EMPA-KIDNEY (The Study of Heart and Kidney Protection With Empagliflozin)

Phase 3

Completed

Conditions: Chronic Kidney Disease

Interventions: Drug: Empagliflozin
Drug: Matching placebo

Registration Number: NCT03594110

Lead Sponsor: Boehringer Ingelheim

Brief Summary: The primary aim of the study is to investigate the effect of empagliflozin on kidney disease progression or cardiovascular death versus placebo on top of standard of care in patients with pre-existing chronic kidney disease. After completion of the interventional part of the study (primary study completion) a subset of participants will be followed up in a post-trial observational (non-interventional) manner for cardio-renal outcomes (estimated study completion date).

Detailed Description: Not available

Recruitment & Eligibility

Status: COMPLETED

Sex: All

Target Recruitment: 6609

Inclusion Criteria

Age ≥18 years or at "full age" as required by local regulation
Evidence of chronic kidney disease at risk of kidney disease progression defined by at least 3 months before and at the time of Screening Visit
- CKD-EPI eGFR ≥20 to <45 mL/min/1.73m² or
- CKD-EPI eGFR ≥45 to <90 mL/min/1.73m² with urinary albumin:creatinine ratio ≥200 mg/g (or protein:creatinine ratio ≥300 mg/g);
Clinically appropriate doses of single agent RAS-inhibition with either ACEi or ARB unless such treatment is either not tolerated or not indicated
A local Investigator judges that the participant neither requires empagliflozin (or any other SGLT-2 or SGLT-1/2 inhibitor), nor that such treatment is inappropriate;

Key

Exclusion Criteria

Currently receiving SGLT-2 or SGLT-1/2 inhibitor
Diabetes mellitus type 2 and prior atherosclerotic cardiovascular disease with an eGFR >60 mL/min/1.73m2 at Screening
Receiving combined ACEi and ARB treatment
Maintenance dialysis, functioning kidney transplant, or scheduled living donor transplant
Polycystic kidney disease
Previous or scheduled bariatric surgery
Ketoacidosis in the past 5 years
Symptomatic hypotension, or systolic blood pressure <90 or >180 mmHg at Screening
ALT or AST >3x ULN at Screening
Hypersensitivity to empagliflozin or other SGLT-2 inhibitor
Any intravenous immunosuppression therapy in last 3 months; or anyone currently on >45 mg prednisolone (or equivalent)
Use of an investigational medicinal product in the 30 days prior to Screening visit
Known to be poorly compliant with clinic visits or prescribed medication
Medical history that might limit the individual's ability to take trial treatments for the duration of the study (e.g. severe respiratory disease; history of cancer or evidence of spread within last 4 years, other than non-melanoma skin cancer; or recent history of alcohol or substance misuse)
Current pregnancy, lactation or women of childbearing potential (WOCBP), unless using highly-effective contraception
Type 1 diabetes mellitus

Study & Design

Study Type: INTERVENTIONAL

Study Design: PARALLEL

Arm && Interventions

Group	Intervention	Description
Empagliflozin 10 mg	Empagliflozin	Patients with evidence of chronic kidney disease (CKD) at risk of kidney disease progression, with or without diagnosed diabetes mellitus administered orally once daily 10 milligram (mg) film-coated tablets of empagliflozin.
Placebo	Matching placebo	Patients with evidence of chronic kidney disease (CKD) at risk of kidney disease progression, with or without diagnosed diabetes mellitus administered orally once daily film-coated tablets of placebo to match empagliflozin.

Primary Outcome Measures

Name	Time	Method
Interventional Part: Time to First Occurrence of Kidney Disease Progression or Cardiovascular Death ('as Adjudicated')	From the day of randomisation to the day of the final follow-up visit in the interventional part of the trial, up to 1136 days.	Time to first occurrence of kidney disease progression (KDP) or cardiovascular death is reported as incidence rate of first occurrence of KDP or adjudicated cardiovascular death. Incidence rate= (Number of patients who experienced the event of first occurrence of KDP or cardiovascular death)\100/(patient years at risk (pt-yrs at risk). pt-yrs at risk= sum of time at risk \[days\] over all patients in a treatment group / 365.25. Kidney disease progression was defined as: end stage kidney disease (defined as the initiation of maintenance dialysis or receipt of a kidney transplant) OR * a sustained decline in estimated glomerular filtration rate (eGFR) to \<10 mL/min/1.73m\^2 OR * renal death OR * a sustained decline of ≥40% in eGFR from randomisation.
Overall Study: Time to the First Occurrence of Kidney Disease Progression or Cardiovascular Death ('as Adjudicated')	From the day of randomization in the interventional part of the trial until the individual day of end of study in the non-interventional part of the trial. Up to 1869 days.	Time to first occurrence of kidney disease progression (KDP) or cardiovascular death is reported as incidence of progression of kidney disease or death from cardiovascular causes in the interventional part of the trial and in the post-trial follow-up (non-interventional part). Incidence rate= (Number of patients who experienced the event of first occurrence of KDP or cardiovascular death)\100/(patient years at risk (pt-yrs at risk). pt-yrs at risk= sum of time at risk \[days\] over all patients in a treatment group / 365.25. Kidney disease progression was defined as: a sustained decline in eGFR to less than 10 mL/min/1.73m\^2 OR * renal death OR * sustained decline of more than 40% in eGFR from randomization.

