Clinical Trials Register

Summary
EudraCT Number:	2016-002885-30
Sponsor's Protocol Code Number:	ARES
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:	2020-11-04
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

2016-002885-30

A.3

Full title of the trial

Novel strategies of antithrombotic prophylaxis in patients with Essential Thrombocythemia (ET) at high risk of cardiovascular events: comparison of different dosing regimens of administration of
low-dose acetylsalicylic acid

Nuove strategie di profilassi antitrombotica in pazienti con Trombocitemia Essenziale (TE): valutazione di differenti regimi posologici di acido acetilsalicilico a basse dosi.

A.3.1

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

A.3.2

Name or abbreviated title of the trial where available

ARES-Aspirin Regimens in ESsential thrombocythemia

ARES

A.4.1

Sponsor's protocol code number

ARES

A.5.4

Other Identifiers

Name:

FARM12Y8HH

Number:

ARES

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	FONDAZIONE POLICLINICO UNIVERSITARIO AGOSTINO GEMELLI IRCCS UNIVERSITA' CATTOLICA DEL SACRO CUORE
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 - Italian Medicines Agency
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	FONDAZIONE POLICLINICO GEMELLI
B.5.2	Functional name of contact point	Area di ematologia
B.5.3	Address:
B.5.3.1	Street Address	L.go Gemelli 8
B.5.3.2	Town/ city	Roma
B.5.3.3	Post code	00168
B.5.3.4	Country	Italy
B.5.4	Telephone number	0630154968
B.5.5	Fax number	0630155209
B.5.6	E-mail	valerio.destefano@policlinicogemelli.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	CARDIOASPIRIN - 100 MG COMPRESSE GASTRORESISTENTI30 COMPRESSE
D.2.1.1.2	Name of the Marketing Authorisation holder	BAYER 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	cardioaspirina
D.3.2	Product code	[nd]
D.3.4	Pharmaceutical form	Gastro-resistant 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	ACIDO ACETILSALICILICO
D.3.9.2	Current sponsor code	nd
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	CARDIOASPIRIN - 100 MG COMPRESSE GASTRORESISTENTI30 COMPRESSE
D.2.1.1.2	Name of the Marketing Authorisation holder	BAYER 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	cardioaspirina
D.3.2	Product code	[nd]
D.3.4	Pharmaceutical form	Gastro-resistant 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	ACIDO ACETILSALICILICO
D.3.9.2	Current sponsor code	nd
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	100
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
D.8 Placebo: 1
D.8.1	Is a Placebo used in this Trial?	Yes
D.8.3	Pharmaceutical form of the placebo	Gastro-resistant tablet
D.8.4	Route of administration of the placebo	Oral use

E. General Information on the Trial

E.1 Medical condition or disease under investigation

E.1.1

Medical condition(s) being investigated

Essential thrombocytemia

Trombocitemia essenziale

E.1.1.1

Medical condition in easily understood language

E.1.1.2

Therapeutic area

Diseases [C] - Blood and lymphatic diseases [C15]

MedDRA Classification

E.1.2 Medical condition or disease under investigation

E.1.2	Version	21.0
E.1.2	Level	PT
E.1.2	Classification code	10015493
E.1.2	Term	Essential thrombocythaemia
E.1.2	System Organ Class	10029104 - Neoplasms benign, malignant and unspecified (incl cysts and polyps)

E.1.3

Condition being studied is a rare disease

Yes

E.2 Objective of the trial

E.2.1

Main objective of the trial

1- To investigate whether aspirin regimens based on twice or three times daily derived TXA2, without significantly affecting in vivo PGI2 biosynthesis, as compared to the standard, once daily 100 mg regimen. The comparison between aspirin 100 mg twice or 3 times daily vs. 100 mg od will test a superiority hypothesis in terms of serum TXB2 levels associated with each new regimen vs. standard treatment. PGIM comparisons will assess the non-inferiority of any multiple daily dosing vs standard od regimen.
2- To evaluate the long-term persistence of superior biochemical efficacy of an optimized, multiple daily dosing regimen of aspirin, as compared to the standard 100 mg od regimen.

