Clinical trial NCT02155725
Conditions: Post-Partum Hemorrhage
Keywords: PPH fibrinogen vaginal delivery
Sponsor: Laboratoire français de Fractionnement et de Biotechnologies
Start date: 2014-04-10; Completion date: 2018-08-06
Enrollment: 448 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
The purpose of the study is to assess the benefits of a therapeutic strategy that associates an early administration of human fibrinogen concentrate in the management of PPH on the reduction of bleeding after the initiation of prostaglandins intravenous infusion, following vaginal delivery.

Detailed description:
Randomised, double-blind,multicenter, placebo-controlled study

Arms: arm 1: 2 vials (200ml) / 3g intravenous arm 2: 2 vials (200ml)
Interventions: intervention 1: Human Fibrinogen concentrate intervention 2: Placebo
Intervention descriptions: intervention 1: Injection as soon as possible and within 30 min following the start of prostaglandin infusion intervention 2: As soon as possible and within 30 min following the start of prostaglandin infusion

Protocol documents:
ICF_002.pdf: 
 
COVER PAGE 
 
 
TITLE: A randomised, multicentre, double-blind, placebo-controlled study on the efficacy 
and safety of a therapeutic strategy of post-partum haemorrhage comparing early 
administration of human fibrinogen versus placebo in patients treated with intravenous 
prostaglandins following vaginal delivery.  
 
NCT Number: NCT02155725 
 
DOCUMENT: Informed consent form (v 7.0)  
 
 
VERSION & DATE OF DOCUMENT: Version 7.0; March 06, 2018 


 
INFORMATION SHEET IN EMERGENCY SITUATION 
 
FIDEL STUDY 
 
 
Version 7.0 of 06/03/2018 
 
page 1/4 
 
 
                                                                          
CONFIDENTIAL 
 
This information document is intended for the patient. However, in the case of an emergency 
situation, if the patient cannot receive this information, then it must be delivered to a family member 
or trusted person designated by the patient. 
 
Dr ………...…….......……….. is proposing that you participate in a biomedical study entitled:  
“A multicentre, controlled, randomised, double-blind study to evaluate the benefits and tolerance of a 
treatment strategy for postpartum haemorrhage associating early administration of human fibrinogen 
versus placebo in patients treated with intravenous prostaglandins after vaginal delivery – FIDEL” 
 
This study is conducted by the Laboratoire français du Fractionnement et des Biotechnologies [French 
Laboratory for Fractionation and Biotechnologies] (LFB BIOMEDICAMENTS, 3 avenue des Tropiques, 
BP50052, Les Ulis, 91942 Courtaboeuf Cedex). 
The Lille Ethics Committee gave its favourable opinion on 10/12/2013. The French National Agency for 
Medicines and Health Products Safety (ANSM) also gave its authorisation on 25/11/2013.  
You have just given birth and persistent bleeding, also called Postpartum Haemorrhage (PPH), has been 
observed. Therefore, you may be able to participate in the study. 
PPH is excessive bleeding that occurs after childbirth.  
The haemorrhage is associated with loss of blood proteins, including fibrinogen, which plays an important 
role in clotting. The administration of a fibrinogen concentrate could therefore compensate for the loss of 
this protein and help stop the bleeding.  
Fibrinogen has been available in France as a medicine called Clottafact® since May 2009. Its use is 
authorised in the management of postpartum haemorrhages. 
The aim of the study is to evaluate whether the early administration of Clottafact could help control the 
bleeding. 
The study will take place in France, in around twenty hospitals and, if you accept, you will be one of the 
470 patients who will participate. 
 
1. BIOMEDICAL STUDY PROCEDURES 
 
Allocation of the study treatment: 
In this study you will receive by drawing lots either 3g of fibrinogen, that is to say Clottafact®, or a placebo 
which contains no active substance.  
However, the doctor can find out the treatment if he/she deems this necessary. 
 
Your follow-up during the study: 
Before the study treatment is administered, you will have a blood sample taken from your arm (24 ml or 
about 1.5 tablespoons) to perform blood tests including the assay of fibrinogen.  
Your treatment (Clottafact® or placebo) will then be administered to you all at once by an infusion into a 
vein, which will last about twenty minutes. 
You will then be examined by the study doctor and a blood sample will be 3 more times: 2 hours, 6 hours, 
then the second day after administration of the study treatment. 
If the study doctor deems it necessary, he/she may administer fibrinogen even if you are in the group of 
patients who received placebo. 
 


 
INFORMATION SHEET IN EMERGENCY SITUATION 
 
FIDEL STUDY 
 
 
Version 7.0 of 06/03/2018 
 
page 2/4 
 
 
                                                                          
CONFIDENTIAL 
 
Throughout your stay in the hospital, your treatment will be identical to that which you would have received 
if you had not participated in the study. 
2. POSSIBLE BENEFITS  
Early administration of Clottafact may help to control the bleeding, for example by reducing the need for 
blood transfusions and more invasive treatments. 
You may not derive any particular benefit from this study if you receive the placebo.  
But, in any case, your participation will be useful, in the future, to other patients who will be in the same 
situation as you, by helping us to better understand PPH and better manage it. 
3. RISKS AND POSSIBLE INCONVENIENCES 
Like all medicines, Clottafact can cause adverse effects, although not everybody gets them. 
• Headache, dizziness, ringing in the ears, difficulty breathing (asthma), vomiting associated with 
headaches, redness, itching, skin rash, night sweats, feeling hot, 
• Blood circulation disorders (deep vein thrombosis, superficial thrombophlebitis, pulmonary 
embolism) from the formation of a blood clot in an artery or vein. However, it is known that the risk 
of having this type of event is increased after childbirth, even in the absence of treatment with 
Clottafact®,  
• Allergic reaction (including anaphylactic shock, paleness, vomiting, cough, low blood pressure, 
chills, hives) as with medicine containing proteins that is administered intravenously. 
4. CONFIDENTIALITY 
Your file will be viewed by LFB BIOMEDICAMENTS, or its representatives, in order to verify the validity 
of the clinical data collected. 
All personal information about you collected and processed by computer for the purposes of the study (age, 
sex, height, weight, medical history) will be kept strictly confidential. 
5. INSURANCE  
LFB BIOMEDICAMENTS has taken out civil liability insurance covering any health problem related to 
your participation in the study (company: HDI-GERLING - Contract no.: 01010260-14023). 
 
Your participation in the study is completely free and voluntary and you can refuse if you wish.  
If you authorise your doctor to include you in the study, he/she will get back to you as soon as your 
state of health allows it to give you more detailed information. You will then have time to ask him/her 
any questions you want. He/she will then ask you to confirm that you agree to your data being used. 
If you refuse to participate or if, at any time, you decide to withdraw, your decision will in no way 
affect the quality of the care you will receive or the relationship with your doctor 


 
PATIENT CONSENT IN EMERGENCY SITUATION 
FIDEL STUDY 
 
Version 7.0 of 06/03/2018 
 
 
CONFIDENTIAL 
page 3/4 
 
“A multicentre, controlled, randomised, double-blind study to evaluate the benefits and tolerance of 
a treatment strategy for postpartum haemorrhage associating early administration of human 
fibrinogen versus placebo in patients treated with intravenous prostaglandins after vaginal delivery 
– FIDEL” 
 
 
I the undersigned (LAST NAME, First name) …………………………………………… agree to 
participate in the study. 
 
 
It was clearly explained to me that I am free to accept or refuse to participate in this study. 
I was given a written information sheet describing what the study entails. 
My data will be processed by computer to allow for analysis of the study results. As soon as my 
condition allows, I will be able, if I wish, to oppose the computer processing of my medical data 
collected previously. 
 
 
THE PATIENT  
Date 
(dd/mm/yyyy) 
|___|___| / |___|___| / |___|___|___|___|   
Time (24 
hour format) 
|___|___| / |___|___|  
 
(Signature) 
 
 
THE INVESTIGATOR 
I the undersigned (LAST 
NAME, First name) 
……………………………………………………………………………………………. 
Date 
(dd/mm/yyyy) 
|___|___| / |___|___| / |___|___|___|___|   
Time (24 
hour 
format) 
|___|___| / |___|___|  
 
(Signature) 
 
 
 


 
RELATIVE/TRUSTED PERSON CONSENT IN EMERGENCY SITUATION 
FIDEL STUDY 
 
Version 7.0 of 06/03/2018 
 
4/4 
 
CONFIDENTIAL 
 
“A multicentre, controlled, randomised, double-blind study to evaluate the benefits and tolerance of 
a treatment strategy for postpartum haemorrhage associating early administration of human 
fibrinogen versus placebo in patients treated with intravenous prostaglandins after vaginal delivery 
– FIDEL” 
 
I the undersigned (LAST NAME, First name) ………………………………………………………, 
confirm 
 
that I was given a written information sheet describing what the study entails. 
 
 The patient has given her oral consent to 
participate but is physically unable to sign 
her consent 
 
I certify as a relative or a trusted person, that  
Ms ……………………….….  
has received minimal oral information on the 
nature of the study and has given her oral 
agreement to participate in the study but is 
physically unable to sign the emergency consent 
herself. 
 
 The patient is unable to give her oral 
consent to participate in the study 
 
 
 
I accept as a relative or trusted person that  
Ms ……………………………. 
is participating in the study. 
 
It was clearly explained to me that I am free to 
accept or refuse her participation in this study. 
 
 
Her data will be used to allow for analysis of the results of the study. As soon as her condition 
allows, she can, if she wishes, oppose the computer processing of her medical data collected 
previously. 
 
 
 
 
THE RELATIVE / TRUSTED PERSON  
 
Date 
(dd/mm/yyyy) 
|___|___| / |___|___| / |___|___|___|___|   Time (24-
hour format) 
|___|___| / |___|___|  
 
(Signature) 
 
 
THE INVESTIGATOR 
I the undersigned (LAST 
NAME, First name) 
……………………………………………………………………………………………. 
Date 
(dd/mm/yyyy) 
|___|___| / |___|___| / |___|___|___|___|   Time (24-
hour format) 
|___|___| / |___|___|  
 
(Signature) 
 


 
POST-INCLUSION INFORMATION SHEET   
 
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                                                 Patient initials _________ 
CONFIDENTIAL 
 On [date] ……………………….., after your initial consent was signed, you were included by  
Dr ………………………..……….. in the biomedical study entitled:  
 
OR 
 
 On [date] ……………………….., after the written declaration of your relative (or trusted person) 
confirming your oral consent was signed, you were included by Dr ………………………..……….. 
in the biomedical study entitled: 
 
OR 
 
 On [date] ……..…………………….., after the initial authorisation signed by your relative (or 
trusted person) Mr/Ms …………………………..…………….., you were included in the biomedical 
study entitled: 
 
“A multicentre, randomised, double-blind study to evaluate the benefits and tolerance of a 
treatment strategy for postpartum haemorrhage associating early administration of human 
fibrinogen versus placebo in patients treated with intravenous prostaglandins after vaginal 
delivery – FIDEL” 
You were included in this biomedical study in an emergency situation and the purpose of this second 
information sheet is to allow you to decide whether to continue or stop participating in it. 
 
This biomedical study (also called a “clinical study”) is conducted by the Laboratoire français du 
Fractionnement et des Biotechnologies [French Laboratory for Fractionation and Biotechnologies] 
(LFB BIOMEDICAMENTS, 3 avenue des Tropiques, BP50052, Les Ulis, 91942 Courtaboeuf 
Cedex, FRANCE). 
 
Please take your time to read this information sheet carefully. It will give you the necessary 
information on why this study is carried out and what it will imply for you if you decide to continue 
participating. If you would like further information or clarifications, do not hesitate to ask the study 
doctor (called “investigator”) any questions you may have.  
 
Your participation in the study is completely free and voluntary and you can refuse if you wish. If 
you agree to continue participating, you will need to sign a new informed consent form. By signing 
this document, you do not waive any of your legal rights, you certify that you have received and 
understood the information relating to the FIDEL biomedical study.  
A copy of this information sheet and signed consent will be given to you, as well as a copy of the 
first information sheet and initial consent. 
If you refuse to continue participating or if you decide to withdraw at any time, your decision will 
not affect the quality of the care you receive or the relationship with your doctor.  
 
The Independent Ethics Committee (Lille Ethics Committee) gave its favourable opinion on 
10/12/2013. The French National Agency for Medicines and Health Products Safety (ANSM) also 
gave its authorisation on 25/11/2013.  


 
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CONFIDENTIAL 
 
1. AIM OF THE BIOMEDICAL STUDY 
You were included in the study in an emergency situation, when significant and persistent bleeding, 
also called Postpartum Haemorrhage (PPH), was observed after your childbirth.  
 
PPH is excessive bleeding that occurs after childbirth. It is one of the main causes of maternal 
mortality in the world and a very widespread cause of serious maternal pathologies in developed 
countries. PPH is first managed with treatments called uterotonics, such as oxytocin, which help the 
uterus to contract and eventually stop the bleeding. If this treatment fails, another uterotonic is 
given, called prostaglandin. If this second treatment still does not stop the bleeding, other more 
invasive procedures must then be considered, such as vascular ligation (certain blood vessels which 
bring blood to the uterus are tied with absorbable thread), arterial embolisation (injection of a 
resorbable biological substance that temporarily blocks blood supply to the uterus) or hysterectomy 
(removal of the uterus) in the most severe cases.   
 
The blood loss is also known to be associated with the loss of a blood protein called fibrinogen. This 
protein is involved in blood clotting. Too little fibrinogen in the blood has been shown to help 
maintain haemorrhaging. Fibrinogen is therefore used commonly in many hospitals in France to 
treat women in your situation when the bleeding does not stop despite proper care. 
 
Fibrinogen has been available in France as an antihaemorrhagic drug under the name Clottafact® 
since May 2009. It is manufactured by LFB BIOMEDICAMENTS. Approximately 46,000 units of 
Clottafact were administered to patients between May 2009 and December 2012.  
It is authorised for use in the management of severe haemorrhages such as PPH, but the time of its 
administration after the start of bleeding needs to be better specified. 
 
LFB BIOMEDICAMENTS’ fibrinogen concentrate, Clottafact, is therefore already used in women 
with PPH, but generally after the decreased fibrinogen level has been demonstrated by a blood test.  
The aim of the study is to evaluate whether early administration of Clottafact, with the start of a 
prostaglandin infusion, could help control the haemorrhage and its consequences, such as by 
reducing the need for blood transfusions or the need for more invasive treatments. The study will 
also assess the safety of early administration of Clottafact. 
 
The study takes place in France, in around twenty hospitals.  A total of 470 patients are planned to 
be included. 
 
2. BIOMEDICAL STUDY PROCEDURES 
 
Allocation of the study treatment: 
You have already received the study treatment because it was to be given as soon as possible after 
the start of the prostaglandin infusion.  
This study is called a “double-blind” study, which means that neither you nor the study doctor will 
know which treatment you were given. This procedure is used to be sure that the doctor's assessment 
will be completely objective.  


 
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You therefore received one of the following 2 treatments : 
1. Active treatment: Clottafact (3g of fibrinogen), 
2. Placebo: this is a treatment that contains no active substance. 
 
The study is also “randomised” (the treatments were allocated by drawing lots), which means that 
half of the patients included in the study receive Clottafact and the other half receive placebo. You 
therefore have a 50% chance of having received Clottafact. 
 
Your follow-up during the study: 
Before administering the study treatment, the study doctor examined you (measured your blood 
pressure and heart rate) and checked your medical history, the medicines you usually take and the 
ones you took before you came to the hospital. 
 
Then you gave a blood sample from the arm (24 ml or about 1.5 tablespoons) for biological tests: 
haematological tests (blood count, haemoglobin, haematocrit, platelets), biochemical tests (urea, 
creatinine) and tests of certain coagulation parameters including fibrinogen. This blood sample 
would have been taken in the same way even if you were not participating in the study.  
 
Your treatment (3g of Clottafact or placebo) was then administered all at once by an infusion which 
lasted about twenty minutes.  
 
As part of the study, your doctor will then perform a new examination (blood pressure and heart 
rate) and take 3 blood samples: 2 hours (15 ml or 1 tablespoon of blood), 6 hours (15 ml or 
1 tablespoon of blood) and then the morning of the second day (24 ml or approximately 
1.5 tablespoons of blood) after administration of the study treatment.  
The same tests as for the first blood sample will be carried out: haematological, biochemical tests 
(except at hours 2 and 6) and coagulation parameters including fibrinogen.  
Throughout the duration of the study, a total volume of 78 ml or approximately 5 tablespoons of 
blood will be taken from you. For information, when donating blood, the volume collected is around 
450 ml. 
 
Throughout your stay in the hospital, your treatment will be identical to that which you would have 
received if you had not participated in the study, apart from the administration of the study treatment 
and the blood sample at 6 hours. 
 
Whichever treatment you are given, if the study doctor deemed it necessary and based on the level 
of fibrinogen in your blood, he/she may have administered fibrinogen to you, provided that 2 units 
of blood cells were administered to you or one hour had elapsed since the study treatment was 
administered. 
This administration of fibrinogen can be done provided that you have received Clottafact or placebo. 
Furthermore, since this was not blinded, your doctor will be able to tell you if you received more 
fibrinogen, when and at what dose. 
 


 
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End-of-study visit/call: 
You will be followed as part of the study from the time the informed consent was signed in an 
emergency situation until your discharge from the hospital.  
Then, 4 to 8 weeks after giving birth, your doctor will see you during an obstetrical follow-up visit 
or he/she will call you (if no visit is scheduled) to collect information on the medicines you have 
taken and any complications that have occurred since your discharge from the hospital. No other 
examination or collection of additional information will be carried out during this last contact with 
the study doctor. 
 
Your doctor may decide to withdraw you from the study if he/she considers it in your interest, in 
case of non-compliance with the study procedures or on the decision of LFB BIOMEDICAMENTS 
or the health authorities. 
 
Your doctor may have to inform your treating doctor about your participation in the study, after 
having obtained your agreement. 
 
Your participation in the study is completely free and voluntary and you can refuse if you wish. If 
you refuse to continue participating or if, at any time, you decide to withdraw, your decision will in 
no way affect the quality of the care you will receive or the relationship with your doctor. 
In this case, your doctor will ask you to confirm that you agree to the use of your data collected 
during the study. 
 
3. CONSTRAINTS 
You will be asked to comply with all of the steps taken by the study doctor throughout your  
follow-up:  
- that you answer as precisely as possible about your medical history, your allergies to certain 
medicines, the medicines that you usually take or that you took before your arrival at the hospital,  
- that you accept the blood samples, 
- that you report immediately to your doctor any adverse events which you note, even if you think 
that they are not related to the study treatment,  
- that you make yourself available for the telephone call or the end-of-study visit. 
  
4. POSSIBLE BENEFITS  
Postpartum Haemorrhage (PPH) is characterised by bleeding which can be severe and therefore life-
threatening for the patient.  
 
Early administration of Clottafact®, as soon as possible after the start of administration of 
prostaglandins, may help to control the bleeding, for example by reducing the need for blood 
transfusions and more invasive treatments. 
 
However, you may not derive any particular benefit from this study, especially if you received the 
placebo.  
However, in any case, your participation will be useful, in the future, to other patients who will be in 
the same situation as you, by helping us to better understand PPH and better manage it. 


 
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5. RISKS AND POSSIBLE INCONVENIENCES 
Since it was launched on the market in France in 2009, Clottafact® has been administered not only 
to many patients with PPH but also to patients with other pathologies. As an indication: around 
6000 patients received it in 2010 and around 9000 received it in 2011. The data for 2012 and 2013 
are yet not available at this time. 
 
In addition, as part of the study, an expert committee will regularly review any adverse events that 
occur and ensure that the benefits for patients outweigh the risks.  
 
5.1 Potential adverse events and inconveniences connected with the study treatment  
 
In any clinical study, the study drug and other therapeutic measures may involve risks, some of 
which are already known and others that are not yet described.  
 
You should be aware that Clottafact may present the risks and disadvantages described below:  
 
• Common: headaches, 
 
• Uncommon: 
o An allergic reaction (including anaphylactic shock (severe allergic reaction), paleness, 
vomiting, cough, low blood pressure, chills, itching (hives)), as with any medicine 
containing proteins that is administered intravenously,  
o Dizziness, 
o Ringing in the ears, 
o Blood circulation disorders (deep vein thrombosis, superficial thrombophlebitis, 
pulmonary embolism) from the formation of a blood clot in an artery or vein. However, it 
is known that the risk of having this type of event is increased after childbirth, even in the 
absence of treatment with Clottafact®, 
o Difficulty breathing (asthma), 
o Vomiting associated with headaches, 
o Redness, itching, skin rash, and night sweats, 
o Feeling hot 
 
 
Clottafact is purified from the blood of selected donors and according to a manufacturing process 
that includes three steps to remove/inactive viruses and infectious agents (solvent-detergent, dry 
heating, nanofiltration). Despite these highly secure measures, the risk of infectious disease due to 
the transmission of infectious agents, including those whose nature is still unknown, cannot be 
definitively excluded. 
 
To date, no drug-drug interaction has been described with other treatments that may be administered 
to you to manage your PPH. 
However, you must inform the study doctor of any modification of the medicines that you take 
between your discharge from the hospital and the last visit or telephone call at the end of the study. 
 


 
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5.2 Potential adverse events and inconveniences connected with the study-specific procedures 
 
Administration of the study treatment requires the use of a needle inserted into a vein. This needle 
was also used to take the blood samples. These procedures may involve the following 
inconveniences: 
• 
Mild pain at the injection site,  
 
• 
Feeling dizzy, 
 
            
• 
Bruise, 
• 
Exceptionally, an infection (risk present each time the skin is injured) or bleeding at the 
puncture site. 
 
However, as with any delivery, whether or not the patient participates in the study, an intravenous 
line is installed for any blood samples and infusions required. This means that there are no 
additional disadvantages associated with the study-specific procedures. 
 
6. PREGNANCY AND BREAST-FEEDING 
The safety of Clottafact during pregnancy and breast-feeding has not been evaluated in controlled 
clinical trials. 
However, clinical experience in the treatment of obstetrical complications does not suggest that any 
adverse effects should be expected on the outcome of pregnancy or on the development of the foetus 
or newborn. 
 
Clottafact was administered to you after you gave birth. It therefore poses no risk to your pregnancy 
and will not prevent you from breast-feeding if you wish. 
 
7. FINANCIAL ASPECTS 
Your participation in the study is completely free: all examinations and other medical costs specific 
to the study as well as the study treatment will be covered by LFB BIOMEDICAMENTS. 
 
The 
study 
doctor 
and 
the 
hospital 
are 
receiving 
financial 
compensation 
from 
LFB BIOMEDICAMENTS for this study. 
 
8. CONFIDENTIALITY 
All personal information about you collected for the purposes of the study (age, sex, height, weight, 
medical history) will be kept strictly confidential. 
 
In order to respect your privacy and guarantee professional secrecy, you will only be identified by 
an identification number and your initials (1st letter of your last name and 1st letter of your first 
name) for all the data collected and in the database in which the information will be stored. The 
confidentiality of your data will be ensured in accordance with what is permitted by the laws in 
force at this time.   
 


 
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Your medical file will be viewed by LFB BIOMEDICAMENTS, or its representatives, in order to 
verify the validity of the clinical data collected. This will be done in total respect for your privacy. 
The Ethics Committee as well as the Health Authorities could also request to have direct access to 
your file if necessary. 
 
If information relating to this study is published or presented at scientific conferences, neither your 
identification number nor other personal information will be used and all data will remain 
confidential. 
 
By signing the informed consent, you authorise access to and use of your data under the conditions 
described above, to allow for analysis of the results of the biomedical study in accordance with its 
aim as it was presented to you.  
 
To that end, medical data concerning you will be transmitted to LFB or to persons or companies 
acting on its behalf, in France or abroad. These data may also, under conditions ensuring their 
confidentiality, be transmitted for regulatory submission purposes and/or monitoring of the 
medicinal product to French or foreign health authorities and/or to LFB BIOMEDICAMENTS 
subsidiaries as well as to companies acting on its behalf that may be located outside the European 
Union. 
 
In accordance with the French Data Protection Law (CNIL): Law no. 2004-801 of 6 August 2004 on 
the protection of individuals with regard to the processing of personal data and amending Law no. 
78-17 of 6 January 1978 on data processing, files and freedoms, you have a right of access and 
rectification. You also have a right of opposition to the transmission of data covered by professional 
secrecy likely to be used within the framework of this study and analysed, it being specified that you 
cannot exercise this right of opposition on data falling under a legal obligation of LFB 
BIOMEDICAMENTS, in particular with regard to monitoring of the medicinal product.  
You can exercise these rights at any time through the study doctor.    
If you withdraw your consent during the study, LFB BIOMEDICAMENTS will ensure that no 
additional data concerning you are collected from that time forward. 
 
9. INSURANCE  
LFB BIOMEDICAMENTS has taken out civil liability insurance covering any health problem 
related to your participation in the study (company: HDI-GERLING - Contract no.: 01010260-
14023). 
If you are harmed by the study, tell your doctor. 
 
10. NEW INFORMATION  
Your doctor will inform you of any new information or changes to the study that may have an 
impact on your health or on your wish to continue the study. 
If the study is stopped for any reason, you will be notified. 
If you wish, your doctor will inform you of the general results of the study approximately one year 
after the last patient has completed her end-of-study visit. 


 
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11. CONTACTS 
If you have any further questions about the study, before, during or after your participation, you can 
always ask your doctor.  
 
STUDY DOCTOR 
 
Name: ………………………………………………………………………………………………… 
 
Address: ……………………………………………………………………………………………… 
 
Telephone number: ………………………………………………………………………………. 
 
 
 
Thank you for having taken the time to read this information sheet. If you agree to continue 
the study, please date and sign the 2 copies of the attached consent and initial each page of this 
document.   


PATIENT POST-INCLUSION CONSENT 
FIDEL STUDY 
 
 
Version V7.0 of 06/03/2018 
 
9/10 
 
CONFIDENTIAL 
 
“A multicentre, randomised, double-blind study to evaluate the benefits and tolerance of a treatment strategy for postpartum 
haemorrhage associating early administration of human fibrinogen versus placebo in patients treated with intravenous 
prostaglandins after vaginal delivery – FIDEL” 
 
I the undersigned, (last name, first name) ………………………………….…………………. , confirm: 
 
In the case of a written declaration from my relative (or trusted person), to have given my oral agreement to 
participate in the study but was physically unable to sign the emergency consent myself  
 
I certify in the context of this post-inclusion consent that I: 
 
• have read the attached information sheet and understand the nature and aim of the study,  
• was able to ask any questions I had regarding the study and received satisfactory answers from the study doctor, 
• had enough time to decide whether to continue participating in the study, 
• have understood that my participation in the study is completely free and voluntary as well as the implications of my 
participation. I can withdraw from the study at any time without affecting my medical care or my rights,   
• have understood that I can exercise my rights of access, rectification and opposition regarding my data at any time by 
contacting the study doctor, 
• know that I can access the personal data concerning my health that are kept by the investigator at any time during the study 
or after it, in accordance with article L. 1111-7 of the French Public Health Code, 
• accept the transmission for regulatory submission purposes and/or monitoring of the medicinal product of my personal data 
to the health authorities of foreign countries and to any company or companies including their subsidiaries mandated by 
LFB BIOMEDICAMENTS, which may be located outside the European Union, 
• accept that representatives of LFB BIOMEDICAMENTS, the Ethics Committee or the Health Authorities may access my 
personal data,  
• have understood that a specific insurance policy has been taken out by LFB BIOMEDICAMENTS to cover my 
participation in the study,  
• have noted that, if I wish, I can be informed of the results of the study by the study doctor,  
• have understood that a copy of the information sheet and consent will be given to me, 
 
 
agree to continue participating in the study and authorise computer processing by the Sponsor or on its behalf of my 
anonymised data already collected and that will be collected, 
 
 
OR refuse to continue the study, but authorise computer processing by the Sponsor or on its behalf of my anonymised 
data already collected, 
 
 
OR refuse to continue the study and opposes computer processing by the Sponsor or on its behalf of my anonymised 
data already collected. 
THE PATIENT (to be completed personally by the patient) 
Date (dd/mm/yyyy) 
|___|___| / |___|___| / |___|___|___|___|   
Time (24 hour format) 
|___|___| / |___|___|  
 
(Signature) 
THE INVESTIGATOR 
I the undersigned (LAST NAME, First name) 
……………………………………………………………………………………………. 
 
certify that the patient who signed this consent has received and understood the required information about the nature of the 
study as well as the risks and benefits that her participation may entail. 
Date (dd/mm/yyyy) 
|___|___| / |___|___| / |___|___|___|___|   
Time (24 hour format) 
|___|___| / |___|___|  


PATIENT POST-INCLUSION CONSENT 
FIDEL STUDY 
 
 
Version V7.0 of 06/03/2018 
 
10/10 
 
CONFIDENTIAL 
 
 
(Signature) 
 
 
 

Prot_000.pdf: 
 
COVER PAGE 
 
 
TITLE: A randomised, multicentre, double-blind, placebo-controlled study on the efficacy 
and safety of a therapeutic strategy of post-partum haemorrhage comparing early 
administration of human fibrinogen versus placebo in patients treated with intravenous 
prostaglandins following vaginal delivery.  
 
