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    The EU Clinical Trials Register currently displays   43846   clinical trials with a EudraCT protocol, of which   7282   are clinical trials conducted with subjects less than 18 years old.   The register also displays information on   18700   older paediatric trials (in scope of Article 45 of the Paediatric Regulation (EC) No 1901/2006).

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    Summary
    EudraCT Number:2008-007455-26
    Sponsor's Protocol Code Number:GS-US-235-0101
    National Competent Authority:Belgium - FPS Health-DGM
    Clinical Trial Type:EEA CTA
    Trial Status:Prematurely Ended
    Date on which this record was first entered in the EudraCT database:2009-03-30
    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 ConcernedBelgium - FPS Health-DGM
    A.2EudraCT number2008-007455-26
    A.3Full title of the trial
    A Phase 2, Randomized, Double-blind, Placebo-controlled, Multicenter, Dose-ranging Study of Cicletanine in Subjects with Pulmonary Arterial Hypertension
    A.4.1Sponsor's protocol code numberGS-US-235-0101
    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 SponsorGilead Sciences, Inc.
    B.1.3.4CountryUnited States
    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.2.5The 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.3.1Product nameCicletanine hydrochloride
    D.3.4Pharmaceutical form Capsule, hard
    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.3.9.1CAS number 89943-82-8
    D.3.9.2Current sponsor codeGS-9555
    D.3.10 Strength
    D.3.10.1Concentration unit mg milligram(s)
    D.3.10.2Concentration typeequal
    D.3.10.3Concentration number75
    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.IMP: 2
    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.2.5The 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.3.1Product nameCicletanine hydrochloride
    D.3.4Pharmaceutical form Capsule, hard
    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.3.9.1CAS number 89943-82-8
    D.3.9.2Current sponsor codeGS-9555
    D.3.10 Strength
    D.3.10.1Concentration unit mg milligram(s)
    D.3.10.2Concentration typeequal
    D.3.10.3Concentration number150
    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 placeboCapsule, hard
    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 hypertension (PH) is a serious and life-threatening disease of the pulmonary vasculature, characterized by profound vasoconstriction and an abnormal proliferation of smooth muscle cells in the walls of the pulmonary arteries.
    MedDRA Classification
    E.1.2 Medical condition or disease under investigation
    E.1.2Version 13.1
    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 No
    E.2 Objective of the trial
    E.2.1Main objective of the trial
    The primary objective of this study is to compare the change in exercise capacity following treatment with cicletanine hydrochloride (HCl) or placebo in subjects with pulmonary arterial hypertension (PAH).
    E.2.2Secondary objectives of the trial
    The secondary objectives of this study are:
    • To compare the change in other clinical measures of PAH following treatment with
    cicletanine HCl or placebo in subjects with PAH
    • To compare the safety and tolerability of cicletanine HCl to placebo in subjects with
    PAH
    Additionally, the long-term safety, tolerability, and efficacy of cicletanine HCl treatment will be evaluated.
    E.2.3Trial contains a sub-study Yes
    E.2.3.1Full title, date and version of each sub-study and their related objectives
    There are 3 addtional sub studies as detailed in the main protocol. Information can be found on the following pages;

    Cardiopulmonary Hemodynamic Substudy
    Steady-state Cicletanine Pharmacokinetics Substudy
    Fractional Exhaled Nitric Oxide Substudy
    E.3Principal inclusion criteria
    1. Subject must be between 16 and 70 years of age, inclusive, at the Screening Visit
    2. Subject must weigh ≥40 kg at the Screening Visit
    3. Subject must have a current diagnosis of IPAH, FPAH, or PAH that is primarily due to:
    a. Connective tissue disease (e.g., limited scleroderma, diffuse scleroderma, mixed CTD,
    systemic lupus erythematosus, or overlap syndrome)
    b. Congenital heart defects repaired greater than 1 year prior to Screening (i.e., atrial septal
    defects, ventricular septal defects, and patent ductus arteriosus)
    c. Drug and toxin use
    d. HIV infection
    4. Subject must meet all of the following hemodynamic criteria by means of a RHC completed prior or during Screening:
    a. mPAP of ≥25 mmHg
    b. PVR >240 dyne-sec/cm5 c. PCWP or LVEDP of ≤15 mmHg
    c. PCWP or LVEDP of ≤15 mmHg
    5. Subject must walk a distance of at least 100 m but no more than 450 m during the screening 6MWT
    6. Subject must have WHO functional class II, III, or IV symptoms at the Screening Visit, as assessed by the Investigator
    7. Subject must meet all of the following pulmonary function tests completed no more than 12 weeks before the Screening visit, performed with or without bronchodilation:
    a. Total lung capacity (TLC) ≥60% of predicted normal and
    b. Forced expiratory volume in one second (FEV1) ≥65% of predicted normal
    c. FEV1:FVC ratio >0.60
    8. Subject must have laboratory results within 90% of the lower limit of normal (≥0.9xLLN) to 1.5 times the upper limit of normal (≤1.5xULN) for serum sodium, serum potassium, serum chloride, and serum magnesium at the Screening Visit
    9. Subject currently receiving treatment with an approved ERA , PDE5i, and /or parenteral prostanoid must be receiving this therapy for ≥12 weeks prior to the Screening Visit and must be at a stable dose for ≥4 consecutive weeks prior to the Screening Visit. Eligible therapies allowed at Screening include:
    a. Monotherapy with an ERA, PDE5i, or parenteral prostnoid that is approved for the treatment of PAH.
