E.1 Medical condition or disease under investigation |
E.1.1 | Medical condition(s) being investigated |
pulmonary arterial hypertension (PAH) |
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E.1.1.1 | Medical condition in easily understood language |
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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 | LLT |
E.1.2 | Classification code | 10077731 |
E.1.2 | Term | Pulmonary hypertension WHO functional class I |
E.1.2 | System Organ Class | 100000004855 |
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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 |
To evaluate the effects of ralinepag therapy on exercise capacity as assessed by change in peak oxygen consumption (VO2) derived from cardiopulmonary exercise testing (CPET) after 28 weeks of treatment |
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E.2.2 | Secondary objectives of the trial |
To evaluate the effects of ralinepag on: 1. N-terminal pro b-type natriuretic peptide (NT-proBNP) 2. Minute ventilation (VE)/carbon dioxide output (VCO2) slope 3. WHO/New York Heart Association (NYHA) Functional Class (FC) 4. Health-related quality of life (HRQoL) measured by the Short Form (36) Health Survey (SF-36) 5. Time to first all-cause nonelective hospitalization 6. Safety and tolerability Note: Other protocol defined exploratory objectives may apply. |
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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 |
Optional evaluation of proteomics, metabolomics, transcriptomics, and pharmacogenetic analysis: For subjects who agree to participate in the optional proteomics, metabolomics, and transcriptomics analyses, blood samples will be collected at Baseline, the Week 28 Visit, or the Study Drug Termination Visit; for subjects who agree to participate in the optional genetic analysis, a blood sample will be collected at Baseline. |
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E.3 | Principal inclusion criteria |
Each subject must meet ALL of the following inclusion criteria to be eligible for enrollment into the study: 1) Evidence of a personally signed and dated Informed Consent Form (ICF) indicating that the subject has been informed of all pertinent aspects of the study prior to initiation of any study-related procedures. 2) At least 18 years of age at the time of consent. 3) Primary diagnosis of PAH classified by one of the following subgroups: a. Idiopathic pulmonary arterial hypertension (IPAH) b. Heritable pulmonary arterial hypertension (HPAH) c. Drugs or toxins induced based on prior exposure to drugs, chemicals, or toxins, such as fenfluramine derivatives, other anorexigens, toxic rapeseed oil, or L-tryptophan d. PAH associated with: i. Connective tissue disease (CTD) ii. Human immunodeficiency virus (HIV) infection iii. Congenital systemic-pulmonary shunt (must have undergone surgical correction at least 1 year prior to Screening) and have no, or a clinically insignificant, shunt fraction (1.0≤pulmonary-systemic flow ratio [QP/QS] ≤1.5) 4. Has had a diagnostic right heart catheterization (RHC) performed within 1 year of Screening (or during Screening if one is not available) that is consistent with the diagnosis of PAH, meeting all of the following criteria: a) Pulmonary artery pressure mean (PAPm) >20 mmHg (at rest) b) Pulmonary artery wedge pressure (PAWP) ≤15 mmHg (If PAWP cannot be reliably attained, then left ventricular end diastolic pressure [LVEDP] ≤15 mmHg) c) Pulmonary vascular resistance (PVR) ≥3 Wood units or ≥240 dynes/sec/cm5 If more than 1 RHC was performed within 1 year of Screening, the most recent RHC that includes parameters sufficient to evaluate the above criteria must be used for this assessment. 5) Has WHO/NYHA FC 2 to 3 symptoms at Baseline. 6) Must have initiated first PAH-specific oral therapy with an endothelin receptor antagonist (ERA) and/or a phosphodiesterase type 5 inhibitor (PDE5-I) or a soluble guanylate cyclase (sGC) stimulator within 9 months prior to Screening, and be on a stable dose(s), defined as no change in dose or regimen for at least 30 days prior to Screening. Subjects may be on a stable dose of either a PDE5-I or a sGC stimulator, not both. a) If the subject’s disease-specific PAH therapy does not include a PDE5-I, the use of PDE5-I as needed for erectile dysfunction (ED), up to 3 doses per week, is permitted. The subject should not have taken a dose within 48 hours of Baseline. 7) Has a 6MWD of ≥150 meters during Screening. 