| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
| Type 2 Diabetes in subjects who have Inadequate Glycemic Control on Metformin Alone |
| diabete di tipo 2 in soggetti che hanno un controllo glicemico inadeguato con Metformina in monoterapia |
|
| E.1.1.1 | Medical condition in easily understood language |
| Type 2 Diabetes |
| diabete di tipo 2 |
|
| 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 | SOC |
| E.1.2 | Classification code | 10027433 |
| E.1.2 | Term | Metabolism and nutrition disorders |
| E.1.2 | System Organ Class | 10027433 - Metabolism and nutrition disorders |
|
| 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 compare the mean change from baseline in glycosylated hemoglobin (HbA1c) achieved with concurrent addition of saxagliptin and dapagliflozin to metformin versus the addition of placebo & saxagliptin to metformin & versus the addition of placebo plus dapagliflozin to metformin after 24 weeks of double-blind treatment. |
| Confrontare la variazione media dal basale nell’emoglobina glicosilata (HbA1c) ottenuta con l’aggiunta contemporanea di saxagliptin e dapagliflozin a metformina rispetto (vs.) all’aggiunta di placebo e saxagliptin a metformina e rispetto all’aggiunta di placebo più dapagliflozin a metformina dopo 24 settimane di trattamento in doppio cieco. |
|
| E.2.2 | Secondary objectives of the trial |
| To compare the mean change from baseline achieved with concurrent addition of saxagliptin and dapagliflozin to MTF (metformin) vs. the addition of placebo and saxagliptin to MTF and vs. the addition of placebo plus dapagliflozin to MTF after 24weeks of double-blind treatment in: 1. 2-hour post prandial glucose from a liquid meal tolerance test(2-h MTT) 2. Fasting plasma glucose(FPG) • To compare the proportion of subjects achieving therapeutic glycemic response, defined as HbA1c<7.0%, after 24weeks of double-blind treatment with concurrent addition of saxagliptin and dapagliflozin to MTF vs. the addition placebo and saxagliptin to MTF and vs. the addition of placebo plus dapagliflozin to MTF • To compare the mean change in total body weight achieved with the addition of saxagliptin and dapagliflozin to MTF vs. the addition of placebo and saxagliptin to MTF |
| Confront. la variazione media dal basale ottenuta con l’aggiunta contemporanea di saxagliptin e dapagliflozin a MTF risp. all’aggiunta di placebo e saxagliptin a MTF e risp. all’aggiunta di placebo+dapagliflozin a MTF dopo 24sett. di trattamento in doppio cieco in: 1.glicemia postprandiale a 2ore da un test di tolleranza di un pasto liquido(2-h MTT) 2.glicemia plasmatica a digiuno(Fasting Plasma Glucose,FPG) Confront. la proporzione dei sogg. che ottengono una risposta glicemica terapeutica, definita come HbA1c<7,0%, dopo 24sett. di trattam. in doppio cieco con l’aggiunta contemporanea di saxagliptin e dapagliflozin a MTF risp. all’aggiunta di placebo e saxagliptin a MTF e risp. all’aggiunta di placebo+dapagliflozin a MTF. Confront. la variazione media del peso corporeo tot ottenuta con l’aggiunta di saxagliptin e dapagliflozin a MTF risp. all’aggiunta di placebo e saxagliptin a MTF |
|
| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal inclusion criteria |
| Men and women, aged ≥ 18 years old at time of screening visit • Subjects with T2DM with inadequate glycemic control defined as central laboratory HbA1c ≥ 8.0 and ≤ 12.0 % at the screening visit. • Stable metformin therapy for at least 8 weeks prior to screening at a dose ≥ 1500 mg per day • C-peptide ≥ 1.0 ng/mL (0.34 nmol/L) at screening visit • BMI ≤ 45.0 kg/m2 at the screening visit |
| Uomini e donne, di età ≥ 18 anni al momento della visita di screening •Soggetti con diabete mellito di tipo 2 (T2DM) con controllo glicemico inadeguato definito dai valori dell’HbA1c misurati dal laboratorio centrale ≥ 8,0 e ≤ 12,0 % alla visita di screening. •Terapia stabile di metformina per almeno 8 settimane prima dello screening a un dosaggio ≥1500 mg al giorno •C-peptide ≥ 1,0 ng/ml (0,34 nmol/L) alla visita di screening •Indice di massa corporea (BMI) ≤ 45,0 kg/m2 alla visita di screening |
