Therapy of Pulmonary Arterial Hypertension (PAH) - Treatment With Sildenafil in Eisenmenger Patients - Full Text View

Sponsor:	Competence Network for Congenital Heart Defects
Collaborator:	German Federal Ministry of Education and Research
Information provided by:	Competence Network for Congenital Heart Defects
ClinicalTrials.gov Identifier:	NCT00586794

Purpose

Eisenmenger's syndrome presents as a severe clinical picture of polymorbidity that constitutes a great burden at the individual as well as the familial and social level. The combination of critically increased pulmonary vascular resistance, progressive pressure load of the right ventricle and disturbance of pulmonary gas exchange result in long-term polymorbidity. The objective of this study is to provide evidence of improvement of patients exercise tolerance as well as general conditions by treatment with oral sildenafil as a specific pulmonary vasodilator.

Condition	Intervention	Phase
Pulmonary Arterial Hypertension (PAH)	Drug: Sildenafil Drug: Placebo	Phase III

Study Type:	Interventional
Study Design:	Treatment, Randomized, Double Blind (Subject, Investigator), Placebo Control, Parallel Assignment, Efficacy Study
Official Title:	Therapy of Pulmonary Arterial Hypertension (PAH) - Treatment With Sildenafil in Eisenmenger Patients

Resource links provided by NLM:

Genetics Home Reference related topics: pulmonary arterial hypertension

MedlinePlus related topics: High Blood Pressure

Drug Information available for: Sildenafil Sildenafil citrate

U.S. FDA Resources

Further study details as provided by Competence Network for Congenital Heart Defects:

Primary Outcome Measures:

To determine the distance of walking, which is performed during a 6- min walking test; oxygen saturation and relation of resistance Rp : Rs during the examination with "Herzkatheter", described as the difference between visit 1 (baseline) and visit 4 [ Time Frame: visit 1 and visit 4 (after 26 weeks) ] [ Designated as safety issue: No ]

Secondary Outcome Measures:

To provide normalization of pulmonary vascular function (reagibility and vasoactive mediators) in dependence on duration of the therapy [ Time Frame: 78 weeks ] [ Designated as safety issue: Yes ]
Parameters of MRI and Echo-diagnostic [ Time Frame: 78 weeks ] [ Designated as safety issue: Yes ]
Quality of life (SF-36) [ Time Frame: 78 weeks ] [ Designated as safety issue: Yes ]
Safety and tolerance of the treatment [ Time Frame: 78 weeks ] [ Designated as safety issue: Yes ]

Estimated Enrollment:	80
Study Start Date:	December 2007
Estimated Study Completion Date:	March 2012
Estimated Primary Completion Date:	March 2012 (Final data collection date for primary outcome measure)

Arms	Assigned Interventions
A: Active Comparator	Drug: Sildenafil 3x per day 20 mg TID
B: Placebo Comparator from the 26th weeks on open-label, all patients were treated with Sildenafil	Drug: Placebo 3x per day, 20 mg TID

Detailed Description:

Eisenmenger's syndrome presents as a severe clinical picture of polymorbidity that constitutes a great burden at the individual as well as the familial and social level. The combination of critically increased pulmonary vascular resistance, progressive pressure load of the right ventricle and disturbance of pulmonary gas exchange result in long-term polymorbidity. While the patient's ability to care for him-/ herself gets lost over time, the financial burden due to the need for medical consultations and hospital stays increases. This is distressing to both the patient and the family. Usually, death results from cardiac decompensation in the presence of gradually increasing pulmonary vascular resistance and hypoxic lesion of organs including the myocardium (Hopkins, AJC 2002).

With a better understanding of the pathophysiology underlying pulmonary hypertension, novel therapeutic approaches have been developed during the past few years. These include a) inhibition of the NO-cGMP-degrading type 5 phosphodiesterase (PDE-5) and b) antagonising the endothelin system (Krum, Curr Opin Investig Drugs 2003). The goal is a dilatation of the abnormally constricted pulmonary arterial vessels by relaxation of the vascular smooth muscle cells with a reversal of pulmonary vascular remodelling (Ghofrani, Pneumologie 2002).

