Hemorrhagic ShockPhase 1/2TRFLNCT00945542
The Trauma- Formula-Driven Versus Lab-Guided Study (TRFL Study)
A Phase 1/2 study testing Massive transfusion protocol in people with Hemorrhagic Shock and Trauma Coagulopathy, run by Sunnybrook Health Sciences Centre at 1 site in Canada.
Trial summary
Background: Bleeding and coagulopathy still accounts for the majority of early in-hospital deaths following trauma. There have been lately several published studies suggesting that higher transfusion ratios of fresh frozen plasma (FFP), platelets (PTL) and cryoprecipitate (CRYO) to red blood cell (RBC) are associated… Read more about this study
- Who is it for?
- Any age
- Conditions the study is for
- Hemorrhagic Shock, Trauma Coagulopathy
- What is being tested?
- Massive transfusion protocol
- Could I receive a placebo?
- No, everyone receives an active treatment
- How many people
- 70 participants
- Where
- 1 siteCanada
- Study dates
- Jul 2009to Dec 2011
- Phase
- Phase 1/2
- Are there results?
- None posted in the registry
Key requirements
Who can take part, as listed by the sponsor. Only the study team can confirm whether you are eligible, so take this list to your doctor.
- Ages Any age
- All sexes
- No healthy volunteers
- Child, Adult, Older adult
Who may be able to join
- Patients were eligible for this study if they:
- were adult trauma patients assessed by the trauma team; and ii) suffered either penetrating or blunt mechanism of injury; and
- were bleeding and expected to require massive transfusion (either 4 units within the next 2 hours or ≥ 10 units of RBC in 24 h) or required transfusion of un-cross matched emergency stock red blood cells; and
- had an episode of hypotension (systolic bp ≤ 90mmHg).
Who cannot join
- Patients were excluded if:
- they were assessed in the trauma room more than six hours after injury; or ii) they received more than two units of RBC transfusion prior to arrival; or iii) they had suffered a concomitant severe brain injury (defined as any of the following: Glasgow Coma Scale of 3 due to severe traumatic brain injury; clear indication of immediate neurosurgical intervention based on clinical findings, mechanism of trauma associated with focal signs (anisocoria, CT evidence of intracranial bleeding with mass effect); or iv) they had evidence of having a catastrophic head injury (such as transcranial gunshot wound, open skull fracture with exposure/loss of brain tissue, or expert opinion by either the trauma team leader or neurosurgical consultant based on initial clinical or initial CT findings); or v) they had evidence that their shock state was unrelated to hemorrhage (ie cardiogenic, septic, anaphylactic, acute adrenal insufficiency, neurogenic, or obstructive (cardiac tamponade, tension pneumothorax and massive pulmonary emboli); or vi) they had a known hereditary or acquired coagulopathy unrelated to the trauma resuscitation (for example: hemophilia, hepatic insufficiency, or anti-coagulant medications); or vii) they were moribund with evidence of unsalvageable injuries.
Trial locations and contacts
1 site in 1 country.
About this study
Official title: Formula-driven vs Laboratory-guided Transfusion Practices in Bleeding Trauma Patients: A Feasibility Randomized Controlled Study
Background: Bleeding and coagulopathy still accounts for the majority of early in-hospital deaths following trauma. There have been lately several published studies suggesting that higher transfusion ratios of fresh frozen plasma (FFP), platelets (PTL) and cryoprecipitate (CRYO) to red blood cell (RBC) are associated with survival advantages. However, the evidence comes from retrospective data limited by a significant number of unaddressed confounders. In addition, the use of blood products bears known and important risks of complications.
Hypothesis: The adoption of a formula-driven transfusion practice with pre-defined ratios of FFP to PTL to RBC transfusion (1:1:1) is feasible and superior to current laboratory-guided transfusion practice in treating and/or preventing early coagulopathy improving survival rates in massively bleeding trauma patients .
