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

• ClinicalTrials.gov Identifier: NCT03594110
• Recruitment Status: Active, not recruiting
• First Posted: July 20, 2018
• Results First Posted: July 27, 2023
• Last Update Posted: August 3, 2023
• Sponsor: Boehringer Ingelheim
• Collaborators: Medical Research Council Population Health Research Unit, CTSU, University of Oxford (academic lead); Eli Lilly and Company
• Information provided by (Responsible Party): Boehringer Ingelheim

Tracking Information

• First Submitted Date: July 10, 2018
• First Posted Date: July 20, 2018
• Results First Submitted Date: June 30, 2023
• Results First Posted Date: July 27, 2023
• Last Update Posted Date: August 3, 2023
• Actual Study Start Date: January 31, 2019
• Actual Primary Completion Date: July 5, 2022 (Final data collection date for primary outcome measure)

Current Primary Outcome Measures (submitted: June 30, 2023)

Interventional Part: Time to First Occurrence of Kidney Disease Progression or Cardiovascular Death ('as Adjudicated') [ Time Frame: Follow-up period: From the day of randomisation to the day of the final follow-up visit, up to 1136 days. ]

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.

Original Primary Outcome Measures (submitted: July 10, 2018)

Composite primary outcome:Time to first occurrence of (i) kidney disease progression (defined as ESKD, a sustained decline in eGFR to <10 mL/min/1.73m², renal death, or a sustained decline of ≥40% in eGFR from randomization) or (ii) Cardiovascular death [ Time Frame: Median follow-up approx. 3.1 years ]

End Stage Kidney Disease (ESKD) is defined as the initiation of maintenance dialysis or receipt of a kidney transplant

Current Secondary Outcome Measures (submitted: June 30, 2023)

• Key Secondary Endpoint: Interventional Part - Time to First Hospitalization for Heart Failure ('as Adjudicated') or Cardiovascular Death ('as Adjudicated') [ Time Frame: Follow-up period: From the day of randomisation to the day of the final follow-up visit, up to 1140 days. ]
  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.
• Key Secondary Endpoint: Interventional Part - Time to Occurrences of All-cause Hospitalizations (First and Recurrent Combined) [ Time Frame: Follow-up period: From the day of randomisation to the day of the final follow-up visit, up to 1140 days. ]
  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.
• Key Secondary Endpoint: Interventional Part - Time to Death From Any Cause ('as Adjudicated') [ Time Frame: Follow-up period: From the day of randomisation to the day of the final follow-up visit, up to 1140 days. ]
  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.
• Interventional Part: Time to First Occurrence of Kidney Disease Progression [ Time Frame: Follow-up period: From the day of randomisation to the day of the final follow-up visit, up to 1136 days. ]
  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).
• Interventional Part: Time to Cardiovascular Death ('as Adjudicated') [ Time Frame: Follow-up period: From the day of randomisation to the day of the final follow-up visit, up to 1140 days. ]
  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.
• Interventional Part: Time to First Occurrence Cardiovascular Death ('as Adjudicated') or End Stage Kidney Disease (ESKD) [ Time Frame: Follow-up period: From the day of randomisation to the day of the final follow-up visit, up to 1140 days. ]
  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.

Original Secondary Outcome Measures (submitted: July 10, 2018)

• Time to first hospitalization for heart failure or cardiovascular death [ Time Frame: Median follow-up approx. 3.1 years ]
• Occurrences of all-cause hospitalization (first and recurrent) [ Time Frame: Median follow-up approx. 3.1 years ]
• Time to death from any cause [ Time Frame: Median follow-up approx. 3.1 years ]
• Time to first occurrence of kidney disease progression [ Time Frame: Median follow-up approx. 3.1 years ]
• Time to cardiovascular death [ Time Frame: Median follow-up approx. 3.1 years ]
• Time to cardiovascular death or ESKD [ Time Frame: Median follow-up approx. 3.1 years ]

• Current Other Pre-specified Outcome Measures: Not Provided
• Original Other Pre-specified Outcome Measures: Not Provided

Descriptive Information

• Brief Title: EMPA-KIDNEY (The Study of Heart and Kidney Protection With Empagliflozin)
• Official Title: 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
• 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 Provided
• Study Type: Interventional
• Study Phase: Phase 3
• Study Design: Allocation: Randomized; Intervention Model: Parallel Assignment; Masking: Double (Participant, Investigator); Primary Purpose: Treatment
• Condition: Chronic Kidney Disease

Intervention

• Drug: Empagliflozin
  Taken daily with or without food
• Drug: Matching placebo
  Taken daily with or without food

Study Arms

• Experimental: 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.
  Intervention: Drug: Empagliflozin
• Placebo Comparator: 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.
  Intervention: Drug: Matching placebo

