E.1 Medical condition or disease under investigation |
E.1.1 | Medical condition(s) being investigated |
Chronic Kidney Deseas |
Insufficienza renale cronica |
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E.1.1.1 | Medical condition in easily understood language |
Chronic Kidney Deseas |
Malattia renale cronica |
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E.1.1.2 | Therapeutic area | Body processes [G] - Reproductive physiologi cal processes [G08] |
MedDRA Classification |
E.1.2 Medical condition or disease under investigation |
E.1.2 | Version | 21.1 |
E.1.2 | Level | LLT |
E.1.2 | Classification code | 10050441 |
E.1.2 | Term | Chronic renal insufficiency |
E.1.2 | System Organ Class | 100000004857 |
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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 |
Evaluate the role of dapagliflozin in confront to placebo on changes in markers of inflammation, on the activation of innate immunity and tubulointerstitial fibrosis in the kidney of patients with CKD. |
Valutare il ruolo di dapagliflozin rispetto al placebo sui cambiamenti nei marker di infiammazione, sull'attivazione dell'immunità innata e della fibrosi tubulointerstiziale nel rene di pazienti con CKD. |
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E.2.2 | Secondary objectives of the trial |
The secondary objective is to describe changes from baseline in albuminuria, eGFR, blood pressure, body volume status, body weight, serum uric acid, lipids, glucose and HbA1c levels, after 6 months of treatment with dapagliflozin or placebo and to define their relationship with the changes in the markers of renal senescence, inflammation and tubulointerstitial damage. |
Descrivere le variazioni rispetto al basale di albuminuria, eGFR, pressione sanguigna, stato del volume corporeo, peso corporeo, acido urico sierico, lipidi, glucosio e livelli di HbA1c, dopo 6 mesi di trattamento con dapagliflozin o placebo e definire la loro relazione con i cambiamenti nei marker di senescenza renale, infiammazione e danno tubulo-interstiziale. |
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E.2.3 | Trial contains a sub-study | No |
E.3 | Principal inclusion criteria |
- Adult (age 18-75 years) - Albuminuria defined as urinary albumin ratio: creatinine = 25 mg / g (or protein ratio: creatinine = 30 mg / g) or albuminuria> 30 mg / 24h - eGFR> 25 and <75 ml / minute 1.73 m2 - BMI between 19 kg / m2 and 30 kg / m2 - Treatment with an ACE inhibitor and / or ARB at the maximum tolerated dose (for the individual subject). The maximum tolerated dose for an individual subject may be less than the maximum labeled dose or may be zero if the medical reason is documented. - Mean systolic and diastolic blood pressure (determined as the average of three repeated measurements) should be <180/90 mmHg - Willingness to participate in the study (signing of informed consent)
Specific inclusion criteria
CKD AND T2DM - Clinical diagnosis of T2DM for at least 1 year - Value of hemoglobin A1c (HbA1c) <9.5% -Patients treated only with metformin and/or repaglinide - Diagnosis of diabetic nephropathy after renal biopsy made not more than 6 months before the screening visit (only for the subgroup of patients candidates for the second renal biopsy) - Proteinuria> 1g / 24h (only for the subgroup of patients candidates for the second renal biopsy) - Hemoglobin A1c (HbA1c) value> 6.5% (only for patients candidates for the second renal biopsy)
CKD WITHOUT T2DM diagnosed with hypertension for at least 5 years |
- Adulto (età 18-75 anni) - Albuminuria definita come rapporto albumina urinaria: creatinina = 25 mg / g (o rapporto proteine: creatinina = 30 mg / g) o albuminuria> 30 mg / 24h - eGFR> 25 e <75 ml / minuto 1,73 m2 - BMI compreso tra 19 kg / m2 e 30 kg / m2 - Trattamento con un ACE inibitore e / o ARB alla dose massima tollerata (per il singolo soggetto). La dose massima tollerata per un singolo soggetto può essere inferiore alla dose massima etichettata o può essere zero se la ragione medica è documentata. - La pressione sanguigna sistolica e diastolica media (determinata come la media di tre misure ripetute) deve essere <180/90 mmHg - Disponibilità a partecipare allo studio (firma del consenso informato)
CKD E T2DM - Diagnosi clinica di T2DM da almeno 1 anno - Valore dell'emoglobina A1c (HbA1c) <9,5% - Pazienti trattati solo con metformina e / o repaglinide - Diagnosi di nefropatia diabetica dopo biopsia renale eseguita non più di 6 mesi prima della fase di run-in (solo per il sottogruppo di pazienti candidati alla seconda biopsia renale) - Proteinuria> 1g / 24h (solo per il sottogruppo di pazienti candidati alla seconda biopsia renale) - Valore dell'emoglobina A1c (HbA1c)> 6,5% (solo per i pazienti candidati alla seconda biopsia renale)
CKD SENZA T2DM - diagnosi di ipertensione da almeno 5 anni |
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E.4 | Principal exclusion criteria |
