Chronic Kidney Disease
Conditions
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).
Interventions
DRUGEmpagliflozin
Taken daily with or without food
DRUGMatching placebo
Taken daily with or without food
Sponsors
University of Oxford
Eli Lilly and Company
Boehringer Ingelheim
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
DOUBLE (Subject, Investigator)
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
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
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| 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
| Measure | Time frame | Description |
|---|---|---|
| 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. |
| 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. |
| 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. |
| 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. |
| 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). |
Countries
Canada, China, Germany, Italy, Japan, Malaysia, United Kingdom, United States
Participant flow
Recruitment details
Trial with a interventional and a non-interventional part (post-trial follow-up). Interventional part: event-driven (ca. 1070 primary outcome events). Alongside the trial, a fraction of patients randomized in the interventional part gave consent to two sub-studies: body composition measurement and magnetic resonance imaging. Non-interventional part: patients who gave consent were observed for ca. 2 years.
Pre-assignment details
All subjects were screened for eligibility prior to participation in the trial. Subjects attended a specialist site which ensured that they (the subjects) strictly met all inclusion and none of the exclusion criteria. Subjects were not to be allocated to a treatment group if any of the entry criteria were violated.
Participants by arm
| Arm | Count |
|---|---|
| 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. | 3,305 |
| Empagliflozin 10 mg 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. | 3,304 |
| Total | 6,609 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Interventional Part | Adverse event-non-fatal events | 119 | 116 |
| Interventional Part | Adverse event-Serious fatal events | 130 | 121 |
| Interventional Part | Cannot attend clinic because moving out of the area | 15 | 9 |
| Interventional Part | Cannot attend clinic because of personal problems | 8 | 16 |
| Interventional Part | Contraindicated drug started | 32 | 18 |
| Interventional Part | Doctor advice | 38 | 40 |
| Interventional Part | Other reasons (include any category with a frequency <20 patients in total) | 58 | 45 |
| Interventional Part | Participant concerned about study treatment | 23 | 28 |
| Interventional Part | Participants' wish | 89 | 68 |
| Interventional Part | Study drug stopped, reason missing | 336 | 294 |
| Non-interventional Part | Lost to Follow-up | 45 | 41 |
| Non-interventional Part | Withdrawal by Subject | 3 | 4 |
Baseline characteristics
| Characteristic | Placebo | Empagliflozin 10 mg | Total |
|---|---|---|---|
| Age, Continuous | 63.3 Years STANDARD_DEVIATION 13.9 | 63.4 Years STANDARD_DEVIATION 13.9 | 63.3 Years STANDARD_DEVIATION 13.9 |
| Ethnicity (NIH/OMB) Hispanic or Latino | 119 Participants | 103 Participants | 222 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 723 Participants | 708 Participants | 1431 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 2463 Participants | 2493 Participants | 4956 Participants |
| Race/Ethnicity, Customized Asian | 1199 Participants | 1194 Participants | 2393 Participants |
| Race/Ethnicity, Customized Black/ African-American | 134 Participants | 128 Participants | 262 Participants |
| Race/Ethnicity, Customized Other including mixed race | 52 Participants | 43 Participants | 95 Participants |
| Race/Ethnicity, Customized White | 1920 Participants | 1939 Participants | 3859 Participants |
| Sex: Female, Male Female | 1095 Participants | 1097 Participants | 2192 Participants |
| Sex: Female, Male Male | 2210 Participants | 2207 Participants | 4417 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | 353 / 3,305 | 314 / 3,304 |
| other Total, other adverse events | 262 / 3,305 | 228 / 3,304 |
| serious Total, serious adverse events | 1,167 / 3,305 | 1,089 / 3,304 |
Outcome results
Primary
Interventional Part: Time to First Occurrence of Kidney Disease Progression or Cardiovascular Death ('as Adjudicated')
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.
Time frame: 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.
