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    The EU Clinical Trials Register currently displays   40653   clinical trials with a EudraCT protocol, of which   6635   are clinical trials conducted with subjects less than 18 years old.
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    Summary
    EudraCT Number:2006-001464-23
    Sponsor's Protocol Code Number:A1481243
    National Competent Authority:Germany - BfArM
    Clinical Trial Type:EEA CTA
    Trial Status:Completed
    Date on which this record was first entered in the EudraCT database:2006-05-05
    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
    Expand All   Collapse All
    A. Protocol Information
    A.1Member State ConcernedGermany - BfArM
    A.2EudraCT number2006-001464-23
    A.3Full title of the trial
    A multinational, multicentre, randomized, double-blind study to assess the efficacy and safety of oral sildenafil 20mg TID or placebo when added to Bosentan in the treatement of subjects , aged 18 years and above, with pulmonary arterial hypertension (PAH)
    A.3.1Title of the trial for lay people, in easily understood, i.e. non-technical, language
    A multinational, multicentre, randomized, double-blind study to assess the efficacy and safety of oral sildenafil 20mg three times daily or placebo when added to bosentan in the treatment of adult subjects, with
    pulmonary arterial hypertension.
    A.3.2Name or abbreviated title of the trial where available
    N/A
    A.4.1Sponsor's protocol code numberA1481243
    A.7Trial is part of a Paediatric Investigation Plan No
    A.8EMA Decision number of Paediatric Investigation Plan
    B. Sponsor Information
    B.Sponsor: 1
    B.1.1Name of SponsorPfizer Ltd, Ramsgate Road, Sandwich, Kent, CT13 9NJ, UK
    B.1.3.4CountryGermany
    B.3.1 and B.3.2Status of the sponsorCommercial
    B.4 Source(s) of Monetary or Material Support for the clinical trial:
    B.4.1Name of organisation providing supportPfizer Ltd
    B.4.2CountryGermany
    B.5 Contact point designated by the sponsor for further information on the trial
    B.5.1Name of organisationPfizer Inc
    B.5.2Functional name of contact pointClinical Trials.gov Call Centre
    B.5.3 Address:
    B.5.3.1Street Address235 E 42nd Street
    B.5.3.2Town/ cityNew York
    B.5.3.3Post codeNY 10017
    B.5.3.4CountryUnited States
    B.5.4Telephone number+18007181021
    B.5.5Fax number+13037391119
    B.5.6E-mailClinicalTrials.gov_Inquiries@pfizer.com
    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 Ltd.
    D.2.1.2Country which granted the Marketing AuthorisationEuropean Union
    D.2.5The IMP has been designated in this indication as an orphan drug in the Community Yes
    D.2.5.1Orphan drug designation numberEU/3/03/178
    D.3 Description of the IMP
    D.3.1Product nameRevatio®
    D.3.2Product code UK-92,480
    D.3.4Pharmaceutical form Film-coated tablet
    D.3.4.1Specific paediatric formulation No
    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 n/a
    D.3.9.2Current sponsor coden/a
    D.3.9.3Other descriptive namen/a
    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) No
    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 No
    D.3.11.3.4Combination ATIMP (i.e. one involving a medical device) No
    D.3.11.3.5Committee on Advanced therapies (CAT) has issued a classification for this product No
    D.3.11.4Combination product that includes a device, but does not involve an Advanced Therapy No
    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 No
    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
    Pulmonary Arterial Hypertension
    E.1.1.1Medical condition in easily understood language
    Pulmonary arterial hypertension (PAH) is characterized by a progressive
    increase in pulmonary vascular resistance, leading to right ventricular
    failure and premature death.
