Clinical Trials Register

Summary
EudraCT Number:	2016-004806-32
Sponsor's Protocol Code Number:	RAMSES
National Competent Authority:	Italy - Italian Medicines Agency
Clinical Trial Type:	EEA CTA
Trial Status:	Prematurely Ended
Date on which this record was first entered in the EudraCT database:	2021-05-24
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

2016-004806-32

A.3

Full title of the trial

Right ventriculAr reverse reModeling and hemodynamic improvement after add-on combination therapy (ambriSentan/PDE-5i) in PAH patientS (RAMSES)

Rimodellamento inverso del ventricolo destro e miglioramento emodinamico dopo aggiunta della terapia di combinazione (ambrisentan/inibitori della PDE-5) in pazienti con ipertensione polmonare arteriosa

A.3.1

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

Right ventriculAr reverse reModeling and hemodynamic improvement after add-on combination therapy (ambriSentan/PDE-5i) in PAH patientS (RAMSES)

A.3.2

Name or abbreviated title of the trial where available

RAMSES

A.4.1

Sponsor's protocol code number

RAMSES

A.5.4

Other Identifiers

Name:

Number:

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	ITALIAN PULMONARY HYPERTENSION NETWORK, IPHNET
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	Glaxo Smith Kline S.p.A
B.4.2	Country	Italy
B.4.1	Name of organisation providing support	Glaxo Smith Kline S.p.A. Italia
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	IPHNET
B.5.2	Functional name of contact point	Dott. Stefano Ghio
B.5.3	Address:
B.5.3.1	Street Address	Via Guelfa 9
B.5.3.2	Town/ city	Bologna
B.5.3.3	Post code	40138
B.5.3.4	Country	Italy
B.5.4	Telephone number	0382503460
B.5.5	Fax number	0382501279
B.5.6	E-mail	s.ghio@smatteo.pv.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	na
D.2.1.1.2	Name of the Marketing Authorisation holder	na
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.3.1	Product name	Volibris
D.3.2	Product code	[EU/1/08/451/004]
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	AMBRISENTAN
D.3.9.1	CAS number	177036-94-1
D.3.9.2	Current sponsor code	NA
D.3.10	Strength
D.3.10.1	Concentration unit	mg milligram(s)
D.3.10.2	Concentration type	up to
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	Information not present in EudraCT
D.3.11.3.2	Gene therapy medical product	Information not present in EudraCT
D.3.11.3.3	Tissue Engineered Product	Information not present in EudraCT
D.3.11.3.4	Combination ATIMP (i.e. one involving a medical device)	Information not present in EudraCT
D.3.11.3.5	Committee on Advanced therapies (CAT) has issued a classification for this product	Information not present in EudraCT
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

patients with pulmonary arterial hypertention

pazienti con ipertensione polmonare arteriosa

E.1.1.1

Medical condition in easily understood language

patients with pulmonary arterial hypertention

pazienti con 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	21.1
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

E.2 Objective of the trial

E.2.1

Main objective of the trial

Valutare il miglioramento emodinamico, indotto dall’aggiunta di ambrisentan 10 mg/die (OS), in pazienti con IAP già in trattamento in monoterapia con un iPDE-5. I parametri emodinamici misurati/calcolati mediante cateterismo cardiaco destro (CCD) saranno valutati alla visita di base (T0) e confrontati con i valori ottenuti alla visita di fine studio (T2).

E.2.2

Secondary objectives of the trial

Valutare i cambiamenti alla visita di fine studio (T2) rispetto ai valori misurati alla visita di base (T0), dei seguenti parametri:
Parametri indicativi di morfologia e funzione del VD, valutati mediante RMC*
Parametri indicativi di morfologia e funzione del VD, misurati mediante ecocardiografia*.
* Tutti gli esami di RMC ed ecocardiografia eseguiti nello studio saranno valutati tramite lettura centralizzata.

