FIDEL: Fibrinogen in Haemorrhage of Delivery

• Sponsor: Laboratoire français de Fractionnement et de Biotechnologies (Industry)
• Overall Status: Completed
• CT.gov ID: NCT02155725
• Collaborator: (none)
• Enrollment: 448
• Locations: 31
• Arms: 2
• Duration (Months): 51.9
• Patients Per Site: 14.5
• Patients Per Site Per Month: 0.3

Study Details

Study Description

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.

Condition or Disease	Intervention/Treatment	Phase
Post-Partum Hemorrhage	Drug: Human Fibrinogen concentrate; Drug: Placebo	Phase 4

Detailed Description

Randomised, double-blind,multicenter, placebo-controlled study

Study Design

• Study Type: Interventional
• Actual Enrollment: 448 participants
• Allocation: Randomized
• Intervention Model: Parallel Assignment
• Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
• Primary Purpose: Treatment
• Official Title: Study on the Efficacy and Safety of a Therapeutic Strategy of PPH Comparing Early Administration of Human Fibrinogen vs Placebo in Patients Treated With IV Prostaglandins Following Vaginal Delivery
• Study Start Date: Apr 10, 2014
• Actual Primary Completion Date: Aug 6, 2018
• Actual Study Completion Date: Aug 6, 2018

Arms and Interventions

Arm	Intervention/Treatment
Experimental: Human Fibrinogen concentrate 2 vials (200ml) / 3g intravenous	Drug: Human Fibrinogen concentrate; Injection as soon as possible and within 30 min following the start of prostaglandin infusion; Other Names: Clottafact, LFB
Placebo Comparator: Placebo 2 vials (200ml)	Drug: Placebo; As soon as possible and within 30 min following the start of prostaglandin infusion

Outcome Measures

Primary Outcome Measures

1. Failure Rate of PPH Management [Evaluation of the two criteria that form the primary endpoint within the 48 h following the administration]

   The primary efficacy variable is a binary (Failure versus Success) composite endpoint. Failure is defined when a patient: loses at least 4 g/dL of Hb compared to the reference Hb level , AND/OR requires the transfusion of at least 2 units of packed RBCs.

Secondary Outcome Measures

1. Patients With at Least Administration of 2 Units of RBCs [from H0 to Day 2]

   Considering failure as the fact of requiring at least 2 units of RBCs.

2. Patients With Loss of at Least 4 g/dL of Hb [From reference value to Day 2]

   Considering failure as the fact of having lost at least 4 g/dL of Hb.

Eligibility Criteria

Criteria

• Ages Eligible for Study: 18 Years and Older
• Sexes Eligible for Study: Female
• Accepts Healthy Volunteers: No

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

Exclusion 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 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 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

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	CH Félix Guyon	Saint Denis	Réunion	France	97405
2	Groupe Hospitalier Sud Réunion	Saint Pierre	Réunion	France	97448
3	CHU d'Angers	Angers		France	49933
4	Hôpital Privé d'Antony	Antony		France	92160
5	Centre Hospitalier Fleyriat	Bourg en Bresse		France	01012
6	Hôpital Femme Mère Enfant	Bron		France	69500
7	Hôpital Antoine Béclère	Clamart		France	92141
8	CHU Estaing	Clermont-Ferrand		France	63000
9	Hôpital Louis Mourier	Colombes		France	92701
10	Les Hôpitaux de Chartres (Hôpital Pasteur)	Le Coudray		France	28630
11	Hôpital Bicêtre	Le Kremlin-bicetre		France	94275
12	Centre Hospitalier de Lens	Lens		France	62307
13	CHU de Lille, Maternité Jeanne de Flandre	Lille		France	59037
14	CHU de Limoges	Limoges		France	87042
15	Hôpital de la Croix Rousse	Lyon		France	69004
16	Hôpital Saint-Joseph / Pôle Parents - Enfants	Marseille		France	13008
17	CHRU de Montpellier	Montpellier		France	34295
18	Maternité Régionale Universitaire de Nancy	Nancy		France	54042
19	Hôpital Necker - Enfants malades	Paris		France	75015
20	Hôpital Armand Trousseau	Paris		France	75571
21	Hôpital Cochin	Paris		France	75679
22	Hôpital Tenon	Paris		France	75970
23	CHU de Reims, Hôpital Maison Blanche	Reims		France	51092
24	CHU de Rennes - Hôpital Sud	Rennes		France	35203
25	Polyclinique de l'Atlantique	Saint-Herblain		France	44819
26	Hôpital de Hautepierre	Strasbourg		France	67200
27	Hôpital Foch	Suresnes		France	92151
28	Hôpital Paul de Viguier - Site Purpan	Toulouse		France	31059
29	CHU de Tours	Tours		France	37044
30	CH de Valenciennes	Valenciennes		France	59300
31	CHR de Martinique	Fort de France		Martinique	97261

