Atherosclerotic Cardiovascular Disease, Hypertriglyceridemia, Severe Hypertriglyceridemia
Conditions
Brief summary
The purpose of the study was to evaluate the effect of olezarsen on percent change in fasting triglyceride (TG) levels compared to placebo at Months 6 and 12 and the proportion of participants who achieve different thresholds in fasting TG. Other objectives were to evaluate the effect of olezarsen on percent change in fasting apolipoprotein C-III (apoC-III), very low-density lipoprotein cholesterol (VLDL-C), remnant cholesterol, non-high-density lipoprotein cholesterol (non-HDL-C), HDL-C, total cholesterol (TC), apolipoprotein B (apoB), low-density lipoprotein cholesterol (LDL-C), and apolipoprotein A-1 (apoA-1).
Detailed description
This was a multi-center, randomized, double-blind, placebo-controlled study in participants with hypertriglyceridemia (triglycerides \> 150 milligrams per deciliter \[mg/dL\]) and established or at increased risk for atherosclerotic cardiovascular disease, and/or with severe hypertriglyceridemia. The study had an up to 8-week screening period, a 53-week treatment period, and a 13-week post-treatment follow-up period.
Interventions
DRUGOlezarsen
SC injection.
DRUGPlacebo
SC injection.
Sponsors
Ionis Pharmaceuticals, Inc.
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
1. Aged ≥ 18 years at the time of informed consent 2. Fall into at least 1 of the following groups (a or b): 1. Hypertriglyceridemia with fasting TG ≥ 150 mg/dL (1.69 millimoles per liter \[mmol/L\]) and \< 500 mg/dL (5.65 mmol/L) with either clinical diagnosis of atherosclerotic cardiovascular disease (ASCVD) or at increased risk for ASCVD 2. Severe hypertriglyceridemia with fasting TG ≥ 500 mg/dL (5.65 mmol/L). 3. Participants must be on standard-of-care (SOC), lipid-lowering medications per local guidelines. 4. Participants must be willing to comply with diet and lifestyle recommendations as able.
Exclusion criteria
1. Diabetes with any of the following: 1. Newly diagnosed within 12 weeks of screening 2. Hemoglobin A1C (HbA1c) ≥ 9.5% at Screening 3. Change in basal insulin regimen \> 20% within 3 months prior to Screening 4. For participants with type 1 diabetes: episode of diabetic ketoacidosis, or ≥ 3 episodes of severe hypoglycemia within 6 months prior to Screening 2. Acute coronary syndrome or stroke/transient ischemic attack (TIA) within 6 months prior to Screening 3. Major surgery, peripheral revascularization, or non-urgent percutaneous coronary intervention (PCI) within 3 months prior to Screening, or upcoming planned major surgery or major procedure (e.g., arterial revascularization) during the course of the study 4. Active pancreatitis within 4 weeks prior to Screening
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Percent Change From Baseline in Fasting TG at Month 6 | Baseline, Month 6 | Baseline was defined as the average of the pre-dose measurement on Day 1 and all non-missing measurements from the qualification period. If the Day 1 pre-dose and qualification period measurements were all missing, then the last non-missing measurement from the screening period was used as baseline. Month 6 was defined as the average of Weeks 25 and 27. If 1 of the 2 assessments was missing, then the non-missing assessment was used. Missing data after the last observed value for participants in the olezarsen arms were imputed using the jump to reference (J2R) approach. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Percent Change From Baseline in Fasting TG at Month 12 | Baseline, Month 12 | Baseline was defined as the average of the pre-dose measurement on Day 1 and all non-missing measurements from the qualification period. If the Day 1 pre-dose and qualification period measurements were all missing, then the last non-missing measurement from the screening period was used as baseline. Month 12 was defined as the average of Weeks 51 and 53. If 1 of the 2 assessments was missing, then the non-missing assessment was used. Missing data after the last observed value for participants in the olezarsen arms were imputed using the J2R approach. |