NCT Number: NCT02155725 
 
DOCUMENT: Protocole (v11.0)  
 
 
VERSION & DATE OF DOCUMENT: Version 11.0; March 06, 2018 




 
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TABLE OF CONTENTS 
 
SYNOPSIS ............................................................................................................................................ 8 
1. 
INTRODUCTION AND BACKGROUND INFORMATION ............................................... 18 
1.1. 
Disease and context .............................................................................................................. 18 
1.1.1. 
Physiopathology of post-partum haemorrhage ............................................................ 18 
1.1.2. 
Epidemiology of PPH .................................................................................................. 18 
1.1.3. 
Types of PPH ............................................................................................................... 19 
1.1.4. 
Management / Treatment of PPH ................................................................................. 19 
1.1.5. 
PPH associated coagulopathy ...................................................................................... 20 
1.2. 
Non-Clinical and Clinical Information ................................................................................ 20 
1.3. 
Rationale of the study........................................................................................................... 21 
1.3.1. 
Clinical study rationale ................................................................................................ 21 
1.3.2. 
CLOTTAFACT® dose regimen and infusion rationale ............................................... 22 
1.3.3. 
Rationale of the population studied.............................................................................. 22 
2. 
STUDY OBJECTIVES .............................................................................................................. 22 
2.1. 
Primary objective ................................................................................................................. 22 
2.2. 
Secondary objectives ............................................................................................................ 22 
3. 
STUDY DESIGN ........................................................................................................................ 23 
3.1. 
Design .................................................................................................................................. 23 
3.2. 
Endpoints ............................................................................................................................. 23 
3.2.1. 
Primary endpoint .......................................................................................................... 23 
3.2.2. 
Secondary endpoints .................................................................................................... 24 
3.2.2. 1. 
Evolution of haemorrhage .................................................................................... 24 
3.2.2. 2. 
Need for haemostatic intervention ....................................................................... 24 
3.2.2. 3. 
Need for intrauterine balloon ............................................................................... 24 
3.2.2. 4. 
Maternal morbi-mortality ..................................................................................... 25 
3.2.2. 5. 
Biological effects of fibrinogen concentrate administration ................................ 25 
3.2.2. 6. 
Tolerance of fibrinogen concentrate administration ............................................ 25 
3.3. 
Measures to avoid/minimise bias ......................................................................................... 25 
3.4. 
Study Investigational Centres .............................................................................................. 25 
3.5. 
Data and Safety Monitoring Board/Scientific Committee ................................................... 26 
4. 
DURATION AND DATES OF THE STUDY ......................................................................... 27 
5. 
STUDY POPULATION............................................................................................................. 27 
5.1. 
Number of patients ............................................................................................................... 27 
5.2. 
Eligibility Criteria ................................................................................................................ 27 
5.2.1. 
Inclusion criteria........................................................................................................... 27 
5.2.2. 
Non-inclusion criteria................................................................................................... 28 
5.3. 
Duration of Patient participation .......................................................................................... 29 
5.4. 
Discontinuation criteria ........................................................................................................ 29 
5.5. 
Lost to Follow-up ................................................................................................................. 29 
6. 
INVESTIGATIONAL MEDICINAL PRODUCTS (IMPS) .................................................. 30 


 
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6.1. 
Description of IMPs ............................................................................................................. 30 
6.1.1. 
Fibrinogen .................................................................................................................... 30 
6.1.2. 
Placebo ......................................................................................................................... 30 
6.2. 
IMP packaging and labelling ............................................................................................... 31 
6.2.1. 
Packaging ..................................................................................................................... 31 
6.2.2. 
Labelling ...................................................................................................................... 31 
6.3. 
Management of IMP ............................................................................................................ 32 
6.3.1. 
Shipment and receipt .................................................................................................... 32 
6.3.2. 
Storage requirements .................................................................................................... 32 
6.3.3. 
IMP re-supplying ......................................................................................................... 33 
6.3.4. 
IMP return, destruction and recall ................................................................................ 33 
6.3.4. 1. 
Return and destruction ......................................................................................... 33 
6.3.4. 2. 
Recall.................................................................................................................... 33 
6.4. 
Treatment of patients............................................................................................................ 33 
6.4.1. 
Methods for Assigning Patients to Treatment Groups ................................................. 33 
6.4.2. 
Dispensing .................................................................................................................... 34 
6.4.3. 
Misuse /Overdose ......................................................................................................... 36 
6.4.4. 
Compliance .................................................................................................................. 36 
6.5. 
IMP accountability ............................................................................................................... 36 
6.6. 
Randomisation Codes and Procedures for Unblinding ........................................................ 36 
7. 
PRIOR AND CONCOMITANT MEDICATION ................................................................... 37 
7.1. 
Prior Medication................................................................................................................... 37 
7.2. 
Concomitant Medication ...................................................................................................... 37 
8. 
STUDY PLAN ............................................................................................................................ 38 
8.1. 
Patient recruitment ............................................................................................................... 38 
8.1.1. 
Informed Consent ......................................................................................................... 38 
8.1.2. 
Patient Inclusion ........................................................................................................... 40 
8.1.3. 
Patient Randomisation ................................................................................................. 40 
8.1.4. 
Replacement of early withdrawals ............................................................................... 41 
8.2. 
Schedule of visits ................................................................................................................. 41 
8.2.1. 
Visit 1: Inclusion / Blood sampling 1 .......................................................................... 41 
8.2.2. 
Visit 2: Randomisation and IMP infusion .................................................................... 42 
8.2.3. 
Visit 3: H2 (120 ± 30 min) / Blood sampling 2 ........................................................... 42 
8.2.4. 
Visit 4: H6 (360 ± 30 mn) / Blood sampling 3 ............................................................ 42 
8.2.5. 
Visit 5: morning of D2 / Blood sampling 4 ................................................................. 43 
8.2.6. 
Visit 6: Hospital discharge ........................................................................................... 44 
8.2.7. 
Visit 7: End of Study Visit/Contact ............................................................................. 45 
8.3. 
Assessments ......................................................................................................................... 45 
8.4. 
Compliance with the Study Plan .......................................................................................... 46 
9. 
SAFETY ...................................................................................................................................... 46 
9.1. 
Safety Reference Document ................................................................................................. 46 
9.2. 
Benefit/Risk Information ..................................................................................................... 46 
9.2.1. 
Known and potential risk(s) related to the IMPs ......................................................... 47 
9.2.2. 
Other expected or potential risk(s) ............................................................................... 48 
9.2.3. 
Benefit/Risk balance .................................................................................................... 48 


 
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9.3. 
Risk Minimisation Actions Throughout the Protocol .......................................................... 48 
9.4. 
Alternative Therapeutic Management - Emergencies Handling .......................................... 49 
9.5. 
Definition and Reporting of (Serious) Adverse Events ....................................................... 49 
9.5.1. 
Adverse Event (AE) ..................................................................................................... 49 
9.5.2. 
Serious Adverse Event (SAE) ...................................................................................... 50 
9.5.3. 
Definition of Specific Events in the Study ................................................................... 50 
9.5.4. 
Period of (Serious) Adverse Event Data Collection .................................................... 51 
9.5.5. 
Recording and Description of (Serious) Adverse Event .............................................. 51 
9.5.6. 
Procedures for reporting Serious Adverse Events ....................................................... 52 
9.5.7. 
LFB MEDICAL contact ............................................................................................... 53 
9.5.8. 
Follow-up of Adverse Events....................................................................................... 53 
9.6. 
Regulatory Safety Requirements.......................................................................................... 54 
10. 
PARAMETERS AND ASSESSMENT CRITERIA ............................................................ 54 
10.1. Assessment of Efficacy ........................................................................................................ 54 
10.1.1. 
Primary Variable .......................................................................................................... 54 
10.1.2. 
Secondary variables ..................................................................................................... 54 
10.2. Assessment of Safety ........................................................................................................... 56 
11. 
DATA MANAGEMENT ....................................................................................................... 56 
11.1. CRF completion guidelines .................................................................................................. 56 
11.1.1. 
Introduction .................................................................................................................. 56 
11.1.2. 
General instructions ..................................................................................................... 56 
11.1.2. 1. 
Overview .............................................................................................................. 56 
11.1.2. 2. 
Header information .............................................................................................. 57 
11.1.2. 3. 
Recording dates and time ..................................................................................... 57 
11.1.2. 4. 
Recording of missing data .................................................................................... 57 
11.1.2. 5. 
CRF corrections ................................................................................................... 58 
11.1.2. 6. 
Confidentiality ..................................................................................................... 58 
11.1.2. 7. 
CRF Completion in case of screening failure or premature withdrawal .............. 58 
11.1.3. 
Collection of CRF ........................................................................................................ 58 
11.1.4. 
Specific Case Report Form instructions ....................................................................... 58 
11.2. CRF and Data Handling ....................................................................................................... 58 
12. 
STATISTICS .......................................................................................................................... 59 
12.1. Trial Objectives and Design ................................................................................................. 59 
12.2. Statistical Analysis Plan ....................................................................................................... 59 
12.3. Sample Size Determination .................................................................................................. 60 
12.4. Randomisation ..................................................................................................................... 60 
12.5. Interim analysis .................................................................................................................... 61 
12.6. Protocol Deviations and Analysis Sets ................................................................................ 61 
12.7. General Rules for Handling of Missing or Inconsistent Data .............................................. 61 
12.8. Demographic and Baseline Characteristics .......................................................................... 62 
12.8.1. 
Demographic Characteristics, Medicinal History, Diagnoses ..................................... 62 
12.8.2. 
Previous Treatments ..................................................................................................... 62 
12.8.3. 
Baseline Efficacy Variables ......................................................................................... 62 
12.8.4. 
Baseline Safety Variables ............................................................................................ 62 
12.9. Investigational Product (IMP) and Concomitant Treatments .............................................. 63 


 
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12.9.1. 
Extent of Exposure ....................................................................................................... 63 
12.9.2. 
Treatment Compliance ................................................................................................. 63 
12.9.3. 
Concomitant Treatment ................................................................................................ 63 
12.10. 
Efficacy Analysis ............................................................................................................. 63 
12.10.1. 
Primary Efficacy Variable(s) ................................................................................... 63 
12.10.1. 1. Description of the primary efficacy variable(s) .................................................. 63 
12.10.1. 2. Primary analysis .................................................................................................. 63 
12.10.1. 3. Secondary efficacy variables ............................................................................... 65 
12.11. 
Safety Analysis ................................................................................................................ 66 
13. 
STUDY REPORT .................................................................................................................. 66 
14. 
CONFIDENTIALITY AND PUBLICATION ..................................................................... 67 
14.1. Patient confidentiality .......................................................................................................... 67 
14.2. Use of information ............................................................................................................... 67 
15. 
ARCHIVING .......................................................................................................................... 68 
16. 
RESPONSIBILITIES OF PARTICIPANTS ....................................................................... 68 
16.1. Responsibilities of the Investigator(s) .................................................................................. 69 
16.1.1. 
Patient information and consent ................................................................................... 69 
16.1.2. 
Information on the overall results of the study ............................................................ 69 
16.1.3. 
Information to other practitioners (if relevant) ............................................................ 69 
16.1.4. 
Adverse events ............................................................................................................. 69 
16.1.5. 
Data recording .............................................................................................................. 69 
16.1.6. 
Record retention ........................................................................................................... 70 
16.1.7. 
Use of study-related information ................................................................................. 70 
16.1.8. 
IMP ............................................................................................................................... 70 
16.1.9. 
Quality control ............................................................................................................. 70 
16.1.10. 
Study discontinuation ............................................................................................... 70 
16.1.11. 
Liability and insurance ............................................................................................. 70 
16.1.12. 
Delegation of Investigator duties ............................................................................. 71 
16.1.13. 
Study agreement discontinuation ............................................................................. 71 
16.2. Responsibilities of the Monitor ............................................................................................ 71 
16.2.1. 
Communication ............................................................................................................ 71 
16.2.2. 
Training ........................................................................................................................ 71 
16.2.3. 
Compliance .................................................................................................................. 71 
16.2.4. 
Source data verification................................................................................................ 72 
16.2.5. 
IMP ............................................................................................................................... 72 
16.3. Responsibilities of the Data Manager .................................................................................. 72 
17. 
ETHICS AND REGULATORY CONSIDERATIONS ...................................................... 72 
18. 
AUDIT AND INSPECTION ................................................................................................. 73 
19. 
REFERENCE ......................................................................................................................... 74 
 
 
 


 
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List of abbreviations and definition of terms 
 
aPTT 
Activated Partial Thromboplastin Time 
AE 
Adverse Event 
ANOVA 
ANalysis Of VAriance 
ATC 
Anatomical Therapeutic Chemical 
CRF 
Case Report Form 
CRO 
Contract Research Organisation 
CSP 
Code de la Santé Publique 
CV 
Curriculum Vitae 
D 
Day  
DSMB 
Data and Safety Monitoring Board 
EC 
Ethics Committee 
FAS 
Full Analysis Set 
FFP 
Fresh Frozen Plasma 
FIGO 
International Federation of Gynecology and Obstetrics  
FU 
Follow-up 
GCP 
Good Clinical Practice 
h 
Hour 
HAS 
Haute Autorité de Santé 
Hb 
Haemoglobin 
HES 
Hydroxyethylstarch 
Ht 
Haematocrit 
ICH 
International Conference on Harmonisation of Technical Requirements for Registration of 
Pharmaceuticals for Human Use 
ICM 
International Confederation of Midwives  
IEC/IRB 
Independent Ethics Committee (IEC) or International Review Board (IRB) 
IMP 
Investigational Medicinal Product 
IV 
IntraVenous 
LDH 
Lactate DeHydrogenase 
LFB 
Laboratoire français du Fractionnement et des Biotechnologies 
LLT 
Lowest Level Term 
LMWH 
Low-Molecular-Weight Heparin 
LOCF 
Last Observation Carried Forward 
MedDRA Medicinal Dictionary for Regulatory Activities 
min 
Minute 
NA 
Not Applicable 
NCR 
No Carbon Required 
ND 
Not Done 
PCC 
Prothrombin Complex Concentrates 
PICU 
Post Interventional Care Unit 
PPH 
Post-Partum Hemorrhage 
PT 
Preferred Terms 
PT 
Prothrombin Time 
QT 
Quick's Test 
RBC 
Red Blood Cells 


 
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rFVIIa 
Recombinant activated Factor VII 
SAE 
Serious Adverse Event 
SAP 
Statistical Analysis Plan 
SOC 
System Organ Class 
SPC 
Summary of Product Characteristics 
SOFA 
Sequential Organ Failure Assessment 
TRALI 
Transfusion-Related Acute Lung Injury 
UNK 
UNKnown 
VBL 
Volume of Blood Loss 
WHO 
World Health Organization 
 
  


 
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SYNOPSIS 
TITLE 
A randomised, multicentre, double-blind, placebo-controlled study on 
the efficacy and safety of a therapeutic strategy of post-partum 
haemorrhage comparing early administration of human fibrinogen 
versus placebo in patients treated with intravenous prostaglandins 
following vaginal delivery. 
 
Short title: FIbrinogen in haemorrhage of DELivery: FIDEL 
SPONSOR 
LFB BIOMEDICAMENTS 
ZA de COURTABOEUF 
3, avenue des Tropiques - 91940 LES ULIS (France) 
COORDINATING 
INVESTIGATOR / 
SCIENTIFIC COMMITTEE 
Coordinating Investigator: 
 
 
e 
 
 
 
Scientific Committee: 
 
 
 
 
INVESTIGATIONAL 
MEDICINAL PRODUCT 
(IMP) AND ASSOCIATED 
TREATMENTS 
Investigational medicinal products (IMP): 
The participants are assigned to either: 
o Fibrinogen (Clottafact®): 3g (2 vials of 1.5g/100 ml) or, 
o Placebo: 2 vials of 100 ml 
 
Route of administration: 
o As soon as possible during the 30 minutes following the start of 
prostaglandin infusion 
o Intravenous (IV) administration with a flow rate ≤ 20 ml/min 
 
Treatment allocation: 
o The treatment will be double-blind. 
o Randomisation will be stratified on the centre. 
o Each treatment unit contains 2 vials of powder and 2 solvent 
vials of 100 ml. 
o Treatment units will be numbered and will be allocated in 
chronological order of inclusion by ascending number. 


 
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Associated treatments: 
o IMP is administered as soon as possible after start of 
prostaglandin infusion. The dose of prostaglandin will be 
administered according to the 2004-recommendations provided by 
the French National Authority for Health (Haute Autorité de 
Santé, or HAS). 
o Following the administration of IMP, the therapeutic management 
will be totally left to the discretion of the investigator. 
o However, some concomitant treatments will be administered in 
accordance with the following recommendations: 
o Fibrinogen concentrate as rescue therapy: if administered, it will 
not be administered: 
 
within 60 minutes following the start of IMP 
administration, 
OR 
 
before at least 2 units of packed RBCs have been 
administered to the patient. 
o Tranexamic acid:  
 The administration of tranexamic acid will be 
allowed only after prostaglandin infusion has been 
decided. 
 Recommended dose: 1 g IV to be renewed once after 
30 min. 
o Transfusional strategy: in accordance with the following 
objectives: 
- 
Hemoglobin (Hb) ≥ 8 g /100 ml, 
- 
PT ≥ 40%, 
- 
Platelets count ≥ 50 000/mm3, 
Transfusions of red blood cells (RBC), fresh frozen plasma 
(FFP) and platelets units can be performed before availability of 
laboratory results, when indicated. 
o Hydroxyethylstarch (HES): maximum dose of 1.5 L during the 
first 24 hours. 
STUDY DESIGN 
Phase IV multicentre, randomised, double-blind, placebo-controlled, 
parallel-group study 
OBJECTIVES 
Primary: 
• 
To assess the benefits of a therapeutic strategy that associates an 
early administration of human fibrinogen concentrate in the 
management of PPH on the reduction of bleeding after the initiation 
of prostaglandins intravenous infusion. 
Secondary: 
• 
To assess the evolution of haemorrhage 
• 
To assess the need for haemostatic intervention 
• 
To assess the need for intrauterine balloon 


 
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• 
To assess the maternal morbi-mortality 
• 
To assess the biological effects of fibrinogen concentrate 
administration 
• 
To assess the tolerance of fibrinogen concentrate administration 
NUMBER OF PATIENTS 
It is estimated that, in the control group, 42% of patients will fulfill the 
primary endpoint. With an expected percentage of patients in the 
Clottafact®-treated group of 27%, the difference between the two groups 
will be 15%. With a power (1-ß) = 90%, an α risk-error = 5% and a two-
sided test (Z test, unpooled variance), a sample size of 412= 2x206 
evaluable patients is needed per group of treatment.  Assuming a 5% rate 
of dropouts, about 434 patients are planned to be randomized  in the study. 
As there is some uncertainty about the test Z variance depending itself on 
the expected rates, the variance will be re-estimated in a blind way at 80% 
of the initially planned sample size and the sample size will be increased 
according to the new estimated variance so as to maintain the power to 
90% while still considering the same originally planned difference in 
failure rates, i.e. 15%.  It can be shown that the possible increase in 
sample size (after adjusting for drop-outs) cannot exceed 50 additionnal 
patients. Hence the restimated sample size will not exceed 484 patients. 
 
STUDY POPULATION 
(ELIGIBILITY CRITERIA) 
Inclusion criteria: 
• 
Signed and dated informed consent form 
• 
Vaginal delivery 
• 
PPH requiring IV administration of prostaglandins 
• 
At least one available result of Hb level during the third trimester of 
pregnancy 
• 
18-year-old female patients and older 
• 
Covered by healthcare insurance in accordance with local requirements 
 
Non-inclusion criteria: 
• 
Caesarean section 
• 
Haemostatic intervention (as ligation, embolization or hysterectomy) 
already decided at the time of inclusion 
• 
Known placenta praevia or accreta 
• 
Hb level < 10g/dl during the third trimester of pregnancy 
• 
History of venous or arterial thromboembolic event 
• 
Known inherited bleeding or thrombotic disorders 
• 
Treatment with low-molecular-weight heparin (LMWH) within 24 
hours prior to the inclusion 
• 
Treatment with acetylsalicylic acid within 5 days prior to the inclusion 
• 
Treatment with vitamin K antagonists within 7 days prior to the 
inclusion 
• 
Administration of fibrinogen concentrate within 48 hours prior to the 


 
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inclusion 
• 
Administration of FFP, platelets units or prohaemostatic drugs, 
tranexamic acid and rFVIIa or prothrombin complex concentrates 
(PCC) within 48 hours prior to the inclusion 
• 
Administration of RBCs within 3 months prior to the inclusion 
• 
Participation in another interventional clinical study using an 
investigational medicinal product within 30 days prior to the inclusion 
• 
Previous inclusion/enrolment in the present clinical study 
• 
Known history of hypersensitivity or other severe reaction to any 
component of Clottafact® or placebo 
• 
Minors, majors under guardianship, persons staying in health or social 
institutes and people deprived of their freedom 
• 
Known drug or alcohol abuse 
• 
Patients whose use of concomitant medication may interfere with the 
interpretation of data 
• 
Any other current significant medical condition that might interfere 
with treatment evaluation according to the investigator’s judgement 
• 
Patients who are unlikely to survive through the treatment period and 
evaluation 
• Patients transferred from another service after the delivery 
DURATION OF PATIENT 
PARTICIPATION 
6 ± 2 weeks after the delivery 
DATES OF BEGINNING 
AND END OF STUDY 
• 
Planned date of inclusion of first patient: December 2013 
• 
Planned date of last patient out: August 2018 at the latest 
STUDY DESCRIPTION 
Consent: 
Informed consent will be obtained through an emergency procedure. 
Inclusion: 
• Will take place after signing the emergency informed consent and 
checking the eligibility criteria. 
• Blood sampling no 1 for biological data at inclusion. 
 
Randomisation: 
• Will be stratified on the centre. 
• The start of IMP administration corresponds to H0 (D0). 
• Recording of the time (start, end) of IMP infusion, 
 
H2 (120 ± 30 min): 
Blood sampling no 2. 
 
H6 (360 ± 30 min):  
• Blood sampling no 3. 
 


 
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Morning of D2: 
• Blood sampling no 4. 
 
Hospital discharge: 
• Parameters of therapeutic management and events that occurred 
during the admission in an ICU, including maximum SOFA score (if 
applicable), 
• PPH management summary 
 
At 6 ± 2 weeks following delivery: 
Collection of tolerance data on the IMP during an obstetrical follow-
up visit or a phone contact. 
DESCRIPTION OF AND 
JUSTIFICATION FOR DATA 
COLLECTED 
Anamnestic parameters: 
• 
Demographic parameters: height, weight prior to pregnancy and last 
known weight, 
• 
History of thromboembolic, obstetrical events and any clinically 
relevant medical conditions. 
• 
Obstetrical parameters of the pregnancy, mainly:  
o Date of last menstrual period, gestational age, levels of Hb of 
the third trimester of pregnancy, 
o Ht and platelets will be collected if available. 
 
Delivery parameters: 
• 
Times of the start and the end of delivery and number of live births 
and/or stillbirths, 
• 
Start and end hours of haemorrhage, 
• Initial obstetrical management of the haemorrhage : artificial 
delivery, uterine or genital examination, 
• 
Any haemostatic intervention (intrauterine balloon, uterine ligation, 
embolization, vascular ligation, hysterectomy), 
• 
Vascular filling (if any): volumes and types of filling solutes since 
the start of delivery until D2, 
• 
Transfusions: types and number of transfused blood products since 
the start of delivery. 
 
Clinical events until hospital discharge: 
• 
Duration of stay in the obstetrics room (arrival and discharge hours), 
• 
Number of days of hospital stay following delivery, 
• 
Number of days in resuscitation and/or intensive care and/or PICU 
and/or continuous care units, 
• 
Number of days with assisted ventilation, 
• 
Maximum SOFA score for patients transferred in resuscitation and/or 
intensive care and/or PICU and/or continuous care units, 


 
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• 
Renal failure requiring dialysis, 
• 
Hypotension episodes that required continuous vasopressor therapy, 
• 
Acute pulmonary oedema, acute respiratory distress syndrome, 
transfusion-related acute lung injury (TRALI), 
• 
Measured and/or estimated volumes of total blood loss, 
• 
Blood-collecting containers (if any): date, time and duration of 
setting and removal, 
 
Adverse events during the study  
• 
From the signature of the informed consent form to the end of study 
visit (6 ± 2 weeks after delivery): serious and non-serious AEs 
whether or not considered to be causally related to the investigational 
medicinal product (IMP). 
 
Laboratory parameters (at inclusion, H2, H6, D2): 
• 
Complete blood count, Hb, Ht and platelets 
• 
Plasma fibrinogen 
• 
Haemostatic profile: PT, QT, aPTT, D-dimers 
• 
Plasma creatinine and urea at inclusion and D2 
 
Prior/Concomitant treatments (total dose, modalities, start and end of 
administration): 
• 
Prior treatment: all relevant prior medication taken within 7 days 
before inclusion, including all medication administered since the 
beginning of the delivery 
• 
Concomitant treatments including intravenous fluids, blood products, 
tranexamic acid and fibrinogen concentrate as rescue therapy  
ENDPOINTS AND 
EVALUATION 
PARAMETERS 
Primary endpoint: 
Percentage of patients losing at least 4 g/dl of Hb, and/or requiring the 
transfusion of at least 2 units of packed RBCs within the 48 hours 
following the administration of IMP. 
The reference for Hb level is the most recent value recorded during the 
third trimester of pregnancy. 
 
Secondary endpoints: 
• 
Evolution of haemorrhage 
o Percentage of patients losing at least 4 g/dl of Hb, 48 hours 
following the IMP administration, with regards to the Hb 
reference level. 
o Percentage of patients losing at least 3 g/dl of Hb, 48 hours 
following the IMP administration, with regards to the Hb 
reference level. 
o Percentage of patients requiring transfusion of at least 2 units 
of packed RBCs, 48 hours following the IMP administration. 
o Percentage of patients losing at least 4 g/dl of Hb, 48 hours 


 
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following the IMP administration, with regards to the level 
of Hb measured at inclusion. 
o Percentage of patients with an occurrence of Hb level < 
9 g/dl within the 48 hours period following inclusion. 
o Number of units of transfused blood products within the 48 
hours period following IMP administration. 
o Calculated volume of total blood loss, 48 hours following the 
IMP administration. 
• 
Need for haemostatic intervention  
o Percentage of patients requiring at least one of the following 
interventions 
within 
48 
hours 
following 
the 
IMP 
administration: 
uterine ligation (B 
Lynch 
or 
other 
techniques), pelvic arteries embolization, surgical vascular 
ligation, administration of rFVIIa and hysterectomy.  
• Need for intrauterine balloon 
o Percentage of patients requiring the use of intrauterine balloon 
within 48 hours following the administration of IMP. 
o Time of intrauterine balloon placement. 
• 
Maternal morbi-mortality 
o Length of stay in resuscitation and/or intensive care and/or 
post interventional care units (PICU) and/or continuous care. 
o Duration of admission in obstetrics unit. 
o Single or multi-organ failure (SOFA score) in case of 
transfer to resuscitation and/or intensive care and/or PICU 
and/or continuous care units. 
o Death during the study. 
• 
Biological effects of fibrinogen concentrate administration  
o Evolution of blood fibrinogen level and hemoconcentration 
between H0 (start of IMP infusion) and D2. 
• 
Tolerance of fibrinogen concentrate administration 
o Serious and non-serious adverse events (AE). 
STATISTICS  
The distribution of parameters will be summarised using descriptive 
statistics according to the study variable: 
• 
Quantitative variables will be presented by their mean, standard 
deviation, standard error, median, quartiles and range, minimum and 
maximum values. The number of documented values will also be 
mentioned. 
• 
Categorical variables (binary, nominal and ordinal) will be presented 
by contingency tables (frequencies and percents). Number and 
percentages of missing data will also be mentioned. 
All statistical tests will be two-sided with a threshold of statistical 
significance of 0.05. 
The statistical analysis will be carried out according to the Intent-to-Treat 
(ITT) principle, depending on the group of randomisation regardless of the 
received treatment. 
A per-protocol analysis will be carried out on the subgroup of patients with 


 
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no major protocol deviation if the per-protocol set represents less than 80% 
of the ITT set. 
Unless otherwise specified, the following statistical tests will be used: 
• 
Categorical data will be compared using chi-square test or Fisher exact 
test if a theoretical number of one category or more is below 5. 
• 
Continuous quantitative data will be compared by t test or, if normality 
of distribution is rejected, by Wilcoxon non parametric test. 
No subgroup analysis is planned. 
The primary analysis will be conducted in the ITT set. Missing data will 
not be replaced in the primary analysis. 
The primary model of analysis will be an exact logistic regression 
adjusting for treatment, centre, and baseline fibrinogen (categorized into 
three classes, ≤ 2 g L-1 ,   ] 2 g L-1 4 - g L-1  ] , > 4 g L-1  ). 
The treatment effect (odds ratio of failure) with its 95% confidence interval 
will be estimated in this model. 
The same analysis proposed will be performed in the ITT and PP sets. 
Sensitivity analyses replacing missing data with failures regardless of the 
treated group will be implemented. 
Analysis of tolerance will be carried out on women at least one dose of 
IMP. 
No interim analysis is planned. 
 






 
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1. INTRODUCTION AND BACKGROUND INFORMATION 
1.1. Disease and context 
1.1.1. Physiopathology of post-partum haemorrhage 
Pregnancy induces changes in coagulation towards a more procoagulant state with mild 
thrombocytopenia, increased procoagulant factors and diminished fibrinolysis (1), ultimately serving 
as physiological protection against postpartum bleeding. However, postpartum haemorrhage (PPH), 
which was defined by the World Health Organization (WHO) as ‘blood loss greater than or equal to 
500ml (vaginal delivery) or 1000ml (caesarean section) within 24 hours after birth’, is the leading 
cause of maternal mortality (2). 
 
