Clinical Trials Register

Summary
EudraCT Number:	2016-004193-18
Sponsor's Protocol Code Number:	LEVOS-001
National Competent Authority:	Hungary - National Institute of Pharmacy
Clinical Trial Type:	EEA CTA
Trial Status:	Completed
Date on which this record was first entered in the EudraCT database:	2016-10-24
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

Hungary - National Institute of Pharmacy

A.2

EudraCT number

2016-004193-18

A.3

Full title of the trial

Effect of repetitive levosimendan treatment on clinical outcomes of chronic heart failure patients: focus on optimal patient selection based on novel cardiac biomarkers.

Ismételt levosimendan alkalmazás hatásának vizsgálata krónikus szisztolés szívelégtelenségben szenvedő betegek életminőségére és halálozására: új kardiális biomarkerek szerepe a betegkiválasztásban.

A.3.1

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

Effect of repetitive levosimendan treatment on clinical outcomes of chronic heart failure patients: focus on optimal patient selection based on novel cardiac biomarkers.

A.4.1

Sponsor's protocol code number

LEVOS-001

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	Semmelweis University, Heart and Vascular Center
B.1.3.4	Country	Hungary
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	Semmelweis University
B.4.2	Country	Hungary
B.5 Contact point designated by the sponsor for further information on the trial
B.5.1	Name of organisation	Semmelweis University, Heart and Vascular Center
B.5.2	Functional name of contact point	Zsófia Doros
B.5.3	Address:
B.5.3.1	Street Address	Városmajor Str. 68.
B.5.3.2	Town/ city	Budapest
B.5.3.3	Post code	1122
B.5.3.4	Country	Hungary
B.5.6	E-mail	studycenter.sekk6@gmail.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	Simdax
D.2.1.1.2	Name of the Marketing Authorisation holder	Orion Pharma
D.2.1.2	Country which granted the Marketing Authorisation	Finland
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	SIMDAX
D.3.2	Product code	Not applicable
D.3.4	Pharmaceutical form	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
D.8 Placebo: 1
D.8.1	Is a Placebo used in this Trial?	Yes
D.8.3	Pharmaceutical form of the placebo	Solution for infusion in administration system
D.8.4	Route of administration of the placebo	Intravenous use

E. General Information on the Trial

E.1 Medical condition or disease under investigation

E.1.1

Medical condition(s) being investigated

A total of 80 symptomatic patients with severe ischaemic or non-ischaemic cardiomyopathy will be enrolled in the study. Those, who were implanted a device and proved to be non-responders or low responders with ischaemic etiology would be separetly investigated.

A vizsgálatba összesen 80 tünetes, előrehaladott szisztolés szívelégtelenségben (iszkémiás vagy nem iszkémiás cardiomyopathia) szenvedő beteg bevonását tervezzük. A korábban kardiális reszinkronizációs pacemaker/defibrillátor (CRT-P/CRT-D) beültetésen átesett non-responder vagy low-responder, iszkémiás cardiomyopathiában szenvedő betegeket külön csoportként kezeljük.

E.1.1.1

Medical condition in easily understood language

Patients with severe heart failure symptoms and ischaemic or non-ischaemic etiology will be enrolled in the study.

Előrehaladott szisztolés szívelégtelenségben (iszkémiás vagy nem iszkémiás cardiomyopathia) szenvedő betegek vizsgálatát tervezzük.

E.1.1.2

Therapeutic area

Diseases [C] - Cardiovascular Diseases [C14]

MedDRA Classification

E.1.3

Condition being studied is a rare disease

E.2 Objective of the trial

E.2.1

Main objective of the trial

The main objective of the study is to identify patients who benefit the most from intermittent levosimendan treatment using correlations between quality of life.

Aa repetitív levosimendan alkalmazásra legjobban reagáló, abból a legtöbbet profitáló előrehaladott, szisztolés szívelégtelen betegek azonosítása.

E.2.2

Secondary objectives of the trial

- Cardiac death/HTX or hospitalization due to heart failure
- All- cause mortality
- 6 MWT
- Minnesota questionnaire
- Echocardiographic improvement
- Laboratory parameters
- Traditional and novel biomarkers
- Hemodynamic parameters
- Incidence or new onset of arrhythmic events

- Kardiális okból bekövetkező halálozás/szívtranszplantáció vagy szívelégtelenség miatti hospitalizáció közös végpontja
- Kardiális okból bekövetkező halálozás
- Szívelégtelenség miatti hospitalizáció
- Összhalálozás
- Funkcionális kapacitás (6 perces sétateszt (6MWT))
- Minnesota kérdőív
- Echokardiográfiás paraméterek változásai
- Laboratóriumi paraméterek (változásai
- Hagyományos és új biomarkerek változásai
- Hemodinamikai paraméterek változásai
- Ritmuszavarok kialakulása

