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Trial details imported from ClinicalTrials.gov
For full trial details, please see the original record at
https://clinicaltrials.gov/ct2/show/NCT01560624
Registration number
NCT01560624
Ethics application status
Date submitted
9/03/2012
Date registered
22/03/2012
Date last updated
13/02/2020
Titles & IDs
Public title
Phase III Clinical Worsening Study of UT-15C in Subjects With PAH Receiving Background Oral Monotherapy
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Scientific title
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
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Secondary ID [1]
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TDE-PH-310
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Universal Trial Number (UTN)
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Trial acronym
FREEDOM-EV
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Linked study record
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Health condition
Health condition(s) or problem(s) studied:
Pulmonary Arterial Hypertension
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Condition category
Condition code
Respiratory
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Other respiratory disorders / diseases
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Human Genetics and Inherited Disorders
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Other human genetics and inherited disorders
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Cardiovascular
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0
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Hypertension
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Intervention/exposure
Study type
Interventional
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Description of intervention(s) / exposure
Treatment: Drugs - Treprostinil Diolamine
Treatment: Drugs - Placebo
Experimental: UT-15C - Treprostinil diolamine extended-release tablets (oral) 0.125 to 12 mg TID
Placebo Comparator: Placebo - Matching placebo tablets (oral)
Treatment: Drugs: Treprostinil Diolamine
Active
Treatment: Drugs: Placebo
Placebo
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Intervention code [1]
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Treatment: Drugs
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Comparator / control treatment
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Control group
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Outcomes
Primary outcome [1]
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Time to First Clinical Worsening Event
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Assessment method [1]
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Clinical worsening was assessed continuously from randomization until the subject's last study visit. Clinical worsening events were defined as death (all causes), hospitalizations due to worsening pulmonary arterial hypertension (PAH), initiation of an inhaled or infused prostacyclin (PGI2) for the treatment of worsening PAH, disease progression, or unsatisfactory long-term clinical response. All clinical worsening events reported by the study sites were reviewed by the Sponsor Medical Monitors. Once a clinical worsening event occurred, it was entered in the eCRF and a narrative was submitted for review by the Sponsor's Medical Monitor within 48 hours after the event became known to the Investigator or designee. Subsequently, the narratives for subjects with the reported clinical worsening events were sent to an independent adjudication committee. The independent adjudication committee reviewed and adjudicated all clinical worsening events throughout the study.
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Timepoint [1]
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From randomization to approximately 4 years
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Secondary outcome [1]
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Change in 6-Minute Walk Distance
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Assessment method [1]
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The intent of the 6-Minute Walk Test (6MWT) is to evaluate exercise capacity associated with carrying out activities of daily living. A baseline 6MWT was performed prior to initiation of study drug on the day of randomization. 6MWTs were conducted at Weeks 4, 8, 12, 24, and every 12 weeks thereafter. The change between Baseline and Week 24 is reported.
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Timepoint [1]
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From Baseline to Week 24
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Secondary outcome [2]
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Change in Plasma N-Terminal Pro-brain Natriuretic Peptide (NT-proBNP) From Baseline to Week 24
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Assessment method [2]
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Plasma NT-proBNP concentration is a useful biomarker for the severity of PAH as it is associated with changes in right heart morphology and function. NT-proBNP sample collection occurred at Baseline (prior to starting study drug), Week 12, Week 24, the first Continued Visit, and every other Continued Visit thereafter (ie, Continued Visits 3, 5, 7, etc). NT-proBNP was also assessed at the Study Drug Termination Visit. The change between Baseline and Week 24 is reported.
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Timepoint [2]
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From Baseline to Week 24
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Secondary outcome [3]
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Change in World Health Organization Functional Class (WHO FC) From Baseline to Week 48
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Assessment method [3]
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The WHO FC for PAH was assessed at Baseline prior to starting study drug, at all subsequent scheduled study visits, and every time the 6MWT was performed for purposes of assessing clinical worsening status.
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Timepoint [3]
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Baseline to Week 48
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Eligibility
Key inclusion criteria
Subject
1. Voluntarily gave informed consent to participate in the study.
2. Are 18 to 75 years of age (inclusive) at Screening.
3. Women of childbearing potential must practice abstinence from intercourse when in line
with their preferred and usual lifestyle, or use 2 different forms of highly effective
contraception for the duration of the study, and for at least 30 days after
discontinuing study medication. A negative urine pregnancy test is required at
Screening and Baseline prior to initiating study medication.
