E.1 Medical condition or disease under investigation |
E.1.1 | Medical condition(s) being investigated |
Primary hypercholesterolaemia |
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E.1.1.1 | Medical condition in easily understood language |
High blood cholesterol levels not caused by other illness, disease, or condition |
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E.1.1.2 | Therapeutic area | Diseases [C] - Cardiovascular Diseases [C14] |
MedDRA Classification |
E.1.2 Medical condition or disease under investigation |
E.1.2 | Version | 14.1 |
E.1.2 | Level | PT |
E.1.2 | Classification code | 10020603 |
E.1.2 | Term | Hypercholesterolaemia |
E.1.2 | System Organ Class | 10027433 - Metabolism and nutrition disorders |
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E.1.3 | Condition being studied is a rare disease | No |
E.2 Objective of the trial |
E.2.1 | Main objective of the trial |
The primary objective of this study is to assess the mean percentage change from baseline to week 16 in low-density lipoprotein cholesterol (LDL-C) measured using beta quantification with LY3015014 compared with placebo, in patients with primary hypercholesterolemia, when added to statin and diet (or diet alone in statin-intolerant patients) with or without ezetimibe. |
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E.2.2 | Secondary objectives of the trial |
• To assess the absolute change in LDL-C measured using beta quantification from baseline to week 16 with LY3015014 compared with placebo
• To assess the dose-response, exposure-response and time-response relationships for LDL-C over a 16-week time course for LY3015014
• To assess the proportion of patients achieving an LDL-C level lower than 100 mg/dL (2.6 mmol/L) and lower than 70 mg/dL (1.8 mmol/L) for LY3015014 compared with placebo
• To assess effects of LY3015014 in subgroups based on disease classification, region, diabetes status, statin dose, ezetimibe use, baseline LDL-C and PCSK9 levels, and prior exposure to PCSK9 antibodies on change in LDL-C
• To assess other PD markers
• To characterize the pharmacokinetic (PK) profile of LY3015014
• To assess the safety and tolerability of LY3015014, including muscle, hepatic and cardiovascular safety |
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E.2.3 | Trial contains a sub-study | Yes |
E.2.3.1 | Full title, date and version of each sub-study and their related objectives |
I5S-MC-EFJE(1) - pharmacokinetic/pharmacodynamic substudy, 05Mar2013. The objectives of this substudy are to collect additional PK, LDL-C, and other PD data to better understand the LY3015014 exposure/response relationship and to assess the effect of concomitant statin treatment on the LY3015014 PK/PD profile. |
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E.3 | Principal inclusion criteria |
[1] Men or women greater than or equal to 18 years of age and less than or equal to 80 years of age
[2] Diagnosed with primary hypercholesterolemia (HC) defined as LDL ≥100 mg/dL (2.6 mmol/L) and TG ≤450 mg/dL (5.1 mmol/L)
o A subset of patients (~ 20%) with an LDL-C ≥80 mg/dL to <100 mg/dL (≥2.1 mmol/L to <2. 6 mmol/L) will also be allowed.
o Includes at least ~20% heterozygous familial hypercholesterolemia (HeFH) and polygenic (non-familial) HC patients.
[3] Are on a stable diet and stable daily dose of atorvastatin, simvastatin, rosuvastatin, pravastatin, lovastatin, fluvastatin, or pitavastatin for at least 6 weeks and further adjustments of statin dose are not deemed clinically indicated by the investigator, or up to ~20% of patients with history of statin intolerance (i.e. patients who cannot tolerate any dose of at least 1 statin) who are not on statin treatment for at least 6 weeks, with or without a stable dose of ezetimibe for at least 6 weeks.
[4] Male patients with partner of childbearing potential: agree to use barrier protection during sexual intercourse during the study and for 3 months following the administration of the last dose of investigational product.
[5] Female patients including:
• Women not of child bearing potential due to surgical sterilization (hysterectomy or bilateral oophorectomy or tubal ligation) or menopause. Women with an intact uterus are deemed postmenopausal if they have a cessation of menses for at least 1 year (or 6 to 12 months of spontaneous amenorrhea with follicle stimulating hormone >40 mIU/mL (>40 IU/L); not taking hormones or oral contraceptives within 1 year.
• Women of child bearing potential who have a negative urine or serum pregnancy test, are not breast feeding, and agree to use a reliable method of birth control up to at least 3 months following the last dose of study drug, where reliable is defined as birth control that results in a low failure rate (i.e., <1% per year) when used consistently and correctly.
