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Trial registered on ANZCTR


Registration number
ACTRN12618002056279
Ethics application status
Approved
Date submitted
19/12/2018
Date registered
21/12/2018
Date last updated
18/06/2019
Date data sharing statement initially provided
21/12/2018
Type of registration
Prospectively registered

Titles & IDs
Public title
Effect of heart rate reduction on kidney, eye and skin complications of type 2 diabetes mellitus study
Scientific title
IvaBRADine to reduce renal, retinal and skin mICrovasculAR complications of type 2 DIAbetes mellitus (BRADiCARDIA) study
Secondary ID [1] 296876 0
Nil known
Universal Trial Number (UTN)
U1111-1225-5144
Trial acronym
BRADiCARDIA
Linked study record

Health condition
Health condition(s) or problem(s) studied:
Type 2 diabetes mellitus 310802 0
Condition category
Condition code
Metabolic and Endocrine 309477 309477 0 0
Diabetes

Intervention/exposure
Study type
Interventional
Description of intervention(s) / exposure
The ivaBRADine to reduce mICrovasculAR complications of type 2 DIAbetes mellitus (BRADiCARDIA) study is a prospective randomised open blinded end-point (PROBE) design trial. This study examines the hypothesis that heart rate reduction improves, or reduces the progression of, microvascular (dys)function in patients with type 2 diabetes mellitus. The study will randomise 50 patients with type 2 diabetes mellitus 1:1 (25 given ivabradine 5 mg twice daily increasing to 7.5 mg twice daily in addition to standard care in the intervention group vs 25 given standard care in the control group) for 90 days. Study personnel who conducts assessments will be unaware of treatment allocation (blinded assessment).

Clinical data, medications, estimated glomerular filtration rate (GFR), urinary albumin creatinine ratio (UACR), retinal imaging and skin micro-vessel function tests (laser Doppler assessment and 3-D forearm skin optical coherence tomography (OCT) examinations at rest and during maximal hyperaemia) will be undertaken and recorded at baseline (pre-intervention). UACR will be the average of three first void urine samples taken on three separate days in the week prior to commencing treatment and separate from the ‘screening’ measures which would have been conducted to determine eligibility. After baseline assessments, study participants in the intervention group will commence on ivabradine 5 mg twice daily (t=0). Patients will be reviewed at 30 (±3) days (t=30), and if the participant is tolerating their medication and their heart rate is above 60 bpm, treatment will be increased to ivabradine 7.5 mg twice daily. After 90 (±3) days (t=90), patients will attend for their final visit. Patients will be requested to bring three first morning void urine samples collected on three separate days in the prior week for their 90-day UACR. Patients will also undergo further retinal imaging, laser Doppler assessment and skin OCT examination. Clinical data, medications and GFR will be re-assessed. Information will be collected on the tolerability of the study medication and reported compliance. A pill count of remaining study medication will also be recorded.
Intervention code [1] 313153 0
Treatment: Drugs
Comparator / control treatment
Participants in the control group will not receive ivabradine. These patients will still receive routine standard care, including scheduled visits to their regular clinicians and medications or therapies for the management of their other medical conditions.
Control group
Active

Outcomes
Primary outcome [1] 308437 0
Renal function: change in urinary albumin creatinine ratio (average of three first-void urine samples taken on three separate days in the week prior to commencing treatment and final visit).
Timepoint [1] 308437 0
Baseline and at 90 days after intervention commencement
Secondary outcome [1] 354959 0
Retinal: change in retinal microvascular structure/pattern from retinal imaging
Timepoint [1] 354959 0
Baseline and at 90 days after intervention commencement
Secondary outcome [2] 354960 0
Skin: change in skin micro-vessel function/structure from laser Doppler and 3-D optical coherence tomography
Timepoint [2] 354960 0
Baseline and at 90 days after intervention commencement

Eligibility
Key inclusion criteria
Patients with type 2 diabetes mellitus (T2DM), plus all of the following:
• albuminuria (UACR > 2.5 mg/mmol in men, > 3.5 mg/mmol in women), documented on at least two out of three first void morning urine samples; and
• resting heart rate (HR) of > 70 bpm on two consecutive electrocardiograms (ECGs) at least 24 hours apart and with the second of these < 24 hours before randomisation; and
• in sinus rhythm with no history of atrial fibrillation; and
• stable treatment of T2DM and hypertension for a minimum of three months (HbA1c < 8.5% and BP less than or equal to 140/90); and
• optimal and stable treatment of coronary heart disease and/or heart failure for a minimum of three months (to minimise risk of titration of other medications that might impact on UACR and HR).
Minimum age
18 Years
Maximum age
No limit
Gender
Both males and females
Can healthy volunteers participate?
No
Key exclusion criteria
Patients with:
• current treatment with or previous intolerance of ivabradine; or
• current treatment with diltiazem or verapamil (contraindicated by manufacturer); or
• transplanted heart, implanted pacemaker, cardioverter-defibrillator or cardiac resynchronization therapy; or
• scheduled for coronary revascularization, or likely to require surgery for valvular disease; or
• sick sinus syndrome, sinoatrial block, congenital long QT, 2nd degree and complete atrio-ventricular block; or
• abnormal serum creatinine (> 200 mol/L), transaminases (> 3 x ULN), or haemoglobin (men < 110 g/L, women < 100 g/L); or
• pregnant, lactating or women of childbearing age not using contraception.