Published data have shown the difficulty of an exact blood loss measurement in clinical obstetrics 
(3). Severe then massive haemorrhages are also defined by a volume of blood loss greater than 1000 
ml and 1500 ml that represent respectively around 1% and 0.5% of vaginal deliveries. For caesarean 
section, volume of blood loss defining a severe haemorrhage is greater than 1500 ml. 
However, this definition cannot be used in clinical practice because blood loss assessment is 
inaccurate in such emergency situations (4).  
 
The most common causes of PPH are uterine atony, retained placental products, genital-tract trauma. 
Pre-existing coagulation abnormalities can also be the cause, but more frequently the important 
aggravating factor is the acquired coagulopathy. 
Uterine atony is the main cause of PPH and is observed as a single cause in 50-60% of cases (5), a 
uterine massage followed by the infusion of uterotonic drugs is the first step of the medical 
management. The different uterotonics are used in different algorithms, 3 main kinds of uterotonic 
drugs – oxytocin, prostaglandins and methylergometrine are used to stimulate uterine contraction. 
The European and American practices tend to remain with just 2 drugs i.e. i.v. oxytocin as the 1st 
line uterotonic and i.v. sulprotone (prostaglandin E2) – as the 2nd line uterotonic treatment. The 
administration schemes of oxytocin vary, the sulprostone is dosed more uniformly according to its 
SPC. The current protocol is based on the standard of care algorithm, which is derived from the 
American and French guidelines (5). 
Except the incision in the caesarean delivery that itself causes additional blood loss, there is no other 
underlying difference in mechanisms between the 2 types of delivery. There are differences in the 
management of the PPH during Caesarean section – some centres tend to implement the ultimate 
measures – uterine artery ligations or haemostatic hysterectomy earlier, compared to the PPH after 
vaginal delivery (the guidelines permit at least 30 min after the start of the 2nd line uterotonic for the 
evaluation of the effect and before deciding for intervention) (5). 
 
1.1.2. Epidemiology of PPH 
PPH is a major cause of maternal death worldwide and an important cause of severe maternal 
morbidity in high income countries (6,7,8): 


 
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 The incidence of PPH is estimated to be around 5% of deliveries (9). 
 This accounts for about 100 000 deaths every year, nearly 25% of all maternal deaths 
throughout the world (10). 
 In Europe, 1.75% of births are complicated by severe PPH (blood loss > 1000 mL) (11) with 
the risk of death in western countries at 1:100 000 births (12). 
 
Moreover, it can kill a healthy woman within 2 hours and is the quickest maternal killer (8).   
1.1.3. Types of PPH 
There are two clinical types of PPH (2): 
 Primary PPH: bleeding that occurs in the first 24 hours following delivery. Most cases of 
morbidity and mortality are due to primary PPH. Primary PPH is also divided into two types: 
o Third stage haemorrhage: primary haemorrhage that occurs after the delivery of the 
baby but before the expulsion of the placenta. 
o True primary PPH: haemorrhage that occurs after the delivery of the placenta at any 
time within 24 hours of the birth of the baby.  
 Secondary PPH: any abnormal or excessive bleeding from the birth canal occurring between 
24 hours and 12 weeks postnatally. 
The present protocol will focus only on primary PPH. 
To be sure of the mechanism involved in the development of the acquired PPH related 
coagulopathy, caesarean section and abnormal placental insertion will not be included to avoid 
surgical and placental bleeding.  
1.1.4. Management / Treatment of PPH 
According to French guidelines issued in 2004 (13) and the International Confederation of 
Midwives (ICM), the International Federation of Gynecology and Obstetrics (FIGO) (14) and the 
WHO's Integrated Management of Pregnancy and Childbirth guidelines (2), the PPH management is 
a step by step approach including: 
1. Step 1: The obstetric team needs to focus on the search and basic treatment of the most commun     
causes of PPH such as utrine atony (IV oxytocin ± uterine massage). 
While the anesthetic one provides basic rescucitation and adequate analgesia 
2. Step 2: If uterine atony is resistant and oxytocin ineffective, prostaglandins must be used within 
a maximum delay of 15 to 30 mn. 
More advanced rescucitation and monitoring are also usually needed. 


 
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3. Step 3: When medical treatment fails, arterial embolization, intrauterine balloon (e.g : Bakri or 
Belfort-Dildy balloon) or surgical ligation is applied. 
4. The last step is hysterectomy; meanwhile, the use of recombinant activated factor VII (rFVIIa) 
can be considered. 
1.1.5. PPH associated coagulopathy 
Fibrinogen is essential in the development of a strong and functional blood clot. It is produced in the 
liver and the average plasma level is 2.0 to 4.5 g/L. In relation with pregnancy (especially the third 
trimester) the level of fibrinogen rises to an average of 5 g/L (15,16,17). 
Upon activation by thrombin, factor XIII is activated into FXIIIa. FXIIIa is a transglutaminase, 
which acts on fibrin to form cross links between fibrin molecules. Consequently, polymerized fibrin 
is held together and forms an insoluble clot. Fibrin can therefore be seen as the end product of the 
coagulation cascade. 
Besides its central position in the coagulation process, fibrinogen is also involved in primary 
haemostasis through its platelet receptor. This receptor is a heterodimer consisting of the plasma-
membrane glycoproteins GPIIb/IIIa (also known as αIIbβ3). GPIIb/IIIa belongs to the integrin 
family, which not only bind adhesive ligands, but also act as signalling receptors for platelet 
aggregation. 
In summary, fibrinogen is a major component of both coagulation and primary haemostasis, which 
explain the bleeding phenotype in case of acquired or inherited fibrinogen deficiencies. 
During progressive blood loss, fibrinogen appears to represent the coagulation factor first reaching a 
critical low threshold level at around 1 g/L (18). This state of impaired haemostasis also develops in 
relation to PPH (15,19). The decrease of fibrinogen is the sole independent factor that predicts the 
severity of PPH as shown by Charbit and al (19) 2 hours after the beginning of PPH and more 
recently, by Cortet and al (16) 45 minutes after the beginning of PPH. 
It has been previously shown that treatment with fibrinogen concentrates was highly useful for 
controlling massive PPH (15,20,21). Such beneficial effect would be of high interest in the control 
of massive or oxytocin-resistant PPH. 
The threshold at which fibrinogen concentrate should be administered and its therapeutic target have 
not been studied in PPH but determined in polytrauma and surgery. The restoration of a plasma 
fibrinogen level between 1.5 g/L to 2 g/L is one of the treatment objectives (22,23). In trauma and 
surgery massive bleedings, the earlier coaguloapthy is corrected, the better outcome is (24). 
1.2. Non-Clinical and Clinical Information 
Clottafact® is a human fibrinogen concentrate that had a marketing authorization in France since 
May 2009 and in Lebanon since January 2013. Clottafact® is labellized in France as a 
complementary treatment for the management of severe uncontrolled bleeding resulting in acquired 
hypofibrinogenaemia (25,26)  which can be due to an increased consumption of fibrinogen that is 


 
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associated with a life-threatening uncontrolled haemorrhage encountered in obstetrical, surgical, or 
traumatic conditions and also to impaired hepatic synthesis. 
Clottafact is also labellized in France for constitutional hypo-, dys- or afibrinogenaemia in patients 
with spontaneous or posttraumatic haemorrhage.  
 
Clottafact® has been developed in accordance with European "Note for guidance on plasma-derived 
medicinal products" (CPMP/BWP/269/95 rev.3) (27), which specifies that all plasma derived 
products must incorporate effective steps for inactivation/ removal of viruses. The manufacturing 
process of Clottafact® includes two viral inactivation steps, i.e. solvent and detergent treatment and 
dry heating, and one viral removal step, i.e. 35 nm filtration. 
 
1.3. Rationale of the study 
1.3.1. Clinical study rationale 
As plasma fibrinogen level is essential for the formation of the fibrin clot, it could be considered as a 
relevant predictor of severity in massive bleeding and PPH (16,19). Although physicians 
acknowledged that it was unclear whether low fibrinogen contributed to PPH or reflected its 
severity, it was demonstrated that fibrinogen levels obtained at the time of PPH were more 
predictive than other coagulation studies such as Prothrombin Time, Partial Thromboplastin Time, 
and platelet counts in determining the severity of PPH (19,28). 
An early treatment with a transfusion of fresh frozen plasma (in association with packed RBCs in a 
ratio of 1:2 to 1:1 has been recommended for the control of severe post-traumatic haemorrhage 
(1,29).  Two retrospective publications give some information on this strategy in severe PPH 
(30,31). 
In view of the above data, the correction of hypofibrinogenaemia has been suggested in large 
cohorts of polytrauma or surgery to be useful in the control of massive bleeding. Historical 
comparison showed that fibrinogen concentrate administration was more effective than fresh frozen 
plasma in the treatment of PPH (32,33). 
Coagulopathy contributes to the persistence and severity of bleeding. Fibrinogen is the first 
coagulation factor to fall below physiological levels during haemorrhage, contributing further to 
excessive bleeding (19). 
In current practice fibrinogen concentrate is administered after the determination of fibrinogen level 
in order to correct hypofibrinogenaemia (20,32). Time between blood sampling and results delays 
the time of administration of fibrinogen concentrate when it has been shown that the sharp fall of 
fibrinogenaemia is time dependent (16,19) 
Therefore, a randomised, double-blind, placebo-controlled study is highly required to evaluate the 
benefit of a therapeutic strategy with an early bolus dose of human fibrinogen concentrate in PPH. 


 
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1.3.2. CLOTTAFACT® dose regimen and infusion rationale 
Clottafact is a human fibrinogen concentrate. According to the current SPC of Clottafact® (26), the 
dose of Clottafact® depends on the severity of haemorrhage and the patient’s clinical condition. 
Clottafact® is for intravenous route only and available as vials of 1.5g. An initial dose of 1 to 2 g is 
usually administered and could eventually be repeated. In case of severe acute obstetrical 
haemorrhage, larger doses of fibrinogen concentrate (4 to 8 g) may be necessary. 
In this study, Clottafact® will be administered at a bolus dose of 3 g. This dose was chosen according 
to the anticipated amount of blood loss and corresponding loss of fibrinogen. As the main objective 
of the study is to assess the benefit of a therapeutic strategy that associates an early administration of 
fibrinogen, the 3-g dose of the protocol is lower than the 4 to 8 g mentioned in the SPC. In both 
group, additional open-label administrations of fibrinogen concentrate will be allowed as a rescue 
therapy if the severity of the clinical situation required such additional fibrinogen administration 
according to the investigator.(cf 7.2.)  
1.3.3. Rationale of the population studied 
As a general preventive approach, the use of oxytocin for active management of the third stage of 
labour is strongly recommended, because it reduces PPH by more than 60% (34). However, as 
previously mentioned, in case of oxytocin-resistant PPH, prostaglandins are the second-line 
treatment that should be associated with transfusion (33,35). Therefore, in the present study, only 
patients with oxytocin-resistant PPH will be included. To make sure only oxytocin-resistant PPH 
patients will be selected, inclusion will be performed after the decision of administration of 
prostaglandins has been taken. 
Bleeding related to caesarean section may be due to surgical injury therefore only patients with PPH 
occurring after vaginal delivery will be included in the present study to select a more homogeneous 
population of patients. 
2. STUDY OBJECTIVES 
2.1. Primary objective 
The primary objective of this study is to assess the benefits of a therapeutic strategy that associates 
an early administration of human fibrinogen concentrate in the management of PPH on the reduction 
of bleeding after the initiation of prostaglandins intravenous infusion. 
2.2. Secondary objectives 
The secondary objectives of the study are: 
 To assess the evolution of haemorrhage, 
 To assess the need for haemostatic intervention, 
 To assess the need for intrauterine balloon, 


 
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 To assess the maternal morbi-mortality, 
 To assess the biological effects of fibrinogen concentrate administration, 
 To assess the tolerance of fibrinogen concentrate administration. 
 
3. STUDY DESIGN 
3.1. Design 
A study flow-chart is available in the protocol synopsis section. 
The present study is a phase IV, multicentre, randomised, double-blind, placebo-controlled, parallel-
group study. 
The patients will be randomly allocated to one of the two groups of treatment: 
1. Active treatment: fibrinogen concentrate (Clottafact®) 3g, or,  
2. Placebo treatment. 
The investigational medicinal product (IMP) is administered as a single-dose as soon as possible 
during the 30 minutes after the start of prostaglandin infusion. 
The duration of participation of each patient is 6 ± 2 weeks after randomisation. 
No interim analysis is planned. 
3.2. Endpoints 
3.2.1. Primary endpoint 
The primary endpoint is a composite endpoint defined as the percentage of patients: 
• Losing at least 4 g/dl of Hb, within the 48 hours following IMP administration 
and/or  
• Requiring the transfusion of at least 2 units of packed RBCs within the 48 hours following 
the administration of IMP. 
The reference of Hb level is the most recent Hb value recorded within the third trimester of 
pregnancy. 
The 4-g/l threshold has been used to define the severity of PPH in several studies (16,19). The 
determination of Hb level during the third trimester is mandatory in France and is independent of 
delivery, PPH and vascular loading. It is the reason why it was chosen preferably to Hb at the time 
of the inclusion. 


 
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The Hb might be modified by transfusion therefore transfusion is also included in the composite 
endpoint. The amount of transfusion is physician dependent and it is the reason why it has been 
decided not to use this sole criterion, and in addition, a minimum of 2 packs of RBCs has been 
defined. The 48-hour follow-up duration is chosen according to Ozier et al (36) because of the 
stabilisation of the hemoconcentration after PPH. In order to determine the time point evaluation at 
48 hours after delivery (H48), a 20-hour time interval (from H32 to H52) will be allowed to show 
more flexibility towards the variability of the time of delivery and the hour of IMP administration 
(H0).  
3.2.2. Secondary endpoints 
3.2.2. 1. Evolution of haemorrhage 
 Percentage of patients losing at least 4 g/dl of Hb, 48 hours following IMP administration 
with regards to the Hb reference level. 
 Percentage of patients losing at least 3 g/dl of Hb, 48 hours following IMP administration 
with regards to the Hb reference level. 
 Percentage of patients requiring the transfusion of at least 2 units of RBCs, 48 hours 
following IMP administration. 
 Percentage of patients losing at least 4 g/dl of Hb, 48 hours following IMP administration 
with regards to the level of Hb measured at inclusion. 
 Percentage of patients with an occurrence of Hb level < 9 g/dl within the 48 hours period 
following inclusion. 
 Number of units of transfused blood products within the 48 hours period following IMP 
administration. 
 Calculated volume of total blood loss, 48 hours following IMP administration. 
3.2.2. 2. Need for haemostatic intervention 
 Percentage of patients requiring at least one of the following interventions within 48 hours 
following the administration of IMP: pelvic arteries embolization, surgical vascular ligation, 
uterine ligation (B Lynch or other techniques), administration of recombinant activated 
Factor VII (rFVIIa) and hysterectomy. 
3.2.2. 3. Need for intrauterine balloon 
 Percentage of patients requiring the use of intrauterine balloon within 48 hours following the 
administration of IMP. 
 Time of intrauterine balloon placement 


 
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3.2.2. 4. Maternal morbi-mortality 
 Length of stay in resuscitation and/or intensive care and/or post interventional care units 
(PICU) and/or continuous care. 
 Length of stay in obstetrics units. 
 Single or multi-organ failure (SOFA score) in women transferred to resuscitation and/or 
intensive care and/or PICU and/or continuous care units. 
 Death during the study. 
3.2.2. 5. Biological effects of fibrinogen concentrate administration 
 Evolution of blood fibrinogen level between inclusion (blood sampling 1) and D2 (blood 
sampling 4). 
 Evolution of haemoconcentration between H0 and D2. 
3.2.2. 6. Tolerance of fibrinogen concentrate administration 
 Serious and non-serious adverse events (AE). 
3.3. Measures to avoid/minimise bias 
All patients will be randomly assigned to one of two groups of treatment, at a ratio of 1:1. Full 
information about the randomisation procedure is provided in Section 8.2.2. 
To avoid any bias in assessing the efficacy and safety of Clottafact®, the use of placebo as a control 
group should ensure objective assessment of the clinical endpoints. 
Furthermore the primary endpoint has been defined independently of the clinical practices in order 
to limit the influence of centre effect. 
Rules for the use of concomitant medication that has an effect on coagulation status and for the 
transfusion of blood products will be proposed to the investigators in order to limit the differences in 
PPH management among centres. The global algorithm of the PPH treatment (derived from French 
guidelines) (37,38) will be provided at the end of protocol (See Appendix 20.3). Adherence to this 
algorithm will be checked for each centre during the feasibility/selection process. In case of none or 
partial acceptance of the algorithm the final selection of the centre will be discussed with the 
scientific committee. 
3.4. Study Investigational Centres 
The study will be conducted in approximately 25 French investigational centres. 
Each centre is expected to enrol a mean of 29 eligible patients. 


 
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Investigators will be the physicians who usually treat the patient with haemostatic drugs (including 
fibrinogen concentrate) in the centre according to the local established practice. 
Midwives can also shoulder investigator’s responsibilities except for haemostatic treatments 
prescription which is made by the physician. 
The investigational centres should have immediate access to equipment and staff for resuscitation. 
The participating centre should have an organisation allowing a third-party, not involved in patient 
care, to reconstitute the IMP before its administration by the medical team. The procedure 
describing such process and the persons involved will be established for each centre (see Section 
6.4.2). 
3.5. Data and Safety Monitoring Board/Scientific Committee 
3.5.1 Scientific Committee 
A Scientific Committee has been set-up for the study. Its main responsibilities are: 
• To define the study global methodology and design, 
• To propose a study synopsis, 
• To participate to the study protocol writing and to validate the final version of the protocol 
and of the amendments if any, 
• To validate the final selection of each centre, 
• To maintain a continuous communication with the investigators during the study, 
• To review the data before the database lock, 
• To validate the clinical study report before writing all reports and publications. 
3.5.2 Data and Safety Monitoring Board 
A Data and Safety Monitoring Board (DSMB) will be set up to ensure patient’s safety. 
The DSMB is an expert committee, independent of the Investigators and the Sponsor of the clinical 
study. This committee will periodically examine data accumulated during the study and ensures that 
the benefit/risk ratio remains acceptable for participating patients. 
The Sponsor will timely provide the members of the DSMB with the safety data of patients. 
The DSMB will be asked to regularly review safety data and especially all reported serious adverse 
events (SAE) in order to decide if it would be necessary to generate an amendment or even to 
discontinue the study for security reasons. 
Quality of the DSMB members, the board organisation and its mode of operation will be described 
in an ad-hoc document before the start of the study. 
The DSMB will include a board steering experts who are not involved in the study (apart from the 
Sponsor, subsidiaries or study team): 
 A specialist in anaesthesia and resuscitation (MD, PhD), 


 
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 A specialist in Obstetrics and Gynaecology (MD, PhD), 
 An expert in biostatistics (MD, PhD). 
4. DURATION AND DATES OF THE STUDY 
The duration of this study is expected to be approximately 4 years. The first patient’s first visit  took 
place on April 10th, 2014, and the last patient’s last visit is expected in August 2018 at the latest. 
 
5. STUDY POPULATION 
5.1. Number of patients 
Sample size calculation is determined as a total of 412 evaluable patients (206 in each group) 
completing the study. Since the primary endpoint is measured shortly after the inclusion, the rate of 
drop-out is assumed to be approximately 5%. Then 434 patients will be included in this study (see 
Section 12.3). 
As there is some uncertainty about the variance of the test statistics, the variance will be re-
estimated in a blind way so as to maintain the power to 90% while still considering the same 
originally planned difference in failure rates, i.e. 15%.   It can be shown that the possible increase in 
sample size (after adjusting for drop-outs) cannot exceed 50 additionnal patients. Hence the 
restimated sample size will not exceed 484 patients ( see Section 12.3).  
In this multicentre study, a mean number of 29 patients is expected to be enrolled by each centre. 
The enrolment objectives for each centre will take into consideration the enrolment period, i.e. 
approximately 1 patient per month. 
5.2. Eligibility Criteria 
Before any study-related procedure is undertaken, a written informed consent must be obtained (see 
Section 8.1.1). 
For a patient to be eligible, all of the inclusion criteria and none of the exclusion criteria must be 
met. 
5.2.1. Inclusion criteria 
For patient inclusion, all of the following criteria must be met: 
a. Signed and dated informed consent form, 
b. Vaginal delivery, 
c. PPH requiring IV administration of prostaglandin, 


 
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d. At least one available result of Hb level during the third trimester of pregnancy, 
e. 18-year-old female patients and older, 
f. Covered by healthcare insurance in accordance with local requirements. 
5.2.2. Non-inclusion criteria 
Patients will not be eligible for inclusion in this study if any of the following criteria is met: 
a. 
Caesarean section, 
b. Haemostatic intervention (as ligation, embolization or hysterectomy) already 
decided at the time of inclusion, 
c. Known placenta praevia or accreta, 
d. Hb level < 10g/dL during the third trimester of pregnancy,  
e. History of venous or arterial thromboembolic event, 
f. Known inherited bleeding or thrombotic disorders, 
g. Treatment with low-molecular-weight heparin (LMWH) within 24 hours prior to 
the inclusion, 
h. Treatment with acetylsalicylic acid within 5 days prior to the inclusion, 
i. Treatment with vitamin K antagonists within 7 days prior to the inclusion, 
j. Administration of fibrinogen concentrate within 48 hours prior to the inclusion, 
k. Administration of FFP, platelets units or prohaemostatic drugs, tranexamic acid 
and rFVIIa or PCC within 48 hours prior to the inclusion, 
l. Administration of RBCs within 3 months prior to the inclusion, 
m. Participation in another interventional clinical study using an investigational 
medicinal product within 30 days prior to the inclusion, 
n. Previous inclusion in the present clinical study, 
o. Known history of hypersensitivity or other severe reaction to any component of 
Clottafact® or placebo, 
p. Minors, majors under guardianship, persons staying in health or social institutes 
and people deprived of their freedom, 
q. Known drug or alcohol abuse, 


 
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r. Patients whose use of concomitant medication may interfere with the 
interpretation of data, 
s. Any other current significant medical condition that might interfere with 
treatment evaluation according to the investigator’s judgement, 
t. Patients who are unlikely to survive through the treatment period and evaluation, 
u. Patients transferred from another service after the delivery 
5.3. Duration of Patient participation 
For each patient, the participation will last for 6 ± 2 weeks after the delivery. 
The exclusion period defined for this study is 1 month. During this period the patient can not 
participate to another biomedical research after the end of the study or its early termination. 
5.4. Discontinuation criteria 
The Investigator must document the date and the reason of any patient withdrawal or discontinuation 
by a narrative description in the patient’s medical records. 
A patient may be discontinued from the study at any time for one or more of the following reasons: 
a. 
Non randomised patient, 
b. Worsening of the patient’s condition requiring emergency measures that do not 
allow the administration of IMP, 
c. 
Withdrawal of consent for any reason, at any time, 
d. Lost to follow-up. 
Data to be collected are detailed in Section 8. 
If at the time of withdrawal, the patient has received the IMP (partially or totally), she must be 
advised to agree to follow up safety investigations. 
If a patient withdraws from the study, the investigator will make every effort to complete the final 
evaluation by performing an "end of study visit". All evaluation results, the date and a narrative 
description of the reason(s) for discontinuation must be recorded in the source documents and in the 
Case Report Form (CRF). 
5.5. Lost to Follow-up 
Investigators should make every effort to minimise the number of patients lost to follow-up and to 
obtain a maximum of information on patients lost to follow-up. All attempts will be documented in 
the patient’s medical record. 


 
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6. INVESTIGATIONAL MEDICINAL PRODUCTS (IMPS) 
6.1. Description of IMPs 
The active investigational product Clottafact® and placebo will be supplied, free of charge, by the 
sponsor. Their management at the investigational centre will be under the responsibility of the 
investigator. 
6.1.1. Fibrinogen 
Clottafact® is an anti-haemorrhagic drug (B02BB01) composed of a fibrinogen concentrate derived 
from human plasma. 
Clottafact® is manufactured by LFB BIOMEDICAMENTS and has obtained a marketing 
authorization in France in May 2009 for congenital and acquired fibrinogen deficiencies. 
The manufacturing process of Clottatact® includes three viral inactivation/removal steps: 
- A solvent-detergent treatment which has been shown to be effective in the inactivation of 
enveloped viruses such as Human Immunodeficiency Virus, hepatitis B and C viruses, 
- A dry heating which inactivates small non-enveloped viruses, especially parvovirus B19 and 
hepatitis A virus, 
- A 35 nm filtration which eliminates both enveloped and non-enveloped viruses that are 
larger than 35 nm, and thus, contributes to the reduction of the theoretical risk of 
transmission of unconventional agents such as prions. 
Clottafact® is available in the form of a glass vial containing a freeze-dried powder, along with a 
solvent for reconstitution in the form of 100 mL of sterile water ready for injection. Each vial 
contains approximately 1.5 g of fibrinogen. 
Clottafact® also contains relative amounts of other co-purified plasma proteins: fibronectin (5.3%), 
IgM (1.2%), C4 (0.57%), FXIII (0.40%) and plasminogen (0.40%). 
 
The principal excipients are: 
- Arginine hydrochloride (4.0 g) 
- Isoleucine (1.0 g) 
- Sodium citrate (0.25 g) 
- Lysine hydrochloride (0.2 g) 
- Glycine (0.1 g) 
The reconstituted solution contains approximately 15 mg/mL of human fibrinogen. 
For more information, see the Summary Product Characteristics (SPC). 
6.1.2. Placebo 
The placebo will be supplied in identical glass vial containing a freeze-dried powder, along with a 
solvent for reconstitution in the form of 100 mL of sterile water ready for injection. 


 
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In order to offer appearance, consistency and observable properties as close as possible to 
Clottafact® that contains proteins, the vial of placebo is composed of the following excipients: 
- Mannitol (3.5 g) 
- Saccharose (4.4 g) 
- Sodium chloride (0.18 g) 
- Polysorbate 80 (5 mg) 
 
6.2. IMP packaging and labelling 
6.2.1. Packaging 
Clottafact® and placebo will be packaged in the same type of vials and boxes to guarantee the 
blinding. 
The IMP (Clottafact® or placebo) is composed with: 
 1 vial of IMP (Clottafact® 1,5g or placebo), 
 1 vial of 100 ml sterile water, 
 1 transfer system. 
 
Then, two IMPs will be packed as a set which will contain the treatment needed for one 
patient/injection so two boxes of IMP. Each set will also contain: 
 1 tinted tubing for the infusion in order to ensure blinding during the administration of the 
reconstituted IMPs, 
 Adhesive film (blinding label) to mask the 2 vials of reconstituted IMPs. 
IMP sets will be packaged and sent to the investigational centres in dispatch boxes containing the 
treatment for 4 patients. 
6.2.2. Labelling 
The labels will carry required regulatory texts. Each vial and external packaging will be labelled at 
least with the following information: 
 
 FIDEL Study 
 Number of treatment unit 
 Batch No:  
 Expiry date: MM/AAAA 
 Patient N°|__|__|-|__|__| (to be filled in) 
 Investigator’s name (to be filled in) 
 Read the package leaflet before use 
 For intravenous use only 
 Powder and solvent for solution for injection 
 Storage requirements: do not store above +25°C, protect from light, do not freeze 
 To be used within 6 hours following reconstitution 


 
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 Medicinal product derived from human plasma 
 For clinical use only 
 For use under medical supervision 
  
 LFB BIOMEDICAMENTS contact details : 
3, avenue des Tropiques - BP 40305 
91958 COURTABŒUF Cedex - France 
Phone number: (+33) (0)1 69 82 70 10 
The IMP vials will bear two tear-off labels as well as the external packaging, a label for plasma-
derived product traceability with two stickers. Traceability label will be stuck on CRF, patient’s 
medical record and pharmacy site file. 
6.3. Management of IMP 
Clottafact® and placebo will be supplied by the Sponsor in blind packages to the Hospital 
Pharmacist in investigational sites, free of charge for the hospital and the patient. 
6.3.1. Shipment and receipt 
The IMP will be shipped to the Hospital Pharmacist by a Drug Distributor (under the Sponsor 
responsibility) in accordance with local requirements. Shipment of IMP will be done at refrigerated 
temperature (+2°C/+8°C), these conditions being ensured by the use of a temperature monitoring 
device.  
A first shipment of 2 dispatch boxes (each box containing the IMPs for 4 patients) will be performed 
to each centre as soon as the initiation of the centre is validated by the Sponsor. 
Upon receipt of the IMPs at site, the Pharmacist will inventory the study treatment and complete the 
acknowledgment of receipt form. Should any abnormality of the supplied boxes be observed, the 
Pharmacist must immediately inform the Monitor/Sponsor. The acknowledgment of receipt form 
must be returned to the Sponsor or representative as instructed. 
6.3.2. Storage requirements 
The IMP must be protected from light, stored in a secured limited-access area and maintained at a 
temperature below +25°C without being frozen. They must be kept in their original dispatch boxes. 
If the reconstituted IMP is not administered immediately, storage must not exceed 6 hours. 
Reconstituted IMP must be stored below +25°C and must not be frozen (for additional information, 
see SPC). 
The Investigator and/or the Hospital Pharmacist are responsible for the appropriate storage of the 
IMP at the investigational centre. 
If the required storage conditions are not respected, the Investigator and/or the Hospital Pharmacist 
must immediately inform the Monitor/Sponsor. 