Publications *

• The EMPA-KIDNEY Collaborative Group; Herrington WG, Staplin N, Wanner C, Green JB, Hauske SJ, Emberson JR, Preiss D, Judge P, Mayne KJ, Ng SYA, Sammons E, Zhu D, Hill M, Stevens W, Wallendszus K, Brenner S, Cheung AK, Liu ZH, Li J, Hooi LS, Liu W, Kadowaki T, Nangaku M, Levin A, Cherney D, Maggioni AP, Pontremoli R, Deo R, Goto S, Rossello X, Tuttle KR, Steubl D, Petrini M, Massey D, Eilbracht J, Brueckmann M, Landray MJ, Baigent C, Haynes R. Empagliflozin in Patients with Chronic Kidney Disease. N Engl J Med. 2023 Jan 12;388(2):117-127. doi: 10.1056/NEJMoa2204233. Epub 2022 Nov 4.
• Tuttle KR, Levin A, Nangaku M, Kadowaki T, Agarwal R, Hauske SJ, Elsasser A, Ritter I, Steubl D, Wanner C, Wheeler DC. Safety of Empagliflozin in Patients With Type 2 Diabetes and Chronic Kidney Disease: Pooled Analysis of Placebo-Controlled Clinical Trials. Diabetes Care. 2022 Jun 2;45(6):1445-1452. doi: 10.2337/dc21-2034.
• Almaimani M, Sridhar VS, Cherney DZI. Sodium-glucose cotransporter 2 inhibition in non-diabetic kidney disease. Curr Opin Nephrol Hypertens. 2021 Sep 1;30(5):474-481. doi: 10.1097/MNH.0000000000000724.
• Piperidou A, Loutradis C, Sarafidis P. SGLT-2 inhibitors and nephroprotection: current evidence and future perspectives. J Hum Hypertens. 2021 Jan;35(1):12-25. doi: 10.1038/s41371-020-00393-4. Epub 2020 Aug 10.
• Gonzalez DE, Foresto RD, Ribeiro AB. SGLT-2 inhibitors in diabetes: a focus on renoprotection. Rev Assoc Med Bras (1992). 2020 Jan 13;66Suppl 1(Suppl 1):s17-s24. doi: 10.1590/1806-9282.66.S1.17.

Recruitment Information

• Recruitment Status: Active, not recruiting
• Actual Enrollment (submitted: May 27, 2021): 6609
• Original Estimated Enrollment (submitted: July 10, 2018): 5000
• Estimated Study Completion Date: January 31, 2025
• Actual Primary Completion Date: July 5, 2022 (Final data collection date for primary outcome measure)

Eligibility Criteria

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

Sex/Gender

• Sexes Eligible for Study: All

• Ages: 18 Years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Contacts: Contact information is only displayed when the study is recruiting subjects
• Listed Location Countries: Canada, China, Germany, Italy, Japan, Malaysia, United Kingdom, United States

Administrative Information

• NCT Number: NCT03594110
• Other Study ID Numbers: 1245-0137; 2017-002971-24 ( EudraCT Number )
• Has Data Monitoring Committee: Not Provided

U.S. FDA-regulated Product

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

IPD Sharing Statement

• Plan to Share IPD: Yes
• Plan Description: After the study is completed and the primary manuscript is accepted for publishing, researchers can use this following link https://www.mystudywindow.com/msw/datasharing to request access to the clinical study documents regarding this study, and upon a signed "Document Sharing Agreement". Also, Researchers can use the following link https://www.mystudywindow.com/msw/datasharing to find information in order to request access to the clinical study data, for this and other listed studies, after the submission of a research proposal and according to the terms outlined in the website. The data shared are the raw clinical study data sets.
• Supporting Materials: Study Protocol
• Supporting Materials: Statistical Analysis Plan (SAP)
• Supporting Materials: Clinical Study Report (CSR)
• Time Frame: After all regulatory activities are completed in the US and EU for the product and indication, and after the primary manuscript has been accepted for publication.
• Access Criteria: For study documents - upon signing of a 'Document Sharing Agreement'. For study data - 1. after the submission and approval of the research proposal (checks will be performed by both the independent review panel and the sponsor, including checking that the planned analysis does not compete with sponsor's publication plan); 2. and upon signing of a 'Data Sharing Agreement'.
• URL: https://www.mystudywindow.com/msw/datasharing

• Current Responsible Party: Boehringer Ingelheim
• Original Responsible Party: Same as current
• Current Study Sponsor: Boehringer Ingelheim
• Original Study Sponsor: Same as current

Collaborators

• Medical Research Council Population Health Research Unit, CTSU, University of Oxford (academic lead)
• Eli Lilly and Company

• Investigators: Not Provided
• PRS Account: Boehringer Ingelheim
• Verification Date: August 2023