Clinical Trials Register

Summary
EudraCT Number:	2016-001199-31
Sponsor's Protocol Code Number:	57231
National Competent Authority:	Netherlands - Competent Authority
Clinical Trial Type:	EEA CTA
Trial Status:	Ongoing
Date on which this record was first entered in the EudraCT database:	2017-02-02
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

Netherlands - Competent Authority

A.2

EudraCT number

2016-001199-31

A.3

Full title of the trial

Improving treatment of right ventricular failure in pulmonary hypertension patients.

Het verbeteren van de behandeling van rechter hartfalen in patiënten met pulmonale hypertensie.

A.3.1

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

Improving treatment of right heart failure in patients with pulmonary hypertension.

Het verbeteren van de behandeling van rechter hartfalen in patiënten met pulmonale hypertensie.

A.3.2

Name or abbreviated title of the trial where available

Improving treatment of RHF in PH patients.

Het verbeteren van de behandeling van RHF in PH patiënten

A.4.1

Sponsor's protocol code number

57231

A.7

Trial is part of a Paediatric Investigation Plan

A.8

EMA Decision number of Paediatric Investigation Plan

B. Sponsor Information

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	Terlipressin
D.2.1.1.2	Name of the Marketing Authorisation holder	Sun Pharmaceutical Industries Europe B.V.
D.2.1.2	Country which granted the Marketing Authorisation	Netherlands
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	Solution for injection/infusion
D.3.4.1	Specific paediatric formulation	No
D.3.7	Routes of administration for this IMP	Intravenous 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

End stage right ventricular failure in pulmonary hypertension patients

Eindstadium rechter hartfalen in patiënten met pulmonale hypertensie.

E.1.1.1

Medical condition in easily understood language

End stage right heart failure in patients with pulmonary hypertension.

Eindstadium rechter hartfalen in patiënten met hoge bloeddruk in de longen.

E.1.1.2

Therapeutic area

Analytical, Diagnostic and Therapeutic Techniques and Equipment [E] - Therapeutic techniques [E02]

MedDRA Classification

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 explore efficacy and safety of terlipressin as add on therapy to loop diuretics in patients with pre-capillary pulmonary hypertension who are hospitalized for right ventricular failure.

Het effect van het toevoegen van terlipressine aan lisdiuretica als
behandeling van eindstadium rechterventrikelfalen in patiënten met
pulmonale arteriële hypertensie of chronische trombo-embolische
pulmonale hypertensie onderzoeken.

E.2.2

Secondary objectives of the trial

Not applicable

N.v.t.

E.2.3

Trial contains a sub-study

E.3

Principal inclusion criteria

In order to be eligible to participate in this study, a subject must meet all of the following criteria:
• Patients should be diagnosed with pre-capillary pulmonary hypertension either PAH or CTEPH, have clinical signs of decompensated right heart failure, and needing hospital - or ICU admission for IV diuretics.
• PAH (group 1 and 1’) or CTEPH (group 2), diagnosed according ESC/ERS guidelines;
o Mean Pulmonary Artery Pressure (mPAP) ≥ 25 mmHg
o Pulmonary Arterial Wedge Pressure (PCWP) <15 mmHg
o Other possible causes of PH are excluded
• 18-70 years old
• Increased body weight despite increased dose diuretics in past month
• Clinical signs of decompensated right heart failure: ankle edema and/or ascites
• eGFR > 30 ml/min/1.73m2
• Sinus rhythm

Om aan de studie te kunnen deelnemen moet de patiënt voldoen aan de
volgende inclusiecriteria:
- Patiënt is gediagnosticeerd met PAH of CTEPH, klinische tekenen
hebben van decompensatio cordis en klinische opname ter behandeling
is noodzakelijk.
- Patiënt is gediagnosticeerd met PAH of CTEPH volgens de ESC/ERS
guidelines; d.w.z.: een gemiddelde pulmonaal arterie druk (MPAP) ≥ 25
mmHg, een pulmonaal arterie wiggedruk <15 mmHg, geen andere
oorzaken bekend voor het veroorzaken van de pulmonale hypertensie.
• Leeftijd ≥18 jaar oud
• Toename in lichaamsgewicht, ondanks het ophogen van de dosis
diuretica in de afgelopen maand.
• Leeftijd 18-70 jaar
• Klinische tekenen van rechts decompensatio cordis; enkel oedeem
en/of ascites.
• eGFR > 30 ml/min/1.73m2
• Sinus ritme

