Multicenter, Prospective, Open-Label, Single-Arm Trial to Evaluate the Pharmacokinetics, Efficacy, and Safety of Human Plasma-Derived Fibrinogen (FIB Grifols) in Patients With Congenital Afibrinogenemia
Phase: PHASE1
Conditions: Congenital Afibrinogenemia
Sponsor: Grifols Therapeutics LLC

 
Official Title: 
 
Multicenter, Prospective, Open-Label, Single-Arm Trial to Evaluate the 
Pharmacokinetics, Efficacy, and Safety of Human Plasma-Derived Fibrinogen 
(FIB Grifols) in Patients with Congenital Afibrinogenemia 
 
NCT Number: 
NCT02281500 
 
Document Date: 
 
Protocol Version 3.0: 08 October 2018 
 
 
 
 
 
 
 
 

                                                Protocol IG0902 Version 3.0
    Dated 08 Oct 2018
CONFIDENTIAL
Multicenter, Prospective, Open-Label, Single-Arm Trial to Evaluate the 
Pharmacokinetics, Efficacy, and Safety of Human Plasma-Derived 
Fibrinogen (FIB Grifols) in Patients with Congenital Afibrinogenemia
Clinical Trial Sponsor:
Instituto Grifols, S.A.
Can Guasch, 2 
08150 Parets del Vallès
Barcelona
Spain
Product:
Human plasma-derived fibrinogen concentrate 
(FIB Grifols)  
Study Phase:
I-II
Protocol Number:
IG0902
Version Number:
3.0
Includes IG0902/Version 2.3/12 Feb 2016, 
IG0902/Version 2.2/29 Sep 2015, 
IG0902/Versioni 2.1/08 Jul 2015 and 
IG0902/Version 2.0/21 Aug 2014
Date:
08 Oct 2018
EudraCT Number: 
2013-004343-23
Confidentiality Statement:
The information contained in this protocol is provided to you in confidence, for review 
by you, your staff, and any applicable regulatory authority or institutional review 
committee. It is understood that this information may not be disclosed to any other party, 
in any form, without prior authorization from Instituto Grifols, S.A., except to the extent 
necessary to obtain informed consent from the persons to whom the drug may be 
administered.

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Multicenter, Prospective, Open-Label, Single-Arm Trial to Evaluate the 
Pharmacokinetics, Efficacy, and Safety of Human Plasma-Derived Fibrinogen (FIB 
Grifols) in Patients with Congenital Afibrinogenemia
Protocol Number: IG0902
EudraCT Number: 2013-004343-23
Version Number: 3.0
Version Date: 08 Oct 2018
INVESTIGATOR SIGNATURE PAGE
I have read this protocol and agree to conduct this trial in accordance with all stipulations of 
the protocol, Good Clinical Practice (GCP), the Declaration of Helsinki, and applicable 
regulatory requirements.
___________________________________
______________________
INVESTIGATOR NAME (Please Print)
LOCATION
___________________________________
______________________
INVESTIGATOR SIGNATURE
DATE

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PROTOCOL SUMMARY
Protocol Title:
Multicenter, Prospective, Open-Label, Single-Arm Trial to 
Evaluate the Pharmacokinetics, Efficacy, and Safety of Human 
Plasma-Derived Fibrinogen (FIB Grifols) in Patients with 
Congenital Afibrinogenemia
Protocol Number:
IG0902
Protocol Version 
and Date:
Version 3.0, 08 Oct 2018
Sponsor:
Instituto Grifols, S.A.
Can Guasch, 2
08150 Parets del Vallès
Barcelona
Spain
Coordinating 
Investigator:
Flora Peyvandi, MD
Milano, Italy
Investigational 
Product (Test):
Human Plasma-Derived Fibrinogen Concentrate Grifols (FIB 
Grifols):

A Type II glass vial containing 1.0 g of Fibrinogen 
(powder for infusion).

A Type II glass vial containing 50 mL of sterile water for 
injection (SWFI) as solvent.
Indication:
Treatment of subjects with congenital afibrinogenemia (fibrinogen 
deficiency)
Trial Phase:
I/II
Trial Sites:
Multi-center study is planned to be conducted in multiple sites in 
multiple countries including India, Italy (European Union), 
Turkey, Lebanon, and the United States of America (USA).
Study Objectives:
To evaluate the pharmacokinetics, efficacy, and safety of human 
plasma-derived fibrinogen concentrate FIB Grifols after a single-
dose 70 mg/kg body weight administration.
Trial Design:
This study is a phase I-II, multi-center, prospective, open-label, 
single-arm clinical study to evaluate the PK, efficacy, and safety of 
human plasma-derived fibrinogen concentrate FIB Grifols in adult 
and pediatric subjects with congenital afibrinogenemia. 
Approximately 10 adult subjects (≥18 years) with congenital 
afibrinogenemia will be administered a single dose of study drug 

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at 70 mg/kg body weight and will be followed for PK, efficacy, 
and safety assessments.  
After the safety of fibrinogen concentrate FIB Grifols is assessed 
in at least 10 adult subjects and no safety issues are raised by the 
sponsor, the study will start to enroll approximately 10 pediatric 
subjects (<18 years) who will be dosed with study drug and 
followed for PK, efficacy, and safety assessments.
All enrolled subjects (both adult and pediatric) will have 
documented congenital fibrinogen deficiency manifested as 
afibrinogenemia but will not have received any fibrinogen-
containing product therapy within the preceding 21 days before the  
infusion of study drug.
All subjects (both adult and pediatric) will be infused with the 
investigational product at 70 mg/kg body weight. PK parameters  
that will be calculated from plasma fibrinogen levels measured at 
different time points include: incremental in vivo recovery (IVR), 
area under the curve (AUC) calculated as AUC from zero to 14 
days (AUC0-14days) and AUC from zero to infinity (AUC0-∞), 
maximum plasma concentration (Cmax), time to the observed 
maximum plasma concentration (tmax), half-life (t1/2), mean 
residence time (MRT), volume of distribution (Vd), and clearance 
(Cl).
Hemostatic efficacy of the investigational product will be assessed 
by means of rotational thromboelastometry (ROTEM) measure of 
maximum clot firmness (MCF) at baseline and 1-hour post-
infusion. Other thromboelastographic measures as well as standard 
coagulation tests will be also determined pre- and post-infusion.
Clinical safety, virus safety, and immunogenicity will be assessed 
in this clinical trial. Safety variables include adverse events (AEs), 
vital signs, physical assessments, laboratory tests, viral markers, 
and antibodies against human fibrinogen.
Allergic/hypersensitivity reactions and thrombotic events will be 
monitored during the study.
Stopping criteria have been established for immunogenic and 
thrombogenic events. Briefly, if a confirmed, single case of any of 
these events is reported after a subject has been dosed with study 
drug, any further enrollment and dosing of subjects in the study 
will be suspended until the event can be adequately assessed by the 
sponsor. The enrollment and dosing will only resume after explicit 
authorization by the sponsor.
Study Population 
and Sample Size:
Adult and pediatric subjects with congenital fibrinogen deficiency 
manifested as afibrinogenemia.
Ten (10) evaluable adult subjects (≥18 years) will be sufficient for 

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the purpose of establishing a PK profile of the investigational 
product. In order to allow for possible drop-outs, 11 subjects will 
be enrolled in the study.
Only after the safety of the study drug has been assessed and 
established in the adult population, the study will start to enroll 
pediatric subjects. It is planned that 11 pediatric subjects will be 
enrolled to achieve 10 evaluable pediatric subjects.  
Clinical Trial 
Duration:
Subjects’ participation in this clinical trial will be approximately 3 
months and 3 weeks:

Screening Visit: up to 21 days before study drug infusion 
visit (Day 0)

Study drug infusion visit: administration of study drug 
(Day 0)

PK, efficacy, and clinical safety follow-up period: Day 0 to 
Day 14 post-infusion

Safety follow-up period (Day 21, Week 4, and Month 3 
Visits)
Main Subject 
Inclusion Criteria:
Subjects (both adult and pediatric) will be eligible for entry into 
the study once they meet ALL of the following inclusion criteria:
1. Male or female subjects less than 70 years olda.
2. Sign the written Informed Consent Form (ICF), or the subject’s 
parent or legal guardian signs the ICF where applicable, and 
the Subject Authorization Form (SAF) where applicable. 
Pediatric subjects, as defined by local regulations, will be 
asked to sign an age appropriate assent form.
3. Subjects diagnosed with congenital fibrinogen deficiency 
manifested as afibrinogenemia.
4. Subjects with a fibrinogen level undetectable1, or equal or less 
than 30 mg/dL determined by both Clauss and antigen methods 
at baseline2 (samples drawn within 24 hours prior to infusion 
on Day 0 Visit will be tested locally) or at Screening Visit3
(samples should be drawn at least 14 days prior to infusion on 
Day 0 Visit to be tested at central laboratory).
1 Limit of detection for fibrinogen level determination  must be 
30 mg/dL or lower for both methods.
2For sites that have the capability of performing fibrinogen 
level determinations locally by both Clauss and antigen 
methods with a limit of detection of 30 mg/dL or lower.
3For sites that do not have the capability of performing 
fibrinogen level determinations by both Clauss and antigen 
methods locally or have methods that are not sensitive enough 

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(limit of detection: larger than 30 mg/dL).
5. Female subjects of child-bearing potentialb must have a 
negative test for pregnancy blood or urine human chorionic 
gonadotropin (HCG-based assay) at baseline (sample drawn 
within 24 hours prior to infusion on Day 0 Visit).
6. Female subjects of child-bearing potentialb and their partners 
have agreed to practice contraception using a method of proven 
reliability (ie, hormonal methods, barrier methods, intrauterine 
devices methods, or abstinence) to prevent a pregnancy during 
the course of the clinical trial.
7. Subjects must be willing to comply with all aspects of the 
clinical trial protocol, including blood sampling, for the whole 
duration of the study.
aThe enrollment of pediatric subjects (<18 years of age) will 
be initiated only after the safety of FIB Grifols in all adult 
subjects has been evaluated by the sponsor.
bWomen of child-bearing potential include any female who has 
experienced menarche and who has not undergone successful 
surgical sterilisation (hysterectomy, bilateral tubal ligation or 
bilateral oophorectomy), or is not postmenopausal (post-
menopausal is defined as amenorrhea for >12 consecutive 
months or women on hormone replacement therapy with 
documented serum follicle stimulating hormone level <35 
mIU/mL). Even in women who are using oral, implanted, or 
injectable contraceptive hormones or mechanical products 
such as an intrauterine device or barrier methods (diaphragm, 
condoms, spermicides) to prevent pregnancy or practicing 
abstinence or where partner is sterile, eg, vasectomy, should 
be considered to be of child bearing potential.
Main Exclusion 
Criteria:
Subjects will be ineligible for entry into the study if they meet 
ANY of the following exclusion criteria:
1. Subjects who received any fibrinogen-containing product 
within 21 days prior to Day 0 Visit.
2. Subjects who present with active bleeding within 10 days prior 
to infusion on Day 0.
3. Subjects with acquired (secondary) fibrinogen deficiency.
4. Subjects diagnosed with dysfibrinogenemia.
5. Subjects with documented history of deep vein thrombosis 
(DVT), pulmonary embolism, or arterial thrombosis within
1 year prior to enrolment in this clinical trial.
6. Subjects with known antibodies against fibrinogen.
7. Subjects with a history of severe anaphylactic reactions or 

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reactions to any blood-derived product.
8. Subjects with a history of intolerance to any component of the 
investigational product.
9. Subjects with a documented history of IgA deficiency and 
antibodies against IgA.
10. Females who are pregnant or breastfeeding.
11. Subjects with renal impairment (ie, serum creatinine exceeds 
more than 2.0 times the upper limit of normal [ULN]) at 
baseline (sample drawn within 24 hours prior to infusion on 
Day 0 Visit).
12. Subjects with aspartate aminotransferase (AST) or alanine 
aminotransferase (ALT) levels exceeding more than 2.5 times 
the ULN at baseline (sample drawn within 24 hours prior to 
infusion on Day 0 Visit).
13. Subjects with a history of chronic alcoholism or illicit drug 
addiction in the preceding 12 months prior to enrollment in this 
clinical trial.
14. Subjects with any medical condition which is likely to interfere 
with the evaluation of the study drug and/or the satisfactory 
conduct of the clinical trial according to the investigator’s 
judgment (eg, congenital or acquired bleeding disorders other 
than congenital fibrinogen deficiency, planned surgery needing 
blood transfusion).
15. Subjects who received aspirin-containing products and 
nonsteroidal anti-inflammatory drugs (NSAIDs) within 7 days 
prior to the Day 0 Visit.
16. Subjects currently receiving, or having received within 
3 months prior to enrolment into this clinical trial, any 
investigational drug or device.
17. Subjects who were previously administered the investigational 
product FIB Grifols during this clinical trial (ie, every subject 
can only participate in the study once).
18. Subjects who are unlikely to adhere to the protocol 
requirements, are likely to be uncooperative, or are unable to 
provide a storage serum sample prior to investigational drug 
infusion.
Pharmacokinetic 
Endpoints:
The following PK parameters will be calculated for fibrinogen by 
non-compartmental PK method determined from plasma levels 
before and at 30 minutes, 1 hour, 2 hour, 4 hour, 8 hour, 1 day 
(24 hours), 2 days (48 hours), 4 days (96 hours), 6 days 
(144 hours), 9 days (216 hours), and 14 days (336 hours) after the 
end of the infusion: 
1.
AUC0-14days
2.
AUC0-∞

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potassium, chloride, and calcium.
Hematological parameters: complete blood count (CBC), 
including platelet count and differential leukocyte count.
Markers of activation of coagulation (not applicable for pediatric 
subjects): different measures indicative of activation in the 
coagulation pathway (D-dimer, antithrombin III [ATIII], 
thrombin-antithrombin III complex [TAT] prothrombin fragments 
[F1+2]).
5. Antibodies against human fibrinogen (not applicable for 
pediatric subjects)
Evidence of any possible immunogenicity of the investigational 
product will be assessed at the sponsor’s laboratory. Samples from 
adult subjects will be assayed for generation of fibrinogen 
antibodies on an ongoing basis for the duration of the study. If a 
confirmed, single case of immunogenicity is reported after a 
subject was dosed with study drug, any further enrollment and 
dosing of subjects in the study will be suspended until the event 
can be adquately assessed by the sponsor. The enrollment and 
dosing will only resume after explicit authorization by the 
sponsor.
6. Allergic/hypersensitivity reactions 
Subjects will be carefully monitored for signs and symptoms of 
allergic/hypersensitivity reactions. The sponsor will routinely 
review reported AEs for possible allergic/hypersensitivity 
reactions.
7. Thrombotic events 
Subjects will be monitored for signs and symptoms of arterial and 
venous thrombotic events. If a confirmed, single case of a 
thrombotic event is reported by an investigator after a subject was 
dosed with study drug, any further enrollment and dosing of 
subjects in the study will be suspended until the event can be 
adequately assessed by the sponsor. The enrollment and dosing 
will only resume after explicit authorization by the sponsor.
8. Virus safety (not applicable for pediatric subjects)
Hepatitis A virus (HAV), hepatitis B virus (HBV), hepatitis C 
virus (HCV), human immunodeficiency virus, types 1 and 2 
(HIV-1 and HIV-2), and parvovirus B19 (B19) will be monitored 
to assess virus safety.
Methodology:
Clinical trial procedures:
After a Screening Visit, the enrolled subjects will undergo the 
Infusion Visit (Day 0), during which the subject will be 
administered study drug. After that, there will be a PK, efficacy, 

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and clinical safety evaluation period (Day 0 to Day 14 Visits). 
There will be a follow-up period for safety and virology (visits at 
Day 21, Week 4, and Month 3) and immunogenicity (Day 0, Day 
14, and Week 4).
Medical history
At Screening Visit, a complete medical history will be recorded for 
all study subjects.
Physical assessments
Several physical examinations by body systems will be performed 
at different time points throughout the study according to the 
schedules shown in adult (Table 4-1 and Table 4-3) and pediatric 
(Table 4-4 and Table 4-5) subjects.
Height and weight
Height and weight will be measured for all subjects at Baseline 
Visit. The weight value will be used for calculation of dose of IMP 
to be administered.
Serum clinical chemistry
Several serum clinical chemistry laboratory tests will be performed 
at different time points throughout the study according to the 
schedules shown in adult (Table 4-1 and Table 4-3) and pediatric 
(Table 4-4 and Table 4-5) subjects.
Hematology
Several hematology laboratory tests will be performed at different 
time points throughout the study according to the schedules shown 
in adult (Table 4-1 and Table 4-3) and pediatric (Table 4-4 and
Table 4-5) subjects.
Fibrinogen levels
Plasma samples will be obtained for measurement of fibrinogen 
levels at several time points throughout the study according to the 
schedule shown in adult (Table 4-1 and Table 4-3) and pediatric
(Table 4-4 and Table 4-5) subjects by two methods:
1. Fibrinogen activity (Clauss method)
2. Fibrinogen antigen 
Rotational Thromboelastometry
ROTEM will be performed on frozen plasma samples taken at 
several time points throughout the study according to the schedules
shown in adult (Table 4-1 and Table 4-3) and pediatric (Table 4-4
and Table 4-5) subjects by the central laboratory and following 
parameters measured: CT, CFT, MCF, and α.

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Markers of activation of coagulation (not applicable for pediatric 
subjects)
The following tests, indicative of activation of the coagulation: D-
dimer, ATIII, thrombin-antithrombin III complex (TAT), and F1+2
will be performed on frozen plasma samples taken at several time 
points throughout the study according to the schedule shown in 
Table 4-1 and Table 4-3 by the central laboratory of the study.
Immunogenicity (not applicable for pediatric subjects)
Serum/plasma samples taken only from adult subjects at several 
time points throughout the study according to the schedule shown 
in Table 4-1 and Table 4-3 will be analyzed for the generation of 
antibodies to fibrinogen by using a stepwise approach starting with 
a functional screening assay to detect neutralizing activity. In the 
event neutralizing activity is detected, samples will be further 
assessed by a confirmatory ELISA for the presence of antibodies 
to fibrinogen.   
An additional aliquot of serum/plasma will be retained from all 
immunogenicity testing time points for re-testing if necessary.
Viral panel (not applicable for pediatric subjects)
Viral monitoring for each adult subject will be performed by 
means of serology and nucleic acid amplification technology 
(NAT) tests for following viruses: HAV, HBV, HCV, HIV-1 and 
HIV-2, and B19.
Serum/plasma samples from all subjects will be examined at 
baseline (prior to infusion on Day 0) and at different time points 
according to the schedule shown in Table 4-1, Table 4-2, and 
Table 4-3.
All serum/plasma samples will be sent to the central laboratory of 
the study for measurement of viral status. In case a subject is found 
to be positive for a particular virus at baseline, tests for this 
particular virus will not be performed at later time points during 
the study.
An additional aliquot of serum/plasma will be retained from all 
viral time points for re-testing if necessary.
Infusion and vital signs
During the treatment infusion, all subjects’ vital signs (T, RR, HR, 
SBP, and DBP) will be monitored. Monitoring will be performed 
within 60 minutes before the beginning of the infusion, at the 
completion of the infusion, and within 30 minutes after conclusion 
of each infusion. During the infusion, vitals signs will be recorded 
every 20 ± 5 minutes.

