Clinical Trials Register

Summary
EudraCT Number:	2020-001708-41
Sponsor's Protocol Code Number:	X-COVID19
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:	2020-06-24
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

2020-001708-41

A.3

Full title of the trial

Enoxaparin for thromboprophylaxis in hospitalized COVID-19 patients: comparison of 40 mg o.d. versus 40 mg b.i.d. A randomized Clinical Trial

Enoxaparina per la tromboprofilassi di pazienti ospedalizzati COVID-19 positivi: comparazione fra dosaggio di 40 mg in monosomministrazione versus 40 mg bigiornalieri. Un trial clinico randomizzato

A.3.1

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

Enoxaparin for thromboprophylaxis in hospitalized COVID-19 patients: comparison of 40 mg o.d. versus 40 mg b.i.d. A randomized Clinical Trial

Enoxaparina per la tromboprofilassi di pazienti ospedalizzati COVID-19 positivi: comparazione fra dosaggio di 40 mg in monosomministrazione versus 40 mg bigiornalieri. Un trial clinico randomizzato

A.3.2

Name or abbreviated title of the trial where available

X-COVID 19

A.4.1

Sponsor's protocol code number

X-COVID19

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 OSPEDALIERA AO OSPEDALE NIGUARDA CA' GRANDA
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	ASST Grande Ospedale Metropolitano Niguarda
B.5.2	Functional name of contact point	Segreteria Unità Intensive Cure Car
B.5.3	Address:
B.5.3.1	Street Address	Piazza Ospedale Maggiore 3
B.5.3.2	Town/ city	Milano
B.5.3.3	Post code	20162
B.5.3.4	Country	Italy
B.5.4	Telephone number	0264442576
B.5.5	Fax number	0264442566
B.5.6	E-mail	ucict@ospedaleniguarda.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	Enoxaparina sodica
D.3.2	Product code	[Enoxaparina sodica]
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.3.9.1	CAS number	9005-49-6
D.3.9.2	Current sponsor code	Enoxaparina sodica
D.3.9.4	EV Substance Code	NK
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	40
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.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

SARS-CoV-2 Infection

Infezione da SARS-CoV-2

E.1.1.1

Medical condition in easily understood language

SARS-CoV-2 Infection

Infezione da SARS-CoV-2

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	PT
E.1.2	Classification code	10070255
E.1.2	Term	Coronavirus test positive
E.1.2	System Organ Class	10022891 - Investigations

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 compare the effects of 40 mg subcutaneous enoxaparin o.d. versus 40 mg enoxaparin b.i.d on the incidence of venous thromboembolism (VTE) [a composite of incident asymptomatic and symptomatic proximal deep vein thrombosis (DVT) diagnosed by serial compression ultrasonography (CUS), and symptomatic pulmonary embolism (PE) diagnosed by CT scan], in patients with SARS-CoV-2 infection.

Confrontare l’effetto di 40 mg di enoxaparina subcutanea giornaliera con 40 mg di enoxaparina bigiornaliera sull’incidenza di tromboembolismo venoso (VTE) [un composito di incidente asintomatica o sintomatica trombosi di vena profonda prossimale (DVT) diagnosticata tramite ultrasonografia a compressione seriale (CUS) ed embolia sistematica polmonare (PE) diagnosticata tramite TAC], in pazienti con infezione da SARS-CoV-2.

E.2.2

Secondary objectives of the trial

To compare the effects of 40 mg subcutaneous enoxaparin o.d. versus 40 mg enoxaparin b.i.d on the incidence of in-hospital major complications, defined as the composite of death, VTE, use of mechanical ventilation, stroke, acute myocardial infarction and admission to an intensive care in patients with SARS-CoV-2.
• To compare each single component of the primary endpoint between the two groups.
• To compare maximum sequential organ failure assessment (SOFA) score between the two groups.
• To compare C-reactive protein, D-dimer, IL-6 and hs-troponin levels (as % above the upper reference limit [URL]) among the two groups.
• To compare the incidence of SARS-CoV-2-related Acute Respiratory Distress Syndrome (ARDS) between the two groups.
• To compare length of hospital stay between the two groups.
• To compare measures of right ventricular function at trans-thoracic echocardiography or CT between admission and follow-up, whenever available

