Clinical Trials Register

Summary
EudraCT Number:	2012-003335-33
Sponsor's Protocol Code Number:	AC-055-305
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:	2013-01-11
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

2012-003335-33

A.3

Full title of the trial

A multi-center, double-blind, randomized, placebo-controlled, parallel-group, Phase 3 study to evaluate the effects of macitentan on exercise capacity in subjects with Eisenmenger Syndrome.

Studio di fase III, multicentrico, in doppio cieco, randomizzato, controllato con placebo, a gruppi paralleli per valutare gli effetti di macitentan sulla capacità di esercizio fisico in soggetti affetti dalla Sindrome di Eisenmenger.

A.3.1

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

Study to evaluate if macitentan is efficient, safe and tolerable to be used for treatment of Eisenmenger Syndrome.

Studio per valutare se macitentan è efficace, sicuro e tollerabile per il trattamento della Sindrome di Eisenmenger.

A.3.2

Name or abbreviated title of the trial where available

MAESTRO

A.4.1

Sponsor's protocol code number

AC-055-305

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	ACTELION PHARMACEUTICALS LTD.
B.1.3.4	Country	Switzerland
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	Actelion Pharmaceuticals Ltd.
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	Actelion Pharmaceuticals Ltd.
B.5.2	Functional name of contact point	Global Medical Information
B.5.3	Address:
B.5.3.1	Street Address	Gewerbestrasse 16
B.5.3.2	Town/ city	Allschwil
B.5.3.3	Post code	4123
B.5.3.4	Country	Switzerland
B.5.4	Telephone number	.
B.5.5	Fax number	.
B.5.6	E-mail	medinfo_ch@actelion.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	No
D.2.5	The IMP has been designated in this indication as an orphan drug in the Community	Yes
D.2.5.1	Orphan drug designation number	EU/3/11/909
D.3 Description of the IMP
D.3.1	Product name	Macitentan
D.3.2	Product code	ACT-064992
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	Macitentan
D.3.9.1	CAS number	441798-33-0
D.3.9.2	Current sponsor code	ACT-064992
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	10
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
D.8 Placebo: 1
D.8.1	Is a Placebo used in this Trial?	Yes
D.8.3	Pharmaceutical form of the placebo	Film-coated 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

Eisenmenger Syndrome

Sindrome di Eisenmenger

E.1.1.1

Medical condition in easily understood language

Condition caused by a defect in the heart that affects blood flow between the heart and the lungs.

Condizione causata da un difetto del cuore che interessa il flusso sanguigno tra il cuore e i polmoni.

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	10058554
E.1.2	Term	Eisenmenger's syndrome
E.1.2	System Organ Class	10010331 - Congenital, familial and genetic disorders

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

To demonstrate that macitentan improves exercise capacity in
comparison with placebo in subjects with Eisenmenger Syndrome (ES).

Dimostrare che macitentan migliora la capacità di esercizio fisico rispetto al placebo in soggetti affetti dalla Sindrome di Eisenmenger (SE).

E.2.2

Secondary objectives of the trial

To evaluate the effects of macitentan in comparison with placebo on:
– World Health Organization (WHO) functional class,
– Dyspnea (assessed by the Borg dyspnea index),
– Quality of life (QoL; assessed by the Short-Form 36(SF-36)questionnaire).

Valutare gli effetti di macitentan rispetto al placebo per:
– Classe funzionale WHO,
– Dispnea (valutata con la scala di Borg),
– Qualità della vita (QoL; misurata con il questionario Short-Form 36 (F36)).

E.2.3

Trial contains a sub-study

Yes

E.2.3.1

Full title, date and version of each sub-study and their related objectives

OTHER SUBSTUDIES:
"Hemodynamic sub-study", Version 1.ITA.A, date 23-10-2012

ALTRI SOTTOSTUDI:
"Sottostudio di emodinamica", Versione 1.ITA.A, data 23-10-2012

E.3

Principal inclusion criteria

- Males or females ≥ 18 and ≤ 70 years of age.
- Subjects with confirmed ES (European Society of Cardiology
[ESC] and the European Respiratory Society [ERS]
guidelines):
 Established by echocardiography as:
o Isolated ASD > 2 cm in diameter,
o or isolated VSD > 1 cm in diameter,
o or presence of both ASD and VSD (with either VSD
≤ 1 cm in diameter and ASD > 2 cm in diameter, or
VSD > 1 cm in diameter and ASD ≤ 2 cm in diameter,
or VSD > 1 cm in diameter and ASD > 2 cm in diameter),
o and right to left shunt or bi-directional shunt with
prevalent right to left direction.
 Unoperated, or previously palliated surgically for defects
mentioned above (incomplete closure).
 Resting peripheral arterial oxygen saturation (SaO2)
≤ 90% and >70% (pulse oximetry, room air).
- Cardiac catheterization measurements must show the following:
 Mean resting pulmonary arterial pressure (mPAP)> 25 mmHg,
 Pulmonary capillary wedge pressure (PCWP) or mean left atrial pressure (LAP) or left ventricular end diastolic
pressure (LVED) ≤ 15 mmHg,
 Pulmonary vascular resistance (PVR) ≥ 800 dyn∙s/cm5 or ≥ 10 Wood units.
- Subjects with WHO functional class ≥ II.
- Subjects able to perform the 6-minute walk test (6MWT)with a minimum distance of 50 m and a maximum distance
of 450 m.

