Hypertriglyceridemia, Cardiovascular Diseases
Conditions
Keywords
AKCEA-APOCIII-LRx, IONIS-APOCIII-LRx, Dyslipidemia, Metabolic Disease, Hyperlipidemia, Cardiac Disease, Lipid Metabolism Disorders, Triglycerides High, Vascular Diseases
Brief summary
This was a multicenter, randomized, double-blind, placebo-controlled, dose-ranging study to evaluate the safety, including tolerability, of ISIS 678354 and to assess the efficacy of different doses and dosing regimens of ISIS 678354 for reduction of serum triglyceride (TG) levels in participants with hypertriglyceridemia and established CVD or at a high risk for CVD.
Interventions
DRUGISIS 678354
ISIS 678354 solution for SC injection.
DRUGPlacebo
Sterile Normal Saline (0.9% NaCl).
Sponsors
Ionis Pharmaceuticals, Inc.
Akcea Therapeutics
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
TRIPLE (Subject, Investigator, Outcomes Assessor)
Eligibility
Sex/Gender
ALL
Age
18 Years to 80 Years
Healthy volunteers
No
Inclusion criteria
Key Inclusion Criteria: * Clinical diagnosis of CVD (defined as documented coronary artery disease, stroke, or peripheral artery disease). * Fasting serum triglycerides (TG) greater than or equal to (≥) 200 milligrams per deciliter (mg/dL) (≥ 2.3 millimoles per liter (mmol/L)) and less than or equal to (≤) 500 mg/dL (≥ 5.7 mmol/L) at Screening. * Fasting TG ≥ 200 mg/dL and ≤ 500 mg/dL at Qualification visit. * Must be on standard-of-care preventative therapy for known CVD risk factors. Key
Exclusion criteria
* Within 6 months of Screening: acute coronary syndrome, major cardiac surgery, or stroke/transient ischemic attack (TIA). * Within 3 months of Screening: coronary, carotid, or peripheral arterial revascularization, major non-cardiac surgery, or lipoprotein apheresis. * Heart failure New York Heart Association (NYHA) class IV. * Type 1 diabetes mellitus. * Type 2 diabetes mellitus with any of the following: * Newly diagnosed within 12 weeks of Screening. * Glycated hemoglobin (HbA1c) ≥ 9.0% at Screening. * Recent change in anti-diabetic pharmacotherapy (change in dosage or addition of new medication within 12 weeks of Screening \[with the exception of ± 10 units of insulin\]. * Body Mass Index (BMI) greater than (\>) 40 kilograms per square meter (kg/m\^2).
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Percent Change From Baseline in Fasting Triglycerides (TG) at the Primary Analysis Time Point | Baseline and Month 6 (Week 25 for Cohorts A and B and Week 27 for Cohorts C and D) | An analysis of covariance (ANCOVA) model was performed on the log ratio of TG value at the Primary Analysis Time Point to TG value at Baseline. The estimate of the log ratio was converted back to the original scale and percent change was calculated using formula: (ratio of TG value at the Primary Analysis Time Point to TG value at Baseline - 1) × 100. |
| Number of Participants With Treatment-Emergent Adverse Events (TEAEs) | Up to the 13-week post-treatment follow-up period (Up to approximately 15 months) | An adverse event (AE) was defined as any unfavorable and unintended sign (including a clinically-significant abnormal laboratory finding, for example), symptom, or disease temporally associated with the study or use of investigational drug product, whether or not the AE was considered to be related to the investigational drug product. A TEAE was defined as any AE starting on or after the first dose of the study drug. