Mixed Dyslipidemia
Conditions
Brief summary
Participants who have met all protocol eligibility criteria will be randomly assigned to treatment (ARO-APOC3 or placebo) in a double-blind fashion and will be evaluated for safety and efficacy over 48 weeks. Participants will be counseled to remain on a specified diet throughout the study, as recommended by the Investigator in accordance with local standards of care. After week 48, participants will be eligible and invited to consent and continue in an open-label extension study. All placebo participants who opt to continue will switch to active drug (ARO-APOC3) during the extension study.
Interventions
DRUGARO-APOC3
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
Key Inclusion Criteria: Based on medical history, prior evidence of triglycerides (TG) ≥ 150 milligrams (mg)/deciliter (dL) and ≤ 499 mg/dL * Fasting levels at Screening of non-high-density lipoprotein cholesterol (non-HDL-C) ≥ 100 mg/dL or low-density lipoprotein cholesterol (LDL-C) ≥ 70 mg/dL after at least 2 weeks of stable diet and 4 weeks on stable optimal statin therapy * Mean fasting TG ≥ 150 mg/dL and ≤ 499 mg/dL during Screening collected at two separate and consecutive visits and at least 7 days apart and not more than 17 days apart * Willing to follow diet counseling as per Investigator judgment based on local standard of care * Participants of childbearing potential (males \& females) must use highly effective contraception during the study and for at least 24 weeks following the last dose of study medication. Males must not donate sperm and females must not donate eggs during the study and for at least 24 weeks following the last dose of study medication. * Women of childbearing potential must have a negative pregnancy test at Screening and cannot be breastfeeding * Women of childbearing potential on hormonal contraceptives must be stable on the medication for ≥ 2 menstrual cycles prior to Day 1 * Willing to provide written informed consent and to comply with study requirements Key
Exclusion criteria
* Current use or use within 365 days from Day 1 of any hepatocyte targeted short interfering RNA oligonucleotides (siRNA) or antisense oligonucleotide molecule * Active pancreatitis within 12 weeks prior to Day 1 * Any planned bariatric surgery or similar procedures to induce weight loss from consent through end of study * Acute coronary syndrome event within 24 weeks of Day 1 * History of major surgery within 12 weeks of Day 1 or planned major surgery during the study * Planned coronary intervention (such as, stent placement or heart bypass) during the study * New York Heart Association (NYHA) Class II, III or IV heart failure or last known ejection fraction of \<30% * Uncontrolled hypertension * Known history of human immunodeficiency virus (HIV) infection, seropositive for Hepatitis B virus (HBV), seropositive for Hepatitis C virus (HCV) * Uncontrolled hypothyroidism or hyperthyroidism * Hemorrhagic stroke within 24 weeks of Day 1 * History of bleeding diathesis or coagulopathy * Current diagnosis of nephrotic syndrome * Systemic use of corticosteroids or anabolic steroids within 4 weeks prior to Day 1 or planned use during the study * Malignancy within the last 2 years prior to date of consent requiring systemic treatment (some exceptions apply) Note: Additional inclusion/
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Percent Change From Baseline at Week 24 in Fasting TG | Baseline, Week 24 | Least square (LS) mean and standard error (SE) were calculated using mixed model repeated measures (MMRM) which included treatment arm, study visit, and baseline value as model terms and treatment by visit and treatment by baseline as interaction terms. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Percent Change From Baseline Over Time Through Week 48 in Fasting TG | Baseline, Weeks 4, 8, 12, 16, 20, 24, 28, 36, 48/early termination (ET) | LS mean and SE were calculated using MMRM which included treatment arm, study visit, and baseline value as model terms and treatment by visit and treatment by baseline as interaction terms. |
| Percent Change From Baseline at Week 24 in Apolipoprotein (Apo)C-III | Baseline, Week 24 | LS mean and SE were calculated using MMRM which included treatment arm, study visit, and baseline value as model terms and treatment by visit and treatment by baseline as interaction terms. |
| Percent Change From Baseline Over Time Through Week 48 in ApoC-III | Baseline, Weeks 4, 8, 12, 16, 20, 24, 28, 36, 48/ET | LS mean and SE were calculated using MMRM which included treatment arm, study visit, and baseline value as model terms and treatment by visit and treatment by baseline as interaction terms. |
