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    Summary
    EudraCT Number:2007-002774-64
    Sponsor's Protocol Code Number:HP 3.1
    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:2007-08-20
    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
    Expand All   Collapse All
    A. Protocol Information
    A.1Member State ConcernedGermany - BfArM
    A.2EudraCT number2007-002774-64
    A.3Full title of the trial
    Therapy of PAH – Treatment with Sildenafil in Eisenmenger Patients
    A.3.2Name or abbreviated title of the trial where available
    Sildenafil
    A.4.1Sponsor's protocol code numberHP 3.1
    A.7Trial is part of a Paediatric Investigation Plan Information not present in EudraCT
    A.8EMA Decision number of Paediatric Investigation Plan
    B. Sponsor Information
    B.Sponsor: 1
    B.1.1Name of SponsorDeutsches Herzzentrum Berlin, Kompetenznetz Angeborene Herzfehler
    B.1.3.4CountryGermany
    B.3.1 and B.3.2Status of the sponsorNon-Commercial
    B.4 Source(s) of Monetary or Material Support for the clinical trial:
    B.4.1Name of organisation providing support
    B.4.2Country
    B.5 Contact point designated by the sponsor for further information on the trial
    B.5.1Name of organisation
    B.5.2Functional name of contact point
    D. IMP Identification
    D.IMP: 1
    D.1.2 and D.1.3IMP RoleTest
    D.2 Status of the IMP to be used in the clinical trial
    D.2.1IMP to be used in the trial has a marketing authorisation Yes
    D.2.1.1.1Trade name Revatio
    D.2.1.1.2Name of the Marketing Authorisation holderPfizer Limited
    D.2.1.2Country which granted the Marketing AuthorisationGermany
    D.2.5The IMP has been designated in this indication as an orphan drug in the Community No
    D.2.5.1Orphan drug designation number
    D.3 Description of the IMP
    D.3.4Pharmaceutical form Film-coated tablet
    D.3.4.1Specific paediatric formulation Information not present in EudraCT
    D.3.7Routes of administration for this IMPOral use
    D.3.8 to D.3.10 IMP Identification Details (Active Substances)
    D.3.8INN - Proposed INNSILDENAFIL
    D.3.9.1CAS number 139755832
    D.3.10 Strength
    D.3.10.1Concentration unit mg milligram(s)
    D.3.10.2Concentration typeequal
    D.3.10.3Concentration number20
    D.3.11 The IMP contains an:
    D.3.11.1Active substance of chemical origin Yes
    D.3.11.2Active substance of biological/ biotechnological origin (other than Advanced Therapy IMP (ATIMP) No
    The IMP is a:
    D.3.11.3Advanced Therapy IMP (ATIMP) Information not present in EudraCT
    D.3.11.3.1Somatic cell therapy medicinal product No
    D.3.11.3.2Gene therapy medical product No
    D.3.11.3.3Tissue Engineered Product Information not present in EudraCT
    D.3.11.3.4Combination ATIMP (i.e. one involving a medical device) Information not present in EudraCT
    D.3.11.3.5Committee on Advanced therapies (CAT) has issued a classification for this product Information not present in EudraCT
    D.3.11.4Combination product that includes a device, but does not involve an Advanced Therapy Information not present in EudraCT
    D.3.11.5Radiopharmaceutical medicinal product No
    D.3.11.6Immunological medicinal product (such as vaccine, allergen, immune serum) No
    D.3.11.7Plasma derived medicinal product No
    D.3.11.8Extractive medicinal product No
    D.3.11.9Recombinant medicinal product Information not present in EudraCT
    D.3.11.10Medicinal product containing genetically modified organisms No
    D.3.11.11Herbal medicinal product No
    D.3.11.12Homeopathic medicinal product No
    D.3.11.13Another type of medicinal product No
    D.8 Information on Placebo
    D.8 Placebo: 1
    D.8.1Is a Placebo used in this Trial?Yes
    D.8.3Pharmaceutical form of the placeboFilm-coated tablet
    D.8.4Route of administration of the placeboOral use
    E. General Information on the Trial
    E.1 Medical condition or disease under investigation
    E.1.1Medical condition(s) being investigated
    Patients with pre-existing congenital heart disease may develop Eisenmenger physiology (EP), characterized by development of pulmonary arterial hypertension and intracardiac right to left shunt. This Patients suffer from cyanosis and reduced quality of life. While EP has been regarded as not amenable to conventional treatments, new oral drugs as Sildenafil have been used successfully to improve primary arterial hypertension. Thus may be an important treatment option for patients with EP, too.
    MedDRA Classification
    E.1.3Condition being studied is a rare disease Yes
    E.2 Objective of the trial
    E.2.1Main objective of the trial
    To determine the walking distance (during 6- min walking test) and oxygen saturation as well as relation of Rp : Rs during cardiac catheter, described as the difference between visite 1 (baseline) and visite 4 (end of the randomized part of the trial).
    E.2.2Secondary objectives of the trial
    To provide normalization of pulmonary vascular function (reagibility and vasoactive mediators) in dependence of duration of the Sildenafil-therapy. Changes in Parameters of MRI, Echo-diagnostics and qualitiy of life as well as safety and tolerance of the treatment will be discovered.
