Clinical Trials Register

Summary
EudraCT Number:	2020-002035-30
Sponsor's Protocol Code Number:	TOFACOV-2
National Competent Authority:	Italy - Italian Medicines Agency
Clinical Trial Type:	EEA CTA
Trial Status:	Ongoing
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

2020-002035-30

A.3

Full title of the trial

TOFAcitinib plus Hydroxycloroquine vs Hydroxycloroquine in patients with early onset SARS-CoV2 (COVID-19) interstitial pneumonia: a multicenter randomized controlled open label trial

Tofacitinib associato ad Idrossiclorochina confrontato con Idrossiclorochina in pazienti con polmonite associata ad infezione da COVID-19 in fase precoce: trial randomizzato controllato, multicentrico, in aperto

A.3.1

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

Multicenter, randomized, open trial comparing Tofacitinb together with Hydroxycloroquine vs Hydroxycloroquine alone in patients affected by COVID-19 related pneumonitis.

Studio randomizzato multicentrico di confronto tra Tofacitinib associato ad Idrossiclorochina (ICQ) e Idrossiclorochina da sola nel trattamento di pazienti con forme precoci di polmonite da COVID-19

A.3.2

Name or abbreviated title of the trial where available

Tofactinib+HYQ vs HYQ in early COVID-19 pneuminitis

Tofacitinib+ICQ vs ICQ nel trattamento della polmonite da COVID-19

A.4.1

Sponsor's protocol code number

TOFACOV-2

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 OSPEDALIERO-UNIVERSITARIA OSPEDALI RIUNITI DI ANCONA
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	ospedali riuniti ancona
B.5.2	Functional name of contact point	clinica medica
B.5.3	Address:
B.5.3.1	Street Address	via conca 71
B.5.3.2	Town/ city	ancona
B.5.3.3	Post code	60126
B.5.3.4	Country	Italy
B.5.6	E-mail	giovanni.pomponio@ospedaliriuniti.marche.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.2.1.1.1	Trade name	XELJANZ -
D.2.1.1.2	Name of the Marketing Authorisation holder	PFIZER EUROPE MA EEIG
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	tofacitinib
D.3.2	Product code	[L04AA29]
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	JNK INIBITORE (AS604748)
D.3.9.1	CAS number	477600-75-2
D.3.9.2	Current sponsor code	0000
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	5
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	Yes
D.3.11.13.1	Other medicinal product type	TOFACITINIB
D.IMP: 2
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 - 200 MG COMPRESSE RIVESTITE 30 COMPRESSE
D.2.1.1.2	Name of the Marketing Authorisation holder	SANOFI-AVENTIS S.P.A.
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	[P01BA02]
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.3.9.1	CAS number	118-42-3
D.3.9.2	Current sponsor code	00000
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.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-CoV2 related Interstitial Pneumonia

Polmonite interstiziale sostenuta da infezione da SARS-CoV2

E.1.1.1

Medical condition in easily understood language

COVID-19 related pneumonitis

Polmonite da COVID 19 in fase precoce

E.1.1.2

Therapeutic area

Diseases [C] - Respiratory Tract Diseases [C08]

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	10076502
E.1.2	Term	Viral pneumonitis
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

The main aim of the study (primary outcome) is to verify the effect of adding Tofacitinib to the standard therapy in order to reduce the rate of patients who need mechanical ventilation and/or oro-tracheal intubation.

Verificare l'effetto dell'aggiunta di Tofacitinib alla terapia standard con Idrossiclorochina nel ridurre la percentuale di pazienti che necessitano di ventilazione meccanica e/o intubazione

E.2.2

Secondary objectives of the trial

Other aims are to verify the safety of TOFA-HYQ combination in these patients and to individuate clinical and/or laboratory factors predictive of good clinical response.

verificare la sicurezza della combinazione tofacitinib-idrossiclorochina in questa patologia e individuare fattori clinici e/o di laboratorio predittivi di buona risposta clinica

E.2.3

Trial contains a sub-study

E.3

Principal inclusion criteria

• SARS-CoV2 Infection diagnosed by rt-PCR
• CT-scan confirmed interstitial pneumonia
• Hospital admission from less than 24h
• Written Informed Consent