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Percentage of Participants Who Achieved Fasting Triglycerides (TG) <= 100 mg/dL (<= 1.13 mmol/L) | Baseline and Month 6 (Week 25 for Cohorts A and B and Week 27 for Cohorts C and D) | The percentage of participants who achieved \<= 100 mg/dL or \<= 1.13 mmol/L of fasting TG levels at the primary analysis time point were compared between each ISIS 678354 treatment group and pooled placebo group using a logistic regression model with log-transformed baseline TG value as a covariate. |
| Maximum Plasma Concentration (Cmax) of ISIS 678354 | Predose, 1, 2, 4, 8, 24 hours post the first dose (Day 1), Week 21 (for Cohorts A and B) and Week 25 (for Cohorts C and D) | — |
| Percent Change From Baseline in ApoC-III, TC, LDL-C, HDL-C, Non-HDL-C, VLDL-C, ApoB, and ApoA-I at the Primary Analysis Time Point | Baseline and Month 6 (Week 25 for Cohorts A and B and Week 27 for Cohorts C and D) | An ANCOVA model was performed on the log ratio of Primary Analysis Time Point value to Baseline value for ApoC-III, TC, LDL-C, HDL-C, Non-HDL-C, VLDL-C, ApoB, and ApoA-I. The estimate of the log ratio was converted back to the original scale and percent change for each lipid parameter was calculated using formula: (ratio of Primary Analysis Time Point value to Baseline value - 1) × 100. |
| Area Under the Plasma Concentration Versus Time Curve From Time Zero to 24 Hours (AUC0-24) of ISIS 678354 | Predose, 1, 2, 4, 8, 24 hours post the first dose (Day 1), Week 21 (for Cohorts A and B) and Week 25 (for Cohorts C and D) | — |
| Time to Reach Maximum Plasma Concentration (Tmax) of ISIS 678354 | Predose, 1, 2, 4, 8, 24 hours post the first dose (Day 1), Week 21 (for Cohorts A and B) and Week 25 (for Cohorts C and D) | — |
| Percentage of Participants Who Achieved Fasting Triglycerides (TG) <= 150 mg/dL (<= 1.7 Millimoles Per Liter [mmol/L]) | Baseline and Month 6 (Week 25 for Cohorts A and B and Week 27 for Cohorts C and D) | The percentage of participants who achieved \<= 150 mg/dL or \<= 1.7 mmol/L of fasting TG levels at the primary analysis time point were compared between each ISIS 678354 treatment group and pooled placebo group using a logistic regression model with log-transformed baseline TG value as a covariate. |
Countries
Canada, United States
Participant flow
Recruitment details
Participants with a clinical diagnosis of hypertriglyceridemia and established cardiovascular disease (CVD) or at high risk for CVD were enrolled in 32 study sites in United States and Canada between 30 January 2018 to 25 February 2020.
Pre-assignment details
114 participants were randomized in a 1:1:1:1 ratio to Cohorts A, B, C or D. In each cohort, participants were randomized in a 4:1 ratio to receive ISIS 678354 or placebo. Placebo participants from all cohorts were pooled for analysis and presented as the pooled placebo group.
Participants by arm
| Arm | Count |
|---|---|
| Pooled Placebo Participants in each cohort were randomized to receive placebo at a dose-matched volume of study drug (ISIS 678354). | 24 |
| Cohort A: ISIS 678354: 10 mg Q4W Cohort A participants received 10 mg ISIS 678354, SC injection, Q4W, for up to 49 weeks and a maximum of 13 doses. | 22 |
| Cohort C: ISIS 678354: 15 mg Q2W Cohort C participants received 15 mg ISIS 678354, SC injection, Q2W for up to 51 weeks and a maximum of 26 doses. | 23 |
