| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
| Patients With Type 2 Diabetes Mellitus Who Have Inadequate Glycemic Control on Insulin Alone or in Combination With Metformin |
| pazienti affetti da Diabete Mellito di tipo II con inadeguato controllo glicemico in monoterapia con insulina o associata a Metformina |
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| E.1.1.1 | Medical condition in easily understood language |
| Patients With Type 2 Diabetes Mellitus Who Have Inadequate Glycemic Control on Insulin Alone or in Combination With Metformin |
| pazienti affetti da Diabete Mellito di tipo II con inadeguato controllo glicemico in monoterapia con insulina o associata a Metformina |
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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 | 10049746 |
| E.1.2 | Term | Insulin-requiring type II 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 |
| After 24 weeks, to assess the effect of sitagliptin compared with placebo on the change in insulin dose in IU per day in patients with type 2 diabetes mellitus (T2DM) with inadequate glycemic control on insulin with or without metformin, who titrate insulin glargine (Treat-to-Target). To assess the safety and tolerability of sitagliptin |
| valutare l'efficacia di Sitagliptin 100 mg una volta al giorno rispetto al placebo sulla riduzione del dosaggio dell'insulina per un periodo di 24 settimane in pazienti con Diabete Mellito Tipo 2 (T2DM) che hanno un inadeguato controllo glicemico in monoterapia con insulina o associata alla Metformina |
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| E.2.2 | Secondary objectives of the trial |
| In patients with T2DM with inadequate glycemic control on insulin with or without metformin, who titrate insulin glargine (Treat-to-Target): (1) After 24 weeks, to estimate the difference between sitagliptin and placebo on hemoglobin A1c . (2) After 24 weeks, to estimate the difference between sitagliptin and placebo on fasting plasma glucose. (3) After 24 weeks, to estimate the difference between sitagliptin and placebo on body weight. (4) After 24 weeks, to estimate the difference between sitagliptin and placebo in the proportion of patients who achieve the fasting glucose target of 72-100 mg/dL (4.0-5.6 mmol/L). (5) To estimate the difference between sitagliptin and placebo in the time to achieve the fasting glucose target of 72-100 mg/dL (4.0-5.6 mmol/L) for the first time. |
| In pazienti con diabete mellito Tipo 2 con inadeguato controllo glicemico ed in trattamento con insulina con o senza metformina, che titolano l' insulina glargine (Treat to Target): (1) Obiettivo: Dopo 24 settimane valutare la differenza tra sitagliptin e placebo sul valore di A1C. (2) Obiettivo: Dopo 24 settimane valutare la differenza tra sitagliptin e placebo sul valore della glicemia plasmatica a digiuno (FPG). (3) Obiettivo: Dopo 24 settimane valutare la differenza tra sitagliptin e placebo sul peso corporeo. (4) Obiettivo: Dopo 24 settimane valutare la differenza tra stagliptin e placebo nella percentuale di pazienti che raggiungono il valore target della glicemia a digiuno di 72-100 mg/dL (4.0-5.6 mmol/L). (5) Obiettivo: Valutare la differenza tra sitagliptin e placebo nel tempo in cui si raggiunge il valore target della glicemia a digiuno di 72-100 mg/dL (4.0-5.6 mmol/L) per la |
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| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal inclusion criteria |
| At Visit 1/Screening Visit: 1. Patient has type 2 diabetes mellitus (T2DM). 2. Patient meets one of the following criteria: A. Patient was diagnosed with diabetes after age 40 years and insulin therapy was initiated at least 3 years after the diagnosis of diabetes, OR - B.Patient does not meet the criteria in (A) above (i.e., diagnosis < age 40 years or insulin started earlier than 3 years after diagnosis), but has a fasting C-peptide of >0.7 ng/mL. Note: Only patients who do not meet the criteria in (A) should have a C-peptide level measured. 3. Patient must be ≥18 and ≤80 years of age on the day of signing informed consent. 4. Patient is on a stable insulin regimen for ≥10 weeks metformin (immediate-release or extended-release formulation) at ≥1500 mg/day for ≥10 weeks sulfonylurea for ≥10 weeks, with one of the following insulins (at a dose of at least 15 U/day and a maximum dose of 150 U/day) and has a Visit 1/Screening Visit A1C ≥7.5% and ≤11.0% (for patients not on sulfonylurea) or A1C ≥7.0% and ≤10.0% (for patients on sulfonylurea): • Pre-mixed insulin with at least 70% basal insulin (e.g., Novolog 70/30, Novolin 70/30, Humalog 75/25, or Humulin 70/30) once-daily or twice-daily. • Intermediate-acting insulin (e.g., NPH/Isophane) once-daily or twicedaily. • Long-acting insulin (e.g., Glargine [Lantus] and Detemir [Levemir]) once-daily or twice-daily. Note: A stable insulin regimen is defined as all daily doses within 10% (or within 2 units for patient taking ≤20U/day) of the usual administered dose (e.g., if usual insulin dose is 50 U/day, then doses of 45-55 U/day would be considered stable) |
