E.1 Medical condition or disease under investigation |
E.1.1 | Medical condition(s) being investigated |
Pulmonary Arterial Hypertension |
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E.1.1.1 | Medical condition in easily understood language |
Pulmonary Arterial Hypertension |
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E.1.1.2 | Therapeutic area | Diseases [C] - Cardiovascular Diseases [C14] |
MedDRA Classification |
E.1.2 Medical condition or disease under investigation |
E.1.2 | Version | 17.0 |
E.1.2 | Level | PT |
E.1.2 | Classification code | 10064911 |
E.1.2 | Term | Pulmonary arterial hypertension |
E.1.2 | System Organ Class | 10038738 - Respiratory, thoracic and mediastinal disorders |
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E.1.3 | Condition being studied is a rare disease | Yes |
E.2 Objective of the trial |
E.2.1 | Main 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 compared 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). 2.To assess the effect of UT-15C with PAH approved oral monotherapy compared to placebo combined with PAH approved oral monotherapy on 6MWD measured at Week 24 |
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E.2.2 | Secondary 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) |
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E.2.3 | Trial contains a sub-study | No |
E.3 | Principal 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 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 but no more than 365 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 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. |
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E.4 | Principal 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 or more than one year (365 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, 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 μmol/L) or the requirement for dialysis |
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E.5 End points |
E.5.1 | 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 at 0.05, time to clinical worsening will be tested at the 0.04 level and change in 6MWD will be tested at the 0.01 level. |
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E.5.1.1 | 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. |
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E.5.2 | 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 |
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E.5.2.1 | Timepoint(s) of evaluation of this end point |
-The Borg dyspnea score will be assessed following each 6MWT. -The WHO functional classification for PAH will be assessed at Baseline prior to starting study drug and at all subsequent scheduled study visits, and every time the 6MWT is performed for purposes of assessing clinical worsening status. -NT pro-BNP sample collection will occur at Baseline (prior to starting study drug), Weeks 12, Week 24, the first Continued Visit, and every other Continued Visit thereafter. -Haemodynamics (optional) may be conducted at baseline and week 24. -Safety will be conducted at Screening, Baseline, Weeks 4, 8, 12, 24, every 12 weeks thereafter, and at the Study Termination Visit. |
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E.6 and E.7 Scope of the trial |
E.6 | Scope of the trial |
E.6.1 | Diagnosis | No |
E.6.2 | Prophylaxis | No |
E.6.3 | Therapy | No |
E.6.4 | Safety | Yes |
E.6.5 | Efficacy | Yes |
E.6.6 | Pharmacokinetic | No |
E.6.7 | Pharmacodynamic | No |
E.6.8 | Bioequivalence | No |
E.6.9 | Dose response | No |
E.6.10 | Pharmacogenetic | No |
E.6.11 | Pharmacogenomic | No |
E.6.12 | Pharmacoeconomic | No |
E.6.13 | Others | No |
E.7 | Trial type and phase |
E.7.1 | Human pharmacology (Phase I) | No |
E.7.1.1 | First administration to humans | No |
E.7.1.2 | Bioequivalence study | No |
E.7.1.3 | Other | No |
E.7.1.3.1 | Other trial type description | |
E.7.2 | Therapeutic exploratory (Phase II) | No |
E.7.3 | Therapeutic confirmatory (Phase III) | Yes |
E.7.4 | Therapeutic use (Phase IV) | No |
E.8 Design of the trial |
E.8.1 | Controlled | Yes |
E.8.1.1 | Randomised | Yes |
E.8.1.2 | Open | No |
E.8.1.3 | Single blind | No |
E.8.1.4 | Double blind | Yes |
E.8.1.5 | Parallel group | Yes |
E.8.1.6 | Cross over | No |
E.8.1.7 | Other | Yes |
E.8.1.7.1 | Other trial design description |
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E.8.2 | Comparator of controlled trial |
E.8.2.1 | Other medicinal product(s) | No |
E.8.2.2 | Placebo | Yes |
E.8.2.3 | Other | No |
E.8.2.4 | Number of treatment arms in the trial | 2 |
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.8.4.1 | Number of sites anticipated in Member State concerned | 2 |
E.8.5 | The trial involves multiple Member States | Yes |
E.8.5.1 | Number of sites anticipated in the EEA | 37 |
E.8.6 Trial involving sites outside the EEA |
E.8.6.1 | Trial being conducted both within and outside the EEA | Yes |
E.8.6.2 | Trial being conducted completely outside of the EEA | No |
E.8.6.3 | If E.8.6.1 or E.8.6.2 are Yes, specify the regions in which trial sites are planned |
Argentina |
Australia |
Austria |
Belgium |
Brazil |
Canada |
China |
France |
Germany |
Greece |
India |
Israel |
Italy |
Korea, Republic of |
Mexico |
Netherlands |
Peru |
Singapore |
Sweden |
Taiwan |
United Kingdom |
United States |
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E.8.7 | Trial 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
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The study will complete when at least 394 clinical worsening events have occurred. |
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E.8.9 Initial estimate of the duration of the trial |
E.8.9.1 | In the Member State concerned years | 2 |
E.8.9.1 | In the Member State concerned months | 3 |
E.8.9.1 | In the Member State concerned days | 0 |
E.8.9.2 | In all countries concerned by the trial years | 4 |
E.8.9.2 | In all countries concerned by the trial months | 0 |
E.8.9.2 | In all countries concerned by the trial days | 0 |