E.1 Medical condition or disease under investigation |
E.1.1 | Medical condition(s) being investigated |
Patients with type 2 diabetes mellitus and normoalbuminuria |
Pazienti affetti da diabete tipo 2 normoalbuminurici |
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E.1.1.1 | Medical condition in easily understood language |
Diabetic patients with normal concentration of albumin in urine |
Pazienti diabetici normoalbuminurici |
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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 | 14.1 |
E.1.2 | Level | PT |
E.1.2 | Classification code | 10067585 |
E.1.2 | Term | Type 2 diabetes mellitus |
E.1.2 | System Organ Class | 10027433 - Metabolism and nutrition 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 confirm that urinary proteomics can predict development of microalbuminuria (as a surrogate marker for the development of overt nephropathy) in a cohort of 3280 type 2 diabetic patients with normal urinary albumin excretion. |
Confermare che l’analisi proteomica delle urine può predire lo sviluppo di microalbuminuria (marker surrogato per lo sviluppo di una futura nefropatia conclamata) in una coorte di 3280 pazienti affetti da diabete di tipo 2 e normoalbuminurici. |
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E.2.2 | Secondary objectives of the trial |
-To investigate if early initiation of preventive therapy with spironolactone 25 mg once daily reduces risk of transition to microalbuminuria in those patients identified by urinary proteomics to be at high risk -Assessment of safety in the intervention group -To compare the rate of change in UAER in high- vs. low-risk patients (based on the proteomic test), and to compare the effect of spironolactone on rate of change in UACR in the intervention study. -In addition, the objective is to study the rate of change in eGFR in relation to urinary marker pattern (CKD 273) and the intervention with spironolactone. -To study the ability of urinary proteomic patterns to predict cardiovascular or renal events during the study, as well as response to intervention in relation to study endpoints -To establish a biobank that will allow testing of additional putative markers for progression of diabetic nephropathy, development of cardiovascular events and death
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- Valutare se una terapia preventiva con Spironolattone (25 mg al giorno) possa ridurre il rischio di sviluppare microalbuminuria nei pazienti ad alto rischio sulla base dell’analisi proteomica. - Valutare la sicurezza del farmaco nel gruppo in trattamento. - Paragonare la velocità di variazione dell’escrezione urinaria di albumina nei due gruppi di pazienti e valutare l’effetto dello spironolattone sulla velocità di cambiamento del rapporto urinario albumina/creatinina (UACR) nel gruppo di intervento. - Studiare la velocità di variazione del GFR stimato in relazione ai marcatori CKD 273 e alla terapia con spironolattone; - Studiare la capacità dell’analisi proteomica di predire l’insorgenza di eventi renali e cardiovascolari così come la risposta alla terapia in relazione agli endpoint dello studio; - Istituire una biobanca che permetterà di testare marker putativi addizionali per la progressione della nefropatia diabetica, l’insorgenza di eventi cardiovascolari e la morte.