| Percentage of Participants Who Achieved Fasting TG <150 mg/dL (1.69 Millimoles Per Liter [mmol/L]) at Month 6 With Baseline TG <500 mg/dL (5.65 mmol/L) | Baseline, Month 6 | Baseline was defined as the average of the pre-dose measurement on Day 1 and all non-missing measurements from the qualification period. If the Day 1 pre-dose and qualification period measurements were all missing, then the last non-missing measurement from the screening period was used as baseline. Month 6 was defined as the average of Weeks 25 and 27. If 1 of the 2 assessments was missing, then the non-missing assessment was used. Missing data after the last observed value for participants in the olezarsen arms were imputed using the J2R approach. |
| Percentage of Participants Who Achieved Fasting TG <150 mg/dL (1.69 mmol/L) at Month 12 With Baseline TG <500 mg/dL (5.65 mmol/L) | Baseline, Month 12 | Baseline was defined as the average of the pre-dose measurement on Day 1 and all non-missing measurements from the qualification period. If the Day 1 pre-dose and qualification period measurements were all missing, then the last non-missing measurement from the screening period was used as baseline. Month 12 was defined as the average of Weeks 51 and 53. If 1 of the 2 assessments was missing, then the non-missing assessment was used. Missing data after the last observed value for participants in the olezarsen arms were imputed using the J2R approach. |
| Percent Change From Baseline in Fasting Apolipoprotein C-III (ApoC-III) at Month 6 | Baseline, Month 6 | Baseline was defined as the average of the pre-dose measurement on Day 1 and all non-missing measurements from the qualification period. If the Day 1 pre-dose and qualification period measurements were all missing, then the last non-missing measurement from the screening period was used as baseline. Month 6 was defined as the average of Weeks 25 and 27. If 1 of the 2 assessments was missing, then the non-missing assessment was used. Missing data after the last observed value for participants in the olezarsen arms were imputed using the J2R approach. |
| Percent Change From Baseline in Fasting ApoC-III at Month 12 | Baseline, Month 12 | Baseline was defined as the average of the pre-dose measurement on Day 1 and all non-missing measurements from the qualification period. If the Day 1 pre-dose and qualification period measurements were all missing, then the last non-missing measurement from the screening period was used as baseline. Month 12 was defined as the average of Weeks 51 and 53. If 1 of the 2 assessments was missing, then the non-missing assessment was used. Missing data after the last observed value for participants in the olezarsen arms were imputed using the J2R approach. |
| Percent Change From Baseline in Fasting Very Low-density Lipoprotein Cholesterol (VLDL-C) at Month 6 | Baseline, Month 6 | Baseline was defined as the average of the pre-dose measurement on Day 1 and all non-missing measurements from the qualification period. If the Day 1 pre-dose and qualification period measurements were all missing, then the last non-missing measurement from the screening period was used as baseline. Month 6 was defined as the average of Weeks 25 and 27. If 1 of the 2 assessments was missing, then the non-missing assessment was used. Missing data after the last observed value for participants in the olezarsen arms were imputed using the J2R approach. |
| Percent Change From Baseline in VLDL-C at Month 12 | Baseline, Month 12 | Baseline was defined as the average of the pre-dose measurement on Day 1 and all non-missing measurements from the qualification period. If the Day 1 pre-dose and qualification period measurements were all missing, then the last non-missing measurement from the screening period was used as baseline. Month 12 was defined as the average of Weeks 51 and 53. If 1 of the 2 assessments was missing, then the non-missing assessment was used. Missing data after the last observed value for participants in the olezarsen arms were imputed using the J2R approach. |
| Percent Change From Baseline in Fasting Non-high-density Lipoprotein Cholesterol (Non-HDL-C) at Month 6 | Baseline, Month 6 | Baseline was defined as the average of the pre-dose measurement on Day 1 and all non-missing measurements from the qualification period. If the Day 1 pre-dose and qualification period measurements were all missing, then the last non-missing measurement from the screening period was used as baseline. Month 6 was defined as the average of Weeks 25 and 27. If 1 of the 2 assessments was missing, then the non-missing assessment was used. Missing data after the last observed value for participants in the olezarsen arms were imputed using the J2R approach. |
