Clinical Trials Register

Summary
EudraCT Number:	2020-001162-12
Sponsor's Protocol Code Number:	EFC16844
National Competent Authority:	Italy - Italian Medicines Agency
Clinical Trial Type:	EEA CTA
Trial Status:	Completed
Date on which this record was first entered in the EudraCT database:	2020-03-31
Trial results	View 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

2020-001162-12

A.3

Full title of the trial

An adaptive phase 2/3, randomized, double-blind, placebo-controlled, study assessing efficacy and safety of sarilumab for hospitalized patients with COVID-19

Studio adattativo di fase 2/3, randomizzato, in doppio cieco, controllato verso placebo, per valutare l’efficacia e la sicurezza di sarilumab in pazienti ospedalizzati affetti da COVID-19

A.3.1

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

.Sarilumab COVID-19

A.4.1

Sponsor's protocol code number

EFC16844

A.5.3

WHO Universal Trial Reference Number (UTRN)

U1111-1249-6021

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	Sanofi-aventis Recherche et Développement
B.1.3.4	Country	France
B.3.1 and B.3.2	Status of the sponsor	Commercial
B.4 Source(s) of Monetary or Material Support for the clinical trial:
B.4.1	Name of organisation providing support	Sanofi-aventis Recherche et Développement
B.4.2	Country	France
B.5 Contact point designated by the sponsor for further information on the trial
B.5.1	Name of organisation	SANOFI S.P.A.
B.5.2	Functional name of contact point	CONTACT POINT
B.5.3	Address:
B.5.3.1	Street Address	VIALE BODIO, 37/B
B.5.3.2	Town/ city	MILANO
B.5.3.3	Post code	20158
B.5.3.4	Country	Italy
B.5.4	Telephone number	800226343
B.5.5	Fax number	00290239394168
B.5.6	E-mail	informazioni.medicoscientifiche@sanofi.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	Kevzara®
D.2.1.1.2	Name of the Marketing Authorisation holder	Sanofi-Aventis Groupe
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.3.4	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	Intravenous use
D.3.8 to D.3.10 IMP Identification Details (Active Substances)
D.3.8	INN - Proposed INN	SARILUMAB
D.3.9.2	Current sponsor code	SAR153191
D.3.9.4	EV Substance Code	SUB177914
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	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)	Yes
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
D.8 Placebo: 1
D.8.1	Is a Placebo used in this Trial?	Yes
D.8.3	Pharmaceutical form of the placebo	Solution for injection
D.8.4	Route of administration of the placebo	Intravenous use

E. General Information on the Trial

E.1 Medical condition or disease under investigation

E.1.1

Medical condition(s) being investigated

Corona virus Infection

Infezione da Coronavirus

E.1.1.1

Medical condition in easily understood language

Corona virus infection

Infezione da Coronavirus

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	20.0
E.1.2	Level	LLT
E.1.2	Classification code	10051905
E.1.2	Term	Coronavirus 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

Phase 2: To evaluate the clinical efficacy of sarilumab relative to the control arm in adult patients hospitalized with severe COVID-19
Phase 3: To evaluate the clinical efficacy of sarilumab relative to thecontrol arm in adult patients hospitalized with severe or critical COVID-19

Valutare l’efficacia clinica di sarilumab rispetto al braccio di controllo in pazienti adulti ricoverati con COVID-19 grave
Valutare l’efficacia clinica di sarilumab rispetto al braccio di controllo in pazienti adulti ricoverati con COVID-19 grave o critico

E.2.2

Secondary objectives of the trial

Evaluate the clinical efficacy of sarilumab compared to the control arm by clinical severity, changes in the National Early Warning Score 2, duration of predefined symptoms and signs, duration of supplemental, oxygen dependency, incidence of new mechanical ventilation use, the duration of new mechanical ventilation use, need for admission into ICU, duration of hospitalization, 28-day mortality rate.
Secondary safety objectives are to evaluate the safety of sarilumab compared to the control arm as assessed by incidence of: SAEs, Grade 4 neutropenia (ANC<500/mm3) with concurrent severe or life-threatening bacterial, invasive fungal, or opportunistic infection, Grade >/= 2 infusion related reactions, Grade >/= 2 hypersensitivity reactions, Increase in ALT >/= 3X ULN (for patients with normal baseline) or >3X ULN and at least 2-fold increase from baseline value (for patients with abnormal baseline), Invasive bacterial or fungal infections of clinical significance with confirmed diagnosis

