Clinical Trials Register

Summary
EudraCT Number:	2020-001409-21
Sponsor's Protocol Code Number:	IMIB-DFC-2020-02
National Competent Authority:	Spain - AEMPS
Clinical Trial Type:	EEA CTA
Trial Status:	Ongoing
Date on which this record was first entered in the EudraCT database:	2020-04-03
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

Spain - AEMPS

A.2

EudraCT number

2020-001409-21

A.3

Full title of the trial

A prospective, multicenter, randomized, parallel, double-blind, placebo-controlled phase IIb clinical trial to evaluate intravenous infusion of Defibrotide in the prevention and treatment of respiratory distress and cytokine release syndrome in patients with COVID-19.

Ensayo clínico en fase IIb prospectivo, multicéntrico, aleatorizado, paralelo, doble ciego, controlado con placebo para evaluar la infusión intravenosa de Defibrotide en la prevención y tratamiento del distrés respiratorio y síndrome de liberación de citoquinas en pacientes con COVID-19.

A.3.1

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

DEFIBROTIDE AS PREVENTION AND TREATMENT OF RESPIRATORY DISTRESS AND CYTOKINE RELEASE SYNDROME OF COVID-19

DEFIBROTIDE COMO PREVENCIÓN Y TRATAMIENTO DEL DISTRÉS RESPIRATORIO Y SÍNDROME DE LIBERACIÓN DE CITOQUINAS DEL COVID-19

A.3.2

Name or abbreviated title of the trial where available

DEFACOVID

A.4.1

Sponsor's protocol code number

IMIB-DFC-2020-02

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	FFIS
B.1.3.4	Country	Spain
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	ISCARLOS III
B.4.2	Country	Spain
B.5 Contact point designated by the sponsor for further information on the trial
B.5.1	Name of organisation	FFIS
B.5.2	Functional name of contact point	LOLA SERNA GUIRAO
B.5.3	Address:
B.5.3.1	Street Address	LUIS FONTES PAGAN 9
B.5.3.2	Town/ city	MURCIA
B.5.3.3	Post code	30003
B.5.3.4	Country	Spain
B.5.6	E-mail	lola.serna@carm.es

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	Yes
D.2.1.1.1	Trade name	DEFITELIO
D.2.1.1.2	Name of the Marketing Authorisation holder	Jazz Pharmaceuticals
D.2.1.2	Country which granted the Marketing Authorisation	European Union
D.2.5	The IMP has been designated in this indication as an orphan drug in the Community	Yes
D.2.5.1	Orphan drug designation number	EU/3/04/212
D.3 Description of the IMP
D.3.1	Product name	DEFITELIO
D.3.4	Pharmaceutical form	Solution for infusion
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	DEFIBROTIDE
D.3.9.1	CAS number	83712-60-1
D.3.9.4	EV Substance Code	SUB01572MIG
D.3.10	Strength
D.3.10.1	Concentration unit	mg/kg milligram(s)/kilogram
D.3.10.2	Concentration type	equal
D.3.10.3	Concentration number	25
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 infusion
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

COVID-19

COVID19

E.1.1.1

Medical condition in easily understood language

COVID19

E.1.1.2

Therapeutic area

Body processes [G] - Immune system processes [G12]

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

To determine the efficacy of the intravenous infusion of Defibrotide (Defitelio) to reduce mortality in patients with SARS-CoV-2 infection with clinical status grade 4, 5 or 6 according to the WHO classification.

Determinar la eficacia de la infusión intravenosa de Defibrotide (Defitelio) para reducir la mortalidad en pacientes con infección por SARS-CoV-2 con estado clínico grado 4, 5 o 6 según clasificación de la OMS.