    E.1.1.2Therapeutic area Body processes [G] - Circulatory and Respiratory Physiological Phenomena [G09]
    MedDRA Classification
    E.1.2 Medical condition or disease under investigation
    E.1.2Version 14.1
    E.1.2Level PT
    E.1.2Classification code 10064911
    E.1.2Term Pulmonary arterial hypertension
    E.1.2System Organ Class 10038738 - Respiratory, thoracic and mediastinal disorders
    E.1.3Condition being studied is a rare disease Yes
    E.2 Objective of the trial
    E.2.1Main objective of the trial
    To assess the effect on exercise capacity (as measured by the 6 Minute Walk Distance) after 12 weeks of treatment of sildenafil (20mg TID) or placebo when added to subjects with PAH who are stabilized on bosentan therapy
    E.2.2Secondary objectives of the trial
    1. To assess the safety and tolerability of sildenafil (20mg TID) or placebo, when added to subjects with PAH who are currently treated with bosentan, after 12 weeks of treatment.
    2. To assess the safety and tolerability of the open label treatment of sildenafil (20mg TID) and bosentan therapy in subjects with PAH after 12 months of treatment.
    3. To assess the effect on other clinical outcome measures (clinical worsening, Borg dyspnoea score and PAH functional class) after 12 weeks of treatment of sildenafil (20mg TID) or placebo when added to bosentan therapy in subjects with PAH.
    4. To determine the population pharmacokinetic parameters of sildenafil and bosentan and to investigate potential pharmacokinetic interactions between the two compounds in the target patient population.
    5. To investigate the PK/PD relationship between sildenafil and bosentan exposure on the 6-Minute Walk Test

    Tertiary Objective
    To investigate the effects on BNP and N-terminal pro-BNP
    E.2.3Trial contains a sub-study No
    E.3Principal inclusion criteria
    1. Subjects aged 18 and above at the time of the screening visit who have any of the following types of pulmonary arterial hypertension and functional class, and for which bosentan therapy is indicated according to EU Marketing Authorisation:
    · Idiopathic ‘Primary’ Pulmonary Arterial Hypertension (PAH)
    . Pulmonary Hypertension secondary to Scleroderma.
    · Subjects with WHO functional class III prior to initiation of bosentan therapy.
    2. Subjects must have been treated continually with a stable dose of bosentan (62.5mg bid or 125mg bid) for a minimum of three months prior to randomization.
    3. Subject with a mean pulmonary artery pressure ≥25 mmHg and a pulmonary capillary wedge pressure of < 15 mmHg at rest, via right heart catheterization within 3 years prior to randomization.
    4. Subjects whose baseline 6-Minute Walk Test distrance is ≥100m and ≤450m.
    5. Evidence of a personally signed and dated informed consent document indicating that the subject (or a legal representative) has been informed of all pertinent aspects of the study.
    6. Subjects who are willing and able to comply with scheduled visits, treatment plan, laboratory tests, and other study procedures.
    7. All women of childbearing potential must have a negative screening serum pregnancy test and:
     Must agree to use a highly effective method of contraception (ie, hormonal in conjunction with intrauterine device or barrier methods with spermicide) throughout the study and for the duration of their bosentan therapy or
     Must be celibate or
     Their partner must have had vasectomy.
    8. Women who are not of childbearing potential may be enrolled and do not need to use birth control, provided they meet at least one of the following criteria:
     Have undergone hysterectomy or bilateral oopherectomy or
     Have medically confirmed ovarian failure or
     Are medically confirmed to be post-menopausal (cessation of regular menses for at least 12 consecutive months with no alternative pathological or physiological cause.
