| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
| Type 2 Diabetes Mellitus and Hypercholesterolemia/Mixed Dyslipidemia |
| Diabete mellito tipo 2 e ipercolestrolemia/dislipidemia mista |
|
| E.1.1.1 | Medical condition in easily understood language |
| Type 2 diabetes mellitus with high cholesterol ( elevated LDL-cholesterol in blood) and/or mixed dyslipidemia (abnormal amounts of lipids in blood). |
| Diabete mellito tipo 2 con elevato colesterolo (elevato colesterolo LDL nel sangue) e/o dislipidemia mista (quantità anormali di grassi nel sangue) |
|
| 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 | 10020604 |
| E.1.2 | Term | Hypercholesterolemia |
| E.1.2 | System Organ Class | 10027433 - Metabolism and nutrition disorders |
|
| E.1.2 Medical condition or disease under investigation |
| E.1.2 | Version | 20.0 |
| 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 |
|
| E.1.2 Medical condition or disease under investigation |
| E.1.2 | Version | 20.0 |
| E.1.2 | Level | LLT |
| E.1.2 | Classification code | 10058110 |
| E.1.2 | Term | Dyslipidemia |
| E.1.2 | System Organ Class | 10027433 - Metabolism and nutrition disorders |
|
| 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 evaluate the effect, tthe safety and tolerability of 12 weeks of subcutaneous (SC) evolocumab monthly (QM) compared with placebo QM on percent change from baseline in low-density lipoprotein cholesterol (LDL-C) in subjects with type 2 diabetes mellitus and hypercholesterolemia or mixed dyslipidemia on maximally tolerated dose of statin of at least moderate-intensity oral daily. |
| Valutare l’effetto di evolocumab, assunto una volta al mese (QM) per via sottocutanea (sc) nel corso di 12 settimane, rispetto al placebo assunto QM, sulla variazione percentuale dal basale del colesterolo legato alle proteine a bassa densità (C-LDL) nei soggetti con diabete mellito di tipo 2 e ipercolesterolemia o dislipidemia mista a una dose massima tollerata di statine con intensità almeno moderata assunta giornalmente per via orale. |
|
| E.2.2 | Secondary objectives of the trial |
To assess the effects of 12 weeks of SC evolocumab QM compared
with placebo QM, in subjects with type 2 diabetes mellitus and hypercholesterolemia or mixed dyslipidemia in combination with maximally tolerated dose of statin of at least moderate-intensity oral daily on the following:
- Change from baseline in LDL-C, and percent change from baseline in non-high-density lipoprotein cholesterol (HDL-C), apolipoprotein B (ApoB), total cholesterol (TC), lipoprotein(a) (Lp[a]), triglycerides, HDL-C, and very low-density lipoprotein cholesterol (VLDL-C)
- Percent of subjects attaining LDL-C < 70 mg/dL (1.8 mmol/L)
- Percent of subjects attaining a 50% reduction in LDL-C from baseline |
Valutare gli effetti di evolocumab QM sc su 12 settimane, rispetto al placebo QM, nei soggetti con diabete mellito di tipo 2 e ipercolesterolemia o dislipidemia mista in combinazione con la dose massima tollerata di statine con intensità almeno moderata assunte giornalmente per via orale su quanto segue:
- Variazione rispetto al basale dei livelli di C-LDL e variazione percentuale rispetto al basale dei livelli di colesterolo legato alle lipoproteine non ad alta densità (C-non HDL), apolipoproteina B (ApoB), colesterolo totale (CT), lipoproteina(a) [Lp(a)], trigliceridi, C-HDL e colesterolo legato a lipoproteine a bassissima densità (C-VLDL)
- Percentuale di pazienti che raggiungano livelli di C-LDL <70 mg/dL (1,8 mmol/L)
- Percentuale di pazienti che raggiungano una riduzione del 50% in C-LDL rispetto al basale |
|
| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal inclusion criteria |
-Subject has provided written informed consent
-Male or female ≥ 18 years of age at signing of informed consent
-Type 2 diabetes mellitus:
•with hemoglobin A1c (HbA1c) < 10%
•receiving pharmacologic treatment for diabetes mellitus for ≥ 6 months prior to screening
•stable diabetes therapy prior to randomization to IP and not expected to change during the duration of study participation. Stable diabetes therapy is defined as no new agents added, and no dose change of any antihyperglycemic drug within 2 months prior to randomization and daily insulin dose not changed by > 25% and > 25 units within 1 month prior to randomization
-Subject must be on maximally tolerated dose of statin of at least moderate intensity at signing of the informed consent (see Appendix D) and is expected to remain on stable statin intensity for the duration of study in the opinion of the investigator:
•subjects without known clinical CVD must be on at least moderate-intensity statin prior to randomization
• subjects with known clinical CVD must be on high intensity statin (or moderate intensity if certified by principal investigator to be highest tolerated dose) prior to randomization). Clinical CVD is defined as a history of myocardial infarction, stable or unstable angina, coronary or other arterial revascularization, stroke, transient ischemic attack, or peripheral arterial disease presumed to be of atherosclerotic origin.