Secondary Outcome Measures

Name	Time	Method
Key Secondary Endpoint: Interventional Part - Time to First Hospitalization for Heart Failure ('as Adjudicated') or Cardiovascular Death ('as Adjudicated')	From the day of randomisation to the day of the final follow-up visit of the interventional part, up to 1140 days.	Time to first hospitalization for heart failure ('as adjudicated') or cardiovascular death ('as adjudicated') is reported as incidence rate of first hospitalization for heart failure or cardiovascular death. Incidence rate= (Number of patients who experienced the event of first hospitalization for heart failure or cardiovascular death) \*100/(patient years at risk (pt-yrs at risk)). pt-yrs at risk= sum of time at risk \[days\] over all patients in a treatment group / 365.25.
Key Secondary Endpoint: Interventional Part - Time to Occurrences of All-cause Hospitalizations (First and Recurrent Combined)	From the day of randomisation to the day of the final follow-up visit of the interventional part, up to 1140 days.	Time to occurrences of all-cause hospitalizations is reported as total number of all-cause hospitalizations (first and recurrent combined).
Key Secondary Endpoint: Interventional Part - Time to Death From Any Cause ('as Adjudicated')	From the day of randomisation to the day of the final follow-up visit in the interventional part of the trial, up to 1140 days.	Time to death from any cause is reported as incidence rate of death from any cause. Incidence rate of death from any cause = (Number of patients who experienced the event of death from any cause) \* 100/(patient years at risk (pt-yrs at risk)). pt-yrs at risk= sum of time at risk \[days\] over all patients in a treatment group / 365.25.
Interventional Part: Time to First Occurrence of Kidney Disease Progression	From the day of randomisation to the day of the final follow-up visit of the interventional part, up to 1136 days.	Time to first occurrence of kidney disease progression (KDP) is reported as incidence rate of first occurrence of kidney disease progression. Incidence rate of first occurrence of kidney disease progression= (Number of patients who experienced the event of first occurrence of kidney disease progression) \100/(patient years at risk (pt-yrs at risk)). pt-yrs at risk= sum of time at risk \[days\] over all patients in a treatment group / 365.25. Kidney disease progression was defined as: end stage kidney disease (defined as the initiation of maintenance dialysis or receipt of a kidney transplant) OR * a sustained decline in estimated glomerular filtration rate (eGFR) to \<10 mL/min/1.73m\^2 OR * renal death OR * a sustained decline of ≥40% in eGFR from randomisation).
Interventional Part: Time to Cardiovascular Death ('as Adjudicated')	From the day of randomisation to the day of the final follow-up visit of the interventional part, up to 1140 days.	Time to cardiovascular death ('as adjudicated') is reported as incidence rate of cardiovascular death. Incidence rate of cardiovascular death= (Number of patients who experienced the event of cardiovascular death) \*100/(patient years at risk (pt-yrs at risk)). pt-yrs at risk= sum of time at risk \[days\] over all patients in a treatment group / 365.25.
Interventional Part: Time to First Occurrence Cardiovascular Death ('as Adjudicated') or End Stage Kidney Disease (ESKD)	From the day of randomization to the day of the final follow-up visit in the interventional part of the trial, up to 1140 days.	Time to first occurrence of cardiovascular death ('as adjudicated') or end stage kidney disease is reported as incidence rate of first occurrence of cardiovascular death or end stage kidney disease (ESKD). Incidence rate of first occurrence cardiovascular death or end stage kidney disease (ESKD)= (Number of patients who experienced the event of first occurrence of cardiovascular death or end stage kidney disease (ESKD)) \*100/(patient years at risk (pt-yrs at risk)). pt-yrs at risk= sum of time at risk \[days\] over all patients in a treatment group / 365.25. ESKD was defined as the initiation of maintenance dialysis or receipt of a kidney transplant.