    E.4Principal exclusion criteria
    1. PAH secondary to any aetiology including congenital heart disease other than those specified in the inclusion criteria. 2. With the exception of bosentan therapy, subjects who are currently receiving any forms of chronic treatment for PAH such as any formulations of prostacyclin, PDE-5 inhibitors, other endothelin-receptor antagonists, nitrates or nitric oxide donors (e.g. arginine supplements) including nicorandil in any form or any potent CYP3A4 inhibitors (e.g. Cyclosporin A and Glibenclamide). 3. Subjects with significant (i.e. > 2+) valvular disease other than tricuspid regurgitation or pulmonary regurgitation. Subjects with previous surgical replacement of a valve may be eligible for entry into the study after consultation with a Pfizer study clinician provided the following conditions are satisfied:That there was no evidence of PAH secondary to valvular disease prior to surgery; The prosthetic valve is functioning normally on echocardiography; The valve replacement occurred at least one year prior to randomization. 4. Subjects with acutely decompensated heart failure within 30 days prior to randomization. 5. Subjects with LV Ejection Fraction of <45% or LV shortening fraction of <0.2 within three months prior to randomization. 6. Subjects who have had a myocardial infarction within 6 months prior to randomization 7. Subjects who have had a change of dose or class of standard background therapy used for treatment of PAH (i.e. oxygen, calcium channel blockers, digoxin, diuretics) used for the treatment of PAH within 30 days prior to randomization. Note: a change in the dose or oral anticoagulant therapy within this timeframe to maintain the INR within the therapeutic range is acceptable. 8. Subjects with congenital heart disease (unless they fulfill inclusion 1.), pulmonary hypertension due to thromboembolism, HIV or schistosomiasis. 9. Subjects who have undergone atrial septostomy within six months prior to randomization. 10. Subjects with uncontrolled brady- or tachyarrhythmias, placement of pacemakers orimplantable defibrillators <60 days prior to randomization. 11. Subjects whose 6 Minute Walk Test distance may be limited by conditions other than PAH related dyspnoea or fatigue e.g. claudication from vascular insufficiency or arthritis. 12. Pregnant or lactating women. 13. Subjects with a history or pulmonary embolism verified by ventilation/perfusion scan, angiogram or spiral chest CT scan. 14. Subjects with hypotension defined as systolic arterial pressure <90 mm Hg after sitting for 5 minutes at either screening or baseline. 15. Subjects with known hereditary degenerative retinal disorders (such as retinitis pigmentosa) or history of non-arteritic ischemic optic neuropathy (NAION). 16. Subjects with history of chronic lung diseases / restrictive lung disease (e.g. COPD or scleroderma) with impairment of lung function as defined by TLC <60% and/or FEV1 ≤80% predicted within 30 days or randomization. 17. Subjects who have previously failed on bosentan or sildenafil therapy (defined as those subjects who had no evidence of clinical improvement whilst on the medicines, and no worsening in symptoms or clinical status, on discontinuation of the medicines). 18. Subjects at screening with impairment of renal function (serum creatinine > 2.5 X Upper Limits of Normal (ULN)). 19. Subjects at screening with severe hepatic impairment (ALT/AST > 3X ULN) or portalpulmonary hypertension. 20. Subjects using chronic arginine supplementation including HeartBar® 21. Subjects who have received any experimental drug within the past four months prior to randomization. An experimental drug is defined as any drug that does not have regulatory approval for the indication that it is being prescribed for.
    22. Subjects who have evidence of any drug abuse, including alcohol.
    23. Subjects who have donated blood during the previous month or intend to donate blood or blood products during the study or for one month following the completion of the study. 24. In the opinion of the investigator, a subject who is not likely to complete the study forwhatever reason. 25. Subjects who have untreated proliferative diabetic retinopathy.
    26. Subjects with a history of multiple clinically significant allergies (including those with known allergies or intolerances to sildenafil).
    27. Other severe acute or chronic medical or psychiatric condition or laboratory abnormality that may increase the risk associated with trial participation or investigational product administration or may interfere with the interpretation of trial results and, in the judgment of the investigator, would make the subject inappropriate for entry into this trial.
    28. Subjects who are investigational site staff members or relatives of those site staff members or subjects who are Pfizer employees directly involved in the conduct of the trial.
