Clinical Trials Register

Summary
EudraCT Number:	2020-002056-20
Sponsor's Protocol Code Number:	APHP200495
National Competent Authority:	France - ANSM
Clinical Trial Type:	EEA CTA
Trial Status:	Completed
Date on which this record was first entered in the EudraCT database:	2020-06-15
Trial results

Index
A. PROTOCOL INFORMATION
B. SPONSOR INFORMATION
C. APPLICANT IDENTIFICATION
D. IMP IDENTIFICATION
D.8 INFORMATION ON PLACEBO
E. GENERAL INFORMATION ON THE TRIAL
F. POPULATION OF TRIAL SUBJECTS
G. INVESTIGATOR NETWORKS TO BE INVOLVED IN THE TRIAL
N. REVIEW BY THE COMPETENT AUTHORITY OR ETHICS COMMITTEE IN THE COUNTRY CONCERNED
P. END OF TRIAL

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A. Protocol Information

A.1

Member State Concerned

France - ANSM

A.2

EudraCT number

2020-002056-20

A.3

Full title of the trial

FX06 to rescue acute respiratory distress syndrome
during Covid-19 pneumonia : FX-COVID

Intérêt du FX06 dans le traitement du syndrome de détresse respiratoire aiguë
induit par l’infection à COVID-19 : ESSAI FX-COVID

A.3.1

Title of the trial for lay people, in easily understood, i.e. non-technical, language

X06 to rescue acute respiratory distress syndrome
during Covid-19 pneumonia : FX-COVID

Intérêt du FX06 dans le traitement du syndrome de détresse respiratoire aiguë
induit par l’infection à COVID-19 : ESSAI FX-COVID

A.3.2

Name or abbreviated title of the trial where available

FX-COVID

A.4.1

Sponsor's protocol code number

APHP200495

A.7

Trial is part of a Paediatric Investigation Plan

A.8

EMA Decision number of Paediatric Investigation Plan

B. Sponsor Information
B.Sponsor: 1
B.1.1	Name of Sponsor	Assistance Publique -Hôpitaux de Paris
B.1.3.4	Country	France
B.3.1 and B.3.2	Status of the sponsor	Non-Commercial
B.4 Source(s) of Monetary or Material Support for the clinical trial:
B.4.1	Name of organisation providing support	MChE Handelsges m.b.H (F4-Pharma)
B.4.2	Country	Austria
B.4.1	Name of organisation providing support	Sanofi
B.4.2	Country	France
B.4.1	Name of organisation providing support	Bouygues
B.4.2	Country	France
B.5 Contact point designated by the sponsor for further information on the trial
B.5.1	Name of organisation	Assistance Publique -Hôpitaux de Paris
B.5.2	Functional name of contact point	Carla VANDENABELE
B.5.3	Address:
B.5.3.1	Street Address	DRCI Hôpital St Louis, 1 av. Claude Vellefaux
B.5.3.2	Town/ city	Paris
B.5.3.3	Post code	75010
B.5.3.4	Country	France
B.5.4	Telephone number	+33140 27 57 27
B.5.5	Fax number	+33144 84 17 71
B.5.6	E-mail	carla.vandenabele@aphp.fr

