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1. TITLE PAGE BEMPEDOIC ACID (ETC-1002) 1002-039 A RANDOMIZED, DOUBLE-BLIND, PARALLEL GROUP, MULTICENTER STUDY TO EVALUATE THE EFFICACY AND SAFETY OF BEMPEDOIC ACID (ETC-1002) 180 MG QD WHEN ADDED TO PROPROTEIN CONVERTASE SUBTILISIN/KEXIN TYPE 9 (PCSK9)-INHIBITOR THERAPY Study Phase: 2 IND Number: 106,654 EudraCT Number: n/a Indication: Treatment of hyperlipidemia Investigators: Approximately 20-30 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 22 November 2016 Protocol Amendment 1: 05 March 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: NCT03193047 This NCT number has been applied to the document for purposes of posting on clinicaltrials.gov Confidential Page 1 of 114 Bempedoic Acid Esperion Therapeutics, Inc. Clinical Study Protocol 1002-039 Amendment 1, 05 March 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 QD when added to PCSK9-Inhibitor Therapy Study Number: 1002-039 Phase of Development: 2 Clinical Sites: Approximately 20 sites located in North America Objectives: Primary: • To assess the 2-month efficacy of bempedoic acid 180 mg/day vs placebo in the reduction of low- density lipoprotein cholesterol (LDL-C) in patients on proprotein convertase subtilisin/kexin type 9 inhibitor (PCSK9i) therapy Secondary: • To assess the 1-month efficacy of bempedoic acid 180 mg/day vs placebo in the reduction of LDL-C in patients on PCSK9i therapy • To evaluate the effect of bempedoic acid 180 mg/day vs placebo on apolipoprotein B (ApoB), non-high-density lipoprotein cholesterol (non-HDL-C), total cholesterol (TC), and high- sensitivity C-reactive protein (hs-CRP) after 1 and 2 months of treatment • To evaluate the safety and tolerability of bempedoic acid 180 mg/day compared to placebo in patients on PCSK9i therapy Exploratory: Confidential Page 2 of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empedoic Acid Esperion Therapeutics, Inc. Clinical Study Protocol 1002-039 Amendment 1, 05 March 2017 Primary Endpoint The primary efficacy endpoint for this study is the percent change from baseline to Month 2 in LDL-C. Secondary Endpoints 1. Percent change from baseline to Month 1 in LDL-C 2. Change from baseline to Month 1 and Month 2 in LDL-C 3. Percent change from baseline to Month 1 and Month 2 in ApoB, non-HDL-C, TC, and hs-CRP 4. Safety and tolerability of bempedoic acid in this patient population over 2 months, as assessed by adverse events (AEs) and clinical laboratory values Exploratory Endpoints For details of study assessments, see the Schedule of Events (Appendix 1). Number of patients (planned): Approximately 52 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. Age ≥18 years or legal age of majority depending on regional law, whichever is greater at Month -4.5 (Visit S1) 3. Fasting, calculated LDL-C at screening (Visit S2) ≥160 mg/dL and ≥70 mg/dL at Visit S4 Note: A single repeat of LDL-C may be completed. For those patients who have a repeat LDL-C, the average of the 2 values will be used to determine eligibility. 4. Men and nonpregnant, nonlactating women. Women must be: a. Naturally postmenopausal defined as ≥1 year without menses and: − ≥55 years, or − <55 years with follicle-stimulating hormone (FSH) ≥40.0 IU/L; or b. Surgically sterile including hysterectomy, bilateral oophorectomy, and/or tubal ligation; or c. Women of childbearing potential willing to use 2 acceptable methods of birth control including: − 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. Confidential Page 4 of 114 Bempedoic Acid Esperion Therapeutics, Inc. Clinical Study Protocol 1002-039 Amendment 1, 05 March 2017 Key exclusion criteria 1. Homozygous Familial Hypercholesterolemia (HoFH) 2. Total fasting TG ≥500 mg/dL (5.6 mmol/L at Month -3 (Visit S2). Note: A single repeat of TG may be completed. For those patients who have a repeat TG, the average of the 2 values will be used to determine eligibility. 3. Renal dysfunction or a glomerulonephropathy defined as either nephritic or nephrotic syndrome, including estimated glomerular filtration rate (eGFR; using central laboratory determined Modification of Diet in Renal Disease [MDRD] formula) <30 mL/min/1.73 m2 at Month -4.5 (Visit S1). Note: A single repeat of eGFR may be completed prior to randomization. For those patients who have a repeat eGFR, the average of the 2 values will be used to determine eligibility. 4. All patients with known cardiovascular disease (CVD) or peripheral arterial disease (PAD) or cerebrovascular disease (CD). 5. History of type 1 or type 2 diabetes or laboratory evidence of diabetes (fasting blood glucose [FBG] >126 mg/dL or glycosylated hemoglobin, Type A1C [HbA1C] >6.5%) without prior diagnosis of diabetes at Month -4.5 (Visit S1) 6. Uncontrolled hypertension defined as sitting systolic blood pressure (SBP) >160 mmHg or diastolic blood pressure (DBP) >100 mmHg at Month -4.5 (Visit S1). 