Clinical Trials Register

Summary
EudraCT Number:	2010-018322-40
Sponsor's Protocol Code Number:	AC-066A301
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:	2012-01-05
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

2010-018322-40

A.3

Full title of the trial

Uno studio multicentrico, a braccio singolo, in aperto, di fase 3b, per valutare gli effetti del passaggio da Flolan ad ACT 385781A nei pazienti con ipertensione arteriosa polmonare

A multicenter, single-arm, open-label, Phase IIIb Study to Assess the Effects of Switching From Flolan to ACT-385781A in patients with Pulmonary Arterial Hypertension

A.3.1

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

A clinical research study to evaluate the safety of changing from Flolan
to a new drug called Epoprostenol-Actelion in patients suffering from
pulmonary arterial hypertension

Studio clinico per valutare la sicurezza del passaggio da Flolan ad un nuovo farmaco chimato Epoprostenol-Actelion in pazienti con ipertensione arteriosa polmonare.

A.3.2

Name or abbreviated title of the trial where available

EPITOME-2

A.4.1

Sponsor's protocol code number

AC-066A301

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	Allschwill
B.5.3.3	Post code	4123
B.5.3.4	Country	Switzerland
B.5.4	Telephone number	+41 61 565 65 65
B.5.5	Fax number	+41 61 565 65 00
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	Yes
D.2.1.1.1	Trade name	Epoprostenolo per iniezione
D.2.1.1.2	Name of the Marketing Authorisation holder	Actelion Pharmaceutical Ltd
D.2.1.2	Country which granted the Marketing Authorisation	United States
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	Powder for solution for infusion
D.3.4.1	Specific paediatric formulation	No
D.3.7	Routes of administration for this IMP	Intravenous use
D.3.8 to D.3.10 IMP Identification Details (Active Substances)
D.3.8	INN - Proposed INN	Epoprostenol
D.3.9.1	CAS number	61849-14-7
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	1.5
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	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	Epoprostenol for injection
D.2.1.1.2	Name of the Marketing Authorisation holder	Actelion Pharmaceutical Ltd
D.2.1.2	Country which granted the Marketing Authorisation	United States
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	Powder for solution for infusion
D.3.4.1	Specific paediatric formulation	No
D.3.7	Routes of administration for this IMP	Intravenous use
D.3.8 to D.3.10 IMP Identification Details (Active Substances)
D.3.8	INN - Proposed INN	Epoprostenol
D.3.9.1	CAS number	61849-14-7
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	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

Pulmonary Arterial Hypertension

Ipertensione arteriosa polmonare

E.1.1.1

Medical condition in easily understood language

Pulmonary Arterial Hypertension is a condition in which the pressure in the blood vessels going to the lungs (the pulmonary arteries) is higher than normal

ipertensione arteriosa polmonare è una condizione in cui la pressione nei vasi sanguigni che vanno ai polmoni (le arterie polmonari) è superiore rispetto al normale

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	10064911
E.1.2	Term	Pulmonary arterial 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 evaluate the change in cardiac hemodynamics from baseline to 3-month following switch from Flolan to EFI on in patients with pulmonary arterial hypertension (PAH). • To evaluate the safety and tolerability of switching from Flolan to EFI in patients with PAH.

• Valutare il cambiamento nell'emodinamica cardiaca dalla baseline a 3 mesi dopo il passaggio da Flolan ad Epoprostenol per iniezione in pazienti con ipertensione arteriosa polmonare. • Valutare la sicurezza e la tollerabilita' del passaggio da Flolan ad Epoprostenol per iniezione in pazienti con ipertensione arteriosa polmonare.