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The rate of infusion will be controlled by means of an infusion 
pump at a constant rate of not more than 5 mL/minute (it is 
acceptable to titrate up to this rate at the investigator’s discretion). 
If an AE occurs during the infusion, the infusion rate may be 
reduced or the infusion may be interrupted until symptoms 
subside. Subsequently, the infusion may be resumed at a rate 
tolerated by the subject, but not exceeding 5mL/minute.
Adverse events
AEs occurring at any time between signature of the informed 
consent and the last day of the subject’s participation in the safety 
follow-up period (Week 4 Visit) after investigational medicinal 
product infusion will be reported on the appropriate subject’s case 
report form (CRF/eCRF). Nature, severity, seriousness 
(serious/non-serious) and causal-relationship to the study product 
will be assessed. Infusional AEs (ie, AEs temporally associated 
with an infusion of investigational product) will be defined and 
reported. Any AE occurred during infusion or within 24 and 
72 hours after completion of infusion will be considered 
temporally associated with the infusion and labelled as infusional 
AEs.
Monitoring of immunogenicity
Evidence of any possible immunogenicity of the investigational 
product will be assessed by assaying for appearance of antibodies 
to fibrinogen. If a confirmed, single case of immunogenicity is 
reported after a subject was dosed with study drug, any further 
enrollment and dosing of subjects in the study will be suspended 
until the event can be adquately assessed by the safety group of the 
sponsor. The enrollment and dosing will only resume after explicit 
authorization by the sponsor.
Monitoring of allergic/hypersensitivity reactions  
Subjects will be carefully monitored for signs and symptoms of 
allergic/hypersensitivity reactions. The Grifols Medical Monitor 
will routinely review reported AEs for possible 
allergic/hypersensitivity reactions. 
Monitoring of thrombotic events
Subjects will be monitored for signs and symptoms of arterial and 
venous thromboses. In addition, the Grifols Medical Monitor will 
routinely review reported AEs for possible thromboses. Arterial 
and venous thromboses will be identified according to definitions 
in the International Classification of Diseases, Ninth Revision, 
Clinical Modification (ICD-9-CM). Such thrombotic events 
include, but are not limited to, DVT, pulmonary embolism (PE), 
myocardial infarction, cerebrovascular accident, acute coronary 

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syndrome, limb thrombosis, sagittal sinus thrombosis, and portal 
vein or mesenteric artery thrombosis. All thromboses will be 
recorded as AEs and reported accordingly. If a confirmed single 
case of thrombotic event is reported by an investigator after a 
subject was dosed with study drug, any further enrollment and 
dosing of subjects in the study will be suspended until the event 
can be adquately assessed by the sponsor. The enrollment and 
dosing will only resume after explicit authorization by the sponsor. 
Concomitant medication
All medications, other than the investigational product, 
administered to subjects will be recorded during the clinical study.
Prohibited 
Concomitant 
Medications
Use of the following medications is prohibited during study 
participation: 
Aspirin-containing products and NSAIDs
Analytical 
Plan/Statistical 
Method:
The sample size in this study is based on the PK assessment. The 
sample size of 10 adult subjects is deemed sufficient for PK 
assessments. Assuming a 10% dropout rate, a total of 11 adult 
subjects need to be enrolled. In this study, the 10 adult subjects 
will be enrolled first. Only after the safety of the product has been 
assessed in these adults, will 10 pediatric subjects be enrolled into 
the study. Assuming a 10% dropout rate, a total of 11 pediatric 
subjects need to be enrolled.
PK analysis
The PK population will consist of all subjects who have received 
study medication and have sufficient fibrinogen plasma 
concentration data to facilitate calculation of PK parameters. The 
PK population will be used for the analyses of the PK parameters. 
PK analysis will be performed independently for the adult and 
pediatric populations.
All PK parameters will be calculated using non-compartmental 
methods using the fibrinogen concentration values obtained by 
both Clauss method and antigen (ELISA) methods.
Efficacy analysis
Primary efficacy analysis will be performed on the evaluable 
population. In addition, efficacy analysis will be also run on the 
per protocol (PP) population if it is different from the evaluable 
population. 
The evaluable population will include all individuals who received 
the investigational product of any amount and who have at least 
two measurements for the primary efficacy variable: one pre-
infusion MCF and one 1-hour post-infusion MCF measurement by 

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 efficacy endpoints) will be carried out in the 
overall study population (both adult and pediatric populations), 
and will also be conducted in the adult population and the pediatric 
population, separately. Primary efficacy analyses will be the ones 
performed on the overall study population.
Safety analysis
Safety analysis for FIB Grifols will be performed on the overall 
population (both adult and pediatric populations). FIB Grifols 
safety will also be assessed independently for both adult and 
pediatric populations.
All AEs occurring in subjects who are infused with study drug will 
be listed in the clinical report of the study. Treatment-emergent 
AEs will be listed and tabulated by body system and they will be 
summarized by presenting individual incidences and percentages. 
In addition, treatment-emergent AEs will be also summarized by 
severity (intensity), seriousness (serious versus non-serious) and 
causal-relationship to the study product. Similarly, all treatment-
emergent AEs potentially related to the investigational product 
will be summarized by presenting individual incidences and 
percentages, and will be also summarized by severity (intensity) 
and seriousness (serious versus non-serious).
Infusional AEs will be defined as any AE that occurred during 
infusion or within 24 and 72 hours after completion of infusion. 
Infusional AEs will be summarized by presenting
infusion’s/subject’s incidences and percentages (each subject 
contributes a single count to a category). AEs will be also 
tabulated by whether or not the AE occurred during the infusion or 
within 24 and 72 hours after completion of the infusion.
Subjects who die, report a serious AE (SAE), or withdraw from the 
study because of AEs will be also individually listed and 
summarized.
Events of special interest such as allergic/hypersensitivity 
reactions and thrombotic events will be individually listed and 
summarized.
Vital signs (T, RR, HR, SBP, DBP) will be listed for each subject. 
Clinically relevant vital signs variations will be flagged.
Clinical laboratory data for renal (creatinine, BUN), hepatic (ALT, 
AST, ALP, TB) and haematological parameters (CBC, including 
differential leukocyte count) will be listed for each subject. Values 
outside the upper or lower limit of the normal range for the 
respective testing laboratory will be flagged.
For virus safety, the proportion of adult subjects who 
seroconverted during the study will be individually reported and 

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discussed.
Evidence of any possible immunogenicity will be assessed in the 
adult subjects by assaying for generation of antibodies to 
fibrinogen by using a stepwise approach starting with a functional 
screening assay to detect neutralizing activity. In the event 
neutralizing activity is detected, samples will be further assessed 
by a confirmatory ELISA for the presence of antibodies to 
fibrinogen.

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ABBREVIATIONS
α
Alpha angle
ADR
Adverse drug reaction
aPTT
Activated partial thromoplastin time
AE
Adverse event
ALP
Alkaline phosphatase 
ALT
Alanine aminotransferase
AST
Aspartate aminotransferase
ATIII
Antithrombin III
AUC
Area under the curve
AUC0-14days
Area under the curve from zero to 14 days
AUC0-∞
Area under the curve from zero to infinity
B19
Parvovirus B19
BUN
Blood urea nitrogen
CBC
Complete blood count
CFT
Clot formation time
Cl
Clearance
Cmax
Maximum plasma concentration
CRF/eCRF
Case report form/electronic case report form
CRO
Contract research organization
CT
Clotting time
DBP
Diastolic blood pressure
dL
Deciliter
DVT
Deep vein thrombosis
ELISA
Enzyme-linked immunosorbent assay
F1+2
Prothrombin fragments F1+2
FXIIIa
Activated factor XIII
GCP
Good clinical practice
HAV
Hepatitis A virus
HBsAg
Hepatitis B virus surface antigen
HBV
Hepatitis B virus
Hct
Haematocrit
HCG
Human chorionic gonadotropin
HCV
Hepatitis C virus

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Hgb
Haemoglobin
HIPAA
Health Information Portability and Accountability Act
HIV-1/HIV-2
Human immunodeficiency virus 1 and 2
HR
Heart rate
ICF
Informed consent form
ICD-9-CM
International Classification of Diseases, Ninth Revision, Clinical 
Modification
ICH
International Conference on Harmonisation
IEC
Independent ethics committee
IgA
Immune globulin A
IRB
Institutional review board
IVR
In vivo recovery
kg
Kilogram
LDH
Lactate dehydrogenase
LSM
Least square mean
MCF
Maximum clot firmness
MCH
Mean corpuscular haemoglobin 
MCHC
Mean corpuscular haemoglobin concentration
MCV
Mean corpuscular volume
MedDRA
Medical Dictionary for Regulatory Activities
mg
Milligram
mm
Millimeter
mmHg
Arterial pressure in millimetres of mercury
mL
Milliliter
MRT
Mean residence time
NAT
Nucleic acid amplification technology
NSAID
Nonsteroidal anti-inflammatory drugs
PE
Pulmonary embolism
PK
Pharmacokinetic
PP
Per protocol
PT
Prothrombin time
QA
Quality assurance
RBC
Red blood cells
ROTEM
Rotational thromboelastometry
RR
Respiratory rate
SAE
Serious adverse event

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SAF
Subjects authorization form
SBP
Systolic blood pressure
SWFI
Sterile water for injection
T
Temperature
t1/2
Half-life
TAT
Thrombin-antithrombin III complex
TB
Total bilirubin
tmax
Time to the observed maximum plasma concentration
TRALI
Transfusion-related acute lung injury
TT
Thrombin time
ULN
Upper limit of normal
USA
United States of America
Vd
Volume of distribution
WBC
White blood cell

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TABLE OF CONTENTS
1.
GENERAL INFORMATION.......................................................................................... 27
1.1
Protocol Title ...................................................................................................................... 27
1.2
Protocol number, version, date, and EudraCT number....................................................... 27
1.3
Name and address of sponsor and monitor ......................................................................... 27
1.4
Name and title of people authorized to sign the protocol and the protocol amendment(s) for 
sponsor................................................................................................................................ 27
1.5
Name, title, address, and telephone number of sponsor’s medical expert for the trial ....... 27
1.6
Name and title of investigators who are responsible for conducting the trial, and address and 
telephone number of trial sites............................................................................................ 28
2.
BACKGROUND INFORMATION................................................................................. 28
2.1
Name and description of the investigational product.......................................................... 28
2.2
Summary of findings from nonclinical studies and clinical trials that are relevant to the trial
............................................................................................................................................. 28
2.3
Summary of the known and potential risks and benefits to human subjects....................... 29
2.4
Description of and justification for the route administration, dosage, dosage regimen, and 
treatment period(s).............................................................................................................. 30
2.5
Compliance with the protocol, good clinical practice and the applicable regulatory 
requirements........................................................................................................................ 30
2.6
Description of the population to be studied ........................................................................ 30
2.7
Reference to literature and data that are relevant to the trial and that provide background for 
the trial ................................................................................................................................ 31
3.
TRIAL OBJECTIVES AND PURPOSES ...................................................................... 34
4.
TRIAL DESIGN................................................................................................................ 34
4.1
Pharmacokinetic endpoints ................................................................................................. 34
4.2
Primary and secondary efficacy endpoints ......................................................................... 35
4.3
Description of the design of the trial to be conducted......................................................... 36
4.4
Measures to minimize/avoid bias........................................................................................ 39
4.4.1
Randomization .................................................................................................................... 39
4.4.2
Blinding............................................................................................................................... 39
4.5
Description of the investigational product.......................................................................... 39
4.5.1
Investigational product identification ................................................................................. 39
4.5.2
Dosage and dosage regimen of the investigational product................................................ 39
4.5.2.1 Dosage of investigational product....................................................................................... 39
4.5.2.2 Dosage regimen of investigational product......................................................................... 39
4.5.3
Packaging and labelling of the investigational product ...................................................... 40
4.5.4
Storage, preparation, dispensation and administration of the investigational product........ 40
4.5.4.1 Storage and preparation of the investigational product....................................................... 40
4.5.4.2 Dispensation and administration of the investigational product......................................... 41
4.6
Expected duration of subject’s participation and description of the sequence and duration of 
the trial period..................................................................................................................... 41
4.6.1
Description of the clinical trial procedures......................................................................... 52
4.6.1.1 Medical history ................................................................................................................... 52
4.6.1.2 Physical assessment ............................................................................................................ 52

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4.6.1.3 Height and weight............................................................................................................... 52
4.6.1.4 Serum clinical chemistry..................................................................................................... 52
4.6.1.5 Hematology......................................................................................................................... 52
4.6.1.6 Fibrinogen Levels ............................................................................................................... 53
4.6.1.7 Rotational Thromboelastometry ......................................................................................... 54
4.6.1.8 Standard coagulation tests................................................................................................... 54
4.6.1.9 Markers of activation of coagulation .................................................................................. 55
4.6.1.10Immunogenicity testing....................................................................................................... 55
4.6.1.11Viral panel........................................................................................................................... 55
4.6.1.12Vital signs ........................................................................................................................... 55
4.6.1.13Adverse events.................................................................................................................... 56
4.6.1.14Monitoring of allergic/hypersensitivity reactions ............................................................... 56
4.6.1.15Monitoring of thrombotic events ........................................................................................ 56
4.6.1.16Retention sample................................................................................................................. 56
4.6.1.17Concomitant medication ..................................................................................................... 57
4.6.1.18Pregnancy test ..................................................................................................................... 57
4.6.2
Clinical trial visits............................................................................................................... 57
4.7
Premature discontinuation of participating subjects ........................................................... 74
4.8
Accountability procedures for the investigational product ................................................. 74
4.9
Source data.......................................................................................................................... 75
5.
SELECTION AND WITHDRAWAL OF SUBJECTS ................................................. 75
5.1
Subject inclusion criteria..................................................................................................... 75
5.2
Subject exclusion criteria.................................................................................................... 76
5.3
Subject withdrawal criteria and procedures........................................................................ 77
6.
TREATMENT OF SUBJECTS ....................................................................................... 78
6.1
Treatment to be administered.............................................................................................. 78
6.2
Medication(s)/treatment(s) permitted (including rescue medication) and not permited before 
and/or during the trial.......................................................................................................... 78
6.3
Procedures for monitoring subject compliance................................................................... 79
6.4
Stopping rules and discontinuation criteria......................................................................... 79
7.
ASSESSMENT OF EFFICACY...................................................................................... 80
7.1
Specification of efficacy parameters................................................................................... 80
7.2
Methods and timing for assessing, recording, and analysing of efficacy parameters......... 80
7.2.1
Change on maximum clot firmness (mcf) measured by rotational thromboeslatography 
(ROTEM)............................................................................................................................ 80
7.2.2
Change on other thromboelastographic variables............................................................... 81
7.2.3
Change on standard coagulation tests ................................................................................. 81
7.2.4
change on thromboelastographic variables over time......................................................... 81
7.2.5
Change on standard coagulation tests over time................................................................. 81
8.
ASSESSMENT OF SAFETY........................................................................................... 81
8.1
Specification of safety parameters ...................................................................................... 81
8.2
Methods and timing for assessing, recording, and analysing of safety parameters ............ 82
8.2.1
Adverse events.................................................................................................................... 82
8.2.2
Vital signs ........................................................................................................................... 82
8.2.3
Physical assessment ............................................................................................................ 82

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8.2.4
Laboratory panels................................................................................................................ 82
8.2.5
Antibodies against fibrinogen determination (Immunogenicity Testing)........................... 83
8.2.6
Monitoring of Allergic/Hypersensitivity Reactions............................................................ 84
8.2.7
Monitoring of Thrombotic Events ...................................................................................... 84
8.2.8
Virology Testing ................................................................................................................. 84
8.3
Procedures for eliciting reports of and for recording and reporting adverse event and 
intercurrent illnesses ........................................................................................................... 85
8.3.1
Adverse event...................................................................................................................... 85
8.3.2
Causality of adverse event .................................................................................................. 85
8.3.3
Suspected Adverse drug reaction........................................................................................ 86
8.3.4
Severity of adverse event or suspected adverse drug reaction............................................ 86
8.3.5
serious adverse event .......................................................................................................... 86
8.3.6
Collection and reporting of adverse events and suspected adverse drug reactions............. 87
8.3.7
Timelines and reporting of serious adverse events ............................................................. 89
8.4
Type and duration of the follow-up of subjects after adverse events.................................. 89
9.
STATISTICS..................................................................................................................... 90
9.1
Statistical methods to be employed and timing of planned interim analysis(ses)............... 90
9.1.1
Statistical analysis of demographic data and baseline characteristics................................. 90
9.1.2
Statistical analysis of pharmacokinetics.............................................................................. 90
9.1.2.1 Analysis of PK concentration and dosing data ................................................................... 90
9.1.2.2 Calculation of PK parameters ............................................................................................. 90
9.1.2.3 Analyses of PK parameters................................................................................................. 90
9.1.3
Statistical analysis of efficacy............................................................................................. 90
9.1.3.1 Analysis of primary efficacy endpoint................................................................................ 91
9.1.3.2 Analysis of secondary efficacy endpoints........................................................................... 91
91
9.1.4
Statistical analysis of safety................................................................................................ 92
9.1.5
Timing of planned interim analysis..................................................................................... 94
9.2
Sample size determination .................................................................................................. 94
9.3
Level of significance........................................................................................................... 94
9.4
Criteria for the termination of the trial................................................................................ 94
9.5
Procedures for accounting for missing, unused, and spurious data .................................... 94
9.6
Procedures for reporting any deviation from the original statistical plan........................... 94
9.7
Selection of subjects to be included in the analyses ........................................................... 94
9.7.1
Population for pharmacokinetic analysis ............................................................................ 94
9.7.2
Population for statistical analysis of efficacy...................................................................... 95
9.7.3
Population for statistical analysis of safety......................................................................... 95
10.
DIRECT ACCESS TO SOURCE DATA/DOCUMENTS............................................. 95
11.
QUALITY CONTROL AND QUALITY ASSURANCE .............................................. 96
11.1
Quality control by the clinical trial monitoring team.......................................................... 96
11.2
Quality assurance by the clinical trial audit team ............................................................... 96
12.
ETHICS ............................................................................................................................. 96
12.1
Ethical considerations and ethics committee ...................................................................... 96

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12.2
Informed consent and information sheets ........................................................................... 97
12.3
Confidentiality .................................................................................................................... 97
13.
DATA HANDLING AND RECORD KEEPING........................................................... 98
13.1
Data collection and management ........................................................................................ 98
13.2
Record keeping ................................................................................................................... 98
14.
FINANCING AND INSURANCE ................................................................................... 98
15.
PUBLICATION POLICY................................................................................................ 99
REFERENCES............................................................................................................................. 100
IN-TEXT TABLES
TABLE  2-1 INVESTIGATIONAL PRODUCT............................................................................................... 28
TABLE  4-1 SCHEDULE OF PROCEDURES OF THE STUDY IN ADULT SUBJECTS............................ 43
TABLE  4-2 SCHEDULE FOR VIROLOGY TESTING (ADULT SUBJECTS ONLY) ................................ 45
TABLE  4-3 SCHEDULE OF PROCEDURES DURING DAY 0 (INFUSION VISIT) IN ADULT SUBJECTS
................................................................................................................................................................. 46
TABLE  4-4 SCHEDULE OF PROCEDURES OF THE STUDY IN PEDIATRIC SUBJECTS..................... 48
TABLE  4-5 SCHEDULE OF PROCEDURES DURING DAY 0 (INFUSION VISIT) IN PEDIATRIC 
SUBJECTS.............................................................................................................................................. 50
TABLE  4-6 BASELINE VIROLOGY SCHEDULE FOR DAY 0 .................................................................. 61
TABLE  4-7 VIROLOGY SCHEDULE FOR DAY 9 ...................................................................................... 70
TABLE  4-8 VIROLOGY SCHEDULE FOR DAY 14 .................................................................................... 71
TABLE  4-9 VIROLOGY SCHEDULE FOR DAY 21 ± 1 DAY VISIT.......................................................... 72
TABLE  4-10 VIROLOGY SCHEDULE FOR WEEK 4 ± 3 DAYS................................................................ 73
TABLE  4-11 VIROLOGY SCHEDULE FOR MONTH 3 ± 7 DAYS............................................................. 74
IN-TEXT FIGURE
FIGURE  4-1 OVERALL STUDY SCHEMA AND STUDY VISITS......................................................... 38
ANNEXES
ANNEX 1 MONITORING OF THROMBOTIC EVENTS RISK
ANNEX 2 MONITORING OF ALLERGIC/HYPERSENSITIVITY REACTIONS

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1.6
NAME AND TITLE OF INVESTIGATORS WHO ARE RESPONSIBLE FOR 
CONDUCTING THE TRIAL, AND ADDRESS AND TELEPHONE 
NUMBER OF TRIAL SITES
Flora Peyvandi, MD
Coordinating Investigator
Angelo Bianchi Bonomi Hemophilia and Thrombosis Center.
IRCCS Maggiore Hospital.
Via Pace 9, 20122.
Milan
Italy
Tel: 
Information for other centers and investigators can be found in the trial master file.
2.
BACKGROUND INFORMATION
2.1
NAME AND DESCRIPTION OF THE INVESTIGATIONAL PRODUCT
The following investigational product will be used in this clinical trial:
Table 2-1 Investigational product
INVESTIGATIONAL PRODUCT 
FIB Grifols
Separate primary conditioning materials for lyophilized powder and solvent:
- Vials containing 1.0 g of human FIB Grifols (powder for infusion)
- Vials containing 50 mL of sterile water for injection (solvent)
FIB Grifols is a lyophilized and sterile preparation of fibrinogen highly purified from 
human plasma, subjected to three specific pathogen elimination steps (solvent/detergent, 
nanofiltration, and heat treatment) during its purification performed by Instituto Grifols, 
S.A. (Barcelona, Spain). FIB Grifols has not been tested in human subjects.
2.2
SUMMARY OF FINDINGS FROM NONCLINICAL STUDIES AND 
CLINICAL TRIALS THAT ARE RELEVANT TO THE TRIAL
All nonclinical data related to efficacy and safety of FIB Grifols is summarized in Human 
Plasma-derived Intravenous Fibrinogen Grifols Investigator’s Brochure [1].
Regarding clinical data, the present clinical trial will constitute the first use of this product 
in human subjects.

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2.3
SUMMARY OF THE KNOWN AND POTENTIAL RISKS AND BENEFITS 
TO HUMAN SUBJECTS
Intended benefit of fibrinogen concentrates is to avoid hemorrhagic manifestations in 
subjects with fibrinogen deficiencies. Already licensed products are indicated for treatment 
of acute bleeding episodes and as replacement therapy in subjects with congenital 
deficiency of fibrinogen and bleeding tendency, for peri-operative prophylaxis and before 
or during pregnancy and obstetrics. [2, 3, 4]
Fibrinogen concentrates are also indicated [5] as complementary therapy to management of 
life threatening bleeding in cases of acquired hypofibrinogenaemia, eg:
1. Increased consumption of fibrinogen associated with otherwise uncontrolled life 
threatening bleeding in obstetric complications
2. Dilutional hypofibrinogenemia in, for example, trauma-patients with severe blood 
loss after massive replacement therapy with colloid and crystalloid solutions
3. Disorders of synthesis of coagulation factors – eg, severe liver parenchyma damage 
with fibrinogen deficiency
4. Increased consumption of fibrinogen associated with otherwise uncontrolled life 
threatening bleeding due to disseminated intravascular coagulation syndrome and 
hyperfibrinolysis
Potential risks associated with the use of other fibrinogen products in the market include but 
are not limited to: thrombotic events, including myocardial infarction, pulmonary embolism 
(PE), deep vein thrombosis (DVT) and arterial thrombosis and allergic-anaphylactic 
reactions. [2, 3, 4, 5]
Thrombotic events may occur spontaneously in subjects with congenital deficiency with or 
without the use of fibrinogen replacement therapy. Thrombotic events have been reported in 
subjects treated with fibrinogen concentrates. Subjects receiving fibrinogen concentrates 
should be closely monitored for signs and symptoms of thrombosis.
Since FIB Grifols and other licensed fibrinogen concentrates are prepared from human 
plasma, infectious diseases due to transmission of infective agents cannot be totally 
excluded. This also applies to pathogens of unknown nature. In the case of FIB Grifols, the 
risk of transmission of infective agents is, however, reduced by: 1) selection of donors by a 
medical interview and screening of individual donations and plasma pools for hepatitis B 
surface antigen (HBsAg) and antibodies to human immunodeficiency virus (HIV) and 
hepatitis C virus (HCV), 2) testing of plasma pools for HCV genomic material, and 3) 
inactivation/removal procedures included in the production process that have been validated 
using model viruses. These procedures are considered effective for HIV, HCV, hepatitis A
virus (HAV), parvovirus B19 (B19), and hepatitis B virus (HBV). [1] As with all products 
containing human origin proteins, allergic reactions may occur. Symptoms of allergic or 
early signs of hypersensitivity reactions include hives, generalized urticaria, tightness of the 
chest, wheezing and hypotension. More serious hypersensitivity reactions cannot be ruled 
out, including anaphylactic shock, in the product administration, especially when immune 
globulin A (IgA) deficient subjects who present antibodies against IgA are administered. 
Fibrinogen concentrates should not be administered in subjects with selective IgA 
deficiency and who have antibodies against IgA or in subjects with known marked 

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hypersensitivity to the active substance or to any of the excipients contained in the product, 
described in FIB Grifols Investigator’s Brochure [1].
In the case of replacement therapy with coagulation factors in other congenital deficiencies, 
antibody reactions have been observed, but there is currently no data with fibrinogen.
Other adverse reactions reported after treatment with fibrinogen concentrates are 
generalized reactions such as chills, fever, nausea and vomiting [2].
2.4
DESCRIPTION OF AND JUSTIFICATION FOR THE ROUTE 
ADMINISTRATION, DOSAGE, DOSAGE REGIMEN, AND TREATMENT 
PERIOD(S)
In order to exert its hemostatic properties, fibrinogen must be present intravascularly,
therefore the product is to be administered by slow intravenous infusion. The dose to be 
administered in the study (single-dose intravenous infusion of FIB Grifols at a dosage of 
70 mg/kg of body weight) is deemed sufficient to reach the generally accepted minimum 
threshold for hemostasis in subjects with congenital deficiency of not less than 1g of 
fibrinogen per liter [6].
The usual dosage and dosage regimen of chronic replacement therapy (prophylaxis in 
subjects with congenital fibrinogen deficiency and bleeding tendency) with human 
fibrinogen has not been yet clearly established. [5]
In this study, the rate of infusion is to be controlled by means of an infusion pump. Delivery 
will be performed at a rate not higher than 5 mL/minute (it is acceptable to titrate up to this 
rate at the investigator’s discretion). If an adverse event (AE) occurs during the infusion, 
the infusion rate may be reduced or the infusion interrupted until symptoms subside. 
Subsequently, the infusion may be resumed at a rate tolerated by the subject, but not 
exceeding 5 mL/minute. All subjects will be monitored at different time points after the 
infusion ends for any signs of AE.
2.5
COMPLIANCE WITH THE PROTOCOL, GOOD CLINICAL PRACTICE 
AND THE APPLICABLE REGULATORY REQUIREMENTS
This clinical trial will be conducted in accordance with the ethical principles that have their 
origins in the Declaration of Helsinki of the 18th World Medical Assembly, June 1964, and 
consecutive updates, in compliance with the approved protocol of the study, with any 
approved amendment of the protocol, in compliance with International Conference on 
Harmonisation Good Clinical Practices (ICH GCP, Topic E6), and in compliance with 
other applicable regulatory requirements. 
2.6
DESCRIPTION OF THE POPULATION TO BE STUDIED
Study population will be made up of adult and pediatric subjects with asymptomatic (non-
bleeding) congenital fibrinogen deficiency (afibrinogenemia).

