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    Summary
    EudraCT Number:2012-000097-26
    Sponsor's Protocol Code Number:TDE-PH-310
    National Competent Authority:UK - MHRA
    Clinical Trial Type:EEA CTA
    Trial Status:Ongoing
    Date on which this record was first entered in the EudraCT database:2012-08-01
    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 ConcernedUK - MHRA
    A.2EudraCT number2012-000097-26
    A.3Full title of the trial
    A Phase III, International, Multi-Center, Randomized, Double-Blind, Placebo-Controlled, Clinical Worsening Study of UT-15C in Subjects with Pulmonary Arterial Hypertension Receiving Background Oral Monotherapy.
    A.3.1Title of the trial for lay people, in easily understood, i.e. non-technical, language
    International, multicenter, randomized (1:1 oral treprostinil (UT-15C): placebo), double-blind, placebo-controlled study in subjects with Pulmonary Arterial Hypertension (PAH) who are receiving background oral monotherapy
    A.4.1Sponsor's protocol code numberTDE-PH-310
    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 SponsorUnited Therapeutics Corporation
    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 supportUnited Therapeutics Corporation
    B.4.2CountryUnited States
    B.5 Contact point designated by the sponsor for further information on the trial
    B.5.1Name of organisationUnited Therapeutics Europe Ltd
    B.5.2Functional name of contact pointRegulatory Department
    B.5.3 Address:
    B.5.3.1Street AddressUnither House, Curfew Bell Road,
    B.5.3.2Town/ cityChertsey, Surrey
    B.5.3.3Post codeKT16 9FG
    B.5.3.4CountryUnited Kingdom
    B.5.4Telephone number004401932573855
    B.5.5Fax number004401932573856
    B.5.6E-mailinfo1@unither.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 No
    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/3/05/310
    D.3 Description of the IMP
    D.3.1Product nametreprostinil diethanolamine
    D.3.2Product code UT-15C
    D.3.4Pharmaceutical form Prolonged-release 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 INNtreprostinil diethanolamine
    D.3.9.1CAS number 830354-48-8
    D.3.9.2Current sponsor codeUT-15C SR
    D.3.10 Strength
    D.3.10.1Concentration unit mg milligram(s)
    D.3.10.2Concentration typeequal
    D.3.10.3Concentration number0.125
    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.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 Yes
    D.2.5.1Orphan drug designation numberEU/3/05/310
    D.3 Description of the IMP
    D.3.1Product nametreprostinil diethanolamine
    D.3.2Product code UT-15C
    D.3.4Pharmaceutical form Prolonged-release 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 INNtreprostinil diethanolamine
    D.3.9.1CAS number 830354-48-8
    D.3.9.2Current sponsor codeUT-15C SR
    D.3.10 Strength
    D.3.10.1Concentration unit mg milligram(s)
    D.3.10.2Concentration typeequal
    D.3.10.3Concentration number0.25
    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.IMP: 3
    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 Yes
    D.2.5.1Orphan drug designation numberEU/3/05/310
    D.3 Description of the IMP
    D.3.1Product nametreprostinil diethanolamine
    D.3.2Product code UT-15C
    D.3.4Pharmaceutical form Prolonged-release 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 INNtreprostinil diethanolamine
    D.3.9.1CAS number 830354-48-8
    D.3.9.2Current sponsor codeUT-15C SR
    D.3.10 Strength
    D.3.10.1Concentration unit mg milligram(s)
    D.3.10.2Concentration typeequal
    D.3.10.3Concentration number0.5
    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.IMP: 4
    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 Yes
    D.2.5.1Orphan drug designation numberEU/3/05/310
    D.3 Description of the IMP
    D.3.1Product nametreprostinil diethanolamine
    D.3.2Product code UT-15C
    D.3.4Pharmaceutical form Prolonged-release 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 INNtreprostinil diethanolamine
    D.3.9.1CAS number 830354-48-8
    D.3.9.2Current sponsor codeUT-15C SR
    D.3.10 Strength
    D.3.10.1Concentration unit mg milligram(s)
    D.3.10.2Concentration typeequal
    D.3.10.3Concentration number1.0
    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.IMP: 5
    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 Yes
    D.2.5.1Orphan drug designation numberEU/3/05/310
    D.3 Description of the IMP
    D.3.1Product nametreprostinil diethanolamine
    D.3.2Product code UT-15C
    D.3.4Pharmaceutical form Prolonged-release 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 INNtreprostinil diethanolamine
    D.3.9.1CAS number 830354-48-8
    D.3.9.2Current sponsor codeUT-15C SR
    D.3.10 Strength