-Subjects without known clinical CVD must have a fasting LDL-C during lipid stabilization of ≥ 100 mg/dL (2.6 mmol/L) or non-HDL-C ≥ 130 mg/dL (3.4 mmol/L) as determined by the central laboratory
-Subjects with known clinical CVD must have a fasting LDL-C during lipid stabilization of ≥ 70 mg/dL (1.8 mmol/L) or Non-HDL-C ≥ 100 mg/dL (2.6 mmol/L) as determined by the central laboratory
-Fasting triglycerides ≤ 600 mg/dL (6.8 mmol/L) by central laboratory prior to randomization
-Subject tolerates screening placebo injection
|
Lo studio arruolerà soggetti adulti (>=18 anni di età) con diabete mellito di tipo 2 e livelli elevati di C-LDL o C-non HDL a una dose massima tollerata stabile di statine con intensità almeno moderata al momento della firma del consenso informato; la terapia con statine deve restare invariata durante lo screening e il resto dello studio.
I soggetti devono avere valori di emoglobina A1c (HbA1c) <10%, devono assumere un trattamento farmacologico per il diabete mellito da 6 mesi prima dello screening, con terapia stabile per il diabete prima della randomizzazione al prodotto sperimentale senza variazioni previste per tutto il periodo di partecipazione allo studio. Per un elenco completo dei criteri di eleggibilità, consultare dalla Sezione 4.1 alla Sezione 4.1.2 del protocollo
|
|
| E.4 | Principal exclusion criteria |
-Myocardial infarction, unstable angina, percutaneous coronary intervention, coronary artery bypass graft or stroke within 3 months prior to randomization
-Uncontrolled hypertension defined as sitting systolic blood pressure (BP) > 180 mmHg or diastolic BP > 110 mmHg
-Subject has taken a cholesterylester transfer protein inhibitor in the last 12 months prior to randomization, such as: anacetrapib, dalcetrapib, or evacetrapib
-Moderate to severe renal dysfunction, defined as an estimated glomerular filtration rate < 20 mL/min/1.73 m2 during screening
-Persistent active liver disease or hepatic dysfunction, defined as Child-Pugh score of C
-Female subject of childbearing potential not willing to use an acceptable method(s) of effective birth control during the screening/lipid stabilization period, during treatment with IP and for an additional 15 weeks after the end of treatment with IP.
Female subjects of non-childbearing potential are not required to use contraception during the study and include those who have had a hysterectomy, bilateral salpingectomy, bilateral oophorectomy, or who are postmenopausal. Postmenopausal is defined as 12 months of spontaneous and continuous amenorrhea in a female ≥ 55 years old; or age < 55 years but no spontaneous menses for at least 2 years; or age < 55 years and spontaneous menses within the past 1 year, but currently amenorrheic (eg, spontaneous or secondary to hysterectomy), and with postmenopausal gonadotropin levels (luteinizing hormone and follicle stimulating hormone levels > 40 IU/L) or postmenopausal estradiol levels (< 5 ng/dL) or according to the definition of "postmenopausal range" for the laboratory involved.
