E.1 Medical condition or disease under investigation |
E.1.1 | Medical condition(s) being investigated |
Type 2 Diabetes mellitus |
Diabete mellito di tipo 2 |
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E.1.1.1 | Medical condition in easily understood language |
Type 2 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 | 17.1 |
E.1.2 | Level | HLGT |
E.1.2 | Classification code | 10018424 |
E.1.2 | Term | Glucose metabolism disorders (incl diabetes mellitus) |
E.1.2 | System Organ Class | 10014698 - Endocrine disorders |
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E.1.2 Medical condition or disease under investigation |
E.1.2 | Version | 17.1 |
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.1.2 Medical condition or disease under investigation |
E.1.2 | Version | 17.1 |
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 |
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E.1.2 Medical condition or disease under investigation |
E.1.2 | Version | 17.1 |
E.1.2 | Level | HLT |
E.1.2 | Classification code | 10012602 |
E.1.2 | Term | Diabetes mellitus (incl subtypes) |
E.1.2 | System Organ Class | 10014698 - Endocrine 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 |
The primary objective of the study is to evaluate the effect of linagliptin 5 mg daily versus the corresponding placebo on the LV systolic function (measured by midwall shortening analysis) in patients with T2DM and a documented baseline concentric LV geometry and LV systolic dysfunction. |
L'obiettivo primario dello studio è quello di valutare l’effetto di linagliptin 5 mg/die rispetto al placebo sulla funzione sistolica LV (valutata come percentuale dell’accorciamento delle fibre circonferenziali miocardiche presenti a livello centroparietale [midwall shortening, MFS]) in pazienti affetti da DMT2 con geometria LV concentrica e disfunzione sistolica LV asintomatica |
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E.2.2 | Secondary objectives of the trial |
1.Assessment of changes in diastolic LV function. Transmitral peak E wave (pulse Doppler) and early diastolic Tissue Doppler velocity of mitral annulus (E’) will be used to classify LV diastolic function together with other parameters (E/A ratio of transmitral flow, deceleration time of E, left atrial volume, pulmonary artery systolic pressure) in 4 degrees: normal, mild dysfunction, moderate dysfunction and severe dysfunction. Changes from baseline and 48-weeks evaluation will be analyzed.
2.Assessment of changes in LV systolic longitudinal function (measured by tissue Doppler technique) (peak systolic velocity of S’ wave of mitral annulus). Changes from baseline and 48-weeks evaluation will be analyzed. Incidence of patients who have an improvement in S’> 25% from baseline (comparison between treated and not treated group).
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1.Valutazione delle variazioni nella funzione diastolica LV. Il picco dell’onda E del flusso transmitralico (Doppler pulsato) e la velocità dell’anello mitralico nella prima fase della diastole al Doppler Tessutale (E’) saranno utilizzati insieme ad altri parametri (rapporto E/A del flusso transmitralico, tempo di decelerazione di E, volume atriale sinistro, pressione arteriosa sistolica polmonare) per classificare la funzione diastolica LV in 4 gradi: normale, disfunzione lieve, disfunzione moderata e disfunzione grave. Saranno analizzate le variazioni tra la valutazione basale e quella a 48 settimane.
2.Valutazione delle variazioni della funzione sistolica longitudinale LV (misurata mediante Doppler tessutale) (velocità sistolica di picco dell’onda S’ dell’anello mitralico). Saranno analizzate le variazioni tra la valutazione basale e a 48 settimane. Incidenza dei pazienti che mostrano un miglioramento in S’ superiore al 25% rispetto al basale (confronto gruppo vs non trattato)
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E.2.3 | Trial contains a sub-study | No |
E.3 | Principal inclusion criteria |
• Men and women aged equal to or more than 40 years at screening.
• Patients with history of T2DM lasting at least six month prior to the screening visit.
• HbA1c ≤ 8.0% (≤ 64 mmol/mol) at screening.
• Evidence of sinus rhythm at screening ECG evaluation
• No clinical signs/symptoms of a cardiac disease and no evidence of coronary artery disease on the basis of clinical, electrocardiographic and echocardiographic evaluation at screening.
• Evidence at baseline echocardiographic examination of concentric left ventricular geometry, defined as relative wall thickness ≥ 0.42. Relative wall thickness was calculated as the end-diastolic ratio 2* posterior wall thickness/LV diameter.
