Pulmonary Arterial Hypertension MedDRA version: 17.1 Level: PT Classification code 10064911 Term: Pulmonary arterial hypertension System Organ Class: 10038738 - Respiratory, thoracic and mediastinal disorders
Conditions
Interventions
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 co
Sponsors
United Therapeutics Corporation
Eligibility
Sex/Gender
All
Inclusion criteria
Inclusion criteria: 1. The 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 durationof 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.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 theevent that a reliable PCWP or LVEDP are unable to be obtained during cardiac catheterization, subjects with clinically normal left heart functionand 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 val
Exclusion criteria
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 butnot 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. 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, orknown 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 µmol/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) =
Design outcomes
Primary
| Measure | Time frame |
|---|---|
| Main Objective: 1.To assess the effect of oral UT-15C with PAH approved oral monotherapy compared to placebo with PAH approved oral monotherapycompared to placebo with PAH approved oral monotherapy on time to first clinical worsening event (adjudicated), 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).;Secondary Objective: To assess the effect of oral UT-15C combined with ERA or PDE5-I therapy compared with placebo combined with oral ERA or PDE5-I therapy 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 (clinical laboratory parameters, vital signs,AEs,ECG);Primary end point(s): The co-primary hypotheses are that combination therapy with PAH approved oral monotherapy in combination with UT-15C will prolong the time to clinical worsening and/or increase exercise capacity (as measured by the change from Baseline in 6MWD at Week 24) when compared to PAH approved oral monotherapy in combination with placebo in subjects with PAH. To preserve the overall type I error rate at0.05, time to clinical worsening will be tested at the 0.04 level and change in 6MWD will be tested at the 0.01 level. ;Timepoint(s) of evaluation of this end point: Clinical worsening will be assessed continuously from randomisation until the subject's last study visit.6MWTs will be conducted at Screening/Baseline, weeks 4, 8, 12, 24, continued visits every 12 weeks and at study termination. The 6MWT should be conducted 3–6 hours following the previous dose of study medication, to coincide approximately with peak study drug exposure. | — |
Secondary
| Measure | Time frame |
|---|---|
| Secondary end point(s): -Borg Dyspnea Score -Combined 6MWD and Borg Dyspnea Score -WHO Functional Class for Pulmonary Hypertension -N-terminal proBNP -RHC Haemodynamics (optional) -Safety Analyses ;Timepoint(s) of evaluation of this end point: The effect of treatment will be formally tested on the following three secondary endpoints: ? NT-pro-BNP at Week 24 ? Combined 6MWD/Borg dyspnea score at Week 24 ? 6MWD at week 48 In order to control the Type 1 error rate, the p-value for the NT-pro-BNP at week 24 will be tested at a two-sided Type I error rate of 0.05. If the p-value for NT-pro-BNP is less than 0.05, then the other two endpoints will be tested using the Hochberg approach: Orderof the p-values from largest to smallest as p(1)>p(2). Specifically: 1. If p(1) 0.05, but p(2) < 0.025, then reject the null hypothesis associated with p(2). All other secondary endpoints will be summarized using descriptive statistics | — |
Countries
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
Public ContactRegulatory Department
United Therapeutics Europe Ltd
Outcome results
None listed