| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
| pulmonary arterial hypertension (PAH) |
|
| E.1.1.1 | Medical condition in easily understood language |
|
| 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 |
|
| 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 on the time to first adjudicated protocol-defined clinical worsening event in subjects with PAH. |
|
| E.2.2 | Secondary objectives of the trial |
The secondary objectives of the study are:
1) To evaluate the effects of ralinepag from Baseline to Week 28 on:
• N-terminal pro b-type natriuretic peptide (NT-proBNP)
• 6 minute walk distance (6MWD)
• WHO/ New York Heart Association (NYHA) functional class
• Shift and proportion of subjects who attain all three of the following:
o NT-proBNP <300 pg/mL
o 6MWD >440 meters
o WHO/NYHA functional class I or II
• Health-related quality of life (HRQoL) measures
• Heart rate recovery (HRR) following completion of the 6-minute walk test (6MWT)
2) To evaluate the time to all-cause hospitalization
3) To evaluate the time to all-cause mortality
4) To evaluate the safety and tolerability of ralinepag in subjects with PAH |
|
| 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
genetics:
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, and the Study Drug Termination
Visit; for subjects who agree to participate in the optional genetic
analysis, a blood sample will be collected at Baseline. Comparing
treatment responses and treatment-related change to these parameters
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.
Subjects can consent to participate in all, part, or none of these
analyses, and subjects who do not wish to participate may still
participate in the main clinical study. |
|
| 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. Primary diagnosis of symptomatic 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 and have no, or a clinically
insignificant, shunt fraction [1.0 ≤pulmonary-systemic flow ratio
(Qp/Qs) ≤1.5]) in the opinion of the Investigator.
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. PAWP ≤15 mmHg (if PAWP cannot be reliably attained, then left
ventricular end diastolic pressure [LVEDP] ≤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 oral therapy, subject is on stable
therapy with either an endothelin receptor antagonist (ERA) and/or a
PDE5-I or a soluble guanylate cyclase (sGC) stimulator. Subjects may be
naïve to PAH specific treatments; however, subjects must have access to
locally available standard of care treatment in accordance with national
guidelines
a. Stable is defined as no change in dose or regimen within 30 days prior
to Baseline and for the duration of the study.
b. Subjects may be on 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 PDE5-I as needed for erectile dysfunction, up to 3
doses per week, is permitted. The subject should not have taken a dose
within 48-hours of any Baseline or study related efficacy assessment.
8. Has a 6MWD of ≥150 meters.
9. If the subject is taking concomitant medications that may affect PAH
(e.g., calcium channel blockers, digoxin, or L-arginine supplementation),
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.
10. Both male and female subjects agree to use a highly effective
method of birth control throughout the entire study period from
informed consent through the 30-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 (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. |
|
| 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. For subjects with known HIV-associated PAH, a cluster designation 4
(CD4+) T-cell count <200/mm3 within 90 days of Baseline.
2. Subjects must not have 3 or more of the following left ventricular
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: History of myocardial infarction or
percutaneous coronary intervention or angiographic evidence of
coronary artery disease (>50% stenosis in at least 1 coronary artery);
Positive stress test with imaging; Previous coronary artery bypass graft;
Angina
e. Any chronic atrial fibrillation.
3. Has evidence of more than mild lung disease on PFTs performed
within 180 days 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.
4. Has evidence of thromboembolic disease as determined by a V/Q lung
scan or local standard of care diagnostic evaluation at or after diagnosis
of PAH.
5. Current diagnosis of uncontrolled sleep apnea as defined by the
Investigator.
6. Male subjects with a corrected QT interval using Fridericia's formula (QTcF) >450 msec and female subjects with a QTcF >470 msec on ECG recorded at Screening and analyzed by the central ECG laboratory. Subjects with evidence of intraventricular conduction delay (IVCD) will be excluded if the QTcF is >500 msec for both males and females.
7. Severe chronic liver disease (i.e., Child-Pugh C), portal hypertension, cirrhosis or complications of cirrhosis/portal hypertension (e.g., history of variceal hemorrhage, encephalopathy).
8. Confirmed active infection with hepatitis B virus (HBV) or hepatitis C virus (HCV).
9. Subjects with alanine aminotransferase (ALT) or aspartate aminotransferase (AST) ≥3 times the upper limit of normal (ULN) or total bilirubin ≥2 × ULN at Screening.
10. Chronic renal insufficiency as defined by serum creatinine >2.5 mg/dL or requiring dialysis at Screening.
11. Hemoglobin concentration <9 g/dL at Screening.
12. Subjects treated with an IV or SC prostacyclin pathway agent (e.g., epoprostenol, treprostinil, or iloprost) at any time prior to Baseline (use in vasoreactive testing is permitted).
13. Subjects currently on or who were treated with an inhaled or oral prostacyclin pathway agent (iloprost, treprostinil, beraprost, or selexipag).
- Subject is not eligible if treatment was stopped for a safety or tolerability issue at any time.
- If a subject discontinued for other reasons, the subject may be eligible if the subject has been off therapy and stable (i.e., no change in WHO/NYHA FC or change in PAHspecific background oral therapy) for at least 90 days prior to Baseline.
14. Subject has pulmonary veno-occlusive disease.
15. Malignancy diagnosed and/or treated within 5 years prior to 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.
16. 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.
17. Initiation of a cardio-pulmonary rehabilitation program based upon exercise within 90 days prior to Screening and/or planned during study participation.
18. Prior participation in any study of ralinepag or participation in another interventional clinical study with investigational or approved medical products 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.
19. Any reason that, in the opinion of the Investigator or Medical Monitor, precludes the subject from participating in the study (e.g., any previous or intercurrent medical condition) that may increase the risk associated with study participation or that would confound study analysis or impair study participation or cooperation.
20. Known hypersensitivity to ralinepag or any of the excipients.
21. Life expectancy <12 months based on the Investigator's opinion.
22. Women who are pregnant, lactating, or breast-feeding. |
|
| 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 worsening event. Subjects without a protocol-defined clinical worsening event will be censored at date of last contact, 7 days after last study dose, or end of study date, whichever is the earliest. |
|
| E.5.1.1 | Timepoint(s) of evaluation of this end point |
|
| E.5.2 | Secondary end point(s) |
• NT-proBNP with log transformation 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 measured >12 hours post dose, 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 first 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 (PAH-SYMPACT Questionnaire and SF - 36) 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. |
|
| 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. |
|
| 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 |
|
| 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 | 5 |
| 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 |
| Korea, Republic of |
| Mexico |
| Serbia |
| Singapore |
| Taiwan |
| Turkey |
| Ukraine |
| United States |
|
| 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
|
|
| E.8.9 Initial estimate of the duration of the trial |
| E.8.9.1 | In the Member State concerned years | 4 |
| E.8.9.1 | In the Member State concerned months | 3 |
| E.8.9.1 | In the Member State concerned days | 15 |
| 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 | 3 |
| E.8.9.2 | In all countries concerned by the trial days | 15 |
Print