E.2.2

Secondary objectives of the trial

E.2.3

Trial contains a sub-study

E.3

Principal inclusion criteria

1. Male or female aged 18 years and above 2. Patients with the following types of pulmonary arterial hypertension (PAH) belonging to WHO Group I: •Idiopathic (IPAH) •Heritable (HPAH) •Associated (APAH) with o Connective tissue diseases o Drugs and toxins 3. Patients treated with Flolan for at least 12 months and on a stable dose for at least 3 month prior to enrollment 4. Patients who are currently treated with concomitant PAH therapy listed below must have been treated for at least 90 days and on a stable dose for 30 days prior to enrollment: • Bosentan • Ambrisentan • Sitaxsentan • Sildenafil • Tadalafil 5. Women of childbearing potential must use a reliable method of contraception 6. Signed informed consent prior to initiation of any study mandated procedure

1. Sesso maschile o femminile, eta' minima 18 anni 2. Pazienti con i seguenti tipi di ipertensione arteriosa polmonare appartenenti al gruppo I OMS: • Idiopatici (IPAH) • Ereditari (HPAH) • Associati (APAH) a o Patologie del tessuto connettivo o Farmaci e tossine 3. Pazienti trattati con Flolan per almeno 12 mesi e con una dose stabile per almeno 3 mesi prima dell'arruolamento 4. I pazienti che sono attualmente trattati con terapia concomitante per l'ipertensione arteriosa polmonare elencata nel seguito devono essere stati trattati per almeno 90 giorni e con una dose stabile per 30 giorni prima dell'arruolamento: • Bosentan • Ambrisentan • Sitaxentan • Sildenafil • Tadalafil 5. Le donne in grado di concepire devono utilizzare un metodo di contraccezione affidabile 6. Consenso informato firmato prima dell'inizio di qualsiasi procedura obbligatoria per lo studio

E.4

Principal exclusion criteria

1. Patients with respiratory and/or cardiovascular distress in need of emergency care 2. Known or suspicion of pulmonary veno-occlusive disease (PVOD) 3. Current use of IV inotropic agents 4. Current use of any prostacyclin or prostacyclin analog other than Flolan 5. Tachycardia with heart rate > 120 beats/min at rest 6. PAH related to any condition other than those specified in the inclusion criteria 7. Known hypersensitivity to the formulation of EFI or any of its excipients, and Flolan or any of its excipients 8. Cerebrovascular events (e.g., transient ischemic attack or stroke) within 6 months of screening 9. History of myocardial infarction 10. History of left-sided heart disease, including any of the following: • hemodynamically significant aortic or mitral valve disease • restrictive or congestive cardiomyopathy • left ventricular ejection fraction < 40% by multigated radionucleotide angiogram (MUGA), angiography, or echocardiography • unstable angina pectoris • life-threatening cardiac arrhythmias 11. Chronic bleeding disorders 12. Central venous line infection within 90 days prior to screening and/or a history of recurring line infections 13. Women who are pregnant or breast-feeding 14. Participation in another clinical trial, except observational, or receipt of an investigational product within 30 days prior to inclusion 15. Any known factor or disease that might interfere with treatment compliance, study conduct or interpretation of the results such as drug or alcohol dependence or psychiatric disease 16. Known concomitant life-threatening disease other than PAH with a life expectancy < 12 months

1. Pazienti con disturbi respiratori e/o cardiovascolari con esigenza di cure di emergenza 2. Patologia venocclusiva polmonare nota o sospetta 3. Utilizzo attuale di agenti inotropici endovenosi 4. Utilizzo attuale di qualsiasi prostaciclina o analogo della prostaciclina diversi dal Flolan 5. Tachicardia con frequenza cardiaca > 120 battiti/min a riposo 6. Ipertensione arteriosa polmonare correlata a qualsiasi condizione diversa da quelle specificate nei criteri di inclusione 7. Ipersensibilita' nota alle formulazioni Epoprostenol per iniezione o a qualsiasi suo eccipiente e al Flolan o a qualsiasi suo eccipiente 8. Eventi cerebrovascolari (ad es. attacco ischemico transitorio o ictus) entro 6 mesi dallo screening 9. Anamnesi di infarto del miocardio 10. Anamnesi di patologia cardiaca del lato sinistro, compresa una qualsiasi delle seguenti: • patologia emodinamicamente significativa della valvola aortica o della valvola mitrale • cardiomiopatia restrittiva o congestizia • frazione di eiezione ventricolare sinistra < 40% secondo quanto evidenziato da angiogramma MUGA, angiografia o ecocardiografia • angina pectoris instabile • aritmie cardiache pericolose per la vita 11. Disturbi cronici da sanguinamento 12. Infezione della linea venosa centrale entro 90 giorni prima dello screening e/o anamnesi di infezioni di linea recidive 13. Donne in gravidanza o in allattamento al seno 14. Partecipazione ad un altro trial clinico, tranne quelli di osservazione, oppure ricevimento di un prodotto di ricerca entro 30 giorni prima dell’arruolamento 15. Qualsiasi fattore o patologia noti che possano interferire con la conformita' al trattamento, la condotta dello studio o l'interpretazione dei risultati, ad esempio dipendenza da farmaci o da alcool o disturbi psichiatrici 16. Patologia concomitante nota pericolosa per la vita, diversa dall'ipertensione arteriosa polmonare, con aspettativa di vita < 12 mesi

