Clinical Trials Register

Summary
EudraCT Number:	2020-002752-20
Sponsor's Protocol Code Number:	LAN_POAF_01
National Competent Authority:	Austria - BASG
Clinical Trial Type:	EEA CTA
Trial Status:	Ongoing
Date on which this record was first entered in the EudraCT database:	2020-11-12
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

Austria - BASG

A.2

EudraCT number

2020-002752-20

A.3

Full title of the trial

A prospective, randomized, double- blind, placebo- controlled study to evaluate the efficacy of Landiolol hydrochloride for prevention of atrial fibrillation in patients undergoing cardiac surgery

A.3.1

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

A prospective, randomized, double- blind, placebo- controlled study to evaluate Landiolol hydrochloride as a prevention of atrial fibrillation in patients undergoing cardiac surgery

Eine prospektive, randomisierte, doppelblinde, Placebo kontrollierte Studie zur Prüfung der Wirksamkeit von Landiololhydrochlorid in der Vorbeugung von Vorhofflimmern bei Patienten mit Herzoperation

A.3.2

Name or abbreviated title of the trial where available

LANDI-POAF

A.4.1

Sponsor's protocol code number

LAN_POAF_01

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	Medical University of Vienna
B.1.3.4	Country	Austria
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
B.4.2	Country
B.5 Contact point designated by the sponsor for further information on the trial
B.5.1	Name of organisation	Medical University of Vienna, Department of Anaesthesiology, Division of cardiothoracic and vascular anaesthesiology
B.5.2	Functional name of contact point	Klin. Abt. für HTG-Anästhesie
B.5.3	Address:
B.5.3.1	Street Address	Währinger Gürtel 18-20
B.5.3.2	Town/ city	Vienna
B.5.3.3	Post code	1090
B.5.3.4	Country	Austria
B.5.6	E-mail	htg@meduniwien.ac.at

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	Rapibloc
D.2.1.1.2	Name of the Marketing Authorisation holder	Amomed Pharma GmbH
D.2.1.2	Country which granted the Marketing Authorisation	Austria
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 dispersion 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.3.9.1	CAS number	144481-98-1
D.3.9.3	Other descriptive name	LANDIOLOL HYDROCHLORIDE
D.3.9.4	EV Substance Code	SUB21964
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	300
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
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

Perioperative atrial fibrillation (POAF) is the most common arryhthmia after cardiac surgery with incidences ranging from 20% to 40%, depending on various patient's risk factors and the type of surgery performed. It's not only causing problems in the immediate postoperative period due to hemodynamic instability and a increased need for catecholamines to stabilise the patient, it also leads to increased mortality and morbidity and longer hospital stays, increasing costs to healthcare system.

Perioperatives Vorhofflimmern ist die häufigstes Rhythmusstörung nach cardiochirurgischen Eingriffen mit Inzidenzen zwischen 20% bis 40%, abhängig von versch. Risikofaktoren und der Art des Eingriffes. Dabei führt es nicht nur zu unmittelbaren Problemen wie hämodynamischer Instabilität und erhöhtem Katecholaminbedarf, langfristig ist auch die Mortalität und Morbidität erhöht und die Krankenhausaufenthalt verlängert und führt so zu erhöhten Kosten für das Gesundheitssystem

E.1.1.1

Medical condition in easily understood language

Perioperative atrial fibrillation (POAF) is the most common arryhthmia after cardiac surgery causing not only severe short term consequencs, but can also lead to negative long term outcomes.

Perioperatives Vorhofflimmern ist die häufigste Rhythmusstörung nach Herzoperationen und kann sowohl unmittelbar postoperativ Komplikationen verursachen, als auch im weiteren Verlauf.

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	20.0
E.1.2	Level	PT
E.1.2	Classification code	10003658
E.1.2	Term	Atrial fibrillation
E.1.2	System Organ Class	10007541 - Cardiac 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

Prevention of peri- and postoperative atrial fibrillation using landiolol hydrochloride in patients undergoing elective on-pump cardiac surgery

Prävention von peri-und postoperativem Vorhofflimmern durch Landiololhydrochlorid bei Patienten nach Herzoperationen an der Herz-Lungen-Maschine

E.2.2

Secondary objectives of the trial

• Incidence/ frequency of occurrence of atrial fibrillation during the first seven days after cardiac surgery.
• Hemodynamic stability during treatment with IMP
• Length of ICU stay
• Requirement of intensive respiratory and circulatory support
• Peri- and postoperative mortality
• Assessment of biomarkers as surrogate parameters for cardiac dysfunction
• Impact of IMP on cardiac function
• Incidence of serious adverse events