Read more
Objective: To exam the feasibility of implementing a pre-defined ratio of FFP to PTL to RBC (1:1:1) transfusion protocol and its impact on a population of bleeding trauma patients.
Design: A two-year pilot feasibility randomized control trial at Sunnybrook Health Sciences Centre. Randomization: 70 patients are expected to be randomized to lab-driven or to formula-driven massive transfusion protocol and followed-up to 28 days or hospital discharge.
Study outcomes: protocol violation; in-hospital mortality by exsanguination; death at 28 days; coagulation competence defined by current standard coagulation tests (INR \& PTT < 1.5 times normal; PTL ≥ 50 and Fibrinogen ≥ 1.0) or clotting factor levels ≥ 30%; correlation of current standard coagulation tests with clotting factors levels; cessation of bleeding; incidence of ALI, sepsis, MOF, transfusion-related circulatory overload, transfusion reactions; Ventilator-free days; ICU \& Hospital LOS; thromboembolic events.
Intervention protocol: Transfusion of pre-defined ratios of FFP and PTL to RBC (1:1:1) (formula-driven) for the first 12h of hospitalization without coagulation tests guidance while patient is hemorrhaging or before if bleeding stops.
Statistical analysis: protocol compliance rate and in-hospital mortality rates within 24h and at 28 days will be assessed using Chi-square test. ROC analysis will be used to analyze coagulation competence.
Main expected outcomes: implementation of a formula-driven transfusion protocol is feasible and coagulation competence will be achieved faster and more efficiently in the study group.
- Conditions
- Hemorrhagic Shock, Trauma Coagulopathy
- Being tested
- Massive transfusion protocol, Standard of care
- Keywords
- Trauma, Coagulopathy, Transfusion, Plasma, Massive Transfusion
- Medical subject headings
- Shock, Hemorrhagic, Wounds and Injuries, Hemostatic Disorders
What participants receive
What participants receive. In a randomised study each person is assigned to one group by chance.
Massive transfusion protocolOther
Also called Early and aggressive FFP transfusion, 1:1, FFP:RBC transfusion, Damage Control Resuscitation, Hemostatic Resuscitation
Patients randomized to this arm will be transfused based on a pre-defined massive transfusion protocol. Blood bank will release blood a pre-defined packages. Blood will be received in aliquots containing 4 units off FFP, 1 pool of buffy coat platelet (4 units) and 4 units of RBC. As discussed previously, this would correspond to an FFP:RBC transfusion ratio of 1:1.
Patients randomized to the study protocol will be receiving the FFP and PTL at pre-defined ratios to RBC (1:1:1) up to 12h of hospitalization or earlier if cessation of the massive transfusion requested at the discretion of the treating physicians.
Standard of careOther
Patients randomized to this arm will be treated as per Sunnybrook's current standard of care massive transfusion protocol. Crystalloid and red cell transfusions are performed to maintain volume status, and to maintain haemoglobin levels above 70 g/L. FFP is transfused based in 3-4 unit aliquots, for INR>1.5. Platelets are transfused 1 pool at a time (4 units Buffy coat platelets) to maintain platelet counts above 50 x 109/mL. Cryoprecipitate is transfused 8-12 units at a time to keep fibrinogen above 0.8 gram/L.
| Study group | Role | What they receive |
|---|---|---|
| Standard of care | Other | Patients randomized to this arm will be treated as per Sunnybrook's current standard of care massive transfusion protocol. Crystalloid and red cell transfusions are performed to maintain volume status, and to maintain haemoglobin levels above 70 g/L. FFP is transfused based in 3-4 unit aliquots, for INR>1.5. Platelets are transfused 1 pool at a time (4 units Buffy coat platelets) to maintain platelet counts above 50 x 109/mL. Cryoprecipitate is transfused 8-12 units at a time to keep fibrinogen above 0.8 gram/L. Receives: Other: Standard of care |
| Preemptive transfusion | Experimental | Patients randomized to this arm will be transfused based on a pre-defined massive transfusion protocol. Blood bank will release blood a pre-defined packages. Blood will be received in aliquots containing 4 units off FFP, 1 pool of buffy coat platelet (4 units) and 4 units of RBC. This corresponds to an FFP:RBC transfusion ratio of 1:1.
