Clinical Trials Register

Summary
EudraCT Number:	2020-001501-24
Sponsor's Protocol Code Number:	IRST100.47
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

2020-001501-24

A.3

Full title of the trial

PROTECT: A randomized study with Hydroxychloroquine versus observational support for prevention or early phase treatment of Coronavirus disease (COVID-19).

PROTECT: studio randomizzato con idrossiclorochina vs osservazione per la prevenzione e il trattamento precoce della malattia da coronavirus (COVID-19)

A.3.1

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

PROTECT: studio randomizzato con idrossiclorochina vs osservazione per la prevenzione e il trattamento precoce della malattia da coronavirus (COVID-19)

A.3.2

Name or abbreviated title of the trial where available

PROTECT

A.4.1

Sponsor's protocol code number

IRST100.47

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	ISTITUTO SCIENTIFICO ROMAGNOLO PER LO STUDIO E LA CURA DEI TUMORI (IRST) S.R.L. IRCCS
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	ISTITUTO SCIENTIFICO ROMAGNOLO PER LO STUDIO E LA CURA DEI TUMORI - IRST IRCCS - MELDOLA (FC)
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	ISTITUTO SCIENTIFICO ROMAGNOLO PER LO STUDIO E LA CURA DEI TUMORI - IRST IRCCS - MELDOLA (FC)
B.5.2	Functional name of contact point	Centro di Coordinamento Studi IRST
B.5.3	Address:
B.5.3.1	Street Address	via Piero Maroncelli, 40
B.5.3.2	Town/ city	Meldola (FC)
B.5.3.3	Post code	47014
B.5.3.4	Country	Italy
B.5.4	Telephone number	0547394547
B.5.5	Fax number	0544285330
B.5.6	E-mail	cc.ubsc@irst.emr.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.2.1.2	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_IRSTIRCCS
D.3.2	Product code	[IDROSSICLOROCHINA_IRSTIRCCS]
D.3.4	Pharmaceutical form	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	IDROSSICLOROCHINA SOLFATO
D.3.9.1	CAS number	118-42-3
D.3.9.2	Current sponsor code	IDROSSICLOROCHINA_IRSTIRCCS
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

Group 1: SARS-CoV-2-exposed subjects, as household members/contacts of COVID-19 patients
Group 2: Patients with COVID-19 asymptomatic or paucisymptomatic in home situation

Gruppo 1: Soggetti esposti a SARS-CoV-2 come conviventi e/o contatti di pazienti con COVID-19
Gruppo 2: Pazienti con COVID-19 confermato, asintomatici o paucisintomatici in confinamento domiciliare non in trattamento specifico per COVID-19

E.1.1.1

Medical condition in easily understood language

Group 1: SARS-CoV-2-exposed subjects , as household members/contacts of COVID-19 patients
Group 2: Patients with COVID-19 asymptomatic or paucisymptomatic in home situation

Gruppo 1: Soggetti esposti a SARS-CoV-2 come conviventi e/o contatti di pazienti con COVID-19
Gruppo 2: Pazienti con COVID-19 confermato, asintomatici o paucisintomatici in confinamento domiciliare

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

Group 1: Prevention of COVID-19 or related symptoms in SARS-CoV-2-exposed subjects, as household members/contacts of COVID-19 patients within one month from randomization
Group 2: Efficacy of Hydroxychloroquine in early phase COVID-19 within 14 days from randomization

Gruppo 1: Prevenzione dell’insorgenza di COVID-19 o dei sintomi correlati nei membri del nucleo familiare / contatti di pazienti con COVID-19 entro un mese dalla randomizzazione
Gruppo 2: Efficacia della idrossiclorochina nei pazienti con COVID-19 in fase precoce entro 14 giorni dalla randomizzazione

E.2.2

Secondary objectives of the trial

To compare the efficacy of Hydroxychloroquine:
- as prophylaxis, in prevention of COVID-19 infection in a population of SARS-CoV-2-exposed subjects (household members/contacts of COVID-19 pts) respect to observation only
- as prophylaxis, in subgroup population (stratification factors, class of age, gender)
- in early phase COVID-19 pts within 14 days from randomization in subgroup population (stratification factors, class of age, gender)
- in early phase COVID-19 pts within 1 month from randomization in overall population and in subgroup population (stratification factors, class of age, gender)
To evaluate in study groups:
- treatment toxicity
- QoL
To participate in European network for meta analysis of similar studies or in data collection for identifying prediction rule of outcomes.

