A 12-Week Study to Assess the Efficacy Safety and Tolerability of Gemcabene in Subjects With Severe Hypertriglyceridemia

A 12-Week, Phase 2 Randomized, Double-Blind, Placebo-Controlled Study to Assess the Efficacy Safety and Tolerability of Gemcabene in Subjects with Severe Hypertriglyceridemia (INDIGO-1)


Eligibility Criteria:
Inclusion Criteria:

Subjects who meet all of the following criteria will be eligible to participate in the study:

1. Provision of written and signed informed consent (by subject or legal guardian) prior to any study-specific procedure;
2. Male or female (neither pregnant or lactating) ≥18 years of age at time of consent;

   1. Women of child-bearing potential must have a negative serum pregnancy test at the Screening Visit and negative urine dipstick on Study 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;
   2. 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.
3. Currently on a self-reported, stable, low-fat, low-cholesterol diet in combination with stable statins with or without ezetimibe (10 mg QD) for at least 12 weeks prior to the Screening Visit;
4. Mean fasting TG value ≥ 500 mg/dL to \< 1500 mg/dL (with the higher value no more than 50% greater than the lower value) from the S1 and S2 Visits (or alternatively S2 and S3);
5. Physical examination, including vital signs, that is within normal limits or clinically acceptable to the Investigator;
6. Weight ≥ 50 kg; with a body mass index (BMI) ≤ 45 kg/m²; and
7. Subjects with Type 2 diabetes who take anti-diabetes pharmacologic therapy must be on a stable a regimen for at least 3 months, with no planned changes in medications for the study duration.

Exclusion Criteria:

Subjects who meet any of the following criteria will be excluded from participation in the study:

1. Known and previously documented homozygous genetic deficiencies (LPL, ApoC-II, ApoC-III, ApoA-V, GPIHBP1, or LMF1);
2. History of pancreatitis within the last 6 months prior to screening (Visit S1);
3. History of bariatric surgery; symptomatic gallstone disease, unless treated with cholecystectomy;
4. Abnormal liver function test at the Pre-Screening Visit or any of the Screening Visits (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). Subjects 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;
5. Active liver disease (e.g., cirrhosis, alcoholic liver disease, hepatitis B \[HBV\], hepatitis C \[HCV\], autoimmune hepatitis, liver failure, liver cancer), history of liver transplant, known diagnosis of human immunodeficiency virus (HIV), or acquired immune deficiency virus;
6. Moderate to severe renal insufficiency defined as an estimated GFR \< 60 mL/min/1.73 m2 (calculated using The Chronic Kidney Disease Epidemiology Collaboration equation) at the Pre-Screening Visit or at any of the Screening Visits;
7. 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;
8. Uncontrolled thyroid disease: hyperthyroidism or hypothyroidism as defined by thyroid stimulating hormone (TSH) below the lower limit of normal or \> 1.5 × ULN, respectively, based on results from the Pre-Screening Visit or the Screening Visit. If controlled, treatment should be stable for at least 3 months prior to the Screening Visit;
9. Type 1 diabetes mellitus or uncontrolled type 2 diabetes mellitus HbA1c value ≥8.5% based on results from the Pre-Screening Visit or the Screening Visit), or any diabetic subject taking a thiazolidinedione (e.g., pioglitazone, rosiglitazone);
10. New York Heart Association Class III or IV heart failure (see Appendix C);
11. 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 (S1). Subjects with adequately treated stable angina, per Investigator assessment, may be included;
12. Uncontrolled cardiac arrhythmia or prolonged QT on the Screening Visit or Study 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;
13. Uncontrolled hypertension, defined as sitting systolic blood pressure ≥ 180 mmHg or diastolic blood pressure ≥ 110 mmHg, and confirmed by repeat measurement;
14. Currently receiving cancer treatment(s) or, in the Investigator's opinion, at risk of relapse for recent cancer;
15. Inadequate washout of a PCSK9 inhibitor (8 weeks prior to the Screening Visit S1), a fibrate lipid lowering agent (6 weeks prior to the Screening Visit S1), niacin \> 200 mg/day, OMG-3, bile acid sequestrants or other lipid lowering therapies (4 weeks prior to the Screening Visit S1);
16. Use of any excluded medications or supplements within 3 months prior to S1 (e.g., potent cytochrome P450 \[CYP\] 3A4 inhibitors, see Appendix D);
17. Hypersensitivity to or a history of significant adverse reactions to any fibrate lipid regulating agent;
18. History of drug or alcohol abuse within the past year or inability to comply with protocol requirements, including subject alcohol restrictions (see Section 5.6.3);
19. Previously treated with gemcabene (i.e., CI-1027); 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
20. Any other finding which, in the opinion of the Investigator, would compromise the subject's safety or participation in the study.