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

• ClinicalTrials.gov Identifier: NCT04266197
• Recruitment Status: Recruiting
• First Posted: February 12, 2020
• Last Update Posted: February 10, 2023
• Sponsor: Respira Therapeutics, Inc.
• Information provided by (Responsible Party): Respira Therapeutics, Inc.

Tracking Information

• First Submitted Date: January 22, 2020
• First Posted Date: February 12, 2020
• Last Update Posted Date: February 10, 2023
• Actual Study Start Date: September 25, 2020
• Estimated Primary Completion Date: December 2023 (Final data collection date for primary outcome measure)

Current Primary Outcome Measures (submitted: April 2, 2022)

• Incidence and severity of Treatment-Emergent Adverse Events (TEAEs) [ Time Frame: From baseline to follow-up day 15 post-treatment ]
  TEAEs as grouped by MedDRA system organ class and relationship to treatment.
• Change in Vital Signs [ Time Frame: From baseline to follow-up day 15 post-treatment ]
  This variable will include mean arterial blood pressure expressed in mmHg (calculated utilizing recorded systolic and diastolic blood pressures in mmHg).
• Change in peak oxygen consumption (VO2) assessed by CPET [ Time Frame: From baseline to 15 minutes post-treatment ]
  This variable will be assessed by ventilatory expired gas analysis during exercise testing and will be expressed in ml/ kg/min. Mean values from baseline to post-treatment will be compared.

Original Primary Outcome Measures (submitted: February 10, 2020)

• Incidence and severity of Treatment-Emergent Adverse Events (TEAEs) [ Time Frame: From screening to follow-up day 5 post-treatment CPET ]
  TEAEs as grouped by MedDRA system organ class and relationship to treatment.
• Change in Blood Pressure [ Time Frame: From screening to follow-up day 5 post-treatment CPET ]
  This variable will include mean arterial blood pressure expressed in mmHg (calculated utilizing recorded systolic and diastolic blood pressures in mmHg).
• Change in peak oxygen consumption (VO2) assessed by CPET [ Time Frame: Baseline CPET to post-treatment CPET at 7 to 14 days following Baseline CPET ]
  This variable will be assessed by ventilatory expired gas analysis during exercise testing and will be expressed in ml/kg/min. Mean values from baseline to post-treatment will be compared.
• Change in Patient Global Impression of Severity (PGI-S) from baseline to post dose. [ Time Frame: Baseline CPET to post-treatment CPET at 7 to 14 days following Baseline CPET ]
  The PGI-S score is a self-rating scale to evaluate Shortness of Breath, Physical Fatigue, and Overall Symptom Severity.
• Change in minute ventilation to carbon dioxide production (VE/VCO2) slope [ Time Frame: Baseline CPET to post-treatment CPET at 7 to 14 days following Baseline CPET ]
  This variable will be assessed by ventilatory expired gas analysis during exercise testing and will be expressed as a slope value. Mean values from baseline to post-treatment will be compared.
• Change in PETCO2 apex response to exercise from baseline to post dose [ Time Frame: Baseline CPET to post-treatment CPET at 7 to 14 days following Baseline CPET ]
  This variable will be assessed by ventilatory expired gas analysis during exercise testing and will be expressed in mmHg. Mean values from baseline to post-treatment will be compared.
• Change in duration of exercise during CPET from baseline to post dose [ Time Frame: Baseline CPET to post-treatment CPET at 7 to 14 days following Baseline CPET ]
  This variable will be assessed during exercise testing and will be expressed in seconds. Mean values from baseline to post-treatment will be compared.

Current Secondary Outcome Measures (submitted: April 2, 2022)

Change in 6-minute walk distance (6MWD) [ Time Frame: From baseline to 15 minutes post-treatment ]

Change from mean Screening in 6MWD when 6-minute walk test (6MWT) is performed 15 minutes post-RT234 dosing.

Original Secondary Outcome Measures (submitted: February 10, 2020)

