Clinical Trials Register

Summary
EudraCT Number:	2010-022970-14
Sponsor's Protocol Code Number:	CACZ885M2301
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:	2012-03-20
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

2010-022970-14

A.3

Full title of the trial

A randomized, double-blind, placebo-controlled, eventdriven trial of quarterly subcutaneous canakinumab in the prevention of recurrent cardiovascular events among stable post-myocardial infarction patients with elevated hsCRP

Studio randomizzato, in doppio-cieco, controllato verso placebo, evento-dipendente, di canakinumab somministrato sottocute con frequenza trimestrale nella prevenzione di eventi cardiovascolari ricorrenti in pazienti con pregresso infarto miocardico clinicamente stabili e con elevati livelli di proteina C-reattiva ad alta sensibilita' (hsCRP)

A.3.1

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

CV Risk Reduction study (Reduction in Recurrent Major CV Disease Events)

Studio per la riduzione del rischio cardiovascolare (Riduzione degli eventi ricorrenti delle principali malattie cardiovascolari))

A.4.1

Sponsor's protocol code number

CACZ885M2301

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	NOVARTIS FARMA
B.1.3.4	Country	Italy
B.3.1 and B.3.2	Status of the sponsor	Commercial
B.4 Source(s) of Monetary or Material Support for the clinical trial:
B.4.1	Name of organisation providing support	Novartis Pharma
B.4.2	Country	Switzerland
B.5 Contact point designated by the sponsor for further information on the trial
B.5.1	Name of organisation	Novartis Farma
B.5.2	Functional name of contact point	Drug Regulatory Affairs
B.5.3	Address:
B.5.3.1	Street Address	Largo Umberto Boccioni, 1
B.5.3.2	Town/ city	Origgio (VA)
B.5.3.3	Post code	21040
B.5.3.4	Country	Italy
B.5.4	Telephone number	+39 02 96541
B.5.5	Fax number	+39 02 9659066
B.5.6	E-mail	info.studiclinici@novartis.com

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	ILARIS*SC 1FL 150MG
D.2.1.1.2	Name of the Marketing Authorisation holder	NOVARTIS FARMA SpA
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.3.4	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.3.8	INN - Proposed INN	canakinumab
D.3.9.1	CAS number	914613-48-2
D.3.9.2	Current sponsor code	ACZ885
D.3.9.4	EV Substance Code	NA
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	150
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	No
D.3.11.3.2	Gene therapy medical product	No
D.3.11.3.3	Tissue Engineered Product	No
D.3.11.3.4	Combination ATIMP (i.e. one involving a medical device)	No
D.3.11.3.5	Committee on Advanced therapies (CAT) has issued a classification for this product	No
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)	Yes
D.3.11.7	Plasma derived medicinal product	No
D.3.11.8	Extractive medicinal product	No
D.3.11.9	Recombinant medicinal product	Yes
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	ILARIS*SC 1FL 150MG
D.2.1.1.2	Name of the Marketing Authorisation holder	NOVARTIS FARMA SpA
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.3.4	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.3.8	INN - Proposed INN	canakinumab
D.3.9.1	CAS number	914613-48-2
D.3.9.2	Current sponsor code	ACZ885
D.3.9.4	EV Substance Code	NA
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	150
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	No
D.3.11.3.2	Gene therapy medical product	No
D.3.11.3.3	Tissue Engineered Product	No
D.3.11.3.4	Combination ATIMP (i.e. one involving a medical device)	No
D.3.11.3.5	Committee on Advanced therapies (CAT) has issued a classification for this product	No
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)	Yes
D.3.11.7	Plasma derived medicinal product	No
D.3.11.8	Extractive medicinal product	No
D.3.11.9	Recombinant medicinal product	Yes
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	Solution for injection
D.8.4	Route of administration of the placebo	Subcutaneous use

E. General Information on the Trial

E.1 Medical condition or disease under investigation

E.1.1

Medical condition(s) being investigated

atherosclerosis

aterosclerosi

E.1.1.1

Medical condition in easily understood language

atherosclerosis

aterosclerosi

E.1.1.2

Therapeutic area

Diseases [C] - Cardiovascular Diseases [C14]

