Clinical Trials Register

Summary
EudraCT Number:	2020-001722-66
Sponsor's Protocol Code Number:	REP_COVID
National Competent Authority:	Spain - AEMPS
Clinical Trial Type:	EEA CTA
Trial Status:	Prematurely Ended
Date on which this record was first entered in the EudraCT database:	2020-04-27
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

2020-001722-66

A.3

Full title of the trial

Plasma turnover in patients with COVID-19 disease and invasive mechanical ventilation: a randomized study

Recambio plasmático en pacientes con enfermedad COVID-19 y ventilación mecánica invasiva: estudio aleatorizado

A.3.1

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

Plasma turnover in patients with COVID-19 disease and invasive mechanical ventilation

Recambio plasmático en pacientes con enfermedad COVID-19 y ventilación mecánica invasiva

A.3.2

Name or abbreviated title of the trial where available

REP-COVID

RE_COVID

A.4.1

Sponsor's protocol code number

REP_COVID

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	Fundació Clínic per a la recerca Biomèdica
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	BecaFis Instituto Nacional Carlos III
B.4.2	Country	Spain
B.4.1	Name of organisation providing support	Institut Grifols
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	Clinical Trial Unit
B.5.2	Functional name of contact point	CTU
B.5.3	Address:
B.5.3.1	Street Address	Mallorca 183
B.5.3.2	Town/ city	Baecelona
B.5.3.3	Post code	08026
B.5.3.4	Country	Spain
B.5.4	Telephone number	00349322754004380
B.5.5	Fax number	0034932279877
B.5.6	E-mail	acruceta@clinic.cat

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	Albutein 5% solutión for infusion
D.2.1.1.2	Name of the Marketing Authorisation holder	Instituto Grifols, S.A. Can Guasch, 2 - Parets del Vallès 08150 Barcelona - ESPAÑA
D.2.1.2	Country which granted the Marketing Authorisation	Spain
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	Human Albumin
D.3.2	Product code	B05AA01
D.3.4	Pharmaceutical form	Solution for infusion
D.3.4.1	Specific paediatric formulation	Yes
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 SERUM ALBUMIN
D.3.9.3	Other descriptive name	ALBUMIN NORMAL HUMAN SERUM
D.3.9.4	EV Substance Code	SUB12762MIG
D.3.10	Strength
D.3.10.1	Concentration unit	g/ml gram(s)/millilitre
D.3.10.2	Concentration type	equal
D.3.10.3	Concentration number	40
D.3.11 The IMP contains an:
D.3.11.1	Active substance of chemical origin	No
D.3.11.2	Active substance of biological/ biotechnological origin (other than Advanced Therapy IMP (ATIMP)	Yes
	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	Yes
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.IMP: 2
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	Flebogamma DIF/100 Human Inmunoglobulin normal
D.2.1.1.2	Name of the Marketing Authorisation holder	Flebogamma DIF 100
D.2.1.2	Country which granted the Marketing Authorisation	Spain
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	Human Immunoglobuline normal
D.3.2	Product code	Flebogamma DIF 50 mg/ml solución para perfusión
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	Human normal immunoglobulin
D.3.9.3	Other descriptive name	HUMAN NORMAL IMMUNOGLOBULIN
D.3.9.4	EV Substance Code	SUB14196MIG
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	100
D.3.11 The IMP contains an:
D.3.11.1	Active substance of chemical origin	No
D.3.11.2	Active substance of biological/ biotechnological origin (other than Advanced Therapy IMP (ATIMP)	Yes
	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)	Yes
D.3.11.7	Plasma derived medicinal product	Yes
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

E. General Information on the Trial

E.1 Medical condition or disease under investigation

E.1.1

Medical condition(s) being investigated

coronavirus (covid-19) infection with respiratory failure requiring mechanical ventilation.

infección por coronavirus (covid-19) con insuficiencia respiratoria que requiere ventilación mecánica.

E.1.1.1

Medical condition in easily understood language

coronavirus (covid-19) infection with respiratory failure requiring mechanical ventilation.

infección por coronavirus (covid-19) con insuficiencia respiratoria que requiere ventilación mecánica.

E.1.1.2

Therapeutic area

Diseases [C] - Virus Diseases [C02]

MedDRA Classification

E.1.2 Medical condition or disease under investigation

E.1.2	Version	23.0
E.1.2	Level	PT
E.1.2	Classification code	10051905
E.1.2	Term	Coronavirus infection
E.1.2	System Organ Class	10021881 - Infections and infestations

E.1.2 Medical condition or disease under investigation

E.1.2	Version	21.1
E.1.2	Level	PT
E.1.2	Classification code	10067221
E.1.2	Term	Mechanical ventilation
E.1.2	System Organ Class	10042613 - Surgical and medical procedures

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 assess the impact of plasma exchange on mortality at 28 days in patients with covid-19 disease and invasive mechanical ventilation.

