E.1 Medical condition or disease under investigation |
E.1.1 | Medical condition(s) being investigated |
Diabetes Mellitus, Type 2 |
Šećerna bolest tipa 2 |
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E.1.1.1 | Medical condition in easily understood language |
Type 2 diabetes |
Šećerna bolest tipa 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 | 20.1 |
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 |
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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 effect on glycaemic control of once weekly insulin 287 using 3 different titration algorithms, versus once daily insulin glargine U100, both in combination with metformin ± DPP4i ± SGLT2i in insulin-naïve T2DM subjects |
Usporedba učinka na kontrolu glikemije jednom tjedno primjenjenog inzulina 287 u tri titracijska algoritma naspram jednom dnevno primjenjenog glargin inzulina U100, oba u kombinaciji s metforminom i/ili inhibitorom DPP4 i/ili inhibitorom SGLT2 u ispitanika sa šećernom bolešću tipa 2 koji prethodno nisu bili liječeni inzulinom |
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E.2.2 | Secondary objectives of the trial |
To compare the safety and tolerability of once weekly insulin 287 using 3 different titration algorithms versus once daily insulin glargine U100 both in combination with metformin ± DPP4i ± SGLT2i in insulin-naïve T2DM subjects |
Usporedba sigurnosti i podnošljivosti jednom tjedno primjenjenog inzulina 287 u tri titracijska algoritma naspram jednom dnevno primjenjenog glargin inzulina U100, oba u kombinaciji s metforminom i/ili inhibitorom DPP4 i/ili inhibitorom SGLT2 u ispitanika sa šećernom bolešću tipa 2 koji prethodno nisu bili liječeni inzulinom |
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E.2.3 | Trial contains a sub-study | No |
E.3 | Principal inclusion criteria |
1. Male or female, aged 18-75 years (both inclusive) at the time of signing informed consent. 2. Diagnosed with type 2 diabetes mellitus 180 days or longer prior to the day of screening. 3. HbA1c of 7.0-10.0% (53.0-85.8 mmol/mol) (both inclusive) as assessed by central laboratory. 4. Stable daily dose(s) for 90 days prior to the day of screening of any of the following antidiabetic drug(s) or combination regime(s): a. Any metformin formulations equal to or above 1500 mg or maximum tolerated or effective dose (as documented in subject’s medical records) b. Free or fixed combination therapy: Metformin as outlined above with or without DPP4i with or without SGLT2i is allowed: b. 1: DPP4i (equal to or above half of the maximum approved dose according to local label or maximum tolerated or effective dose) b.2: SGLT2i (equal to or above half of the maximum approved dose according to local label or maximum tolerated or effective dose ) 5. Insulin-naïve. However, short term insulin treatment for a maximum of 14 days prior to the day of screening is allowed, as is prior insulin treatment for gestational diabetes. 6. Body mass index (BMI) equal to or below 40.0 kg/m^2 |
1. Muškarci i žene, u dobi 18-75 godina (obje uključive) u vrijeme potpisivanja Informiranog pristanka 2. Dijagnoza šećerne bolesti tipa 2 ≥ 180 dana prije probira 3. HbA1c od 7,0-10,0% (oboje uključivo) prema nalazu centralnog laboratorija 4. Stabilna doza 90 dana prije probira bilo kojih antidijabetičkih lijekova i/ili kombinacija: a. bilo koja formulacija metformina ≥ 1500 mg ili maksimalna tolerirajuća ili učinkovita doza b. slobodna ili fiksna kombinacija: dozvoljen je metformin kao što je navedeno gore +/- inhibitor DPP4 +/- inhibitor SGLT2: i. inhibitor DPP4 (≥ pola maksimalne odobrene doze prema lokalnom odobrenju ili maksimalna tolerirajuća ili učinkovita doza) ii. inhibitor SGLT2 (≥ pola maksimalne odobrene doze prema lokalnom odobrenju ili maksimalna tolerirajuća ili učinkovita doza) 5. Ispitanici koji nisu bilo liječeni inzulinom, osim kratkotrajno maksimalno 14 dana ili u gestacijskom dijabetesu 6. Indeks tjelesne težine jednak ili manji od 40.0 |
