Clinical Trials Register

Summary
EudraCT Number:	2014-004066-20
Sponsor's Protocol Code Number:	AC-055-403
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:	2015-05-22
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

2014-004066-20

A.3

Full title of the trial

Studio prospettico, multicentrico, a braccio singolo, in aperto, di fase 4 per la valutazione degli effetti del macitentan sul rimodellamento del ventricolo destro nell'ipertensione arteriosa polmonare (Right vEntricular remodeling in Pulmonary ArterIal hypeRtension) accertata mediante risonanza magnetica cardiaca per immagini.

A prospective, multicenter, single-arm, open-label, Phase 4 study to evaluate the effects of macitentan on Right vEntricular remodeling in Pulmonary ArterIal hypeRtension assessed by cardiac magnetic resonance imaging

A.3.1

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

Phase IV study on right ventricular remodeling in Pulmonary arterial hypertension

Studio di fase IV sul rimodellamento del ventricolo destro nell'ipertensione arteriosa polmonare

A.3.2

Name or abbreviated title of the trial where available

REPAIR

A.4.1

Sponsor's protocol code number

AC-055-403

A.5.4

Other Identifiers

Name:

AC-055-403

Number:

AC-055-403

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
B.4 Source(s) of Monetary or Material Support for the clinical trial:
B.4.1	Name of organisation providing support	Azienda Farmaceutica: Actelion Pharmaceuticals -
B.4.2	Country	United Kingdom
B.5 Contact point designated by the sponsor for further information on the trial
B.5.1	Name of organisation	Actelion Pharmaceurical 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	0041 61 5658336
B.5.5	Fax number	0041 61 5656410
B.5.6	E-mail	medinfo@actelio.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.2.1.1.2	Name of the Marketing Authorisation holder	ACTELION REGISTRATION LIMITED
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/3/11/909
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.3.11 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 Polmonare Arteriosa

E.1.1.1

Medical condition in easily understood language

Pulmonary Arterial Hypertension

Ipertensione Polmonare 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	18.0
E.1.2	Level	SOC
E.1.2	Classification code	10038738
E.1.2	Term	Respiratory, thoracic and mediastinal disorders
E.1.2	System Organ Class	10038738 - Respiratory, thoracic and mediastinal 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 macitentan on right ventricular and hemodynamic properties in patients with symptomatic pulmonary arterial hypertension (PAH).

Valutare l'effetto del macitentan sulle proprietà emodinamiche e del ventricolo destro nei pazienti affetti da ipertensione arteriosa polomonare (PAH) sintomatica

E.2.2

Secondary objectives of the trial

To investigate the effect of macitentan on ventriculo-arterial coupling in patients with symptomatic PAH.
To evaluate the safety and tolerability of macitentan in patients with symptomatic PAH.

Indagare l'effetto del macitentan sull'accoppiamento ventricolo-arterioso nei pazienti affetti da PAF sintomatica
Valutare la sicurezza e tollerabilità del macitentan nei pazienti affetti da PAH sintomatica.

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

Three substudies described in the study protocol.
The substudies will be performed in the selected studies each one will participate to one each selected subsudy
- Substudy on metabolism, onlys United States
-Substudy on biopsy
-Substudy on echocardiography

Sono previsti tre sottostudi, descritti nello stesso protocollo.
I sottostudi saranno effettuati in centri selezionati, ciascuno dei quali parteciperà a un solo sottostudio. In questi centri, tutti i pazienti idonei a partecipare allo studio principale saranno invitati a prendere parte a un sottostudio.
-Sottostudio sul metabolismo, solo negli Stati Uniti
-Sottostudio sulla biopsia
-Sottostudio sull'ecocardiografia

