Clinical Trials Register

Summary
EudraCT Number:	2020-001437-12
Sponsor's Protocol Code Number:	COVID-19_ASS
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:	2020-04-13
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

2020-001437-12

A.3

Full title of the trial

Random, controlled, open, one-site clinical trial in adult patients with COVID-19 severe pneumonia treated with immunomodulatory drugs

ENSAYO CLÍNICO ALEATORIZADO, CONTROLADO, ABIERTO, UNICÉNTRICO, DE TRATAMIENTO INMUNOMODULADOR EN PACIENTES ADULTOS CON NEUMONIA GRAVE COVID-19

A.3.1

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

Random, controlled, open, one-site clinical trial in adult patients with COVID-19 severe pneumonia treated with immunomodulatory drugs

ENSAYO CLÍNICO ALEATORIZADO, CONTROLADO, ABIERTO, UNICÉNTRICO, DE TRATAMIENTO INMUNOMODULADOR EN PACIENTES ADULTOS CON NEUMONIA GRAVE COVID-19

A.4.1

Sponsor's protocol code number

COVID-19_ASS

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 Hospital Universitari Vall d'Hebron - Institut de Recerca (VHIR)
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	Fundació Hospital Universitari Vall d'Hebron - Institut de Recerca (VHIR)
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	Fundació Hospital Universitari Vall d'Hebron - Institut de Recerca (VHIR)
B.5.2	Functional name of contact point	Salvador Augustin
B.5.3	Address:
B.5.3.1	Street Address	Passeig Vall d'Hebron, 119
B.5.3.2	Town/ city	Barcelona
B.5.3.3	Post code	08035
B.5.3.4	Country	Spain
B.5.4	Telephone number	0034934893000

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	Sandimmun
D.2.1.1.2	Name of the Marketing Authorisation holder	Novartis Farmacéutica, S.A.
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.3.4	Pharmaceutical form	Concentrate for 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	CICLOSPORIN
D.3.9.1	CAS number	59865-13-3
D.3.9.4	EV Substance Code	SUB06250MIG
D.3.10	Strength
D.3.10.1	Concentration unit	mg/kg milligram(s)/kilogram
D.3.10.2	Concentration type	range
D.3.10.3	Concentration number	10 to 15
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.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	RoActemra
D.2.1.1.2	Name of the Marketing Authorisation holder	EU/1/08/492/010
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	RoActemra
D.3.4	Pharmaceutical form	Concentrate for 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	TOCILIZUMAB
D.3.9.1	CAS number	375823-41-9
D.3.9.4	EV Substance Code	SUB20313
D.3.10	Strength
D.3.10.1	Concentration unit	mg milligram(s)
D.3.10.2	Concentration type	range
D.3.10.3	Concentration number	800 to 1200
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	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.IMP: 3
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	Sandimmun
D.2.1.1.2	Name of the Marketing Authorisation holder	Novartis Farmacéutica, S.A.
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.3.4	Pharmaceutical form	Capsule, soft
D.3.4.1	Specific paediatric formulation	No
D.3.7	Routes of administration for this IMP	Oral use
D.3.8 to D.3.10 IMP Identification Details (Active Substances)
D.3.8	INN - Proposed INN	CICLOSPORIN
D.3.9.1	CAS number	59865-13-3
D.3.9.4	EV Substance Code	SUB06250MIG
D.3.10	Strength
D.3.10.1	Concentration unit	mg milligram(s)
D.3.10.2	Concentration type	equal
D.3.10.3	Concentration number	75
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

E. General Information on the Trial

E.1 Medical condition or disease under investigation

E.1.1

Medical condition(s) being investigated

Severe COVID-19 pneumonia

Neumonía grave COVID-19

E.1.1.1

Medical condition in easily understood language

Severe COVID-19 pneumonia

Neumonía grave COVID-19

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	21.1
E.1.2	Level	PT
E.1.2	Classification code	10035737
E.1.2	Term	Pneumonia viral
E.1.2	System Organ Class	10021881 - Infections and infestations

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 mortality impact at 28 days of an immunomodulatory strategy with 2 treatment regimens stratified according to IL-6 plasma levels, administered in addition to standard treatment, in adult patients with severe COVID-19 pneumonia.