 
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For any temperature deviation, a written approval from the Sponsor must be obtained prior to any 
dispensation/administration. During the evaluation of the temperature deviation, the concerned IMP 
must be placed under quarantine. If the decision is not to use the quarantined IMP, the vials will 
remain under quarantine until shipment back to the Drug Distributor. 
6.3.3. IMP re-supplying 
The investigational centres will be re-supplied with IMPs according to their respective enrolment 
rates. 
One, or more, dispatch box will be sent accordingly. 
 
The IMPs will be sent to the centre within 5 working days from the request. 
 
6.3.4. IMP return, destruction and recall 
6.3.4. 1. Return and destruction 
Used and unused IMPs will be returned back to the Sponsor’s Drug Distributor at the close-out visit 
at the latest. IMPs return will be organised by the Hospital Pharmacist and the Monitor. The 
Hospital Pharmacist or a delegate should be available at the predetermined date and time when the 
boxes will be collected from the investigational centre. 
The used/unused IMPs (vials, tubings and original containers) must NOT be destroyed at the 
Hospital Pharmacy without a written authorisation from the Sponsor. If an on-site destruction is 
required, the site must have a written authorisation from the Sponsor for destruction which will be 
filed along with the certificate of destruction in the IMP section of the Pharmacy site file. 
At the end of the study, a final reconciliation between delivered, dispensed, used/unused and 
returned IMPs will be conducted by the Monitor. 
6.3.4. 2. Recall 
If an IMP batch is suspected to be defective, the Investigator and the Hospital Pharmacist will be 
immediately informed by the Sponsor. 
The Monitor will organise with the Hospital Pharmacist the return of the concerned batch(es) as per 
the return procedure. Depending on the study stage, new batch(es) may be sent to the investigational 
centre. 
6.4. Treatment of patients 
6.4.1. Methods for Assigning Patients to Treatment Groups 
IMP will be numbered and treatment will be assigned to eligible patients according to the ascending 
order of their randomisation. 
The steps for assigning patients to treatment groups are described in Section 8.1.3. 


 
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6.4.2. Dispensing 
Under no circumstances will the Investigator allow the IMP to be used other than as directed in the 
protocol. 
 IMP reconstitution 
 
To prevent any risk of unblinding of the investigating study team which may occur during 
IMP preparation, a third party not involved in patient care will be in charge of this task. 
o IMP is to be reconstituted before infusion: 2 vials of powder (Clottafact® or placebo) 
will be reconstituted each with 100 mL of sterile water for injection, in order to 
administer 200 mL of reconstituted IMP to the patient. 
o Participants, outcome assessors, trials investigators, statisticians and monitors are 
blinded, as well as care providers such as midwives, obstetricians, anaesthesiologists 
and anaesthetist nurses. 
 Use current guidelines for aseptic procedure. 
 If necessary, bring the two vials (powder and solvent) to ambient temperature. 
 Remove the protective cap from the solvent vial (water for injection) and 
from the powder vial. 
 Disinfect the surface of each stopper. 
 Remove the translucent protective sheath from the transfer system, and 
completely insert the exposed needle through the centre of the stopper of the 
solvent vial while simultaneously twisting the needle. 
 Remove the second protective sheath from the other end of the transfer 
system. 
 Keeping both vials horizontal (vented spike pointing upwards), quickly push 
the free end of the needle in the centre of the stopper of the powder vial. 
 Ensure that the needle always remains immersed in the solvent to avoid 
releasing the vacuum prematurely. 
 Immediately place the system upright in a vertical position, keeping the 
solvent vial directly above the powder vial, to allow the solvent to transfer 
into the powder. 
 During transfer, direct the jet of solvent over the whole surface of the powder. 
Ensure that all of the solvent is transferred. 
 The vacuum is automatically released at the end of the transfer procedure 
(sterile air). 
 Remove the empty vial (solvent) with the transfer system. 
 Lightly swirl with a rotating movement to avoid the formation of foam until 
the powder has completely dissolved. 


 
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o The reconstituted product should be examined visually in order to ensure that it does 
not contain particulate matter. The reconstituted solution should be slightly or more 
markedly opalescent. Do not use solutions which are cloudy or contains deposits. 
o Note that in light of its stability after reconstitution, the injection may be performed 
within a period of six hours. 
 The IMP must not be administered if it does not conform to the description. 
The 
Investigator/Hospital Pharmacist should immediately 
alert 
the 
Monitor/Sponsor. 
o The 2 vials of IMP should be masked with an adhesive film (blinding label): 
 While wrapping the blinding label around the vial, the third party pushes the 
small flaps on the upper edge of the label against the vial carefully. He/she 
will then write the patient number on the blinded vial. 
o For additional information on IMP reconstitution, see SPC of Clottafact® (26) and the 
study document entitled “Guidelines for IMP reconstitution”. 
 Treatment dose and schedule 
o IMP is administered at a fixed dose: a total volume of 200 mL of IMP (2 vials of 
100 mL of reconstituted IMP) are injected to every patient. 
o Only one injection of IMP will be performed to the patient throughout the study. 
o Injection of IMP must start as soon as possible and within 30 minutes following the 
start of prostaglandin infusion. 
 Method and route of administration 
o Only intravenous route is allowed for the administration of the reconstituted solution 
of IMP. 
o The administration will be performed using the tinted tubing provided with the IMP. 
o The reconstituted solution of each IMP should be warmed up to room or body 
temperature before administration, and then infused at a flow rate ≤ 20 mL/min. 
o Date and time of administration (start/end) are to be reported in the CRF and patient’s 
medical records. 
o IMP label (tear-off part on the masking system) has to be stuck on corresponding 
visit page in CRF. 
o Following the administration of IMP, the therapeutic management of PPH will be left 
to the discretion of the Investigator. 


 
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6.4.3. Misuse /Overdose 
Any IMP misuse/or overdose associated or not with any adverse event should be reported on an 
Adverse Event form and faxed to the Sponsor immediately and no later than 24 hours (see Section 
9.5.6). 
6.4.4. Compliance 
Compliance with treatment is defined as the administration of IMP to the patient performed entirely 
(2 vials) according to the investigator’s judgement. 
The compliance will be considered as non-optimal if, for any reason, the infusion of at least 1 of the 
2 IMP vials has been stopped before the total volume has been administered. 
6.5. IMP accountability 
The Sponsor will provide specific forms for drug accountability, which will be kept up-to-date by 
the Investigator and/or Hospital Pharmacist throughout the study. 
All reasons for non-compliance must be carefully monitored, recorded and tracked. 
The accountability forms should be filed in the investigator site file. The Monitor will verify the 
drug accountability forms for completeness and accuracy at each site visit. 
At the end of the study, it must be possible to reconcile delivery records with dispensing and 
used/unused records. Any discrepancy must be accounted for. 
Used/unused IMP should be kept in a secured place at the centre until the verification of records by 
the Monitor and organisation of return to Drug Distributor. 
6.6. Randomisation Codes and Procedures for Unblinding 
The Sponsor will provide the Investigator or Pharmacist with decoding devices in sealed envelopes 
with an acknowledgement of receipt at the same time as the IMP. These codes should be kept in a 
secured place with restricted access and returned to the Sponsor at the end of the study. 
The Investigator is entitled to unblind the treatment in case of medical emergency when the identity 
of the administered treatment may determine the strategy of patient management. 
The Sponsor should preferably be consulted prior to the blind being broken, but in any case, 
unblinding must be reported to the Sponsor immediately. 
In the case of premature unblinding, the following items must be recorded on the decoding device: 
the date and time of unblinding, the name of the person responsible and the reason for unblinding. 
The Investigator must sign and date the decoding envelop just before opening it, and document the 
unblinding in the patient’s file. 


 
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The circumstances under which the code for a given patient has been broken should be fully 
documented in the Investigator’s file. 
7. PRIOR AND CONCOMITANT MEDICATION 
7.1. Prior Medication 
The term ‘prior medication’ refers to any medication given before inclusion, i.e. before the informed 
consent form was signed. 
All prior medication relevant with regard to the patient’s baseline description, taken within 7 days 
before inclusion, including all medication administered since the beginning of the delivery, must be 
recorded in the patient’s medical records and documented on the appropriate pages of the CRF. 
Non-inclusion criteria related to prior medication are: 
 Treatment with Low Molecular Weight Heparin (LMWH) within 24 hours prior to the 
inclusion, 
 Treatment with acetylsalicylic acid within 5 days prior to the inclusion, 
 Treatment with vitamin K antagonists within 7 days prior to the inclusion, 
 Administration of fibrinogen concentrate within 48 hours prior to the inclusion, 
 Administration of RBCs, FFP, platelets units or prohaemostatic drugs, tranexamic acid and 
rFVIIa or PCC within 48 hours prior to the inclusion. 
All authorised medications taken regularly at baseline will be continued and documented as a 
concomitant medication throughout the study protocol. 
7.2. Concomitant Medication 
The term ‘concomitant medication’ refers to any medication that the patient receives at any time 
during the study, i.e. from inclusion to the end of study visit/phone call. 
The concomitant treatments below will be administered in accordance with the following 
recommendations: 
 The dose of prostaglandins will be administered according to the 2004-recommendations 
provided by the French National Authority for Health (Haute Autorité de Santé, or HAS) 
(13). 
 Fibrinogen concentrate as rescue therapy will not be administered : 
o within 60 minutes following the start of IMP  
or  
o before the administration of at least 2 units of packed RBCs. 


 
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o In clinical situation where severe uncontrolled haemorrhage require immediate 
coagulopathy management including blood product transfusion and fibrinogen 
concentrate, RBC would be administrated within a short period of time after the start 
of IMP infusion. Therefore in such cases, the fibrinogen concentrates as rescue 
therapy would be administrated after the RBC infusion and before the 60 minutes 
period. Then, this administration will not interfere with the assessment of the primary 
criteria. 
 Tranexamic acid:  
o The administration of tranexamic acid will be allowed only after prostaglandin 
infusion has been decided. 
o Recommended dose: 1 g IV to be renewed once after 30 min. 
 Blood transfusion in accordance with the following objectives: 
o Hb ≥ 8 g/100 ml, 
o PT ≥ 40%, 
o Platelets count ≥ 50 000/mm3, 
o Transfusions of RBC, FFP and platelets units can be performed before the 
availability of laboratory results, when indicated (29, appendix 20.4). 
  Hydroxyethylstarch (HES): maximum dose of 1.5 litres during the first 24 hours. 
All concomitant medication, including intravenous fluids and blood products, must be recorded in 
the patient’s medical records and documented on the appropriate pages of the CRF. 
8. STUDY PLAN 
The method for assessing each study parameters is described in Section 10. 
Investigators may also refer to the study flow-chart (Table 1). 
8.1. Patient recruitment 
8.1.1. Informed Consent 
Patients with significant blood loss may have impaired consciousness and may be unable to give 
properly informed consent. In this emergency situation it may not be medically appropriate to delay 
the start of treatment. In this study, informed consent will be obtained from either the patient or a 
member of her family or the reliable person depending of the patient's level of consciousness. 
The EU Directive (2001/20/EC) requires that, prior to participation in a trial, written informed 
consent from a legal representative of any person unable to consent for herself has to be obtained. 
The requirements of the relevant ethics committee will be adhered to at all times. An informed 


 
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consent form for legal representative will be available in addition to an inform consent form for 
patients.  
Under certain circumstances, PPH may represent a critical condition for both the patient and her 
family (her husband the most often) or any other person in a position of trust.  In such an 
emergency, it would be impossible to ask them to read a complete and very detailed information 
sheet at the moment of inclusion.  Therefore, concise information on the study will be given as soon 
as PPH is diagnosed.  Depending on the patient’s physical condition, the concise information will be 
given to the patient or a family member or the person of trust. 
The initial information may be given to the patient during the last prenatal consultation (with the 
obstetrician or the anaesthetist) by the sites which would prefer to anticipate this procedure. 
The procedures for collecting written informed consent in emergency situation are described on the 
next page. 
In all cases, as soon as the patient regains competence, she will receive full required information 
about the study.  Her post-inclusion consent to continue the study must be requested. 
She should have enough time and opportunity to inquire about study details.  All her questions 
should be answered with complete satisfaction.  The patient must be informed about her right to 
withdraw from the study at any time. 
She may also decide to reject the use of her data in the context of the study. 
An NCR (No Carbon Required) copy of the informed consent form (emergency and post-inclusion), 
signed and dated by both the patient (or the designated person as described above) and the 
Investigator should be given to the patient (or the designated person as described above). The 
process for obtaining consent will be documented in the patient’s file and in the CRF. 


 
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8.1.2. Patient Inclusion 
The patient is considered as included when emergency informed consent form has been signed by 
the patient or a member of her family or the person of trust (see Section 8.1.1).   
8.1.3. Patient Randomisation 
Randomisation corresponds to the attribution of a study treatment unit to the patient. 
As soon as prostaglandin infusion has been decided, the patient will be randomly allocated to one of 
the two groups of treatment: 
1. Active treatment group: fibrinogen (Clottafact®) 3g or, 
2. Placebo group. 
The treatment will be double-blind. 


 
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Given that the inclusion will be realised in emergency situation, the randomisation will be done in 
the centre. Each centre will receive pre-numbered treatments in dispatch boxes. According to the 
time of inclusion, study treatment units will be allocated sequentially in chronological order of 
randomisation in ascending manner. 
An inclusion fax will be sent to the Monitor within the 24 hours after inclusion. 
Randomisation will be stratified on the centre. 
8.1.4. Replacement of early withdrawals 
No patient will be replaced. 
8.2. Schedule of visits 
The duration of patient participation is 6 ± 2 weeks starting from randomisation. After enrolment, all 
patients will be treated with IMP. The start of IMP administration corresponds to H0. 
8.2.1. Visit 1: Inclusion / Blood sampling 1 
Information on the study will be given at the moment of the diagnosis of haemorrhage (see Section 
8.1.1). 
• Informed consent must be obtained before any study procedure; 
• Eligibility criteria check (inclusion and non-inclusion criteria); 
• Date and start time of prostaglandin infusion; 
• Demographics (height, weight prior to pregnancy and last known weight); 
• Thromboembolic and obstetrical events and any clinically relevant medical conditions; 
• Pregnancy parameters: 
o Hb level during the third trimester, 
o Hb level at the sixth month, 
o Ht and platelets will be collected if available 
o Date of last menstrual period, gestational age, 
• Delivery parameters 
o Times of the start and the end of delivery; 
o Number of live births and/or stillbirths; 
o Procedures: artificial delivery, uterine or genital examination 
• Prior and concomitant treatment (see Section 7) including intravenous fluids and blood 
products since the start of delivery; 
• Haemorrhage parameters : 
o Haemorrhage start time; 
o Measured or estimated volume of blood loss at the start of prostaglandin infusion; 
• Physical examination will include a comprehensive standard evaluation of all systems: 
cardiovascular system, respiratory system, skin and appendices, gastrointestinal system, ear-


 
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nose-throat, lymphatic nodes, spleen, central nervous system, eyes, musculoskeletal system, 
endocrine system, argental system, psychiatric state. Signs for possible thrombosis will be 
checked. 
• Vital signs:  
o Measurement of arterial blood pressure (systolic and diastolic), 
o Heart rate. 
• Blood sampling for laboratory parameters at inclusion: 
o Complete blood count, Hb, Ht, platelets, 
o Haemostatic profile: fibrinogen, PT, QT, aPTT, D-dimers, 
o Blood urea and serum creatinine. 
8.2.2. Visit 2: Randomisation and IMP infusion 
• Randomisation will be performed as soon as possible after inclusion and after the start of 
prostaglandins infusion (see Section 8.1.3). 
• IMP administration 
o A third party reconstitutes the IMP (see Section 6.4.2). 
o The start of IMP infusion corresponds to H0 and should be within the 30 minutes 
following the start of prostaglandins infusion. 
o The start and the end times and the administered volume will be collected in the CRF. 
• Concomitant treatments including intravenous fluids and blood products; 
• Local tolerance which occurred during IMP infusion and AEs if any. 
8.2.3. Visit 3: H2 (120 ± 30 min) / Blood sampling 2 
The following data will be collected in the CRF: 
• Blood sampling: 
o Complete blood count, Hb, Ht, platelets, 
o Haemostatic profile: fibrinogen, PT, QT, aPTT, D-dimers, 
• Vital signs 
o Measurement of arterial blood pressure (systolic and diastolic), 
o Heart rate; 
• Haemorrhage parameters: 
o Measured or estimated volume of blood loss from the start of bleeding; 
• Concomitant treatments including intravenous fluids, blood products, tranexamic acid and 
fibrinogen concentrate as rescue therapy: any modification or institution of a new treatment; 
• AEs if any. 
8.2.4. Visit 4: H6 (360 ± 30 mn) / Blood sampling 3  
The following data will be collected in the CRF: 




 
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• Concomitant treatments including intravenous fluids, blood products, tranexamic acid and 
fibrinogen concentrate as rescue therapy: any modification or institution of a new treatment; 
• AEs if any. 
8.2.6. Visit 6: Hospital discharge 
Visit 6 corresponds to the final hospital discharge regardless the site of the patient’s last admission 
after delivery and 6 weeks after delivery at the latest. 
The data for this visit will also be collected if the patient is prematurely withdrawn after 
randomisation. 
• Date of discharge; 
• Date and time of obstetric room discharge; 
• Stay in resuscitation and/or intensive care and/or PICU and/or continuous care units during 
hospitalisation (yes/no); if yes: 
o Length of stay in the unit; 
o Maximum SOFA score during the stay in the unit; 
o Number of days with assisted ventilation; 
o Renal failure that required dialysis; 
o Hypotension episodes that required continuous vasopressor therapy; 
o Acute pulmonary oedema, acute respiratory distress syndrome, transfusion-related 
acute lung injury (TRALI); 
• Haemorrhage parameters: 
o Haemorrhage end date and time; 
o Total volume of blood loss: measured or estimated; 
o Blood-draining containers (if any): date and time of setting and removal and the total 
volume collected; 
o Possible haemostatic intervention needed: uterine tamponade by compression balloon 
(Bakri or Belfort-Dildy balloon), uterine compression sutures (B-Lynch suture, 
multiple squares/rectangles technique of Cho), arterial embolization or ligature, 
hysterectomy. 
• Physical examination; 
• Vital signs: 
o Measurement of arterial blood pressure (systolic and diastolic); 
o Heart rate; 
• Concomitant treatments including intravenous fluids, blood products, tranexamic acid and 
fibrinogen concentrate as rescue therapy: any modification or institution of a new treatment; 
• AEs if any. 


 
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8.2.7. Visit 7: End of Study Visit/Contact  
The following tolerance data will be collected by the Investigator during an obstetrical follow-up 
visit or a phone contact at 6 ± 2 weeks after delivery, and reported in the CRF: 
• Administration of any antithrombotic treatment since hospital discharge; 
• Administration of iron (IV or oral) including the dose and the date of last administration, 
since hospital discharge; 
• Serious and non-serious AEs. 
8.3. Assessments 
1) Clinical assessments 
 
Clinical assessment 
Time of assessment 
Physical examination: 
It will include a comprehensive standard evaluation of all 
systems, like: cardiovascular system, respiratory system, 
skin and appendices, gastrointestinal system, ear-nose-
throat, lymphatic nodes, spleen, central nervous system, 
eyes, musculoskeletal system, endocrine system, argental 
system, psychiatric state. Signs for possible thrombosis 
will be checked. 
Inclusion  
Discharge of the hospital 
Vital signs (arterial blood pressure and heart rate) 
Inclusion 
H2, H6 
Morning of D2 
Hospital discharge 
Maximum SOFA score  
Upon discharge of resuscitation 
and/or intensive care and/or PICU 
and/or continuous care units (if any) 
 
2) Laboratory assessments 
 
Plasmatic assessments 
Volume of 
blood sample 
Type of tube 
Time of assessment 
Complete blood count, 
platelets, Hb, Ht 
10 ml  
EDTA 
Inclusion, H2, H6 and D2 
Fibrinogen, PT, QT, aPTT, 
D-dimers 
5 ml  
Sodium citrate 
Creatinine 
5 ml  
EDTA 
Inclusion and D2 


 
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Urea 
4 ml  
Lithium heparinate 
A total of 78 mL of blood will be collected throughout the study according to the protocol. All 
biological parameters will be determined locally. 
Any abnormal laboratory finding judged clinically significant by the investigator will be considered 
as an adverse event. 
8.4. Compliance with the Study Plan 
The Investigator should make every effort to comply with the study plan. If the Investigator 
encounters difficulties in complying with the study plan, e.g. with regard to the schedule of visits or 
the required procedures, he/she must alert the Sponsor or his/her designee. The Sponsor may 
consider it relevant to generate an amendment. 
The Investigator should make every effort to avoid the occurrence of deviations from the study plan. 
If deviations occur or if the Investigator knows that a deviation will occur, he/she must promptly 
inform the Sponsor to determine how to manage the deviation. 
9. SAFETY 
9.1. Safety Reference Document 
In this study, the Clottafact® current SPC, applicable at the time of an adverse event occurrence, will 
be considered as the Safety Reference Document, based on which evaluation of the adverse event 
will be performed, in particular regarding expectedness. 
9.2. Benefit/Risk Information 
The safety information received during the period covered by the PSUR (from 05/May/2009 to 
31/Oct/2012), did not modify the safety profile of CLOTTAFACT as described in the SPC.During 
that period, no case with a fatal outcome related to CLOTTAFACT administration has been 
reported. 
 
During the period covered by the PSUR (from 05/May/2009 to 31/Oct/2012), approximately 
119 739 g of CLOTTAFACT were sold (among which more than 98 % in France).  
An estimate of the number of treatments potentially administered has been calculated based on 
volume of CLOTTAFACT, sold in France and outside France, during the period and the estimated 
mean dose per treatment of 3.4 g. The estimated exposure was around 35,217 treatments. 
 
During the period covered by the PSUR, the reporting rate was estimated to 0.06 %. There was no 
evidence of any significant increase in the frequency of ICSRs (Individual Case Safety Reports) 
with ADRs (Adverse Drug Reactions) reported over the time. 
 
The non-interventional Post –Authorization safety Study (PASS) study was initiated at the time of 
CLOTTAFACT launch on the market and has been completed. 


 
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The primary objective was the assessment of CLOTTAFACT safety in current use and the 
secondary objective was the collection of efficacy data to better document the benefit/risk balance. 
 
The PASS included 2 cohorts : 
 “Acquired fibrinogen deficiency” cohort: 156 patients were included and received 
CLOTTAFACT. 
  “Congenital fibrinogen deficiency” cohort: 14 patients were included and received 
CLOTTAFACT. 
 
Concerning the “Acquired fibrinogen deficiency” cohort the report concluded:  
 Concerning the safety, the investigators assessed CLOTTAFACT safety as good for the 
overall patient treated considering the patients’ medical history. Based on this report, 
CLOTTAFACT safety was assessed as satisfactory. 
 As regards to the efficacy, no new relevant information about CLOTTAFACT benefit has 
been raised in this study (the efficacy was the secondary endpoint). The investigators 
considered CLOTTAFACT efficacy with a success for 73.8 % of infusions (124/168 
infusions). 
The report concerning the “Congenital fibrinogen deficiency” cohort is under preparation. 
Based on marketing experience including PASS with Clottafact®, the benefit/risk balance of 
Clottafact® remains favourable in the granted indications. 
9.2.1. Known and potential risk(s) related to the IMPs 
• Clottafact® 
As specified in the Risk Management Plan of Clottafact®, the potential risks are: 
Thromboembolic events: 
Venous and arterial thromboembolic events are the main safety concerns associated with the use of 
fibrinogen concentrate. However, several minimisation actions are taken in order to limit the 
potential risks, which are detailed thereafter (see Section 9.3). 
 
Anaphylactic reactions: 
Immunoallergic events and anaphylactic accidents are potential concerns, which will be minimised 
by patient monitoring during administration. 
 
Immunogenicity: 
The occurrence of antibodies against fibrinogen is a very rare complication of fibrinogen 
replacement therapy. The risk of antifibrinogen antibodies appearance has been described only once 
in a patient with congenital afibrinogenaemia and rheumatic valvular heart disease. 
Viral safety: 
Clottafact® is purified from human blood of selected donors and its manufacturing process includes 
three viral/non-conventional transmissible agents removal/inactivation steps (solvent-detergent, dry 
heating and 35 nm filtration). Despite these highly secured procedures, the risk of viral infection or 
non-conventional transmissible agents cannot be totally ruled out. 


 
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Standard measures to prevent infections resulting from the use of medicinal products prepared from 
human blood or plasma include: selection of donors, screening of individual donations and plasma 
pools for specific markers of infection and the inclusion of effective manufacturing steps for the 
inactivation/removal of viruses. Despite these safety procedures, when medicinal products prepared 
from human blood or plasma are administered, the possibility of transmitting infectious agents 
cannot be totally excluded. This is also applied to unknown or emerging viruses and other 
pathogens. The previously mentioned measures are considered to be effective against enveloped 
viruses such as HIV, HBV, HCV and for the non-enveloped viruses HAV and parvovirus B19. 
There is reassuring clinical experience regarding the lack of hepatitis A or parvovirus B19 
transmission and it is also assumed that the antibody content makes an important contribution to the 
viral safety. 
• Placebo 
At the planned conditions of use of Clottafact® placebo, no risk is expected. 
9.2.2. Other expected or potential risk(s) 
None. 
9.2.3. Benefit/Risk balance 
Clottafact® is already indicated in France as a complementary treatment for the management of 
severe uncontrolled bleeding resulting in acquired hypofibrinogenaemia (25,26). The aim of the 
present study is to show the benefit of an early administration of Clottafact® before 
hypofibrinogenaemia has been shown. The expected benefit of the proposed therapeutic strategy is 
to reduce the oxytocin-resistant PPH by the early administration of human fibrinogen concentrate at 
the time of prostaglandins infusion (see Section 1.3.3.). It is worthy to note that there is still no non 
invasive treatment that would be totally effective in preventing the morbidity and mortality of 
intractable PPH (see Section 1.1.4). This protocol will allow the evaluation of the therapeutic 
relevance of the proposed strategy by reliable and clinically approved endpoints. 
Arterial and/or venous thromboembolic complications are the main known risk of the administration 
of fibrinogen concentrate. This risk is theoretically increased by the fact that women are in general 
more at risk of thromboembolic complications during pregnancy and after delivery (39). However, 
the hypothesis of an increased risk of post-partum thromboembolism is not highly plausible in this 
context. This is due to the fact that fibrinogen is the first coagulation factor to fall below 
physiological levels during PPH, contributing further to excessive bleeding (19). Nevertheless, this 
protocol will assess the safety and efficacy of early administration strategy of fibrinogen concentrate 
over placebo. Moreover, a DSMB, as an expert committee, will be constituted to ensure patient 
safety. 
9.3. Risk Minimisation Actions Throughout the Protocol  
Regarding the venous and arterial thromboembolic risk, the following risk mitigation measures will 
be taken: 


 
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o 
Exclusion of patients with documented history of venous or arterial thromboembolic event or 
known inherited bleeding or thromboembolic disorders. 
o 
Exclusion of patients who would have received tranexamic acid within 48 hours prior to the 
inclusion. 
o 
A DSMB will monitor patient data regularly during the study and will make recommendations 
to the Sponsor. 
The risks of immunoallergic events and anaphylactic reactions will be mitigated by the exclusion of 
patients with known hypersensitivity or other severe reaction to any component of the 
investigational medicinal products including the placebo. 
In order to minimize the immunogenicity risk, the patients with known inherited bleeding disorders 
(including congenital afibrinogenaemia) will not be included in the study. 
Furthermore, physical examination and regular assessment of vital signs will be performed in order 
to early detect and treat any eventual adverse event. 
9.4. Alternative Therapeutic Management - Emergencies Handling 
If allergic or anaphylactic/anaphylactoid reactions occur, the infusion should be stopped 
immediately. In case of anaphylactic shock, standard medical treatment should be implemented. 
In case of abnormally persistent bleeding, medical care will be given according to local management 
strategies. 
In case of misuse or overdose, emergency care is left to the discretion of the investigator. 
9.5. Definition and Reporting of (Serious) Adverse Events 
9.5.1. Adverse Event (AE)  
An adverse event (AE) is any untoward medical occurrence in a patient or clinical investigation 
subject administered a medicinal product that does not necessarily have a causal relationship with 
this treatment. An adverse event can therefore be any unfavourable and unintended sign, any 
symptom, syndrome, or disease, whether new or exacerbated, temporally associated with the use of 
a medicinal product, whether or not related to the IMPs. 
An adverse event, whether or not considered to be causally related to the IMP, may be: 
• The deterioration of a pre-existing chronic disease or aggravation of a symptom or disease 
that was present at the patient's enrolment in the study, 
• A symptom or disease discovered after the start of the study even if it was probably present 
prior to the patient's enrolment, 
• An abnormal laboratory finding when it is considered/judged as clinically significant by the 
investigator. 


