Clinical Trials Register

Summary
EudraCT Number:	2020-001386-37
Sponsor's Protocol Code Number:	RCT-TCZ-COVID-19
National Competent Authority:	Italy - Italian Medicines Agency
Clinical Trial Type:	EEA CTA
Trial Status:	Prematurely Ended
Date on which this record was first entered in the EudraCT database:	2020-04-02
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

Italy - Italian Medicines Agency

A.2

EudraCT number

2020-001386-37

A.3

Full title of the trial

Uno studio randomizzato multicentrico in aperto per valutare l’efficacia della somministrazione precoce del Tocilizumab (TCZ) in pazienti affetti da polmonite da COVID-19.

A.3.1

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

Efficacy of Tocilizumab - COVID-19

Efficacia del Tocilizumab - COVID-19

A.3.2

Name or abbreviated title of the trial where available

TOCI-RE

A.4.1

Sponsor's protocol code number

RCT-TCZ-COVID-19

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	Azienda Unità Sanitaria Locale-IRCCS di Reggio Emilia
B.1.3.4	Country	Italy
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
B.4.2	Country
B.5 Contact point designated by the sponsor for further information on the trial
B.5.1	Name of organisation	F. Hoffmann-La Roche Ltd
B.5.2	Functional name of contact point	Trial Information Support Line-TISL
B.5.3	Address:
B.5.3.1	Street Address	Grenzacherstrasse 124
B.5.3.2	Town/ city	Basel
B.5.3.3	Post code	4070
B.5.3.4	Country	Switzerland
B.5.6	E-mail	global.rochegenentechtrials@roche.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 20 mg/mL concentrato per soluzione per infusione – flacone 20 ml (400 mg)
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 20 mg/mL concentrato per soluzione per infusione – flacone 20 ml (400 mg)
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	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	RoActemra 20 mg/mL concentrato per soluzione per infusione – flacone 10 ml (200 mg)
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 20 mg/mL concentrato per soluzione per infusione – flacone 10 ml (200 mg)
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	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: 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	RoActemra 20 mg/mL concentrato per soluzione per infusione – flacone 4 ml (80 mg)
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 20 mg/mL concentrato per soluzione per infusione – flacone 4 ml (80 mg)
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	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

COVID-19 infection

infezione da Covid-19

E.1.1.1

Medical condition in easily understood language

COVID-19 pneumonia

Polmonite da COVID-19

E.1.1.2

Therapeutic area

Diseases [C] - Respiratory Tract Diseases [C08]

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

L’obiettivo generale di questo studio è valutare se la terapia precoce con Tocilizumab è in grado di ridurre il numero dei pazienti con polmonite da SARS-CoV2 che richiedono una ventilazione meccanica.

E.2.2

Secondary objectives of the trial

1. Confrontare l’efficacia del Tocilizumab in termini di ingresso in Terapia Intensiva con ventilazione meccanica invasiva in due gruppi:
a. pazienti nei quali è somministrato precocemente come da protocollo
b. pazienti nei quali viene somministrato all’aggravamento clinico (per un rapporto PaO2/FiO2 < 150)
2. Confrontare l’efficacia del Tocilizumab in termini di mortalità per tutte le cause in due gruppi:
a. pazienti nei quali è somministrato precocemente come da protocollo
b. pazienti nei quali viene somministrato all’aggravamento clinico (per un rapporto PaO2/FiO2 < 150) oppure nelle prime 24 ore dopo l’ingresso in Terapia Intensiva.
3. valutare la tossicità del Tocilizumab.
4. Valutare i livelli di IL-6 e PCR e loro correlazione con l’efficacia del trattamento
5. Valutare i livelli di ferritina, LDH e D-dimero e loro correlazione con l’effetto del trattamento
6. valutarne l’andamento del rapport PaO2 / FiO2
7. Valutare l’andamento nel tempo della conta dei linfociti