Parte A Determinare se somministrazioni ripetute di 100 mg di aspirina nelle 24 ore (100 mg x 2 e 100 mg x 3) siano superiori al trattamento standard di 100 mg una volta al giorno nell’inibire il trombossano (TX) A2 piastrinico senza modificare significativamente la produzione di prostaciclina (PGI2) vascolare (= 30%)
Parte B: valutare la persistenza della superiore efficacia biochimica a lungo termine di somministrazioni ripetute giornaliere di 100 mg di aspirina (la migliore posologia rilevata nella Parte A nel rapporto inibizione TXA2/inibizione PGI2) vs. una posologia standard di una volta al giorno mediante misurazioni ripetute di TXB2 sierico.

E.2.2

Secondary objectives of the trial

1. Safety. The safety of the multiple daily aspirin regimen will be assessed in an exploratory fashion by recording major bleeding and clinically relevant non-major bleeding.
Any thrombotic complication (major and minor) will also be recorded.
These objectives will be explored in part B of the study, over 20-month treatment, with descriptive statistics.
2. Tolerability. The tolerability will be assessed in an exploratory fashion by recording: a. the gastrointestinal symptoms; b. the MPN symptom burden as scored by the MPN-SAF questionnaire modified to capture all microvascular symptoms and a pain numeric rating scale (NRS) for erythromelalgia
3. Stability over time of in vivo platelet activation, as assessed by the urinary biomarker TXM, will be e

Sicurezza a lungo termine della posologia con somministrazioni ripetute giornaliere, rispetto alla posologia standard di una volta al giorno valutata come:
- Eventi emorragici maggiori o clinicamente rilevanti
- Eventi avversi gastrointestinali maggiori non emorragici
- Eventi trombotici
- Tollerabilità a lungo termine della posologia a somministrazioni ripetute giornaliere rispetto alla posologia standard di una volta al giorno valutata come:
- Sintomi gastrointestinali
- Effetto sulla sintomatologia generale legata alla TE
- Effetto sui disturbi del microcircolo associati alla TE

E.2.3

Trial contains a sub-study

E.3

Principal inclusion criteria

A patient will be eligible if all of the following criteria apply:
- age between 18 and 75 years;
- an ET diagnosis according to WHO 2008 criteria;2
- ongoing aspirin 100 mg daily since at least 1 month, according to the judgement of the referring Hematologist;
- the patient understands and voluntarily signs an informed consent.

- età di 18-75 anni
- diagnosi di TE secondo i criteri WHO 2008;
- trattamento con aspirina 100 mg/die da almeno 1 mese, prescritto dall’Ematologo di riferimento
- capacità di comprendere e firmare volontariamente il consenso informato

E.4

Principal exclusion criteria

A patient is not eligible if any of the following criteria apply:
- platelet count >1,000,000/µL on three occasions over the 2 months before enrolment;
- creatinine level >1.5 x upper limit of normal;
- liver disease defined as AST and/or ALT values >3 x upper limit of normal;
- BMI >35 kg/m2;
- history of major bleeding that in the referring Hematologist's judgement may expose the patient to increased risk of bleeding recurrence
- active cancer or cancer in complete remission from less than one year, except for treated early-stage squamous or basal cell skin carcinomas;
- pregnancy or lactation;
- use of non-steroidal anti-inflammatory drugs (NSAIDs) >3 times/week;
- use of antiplatelet agents other than aspirin 100 mg od;
- use of oral anticoagulants including vitamin K antagonists, anti-Xa or -IIa agents;
- use of heparins or fondaparinux
- chronic use of steroids (prednisone >5 mg/die or equivalent)

Uno qualsiasi dei criteri di seguito elencati:
- conta piastrinica >1,000,000/µL in almeno 3 determinazioni nei 2 mesi precedenti l’arruolamento
- creatinina >1.5 x il limite superiore della norma;
- valori di AST e/o ALT >3 x il limite superiore della norma;
- BMI >35 kg/m2;
-storia di pregresso evento emorragico che, a giudizio dell’Ematologo di riferimento, potrebbe esporre il paziente ad un aumentato rischio di recidiva di emorragia se arruolato nello studio;
- patologia oncologica attiva o in remissione completa da < 1 anno, eccetto i carcinomi cutanei squamosi o basaliomi in stadio iniziale;
- gravidanza o allattamento;
- uso di FANS >3 giorni/settimana;
- uso di antiaggreganti diversi dall’aspirina;
- uso di anticoagulanti orali (anti-vitamina K, anticoagulanti diretti);
- uso di eparine o fondaparinux
- uso cronico di steroidi (prednisone >5 mg/die o equivalente)

