Pulmonary artery hypertension(PAH)

Primary Objective 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. Secondary Objectives The secondary objectives of the study are: • To evaluate the effects of ralinepag on the following parameters: o N-terminal pro b-type natriuretic peptide (NT-proBNP) o 6-minute walk distance (6MWD) o WHO/ New York Heart Association (NYHA) functional class o Time to all-cause hospitalization o Time to all-cause mortality o Heart rate recovery (HRR) following completion of the 6MWT o Proportion of subjects who attain all three of the following:  NT-proBNP <300 pg/mL  6MWD >440 meters  WHO/NYHA functional class II status or better o Health-related quality of life (HRQoL) measures • To assess ongoing safety and tolerability of ralinepag when added to standard of care or PAH-specific background therapy.

Ralinepag

Ralinepag

Extended-Release Tablet

50 or 250 or 400

Primary Outcome Measures :
Time from randomization to the first adjudicated protocol-defined clinical worsening event [ Time Frame: The study duration was event-based. This parameter was assessed from randomization until the conclusion of the study, up to 3 years ]
Clinical worsening events are defined as death, nonelective hospital admission for worsening PAH (further defined in clinical study protocol), initiation of parenteral or inhaled prostacyclin pathway agent for treatment of worsening PAH, disease progression (further defined in clinical study protocol), or unsatisfactory long-term clinical response (further defined in clinical study protocol).


Secondary Outcome Measures :
Change from Baseline in N-terminal pro-brain natriuretic peptide (NT-proBNP) [ Time Frame: Baseline to Week 28 ]
NT-proBNP was measured at Baseline (prior to starting study drug) and Week 4, 8, 12, and 16, then every 12 weeks thereafter including the End of Study/Early Termination Visit.

Change from Baseline in 6-minute walk distance (6MWD) [ Time Frame: Baseline to Week 28 ]
6MWD was measured at Baseline (prior to starting study drug) and Week 4, 8, 12, and 16, then every 12 weeks thereafter including the End of Study/Early Termination Visit.

Change from Baseline in WHO/New York Heart Association (NYHA) Functional Class [ Time Frame: Baseline to Week 28 ]
The severity of PAH was graded according to the functional status of the subject and assessed at every visit.

Shift and proportion of subjects who attain all 3 of the following: NT-proBNP level <300 pg/mL, 6MWD >440 meters, and WHO/NYHA Functional Class I or II [ Time Frame: Baseline to Week 28 ]
Data from NT-proBNP, 6MWD, and WHO/NYHA functional class assessment were compiled as a composite endpoint at visits through Week 28.

Change from Baseline in health-related quality of life as measured by patient-reported outcomes. [ Time Frame: Baseline to Week 28 ]
Quality of life was assessed using patient-reported outcomes at Baseline (prior to starting study drug) and Week 16, then every 12 weeks thereafter including the End of Study/Early Termination Visit.

Change from Baseline in heart rate recovery (HRR) following completion of the 6MWT [ Time Frame: Baseline to Week 28 ]
HRR was measured at Baseline (prior to starting study drug) and Week 4, 8, 12, and 16, then every 12 weeks thereafter including the End of Study/Early Termination Visit.

Time to all-cause nonelective hospitalization [ Time Frame: The study duration was event-based. This parameter was assessed from randomization until the conclusion of the study (when the target number of adjudicated events was achieved, as defined in the study protocol). ]
All nonelective hopsitalizations during the study period were collected.

Time to all-cause mortality [ Time Frame: The study duration was event-based. This parameter was assessed from randomization until the conclusion of the study (when the target number of adjudicated events was achieved, as defined in the study protocol). ]
All deaths during the study period were collected.

Safety and tolerability of ralinepag in subjects with PAH [ Time Frame: Baseline to Week 28 ]
Safety and tolerability were assessed by adverse events.

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 studyrelated 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 by the medical monitor; and, in the
investigator’s opinion, is compliant with his or her current medication regimen and
overall PAH care.
d. PAH associated with:
i. Connective tissue disease (CTD)
ii. HIV infection
iii. 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 of:
i. ≤12 mmHg if PVR ≥240 to <500 dynes/sec/cm5 OR
ii. ≤15 mmHg if PVR ≥500 dynes/sec/cm5
iii. If PCWP is not available, then left ventricular end diastolic pressure (LVEDP)
≤15 mmHg
c. PVR >3.00 Wood units or >240 dynes/sec/cm5
.
If more than one RHC was performed in the last 365 days prior to Screening, the most recent
RHC that includes parameters sufficient to evaluate the above criteria must be used for this
assessment.
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 ERA
and/or an agent acting on the nitric oxide (NO) pathway, a PDE5 inhibitor or a 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 PDE5 inhibitor, the use
of PDE5 inhibitor 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. If both tests are done on the same day, then
they must be completed >4 hours apart.
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 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. Medically acceptable methods of contraception include the following:
• oral, implantable, or injectable contraceptives (starting ≥60 days before dosing) and
diaphragm with vaginal spermicide, cervical cap with vaginal spermicide, or male
condom;
• male condom and partner using diaphragm with vaginal spermicide or cervical cap
with vaginal spermicide;
• standard intrauterine device (IUD; e.g., Copper T 380A IUD), intrauterine system
(IUS; e.g., LNg 20 IUS - progesterone IUD), progesterone implant, or tubal
sterilization (≥180 days after surgery);
• post vasectomy and male condom, partner using diaphragm with spermicide, cervical
cap with spermicide, estrogen and progesterone oral contraceptives (“the pill”),
estrogen and progesterone transdermal patch, vaginal ring, or progesterone injection

