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Trial registered on ANZCTR


Registration number
ACTRN12619001178134
Ethics application status
Approved
Date submitted
30/07/2019
Date registered
20/08/2019
Date last updated
18/10/2019
Date data sharing statement initially provided
20/08/2019
Type of registration
Retrospectively registered

Titles & IDs
Public title
To identify the effective dose(s) of RT234 (vardenafil inhalation powder) to acutely improve pulmonary vascular haemodynamics in study participants with Pulmonary Arterial Hypertension (PAH).
Scientific title
A Dose Escalation Study to Evaluate the Effect of RT234 on Cardiopulmonary Haemodynamics in Subjects with Pulmonary Arterial Hypertension.
Secondary ID [1] 298594 0
RT234-CL201
Universal Trial Number (UTN)
U1111-1214-5515
Trial acronym
None
Linked study record
Not applicable

Health condition
Health condition(s) or problem(s) studied:
Pulmonary Arterial Hypertension 313441 0
Condition category
Condition code
Cardiovascular 311876 311876 0 0
Other cardiovascular diseases

Intervention/exposure
Study type
Interventional
Description of intervention(s) / exposure
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.
Intervention code [1] 314854 0
Treatment: Drugs
Intervention code [2] 314855 0
Treatment: Devices
Comparator / control treatment
The comparator cohort is the individual subject's baseline haemodynamic profile established prior to administration of inhaled RT234.
Control group
Dose comparison

Outcomes
Primary outcome [1] 320717 0
Evaluation of adverse events (AEs) will be measured by clinical examination and participant self-reporting. Known or possible adverse events include headache, lightheadedness and cough.
Timepoint [1] 320717 0
Screening to Day 30.

Primary outcome [2] 320718 0
Change in baseline plasma Pharmacokinetic (PK) measures (Cmax, Tmax, AUC, terminal half-life) of drug exposure at each dose level on Day 1.
Timepoint [2] 320718 0
At baseline, 5, 15, 30, 45 and 60 minutes post-end of inhalation for the first RT234 dose and at 5, 15, 30, 45, 60, 75, 90, 105 and 120 minutes post-end of inhalation for the second RT234 dose.
Primary outcome [3] 320719 0
Maximal change from baseline in pulmonary vascular resistance (PVR) assessed at the time by right heart catheterisation (RHC).
Timepoint [3] 320719 0
At baseline, 5, 15, 30, 45 and 60 minutes post-end of inhalation for the first RT234 dose and at 5, 15, 30, 45, 60, 75, 90, 105 and 120 minutes post-end of inhalation for the second RT234 dose on Day 1.
Secondary outcome [1] 372596 0
Time (in minutes) to maximum PVR decrease as assessed at the time by RHC.
Timepoint [1] 372596 0
At baseline, 5, 15, 30, 45 and 60 minutes post-end of inhalation for the first RT234 dose and at 5, 15, 30, 45, 60, 75, 90, 105 and 120 minutes post-end of inhalation for the second RT234 dose on Day 1.
Secondary outcome [2] 372598 0
Change from baseline in mean pulmonary artery pressure (mPAP) as assessed at the time by RHC.
Timepoint [2] 372598 0
At baseline, 5, 15, 30, 45 and 60 minutes post-end of inhalation for the first RT234 dose and at 5, 15, 30, 45, 60, 75, 90, 105 and 120 minutes post-end of inhalation for the second RT234 dose on Day 1.
Secondary outcome [3] 372599 0
Change from baseline in transpulmonary gradient as assessed at the time by RHC.
Timepoint [3] 372599 0
At baseline, 5, 15, 30, 45 and 60 minutes post-end of inhalation for the first RT234 dose and at 5, 15, 30, 45, 60, 75, 90, 105 and 120 minutes post-end of inhalation for the second RT234 dose on Day 1.
Secondary outcome [4] 372600 0
Change from baseline in cardiac output (CO)/cardiac index (CI) as assessed at the time by RHC.
Timepoint [4] 372600 0
At baseline, 5, 15, 30, 45 and 60 minutes post-end of inhalation for the first RT234 dose and at 5, 15, 30, 45, 60, 75, 90, 105 and 120 minutes post-end of inhalation for the second RT234 dose on Day 1.
Secondary outcome [5] 373510 0
Change from baseline in systemic blood pressure.
Timepoint [5] 373510 0
At baseline, 5, 15, 30, 45 and 60 minutes post-end of inhalation for the first RT234 dose and at 5, 15, 30, 45, 60, 75, 90, 105 and 120 minutes post-end of inhalation for the second RT234 dose on Day 1.
Secondary outcome [6] 373511 0
Change from baseline in systemic vascular resistance (SVR) as assessed at the time by RHC.
Timepoint [6] 373511 0
At baseline, 5, 15, 30, 45 and 60 minutes post-end of inhalation for the first RT234 dose and at 5, 15, 30, 45, 60, 75, 90, 105 and 120 minutes post-end of inhalation for the second RT234 dose on Day 1.
Secondary outcome [7] 373512 0
Change from baseline in right ventricular (RV) systolic pressure as assessed at the time by RHC.
Timepoint [7] 373512 0
At baseline and 120 minutes post second RT234 dose on Day 1.
Secondary outcome [8] 373513 0
Change in baseline in mixed venous blood gas parameters measured by a blood gas analyser.
Timepoint [8] 373513 0
At baseline pre-first RT234 dose, 15 minutes post first RT234 dose, baseline pre-second RT234 dose and 15 minutes post second RT234 dose on Day 1.
Secondary outcome [9] 373514 0
Change from baseline in exercise haemodynamics (sub-study only) systemic systolic pressure, systemic diastolic pressure, mean arterial pressure, pulmonary artery systolic pressure, pulmonary artery diastolic pressure, mPAP, pulmonary capillary wedge pressure, mean right atrial pressure and mixed venous oxygen saturation as assessed at the time by RHC.
Timepoint [9] 373514 0
At baseline pre-first RT234 dose and 10 minutes post second RT234 dose on Day 1. If the subject does not receive a second dose of RT234, the second exercise measurement will be performed post first RT234 dose.
Secondary outcome [10] 373518 0
Change from screening six minute walk distance (6MWD).
Timepoint [10] 373518 0
Screening and at 10 minutes post RT234 dosing on Day 15.

