| 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 |
|
| E.1.1.1 | Medical condition in easily understood language |
| Type 2 diabetes mellitus |
| Diabete mellito di tipo 2 |
|
| E.1.1.2 | Therapeutic area | Diseases [C] - Hormonal diseases [C19] |
| MedDRA Classification |
| E.1.2 Medical condition or disease under investigation |
| E.1.2 | Version | 21.1 |
| 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 |
|
| 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 assess efficacy of maximally tolerated tirzepatide dose up to 15 mg QW compared to QW dulaglutide 1.5 mg on time to first occurrence of the composite endpoint of death from CV causes, MI, or stroke (MACE-3) when both are added to standard of care in patients with T2DM and high CV risk.
Primary analysis will be an assessment of NI of tirzepatide to dulaglutide for MACE-3. After establishing NI, superiority of tirzepatide compared to dulaglutide for MACE-3 will be evaluated.
|
Valutare l’efficacia della massima dose tollerata di tirzepatide fino a 15 mg QW rispetto a dulaglutide 1,5 mg QW per quanto riguarda il tempo trascorso sino alla prima occorrenza dell’endpoint composito di morte per cause CV, IM o ictus (MACE-3) aggiungendo entrambi i trattamenti allo standard di cura in pazienti con T2DM ed elevato rischio CV.
L’analisi primaria consisterà in una valutazione della non inferiorità (NI) di tirzepatide rispetto a dulaglutide per MACE-3. Una volta stabilita la NI, sarà valutata la superiorità di tirzepatide rispetto a dulaglutide per MACE-3. |
|
| E.2.2 | Secondary objectives of the trial |
| To assess the superiority of tirzepatide up to 15 mg QW compared to dulaglutide 1.5 mg QW for time to death due to any cause, time to CV death, time to first occurrence of MI and time to first occurrence of stroke. |
| Valutare la superiorità di tirzepatide fino a 15 mg QW rispetto a dulaglutide 1,5 mg QW per tempo trascorso sino alla morte per qualsiasi causa, tempo trascorso sino alla morte per cause CV, tempo trascorso sino alla prima occorrenza di IM e tempo trascorso sino alla prima occorrenza di ictus. |
|
| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal inclusion criteria |
[1] Men or women at least 40 years old with a diagnosis of T2DM (WHO 2019).
[2] Established CVD, including at least 1 of the following (a-c):
a. Coronary artery disease (CAD) with EITHER of the following:
- Documented history of spontaneous MI
- =50% stenosis in 1 or more major coronary arteries, determined by invasive angiography
- =50% stenosis in 2 or more major coronary arteries, determined by computed tomography coronary angiography (CTCA), or
- History of surgical or percutaneous coronary revascularization procedure;
b. Cerebrovascular disease – ANY of the following:
- Documented history of ischemic stroke
- Carotid arterial disease with =50% stenosis, documented by carotid ultrasound, magnetic resonance imaging (MRI), or angiography
- Carotid stenting or surgical revascularization;
c. Peripheral arterial disease with EITHER of the following:
- Intermittent claudication and ankle-brachial index <0.9
- Prior nontraumatic amputation or peripheral vascular procedure (eg, stenting or surgical revascularization), due to peripheral arterial ischemia.
[3] HbA1c =7% (=53 mmol/mol) and =10.5% (=91.3 mmol/mol) based on central laboratory assessment at screening.
[4] Body mass index (BMI) =25 kg/m2.
[5] At the time of signing the informed consent: Contraceptive use by men or women should be consistent with local regulations regarding the methods of contraception for those participating in clinical trials.
[6] In the investigator’s opinion, patients are well motivated, capable, and willing to learn how to self-inject treatment (tirzepatide or dulaglutide), as required for this protocol (visually impaired persons and/or persons with physical limitations who are not able to perform the injections must have the assistance of an individual trained to inject the study drug).
[7] Patients are capable of giving signed informed consent. |
[1] Uomini o donne di almeno 40 anni di età con una diagnosi di T2DM (OMS2019).
