Hypertriglyceridemia
Conditions
Brief summary
The purpose of this study is to evaluate the efficacy and safety of volanesorsen given for 26 weeks in participants with Hypertriglyceridemia.
Interventions
DRUGPlacebo
Volanesorsen-matching placebo administered subcutaneously once-weekly for 26 weeks.
DRUGVolanesorsen
300 mg volanesorsen administered subcutaneously once-weekly for 26 weeks.
Sponsors
Akcea Therapeutics
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. Body mass index (BMI) ≤ 45 kg/m2 2. Fasting Triglycerides (TG) ≥ 500 mg/dL (≥ 5.7 mmol/L) at Screening. 3. If on statin or fibrate, participants must be on stable, labeled dose for at least 3 months prior to screening. Participants not receiving these drugs within 4 weeks prior to screening are also eligible.
Exclusion criteria
1. Type 1 diabetes mellitus 2. Newly diagnosed type 2 diabetes mellitus (within 12 weeks of screening) or HbA1c ≥ 9.0% at Screening 3. Acute pancreatitis within 3 months of screening 4. Acute Coronary Syndrome within 6 months of screening 5. Major surgery within 3 months of screening 6. Prior exposure to ISIS 304801 7. Have any other conditions in the opinion of the investigator which could interfere with the participant participating in or completing the study
Design outcomes
Primary
| Measure | Time frame |
|---|---|
| Percent Change in Fasting Triglycerides (TG) From Baseline to Month 3 | Baseline to 3 months |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Treatment Response Rate Defined as Participants With Fasting TG ≥ 40% Reduction From Baseline at Month 3 | Baseline to 3 months | — |
| Percent Change in High-density Lipoprotein-cholesterol (HDL-C) From Baseline | Baseline to 3 months | — |
| Absolute Change in Fasting TG From Baseline to Month 3 | Baseline to 3 months | — |
| Change From Baseline in Homeostasis Model Assessment-estimated Insulin Resistance (HOMA-IR) | Baseline to 3 and 6 months | HOMA-IR was calculated using the following formula: fasting insulin micro-international units per millimeter (μIU/mL) x fasting glucose mg/dL\]/405. A negative change from baseline indicates improvement; a positive change from baseline indicates worsening. |
| Change From Baseline in Glycated Hemoglobin (HbA1c) in Type 2 Diabetes Mellitus (T2DM) Participants | Baseline to 3 and 6 months | — |
| Treatment Response Rate Defined as Participants With Fasting TG < 150 mg/dL Reduction From Baseline at Month 3 | Baseline to 3 months | mg/dL = milligrams per deciliter |
Countries
Canada, France, Germany, Netherlands, United Kingdom, United States
Participant flow
Recruitment details
A total of 114 participants were randomized at multiple study centers worldwide.
Pre-assignment details
114 participants were randomized, and 113 received study drug. One patient was randomized, but discontinued before dosing, and thus included only in the volanesorsen Total (Not public) column. The study included a ≤ 8-week screening period (including a diet-stabilization period), a 26-week treatment period, and a 13-week post-treatment evaluation period.
Participants by arm
| Arm | Count |
|---|---|
| Placebo Volanesorsen-matching placebo administered subcutaneously once-weekly for 26 weeks. | 38 |
| Volanesorsen 300 mg Weekly Volanesorsen 300 mg administered subcutaneously once-weekly for 26 weeks. | 25 |
| Volanesorsen 300 mg Biweekly, Post Week 13 Volanesorsen 300 mg administered subcutaneously once-weekly for 13 weeks, then bi-weekly for 13 weeks. | 50 |
| Total | 113 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 | FG002 |
|---|---|---|---|---|
| Overall Study | Adverse Event or Serious Adverse Event | 3 | 1 | 14 |
| Overall Study | Investigator Judgement | 0 | 0 | 1 |
| Overall Study | Reason Not Specified | 0 | 0 | 5 |
| Overall Study | Withdrawal by Subject | 1 | 0 | 3 |
Baseline characteristics
| Characteristic | Total | Volanesorsen 300 mg Biweekly, Post Week 13 | Placebo | Volanesorsen 300 mg Weekly |
|---|---|---|---|---|
| Age, Continuous | 51 years STANDARD_DEVIATION 10 | 51 years STANDARD_DEVIATION 11 | 53 years STANDARD_DEVIATION 10 | 50 years STANDARD_DEVIATION 9 |
| Fasting Triglycerides | 1261 milligrams per deciliter (mg/dL) STANDARD_DEVIATION 955 | 1251 milligrams per deciliter (mg/dL) STANDARD_DEVIATION 838 | 1414 milligrams per deciliter (mg/dL) STANDARD_DEVIATION 1253 | 1046 milligrams per deciliter (mg/dL) STANDARD_DEVIATION 560 |
| Race/Ethnicity, Customized American Indian or Alaskan Native | 1 Participants | 1 Participants | 0 Participants | 0 Participants |