E.2.3

Trial contains a sub-study

E.3

Principal inclusion criteria

La popolazione in studio include i pazienti con polmonite da Covid-19 di recente insorgenza che richiedono assistenza ospedaliera, ma non procedure di ventilazione meccanica invasiva o semi-invasiva.
1. età > 18 anni
2. Consenso informato per la partecipazione allo studio
3. Diagnosi real time PCR dell'infezione da Sars-CoV2
4. Ricovero in Ospedale a causa della diagnosi clinica/strumentale (TAC torace ad alta risoluzione, Rx torace o ecografia polmonare)
5. Presenza di sindrome da distress respiratorio acuta con PaO2/FiO2 compresi tra 200 e 300 mm/Hg
6. Presenza di esagerata risposta infiammatoria definita dalla presenza di almeno 1 dei seguenti 3 criteri:
 Almeno una misurazione della temperatura corporea superiore ai 38°C negli ultimi due giorni;
 Proteina C reattiva sierica maggiore o uguale a 10 mg/dl
 Incremento della PCR di almeno 2 volte il valore basale

E.4

Principal exclusion criteria

1. Paziente con sindrome da distress respiratorio con PaO2/FiO2 < 200 mm/Hg o in ventilazione non invasiva o in ventilazione invasiva o presenza di shock o presenza di concomitante insufficienza d’organo che richiede ammissione all’Unità di Cura Intensiva
2. Insufficienza cardiaca e renale gravi
3. Paziente gravida o in allattamento
4. Paziente che, a giudizio del clinico o per espressa volontà del paziente, non andrà in terapia intensiva indipendentemente dall’evoluzione del quadro polmonare.
5. Ipersensibilità nota al Tocilizumab o ai suoi eccipienti
6. Paziente in trattamento con immunodepressori o farmaci antirigetto
7. Infezioni attive note o altre condizioni cliniche che controindicano Tocilizumab e non possono essere trattate o risolte secondo il giudizio del medico
8. ALT o AST > 5 volte il limite superiore della norma
9. Neutrofili < 500/mmc
10. Piastrine < 50.000/mmc
11. Diverticolite o perforazione intestinale
12. Sospetto clinico di tubercolosi latente

E.5 End points

E.5.1

Primary end point(s)

Comparsa di uno di questi 3 eventi:
a. entrata in Terapia Intensiva con ventilazione meccanica invasiva
b. morte per tutte le cause
c. aggravamento clinico documentato dal riscontro di un rapporto PaO2/FiO2 < 150mm/Hg ad una delle misurazioni di EGA programmate o ad una misurazione in urgenza, ma comunque confermata da un secondo esame negativo entro 4 ore

E.5.1.1

Timepoint(s) of evaluation of this end point

14 giorni dalla randomizzazione

E.5.2

Secondary end point(s)

La valutazione degli endpoint secondari viene fatta seguendo l’ordine con cui sono presentati gli obiettivi dello studio. Più precisamente:
1. ingresso in Terapia Intensiva con ventilazione meccanica invasiva
2. mortalità per tutte le cause
3. tossicità misurata secondo gli standard internazionalmente riconosciuti

E.5.2.1

Timepoint(s) of evaluation of this end point

14 giorni dalla randomizzazione

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

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

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

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.8.5

The trial involves multiple Member States

Yes

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

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.1.3

Elderly (>=65 years)

Yes

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 For clinical trials recorded in the database before the 10th March 2011 this question read: "Women of childbearing potential" and did not include the words "not using contraception". An answer of yes could have included women of child bearing potential whether or not they would be using contraception. The answer should therefore be understood in that context. This trial was recorded in the database on 2020-04-02.

Yes

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

398

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)

viene confrontata la somministrazione precoce del Tocilizumab verso la somministrazione del Tocilizumab all’aggravamento. Più specificatamente:
• il braccio sperimentale riceverà la terapia con Tocilizumab entro 8 ore dall’ingresso in studio + la terapia standard.
• il braccio di controllo riceverà la terapia standard. In caso di aggravamento o di ingresso in terapia intensiva, i pazienti riceveranno Tocilizumab

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

2020-03-27

Ethics Committee Opinion of the trial application

Favourable

Ethics Committee Opinion: Reason(s) for unfavourable opinion

Date of Ethics Committee Opinion

2020-03-27

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

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