Clinical Trials Register

Summary
EudraCT Number:	2004-000478-30
Sponsor's Protocol Code Number:	AC-052-364(EARLY)
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:	2007-07-11
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

2004-000478-30

A.3

Full title of the trial

A randomized, double-blind, placebo-controlled, multicenter study to assess the efficacy, safety, and tolerability of bosentan in patients with mildly symptomatic pulmonary arterial hypertension.

Studio in doppio cieco, randomizzato, controllato con placebo, multicentrico per valutare l'efficacia, la sicurezza e la tollerabilita` del bosentan in pazienti affetti da ipertensione arteriosa polmonare (IAP) moderatamente sintomatica.

A.3.2

Name or abbreviated title of the trial where available

EARLY

A.4.1

Sponsor's protocol code number

AC-052-364(EARLY)

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
B.4.2	Country
B.5 Contact point designated by the sponsor for further information on the trial
B.5.1	Name of organisation
B.5.2	Functional name of contact point

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	TRACLEER*56CPR RIV 125MG
D.2.1.1.2	Name of the Marketing Authorisation holder	ACTELION PHARM.ITALIA Srl
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	Yes
D.2.5.1	Orphan drug designation number	EU/3/01/019
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	Bosentan
D.3.10	Strength
D.3.10.1	Concentration unit	mg milligram(s)
D.3.10.3	Concentration number	125
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	Non Applicabile

D.8 Information on Placebo
D.8 Placebo: 1
D.8.1	Is a Placebo used in this Trial?	Yes

E. General Information on the Trial

E.1 Medical condition or disease under investigation

E.1.1

Medical condition(s) being investigated

Treatment of pulmonary arterial hypertension (PAH) in patients with grade II modified NYHA

Trattamento dell Ipertensione Arteriosa Polmonare in pazienti di classe funzionale II modificata NYHA

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	10037400
E.1.2	Term	Pulmonary hypertension
E.1.2	System Organ Class	10038738 - Respiratory, thoracic and mediastinal 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 bosentan improves cardiac hemodynamics and, as subordinate, exercise capacity in mildly symptomatic PAH patients

Dimostrare che il bosentan migliora la capacita' di attivita' fisica e/o lemodinamica cardiaca nei pazienti affetti da IAP moderatamente sintomatica

E.2.2

Secondary objectives of the trial

To evaluate the effect of bosentan on time to clinical worsening, dyspnea, NYHA Class, and quality of life.

Dimostrare che il bosentan ritarda i tempi di peggioramento clinico e migliora i sintomi di dispnea,la Classe NYHA e la qualita' della vita.Dimostrare che il bosentan e' sicuro e ben tollerato in questa popolazione di pazienti.

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

PHARMACOECONOMIC:
Vers:
Date:
Title:
Objectives:

PHARMACOKINETIC/PHARMACODYNAMIC:
Vers:
Date:
Title:
Objectives:

LIFE QUALITY:
Vers:
Date:
Title:
Objectives:

FARMACOECONOMIA:
Vers:
Data:
Titolo:
Obiettivi:

FARMACOCINETICA/FARMACODINAMICA:
Vers:
Data:
Titolo:
Obiettivi:

QUALITA DELLA VITA:
Vers:
Data:
Titolo:
Obiettivi:

ALTRI SOTTOSTUDI:
Uno studio secondario esplorativo basato sulle valutazioni riguardanti lemodinamica durante lattivita' sara' condotto in centri prestabiliti.

E.3

Principal inclusion criteria

· PAH in modified NYHA functional class II due to:- PAH idiopathic (Primary Pulmonary Hypertension)- PAH secondary to human immunodeficiency virus (HIV)- PAH secondary to anorexigens- PAH secondary to atrial septum defect (ASD) < 2 cm, ventricular septum defect (VSD) < 1 cm or patent ductus arteriosus (PDA)- PAH secondary to connective tissue or auto-immune diseases· 6-minute walk test (6MWT) distance < 80% of normal predicted value, or < 500 m associated with Borg dyspnea index score of ³2 points

· IAP in Classe funzionale II modificata della NYHA, dovuta a:- IAP idiopatica (ipertensione polmonare primaria)- IAP secondaria al virus dell'immunodeficienza umana (HIV)- IAP secondaria agli anoressizzanti- IAP secondaria a un difetto del setto atriale (ASD, Atrial Septum Defect) < 2 cm, a un difetto del setto ventricolare (VSD, Ventricular Septum Defect) < 1 cm oppure a dotto arterioso pervio (DAP)- IAP secondaria a malattie dei tessuti connettivi o autoimmunitarie· Distanza percorsa nel test dei 6 minuti di marcia (6MWT, 6 Minute Walk Test) < 80% del valore normale previsto o < 500m se associato ad un punteggio dell'indice di dispnea di Borg > 2 punti.