D. IMP Identification
D.IMP: 1
D.1.2 and D.1.3	IMP Role	Test
D.2	Status of the IMP to be used in the clinical trial
D.2.1	IMP to be used in the trial has a marketing authorisation	Information not present in EudraCT
D.2.1.2	Country which granted the Marketing Authorisation	France
D.2.5	The IMP has been designated in this indication as an orphan drug in the Community	No
D.2.5.1	Orphan drug designation number
D.3 Description of the IMP
D.3.1	Product name	FX06
D.3.2	Product code	FX06
D.3.4	Pharmaceutical form	Solution for injection
D.3.4.1	Specific paediatric formulation	No
D.3.7	Routes of administration for this IMP	Intravenous use
D.3.8 to D.3.10 IMP Identification Details (Active Substances)
D.3.8	INN - Proposed INN	Human Fibrinopeptide Bβ15-42
D.3.9.3	Other descriptive name	FX06
D.3.9.4	EV Substance Code	SUB26822
D.3.10	Strength
D.3.10.1	Concentration unit	mg/ml milligram(s)/millilitre
D.3.10.2	Concentration type	equal
D.3.10.3	Concentration number	80
D.3.11 The IMP contains an:
D.3.11.1	Active substance of chemical origin	Yes
D.3.11.2	Active substance of biological/ biotechnological origin (other than Advanced Therapy IMP (ATIMP)	No
	The IMP is a:
D.3.11.3	Advanced Therapy IMP (ATIMP)	No
D.3.11.3.1	Somatic cell therapy medicinal product	No
D.3.11.3.2	Gene therapy medical product	No
D.3.11.3.3	Tissue Engineered Product	No
D.3.11.3.4	Combination ATIMP (i.e. one involving a medical device)	No
D.3.11.3.5	Committee on Advanced therapies (CAT) has issued a classification for this product	No
D.3.11.4	Combination product that includes a device, but does not involve an Advanced Therapy	No
D.3.11.5	Radiopharmaceutical medicinal product	No
D.3.11.6	Immunological medicinal product (such as vaccine, allergen, immune serum)	No
D.3.11.7	Plasma derived medicinal product	No
D.3.11.8	Extractive medicinal product	No
D.3.11.9	Recombinant medicinal product	No
D.3.11.10	Medicinal product containing genetically modified organisms	No
D.3.11.11	Herbal medicinal product	No
D.3.11.12	Homeopathic medicinal product	No
D.3.11.13	Another type of medicinal product	No

D.8 Information on Placebo
D.8 Placebo: 1
D.8.1	Is a Placebo used in this Trial?	Yes
D.8.3	Pharmaceutical form of the placebo	Solution for injection
D.8.4	Route of administration of the placebo	Intravenous use

E. General Information on the Trial

E.1 Medical condition or disease under investigation

E.1.1

Medical condition(s) being investigated

Patients admitted in participating ICUs who received mechanical ventilation for SARS-CoV-2 induced acute respiratory distress syndrome (ARDS)

Tout patient admis dans les réanimations participant, et recevant une ventilation mécanique pour un SDRA compliquant une infection par COVID-19.

E.1.1.1

Medical condition in easily understood language

Patients admitted in participating ICUs who received mechanical ventilation for SARS-CoV-2 induced acute respiratory distress syndrome (ARDS)

out patient admis dans les réanimations participant, et recevant une ventilation mécanique pour un SDRA compliquant une infection par COVID-19.

E.1.1.2

Therapeutic area

Diseases [C] - Virus Diseases [C02]

MedDRA Classification

E.1.3

Condition being studied is a rare disease

E.2 Objective of the trial

E.2.1

Main objective of the trial

FX06 infusion in conjunction with optimal medical treatment during SARS-CoV-2 induced ARDS reduces pulmonary vascular hyperpermeability at 7 days, compared to optimal medical treatment alone.

FX06, en adjonction à une prise en charge médicale optimale du SDRA, réduit l’œdème pulmonaire lésionnel à J7

E.2.2

Secondary objectives of the trial

Secondary objectives will be to test the hypothesis that FX06 infusion:
- improves mortality at 30 days following randomization
- reduces capillary leak (weight, fluid balance, systolic, diastolic, mean blood pressure, heart rate, catecholamine and lactate clearance)
- improves pulmonary recovery
- improves the evolution of organ failure
- reduces the need for hemodynamic support with catecholamines
- reduces the need for renal dialysis

The study will also evaluate determine
• the tolerance of FX06
• its pharmacokinetic
• PK/PD parameters of the drug
• Immunogenicity induced by the drug

L’essai testera également les hypothèses que l’injection de FX06 :
- Diminue la mortalité à 30 jours après randomisation
- Diminue la fuite capillaire (poids, bilan entrées-sorties, pression artérielle systolique, diastolique et moyenne, fréquence cardiaque, niveau de vasopresseurs et clairance du lactate)
- Améliore la récupération pulmonaire
- Améliore la résolution des défaillances d’organes
- Permet la diminution des doses d’amines vasoactives
- Diminue le recours à une épuration extra-rénale

L’étude évaluera également la tolérance du FX06, sa pharmacocinétique et son immunogénicité.

