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

• Register: ClinicalTrials.gov
• Last refreshed on: 19 February 2015
• Main ID: NCT00586794
• Date of registration: 21/12/2007
• Prospective Registration: No
• Primary sponsor: Competence Network for Congenital Heart Defects
• Public title: Therapy of Pulmonary Arterial Hypertension (PAH) - Treatment With Sildenafil in Eisenmenger Patients
• Scientific title: Therapy of Pulmonary Arterial Hypertension (PAH) - Treatment With Sildenafil in Eisenmenger Patients
• Date of first enrolment: December 2007
• Target sample size: 24
• Recruitment status: Terminated
• URL: http://clinicaltrials.gov/show/NCT00586794
• Study type: Interventional
• Study design: Allocation: Randomized, Endpoint Classification: Efficacy Study, Intervention Model: Parallel Assignment, Masking: Double Blind (Subject, Investigator), Primary Purpose: Treatment
• Phase: Phase 3

Countries of recruitment

Germany

Contacts

• Name: Ingram Schulze-Neick, MD
• Affiliation: Great Ormond Street Hospital for Sick Children,London

• Name: Siegrun Mebus, MD
• Affiliation: German Heart Institute Munich, Competence Network for Congenital Heart Defects

Key inclusion & exclusion criteria

Inclusion Criteria:

Non-specific:

1. Written informed consent obtained.

2. No participation in another AMG driven study attendancing this treatment protocol

Specific:

1. Age at least 14 years

2. Presence of cyanosis with < 93 % arterial oxygen saturation (measured by
transcutaneous pulse oximetry)

3. 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)

4. Presence of PAH as diagnosed by invasive methods with Rp:Rs > 0.5 measured at rest,
before testing of pulmonary vasodilatory reserve

5. 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:

1. pregnancy or lactation

2. women of child-bearing age who are sexually active without practising highly
effective methods of contraception

3. any diseases or impairment that, in the opinion of the investigator exclude a subject
from participation

4. substance abuse (alcohol, medicines, drugs)

5. 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

6. insufficient compliance

7. missing willingness to storaging and transferring pseudonymous disease data within
this study.

8. subjects who are not able to perform Cardio-Pulmonary Exercise Testing (CPX).

Specific:

1. pulmonary hypertension secondary to any etiology other than those specified in the
inclusion criteria

2. subjects with known intolerance of NO and iloprost or their constituents

3. acute decompensated heart failure within the 7 days before the invasive diagnostic
procedure

4. clinically significant haemoptysis within the last 6 months

5. hemodynamic instability which would represent an unjustifiable risk during testing of
pulmonary arterial vasoreagibility

6. arterial hypotension (as defined by age-specific values)

7. anemia (Hb < 10 g/dl)

8. decompensated symptomatic policythemia; (details: 4.2.2. exclusion criteria)

9. thrombocytopenia (< 50.000/µl)

10. 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)

11. 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)

12. Obstruction of pulmonary blood outflow:

- obstruction of pulmonary venous return

- mitral valve dysfunction

13. Left heart diseases:

- aortic or mitral valve disease (more severe than "mild")

- restrictive or congestive cardiomyopathy

- PCWP/LVEDP > 15 mmHg

- symptomatic coronary artery disease

14. Significant valvular diseases other than tricuspid or pulmonary regurgitation (these
are not exclusion criteria; details: 4.2.2. exclusion criteria).

15. Pericardial constriction

16. History of stroke, myocardial infarction or life-threatening arrhythmia within the 6
months before screening

17. Bronchopulmonary dysplasia (BPD) and other chronic lung diseases

18. History of significant pulmonary embolism

19. Other relevant diseases (e.g. HIV, diabetes mellitus requiring medical treatment)

20. Subjects with trisomy 21 (reproducibility of 6-MWT and CPX doubtful; communication as
to side effects and subjective quality of life doubtful)

21. 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.

1. Unspecified concomitant medication

2. Other significant medication (a.o. chronic intake of systemic immunosuppression as
e.g. systemic glucocorticoids, cytostatic drugs, ciclosporin)

3. 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

4. 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.

5. Other medication with vascular action:

- alpha blockers

- L-arginin (acts through NO axis)

- ritonavir, nicorandil (act through K+ channels)

6. 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.



Age minimum: 14 Years
Age maximum: N/A
Gender: Both

Health Condition(s) or Problem(s) studied

Pulmonary Arterial Hypertension (PAH)

Intervention(s)

Drug: Placebo

Drug: Sildenafil

Primary Outcome(s)

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)]

Secondary Outcome(s)

Safety and tolerance of the treatment [Time Frame: 78 weeks]

Quality of life (SF-36) [Time Frame: 78 weeks]

Parameters of MRI and Echo-diagnostic [Time Frame: 78 weeks]

To provide normalization of pulmonary vascular function (reagibility and vasoactive mediators) in dependence on duration of the therapy [Time Frame: 78 weeks]

Secondary ID(s)

MP 3.1 Sildenafil

Source(s) of Monetary Support

Please refer to primary and secondary sponsors

Secondary Sponsor(s)

German Federal Ministry of Education and Research