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E.4 | Principal exclusion criteria |
1. Known or suspected hypersensitivity to trial product(s) or related products. 2. Previous participation in this trial. Participation is defined as signed informed consent. 3. Female who is pregnant, breast-feeding or intends to become pregnant or is of child-bearing potential and not using an adequate contraceptive method. 4. Participation in any clinical trial, of an approved or non-approved investigational medicinal product within 90 days before screening. 5. Any disorder, except for conditions associated with type 2 diabetes mellitus, which in the investigator’s opinion might jeopardise subject’s safety or compliance with the protocol. 6. Any episodes of diabetic ketoacidosis within the past 90 days, prior to the day of screening and between screening and randomisation. 7. Myocardial infarction, stroke, hospitalisation for unstable angina pectoris or transient ischaemic attack within 180 days prior to the day of screening and between screening and randomisation. 8. Presently classified as being in New York Heart Association (NYHA) Class IV. 9. Planned coronary, carotid or peripheral artery revascularisation between screening and randomisation. 10. Renal impairment measured as estimated Glomerular Filtration Rate (eGFR) value of eGFR below 60 ml/min/1.73 m^2 as defined by KDIGO 2012. 11. Impaired liver function, defined as Alanine Aminotransferase (ALT) equal to or above 2.5 times or Bilirubin above 1.5 times upper normal limit at screening. 12. Inadequately treated blood pressure, defined as Grade 3 hypertension or higher (Systolic equal to or above 180 mmHg or diastolic equal to or above 110 mmHg) at screening. 13. Treatment with any medication for the indication of diabetes, or obesity other than stated in the inclusion criteria within the past 90 days, prior to the day of screening. However, short term insulin treatment for a maximum of 14 days prior to the day of screening is allowed, as is prior insulin treatment for gestational diabetes. 14. Uncontrolled and potentially unstable diabetic retinopathy or maculopathy. Verified by a fundus examination performed within the past 90 days prior to screening or in the period between screening and randomisation. Pharmacological pupil-dilation is a requirement unless using a digital fundus photography camera specified for non-dilated examination. 15. Presence or history of malignant neoplasms within 5 years prior to the day of screening. Basal and squamous cell skin cancer and any carcinoma in-situ are allowed. |
1. Poznata preosjetljivost ili sumnja preosjetljivosti na ispitivani lijek(ove) ili slične lijekove 2. Prethodno sudjelovanje u ovom ispitivanju Sudjelovanje je definirano potpisivanjem informiranog pristanka. 3. Žena koje je trudna, doji ili planira trudnoću ili je reproduktivne dobi, a ne koristi visoko učinkovitu kontraceptivnu metodu 4. Sudjelovanje u bilo kojem kliničkom ispitivanju odobrenog ili neodobrenog ispitivanog lijeka unutar 90 dana prije probira 5. Bilo koji poremećaj, osim stanja povezanih sa šećernom bolešću tipa 2, koji prema procjeni ispitivača može ugroziti sigurnost ispitanika i pridržavanje Planu ispitivanja 6. Bilo koja epizoda dijabetičke ketoacidoze unutar 90 dana od probira ili između probira i randomizacije 7. Infarkt miokarda, moždani udar, hospitalizacija zbog nestabilne angine pectoris ili prolazne ishemične atake u proteklih 180 dana prije dana probira i zmeđu probira i randomizacije 8. Utvrđeno zatajenje srca stupnja NYHA 4 9. Planiran postupak revaskularizacije koronarne, karotidne ili periferne arterije između probira i randomizacije 10. Oštećenje bubrežne funkcije sa eGFR manjom od 60 mlo/min/1.73 m2 definirano prema KDIGO 2012 11. Oštećenje jetrene funkcije definirano alanin aminotransferazom (ALT) jednakom ili 2.5 puta većom od normalne granice ili builirubinom 1.5 puta većim od normalne granice na probiru 12. Nezadovoljavajuće liječen krvni tlak definiran kao stupanj 3 ili veći (sistoloički veći ili jednak 180 mmHg ili dijastolički veći ili jednak 110 