8) Has a VE/VCO2 slope ≥38 during the Screening CPET, as assessed by the CPET core lab. 9) Has a peak VO2 of ≥10 to <18 mL·kg-1·min-1 during the Screening CPET, as assessed by the CPET core lab. 10) If the subject is taking concomitant medications that may affect PAH (ie, calcium channel blockers, digoxin, diuretics, beta blockers, Angiotensin-converting enzyme inhibitors, angiotensin II receptor blockers, or L-arginine), the subject must be on a stable dose for at least 30 days prior to the Baseline Visit and the dosage maintained throughout the study. The exception is that the dose of diuretics should remain stable for at least the 10 days prior to Baseline. 11. Both male and female subjects agree to use a highly effective method of birth control throughout the entire study period from informed consent through to the Week 28 Visit/28-day Follow-up Visit, if the possibility of conception exists. Eligible male and female subjects must also agree not to participate in a conception process (ie, actively attempt to become pregnant or to impregnate, sperm donation, in vitro fertilization) during the study and for 4 weeks after the last dose of study drug. |
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E.4 | Principal exclusion criteria |
Subjects must not meet ANY of the following exclusion criteria to be eligible for enrollment into the study: 1) For subjects with known HIV-associated PAH, a cluster designation 4 (CD4+) T-cell count <200/mm3 at Screening. ]2) Has 3 or more of the following left ventricular disease/dysfunction risk factors: a) Body mass index (BMI) ≥30 kg/m2 b) History of systemic hypertension c) Diabetes mellitus - any type d) Historical evidence of significant coronary artery disease established by any 1 of the following: i) History of myocardial infarction or percutaneous coronary intervention or angiographic evidence of coronary artery disease (>50% stenosis in at least 1 coronary artery) ii) Positive stress test with imaging iii) Previous coronary artery bypass graft iv) Angina e) Chronic atrial fibrillation 3) Current unstable angina. 4) Symptomatic coronary disease and/or myocardial infarction within past 6 months. 5) Current symptomatic aortic or mitral valve disease. 6) Has evidence of more than mild lung disease on pulmonary function tests (PFTs) performed within 1 year prior to, or during, Screening. Subjects with any of the following criteria will be excluded: a. Forced expiratory volume in 1 second (FEV1) <60% predicted; or b. Total lung capacity (TLC) <60% predicted 7) Has evidence of thromboembolic disease as determined by ventilation-perfusion (V/Q) lung scan or local standard of care diagnostic evaluation at or after diagnosis of PAH. 8) Current diagnosis of uncontrolled sleep apnea in the clinical opinion of the Investigator. 9) Requires use of supplemental oxygen during CPET procedures. 10) Respiratory exchange ratio (RER) <1.0 at Screening CPET, as determined by the CPET core laboratory. 11) Acute non-cardiac disorder that may affect exercise performance or be aggravated by exercise (eg, infection, renal failure, thyrotoxicosis). 12) Male subjects with a corrected QT interval using Fridericia’s formula (QTcF) >450 msec and female subjects with QTcF >470 msec on electrocardiogram (ECG) recorded in triplicate at Screening in subjects without evidence of intraventricular conduction delay (IVCD). In presence of IVCD, subjects will be excluded if QTcF is >500 msec for both males and females. 13) Severe chronic liver disease (ie, Child-Pugh C), portal hypertension, cirrhosis, or complications of cirrhosis/portal hypertension (eg, history of variceal hemorrhage, encephalopathy). 14) Confirmed active infection with hepatitis B virus (HBV) or hepatitis C virus (HCV). 15) Subjects with alanine aminotransferase (ALT) or aspartate aminotransferase (AST) ≥3 times the upper limit of normal (ULN) or total bilirubin ≥2 × ULN at Screening. 16) Chronic renal insufficiency as defined by serum creatinine >2.5 mg/dL or requiring dialysis at Screening. 17) Hemoglobin concentration <9 g/dL at Screening. 18) Subjects treated with an intravenous (IV) or subcutaneous (SC) prostacyclin pathway agent (eg, epoprostenol, treprostinil, or iloprost) at any time prior to Baseline (use in vasoreactive testing is permitted). 19) Subjects treated with an inhaled or oral prostacyclin pathway agent (iloprost, treprostinil, beraprost, or selexipag) that was stopped for a safety or tolerability issue. • If a subject discontinued for other reasons, the subject is eligible if the subject has been off therapy and stable (ie, no change in WHO/NYHA FC or change in PAH-specific background therapy) for 90 days prior to Baseline. 