E.4

Principal exclusion criteria

• Age <18 ys or >65
• Patients in mechanical ventilation at time of admission
• Severe Hearth failure (NYHA 3 or 4)
• QTc > 470 ms or >500 ms in wide QRS patients
• Severe History of Chronic Ischemic Heart Disease, defined as history of Major Adverse Cardiovascular Event and/or recent (one year) revascularization.
• History of recurrent Deep Venous Thrombosis and Pulmonary Embolism or established thrombophilic conditions (e.g. history of anti-phospholipid antibodies, …)
• Active Bacterial or Fungal Infection
• Hematological cancer
• Metastatic or intractable cancer
• Pre-existent neurodegenerative disease
• Severe Hepatic Impairment,
• History of acute diverticular disease or intestinal perforation
• HBsAg positive and/or HBV-DNA positive patients
• Severe Renal Failure (Creatinine Clearance <30ml/h)
• Active Herpes zoster infection
• Patients with active or latent TB
• Severe anemia (Hb<9g/dl)
• Lymphocyte count below 750/mcl
• Neutrophil count below 1000/mcl
• Platelet count below 50000/mcl
• Pregnancy or Lactation
• History of intolerance to the experimental drugs or excipients
• Degenerative maculopathy or other relevant retinal disease
• Inability to give informed consent (severe transitory or permanent mental impairment, incapacitation)

• Età <18 ys or >65 (il limite di 65 anni è stato scelto per ridurre al minimo il rischio di sovrapposizioni infettive)
• Pazienti in ventilazione meccanica già al momento dle ricovero
• Scompenso cardiaco severo (NYHA 3 or 4)
• QT allungato
• Storia di cardiopatia ischemica
• Storia di trombosi venosa o embolia polmonare
• Storia di sindrome trombofilica
• Storia di malattia diverticolare acuta o di perforazione intastinale
• Infezioni batteriche o fungine in atto
• Neoplasia ematologica
• Neoplasia metastatica o avanzata
• Malattia neurodegenerative avanzata
• Severa insuffcienza epatica
• Severa insufficienza renale
• Infezione attiva da Herpes Zoster
• Anemia severa (Hb<9g/dl)
• Lymphocyte count below 750/mcl
• Neutrophil count below 1000/mcl
• Platelet count below 50000/mcl
• Pazienti con TBC attiva
• Gravidanza o allattamento
• Inabilità a fornire valido consenso informato

E.5 End points

E.5.1

Primary end point(s)

Rate of patients needing mechanical ventilation to maintain PaO2/FIO2>150 or, if PaO2 data not available, to maintain SO2>94% with max FiO2 0,5

Percentuale di pazienti che necessitano di ventilazione meccanica per mantenere un rapporto PaO2/FIO2>150mm/Hg or, if PaO2 non disponibile, per mantenere una SO2>94% with FiO2 0,5.

E.5.1.1

Timepoint(s) of evaluation of this end point

Primary Outcome will be assessed at day +14

L'end-point primario verrà verificato al giorno +14

E.5.2

Secondary end point(s)

Rate of patients needing admission to the intensive care unit for oro-tracheal intubation and/or evidence of Multiple Organ Dysfunction; death; Role of some clinical and laboratory factors in predicting outcome (pre-defined list -->see protocol)

Percentuale di pazienti che richiedono trasferimento in Rianimazione per intubazione oro-tracheale e/o evidenza di MOD (Multiple Organ Disfunction); morte; verifica della capacità di fattori clinici o biologici (lista predefinita specificata nel protocollo) di predire una buona risposta al trattamento

E.5.2.1

Timepoint(s) of evaluation of this end point

day +28; day +28; day +14

al giorno +28; giorno +28; giorno +14

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

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

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:

116

F.1.3

Elderly (>=65 years)

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 2020-06-26.

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

116

F.4.2

For a multinational trial

F.4.2.1

In the EEA

116

F.4.2.2

In the whole clinical trial

116

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)

Women in childbirth age must be tested for pregnancy before starting treatment. They will be informed that an effective contraception is mandatory in the 4 weeks following the last dose of the drug.

Le donne in età fertile verranno informate della necessità di utilizzare un valido sistema contraccettivo fino a 4 settimane dopo l'assunzione dell'ultima dose

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

2020-05-12

Ethics Committee Opinion of the trial application

Favourable

Ethics Committee Opinion: Reason(s) for unfavourable opinion

Date of Ethics Committee Opinion

2020-05-15

P. End of Trial
P.	End of Trial Status	Ongoing

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