• Evidence at baseline echocardiographic examination of LV systolic dysfunction defined as Midwall shortening (MFS) ≤15%
• Obtained informed consent
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• Uomini e donne di età ≥ 40 anni allo screening
• Positività anamnestica per DMT2 diagnosticato almeno 6 mesi prima della visita di screening
• HbA1c ≤8.0% (≤ 64 mmol/mol) allo screening
• Ritmo sinusale all’ECG di screening
• Assenza di segni e sintomi clinici di malattia cardiaca e nessuna evidenza di coronaropatia in base alla valutazione clinica, elettrocardiografica ed ecocardiografica di screening
• Evidenza all’ecocardiogramma di screening di geometria ventricolare sinistra di tipo concentrico, definita come spessore relativo di parete ≥ 0.42. Lo spessore relativo di parete (RWT) è calcolato come rapporto tra il doppio dello spessore della parete posteriore del ventricolo sinistro in telediastole e il diametro telediastolico del ventricolo sinistro
• Evidenza all’ecocardiogramma di screening di disfunzione sistolica del ventricolo sinistro definita come accorciamento centroparietale (midwall shortening, MFS) ≤15%
• Firma del consenso informato
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E.4 | Principal exclusion criteria |
• Patients with a confirmed indication for an incretin treatment
• Uncontrolled diabetes: HbA1c >8.0% (> 64 mmol/mol) or Fasting Plasma Glucose > 300 mg/dL measured at screening visit.
• Glitazones within the last three months
• Permanent atrial fibrillation
• Uncontrolled hypertension (defined as systolic blood pressure>160 and/or diastolic blood pressure >90)
• Unstable dosage and changes in type of antihypertensive, lipid lowering and antidiabetic drugs within 4 weeks before the screening visit.
• Severe chronic renal dysfunction (defined as estimated glomerular filtration rate < 30 ml/min/1.73 m2).
• Previous or current documented history of untreated (by using CPAP) obstructive sleep apnea syndrome
• Rheumatoid arthritis, psoriatic arthritis, ankylosing spondylitis.
• Previous or current documented history of malignant disease
• Pregnancy and breast feeding
• Documented alcohol and drug abuse
• Anticipated poor compliance
• Current participation in a clinical trial with other investigational products
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Criteri di esclusione:
• Indicazione al trattamento con incretine
• Diabete non controllato: HbA1c >8% (>64 mmol/mol) o glicemia a digiuno > 300 mg/dL allo screening
• Utilizzo di glitazoni negli ultimi 3 mesi
• Fibrillazione atriale permanente
• Ipertensione non controllata (definita come PAS>160 e/o PAD>90)
• Variazione di dosaggio o della terapia antipertensiva, ipolipemizzante o antidiabetica nelle 4 settimane precedenti lo screening
• Disfunzione renale cronica severa (definita come eGFR< 30 ml/min/1.73 m2)
• Sindrome delle apnee notturne (non trattata con CPAP) attuale o pregressa
• Artrite reumatoide, artrite psoriasica, spondilite anchilosante
• Pregressa o attuale documentazione di malattia neoplastica maligna
• Gravidanza o allattamento
• Documentato abuso di alcool e/o droghe
• Previsione di scarsa compliance alle procedure dello studio
• Partecipazione a studi clinici con prodotti sperimentali
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E.5 End points |
E.5.1 | Primary end point(s) |
Changes from baseline to 48-weeks of LV systolic function measured by midwall shortening analysis. |
Variazione statisticamente significativa (equivalente ad un incremento del 10%) dalla valutazione basale a 48 settimane della funzione sistolica LV misurata mediante analisi del MFS (lettura centralizzata). |
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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) |
- Changes from baseline to 48-weeks in diastolic LV function: Transmitral peak E wave (pulse Doppler) and early diastolic Tissue Doppler velocity of mitral annulus (E’) will be used to classify LV diastolic function together with other parameters (E/A ratio of transmitral flow, deceleration time of E, left atrial volume, pulmonary artery systolic pressure) in 4 degrees: normal, mild dysfunction, moderate dysfunction and severe dysfunction.
- Changes from baseline to 48-weeks in LV systolic longitudinal function measured by tissue Doppler technique (peak systolic velocity of S’ wave of mitral annulus); Incidence of patients who have an improvement in S’> 25% from baseline.
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- Variazioni dal basale a 48 settimane della funzione diastolica LV (lettura centralizzata) classificata nei due momenti di valutazione in 4 gradi: normale, disfunzione lieve, disfunzione moderata e disfunzione grave. L’efficacia del trattamento sarà valutata sia in termini di riduzione significativa del parametro E/E’ espresso come variabile continua sia come miglioramento dell’entità della disfunzione analizzata per gradi, come sopra descritto.
- Variazioni dal basale a 48 settimane della funzione sistolica longitudinale LV (lettura centralizzata) misurata mediante Doppler tessutale (velocità sistolica di picco dell’onda S’ dell’anello mitralico); incidenza dei pazienti che mostrano un miglioramento di S’ > 25% rispetto al basale.
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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 | 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) | 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 | 20 |
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 | No |
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 | 2 |
E.8.9.1 | In the Member State concerned months | |
E.8.9.1 | In the Member State concerned days | |