| 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 | No |
| E.2 Objective of the trial |
| E.2.1 | Main objective of the trial |
The primary objective of this study is:
To compare the effect of ralinepag versus placebo in subjects with standard of care or PAH-specific background therapy on disease progression and achievement of a satisfactory clinical response in subjects with WHO Group 1 PAH. |
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| E.2.2 | Secondary objectives of the trial |
The secondary objectives of the study are:
1) To evaluate the effects of ralinepag on the following parameters:
• N-terminal pro b-type natriuretic peptide (NT-proBNP)
• 6 minute walk distance (6MWD)
• WHO/ New York Heart Association (NYHA) functional class
• Time to all-cause hospitalization
• Time to all-cause mortality
• Heart rate recovery (HRR) following completion of the 6-minute walk test (6MWT)
• Proportion of subjects who attain all three of the following (at specified time points):
o NT-proBNP <300 pg/mL
o 6MWD >440 meters
o WHO/NYHA functional class II status or better
• Health-related quality of life (HRQoL) measures
2) To assess ongoing safety and tolerability of ralinepag when added to standard of care or PAH-specific background therapy. |
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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. Cardiac Magnetic Resonance Imaging (cMRI) Substudy:
An MRI substudy to assess the change in right ventricular size and function is planned at selected sites. A substudy to evaluate the effect of ralinepag by cardiac magnetic resonance imaging (cMRI) will be performed at selected sites to evaluate functional changes in the right heart (i.e. enhanced volume and pressure measurements by visualization and direct measurement of anatomical and
cMRI-derived parameters, such as right ventricular (RV) volumes and ejection fraction. This substudy will be performed as in a separate protocol and cMRI manual.
2. Proteomics, Metabolomics, and Gene Expression Substudy:
A substudy to evaluate the effect of ralinepag on proteomics and gene expression is planned at selected sites.
For subjects who agree to participate in the Proteomics, Metabolomics, and Gene expression substudy, blood samples will be collected at randomization and at end of study. Comparing
treatment responses and treatment-related change in proteomics, metabolomics, and gene expression may reveal important information with regard to: 1) the pathophysiology and natural history of PAH, 2) treatment response and effect of treatment on proteomics, and 3) ralinepag mechanism of action. |
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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. Males or females aged 18-75 years, inclusive.
2. Evidence of a personally signed and dated informed consent document indicating that the subject has been informed of all pertinent aspects of the study prior to initiation of any study-related procedures.
3. Subjects who are willing and able to comply with scheduled visits, treatment plan, laboratory tests, and other study procedures.
4. Diagnosis of symptomatic WHO Group 1 PAH classified by one of the following subgroups:
a. Idiopathic pulmonary arterial hypertension (IPAH);
b. Heritable pulmonary arterial hypertension (HPAH);
c. Drugs and toxins induced based on prior exposure to legal drugs, chemicals, and toxins, such as fenfluramine derivatives, other anorexigens, toxic rapeseed oil, or L-tryptophan. A subject with PAH associated with illegal drug use, such as methamphetamine, may be included if the subject has been abstinent and under the care of the investigator for at least 1 year immediately before Screening, with at least 2 negative urine drug screening examinations performed and available for review.
d. PAH associated with: Connective tissue disease (CTD), HIV infection, Congenital systemic-pulmonary shunt (must have undergone surgical correction at least 1 year prior to Screening).
5. Has had a right heart catheterization (RHC) performed at or within 365 days of Screening (RHC will be performed during Screening if not available) that is consistent with the diagnosis of PAH, meeting all of the following criteria:
a. Mean pulmonary arterial pressure (mPAP) ≥25 mmHg (at rest)
b. PCWP ≤15 mmHg
c. PVR >3.00 Wood units or >240 dynes/sec/cm5.
6. Has WHO/NYHA functional class II to IV symptoms.
7. If on PAH-specific background therapy, subject is on stable therapy with either an endothelin receptor antagonist (ERA) and/or an agent acting on the nitric oxide (NO) pathway, a phosphodiesterase type 5 (PDE5) inhibitor or a soluble guanylate cyclase (sGC) stimulator. Subjects may be naïve to PAH-specific treatments.
a. Stable is defined as no change in dose or regimen within 90 days of Screening and for the duration of the study.
b. Subjects may be on 1 agent active in the NO pathway, i.e., either a PDE5 inhibitor or an sGC at stable dose (but not both).
c. If the subject’s disease-specific PAH therapy does not include a PDE-5 inhibitor, the use of PDE-5i as needed for erectile dysfunction (ED) is permitted as long as the subject has not taken a dose within 48-hours of any Baseline or study related efficacy assessment. In addition, the subject must not take more than 8 sildenafil tablets, 6 vardenafil, or 4 tadalafil tablets per month for ED.
8. Has a 6MWD of ≥50 meters on two consecutive tests, within 15% of each other, preferably performed on different days during Screening.
9. If the subject is taking the following concomitant medications that may affect PAH, the subject must be on a stable dose for at least 30 days prior to the start of Screening and the dosage maintained throughout the study.
a. Calcium channel blockers, digoxin, or L-arginine supplementation;
b. If the subject is taking anticoagulants, anticoagulation status must be maintained/stable in the therapeutic range for at least 30 days prior to the start of Screening.
10. Both male and female subjects agree to use a highly effective method of birth control medically acceptable method of contraception throughout the entire study period from informed consent through the Follow-up Visit, if the possibility of conception exists. Eligible male and female subjects must also agree not to participate in a conception process (i.e., actively attempt to become pregnant or to impregnate, sperm donation, in vitro fertilization) during the study and for 30 days after the last dose of IMP.
