Purpose

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.

Conditions

Eligibility

Eligible Ages
Between 18 Years and 75 Years
Eligible Genders
All
Accepts Healthy Volunteers
No

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 participation.

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 stenting
  • 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.

Study Design

Phase
Phase 3
Study Type
Interventional
Allocation
Randomized
Intervention Model
Parallel Assignment
Primary Purpose
Treatment
Masking
Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)

Arm Groups

ArmDescriptionAssigned Intervention
Experimental
Ralinepag
Ralinepag once daily extended-release tablets (oral) 50, 250, and 400 mcg titrated to the highest tolerated dose (maximum dose of 1450 mcg)
  • Drug: Ralinepag
    Active
    Other names:
    • APD811
Placebo Comparator
Placebo
Matching placebo tablets (oral)
  • Drug: Placebo
    Placebo

Recruiting Locations

University of Maryland Medical Center
Baltimore, Maryland 21201
Contact:
Jennifer Marshall
410-328-7623
jmarshall1@som.umaryland.edu

More Details

NCT ID
NCT03626688
Status
Recruiting
Sponsor
United Therapeutics

Study Contact

Derek Solum, PhD
919-425-8122
dsolum@unither.com

Detailed Description

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 applicable.

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.

Notice

Study information shown on this site is derived from ClinicalTrials.gov (a public registry operated by the National Institutes of Health). The listing of studies provided is not certain to be all studies for which you might be eligible. Furthermore, study eligibility requirements can be difficult to understand and may change over time, so it is wise to speak with your medical care provider and individual research study teams when making decisions related to participation.