    D.3.10.1Concentration unit mg milligram(s)
    D.3.10.2Concentration typeequal
    D.3.10.3Concentration number2.5
    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 placeboProlonged-release 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 placeboProlonged-release tablet
    D.8.4Route of administration of the placeboOral use
    D.8 Placebo: 3
    D.8.1Is a Placebo used in this Trial?Yes
    D.8.3Pharmaceutical form of the placeboProlonged-release tablet
    D.8.4Route of administration of the placeboOral use
    D.8 Placebo: 4
    D.8.1Is a Placebo used in this Trial?Yes
    D.8.3Pharmaceutical form of the placeboProlonged-release tablet
    D.8.4Route of administration of the placeboOral use
    D.8 Placebo: 5
    D.8.1Is a Placebo used in this Trial?Yes
    D.8.3Pharmaceutical form of the placeboProlonged-release 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
    E.1.1.2Therapeutic area Diseases [C] - Cardiovascular Diseases [C14]
    MedDRA Classification
    E.1.2 Medical condition or disease under investigation
    E.1.2Version 19.0
    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
    1.To assess the effect of oral UT-15C with PAH-approved oral monotherapy compared to placebo with PAH-approved oral monotherapy on time to first adjudicated clinical worsening (morbidity/mortality) event, as defined by at least one of the events: Death (all causes),Hospitalization due to worsening PAH, Initiation of an inhaled or infused prostacyclin for the treatment of worsening PAH, Disease progression (all criteria required), Unsatisfactory long-term clinical response (all criteria required).
    2.To assess the effect of UT-15C with PAH-approved oral monotherapy compared to placebo combined with PAH-approved oral monotherapy on 6MWD, NT-proBNP, Combined 6MWD/Borg dyspnea score, Exercise capacity as assessed by 6MWD, Borg dyspnea score, WHO Functional Class, Right heart catheterization hemodynamics, safety, clinical laboratory parameters, vials signs, AEs, ECG.
    E.2.2Secondary objectives of the trial
    To assess the effect of UT-15C with PAH approved oral monotherapy compared to placebo combined with PAH approved oral monotherapy on the following:
    -Exercise capacity as assessed by 6MWD
    -Borg dyspnea score
    -Combined walk distance / Borg dyspnea score
    -WHO functional class
    -NT-proBNP
    -RHC hemodynamics at Week 24 (optional)
    -Safety (vital signs, adverse events, clinical laboratory parameters,ECG)
    E.2.3Trial contains a sub-study Yes
    E.2.3.1Full title, date and version of each sub-study and their related objectives
    1 BACKGROUND AND RATIONALE
    Even though subjects may discontinue from the study or open-label extension study (TDE-PH-311) for a variety of reasons, it is important to continue collecting vital status data on such subjects until the study is completed. Collection of the vital status data will allow an intention-to-treat overall survival analysis to be conducted using actual rather than imputed vital status data. This will be a separate analysis from the primary and secondary efficacy analysis and will provide supportive data for regulatory filings of oral treprostinil. If and when a subject discontinues from the study or open-label extension study (TDE-PH-311), attempts should be made to obtain their consent to record their vital status up to the date of final completion of the study (i.e., when all patient have exited the study). Attempts should be made to collect survival data on all subjects, even those who are apparently lost to follow-up.

    2 OBJECTIVE
    To collect vital status data for subjects who discontinue from the study or open-label extension study (TDE-PH-311) to support an overall survival analysis of study participants

    3 EXPERIMENTAL PLAN
    Vital status for subjects who discontinue from the study or open label extension study (TDE-PH-311) will be assessed every 6-months from their date of discontinuation via telephone calls and/or other methods as described below for the duration of the study. The data will continue to be collected in this study until the last subject has exited from the study.
    Subjects are considered to have discontinued from the study if and when they discontinue and do not enroll into the open-label extension study (TDE-PH-311). Subjects are considered to have prematurely discontinued from the open-label extension study (TDE PH-311) if they discontinue before the completion of the study (i.e. before the last subject has exited the study).

    4 ESTIMATED STUDY DURATION
    Vital status data will be collected every 6 months beginning from the date that each subject discontinues either the study or open-label extension study (TDE-PH-311) until the last subject exits the study.

