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

Study Overview
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Brief Summary
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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).

Official Title
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A Multicentre International Randomized Parallel Group Double-blind Placebo-controlled Clinical Trial of EMPAgliflozin Once Daily to Assess Cardio-renal Outcomes in Patients With Chronic KIDNEY Disease

Conditions
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Chronic Kidney Disease

Intervention / Treatment
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* Drug: Empagliflozin
* Drug: Matching placebo


Participation Criteria
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Eligibility Criteria
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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 diseasee with an eGFR >60 mL/min/1.73m2 at Screening Receiving combined ACEi and ARBf 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 hypotensiond, 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

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Double


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Empagliflozin 10 mg<br>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. | Drug: Empagliflozin<br>* Taken daily with or without food<br>|
| Placebo Comparator: Placebo<br>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. | Drug: Matching placebo<br>* Taken daily with or without food<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Interventional Part: Time to First Occurrence of Kidney Disease Progression or Cardiovascular Death ('as Adjudicated') | Incidence rate of first occurrence of kidney disease progression (KDP) or adjudicated cardiovascular death is reported in the Outcome Measure Data Table. Metrics such as the median time-to-event (TTE) was not estimable due to insufficient events being experienced. 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. | Follow-up period: From the day of randomisation to the day of the final follow-up visit, up to 1136 days. | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Key Secondary Endpoint: Interventional Part - Time to First Hospitalization for Heart Failure ('as Adjudicated') or Cardiovascular Death ('as Adjudicated') | Incidence rate of first hospitalization for heart failure or cardiovascular death is reported in the Outcome Measure Data Table because metrics such as the median time-to-event (TTE) not estimable due to insufficient events being experienced. 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. | Follow-up period: From the day of randomisation to the day of the final follow-up visit, up to 1140 days. | 
| Key Secondary Endpoint: Interventional Part - Time to Occurrences of All-cause Hospitalizations (First and Recurrent Combined) | Total number of all-cause hospitalizations (first and recurrent combined) is reported in the Outcome Measure Data Table. Conventional time-to-event (TTE) metrics such as the median not calculable for a recurrent TTE analysis. | Follow-up period: From the day of randomisation to the day of the final follow-up visit, up to 1140 days. | 
| Key Secondary Endpoint: Interventional Part - Time to Death From Any Cause ('as Adjudicated') | Incidence rate of death from any cause is reported in the Outcome Measure Data Table. Metrics such as the median time-to-event (TTE) not estimable due to insufficient events being experienced. 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. | Follow-up period: From the day of randomisation to the day of the final follow-up visit, up to 1140 days. | 
| Interventional Part: Time to First Occurrence of Kidney Disease Progression | Incidence rate of first occurrence of kidney disease progression is reported in the Outcome Measure Data Table. Metrics such as the median time-to-event (TTE) not estimable due to insufficient events being experienced. 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). | Follow-up period: From the day of randomisation to the day of the final follow-up visit, up to 1136 days. | 
| Interventional Part: Time to Cardiovascular Death ('as Adjudicated') | Incidence rate of first occurrence of kidney disease progression is reported in the Outcome Measure Data Table. Metrics such as the median time-to-event (TTE) not estimable due to insufficient events being experienced. Incidence rate of cardiovascular death is reported in the Outcome Measure Data Table. Metrics such as the median time-to-event (TTE) not estimable due to too few events being experienced. 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. | Follow-up period: From the day of randomisation to the day of the final follow-up visit, up to 1140 days. | 
| Interventional Part: Time to First Occurrence Cardiovascular Death ('as Adjudicated') or End Stage Kidney Disease (ESKD) | Incidence rate of first occurrence of cardiovascular death or end stage kidney disease (ESKD) is reported in the Outcome Measure Data Table. Metrics such as the median time-to-event (TTE) not estimable due to insufficient events being experienced. 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. | Follow-up period: From the day of randomisation to the day of the final follow-up visit, up to 1140 days. |