Eligibility
Key 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.







Minimum age
18 Years
Maximum age
75 Years
Gender
Both males and females
Can healthy volunteers participate?
No
Key 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.


Study design
Purpose of the study
Treatment
Allocation to intervention
Non-randomised trial
Procedure for enrolling a subject and allocating the treatment (allocation concealment procedures)
Allocation is not concealed
Methods used to generate the sequence in which subjects will be randomised (sequence generation)
Masking / blinding
Open (masking not used)
Who is / are masked / blinded?



Intervention assignment
Parallel
Other design features
Phase
Phase 2
Type of endpoint(s)
Safety/efficacy
Statistical methods / analysis
Descriptive statistics (for example, arithmetic mean, standard deviation, median, minimum and maximum) will be summarized using mean, standard deviation, median, minimum and maximum and categorical data will be summarized using frequencies and percentages. Data will be summarized at protocol-specified time points overall and by dose. Adverse events and other safety endpoint will be summarized.

No formal hypothesis testing will be performed for this study.

Recruitment
Recruitment status
Recruiting
Date of first participant enrolment
Anticipated
Actual
Date of last participant enrolment
Anticipated
Actual
Date of last data collection
Anticipated
Actual
Sample size
Target
Accrual to date
Final
Recruitment in Australia
Recruitment state(s)
NSW,TAS,VIC
Recruitment hospital [1] 14274 0
St Vincent's Hospital (Darlinghurst) - Darlinghurst
Recruitment hospital [2] 14275 0
The Alfred - Prahran
Recruitment hospital [3] 14276 0
Royal Hobart Hospital - Hobart
Recruitment postcode(s) [1] 27270 0
2010 - Darlinghurst
Recruitment postcode(s) [2] 27271 0
3004 - Prahran
Recruitment postcode(s) [3] 27272 0
7000 - Hobart

Funding & Sponsors
Funding source category [1] 303136 0
Commercial sector/Industry
Name [1] 303136 0
Respira Therapeutics Australia Pty Ltd
Address [1] 303136 0
C/- HLB Mann Judd
Level 15, Central Plaza Two
66 Eagle Street
Brisbane QLD 4000
Country [1] 303136 0
Australia
Primary sponsor type
Commercial sector/Industry
Name
Respira Therapeutics Australia Pty Ltd
Address
C/- HLB Mann Judd
Level 15, Central Plaza Two
66 Eagle Street
Brisbane QLD 4000
Country
Australia
Secondary sponsor category [1] 303312 0
None
Name [1] 303312 0
Address [1] 303312 0
Country [1] 303312 0

Ethics approval
Ethics application status
Approved
Ethics committee name [1] 303685 0
St Vincent's Hospital Sydney HREC
Ethics committee address [1] 303685 0
St Vincent's Hospital Health Network
97-105 Boundary Street
Darlinghurst NSW 2010
Ethics committee country [1] 303685 0
Australia
Date submitted for ethics approval [1] 303685 0
21/02/2019
Approval date [1] 303685 0
03/05/2019
Ethics approval number [1] 303685 0
Ethics committee name [2] 303843 0
Tasmania Health and Medical HREC
Ethics committee address [2] 303843 0
Research Ethics and Integrity Unit
Office of Research Services
Private Bag 1
Hobart TAS 7001
Ethics committee country [2] 303843 0
Australia
Date submitted for ethics approval [2] 303843 0
16/05/2019
Approval date [2] 303843 0
04/06/2019
Ethics approval number [2] 303843 0

Summary
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.
Trial website
Trial related presentations / publications
Public notes

Contacts
Principal investigator
Name 94486 0
Prof Anne Keogh
Address 94486 0
St Vincent's Hospital Sydney
Heart/Lung Transplant Unit
Level 4, Xavier Building
390 Victoria Street
Darlinghurst NSW 2010
Country 94486 0
Australia
Phone 94486 0
+61 2 8382 3723
Fax 94486 0
Email 94486 0
Anne.Keogh@svha.org.au
Contact person for public queries
Name 94487 0
Ms Mari Maurer
Address 94487 0
Respira Therapeutics Inc
1828 El Camino Real
No.806
Burlingame, CA 94010
Country 94487 0
United States of America
Phone 94487 0
+1 415 827 6713
Fax 94487 0
Email 94487 0
mmaurer@respiratherapeutics.com
Contact person for scientific queries
Name 94488 0
Dr Edwin Parsley
Address 94488 0
Respira Therapeutics Inc
1828 El Camino Real
No.806
Burlingame, CA 94010
Country 94488 0
United States of America
Phone 94488 0
+1 713 899 2450
Fax 94488 0
Email 94488 0
eparsley@respiratherapeutics.com

Data sharing statement
Will individual participant data (IPD) for this trial be available (including data dictionaries)?
No
No/undecided IPD sharing reason/comment
This is a hemodynamic and pharmacokinetic study and the individual participant data will not be valuable to the participants or to others outside of the sponsor.
What supporting documents are/will be available?
No other documents available
Summary results
No Results