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EMPRA (EMPagliflozin and RAs in Kidney Disease) (EMPRA)

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ClinicalTrials.gov Identifier: NCT03078101
Recruitment Status : Recruiting
First Posted : March 13, 2017
Last Update Posted : November 9, 2018
Sponsor:
Collaborator:
Attoquant Diagnostics
Information provided by (Responsible Party):
Ass. Prof. Dr. Manfred Hecking, MD, Medical University of Vienna

Brief Summary:

This study will be a prospective, clinical pilot study in CKD patients to show whether Empagliflozin in addition to ACEi treatment significantly increases Ang 1-7 levels compared to ACEi treatment alone.

Null and alternative hypotheses:

H0: Empagliflozin in addition to ACEi treatment does not increase Ang 1-7 levels more than ACEi treatment alone.

H1: Empagliflozin in addition to ACEi treatment significantly increases Ang 1-7 levels compared to ACEi treatment alone

Methodology:

Two groups of 24 chronic kidney disease (CKD) patients, respectively, with and without type 2 diabetes will be randomized into the study medication or placebo group. The number of patients per treatment arms is n = 12. Included and consented patients will be subjected to an initial 2-week run-in period for conversion of current RAS blocking medications to ACEi therapy with enalapril or ramipril and respective dose titration to 10 mg enalapril 2 x daily and 10 mg ramipril 1 x daily. Additional antihypertensive medication will be standardized as feasible, with the primary goal of keeping blood pressure as recommended by KDIGO. Following the 2-week run-in phase, all study patients will be subjected to blood collection including the first RAS quantification (RAS Fingerprint) and assessment of HDL composition, as well as urinary analysis and bioimpedance fluid status assessment (BCM measurement). Subsequently, patients will be randomized to either receive empagliflozin (at a dose of 10 mg daily) or placebo. Subsequently, biweekly study visits including electrolyte and glucose (plasma and urine) monitoring as well as BCM measurement will take place. After 12 weeks of study medication intake, a concluding study visit will be scheduled for final RAS quantification (RAS Fingerprint) and HDL analyses as well as final blood and urinary analysis and BCM measurement. Initially, blood and urine will be collected at the clinical visit as part of the routine blood obtainment (no additional effort on patients). From these routine measurements we will be able to extract information regarding the patient's current CKD stage as well as other relevant laboratory parameters (e.g. HbA1c, UACR, etc.). Furthermore, we will document the patient's current medication and significant comorbidities.

Primary analysis variable/endpoint:

The difference of Ang 1-7 increase from baseline between a 3-month treatment with empagliflozin on top of ACEi treatment compared to ACEi treatment alone

Most important secondary analysis variables/endpoints:

  1. Simultaneous quantitative changes of multiple RAS effector angiotensin levels determined by mass-spectrometry
  2. Recurrence of Ang II levels determined by mass-spectrometry
  3. HDL parameters (protein composition of HDL)
  4. Renal parameters (albuminuria reduction measured by urinary albumin-creatinine ratio (UACR), renal function (estimated glomerular filtration rate (GFR), serum-creatinine)
  5. Urinary electrolyte levels
  6. Urinary glucose levels
  7. Urinary RAS metabolites (angiotensinogen, ACE and ACE2 levels, ACE2 activity)
  8. Blood pressure determined by ambulatory blood pressure measurements
  9. Body volume determined by bioimpedance fluid status assessment (BCM measurement)
  10. OCR and ECAR in PBMCs determined by Seahorse Flux Analyzer
  11. Assessment of reduction of salt sensitivity by using salt sensitivity test with empagliflozin

Condition or disease Intervention/treatment Phase
Diabetic Kidney Disease Diabetes Mellitus, Type 2 Chronic Kidney Disease stage3 Chronic Kidney Disease stage4 Drug: Empagliflozin 10 MG [Jardiance] Drug: Placebo Oral Tablet Phase 2

Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 48 participants
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Triple (Participant, Investigator, Outcomes Assessor)
Primary Purpose: Treatment
Official Title: Effect of Empagliflozin on the Renin-angiotensin System in Patients With Chronic
Actual Study Start Date : April 15, 2017
Estimated Primary Completion Date : May 2019
Estimated Study Completion Date : August 2019

Resource links provided by the National Library of Medicine

MedlinePlus related topics: Kidney Diseases

Arm Intervention/treatment
Experimental: Group A
Diabetic CKD patients receiving Empagliflozin 10 MG [Jardiance]
Drug: Empagliflozin 10 MG [Jardiance]
administered orally once daily

