Clinical Trials Register

Summary
EudraCT Number:	2020-001442-19
Sponsor's Protocol Code Number:	IIBSP-COV-2020-23
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:	2020-04-03
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

2020-001442-19

A.3

Full title of the trial

Pilot, randomized, multicenter, open-label clinical trial of combined use of hydroxychloroquine, azithromycin, and tocilizumab for the treatment of SARS-CoV-2 infection (COVID-19)

Ensayo clínico piloto, aleatorizado, multicéntrico y abierto de uso combinado de hidroxicloroquina, azitromicina y tocilizumab para el tratamiento de la infección por SARS-CoV-2 (COVID-19)

A.3.1

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

Clinical trial of combined use of hydroxychloroquine, azithromycin, and tocilizumab for the treatment of COVID-19

Ensayo clínico para evaluar el uso combinado de hidroxicloroquina, azitromicina y tocilizumab para el tratamiento de COVID-19

A.3.2

Name or abbreviated title of the trial where available

TCOVID

TOCOVID

A.4.1

Sponsor's protocol code number

IIBSP-COV-2020-23

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	INSTITUT DE RECERCA H. SANTA CREU I SANT PAU
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	Instituto de Salud Carlos 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	INSTITUT DE RECERCA H. SANTA CREU I SANT PAU
B.5.2	Functional name of contact point	UICEC Sant Pau
B.5.3	Address:
B.5.3.1	Street Address	Sant Quintí 77-79
B.5.3.2	Town/ city	Barcelona
B.5.3.3	Post code	08041
B.5.3.4	Country	Spain
B.5.4	Telephone number	34935537636
B.5.5	Fax number	34935537860
B.5.6	E-mail	epenag@santpau.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	RoActemra
D.2.1.1.2	Name of the Marketing Authorisation holder	ROCHE REGISTRATION GMBH
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 syringe
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	TOCILIZUMAB
D.3.9.1	CAS number	375823-41-9
D.3.9.3	Other descriptive name	TOCILIZUMAB
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	equal
D.3.10.3	Concentration number	648
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.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

COVID19

E.1.1.1

Medical condition in easily understood language

COVID19

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

To evaluate in-hospital mortality or mechanical ventilation in the Intensive Care Unit (ICU), or need for a rescue dose of tocilizumab in patients with confirmed infection by COVID-19 in treatment with hydroxychloroquine and azithromycin combined or non-tocilizumab.

Evaluar la mortalidad intrahospitalaria o ventilación mecánica en la Unidad de Cuidados Intensivos (UCI), o necesidad de dosis de rescate de tocilizumab en los pacientes con infección confirmada por COVID-19 en tratamiento con hidroxicloroquina y azitromicina combinado o no tocilizumab.

E.2.2

Secondary objectives of the trial

To assess the clinical efficacy of tocilizumab in COVID-19 infection compared to the control arm by:

Clinical severity:
Patient score according to the WHO 7-point ordinal scale
National Early Warning Score (NEWS)
Oxygen therapy
Mechanic ventilation
Hospitalization
Mortality at 15, 30 and 90 days

To assess the safety of the intervention 30 days after treatment compared to the control arm.

To assess the safety of the intervention at 90 days of treatment compared to the control arm.
- Cumulative incidence of serious adverse effects (SAEs).
- Cumulative incidence of grade 3 and 4 adverse effects (AEs).
- Discontinuation or suspension of treatment for any reason.
- Changes in the white blood cell count, hemoglobin, platelets, creatinine, glucose, total bilirubin, AST, ALT, GGT, LDH, C-reactive protein, D-dimer, troponin, ferritin, fibrinogen, KL-6 during follow-up.

Evaluar la eficacia clínica del tocilizumab en la infección por COVID-19 comparado con la rama control mediante:

Severidad clínica:
Puntuación del paciente según la escala ordinal de 7 puntos de la OMS
National Early Warning Score (NEWS)
Oxigenoterapia
Ventilación mecánica
Hospitalización
Mortalidad a los 15, 30 y 90 días

Evaluar la seguridad de la intervención a los 30 días del tratamiento comparado con la rama control.

Evaluar la seguridad de la intervención a los 90 días de tratamiento comparado con la rama control.
- Incidencia acumulativa de efectos adversos graves (SAEs).
- Incidencia acumulativa de efectos adversos grado 3 y 4 (AEs).
- Discontinuación o suspensión del tratamiento por cualquier razón.
- Cambios en el recuento leucocitario, hemoglobina, plaquetas, creatinina, glucosa, bilirrubina total, AST, ALT, GGT, LDH, proteína C reactiva, dímero D, troponina, ferritina, fibrinógeno, KL-6 durante el seguimiento.

