Clinical Trials Register

Summary
EudraCT Number:	2011-002587-24
Sponsor's Protocol Code Number:	CMD_ALISKIREN
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:	2012-01-10
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

2011-002587-24

A.3

Full title of the trial

Effects of Aliskiren on microcirculation dysfunction in patients affected by hypertension

Effetti del farmaco Aliskiren sulla disfunzione del microcircolo nei pazienti con ipertensione arteriosa

A.3.1

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

Effect of Aliskiren drug in patients with high blood pressure

Effetto del farmaco Aliskiren in pazienti con pressione alta

A.4.1

Sponsor's protocol code number

CMD_ALISKIREN

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 CENTRO S. RAFFAELE DEL MONTE TABOR
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	Novartis
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 San Raffaele del Monte Tabor
B.5.2	Functional name of contact point	Cardiologia
B.5.3	Address:
B.5.3.1	Street Address	via Olgettina, 60
B.5.3.2	Town/ city	milano
B.5.3.3	Post code	20132
B.5.3.4	Country	Italy
B.5.4	Telephone number	02-26436206
B.5.5	Fax number	02-264326218
B.5.6	E-mail	camici.paolo@hsr.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	ENALAPRIL S.G.*28CPR 5MG
D.2.1.1.2	Name of the Marketing Authorisation holder	SIGMATAU GENERICS 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	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	ENALAPRIL
D.3.9.1	CAS number	75847-73-3
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	5
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	Yes
D.3.11.13.1	Other medicinal product type	natura chimica
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	RASILEZ*56CPR RIV 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	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	ALISKIREN
D.3.9.1	CAS number	173334-57-1
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	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	Yes
D.3.11.13.1	Other medicinal product type	natura chimica

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

dysfunction of coronary microcirculation in arterial hypertension

disfunzione del microcircolo coronarico nell'ipertensione arteriosa

E.1.1.1

Medical condition in easily understood language

ipertensione arteriosa

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	HLT
E.1.2	Classification code	10010164
E.1.2	Term	Hypertension complications
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

to evaluate the effect of aliskiren compared to enelapril in improving myocardial blood pressure in patients with hypertensive heart disease

valutare l'effetto di aliskiren rispetto a quello di enelapril nel migliorare l'ipertensione miocardica in pazienti con cardiopatia ipertensiva

E.2.2

Secondary objectives of the trial

Significant correlation between:
-levels of plasma renin activity (PRA) at baseline and at 6 months maximum MBF
-delta pressure and delta of myocardial mass indexed (LVMI)
-improvement of the indices of systolic-diastolic function of left ventricle and the delta maximum MBF.
-delta LVMI and plasma levels of PRA, aldosterone.
-No significant correlation between:
-delta of maximum pressure and delta MBF (start-end study).
-maximum delta-delta LVMI and MBF.

Correlazione significativa tra:
-livelli di attività reninica plasmatica (PRA) basale e maximum MBF a 6 mesi,
-delta pressorio e delta massa miocardica indicizzata (LVMI)
-miglioramento degli indici di funzione sisto-diastolica del ventricolo sinistro e delta di maximum MBF.
-delta LVMI e livelli plasmatici di PRA, aldosterone.
Assenza di correlazione significativa fra:
-delta pressorio e delta di maximum MBF (inizio-fine studio)
-delta LVMI e delta maximum MBF.

E.2.3

Trial contains a sub-study

E.3

Principal inclusion criteria

•Age ≥40 and ≤75 yr.
•Body mass index (BMI) ≤32 kg/m2;
•Diastolic BP (DBP) <110 mmHg and systolic BP (SBP) <180 mmHg in patients previously treated;
•On therapy with amlodipine with or without a thiazide diuretic;
•Left ventricular mass index (LVMI) ≥115 g/m2 (men) or ≥100 g/m2 (women) quantified by two dimensional echocardiography;
•Left ventricular ejection fraction ≥55% at two-dimensional echocardiography;
•Valid informed consent obtained from participants.

-Età ≥ 40 e ≤ 75 anni.
-Indice di massa corporea (BMI) ≤ 32 kg/m2;
-pressione diastolica (DBP) <110 mmHg e pressione sistolica (SBP) <180 mmHg nei pazienti precedentemente trattati;
-pazienti in terapia con amlodipina con o senza un diuretico tiazidico;
-indice di massa ventricolare sinistra (LVMI) ≥ 115 g/m2 (uomini) o ≥ 100 g/m2 (donne) quantificati da due ecocardiografie dimensionale;
-frazione di eiezione del ventricolo sinistro ≥ 55% a ecocardiografia bidimensionale;
-consenso informato valido ottenuto dai partecipanti.

