Clinical Trials Register

Summary
EudraCT Number:	2012-001675-37
Sponsor's Protocol Code Number:	Lis-Safe
National Competent Authority:	Germany - BfArM
Clinical Trial Type:	EEA CTA
Trial Status:	Prematurely Ended
Date on which this record was first entered in the EudraCT database:	2012-05-16
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

Germany - BfArM

A.2

EudraCT number

2012-001675-37

A.3

Full title of the trial

A Prospective, Open-label, Exploratory Study to Investigate the Safety, Efficacy, and Haemodynamics of Lisuride Subcutaneous Infusion as Add-on to Conventional Treatment in Patients with Pulmonary Arterial Hypertension

Eine prospektive, offene, explorative Studie zur Beurteilung der Sicherheit, Wirksamkeit und Auswirkungen auf die Hämodynamik von subkutanen Lisurid-Infusionen zusätzlich zur Standardtherapie bei Patienten mit Pulmonaler Arterieller Hypertonie

A.3.1

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

A Study to Investigate the Effects of Lisuride in addition to Conventional Treatment in Patients with Pulmonary Arterial Hypertension

Studie zur Beurteilung der Wirkungen von Lisurid zusätzlich zur Standardbehandlung bei Patienten mit Pulmonaler Arterieller Hypertonie

A.3.2

Name or abbreviated title of the trial where available

Lis-Safe

A.4.1

Sponsor's protocol code number

Lis-Safe

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	Sinoxa Pharma GmbH
B.1.3.4	Country	Germany
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	Sinoxa Pharma GmbH
B.4.2	Country	Germany
B.5 Contact point designated by the sponsor for further information on the trial
B.5.1	Name of organisation	Sinoxa Pharma GmbH
B.5.2	Functional name of contact point	Medical Department
B.5.3	Address:
B.5.3.1	Street Address	Königin-Luise-Str. 27
B.5.3.2	Town/ city	Berlin
B.5.3.3	Post code	14195
B.5.3.4	Country	Germany
B.5.4	Telephone number	004903028869878
B.5.5	Fax number	004903028869696
B.5.6	E-mail	r.horowski@sinoxa.eu

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	No
D.2.5	The IMP has been designated in this indication as an orphan drug in the Community	Yes
D.2.5.1	Orphan drug designation number	EU/3/11/869
D.3 Description of the IMP
D.3.1	Product name	Lisuride
D.3.4	Pharmaceutical form	Powder for solution for infusion
D.3.4.1	Specific paediatric formulation	No
D.3.7	Routes of administration for this IMP	Subcutaneous use
D.3.8 to D.3.10 IMP Identification Details (Active Substances)
D.3.8	INN - Proposed INN	Lisuride
D.3.9.1	CAS number	18016-80-3
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	2
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

Pulmonary Arterial Hypertension

Pulmonale Arterielle Hypertonie

E.1.1.1

Medical condition in easily understood language

High blood pressure in lung arteries

Hoher Blutdruck in den Lungenarterien ("Lungenhochdruck")

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	16.0
E.1.2	Level	LLT
E.1.2	Classification code	10036727
E.1.2	Term	Primary pulmonary hypertension
E.1.2	System Organ Class	100000004855

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

Primary objective: To investigate the safety of continuous treatment with sc lisuride infusions as add-on treatment to stable conventional therapy in patients with pulmonary arterial hypertension (PAH).

Primäres Ziel: Untersuchung der Sicherheit kontinuierlicher subkutaner Lisurid-Infusionen als zusätzliche Therapie zu einer stabilen konventionellen Therapie bei Patienten mit Pulmonaler Arterieller Hypertonie (PAH).

E.2.2

Secondary objectives of the trial

Secondary objective: To investigate the efficacy of continuous treatment with sc lisuride infusions as add-on treatment to stable conventional therapy in patients with pulmonary arterial hypertension (PAH).

Sekundäres Ziel: Untersuchung der Wirksamkeit kontinuierlicher subkutaner Lisurid-Infusionen als zusätzliche Therapie zu einer stabilen konventionellen Therapie bei Patienten mit Pulmonaler Arterieller Hypertonie (PAH).