E.2.3

Trial contains a sub-study

E.3

Principal inclusion criteria

1. Age ≥ 18 years
2. SARS-CoV-2 induced pneumonia confirmed by a positive PCR test in nasopharyngeal swab or respiratory tract secretions
3. Acute respiratory distress syndrome (ARDS) according to Berlin criteria (bilateral pulmonary infiltrates on frontal chest x-ray, PaO2/FiO2 ratio ≤300 mmHg, objective assessment excluding hydrostatic pulmonary oedema)
4. Need for endotracheal intubation and mechanical ventilation
5. Informed consent by patient or legal representative According to the specifications of emergency consent, randomization without the close relative or surrogate consent could be performed.
6. Affiliated to a social security system
7. Highly effective method of contraception (oral contraception associated with inhibition of ovulation, intrauterine device or hormone releasing system, bilateral tubal occlusion, vasectomized partner or sexual abstinence for more than three months before inclusion) and negative highly sensitive pregnancy test, for women of childbearing potential

1. Age ≥ 18 ans
2. Pneumonie à SARS-COV-2 confirmé par un test PCR sur prélèvement nasopharyngés ou sécrétions respiratoires
3. Syndrome de détresse respiratoire aigüe , suivant les critères de Berlin (opacités radiologiques bilatérales sur une imagerie pulmonaire, rapport PaO2/FiO2 ≤300 mmHg, mesure objective excluant une surcharge pulmonaire d’origine cardiaque)
4. Patient intubé et recevant une ventilation mécanique
5. Consentement éclairé du patient ou de son représentant légal. En cas d’absence du proche/parent/personne de confiance, le patient peut être inclus en procédure d’urgence.
6. Affiliation à un régime de sécurité sociale
7. Méthode de contraception efficace et test de grossesse négative pour les femmes en âge de procréer

E.4

Principal exclusion criteria

1. Mechanically ventilation for more than 4 days
2. Patient receiving drugs interfering with inflammation: non-steroidal anti-inflammatory drugs, immunoglobulins.
3. Patients receiving chemotherapy, radiotherapy or immunotherapy for malignancy
4. Participation in another interventional clinical trial
5. Women pregnant or lactating
6. Patient moribund on the day of randomization, defined by a SAPS-II score>90
7. Contra-indication for vascular access implantation for transpulmonary thermodilution monitoring
8. Severe or terminal renal insufficiency (creatinine clearance <30 ml/min)
9. Severe hepatic insufficiency (hepatic SOFA score>2)
10. Severe cardiac insufficiency, with left ventricular ejection fraction<30%
11. Any history of severe allergic drug reaction (anaphylactic shock or allergic angioedema)
12. Persons deprived of their liberty by a judicial or administrative decision (guardianship or tutelage measure)

1. Ventilation mécanique depuis plus de 4 jours
2. Patient recevant des drogues immuno-modulatrices : AINS
3. Patient recevant des traitements comme : chimiothérapie, immunoglubulines.
4. Inclusion dans un autre essai interventionnel
5. Patiente enceinte ou allaitant
6. Etat moribond le jour de la randomisation (Score SAPS-II >90)
7. Contre-indication pour l'implantation d'un accès vasculaire pour la surveillance de la thermodilution transpulmonaire
8. Insuffisance rénale sévère ou terminale (clairance de la créatinine <30 ml / min)
9. Insuffisance hépatique sévère (score SOFA hépatique> 2)
10. Insuffisance cardiaque sévère, avec fraction d'éjection ventriculaire gauche <30%
11. Tout antécédent de réaction allergique grave à un médicament (choc anaphylactique ou angio-œdème allergique)
12. Personnes privées de liberté par décision de justice (prisonniers), patient sous tutelle, curatelle)

E.5 End points

E.5.1

Primary end point(s)

Change in extravascular lung water index (EVLWi) assessed by transpulmonary thermodilution between D1 and Day 7 after inclusion.

Transpulmonary thermodilution systems, part of the standard management in ICU, allow a direct evaluation of vascular hyperpermeability in the lungs. Extra-vascular lung water index (EVLWi) is a reliable parameter, independently associated with mortality during ARDS [2].

Le critère de jugement principal sera la variation de l’eau pulmonaire extra-vasculaire mesurée par thermodilution transpulmonaire, de J1 à J7.