Explorative: To identify biologic features that correlate with susceptibility or resistance to SARs-CoV2 infection or treatment with Hydroxychloroquine in study subgroups.

Confrontare l'efficacia dell'idrossiclorochina:
- come profilassi, nella prevenzione dell'infezione nella popolaz. di soggetti esposti a SARS-CoV-2 (membri della famiglia/contatti di paz. COVID-19) rispetto alla sola osservazione
- come profilassi, nei sottogruppi della popolaz. in studio (fattori di stratificazione, età, genere)
- nei paz. COVID-19 in fase precoce entro 14 gg dalla randomiz. nei sottogruppi di popolaz. (fattori di stratificazione, età, genere)
- nei paz. COVID-19 in fase precoce entro 1 mese dalla randomiz. nella popolaz. generale e nei sottogruppi (fattori di stratificazione, età, genere)
Valutare nei 2 gruppi:
- tossicità
- QoL
Partecipare alla rete europea per la meta analisi di studi simili o alla raccolta di dati per identificare la regola predittiva degli outcomes.

Obiettivo esplorativo: Identificare le caratteristiche biologiche correlate alla suscettibilità o alla resistenza all'infezione o al trattamento con idrossiclorochina nei sottogruppi in studio.

E.2.3

Trial contains a sub-study

E.3

Principal inclusion criteria

1) Male or Female, aged >= 18 years
2) SARS-CoV-2-exposed subjects, as household members and/or contacts of COVID-19 patients (GROUP 1). In this group are included Health care professionals in contact with COVID-19 patients. or
3) COVID-19 patients, asymptomatic or paucisymptomatic in home situation who are not in treatment with any anti COVID-19 medication (GROUP 2)
4) Absence of any COVID-19 symptom in last week before randomization (fever >37.5°C, cough, dyspnea) (only for GROUP 1 subjects)
5) Paracetamol treatment is accepted only for GROUP 2.
6) Participant is willing and able to give informed consent for participation in the study (either recorded during a telephonic interview or signed in person) and agrees with the study and its conduct.

1) Maschi o femmine con età >= 18 anni
2) Soggetti esposti a SARS-CoV-2, come conviventi e / o contatti di pazienti con COVID-19 (GRUPPO 1). In questo gruppo sono inclusi gli operatori sanitari a contatto con pazienti con COVID-19
Oppure
3) Pazienti con COVID-19 asintomatici o paucisintomatici in confinamento domiciliare, che non sono in trattamento con alcun farmaco anti COVID-19 (GRUPPO 2)
4) Assenza di qualsiasi sintomo compatibile con COVID-19 nell'ultima settimana prima della randomizzazione (febbre>37,5 °C, tosse, dispnea) (solo per soggetti del GRUPPO 1)
5) Il trattamento con paracetamolo è accettato solo per i soggetti del GRUPPO 2.
6) Il soggetto è in grado di fornire il consenso informato per la partecipazione allo studio (registrato durante un colloquio telefonico o firmato di persona) e accetta di seguire le procedure dello studio.

