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Trial registered on ANZCTR


Registration number
ACTRN12622000671763
Ethics application status
Approved
Date submitted
21/04/2022
Date registered
9/05/2022
Date last updated
28/06/2023
Date data sharing statement initially provided
9/05/2022
Type of registration
Prospectively registered

Titles & IDs
Public title
Can Mineralocorticoid Receptor Antagonism Counteract Cardiometabolic Long-term Effects of Steroids? (MiRACCLES study)
Scientific title
Can Mineralocorticoid Receptor Antagonism Counteract Cardiometabolic Long-term Effects of Steroids in Females on Long-Term Glucocorticoid Therapy? (MiRACCLES study)
Secondary ID [1] 306723 0
nil
Universal Trial Number (UTN)
Trial acronym
MiRACCLES Study
Linked study record

Health condition
Health condition(s) or problem(s) studied:
Cardiometabolic complications of excess glucocorticoid exposure 325909 0
Condition category
Condition code
Metabolic and Endocrine 323221 323221 0 0
Metabolic disorders
Cardiovascular 323222 323222 0 0
Other cardiovascular diseases

Intervention/exposure
Study type
Interventional
Description of intervention(s) / exposure
Arm 1 - oral spironolactone capsule 100mg daily for 12 weeks in a double-blind RCT followed by an open label phase comprising treatment with oral spironolactone capsule 100mg daily x another 12 weeks
Intervention code [1] 323289 0
Treatment: Drugs
Comparator / control treatment
Arm 2: oral placebo (microcrystalline cellulose) capsule 1 daily for 12 weeks in a double-blind RCT followed by an open label phase comprising treatment with oral spironolactone capsule 100mg daily x another 12 weeks
Control group
Placebo

Outcomes
Primary outcome [1] 331145 0
Change in total body fat mass on dual-energy X-ray absorptiometry (DEXA)
Timepoint [1] 331145 0
baseline, 12 weeks post intervention commencement (primary endpoint) and 24 weeks post intervention commencement
Primary outcome [2] 331146 0
Change in left ventricular (LV) systolic function as assessed by global longitudinal strain (GLS) on echocardiogram
Timepoint [2] 331146 0
baseline, 12 weeks post intervention commencement (primary endpoint) and 24 weeks post intervention commencement
Secondary outcome [1] 408981 0
Change in insulin resistance as assessed by Homeostatic model assessment (HOMA-IR)
Timepoint [1] 408981 0
baseline, 12 weeks post intervention commencement and 24 weeks post intervention commencement
Secondary outcome [2] 408982 0
Change in whole-body insulin sensitivity assessed by Matsuda index from a 75-gram oral glucose tolerance test
Timepoint [2] 408982 0
baseline, 12 weeks post intervention commencement and 24 weeks post intervention commencement
Secondary outcome [3] 408984 0
Change in diastolic function assessed by peak early diastolic velocity (Em) and the ratio of mitral inflow early diastolic velocity to peak early diastolic mitral annular velocity (E/e’) on echocardiogram
Timepoint [3] 408984 0
baseline, 12 weeks post intervention commencement and 24 weeks post intervention commencement
Secondary outcome [4] 408985 0
Changes in myocardial strain and fibrosis estimated by integrated backscatter on echocardiogram
Timepoint [4] 408985 0
baseline, 12 weeks post intervention commencement and 24 weeks post intervention commencement
Secondary outcome [5] 408986 0
Changes in monocyte, dendritic cell, T cell activation markers, macrophage polarisation, phagocytosis and cytokine production assessed by flow cytometry in peripheral blood
Timepoint [5] 408986 0
baseline, 12 weeks post intervention commencement
Secondary outcome [6] 408987 0
Changes in serum inflammatory markers (Interleukin-6, tumour necrosis factor-a, C-reactive protein) measured by Enzyme-Linked Immunosorbent Assay (ELISA)
Timepoint [6] 408987 0
baseline, 12 weeks post intervention commencement
Secondary outcome [7] 408990 0
change in fasting serum lipids
Timepoint [7] 408990 0
baseline, 12 weeks post intervention commencement and 24 weeks post intervention commencement
Secondary outcome [8] 408992 0
change in serum HbA1C
Timepoint [8] 408992 0
baseline, 12 weeks post intervention commencement and 24 weeks post intervention commencement

