Pilot Clinical Trial of Transfusion of Pathogen Reduced Cryoprecipitated Fibrinogen (INTERCEPT Fibrinogen Complex) in Patients With Bleeding to Expedite Product Availability and Improve Outcomes in Perioperative Bleeding
Phase: PHASE4
Conditions: Hypofibrinogenemia, Bleeding
Sponsor: Weill Medical College of Cornell University

 
 
 
 
 
 
 
 
 
TITLE: Transfusion of Pathogen Reduced Cryoprecipitated Fibrinogen to Expedite 
Product Availability in Perioperative Bleeding 
 
NCT Number: NCT05711524 
 
Document Date: 01/24/2023 

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Pilot Observational Study of Transfusion of Pathogen Reduced Cryoprecipitated Fibrinogen 
(INTERCEPT Fibrinogen Complex) in Patients with Bleeding to Expedite Product Availability in 
Perioperative Bleeding
SUMMARY
Immediately replacing fibrinogen in perioperative bleeding patients with acquired fibrinogen 
deficiency improves outcomes.  The product that is primarily used for fibrinogen replacement 
in the US, cryoprecipitate, must be stored frozen and expires six hours after thawing, 
resulting in a delay in transfusion of approximately 50 minutes from the time it is ordered, as 
well as unnecessary transfusion of more readily available but not indicated blood 
components that are transfused while the patients waits for cryo . A modified version of the 
product, pathogen reduced (PR) cryo, is now FDA approved and can be thawed and stored for 
5 days, allowing the product to be available immediately when needed.  No clinical studies 
are available for this product.  In this quality improvement study, we will compare the effect 
that readily available, pre-thawed PR cryo has on transfusion practice in cardiovascular and 
liver transplant patients who receive PR cryo versus those who receive traditional cryo by 
randomizing cryo transfusions in the blood bank by month to all cryo or all PR cryo.  All 
clinical decisions, including the need for cryoprecipitate, and laboratory testing will occur per 
standard of care.  
INTRODUCTION
Cryoprecipitated AHF product (cryo), a pooled product from 5-10 blood donors,  is the primary 
source of fibrinogen replacement for bleeding patients in the United States. When stored 
frozen, it has a shelf life of one year; however, it must be thawed prior to use.  Thawing, 
labeling and dispensing cryo can take 28-97 minutes and then it must be transfused within 6 
hours due to a theoretical risk of bacterial contamination. 
The competing need to have cryo rapidly available for urgent transfusions and the need to 
avoid wasting product has led to the development of pathogen reduced (PR) cryo, which 
recently received FDA approval. This product is also called Intercept Fibrinogen Complex (IFC) 
and can be kept thawed at room temperature for up to 5 days after thawing. 
PR cryoprecipitate is derived from a traditional cryoprecipitate product that is treated with 
amotosalen.  
 
 
The inactivation of pathogens 
allows thawed PR cryo to have a shelf-life of 5 days without the risk of microbial contamination.  
Furthermore, multiple studies have shown that fibrinogen is stable when thawed at room 
temperature for up to 35 days.  The longer shelf-life should reduce product wastage which 
 
 
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would offset the increased cost of PR cryo over traditional cryo.  In vitro studies have shown no 
differences in efficacy between traditional and PR cryo.  No safety differences are expected 
between the two products, as evidenced by the FDA approving PR cryo without any clinical 
studies. 
The same pathogen reduction process used for PR cryo/IFC that was developed by Cerus 
Corporation has been in use in the United States since 2014 for platelet and plasma products.  
Cryoprecipitate is a derivative of plasma, and the pathogen reduction process was already FDA 
approved. Therefore, the FDA approved this blood product and its pathogen inactivation 
process, without any clinical trials or observational studies.   
 
    
PR cryo/IFC, the product we are studying, is a biological blood component and the process used 
to treat PR cryo, known as INTERCEPT® Blood System for Cryoprecipitation (package insert 
included in IRB application) is the same process used for PR platelets and PR plasma.  The 
pathogen reduction process occurs at the blood supplier and then the product is received by 
our hospital.   T
Since PR cryo can be kept at room temperature for 5 days, similar to thawed plasma, the blood 
bank can opt to have a PR cryo supply thawed and immediately available for use.  This can 
prevent delays in treatment in bleeding patients. 
 