Specific drugs affecting pulmonary vascular resistance have been studied. Intravenous prostacyclin has major disadvantages: high cost, tachyphylaxis, risk of infection and rebound hypertension upon discontinuation. Inhalative pulmonary vasodilators, in particular iloprost, may be effective in primary pulmonary hypertension (Olschewski, Ann Int Med 1996; Hoeper, Pneumologie 2001), but administration is time-consuming, and due to its mode of application its effects are intermittent, lasting only about 75 minutes (Hoeper, JACC 2000). Considering this, oral treatments appear preferable, because of easy administration and, hence, better patient compliance.

Sildenafil (Revatio®) an inhibitor of the phosphodiesterase 5 (PDE-5) was used in many individual cases (Abrams, Schulze-Neick et al, Heart 2000), some acute studies and two long-term studies in humans to reduce the pulmonary vessel resistance. Significant effects on reduction of the pulmonary vessel resistance were demonstrated for the combination with an inhalational prostanoid (Ghofrani et al, Ann Int Med 2002).Good long-term tolerability and effectiveness over a period of two year were demonstrated by this working group.

The objective of this study is to provide evidence of improvement of patients exercise tolerance as well as general conditions by treatment with oral sildenafil as a specific pulmonary vasodilator. The data obtained are supposed to contribute to the development of guidelines for the treatment of Pulmonary Arterial Hypertension (PAH)caused by congenital heart defects.

The hypotheses are:

Sildenafil heales specific pulmonary vascular damage, which occurs by hypercirculation as quick-acting inhibiting vasoconstriction.
Through this there will be a reduction of pulmonary vessel resistance and a normalization of pulmonary reagibility in patients with Eisenmenger syndrome.
Pulmonary blood circulation and so systemic arterial oxygen delivery will increase.
The patient benefits from this by improving his exercise tolerance as well as general and clinical condition.

These hypotheses will be tested by comparing findings of the following examinations before, during and after the 52 or 78-week treatment with sildenafil: clinical examination, Electrocardiogram (ECG), echocardiography, ergospirometry, Magnetic Resonance Imaging (MRI), cardiac catheterization with pulmonary artery manometry, and laboratory tests.

Eligibility

Ages Eligible for Study:	14 Years and older
Genders Eligible for Study:	Both
Accepts Healthy Volunteers:	No

Criteria

Inclusion Criteria:

Non-specific:

Written informed consent obtained.
No participation in another AMG driven study attendancing this treatment protocol

Specific:

Age at least 14 years
Presence of cyanosis with < 93 % arterial oxygen saturation (measured by transcutaneous pulse oximetry)
Clinical indication for the invasive diagnostic procedures planned for the study is given; this is evaluated on the basis of observation before, during and after medicinal therapy)
Presence of PAH as diagnosed by invasive methods with Rp:Rs > 0.5 measured at rest, before testing of pulmonary vasodilatory reserve
One of the following diagnoses:
1. non-corrected large congenital shunting defect at atrial, ventricular or arterial level:
  - PAPVD
  - ASD
  - SVD
  - VSD
  - AVSD
  - TAC
  - APW
  - PDA
  - combinations thereof.
2. Surgically corrected shunting defect (diagnoses as above) with significant residual defect
3. Other diagnoses with univentricular physiology/ hemodynamics.

Exclusion Criteria:

Non-specific:

pregnancy or lactation
women of child-bearing age who are sexually active without practising highly effective methods of contraception
any diseases or impairment that, in the opinion of the investigator exclude a subject from participation
substance abuse (alcohol, medicines, drugs)
other medical, psychological or social circumstances that would adversely affect a patient's ability to participate reliably in the study or increase the risk to themselves or others if they participated
insufficient compliance
missing willingness to storaging and transferring pseudonymous disease data within this study.
subjects who are not able to perform Cardio-Pulmonary Exercise Testing (CPX).

Specific:

