Clinical Trials Register

Summary
EudraCT Number:	2016-003036-20
Sponsor's Protocol Code Number:	1-2016
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:	2021-06-08
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

2016-003036-20

A.3

Full title of the trial

A randomized trial of multifactorial primary prevention in high risk subjects candidate to a lung cancer early detection CT program

Studio randomizzato di prevenzione primaria multifattoriale in soggetti ad alto rischio eleggibili a screening con TC torace
Studio SMILE

A.3.1

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

Prevention study for high risk subjects for age, sigarette smoking and inflammatory status candidate to a lung cancer early detection CT program

Studio di prevenzione per soggetti considerati ad alto rischio per et¿, fumo di sigaretta e stato infiammatorio, candidati a un programma di diagnosi precoce del tumore polmonare con TAC torace

A.3.2

Name or abbreviated title of the trial where available

SMILE

A.4.1

Sponsor's protocol code number

1-2016

A.5.1

ISRCTN (International Standard Randomised Controlled Trial) Number

ISRCTN00000000

A.5.2

US NCT (ClinicalTrials.gov registry) number

NCT00000000

A.5.3

WHO Universal Trial Reference Number (UTRN)

U0000-0000-0000

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 IRCCS "ISTITUTO NAZIONALE DEI TUMORI"
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	Fondazione IRCCS Istituto Nazionale dei Tumori
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 IRCCS Istituto Nazionale dei Tumori
B.5.2	Functional name of contact point	Chirurgia Toracica Ricerca
B.5.3	Address:
B.5.3.1	Street Address	Via G. Venezian 1
B.5.3.2	Town/ city	Milano
B.5.3.3	Post code	20133
B.5.3.4	Country	Italy
B.5.4	Telephone number	0223903759
B.5.5	Fax number	0223903308
B.5.6	E-mail	elena.bertocchi@istitutotumori.mi.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 GASTRORESISTENTI90 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	Cardioaspirin
D.3.2	Product code	024840
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	03092200
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.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	Tabex
D.2.1.1.2	Name of the Marketing Authorisation holder	Sopharma Warszawa sp
D.2.1.2	Country which granted the Marketing Authorisation	Poland
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	Capsule, hard
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	Citisina
D.3.9.1	CAS number	485-35-8
D.3.9.2	Current sponsor code	000000
D.3.9.3	Other descriptive name	Cytisine
D.3.9.4	EV Substance Code	SUB31171
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	1
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

health subjects (multifactorial primary prevention)

volontari sani (prevenzione primaria multifattoriale)

E.1.1.1

Medical condition in easily understood language

health subjects (prevention)

volontari sani (prevenzione)

E.1.1.2

Therapeutic area

Diseases [C] - Symptoms and general pathology [C23]

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	10036654
E.1.2	Term	Prevention
E.1.2	System Organ Class	100000004865

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 objective of the study is to evaluate the efficacy of multi-factor intervention in high risk subjects in terms of inflammatory inflammation. The primary endpoint is therefore the reduction in the percentage of subjects with high PCR (ie with PCR =2 mg / L).

L¿obiettivo primario dello studio ¿ quello di valutare l¿efficacia dell¿intervento multi-fattoriale in soggetti ad alto rischio in termini di riduzione dello stato infiammatorio. L¿endpoint primario risulta pertanto la riduzione della percentuale di soggetti con PCR elevata (cio¿ con PCR =2 mg/L).

E.2.2

Secondary objectives of the trial

¿ Reduction in the proportion of smokers;
¿ Improving the efficacy and safety of Varenicline for smoking cessation, using an alternative way of administering the drug;
¿ Improvement of diet and physical activity;
¿ Improvement of anthropometric parameters in overweight / obese and underweight subjects;
¿ Improvement of metabolic values;
¿ Improving the quality of life;
¿ Reduction in the percentage of subjects with lung cancer;
¿ Reduction of total mortality;
¿ Evaluation of the relationship between inflammatory profile (PCR) plasma biomarkers and those related to the metabolic profile and microRNA profile
¿ Evaluation of the adherence, feasibility and tolerability of multi-factor prevention intervention

¿ Riduzione della percentuale di fumatori;
¿ Miglioramento dell¿efficacia e sicurezza della Vareniclina per la cessazione al fumo, utilizzando una modalit¿ alternativa di somministrazione del farmaco;
¿ Miglioramento della dieta e dell¿attivit¿ fisica;
¿ Miglioramento dei parametri antropometrici in soggetti sovrappesso/obesi e in quelli sottopeso;
¿ Miglioramento dei valori metabolici;
¿ Miglioramento della qualit¿ della vita;
¿ Riduzione della percentuale di soggetti con tumore del polmone;
¿ Riduzione della mortalit¿ totale;
¿ Valutazione della relazione tra biomarcatori plasmatici relativi al profilo infiammatorio (PCR) e quelli relativi al profilo metabolico e profilo microRNA.
¿ Valutazione dell'aderenza, fattibilit¿ e tollerabilit¿ dell'intervento multi-fattoriale di prevenzione