BACKGROUND OF CRYO USE AT NYP/WC
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Given PR cryo’s recent FDA approval, no real-world studies or clinical trials exist directly 
comparing conventional cryoprecipitate and pathogen reduced cryoprecipitate use in the 
perioperative setting. The relative frequency of cryoprecipitate usage in our large cardiac and 
 
 

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liver transplant programs at Weill Cornell provides an ideal setting to compare the two 
products.
STUDY DESIGN
Given that PR cryo can be more readily available for urgent perioperative need, the transfusion 
medicine service and anesthesiologists at NYP/WC would like to transition to this product.   PR 
cryo is a more expensive product, so it is necessary to evaluate whether its availability will 
reduce the need for other blood products or reduce traditional cryo wastage, prior to fully 
converting to this product. A single center prospective, pilot cluster randomized study with an 
adaptive design will be used to compare the availability and cost effectiveness of cryo and PR 
cryo when it is ordered for standard clinical indications. In this design, the intervention and 
randomization are not made at the level of the individual patient, but rather on clusters of 
patients by month.  The clusters will include all patients at NYP/WC for whom pooled cryo is 
ordered during a single month, not just liver transplant and cardiovascular surgery patients.  
Since both products are considered clinically equivalent, the blood bank will alternate use of PR 
cryo and regular cryo each month for all patients with a cryo order over a one year period 
during the transition to the use of this new product.  All patients will receive either traditional 
cryo or PR cryo in a given month; however, only a subset (CV and LT patients) will be studied. 
Data from the EMR and lab systems will be collected from the NYP data warehouse during the 
one-year QA study and included in the data analysis.   The following demographic variables will 
be collected:  age, ethnicity, race, gender, underlying diseases, surgery type, medications given 
within 5 days of surgery.
The primary outcome will be the total number of blood components (RBCs, platelets, plasma) 
used over the admission within the first 30 days after surgery.  
REDCap will be used for data collection/storage.  Our data scientist, who is an Epic Clinical Data 
Navigator (CDN), will use SQL queries through the NYP Jupiter data warehouse for automated 
data extractions of clinical and laboratory data. A TRAC request will be submitted once the IRB 
is approved.  Any variables not available through Jupiter will be extracted manually from the 
electronic medical record by the research coordinator and entered manually in REDCap.  We 
will use the Safe Harbor method for de-identification of data. We will remove all 18 PHI 
elements referenced by HHS that could identify a patient.
The secondary outcomes, which are all routinely available in the EMR per standard of care, will 
include:
1. Number of cryo or fibrinogen concentrate products used perioperatively (defined as 
anesthesia start time to 3 days post-procedure)
 
 
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2. Number of RBC, plasma, and platelet products used perioperatively (defined as 
anesthesia start time to 3 days post-procedure)
3. Time from OR start time to start of cryo transfusion
4. Time from cryo order to start of transfusion
5. Number of cryo units wasted by blood bank per month during study periods. 
6. Laboratory measures, as available in the medical record, related to the indications for 
cryo: pre and post transfusion FIBTEM amplitude at 10 mins and maximum clot firmness 
& fibrinogen level within 10 minutes to one hour after the end of the first cryo 
transfusion.   
7. Highest and lowest fibrinogen level or ROTEM FIBTEM within 24 hours after surgery. 
8. Volume in drains (e.g. chest tube for CV surgery) at 24 hours or until removed, 
whichever is sooner. 
9. Time from end of bypass pump until end of surgery (reflects time to hemostasis) for CV 
surgery
10. Length of stay (OR, ICU and hospital)
11. Need for ventilator
12. Time on ventilator
13. Overall cost of cryo vs PR cryo, when factoring wastage, during each 1-month period
14. Adverse events: fevers, infections, transfusion reactions within 5 days of surgery start 
time, need for surgical re-exploration, multiorgan system failure
15. Fibrinogen level most proximal to end of procedure
STUDY PATIENT POPULATION
Liver transplant and cardiovascular surgery populations were chosen because they are the 2 
patient populations which receive cryo during massive blood loss most frequently in the 
operating room.  Although they don’t have the same mechanisms of injury and coagulation 
dysregulation, they both are prone to severe and early hypofibrinogenemia, hyperfibrinolysis, 
thrombocytopenia, platelet dysfunction and dilutional coagulopathy during surgery.   The CV 
surgery and liver transplant anesthesiology groups at Weill Cornell faithfully use ROTEM for real 
time goal directed blood product therapy.  Other patient populations may receive cryo, but 
cryo tends to be less predictably used in these populations, less evidence based (i.e., less based 
on immediately available point of care coagulation lab results) and more of a last resort option, 
rather than an early planned intervention. The other groups of patients who require cryo are 
smaller, more heterogeneous and have more covariates that will make data analysis more 
difficult to interpret. Thus, the focus is on two fairly homogeneous patient groups at high 
probability to require cryo transfusion.
Inclusion criteria: Adult patients undergoing cardiovascular surgery or liver transplant who 
receive cryo during surgery during the two year study period.   Cardiovascular surgery includes 
the following procedures: coronary artery bypass grafting, valve repair or replacement, open 
thoracic aortic and thoracoabdominal aortic surgery, atrial or ventricular septal defects, 
ventricular assist device implantation or revision, or any combination of the above.  
 
