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Trial registered on ANZCTR


Registration number
ACTRN12620001076965p
Ethics application status
Submitted, not yet approved
Date submitted
21/07/2020
Date registered
19/10/2020
Date last updated
19/10/2020
Date data sharing statement initially provided
19/10/2020
Type of registration
Prospectively registered

Titles & IDs
Public title
Empagliflozin in Cirrhosis (EmC) Safety Study
Scientific title
Empagliflozin in Cirrhosis (EmC) Safety Study: A safety and pharmacokinetic study
Secondary ID [1] 301848 0
Nil Known
Universal Trial Number (UTN)
Trial acronym
EcM Safety Study
Linked study record

Health condition
Health condition(s) or problem(s) studied:
cirrhosis 318336 0
portal hypertension 318338 0
Condition category
Condition code
Oral and Gastrointestinal 316348 316348 0 0
Other diseases of the mouth, teeth, oesophagus, digestive system including liver and colon

Intervention/exposure
Study type
Interventional
Description of intervention(s) / exposure
To determine the safety of empagliflozin in cirrhosis with and without diabetes, an oral dose of empagliflozin 10 mg oral tablet daily will be given for a four week period to three groups of participants:
1. Cirrhosis compensated (Childs-Pugh A) n=5
2. Cirrhosis decompensated (Childs-Pugh B n=5
3. Cirrhosis decompensated (Childs-Pugh C) n=5

Each participant will undergo: Clinical Assessment; Tablet return to assess medication compliance, Monitoring of safety, clinical, empagliflozin concentrations, renal, diabetic, liver parameters, renin-angiotensin levels, microbiome parameters and QOL.
Intervention code [1] 318143 0
Treatment: Drugs
Comparator / control treatment
There is no healthy control group. The comparison will be made with the current available data on empagliflozin and between the cirrhosis groups. The reference group will be the Cirrhosis compensated (Childs-Pugh A) group.
Control group
Active

Outcomes
Primary outcome [1] 324513 0
Determine adverse events as coded using the Medical Dictionary for Regulatory Activities determined by weekly clinical assessment, including patient reported history and examination.
• Kidney injury – Empagliflozin was associated with a minor elevation of renal blood tests but not significant injury.
• Increased urination – occurs in 0.4% of patients (similar to placebo)
• Urinary tract infection – occurs in 5.4% of patients (and 3.2% of placebo)
• Low blood sugar levels – occurs in 0.4% of patients (similar to placebo)
• Genital fungal infection – occurs in 4.1% of patients (and 0.9% of placebo)
• Perineal necrotising fasciitis – This is a very rare (<1 in 1000) but serious complication that is an inflammation of the skin around the genitals.
• Ketoacidosis – this is rare (1 in 100) but has been reported and occurs in patients on empagliflozin having surgical procedures and becoming dehydrated.
• Increased blood lipids.
• Allergic or hypersensitivity reactions.
Timepoint [1] 324513 0
Six weeks post-commencement of empagliflozin medication.
Primary outcome [2] 324514 0
Determine temporal pharmacokinetics including drug exposure (AUC) of empagliflozin in compensated and decompensated cirrhosis over time. The pharmacokinetics of empagliflozin will be determined using standard liquid chromatography techniques derived from the blood samples to calculate AUC and Cmax at each time-point..
Timepoint [2] 324514 0
Six weeks post-commencement of empagliflozin medication.

Data and samples will be collected weekly from baseline week 0, weeks 1,2,3,and 4 on treatment and then weeks 5 and 6 post treatment.
Secondary outcome [1] 384845 0
Determine impact on liver function through change from baseline liver function – Model of End-Stage Liver Disease (MELD), Child's-Pugh (CP) score and liver-related complications, which include: development of ascites, oedema, hepatic encephalopathy, jaundice, or gastrointestinal bleeding. This is a composite secondary endpoint. These are objective measures based on clinical assessment and blood tests.
Timepoint [1] 384845 0
Data and samples to calculate the MELD and CP score will be collected weekly from baseline week 0, weeks 1,2,3,and 4 on treatment and then weeks 5 and 6 post treatment.
Secondary outcome [2] 384846 0
Determine impact on renal function by calculating eGFR- assessed using CKD-EPI calculation based on sex, age and creatinine serum biochemistry.
Timepoint [2] 384846 0
Data and samples to calculate the MELD and CP score will be collected weekly from baseline week 0, weeks 1,2,3,and 4 on treatment and then weeks 5 and 6 post treatment.
Secondary outcome [3] 384847 0
Determine change in blood glucose from baseline by serum analysis of HbA1C levels
Timepoint [3] 384847 0
Data and samples will be collected weekly from baseline week 0, weeks 1,2,3,and 4 on treatment and then weeks 5 and 6 post treatment.
Secondary outcome [4] 384848 0
Haemodynamic effects of empagliflozin will be assessed by measurement of blood pressure using a sphygmomanometer.
Timepoint [4] 384848 0
Data will be collected weekly from baseline week 0, weeks 1,2,3,and 4 on treatment and then weeks 5 and 6 post treatment.
Secondary outcome [5] 384849 0
Change in gut flora present in the microbiome will be assessed by faecal analysis
Timepoint [5] 384849 0
Data and samples will be collected weekly from baseline week 0, weeks 1,2,3,and 4 on treatment and then weeks 5 and 6 post treatment.
Secondary outcome [6] 384850 0
Determine impact on quality of life assessed using the Chronic Liver Disease Questionnaire (CLDQ).
Timepoint [6] 384850 0
Data will be collected weekly from baseline week 0, weeks 1,2,3,and 4 on treatment and then weeks 5 and 6 post treatment.
Secondary outcome [7] 385800 0
Determine impact on renal function as a change in urine sodium using urine sodium concentration measurement.
Timepoint [7] 385800 0
Data and samples will be collected weekly from baseline week 0, weeks 1,2,3,and 4 on treatment and then weeks 5 and 6 post treatment.
Secondary outcome [8] 385801 0
Determine change in urine glucose (mmol/L) concentration in the urine at each time-point.
Timepoint [8] 385801 0
Data and samples will be collected weekly from baseline week 0, weeks 1,2,3,and 4 on treatment and then weeks 5 and 6 post treatment.

Eligibility
Key inclusion criteria
Inclusion Criteria for liver disease:
• Age: 18 years or older, AND;
• Provision of written, informed consent, AND;
• Known or evident liver cirrhosis. Diagnosis of liver cirrhosis may be based on clinical, radiological, and or histological criteria, including 1 or more of the following:
a) Previous histologic diagnosis on liver biopsy; or
b) Clinical evidence of cirrhosis, defined as aspartate aminotransferase > alanine aminotransferase (i.e., AST > ALT), platelet count < 150,000, and nodular liver surface on computed tomography (CT) scan or magnetic resonance imaging (MRI); or
c) Clinical evidence of significant portal hypertension, based on current or history of gastroesophageal varices on endoscopy, evidence of portosystemic collaterals (on contrast CT or MRI with contrast), and/or presence of ascites; or
d) Transient elastography consistent with cirrhosis, i.e., result of > 13.0 kPa.
Minimum age
18 Years
Maximum age
80 Years
Sex
Both males and females
Can healthy volunteers participate?
Yes
Key exclusion criteria
• Patients with kidney disease (creatinine clearance < 30 ml/min) OR;
• Women lactating, pregnant or of childbearing potential and unwilling to avoid becoming pregnant during the study, OR;
• Patients with a history of a psychological illness or condition such as to interfere with the patient's ability to understand the requirements of the study, OR;
• Significant cardiac failure with left ventricular ejection fraction <30%, OR;
• Gastrointestinal surgery that would interfere with medication absorption.

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)
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
Statistical methods / analysis
The safety of empagliflozin: The safety endpoints will be characterised using descriptive statistics and frequency overviews.