E.3

Principal inclusion criteria

1. Signed informed consent prior to any study-mandated procedure.
2. Symptomatic PAH.
3. World Health Organization (WHO) Functional Class (FC) I to III.
4. PAH etiology belonging to one of the following groups according to Nice classification:
1.1 Idiopathic PAH
1.2 Heritable PAH
1.3 Drug- and toxin-induced PAH
1.4.4 PAH associated with congenital heart diseases: only simple (atrial septal defect, ventricular septal defect, patent ductus arteriosus) congenital systemic to pulmonary shunts at least 2 year post surgical repair.
5. Hemodynamic diagnosis of PAH confirmed by right heart catheterization (RHC) during screening showing:
• Mean pulmonary arterial pressure (mPAP) ≥ 25 mmHg and
o Pulmonary capillary wedge pressure (PCWP) or left ventricular end diastolic pressure (LVEDP) ≤ 12 mmHg and pulmonary vascular resistance (PVR) ≥ 4 Woods Units (WU) (320 dyn.sec.cm-5) or
o 12 mmHg ≤ PCWP or LVEDP ≤ 15 mmHg and PVR ≥ 6 WU (480 dyn.sec.cm-5).
6. 6-minute walk distance (6MWD) ≥ 150 m during screening.
7. For patients treated with oral diuretics, treatment dose must have been stable at least 1 month prior to RHC during the screening period.
8. For patients treated with phosphodiesterase type-5 (PDE-5) inhibitors, treatment dose must have been stable at least 3 months prior to RHC during the screening period.
9. For patients treated with beta blockers, treatment dose must have been stable at least 1 month prior to the RHC during the screening period.
10. Men or women ≥ 18 and < 65 years.
11. Women of childbearing potential [see Section 4.5.1] must:
a. Have a negative serum pregnancy test during screening and a negative urine pregnancy test on Day 1, and
b. Agree to use reliable methods of contraception [see Section 4.5] from screening up to 30 days after study treatment discontinuation, and
Agree to perform monthly pregnancy tests up to 30 days after study treatment discontinuation.
b. Agree to use reliable methods of contraception [see Section 4.5] from screening up to 30 days after study treatment discontinuation, and
c. Agree to perform monthly pregnancy tests up to 30 days after study treatment discontinuation.

1. Firma del consenso informato prima di qualsiasi procedura richiesta dallo studio.
2. PAH sintomatica.
3. Classe funzionale (FC) dell'Organizzazione mondiale della sanità (WHO) II e III.
4. Eziologia PAH riconducibile a uno dei seguenti gruppi secondo la classificazione Nice:
1.1 PAH idiopatica
1.2 PAH ereditabile
1.3 PAH indotta da farmaci e tossine
1.4.4 PAH associata a cardiopatie congenite: solo semplici (difetto settale atriale, difetto settale ventricolare, dotto arterioso pervio) con shunt sistemico-polmonare due anni almeno dopo la riparazione chirurgica
5. Diagnosi emodinamica di PAH confermata dalla
cateterizzazione cardiaca destra (RHC) durante lo screening che mostri:
• Pressione arteriosa polmonare media (mPAP) ≥25 mmHg e
o Pressione wedge (pressione di incuneamento dei capillari polmonari) (PCWP) o pressione telediastolica ventricolare sinistra finale (LVEDP) ≤12 mm Hg e resistenza vascolare polmonare (PVR) ≥4 unità Wood (WU) (320 dyne/sec/cm-5) o
o 12 mmHg ≤PCWP o LVEDP ≤15 mm Hg e PVR ≥6 WU (480 dyne/sec/cm-5).
6. Distanza percorsa a piedi in 6 minuti (6MWD) ≥150 m durante lo screening.
7. Per i pazienti trattati con diuretici orali, la dose di trattamento deve essere rimasta stabile per almeno un mese prima della cateterizzazione cardiaca destra durante il periodo di screening.
8. Per i pazienti trattati con inibitori della fosfodiesterasi di tipo 5 (PDE-5), la dose di trattamento deve essere rimasta stabile per almeno tre mesi prima della cateterizzazione cardiaca destra durante il periodo di screening.
9. Per i pazienti trattati con betabloccanti, la dose di trattamento deve essere rimasta stabile per almeno un mese prima della cateterizzazione cardiaca destra durante il periodo di screening.
10. Uomini o donne ≥18 e <65 anni.
11. Le donne in età fertile [vedere la sezione 4.5.1] devono:
a. ottenere un test di gravidanza su siero negativo durante lo screening e un test di gravidanza su urine negativo il giorno 1 e
b. accettare di usare metodi contraccettivi affidabili [vedere la sezione 4.5] dallo screening fino a 30 giorni dopo che avranno cessato di assumere il farmaco oggetto dello studio e
c. accettare di eseguire il test di gravidanza ogni mese fino a 30 giorni dopo che avranno cessato di assumere il farmaco oggetto dello studio.