MedDRA Classification

E.1.2 Medical condition or disease under investigation

E.1.2	Version	14.1
E.1.2	Level	PT
E.1.2	Classification code	10066537
E.1.2	Term	Atherosclerosis prophylaxis
E.1.2	System Organ Class	10042613 - Surgical and medical procedures

E.1.2 Medical condition or disease under investigation

E.1.2	Version	14.1
E.1.2	Level	LLT
E.1.2	Classification code	10003601
E.1.2	Term	Atherosclerosis
E.1.2	System Organ Class	10047065 - Vascular disorders

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 primary objective of this clinical trial is to demonstrate the superiority of at least one dose of canakinumab compared to placebo in reducing the risk of recurrent major cardiovascular disease events (cardiovascular death, non-fatal MI and stroke) in a population of clinically stable post-MI patients with elevated hsCRP receiving standard of care.

L’obiettivo primario di questo studio clinico e' dimostrare la superiorita' vs. placebo di almeno una dose di canakinumab nel ridurre il rischio di eventi cardiovascolari maggiori ricorrenti (morte cardiovascolare, infarto miocardico non fatale e ictus) in una popolazione di pazienti con pregresso infarto miocardico clinicamente stabili, con livelli elevati di hsCRP e che ricevono le terapie standard

E.2.2

Secondary objectives of the trial

- To demonstrate superiority of canakinumab compared to placebo on the composite endpoint of CV death, non-fatal MI, stroke, and hospitalization for unstable angina requiring unplanned revascularizations. - To demonstrate superiority of canakinumab compared to placebo on the endpoint of new onset type 2 diabetes among those with prediabetes at randomization - To demonstrate superiority of canakinumab compared to placebo on the composite endpoint of all-cause mortality, non-fatal MI and stroke. - To demonstrate superiority of canakinumab as compared to placebo on the endpoint of allcause mortality - To evaluate the long-term safety of canakinumab therapy in a placebo(standard of care) - controlled setting

 Dimostrare la superiorita' di canakinumab rispetto a placebo sull’endpoint composito di morte cardiovascolare, infarto miocardico non fatale, ictus e ospedalizzazione per angina instabile che richiede una rivascolarizzazione non pianificata.  Dimostrare la superiorita' di canakinumab rispetto a placebo sull’endpoint di insorgenza di DMT2 nei soggetti con pre-diabete alla randomizzazione.  Dimostrare la superiorita' di canakinumab rispetto a placebo sull’endpoint composto di mortalita' per tutte le cause, infarto miocardico non fatale e ictus.  Dimostrare la superiorita' di canakinumab rispetto a placebo sull’endpoint di mortalita' per tutte le cause.  Valutare la sicurezza a lungo termine della terapia con canakinumab rispetto a placebo.

E.2.3

Trial contains a sub-study

E.3

Principal inclusion criteria

- Written informed consent - Male, or Female of non-child-bearing potential - Age ≥ 18 years - Spontaneous MI at least 30 days before randomization. - hsCRP ≥ 2 mg/L

I pazienti eleggibili per l’inclusione in questo studio devono soddisfare tutti i seguenti criteri: 1. Consenso informato scritto ottenuto prima dell’effettuazione di qualsiasi valutazione. 2. Maschi, o femmine quest’ultime non potenzialmente in grado di avere figli. 3. Eta' ≥ 18 anni alla Visita 1. 4. Infarto del miocardio spontaneo documentato (diagnosticato secondo i criteri universali per l’infarto miocardico con o senza evidenza di sopra-slivellamento del tratto ST), occorso almeno 30 giorni prima della randomizzazione. La diagnosi di pregresso infarto miocardico deve essere basata su un’anamnesi positiva per sintomi clinici suggestivi di ischemia miocardica associati ad aumento dei biomarcatori cardiaci al di sopra dell 99esimo percentile del limite superiore di riferimento (preferibilmente troponina) OPPURE comparsa di nuove onde Q patologiche indipendentemente dai sintomi o variazioni all’ECG associate a infarto miocardico pregresso. Per ulteriori dettagli, fare riferimento alla Definizione Universale di infarto miocardico (Thygesen et al 2007). I pazienti con infarto miocardico secondario a PCI o CABG non saranno eleggibili. 5. Pazienti con livelli di hsCRP ≥ 2 mg/L allo screening (Visita 1, che sara' effettuata almeno 28 giorni dopo l’infarto miocardico o dopo qualsiasi PCI effettuata separatamente da esso) in terapia stabile (da almeno 4 settimane) a lungo termine.