[6] Have given informed consent to participate in the study. |
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E.4 | Principal exclusion criteria |
[1] Have secondary HC or homozygous familial HC.
[2] Have had myocardial infarction (MI), unstable angina (UA), percutaneous coronary intervention, coronary artery bypass graft, stroke, or deep vein thrombosis/pulmonary embolism within 3 months of screening, or have planned cardiovascular surgery or percutaneous coronary intervention.
[3] Have symptoms consistent with moderate or severe heart failure or are receiving treatment for symptomatic congestive heart failure (CHF) or known left ventricular ejection fraction (LVEF) <30%.
[4] Uncontrolled hypertension characterized by a systolic blood pressure >160 mmHg or
diastolic blood pressure >100 mmHg.
[5] Have diabetes mellitus (type 1 or 2) that requires or is likely to require any injectable glucose lowering therapy (including insulins) during the course of the study or have
hemoglobin A1c (HbA1c) ≥8.5%.
[6] Have thyroid-stimulating hormone (TSH) levels outside normal reference range for the central laboratory. Patients who are clinically euthyroid and on stable thyroid replacement therapy for at least 2 months prior to screening and who are anticipated to remain on this dose throughout the trial period are acceptable exceptions to this criterion.
[7] Have a history of adrenal insufficiency, Cushing's syndrome, or other adrenal gland disorder.
[8] Have a history of vitamin E deficiency or fat malabsorption syndrome.
[9] Have a serum creatinine ≥176.8 µM/L, nephrotic syndrome, or end stage renal disease and use renal replacement therapy such as hemodialysis or peritoneal dialysis
[10] Have active hepatobiliary disease, serologic evidence of past or active hepatitis B or C, or past or active gallbladder disease.
[11] Have aspartate aminotransferase (AST), alanine aminotransferase (ALT), alkaline phosphatase (ALP), or total bilirubin >2X ULN.
[12] Have a history or presence of a chronic muscular or neuromuscular disease including prior rhabdomyolysis or drug-induced myopathy or an unexplained/documented elevation in creatine kinase (CK) >3X ULN.
[13]Have hemoglobin <10 g/dL (6.2 mmol/L) in women and <11 g/dL (6.83 mmol/L) in men.
[14] Have a history of allergy, hypersensitivity or intolerance to drug preparations containing LY3015014, other PCSK9 antibodies, other monoclonal antibodies or any components of the formulation.
[15] Have a history of human immunodeficiency virus infection (HIV) infection, positive human HIV antibodies or other immune deficiency disorder.
[16] Have planned or are likely to require major surgery requiring anesthesia or hospitalization during the course of the study.
[17] Have chronic alcohol or drug abuse or dependency.
[18] Are currently under suspicion of having any cancer or malignancy or have had a history of cancer in the past 2 years, with the exception of non-melanoma skin cancers, cervical cancer in situ, breast ductal carcinoma in situ or stage 1 prostate cancer.
[19] Have an active serious infection.
[20] Have a history or presence of cardiovascular, respiratory, endocrine, gastrointestinal, hematological, autoimmune, metabolic, neurological, or neuropsychiatric disorders or any other serious and/or unstable illness that, in the opinion of the investigator, could constitute a risk when taking investigational product or could interfere with the interpretation of data.
[21] Have started or stopped taking a statin or ezetimibe medication, or changed statin dose regimen within 6 weeks of randomization.
[22] Are on a statin regimen other than daily dosing (for example, an every-other-day statin regimen).
[23] Have used or are likely to require, any lipid-regulating medication (with the exception of atorvastatin, simvastatin, rosuvastatin, pravastatin, lovastatin, fluvastatin, pitavastatin, or ezetimibe)
[24] Have undergone LDL apheresis within 12 months before screening
[25] Have used within 3 months prior to screening, plan to use, or are likely to require during the course of the study systemic corticosteroids, cyclosporine, isoretinoin or anabolic agents other than stable doses of estrogen, estrogen/progestin or testosterone replacement therapy.
[26] Have used any immunosuppressive therapy within 2 months prior to screening or are likely to require immunosuppressive therapy during the course of the study.
[27] Have received treatment with biologic agents (such as monoclonal antibodies) within 3 months or 5 half-lives (whichever is longer) prior to dosing
[28] Are currently using or will require during the course of the study any subcutaneously injectable medication, with the exception of single injections, for example flu vaccines.