• Type 1 Diabetes • Hemoglobin A1c (HbA1c) value of > 9.5% during the Screening period (based on central laboratory measurement). • need for an adjunctive drugs on top on metformin and repaglinide • Hemoglobin A1c (HbA1c) value of < 6.5% only for patients candidated to the second kidney biopsy • Estimated glomerular filtration rate < 25 or > 75 ml/min/1.73m2 (according to the CKD-EPI) at screening • Untreated urinary or genital infection at screening and follow-up • Clear signs of volume depletion • Symptomatic hypotension, or systolic blood pressure < 90 or non-controlled hypertension • History of alcohol or drug abuse, anuria, dialysis, or acute kidney injury/acute renal failure in the 3 months prior to Screening Period • Heart, liver or kidney transplant • Acute coronary syndrome, stroke, or transient ischemic attack within 3 months prior to informed consent • Liver disease, defined by serum levels of alanine aminotransferase, aspartate aminotransferase, or alkaline phosphatase above 3 x upper limit of normal (ULN) during screening • Planned cardiac surgery or angioplasty within 3 months • Cancer or medical history of cancer (except for basal cell carcinoma) within the last 5 years • Treatment with anti-obesity drugs 3 months prior to informed consent or any other treatment at time of screening leading to unstable body weight (e.g. surgery, aggressive diet regimen, etc.) • SGLT2i treatment in the 10 weeks before the Screening Period • Treatment with systemic steroids at time of informed consent or change in dosage of thyroid hormones within 6 weeks prior to informed consent • Any uncontrolled endocrine disorder except T2DM • Women who are pregnant or breastfeeding • Pre-menopausal women of child bearing potential who are not willing to employ effective contraception according to 2007 CTFG Recommendations related to contraception and pregnancy testing in clinical trials from screening for all the duration of the study • Patients with a known hypersensitivity to Dapagliflozin or other SGLT2- inhibitors, including hypersensitivity to excipients (e.g. lactose) • History of pancreatitis, or pancreatic surgery, diabetic ketoacidosis • Prior lower extremity amputation or current threat of amputation (eg, lower extremity ulcer and peripheral artery disease) • History of severe hypoglycaemia and hypoglycaemia unawareness. • Contraindication to MRI |
- Diabete di tipo 1 • Valore dell'emoglobina A1c (HbA1c)> 9,5% durante il periodo di screening (basato sulla misurazione del laboratorio centrale). • Necessità di trattamento aggiuntivo oltre a metformina e/o repaglinide • Valore dell'emoglobina A1c (HbA1c) <6,5% solo per i pazienti candidati alla seconda biopsia renale • Velocità di filtrazione glomerulare stimata <25 o> 75 ml / min / 1,73 m2 (secondo CKD-EPI) allo screening • Infezione urinaria o genitale non trattata allo screening e al follow-up • Chiari segni di esaurimento del volume • Ipotensione sintomatica o pressione sanguigna sistolica <90 o ipertensione non controllata • Storia di abuso di alcol o droghe, anuria, dialisi o danno renale acuto / insufficienza renale acuta nei 3 mesi precedenti il periodo di screening • Trapianto di cuore, fegato o rene • Sindrome coronarica acuta, ictus o attacco ischemico transitorio nei 3 mesi prima del consenso informato • Malattia epatica, definita dai livelli sierici di alanina aminotransferasi, aspartato aminotransferasi o fosfatasi alcalina superiori a 3 volte il limite superiore della norma (ULN) durante lo screening • Cardiochirurgia o angioplastica programmata entro 3 mesi • Cancro o storia medica di cancro (ad eccezione del carcinoma basocellulare) negli ultimi 5 anni • Trattamento con farmaci anti-obesità nei 3 mesi prima del consenso informato o qualsiasi altro trattamento al momento dello screening che porta a un peso corporeo instabile (ad es. Chirurgia, dieta aggressiva, ecc.) • Trattamento SGLT2i nelle 10 settimane precedenti il periodo di screening • Trattamento con steroidi sistemici al momento del consenso informato o modifica del dosaggio degli ormoni tiroidei entro 6 settimane prima del consenso informato • Qualsiasi disturbo endocrino non controllato eccetto T2DM •Gravidanza o allattamento •Donne in età fertile che non praticano contraccezione • Pazienti con ipersensibilità nota a Dapagliflozin o altri inibitori del SGLT2, inclusa ipersensibilità agli eccipienti (ad es. Lattosio). • Storia di pancreatite o chirurgia pancreatica, chetoacidosi diabetica • Precedente amputazione degli arti inferiori o pericolo di amputazione ( Es., Ulcera degli arti inferiori e malattia delle arterie periferiche). • Storia di ipoglicemia grave e inconsapevolezza di ipoglicemia. • Controindicazione alla risonanza magnetica |
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E.5 End points |
E.5.1 | Primary end point(s) |
1) In the proximal tubule cells of the whole study population, changes in:
a) protein expression of target inflammatory genes (such as p16ink4a, TLR-4, phospho-p65, DKK3, Myostatin, TGFß, SMAD 2,3 and MAPK pathways) and in epithelial-mesenchymal transition (EMT).
b) target genes of inflammation, apoptosis, senescence such as type IV collagen fibronectin, TGF-ß, TNF receptor 1, EMF cadherin production, NF-kB, MCP-1 , DKK3, myostatin and Activin A responses.
