| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
| Proteinuric Kidney disease |
| Insufficienza Renale Cronica Proteinurica |
| Enfermedad Renal Crónica Proteinúrica |
|
| E.1.1.1 | Medical condition in easily understood language |
| Reduction in kidney function with increasing in protein in the urine |
| Peggioramento della funzione renale con aumento delle proteine nelle urine |
| Deterioro de la función renal con aumento de la proteinuria en orina |
|
| E.1.1.2 | Therapeutic area | Diseases [C] - Cardiovascular Diseases [C14] |
| MedDRA Classification |
| 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 determine the individual albuminuria lowering response to eplerenone, dapaglifozin and their combination |
| Determinare la risposta antiproteinurica individuale all'eplerenone, al dapaglifozin ed alla loro combinazione |
| Determinar la respuesta antiproteinúrica individual a la eplerenona, la dapaglifozina y a la combinación de ambos fármacos. |
|
| E.2.2 | Secondary objectives of the trial |
To determine the individual office blood pressure lowering response to eplerenone, dapaglifozin and their combination
To determine the individual home blood pressure lowering response to eplerenone, dapaglifozin and their combination |
Determinare la risposta antiipertensiva (pressione arteriosa ambulatoriale) individuale all'eplerenone, al dapaglifozin ed alla loro combinazione
Determinare la risposta antiipertensiva (pressione arteriosa domiciliare) individuale all'eplerenone, al dapaglifozin ed alla loro combinazione |
Determinar la respuesta indiviual antihipertensiva (reducción de la presión arterial) en la consulta a la eplerenona, la dapaglifozina o a la combinación de ambas.
Determinar la respuesta indiviual antihipertensiva (reducción de la presión arterial) en el domicilio a la eplerenona, la dapaglifozina o a la combinación de ambas |
|
| 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 |
| To determine which patients characteristics as well as plasma or urinary biomarkers predict the albuminuria and blood pressure response to eplerenone, dapagliflozin and their combination |
| Determinare quali fattori legati al paziente cosí come biomarcatori plasmatici ed urinari possano predire la risposta antiproteinurica ed antiipertensiva individuale all'eplerenone, al dapaglifozin ed alla loro combinazione |
| Determinar que características individuales de cada paciente, estudiadas a través de marcadores tanto plasmáticos como urinarios, predicen la reducción de la albuminuria y la presión arterial a la eplerenona, la dapaglifozina o a la combinación de ambos |
|
| E.3 | Principal inclusion criteria |
| eGFR > 30 and < 90 ml/min/1.73m2; albuminuria ≥ 100 mg/24 hour and ≤ 3500 mg/24 hour; serum potassium ≤ 5.0 mmol/L; treatment with ACEi or ARB ; age ≥ 18 years; written informed consent |
| eGFR > 30 and < 90 ml/min/1.73m2; albuminuria ≥ 100 mg/24 ore and ≤ 3500 mg/24 ore; potassio serico ≤ 5.0 mmol/L; trattamento con ACEi o ARB ; etá ≥ 18 anni; consenso informato scritto |
| Filtrado Glomerular estimado > 30 y < 90 ml/min/1.73m2; albuminuria ≥ 100 mg/24 horas y ≤ 3500 mg/24 horas; potasio sérico ≤ 5.0 mmol/L; tratamiento con IECA o ARA II ; edad ≥ 18 años; firma de consentimiento informado |
|
| E.4 | Principal exclusion criteria |
- Diagnosis of type 1 diabetes mellitus
- Urinary protein excretion > 3500 mg/24 hour
- Autosomal dominant polycystic kidney disease or autosomal recessive polycystic kidney disease, lupus nephritis, or ANCA-associated vasculitis
- Indication for immunosuppressants as per the treating physician’s judgment.
- Receiving cytotoxic therapy, immunosuppressive therapy, or other immunotherapy for primary or secondary renal disease within 6 months prior to enrolment.
- Active malignancy aside from treated squamous cell or basal cell carcinoma of the skin.