Evaluar el impacto en mortalidad a 28 días de una estrategia inmunomoduladora con 2 pautas de tratamiento estratificadas según niveles plasmáticos de IL-6, administradas en adición al tratamiento estándar, en pacientes adultos con neumonía grave COVID-19.

E.2.2

Secondary objectives of the trial

To assess the impact of this strategy on the following variables: premature mortality (48 hours, 7 days and at hospital), mortality at intensive care unit, days of mechanical ventilation, virus clearance (viral clearance / viral shedding), time to normalization of oxygen saturation , time to defervescence, improvement of inflammatory reaction, days of hospitalization, days of intubation, safety and tolerability of the intervention

Evaluar el impacto de dicha estrategia en las siguientes variables: mortalidad precoz (48 horas, 7 días y hospitalaria), mortalidad en UCI, días de ventilación mecánica, aclaramiento del virus (viral clearance / viral shedding), tiempo hasta normalización de saturación de oxígeno, tiempo hasta defervescencia, mejoría de reacción inflamatoria, días de hospitalización, días intubación, seguridad y tolerabilidad de la intervención

E.2.3

Trial contains a sub-study

E.3

Principal inclusion criteria

1. Age 18-80 years
2. Severe COVID-19 pneumonia definied as:
- Nasnopharyngeal smear SARS-CoV-2 PCR positive
- Pulmonary infiltrates by simple X-ray (or other technique) compatible with pneumonia
- One or more of the following criteria:
o Room air oxygen saturation <= 94% measured by pulse oximeter
o Pa:FiO2 (partial pressure O2/fraction of inspired O2) <=300
o Sa:FiO2 (O2 saturation measured by pulse oximeter/ fraction of inspired O2) <=350
3. Informed Consent according to protocol instructions.

1. Edad 18-80 años
2. Neumonía grave COVID-19 definida como:
- Frotis nasofaríngeo con PCR positiva para SARS-CoV-2
- Infiltrados pulmonares por Rx simple (u otra técnica) compatibles con neumonía
- Uno o más de los siguientes criterios:
o Saturación de oxígeno aire ambiente <= 94% medida con pulsioxímetro
o Pa:FiO2 (presión parcial O2/fracción de O2 inspirado) <=300
o Sa:FiO2 (saturación de O2 medida con pulsioxímetro/ fracción de O2 inspirado) <=350
3. Consentimiento informado (especificaciones sobre la obtención del mismo desarrolladas en el protocolo)

E.4

Principal exclusion criteria

1. GOT/GPT > 5 the institutional ULN
2. Neutrophils < 500 cell/mmc.
3. Petelet < 50.000 cell/mmc.
4. Documented sepsis o pneumonia different from COVID-19.
5. According to clinician criteria, comorbilities with poor prognosis
6. Compliate Diverticulitis or bowel perforation
7. Current skin infection (p.e piodermitis)
8. According to the clinician criteria, any contraindication for using inmunomodulator tretament.

1. AST/ALT con valores superiores a 5 veces los niveles de normalidad.
2. Neutrófilos < 500 cell/mmc.
3. Plaquetas < 50.000 cell/mmc.
4. Sepsis o neumonía documentada por otros patógenos que no sean COVID-19.
5. Presencia de comorbilidad que puede llevar según juicio clínico a mal pronostico
6. Diverticulitis complicada o perforación intestinal
7. Infección cutánea en curso (p.e piodermitis)
8.Cualquier otra contraindicación al uso de tratamiento inmunomodulador individualizada según criterio clínico de equipo asistencial tratante

E.5 End points

E.5.1

Primary end point(s)

Mortality at day 28 after treatment initiation (proportion of patient died that day)