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2.7
REFERENCE TO LITERATURE AND DATA THAT ARE RELEVANT TO
THE TRIAL AND THAT PROVIDE BACKGROUND FOR THE TRIAL
Human fibrinogen (factor I) is a soluble plasma glycoprotein with a molecular weight of 
330-340 kDa. The molecule is a hexamer containing two sets of three different chains (Aα, 
Bβ, γ)2 with three parent chains, α, β and γ, and fibrinopeptide A and fibrinopeptide B, 
respectively. Both fibrinopeptides are cleaved from fibrinogen by thrombin. [7, 8]
Fibrinogen is synthesized by hepatocytes in the liver [9] and is essential for hemostasis, 
wound healing, fibrinolysis, inflammation, angiogenesis, cellular and matrix interactions, 
and neoplasia. These processes involve the conversion of fibrinogen to fibrin, and often the 
interaction of fibrinogen with various proteins and cells. Normal plasma levels are about 
2.5 g fibrinogen/L of blood, however, concentrations of fibrinogen can increase by as much 
as 200-400% during times of physiological stress (primarily due to the actions of 
macrophage-derived interleukin-6, an acute phase reactant).
When fibrinopeptides A and B are cleaved from fibrinogen by thrombin, fibrin monomers 
are formed. The formed soluble fibrin monomers polymerize forming protofibrils. When 
protofibrils reach a sufficient length (usually about 600-800 nm), they aggregate laterally 
forming fibers. The fibrin clot is formed by branching of the fibers. [7] 
Initially, the fibrin polymers are linked by hydrogen and electrostatic bonds and the 
structure (unstable or non-intercrossed clot) is easily dissolved by chaotropic agents such as 
5M urea and proteolytic enzymes such as plasmin. The transglutaminase, activated factor 
XIII (FXIIIa), covalently binds specific glutamine residues in one fibrin molecule to lysine 
residues in another via isopeptide bonds, and covalent links are formed between the C-
terminal of the γ-chains. Thus, fibrin polymers are formed. Stable or intercrossed clots are 
formed when the fibrin mesh is covalently linked. This intercrossing of the fibrin polymers 
delays proteolytic degradation of the meshed clot, reinforces its mechanical properties, and 
the clot is stabilized against mechanical, chemical, and proteolytic insults.[7]
The concentration of fibrinogen circulating in normal plasma ranges from 2.0 to 4.5 g/L 
however, in subjects with various congenital or acquired conditions, the levels of clottable 
fibrinogen are markedly reduced or undetectable. Conditions of congenital fibrinogen 
deficiency include afibrinogenemia (complete absence or extremely low levels of plasma 
fibrinogen), hypofibrinogenemia (reduced concentration (<150 mg/dL) of structurally 
normal plasma fibrinogen), and dysfibrinogenemia (normal plasma levels of abnormal or 
dysfunctional fibrinogen molecules). Qualitative and quantitative abnormalities can also co-
exist as hypodysfibrinogenemia. [10, 11, 12]
Congenital afibrinogenemia is a rare coagulation disorder usually with an autosomal 
recessive mode of inheritance. According to the literature, in the Western countries its 
prevalence is estimated to be 1 subject per million people. In countries or regions with 
higher rates of consanguinity, this numbers may be increased. It is characterized by 
moderate to severe bleeding manifestations that often start at birth with uncontrolled 
umbilical cord hemorrhages. Bleeding may occur spontaneously or after minor trauma or 
small surgical intervention, into skin, mucosa, muscles, gastrointestinal tract or the central 
nervous system, with intracranial hemorrhage being the major cause of death.[10, 11, 13, 
14, 15] Spontaneous spleen rupture has been also reported.[16] Affected women usually 
have menorrhagia and pregnancy is also frequently interrupted during the first trimester due 

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to the lack of proper stabilization of placental-maternal attachment by fibrinogen.[17, 18, 
19, 20] In some cases, paradoxical arterial and venous thromboembolic complications may 
occur. [21, 22, 23, 24, 25] Typical laboratory findings in subjects with congenital 
afibrinogenemia include prolonged prothrombin time (PT), partial thromboplastin time, 
thrombin time (TT), and reptilase time. Mutations leading to congenital afibrinogenemia 
have been discovered in all three fibrinogen chains although the majority of subjects seem 
to have mutations in the Aα gene. [26, 27, 28, 29]
Clinical symptoms of hypofibrinogenemia are usually milder compared with 
afibrinogenemia, and the condition is frequently combined with a dysfibrinogenemia that is 
characterized with an abnormal fibrinogen variant (hypodysfibrinogenemia). Several 
missense mutations in the three fibrinogen genes have been identified as the cause of 
dysfibrinogenemia and hypofibrinogenemia that lead to abnormal gene expression resulting 
in the decreased fibrinogen concentration or dysfunctional fibrinogen molecules. [6, 12]
Subjects with any of these conditions are treated for bleeding either by substitution with a 
fibrinogen concentrate in countries where it is available, with cryoprecipitate (Cohn I 
fraction) or with fresh frozen plasma. [6, 10, 30]
Theoretically, fibrinogen concentrates would be the preferred option because of 
demonstrated and potential advantages when compared with cryoprecipitate and plasma in 
terms of safety, efficacy, access to timely intervention, and precise dosing.
Potential disadvantages associated with the use of cryoprecipitate and plasma would be:
1.
Immune reactions including but not limited to allergic reactions, 
anaphylactic/anaphylactoid reactions, intravascular hemolysis and transfusion-
related acute lung injury (TRALI)
2.
Fluid overload due to the amount of volume needed for achieving required 
fibrinogen levels
3.
Viral infection risks due to the lack of viral inactivation/removal steps
4.
Precise dosing not feasible due to the lack of precise fibrinogen content and volume 
measurement
5.
Preparation time as these products must be thawed, pooled and eventually ABO 
blood type matched prior to infusion.
Due to the low prevalence of this disease, there is an absolute lack of adequately well-
designed, controlled studies in subjects with active bleeding and the only available data on 
fibrinogen concentrates’ efficacy come from anecdotal case reports and retrospective 
studies and surveys. [13, 16, 19, 31, 32, 33, 34, 35, 36, 37, 38, 39] From these studies it can 
be concluded that the clinical efficacy of fibrinogen concentrates in achieving hemostasis in 
actively bleeding subjects and subjects at high risk situations (eg, undergoing surgery) is 
adequate and equivalent to those achieved by subjects treated with cryoprecipitate. 
To date, the adequate prophylactic regimen to treat subjects with congenital deficiency and 
severe life-threatening bleeding tendency has not been yet clearly established and its 
efficacy remains controversial, although positive trends have been reported from 
retrospective studies and case reports. [6, 13, 18, 36]

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Other clinical trials have studied the safety, pharmacokinetics and pharmacodynamics of 
fibrinogen concentrates in congenitally deficient subjects. [2, 40, 41] These studies showed 
a good correlation between fibrinogen levels determined by functional (Clauss) and antigen 
methods and confirmed previous data indicating a terminal half-life (t1/2) of 3.0 to 5.3 days. 
For other PK parameters (volume of distribution [Vd], clearance [Cl], incremental in vivo 
recovery [IVR]), larger differences were found depending on the product used, reporting in 
vivo recoveries of 94% in one case and 54% in the other and 2-3 fold differences in Vd and 
Cl. For the same parameters, large differences (2-fold) were also found in terms of 
between-subject variability.
In all cases, fibrinogen capacity for restoring normal hemostasis was demonstrated by 
normalization of previously abnormal (prolonged) standard coagulation tests: TT, PT, and 
activated partial thromboplastin time (aPTT) values.
Hemostatic efficacy of treatment with fibrinogen concentrates has also been evaluated both 
in vitro and in vivo as well as in clinical studies in congenital and acquired fibrinogen 
deficiency. [42, 43, 44, 45, 46, 47, 48] Many of these studies have used pre-infusion and 
post-infusion rotational thromboelastometry (ROTEM) parameters, mainly maximum clot 
firmness (MCF) to demonstrate hemostatic efficacy. MCF is highly dependent on the 
concentration and activity of platelets and fibrinogen and is considered a functional 
marker/surrogate endpoint indicative of a subject’s hemostatic competency. Many studies 
and papers have evaluated the correlation of thromboelastographic parameters with clinical 
bleeding occurrence and support the increasing use of this device for bedside monitoring of 
high-risk subjects in order to provide guidance for use of blood components and hemostatic 
products administration. [49, 50, 51, 52, 53, 54, 55, 56, 57, 58]
From these studies, as well as from years of clinical experience in the use of fibrinogen 
concentrates, it has been demonstrated that fibrinogen infusions were well tolerated and 
fibrinogen concentrates have a good safety profile.
The biggest concern with the use of this kind of product in subjects with congenital 
afibrinogenemia is the risk of thrombotic events. The occurrence of arterial and venous 
thromboembolism in this population with or without the use of fibrinogen-containing 
products has been extensively reported in the literature. [13, 14, 21, 22, 23, 24, 25, 59, 60]
It has been speculated that in subjects lacking fibrinogen but with the hemostatic system 
otherwise intact, platelet aggregation can occur. Interestingly, a study performed on mice 
lacking fibrinogen demonstrated that clots rich in platelets and von Willebrand factor were 
formed with no differences with respect to wild type mice in platelet deposition or 
thrombus initiation phases. However, during the propagation phase, where fibrinogen is 
supposed to exert its function, growing clots did not resist shear stress and were stripped off 
and carried away causing downstream from the injury site embolization. [61]
Equally, thrombin generation is not disturbed in subjects suffering from isolated fibrinogen 
deficiency and the lack of fibrinogen to sequester the formed thrombin molecules into the 
fibrin (antithrombin I) clots would then cause elevated levels of circulating thrombin. In 
this regard, some studies and case reports have indicated that fibrinogen deficient subjects 
have increased levels of some markers of activation of coagulation as prothrombin 
activation fragments or thrombin-antithrombin complexes. This baseline overcoming of 
natural anticoagulation proteins as antithrombin III (ATIII) could explain the apparent 
reported lack of efficacy of heparins for prevention of thrombotic events in subjects with 

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fibrinogen congenital deficiency and the success when switching to treatment with direct 
thrombin inhibitors. [62, 63]
Due to the high frequency of fibrinogen-deficient subjects that suffer from life-threatening 
haemorrhagic events and the confines of having only a few approved products in the 
marketplace, Grifols has planned a clinical development program for FIB Grifols in 
subjects with congenital afibrinogenemia. The present study designed to obtain PK, safety, 
and hemostatic efficacy data is the first trial of the clinical program.
3.
TRIAL OBJECTIVES AND PURPOSES
1. To evaluate the PK profile of FIB Grifols following single-dose administration of 70 
mg/kg body weight.
2. To evaluate hemostatic efficacy of FIB Grifols by means of thromboelastographic 
MCF values’ comparison at baseline and one hour after investigational product 
administration. Other thromboelastographic measures as well as standard 
coagulation tests measured at different time points will also serve as secondary 
 
 efficacy endpoints.
3. To evaluate the safety of FIB Grifols. Clinical safety, virus safety, and 
immunogenicity will be assessed in this clinical trial. Safety variables include AEs, 
vital signs, physical assessments, laboratory tests, viral markers, and antibodies 
against human fibrinogen.
4.
TRIAL DESIGN
4.1
PHARMACOKINETIC ENDPOINTS
Plasma fibrinogen activity will be determined by the activity (Clauss) method and antigen 
method (enzyme-linked immunosorbent assay [ELISA]) in the central laboratory of the 
study. Fibrinogen activity levels will be determined immediately before infusion and at 
different time points after infusion.
The following PK parameters will be calculated for fibrinogen by a non-compartmental PK 
method determined from plasma levels before and at 30 minutes, 1 hour, 2 hours, 4 hours, 
8 hours, 1 day (24 hours), 2 days (48 hours), 4 days (96 hours), 6 days (144 hours), 9 days 
(216 hours), and 14 days (336 hours) after the end of the infusion: 
1. Area under the curve (AUC) including AUC from zero to 14 days (AUC0-14days) and 
AUC from zero to infinity (AUC0-∞)
2. Maximum plasma concentration (Cmax)
3. Time to the observed maximum plasma concentration (tmax)
4. Half-life (t1/2)
5. Mean residence time (MRT)
6. Volume of distribution (Vd)
7. Clearance (Cl)

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-
Blood extraction and sample processing for shipment.
-
Vital signs measurement (including heart rate [HR], respiration rate [RR], 
systolic and diastolic blood pressure [SBP and DBP], and temperature [T]).
-
Subject interview and recording of potential AEs to be communicated to the 
principal investigator.
-
Concomitant medications recording.
The overall study schema is shown in Figure 4-1.

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Screening Visit
(Day -21)
Safety Follow-up (up to 3 Month)
Day 0
Study Drug 
Infusion
PK, Efficacy, and Clinical Safety Evaluation
Day 0 to Day 14
  
Week 4 
visit 
Month 3 visit
(adult subjects only)
Day 1 
visit 
Day 14 
visit 
Day 6 
visit 
Day 21
visit 
Day 9 
visit 
Day 4 
visit 
Overall Study Schema
Study Visits
FIB Grifols 
- Adult Subjects: N = 10
- Single dose infusion: 70 mg/kg
Screening Visit
(Day -21)
Safety Follow-
up
Safety 
Assessment in 
Adult Subjects
FIB Grifols
- Pediatric Subjects: N = 10
- Single dose infusion: 70 mg/kg
Screening Visit
(Day -21)
Safety Follow-
up
Day 2 
visit 
Figure 4-1 Overall Study Schema and Study Visits

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4.4
MEASURES TO MINIMIZE/AVOID BIAS
4.4.1
RANDOMIZATION
This is a single-arm study and no randomization is applied.
4.4.2
BLINDING
This is an open-label study. No blinding is required.
4.5
DESCRIPTION OF THE INVESTIGATIONAL PRODUCT
4.5.1
INVESTIGATIONAL PRODUCT IDENTIFICATION
Drug name:
FIB Grifols 1.0 g powder and solvent for infusion
ATC code:
B02BB01.
Active principle:
Human fibrinogen 1.0 g/vial.
Pharmaceutic form:
Vials containing 1.0 g of FIB Grifols powder and vials 
containing 50 ml of sterile water as solvent for infusion.
Manufacturer and sponsor:
Instituto Grifols, S.A.
Can Guasch, 2.
08150 Parets del Vallès.
Barcelona
Spain
4.5.2
DOSAGE AND DOSAGE REGIMEN OF THE INVESTIGATIONAL PRODUCT
4.5.2.1
Dosage of investigational product
Dosage and regimen:
70 mg/kg body weight single dose
Administration via:
Intravenously
Administration form:
Investigational product will be prepared and administered as 
specified in the protocol Section 4.5.4
4.5.2.2
Dosage regimen of investigational product
A single infusion of fibrinogen concentrate at a dosage of 70 mg/kg body weight will be 
administered.
Only qualified health staff will administer the investigational product at the investigational 
site. Compliance with treatment will be recorded in the Subject’s Specific Administration 
Log by the health staff. 
During the treatment infusion, the subject’s vital signs (temperature [T]; respiratory rate 
[RR]; heart rate [HR]; systolic blood pressure [SBP]; diastolic blood pressure [DBP]) will be 
monitored and recorded in the Day 0 Vital Signs worksheet as follows: 1) within 60 

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minutes before the beginning of the infusion; 2) at the beginning of the infusion, 3) every 
20 ± 5 minutes during the infusion; 4) at the completion of the infusion and 5) within one 
hour after conclusion of the infusion.
The rate of infusion will be controlled by means of an infusion pump. The investigational 
medicinal product must be at room temperature and delivery will be performed at a constant 
rate not exceeding 5 mL/minute (it is acceptable to titrate up to this rate at the investigator’s 
discretion). If an AE occurs during the infusion, the infusion rate may be reduced or the 
infusion may be interrupted until symptoms subside. Then, the infusion may be resumed up 
to a rate tolerated by the subject, but not exceeding 5 mL/minute.
4.5.3
PACKAGING AND LABELLING OF THE INVESTIGATIONAL PRODUCT
FIB Grifols will be supplied in type II glass vials containing 1 g of human fibrinogen 
(powder for infusion) and a vial containing 50 mL of water for injection (solvent). 
Packaging and labeling of FIB Grifols supplies will comply with local regulatory 
requirements and will be translated into local languages when required per local 
regulations.
IMPORTANT:
INVESTIGATIONAL PRODUCT PACKAGINGS SHOULD BE STORED FOR 
ACCOUNTABILITY RECONCILIATION BY THE CLINICAL MONITOR BEFORE 
BEING DESTROYED.
4.5.4
STORAGE, PREPARATION, DISPENSATION AND ADMINISTRATION OF 
THE INVESTIGATIONAL PRODUCT
Instituto Grifols, S.A. will supply vials for intravenous administration of investigational 
product (FIB Grifols). 
A drug repository company may be contracted for drug distribution to investigational sites 
where applicable. Investigational product will be maintained within respective 
recommended temperature conditions.
4.5.4.1
Storage and preparation of the investigational product
FIB Grifols must be stored between 2ºC and 25C and must not be frozen. Moreover, FIB 
Grifols must be kept in a secure room with access restricted to necessary study site 
personnel. 
The pharmacist must keep the investigational product accountability by means of the 
Investigational Site Specific Drug Accountability Log. 
FIB Grifols solution preparation:
FIB Grifols solution will be prepared at investigational site pharmacy by the pharmacist 
responsible of the investigational product or by qualified personnel delegated, as indicated 
in the Human Plasma-derived Intravenous Fibrinogen Grifols Investigator’s Brochure [1].

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The product should be administered intravenously within 12 hours after reconstitution with 
the solvent supplied. Meanwhile, it should be stored between 2ºC and 25C, for a maximum 
time of 12 hours.
Total dose or volume of the investigational product to be administered will be calculated 
according to the following formula:
Total dose (mg) = Body weight (kg) × 70 mg/ kg
Approximate total volume (mL) =  Total dose (mg) × 0.05 mL/mg
IMPORTANT: 
INVESTIGATIONAL PRODUCT PACKAGINGS SHOULD BE STORED FOR 
ACCOUNTABILITY RECONCILIATION BY THE CLINICAL MONITOR BEFORE 
BEING DESTROYED.
4.5.4.2
Dispensation and administration of the investigational product 
Investigational product dispensation:
The pharmacist or the delegated qualified person is responsible for preparing the 
investigational product and must complete a dispensation register (Subject Specific 
Dispensing Log). The investigational product will be delivered to the staff performing the 
infusion.
Investigational product administration:
Qualified health staff will administer the investigational product, keeping maximum 
asepsis, at the investigational site. These qualified health staff must also complete an 
administration register in order to check treatment compliance (Subject’s Specific 
Administration Log).
The investigational medicinal product to be administered must be at room temperature
before administration and the administration should be performed by slow intravenous 
infusion at an infusion rate not exceeding 5 mL/minute. It is advisable to start the infusion 
with a slow rate and, if well-tolerated by the subject, then to incrementally increase it. 
If the administration is problematic (ie, AEs or intolerance occurs), the rate of 
administration should be reduced, and even temporarily stopped until symptoms subside. In 
case of an anaphylactic shock, the administration of the product must be immediately 
discontinued, and the hospitals/centers current specific guidelines for shock therapy should 
be followed.
4.6
EXPECTED DURATION OF SUBJECT’S PARTICIPATION AND
DESCRIPTION OF THE SEQUENCE AND DURATION OF THE TRIAL 
PERIOD
The total estimated maximum duration of subject’s participation could be approximately 
3 months and 3 weeks for adult subjects, starting with the Screening Visit (within 21 days 

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before Day 0). After infusion of the investigational product on Day 0, the PK, efficacy, and 
clinical safety evaluation period (Day 0 to Day 14) will commence. The subjects will be 
followed up for up to 3 months for safety, virology, and immunogenicity assessments. 
Pediatric subjects will not undergo Month 3 assessments and their study participation will 
conclude after the Week 4 Visit.
Clinical trial consists of:
1. Screening Visit: up to 21 days before the infusion visit (Day 0)
2. Infusion Visit: administration of the investigational medicinal product on Day 0
3. PK, Efficacy, and Clinical Safety Evaluation Visits: Day 0 to Day 14
4. Follow-Up Period up to 3 months: including safety follow-up visits (virology and 
immunogenicity assessments) on Day 21 1 day, Week 4 ± 3 days
5. Month 3 ± 7 days (adult subjects only)
Clinical trial finalization will coincide with the last visit of the last subject included in the 
study.
Schedules of procedures for adult subjects are provided in Table 4-1, Table 4-2, and 
Table 4-3. Schedules of procedures for pediatric subjects are provided in Table 4-4 and 
Table 4-5.