 
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Exclusion criteria: 
1) Patients who do not receive any cryo product in the OR.
2) Patients who are not cardiovascular surgery or liver transplant patients
3) Cardiac transplantation surgery 
4) Patients who receive a product in error within either the cryo time period or the 
PR cryo time period.  For example, PR cryo during a cryo month or cryo during a 
PR cryo time month.
5) Patients who receive less than 1 pool (5 units) of cryo
6) Pediatric patients (less than 18 years of age).
7) Patients who received both PR cryo and traditional cryo
8) Pregnant women
Investigators:
Transfusion Medicine: Dr. Robert DeSimone, Dr. Melissa Cushing, Dr. Maria Angie Muniz, Dr. 
Ljiljana Vasovic
Anesthesiology: Dr. Natalia Ivascu, Dr Meghann Fitzgerald, Dr. Shanna Hill, Dr. Christine Lennon
Coagulation: Dr. Sabrina Racine-Brosztek
Data scientist: Sophie Rand
Research coordinator: Pranesh Rajendran
Statistician: Caroline Andy 
LABORATORY TESTING
Patients requiring transfusions intraoperatively or post-operatively are currently already 
assessed via ROTEM pre and post product transfusions to guide product selection for clinical 
purposes.  A ROTEM transfusion algorithm is already in use for both cardiovascular surgery and 
liver transplant. All laboratory testing will be standard of care for labs and ROTEM. Patients will 
have a ROTEM performed on the ROTEM Delta instrument either in the blood bank or in the 
OR.
CONSENT
Consent will not be obtained at the level of the individual patient prior to transfusion because 
both products are FDA approved and considered standard of care.  This is a quality 
improvement study to understand whether improved logistics (i.e. more ready and immediate 
access to cryo) can avoid the use of other unnecessary blood products and decrease costs 
associated with those products.    In addition, there is no accurate method to predict the need 
for fibrinogen replacement in bleeding patients during surgery so consent could not be 
obtained prior to surgery.  The decision to transfuse cryo during surgery occurs urgently during 
hemorrhage while patients are under anesthesia. 
 
 
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All CV and LT patients will be retrospectively provided with a patient information sheet about 
the study after the transfusion in the OR.  
  All decisions about when to transfuse will be made by clinical providers 
according to their clinical judgement and unrelated to the study.
 
STATISTICAL ANALYSIS
RATIONALE FOR A CLUSTER RANDOMIZED TRIAL
Individual patient efficacy clinical trials are useful to establish the clinical efficacy of an 
intervention amongst a carefully selected population under optimal conditions following 
detailed protocols. However, such trials do not address questions about how an intervention or 
logistical change affects clinical practice in the real world. 
The surgical care of patients in our hospital is undertaken using standardized procedures that 
optimize outcomes, such as standard preoperative assessment and pre-and postoperative care 
pathways. Because our cardiac surgery and liver transplant services deliver care through 
standard institutional policies, it is appropriate to address whether either of the two FDA-
approved blood products for fibrinogen replacement in acquired hypofibrinogenemia used 
during surgery to treat bleeding would reduce the total amount of blood products transfused. 
Testing the effects of the two products mandates a pragmatic trial done with randomization of 
product used by month rather than by patient. It is extremely difficult to predict which patients 
will receive fibrinogen replacement during surgery and thus impossible to predict which 
patients to consent ahead of time.  At the time the decision is made to transfuse 
cryoprecipitate, a patient is already bleeding and under anesthesia, and thus there is no 
opportunity to consent in real time. Thus, this study will use a cluster randomization treatment 
assignment design with a calendar month time period as the cluster; specifically addressing 
whether the use of cryoprecipitate or PR cryoprecipitate reduces overall blood transfusions 
without any contamination of study groups by the inability to fulfill the appropriate cryo use if 
individual randomization had been used. 
The main challenge of a cluster-randomized trial is the need for inflated sample size (relative to 
a non-clustered design) that results from clustering. Individuals within a cluster tend to have a 
smaller degree of variation compared to the variation between clusters, which is measured 
statistically by the intra-cluster correlation coefficient (ICC) (Arnup SJ et al). If the ICC is greater 
than 1, then this cluster effect will incorrectly reduce the standard error of the model estimates 
 
