Alirocumab in Patients on a Stable Dialysis Regimen

12-week study of the efficacy and safety of alirocumab in patients maintained stably on hemodialysis or peritoneal dialysis. Measures of cholesterol levels, drug levels, PCSK9 levels, routine chemistry and cell counts, and biomarkers will be obtained at baseline and at weeks 4, 8, 10 and 12 weeks. Safety events will be obtained throughout the study.

Primary objective: The objective of this trial is to demonstrate the efficacy of alirocumab 150 mg every 2 weeks over 12 weeks on cholesterol levels.

Secondary objective: To assess the safety of treating chronic dialysis patients with alirocumab 150 mg subcutaneously every 2 weeks for 12 weeks.

Secondary objective: To demonstrate the efficacy of alirocumab 150 mg every 2 weeks over 12 weeks on biomarkers.

Exploratory objective: To assess alirocumab drug levels in subjects maintained on hemodialysis and peritoneal dialysis.

Methodology: Open-label, nonrandomized study

Number of patients Ten patients maintained on stable hemodialysis for a minimum of 3 months and ten patients maintained on stable peritoneal dialysis for a minimum of 3 months

Test product: alirocumab 150 mg

Mode of administration: administered subcutaneously

Dosing interval: every 2 weeks

Duration of treatment: 12 weeks

Primary endpoint: Levels of LDL-cholesterol at 12 weeks

Secondary endpoints: Levels of total cholesterol, triglycerides, apoprotein B, Cystatin-C, fibrinogen, hsCRP, IL-6, NGAL, NT-proBNP, soluble CD40 ligand, troponin T, VCAM

Safety criteria: Adverse events, Incidence and intensity of AE, including serious AE (SAE), Withdrawal from study medication due to AE, Clinical relevant new findings or worsening of existing conditions physical examination, Clinically relevant changes in laboratory measurements from baseline

Eligibility Criteria:
Inclusion Criteria:

1. Male or female patients, ages 18 to 80 years.
2. Written informed consent will be obtained before any study assessment is performed.
3. Diagnosis of end-stage renal disease, maintained on dialysis, without dialysis complications, for at least 3 months.
4. Patients may or may not have a diagnosis of atherosclerotic disease, such as a history of myocardial infarction (MI), cardiac percutaneous coronary intervention (PCI), coronary artery bypass (CABG) surgery, atherosclerotic transient ischemic attack (TIA) or cerebrovascular attack (CVA), or peripheral arterial disease (PAD).
5. A total of 20 patients will be enrolled, 10 patients on hemodialysis and 10 patients on peritoneal dialysis.

Exclusion Criteria:

1. LDL-cholesterol level of \< 70 mg/dL.
2. Any contraindication to subcutaneous injections.
3. Patients on statin and/or ezetimibe therapy will have their cholesterol-lowering therapy continued as is without change during the time of the study.
4. History of any allergy or intolerance to the study drug or drugs of the same class.
5. A history of MI, PCI, CABG surgery, TIA, CVA, or PAD events within 3 months of enrollment.
6. History of malignant cancer within the past 3 years, excepting basal cell skin cancer or cervical cancer in situ.
7. Women of child-bearing potential, defined as all women physiologically capable of becoming pregnant, unless they are using highly effective methods of contraception during dosing of the drug and for 2 weeks after the last injection of the drug. Highly effective methods of contraception include:

   1. Total abstinence (when this is in line with the preferred and usual lifestyle of the patient). Periodic abstinence (e.g., calendar, ovulation, symptothermal, post-ovulation methods) and withdrawal are not acceptable methods of contraception.
   2. Female sterilization (have had surgical bilateral oophorectomy with or without hysterectomy) or tubal ligation at least 6 weeks before taking study treatment. In case of oophorectomy alone, only when the reproductive status of the woman has been confirmed by follow-up hormone level assessment.
   3. Male sterilization (at least 6 months prior to enrollment). For female patients in the study, the vasectomized male partner should be the sole partner for that patient.
   4. Use of oral (estrogen and/or progesterone), injected, or implanted hormonal methods of contraception or placement of an intrauterine device or intrauterine system or other forms of hormonal contraception that have comparable efficacy (failure rate \< 1%), for example hormone vaginal ring or transdermal hormone contraception.
   5. In case of use of oral contraception, women should have been stable on the same pill for a minimum of 3 months before taking study treatment.
   6. Women are considered post-menopausal and not of child-bearing potential if they have had 12 months of natural amenorrhea with an appropriate clinical profile (e.g. age appropriate, history of vasomotor symptoms) or have had surgical bilateral oophorectomy (with or without hysterectomy) or tubal ligation at least six weeks before enrollment.
8. Pregnant or lactating women.
9. Any surgical or medical condition which might significantly alter the absorption, distribution, metabolism, or extraction of study drug, at investigator's discretion.
10. History or evidence of drug or alcohol abuse within the last 12 months.
11. Patients considered unsuitable for the study, including patients with psychiatric, behavioral or cognitive disorders, sufficient to interfere with the patient's ability to understand and comply with the protocol instructions or follow-up procedures.