E.1 Medical condition or disease under investigation |
E.1.1 | Medical condition(s) being investigated |
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E.1.1.1 | Medical condition in easily understood language |
Long-standing problem with kidney function |
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E.1.1.2 | Therapeutic area | Diseases [C] - Nutritional and Metabolic Diseases [C18] |
MedDRA Classification |
E.1.2 Medical condition or disease under investigation |
E.1.2 | Version | 21.1 |
E.1.2 | Level | PT |
E.1.2 | Classification code | 10064848 |
E.1.2 | Term | Chronic kidney disease |
E.1.2 | System Organ Class | 10038359 - Renal and urinary disorders |
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E.1.3 | Condition being studied is a rare disease | No |
E.2 Objective of the trial |
E.2.1 | Main objective of the trial |
The main question is whether taking an empagliflozin pill once a day compared to an inactive pill (placebo) prevents worsening of kidney disease or death from heart disease in people with kidney disease. |
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E.2.2 | Secondary objectives of the trial |
Secondary questions are whether taking empagliflozin pill once a day compared to an inactive pill (placebo) prevents:
- hospitalization with heart failure or death from heart disease
- death from any cause
- hospitalization from any cause
in people with kidney disease.
Other questions include the safety and tolerability of empagliflozin compared to placebo. |
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E.2.3 | Trial contains a sub-study | Yes |
E.2.3.1 | Full title, date and version of each sub-study and their related objectives |
Title: EMPA-KIDNEY Body Composition Measurement Substudy
Protocol: EMPA-KIDNEY Body composition measurement substudy justification and design V1.0 – 02-MAR-2019
Objectives:
The primary aim of this substudy is to use bioimpedance spectroscopy to assess, in a subset of EMPA-KIDNEY participants, the effect of empagliflozin 10 mg versus matching placebo on "Fluid Overload" at Randomisation, 2 month and 18 month Follow-up Visits.
Secondary aims are to use bioimpedance spectroscopy to assess:
1. Whether any effects of empagliflozin 10 mg versus matching placebo on "Fluid Overload" are modified by baseline factors, in particular by level of kidney function, glycosylated haemoglobin, body mass index, NT-proBNP, age, sex, RAS inhibitor use, and different diuretics
2. The effects of empagliflozin 10 mg versus matching placebo early and later during follow-up on:
- ECW
- Intracellular water (ICW)
- Adipose tissue mass indexed to weight (i.e. %)
- Lean tissue mass indexed to weight (i.e. %)
Exploratory aims are to:
- Assess if changes in ECW, ICW, % adipose tissue mass, % lean tissue mass and "Fluid Overload" correlate with changes in blood pressure and relevant other biomarkers
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E.3 | Principal inclusion criteria |
Age >=18 years at Screening.
Evidence of progressive CKD at risk of kidney disease progression is defined on the basis of local laboratory results recorded at least 3 months before and at the time of the Screening visit, and requires that:
(a) CKD-EPI eGFR ≥20 <45 mL/min/1.73m²; or
(b) CKD-EPI eGFR ≥45 <90 mL/min/1.73m² with urinary albumin:creatinine ratio ≥200 mg/g (or protein:creatinine ratio ≥300 mg/g)
Note: the number of participants with or without diabetes mellitus (of any type) will be at least one-third of each, and the number of participants with an eGFR >45 mL/min/1.73m² limited to about one-third. The Steering Committee will monitor these proportions and will limit recruitment of particular categories of participants in whom sufficient numbers have already been screened or randomized. |
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E.4 | Principal exclusion criteria |
None of the following must be fulfilled:
(i) Currently receiving SGLT-2 or SGLT-1/2 inhibitor;
(ii) Diabetes mellitus type 2 and prior atherosclerotic cardiovascular disease with an eGFR >60 mL/min/1.73m² at Screening;
(iii) Receiving combined ACEi and ARB treatment;
(iv) Maintenance dialysis, functioning kidney transplant, or scheduled living donor transplant;
(v) Polycystic kidney disease;
(vi) Previous or scheduled bariatric surgery;
(vii) Ketoacidosis in the past 5 years;
(viii) Symptomatic hypotension, or systolic blood pressure <90 or >180 mmHg at Screening;
(ix) ALT or AST >3x ULN at Screening;
(x) Hypersensitivity to empagliflozin or other SGLT-2 inhibitors;
(xi) Any immunosuppression therapy in last 3 months; or anyone currently on >45 mg prednisolone (or equivalent);
(xii) Use of an investigational medicinal product in the 30 days prior to Screening visit;
(xiii) Known to be poorly compliant with clinic visits or prescribed medication;
(xiv) 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);
(xv) Current pregnancy, lactation or women of childbearing potential (WOCBP), unless using highly-effective contraception;
(xvi) Type 1 Diabetes mellitus.