Population: Randomised set (RS) included all randomised participants, whether treated or not.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Placebo | Interventional Part: Time to First Occurrence of Kidney Disease Progression or Cardiovascular Death ('as Adjudicated') | 8.96 patients with events/100 pt-yrs at risk |
| Empagliflozin 10 mg | Interventional Part: Time to First Occurrence of Kidney Disease Progression or Cardiovascular Death ('as Adjudicated') | 6.85 patients with events/100 pt-yrs at risk |
Comparison: Hazard ratio (HR) of the time to first occurrence of kidney disease progression or CV death. HR is based on a Cox regression model with terms for age, sex, screening diabetes status, local screening estimated glomerular filtration rate Chronic Kidney Disease Epidemiology Collaboration (eGFR (CKD-EPI)), local screening Urine albumin-to-creatinine ratio (UACR), region and treatment.p-value: <0.000199.83% CI: [0.59, 0.89]Regression, Cox
Primary
Overall Study: Time to the First Occurrence of Kidney Disease Progression or Cardiovascular Death ('as Adjudicated')
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.
Time frame: 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.
Population: Randomised set (RS): included all randomised participants, whether treated or not.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Placebo | Overall Study: Time to the First Occurrence of Kidney Disease Progression or Cardiovascular Death ('as Adjudicated') | 9.99 patients with events/100 pt-yrs at risk |
| Empagliflozin 10 mg | Overall Study: Time to the First Occurrence of Kidney Disease Progression or Cardiovascular Death ('as Adjudicated') | 8.36 patients with events/100 pt-yrs at risk |
Comparison: Hazard ratio (HR) of the time to first occurrence of kidney disease progression or CV death. HR is based on a Cox regression model with terms for age, sex, screening diabetes status, local screening estimated glomerular filtration rate Chronic Kidney Disease Epidemiology Collaboration (eGFR (CKD-EPI)), local screening Urine albumin-to-creatinine ratio (UACR), region and treatment.95% CI: [0.72, 0.87]
Secondary
Body Composition Measurement Sub-study: Mean Absolute Fluid Overload, Averaged Over Time
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.
Time frame: MMRM included measurements at baseline, 2 months, and 18 months.
Population: Body composition measurement sub-study: all randomized patients who signed the informed consent form to participate in the body composition measurement sub-study, whether treated or not, with at least one valid BCM measurement. Patients with non-valid follow-up measurements were excluded from the analysis.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| Placebo | Body Composition Measurement Sub-study: Mean Absolute Fluid Overload, Averaged Over Time | 0.34 Liters | Standard Error 0.05 |
| Empagliflozin 10 mg | Body Composition Measurement Sub-study: Mean Absolute Fluid Overload, Averaged Over Time | 0.10 Liters | Standard Error 0.05 |
Comparison: 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.p-value: <0.00195% CI: [-0.38, -0.11]Mixed Models Analysis
Secondary
Interventional Part: Time to Cardiovascular Death ('as Adjudicated')
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.
Time frame: From the day of randomisation to the day of the final follow-up visit of the interventional part, up to 1140 days.
Population: Randomised set (RS) included all randomised participants, whether treated or not.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Placebo | Interventional Part: Time to Cardiovascular Death ('as Adjudicated') | 1.08 patients with events/100 pt-yrs at risk |
| Empagliflozin 10 mg | Interventional Part: Time to Cardiovascular Death ('as Adjudicated') | 0.91 patients with events/100 pt-yrs at risk |
Comparison: Hazard ratio (HR) of the time to cardiovascular death. HR is based on a Cox regression model with terms for age, sex, screening diabetes status, local screening estimated glomerular filtration rate Chronic Kidney Disease Epidemiology Collaboration (eGFR (CKD-EPI)), local screening urine albumin-to-creatinine ratio (UACR), region and treatment.p-value: 0.293295% CI: [0.59, 1.17]Regression, Cox
Secondary
Interventional Part: Time to First Occurrence Cardiovascular Death ('as Adjudicated') or End Stage Kidney Disease (ESKD)
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.
Time frame: 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.
Population: Randomised set (RS) included all randomised participants, whether treated or not.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Placebo | Interventional Part: Time to First Occurrence Cardiovascular Death ('as Adjudicated') or End Stage Kidney Disease (ESKD) | 3.45 patients with events/100 pt-yrs at risk |
| Empagliflozin 10 mg | Interventional Part: Time to First Occurrence Cardiovascular Death ('as Adjudicated') or End Stage Kidney Disease (ESKD) | 2.55 patients with events/100 pt-yrs at risk |
Comparison: Hazard ratio (HR) of the time to first occurrence cardiovascular death or end stage kidney disease (ESKD). HR is based on a Cox regression model with terms for age, sex, screening diabetes status, local screening estimated glomerular filtration rate Chronic Kidney Disease Epidemiology Collaboration (eGFR (CKD-EPI)), local screening urine albumin-to-creatinine ratio (UACR), region and treatment.p-value: 0.001795% CI: [0.59, 0.89]Regression, Cox
Secondary
Interventional Part: Time to First Occurrence of Kidney Disease Progression
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).