Sponsors and Collaborators

• Laboratoire français de Fractionnement et de Biotechnologies

Investigators

• Principal Investigator: Anne-Sophie DUCLOY-BOUTHORS, Dr, Maternité Jeanne de Flandre - 59037 LILLE
• Study Chair: Frédéric MERCIER, Pr, Hôpital Antoine Béclère - 92140 CLAMART
• Study Chair: Alexandre MIGNON, Pr, Hôpital Cochin - 75014 PARIS
• Study Chair: Cyril HUISSOUD, Pr, Hôpital Croix Rousse - 69004 LYON
• Study Chair: Jean-Marie GROUIN, Université de Rouen - 76100 ROUEN

Study Documents (Full-Text)

• Study Protocol - Mar 6, 2018
• Statistical Analysis Plan - Dec 20, 2018
• Informed Consent Form - Mar 6, 2018

More Information

Publications

None provided.

• Responsible Party: Laboratoire français de Fractionnement et de Biotechnologies
• ClinicalTrials.gov Identifier: NCT02155725
• Other Study ID Numbers: FIDEL; 2013-002484-26
• First Posted: Jun 4, 2014
• Last Update Posted: Sep 25, 2020
• Last Verified: Jul 1, 2020

• Keywords provided by Laboratoire français de Fractionnement et de Biotechnologies: PPH; fibrinogen; vaginal delivery
• Additional relevant MeSH terms: Postpartum Hemorrhage; Hemorrhage

Study Results

Participant Flow

Recruitment Details	Between 10 April 2014 and 20 June 2018, 448 patients from 30 sites signed an informed consent.
Pre-assignment Detail	During the pre-assigment period 11 patients withdrawn before treatment period. (1 treated with another IMP, 5 not treated, 2 no emergency consent signed, 1 no post inclusion consent signed, 2 refused to continue the study)

Arm/Group Title	Clottafact	Placebo
Arm/Group Description	Human fibrinogen concentrate 3g intravenous use. 2 vials of 1,5 g/100mL, each vial of powder was reconstituted with 100 mL of sterile water for injection.	Placebo intravenous use. 2 vials of 100 mL, each vial of powder was reconstituted with 100 mL of sterile water.
Period Title: Treatment Period
STARTED	224	213
COMPLETED	224	213
NOT COMPLETED	0	0
Period Title: Treatment Period
STARTED	224	213
COMPLETED	207	202
NOT COMPLETED	17	11

Baseline Characteristics

Arm/Group Title	Clottafact	Placebo	Total
Arm/Group Description	Human fibrinogen concentrate 3g intravenous use. 2 vials of 1,5 g/100mL, each vial of powder was reconstitued with 100 mL of sterile water for injection.	Placebo intravenous use. 2 vials of 100 mL, eache vial of powder was reconttitued with 100 mL of sterile water for injection.	Total of all reporting groups
Overall Participants	224	213	437
Age (Count of Participants)
<=18 years	0 0%	0 0%	0 0%
Between 18 and 65 years	224 100%	213 100%	437 100%
>=65 years	0 0%	0 0%	0 0%
Age (years) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [years]	30.5 (5.6)	30.3 (5.4)	30.4 (5.5)
Sex: Female, Male (Count of Participants)
Female	224 100%	213 100%	437 100%
Male	0 0%	0 0%	0 0%
Race and Ethnicity Not Collected (Count of Participants)
Count of Participants [Participants]	0 0%

Outcome Measures

1. Primary Outcome

Title	Failure Rate of PPH Management
Description	The primary efficacy variable is a binary (Failure versus Success) composite endpoint. Failure is defined when a patient: loses at least 4 g/dL of Hb compared to the reference Hb level , AND/OR requires the transfusion of at least 2 units of packed RBCs.
Time Frame	Evaluation of the two criteria that form the primary endpoint within the 48 h following the administration