 
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9.5.2. Serious Adverse Event (SAE)  
A Serious Adverse Event (SAE) is an AE that, at any time, fulfils one or more of the following 
criteria: 
• results in death, 
• is life threatening, i.e. the patient was at immediate risk of death at the time of the event; it does 
NOT refer to an event which might have caused death if it was more severe, 
• requires in-patient hospitalisation or prolongation of existing hospitalisation, i.e. 
hospitalisation signifies that the patient has been detained, usually (but not systematically) 
involving at least an overnight stay, 
• results in persistent or significant disability/incapacity, i.e. substantial disruption of a person’s 
ability to carry out normal life functions, 
• is a congenital anomaly/birth defect, 
• is any important medical event that may not be immediately life threatening or result in death 
or hospitalisation, but, based on appropriate medical judgment, may endanger the patient or may 
require intervention to prevent one of the other outcomes listed above. 
 
Distinction should be made between serious and severe AEs. Severity is a measure of intensity 
whereas seriousness is based on the outcome or the action criteria described above. For example, 
nausea that persists for several hours may be considered as “severe”, but not as a “SAE”. On the 
contrary, a cardiovascular event that causes limited degree of disability may be considered as “not 
severe” but would be recorded as a “SAE”. 
 
- Surgical intervention is not considered as SAE but the medical condition requiring the surgery is 
to be reported as such. 
 
- Events initially reported as an AE may become serious. For example, diarrhoea may become 
debilitating and require hospitalisation or prolongation of hospitalisation and is then reported as 
SAE. 
 
-  Occurence of IMP overdose, abuse/misuse, or drug dependency, whether or not clinical signs 
or symptoms are present, should be reported as an “AE” to the sponsor but immediately and no 
later than 24 hours. 
If IMP overdose, abuse/misuse, or drug dependency is associated with a SAE, it should be reported 
in a SAE Form. 
 
9.5.3. Definition of Specific Events in the Study 
All PPH including their time course and progression will be appropriately documented on the case 
report form as part of the efficacy parameters as well as all transfused units and/or procedures 
required to manage and treat them. They will not be reported as AEs/SAEs. 
Patients who suffered from PPH may develop signs and symptoms related directly to that bleeding 
such as anaemia, thrombocytopenia, hypofibrinogenemia, worsening of haemorrhage. PPH may also 
lead to occurrence of morbidity (corresponding to any haemostatic intervention: uterine ligation, 
embolization, intrauterine balloon, vascular ligation, hysterectomy) being considered as disease-


 
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related. All these signs, symptoms and procedures will not be reported as adverse events or as 
serious adverse events. 
Although they may be emergent when treated with IMP, the investigator has to describe them as part 
of the bleeding (efficacy parameters) and not as AEs/SAEs if they are directly and unequivocally 
related to the bleeding. 
 
In this trial, the following adverse events should always be considered and reported as serious 
adverse events: 
 
- 
Any deep venous or arterial thromboembolic event, whatever the causality assessment. 
 -  Any suspicion of infectious agents transmission by the IMP. 
9.5.4. Period of (Serious) Adverse Event Data Collection 
In order to ensure complete safety data collection, recording and reporting, all (S)AEs occurring 
during the study, i.e. after signature of the Informed Consent, including any pre- and post-treatment 
periods required by the protocol, must be recorded, even if no IMP was taken. These include all AEs 
occurring, recurring, or worsening after the signature of the Informed Consent. 
The period of observation for this study is from Visit 1 (signature of the Informed Consent) to the 
end of study visit (6 ± 2 weeks after delivery) (see Section 8.2.7). 
If the investigator becomes aware, after that period, of any unusual safety information or any safety 
information that appears to be IMP-related involving a patient who had participated in the study, 
even after the patient has completed the study, he should contact the sponsor to determine how it 
should be documented and reported. 
9.5.5. Recording and Description of (Serious) Adverse Event 
Apart from adverse events clinically observed by the Investigator, the patient will be given the 
opportunity to report adverse events spontaneously. A general prompt will also be given to detect 
adverse events, e.g. “Did you notice anything unusual about your health since your last visit ?” 
It is the responsibility of the Investigator to record all relevant information regarding the event. 
Each individual AE is to be listed as a separate entry on the AE CRF page. The investigator will 
provide information on dates of onset and resolution, seriousness, severity, frequency, action(s) 
taken with regard to corrective therapy or to the IMP and outcome. 
The Investigator is also requested to assess the relationship between the investigational product and 
the occurrence of each (S)AE. Alternative causes, such as the underlying diseases, concomitant 
therapy or the temporal relationship of the event to the investigational product will be considered. 
The investigator must report to the Sponsor or its designee all AEs that occur during the study from 
the time the written informed consent has been  given until the final study visit or early termination, 
regardless of their relationship to the IMP. 




 
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In rare circumstances, when fax or e-mail transmission is not possible, reporting by telephone is 
acceptable. However, this should be followed with a completed “SERIOUS ADVERSE EVENT 
FORM” signed and faxed by the investigator as soon as possible.  
9.5.7. LFB MEDICAL contact 
For urgent medical matters or questions, the investigator may contact: 
• 
 (Medical Head of Intensive Care Unit – LFB BIOMEDICAMENTS) 
 
           
 
9.5.8. Follow-up of Adverse Events 
During the study: 
All AEs and SAEs must be followed-up during the study period until resolution or stabilisation. 
After the end of the study, or at patient's premature discontinuation: 
Only AEs or SAEs related to the study IMP that occurred during the study and: 
- That are still recorded as “recovering”, “not recovered” or “worsening” at the end of the study, 
must be continuously followed-up as part of the study data, as long as necessary to adequately 
evaluate the patient’s safety, or until they are considered as “resolved”, or until the condition is 
stabilised, or until the Investigator no longer estimates that they are clinically significant. If 
resolved, a resolution date must be provided. 
If a patient is withdrawn from the study due to safety reasons, she should be followed until the event 
disappears, is otherwise explained or the patient’s condition has stabilised. 
Any patient who voluntarily withdraws from the study should be carefully questioned for the 
possible occurrence of an adverse event. 
If no follow-up information can be provided, the Investigator must: 
- Provide a written justification and 
- Document the outcome as “unknown” (except for cases where the outcome is known, such as 
death for instance) 
(Reminder: if the Investigator detects a new (S)AE after the end of the study and considers the event 
as possibly related to the IMP, he/she has to contact the Sponsor to determine how it should be 
documented and reported.) 
Follow-up documentation 
• In case of follow-up of an AE that worsened in nature or in severity, the follow-up will be 
documented on a new AE column in the CRF, with the box "follow-up" being ticked  


 
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• In case of follow-up of an SAE for which additional information/modification is provided, 
the follow-up will be reported on a new “SERIOUS ADVERSE EVENT FORM", with the 
box "follow-up" being ticked  
9.6. Regulatory Safety Requirements 
The decision to notify SAEs to competent Authorities/Ethics Committee is under the responsibility 
of the Sponsor. 
The Sponsor will ensure that the Investigators, and all other appropriate persons, are informed in a 
timely manner of findings that could adversely affect the safety of patients. 
The Sponsor will communicate additional safety information, when available, to the appropriate 
Health Authorities/Ethics Committee and all Investigators. 
10. 
PARAMETERS AND ASSESSMENT CRITERIA 
10.1. 
Assessment of Efficacy 
10.1.1. Primary Variable 
The primary efficacy variable is a binary composite endpoint (failure versus success). Failure is 
defined when a patient loses at least 4 g/dL of Hb, and/or requires the transfusion of at least 2 units 
of RBCs within 48 hours following the administration of IMP. 
The reference Hb level is the most recent Hb value recorded during the third trimester of pregnancy. 
10.1.2. Secondary variables 
The following efficacy criteria will be assessed by the investigators: 
 Evolution of haemorrhage 
o Percentage of patients losing at least 4 g/dL of Hb, 48 hours following IMP 
administration with regards to the Hb reference level. 
o Percentage of patients losing at least 3 g/dL of Hb, 48 hours following the IMP 
administration with regards to the Hb reference level. 
o Percentage of patients requiring the transfusion of at least 2 units of packed RBCs, 48 
hours following the IMP administration. 
o Percentage of patients losing at least 4 g/dL of Hb, 48 hours following the IMP 
administration with regards to the Hb level measured at inclusion. 
o Percentage of patients with an occurrence of Hb level < 9 g/dL within the 48 hours 
period following inclusion. 
o Number of units of transfused blood products within the 48 hours period following 
the IMP administration. 
o Calculated volume of total blood loss, 48 hours following the IMP administration. 


 
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The calculation and adjustment of total blood loss with regards to transfusional needs will be 
calculated at time of statistical analysis as follows: 
o Total blood loss (mL) = blood loss calculated + blood loss compensated by 
transfusion  
o Calculated blood loss: Pregnancy total blood volume x (Ht0 – Htf) x (100/35) 
 Pregnancy total blood volume = (Maternal weight measured before pregnancy 
x 65 mL/kg) x 1.4 (40,41) 
 Ht0: last available value of haematocrit before delivery 
 Htf: value of haematocrit in the morning of D2  
o Blood loss compensated by transfusion (mL): n RBC x 500mL (with n corresponding 
to the number of transfused units and 500mL = total transfusated blood volume of 
300 mL RBC with Ht of 60%) (36) 
 Need for haemostatic intervention 
o Percentage of patients requiring at least one of the following interventions within 48 
hours following the administration of IMP: uterine ligation (B Lynch or other 
techniques), pelvic arteries embolization, surgical vascular ligation, administration of 
recombinant activated Factor VII (rFVIIa) and hysterectomy. 
 Need for intrauterine balloon 
o Percentage of patients requiring the use of intrauterine balloon within 48 hours following 
the administration of IMP. 
o Time of intrauterine balloon placement. 
 Maternal morbi-mortality 
o Length of stay in resuscitation and/or intensive care and/or PICU and/or continuous 
care 
o Length of stay in obstetrics units 
o Single or multi-organ failure (SOFA) score in women transferred to resuscitation 
and/or intensive care and/or PICU and/or continuous care units 
o Death during the study 
 Evolution of blood fibrinogen level after early administration 
o Change in plasma fibrinogen level between H0 (start of IMP infusion) and D2. 
 Evolution of hemoconcentration 
o Change in Hb level between each determination and H0 
o Change in Ht level between each determination and H0 
o Change in RBCs count between each determination and H0 


 
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10.2. 
Assessment of Safety 
AEs and SAEs from all patients followed throughout the study will be recorded and reported, as 
described inSection 9.5, whether or not the AE was determined to be related to the administration of 
IMP. 
Safety evaluation will include the monitoring of the following items: 
 Physical examination performed at inclusion and hospital discharge; 
 Vital signs (blood pressure and heart rate) will be monitored at inclusion visit, 
randomisation, H2, H6, discharge from the obstetrics room, morning of D2, intensive care 
unit discharge (if applicable) and hospital discharge. 
 Tolerance of fibrinogen concentrate administration 
o Serious and non-serious adverse events (AE) 
o Symptomatic thromboembolic events within the 6 weeks following the administration 
of IMP. 
In this study, all events related to PPH (anaemia, progressing or worsening of haemorrhage) will not 
be reported as AEs as they are already reported as efficacy criteria. 
 Laboratory parameters:  
o Change in creatinine and urea between inclusion and D2 
o Change in TP, aPTT, D-dimers, platelets between inclusion and each determination 
times. 
11. 
DATA MANAGEMENT 
11.1. 
CRF completion guidelines 
11.1.1. Introduction 
All of the information required to be reported to the Sponsor as per protocol will be entered in the 
printed Case Report Forms (CRFs) for each study patient. The CRFs must be completed by the 
Investigator or any study centre staff designated by the Investigator. 
The Investigator is responsible for ensuring that data recorded in the CRFs are complete, accurate 
and legible. The CRFs should be completed as soon as possible after the patient’s visit and before 
review by the Monitor at the latest. 
11.1.2. General instructions 
11.1.2. 1. Overview 
The CRFs are printed on NCR paper (triplicate). CRFs should be completed in English with a black 
ballpoint pen. 


 
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All data in the CRFs must come from and be consistent with the source documents, i.e. patient’s file 
or medical records. 
Any discrepancy between the data in the CRF and those in the source documents should be 
documented by the Investigator. 
No data field will be left blank. 
Abbreviations will be avoided since they are often ambiguous. 
No data should be written in the margins. 
11.1.2. 2. Header information 
Header information should include at least: 
• The protocol number, 
• The name of the visit, 
• Patient’s identification: 
a) Initials by default: the first letter of the last name (surname) and the first letter of the first 
name (name) are recorded. Example: Robert Smith: | S |-| R 
b) Patient identification number according to local requirements: patient number is recorded 
with the centre number provided by the Monitor at the set-up visit. The patient number is a 
sequential number incremented with each patient included in the order of signature of 
informed consent. Example: 3rd patient included in the centre number 10 : | 1 | 0 |-| 0 | 3 | 
11.1.2. 3. Recording dates and time 
Dates will be recorded in the CRF using two digits for the day and the month and four digits for the 
year. 
• Example: February 28, 2005 must be entered as 28/02/2005. 
Time will be recorded using four digits according to the 24-hour clock. 
• Example: 3:25 pm must be entered as 15:25. 
11.1.2. 4. Recording of missing data 
Before the Monitor reviews the data during the monitoring visits, the Investigator should make 
every effort to provide the information required. Use of the following codes should be kept to a 
minimum. 
The Investigator should enter in the CRF: 
• If the requested item is unknown or not available: UNK. 
• If the requested item is not applicable: NA 
• If the requested item was not done: ND 


 
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11.1.2. 5. CRF corrections 
If the Investigator makes an error, he/she should cross out the data item, clearly enter the new data 
item and initial and date the correction. The use of opaque white correction fluid is prohibited. The 
corrections should be made while the NCR copies are still together on site. 
11.1.2. 6. Confidentiality 
Patient names must be kept confidential and should not appear on any CRF page or study-specific 
documents. 
11.1.2. 7. CRF Completion in case of screening failure or premature withdrawal 
A CRF must be completed for all patients with a signed informed consent up. Screening failure and 
premature withdrawal must be documented on the end of study form of the CRF with the cause that 
has led to screening failure/premature withdrawal. 
11.1.3. Collection of CRF 
The CRF will be checked by the Monitor during monitoring visits. 
After the required corrections have been done by the investigator, the Monitor will collect two 
copies of each page of the CRF (the original which will be sent to the data manager and one copy 
which will be kept by the Monitor). The third copy will be archived by the Investigator. 
The frequency of monitoring visits will depend on the recruitment rate of each centre. 
11.1.4. Specific Case Report Form instructions 
Specific instructions for completing the case report form will be detailed in a specific document 
“CRF completion guidelines”. 
11.2. 
CRF and Data Handling 
Data processing, from data collection to database lock, will be carried out in accordance with GCP 
(see ICH-E6, Section 5). 
The data handling documents, e.g. annotated CRF, database structure, data entry manual, coding 
rules and computerised validation, are defined in a Data Management Plan. 
The database and data entry screens will be created in a software specifically designed for clinical 
data management, in compliance with ICH-E6 requirements. 
All CRFs received in the Data Management Unit will be tracked and reviewed by the Data Manager 
before double data entry. The consistency of data will be checked by computerised programs and 
related queries will be generated for resolution by the Investigator. The database will then be 
updated accordingly. 


 
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Medical terms and drug names will be coded. Quality controls will be made to ensure the overall 
quality and consistency of the database. Reconciliation of SAE reports with the pharmacovigilance 
database will also be carried out. 
At the end of the data handling process, a data review meeting will be held in order to prepare the 
database lock. After database lock, data will be transferred into SAS and STDM CDISC file formats 
for performing statistical analyses. 
12. 
STATISTICS 
12.1. 
Trial Objectives and Design 
The main objective of this study is to assess the superiority of the early administration of IMP versus 
placebo in patients suffering from PPH and treated with intravenous infusion of prostaglandin. 
The present study is a phase IV, multicentre, randomised, double-blind and placebo-controlled, 
comparing 2 parallel groups. 
12.2. 
Statistical Analysis Plan 
The material of this section is the basis for the Statistical Analysis Plan (SAP) of the study. 
The detailed technical aspects of the statistical analyses will be provided in the SAP. The SAP will 
possibly take protocol amendments into account and adapt to unexpected issues raised by the trial 
running and/or data that affect planned analyses in the protocol. 
Any deviation from the protocol regarding the description of statistical analysis in the SAP will be 
discussed in the study report. 
Prior to locking the database and unblinding the randomisation code, a data review meeting will be 
planned in order to review individual data and validate the SAP. 
The distribution of parameters will be summarised using descriptive statistics according to the study 
variable: 
• Categorical variables (binary, nominal and ordinal) will be presented by contingency tables 
(frequencies and percents). Number and percentages of missing data will also be mentioned. 
• Quantitative variables will be presented by their mean, standard deviation, standard error, 
median, quartiles and range, minimum and maximum values. The number of documented values 
will also be mentioned. 
Efficacy data will be presented by randomisation group. Safety data will be presented by treated 
group (IMP that was effectively administered). 
Unless otherwise specified, the following statistical tests will be used: 


 
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• 
Categorical data will be compared using chi-square test or Fisher exact test if a theoretical 
number of one category or more is below 5. 
• 
Continuous quantitative data will be compared by t test or, if normality of distribution is 
rejected, by Wilcoxon non parametric test. 
Thereafter only parametric tests are mentioned. 
No subgroup analysis is planned. 
All statistical tests will be two-sided with a threshold of statistical significance of 0.05. 
12.3. 
Sample Size Determination 
It is estimated that, in the control group, 42% of patients will fulfil the primary endpoint 
(unpublished data from the Pithagore cohort). With an expected percentage of patients in the 
Clottafact® treated group of 27%, the difference between the two groups will be of 15%. With a 
power (1-ß) of 90%, a type I error (α) of 5% and a two-sided test (Z test, unpooled variance), a 
sample size of 206 patients per treatment group is needed. 
The rate of drop-out is assumed to be approximately 5%. Therefore, 434 patients will be included in 
the study. 
 
As there is some uncertainty about the test Z variance depending itself on the expected rates, the 
variance will be re-estimated in a blind way at 80% of the initially planned sample size (i.e. 80% of 
412=326 evaluable patients or 348 patients with adjustment for a 5% dropout rate) and the sample 
size will be increased according to the new estimated variance so as to maintain the power to 90% 
while still considering the same originally planned difference in failure rates, i.e. 15%.    
 
It can be shown that the possible increase in sample size with adjustment for a 5% dropout rate 
cannot exceed 50 additionnal patients. Therefore, the new sample size will not exceed 484 patients.“ 
 
Of note, as the sample size reassessment is performed in a blind way, i.e. based on an overall 
estimate of the overall failure rate, it is known to not inflate the type I error of the primary analysis.  
An additional rule for the reassessment of the sample size is as follows:   only an increase (i.e. no 
decrease) in the sample size will be allowed at the blind interim analysis. 
12.4. 
Randomisation 
Treatment units will be pre-numbered and allocated by the Investigator sequentially, in ascending 
number, and in chronological order of inclusion. 
Randomisation will be stratified on the centre using fixed block size and a ratio active 
treatment/placebo of 1:1. 


 
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The randomisation list will be generated with validated SAS program by a subcontractor (not 
involved in the statistical analysis). LFB BIOMEDICAMENTS keeps a paper copy and an 
electronic format copy together in a confidential place. 
The blindness will be maintained throughout the trial and up to the database lock. 
For DSMB activity purpose (if needed), the randomisation list may be transmitted to an independent 
statistician, external to the sponsor, with high confidentiality. 
For details about how blindness is maintained throughout the study, see Section 3.3. 
12.5. 
Interim analysis  
No interim analysis is planned. 
12.6. 
Protocol Deviations and Analysis Sets 
All deviations from the protocol will be listed and defined as major or minor deviations in the SAP. 
According to the proposed analysis, the definition of analysis sets is recommended as follows: 
- Efficacy sets: 
• 
ITT set: all randomised patients  
• 
Per Protocol set: all ITT patients receiving at least one dose of IMP and without any major 
deviations. These major deviations will be defined in the SAP prior to unblinding. 
- Safety set: 
• 
All patients who received at least one dose of IMP. 
12.7. 
General Rules for Handling of Missing or Inconsistent Data 
Every effort should be made to collect the complete CRF and minimise the amount of missing data. 
As a general rule, missing data will not be replaced. 
However, concerning the primary efficacy endpoint, missing data (including incomplete dates) will 
be estimated as failures. 
When needed to be able to calculate durations, incomplete dates will be estimated according rules 
specified in the SAP. 
All estimated or replaced data will be edited along with a flag in the statistical appendices. 


 
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12.8. 
Demographic and Baseline Characteristics 
Demographic and baseline characteristics of patients will be analysed on the ITT set. Data will be 
presented per randomisation group. 
Statistical tests will not be performed to compare randomisation groups at baseline. Possible 
differences between groups at baseline will be judged from a clinical viewpoint only. If the PP set 
represents less than 80% of the ITT set, demographic and baseline characteristics will also be 
presented on the PP set. 
12.8.1. Demographic Characteristics, Medicinal History, Diagnoses 
All demographic characteristics and all medical history data will be presented per randomisation 
group. Pregnancy and data related to the delivery up to randomisation will also be presented in this 
section. 
12.8.2. Previous Treatments 
All previous treatments will be listed by patient with the associated ATC codes for the WHO drug 
dictionary. 
Descriptive statistics will be produced to analyse the previous treatments by therapeutic class as 
defined in Section 7.1. 
12.8.3. Baseline Efficacy Variables 
All efficacy variables will be presented by randomisation group. Baseline data are defined as the last 
available data before the start of IMP infusion. 
Date and time of the last available Hb (g/dL) determination will be presented. The month of last 
recorded Hb value during pregnancy will be mentioned. 
Fibrinogen, Hb, Ht and RBCs count will be displayed in the efficacy analysis section in order to 
display baseline and follow-up results in the same tables. 
Exploratory variables are efficacy laboratory data and will be displayed in the efficacy analysis 
section. 
12.8.4. Baseline Safety Variables 
All safety variables will be presented by randomisation group. Baseline data are defined as the last 
available data before the start of IMP infusion. 
All laboratory data except those defined as efficacy variables (in the above section) or as exploratory 
variables will be defined as safety criteria. All laboratory data will not be displayed in the baseline 
section but in the analysis of safety in order to display in the same table the baseline and other data. 


 
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12.9. 
Investigational Product (IMP) and Concomitant Treatments 
12.9.1. Extent of Exposure 
Summary tables will display the number of patients exposed, duration of exposure (in minutes, 
automatically derived from the start and end times of IMP infusion), in each randomisation group 
and, if applicable (any error in allocation treatment), in each treatment group. 
12.9.2. Treatment Compliance 
The delay between the start of prostaglandin infusion and the start of IMP infusion (in minutes), will 
be presented as a continuous variable. 
The same variables will be estimated and presented on the total treated set in each treatment group. 
12.9.3. Concomitant Treatment 
All concomitant treatments will be listed by patient with their ATC codes. 
Descriptive statistics will be produced to analyse the concomitant treatments by therapeutic class as 
defined in Section 7.2. 
12.10. 
Efficacy Analysis 
12.10.1. 
Primary Efficacy Variable(s) 
12.10.1. 1. 
Description of the primary efficacy variable(s) 
The primary efficacy variable is a binary composite endpoint (failure versus success). Failure is 
defined when a patient loses at least 4 g/dL of Hb, and/or requires the transfusion of at least 2 units 
of packed RBCs within 48 hours following the administration of IMP. 
The reference of Hb level is the most recent Hb value recorded during the third trimester of 
pregnancy. 
Raw percentages of failures will be estimated within each treatment group (placebo or Clottafact®). 
Raw percentages of failures will also be provided by centre, by tranexamic acid intake (yes versus 
no) and by baseline fibrinogen (categorized into three classes ≤ 2 g L-1 ,    ] 2 g L-1 4 - g L -1  ] , > 4 g 
L -1   , 19). 
12.10.1. 2. 
Primary analysis 
12.10.1. 2.1. Handling of dropouts and missing data 
See Section 12.7. 


 
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12.10.1. 2.2. Prognostic factors and covariates 
Stratified centre and baseline fibrinogen are considered as major prognostic factors for the primary 
outcome. They will be adjusted in the primary model. As the relationship between baseline 
fibrinogen and the primary binary outcome (on the logit scale) is unknown, baseline fibrinogen will 
be categorized into three classes (≤ 2 g L-1 ,    ] 2 g L-1 4 - g L -1  ] , > 4 g L -1 ) as suggested by 
Charbit and al (2007). 
The influence of possible administration of tranexamic acid defined as a binary covariate, (i.e. yes 
versus no) on the primary outcome during the trial will be evaluated in a separate model. 
12.10.1. 2.3. Primary Analysis of the primary endpoint 
The following hypothesis test will be considered: 
• Null hypothesis: 
H0: the true failure rate in the Clottafact® randomised group = the true failure rate in the placebo 
group. 
 
• Alternative hypothesis: 
H1: the true failure rate in the Clottafact® randomised group ≠ the true failure rate in the placebo 
group. 
The nominal two-sided level of significance is set to 5%. 
The primary analysis will be conducted in the ITT set. The primary model of analysis will be an 
exact logistic regression adjusting for treatment, centre, and baseline fibrinogen (categorized into 
three classes, ≤ 2 g L-1 ,   ] 2 g L-1 4 - g L-1  ] , > 4 g L-1  ). 
The treatment effect (odds ratio of failure) with its 95% confidence interval will be estimated in this 
model. 
12.10.1. 2.4. Sensitivity Analyses and secondary analyses of the primary endpoint 
The same analysis proposed here above will be performed in the PP set. 
As a sensitivity analysis, missing data will not be estimated as failures and will not be replaced.  
Treatment by centre and treatment by baseline fibrinogen interactions will be investigated in 
secondary logistic regression models. Odds ratios with their 95% CIs will be provided by baseline 
fibrinogen class. 
Influence of tranexamic acid administration and the possible treatment by tranexamic acid 
administration interactions will be assessed in a secondary logistic regression model. Odds ratios 
with their 95% CIs will be provided by tranexamic acid administration class (yes versus no). 


 
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12.10.1. 2.5. Multiple comparisons and interim analyses 
No interim analysis is planned. 
 
12.10.1. 3. 
Secondary efficacy variables 
Analyses of secondary efficacy endpoints will be primarily conducted in the ITT set. Sensitivity 
analyses will be performed in the PP set. Missing data will not be replaced. 
12.10.1. 3.1. Description of secondary efficacy variables 
Secondary efficacy variable are listed in Section 10.1.2. 
The following parameters will also be derived: 
1. Change in plasma fibrinogen level (g/L) between H2 and H0 
2. Change in plasma fibrinogen level (g/L) between H6 and H0 
3. Change in plasma fibrinogen level (g/L) between D2 and H0 
4. The same changes will be calculated for Hb, Ht and RBCs 
5. Duration of haemorrhage (hours): end time of haemorrhage – start time of haemorrhage 
6. Length of stay in the obstetrics room (arrival and discharge hours) 
7. Length of stay in obstetrics units (date of delivery and discharge date) 
8. Number of days in resuscitation and/or intensive care and/or PICU and/or continuous care 
units (admission date and discharge date) 
9. Number of days with assisted ventilation 
12.10.1. 3.2. Analysis of secondary efficacy variables 
Otherwise specified thereafter, all secondary efficacy variables will be compared between the 2 
groups using chi-square for categorical data and using t test for continuous quantitative data or other 
appropriate tests. 
Raw laboratory variables (including baseline data) will be presented by randomisation group at each 
determination (H0, H2, H6 and D2) and shift tables will also be displayed at the same periods.  No 
statistical test will be performed on those data.  Determinations at other sampling times will be listed 
except if other specific times are defined in the SAP.  
Changes in laboratory parameters will be presented by randomization group and t test will be 
performed to test the hypothesis H0: no difference between the 2 randomization groups versus H1: 
any difference between the 2 randomization groups. 


 
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Furthermore, will be compared by t test in the subgroup of patients transferred in resuscitation 
and/or intensive care and/or PICU and/or continuous care units: 
1. Number of days in resuscitation and/or intensive care and/or PICU and/or continuous care 
units, 
2. Number of days with assisted ventilation. 
12.11. 
Safety Analysis 
 
Analyses of safety endpoints will be conducted in the safety set. Missing data will not be replaced. 
With respect to AEs, all AEs occurring during the treatment period will be classified using the 
Lowest Level Term (LLT), Preferred Terms (PT) and System Organ Class (SOC). The duration of 
the AE and the duration between the last dose of IMP and onset of the adverse event will be 
calculated. 
The number of patients with at least one AE will be tabulated by treatment group, SOC, PT and 
LLT. Patients with SAEs, IMP-related AEs and other significant AEs will be tabulated by treatment 
group, SOC, PT and LLT. 
The number of AEs will be tabulated by treatment group, SOC, PT and LLT. 
All SAEs, IMP-related AEs and other significant AEs will be listed by treatment group, SOC, PT 
and LLT. 
The standard dictionary for coding events will be the MedDRA (version 16.0). 
AEs reported before the start of IMP infusion will only be listed with individual patient’s AE data 
collected, if applicable. 
Raw laboratory variables (including baseline data) will be presented by treatment group at each 
determination (H0, H6 and D2) and shift tables will also be displayed at the same periods. 
Determinations at other sampling times will be listed except if other specific times are defined in the 
SAP. 
Arterial and venous thromboembolic events over the study period will be compared between 
treatment groups by chi-square. 
No statistical tests will be performed on other variables except if it is needed to explore any AE with 
possible clinical significance. 
 
13. 
STUDY REPORT 
In accordance with the ICH-E3 guidelines, a clinical final study report will be prepared by the 
Sponsor or subcontractor in collaboration with the coordinating Investigator and, if any, with the 
scientific committee. 


