Clinical Trials Register

Summary
EudraCT Number:	2020-001531-27
Sponsor's Protocol Code Number:	SARICOR
National Competent Authority:	Spain - AEMPS
Clinical Trial Type:	EEA CTA
Trial Status:	Completed
Date on which this record was first entered in the EudraCT database:	2020-04-20
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

2020-001531-27

A.3

Full title of the trial

Clinical trial of Sarilumab in adults hospitalized with COVID-19 presenting cytokine release syndrome

Ensayo clínico de Sarilumab en adultos hospitalizados con COVID-19 que presentan síndrome de liberación de citoquinas

A.3.1

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

Clinical trial of Sarilumab in adults hospitalized with COVID-19

Ensayo clínico de Sarilumab en adultos hospitalizados con COVID-19

A.4.1

Sponsor's protocol code number

SARICOR

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	Fundación para la Investigación Biomédica de Córdoba
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	Consejería de Salud y Familias - Junta de Andalucía
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	Fundación para la Investigación Biomédica de Córdoba
B.5.2	Functional name of contact point	Antonio Luque
B.5.3	Address:
B.5.3.1	Street Address	Edificio IMIBIC. Avenida Menéndez Pidal s/n
B.5.3.2	Town/ city	Córdoba
B.5.3.3	Post code	14004
B.5.3.4	Country	Spain
B.5.4	Telephone number	0034671596070
B.5.5	Fax number	0034957736571
B.5.6	E-mail	uicec@imibic.org

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	Kevzara 200mg
D.2.1.1.2	Name of the Marketing Authorisation holder	Sanofi-Aventis groupe
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	Solution for injection in pre-filled pen
D.3.4.1	Specific paediatric formulation	No
D.3.7	Routes of administration for this IMP	Subcutaneous use
D.3.8 to D.3.10 IMP Identification Details (Active Substances)
D.3.8	INN - Proposed INN	SARILUMAB
D.3.9.1	CAS number	1189541-98-7
D.3.9.4	EV Substance Code	SUB177914
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	175
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	Yes
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	Kevzara 400mg
D.2.1.1.2	Name of the Marketing Authorisation holder	Sanofi-Aventis groupe
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	Solution for injection in pre-filled pen
D.3.4.1	Specific paediatric formulation	No
D.3.7	Routes of administration for this IMP	Subcutaneous use
D.3.8 to D.3.10 IMP Identification Details (Active Substances)
D.3.8	INN - Proposed INN	SARILUMAB
D.3.9.1	CAS number	1189541-98-7
D.3.9.4	EV Substance Code	SUB177914
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	175
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	Yes
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

SARS-CoV-2 infection causing respiratory disease and cytokine release syndrome

Infección por SARS-CoV-2 que causa enfermedad respiratoria y síndrome de liberación de citocinas

E.1.1.1

Medical condition in easily understood language

Coronavirus infection causing respiratory disease

Infección por coronavirus que causa enfermedad respiratoria

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	20.0
E.1.2	Level	LLT
E.1.2	Classification code	10051905
E.1.2	Term	Coronavirus infection
E.1.2	System Organ Class	100000004862

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	10001052
E.1.2	Term	Acute respiratory distress syndrome
E.1.2	System Organ Class	10038738 - Respiratory, thoracic and mediastinal disorders

E.1.3

Condition being studied is a rare disease

E.2 Objective of the trial

E.2.1

Main objective of the trial

Decrease cases of ARDS in adults requiring HFNO or either non-invasive or invasive mechanical ventilation

Disminuir los casos de síndrome del distress respiratorio del adulto que requieren oxigenación nasal de alto flujo (ONAF) o ventilación mecánica tanto no invasiva como invasiva

E.2.2

Secondary objectives of the trial

To reduce crude mortality at 28 days
To reduce the time (in days) to clinical improvement
To reduce the time (in days) until improvement in oxygenation for at least 48 hours
To reduce the proportion of patients who require invasive mechanical ventilation
To study the effect of the drug on the negativization of the PCR to COVID-19
To study the effect of the drug on the profile of cytokines
To study the safety of the experimental drug

Reducir la mortalidad cruda a los 28 días
Reducir el tiempo (en días) hasta la mejoría clínica
Reducir el tiempo (en días) hasta la mejoría en oxigenación durante al menos 48 horas
Reducir la proporción de pacientes que precisan ventilación mecánica invasiva
Estudiar el efecto del fármaco sobre la negativización de la PCR a COVID-19
Estudiar el efecto del fármaco sobre el perfil de citoquinas
Estudiar la seguridad del fármaco experimental

E.2.3

Trial contains a sub-study

E.3

Principal inclusion criteria

1. Age ≥ 18 years and <75 years
2. Admission for confirmed respiratory symptoms to COVID-19 based on a positive PCR in a sample of the respiratory tract in the local laboratory in the absence of respiratory distress syndrome requiring ONAF or mechanical ventilation
3. Interstitial pneumonia confirmed by chest radiography or CT
4. IL-6 levels> 40 pg / ml. In its absence, D-Dimer (DD)> 1500 or> 1000 may be included if progressive increases are documented
5. Negative pregnancy test in women of childbearing age
6. Signature of informed consent

