Safety and Efficacy of Evolocumab in Addition to Optimal Stable Background Statin Therapy in Chinese Participants With Primary Hypercholesterolemia and Mixed Dyslipidemia

A Double-blind, Randomized, Placebo-controlled, Multicenter Study to Evaluate Safety and Efficacy of Evolocumab (AMG 145) in Addition to Optimal Stable Background Statin Therapy in Chinese Subjects With Primary Hypercholesterolemia and Mixed Dyslipidemia

This study is being done to learn more about evolocumab in Chinese people with primary hypercholesterolemia or mixed dyslipidemia. This study will see if evolocumab will reduce low density lipoprotein cholesterol (LDL-C) in Chinese people who are also taking a certain type of lipid-lowering medication (statins with or without ezetimibe) and whether it causes any side effects.

This is a phase 3, multicenter, double-blind, randomized, placebo-controlled study of evolocumab in Chinese participants with hypercholesterolemia and mixed dyslipidemia. Participants who have signed the informed consent form (ICF) will have fasting lipids measured and all inclusion and exclusion criteria assessed. All eligible participants must be taking a maximum appropriate dose of an approved statin, not requiring up titration. Participants should maintain their current diet and exercise regimen.

Treatment and follow-up period will be 12 weeks with an additional phone call or other participant contact at week 14 for those receiving investigational product every 2 weeks (Q2W). The end of study (EOS) for participants on once monthly (QM) investigational product is at the week 12 visit, which must be at least 30 days post last dose of investigational product.

Evolocumab or placebo will be administered by self-injection under the skin at the study site or in an appropriate non-clinic setting (e.g., at home) by spring based prefilled auto injector/pen (AI/Pen). Participants must tolerate an injection of placebo with a prefilled auto injector/pen device to be used during the study prior to randomization.

Participants will be randomly added to 1 of 4 groups using a 2:2:1:1 ratio:

evolocumab 140 mg Q2W (86 participants total) evolocumab 420 mg QM (86 participants total) placebo Q2W (44 participants total) placebo QM (43 participants total). The dose frequencies of Q2W and QM will not be blinded but the identity of investigational product evolocumab or placebo will be blinded.

Inclusion Criteria:

• Male or female ≥ 18 years of age at signing of informed consent form

• On an approved statin, with or without ezetimibe, at optimal stable daily dose(s) for at least 4 weeks before LDL-C screening and, in the opinion of the investigator, not requiring uptitration

• Fasting LDL-C as determined by central laboratory at screening ≥ 80 mg/dL

• Subject meets at least 1 of the following criteria for high/very high cardiovascular (CV) risk：

  • history of coronary artery disease
  • history of ischemic stroke
  • diagnosis of peripheral artery disease
  • an estimated glomerular filtration rate (eGFR) as determined by central laboratory at screening of ≥ 30 but < 60 ml/min/1.73m^2
  • diagnosis of diabetes mellitus type 2
  • presence of ≥ 3 of the following risk factors: ≥ 45 years of age if male; ≥ 55 years of age if female; hypertension; smoking; family history of premature cardiovascular disease (CVD; 1st degree of relative: male < 55 yr, female < 65 yr); high-density lipoprotein (HDL) cholesterol < 40 mg/dL; obesity (body mass index ≥ 28 kg/m^2)

OR

Subject does not meet high/very high CV risk criteria but fasting LDL-C as determined by central laboratory at screening ≥ 130 mg/dl

• Fasting triglycerides ≤ 400 mg/dL (4.5 mmol/L) by determined by central laboratory at screening
• Subject tolerates a screening placebo injection.

Exclusion Criteria:

• Myocardial infarction, unstable angina, percutaneous coronary intervention (PCI), coronary artery bypass graft (CABG) or stroke within 3 months prior to randomization

• Planned coronary or other revascularization within 20 weeks of screening

• New York Heart Association (NYHA) III or IV heart failure, or last known left ventricular ejection fraction < 30

• Uncontrolled serious cardiac arrhythmia defined as recurrent and highly symptomatic ventricular tachycardia, atrial fibrillation with rapid ventricular response, or supraventricular tachycardia that are not controlled by medications, in the past 3 months prior to randomization

• Type 1 diabetes, new-onset (hemoglobin [Hb]A1c ≥ 6.5% or fasting plasma glucose (FPG) ≥ 126 mg/dL at screening without known diagnosis) or poorly controlled (HbA1c ≥ 8.5%) type 2 diabetes, as determined by central laboratory at screening