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Table 4-1 Schedule of Procedures of the Study in Adult Subjects
                                    Visits
Procedures and 
assessments
Screening Visit 
(up to 21 days 
prior to 
infusion visit)
Infusion 
Visit*
Pharmacokinetic, Efficacy, and Clinical Safety Evaluation 
Visits                                             
Safety, Virology, and 
Immunogenicity Follow-Up Visits 
Day 0   
Day 1 
Day 2 
Day 4 
Day 6 
Day 9 
Day 14 Day 21 ± 1 
Day 
Week 4 ± 3 
Days 
Month 3 ± 7
Days 
Informed Consent
X
HIPAA1
X
Demographics2
X
Medical History
X
Height and Weight
X
Inclusion/Exclusion Criteria
X
X
Physical Assessment
X
X
X
X
Medications3
X
X
X
X
X
X
X
X
X
X
X
Pregnancy Test4
XB
Serum Clinical Chemistry5
XB
X
X
X
Hematology6
X
X
X
X
Fibrinogen Levels (Clauss and Antigen)
XA
XB,C
XC
XC
XC
XC
XC
XC
Rotational Thromboelastometry7
X
X
X
X
X
X
Standard Coagulation Tests8
X
X
X
X
X
X
Markers of Activation of Coagulation9
X
X
X
X
X
X
Immunogenicity Testing10
X
X
X
Viral Panel11
X
X
X
X
X
X
Vital Signs12
X
X
X
X
Adverse Events
X
X
X
X
X
X
X
X
X
X
Thrombotic Events Risk Assessment
(including Wells Score)
X
X
X
X
X
X
X
X
X
Allergic/hypersensitivity Reactions 
Risk Assessment
X
X
X
X
X
X
X
X
X
Retention Sample13
X
X
X
X
X
X
* See specific Day 0 flowchart for adult subjects (Table 4-3)

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1.
Health Information and Accountability Act authorization form (if applicable).
2.
Date of birth, gender, and ethnic origin.
3.
Prior medications for the last 3 months (Screening Visit only) and concomitant medications.
4.
Human chorionic gonadotropin-based blood or urine assay for women of childbearing potential.
5.
Creatinine, blood urea nitrogen (BUN), total bilirubin (TB), alkaline phosphatase (ALP), alanine aminotransferase (ALT), aspartate aminotransferase (AST), lactate 
dehydrogenase (LDH), glucose, sodium, potassium, chloride, and calcium.
6.
Red blood cells (RBC) count, hemoglobin (Hgb), hematocrit (Hct), mean corpuscular hemoglobin (MCH), mean corpuscular hemoglobin concentration (MCHC), mean 
corpuscular volume (MCV), white blood cell (WBC) count and differential, and platelet count.
7.
Thromboelastographic parameters: clotting time (CT), clot formation time (CFT), maximum clot firmness (MCF), and alpha angle (α).
8.
Thrombin time (TT), prothrombin time (PT), and activated partial thromboplastin time (aPTT).
9.
D-dimer, antithrombin III (ATIII), thrombin-antithrombin III complex (TAT), prothrombin fragments F1+2 (F1+2)
10. Antibodies to fibrinogen. Day 0 sample to be collected pre-infusion. For details, see specific Day 0 flowchart for adult subjects (Table 4-3).
11. Serology and nucleic acid amplification technology (NAT) testing for virus safety. For details, see the corresponding Schedule for Virology Testing (Table 4-2).
12. Heart rate (HR), respiration rate (RR), systolic and diastolic blood pressure (SBP and DBP), and temperature (T).
13. A serum/plasma retention sample will be kept frozen at -70ºC.
ASites that cannot perform fibrinogen levels determinations (by both Clauss and antigen method) locally will have a blood sample taken at Screening Visit 14 days prior to 
Baseline Visit and have it analyzed for this parameter by both methods at the central laboratory of the study for verification of the eligibility against the Inclusion/Exclusion  
criteria. In these cases, the sample for assessing the Inclusion/Exclusion criteria will not be taken at Baseline Visit. Samples for pharmacokinetic (PK) will still be taken at 
Baseline Visit.
BBaseline pregnancy test (when applicable), serum clinical chemistry and fibrinogen levels (when applicable) results from samples drawn within 24 hours prior to the 
scheduled infusion and tested locally must be available prior to infusion for verification of the eligibility against the Inclusion/Exclusion criteria.
CBaseline (and subsequent) fibrinogen levels for PK calculations (Clauss and antigen methods [ELISA]) will be measured at the central laboratory of the study.

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Table 4-2 Schedule for Virology Testing (Adult Subjects Only)
Visits
Viruses
Viral Panel
Day 0 Baseline (within 
60 min prior to the 
infusion)
Day 9A
Day 14A
Day 21 ± 1 Day A
Week 4 ± 3 Days A
Month 3 ± 7 Days A
Serology
NAT*
Serology
NAT
Serology
NAT
Serology
NAT
Serology
NAT
Serology
NAT
Hepatitis A Virus 
(HAV)
X1
(IgM&IgG)
X1
X
X
(IgM&IgG)
X
X
(IgM&IgG)
X
Hepatitis B Virus 
(HBV)
X1,2
X1
X
X
X4
X
X4
Hepatitis C Virus 
(HCV)
X1
X1
X
X5
X
Human 
Immunodeficiency 
Viruses, types 1 
and 2 (HIV-1/2)
X1
X1,3
X3
X6
X3
Parvovirus B19
X1
(IgM&IgG)
X1
X  
(IgM&IgG)
X
X 
(IgM&IgG)
X
1. Sample will be always analyzed.
2. Total anti-HBc (IgM & IgG)
3. NAT for HIV-1 only
4. HBsAg
5. In case of HCV positive antibody screen, a recombinant immunoblot assay will be performed.
6. In case of HIV positive antibody screen, a Western blot assay for HIV-1 will be performed.
A Samples would be analyzed for a particular virus only in the event of negative results of analysis of NAT, IgM, and IgG for that particular virus performed on all previous 
samples.
* NAT = Nucleic acid amplification technology

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Table 4-3 Schedule of Procedures During Day 0 (Infusion Visit) in Adult Subjects
Visits
Procedures and assessments
Baseline
(prior to infusion)
During infusion
After Infusion
30 minutes
1 hour
2 hours
4 hours
8 hours
Inclusion/Exclusion Criteria
X
Height and weight
X
Physical Assessment
X
X
Medications1
X
X
X
X
X
X
X
Pregnancy Test2
XA
Serum Clinical Chemistry3
XA
Hematology4
X
Fibrinogen Levels (Clauss and Antigen)
XA,B
X
X
X
X
X
Rotational Thromboelastometry5
X
X
X
X
Standard Coagulation Tests6
X
X
X
X
Markers of Activation of Coagulation7
X
X
X
Immunogenicity Testing
X
Viral Panel8
X
Vital Signs9
X
X
X
Adverse Events
X
X
X
X
X
X
X
Thrombotic Events Risk Assessment
X
X
X
Allergic/hypersensitivity Reactions Risk 
Assessment
X
X
X
Retention Sample10
X
X
X
Footnotes continued on next page

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1.
Concomitant medications.
2.
Human chorionic gonadotropin (HCG)-based blood or urine assay for women of childbearing potential.
3.
Creatinine, blood urea nitrogen (BUN), total bilirubin (TB), alkaline phosphatase (ALP), alanine aminotransferase (ALT), aspartate aminotransferase (AST), lactate 
dehydrogenase (LDH), glucose, sodium, potassium, chloride, and calcium.
4.
Red blood cells (RBC) count, hemoglobin (Hgb), hematocrit (Hct), mean corpuscular hemoglobin (MCH), mean corpuscular hemoglobin concentration (MCHC), mean 
corpuscular volume (MCV), white blood cell (WBC) count and differential and platelet count.
5.
Thromboelastographic parameters: clotting time (CT), clot formation time (CFT), maximum clot firmness (MCF), and alpha angle (α)
6.
Thrombin time (TT), prothrombin time (PT) and activated partial thromboplastin time (aPTT).
7.
D-dimer, antithrombin III (ATIII), thrombin-antithrombin III complex (TAT), prothrombin fragments F1+2 (F1+2)
8.
Serology and nucleic acid amplification technology (NAT) testing for virus safety. For details, see the corresponding Schedule for Virology Testing (Table 4-2).
9.
Heart rate (HR), respiration rate (RR), systolic and diastolic blood pressure (SBP and DBP), and temperature (T).
10. A serum/plasma retention sample will be kept frozen at -70ºC.
A The results from baseline pregnancy test (when applicable), serum clinical chemistry and fibrinogen levels (when applicable) from samples drawn within 24 hours prior to 
the scheduled infusion and tested locally must be available prior to infusion for verification of the eligibility against the Inclusion/Exclusion criteria. In case fibrinogen 
levels determination for verification of the Inclusion/Exclusion criteria is performed at the Screening Visit, this sample will not be taken at Baseline Visit. Sample for PK 
will still be taken at Baseline Visit.
B Baseline fibrinogen levels for PK calculations (Clauss and antigen methods [ELISA]) will be measured at the central laboratory of the study.

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Table 4-4 Schedule of Procedures of the Study in Pediatric Subjects
Visits
Procedures and 
assessments
Screening Visit 
(up to 21 days 
prior to 
infusion visit)
Infusion 
Visit*
Pharmacokinetic, Efficacy, and Clinical Safety Evaluation 
Visits                                             
Safety Follow-Up Visits11
Day 0   
Day 1 
Day 2 
Day 4 
Day 6 
Day 9 
Day 14 
Day 21 ± 1 Day 
Week 4 ± 3 Days 
Informed Consent
X
HIPAA1
X
Demographics2
X
Medical History
X
Height and Weight
X
Inclusion/Exclusion Criteria
X
X
Physical Assessment
X
X
X
X
Medications3
X
X
X
X
X
X
X
X
X
X
Pregnancy Test4
XB
Serum Clinical Chemistry5
XB
X
X
X
Hematology6
X
X
X
X
Fibrinogen Levels (Clauss and Antigen)
XA
XB,C
XC
XC,12
XC
XC
XC
XC,12
Rotational Thromboelastometry7
X
Standard Coagulation Tests8
X
Vital Signs9
X
X
X
X
Adverse Events
X
X
X
X
X
X
X
X
X
X
Thrombotic Events Risk Assessment 
(including Wells Score)
X
X
X
X
X
X
X
X
X
Allergic/hypersensitivity Reactions 
Risk Assessment
X
X
X
X
X
X
X
X
X
Retention Sample10
X

See specific Day 0 flowchart for pediatric subjects (Table 4-5).

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1.
Health Information and Accountability Act (HIPAA) authorization form (if applicable).
2.
Date of birth, gender, and ethnic origin.
3.
Prior medications for the last 3 months (Screening Visit only) and concomitant medications.
4.
Human chorionic gonadotropin (HCG)-based blood or urine assay for females of childbearing potential.
5.
Creatinine, blood urea nitrogen (BUN), total bilirubin (TB), alkaline phosphatase (ALP), alanine aminotransferase (ALT), aspartate aminotransferase (AST), lactate 
dehydrogenase (LDH), glucose, sodium, potassium, chloride, and calcium.
6.
Red blood cells (RBC) count, hemoglobin (Hgb), hematocrit (Hct), mean corpuscular hemoglobin (MCH), mean corpuscular hemoglobin concentration (MCHC), mean 
corpuscular volume (MCV), white blood cell (WBC) count and differential, and platelet count.
7.
Thromboelastographic parameters: clotting time (CT), clot formation time (CFT), maximum clot firmness (MCF), and alpha angle (α).
8.
Thrombin time (TT), prothrombin time (PT), and activated partial thromboplastin time (aPTT).
9.
Heart rate (HR), respiration rate (RR), systolic and diastolic blood pressure (SBP and DBP), and temperature (T).
10. A serum/plasma retention sample will be kept frozen at -70ºC.
11. Pediatric subjects will not undergo Month 3 virology and immunogenicity follow-up visits.
12. Not applicable for pediatric subjects weighing <30 kg.
ASites that cannot perform fibrinogen levels determinations (by both Clauss and antigen method) locally will have a blood sample taken at Screening Visit 14 days prior to 
Baseline Visit and have it analyzed for this parameter by both methods at the central laboratory of the study for verification of the eligibility against the Inclusion/Exclusion  
criteria. In these cases, the sample for assessing the Inclusion/Exclusion criteria will not be taken at Baseline Visit. Samples for pharmacokinetic (PK) will still be taken at 
Baseline Visit.
BBaseline pregnancy test (when applicable), serum clinical chemistry and fibrinogen levels (when applicable) results from samples drawn within 24 hours prior to the 
scheduled infusion and tested locally must be available prior to infusion for verification of the eligibility against the Inclusion/Exclusion criteria.
CBaseline (and subsequent) fibrinogen levels for PK calculations (Clauss and antigen methods [ELISA]) will be measured at the central laboratory of the study.

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Table 4-5 Schedule of Procedures During Day 0 (Infusion Visit) in Pediatric Subjects 
Visits
Procedures and assessments
Baseline
(prior to infusion)
During infusion
After Infusion
30 minutes
1 hour
2 hours
4 hours
8 hours
Inclusion/Exclusion Criteria
X
Height and Weight
X
Physical Assessment
X
X
Medications1
X
X
X
X
X
X
X
Pregnancy Test2
XA
Serum Clinical Chemistry3
XA
Hematology4
X
Fibrinogen Levels (Clauss and Antigen)
XA,B
X9
X
X9
X9
X
Rotational Thromboelastometry5
X
X
Standard Coagulation Tests6
X
X
Vital Signs7
X
X
X
Adverse Events
X
X
X
X
X
X
X
Thrombotic Events Risk Assessment
X
X
X
Allergic/hypersensitivity Reactions Risk 
Assessment
X
X
X
Retention Sample8
X
Footnotes continued on next page

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1.
Concomitant medications.
2.
Human chorionic gonadotropin (HCG)-based blood or urine assay for females of childbearing potential.
3.
Creatinine, blood urea nitrogen (BUN), total bilirubin (TB), alkaline phosphatase (ALP), alanine aminotransferase (ALT), aspartate aminotransferase (AST), lactate 
dehydrogenase (LDH), glucose, sodium, potassium, chloride, and calcium.
4.
Red blood cells (RBC) count, hemoglobin (Hgb), hematocrit (Hct), mean corpuscular hemoglobin (MCH), mean corpuscular hemoglobin concentration (MCHC), mean 
corpuscular volume (MCV), white blood cell (WBC) count and differential and platelet count.
5.
Thromboelastographic parameters: clotting time (CT), clot formation time (CFT), maximum clot firmness (MCF), and alpha angle (α).
6.
Thrombin time (TT), prothrombin time (PT) and activated partial thromboplastin time (aPTT).
7.
Heart rate (HR), respiration rate (RR), systolic and diastolic blood pressure (SBP and DBP), and temperature (T).
8.
A serum/plasma retention sample will be kept frozen at -70ºC.
9.
Not applicable for pediatric subjects weighing <30 kg.
A The results from baseline pregnancy test (when applicable), serum clinical chemistry and fibrinogen levels (when applicable) from samples drawn within 24 hours prior to 
the scheduled infusion and tested locally must be available prior to infusion for verification of the eligibility against the Inclusion/Exclusion criteria. In case fibrinogen 
levels determination for verification of the Inclusion/Exclusion criteria is performed at the Screening Visit, this sample will not be taken at Baseline Visit. Sample for PK 
will still be taken at Baseline Visit.
B Baseline fibrinogen levels for PK calculations (Clauss and antigen methods [ELISA]) will be measured at the central laboratory of the study.

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4.6.1
DESCRIPTION OF THE CLINICAL TRIAL PROCEDURES
4.6.1.1
Medical history
A complete medical history will be carried out for all subjects at the Screening Visit. 
4.6.1.2
Physical assessment
A physical assessment by body systems will be performed by the investigator or its 
designee (eg, a medical doctor designated as sub-investigator) at:
1. Screening Visit
2. Infusion Visit (Day 0): immediately prior (within 60 minutes prior) to the scheduled 
infusion and 8 hours post-infusion
3. Day 1 Visit (24 hours post-infusion)
4. Week 4 Visit
4.6.1.3
Height and weight
Height and weight will be measured for all subjects at Baseline Visit. The weight value will 
be used for calculation of dose of IMP to be administered.
4.6.1.4
Serum clinical chemistry
Laboratory test will include creatinine, blood urea nitrogen (BUN), total bilirubin (TB), 
alkaline phosphatase (ALP), alanine aminotransferase (ALT), aspartate aminotransferase 
(AST), lactate dehydrogenase (LDH), glucose, sodium, potassium, chloride, and calcium.
Blood specimens for laboratory tests will be collected for every subject at:
1. Infusion Visit (Day 0):
A sample will be drawn within 24 hours prior to the scheduled infusion. In the case 
of the infusion, the sample will be also analyzed in due course locally in order to 
have the results available immediately prior to the scheduled infusion in order to 
verify that the subject fulfills the inclusion/exclusion criteria.
2. Day 1 (24 hours post-infusion)
3. Day 6 (144 hours post-infusion)
4. Day 14 (336 hours post-infusion)
All samples will be analyzed at the central laboratory.
4.6.1.5
Hematology
Laboratory test will include complete blood count (CBC): red blood cells (RBC) count, 
hemoglobin (Hgb), hematocrit (Hct), mean corpuscular hemoglobin (MCH), mean 
corpuscular hemoglobin concentration (MCHC), mean corpuscular volume (MCV), white 
blood cell (WBC) count and differential, and platelet count.
Blood specimens for laboratory tests will be collected for every subject at:
1. Infusion Visit (Day 0): within 24 hours prior to the scheduled infusion

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2. Day 1 (24 hours post-infusion)
3. Day 6 (144 hours post-infusion)
4. Day 14 (336 hours post-infusion)
All samples will be analyzed at the central laboratory.
4.6.1.6
Fibrinogen Levels
Plasma samples will be obtained for measurement of fibrinogen levels by two methods:
1. Fibrinogen activity (Clauss method)
2. Fibrinogen antigen 
Samples for fibrinogen determination will be taken at:
1. Screening Visit (up to 21 days prior to Infusion Visit): Sites that cannot perform 
fibrinogen levels determinations (by both Clauss and antigen method) locally will 
have a blood sample taken at Screening Visit and have it analyzed for this parameter 
by both methods at the central laboratory of the study for verification of the 
eligibility against the Inclusion/Exclusion criteria. In these cases, sample for the 
Inclusion/Exclusion criteria assessment will not be taken at Baseline Visit. Sample 
for PK will still be taken at Baseline Visit. 
In order to allow sufficient time for samples shipment and analysis and reporting of 
results back to the site, the sample for determination of the eligibility should be 
drawn at least 14 days prior to the planned infusion.
2. Infusion Visit (Day 0):
i. For sites that have the capability of performing fibrinogen level determinations 
by both Clauss and antigen methods locally, a sample will be drawn within 24 
hours of the scheduled infusion and analyzed at the local laboratory of the site in 
order to have the results available prior to the scheduled infusion in order to 
verify that the subject fulfills the inclusion criteria. In case fibrinogen levels 
determination for verification of the Inclusion/Exclusion criteria is performed at 
the screening visit, this sample will not be taken at Baseline Visit. Sample for 
PK as described below will still be taken at Baseline Visit.
ii. Immediately prior (within 60 minutes prior) to the scheduled infusion a sample 
will be taken and analyzed at the central laboratory for fibrinogen levels. The 
value to be used for PK calculations as baseline value will be the central 
laboratory one, unless there is any technical issue with the PK central laboratory 
measurement that recommends not using this value, in which case the value for 
the Inclusion/Exclusion criteria assessment could be used for this purpose.
iii. At 30 minutes (not applicable for pediatric subjects weighing <30 kg), 1 hour, 
2 hours (not applicable for pediatric subjects weighing <30 kg), 4 hours (not 
applicable for pediatric subjects weighing <30 kg), and 8 hours after infusion 
end. These samples will be analyzed by central laboratory.
3. Day 1 (24 hours post-infusion): central laboratory testing only

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4. Day 2 (48 hours post-infusion): central laboratory testing only (not applicable for 
pediatric subjects weighing <30 kg)
5. Day 4 (96 hours post-infusion): central laboratory testing only
6. Day 6 (144 hours post-infusion): central laboratory testing only
7. Day 9 (216 hours post-infusion): central laboratory testing only
8. Day 14 (336 hours post-infusion): central laboratory testing only (not applicable for 
pediatric subjects weighing <30 kg)
The exact time and date of taking the samples for the PK analysis will be recorded by the 
study staff for the PK analysis.
4.6.1.7
Rotational Thromboelastometry
ROTEM will be performed on frozen plasma samples by the central laboratory and 
following parameters measured: CT, CFT, MCF, and α. 
Samples for ROTEM will be taken at:
1. Infusion Visit (Day 0):
i. Immediately prior (within 60 minutes prior) to the scheduled infusion
ii. At 30 minutes (not applicable for pediatric subjects), 1 hour, and 4 hours (not 
applicable for pediatric subjects) after completion of the infusion
2. Day 1 (24 hours post-infusion, not applicable for pediatric subjects)
3. Day 2 (48 hours post-infusion, not applicable for pediatric subjects)
4. Day 4 (96 hours post-infusion, not applicable for pediatric subjects)
5. Day 6 (144 hours post-infusion, not applicable for pediatric subjects)
6. Day 9 (216 hours post-infusion, not applicable for pediatric subjects)
4.6.1.8
Standard coagulation tests
Following standard coagulation tests: TT, PT, and aPTT will be performed on frozen 
plasma samples at the central laboratory of the study. 
Samples for standard coagulation tests will be taken at:
1. Infusion Visit (Day 0):
iii. Immediately prior (within 60 minutes prior) to the scheduled infusion
iv. At 30 minutes (not applicable for pediatric subjects), 1 hour, and 4 hours (not 
applicable for pediatric subjects) after completion of the infusion
2. Day 1 (24 hours post-infusion, not applicable for pediatric subjects)
3. Day 2 (48 hours post-infusion, not applicable for pediatric subjects)
4. Day 4 (96 hours post-infusion, not applicable for pediatric subjects)
5. Day 6 (144 hours post-infusion, not applicable for pediatric subjects)
6. Day 9 (216 hours post-infusion, not applicable for pediatric subjects)