E.2.3

Trial contains a sub-study

E.3

Principal inclusion criteria

1. Female and male patients of any racial origin with PAH (WHO classification II-III).
2. On stable treatment with best supportive care with conventional PAH therapy, i.e. anticoagulant drugs, diuretics, cardiac glycosides, supplemental oxygen and calcium channels blockers, adjusted to the individual need of the respective patient. Specific PAH mono-therapy (preferably with Bosentan) or combination-therapy (not exceeding two PAH specific drugs) with either endothelin receptor antagonists or phosphodiesterase type 5 inhibitors or non-sc/iv prostanoids (i.e. inhaled, oral). The dose of PAH specific therapy must be stable 3 months before entering the study and should remain unchanged throughout the study.
3. Having fulfilled his/her 18th birthday at Screening/Baseline Visit of the study but not older than 80 years (up to the patient's 81st birthday).
4. PAH due to idiopathic pulmonary arterial hypertension or connective tissue disease associated PAH
5. Right heart catheterisation 6 weeks prior to screening or at screening with PAH, specifically PAPm >25 mmHg (at rest), Pulmonary capillary wedge pressure (PCWP) ≤15 mmHg, pulmonary vascular resistance >500 dyn x sec x cm-5. Echocardiogram at screening consistent with PAH, specifically evidence of right ventricular hypertrophy or dilation, evidence of normal left ventricular function, and absence of mitral valve stenosis.
6. Six minute walk distance ≥ 200m.
7. Receiving conventional PAH therapy, stable for one month.
8. Able to understand and willing to sign the Informed Consent Form. Written informed consent must be given before any study procedure is performed

1. Weibliche und männliche Patienten unabhängig ihrer ethnischen Herkunft, die an PAH leiden WHO-Funktionsklasse II-III).
2. Patienten mit stabil eingestellter Therapie/bestmöglicher Behandlung mit Antikoagulantien, Diuretika, Herz-Glykoside, Sauerstoff-Supplementation, und Ca-Kanal-Blocker, angepasst an die individuellen Bedürfnisse des Patienten. Spezifische PAH Monotherapie (vorzugsweise mit Bosentan) oder Kombinationstherapie (mit nicht mehr als 2 spezifischen PAH Medikamenten) entweder mit Endothelin-Rezeptor Antagonisten oder Phosphodiesterase Typ 5 Inhibitoren oder nicht-sc/iv Prostanoiden (z.B. inhaliert oder oral). Die Dosierung der spezifischen PAH Medikamente muss mindestens 3 Monate vor Einschluß gleich bleibend gewesen sein und sollte im Verlauf der Studie nicht geändert werden.
3. Vollendetes 18. Lebensjahr zu Screening/Baseline und nicht älter als 80 Jahre (vor dem 81. Geburtstag).
4. PAH aufgrund idiopathischer pulmonaler arterieller Hypertonie oder PAH in Verbindung mit Kollagenosen.
5. Rechtsherz-Katheter 6 Wochen vor Screening oder bei Screening mit der Diagnose PAH, im Speziellen: pulmonaler arterieller Druck (PAPm) > 25 mmHg (in Ruhe), Pulmonalkapillarenverschlussdruck (PCWP) ≤ 15 mmHg, pulmonaler Gefässwiderstand > 500 dyn x sec x cm-5. Echokardiogramm bei Screening übereinstimmend mit PAH, im Speziellen: Nachweis von Rechtsherzhypertrophie oder Dilatation, Nachweis auf normale linksventrikuläre Funktion und Abwesenheit von Mitralklappenstenose.
6. Gehstrecke von ≥ 200 m beim 6-Minuten-Gehtest.
7. Behandlung mit konventioneller PAH-Therapie auf stabiler Dosis für mindestens ein Monat.
8. Fähigkeit die Patienteninformation/Einwilligungserklärung zu verstehen und zu unterschreiben. Die schriftliche Einwilligung muss gegeben worden sein bevor studienbedingte Maßnahmen durchgeführt werden.

