Trial Review

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Trial registered on ANZCTR


Registration number
ACTRN12622000978763
Ethics application status
Approved
Date submitted
7/07/2022
Date registered
11/07/2022
Date last updated
2/11/2022
Date data sharing statement initially provided
11/07/2022
Type of registration
Prospectively registered

Titles & IDs
Public title
SGLT2 Inhibition with Empagliflozin on Metabolic, Cardiac and Renal Outcomes in Recent Cardiac Transplant Recipients
Scientific title
SGLT2 Inhibition with Empagliflozin on Metabolic, Cardiac and Renal Outcomes in Recent Cardiac Transplant Recipients
Secondary ID [1] 307157 0
Nil known
Universal Trial Number (UTN)
U1111-1278-3639
Trial acronym
EMPA-HTx
Linked study record

Health condition
Health condition(s) or problem(s) studied:
Cardiac transplant 326361 0
Diabetes 326362 0
Renal disease 326363 0
Condition category
Condition code
Cardiovascular 323661 323661 0 0
Other cardiovascular diseases
Metabolic and Endocrine 323662 323662 0 0
Diabetes
Renal and Urogenital 323663 323663 0 0
Kidney disease

Intervention/exposure
Study type
Interventional
Description of intervention(s) / exposure
Empagliflozin orally 10mg daily for 46 weeks. Empagliflozin film coated tablet encapsulated inside a hard gelatin capsule to match placebo.
Strategies to monitor adherence include a study medication diary, and return of the drug bottle.
Intervention code [1] 323613 0
Treatment: Drugs
Comparator / control treatment
Placebo capsule; StarCap 1500, a proprietary mix from Colorcon; Maize Starch & Pregelatinised Maize Starch.
Control group
Placebo

Outcomes
Primary outcome [1] 331408 0
Change in glycaemia defined as change in serum HbA1c and/or fructosamine from baseline, collected via blood test.
Timepoint [1] 331408 0
Primary timepoint: 12 months post cardiac transplantation (46 weeks after randomisation); with measure of HbA1c also collected at 3, 6, 9 after transplantation; and fructosamine measurement also collected every 1 month from randomisation until 12 months post-transplant
Secondary outcome [1] 409748 0
Mean change in left ventricular interstitial fibrosis and mass as assessed by Cardiovascular Magnetic Resonance (CMR) from baseline
Timepoint [1] 409748 0
Baseline and 46 weeks after randomisation
Secondary outcome [2] 409749 0
Mean change in eGFR from baseline, with data collected via serum blood test.
Timepoint [2] 409749 0
Primary timepoint is 46 weeks after randomisation, with measurement reviewed monthly
Secondary outcome [3] 409750 0
Development of diabetes defined as HbA1c >/=6.5%, and/or fasting plasma glucose (FPG) >/=7.0 mmol/L; or clinically diagnosed by treating physician; serum results collected via blood test or clinical diagnosis through medical records.
Timepoint [3] 409750 0
Primary timepoint will be at 46 weeks after randomisation
Secondary outcome [4] 409751 0
Number of hospitalisations for any reason, as assessed by medical records review and discussion with participant on history taking at follow up appointments.
Timepoint [4] 409751 0
46 weeks after randomisation
Secondary outcome [5] 409752 0
All cause mortality, as assessed by medical records review.
Timepoint [5] 409752 0
46 weeks after randomisation
Secondary outcome [6] 409753 0
Change in weight (kg), as assessed by measurement on digital scales.
Timepoint [6] 409753 0
46 weeks after randomisation
Secondary outcome [7] 409754 0
Change in waist circumference (cm), as assessed by tape measure
Timepoint [7] 409754 0
46 weeks after randomisation
Secondary outcome [8] 409755 0
Change in other medications (dose): diuretic, insulin, metformin, gliclazide; as assessed by medical records review and history taking from participant on follow up review.
Timepoint [8] 409755 0
46 weeks from randomisation
Secondary outcome [9] 409756 0
Change in urine albumin creatinine ratio
Timepoint [9] 409756 0
46 weeks after randomisation
Secondary outcome [10] 409757 0
Change in cholesterol level (mmol/L), as measured by serum blood test
Timepoint [10] 409757 0
46 weeks after randomisation
Secondary outcome [11] 409758 0
Change in myocardial tissue characterisation and performance on cardiovascular magnetic resonance
Timepoint [11] 409758 0
46 weeks after randomisation
Secondary outcome [12] 409759 0
Change in oral glucose tolerance test, as measured by serum glucose level (mmol/L) and area under the curve; blood test
Timepoint [12] 409759 0
46 weeks after randomisation
Secondary outcome [13] 411685 0
Change in triglyceride level (mmol/L), as measured by serum blood test
Timepoint [13] 411685 0
46 weeks after randomisation

Eligibility
Key inclusion criteria
• Sex: men and women
• Age range: over 18 years old
• Cardiac transplant recipients recruited within 6-8 weeks from the date of cardiac transplant
• Free from major rejection at enrolment
• Baseline eGFR >30 mL/min/1.73m2
• Willingness to give written informed consent and willingness to participate to and comply with the study
Minimum age
18 Years
Maximum age
No limit
Sex
Both males and females
Can healthy volunteers participate?
No
Key exclusion criteria
• Exposure to an SGLT2 inhibitor within the last 30 days
• Previous adverse event related to SGLT2 inhibitor use
• History of diabetic ketoacidosis
• History of urosepsis
• Fasting beta hydroxybutyrate >1.7 mmol/L at baseline
• Known major organ dysfunction (eGFR < 30 mL/min/1.73m2, liver disease transaminases > 5 times the upper limit of normal, current cancer or uncontrolled thyroid dysfunction). These conditions either interfere with the excretion or metabolism of the test medication, or would interfere with measurement of the study outcome.
• Women lactating, pregnant or of childbearing potential who are not willing to avoid becoming pregnant during the study

