A Healthy Volunteer Study Evaluating the the Safety, Tolerability, and Pharmacokinetics of RT234

Study Overview
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Brief Summary
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The objective of this two part study was to demonstrate safety, tolerability, and pharmacokinetics of RT234 in healthy volunteers. This study is also known as Vardenafil Inhaled for Pulmonary Arterial Hypertension PRN Phase 1 (VIPAH-PRN 1) study

Detailed Description
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This study was designed to evaluate safety and tolerability and to characterize the PK profiles of single and repeated doses of inhaled vardenafil as RT234. In addition, vardenafil PK after single 0.6 mg doses of RT234 was compared to that following administration of a single 20 mg dose of oral vardenafil tablets.

Official Title
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A Phase 1, Two-Part, Single-Center, Open-Label, Randomized, Cross-Over, Single Ascending Doses (SAD), Followed by a Multiple Ascending Doses (MAD) Safety and Pharmacokinetic Study of RT234 in Healthy Subjects

Conditions
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Healthy Volunteer

Intervention / Treatment
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* Combination Product: Drug: RT234 - vardenafil inhalation powder; Device: RS01 dry powder inhaler (RS01 DPI)
* Drug: Vardenafil Oral Tablet


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Healthy male or female, 18 to 45 years of age (inclusive at time of informed consent) Normal heart, lung, kidney, and liver function based on physical examination Systolic blood pressure of 100-145 mmHg, diastolic blood pressure of 50-90 mmHg, and a resting heart rate of 40-100 bpm at Screening A body mass index (BMI) of ≤18 to ≥30 kg/m2 at Screening Must be a non-smoker or ex-smoker with less than a 5-pack year history of smoking (including the use of electronic cigarettes) and have ceased smoking ≥1 year prior to Screening; or a social smoker (defined as less than 10 cigarettes in the previous 12 months) Exclusion Criteria: Has serum transaminase (i.e., alanine aminotransferase [ALT], aspartate aminotransferase [AST], or gamma-glutamyl transferase [GGT]) levels greater than three times the upper level of normal Abnormal orthostatic vital signs (at screening) defined as a decrease of ≥20 mmHg in systolic blood pressure and/or a decrease of ≥10 mmHg in diastolic blood pressure and/or >25 bpm increase in heart rate within 3 minutes of standing, or with symptoms of light-headedness, dizziness, or fainting upon standing. History of hypotension including fainting, syncope, orthostatic hypotension, and/or vasovagal reactions History of retinitis pigmentosa Vision loss due to non-arteritic anterior ischemic optic neuropathy (NAION) or other optic perfusion impairment History of priapism or anatomical deformation of the penis History of sudden sensorineural hearing loss (SSHL), need for hearing aids, and/or other documented hearing loss A corrected QT interval using Fridericia's formula (QTcF) >450 msec Has evidence of significant obstructive lung disease on spirometry. Subjects with any of the following criteria will be excluded: FEV1 <60% (predicted) (pre-bronchodilators); or FEV1/FVC <65% (pre-bronchodilators)

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 45 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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Accepts Healthy Volunteers

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: RT234 0.2 mg, Single Ascending Dose (SAD)<br>Part 1, SAD Cohort 1A | Combination Product: Drug: RT234 - vardenafil inhalation powder; Device: RS01 dry powder inhaler (RS01 DPI)<br>* RT234 is a drug/device combination product composed of vardenafil hydrochloride as the drug constituent and will utilize RS01 DPI device.<br>* Other names: vardenafil inhalation powder;|
| Experimental: RT234 0.6 mg followed by oral vardenafil 20mg on day 3, SAD<br>Part 1, SAD Cohort 2A1 | Combination Product: Drug: RT234 - vardenafil inhalation powder; Device: RS01 dry powder inhaler (RS01 DPI)<br>* RT234 is a drug/device combination product composed of vardenafil hydrochloride as the drug constituent and will utilize RS01 DPI device.<br>* Other names: vardenafil inhalation powder;Drug: Vardenafil Oral Tablet<br>* 20 mg oral vardenafil tablet.<br>* Other names: Levitra;|
| Experimental: Oral vardenafil 20mg followed by RT234 0.6 mg on day 3, SAD<br>Part 1, SAD Cohort 2A2 | Combination Product: Drug: RT234 - vardenafil inhalation powder; Device: RS01 dry powder inhaler (RS01 DPI)<br>* RT234 is a drug/device combination product composed of vardenafil hydrochloride as the drug constituent and will utilize RS01 DPI device.<br>* Other names: vardenafil inhalation powder;Drug: Vardenafil Oral Tablet<br>* 20 mg oral vardenafil tablet.<br>* Other names: Levitra;|
| Experimental: RT234 1.2 mg, SAD<br>Part 1, SAD Cohort 3A | Combination Product: Drug: RT234 - vardenafil inhalation powder; Device: RS01 dry powder inhaler (RS01 DPI)<br>* RT234 is a drug/device combination product composed of vardenafil hydrochloride as the drug constituent and will utilize RS01 DPI device.<br>* Other names: vardenafil inhalation powder;|
| Experimental: RT234 2.4 mg, SAD<br>Part 1, SAD Cohort 4A | Combination Product: Drug: RT234 - vardenafil inhalation powder; Device: RS01 dry powder inhaler (RS01 DPI)<br>* RT234 is a drug/device combination product composed of vardenafil hydrochloride as the drug constituent and will utilize RS01 DPI device.<br>* Other names: vardenafil inhalation powder;|
| Experimental: RT234 2.4 mg, Multiple Ascending Dose (MAD)<br>Part 2, MAD Cohort 1B | Combination Product: Drug: RT234 - vardenafil inhalation powder; Device: RS01 dry powder inhaler (RS01 DPI)<br>* RT234 is a drug/device combination product composed of vardenafil hydrochloride as the drug constituent and will utilize RS01 DPI device.<br>* Other names: vardenafil inhalation powder;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Number of participants with treatment related adverse events as assessed by CTCAE v5.0 | Adverse events reported by participants and those observed by the investigator in relation to laboratory tests, vital signs, ECGs, medications used to treat adverse events, and physical examinations were analyzed. | Up to to 10 days | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Peak plasma concentration (Cmax) | Cmax was measured for 4 single doses of oral vardenafil. | Up to 10 days | 
| Time to reach maximum concentration (Tmax) | Tmax was measured for 4 single doses of oral vardenafil. | Up to 10 days | 
| Area under the curve (AUC) | AUC was measured for 4 single doses of RT234 | Up to 10 days | 
| Half life (t1/2) | t1/2 was measured for 4 single doses of RT234 | Up to 10 days | 
| Terminal elimination rate constant (Kel) | Kel was measured for 4 single doses of RT234 | Up to 10 days | 
| Total body clearance (CL/F) | CL/F was measured for 4 single doses of RT234 | Up to 10 days | 
| Total volume of distribution at the terminal phase | measured for 4 single doses of RT234 | Up to 10 days | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Pulmonary Arterial Hypertension, Familial Primary Pulmonary Hypertension, Vascular Diseases, Cardiovascular Diseases, Hypertension, Pulmonary, Lung Diseases, Respiratory Tract Diseases, Vardenafil Dihydrochloride, Inhaled Vardenafil, Vasodilator Agents, Phosphodiesterase 5 Inhibitors, Phosphodiesterase Inhibitors, Enzyme Inhibitors, Molecular Mechanisms of Pharmacological Action