Clinical Trials Register

Summary
EudraCT Number:	2020-001854-23
Sponsor's Protocol Code Number:	AMMURAVID
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:	2020-06-26
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

2020-001854-23

A.3

Full title of the trial

Cumulative adaptive, multiarm, multistage and multicentre randomized clinical trial with immunotherapy for Moderate COVID-19

Trial randomizzato cumulativo, adattivo, multibraccio, e multifase dell'immunoterapia per forme moderate di COVID-19

A.3.1

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

A study with immunotherapy for Moderate COVID-19

Studio dell'immunoterapia per forme moderate di COVID-19

A.3.2

Name or abbreviated title of the trial where available

AMMURAVID

A.4.1

Sponsor's protocol code number

AMMURAVID

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	SOCIETA' ITALIANA MALATTIE INFETTIVE E TROPICALI
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	AIFA
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	AOUI VERONA
B.5.2	Functional name of contact point	Malattie Infettive
B.5.3	Address:
B.5.3.1	Street Address	PIAZZALE SCURO 10
B.5.3.2	Town/ city	VERONA
B.5.3.3	Post code	37134
B.5.3.4	Country	Italy
B.5.4	Telephone number	0458128243
B.5.6	E-mail	evelina.tacconelli@univr.it

D. IMP Identification
D.IMP: 1
D.1.2 and D.1.3	IMP Role	Comparator
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	Plaquenil
D.2.1.1.2	Name of the Marketing Authorisation holder	Sanofi
D.2.1.2	Country which granted the Marketing Authorisation	Italy
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	Idrossiclorochina
D.3.2	Product code	[Idrossiclorichina]
D.3.4	Pharmaceutical form	Tablet
D.3.4.1	Specific paediatric formulation	No
D.3.7	Routes of administration for this IMP	Oral use
D.3.8 to D.3.10 IMP Identification Details (Active Substances)
D.3.8	INN - Proposed INN	IDROSSICLOROCHINA SOLFATO
D.3.9.2	Current sponsor code	idrossiclorochina
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	200
D.3.11 The IMP contains an:
D.3.11.1	Active substance of chemical origin	Yes
D.3.11.2	Active substance of biological/ biotechnological origin (other than Advanced Therapy IMP (ATIMP)	No
	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	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.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
D.2.1.1.2	Name of the Marketing Authorisation holder	Roche
D.2.1.2	Country which granted the Marketing Authorisation	Italy
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.3.2	Product code	[Tocilizumab]
D.3.4	Pharmaceutical form	Solution for injection
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.3.9.2	Current sponsor code	tocilizumab
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	162
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	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.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	Kevzara
D.2.1.1.2	Name of the Marketing Authorisation holder	SANOFI
D.2.1.2	Country which granted the Marketing Authorisation	Italy
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	sarilumab
D.3.2	Product code	[sarilumab]
D.3.4	Pharmaceutical form	Solution for injection
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.3.9.2	Current sponsor code	sarilumab
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	150
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	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.IMP: 4
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	SYLVANT
D.2.1.1.2	Name of the Marketing Authorisation holder	EUSA PHARMA
D.2.1.2	Country which granted the Marketing Authorisation	Italy
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	siltuximab
D.3.2	Product code	[siltuximab]
D.3.4	Pharmaceutical form	Powder and solvent for solution for injection
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.3.9.2	Current sponsor code	siltuximab
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	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.IMP: 5
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	Ilaris
D.2.1.1.2	Name of the Marketing Authorisation holder	Novartis
D.2.1.2	Country which granted the Marketing Authorisation	Italy
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	canakinumab
D.3.2	Product code	[canakinumab]
D.3.4	Pharmaceutical form	Powder for solution for injection
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	CANAKINUMAB
D.3.9.2	Current sponsor code	canakinumab
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	150
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	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.IMP: 6
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	Olumiant
D.2.1.1.2	Name of the Marketing Authorisation holder	ELI LILLY
D.2.1.2	Country which granted the Marketing Authorisation	Italy
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	Olumiant
D.3.2	Product code	[Olumiant]
D.3.4	Pharmaceutical form	Film-coated tablet
D.3.4.1	Specific paediatric formulation	No
D.3.7	Routes of administration for this IMP	Oral use
D.3.8 to D.3.10 IMP Identification Details (Active Substances)
D.3.8	INN - Proposed INN	BARICITINIB
D.3.9.2	Current sponsor code	baricitinib
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	2
D.3.8 to D.3.10 IMP Identification Details (Active Substances)
D.3.8	INN - Proposed INN	BARICITINIB
D.3.9.2	Current sponsor code	baricitinib
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	4
D.3.11 The IMP contains an:
D.3.11.1	Active substance of chemical origin	Yes
D.3.11.2	Active substance of biological/ biotechnological origin (other than Advanced Therapy IMP (ATIMP)	No
	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	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.IMP: 7
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	Urbason
D.2.1.1.2	Name of the Marketing Authorisation holder	SANOFI
D.2.1.2	Country which granted the Marketing Authorisation	Italy
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	Urbason
D.3.2	Product code	[Urbason]
D.3.4	Pharmaceutical form	Powder and solvent for solution for injection
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	METILPREDNISOLONE EMISUCCINATO SODICO
D.3.9.2	Current sponsor code	metilprednisolone
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	250
D.3.11 The IMP contains an:
D.3.11.1	Active substance of chemical origin	Yes
D.3.11.2	Active substance of biological/ biotechnological origin (other than Advanced Therapy IMP (ATIMP)	No
	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	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