| Race/Ethnicity, Customized Asian | 4 Participants | 1 Participants | 3 Participants | 0 Participants |
| Race/Ethnicity, Customized Hispanic or Latino | 2 Participants | 0 Participants | 1 Participants | 1 Participants |
| Race/Ethnicity, Customized Multiple | 1 Participants | 0 Participants | 1 Participants | 0 Participants |
| Race/Ethnicity, Customized Not Hispanic or Latino | 111 Participants | 50 Participants | 37 Participants | 24 Participants |
| Race/Ethnicity, Customized Other Race | 2 Participants | 1 Participants | 1 Participants | 0 Participants |
| Race/Ethnicity, Customized White | 105 Participants | 47 Participants | 33 Participants | 25 Participants |
| Sex: Female, Male Female | 27 Participants | 14 Participants | 8 Participants | 5 Participants |
| Sex: Female, Male Male | 86 Participants | 36 Participants | 30 Participants | 20 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk |
|---|---|---|---|
| deaths Total, all-cause mortality | 0 / 38 | 0 / 25 | 0 / 50 |
| other Total, other adverse events | 31 / 38 | 24 / 25 | 49 / 50 |
| serious Total, serious adverse events | 4 / 38 | 2 / 25 | 6 / 50 |
Outcome results
Primary
Percent Change in Fasting Triglycerides (TG) From Baseline to Month 3
Time frame: Baseline to 3 months
Population: The full analysis set (FAS) included all participants who were randomized, received at least one dose of study drug, and had a baseline TG assessment.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) |
|---|---|---|
| Placebo | Percent Change in Fasting Triglycerides (TG) From Baseline to Month 3 | -0.9 percent change |
| Volanesorsen Total | Percent Change in Fasting Triglycerides (TG) From Baseline to Month 3 | -71.2 percent change |
p-value: <0.000195% CI: [-85.4, -55.3]ANCOVA
Secondary
Absolute Change in Fasting TG From Baseline to Month 3
Time frame: Baseline to 3 months
Population: The FAS included all participants who were randomized, received at least one dose of study drug, and had a baseline TG assessment. Volanesorsen 300 mg biweekly group includes patients who received weekly dosing in first 13 weeks, and then bi-weekly for 13 weeks. For month 3 assessments, the results were combined since all patients were on weekly dosing. And for month 6 assessments, the results were split to show the results in each dosing group.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) |
|---|---|---|
| Placebo | Absolute Change in Fasting TG From Baseline to Month 3 | 74 mg/dL |
| Volanesorsen Total | Absolute Change in Fasting TG From Baseline to Month 3 | -869 mg/dL |
p-value: <0.000195% CI: [-1197, -689]ANCOVA
Secondary
Change From Baseline in Glycated Hemoglobin (HbA1c) in Type 2 Diabetes Mellitus (T2DM) Participants
Time frame: Baseline to 3 and 6 months
Population: The FAS included all participants who were randomized, received at least one dose of study drug, and had a baseline TG assessment. Number analyzed were the T2DM participants evaluated at the given time point.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Placebo | Change From Baseline in Glycated Hemoglobin (HbA1c) in Type 2 Diabetes Mellitus (T2DM) Participants | Month 6 | -0.2 percentage | Standard Deviation 0.6 |
| Placebo | Change From Baseline in Glycated Hemoglobin (HbA1c) in Type 2 Diabetes Mellitus (T2DM) Participants | Month 3 | -0.0 percentage | Standard Deviation 0.5 |
| Volanesorsen Total | Change From Baseline in Glycated Hemoglobin (HbA1c) in Type 2 Diabetes Mellitus (T2DM) Participants | Month 3 | 0.4 percentage | Standard Deviation 0.6 |
| Volanesorsen Total | Change From Baseline in Glycated Hemoglobin (HbA1c) in Type 2 Diabetes Mellitus (T2DM) Participants | Month 6 | 0.8 percentage | Standard Deviation 0.9 |
| Volanesorsen 300 mg Biweekly, Post Week 13 | Change From Baseline in Glycated Hemoglobin (HbA1c) in Type 2 Diabetes Mellitus (T2DM) Participants | Month 3 | 0.1 percentage | Standard Deviation 0.5 |
| Volanesorsen 300 mg Biweekly, Post Week 13 | Change From Baseline in Glycated Hemoglobin (HbA1c) in Type 2 Diabetes Mellitus (T2DM) Participants | Month 6 | 0.3 percentage | Standard Deviation 0.9 |
Secondary
Change From Baseline in Homeostasis Model Assessment-estimated Insulin Resistance (HOMA-IR)
HOMA-IR was calculated using the following formula: fasting insulin micro-international units per millimeter (μIU/mL) x fasting glucose mg/dL\]/405. A negative change from baseline indicates improvement; a positive change from baseline indicates worsening.
