Efficacy and Safety of Gemcabene in Patients With Homozygous Familial Hypercholesterolemia on Stable, Lipid-Lowering Therapy (COBALT-1)
Condition: Hypercholesteremia
MeSH terms: Hyperlipoproteinemia Type II; Homozygous Familial Hypercholesterolemia; Hypercholesterolemia
Intervention: Gemcabene
Intervention description: 300 mg tablet orally once daily for four weeks followed by 600 mg tablet orally once daily for four weeks followed by 900 mg tablet orally once daily for four weeks.
Phase: Phase 2
Study type: Interventional
Primary purpose: Treatment
Intervention model: Single Group Assignment
Masking: None (Open Label)
Enrollment: 8.0
Sex: All
Minimum age: 17 Years
Healthy volunteers: No
Keywords: LDL-C; Lipid Regulator

Summary:

      The purpose of this study was to assess the efficacy, safety, and tolerability of multiple
      doses of Gemcabene in patients with HoFH on stable, lipid-lowering therapy.
    

Eligibility criteria:

        Inclusion Criteria:

          -  Provision of written and signed informed consent (by patient or legal guardian) prior
             to any study-specific procedure;

          -  Male or female ≥17 years of age at time of consent;

          -  Diagnosis of HoFH by genetic confirmation (including compound heterozygosity) or a
             clinical diagnosis based on either (1) a history of an untreated LDL-C concentration
             >500 mg/dL (12.92 mmol/L) together with either appearance of xanthoma before 10 years
             of age, or evidence of heterozygous familial hypercholesterolemia in both parents or,
             if history is unavailable, (2) LDL-C >300 mg/dL (7.76 mmol/L) on maximally tolerated
             lipid-lowering drug therapy;

          -  Currently on a stable, low-fat, low-cholesterol diet in combination with a
             pre-existing, regulatory-approved, not excluded lipid-lowering therapy (i.e., statins,
             monoclonal antibodies to PCSK9, cholesterol absorption inhibitors, bile acid
             sequestrants, or nicotinic acid, or any combination thereof) at a stable dose for at
             least 4 weeks prior to the Screening Visit;

          -  Fasting LDL-C value >130 mg/dL (3.36 mmol/L) at the Screening Visit;

          -  Physical examination, including vital signs, that is within normal limits or
             clinically acceptable to the Investigator;

          -  Weight ≥50 kg;

          -  Female patients must not be pregnant or lactating. Women of child-bearing potential
             must have a negative serum pregnancy test at the Screening Visit and negative urine
             dipstick on Day 1 prior to dosing in order to qualify for the study. Women who are
             surgically sterile or are clinically confirmed to be post-menopausal (i.e., documented
             amenorrhea for ≥1 year in the absence of other biological or physiological causes) are
             not considered to be of child-bearing potential; and

          -  Women of child-bearing potential must agree to use acceptable methods of contraception
             throughout the duration of the study and for 30 days after the last dose of study
             drug. For this study, double-barrier contraception is required.

        Exclusion Criteria:

          -  Other forms of primary hyperlipoproteinemia and secondary causes of
             hypercholesterolemia (e.g., nephrotic syndrome or hypothyroidism);

          -  Abnormal liver function test at the Screening Visit (aspartate aminotransferase or
             alanine aminotransferase >2 × the upper limit of normal [ULN]; total bilirubin >1.5 ×
             ULN; or alkaline phosphatase >2 × ULN based on appropriate age and gender normal
             values). Patients with bilirubin >1.5 × ULN and history of Gilbert's syndrome may be
             included; reflexive direct bilirubin testing will be used to confirm Gilbert's
             syndrome;

          -  Moderate (Grade B) or severe (Grade C) chronic hepatic impairment according to the
             Child Pugh classification;

          -  Active liver disease (e.g., cirrhosis, alcoholic liver disease, hepatitis B virus
             [HBV], hepatitis C virus [HCV], autoimmune hepatitis, liver failure, liver cancer),
             history of liver transplant, or known diagnosis of human immunodeficiency virus (HIV);

          -  Triglycerides value >400 mg/dL (4.52 mmol/L) at the Screening Visit;

          -  Moderate to severe renal insufficiency defined as an estimated GFR <30 mL/min/1.73m2
             (calculated using The Chronic Kidney Disease Epidemiology Collaboration equation) at
             the Screening Visit;

          -  Abnormal urinalysis (proteinuria greater than trace or any male or non-menstruating
             female with greater than trace hematuria), confirmed by reflexive urine
             protein:creatinine ratio testing;

          -  Uncontrolled thyroid disease: hyperthyroidism or hypothyroidism as defined by thyroid
             stimulating hormone (TSH) below the lower limit of normal or >1.5 × ULN, respectively,
             at the Screening Visit. If controlled, treatment should be stable for at least 3
             months prior to the Screening Visit;

          -  Type 1 diabetes mellitus or uncontrolled type 2 diabetes mellitus (hemoglobin A1c
             [HbA1c] value >8%), or any diabetic patient taking insulin and/or thiazolidinediones;

          -  New York Heart Association Class III or IV heart failure;

          -  Myocardial infarction, severe or unstable angina pectoris, coronary angioplasty,
             coronary artery bypass graft, or other major cardiovascular events resulting in
             hospitalization within 3 months of the Screening Visit. Patients with adequately
             treated stable angina, per Investigator assessment, may be included;

          -  Uncontrolled cardiac arrhythmia or prolonged QT on the Screening Visit or Day 1 prior
             to dosing ECG (QTcF >450 msec for men and >470 msec for women) or known family history
             of prolonged QT or unexplained sudden cardiac death;

          -  Uncontrolled hypertension, defined as sitting systolic blood pressure >180 mmHg or
             diastolic blood pressure >110 mmHg, and confirmed by repeat measurement;

          -  Currently receiving cancer treatments or, in the Investigator's opinion, at risk of
             relapse for recent cancer;

          -  Use of fibrate lipid-lowering agent 6 weeks prior to the Screening Visit;

          -  Hypersensitivity to or a history of significant adverse reactions to any fibrate lipid
             lowering agent;

          -  Use of apheresis (LDL or plasma) 8 weeks prior to the Screening Visit;

          -  Use of lomitapide 2 months prior to the Screening Visit;

          -  Use of mipomersen 5 months prior to the Screening Visit;

          -  Use of any excluded medications or supplements (e.g., potent cytochrome P450 [CYP] 3A4
             inhibitors);

          -  History of drug or alcohol abuse within the past year or inability to comply with
             protocol requirements, including subject restrictions;

          -  Previously treated with gemcabene;

          -  Participation in another clinical study of an investigational agent or device
             concurrently or within 1 month prior to the Screening Visit, or use of an
             investigational agent within 1 month or 5 half-lives (if known), whichever is longer,
             prior to the Screening Visit; or

          -  Any other finding which, in the opinion of the Investigator, would compromise the
             patient's safety or participation in the study.