COVID-19

E.1.1.1

Medical condition in easily understood language

COVID-19

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

The primary objective of this nation-wide randomised trial is to assess whether immunosuppressive agents in addition to hydroxicloroquine can reduce the progression to very severe respiratory failure with PaO2/FiO2 ratio < 200 mmHg (ARDS-range).

L’obiettivo primario è verificare se l’aggiunta di farmaci immunomodulatori all’idrossiclorochina e possa ridurre la progressione verso un’insufficienza respiratoria molto grave con PaO2/FiO2 ratio < 200 mmHg (outcome primario: evidenza di PaO2/FiO2 ratio < 200 mmHg entro il giorno 10).

E.2.2

Secondary objectives of the trial

The secondary objectives are to assess any effects of these immunomodulatory drugs on surrogate markers of COVID-19 severity and course with particular attention towards modelling kinetics of markers of immune response associated with disease evolution. Another secondary objective is to verify the safety of the immunomodulatory agents for during COVID-19. Surrogate markers of COVID-19 course will include:
a) Clinical deterioration, defined as at least one of the following:
• Death
• Need of orotracheal intubation/ECMO
• Increase in NEWS-2 score ¿ 2 from baseline
• Increase in MELD score ¿ 8 from baseline
b) Mortality
c) Need of orotracheal intubation or ECMO
d) Evolution of NEWS-2 and MELD scores
e) Clinical improvement, defined as one of the following
• Discharge
• Absent ventilator support, NEWS-2 score =3 and MELD =13
f) Discharge
g) Defervescence
h) Course of blood tests and PaO2/FiO2

Gli obiettivi secondari sono la verifica degli effetti degli immunomodulanti su marker surrogati di gravità ed evoluzione del COVID-19. Un altro obiettivo secondario è la valutazione della safety di queste terapie.
Marker surrogati dell’evoluzione e gravità del COVID-19 saranno:
a) Peggioramento clinico, definito come uno fra:
• Necessità di intubazione orotracheale/ECMO
• Incremento del punteggio NEWS-2 score ¿ 2 rispetto all’arruolamento
• Incremento del punteggio MELD score ¿ 8 rispetto all’arruolamento
b) Mortalità
c) Necessità di intubazione orotracheale/ECMO
d) Evoluzione dei punteggi di NEWS-2 e MELD
e) Miglioramento clinico, definito come uno fra:
• Dimissione
• Assenza di supporto ventilatorio, con punteggi di NEWS-2 =3 e MELD =13
f) Dimissione
g) Defervescenza
h) evoluzione degli esami ematochimici e del rapporto PaO2/FiO2

E.2.3

Trial contains a sub-study

E.3

Principal inclusion criteria

• Adults aged >= 18 years able to provide a valid informed consent to the study
• Documented COVID-19 according to local requirements, with pneumonia at imaging (Chest-X ray or CT)
• High inflammation, one of the following:
¿ CRP > 6 times UNL
¿ D-dimer > 1500 ng/ml
• PaO2/FiO2 250-400 mmHg