• Inzidenz und Frequenz des Auftretens von Vorhofflimmern innerhalb der ersten 7 Tage nach Operation
• Hämodynamische Stabilität während der Behandlung mit dem IMP
• Dauer des Intensivaufenthaltes
• Notwendigkeit und Dauer invasiver Beatmung und Kreislauf unterstützender Maßnahmen
• Peri- und postoperative Mortalität
• Auswertung kardialer Biomarker als Surrogatparameter für die Herzfunktion
• Einfluss des IMP auf die Herzfunktion
• Inzidenz/Auftreten von schädlichen Events

E.2.3

Trial contains a sub-study

E.3

Principal inclusion criteria

1. Male or female patients ≥ 18 years old
2. Written informed consent from patient
3. Oral Betablocker in the patients long-term medication
4. Patient is in Sinusrhythm at screening
5. One of the following cardiac surgical procedures which is planned on cardiopulmonary bypass (CPB):
a. Single valve surgery
b. Single or multiple CABG procedures
c. Single valve surgery in combination with one or multiple coronary artery bypass grafts (CABGs)
d. Multiple valve surgery in combination with or without CABG
e. Single or multiple valve surgery in combination with ascending aorta procedure with or without additional CABG
f. Re-surgery of aortic valve, mitral valve, aortic arch or ascending aorta with or without CABG
6. Cardiac surgery is performed electively

• Weibliche oder männliche PatientInnen ab einem Alter von 18 Jahren
• schriftliche Einwilligung
• Vorbestehende Dauertherapie mit Betablockern
• Patient ist im Sinusrhythmus zum Zeitpunkt des Screenings
Elektive Chirurgie an der Herz-Lungen-Maschine von:
• Einfach-, sowie Mehrfachklappeneingriffe
• Einfach- und Mehrfachklappeneingriffe mit oder ohne zusätzlichen Corona-arteriellem Bypassgrafts (CABG)
• Einfach- oder Mehrfachklappeneingriffe mit Eingriffen an der Aorta ascendens
• Re-Operationen des Klappenapparetes sowie der Aorta ascendens oder des Aortenbogens mit oder ohne CABG

E.4

Principal exclusion criteria

1. Bodyweight > 101kg and/or BMI ≥ 40
2. Cardiac surgery is planned as minimally invasive procedure (e.g., without thoracotomy or with lateral incision, minimal thoracotomy) or planned as off-pump surgery
3. Planned maze procedure, radiofrequency ablation, pulmonary vein ablation, resection of the atrial appendix or atrial resections during the surgery
4. Sinus bradycardia (resting heart rate < 50/min) at screening and before start of IMP treatment
5. Second- or third-degree atrioventricular block at screening and before start of IMP treatment
6. Clinical hypothyroidism or hyperthyroidism at screening
7. History of ventricular arrhythmia
8. Permanent atrial fibrillation or atrial fibrillation at time of screening and IMP administration
9. Emergency cardiac surgery
10. Requiring inotropic, vasopressor or requiring ventilatory support at time of screening
11. Circulatory shock requiring mechanical circulatory support before initiation of study medication
12. Distributive shock (cardiac index>2.2 L/min with norepinephrine dose > 0.3 µg/kg/min to reach mean arterial pressure > 65mmHg) before initiation of study medication
13. More than 5 units of RBC necessary to maintain a haemoglobin level >8mg/dl at the end of surgery
14. Prior cardiac surgery within the past 6 months
15. History of heart transplantation or planned heart transplantation
16. Any other disease or condition that is likely to interfere with the evaluation of the study drug, outcome assessment or satisfactory conduct of the study:
a. Active infective endocarditis
b. Stroke or transient ischemic attack (TIA) within the last 6 months
c. Concomitant disease with a life expectancy of less than 6 months
d. Cardiopulmonary resuscitation within the last 4 weeks
e. Patients requiring renal replacement therapy
17. Active infection on current systemic antibiotics and/ or temperature greater than 38°C at time of screening and before start of surgery
18. Haemoglobin < 5 mmol/l (< 8.06 g/dl)
19. Any systemic anti-cancer therapy within past 3 months