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)
An investigator not involved with recruitment or clinical care of participants will perform the randomisation and communicate directly with the pharmacy who will provide the medication in numbered containers
Methods used to generate the sequence in which subjects will be randomised (sequence generation)
Participants will be randomised using minimisation (Minitable program) modified from Saghaei et al. Factors will be weighted for importance and include history of type 2 diabetes, BMI, gender and age.
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
Parallel
Other design features
Phase
Phase 2 / Phase 3
Type of endpoint/s
Safety/efficacy
Statistical methods / analysis
Sample size or power calculation
Assuming </=10% rate of withdrawal, our study will be at least 80% powered to demonstrate an effect size of 0.6 (Cohen’s d) in primary endpoint between empagliflozin and placebo with a two sided significance level of 0.05 based on the following assumptions:
- Clinically significant reduction defined as reduction in HbA1c of >/=0.5%, and/or reduction in fructosamine of >/=20 umol/L
- Improvement of 0.6% or 7 mmol/mol in HbA1c over 12 months in cardiac transplant cohort of 20 patients (Cehic et al. Transplant Direct. 2019).
- Improvement of 0.2% or 2.0 mmol/mol in HbA1c over 24 weeks in a renal transplant cohort of 44 patients (22 empagliflozin, 22 placebo) (Halden et al. Diabetes Care. 2019).

Statistical Plan
Summary statistics for categorical measures will include sample size, frequency, and percentages. For continuous measures, summary statistics will include sample size, mean, and standard deviation or median and interquartile range. A likelihood-based mixed effect regression model approach will be used for the primary efficacy analysis. The HbA1c measure at baseline and all post baseline measurements will be the dependent variable, and treatment by visit interaction will be the fixed effect of interest. The primary comparison will be the difference in mean change of HbA1C at 12 month from baseline between treatment and control groups. Chi-square test will be used to examine the association between treatment arm and the categorical outcomes. Logistic regression and ordinal logistics regression models will be used to examine the intervention effect on the binary or ordinal outcome measures, with controlling for key patients baseline characteristics such as pre-transplant diabetic status. The Kaplan-Meier method will be used for estimation of cumulative event-free survival rates and Cox proportional hazards regression analysis will be used to compare hazard rates between empagliflozin and placebo.

Recruitment
Recruitment status
Recruiting
Date of first participant enrolment
Anticipated
18/07/2022
Actual
1/11/2022
Date of last participant enrolment
Anticipated
Actual
Date of last data collection
Anticipated
Actual
Sample size
Target
100
Accrual to date
0
Final
Recruitment in Australia
Recruitment state(s)
NSW
Recruitment hospital [1] 22391 0
St Vincent's Hospital (Darlinghurst) - Darlinghurst
Recruitment postcode(s) [1] 37556 0
2010 - Darlinghurst

Funding & Sponsors
Funding source category [1] 311461 0
Charities/Societies/Foundations
Name [1] 311461 0
St Vincent's Clinic Foundation
Country [1] 311461 0
Australia
Primary sponsor type
Other Collaborative groups
Name
Garvan Institute of Medical Research
Address
384 Victoria Street, Darlinghurst NSW 2010
Country
Australia
Secondary sponsor category [1] 312856 0
None
Name [1] 312856 0
N/A
Address [1] 312856 0
N/A
Country [1] 312856 0
Other collaborator category [1] 282357 0
Hospital
Name [1] 282357 0
St Vincent's Hospital Sydney
Address [1] 282357 0
390 Victoria Street,
Darlinghurst NSW 2010
Country [1] 282357 0
Australia

Ethics approval
Ethics application status
Approved
Ethics committee name [1] 310931 0
St Vincent’s Hospital Sydney Human Research Ethics Committee
Ethics committee address [1] 310931 0
Ethics committee country [1] 310931 0
Australia
Date submitted for ethics approval [1] 310931 0
02/12/2021
Approval date [1] 310931 0
19/01/2022
Ethics approval number [1] 310931 0
2021/ETH12184

Summary
Brief summary
Trial website
Trial related presentations / publications
Public notes

Contacts
Principal investigator
Name 119394 0
Prof Jerry Greenfield
Address 119394 0
Garvan Institute of Medical Research
384 Victoria Street, Darlinghurst NSW 2010
Country 119394 0
Australia
Phone 119394 0
+61292958217
Fax 119394 0
Email 119394 0
[email protected]
Contact person for public queries
Name 119395 0
Lisa Raven
Address 119395 0
Garvan Institute of Medical Research
384 Victoria Street, Darlinghurst NSW 2010
Country 119395 0
Australia
Phone 119395 0
+61283822622
Fax 119395 0
Email 119395 0
[email protected]
Contact person for scientific queries
Name 119396 0
Lisa Raven
Address 119396 0
Garvan Institute of Medical Research
384 Victoria Street, Darlinghurst NSW 2010
Country 119396 0
Australia
Phone 119396 0
+61283822622
Fax 119396 0
Email 119396 0
[email protected]

Data sharing statement
Will individual participant data (IPD) for this trial be available (including data dictionaries)?
No
No/undecided IPD sharing reason/comment


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
SourceTitleYear of PublicationDOI
EmbaseSodium glucose co-transporter 2 inhibition with empagliflozin on metabolic, cardiac and renal outcomes in recent cardiac transplant recipients (EMPA-HTx): Protocol for a randomised controlled trial.2023https://dx.doi.org/10.1136/bmjopen-2022-069641
N.B. These documents automatically identified may not have been verified by the study sponsor.