Evaluar el impacto del recambio plasmático sobre la mortalidad a los 28 días en pacientes con enfermedad covid-19 y ventilación mecánica invasiva

E.2.2

Secondary objectives of the trial

1– Evaluate survival variables
2– Time in which mechanical ventilation, vasoactive support and renal support have been necessary.
3- Days of ICU stay, days of hospitalization.
4- Evaluation of the degree of organic failure (s) by daily calculation of SOFA and APACHE score during the intervention period (from day 1 to day 7), at discharge from the ICU and from the hospital.
5- Measure the basic systemic inflammatory response.
6- Measure the inflammatory response of advanced inflammatory serum mediators.
7. Evaluate which blood components and molecular pathways are altered and the impact of plasma turnover.
8- Safety variables and adverse events related or not to treatment during its administration period.

1– Evaluar variables de supervivencia
2– Tiempo en que ha sido necesaria la ventilación mecánica, el soporte vasoactivo y el soporte renal.
3- Días de estancia en UCI, días de hospitalización.
4- Evaluación del grado de fallo orgánico(s) mediante el cálculo diario de SOFA y APACHE score durante el periodo de intervención (del día 1 al día 7), al alta de UCI y del hospital.
5- Medir la respuesta inflamatoria sistémica básica.
6- Medir la respuesta inflamatoria de mediadores séricos inflamatorios avanzados.
7. Evaluar que componentes sanguíneos y vías moleculares están alterados y el impacto del recambio plasmático.
8- Variables de seguridad y los eventos adversos relacionados con el tratamiento durante el periodo de administración del mismo y eventos no relacionados con el tratamiento

E.2.3

Trial contains a sub-study

E.3

Principal inclusion criteria

1-Age 18-79 years;

2-Diagnosis of COVID-19 by PCR in nasopharyngeal, sputum or bronchial aspirate smears :

3-Admission to ICU with invasive mechanical ventilation;

4-Telephone informed consent granted by family members or legal representative.

1-Edad 18-79 años;

2-Diagnóstico de enfermedad COVID-19 por PCR en frotis nasofaringeo, esputo o broncoaspirado 3;

3-Ingreso en UCI con ventilación mecánica invasiva;

4-Consentimiento informado telefónico otorgado por familiares o representante legal.

E.4

Principal exclusion criteria

1-> 7 days of invasive mechanical ventilation, 2- Refractory shock (norepinephrine> 0.5 microg / Kg / min), 3- Decompensated liver cirrhosis 4- Chronic hemodialysis 5- Active neoplastic disease 6- Moderate or severe heart failure (NYHA III- IV), 7- Moderate-severe lung disease (GOLD III-IV), 8- HIV with AIDS criteria.

1- > 7 días de ventilación mecánica invasiva, 2- Shock refractario (noradrenalina > 0.5 microg/Kg/min), 3- Cirrosis hepática descompensada 4- Hemodiálisis crónica 5- Enfermedad neoplásica activa 6- Insuficiencia cardiaca moderada o grave (NYHA III-IV), 7- Enfermedad pulmonar moderada-grave (GOLD III-IV), 8- VIH con criterios SIDA.

E.5 End points

E.5.1

Primary end point(s)

Impact of plasma exchange on the rate and probability of survival 28 days after inclusion.

Impacto del recambio plasmático sobre la tasa y probabilidad de supervivencia a los 28 días de la inclusión

E.5.1.1

Timepoint(s) of evaluation of this end point

Impact of plasma exchange on the rate and probability of survival 28 days after inclusion.

Impacto del intercambio de plasma en la tasa y probabilidad de supervivencia a los 28 dias de la inclusión

E.5.2

Secondary end point(s)

1- Survival variables: rate and probability of survival in the ICU, in the hospital and at 90 days.

2- Days of mechanical ventilation, rate and days of vasoactive support and renal support.

3-Days of ICU stay, days of hospitalization.

4- Evolution of SOFA and APACHE score during the intervention period (from day 1 to day 7), at the time of ICU discharge.

5- Basic systemic inflammatory response: count of leukocytes and lymphocytes in peripheral blood, serum levels of PCR, procalcitonin, serum parameters of macrophage activation and microangiopathy (LDH, triglycerides, ferritin, D-dimer) at inclusion, daily during the period of intervention (from day 1 to day 7) and discharge from the ICU.

6- Advanced serum inflammatory mediators at inclusion, day 3 and day 7 (10 ml of blood = 30 ml): EGF, eotaxin, TGF-2, FGF-alpha, G-CSF, Fit-3L, GM-CSF, Fractalkine, IFNα2, IFNγ, GRO, IL-10, MCP-3, IL-12P40, MDC, IL-12P70, IL-13, IL-15, sCD40L, IL-17, IL-1RA, IL-1α, IL-9 , IL-1β, IL-2, IL-3, IL-4, IL-5, IL-6, IL-7, IL-8, IP-10, MCP-1, MIP-1α, MIP-1β, TNFα , TNFβ, VEGF, sICAM-1, sVCAM-1, tPAI-1, MIF (Milliplex MAP Human Cytokine / Chemokine Magnetic Bead Panel; Merck Millipore, Darmstadt, Germany; Luminex Corp., Austin, TX).
7- Whole blood for RNA sequencing at inclusion, day 3 and day 7 (6ml x3 = 18 ml; tempus tubes; Applied biosystems, Ambion).
8- plasma samples extracted the first 15 minutes of each refill (10ml x4 = 40ml
9- Safety variables: percentage of plasma changes associated with, at least one adverse event, related to the procedure or not.