- Diabetes type 2 patients with recent (last 6 months) of hyperosmolar hyperglicemic state who are prone to development redistributive hyperkalemia (movement of potassium out of the cells)
- Pregnant women and women of child-bearing potential who are not using reliable contraception
- Cardiovascular disease: myocardial infarction, angina pectoris, percutanous transluminal coronary angioplasty, coronary artery bypass grafting, stroke, heart failure (NYHA I-IV) < 6 months before inclusion
- Uncontrolled blood pressure (office blood pressure > 160 / 100 mmHg)
- History of autonomic dysfunction (e.g. history of fainting or clinically significant orthostatic hypotension)
- History of amputations
- eGFR change > 30% in the last six months before study randomization
- Current therapy with renin inhibitor or MRA
- Concomitant treatment with ACEi and ARB
- Intolerance or contraindications to drugs inhibiting the Renin-Angiotensin-Aldosterone System (RAAS). Cyclosporine A, tacrolimus, trimethoprim due to increased risk of hyperkalemia in combination with eplerenone. Ketoconazole, itraconazole, ritonavir, nelfinavir, clarithromycin, telithromycin and nefazadone, lithium, amiodarone, diltiazem, verapamil due to increase in toxicity when combined with eplerenone. Rifampicin, carbamazepine, phenytoin, phenobarbital due the risk of decreased eplerenone efficacy.
- Participation in any clinical investigation within 3 months prior to initial dosing or longer if required by local regulations, and for any other limitation of participation based on local regulations.
- Donation or loss of 400 ml or more of blood within 8 weeks prior to initial dosing
- History of drug or alcohol abuse within the 12 months prior to dosing, or evidence of such abuse as indicated by the laboratory assays conducted during the screening.
- Any medication, surgical or medical condition which might significantly alter the absorption, distribution, metabolism, or excretion of medications including, but not limited to any of the following:major gastrointestinal tract surgery such as gastrectomy, gastroenterostomy, or bowel resection;
gastro-intestinal ulcers and/or gastrointestinal or rectal bleeding within last six months; evidence of hepatic disease as determined by any one of the following: ALT or AST values exceeding 3x ULN at inclusion visit, a history of hepatic encephalopathy, a history of esophageal varices, or a history of portocaval shunt |
- Diagnosi di diabete mellito tipo 1
- Albuminuria > 3500 mg/24 ore
- Malattia del rene policistico autosomica dominante o recessiva, nefrite lupica o vasculiti ANCA-associate
- Indicazione al trattamento immunosoppressivo a discrezione del medico.
- Pazienti in trattamento con terapie citotossiche, immunosoppressive o oltre immunoterapie per malatite renali pimitive o secondarie nei precedenti 6 mesi.
- Neoplasie malige tranne il carcinoma basocellulare o squamoso della cute precedentemente trattato.
- Pazienti con diabete tipo 2 e con recente storia (precedenti 6 mesi) di stato iperglicemico iperosmolare che sono suscettibili a sviluppare iperpotassiemia redistributiva (fuoriuscita di potassio all'esterno delle cellule).
- Donne gravide o donne in etá fertile che non usano un metodo contraccettivo affidabile.
- Malattia cardiovascolare: infarto del miocardio, angina pectoris, angioplastica coronarica percutanea, bypass aorto-coronarico, ictus, scompenso cardiaco (NYHA I-IV) nei 6 mesi che precedono l'inclusione.
- Pressione arteriosa non controllata (valore ambulatoriale di pressione arteriosa > 160 / 100 mmHg)
- Storia di disfunzione autonomica (es. storia di svenimenti o ipotensione ortostatica clinicamente significativa)
- Storia di amputazione
- cambiamento dell'eGFR > 30% nei 6 mesi che precedono la randomizzazione
- Terapia in atto con inibitori della renina o MRA
- Trattamento concomitante con ACEi e ARB
- Intolleranza o controindicazioni a farmaci che inibiscono il sistema Renina-Angiotensina-Aldosterone (RAAS). Ciclosporina A, tacrolimus, trimethoprim per l’aumentato rischio di sviluppare iperpotassiemia in combinazione con eplerenone. Ketoconazolo, itraconazolo, ritonavir, nelfinavir, claritromicina, telitromcina e nefazadone, litio, amiodarone, diltiazem, verapamil per l’aumentata tossicitá quando combinati con eplerenone. Rifampicina, carbamazepina, fenitoina, fenobarbitale per il rischio di ridurre l’efficacia dell’eplerenone.