7. Uncontrolled hypothyroidism, including thyroid-stimulating hormone (TSH) >1.5 × the upper limit of normal (ULN) at Month -4.5 (Visit S1). 8. Liver disease or dysfunction, including: a. Alanine aminotransferase (ALT) and/or aspartate aminotransferase (AST) ≥2.0 × ULN at Month -4.5 (Visit S1). b. Positive serology for hepatitis B surface antigen (HBsAg) and/or hepatitis C antibodies (HCV-ABVivi) at Month -4.5 (Visit S1). Note: If total bilirubin (TB) ≥1.2 × ULN, a reflex indirect (unconjugated) bilirubin will be obtained and if consistent with Gilbert’s disease, the patient may be enrolled in the study. Note: At the discretion of the investigator, a single repeat of ALT and/or AST may be completed. For those patients who have a repeat ALT and/or AST, the average of the 2 values will be used to determine eligibility. Also, if test for hepatitis C antibody is positive, but reflexive test for Hepatitis C ribonucleic acid (RNA) is negative, patient can be enrolled. 9. Gastrointestinal conditions or procedures (including weight loss surgery; eg, Lap-Band®
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    Trial Design Study design of Dal-GenE, a pharmacogenetic trial targeting reduction of cardiovascular events with dalcetrapib Jean-Claude Tardif, MD, a Marie-Pierre Dubé, PhD, a,b Marc A. Pfeffer, MD, PhD, c David D. Waters, MD, d Wolfgang Koenig, MD, PhD, e Aldo P. Maggioni, MD, f John J. V. McMurray, MB, ChB, g Vincent Mooser, MD, h Harvey D. White, DsC, i Therese Heinonen, DVM, j Donald M. Black, MD, j and Marie-Claude Guertin, PhD k, for the dal-GenE Investigators 1 The objectives of precision medicine are to better match patient characteristics with the therapeutic intervention to optimize the chances of beneficial actions while reducing the exposure to unneeded adverse drug experiences. In a retrospective genome- wide association study of the overall neutral placebo-controlled dal-Outcomes trial, the effect of the cholesteryl ester transfer protein (CETP) modulator dalcetrapib on the composite of cardiovascular death, myocardial infarction or stroke was found to be influenced by a polymorphism in the adenylate cyclase type 9 (ADCY9) gene. Whereas patients with the AA genotype at position rs1967309 experienced fewer cardiovascular events with dalcetrapib, those with the GG genotype had an increased rate and the heterozygous AG genotype exhibited no difference from placebo. Measurements of cholesterol efflux and C- reactive protein (CRP) offered directionally supportive genotype-specific findings. In a separate, smaller, placebo-controlled trial, regression of ultrasonography-determined carotid intimal-medial thickness was only observed in dalcetrapib-treated patients with the AA genotype. Collectively, these observations led to the hypothesis that the cardiovascular effects of dalcetrapib may be pharmacogenetically determined, with a favorable benefit-risk ratio only for patients with this specific genotype.
  • Efficacy and Safety of Further Lowering of Low- Density Lipoprotein Cholesterol in Patients Starting with Very Low Levels: a Meta-Analysis

    Efficacy and Safety of Further Lowering of Low- Density Lipoprotein Cholesterol in Patients Starting with Very Low Levels: a Meta-Analysis

    Supplementary Online Content Sabatine MS, Wiviott SD, Im KA, Murphy SA, Giugliano RP. Efficacy and safety of further lowering of low- density lipoprotein cholesterol in patients starting with very low levels: a meta-analysis. JAMA Cardiol. Published online August 1, 2018. doi:10.1001/jamacardio.2018.2258. eMethods. eResults. eFigure. Literature Search This supplementary material has been provided by the authors to give readers additional information about their work. © 2018 American Medical Association. All rights reserved. Downloaded From: https://jamanetwork.com/ on 09/25/2021 eMethods Potential trials were identified from MEDLINE. The following search terms were used: Cholesterol, LDL and [Anticholesteremic Agents or Hypolipidemic Agents] and Cardiovascular Diseases. The MEDLINE search was limited to randomized controlled trials, human, and published between 2015 and April 2018. Results were supplemented from the reference files of all authors and from reference lists of original articles, reviews, and meta-analyses. To qualify trials had to be a double-blind, controlled, dedicated cardiovascular outcomes trial of an LDL-C lowering drug, had to use a reliable method of LDL-C measurement (ie, preparative ultracentrifugation if a CETP inhibitor was used), have a median follow-up for at least 2 years, and present data on patients starting with a mean or median LDL-C ≤1.8 mmol/L (70 mg/dL), as that is a treatment threshold recommended in multiple guidelines.1-3 Lipid data, cardiovascular outcome data and safety data for each relevant trial were extracted using a structured form and reviewed by ≥2 authors. Whenever possible, we used the difference in LDL-C between treatment arms in a trial that was calculated using imputation for missing values as per the CTTC method.