• The proportion of subjects with improvement in risk category (i.e., low, intermediate, high) for VE/VCO2 slope criteria. [ Time Frame: Baseline CPET to post-treatment CPET at 7 to 14 days following Baseline CPET ]
  As defined in the European Society of Cardiology (ESC)/European Respiratory Society (ERS) Guidelines for the diagnosis and treatment of pulmonary hypertension.
• Change in Modified Borg Dyspnea Score [ Time Frame: Baseline CPET to post-treatment CPET at 7 to 14 days following Baseline CPET ]
  The Modified Borg dyspnea score is a self-rating scale to evaluate the severity of dyspnea (from 0 "no breathlessness at all" to 10 "very, very severe / maximal"). It will be assessed every minute during exercise testing and 6-minutes in to recovery. Mean values from baseline to post-treatment will be compared.
• Change in Borg Rating of Perceived Exertion (RPE) Score [ Time Frame: Baseline CPET to post-treatment CPET at 7 to 14 days following Baseline CPET ]
  The Borg RPE score is a self-rating scale to evaluate the severity of fatigue (from 6 "no exertion at all" to 20 "maximal exertion"). It will be assessed every 2-minutes during exercise testing and 6-minutes in to recovery. Mean values from baseline to post-treatment will be compared.
• Change in oxygen consumption (VO2) at ventilatory threshold (VT) assessed by CPET [ Time Frame: Baseline CPET to post-treatment CPET at 7 to 14 days following Baseline CPET ]
  This variable will be assessed by ventilatory expired gas analysis during exercise testing and will be expressed in ml/kg/min. Mean values from baseline to post-treatment will be compared.
• Change in Oxygen Uptake Efficiency Slope (OUES) [ Time Frame: Baseline CPET to post-treatment CPET at 7 to 14 days following Baseline CPET ]
  This variable will be assessed by ventilatory expired gas analysis during exercise testing and will be expressed as a slope value. Mean values from baseline to post-treatment will be compared.
• Change in Respiratory Exchange Ratio (RER) [ Time Frame: Baseline CPET to post-treatment CPET at 7 to 14 days following Baseline CPET ]
  This variable will be assessed by ventilatory expired gas analysis during exercise testing and will be expressed as a ratio. Mean values from baseline to post-treatment will be compared.
• Change in Systolic Blood Pressure (SBP) response to exercise from baseline to post dose [ Time Frame: Baseline CPET to post-treatment CPET at 7 to 14 days following Baseline CPET ]
  This variable will be assessed during exercise testing and will be expressed in mmHg. It will be assessed every 2-minutes during exercise testing and 6-minutes in to recovery. Mean values from baseline to post-treatment will be compared.
• Change in pulse oximetry response to exercise from baseline to post dose [ Time Frame: Baseline CPET to post-treatment CPET at 7 to 14 days following Baseline CPET ]
  This variable will be assessed during exercise testing and will be expressed as a percentage (%). It will be assessed every minute during exercise testing and 6-minutes in to recovery. Mean values from baseline to post-treatment will be compared.
• Change in atrial arrhythmia frequency during exercise from baseline to post dose [ Time Frame: Baseline CPET to post-treatment CPET at 7 to 14 days following Baseline CPET ]
  This variable will be assessed by electrocardiogram (ECG) during exercise testing. It will be assessed continuously during exercise testing and 6-minutes in to recovery. Frequency of atrial arrhythmias from baseline to post-treatment will be compared.
• Change in ventricular arrhythmia frequency during exercise from baseline to post dose [ Time Frame: Baseline CPET to post-treatment CPET at 7 to 14 days following Baseline CPET ]
  This variable will be assessed by electrocardiogram (ECG) during exercise testing. It will be assessed continuously during exercise testing and 6-minutes in to recovery. Frequency of ventricular arrhythmias from baseline to post-treatment will be compared.

• Current Other Pre-specified Outcome Measures: Not Provided

Original Other Pre-specified Outcome Measures (submitted: February 10, 2020)

Change in Duke Activity Status Index (DASI) [ Time Frame: Baseline CPET to post-treatment CPET at 7 to 14 days following Baseline CPET ]

The DASI is a a self-rating questionnaire that allows for an estimation of a subject's perceived exercise capacity.

Descriptive Information

• Brief Title: Vardenafil Inhaled for Pulmonary Arterial Hypertension PRN Phase 2B Study
• Official Title: A Phase 2b, Open-label, Single Dose Study to Evaluated the Safety and Efficacy of RT234 on Exercise Parameters Assessed by Cardiopulmonary Exercise Testing (CPET) in Subjects With Pulmonary Arterial Hypertension (PAH)
• Brief Summary: The objectives of this study are to evaluate the effects of RT234 on exercise parameters assessed by a specialized exercise test (Cardiopulmonary Exercise Test or CPET) in patients with pulmonary arterial hypertension (PAH).
• Detailed Description: Consequences of PAH are 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 lower the sensation of dyspnea with physical exertion compared to baseline CPET measures.
• Study Type: Interventional
• Study Phase: Phase 2
• Study Design: Allocation: Non-Randomized; Intervention Model: Sequential Assignment; Masking: None (Open Label); Primary Purpose: Treatment
• Condition: Pulmonary Arterial Hypertension

Intervention

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 Name: inhaled vardenafil

Study Arms

• Experimental: RT234 0.5 mg Cohort 1
  RT234 at a capsule dose strength of 0.5 mg.
  Intervention: Combination Product: Drug: RT234 - vardenafil inhalation powder; Device: Axially Oscillating Sphere dry powder inhaler (AOS DPI)
• Experimental: RT234 1.0 mg Cohort 2
  RT234 at a capsule dose strength of 1.0 mg.
  Intervention: Combination Product: Drug: RT234 - vardenafil inhalation powder; Device: Axially Oscillating Sphere dry powder inhaler (AOS DPI)