4. Male subjects must consent to use a condom during intercourse for the duration of the
study, and for at least 48 hours after discontinuing study medication.
5. Have a diagnosis of symptomatic idiopathic or heritable PAH, PAH associated with
connective tissue disease (CTD), PAH associated with HIV infection, PAH associated
with repaired congenital systemic-to-pulmonary shunt, or PAH associated with appetite
suppressant or toxin use.
6. If known to be positive for HIV infection, have a CD4 lymphocyte count of at least 200
cells/mm^3 assessed at Screening and are receiving current standard of care anti
retroviral or other effective medication for the treatment of HIV infection.
7. Have a baseline 6MWD greater than or equal to 150 m in the absence of a concurrent
injury, illness, or other confounding factor including, but not limited to, use of an
aid for ambulation or connection to a nonportable machine, that would have prevented
the accurate assessment of the subject's exercise capacity.
8. Are optimally treated with conventional pulmonary hypertension therapy 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. Are 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 are receiving a stable dose for at least 10 days prior to
randomization.
10. Have had previously undergone a cardiac catheterization within 3 years prior to the
start of Screening or during the Screening Period, and the most recent assessment
documented a pulmonary artery pressure mean of at least 25 mmHg, a pulmonary capillary
wedge pressure (PCWP) (or in the event a PCWP could not be reliably obtained, a left
ventricular end diastolic pressure [LVEDP]) less than or equal to 15 mmHg, and absence
of unrepaired congenital heart disease (other than patent foramen ovale). If 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. Undergo echocardiography with evidence of clinically normal systolic and diastolic
left ventricular function and absence of any clinically significant left sided heart
disease (eg, mitral valve disease). Subjects with clinically insignificant left
ventricular diastolic dysfunction due to the effects of right ventricular overload
(ie, right ventricular hypertrophy and/or dilatation) are eligible.
12. Have a previous ventilation perfusion lung scan, high-resolution computerized
tomography scan of the chest, and/or pulmonary angiography that are consistent with
the diagnosis of PAH.
13. Have pulmonary function tests conducted within 6 months before Screening or during the
Screening Period to confirm the following:
1. Total lung capacity is at least 60%
2. Forced expiratory volume at 1 second is at least 50%
14. In the opinion of the Principal Investigator, is able to communicate effectively with
study personnel and is considered reliable, willing, and likely to cooperate with
protocol requirements, including attending all study visits.
Subject
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Minimum age
18
Years
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Maximum age
75
Years
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Sex
Both males and females
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Can healthy volunteers participate?
No
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Key exclusion criteria
1. Is pregnant or lactating.
2. Have previously received oral treprostinil.
3. Have received a PGI2 (except if used during acute vasoreactivity testing) within 30
days prior to randomization or have previous intolerance or significant lack of
efficacy to any PGI2 or PGI2 analogue that resulted in discontinuation or inability to
titrate that therapy effectively.
4. Have any background conventional therapies for PAH added, removed, or dose-adjusted
within 10 days prior to randomization. The exceptions are removal or dose adjustments
of anticoagulants and/or dose adjustments of diuretics.
5. Receive their first dose of a PAH-approved oral monotherapy less than 30 days prior to
randomization, or have their PAH-approved oral monotherapy dose changed within 10 days
prior to randomization, or the subject discontinues any PAH approved therapy within 30
days prior to Screening, or the subject has previously received 2 PAH approved oral
therapies at the same time (specifically, a PDE5-I, an ERA, or a sGC stimulator)
concomitantly for more than 90 days cumulatively.
6. Have any disease associated with PAH other than CTD, HIV infection, repaired (for at
least 1 year) congenital systemic-to-pulmonary shunt, PAH associated with appetite
suppressant/toxin use, or have an atrial septostomy.
7. Have a current diagnosis of uncontrolled sleep apnea as defined by their physician.
8. Have 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 LVEDP) greater than
15 mmHg or left ventricular ejection fraction less than 40% as assessed by either
multigated angiogram, angiography, or echocardiography.
9. Have uncontrolled systemic hypertension as evidenced by systolic blood pressure (BP)
greater than 160 mmHg or diastolic BP greater than 100 mmHg.