 
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Within 1 year after the end of the study, the Sponsor will provide the Health Authorities with the full 
study report or summary. Only the Sponsor is entitled to make the study report available to the 
Authorities. 
Neither the complete report nor any part of the study report may be used without the approval of the 
Sponsor. 
14. 
CONFIDENTIALITY AND PUBLICATION 
14.1. 
Patient confidentiality 
Patient data will be kept strictly confidential and patient anonymity will be protected by using 
number codes and/or initials. 
The Sponsor or its representative(s) and the Health Authorities have the obligation to respect 
medical secrecy and to refrain from divulging any personal patient information they might 
fortuitously be aware of. 
14.2. 
Use of information 
The Investigator shall not divulge unpublished data or information related to the study provided by 
the Sponsor, including but not limited to the study product characteristics, study protocol, case 
report forms, assay methods and scientific data, to any third party without written approval from the 
Sponsor. 
In addition, any new information that may become available during the course of the study shall be 
considered as confidential and shall not be used for any purpose other than the performance of the 
clinical study. 
The study data are the property of the Sponsor. The Investigator and any of the research staff shall 
obtain written approval from the Sponsor prior to the publication/communication of the results of 
any work carried out during or in relation with the study. 
Publication and/or communication of the results of the clinical study will be of a cooperative nature 
involving authors representing the Sponsor, the Investigators and the scientific committee, if any. 
The Sponsor reserves the right to request modification of the content and/or timing of any 
publication or presentation if a patent application, an existing patent or other proprietary rights may 
be jeopardized. 
Authorship of any publication related to the study and the order of presentation of the author’s 
names shall be approved by the Sponsor. The Sponsor shall not use an Investigator’s name in any 
publication without his/her written permission and vice versa. 


 
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15. 
ARCHIVING 
The Investigators should retain all essential study-related documents, i.e. documents which permit 
evaluation of the conduct of the study and the quality of the data produced, in accordance with the 
applicable regulatory requirements of his/her country. These essential documents include but are not 
limited to signed protocol, CRFs, medical records, laboratory reports, informed consent forms, drug 
disposition records, safety reports, information regarding participants who discontinued, and other 
relevant documents and data. 
The study-related documents should be kept together in the Investigator Site File provided to the 
Investigator by the Sponsor. 
Sufficient information about the identity of all study patients, e.g. name, medical records number, 
patient number and study number, should be retained by the Investigator so that any Sponsor 
representatives, auditors or inspectors may have access to this information if required. 
The Investigator must retain all records for 40 years. 
The Investigator will contact the Sponsor for authorization prior to the destruction of any study 
records or in case of accidental loss or destruction of any of them. 
The Investigator will also notify the Sponsor should he/she relocate or move the study-related files 
to a location other than that specified in the Sponsor’s Study Master File. 
All records should be kept in a secured area. However, in case of audit or inspection, they should be 
rapidly made available. 
16. 
RESPONSIBILITIES OF PARTICIPANTS 
Upon a request for proposal issued by LFB (from October 2012 to January 2013), a Contract 
Research Organisation (CRO) has been selected in order to assume competences delegation under 
an outsourcing contract that will ensure the performance of the following tasks: 
 Preparation of study files and all trial documents (TMF, SMF, ...) 
 Monitoring 
 Data Management and Biometrics 
 Bio-analysis and Statistics 
 Clinical reporting of the study including regulatory documents (Clinical study Report, Data 
listings to be reviewed by DSMB and/or reference centres) 
All activities will be performed by the CRO as a subsidiary, under GCP Management structure, plan 
and procedures under the governance of the Sponsor. 


 
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16.1. 
Responsibilities of the Investigator(s) 
The Investigators will conduct the study in accordance with ICH-E6, all applicable laws in the 
country where the study is conducted and in accordance with this study protocol. 
The Investigator’s responsibilities, summarised below, include but are not limited to: 
16.1.1. Patient information and consent 
Prior to undertaking any study-related procedure, it is the Investigator’s responsibility, or that of a 
formal designee, to provide each patient and/or a member of her family or the reliable person (see 
Section 8.1.1), with relevant, comprehensive, verbal and written information, including the written 
information which received approval or a favourable opinion from the IEC/IRB and the Health 
Authorities. 
Signed informed consent must be obtained prior to undertaking any study-related procedure. 
All data concerning the obtainment of consent must be described and documented in the patient’s 
file. 
16.1.2. Information on the overall results of the study 
Pursuant to the French law of “Patient’s rights” that was adopted on the 9th of August 2004, the 
Investigator must provide any patient who so requests it with the overall results of the study. The 
Sponsor will provide the Investigator with the overall results beforehand. 
The Investigator should document in the patient’s file the fact that the information has been 
provided. 
16.1.3. Information to other practitioners (if relevant) 
In agreement with the patient, the Investigator will formally inform other practitioners of the 
patient’s participation in the study, to avoid any interference or bias in the conduct of the study. 
16.1.4. Adverse events 
The investigator is responsible for ensuring an adequate safety monitoring and follow-up of the 
study patients. 
The Investigator must report and handle any serious adverse event immediately and no later than 24 
hours, and non-serious adverse event, whether clinically observed or spontaneously reported by the 
patient, using concise medical terminology in accordance with Section 9 of the protocol. 
16.1.5. Data recording 
It is the Investigator’s responsibility to ensure, on an on-going basis, the completion and validation 
of all case report forms as well as the study-related supportive data.  


 
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The Investigator can delegate completion of the CRFs to qualified and trained staff, but the signature 
of CRFs can only be delegated to physicians or midwives, who are also authorized to include and 
treat patients as mentioned in section 3.4 of this protocol. The aim of CRFs signature is to certify the 
accuracy and reliability of the data recorded therein. 
16.1.6. Record retention 
To enable inspections and audits from Health Authorities or the Sponsor, the Investigator has to 
agree to keep records, including the identity of all participating patients, i.e. sufficient information to 
link records, all original signed informed consent forms, copies of all CRFs and detailed records of 
treatment disposition. The Investigator should maintain a site file with all essential documents (for 
Archiving, also refer to Section 15). 
16.1.7. Use of study-related information 
The Investigator has the obligation to provide the Sponsor with complete test results and all data 
derived from the study. 
Only the Sponsor may make information available to physicians, Health Authorities and/or patients 
enrolled in the study, except as required by local regulations. 
16.1.8. IMP 
The Investigator is responsible for IMP accountability at the study centre. 
16.1.9. Quality control 
The Investigator and the relevant staff members should be available during monitoring visits and 
possible audits or inspections and must ensure that sufficient time is devoted to the process. 
The Investigator guarantees the Sponsor or its representative and appropriate Health Authorities the 
direct access to source documents. 
16.1.10. Study discontinuation 
Should the Health Authorities or the Sponsor decide to discontinue the study prematurely for any 
reason, the Investigator must promptly, i.e. within 5 days, contact all participating patients so that 
they can be appropriately followed-up. 
All study supplies must be collected and all case report forms must be completed as fully as 
possible. 
16.1.11. Liability and insurance 
Liability and insurance provisions for this study are set out in separate agreements. 


 
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16.1.12. Delegation of Investigator duties 
The Investigator can delegate certain tasks to the research team but he/she remains responsible for 
coordinating and informing his/her staff about the protocol and the possible amendments made to it. 
The Investigator should ensure that all persons assisting with the study are adequately qualified, and 
are informed about the study protocol, any amendments to the protocol, the study treatments, and 
their study-related duties and functions. 
The Investigator should maintain a list of appropriately qualified persons to whom significant study-
related duties will be delegated. The list is to be kept up-to-date. 
The Investigator should supply an up-to-date curriculum vitae (CV) in English, dated and signed, 
together with a list of his/her collaborators responsible for the practical conduct of the study. These 
collaborators should also provide a recent English version of their CVs, dated and signed. 
16.1.13. Study agreement discontinuation 
During the study, if events such as retirement, promotion or relocation prevent the Investigator from 
conducting the study as agreed, the Investigator should appropriately transfer his/her 
responsibilities, knowledge and documents to another willing individual, with the agreement of the 
Sponsor. Study specific contracts must be signed between the Sponsor and the newly assigned 
Investigator. 
16.2. 
Responsibilities of the Monitor 
The responsibilities of the study Monitor are defined in ICH-E6, Chapter 5. The Monitor, who is 
mandated by the Sponsor, must ensure that the study is conducted in accordance with GCP 
guidelines and all applicable local laws, and that the rights, the security and the well-being of the 
patients are respected. 
During the conduct of the study, the Monitor reports any deviation or persistent poor compliance 
with the study requirements. In such case, the Sponsor should make decisions about appropriate 
corrective actions. 
16.2.1. Communication 
The Monitor is the main line of communication between the Investigator and the Sponsor. 
16.2.2. Training 
The Monitor must present the protocol and all procedures related to the study during the study set-up 
visit and provide the Investigator with case report form completion guidelines. 
16.2.3. Compliance 
During periodic monitoring visits at mutually convenient times, the Monitor is responsible for 
assessing the progress of the study, checking that the informed consent forms have been signed, 
ensuring adhesion to and compliance with the study protocol and other study-related documents, and 


 
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ensuring the accuracy and completeness of the CRFs. Inconsistencies in the study records are to be 
resolved. 
16.2.4. Source data verification 
The Monitor will examine source documents, validate and request clarifications to ensure the 
accuracy, completeness and reliability of data. 
16.2.5. IMP 
The Monitor must ensure that IMP handling is properly carried out and documented. 
He/she must ensure that the investigator file is up-to-date with regard to essential documents. 
16.3. 
Responsibilities of the Data Manager 
The Data Manager is responsible for the management of clinical data from data entry to database 
lock. 
17. 
ETHICS AND REGULATORY CONSIDERATIONS 
The current study is to be conducted in accordance with globally accepted standards of Good 
Clinical Practice (ICH-E6), European Directive 2001/20/EC, and the revised version of the 
Declaration of Helsinki set out in the European Directive, as well as with applicable local 
requirements. 
In France, this study will be conducted in accordance with the ‘Code de la Santé Publique’ (CSP). 
The protocol will be submitted to the Health Authorities and a properly constituted Ethics 
Committee (EC) for formal approval of the study conduct in accordance with local regulations. 
The study may not begin until the protocol has received written approval from the Health 
Authorities and Ethics Committee (EC) in accordance with local requirements. 
During the study, the Sponsor should promptly notify the Investigators, Health Authorities and EC 
of any relevant information that could influence the safety of patients and could have an impact on 
the conduct of the study. 
Personal Data Protection Committee 
For biomedical research in France: the Sponsor attests his conformity regarding the Personal Data 
Protection French requirements ("Méthodologie de Réference MR001" dated the 5th of January 
2006). 
Insurance 


 
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The Sponsor will contract civil liability insurance to provide patients with compensation for any 
injury, including the consequences of administration of the investigational medicinal product and of 
the study procedures. 
The insurance company is HDI-GERLING. 
N° of insurance: 01010260-14023 
In case of injury or disability resulting from participation in the study, the patient is requested to 
promptly inform the Investigator responsible for the study. 
Indemnity 
Participation in this study will not entail any financial compensation to the patient. 
 
Changes to the protocol 
The Sponsor will not assume any responsibility or liability resulting from the implementation of 
unapproved deviations or changes. 
The only condition in which an amendment may be initiated prior to approval by the Health 
Authorities is when the change is necessary to eliminate apparent immediate hazards to the patients. 
In such case, the Investigator must notify the Sponsor, and if applicable the Ethics Committee, in 
writing within 5 working days after implementation. 
18. 
AUDIT AND INSPECTION 
An audit/inspection may be carried out by qualified Sponsor staff, subcontracted auditors or 
representatives of national or foreign Health Authorities. This procedure aims to ensure that the 
study is conducted as per protocol and in accordance with regulatory requirements, and to ensure the 
validity of the data. 
Participation in this study implies the acceptance to cooperate in any potential audit/inspection. 
The audit/inspection may consist of an inspection of the premises and equipment together with 
verification of the study documents and data. 
The investigational team must be available for inspection or audit. 
When the Sponsor or the Investigator is informed that an inspection is to be performed, the other 
party must be informed immediately. 
Audits/inspection may take place after the end of the study. 
 
 


 
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19. 
REFERENCE 
                                                 
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Paidas MJ, Hossain N, Shamsi TS et al. Hemostasis and Thrombosis in Obstetrics & 
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2  
WHO (2009) WHO guidelines for the management of postpartum haemorrhage and retained 
placenta. 
Available 
from: 
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3  
Jansen AJG, van Rhene DJ, Steegers EAP, Duvekot JJ. Postpartum Hemorrhage and 
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4  
Mercier FJ, Roger-Christoph S. Hémorragie du post-partum. Congrès national d’anesthésie 
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5  
Mercier FJ, Van de Velde M. Major obstetric hemorrhage. Anesthesiol Clin. 2008;26:53-66. 
6  
Wise A, Clark V. Strategies to manage major obstetric haemorrhage. Curr Opin Anaesthesiol 
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7  
Bonnar J. Massive obstetric haemorrhage. Baillieres Best Pract Res Clin Obstet Gynaecol 
2000;14:1-18. 
8  
WHO (2005) World Health Report 2005: Chap 4—make every mother and child count. 
Available from: http://www.who.int/whr/2005/chap4-en.pdf on November 2nd, 2012. 
9  
Waterstone M, Bewley S, Wolfe C. Incidence and predictors of severe obstetric morbidity: 
case­control study. BMJ 2001;322:1089–94 
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Affairs, U.N.D.o.E.a.S (2010). The millennium development goals report 2010. 
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11  
Carroli G, Cuesta C, Abalos E et al. Epidemiology of postpartum haemorrhage: a systematic 
review. Best Pract Res Clin Obstet Gynaecol 2008;22:999-1012. 
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Mousa HA, Alfirevic Z: Treatment for primary postpartum haemorrhage. Cochrane D 
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HAS. Recommandations pour la pratique clinique - Hémorragies du post-partum immédiat. 
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Lalonde A, Daviss BA, Acosta A et al. Postpartum hemorrhage today: ICM/FIGO initiative 
2004-2006. Int.J.Gynecol.Obstet. 2006;94:243-53. 
15  
Bell SF, Rayment R, Collins PW, Collis RE. The use of fibrinogen concentrate to correct 
hypofibrinogenaemia rapidly during obstetric haemorrhage. Int J Obstet Anesth. 
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MH, Huissoud C. Association between fibrinogen level and severity of postpartum 
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Hui C, Lili M, Libin C, Rui Z, Fang G, Ling G, Jianping Z. Changes in coagulation and 
hemodynamics during pregnancy: a prospective longitudinal study of 58 cases. Arch 
Gynecol Obstet. 2012;285:1231-6 


 
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18  
Fenger-Eriksen C, Lindberg-Larsen M, Christensen AQ et al. Fibrinogen concentrate 
substitution therapy in patients with massive haemorrhage and low plasma fibrinogen 
concentrations. Br J Anaesth 2008;101:769-73. 
19  
Charbit B, Mandelbrot L, Samain E et al. PPH Study Group: The decrease of fibrinogen is an 
early predictor of the severity of postpartum hemorrhage. J Thromb Haemost 2007, 5:266-
73. 
20  
Annecke T, Geisenberger T, Kûrzl R, Penning R, Heindl B. Algorithm-based coagulation 
management of catastrophic amniotic fluid embolism. Blood Coagul Fibrinolysis 
2010;21:95–100. 
21  
Glover NJ, Collis RE, Collins P. Fibrinogen concentrate use during major obstetric 
haemorrhage. Anaesthesia. 2010;65:1229-30. 
22  
Spahn DR, Bouillon B, Cerny V, Coats TJ, Duranteau J, Management of bleeding and 
coagulopathy following major trauma: an updated European guideline. Crit Care. 
2013;17:R76 
23  
Ickx BE. Fluid and blood transfusion management in obstetrics. Eur J Anaesthesiol 
2010;27:1031-5 
24  
Sawamura A, Hayakawa M, Gando S, Kubota N, Sugano M, Wada T, Katabami K. 
Disseminated intravascular coagulation with a fibrinolytic phenotype at an early phase of 
trauma predicts mortality. Thromb Res. 2009;124:608-13. 
25  
Négrier C, Rothschild C,Goudemand J et al. Pharmacokinetics and pharmacodynamics of a 
new highly secured fibrinogen concentrate. J Thromb Haemost.2008;6:1494-9. 
26  
Clottafact® : Résumé des caractéristiques du produit. Available at http://agence-
prd.ansm.sante.fr/php/ecodex/frames.php?specid=64421453&typedoc=R&ref=R0188075.ht
m Last access November 5th, 2012.  
27  
CPMP/BWP/269/95 rev. 3. EMEA 2001. 1/31. Note for guidance on plasma-derived 
medicinal. Products. Available at www.ema.europa.eu/pdfs/human/bwp/026995en.pdf  Last 
access June 5th, 2013 
28  
Kelsey MB, Muirhead JMB. Severe postpartum haemorrhage associated with fibrinogen 
deficiency. Lancet 1955;269:705–706. 
29  
Agence nationale de sécurité du medicament et des produits de santé (2012). Transfusion de 
plasma 
thérapeutique 
: 
Produits, 
indications 
(actualisation 
2012). 
http://ansm.sante.fr/var/ansm_site/storage/original/application/0d50cc90b74fa77a16ae653db
8972811.pdf  
30  
Gutierrez MC, Goodnough LT, Druzin M, Butwick AJ.. Postpartum hemorrhage treated with 
a massive transfusion protocol at a tertiary obstetric center: a retrospective study.  Int J 
Obstet Anesth. 2012;21:230-5. 
31  
Pasquier P, Gayat E, Rackelboom T, La Rosa J,et al  An observational study of the fresh 
frozen plasma: red blood cell ratio in postpartum hemorrhage. Anesth Analg. 2013;116:155-
6. 
32  
Ahmed S, Harrity C, Johnson S, Varadkar S et al. The efficacy of fibrinogen concentrate 
compared with cryoprecipitate in major obstetric haemorrhage--an observational study. 
Transfus Med. 2012;22:344-9 
33  
Goffinet F. Hémorragie de la délivrance : prise en charge en France et intérêt des 
prostaglandines. J Gynecol Obstet Biol Reprod 1997;26:26-33. 


 
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34  
Prendiville WJ, Elbourne D, McDonald S. Active versus expectant management in the third 
stage of labour. Cochrane Database of Systematic Reviews, 2000; Issue 2. Art. No.: 
CD000007. 
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Dupont C, Touzet S, Colin C, Deneux-Tharaux C, Rabilloud M, Clement HJ, Lansac J, Colle 
MH, Rudigoz RC; Groupe PITHAGORE 6. Incidence and management of postpartum 
haemorrhage following the dissemination of guidelines in a network of 16 maternity units in 
France.  Int J Obstet Anesth. 2009;18:320-7. 
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Ozier Y, Pessione F, Samain E, Courtois F; French Study Group on Blood Transfusion in 
Liver 
Transplantation. 
Institutional variability in transfusion practice for liver 
transplantation. Anesth Analg. 2003;97:671-9. 
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Goffinet F. [Postpartum haemorrhage: methods used and topics discussed in the CNGOF 
Recommendations for clinical practice (December 2004)]. Gynecol Obstet Fertil. 
2005;33:266-7. 
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Goffinet F, Mercier F, Teyssier V, Pierre F, Dreyfus M, Mignon A, Carbonne B, Lévy G; 
Groupe de Travail des RPC sur l'HPP. [Postpartum haemorrhage: recommendations for 
clinical practice by the CNGOF (December 2004)]. Gynecol Obstet Fertil. 2005;33:268-74. 
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Venous thromboembolism, thrombophilia, antithrombotic therapy, and pregnancy: American 
College of Chest Physicians Evidence-Based Clinical Practice Guidelines (8th Edition).  
Chest. 2008;133(6 Suppl):844S-86S. 
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Stafford I, Dildy GA, Clark SL et al. Visually estimated and calculated blood loss in vaginal 
and cesarean delivery. Am J Obstet Gynecol. 2008;199:519.e1-7. 
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Brecher ME, Monk T, Goodnough LT. A standardized method for calculating blood loss. 
Transfusion.1997;37:1070-4. 
 

SAP_001.pdf: 
 
COVER PAGE 
 
 
TITLE: A randomised, multicentre, double-blind, placebo-controlled study on the efficacy 
and safety of a therapeutic strategy of post-partum haemorrhage comparing early 
administration of human fibrinogen versus placebo in patients treated with intravenous 
prostaglandins following vaginal delivery.  
 
NCT Number: NCT02155725 
 
DOCUMENT: SAP (v 2.0)  
 
 
VERSION & DATE OF DOCUMENT: Version 2.0; December 20, 2018 


LFB BIOMEDICAMENTS 
ZA de Courtaboeuf  
3, avenue des Tropiques 
91940 LES ULIS 
France 
 
 
 
 
 
A randomised, multicentre, double-blind, placebo-controlled study on the efficacy 
and safety of a therapeutic strategy of post-partum haemorrhage comparing early 
administration of human fibrinogen versus placebo in patients treated with 
intravenous prostaglandins following vaginal delivery 
 
 
 
Phase IV study 
 
STATISTICAL ANALYSIS PLAN 
 
 
 
 
 
 
 
 
 
Product:  
Clottafact® 
 
Study No:  
FIDEL (FIbrinogen in DELivery)  
 
 
 
Date:  
December 20th, 2018 
 
Version:  
Final 2.0 
 
 
 
 
 
 
 
 
 
 
 
 
CONFIDENTIAL 
This document and all the information relating to this study are confidential and are 
the property of the sponsor, LFB BIOMEDICAMENTS.






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Table of Contents 
VERSION HISTORY 
2 
LIST OF ABBREVIATIONS 
7 
1. 
INTRODUCTION 
9 
1.1 
Study Objectives 
9 
1.1.1 
Main objective 
9 
1.1.2 
Secondary objectives 
9 
1.2 
Study Design 
9 
1.2.1 
Experimental Design 
9 
1.3 
Flow chart 
9 
1.4 
TREATMENT 
12 
1.5 
ELIGIBILITY CRITERIA 
13 
1.5.1 
Inclusion criteria 
13 
1.5.2 
Non-inclusion criteria 
13 
1.6 
DURATION OF PATIENT PARTICIPATION 
14 
1.7 
NUMBER OF INVESTIGATORS 
14 
1.8 
DISCONTINUATION CRITERIA 
14 
1.9 
LOST TO FOLLOW-UP 
15 
1.10 
EFFICACY AND SAFETY ENDPOINTS 
15 
1.10.1 
Primary endpoint 
15 
1.10.2 
Secondary endpoints 
16 
1.10.2.1 
Evolution of haemorrhage 
16 
1.10.2.2 
Need for haemostatic intervention 
17 
1.10.2.3 
Need for intrauterine balloon 
17 
1.10.2.4 
Maternal morbi-mortality 
17 
1.10.2.5 
Biological effects of fibrinogen concentrate administration 
17 
1.10.2.6 
Tolerance of fibrinogen concentrate administration 
17 
1.11 
SAMPLE SIZE CALCULATION 
17 
2. 
CHANGES IN THE CONDUCT OF THE STUDY OR PLANNED ANALYSES 
18 
2.1 
PROTOCOL AMENDMENTS 
18 
2.1.1 
Amendment 1 - 12/15/2014 
18 
2.1.2 
Amendment 2 - 11/13/2015 
19 
2.1.3 
Amendment 3 - 07/11/2016 
19 
2.1.4 
Amendment 4 - 04/13/2017 
20 
2.1.5 
Amendment 5 - 10/26/2017 
20 
2.1.6 
Amendment 6 - 11/24/2017 
20 
2.1.7 
Amendment 7 - 03/06/2018 
21 


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2.2 
CHANGES IN THE STATISTICAL ANALYSIS PLAN 
21 
3. 
STATISTICAL METHODS 
24 
3.1 
DEFINITION OF THE ANALYSED DATA SETS 
24 
3.1.1 
Efficacy sets 
24 
3.1.1.1 
Intent-To-Treat Set (ITT) 
24 
3.1.1.2 
Per Protocol Set (PP) 
24 
3.1.2 
Safety set (SS) 
24 
3.2 
DATA REVIEW COMMITTEE 
25 
3.3 
STATISTICAL ANALYSES 
25 
3.3.1 
Generalities 
25 
3.3.2 
Interim analyses and Multiplicity issue 
25 
3.3.3 
Handling of Missing Data 
26 
3.3.4 
Study Patients 
27 
3.3.4.1 
Patient Disposition 
27 
3.3.4.2 
Protocol deviations 
27 
3.3.4.3 
Analysis set 
27 
3.3.5 
Demographics and Other Baseline Characteristics 
27 
3.3.5.1 
Demographic Characteristics, Medical History and Diagnoses 
28 
3.3.5.2 
Previous Treatments 
28 
3.3.5.3 
Baseline Efficacy Variables 
28 
3.3.5.4 
Baseline Safety Variables 
29 
3.3.5.5 
Investigational Product (IMP) and Concomitant Treatments 
29 
3.3.5.5.1 
Extent of Exposure 
29 
3.3.5.5.2 
Treatment Compliance 
29 
3.3.5.5.3 
Concomitant Treatment 
29 
3.3.6 
Efficacy analyses 
29 
3.3.6.1 
Primary Efficacy Variable(s) and prognostic factors 
29 
3.3.6.1.1 
Description of the primary efficacy variable(s) 
29 
3.3.6.1.2 
Description of prognostic factors and covariates of the primary efficacy variable(s) 
30 
3.3.6.2 
Primary analysis of the primary endpoint 
31 
3.3.6.2.1 
Hypothesis 
31 
3.3.6.2.2 
Model of analysis of the primary endpoint 
31 
3.3.6.2.3 
Sensitivity Analyses of the primary endpoint 
32 
3.3.6.2.3.1 
Primary sensitivity analysis (MAR assumption) 
32 
3.3.6.2.3.2 
Secondary sensitivity analysis (MNAR assumption) 
32 
3.3.6.2.3.3 
Per Protocol analyses 
32 
3.3.6.2.4 
Other efficacy analyses of the primary endpoint 
33 
3.3.6.2.5 
Individual component analyses of the primary endpoint 
33 
3.3.6.2.5.1 
Administration of RBCs from H0 to D2 
33 
3.3.6.2.5.2 
Percentage of patients losing at least 4g/dL of haemoglobin from H0 to D2 
33 
3.3.6.2.6 
Subset analyses 
34 
3.3.6.3 
Secondary efficacy variables 
34 
3.3.6.3.1 
Description of secondary efficacy variables 
34 
3.3.6.3.2 
Analyses of secondary efficacy variables 
36 
3.3.6.3.2.1 
Analyses of key secondary variables 
36 
3.3.6.3.2.2 
Other analyses of secondary variables 
36 
3.3.6.3.2.2.1 
Analyses of the change from baseline in plasma fibrinogen level, Hb and Ht 
37 
3.3.6.3.2.2.2 
Analyses of the evolution of haemorrhage 
37 
3.3.6.3.2.2.3 
Description of haemostatic intervention 
37 
3.3.6.3.2.2.4 
Description of maternal morbidity 
38 


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4. 
SAFETY EVALUATION 
38 
4.1 
Summary of AEs and TEAEs 
38 
4.2 
AEs and TEAEs by System Organ Class and Preferred Term 
39 
4.3 
Laboratory Data 
39 
4.4 
Vital signs 
40 
4.5 
Physical examination 
40 
5. 
TABLES, FIGURES AND GRAPHS 
41 
5.1 
General Remarks about Tables 
41 
5.2 
List of tables 
41 
6. 
DOCUMENTATION OF STATISTICAL METHODS 
46 
6.1 
General Remarks 
46 
6.1.1 
Missing and Partially Known Dates 
46 
6.2 
Demographics 
46 
6.3 
Durations 
47 
6.4 
Previous and Concomitant Treatments 
47 
6.5 
Adverse Events 
48 
6.6 
Laboratory Data 
48 
6.7 
Vital Signs 
49 
7. 
SAS CODE 
50 
7.1 
SAS code fragments for primary analysis of the primary endpoint 
50 
7.2 
SAS code fragments for sensitivity analyses (FCS model) of the primary endpoint 
50 
7.3 
SAS code fragments for other efficacy analyses (interactions testing) 
51 
7.4 
SAS code fragments for other efficacy analyses (subgroup analyses) 
51 
 
 
 


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List of Abbreviations 
 
AE 
Adverse Event 
ATC 
Anatomical Therapeutic Chemical 
BMI 
Body Mass Index 
CRF 
DSMB 
FCS 
Case Report Form 
Data Safety Monitoring Board 
Fully Conditional Specification 
FFP 
Fresh Frozen Plasma 
Hb 
Haemoglobin 
Ht 
Haematocrit 
HES 
Hydroxyethylstarch 
IMP 
ITT 
Investigational Medicinal Product 
Intent To Treat 
LFB 
MAR 
MCAR 
MedDRA 
MI 
MMRM 
MNAR 
PICU 
PP 
PPH 
PT 
RBC 
Laboratoire français du Fractionnement et des Biotechnologies 
Missing at Random 
Missing Completely at Random 
Medicinal Dictionary for Regulatory Activities 
Multiple Imputation 
Mixed Model for Repeated Measures 
Missing Not at Random 
Post-Interventional Care Unit 
Per Protocol 
Post-Partum Haemorrhage 
Preferred Term 
Red Blood Cells 


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SAE 
SOC 
SOFA 
SPC 
SS 
Serious Adverse Event 
System Organ Class 
Single Or Multiorgan Failure 
Summary of Product Characteristics 
Safety Set 
TEAE 
VIF 
Treatment Emergent Adverse Event 
Variance Inflation Factor 
WHO 
World Health Organisation 


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1. 
INTRODUCTION 
1.1 
Study Objectives 
1.1.1 
Main objective 
The primary objective of this study is to assess the benefits of a therapeutic strategy 
that associates an early administration of human fibrinogen concentrate in the 
management of PPH on the reduction of bleeding after the initiation of 
prostaglandins intravenous infusion. 
 