E.2.3

Trial contains a sub-study

E.3

Principal inclusion criteria

1. Subject (or authorized legal representative) who can provide written informed consent before beginning any study procedure.
2. Understand and agree to abide by the study procedures.
3. Adult ≥18 years of age at the time of inclusion in the study.
4. Confirmation of SARS-CoV-2 infection by a microbiological test performed before randomization, no longer than 72 hours.
5. Gravity 3-4 according to the WHO 7-point ordinal scale:
- Severity 3. Hospitalized, which does not require supplemental oxygen
- Severity 4. Hospitalized, requiring supplemental oxygen

1. Sujeto (o representante legal autorizado) que pueda proporcionar un consentimiento informado por escrito antes de iniciar cualquier procedimiento del estudio.
2. Entienda y acepte cumplir los procedimientos del estudio.
3. Adulto ≥18 años de edad en el momento de inclusión en el estudio.
4. Confirmación de la infección por SARS-CoV-2 mediante una prueba microbiológica realizada antes de la aleatorización, no mayor a 72 horas.
5. Gravedad 3-4 según la escala ordinal de 7 puntos de la OMS:
- Gravedad 3. Hospitalizado, que no requiere oxígeno suplementario
- Gravedad 4. Hospitalizado, que requiere oxígeno suplementario

E.4

Principal exclusion criteria

1. ALT / AST> 5 times the normal limit
2. Stage 4 chronic kidney disease (GFR <30) or requiring dialysis.
3. Presence of comorbidities that imply a poor prognosis (according to clinical judgment).
4. Advanced dementia.
5. Pregnancy or breastfeeding.
6. Forecast of transfer to another center in the 12 hours at the beginning of the study.
7. Allergy to study medication.
8. Serious or active bacterial infections or documented sepsis by pathogens other than SARS-CoV-2.
9. Streptococcus pneumoniae antigenuria positive before study start.
10. Neutropenia <500 / mm3.
11. Plateletpenia <100,000 / mm3.
12. History of diverticulosis.
13. Ongoing skin infection (eg, pyodermitis).
14. Transplanted patient under immunosuppressive treatment.
15. Previous evidence of latent untreated tuberculosis.

1. ALT/AST >5 veces el límite normal
2. Enfermedad renal crónica estadio 4 (FG<30) o que requiera diálisis.
3. Presencia de comorbilidades que impliquen mal pronóstico (según juicio clínico).
4. Demencia avanzada.
5. Embarazo o lactancia materna.
6. Previsión de traslado a otro centro en las 12 horas al inicio del estudio.
7. Alergia a la medicación de estudio.
8. Infecciones bacterianas activas o graves o sepsis documentada por otros patógenos diferentes de SARS-CoV-2.
9. Antigenuria de Streptococcus pneumoniae positivo antes de inicio del estudio.
10. Neutropenia <500/mm3.
11. Plaquetopenia <100.000/mm3.
12. Historia de diverticulosis.
13. Infección cutánea en curso (por ejemplo, piodermitis).
14. Paciente trasplantado en tratamiento inmunosupresor.
15. Evidencia previa de tuberculosis latente no tratada.

E.5 End points

E.5.1

Primary end point(s)

In-hospital mortality or need for mechanical ventilation in the Intensive Care Unit.

Mortalidad intrahospitalaria o necesidad de ventilación mecánica en la Unidad de Cuidados Intensivos.

E.5.1.1

Timepoint(s) of evaluation of this end point

During hospitalization

Durante la hospitalización

E.5.2

Secondary end point(s)

- Status of the ordinal scale evaluated on days 3, 5, 12, 15 and 30.
- Evaluate the NEWS scale on days 3, 5, 12, 15 and 30.
- Duration of oxygen therapy.
- Duration of mechanical ventilation (if applicable).
- Duration of hospitalization.
- Date and cause of death (if applicable).
- Grade 3 and 4 adverse effects.
- SAEs.
- Leukocyte count, hemoglobin, platelets, creatinine, glucose, total bilirubin, AST, ALT, GGT, LDH, C-reactive protein, D-dimer, troponin, KL-6, ferritin, fibrinogen on days 1, 3, 5, 12 ( while hospitalization lasts) and 30 (if possible or if you are still admitted).

- Estado de la escala ordinal evaluado en los días 3, 5, 12, 15 y 30.
- Evaluar la escala NEWS en los días 3, 5, 12, 15 y 30.
- Duración de la oxigenoterapia.
- Duración de la ventilación mecánica (si aplica).
- Duración de la hospitalización.
- Fecha y causa de la muerte (si aplica).
- Efectos adversos grado 3 y 4.
- SAEs.
- Recuento leucocitario, hemoglobina, plaquetas, creatinina, glucosa, bilirrubina total, AST, ALT, GGT, LDH, proteína C reactiva, dímero D, troponina, KL-6, ferritina, fibrinógeno en los días 1, 3, 5, 12 (mientras dure la hospitalización) y 30 (si es posible realizarla o está todavía ingresado).

E.5.2.1

Timepoint(s) of evaluation of this end point

3, 5, 12, 15 and 30 days

3, 5, 12, 15 y 30 días

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

Última visita del último sujeto

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:

276

F.1.3

Elderly (>=65 years)

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

276

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)

Expected normal treatment of the condition

Tratamiento habitual de la patología

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

2020-04-02

Ethics Committee Opinion of the trial application

Favourable

Ethics Committee Opinion: Reason(s) for unfavourable opinion

Date of Ethics Committee Opinion

2020-04-01

P. End of Trial
P.	End of Trial Status	Completed

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IMP with orphan designation in the indication
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