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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, unless otherwise indicated:
1. Body weight <40 kg.
2. Body mass index (BMI) ≥40 kg/m2.
3. Group 2 to 5 pulmonary hypertension according to the Nice classification [Simonneau, 2013].
4. PAH diagnosis ≥5 years at Screening.
5. For subjects with HIV-associated PAH, any of the following: concomitant active opportunistic infections within 180 days of Screening, detectable viral load within 90 days of Screening, cluster designation 4 (CD4+) T-cell count <200/mm3 within 90 days of Screening, changes in antiretroviral regimen within 90 days of Screening.
6. Presence of 3 or more of the following risk factors for heart failure with preserved ejection fraction at Screening:
a. BMI >30 kg/m2.
b. Diabetes mellitus of any type.
c. Essential hypertension.
d. Significant coronary artery disease, i.e., any of the following: Angina, More than 50% stenosis in a coronary artery (by coronary angiography), Previous myocardial infarction, Previous or planned coronary artery bypass grafting and/or coronary artery stenting
e. Left atrial volume index (LAVi) >30 mL/m2.
7. Echocardiogram (ECHO) within 365 days prior to Screening demonstrating significant left-sided heart disease, including any of the following: left ventricular (LV) ejection fraction <40%, LVEF ≥50% but with impaired left ventricular (LV) relaxation.
8. Has a cardiac index (CI) of >3.2 L/min/m2 obtained from a RHC performed at or within 365 days of Screening
9. Acutely decompensated heart failure within 30 days prior to Screening.
10. Evidence of protocol-defined significant cardiac disease history including, but not limited to: a/ Restrictive, dilated or obstructive cardiomyopathy b/ Percutaneous coronary intervention or coronary artery bypass surgery within 180 days prior to Screening c/ Any persistent (chronic) or permanent atrial fibrillation.
11. Has evidence of more than mild parenchymal lung disease on PFTs performed within 180 days prior to Screening.
Subjects with any of the following criteria will be excluded:
a. Forced expiratory volume in 1 second (FEV1) <60% (predicted) (pre-bronchodilators); or
b. Forced expiratory volume in 1 second/forced vital capacity ratio (FEV1/FVC) <65% (pre-bronchodilators); or
c. Total lung capacity (TLC) <70% predicted.
For criteria 12 to 33 see protocol. |
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| E.5 End points |
| E.5.1 | Primary end point(s) |
| The primary endpoint is the time (in days) from randomization to the first adjudicated protocol-defined clinical failure event. Subjects without a protocol-defined clinical failure event will be censored at date of last contact, 7 days after last study dose, interim analysis data cut date, or end of study date, whichever is the earliest. |
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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) |
• NT-proBNP will be analyzed using MMRM analysis with treatment, the stratification factors, week, and treatment-by-week interaction as factors and baseline NT-proBNP as a covariate. Least squares means, standard errors (SE), and 95% CIs for the treatments and their difference will be presented together with the p-value.
• 6MWD will be analyzed using MMRM analysis with treatment, the stratification factors (less 6MWD stratum), week, and treatment-by-week interaction as factors and baseline 6MWD as a covariate. Least squares means, SEs, and 95% CIs for the treatments and their difference will be presented together with the p-value.
• WHO/NYHA functional class will be analyzed using using CMH method adjusted for baseline WHO/NYHA functional class and using modified ridit scores to compute the test statistic and p-value for the between treatment comparison.
• Time to all-cause hospitalization will be analyzed using Cox regression with a model that includes treatment and the stratification factors. The hazard ratio for treatment together with its 95% CI and p-value will be presented.
• Time to all-cause mortality will be analyzed using Cox regression with a model that includes treatment and the stratification factors. The hazard ratio for treatment together with its 95% CI and p-value will be presented.
• HRR following completion of 6MWT will be analyzed using MMRM analysis with treatment, the stratification factors, week, and treatment-by-week interaction as factors and baseline HRR as a covariate. Least squares means, SEs, and 95% CIs for the treatments and their difference will be presented together with the p-value.
• The proportion of subjects who achieve all three of the following: NT-proBNP <300 pg/mL, 6MWD >440 meters, WHO/NYHA functional class II status or better will be analyzed using CMH method. The odds ratio will be presented together with 95% CIs and the p-value.
• HRQoL measures will be analyzed using MMRM analysis with treatment, the stratification factors, week, and treatment-by-week interaction as factors and baseline domain score as a covariate. Least squares means, SEs, and 95% CIs for the treatments and their difference will be presented together with the p-value. |
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| E.5.2.1 | Timepoint(s) of evaluation of this end point |
| Throughout the study; secondary endpoints will be assessed as the change from baseline to Week 28, except for time to all-cause hospitalization and time to all-cause mortality. |
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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 |
Proteomics, Metabolomics, and Gene Expression
Cardiac Magnetic Resonance Imaging (cMRI) |
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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 | 7 |
| E.8.5 | The trial involves multiple Member States | Yes |
| E.8.5.1 | Number of sites anticipated in the EEA | 67 |
| 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 |
| Brazil |
| Canada |
| Chile |
| China |
| European Union |
| Israel |
| Japan |
| Korea, Republic of |
| Mexico |
| Serbia |
| Singapore |
| Switzerland |
| Taiwan |
| Thailand |
| Turkey |
| Ukraine |
| 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 | 3 |
| 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 | 6 |
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