E.2.2

Secondary objectives of the trial

To assess the safety of intravenous Defibrotide (Defitelio) infusion in patients with SARS-CoV-2 infection with clinical status grade 4, 5 or 6 according to the WHO classification.
 To analyze the effects of the intravenous infusion of Defibrotide (Defitelio) on the clinical state of patients with SARS-CoV-2 infection with clinical status grade 4, 5 or 6 according to the WHO classification.
 Assess the capacity of intravenous infusion of Defibrotide (Defitelio) to improve the radiological response of patients with SARS-CoV-2 infection with clinical status grade 4, 5 or 6 according to the WHO classification.
 Study the action of Defibrotide (Defitelio) on risk biomarkers in patients with SARS-CoV-2 infection with grade 4, 5 or 6 clinical status according to the WHO classification.

Evaluar la seguridad de la infusión intravenosa de Defibrotide (Defitelio) en pacientes con infección por SARS-CoV-2 con estado clínico grado 4, 5 o 6 según clasificación de la OMS.
 Analizar los efectos de la infusión intravenosa de Defibrotide (Defitelio) en el estado clínico de los pacientes con infección por SARS-CoV-2 con estado clínico grado 4, 5 o 6 según clasificación de la OMS.
 Valorar la capacidad de la infusión intravenosa de Defibrotide (Defitelio) de mejorar la respuesta radiológica de los pacientes con infección por SARS-CoV-2 con estado clínico grado 4, 5 o 6 según clasificación de la OMS.
 Estudiar la acción de Defibrotide (Defitelio) sobre biomarcadores de riesgo en pacientes con infección por SARS-CoV-2 con estado clínico grado 4, 5 o 6 según clasificación de la OMS.

E.2.3

Trial contains a sub-study

E.3

Principal inclusion criteria

 Patients of both sexes with an age greater than or equal to 18 years.
 Patients with a diagnosis of SARS-CoV-2 infection confirmed by RT-PCR.
 Patients with grade 4, 5 or 6 clinical status according to the WHO classification.
- Grade 4: Hospitalized patients requiring oxygen therapy.
- Grade 5: Hospitalized patients requiring high-flow oxygen therapy, non-invasive mechanical ventilation, or both.
- Grade 6: Hospitalized patients requiring extracorporeal membrane oxygenation or invasive mechanical ventilation.
 Patients with IL-6 levels equal to or greater than 3 times the value of normality
 Potentially fertile patients should have a negative pregnancy test in serum (beta-HCG) or urine (evaluated between 2 and 1 days prior to administration of the study medication).
 Patients who offer sufficient guarantees of adherence to the protocol.
 Patients who give their written informed consent to participate in the study

 Pacientes de ambos sexos con edad mayor o igual a 18 años.
 Pacientes con diagnóstico de infección por SARS-CoV-2 confirmado por RT-PCR.
 Pacientes con estado clínico grado 4, 5 o 6 según clasificación de la OMS.
- Grado 4: Pacientes hospitalizados que requieren oxigenoterapia.
- Grado 5: Pacientes hospitalizados que requieren oxigenoterapia de alto flujo, ventilación mecánica no invasiva o ambas.
- Grado 6: Pacientes hospitalizados que requieren oxigenación por membrana extracorpórea o ventilación mecánica invasiva.
 Pacientes con niveles de IL-6 igual o superior a 3 veces el valor de la normalidad
 Pacientes potencialmente fértiles deberán tener una prueba de embarazo negativo en suero (beta-HCG) u orina (evaluada entre 2 y 1 días previos a la administración de la medicación del estudio).
 Pacientes que ofrezcan garantías suficientes de adhesión al protocolo.
 Pacientes que otorguen su consentimiento informado por escrito para participar en el estudio

E.4

Principal exclusion criteria

 Patients with acute bleeding.
 Patients with thrombolytic treatment and anticoagulant treatment at therapeutic doses.
 Patients with an active malignant tumor.
 Patients with severe systemic or neuropsychiatric diseases.
 Patients with hypersensitivity to the active substance or to any of the excipients of the study drug.
 Patients who are participating in other clinical trials.
 Patients with an inability to understand informed consent.
 Pregnant patientsb, in the postpartum period or in the period of active lactation.
Physically fertile patients, UNLESS they are using a highly effective contraceptive method

