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Trial registered on ANZCTR


Registration number
ACTRN12620001349932
Ethics application status
Approved
Date submitted
30/09/2020
Date registered
14/12/2020
Date last updated
14/12/2020
Date data sharing statement initially provided
14/12/2020
Type of registration
Prospectively registered

Titles & IDs
Public title
Assessing the effect of mirabegron to treat high blood pressure in the lungs
Scientific title
Acute Haemodynamic Study of Mirabegron in Pulmonary Arterial Hypertension: Effect on Pulmonary Vascular Resistance
Secondary ID [1] 302439 0
N/A
Universal Trial Number (UTN)
U1111-1258-9683
Trial acronym
BEAT-PH (BEta3 adrenergic AgonisT in Pulmonary Hypertension)
Linked study record
N/A

Health condition
Health condition(s) or problem(s) studied:
Pulmonary Hypertension 319255 0
Right heart failure 319256 0
Condition category
Condition code
Cardiovascular 317224 317224 0 0
Hypertension
Respiratory 317617 317617 0 0
Other respiratory disorders / diseases
Cardiovascular 317618 317618 0 0
Other cardiovascular diseases

Intervention/exposure
Study type
Interventional
Description of intervention(s) / exposure
Participants in Part A of the study will receive 25 mg Mirabegron as a single oral dose at the hospital.

In Part B, 50 mg Mirabegron will be given orally as a single dose at the hospital. Mirabegron will then be continued as a daily dose for 8 days as an outpatient. The adherence in the outpatient setting in Part B will be monitored by drug tablet return.

Part B of the study will commence after completion of Part A, if Mirabegron is proven to be safely tolerated by patients in Part A.

Inclusion and exclusion criteria are the same for Part A and B of the study.
Intervention code [1] 318724 0
Treatment: Drugs
Comparator / control treatment
This study is single-arm, and open label where the response in pulmonary vascular resistance to the study drug Mirabegron will be compared to the response to inhaled nitric oxide (10-50 ppm administered for 15 minutes) in the same subject. Mirabegron will be given orally 30 minutes after completion of nitric oxide vasoreactivity testing.
Control group
Active

Outcomes
Primary outcome [1] 325289 0
Changes in pulmonary vascular resistance post-mirabegron administration assessed by right heart catheterisation compared with the changes in pulmonary vascular resistance post-inhalation of nitric oxide assessed by right heart catheterisation in the same subject (composite outcome).
Timepoint [1] 325289 0
Change in pulmonary vascular resistance 15 minutes after nitric oxide administration and then hourly for 6 hours post-mirabegron administration,
Secondary outcome [1] 387413 0
o compare changes in mean pulmonary artery pressure from baseline with Mirabegron to changes in mean pulmonary arterial pressure with inhaled nitric oxide assessed by right heart catheterisation in the same subject (composite outcome).
Timepoint [1] 387413 0
15 minutes after nitric oxide administration and then hourly for 6 hours post-mirabegron administration
Secondary outcome [2] 388718 0
To measure the plasma levels of Mirabegron.

Timepoint [2] 388718 0
Hourly for 6 hours post-mirabegron administration
Secondary outcome [3] 388719 0
To assess the effects of short-term administration of Mirabegron (8 days) on estimated pulmonary arterial pressure as assessed by tricuspid regurgitation jet velocity on echocardiography.
Timepoint [3] 388719 0
At baseline and after 8 days of daily treatment with Mirabegorn (50 mg).
Secondary outcome [4] 388720 0
To compare changes in cardiac output from baseline with Mirabegron to changes in cardiac output with inhaled nitric oxide assessed by right heart catheterisation.
Timepoint [4] 388720 0
15 minutes after nitric oxide administration and then hourly for 6 hours post-mirabegron administration,
Secondary outcome [5] 388721 0
To compare the effects of Mirabegron with inhaled nitric oxide on pulmonary capillary wedge pressure assessed by right heart catheterisation
Timepoint [5] 388721 0
Hourly for 6 hours post-Mirabegron administration
Secondary outcome [6] 388722 0
To assess the effects of short-term administration of Mirabegron (8 days) on estimated pulmonary arterial pressure as assessed by pulmonary acceleration time on echocardiography.
Timepoint [6] 388722 0
At baseline and after 8 days of treatment with Mirabegron (50 mg daily)
Secondary outcome [7] 389815 0
To compare changes in cardiac output from baseline with Mirabegron to changes in cardiac output with inhaled nitric oxide assessed by right heart catheterisation.
Timepoint [7] 389815 0
15 minutes after nitric oxide administration and then hourly for 6 hours post-mirabegron administration,