[2] Patologie cardiovascolari confermate, tra cui almeno 1 delle seguenti (a-c):
a. Coronaropatia (CAD) con UNA delle seguenti caratteristiche:
- Anamnesi documentata di IM spontaneo
- stenosi =50% in 1 o più arterie coronariche principali, stabilita da angiografia invasiva
- stenosi =50% in 2 o più arterie coronariche principali, stabilita da angiografia coronarica con tomografia computerizzata (CTCA), oppure
- Anamnesi di procedura di rivascolarizzazione coronarica chirurgica o percutanea;
b. Malattia cerebrovascolare – UNA QUALSIASI delle seguenti caratteristiche:
- Anamnesi documentata di ictus ischemico
- Arteriopatia carotidea con stenosi =50%, documentata da ecografia alla carotide, risonanza magnetica (RM) o angiografia
- Stenting della carotide o rivascolarizzazione chirurgica;
c. Arteriopatia periferica con UNA delle seguenti caratteristiche:
- Claudicazione intermittente e indice caviglia-braccio (ABI) <0,9
- Precedente amputazione non traumatica o procedura vascolare periferica (es.stenting o rivascolarizzazione chirurgica) dovuta a ischemia arteriosa periferica.
[3] HbA1c =7% (=53 mmol/mol) e =10,5% (=91,3 mmol/mol) secondo le analisi del laboratorio centrale al momento dello screening.
[4] Indice di massa corporea (BMI) =25 kg/m2.
[5] Al momento della firma del consenso informato: L’uso di contraccettivi da parte di uomini o donne deve essere conforme alle leggi locali in materia di metodi di contraccezione per i partecipanti a studi clinici.
[6] Secondo il parere dello sperimentatore, i pazienti sono motivati, capaci e intenzionati ad apprendere come eseguire le iniezioni del trattamento in autonomia (tirzepatide o dulaglutide), come richiesto da questo protocollo (le persone ipovedenti
e/o con limitazioni fisiche non in grado di eseguire le iniezioni in autonomia devono essere assistite da un individuo adeguatamente formato a eseguire le iniezioni di farmaco sperimentale).
[7] I pazienti sono in grado di fornire il proprio consenso informato. |
|
| E.4 | Principal exclusion criteria |
Have type 1 diabetes mellitus
Have uncontrolled diabetes requiring immediate therapy (eg. diabetic ketoacidosis) at screening or randomization, in judgment of physician.
Have had 1 or more events of severe hypoglycemia and/or 1 or more events of hypoglycemia unawareness within 6 months prior to screening.
[11] Are currently planning treatment for diabetic retinopathy and/or
macular edema.
Have been hospitalized for CHF within 2 months prior to screening.
Have chronic NY Heart Association Functional Classification IV CHF.
Are currently planning a coronary, carotid, or peripheral artery revascularization.
Had chronic or acute pancreatitis any time prior to screening, irrespective of etiology.
[16] Have a known clinically significant gastric emptying abnormality
such as severe gastroparesis or gastric outlet obstruction or have
undergone or currently planning any gastric bypass (bariatric) surgery
or restrictive bariatric surgery.
Have acute/chronic hepatitis, signs/symptoms of other liver disease, or an ALT level =3X the upper limit of normal (ULN) for reference range determined by central laboratory.
Known chronic severe renal failure (defined as a known eGFR <15 mL/minute/1.73 m2) or are on chronic dialysis.
Have evidence of significant, uncontrolled endocrine abnormality (thyrotoxicosis or adrenal crises).
Have family or personal history of MEN2 or familial medullary thyroid carcinoma (MTC) or personal history of nonfamilial MTC.
Have a serum calcitonin level at screening of: (based on central laboratory results)
- =20 ng/L at Visit 1, if eGFR =60 mL/min/1.73 m2, or
- =35 ng/L at Visit 1, if eGFR <60 mL/min/1.73 m2.
History of active/untreated malignancy or in remission from clinically significant malignancy for less than 5 years. An exception for this criterion is basal/squamous cell skin cancer, in situ carcinomas of the cervix, or in situ prostate cancer.
History of other condition (such as known drug or alcohol abuse or psychiatric disorder) that, in the opinion of the investigator, may preclude the patient from following and completing the protocol.
Have had a transplanted organ (corneal transplants [keratoplasty] allowed) or awaiting an organ transplant.
Have any other condition (eg, hypersensitivity) that is a contraindication to any incretin or GLP-1 RAs.
Have had an MI, surgical or percutaneous coronary revascularization procedure, ischemic stroke, carotid stenting or surgical revascularization, nontraumatic amputation or peripheral vascular procedure (eg, stenting or surgical revascularization) less than 60 days prior to screening.
[28] Treatment with GLP-1 RA, or pramlintide in a period of 3 months
prior to Visit 1.
[29] Discontinuation of GLP-1 RA, or pramlintide due to intolerability any
time prior to Visit 1.
[30] Exclusion Criterion [30] has been deleted.
Are currently enrolled in any other clinical study involving an investigational product or any other type of medical research judged not to be scientifically or medically compatible with this study.
