E.1 Medical condition or disease under investigation |
E.1.1 | Medical condition(s) being investigated |
Treatment of cardiovascular and renal disease in patients with chronic kidney disease |
Tratamiento de la enfermedad cardiovascular y renal en pacientes con insuficiencia renal crónica. |
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E.1.1.1 | Medical condition in easily understood language |
chronic kidney disease |
Insuficiencia renal crónica |
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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 | 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.1.2 Medical condition or disease under investigation |
E.1.2 | Version | 20.0 |
E.1.2 | Level | PT |
E.1.2 | Classification code | 10001580 |
E.1.2 | Term | Albuminuria |
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 |
To investigate the change in albuminuria by urinary albumin-to-creatinine ratio (UACR) after treatment with titrated doses of runcaciguat given once daily from baseline to day 57 (+/-3) |
Evaluar el cambio en la albuminuria mediante el cociente de albúmina/creatinina en orina (CAC) después del tratamiento con dosis ajustadas de runcaciguat administradas una vez al día desde el inicio hasta el día 57 (+/-3). |
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E.2.2 | Secondary objectives of the trial |
To investigate the overall safety and tolerability of runcaciguat |
Evaluar la seguridad y la tolerabilidad generales de runcaciguat. |
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E.2.3 | Trial contains a sub-study | No |
E.3 | Principal inclusion criteria |
Age 1. Participant must be ≥ 45 of age inclusive, at the time of signing the informed consent. Type of Participant and Disease Characteristics 2. Participants who have: • history of any of the following: - type 2 diabetes mellitus as defined by the American Diabetes Association (on treatment with glucose-lowering medications and/or insulin) for at least 2 years, and/or - diagnosis of hypertension (defined as systolic blood pressure [BP] values ≥ 140 mmHg and/or diastolic BP values ≥90 mmHg) and on hypertension medication for at least 5 years • established atherosclerotic cardiovascular disease (e.g. coronary artery disease, peripheral arterial disease, cerebrovascular disease) or heart failure • a clinical diagnosis of CKD based on all of the following criteria: - (estimated) glomerular filtration rate (eGFR) ≥ 25 mL/min/1.73 m2 but ≤ 60 mL/min/1.73 m2 (acc. Percentage of decrease in eGFR [CKD EPI]) - persistent high albuminuria defined as urine albumin-to-creatinine ratio [UACR] of between 30 mg/g and 3000 mg/g in 2 first morning void samples (collected at least 1 week apart) - Stable treatment with angiotensin-converting enzyme inhibitor (ACEi) or angiotensin-receptor blocker (ARB) for the participant maximum tolerated labelled daily dose and otherwise stable antihypertensive treatment both for at least 3 months before randomization, without any adjustments to this therapy for at least 4 weeks prior to randomization. • Diabetes patients that are on SGLT2-inhibitor (SGLT: sodium glucose transport protein) have to be on stable treatment for at least 3 months before Screening visit. |
Edad 1. El sujeto debe tener una edad de ≥ 45 años en el momento de firmar el consentimiento informado. Tipo de sujeto y características de la enfermedad: 2. Sujetos que tengan: • Antecedentes de cualquiera de las siguientes: -diabetes mellitus de tipo 2 según la definición de la American Diabetes Association (en tratamiento con medicamentos hipoglucemiantes o insulina) durante al menos 2 años, y/o -diagnóstico de hipertensión (definida como valores de PA sistólica ≥140 mm Hg y/o valores de PA diastólica ≥90 mm Hg) y con medicamentos para la hipertensión durante al menos 5 años • enfermedad cardiovascular aterosclerótica establecida (p. ej., arteriopatía coronaria, arteriopatía periférica, enfermedad cerebrovascular) o insuficiencia cardíaca •diagnóstico clínico de IRC basado en todos los siguientes criterios: - TFGe ≥25 ml/min/1,73 m2, pero ≤60 ml/min/1,73 m2 (conforme a CKD EPI); - albuminuria alta persistente definida como CAC entre 30 mg/g y 3000 mg/g en 2 muestras de la primera orina de la mañana (recogidas con al menos 1 semana de diferencia). - Tratamiento estable con IECA o ARA II en la dosis diaria máxima tolerada por el participante y, de lo contrario, tratamiento antihipertensor estable, en ambos casos por lo menos durante 3 meses antes de la aleatorización, sin ningún ajuste en dichos tratamientos durante al menos 4 semanas antes de la aleatorización. •Los sujetos con diabetes que reciben inhibidores de SGLT2 deben estar en tratamiento estable durante al menos 3 meses antes de la visita de selección. |
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E.4 | Principal exclusion criteria |
Medical Conditions 1. Known non-diabetic and non-hypertension related renal diseases as autosomal dominant polycystic kidney disease, bilateral clinically relevant renal artery stenosis, lupus nephritis, or ANCA-associated vasculitis, IgA nephropathy without hypertension, or any other secondary glomerulonephritis 2. Clinical diagnoses of heart failure and persistent symptoms (New York Heart Association (NYHA class III - IV) 3. Uncontrolled hypertension indicated by >160 mmHg systolic BP or ≥100 mmHg diastolic BP 4. History of secondary hypertension (i.e., renal artery stenosis, primary aldosteronism, or pheochromocytoma). 