• Confrontare l’effetto di 40mg di enoxaparina subcutanea giornaliera con 40mg di enoxaparina bigiornaliera sull’incidenza di complicanze maggiorni intra-ospedaliere, definite come un composito di morte, VTE, necessità di ventilazione meccanica, ictus, infarto miocardico acuto e trasferimento in Unità di Terapia Intensiva in pazienti con infezione da SARS-CoV-2.
• Confr. ogni singolo componente dell’endpoint primario tra i due gruppi.
• Confr. il valore massimo di disfuzione sequenziale d’organo (SOFA).
• Confr. i livelli di PCR, D-dimero, IL-6 e troponina ad alta sensibilità (come % di incremento rispetto al limite di riferimento superiore [URL]) tra i due gruppi.
• Confr. l’incidenza di Sindrome Acuta da Distress Respiratorio (ARDS) correlata a SARS-CoV-2 nei due gruppi.
• Confr. la durata dell’ospedalizzazione tra i due gruppi.
• Confr. le misurazioni della funzione ventricolare destra tramite ecocardiografia transtoracica o TC tra l’ingresso ed il follow-up, quando disponibile.

E.2.3

Trial contains a sub-study

E.3

Principal inclusion criteria

All-comers patients aged >=18 years and admitted to hospital with laboratory-confirmed SARS-CoV-2 infection.

Tutti i pazienti consecutivi con età >=18 anni ricoverati in ospedale con conferma laboratoristica di infezione da SARS-CoV-2.

E.4

Principal exclusion criteria

• Patients admitted directly to an intensive care unit;
• Estimated creatinine clearance <15 ml/min/1.73m2;
• Patients needing anticoagulant for prior indication;
• Patients treated with heparin at any increased dose compared to prophylactic regimen before enrolment;
• Patients at high bleeding risk or experiencing clinically significant bleeding;
• Patients involved in competitive clinical trials exploring antithrombotic treatments;
• Any other significant disease or disorder which, in the opinion of the investigator, may either put the participants at risk because of participation in the trial, or may influence the result of the trial, or the participant’s ability to participate in the trial

• Pazienti ricoverati direttamente in Unità di Terapia Intensiva;
• Stima della clearance della creatinina <15 ml/min/1.73m2;
• Pazienti che necessitino di anticoagulanti per precedenti indicazione;
• Pazienti trattati con eparina a qualsiasi dose superiore al regime profilattico prima dell’arruolamento;
• Presenza di sanguinamento clinicamente significativo e condizioni ad alto rischio emorragico;
• Arruolamento in altri trials clinici di tipo competitivo esplorativi per trattamenti antitrombotici;
• Qualsiasi altra malattia o condizione che, nell’opinione dell’investigatore, possa porre il partecipante a rischio a causa della partecipazione allo studio, o possa influenzare il risultato dello studio, o la capacità del soggetto di partecipare allo studio

E.5 End points

E.5.1

Primary end point(s)

E.5.1.1

Timepoint(s) of evaluation of this end point

30 days

30 giorni

E.5.2

Secondary end point(s)

• Confrontare l’effetto di 40mg di enoxaparina subcutanea giornaliera con 40mg di enoxaparina bigiornaliera sull’incidenza di complicanze maggiorni intra-ospedaliere, definite come un composito di morte, VTE, necessità di ventilazione meccanica, ictus, infarto miocardico acuto e trasferimento in Unità di Terapia Intensiva in pazienti con infezione da SARS-CoV-2.
• Confrontare ogni singolo componente dell’endpoint primario tra i due gruppi.
• Confrontare il valore massimo di disfuzione sequenziale d’organo (SOFA).
• Cofrontare i livelli di PCR, D-dimero, IL-6 e troponina ad alta sensibilità (come % di incremento rispetto al limite di riferimento superiore [URL]) tra i due gruppi.
• Confrontare l’incidenza di Sindrome Acuta da Distress Respiratorio (ARDS) correlata a SARS-CoV-2 nei due gruppi.
• Confrontare la durata dell’ospedalizzazione tra i due gruppi
• Confrontare le misurazioni della funzione ventricolare destra tramite ecocardiografia transtoracica o TC tra l’ingresso ed il follow-up, quando disponibile.

E.5.2.1

Timepoint(s) of evaluation of this end point

30 days

30 giorni

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

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

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

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:

2000

F.1.3

Elderly (>=65 years)

Yes

F.1.3.1

Number of subjects for this age range:

700

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 2020-06-24.

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

F.3.3.7

Others

F.4 Planned number of subjects to be included

F.4.1

In the member state

2712

F.4.2

For a multinational trial

F.4.2.1

In the EEA

2712

F.4.2.2

In the whole clinical trial

2712

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)

There are no specific post-study treatment or post-study care programmes.

Non sono previsti specifici programmi di trattamento o assistenza successivi al termine dello studio

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

2020-04-24

Ethics Committee Opinion of the trial application

Favourable

Ethics Committee Opinion: Reason(s) for unfavourable opinion

Date of Ethics Committee Opinion

2020-04-20

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

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