| Cohort D: ISIS 678354: 10 mg QW Cohort D participants received 10 mg ISIS 678354, SC injection, QW for up to 52 weeks and a maximum of 52 doses. | 23 |
| Cohort B: ISIS 678354: 50 mg Q4W Cohort B participants received 50 mg ISIS 678354, SC injection, once Q4W for up to 49 weeks and a maximum of 13 doses. | 22 |
| Total | 114 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 | FG002 | FG003 | FG004 |
|---|---|---|---|---|---|---|
| Overall Study | Adverse Event | 0 | 0 | 1 | 0 | 0 |
| Overall Study | Other | 0 | 0 | 0 | 1 | 0 |
| Overall Study | Voluntary Withdrawal | 2 | 3 | 2 | 3 | 0 |
Baseline characteristics
| Characteristic | Total | Cohort B: ISIS 678354: 50 mg Q4W | Cohort D: ISIS 678354: 10 mg QW | Cohort A: ISIS 678354: 10 mg Q4W | Cohort C: ISIS 678354: 15 mg Q2W | Pooled Placebo |
|---|---|---|---|---|---|---|
| Age, Continuous | 65.3 years STANDARD_DEVIATION 8.1 | 62.9 years STANDARD_DEVIATION 7.4 | 65.6 years STANDARD_DEVIATION 8.48 | 64.4 years STANDARD_DEVIATION 9.13 | 68.9 years STANDARD_DEVIATION 6.82 | 64.6 years STANDARD_DEVIATION 7.93 |
| Apolipoprotein A1 (ApoA-I) | 131.9 mg/dL STANDARD_DEVIATION 20.14 | 136.3 mg/dL STANDARD_DEVIATION 23.07 | 132.5 mg/dL STANDARD_DEVIATION 22.95 | 130.2 mg/dL STANDARD_DEVIATION 19.15 | 129.0 mg/dL STANDARD_DEVIATION 16.69 | 131.4 mg/dL STANDARD_DEVIATION 19.28 |
| Apolipoprotein B (ApoB) | 83.9 mg/dL STANDARD_DEVIATION 18.65 | 88.5 mg/dL STANDARD_DEVIATION 14.29 | 86.8 mg/dL STANDARD_DEVIATION 19.62 | 79.6 mg/dL STANDARD_DEVIATION 16.55 | 87.9 mg/dL STANDARD_DEVIATION 20.6 | 77.1 mg/dL STANDARD_DEVIATION 19.71 |
| Apolipoprotein CIII (ApoC-III) | 16.205 mg/dL STANDARD_DEVIATION 4.0466 | 15.669 mg/dL STANDARD_DEVIATION 3.2484 | 16.810 mg/dL STANDARD_DEVIATION 4.2021 | 16.030 mg/dL STANDARD_DEVIATION 4.1482 | 15.849 mg/dL STANDARD_DEVIATION 4.2456 | 16.618 mg/dL STANDARD_DEVIATION 4.472 |
| Ethnicity (NIH/OMB) Hispanic or Latino | 7 Participants | 0 Participants | 1 Participants | 3 Participants | 2 Participants | 1 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 107 Participants | 22 Participants | 22 Participants | 19 Participants | 21 Participants | 23 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Fasting Triglycerides (TG) | 284.4 milligrams per deciliter (mg/dL) STANDARD_DEVIATION 85.16 | 268.4 milligrams per deciliter (mg/dL) STANDARD_DEVIATION 85.08 | 292.3 milligrams per deciliter (mg/dL) STANDARD_DEVIATION 89.29 | 281.6 milligrams per deciliter (mg/dL) STANDARD_DEVIATION 73.43 | 284.8 milligrams per deciliter (mg/dL) STANDARD_DEVIATION 94.54 | 293.8 milligrams per deciliter (mg/dL) STANDARD_DEVIATION 86.68 |
| HDL Cholesterol (HDL-C) | 34.8 mg/dL STANDARD_DEVIATION 9.16 | 36.8 mg/dL STANDARD_DEVIATION 10.54 | 34.8 mg/dL STANDARD_DEVIATION 8.61 | 34.1 mg/dL STANDARD_DEVIATION 9.07 | 33.9 mg/dL STANDARD_DEVIATION 9.48 | 34.6 mg/dL STANDARD_DEVIATION 8.61 |
| LDL Cholesterol (LDL-C) | 67.4 mg/dL STANDARD_DEVIATION 27.02 | 74.8 mg/dL STANDARD_DEVIATION 22.47 | 71.2 mg/dL STANDARD_DEVIATION 30.24 | 62.4 mg/dL STANDARD_DEVIATION 22.57 | 73.1 mg/dL STANDARD_DEVIATION 29.73 | 55.9 mg/dL STANDARD_DEVIATION 26.06 |
| Non-HDL Cholesterol (Non-HDL-C) | 121.9 mg/dL STANDARD_DEVIATION 30.52 | 130.1 mg/dL STANDARD_DEVIATION 31.02 | 125.3 mg/dL STANDARD_DEVIATION 32.09 | 115.1 mg/dL STANDARD_DEVIATION 28.93 | 129.2 mg/dL STANDARD_DEVIATION 33.32 | 110.3 mg/dL STANDARD_DEVIATION 23.96 |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Asian | 1 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 1 Participants |
