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    Summary
    EudraCT Number:2006-001464-23
    Sponsor's Protocol Code Number:A1481243
    National Competent Authority:Italy - Italian Medicines Agency
    Clinical Trial Type:EEA CTA
    Trial Status:Completed
    Date on which this record was first entered in the EudraCT database:2007-02-19
    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 ConcernedItaly - Italian Medicines Agency
    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 TREATMENT OF SUBJECTS, AGED 18 YEARS AND ABOVE, WITH PULMONARY ARTERIAL HYPERTENSION PAH
    A.3.2Name or abbreviated title of the trial where available
    ND
    A.4.1Sponsor's protocol code numberA1481243
    A.5.1ISRCTN (International Standard Randomised Controlled Trial) NumberND
    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 SponsorPFIZER
    B.1.3.4CountryItaly
    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 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 No
    D.2.1.1.1Trade name G04BE03- Sildenafil - sildenafil (citrato)
    D.2.1.1.2Name of the Marketing Authorisation holderPfizer Itd
    D.2.1.2Country which granted the Marketing AuthorisationItaly
    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 nameSildenafil
    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.3.9.2Current sponsor codeA1481243
    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 Information not present in EudraCT
    D.3.11.8Extractive medicinal product Information not present in EudraCT
    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
    D.8 Placebo: 2
    D.8.1Is a Placebo used in this Trial?Yes
    D.8.3Pharmaceutical form of the placeboCoated 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 PAH .
    MedDRA Classification
    E.1.2 Medical condition or disease under investigation
    E.1.2Version 6.1
    E.1.2Level PT
    E.1.2Classification code 10037400
    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 Test after 12 weeks of treatment of sildenafil 20mg Three Times a Day TID or placebo, when added to subjects with PAH who are stabilized on bosentan therapy.
    E.2.2Secondary objectives of the trial
    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. 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. 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. 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. To investigate the Pharmacokinetic/Pharmacodynamic PK/PD relationship between sildenafil and bosentan exposure on the 6-Minute Walk Test.
    E.2.3Trial contains a sub-study Information not present in EudraCT
    E.3Principal inclusion criteria
    . 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 national license Idiopathic Primary Pulmonary Arterial Hypertension PAH . Pulmonary Hypertension secondary to Scleroderma. Subjects with WHO functional class III prior to initiation of bosentan therapy 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. . 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 12 months prior to randomization. . Subjects whose baseline 6-Minute Walk Test distance is / 100m and / 400m. . who have given written informed consent to participate in the study before being screened for the study. . All women of childbearing potential must use adequate contraception i.e. 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. The screening serum pregnancy test must be negative. Women who have been surgically sterilized or are at least two years postmenopausal may be enrolled and do not need to use birth control.
    E.4Principal exclusion criteria
    . PAH secondary to any aetiology including congenital heart disease other than those specified in the inclusion criteria. .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 . Note Acute vasodilator response testing with any short acting vasodilators such as prostacyclin or inhaled NO during right heart catherization is permitted. . 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. .Subjects with acutely decompensated heart failure within 30 days prior to randomization. . Subjects with LV Ejection Fraction of 45 or LV shortening fraction of 0.2 within three months prior to randomization. . Subjects who have had a myocardial infarction or stroke within 6 months prior to randomization. . 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. . Subjects with congenital heart disease unless they fulfill inclusion 4.1.1 , pulmonary hypertension due to thromboembolism, HIV or schistosomiasis. . Subjects who have undergone atrial septostomy within six months prior to randomization. . Subjects with uncontrolled brady- or tachyarrhythmias, placement of pacemakers or implantable defibrillators 60 days prior to randomization. . 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. .Pregnant or lactating women. .Subjects with a history or pulmonary embolism verified by ventilation/perfusion scan, angiogram or spiral chest CT scan. .Subjects with hypotension defined as systolic arterial pressure 90 mm Hg after sitting for 5 minutes at either screening or baseline. .Subjects with known hereditary degenerative retinal disorders such as retinitis pigmentosa or history of non-arteritic ischemic optic neuropathy NAION . .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. . 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 .
    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.6 and E.7 Scope of the trial
    E.6Scope of the trial
    E.6.1Diagnosis No
    E.6.2Prophylaxis No
    E.6.3Therapy No
    E.6.4Safety Yes
    E.6.5Efficacy Yes
    E.6.6Pharmacokinetic Yes
    E.6.7Pharmacodynamic Yes
    E.6.8Bioequivalence Information not present in EudraCT
    E.6.9Dose response No
    E.6.10Pharmacogenetic Information not present in EudraCT
    E.6.11Pharmacogenomic No
    E.6.12Pharmacoeconomic No
    E.6.13Others Information not present in EudraCT
    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 No
    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.8.5The trial involves multiple Member States Yes
    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 Information not present in EudraCT
    E.8.6.3If E.8.6.1 or E.8.6.2 are Yes, specify the regions in which trial sites are planned
    E.8.7Trial has a data monitoring committee Information not present in EudraCT
    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 years1
    E.8.9.1In the Member State concerned months6
    E.8.9.1In the Member State concerned days
    E.8.9.2In all countries concerned by the trial years1
    E.8.9.2In all countries concerned by the trial months6
    F. Population of Trial Subjects
    F.1 Age Range
    F.1.1Trial has subjects under 18 No
    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) No
    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 Information not present in EudraCT
    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 2007-02-19. Yes
    F.3.3.2Women of child-bearing potential using contraception Information not present in EudraCT
    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 state10
    F.4.2 For a multinational trial
    F.4.2.1In the EEA 50
    F.4.2.2In the whole clinical trial 106
    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 Decision2006-11-03
    N.Ethics Committee Opinion of the trial applicationFavourable
    N.Ethics Committee Opinion: Reason(s) for unfavourable opinion
    N.Date of Ethics Committee Opinion2006-09-14
    P. End of Trial
    P.End of Trial StatusCompleted
    P.Date of the global end of the trial2013-08-20
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