    5 DATA COLLECTION AND FOLLOW-UP OF SUBJECTS
    Survival status for discontinued subjects will be collected every 6 months from the date of discontinuation via telephone calls or other methods as described below. The collection of vital status should include whether or not the subject is alive.
    • If dead, the date of death must be obtained
    • If alive, the last known date the subject was confirmed to be alive must be provided.
    • For those subjects who are lost to follow-up, the last known date that the subject was confirmed to be alive will be their date of the last contact with the site.
    Methods to confirm subjects’ survival status other than the recommended telephone calls every 6 months, may include and are not limited to, in-person study visits, searching of hospital records, and searching local and/or national public registries following applicable laws and regulations.
    Any adverse events that are spontaneously reported by the subject that occur on the commercially-available United Therapeutics drug should not be submitted as part of the study, rather, they will be subject to AE/SAE reporting under local government post-marketing AE/SAE reporting requirements.

    6 STATISTICAL CONSIDERATIONS
    Vital status data collected from subjects who discontinue from the study or open-label extension study (TDE-PH-311) will be combined with the data collected during the study and the open-label extension study (TDE-PH-311) for sensitivity analysis of time to overall survival. Vital status data collection from subjects who have discontinued the study minimizes the missing data for these analysis
    E.3Principal inclusion criteria
    1. Subject voluntarily gives informed consent to participate in the study.
    2.18–75 years of age (inclusive) at Screening (i.e. date of providing written informed consent).
    3.Women of childbearing potential must practice true abstinence from intercourse when it is in line with their preferred and usual lifestyle, or use two different forms of highly effective contraception for the duration of the study, and for at least 30 days after discontinuing study medication. Medically acceptable forms of effective contraception include:(1) approved hormonal contraceptives,(2) barrier methods used with a spermicide,(3) an intrauterine device (IUD),or (4) partner vasectomy. For WOCBP,a negative urine pregnancy test is required at Screening and Baseline prior to initiating study medication.
    4.If male, must use a condom during the length of the study, and for at least 48 hours after discontinuing study medication.
    5. Has a diagnosis of symptomatic idiopathic or heritable PAH, PAH associated with CTD, PAH associated with HIV infection, PAH associated with repaired congenital systemic-to-pulmonary shunt (at least 1 (one) year since repair with respect to the date of providing informed consent) or PAH associated with appetite suppressant or toxin use.
    6.If known positive for HIV infection, has a CD4 lymphocyte count of at least 200 cells/mm3 assessed at Screening and is receiving current standard of care anti-retroviral or other effective medication for treatment of HIV infection.
    7.Must have a Baseline 6MWD greater than or equal to 150 meters, in the absence of a concurrent injury, illness (other than PAH or a PAH related condition), or other confounding factor including, but not limited to, use of an aid for ambulation (e.g., use of a cane or walker) or connection to a non-portable machine, that would prevent the accurate assessment of the subject’s exercise capacity.
    8.Must be optimally treated with conventional pulmonary hypertension therapy (e.g., oral vasodilators, oxygen, digoxin, diuretics, anticoagulants as deemed appropriate by the investigator) with no additions, discontinuations, or dose changes for a minimum of 10 days prior to randomization. The exceptions are the discontinuation or dose changes of anticoagulants and / or dose change of diuretics.
    9.Must have been receiving a PAH approved oral monotherapy at a minimum dose that complies with the approved prescribing information for the product for at least 30 days prior to randomization and must have been receiving a stable dose for at least 10 days prior to randomization. A subject who previously received 2 PAH approved oral therapies at the same time will be eligible provided they received these medications concomitantly for less than or equal to 90 days cumulatively. Must have taken only one PAH approved therapy for at least 30 days and must be receiving a stable dose at least 10 days prior to randomization.
    10.Has previously undergone a cardiac catheterization within three years prior to the start of screening and the most recent assessment has documented a mean pulmonary artery pressure (PAPm) of at least 25 mmHg, a pulmonary capillary wedge pressure (PCWP) (or in the event a PCWP cannot be reliably obtained, a left ventricular end diastolic pressure (LVEDP)) less than 15 mmHg, and absence of unrepaired congenital heart disease (other than patent foramen ovale (PFO)). In the event that a reliable PCWP or LVEDP are unable to be obtained during cardiac catheterization, subjects with clinically normal left heart function and absence of clinically relevant mitral valve disease on echocardiography are eligible for enrollment.