 Pacientes con sangrado agudo.
 Pacientes con tratamiento trombolítico y tratamiento anticoagulante a dosis terapéuticas.
 Pacientes con tumor maligno activo.
 Pacientes con enfermedades sistémicas o neuropsiquiátricas graves.
 Pacientes con hipersensibilidad al principio activo o a alguno de los excipientes del fármaco en estudio.
 Pacientes que estén participando en otros ensayos clínicos.
 Pacientes con incapacidad para comprender el consentimiento informado.
 Pacientes embarazadasb, en periodo postparto o en periodo de lactancia activa.
 Pacientes físicamente fértilesa, A NO SER QUE estén utilizando un método anticonceptivo altamente efectivo

E.5 End points

E.5.1

Primary end point(s)

Mortality rate 30 days after starting treatment.

Tasa de mortalidad a los 30 días de inicio de tratamiento.

E.5.1.1

Timepoint(s) of evaluation of this end point

15, 30 ,60 days

15, 30 y 60 dias

E.5.2

Secondary end point(s)

Adverse reactions observed by organ classes and systems described in the Defibrotide (Defitelio) data sheet
- Proportion of subjects with clinical improvement defined as a decrease of at least 1 category from the start of treatment on the ordinal scale of 7 categories of clinical status.
- Time to clinical improvement defined as a decrease of at least 1 categories from the start of treatment on the ordinal scale of 7 categories of clinical status (days).
- Proportion of subjects with clinical status grades 4 and 5 according to the WHO classification who require invasive mechanical ventilation.
- Time until the start of invasive mechanical ventilation (days).
- Invasive mechanical ventilation time in patients with clinical status grade 6 according to the WHO classification (days).
- Length of hospital stay (days).
- Proportion of subjects with a decrease of at least 2 points on the NEWS2 scale maintained for 24 hours.
- Time to decrease of at least 2 points on the NEWS2 scale maintained for 24 hours.

Reacciones adversas observadas por clases de órganos y sistemas descritas en la ficha técnica de Defibrotide (Defitelio)
- Proporción de sujetos con mejora clínica definida como disminución de al menos 1 categoría desde el inicio de tratamiento en la escala ordinal de 7 categorías de estado clínico.
- Tiempo hasta la mejora clínica definida como disminución de al menos 1 categorías desde el inicio de tratamiento en la escala ordinal de 7 categorías de estado clínico (días).
- Proporción de sujetos con estado clínico grados 4 y 5 según clasificación de la OMS que precisan de ventilación mecánica invasiva.
- Tiempo hasta el inicio de ventilación mecánica invasiva (días).
- Tiempo de la ventilación mecánica invasiva en pacientes con estado clínico grado 6 según clasificación de la OMS (días).
- Tiempo de la estancia hospitalaria (días).
- Proporción de sujetos con disminución de al menos 2 puntos en la escala NEWS2 mantenida durante 24 horas.
- Tiempo hasta la disminución de al menos 2 puntos en la escala NEWS2 mantenida durante 24 horas.

E.5.2.1

Timepoint(s) of evaluation of this end point

0, +7,+15,+30, +60

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

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

Yes

E.8.2.3.1

Comparator description

tratamiento convencional de eleccion

conventional treatment

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

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

LVLP

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

E.8.9.2

In all countries concerned by the trial months

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

F.3.3.7

Others

F.4 Planned number of subjects to be included

F.4.1

In the member state

120

F.4.2

For a multinational trial

F.4.2.1

In the EEA

120

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

Ninguno

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

2020-04-01

Ethics Committee Opinion of the trial application

Favourable

Ethics Committee Opinion: Reason(s) for unfavourable opinion

Date of Ethics Committee Opinion

2020-03-31

P. End of Trial
P.	End of Trial Status	Ongoing

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