E.4

Principal exclusion criteria

1. Body weight < 40 kg.
2. Body mass index (BMI) > 35kg/m2. For patients with 30kg/m2 < BMI < 35kg/m2, an eligibility form will be submitted to a Steering Committee member who will reserve the right to exclude the patient.
3. Pregnancy, breastfeeding, or intention to become pregnant during the study.
4. Recently started (< 8 weeks prior to informed consent signature) or planned cardio-pulmonary rehabilitation program.
5. Known concomitant life-threatening disease with a life expectancy < 12 months.
6. Any condition likely to affect protocol or treatment compliance.
7. Hospitalization for PAH within 3 months prior to informed consent signature.
8. Left atrial volume indexed for body surface area ≥ 43mL/m2 by echocardiography or cardiac MRI.
9. Valvular disease grade 2 or higher.
10. History of pulmonary embolism or deep vein thrombosis.
11. Documented moderate to severe chronic obstructive pulmonary disease.
12. Documented moderate to severe restrictive lung disease.
13. Historical evidence of significant coronary artery disease established by:
o History of myocardial infarction or
o More than 50% stenosis in a coronary artery (by percutaneous coronary intervention or angiography) or
o Elevation of the ST segment on electrocardiogram or
o History of coronary artery bypass grafting or
o Stable angina.
14. Diabetes mellitus.
15. Moderate to severe renal insufficiency (calculated creatinine clearance < 60 mL/min/1.73 m2).
16. Cancer.
17. Systolic blood pressure < 90 mmHg.
18. Severe hepatic impairment (with or without cirrhosis) according to National Cancer Institute organ dysfunction working group criteria, defined as total bilirubin > 3 × upper limit of the normal range (ULN) accompanied by an aspartate aminotransferase (AST) elevation > ULN at screening.
19. Hemoglobin < 100g/L.
20. Serum AST and/or alanine aminotransferase (ALT) > 3 × ULN.
21. Need for dialysis.
22. Responders to acute vasoreactivity test based on medical history.
23. Prior use of endothelin receptor antagonists (ERAs), stimulators of soluble guanylate cyclase or prostacyclin or prostacyclin analogues.
24. Treatment with strong inducers of cytochrome P450 isozyme 3A4 (CYP3A4) within 4 weeks prior to study treatment initiation (e.g., carbamazepine, rifampicin, rifabutin, phenytoin and St. John’s Wort).
25. Treatment with strong inhibitors of CYP3A4 within 4 weeks prior to study treatment initiation (e.g., ketoconazole, itraconazole, voriconazole, clarithromycin, telithromycin, nefazodone, ritonavir, and saquinavir).
26. Treatment with another investigational drug (planned, or taken within the 3 months prior to study treatment initiation).
27. Hypersensitivity to any ERA or any excipients of the formulation of macitentan (lactose, magnesium stearate, microcrystalline cellulose, povidone, sodium starch glycolate, polyvinyl alcohol, polysorbate, titanium dioxide, talc, xanthan gum, and lecithin soya).
28. Claustrophobia.
29. Permanent cardiac pacemaker, automatic internal cardioverter.
30. Metallic implant (e.g., defibrillator, neurostimulator, hearing aid, permanent use of infusion device).
31. Atrial fibrillation, multiple premature ventricular or atrial contractions, or any other condition that would interfere with proper cardiac gating during MRI.
32. For patients enrolling in the metabolism sub-study only: glucose intolerance.
33. For patients enrolling in the biopsy sub-study only: PAH etiology belonging to Nice classification 1.4.4: PAH associated with congenital heart diseases.