1. Edad ≥ 18 años y < 75 años
2. Ingreso por cuadro respiratorio confirmado a COVID-19 en base a una PCR positiva en una muestra del tracto respiratorio en el laboratorio local en ausencia de síndrome de distress respiratorio que precise ONAF o ventilación mecánica
3. Neumonía intersticial confirmada por radiografía o TAC de tórax
4. Niveles de IL-6 > 40 pg/ml. En su ausencia puede incluirse Dímero D (DD) > 1500 ó > 1000 si se documenta incrementos progresivos
5. En mujeres en edad fértil, test de embarazo negativo
6. Firma de consentimiento informado

E.4

Principal exclusion criteria

1. SOFA score> 6 points
2. Patient who, in the researcher's opinion, is not a subsidiary of invasive mechanical ventilation
3. Neutrophil count <2 x 103 / μL
4. Platelet count <100 x 103 / μL
5. ALT or AST levels> 5 times the upper limit of normal
6. Severe renal failure (CrCr <30 ml / min)
7. Active bacterial infectious process
8. Active tuberculosis, history of not completing treatment against tuberculosis, suspicion of extrapulmonary tuberculosis
9. History of intestinal ulcer or diverticulitis
10. History of hypersensitivity reactions to Sarilumab or its excipients
11. Treatment with TNF antagonists
13. Previous treatment with anti-IL6 in the previous 30 days
14. Chronic prior treatment with corticosteroids at doses greater than 0.5 mg / kg / day of prednisone or equivalent. Yes, inhaled and topical corticosteroids are acceptable
15. Concomitant treatment with immunomodulators, among which are Vitamin D or statins. Macrolides such as azithromycin are acceptable
16. Patients on immunosuppressive treatment for any cause
17. HIV-infected patients with CD4 <200 / mm3
18. Past or current history of autoimmune disease or systemic inflammatory disease
19. Patients who have received or are planning therapy with immunomodulatory antibodies, including immunoglobulins
20. Participation in any clinical trial that evaluated any investigational product in the last 3 months or less than 5 half-lives of the investigational product
21. Pregnancy
22. Any other condition that, in clinical judgment, prevents adherence to the patient's protocol

1. SOFA score > 6 puntos
2. Paciente que a criterio del investigador no sea subsidiario de ventilación mecánica invasiva
3. Recuento de neutrófilos < 2 x 103/μL
4. Recuento de plaquetas < 100 x 103/μL
5. Niveles de ALT o AST > 5 veces el límite superior de la normalidad
6. Insuficiencia renal grave (ClCr < 30 ml/min)
7. Proceso infeccioso bacteriano activo
8. Tuberculosis activa, historia de no completar un tratamiento frente a la tuberculosis, sospecha de tuberculosis extrapulmonar
9. Antecedentes de úlcera intestinal o diverticulitis
10. Antecedentes de reacciones de hipersensibilidad a Sarilumab o a sus excipientes
11. Tratamiento con antagonistas de TNF
13. Tratamiento previo con anti-IL6 en los 30 días previos
14. Tratamiento previo de forma crónica con corticoides en dosis mayores a 0,5 mg/kg/día de prednisona o equivalente. Sí son aceptables los corticoides inhalados y tópicos
15. Tratamiento concomitante con inmunomoduladores, entre los que se encuentran Vitamina D o estatinas. Sí son aceptables los macrólidos como la azitromicina
16. Pacientes en tratamiento inmunosupresor por cualquier causa
17. Pacientes infectados por VIH con CD4 < 200/mm3
18. Historia pasada o actual de enfermedad autoinmune o enfermedad inflamatoria sistémica
19. Pacientes que han recibido o se prevea terapia con anticuerpos inmunomoduladores, incluidas inmunoglobulinas
20. Participación en cualquier ensayo clínico que evalué cualquier producto en investigación en los 3 últimos meses o inferior a 5 vidas medias del producto en investigación
21. Embarazo
22. Cualquier otra condición que a criterio clínico impidiera la adherencia al protocolo del paciente

E.5 End points

E.5.1

Primary end point(s)

Proportion of patients requiring or time (in days) until required:
- High flow nasal oxygenation (HFNO)
- Non-invasive mechanical ventilation type BiPAP
- Non-invasive mechanical ventilation type CPAP
- Invasive mechanical ventilation

Proporción de pacientes que requieren o tiempo (en días) hasta que se requiera:
- Oxigenación nasal del alto flujo (ONAF)
- Ventilación mecánica no invasiva tipo BiPAP
- Ventilación mecánica no invasiva tipo CPAP
- Ventilación mecánica invasiva

E.5.1.1

Timepoint(s) of evaluation of this end point

At day 28 or when the subject is discharged (whichever occurs first)

En el día 28 o cuando el sujeto es dado de alta (lo que ocurra primero)