Patients randomized to the study protocol will be receiving the FFP and PTL at pre-defined ratios to RBC (1:1:1) up to 12h of hospitalization or earlier if cessation of the massive transfusion requested at the discretion of the treating physicians. Receives: Other: Massive transfusion protocol |
What is being measured
The primary outcome is the main question the study is designed to answer.
Protocol compliance
Measured: 12 hours
Secondary outcomes (1)
Mortality by Exsanguination; Hospital mortality; Cessation of Bleeding; Coagulation competence; Multiple Organ Dysfunction; Transfusion complications.
Measured: early and at 28 days
Timeline
From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.
- First posted24 Jul 2009 (estimated)
- Study startJul 2009
- Primary completionDec 2011
- Study completionDec 2011
Resources
- Official record on ClinicalTrials.govThe registry entry this page is built from, with its full change history.
- Publications (2)Papers the sponsor has linked to this study.
- Other trials for Hemorrhagic ShockStudies of the same condition, open and under way.
- What the trial phases meanHow a treatment moves from first tests in people to approval.
More details
For doctors and researchers: how the study is designed, who runs it, and its registry IDs.
Study design
- Study type
- Interventional
- Phase
- Phase 1/2
- Primary purpose
- Treatment
- Allocation
- Randomised
- Intervention model
- Parallel groups
- Masking
- Single blind
- Who is masked
- Outcomes assessor
- Enrolment
- 70 participants (estimated)
Sponsor and investigators
- Lead sponsor
- Sunnybrook Health Sciences Centre
- Sponsor type
- University, hospital or other
- Collaborators
- Canadian Department of National Defence, Canadian Blood Services, National Blood Foundation
- Responsible party
- Principal investigator, Dr. Jeannie Callum, Sunnybrook Health Sciences Centre
- Investigators
- Sandro B Rizoli, MD PhD, Principal investigator, Sunnybrook Health Sciences CentreGordon D Rubenfeld, MD, MSc, Principal investigator, Sunnybrook Health Sciences CentreHomer C Tien, MD, MSc, Principal investigator, Sunnybrook Health Sciences Centre
IDs, dates and publications
- ClinicalTrials.gov ID
- NCT00945542
- Sponsor's protocol ID
- 461-2008
- Acronym
- TRFL
- Status last verified
- Dec 2011
- First submitted
- 22 Jul 2009
- Last updated
- 2 Dec 2011
- Results posted
- No
- Data monitoring committee
- Yes
Publications
Nascimento B, Callum J, Tien H, Rubenfeld G, Pinto R, Lin Y, Rizoli S. Effect of a fixed-ratio (1:1:1) transfusion protocol versus laboratory-results-guided transfusion in patients with severe trauma: a randomized feasibility trial. CMAJ. 2013 Sep 3;185(12):E583-9. doi: 10.1503/cmaj.121986. Epub 2013 Jul 15.
PubMed 23857856Nascimento B, Rizoli S, Rubenfeld G, Lin Y, Callum J, Tien HC. Design and preliminary results of a pilot randomized controlled trial on a 1:1:1 transfusion strategy: the trauma formula-driven versus laboratory-guided study. J Trauma. 2011 Nov;71(5 Suppl 1):S418-26. doi: 10.1097/TA.0b013e318232e591.
PubMed 22071998
Study at a glance
From the registry record, last updated by the sponsor on 2 Dec 2011. Recruitment status is as the sponsor reported it: confirm with the study team.