1.1.2 
Secondary objectives 
The secondary objectives of the study are:  
• To assess the evolution of haemorrhage, 
• To assess the need for haemostatic intervention, 
• To assess the need for intrauterine ballon, 
• To assess the maternal morbi-mortality, 
• To assess the biological effects of fibrinogen concentrate administration, 
• To assess the tolerance of fibrinogen concentrates administration. 
 
1.2 
Study Design 
1.2.1 
Experimental Design 
The study is a phase IV, multicentre, randomized, double-blind, placebo-controlled, 
parallel-group study. 
The patients are randomly allocated to one of the two groups of treatment:  
• Active treatment: fibrinogen concentrate (Clottafact®) 3g, or, 
• Placebo treatment. 
 
1.3 
Flow chart 
An outline of the study procedures is presented in the table below. 






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1.4 
TREATMENT 
The investigational medicinal product (IMP) is either Clottafact® or placebo. 
 
Injection of IMP must start as soon as possible and within 30 minutes following the 
start of prostaglandin infusion. 
 
It is administered as a single-dose. A total volume of 200 mL of IMP (2 vials of 100 
mL of reconstituted IMP) is injected to every patient. 
 
Only one injection of IMP is performed to the patient throughout the study. 
 
Following the administration of IMP, the therapeutic management is totally left to the 
discretion of the investigator. However, some concomitant treatments may be 
administered in accordance with the following recommendations: 
 
• Fibrinogen concentrate as rescue therapy: if administered, it can’t be 
administered: 
• within 60 minutes following the start of IMP administration, 
 
OR 
• before at least 2 units of packed red blood cells (RBCs) have been 
administered to the patient. 
 
• Tranexamic acid: 
• The administration of tranexamic acid is allowed only after prostaglandin 
infusion has been decided. 
• Recommended dose: 1 g IV to be renewed once after 30 min. 
 
• Transfusional strategy: in accordance with the following objectives: 
• Haemoglobin (Hb) ≥ 8 g /100 ml, 
• Prothrombin time ≥ 40%, 
• Platelets count ≥ 50 000/mm3, 
• Transfusions of RBC, FFP and platelets units can be performed before 
availability of laboratory results, when indicated. 


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• Hydroxyethylstarch (HES): maximum dose of 1.5 L during the first 24 hours. 
 
1.5 
ELIGIBILITY CRITERIA 
Before any study-related procedure is undertaken, a written informed consent must 
be obtained. For a patient to be eligible, all of the inclusion criteria and none of the 
exclusion criteria must be met. 
 
1.5.1 
Inclusion criteria 
For patient inclusion, all of the following criteria must be met:  
a. Signed and dated informed consent form, 
b. Vaginal delivery, 
c. PPH requiring IV administration of prostaglandin, 
d. At least one available result of Hb level during the third trimester of 
pregnancy, 
e. 18-year-old female patients and older, 
f. Covered by healthcare insurance in accordance with local requirements. 
 
1.5.2 
Non-inclusion criteria 
Patients are not eligible for inclusion in this study if any of the following criteria is 
met: 
a. Caesarean section, 
b. Haemostatic intervention (as ligation, embolization or hysterectomy) already 
decided at the time of inclusion, 
c. Known placenta praevia or accrete,  
d. Hb level < 10 g/dL during the third trimester of pregnancy,  
e. History of venous or arterial thromboembolic event, 
f. Known inherited bleeding or thrombotic disorders, 
g. Treatment with low-molecular-weight heparin within 24 hours prior the 
inclusion, 
h. Treatment with acetylsalicylic acid within 5 days prior to the inclusion, 
i. Treatment with vitamin K antagonists within 7 days prior to the inclusion, 
j. Administration of fibrinogen concentrate within 48 hours prior to the inclusion, 


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k. Administration of fresh frozen plasma (FFP), platelets units or prohaemostatic 
drugs, tranexamic acid and recombinant activitated factor VII or prothrombin 
complex concentrate within 48 hours prior to the inclusion, 
l. Administration of RBC within 3 months prior to the inclusion, 
m. Participation in another interventional clinical study using an investigational 
medicinal product, within 30 days prior to the inclusion, 
n. Previous inclusion in the present clinical study, 
o. Known history of hypersensitivity or other severe reaction to any component 
of Clottafact® or placebo, 
p. Minors, majors under guardianship, persons staying in health or social 
institutes and people deprived of their freedom, 
q. Known drug or alcohol abuse, 
r. Patients whose use of concomitant medication may interfere with the 
interpretation of data, 
s. Any other current significant medical condition that might interfere with 
treatment evaluation according to the investigator’s judgment, 
t. Patients who are unlikely to survive through the treatment period and 
evaluation, 
u. Patients transferred from another service after the delivery. 
 
1.6 
DURATION OF PATIENT PARTICIPATION 
The duration of participation of each patient is 6 ± 2 weeks after randomization. 
 
1.7 
NUMBER OF INVESTIGATORS 
The study was expected to be conducted in approximately 25 French investigational 
centers. 
 
Each centre was expected to enrol a mean of 29 eligible patients. 
 
1.8 
DISCONTINUATION CRITERIA 
The Investigator must document the date and the reason of any patient withdrawal or 
discontinuation by a narrative description in the patient’s medical records. 
A patient may be discontinued from the study at any time for one or more of the 
following reasons: 


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-Non randomised patient, 
-Worsening of the patient’s condition requiring emergency measures that do not 
allow the administration of IMP, 
-Withdrawal of consent for any reason, at any time, 
-Lost to follow-up. 
 
If at the time of withdrawal, the patient has received the IMP (partially or totally), she 
must be advised to agree to follow up safety investigations. 
If a patient withdraws from the study, the investigator is to make every effort to 
complete the final evaluation by performing an "end of study visit". All evaluation 
results, the date and a narrative description of the reason(s) for discontinuation must 
be recorded in the source documents and in the Case Report Form (CRF). 
 
1.9 
LOST TO FOLLOW-UP 
Investigators should make every effort to minimise the number of patients lost to 
follow-up and to obtain a maximum of information on patients lost to follow-up. All 
attempts have to be documented in the patient’s medical record. 
 
1.10 
EFFICACY AND SAFETY ENDPOINTS 
1.10.1 Primary endpoint 
The primary endpoint is a composite binary failure endpoint. Failure is defined when 
a patient: 
• Loses at least 4 g/dL of Hb, compared to the reference Hb level, within the 48 
hours following IMP administration 
AND/OR  
• Requires the transfusion of at least 2 units of packed RBCs within 48 hours 
following IMP administration. 
 
The reference Hb level is the most recent Hb value recorded within the third 
trimester of pregnancy. The determination of Hb level during the third trimester is 
mandatory in France and is independent of delivery, PPH and vascular loading. It is 
the reason why it was chosen preferably to Hb at the time of the inclusion. 


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The primary endpoint is 48h (H48) after IMP administration (H0). A 20h time window 
(from H32 to H52) is authorized to account for the time of delivery that may occur 
during the night. 
 
1.10.2 Secondary endpoints 
1.10.2.1 
Evolution of haemorrhage 
 Percentage of patients losing at least 4 g/dL of Hb within 48 hours following 
IMP administration with regards to the Hb reference level. 
 Percentage of patients losing at least 3 g/dL of Hb within 48 hours following 
IMP administration with regards to the Hb reference level. 
 Percentage of patients requiring the transfusion of at least 2 units of RBCs 
within 48 hours following IMP administration. 
 Percentage of patients losing at least 4 g/dL of Hb within 48 hours following 
IMP administration with regards to the level of Hb measured at inclusion. 
 Percentage of patients with an occurrence of Hb level < 9 g/dl within 48 hours 
following IMP administration. 
 Number of units of transfused blood products within 48 hours following IMP 
administration. 
 Calculated volume of total blood loss, 48 hours following IMP administration. 
The calculation and adjustment of total blood loss with regards to transfusional 
needs will be calculated at time of statistical analysis as follows: 
- 
 Total blood loss (mL) = blood loss calculated + blood loss compensated by 
transfusion 
- 
Calculated blood loss: Pregnancy total blood volume x (Ht0 – Htf) x (100/35) 
o Pregnancy total blood volume = (Maternal weight measured before 
pregnancy x 65 mL/kg) x 1.4  
o Ht0: last available value of haematocrit before delivery 
o Htf: value of haematocrit in the morning of D2 
Blood loss compensated by transfusion (mL): n RBC x 500mL (with n corresponding 
to the number of transfused units and 500mL = total transfusated blood volume of  
300 mL RBC with Ht of 60%). 
 


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1.10.2.2 
Need for haemostatic intervention 
 Percentage of patients requiring at least one of the following interventions 
within 48 hours following IMP administration of: pelvic arteries embolization, 
surgical vascular ligation, uterine ligation (B Lynch or other techniques), 
administration of recombinant activated Factor VII (rFVIIa) and hysterectomy. 
 
1.10.2.3 
Need for intrauterine balloon 
 Percentage of patients requiring the use of intrauterine balloon within 48 
hours following the administration of IMP. 
 Time of intrauterine balloon placement. 
 
1.10.2.4 
Maternal morbi-mortality 
 Length of stay in resuscitation and/or intensive care and/or post interventional 
care units (PICU) and/or continuous care. 
 Length of stay in obstetrics units. 
 Single or multi-organ failure (SOFA score) in women transferred to 
resuscitation and/or intensive care and/or PICU and/or continuous care units. 
 Death during the study. 
 
1.10.2.5 
Biological effects of fibrinogen concentrate administration 
 Change in plasma fibrinogen level between H0 (start if IMP infusion) and D2; 
 Evolution of hemoconcentration between H0 and D2 
o Change in Hb level between each determination and H0 
o Change in Ht level between each determination and H0 
o Change in RBCs count between each determination and H0 
 
1.10.2.6 
Tolerance of fibrinogen concentrate administration 
 Serious and non-serious adverse events (AE). 
 
1.11 
SAMPLE SIZE CALCULATION 
It has been estimated that, in the control group, 42% of patients will fulfil the primary 
endpoint (unpublished data from the Pithagore cohort). With an expected percentage 
of patients in the Clottafact® treated group of 27%, the difference between the two 
groups will be 15%. With a power (1-ß) of 90%, a type I error (α) of 5% and a two-


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sided test (Z test, unpooled variance), a sample size of 206 patients is needed per 
treatment group. The rate of drop-out is assumed to be approximately 5%. 
Therefore, 434 patients will be included in the study. 
 
As there is some uncertainty about the test Z variance depending itself on the 
expected rates, the variance is re-estimated in a blind way at 80% of the initially 
planned sample size (i.e. 80% of 412=326 evaluable patients or 348 patients with 
adjustment for a 5% dropout rate) to maintain the power to 90% while still 
considering the same originally planned difference in failure rates, i.e. 15%. Given an 
estimated overall rate of failures higher than expected, the sample size was re-
estimated at 470 patients to maintain the power to 90%.  The recruitment period 
ended on June 30th, 2018 with 448 patients at this date. Based on this sample size of 
448, and assuming that 1.55% of patients excluded from the ITT analysis (i.e. 
patients without receiving at least a dose of the IMP) the current power of the trial is 
89.6%, which remains very close to the targeted power of 90%.  
 
2. 
CHANGES IN THE CONDUCT OF THE STUDY OR PLANNED ANALYSES 
2.1 
PROTOCOL AMENDMENTS 
2.1.1 
Amendment 1 - 12/15/2014  
• Bakri balloon 
The term of Bakri balloon (brand name) is replaced by the term intrauterine balloon 
(generic name). To date the Bakri balloon is no longer the only device available. 
• Intrauterine balloon in the PPH management 
The place of the intrauterine balloon in the PPH management has changed since the 
initial protocol writing. To date it may be used earlier in the management of PPH as it 
was before. Then it can no longer be considered as a final haemostatic intervention 
in the same way as these which are mentioned in the 3.2.2.2 section of the protocol. 
The use of an intrauterine balloon will be analyzed as a Secondary Endpoint 
separately from the other haemostatic interventions. 
• Informed Consent Form 
As it has been anticipated, investigational sites confirmed that informed consent 
signature by the patients in an emergency situation, as PPH, is an extremely 
sensitive procedure. The very short timing requested by the protocol makes it even 


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more complicate. In a purpose to facilitate the emergency procedure, the information 
sheet and the informed consent have been simplified in terms of both content and 
form, without modifying the meaning and the purpose of the provided information. 
Precisions have been added in the post-inclusion information sheet and consent 
form in order to be compliant with the updated version of LFB Informed Consent 
Form template. 
• Non-inclusion criteria 
The non-inclusion criteria « m » and « u » have been clarified following investigator’s 
request. 
• Blood sampling timing 
For feasibility reasons, the authorized time frame for blood sampling has been 
extended from 15 min to 30 min for H2 and H6 assessments. 
 
2.1.2 
Amendment 2 - 11/13/2015  
Only administrative changes (recruitment period extended and number of sites 
increased) 
 
2.1.3 
Amendment 3 - 07/11/2016  
• Sample size determination 
The purpose of this amendment is to estimate the overall failure rate (i.e. both 
treatment groups confounded) in a blind way during the trial and therefore re-
estimate the possible variance of the difference in failure rates between both 
treatment groups compared. A new sample size will be accordingly calculated so as 
to maintain the power to 90% while assuming the same planned expected treatment 
difference in the primary endpoint between both treatment groups (i.e. Clottafact 
versus placebo). 
Assuming the same expected 15% difference in failure rates, an expected failure of 
57.5% in the control group and an expected rate of 42.5% in the Clottafact treated 
group, the variance of the Z test becomes higher and this increase in variance 
requires a sample size of 2 x 229 =458 patients to maintain the power to 90%, 
compared to the 2x 206 = 412 patients initially planned in the protocol. Of note, this 
is the configuration of failure rates (57.5% vs 42.5%) that leads to the largest 
variance of the statistics. Hence, in the worst configuration, the increase in sample 


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size should not exceed 2x23 = 46 evaluable patients and if a drop-out rate of 5% is 
still assumed, 484 = 2 x 242 are needed and the increase in sample size adjusted for 
drop-outs will not exceed 2x25 =50 patients (50 = 484-434). 
Hence, this amendment to the protocol aims to estimate the Overall Failure Rate (i.e. 
both groups confounded), denoted as OFRinterim below, at a blind interim analysis 
performed at 80% of the initially planned sample size, i.e. when the primary endpoint 
is available on approximately 326 evaluable patients or 348 patients with adjustment 
for a 5% drop-out rate.  
Given this estimated overall failure rate at this interim stage and assuming the same 
expected difference in failure rates of 15% in the Clottafact® treated group compared 
to the control group (as planned in the protocol), the variance of the Z statistics will 
be reestimated assuming an expected failure rate of OFRinterim – 7.5% in the 
Clottafact treated group and an expected failure rate of OFRinterim + 7.5% in the 
control group. The sample size will be subsequently reassessed so as to maintain a 
90% power for the primary analysis. As mentioned above, the increase in sample 
size adjusted for drop-outs will not exceed 50 additional patients. Of note, as the 
sample size reassessment is performed in a blind way, i.e. based on an overall 
estimate of the overall failure rate, it is known to not inflate the type I error of the 
primary analysis.  
An additional rule for the reassessment of the sample size is as follows: only an 
increase (i.e. no decrease) in the sample size will be allowed at the blind interim 
analysis. 
 
2.1.4 
Amendment 4 - 04/13/2017  
No impact on the statistical analysis (recruitment period extended, status of the 
investigator and SAE reporting timeframe precised). 
 
2.1.5 
Amendment 5 - 10/26/2017  
The purpose of this amendment is to update the patient information leaflet 
(emergency and post-inclusion) according to the new version of the Clottafact SPC 
(version 237119/1.0). 
 
2.1.6 
Amendment 6 - 11/24/2017  
Administrative changes:  


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• 
Recruitment period extended until the date of the inclusion of the 470th 
patient if this inclusion occurs before June 30th, 2018 or until June 30th, 2018 
considered as the end date for inclusions;  
• 
The investigator can delegate completion of the CRFs to qualidied and 
trained staff, but the signature of CRFs can only be delegated to physicians or 
midwives). 
 
2.1.7 
Amendment 7 - 03/06/2018  
The purpose of this amendment is to update the patient information leaflet 
(emergency and post-inclusion) according to the new version of the Clottafact SPC 
(version February 2018). 
 
2.2 
CHANGES IN THE STATISTICAL ANALYSIS PLAN 
Section 
Protocol  
SAP and rationale for changes  
 
 
 
Analysed data sets 
12.6. Protocol Deviations and Analysis 
Set 
“ITT set : all randomized patients” 
SAP: 
“ITT 
set: 
all 
randomized 
patients 
considered 
as 
randomized 
patients 
(i.e. 
regardless of allocation errors) and having 
received at least one dose of the IMP.” 
 
 
Rationale for change:  this definition of the ITT 
set is the most commonly accepted. As 
specified in ICH E9, In some situations, it may 
be reasonable to eliminate from the set of all 
randomised subjects any subject who took no 
trial 
medication. 
The 
intention-to-treat 
principle would be preserved despite the 
exclusion of these patients provided, for 
example, that the decision of whether or not to 
begin treatment could not be influenced by 
knowledge of the assigned treatment. This 
assumption should hold in this double blind 
randomized trial.  
   
 
 
“Safety set : all patients who received 
at least one dose of IMP” 
SAP : all patients receiving at least one dose of 
IMP and considered ‘as treated’ (i.e. assigned 
to the ‘as treated’ group regardless of 
randomization errors).  
If all randomized patients received their 
allocated treatment and if there is no 
randomization error, the ‘as treated’ analysis 
will be the same ‘as randomized’ analysis and 
Safety set will be the same than Intent-to-treat 
set. 
 
 
 
Demographics and 
other baseline 
“If the PP set represents less than 80% 
of the ITT set, demographic and 
SAP: “Demographic and baseline characteristics 
of patients will be analysed on the ITT and PP 


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characteristics 
baseline characteristics will also be 
presented on the PP set.” 
set.” 
 
 
 
Handling missing 
data 
12.7. General Rules for Handling of 
Missing or Inconsistent Data 
“Concerning the primary efficacy 
endpoint, missing data (including 
incomplete dates) will be estimated as 
failures.” 
SAP: “No imputation of missing data will be 
proposed for the primary analysis of the 
primary endpoint. “ 
Rationale for change: There is no best method 
for handling missing data.  The approach for 
handling missing data as recommended by the 
EMA guideline on missing data in confirmatory 
trials (EMA, 2010) should consider various 
missingness 
mechanisms 
along 
with 
subsequent analyses.   
 
Three methods for handling missing data will 
be considered. 
- 
The 
method 
n°1 
considers 
no 
replacement of missing data (which is 
considered as the primary method).  
- 
The method n°2 replaces missing data 
by 
failures 
regardless 
of 
the 
randomized 
treatment 
(which 
is 
considered as a sensitivity method). 
This 
method 
relies 
on 
strong 
assumptions 
corresponding 
to 
a 
particular 
MNAR 
missingness 
mechanism, and should thus not be 
envisaged in first place.   
- 
The method n°3 (which is considered 
as 
another 
sensitivity 
method) 
performs multiple imputations (MI) for 
missing 
data, 
assuming 
a 
MAR  
missingness mechanism.  As there is 
no 
other 
post 
randomization 
assessment of the primary endpoint 
when this latter is missing, the 
multiple imputation process must be 
based 
on 
baseline 
and 
post 
randomization covariates other than 
intermediate 
assessments 
of 
the 
primary endpoint. Blinded simulations 
have shown that important prognostic 
factors (such as country) could not be 
fitted 
as 
the 
model 
could 
not 
converge. Hence, this method based 
on multiple imputations relies on a 
somewhat 
subjective 
choice 
of 
covariates 
and 
should 
not 
be 
considered as the primary one.    
 
       
Primary Analysis 
12.10.1.2. Primary analysis 
“The primary model analysis will be an 
exact logistic regression adjusting for 
treatment, centre, and baseline 
fibrinogen (categorized into three 
classes, ≤ 2 g/L, ]2 g/L; 4g/L], > 4g/L)” 
SAP:  The primary model of analysis will be a 
logistic regression to assess the association 
between a binary exposure variable treatment 
(variable “_trt”) and the binary outcome 
(variable “_resp”), adjusting for centre and 
baseline fibrinogen (variable “_b_fibrinogen”, 


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12.10.1.2.2. Prognistic factors and 
covariates 
“Stratified center and baseline 
fibrinogen are considered as major 
prognostic factors for the primary 
outcome” 
categorized into four classes (≤ 2 g/L, ]2;3] g/L, 
]3,4] g/L, > 4 g/L)”. 
Rationale for change: as some centers would 
enroll too few patients, centres with small 
number of enrolled patients (< 20 patients) will 
be pooled into one group of centers. The 
interaction 
of 
adjusted 
variables 
with 
treatment effect will be estimated in another 
standard logistic regression models. If feasible, 
Influence of centre will be secondarily studied 
in a logistic regression model adjusting for 
center as an additional term.        
 
Prognostic factors 
and covariates 
12.10.1.2.2. Prognistic factors and 
covariates 
“Stratified center and baseline 
fibrinogen” 
“Possible administration of tranexamic 
acid defined as a binary covariate, (i.e. 
yes versus no) on the primary outcome 
during the trial will be evaluated in a 
separate model” 
SAP: “Baseline fibrinogen will be considered as 
a major prognostic factor of the primary 
outcome. Baseline fibrinogen will be adjusted 
in the primary model as described above. As 
the linear relationship between baseline 
fibrinogen and the primary binary outcome (on 
the logit scale) is a priori ascertained, baseline 
fibrinogen will be categorized into four classes 
(≤ 2 g/L, ]2;3] g/L, ]3,4] g/L, > 4 g/L).  
Other possible prognostic factors will be 
considered as secondary and listed as follows : 
Other baseline covariates :  
-Center,  
-Tranexamic acid intake,  
-Lost of at least 2g/dl of haemoglobin (at the 
inclusion) compared to the reference level,  
-Heart rate ≥100beats/min at the inclusion,  
-Measured/estimated total blood loss volume. 
Post-randomization covariates:  
-Fibrinogen concentrate as rescue therapy,  
-Tranexamic acid intake,  
-Fresh frozen plasma,  
-Administration of platelet units,  
-Haemostatic intervention by bakri balloon,  
-Haemostatic invasive procedures,  
-Transfer to intensive care unit,  
-Heart rate ≥ 100 beats/min 
” 
Rationale for change:: See primary analysis 
 
 
 
Individual analyses 
of the composite 
primary endpoint 
None 
SAP: “[…] logistic regression adjusting for 
baseline fibrinogen value (categorized) will be 
used to compare Clottafact® and placebo 
groups.“ 
Each component of the primary endpoint will 
be analyzed separately according to the same 
logistic regression analyses planned for the 
primary endpoint. 
 
 
 
Secondary analyses 
“[…] all secondary efficacy variables 
will be compared between the 2groups 
using chi-square for categorical data 
and using t test for continuous 
quantitative data or other appropriate 
SAP:  “The change in plasma fibrinogen level, 
Hb and Ht will be analysed at H2, H6 and D2 
following IMP administration with a Mixed 
Model for Repeated Measures (MMRM)  
comparing the Clottafact® group and placebo 


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tests.” 
group.” 
 
Multiplicity 
 
 
None 
SAP: “No multiplicity adjustment is necessary 
for the primary analysis as there is only one 
primary criterion and two arms compared. The 
2-sided nominal alpha level of significance is set 
to 5%. Results for the two components of the 
composite primary endpoint will be individualy 
examined without statistical hypothesis testing.  
 
Secondary efficacy parameters will be tested 
for superiority at the 5% level of the Clottafact® 
arm, compared to the placebo arm. Secondary 
efficacy variables willl be examined and may 
contribute to supportive information to the 
effectiveness. We distinguish two types of 
secondary 
endpoints: 
(1) 
Key 
secondary 
endpoints are defined as highly clinically 
relevant endpoints. Statistical methods for 
addressing multiplicity issues will be used to 
test sequentialy key secondary endpoints (ie. 
Hochberg procedure); (2) other secondary 
endpoints will be analysed in an exploratory 
purpose.” 
 
 
 
 
3. 
STATISTICAL METHODS 
3.1 
DEFINITION OF THE ANALYSED DATA SETS  
According to the proposed analysis, several analysis sets have been defined as 
follows: 
3.1.1 
Efficacy sets  
3.1.1.1  Intent-To-Treat Set (ITT)  
This set is defined as all randomized patients considered as randomised (i.e. 
regardless of allocation errors) patients and having received at least one dose of the 
IMP.  
3.1.1.2 Per Protocol Set (PP) 
It includes all ITT patients without any major protocol deviation. These major 
deviations will be reviewed by the data review committee and listed in the final 
version SAP prior to final database lock.   
 
3.1.2 
Safety set (SS) 
This set is defined as all patients receiving at least one dose of IMP and considered 
‘as treated’ (i.e. assigned to the ‘as treated’ group regardless of randomization 
errors). If all randomized patients received their allocated treatment and if there is no 


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randomization error, the ‘as treated’ analysis will be the same ‘as randomized’ 
analysis and Safety set will be the same than Intent-to-treat set. 
 
3.2 
DATA REVIEW COMMITTEE 
The members of the data review committee are the study coordinator, members of 
the scientific committee, representatives of the sponsor, members of the CRO 
(project manager, data manager, statistician, medical writer). 
The data will be reviewed during a meeting in a blinded manner.  
The data review committee will define : 
1) the deviations to the protocol as minor and major, thus enabling the specific 
definition of each of the populations.  
2) Missing data for the primary endpoint: missing data will be confirmed by the 
scientific committee.  
Final decisions will be taken by the scientific committee only. 
    
3.3 
STATISTICAL ANALYSES 
3.3.1 
Generalities  
The analysis is carried out on a PC provided with Windows Seven operating system. 
The analysis is performed with the software SAS version 9.4.  
The inferential analyses are preceded by descriptive analyses.  
The quantitative variables are described by number of data available and missing, 
mean, standard deviation, the 1st and the 3rd quartile, median, minimum and 
maximum.  
The qualitative variables are described by number of data available and missing, 
frequency and percentage per modality. The category missing are displayed only if 
there are actually missing values. Percentages are calculated on the total of non-
missing recorded categories. 
 
3.3.2 
Interim analyses and Multiplicity issue 
No interim analysis is planned. 
 
No multiplicity adjustment is necessary for the primary analysis as there is only one 
primary criterion and two arms compared. The 2-sided nominal alpha level of 


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significance is set to 5%. Results for the two components of the composite primary 
endpoint will be individualy examined without statistical hypothesis testing.  
 
Secondary efficacy parameters will be tested for superiority at the 5% level of the 
Clottafact® arm, compared to the placebo arm. Secondary efficacy variables willl be 
examined and may contribute to supportive information to the effectiveness. We 
distinguish two types of secondary endpoints: (1) Key secondary endpoints are 
defined as highly clinically relevant endpoints (ie. based on clinical practices). 
Statistical methods for addressing multiplicity issues will be used to test sequentialy 
key secondary endpoints (ie. Hochberg procedure); (2) other secondary endpoints 
will be analysed in an exploratory purpose. 
 
3.3.3 
Handling of Missing Data 
As a general rule, missing data will not be replaced.  
 
Missing data for the primary endpoint occurs when the primary endpoint cannot be 
evaluated. Missing data will be confirmed by the scientific committee during the data 
review meeting (see 3.2). When the Hb level within the 48 hours following IMP 
administration is missing, the Hb value in the 48 hours following inclusion that not be 
collected as part of the study will be used to calculate the lose of Hb compared to the 
reference Hb level and for the primary endpoint evaluation.  
 
No imputation of missing data will be proposed for the primary analysis of primary 
endpoint. The primary analysis will thus be performed on the Full analysis set (FAS), 
which will be as close as possible to the randomized set.  
 
Sensitivity analyses of the primary endpoint will be proposed as follows:  
- 
Primary sensitivity analysis (MAR assumption): a multiple imputation 
approach (MI) will be used assuming a missing at random (MAR) mechanism 
will be used to handle missing data. A multiple imputation approach by Fully 
Conditional Specification (FCS) will be used to handle missing data of the 
primary efficacy endpoint.  
.  


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- 
Secondary sensitivity analysis (MNAR assumption): all missing data for the 
primary endpoint will be estimated as failures assuming a missing not at 
random mechanism.  
 
When needed, to be able to calculate durations, incomplete dates will be estimated 
according rules specified in the section 6.1.1. and will be reviewed by the scientific 
committee. 
All estimated or replaced data will be edited along with a flag in the statistical 
appendices. 
 