E.4

Principal exclusion criteria

1) Reported anamnesis for:
a. Intolerance or previous toxicity for hydroxychloroquine/chloroquine
b. Bradycardia or reduction rhythm of heart with arrythmias
c. Ischemic heart disease
d. Retinopathy
e. Congestive heart failure under/with use of diuretics
f. Favism or glucose-6-phosphate dehydrogenase (G6PD) deficiency
g. Diabetes type 1
h. Major comorbidities like advanced chronic kidney disease or dialysis therapy, known history of ventricular arrhythmias, any oncologic/hematologic malignancy.
i. Severe neurological and mental illness
2) Any other contraindication to take hydroxychloroquine
3) Already taking chloroquine, hydroxychloroquine or analogous during the past 3 weeks
4) Use of other antiviral agents in the last 3 weeks
5) Known positiveness for HIV, active HCV, HBV infection
6) Subject with a positive test for SARS-CoV-2 (for Group 1)
7) Pregnant or lactating
8) Current use of medications with known significant drug-drug interactions: digoxin, hypoglycemic agents, anticonvulsant, Cyclosporine, Phenylbutazone, drugs that inhibit CYP2D6
9) Known prolonged QT syndrome or current use of drugs with known QT prolungation
10) Participation in another clinical trial with any investigational agents within 30 days prior to study screening.

1) Anamnesi segnalata per:
a. Intolleranza o tossicità per idrossiclorochina / clorochina
b. Bradicardia o riduzione del ritmo cardiaco con aritmie
c. Cardiopatia ischemica
d. Retinopatia
e. Insufficienza cardiaca congestizia sotto/con uso di diuretici
f. Favismo o carenza di glucosio-6-fosfato deidrogenasi (G6PD)
g. Diabete di tipo 1
h. Comorbidità maggiori come malattia renale cronica avanzata o terapia dialitica, anamnesi nota di aritmie ventricolari, qualsiasi neoplasia oncoematologica
i. Grave malattia neurologica e mentale
2) Qualsiasi altra controindicazione all'assunzione di idrossiclorochina
3) Assunzione di clorochina, idrossiclorochina o analogo nelle ultime 3 settimane
4) Uso di altri agenti antivirali nelle ultime 3 settimane
5) Positività nota per l'infezione da HIV, HCV attiva, HBV
6) Soggetto con un test positivo per SARS-CoV-2 (per il GRUPPO 1)
7) Donne in gravidanza o in allattamento
8) Assunzione di farmaci con note e significative interazioni farmacologiche: digossina, agenti ipoglicemizzanti, anticonvulsivanti, Ciclosporina, Fenilbutazone, farmaci che inibiscono il CYP2D6
9) Nota Sindrome del QT lungo o assunzione di farmaci che prolungano il QT
10) Partecipazione a un'altra sperimentazione clinica con agenti sperimentali entro 30 giorni dallo screening dello studio.

E.5 End points

E.5.1

Primary end point(s)

Group 1: the proportion of subjects of Group 1 who become symptomatic and/or swab positive in each arm within 1 month from randomization
Group 2: the proportion of subjects of Group 2 who become swab negative in each arm within 14 days from randomization

Gruppo 1: la percentuale di soggetti del Gruppo 1, che diventano sintomatici e / o positivi in ciascun braccio entro 1 mese dalla randomizzazione.
Gruppo 2: la percentuale di soggetti del Gruppo 2 che diventano negativi al tampone in ciascun braccio entro 14 giorni dalla randomizzazione.

E.5.1.1

Timepoint(s) of evaluation of this end point

4 months

4 mesi

E.5.2

Secondary end point(s)

Variation in Quality of Life scores in different time points (weekly) respect to baseline values in both Group 1 and Group 2 populations.; Absolute and relative frequencies of Serious Adverse Events (CTCAE version 5.0) in both arms for the Group 1 and Group 2.; To participate in European network for meta-analysis of similar studies or in data collection for identifying prediction rule of outcomes.; Explorative Objective; To identify biologic features that correlate with susceptibility or resistance to SARS-CoV-2 infection or treatment with Hydroxychloroquine in a subgroup of household members/contacts of COVID-19 patients or COVID-19 patients enrolled.; The proportion of subjects with positive swabs in randomized population of SARS-CoV-2-exposed subjects (Group 1) within 1 month from randomization in both arms.; The proportion of subjects of Group 1 who become symptomatic in each arm within 1 month from randomization, in subgroup population identified by stratification factors, class of age and gender.; The proportion of subjects of Group 2 who become swab negative in each arm within within 14 days from randomization, in subgroup population identified by stratification factors, class of age and gender.; The proportion of subjects of Group 2 who become swab negative in each arm within 1 month from randomization in overall population and in subgroup population identified by stratification factors, class of age and gender.