Eligibility
Key inclusion criteria
(i) female
(ii) age at least 18 years
(iii) requiring glucocorticoids (GC) therapy (equivalent to at least 7.5mg/day of prednisolone average) for at least the next 3 months
(iv) on nil or stable other systemic immunomodulatory drugs
Minimum age
18 Years
Maximum age
No limit
Sex
Females
Can healthy volunteers participate?
No
Key exclusion criteria
any of the following -
(i) upright systolic blood pressure <100 mmHg
(ii) estimated glomerular filtration rate (eGFR) less than 60 ml/min
(iii) serum potassium more than 5mmol/L in a non-haemolysed blood sample
(iv) thyroid or endocrine dysfunction, other than diabetes
(v) significant organ dysfunction such as heart failure, liver failure
(vi) moderate-severe valvular or unstable ischaemic heart disease or rhythm disturbances

(vii) active malignancy
(viii) transplant recipient
(ix) undertaking a weight loss regimen or history of previous bariatric surgery
(x) pregnant or planning pregnancy, or not willing to use effective birth control measures throughout the study period while sexually active in a heterosexual relationship and of reproductive age
(xi) unable to provide informed consent

Study design
Purpose of the study
Treatment
Allocation to intervention
Randomised controlled trial
Procedure for enrolling a subject and allocating the treatment (allocation concealment procedures)
Sealed opaque envelopes
Methods used to generate the sequence in which subjects will be randomised (sequence generation)
Stratified randomisation in 1:1 ratio according to age (>50 years or younger), BMI (>30 kg/m2 or lower), average dosage of GC (>25mg/day of prednisolone equivalent or lower dosage) and duration of prior GC treatment (>3 months preceding the enrolment or shorter duration).
Masking / blinding
Blinded (masking used)
Who is / are masked / blinded?
The people receiving the treatment/s
The people administering the treatment/s
The people assessing the outcomes
The people analysing the results/data
Intervention assignment
Other
Other design features
A 12 week parallel randomised phase, followed by a single group open label phase where the same participants from both the intervention and placebo groups proceed to receive the intervention for a further 12 weeks.
Phase
Phase 2
Type of endpoint/s
Efficacy
Statistical methods / analysis
Sample size of 60 is estimated to detect a significant (P<0.05, 2-sided) difference in fat mass of 1 ± 0.95kg (mean ± standard deviation) and GLS of 10 ± 10% between the placebo and spironolactone arms with 90% power, assuming a drop-out rate of 20%.
The differences in outcomes from baseline after spironolactone vs that after placebo will be compared using 2-tailed t-test or ANOVA as appropriate.

Recruitment
Recruitment status
Not yet recruiting
Date of first participant enrolment
Anticipated
3/07/2023
Actual
Date of last participant enrolment
Anticipated
Actual
Date of last data collection
Anticipated
Actual
Sample size
Target
60
Accrual to date
Final
Recruitment in Australia
Recruitment state(s)
QLD