    11.The subject has undergone echocardiography with evidence of clinically normal left systolic and diastolic ventricular function and absence of any clinically significant left sided heart disease (e.g. mitral valve disease). Subjects with clinically insignificant left ventricular diastolic dysfunction due to the effects of right ventricular overload (i.e., right ventricular hypertrophy and/or dilatation) are eligible.
    12.The subject has a previous ventilation perfusion lung scan, and/or high resolution computerized tomography scan of the chest, and/or pulmonary angiography that are consistent with the diagnosis of PAH (e.g., low probability of pulmonary embolism; absence of major perfusion defects).
    13.The subject has pulmonary function tests conducted within 6 months before screening or during the Screening period to confirm the following:a. Total lung capacity (TLC) is at least 60% (predicted value) assessed by either whole body plethysmography or helium dilution or nitrogen washout technique. b. Forced expiratory volume at one second (FEV1) of at least 50% (predicted value).
    14.In the opinion of the Principal Investigator, the subject is able to communicate effectively with study personnel, and is considered reliable, willing and likely to be cooperative with protocol requirements, including attending all study visits.
    E.4Principal exclusion criteria
    1.The subject is pregnant or lactating.
    2.The subject has previously received UT-15C.
    3.The subject has received a prostacyclin, (except if used during acute vasoreactivity testing) within 30 days prior to randomization or had previous intolerance or significant lack of efficacy to any prostacyclin, prostacyclin analogue, that resulted in discontinuation or inability to titrate that therapy effectively.
    4.The subject has had any background conventional therapies for pulmonary hypertension added, removed or dose adjusted (including but not limited to oxygen, vasodilators, diuretics, digoxin, anticoagulants) within 10 days prior to randomization. The exceptions are removal or dose adjustments of anticoagulants and / or dose adjustments of diuretics.
    5.The subject has received their first dose of a PAH approved therapy less than 30 days prior to randomization, or has had their PAH approved oral monotherapy dose changed within 10 days prior to Randomisation, or the subject discontinued any PAH approved therapy within 30 days prior to Screening, or the subject previously received two PAH approved oral therapies art the same time concomitantly for more than 90 days cumulatively.
    6.The subject has any disease associated with PAH other than CTD, HIV infection, repaired (for at least one year) congenital systemic-to-pulmonary shunt, PAH associated with appetite suppressant / toxin use (e.g., portal hypertension, chronic thromboembolic disease, pulmonary veno-occlusive disease, etc.) or has had an atrial septostomy.
    7.The subject has a current diagnosis of uncontrolled sleep apnea as defined by their physician.
    8.The subject has a history of ischemic heart disease, including a previous myocardial infarction or symptomatic coronary artery disease within 6 months prior to Screening or a history of left sided myocardial disease as evidenced by a mean PCWP (or a left ventricular end diastolic pressure (LVEDP)) greater than 15 mmHg or left ventricular ejection fraction less than 40% as assessed by either multigated angiogram (MUGA), angiography, or echocardiography.
    9.The subject has uncontrolled systemic hypertension as evidenced by systolic blood pressure greater than 160 mmHg or diastolic blood pressure greater than 100 mmHg.
    10.The subject has ALT or AST levels at least greater than 3 times the upper limit of normal, clinically significant liver disease / dysfunction, or known Child-Pugh Class C hepatic disease at Screening.
    11.The subject has any other disease or condition that would interfere with the interpretation of study assessments.
    12.The subject has a musculoskeletal disorder (e.g., arthritis affecting the lower limbs, recent hip or knee joint replacement, artificial leg), is using a device to assist walking (e.g. cane or walker), or any disease that is likely to limit ambulation, or is connected to a machine that is not portable.
    13.The subject has an unstable psychiatric condition or is mentally incapable of understanding the objectives, nature, or consequences of the trial, or has any condition which in the Investigator’s opinion would constitute an unacceptable risk to the subject’s safety.
    14.The subject is receiving an investigational drug, has an investigational device in place,
    or has participated in an investigational drug or device study within 30 days prior to Screening.