Outcome Measure Data

Analysis Population Description

Number of patients with failure

Arm/Group Title	Per Protocole (PP) Set Clottafact	Per Protocole (PP) Set Placebo	Intention To Treat (ITT) Set Clottafact	Intention To Treat (ITT) Set Placebo	Full Analysis Set (FAS) Clottafact	Full Analysis Set (FAS) Placebo
Arm/Group Description	Patients with no missing data for the primary criterion.	Patients with no missing data for the primary criterion.	All patients treated with Clottafact. (patients who received at least one infusion of Clottafact)	All patients treated with Placebo. (patients who received at least one infusion of placebo)	Patients treated with Clottafact of the ITT Set with no missing data for the primary criteria.	Patients treated with Placebo of the ITT Set with no missing data for the primary criteria.
Measure Participants	195	193	224	213	220	210
Count of Participants [Participants]	75 33.5%	80 37.6%	92 21.1%	92 NaN	88 NaN	89 NaN

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Full Analysis Set (FAS) Clottafact, Full Analysis Set (FAS) Placebo
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.9563
	Comments
	Method	Regression, Logistic
	Comments
Method of Estimation	Estimation Parameter	Odds Ratio (OR)
	Estimated Value	0.9889
	Confidence Interval	(2-Sided) 95%; 0.6633 to 1.4744
	Parameter Dispersion	Type: Value:
	Estimation Comments

2. Secondary Outcome

Title	Patients With at Least Administration of 2 Units of RBCs
Description	Considering failure as the fact of requiring at least 2 units of RBCs.
Time Frame	from H0 to Day 2

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	FAS Set Clottafact	FAS Set Placebo
Arm/Group Description	Patients treated with Clottafact of the ITT Set with no missing data for the primary criteria.	Patients treated with Placebo of the ITT Set with no missing data for the primary criteria.
Measure Participants	220	210
Count of Participants [Participants]	51 22.8%	52 24.4%

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Per Protocole (PP) Set Clottafact, Per Protocole (PP) Set Placebo
	Comments	Failure on individual component of the primary endpoint defined as administration of 2 units of RBCs.
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.9786
	Comments
	Method	Regression, Logistic
	Comments
Method of Estimation	Estimation Parameter	Odds Ratio (OR)
	Estimated Value	1.0064
	Confidence Interval	(2-Sided) 95%; 0.6321 to 1.6022
	Parameter Dispersion	Type: Value:
	Estimation Comments

3. Secondary Outcome

Title	Patients With Loss of at Least 4 g/dL of Hb
Description	Considering failure as the fact of having lost at least 4 g/dL of Hb.
Time Frame	From reference value to Day 2

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	FAS Set Clottafact	FAS Set Placebo
Arm/Group Description	Patients treated with Clottafact of the ITT Set with no missing data for the primary criteria.	Patients treated with Placebo of the ITT Set with no missing data for the primary criteria.
Measure Participants	220	210
Count of Participants [Participants]	42 18.8%	41 19.2%

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Per Protocole (PP) Set Clottafact, Per Protocole (PP) Set Placebo
	Comments	Failure on individual component of the primary endpoint defined as a loss of at least 4 g/dL of Hb.
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.9474
	Comments
	Method	Regression, Logistic
	Comments
Method of Estimation	Estimation Parameter	Odds Ratio (OR)
	Estimated Value	1.0169
	Confidence Interval	(2-Sided) 95%; 0.6177 to 1.6741
	Parameter Dispersion	Type: Value:
	Estimation Comments