1. Körpergewicht >100kg und/oder BMI ≥ 40
2. Minimalinvasiv durchgeführte Herzoperationen und Eingriffe ohne HLM (off pump)
3. Operationen bei denen eine Maze Prozedur, eine Radiofrequenzablation, eine Pulmonalvenenablation, oder eine (Teil-)Resektion des Atriums und/oder des Vorhofohres geplant ist
4. Sinus-bradykardie(Ruhefrequenz< 50/min) zum Zeitpunkt des Screenings oder vor dem Start der Studienmedikation
5. AV-Block II° oder III° zum Zeitpunkt des Screenings oder vor dem Start der Studienmedikation
6. Klinische Anzeichen Hypo- oder Hyperthyreodismus
7. Ventrikuläre Arrhythmien in der Anamnese
8. Permanentes Vorhofflimmern in der Anamnese oder Vorhofflimmern bei Start der Studienmedikation
9. Notfallchirurgie
10. Vasopressor-, Inotropie, oder Beatmungsbedarf d. Patienten zum Zeitpunkt des Screenings
11. Schockzustände die mechanische Kreislaufunterstützung erfordern bevor mit der Studienmedikation begonnen wird.
12. Distributiver Schock (cardiac index>2.2 L/min mit Noradrenalindosen > 0.3 µg/kg/min um einen mittleren arteriellen Druck > 65mmHg zu erreichen) bevor mit der Studienmedikaion begonnen wird.
13. Die Notwendigkeit der Transfusion von mehr als 5 Erythrozytenkonzentraten um am OP-Ende einen Hb>8 mg/dl zu erreichen
14. Stattgefunden Herzoperation in den letzten 6 Monaten zum Zeitpunkt des Screenings
15. Zustand nach Herztransplantation oder geplante Herztransplantation
16. Jegliche andere Erkrankung die die Überprüfung des Studienmedikaments beeinflusst
a. aktive Endokarditis
b. Zerebraler Insult oder eine transients ischämische Attacke (TIA) in den letzten 6 Monaten
c. Begleiterkrankung die eine erwartete Lebensdauer von <6 Monate bedingt
d. Cardioplumonale Reanimation 4 Wochen vor Screening
e. Patienten die chronische Nierenersatzverfahren benötigen
17. Aktive Infektion unter antibiotische Behandlung und/oder eine Körpertemperatur größer 38°C zum Zeitpunkt des Screening oder des OP-Beginns
18. Hämoglobin < 8mg/dl
19. Jegliche Form einer systematischen Therapie gegen Krebs
10. Patienten mit bekannter Überempfindlichkeit gegen das Studienmedikament oder eines seiner Bestandteile
21. Generelle Ausschlusskriterien:
a. Schwanger Teilnehmerinnen (gebährfähige Frauen müssen einen negativen Schwangerschaftstest vorweisen) oder stillende Frauen. Gebärfähige Frauen (definiert als Zeitpunkt der letzten Menstruation innerhalb der letzten zwei Jahre) die während der Teilnahme an der Studie keine verlässliche Empfängnisverhütung anwenden (z.b.: Implanon, Injektionen, orale Kontraceptiva, IUD, Partner mit Zustand nach Vasektomie, Abstinenz)
b. Teilnahme an einer anderen interventionellen Studie innerhalb des letzten Montas vor Randomisierung dieser Studie (mit Möglichkeit auf Re-screening besteht)
c. Alkohol-, Drogen-, oder Medikamentenabusus
d. MitarbeiterIn am Studienzentrum, Lebensgefährte/Partner oder Verwandte der an der Studie beteiligten Personen oder Personen mit einer Beziehung/einem Nahverhältnis zum Sponsor

E.5 End points

E.5.1

Primary end point(s)

The primary end point is a combined endpoint consisting of the occurrence of atrial fibrillation and mortality during the initial 72 hours period after surgery.

Kombinierter primärer Endpunkt bestehend aus dem Auftreten von Vorhofflimmern innerhalb der ersten 72h sowie der Mortalität in diesem Zeitraum.

E.5.1.1

Timepoint(s) of evaluation of this end point

Continously per Holter ECG monitoring on the first seven days after operation.
During the IMP application one ECG control per day

Kontinuierliches Holter EKG für 7 Tage
Während Applikation der Studienmedikation eine EKG Kontrolle pro Tag zusätzlich

E.5.2

Secondary end point(s)

E.5.2.1

Timepoint(s) of evaluation of this end point

During visits at defined timepoints:
Start of surgery
End of surgery
Start Holter ECG and Start of IMP (immediate after end of surgery)
ICU-Admission
24h after ICU admission
48h after ICU admission
72h after ICU admission
Day 7
Day 30 Follow up phone call

Visiten an definierten Zeitpunkten:
OP Beginn
OP Ende
Start Holter EKG und Start Studienmedikament (unmittelbar nach OP Ende)
ICU-Aufnahme
24h nach ICU Aufnahme
48h nach ICU Aufnahme
72h nach ICU Aufnahme
Day 7
Day 30 telefonische Follow-Up per Fragebogen

E.6 and E.7 Scope of the trial

E.6

Scope of the trial

E.6.1

Diagnosis

E.6.2

Prophylaxis

Yes

E.6.3

Therapy

E.6.4

Safety

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)

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

Yes

E.8.1.1

Randomised

Yes

E.8.1.2

Open

E.8.1.3

Single blind

E.8.1.4

Double blind

Yes

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

Yes

E.8.4

The trial involves multiple sites in the 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

LVLS

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:

100

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

164

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 of care after cardiac surgery

Versorgung nach dem Standard nach cardiochirurgischen Eingriffen

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

2020-12-17

Ethics Committee Opinion of the trial application

Favourable

Ethics Committee Opinion: Reason(s) for unfavourable opinion

Date of Ethics Committee Opinion

2020-10-09

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

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