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E.2.3 | Trial contains a sub-study | No |
E.3 | Principal inclusion criteria |
• Written informed consent must be provided before participation. Patient information and consent form must be approved by relevant independent EC. Specifically, all participating patients will be asked to give informed consent for long-term follow-up and collection of follow-up data • Male or female patients ≥ 18 years and < 75 years of age at Screening visit • Type 2 DM (WHO criteria) • Persistent normoalbuminuria (at least 2 of 3 UACR < 30 mg/g samples from ”run in” period) • eGFR > 45 ml/min/1.73m2 (MDRD formula) at Screening visit • HbA1c ≥ 6.5% (48 mmol / mol) and < 13% (119 mmol / mol) at Screening visit • The patient must be willing and able to comply with the protocol for the duration of the study • Female without child-bearing potential at the screening visit. Defined as one or more of following: - Female patients ≥ 50 years of age at the day of inclusion, who have been postmenopausal for at least 1 year - Female patients < 50 years of age at the day of inclusion, who have been postmenopausal for at least 1 year and serum FSH levels > 40 mIU/mL as well as serum estrogen levels < 30 pg/ml or a negative estrogen test - 6 weeks after surgical sterilization by bilateral tubal ligation or bilateral ovariectomy with or without hysterectomy OR a negative urine pregnancy test at the Screening visit AND one or more of the following: - Correct use of reliable contraception methods. This includes one or more ofthe following: hormonal contraceptive (such as injection, transdermal patch, implant, cervical ring or oral) or an intrauterine device (IUD) OR correct use of double barrier with one of the following: barrier methods (diaphragm, cervical cap, Lea contraceptive, femidom or condom) AND in combination with a spermicide - General sexual abstinence from the time of screening, during the study until a minimum of 30 days after the last administration of study medication if this is already established as the patient’s preferred and usual lifestyle. - Having only female sexual partners - Sexual relationship with sterile male partners only
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• Consenso informato scritto, sia per la partecipazione allo studio che al follow-up • Maschi e femmine di età compresa tra i 18 e i 75 anni alla visita di screening • DM di tipo 2 (in accordo con la classificazione WHO) • Normoalbuminuria persistente (almeno 2 delle 3 UACR < 30 mg/g durante il periodo di run-in) • eGFR>45 ml/min/1.73m2 (calcolato con la formula MDRD) alla visita di screening • HbA1c ≥ 6.5% (48 mmol /mol) e < 13% (119 mmol /mol) alla visita di screening • Pazienti disponibili a partecipare allo studio e in grado di eseguire tutte le procedure richieste dal protocollo per tutta la durata dello studio • Donne non potenzialmente fertili alla visita di screening che rispondono a uno o più dei seguenti criteri • Donne di età 50 anni alla data di inclusione nello studio, in menopausa da almeno un anno • Donne in menopausa da almeno un anno, con valori di FSH serico > 40 mIU/mL, e livelli di estrogeno nel siero < 30 pg/ml o negative al test degli estrogeni • Sterilizzazione chirurgica eseguita da almeno 6 settimane attraverso legatura bilaterale delle tube o ovariectomia bilaterale con o senza isterectomia Oppure negative al test di gravidanza alla visita di screening che rispondono ad uno o più dei seguenti criteri • Uso corretto di metodi contraccettivi sicuri. I metodi contraccettivi devono essere uno o più dei seguenti: contraccettivi ormonali (iniezioni, cerotti, anelli cervicali o compresse) o dispositivi intrauterini (IUD) oppure l’uso corretto di una doppia barriera con uno dei seguenti metodi: diaframma, cappuccio cervicale, condom femminile o condom, in combinazione con uno spermicida • Astinenza dai rapporti sessuali dal momento della visita di screening e per tutta la durata dello studio fino a 30 giorni dopo l’ultima somministrazione di farmaco sperimentale se ciò si adatta alle preferenze e allo stile di vita del paziente • Donne che hanno solo partners di sesso femminile • Donne che hanno solo partners sterili
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E.4 | Principal exclusion criteria |
• Average of systolic BP < 110 or > 160 mm Hg at baseline • Average of diastolic BP > 100 mm Hg at baseline • Type 1 DM (WHO criteria) • Current in treatment with more than one RAAS blocking agent (Angiotensin Converting Enzyme inhibitor, Angiotensin Receptor Blocker or Direct Renin Inhibitor) • Current lithium treatment • Known or suspected hypersensitivity to Spironolactone or to any of its excipients • Current use of potassium sparing diuretics, such as: Spironolactone, Eplerenone or amiloride etc • Screening (week -6) plasma (or serum) potassium level >5.0 mmol/L • Hyponatriemia determine by the investigator • Current cancer treatment or within five years from baseline (except basal cell skin cancer or squamous cell skin cancer) • Any clinically significant disorder, except