| Race (NIH/OMB) Black or African American | 4 Participants | 2 Participants | 0 Participants | 1 Participants | 0 Participants | 1 Participants |
| Race (NIH/OMB) More than one race | 3 Participants | 2 Participants | 0 Participants | 1 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) White | 106 Participants | 18 Participants | 23 Participants | 20 Participants | 23 Participants | 22 Participants |
| Sex: Female, Male Female | 28 Participants | 7 Participants | 5 Participants | 8 Participants | 4 Participants | 4 Participants |
| Sex: Female, Male Male | 86 Participants | 15 Participants | 18 Participants | 14 Participants | 19 Participants | 20 Participants |
| Total Cholesterol (TC) | 156.7 mg/dL STANDARD_DEVIATION 32.66 | 166.8 mg/dL STANDARD_DEVIATION 35.3 | 160.0 mg/dL STANDARD_DEVIATION 34.55 | 149.2 mg/dL STANDARD_DEVIATION 28.81 | 163.1 mg/dL STANDARD_DEVIATION 35.09 | 144.8 mg/dL STANDARD_DEVIATION 26 |
| VLDL Cholesterol (VLDL-C) | 54.9 mg/dL STANDARD_DEVIATION 17.51 | 55.2 mg/dL STANDARD_DEVIATION 26.84 | 54.1 mg/dL STANDARD_DEVIATION 11.8 | 54.0 mg/dL STANDARD_DEVIATION 10.99 | 56.1 mg/dL STANDARD_DEVIATION 21.45 | 54.9 mg/dL STANDARD_DEVIATION 12.71 |
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 / 24 | 0 / 22 | 1 / 23 | 0 / 23 | 0 / 22 |
| other Total, other adverse events | 16 / 24 | 15 / 22 | 19 / 23 | 20 / 23 | 22 / 22 |
| serious Total, serious adverse events | 2 / 24 | 3 / 22 | 4 / 23 | 1 / 23 | 3 / 22 |
Outcome results
Primary
Number of Participants With Treatment-Emergent Adverse Events (TEAEs)
An adverse event (AE) was defined as any unfavorable and unintended sign (including a clinically-significant abnormal laboratory finding, for example), symptom, or disease temporally associated with the study or use of investigational drug product, whether or not the AE was considered to be related to the investigational drug product. A TEAE was defined as any AE starting on or after the first dose of the study drug.
Time frame: Up to the 13-week post-treatment follow-up period (Up to approximately 15 months)
Population: Safety set included all participants who were randomized and received at least 1 dose of study drug (ISIS 678354 or placebo).
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Pooled Placebo | Number of Participants With Treatment-Emergent Adverse Events (TEAEs) | 20 Participants |
| Cohort A: ISIS 678354: 10 mg Q4W | Number of Participants With Treatment-Emergent Adverse Events (TEAEs) | 17 Participants |
| Cohort C: ISIS 678354: 15 mg Q2W | Number of Participants With Treatment-Emergent Adverse Events (TEAEs) | 20 Participants |
| Cohort D: ISIS 678354: 10 mg QW | Number of Participants With Treatment-Emergent Adverse Events (TEAEs) | 22 Participants |
| Cohort B: ISIS 678354: 50 mg Q4W | Number of Participants With Treatment-Emergent Adverse Events (TEAEs) | 21 Participants |
Primary
Percent Change From Baseline in Fasting Triglycerides (TG) at the Primary Analysis Time Point
An analysis of covariance (ANCOVA) model was performed on the log ratio of TG value at the Primary Analysis Time Point to TG value at Baseline. The estimate of the log ratio was converted back to the original scale and percent change was calculated using formula: (ratio of TG value at the Primary Analysis Time Point to TG value at Baseline - 1) × 100.