• Publications *: Not Provided

Recruitment Information

• Recruitment Status: Recruiting
• Estimated Enrollment (submitted: October 27, 2022): 86
• Original Estimated Enrollment (submitted: February 10, 2020): 20
• Estimated Study Completion Date: April 2024
• Estimated Primary Completion Date: December 2023 (Final data collection date for primary outcome measure)

Eligibility Criteria

Inclusion Criteria:

1. Ages 18 and 80 years, inclusive.

2. Diagnosis of 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
   3. PAH associated with: i. Human immunodeficiency virus (HIV) infection with no evidence of opportunistic infection in the preceding 6 months; ii. Simple, congenital systemic-to-pulmonary shunts at least 1-year post-surgical repair; iii. Exposure to legal drugs, chemicals and toxins, such as fenfluramine, derivatives, other anorexigens, toxic rapeseed oil, or L-tryptophan.
3. The patient must have had a ventilation/perfusion (V/Q) scan, computerized tomography angiogram, or pulmonary arteriogram that rules out chronic thromboembolic pulmonary hypertension (CTEPH).

4. Previous diagnosis with 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 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 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.
5. PFT within 6 months prior to the baseline CPET.
6. Has had RHC performed prior to Screening which is consistent with the diagnosis of PAH.
7. Has WHO/NYHA functional class II-IV symptomatology.
8. On stable oral PAH disease-specific background therapy of up to 3 oral therapies (any combination of an ERA, PDE5 inhibitor, and/or a prostacyclin or prostacyclin receptor agonist) and/or inhaled therapy. 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 within 1 month of Screening.
9. Must be able to walk a distance of at least 150 meters on the 6MWT. This will be determined using the mean of the two 6MWT results done between Visits 1 and 2.

10. 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
    2. Anticoagulants

Exclusion Criteria:

1. Baseline systemic hypotension defined as MAP < 50 mmHg or SBP < 90 mmHg at Screening.
2. History of chronic uncontrolled asthma.
3. Requirement of intravenous inotropes therapies within 30 days prior to the baseline CPET procedure.
4. Use of PAH medications that are not taken by mouth.
5. Use of oral, topical, or inhaled nitrates within 2 weeks prior to the baseline CPET procedure.
6. Has uncontrolled systemic hypertension
7. 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 allowed.
8. Evidence or history of left-sided heart disease and/or clinically significant cardiac disease.
9. History of atrial septostomy.
10. History of known uncorrected right-to-left shunt, clinically significant persistently patent foramen ovale, or known Eisenmenger's physiology.
11. Paroxysmal or uncontrolled atrial fibrillation.
12. Diagnosis of Down syndrome.
13. 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.
14. Serum alanine aminotransferase (ALT) or aspartate aminotransferase (AST) value that is ≥3 x the upper limit of the normal range.
15. Platelets below 50,000/μL at Screening.
16. Hemoglobin (Hgb) concentration < 9 g/dL at Screening.

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

    1. Concomitant active opportunistic infections within 6 months prior to Screening;
    2. Detectable viral load within 3 months of Screening;
    3. CD4+ T-cell count < 200/mm^3 within 3 months prior to Screening;
    4. Changes in antiretroviral regimen within 3 months prior to Screening.
18. Malignancy within 5 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.
19. 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 electrocardiogram (ECG) measured at Screening.
23. Participation in a drug, device, or other interventional clinical study, other than post-marketing observational extension study, within 30 days prior to Screening.
24. Participation in the active phase (other than the maintenance phase) of a pulmonary rehabilitation/structured exercise training program within 6 months prior to Screening.

Sex/Gender

• Sexes Eligible for Study: All

• Ages: 18 Years to 80 Years (Adult, Older Adult)
• Accepts Healthy Volunteers: No

Contacts

Contact: Study Director; 646-224-4901; csatler@respiratherapeutics.com

• Listed Location Countries: United States
• Removed Location Countries: Serbia

Administrative Information

• NCT Number: NCT04266197
• Other Study ID Numbers: RT234-PAH-CL202
• Has Data Monitoring Committee: Yes

U.S. FDA-regulated Product

• Studies a U.S. FDA-regulated Drug Product: Yes
• Studies a U.S. FDA-regulated Device Product: Yes
• Device Product Not Approved or Cleared by U.S. FDA: Yes

IPD Sharing Statement

• Plan to Share IPD: No

• Current Responsible Party: Respira Therapeutics, Inc.
• Original Responsible Party: Same as current
• Current Study Sponsor: Respira Therapeutics, Inc.
• Original Study Sponsor: Same as current
• Collaborators: Not Provided
• Investigators: Not Provided
• PRS Account: Respira Therapeutics, Inc.
• Verification Date: August 2022