A Study Evaluating the Efficacy and Safety of Ralinepag to Improve Treatment Outcomes in PAH Patients

Conditions:High Blood Pressure (Hypertension), High Blood Pressure (Hypertension), Peripheral Vascular Disease, Cardiology, Orthopedic, Pulmonary
Therapuetic Areas:Cardiology / Vascular Diseases, Pulmonary / Respiratory Diseases, Orthopedics / Podiatry
Age Range:18 - 75
Start Date:August 30, 2018
End Date:December 2021
Contact:Derek Solum, PhD

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A Phase 3, Randomized, Double-blind, Placebo-controlled Study to Evaluate the Efficacy and Safety of Ralinepag When Added to PAH Standard of Care or PAH Specific Background Therapy in Subjects With WHO Group 1 PAH

Study ROR-PH-301, ADVANCE OUTCOMES, is designed to assess the efficacy and safety of
ralinepag when added to pulmonary arterial hypertension (PAH) standard of care or
PAH-specific background therapy in subjects with World Health Organization (WHO) Group 1 PAH.

Study ROR-PH-301 is a multicenter, randomized, double-blind, placebo-controlled study that
includes a Screening period of up to 28 days in duration, a 16-week (112±3 days) Dose
Titration Period, and a Treatment Period of variable duration, depending upon the overall
duration of the trial. A total of 700 subjects with WHO Group 1 PAH are planned to be
enrolled. Subjects who meet all entry criteria will be randomized 1:1 to receive ralinepag or
placebo, in addition to their standard of care or PAH-specific background therapy, as

Randomization will be stratified by: Screening 6MWD <400 meters versus ≥400 meters, PAH
associated with connective tissue disease (CTD) versus other etiologies, and PAH specific
background therapy (2 versus 1 or none).

On Day 1, investigational medicinal product (IMP) (ralinepag or placebo) will be initiated at
a dose of 50 mcg once daily for the first week of treatment. During each subsequent week of
the 16 week Dose Titration Period, the dose of IMP will be increased in 50 mcg increments to
a dose of 800 mcg once daily or until the highest tolerated dose is achieved.

Subjects will be required to attend clinic visits on Day 1 (Baseline) and at Weeks 4, 8, and
12 during the Dose Titration Period. Between scheduled clinic visits during the Dose
Titration Period, subjects will be contacted at least once per week by telephone to titrate
IMP dose (up or down), review IMP administration instructions, assess adverse events (AEs),
and record concomitant medications. If the highest tolerated dose of IMP is achieved prior to
Week 16, the subject will remain on that dose until the completion of the Dose Titration
Period. Decreases in IMP dose (in 50 mcg increments) will be allowed at any time during the
Dose Titration Period to manage AEs and attain the highest tolerated dose. Background PAH
therapies (regimen and doses) must remain stable throughout the Dose Titration Period.

Further increases in IMP dose (in increments of 50 mcg per week) up to a maximum dose of 1450
mcg once daily will be permitted during the Treatment Period, according to investigator
discretion. No IMP dose increases will be allowed within 6 weeks prior to a
protocol-specified efficacy evaluation. IMP dose decreases will be allowed at any time during
the Treatment Period to manage tolerability and AEs. IMP dose adjustments (up or down) may be
implemented by phone or during an Unscheduled Visit between protocol-specified clinic visits.

Subjects will attend clinic visits at Week 16 and every 12 weeks (84±3 days) thereafter
during the Treatment Period. Efficacy and safety assessments will be performed at every visit
until a total of 253 primary endpoint events have occurred. All primary endpoint events will
be adjudicated by an independent Clinical Event Committee (CEC). The CEC will remain blinded
to treatment assignments throughout the duration of the study.

All subjects should remain on IMP for the duration of the trial. Subjects who prematurely
discontinue IMP should continue in the study and complete remaining scheduled visits
according to the protocol. Subjects who withdraw from the study (during the Dose Titration
Period or the Treatment Period) and do not agree to complete their remaining scheduled visits
will be requested to return to clinic for the End of Study/Early Termination Visit and for a
Follow up Visit approximately 30 days after discontinuation of IMP. Subjects who prematurely
discontinue IMP or withdraw from the study will also be contacted each year and at the end of
the study to determine vital status (unless consent is withdrawn).

Subjects who have a confirmed primary endpoint event adjudicated by the CEC at any time
during the study and all subjects on IMP at the conclusion of the study (after the target
number of events is achieved) will have the option to enroll in an open-label extension (OLE)
study and receive treatment with ralinepag. Subjects who do not choose to participate in the
OLE will discontinue IMP and may receive standard of care PAH treatment off-study, at the
discretion of the treating physician. Subjects who do not participate in the OLE study will
attend a Follow-up Visit approximately 30 days after discontinuation of IMP. Subjects who
prematurely discontinue IMP or withdraw from Study ROR-PH-301 for any reason (other than
experiencing a confirmed primary endpoint event) will not be eligible to continue into the
OLE study.

Inclusion Criteria:

- Males or females aged 18-75 years, inclusive.

- 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.

- Subjects who are willing and able to comply with scheduled visits, treatment plan,
laboratory tests, and other study procedures.

- Diagnosis of symptomatic WHO Group 1

- 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

- Has WHO/ NYHA functional class II to IV symptoms.

- 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.

- Stable is defined as no change in dose or regimen within 90 days of Screening and
for the duration of the study.

- Subjects may be on 1 agent active in the NO pathway, i.e., either a PDE5
inhibitor or an sGC stimulator at stable dose (but not both).

- 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.

- 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.

- Both male and female subjects agree to use a medically acceptable method of
contraception throughout the entire study period from informed consent through to 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. Women who are surgically sterile or postmenopausal for at least 12
months are not considered to be of childbearing potential. If of childbearing
potential, female partners of male study participants should agree to utilize
medically acceptable methods of contraception for the duration of study

Exclusion Criteria:

- Body weight <40 kg.

- Body mass index (BMI) ≥40 kg/m2.

- Group 2 to 5 pulmonary hypertension.

- PAH diagnosis ≥5 years at Screening.

- For subjects with HIV-associated PAH, any of the following:

- concomitant active opportunistic infections within 180 days of Screening.

- detectable viral load at Screening.

- cluster designation 4 (CD4+) T-cell count <200/mm3 within 90 days of Screening.

- changes in antiretroviral regimen within 90 days of Screening.

- Presence of 3 or more of the following risk factors for heart failure with preserved
ejection fraction at Screening:

- BMI >30 kg/m2.

- Diabetes mellitus of any type.

- Systemic hypertension.

- 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

- Left atrial volume index (LAVi) >30 mL/m2.

- 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.

- 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.

- Recent history (i.e., within 1 year prior to Screening) of alcohol or drug abuse.

- Initiation of a cardio-pulmonary rehabilitation program based upon exercise within 90
days prior to Screening and/or planned during study participation.
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