| Percent Change From Baseline in Fasting Non-HDL-C at Month 12 | Baseline, Month 12 | Baseline was defined as the average of the pre-dose measurement on Day 1 and all non-missing measurements from the qualification period. If the Day 1 pre-dose and qualification period measurements were all missing, then the last non-missing measurement from the screening period was used as baseline. Month 12 was defined as the average of Weeks 51 and 53. If 1 of the 2 assessments was missing, then the non-missing assessment was used. Missing data after the last observed value for participants in the olezarsen arms were imputed using the J2R approach. |
| Percent Change From Baseline in Fasting High-density Lipoprotein Cholesterol (HDL-C) at Month 6 | Baseline, Month 6 | Baseline was defined as the average of the pre-dose measurement on Day 1 and all non-missing measurements from the qualification period. If the Day 1 pre-dose and qualification period measurements were all missing, then the last non-missing measurement from the screening period was used as baseline. Month 6 was defined as the average of Weeks 25 and 27. If 1 of the 2 assessments was missing, then the non-missing assessment was used. Missing data after the last observed value for participants in the olezarsen arms were imputed using the J2R approach. |
| Percent Change From Baseline in Fasting HDL-C at Month 12 | Baseline, Month 12 | Baseline was defined as the average of the pre-dose measurement on Day 1 and all non-missing measurements from the qualification period. If the Day 1 pre-dose and qualification period measurements were all missing, then the last non-missing measurement from the screening period was used as baseline. Month 12 was defined as the average of Weeks 51 and 53. If 1 of the 2 assessments was missing, then the non-missing assessment was used. Missing data after the last observed value for participants in the olezarsen arms were imputed using the J2R approach. |
| Percent Change From Baseline Fasting Remnant Cholesterol (Remnant-C) at Month 6 | Baseline, Month 6 | Baseline was defined as the average of the pre-dose measurement on Day 1 and all non-missing measurements from the qualification period. If the Day 1 pre-dose and qualification period measurements were all missing, then the last non-missing measurement from the screening period was used as baseline. Month 6 was defined as the average of Weeks 25 and 27. If 1 of the 2 assessments was missing, then the non-missing assessment was used. Missing data after the last observed value for participants in the olezarsen arms were imputed using the J2R approach. |
| Percent Change From Baseline in Fasting Remnant-C at Month 12 | Baseline, Month 12 | Baseline was defined as the average of the pre-dose measurement on Day 1 and all non-missing measurements from the qualification period. If the Day 1 pre-dose and qualification period measurements were all missing, then the last non-missing measurement from the screening period was used as baseline. Month 12 was defined as the average of Weeks 51 and 53. If 1 of the 2 assessments was missing, then the non-missing assessment was used. Missing data after the last observed value for participants in the olezarsen arms were imputed using the J2R approach. |
| Percent Change From Baseline in Fasting Apolipoprotein B (ApoB) at Month 6 | Baseline, Month 6 | Baseline was defined as the average of the pre-dose measurement on Day 1 and all non-missing measurements from the qualification period. If the Day 1 pre-dose and qualification period measurements were all missing, then the last non-missing measurement from the screening period was used as baseline. Month 6 was defined as the average of Weeks 25 and 27. If 1 of the 2 assessments was missing, then the non-missing assessment was used. Missing data after the last observed value for participants in the olezarsen arms were imputed using the J2R approach. |