    E.5 End points
    E.5.1Primary end point(s)
    The change from baseline in the total distance walked during the 6-Minute Walk Test at Week 12 of the study.
    E.5.1.1Timepoint(s) of evaluation of this end point
    Baseline, Week 4, Week 8, Week 12 and Weeks 28, 40, 52 and 64.
    E.5.2Secondary end point(s)
    Borg Dyspnoea Score, WHO Functional Capacity and Therapeutic Class, Time to Clinical Worsening.
    E.5.2.1Timepoint(s) of evaluation of this end point
    Baseline, Week 4, Week 8, Week 12 and Weeks 28, 40, 52 and 64; Time to Clinical Worsening at weeks 4, 8 and 12.
    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 Yes
    E.6.7Pharmacodynamic Yes
    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) No
    E.7.4Therapeutic use (Phase IV) Yes
    E.8 Design of the trial
    E.8.1Controlled Yes
    E.8.1.1Randomised Yes
    E.8.1.2Open No
    E.8.1.3Single blind No
    E.8.1.4Double blind Yes
    E.8.1.5Parallel group Yes
    E.8.1.6Cross over No
    E.8.1.7Other Yes
    E.8.1.7.1Other trial design description
    Second phase of the study will be open-label
    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.8.2.4Number of treatment arms in the trial2
    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 concerned9
    E.8.5The trial involves multiple Member States Yes
    E.8.5.1Number of sites anticipated in the EEA12
    E.8.6 Trial involving sites outside the EEA
    E.8.6.1Trial being conducted both within and outside the EEA Yes
    E.8.6.2Trial being conducted completely outside of the EEA No
    E.8.6.3If E.8.6.1 or E.8.6.2 are Yes, specify the regions in which trial sites are planned
    Australia
    Belgium
    Czech Republic
    France
    Germany
    Greece
    Israel
    Italy
    Taiwan
    United Kingdom
    E.8.7Trial has a data monitoring committee No
    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
    End of trial in all participating countries is defined as Last Patient Last Visit
    E.8.9 Initial estimate of the duration of the trial
    E.8.9.1In the Member State concerned years2
    E.8.9.1In the Member State concerned months4
    E.8.9.1In the Member State concerned days0
    E.8.9.2In all countries concerned by the trial years2
    E.8.9.2In all countries concerned by the trial months4
    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 No
    F.1.1Number of subjects for this age range: 0
    F.1.1.1In Utero No
    F.1.1.1.1Number of subjects for this age range: 0
    F.1.1.2Preterm newborn infants (up to gestational age < 37 weeks) No
    F.1.1.2.1Number of subjects for this age range: 0
    F.1.1.3Newborns (0-27 days) No
    F.1.1.3.1Number of subjects for this age range: 0
    F.1.1.4Infants and toddlers (28 days-23 months) No
    F.1.1.4.1Number of subjects for this age range: 0
    F.1.1.5Children (2-11years) No
    F.1.1.5.1Number of subjects for this age range: 0
    F.1.1.6Adolescents (12-17 years) No
    F.1.1.6.1Number of subjects for this age range: 0
    F.1.2Adults (18-64 years) Yes
    F.1.2.1Number of subjects for this age range: 76
    F.1.3Elderly (>=65 years) Yes
    F.1.3.1Number of subjects for this age range: 30
    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 2006-05-05. 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 No
    F.3.3.7Others No
    F.4 Planned number of subjects to be included
    F.4.1In the member state30
    F.4.2 For a multinational trial
    F.4.2.1In the EEA 50
    F.4.2.2In the whole clinical trial 106
    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)
    See protocol
    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 Decision2006-06-01
    N.Ethics Committee Opinion of the trial applicationFavourable
    N.Ethics Committee Opinion: Reason(s) for unfavourable opinion
    N.Date of Ethics Committee Opinion2006-07-04
    P. End of Trial
    P.End of Trial StatusCompleted
    P.Date of the global end of the trial2013-08-20
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