Mortalidad a los 28 días de inicio del tratamiento (proporción de pacientes muertos a dicho día)

E.5.1.1

Timepoint(s) of evaluation of this end point

Day 28 after treatment initiation

Día 28 tras inicio del tratamiento

E.5.2

Secondary end point(s)

- Mortality at 48 hours, 7 days, at Intensive Care Unit and at hospital
- Days with mechanical ventilation, days at Intensive Care Unit and days at hospital
- Viral clearance (viral clearance / viral shedding)
- Time until normal Oxygen saturation
- Time until defervescence
- Inflamatory reaction improvement (IL1b, IL12, IL2, TNF, IFN, IL2Rs, IL6, Il10, ferritine, D-dimer, triglycerides, lymphopenia, protein C reactive, VSG)
- Frequency and severity of adverse events according to common scales, proportion of patients drop-out due adverse events. Secondary infections.
- Plasmatic parameters, direct or indirect: IL1b, IL12, IL2, TNF, IFN, IL2Rs, IL6, Il10, ferritine, D-dimer, triglycerides, lymphopenia, protein C reactive, VSG)
- Clinic Oxygenation parameters (PaO2, pulse oximetry).
- Viral Clearance (viral clearance / viral shedding): PCR SARS-CoV-2 control.
- Standard Intensive Care Unit parameters: SOFA and APACHE II at hospitalisation, intubation day, mechanical ventilation withdrawal day, Intensive Care Unit discharge, Hospital discharge.

- Mortalidad 48 horas, 7 días, en UCI y hospitalaria
- Días de ventilación mecánica, estancia en UCI, hospitalización
- Aclaramiento del virus (viral clearance / viral shedding)
- Tiempo hasta normalización de saturación de oxígeno
- Tiempo hasta defervescencia
- Mejoría de reacción inflamatoria (IL1b, IL12, IL2, TNF, IFN, IL2Rs, IL6, Il10, ferritina, Dímero D, triglicéridos, linfopenia, proteína C reactiva, VSG)
- Frecuencia y gravedad de efectos adversos según escalas habituales, proporción de pacientes en los que se retira la intervención por efectos adversos. Infecciones oportunistas o secundarias

El resto del manejo diagnóstico y terapéutico será, en todos los brazos, el que se esté realizando según protocolo vigente del centro en cada momento. Entre los parámetros que se medirán, cabe destacar en relación al ensayo:
- Parámetros plasmáticos directos e indirectos de tormenta citocínica: IL1b, IL12, IL2, TNF, IFN, IL2Rs, IL6, Il10, ferritina, Dímero D, triglicéridos, linfopenia, proteína C reactiva, VSG.
- Parámetros clínicos de oxigenación (PaO2, pulsioximetría).
- Aclaramiento del virus (viral clearance / viral shedding): PCR SARS-CoV-2 control.
- En paciente de UCI, parámetros habituales: SOFA y APACHE II al ingreso, dia intubación, dia retirada ventilación mecánica, dia de alta UCI, dia alta hospital.

E.5.2.1

Timepoint(s) of evaluation of this end point

48 hours
7 days
Stay days
Mechanical ventilation days

48 horas
7 días
Días de estancia
Días de ventilación mecánica

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)

E.7.3

Therapeutic confirmatory (Phase III)

E.7.4

Therapeutic use (Phase IV)

Yes

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

Yes

E.8.4

The trial involves multiple sites in the 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

Day 28 or hospital discharge

Día 28 o alta hospitalaria

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:

145

F.1.3

Elderly (>=65 years)

Yes

F.1.3.1

Number of subjects for this age range:

145

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

F.3.3.3

Pregnant women

F.3.3.4

Nursing women

F.3.3.5

Emergency situation

Yes

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

290

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)

According to SOC

De acuerdo a las guías terapéuticas del centro

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

2020-04-09

Ethics Committee Opinion of the trial application

Favourable

Ethics Committee Opinion: Reason(s) for unfavourable opinion

Date of Ethics Committee Opinion

2020-04-08

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

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