E.4

Principal exclusion criteria

1. PAH of any cause other than permitted in the entry criteria
2. Contraindication for heart catheterisation
3. Any change in conventional PAH therapy within the last month before study start
4. Any change in PAH specific therapy within 3 months prior to study start
5. Patients requiring intravenous prostanoid therapy within 3 month prior to study start
6. Any subject who had received any investigational medication within 1 month prior to study start or who is scheduled to receive another investigational drug during the course of this study.
7. Known intolerance to lisuride.
8. Patients on concurrent treatment with phenylpropanolamin
9. Active liver disease, porphyria or elevations of serum transaminases >3 x ULN (upper limit of normal) or bilirubin > 1.5 x ULN
10. Chronic renal insufficiency as defined by a creatinine > 2.5 mg/dL or requires dialysis?
11. Obstructive or restrictive lung disease as evidenced by pulmonary function tests within 3 months before study entry, showing any of the following: VC < 65% of normal value, FEV1 < 65% of normal value
12. History of left heart disease, including any of the following: aortic or mitral valve disease, pericardial constriction, restrictive or congestive cardiomyopathy, left ventricular ejection fraction < 55%
13. History of suspicion of inability to cooperate adequately
14. Psychiatric, addictive, or other disorder that compromises the ability to participating in this study?
15. Cancer or other malignant haematological disease
16. Pulmonary Hypertension caused by left heart disease
17. Pulmonary Arterial Hypertension associated with congenital heart disease (PAH-CHD)
18. Pulmonary Arterial Hypertension associated with human immunodeficiency virus infection (PAH-HIV)
19. Portopulmonary Hypertension (PPHT)
20. CTEPH Chronic Thromboembolic Pulmonary Hypertension
21. Pulmonary Hypertension associated with other diseases excluding aforementioned: PAH due to idiopathic pulmonary arterial hypertension or connective tissue disease associated PAH including systemic sclerosis (sclerodermia) and systemic lupus erythematosus (SLE)
22. Pulmonary Hypertension associated with other chronic lung diseases
23. Patients on concurrent treatment with dopaminergic drugs
24. Women of child bearing potential must be excluded if:
• they have not used reliable contraception in the cycle before the study. According to CPMP/ICH/286/95 (modification) highly effective methods of birth control (defined by a failure rate < 1% per year) include the consistent and correct use of implants, injectables, combined oral contraceptives, selected intrauterine devices (IUD), sexual abstinence or vasectomised partner. The subject has to agree to continue using such highly reliable contraception during the entire study period and the cycle after the study;
• they are pregnant or lactating. (A negative pregnancy test must be provided for all women of reproductive age)
25. Patients committed to an institution by virtue of an order issued either by the judicial or the administrative authorities?

1. PAH durch andere als in den Einschlusskriterien erlaubte Ursachen verursacht.
2. Kontraindikation für die Herzkatheteruntersuchung.
3. Jegliche Änderung der konventionellen PAH-Therapie innerhalb des letzten Monats vor Studienbeginn.
4. Jegliche Änderung der spezifischen PAH-Therapie innerhalb der letzten 3 Monate vor Studienbeginn.
5. Patienten, die eine intravenöse Therapie mit Prostanoiden innerhalb der letzten 3 Monate vor Studienbeginn benötigen.
6. Patienten, die Studienmedikation jeglicher Art innerhalb eines Monats vor Studienbeginn erhalten haben, bzw. für die eine Behandlung mit einer anderen Studienmedikation im Verlauf der Studie geplant ist.
7. Bekannte Intoleranz gegenüber Lisurid.
8. Gleichzeitige Anwendung von Phenylpropanolamin
9. Bestehender Leberschaden, Porphyrie oder Erhöhung der Serum-Transaminasen auf > 3 x ULN oder Bilirubin auf > 1.5 x ULN (ULN = Upper Limit of Normal = oberer Grenzwert).
10. Chronische Niereninsuffizienz mit Kreatinin > 2,5 mg/dL oder dialysepflichtige Patienten.
11. Obstruktive oder restriktive Lungenerkrankung, nachgewiesen durch einen Lungenfunktionstest innerhalb von 3 Monaten vor Studieneintritt mit VC < 65% des Normalwerts und FEV1 < 65% des Normalwerts.
12. Vorgeschichte von Linksherzinsuffizienz einschliesslich: Erkrankung der Aortenklappe oder Mitralklappe, Perikardkonstriktion, restriktive oder kongestive Kardiomyopathie, Linksventrikuläre Ejektionsfraktion < 55%
13. Vorgeschichte oder Verdacht auf Unvermögen, angemessen zu kooperieren.
14. Psychiatrische Störungen, Abhängigkeiten oder andere Störungen, die die Fähigkeit zur Studienteilnahme beeinträchtigen.
15. Krebs oder andere maligne hämatologische Erkrankung.
16. PAH verursacht durch Erkrankungen des linken Herzens.
17. PAH in Verbindung mit angeborener Herzerkrankung (PAH-CHD).
18. PAH in Verbindung mit humanem Immundefizienzvirus (PAH-HIV).
19. Porto-pulmonale Hypertension (PPHT).
20. Chronische thromboembolische pulmonale Hypertension (CTEPH).
21. PAH assoziiert mit anderen Erkrankungen (außer den oben genannten): PAH infolge ideopathischer PAH oder mit Bindegewebserkrankunug assoziierter PAH einschließlich systemischer Sklerose (Sklerodermie) und systemischem Lupus Erythematosus (SLE).
22. PAH assoziiert mit anderen chronischen Lungenkrankheiten.
23. Patienten, die gleichzeitig mit dopaminergen Medikamenten behandelt werden
24. Gebärfähige Frauen müssen ausgeschlossen werden, wenn:
- sie im Zyklus vor Studienbeginn keine verläßliche Methode der
Kontrazeption angewendet haben (gemäß CPMP/ICH/286/95 mit
einer Versagerquote <1% pro Jahr).
- sie schwanger sind oder stillen.
25. Patienten, die aufgrund behördlicher oder gerichtlicher Anordnung in einer Anstalt untergebracht wurden.

