A Double-blind, Randomized, Placebo-Controlled, Multicenter Study to Evaluate Safety and Efficacy of Evolocumab (AMG 145) in Combination With Statin Therapy in Diabetic Subjects With Hyperlipidemia or Mixed Dyslipidemia

INTERVENTION:

Product Name: Evolocumab Product Code: Evolocumab Pharmaceutical Form: Solution for injection in pre‐filled pen INN or Proposed

INN:

Evolocumab Current Sponsor code: Evolocumab Other descriptive name: AMG145 Concentration unit: mg/ml milligram(s)/millilitre Concentration type: equal Concentration number: 140‐ Pharmaceutical form of the placebo: Solution for injection in pre‐filled pen Route of administration of the placebo: Subcutaneous use Product Name: Evolocumab Product Code: Evolocumab Pharmaceutical Form: Solution for injection in cartridge INN or Proposed

INN:

Evolocumab Current Sponsor code: Evolocumab Other descriptive name: AMG145 Concentration unit: mg/ml milligram(s)/millilitre Concentration type: equal Concentration number: 120‐ Pharmaceutical form of the placebo: Solution for injection in cartridge Route of administration of the placebo: Subcutaneous use

CONDITION:

Hyperlipidemia or mixed dyslipidemia in Diabetic Subjects Therapeutic area: Diseases [C] ‐ Cardiovascular Diseases [C14]

PRIMARY OUTCOME:

Main Objective: 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. 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 Secondary Objective: •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 Timepoint(s) of evaluation of this end point: a) Weeks 10 and 12; b) Week 12

SECONDARY OUTCOME:

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 Timepoint(s) of evaluation of this end point: Weeks 10 and 12

INCLUSION CRITERIA:

1) Subject has provided written informed consent. 2) Male or female, = 18 to = 80 years of age at signing of informed consent. 5) Subjects receiving statin therapy at screening must have a fasting LDL‐C at screening of = 100 mg/dL (2.6 mmol/L) as det 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.