Clinical Trials Register

Summary
EudraCT Number:	2020-002032-69
Sponsor's Protocol Code Number:	COVITOZ-01
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:	2020-05-05
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

2020-002032-69

A.3

Full title of the trial

Single-center, randomized, open-label clinical trial on the efficacy of tocilizumab in modifying the inflammatory parameters of patients with COVID-19

Ensayo clínico unicéntrico, aleatorizado y abierto, sobre la eficacia de tocilizumab en la modificación de los parámetros inflamatorios de pacientes con COVID-19

A.3.1

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

Clinical trial on the efficacy of tocilizumab in modifying the inflammatory parameters of patients with COVID-19

Ensayo clínico sobre la eficacia de tocilizumab en la modificación de los parámetros inflamatorios de pacientes con COVID-19

A.4.1

Sponsor's protocol code number

COVITOZ-01

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 del Hospital Universitario Ramón y Cajal
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	Fundación para la Investigación Biomédica del Hospital Universitario Ramón y Cajal
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	Dynamic Science S.L.
B.5.2	Functional name of contact point	Departamento de Ensayos Clínicos
B.5.3	Address:
B.5.3.1	Street Address	c/ Azcona, 31
B.5.3.2	Town/ city	Madrid
B.5.3.3	Post code	28028
B.5.3.4	Country	Spain
B.5.4	Telephone number	0034914561105
B.5.5	Fax number	0034914561126
B.5.6	E-mail	ensayosclinicos@dynasolutions.com

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	European Union
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.3.9.3	Other descriptive name	TOCILIZUMAB
D.3.9.4	EV Substance Code	SUB20313
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	20
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

Non-severe pneumonia caused by COVID-19

Neumonía no grave por COVID-19

E.1.1.1

Medical condition in easily understood language

Pneumonia caused by COVID-19

Neumonía por 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	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.1.3

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 administering two different tocilizumab regimens versus the standard of care on IL-12 levels in patients with non-severe COVID-19 pneumonia.

Evaluar el impacto sobre los niveles de IL-12 de la administración de dos pautas diferentes de tocilizumab, en comparación con el estándar de cuidados, en pacientes con neumonía no grave por COVID-19.

E.2.2

Secondary objectives of the trial

1. To evaluate and compare the clinical course and mortality of the patients assigned to the three treatment groups.
2. To evaluate and compare other inflammatory parameters and their changes over time in patients assigned to the three treatment groups.
3. To assess the safety of tocilizumab treatment for mild-to-moderate COVID-19 pneumonia.
4. To evaluate and compare pharmacokynetics of tocilizumab based on regimens administered

1. Evaluar y comparar la evolución clínica y la mortalidad de los pacientes asignados a los tres grupos de tratamiento.
2. Evaluar y comparar otros parámetros inflamatorios y su evolución temporal en los pacientes asignados a los tres grupos de tratamiento
3. Evaluar la seguridad del tratamiento con TCZ para la neumonía leve-moderada por COVID-19
4. Evaluar y comparar la farmacocinética de tocilizumab según la pauta recibida.

E.2.3

Trial contains a sub-study

E.3

Principal inclusion criteria

1. Patients over 18 years old and under 80 years old who have given their informed consent. This will be collected verbally and will be recorded in the medical record by the investigator.
2. The patient is diagnosed with mild-moderate SARS-CoV-2 pneumonia confirmed microbiologically ≤7 days before randomization, and presents:
a. Basal oxygen saturation> 90%
b. IL-6 levels> 40 pg / ml
c. CURB-65 ≤1
d. PaO2 / FiO2≥300 or SatO2/FiO2≥315
3. The patient is hospitalized or meets hospital admission criteria.
4. The patient is not expected to enter the ICU or die in the next 24 hours.

1. Pacientes mayores de 18 años y menores de 80 años que hayan prestado su consentimiento informado. Éste se recogerá verbalmente y quedará registrado en la historia clínica por el médico investigador.
2. El paciente está diagnosticado de neumonía leve-moderada por SARS-CoV-2 confirmada microbiológicamente ≤7 días antes de la aleatorización, y presenta:
a. Saturación basal de oxígeno >90%
b. Niveles de IL-6 >40 pg/ml
c. CURB-65 ≤1
d. PaO2/FiO2≥300 o SatO2/FiO2≥315
3. El paciente se encuentra hospitalizado o cumple criterios de ingreso hospitalario.
4. El paciente no se espera que entre en UCI o fallezca en las siguientes 24h.