- Uomini o donne di età ≥ 18 e ≤ 70 anni.
- Soggetti con Sindrome di Eisenmenger confermata (Linee guida della Società Europea di Cardiologia [ESC] e della Società Europea per le Malattie Respiratorie [ERS]):
• Accertata da ecocardiografia come:
o ASD isolato > 2 cm di diametro
o oppure VSD isolato > 1cm di diametro
o oppure presenza di entrambi ASD e VSD (con VSD ≤ 1 cm di diametro e ASD > 2 cm di diametro, o VSD > 1 cm di diametro e ASD ≤ 2 cm di diametro, o VSD > 1 cm di diametro e ASD > 2 cm di diametro)
o e shunt da destra a sinistra o shunt bidirezionale con direzione prevalente da destra a sinistra.
• Non operato o precedentemente sottoposto a chirurgia palliativa per i difetti suddetti (chiusura incompleta).
• Saturazione arteriosa periferica dell'ossigeno a riposo (SaO2) ≤ 90% e >70% (pulsossimetria, aria ambiente).
- Le misurazioni del cateterismo cardiaco devono evidenziarequanto segue:
• Pressione arteriosa polmonare media a riposo (mPAP) > 25 mmHg
• Pressione capillare polmonare incuneata (PCWP) o pressione atriale sinistra media (LAP) o pressione diastolica terminale ventricolare sinistra (LVED) ≤ 15 mmHg
• Resistenza vascolare polmonare (PVR) ≥ 800 dyn∙s/cm5 o ≥ 10 unità Wood.
- Soggetti con classe funzionale WHO ≥ II.
- Soggetti capaci di eseguire il test della camminata in 6 minuti (6MWT) con una distanza minima di 50 m e una distanza massima di 450 m.

E.4

Principal exclusion criteria

- Pulmonary arterial hypertension (PAH) not fulfilling the
criteria of ES as described in inclusion criterion 3 (e.g.,complex cardiac defects, single ventricle, and patent ductus arteriosus).
- Known moderate-to-severe restrictive (i.e., total lung capacity [TLC] < 60% of predicted value) or obstructive lung
disease (i.e., forced expiratory volume in one second [FEV1]
< 80 % of predicted, with FEV1 / forced vital capacity [FVC] < 70%).
- Down Syndrome
- Treatment with phosphodiesterase-5 (PDE-5) inhibitors or prostanoids within 1 month prior to Randomization.
- Treatment with endothelin receptor antagonists (ERAs) within 1 month prior to Randomization.
- Subjects who initiated diuretics within 1 week prior to Randomization or subjects whose diuretic treatment has not been stable within 1 week prior to Randomization.
- Subjects being considered for an organ transplant.

- Ipertensione Arteriosa Polmonare (PAH) che non soddisfa i criteri della Sindrome di Eisenmenger come descritto nel criterio di inclusione 3 (per esempio, difetti cardiaci complessi, ventricolo unico e dotto arterioso pervio).
- Nota malattia polmonare restrittiva (ossia, capacità polmonare totale [TLC] < 60% del valore predetto) o ostruttiva (ossia, volume espiratorio forzato in un secondo [FEV1] < 80 % del valore predetto, con FEV1 / capacità vitale forzata [FVC] < 70%) da moderata a grave.
- Sindrome di Down.
- Trattamento con inibitori della fosfodiesterasi di tipo 5 (PDE-5) o prostanoidi nel mese precedente la Randomizzazione.
- Trattamento con antagonisti del recettore dell'endotelina (ERAs) nel mese precedente la Randomizzazione.
- Soggetti che hanno iniziato l'assunzione di diuretici entro 1 settimana prima della Randomizzazione o soggetti il cui trattamento diuretico non è stato stabile nella settimana precedente la Randomizzazione.
- Soggetti in lista per trapianto di organo.

E.5 End points

E.5.1

Primary end point(s)

Change from baseline to Week 16 in exercise capacity, as
measured by the 6MWD.

Variazione dal basale alla Settimana 16 della capacità di esercizio, misurata con la 6MWD.

E.5.1.1

Timepoint(s) of evaluation of this end point

- Baseline
- Week 16

- Baseline
- Settimana 16

E.5.2

Secondary end point(s)

Change from baseline to Week 16* in:
 WHO functional class,
 Dyspnea (assessed by the Borg dyspnea index),
 QoL (assessed by the SF-36 questionnaire).

Variazione dal basale alla Settimana 16* per:
• Classe funzionale WHO
• Dispnea (valutata con la scala di Borg)
• QoL (valutata con il questionario SF-36).

E.5.2.1

Timepoint(s) of evaluation of this end point

- Baseline
- Week 16

- Baseline
- Settimana 16

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

Yes

E.6.13.1

Other scope of the trial description

tolerability; hemodynamic for sub-study only

tollerabilità; emodinamica per il solo sottostudio

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

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

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

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

Canada

Chile

China

India

Israel

Malaysia

Mexico

Philippines

Russian Federation

South Africa

Taiwan

Turkey

United States

Vietnam

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

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:

200

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.4.2

For a multinational trial

F.4.2.1

In the EEA

F.4.2.2

In the whole clinical trial

220

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)

An Open Label extension study will be considered for subjects who
complete the 16 weeks of double-blind treatment, as scheduled and for
subjects who prematurely discontinue study drug, provided they return
to the site for Visit 6a / Week 16.

Uno studio di estensione in aperto sarà considerato per i soggetti che completano la Settimana 16 del trattamento in doppio cieco come previsto e per i soggetti che interrompono prematuramente il farmaco in studio purchè ritornino al centro per la Visita 6a/Settimana 16.

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

2013-02-01

Ethics Committee Opinion of the trial application

Favourable

Ethics Committee Opinion: Reason(s) for unfavourable opinion

Date of Ethics Committee Opinion

2013-01-15

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

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