1. Peso corporeo <40 kg.
2. Indice di massa corporea (IMC) >35 kg/m2. Per i pazienti con IMC 30 kg/m2 - <35 kg/m2, sarà presentato il modulo di idoneità a un membro del Comitato direttivo che si riserverà il diritto di escludere il paziente.
3. Gravidanza in corso o programmata e allattamento durante lo studio.
4. Programma di riabilitazione cardiopolmonare iniziato di recente (<8 settimane dalla firma del consenso informato) o pianificato.
5. Malattia concomitante nota, pericolosa per la vita, con aspettativa di vita <12 mesi.
6. Qualsiasi condizione che presumibilmente influisce sulla conformità al protocollo o al trattamento.
7. Ricovero in ospedale per PAH nei tre mesi precedenti la firma del consenso informato.
8. Volume atriale sinistro indicizzato per l'area della superficie corporea ≥43 ml/m2 in base a ecocardiografia o RMI cardiaca.
9. Malattia valvolare grado 2 o superiore.
10. Storia di embolia polmonare o trombosi venosa profonda.
11. Pneumopatia ostruttiva cronica documentata da moderata a grave.
12. Malattia polmonare restrittiva documentata da moderata a grave.
13. Prova storica di malattia arteriosa coronarica importante determinata in base a:
o Storia di infarto miocardico o
o Oltre il 50% di stenosi arteriosa coronarica (mediante intervento coronarico percutaneo o angiografia) o
o Elevazione del segmento ST nell'elettrocardiogramma o
o Storia di innesto di bypass aorto-coronarico o
o Angina stabile.
14. Diabete mellito.
15. Insufficienza renale da moderata a grave (clearance della creatinina calcolata <60 ml/min/1,73 m2).
16. Cancro.
17. Pressione sanguigna sistolica <90 mm Hg.
18. insufficienza epatica grave (con o senza cirrosi epatica) in conformità ai criteri della classificazione National Cancer Institute Organ Dysfunction Working Group, definita come bilirubina totale >3 volte il limite superiore del valore normale (ULN) accompagnata da aumento dell'aspartato aminotransferasi (AST) >ULN durante lo screening.
19. Emoglobina <100 g/l.
20. AST e/o alanina aminotransferasi (ALT) nel siero >3 volte l'ULN.
21. Necessità di dialisi.
22. Responder al test acuto di vasoreattività in base alla storia clinica
23. Precedente uso di antagonisti dei recettori dell'endotelina (ERA), stimolatori della guanilato ciclasi solubile, prostacicline o analoghi delle prostacicline.
24. Trattamento con forti induttori dell'isoenzima 3A4 del citocromo P450 (CYP3A4) entro le quattro settimane precedenti l'inizio del trattamento oggetto dello studio (per esempio, carbamazepina, rifampicina, rifabutina, fenitoina e iperico).
25. Trattamento con forti inibitori del CYP3A4 entro le quattro settimane precedenti l'inizio del trattamento oggetto dello studio (per esempio, ketoconazolo, itraconazolo, voriconazolo, claritromicina, telitromicina, nefazodone, ritonavir e saquinavir).
26. Trattamento con un altro farmaco sperimentale (pianificato o effettuato entro i tre mesi precedenti l'inizio del trattamento oggetto dello studio).
27. Ipersensibilità a un qualsiasi ERA o a qualsiasi eccipiente della formulazione del macitentan (lattosio, magnesio stearato, cellulosa microcristallina, povidone, glicolato di amido di sodio, alcool polivinilico, polisorbato, biossido di titanio, talco, gomma xantana e lecitina di soia).
28. Claustrofobia.
29. Pacemaker cardiaco permanente, cardiovertitore automatico.
30. Impianto metallico (per esempio, defibrillatore, neurostimolatore, apparecchio acustico, uso permanente di dispositivo di infusione).
31. Fibrillazione atriale, contrazioni ventricolari o atriali premature multiple o qualsiasi altra condizione che interferisca con l'adeguato gating cardiaco durante la RMI.
32. Per i pazienti che partecipano esclusivamente al sottostudio sul metabolismo: intolleranza al glucosio.
33. Per i pazienti che partecipano esclusivamente al sottostudio sulla biopsia: Eziologia PAH riconducibile alla classificazione Nice 1.4.4: PAH associata a cardiopatie congenite.

E.5 End points

E.5.1

Primary end point(s)

Primary efficacy endpoints The study has two primary efficacy endpoints: - Change from baseline to Week 26 in Right Ventricular (RV) Stroke Volume (RVSV) assessed by cardiac MRI from pulmonary artery flow. - Ratio of Week 26 to baseline PVR assessed by RHC.

Endpoint di efficacia primari Lo studio ha due endpoint di efficacia primari: - Variazione, tra il basale e la settimana 26, dello stroke volume (SV) del ventricolo destro valutata mediante RMI cardiaca in base al flusso dell'arteria polmonare - PVR alla settimana 26 rispetto al basale valutata mediante cateterizzazione cardiaca destra.

E.5.1.1

Timepoint(s) of evaluation of this end point

week 26

settimana 26

E.5.2

Secondary end point(s)

Change from baseline to Week 26 in: - RV End Diastolic Volume (RVEDV) - RV End Systolic Volume (RVESV) - RV Ejection Fraction (RVEF) - RV mass - Arterial elastance - RV end-systolic elastance - RV maximum isovolumic pressure - 6MWD - WHO FC

Variazione tra il basale e la settimana 26 di: - Volume telediastolico (EDV) del ventricolo destro - Volume telesistolico (ESV) del ventricolo destro - Frazione di eiezione (EF) del ventricolo destro - Massa del ventricolo destro - Elastanza arteriosa - Elastanza telesistolica del ventricolo destro - Pressione isovolumetrica massima del ventricolo destro - 6MWD - FC WHO

E.5.2.1

Timepoint(s) of evaluation of this end point

week 26

settimana 26

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

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

E.8.1.1

Randomised