Time frame: Baseline and Month 6 (Week 25 for Cohorts A and B and Week 27 for Cohorts C and D)
Population: FAS included all participants who were randomized and received at least 1 dose of study drug (ISIS 678354 or placebo). Here, 'Number analyzed' ('n') = Participants evaluable for this outcome measure at the specified timepoint.
| Arm | Measure | Value (MEAN) |
|---|---|---|
| Pooled Placebo | Percent Change From Baseline in Fasting Triglycerides (TG) at the Primary Analysis Time Point | 6 percent change |
| Cohort A: ISIS 678354: 10 mg Q4W | Percent Change From Baseline in Fasting Triglycerides (TG) at the Primary Analysis Time Point | -23 percent change |
| Cohort C: ISIS 678354: 15 mg Q2W | Percent Change From Baseline in Fasting Triglycerides (TG) at the Primary Analysis Time Point | -56 percent change |
| Cohort D: ISIS 678354: 10 mg QW | Percent Change From Baseline in Fasting Triglycerides (TG) at the Primary Analysis Time Point | -60 percent change |
| Cohort B: ISIS 678354: 50 mg Q4W | Percent Change From Baseline in Fasting Triglycerides (TG) at the Primary Analysis Time Point | -60 percent change |
p-value: 0.004295% CI: [-41, -10]ANCOVA
p-value: <0.000195% CI: [-66, -48]ANCOVA
p-value: <0.000195% CI: [-70, -54]ANCOVA
p-value: <0.000195% CI: [-69, -53]ANCOVA
Secondary
Area Under the Plasma Concentration Versus Time Curve From Time Zero to 24 Hours (AUC0-24) of ISIS 678354
Time frame: Predose, 1, 2, 4, 8, 24 hours post the first dose (Day 1), Week 21 (for Cohorts A and B) and Week 25 (for Cohorts C and D)
Population: PK subgroup: Subset of participants who were randomized, received \>= 1 dose of ISIS 678354, had \>= 1 evaluable concentration result post first dose and had additional PK sampling after dose administration on Day 1 and Week 21 (Cohorts A and B) or Week 25 (Cohorts C and D). 'Number analyzed' = participants evaluable for this outcome measure at specified time points.
| Arm | Measure | Group | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|---|
| Pooled Placebo | Area Under the Plasma Concentration Versus Time Curve From Time Zero to 24 Hours (AUC0-24) of ISIS 678354 | Day 1 | 618 nanograms*hours per milliliter (ng*h/mL) | Geometric Coefficient of Variation 115.6 |
| Pooled Placebo | Area Under the Plasma Concentration Versus Time Curve From Time Zero to 24 Hours (AUC0-24) of ISIS 678354 | Week 21 (for Cohorts A and B) and Week 25 (for Cohorts C and D) | 468 nanograms*hours per milliliter (ng*h/mL) | Geometric Coefficient of Variation 258.4 |
| Cohort A: ISIS 678354: 10 mg Q4W | Area Under the Plasma Concentration Versus Time Curve From Time Zero to 24 Hours (AUC0-24) of ISIS 678354 | Week 21 (for Cohorts A and B) and Week 25 (for Cohorts C and D) | 499 nanograms*hours per milliliter (ng*h/mL) | Geometric Coefficient of Variation 11.2 |
| Cohort A: ISIS 678354: 10 mg Q4W | Area Under the Plasma Concentration Versus Time Curve From Time Zero to 24 Hours (AUC0-24) of ISIS 678354 | Day 1 | 499 nanograms*hours per milliliter (ng*h/mL) | Geometric Coefficient of Variation 31.1 |
| Cohort C: ISIS 678354: 15 mg Q2W | Area Under the Plasma Concentration Versus Time Curve From Time Zero to 24 Hours (AUC0-24) of ISIS 678354 | Day 1 | 411 nanograms*hours per milliliter (ng*h/mL) | Geometric Coefficient of Variation 59 |
| Cohort C: ISIS 678354: 15 mg Q2W | Area Under the Plasma Concentration Versus Time Curve From Time Zero to 24 Hours (AUC0-24) of ISIS 678354 | Week 21 (for Cohorts A and B) and Week 25 (for Cohorts C and D) | 454 nanograms*hours per milliliter (ng*h/mL) | Geometric Coefficient of Variation 26.3 |
