Vardenafil Inhaled for Pulmonary Arterial Hypertension PRN Phase 2B Study (VIPAH-PRN_2B)

A Phase 2b, Open-label, Single Dose Study to Evaluate the Safety and Efficacy of RT234 on Exercise Parameters Assessed by Cardiopulmonary Exercise Testing (CPET) in Subjects With Pulmonary Arterial Hypertension (PAH)

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).

Study Overview

• Status: Completed
• Conditions: Pulmonary Arterial Hypertension
• Intervention / Treatment: Combination product: Drug: RT234 - vardenafil inhalation powder; Device: Axially Oscillating Sphere dry powder inhaler (AOS DPI)

Detailed Description

PAH results in significant limitations in cardiorespiratory fitness (CRF), exercise capacity, and profound dyspnea with physical exertion. The objective of this study is to assess the ability of a single inhaled dose of RT234 to acutely improve primary CPET measures of CRF and exercise capacity, and to decrease the experience of lower the sensation of dyspnea with physical exertion compared to baseline CPET measures.

• Study Type: Interventional
• Enrollment (Actual): 42
• Phase: Phase 2

Contacts and Locations

Study Locations

• United States
  • Alabama
    • Birmingham, Alabama, United States, 35294
      • University of Alabama
  • Arizona
    • Tucson, Arizona, United States, 85724
      • University of Arizona
  • California
    • Los Angeles, California, United States, 90033
      • University of Southern California
    • Los Angeles, California, United States, 90024
      • UCLA
    • Sacramento, California, United States, 95618
      • UC Davis
    • San Francisco, California, United States, 94143
      • University of California San Francisco
    • Torrance, California, United States, 90502
      • The Lundquist Institute for Biomedical Innovation at Harbor-UCLA Medical Center
  • District of Columbia
    • Washington D.C., District of Columbia, United States, 20010
      • MedStar Heart and Vascular Institute
  • Georgia
    • Augusta, Georgia, United States, 30912
      • Augusta University
  • Kansas
    • Kansas City, Kansas, United States, 66160
      • The University of Kansas Medical Center
  • Kentucky
    • Louisville, Kentucky, United States, 40202
      • Norton Health
  • Louisiana
    • Shreveport, Louisiana, United States, 71103
      • Ochsner Louisiana State University Health
  • Massachusetts
    • Boston, Massachusetts, United States, 02111
      • Tufts University
  • Minnesota
    • Rochester, Minnesota, United States, 20010
      • Mayo Clinic
  • Missouri
    • St Louis, Missouri, United States, 63110
      • Washington University
  • New Mexico
    • Albuquerque, New Mexico, United States, 87131
      • University of New Mexico
  • New York
    • New York, New York, United States, 10029
      • Mount Sinai Hospital
  • North Carolina
    • Chapel Hill, North Carolina, United States, 27514
      • University of North Carolina at Chapel Hill
  • Ohio
    • Cleveland, Ohio, United States, 44106
      • University Hospital
    • Columbus, Ohio, United States, 43210
      • The Ohio State University
  • South Carolina
    • Charleston, South Carolina, United States, 29425
      • Medical University of South Carolina
  • Texas
    • Austin, Texas, United States, 78705
      • Ascension Seton Medical Center Austin
    • Dallas, Texas, United States, 75246
      • Baylor Scott and White Institute
    • Houston, Texas, United States, 77030
      • Houston Methodist Hospital
  • Virginia
    • Richmond, Virginia, United States, 23284
      • Virginia Commonwealth University
  • Wisconsin
    • Milwaukee, Wisconsin, United States, 53215
      • Aurora St. Luke's Medical Center

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years to 80 years (Adult, Older Adult)
• Accepts Healthy Volunteers: No

Description

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:

   i) 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 signing the Informed Consent Form 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 oral or inhaled 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. Parenteral prostacyclin subjects will be limited to up to 20% of a particular cohort with approval of Sponsor Medical Monitor. 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 ≤ 20 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 must agree to additional urine pregnancy tests prior to each dose of study medication 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
28. Post COVID-19 chronic symptoms ("Long COVID") at Screening. NOTE: Investigators, study staff, or their immediate family members may not participate in the study.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Non-Randomized
• Interventional Model: Sequential Assignment
• Masking: None (Open Label)

Number of Arms

3

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: RT234 0.5 mg Cohort 1; RT234 at a capsule dose strength of 0.5 mg.	Combination product: Drug: RT234 - vardenafil inhalation powder; Device: Axially Oscillating Sphere dry powder inhaler (AOS DPI); RT234 capsules of a dry powder formulation containing vardenafil administered via oral inhalation with a non-invasive AOS DPI.; Other Names: inhaled vardenafil
Experimental: RT234 1.0 mg Cohort 2; RT234 at a capsule dose strength of 1.0 mg.	Combination product: Drug: RT234 - vardenafil inhalation powder; Device: Axially Oscillating Sphere dry powder inhaler (AOS DPI); RT234 capsules of a dry powder formulation containing vardenafil administered via oral inhalation with a non-invasive AOS DPI.; Other Names: inhaled vardenafil
Experimental: RT234 2.0 mg Cohort 3; RT234 at a capsule dose strength of 2.0 mg.	Combination product: Drug: RT234 - vardenafil inhalation powder; Device: Axially Oscillating Sphere dry powder inhaler (AOS DPI); RT234 capsules of a dry powder formulation containing vardenafil administered via oral inhalation with a non-invasive AOS DPI.; Other Names: inhaled vardenafil