for conditions as-sociated with type 2 DM history, which in the Investigators opinion could interfere with the results of the trial • Cardiac disease defined as: Heart failure (NYHA class III-IV) and/or diagnosis of unstable angina pectoris and/or MI, stroke, PTCA or CABG within the last 3 months • Body mass index < 18.5 or > 40 kg/m2 • Diagnosis of non-Diabetic CKD current or in the past • Diagnosis of liver cirrhosis with current impaired liver function within the last 3 years. • Diagnosis of Addison's disease • Being lactating • Intend to become pregnant within the duration of the study or not use adequate birth control. • Known or suspected abuse of alcohol or narcotics • Not able to understand informed consent form • Participation in any other intervention trial than PRIORITY or a related sub-study is not allowed within 30 days before inclusion or concurrent to this study |
• Pressione sistolica media < 110 o >160 mm Hg al basale • Pressione diastolica media > 100 mm Hg al basale • Diabete mellito di tipo 1 (in accordo con la classificazione WHO) • Trattamento in corso con più di un agente bloccante del sistema RAAS (ACE inibitore, ARB o inibitore della renina) • Trattamento in corso con litio • Sensibilità nota o sospetta allo Spironolattone o a uno degli eccipienti • Trattamento in corso con farmaci risparmiatori di potassio come Spironolattone, Eplerenone o Amiloride • Livelli di potassio nel siero o nel plasma >5.0 mmol/L alla visita di screening • Iponatremia • Trattamento antitumorale in corso o nei 5 anni precedenti il basale (con l’eccezione dei tumori della pelle a cellule basali o a cellule squamose) • Qualsiasi alterazione clinica significativa, fatta eccezione per i disturbi associati al diabete di tipo 2, che a giudizio del medico possa interferire con i risultati dello studio • Una delle seguenti malattie cardiache nei tre mesi precedenti alla partecipazione allo studio : Insufficienza cardiaca (classe NYHA III-IV) e/o diagnosi di angina pectoris instabile e/o MI, stroke, PTCA o CABG • Indice di massa corporea <18.5 o >40 kg/m2 • Diagnosi di CKD non-diabetica attuale o pregressa • Diagnosi di cirrosi epatica con funzione epatica compromessa nei tre anni precedenti lo studio • Diagnosi di malattia di Addison • Donne fertili in allattamento o che desiderano avere figli o non adottano un sistema contraccettivo efficace • Abuso noto o presunto di alcool e droghe • Incapacità di comprendere la scheda informativa
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E.5 End points |
E.5.1 | Primary end point(s) |
Development of confirmed microalbuminuria UACR >30 mg/g in at least two out of three first morning voids with ≥ 30% increase in UACR from "run-in" period samples. |
Sviluppo di microalbuminuria, UACR>30 mg/g in almeno due delle tre raccolte urinarie del mattino con un aumento ≥ 30% rispetto ai campioni raccolti durante il periodo di run-in |
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E.5.1.1 | Timepoint(s) of evaluation of this end point |
Every 13 weeks and week 156 or early termination (treatment group) Every 52 weeks and week 156 or early termination (observational group) |
Ogni 13 settimane e alla fine, da protocollo (156 settimane) o anticipata dello studio (gruppo di trattamento) Ogni 52 settimane e alla fine, da protocollo (156 settimane) o anticipata dello studio (gruppo di trattamento) |
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E.5.2 | Secondary end point(s) |
In the following paragraphs patients in the intervention group, (group B) and observation group (group A) will be compared
1) Comparison of composite fatal and non-fatal cardiovascular outcome (MI, stroke, CABG, PTCA, hospitalization for heart failure and CVD), and all cause mortality during the study 2) Comparison of incidence of retinopathy and frequency of laser treatment. Data collected from self-reported AEs 3) In addition to the categorical analysis of urinary albumin excretion, an analysis will be performed with changes in geometric mean albuminuria throughout the study period in all patients by assessing the slope of albuminuria changes and absolute changes from inclusion to end of trial 4) Development of microalbuminuria (UACR >30 mg/g) in at least one morning void urine sample will be used as a secondary outcome instead of confirmed microalbuminuria 5) Development of macroalbuminuria (UACR >300 mg/g) in 2 out 3 first morning void urine samples) 6) For patients with eGFR ≥ 60 at baseline, development of eGFR<60 ml/min/1.73m2. eGFR will be measured from serum creatinine (standardized traceable method) on blood samples tested in local laboratories. Serum creatinine (mg/dL) will be recorded on eCRFs and used to calculate estimated glomerular filtration rate using the MDRD equation [eGFR ml/min/ 1.73m2 =186 x serum creatinine-1.154 x age-0.203 x (1.210 if black) x (0.742 if female)] 7) Change in eGFR (slope and absolute from baseline and from 3 month post-baseline to end of study)
In the following paragraphs patients receiving active medication will be compared to placebo treatment.
