Clinical Trials Register

Summary
EudraCT Number:	2020-005291-35
Sponsor's Protocol Code Number:	ANTICIPANT
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:	2021-03-22
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

2020-005291-35

A.3

Full title of the trial

A multicenter randomized trial to evaluate the efficacy of tocilizumab in patients with severe Coronavirus Disease 2019 (Covid-19) pneumonia failing glucocorticoids.

Studio multicentrico randomizzato per valutare l'efficacia di tocilizumab in pazienti con polmonite severa da Coronavirus 2019 (Covid-19) che falliscono la terapia con glucocorticoidi.

A.3.1

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

A multicenter randomized trial to evaluate the efficacy of tocilizumab in patients with severe Coronavirus Disease 2019 (Covid-19) pneumonia failing glucocorticoids.

Studio multicentrico randomizzato per valutare l'efficacia di tocilizumab in pazienti con polmonite severa da Coronavirus 2019 (Covid-19) che falliscono la terapia con glucocorticoidi.

A.3.2

Name or abbreviated title of the trial where available

ANTICIPANT

A.4.1

Sponsor's protocol code number

ANTICIPANT

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	AOU POLICLINICO DI MODENA
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	Regione Emilia Romagna
B.4.2	Country	Italy
B.4.1	Name of organisation providing support	Fondazione Cassa di Risparmio di Modena
B.4.2	Country	Italy
B.5 Contact point designated by the sponsor for further information on the trial
B.5.1	Name of organisation	AOU di Modena
B.5.2	Functional name of contact point	Ufficio Sperimentazioni Cliniche
B.5.3	Address:
B.5.3.1	Street Address	via del Pozzo 71
B.5.3.2	Town/ city	Modena
B.5.3.3	Post code	41124
B.5.3.4	Country	Italy
B.5.5	Fax number	+390594222604
B.5.6	E-mail	nb.protocolli@unimore.it

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.2.5	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	tocilizumab
D.3.2	Product code	[DB06273]
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.3.9.2	Current sponsor code	DB06273
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	Information not present in EudraCT
D.3.11.3.2	Gene therapy medical product	Information not present in EudraCT
D.3.11.3.3	Tissue Engineered Product	Information not present in EudraCT
D.3.11.3.4	Combination ATIMP (i.e. one involving a medical device)	Information not present in EudraCT
D.3.11.3.5	Committee on Advanced therapies (CAT) has issued a classification for this product	Information not present in EudraCT
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

polmonite severa da coronavirus 2019

severe Coronavirus Disease 2019

E.1.1.1

Medical condition in easily understood language

polmonite severa da coronavirus 2019

severe Coronavirus Disease 2019

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	LLT
E.1.2	Classification code	10053983
E.1.2	Term	Corona virus infection
E.1.2	System Organ Class	100000004862

E.1.3

Condition being studied is a rare disease

E.2 Objective of the trial

E.2.1

Main objective of the trial

Evaluate the efficacy of tocilizumab in preventing intubation or death in patients with COVID-19 severe pneumonia who are deteriorating their respiratory function on glucocorticoids.

Valutare l'efficacia di tocilizumab nel prevenire l'intubazione o la morte in pazienti con polmonite grave da COVID-19 la cui funzione respiratoria peggiora in presenza di glucocorticoidi.

E.2.2

Secondary objectives of the trial

Valutare la corretta tempistica di somministrazione di tocilizumab.
Valutare la sicurezza di tocilizumab dopo glucocorticoidi.

Evaluate the correct timing for tocilizumab administration.
Evaluate the safety of tocilizumab after glucocorticoids.

E.2.3

Trial contains a sub-study

E.3

Principal inclusion criteria

• age>= 18 years;
• Informed consent for participation in the study;
• Polymerase Chain Reaction (Real-time PCR) diagnosis of Sars-CoV2 infection;
• Hospitalization;
• Clinical/instrumental diagnosis (high resolution chest computed tomography scan or chest x-ray or pulmonary ultrasound) of COVID-19 pneumonia;
• PaO2/FiO2 ratio in room air <250 mmHg and decreased by more than 20% and/or respiratory distress (RR> 30 bpm and/or use of accessory respiratory muscles) occurs despite treatment at least 36 hours from first dexamethasone dose. The interval has been chosen on the basis of clinical experience with the timing of clinical improvement after starting this treatment.
• An hyperinflammation condition defined by the presence of at least two of the following criteria at any time from admission: a) blood lymphocytes < 1000/mmc; b) ferritin > 500ng/mL; c) LDH > 300 U/L; d) D-dimers > 1000 ng/mL; e) Creactive protein > 3mg/dL

