Safety, Tolerability, and Effect of Alirocumab in High Cardiovascular Risk Patients With Severe Hypercholesterolemia Not Adequately Controlled With Conventional Lipid-modifying Therapies (ODYSSEY APPRISE)
Condition: Hypercholesterolemia
MeSH terms: Hypercholesterolemia
Intervention: ALIROCUMAB SAR236553 (REGN727); placebo (for injection training only); ezetimibe; atorvastatin; rosuvastatin; simvastatin
Intervention description: Pharmaceutical form:solution Route of administration: subcutaneous; Pharmaceutical form:solution Route of administration: subcutaneous; Pharmaceutical form:capsule Route of administration: oral; Pharmaceutical form:tablet Route of administration: oral; Pharmaceutical form:tablet Route of administration: oral; Pharmaceutical form:tablet Route of administration: oral
Intervention MeSH terms: Atorvastatin; Rosuvastatin Calcium; Simvastatin; Ezetimibe; Alirocumab
Phase: Phase 3
Study type: Interventional
Primary purpose: Treatment
Intervention model: Single Group Assignment
Masking: None (Open Label)
Enrollment: 998.0
Sex: All
Minimum age: 18 Years
Healthy volunteers: No

Summary:

      Primary Objective:

      To provide participants with severe hypercholesterolemia at risk for subsequent
      cardiovascular (CV) events and not adequately controlled with currently available
      lipid-modifying therapy (LMT) access to alirocumab ahead of commercial availability and to
      document the overall safety and tolerability of alirocumab in this participant population.

      Secondary Objectives:

      To document the effect of alirocumab on low-density lipoprotein cholesterol (LDL-C) levels as
      well as non-high-density lipoprotein cholesterol (non-HDL-C), total cholesterol (total-C),
      high-density lipoprotein cholesterol (HDL-C), and triglyceride (TG) levels after 12 weeks of
      treatment.

      To document participant's acceptability of self-injection (Self Injection Assessment
      Questionnaire, SIAQ).
    

Eligibility criteria:

        Inclusion criteria:

        Either A, B, C, D, or E below and not adequately controlled with a maximally tolerated dose
        of statin with or without other LMTs, all at stable doses for at least 4 weeks prior to the
        screening visit (Week-3):

        A. Participants suffering from heterozygous familial hypercholesterolemia (heFH) with LDL-C
        concentrations greater than or equal to (>=)160 mg/dL (4.14 millimoles per liter [mmol/L])
        despite treatment.

        B. Participants suffering from heFH with LDL-C concentrations >=130 mg/dL (3.36 mmol/L)
        despite treatment and two or more CV risk factors among this list:

          -  LDL-C greater than (>) 250 milligrams per deciliter (mg/dL) (6.46 mmol/L) at the time
             of the familial hypercholesterolemia (FH) diagnosis (before treatment).

          -  Family history of premature-onset coronary heart disease (CHD; first-degree male
             relative with onset before age 55 years; first-degree female relative with onset
             before age 65 years).

          -  Metabolic syndrome.

          -  HDL-C less than (<) 40 mg/dL (1.03 mmol/L).

          -  Hypertension (blood pressure >140/90 mmHg or drug treatment).

          -  Lipoprotein a (Lp[a]) >=50 mg/dL (1.78 µmol/L).

          -  Tendon xanthoma.

        C. Participants suffering from heFH with LDL-C concentrations >=130 mg/dL (3.36 mmol/L)
        despite treatment and one of the following characteristics:

          -  Established CHD or other cardiovascular disease (CVD; history of acute myocardial
             infarction, ischemic stroke, peripheral arterial disease, coronary or peripheral
             arterial revascularization, stable or unstable angina, transient ischemic attack,
             carotid artery stenosis >=50 percent (%), or aortic abdominal aneurysm).

          -  Drug-treated type 2 diabetes mellitus or type 1 with target organ damage.

          -  Family history of first- or second-degree relative with very premature onset CHD
             (first- or second-degree male relative with onset before age 45; first- or
             second-degree female relative with onset before age 55).

        D. Non-FH participants suffering from established CHD or other CVD (history of acute
        myocardial infarction (MI), ischemic stroke, peripheral arterial disease, coronary or
        peripheral arterial revascularization, stable or unstable angina, transient ischemic
        attack, carotid artery stenosis >=50%, or aortic abdominal aneurysm) and with LDL-C
        concentrations >=130 mg/dL (3.36 mmol/L).

        E. Participants suffering from progressive CVD (coronary artery disease, or peripheral
        arterial occlusive disease or cerebrovascular disease as documented clinically or by
        imaging techniques, with a subsequent CV event [acute MI, ischemic stroke, ischemia-driven
        revascularization, unstable angina, transient ischemic attack] occurring despite stable
        doses of maximally tolerated LMT) with LDL-C concentrations >=100 mg/dL (2.59 mmol/L).

        Exclusion criteria:

        Not on a stable dose of LMT (including statin) for at least 4 weeks prior to the screening
        visit (Week -3) and from screening to enrollment.

        Use of a fibrate other than fenofibrate within 4 weeks of the screening visit (Week-3) or
        between screening and enrollment.

        Daily doses above atorvastatin 80 mg, rosuvastatin 40 mg, or simvastatin 40 mg (except for
        participants on simvastatin 80 mg for more than one year, who were eligible).

        Use of statin other than simvastatin, atorvastatin, or rosuvastatin prior to the screening
        visit (Week-3) or between screening and enrollment, except when there was a documented
        reason for intolerance to the above mentioned potent statins (in which case the use of a
        different statin was allowed).

        Fasting serum TG >400 mg/dL (>4.52 mmol/L) at the screening visit (Week -3). Uncontrolled
        hypertension (>180 mmHg systolic and/or >110 mmHg diastolic at randomization visit).

        New York Heart Association Class III or IV congestive heart failure persisting despite
        treatment.

        History of hemorrhagic stroke. Liver transaminases >3 times the upper limit of normal.
        Laboratory evidence of current hepatitis B or C infection. Creatine kinase >3 times the
        upper limit of normal. Estimated glomerular filtration rate <30 mL/min/1.73 m^2. Pregnant
        or breastfeeding woman or with childbearing potential without appropriate contraception.

        Male participant with a female partner of childbearing potential not protected by a
        highly-effective method(s) of birth control.

        Participants eligible for enrollment into an ongoing clinical study of alirocumab conducted
        at the same investigational site.

        Hypersensitivity to alirocumab or any of the excipients.

        The above information was not intended to contain all considerations relevant to a
        participant's potential participation in a clinical trial.