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Study Protocol 1002-046 Amendment 1, 10 April 2017

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Study Protocol 1002-046 Amendment 1, 10 April 2017 1. TITLE PAGE BEMPEDOIC ACID 1002-046 A RANDOMIZED, DOUBLE-BLIND, PARALLEL GROUP, MULTICENTER STUDY TO EVALUATE THE EFFICACY AND SAFETY OF BEMPEDOIC ACID (ETC-1002) 180 MG COMPARED TO PLACEBO ADDED TO BACKGROUND LIPID-MODIFYING THERAPY IN PATIENTS WITH ELEVATED LDL-C WHO ARE STATIN INTOLERANT Study Phase: 3 IND Number: 106654 EudraCT Number: NA Indication: Treatment of hyperlipidemia Investigators: Approximately 71 sites located in North America Sponsor: Esperion Therapeutics, Inc. 3891 Ranchero Drive, Suite 150 Ann Arbor, MI 48108 Phone: 734-862-4840 Fax: 734-582-9720 Sponsor Contact: Medical Monitor: Version Date Original Protocol: 25 August 2016 Amendment 1: 10 April 2017 Confidentiality Statement THIS CONFIDENTIAL INFORMATION IS ABOUT AN INVESTIGATIONAL DRUG PROVIDED FOR THE EXCLUSIVE USE OF INVESTIGATORS OF THIS DRUG AND IS SUBJECT TO RECALL AT ANY TIME. THE INFORMATION IN THIS DOCUMENT MAY NOT BE DISCLOSED UNLESS SUCH DISCLOSURE IS REQUIRED BY FEDERAL OR STATE LAW OR REGULATIONS. SUBJECT TO THE FOREGOING, THIS INFORMATION MAY BE DISCLOSED ONLY TO THOSE PERSONS INVOLVED IN THE STUDY WHO HAVE NEED TO KNOW, WITH THE OBLIGATION NOT TO FURTHER DISSEMINATE THIS INFORMATION. THESE RESTRICTIONS ON DISCLOSURE WILL APPLY EQUALLY TO ALL FUTURE ORAL OR WRITTEN INFORMATION, SUPPLIED TO YOU BY ESPERION THERAPEUTICS, INC., WHICH IS DESIGNATED AS “PRIVILEGED” OR “CONFIDENTIAL. NCT number: NCT02988115 This NCT number has been applied to the document for purposes of posting on clinicaltrials.gov Confidential Page 1 of 153 Bempedoic Acid Esperion Therapeutics, Inc. Clinical Study Protocol 1002-046 Amendment 1, 10 April 2017 2. SYNOPSIS Name of Sponsor: Esperion Therapeutics, Inc. Name of Investigational Product: Bempedoic acid (ETC-1002) film-coated tablets Name of Active Ingredient: Bempedoic acid Title of Study: A Randomized, Double-Blind, Parallel Group, Multicenter Study to Evaluate the Efficacy and Safety of Bempedoic Acid (ETC-1002) 180 mg Compared to Placebo Added to Background Lipid-Modifying Therapy in Patients with Elevated LDL-C Who are Statin Intolerant Study Number: 1002-046 Phase of Development: 3 Clinical Sites: Approximately 71 sites located in North America Objectives: Primary: • To assess the 12-week efficacy of bempedoic acid 180 mg/day versus placebo in decreasing low- density lipoprotein cholesterol (LDL-C) in statin intolerant patients with elevated LDL-C Secondary: • To evaluate the effect of 24-week treatment with bempedoic acid 180 mg/day versus placebo on LDL-C • To evaluate the effect of bempedoic acid 180 mg/day versus placebo on non-high-density lipoprotein cholesterol (non-HDL-C), total cholesterol (TC), high-sensitivity C-reactive protein (hs-CRP), and apolipoprotein B (apoB) after 12 weeks of treatment • To evaluate the 24-week safety and tolerability of bempedoic acid 180 mg/day compared to placebo Tertiary: Confidential Page 2 of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empedoic Acid Esperion Therapeutics, Inc. Clinical Study Protocol 1002-046 Amendment 1, 10 April 2017 Primary Endpoint The primary efficacy endpoint for this study is the percent change from baseline to Week 12 in LDL-C Secondary Endpoints 1. Percent change from baseline to Week 24 in LDL-C 2. Percent change from baseline to Week 12 in non-HDL-C, TC, apoB, and hs-CRP 3. Absolute change from baseline to Weeks 12 and 24 in LDL-C Tertiary Endpoints Safety Endpoints 1. Patient incidence of treatment-emergent adverse event (TEAE) 2. Safety laboratory values and vital signs 3. Cardiovascular event rates Number of patients (planned): Approximately 300 adult male and female patients Diagnosis and Criteria for Inclusion: Key inclusion criteria 1. Provision of written informed consent must be obtained prior to any study-specific procedure. 