| Percent Change From Baseline in Fasting ApoB at Month 12 | Baseline, Month 12 | Baseline was defined as the average of the pre-dose measurement on Day 1 and all non-missing measurements from the qualification period. If the Day 1 pre-dose and qualification period measurements were all missing, then the last non-missing measurement from the screening period was used as baseline. Month 12 was defined as the average of Weeks 51 and 53. If 1 of the 2 assessments was missing, then the non-missing assessment was used. Missing data after the last observed value for participants in the olezarsen arms were imputed using the J2R approach. |
| Percent Change From Baseline in Fasting Apolipoprotein A-1 (ApoA-1) at Month 6 | Baseline, Month 6 | Baseline was defined as the average of the pre-dose measurement on Day 1 and all non-missing measurements from the qualification period. If the Day 1 pre-dose and qualification period measurements were all missing, then the last non-missing measurement from the screening period was used as baseline. Month 6 was defined as the average of Weeks 25 and 27. If 1 of the 2 assessments was missing, then the non-missing assessment was used. Missing data after the last observed value for participants in the olezarsen arms were imputed using the J2R approach. |
| Percent Change From Baseline in Fasting ApoA-1 at Month 12 | Baseline, Month 12 | Baseline was defined as the average of the pre-dose measurement on Day 1 and all non-missing measurements from the qualification period. If the Day 1 pre-dose and qualification period measurements were all missing, then the last non-missing measurement from the screening period was used as baseline. Month 12 was defined as the average of Weeks 51 and 53. If 1 of the 2 assessments was missing, then the non-missing assessment was used. Missing data after the last observed value for participants in the olezarsen arms were imputed using the J2R approach. |
| Percent Change From Baseline in Fasting Low-density Lipoprotein Cholesterol (LDL-C) at Month 6 | Baseline, Month 6 | Baseline was defined as the average of the pre-dose measurement on Day 1 and all non-missing measurements from the qualification period. If the Day 1 pre-dose and qualification period measurements were all missing, then the last non-missing measurement from the screening period was used as baseline. Month 6 was defined as the average of Weeks 25 and 27. If 1 of the 2 assessments was missing, then the non-missing assessment was used. Missing data after the last observed value for participants in the olezarsen arms were imputed using the J2R approach. |
| Percent Change From Baseline in Fasting LDL-C at Month 12 | Baseline, Month 12 | Baseline was defined as the average of the pre-dose measurement on Day 1 and all non-missing measurements from the qualification period. If the Day 1 pre-dose and qualification period measurements were all missing, then the last non-missing measurement from the screening period was used as baseline. Month 12 was defined as the average of Weeks 51 and 53. If 1 of the 2 assessments was missing, then the non-missing assessment was used. Missing data after the last observed value for participants in the olezarsen arms were imputed using the J2R approach. |
| Percent Change From Baseline in Fasting Total Cholesterol (Total-C) at Month 6 | Baseline, Month 6 | Baseline was defined as the average of the pre-dose measurement on Day 1 and all non-missing measurements from the qualification period. If the Day 1 pre-dose and qualification period measurements were all missing, then the last non-missing measurement from the screening period was used as baseline. Month 6 was defined as the average of Weeks 25 and 27. If 1 of the 2 assessments was missing, then the non-missing assessment was used. Missing data after the last observed value for participants in the olezarsen arms were imputed using the J2R approach. |
| Percent Change From Baseline in Fasting Total-C at Month 12 | Baseline, Month 12 | Baseline was defined as the average of the pre-dose measurement on Day 1 and all non-missing measurements from the qualification period. If the Day 1 pre-dose and qualification period measurements were all missing, then the last non-missing measurement from the screening period was used as baseline. Month 12 was defined as the average of Weeks 51 and 53. If 1 of the 2 assessments was missing, then the non-missing assessment was used. Missing data after the last observed value for participants in the olezarsen arms were imputed using the J2R approach. |
