A study comparing several dose levels of LY3015014 in patients with high cholesterol studying the safety and ability of LY3015014 to reduce cholesterol

• Register: EUCTR
• Last refreshed on: 5 August 2014
• Main ID: EUCTR2013-000622-55-PL
• Date of registration: 09/07/2013
• Prospective Registration: Yes
• Primary sponsor: Eli Lilly and Company
• Public title: A study comparing several dose levels of LY3015014 in patients with high cholesterol studying the safety and ability of LY3015014 to reduce cholesterol
• Scientific title: A Phase 2 Efficacy and Safety Dose-Ranging Study of LY3015014 in Patients with Primary Hypercholesterolemia
• Date of first enrolment: 23/08/2013
• Target sample size: 528
• Recruitment status: Not Recruiting
• URL: https://www.clinicaltrialsregister.eu/ctr-search/search?query=eudract_number:2013-000622-55
• Study type: Interventional clinical trial of medicinal product
• Study design: Controlled: yes Randomised: yes Open: no Single blind: no Double blind: yes Parallel group: yes Cross over: no Other: no If controlled, specify comparator, Other Medicinial Product: no Placebo: yes Other: no Number of treatment arms in the trial: 6

Countries of recruitment

Canada, Czech Republic, Denmark, Japan, Netherlands, Poland, United States

Contacts

• Name: Clinical Trial Information
• Affiliation: Eli Lilly

• Name: Clinical Trial Information
• Affiliation: Eli Lilly

Key inclusion & exclusion criteria

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.
Are the trial subjects under 18? no
Number of subjects for this age range:
F.1.2 Adults (18-64 years) yes
F.1.2.1 Number of subjects for this age range 317
F.1.3 Elderly (>=65 years) yes
F.1.3.1 Number of subjects for this age range 211

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 stati

Age minimum:
Age maximum:
Gender:
Female: yes
Male: yes

Health Condition(s) or Problem(s) studied

Therapeutic area: Diseases [C] - Cardiovascular Diseases [C14]

Primary hypercholesterolaemia
MedDRA version: 14.1 Level: PT Classification code 10020603 Term: Hypercholesterolaemia System Organ Class: 10027433 - Metabolism and nutrition disorders

Intervention(s)

Product Name: LY3015014
Pharmaceutical Form: Lyophilisate for solution for injection
INN or Proposed INN: Not available
Current Sponsor code: LY3015014
Other descriptive name: LY3015014
Concentration unit: mg milligram(s)
Concentration type: equal
Concentration number: 75-
Pharmaceutical form of the placebo: Solution for injection
Route of administration of the placebo: Subcutaneous use

Primary Outcome(s)

Main Objective: 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.

Primary end point(s): Low-density lipoprotein cholesterol (LDL-C) by beta quantification will be measured

Timepoint(s) of evaluation of this end point: Baseline and end of 16 weeks of treatment

Secondary Objective: • 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

Secondary Outcome(s)

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

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.

Secondary ID(s)

2013-000622-55-CZ

I5S-MC-EFJE