10. Have alanine aminotransferase or aspartate aminotransferase levels at least 3 times
greater than the upper limit of normal, clinically significant liver
disease/dysfunction, or known Child-Pugh Class C hepatic disease at Screening.
11. Have any other disease or condition that would interfere with the interpretation of
study assessments.
12. Have a musculoskeletal disorder, is using a device to assist walking, or any disease
that is likely to limit ambulation, or is connected to a machine that is nonportable.
13. Have an unstable psychiatric condition or is mentally incapable of understanding the
objectives, nature, or consequences of the study, or has any condition which in the
Investigator's opinion would constitute an unacceptable risk to the subject's safety.
14. Is receiving an investigational drug, have an investigational device in place, or have
participated in an investigational drug or device study within 30 days prior to
Screening.
15. Have chronic renal insufficiency as defined by either a Screening creatinine value
greater than 2.5 mg/dL or the requirement for dialysis.
16. Does not have 3 or more of the following left ventricular disease/dysfunction risk
factors:
1. Body mass index at least 30 kg/m^2
2. History of essential hypertension
3. Diabetes mellitus (any type)
4. Historical evidence of significant coronary artery disease established by any 1
of the following: history of myocardial infarction, percutaneous coronary
intervention, or angiographic evidence of coronary artery disease; positive
stress test with imaging; previous coronary artery bypass graft; or stable
angina.
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Study design
Purpose of the study
Treatment
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Allocation to intervention
Randomised controlled trial
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Procedure for enrolling a subject and allocating the treatment (allocation concealment procedures)
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Methods used to generate the sequence in which subjects will be randomised (sequence generation)
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Masking / blinding
Blinded (masking used)
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Who is / are masked / blinded?
The people receiving the treatment/s
The people administering the treatment/s
The people assessing the outcomes
The people analysing the results/data
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Intervention assignment
Parallel
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Other design features
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Phase
Phase 3
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Type of endpoint/s
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Statistical methods / analysis
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Recruitment
Recruitment status
Completed
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Data analysis
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Reason for early stopping/withdrawal
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Other reasons
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Date of first participant enrolment
Anticipated
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Actual
26/06/2012
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Date of last participant enrolment
Anticipated
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Actual
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Date of last data collection
Anticipated
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Actual
24/06/2018
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Sample size
Target
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Accrual to date
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Final
690
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Recruitment in Australia
Recruitment state(s)
NSW,QLD,TAS,VIC
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Recruitment hospital [1]
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Royal Prince Alfred Hospital - Camperdown
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Nepean Hospital - Kingswood
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Saint Vincents Hospital - Sydney
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Macquarie University - Sydney
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Prince Charles Hospital - Chermside
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Royal Hobart Hospital - Hobart
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The Alfred Hospital - Melbourne
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Royal Melbourne Hospital - Parkville
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2050 - Camperdown
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2751 - Kingswood
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2010 - Sydney
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2109 - Sydney
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4032 - Chermside
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7000 - Hobart
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3004 - Melbourne
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Recruitment postcode(s) [8]
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3052 - Parkville
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Recruitment outside Australia
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Roma
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Incheon
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Singapore
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Country [93]
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Sweden
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State/province [93]
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Vastra Gotaland
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Country [94]
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Sweden
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State/province [94]
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Stockholm
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Country [95]
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Taiwan
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State/province [95]
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Tainan CITY
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Country [96]
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Taiwan
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State/province [96]
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Kaohsiung
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Country [97]
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Taiwan
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State/province [97]
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Taichung
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Country [98]
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Taiwan
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State/province [98]
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Taipei
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Country [99]
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United Kingdom
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State/province [99]
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Cambridgshire
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Country [100]
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United Kingdom
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State/province [100]
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England
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Funding & Sponsors
Primary sponsor type
Commercial sector/Industry
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Name
United Therapeutics
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Ethics approval
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Summary
Brief summary
This is an international, multicenter, randomized, double-blind, placebo-controlled, event
driven study in subjects with pulmonary arterial hypertension.
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Trial website
https://clinicaltrials.gov/ct2/show/NCT01560624
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Public notes
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Contacts
Principal investigator
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James White, MD, PhD
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Mary M. Parkes Center
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Contact person for scientific queries
Summary Results
For IPD and results data, please see
https://clinicaltrials.gov/ct2/show/NCT01560624
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