E.2.3

Trial contains a sub-study

E.3

Principal inclusion criteria

1. Symptomatic heart failure at enrollment – NYHA III-IV treated with augmented / iv. diuretics with optimal heart failure medical treatment
2. Ischaemic patients (no STEMI/ NSTEMI in 6 months) with a device specified as: Non reposponders or low responders after CRT-P/CRT-D or after ICD implantation (at least for 6 months)
3. Ischaemic or non-ischaemic chronic heart failure without any device.
4. Age: 18-80 years
5. LVEF<35%

1. Optimális gyógyszeres kezelés ellenére tünetes, emelt dózisú vagy intravénás diuretikum adását igénylő szívelégtelenség (funkcionális stádium NYHA III-IV)
2. Iszkémiás cardiomyopathiában szenvedő, 6 hónapnál régebben kardiális reszinkronizációs pacemaker/defibrillátor (CRT-P/CRT-D) vagy ICD beültetésen átesett non-responder vagy low-responder betegek
3. Iszkémiás és nem iszkémiás cardiomyopathiában szenvedő betegek, akiknél nem történt CRT-P/CRT-D vagy ICD beültetés
4. életkor 18-80 év
5. BKEF < 35%

E.4

Principal exclusion criteria

SBP<100 Hgmm
AMI, stroke or life-threatening arrhytmia in the last 3 months
Multiorgan failure
Chronic kidney disease kreat >250
Severe COPD treated with steroid or more than 2 inh. therapy
Severe anaemia <100 mg/dl
GOT / GPT > 100 U/L
Any planned surgical event or TX
Pregnant
Non-consent or low compliant
Use of levosimendan in the patients’ history in the past 6 months

1. Szisztolés vérnyomás <100 Hgmm
2. STEMI vagy NSTEMI az elmúlt 6 hónapban
3. Stroke az elmúlt 3 hónapban
4. Életet veszélyeztető arritmia az elmúlt 3 hónapban
5. Többszervi elégtelenség
6. Krónikus veseelégtelenség (szérum kreatinin > 250 μmol/l)
7. Súlyos COPD (szteroid kezelés vagy kombinált (> 2) inhalációs terápia)
8. Anémia (Hgb < 100 g/l)
9. GOT / GPT > 100 U/L
10. Tervezett sebészeti beavatkozás vagy szívtranszplantáció
11. Terhesség
12. Levosimendan kezelés az elmúlt 6 hónapban
13. Alacsony compliance

E.5 End points

E.5.1

Primary end point(s)

Quality of Life: Kansas city questionnaire

Életminőség (Kansas city kérdőív)

E.5.1.1

Timepoint(s) of evaluation of this end point

Baseline (enrollment), 4 times during the treatment monthly, 6 months after enrollment

Bevonáskor/ 4 alklommal történő havonkénti levosimendan kezelés előtt és után és a bevonástól számított 6 hónap múlva

E.5.2

Secondary end point(s)

E.5.2.1

Timepoint(s) of evaluation of this end point

Baseline (enrollment), 4 times during the treatment monthly, 6 months after enrollment

Bevonáskor/ 4 alklommal történő havonkénti levosimendan kezelés előtt és után és a bevonástól számított 6 hónap múlva

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

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

Yes

E.8.1.1

Randomised

Yes

E.8.1.2

Open

E.8.1.3

Single blind

Yes

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

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

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

31 st of December 2017

2017. december 31.

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)

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

F.3.3.1

Women of childbearing potential not using contraception

F.3.3.2

Women of child-bearing potential using contraception

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.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)

Standard hospital care.

G. Investigator Networks to be involved in the Trial
G.4 Investigator Network to be involved in the Trial: 1
G.4.1	Name of Organisation	Semmelweis University, Vascular and Heart Center
G.4.3.4	Network Country	Hungary
G.4 Investigator Network to be involved in the Trial: 2
G.4.1	Name of Organisation	University of Debrecen
G.4.3.4	Network Country	Hungary

N. Review by the Competent Authority or Ethics Committee in the country concerned

Competent Authority Decision

Authorised

Date of Competent Authority Decision

2017-02-16

Ethics Committee Opinion of the trial application

Favourable

Ethics Committee Opinion: Reason(s) for unfavourable opinion

Date of Ethics Committee Opinion

2016-12-20

P. End of Trial
P.	End of Trial Status	Completed

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IMP with orphan designation in the indication
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