2) In the first six patients with T2DM, proteinuria > 1 g/day and biopsy proven diabetic kidney disese allocated to the treatment with dapagliflozin, changes in the protocol kidney biopsy at the end of the treatment period will be evaluated as follows:
a) expression and location of senescence (p16inkA, SA-beta-galactosidase), and apoptosis markers (TNF receptor 1, EMF cadherin NF-kB). b) target inflammatory gene responses (of inflammation, apoptosis, senescence such as type IV collagen fibronectin, TGF-ß, TNF receptor 1, EMF cadherin production, NF-kB, MCP-1 , DKK3, myostatin and Activin A activation) c) expression and location of pro-inflammatory cytokine expression in kidney biopsies (for pro-inflammatory and pro-fibrotic cytokines expression such as MCP-1, DKK3, TLR-4, CCR-2, Myostatin, TGFß and Activin A will be evaluated by immunohistochemistry) |
1) Nelle cellule tubulari prossimali dell'intera popolazione in studio, cambiamenti in: a) espressione proteica dei geni infiammatori bersaglio (come p16ink4a, TLR-4, fosfo-p65, DKK3, Miostatina, TGFß, SMAD 2,3 e MAPK pathways) e nella transizione epiteliale-mesenchimale (EMT). b) geni bersaglio di infiammazione, apoptosi, senescenza come fibronectina di collagene di tipo IV, TGF-ß, recettore 1 del TNF, produzione di caderina EMF, risposte NF-kB, MCP-1, DKK3, miostatina e Activina A.
2) Nei primi sei pazienti con T2DM, proteinuria> 1 g / die e malattia renale diabetica comprovata da biopsia assegnata al trattamento con dapagliflozin, le modifiche al protocollo biopsia renale al termine del periodo di trattamento saranno valutate come segue: a) espressione e localizzazione della senescenza (p16inkA, SA-beta-galattosidasi) e marcatori di apoptosi (recettore 1 del TNF, caderina EMF NF-kB). b) risposte di geni target (di infiammazione, apoptosi, senescenza come fibronectina di collagene di tipo IV, TGF-ß, recettore TNF 1, produzione di caderina EMF, NF-kB, MCP-1, DKK3, miostatina e attivazione di Activin A) c) espressione e localizzazione dell'espressione di citochine pro-infiammatorie nelle biopsie renali (sarà valutata l'espressione di citochine pro-infiammatorie e pro-fibrotiche come MCP-1, DKK3, TLR-4, CCR-2, Miostatina, TGFß e Activin A per immunoistochimica) |
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E.5.1.1 | Timepoint(s) of evaluation of this end point |
12 and 24 weeks |
12 settimane e 24 settimane |
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E.5.2 | Secondary end point(s) |
a) Changes in global and segmental renal oxygenation estimated by BOLD MRI (changes in R2* value defined as 1/T2*) b) Changes in urinary markers of a proxy of interstitial fibrosis in patients with CKD (Mir 20) c) Changes in urinary albumin excretion, eGFR, serum uric acid, HbA1c, lipid profile and body weight, blood pressure levels measured by ABPM and in the need of antihypertensive drugs |
a) Cambiamenti nell'ossigenazione renale globale e segmentale stimati da RM BOLD (variazioni nel valore R2 * definito come 1 / T2 *) b) Cambiamenti nei marker urinari di un proxy di fibrosi interstiziale in pazienti con CKD (Mir 20) c) Cambiamenti nell'escrezione urinaria di albumina, eGFR, acido urico sierico, HbA1c, profilo lipidico e peso corporeo, livelli di pressione sanguigna misurati con ABPM e necessità di farmaci antipertensivi |
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E.5.2.1 | Timepoint(s) of evaluation of this end point |
12 and 24 weeks |
12 e 24 settimane |
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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 | No |
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
| Yes |
E.8.4 | The trial involves multiple sites in the Member State concerned | No |
E.8.4.1 | Number of sites anticipated in Member State concerned | 1 |
E.8.5 | The trial involves multiple Member States | No |
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 | Information not present in EudraCT |
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
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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 | 0 |
E.8.9.1 | In the Member State concerned months | 18 |
E.8.9.1 | In the Member State concerned days | 0 |
E.8.9.2 | In all countries concerned by the trial years | 0 |
E.8.9.2 | In all countries concerned by the trial months | 18 |
E.8.9.2 | In all countries concerned by the trial days | 0 |