|
| E.4 | Principal exclusion criteria |
| Moderate or severe impairment of renal function [defined as eGFR <60mL/min/1.73 m2 (estimated by MDRD) or serum creatinine (Scr) ≥ 1.5 mg/dL in males or ≥ 1.4 mg/dL in females] • Uncontrolled hypertension defined as systolic blood pressure (SBP) ≥ 160 mmHg and/or diastolic blood pressure (DBP) ≥ 100 mmHg Note: Subjects with SBP ≥ 160mmHg and < 180mmHg or a DBP ≥ 100 mmHg and < 110 mmHg will be able to enter the lead-in period, provided their hypertension treatment is adjusted as deemed appropriate by the investigator. These subjects can not be randomized if their blood pressure remains SBP ≥ 160 mmHg or DBP ≥ 100 mmHg measured at Day 1. • Cardiovascular diseases within 3 months of the screening visit • Significant hepatic disease, including, but not limited to, chronic active hepatitis and/or severe hepatic insufficiency, including subjects with ALT and/or AST > 3x ULN and or Total Bilirubin > 2.5xULN. • Male subjects with microscopic hematuria present at week -6 or -4 AND no common cause that can be confirmed. Male subjects with a confirmed common cause can be randomized with a documented negative microscopic urinalysis. NOTE: Female subjects with hematuria can be randomized, but should be investigated according to local standards and best clinical practices. (See Appendix 3). • Malignancy within 5 years of the screening visit (with the exception of treated basal cell or treated squamous cell carcinoma) • Subjects who have contraindications, including but not limited to a history of serious hypersensitivity reaction to saxagliptin, as outlined in the saxagliptin and dapagliflozin Investigator Brochure, the local saxagliptin package insert or the local metformin package insert. • Administration of any antihyperglycemic therapy, other than metformin, for more than 14 days (consecutive or not) during the 12 weeks prior to screening, as well as exposure to any DPP-4 or SGLT-2 inhibitor is an exclusion criterion. • Current treatment with potent cytochrome P450 3A4/5 inhibitors (in countries where dose adjustment would be required by the saxagliptin label). Randomization Criteria Exclusion: • FPG >270mg/dl as measured at Week -4 Note: At Week -4 a qualification check will be performed and subjects will be excluded, if their FPG is > 270 mg/dl. A re-test will be permitted within 7 days if the initial result was > 270mg/dl but < 300 mg/dl. Subjects will be excluded if the mean value of the Week -4 result and the re-test result is > 270mg/dl. |
| Insufficienza moderata o grave della funzione renale [definita come eGFR < 60 ml/min/1,73 m2 (stimata con la formula MDRD) o creatinina sierica (Scr) ≥ 1,5 mg/dl nei maschi o ≥ 1,4 mg/dl nelle femmine] • Ipertensione non controllata definita come pressione sanguigna sistolica (SBP) ≥ 160 mmHg e/o pressione sanguigna diastolica (DBP) ≥ 100 mmHg Nota: i soggetti con SBP ≥ 160 mmHg e < 180 mmHg o con DBP ≥ 100 mmHg e < 110 mmHg potranno essere ammessi al periodo di introduzione, purché il trattamento dell’ipertensione sia per loro aggiustato secondo quanto ritenuto opportuno dallo sperimentatore. Tali soggetti non possono essere randomizzati nel caso la loro pressione sanguigna rimanga SBP ≥ 160 mmHg o DBP ≥ 100 mmHg misurate al Giorno 1. • Malattie cardiovascolari nel corso degli ultimi 3 mesi prima della visita di screening • Malattia epatica significativa, comprese, a titolo non limitativo, un’epatite cronica attiva e/o una grave insufficienza epatica, compresi soggetti con ALT e/o AST > 3x ULN e o bilirubina totale > 2,5xULN. • Soggetti maschi con ematuria microscopica presente alla settimana -6 o -4 E nessuna causa comune che possa essere confermata. I soggetti maschi con una causa comune confermata possono essere randomizzati con un esame microscopico delle urine negativo documentato. NOTA: i soggetti femmine con ematuria possono essere randomizzati, ma dovranno essere esaminati secondo gli standard locali e le migliori pratiche cliniche (vedi Appendice 3). • Malignità nel corso degli ultimi 5 anni prima della visita di screening (con l’eccezione del carcinoma a cellule basali trattato o del carcinoma a cellule squamose trattato) • Soggetti che hanno controindicazioni, compresa, a titolo non limitativo, un’anamnesi di reazione grave di ipersensibilità a saxagliptin, come descritto nel Dossier dello Sperimentatore di saxagliptin e dapagliflozin, nel foglietto illustrativo locale del saxagliptin o del metformina. • Somministrazione di qualsiasi terapia antiperglicemica, diversa da metformina, per più di 14 giorni (consecutivi o meno) durante le 12 settimane precedenti lo screening, come anche l’esposizione a qualsiasi inibitore DPP-4 o SGLT2 rappresenta un criterio di esclusione. • Trattamento attuale con potenti inibitori del citocromo P450 3A4/5 (nei paesi in cui sarebbe richiesto un aggiustamento della dose secondo l’etichetta del saxagliptin). Criteri di randomizzazione Esclusione: • FPG >270 mg/dl come misurata alla Settimana -4 Nota: alla Settimana -4 sarà eseguito un controllo di qualificazione e i soggetti saranno esclusi se la loro FPG risulterà > 270 mg/dl. Sarà consentito un retest entro 7 giorni se il risultato iniziale era > 270 mg/dl ma < 300 mg/dl. I soggetti saranno esclusi se il valore medio del risultato della Settimana -4 e il risultato del retest sarà > 270 mg/dl. |
|
| E.5 End points |
| E.5.1 | Primary end point(s) |
| Mean change from baseline in HbA1c at Week 24 |
| variazione media dal basale nell’emoglobina glicosilata (HbA1c) alla settimana 24 |
|
| E.5.1.1 | Timepoint(s) of evaluation of this end point |
| From baseline lead-in period through week 24 treatment period. |
| Dal periodo di introduzione basale per tutto il periodo di trattamento di 24 settimane |
|
| E.5.2 | Secondary end point(s) |
| - Mean change from baseline in 2-hour post-prandial glucose during a liquid meal test (2-h MTT) at Week 24 - Mean change from baseline in fasting plasma glucose (FPG) at Week 24- Percent of subjects achieving a therapeutic glycaemic response, defined as a HbA1c < 7.0% at Week 24 - Mean change from baseline in body weight at Week 24 with the addition of saxagliptin and dapagliflozin to metformin vs. the addition of placebo and saxagliptin to metformin. |
| •variazione media dal basale nella glicemia postprandiale a 2 ore durante un test di tolleranza di un pasto liquido (2-h MTT) alla settimana 24 •variazione media dal basale nella glicemia plasmatica a digiuno (FPG) alla settimana 24 •percentuale dei soggetti che ottengono una risposta glicemica terapeutica, definita come HbA1c < 7,0% alla settimana 24 •variazione media dal basale del peso corporeo alla settimana 24 con l’aggiunta di saxagliptin e dapagliflozin a metformina rispetto all’aggiunta di placebo e saxagliptin a metformina. |
|
| E.5.2.1 | Timepoint(s) of evaluation of this end point |
| From baseline lead-in period through week 24 treatment period. |
| Dal periodo di introduzione basale per tutto il periodo di trattamento di 24 settimane |
|
| 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 | 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) | 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 | 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) | Yes |
| E.8.2.2 | Placebo | No |
| E.8.2.3 | Other | No |
| E.8.2.4 | Number of treatment arms in the trial | 3 |
| 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 | 5 |
| E.8.5 | The trial involves multiple Member States | Yes |
| E.8.5.1 | Number of sites anticipated in the EEA | 32 |
| 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 |
| Argentina |
| Brazil |
| Canada |
| India |
| Korea, Republic of |
| Mexico |
| Puerto Rico |
| South Africa |
| United States |
|
| 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
|
|
| 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 | 8 |
| 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 | 10 |
| E.8.9.2 | In all countries concerned by the trial days | 0 |
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