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4.6.1.9
Markers of activation of coagulation
Following tests, indicative of activation of the coagulation: D-dimer, ATIII, thrombin-
antithrombin III complex (TAT) and prothrombin fragments F1+2 (F1+2) will be performed 
in adult subjects only on frozen plasma samples at the central laboratory of the study. 
Samples for markers of activation of the coagulation tests will be taken at:
1. Infusion Visit (Day 0):
i. Immediately prior (within 60 minutes prior) to the scheduled infusion
ii. At 1 hour and 4 hours after completion of the infusion
2. Day 1 (24 hours post-infusion)
2. Day 2 (48 hours post-infusion)
3. Day 4 (96 hours post-infusion)
4. Day 6 (144 hours post-infusion)
5. Day 9 (216 hours post-infusion)
4.6.1.10
Immunogenicity testing
Serum/plasma samples from adult subjects only will be analyzed for the generation of 
antibodies to fibrinogen by using a stepwise approach starting with a functional screening 
assay to detect neutralizing activity. These samples will be analyzed at the sponsor’s 
laboratory. In the event neutralizing activity is detected, samples will be further assessed by 
a confirmatory ELISA for the presence of antibodies to fibrinogen.
Samples for immunogenicity testing will be taken at:
1. Day 0, pre-infusion
2. Day 14 (± 1 day) post-infusion
3. Week 4 (± 3 days) post-infusion
4.6.1.11
Viral panel
Viral monitoring for each adult subject will be performed by means of serology and nucleic 
acid amplification technology (NAT) tests for the following viruses: HAV, HBV, HCV, 
HIV-1 and HIV-2, and B19. 
Serum/plasma samples from all enrolled adult subjects will be examined at Baseline (prior 
to infusion on Day 0) and at different time points according to the schedule shown in 
Table 4-2.
All serum/plasma samples will be sent to the central laboratory of the study for 
measurement of serum viral status. If a subject is found to be positive for a particular virus 
at Baseline, tests for this particular virus would not be performed at later time points during 
the study. 
4.6.1.12
Vital signs
Subject’s following vital signs: T, RR, HR, SBP, and DBP will be monitored and recorded 
as follows: 

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1. Infusion Visit (Day 0):
i. Immediately prior (within 60 minutes prior) to the scheduled infusion (baseline 
vital signs).
ii. At the beginning of the infusion
iii. Every 20 ± 5 minutes during the infusion
iv. At the completion of the infusion
v. 1 hour after infusion completion
2. Day 1 (24 hours post-infusion)
3. Day 6 (144 hours post-infusion)
4. Day 14 (336 hours post-infusion)
4.6.1.13
Adverse events
AEs that occurred at any time between signing of the informed consent and Week 4 post-
infusion will be reported on the appropriate subject’s case report form (CRF/eCRF) entry.
AEs assessment must be performed only by the investigator or its designee (eg, a medical 
doctor designated as sub-investigator). Under no circumstances should the assessment be 
performed by a study nurse (either site nurse or home health nurse).
4.6.1.14
Monitoring of allergic/hypersensitivity reactions  
Subjects will be carefully monitored by the investigator and/or study staff for signs and 
symptoms of allergic/hypersensitivity reactions occuring between Baseline Visit and 
Week 4 Visit. The Grifols Medical Monitor will routinely review reported AEs for possible 
allergic/hypersensitivity reactions, according to algorithm described in Annex 2. 
4.6.1.15
Monitoring of thrombotic events
Subjects will be monitored by the investigator and/or study staff for signs and symptoms of 
arterial and venous thromboses occuring between Baseline Visit and Week 4 Visit. The 
algorithms described in Annex 1, which include the Wells Score assessment, will be 
observed for evaluation and assessment of thrombotic events risk. In addition, the Grifols 
Medical Monitor will routinely review reported AEs for possible thrombotic events. 
Arterial and venous thromboses will be identified according to definitions in the 
International Classification of Diseases, Ninth Revision, Clinical Modification 
(ICD-9-CM). Such thrombotic events include, but are not limited to, DVT, pumonary 
embolism (PE), myocardial infarction, cerebrovascular accident, acute coronary syndrome, 
limb thrombosis, sagittal sinus thrombosis, and portal vein or mesenteric artery thrombosis. 
All thromboses will be recorded as AEs and reported accordingly.
4.6.1.16
Retention sample 
An additional appropriate volume of blood (specific volumes per visit indicated in 
Section 4.6.2) will be drawn in order to obtain a serum/plasma retention sample from each 
adult subject, with the exception of Day 0 pre-infusion sample, which will also be obtained 
from pediatric subjects. The retention sample will be frozen and stored in the event that 
additional testing is required in the future for purposes of this study only (ie, repeat testing, 
confirmation of virology results, or immunogenicity testing).

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Retention samples will be drawn at:
1. Infusion Visit (Day 0): immediately prior (within 60 minutes prior) to the scheduled 
infusion. This sample will be also drawn from pediatric subjects. Additional
samples will be drawn for enrolled adult subjects at 1 hour and 4 hours after 
completion of the infusion.
2. Day 9 (216 hours post-infusion, not applicable for pediatric subjects)
3. Day 14 (336 hours post-infusion, not applicable for pediatric subjects)
4. Day 21 ± 1 day post-infusion (not applicable for pediatric subjects)
5. Week 4 ± 3 days post-infusion (not applicable for pediatric subjects)
6. Month 3 ± 7 days post-infusion (not applicable for pediatric subjects)
4.6.1.17
Concomitant medication 
All medications other than the investigational product administered to study subjects will 
be recorded during the conduct of the clinical trial.
4.6.1.18
Pregnancy test
Pregnancy test [human chorionic gonadotropin (HCG)-based blood or urine assay] for 
women of childbearing potential will be performed on a sample drawn within 24 hours of 
the scheduled infusion and analyzed at the local laboratory of the site in order to have the 
results available immediately prior to the scheduled infusion in order to verify that the 
subject fulfills the inclusion/exclusion criteria.
4.6.2
CLINICAL TRIAL VISITS
Screening Visit
This will be the first clinical trial visit for all subjects. The investigator will provide 
potential study participants with complete information about all clinical trial procedures as 
well as conditions of subject’s participation. 
During the Screening Visit, the investigator will determine subject’s eligibility for the 
inclusion in this clinical trial. 
The Screening Visit may take place for up to 21 days prior to the investigational medicinal 
product infusion (Day 0) to allow sufficient time for a wash-out period for those subjects 
that have recently received any administration of a fibrinogen-containing product (eg.
fibrinogen concentrates, cryoprecipitate, fresh frozen plasma). 
Assessments and procedures planned to be conducted during the Screening Visit will be 
performed only in the following order to avoid unnecessary assessments or procedures:
1. Information to be given to potential clinical trial subjects:

Subjects will be informed of the nature, purpose and procedures of the study, 
with a description of the possible risks involved.

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
Subjects will be informed of the voluntary nature of participation, and of the 
right to withdraw from the study at any time, without this implying any negative 
consequences for the subject. 

Subjects will receive a Patient Information Sheet to take at home and they will 
be given enough time to think about their clinical trial participation.

Investigator will make sure that potential subjects fully understand the elements 
of the Patient Information Sheet. 
2. Clinical Trial Informed Consent: 
Before any study-specific screening procedures will be performed, and after 
completely understanding the nature of the clinical trial, potential subjects or their 
parents or legal guardian for those subjects not qualified to give legal consent, must 
sign and date a Clinical Trial Informed Consent. The investigator will also sign and 
date it, thus reflecting that Clinical Trial Informed Consent has been obtained, and 
that the subject has had the opportunity to ask questions, and has received adequate 
answers. The subject will receive a signed copy of the informed consent form (ICF) 
and the original will be filed along with the study documentation. 
3. Health Information Portability and Accountability Act (HIPAA)  
The subject will be asked to sign HIPAA Authorization Form where necessary 
(Note: The HIPAA authorization may be included with the ICF). 
4. Allocation of subject number:
Following the signature of the Clinical Trial Informed Consent, the investigator will 
include the subject in the Subject’s Screening Log, assignment of an individual 
inclusion number to each study subject. 
5. Documentation of demography: date of birth, gender, and ethnic origin.
6. Documentation of the medical and surgical history for the last year.
7. Documentation of medications that the subject is taking or has taken within the last 
3 months (it includes transfusion of blood or any blood-derived product). 
8. Physical assessment by body systems.
9. Review of inclusion and exclusion criteria to confirm subject eligibility (see 
Sections 5.1 and 5.2).
Subjects who do not fulfill all inclusion criteria (except laboratory criteria for which 
results may not be available at Screening Visit) or meet any exclusion criteria 
(except laboratory criteria for which results may not be available at Screening Visit) 
will be considered screening failures.
Only subjects who fulfill all inclusion criteria (except laboratory criteria for which 
results may not be available at Screening Visit) and do not meet any of the 
exclusion criteria (except laboratory criteria for which results may not be available 
at Screening Visit) will be considered eligible to continue with the following 
assessments.

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10. Assessment of AEs.
11. Fibrinogen levels: Plasma samples will be obtained for measurement of fibrinogen
levels at those sites that cannot perform fibrinogen levels determinations by two 
methods: fibrinogen activity (Clauss method) and fibrinogen antigen locally. In 
these cases the subject will have a blood sample taken at Screening Visit and have it 
analyzed for this parameter by both methods at the central laboratory of the study 
for verification of the eligibility against the Inclusion/Exclusion criteria. In these 
cases, samples for the Inclusion/Exclusion criteria assessment will not be taken at 
Baseline Visit. Samples for PK will still be taken at Baseline Visit. 
In order to allow sufficient time for samples shipment and analysis and reporting of 
results back to the site, the sample for the Inclusion/Exclusion criteria
assessment should be drawn at least 14 days prior to the planned infusion.
Possible outcomes of the screening assessments:
Subjects who have undergone all Screening Visit assessments, fulfill all inclusion criteria 
(except laboratory criteria for which results may not be available at Screening Visit), and do 
not meet any exclusion criteria (except laboratory criteria for which results may not be 
available at Screening Visit) will be considered eligible to participate in the clinical trial. 
These subjects will be included in the Subject’s Identification Log.
Subjects who have not undergone all Screening Visit assessments, do not fulfill all 
inclusion criteria (except laboratory criteria for which results may not be available at 
Screening Visit), and/or meet any exclusion criteria (except laboratory criteria for which 
results may not be available at Screening Visit) will be considered screening failures. If a 
subject is ineligible for the clinical trial, their demographic data and specific reason for 
ineligibility will be captured on the Screen Failure CRF/eCRF page and on the Subject’s 
Screening Log.
If suitable for logistic reasons, the procedures scheduled at the Screening Visit may be 
performed during the Infusion Visit (Day 0) Baseline (within 24 hours prior to infusion). In 
this case, the Screening Visit will be combined with the Infusion Visit (Day 0) Baseline. In 
this case, assessments and procedures required during both visits (Screening Visit and 
Infusion Visit [Day 0] Baseline) have to be performed.
Infusion Visit (Day 0) – Baseline
The following assessments and/or procedures will be carried out on or before Day 0 as 
Baseline (within 24 hours prior to infusion, unless otherwise noted below): 
1. Physical assessment by body systems performed by a medical doctor.
2. Laboratory testing:  

Pregnancy test: pregnancy test [HCG-based blood or urine assay] will be 
performed for women of childbearing potential. 
Samples will be drawn within 24 hours prior to the scheduled infusion and 
analyzed by the local laboratory of the site in order to make these results available 
to the study team to verify compliance with Inclusion/Exclusion criteria before the 
infusion.

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
Serum clinical chemistry: laboratory test will include creatinine, BUN, TB, ALP, 
ALT, AST, LDH, glucose, sodium, potassium, chloride, and calcium.
Samples will be drawn within 24 hours prior to the scheduled infusion and 
analyzed by the local laboratory of the site in order to make these results available 
to the study team to verify compliance with Inclusion/Exclusion criteria before the 
infusion. Samples will also be analyzed by the central laboratory of the study.

Hematology: laboratory test will include CBC: RBC count, Hgb, Hct, MCH, 
MCHC, MCV, WBC count and differential, and platelet count.
Samples must be taken within 24 hours prior to the scheduled infusion to be 
analyzed by the central laboratory of the study. 

Fibrinogen levels: plasma samples will be obtained for measurement of 
fibrinogen levels by two methods: fibrinogen activity (Clauss method) and 
fibrinogen antigen.
For sites that have the capability of performing fibrinogen level determinations by 
both Clauss and antigen methods locally, samples will be drawn within 24 hours 
prior to the scheduled infusion and analyzed by the local laboratory of the site in 
order to have these results available to the study team to verify compliance with 
Inclusion/Exclusion criteria before the infusion. In case fibrinogen levels 
determination for verification of Inclusion/Exclusion criteria is performed at the 
Screening Visit, this sample will not be taken at Baseline Visit. Sample for PK as 
described below will still be taken at Baseline Visit.
Another sample for measuring baseline fibrinogen levels by both activity (Clauss) 
and antigen (ELISA) methods for PK calculations by the central laboratory of the 
study will be drawn within 60 minutes prior to the scheduled infusion.

Rotational thromboelastometry: ROTEM will be performed on frozen plasma 
samples by the central laboratory and following parameters measured: CT, CFT, 
MCF, and α.
Samples must be taken within 60 minutes prior to the scheduled infusion to be 
analyzed by the central laboratory of the study. 

Standard coagulation tests: following standard coagulation tests: TT, PT, and 
aPTT will be performed on frozen plasma samples at the central laboratory of the 
study.
Samples must be taken within 60 minutes prior to the scheduled infusion to be 
analyzed by the central laboratory of the study. 

Markers of activation of coagulation (not applicable for pediatric subjects): 
following tests, indicative of activation of the coagulation: D-dimer, ATIII, TAT, 
and F1+2 will be performed on frozen plasma samples at the central laboratory of 
the study.

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Samples must be taken within 60 minutes prior to the scheduled infusion to be 
analyzed by the central laboratory of the study.

Immunogenicity testing (not applicable for pediatric subjects): serum/plasma 
samples must be taken prior to the scheduled  infusion to be tested for antibodies 
to fibrinogen at the sponsor’s laboratory.

Viral panel (not applicable for pediatric subjects): viral monitoring for each 
subject will be performed at the central laboratory of the study by means of 
serology and NAT tests for the following viruses: HAV, HBV, HCV, HIV-1 and 
HIV-2, and B19. The following table (Table 4-6) provides a schedule of the 
virology testing on Day 0 (Baseline).
Table 4-6 Baseline Virology Schedule for Day 0
Virus
Serology
NAT
Hepatitis A virus (HAV) 
X1
(IgM & IgG)
X1
Hepatitis B virus (HBV)
X1,2
X1
Hepatitis C virus (HCV)
X1
X1
Human immunodeficiency virus type 
1 and type 2 (HIV-1 & HIV-2)
X1
X1,3
Parvovirus B19 
X1                
(IgM & IgG)
X1
1 Sample will be always analyzed.
2 Total anti-HBc (IgM & IgG). 
3 NAT for HIV-1 only.
Samples must be taken within 60 minutes prior to the scheduled infusion to be 
analyzed by the central laboratory of the study.

Retention sample: An additional blood amount of approximately 20 mL will be 
drawn within 60 minutes prior to the scheduled infusion in order to obtain a 
serum/plasma retention sample from each subject. The retention sample will be 
frozen and stored at the central laboratory of the study in the event that additional 
testing is required in the future for purposes of this study only.
3. Vital signs: subject vital signs (T, RR, HR, SBP, DBP) will be monitored within 60 
minutes before the beginning of the infusion (baseline vital signs).
4. Height and weight: Subject height and weight will be measured for all subjects at 
Baseline Visit. Weight value will be used for calculation of dose to be administered.
5. Assessment of AEs: AE occurring at any time between signature of Clinical Trial 
Informed Consent and the Week 4 Visit will be reported. 

Subjects will be monitored for signs and symptoms of allergic/hypersensitivity 
reactions occurring between the Baseline Visit and Week 4 Visit.

Subjects will be also monitored for signs and symptoms of arterial and venous 
thromboses occurring between the Baseline Visit and Week 4 Visit.

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6. Assessment of concomitant medication: All concomitant medications, other than the 
investigational product, administered to the subject will be recorded. 
The use of any concomitant medications during the PK study (between 1 week before 
the infusion and Day 14 post-infusion) should be avoided as much as possible. If 
clinical reasons make necessary the use of concomitant drugs, the treating physician 
will evaluate each case.
7. Review of inclusion and exclusion criteria to confirm subject eligibility (see 
Sections 5.1 and 5.2).   
Subjects who do not fulfill all inclusion criteria (including laboratory criteria to be 
verified on Day 0 prior to the infusion) and/or fulfill any exclusion criteria (including 
laboratory criteria to be verified on Day 0 prior to the infusion) will be considered 
screening failures.
Only subjects who fulfill all inclusion criteria (including laboratory criteria to be 
verified on Day 0 prior to the infusion) and do not meet any exclusion criteria 
(including laboratory criteria to be verified on Day 0 prior to the infusion) will be 
considered eligible to continue with the following procedures of the study.
Infusion Visit (Day 0) - Infusion 
After verification of compliance with all applicable Inclusion/Exclusion criteria, study staff 
may proceed with infusion of the investigational medicinal product according to the 
Section 4.5.4.2 Dispensation and administration of the investigational product.
If the subject had a bleeding requiring replacement therapy with any fibrinogen-containing 
product between Screening Visit and investigational medicinal product infusion then, the 
investigational medicinal product infusion should not be carried out and the 21-day 
washout period be observed, thus postponing investigational medicinal product infusion 
(Day 0 Visit) as appropriate. In this case, screening/baseline (pre-infusion) samples should 
be taken again, and laboratory inclusion/exclusion criteria verified with the results of the 
most recent sample.
Briefly, a 70 mg/kg body weight single-dose of FIB Grifols will be intravenously 
administered at a rate that must not exceed 5 mL/minute. Study staff should make sure that 
the product is at room temperature before being administered. The exact volume infused to 
the subject will be recorded in subject's source documents and CRF/eCRF. The exact date 
and time of start and completion of the infusion will be also recorded.
The following assessments and/or procedures will be carried out during infusion of the 
investigational medicinal product: 
1. Vital signs: subject vital signs (T; RR; HR; SBP; DBP) will be monitored: 
i. At the beginning of the infusion
ii. Every 20 ± 5 minutes during infusion
iii. At the completion of the infusion
2. Assessment of AEs: Any AE occurred during infusion will be recorded, including 
the infusion time elapsed and the infusion rate at the time of onset. 

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3. Assessment of concomitant medication: all medications other than investigational 
product administered to the subject during infusion will be recorded.
Infusion Visit (Day 0) – Post-Infusion 
Blood samples taken on Infusion Visit (Day 0) Post-infusion period should be taken from 
the contralateral arm where the investigational medicinal product has been infused. 
Infusion Visit (Day 0) – 30 Minutes Post-Infusion 
The following assessments and/or procedures will be carried out 30 minutes after the 
completion of the infusion of the investigational medicinal product (± 5 minutes):
1. Fibrinogen levels (not applicable for pediatric subjects weighing <30 kg): plasma 
samples will be obtained for measurement of fibrinogen levels by two methods: 
fibrinogen activity (Clauss method), and fibrinogen antigen (ELISA).
Fibrinogen levels for PK calculations will be made by the central laboratory of the 
study.
2. Rotational thromboelastometry (not applicable for pediatric subjects): ROTEM will 
be performed on frozen plasma samples by the central laboratory and following 
parameters measured: CT, CFT, MCF, and α.
3. Standard coagulation tests (not applicable for pediatric subjects): following standard 
coagulation tests: TT, PT, and aPTT will be performed on frozen plasma samples at 
the central laboratory of the study.
4. Assessment of AEs: any new AE occurred will be recorded.
5. Assessment of concomitant medication: all new medications other than 
investigational product administered to the subject will be recorded.
Infusion Visit (Day 0) – 1 Hour Post-Infusion
The following assessments and/or procedures will be carried out one (1) hour after the end 
of infusion of the investigational medicinal product (± 10 minutes):
1. Vital signs: subject vital signs (T; RR; HR; SBP; DBP) will be monitored.
2. Fibrinogen levels: plasma samples will be obtained for measurement of fibrinogen 
levels by two methods: fibrinogen activity (Clauss method) and fibrinogen antigen 
(ELISA).
Fibrinogen levels for PK calculations will be made by the central laboratory of the 
study.
3. Rotational thromboelastometry: ROTEM will be performed on frozen plasma 
samples by the central laboratory and following parameters measured: CT, CFT, 
MCF, and α.
4. Standard coagulation tests: following standard coagulation tests: TT, PT, and aPTT 
will be performed on frozen plasma samples at the central laboratory of the study.

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5. Markers of activation of coagulation (not applicable for pediatric subjects):
following tests, indicative of activation of the coagulation: D-dimer, ATIII, TAT, 
and F1+2 will be performed on frozen plasma samples at the central laboratory of the 
study.
6. Retention sample (not applicable for pediatric subjects): an additional blood amount 
of approximately 20 mL will be drawn in order to obtain a serum/plasma retention 
sample from each subject. The retention sample will be frozen and stored at the 
central laboratory of the study in the event that additional testing is required in the 
future for purposes of this study only.
7. Assessment of AEs: any new AE occurred will be recorded.

Subjects will be monitored for signs and symptoms of allergic/hypersensitivity 
reactions.

Subjects will also be monitored for signs and symptoms of arterial and venous 
thromboses.
8. Assessment of concomitant medication: all new medications other than the 
investigational product administered to the subject will be recorded.
Infusion Visit (Day 0) – 2 Hours Post-Infusion 
The following assessments and/or procedures will be carried out two (2) hours after the end 
of infusion of the investigational medicinal product (± 10 minutes):
1. Fibrinogen levels (not applicable for pediatric subjects weighing <30 kg): plasma 
samples will be obtained for measurement of fibrinogen levels by two methods: 
fibrinogen activity (Clauss method) and fibrinogen antigen (ELISA).
Fibrinogen levels for PK calculations will be made by the central laboratory of the 
study.
2. Assessment of AEs: any new AE occurred will be recorded.
3. Assessment of concomitant medication: all new medications other than the 
investigational product administered to the subject will be recorded.
Infusion Visit (Day 0) – 4 Hours Post-Infusion 
The following assessments and/or procedures will be carried out four (4) hours after the end 
of infusion of the investigational medicinal product (± 10 minutes):
1. Fibrinogen levels (not applicable for pediatric subjects weighing <30 kg): plasma 
samples will be obtained for measurement of fibrinogen levels by two methods: 
fibrinogen activity (Clauss method) and fibrinogen antigen (ELISA).
Fibrinogen levels for PK calculations will be made by the central laboratory of the 
study.
2. Rotational thromboelastometry (not applicable for pediatric subjects): ROTEM will 
be performed on frozen plasma samples by the central laboratory and following 
parameters measured: CT, CFT, MCF, and α.

