Phase III Clinical Worsening Study of UT-15C in Subjects With PAH Receiving Background Oral Monotherapy

• Register: ClinicalTrials.gov
• Last refreshed on: 12 December 2020
• Main ID: NCT01560624
• Date of registration: 09/03/2012
• Prospective Registration: Yes
• Primary sponsor: United Therapeutics
• Public title: Phase III Clinical Worsening Study of UT-15C in Subjects With PAH Receiving Background Oral Monotherapy FREEDOM-EV
• 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
• Date of first enrolment: June 26, 2012
• Target sample size: 690
• Recruitment status: Completed
• URL: https://clinicaltrials.gov/show/NCT01560624
• Study type: Interventional
• Study design: Allocation: Randomized. Intervention model: Parallel Assignment. Primary purpose: Treatment. Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor).
• Phase: Phase 3

Countries of recruitment

Argentina, Australia, Austria, Brazil, Canada, Chile, China, Denmark, France, Germany, Greece, India, Israel, Italy, Korea, Republic of, Mexico, Netherlands, Poland, Singapore, Sweden, Taiwan, United Kingdom, United States

Contacts

• Name: James White, MD, PhD
• Affiliation: Mary M. Parkes Center

Key inclusion & exclusion criteria

Subject Inclusion Criteria:

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 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


Age minimum: 18 Years
Age maximum: 75 Years
Gender: All

Health Condition(s) or Problem(s) studied

Pulmonary Arterial Hypertension

Intervention(s)

Drug: Treprostinil Diolamine

Drug: Placebo

Primary Outcome(s)

Time to First Clinical Worsening Event [Time Frame: From randomization to approximately 4 years]

Secondary Outcome(s)

Change in Plasma N-Terminal Pro-brain Natriuretic Peptide (NT-proBNP) From Baseline to Week 24 [Time Frame: From Baseline to Week 24]

Change in 6-Minute Walk Distance [Time Frame: From Baseline to Week 24]

Change in World Health Organization Functional Class (WHO FC) From Baseline to Week 48 [Time Frame: Baseline to Week 48]

Secondary ID(s)

TDE-PH-310

Source(s) of Monetary Support

Please refer to primary and secondary sponsors

Results

• Results available: Yes
• Date Posted: 13/02/2020
• URL: https://clinicaltrials.gov/ct2/show/results/NCT01560624