| Percentage of Participants Who Achieved Fasting TG <500 mg/dL (5.65 mmol/L) With Baseline TG ≥500 mg/dL at Month 6 | Baseline, Month 6 | Baseline was defined as the average of the pre-dose measurement on Day 1 and all non-missing measurements from the qualification period. If the Day 1 pre-dose and qualification period measurements were all missing, then the last non-missing measurement from the screening period was used as baseline. Month 6 was defined as the average of Weeks 25 and 27. If 1 of the 2 assessments was missing, then the non-missing assessment was used. Missing data after the last observed value for participants in the olezarsen arms were imputed using the J2R approach. |
| Percentage of Participants Who Achieved Fasting TG <500 mg/dL (5.65 mmol/L) With Baseline TG ≥500 mg/dL at Month 12 | Baseline, Month 12 | Baseline was defined as the average of the pre-dose measurement on Day 1 and all non-missing measurements from the qualification period. If the Day 1 pre-dose and qualification period measurements were all missing, then the last non-missing measurement from the screening period was used as baseline. Month 12 was defined as the average of Weeks 51 and 53. If 1 of the 2 assessments was missing, then the non-missing assessment was used. Missing data after the last observed value for participants in the olezarsen arms were imputed using the J2R approach. |
| Number of Participants With Adjudicated Acute Pancreatitis Events | Up to 12 months | All adverse events (AEs) and serious adverse events (SAEs) that consistently occurred during the study with an event of acute pancreatitis were adjudicated by a blinded, independent committee according to the Atlanta classification of acute pancreatitis as outlined in the Acute Pancreatitis Adjudication Committee (PAC) Charter. These events were categorized as 1) documented pancreatitis, 2) probable pancreatitis, 3) possible pancreatitis, 4) unable to adjudicate and 5) no diagnosis of acute pancreatitis. Number of participants with adjudicated acute pancreatitis events were reported. |
| Number of Participants With Adjudicated Acute Pancreatitis Events (≥2 Events in 5 Years Prior to Enrollment) | Up to 12 months | The adjudicated acute pancreatitis event rates were compared between pooled olezarsen treatment and placebo group using a negative binomial regression model or Poisson regression model with the treatment group and natural log transformed baseline fasting TG as the factors, and number of adjudicated acute pancreatitis events in 5 years prior to enrollment as a covariate. The logarithm of time in year that each participant observed during the treatment period were used as an offset variable. Number of participants with adjudicated acute pancreatitis events with ≥2 events in 5 years prior to enrollment were reported. |
Countries
Canada, United States
Participant flow
Recruitment details
Participants took part at 28 clinical sites including 21 sites in the United States (US) and 7 sites in Canada from 01 June 2022 to 17 January 2023.
Pre-assignment details
A total of 154 participants were enrolled in the study. All Participants were randomized in 1:1 ratio in two cohorts to receive either 50 mg, or 80 mg, and each cohort was further randomly assigned in a 3:1 ratio to receive olezarsen or olezarsen-matching placebo.
Baseline characteristics
| Characteristic | — |
|---|---|
| Age, Continuous | 62.3 years STANDARD_DEVIATION 10.15 |
| Fasting Triglycerides (TG) | 302.1 milligrams/deciliter (mg/dL) STANDARD_DEVIATION 201.91 |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants |
| Race (NIH/OMB) Asian | 1 Participants |
| Race (NIH/OMB) Black or African American | 3 Participants |
| Race (NIH/OMB) More than one race | 0 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 0 Participants |
| Race (NIH/OMB) White | 140 Participants |
| Sex: Female, Male Female | 65 Participants |
| Sex: Female, Male Male | 40 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk |
|---|---|---|---|
| deaths Total, all-cause mortality | 0 / 39 | 1 / 58 | 0 / 57 |
| other Total, other adverse events | 22 / 39 | 32 / 58 | 24 / 57 |
| serious Total, serious adverse events | 2 / 39 | 6 / 58 | 8 / 57 |
Outcome results
None listed