 
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if it is not properly accounted for in the analysis. This study will use randomization between 
intervention arms each month with a design known as the cluster randomized trial. This allows 
for the ability to assure that all research subjects in a given month will receive a particular cryo 
product and ensure the reduction in contamination of the two study arms (one of the primary 
reasons for designing studies in this fashion). In the planned trial, each month the Weill Cornell 
blood bank will be randomized to one of the two cryoprecipitates as part of a quality 
improvement study, the randomized product will be used as standard institutional policy for an 
entire calendar month. At the end of each month, the blood bank is re-randomized to a new 
standard policy that is used for the subsequent calendar month. This design is methodologically 
rigorous and tests the effect of a change in standard policy as it would actually be used in the 
clinical setting.
SAMPLE SIZE ANALYSIS
The primary endpoint of the study is total number of blood components other than cryo (RBCs, 
platelets, plasma) used over the hospital admission within the first 30 days after surgery. The 
goal of the trial is to demonstrate a 20% reduction in this total blood product use for PR cryo 
compared to the total observed with conventional cryo. In order to determine this effect size 
and the patient variability associated with this outcome, data were collected from 150 
cardiovascular surgery and liver transplant cases at the study center during 6 months in 2021. 
Because the number of units used was clearly right-skewed and, therefore, possibly log-
normally distributed, the sample size determination was based on the hypothesized ratio of 
means (effect size) of 0.8. In addition, the coefficient of variation is the key determinant of 
variability with log-normal data, and this was seen with the recent data to be a value of 1.1. The 
other issue to consider in this calculation is the cluster randomization. However, the cluster in 
this study is the month when the surgery is performed. The assumption is made that the intra-
cluster correlation of the primary outcome within a given month should be very small, say 
0.0001. As a result, this would have very little effect on the sample size (the Kish design effect is 
about 1.01 assuming approximately 100 subjects per month). Then with 80% power and 5% 
significance (two-sided), the number of subjects per group would be 251.
However, there is a possibility that the effect size has been overestimated. Thus, a sample size 
re-estimation will be conducted after 60% of the subjects have been included in the trial. The 
method of Gould (Gould AL. Interim analyses for monitoring clinical trials that do not materially 
affect the type I error rate. Stat Med 1992; 11:55-66.) will be used to re-evaluate the sample 
size.
EQUIVALENCY BETWEEN COHORTS
In order to control for possible patient population variations between the patients transfused 
with cryo and PR cryo, clinical scoring systems will be utilized to ensure the two groups are 
similar: MELD score for liver transplant patients and EUROSCORE for cardiovascular surgery 
patients.
 
 
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EVALUATION OF PRODUCT SUPERIORITY
The primary outcome of total number of blood components (RBCs, platelets, plasma) used over 
the admission within the first 30 days after surgery will be evaluated using a two-sample t-test 
on the log-transformed values or the Wilcoxon rank-sum test if the log-transform does not 
result in an acceptable comparability to a normal distribution. This will be based on an intent-
to-treat paradigm (all subjects randomized will be evaluated and in the group they were 
randomized to). However, it is assumed that all of the subjects will be appropriately evaluated 
for this endpoint.
There are a number of secondary endpoints, and the specific statistical method is indicated 
below:
1. Number of cryo or fibrinogen concentrate products used perioperatively (defined as 
anesthesia start to 24 hours post-procedure): Wilcoxon rank-sum test
2. Number of RBC, plasma, and platelet products used perioperatively (defined as 
anesthesia start to 24 hours post-procedure): Wilcoxon rank-sum test
3. Time from cryo order to ready in the blood bank: Wilcoxon rank-sum test
4. Time from cryo order to start of infusion: Wilcoxon rank-sum test 
5. Number of cryo units wasted by blood bank per day during study periods: Wilcoxon 
rank-sum test 
6. Laboratory measures for cryo and PR cryo (pre and post transfusion FIBTEM amplitude 
at 10 mins and maximum clot firmness, fibrinogen): Wilcoxon rank-sum test 
7. Volume in mediastinal drains (e.g. chest tube for CV surgery) at 24 hours (or until 
removed): Wilcoxon rank-sum test
8. Length of stay (OR, ICU and hospital) & time on ventilator: log-rank test, particularly if 
there is any censoring
9. Overall cost of cryo vs PR cryo, when factoring wastage, during each 1-month period: 
Wilcoxon rank-sum test
10. Fibrinogen level most proximal to end of procedure, with adjustment for fibrinogen 
dose administered (if known): without adjustment the Wilcoxon rank-sum test can be 
used; with adjustment a properly selected linear model (depending on the link function 
required)
In order to control statistical significance for this number of endpoints, the Holm procedure will 
be used. 
Many of the endpoints noted above can be evaluated after adjustment with selected covariates 
using a properly selected linear model (depending on the link function required).
INTERIM ANALYSIS
 
 
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A separate interim analysis for futility will be conducted on the primary endpoint when 60% of 
the subjects have completed the trial.  Sixty percent of 502 (251 per group) is 302. We expect to 
accrue 302 patients in approximately 1 year. During the interim analysis we will decide if the 
study will continue or stop.   This will involve the calculation of conditional power and a 
potential stopping rule of a value for this calculation of <10%.
 
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