| Cohort D: ISIS 678354: 10 mg QW | Area Under the Plasma Concentration Versus Time Curve From Time Zero to 24 Hours (AUC0-24) of ISIS 678354 | Day 1 | 563 nanograms*hours per milliliter (ng*h/mL) | Geometric Coefficient of Variation 334.6 |
| Cohort D: ISIS 678354: 10 mg QW | Area Under the Plasma Concentration Versus Time Curve From Time Zero to 24 Hours (AUC0-24) of ISIS 678354 | Week 21 (for Cohorts A and B) and Week 25 (for Cohorts C and D) | 1460 nanograms*hours per milliliter (ng*h/mL) | Geometric Coefficient of Variation 13.6 |
Secondary
Maximum Plasma Concentration (Cmax) of ISIS 678354
Time frame: Predose, 1, 2, 4, 8, 24 hours post the first dose (Day 1), Week 21 (for Cohorts A and B) and Week 25 (for Cohorts C and D)
Population: Pharmacokinetic (PK) subgroup: Subset of participants who were randomized, received at least (\>=) 1 dose of ISIS 678354, had \>= 1 evaluable concentration result post first dose and had additional PK sampling after dose administration on Day 1 and Week 21 (Cohorts A and B) or Week 25 (Cohorts C and D). 'Number analyzed' = participants evaluable for this outcome measure at specified time points.
| Arm | Measure | Group | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|---|
| Pooled Placebo | Maximum Plasma Concentration (Cmax) of ISIS 678354 | Week 21 (for Cohorts A and B) and Week 25 (for Cohorts C and D) | 41.0 nanograms per milliliter (ng/mL) | Geometric Coefficient of Variation 324.1 |
| Pooled Placebo | Maximum Plasma Concentration (Cmax) of ISIS 678354 | Day 1 | 53.7 nanograms per milliliter (ng/mL) | Geometric Coefficient of Variation 181.2 |
| Cohort A: ISIS 678354: 10 mg Q4W | Maximum Plasma Concentration (Cmax) of ISIS 678354 | Day 1 | 45.9 nanograms per milliliter (ng/mL) | Geometric Coefficient of Variation 36.2 |
| Cohort A: ISIS 678354: 10 mg Q4W | Maximum Plasma Concentration (Cmax) of ISIS 678354 | Week 21 (for Cohorts A and B) and Week 25 (for Cohorts C and D) | 48.0 nanograms per milliliter (ng/mL) | Geometric Coefficient of Variation 29.9 |
| Cohort C: ISIS 678354: 15 mg Q2W | Maximum Plasma Concentration (Cmax) of ISIS 678354 | Day 1 | 35.8 nanograms per milliliter (ng/mL) | Geometric Coefficient of Variation 71.1 |
| Cohort C: ISIS 678354: 15 mg Q2W | Maximum Plasma Concentration (Cmax) of ISIS 678354 | Week 21 (for Cohorts A and B) and Week 25 (for Cohorts C and D) | 45.1 nanograms per milliliter (ng/mL) | Geometric Coefficient of Variation 47.4 |
| Cohort D: ISIS 678354: 10 mg QW | Maximum Plasma Concentration (Cmax) of ISIS 678354 | Week 21 (for Cohorts A and B) and Week 25 (for Cohorts C and D) | 127 nanograms per milliliter (ng/mL) | Geometric Coefficient of Variation 29.9 |
| Cohort D: ISIS 678354: 10 mg QW | Maximum Plasma Concentration (Cmax) of ISIS 678354 | Day 1 | 48.8 nanograms per milliliter (ng/mL) | Geometric Coefficient of Variation 333.3 |
Secondary
Percentage of Participants Who Achieved Fasting Triglycerides (TG) <= 100 mg/dL (<= 1.13 mmol/L)
The percentage of participants who achieved \<= 100 mg/dL or \<= 1.13 mmol/L of fasting TG levels at the primary analysis time point were compared between each ISIS 678354 treatment group and pooled placebo group using a logistic regression model with log-transformed baseline TG value as a covariate.
Time frame: Baseline and Month 6 (Week 25 for Cohorts A and B and Week 27 for Cohorts C and D)
Population: FAS included all participants who were randomized and received at least 1 dose of study drug (ISIS 678354 or placebo).