Overall Study: Time to First Occurrence of Kidney Disease Progression	From the day of randomization in the interventional part of the trial until the individual day of end of study in the non-interventional part of the trial. Up to 1869 days.	The time to first occurrence of kidney disease progression in the interventional part of the trial and in the post-trial follow-up (non-interventional part) is reported as the incidence rate of first occurrence of kidney disease progression. Incidence rate of first occurrence of kidney disease progression= (Number of patients who experienced the event of first occurrence of kidney disease progression) \100/(patient years at risk (pt-yrs at risk)). pt-yrs at risk= sum of time at risk \[days\] over all patients in a treatment group / 365.25. Kidney disease progression was defined as: end stage kidney disease (defined as the initiation of maintenance dialysis or receipt of a kidney transplant) OR * a sustained decline in estimated glomerular filtration rate (eGFR) to \<10 mL/min/1.73m\^2 OR * renal death OR * a sustained decline of ≥40% in eGFR from randomisation.
Overall Study: Time to First Occurrence of Death From Any Cause or ESKD	From the day of randomization in the interventional part of the trial until the individual day of end of study in the non-interventional part of the trial. Up to 1869 days.	Time to first occurrence of death from any cause or end stage kidney disease (ESKD) in the interventional part of the trial and in the post-trial follow-up (non-interventional part) is reported as incidence rate of first occurrence of death from any cause or ESKD. Incidence rate of first occurrence of death from any cause or end stage kidney disease (ESKD)= (Number of patients who experienced the event of first occurrence of death any cause or end stage kidney disease (ESKD)) \*100/(patient years at risk (pt-yrs at risk)). pt-yrs at risk= sum of time at risk \[days\] over all patients in a treatment group / 365.25. ESKD was defined as the initiation of maintenance dialysis or receipt of a kidney transplant.
Overall Study: Time to First Occurrence of ESKD	From the day of randomization in the interventional part of the trial until the individual day of end of study in the non-interventional part of the trial. Up to 1869 days.	Time to first occurrence of end stage kidney disease (ESKD) in the interventional part of the trial and in the post-trial follow-up (non-interventional part) is reported as incidence rate of first occurrence of ESKD. Incidence rate of first occurrence of end stage kidney disease (ESKD)= (Number of patients who experienced the event of first occurrence of ESKD) \*100/(patient years at risk (pt-yrs at risk)). pt-yrs at risk= sum of time at risk \[days\] over all patients in a treatment group / 365.25. ESKD was defined as the initiation of maintenance dialysis or receipt of a kidney transplant.
Body Composition Measurement Sub-study: Mean Absolute Fluid Overload, Averaged Over Time	MMRM included measurements at baseline, 2 months, and 18 months.	Mean absolute fluid overload averaged over time in the body composition measurement sub-study. Fluid overload or overhydration was measured using bioimpedance spectroscopy which derives the amount of water in liters (L) in the adipose tissue and lean mass tissues and computed as the difference between expected (based upon weight and body composition) versus measured extracellular water volume, with positive values representing excess fluid. A mixed model of repeated measures (MMRM) with terms for baseline, age, sex, screening diabetes status, local screening eGFR, local screening UACR, treatment, treatment-by-time interaction and baseline-by-time interaction was used for the analysis. The weighted mean of the values at 2 and 18 months.
Magnetic Resonance Imaging Sub-study: Kidney Cortical T1 Mapping as Measured by Modified Look-Locker Inversion Recovery (MOLLI) at 18 Months	At 18 months.	Kidney cortical T1 mapping using the modified Look-Locker inversion recovery (MOLLI) measured by magnetic resonance imaging (MRI) in the placebo and empagliflozin groups. A linear regression with terms for age, sex, screening diabetes status, local screening eGFR, local screening UACR was used in the analysis.

Trial Locations

Locations (237): Nephrology Consultants, LLC
🇺🇸
Huntsville, Alabama, United States
Aventiv Research, Inc
🇺🇸
Mesa, Arizona, United States
Southern California Permanente Medical Group
🇺🇸
San Diego, California, United States
University of California Los Angeles
🇺🇸
Torrance, California, United States
Yale University School of Medicine
🇺🇸
New Haven, Connecticut, United States
Chase Medical Research, LLC
🇺🇸
Thomaston, Connecticut, United States
Midland Florida Clinical Reearch Center, LLC
🇺🇸
DeLand, Florida, United States
University of Florida
🇺🇸
Gainesville, Florida, United States
East Coast Institute for Research, LLC
🇺🇸
Jacksonville, Florida, United States
East Coast Clinical Research, Inc
🇺🇸
Lake City, Florida, United States
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Nephrology Consultants, LLC
🇺🇸Huntsville, Alabama, United States