Time frame: From the day of randomisation to the day of the final follow-up visit of the interventional part, up to 1136 days.
Population: Randomised set (RS) included all randomised participants, whether treated or not.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Placebo | Interventional Part: Time to First Occurrence of Kidney Disease Progression | 8.09 patients with events/100 pt-yrs at risk |
| Empagliflozin 10 mg | Interventional Part: Time to First Occurrence of Kidney Disease Progression | 6.09 patients with events/100 pt-yrs at risk |
Comparison: Hazard ratio (HR) of the time to first occurrence of kidney disease progression. HR is based on a Cox regression model with terms for age, sex, screening diabetes status, local screening estimated glomerular filtration rate Chronic Kidney Disease Epidemiology Collaboration (eGFR (CKD-EPI)), local screening urine albumin-to-creatinine ratio (UACR), region and treatment.p-value: <0.000195% CI: [0.62, 0.81]Regression, Cox
Secondary
Key Secondary Endpoint: Interventional Part - Time to Death From Any Cause ('as Adjudicated')
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.
Time frame: 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.
Population: Randomised set (RS) included all randomised participants, whether treated or not.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Placebo | Key Secondary Endpoint: Interventional Part - Time to Death From Any Cause ('as Adjudicated') | 2.59 patients with events/100 pt-yrs at risk |
| Empagliflozin 10 mg | Key Secondary Endpoint: Interventional Part - Time to Death From Any Cause ('as Adjudicated') | 2.29 patients with events/100 pt-yrs at risk |
Comparison: Hazard ratio (HR) of the time to death from any cause. HR is based on a Cox regression model with terms for age, sex, screening diabetes status, local screening estimated glomerular filtration rate Chronic Kidney Disease Epidemiology Collaboration (eGFR (CKD-EPI)), local screening Urine albumin-to-creatinine ratio (UACR), region and treatment.p-value: 0.212297.1% CI: [0.68, 1.11]Regression, Cox
Secondary
Key Secondary Endpoint: Interventional Part - Time to First Hospitalization for Heart Failure ('as Adjudicated') or Cardiovascular Death ('as Adjudicated')
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.
Time frame: From the day of randomisation to the day of the final follow-up visit of the interventional part, up to 1140 days.
Population: Randomised set (RS) included all randomised participants, whether treated or not.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Placebo | Key Secondary Endpoint: Interventional Part - Time to First Hospitalization for Heart Failure ('as Adjudicated') or Cardiovascular Death ('as Adjudicated') | 2.39 patients with events/100 pt-yrs at risk |
| Empagliflozin 10 mg | Key Secondary Endpoint: Interventional Part - Time to First Hospitalization for Heart Failure ('as Adjudicated') or Cardiovascular Death ('as Adjudicated') | 2.04 patients with events/100 pt-yrs at risk |
Comparison: Hazard ratio (HR) of the time to first hospitalization for heart failure or cardiovascular death. HR is based on a Cox regression model with terms for age, sex, screening diabetes status, local screening estimated glomerular filtration rate Chronic Kidney Disease Epidemiology Collaboration (eGFR (CKD-EPI)), local screening Urine albumin-to-creatinine ratio (UACR), region and treatment.p-value: 0.136398.55% CI: [0.63, 1.12]Regression, Cox
Secondary
Key Secondary Endpoint: Interventional Part - Time to Occurrences of All-cause Hospitalizations (First and Recurrent Combined)
Time to occurrences of all-cause hospitalizations is reported as total number of all-cause hospitalizations (first and recurrent combined).
Time frame: From the day of randomisation to the day of the final follow-up visit of the interventional part, up to 1140 days.