E.4

Principal exclusion criteria

- Pregnant or nursing (lactating) women - Women of child-bearing potential - Any of the following concomitant diseases: 1. Planned coronary revascularization (PCI or CABG) 2. Major non-cardiac surgical or endoscopic procedure within past 6 months 3. Multi-vessel CABG surgery within the past 3 years Symptomatic patients with Class IV heart failure (HF) (New York Heart Association [NYHA] 4. Uncontrolled hypertension 5. Uncontrolled diabetes - History or evidence of active tuberculosis (TB) infection Other protocol-defined inclusion/exclusion criteria may apply

I pazienti che soddisfano uno qualsiasi dei seguenti criteri non sono eleggibili per l’inclusione in questo studio: 1. Donne in gravidanza o allattamento, essendo la gravidanza definita come lo stato di una donna dopo il concepimento e fino al termine della gestazione, confermata da un test di laboratorio positivo per gonadotropina corionica umana (hCG) > 5 mlU/mI. 2. Donne potenzialmente fertili, definite come tutte le donne fisiologicamente in grado di iniziare una gravidanza, A MENO CHE queste siano: donne considerate in stato di post-menopausa e non in grado di avere figli, se presentano amenorrea naturale (spontanea) da almeno 12 mesi con un appropriato profilo clinico (ad es. eta' appropriata, storia di sintomi vasomotori) o amenorrea spontanea da sei mesi con livelli sierici di FSH > 40 mlU/ml o sottoposte ad ooforectomia bilaterale chirurgica (con o senza isterectomia) almeno sei settimane prima dell’ingresso nello studio. In caso di sola ooforectomia, la donna sara' considerata non in grado di avere figli solo quando lo stato riproduttivo sara' stato confermato da una valutazione ormonale di controllo. 3. Presenza di una qualsiasi delle seguenti patologie concomitanti: - rivascolarizzazione coronarica pianificata (PCI o CABG) o qualsiasi altra procedura chirurgica maggiore - procedura chirurgica non-cardiaca o endoscopica maggiore nei 6 mesi precedenti alla Visita 1 - Intervento chirurgico di CABG multivasale nei 3 anni precedenti - pazienti sintomatici con insufficienza cardiaca di Classe IV NYHA (New York Heart Association) - ipertensione non controllata (definita come pressione sistolica media > 160 mmHg oppure pressione diastolica media > 100 mmHg alla Visita 1). I pazienti potranno essere rivalutati per questo criterio, a giudizio dello sperimentatore, se e' stata iniziata o incrementata la terapia anti-ipertensiva, come risultato dei valori di pressione arteriosa allo screening iniziale al di sopra di questi limiti - diabete non controllato come definito dallo sperimentatore - sindrome nefrosica o eGFR (velocita' di filtrazione glomerulare) < 30 mL/min/1.73 m2 secondo la formula MDRD o trapianto di rene (indipendentemente dalla funzionalita' renale) alla Visita 1 - epatopatia nota attiva o ricorrente (incluse cirrosi, epatite B ed epatite C, o livelli di ALT/AST > 3 volte il limite superiore di normalita' o bilirubina totale > 2 volte il limite superiore di normalita') alla Visita 1 - tumore maligno pregresso, diverso dal carcinoma basocellulare cutaneo. 4. Storia di abuso di alcol e/o di sostanze che potrebbero interferire con la conduzione dello studio. 5. Storia o evidenza di infezione tubercolare attiva alla Visita 1 o uno dei fattori di rischio per la tubercolosi quali: - storia di: residenza in un ambiente comunitario (ad esempio carcere, ospizio senza dimora o struttura per lungodegenti), abuso di sostanze (ad es. iniettive o non iniettive), operatori sanitari esposti in modo non protetto a pazienti ad alto rischio di tubercolosi (TB) o pazienti con TB prima dell’identificazione e delle corrette precauzioni per le vie aeree del paziente oppure - contatto ravvicinato (cioe' condivisione dello stesso ambiente aereo in una casa o altri ambienti chiusi per un periodo prolungato (giorni o settimane, non minuti od ore)) con una persona con TB polmonare attiva nei 12 mesi precedenti. 6. Storia di malattia infettiva in corso, cronica o ricorrente, o evidenza di infezione tubercolare, alla Visita 1, determinata sulla base di quanto definito dalla pratica clinica locale/linee guida locali. Se viene stabilita la presenza di tubercolosi, il trattamento (secondo le linee guida locali) deve essere stato completato prima della randomizzazione. 7. Pazienti con compromissione del sistema immunitario, sospetta o provata, compresi (a) pazienti con infezione da HIV; sono esclusi i pazienti in trattamento con terapia antiretrovirale PER FAVORE VEDERE SINOSSI IN ITALIANO