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3. Standard coagulation tests (not applicable for pediatric subjects): following standard 
coagulation tests: TT, PT, and aPTT will be performed on frozen plasma samples at 
the central laboratory of the study.
4. Markers of activation of coagulation (not applicable for pediatric subjects):
following tests, indicative of activation of the coagulation: D-dimer, ATIII, TAT, 
and F1+2 will be performed on frozen plasma samples at the central laboratory of the 
study.
5. Retention sample (not applicable for pediatric subjects): an additional blood amount 
of approximately 20 mL will be drawn in order to obtain a serum/plasma retention 
sample from each subject. The retention sample will be frozen and stored at the 
central laboratory of the study in the event that additional testing is required in the 
future for purposes of this study only.
6. Assessment of AEs: any new AE occurred will be recorded.

Subjects will be monitored for signs and symptoms of allergic/hypersensitivity 
reactions.

Subjects will also be monitored for signs and symptoms of arterial and venous 
thromboses.
7. Assessment of concomitant medication: all new medications other than the 
investigational product administered to the subject will be recorded.
Infusion Visit (Day 0) – 8 Hours Post-Infusion 
The following assessments and/or procedures will be carried out 8 hours after the end of 
infusion of the investigational medicinal product (± 10 minutes):
1. Physical assessment: physical examination by body systems performed by a medical 
doctor.
2. Fibrinogen levels: plasma samples will be obtained for measurement of fibrinogen 
levels by two methods: fibrinogen activity (Clauss method) and fibrinogen antigen 
(ELISA).
Fibrinogen levels for PK calculations will be made by the central laboratory of the 
study.
3. Assessment of AEs: any new AE occurred will be recorded.

Subjects will be monitored for signs and symptoms of allergic/hypersensitivity 
reactions.

Subjects will also be monitored for signs and symptoms of arterial and venous 
thromboses.
4. Assessment of concomitant medication: all new medications other than 
investigational product administered to the subject will be recorded.
Day 1 Visit (24 hours Post-Infusion) 

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The following assessments and/or procedures will be carried out at Day 1 (24 hours after 
the infusion ± 30 minutes): 
1. Physical assessment: physical examination by body systems performed by the 
investigator or its designee (eg, a medical doctor designated as sub-investigator).
2. Laboratory testing:
Serum clinical chemistry: laboratory test will include creatinine, BUN, TB, ALP, 
ALT, AST, LDH, glucose, sodium, potassium, chloride and calcium.
Samples taken 24 hours after infusion will be analyzed by the central laboratory of 
the study. 
Hematology: laboratory test will include CBC: RBC count, Hgb, Hct, MCH, MCHC, 
MCV, WBC count and differential, and platelet count.
Samples taken within 24 hours after the infusion will be analyzed by the central 
laboratory of the study. 
Fibrinogen levels: plasma samples will be obtained for measurement of fibrinogen 
levels by two methods: fibrinogen activity (Clauss method) and fibrinogen antigen 
(ELISA).
Samples taken 24 hours after the infusion will be analyzed for measuring fibrinogen 
levels for PK calculations by the central laboratory of the study. 
Rotational thromboelastometry (not applicable for pediatric subjects): ROTEM will 
be performed on frozen plasma samples by the central laboratory and following 
parameters measured: CT, CFT, MCF, and α.
Samples taken 24 hours after the infusion will be analyzed by the central laboratory 
of the study. 
Standard coagulation tests (not applicable for pediatric subjects): following 
standard coagulation tests: TT, PT, and aPTT will be performed on frozen plasma 
samples at the central laboratory of the study.
Markers of activation of coagulation (not applicable for pediatric subjects): 
following tests, indicative of activation of the coagulation: D-dimer, ATIII, TAT, 
and F1+2 will be performed on frozen plasma samples at the central laboratory of 
the study.
3. Vital signs: subject vital signs (T, RR, HR, SBP, DBP) will be monitored. 
4. Assessment of AEs: any new AE occurred will be recorded.
Subjects will be monitored for signs and symptoms of allergic/hypersensitivity 
reactions.
Subjects will be also monitored for signs and symptoms of arterial and venous 
thromboses.

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5. Assessment of concomitant medication: all new medications administered to the 
subject will be recorded.
This visit will ALWAYS be performed at the study center by the investigative staff. 
Day 2 Visit (48 hours Post-infusion) 
The following assessments and/or procedures will be carried out at Day 2 (48 hours after 
the infusion ± 60 minutes): 
1. Laboratory testing:

Fibrinogen levels (not applicable for pediatric subjects weighing <30 kg): 
Plasma samples will be obtained for measurement of fibrinogen levels by two 
methods: fibrinogen activity (Clauss method) and fibrinogen antigen (ELISA).
Samples taken 48 hours after the infusion will be analyzed for measuring 
fibrinogen levels for PK calculations by the central laboratory of the study. 
Rotational thromboelastometry (not applicable for pediatric subjects): ROTEM 
will be performed on frozen plasma samples by the central laboratory and 
following parameters measured: CT, CFT, MCF, and α.
Samples taken 48 hours after the infusion will be analyzed by the central 
laboratory of the study. 
Standard coagulation tests (not applicable for pediatric subjects): following 
standard coagulation tests: TT, PT, and aPTT will be performed on frozen plasma 
samples at the central laboratory of the study.
Markers of activation of coagulation (not applicable for pediatric subjects):
following tests, indicative of activation of the coagulation: D-dimer, ATIII, TAT, 
and F1+2 will be performed on frozen plasma samples at the central laboratory of 
the study.
2. Assessment of AEs: any new AE occurred will be recorded.
Subjects will be monitored for signs and symptoms of allergic/hypersensitivity 
reactions.
Subjects will also be monitored for signs and symptoms of arterial and venous 
thromboses.
3. Assessment of concomitant medication: all new medications administered to the 
subject will be recorded.
This visit, and all subsequent follow-up visits except Week 4 Visit may be conducted in the 
subject’s home by designated study staff (eg, homecare nurses) if approved by the study 
subject and the investigator.
Day 4 Visit (96 Hours Post-Infusion) 

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The following assessments and/or procedures will be carried out at Day 4 (96 hours after 
the infusion ± 60 minutes): 
1. Laboratory testing:
Fibrinogen levels: plasma samples will be obtained for measurement of 
fibrinogen levels by two methods: fibrinogen activity (Clauss method) and 
fibrinogen antigen (ELISA)
Samples taken 96 hours after the infusion will be analyzed for measuring 
fibrinogen levels for PK calculations by the central laboratory of the study. 
Rotational thromboelastometry (not applicable for pediatric subjects): ROTEM 
will be performed on frozen plasma samples by the central laboratory and 
following parameters measured: CT, CFT, MCF, and α.
Samples taken 96 hours after the infusion will be analyzed by the central 
laboratory of the study. 
Standard coagulation tests (not applicable for pediatric subjects): following 
standard coagulation tests: TT, PT, and aPTT will be performed on frozen plasma 
samples at the central laboratory of the study.
Markers of activation of coagulation (not applicable for pediatric subjects): 
following tests, indicative of activation of the coagulation: D-dimer, ATIII, TAT, 
and F1+2 will be performed on frozen plasma samples at the central laboratory of 
the study.
2. Assessment of AEs: any new AE occurred will be recorded. 
Subjects will be monitored for signs and symptoms of allergic/hypersensitivity 
reactions.
Subjects will also be monitored for signs and symptoms of arterial and venous 
thromboses.
3. Assessment of concomitant medication: all new medications administered to the 
subject will be recorded.
Day 6 Visit (144 Hours Post-Infusion) 
The following assessments and/or procedures will be carried out at Day 6 (144 hours after 
the infusion ± 60 minutes): 
1. Laboratory testing:
Serum clinical chemistry: laboratory test will include creatinine, BUN, TB, ALP, 
ALT, AST, LDH, glucose, sodium, potassium, chloride, and calcium.
Samples taken 144 hours after the infusion will be analyzed by the central 
laboratory of the study. 
Hematology: laboratory test will include CBC: RBC count, Hgb, Hct, MCH, 
MCHC, MCV, WBC count and differential, and platelet count.

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Samples taken 144 hours after the infusion will be analyzed by the central 
laboratory of the study. 
Fibrinogen levels: plasma samples will be obtained for measurement of 
fibrinogen levels by two methods: fibrinogen activity (Clauss method) and 
fibrinogen antigen (ELISA).
Samples taken 144 hours after the infusion will be analyzed for measuring 
fibrinogen levels for PK calculations by the central laboratory of the study. 
Rotational thromboelastometry (not applicable for pediatric subjects): ROTEM 
will be performed on frozen plasma samples by the central laboratory and 
following parameters measured: CT, CFT, MCF, and α.
Samples taken 144 hours after the infusion will be analyzed by the central 
laboratory of the study. 
Standard coagulation tests (not applicable for pediatric subjects): following 
standard coagulation tests: TT, PT, and aPTT will be performed on frozen plasma 
samples at the central laboratory of the study.
Markers of activation of coagulation (not applicable for pediatric subjects): 
following tests, indicative of activation of the coagulation: D-dimer, ATIII, TAT, 
and F1+2 will be performed on frozen plasma samples at the central laboratory of 
the study.
2. Vital signs: subject vital signs (T, RR, HR, SBP, and DBP) will be monitored
3. Assessment of AEs: any new AE occurred will be recorded. 
Subjects will be monitored for signs and symptoms of allergic/hypersensitivity 
reactions.
Subjects will also be monitored for signs and symptoms of arterial and venous 
thromboses.
4. Assessment of concomitant medication: all new medications administered to the 
subject will be recorded.
Day 9 Visit (216 Hours Post-Infusion ) 
The following assessments and/or procedures will be carried out at Day 9 (216 hours after 
the infusion ± 60 minutes): 
1. Laboratory testing:
Fibrinogen levels: plasma samples will be obtained for measurement of 
fibrinogen levels by two methods: fibrinogen activity (Clauss method) and 
fibrinogen antigen (ELISA).
Samples taken 216 hours after the infusion will be analyzed for measuring 
fibrinogen levels for PK calculations by the central laboratory of the study. 

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Rotational thromboelastometry (not applicable for pediatric subjects): ROTEM 
will be performed on frozen plasma samples by the central laboratory and 
following parameters measured: CT, CFT, MCF, and α.
Samples taken 216 hours after the infusion will be analyzed by the central 
laboratory of the study. 
Standard coagulation tests (not applicable for pediatric subjects): following 
standard coagulation tests: TT, PT, and aPTT will be performed on frozen plasma 
samples at the central laboratory of the study.
Markers of activation of coagulation (not applicable for pediatric subjects):
following tests, indicative of activation of the coagulation: D-dimer, ATIII, TAT, 
and F1+2 will be performed on frozen plasma samples at the central laboratory of 
the study.
Viral panel (not applicable for pediatric subjects): viral monitoring for each adult 
subject will be performed at the central laboratory of the study according to the 
following table (Table 4-7), which provides a schedule of the virology testing on 
Day 9 (216 hours after the infusion).
Table 4-7 Virology Schedule for Day 9
Virus
Serology
NAT
Parvovirus B191
X                                      
(IgM & IgG)
X
1 The samples drawn on Day 9 will be analyzed only in the event of negative results of NAT, 
IgM, and IgG analysis for the presence of B19 performed on Baseline sample.
Retention sample (not applicable for pediatric subjects): an additional blood 
amount of approximately 5 mL will be drawn on Day 9 (216 hours after the 
infusion) in order to obtain a serum/plasma retention sample from each adult 
subject. The retention sample will be frozen and stored at the central laboratory of 
the study in the event that additional testing is required in the future for purposes 
of this study only.
2. Assessment of AEs: any new AE occurred will be recorded.
Subjects will be monitored for signs and symptoms of allergic/hypersensitivity 
reactions.
Subjects will also be monitored for signs and symptoms of arterial and venous 
thromboses.
3. Assessment of concomitant medication: all new medications administered to the 
subject will be recorded.
Day 14 Visit (336 Hours Post-Infusion) 
The following assessments and/or procedures will be carried out at Day 14 (336 hours after 
the infusion ± 60 minutes): 
1. Laboratory testing:

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Serum clinical chemistry: laboratory test will include creatinine, BUN, TB, ALP, 
ALT, AST, LDH, glucose, sodium, potassium, chloride, and calcium.
Samples taken 336 hours after the infusion will be analyzed by the central 
laboratory of the study. 
Hematology: laboratory test will include CBC: RBC count, Hgb, Hct, MCH, 
MCHC, MCV, WBC count and differential, and platelet count.
Samples taken 336 hours after the infusion will be analyzed by the central 
laboratory of the study.
Fibrinogen levels (not applicable for pediatric subjects weighing <30 kg): plasma 
samples will be obtained for measurement of fibrinogen levels by two methods: 
fibrinogen activity (Clauss method) and fibrinogen antigen (ELISA).
Samples taken 336 hours after the infusion will be analyzed for measuring 
fibrinogen levels for PK calculations by the central laboratory of the study. 
Immunogenicity testing (not applicable for pediatric subjects): Serum/plasma 
samples to be tested for antibodies to fibrinogen
Viral panel (not applicable for pediatric subjects): viral monitoring for each adult 
subject will be performed at the central laboratory of the study according to the 
following table (Table 4-8), which provides a schedule of the virology testing on 
Day 14 (336 hours after the infusion).
Table 4-8 Virology Schedule for Day 14
Virus
Serology
NAT
HAV1
X
HBV1
X
Parvovirus B191
X                        
(IgM & IgG)
X
1 The samples drawn on Day 14 will be analyzed for a particular virus only in the event of 
negative results of analysis of NAT, IgM, and IgG for that particular virus performed on 
the samples from all previous visits.
Retention sample (not applicable for pediatric subjects): An additional blood 
amount of approximately 20 mL will be drawn on Day 14 (336 hours after the 
infusion) in order to obtain a serum/plasma retention sample from each adult 
subject. The retention sample will be frozen and stored at the central laboratory of 
the study in the event that additional testing is required in the future for purposes 
of this study only.
2. Vital signs: Subject vital signs (T, RR, HR, SBP, DBP) will be monitored. 
3. Assessment of AEs: Any new AE occurred will be recorded.
Subjects will be monitored for signs and symptoms of allergic/hypersensitivity 
reactions.
Subjects will also be monitored for signs and symptoms of arterial and venous 
thromboses.

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4. Assessment of concomitant medication: all new medications administered to the 
subject will be recorded.
Day 21 ± 1 Day Visit 
The following assessments and/or procedures will be carried out at Day 21 ± 1 days after 
the infusion: 
1. Laboratory testing:
Viral panel (not applicable for pediatric subjects): viral monitoring for each adult 
subject will be performed at the central laboratory of the study according to the 
following table (Table 4-9), which provides a schedule of the virology testing on 
Day 21 ± 1 day after the infusion.
Table 4-9 Virology Schedule for Day 21 ± 1 Day Visit 
Virus
Serology
NAT
HAV1
X                       
(IgM & IgG)
X
HBV1
X
1The samples drawn on Day 21 will be analyzed for a particular virus only in the event of 
negative results of analysis of NAT, IgM, and IgG for that particular virus performed on 
the samples from all previous visits.
Retention sample (not applicable for pediatric subjects): an additional blood 
amount of approximately 10 mL will be drawn on Day 21 ± 1 day after the 
infusion in order to obtain a serum/plasma retention sample from each adult 
subject. The retention sample will be frozen and stored at the central laboratory of 
the study in the event that additional testing is required in the future for purposes 
of this study only.
2. Assessment of AEs: any new AE occurred will be recorded.
Subjects will be monitored for signs and symptoms of allergic/hypersensitivity 
reactions.
Subjects will also be monitored for signs and symptoms of arterial and venous 
thromboses.
3. Assessment of concomitant medication: all new medications administered to the 
subject will be recorded.
Week 4 ± 3 Days Visit 
The following assessments and/or procedures will be carried out at Week 4 ± 3 days after 
the infusion: 
1. Physical assessment: physical examination by body systems performed by the 
investigator or its designee (eg, a medical doctor designated as sub-investigator).
2. Laboratory testing:
Immunogenicity testing (not applicable for pediatric subjects): serum/plasma 
samples to be tested for antibodies to fibrinogen.

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Viral panel (not applicable for pediatric subjects): viral monitoring for each adult 
subject will be performed at the central laboratory of the study according to the 
following table (Table 4-10), which provides a schedule of the virology testing on 
Week 4 ± 3 days after the Infusion Visit.
Table 4-10 Virology Schedule for Week 4 ± 3 Days
Virus
Serology
NAT
HAV1
X                          
(IgM & IgG)
X
HBV1
X2
X
HCV1
X
HIV-11
X
1 The samples drawn on Week 4 ± 3 Days will be analyzed for a particular virus only in the event 
of negative results of analysis of NAT, IgM, and IgG for that particular virus performed on the 
samples from all previous visits.
2 HBsAg
Retention sample (not applicable for pediatric subjects): an additional blood 
amount of approximately 10 mL will be drawn on Week 4 ± 3 days after the 
Infusion Visit in order to obtain a serum/plasma retention sample from each adult 
subject. The retention sample will be frozen and stored at the central laboratory of 
the study in the event that additional testing is required in the future for purposes 
of this study only.
3. Assessment of AEs: Any new AE occurred will be recorded.
Subjects will be monitored for signs and symptoms of allergic/hypersensitivity 
reactions.
Subjects will also be monitored for signs and symptoms of arterial and venous 
thromboses.
4. Assessment of concomitant medication: all new medications administered to the 
subject will be recorded.
This visit will always be performed at the study center by the investigator.
Month 3 ± 7 Days Visit
This visit is not applicable to pediatric subjects. The following assessments and/or 
procedures will be carried out at Month 3 ± 7 days after the infusion: 
1. Laboratory testing:
Viral panel: viral monitoring for each subject will be performed at the central 
laboratory of the study according to the following table (Table 4-11), which 
provides a schedule of the virology testing on Month 3 ± 7 days after the Infusion 
Visit.

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Table 4-11 Virology Schedule for Month 3 ± 7 Days 
Virus
Serology
NAT
HBV1
X2
HCV1
X3
X
HIV-11 and HIV-21
X4
X5
1 The samples drawn on Month 3 ± 7 Days will be analyzed for a particular virus only in the event of 
negative results of analysis of NAT, IgM, and IgG for that particular virus performed on the sample 
from Day 0 Visit (Baseline).
2 HBsAg
3 In case of HCV positive antibody screen, a recombinant immunoblot assay will be performed. 
4 In case of HIV positive antibody screen, a Western blot assay for HIV-1 will be performed.
5 NAT for HIV-1 only.

Retention sample: an additional blood amount of approximately 10 mL will be 
drawn on Month 3 ± 7 days after the Infusion Visit in order to obtain a 
serum/plasma retention sample from each subject. The retention sample will be 
frozen and stored at the central laboratory of the study in the event that 
additional testing is required in the future for purposes of this study only.
2. Assessment of concomitant medication: a registry of medications, other than the 
investigational product, administered to the subject.
4.7
PREMATURE DISCONTINUATION OF PARTICIPATING SUBJECTS 
Study participation is strictly voluntary. Study subjects have the right to withdraw from the 
study at any time for any reason. Likewise the investigator can withdraw a subject from the 
clinical trial at any time if it is deemed in the subject’s best interest
In any case, the investigator must document the reason(s) for withdrawal of each subject in 
the medical history and in the CRF/eCRF. Moreover, after subject’s withdrawal it is 
suggested to perform a last visit as soon as possible so that all study-related information can 
be recorded. The sponsor will have access to all data gathered on subjects prior to 
termination.
Since premature discontinuations could lead to missing data, it will be possible to substitute 
certain discontinued subjects for new ones in order to get number of evaluable subjects. 
These substitutions will be only allowed when premature discontinuations happen before 
the infusion of investigational product during the enrolment period. 
Subject withdrawal criteria and procedures are described in Section 5.3.
4.8
ACCOUNTABILITY PROCEDURES FOR THE INVESTIGATIONAL 
PRODUCT
The investigational site must keep accurate drug accountability records. These will include: 
1) dates of receipt for investigational product; 2) when and how much investigational 
product was dispensed; 3) when and how much investigational product was administered to 
each study subject. 
In addition, reasons for deviations from the expected dispensing/administration regimen 
must also be recorded. 

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All study medication will be reconciled before completion of the clinical trial within each 
clinical site.
4.9
SOURCE DATA
All information contained in the medical history, complementary exploration reports 
including laboratory test will be considered as clinical trial source data.
Any data entered in the CRF/eCRF should have written or electronic record in the subject’s 
medical records. These written or electronic records will be considered source data and 
should be dated and signed by the investigator or by the qualified delegated person (eg, 
results of physical examinations, vital signs testing, or the investigational product 
administration procedure).
For every single subject enrolled, the investigator will write into his/her medical history 
that he/she has been enrolled in a clinical trial, specifying its title, study number and 
sponsor (Instituto Grifols, S.A.), as well as the inclusion date.
The investigator is responsible for maintaining complete and adequate case histories in 
source records of each subject. All study-specific data necessary to be recorded in the 
CRF/eCRF that cannot be found in subject’s past medical records (such as medical history, 
past medications, etc, to be recorded at screening visit) should be recorded by the 
investigator or its designee in subject’s medical file, dating and signing all new entries.
Source data must be preserved for the maximum period of time permitted by local 
regulations and made available by the investigator in the cases described above.
5.
SELECTION AND WITHDRAWAL OF SUBJECTS
5.1
SUBJECT INCLUSION CRITERIA
Subject eligibility will be based on the presence of congenital fibrinogen deficiency 
manifested as afibrinogenemia and the willingness to participate the study.
Subjects fulfilling the following inclusion criteria are eligible for participation in the study:
1. Male or female subjects less than 70 years olda.
2. Sign the written ICF, or the subject’s parent or legal guardian signs the ICF where 
applicable, and the Subject Authorization Form (SAF) where applicable. Pediatric 
subjects, as defined by local regulations, will be asked to sign an age appropriate assent 
form.
3. Subjects diagnosed with congenital fibrinogen deficiency manifested as 
afibrinogenemia.
4. Subjects with a fibrinogen level undetectable1, or equal or less than 30 mg/dL 
determined by both Clauss and antigen methods at baseline2 (sample drawn within 24 
hours prior to infusion on Day 0 Visit will be tested locally) or at Screening Visit3
(sample should be drawn at least 14 days prior to infusion on Day 0 Visit to be tested at 
central laboratory).

