Clinical Trials Register

Summary
EudraCT Number:	2015-001129-17
Sponsor's Protocol Code Number:	LDLL300.301
National Competent Authority:	Austria - BASG
Clinical Trial Type:	EEA CTA
Trial Status:	Completed
Date on which this record was first entered in the EudraCT database:	2017-05-15
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

Austria - BASG

A.2

EudraCT number

2015-001129-17

A.3

Full title of the trial

A multicenter, open-label study to investigate the effectiveness and safety of AOP Landiolol in controlling supraventricular tachycardia in pediatric patients (LANDI-PED).

Multizentrische, offene Studie zur Untersuchung der Wirksamkeit und Sicherheit von AOP Landiolol zur Regulierung supraventrikulärer Tachykardien bei pädiatrischen Patienten (LANDI-PED)

A.3.1

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

Study to investigate the effectiveness and safety of AOP Landiolol in controlling supraventricular tachycardia in children.

Studie zur Untersuchung der Wirksamkeit und Sicherheit von AOP Landiolol zur Regulierung von schnellen Herzrhythmusstörungen bei Kindern.

A.3.2

Name or abbreviated title of the trial where available

LANDI-PED

A.4.1

Sponsor's protocol code number

LDLL300.301

A.7

Trial is part of a Paediatric Investigation Plan

Yes

A.8

EMA Decision number of Paediatric Investigation Plan

P/283/2014

B. Sponsor Information
B.Sponsor: 1
B.1.1	Name of Sponsor	AOP Orphan Pharmaceuticals GmbH
B.1.3.4	Country	Austria
B.3.1 and B.3.2	Status of the sponsor	Commercial
B.4 Source(s) of Monetary or Material Support for the clinical trial:
B.4.1	Name of organisation providing support	AOP Orphan Pharmaceuticals GmbH
B.4.2	Country	Austria
B.5 Contact point designated by the sponsor for further information on the trial
B.5.1	Name of organisation	AOP Orphan Pharmaceuticals GmbH
B.5.2	Functional name of contact point	Clinical Operations
B.5.3	Address:
B.5.3.1	Street Address	Leopold-Ungar-Platz 2
B.5.3.2	Town/ city	Vienna
B.5.3.3	Post code	1190
B.5.3.4	Country	Austria
B.5.4	Telephone number	436763434446
B.5.6	E-mail	landi-ped@aoporphan.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	RAPIBLOC 300 mg
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.3.1	Product name	RAPIBLOC (Landiolol hydrochloride lyophilized powder 300 mg/50 ml)
D.3.2	Product code	LDLL300
D.3.4	Pharmaceutical form	Powder 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.3.8	INN - Proposed INN	Landiolol Hydrochloride
D.3.9.1	CAS number	144481-98-1
D.3.9.2	Current sponsor code	LDLL300
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

E. General Information on the Trial

E.1 Medical condition or disease under investigation

E.1.1

Medical condition(s) being investigated

Supraventricular tachycardia in pediatric patients.

Supraventrikuläre Tachykardie bei pädiatrischen Patienten.

E.1.1.1

Medical condition in easily understood language

Supraventricular tachycardia in children.

Schnelle Herzrhythmusstörungen bei Kindern.

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.1.2 Medical condition or disease under investigation

E.1.2	Version	20.0
E.1.2	Level	PT
E.1.2	Classification code	10074640
E.1.2	Term	Junctional ectopic tachycardia
E.1.2	System Organ Class	10007541 - Cardiac disorders

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	10042604
E.1.2	Term	Supraventricular tachycardia
E.1.2	System Organ Class	10007541 - Cardiac disorders

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	10003662
E.1.2	Term	Atrial flutter
E.1.2	System Organ Class	10007541 - Cardiac disorders

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	10040752
E.1.2	Term	Sinus tachycardia
E.1.2	System Organ Class	10007541 - Cardiac disorders

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	10003668
E.1.2	Term	Atrial tachycardia
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

To assess the pharmacokinetic (PK) and pharmacodynamic (PD) profile of LDLL300 in the pediatric population.

Beurteilung des pharmakokinetischen (PK) und pharmakodynamischen (PD) Profils von LDLL300 in der pädiatrischen Population.

E.2.2

Secondary objectives of the trial

- Controlling supraventricular tachyarrhythmias in the pediatric population.
- Assessment of safety of LDLL300 in the pediatric population.
- Dose-response assessment for LDLL300 in the pediatric population.

- Kontrolle von supraventrikulären Tachyarrhythmien in der pädiatrischen Population
- Beurteilung der Sicherheit von LDLL300 in der pädiatrischen Population
- Beurteilung des Dosis-Wirkungsprofils von LDLL300 in der pädiatrischen Population

E.2.3

Trial contains a sub-study

E.3

Principal inclusion criteria

1. Informed consent/assent from parents/legal representative(s) and children, if applicable.
2. Age: from birth to the day before the 18th birthday.
3. Body weight at least 2.5 kg.
4. Sustained supraventricular tachyarrhythmia for more than 1 min.
5. If sub-type paroxysmal supraventricular tachycardia (AVRT, AVNRT), refractory to treatment with adenosine, adenosine treatment relapsers and patients with contraindications to adenosine; or other forms of paroxysmal SVT not indicated for adenosine.