1- Variables de supervivencia: tasa y probabilidad de supervivencia en UCI, en el hospital y a 90 días.

2- Días de ventilación mecánica, tasa y días de soporte vasoactivo y de soporte renal.

3-Días de estancia en UCI, días de hospitalización.

4- Evolución de SOFA y APACHE score durante el periodo de intervención (del día 1 al día 7), en el momento del alta de UCI .

5- Respuesta inflamatoria sistémica básica: recuento de leucocitos y linfocitos en sangre periférica, niveles séricos de PCR, procalcitonina, parámetros séricos de activación macrofágica y de microangiopatía (LDH, triglicéridos, ferritina, D-dímero) a la inclusión, diariamente durante el periodo de intervención (del día 1 al día 7) y al alta de UCI.

6- Mediadores séricos inflamatorios avanzados a la inclusión, día 3 y día 7 (10ml de sangre=30 ml): EGF, eotaxin,TGF-2, FGF-alpha, G-CSF, Fit-3L, GM-CSF, Fractalkine, IFNα2, IFNγ, GRO, IL-10, MCP-3, IL-12P40, MDC, IL-12P70, IL-13, IL-15, sCD40L, IL-17, IL-1RA, IL-1α, IL-9, IL-1β, IL-2, IL-3, IL-4, IL-5, IL-6, IL-7, IL-8, IP-10, MCP-1, MIP-1α, MIP-1β, TNFα, TNFβ, VEGF, sICAM-1, sVCAM-1, tPAI-1, MIF (Milliplex MAP Human Cytokine/Chemokine Magnetic Bead Panel; Merck Millipore, Darmstadt, Germany; Luminex Corp., Austin, TX).
7- Sangre total para secuenciación de RNA a la inclusión, día 3 y día 7 (6ml x3=18 ml; tempus tubes; Applied biosystems, Ambion).
8- muestras de plasma extraído los 15 primeros minutos de cada recambio (10ml x4= 40 ml
9- Variables de seguridad: porcentaje de recambios plasmáticos asociados a, al menos un evento adverso, relacionado con el procedimiento o no .

E.5.2.1

Timepoint(s) of evaluation of this end point

1- rate and probability of survival in the ICU, at 28 and 90 days.
2- Days of mechanical ventilation, frequency and days of vasoactive support and renal support.
3 days of being in the ICU, days of hospitalization.
4- Evolution of the SOFA and APACHE score (day 1 to day 7), discharge from the ICU and hospital.
5- Basic systemic inflammatory response: inclusion, daily during the intervention (from day 1 to day 7) and high ICU.
6- advanced serum inflammatory mediators at inclusion, day 3 and day 7:
7- Whole blood for RNA sequencing in the inclusion, day 3 and day 7.
8-plasma samples collected the first 15 minutes of each exchange
9-. Safety: associated with number of adverse events related or not to plasma exchange

1- tasa y probabilidad de supervivencia en la UCI, a los 28 y 90 días.
2- Días de ventilación mecánica, frecuencia y días de soporte vasoactivo y soporte renal.
3 días de estar en la UCI, días de hospitalización.
4- Evolución de la puntuación SOFA y APACHE ( día 1 al día 7), alta de la UCI yhospital.
5- Respuesta inflamatoria sistémica básica: inclusión, diariamente durante intervención (desde el día 1 hasta el día 7) y alta UCI.
6- mediadores inflamatorios séricos avanzados en la inclusión, día 3 y día 7:
7- Sangre completa para la secuenciación de ARN en la inclusión, día 3 y día 7.
8-muestras de plasma extraídas los primeros 15 minutos de cada intercambio
9-.Seguridad: asociados con numero de eventos adverso srelacionadoS o no al recambio plasmático

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

Yes

E.8.1.3

Single blind

E.8.1.4

Double blind

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)

Yes

E.8.2.2

Placebo

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

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

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

Yes

F.3.3.1

Women of childbearing potential not using contraception

F.3.3.2

Women of child-bearing potential using contraception

Yes

F.3.3.3

Pregnant women

Yes

F.3.3.4

Nursing women

Yes

F.3.3.5

Emergency situation

Yes

F.3.3.6

Subjects incapable of giving consent personally

Yes

F.3.3.6.1

Details of subjects incapable of giving consent

Informed consent will be obtained from a family or legal representative. Before discharge, the patient's consent will also be obtained if possible.

Se obtendrá el consentimiento informado de un familiar o representante legal. Antes del alta, también se obtendrá el consentimiento del paciente si es posible.

F.3.3.7

Others

F.4 Planned number of subjects to be included

F.4.1

In the member state

116

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

2020-04-23

Ethics Committee Opinion of the trial application

Favourable

Ethics Committee Opinion: Reason(s) for unfavourable opinion

Date of Ethics Committee Opinion

2020-04-21

P. End of Trial
P.	End of Trial Status	Prematurely Ended

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IMP with orphan designation in the indication
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