None listed
Conditions
Brief summary
The drawbacks of current therapies and the lack of an approved as needed (PRN) treatment for Pulmonary Arterial Hypertension (PAH) that improves exercise ability and quality of life, form the basis for development of RT234 (inhaled vardenafil). The current study will identify the effective dose(s) of RT234 to acutely improve pulmonary vascular haemodynamics when delivered in a dose escalation manner in subjects with World Health Organisation (WHO) Group 1 PAH undergoing right heart catheterisation (RHC). In addition, this study will also provide valuable efficacy and safety insights into the interactions between RT234 and background disease-specific PAH therapy on pulmonary haemodynamics and right heart function.
Interventions
This is an open label, phase 2a study evaluating the effect of inhaled RT234 (vardenafil inhalation powder) delivered in a dose escalation manner on the change in pulmonary vascular resistance (PVR) in subjects with PAH undergoing a right heart catheterisation (RHC). There are 3 dosing cohorts with two inhalation manoeuvres per dose. Cohort 1 - 200mcg (first dose), 600mcg (second dose) and 600mcg (third dose). Cohort 2 - 600mcg (first dose), 1200mcg (second dose) and 1200mcg (third dose). Cohort
This is an open label, phase 2a study evaluating the effect of inhaled RT234 (vardenafil inhalation powder) delivered in a dose escalation manner on the change in pulmonary vascular resistance (PVR) in subjects with PAH undergoing a right heart catheterisation (RHC). There are 3 dosing cohorts with two inhalation manoeuvres per dose. Cohort 1 - 200mcg (first dose), 600mcg (second dose) and 600mcg (third dose). Cohort 2 - 600mcg (first dose), 1200mcg (second dose) and 1200mcg (third dose). Cohort 3 - 1200mcg (first dose) and 2400mcg (second dose) and 2400mcg (third dose). After stabilisation of the catheter placement, subjects will receive a starting dose of RT234 with a second dose administered approximately 60 minutes after the first dose based on PVR response, safety and tolerability. Subjects will be assigned to each cohort based on the sequential time of their enrolment. The study will be conducted over 2 clinic visits (Day 1 - first and second dose; Day 15 - third dose) with phone assessments on Day 3 and Day 30 to evaluate safety. A cycle ergometry during RHC (exercise sub-study) will be conducted at one site to evaluate the effect of RT234 on exercise-related haemodynamics. Eligible subjects will undergo exercise assessments during the RHC, in addition to all other scheduled assessments. Exercise measurements will be obtained prior to dosing with RT234 and immediately after Dose 2 during the RHC procedure on Day 1. The cycle ergometry (submaximal exercise test) will be performed by the same site staff administering the RHC procedure. It is anticipated that the duration of the exercise phase will be at least 5 minutes, though preferably 8 to 10 minutes of exercise before the completion of the test.
Sponsors
Respira Therapeutics Australia Pty Ltd
Study design
Allocation
Non-randomised trial
Intervention model
Parallel
Primary purpose
Treatment
Masking
Open (masking not used)
Eligibility
Sex/Gender
All
Age
18 Years to 75 Years
Healthy volunteers
No
Inclusion criteria
1. Diagnosis of RHC-confirmed WHO Group 1 PAH in any of the following three categories: a) Idiopathic, primary or familial pulmonary arterial hypertension (IPAH, PPH, or FPAH); OR b) PAH associated with one of the following connective tissue diseases (CTD): i) Systemic sclerosis (scleroderma) ii) Limited scleroderma iii) Mixed connective tissue disease iv) Systemic lupus erythematosus v) Overlap syndrome; OR c) 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 one-year post-surgical repair. iii) Exposure to legal drugs, chemicals and toxins, such as fenfluramine, derivatives, other anorexigens, toxic rapeseed oil or L-tryptophan. 2. Previously diagnosed with PAH but with the following conditions: a) Stable PAH without significant adjustments of disease-specific background PAH therapy, at least 3 months prior to RHC procedure; b) If on corticosteroids, has been receiving a stable dose of less than or equal to 20 mg/day of prednisone (or equivalent dose of other corticosteroid) for at least 30 days prior to RHC procedure. 3. Pulmonary Function Tests (PFT) within 24 months prior to RHC procedure that fulfill the following criteria: a) Forced Expiratory volume in one second (FEV1) greater than or equal to 70% predicted (pre-bronchodilators); b) FEV1/forced expiratory vital capacity (FVC) greater than or equal to 70% and less than or equal to 90% (pre-bronchodilators); c) FVC greater than or equal to 70% predicted. 4. Females of childbearing potential must have a negative pregnancy test at Screening, Day 1 and Day 15 5. Females not of childbearing potential must be post-menopausal (defined as cessation of regular menstrual periods for at least 12 months) or have documented evidence of surgical sterilization at least 6 months prior to Screening.
Exclusion criteria
1. Baseline systemic hypotension, defined as MAP <50 mmHg or systolic blood pressure (SBP) <90 mmHg at Screening 2. Requirement of intravenous inotropes within 30 days prior to RHC procedure 3. Use of oral, topical or inhaled nitrates within 2 weeks prior to RHC procedure 4. Uncontrolled systemic hypertension: SBP >160 mmHg or diastolic blood pressure (DBP) >100 mmHg during Screening 5. History of portal hypertension or chronic liver disease, including active viral replication of hepatitis B and/or hepatitis C, or classified as having moderate to severe hepatic impairment (Child-Pugh Class B-C) 6. Chronic renal insufficiency as defined by serum creatinine >2.5 mg/dL at Screening or requires dialysis 7. History of atrial septostomy 8. Unrepaired congenital heart disease 9. Pericardial constriction; restrictive or congestive cardiomyopathy 10. History of left ventricular ejection fraction (EF) < 40% 11. Symptomatic coronary disease with demonstrable ischemia 12. Poorly controlled asthma 13. Clinically significant intercurrent illness or surgery within 30 days of Day 1 14. Known or suspected hypersensitivity or allergic reaction to vardenafil Clinical RHC <2 weeks from Screening 15. History of non-arteritic anterior ischemic optic neuropathy (NAION) or retinitis pigmentosa 16. QTcF) >450 msec on an electrocardiogram (ECG) at Screening.
Outcome results
None listed