| 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 | 20.0 |
| 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 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. |
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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 | Yes |
| E.2.3.1 | Full title, date and version of each sub-study and their related objectives |
1 BACKGROUND AND RATIONALE
Even though subjects may discontinue from the study or open-label extension study (TDE-PH-311) for a variety of reasons, it is important to continue collecting vital status data on such subjects until the study is completed. Collection of the vital status data will allow an intention-to-treat overall survival analysis to be conducted using actual rather than imputed vital status data. This will be a separate analysis from the primary and secondary efficacy analysis and will provide supportive data for regulatory filings of oral treprostinil. If and when a subject discontinues from the study or open-label extension study (TDE-PH-311), attempts should be made to obtain their consent to record their vital status up to the date of final completion of the study (i.e., when all patient have exited the study). Attempts should be made to collect survival data on all subjects, even those who are apparently lost to follow-up.
2 OBJECTIVE
To collect vital status data for subjects who discontinue from the study or open-label extension study (TDE-PH-311) to support an overall survival analysis of study participants
3 EXPERIMENTAL PLAN
Vital status for subjects who discontinue from the study or open label extension study (TDE-PH-311) will be assessed every 6-months from their date of discontinuation via telephone calls and/or other methods as described below for the duration of the study. The data will continue to be collected in this study until the last subject has exited from the study.
Subjects are considered to have discontinued from the study if and when they discontinue and do not enroll into the open-label extension study (TDE-PH-311). Subjects are considered to have prematurely discontinued from the open-label extension study (TDE PH-311) if they discontinue before the completion of the study (i.e. before the last subject has exited the study).
4 ESTIMATED STUDY DURATION
Vital status data will be collected every 6 months beginning from the date that each subject discontinues either the study or open-label extension study (TDE-PH-311) until the last subject exits the study.
5 DATA COLLECTION AND FOLLOW-UP OF SUBJECTS
Survival status for discontinued subjects will be collected every 6 months from the date of discontinuation via telephone calls or other methods as described below. The collection of vital status should include whether or not the subject is alive.
• If dead, the date of death must be obtained
• If alive, the last known date the subject was confirmed to be alive must be provided.
• For those subjects who are lost to follow-up, the last known date that the subject was confirmed to be alive will be their date of the last contact with the site.
Methods to confirm subjects’ survival status other than the recommended telephone calls every 6 months, may include and are not limited to, in-person study visits, searching of hospital records, and searching local and/or national public registries following applicable laws and regulations.
Any adverse events that are spontaneously reported by the subject that occur on the commercially-available United Therapeutics drug should not be submitted as part of the study, rather, they will be subject to AE/SAE reporting under local government post-marketing AE/SAE reporting requirements.
6 STATISTICAL CONSIDERATIONS
Vital status data collected from subjects who discontinue from the study or open-label extension study (TDE-PH-311) will be combined with the data collected during the study and the open-label extension study (TDE-PH-311) for sensitivity analysis of time to overall survival. Vital status data collection from subjects who have discontinued the study minimizes the missing data for these analysis
7 EXPLORATORY OBJECTIVES:
- Optional Evaluation of Biomarkers: blood and urine will be collected at the EoS Visit
- Optional Evaluation of pharmacogenomics: blood samples will be collected at the EoS Visit
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| E.3 | Principal 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 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 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 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) ≥ 30 kg/m2
ii. History of Essential Hypertension
iii. Diabetes Mellitus – any type
iv. Historical evidence of significant coronary disease established by any one of: history of myocardial infarction or percutaneous coronary intervention or angiographic evidence of coronary artery disease (>50% stenosis in at least one coronary artery), positive stress test with imaging, previous coronary artery bypass graft, stable angina
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| E.5 End points |
| E.5.1 | 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. |
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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.
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| E.5.2 | 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.
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| E.5.2.1 | 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. |
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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 |
| Brazil |
| Canada |
| Chile |
| China |
| Denmark |
| France |
| Germany |
| Greece |
| India |
| Israel |
| Italy |
| Korea, Republic of |
| Mexico |
| Netherlands |
| 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 approximately 205 adjudicated 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 | 6 |
| 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 | 6 |
| E.8.9.2 | In all countries concerned by the trial months | 3 |
| E.8.9.2 | In all countries concerned by the trial days | 0 |
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