Severe Hypertriglyceridemia
Conditions
Brief summary
This Phase 3 study will evaluate the safety and efficacy of plozasiran injection (ARO-APOC3) in adult participants with severe hypertriglyceridemia (SHTG). After providing informed consent eligible participants will be randomized to receive 4 doses (once every 3 months) of plozasiran or placebo, and be evaluated for efficacy and safety. After Month 12, eligible participants will be offered an opportunity to continue in an optional open-label extension under a separate protocol.
Interventions
ARO-APOC3 Injection
DRUGPlacebo
sterile normal saline (0.9% NaCl)
Sponsors
Arrowhead Pharmaceuticals
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
QUADRUPLE (Subject, Caregiver, Investigator, Outcomes Assessor)
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
* Established diagnosis of severe hypertriglyceridemia (SHTG) and prior documented evidence (medical history) of fasting TG levels of ≥500 mg/dL (≥5.65 mmol/L) * Mean fasting TG level ≥500 mg/dL (≥5.65 mmol/L) collected at 2 separate and consecutive visits at least 7 days apart and no more than 17 days apart during the screening period * Fasting low density lipoprotein-cholesterol (LDL-C) ≤130 mg/dL (≤3.37 mmol/L) at screening * Screening HbA1C ≤9.0% * Must be on standard of care lipid-lowering medications per local guidelines (unless documented as intolerant as determined by the Investigator, including an inability to safely administer or re-administer a specific drug because of fear, preference, genetic, clinical, or metabolic considerations, or due to a previous adverse reaction associated with, attributed to, or caused by specific drug)
Exclusion criteria
* Use of any hepatocyte-targeted small interfering ribonucleic acid (siRNA) that targets lipids and/or triglycerides within 365 days before Day 1 (except inclisiran, which is permitted). Administration of investigational drug and inclisiran must be separated by at least 4 weeks * Use of any other hepatocyte-targeted siRNA or antisense oligonucleotide molecule within 60 days or within 5-half-lives before Day 1 based on plasma pharmacokinetics (PK), whichever is longer (except inclisiran, which is permitted) * Known diagnosis of familial chylomicronemia syndrome (FCS) (type 1 Hyperlipoproteinemia) by documentation of confirmed homozygote or double heterozygote for loss-of-function mutations in type 1- causing genes * Body mass index \>45kg/m\^2 Note: Additional Inclusion/
Design outcomes
Primary
| Measure | Time frame |
|---|---|
| Percent change in fasting serum TG levels from baseline to Month 12 compared to placebo | Baseline, Month 12 |
Secondary
| Measure | Time frame |
|---|---|
| Percent Change in Fasting Serum TG Levels from Baseline to Month 10 Compared to Placebo | Baseline, Month 10 |
| Proportion of subjects who achieve fasting TG levels of <500 mg/dL (<5.65 mmol/L) at Month 12 compared to placebo | Baseline, Month 12 |
| Proportion of Subjects Who Achieve Fasting TG Levels of < 150 mg/dL (<1.69 mmol/L) at Month 12 compared to placebo | Baseline, Month 12 |
| Percent change in remnant cholesterol (VLDL-C) from baseline to Month 12 compared to placebo | Baseline, Month 12 |
| Percent change in non-HDL-C from baseline to Month 12 compared to placebo | Baseline, Month 12 |
| Adjudicated AP Event Rate During the Treatment Period Compared to Placebo From Day 1 to Month 12 | Month 12 |
| Number of Subjects with Adverse Events (AEs) and Serious Adverse Events (SAEs) Over Time through Month 12 as Compared to Placebo | From first dose of study drug through Month 12 |
| Incidence Rates of New-Onset Diabetes Mellitus (NODM) Throughout the Course of Treatment | From first dose of study drug through Month 12 |
| Incidence Rates of Impaired Glucose Tolerance Throughout the Course of Treatment | From first dose of study drug through Month 12 |
| Incidence Rates of Worsening of Existing Diabetes Throughout the Course of Treatment | From first dose of study drug through Month 12 |
| Change from Baseline in Hemoglobin A1c (HbA1c) and Other Glycemic Control Parameters During the Treatment Period Compared to Placebo | From first dose of study drug through Month 12 |
| Change from Baseline in Fasting Blood Glucose During the Treatment Period Compared to Placebo | From first dose of study drug through Month 12 |
| Change from Baseline in C-Peptide During the Treatment Period Compared to Placebo | From first dose of study drug through Month 12 |
| Change from Baseline in Homeostatic Model Assessment for Insulin Resistance (HOMA-IR) During the Treatment Period Compared to Placebo | From first dose of study drug through Month 12 |
| Change from Baseline in Treatment-Emergent Adverse Events (TEAEs) and Treatment-Related Adverse Events (TRAEs) Associated with Worsening Glycemic Control During the Treatment Period Compared to Placebo | From first dose of study drug through Month 12 |
| Initiation of New Medication for Hyperglycemia among Study Participants Not Known to Have Pre-existing Diabetes Mellitus During the Treatment Period Compared to Placebo | From first dose of study drug through Month 12 |
| Adjudicated Major Adverse Cardiovascular Events (MACE) Rates During the Treatment Period Compared to Placebo | From first dose of study drug through Month 12 |
| Incidence of Anti-drug Antibodies (ADA) to Plozasiran in Subjects Receiving Plozasiran Over Time Through Month 12 | From first dose of study drug through Month 12 |
| Titers of Anti-drug Antibodies (ADA) to Plozasiran in Subjects Receiving Plozasiran Over Time Through Month 12 | From first dose of study drug through Month 12 |
Countries
Argentina, Brazil, Bulgaria, Canada, Czechia, France, Germany, Hungary, Latvia, Lithuania, New Zealand, Poland, Slovakia, South Africa, Spain, United States
Outcome results
None listed