3.3.4 
 Study Patients 
3.3.4.1 Patient Disposition 
The number of patients who were enrolled and having been treated at least once by 
the IMP as well as those who fulfilled the inclusion and exclusion criteria will be 
summarised overall.  
The number of patients in each center will be displayed overall and by group by 
means of contingency table in the ITT Set. 
3.3.4.2 Protocol deviations 
The number and percentage of patients with any protocol deviation, which is listed 
by deviation category, will be tabulated overall and by study treatment group in the 
ITT Set. 
3.3.4.3 Analysis set 
The number and percentage of patients in each analysis set will be displayed overall 
and by group in the ITT Set. The number and percentage of patients with definitive 
discontinuation and their reasons will be tabulated overall and by group in the ITT 
Set. 
3.3.5 
Demographics and Other Baseline Characteristics 
Demographic and baseline characteristics of patients will be analysed on the ITT and 
PP set. Data will be presented per randomisation group. Statistical tests will not be 
performed to compare randomisation groups at baseline. Possible differences 
between groups at baseline will be judged from a clinical point of view only.  
 


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3.3.5.1 Demographic Characteristics, Medical History and Diagnoses 
All demographic characteristics and all medical history data will be presented per 
randomisation group. Medical and surgical history data recorded at inclusion visit will 
be coded using the MedDRA dictionary version 17.1. All data will be summarised by 
Primary System Organ Class (SOC) and Preferred Term (PT) according to treatment 
group. 
Pregnancy and data related to the delivery up to randomisation will also be 
presented in this section. 
 
3.3.5.2 Previous Treatments 
All previous treatments will be listed by patient with the associated Anatomical 
Therapeutic Chemical (ATC) codes for the WHO drug dictionary March 1, 2014 
version. 
Descriptive statistics will be produced to describe the previous treatments by 
anatomical therapeutic (ATC) name and preferred name according to treatment 
group. 
 
Intravenous fluids and tranexamic acid before study treatment administration will be 
described according to treatment group. 
Volume administered (mL), dose (g), duration of treatment administration and 
duration since start of delivery will be also presented. 
 
3.3.5.3 Baseline Efficacy Variables 
All efficacy variables will be presented by randomisation group. Baseline data are 
defined as the last available data before the start of IMP infusion. 
Date and time of the last available Hb (g/dL) determination will be presented. The 
month of last recorded Hb value during pregnancy will be mentioned. 
Fibrinogen, Hb, Ht and RBCs count will be displayed in the efficacy analysis section 
in order to display baseline and follow-up results in the same tables. 
Exploratory variables are efficacy laboratory data and will be displayed in the efficacy 
analysis section. 
 


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3.3.5.4 Baseline Safety Variables 
All safety variables will be presented by study treatment group. Baseline data are 
defined as the last available data before the start of IMP infusion. 
All laboratory data except those defined as efficacy variables (in the above section) 
or as exploratory variables will be defined as safety criteria. All laboratory data will 
not be displayed in the baseline section but in the analysis of safety in order to 
display in the same table the baseline and other data. 
 
3.3.5.5 Investigational Product (IMP) and Concomitant Treatments 
3.3.5.5.1 
Extent of Exposure 
Summary tables will display the number of patients exposed, duration of exposure 
(in minutes, automatically derived from the start and end times of IMP infusion), in 
each randomisation group and, if applicable (any error in allocation treatment), in 
each treatment group. 
 
3.3.5.5.2 
Treatment Compliance 
The delay between the start of prostaglandin infusion and the start of IMP infusion (in 
minutes) will be presented as a continuous variable. 
The same variables will be estimated and presented on the “as treated” set (SS set) 
in each treatment group.   
 
3.3.5.5.3 
Concomitant Treatment 
Concomitant treatments will be coded using the WHO DDE March 1, 2014 version. 
The number and percentage of patients with at least one concomitant medication will 
be summarised by group. Concomitant medications will be described on SS set by 
anatomical therapeutic chemical (ATC) name, overall and by group.  
 
3.3.6 
Efficacy analyses 
3.3.6.1 Primary Efficacy Variable(s) and prognostic factors 
3.3.6.1.1 
Description of the primary efficacy variable(s) 
The primary efficacy variable is a binary composite endpoint (failure versus 
success). Failure is defined when a patient  
• loses at least 4 g/dL of Hb compared to the reference Hb level,  


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and/or  
• requires the transfusion of at least 2 units of packed RBCs within 48 hours 
following the administration of IMP. 
The reference Hb level is the most recent Hb value recorded during the third 
trimester of pregnancy. 
Raw percentages of failures will be estimated within each treatment group (placebo 
or Clottafact®). 
 
3.3.6.1.2 
Description of prognostic factors and covariates of the primary efficacy 
variable(s) 
Baseline fibrinogen will be considered as a major prognostic factor of the primary 
outcome. Baseline fibrinogen and centre (Centres with small number of enrolled 
patients (<20 patients) will be pooled arbitrary into one) will be adjusted in the 
primary model as described below. As the linear relationship between baseline 
fibrinogen and the primary binary outcome (on the logit scale) is a priori ascertained, 
baseline fibrinogen will be categorized into four classes (≤ 2 g/L, ]2;3] g/L, ]3,4] g/L, > 
4 g/L).  
Other possible prognostic factors will be considered secondarily and listed as 
follows: 
- 
Other baseline covariates :  
o tranexamic acid intake (Yes/No), 
o lost of at least 2g/dl of haemoglobin (at V1) compared to the reference 
level (the last assessment during the third trimester),  
o heart rate at the inclusion (<100 beats/min vs. ≥100 beats/min)  
o measured/estimated total blood loss volume (<1000 ml vs. ≥1000 ml). 
 
Raw percentages of failures will also be provided by centre, by tranexamic acid 
intake. (Yes versus No), by baseline fibrinogen (categorized into four classes: 
≤ 2 g/L, ]2;3] g/L, ]3,4] g/L, > 4 g/L  and by other covariates levels identified above.  
 
- 
Post-randomization 
covariates 
(within 
the 
48 
hours 
following 
IMP 
administration):  
o fibrinogen concentrate as rescue therapy,  
o tranexamic acid intake,  


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o administration of fresh frozen plasma,  
o administration of platelet units,  
o haemostatic intervention by bakri balloon,  
o haemostatic invasive procedures,  
o transfer to intensive care unit,  
o heart rate ≥ 100 beats/min. 
 
Post-randomization covariates will be mainly used to implement the multiple 
imputation model for the primary analysis. Although partially confounded with the 
treatment effect, these post-randomization covariates will also be investigated to 
check whether they are treatment effect modifiers. Raw percentages of failures will 
be provided by post-randomization covariates levels. 
 
3.3.6.2 Primary analysis of the primary endpoint 
3.3.6.2.1 
Hypothesis 
• Null hypothesis: 
H0: the true failure rate in the Clottafact® randomised group = the true failure rate in 
the placebo group. 
• Alternative hypothesis: 
H1: the true failure rate in the Clottafact® randomised group ≠ the true failure rate in 
the placebo group. 
The nominal two-sided level of significance is set to 5%. 
The primary analysis will be conducted primarily in the ITT set.   
 
3.3.6.2.2 
Model of analysis of the primary endpoint 
The primary model of analysis will be a logistic regression to assess the association 
between a binary exposure variable treatment (variable “_trt”) and the binary 
outcome 
(variable 
“_resp”), 
adjusting 
for 
baseline 
fibrinogen 
(variable 
“_b_fibrinogen”, categorized into four classes (≤ 2 g/L, ]2;3] g/L, ]3,4] g/L, > 4 g/L) 
and centre (see SAS code in §7.1). Missing data will be not imputed, assuming the 
missing completely at random (MCAR) assumption.  
 


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The treatment effect (odds ratio of failure) with its 95% confidence interval (95%CIs) 
will be provided by treatment group and tested at the 5% two-sided level of 
significance in this model.  
Validity of the primary analysis: A graphical analysis of residuals will be done for 
verifying that assumptions for the primary analysis are met. If adjusting for centre 
effects lead to convergence issues or unstable estimates, centre effect will be 
ignored in the analysis.  
 
3.3.6.2.3 
Sensitivity Analyses of the primary endpoint  
3.3.6.2.3.1 
Primary sensitivity analysis (MAR assumption)  
Assuming the missing at random (MAR) mechanism, multiple imputation (MI) 
approach by Fully Conditionnal Specification (FCS) will be used to handle missing 
data of the primary efficacy endpoint. 
A stepwise logistic regression will be done to identify relevant covariates by a 
backward elimination analysis based on iterative maximum likelihood with the 
Newton-Raphson algorithm using a significance level of 0.2 to retain variables in the 
model. Only relevant covariates will be introduced in the MI process. The number of 
imputations needed will be verified with relative efficiency (RE) for the fully efficient 
imputation (in unit of variance) and by replicating sets of imputations checking 
whether the estimates are stable between imputation sets. With a little of missing 
information (10%), only a small number of imputations are necessary. 
The final set of key covariates (referenced here below in the SAS syntax as 
“key_covariates_for_MI”, see §7.2 for SAS code) to be accounted for in the MI model 
in addition to treatment and categorized baseline fibrinogen will be defined before 
breaking the blind.  
 
3.3.6.2.3.2 
Secondary sensitivity analysis (MNAR assumption)  
All missing data for the primary endpoint will be estimated as failures assuming a 
missing not at random (MNAR) mechanism. The same model as the one proposed 
for the primary analysis will be fitted on the new data set considering missing data as 
failures. 
 
3.3.6.2.3.3 
Per Protocol analyses 


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Same primary model analyses will also be performed in the PP set assuming the 
MAR, MCAR and MNAR assumptions to handle missing data of the primary efficacy 
endpoint.  
 
3.3.6.2.4 
Other efficacy analyses of the primary endpoint  
- 
Analysis of the baseline fibrinogen as continuous:  
A logistic model will be fitted adjusting linear and quadratic effects of baseline 
fibrinogen. 
- 
Analysis of the centre and baseline fibrinogene interactions with treatment:  
Treatment by center and treatment by categorized baseline fibrinogen interactions 
will be investigated in a logistic regression adjusting for baseline fibrinogen, centre 
and interactions (see §7.3 for SAS code).  
Odds ratios with their 95%CIs will be provided by centre and treatment group and 
illustrated in forest plots. 
 
3.3.6.2.5 
Individual component analyses of the primary endpoint  
The analysis of the contribution of each component of the composite primary 
endpoint will be considered as descriptive analyses. Odds ratios and 95%CIs will be 
provided.  
 
3.3.6.2.5.1 
Administration of RBCs from H0 to D2 
The percentage of patients requiring the transfusion of at least 2 units of RBCs within 
48 hours following IMP administration will be calculated and logistic regression 
adjusting for baseline fibrinogen value (categorized) will be used to compare the 
Clottafact® group and placebo group.  
The same subgroup analyses planned for the primary endpoint will be performed as 
well. 
 
3.3.6.2.5.2 
Percentage of patients losing at least 4g/dL of haemoglobin from H0 to 
D2 
The percentage of patients losing at least 4 g/dL of haemoglobin within 48 hours 
following IMP administration with regards to the haemoglobin reference level will be 
calculated. A logistic regression adjusting for baseline fibrinogen value (categorized) 
will be used to compare the Clottafact® group and placebo group.  


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The same subgroup analyses planned for the primary endpoint will be performed as 
well. 
 
3.3.6.2.6 
Subset analyses  
Subset analyses will be performed to estimate the percentage of failure by treatment 
group and by baseline covariates level in ITT and PP sets. 
 
Baseline covariates will be tested separately in univariate logistic regression models 
which will be the primary model to estimate the treatment effect by covariate level 
with its 95%CI (see §7.4 for SAS code). Forest plots displaying treatment effects 
(odds ratios) along with their 95%CIs will be displayed across covariates levels.  
 
A multivariate analysis will be done to test in the model the following relevant 
covariates and interactions. Center, the total blood lost, the tranexamic acid intake, 
lost of haemoglobin compared to the reference level, heart rate and their interactions 
will be analysed in a stepwise logistic regression model. 
 
3.3.6.3 Secondary efficacy variables 
Analyses of secondary efficacy endpoints will be primarily conducted in the ITT set. 
Sensitivity analyses will be performed in the PP set.  
 
3.3.6.3.1 
Description of secondary efficacy variables 
Secondary efficacy variables are detailed in §1.10.2. We distinguish two types of 
secondary endpoints:  
• Key secondary efficacy variables : 
1- Calculated and adjustment of total blood loss 48 hours following IMP 
administration 
The calculation and adjustment of total blood loss with regards to transfusional 
needs will be calculated as follows: 
Total blood loss (mL) = blood loss calculated + blood loss compensated by 
transfusion 
With: 


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-Calculated blood loss = Pregnancy total blood volume x (Ht0 – Htf) x 
(100/35) 
 Pregnancy total blood volume = (Maternal weight measured before 
pregnancy x 65 mL/kg) x 1.4  
 Ht0: last available value of haematocrit before delivery 
 Htf: value of haematocrit in the morning of D2 
-Blood loss compensated by transfusion (mL) = n RBC x 500mL (with n 
corresponding to the number of transfused units and 500mL = total transfusated 
blood volume of 300 mL RBC with Ht of 60%). 
 
2- Percentage of patients requiring any need for rescue procedure  
The percentage of patients requiring any need for rescue procedure is defined as 
follows: 
- 
at least one of the following invasive procedure within 48 hours following IMP 
administration :  
 pelvic arteries embolization,  
 surgical vascular ligation,  
 uterine ligation (B Lynch or other techniques),  
 hysterectomy  
 intrauterine ballon 
- 
and/or administration of recombinant active Factor VII (rFVIIa),  
- 
and/or fibrinogen rescue. 
 
3- Percentage of patients requiring the use of intrauterine balloon within 48 
hours following IMP administration. 
 
• Other secondary efficacy variables : 
1- Change in plasma fibrinogen level (g/L) between H2 and H0 
2- Change in plasma fibrinogen level (g/L) between H6 and H0 
3- Change in plasma fibrinogen level (g/L) between D2 and H0 
4- The same changes will be calculated for Hb, Ht and RBCs  
5- Duration of haemoorhage (hours): end time of haemorrhage – start time 
of haemorrhage 


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6- Duration in the obstetrics room (from arrival hour in obstetrics room to 
delivery hour) 
7- Duration of hospitalization (from arrival date in obstetrics room to 
hospital discharge date) 
8- Number of days in resuscitation and/or intensive care and/or PICU 
and/or continuous care units (admission date and discharge date) 
9- Number of days with assisted ventilation 
 
3.3.6.3.2 
Analyses of secondary efficacy variables 
3.3.6.3.2.1 
Analyses of key secondary variables 
The analyses of key secondary variables will be tested with the Hochberg step-up 
method: 
1- Calculated/estimated volume of total blood loss, 48 hours following IMP 
administration 
The estimated/calculated volume of total blood loss 48 hour after IMP 
administration will be compared between the Clottafact® group and 
placebo group by a t test or non parametric test.  
 
2- Percentage of patients requiring any need for rescue procedure  
The percentage of patients requiring any need for rescue procedure within 
48 hours following IMP administration will be calculated and chi-square or 
Fisher exact tests will be used to compare between the Clottafact® group 
and placebo group.  
 
3- Percentage of patients requiring the use of intrauterine balloon within 48 
hours following IMP administration  
The percentage of patients requiring the use of intrauterine balloon within 
48 hours following the administration will be calculated and chi-square or 
Fisher exact tests will be used to compare between the Clottafact® group 
and placebo group. 
 
3.3.6.3.2.2 
Other analyses of secondary variables 
Other secondary endpoints will be analysed in an exploratory purpose. 


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3.3.6.3.2.2.1 Analyses of the change from baseline in plasma fibrinogen level, Hb 
and Ht  
The evolution in plasma fibrinogen level, Hb and Ht will be analysed at H2, H6 and 
D2 following IMP administration with a Mixed Model of Repeated Measurements 
comparing the Clottafact® group and placebo group. 
 
3.3.6.3.2.2.2 Analyses of the evolution of haemorrhage 
3.3.6.3.2.2.2.1 
Analyses of haemoglobin level 
- 
The percentage of patients losing at least 3 g/dL of Hb within 48 hours 
following IMP administration with regards to the Hb reference level will be 
calculated and chi-square or Fisher exact tests will be used to compare 
between the Clottafact® group and placebo group. 
- 
The percentage of patients with an occurrence of Hb level < 9 g/dL within 48 
hours following IMP administration will be calculated and chi-square or Fisher 
exact tests will be used to compare between the Clottafact® group and 
placebo group. 
 
3.3.6.3.2.2.2.2 
Analyses of the number of units of transfused blood units 
The number of units of transfused blood products within 48 hours following 
IMP administration with be calculated for the Clottafact® group and placebo 
group and compared using a Chi-square or generalized Fisher exact test. 
 
3.3.6.3.2.2.2.3 
Duration of haemorrhage 
The time to the end of haemorrhage (hours) will be summarised by treatment 
group. The duration of the haemorrhage will be presented using Kaplan-Meier 
estimates to the end of haemorrhage. A log rank test will be used to compare 
the duration of haemorrhage curves between the Clottafact® group and 
placebo group.  
 
3.3.6.3.2.2.3 Description of haemostatic intervention 
The percentage of patients with haemorrhage leading to the occurrence of morbidity 
will be compared by treatment group using Fisher exact test. The percentage of 
patients requiring at least pelvic arteries embolization, surgical vascular ligation, 
uterine ligation, administration of recombinant activated Factor VII, intrauterine 


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ballon, and hysterectomy within 48 hours following the IMP administration will be 
calculated by group.  
The time of intrauterine balloon placement will be described as other haemostatic 
interventions.  
Fisher exact tests will be performed to compare the occurrence of heamostactic 
interventions by treatment groups. 
 
3.3.6.3.2.2.4 Description of maternal morbidity 
The maternal morbidity will be analyzed in the subgroup of patients transferred in 
resuscitation and/or intensive care and/or PICU and/or continuous care units with: 
1. Duration (days) in resuscitation and/or intensive care and/or PICU and/or 
continuous care units.  
2. The maximal SOFA score, 
3. Duration of admission in obstetrics room (hours), duration of hospitalization 
and number of days with assisted ventilation 
 
Chi-square or Fisher exact tests will be performed for categorical data and t test for 
continuous quantitative data or other appropriate tests (ie non parametric tests).  
 
4. 
SAFETY EVALUATION 
Analyses of safety endpoints will be conducted in the safety set (SS).  
Missing data will not be replaced. 
The standard dictionary for coding adverse events will be the MedDRA (version 
17.1).  
All AEs will be classified as emergent (i.e. happening or worsening after the time of 
start of IMP perfusion, defined as treatment-emergent adverse event, TEAEs) or not 
emergent.  
 
4.1 
Summary of AEs and TEAEs 
Numbers and percentages of patients will be summarised overall by treatment 
group, with at least one AE, one serious AE (SAE), one maximal severity AE, one 
strongest relationship AE, the action taken, the treatment provided and the outcome. 
The duration of AE will be also presented. 


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Summary of TEAEs will include the same information as the summary AEs. 
 
4.2 
AEs and TEAEs by System Organ Class and Preferred Term 
Numbers and percentages of patients with at leat one AE and numbers and 
percentages of patients with at leat one emergent AE will be presented by treatment 
group according to SOC and PT : 
• for all AEs, 
• for SAEs, 
• for AEs related to study treatment, 
• for AEs leading to study treatment discontinuation. 
 
The duration of the AE and the duration between the last dose of IMP and onset of 
the adverse event will be calculated. 
 
Arterial and venous thromboembolic events over the study period will be compared 
between treatment groups by chi-square tests or Fisher tests. 
 
No statistical tests will be performed on other variables. 
 
The following listings will be produced: 
• Individual data listing of related adverse events,  
• Individual data listing of adverse events leading to Treatment discontinuation,  
• Individual data listing of SAEs,  
• Individual data listing of deaths. 
 
4.3 
Laboratory Data 
Raw laboratory variables (including baseline data) will be presented by treatment 
group at each determination (H0, H2, H6 and D2) and contengency tables will also 
be displayed at the same periods.  
Descriptive statistics will be presented graphically by visit according to treatment 
group for a selection of haematological, biochemistry and coagulation test 
parameters: 


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• Haematology: Haemoglobin (g/dL), Red cells (count/L), Hematocrit (%), 
Leucocytes (/mm3) and Platelets (109/L); 
Biochemistry: Urea (mmol/L) and Creatinin (µmol/L);  
• Coagulation tests: Fibrinogen (g/L), Prothrombin (%), Quick’s time (sec), Activated 
Thromboplastin Time Ratio and D-Dimer. The activated thromboplastin time ratio 
will be computed as the ratio beween activated thromboplastin time “patient” (sec) 
and activated thromboplastin time “control” (sec). 
• Factor II, Factor V and Fibrin monomer  
The change from baseline for each laboratory parameter will be analysed at D2 by t 
test for comparing treatment groups. 
 
4.4 
Vital signs 
Vital sign parameters will be described at inclusion visit, H2, H6, discharge from the 
obstetrics room, D2, intensive care unit discharge (if applicable) and hospital 
discharge :  
• Systolic blood pressure (mmHg) at each visit and minimal value since last visit 
• Diastolic blood pressure (mmHg) at each visit and minimal value since last visit 
• Heart rate (beats/min) at each visit and minimal value since last visit 
 
4.5 
Physical examination 
Physical examination will be described at inclusion and at hospital discharge.  
 
 












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6. 
DOCUMENTATION OF STATISTICAL METHODS 
6.1 
General Remarks 
6.1.1 
Missing and Partially Known Dates  
Missing dates will not be replaced. Unless specified otherwise, partially known dates 
will be defined as follows for duration computation: 
• Partially known begin date: 
• If only the day is missing, it is estimated as the first day of the month or the day 
of the inclusion date (if the month of the inclusion date is the same as the 
month of the begin date). 
• If month and day are missing, they are estimated as January 1 or the month 
and day of the inclusion date (if the month and day of the inclusion date are the 
same as the month and day of the begin date). 
• Partially known end date: 
• If only the day is missing, it is estimated as the last day of the month or the day 
of the last visit date (if the month of the last visit date is the same as the month 
of the end date). 
• If month and day are missing, they are estimated as December 31 or the month 
and day of the last visit date (if the month and day of the last visit date are the 
same as the month and day of the end date). 
Partially known dates and duration calculations with day/month imputations will be 
presented during the data review meeting for reviewed in a blinded manner.   
6.2 
Demographics 
The following rules will be applied for the computation of age and BMI: 
• Age will be calculated in years using the following formula: age = (initial visit date 
– birth date) / 365.25. Date of initial visit will be taken at inclusion visit (Visit 1). 
Results will be expressed with two decimals. 
• BMI will be calculated in kg/m² using the following formula: [Last known weight 
(Kg) / Height (cm) * Height (cm)] * 10000. Results will be expressed with two 
decimals. 


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6.3 
Durations 
The following durations will be computed for the analyses:  
• Duration of delivery will be defined in hours as: end date/time of delivery – start 
date/time of delivery. 
• Duration since start of delivery until start of previous/concomitant treatment 
administration will be defined in hours as: start date/time of treatment 
administration – start date/time of delivery. 
• Follow-up duration in the study will be defined in days as: hospital discharge or 
premature withdrawal date – date of V1. 
• Duration of haemorrhage will be defined in hours as: end date/time of 
haemorrhage – start date/time of haemorrhage. 
• Duration since H0 before haemostatic intervention will be defined in hours as: 
date/time of haemostatic intervention – start date/time of study treatment 
administration (H0). 
 
6.4 
Previous and Concomitant Treatments 
Descriptive statistics for treatments collected on an ongoing basis during the study 
and coded with the WHO Drug dictionary will be presented by treatment group 
according to the pharmacological class of the ATC classification system (four first 
letters of ATC code) and the drug generic name (preferred name). 
 
Previous and concomitant treatments will be distinguished as follows: 
• A previous treatment is a treatment, whether ongoing or not, which was started 
before the start of IMP administration: treatment start date/time < study treatment 
administration start date/time (H0). 
• A concomitant treatment is a treatment which started after the start of IMP 
administration: treatment start date/time ≥ study treatment administration start 
date/time (H0). 


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6.5 
Adverse Events 
All Aes will be categorised as emergent (TEAEs) or not emergent as follows: 
• Not emergent: start date/time before the start date/time of IMP perfusion (H0) or 
after the date of hospital discharge (Visit 6). 
• Emergent: start date/time on or after the start date/time of IMP perfusion (H0) and 
on or before the date of hospital discharge (Visit 6). 
 
The period between the start date/time of IMP perfusion (H0) and the date of hospital 
discharge is retained for the definition of an emergent AE as it is expected to cover 
the duration of Clottafact® exposure (including elimination half-life). 
If start and/or end dates/times of an AE are missing, partially missing or unknown, 
the AE will be considered as emergent. 
 
The duration of the AE will be computed in days as the difference between the end 
and start dates/times using the following formula: AE end date/time – start date/time 
+ 1.  
 
Treatment-related Aes are those described by the investigator as possibly related 
to study treatment or as Aes with unknown relationship. 
 
6.6 
Laboratory Data 
Haematology, biochemistry and coagulation test laboratory parameters and 
corresponding units are listed below. 
 
• Haematology parameters:  
Parameter 
Unit 
Hb 
g/dL 
Red cell 
Count/L 
Ht 
% 
Leucocyte 
/mm3 
Platelets 
109/L 
 


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• Biochemistry parameters: 
Parameter 
Unit 
Urea 
mmol/L 
Creatinine 
µmol/L 
 
• Coagulation tests 
Parameter 
Unit 
Prothrombin 
% 
Activated thromboplastin time ratio 
- 
D-Dimer 
ng/mL 
Factor II 
% 
Factor V 
% 
Fibrin monomer 
µg/mL 
 
The activated thromboplastin time ratio will be computed as the ratio beween 
activated thromboplastin time “patient” (sec) and activated thromboplastin time 
“control” (sec). 
 
6.7 
Vital Signs 
Vital sign parameters and corresponding units are listed below. 
Parameter 
Unit 
Systolic blood pressure 
mmHg 
Diastolic blood pressure 
mmHg 
Heart rate 
Beats/minute 
Peripheral oxygen saturation 
% 
 
 
 


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7. 
SAS CODE 
 
7.1 
SAS code fragments for primary analysis of the primary endpoint 
 
The SAS code for the primary model is written as follows: 
/*************************************************************************/
/* EURAXI PHARMA - SAS version 9.4  Programme created by B.BERGE         */ 
/* Date: 26/10/2018    Last modifications:       
 
 
 
 */ 
/* Risk level : 
IIb 
 
    
 
 
 
 
 
 
 */ 
/* 
 
 
 
 
 
 
 
 
 
 
       */ 
/* PROGRAM : F:\Data-Management\01 - Etudes\1016 - Fidel\11 - 
Stat\Programmes\1016_FIDEL_EFFICACY_I.sas  
 
 
 
       */  
/* 
 
 
 
 
 
 
 
 
 
 
       */ 
/* MACRO: 
%detect, %Stat_des 
 
 
 
        
 
 */ 
/* 
 
 
 
 
 
 
 
 
 
 
 
 */  
/* Description :  PRIMARY ANALYSIS (logistic model)    
 
 
 */  
/*************************************************************************/ 
ods graphics on; 
ods output ParameterEstimates =_est  OddsRatios =_or; 
proc logistic data = Main_analysis descending; 
class _trt centre  _b_fibrinogen(PARAM=REF REF="> 4 g/L") / param=glm; 
model _resp = _trt centre _b_fibrinogen /influence iplots; 
run; 
ods graphics off; 
 
7.2 
SAS code fragments for sensitivity analyses (FCS model) of the 
primary endpoint 
 
The SAS code for MI imputation with FCS model is written as follows: 
 
/* Model MI FCS */ 
Proc MI data= Main_analysis  seed =xxx nimpute =100 out = logistic_ficout; 
Var _trt centre  _b_fibrinogen_ key_covariates_for_MI Resp; 
class _trt centre  _b_fibrinogen_ key_covariates_for_MI  resp; 
fcs logistic(resp  = _trt centre _b_fibrinogen key_covariates_for_MI 
/details) ; 
run; 
/* PRIMARY MODEL OF ANLYSIS */ 
proc logistic data = logistic_ficout descending; 
class _trt centre _b_fibrinogen(PARAM=REF REF="> 4 g/L") / param=glm; 
model _resp = _trt centre  _b_fibrinogen  /influence iplots; 
ods output ParameterEstimates =_ logistic_parms  ; 
by _imputation_; 
run; 
 
 


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/* COMBINE RESULTS OF MULTIPLE IMPUTATIONS, INFERENCES */ 
proc mianalyze parms (classvar =classval) = logistic_parms; 
class _trt; 
modeleffects _trt; 
ods output parameterestimates=  logistic_outcome; 
run; 
data res; 
set logistic_outcome; 
estimate_back=exp(estimate); 
lcl_back= exp(estimate -1.96*stderr); 
ucl_back= exp(estimate +1.96*stderr); 
run; 
proc print data= res;run; 
 
7.3 
SAS code fragments for other efficacy analyses (interactions testing) 
 
ods graphics on; 
ods output ParameterEstimates =_est  OddsRatios =_or; 
proc logistic data = Main_analysis descending; 
class _trt centre  _b_fibrinogen(PARAM=REF REF="> 4 g/L") / param=glm; 
model _resp = _trt centre _b_fibrinogen centre*_trt centre*_b_fibrinogen  
_b_fibrinogen*_trt /influence iplots; 
run; 
ods graphics off; 
 
7.4 
SAS code fragments for other efficacy analyses (subgroup analyses) 
 
ods output ParameterEstimates =_est  OddsRatios =_or;  
proc logistic data = Main_analysis descending; 
class _trt _covariate(PARAM=REF REF="covariate ref class") / param=glm; 
model _resp = _trt _covariate _covariate *_trt ; 
run;