Population: Randomised set (RS) included all randomised participants, whether treated or not.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Placebo | Key Secondary Endpoint: Interventional Part - Time to Occurrences of All-cause Hospitalizations (First and Recurrent Combined) | 1895 events (first and recurrent) |
| Empagliflozin 10 mg | Key Secondary Endpoint: Interventional Part - Time to Occurrences of All-cause Hospitalizations (First and Recurrent Combined) | 1612 events (first and recurrent) |
Comparison: Hazard ratio (HR) of the time to occurrences of all-cause hospitalizations (first and recurrent combined). HR based on an analysis of recurrent events accounting for terminal events using a joint frailty model with terms for age, log(local screening UACR), local screening Chronic Kidney Disease Epidemiology Collaboration (eGFR (CKD-EPI)), treatment, sex, screening diabetes status, region.p-value: 0.002299.03% CI: [0.76, 0.98]Joint frailty model
Secondary
Magnetic Resonance Imaging Sub-study: Kidney Cortical T1 Mapping as Measured by Modified Look-Locker Inversion Recovery (MOLLI) 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.
Time frame: At 18 months.
Population: Magnetic resonance imaging sub-study: all randomized patients who signed the informed consent form to participate in magnetic resonance imaging sub-study, whether treated or not.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| Placebo | Magnetic Resonance Imaging Sub-study: Kidney Cortical T1 Mapping as Measured by Modified Look-Locker Inversion Recovery (MOLLI) at 18 Months | 1634 milliseconds | Standard Error 11 |
| Empagliflozin 10 mg | Magnetic Resonance Imaging Sub-study: Kidney Cortical T1 Mapping as Measured by Modified Look-Locker Inversion Recovery (MOLLI) at 18 Months | 1622 milliseconds | Standard Error 10 |
Comparison: Differences in MRI measurements between treatment groups were assessed using a linear regression with terms for age, sex, screening diabetes status, local screening eGFR, local screening UACR was used in the analysis.p-value: 0.4195% CI: [-42, 17]Regression, Linear
Secondary
Overall Study: Time to First Occurrence of Death From Any Cause or ESKD
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.
Time frame: 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.
Population: Randomised set (RS) included all randomised participants, whether treated or not.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Placebo | Overall Study: Time to First Occurrence of Death From Any Cause or ESKD | 6.08 patients with events/100 pt-yrs at risk |
| Empagliflozin 10 mg | Overall Study: Time to First Occurrence of Death From Any Cause or ESKD | 5.13 patients with events/100 pt-yrs at risk |
Comparison: Hazard ratio (HR) of the time to first occurrence of death from any cause or ESKD. HR is based on a Cox regression model with terms for age, sex, screening diabetes status, local screening estimated glomerular filtration rate Chronic Kidney Disease Epidemiology Collaboration (eGFR (CKD-EPI)), local screening urine albumin-to-creatinine ratio (UACR), region and treatment.95% CI: [0.72, 0.9]
Secondary
Overall Study: Time to First Occurrence of ESKD
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.
Time frame: 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.
Population: Randomised set (RS) included all randomised participants, whether treated or not.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Placebo | Overall Study: Time to First Occurrence of ESKD | 3.49 patients with events/100 pt-yrs at risk |
| Empagliflozin 10 mg | Overall Study: Time to First Occurrence of ESKD | 2.72 patients with events/100 pt-yrs at risk |
Comparison: Hazard ratio (HR) of ESKD. HR is based on a Cox regression model with terms for age, sex, screening diabetes status, local screening estimated glomerular filtration rate Chronic Kidney Disease Epidemiology Collaboration (eGFR (CKD-EPI)), local screening urine albumin-to-creatinine ratio (UACR), region and treatment.95% CI: [0.64, 0.87]
Secondary
Overall Study: Time to First Occurrence of Kidney Disease Progression
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.
Time frame: 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.
Population: Randomised set (RS) included all randomised participants, whether treated or not.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Placebo | Overall Study: Time to First Occurrence of Kidney Disease Progression | 8.95 patients with events/100 pt-yrs at risk |
| Empagliflozin 10 mg | Overall Study: Time to First Occurrence of Kidney Disease Progression | 7.52 patients with events/100 pt-yrs at risk |
Comparison: Hazard ratio (HR) of the time to first occurrence of kidney disease progression. HR is based on a Cox regression model with terms for age, sex, screening diabetes status, local screening estimated glomerular filtration rate Chronic Kidney Disease Epidemiology Collaboration (eGFR (CKD-EPI)), local screening urine albumin-to-creatinine ratio (UACR), region and treatment.95% CI: [0.72, 0.87]