Safety and Efficacy of Evolocumab in Addition to Optimal Stable Background Statin Therapy in Chinese Participants With Primary Hypercholesterolemia and Mixed Dyslipidemia
Condition: Primary Hypercholesterolemia; Mixed Dyslipidemia
MeSH terms: Hypercholesterolemia; Dyslipidemias
Intervention: evolocumab; placebo
Intervention description: Evolocumab will be administered per pre-filled auto-injector pen (AI/Pen). Participants will receive evolocumab (AMG 145) every 2 weeks or monthly subcutaneously.; Placebo will be administered per pre-filled auto-injector pen (AI/Pen). Participants will receive placebo every 2 weeks or monthly subcutaneously.
Intervention MeSH terms: Evolocumab
Phase: Phase 3
Study type: Interventional
Primary purpose: Treatment
Allocation: Randomized
Intervention model: Parallel Assignment
Intervention model description: Participants will be screened for this study and if found eligible as described by the study protocol may be randomized into 1 of 4 groups. Randomized means that you are put into a group by chance. It is like drawing numbers out of a hat. Randomization will be done using a 2:2:1:1 ratio. This means for every 6 participants randomized:
2 participants will be randomized to evolocumab 140 mg every 2 weeks
2 participants will be randomized to evolocumab 420 mg once a month
1 participant will be randomized to placebo every 2 weeks
1 participant will be randomized to placebo once a month.
Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
Masking description: The dose frequencies of Q2W and QM will not be blinded but the identity of investigational product (evolocumab or matching SC placebo) will be blinded. In order to protect the blinding of the double-blind treatment period the following labs will be blinded post-investigational product treatment until unblinding of the clinical database and not reported to sites as noted below:
• Blinded to the Amgen study team and site staff: lipid panel, Apolipoprotein A1 (ApoA1), Apolipoprotein B (ApoB), lipoprotein(a), high-sensitivity C-reactive protein (hs-CRP), and Proprotein convertase subtilisin/kexin type 9 (PCSK9).
Enrollment: 259.0
Sex: All
Minimum age: 18 Years
Maximum age: 99 Years
Healthy volunteers: No
Keywords: Evolocumab; Repatha; Statin; Chinese; China; Hypercholesterolemia; Mixed Dyslipidemia; High Cholesterol; Lowering cholesterol

Summary:

      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.
    

Eligibility criteria:

        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.