Placebo Comparator: Group B
Diabetic CKD patients receiving Placebo Oral Tablet
Drug: Placebo Oral Tablet
administered orally once daily

Experimental: Group C
Non-diabetic CKD patients receiving Empagliflozin 10 MG [Jardiance]
Drug: Empagliflozin 10 MG [Jardiance]
administered orally once daily

Placebo Comparator: Group D
Non-diabetic CKD patients receiving 'Placebo Oral Tablet
Drug: Placebo Oral Tablet
administered orally once daily




Primary Outcome Measures :
  1. The difference of Ang 1-7 increase from baseline between a 3-month treatment with empagliflozin on top of ACEi treatment compared to ACEi treatment alone [ Time Frame: Visit 2 and Visit 8; 3 months ]
    The difference of Ang 1-7 increase from baseline between a 3-month treatment with empagliflozin on top of ACEi treatment compared to ACEi treatment alone


Secondary Outcome Measures :
  1. Mean quantitative changes of baseline multiple RAS effector angiotensin levels after 3 months of empagaliflozin treatment [ Time Frame: Visit 2 and Visit 8; 3 months ]
    Mean quantitative changes of baseline multiple RAS effector angiotensin levels after 3 months of empagaliflozin treatment

  2. Mean changes of baseline Ang II levels after 3 months of empagaliflozin treatment [ Time Frame: Visit 2 and Visit 8; : 3 months ]
    Mean changes of baseline Ang II levels after 3 months of empagaliflozin treatment

  3. Mean changes of baseline specific protein amount on HDL after 3 months of empagaliflozin treatment [ Time Frame: Visit 2 and Visit 8; 3 months ]
    Mean changes of baseline specific protein amount on HDL after 3 months of empagaliflozin treatment

  4. Mean changes in specific renal parameters from baseline in 3 months of empagaliflozin treatment (albuminuria reduction, renal function) [ Time Frame: Visit 2 ,3,4,5,6,7,8; 3 months ]
    Mean changes in specific renal parameters from baseline in 3 months of empagaliflozin treatment (albuminuria reduction, renal function)

  5. Mean changes from baseline relevant blood parameters (HbA1c, β-hydroxybutyrat, elektrolytes, lipids, etc.) after 3 months of empagaliflozin treatment [ Time Frame: Visit 2 ,3,4,5,6,7,8; 3 months ]
    Mean changes from baseline relevant blood parameters (HbA1c, β-hydroxybutyrat, elektrolytes, lipids, etc.) after 3 months of empagaliflozin treatment

  6. Mean changes from baseline urinary RAS metabolites (angiotensinogen, ACE and ACE2 levels, ACE2 activity) after 3 months of empagaliflozin treatment [ Time Frame: Visit 2 and Visit 8; 3 months ]
    Mean changes from baseline urinary RAS metabolites (angiotensinogen, ACE and ACE2 levels, ACE2 activity) after 3 months of empagaliflozin treatment

  7. Mean changes in baseline blood pressure after 3 months of empagaliflozin treatment [ Time Frame: Visit 2 ,3,4,5,6,7,8; 3 months ]
    Mean changes in baseline blood pressure after 3 months of empagaliflozin treatment

  8. Mean changes in body fluid status after 3 months of empagaliflozin treatment [ Time Frame: Visit 2 and Visit 8; 3 months ]
    Mean changes in body fluid status after 3 months of empagaliflozin treatment

  9. Mean changes in baseline oxygen consumption rate (OCR) and the extracellular acidification rate (ECAR) in peripheral peripheral blood mononuclear cells (PBMCs) after 3 months of empagliflozin treatment [ Time Frame: Visit 2 and Visit 8; 3 months ]
    Mean changes in baseline oxygen consumption rate (OCR) and the extracellular acidification rate (ECAR) in peripheral peripheral blood mononuclear cells (PBMCs) after 3 months of empagliflozin treatment

  10. Mean changes in salt sensitivity after 3 months of empagliflozin treatment [ Time Frame: Visit 2 and Visit 8; 3 months ]
    Mean changes in salt sensitivity after 3 months of empagliflozin treatment


Other Outcome Measures:
  1. Number of symptomatic hypoglycemia and confirmed hypoglycemic events (plasma glucose level ≤70 mg/dl or an event requiring assistance) [ Time Frame: Visit 2 ,3,4,5,6,7,8; timeframe: 3 months ]
    Number of symptomatic hypoglycemia and confirmed hypoglycemic events (plasma glucose level ≤70 mg/dl or an event requiring assistance)

  2. Number of adverse events reflecting urinary tract infections, genital infections, volume depletion, acute renal failure, bone fractures, diabetic ketoacidosis and thromboembolic events. [ Time Frame: Visit 2 ,3,4,5,6,7,8; 3 months ]
    Number of adverse events reflecting urinary tract infections, genital infections, volume depletion, acute renal failure, bone fractures, diabetic ketoacidosis and thromboembolic events.