Funding & Sponsors
Funding source category [1] 311054 0
Government body
Name [1] 311054 0
Metro South Research Support Scheme - Study, Education and Research Trust, Metro South Health
Country [1] 311054 0
Australia
Primary sponsor type
Individual
Name
Dr Moe Thuzar
Address
Princess Alexandra Hospital
199 Ipswich Road, Woolloongabba, Brisbane, Queensland 4102
Country
Australia
Secondary sponsor category [1] 312384 0
Hospital
Name [1] 312384 0
Princess Alexandra Hospital, Metro South Health
Address [1] 312384 0
199 Ipswich Road, Woolloongabba, Brisbane, Queensland 4102
Country [1] 312384 0
Australia
Secondary sponsor category [2] 312652 0
University
Name [2] 312652 0
University of Queensland
Address [2] 312652 0
Translational Research Institute
37 Kent Street, Woolloongabba, Brisbane, Queensland 4102
Country [2] 312652 0
Australia
Secondary sponsor category [3] 312653 0
Individual
Name [3] 312653 0
Professor Michael Stowasser
Address [3] 312653 0
Princess Alexandra Hospital
199 Ipswich Road, Woolloongabba, Brisbane, Queensland 4102
Country [3] 312653 0
Australia

Ethics approval
Ethics application status
Approved
Ethics committee name [1] 310600 0
Metro South Human Research Ethics Committee
Ethics committee address [1] 310600 0
Translational Research Institute
37 Kent Street, Woolloongabba, Brisbane, Queensland 4102
Ethics committee country [1] 310600 0
Australia
Date submitted for ethics approval [1] 310600 0
22/04/2022
Approval date [1] 310600 0
24/06/2022
Ethics approval number [1] 310600 0

Summary
Brief summary
Metabolic syndrome and cardiovascular diseases (CVDs) represent the major cause of
morbidity and mortality globally. According to the World Health Organisation, more people die annually from CVDs than from any other cause. Hormones underpin the pathophysiological changes surrounding the disease progression. Steroids such as prednisolone are one of the most widely prescribed and effective therapeutics for a variety of inflammatory and autoimmune conditions including inflammatory arthritis, arteritis, asthma, sarcoidosis and nephritis due to their powerful anti-inflammatory effects, but benefits are limited by serious cardiometabolic adverse effects. To date, there is no established specific means to counteract the cardiometabolic complications. There is strong evidence in animals that the adverse cardiometabolic effects of steroids are mediated by closely-related hormone receptors called mineralocorticoid receptors (MRs) which are present on fat cells, heart and immune cells, and that blockade of MRs (MR antagonism) protects against steroid-induced cardiometabolic complications while maintaining the anti-inflammatory benefit. This body of work will define, for the first time in humans, the therapeutic potential of MR antagonism to counteract steroid-induced adverse metabolic and cardiac complications, and provide novel evidence for paradigm shifts in the management of patients exposed to excess steroids.
Trial website
Trial related presentations / publications
Public notes

Contacts
Principal investigator
Name 118218 0
Dr Moe Thuzar
Address 118218 0
Department of Endocrinology & Diabetes
Princess Alexandra Hospital
199 Ipswich Road, Woolloongabba, Brisbane, Queensland 4102
Country 118218 0
Australia
Phone 118218 0
+61 7 31761062
Fax 118218 0
Email 118218 0
m.thuzar@uq.edu.au
Contact person for public queries
Name 118219 0
Dr Moe Thuzar
Address 118219 0
Department of Endocrinology & Diabetes
Princess Alexandra Hospital
199 Ipswich Road, Woolloongabba, Brisbane, Queensland 4102
Country 118219 0
Australia
Phone 118219 0
+61 7 31762111
Fax 118219 0
Email 118219 0
m.thuzar@uq.edu.au
Contact person for scientific queries
Name 118220 0
Dr Moe Thuzar
Address 118220 0
Department of Endocrinology & Diabetes
Princess Alexandra Hospital
199 Ipswich Road, Woolloongabba, Brisbane, Queensland 4102
Country 118220 0
Australia
Phone 118220 0
+61 7 31762111
Fax 118220 0
Email 118220 0
m.thuzar@uq.edu.au

Data sharing statement
Will individual participant data (IPD) for this trial be available (including data dictionaries)?
No
No/undecided IPD sharing reason/comment
Only group data will be reported to public


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.