Acceptable methods of effective birth control include:
•true sexual abstinence when this is in line with the preferred and usual lifestyle of the subject (periodic abstinence [eg, calendar, ovulation, symptothermal, post-ovulation methods], declaration of abstinence for the duration of a trial, and withdrawal are not acceptable methods of contraception),
•vasectomized partner (provided that partner is the sole sexual partner of the female participant who is of childbearing potential and that the vasectomized partner has received medical assessment of the surgical success),
•bilateral tubal ligation/occlusion, use of hormonal birth control methods (oral, intravaginal, [eg, vaginal ring], transdermal, injectable, or implantable),
• intrauterine devices,
•intrauterine hormonal releasing system, or
•2 barrier methods (each partner must use one barrier method) and the female partner must use if available spermicide in addition to a barrier – males must use a condom; females must choose either a diaphragm, OR cervical cap, OR contraceptive sponge. (Note: If spermicide is not commercially available in the country or region, the two barrier method without spermicide iswould then be considered acceptable.).
Note: Additional medications given during the study may alter the contraceptive requirements. These additional medications may require an increase in the number of contraceptive methods, the change in type of contraceptive methods and/or length of time that contraception is to be utilized and/or length of time breastfeeding is to be avoided. The investigator is to discuss these contraceptive changes with the study subject.
- Female subject is pregnant or breast feeding, or planning to become pregnant or planning to breastfeed during the screening/lipid stabilization period, during treatment with IP and for an additional 15 weeks after the end of treatment with IP
-Malignancy (except non-melanoma skin cancers, cervical in situ carcinoma, breast ductal carcinoma in situ, or stage 1 prostate carcinoma) within the last 1 year prior to randomization
-Subject has previously received evolocumab or any other therapy to inhibit PCSK9
-Currently receiving treatment in another investigational device or IP, or < 30 days since ending treatment on another investigational device or drug study(s) or planning to receive other investigational procedures while participating in this study
-Subject has known sensitivity to any of the active substances or their excipients to be administered during dosing, eg, carboxymethylcellulose
-Subject likely to not be available to complete all protocol required study visits or procedures, and/or to comply with all required study procedures to the best of the subject and investigator’s knowledge
- History or evidence of any other clinically significant disorder, condition or disease (with the exception of those outlined above) that, in the opinion of the investigator or Amgen physician, if consulted, would pose a risk to subject safety or interfere with the study evaluation, procedures, or completion
|
- Infarto del miocardio, angina instabile, intervento coronarico percutaneo, impianto di bypass coronarico o ictus entro 3 mesi prima della randomizzazione
- ipertensione non controllata definita come pressione sistolica da seduto (BP)> 180 mmHg o diastolica> 110 mmHg
- Il soggetto ha assunto un inibitore della proteina di trasferimento colesteril estere negli utlimi 12 mesi prima della randomizzazione, come ad esempio: anacetrapib, Dalcetrapib, o
evacetrapib
- Disfunzione renale da moderata a grave, definita come una stima della velocità di filtrazione glomerulare <20 mL / min / 1,73 m2 durante lo screening
- malattia epatica persistente e attiva o disfunzione epatica, definita come livello C di Child- Pugh
- Soggetto femminile in età fertile non disposto a utilizzare un metodo accettabile efficace di controllo delle nascite durante il periodo di stabilizzazione/screening dei lipidi, durante il trattamento con l’ IP e per ulteriori 15 settimane dopo la fine del trattamento con l’IP.
- Soggetti di sesso femminile non-fertili, non sono tenuti ad utilizzare contraccezione durante lo studio e sono inclusi coloro che hanno avuto un isterectomia, salpingectomia bilaterale, ooforectomia bilaterale, o che sono in post-menopausa. Postmenopausa è definita come 12 mesi di amenorrea spontanea e continua in donne ≥ 55 anni; o di età <55 anni, ma senza mestruazioni spontanee per almeno 2 anni; o di età < 55 anni e mestruazioni spontanee durante l’ultimo anno, ma al momento amenorrea (ad esempio, spontanea o secondaria a isterectomia), e con livelli di gonadotropina in post-menopausa (ormone luteinizzante e follicolo stimolando con livelli di ormone> 40 UI / l) o estradiolo in post-menopausa livelli (<5 ng / dL).