E.4

Principal exclusion criteria

1. Participants in another simultaneous clinical trial.
2. Use of other immunomodulators.
3. Coinfection with the hepatitis B virus (detectable AgSup-HBV).
4. Pregnancy (or planning to become pregnant during the course of the study), or lactation period.
5. Presence of laboratory abnormalities of grade ≥ 4.

1. Participantes en otro ensayo clínico simultáneo.
2. Uso de otros inmunomoduladores.
3. Coinfección por el virus de la hepatitis B (AgSup-VHB detectable).
4. Embarazo (o planificación de quedarse embarazada durante el transcurso del estudio), o periodo de lactancia.
5. Presencia de alteraciones de laboratorio de grado ≥ 4.

E.5 End points

E.5.1

Primary end point(s)

Mean increase in IL-12 levels in the 3 study groups from the start of treatment (D0) to days D+1 and D+3.
A mean difference >0.2 units between any of the three study groups will be considered a significant response in terms of IL-12 levels.

Incremento medio de los valores de IL-12 en los 3 grupos de estudio desde el inicio del tratamiento (D0) y en los días D+1 y D+3.
Se considerará una respuesta clínica significativa en términos de niveles de IL-12 una diferencia media superior a 0,2 pg/ml entre cualquiera de los tres grupos de estudio.

E.5.1.1

Timepoint(s) of evaluation of this end point

Day 0, day +1 and Day +3

Día 0, día +1 y día +3

E.5.2

Secondary end point(s)

• Percentage of patients per group with cure/improvement/progression of pneumonia at D+3, D+7, and D+28.
• Proportion of patients with PaO2/FiO2 <300 (or SatO2/FiO2 ≤315) at some point over their course.
• All-cause mortality throughout 28 days.
• Length of hospital stay.
• Percentage of patients requiring ICU admission.
• Length of ICU stay.
• IL-12 levels at D+7
• IL-10, IL-1, IL-6, IL-17 and IFN-gamma levels at D0, D+1, D+3 and D+7
• IL-6, procalcitonin (PCT), C-reactive protein (CRP), D-dimer y ferritin levels at D0, D+1, D+3 and D+7.
• Pharmacokinetic endpoints: Cmin, Cmax, Cmedia, Tmax and AUC on days D0, D + 1, D + 3 and D + 7.
• Serious and non-serious adverse events.
• Adverse events leading to treatment discontinuation.
• Number of deaths.
• Abnormalities in laboratory findings unrelated to COVID-19 disease.

• Porcentaje de pacientes por grupo con progresión de la neumonía en el D+3, D+7 y D+28.
• Proporción de pacientes con PaO2/FiO2 <300 o SatO2/FiO2 ≤315) en algún momento de la evolución.
• Mortalidad por todas las causas a los 28 días.
• Duración de la estancia hospitalaria.
• Porcentaje de pacientes que requieren ingreso en UCI.
• Duración de la estancia en UCI.
• Niveles de IL-12 en el D+7.
• Niveles de IL-10 en los días D0, D+1, D+3 y D+7.
• Niveles de IL-10, IL-1, IL-6, IL-17 e IFN-gamma en los días D0, D+1, D+3 y D+7.
• Niveles de procalcitonina (PCT), proteína C-reactiva (PCR), dímero D y ferritina en los días D0, D+1, D+3 y D+7.
• Farmacocinética: Cmin, Cmax, Cmedia, Tmax y AUC en los días D0, D+1, D+3 y D+7.
• Eventos adversos y eventos adversos graves
• Frecuencia de efectos adversos que conlleven la interrupción del tratamiento
• Número de muertes
• Frecuencia de alteraciones de laboratorio no directamente relacionados con la enfermedad por COVID-19

E.5.2.1

Timepoint(s) of evaluation of this end point

Day 0, day +1, day +3, day +7, day +28.

Día 0, día +1, día +3, día +7, día +28.

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

Yes

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

Tratamiento habitual/estándar de cuidados

Routine/standard 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

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

LVLS

UVUP

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 years

E.8.9.2

In all countries concerned by the trial months

E.8.9.2

In all countries concerned by the trial 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

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

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

Tratamiento estándar

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

2020-05-04

Ethics Committee Opinion of the trial application

Favourable

Ethics Committee Opinion: Reason(s) for unfavourable opinion

Date of Ethics Committee Opinion

2020-04-29

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

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