E.1 Medical condition or disease under investigation |
E.1.1 | Medical condition(s) being investigated |
Type II Diabetes Mellitus |
Diabete Mellito di tipo 2 |
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E.1.1.1 | Medical condition in easily understood language |
Type II Diabetes Mellitus |
Diabete Mellito di tipo 2 |
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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 compare the insulin glargine/lixisenatide fixed ratio combination to lixisenatide alone and to insulin glargine alone (on top of metformin treatment) in HbA1c change from baseline to week 30 |
Confrontare la combinazione a rapporto fisso insulina glargine/lixisenatide verso la monoterapia con insulina glargine e verso la monoterapia con lixisenatide (in aggiunta al trattamento con metformina) per quanto riguarda la variazione dei livelli di HbA1c alla settimana 30 rispetto al basale |
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E.2.2 | Secondary objectives of the trial |
To compare the overall efficacy and safety of insulin glargine/lixisenatide fixed ratio combination to insulin glargine alone and to lixisenatide alone (on top of metformin treatment) over a 30 week treatment period in patients with type 2 diabetes |
Confrontare l’efficacia e sicurezza della combinazione a rapporto fisso insulina glargine/lixisenatide verso la monoterapia con insulina glargine e verso la monoterapia con lixisenatide (in aggiunta al trattamento con metformina) per un periodo di trattamento di 30 settimane in pazienti con diabete di tipo 2. |
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E.2.3 | Trial contains a sub-study | No |
E.3 | Principal inclusion criteria |
• Patients with type 2 diabetes mellitus diagnosed for at least 1 year before the screening visit, treated for at least 3 months prior to visit 1 with metformin alone or metformin and a second oral anti-diabetic treatment that can be a sulfonylurea, or a glinide, or a sodium glucose co-transporter 2 inhibitor, and who are not adequately controlled with this treatment;
• Signed written informed consent
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- Pazienti con diabete mellito di tipo 2, diagnosticato da almeno 1 anno prima della visita di screening, trattati per almeno 3 mesi prima della visita 1 con metformina in monoterapia o con metformina e un secondo antidiabetico orale che può essere una sulfanilurea (SU) o una glinide o un inibitore di SGLT-2, e non adeguatamente controllati con questo trattamento;
- Consenso informato scritto firmato
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E.4 | Principal exclusion criteria |
• HbA1c at screening visit:
- less than 7.5% or more than 10% for patients previously treated with metformin alone,
- less than 7.0% or more than 9 % for patients previously treated with metformin and a second oral anti-diabetic treatment;
• Pregnancy or lactation, women of childbearing potential with no effective contraceptive method;
• Use of oral glucose-lowering agents other than those stated in the inclusion criteria or any
injectable glucose-lowering agents during the 3 months before screening.
• Previous Treatment with insulin (except for short-term treatment due to intercurrent illness
including gestational diabetes, at the discretion of the trial physician)
• History of discontinuation of a previous treatment with a GLP-1 receptor agonist (GLP-1 RA) due to safety/tolerability issue or lack of efficacy;
• Patient who has previously participated in any clinical trial with lixisenatide or the insulin
glargine/lixisenatide fixed ratio combination or has previously received lixisenatide.
• Any contraindication to metformin use, according to local labeling
• Use of weight loss drugs within 3 months prior to screening visit.
• Within the last 6 months prior to screening visit: history of stroke, myocardial infarction, unstable angina, or heart failure requiring hospitalization. Planned coronary, carotid or peripheral artery revascularisation procedures to be performed during the study period.
• History of pancreatitis (unless pancreatitis was related to gallstones and cholecystectomy was already performed), chronic pancreatitis, pancreatitis during a previous treatment with incretin therapies, pancreatectomy, stomach/gastric surgery.
• Personal or immediate family history of medullary thyroid cancer (MTC) or genetic conditions that predispose to MTC (eg, multiple endocrine neoplasia syndromes).