Valutare efficacia clinica di sarilumab rispetto a braccio di controllo per gravità clinica,cambiamenti NEWS2,durata di sintomi e segni predefiniti,durata della dipendenza da ossigeno supplement,incidenza di nuovo utilizzo di ventilaz meccanica,durata del nuovo utilizzo di ventilaz meccanica,necessità di ricovero in unità di terapia intensiva,durata del ricovero,tasso di mortalità a 28 gg
Obiettivi secondari di sicurezza sono valutare sicurezza di sarilumab rispetto a braccio di controllo,valutata come incidenz di:
SAE
Neutropenia gr4(conta ass dei neutrofili<500/mm3)con infez batterica, micotica invasiva o opportunistica grave o potenzialmente letale concomitante
Reazioni correlate all’infusione gr>/=2
Reazioni ipersensibilità gr>/=2
Aumento di ALT>/=3XULN (per pts con valori basali normali)o>3XULN E almeno 2 volte maggiore rispetto al valore basale (per pts con valori basali anomali)
Infezioni batteriche o micotiche invasive di rilevanza clinica con diagnosi confermata

E.2.3

Trial contains a sub-study

E.3

Principal inclusion criteria

Participants must have severe disease, multi-system organ dysfunction or critical disease
Laboratory-confirmed SARS-CoV-2 infection

I partecipanti devono avere una malattia grave, disfunzionalità d’organo multi sistemica o malattia critica
Infezione da SARS_CoV-2 confermata da analisi di laboratorio

E.4

Principal exclusion criteria

Unlikely to survive for >48 hours from screening
Presence of neutropenia less than 2000/mmˆ3, AST or ALT greater than 5 X ULN, platelets less than 50,000/mmˆ3
Prior immunosuppressive therapies
Use of chronic oral corticosteroids for non-COVID-19 related condition
Past or current history of autoimmune or inflammatory disease(s)
Known or suspected history of tuberculosis
Suspected or known active systemic bacterial or fungal infections

improbabile che sopravviva per >48 ore dallo screening
Presenza di neutropenia con neutrofili <2.000/mm3, AST o ALT superiore a 5 x ULN, piastrine <50.000 per mm3
Precedenti terapie immunosoppressive
Uso di corticosteroidi cronici per via orale per una patologia non correlata a COVID-19
Anamnesi pregressa o in corso di una o più malattie autoimmuni o infiammatorie
Anamnesi nota o sospetta di Tubercolosi
Infezioni batteriche o micotiche sistemiche sospette o note

E.5 End points

E.5.1

Primary end point(s)

Phase 2: time to resolution of fever for at least 48 hours without antipyretics or until discharge, whichever is sooner
Phase 3: The percentage of patients reporting each severity rating on the 7-point ordinal scale

Fase2: tempo alla risoluzione della febbre per almeno 48 ore senza antipiretici o fino a dimissione, a seconda di quale evento si verifichi prima
Fase 3: percentuale di pazienti che segnalano una qualsiasi valutazione di gravità sulla scala ordinale a 7 punti

E.5.1.1

Timepoint(s) of evaluation of this end point

Baseline to Day 29

Dal basale al giorno 29

E.5.2

Secondary end point(s)

Phase 2
1- The time to improvement in oxygenation
2- Mean change in 7-point ordinal scale from baseline to Day 15
3- Clinical status using the 7-point ordinal scale at Day 15
4- Time to improvement of two categories from admission using the 7- point ordinal

Phase 2 and 3
5- Time to resolution of fever
6- Time to improvement in oxygenation
7- Time to resolution of fever and improvement in oxygenation
8- Time to change in NEWS2 from baseline
9- Time to NEWS2 of <2 and maintained for 24 hours
10- Mean change from baseline to days 3, 5, 8, 11, 15, and 29 in NEWS2
11- Days with fever
12- Alive off supplemental oxygen at day 29
13- Days of resting respiratory rate >24 breaths/min
14- Days of hypoxemia
15- Days of supplemental oxygen use
16- Time to saturation >/= 94% on room air
17- Ventilator free days in the first 28 days (to day 29)
18- The number of patients with Initiation of mechanical ventilation, non-invasive ventilation, or use of high flow nasal cannula
19- The number of patients transferred to the ICU or the need to transfer to the ICU (if the ICU is not available)
20- Days of hospitalization among survivors
21- Incidence of death
Phase 3
22- Mean change in the 7-point ordinal scale from baseline to days 3, 5, 8, 11, 15, and 29 (or until discharge)
23- Clinical status using the 7-point ordinal scale at days 3, 5, 8, 11,15, and 29
24- Time to improvement of two categories from admission using the 7- point ordinal scale
Phase 2 and 3
25- Incidence of serious adverse events
26- The incidence of major or opportunistic bacterial or fungal infections
27- The incidence of major or opportunistic bacterial or fungal infections in patients with grade 4 neutropenia
28- The incidence of hypersensitivity reactions, infusion reactions, gastrointestinal perforation
29- The number of patients with clinically significant laboratory abnormalities.