- Soggetti femminili in gravidanza o l'allattamento, o che stanno pianificando di rimanere incinte o pianificando di allattare al seno durante lo screening o il periodo di stabilizzazione dei lipidi, durante il trattamento con l’IP e per altri 15 settimane dopo la fine del trattamento con IP
- Malignità (salvo melanoma, carcinoma cervicale in situ, carcinoma duttale in situ della mammella, o carcinoma alla prostata di fase 1) nell’ultimo anno prima della randomizzazione
- Il soggetto ha ricevuto in precedenza evolocumab o qualsiasi altra terapia per inibire PCSK9
- Il soggetto ha ricevuto in precedenza evolocumab o qualsiasi altra terapia per inibire PCSK9
- Attualmente in trattamento con un altro dispositivo sperimentale o IP, oppure
<30 giorni dalla fine del trattamento su un altro dispositivo sperimentale o
farmaco in studio, o che pianifica di per ricevere altre procedure di sperimentazione
durante la partecipazione a questo studio
- Soggetti con conosciuta sensibilità a qualsiasi sostanza attiva o suoi eccipienti da somministrare durante il dosaggio, per esempio, carbossimetilcellulosa
- Soggetti con probabilità di non riuscire a completare tutte le visite o procedure del protocollo
- Storia o evidenza di qualsiasi altro disturbo clinicamente significativo, condizione o malattia (ad eccezione di quelli sopra indicati) che, al parere dello sperimentatore o Amgen, se consultata, potrebbe rappresentare un rischio di sicurezza o interferire con la valutazione dello studio, le sue procedure o il suo completamento
|
|
| E.5 End points |
| E.5.1 | Primary end point(s) |
- Mean percent change from baseline in LDL-C at weeks 10 and 12
- Percent change from baseline in LDL-C at week 12
- Subject incidence of treatment emergent adverse events
- Safety laboratory values and vital signs at each scheduled assessment |
- variazione percentuale media rispetto al basale dei valori di C-LDL alle settimane 10 e 12
- variazione percentuale rispetto al basale dei valori di C-LDL alla settimana 12
- incidenza eventi Avversi emergenti
- valori di safety di laboratorio e segni vitali ad ogni valutazione pianificata
|
|
| E.5.1.1 | Timepoint(s) of evaluation of this end point |
| At day 1, week 8, week 10, and week 12. |
| Giorno 1, Settimane 8, 10 e 12 |
|
| E.5.2 | Secondary end point(s) |
For the mean of weeks 10 and 12 and for week 12:
• Tier 1
− Change from baseline in LDL-C
− Percent change from baseline in non-HDL-C
− Percent change from baseline in ApoB
− Percent change from baseline in TC
− Achievement of target LDL-C < 70 mg/dL (1.8 mmol/L)
− LDL-C response (50% reduction of LDL-C from baseline)
• Tier 2
− Percent change from baseline in Lp(a)
− Percent change from baseline in triglycerides
− Percent change from baseline in HDL-C
− Percent change from baseline in VLDL-C |
Per la media delle settimane 10 e 12 e per la settimana 12:
Livello 1
- Variazione rispetto al basale dei valori di C-LDL
-Variazione rispetto al basale dei valori di C- non HDL
- Variazione rispetto al basale dei valori di ApoB
- Variazione percentuale rispetto al basale dei valori di CT
- Raggiungimento di un valore target di C-LDL <70 mg/dL (1,8 mmol/L)
- Risposta C-LDL (riduzione del 50% di C-LDL rispetto al basale)
Livello 2
- Variazione percentuale rispetto al basale dei valori di Lp(a)
- Variazione percentuale rispetto al basale dei valori dei trigliceridi
Variazione percentuale rispetto al basale dei valori di C-LDL
- Variazione percentuale rispetto al basale dei valori di C-VLDL
|
|
| E.5.2.1 | Timepoint(s) of evaluation of this end point |
| At day 1, week 8, week 10, and week 12. |
| Al giorno 1, settimane 8, 10 e 12 |
|
| 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 | 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 | 3 |
| E.8.5 | The trial involves multiple Member States | Yes |
| E.8.5.1 | Number of sites anticipated in the EEA | 21 |
| 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 |
| Canada |
| Mexico |
| United States |
|
| 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
|
|
| E.8.9 Initial estimate of the duration of the trial |
| E.8.9.1 | In the Member State concerned years | |
| E.8.9.1 | In the Member State concerned months | 4 |
| E.8.9.1 | In the Member State concerned days | 15 |
| E.8.9.2 | In all countries concerned by the trial months | 4 |
| E.8.9.2 | In all countries concerned by the trial days | 15 |
Print