20) Subject has pulmonary veno-occlusive disease. 21) Malignancy diagnosed and/or treated within 5 years of Screening, with the exception of localized non-metastatic basal cell or squamous cell carcinoma of the skin or in-situ carcinoma of the cervix excised with curative intent. 22. Subject tests positive for amphetamine, cocaine, methamphetamine, methylenedioxymethamphetamine, or phencyclidine in urine drug screen performed at Screening or has a recent history (6 months) of alcohol or drug abuse. 23) Initiation or discontinuation of a cardio-pulmonary rehabilitation program based upon exercise within 90 days prior to Screening and/or planned during study participation. 24) Prior participation in any study of ralinepag or participation in another interventional clinical study within 30 days prior to Screening. Concurrent participation in registry or observational studies is allowed, as long as the subject can fulfill all other entry criteria and comply with all study procedures. 25) Any reason that, in the opinion of the Investigator, precludes the subject from participating in the study (eg, any previous or intercurrent medical condition) that may increase the risk associated with study participation or that would confound study analysis (eg, right-to-left shunt detected during CPET) or impair study participation or cooperation. 26) Known hypersensitivity to ralinepag or any of the excipients. 27) Life expectancy <12 months. 28. Women who are pregnant, lactating, or breast-feeding. |
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E.5 End points |
E.5.1 | Primary end point(s) |
The primary endpoint of the study is the change from Baseline in peak VO2 after 28 weeks of treatment with study drug. |
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E.5.1.1 | Timepoint(s) of evaluation of this end point |
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E.5.2 | Secondary end point(s) |
The following secondary endpoints will be analyzed in hierarchical order: • Change from Baseline at Week 28 in NT-proBNP: NT-proBNP with log transformation will be analyzed in the ITT population using mixed-effect model repeated measures (MMRM) analysis with treatment, the stratification factors, week, and treatment-by-week interaction as factors and baseline NT-proBNP as a covariate • Change from Baseline at Week 28 in VE/VCO2 slope: VE/VCO2 slope will be analyzed in the mITT population and repeated in the ITT population using ANCOVA with a model that includes treatment and the stratification factors as factors and Baseline VE/VCO2 slope as a covariate. • Change in SF-36 scores from Baseline to Week 28: the component and domain scores will be analyzed in the ITT population using MMRM analysis with treatment, the stratification factors, week, and treatment-by-week interaction as factors and baseline component/domain score as a covariate. • Time to first all-cause nonelective hospitalization in randomized subjects during the study period will be analyzed in the ITT population using Cox proportional hazard regression model that includes treatment and the stratification factors. |
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E.5.2.1 | Timepoint(s) of evaluation of this end point |
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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 | Yes |
E.6.4 | Safety | Yes |
E.6.5 | Efficacy | Yes |
E.6.6 | Pharmacokinetic | Yes |
E.6.7 | Pharmacodynamic | No |
E.6.8 | Bioequivalence | No |
E.6.9 | Dose response | No |
E.6.10 | Pharmacogenetic | Yes |
E.6.11 | Pharmacogenomic | No |
E.6.12 | Pharmacoeconomic | No |
E.6.13 | Others | Yes |
E.6.13.1 | Other scope of the trial description |
Optional evaluation of proteomics, metabolomics, transcriptomics, and genetics |
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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 | No |
E.8.1.6 | Cross over | No |
E.8.1.7 | Other | No |
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 | 3 |
E.8.5 | The trial involves multiple Member States | Yes |
E.8.5.1 | Number of sites anticipated in the EEA | 24 |
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 |
Czech Republic |
Germany |
Italy |
Poland |
Spain |
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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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 | 6 |
E.8.9.1 | In the Member State concerned days | |
E.8.9.2 | In all countries concerned by the trial years | 3 |
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 |