• Uncontrolled or inadequately controlled hypertension (systolic blood pressure above 180 mmHg or diastolic blood pressure above 95 mmHg) at screening visit
• At screening visit, Body Mass Index (BMI) less than or equal to 20 or above 40 kg/m²
• At screening visit amylase and/or lipase more than 3 times the upper limit of the normal (ULN)
laboratory range,
• At screening visit ALT or AST more than 3 ULN
• At screening visit calcitonin above or equal to 20 pg/mL (5.9 pmol/L)
Exclusion Criteria for randomization at the end of the screening period:
• HbA1c less than 7% or above 10%;
• Fasting Plasma glucose above 250mg/dL (13.9 mmol/L);
• Metformin maximal tolerated dose less than 1500 mg/day;
• Amylase and/or lipase more than 3 ULN; |
- Valore di HbA1c alla visita di screening:
- < 7,5% e > 10% per i pazienti precedentemente trattati con metformina in monoterapia,
- < 7,0% e > 9% per i pazienti precedentemente trattati con metformina e un secondo antidiabetico orale;
- Gravidanza o allattamento, donne in età fertile che non fanno uso di un metodo contraccettivo efficace;
- Uso di ipoglicemizzanti orali diversi da quelli indicati nei criteri di inclusione o di qualsiasi ipoglicemizzante iniettabile nei 3 mesi precedenti lo screening;
- Precedente trattamento con insulina (eccetto trattamento a breve termine a causa di malattia intercorrente, compreso il diabete gestazionale, a discrezione dello sperimentatore);
- Anamnesi di interruzione di un precedente trattamento con agonisti del recettore GLP-1 per motivi di sicurezza/tollerabilità o per mancanza di efficacia;
- Pazienti che abbiano precedentemente partecipato ad uno studio clinico con lixisenatide o con combinazione a rapporto fisso insulina glargine/lixisenatide o che abbiano precedentemente assunto lixisenatide;
- Qualsiasi controindicazione al trattamento con metformina, in base al foglietto illustrativo locale;
- Assunzione di farmaci per la perdita di peso nei 3 mesi precedenti la vista di screening;
- Nei 6 mesi precedenti la visita di screening: anamnesi di ictus, infarto del miocardio, angina instabile o insufficienza cardiaca che richieda l’ospedalizzazione. Procedure pianificate di rivascolarizzazione dell’arteria coronarica, carotidea o periferica da eseguirsi durante il corso dello studio;
- Anamnesi di pancreatite ( a meno che la pancreatite non fosse correlata a calcoli biliari con colecistectomia già effettuata), pancreatite cronica, pancreatite durante un precedente trattamento con incretine, pancreatectomia, interventi chirurgiici allo stomaco/gastrici;
- Anamnesi personale o familiare di carcinoma midollare della tiroide (MTC) o condizione genetica predisponente al MTC (ad esempio sindrome da neoplasia endocrina multipla);
- Ipertensione non controllata o inadeguatamente controllata (pressione sanguigna sistolica >180 mmHg o pressione sanguigna diastolica > 95 mmHg) alla visita di screening;
- Alla visita di screening: Indice di Massa Corporea (BMI) < a 20 kg/m2 o > a 40kg/m2;
- Alla visita di screening amilasi e/o lipasi > di 3 volte il limite del superiore di normalità (ULN);
- Alla visita di screening: ALT o AST >3 x ULN;
- Alla visita di screening: Calcitonina > 20pg/mL (5.9 pmol/L).
Criteri di esclusione per la randomizzazione al termine del periodo di screening:
- HbA1c <7% o >10%;
- Glicemia a digiuno >250 mg/dL (13.9 mmol/L);
- Dose massima tollerata di metformina < 1500 mg/giorno;
- Amilasi e/o lipasi > 3 x ULN
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E.5 End points |
E.5.1 | Primary end point(s) |
Change in HbA1c from baseline |
Variazioni dei valori HbAC1 rispetto al basale |
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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) |
- Percentage of patients reaching HbA1c targets
- Change in 2-hour Post Prandial Glucose and in blood glucose excursion during standardized meal test from baseline
- Change in body weight from baseline
- Change in 7-point Self Measured Plasma Glucose profiles from baseline
- Daily dose of insulin glargine
- Change in Fasting Plasma Glucose from baseline
- Documented (plasma glucose less than or equal to 70 mg/dl) symptomatic hypoglycemia
- Severe symptomatic hypoglycemia |
- Percentuale di pazienti che raggiungono i valori target di HbAC1;
- Variazione della glicemia post-prandiale (PPG) a 2 ore e dell’escursione della glicemia durante il test con pasto standardizzato rispetto al basale;
- Variazione del peso corporeo rispetto la basale;
- Variazione dei profili glicemici a 7 punti monitorati dai pazienti rispetto al basale;
- Dose giornaliera di insulina glargine;
- Variazione nella glicemia a digiuno rispetto al basale;
- Ipoglicemia sintomatica documentata (glicemia <70 mg/dl);
- Ipoglicemia grave sintomatica.
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E.5.2.1 | Timepoint(s) of evaluation of this end point |
Week 30/ 30 weeks |
Settimana 30 |
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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 | Yes |
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 | Yes |
E.8.1.3 | Single blind | No |
E.8.1.4 | Double blind | No |
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 | 6 |
E.8.5 | The trial involves multiple Member States | Yes |
E.8.5.1 | Number of sites anticipated in the EEA | 100 |
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 |
Belgium |
Denmark |
Estonia |
France |
Germany |
Hungary |
Italy |
Latvia |
Lithuania |
Mexico |
Poland |
Romania |
Russian Federation |
Ukraine |
Czech Republic |
South Africa |
Spain |
Sweden |
United Kingdom |
United States |
Chile |
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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 | 1 |
E.8.9.1 | In the Member State concerned months | 5 |
E.8.9.1 | In the Member State concerned days | 14 |
E.8.9.2 | In all countries concerned by the trial years | 1 |
E.8.9.2 | In all countries concerned by the trial months | 5 |
E.8.9.2 | In all countries concerned by the trial days | 14 |