• Uncontrolled hypertension defined as sitting systolic blood pressure (SBP) > 180 mmHg or diastolic blood pressure (DBP) > 110 mmHg

• Subject has taken a cholesterylester transfer protein (CETP) inhibitor in the 12 months prior to randomization

• Subject has taken in the 6 weeks prior to LDL-C screening: red yeast rice, > 200 mg/day niacin, > 1000 mg/day omega-3 fatty acids (eg, dihydroxyacetone docosahexaenoic acid and eicosapentaenoic acid), stanols or prescription lipid-regulating drugs (eg, bile-acid sequestering resins, fibrates and derivatives) or other cholesterol lowering drugs or lipid-lowering dietary supplements or food additives other than statins and ezetimibe

• Treatment 3 months prior to LDL-C screening with any of the following drugs: systemic cyclosporine, systemic steroids, (intravenous [IV], intramuscular [IM], or by-mouth [PO]) (Note: hormone replacement therapy is permitted), vitamin A derivatives and retinol derivatives for the treatment of dermatologic conditions (eg, Accutane) (Note: vitamin A in a multivitamin preparation is permitted)

• Uncontrolled hypothyroidism or hyperthyroidism as defined by thyroid stimulating hormone (TSH) < 1.0 time the lower limit of normal (LLN) or > 1.5 times the upper limit of normal (ULN), respectively, at screening

• Severe renal dysfunction, defined as an eGFR < 30 ml/min/1.73m^2 at screening as estimated by Cockcroft-Gault method

• Active liver disease or hepatic dysfunction, defined as aspartate aminotransferase (AST) or alanine aminotransferase (ALT) > 3 times the ULN as determined by central laboratory analysis at screening

• Creatinine kinase (CK) > 5 times the ULN at screening

• 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 randomization

• Subject has previously received evolocumab or any other therapy to inhibit PCSK9

• 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.

• Currently receiving treatment in another investigational device or drug study, or less than 30 days before randomization since ending treatment on another investigational device or drug study(s) or planning to receive other investigational procedures while participating in this study

• Female subject of childbearing potential not willing to use an acceptable method(s) of effective birth control during treatment with investigational product and for an additional 15 weeks after the end of treatment with investigational product. Female subjects of non-childbearing potential who 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 i. A postmenopausal state is defined as no menses for 12 months without an alternative medical cause. [A high follicle stimulating hormone (FSH) level in the postmenopausal range may be used to confirm a postmenopausal state in women not using hormonal contraception or hormonal replacement therapy (HRT). However, in the absence of 12 months of amenorrhea, a single FSH measurement is insufficient.

ii. Females on HRT and whose menopausal status is in doubt will be required to use one of the non-hormonal highly effective contraception methods if they wish to continue their HRT during the study. Otherwise, they must discontinue HRT to allow confirmation of postmenopausal status before study enrollment.

Acceptable methods of effective birth control include:

• sexual abstinence (defined as refraining from heterosexual intercourse during the entire period of risk associated with the study treatments; the reliability of sexual abstinence must be evaluated in relation to the duration of the trial and the preferred and usual lifestyle of the subject. [Periodic abstinence (eg., calendar, ovulation, symptothermal, postovulation methods), declaration of abstinence for the duration of a study, and withdrawal are not acceptable methods of contraception])

• bilateral tubal ligation/occlusion

• vasectomized partner (provided that partner is the sole sexual partner of the female subject of childbearing potential and that the vasectomized partner has received medical assessment of the surgical success)

• use of hormonal birth control methods (oral, intravaginal (eg. vaginal ring(s), transdermal, injectable, or implantable)

• intrauterine devices (IUDs)

• intrauterine hormonal releasing system (IUS)

• 2 barrier methods (each partner must use 1 barrier method) the male uses a condom and the female must choose either a diaphragm, OR cervical cap, OR contraceptive sponge with spermicide. If spermicide is not commercially available in the country or region, the 2 barrier method without spermicide is acceptable. (A female condom is not an option due to the risk of tearing when both partners use a condom.)

  • Female subject is pregnant or breast feeding (nursing), planning to become pregnant or planning to breastfeed (nurse) during treatment with investigational product and/or within 15 weeks after the end of treatment with investigational product.