Vardenafil Inhaled for Pulmonary Arterial Hypertension PRN Phase 2B Study

Study Overview
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Brief Summary
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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
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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.

Official Title
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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)

Conditions
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Pulmonary Arterial Hypertension

Intervention / Treatment
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* Combination Product: Drug: RT234 - vardenafil inhalation powder; Device: Axially Oscillating Sphere dry powder inhaler (AOS DPI)


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Ages 18 and 80 years, inclusive. Diagnosis of Right Heart Catheterization (RHC)-confirmed WHO Group 1 PAH in any of the following 3 categories: Idiopathic, primary, or familial pulmonary arterial hypertension (IPAH, PPH, or FPAH) OR 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 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. 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). Previous diagnosis with PAH, but with the following conditions: 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 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. PFT within 6 months prior to the baseline CPET. Has had RHC performed prior to Screening which is consistent with the diagnosis of PAH. Has WHO/NYHA functional class II-IV symptomatology. 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. 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. 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. Vasodilators Anticoagulants Exclusion Criteria: Baseline systemic hypotension defined as MAP < 50 mmHg or SBP < 90 mmHg at Screening. History of chronic uncontrolled asthma. Requirement of intravenous inotropes therapies within 30 days prior to the baseline CPET procedure. Use of PAH medications that are not taken by mouth. Use of oral, topical, or inhaled nitrates within 2 weeks prior to the baseline CPET procedure. Has uncontrolled systemic hypertension 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. Evidence or history of left-sided heart disease and/or clinically significant cardiac disease. History of atrial septostomy. History of known uncorrected right-to-left shunt, clinically significant persistently patent foramen ovale, or known Eisenmenger's physiology. Paroxysmal or uncontrolled atrial fibrillation. Diagnosis of Down syndrome. 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. Serum alanine aminotransferase (ALT) or aspartate aminotransferase (AST) value that is ≥3 x the upper limit of the normal range. Platelets below 50,000/μL at Screening. Hemoglobin (Hgb) concentration < 9 g/dL at Screening. For subjects with HIV-associated PAH, any of the following: Concomitant active opportunistic infections within 6 months prior to Screening; Detectable viral load within 3 months of Screening; CD4+ T-cell count < 200/mm^3 within 3 months prior to Screening; Changes in antiretroviral regimen within 3 months prior to Screening. 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. History of hypotension including fainting, syncope, orthostatic hypotension, and/or vasovagal reactions. Vision loss due to non-arteritic anterior ischemic optic neuropathy or other optic perfusion impairment. History of sudden sensorineural hearing loss. 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. Participation in a drug, device, or other interventional clinical study, other than post-marketing observational extension study, within 30 days prior to Screening. Participation in the active phase (other than the maintenance phase) of a pulmonary rehabilitation/structured exercise training program within 6 months prior to Screening.

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 80 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

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


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: RT234 0.5 mg Cohort 1<br>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)<br>* RT234 capsules of a dry powder formulation containing vardenafil administered via oral inhalation with a non-invasive AOS DPI.<br>* Other names: inhaled vardenafil;|
| Experimental: RT234 1.0 mg Cohort 2<br>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)<br>* RT234 capsules of a dry powder formulation containing vardenafil administered via oral inhalation with a non-invasive AOS DPI.<br>* Other names: inhaled vardenafil;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Incidence and severity of Treatment-Emergent Adverse Events (TEAEs) | TEAEs as grouped by MedDRA system organ class and relationship to treatment. | From baseline to follow-up day 15 post-treatment | 
| Change in Vital Signs | This variable will include mean arterial blood pressure expressed in mmHg (calculated utilizing recorded systolic and diastolic blood pressures in mmHg). | From baseline to follow-up day 15 post-treatment | 
| Change in peak oxygen consumption (VO2) assessed by 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. | From baseline to 15 minutes post-treatment | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change in 6-minute walk distance (6MWD) | Change from mean Screening in 6MWD when 6-minute walk test (6MWT) is performed 15 minutes post-RT234 dosing. | From baseline to 15 minutes post-treatment | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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6MWT, Cardiopulmonary Exercise Test