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Pooled Placebo | Percentage of Participants Who Achieved Fasting Triglycerides (TG) <= 100 mg/dL (<= 1.13 mmol/L) | 0 percentage of participants |
| Cohort A: ISIS 678354: 10 mg Q4W | Percentage of Participants Who Achieved Fasting Triglycerides (TG) <= 100 mg/dL (<= 1.13 mmol/L) | 0 percentage of participants |
| Cohort C: ISIS 678354: 15 mg Q2W | Percentage of Participants Who Achieved Fasting Triglycerides (TG) <= 100 mg/dL (<= 1.13 mmol/L) | 30.4 percentage of participants |
| Cohort D: ISIS 678354: 10 mg QW | Percentage of Participants Who Achieved Fasting Triglycerides (TG) <= 100 mg/dL (<= 1.13 mmol/L) | 26.1 percentage of participants |
| Cohort B: ISIS 678354: 50 mg Q4W | Percentage of Participants Who Achieved Fasting Triglycerides (TG) <= 100 mg/dL (<= 1.13 mmol/L) | 45.5 percentage of participants |
p-value: 0.911995% CI: [0.02, 69.88]Regression, Logistic
p-value: 0.030695% CI: [1.36, 542.48]Regression, Logistic
p-value: 0.034495% CI: [1.27, 514.2]Regression, Logistic
p-value: 0.012395% CI: [2.28, 866.49]Regression, Logistic
Secondary
Percentage of Participants Who Achieved Fasting Triglycerides (TG) <= 150 mg/dL (<= 1.7 Millimoles Per Liter [mmol/L])
The percentage of participants who achieved \<= 150 mg/dL or \<= 1.7 mmol/L of fasting TG levels at the primary analysis time point were compared between each ISIS 678354 treatment group and pooled placebo group using a logistic regression model with log-transformed baseline TG value as a covariate.
Time frame: Baseline and Month 6 (Week 25 for Cohorts A and B and Week 27 for Cohorts C and D)
Population: FAS included all participants who were randomized and received at least 1 dose of study drug (ISIS 678354 or placebo).
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Pooled Placebo | Percentage of Participants Who Achieved Fasting Triglycerides (TG) <= 150 mg/dL (<= 1.7 Millimoles Per Liter [mmol/L]) | 4.2 percentage of participants |
| Cohort A: ISIS 678354: 10 mg Q4W | Percentage of Participants Who Achieved Fasting Triglycerides (TG) <= 150 mg/dL (<= 1.7 Millimoles Per Liter [mmol/L]) | 13.6 percentage of participants |
| Cohort C: ISIS 678354: 15 mg Q2W | Percentage of Participants Who Achieved Fasting Triglycerides (TG) <= 150 mg/dL (<= 1.7 Millimoles Per Liter [mmol/L]) | 65.2 percentage of participants |
| Cohort D: ISIS 678354: 10 mg QW | Percentage of Participants Who Achieved Fasting Triglycerides (TG) <= 150 mg/dL (<= 1.7 Millimoles Per Liter [mmol/L]) | 73.9 percentage of participants |
| Cohort B: ISIS 678354: 50 mg Q4W | Percentage of Participants Who Achieved Fasting Triglycerides (TG) <= 150 mg/dL (<= 1.7 Millimoles Per Liter [mmol/L]) | 90.9 percentage of participants |
p-value: 0.259195% CI: [0.41, 27.2]Regression, Logistic
p-value: <0.000195% CI: [9.54, 740.02]Regression, Logistic
p-value: <0.000195% CI: [20.31, 5130.99]Regression, Logistic
p-value: <0.000195% CI: [23.72, 4933.89]Regression, Logistic
Secondary
Percent Change From Baseline in ApoC-III, TC, LDL-C, HDL-C, Non-HDL-C, VLDL-C, ApoB, and ApoA-I at the Primary Analysis Time Point
An ANCOVA model was performed on the log ratio of Primary Analysis Time Point value to Baseline value for ApoC-III, TC, LDL-C, HDL-C, Non-HDL-C, VLDL-C, ApoB, and ApoA-I. The estimate of the log ratio was converted back to the original scale and percent change for each lipid parameter was calculated using formula: (ratio of Primary Analysis Time Point value to Baseline value - 1) × 100.