    E.2.3Trial contains a sub-study No
    E.3Principal 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:
    a) non-corrected large congenital shunting defect at atrial, ventricular or arterial level:
    - PAPVD
    - ASD
    - SVD
    - VSD
    - AVSD
    - TAC
    - APW
    - PDA
    - combinations thereof.
    b) Surgically corrected shunting defect (diagnoses as above) with significant residual defect
    c) Other diagnoses with univentricular physiology/ hemodynamics.
    E.4Principal 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 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 body surface)
    - 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 pharmacologic 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 (e.g. diabetes medication, immunosuppression like glucocorticoids, cytostatics)
    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.
    E.5 End points
    E.5.1Primary end point(s)
    Improvement of walking distance (during 6- min walking test), oxygen saturation and relation of Rp : Rs during cardiac catheter, described as the difference between visite 1 (baseline) and visite 4 (end of the randomized part of the trial).
    E.6 and E.7 Scope of the trial
    E.6Scope of the trial
    E.6.1Diagnosis No
    E.6.2Prophylaxis No
    E.6.3Therapy Yes
    E.6.4Safety Yes
    E.6.5Efficacy Yes
    E.6.6Pharmacokinetic No
    E.6.7Pharmacodynamic No
    E.6.8Bioequivalence No
    E.6.9Dose response No
    E.6.10Pharmacogenetic No
    E.6.11Pharmacogenomic No
    E.6.12Pharmacoeconomic No
    E.6.13Others No
    E.7Trial type and phase
    E.7.1Human pharmacology (Phase I) No
    E.7.1.1First administration to humans No
    E.7.1.2Bioequivalence study No
    E.7.1.3Other No
    E.7.1.3.1Other trial type description
    E.7.2Therapeutic exploratory (Phase II) No
    E.7.3Therapeutic confirmatory (Phase III) Yes
    E.7.4Therapeutic use (Phase IV) No
    E.8 Design of the trial
    E.8.1Controlled Yes
    E.8.1.1Randomised Yes
    E.8.1.2Open Yes
    E.8.1.3Single blind No
    E.8.1.4Double blind Yes
    E.8.1.5Parallel group No
    E.8.1.6Cross over No
    E.8.1.7Other No
    E.8.1.7.1Other trial design description
    double blind till week 26, then open (open-label-phase)
    E.8.2 Comparator of controlled trial
    E.8.2.1Other medicinal product(s) No
    E.8.2.2Placebo Yes
    E.8.2.3Other No
    E.8.3 The trial involves single site in the Member State concerned No
    E.8.4 The trial involves multiple sites in the Member State concerned Yes
    E.8.4.1Number of sites anticipated in Member State concerned13
    E.8.5The trial involves multiple Member States No
    E.8.6 Trial involving sites outside the EEA
    E.8.6.1Trial being conducted both within and outside the EEA No
    E.8.6.2Trial being conducted completely outside of the EEA Information not present in EudraCT
    E.8.7Trial 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
    E.8.9 Initial estimate of the duration of the trial
    E.8.9.1In the Member State concerned years3
    E.8.9.1In the Member State concerned months0
    E.8.9.1In the Member State concerned days0
    E.8.9.2In all countries concerned by the trial years3
    E.8.9.2In all countries concerned by the trial months0
    E.8.9.2In all countries concerned by the trial days0
    F. Population of Trial Subjects
    F.1 Age Range
    F.1.1Trial has subjects under 18 Yes
    F.1.1.1In Utero No
    F.1.1.2Preterm newborn infants (up to gestational age < 37 weeks) No
    F.1.1.3Newborns (0-27 days) No
    F.1.1.4Infants and toddlers (28 days-23 months) No
    F.1.1.5Children (2-11years) No
    F.1.1.6Adolescents (12-17 years) Yes
    F.1.2Adults (18-64 years) Yes
    F.1.3Elderly (>=65 years) Yes
    F.2 Gender
    F.2.1Female Yes
    F.2.2Male Yes
    F.3 Group of trial subjects
    F.3.1Healthy volunteers No
    F.3.2Patients Yes
    F.3.3Specific vulnerable populations Yes
    F.3.3.1Women 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 2007-08-20. Yes
    F.3.3.2Women of child-bearing potential using contraception Yes
    F.3.3.3Pregnant women No
    F.3.3.4Nursing women No
    F.3.3.5Emergency situation No
    F.3.3.6Subjects incapable of giving consent personally Yes
    F.3.3.6.1Details of subjects incapable of giving consent
    Handicapped patients with Eisenmenger´s Syndrome with person in support.
    F.3.3.7Others No
    F.4 Planned number of subjects to be included
    F.4.1In the member state80
    F.4.2 For a multinational trial
    F.4.2.2In the whole clinical trial 80
    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)
    Patients who drop out of the study will be treated with medical care according to the best standard of knowledge (there are no guidelines in terms of an established standard therapy for Eisenmenger´s patients).
    G. Investigator Networks to be involved in the Trial
    N. Review by the Competent Authority or Ethics Committee in the country concerned
    N.Competent Authority Decision Authorised
    N.Date of Competent Authority Decision2007-12-04
    N.Ethics Committee Opinion of the trial applicationFavourable
    N.Ethics Committee Opinion: Reason(s) for unfavourable opinion
    N.Date of Ethics Committee Opinion2007-09-27
    P. End of Trial
    P.End of Trial StatusPrematurely Ended
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