- Official title
- Formula-driven vs Laboratory-guided Transfusion Practices in Bleeding Trauma Patients: A Feasibility Randomized Controlled Study
- ClinicalTrials.gov ID
- NCT00945542
- Acronym / sponsor ID
- TRFL / 461-2008
- Conditions
- Hemorrhagic Shock, Trauma Coagulopathy
- Keywords
- Trauma, Coagulopathy, Transfusion, Plasma, Massive Transfusion
- Phase
- Phase 1/2
- Study type
- Interventional
- Recruitment status
- Completed
- Enrolment
- 70 participants (estimated)
- Lead sponsor
- Sunnybrook Health Sciences CentreUniversity, hospital or other
- Collaborators
- Canadian Department of National Defence, Canadian Blood Services, National Blood Foundation
- Study start
- Jul 2009
- Primary completion
- Dec 2011 (actual)
- Study completion
- Dec 2011 (actual)
- First posted
- 24 Jul 2009 (estimated)
- Results
- Not posted in the source record
Clinical summary
The research question as the sponsor registered it. This describes what the study plans to test, not what it found.
Background: Bleeding and coagulopathy still accounts for the majority of early in-hospital deaths following trauma. There have been lately several published studies suggesting that higher transfusion ratios of fresh frozen plasma (FFP), platelets (PTL) and cryoprecipitate (CRYO) to red blood cell (RBC) are associated with survival advantages. However, the evidence comes from retrospective data limited by a significant number of unaddressed confounders. In addition, the use of blood products bears known and important risks of complications.
Hypothesis: The adoption of a formula-driven transfusion practice with pre-defined ratios of FFP to PTL to RBC transfusion (1:1:1) is feasible and superior to current laboratory-guided transfusion practice in treating and/or preventing early coagulopathy improving survival rates in massively bleeding trauma patients .
Objective: To exam the feasibility of implementing a pre-defined ratio of FFP to PTL to RBC (1:1:1) transfusion protocol and its impact on a population of bleeding trauma patients.
Design: A two-year pilot feasibility randomized control trial at Sunnybrook Health Sciences Centre. Randomization: 70 patients are expected to be randomized to lab-driven or to formula-driven massive transfusion protocol and followed-up to 28 days or hospital discharge.
Study outcomes: protocol violation; in-hospital mortality by exsanguination; death at 28 days; coagulation competence defined by current standard coagulation tests (INR \& PTT < 1.5 times normal; PTL ≥ 50 and Fibrinogen ≥ 1.0) or clotting factor levels ≥ 30%; correlation of current standard coagulation tests with clotting factors levels; cessation of bleeding; incidence of ALI, sepsis, MOF, transfusion-related circulatory overload, transfusion reactions; Ventilator-free days; ICU \& Hospital LOS; thromboembolic events.
Intervention protocol: Transfusion of pre-defined ratios of FFP and PTL to RBC (1:1:1) (formula-driven) for the first 12h of hospitalization without coagulation tests guidance while patient is hemorrhaging or before if bleeding stops.
Statistical analysis: protocol compliance rate and in-hospital mortality rates within 24h and at 28 days will be assessed using Chi-square test. ROC analysis will be used to analyze coagulation competence.
Main expected outcomes: implementation of a formula-driven transfusion protocol is feasible and coagulation competence will be achieved faster and more efficiently in the study group.
