E.1 Medical condition or disease under investigation |
E.1.1 | Medical condition(s) being investigated |
Type 2 diabetes mellitus |
Diabete mellito di tipo II |
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E.1.1.1 | Medical condition in easily understood language |
Increased blood sugar |
Aumento del glucosio nel sangue |
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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 | LLT |
E.1.2 | Classification code | 10045242 |
E.1.2 | Term | Type II diabetes mellitus |
E.1.2 | System Organ Class | 100000004861 |
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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 efficacy and safety of different dosage regimens of empagliflozin, 5mg twice daily compared to 10 mg once daily versus placebo and 12.5 mg twice daily compared to 25 mg once daily versus placebo, administered orally as add-on therapy to metformin in patients with T2DM and insufficient glycaemic control |
Obiettivo dello studio e' valutare l'efficacia e la sicurezza di diversi regimi di somministrazione di empagliflozin, 5 mg b.i.d in confronto a 10 mg q.d. verso placebo e 12.5 mg b.i.d. in confronto a 25 mg q.d. verso placebo, somministrati oralmente come terapia aggiuntiva a metformina in pazienti con diabete mellito di tipo 2 con insufficiente controllo glicemico |
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E.2.2 | Secondary objectives of the trial |
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E.2.3 | Trial contains a sub-study | No |
E.3 | Principal inclusion criteria |
1. Diagnosis of type 2 diabetes mellitus prior to informed consent. 2. Male and female patients on diet and exercise regimen currently treated with metformin (IR) alone. A total daily dose of >=1500 mg/day metformin divided into twice daily administration (e.g., 850 mg bid, 1000 mg bid, 850/1000 mg bid or 500/1000 mg bid) is required for inclusion into the trial. A patient taking metformin tid can be included if switched to a bid dosing regimen at the time of informed consent. In this case, the total daily dose must be maintained (e.g., 500 mg tid to 1000/500 mg bid, 1000/500/500 mg tid to 1000 bid, 500/500/850 mg tid to 1000/850 mg bid). 3. The total daily dosage of metformin needs to be stable for at least 12 weeks prior to randomisation and is expected to be stable throughout the duration of the study. 4. HbA1c >= 7.0% and <= 10% (>=53.0 mmol/mol and <=85.8 mmol/mol) at Visit 1 (screening) 5. Age >=18 at Visit 1 (screening) 6. BMI <=45 kg/m**2 (Body Mass Index) at Visit 1 (screening). 7. Signed and dated written informed consent by date of Visit 1 in accordance with GCP and local legislation. |
1.Diagnosi di diabete mellito di tipo 2 prima della firma del consenso informato (CI) 2.Pazienti maschi e femmine con regime dietetico e di esercizio fisico in trattamento con metformina come monoterapia. E' richiesto un dosaggio totale giornaliero di metformina >=1500 mg/dì suddiviso in due somministrazioni giornaliere (ad es. 850 mg b.i.d, 850/1000 mg b.i.d oppure 500/1000 mg b.i.d.). Un paziente che prenda metformina t.i.d. puo' essere incluso se passa ad un regime b.i.d. al momento della firma del consenso informato. In tal caso, la dose giornaliera totale deve essere mantenuta (ad es. da 500 mg t.i.d a 1000/500 mg b.i.d, da 1000/500/500 t.i.d. a 1000 b.i.d, da 500/500/850 t.i.d. a 1000/850 b.i.d.). 3.Il dosaggio totale giornaliero di metformina deve essere stabile da almeno 12 settimane prima della randomizzazione e dovrebbe rimanere stabile per tutta la durata della sperimentazione. 4.HbA1c >= 7.0% e <= 10% (>= 53.0 mmol/mol e <= 85.8 mmol/mol) alla Visita 1 (screening). 5.Eta' >= 18 anni alla Visita 1 (screening). 6.Body Mass Index (BMI) <=45 kg/m**2 alla Visita 1 (screening). 7.Consenso informato scritto, firmato e datato entro la data della Visita 1, in accordo con le GCP e la legislazione nazionale. |
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E.4 | Principal exclusion criteria |
