severe high fats (triglycerides) levels severe hypertriglyceridemia
Conditions
Interventions
Olezarsen (ISIS 678354, an antisense oligonucleotide inhibitor of
Apolipoprotein C-III production) or placebo will be administered as
subcutaneous (SC) injections. Doses of 50 and 80 mg olezarsen ad
Sponsors
Ionis Pharmaceuticals, Inc.
Eligibility
Age
18 Years to 99 Years
Inclusion criteria
Inclusion criteria: 1. Must have given written informed consent (signed and dated) and any authorizations required by local law and be able to comply with all study requirements 2. Aged >= 18 years at the time of informed consent 3. Fasting Triglycerides (TG) >= 500 mg/dL (5.65 mmol/L) at both the Run-in period and the Qualification Period as follows: a. Fasting TG >= 500 mg/dL (5.65 mmol/L) at Screening run-in visit. If the fasting TG is = 350 mg/dL (3.95 mmol/L) up to 2 additional tests may be performed with the average of the tests used to be considered eligible b. Fasting TG >= 500 mg/dL (5.65 mmol/L) at Screening Qualification visit. If the fasting TG is = 350 mg/dL (3.95 mmol/L) up to 2 additional tests may be performed with the average of the tests used for qualification 4. Patients must be on lipid-lowering therapy that should adhere to standard of care (SOC) per local guidelines. Lipid-lowering medications should be optimized and stabilized for at least 4 weeks prior to Screening to minimize changes in these medications during the study. Patients taking over-the-counter (OTC) omega-3 fatty acids should make every effort to remain on the same brand through the end of the study 5. Satisfy the following: a. Females: must be non-pregnant and non-lactating and either: a. surgically sterile (e.g., tubal occlusion, hysterectomy, bilateral salpingectomy, bilateral oophorectomy) b. post-menopausal (defined as 12 months of spontaneous amenorrhea in females > 55 years of age or, in females
Exclusion criteria
Exclusion criteria: 1. Diabetes mellitus with any of the following: a. Newly diagnosed within 12 weeks prior to Screening or during the screening period b. HbA1c >= 9.5% at Screening c. Change in basal insulin regimen > 20% within 3 months prior to Screening or during the Screening period. d. For patients with type 1 diabetes: episode of diabetic ketoacidosis, or >= 3 episodes of severe hypoglycemia within the 6 months prior to Screening or during the Screening period. 2. Acute coronary syndrome or stroke/TIA within 6 months prior to Screening or during the screening period. Major surgery, peripheral revascularization, or non-urgent percutaneous coronary intervention within 3 months prior to, or during Screening, or upcoming planned major surgery or major procedure (e.g., arterial revascularization) during the course of the study 3. Active pancreatitis within 4 weeks prior to Screening or during the screening period. 4. Screening laboratory results as follows, or any other clinically significant abnormalities in screening laboratory values that would render a patient unsuitable for inclusion: a. Alanine aminotransferase (ALT) or aspartate aminotransferase (AST) > 3.0 × ULN b. Total bilirubin > 1.5 ULN unless due to Gilbert*s syndrome c. Estimated GFR (eGFR) = 500 mg/g (56.5 mg/mmol) 5. Uncontrolled arterial hypertension (BP > 180/ /100 mmHg) despite antihypertensive therapy 6. Uncontrolled hypothyroidism such as those with thyroid-stimulating hormone (TSH) > 1.5 × ULN and free thyroxine (T4) = 4 weeks prior to, or during Screening 7. Active infection requiring systemic antiviral or antimicrobial therapy that will not be completed prior to Study Day 1 or active Covid-19 infection with or without therapy that will not be resolved by Study Day 1 8. Active infection with human immunodeficiency virus (HIV), hepatitis C or hepatitis B diagnosed by initial serological testing and confirmed with RNA testing (HIV, Hepatitis C), or positive HBsAg (hepatitis B), respectively, or treatment for hepatitis C within 6 months prior to Screening. Patients at Screening who test positive by serology (for example, positive for Hepatitis C antibody), but negative by RNA may be allowed in consultation with the Sponsor Medical Monitor or designee 9. Malignancy diagnosed or treated within 5 years prior to Screening or during the Screening period, except for non-melanoma skin cancers, cervical in situ carcinoma, breast ductal carcinoma in situ, or stage 1 prostate carcinoma that has been successfully treated. Patients with a history of other malignancies that have been treated with curative intent and which have no recurrence within 5 years may also be eligible if approved by the Sponsor Medical Monitor or designee 10. A diagnosis of FCS (type 1 Hyperlipoproteinemia) by documentation of confirmed homozygote, compound heterozygote or double heterozygote for loss-of-function mutations in type 1-causing genes (such as LPL, GPIHBP1, APOA5, APOC2, GPD1, or LMF1). Patients with suspected FCS and no prior such diagnosis should be genetically tested pr
Design outcomes
Secondary
| Measure | Time frame |
|---|---|
| Secondary endpoints include the following: • Percent change in fasting TG from Baseline at Month 12 (average of Week 51 and Week 53) compared to placebo • Proportion of patients who achieve fasting TG = 880 mg/dL • Proportion of patients who achieve fasting TG = 1000 mg • Percent change from Baseline at Month 6 and at Month 12 compared to placebo in fasting: o apoC-III o VLDL-C o Non-HDL-C o HDL-C • Adjudicated acute pancreatitis event rate during the Treatment Period compared to placebo in patients with >= 2 events of adjudicated acute pancreatitis in 5 years prior to enrollment. This endpoint will be evaluated in the combined data from this study and ISIS 678354-CS6 (another Phase 3 study in patients with severe hypertriglyceridemia) as the individual studies may not have sufficient sample size to support meaningful conclusions. • Adjudicated acute pancreatitis event rate from Week 13 to Week 53 compared to placebo in patients with >= 2 events of adjudicated acute pancreatitis in 5 years prior to enrollment. This endpoint will be evaluated in the combined data from this study and ISIS 678354-CS6 for the same reason as above • Adjudicated acute pancreatitis event rate during the Treatment Period compared to placebo. This endpoint will be evaluated in the combined data from this study and ISIS 678354-CS6 for the same reason as above. • Adjudicated acute pancreatitis event rate from Week 13 to Week 53 compared to placebo. This endpoint will be evaluated in the combined data from this study and ISIS 678354-CS6 for the same reason as above Additional/Exploratory endpoints: Change or percent change from Baseline compared to placebo in the following: • Proportion of patients who achieve various % reductions in fasting TG from Baseline at Month 6 and proportion of patients who achieve various % reductions in fasting TG from Baseline at Month 12 compared to placebo • Proportion of patients who achieve various thresholds in fasting TG at Mont | — |
Primary
| Measure | Time frame |
|---|---|
| The primary endpoint is the percent change in fasting triglycerides (TG) from Baseline at month 6 (average of Weeks 25 and 27) compared to placebo | — |
Countries
Netherlands
Outcome results
None listed