E.2.3

Trial contains a sub-study

E.3

Principal inclusion criteria

• Age between 55 and 75 years
• Heavy smoker (=30 packages/year)
• Eligibility to screening with annual chest CT
• Availability and ability to use the Internet via PC, tablet or smartphone
• Ability to understand the project to which you intend to participate
• No tumors in the last 5 years
• Signature of informed consent for enrollment in the study and for the processing of personal data

• Età compresa tra 55 e 75 anni
• Forte fumatore (=30 pacchetti/anno)
• Eleggibilità a screening con TC torace annuale
• Disponibilità e capacità di utilizzo di internet tramite PC, tablet o smartphone
• Capacità di comprendere il progetto a cui si intende partecipare
• Assenza di tumori da almeno 5 anni
• Firma del consenso informato per l’arruolamento in studio e il trattamento dei dati personali

E.4

Principal exclusion criteria

• Hypersensitivity to acetylsalicylic acid, salicylates or any of the excipients (excipients: cellulose powder, corn starch; coating: copolymers of methacrylic acid, sodium lauryl sulfate, polysorbate 80, talc, triethyl citrate)
• Chronic treatment with cardioASA, or other anti-clotting or anti-coagulant drugs (for example: heparin, dicumarol)
• Treatment with methotrexate
• Existing Mastocytosis
• History of asthma induced by the administration of salicylates or substances to similar activity, particularly non-steroidal anti-inflammatory drugs
• Gastroduodenal ulcer
• Hemorrhagic diathesis
• Severe chronic pathology (eg: severe respiratory and / or renal and / or hepatic and / or cardiac insufficiency)
• Severe kidney failure
• Serious psychiatric problems
• Previous treatment with Cytisine
• Abuse of alcohol or other substances (even before)

• Ipersensibilità all’acido acetilsalicilico, ai salicilati o a uno qualsiasi degli eccipienti (eccipienti: polvere di cellulosa, amido di mais; rivestimento: copolimeri dell’acido metacrilico, sodio laurilsolfato, polisorbato 80, talco, trietile citrato)
• Trattamento cronico con cardioASA, o altri farmaci anti-aggreganti o anti-coagulanti (ad esempio: eparina, dicumarolici)
• Trattamento con metotrexato
• Mastocitosi preesistente
• Anamnesi di asma indotta dalla somministrazione di salicilati o sostanze ad attività simile, in particolare i farmaci antinfiammatori non steroidei
• Ulcera gastroduodenale
• Diatesi emorragica
• Patologia cronica severa (ad esempio: grave insufficienza respiratoria e/o renale e/o epatica e/o cardiaca)
• Grave insufficienza renale
• Gravi problemi psichiatrici
• Precedente trattamento con Citisina
• Abuso di alcool o altre sostanze (anche pregresso)

E.5 End points

E.5.1

Primary end point(s)

Reduction in the percentage of subjects with PCR =2 mg/L after one year of treatment in the interventional groups versus control group.

Riduzione della percentuale di soggetti con PCR =2 mg/L dopo un anno di intervento nei gruppi di intervento rispetto al gruppo di controllo.

E.5.1.1

Timepoint(s) of evaluation of this end point

12 months

12 mesi

E.5.2

Secondary end point(s)

¿ Reduction of the proportion of smokers after one year of follow-up in the intervention group on smoking cessation over the control group;; ¿ Greater adherence to the Mediterranean Diet, measured through specific indexes defined in scientific literature (such as the MDS), The inflammatory status group with respect to the control group;; ¿ Increased physical activity, quantified in terms of Metabolic Equivalence of the Task (MET) in the inflammatory response group compared to the control group;; ¿ Reduction of the various anthropometric parameters (IMC, waist circumference, waist circumference / waist ratio) and greater prevalence of weight-weight subjects in the inflammatory intervention group versus the control group;; ¿ Reduction of cardio-metabolic markers in the blood in the inflammatory group compared to the control group;; ¿ Better quality of life, quantified by SF-12 in intervention groups compared to control group;; ¿ Reduction of the incidence rate of lung cancer in the intervention group on smoking cessation with respect to the control group;; ¿ Reduction of the total mortality rate in the intervention groups compared to the control group;; ¿ Evaluation of the relationship between inflammatory profile (PCR) plasma biomarkers and cardio-metabolic profile and microRNA profile.; ¿ Reduction in percentage of smokers and adverse reactions after one year of follow-up in subjects treated with Cytisine with prolonged administration compared to standard drug administration;