E.4

Principal exclusion criteria

· PAH associated with conditions other than those mentioned above, e.g., PAH secondary to portal hypertension, complex congenital heart disease or reverse shunt· Severe obstructive lung disease: FEV1/FVC < 0.5· Total lung capacity < 80% of normal predicted value· Significant vasoreactivity during right heart catheterization: i.e., a fall in mPAP to < 40 mmHg with a decrease ³ 10 mmHg and with a normal cardiac index (³ 2.5 l/min.m2)· Acute or chronic impairment (other than dyspnea), limiting the ability to comply with study requirements (in particular with 6MWT)

· IAP associata a patologie diverse da quelle descritte sopra, ad es. IAP secondaria a ipertensione portale, cardiopatia congenita complessa o shunt invertito.· Pneumopatia ostruttiva grave: rapporto FEV1/FVC < 0,5 Capacita` polmonare totale < 80% del valore normale previsto· Vasoreattivita` significativa durante il cateterismo cardiaco destro: ossia una diminuzione dell'mPAP fino a livelli <40mmHg, con una riduzione ³ 10 mmHg e un indice cardiaco normale (³2,5 l/min.m2)· Disfunzione acuta o cronica (diversa dalla dispnea) che limita l'idoneita` del paziente a soddisfare i requisiti dello studio (in particolare il 6MWT)

E.5 End points

E.5.1

Primary end point(s)

· PVR at rest at EOS expressed as percent of baseline value. A geometric mean in the active group showing a reduction of at least 20% when compared to the placebo geometric mean is considered clinically relevant.

· PVR a riposo alla EOS espressa come percentuale del valore di vaseline. Si considera clinicamente rilevante la media geometrica nel gruppo attivo che mostri una riduzione di almeno il 20% rispetto al placebo.

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

E.6.8

Bioequivalence

E.6.9

Dose response

E.6.10

Pharmacogenetic

E.6.11

Pharmacogenomic

E.6.12

Pharmacoeconomic

Yes

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

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

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

Information not present in EudraCT

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

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	Yes
F.1.1	Number of subjects for this age range:	0
F.1.1.1	In Utero	No
F.1.1.2	Preterm newborn infants (up to gestational age < 37 weeks)	No
F.1.1.3	Newborns (0-27 days)	No
F.1.1.4	Infants and toddlers (28 days-23 months)	No
F.1.1.5	Children (2-11years)	No
F.1.1.6	Adolescents (12-17 years)	Yes
F.1.2	Adults (18-64 years)	Yes
F.1.3	Elderly (>=65 years)	Yes
F.2 Gender
F.2.1	Female	Yes
F.2.2	Male	Yes
F.3 Group of trial subjects
F.3.1	Healthy volunteers	No
F.3.2	Patients	Yes
F.3.3	Specific vulnerable populations	Yes
F.3.3.1	Women of childbearing potential not using contraception	Yes
F.3.3.2	Women of child-bearing potential using contraception	No
F.3.3.3	Pregnant women	No
F.3.3.4	Nursing women	No
F.3.3.5	Emergency situation	No
F.3.3.6	Subjects incapable of giving consent personally	No
F.3.3.7	Others	No
F.4 Planned number of subjects to be included
F.4.1	In the member state	16
F.4.2	For a multinational trial
F.4.2.1	In the EEA	80
F.4.2.2	In the whole clinical trial	170

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

2004-09-09

Ethics Committee Opinion of the trial application

Favourable

Ethics Committee Opinion: Reason(s) for unfavourable opinion

Date of Ethics Committee Opinion

2004-09-08

P. End of Trial
P.	End of Trial Status	Completed
P.	Date of the global end of the trial	2011-02-11

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