Eligibility
Key inclusion criteria
We will enrol patients with a diagnosis of PH that fulfil all of the following criteria:
A- PH due to following aetiologies/diagnostic classifications:
- Group 1 pulmonary hypertension
- Chronic pulmonary hypertension due to inoperable small distal pulmonary emboli (also known as CTEPH

AND
B-The patient is:
-PH treatment naïve or,
-on an endothelin receptor antagonist (ERA) (Bosentan, Macitentan or Ambrisentan) as monotherapy, or,
- on combination therapy with an ERA (Bosentan, Macitentan or Ambrisentan) plus an agent in the NO pathway (Sildenafil, Tadalafil or Riociguat) when the NO-related therapy can be safely withheld in short-term
AND
C-The right heart catheterisation is clinically indicated.
AND
D- The participant does not meet any of the exclusion criteria
Minimum age
19 Years
Maximum age
80 Years
Gender
Both males and females
Can healthy volunteers participate?
No
Key exclusion criteria
• Significant hepatic (transaminases or bilirubin x 3 above upper reference level) or renal impairment (GFR< 30 ml/min/1,73 m2).
• Significant hypotension (defined as symptomatic systolic blood pressure < 80 mmHg) or hypertension (defined as systolic >180 mmHg and/or diastolic blood pressure >110 mmHg).
• Right heart failure defined with PH associated with systemic venous congestion and fluid retention (e.g. peripheral oedema, ascites)
• Left heart failure (LVEF <50% and clinical signs of left heart failure).
• Severe interstitial lung disease with forced vital capacity (FVC) < 70%
• Congenital or drug-induced QT prolongation.
• Patients with known bladder outlet obstruction and patients taking antimuscarinic medications for overactive bladder syndrome.
• Anaemic patients with Hb <100 mg/dL and iron deficiency or gastrointestinal bleed within 6 months.
• Treatment with a tricyclic antidepressant or CYP2D6 substrates other than beta-blockers or treatment with digoxin.
• Pregnancy in female participants : female subjects of childbearing potential must have a pregnancy test performed with negative results known within 7 days prior to the index procedure.
• Breast feeding in female participants: female subject is not breastfeeding at the time of the screening visit and will not be breast-feeding at the time of the study.
• Subject has participated in another study during the 30 days preceding the current study.
• Hypersensitivity(allergic reaction) to inhaled nitric oxide
• Subject is part of a vulnerable population who, in the judgment of the investigator, is unable to give Informed Consent for reasons of incapacity, immaturity, adverse personal circumstances or lack of autonomy.This may include: Individuals with mental disability, persons in nursing homes, children, impoverished persons, persons in emergency situations, homeless persons, nomads, refugees, and those incapable of giving informed consent. Vulnerable populations also may include members of a group with a hierarchical structure such as university students, subordinate hospital and laboratory personnel, members of the armed forces, and persons kept in detention.


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)
N/A
Methods used to generate the sequence in which subjects will be randomised (sequence generation)
N/A
Masking / blinding
Open (masking not used)
Who is / are masked / blinded?



Intervention assignment
Single group
Other design features
N/A
Phase
Phase 4
Type of endpoint(s)
Safety/efficacy
Statistical methods / analysis
We will compare the baseline haemodynamics to haemodynamics after administration of Mirabegron in the same subject (i.e. a paired comparison). Based on our pre-clinical data, and assuming similar haemodynamic efficacy of Mirabegron at 25 mg or 50 mg to Riociguat at 1 mg or 2.5 mg, we calculate the following sample size for Mirabegron at two different doses.
• Part A: Mirabegron 25 mg – with a predicted reduction in PVR by 18% compared with 3% change with inhaled NO (effect size or delta PVR=15%), SD (delta)=12, N=5 would provide 80% power to detect a statistically significant difference with a two-tailed alpha =0.05.