Les systèmes de monitorage hémodynamiques utilisant la thermodilution transpulmonaire (PICCO ou EV1000), font partie de la prise en charge routinière en Réanimation, et permettent une évaluation directe de l’œdème pulmonaire lésionnel. L’eau pulmonaire extra-vasculaire (EPEV) est un paramètre fiable, indépendamment associé à la mortalité au cours du SDRA

E.5.1.1

Timepoint(s) of evaluation of this end point

Day 7

Jour 7

E.5.2

Secondary end point(s)

- Evolution of daily extravascular lung water index (EVLWi), cardiac index, global end-diastolic volume index, pulmonary vascular permeability index, measured by transpulmonary thermodilution during 7 days.
- Overall survival at 30 days
- Mortality rate in ICU, in hospital
- Rate of withdraw or withhold life-sustaining treatments decision at Day 30
- Vascular leak:
• Daily weight until D7 (% of D1)
• Daily fluid balance until D7
• Evolution of albuminemia until D7
- Pulmonary recovery:
• Duration of mechanical ventilation (MV) and MV free days at D30
• Ventilator-free survival (proportion of participants alive and off invasive mechanical ventilation) at D30
• PaO2/FiO2 and Murray ARDS severity score over 15 days
• Evolution of pulmonary SOFA score over 15 days
• Evolution of radiological Weinberg score over 30 days, analysed by a specialized radiologist, blinded for the treatment group
• Rate of rescue therapy with VV-ECMO
- Evolution of daily sequential organ failure score (SOFA) and organ failure (one or more SOFA sub-score ≥3) failure free days at D15
- Hemodynamic parameters
• systolic, diastolic, mean blood pressure, heart rate twice a day during 7 days
• lactate clearance, measured once a day during 7 days
• catecholamine-free days at D30
- Duration of renal replacement therapy (RRT), and RRT free days at D30
- Nature and frequency of adverse events
- Evolution of FX06 concentration from H0 to H1, measured at time 0 (before FX06 application) and after 5, 15, 30, 60 min
- PK/PD analysis will be performed from those dosages, with a reduction of EVLWi of more than 30% before and 3 hours after injection as primary PD endpoint
- Immunogenicity of the drug will be tested at day 7, according to manufacturer’s procedure

- L’évaluation de l’eau pulmonaire extra-vasculaire (EPEV), indexice cardiaque, volume télédiastolique indexé, indice de perméabilité vasculaire pulmonaire indice global de volume end-diastolique, indice de perméabilité vasculaire pulmonaire durant les 7 premiers jours, mesurée par thermodilution transpulmonaire
- La mortalité à 30 jours
- Mortalité en réanimation et à l’hôpital
- Le taux de limitations thérapeutiques mises en place à 30 jours
- L’évolution de la fuite capillaire :
• Poids journalier jusqu’à J7 (% de J1)
• Bilan entrées-sorties journalier jusqu’à J7
• Évolution du taux d’albuminémie jusqu’à J7
- Récupération pulmonaire:
• Durée de ventilation mécanique et nombre de jours sans ventilation mécanique à J30
• Survie sans ventilation mécanique (nombre de patients vivants sans ventilation mécanique à J30)
• PaO2/FiO2 et score de Murray durant les 15 premiers jours
• Evolution du SOFA pulmonaire sur 15 jours
• Evolution du score radiologique de Weinberg sur 15 jours, analysé par un radiologue, en aveugle du traitement reçu par le patient.
• Taux de sauvetage par ECMO veino-veineuse
- Evolution du score SOFA de défaillances d’organes, journalier sur 30 jours
- Paramètres hémodynamiques
• Pression artérielle systolique, diastolique, moyenne, et fréquence cardiaque sur 7 jours
• Clairance du lactate, mesuré une fois par jour sur 7 jours
• Nombre de jours sans amines vasopressives à J30.
- Durée d’épuration extra-rénale et nombres de jours sans épuration extra-rénale à J30
- Nature et fréquence des effets indésirables
- Évolution de la concentration de FX06 de H0 à H1, mesurée au temps 0 (avant administration du FX06) et après 5, 15, 30, 60 min
- L'analyse PK / PD sera effectuée à partir de ces dosages, avec une réduction de l'EVLWi de plus de 30% avant et 3 heures après l'injection comme critère principal de PD
- L’immunogénicité du médicament sera testée au jour 7, selon la procédure du fabricant

E.5.2.1

Timepoint(s) of evaluation of this end point

D30

Jour30

E.6 and E.7 Scope of the trial

E.6

Scope of the trial

E.6.1

Diagnosis

E.6.2

Prophylaxis

E.6.3

Therapy

Yes

E.6.4

Safety

Yes

E.6.5

Efficacy

Yes

E.6.6

Pharmacokinetic

E.6.7

Pharmacodynamic

E.6.8

Bioequivalence

E.6.9

Dose response

E.6.10

Pharmacogenetic

E.6.11

Pharmacogenomic

E.6.12

Pharmacoeconomic

E.6.13

Others

E.7

Trial type and phase

E.7.1

Human pharmacology (Phase I)