• età>= 18 anni;
• Consenso informato per la partecipazione allo studio;
• diagnosi di infezione da Sars-CoV2 (PCR);
• Ospedalizzazione;
• Diagnosi clinica/strumentale (tomografia computerizzata del torace ad alta risoluzione o radiografia del torace o ecografia polmonare) di polmonite COVID-19;
• Rapporto PaO2 / FiO2 in aria ambiente <250 mmHg e diminuito di oltre il 20% e /o distress respiratorio (RR> 30 atti resp /min e / o uso di muscoli respiratori accessori), nonostante il trattamento ad almeno 36 ore dalla prima dose di desametasone. L’intervallo è stato scelto sulla base dell’esperienza clinica in merito alla tempistica del miglioramento clinico dopo l’inizio di questo trattamento;
• una condizione di iperinfiammazione, definita dalla presenza di almeno 2 dei seguenti criteri in qualsiasi momento dal ricovero: a) linfociti < 1000/mmc; b) ferritina >500 ng/ml; c) LDH >300 U/L; d) D-Dimero> 1000ng/ml; e) PCR >3mmg/dL.

E.4

Principal exclusion criteria

• Patient with acute respiratory distress syndrome with PaO2/FiO2 ratio > 250 mmHg;
• Invasive ventilation (oro-tracheal intubation);
• Known hypersensitivity to TCZ or its excipients;
• Clinical conditions that contraindicate TCZ and cannot be treated or resolved according to the physician's judgment: e.g. Glutamate-pyruvate transaminase (GPT) or glutamine oxaloacetic transaminase (GOT) > 5 times the upper limit of the norm, Neutrophils < 500/mmc, Platelets < 50.000/mmc, Diverticulitis or intestinal perforation, suspicion of latent tuberculosis;
• Previous or concomitant use of other immune-modulants for COVID-19: anti-IL-1, JAK-inhibitors, other anti-IL-6
• PCT > 0.5 ng/mL

• Pazienti con sindrome da distress respiratorio acuto con rapporto PaO2 / FiO2> 250 mmHg;
• Ventilazione invasiva (intubazione oro-tracheale);
• Nota ipersensibilità al TCZ o ai suoi eccipienti;
• Condizioni cliniche che controindicano TCZ e non possono essere trattate o risolte secondo il giudizio del medico: ad es. Glutammato-piruvato transaminasi (GPT) o glutammina ossalacetica transaminasi (GOT)> 5 volte il limite superiore della norma, neutrofili <500 / mmc, piastrine <50.000 / mmc, diverticolite o perforazione intestinale, sospetto di tubercolosi latente;
• Uso precedente o concomitante di altri immunomodulanti per COVID-19: anti-IL-1, JAK-inibitori, altri anti-IL-6
• PCT > 0.5 ng/mL

E.5 End points

E.5.1

Primary end point(s)

The primary endpoint is defined by the occurrence, within 4 weeks of randomization, of one of these 3 events:
a) entry into ICU (Intensive Care Unit) with invasive mechanical ventilation;
b) death from all causes;
c) reaching a PaO2/FiO2 <130 mmHg in room air

L'endpoint primario è definito dal verificarsi, entro 4 settimane dalla randomizzazione, di uno di questi 3 eventi:
a) ingresso in ICU (Unità di Terapia Intensiva) con ventilazione meccanica invasiva;
b) morte per tutte le cause;
c) raggiungendo una PaO2 / FiO2 <130 mmHg nell'aria ambiente

E.5.1.1

Timepoint(s) of evaluation of this end point

4 weeks

4 settimane

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

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)

Yes

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

Yes

E.8.2.3.1

Comparator description

standard of care

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

Information not present in EudraCT

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

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:

200

F.1.3

Elderly (>=65 years)

Yes

F.1.3.1

Number of subjects for this age range:

200

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

640

F.4.2

For a multinational trial

F.4.2.1

In the EEA

640

F.4.2.2

In the whole clinical trial

640

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)

as per clinical practice

come da pratica clinica

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

2021-01-27

Ethics Committee Opinion of the trial application

Favourable

Ethics Committee Opinion: Reason(s) for unfavourable opinion

Date of Ethics Committee Opinion

2021-02-03

P. End of Trial
P.	End of Trial Status	Prematurely Ended
P.	Date of the global end of the trial	2022-09-16

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