Have participated within the last 30 days in a clinical trial involving an investigational product. If the previous investigational product has a long half-life, 3 months or 5 half-lives (whichever is longer) should have passed.
Have previously completed or withdrawn from this study or randomized into any other study investigating tirzepatide.
[36] Any women who are pregnant or breastfeeding.
[37] Have had a blood transfusion or severe blood loss within 90 days
prior to screening or have known hematological conditions that may
interfere with HbA1c measurement. |
Diabete mellito tipo 1Diabete non controllato che richieda trattamento immediato allo screening o randomizzazione, secondo parere medico1 o più eventi di ipoglicemia severa e/o 1 o più eventi di mancata percezione dell’ipoglicemia nei 6 mesi precedenti lo screening
[11] Are currently planning treatment for diabetic retinopathy and/or macular edema.Ricovero per insufficienza cardiaca congestizia nei 2 mesi precedenti lo screening.Insufficienza cardiaca congestizia cronica IV classe sec. classificazione funzionale della NY Heart Association. Previsione rivascolarizzazione coronarica, carotidea o arteriosa periferica.16] Have a known clinically significant gastric emptying abnormalitysuch as severe gastroparesis or gastric outlet obstruction or haveundergone or currently planning any gastric bypass (bariatric) surgeryor restrictive bariatric surgery.Pancreatite acuta/cronica se prima dello screening, indipendentemente dall’eziologia.Anomalie note dello svuotamento gastrico clinicamente significative (gastroparesi diabetica severa/ostruzione dell’uscita gastrica), anamnesi di intervento bypass gastrico (bariatrico), chirurgia bariatrica restrittiva (es. Lap-Band®, gastrectomia verticale parziale), o assunzione cronica di farmaci che influenzano motilità gastrointestinale.Epatite cronica o acuta, segni/sintomi di patologie del fegato o livelli di ALT =3 volte il limite superiore di normalità (ULN) per l’intervallo di riferimento, sec. il laboratorio centrale.Insufficienza renale cronica severa nota (definita come eGFR noto <15 mL/minuto/1,73 m2) o condizione di dialisi cronica.
Evidenze di anomalie endocrine non controllate e significative (es. tireotossicosi o crisi surrenalica).Anamnesi familiare/personale di MEN2 o anamnesi familiare di carcinoma midollare della tiroide (MTC) o anamnesi di MTC non familiare.
Livelli di calcitonina sierica allo screening di:- =20 ng/L alla Visita 1, se eGFR =60 mL/min/1,73 m2, oppure - =35 ng/L alla Visita 1, se eGFR <60 mL/min/1,73 m2.Anamnesi di neoplasia maligna attiva/non trattata/remissione da una neoplasia maligna clinicamente significativa da meno di 5 anni. Eccetto carcinoma basocellulare o squamocellulare, carcinoma in situ della cervice e cancro in situ della prostata.Anamnesi di qualsiasi altra condizione (abuso di sostanze stupefacenti o alcol, disordini psichiatrici) che secondo il parere dello sperimentatore potrebbero impedire al paziente di seguire e completare il protocollo.Ricezione di un trapianto di organi (a eccezione del trapianto di cornea, o cheratoplastica) o attesa di un trapianto di organi.Qualsiasi altra condizione (es. ipersensibilità) che costituisca controindicazione a qualsiasi incretina o GLP-1 RA.[26] Have had an MI, percutaneous coronary revascularizationprocedure, ischemic stroke, carotid stenting or surgicalrevascularization, nontraumatic amputation or peripheral vascular
procedure (eg, stenting or surgical revascularization) less than 60 days prior to screening.Intervento di bypass coronarico a meno di 5 anni prima dello screening.[28] Treatment with GLP-1 RA, or pramlintide in a period of 3 months
prior to Visit 1.[29] Discontinuation of GLP-1 RA, or pramlintide due to intolerability anytime prior to Visit 1.[0] Exclusion Criterion [30] has been deleted.Trattamento con incretine, GLP-1 RA o pramlintide nei 3 mesi precedenti alla V1.Interruzione trattamento con incretine, GLP-1 RA o pramlintide per intollerabilità in qualsiasi momento prima della V1.Terapia con regime insulinico intensivo o diverse combinazioni di insulina basale e prandiale (regimi basale/bolo) e impossibilità o rifiuto di interrompere l’assunzione di componenti prandiali alla randomizzazione.Arruolamento in altro studio clinico con prodotto sperimentale o qualsiasi altro tipo di ricerca medica incompatibile con il presente studio sul piano medico/scientifico |
|
| E.5 End points |
| E.5.1 | Primary end point(s) |
Time to first occurrence of a component event of a MACE-3.
|
| Tempo trascorso sino alla prima occorrenza di un evento componente di MACE-3. |
|
| E.5.1.1 | Timepoint(s) of evaluation of this end point |
An independent CEC will adjudicate all primary endpoint events.