1. Uncontrolled hyperglycaemia with a glucose level >240 mg/dl (>13.3 mmol/L) after an overnight fast during placebo run-in and confirmed by a second measurement (not on the same day). 2. Any other antidiabetic medication within 12 weeks prior to randomisation, except the one defined as the permitted background therapy via inclusion criterion no. 2 3. Treatment with extended release formulations of metformin within 12 weeks prior to consent 4. Acute coronary syndrome (non-STEMI, STEMI and unstable angina pectoris), stroke or transient ischaemic attack (TIA) within 3 months prior to informed consent. 5. Indication of liver disease, defined by serum levels of either ALT (SGPT), AST (SGOT), or alkaline phosphatase above 3 x upper limit of normal (ULN) as determined during screening and/or run-in period 6. Impaired renal function, defined as estimated creatinine clearance rate (eCCr) <60 ml/min (Cockcroft-Gault formula) as determined during screening and/or run-in period 7. Bariatric surgery within the past two years and other gastrointestinal surgeries that induce chronic malabsorption 8. Known medical history of cancer (except for basal cell carcinoma) and/or treatment for cancer within the last 5 years 9. Blood dyscrasias or any disorders causing haemolysis or unstable red blood cell (e.g. malaria, babesiosis, haemolytic anaemia) 10. Contraindications to metformin according to the local label (e.g. SPC) 11. Treatment with anti-obesity drugs 3 months prior to informed consent or any other treatment at the time of screening (i.e. surgery, aggressive diet regimen, etc.) which, in the opinion of Investigator, may lead to unstable body weight 12. Current treatment with systemic steroids at time of informed consent or change in dosage of thyroid hormones within 6 weeks prior to informed consent or other uncontrolled endocrine disorder (except T2DM) 13. Pre-menopausal women (last menstruation <=1 year prior to informed consent) who: -are nursing or pregnant or -are of child-bearing potential and are not practicing an acceptable method of birth control, or do not plan to continue using this method throughout the study and do not agree to submit to periodic pregnancy testing during participation in the trial. Acceptable methods of birth control include tubal ligation, transdermal patch, intra uterine devices/systems (IUDs/IUSs), oral, implantable or injectable contraceptives, sexual abstinence (if acceptable by local authorities), double barrier method and vasectomised partner 14. Alcohol or drug abuse within the 3 months prior to informed consent that, in the opinion of Investigator, would interfere with trial participation or any ongoing condition leading to a decreased compliance to study procedures or study drug intake. 15. Intake of an investigational drug in another trial within 30 days prior to intake of study medication in this trial 16. Any other clinical condition that, in the opinion of the Investigator, would jeopardize patient's safety while participating in this clinical trial |
1.Iperglicemia incontrollata a livelli di glucosio >240 mg/dl (>13.3 mmol/L) dopo digiuno notturno durante la fase di run-in con placebo e confermata da una seconda misurazione (non nel medesimo giorno). 2.Qualunque altro farmaco antidiabetico preso nelle 12 settimane prima della randomizzazione (eccetto metformina come terapia di background come definito nel criterio di inclusione 2). 3.Trattamento con formulazioni di metformina a lento rilascio nelle 12 settimane prima del consenso informato. 4.Sindrome coronarica acuta (non-STEMI, STEMI e angina pectoris instabile), ictus o TIA entro 3 mesi prima del consenso informato. 5.Indicazione di disfunzione epatica definita come livelli serici di ALT (SGPT), AST (SGOT), o fosfatasi alcalina oltre 3 volte il limite superiore di normalita' (ULN) determinato durante lo screening e/o il periodo di run-in. 6.Disfunzione renale, definita come stima del tasso di clerance della creatinina (eCcr) <60 ml/min (formula di Cockcroft-Gault), determinata durante lo screening e/o il periodo di run-in. 7.Chirurgia per il controllo ponderale entro i due anni precedenti ed altri interventi gastrointestinali che inducono malassorbimento cronico. 8.Storia medica di cancro (eccetto carcinoma delle cellule basali) e/o trattamento per cancro negli ultimi 5 anni. 9.Discrasie od altri disturbi che causino emolisi e emivita breve/instabile degli eritrociti (es. malaria, babesiosi, anemia emolitica). 