    15. The subject has chronic renal insufficiency as defined by either a screening creatinine value greater than 2.5 mg/dL (221 ╬╝mol/L) or the requirement for dialysis
    16. Subjects must not have 3 or more of the following left ventricular disease/dysfunction risk factors:
    i. Body Mass Index (BMI) ≥ 30 kg/m2
    ii. History of Essential Hypertension
    iii. Diabetes Mellitus – any type
    iv. Historical evidence of significant coronary disease established by any one of: history of myocardial infarction or percutaneous coronary intervention or angiographic evidence of coronary artery disease (>50% stenosis in at least one coronary artery), positive stress test with imaging, previous coronary artery bypass graft, stable angina
    E.5 End points
    E.5.1Primary end point(s)
    The primary hypothesis is that PAH-approved oral monotherapy in combination with UT-15C will prolong the time to clinical worsening when compared to PAH-approved oral monotherapy in combination with placebo in subjects with PAH. The primary efficacy endpoint will be tested at an interim analysis when 75% of total adjudicated events have occurred with an alpha spending of 0.020 and at the final analysis at an alpha of 0.044 with an overall Type I error rate at 0.05. Efficacy boundaries for early stopping of the trail for efficacy is calculated based on O'Brien-Fleming alpha-spending function.
    E.5.1.1Timepoint(s) of evaluation of this end point
    Clinical worsening will be assessed continuously from randomisation until the subject’s last study visit.
    E.5.2Secondary end point(s)
    The effect of treatment will be formally tested on the following secondary endpoints:
    •Exercise capacity as assessed by 6MWD measured at Week 24
    •NT-pro-BNP at Week 24
    •Combined 6MWD/Borg dyspnea score at Week 24
    In order to control the Type 1 error rate, the secondary efficacy endpoints will be tested using a hierarchical (fixed-sequence) testing procedure. The 6MWD at Week 24 will be tested at a two-sided Type I error rate of 0.05. The subsequent tests for NT-proBNP at Week 24 and then the combined 6MWD/Borg dyspnea score at Week 24 will be tested only if the preceding test is statistically significant. All other secondary endpoints will be summarized using descriptive statistics or analyzed using an exploratory approach.
    E.5.2.1Timepoint(s) of evaluation of this end point
    -6MWTs: Screening/Baseline, weeks 4, 8, 12, 24, every continued visit, study termination. Subjects should rest for 5 minuted prior to each 6MWT. All 6MWTs following randomization must be conducted 3 to 6 hours after the last dose of study drug.
    -Borg dyspnea score: following each 6MWT.
    -WHO functional classification for PAH: Baseline prior to starting study drug, all subsequent scheduled study visits, every time the 6MWT is performed for purposes of assessing clinical worsening status.
    -NT pro-BNP sample collection: Baseline (prior to starting study drug), Weeks 12, Week 24, every Continued Visit
    -Haemodynamics (optional): Baseline and Week 24.
    -Safety: Screening, Baseline, Weeks 4, 8, 12, 24, every 12 weeks thereafter, Study Termination Visit.
    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 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 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
    Event driven
    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 concerned4
    E.8.5The trial involves multiple Member States Yes
    E.8.5.1Number of sites anticipated in the EEA37
    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
    Argentina
    Australia
    Austria
    Brazil
    Canada
    Chile
    China
    Denmark
    France
    Germany
    Greece
    India
    Israel
    Italy
    Korea, Republic of
    Mexico
    Netherlands
    Singapore
    Sweden
    Taiwan
    United Kingdom
    United States
    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
    The study will complete when approximately 205 adjudicated clinical worsening events have occurred.
    E.8.9 Initial estimate of the duration of the trial
    E.8.9.1In the Member State concerned years4
    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 years4
    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 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.1.2.1Number of subjects for this age range: 694
    F.1.3Elderly (>=65 years) Yes
    F.1.3.1Number of subjects for this age range: 156
    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 state28
    F.4.2 For a multinational trial
    F.4.2.1In the EEA 148
    F.4.2.2In the whole clinical trial 850
    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)
    Entry into an Open-label Extension Study of UT-15C in Subjects with Pulmonary Arterial Hypertension - A Long-Term Follow-Up to protocol TDE-PH-310 (TDE-PH-311, EudraCT number 2012-000098-21). See section 7.5 of Protocol for further details.
    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 Decision2012-09-14
    N.Ethics Committee Opinion of the trial applicationFavourable
    N.Ethics Committee Opinion: Reason(s) for unfavourable opinion
    N.Date of Ethics Committee Opinion2012-11-06
    P. End of Trial
    P.End of Trial StatusOngoing
    EU Clinical Trials Register Service Desk: https://servicedesk.ema.europa.eu
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