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

Phase 3

Terminated

Conditions: Primary Hypercholesterolemia
Mixed Dyslipidemia

Interventions: Drug: placebo
Drug: evolocumab

Registration Number: NCT03433755

Lead Sponsor: Amgen

Brief 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.

Detailed Description: 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.

Recruitment & Eligibility

Status: TERMINATED

Sex: All

Target Recruitment: 259

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)

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.

Study & Design

Study Type: INTERVENTIONAL

Study Design: PARALLEL

Arm && Interventions

Group	Intervention	Description
Placebo Q2W	placebo	Placebo subcutaneous (SC) Q2W for 12 weeks
Placebo QM	placebo	Placebo SC QM for 12 weeks
Evolocumab 420 mg QM	evolocumab	Evolocumab 420 mg SC QM for 12 weeks
Evolocumab 140 mg Q2W	evolocumab	Evolocumab 140 mg SC Q2W for 12 weeks

Primary Outcome Measures

Name	Time	Method
Co-Primary Endpoint: Percent Change From Baseline in LDL-C: Mean of Weeks 10 and 12	Baseline, Weeks 10 and 12	Least squares mean is from the repeated measures linear effects model which includes treatment group, stratification factors, scheduled visit and the interaction of treatment with scheduled visit as covariates.
Co-Primary Endpoint: Percent Change From Baseline in LDL-C at Week 12	Baseline, Week 12	Least squares mean is from the repeated measures linear effects model which includes treatment group, stratification factors, scheduled visit and the interaction of treatment with scheduled visit as covariates.

Secondary Outcome Measures

Name	Time	Method
Change From Baseline in LDL-C: Mean of Weeks 10 and 12	Baseline, Weeks 10 and 12	Least squares mean is from the repeated measures linear effects model which includes treatment group, stratification factors, scheduled visit and the interaction of treatment with scheduled visit as covariates.
Percent Change From Baseline in Non-HDL-C at Week 12	Baseline, Week 12	Least squares mean is from the repeated measures linear effects model which includes treatment group, stratification factors, scheduled visit and the interaction of treatment with scheduled visit as covariates.
Percent Change From Baseline in Apolipoprotein B (ApoB): Mean of Weeks 10 and 12	Baseline, Weeks 10 and 12	Least squares mean is from the repeated measures linear effects model which includes treatment group, stratification factors, scheduled visit and the interaction of treatment with scheduled visit as covariates.
Percent Change From Baseline in Total Cholesterol: Mean of Weeks 10 and 12	Baseline, Weeks 10 and 12	Least squares mean is from the repeated measures linear effects model which includes treatment group, stratification factors, scheduled visit and the interaction of treatment with scheduled visit as covariates.
Percentage of Participants With Target LDL-C < 70 mg/dL (1.8 mmol/L): Mean of Weeks 10 and 12	Weeks 10 and 12	Percentage of participants who were below the target LDL-C of 70 mg/dL (1.8 mmol/L) based on the mean LDL-C data collected at weeks 10 and 12.
Change From Baseline in LDL-C at Week 12	Baseline, Week 12	Least squares mean is from the repeated measures linear effects model which includes treatment group, stratification factors, scheduled visit and the interaction of treatment with scheduled visit as covariates.
Percent Change From Baseline in Non-High-Density Lipoprotein Cholesterol (Non-HDL-C): Mean of Weeks 10 and 12	Baseline, Weeks 10 and 12	Least squares mean is from the repeated measures linear effects model which includes treatment group, stratification factors, scheduled visit and the interaction of treatment with scheduled visit as covariates.
Percent Change From Baseline in ApoB at Week 12	Baseline and Week 12	Least squares mean is from the repeated measures linear effects model which includes treatment group, stratification factors, scheduled visit and the interaction of treatment with scheduled visit as covariates.
Percent Change From Baseline in Total Cholesterol at Week 12	Baseline and Week 12	Least squares mean is from the repeated measures linear effects model which includes treatment group, stratification factors, scheduled visit and the interaction of treatment with scheduled visit as covariates.
Percentage of Participants With Target LDL-C < 70 mg/dL (1.8 mmol/L) at Week 12	Week 12
Percentage of Participants With LDL-C Response: Mean of Weeks 10 and 12	Baseline, Weeks 10 and 12	Percentage of participants who had LDL-C response (50% reduction of LDL-C from baseline) based on the mean LDL-C using the data collected at weeks 10 and 12.
Percentage of Participants With LDL-C Response (50% Reduction of LDL-C From Baseline) at Week 12	Baseline and Week 12	LDL-C Response is defined as a 50% reduction of LDL-C from Baseline.
Percent Change From Baseline in Lipoprotein(a) [Lp(a)]: Mean of Weeks 10 and 12	Baseline, Weeks 10 and 12	Least squares mean is from the repeated measures linear effects model which includes treatment group, stratification factors, scheduled visit and the interaction of treatment with scheduled visit as covariates.
Percent Change From Baseline in Lp(a) at Week 12	Baseline and Week 12	Least squares mean is from the repeated measures linear effects model which includes treatment group, stratification factors, scheduled visit and the interaction of treatment with scheduled visit as covariates.
Percent Change From Baseline in Triglycerides: Mean of Weeks 10 and 12	Baseline, Weeks 10 and 12	Least squares mean is from the repeated measures linear effects model which includes treatment group, stratification factors, scheduled visit and the interaction of treatment with scheduled visit as covariates.
Percent Change From Baseline in Triglycerides at Week 12	Baseline and Week 12	Least squares mean is from the repeated measures linear effects model which includes treatment group, stratification factors, scheduled visit and the interaction of treatment with scheduled visit as covariates.
Percent Change From Baseline in High-Density Lipoprotein Cholesterol (HDL-C): Mean of Weeks 10 and 12	Baseline, Weeks 10 and 12	Least squares mean is from the repeated measures linear effects model which includes treatment group, stratification factors, scheduled visit and the interaction of treatment with scheduled visit as covariates.
Percent Change From Baseline in HDL-C at Week 12	Baseline and Week 12	Least squares mean is from the repeated measures linear effects model which includes treatment group, stratification factors, scheduled visit and the interaction of treatment with scheduled visit as covariates.
Percent Change From Baseline in Very Low-Density Lipoprotein Cholesterol (VLDL-C): Mean of Weeks 10 and 12	Baseline, Weeks 10 and 12	Least squares mean is from the repeated measures linear effects model which includes treatment group, stratification factors, scheduled visit and the interaction of treatment with scheduled visit as covariates.
Percent Change From Baseline in VLDL-C at Week 12	Baseline and Week 12	Least squares mean is from the repeated measures linear effects model which includes treatment group, stratification factors, scheduled visit and the interaction of treatment with scheduled visit as covariates.