10.Controindicazioni alla metformina in accordo all'AIC. 11.Trattamento con farmaci anti-obesita' entro 3 mesi prima del consenso informato o qualunque altro trattamento al momento dello screening (cioe' chirurgia, regime dietetico aggressivo, ecc...) che porti ad instabilita' ponderale. 12.Trattamento corrente con steroidi sistemici al momento del consenso informato o modifiche di dosaggio negli ormoni tiroidei entro le 6 settimane precedenti il consenso informato o qualunque altro disturbo endocrino (tranne il T2DM). 13.Donne in pre-menopausa (ultima mestruazione <=1 anno prima del CI) che: -siano in allattamento o in gravidanza; -siano in eta' fertile e non usino un metodo contraccettivo accettabile dal punto di vista medico o che non intendano usarlo per tutta la durata dello studio e che non accettino di effettuare periodicamente un test di gravidanza durante lo studio. Metodi accettabili di contraccezione includono: legamento delle tube, cerotto transdermico, dispositivi intrauterini (IUD/IUS), contraccettivi orali, impiantabili o iniettabili, astinenza sessuale completa (se accettabile dalle Autorita' Sanitarie Nazionali), metodo a doppia barriera e partner vasectomizzato. 14.Abuso di alcol o sostanze stupefacenti entro i 3 mesi prima del consenso informato che possa interferire con la partecipazione allo studio o qualunque condizione presente che possa abbassare la compliance del paziente alle procedure dello studio o all'assunzione del farmaco, a giudizio dello sperimentatore. 15.Assunzione di un farmaco sperimentale in altro studio clinico entro 30 giorni dalla prima assunzione di farmaco per il presente studio. 16.Qualunque altra condizione medica che, a giudizio dello sperimentatore metterebbe a rischio la sicurezza del paziente mentre partecipa allo studio. |
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E.5 End points |
E.5.1 | Primary end point(s) |
The primary endpoint in this study is the change from baseline in HbA1c after 16 weeks of treatment. Throughout the study protocol, the term `baseline` refers to the last observation prior to administration of any randomised study medication |
L`endpoint primario e` la variazione dell`emoglobina glicata (HbA1c) rispetto al dopo 16 settimane di trattamento. Il termine basale si riferisce all`ultima osservazione prima della somministrazione del farmaco in studio in base alla randomizzazione |
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E.5.1.1 | Timepoint(s) of evaluation of this end point |
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E.5.2 | Secondary end point(s) |
1.Fasting plasma glucose (FPG): Change from baseline after 16 weeks of treatment and Change from baseline by visit over time 2.HbA1c: Change from baseline in HbA1c by visit over time |
Gli endpoint secondari principali sono: -la variazione del glucosio nel plasma a digiuno (FPG) dal basale a 16 settimane di trattamento e dal basale a ciascuna visita -la variazione di HbA1c dal basale a ciascuna visita. |
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E.5.2.1 | Timepoint(s) of evaluation of this end point |
16 weeks and by visit over time |
16 settimane e dal basale a ciascuna visita |
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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 | Yes |
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 | Yes |
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 | Yes |
E.8.2.3.1 | Comparator description |
somministarzione empagliflozin bid vs qd |
administration empagliflozin bid vs qd |
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E.8.2.4 | Number of treatment arms in the trial | 5 |
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 | 9 |
E.8.5 | The trial involves multiple Member States | Yes |
E.8.5.1 | Number of sites anticipated in the EEA | 52 |
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 |
Canada |
Georgia |
Guatemala |
Mexico |
New Zealand |
Russian Federation |
South Africa |
Turkey |
Ukraine |
United States |
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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 | 13 |
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 | 13 |
E.8.9.2 | In all countries concerned by the trial days | 0 |