In addition, individuals will be excluded at the Randomization visit if the participant:
(i) Does not adhere to Run-in treatment;
(ii) Is no longer willing to be randomized and followed for at least 3 years;
(iii) Is considered by a local investigator not to be suitable for randomization; or
(iv) Experiences ketoacidosis, heart attack, stroke, or hospitalization for heart failure, or hospitalization for urinary tract infection or acute kidney injury during Run-in.
Note that individuals who do not fulfil one or more inclusion criteria, or who fulfil one or more exclusion criteria, may be re-screened and later become eligible. |
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E.5 End points |
E.5.1 | Primary end point(s) |
Time to first occurrence of:
• Kidney disease progression (end-stage kidney disease, a sustained eGFR <10 mL/min/1.73m², renal death, or a sustained ≥40% decline in eGFR from randomization) or
• Cardiovascular death |
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E.5.1.1 | Timepoint(s) of evaluation of this end point |
After accrual of at least 1070 primary outcome events as defined in E.5.1 |
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E.5.2 | Secondary end point(s) |
a) Time to first hospitalization for heart failure or cardiovascular death;
b) Occurrences of all-cause hospitalizations (first and recurrent);
c) Time to death from any cause. |
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E.5.2.1 | Timepoint(s) of evaluation of this end point |
After accrual of at least 1070 primary outcome events as defined in E.5.1 |
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E.6 and E.7 Scope of the trial |
E.6 | Scope of the trial |
E.6.1 | Diagnosis | No |
E.6.2 | Prophylaxis | No |
E.6.3 | Therapy | No |
E.6.4 | Safety | Yes |
E.6.5 | Efficacy | Yes |
E.6.6 | Pharmacokinetic | No |
E.6.7 | Pharmacodynamic | No |
E.6.8 | Bioequivalence | No |
E.6.9 | Dose response | No |
E.6.10 | Pharmacogenetic | Yes |
E.6.11 | Pharmacogenomic | Yes |
E.6.12 | Pharmacoeconomic | Yes |
E.6.13 | Others | No |
E.7 | Trial type and phase |
E.7.1 | Human pharmacology (Phase I) | No |
E.7.1.1 | First administration to humans | No |
E.7.1.2 | Bioequivalence study | No |
E.7.1.3 | Other | No |
E.7.1.3.1 | Other trial type description | |
E.7.2 | Therapeutic exploratory (Phase II) | No |
E.7.3 | Therapeutic confirmatory (Phase III) | Yes |
E.7.4 | Therapeutic use (Phase IV) | No |
E.8 Design of the trial |
E.8.1 | Controlled | Yes |
E.8.1.1 | Randomised | Yes |
E.8.1.2 | Open | No |
E.8.1.3 | Single blind | No |
E.8.1.4 | Double blind | Yes |
E.8.1.5 | Parallel group | Yes |
E.8.1.6 | Cross over | No |
E.8.1.7 | Other | No |
E.8.2 | Comparator of controlled trial |
E.8.2.1 | Other medicinal product(s) | No |
E.8.2.2 | Placebo | Yes |
E.8.2.3 | Other | No |
E.8.2.4 | Number of treatment arms in the trial | 2 |
E.8.3 |
The trial involves single site in the Member State concerned
| No |
E.8.4 | The trial involves multiple sites in the Member State concerned | Yes |
E.8.4.1 | Number of sites anticipated in Member State concerned | 20 |
E.8.5 | The trial involves multiple Member States | Yes |
E.8.5.1 | Number of sites anticipated in the EEA | 70 |
E.8.6 Trial involving sites outside the EEA |
E.8.6.1 | Trial being conducted both within and outside the EEA | Yes |
E.8.6.2 | Trial being conducted completely outside of the EEA | No |
E.8.6.3 | If E.8.6.1 or E.8.6.2 are Yes, specify the regions in which trial sites are planned |
Canada |
China |
Germany |
Japan |
Malaysia |
Norway |
Sweden |
United Kingdom |
United States |
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E.8.7 | Trial has a data monitoring committee | Yes |
E.8.8 |
Definition of the end of the trial and justification where it is not the last
visit of the last subject undergoing the trial
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When the minimum number of required study outcomes has accrued, or the independent Data Monitoring Committee advises the trial should be stopped early, participants will be invited to Final Follow-up visits. This visit may occur earlier than their planned next 6-monthly visit. The end of the trial is then defined as the latest of the following two dates:
7 days after the last participant’s Final Follow-up visit, or the date of the last 4-week post-Final Follow-up blood draw. |
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E.8.9 Initial estimate of the duration of the trial |
E.8.9.1 | In the Member State concerned years | 4 |
E.8.9.1 | In the Member State concerned months | 0 |
E.8.9.1 | In the Member State concerned days | 0 |
E.8.9.2 | In all countries concerned by the trial years | 4 |
E.8.9.2 | In all countries concerned by the trial months | 0 |
E.8.9.2 | In all countries concerned by the trial days | 0 |