E.5 End points

E.5.1

Primary end point(s)

Tolerability / Safety endpoints: • Treatment-emergent adverse events (AEs) up to 24 hours post-EOT • Change from baseline to EOT in vital signs [heart rate (HR) and blood pressure (BP)] and body weight • AEs leading to premature discontinuation of study drug • Treatment-emergent serious AEs (SAEs) up to 30 days post-EOT Efficacy endpoint: • Change from baseline to EOT in cardiac hemodynamics including: o Pulmonary vascular resistance (PVR) o Mean pulmonary arterial pressure (mPAP) o Right atrial pressure (RAP) o Pulmonary artery occlusion pressure (PAOP) o Cardiac index (CI)

Endpoints di tollerabilita'/sicurezza • Eventi avversi in conseguenza del trattamento fino a 24 ore dopo la fine del trattamento • Cambiamento dalla baseline alla fine del trattamento nei segni vitali (frequenza cardiaca e pressione ematica) e nel peso corporeo • Eventi avversi che portano all’interruzione prematura del farmaco dello studio .Eventi avversi gravi in conseguenza del trattamento fino a 30 giorni dopo la fine del trattamento Endpoint di efficacia • Cambiamento dalla baseline alla fine del trattamento nell'emodinamica cardiaca comprendente: o Resistenza vascolare polmonare o Pressione arteriosa polmonare media o Pressione atriale destra o Pressione di occlusione dell'arteria polmonare o Indice cardiaco

E.5.1.1

Timepoint(s) of evaluation of this end point

-Weekly phone visit : Weeks 1, 2, and 3 - Inpatient Visit : Week 4 - By-weekly phone visit : Weeks 6, 8, and 10 Safety follow up: - 24 hours post-EOT phone call - 30 days post-EOT phone call End of study: - 24 hours post-EOT phone call for patients who participate in the extension study AC-066A302 - 30 days post-EOT phone call for patients not participating in the extension study AC-066A302

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

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, explaratory study phase 3b

Tollerabilita', ''explaratory'' studio di fase 3b

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

E.8.1.1

Randomised

E.8.1.2

Open

Yes

E.8.1.3

Single blind

E.8.1.4

Double blind

E.8.1.5

Parallel group

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)

Information not present in EudraCT

E.8.2.2

Placebo

Information not present in EudraCT

E.8.2.3

Other

Information not present in EudraCT

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

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

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

Last Patient Last End of treatment visit

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	No
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)	No
F.1.2	Adults (18-64 years)	Yes
F.1.2.1	Number of subjects for this age range:	35
F.1.3	Elderly (>=65 years)	No
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	No
F.3.3.2	Women of child-bearing potential using contraception	Yes
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	5
F.4.2	For a multinational trial
F.4.2.1	In the EEA	30
F.4.2.2	In the whole clinical trial	40

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

2011-05-04

Ethics Committee Opinion of the trial application

Favourable

Ethics Committee Opinion: Reason(s) for unfavourable opinion

Date of Ethics Committee Opinion

2011-04-12

P. End of Trial
P.	End of Trial Status	Completed
P.	Date of the global end of the trial	2012-02-02

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