E.7.1.1

First administration to humans

E.7.1.2

Bioequivalence study

E.7.1.3

Other

E.7.1.3.1

Other trial type description

E.7.2

Therapeutic exploratory (Phase II)

Yes

E.7.3

Therapeutic confirmatory (Phase III)

E.7.4

Therapeutic use (Phase IV)

E.8 Design of the trial

E.8.1

Controlled

Yes

E.8.1.1

Randomised

Yes

E.8.1.2

Open

E.8.1.3

Single blind

E.8.1.4

Double blind

Yes

E.8.1.5

Parallel group

Yes

E.8.1.6

Cross over

E.8.1.7

Other

E.8.2

Comparator of controlled trial

E.8.2.1

Other medicinal product(s)

E.8.2.2

Placebo

Yes

E.8.2.3

Other

E.8.2.4

Number of treatment arms in the trial

E.8.3

The trial involves single site in the Member State concerned

E.8.4

The trial involves multiple sites in the Member State concerned

Yes

E.8.4.1

Number of sites anticipated in Member State concerned

E.8.5

The trial involves multiple Member States

E.8.6 Trial involving sites outside the EEA

E.8.6.1

Trial being conducted both within and outside the EEA

E.8.6.2

Trial being conducted completely outside of the EEA

E.8.7

Trial has a data monitoring committee

Yes

E.8.8

Definition of the end of the trial and justification where it is not the last visit of the last subject undergoing the trial

LVLS

Dernière visite du dernier patient inclus

E.8.9 Initial estimate of the duration of the trial

E.8.9.1

In the Member State concerned years

E.8.9.1

In the Member State concerned months

E.8.9.1

In the Member State concerned days

F. Population of Trial Subjects

F.1 Age Range

F.1.1

Trial has subjects under 18

F.1.1.1

In Utero

F.1.1.2

Preterm newborn infants (up to gestational age < 37 weeks)

F.1.1.3

Newborns (0-27 days)

F.1.1.4

Infants and toddlers (28 days-23 months)

F.1.1.5

Children (2-11years)

F.1.1.6

Adolescents (12-17 years)

F.1.2

Adults (18-64 years)

Yes

F.1.2.1

Number of subjects for this age range:

F.1.3

Elderly (>=65 years)

Yes

F.1.3.1

Number of subjects for this age range:

F.2 Gender

F.2.1

Female

Yes

F.2.2

Male

Yes

F.3 Group of trial subjects

F.3.1

Healthy volunteers

F.3.2

Patients

Yes

F.3.3

Specific vulnerable populations

F.3.3.1

Women of childbearing potential not using contraception

F.3.3.2

Women of child-bearing potential using contraception

F.3.3.3

Pregnant women

F.3.3.4

Nursing women

F.3.3.5

Emergency situation

F.3.3.6

Subjects incapable of giving consent personally

Yes

F.3.3.6.1

Details of subjects incapable of giving consent

if the person is unable to express his will and the next-of-kin is unidentified and/or unreachable at time of inclusion, the investigator may proceed to the inclusion of the person without any consent

si la personne n'est pas en mesure d'exprimer sa volonté et que le plus proche parent n'est pas identifié et/ou n'est pas présent au moment de l'inclusion, l'investigateur peut procéder à l'inclusion de la personne sans son consentement.

F.3.3.7

Others

F.4 Planned number of subjects to be included

F.4.1

In the member state

F.5

Plans for treatment or care after the subject has ended the participation in the trial (if it is different from the expected normal treatment of that condition)

None

G. Investigator Networks to be involved in the Trial

N. Review by the Competent Authority or Ethics Committee in the country concerned

Competent Authority Decision

Authorised

Date of Competent Authority Decision

2020-10-14

Ethics Committee Opinion of the trial application

Favourable

Ethics Committee Opinion: Reason(s) for unfavourable opinion

Date of Ethics Committee Opinion

2020-07-08

P. End of Trial
P.	End of Trial Status	Completed
P.	Date of the global end of the trial	2021-06-13

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