EMPRA (EMPagliflozin and RAs in Kidney Disease)

NCT03078101 | Completed Phase 2

• 1 other identifier: EUDRACT-Nr: 2016-002935-14
• Study Type: interventional
• Target: 51
• Locations: 1 country
• Sites: 1

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

Conditions

Diabetic Kidney Disease; Diabetes Mellitus, Type 2; Chronic Kidney Disease stage3; Chronic Kidney Disease stage4

Keywords

Empagliflozin; SGLT-2 Inhibiton and RAS in CKD

Outcome Measures

Primary Outcomes (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

  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

  Visit 2 and Visit 8; 3 months

Secondary Outcomes (10)

• Mean quantitative changes of baseline multiple RAS effector angiotensin levels after 3 months of empagaliflozin treatment

  Visit 2 and Visit 8; 3 months

• Mean changes of baseline Ang II levels after 3 months of empagaliflozin treatment

  Visit 2 and Visit 8; : 3 months

• Mean changes of baseline specific protein amount on HDL after 3 months of empagaliflozin treatment

  Visit 2 and Visit 8; 3 months

• Mean changes in specific renal parameters from baseline in 3 months of empagaliflozin treatment (albuminuria reduction, renal function)

  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

  Visit 2 ,3,4,5,6,7,8; 3 months

Other Outcomes (4)

• Number of symptomatic hypoglycemia and confirmed hypoglycemic events (plasma glucose level ≤70 mg/dl or an event requiring assistance)

  Visit 2 ,3,4,5,6,7,8; timeframe: 3 months

• Number of adverse events reflecting urinary tract infections, genital infections, volume depletion, acute renal failure, bone fractures, diabetic ketoacidosis and thromboembolic events.

  Visit 2 ,3,4,5,6,7,8; 3 months

• Number of cardiovascular events (i.e. stroke, myocardial infarction, heart failure) during the study.

  Visit 2 ,3,4,5,6,7,8; 3 months

Study Arms (4)

Group A

EXPERIMENTAL

Diabetic CKD patients receiving Empagliflozin 10 MG \[Jardiance\]

Drug: Empagliflozin 10 MG [Jardiance]

Group B

PLACEBO COMPARATOR

Diabetic CKD patients receiving Placebo Oral Tablet

Drug: Placebo Oral Tablet

Group C

EXPERIMENTAL

Non-diabetic CKD patients receiving Empagliflozin 10 MG \[Jardiance\]

Drug: Empagliflozin 10 MG [Jardiance]

Group D

PLACEBO COMPARATOR

Non-diabetic CKD patients receiving 'Placebo Oral Tablet

Drug: Placebo Oral Tablet

Interventions

Empagliflozin 10 MG [Jardiance] DRUG

administered orally once daily

Group A; Group C

Placebo Oral Tablet DRUG

administered orally once daily

Group B; Group D

Eligibility Criteria

• Age: 18 Years+
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• 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)

You may not qualify if:

• 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

Sponsors & Collaborators

• Medical University of Vienna: lead
• Attoquant Diagnostics: collaborator

Study Sites (1)

Department of Internal Medicine III, Division of Nephrology and Dialysis, Medical University of Vienna, Austria

Vienna, 1090, Austria

Location

Related Publications (1)

• Natale P, Tunnicliffe DJ, Toyama T, Palmer SC, Saglimbene VM, Ruospo M, Gargano L, Stallone G, Gesualdo L, Strippoli GF. Sodium-glucose co-transporter protein 2 (SGLT2) inhibitors for people with chronic kidney disease and diabetes. Cochrane Database Syst Rev. 2024 May 21;5(5):CD015588. doi: 10.1002/14651858.CD015588.pub2.

  PMID: 38770818 DERIVED

MeSH Terms

Conditions

Diabetic Nephropathies; Diabetes Mellitus, Type 2

Interventions

empagliflozin

Condition Hierarchy (Ancestors)

Kidney Diseases; Urologic Diseases; Female Urogenital Diseases; Female Urogenital Diseases and Pregnancy Complications; Urogenital Diseases; Male Urogenital Diseases; Diabetes Complications; Diabetes Mellitus; Endocrine System Diseases; Glucose Metabolism Disorders; Metabolic Diseases; Nutritional and Metabolic Diseases

Study Officials

• Manfred Hecking, MD

  Department of Internal Medicine III, Division of Nephrology and Dialysis, Medical University of Vienna, Austria

  PRINCIPAL INVESTIGATOR

Study Design

• Study Type: interventional
• Phase: phase 2
• Allocation: RANDOMIZED
• Masking: TRIPLE
• Who Masked: PARTICIPANT, INVESTIGATOR, OUTCOMES ASSESSOR
• Purpose: TREATMENT
• Intervention Model: PARALLEL
• Sponsor Type: OTHER
• Responsible Party: PRINCIPAL INVESTIGATOR
• PI Title: Assoc. Prof. PD. Dr.med.

Study Record Dates

• First Submitted: March 7, 2017
• First Posted: March 13, 2017
• Study Start: April 15, 2017
• Primary Completion: June 18, 2019
• Study Completion: August 7, 2019
• Last Updated: August 8, 2019

Record last verified: 2019-08

Data Sharing

• IPD Sharing: Will not share

Locations

AU (1)