| Percent Change From Baseline at Week 24 in Fasting Non-High-Density Lipoprotein Cholesterol (Non-HDL-C) | Baseline, Week 24 | LS mean and SE were calculated using MMRM which included treatment arm, study visit, and baseline value as model terms and treatment by visit and treatment by baseline as interaction terms. |
| Percent Change From Baseline Over Time Through Week 48 in Fasting Non-HDL-C | Baseline, Weeks 4, 8, 12, 16, 20, 24, 28, 36, 48/ET | LS mean and SE were calculated using MMRM which included treatment arm, study visit, and baseline value as model terms and treatment by visit and treatment by baseline as interaction terms. |
| Percent Change From Baseline at Week 24 in Fasting High-Density Lipoprotein Cholesterol (HDL-C) | Baseline, Week 24 | LS mean and SE were calculated using MMRM which included treatment arm, study visit, and baseline value as model terms and treatment by visit and treatment by baseline as interaction terms. |
| Percent Change From Baseline Over Time Through Week 48 in Fasting HDL-C | Baseline, Weeks 4, 8, 12, 16, 20, 24, 28, 36, 48/ET | LS mean and SE were calculated using MMRM which included treatment arm, study visit, and baseline value as model terms and treatment by visit and treatment by baseline as interaction terms. |
| Percent Change From Baseline at Week 24 in Fasting Total Apolipoprotein B (ApoB) | Baseline, Week 24 | LS mean and SE were calculated using MMRM which included treatment arm, study visit, and baseline value as model terms and treatment by visit and treatment by baseline as interaction terms. |
| Percent Change From Baseline Over Time Through Week 48 in Fasting Total ApoB | Baseline, Weeks 4, 8, 12, 16, 20, 24, 28, 36, 48/ET | LS mean and SE were calculated using MMRM which included treatment arm, study visit, and baseline value as model terms and treatment by visit and treatment by baseline as interaction terms. |
| Percent Change From Baseline at Week 24 in Fasting Low-Density Lipoprotein-Cholesterol (LDL-C) | Baseline, Week 24 | LS mean and SE were calculated using MMRM which included treatment arm, study visit, and baseline value as model terms and treatment by visit and treatment by baseline as interaction terms. |
| Percent Change From Baseline Over Time Through Week 48 in Fasting LDL-C | Baseline, Weeks 4, 8, 12, 16, 20, 24, 28, 36, 48/ET | LS mean and SE were calculated using MMRM which included treatment arm, study visit, and baseline value as model terms and treatment by visit and treatment by baseline as interaction terms. |
| Number of Participants With Treatment-Emergent Adverse Events (TEAEs) | Up to Week 48 | An adverse event (AE) was any untoward medical occurrence, which did not necessarily have to have a causal relationship with this treatment. A serious AE (SAE) was an AE that: resulted in death; was life-threatening; required inpatient hospitalization or prolongation of an existing hospitalization; resulted in persistent or significant disability/incapacity; was a congenital anomaly/birth defect; or was a medically important event or reaction. TEAEs were AEs that occurred following study drug administration or a pre-existing condition exacerbated following study drug administration. |
Countries
Australia, Canada, Hungary, New Zealand, Poland, United States
Participant flow
Pre-assignment details
Participants who successfully passed the requirements during the Screening period were enrolled in the study. All dose cohorts were enrolled in parallel with participants randomized 3:1 to receive ARO-APOC3 or placebo.
Baseline characteristics
| Characteristic | — |
|---|---|
| Age, Continuous | 58.9 years STANDARD_DEVIATION 9.7 |
| Ethnicity (NIH/OMB) Hispanic or Latino | 73 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 279 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 0 Participants |
| Mean Triglycerides (TG) | 244.10 mg/deciliter (dL) STANDARD_DEVIATION 78.289 |
| Race/Ethnicity, Customized Race American Indian or Alaska Native | 1 Participants |
| Race/Ethnicity, Customized Race Asian | 2 Participants |
| Race/Ethnicity, Customized Race Black or African American | 8 Participants |
| Race/Ethnicity, Customized Race Native Hawaiian or Other Pacific Islander | 0 Participants |
| Race/Ethnicity, Customized Race Other | 5 Participants |
| Race/Ethnicity, Customized Race Unknown | 1 Participants |
| Race/Ethnicity, Customized Race White | 79 Participants |
| Sex: Female, Male Female | 30 Participants |
| Sex: Female, Male Male | 43 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk | EG003 affected / at risk | EG004 affected / at risk |
|---|---|---|---|---|---|
| deaths Total, all-cause mortality | 0 / 87 | 0 / 67 | 1 / 67 | 2 / 66 | 1 / 66 |
| other Total, other adverse events | 55 / 87 | 47 / 67 | 44 / 67 | 48 / 66 | 48 / 66 |
| serious Total, serious adverse events | 5 / 87 | 2 / 67 | 5 / 67 | 7 / 66 | 5 / 66 |
Outcome results
None listed