each time
recalculating the model’s results for a total of 2000 times. The
uncertainty will be summarised on the cost-effectiveness
plane and using cost-effectiveness acceptability curves.
For each country, the modelling exercise should provide
an estimate of the probability that VHA-guided therapy
is likely to be cost-effective when compared with
optimised empiric treatment.
Monitoring and quality assurance
Summary monitoring plan
Data coordination and site management services will be
performed at the sponsor institution, Queen Mary
University of London. The site clinical trials coordinator will
perform regular monitoring of trial documentation and
A pre-defined interim analysis will be performed after
the enrolment of 100 patients, including an assessment
of recruitment logistics with the possibility to revise the
planned sample size.
A Data Safety Monitoring Board (DSMB) will review
all data on outcome of the patients in the respective
treatment arms. The DSMB will focus on adherence to
protocol, and present pre-specified criteria that need to
be fulfilled with regard to patient safety for the study to
Audit and inspection
For the purpose of compliance with Good Clinical
Practice (GCP) and Regulatory Agency Guidelines it may be
necessary for the sponsor or a drug regulatory agency to
conduct a site audit. This may occur at any time from
the start to after conclusion of the study.
TIC is present early after injury in a significant
proportion of patients [
], and is associated with increased
bleeding, greater risk of complications and increased
mortality, underlining the importance of early detection
and aggressive treatment [
4, 6, 7, 22
Improvements in transfusion strategies over the last
decade are associated with better outcome [
results of the PROPPR trial  provide the best
evidence to date for ratio-based trauma resuscitation. In
that study, a MTP aiming at a 1:1:1 ratio of plasma 1:
platelets 1: RBC 1 until haemorrhage control was
associated with better outcome than a 1:1:2 ratio. However,
PROPPR did not allow adjustments in the individual
treatment based on results from coagulation tests during
the course of resuscitation.
Traditionally, CCTs such as prothrombin
time/international normalised ratio (PT/INR), activated partial
thromboplastin time (aPTT), fibrinogen concentration
and PLT have been recommended to guide
resuscitation in bleeding trauma patients [
]. However, none
of the existing CCTs have proven to be robust in
detecting TIC or predicting massive transfusion.
Moreover, CCTs are time-consuming laboratory tests only
reflecting the initial steps of blood coagulation and
not taking into account the interaction between
platelets and coagulation factors.
On that background, the potential benefit of
Viscoelastic Haemostatic Assays (VHAs), such as TEG® and
ROTEM®, in the trauma setting has gained much
attention over the last decade. VHAs are dynamic tests; they
may be performed bedside with their first results
available within minutes of initiation. Several algorithms for
guiding resuscitation in bleeding trauma patients based
on VHA parameters have been published [28, 29]. None
of them have been developed based on real-time large
cohorts of trauma patients.
The updated European guidelines addressing the
management of bleeding and coagulopathy following major
trauma recommend the use of viscoelastic methods to
assist in characterising the coagulopathy and in guiding
haemostatic therapy [
] although the evidence to
support the use of VHAs in this category of patients is
Based on limited existing evidence to support the use
of VHA versus CCTs in monitoring the resuscitation of
massively bleeding trauma patients, our aim is to
evaluate the differences between VHA-guided and
CCTguided transfusion in trauma patients, and to create
robust evidence-based guidelines for massive transfusion
in trauma patients.
iTACTIC has obvious limitations, based on the actual
level of evidence in this field. The challenges include the
heterogeneity of, and access to, a population of severely
injured patients as well as the development of relevant
algorithms. Strength and weaknesses will be fully
addressed when the trial results are published.
This study is ongoing and started recruiting June 2016.
Recruitment will be completed mid 2018.
Additional file 1: Protocol version 3.0/14.03.2017. (PDF 2172 kb)
Additional file 2: SPIRIT Checklist. (DOC 129 kb)
Additional file 3: SOFA score. (ZIP 217 kb)
ACIT: Activation of Coagulation and Inflammation in Trauma; ACT
(ROTEM®): Activated clotting time (ROTEM®); AE: Adverse event;
APTT: Activated partial thromboplastin time; ATLS®: Advanced Trauma Life
Support; CA 5 (ROTEM®): Clot Amplitude at 5 min (ROTEM®);
CCT: Conventional coagulation tests; CI: Chief investigator;
CONSORT: Consolidated Standards of Reporting Trials; CRF: Case Report
Form; CT: Computer tomography; CT (ROTEM®): Clotting time (ROTEM®);
DSMB: Data Safety Monitoring Board; DVT: Deep venous thrombosis;
ED: Emergency department; FAST: Focussed Assessment with Sonography in
Trauma; FF (TEG®): Functional fibrinogen (TEG®); FFP: Fresh frozen plasma;
GCP: Good Clinical Practice; ICER: Incremental cost-effectiveness ratio;
ICU: Intensive care unit; JRMO: Joint Research Management Office; LI30
(ROTEM®): Lysis Index at 30 min (ROTEM®); (TEG®): Clot lysis at 30 min (TEG®);
MA: Maximum Amplitude; MREC: Main Research Ethics Committee;
MTP: Massive transfusion protocol; PC: Personal consultee; PCC: Prothrombin
complex concentrate; PE: Pulmonary embolism; PROPPR: Pragmatic,
Randomised Optimal Platelet and Plasma Ratios trial; PTr: Prothrombin Time/
International Ratio (PT/INR); QALY: Quality-adjusted Life Years; QMUL: Queen
Mary University of London; QoL: Quality of life; RBC: Red blood cells;
RCT: Randomised controlled trial; rFVIIa: Activated recombinant factor VII;
ROTEM®: Rotational thromboelastometry; SAE: Serious adverse event;
SOFA: Sequential Organ Failure Assessment; SPIRIT: Standard Protocol Items:
Recommendations for Interventional Trials; Subject: An individual who takes
part in a clinical trial; TEG®: Thromboelastography; TIC: Trauma-induced
coagulopathy; TXA: Tranexamic acid; VHA: Viscoelastic Haemostatic Assays
This trial is part-funded by the European Commission under the FP-7
HEALTH-Contract No. F3-2013-602771, entitled ‘Targeted Action for Curing
Trauma Induced Coagulopathy’ (TACTIC) .