The primary endpoint is the time from randomization to first occurrence of CEC-confirmed CV death, MI, or stroke.
Patients will be followed until approximately 1615 patients experience at least 1 component of the primary composite endpoint of CV death, MI, or stroke. |
Un comitato per gli endpoint clinici (CEC) indipendente confermerà tutti gli eventi di endpoint primario. L’endpoint primario è il tempo trascorso dalla randomizzazione alla prima occorrenza di morte per cause CV, IM o ictus confermata dal CEC.
I pazienti saranno seguiti fino a quando circa 1.615 pazienti avranno sperimentato almeno 1 componente dell’endpoint composito primario di decesso per cause CV, IM o ictus. |
|
| E.5.2 | Secondary end point(s) |
Key Secondary efficacy measures are:
• Time to death due to any cause;
• Time to CV death;
• Time to first occurrence of MI;
• Time to first occurrence of stroke.
• Time to first occurrence of the expanded composite CV outcome,
defined as either CV death, MI, stroke, coronary revascularization,
hospitalization for unstable angina
• Cumulative number of CV deaths and total (first and recurrent) HF
events requiring hospitalization and/or urgent HF visits
Additional secondary measures are:
• Proportion of patients with more than 10% weight loss from screening after 36 months;
• Change from baseline in:
o weight, BMI, and waist circumference
o HbA1c
o urinary albumin to creatinine ratio
o blood lipids: total cholesterol, HDL-cholesterol, LDL-cholesterol, and triglycerides;
• Time to first occurrence of:
o coronary, carotid, or peripheral revascularizations, individually and as composite
o hospitalization due to unstable angina
o composite endpoint of new or worsening nephropathy
o expanded composite CV outcome, defined as either CV death, MI, stroke, coronary revascularization, hospitalization for unstable angina;
• Cumulative number of primary composite events of CV death and total (first and recurrent) MI and/or stroke;
• Cumulative number of CV deaths and total (first and recurrent) HF
events requiring hospitalization and/or urgent HF visits.
Maximally tolerated tirzepatide dose will be measured based on:
• Incidence of TEAEs and permanent discontinuation of study drug due to AEs
• Incidence of:
o pancreatitis
o severe gastrointestinal events
o any malignancy (including medullary and papillary thyroid cancers)
o severe hypoglycemic events
o immune-mediated reactions including serious allergic and hypersensitivity reactions
o hepatobiliary events (eg, acute cholecystitis, acute cholelithiasis and drug-induced liver injury)
o acute renal failure or exacerbation of chronic renal failure
o diabetic retinopathy complications
o supraventricular arrhythmias and cardiac conduction disorders
• Mean change from baseline:
o blood pressure and pulse rate
o lipase
o pancreatic amylase
o calcitonin
o eGFR.
The effects of add-on therapy with up to 15 mg tirzepatide compared to dulaglutide 1.5 mg will be measured based on:
• Change of antihyperglycemic drugs
• Patient-reported outcome
o APPADL
o IW-SP
o EQ-5D-5L
• Time to initiation of insulin of more than 3 months duration for those patients not treated with insulin at study start
• eGFR from Cystatin-C. |
I parametri di efficacia secondari sono:
• Tempo trascorso sino alla morte per qualsiasi causa;
• Tempo trascorso sino alla morte per cause CV;
• Tempo trascorso sino alla prima occorrenza di IM;
• Tempo trascorso sino alla prima occorrenza di ictus.