pulmonary hypertension secondary to any etiology other than those specified in the inclusion criteria
subjects with known intolerance of NO and iloprost or their constituents
acute decompensated heart failure within the 7 days before the invasive diagnostic procedure
clinically significant haemoptysis within the last 6 months
hemodynamic instability which would represent an unjustifiable risk during testing of pulmonary arterial vasoreagibility
arterial hypotension (as defined by age-specific values)
anemia (Hb < 10 g/dl)
decompensated symptomatic policythemia; (details: 4.2.2. exclusion criteria)
thrombocytopenia (< 50.000/µl)
secondary impairment of organic function:
- impairment of renal function (GFR < 30 ml/min/1,73 m2 BSA)
- impairment of hepatic function (ALT and/or AST > 3 x ULN and bilirubin ≥ 2 mg/dl)
other sources of pulmonary blood flow which prohibit measurement of the blood flow into the lungs and therefore of the pulmonary vascular resistance:
- Glenn
- BT shunt
- significant number of MAPCAs; (details: 4.2.2. exclusion criteria)
Obstruction of pulmonary blood outflow:
- obstruction of pulmonary venous return
- mitral valve dysfunction
Left heart diseases:
- aortic or mitral valve disease (more severe than "mild")
- restrictive or congestive cardiomyopathy
- PCWP/LVEDP > 15 mmHg
- symptomatic coronary artery disease
Significant valvular diseases other than tricuspid or pulmonary regurgitation (these are not exclusion criteria; details: 4.2.2. exclusion criteria).
Pericardial constriction
History of stroke, myocardial infarction or life-threatening arrhythmia within the 6 months before screening
Bronchopulmonary dysplasia (BPD) and other chronic lung diseases
History of significant pulmonary embolism
Other relevant diseases (e.g. HIV, diabetes mellitus requiring medical treatment)
Subjects with trisomy 21 (reproducibility of 6-MWT and CPX doubtful; communication as to side effects and subjective quality of life doubtful)
all contraindications against the study medication (see also "4.2.3 concomitant medication")
- hypersensitivity against the active ingredients as well as supplementaries
- patients who lost vision on one eye due to a non arteriitic anterior ischaemic neuropathy of the opticus (NAION).

Prohibited concomitant medication:

Any medication listed below which has not been discontinued at least 30 days prior to screening. Specific pulmonary vasodilators during cardiac catheterization are allowed.

Unspecified concomitant medication
Other significant medication (a.o. chronic intake of systemic immunosuppression as e.g. systemic glucocorticoids, cytostatic drugs, ciclosporin)
Instable medication (details: 4.2.5 prohibited concomitant medication):
- begin of a new medication regimen within the last 30 days before screening
- change in the dosage of existing medication within the last 7 days before cardiac catheterization
Existing anti-pulmonary hypertensive medication (in any form) with:
- PDE-5 antagonists (e.g. sildenafil)
- prostanoids (e.g. iloprost, prostacyclin, beraprost) In case the patient is stable and on Bosentan therapy at least for 6 months. Bosentan (Tracleer®) is unprohibited as concomitant medication.
Other medication with vascular action:
- alpha blockers
- L-arginin (acts through NO axis)
- ritonavir, nicorandil (act through K+ channels)
Medication that is not compatible with sildenafil or interferes with the metabolism:
- cytochrome P450-CYP2C9 and CYP3A4 inhibitors (e.g. erythromycin/ketoconazole/itraconazole/protease inhibitors)
- any existing medication that, in the opinion of the investigator, may interfere with sildenafil treatment.