[29] Are currently adhering to, have used within 2 months prior to screening, or have plans to adopt diets with aggressive carbohydrate restrictions for weight loss. Currently use, have used within 2 months prior to screening, or plan to use during the trial period prescriptions or OTC formulations intended for weight loss. |
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E.5 End points |
E.5.1 | Primary end point(s) |
Low-density lipoprotein cholesterol (LDL-C) by beta quantification will be measured |
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E.5.1.1 | Timepoint(s) of evaluation of this end point |
Baseline and end of 16 weeks of treatment |
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E.5.2 | Secondary end point(s) |
• Lipid and apolipoprotein panel: including TG, TC, HDL C, LDL-C (calculated), apolipoprotein A-1 (Apo A-1) and apolipoprotein B (Apo B), lipoprotein(a) (Lp[a])
• Serum total PCSK9 and free PCSK9
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E.5.2.1 | Timepoint(s) of evaluation of this end point |
At baseline and at various visits occurring every 2 weeks during the 16 week treatment period, and during the follow up period occurring every 4 weeks for a total of 8 weeks. |
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E.6 and E.7 Scope of the trial |
E.6 | Scope of the trial |
E.6.1 | Diagnosis | No |
E.6.2 | Prophylaxis | No |
E.6.3 | Therapy | Yes |
E.6.4 | Safety | Yes |
E.6.5 | Efficacy | Yes |
E.6.6 | Pharmacokinetic | Yes |
E.6.7 | Pharmacodynamic | Yes |
E.6.8 | Bioequivalence | No |
E.6.9 | Dose response | Yes |
E.6.10 | Pharmacogenetic | Yes |
E.6.11 | Pharmacogenomic | No |
E.6.12 | Pharmacoeconomic | No |
E.6.13 | Others | No |
E.7 | Trial type and phase |
E.7.1 | Human pharmacology (Phase I) | No |
E.7.1.1 | First administration to humans | No |
E.7.1.2 | Bioequivalence study | No |
E.7.1.3 | Other | No |
E.7.1.3.1 | Other trial type description | |
E.7.2 | Therapeutic exploratory (Phase II) | Yes |
E.7.3 | Therapeutic confirmatory (Phase III) | No |
E.7.4 | Therapeutic use (Phase IV) | No |
E.8 Design of the trial |
E.8.1 | Controlled | Yes |
E.8.1.1 | Randomised | Yes |
E.8.1.2 | Open | No |
E.8.1.3 | Single blind | No |
E.8.1.4 | Double blind | Yes |
E.8.1.5 | Parallel group | Yes |
E.8.1.6 | Cross over | No |
E.8.1.7 | Other | No |
E.8.2 | Comparator of controlled trial |
E.8.2.1 | Other medicinal product(s) | No |
E.8.2.2 | Placebo | Yes |
E.8.2.3 | Other | No |
E.8.2.4 | Number of treatment arms in the trial | 6 |
E.8.3 |
The trial involves single site in the Member State concerned
| No |
E.8.4 | The trial involves multiple sites in the Member State concerned | Yes |
E.8.4.1 | Number of sites anticipated in Member State concerned | 8 |
E.8.5 | The trial involves multiple Member States | Yes |
E.8.5.1 | Number of sites anticipated in the EEA | 27 |
E.8.6 Trial involving sites outside the EEA |
E.8.6.1 | Trial being conducted both within and outside the EEA | Yes |
E.8.6.2 | Trial being conducted completely outside of the EEA | No |
E.8.6.3 | If E.8.6.1 or E.8.6.2 are Yes, specify the regions in which trial sites are planned |
Canada |
Czech Republic |
Denmark |
Japan |
Netherlands |
Poland |
United States |
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E.8.7 | Trial has a data monitoring committee | Yes |
E.8.8 |
Definition of the end of the trial and justification where it is not the last
visit of the last subject undergoing the trial
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E.8.9 Initial estimate of the duration of the trial |
E.8.9.1 | In the Member State concerned years | 0 |
E.8.9.1 | In the Member State concerned months | 10 |
E.8.9.1 | In the Member State concerned days | 0 |
E.8.9.2 | In all countries concerned by the trial years | 1 |
E.8.9.2 | In all countries concerned by the trial months | 4 |
E.8.9.2 | In all countries concerned by the trial days | 0 |