E.4

Principal exclusion criteria

• History of secondary HT;
• Anamnestic coronary heart disease;
• Renal failure (creatinine >1.69 mg/dl or creatinine clearance <30 ml/min);
• Hypokalemia (<3.4 mEq/l) or hyperkalemia (>5 mEq/l);
• Insulin-dependent diabetes;
• Significant valvular disease or left ventricular systolic dysfunction at echocardiography;
• Treatment with Aliskiren, ACE inhibitors or angiotensin receptor blockers in the month preceding the first selection visit;
• Patients with stress-induced regional perfusion defects at PET will be referred for coronary angiography and excluded from the study if they have coronary artery disease;
• Pregnancy and breastfeeding;
• ACEI angioedema, hereditary and/or idiopathic angioedema;
• Severe hepatic dysfunction

-Storia di HT secondaria;
- malattia coronarica in anamnesi;
-insufficienza renale (creatinina> 1,69 mg / dl o clearance della creatinina <30 ml / min);
-ipokaliemia (<3,4 mEq / l) o iperkaliemia (> 5 mEq / l);
-diabete insulino-dipendente;
-significativa malattia valvolare o disfunzione sistolica ventricolare sinistra all'ecocardiografia;
-trattamento con Aliskiren, ACE-inibitori o bloccanti del recettore dell'angiotensina nel mese precedente la prima visita di selezione;
-per pazienti con stress indotto da difetti di perfusione regionale alla PET si farà riferimento per l'angiografia coronarica e verranno esclusi dallo studio in caso di malattia coronarica;
-gravidanza e allattamento al seno;
-ACEI angioedema ereditario e / o angioedema idiopatico;
-disfunzione epatica grave

E.5 End points

E.5.1

Primary end point(s)

Significant difference (≥0.5 ml/min/g) in maximum MBF between the two treatment groups.

Differenza significativa (≥ 0,5 ml / min / g) in MBF massima tra i due gruppi di trattamento.

E.5.1.1

Timepoint(s) of evaluation of this end point

6 months

6 mesi

E.5.2

Secondary end point(s)

-Significant correlation between baseline PRA (or delta PRA M0-M6) and increase of maximun MBF at M6;
-No significant correlation between delta (resting or ambulatory) BP levels and delta of maximum MBF;
-Significant correlation between delta (resting or ambulatory) BP level and delta of LVMI
-No significant correlation between delta LVMI and delta maximum MBF;
-Significant correlation between improvement of diastolic or systolic markers of LV dysfunction (LV stiffness, E/A ratio , E/Em ratio or TEI index) and delta maximum MBF.
-Significant correlation between delta LVMI and PRA – aldosterone values.

-Correlazione significativa tra il basale PRA (o delta PRA M0-M6) e l'aumento del massimo MBF a M6;
-Nessuna correlazione significativa tra delta (a riposo o ambulatoriale), i livelli di pressione arteriosa e il delta del massimo MBF;
-significativa correlazione tra il delta (a riposo o ambulatoriale) livello BP e delta di LVMI
-nessuna correlazione significativa tra delta e delta massimo LVMI MBF;
-significativa correlazione tra il miglioramento dei marcatori sistolica o diastolica di disfunzione ventricolare sinistra (LV rigidezza, rapporto E / A, E / Em rapporto o indice di TEI) e delta massimo MBF.
-significativa correlazione tra il delta LVMI e PRA - valori di aldosterone.

E.5.2.1

Timepoint(s) of evaluation of this end point

6 months

6 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

Yes

E.6.4

Safety

E.6.5

Efficacy

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

superiority study

studio di superiorita'

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)

E.7.4

Therapeutic use (Phase IV)

Yes

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

valtazione dell'effetto enalapril verso aliskiren

evaluation of the effect of enelapril vs aliskiren

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.8.6 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

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

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)

the regimen of the study will be continued because more appropriate in accordance with current guidelines in place compared with previous therapy

verra' proseguito il regime terapeutico dello studio perche' piu' adeguato in base alle attuali linee guida rispetto alle terapie precedentemente in atto

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

2011-10-20

Ethics Committee Opinion of the trial application

Favourable

Ethics Committee Opinion: Reason(s) for unfavourable opinion

Date of Ethics Committee Opinion

2011-09-15

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

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