- Inclusione in qualunque protocollo di ricerca clinica nei 3 mesi precedenti la somministrazione iniziale del trattamento o più a lungo se richiesto dalle normative locali e per qualsiasi altra limitazione di partecipazione in base alle normative locali.
- Donazione o perdita di 400 ml o piú di sangue entro 8 settimane dalla prima somministrazione del trattamento in studio
- Storia di abuso di farmaci o alcol nei precedenti 12 mesi, o evidenza di tale abuso come risultato degli esami di laboratorio condotti durante lo screening.
- Qualsiasi farmaco, condizione chirurgica o medica che potrebbe alterare in modo significativo l'assorbimento, la distribuzione, il metabolismo o l'escrezione dei trattamenti in studio, tra i quali i seguenti (ed altri): chirurgia del tratto gastrointestinale maggiore come gastrectomia, gastroenterostomia o resezione intestinale, gastro-intestinale ulcere e / o emorragia gastrointestinale o rettale negli ultimi sei mesi; evidenza di malattia epatica determinata da uno dei seguenti valori: valori di ALT o AST superiori a 3 x ULN alla visita di screening, anamnesi di encefalopatia epatica, anamnesi di varici esofagee o anamnesi di shunt portocavale. |
•Diagnóstico de diabetes mellitus tipo 1.
• Excreción urinaria de proteínas > 3500 mg / 24 horas.
•Mujeres gestantes o en periodo de lactancia o con test de embarazo positivo en la visita de screening
• Enfermedad renal poliquística autosómica dominante o enfermedad renal poliquística autosómica recesiva, nefritis lúpica o vasculitis asociada a ANCA
• Indicación de inmunosupresores según el criterio del médico tratante.
• Recibir terapia citotóxica, terapia inmunosupresora u otra inmunoterapia para la enfermedad renal primaria o secundaria dentro de los 6 meses anteriores a la inscripción.
• Enfermedad maligna activa aparte del carcinoma de células escamosas o células basales de la piel.
• Pacientes con diabetes tipo 2 con estado hiperglucémico hiperosmolar reciente (últimos 6 meses) que son propensos a desarrollar hipercaliemia redistributiva (movimiento de potasio fuera de las células)
•Historia de hipoglucemia (síntomas como mareos, sensación de hambre intensa, confusión, dolor de cabeza o incapacidad para concentrase, sudoración profusa, temblores, visión borrosa o o test de glucosa < 54 mg/dl en los últimos tres meses.
• Mujeres embarazadas y mujeres en edad fértil que no estén usando anticoncepción segura
• Enfermedad cardiovascular: infarto de miocardio, angina de pecho, angioplastia coronaria transluminal percutánea, cirugía de revascularización coronaria, accidente cerebrovascular, insuficiencia cardíaca (NYHA I-IV) <6 meses antes de la inclusión
• Presión arterial no controlada (presión arterial de oficina> 160/100 mmHg)
• Historial de disfunción autonómica (por ejemplo, historial de desmayos o clínicamente
hipotensión ortostática significativa)
• Historia de amputaciones.
• Cambio de eGFR> 30% en los últimos seis meses antes de la aleatorización del estudio.
• Terapia actual con inhibidor de renina o antagonista mineralcorticode
• Tratamiento simultáneo con ACEi y ARB.
• Intolerancia o contraindicaciones a fármacos que inhiban el Sistema Renina-Angiotensina-Aldosterona (RAAS). Tratamiento con Ciclosporina A, tacrolimus, trimetoprima debido al aumento del riesgo de hiperpotasemia en combinación con eplerenona. Tratamiento con Ketoconazol, itraconazol, ritonavir, nelfinavir, claritromicina, telitromicina y nefazadona, litio, amiodarona, diltiazem, verapamil debido al aumento de la toxicidad cuando se combina con eplerenona. Tratamiento con Rifampicina, carbamazepina, fenitoína, fenobarbital debido al riesgo de disminución de la eficacia de la eplerenona.
• Participación en cualquier investigación clínica dentro de los 3 meses anteriores al inicio del periodo de tratamiento
• Donación o pérdida de 400 ml o más de sangre dentro de las 8 semanas anteriores al inicio del periodo de tratamiento
• Historial de abuso de drogas o alcohol dentro de los 12 meses anteriores a la dosificación, o
evidencia de tal abuso si así lo indican los análisis de laboratorio realizados durante la selección.