Variazione dei punteggi di qualità della vita in diversi punti temporali (settimanali) rispetto ai valori basali nelle popolazioni del gruppo 1 e del gruppo 2.; Frequenze assolute e relative di eventi avversi gravi (CTCAE versione 5.0) in entrambi i bracci per la popolazione globale (gruppo 1 e 2); Partecipare alla rete europea per la meta analisi di studi simili o alla raccolta di dati per identificare la regola predittiva degli outcomes.; Obiettivo esplorativo: Identificare le caratteristiche biologiche correlate alla suscettibilità o alla resistenza all'infezione o al trattamento con idrossiclorochina in un sottogruppo di membri della famiglia/ contatti di pazienti COVID-19 o pazienti COVID-19 arruolati.; La proporzione di soggetti con tampone positivo nella popolazione randomizzata di soggetti esposti a SARS-CoV-2 (Gruppo 1) entro 1 mese dalla randomizzazione in entrambi i bracci.; La proporzione di soggetti del Gruppo 1 che diventano sintomatici in ciascun braccio di trattamento entro 1 mese dalla randomizzazione nei sottogruppi di popolazione identificati dai fattori di stratificazione, classe di età, genere.; La proporzione di soggetti del Gruppo 2 che diventano negativi al tampone in ciascun braccio entro 14 giorni dalla randomizzazione, nella popolazione di sottogruppi identificata da fattori di stratificazione, classe di età e genere.; La proporzione di soggetti del Gruppo 2 che diventano negativi al tampone in ¿¿ciascun braccio entro 1 mese dalla randomizzazione nella popolazione complessiva e nei sottogruppi di popolazione identificati dai fattori di stratificazione, classe di età e genere.

E.5.2.1

Timepoint(s) of evaluation of this end point

10 months; 10 months; 10 months; 10 months; 4 monts; 4 monts; 4 monts; 4 months

10 mesi; 10 mesi; 10 mesi; 10 mesi; 4 mesi; 4 mesi; 4 mesi; 4 mesi

E.6 and E.7 Scope of the trial

E.6

Scope of the trial

E.6.1

Diagnosis

E.6.2

Prophylaxis

Yes

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

Yes

E.6.13.1

Other scope of the trial description

Quality of life

Qualità della vita

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)

E.8.2.2

Placebo

E.8.2.3

Other

Yes

E.8.2.3.1

Comparator description

Osservazione

Observation

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

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:

1800

F.1.3

Elderly (>=65 years)

Yes

F.1.3.1

Number of subjects for this age range:

500

F.2 Gender

F.2.1

Female

Yes

F.2.2

Male

Yes

F.3 Group of trial subjects

F.3.1

Healthy volunteers

Yes

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

2300

F.4.2

For a multinational trial

F.4.2.1

In the EEA

2300

F.4.2.2

In the whole clinical trial

2300

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)

Telephonic interviews every 4 weeks for up to 6 months, to register:
- changes in body temperature
- general health state
- onset (Group 1) or change (Group 2) of any symptom compatible with COVID-19
- date and result of rhino/oro-pharyngeal swab (if performed)
- any adverse event occurred within one after treatment stop;
- any contact with COVID-19 patient (other than the cohabitant for group 1) or any risk situation
- Quality of Life Questionnaires
- concomitant medications

Interviste telefoniche ogni 4 settimane per 6 mesi, per registrare:
- variazioni della temperatura corporea
- stato di salute
- insorgenza (GRUPPO 1) o modifica (GRUPPO 2) di sintomi compatibili con COVID-19
- data e esito dell’eventuale tampone rino/oro-faringeo
- eventi avversi verificati entro un mese dopo l'ultimo trattamento
- qualsiasi contatto con paz. COVID-19 (diverso dal convivente per il GRUPPO 1) o situazioni di rischio
- Questionari sulla qualità della vita
- farmaci concomitanti

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

2020-04-28

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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