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1 Limit of detection for fibrinogen level determination  must be 30 mg/dL or lower for 
both methods.
2For sites that have the capability of performing fibrinogen level determinations locally 
by both Clauss and antigen methods with a limit of detection of 30 mg/dL or lower.
3For sites that do not have the capability of performing fibrinogen level determinations 
by both Clauss and antigen methods locally or have methods that are not sensitive 
enough (limit of detection: 30 mg/dL).
5. Female subjects of child-bearing potentialb must have a negative test for pregnancy 
blood or urine HCG-based assay at baseline (sample drawn within 24 hours prior to 
infusion on Day 0 Visit)
6. Female subjects of child-bearing potentialb and their partner have agreed to practice 
contraception using a method of proven reliability (ie, hormonal methods, barrier 
methods, intrauterine devices methods) to prevent a pregnancy during the course of the 
clinical trial
7. Subjects must be willing to comply with all aspects of the clinical trial protocol, 
including blood sampling, for the whole duration of the study
aThe enrollment of pediatric subjects (below 18 years of age) will be initiated only after 
the safety of FIB Grifols in the adult subjects has been evaluated by the sponsor.
bWomen of child-bearing potential include any female who has experienced menarche 
and who has not undergone successful surgical sterilisation (hysterectomy, bilateral 
tubal ligation or bilateral oophorectomy) or is not postmenopausal (post-menopausal is 
defined as amenorrhea for >12 consecutive months or women on hormone 
replacement therapy with documented serum follicle stimulating hormone level 
<35 mIU/mL). Even in women who are using oral, implanted or injectable 
contraceptive hormones or mechanical products such as an intrauterine device or 
barrier methods (diaphragm, condoms, spermicides) to prevent pregnancy or 
practicing abstinence or where partner is sterile, eg, vasectomy, should be considered 
to be of child bearing potential.
5.2
SUBJECT EXCLUSION CRITERIA
Subjects who meet any of the following exclusion criteria are to be excluded from study 
participation:
1. Subjects who received any fibrinogen-containing product within 21 days prior to Day 0 
Visit -infusion day.
2. Subjects who present with active bleeding within 10 days prior to infusion on Day 0 
Visit.
3. Subjects with acquired (secondary) fibrinogen deficiency.
4. Subjects diagnosed with dysfibrinogenemia.
5. Subjects with documented history of DVT, PE, or arterial thrombosis within 1 year 
prior to enrolment in this clinical trial.
6. Subjects with known antibodies against fibrinogen.

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7. Subjects with a history of anaphylactic reactions or severe reactions to any blood-
derived product.
8. Subjects with a history of intolerance to any component of the investigational product.
9. Subjects with a documented history of IgA deficiency and antibodies against IgA
10. Females who are pregnant or are breastfeeding.
11. Subjects with renal impairment [ie, serum creatinine exceeds more than 2.0 times the 
upper limit of normal (ULN) for the expected normal range for the testing laboratory] at 
baseline (sample drawn within 24 hours prior to infusion on Day 0 Visit) .
12. Subjects with AST or ALT levels exceeding more than 2.5 times the ULN for the 
expected normal range for the testing laboratory at baseline (sample drawn within 24 
hours prior to infusion on Day 0 Visit).
13. Subjects with a history of chronic alcoholism or illicit drug addiction in the preceding 
12 months prior to enrolment in this clinical trial.
14. Subjects with any medical condition which is likely to interfere with the evaluation of 
the study drug and/or the satisfactory conduct of the clinical trial according to the 
investigator’s judgment (eg, congenital or acquired bleeding disorders other than 
congenital fibrinogen deficiency, planned surgery needing blood transfusion).
15. Subjects who received aspirin-containing products and nonsteroidal anti-inflammatory 
drugs (NSAIDs) within 7 days prior to Day 0 Visit.
16. Subjects currently receiving, or having received within 3 months prior to enrolment into 
this clinical trial, any investigational drug or device.
17. Subjects who were previously administered the investigational product FIB Grifols 
during this clinical trial (ie, every subject can only participate in the study once).
18. Subjects who are unlikely to adhere the protocol requirements, or are likely to be 
uncooperative, or unable to provide a storage serum sample prior to investigational drug 
infusion.
5.3
SUBJECT WITHDRAWAL CRITERIA AND PROCEDURES
Subjects have the right to withdraw from the study at any time for any reason, either before 
or after the infusion of the investigational product. The investigator can withdraw a subject 
from the clinical trial at any time.
The investigator will document the reason(s) for withdrawal of each subject in source 
documents and in the CRF/eCRF. All data gathered on the subject prior to termination will 
be made available to the sponsor. 
Subject participation in the study may be terminated early under the following 
circumstances:
1. The subject withdraws his/her informed consent to participate in the clinical trial or for 
pediatric subjects, subject withdraw informed consent at his/her own request or at the 
request of the legally accepted representatives (eg, parent or legal guardian).
2. The subject discontinues his/her participation in the clinical trial without withdrawing 
his/her informed consent.

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3. The subject does not meet all inclusion criteria and is deemed a screen failure.
4. The subject meets any of the exclusion criteria and is deemed a screen failure.
5. The subject is not able to adhere to the main protocol requirements (major protocol 
violations). 
6. The occurrence of an AE which in the investigator’s opinion requires the withdrawal of 
the subject from the clinical trial.
7. The subject is lost to follow-up.
8. Subject’s death.
9. Any event which in the opinion of the investigator impedes the subject’s participation in 
the study. 
For subjects who are screen failures or early discontinue the clinical trial, study completion 
procedures will be completed as per Section 6.4. 
If the reason for early discontinuation is an AE, in so far as is possible, the subject will be 
followed-up until the event resolves, or has been stabilized, and no further change is 
expected.
Subjects who early discontinue the clinical trial once any amount of investigational product 
has been already administered cannot be replaced.
6.
TREATMENT OF SUBJECTS
6.1
TREATMENT TO BE ADMINISTERED 
During this clinical trial, each subject will receive a single-dose intravenous infusion of 
investigational product 70 mg/kg body weight. The investigational product should be 
administered by slow intravenous infusion, at a rate not exceeding 5 mL/minute. The actual 
doses (volumes) actually administered to the subject will be recorded. 
6.2
MEDICATION(S)/TREATMENT(S) PERMITTED (INCLUDING RESCUE 
MEDICATION) AND NOT PERMITED BEFORE AND/OR DURING THE
TRIAL
Study subjects should not receive other fibrinogen-containing products to treat their 
signs/symptoms of congenital afibrinogenemia during the study course. Nevertheless, the 
use of any non-study medication or any change in long term therapy during the course of 
the study should be avoided when possible. Any other non-study medications are allowed 
only if treatment becomes medically necessary according to the investigator judgment. In 
all cases, the investigator must record all medication administered during the clinical trial in 
the subject’s CRF/eCRF. 
In case the study subject receives any fibrinogen-containing product during the course of 
the PK follow-up period (up to Day 14), PK and efficacy results will not be taken into 
account for PK and efficacy analyses in the PK period starting with the actual time of the 
alternative fibrinogen-containing product administration and going forward.

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No drug-drug interactions have been previously reported with the use of fibrinogen 
products. The subjects who are currently receiving other investigational drug or device (as 
specified in the exclusion criteria) will be excluded.
The following medications are prohibited during study participation:

Aspirin-containing products and NSAIDs
6.3
PROCEDURES FOR MONITORING SUBJECT COMPLIANCE
Since all investigational product administration will be performed only at investigational 
sites by qualified staff, compliance with the clinical trial treatment will be assessed by 
means of the infusion logs. Investigational sites will be provided with logs where to register 
investigational product administration, both volume and rate of administration. (Subject 
Specific Administration Log). These forms will be available for clinical trial monitors to 
check clinical trial treatment compliance. 
6.4
STOPPING RULES AND DISCONTINUATION CRITERIA
Both the investigator and Instituto Grifols, S.A. reserve the right to terminate the study at 
any time. Should this be necessary, the procedures will be arranged on an individual study 
basis after review and consultation by both parties. In terminating the study, Instituto 
Grifols, S.A. and the investigator will ensure that adequate consideration is given to the 
protection of the subjects’ interests. 
A subject may leave the study at any time for any reason and will be permitted to do so 
without penalty. Instituto Grifols, S.A. will be notified by the investigator if a subject 
terminates or is terminated from the study early. The reason for early termination will be 
clearly documented in subject’s medical records and the CRF/eCRF and reasonable efforts 
to perform study completion procedures will be made when appropriate. The investigator 
can withdraw a subject from the clinical trial at any time.
For subjects who are screen failures because they do not meet all inclusion criteria or they 
meet any of the exclusion criteria, it is not necessary to perform additional study 
completion procedures other than recording all the study data gathered until the moment 
when the subjects is deemed to be a screen failure, including the reasons for the screen 
failure. 
For subjects who are not screen failures and withdraw from the clinical trial before the 
beginning of the investigational medicinal product infusion, study completion procedures 
consisting of a physical assessment, recording of vital signs (T, RR, HR, SBP, and DBP,) 
and concomitant medications, and assessment of AEs will be performed during their last 
visit at the site, if possible.  
For subjects administered any amount of investigational medicinal product (infusion) who 
discontinue the clinical trial early, study procedures and assessments scheduled on Infusion 
Visit (Day 0) – 1-Hour Post-Infusion time point (see Section 4.6.2) will be performed as 
study completion procedures when discontinuation is before, or on, Infusion Visit 
(Day 0) - 1-Hour Post-Infusion time point. If early discontinuation occurs after Infusion 
Visit (Day 0) – 1-Hour Post-Infusion time point has occurred, then the assessments for the 
next required scheduled visit/time point will be performed as study completion procedures. 

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6. Allergic/hypersensitivity reaction
7. Thrombotic event
8. Virus safety
8.2
METHODS AND TIMING FOR ASSESSING, RECORDING, AND 
ANALYSING OF SAFETY PARAMETERS
8.2.1
ADVERSE EVENTS 
The occurrence and follow-up details of all AEs experienced by any of the subjects during 
the clinical trial, from the signature of the informed consent to Week 4 Visit will be 
recorded in source documents and in the CRF/eCRF. 
It is investigator’s responsibility to ensure that all AEs are appropriately recorded. 
AEs will be elicited by spontaneous reporting by the study subject or by a non-leading 
inquiry or direct observation by the study staff.
8.2.2
VITAL SIGNS
During the infusion and at different time points throughout the study, vital signs will be 
monitored by the investigator or by qualified staff. 
Clinically relevant vital signs (T, BP, HR, RR) abnormalities will be reported as AEs. 
A vital sign will be considered clinically relevant if it represents a change from the baseline 
value that meets the following criteria:
1.
HR increase or decrease of ≥30 bpm
2.
SBP increase or decrease of ≥30 mm Hg
3.
DBP increase or decrease of ≥30 mm Hg
4.
T change of ≥1ºC
8.2.3
PHYSICAL ASSESSMENT
A physical assessment by body systems will be performed at different time points 
throughout the study by the investigator or a medical doctor designated sub-investigator. 
The investigator will be required to classify the physical finding abnormalities as clinically 
relevant or not according to his/her judgment. Results will be recorded in the source 
documents and on the subject’s CRF/eCRF. Physical assessments abnormalities judged by 
the investigator as clinically relevant will be considered AEs.
8.2.4
LABORATORY PANELS
Laboratory tests will include:
1. Serum clinical chemistry: including creatinine, BUN, ALT, AST, ALP, LDH, TB, 
glucose, sodium, potassium, chloride and calcium.

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2. Hematological parameters: CBC, including platelet count and differential leukocyte 
count. 
3. Markers of activation of coagulation: different measures indicative of activation in the 
coagulation pathway (D-dimer, ATIII, TAT, F1+2).
Blood specimens for laboratory tests will be collected at different time points throughout 
the study. Laboratory tests results will be collected in the corresponding CRF/eCRF entry. 
Abnormal (out of range) results will be flagged by the reporting laboratory. The 
investigator will be required to indicate the clinical relevance of out of range (abnormal) 
results. Laboratory results out of the normal range judged by the investigator as clinically 
relevant will be considered AEs. 
In the case of markers of activation of coagulation, their relationship with plasma 
fibrinogen levels pre- and post-infusion will be studied. 
In case of pediatric sampling, pediatric tubes would be provided to reduce the amount of 
blood drawn for lab works, including the complete elimination of virology,
immunogenicity, and markers of activation of coagulation lab works. Pediatric subjects will 
not undergo Month 3 virology and immunogenicity follow-up visits, and their participation 
in the study will finish at the Week 4 Visit. Pediatric subjects weighing less than 30 kg will 
also have an even more reduced blood sampling schedule as detailed in Table 4-4 and 
Table 4-5:
-
Day 0 - baseline (including the retention sample)
-
Day 0 - 1 hour post-infusion
-
Day 0 - 8 hours post-infusion
-
Day 1 - 24 hours post-infusion
-
Day 4 - 96 hours post-infusion
-
Day 6 - 144 hours post-infusion and
-
Day 9 - 216 hours post-infusion
8.2.5
ANTIBODIES AGAINST FIBRINOGEN DETERMINATION 
(IMMUNOGENICITY TESTING)
Evidence of any possible immunogenicity of the investigational product will be assessed at 
the sponsor’s laboratory. Samples from adult subjects will be assayed for the generation of 
antibodies to fibrinogen by using a stepwise approach starting with a functional screening 
assay to detect neutralizing activity. In the event neutralizing activity is detected, samples 
will be further assessed by a confirmatory ELISA for the presence of antibodies to 
fibrinogen.
If a confirmed, single case of immunogenicity is reported after a subject has been dosed 
with study drug, any further enrollment and dosing of subjects in the study will be 
suspended until the event can be adequately assessed by the safety group of the sponsor. 
The enrollment and dosing will only resume after explicit authorization by the sponsor. 

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8.2.6
MONITORING OF ALLERGIC/HYPERSENSITIVITY REACTIONS  
Subjects will be carefully monitored by the investigator or study staff for signs and 
symptoms of allergic/hypersensitivity reactions occurring between the Baseline Visit and 
the Week 4 Visit. The Grifols Medical Monitor will routinely review reported AEs for 
possible allergic/hypersensitivity reactions according to the algorithm described in 
Annex 2.
8.2.7
MONITORING OF THROMBOTIC EVENTS
Subjects will be monitored by the investigator and/or study staff for signs and symptoms of 
arterial and venous thromboses occurring between the Baseline Visit and the Week 4 Visit. 
The algorithms described in Annex 1, which include the Wells Score assessment, will be 
observed for evaluation and assessment of thrombotic events risk. In addition, the Grifols 
Medical Monitor will routinely review reported AEs for possible thromboses. Arterial and 
venous thromboses will be identified according to definitions in the International 
Classification of Diseases, Ninth Revision, Clinical Modification (ICD-9-CM [66]). Such 
thrombotic events include, but are not limited to, DVT, PE, myocardial infarction, 
cerebrovascular accident, acute coronary syndrome, limb thrombosis, sagital sinus 
thrombosis, and portal vein or mesenteric artery thrombosis. All thromboses will be 
recorded as AEs and reported accordingly. 
If a confirmed single case of thrombosis is reported after a subject has been dosed with 
study drug, any further enrollment and dosing of subjects in the study will be suspended 
until the event can be adequately assessed by the safety group of the sponsor. The 
enrollment and dosing will only resume after explicit authorization by the sponsor. 
8.2.8
VIROLOGY TESTING
Viral monitoring for each adult subject will be performed by mean of serology and nucleic 
acid amplification technology tests. 
Serum/plasma samples from all subjects will be drawn at baseline (prior to the scheduled 
infusion). An additional aliquot of serum/plasma will be retained from all viral time points 
for re-testing if necessary.
During follow-up, viral monitoring will be limited to those subjects and viruses where all 
previous tests were non-reactive (negative) for the target virus at baseline (prior to the 
infusion of the investigational medicinal product) and previous visits. If there is a positive 
virology test result at baseline, laboratory testing for this particular virus will no longer be 
performed during the course of the clinical trial. 
If there is a change from baseline (prior to the infusion of the investigational medicinal 
product) viral status during clinical trial, it must be confirmed by repeating the virology 
test, using the same technique and/or other techniques as deemed appropriate by the 
sponsor (eg, more sensitive techniques), such as nucleic acid amplification technology tests. 
Moreover, if considered necessary by the sponsor, re-analysis of any sample could be 
ordered, including storage samples, by an independent laboratory.

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8.3
PROCEDURES FOR ELICITING REPORTS OF AND FOR RECORDING 
AND REPORTING ADVERSE EVENT AND INTERCURRENT ILLNESSES
8.3.1
ADVERSE EVENT 
An AE is defined as any untoward medical occurrence in a subject or clinical investigation 
subject administered a medicinal product or study treatment and which does not necessarily 
have a causal relationship with this administration. An AE can therefore be any unfavorable 
and unintended sign (including any abnormal laboratory findings, for instance), symptoms, 
or disease temporally associated with the use of a medicinal product or study treatment, 
whether or not considered related to the medicinal product or study treatment. 
Any AE that occurs at any time between signature of the informed consent and last day of 
the subject’s participation in the clinical safety period of the study (Week 4 Visit) must be 
reported on the AE CRF/eCRF entry.
8.3.2
CAUSALITY OF ADVERSE EVENT 
The investigator will be asked to assess the causal relationship of the AE to the study 
treatment according to the following classification based on Karch FE et al [64]:
- Definite: An event that follows a reasonable temporal sequence from administration of 
the treatment or in which the treatment level has been established in body fluids or 
tissues; that follows a known response pattern to the suspected treatment; and that is 
confirmed by improvement on stopping the treatment (dechallenge), and reappearance of 
the event on repeated exposure (rechallenge).
- Probable: An event that follows a reasonable temporal sequence from administration of 
the treatment; that follows a known response pattern to the suspected treatment; that is 
confirmed by dechallenge; and that could not be reasonably explained by the known 
characteristics of the subject’s clinical state. 
- Possible: An event that follows a reasonable temporal sequence from administration of 
the treatment; that follows a known response pattern to the suspected treatment; but that 
could have been produced by the subject’s clinical state or other modes of therapy 
administered to the subject. 
- Doubtful/Unlikely: An event that follows a reasonable temporal sequence from 
administration of the treatment; that does not follow a known response pattern to the 
suspected treatment; but that could not be reasonably explained by the known 
characteristics of the subject’s clinical state.  
- Unrelated: Any event that does not meet the criteria above.
The operational tool to decide the AE causal relationship is based on algorithms by Karch-
Lasagna and Naranjo [64, 65].
When an AE is classified, assessing causal relationship by the investigator, as definitive, 
probable, possible, or doubtful/unlikely, the event will be defined as suspected adverse drug 

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reaction (ADR). When the causal relationship is labeled “Unrelated”, then it will be 
considered that the AE is not imputable to the study treatment and it is not an ADR. 
Any AE experienced by the subject prior to the investigational product infusion on Day 0 
will be labeled as Unrelated to the investigational medicinal product.
8.3.3
SUSPECTED ADVERSE DRUG REACTION  
All noxious and unintended responses to a medicinal product or study treatment related to 
any dose should be considered a suspected ADR. The phrase “responses to a medicinal 
product” means that a causal relationship between a medicinal product or study treatment 
and an AE is at least a reasonable possibility, that is, the relationship cannot be ruled out. In 
the framework of this study, a suspected ADR with a causal relationship of “definite” will 
be named as Adverse Reaction. Adverse reactions are a subset of suspected ADR.   
The sponsor is responsible for assessing the suspected ADR expectedness during the 
clinical trial.
8.3.4
SEVERITY OF ADVERSE EVENT OR SUSPECTED ADVERSE DRUG 
REACTION
AE and suspected ADR will be classified depending on their severity (intensity) according 
to the following definition:
1. Mild: awareness of sign or symptom, but easily tolerated (acceptable)
2. Moderate: discomfort to interfere with usual activity (disturbing)
3. Severe: incapacity to work or to do usual activity (unacceptable)
AE and suspected ADR severity (intensity) gradation must be distinguished from AE and 
suspected ADR seriousness gradation, which is defined according to event consequence. 
For example, a headache could be mild, moderate or severe but unusually is serious in all 
these cases.
The investigator will be responsible for assessing the AE or suspected ADR severity 
(intensity) during the clinical trial, taking into account currently criteria detailed in this 
section.
8.3.5
SERIOUS ADVERSE EVENT
An SAE is an AE or a suspected ADR, occurring at any dose that fulfils one or more of the 
following:
1. Results in death.
2. Is immediately life-threatening (life-threatening in the definition of SAE refers to an 
event in which the subject was at immediate risk of death at the time of the event; it 
does not refer to an event which hypothetically might have caused death if it were more 
severe).

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3. Requires in-subject hospitalisation or requires prolongation of existing hospitalization*.
4. Results in persistent or significant disability/incapacity.
5. Is a congenital anomaly/ birth defect.
6. Is an important medical event: important medical event in the definition of “serious” 
refers to those events which may not be immediately life-threatening, or result in death, 
or hospitalization, but from medical and scientific judgment may jeopardize the subject 
and/or may require medical or surgical intervention to prevent one of the other 
outcomes listed above. Examples of such events are intensive treatment in an 
emergency room or at home for allergic bronchospasm, blood dyscrasias or convulsions 
that do not result in hospitalization. Development of cancer or drug dependency or drug 
abuse will normally be considered serious by this criterion.
*Hospitalization is to be considered only hospital stay for equal or more than 24 hours. 
The following hospitalizations should not be reported as SAEs:
- Hospitalization or prolongation of hospitalization needed for procedures required by 
the clinical trial protocol.
- Hospitalization or prolongation of hospitalization as part of a routine procedure 
followed by the center.
- Hospitalization for a survey visit, annual physicals, or social reasons.
- Elective (pre-planned) hospitalizations for a pre-existing condition that had not 
worsened from Baseline (eg, elective or scheduled surgery arranged prior to start of 
the study).
- Admissions not associated with an AE (eg, social hospitalization for purposes of 
respite care).
A distinction should be drawn between serious and severe AEs. The term “severe” is used 
to describe the severity of a specific event; the event itself, however, may be of relative 
minor medical significance (such as severe headache). This is not the same as “serious”, 
which is defined on subject/event outcome or action criteria usually associated with events 
that pose a threat to a subject’s life or functioning. Seriousness (not severity) is a medical 
term while severity is a subjective term. 
According to the medical criteria, an AE, or a suspected ADR, can be classified as serious, 
although it does not fulfill the conditions detailed in this section, if it is considered 
important from a medical point of view. The investigator is responsible for assessing the 
AE, or suspected ADR, seriousness during the clinical trial, taking into account currently 
criteria detailed in this section.
8.3.6
COLLECTION AND REPORTING OF ADVERSE EVENTS AND SUSPECTED 
ADVERSE DRUG REACTIONS 
AEs will be collected from the time of the subject´s signature of the Clinical Trial Informed 
Consent until Week 4 Visit. All reported AEs will be recorded on the AE CRF/eCRF entry. 

