| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
| chronic kidney disease |
| Enfermedad Renal Crónica |
|
| E.1.1.1 | Medical condition in easily understood language |
| chronic kidney disease |
| Enfermedad Renal Crónica |
|
| E.1.1.2 | Therapeutic area | Diseases [C] - Cardiovascular Diseases [C14] |
| MedDRA Classification |
| E.1.2 Medical condition or disease under investigation |
| E.1.2 | Version | 23.1 |
| 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 |
|
| 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 trial will compare 3 doses of BI 690517 with placebo in patients with diabetic and nondiabetic CKD randomised to empagliflozin or placebo as background therapy (established during the randomised run-in). |
| En el ensayo se compararán 3 dosis de BI 690517 con placebo en pacientes con ERC diabética y no diabética aleatorizados a empagliflozina o placebo como tratamiento de base (establecido durante el ensayo aleatorizado). |
|
| E.2.2 | Secondary objectives of the trial |
| Secondary objectives will be as above but in subpopulations of (1) placebo background therapy (2) empagliflozin background therapy. |
| Los objetivos secundarios serán los indicados anteriormente pero en subpoblaciones de (1) tratamiento de base con placebo (2) tratamiento de base con empagliflozina. |
|
| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal inclusion criteria |
1. Signed and dated written informed consent in accordance with ICH-GCP and local legislation prior to admission to the trial.
2. Male or female patients aged ≥ 18 years at time of consent.
3. eGFR (Chronic Kidney Disease Epidemiology Collaboration [CKD-EPI] formula) ≥ 30 and < 90 mL/min/1.73 m2 at Visit 1 by central laboratory analysis.
4. UACR ≥ 200 and < 5,000 mg/g in spot urine (midstream urine sample) by central laboratory analysis at Visit 1.1
5. If the patient is taking any of the following medications they should be on a stable dose for at least 4 weeks prior to visit 1 and until first randomisation prior to run-in with no planned change of the therapy during the trial: anti-hypertensives, NSAIDs, endothelin receptor antagonists, low dose systemic steroids (e.g. prednisolone ≤10 mg or equivalent).
6. Treatment with a clinically appropriate, stable dose of either ACEi or ARB (but not both together), for ≥ 4 weeks prior to visit 1 and until first randomisation with no planned change of the therapy during the trial.
7. In the Investigator’s opinion, one or more of the following underlying kidney disease causes:
-- Diabetic kidney disease. These patients must have type 2 diabetes mellitus and their treatment (including GLP1 receptor agonist) should be unchanged or changes deemed minor (according to investigator’s judgement) within 4 weeks prior to Visit 1 and until first randomisation.
-- Hypertensive kidney disease
-- Chronic glomerulonephritis defined as one of the following:
o IgA nephropathy,
o Membranous nephropathy
o Focal Segmental Glomerulosclerosis (FSGS)
8. Glycated Haemoglobin (HbA1c) < 10.0% at Visit 1 measured by the central laboratory.
9. Serum potassium ≤ 4.8 mmol/L at Visit 1 measured by the central laboratory.
10. Seated SBP ≥ 110 and ≤ 160 mmHg and DBP ≥ 65 and ≤ 110 mmHg at Visit 1 (mean values from three BP measurements) and optimised anti-hypertensive treatment according to local standard of care and investigator’s judgement.
11. Body Mass Index (BMI) ≥ 18.5 and < 50 kg/m2 at Visit 1.
12. Women of child-bearing potential2 (WOCBP) must be ready and able to use highly effective methods of birth control. Such methods should be used throughout the trial. Men must be vasectomised or willing and able to use a condom if their partner is a WOCBP.
Additional inclusion criteria to be assessed before second randomisation (start of Treatment Period):
1. Serum potassium ≤ 4.8 mmol/L measured by local or central laboratory within 7 days prior to randomisation to the Treatment Period.
2. eGFR (Chronic Kidney Disease Epidemiology Collaboration [CKD-EPI] formula) ≥ 20 mL/min/1.73 m2 measured by local or central laboratory within 7 days prior to randomisation to the Treatment Period. |
1. Consentimiento informado, firmado y fechado, de conformidad con la ICH-GCP y la legislación local antes de la admisión en el ensayo.
