E.1 Medical condition or disease under investigation |
E.1.1 | Medical condition(s) being investigated |
Hyperlipidemia or mixed dyslipidemia in Diabetic Subjects |
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E.1.1.1 | Medical condition in easily understood language |
High cholesterol in subjects with Diabetes |
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E.1.1.2 | Therapeutic area | Diseases [C] - Cardiovascular Diseases [C14] |
MedDRA Classification |
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 of 12 weeks of subcutaneous (SC) evolocumab every 2 weeks (Q2W) and monthly (QM), in combination with oral (PO) atorvastatin daily (QD), compared with placebo Q2W and QM, in combination with PO atorvastatin QD, on percent change from baseline in low-density lipoprotein cholesterol (LDL-C) in diabetic subjects with hyperlipidemia or mixed dyslipidemia. |
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E.2.2 | Secondary objectives of the trial |
•to evaluate the safety and tolerability of SC evolocumab Q2W and QM in combination with atorvastatin QD, compared with placebo Q2W and QM, in combination with atorvastatin QD, in diabetic subjects with hyperlipidemia or mixed dyslipidemia
• to assess the effects of 12 weeks of SC evolocumab Q2W and QM in combination with atorvastatin QD, compared with placebo Q2W and QM, in combination with atorvastatin QD, on change from baseline in LDL-C, and percent change from baseline in non-HDL-C, ApoB100, total cholesterol, total cholesterol/HDL-C ratio, ApoB100/ApoA1 ratio, Lp(a), triglycerides, VLDL-C, and HDL-C in diabetic subjects with hyperlipidemia or mixed dyslipidemia
• to assess the effects of 12 weeks of SC evolocumab Q2W and QM in combination with atorvastatin QD, compared with placebo Q2W and QM, in combination with atorvastatin QD, on percent of subjects attaining LDL-C < 70 mg/dL (1.8 mmol/L) in diabetic subjects with hyperlipidemia or mixed dyslipidemia |
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E.2.3 | Trial contains a sub-study | Yes |
E.2.3.1 | Full title, date and version of each sub-study and their related objectives |
Mixed Meal Tolerance Test (MMTT):
All subjects will complete a liquid MMTT after an overnight fast (no food or drinks other than water for ≥ 9 hours) at the day 1 and week 12 study visits with 1 postprandial blood collection 2 hours after the meal and up to approximately 240 subjects will participate in a MMTT Extended Timepoints Substudy with 2 additional postprandial blood draws at 1 and 3 hours after the meal. The objective is to explore the effect of SC evolocumab Q2W and QM in combination with atorvastatin QD, compared with placebo Q2W and QM, in combination with atorvastatin QD, on fasting and postprandial plasma laboratory parameters of interest.
Pharmacogenetic Study:
If the subject consents to the optional pharmacogenetic portion of this study, DNA analyses may be performed. These optional pharmacogenetics analyses focus on inherited genetic variations such as those of the PCSK9 gene or the LDLR gene to evaluate their possible correlation to the disease and/or responsiveness to the therapies used in this study. The goals of the optional studies include the use of genetic markers to help in the investigation of cardiovascular disease, hyperlipidemia and other metabolic disorders and/or to identify subjects who may have positive or negative response to evolocumab. No additional blood will be collected for this analysis. For subjects who have consented to the pharmacogenetic portion of this study, DNA will be extracted from blood samples already collected. Subjects can participate in the main trial irrespective of whether they do or do not consent to the pharmacogenetic portion of the study. Samples will be stored and destroyed in accordance with the current approved protocol. |
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E.3 | Principal inclusion criteria |
1) Subject has provided written informed consent.
2) Male or female, ≥ 18 to ≤ 80 years of age at signing of informed consent.
3) Type 2 diabetes, defined as receiving pharmacologic treatment for type 2 diabetes for ≥ 6 months prior to screening, with 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, no dose change of any oral antihyperglycemic drug within 2 months, and daily insulin dose not changed by > 25% and > 25 units within 1 month prior to randomization
4) Lipid-lowering therapy status (eg, not receiving any therapy or receiving any statin, ezetimibe, bile-acid sequestering resin, stanols, probucol, omega 3 fatty acids or niacin) must be unchanged for ≥ 4 weeks prior to LDL-C screening.
5) Subjects receiving statin therapy at screening must have a fasting LDL-C at screening of ≥ 100 mg/dL (2.6 mmol/L) as determined by central laboratory.
6) Subjects not receiving statin therapy at screening must have a fasting LDL-C at screening of ≥ 130 mg/dL (3.4 mmol/L) as determined by central laboratory.
7) Fasting triglycerides ≤ 400 mg/dL (4.5 mmol/L) by central laboratory at screening. |
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E.4 | Principal exclusion criteria |
1) Receiving 20 mg atorvastatin QD monotherapy for approximately 16 weeks is medically contraindicated or inappropriate based on opinion of investigator.
2) NYHA III or IV heart failure, or last known left ventricular ejection fraction < 30%.
3) Uncontrolled cardiac arrhythmia defined as recurrent and highly symptomatic ventricular tachycardia, atrial fibrillation with rapid ventricular response, or supraventricular tachycardia that is not controlled by medications, in the past 6 months prior to randomization.
4) Myocardial infarction, unstable angina, percutaneous coronary intervention (PCI), coronary artery bypass graft (CABG) or stroke within 6 months prior to randomization.