Both TEM® International GmbH and Haemonetics® are equal partners in the
TACTIC programme, providing VHA devices and reagents for all participating
Availability of data and materials
Data collection for this study will be accomplished using a paper CRF to
capture data prospectively and transferred to an electronic data capture
system (Discovere). The dataset will not be open access, but available upon
request under the terms of Collaboration Agreement with Consortium.
PIJ, KB, MM, CG, SE, JCG, SJS and SE participated in the design of the study
and achieved funding. PIJ, KB, CG, SJS, MM, JS, SRO, SvD, PAN, JCG, NPJ, CR,
SE, LG and KBA all contributed to protocol development. LG, KBA, CG, KB
and PIJ prepared the first draft of the manuscript. All authors read and
approved the final manuscript.
Ethics approval and consent to participate
This study has been approved by the respective Ethics Committees of the
investigators’ centers: Queen Mary University of London and John Radcliff
Hospital, UK, reference number 16/LO/0004; Oslo University Hospital, Norway,
reference number 2015/1601/REK sør-øst; Rigshospitalet, Denmark, reference
number H-15017330; Academic Medical Centre, The Netherlands, reference
number METC 2016_020#B2016333ENG; and Kliniken der Stadt Köln gGmbH,
Germany, reference number 185/2015.
The investigators have all obtained ethics approval before being allowed to
conduct and participate in the study. The investigator is also responsible for
fulfilling any conditions of approval imposed by the local Ethics Committee,
such as regular reporting, study timing and so on.
The timeframe required for subject or personal consultee (PC) consent/
agreement is not compatible with the time sensitivity of this trial and,
therefore, several approaches to obtaining informed consent/agreement will
be used, all of which are consistent with the Mental Capacity Act (England;
2005) and the Declaration of Helsinki (2013). The subjects will be
incapacitated at the time of eligibility (critical injury, mechanical ventilation,
sedation). This study requires that the intervention to be performed rapidly,
thereby necessitating that eligible patients are included in the trial very soon
after hospital admission. Therefore, declaration for initial enrolment in the
trial will be sought from a nominated consultee (NC), who is familiar with
this study and its consenting process and is present at the trauma call.
As injury is an unexpected event, it is uncommon that relatives are present
at the time of hospital admission. However, if a PC for the patient is present,
bearing in mind the clinical situation and their level of distress, they will be
provided with brief information about the trial either verbally or in writing. If
the PC objects, their wishes will be respected.
If, and when, subjects regain the physical and mental capacity to give
consent, information will be provided to them and written informed consent
will be sought for continuation in the trial. For any patient who was
included but does not regain full capacity, agreement will be sought from a
PC for continuation in the trial. If a patient or PC declines to give consent/
agreement for continuation at this stage, their wishes will be respected.
These attempts will continue until subject consent or PC agreement is
obtained. All interactions and attempts at contact with the PC and/or
subject will be documented in a study consent log.
In participating institutions where this is accepted according to ethics
approval, patients who die before we have had the opportunity to discuss
the trial and obtain consent/agreement from them or their PC, the patient
will remain in the trial based on the signed declaration obtained by the NC.
Should an investigator have had the opportunity to introduce themselves
and discuss the trial with the PC prior to the subject’s death but written
agreement has not yet been obtained, then we will make a maximum of
three further attempts (by any combination of telephone, Email or letter) as
deemed appropriate in each individual case to contact the PC and obtain
written agreement. If after these further attempts, the PC has either not
been contactable or has not returned written agreement, then the subject
will remain in the trial based on the NC declaration. If the PC objects to the
subject remaining in the study at this stage, then their wishes will be
Consent for publication
The authors declare that they have no competing interests.
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Website European Commission FP-7 HEALTH-Contract No . F3 -2013-602771: http://cordis.europa.eu/project/rcn/110071_en. html. Accessed 06 Mar 2017 .