2. Pacientes de sexo masculino o femenino de edad ≥ 18 años en el momento del consentimiento.
3. eGFR (fórmula de Colaboración en Epidemiología de Enfermedad Renal Crónica [CKD-EPI]) ≥ 30 y < 90 mL/min/1,73 m2 en la visita 1 por análisis de laboratorio central.
4. UACR ≥ 200 y < 5.000 mg/g en orina puntual (muestra de orina intermedia) mediante análisis de laboratorio central en la visita 1.1
5. Si el paciente está tomando cualquiera de los siguientes medicamentos, deben mantenerse a una dosis estable durante al menos 4 semanas antes de la visita 1 y hasta la primera aleatorización antes del inicio del tratamiento sin ningún cambio planificado de la terapia durante el ensayo: antihipertensivos, AINEs, antagonistas de los receptores de la endotelina, esteroides sistémicos a dosis bajas (por ejemplo prednisolona ≤10 mg o equivalente).
6. Tratamiento con una dosis estable, clínicamente apropiada, de IECA o ARA (pero no ambos juntos), durante ≥ 4 semanas antes de la visita 1 y hasta la primera aleatorización sin cambio planificado del tratamiento durante el ensayo.
7. En opinión del investigador, una o más de las siguientes causas subyacentes de enfermedad renal:
— Enfermedad renal diabética. Estos pacientes deben tener diabetes mellitus tipo 2 y su tratamiento (incluyendo el agonista del receptor GLP1) debe estar inalterado o los cambios son considerados menores (según el criterio del investigador) dentro de las 4 semanas previas a la visita 1 y hasta la primera aleatorización.
— Enfermedad renal hipertensiva
— Glomerulonefritis crónica, definida como una de las siguientes:
o Nefropatía IgA
o Nefropatía membranosa
o Glomeruloesclerosis Focal y Segmentaria (GESF)
8. Hemoglobina glicada (HbA1c) < 10,0% en la visita 1 medida por el laboratorio central.
9. Potasio sérico ≤ 4,8 mmol/L en la visita 1 medido por el laboratorio central.
10. PAS ≥ 110 y ≤ 160 mmHg y PAD ≥ 65 y ≤ 110 mmHg en la visita 1 (valores medios de tres mediciones de PA) y tratamiento antihipertensivo optimizado de acuerdo con las normas locales de atención y el criterio del investigador.
11. Índice de masa corporal (IMC) ≥ 18,5 y < 50 kg/m2 en la visita 1.
12. Las mujeres en edad fértil (WOCBP) deben estar preparadas y ser capaces de utilizar métodos de control de la natalidad muy eficaces. Estos métodos deben utilizarse durante todo el ensayo. Los hombres deben ser vasectomizados o dispuestos y capaces de usar un preservativo si su pareja es una WOCBP.
Criterios de inclusión adicionales que deben evaluarse antes de la segunda aleatorización (inicio del periodo de tratamiento):
1. Potasio sérico ≤ 4,8 mmol/L medido por laboratorio local o central en los 7 días previos a la aleatorización del periodo de tratamiento.
2. eGFR (fórmula Colaboración en Epidemiología de Enfermedad Renal Crónica [CKD-EPI]) ≥ 20 mL/min/1,73 m2 medido por laboratorio local o central en los 7 días previos a la aleatorización al periodo de tratamiento. |
|
| E.4 | Principal exclusion criteria |
1. Treatment with inhibitors of aldosterone mediated effects (e.g., mineralocorticoid receptor antagonists such as spironolactone), or intake of other potassium sparing diuretics (e.g., amiloride) within 7 days prior to first randomisation or planned during trial treatment phase.
2. Treatment with other Renin Angiotensin Aldosterone System (RAAS) interventions (apart from either ACEi or ARB) within 4 weeks prior to Visit 1 and throughout screening or planned during the trial.
