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

• ClinicalTrials.gov Identifier: NCT03433755
• Recruitment Status: Recruiting
• First Posted: February 15, 2018
• Last Update Posted: November 7, 2019
• Sponsor: Amgen
• Information provided by (Responsible Party): Amgen

Study Description

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.

Condition or disease	Intervention/treatment	Phase
Primary Hypercholesterolemia; Mixed Dyslipidemia	Drug: Evolocumab 140 mg SC Q2W; Drug: Evolocumab 420 mg SC QM; Other: Placebo SC Q2W; Other: Placebo SC QM	Phase 3

Detailed Description:

This is a phase 3, multicenter, double-blind, randomized, placebo-controlled study of evolocumab in Chinese Subjects with hypercholesterolemia and mixed dyslipidemia. Subjects who have signed the informed consent form (ICF), will have fasting lipids measured and all inclusion and exclusion criteria assessed. Subjects should maintain their current diet and exercise regimen. Treatment and follow-up period will be 12 weeks with an additional phone call or other subject contact at week 14 for subjects receiving investigational product Q2W. The EOS for subjects on QM investigational product is at the week 12 visit which must be at least 30 days post last dose of investigational product.

Evolocumab and 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). Subjects must tolerate an injection of placebo with a prefilled auto injector/pen device to be used during the study prior to randomization.

Approximately 40 sites in China will participate in this study. The overall participants to finish the study will be approximately 450 randomly added to one of 4 groups using a 2:2:1:1 ratio.

Evolocumab 140 mg every 2 weeks (Q2W-150 subjects total) Evolocumab 420 mg once a month (QM-150 subjects total) placebo every 2 weeks (75 subjects total) placebo once a month (75 subjects total) The dose frequencies of every 2 weeks and monthly will not be blinded but the identity of investigational product Evolocumab or placebo will be blinded.

Study Design

• Study Type: Interventional (Clinical Trial)
• Estimated Enrollment: 450 participants
• 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, ApoA1,ApoB, lipoprotein(a), hsCRP, and PCSK9.

• Primary Purpose: Treatment
• Official Title: 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
• Actual Study Start Date: May 9, 2019
• Estimated Primary Completion Date: October 9, 2020
• Estimated Study Completion Date: October 23, 2020

Arms and Interventions

Arm	Intervention/treatment
Active Comparator: Evolocumab 140 mg SC Q2W; Approximately 150 Subjects	Drug: Evolocumab 140 mg SC Q2W; Investigational product and placebo will be administered per pre-filled auto-injector pen (AI/Pen). Subjects will receive evolocumab (AMG 145) every 2 weeks or monthly subcutaneously. In addition, all eligible subjects must be taking a maximum appropriate dose of an approved statin, not requiring up titration.
Active Comparator: Evolocumab 420 mg SC QM; Approximately 150 Subjects	Drug: Evolocumab 420 mg SC QM; Investigational product and placebo will be administered per pre-filled auto-injector pen (AI/Pen). Subjects will receive evolocumab (AMG 145) every 2 weeks or monthly subcutaneously. In addition, all eligible subjects must be taking a maximum appropriate dose of an approved statin, not requiring up titration.
Placebo Comparator: Placebo SC Q2W; Approximately 75 Subjects	Other: Placebo SC Q2W; Investigational product and placebo will be administered per pre-filled auto-injector pen (AI/Pen). Subjects will receive placebo every 2 weeks or monthly subcutaneously. In addition, all eligible subjects must be taking a maximum appropriate dose of an approved statin, not requiring up titration.
Placebo Comparator: Placebo SC QM; Approximately 75 Subjects	Other: Placebo SC QM; Investigational product and placebo will be administered per pre-filled auto-injector pen (AI/Pen). Subjects will receive placebo every 2 weeks or monthly subcutaneously. In addition, all eligible subjects must be taking a maximum appropriate dose of an approved statin, not requiring up titration.