Adverse Events

Time Frame	The safety was assessed by recording all AEs occurring during the study, from signature of the informed consent to last study visit (6 +/- 2 weeks after delivery).
Arm/Group Title	Clottafact		Placebo
Arm/Group Description	Human fibrinogen concentrate 3g intravenous use. 2 vials of 1,5 g/100mL, each vial of powder was reconstitued with 100 mL of sterile water for injection.		Placebo intravenous use. 2 vials of 100 mL, eache vial of powder was reconttitued with 100 mL of sterile water.
All Cause Mortality
	Clottafact		Placebo
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	0/224 (0%)		0/213 (0%)
Serious Adverse Events
	Clottafact		Placebo
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	10/224 (4.5%)		10/213 (4.7%)
Eye disorders
Vision blurred	0/224 (0%)	0	1/213 (0.5%)	1
General disorders
Discomfort	0/224 (0%)	0	1/213 (0.5%)	1
Oedema peripheral	1/224 (0.4%)	1	0/213 (0%)	0
Pyrexia	0/224 (0%)	0	1/213 (0.5%)	1
Hepatobiliary disorders
Acute fatty liver of pregnancy	0/224 (0%)	0	1/213 (0.5%)	1
Infections and infestations
Amniotic cavity infection	1/224 (0.4%)	1	0/213 (0%)	0
Endometritis decidual	1/224 (0.4%)	1	1/213 (0.5%)	1
Pyelonephritis acute	1/224 (0.4%)	1	0/213 (0%)	0
Investigations
Blood alkaline phosphatase increased	0/224 (0%)	0	1/213 (0.5%)	1
Blood pressure ambulatory increased	1/224 (0.4%)	1	0/213 (0%)	0
Blood uric acid increased	0/224 (0%)	0	1/213 (0.5%)	1
Metabolism and nutrition disorders
Hyperglycaemia	1/224 (0.4%)	1	0/213 (0%)	0
Nervous system disorders
Headache	1/224 (0.4%)	1	1/213 (0.5%)	1
Pregnancy, puerperium and perinatal conditions
HELLP syndrome	1/224 (0.4%)	1	0/213 (0%)	0
Postpartum haemorrhage	0/224 (0%)	0	1/213 (0.5%)	1
Retained placenta or membranes	1/224 (0.4%)	1	0/213 (0%)	0
Psychiatric disorders
Psychological trauma	1/224 (0.4%)	1	0/213 (0%)	0
Reproductive system and breast disorders
Broad ligament haematoma	1/224 (0.4%)	1	0/213 (0%)	0
Metrorrhagia	1/224 (0.4%)	1	0/213 (0%)	0
Uterine haematoma	1/224 (0.4%)	1	0/213 (0%)	0
Uterine necrosis	0/224 (0%)	0	1/213 (0.5%)	1
Uterine rupture	1/224 (0.4%)	1	0/213 (0%)	0
Respiratory, thoracic and mediastinal disorders
Acute pulmonary oedema	1/224 (0.4%)	1	0/213 (0%)	0
Vascular disorders
Aneurysm	0/224 (0%)	0	1/213 (0.5%)	1
Blood pressure inadequately controlled	0/224 (0%)	0	1/213 (0.5%)	1
Hypotension	0/224 (0%)	0	1/213 (0.5%)	1
Shock haemorrhagic	1/224 (0.4%)	1	0/213 (0%)	0
Thrombosis	0/224 (0%)	0	1/213 (0.5%)	1
Venous thrombosis limb	0/224 (0%)	0	1/213 (0.5%)	1
Other (Not Including Serious) Adverse Events
	Clottafact		Placebo
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	95/224 (42.4%)		106/213 (49.8%)
Gastrointestinal disorders
Abdominal pain	4/224 (1.8%)	4	1/213 (0.5%)	1
Constipation	9/224 (4%)	9	4/213 (1.9%)	4
Haemorrhoids	21/224 (9.4%)	21	29/213 (13.6%)	29
Nausea	0/224 (0%)	0	4/213 (1.9%)	4
Vomiting	1/224 (0.4%)	1	4/213 (1.9%)	4
General disorders
Hyperthermia	2/224 (0.9%)	2	5/213 (2.3%)	5
Influenza like illness	0/224 (0%)	0	3/213 (1.4%)	3
Oedema peripheral	4/224 (1.8%)	4	6/213 (2.8%)	6
Pyrexia	11/224 (4.9%)	11	12/213 (5.6%)	12
Malaise	2/224 (0.9%)	2	4/213 (1.9%)	4
Hepatobiliary disorders
Hepatocellular injury	3/224 (1.3%)	3	0/213 (0%)	0
Infections and infestations
Endometritis decidual	4/224 (1.8%)	4	5/213 (2.3%)	5
Puerperal pyrexia	7/224 (3.1%)	7	4/213 (1.9%)	4
Urinary tract infection	4/224 (1.8%)	4	0/213 (0%)	0
Musculoskeletal and connective tissue disorders
Back pain	3/224 (1.3%)	3	4/213 (1.9%)	4
Nervous system disorders
Dizziness	2/224 (0.9%)	2	3/213 (1.4%)	3
Headache	5/224 (2.2%)	6	7/213 (3.3%)	8
Psychiatric disorders
Anxiety	3/224 (1.3%)	3	1/213 (0.5%)	1
Reproductive system and breast disorders
Metrorrhagia	6/224 (2.7%)	6	3/213 (1.4%)	3
Nipple disorder	0/224 (0%)	0	4/213 (1.9%)	4
Oedema genital	2/224 (0.9%)	2	5/213 (2.3%)	5
Uterine pain	4/224 (1.8%)	4	0/213 (0%)	0
Vulval oedema	0/224 (0%)	0	4/213 (1.9%)	4
Vascular disorders
Hypertension	3/224 (1.3%)	3	6/213 (2.8%)	6
Hypotension	5/224 (2.2%)	5	4/213 (1.9%)	4

Limitations/Caveats

[Not Specified]

More Information

Certain Agreements

Principal Investigators are NOT employed by the organization sponsoring the study.