Clinical Trials Register

Summary
EudraCT Number:	2009-016737-95
Sponsor's Protocol Code Number:	ROSPREC
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:	2012-03-06
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

2009-016737-95

A.3

Full title of the trial

ROSuvastatin Pretreatment to Reduce Embolization during Carotid Artery Stenting

Pretrattamento con Rosuvastatina per Ridurre l'Embolizzazione durante Angioplastica Carotidea con Impianto di Stent

A.3.1

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

ROSuvastatin Pretreatment during Carotid Artery Stenting

Pretrattamento con Rosuvastatina durante Angioplastica Carotidea

A.4.1

Sponsor's protocol code number

ROSPREC

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 PISANA
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	DIPARTIMENTO CARDIOTORACICO E VASCOLARE UNIVERSITA' DI PISA
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	AZIENDA OSPEDALIERO-UNIVERSITARIA PISANA
B.5.2	Functional name of contact point	U.O. Malattie Cardiovascolari I
B.5.3	Address:
B.5.3.1	Street Address	Via Roma n. 67
B.5.3.2	Town/ city	Pisa
B.5.3.3	Post code	56100
B.5.3.4	Country	Italy
B.5.4	Telephone number	050995321
B.5.5	Fax number	050995325
B.5.6	E-mail	marcodecarlo@gmail.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.2.1.2	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	Film-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	NA
D.3.9.1	CAS number	NA
D.3.9.2	Current sponsor code	NA
D.3.9.3	Other descriptive name	NA
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	40
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	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)	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

Asymptomatic carotid stenosis >80% in patients with baseline LDL cholesterol >120 mg/dL.

Stenosi carotidea >80% asintomatica in pazienti con colesterolemia LDL >120 mg/dL.

E.1.1.1

Medical condition in easily understood language

Carotid stenosis

Stenosi carotidea

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	10007687
E.1.2	Term	Carotid artery stenosis
E.1.2	System Organ Class	10029205 - Nervous system 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

To demonstrate that the administration of rosuvastatin 40 mg o.d. for 6 weeks before elective carotid artery stenting in hypercholesterolemic patients reduces the extent of distal embolization during the procedure.

Dimostrare che il trattamento con rosuvastatina 40 mg/die per 6 settimane prima dell'intervento elettivo di angioplastica carotidea in pazienti con colesterolemia determina una riduzione dell'entita' della embolizzazione di frammenti di placca carotidea durante la procedura.

E.2.2

Secondary objectives of the trial

a)To demonstrate that the administration of rosuvastatin 40 mg o.d. for 6 weeks before elective carotid reduces the rate of peri-procedural and 30-day cerebral ischaemic complications (TIA, minor/major stroke, death). b)To demonstrate that the administration of rosuvastatin 40 mg o.d. for 6 weeks modifies the histopathology of embolic debris, by reducing the inflammatory and lipidic components. c)To demonstrate that the administration of rosuvastatin 40 mg o.d. for 6 weeks reduces the circulating levels of inflammatory markers including CRP, interleukin-6, interleukin-18, sLOX-1, sRAGE.

a)Dimostrare che il trattamento con rosuvastatina riduce la prevalenza delle complicanze ischemiche cerebrali peri-procedurali e a 30 giorni (TIA, ictus minore e maggiore, morte). b)Verificare se il pretrattamento con rosuvastatina modifica la caratterizzazione istologica dei frammenti embolici (nei casi in cui sia presente sufficiente tessuto da consentire una analisi istologica e immunoistochimica). c)Verificare se il pretrattamento con rosuvastatina riduce i livelli circolanti del colesterolo LDL, della PCR, della interleuchina 6, della interleuchina 18, del recettore solubile lectino-simile 1 per le LDL ossidate (sLOX-1) e del recettore solubile dei prodotti di glicosilazione avanzata (sRAGE) al momento della randomizzazione, subito prima della procedura, subito dopo la procedura e 30 giorni dopo la procedura.

E.2.3

Trial contains a sub-study

E.3

Principal inclusion criteria

- Carotid stenosis ≥80% at ultrasound in asymptomatic patients; - Male and female; - Age between 18 and 80 years; - No contraindications to CAS (major functional or cognitive impairment; inability to achieve safe vascular access; extreme carotid lesion calcification; visible thrombus in lesion; long subtotal occlusion (string sign); life expectancy <5 years; contraindication to aspirin or thienopyridines; severe renal dysfunction precluding safe contrast medium administration). - Baseline LDL >120 mg/dL and/or baseline CRP level > 4 mg/dL. -Informed consent.

- Stenosi carotidea ≥80% all' ecoDoppler per i pazienti asintomatici; - Maschi e femmine; - Eta' compresa tra 18 e 80 anni; - Nessuna controindicazione all angioplastica con stent carotideo (deficit funzionale o cognitivo maggiore; impossibilita' di ottenere un accesso vascolare sicuro ; - aneurisma intracranico o malformazione artero-venosa che richiedono un trattamento; lesione carotidea estremamente calcificate; trombo visibile in lesione; occlusione subtotale lunga (segno della stringa); aspettativa di vita <5 anni; controindicazioni all aspirina e/o alle tienopiridine; grave disfunzione renale con rischio di nefropatia da somministrazione di mezzo iodato). - Livelli plasmatici di colesterolo LDL >120 mg/dL e/o CRP > 4 mg/dL al momento dello screening. - Consenso informato.