• Time to first occurrence of the expanded composite CV outcome,
defined as either CV death, MI, stroke, coronary revascularization,
hospitalization for unstable angina
• Cumulative number of CV deaths and total (first and recurrent) HF
events requiring hospitalization and/or urgent HF visits
Ulteriori parametri secondari sono:
• Percentuale di pazienti con una riduzione del peso corporeo superiore al 10% rispetto allo screening dopo 36 mesi;
• Variazione rispetto al basale di:
o Peso, BMI e circonferenza della vita
o HbA1c
o Rapporto albumina-creatinina nelle urine
o Lipidi nel sangue: colesterolo totale, HDL, LDL e trigliceridi;
• Tempo trascorso sino alla prima occorrenza di:
o Rivascolarizzazione coronarica, carotidea o periferica, singola e in composito
o Ricovero dovuto ad angina instabile
o Endpoint composito di insorgenza o peggioramento di nefropatia
o Outcome CV composito espanso, definito come morte per cause CV, IM, ictus, rivascolarizzazione coronarica, ricovero per angina instabile;
• Numero cumulativo di eventi compositi primari di morte per cause CV e IM e/o ictus totali (prima insorgenza e recidive);
• Numero cumulativo di decessi per cause CV ed eventi HF totali (prima insorgenza e recidive) che hanno reso necessario il ricovero e/o visite per HF urgenti.
• Cumulative number of CV deaths and total (first and recurrent) HF
events requiring hospitalization and/or urgent HF visits.
La massima dose tollerata di tirzepatide sarà misurata in base a:
• Incidenza degli eventi avversi emersi durante il trattamento (TEAE) e interruzione permanente del farmaco sperimentale a causa di eventi avversi (EA)
• Incidenza di:
o Pancreatite
o Eventi gastrointestinali di grado severo
o Neoplasie maligne di qualsiasi genere (carcinomi midollari e papillari della tiroide inclusi)
o Eventi di ipoglicemia severa
o Reazioni immuno-mediate, reazioni allergiche e di ipersensibilità serie incluse
o Eventi epatobiliari (ad es. colecistite acuta, colelitiasi acuta e danno epatico indotto dal farmaco)
o Insufficienza renale acuta o peggioramento di un’insufficienza renale cronica o Complicanze di retinopatia diabetica
o Aritmie sopraventricolari e disturbi di conduzione cardiaca
• Variazione media rispetto al basale di:
o Pressione arteriosa e frequenza cardiaca
o Lipasi
o Amilasi pancreatica
o Calcitonina
o eGFR.
Gli effetti della terapia in associazione con tirzepatide fino a 15 mg rispetto a dulaglutide 1,5 mg saranno misurati in base a:
• Modifiche alla terapia ipoglicemizzante
• Esiti riferiti dal paziente
o Capacità di eseguire attività fisiche quotidiane
o IW-SP
o EQ-5D-5L
• Tempo all’avvio del trattamento con insulina della durata superiore a 3 mesi per i pazienti non trattati con insulina all’inizio dello studio
• eGFR in base ai livelli di cistacina C. |
|
| E.5.2.1 | Timepoint(s) of evaluation of this end point |
| Secondary outcomes include various glycemic, body weight/composition, renal, biochemical, and health outcome endpoints relevant to the study population. |
| Tra gli outcome secondari sono inclusi vari outcome glicemici, relativi al peso corporeo/alla composizione, renali, biochimici e di salute rilevanti per la popolazione dello studio. |
|
| 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 | Yes |
| E.6.11 | Pharmacogenomic | Yes |
| E.6.12 | Pharmacoeconomic | Yes |
| E.6.13 | Others | Yes |
| E.6.13.1 | Other scope of the trial description |
| Health Economics |
| Economia sanitaria |
|
| 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 | Yes |
| E.8.2.3.1 | Comparator description |
|
| 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 | Yes |
| E.8.5.1 | Number of sites anticipated in the EEA | 241 |
| 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 | Information not present in EudraCT |
| 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 |
| China |
| India |
| Israel |
| Japan |
| Korea, Republic of |
| Mexico |
| Russian Federation |
| Taiwan |
| Turkey |
| Ukraine |
| United States |
| Austria |
| Belgium |
| France |
| Germany |
| Greece |
| Hungary |
| Italy |
| Netherlands |
| Poland |
| Romania |
| Slovakia |
| Spain |
| Sweden |
| United Kingdom |
| Czechia |
| Argentina |
|
| 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
|
| End of the study is the date of the last visit or last scheduled procedure shown in the protocol for the last patient. |
| Il termine dello studio corrisponde alla data dell’ultima visita o dell’ultima procedura programmata indicata nel Protocollo per l’ultimo paziente. |
|
| E.8.9 Initial estimate of the duration of the trial |
| E.8.9.1 | In the Member State concerned years | 4 |
| E.8.9.1 | In the Member State concerned months | 6 |
| E.8.9.1 | In the Member State concerned days | 14 |
| E.8.9.2 | In all countries concerned by the trial years | 4 |
| E.8.9.2 | In all countries concerned by the trial months | 6 |
| E.8.9.2 | In all countries concerned by the trial days | 14 |
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