Study design
- Primary purpose
- Treatment
- Allocation
- Randomised
- Intervention model
- Parallel groups
- Masking
- Single blind (outcomes assessor)
- Number of arms
- 2
| Arm | Type | Receives |
|---|---|---|
| Standard of care | Other | Other: Standard of carePatients randomized to this arm will be treated as per Sunnybrook's current standard of care massive transfusion protocol. Crystalloid and red cell transfusions are performed to maintain volume status, and to maintain haemoglobin levels above 70 g/L. FFP is transfused based in 3-4 unit aliquots, for INR>1.5. Platelets are transfused 1 pool at a time (4 units Buffy coat platelets) to maintain platelet counts above 50 x 109/mL. Cryoprecipitate is transfused 8-12 units at a time to keep fibrinogen above 0.8 gram/L. |
| Preemptive transfusion | Experimental | Other: Massive transfusion protocolPatients randomized to this arm will be transfused based on a pre-defined massive transfusion protocol. Blood bank will release blood a pre-defined packages. Blood will be received in aliquots containing 4 units off FFP, 1 pool of buffy coat platelet (4 units) and 4 units of RBC. This corresponds to an FFP:RBC transfusion ratio of 1:1. Patients randomized to the study protocol will be receiving the FFP and PTL at pre-defined ratios to RBC (1:1:1) up to 12h of hospitalization or earlier if cessation of the massive transfusion requested at the discretion of the treating physicians. |
Who may qualify
- Sex
- All
- Healthy volunteers
- Not accepted
- Age groups
- Child, Adult, Older adult
Key inclusion criteria (4 listed)
- were adult trauma patients assessed by the trauma team; and ii) suffered either penetrating or blunt mechanism of injury; and
- were bleeding and expected to require massive transfusion (either 4 units within the next 2 hours or ≥ 10 units of RBC in 24 h) or required transfusion of un-cross matched emergency stock red blood cells; and
- had an episode of hypotension (systolic bp ≤ 90mmHg).
Key exclusion criteria (2 listed)
- they were assessed in the trauma room more than six hours after injury; or ii) they received more than two units of RBC transfusion prior to arrival; or iii) they had suffered a concomitant severe brain injury (defined as any of the following: Glasgow Coma Scale of 3 due to severe traumatic brain injury; clear indication of immediate neurosurgical intervention based on clinical findings, mechanism of trauma associated with focal signs (anisocoria, CT evidence of intracranial bleeding with mass effect); or iv) they had evidence of having a catastrophic head injury (such as transcranial gunshot wound, open skull fracture with exposure/loss of brain tissue, or expert opinion by either the trauma team leader or neurosurgical consultant based on initial clinical or initial CT findings); or v) they had evidence that their shock state was unrelated to hemorrhage (ie cardiogenic, septic, anaphylactic, acute adrenal insufficiency, neurogenic, or obstructive (cardiac tamponade, tension pneumothorax and massive pulmonary emboli); or vi) they had a known hereditary or acquired coagulopathy unrelated to the trauma resuscitation (for example: hemophilia, hepatic insufficiency, or anti-coagulant medications); or vii) they were moribund with evidence of unsalvageable injuries.
Eligibility is decided by the study team after screening; this overview does not establish that a patient qualifies. Full inclusion and exclusion criteria.
Interventions
| Intervention | Type | Arms |
|---|---|---|
| Massive transfusion protocolAlso: Early and aggressive FFP transfusion, 1:1, FFP:RBC transfusion, Damage Control Resuscitation, Hemostatic ResuscitationPatients randomized to this arm will be transfused based on a pre-defined massive transfusion protocol. Blood bank will release blood a pre-defined packages. Blood will be received in aliquots containing 4 units off FFP, 1 pool of buffy coat platelet (4 units) and 4 units of RBC. As discussed previously, this would correspond to an FFP:RBC transfusion ratio of 1:1. Patients randomized to the study protocol will be receiving the FFP and PTL at pre-defined ratios to RBC (1:1:1) up to 12h of hospitalization or earlier if cessation of the massive transfusion requested at the discretion of the treating physicians. | Other | Preemptive transfusion |
| Standard of carePatients randomized to this arm will be treated as per Sunnybrook's current standard of care massive transfusion protocol. Crystalloid and red cell transfusions are performed to maintain volume status, and to maintain haemoglobin levels above 70 g/L. FFP is transfused based in 3-4 unit aliquots, for INR>1.5. Platelets are transfused 1 pool at a time (4 units Buffy coat platelets) to maintain platelet counts above 50 x 109/mL. Cryoprecipitate is transfused 8-12 units at a time to keep fibrinogen above 0.8 gram/L. | Other | Standard of care |
Primary outcome
Protocol compliance
Time frame: 12 hours
1 secondary outcome
Mortality by Exsanguination; Hospital mortality; Cessation of Bleeding; Coagulation competence; Multiple Organ Dysfunction; Transfusion complications.