  3. Number of cardiovascular events (i.e. stroke, myocardial infarction, heart failure) during the study. [ Time Frame: Visit 2 ,3,4,5,6,7,8; 3 months ]
    Number of cardiovascular events (i.e. stroke, myocardial infarction, heart failure) during the study.

  4. Number of hospitalizations during the study. [ Time Frame: Visit 2 ,3,4,5,6,7,8; 3 months ]
    Number of hospitalizations during the study.



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Ages Eligible for Study:   18 Years and older   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
Criteria

Inclusion Criteria:

for CKD patients with type 2 diabetes

  • Estimated GFR (calculated with the MDRD-IDMS formula) between 15 and 59 ml/min (with CKD stage IIIa/b to IV)
  • Albumin excretion rates of 30-300 mg/24 hours (UACR <300 mg/g)
  • Fasting plasma glucose levels >126 mg/dl [7mmol/L] or HbA1c levels >6.5% (Definition of type 2 diabetes according to the diagnostic criteria set forth by the American Diabetes Association in 2009)

for CKD patients without Diabetes

  • Estimated GFR (calculated with the MDRD-IDMS formula) between 15 and 59 ml/min (with CKD stage IIIa/b to IV)
  • Albumin excretion rates of 30-300 mg/24 hours (UACR <300 mg/g)

Exclusion Criteria:

CKD patients with type 2 diabetes

  • Age <18 years
  • Severely impaired renal function (eGFR <15ml/min)
  • Hyperkalemia above 4.5mmol/L
  • Hypotension (systolic blood pressure lower than 120 mmHg on ambulatory measurement)
  • Pregnant patients
  • Patients planning pregnancy
  • Body mass index < 18.5 kg/m2

for CKD patients without diabetes

  • Age <18 years
  • Diabetic kidney disease
  • Severely impaired renal function (eGFR <15ml/min)
  • Hypotension (systolic blood pressure lower than 120 mmHg on ambulatory measurement)
  • Pregnant patients
  • Patients planning pregnancy
  • Body mass index < 18.5 kg/m2 -

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT03078101


Contacts
Contact: Manfred Hecking, MD 43-699-10580831 manfred.hecking@meduniwien.ac.at
Contact: Marlies Antlanger, MD 43-1-40400-55930 marlies.antlanger@meduniwien.ac.at

Locations
Austria
Department of Internal Medicine III, Division of Nephrology and Dialysis, Medical University of Vienna, Austria Recruiting
Vienna, Austria, 1090
Contact: Manfred Hecking, MD       manfred.hecking@meduniwien.ac.at   
Contact: Marlies Antlanger, MD       marlies.antlanger@meduniwien.ac.at   
Sponsors and Collaborators
Medical University of Vienna
Attoquant Diagnostics
Investigators
Principal Investigator: Manfred Hecking, MD Department of Internal Medicine III, Division of Nephrology and Dialysis, Medical University of Vienna, Austria

Responsible Party: Ass. Prof. Dr. Manfred Hecking, MD, Assoc. Prof. PD. Dr.med., Medical University of Vienna
ClinicalTrials.gov Identifier: NCT03078101     History of Changes
Other Study ID Numbers: EUDRACT-Nr: 2016-002935-14
First Posted: March 13, 2017    Key Record Dates
Last Update Posted: November 9, 2018
Last Verified: November 2018
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD: No

Studies a U.S. FDA-regulated Drug Product: No
Studies a U.S. FDA-regulated Device Product: No

Keywords provided by Ass. Prof. Dr. Manfred Hecking, MD, Medical University of Vienna:
Empagliflozin
SGLT-2 Inhibiton and RAS in CKD

Additional relevant MeSH terms:
Diabetic Nephropathies
Diabetes Mellitus
Kidney Diseases
Renal Insufficiency, Chronic
Diabetes Mellitus, Type 2
Glucose Metabolism Disorders
Metabolic Diseases
Endocrine System Diseases
Urologic Diseases
Renal Insufficiency
Diabetes Complications
Empagliflozin
Hypoglycemic Agents
Physiological Effects of Drugs