• Adulti >= 18 anni in grado di fornire un valido consenso alla partecipazione allo studio
• COVID-19 documentata secondo le line guida locali, con polmonite documentata all’imaging (Rx-torace or TC)
• Stato infiammatorio, uno fra:
¿ PCR > 6 volte UNL
¿ D-dimero > 1500 ng/ml
• PaO2/FiO2 >400-250 mmHg

E.4

Principal exclusion criteria

• Orotracheal intubation or ECMO support
• Active solid / hematologic cancer (including invasive non-melanoma skin cancer)
• Hypersensitivity or contra-indications to one of the investigational agents (including history of deep vein thrombosis / pulmonary thromboembolism or diverticulitis)
• Other active concurrent viral, fungal or bacterial infections (including active tuberculosis, HIV and HCV/HBV infections)
• Pregnancy/breastfeeding
• Incapability to provide a valid informed consent (including age < 18 years old)
• Heart failure with NYHA >= 2 or any acute cardiac or vascular event requiring therapy in the previous 12 months
• Chronic renal failure (baseline GFR < 45 ml/min*1.73m2)
• Liver cirrhosis moderate / severe (Child-Pugh B or C)
• Chronic respiratory failure requiring O2 therapy or ventilation therapy at home
• Blood neutrophils <500/mcL, platelet <50000/mcL, Hb levels <80 g/
• ALT/AST > 5 times UNL
• Use of any biologic agent or small molecule inhibitor and other investigational drugs in the previous 3 months (or 5 half-lives)
• Use of other immunosuppressive agents in the last 3 months
• Any other condition judged by the local investigator as a contra-indication to eligibility

• Intubazione orotracheale o ECMO
• Tumori maligni solidi o ematologici attivi (incluso tumori cutanei invasivi)
• Ipersensibilità o contro-indicazione a uno dei farmaci (inclusa la storia di tromboembolismo venoso o diverticolite)
• Altre infezioni attive di natura virale, fungine o batteriche (incluso tubercolosi attiva, HIV e HCV/HBV)
• Gravidanza ed allattamento
• Incapacità a provvedere un valido consenso informato
• Scompenso cardiaco di classe NYHA >= 2 o qualsiasi evento cardiaco o cardiovascolare richiedente terapia nei precedenti 12 mesi.
• Insufficienza renale cronica (GFR al baseline <45 ml/min*1.73m2)
• Cirrosi epatica moderata/severa (Child-Pugh B o C)
• Insufficienza respiratoria cronica necessitante ossigenoterapia o ventiloterapia al domicilio
• Neutrofili ematici <500/mcL, piastrine <50000/mcL, Hb <80 g/
• ALT/AST > 5 volte UNL
• Utilizzo di qualsiasi terapia biologica o piccolo molecole inibitori, and nei precedenti 3 mesi (o 5 emivite)
• Altre terapie immunosoppressive nei precedenti 3 mesi
• Qualsiasi condizione giudicata dallo Sperimentatore locale giudicata come una contra-indicazione all’eleggibilità

E.5 End points

E.5.1

Primary end point(s)

Proportion of patients with PaO2/FiO2 <200 mmHg at day 10 in each intervention arm as compared to the control arm

Frazione di pazienti con PaO2/FiO2 <200 mmHg al girono 10 in ogni braccio interventistico rispetto al braccio controllo

E.5.1.1

Timepoint(s) of evaluation of this end point

Day 10

Giorno 10

E.5.2

Secondary end point(s)