Time frame: early and at 28 days
Results and safety
The study is completed, but results are not available in the source record. That does not mean the treatment did or did not work.
Research links
- Official record on ClinicalTrials.govLast updated by the sponsor 2 Dec 2011.
- Derived from this study: PubMed 23857856Nascimento B, Callum J, Tien H, Rubenfeld G, Pinto R, Lin Y, Rizoli S. Effect of a fixed-ratio (1:1:1) transfusion protocol versus laboratory-results-guided transfusion in patients with severe trauma: a randomized feasibility trial. CMAJ. 2013 Sep 3;185(12):E583-9. doi: 10.1503/cmaj.121986. Epub 2013 Jul 15.
- Derived from this study: PubMed 22071998Nascimento B, Rizoli S, Rubenfeld G, Lin Y, Callum J, Tien HC. Design and preliminary results of a pilot randomized controlled trial on a 1:1:1 transfusion strategy: the trauma formula-driven versus laboratory-guided study. J Trauma. 2011 Nov;71(5 Suppl 1):S418-26. doi: 10.1097/TA.0b013e318232e591.
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Referral and contact
AzTrials does not enrol participants or take referrals. Contact the study team or a site listed below; they decide who can take part. This study is not recruiting at the moment.
Sandro B Rizoli, MD PhD principal investigator
Sunnybrook Health Sciences Centre
Gordon D Rubenfeld, MD, MSc principal investigator
Sunnybrook Health Sciences Centre
Homer C Tien, MD, MSc principal investigator
Sunnybrook Health Sciences Centre
1 site in 1 country: see every site and its status.
Questions about this trial
What is this clinical trial studying?
A Phase 1/2 study testing Massive transfusion protocol in people with Hemorrhagic Shock and Trauma Coagulopathy, run by Sunnybrook Health Sciences Centre at 1 site in Canada.
The full registered description is in the About this study section and the official record.
Who may be eligible to take part?
The sponsor lists 4 inclusion and 2 exclusion criteria. Eligibility is decided by the study team after screening, so read the full criteria and contact a listed site.
Is this clinical trial currently recruiting?
The record says: finished, as of the sponsor's last update on 2 Dec 2011. Status can change between updates, so confirm with the study contact before making plans.
Where is the study taking place?
The record lists 1 site in Canada. Whether a site is taking part right now should be confirmed with that site. See every site.
What are the possible benefits and risks?
They depend on the study and the treatment, and no study can promise a benefit. The study team explains the known risks during informed consent, before anyone joins; the record itself does not list them.
What does this combined phase mean?
Phase 1 studies test a treatment in a small group of people for the first time or in a new way, mainly to check safety and find the right dose.
Phase 2 studies give the treatment to a larger group to see whether it has the intended effect and to keep checking safety.
Not every study follows the same path, and some studies (observational studies, device studies) have no phase.
Are results available for this study?
The study is completed, but results are not available in the source record. That does not mean the treatment did or did not work.
How can a doctor refer a patient or contact the research team?
The record lists no contact. The official record names the sponsor, who can be asked directly. AzTrials does not enrol participants or take referrals.
What does the primary outcome measure?
Protocol compliance (time frame: 12 hours). It is what the study was designed to measure, not a finding.
Where can I read the original study information?
On the ClinicalTrials.gov record for NCT00945542, which also lists 2 linked publications.
Does a listing mean the treatment is approved or proven to work?
No. A listing means the study is registered. It does not show that the treatment is safe, works, or is approved by a regulator.
How often is this information updated?
AzTrials copies changed records from ClinicalTrials.gov every night and reloads the whole registry every week. The sponsor last updated this record on 2 Dec 2011.