Overview

The objectives of this study are to evaluate the safety of RT234 and the effects of RT234 on exercise capacity as assessed by Cardiopulmonary Exercise Testing (CPET) and six minute walk testing (6MWT) as well as exertional symptoms in patients with pulmonary arterial hypertension (PAH).

Eligibility

Inclusion Criteria:

1. Must be between 18 and 80 years of age, inclusive.
2. Must be willing and able to provide written, signed informed consent after the nature of the study has been explained, and prior to undergoing any research-related procedures.
3. Must be willing and able to comply with all scheduled visits, treatment plan, laboratory tests, and other study procedures.
4. Able to exercise during CPET and ambulate independently.
5. Diagnosis documented and confirmed by Right Heart Catheterization (RHC)-confirmed WHO Group 1 PAH in any of the following 3 categories:
   1. Idiopathic, primary, or familial pulmonary arterial hypertension (IPAH, PPH, or FPAH) OR
   2. PAH associated with one of the following connective tissue diseases:
   3. Systemic sclerosis (scleroderma) ii) Limited scleroderma iii) Mixed connective tissue disease iv) Systemic lupus erythematosus v) Overlap syndrome vi) Other autoimmune disorders OR c) PAH associated with: i) Human immunodeficiency virus (HIV) infection. ii) Simple, congenital systemic-to-pulmonary shunts at least 1-year post-surgical repair.

