ANZCTR - Registration

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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

26/10/2021

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]

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

Condition category

Condition code

Cardiovascular

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]

Treatment: Drugs

Intervention code [2]

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]

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]

Screening to Day 30.

Primary outcome [2]

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]

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]

Maximal change from baseline in pulmonary vascular resistance (PVR) assessed at the time by right heart catheterisation (RHC).

Timepoint [3]

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]

Time (in minutes) to maximum PVR decrease as assessed at the time by RHC.

Timepoint [1]

Secondary outcome [2]

Change from baseline in mean pulmonary artery pressure (mPAP) as assessed at the time by RHC.

Timepoint [2]

Secondary outcome [3]

Change from baseline in transpulmonary gradient as assessed at the time by RHC.

Timepoint [3]

Secondary outcome [4]

Change from baseline in cardiac output (CO)/cardiac index (CI) as assessed at the time by RHC.

Timepoint [4]

Secondary outcome [5]

Change from baseline in systemic blood pressure.

Timepoint [5]

Secondary outcome [6]

Change from baseline in systemic vascular resistance (SVR) as assessed at the time by RHC.

Timepoint [6]

Secondary outcome [7]

Change from baseline in right ventricular (RV) systolic pressure as assessed at the time by RHC.

Timepoint [7]

At baseline and 120 minutes post second RT234 dose on Day 1.

Secondary outcome [8]

Change in baseline in mixed venous blood gas parameters measured by a blood gas analyser.

Timepoint [8]

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]

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]

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]

Change from screening six minute walk distance (6MWD).

Timepoint [10]

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

Sex

Both males and females

Can healthy volunteers participate?

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

Stopped early

Data analysis

Data analysis is complete

Reason for early stopping/withdrawal

Other reasons/comments

Other reasons

Recruitment of the last study participant was stopped early due to COVID-19 concerns.

Date of first participant enrolment

Anticipated

Actual

31/07/2019

Date of last participant enrolment

Anticipated

29/11/2019

Actual

12/12/2019

Date of last data collection

Anticipated

30/12/2019

Actual

17/01/2020

Sample size

Target

Accrual to date

Final

Recruitment in Australia

Recruitment state(s)

NSW,TAS,VIC

Recruitment hospital [1]

St Vincent's Hospital (Darlinghurst) - Darlinghurst

Recruitment hospital [2]

The Alfred - Prahran

Recruitment hospital [3]

Royal Hobart Hospital - Hobart

Recruitment postcode(s) [1]

2010 - Darlinghurst

Recruitment postcode(s) [2]

3004 - Prahran

Recruitment postcode(s) [3]

7000 - Hobart

Funding & Sponsors

Funding source category [1]

Commercial sector/Industry

Name [1]

Respira Therapeutics Australia Pty Ltd

Address [1]

C/- HLB Mann Judd
Level 15, Central Plaza Two
66 Eagle Street
Brisbane QLD 4000

Country [1]

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]

None

Name [1]

Address [1]

Country [1]

Ethics approval

Ethics application status

Approved

Ethics committee name [1]

St Vincent's Hospital Sydney HREC

Ethics committee address [1]

St Vincent's Hospital Health Network
97-105 Boundary Street
Darlinghurst NSW 2010

Ethics committee country [1]

Australia

Date submitted for ethics approval [1]

21/02/2019

Approval date [1]

03/05/2019

Ethics approval number [1]

Ethics committee name [2]

Tasmania Health and Medical HREC

Ethics committee address [2]

Research Ethics and Integrity Unit
Office of Research Services
Private Bag 1
Hobart TAS 7001

Ethics committee country [2]

Australia

Date submitted for ethics approval [2]

16/05/2019

Approval date [2]

04/06/2019

Ethics approval number [2]

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

Prof Anne Keogh

Address

St Vincent's Hospital Sydney
Heart/Lung Transplant Unit
Level 4, Xavier Building
390 Victoria Street
Darlinghurst NSW 2010

Country

Australia

Phone

+61 2 8382 3723

Fax

[email protected]

Contact person for public queries

Name

Kevin Corkery

Address

Respira Therapeutics Inc
1828 El Camino Real
No.806
Burlingame, CA 94010

Country

United States of America

Phone

+1 650 231 2804

Fax

[email protected]

Contact person for scientific queries

Name

Edwin Parsley

Address

Respira Therapeutics Inc, 5901 Indian School Road NE, Albuquerque NM 87110

Country

United States of America

Phone

+1 713 899 2450

Fax

[email protected]

Data sharing statement

Will individual participant data (IPD) for this trial be available (including data dictionaries)?

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 Supporting Document Provided

Results publications and other study-related documents

Documents added manually

No documents have been uploaded by study researchers.

Documents added automatically

No additional documents have been identified.

Trial Review

Documents added manually

Documents added automatically