E.5.2

Secondary end point(s)

a. Crude mortality at 28 days

b. Time to clinical improvement: defined as the mean change or time in days from randomization to any of the following criteria: (i) improvement of two points on the ordinal scale of 7 points of severity or, (ii) hospital discharge with lifetime. The criteria reached before are used. The 7 point gravity scale includes the following categories:
1 - Not hospitalized with normal activity
2 - Not hospitalized but unable to have normal activity
3 - Hospitalized, without requiring oxygen supplementation
4 - Hospitalized, requiring oxygen supplementation
5 - Hospitalized, requiring ONAF, non-invasive mechanical ventilation or both
6 - Hospitalized requiring ECMO, invasive mechanical ventilation or both
7 - Death

c. Time (in days) until improvement in oxygenation for at least 48 hours:
- Time to verify an increase in the SpO2 / FiO2 ratio with respect to the worst SpO2 / FiO2 prior to treatment with Sarilumab and stratified according to levels of IL-6 or DD
- Time to absence of oxygen requirement to maintain saturation in ambient air ≥ 93%
- Number of days in need of supplemental oxygen

d. Proportion of patients requiring invasive mechanical ventilation

e. Proportion of patients having negative COVID-19 CRP at each visit

f. Mean of serum cytokine levels: the panel of cytokines to quantify; IL1-��, IL1-β, IL6, IL8, IL10, IL12, IL18, IL38, INFɣ, TNF��, CCL2, CCL3, CCL4, MIF and PAI-1

g. Incidence of adverse events related to medication and its administration
h. Incidence in the appearance of serious bacterial, fungal or opportunistic infections
i. Incidence of perforation of the gastrointestinal tract
j. Leukocyte and neutrophil count mean
k. Mean hemoglobin levels
l. Platelet count mean
m. Average levels of creatinemia
n. Average bilirubin levels
o. ALT and AST average levels

a. Mortalidad cruda a los 28 días

b. Tiempo hasta la mejoría clínica: se define como cambio medio o tiempo en días desde la aleatorización a cualquiera de los siguientes criterios: (i) mejoría de dos puntos en la escala ordinal de 7 puntos de gravedad o, (ii) alta del hospital con vida. Se utiliza el criterio que se alcance antes. La escala de 7 puntos de gravedad incluye las siguientes categorías:
1 - No hospitalizado con actividad normal
2 - No hospitalizado pero incapaz de tener una actividad normal
3 - Hospitalizado, sin requerir suplemento de oxígeno
4 - Hospitalizado, requiriendo suplemento de oxígeno
5 - Hospitalizado, requiriendo ONAF, ventilación mecánica no invasiva o ambas
6 - Hospitalizado requiriendo ECMO, ventilación mecánica invasiva o ambas
7 - Muerte

c. Tiempo (en días) hasta la mejoría en oxigenación durante al menos 48 horas:
- Tiempo hasta constatar un incremento en la relación SpO2/FiO2 con respecto a la peor SpO2 / FiO2 previo al tratamiento con Sarilumab y estratificado según niveles de IL-6 o DD
- Tiempo hasta la ausencia de necesidad de oxígeno para mantener una saturación a aire ambiente ≥ 93%
- Número de días con necesidad de oxigeno suplementario

d. Proporción de pacientes que precisan ventilación mecánica invasiva

e. Proporción de pacientes que tienen PCR a COVID-19 negativa en cada visita

f. Media de los niveles de citoquinas séricas: el panel de citoquinas a cuantificar; IL1-��, IL1-β, IL6, IL8, IL10, IL12, IL18, IL38, INFɣ, TNF��, CCL2, CCL3, CCL4, MIF y PAI-1

g. Incidencia de eventos adversos relacionados con la medicación y su administración
h. Incidencia en la aparición de infecciones graves bacterianas, fúngicas u oportunistas
i. Incidencia de perforación del tracto gastrointestinal
j. Media de recuento de leucocitos y neutrófilos
k. Media de niveles de hemoglobina
l. Media de recuento de plaquetas
m. Niveles medios de creatinemia
n. Niveles medios de bilirrubina
o. Niveles medios de ALT y AST

E.5.2.1

Timepoint(s) of evaluation of this end point

At day 28 or when the subject is discharged (whichever occurs first)

En el día 28 o cuando el sujeto es dado de alta (lo que ocurra primero)

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)

E.8.2.2

Placebo

E.8.2.3

Other

Yes

E.8.2.3.1

Comparator description

Mejor terapia disponible

Best available therapy

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

Last visit of the last subject undergoing the trial

Última visita del último sujeto en el estudio

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

F.3.3.7

Others

F.4 Planned number of subjects to be included

F.4.1

In the member state

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

2020-04-18

Ethics Committee Opinion of the trial application

Favourable

Ethics Committee Opinion: Reason(s) for unfavourable opinion

Date of Ethics Committee Opinion

2020-04-16

P. End of Trial
P.	End of Trial Status	Completed
P.	Date of the global end of the trial	2021-04-06

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