8) Comparison of composite fatal and non-fatal cardiovascular outcome (MI, stroke, CABG, PTCA, hospitalization for heart failure and CVD) and all cause mortality during the study 9) Comparison of incidence of retinopathy and frequency of laser treatment. Data collected from AEs 10) Development of microalbuminuria (UACR > 30 mg/g) in at least one morning void urine sample will be used as a secondary outcome instead of con-firmed microalbuminuria 11) Development of macroalbuminuria (UACR > 300 mg/g in 2 out 3 first morning void urine samples) 12) For patients with eGFR ≥ 60 at baseline, development of eGFR<60 ml/min/1.73m2 13) Change in eGFR (slope and absolute from baseline and from 3 month post-baseline to end of study)
14) Assessment of safety The assessment of safety will be based primarily on the frequency of eCRF-documented AEs, laboratory abnormalities, and SAEs. Occurrence and frequency of eCRF-documented AEs, SAEs and laboratory abnormalities will be summarized by treatment group. In addition AEs leading to death and AEs leading to discontinuation of study medication and/or withdrawal will be summarized for the two treatment groups.
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E.5.2.1 | Timepoint(s) of evaluation of this end point |
1), 8) during the study 2), 9) Data collected from self-reported AEs 3), throughout the study 4), 5), 10), 11), run-in period, every 13 weeks, week 156 or early termination (treatment group), run-in period, every 52 weeks, week 156 or early termination (observational group) 6),12) screening/baseline, Visit 1, every 13 weeks, week 156 or early termination (treatment group); every 52 weeks and week 156 or early termination (observational group) 7), 13) baseline, every 13 weeks and week 156 or early termination (treatment group); every 52 weeks and week 156 or early termination (observational group) 14) baseline, every Visit, prolonged until all AEs are resolved or until the investigator assess the adverse events as “chronic” or “stable”. |
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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 | Yes |
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 | No |
E.6.10 | Pharmacogenetic | No |
E.6.11 | Pharmacogenomic | No |
E.6.12 | Pharmacoeconomic | No |
E.6.13 | Others | Yes |
E.6.13.1 | Other scope of the trial description |
Predictive value of the urinary proteomics test in regards to renal and cardiovascular events |
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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) | 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 | No |
E.8.1.6 | Cross over | No |
E.8.1.7 | Other | Yes |
E.8.1.7.1 | Other trial design description |
Randomized, double blind, placebo-control trial and prospective observational study |
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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 | 3 |
E.8.5 | The trial involves multiple Member States | Yes |
E.8.5.1 | Number of sites anticipated in the EEA | 9 |
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 |
Czech Republic |
Denmark |
France |
Germany |
Greece |
Italy |
Macedonia, the former Yugoslav Republic of |
Netherlands |
Spain |
Switzerland |
United Kingdom |
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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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LVLS |
Ultima visita dell'ultimo paziente |
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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 | 5 |
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 | 5 |
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 |