• Cualquier medicamento, condición quirúrgica o médica que pueda alterar significativamente
la absorción, distribución, metabolismo o excreción de medicamentos que incluyen, entre otros, cualquiera de los siguientes:
- Cirugía mayor del tracto gastrointestinal, como gastrectomía, gastroenterostomía o resección intestinal;
- Úlceras gastrointestinales y / o hemorragia gastrointestinal o rectal en los últimos seis meses;
- Evidencia de enfermedad hepática según lo determinado por cualquiera de los siguientes: valores de ALT o AST superiores a 3 x ULN en la visita de inclusión, antecedentes de encefalopatía hepática, antecedentes de varices esofágicas o antecedentes de derivación portocava |
|
| E.5 End points |
| E.5.1 | Primary end point(s) |
| correlation between individual albuminuria lowering responses of eplerenone, dapagliflozin and their combination |
| correlazione tra risposte antiproteinuriche individuali all'eplerenone al dapaglifozin e alla loro combinazione |
| Correlación entre respuesta individual a la reducción de la albuminuria a la eplerenona, la dapaglifozina y la combinación de ambas |
|
| E.5.1.1 | Timepoint(s) of evaluation of this end point |
| correlation between home blood pressure-lowering responses of eplerenone, dapaglifozin and their combination; correlation between office blood pressure-lowering responses of eplerenone, dapaglifozin and their combination |
| correlazione tra risposte antiipertensive individuali (pressione arteriosa ambulatoriale) all'eplerenone al dapaglifozin e alla loro combinazione;correlazione tra risposte antiipertensive individuali (pressione arteriosa domiciliare) all'eplerenone al dapaglifozin e alla loro combinazione |
| Correlación entre la disminución de la presión arterial en domicilio como respuesta al tratamiento con eplerenona, dapaglifozina o su combinación; correlación entre la disminucón de la presión arterial en consulta al tratamiento con eplerenona, dapaglifozina o su cominación |
|
| E.5.2 | Secondary end point(s) |
To determine the correlation between office/home blood pressure-lowering responses of eplerenone, dapaglifozin and their combination.
To determine which patients characteristics predict the albuminuria and blood pressure response to eplerenone, dapagliflozin and their combination |
Determinar la correlación entre la respuesta depresora de la presión arterial en la consulta y en casa a eplerenona, dapaglifozina y la combinación de ambos.
Determinar cuáles son las caracteristicas de cada paciente que predicen la disminución de la albuminuria y la presión arterial con eplerenona, dapaglifozina y la combinación de ambas |
|
| E.5.2.1 | Timepoint(s) of evaluation of this end point |
| maximally 42 weeks |
| 42 semanas máximo |
|
| 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 | No |
| E.6.5 | Efficacy | No |
| E.6.6 | Pharmacokinetic | Yes |
| 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 | 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) | 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 | Yes |
| E.8.1.3 | Single blind | No |
| E.8.1.4 | Double blind | No |
| E.8.1.5 | Parallel group | No |
| E.8.1.6 | Cross over | Yes |
| 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 | No |
| E.8.2.3 | Other | No |
| E.8.2.4 | Number of treatment arms in the trial | 6 |
| E.8.3 |
The trial involves single site in the Member State concerned
| Yes |
| E.8.4 | The trial involves multiple sites in the Member State concerned | No |
| E.8.5 | The trial involves multiple Member States | Yes |
| E.8.5.1 | Number of sites anticipated in the EEA | 3 |
| E.8.6 Trial involving sites outside the EEA |
| E.8.6.1 | Trial being conducted both within and outside the EEA | No |
| E.8.6.2 | Trial being conducted completely outside of the EEA | No |
| E.8.7 | Trial has a data monitoring committee | No |
| 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 de estudio |
|
| E.8.9 Initial estimate of the duration of the trial |
| E.8.9.1 | In the Member State concerned years | |
| E.8.9.1 | In the Member State concerned months | 11 |
| E.8.9.1 | In the Member State concerned days | |
| E.8.9.2 | In all countries concerned by the trial months | 11 |
Print