| 1. Il paziente è affetto da diabete mellito Tipo 2 (T2DM). 2. Il paziente soddisfa uno dei seguenti criteri: A. Al paziente è stato diagnosticato il diabete dopo i 40 anni e la terapia insulinica è stata iniziata almeno 3 anni dopo la diagnosi di diabete OR B. Il paziente non soddisfa il criterio A) di cui sopra (ad es. la diagnosi è avvenuta prima dei 40 anni o la terapia con insulina è iniziata prima dei tre anni successivi alla diagnosi), ma ha il valore del C-peptide a digiuno >0.7 ng/mL. 3. Il paziente deve avere un età compresa tra i ≥18 e ≤80 anni al momento della firma del consenso informato. 4. Il paziente è in trattamento stabile con insulina da almeno 10 settimane + metformina (formulazione a rilascio immediato o a rilascio prolungato) ad un dosaggio > 1500 mg/die per almeno 10 settimane + sulfonilurea per almeno 10 settimane . 5. Il paziente comprende le procedure dello studio, i trattamenti alternativi disponibili e i rischi che lo studio comporta, e accetta volontariamente di partecipare dando il consenso informato scritto. Il paziente può anche fornire il consenso per Future Ricerche Biomediche. Tuttavia, il paziente può partecipare allo studio principale senza partecipare alle Future Ricerche Biomediche. 6. Il paziente è un uomo o una donna con una probabilità estremamente bassa di concepire. 7. Il paziente ha > 85% di compliance (valutata con il numero delle compresse ) durante il trattamento con placebo nel periodo di run-in. |
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| E.4 | Principal exclusion criteria |
| At Visit 1/Screening Visit: 1. Patient has been treated with a DPP-4 inhibitor, a thiazolidinedione (TZD), or a GLP-1 mimetic or analogue, within the prior 12 weeks. 2. Patient is currently on treatment with daily use (one or more injections per day) of a pre-prandial short-acting or rapid-acting insulin (e.g., aspart, glulisine, lispro, regular insulin) alone or as part of a basal/bolus insulin regimen. Note: Patients using a pre-mixed insulin containing a short-acting insulin may participate. 3. Patient has symptomatic hyperglycemia that, in the investigator’s opinion, requires immediate initiation, adjustment, or addition of antihyperglycemic therapy. 4. Patient has a history of 2 or more episodes of hypoglycemia resulting in seizure, coma, or loss of consciousness, - or - patient has had recurrent (≥3 times per week) episodes of hypoglycemia over the past 8 weeks. 5. Patient has a history of ketoacidosis. 6. Patient is, as assessed by the investigator, not appropriate for or does not agree to target a fasting glucose of 72-100 mg/dL [4.0-5.6 mmol/L]. 7. Patient has a history of intolerance or hypersensitivity to sitagliptin, insulin, or metformin (if patient on metformin at Visit 1) or any contraindication to sitagliptin, insulin, or metformin (if patient on metformin at Visit 1) based upon the label of the country of the investigational site. 8. Patient is pregnant or breast-feeding, or is expecting to conceive or donate eggs during the study, including 14 days following the last dose of study drug. 9. Patient has a medical history of active liver disease (other than non-alcoholic hepatic steatosis), including chronic active hepatitis B or C (assessed by medical history), primary biliary cirrhosis, or symptomatic gallbladder disease. 10. Patient has had new or worsening signs or symptoms of coronary heart disease or congestive heart failure within the past 3 months, or has any of the following disorders within the past 3 months: a. Acute coronary syndrome (e.g., MI or unstable angina) b. Coronary artery intervention (e.g., CABG or PTCA) c. Stroke or transient ischemic neurological disorder At Visit 4/Randomization: 11. Patient has a site FFSG of <130 mg/dL (7.2 mmol/L) or >270 mg/dL (15.0 mmol/L). Note: If the patient meets this exclusion criterion AND the investigator believes that the value is not consistent with the patient’s current Self-Monitoring Blood Glucose (SMBG) values and Visit 3/Week -2 FPG value, the patient should not be excluded at this time. This visit should be changed to an Unscheduled Visit and the patient should be rescheduled for Visit 4/Day 1 within 7 days. Additional single-blind placebo run-in medication should be dispensed if needed. If the patient meets this FFSG exclusion criterion at the rescheduled Visit 4/Day1, the patient MUST be excluded |