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:
a. concomitant active opportunistic infections within 180 days of Screening.
b. detectable viral load at Screening.
c. cluster designation 4 (CD4+) T-cell count <200/mm3 within 90 days of Screening.
d. 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. Systemic hypertension.
d. Significant coronary artery disease, i.e., any of the following:
i. Angina
ii. More than 50% stenosis in a coronary artery (by coronary angiography)
iii. Previous myocardial infarction
iv. Previous or planned coronary artery bypass grafting and/or coronary artery stenting
e. Left atrial volume index (LAVi) >30 mL/m2
.
7. ECHO within 365 days prior to Screening demonstrating significant left-sided heart disease,
including any of the following:
a. Left ventricular ejection fraction (LVEF) <40%.
b. LVEF ≥50% but with impaired left ventricular (LV) relaxation.
c. Mitral valve E/A ratio ≥2 or,
d. Average mitral valve E/e’ >14 and LV volume index >34 mL/m2
.
e. Moderate or severe left sided valvular disease (aortic or mitral valve stenosis or
regurgitation).
If more than one ECHO was performed in the last 365 days prior to Screening, the most
recent ECHO that includes parameters sufficient to evaluate the above criteria must be used
for this assessment.
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,
any of the following:
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. PFTs will be performed as part of Screening procedures, if data
within 180 days of Screening are not available. 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. If the TLC is >60% predicted and <70%
predicted, then imaging (i.e., high resolution computed tomography [HRCT]) is required
to exclude parenchymal lung disease. The subject may be enrolled pending review and
approval by the medical monitor.
12. Has evidence of thromboembolic disease as determined by ventilation-perfusion (V/Q) lung
scan or local standard of care diagnostic evaluation within 5 years of Screening.
-V/Q scanning is preferred, but if unavailable, spiral/helical/electron beam computed
tomography (CT) angiography is acceptable in subjects with NO history of venous
thromboembolic disease.
-If V/Q scan is unavailable and subject has a prior history of venous thromboembolic
disease, then selective pulmonary angiography is required to exclude chronic
thromboembolic disease.
-If a V/Q scan is abnormal (i.e., anything other than “normal” or “low probability”), then
a selective pulmonary angiography must be conducted to exclude chronic
thromboembolic disease.
All required tests may be requested for medical monitor review if clinically indicated to
exclude chronic thromboembolic pulmonary hypertension.
13. Has obstructive sleep apnea that is symptomatic and/or not treated with stable therapy.
Subjects treated with continuous positive airway pressure (CPAP) or bi-level positive airway
pressure (BiPAP) must have a sleep study within 180 days of Screening that shows an
adequate response (i.e., apnea-hypopnea index [AHI] <7).
14. Uncontrolled systemic hypertension as evidenced by sitting systolic blood pressure (SBP)
>160 mmHg or sitting diastolic blood pressure (DBP) >100 mmHg at Screening.
15. Hypotension (SBP <90 mmHg) at Screening.
16. History of orthostatic hypotension or orthostatic hypotension at Screening, defined as a drop
in SBP ≥20 mmHg or DBP ≥10 mmHg or the development of significant postural symptoms
(syncope, near syncope, lightheadedness, or vertigo) when going from the supine to the
standing position.
17. Male subjects with a corrected QT interval using Fridericia’s formula (QTcF) >450 msec and
female subjects with QTcF >470 msec on ECG measured at Screening or Baseline.
18. History of atrial septostomy within 180 days prior to Screening.
19. Diagnosis of Down syndrome. Subjects with Down syndrome are excluded due to the high
potential of undiagnosed or poorly managed obstructive sleep apnea in this population.
20. Chronic liver disease (i.e., Child-Pugh B or C), portal hypertension, cirrhosis or
complications of cirrhosis/portal hypertension (e.g., variceal hemorrhage, encephalopathy or
ascites).
21. Confirmed active infection with hepatitis B virus (HBV) or hepatitis C virus (HCV) at
Screening.
NOTE: Subjects previously infected with HCV who have a negative viral load after receiving
a course of curative treatment are allowed.
22. Subjects with alanine aminotransferase (ALT) or aspartate aminotransferase (AST) ≥3 times
the upper limit of normal (ULN) or total bilirubin ≥2xULN at Screening.
23. Chronic renal insufficiency as defined by serum creatinine >2.5 mg/dL or estimated
glomerular filtration rate (eGFR) <30 mL/min (calculated using the Modification of Diet in
Renal Disease [MDRD] equation) at Screening or the subject requires dialytic support.
24. Hemoglobin concentration <9 g/dL at Screening.
25. Subject required use of intravenous (i.v.) inotropes including, but not limited to,
levosimendan, dopamine, dobutamine, dopexamine, epinephrine, isoprenaline
(isoproterenol), norepinephrine (noradrenaline), milrinone, or amrinone, within 30 days prior
to Screening.
26. Subject has pulmonary veno-occlusive disease.
27. Malignancy within 5 years of Screening, with the exception of localized non-metastatic basal
cell carcinoma of the skin and in-situ carcinoma of the cervix excised with curative intent.
28. Recent history (i.e., within 1 year prior to Screening) of alcohol or drug abuse.
29. Subject tests positive for amphetamine, cocaine, methamphetamine,
methylenedioxymethamphetamine or phencyclidine in urine drug screen performed at
Screening.
30. Initiation of a cardio-pulmonary rehabilitation program based upon exercise within 90 days
prior to Screening and/or planned during study participation.
31. Prior participation in any study of ralinepag or participation in another interventional clinical
study within 60 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.
32. 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.
33. Life expectancy <12 months.