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An identical entry should be also present in the subject’s hospital record. If no AE has 
occurred during the study period, this should also be indicated in the CRF/eCRF.
At each visit/time point, the occurrence of AEs will be assessed by the study staff. If it is 
possible, AEs will be elicited by asking the subject a non-leading question such as “Do you 
feel different in any way since the last assessment?” Moreover, AE will also be collected 
through directly observed events or spontaneously volunteered by the subject. Signs 
observed by the study staff should also be considered to elicit AEs especially when the 
subjects cannot be asked (eg, the subject is anesthetized). Clearly related signs, symptoms 
and abnormal diagnostic procedures should preferably be grouped together and recorded as 
a single diagnosis or syndrome wherever possible. It is responsibility of the investigator to 
ensure that AEs are appropriately recorded.
Infusional AEs (ie, AEs temporally associated with an infusion of investigational medicinal 
product) will be defined as any AE occurred during the infusion or within 24 after 
completion of the infusion. For example, it will include any clinically relevant 
abnormalities in vital signs during the infusion, as previously defined. 
Other safety variables comprise blood laboratory tests. A clinically relevant deviation from 
normal/reference laboratory ranges based on each individual pre-study (baseline) value (as 
judged by the investigator) may also constitute an AE and should be recorded on the AE 
CRF/eCRF entry. Abnormalitites in laboratory results, vital signs and physical exams 
should not be recorded as AEs if they are known to be a symptom or sign of a syndrome or 
diagnosis that is also being reported as an AE.  
The following variables must be recorded on the AE CRF/eCRF entry:
1. The verbatim term (a diagnosis is preferred)
2. Date/time of onset
3. Date/time of resolution
4. Severity (mild, moderate, severe)
5. Causality (unrelated, doubtful/unlikely, possible, probable, definite)*
6. Seriousness (yes, no)
7. Action taken (with regard to study drug)
8. Other action (to treat the event)
9. Outcome and sequel (follow-up on AE)
* Causality assessment will be only made when the AE occurs after the subject has been 
administered the investigational product (at any dose). AE occurring before subject's 
exposure to study treatment will be always labeled as "Unrelated".
In addition to the investigator’s own description of the AEs, each AE will be encoded by 
the sponsor or designated (eg, contract research organization [CRO]) according to the 
Medical Dictionary for Regulatory Activities (MedDRA®) dictionary of medical codes.
A pregnancy not verified before enrollment but occurring during the course of the study 
will not be considered an AE, unless a causal relationship to the study drug is at least 
suspected. In any case, a Pregnancy Report Form must be completed and sent within 24 

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9.
STATISTICS
9.1
STATISTICAL METHODS TO BE EMPLOYED AND TIMING OF 
PLANNED INTERIM ANALYSIS(SES)
9.1.1
STATISTICAL ANALYSIS OF DEMOGRAPHIC DATA AND BASELINE 
CHARACTERISTICS
Demographic data and other baseline characteristics, for the safety population (see 
Section 9.7.1), will be presented in tabular form and summarized by both adult and 
pediatric populations using descriptive statistics.
9.1.2
STATISTICAL ANALYSIS OF PHARMACOKINETICS
PK analyses will be assessed on the PK population (see Section 9.7.1). PK analyses will be 
performed on both the adult and pediatric populations independently.
9.1.2.1
Analysis of PK concentration and dosing data
Plasma concentrations of fibrinogen will be summarized by visit/time point and by both 
adult and pediatric populations. The summaries will include n, mean (standard deviation 
[SD]), 90% confidence interval (CI) for mean, coefficient of variation (% CV), median, 
minimum, and maximum as well as geometric mean. Plasma fibrinogen concentration 
versus time curves will be presented by both adult and pediatric populations. 
9.1.2.2
Calculation of PK parameters
The PK profiles of the investigational product following single administration will be 
characterized by PK parameters, including IVR, AUC calculated as AUC0-14days, AUC0-∞,
Cmax, tmax, t1/2, MRT, Vd, and Cl. 
All PK parameters will be calculated using non-compartmental methods using the 
fibrinogen concentration values obtained by both Clauss method and antigen (ELISA) 
methods.
9.1.2.3
Analyses of PK parameters
Descriptive statistics (summarized by both adult and pediatric populations), including n, 
mean, SD, 90% CI for mean, % CV, median, minimum, maximum, and geometric mean 
(except tmax) will be calculated for all PK parameters including AUC 0-14 days, and AUC0-. 
PK analysis will be independently performed for adult and pediatric populations.
9.1.3
STATISTICAL ANALYSIS OF EFFICACY
Primary efficacy analyses will be assessed on the evaluable  population (see Section 9.7.1) 
and in addition on the per protocol (PP) population (see Section 9.7.1). Unless otherwise 
specified, the test is two-sided and the significance level is 0.05. All analyses on efficacy 
parameters (for the primary, secondary 
 efficacy endpoints) will be carried 
out in the overall study population (adults subjects plus pediatric subjects), and will also be 
conducted in the adult population and the pediatric population separately. The primary 
efficacy analyses will be the ones performed on the overall study population.

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9.1.4
STATISTICAL ANALYSIS OF SAFETY
Adverse events:
Safety analyses for FIB Grifols will be performed on the overall population (both adult and 
pediatric age groups). FIB Grifols safety will also be assessed independently for both adult 
and pediatric populations.
Any AE that occurs at any time between signing of the Clinical Trial Informed Consent and 
Week 4 Visit will be reported on the appropriate subject’s CRF/eCRF entry for any subject 
who received at least 1 infusion (at any dose) of investigational product.
Treatment-emergent AEs (ie, AEs occurring after the start of the investigational product 
infusion) will be listed and tabulated by body system with subject identification code, and 
they will be also presented as subject incidences and percentages. In addition, treatment-
emergent AEs will be summarized by both adult and pediatric populations as well as 
severity (intensity), seriousness (serious versus non-serious), and causal-relationship to the 
study product.
Similarly, all treatment-emergent AEs potentially related to the investigational product will 
be listed and tabulated by body system with subject identification code, and they will be 
also presented as subject incidences and percentages. In addition, these will be also 
summarized by both adult and pediatric populations as well as severity (intensity) and 
seriousness (serious versus non-serious).
For AEs temporally associated to the infusion, listings of AEs will be presented. AEs will 
be also split between AEs occurring during the infusion or after the infusion completion but 
within 24 and 72 hours after completion of the infusion. For an AE that occurs during an 
infusion, the infusion rate in effect at the time of onset of the AE, the time the AE is first 
reported and the time the AE changes materially in intensity and/or resolves are all to be 
reported and tabulated.
Subjects who die, report a serious AE (SAE), or withdraw from the study because of AEs 
will be also individually listed and summarized. 
AEs will be coded according to the AEs classification of the MedDRA, and will be 
described by a synonym (Preferred Term) and the affected organ / system, the intensity, 
causality and seriousness.
Vital signs:
Vital signs (T, RR, HR, SBP, DBP) will be listed for each clinical trial subject. In case a 
subject presents a clinically relevant variation of vital signs during an infusion will be 
flagged and discussed as an AE temporally associated to the infusion.
Clinically relevant vital signs, as defined in advance in the clinical trial protocol (see 
Section 8.2.2) will be flagged and discussed as an AE. 
Physical assessment:

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Physical findings (normal and abnormal) will be listed for each clinical trial subject. 
Subjects who acquire clinically relevant abnormalities, which were not already present at 
baseline, will be flagged and discussed as an AE. 
Serum clinical chemistry:
All clinical laboratory data for serum clinical chemistry (creatinine, BUN, TB, ALP, ALT, 
AST, LDH, glucose, sodium, potassium, chloride and calcium) will be listed for each 
clinical trial subject and clinically relevant abnormalities (abnormal values are those out of 
the normal range reported by the respective laboratory), as judged by the investigator, will 
be flagged. 
Hematology:
All clinical laboratory data for hematology (CBC): RBC count, Hgb, Hct, MCH, MCHC, 
MCV, WBC count and differential, and platelet count) will be listed for each clinical trial 
subject and clinically relevant abnormalities (abnormal values are those out of the normal 
range reported by the respective laboratory), as judged by the investigator, will be flagged. 
Markers of activation of coagulation:
All clinical laboratory data for markers of activation of coagulation (D-dimer, ATIII, TAT, 
and F1+2) will be listed for each adult clinical trial subject and clinically relevant 
abnormalities (abnormal values are those out of the normal range reported by the respective 
laboratory), as judged by the investigator, will be flagged. 
Immunogenicity testing:
All results of testing for antibodies to fibrinogen will be listed for each adult clinical trial 
subject. 
In the event a subject becomes positive for antibodies to fibrinogen during the study period, 
the case will be evaluated and discussed.
Events of special interest - allergic/hypersensitivity reactions and thrombotic events
Events of special interest such as allergic/hypersensitivity reactions and thrombotic events
(results of the Wells Score will be utilized to assess thrombotic events risk) will be 
individually listed and summarized. These events will be individually summarized and 
evaluated taking into account all available information about predisposing factors in the 
clinical history of the subject, infusion rate at onset (if applicable), time elapsed since 
infusion, fibrinogen levels at/close to onset, markers of activation of coagulation levels (not 
applicable for pediatric subjects) pre-infusion, post-infusion and at/close to onset (if 
available) and any other relevant factors.
Virus safety:
All results of viral markers will be listed for each adult clinical trial subject. 
In case of a potential seroconversion during the study, it will be reported and discussed.

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9.1.5
TIMING OF PLANNED INTERIM ANALYSIS
An interim safety analysis will be performed with the adult population in order to assess the 
safety of FIB Grifols prior to starting enrollment of pediatric subjects. PK and efficacy 
interim analyses of the investigational medicinal product may also be performed in the 
adult population. 
9.2
SAMPLE SIZE DETERMINATION
The sample size in this study is based on the PK assessment. The sample size of 10 adult 
subjects was selected to establish a PK profile of the investigational product. In order to 
allow for possible drop-outs, 11 adult subjects will be enrolled in the study. 
Only after the safety of the product has been assessed and established in the adult subjects 
population, will 10 pediatric subjects be enrolled into the study. Assuming a 10% dropout 
rate, a total of 11 pediatric subjects need to be enrolled.
9.3
LEVEL OF SIGNIFICANCE
Unless otherwise specified, all statistical tests will be two-sided, for which an alpha level of 
0.05 will be considered to indicate statistical significance.
9.4
CRITERIA FOR THE TERMINATION OF THE TRIAL
Not anticipated.
9.5
PROCEDURES FOR ACCOUNTING FOR MISSING, UNUSED, AND 
SPURIOUS DATA
For the PK analysis, any missing or not valid values for fibrinogen concentration will be 
treated as missing, or if necessary, will be interpolated or extrapolated using PK principle, 
as appropriate, and will be documented in the clinical study report.
For primary efficacy endpoint analysis, the missing value in change from baseline in MCF 
will be set to zero.
9.6
PROCEDURES FOR REPORTING ANY DEVIATION FROM THE 
ORIGINAL STATISTICAL PLAN
In case of any deviations from the original statistical plan, these will be documented in the 
final study report.
9.7
SELECTION OF SUBJECTS TO BE INCLUDED IN THE ANALYSES
9.7.1
POPULATION FOR PHARMACOKINETIC ANALYSIS
The PK analysis population will consist of all subjects who have received study medication 
and have sufficient fibrinogen plasma concentration data to facilitate calculation of 

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pharmacokinetic parameters. The PK population will be used for the analyses of the PK 
parameters.
9.7.2
POPULATION FOR STATISTICAL ANALYSIS OF EFFICACY
Two study populations for statistical analysis of efficacy will be used: evaluable population 
and PP population. All efficacy analysis will be primarily run on the evaluable population 
and then they will be also run on PP. 
Definition of evaluable population: 
The evaluable population will include all subjects who received investigational product at 
any amount and who have at least two measurements for the primary efficacy variable: one 
pre-infusion MCF and 1-hour post-infusion MCF measurements by ROTEM. 
Definition of PP: 
The PP population will include all subjects who received planned dose of the 
investigational product (at least 90% of the planned dose), who have no major protocol 
violation (to be defined in a data review meeting prior to database lock), and who have at 
least two measurements for the primary efficacy variable: one baseline (pre-infusion) MCF 
measurement by ROTEM and 1-hour post-infusion MCF measurement by ROTEM for the 
investigational medicinal product.
9.7.3
POPULATION FOR STATISTICAL ANALYSIS OF SAFETY
All subjects who receive infusion (at any dose) of the investigational product will be 
included in the safety population. 
10.
DIRECT ACCESS TO SOURCE DATA/DOCUMENTS
The investigator will permit study-related monitoring, sponsor audits, Institutional Review 
Board’s (IRB) review and health authorities’ inspection(s), providing direct access to 
source data and documents. A person designated by the sponsor will monitor the study to 
ensure that all required documentation is available, and that collected data on the 
CRF/eCRF precisely reflect data on source documents. Access to the history and clinical 
course of the study subjects by the monitor will be granted. A trial quality assurance audit 
may be conducted at any time during the course of the study or after its conclusion at the 
site or vendor.
For each enrolled subject, the investigator or designee will write into the subject’s medical 
history that he/she is enrolled in this study sponsored by Instituto Grifols, S.A., a well as all 
safety and efficacy information. The investigator is responsible for maintaining complete 
and adequate case histories in source records of each subject. Source data must be 
preserved for the maximum period of time permitted by local regulations and made 
available by the investigator in the cases described below.

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11.
QUALITY CONTROL AND QUALITY ASSURANCE
The present clinical trial will be conducted in accordance with the GCP/ICH guidelines. 
Clinical trial monitoring team will systematically control the clinical trial essential 
documents. All clinical trial phases will be monitored and they may be subjected to internal 
audits by quality assurance (QA). All monitoring visits and internal audits will be followed 
by internal reports and corrective actions, if needed. Follow-up letters will be forwarded to 
sites after all clinical visits.
11.1
QUALITY CONTROL BY THE CLINICAL TRIAL MONITORING TEAM
The clinical trial monitoring team will monitor data collected throughout the study. The 
investigator will be available for clinical trial monitors during their visits and will ensure 
that the monitor has access to all documents that they require, including to the subject’s 
files (direct access). The investigator agrees to cooperate with the monitor to make certain 
that any problems detected in the course of these monitoring visits are resolved. Subject’s 
anonimity must be safeguarded and all data checked during these monitoring visits must 
remain confidential.
11.2
QUALITY ASSURANCE BY THE CLINICAL TRIAL AUDIT TEAM
Any study site or vendor may be selected for audit at any moment by a clinical trial audit 
team, originating from the sponsor or from the external CROs acting on behalf of the 
sponsor.
The investigator and audited staff agree to cooperate with the auditor to ensure that any 
problems detected in the course of these audit visits are resolved. Subject’s anonymity must 
be safeguarded and data checked during these audit visits must remain confidential.
12.
ETHICS
12.1
ETHICAL CONSIDERATIONS AND ETHICS COMMITTEE
The ethical standards adopted by the XVIII World Medical Assembly (Helsinki, 1964) (and 
subsequent revisions) will be strictly observed. The clinical trial likewise will be performed 
in compliance with standards of ICH GCP guideline relating to trials involving 
investigational drugs (ICH Topic E6).
The study cannot begin until an independent ethics committee (IEC)/IRB and the health 
authorities (when necessary) have approved the protocol, the informed consent document, 
and the patient information sheets. The investigator will provide the sponsor/CRO with a 
copy of the communication from the IEC/IRB to the investigator indicating approval of the 
protocol and consent form/information sheets before the clinical trial is started. 
The IEC/IRB must be informed of all relevant protocol amendments that may affect the 
safety of the participating subjects or conduction of the clinical trial. All substantial 
amendments to the protocol must be reviewed and approved prior to implementation as 
applicable per local regulations in force, except where necessary to eliminate apparent 
immediate hazards to human subjects. SAEs, unexpected adverse reactions, and other 

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relevant information that may alter the study design or entail subject risk will be reported to 
the IEC/IRB when required per applicable local regulations. Equally, protocol deviations 
and violations may be submitted to IRB according to the requirements of each of these 
institutions.
The investigator will be responsible for obtaining annual IEC/IRB renewal when applicable 
and submitting SAE reports to the IEC/IRB for the duration of the study (as per site policies 
and procedures). Copies of the investigator’s report and/or copies of the IEC/IRB extension 
approval must be made available to the sponsor or designee (eg, CRO).
12.2
INFORMED CONSENT AND INFORMATION SHEETS
The investigator (or designee) will obtain written informed consent from each subject 
participating in this clinical trial, after adequate explanation of the aims, methods, 
anticipated benefits and potential hazards of the study, and prior to initiating any study 
related procedure to a subject. 
For subjects not qualified to give legal consent, written consent must be obtained from the 
parent or legal guardian.  
Each subject will be also informed that his/her source medical records may be scrutinized 
by the clinical trial monitor team, the clinical trial audit team, inspectors from the health 
authorities or reviewers from the IEC/IRB, in accordance with applicable regulations; that 
the investigator will protect any personal information not related to the study; and that these 
persons are bound by the same confidentiality obligations as the subject’s family doctor. 
The investigator (or designee) will explain that subjects are completely free to refuse to 
enter into the clinical trial or to withdraw from it at any time, without any consequences for 
their further care and without the need for them to justify their decision. 
After the subject has had time to read the information and feels all their questions have 
been answered, they will be asked to sign the Clinical Trial Informed Consent. The 
investigator will also sign and date the Clinical Trial Informed Consent, thus reflecting that 
informed consent has been obtained, and that the subject (and his/her representative) has 
had the opportunity to ask questions, and has received adequate answers. The subject will 
receive a signed copy of the Clinical Trial Informed Consent and of the Patient Information 
Sheet. The original Clinical Trial Informed Consent will be filed along with the study 
documentation.
12.3
CONFIDENTIALITY
All data related to procedures, medications, patents, scientific information, and other data 
on materials will be considered confidential, and are sponsor’s property. However, the 
study protocol and other important documents may be submitted to the IEC/IRB and health 
authorities to obtain approval for conducting the study. 
The investigator will ensure that the subjects’ anonymity will be maintained. Applicable 
privacy rules will be followed to obtain authorization for most uses and disclosures of 
Protected Health Information. On CRF/eCRFs or other documents submitted to the sponsor 
or its designee, subjects will not be identified by their names, but by a numeric 
identification code. Documents not for submission to Instituto Grifols, S.A. or its designee, 

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(eg, the site confidential subject enrolment log and original subjects’ consent forms) will be 
maintained by the investigator in strict confidence.
The investigator will accept that the sponsor may use the clinical trial results, including 
CRF/eCRF data, sheets or their copies, or reports with or without comments, and with or 
without analyses, to submit them to regulatory authorities, and may reveal them if needed 
to other investigators. To allow use of the information obtained in the clinical trial, the 
investigator will understand that he/she will be obliged to supply the sponsor with full 
results of the tests and all the information developed during the study.
13.
DATA HANDLING AND RECORD KEEPING
13.1
DATA COLLECTION AND MANAGEMENT
The study data will be recorded and kept current in the CRF/eCRF by the site study 
personnel directly responsible for the information. 
The data in the CRF/eCRF will be monitored at the site by Grifols representatives or 
designee and reviewed for completeness and compared with the available source 
documents. Examples of source documents include individual subject medical records or 
laboratory reports, which are separate from the CRF/eCRFs.  
Coding of AEs will be performed automatically by the data management team using the 
MedDRA dictionary. Similarly, coding of all medications will occur using the WHODrug 
dictionary. SAEs will be also coded using MedDRA.
13.2
RECORD KEEPING
The investigator is responsible for maintaining all records pertaining to the clinical trial and 
for ensuring complete and accurate documentation. 
The investigator is responsible for maintaining a nominative subject enrollment log. This 
confidential subject identification code provides the link between named subject source 
records in the subject file and anonymous CRF/eCRF data provided to sponsor.
Essential documents of the study will be retained by the investigator according to what is 
established in the ICH GCP (ICH E6), or as per local regulations, whichever is longer. 
No study documents will be destroyed without prior written agreement between the 
investigator and Instituto Grifols, S.A. Should the investigator wish to assign the study 
records to another party, or move them to another location, Instituto Grifols, S.A., must be 
notified in writing.
14.
FINANCING AND INSURANCE
The sponsor will acquire an insurance policy to cover possible damage to the subject 
resulting from their participation in the study, in accordance with applicable local 
legislation; such coverage will be renewed periodically for the full duration of the study.

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15.
PUBLICATION POLICY
Institution and the investigator agree that the first publication shall be made in conjunction 
with the presentation of a joint, multi-center publication of the study results from all 
appropriates sites. If such a multi-center publication is not submitted within twelve (12) 
months after conclusion of the study at all sites or after Grifols confirms there will be no 
joint, multi-center publication, then institution and/or investigator shall have the right, at 
their discretion, to publish, either in writing or orally, the results of the study performed 
under the protocol, subject to the conditions outlined below:
1. The results of the study will be reported in the publicly accessible registry(ies).
2. Institution and/or investigator shall furnish Grifols with a copy of any proposed 
publication at least thirty (30) days in advance of the date of submission for publication.  
3. Within said thirty (30) day period, Grifols shall:  

Review such proposed publication for confidential information (other than study 
results) and for subject information subject to the HIPAA and other applicable 
privacy laws;

Review such proposed publication for the unauthorized use of the name, 
symbols and/or trademarks of Grifols;

By written notice to the investigator, identify with specificity the text or 
graphics in such proposed publication that Grifols contends contains 
confidential information, protected subject information, or the unauthorized use 
of Grifols’ name, symbols and/or trademarks so that the proposed publication 
may be edited appropriately to remove such text or graphics before publication; 
and 

By written request, Grifols may delay proposed publications up to sixty (60) 
days to allow Grifols to protect its interests in Grifols Inventions described in 
such publications.  
4. Institution and/or investigator shall give Grifols the option of receiving an 
acknowledgment for its sponsorship of the study in all such publications or 
presentation. 

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