Fase 2:
1. Tempo al miglioramento dell’ossigenazione
2. Variazione media nella scala ordinale a 7 punti dal basale al Giorno 15
3. Stato clinico usando la scala ordinale a 7 punti nel Giorno 15
4. Tempo al miglioramento di due categorie dal ricovero usando la scala ordinale a 7 punti

Fase 2 e 3:
5. Tempo alla risoluzione della febbre
6. Tempo al miglioramento dell’ossigenazione
7. Tempo alla risoluzione della febbre e al miglioramento dell’ossigenazione
8. Tempo al cambiamento del National Early Warning Score 2 (NEWS2) dal basale
9. Tempo a NEWS2 <2 e mantenuto per 24 ore
10. Variazione media rispetto al basale ai Giorni 3, 5, 8, 11, 15, 29 in NEWS2
11. Giorni con febbre
12. In vita senza necessità di ossigeno supplementare al giorno 29
13. Giorni di frequenza respiratoria a riposo >24 respiri/min
14. Giorni di ipossiemia
15. Giorni di uso di ossigeno supplementare
16. Tempo alla saturazione >/= 94% ad aria ambiente
17. Giorni senza ventilatore nei primi 28 giorni (al Giorno 29)
18. Numero di pazienti con avvio di ventilazione meccanica, non invasiva o uso di cannula nasale ad alto flusso
19. Numero di pazienti trasferiti in UTI o che necessitano di essere trasferiti in UTI (se l’UTI non è disponibile)
20. Giorni di ricovero tra i sopravvissuti
21. Incidenza di morte

Fase 3
22. Variazione media nella scala ordinale a 7 punti dal basale ai Giorni 3, 5, 8, 11, 15 e 29 (o fino alla dimissione)
23. Stato clinico usando la scala ordinale a 7 punti nei Giorni 3, 5, 8, 11, 15 e 29
24. Tempo al miglioramento di due categorie dal ricovero usando la scala ordinale a 7 punti
Fase 2 -3
25. Incidenza di eventi avversi seri
26. Incidenza di infezioni batteriche o micotiche importanti o opportunistiche
27. Incidenza di infezioni batteriche o micotiche importanti o opportunistiche nei pazienti con neutropenia di grado 4
28. Incidenza di reazioni di ipersensibilità, reazioni da infusione, perforazione gastrointestinale
29. Numero di pazienti con anomalie di laboratorio clinicamente significative

E.5.2.1

Timepoint(s) of evaluation of this end point

1, 4 to 9, 11 to 17, 24 : Baseline to Day 29
2-3 : Baseline to Day 15
10 : Baseline to Days 3, 5, 8, 11, 15 and 29
18 to 21, 25 to 29 : Baseline to Day 60
22 : Baseline to days 3, 5, 8, 11, 15, and 29 (or until discharge)
23 : Days 3, 5, 8, 11,15, and 29

1, da 4 a 9, da 11 a 17, 24: dal basale al giorno 29
2-3: Dal basale al giorno 15
10: dal basale ai giorni 3, 5, 8, 11, 15 e29
Da 18 a 21, da 25 a 29 : dal Basale al giorno 60
22 : dal basale ai giorni 3, 5, 8, 11, 15, e 29 (o fino a dimissione)
23 : Giorni 3, 5, 8, 11,15, e 29

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

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)

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

E.8.1.3

Single blind

E.8.1.4

Double blind

Yes

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

Yes

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

Yes

E.8.5.1

Number of sites anticipated in the EEA

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

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 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:

184

F.1.3

Elderly (>=65 years)

Yes

F.1.3.1

Number of subjects for this age range:

276

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 2020-03-31.

Yes

F.3.3.2

Women of child-bearing potential using contraception

Yes

F.3.3.3

Pregnant women

Yes

F.3.3.4

Nursing women

Yes

F.3.3.5

Emergency situation

F.3.3.6

Subjects incapable of giving consent personally

Yes

F.3.3.6.1

Details of subjects incapable of giving consent

Legally acceptable representative may provide informed consent.

Rappresentante legale può fornire il consenso informato

F.3.3.7

Others

F.4 Planned number of subjects to be included

F.4.1

In the member state

F.4.2

For a multinational trial

F.4.2.1

In the EEA

240

F.4.2.2

In the whole clinical trial

460

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

2020-03-25

Ethics Committee Opinion of the trial application

Favourable

Ethics Committee Opinion: Reason(s) for unfavourable opinion

Date of Ethics Committee Opinion

2020-03-25

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

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