5. Stroke, transient ischemic cerebral attack, acute coronary syndrome, or hospitalization for worsening heart failure, in the last 3 months prior to the planned randomization 6. Dialysis for acute renal failure within the previous 6 months prior to the planned randomization 7. Renal allograft in place or a scheduled kidney transplant within the next 18 weeks (being on a waiting list does not exclude the subject) 8. Hepatic insufficiency classified as Child-Pugh B or C or other significant liver disease (e.g., acute hepatitis, chronic active hepatitis, cirrhosis as indicated by e.g. aspartate aminotransferase [AST] or Alanine aminotransferase [ALT] >3x upper limit of norm [ULN]). 9. Active malignancy other than treated squamous cell, carcinoma in situ, or basal cell carcinoma of the skin Prior/Concomitant Therapy 10. Non diabetic patients treated with SGLT-2 inhibitors 11. Combination use of ACEi and ARB within 3 months prior to randomization 12. Concomitant therapy with nitrates, PDE5 inhibitors including non-specific inhibitors (e.g. dipyridamole and theophylline), soluble guanylate cyclase [sGC] stimulators, renin inhibitors (within 4 weeks prior to randomization) 13. Participation in another clinical study or treatment with another investigational product 90 days prior to randomization 14. Previous randomization in this study Diagnostic Assessments 15. HbA1c >11% |
Condiciones médicas 1. Nefropatías conocidas no diabéticas y no relacionadas con hipertensión, como poliquistosis renal autosómica dominante, estenosis bilateral de las arterias renales de relevancia clínica, nefritis lúpica o vasculitis asociada a ANCA, nefropatía por IgA sin hipertensión o cualquier otra glomerulonefritis secundaria. 2.Diagnósticos clínicos de insuficiencia cardíaca y síntomas persistentes (clase funcional III o IV de la New York Heart Association [NYHA]). 3.Hipertensión no controlada indicada por >160 mm Hg de PA sistólica o ≥100 mm Hg de PA diastólica. 4.Antecedentes de hipertensión secundaria (es decir, estenosis de la arteria renal, aldosteronismo primario o feocromocitoma). 5. Ictus, accidente cerebral isquémico transitorio, síndrome coronario agudo u hospitalización por empeoramiento de la insuficiencia cardíaca, en los 3 meses previos a la aleatorización programada. 6.Diálisis por insuficiencia renal aguda en los 6 meses previos a la aleatorización programada. 7. Alotrasplante renal o trasplante de riñón programado en las 18 semanas siguientes (estar en lista de espera no excluirá a los pacientes). 8.Insuficiencia hepática clasificada con la clase B o C de la escala Child-Pugh u otra hepatopatía significativa (p. ej., hepatitis aguda, hepatitis crónica activa, cirrosis evaluada mediante p. ej. AST o ALT > 3 × LSN). 9.Neoplasia maligna activa que no sea de células escamosas, carcinoma in situ o carcinoma basocelular de la piel Tratamiento previo y concomitante 10. Pacientes no diabéticos tratados con inhibidores de SGLT-2. 11. Uso combinado de IECA y ARA II en los 3 meses previos a la aleatorización. 12. Tratamiento concomitante con nitratos, inhibidores de PDE5, incluidos inhibidores no específicos (por ejemplo, dipiridamol y teofilina), estimuladores de GCs, inhibidores de renina (en las 4 semanas previas a la aleatorización). 13. Participación en otro ensayo clínico o tratamiento con otro producto en investigación 90 días antes de la aleatorización. 14. Aleatorización previa en este ensayo Evaluaciones diagnósticas 15. HbA1c >11 % |
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E.5 End points |
E.5.1 | Primary end point(s) |
Mean change in UACR from baseline to the average of multiple time points during treatment |
Cambio medio en el CAC desde el inicio hasta el promedio de varios puntos temporales a lo largo del tratamiento |
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E.5.1.1 | Timepoint(s) of evaluation of this end point |
From baseline up to day 57 (± 3) |
Desde el inicio hasta el día 57 (± 3) |
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E.5.2 | Secondary end point(s) |
Number of subjects with treatment emergent adverse event (TEAE) Number of subjects with early discontinuations |
Número de sujetos con acontecimientos adversos aparecidos durante el tratamiento (AADT). Número de sujetos con suspensiones prematuras. |
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E.5.2.1 | Timepoint(s) of evaluation of this end point |
Number of subjects with TEAE: From first treatment administration up to end of follow up (Day 87±7) Number of subjects with early discontinuations: From first treatment administration up to end of treatment (Day 57±3) |
Número de sujetos con AADT: desde el inicio del tratamiento hasta la visita final de seguimiento (Day 87±7) Número de sujetos con suspensiones prematuras: desde el inicio del tratamiento hasta la visita final del tratamiento (Day 57±3) |
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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 | No |
E.6.11 | Pharmacogenomic | No |
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) | 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 | 8 |
E.8.5 | The trial involves multiple Member States | Yes |
E.8.5.1 | Number of sites anticipated in the EEA | 54 |
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 |
Austria |
Belgium |
Bulgaria |
Denmark |
Finland |
Germany |
Israel |
Italy |
Poland |
Spain |
Sweden |
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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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The end of the study is defined as the date of the last visit of the last participant in the study globally. |
El final del ensayo se define como la fecha de la última visita del último sujeto en el estudio a nivel mundial. |
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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 | 1 |
E.8.9.1 | In the Member State concerned months | 1 |
E.8.9.1 | In the Member State concerned days | 0 |
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 | 1 |
E.8.9.2 | In all countries concerned by the trial days | 10 |