5) Planned cardiac surgery or revascularization within 6 months after randomization.
6) Type 1 diabetes or poorly controlled type 2 diabetes (HbA1c > 10.0 % at screening and at lipid stabilization or not on stable pharmacologic therapy for type 2 diabetes. Stable therapy is defined as no new agents added, no dose change of any oral antihyperglycemic drug within 2 months, and daily insulin dose not changed by > 25% and > 25 units within 1 month prior to randomization.
7) Uncontrolled hypertension defined as sitting systolic blood pressure (SBP) > 160 mmHg or diastolic BP (DBP) > 100 mmHg
8) Subject is unwilling or unable to discontinue between start of lipid stabilization with 20 mg/day atorvastatin and end of study (week 12 for QM and week 14 for Q2W subjects) the following drugs or supplements: red yeast rice, niacin (> 200 mg/day), > 1000 mg/day omega-3 fatty acids (eg, Docosahexaenoic acid [DHA] and eicosapentaenoic acid [EPA], prescription and non-prescription combined), and all other prescription lipid-regulating drugs (eg, fibrates and derivatives, ezetimibe, bile-acid sequestering resin, stanols, or probucol) except study-provided atorvastatin.
9) Subject has taken a cholesterylester transfer protein (CETP) inhibitor in the last 12 months prior to randomization, such as: anacetrapib, dalcetrapib or evacetrapib.
10) Treatment in the last 2 months prior to screening and lipid stabilization assessments with any of the following drugs: systemic cyclosporine, systemic steroids (eg, intravenous [IV], intramuscular [IM], or oral [PO] administration), vitamin A derivatives and retinol derivatives for the treatment of dermatologic conditions (eg, Accutane); (Note: vitamin A in a multivitamin preparation is permitted).
11) Hyperthyroidism or hypothyroidism as defined by thyroid stimulating hormone (TSH) below the lower limit of normal (LLN) or > 1.5 times the upper limit of normal (ULN), respectively, at screening.
12) Moderate to severe renal dysfunction, defined as an estimated glomerular filtration rate (eGFR) < 30 mL/min/1.73m2 at screening.
13) Persistent active liver disease or hepatic dysfunction, defined as aspartate aminotransferase (AST) or alanine aminotransferase (ALT) > 2 times the ULN as determined by central laboratory analysis at screening or lipid stabilization assessments.
14) Creatine kinase (CK) > 3 times the ULN at screening or lipid stabilization assessments.
15) Known active infection or major hematologic, renal, metabolic, gastrointestinal or endocrine dysfunction (except diabetes).
16) Deep vein thrombosis or pulmonary embolism within 3 months prior to randomization.
17) Female subject who has either (1) not used (an) acceptable method(s) of birth control (see protocol) for at least 1 month prior to screening or (2) is not willing to inform her partner of her participation in this clinical study and to use such (an) acceptable method(s) during treatment with IP (evolocumab or placebo) and for an additional 15 weeks after the end of treatment with IP (evolocumab or placebo), unless the female subject is sterilized or postmenopausal (see protocol).
18) Subject is pregnant or breast feeding, or planning to become pregnant or planning to breastfeed during treatment with IP (evolocumab or placebo) and/ or within 15 weeks after the end of treatment with IP(evolocumab or placebo).
19) Malignancy (except non-melanoma skin cancers, cervical in-situ carcinoma, breast ductal carcinoma in situ, or stage 1 prostate carcinoma) within the last 5 years prior to screening.
20) Subject has previously received evolocumab or any other investigational therapy to inhibit PCSK9.
21) Currently receiving treatment in another investigational device or drug study, or less than 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.
22) Subject has known sensitivity to any of the active substances or their excipients to be administered during dosing, eg, carboxymethylcellulose, or atorvastatin.
For the final two exclusion criteria please refer to the protocol. |
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E.5 End points |
E.5.1 | Primary end point(s) |
Co-Primary Efficacy Endpoints
a) mean percent change from baseline in LDL-C at weeks 10 and 12
b) percent change from baseline in LDL-C at week 12 |
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E.5.1.1 | Timepoint(s) of evaluation of this end point |
a) Weeks 10 and 12
b) Week 12 |
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E.5.2 | Secondary end point(s) |
Co-secondary efficacy endpoints are (1) the mean of weeks 10 and 12 and (2) week 12 for:
Tier 1 endpoints
• change from baseline in LDL-C • percent change from baseline in non-HDL-C • percent change from baseline in ApoB100
• percent change from baseline in the total cholesterol
• percent change from baseline in the total cholesterol/HDL-C ratio
• percent change from baseline in ApoB100/ApoA1 ratio
• achievement of target LDL-C < 70 mg/dL (1.8 mmol/L)
Tier 2 endpoints
• 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 |
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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 | 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 | Yes |
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 | 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 | 4 |
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 |
Argentina |
Brazil |
Canada |
China |
Colombia |
France |
Korea, Republic of |
Russian Federation |
Turkey |
United States |
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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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The end of the study (primary completion) is defined as the last day on which a randomized subject completes the end-of-study visit or phone follow-up (week 12 for subjects on QM IP administration; week 14 for subjects on Q2W IP administration) or terminates the study early, whichever is later. |
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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 | 10 |
E.8.9.1 | In the Member State concerned days | 0 |
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 | 10 |
E.8.9.2 | In all countries concerned by the trial days | 0 |