• Part B: Mirabegron 50 mg – with a predicted reduction in PVR of 28% compared with 3% change with inhaled NO (effect size or delta PVR=25%), SD(delta)=22, N=6 would provide 80% power to detect a statistically significant difference with a two-tailed alpha =0.05


Recruitment
Recruitment status
Not yet 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
Recruitment hospital [1] 17711 0
Royal Prince Alfred Hospital - Camperdown
Recruitment postcode(s) [1] 31566 0
2050 - Camperdown

Funding & Sponsors
Funding source category [1] 306863 0
Government body
Name [1] 306863 0
NSW Health - Office of Health and Medical Research
Address [1] 306863 0
1 Reserve Road
St Leonards NSW 2065
Australia
Country [1] 306863 0
Australia
Primary sponsor type
Hospital
Name
Royal Prince Alfred Hospital
Address
Royal Prince Alfred Hospital, 50 Missenden Rd, Camperdown NSW 2050
Country
Australia
Secondary sponsor category [1] 307424 0
None
Name [1] 307424 0
Address [1] 307424 0
Country [1] 307424 0

Ethics approval
Ethics application status
Approved
Ethics committee name [1] 307021 0
Sydney Local Health District - RPA Hospital
Ethics committee address [1] 307021 0
Research Ethics & Governance Office | Royal Prince Alfred Hospital
50 Missenden Rd, Camperdown NSW 2050
Ethics committee country [1] 307021 0
Australia
Date submitted for ethics approval [1] 307021 0
06/04/2020
Approval date [1] 307021 0
21/07/2020
Ethics approval number [1] 307021 0
X20-0143 & 2020/ETH00812

Summary
Brief summary
Pulmonary hypertension (PH) is a disease in which blood pressure in lung circulation is abnormally high. PH remains highly-debilitating and deadly – half of patients may die within 5-years of diagnosis. Therefore, new PH treatments are urgently needed.

This project builds on discovery by our group that medications working through "beta3 adrenergic receptors" reduce blood pressure in lung circulation of laboratory animals. This study aims to assess the safety and effect of mirabegron - a medication from this family that is used for overactive bladder in Australia – in adult patients with PH.

We will administer mirabegron at the hospital and closely monitor the patients. We will measure the blood pressure in the lung circulation using special catheters that are routinely used for this purpose. If mirabegron is safe and effective, we will prescribe it for 8 days and assess the effects by ultrasound of heart in follow-up.
Trial website
N/A
Trial related presentations / publications
N/A
Public notes

Contacts
Principal investigator
Name 105766 0
Dr Keyvan Karimi Galougahi
Address 105766 0
Department of Cardiology, Royal Prince Alfred Hospital, 50 Missenden Rd, Camperdown NSW 2050
Country 105766 0
Australia
Phone 105766 0
+61 2 9515 7929
Fax 105766 0
Email 105766 0
keyvan.karimi@gmail.com
Contact person for public queries
Name 105767 0
Dr Keyvan Karimi Galougahi
Address 105767 0
Department of Cardiology, Royal Prince Alfred Hospital, 50 Missenden Rd, Camperdown NSW 2050
Country 105767 0
Australia
Phone 105767 0
+61 2 9515 7929
Fax 105767 0
Email 105767 0
keyvan.karimi@gmail.com
Contact person for scientific queries
Name 105768 0
Dr Keyvan Karimi Galougahi
Address 105768 0
Department of Cardiology, Royal Prince Alfred Hospital, 50 Missenden Rd, Camperdown NSW 2050
Country 105768 0
Australia
Phone 105768 0
+61 2 9515 7929
Fax 105768 0
Email 105768 0
keyvan.karimi@gmail.com

Data sharing statement
Will individual participant data (IPD) for this trial be available (including data dictionaries)?
No
No/undecided IPD sharing reason/comment
We will publish the summary of data in peer reviewed journals and not the IPD.
What supporting documents are/will be available?
No other documents available
Summary results
No Results