Trial Locations

Locations (31): Sun Yat-sen Memorial Hospital Sun Yat-sen University
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Guangzhou, Guangdong, China
The Third Xiangya Hospital of Central South University
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Changsha, Hunan, China
Affiliated Hospital of Jiangsu University
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Zhenjiang, Jiangsu, China
Shanghai Yangpu District Central Hospital
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Shanghai, Shanghai, China
Tianjin Fourth Centre Hospital
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Tianjin, Tianjin, China
Guangzhou First PeoplesÂ Â Hospital
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Guangzhou, Guangdong, China
The Second Nanning Peoples Hospital
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Nanning, Guangxi, China
Guangzhou Red Cross Hospital
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Guangzhou, Guangdong, China
The First Affiliated Hospital of Harbin Medical University
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Harbin, Heilongjiang, China
The Affiliated Hospital of Xuzhou Medical University
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Xuzhou, Jiangsu, China
China-Japan Union Hospital of Jilin University
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Changchun, Jilin, China
Peking University Shenzhen Hospital
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Shenzhen, Guangdong, China
Beijing Hospital
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Beijing, Beijing, China
Wuhan Puai Hospital
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Wuhan, Hubei, China
Peking University Third Hospital
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Beijing, Beijing, China
The Peoples Hospital of Liaoning Province
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Shenyang, Liaoning, China
Suzhou Kowloon Hospital
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Suzhou, Jiangsu, China
Tianjin Medical University General Hospital
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Tianjin, Tianjin, China
Guangdong Provincial Peoples Hospital
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Guangzhou, Guangdong, China
Changsha Central Hospital
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Changsha, Hunan, China
Xiangya Hospital Central South University
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Changsha, Hunan, China
The Second Xiangya Hospital of Central South University
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Changsha, Hunan, China
Inner Mongolia Peoples Hospital
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Huhehaote, Inner Mongolia, China
The Second Affiliated Hospital to Nanchang University
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Nanchang, Jiangxi, China
Jinan Central Hospital
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Jinan, Shandong, China
The First Affiliated Hospital of Xi An Jiao Tong University
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XI An, Shanxi, China
Zhejiang Hospital
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Hangzhou, Zhejiang, China
Taizhou Hospital of Zhejiang Province
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Linhai, Zhejiang, China
The First Affiliated Hospital of Wenzhou Medical University
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Wenzhou, Zhejiang, China
Ningbo First Hospital
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Ningbo, Zhejiang, China
Huashan Hospital Affiliated to Fudan University
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Shanghai, China