mmHg) na probiru 13. Liječenje bilo kojim lijekom za indikaciju šećerne bolesti ili pretilosti osim onih navedenih u uključnim kriterijima, unutar 90 dana od probira. Međutim, dozvoljeno je kratkotrajno liječenje inzulinom u maksimalnom razdoblju od 14 dana prije probira kao i prethodno liječenje gestacijskog dijabetesa inzulinom 14. Nekontrolirana ili potencijalno nestabilna dijabetička retinopatija i makulopatija potvrđena pregledom fundusa unutar 90 dana prije probira ili u razdoblju između probira i randomizacije. Farmakološko širenje zjenica je zahtjev osim ako se ne koristi digitalna kamera za fotografiju fundusa namijenjena za pregled bez proširivanja zjenice. 15. Prisutna maligna neoplazma ili povijest iste unutar 5 godina prije probira. Dozvoljen je rak bazalnih i skvamoznih stanica kože kao i bilo koji karcinom in-situ. |
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E.5 End points |
E.5.1 | Primary end point(s) |
Time in target range 3.9–10.0 mmol/L (70-180 mg/dL) measured using continuous glucose monitoring (CGM) |
Vrijeme u ciljanom rasponu 3.9–10.0 mmol/L mjereno uređajem za kontinuitrano mjerenje glukoze |
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E.5.1.1 | Timepoint(s) of evaluation of this end point |
During the last 2 weeks of treatment (week 15 and 16) |
Tijekom zadnja 2 tjedna od liječenja |
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E.5.2 | Secondary end point(s) |
1. Change in HbA1c 2. Change in fasting plasma glucose (FPG) 3. Change in body weight 4. Weekly insulin dose 5. Number of treatment emergent adverse events (TEAEs) 6. Number of severe hypoglycaemic episodes (level 3) 7. Number of clinically significant hypoglycaemic episodes (level 2) (below 3.0 mmol/L (54 mg/dL), confirmed by BG meter) or severe hypoglycaemic episodes (level 3) 8. Number of hypoglycaemic alert episodes (level 1) (equal to or above 3.0 and below 3.9 mmol/L (equal to or above 54 and below 70 mg/dL), confirmed by BG meter) |
1. Promjena HbA1c 2. Promjena glukoze mjerene natašte 3. Promjena tjelesne težine 4. Tjedna doza inzulina 5. Broj liječenja hitnih štetnih događaja 6. Broj teških epizoda hipoglikemije 7. Broj klinički značajnih epizoda hipoglikemije (razina 2) ispod 3.0 mmol/L potvrđeno glukometrom) ili teških epizoda hipoglikemije (razina 3) 8. Broj upozoravajućih epizoda hipoglikemije (razina 1) (jednak ili iznad 3.0 i ispod 3.9 mmol/L), potvrđeno glukometrom |
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E.5.2.1 | Timepoint(s) of evaluation of this end point |
1.-3. From baseline week 0 (V2) to week 16 (V18) 4. During the last 2 weeks of treatment (week 15 and 16) 5. From baseline week 0 (V2) to week 21 (V20) 6.-8. From baseline week 0 (V2) to week 16 (V18) |
1.-3. Od početka tjedan 0 (V2) do tjedna 16 (V18) 4. Tijekom zadnja 2 tjedna liječenja (tjedan 15 i 16) 5. Od početka tjedan 0 (V2) do tjedna 21 (V20) 6.-8. Od početka tjedan 0 (V2) do tjedna 16 (V18) |
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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 | 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 | Yes |
E.6.13.1 | Other scope of the trial description |
Tolerability |
Podnošljivost |
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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) | Yes |
E.7.3 | Therapeutic confirmatory (Phase III) | No |
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 | 4 |
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 | 26 |
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 |
European Union |
United States |
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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
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LVLS |
Zadnji posjet zadnjeg ispitanika |
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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 | 8 |
E.8.9.1 | In the Member State concerned days | 14 |
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 | 8 |
E.8.9.2 | In all countries concerned by the trial days | 14 |