E.5 End points

E.5.1

Primary end point(s)

1. Change in six minute walk distance (Baseline vs Week 26)
2. Pulmonary vascular resistance (Baseline vs Week 26)
3. Time from start of treatment to clinical worsening (defined as the combined end point of death, lung transplantation, hospitalisation for pulmonary hypertension, leading to discontinuation or need for additional specific PAH therapy)
4. Change in Borg Dyspnea Index (Baseline vs Week 26)
5. Change in WHO functional class [Baseline vs Week 26])
6. Change in cardiac output-index
7. Change in PA pressure
8. Circulating levels of NT-pro-BNP (Baseline vs Week 26)
9. Quality of life questionnaire (SF 36, [Baseline vs Week 26])
10. Change in VO2max (Baseline vs Week 26)
11. Adverse events
12. Concomitant medication

1. Änderung der 6-Minuten Gehstrecke (Baseline vs. Woche 26).
2. Pulmonaler Gefäßwiderstand (Baseline vs. Woche 26).
3. Zeit vom Behandlungsbeginn bis zur klinischen Verschlechterung (definiert als der kombinierte Endpunkt Tod, Lungentransplantation sowie Hospitalisierung aufgrund pulmonaler Hypertension, welche zu Studienabbruch oder zur Notwendigkeit zusätzlicher spezifischer PAH-Behandlung führt.
4. Änderung im Borg Dyspnea Index (Baseline vs. Woche 26).
5. Änderung in der WHO-Funktionsklasse (Baseline vs. Woche 26).
6. Änderung im Herzzeitvolumen (Baseline vs. Woche 26).
7. Änderung im pulmonalen arteriellen Druck (Baseline vs. Woche 26).
8. Konzentration von NT-pro-BNP im Blut (Baseline vs. Woche 26).
9. Fragebogen zur Lebensqualität (SF 36, Baseline vs. Woche 26).
10. Änderung der maximalen Sauerstoffaufnahme (VO2max, Baseline vs. Woche 26).
11. Unerwünschte Ereignisse.
12. Begleitmedikation.

E.5.1.1

Timepoint(s) of evaluation of this end point

After completion of week 26.

Nach Abschluss von Woche 24.

E.5.2

Secondary end point(s)

No secondary end points defined.

Sekundäre Endpunkte nicht definiert.

E.5.2.1

Timepoint(s) of evaluation of this end point

not applicable

nicht zutreffend

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)

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

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

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

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 visit of the last subject.

Letzter Studienbesuch des letzten Studienpatienten.

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)

Subjects will keep receiving their current standard therapy without the study medication as add-on.

Patienten erhalten weiterhin ihre bisherige Standardbehandlung, jedoch ohne die zusätzliche Gabe von Studienmedikation.

G. Investigator Networks to be involved in the Trial
G.4 Investigator Network to be involved in the Trial: 1

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

Competent Authority Decision

Authorised

Date of Competent Authority Decision

2012-07-24

Ethics Committee Opinion of the trial application

Favourable

Ethics Committee Opinion: Reason(s) for unfavourable opinion

Date of Ethics Committee Opinion

2012-07-23

P. End of Trial
P.	End of Trial Status	Prematurely Ended
P.	Date of the global end of the trial	2014-08-19

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