Contacts and Locations

Please refer to this study by its ClinicalTrials.gov identifier: NCT00586794

Contacts

Contact: Siegrun Mebus, MD

+49 89 1218 - 3010

mebus@dhm.mhn.de

Locations

Germany
Deutsches Herzzentrum Berlin, Abt. angeborener Herzfehler/Kinderkardiologie	Recruiting
Berlin, Germany, D-13353
Contact: Oliver Miera, MD +49-30-4593 2800 miera@dhzb.de
Principal Investigator: O. Miera, MD
Sub-Investigator: S. Nordmeyer
Sub-Investigator: B. Farahwaschy
Universitätsklinikum Erlangen, Kinderkardiologische Abteilung, Kinder- und Jugendklinik	Recruiting
Erlangen, Germany, D-91054
Contact: Prof. Sven Dittrich, MD +49-9131-8533750 sven.dittrich@kinder.imed.uni-erlangen.de
Principal Investigator: Prof. S. Dittrich, MD
Sub-Investigator: A. Koch, MD
Universitätsklinikum Charite, Campus Virchow-Klinikum, Otto-Heubner-Centrum für Kinder- und Jugendmedizin	Recruiting
Berlin, Germany, D-13353
Contact: Lothar Schmitz, MD +49-30-450 566 873 lothar.schmitz@charite.de
Principal Investigator: Lothar Schmitz, MD
Sub-Investigator: K. Weiss, MD
Sub-Investigator: B. Opgen-Rhein, MD
Germany, Baden-Wuertemberg
Universitätsklinikum Freiburg, Klinik III Päd. Kardiologie	Recruiting
Freiburg, Baden-Wuertemberg, Germany, D-79106
Contact: Jochen Grohmann, MD +49-761-270 4317 jochen.grohmann@uniklinik-freiburg.de
Contact: Raoul Arnold, MD raoul.arnold@uniklinik-freiburg.de
Principal Investigator: J. Grohmann, MD
Sub-Investigator: R. Arnold, MD
Sub-Investigator: C. Rummer, MD
Medizinische Klinik und Poliklinik, Abteilung Innere Medizin III	Recruiting
Heidelberg, Baden-Wuertemberg, Germany, D-69120
Contact: F. Joachim Meyer, MD +49-6221-5638 635 joachim_meyer@med.uni-heidelberg.de
Principal Investigator: F. J. Meyer, MD
Sub-Investigator: A. Filusch, MD
Sub-Investigator: F. Leuschner, MD
Sub-Investigator: W. Rottbauer, MD
Klinikum der Universität Heidelberg, Pädiatrische Kardiologie	Recruiting
Heidelberg, Baden-Wuertemberg, Germany, D-69120
Contact: Michael Goetze, MD +49-6211-56 2348 michael.goetze@med.uni-heidelberg.de
Principal Investigator: M. Goetze, MD
Sub-Investigator: D. Bucsenez, MD
Sub-Investigator: J. Eichhorn, MD
Germany, Baden-Wuerttemberg
Universitätsklinikum Tübingen, Klinik für Kinderheilkunde und Jugendmedizin	Recruiting
Tübingen, Baden-Wuerttemberg, Germany, D-72076
Contact: Prof. Michael Hofbeck, MD +49-7071-298 4751 michael.hofbeck@med.uni-tuebingen.de
Principal Investigator: Prof. M. Hofbeck, MD
Sub-Investigator: C. Apitz, MD
Sub-Investigator: Prof. L. Sieverding, MD
Klinikum Stuttgart, Olgahospital, Klinik für Kinderheilkunde und Jugendmedizin, Pädiatrie 3	Recruiting
Stuttgart, Baden-Wuerttemberg, Germany, D-70176
Contact: F. Uhlemann, MD +49-711-992-2441 f.uhlemann@olgahospital.de
Principal Investigator: F. Uhlemann, MD
Sub-Investigator: V. Ocker, MD
Germany, Bavaria
Deutsches Herzzentrum München	Recruiting
Munich, Bavaria, Germany, D-80336
Contact: Prof. John Hess, MD +49-89-1218 3011 hess@dhm.mhn.de
Principal Investigator: Prof. J. Hess, MD
Sub-Investigator: A. Hager, MD
Sub-Investigator: G. Balling, MD
Sub-Investigator: Prof. H. Kaemmerer, MD
Sub-Investigator: S. Mebus, MD
Ludwig-Maximilian-Universität München, Klinikum Großhadern, Abt. Kinderkardiologie und Intensivmedizin	Recruiting
München-Großhadern, Bavaria, Germany, D-81377
Contact: Prof. Heinrich Netz, MD +49-89-7095 3941 heinrich.netz@med.uni-muenchen.de
Principal Investigator: Prof. H. Netz, MD
Sub-Investigator: R. Dalla Pozza, MD
Sub-Investigator: S. Urschel, MD
Germany, Hesse
Universitätsklinikum Giessen and Marburg, Zentrum für Kinderheilkunde und Jugendmedizin	Recruiting
Giessen, Hesse, Germany, D-35385
Contact: Karsten R.G. grosse Kreymborg +49-641-99 434 77 karsten.g.kreymborg@paediat.med.uni-giessen.de
Principal Investigator: K. R. G. grosse Kreymborg