1. Patienteneinwilligung von Eltern/ gesetzlichen Vertreter(n) und Kindern, falls zutreffend.
2. Alter: von der Geburt bis zum Tag vor dem 18. Geburtstag.
3. Körpergewicht mindestens 2,5 kg.
4. Anhaltende supraventrikuläre Tachyarrhythmie für mehr als 1 min.
5. Wenn Untertyp Anfallsartige supraventrikuläre Thachykardie (AVRT, AVNRT), die nicht auf die Behandlung mit Adenosin anspricht, Rückfall nach Adenosin-Behandlung und Patienten mit Kontraindikationen zu Adenosin; oder andere Formen von paroxysmalen SVT, für die Adenosin nicht angezeigt ist.

E.4

Principal exclusion criteria

1. Acute cardiogenic shock.
2. Severe, uncorrectable metabolic acidosis.
3. Ventricular tachycardia.
4. Sick sinus syndrome (if there is no possibility for cardiac pacing) or clinically significant bradycardia.
5. Acute asthma.
6. Known pulmonary hypertension
7. Known stage 4 and 5 chronic renal disease (Table 7).
8. AV block 2nd or 3rd degree (if there is no possibility for cardiac pacing).
9. Clinically significant hypotension.
10. Postmenstrual age (gestational age + chronological age) <37 weeks
11. Untreated pheochromocytoma.
12. End-stage disease.
13. Pregnant or breast feeding patients.
14. Known hypersensitivity to any component of the study medication (e.g. Landiolol, mannitol).
15. Participation in a clinical study or exposure to any study medication within 28 days before LDLL300 infusion start, with the exception of LDLL300 (end-of-study visit completed).
16. Decompensated heart failure

1. Akuter kardiogener Schock.
2. Schwere, unkorrigierbare metabolische Acidosis.
3. Ventrikuläre Tachykardie.
4. Sick-Sinus-Syndrom (wenn es keine Möglichkeit für einen Herzschrittmacher gibt) oder klinisch signifikante Bradykardie.
5. Akutes Asthma.
6. Bekannter Lungenhochdruck
7. Bekannte chronische Nierenerkrankung Stadium 4 und 5.
8. AV block 2. oder 3. Grad (wenn es keine Möglichkeit für Herz-Schrittsteuerung gibt).
9. Klinisch signifikante Hypotonie.
10. Postmenstruelles Alter (Gestationsalter + Lebensalter) < 37 Wochen.
11. Unbehandeltes Phäochromozytom.
12. Krankheit im End-Stadium.
13. Schwangere oder Stillende Patientinnen.
14. Bekannte Hypersensitivität auf eine Komponente der Studienmedikation (z.B. Landiolol, Mannitol).
15. Teilnahme an einer klinischen Studie oder Belastung mit einer Studienmedikation innerhalb von 28 Tagen vor IMP Infusionsstart, mit Ausnahme von LDLL300 (End-of-study Visit completed).
16. Dekompensierte Herzinsuffizienz

E.5 End points

E.5.1

Primary end point(s)

Percentage of patients converting to normal sinus rhythm (cardioversion) within 3.5 hours (210 min) of the commencement of the IMP infusion.

Anteil der Patienten, die innerhalb von 3,5 Stunden (210 min) nach Beginn der IMP Infusion zu einem normalen Sinusrhythmus zurückkehren (Kardioversion).

E.5.1.1

Timepoint(s) of evaluation of this end point

3.5 hours (210 min)

3,5 Stunden (210 min)

E.5.2

Secondary end point(s)

- Relative and cumulative improvement rates (at least 20% reduction from baseline HR) at each dosing level (before increase of treatment dose).
- Relative and cumulative non-response* rates at each dosing level.
- Percent change in HR from baseline at each time point.
- Relationship between change in heart rate from baseline and patient’s age.
- Percentage of patients showing sustained restoration of sinus rhythm for more than 24 hours and 1 week after LDLL300 infusion end.
- Percentage of patients for whom the infusion period was prolonged and duration of prolongation.
- Percentage of patients achieving either SR conversion or HR control at any time during the prolongation period.
- Time from start of LDLL300 infusion until 20% reduction of HR is achieved.
- Time from start of LDLL300 infusion until conversion to normal sinus rhythm is achieved.
*Non-responders” are treated patients who have no HR response (≥ 20% reduction of HR from baseline) and/or no conversion to normal sinus rhythm.