2. Men and nonpregnant, nonlactating women. Women must be either: • Naturally postmenopausal defined as ≥1 year without menses and: − ≥55 years, or − <55 years with follicle-stimulating hormone (FSH) ≥40.0 IU/L; or • Surgically sterile including hysterectomy, bilateral oophorectomy, and/or tubal ligation; or • Women of childbearing potential must be willing to use 2 acceptable methods of birth control (unless they have agreed to follow the definition of true abstinence). The minimal requirement for adequate contraception should be started on Day 1, continuing during the study period and for at least 30 days after the last dose of study drug. Acceptable methods of birth control include: − oral, implanted, topical, or injectable birth control medications − placement of an intrauterine device with or without hormones − barrier methods including condom or occlusive cap with spermicidal foam or spermicidal jelly − vasectomized male partner who is the sole partner for this patient − true abstinence: When this is in line with the preferred and usual lifestyle of the subject. (Periodic abstinence [eg, calendar, ovulation, symptothermal, postovulation methods], declaration of abstinence for the duration of a trial, and withdrawal are not acceptable methods of contraception). There are no protocol-specific birth control requirements for men with partners who are able to become pregnant. 3. Age ≥18 years or legal age of majority depending on regional law, whichever is greater at Week -5 (Visit S1) 4. Fasting (minimum of 10 hours) calculated LDL-C at Week -5 (Visit S1) Confidential Page 4 of 153 Bempedoic Acid Esperion Therapeutics, Inc. Clinical Study Protocol 1002-046 Amendment 1, 10 April 2017 • Primary prevention ≥130 mg/dL (3.4 mmol/L) • Secondary prevention and/or heterozygous familial hypercholesterolemia (HeFH) ≥100 mg/dL (2.6 mmol/L) • All patients must have fasting LDL-C ≥70 mg/dL (1.8 mmol/L) at Week -1 (Visit S3) In the case of proprotein convertase subtilisin/kexin type 9 (PCSK9) inhibitor use, the patient must have received 3 stable doses. It is important that lipid values are measured at PCSK9i trough levels. Therefore, study visits should be scheduled in accordance with the patient’s PCSK9i injection regimen so that measurement of lipid values for all visits occurs before the PCSK9i injection but not greater than 48 hours before the next scheduled PCSK9i injection. Patients who have discontinued investigational or commercial PCSK9 inhibitor must have had their last dose at least 4 months prior to Screening Visit S1. 5. Requiring lipid-modifying therapy for the purpose of primary or secondary prevention of cardiovascular events. • Primary Prevention patients must as a minimum have a history of requiring lipid-modifying therapy based on local guidelines (for example, American College of Cardiology [ACC]/American Heart Association [AHA] guidelines, European Society of Cardiology [ESC]/European Atherosclerosis Society [EAS] guidelines, Canadian Cardiovascular Society guidelines). • Secondary prevention and/or HeFH patients must include those with a history of: − HeFH, defined by: − Genotyping or by clinical assessment using either the World Health Organization (WHO) criteria/Dutch Lipid Clinical Network Criteria with a score that is >8 points (see Appendix 5) or the Simon Broome Register Diagnostic Criteria with an assessment of ‘Definite HeFH’ (see Appendix 6). and/or − Coronary artery disease, defined by: ○ MI (either ST-elevation MI or non-ST-elevation MI) occurring greater than
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