Outcome Measures

Primary Outcome Measures :

1. Mean percent change from baseline in low-density lipoprotein cholesterol (LDL-C) at weeks 10 and 12 [ Time Frame: Weeks 10 and 12 ]
   To evaluate the effect of 12 weeks of subcutaneous (SC) evolocumab every 2 weeks or every 4 weeks, compared with placebo, on percent change from baseline in low-density lipoprotein cholesterol (LDL-C) when used in addition to optimal stable background statin therapy in Chinese subjects with primary hypercholesterolemia and mixed dyslipidemia.
2. Percent change from baseline in low-density lipoprotein cholesterol (LDL-C) at week 12 [ Time Frame: Week 12 ]
   To evaluate the effect of 12 weeks of subcutaneous (SC) evolocumab every 2 weeks or every 4 weeks, compared with placebo, on percent change from baseline in low-density lipoprotein cholesterol (LDL-C) when used in addition to optimal stable background statin therapy in Chinese subjects with primary hypercholesterolemia and mixed dyslipidemia.

Secondary Outcome Measures :

1. The mean of weeks 10 and 12 in low-density lipoprotein cholesterol (LDL-C) [ Time Frame: Weeks 10 and 12 ]
2. The mean of weeks 10 and 12 in non-high-density lipoprotein cholesterol (non-HDL-C) [ Time Frame: Weeks 10 and 12 ]
3. The mean of weeks 10 and 12 in apolipoprotein B (ApoB) [ Time Frame: Weeks 10 and 12 ]
4. The mean of weeks 10 and 12 in total cholesterol [ Time Frame: Weeks 10 and 12 ]
5. The mean of weeks 10 and 12 of target low-density lipoprotein cholesterol (LDL-C) < 70 mg/dL (1.8 mmol/L) [ Time Frame: Weeks 10 and 12 ]
6. The mean of weeks 10 and 12 of low-density lipoprotein cholesterol (LDL-C) response [ Time Frame: Weeks 10 and 12 ]
7. The mean of weeks 10 and 12 in lipoprotein(a) [Lp(a)] [ Time Frame: Weeks 10 and 12 ]
8. The mean of weeks 10 and 12 in triglycerides [ Time Frame: Weeks 10 and 12 ]
9. The mean of weeks 10 and 12 in high-density lipoprotein cholesterol (HDL-C) [ Time Frame: Weeks 10 and 12 ]
10. The mean of weeks 10 and 12 in very low-density lipoprotein cholesterol (VLDL-C) [ Time Frame: Weeks 10 and 12 ]
11. For week 12 change from baseline in low-density lipoprotein cholesterol (LDL-C) [ Time Frame: Baseline and Week 12 ]
12. For week 12 percent change from baseline in non-high-density lipoprotein cholesterol (non-HDL-C) [ Time Frame: Baseline and Week 12 ]
13. For week 12 percent change from baseline in apolipoprotein B (ApoB) [ Time Frame: Baseline and Week 12 ]
14. For week 12 percent change from baseline in total cholesterol [ Time Frame: Baseline and Week 12 ]
15. For week 12 achievement of target low-density lipoprotein cholesterol (LDL-C) < 70 mg/dL (1.8 mmol/L) [ Time Frame: Week 12 ]
16. For week 12 low-density lipoprotein cholesterol (LDL-C) response (50% reduction of low-density lipoprotein cholesterol (LDL-C) from baseline) [ Time Frame: Baseline and Week 12 ]
17. For week 12 percent change from baseline in lipoprotein(a) [Lp(a)] [ Time Frame: Baseline and Week 12 ]
18. For week 12 percent change from baseline in triglycerides [ Time Frame: Baseline and Week 12 ]
19. For week 12 percent change from baseline in high-density lipoprotein cholesterol (HDL-C) [ Time Frame: Baseline and Week 12 ]
20. For week 12 percent change from baseline in very low-density lipoprotein cholesterol (VLDL-C) [ Time Frame: Baseline and Week 12 ]

Eligibility Criteria

• Ages Eligible for Study: 18 Years to 99 Years (Adult, Older Adult)
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

Criteria

Inclusion Criteria:

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

102 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

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

104 Subject meets at least one of the following criteria for high/very high 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/1.73m2
• 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 CVD (1st degree of relative: male < 55yr, female < 65yr), HDL cholesterol < 40 mg/dL, obesity(BMI ≥ 28 kg/m2)

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

105 Fasting triglycerides ≤ 400 mg/dL (4.5 mmol/L) by determined by central laboratory at screening

106 Subject tolerates a screening placebo injection

Exclusion Criteria:

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

202. Planned coronary or other revascularization within 20 weeks of screening

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

204. 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

205. 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

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

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

208. 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

209. Treatment 3 months prior to LDL-C screening with any of the following drugs: systemic cyclosporine, systemic steroids , (intravenous [IV], intramuscular [IM], or 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)

210. 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

211. Severe renal dysfunction, defined as an eGFR < 30 ml/min/1.73m2 at screening as estimated by Cockcroft-Gault method

212. 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

213. Creatinine Kinase (CK) > 5 times the ULN at screening

214. 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

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

216. Subject has known sensitivity to any of the active substances or their excipients to be administered during dosing, eg, carboxymethylcellulose

217. 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.

218. 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.

219. 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

220. 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 (Refer to Section 6.9.1 for specific contraceptive information). 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.)

  221. 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.

Contacts and Locations

Contacts

Contact: Amgen Call Center; 866-572-6436; medinfo@amgen.com

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Sponsors and Collaborators

Amgen

Investigators

• Study Director: MD; Amgen

More Information

Additional Information:

AmgenTrials clinical trials website 

• Responsible Party: Amgen
• ClinicalTrials.gov Identifier: NCT03433755 History of Changes
• Other Study ID Numbers: 20150172
• First Posted: February 15, 2018
• Last Update Posted: November 7, 2019
• Last Verified: November 2019

Individual Participant Data (IPD) Sharing Statement:

• Plan to Share IPD: Yes
• Plan Description: De-identified individual patient data for variables necessary to address the specific research question in an approved data sharing request.
• Supporting Materials: Study Protocol; Statistical Analysis Plan (SAP); Informed Consent Form (ICF); Clinical Study Report (CSR)
• Time Frame: Data sharing requests relating to this study will be considered beginning 18 months after the study has ended and either 1) the product and indication (or other new use) have been granted marketing authorization in both the US and Europe or 2) clinical development for the product and/or indication discontinues and the data will not be submitted to regulatory authorities. There is no end date for eligibility to submit a data sharing request for this study.
• Access Criteria: Qualified researchers may submit a request containing the research objectives, the Amgen product(s) and Amgen study/studies in scope, endpoints/outcomes of interest, statistical analysis plan, data requirements, publication plan, and qualifications of the researcher(s). In general, Amgen does not grant external requests for individual patient data for the purpose of re-evaluating safety and efficacy issues already addressed in the product labelling. Requests are reviewed by a committee of internal advisors, and if not approved, may be further arbitrated by a Data Sharing Independent Review Panel. Upon approval, information necessary to address the research question will be provided under the terms of a data sharing agreement. This may include anonymized individual patient data and/or available supporting documents, containing fragments of analysis code where provided in analysis specifications. Further details are available at the link below.
• URL: https://www.amgen.com/datasharing

• Studies a U.S. FDA-regulated Drug Product: Yes
• Studies a U.S. FDA-regulated Device Product: No
• Product Manufactured in and Exported from the U.S.: Yes

Keywords provided by Amgen:

Evolocumab; Repatha; Statin; Chinese; China; Hypercholesterolemia; Mixed Dyslipidemia; High Cholesterol; Lowering cholesterol

Additional relevant MeSH terms:

Hypercholesterolemia; Dyslipidemias; Hyperlipidemias; Lipid Metabolism Disorders; Metabolic Diseases; Hydroxymethylglutaryl-CoA Reductase Inhibitors; Evolocumab; Antibodies, Monoclonal; Anticholesteremic Agents; Hypolipidemic Agents; Antimetabolites; Molecular Mechanisms of Pharmacological Action; Enzyme Inhibitors; Lipid Regulating Agents; Immunologic Factors; Physiological Effects of Drugs