E.5 End points

E.5.1

Primary end point(s)

Time to first occurrence of a major adverse cardiovascular event, which is a composite endpoint consisting of cardiovascular death, non-fatal MI, and stroke.

L’endpoint primario e' definito come il tempo al primo evento cardiovascolare maggiore (Major Cardiovascular Event - MACE) che si verifica durante il periodo di trattamento in doppio-cieco e che e' un composito di morte cardiovascolare, infarto miocardico non fatale e ictus.

E.5.1.1

Timepoint(s) of evaluation of this end point

36 months

36 mesi

E.5.2

Secondary end point(s)

- Time to first occurrence of a major adverse cardiovascular event, which is a composite endpoint consisting of cardiovascular death, non-fatal MI, and stroke, and hospitalization for unstable angina requiring unplanned revascularization - Time to new onset of type 2 diabetes among those with pre-diabetes at randomization - Time to first occurence of non-fatal MI, stroke and all-cause mortality composite - Time to all-cause mortality

 Tempo al primo evento di un endpoint cardiovascolare composito che consiste nell’endpoint primario e nell’ospedalizzazione per angina instabile che richiede una rivascolarizzazione non pianificata  Tempo all’insorgenza di DMT2 nei pazienti con pre-diabete al momento della randomizzazione (tempo al New Onset of Diabetes – NOD)  Tempo al primo evento dell’endpoint composito infarto miocardico non fatale, ictus e morte per tutte le cause  Tempo alla morte per tutte le cause

E.5.2.1

Timepoint(s) of evaluation of this end point

36 months

36 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

Yes

E.6.5

Efficacy

Yes

E.6.6

Pharmacokinetic

Yes

E.6.7

Pharmacodynamic

Yes

E.6.8

Bioequivalence

E.6.9

Dose response

Yes

E.6.10

Pharmacogenetic

Yes

E.6.11

Pharmacogenomic

Yes

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

E.8.1.3

Single blind

Yes

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

E.8.2

Comparator of controlled trial

E.8.2.1

Other medicinal product(s)

E.8.2.2

Placebo

Yes

E.8.2.3

Other

Yes

E.8.2.3.1

Comparator description

- Stesso farmaco ad altro dosaggio

- same IMP used at different dosage

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

Yes

E.8.5.1

Number of sites anticipated in the EEA

170

E.8.6 Trial involving sites outside the EEA

E.8.6.1

Trial being conducted both within and outside the EEA

Yes

E.8.6.2

Trial being conducted completely outside of the EEA

E.8.6.3

If E.8.6.1 or E.8.6.2 are Yes, specify the regions in which trial sites are planned

Argentina

Australia

Brazil

Canada

China

Colombia

India

Japan

Korea, Republic of

Russian Federation

Taiwan

United States

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 : 26/01/2016

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

Number of subjects for this age range:

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:

4746

F.1.3

Elderly (>=65 years)

Yes

F.1.3.1

Number of subjects for this age range:

2556

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

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

400

F.4.2

For a multinational trial

F.4.2.1

In the EEA

2030

F.4.2.2

In the whole clinical trial

7302

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

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

2011-07-19

Ethics Committee Opinion of the trial application

Favourable

Ethics Committee Opinion: Reason(s) for unfavourable opinion

Date of Ethics Committee Opinion

2011-05-16

P. End of Trial
P.	End of Trial Status	Completed
P.	Date of the global end of the trial	2019-04-14

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