| 1. Il paziente trattato con un inibitore del DPP-4 un tiazolinedione (TZD) o con un mimetico o analogo del GLP-1 entro le 12 settimane precedenti. 2. Il paziente attualmente in trattamento con l'uso quotidiano (uno o più iniezioni al giorno) di insulina pre-prandiale ad azione a breve durata o ad azione rapida (ad es. insulina aspartato, glulisina, lispro, regolare) da sola o come parte di un regime bolo/ basale di insulina. 3. Il paziente con una iperglicemia sintomatica che,a giudizio del ricercatore, richiede un immediato inizio, aggiustamento o aggiunta di una terapia anti iperglicemica. 4. Il paziente con una storia di 2 o più episodi di ipoglicemia con conseguente convulsione, coma o perdita di conoscenza, oppure, paziente che ha avuto ricorrenti (> 3 volte alla settimana) episodi di ipoglicemia nelle ultime otto settimane. 5. Il paziente ha una storia di cheto acidosi. 6. Il paziente è, a giudizio del ricercatore, non adatto o non è d’accordo a ad avere come glicemia target a digiuno 72-100 mg/dL [4.0-5.6 mmol/L]. Per altri criteri si veda SINOSSI. |
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| E.5 End points |
| E.5.1 | Primary end point(s) |
| Change from baseline in daily insulin dose at Week 24. |
| Variazione dal basale del dosaggio giornaliero di insulina alla Settimana 24. |
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| E.5.1.1 | Timepoint(s) of evaluation of this end point |
|
| E.5.2 | Secondary end point(s) |
| Efficacy Endpoints: laboratory assessment of: A1C, FPG, and lipid panel endpoints and time when a patient meets the fasting glucose target. Safety endpoints: adverse events, additional hypoglycemia endpoints, percentages of patients meeting predefined limits of change (PDLC) in laboratory parameters (including blood chemistry and hematology), and change (or percent change) from baseline at Week 24 in laboratory parameters, body weight and vital signs. Serious adverse events (SAEs) consistent with vascular events (cardiovascular, cerebrovascular, and peripheral vascular events) and heart failure events, revascularization procedures, and all deaths, regardless of cause, will be subject to adjudication by an expert committee external to the SPONSOR. When an eligible event is identified, the SPONSOR will request copies of additional source documentation related to the event (e.g., hospital records) from the investigator. |
| Endpoint di efficacia: Analisi di laboratorio di: A1C, FPG ed gli endpoint del profilo lipidico ed il tempo in cui il paziente raggiunge il valore target della glicemia a digiuno. Endpoint di sicurezza: eventi avversi, gli endpoint di ipoglicemia aggiuntivi, la percentuale dei pazienti che raggiungono i predefiniti limiti di cambiamento (PDLC) nei parametri di laborastorio (che includono ematochimica ed ematologia), ed il cambiamento (o la percentuale del cambiamento) dal baseline fino a 24 settimane nei partametri di laboratorio, peso corporeo e segni vitali. Gli Eventi avversi seri (SAEs) definiti come eventi vascolari (eventi cardiovascolari, cerebrovascolari e vascolari periferici) ed eventi di insufficienza cardiaca, procedure di rivascolarizzazione, e tutte le morti, indipendentemente dalla causa saranno oggetto di un controllo da parte di un comitato di esperti indipendenti dallo SPONSOR. Se un evento eleggibile viene identificato, allo SPONSOR verranno richieste al ricercatore copie di ulteriore documentazione correlato all'evento (ad es. cartelle cliniche). |
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| E.5.2.1 | Timepoint(s) of evaluation of this end point |
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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 | Yes |
| E.6.4 | Safety | Yes |
| E.6.5 | Efficacy | Yes |
| E.6.6 | Pharmacokinetic | No |
| E.6.7 | Pharmacodynamic | Yes |
| 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) | 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 | 4 |
| E.8.5 | The trial involves multiple Member States | Yes |
| E.8.5.1 | Number of sites anticipated in the EEA | 48 |
| 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 |
| Brazil |
| Canada |
| Guatemala |
| India |
| Israel |
| Korea, Republic of |
| Mexico |
| New Zealand |
| Peru |
| Puerto Rico |
| Russian Federation |
| South Africa |
| Turkey |
| United States |
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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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| 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 | 20 |
| 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 | 20 |
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