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

• Register: EUCTR
• Last refreshed on: 28 February 2019
• Main ID: EUCTR2012-000097-26-GB
• Date of registration: 01/08/2012
• Prospective Registration: Yes
• Primary sponsor: United Therapeutics Corporation
• Public title: 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
• 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: 06/11/2012
• Target sample size: 850
• Recruitment status: Not Recruiting
• URL: https://www.clinicaltrialsregister.eu/ctr-search/search?query=eudract_number:2012-000097-26
• Study type: Interventional clinical trial of medicinal product
• Study design: Controlled: yes Randomised: yes Open: no Single blind: no Double blind: yes Parallel group: yes Cross over: no Other: yes Other trial design description: Event driven If controlled, specify comparator, Other Medicinial Product: no Placebo: yes Other: no Number of treatment arms in the trial: 2
• Phase: Human pharmacology (Phase I): no Therapeutic exploratory (Phase II): no Therapeutic confirmatory - (Phase III): yes Therapeutic use (Phase IV): no

Countries of recruitment

Argentina, Australia, Austria, Belgium, 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: Regulatory Department
• Affiliation: United Therapeutics Europe Ltd

• Name: Regulatory Department
• Affiliation: United Therapeutics Europe Ltd

Key inclusion & exclusion criteria

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 disea
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 participa

Age minimum:
Age maximum:
Gender:
Female: yes
Male: yes

Health Condition(s) or Problem(s) studied

Pulmonary Arterial Hypertension
MedDRA version: 20.0 Level: PT Classification code 10064911 Term: Pulmonary arterial hypertension System Organ Class: 10038738 - Respiratory, thoracic and mediastinal disorders

Therapeutic area: Diseases [C] - Cardiovascular Diseases [C14]

Intervention(s)

Product Name: treprostinil diethanolamine
Product Code: UT-15C
Pharmaceutical Form: Prolonged-release tablet
INN or Proposed INN: treprostinil diethanolamine
CAS Number: 830354-48-8
Current Sponsor code: UT-15C SR
Concentration unit: mg milligram(s)
Concentration type: equal
Concentration number: 0.125-
Pharmaceutical form of the placebo: Prolonged-release tablet
Route of administration of the placebo: Oral use

Product Name: treprostinil diethanolamine
Product Code: UT-15C
Pharmaceutical Form: Prolonged-release tablet
INN or Proposed INN: treprostinil diethanolamine
CAS Number: 830354-48-8
Current Sponsor code: UT-15C SR
Concentration unit: mg milligram(s)
Concentration type: equal
Concentration number: 0.25-
Pharmaceutical form of the placebo: Prolonged-release tablet
Route of administration of the placebo: Oral use

Product Name: treprostinil diethanolamine
Product Code: UT-15C
Pharmaceutical Form: Prolonged-release tablet
INN or Proposed INN: treprostinil diethanolamine
CAS Number: 830354-48-8
Current Sponsor code: UT-15C SR
Concentration unit: mg milligram(s)
Concentration type: equal
Concentration number: 0.5-
Pharmaceutical form of the placebo: Prolonged-release tablet
Route of administration of the placebo: Oral use

Product Name: treprostinil diethanolamine
Product Code: UT-15C
Pharmaceutical Form: Prolonged-release tablet
INN or Proposed INN: treprostinil diethanolamine

Primary Outcome(s)

Primary 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.

Timepoint(s) of evaluation of this end point: Clinical worsening will be assessed continuously from randomisation until the subject’s last study visit.

Main Objective: 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.

Secondary Objective: 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)

Secondary Outcome(s)

Timepoint(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.

Secondary 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.

Secondary ID(s)

TDE-PH-310

Source(s) of Monetary Support

United Therapeutics Corporation

Ethics review

Status: Approved
Approval date:
Contact: