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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
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Scientific title
Empagliflozin in Cirrhosis (EmC) Safety Study: A safety and pharmacokinetic study
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Secondary ID [1]
301848
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Nil Known
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Universal Trial Number (UTN)
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Trial acronym
EcM Safety Study
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Linked study record
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Health condition
Health condition(s) or problem(s) studied:
cirrhosis
318336
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portal hypertension
318338
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Condition category
Condition code
Oral and Gastrointestinal
316348
316348
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0
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Other diseases of the mouth, teeth, oesophagus, digestive system including liver and colon
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Intervention/exposure
Study type
Interventional
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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.
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Intervention code [1]
318143
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Treatment: Drugs
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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.
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Control group
Active
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Outcomes
Primary outcome [1]
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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.
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Assessment method [1]
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Timepoint [1]
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Six weeks post-commencement of empagliflozin medication.
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Primary outcome [2]
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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..
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Assessment method [2]
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Timepoint [2]
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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.
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Secondary outcome [1]
384845
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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.
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Assessment method [1]
384845
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Timepoint [1]
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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.
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Secondary outcome [2]
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Determine impact on renal function by calculating eGFR- assessed using CKD-EPI calculation based on sex, age and creatinine serum biochemistry.
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Assessment method [2]
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Timepoint [2]
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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.
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Secondary outcome [3]
384847
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Determine change in blood glucose from baseline by serum analysis of HbA1C levels
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Assessment method [3]
384847
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Timepoint [3]
384847
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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.
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Secondary outcome [4]
384848
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Haemodynamic effects of empagliflozin will be assessed by measurement of blood pressure using a sphygmomanometer.
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Assessment method [4]
384848
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Timepoint [4]
384848
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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.
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Secondary outcome [5]
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Change in gut flora present in the microbiome will be assessed by faecal analysis
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Assessment method [5]
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Timepoint [5]
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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.
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Secondary outcome [6]
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Determine impact on quality of life assessed using the Chronic Liver Disease Questionnaire (CLDQ).
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Assessment method [6]
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Timepoint [6]
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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.
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Secondary outcome [7]
385800
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Determine impact on renal function as a change in urine sodium using urine sodium concentration measurement.
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Assessment method [7]
385800
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Timepoint [7]
385800
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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.
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Secondary outcome [8]
385801
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Determine change in urine glucose (mmol/L) concentration in the urine at each time-point.
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Assessment method [8]
385801
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Timepoint [8]
385801
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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.
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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.
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Minimum age
18
Years
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Maximum age
80
Years
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Sex
Both males and females
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Can healthy volunteers participate?
Yes
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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.
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Study design
Purpose of the study
Treatment
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Allocation to intervention
Non-randomised trial
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Procedure for enrolling a subject and allocating the treatment (allocation concealment procedures)
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Methods used to generate the sequence in which subjects will be randomised (sequence generation)
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Masking / blinding
Open (masking not used)
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Who is / are masked / blinded?
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Intervention assignment
Parallel
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Other design features
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Phase
Phase 2
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Type of endpoint/s
Safety
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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.
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Recruitment
Recruitment status
Not yet recruiting
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Date of first participant enrolment
Anticipated
2/11/2020
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Actual
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Date of last participant enrolment
Anticipated
6/09/2021
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Actual
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Date of last data collection
Anticipated
15/11/2021
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Actual
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Sample size
Target
23
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Accrual to date
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Final
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Recruitment in Australia
Recruitment state(s)
NSW
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Recruitment hospital [1]
17139
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St Vincent's Hospital (Darlinghurst) - Darlinghurst
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Recruitment postcode(s) [1]
30816
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2010 - Darlinghurst
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Funding & Sponsors
Funding source category [1]
306272
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Charities/Societies/Foundations
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Name [1]
306272
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St Vincent's Clinic Foundation
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Address [1]
306272
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St Vincent's Clinic Foundation, St Vincent's Hospital, 238 Victoria Street, Darlinghurst, Sydney, NSW 2010
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Country [1]
306272
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Australia
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Primary sponsor type
Hospital
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Name
St Vincent's Hospital, Sydney
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Address
St Vincent's Hospital
238 Victoria Street
Darlinghurst, NSW 2010
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Country
Australia
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Secondary sponsor category [1]
306762
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None
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Name [1]
306762
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Address [1]
306762
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Country [1]
306762
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Ethics approval
Ethics application status
Submitted, not yet approved
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Ethics committee name [1]
306479
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St Vincent's Hospital HREC
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Ethics committee address [1]
306479
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Research Office
St Vincent's Hospital
238 Victoria Street
Darlinghurst NSW 2010
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Ethics committee country [1]
306479
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Australia
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Date submitted for ethics approval [1]
306479
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03/08/2020
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Approval date [1]
306479
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Ethics approval number [1]
306479
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Summary
Brief summary
Empagliflozin is a sodium glucose transporter-2 (SGLT2) inhibitor drug, a class of diabetic medication. Interestingly, there is survival benefit in patients with heart failure. There are similarities between heart failure and the complications of severe liver disease, termed cirrhosis. As a result, it has been suggested that the SGLT2 inhibitors, may be of benefit in managing cirrhosis. While safe in liver disease in single dose studies, there is no long-term safety data in patients with cirrhosis. The aim of the study is to assess the safety of empagliflozin in three different groups (n=5) of increasing degrees of severity of cirrhosis and healthy controls (n=8). If this small pilot study demonstrates empagliflozin to be safe, then we will be able to do a larger study to assess the benefit of this medication in cirrhosis. This would be a significant advance in the treatment of cirrhosis.
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Trial website
None
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Trial related presentations / publications
None
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Public notes
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Contacts
Principal investigator
Name
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A/Prof Mark Danta
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Address
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St Vincent's Clinical School
Level 5 De Lacy Building
St Vincent's Hospital
238 Victoria Street
Darlinghurst NSW 2010
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Country
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Australia
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Phone
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+612 8382 2352
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Fax
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+612 8382 2794
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Email
104034
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[email protected]
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Contact person for public queries
Name
104035
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A/Prof Mark Danta
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Address
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St Vincent's Clinical School
Level 5 De Lacy Building
St Vincent's Hospital
238 Victoria Street
Darlinghurst NSW 2010
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Country
104035
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Australia
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Phone
104035
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+612 8382 2352
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Fax
104035
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+612 8382 2794
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Email
104035
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[email protected]
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Contact person for scientific queries
Name
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A/Prof Mark Danta
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Address
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St Vincent's Clinical School
Level 5 De Lacy Building
St Vincent's Hospital
238 Victoria Street
Darlinghurst NSW 2010
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Country
104036
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Australia
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Phone
104036
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+612 8382 2352
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Fax
104036
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+612 8382 2794
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Email
104036
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[email protected]
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Data sharing statement
Will individual participant data (IPD) for this trial be available (including data dictionaries)?
Yes
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What data in particular will be shared?
De-identified individual participant data of published results only.
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When will data be available (start and end dates)?
Immediately following publication of results; no end date.
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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.
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Available for what types of analyses?
Available for use for approved meta-analyses.
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How or where can data be obtained?
Access is subject to approvals by Principal Investigator and HREC, provided by email to
[email protected]
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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.
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