E.2.3

Trial contains a sub-study

E.3

Principal inclusion criteria

E.4

Principal exclusion criteria

Pazienti di età compresa fra 18 e 80 anni.
Volontà del paziente di partecipare allo studio firmando il modulo di Consenso Informato (CI) prima dell’inizio di qualsiasi procedura dello studio e che sia in possesso della capacità di sottoporsi a tutte le visite previste dal protocollo.
Pazienti con IAP confermata da una valutazione emodinamica della circolazione polmonare mediante CCD (Pressione Arteriosa Polmonare media [PAPm] =25 mmHg, Pressione di Incuneamento [PI] <15 mmHg, RVP =240 dyne¿s/cm5)
Sintomi inquadrabili in classe funzionale NYHA/OMS II-III
Diagnosi di una delle seguenti forme di IAP:
IAP idiopatica o ereditaria
IAP associata a malattia del tessuto connettivo, infezione HIV, indotta da farmaci o da tossine
Trattamento specifico per IAP in atto da almeno 3 mesi con un medicinale appartenente alla classe farmacologica iPDE-5 (es. tadalafil, sildenafil, vardenafil).
Donne in età fertile che facciano uso di adeguati metodi anticoncezionali per tutta la durata dello studio.
Disfunzione epatica definita da:
Valori ematici di bilirubina maggiori di 2 volte rispetto al limite superiore dei valori normali (>2 x ULN)
e/o valori ematici di aminotransferasi (ALT, AST) maggiori di 3 volte rispetto al limite superiore dei valori normali (>3 x ULN)
e/o segni d’insufficienza epatica grave (es. compromissione della sintesi di albumina con valori ematici di albumina <32 g/L, encefalopatia epatica di grado >1 secondo i West Haven Criteria of Altered Mental Status in Hepatic Encephalopathy) con o senza cirrosi.
Insufficienza renale grave (velocità di filtrazione glomerulare <30 mL/min calcolata mediante la formula di Cockcroft-Gault).
Soggetti con instabilità mentale, abuso di alcool o alcolismo cronico, uso di droghe.
Soggetti non in grado di deambulare.
Soggetti che si trovino in qualsiasi condizione che pregiudichi l’aderenza alla terapia e/o a qualsiasi altra condizione specificata dal protocollo di studio.
Ipersensibilità ad ambrisentan, alla soia (eccipiente) o ad uno qualsiasi degli altri eccipienti contenuti nella stessa compressa di ambrisentan.

E.5 End points

E.5.1

Primary end point(s)

RVP calcolate al cateterismo cardiaco destro (CCD).

E.5.1.1

Timepoint(s) of evaluation of this end point

Visita di screening e visita di fine studio (T2)

E.5.2

Secondary end point(s)

Parametri misurati mediante RMC*:
Indice di massa ventricolare destra
Volume telediastolico del VD
Volume telesistolico del VD
Frazione di eiezione (FE) del VD
Volume di rigurgito della valvola tricuspide
Stroke volume del VD
Parametri valutati mediante ecocardiografia transtoracica*:
Area dell’atrio destro (AD)
Area telediastolica del VD
Area telesistolica del VD
Variazione dell’area del VD (RVFAC)
Escursione sistolica del piano valvolare tricuspidale (TAPSE)
Grado di rigurgito della valvola tricuspide
Indice di eccentricità telediastolico del ventricolo sinistro (IEVS)
Presenza di effusione pericardica
Parametri emodinamici valutati mediante cateterismo cardiaco destro (CCD)
Portata cardiaca
Indice Cardiaco (IC)
Pressione atriale destra (PAD)
PAPs, PAPd, PAPm
Pressione Capillare Polmonare (PCP)
* Tutti gli esami di RMC ed ecocardiografia eseguiti nello studio saranno valutati tramite lettura centralizzata.

E.5.2.1

Timepoint(s) of evaluation of this end point

Visita di screening e visita di fine studio (T2)

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

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

Valutare il miglioramento emodinamico, indotto dall’aggiunta di ambrisentan 10 mg/die (OS), in pazienti con IAP già in trattamento in monoterapia con un iPDE-5.

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

E.8.1.2

Open

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)

E.8.2.2

Placebo

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

E.8.6.2

Trial being conducted completely outside of the EEA

Information not present in EudraCT

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 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

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.4.2

For a multinational trial

F.4.2.1

In the EEA

F.4.2.2

In the whole clinical trial

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)

Continueranno i trattamenti come da pratica clinica

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

2019-01-07

Ethics Committee Opinion of the trial application

Favourable

Ethics Committee Opinion: Reason(s) for unfavourable opinion

Date of Ethics Committee Opinion

2019-03-02

P. End of Trial
P.	End of Trial Status	Prematurely Ended

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