             iii) Exposure to drugs, chemicals, and toxins, such as fenfluramine derivatives, other
             anorexigens, toxic rapeseed oil, or L-tryptophan.
          6. Subjects with a diagnosis of HIV must have stable disease, defined by:
               1. Unchanged medication treatment regimen for HIV for at least 8 weeks prior to
                  beginning Visit 1 Screen assessments.
               2. No active opportunistic infection during the Screening Period.
               3. No hospitalizations for HIV for at least 4 weeks prior to beginning Visit 1
                  Screen assessments.
          7. The patient must have adequate, documented test results that exclude chronic
             thromboembolic pulmonary hypertension (CTEPH).
          8. Previous diagnosis of PAH, but with the following conditions:
               1. Stable PAH without significant adjustments of disease-specific background PAH
                  therapy, at least 3 months prior to the Baseline CPET procedure. Stable is
                  defined as no change in PAH -specific drug therapy within 3 months of Screening
                  Visit 1, and for the duration of the study, and no change in dose of PAH-specific
                  drug(s) within 1 month of Screening.
                  AND
               2. If on corticosteroids, has been receiving a stable dose of ≤ 20 mg/day of
                  prednisone (or equivalent dose of other corticosteroid) for at least 30 days
                  prior to the Baseline CPET.
          9. PFT within 6 months prior to the Baseline CPET procedure that fulfills the following
             criteria:
               1. FEV1 ≥ 60% predicted (pre-bronchodilators).
               2. FEV1 / FVC ≥ 60% (pre-bronchodilators).
               3. FVC ≥ 60% predicted.
         10. Has had RHC performed and documented prior to Screening that meets the following
             hemodynamic criteria:
               1. mPAP ≥ 20 mmHg.
               2. PVR ≥ 300 dyn·s/cm5.
               3. PCWP or LVEDP of ≤ 12 mmHg if PVR ≥ 300 to < 500 dyn∙s/cm5, or PCWP or LVEDP ≤ 15
                  mmHg if PVR ≥ 500 dyn∙s/cm5.
         11. Has WHO/New York Heart Association (WHO/NYHA) functional class II-IV symptomatology.
         12. On stable oral PAH disease-specific background therapy of up to 3 oral, inhaled, or
             parenteral therapies (any combination of an endothelin receptor antagonist,
             phosphodiesterase type 5 inhibitor, and/or a prostacyclin or prostacyclin receptor
             agonist). Stable is defined as no change in PAH-specific drug therapy within 3 months
             of Screening Visit 1, and for the duration of the study, and no change in dose of
             PAH-specific drug(s) within 1 month of Screening. Sotatercept subjects should have
             been on sotatercept for a minimum of 6 months at the time of screening. Sotatercept
             subjects will be limited to 20% of a particular cohort with approval of the Sponsor
             Medical Monitor.
         13. Must be able to walk a distance of ≥ 150 meters in the Baseline 6MWTs. This will be
             determined using the mean of the two 6MWT results done during Screening. If tolerable
             by the subject, the 2 Baseline 6MWTs will be conducted at Visit 1 with a minimum of 2
             hours of rest between the first and second tests.
         14. Has a VE/VCO2 slope ≥ 36 during the Baseline CPET as assessed by the study CPET Core
             Laboratory.
         15. Evidence of good effort on the Baseline CPET reaching a peak RER > 1.0 as assessed by
             the study CPET Core Laboratory.
         16. Peak VO2 ≤ 15 ml/min/kg during the Baseline CPET as assessed by the study CPET Core
             Laboratory.
         17. If the subject is taking the following concomitant medications which may affect PAH,
             the subject must be on a stable therapeutic dose for at least 1 month prior to the
             start of Screening and the dosage maintained throughout the study.
               1. Vasodilators (including calcium channel blockers - specify the indication e.g.,
                  PAH, hypertension, Raynaud's disease), digoxin, or L-arginine supplement.
               2. If the subject is taking a vitamin K antagonist anticoagulant, then
                  anticoagulation status should be maintained/stable in the therapeutic range for
                  at least 1 month before the start of Screening.
         18. Sexually active subjects must be willing to use an acceptable method of contraception
             while participating in the study through the 30-day post-treatment safety follow-up
             telephone call. Acceptable methods of contraception include hormonal birth control
             (oral, intravaginal, transdermal, implantable, or intrauterine device/system
             [IUD/IUS]), IUDs (non-hormonal), vasectomy (in male partner), or any double-barrier
             methods (combination of male condom and spermicide with either cap, diaphragm, or
             sponge).
         19. Female subjects of childbearing potential must have a negative pregnancy test (urine
             or serum) at Screening and be willing to have additional pregnancy tests while
             participating in the study.
         20. Female subjects considered not of childbearing potential include those who are
             post-menopausal (defined as cessation of regular menstrual periods for at least 1
             year) or have documented evidence of surgical sterilization at least 6 months prior to
             Screening.
         21. No evidence of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2),
             clinically, by polymerase chain reaction (PCR) test, or antigen test as required by
             local site infection control policies at the Screening Visit. Subjects with previous
             coronavirus disease 2019 (COVID-19) infection must have returned to functional
             baseline prior to entering Screening for this study.
        Exclusion Criteria:
        Individuals who meet any of the following exclusion criteria will not be eligible to
        participate in the study:
          1. Baseline systemic hypotension defined as mean arterial pressure (MAP) < 50 mmHg or SBP
             < 90 mmHg at Screening.
          2. History of chronic uncontrolled asthma; subjects with inability to use, or may have
             potential difficulties using, an inhaler device.
          3. Use of continuous, supplemental oxygen. Subject must be able to complete exercise
             tests without the use of supplemental oxygen.
             NOTE: Use of nocturnal oxygen is acceptable.
          4. Requirement of intravenous inotropic therapies within 30 days prior to the Baseline
             CPET procedure.
          5. Use of riociguat (Adempas®) as background PAH therapy as of 1 month prior to
             initiating Screening or during the study through the end of Visit 4.
          6. Use of oral, topical, or inhaled nitrates within 2 weeks prior to the Baseline CPET
             procedure.
          7. Has history of uncontrolled systemic hypertension as evidenced by sitting SBP > 175
             mmHg or sitting diastolic blood pressure (DBP) > 110 mmHg at Screening.
          8. Portopulmonary hypertension, portal hypertension, or chronic liver disease determined
             to be Child-Pugh B or C, including hepatitis B virus and/or hepatitis C virus (HCV).
             Subjects who have had a previous infection with HCV and who have a negative viral load
             after receiving a course of curative treatment are
          9. Subjects who have 3 or more of the following left ventricular disease/dysfunction risk
             factors are not eligible:
               1. Hypertension requiring medication therapy.
               2. Diabetes mellitus - any type.
               3. History of significant coronary artery disease (CAD) established by any one of
                  the following:
             i) Myocardial infarction within 12 months of screening ii) Percutaneous coronary
             intervention within 12 months of screening iii) Angiographic evidence of CAD (> 50%
             stenosis in at least 1 vessel) either by invasive angiography or by CT angiography.
             iv) Positive stress test imaging, either pharmacologic or with exercise. v) Previous
             coronary artery surgery. vi) Chronic stable angina.
         10. Uncorrected right-to-left shunt, clinically relevant persistently patent foramen ovale
             in the judgement of the Investigator or known Eisenmenger's physiology.
         11. Paroxysmal or uncontrolled atrial fibrillation (defined as a resting heart rate
             greater than or equal to 110 bpm).
         12. Chronic renal insufficiency as defined by serum creatinine > 2.5 mg/dL or has an
             estimated glomerular filtration rate (eGFR) < 30 mL/min utilizing the Modification of
             Diet in Renal Disease (MDRD) Study equation at Screening or requires dialytic support.
         13. Serum alanine aminotransferase (ALT) or aspartate aminotransferase (AST) value that is
             ≥ 3x the upper limit of the normal range.
         14. Platelets below 50,000/μL at Screening.
         15. Hemoglobin (Hgb) concentration < 9 g/dL at Screening.
         16. Malignancy within 2 years prior to 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.
         17. Recent history (within 6 months prior to Screening) of, or current alcohol or
             drug/solvent use disorder as assessed by the Investigator.
         18. Known hypersensitivity to active drug substance (vardenafil) or drugs of the same
             class, or any excipients of the drug formulation(s).
         19. Documented history of hypotension including fainting, syncope, orthostatic
             hypotension, and/or vasovagal reactions.
         20. Vision loss due to non-arteritic anterior ischemic optic neuropathy or other optic
             perfusion impairment.
         21. History of sudden sensorineural hearing loss.
         22. 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.
             (Correction of the actual QTc for the conduction defect of left bundle-branch can be
             made by subtracting the prolongation of the QRS due to the block from the actual QTc.
             Correction for the right bundle-branch block can be made by subtracting 20 msec from
             the actual QTc).
         23. Pregnant or breastfeeding at Screening or planning to become pregnant (self or
             partner) at any time while participating in the study.
         24. Participation in a drug, device, or other interventional clinical study, other than a
             post-marketing observational extension study, within 30 days prior to Screening.
         25. Enrolled in an exercise training program within 12 weeks prior to beginning Visit 1
             Screening assessments and must agree not to enroll in an exercise training program
             during the study. Subjects enrolled in an exercise program more than 12 weeks prior to
             beginning Visit 1 Screening assessments may be enrolled if they agree to maintain
             their current level of physical activity throughout the duration of the study.
         26. Has a concurrent disease or condition that in the view of the Principal Investigator,
             places the potential subject at high risk of poor treatment compliance or of not
             completing the study, or would interfere with study participation or would affect
             safety.
         27. Has received the SARS-CoV-2 vaccine or booster within 1 week prior to Screening Post
             COVID-19 chronic symptoms ("Long COVID") at Screening. NOTE: Investigators, study
             staff, or their immediate family members may not participate in the study.