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)
The research assistant who will be recruiting and consenting the participants will be unaware of the allocation (intervention vs control). Allocation will be concealed using sealed opaque envelope that will only be opened once the enrolment process is complete.
Methods used to generate the sequence in which subjects will be randomised (sequence generation)
Simple randomisation using a randomisation table created by computer software (i.e. computerised sequence generation).
Masking / blinding
Open (masking not used)
Who is / are masked / blinded?


The people assessing the outcomes
Intervention assignment
Parallel
Other design features
Phase
Phase 2
Type of endpoint(s)
Efficacy
Statistical methods / analysis
The number of participants was determined based on the timing and the funding available for this project. This is a pilot study to provide preliminary information regarding the potential benefit of ivabradine in this setting and the likely effect size. These data would be used to design an adequately powered trial. The change in primary outcome will be calculated for each participant from baseline to day-90.. The mean change for each group will be compared using Student's t-test.

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)
WA
Recruitment hospital [1] 12721 0
Royal Perth Hospital - Perth
Recruitment hospital [2] 12722 0
Fiona Stanley Hospital - Murdoch
Recruitment postcode(s) [1] 25148 0
6000 - Perth
Recruitment postcode(s) [2] 25149 0
6150 - Murdoch

Funding & Sponsors
Funding source category [1] 301445 0
Charities/Societies/Foundations
Name [1] 301445 0
Heart Foundation
Address [1] 301445 0
334 Rokeby Rd, Subiaco WA 6008
Country [1] 301445 0
Australia
Primary sponsor type
Hospital
Name
Royal Perth Hospital
Address
197 Wellington St, Perth WA 6000
Country
Australia
Secondary sponsor category [1] 301134 0
University
Name [1] 301134 0
Curtin University
Address [1] 301134 0
Kent St, Bentley WA 6102
Country [1] 301134 0
Australia

Ethics approval
Ethics application status
Approved
Ethics committee name [1] 302180 0
Royal Perth Hospital Human Research Ethics Committee
Ethics committee address [1] 302180 0
Level 2, Kirkman House
Royal Perth Hospital
10 Murray Street, PERTH WA 6000
Ethics committee country [1] 302180 0
Australia
Date submitted for ethics approval [1] 302180 0
23/01/2019
Approval date [1] 302180 0
30/05/2019
Ethics approval number [1] 302180 0
RGS0000003099

Summary
Brief summary
The ivaBRADine to reduce mICrovasculAR complications of type 2 DIAbetes mellitus (BRADICARDIA) study is a prospective randomised open blinded
end-point (PROBE) design trial funded by a Heart Foundation Vanguard Grant. It will test the hypothesis that heart rate reduction improves (or reduces progression of) microvascular complications in type 2 diabetes mellitus. It will randomise 50 patients with type 2 diabetes mellitus 1:1 to ivabradine (in the intervention group) or no treatment/standard care (in the control group). Ivabradine works selectively on the sino-atrial node to slow heart rate without any other significant haemodynamic effects. The primary outcome will be change in urinary albumin creatinine ratio (UACR, the average of three first-void urine samples). The secondary outcomes will be change in retinal microvascular structure/pattern from retinal imaging and skin micro-vessel function using the laser Doppler and 3-D optical coherence tomography (OCT) techniques. These outcomes will be measured at baseline and at 90 days post intervention commencement.
Trial website
Trial related presentations / publications
Public notes

Contacts
Principal investigator
Name 89390 0
Prof Graham Hillis
Address 89390 0
Department of Cardiology,
4, South Block, Royal Perth Hospital,
197 Wellington Street, Perth, WA, 6000
Country 89390 0
Australia
Phone 89390 0
+61892243180
Fax 89390 0
Email 89390 0
graham.hillis@health.wa.gov.au
Contact person for public queries
Name 89391 0
Dr Tin Fei Sim
Address 89391 0
Building 306, School of Pharmacy and Biomedical Sciences,
Curtin University,
Kent Street, Bentley WA 6102
Country 89391 0
Australia
Phone 89391 0
+61892663812
Fax 89391 0
Email 89391 0
T.Sim@curtin.edu.au
Contact person for scientific queries
Name 89392 0
Prof Graham Hillis
Address 89392 0
Department of Cardiology,
4, South Block, Royal Perth Hospital,
197 Wellington Street, Perth, WA, 6000
Country 89392 0
Australia
Phone 89392 0
+61892243180
Fax 89392 0
Email 89392 0
graham.hillis@health.wa.gov.au

Data sharing statement
Will individual participant data (IPD) for this trial be available (including data dictionaries)?
No
No/undecided IPD sharing reason/comment
Due to the low number of participants, sharing IPD carries a significant risk of compromising patient confidentiality.
What supporting documents are/will be available?
No other documents available
Summary results
No Results