Secondary pharmacokinetics endpoints:
- PK variables including at least t1/2, AUC, volume of distribution, and total body clearance will be calculated using concentration collected during and after LDLL300 infusion end.

Secondary safety endpoints:
- Incidence and severity/seriousness of adverse events (AE).
- Need for LDLL300 infusion end or dose reduction due to safety reasons (i.e. percentage of patients requiring LDLL300 infusion end or dose reduction due to AE(s) related to IMP).

- Relative und kumulative Verbesserungsrate (min. 20% Reduktion von Baseline HR) bei jeder Dosisstufe (vor Erhöhung der Behandlungsdosis)
- Relative und kumulative non-response* Rate bei jeder Dosisstufe.
- Prozentuelle Änderung der HR von Baseline zu jedem Zeitpunkt.
- Zusammenhang zwischen der Änderung der Herzrate von Baseline und Patientenalter.
- Anteil der Patienten, die eine bleibende Wiederherstellung des Sinusrhythmus für mehr als 24 Stunden und 1 Woche nach LDLL300 Infusionsende haben.
- Anteil der Patienten für welche die Infusionsdauer verlängert wurde und die Dauer der Verlängerung
- Anteil der Patienten, die entweder SR-Wiederherstellung oder HR Kontrolle zu irgendeinem Zeitpunkt während der Verlängerungsperiode erreicht haben.
- Zeit von Start der LDLL300 Infusion bis zum Erreichen von 20% Reduktion der HR
- Zeit von Start der LDLL300 Infusion bis zur Rückkehr zu normalem Sinus Rhythmus.
*Non-responders" sind behandelte Patienten, die kein HR-Ansprechen haben (≥ 20% Reduktion der HR von Baseline) und/ oder keine Rückkehr zum normalen Sinusrhythmus haben.

Sekundäre pharmakokinetische Endpunkte:
- PK Variablen, die zumindest t1/2, AUC, Verteilungsvolumen und Gesamtkörper-clearance beinhalten, werden berechnet unter Verwendung der Konzentration, die während und nach LDLL300 Infusionsende gesammelt wurde

Sekundäre Sicherheits-Endpunkte:
- Vorkommen und die Schwere/ das Ausmaß von Unerwünschten Ereignissen (AE)
- Erfordernis für LDLL300 Infusionsende oder Dosis-Reduktion aufgrund von Sicherheitsgründen (z.B. Anteil von Patienten, die LDLL300 Infusionsende oder Dosis-Reduktion wegen AE(s), die im Zusammenhang mit dem IMP stehen, brauchen)

E.5.2.1

Timepoint(s) of evaluation of this end point

1 week, 24 hrs

1 Woche, 24 Std.

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

Yes

E.6.7

Pharmacodynamic

Yes

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

E.8.1.1

Randomised

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

Yes

E.8.1.7.1

Other trial design description

unkontrolliert

uncontrolled

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

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

LVLS

Letzter Patient letzte Visite

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

F. Population of Trial Subjects

F.1 Age Range

F.1.1

Trial has subjects under 18

Yes

F.1.1

Number of subjects for this age range:

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)

Yes

F.1.1.3.1

Number of subjects for this age range:

F.1.1.4

Infants and toddlers (28 days-23 months)

Yes

F.1.1.4.1

Number of subjects for this age range:

F.1.1.5

Children (2-11years)

Yes

F.1.1.5.1

Number of subjects for this age range:

F.1.1.6

Adolescents (12-17 years)

Yes

F.1.1.6.1

Number of subjects for this age range:

F.1.2

Adults (18-64 years)

F.1.2.1

Number of subjects for this age range:

F.1.3

Elderly (>=65 years)

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 For clinical trials recorded in the database before the 10th March 2011 this question read: "Women of childbearing potential" and did not include the words "not using contraception". An answer of yes could have included women of child bearing potential whether or not they would be using contraception. The answer should therefore be understood in that context. This trial was recorded in the database on 2017-05-15.

Yes

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

Yes

F.3.3.6.1

Details of subjects incapable of giving consent

Minor-aged subjects are planned at age from 0 years on.

Minderjährige Patienten ab Geburt werden eingeschlossen.

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)

After end of treatment, the registered study site will be the first contact for the study participants and the patients will be treated during the routine process.

Nach Beendigung der Studienteilnahme fungiert das gemeldete Prüfzentrum als 1. unmittelbarer Ansprechpartner für die PrüfungsteilnehmerInnen und die Patienten werden routinemäßig weiterbehandelt.

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	OKIDS GmbH
G.4.3.4	Network Country	Austria

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

Competent Authority Decision

Authorised

Date of Competent Authority Decision

2017-06-19

Ethics Committee Opinion of the trial application

Favourable

Ethics Committee Opinion: Reason(s) for unfavourable opinion

Date of Ethics Committee Opinion

2017-05-30

P. End of Trial
P.	End of Trial Status	Completed
P.	Date of the global end of the trial	2023-05-31

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