3. Type 1 diabetes mellitus, or history of other autoimmune causes of diabetes mellitus (e.g. LADA)
4. Patients at increased risk of ketoacidosis in the opinion of the investigator.
5. Currently receiving SGLT-2 or SGLT-1/2 inhibitor or planned initiation during the trial.
Further criteria apply. |
1. Tratamiento con inhibidores de los efectos mediados por la aldosterona (por ejemplo, antagonistas de los receptores mineralocorticoides como la espironolactona), o ingesta de otros diuréticos ahorradores de potasio (por ejemplo, amilorida) en los 7 días previos a la primera aleatorización o planificado durante la fase de tratamiento del ensayo.
2. Tratamiento con otras intervenciones del Sistema Renina Angiotensina Aldosterona (RAAS) (aparte de IECA o ARA) dentro de las 4 semanas previas a la visita 1 y durante el cribado o planificadas durante el ensayo.
3. Diabetes mellitus tipo 1 o antecedentes de otras causas autoinmunes de diabetes mellitus (por ejemplo, LADA)
4. Pacientes con mayor riesgo de cetoacidosis en opinión del investigador.
5. Actualmente recibiendo inhibidor de SGLT-2 o SGLT-1/2 o inicio planificado durante el ensayo.
Se aplican otros criterios. |
|
| E.5 End points |
| E.5.1 | Primary end point(s) |
| Change from treatment period baseline in log transformed Urine Albumin Creatinine Ratio (UACR) measured in First Morning Void urine after 14 weeks. |
| Cambio respecto al inicio en el cociente albúmina/creatina en orina (UACR) transformado logarítmicamente medido en la primera orina de la mañana después de 14 semanas. |
|
| E.5.1.1 | Timepoint(s) of evaluation of this end point |
|
| E.5.2 | Secondary end point(s) |
1) UACR response I, defined as decrease of at least 30% absolute change in First Morning Void urine of UACR from treatment period baseline to 14 weeks.
2) UACR response II, defined as decrease of at least 15% absolute change in First Morning Void urine of UACR from treatment period baseline to 14 weeks. |
1) Respuesta I de UACR, definida como una disminución de al menos un 30% en el cambio absoluto de UACR en la primera orina de la mañana desde el inicio del tratamiento hasta las 14 semanas.
2) Respuesta UACR II, definida como una disminución de al menos un 15% en el cambio absoluto de UACR en la primera orina de la mañana desde el inicio del tratamiento hasta las 14 semanas. |
|
| E.5.2.1 | Timepoint(s) of evaluation of this end point |
1) 14 weeks
2) 14 weeks |
1) 14 semanas
2) 14 semanas |
|
| 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 | Yes |
| 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 | Yes |
| E.6.10 | Pharmacogenetic | No |
| E.6.11 | Pharmacogenomic | Yes |
| E.6.12 | Pharmacoeconomic | No |
| 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) | Yes |
| E.7.3 | Therapeutic confirmatory (Phase III) | No |
| 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) | Yes |
| E.8.2.2 | Placebo | Yes |
| E.8.2.3 | Other | No |
| E.8.2.4 | Number of treatment arms in the trial | 8 |
| 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 | 6 |
| E.8.5 | The trial involves multiple Member States | Yes |
| E.8.5.1 | Number of sites anticipated in the EEA | 75 |
| 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 |
| Australia |
| Hong Kong |
| Mexico |
| Peru |
| Philippines |
| South Africa |
| Turkey |
| Argentina |
| Belgium |
| Brazil |
| Bulgaria |
| Canada |
| China |
| Czechia |
| Denmark |
| Finland |
| Germany |
| Greece |
| Hungary |
| India |
| Israel |
| Italy |
| Japan |
| Korea, Republic of |
| Malaysia |
| Norway |
| Poland |
| Portugal |
| Russian Federation |
| Spain |
| Sweden |
| Switzerland |
| Ukraine |
| United States |
| Vietnam |
| France |
|
| 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
|
| LVLS |
| Última visita del último paciente |
|
| E.8.9 Initial estimate of the duration of the trial |
| E.8.9.1 | In the Member State concerned years | 1 |
| E.8.9.1 | In the Member State concerned months | 6 |
| E.8.9.1 | In the Member State concerned days | |
| E.8.9.2 | In all countries concerned by the trial years | 1 |
| E.8.9.2 | In all countries concerned by the trial months | 7 |
| E.8.9.2 | In all countries concerned by the trial days | 19 |
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