E.4

Principal exclusion criteria

- Baseline LDL ≤120 mg/dL and CRP level ≤ 4 mg/dL. - Impossibility to use embolic protection. - Recent (<3 months) neurologic symptoms (cerebral or ocular ischemia ipsilateral to the carotid stenosis to be treated with CAS) requiring intervention on the carotid artery without delay. - Treatment with any statin within 6 months before the time of screening;- Active internal bleeding. - Recent cranial or spinal trauma or surgery (within 2 months). - Recent gastroenteric or genitourinary bleeding (within 6 weeks) of clinical significance. - Haemorrhagic diathesis- - Thrombocitopenia (<100.000 PLT/ml). - Severe uncontrolled arterial hypertension. - Intracranial neoplasm or arteriovenous malformation or aneurysm. - Contraindication to aspirin and/or thienopyridines. -Pregnancy and lactation. - Women in fertile age or women who do not satisfy the following definition of postmenopause: physiological amenorrhoea dating >12 months or bilateral ovariectomy dating > 6 weeks (in the case of single ovariectomy the reproductive state must be assessed by hormonal determination). -Hypersensitivity to rosuvastatin or to any of the excipients. - Active liver disease including unexplained, persistent elevations of serum transaminases and any serum transaminase elevation exceeding 3 x the upper limit of normal (ULN). Moderate to severe renal impairment (creatinine clearance <60 ml/min). - Myopathy. - Concomitant use of ciclosporin, fibrates, or vitamin K antagonists. - Hypothyroidism. - Personal or family history of hereditary muscular disorders. - Previous history of muscular toxicity with another HMG-CoA reductase inhibitor or fibrate. - Alcohol abuse.

- Livelli plasmatici di colesterolo LDL≤ 120 mg/dL e/o CRP≤ 4 mg/dL al momento dello screening. - Impossibilita' di utilizzare la protezione embolica durante l’angioplastica carotidea. - Sintomi neurologici recenti (<3 mesi) (ischemia cerebrale o oculare ipsilaterale alla stenosi carotidea da trattare) che richiedono un intervento sulla carotide non differibile. -Trattamento con qualsiasi statina nei 6 mesi precedenti il momento dello screening - Presenza di sanguinamento di organi interni. - Trauma cranico o spinale recente o intervento chirurgico (entro 2 mesi). - Sanguinamento gastrointestinale o genitourinario recente (entro 6 settimane) clinicamente rilevante. - Diatesi emorragica. - Trombocitopenia (<100.000 PLT/ml). - Ipertensione arteriosa severa non controllata dalla terapia. - Neoplasia o malformazione arterovenosa o aneurisma intracranici. - Controindicazione all’aspirina e/o alle tienopiridine. -Gravidanza e allattamento. - Donne in eta' fertile o donne che non soddisfano la seguente definizione di postmenopausa: amenorrea fisiologica che data da oltre 12 mesi o ovariectomia bilaterale risalente ad oltre 6 settimane (nel caso di ovariectomia monolaterale lo stato riproduttivo deve essere valutato con determinazione ormonale ). - Ipersensibilita' alla rosuvastatina o ad uno qualsiasi degli eccipienti. -Malattia epatica attiva, inclusi inspiegabili, persistenti aumenti delle transaminasi sieriche e qualsiasi aumento delle transaminasi sieriche oltre 3 volte il limite superiore del normale. - Insufficienza renale da moderata a grave (clearance della creatinina <60 ml/min). -Miopatia. - Uso concomitante di ciclosporina, fibrati, o antagonisti della vitamina K. - Ipotiroidismo. - Storia personale o familiare di malattie muscolari ereditarie. - Storia pregressa di tossicita' muscolare con altri inibitori della HMG-CoA reduttasi o fibrati. - Abuso di alcolici.

E.5 End points

E.5.1

Primary end point(s)

Extent of carotid plaque embolization during the procedure, assessed by visual inspection of the embolic protection filter by a single, expert pathologist, and quantified as scarce embolization (no visible debris or hardly visible debris), or relevant embolization (visible debris in the filter).

Entita' della embolizzazione di frammenti di placca carotidea durante la procedura, valutata attraverso l' ispezione visiva del filtro di protezione embolica da parte di un unico Anatomo Patologo esperto, quantificata semplicemente come embolizzazione scarsa (materiale embolico assente o a mala pena visibile) o embolizzazione rilevante (materiale embolico evidente all ispezione del filtro).

E.5.1.1

Timepoint(s) of evaluation of this end point

Embolization assessment will be performed immediately after CAS.

L'entita' della embolizzazione sarà effettuata immediatamente dopo la CAS.

E.5.2

Secondary end point(s)

Prevalence of death and cerebral ischaemic complication (TIA, minor/major stroke).

Prevalenza delle complicanze ischemiche cerebrali (TIA, ictus minore e maggiore, morte).

E.5.2.1

Timepoint(s) of evaluation of this end point

Prevalence of death and cerebral ischaemic complication (TIA, minor/major stroke) during CAS and at 30 days, 6 months and 1 year.

Prevalenza delle complicanze ischemiche cerebrali peri-procedurali (TIA, ictus minore e maggiore, morte) e a 30 giorni, 6 mesi e 1 anno.

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

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)

E.8.2.2

Placebo

E.8.2.3

Other

Yes

E.8.2.3.1

Comparator description

trattamento standard

standard treatment

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

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

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:

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

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

130

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)

After the end of the trial, the patients will be followed-up by each centre according to good clinical practice

Dopo la chiusura dello studio, i pazienti saranno seguiti da ciascun centro con controlli clinici e strumentali periodici e con la terapia medica appropriata secondo la pratica clinica corrente

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

2011-07-13

Ethics Committee Opinion of the trial application

Favourable

Ethics Committee Opinion: Reason(s) for unfavourable opinion

Date of Ethics Committee Opinion

2011-04-28

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

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