A Study of PCSK9 Inhibitor AK102 in Patients With Hypercholesterolemia

Study Overview
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Brief Summary
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This is a double-blind, randomized, placebo-controlled, multicenter study to evaluate the safety and efficacy of AK102 in patients with Hypercholesterolemia Patients at Very High or High Risk of Cardiovascular Disease . The primary objective of this study is to evaluate the efficacy of AK102 in patients with Hypercholesterolemia Patients at Very High or High Risk of Cardiovascular Disease .

Official Title
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A Double-blind, Randomized, Placebo-controlled, Multicenter Phase II Study of AK102 in the Treatment of Hypercholesterolemia Patients at Very High or High Risk of Cardiovascular Disease

Conditions
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Hypercholesterolemia

Intervention / Treatment
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* Drug: AK102
* Drug: Placebos
* Drug: Statins and/or Ezetimibe


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Voluntarily sign the informed consent form (ICF), and be able to comply with the treatment plan, visit, laboratory examination and other requirements specified in the study; Age ≥ 18, male or female; According to the guidelines for the prevention and treatment of dyslipidemia in Chinese adults (revised in 2016), subjects assessed as very high risk or high risk of cardiovascular disease; Subjects received stable and optimal dose of statins for at least 4 weeks before randomization, either in combination with or without ezetimibe; The blood lipid level of the patients with stable 4-week basic lipid-lowering drug treatment met one of the following conditions by the central laboratory test: LDL-C level in very high risk subjects > 1.8 mmol / L (70 mg / dl) or LDL-C level of high-risk subjects > 2.6 mmol / L (100 mg / dl) TG ≤ 4.5 mmol / L (400 mg / dl) measured by central laboratory at screening； Exclusion Criteria: Has received cholesterol ester transfer protein (CETP) inhibitor within12 months prior to randomization; Has received PCSK9 inhibitors or are known to be allergic to PCSK9 inhibitors or their components; Has received other investigational drugs within 4 weeks or within 5 half lives (whichever was longer) prior to screening. Has previously received biological agent treatment, organ transplantation or gene therapy; Abnormal laboratories prior to the first study drug administration: ALT or AST> 3 × ULN; Creatine kinase > 5 × ULN; eGFR <= 30 ml/min/1.73m2 by Cockcroft Gault method; Uncontrolled hypothyroidism or hyperthyroidism defined as TSH < 1.0 ×LLN or > 1.5 × ULN, respectively; Myocardial infarction, unstable angina pectoris, percutaneous coronary intervention (PCI), coronary bypass grafting (CABG), stroke, severe deep vein thrombosis or pulmonary embolism, or severe arrhythmia occurred within three months prior to randomization ; Grade III or IV according to NYHA assessment; Planned to have heart-related surgery within 3 months after randomization; Type 1 diabetes or poorly controlled type 2 diabetes [HbA1c > 8.5% within 1 month]; Subjects with hypertension that could not be controlled by drugs; Known concomitant diseases that may lead to secondary hyperlipidemia, including nephrotic syndrome, cholestatic liver failure, etc; Positive HBsAg or HCV antibody; Known history of primary immunodeficiency virus infection or positive human immunodeficiency virus (HIV) test; History of drug or alcohol abuse prior to screening; Has taken the following drugs within 6 weeks prior to screening: red koji rice > 200 mg/day; niacin > 1000 mg/day; omega-3 fatty acids; steroids or prescription lipid regulating drugs ; cholesterol lowering drugs, health care products, Chinese patent medicines or other food additives other than statins and ezetimibe; Has taken the following drugs within 3 months prior to screening: systemic cyclosporine, systemic steroids, vitamin A derivatives and retinol derivatives for the treatment of skin diseases (such as retinoic acid).

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Triple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: AK102 450 mg<br>Participants received AK102 450 mg subcutaneous injection once every 4 weeks (Q4W) for 12 weeks | Drug: AK102<br>* Administered by subcutaneous injection<br>Drug: Statins and/or Ezetimibe<br>* Lipid-lowering therapies<br>|
| Experimental: AK102 300 mg<br>Participants received AK102 300 mg subcutaneous injection once every 4 weeks (Q4W) for 12 weeks | Drug: AK102<br>* Administered by subcutaneous injection<br>Drug: Statins and/or Ezetimibe<br>* Lipid-lowering therapies<br>|
| Experimental: AK102 150 mg<br>Participants received AK102 150 mg subcutaneous injection once every 2 weeks (Q2W) for 12 weeks | Drug: AK102<br>* Administered by subcutaneous injection<br>Drug: Statins and/or Ezetimibe<br>* Lipid-lowering therapies<br>|
| Experimental: AK102 75 mg<br>Participants received AK102 75 mg subcutaneous injection once every 2 weeks (Q2W) for 12 weeks | Drug: AK102<br>* Administered by subcutaneous injection<br>Drug: Statins and/or Ezetimibe<br>* Lipid-lowering therapies<br>|
| Placebo Comparator: Placebo Q4W<br>Participants received placebo subcutaneous injection once every 4 weeks (Q4W) for 12 weeks | Drug: Placebos<br>* Administered by subcutaneous injection<br>Drug: Statins and/or Ezetimibe<br>* Lipid-lowering therapies<br>|
| Placebo Comparator: Placebo Q2W<br>Participants received placebo subcutaneous injection once every 2 weeks (Q2W) for 12 weeks | Drug: Placebos<br>* Administered by subcutaneous injection<br>Drug: Statins and/or Ezetimibe<br>* Lipid-lowering therapies<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Percent change from baseline in low-density lipoprotein cholesterol (LDL-C) at Week 12 |  | At baseline and week 12 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Percent change from baseline in low-density lipoprotein cholesterol (LDL-C) |  | From baseline through 12 weeks | 
| Percent change from baseline in high-density lipoprotein cholesterol (HDL-C) |  | From baseline through 12 weeks | 
| Percent change from baseline in non High-density lipoprotein (non-HDL) cholesterol |  | From baseline through 12 weeks | 
| Percent change from baseline in serum Triglyceride (TG) cholesterol |  | From baseline through 12 weeks | 
| Percent change from baseline in Apolipoprotein B (Apo B) |  | From baseline through 12 weeks | 
| Percent change from baseline in Apolipoprotein A-I (ApoA-I) |  | From baseline through 12 weeks | 
| Percent change from baseline in Lipoprotein(a) [Lp-(a)] |  | From baseline through 12 weeks | 
| Percent change from baseline in Total Cholesterol(TC) |  | From baseline through 12 weeks | 
| Incidence of treatment-emergent adverse events |  | From baseline through 12 weeks | 
| Serum concentrations of AK102 |  | From baseline through 12 weeks | 
| Number of subjects who develop detectable anti-drug antibodies (ADAs) | The immunogenicity of AK102 will be assessed by summarizing the number of subjects who develop detectable anti-drug antibodies. | From baseline through 12 weeks | 
| Change from baseline in proprotein convertase subtilisin/kexin type 9 (PCSK9) |  | From baseline through 12 weeks |