The pharmacokinetic and pharmacodynamic analysis: At each of the weekly time points we will collect venous blood samples according to the usual methods. The blood sample for determination of empagliflozin concentrations will be immediately spun and the plasma separated and divided into 1 mL aliquots for separate storage. Blood samples for the determination of empagliflozin concentration will be sent to the University Medical Center Groningen, the Netherlands for analysis. The concentrations of empagliflozin will be measured by the University Medical Center Groningen, the Netherlands using a validated liquid chromatography with tandem mass spectroscopy (LC-MS/MS). The pharmacokinetics of empagliflozin will be determined using standard techniques (calculations derived from the blood samples) and the population pharmacokinetic approach.
Determine secondary objectives: The collected data will be analysed to explore the empagliflozin impact on: liver related outcomes, renal function, haemodynamic parameters, glucose metabolism, the microbiome and quality of life using the relevant statistical approach.

Recruitment
Recruitment status
Not yet recruiting
Date of first participant enrolment
Anticipated
2/11/2020
Actual
Date of last participant enrolment
Anticipated
6/09/2021
Actual
Date of last data collection
Anticipated
15/11/2021
Actual
Sample size
Target
23
Accrual to date
Final
Recruitment in Australia
Recruitment state(s)
NSW
Recruitment hospital [1] 17139 0
St Vincent's Hospital (Darlinghurst) - Darlinghurst
Recruitment postcode(s) [1] 30816 0
2010 - Darlinghurst

Funding & Sponsors
Funding source category [1] 306272 0
Charities/Societies/Foundations
Name [1] 306272 0
St Vincent's Clinic Foundation
Country [1] 306272 0
Australia
Primary sponsor type
Hospital
Name
St Vincent's Hospital, Sydney
Address
St Vincent's Hospital
238 Victoria Street
Darlinghurst, NSW 2010
Country
Australia
Secondary sponsor category [1] 306762 0
None
Name [1] 306762 0
Address [1] 306762 0
Country [1] 306762 0

Ethics approval
Ethics application status
Submitted, not yet approved
Ethics committee name [1] 306479 0
St Vincent's Hospital HREC
Ethics committee address [1] 306479 0
Ethics committee country [1] 306479 0
Australia
Date submitted for ethics approval [1] 306479 0
03/08/2020
Approval date [1] 306479 0
Ethics approval number [1] 306479 0

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

Contacts
Principal investigator
Name 104034 0
A/Prof Mark Danta
Address 104034 0
St Vincent's Clinical School
Level 5 De Lacy Building
St Vincent's Hospital
238 Victoria Street
Darlinghurst NSW 2010
Country 104034 0
Australia
Phone 104034 0
+612 8382 2352
Fax 104034 0
+612 8382 2794
Email 104034 0
m.danta@unsw.edu.au
Contact person for public queries
Name 104035 0
Mark Danta
Address 104035 0
St Vincent's Clinical School
Level 5 De Lacy Building
St Vincent's Hospital
238 Victoria Street
Darlinghurst NSW 2010
Country 104035 0
Australia
Phone 104035 0
+612 8382 2352
Fax 104035 0
+612 8382 2794
Email 104035 0
m.danta@unsw.edu.au
Contact person for scientific queries
Name 104036 0
Mark Danta
Address 104036 0
St Vincent's Clinical School
Level 5 De Lacy Building
St Vincent's Hospital
238 Victoria Street
Darlinghurst NSW 2010
Country 104036 0
Australia
Phone 104036 0
+612 8382 2352
Fax 104036 0
+612 8382 2794
Email 104036 0
m.danta@unsw.edu.au

Data sharing statement
Will individual participant data (IPD) for this trial be available (including data dictionaries)?
Yes
What data in particular will be shared?
De-identified individual participant data of published results only.
When will data be available (start and end dates)?
Immediately following publication of results; no end date.
Available to whom?
Data will be provided to researchers who provide a methodologically sound proposal, case-by-case basis at the discretion of Primary Sponsor.
Available for what types of analyses?
Available for use for approved meta-analyses.
How or where can data be obtained?
Access is subject to approvals by Principal Investigator and HREC, provided by email to m.danta@unsw.edu.au


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.