E.4

Principal exclusion criteria

A potential subject who meets any of the following criteria will be excluded from participation in this study:
• Pulmonary hypertension due to connective tissue disease, and PH due to left heart disease (group 2).
• Hypoxia defined as SaO2 ≤80% and/or ≤ 90% with oxygen suppletion.
• Pregnancy, lactation
• Anuria (urine production <50 ml/day)
• Known intolerance of loop diuretics or terlipressin
• Recent diagnosis (<1 month ago) of acute pulmonary embolism
• Underlying infectious disorder/ bacteremia
• Known history of occlusive arterial disease (e.g. coronary artery disease) and/or peripheral artery disease, exception: pulmonary embolism
• Type 1 and type 2 diabetes mellitus
• Chronic use of NSAIDs
• Pre-existing renal failure from other causes than forward failure (eg diabetes)

Een potentiële deelnemer die voldoet aan een van de volgende criteria
zal worden geëxcludeerd van deelname in deze studie:
- Pulmonale arteriële hypertensie door bindweefsel ziekte
-Hypoxie gedefineerd als een SaO2 ≤80% en/of ≤ 90% met
zuurstofsuppletie.
- Zwangerschap, geven van borstvoeding
- Anurie (urine productie <50 ml/day)
- Bekende intolerantie voor lisdiuretica of terlipressine.
- Recente diagnose van acute longembolie ( <1 maand geleden)
- Onderliggende infectie
- Bekende voorgeschiedenis van arterieel vaatlijden (bijv. coronair lijden)
- Diabetes mellitus
- Chronisch NSAID gebruik
- Pre-existent nierfalen door een andere oorzaak dan forward failure.

E.5 End points

E.5.1

Primary end point(s)

The aim of this study is: “To explore efficacy and safety of terlipressin as add on therapy to loop diuretics in patients with pre-capillary pulmonary hypertension who are hospitalized for right ventricular failure.” Change in creatinine after 48 hours, is considered as a primary safety endpoint. Endpoint assessment will be after 48 hours and when, in opinion of the clinician an optimal volume status of the patient is reached. Primary efficacy endpoint will be weight loss over the first 48 hours after start of drug administration. This study is considered positive when: The weight loss after 48h is higher in the terlipressin treated patients and change in creatinine is smaller or not significantly increased compared to patients who are treated with loop diuretics alone.

Primair veiligheids eindpunt: verandering in kreatinine na 48 uur
Primair effectiviteits eindpunt: gewichtsafname na 48 uur

E.5.1.1

Timepoint(s) of evaluation of this end point

48 hours

48 uur

E.5.2

Secondary end point(s)

Other study parameters and endpoints are:
• Fluid balance (= Fluid intake – urine output) after 48h
• Urine output after 48h
• Final dose of loop diuretics at 48h
• Time interval from treatment start to accomplishing an optimal volume status/ time to dismissal
• Change in creatinine at t = 48h, t = 72h and at dismissal
• N-terminal brain-type natriuretic peptide (NT-proBNP) levels
• Total weight loss at dismissal
• Total urine output at dismissal
• Need for additional treatment (in both treatment arms)

- Vochtbalans
- Diurese
- Dosis lisdiuretica
- Opnameduur en behandelduur tot bereiken optimaal gewicht
- Verandering in creatinine op t= 48 uur, t= 72 uur en ten tijde van ontslag
- Nt-pro-BNP
- Totaal gewichtsverlies op t= 72 h en ten tijde van ontslag
- Totale urine output ten tijde van ontslag
- Aanvullende behandelingen

E.5.2.1

Timepoint(s) of evaluation of this end point

See E.5.2

Zie E 5.2

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

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)

Yes

E.7.3

Therapeutic confirmatory (Phase III)

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

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)

E.8.2.2

Placebo

E.8.2.3

Other

Yes

E.8.2.3.1

Comparator description

Standard clinical care with loop diuretics. Terlipressin is an add-on product.

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

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

The trail will be closed when the last subject is dismissed from the hospital.

De studie zal eindigen wanneer de laatste studiepatiënt is ontslagen uit het ziekenhuis.

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

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

Yes

F.3.3.6

Subjects incapable of giving consent personally

F.3.3.7

Others

Information not present in EudraCT

F.4 Planned number of subjects to be included

F.4.1

In the member state

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)

After 48h patients will be treated according to best clinical practice.

Na 48 uur zullen de studiepatiënten de standaardbehandeling krijgen, hiervoor ligt de keuze bij de behandelend arts.

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

2017-02-02

Ethics Committee Opinion of the trial application

Favourable

Ethics Committee Opinion: Reason(s) for unfavourable opinion

Date of Ethics Committee Opinion

2017-03-20

P. End of Trial
P.	End of Trial Status	Ongoing

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