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Mean Change in Peak Oxygen Uptake at Peak Exercise During CPET (Peak VO2)	The primary efficacy endpoint was the change from Baseline in peak V̇ O2 measured during CPET after RT234 dosing.	Comparison of measure between baseline and treatment CPETs, typically ~14 days apart
Median Change in Peak Oxygen Uptake at Peak Exercise During CPET (Peak VO2)	The primary efficacy endpoint was the change from Baseline in peak V̇ O2 measured during CPET after RT234 dosing.	Comparison of measure between baseline and treatment CPETs, typically ~14 days apart

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Change in Perceived Dyspnea at Peak Exercise During CPET	Self-reported by subjects. Change in perceived dyspnea at peak exercise during CPET as assessed by the Modified Borg Dyspnea Scale Score. (Minimum score: 0 representing no dyspnea; maximum score: 10 representing maximal dyspnea; a reduction in score represents a favorable outcome.)	Comparison of measure between baseline and treatment CPETs, typically ~14 days apart
Change in Perceived Exertion at Peak Exercise During CPET	Self-reported by subjects. Change in perceived exertion at peak exercise during CPET as assessed by the Borg Rating of Perceived Exertion (RPE) Scale score, which rates exertion from a scale of 6 (no exertion) to 20 (maximum effort). A decrease in score is favorable.	Comparison of measure between baseline and treatment CPETs, typically ~14 days apart
Change in Partial Pressure of End-tidal CO2 (PETCO2)	Change in partial pressure of end-tidal CO2 (PETCO2) apex response to exercise, i.e., highest level during CPET	Comparison of measure between baseline and treatment CPETs, typically ~14 days apart
Change in Ramp-incremental Duration of CPET		Comparison of measure between baseline and treatment CPETs, typically ~14 days apart
Change in 6-minute Walk Distance (6MWD)	Change from 6MWD at baseline (during screening visit) to 6MWD following RT234 dosing	Baseline 6MWD at baseline (during screening visit) and 6MWD measured ~ 30 minutes following RT234 dosing at visit 4, which typically occurred 4-6 weeks following the screening visit
Mean Change in Ventilatory Efficiency up to Peak Exercise During CPET	Change from Baseline to postdose in the V̇E/V̇CO2 slope, a recognized measure of ventilatory efficiency, measured up to peak during CPET. VE/VCO2 tracks the ratio between total air breathed in per minute (VE) and the amount of carbon dioxide exhaled (VCO2) during a cardiopulmonary exercise test (CPET). A reduction in the ratio is favorable, as it indicates that less breathed air is required to clear out the same amount of CO2.	Comparison of measure between baseline and treatment CPETs, typically ~14 days apart
Median Change in Ventilatory Efficiency up to Peak Exercise During CPET	Change from Baseline to postdose in the V̇E/V̇CO2 slope, a recognized measure of ventilatory efficiency, measured up to peak during CPET. VE/VCO2 tracks the ratio between total air breathed in per minute (VE) and the amount of carbon dioxide exhaled (VCO2) during a cardiopulmonary exercise test (CPET). A reduction in the ratio is favorable, as it indicates that less breathed air is required to clear out the same amount of CO2.	Comparison of measure between baseline and treatment CPETs, typically ~14 days apart

Other Outcome Measures

Outcome Measure	Measure Description	Time Frame
Responders for Peak VO2	A responder for peak VO2 is defined as any subject who exhibited any increase in peak V̇O2 during the treatment CPET versus the baseline CPET (i.e. change >0).	Comparison of measure between baseline and treatment CPETs, typically ~14 days apart

Collaborators and Investigators

• Sponsor: Respira Therapeutics, Inc.
• Investigators: Study Director: Ed Parsley, DO, Respira Therapeutics

Publications and helpful links

General Publications

• Benza RL, Franco V, Aras MA, Spikes L, Grinnan D, Satler C. Safety and efficacy of RT234 vardenafil inhalation powder on exercise parameters in pulmonary arterial hypertension: phase II, dose-escalation study design. Respir Res. 2022 Dec 17;23(1):355. doi: 10.1186/s12931-022-02262-9.

Study record dates

Study Major Dates

• Study Start (Actual): September 25, 2020
• Primary Completion (Actual): November 20, 2024
• Study Completion (Actual): January 7, 2025

Study Registration Dates

• First Submitted: January 22, 2020
• First Submitted That Met QC Criteria: February 10, 2020
• First Posted (Actual): February 12, 2020

Study Record Updates

• Last Update Posted (Actual): July 13, 2026
• Last Update Submitted That Met QC Criteria: June 17, 2026
• Last Verified: June 1, 2026

More Information

Terms related to this study

• Keywords: Cardiopulmonary Exercise Test; 6MWT
• Additional Relevant MeSH Terms: Respiratory Tract Diseases; Lung Diseases; Hypertension, Pulmonary; Pulmonary Arterial Hypertension; Molecular Mechanisms of Pharmacological Action; Enzyme Inhibitors; Vasodilator Agents; Urological Agents; Phosphodiesterase 5 Inhibitors; Phosphodiesterase Inhibitors; Vardenafil Dihydrochloride
• Other Study ID Numbers: RT234-PAH-CL202

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: NO

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: Yes
• Studies a U.S. FDA-regulated device product: Yes
• product manufactured in and exported from the U.S.: No