• Proportion of patients with PaO2/FiO2 <200 mmHg at day 7, 14, 21, 28 in each intervention arm as compared to the control arm
• Time to development very severe respiratory failure (PaO2/FiO2 <200 mmHg) in each intervention arm as compared to the control arm
• Proportion of patients with clinical deterioration at day 7, 10, 14, 21, 28 of each intervention arm as compared to the control arm
• Time to clinical deterioration of each intervention arm as compared to the control arm
• Proportion of number of AEs and SAEs (according to the Common Terminology Criteria for Adverse Events –CTCAE, Version 5.0) of each arm as compared to the control arm at day 7, 10, 14, 21, and 28
• Proportion of dead patients at day 7, 10, 14, 21, 28 of each intervention arm as compared to the control arm
• Survival analysis of each intervention arm as compared to the control arm
• Proportion of patients requiring orotracheal intubation/ECMO at day 7, 10, 14, 21, 28 of each intervention arm as compared to the control arm
• Comparison of the days with orotracheal intubation/ECMO in each interventional arm as compared to the control arm
• Comparison of the course in the NEWS-2 and MELD scores in each investigational arm as compared to the control arm
• Time to clinical improvement of each intervention arm as compared to the control arm
• Proportion of patients on persistent defervescence (last day of T>37°C, without recurrent T>37.0° for at least 4 days) at day 7, 10, 14, 21, 28 of each interventional arm as compared to the control arm
• Comparison of the time to persistent defervescence (last day of T>37°C, without recurrent T>37.0° for at least 4 days) of each interventional arm as compared to the control arm
• Proportion of patients discharged at day 7, 10, 14, 21, 28 of each interventional arm as compared to the control arm
• Time to discharge of each interventional arm as compared to the control arm
• Comparison of the course of blood test in the different arms:
¿ FBC
¿ Creatinine
¿ Bilirubin
¿ Albumin
¿ LDH
¿ AST/ALT
¿ CK
¿ CRP
¿ IL-6
¿ troponin T
¿ ferritin
¿ prothrombin-time (INR)
¿ lipid profile (triglycerides, HDL-cholesterol, TOTAL-cholesterol)
¿ D-dimer
¿ PaO2 (arterial gas analysis) and PaO2/FiO2

• Frazione di pazienti con PaO2/FiO2 <200 mmHg in ogni braccio interventistico rispetto al controllo
• Tempo di insorgenza di insufficienza respiratoria molto grava (PaO2/FiO2 <200 mmHg) in ogni braccio interventistico rispetto al controllo
• Frazione di pazienti con deterioramento clinico in ogni braccio interventistico rispetto al controllo
• Tempo al deterioramento clinico in ogni braccio interventistico rispetto al controllo
• Frazione di pazienti con eventi avversi ed eventi avversi gravi (secondo il Common Terminology Criteria for Adverse Events –CTCAE, Versione 5.0) in ogni braccio interventistico rispetto al controllo
• Frazione di pazienti deceduti in ogni braccio interventistico rispetto al controllo
• Curva di sopravvivenza in ogni braccio interventistico rispetto al controllo
• Frazione di pazienti necessitanti intubazione o ECMO in ogni braccio interventistico rispetto al controllo
• Giorni con intubazione o ECMO in ogni braccio interventistico rispetto al controllo
• Evoluzione dei punteggi NEWS-2 e MELD in ogni braccio interventistico rispetto al controllo
• Tempo al miglioramento clinico in ogni braccio interventistico rispetto al controllo
• Frazione di pazienti sfebbrati in ogni braccio interventistico rispetto al controllo
• Tempo allo sfebbramento in ogni braccio interventistico rispetto al controllo
• Frazione di pazienti dimessi in ogni braccio interventistico rispetto al controllo
• Tempo alla dimissione in ogni braccio interventistico rispetto al controllo
• Evoluzione degli esami di laboratorio in the different arms:
¿ emocromo
¿ Creatinina
¿ Bilirubina
¿ Albumina
¿ LDH
¿ AST/ALT
¿ CK
¿ PCR
¿ IL-6
¿ troponina T
¿ ferritina
¿ INR
¿ Profilo lipidico
¿ D-dimero
¿ PaO2 (emogas) e PaO2/FiO2

E.5.2.1

Timepoint(s) of evaluation of this end point

Day 7, 10, 14, 21, 28

Giorno 7, 10, 14, 21, 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

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

Yes

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)

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

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

Information not present in EudraCT

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 last subject

Ultima visita ultimo paziente

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:

800

F.1.3

Elderly (>=65 years)

Yes

F.1.3.1

Number of subjects for this age range:

600

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

1400

F.4.2

For a multinational trial

F.4.2.1

In the EEA

1400

F.4.2.2

In the whole clinical trial

1400

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

Nessuno

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

2020-04-27

Ethics Committee Opinion of the trial application

Favourable

Ethics Committee Opinion: Reason(s) for unfavourable opinion

Date of Ethics Committee Opinion

2020-04-27

P. End of Trial
P.	End of Trial Status	Prematurely Ended
P.	Date of the global end of the trial	2022-07-01

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