E.5 End points

E.5.1

Primary end point(s)

Part A:
Primary endpoints:
- platelet thromboxane (TX)A2 production ex vivo, as reflected by serum TXB2 measured in samples collected in a fasting state, in the morning, before the next aspirin intake
- vascular PGI2 biosynthesis in vivo, as reflected by urinary 2,3-dinor-6-keto-PGF1alfa (PGIM) excretion in a urine sample collected in the morning before the next aspirin intake.
Both biomarkers will be measured at 14±2 days after randomization.
Part B
Primary endpoint:
- long-term persistence of superior biochemical efficacy of the optimized vs standard aspirin regimen, as measured by repeated serum TXB2 levels in samples collected in a fasting state, in the morning, before the next aspirin intake

Parte A
Endpoint primario
Miglior rapporto calcolato in relazione alla posologia dei bracci di randomizzazione tra:
- inibizione della biosintesi di TXA2 piastrinico ex vivo, misurato come TXB2 sierico misurato a digiuno prima dell’assunzione della dose successiva di aspirina
e
- inibizione della biosintesi di PGI2 vascolare in vivo, misurata come 2,3-dinor-6-keto-PGF1alfa urinario in un campione raccolto a digiuno prima dell’assunzione della dose successiva di aspirina
Entrambi i biomarcatori verranno misurati dopo 14±2 giorni dalla randomizzazione

Parte B:
Endpoint primario
Persistenza a lungo termine della superiore efficacia biochimica del regime posologico sperimentale rispetto a quello standard, misurata come determinazioni ripetute nel tempo di TXB2 sierico misurato a digiuno prima dell’assunzione della dose successiva di aspirina

E.5.1.1

Timepoint(s) of evaluation of this end point

A: 14 DAYS
B: UP TO 21 MONTHS

A: 14 GIORNI
B: FINO A 21 MESI

E.5.2

Secondary end point(s)

A. Secondary endpoints:
- urinary TXM measured at 14±2 days after randomization
B. Secondary endpoints:
- major bleeding and CRNMB and/or NB-UGI AE > grade 1 attributable to aspirin and/or major thrombotic complications (Appendices 1-3)
- tolerability: gastrointestinal and microvascular symptoms (Appendices 4-6)
- stability over time of in vivo biosynthesis of TXA2 and PGI2 as assesses by urinary TXM and PGIM excretion, respectively (measured in patients from Units 1, 2, 9), and of plasma von Willebrand Factor (vWF). These urinary metabolites will be assessed 3 times during part B.

PARTE A: Endpoint secondario
- metabolita urinario del TXA2 (TXM) all’arruolamento e a 14±2 giorni dalla randomizzazione

PARTE B: Endpoints secondari:
- Emorragie maggiori o non-maggiori clinicamente rilevanti, eventi avversi gastrointestinali sintomatici grado >1 attribuibili all’aspirina, complicanze trombotiche maggiori (Appendici 1-3)
- Sintomi gastrointestinali e microvascolari (Appendici 4-6)
- Stabilità nel tempo della biosintesi in vivo di TXA2 e PGI2, misurate come TXM e PGIM in pazienti afferenti alle Unità 1, 2, 9.

E.5.2.1

Timepoint(s) of evaluation of this end point

A. 14 DAYS
B. UP TO 21 MOUNTHS

A. 14 GIORNI
B. FINO A 21 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

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

Yes

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

E.8.1.3

Single blind

E.8.1.4

Double blind

Yes

E.8.1.5

Parallel group

Yes

E.8.1.6

Cross over

E.8.1.7

Other

Yes

E.8.1.7.1

Other trial design description

disegno applicabile solo alla parte A (14 giorni); la parte B è randomizzata in aperto

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

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:

240

F.1.3

Elderly (>=65 years)

Yes

F.1.3.1

Number of subjects for this age range:

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 2020-11-04.

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

300

F.4.2

For a multinational trial

F.4.2.1

In the EEA

300

F.4.2.2

In the whole clinical trial

300

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)

standard of care

normale pratica clinica

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

2016-09-01

Ethics Committee Opinion of the trial application

Favourable

Ethics Committee Opinion: Reason(s) for unfavourable opinion

Date of Ethics Committee Opinion

2017-07-27

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

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