    b. Combination therapy with two eligible PAH treatments (any combination of ERA, PDE5i or parenteral prostnoid.
    10. Subject receiving diuretic treatment must be on stable therapy for at least 4 weeks prior to the Screening Visit
    11. Subject receiving digitalis, CCBs, angiotensin receptor blockers (ARBs), angiotensin converting enzyme (ACE) inhibitors, or beta-blocking agents must be on stable therapy for at least 4 weeks prior to the Screening Visit
    12. Subject receiving 5-hydroxy-3-methylglutaryl-coenzyme A (HMG-CoA) reductase inhibitors (i.e., statins) must be on stable therapy for at least 4 weeks prior to the Screening Visit
    13. Subject with a diagnosis of HIV must have stable disease status. For this study, stable HIV status is defined as:
    a. No addition of medications for treatment of HIV for at least 8 weeks prior to screening
    b. No active opportunistic infection during the Screening Period
    c. No hospitalizations due to HIV for at least 4 weeks prior to screening
    14. Female subjects of childbearing potential must have a negative serum pregnancy test at the Screening Visit and a negative urine pregnancy test at the Randomization Visit.
    15. Female subjects of childbearing potential must agree to use 2 reliable methods of contraception from the Screening Visit until study completion and for at least 30 days following the last dose of study drug.
    16. Subject must agree not to participate in a clinical study involving another investigational drug or device throughout this study, with the exception of a clinical registry
    17. Subject must be competent to understand the information given in the Institutional Review Board (IRB) or Independent Ethics Committee (IEC) approved informed consent form (ICF) and must sign the form prior to the initiation of any study procedures.
    18. Subject has not enrolled in an exercise training program for pulmonary rehabilitation within 12 weeks prior to the Screening Visit and must agree not to enroll in an exercise training program for pulmonary rehabilitation during the Screening Period and the first 12 weeks of the study
    19. Subject has been enrolled in an exercise training program for pulmonary rehabilitation for >12 weeks prior to the Screening Visit and must agree to maintain their current level of rehabilitation for the first 12 weeks of the study
    20.Subject must be on background PAH therapy at Screening unless the subject does not have access to or can not tolerate currently approved PAH medical therapies.
    E.4Principal exclusion criteria
    1. Subject with a current PH diagnosis other than IPAH, FPAH, or PAH that is primarily due to:
    a. Connective tissue disease (e.g., limited scleroderma, diffuse scleroderma, mixed CTD, systemic lupus erythematosus, or overlap syndrome)
    b. Congenital heart defects repaired greater than 1 year prior to Screening (i.e., atrial septal defects, ventricular septal defects, and patent ductus arteriosus)
    c. Drug and toxin use
    d. HIV infection
    2. Subject with left ventricular ejection fraction (LVEF) ≤40% or clinically significant
    ischemic, valvular, or constrictive heart disease 3. Subject with WHO functional class I symptoms at the Screening Visit, as assessed by the Investigator
    3. Subject with WHO functional class I symptoms at the Screening Visit, as assessed by the Investigator
    4b. Subject has chronically received an ineligible PAH treatment regimen within the 4 weeks prior to the Screening Visit, specifically:
    - inhaled iloprost or inhaled trepostinil
    - combination treatment with three PAH therapies (e.g., ERA, PDE5i, and prostnoid)
    - any investigational therapy for the tretment of PAH
    Chronic use is considered >7 consecutive days of treatment.