¿ La riduzione della percentuale di fumatori dopo un anno di follow-up nel gruppo di intervento sulla cessazione dal fumo rispetto al gruppo di controllo;; ¿ Aumento dell¿aderenza alla dieta Mediterranea, misurata attraverso specifici indici definiti nella letteratura scientifica (come il Mediterranean Diet Score (MDS)) nel gruppo di intervento sullo stato infiammatorio rispetto al gruppo di controllo; ; ¿ Aumento dell'attivit¿ fisica, quantificata in termini di Equivalente Metabolico del Task (MET) nel gruppo di intervento infiammatorio rispetto al gruppo di controllo;; ¿ Riduzione dei vari parametri antropometrici (IMC, circonferenza vita, circonferenza vita / rapporto vita) e maggiore prevalenza di soggetti peso-peso nel gruppo di intervento infiammatorio rispetto al gruppo di controllo;; ¿ Riduzione dei marcatori cardio-metabolici nel flusso sanguigno nel gruppo di intervento infiammatorio rispetto al gruppo di controllo;; ¿ Una migliore qualit¿ della vita, quantificata da SF-12 nei gruppi di intervento rispetto al gruppo di controllo;; ¿ Riduzione del tasso di incidenza del cancro polmonare nel gruppo di intervento sulla cessazione del fumo rispetto al gruppo di controllo;; ¿ Riduzione del tasso di mortalit¿ totale nei gruppi di intervento rispetto al gruppo di controllo;; ¿ Valutazione della relazione tra biomarcatori plasmatici del profilo infiammatorio (PCR) e profilo cardio-metabolico e profilo microRNA.; ¿ La riduzione della percentuale di fumatori e di reazioni avverse, dopo un anno di follow-up, nei soggetti trattati con Citisina con una somministrazione prolungata rispetto alla somministrazione standard del farmaco;

E.5.2.1

Timepoint(s) of evaluation of this end point

12 and 24 months; 12 and 24 months; 12 and 24 months; 12 and 24 months; 12 and 24 months; 12 and 24 months; 12 and 24 months; 12 and 24 months; 12 and 24 months; 12 and 24 months

12 e 24 mesi; 12 e 24 mesi; 12 e 24 mesi; 12 e 24 mesi; 12 e 24 mesi; 12 e 24 mesi; 12 e 24 mesi; 12 e 24 mesi; 12 e 24 mesi; 12 e 24 mesi

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

E.6.4

Safety

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, factibility, reduction in risk factors

qualit¿ di vita, fattibilit¿, riduzione delle condizioni di rischio (% fumatori attivi e soggetti con PCR >2)

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

A)Gruppo di intervento completo: CardioASA + programma dietetico e di attivit¿ fisica + Citisina;
B)

A) Complete intervention group: CardioASA + Dietary and physical activity program+Cytisine;
B) Inter

E.8.2.4

Number of treatment arms in the trial

E.8.3

The trial involves single site in the Member State concerned

Yes

E.8.4

The trial involves multiple sites in the Member State concerned

E.8.4.1

Number of sites anticipated in Member State concerned

E.8.5

The trial involves multiple Member States

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

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

The start date of the study is the date of enrollment of the first subject, and the end date is expected to be after 30 months.
The end of the enrollment will be after 18 months from the beginning of the study. The follow-up will end after 12 months from the first visit of the last patient enrolled.
This will guarantee for the 2000 recruited subjects a minimum follow-up of one year up to a maximum of two years.

La data di inizio dello studio corrisponde alla data dell'arruolamento del primo soggetto, e la data di fine ¿ prevista dopo 30 mesi.
La conclusione dell¿arruolamento ¿ prevista dopo 18 mesi dall¿inizio dello studio. Il follow up si concluder¿ dopo 12 mesi dalla prima visita dell¿ultimo paziente arruolato.
Questo garantir¿ per i 2000 soggetti reclutati un follow-up minimo di un anno fino ad un massimo di due anni.

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:

1350

F.1.3

Elderly (>=65 years)

Yes

F.1.3.1

Number of subjects for this age range:

650

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

F.3.3

Specific vulnerable populations

F.3.3.1

Women of childbearing potential not using contraception

F.3.3.2

Women of child-bearing potential using contraception

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

2000

F.4.2

For a multinational trial

F.4.2.1

In the EEA

2000

F.4.2.2

In the whole clinical trial

2000

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)

telephone follow up

follow up telefonico

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

2017-10-02

Ethics Committee Opinion of the trial application

Favourable

Ethics Committee Opinion: Reason(s) for unfavourable opinion

Date of Ethics Committee Opinion

2017-07-20

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

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IMP with orphan designation in the indication
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