Time frame: Baseline to 3 and 6 months
Population: The FAS included all participants who were randomized, received at least one dose of study drug, and had a baseline TG assessment. Number analyzed were the participants evaluated at the given time point.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Placebo | Change From Baseline in Homeostasis Model Assessment-estimated Insulin Resistance (HOMA-IR) | Month 3 | -0.29 score | Standard Deviation 3.12 |
| Placebo | Change From Baseline in Homeostasis Model Assessment-estimated Insulin Resistance (HOMA-IR) | Month 6 | -0.37 score | Standard Deviation 3.18 |
| Volanesorsen Total | Change From Baseline in Homeostasis Model Assessment-estimated Insulin Resistance (HOMA-IR) | Month 3 | 1.53 score | Standard Deviation 4.89 |
| Volanesorsen Total | Change From Baseline in Homeostasis Model Assessment-estimated Insulin Resistance (HOMA-IR) | Month 6 | 1.54 score | Standard Deviation 7.69 |
| Volanesorsen 300 mg Biweekly, Post Week 13 | Change From Baseline in Homeostasis Model Assessment-estimated Insulin Resistance (HOMA-IR) | Month 3 | -0.45 score | Standard Deviation 4.97 |
| Volanesorsen 300 mg Biweekly, Post Week 13 | Change From Baseline in Homeostasis Model Assessment-estimated Insulin Resistance (HOMA-IR) | Month 6 | 0.56 score | Standard Deviation 2.97 |
Secondary
Percent Change in High-density Lipoprotein-cholesterol (HDL-C) From Baseline
Time frame: Baseline to 3 months
Population: The FAS included all participants who were randomized, received at least one dose of study drug, and had a baseline TG assessment.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) |
|---|---|---|
| Placebo | Percent Change in High-density Lipoprotein-cholesterol (HDL-C) From Baseline | 4.4 percent change |
| Volanesorsen Total | Percent Change in High-density Lipoprotein-cholesterol (HDL-C) From Baseline | 61.2 percent change |
p-value: <0.000195% CI: [45.1, 68.6]ANCOVA
Secondary
Treatment Response Rate Defined as Participants With Fasting TG < 150 mg/dL Reduction From Baseline at Month 3
mg/dL = milligrams per deciliter
Time frame: Baseline to 3 months
Population: The FAS included all participants who were randomized, received at least one dose of study drug, and had a baseline TG assessment.
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Placebo | Treatment Response Rate Defined as Participants With Fasting TG < 150 mg/dL Reduction From Baseline at Month 3 | 0 Participants |
| Volanesorsen Total | Treatment Response Rate Defined as Participants With Fasting TG < 150 mg/dL Reduction From Baseline at Month 3 | 11 Participants |
p-value: 0.047495% CI: [1.03, 215.88]Regression, Logistic
Secondary
Treatment Response Rate Defined as Participants With Fasting TG ≥ 40% Reduction From Baseline at Month 3
Time frame: Baseline to 3 months
Population: The FAS included all participants who were randomized, received at least one dose of study drug, and had a baseline TG assessment.
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Placebo | Treatment Response Rate Defined as Participants With Fasting TG ≥ 40% Reduction From Baseline at Month 3 | 5 Participants |
| Volanesorsen Total | Treatment Response Rate Defined as Participants With Fasting TG ≥ 40% Reduction From Baseline at Month 3 | 65 Participants |
p-value: <0.000195% CI: [19.71, 467.79]Regression, Logistic