    5. Subject receiving iv inotropes within 2 weeks prior to the Screening Visit
    6. Subject with SBP ≥150 mmHg or <90mmHg at the Screening Visit
    7. Subject with moderate to severe liver disease (Child-Pugh Score of ≥7, Class B or C) at the Screening Visit
    8. Subject with moderate or severe renal impairment, defined by an estimated glomerular filtration rate (eGFR) ≤50 mL/min/1.73 m2 at the Screening Visit. The rGFR value will be calculated using the abbreviated Modification of Diet in Renal Disease (MDRD) equation.
    9. Subject receiving lithium within the 2 weeks prior to the Screening Visit
    10. Subject requiring intermittent or chronic treatment with nitrates
    11. Subject receiving non-anti-arrhythmic drugs that induce torsades de pointes within the 2 weeks prior to the Screening Visit. This includes, but is not limited to: astemizole, bepridil, chloroquine, chlorpromazine, cisapride, clarithromycin, domperidone, droperidol, erythromycin, halofantrine, haloperidol, levomethadyl, methadone, pentamidine, pimozide, probucol, procainamide, sparfloxacin, sultopride, terfenadine, thioridazine, or vincamine.
    12. Subject has a diagnosis of long QT syndrome
    13. Subject with evidence of chronic thromboembolic disease, as determined by a computed axial tomography (CT) or ventilation-perfusion scan conducted prior to the Screening Visit
    14. Subject with obstructive lung disease as evidenced by a FEV1:FVC ratio ≤0.60 on pulmonary function tests completed no more than 12 weeks before the Screening visit
    15. Subject with severe arthritis, musculoskeletal problems, or morbid obesity that, in the opinion of the Investigator, would affect the subject’s ability to perform or complete the 6MWT
    16. Subject has a history of malignancies within the past 5 years, except for a subject with localized, non-metastatic basal cell carcinoma of the skin, in situ carcinoma of the cervix, or prostate cancer who is not currently or expected (during the study) to undergo radiation therapy, chemotherapy, hormonal treatment, and/or surgical intervention
    17. Subject with cardiovascular, liver, renal, hematologic, gastrointestinal, immunologic, endocrine, metabolic, or central nervous system disease that, in the opinion of the Investigator, may adversely affect the safety of the subject and/or efficacy of the study drug or severely limit the lifespan of the subject
    18. Female subject who is pregnant or breastfeeding
    19. Subject has demonstrated noncompliance with previous medical regimens
    20. Subject has a recent history of abusing alcohol or illicit drugs
    21. Subject has participated in a clinical study involving another investigational drug or device within 4 weeks before the Screening Visit
    22. Subject has a known hypersensitivity to the study drug, the metabolites, or formulation excipients (i.e., lactose monohydrate, talc).
    23. Subject receiving an oral arginine supplement within 2 weeks prior to the Screening Visit.
    E.5 End points
    E.5.1Primary end point(s)
    • Change from baseline in 6MWD, BDI, WHO functional class, SF-36® Health Survey, and NT-proBNP at other time points
    • Time to clinical worsening of PAH during other intervals
    • Steady-state PK
    • Change from baseline in FE
    • Change in CAMPHOR QoL assessments at other time points
    • Change from baseline in serum L-arginine, L-citrulline, and ADMA
    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 Information not present in EudraCT
    E.6.10Pharmacogenetic Information not present in EudraCT
    E.6.11Pharmacogenomic Information not present in EudraCT
    E.6.12Pharmacoeconomic Information not present in EudraCT
    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 Information not present in EudraCT
    E.7.1.2Bioequivalence study Information not present in EudraCT
    E.7.1.3Other Information not present in EudraCT
    E.7.1.3.1Other trial type description
    E.7.2Therapeutic exploratory (Phase II) Yes
    E.7.3Therapeutic confirmatory (Phase III) No
    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 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.8.4.1Number of sites anticipated in Member State concerned1
    E.8.5The trial involves multiple Member States Yes
    E.8.5.1Number of sites anticipated in the EEA13
    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 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
    Last patient last visit
    E.8.9 Initial estimate of the duration of the trial
    E.8.9.1In the Member State concerned years7
    E.8.9.1In the Member State concerned months
    E.8.9.1In the Member State concerned days
    E.8.9.2In all countries concerned by the trial years7
    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) No
    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 No
    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 state3
    F.4.2 For a multinational trial
    F.4.2.1In the EEA 50
    F.4.2.2In the whole clinical trial 160
    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)
    After the completion of the study participation, long term care for the participants will remain the responsibility of their primary treating physicians.
    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 Decision2009-05-06
    N.Ethics Committee Opinion of the trial applicationFavourable
    N.Ethics Committee Opinion: Reason(s) for unfavourable opinion
    N.Date of Ethics Committee Opinion2009-06-08
    P. End of Trial
    P.End of Trial StatusPrematurely Ended
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