Sub-Investigator: Prof. J. Kreuder, MD
Germany, Lower Saxony
Elisabeth Kinderkrankenhaus, Zentrum für Kinder- und Jugendmedizin	Recruiting
Oldenburg, Lower Saxony, Germany, D-26133
Contact: Reinald Motz, MD +49-441-403 2487 motz.reinald@klinikum-oldenburg.de
Principal Investigator: R. Motz, MD
Sub-Investigator: M. Schumacher, MD
Sub-Investigator: M. Viemann, MD
Sub-Investigator: K. Kronberg, MD
Medizinische Hochschule Hannover, Abt. für Kardiologie und Angiologie	Recruiting
Hannover, Lower Saxony, Germany, D-30625
Contact: Mechthild Westhoff-Bleck, MD +49-511-532 2568 westhoff-bleck.mechthild@mh-hannover.de
Principal Investigator: M. Westhoff-Bleck, MD
Sub-Investigator: G. P. Meyer, MD
Sub-Investigator: O. Tutarel, MD
Medizinische Hochschule Hannover, Klinik für Kinderheilkunde, Pädiatrische Kardiologie und Pädiatrische Intensivmedizin	Recruiting
Hannover, Lower Saxony, Germany, D-30625
Contact: Burkhard Wermter, MD +49-511-532 6750 burkhard_wermter@yahoo.es
Principal Investigator: B. Wermter, MD
Sub-Investigator: F. Danne, MD
Sub-Investigator: H. Bertram, MD
Sub-Investigator: U. Grosser, MD
Sub-Investigator: C. Bara, MD
Sub-Investigator: W. A. Osthaus, MD
Germany, North Rhine-Westphalia
Herz-und Diabeteszentrum NRW	Recruiting
Bad Oeynhausen, North Rhine-Westphalia, Germany, D-32545
Contact: Nikolaus Haas, MD +49-5731-973620 nhaas@hdz-nrw.de
Principal Investigator: Nikolaus Haas, MD
Evangelisches und Johanniter Klinikum Niederrhein gGmbH, Herzzentrum Duisburg	Recruiting
Duisburg, North Rhine-Westphalia, Germany, D-47137
Contact: Otto Krogmann, MD +49-230-451 3301 otto.krogman@ejk.de
Principal Investigator: O. Krogmann, MD
Sub-Investigator: K. Walter, MD
Universitätsklinikum Münster, EMAH-Zentrum	Recruiting
Münster, North Rhine-Westphalia, Germany, D-48149
Contact: Prof. H. Baumgartner, MD +49-251-86-46110 helmut.baumgartner@ukmuenster.de
Principal Investigator: Prof. H. Baumgartner, MD
Sub-Investigator: G. P. Diller, MD
Sub-Investigator: G. Kaleschke, MD
Sub-Investigator: A. Kempny, MD
Germany, Saarland
Universitätsklinikum des Saarlandes	Recruiting
Homburg/Saar, Saarland, Germany, D-66421
Contact: Prof. Hashim Abdul-Khaliq, MD +49-6841-16 28305 abdul-khaliq@uniklinikum-saarland.de
Principal Investigator: Prof. Hashim Abdul-Khaliq, MD
Sub-Investigator: Axel Rentzsch, MD
Sub-Investigator: A. Lindinger, MD
Sub-Investigator: J. Olchvary, MD
Sub-Investigator: P. Schwarz, MD
Sub-Investigator: J. Al Shouli, MD
Germany, Saxony
Universitätsklinikum der Martin-Luther-Universität Halle-Wittenberg	Recruiting
Halle / Saale, Saxony, Germany, D-06120
Contact: Prof. Ralph Grabitz, MD +49-345-557 2762 ralph.grabitz@medizin.uni-halle.de
Principal Investigator: Prof. R. Grabitz, MD
Sub-Investigator: H. Issa, MD
Sub-Investigator: K. Elsner
Germany, Schleswig-Holstein
Universitätsklinikum Schleswig-Holstein Campus Kiel	Recruiting
Kiel, Schleswig-Holstein, Germany, D-24105
Contact: Carsten Rickers, MD +49-431-597 1622 rickers@pedcard.uni-kiel.de
Principal Investigator: C. Rickers, MD
Sub-Investigator: I. Voges, MD

Sponsors and Collaborators

Competence Network for Congenital Heart Defects

German Federal Ministry of Education and Research

Investigators

Principal Investigator:	Siegrun Mebus, MD	German Heart Institute Munich, Competence Network for Congenital Heart Defects
Study Chair:	Ingram Schulze-Neick, MD	Great Ormond Street Hospital for Sick Children,London

Responsible Party:	DHZB,German Heart Institute Munich, Competence Network for Congenital Heart Defects, ( Dr. Siegrun Mebus )
Study ID Numbers:	MP 3.1 Sildenafil
Study First Received:	December 21, 2007
Last Updated:	October 2, 2009
ClinicalTrials.gov Identifier:	NCT00586794 History of Changes
Health Authority:	Germany: Federal Institute for Drugs and Medical Devices