Time frame: Baseline and Month 6 (Week 25 for Cohorts A and B and Week 27 for Cohorts C and D)
Population: FAS included all participants who were randomized and received at least 1 dose of study drug (ISIS 678354 or placebo). Here, 'Number analyzed' ('n') = Participants evaluable for this outcome measure for each specified category.
| Arm | Measure | Group | Value (MEAN) |
|---|---|---|---|
| Pooled Placebo | Percent Change From Baseline in ApoC-III, TC, LDL-C, HDL-C, Non-HDL-C, VLDL-C, ApoB, and ApoA-I at the Primary Analysis Time Point | Apo-C III | 2 percent change |
| Pooled Placebo | Percent Change From Baseline in ApoC-III, TC, LDL-C, HDL-C, Non-HDL-C, VLDL-C, ApoB, and ApoA-I at the Primary Analysis Time Point | TC | 1 percent change |
| Pooled Placebo | Percent Change From Baseline in ApoC-III, TC, LDL-C, HDL-C, Non-HDL-C, VLDL-C, ApoB, and ApoA-I at the Primary Analysis Time Point | LDL-C | -2 percent change |
| Pooled Placebo | Percent Change From Baseline in ApoC-III, TC, LDL-C, HDL-C, Non-HDL-C, VLDL-C, ApoB, and ApoA-I at the Primary Analysis Time Point | HDL-C | -1 percent change |
| Pooled Placebo | Percent Change From Baseline in ApoC-III, TC, LDL-C, HDL-C, Non-HDL-C, VLDL-C, ApoB, and ApoA-I at the Primary Analysis Time Point | Non-HDL-C | 1 percent change |
| Pooled Placebo | Percent Change From Baseline in ApoC-III, TC, LDL-C, HDL-C, Non-HDL-C, VLDL-C, ApoB, and ApoA-I at the Primary Analysis Time Point | VLDL-C | -2 percent change |
| Pooled Placebo | Percent Change From Baseline in ApoC-III, TC, LDL-C, HDL-C, Non-HDL-C, VLDL-C, ApoB, and ApoA-I at the Primary Analysis Time Point | ApoB | -2 percent change |
| Pooled Placebo | Percent Change From Baseline in ApoC-III, TC, LDL-C, HDL-C, Non-HDL-C, VLDL-C, ApoB, and ApoA-I at the Primary Analysis Time Point | ApoA-1 | 0 percent change |
| Cohort A: ISIS 678354: 10 mg Q4W | Percent Change From Baseline in ApoC-III, TC, LDL-C, HDL-C, Non-HDL-C, VLDL-C, ApoB, and ApoA-I at the Primary Analysis Time Point | LDL-C | 5 percent change |
| Cohort A: ISIS 678354: 10 mg Q4W | Percent Change From Baseline in ApoC-III, TC, LDL-C, HDL-C, Non-HDL-C, VLDL-C, ApoB, and ApoA-I at the Primary Analysis Time Point | VLDL-C | -22 percent change |
| Cohort A: ISIS 678354: 10 mg Q4W | Percent Change From Baseline in ApoC-III, TC, LDL-C, HDL-C, Non-HDL-C, VLDL-C, ApoB, and ApoA-I at the Primary Analysis Time Point | Apo-C III | -29 percent change |
| Cohort A: ISIS 678354: 10 mg Q4W | Percent Change From Baseline in ApoC-III, TC, LDL-C, HDL-C, Non-HDL-C, VLDL-C, ApoB, and ApoA-I at the Primary Analysis Time Point | HDL-C | 11 percent change |
| Cohort A: ISIS 678354: 10 mg Q4W | Percent Change From Baseline in ApoC-III, TC, LDL-C, HDL-C, Non-HDL-C, VLDL-C, ApoB, and ApoA-I at the Primary Analysis Time Point | TC | -2 percent change |
| Cohort A: ISIS 678354: 10 mg Q4W | Percent Change From Baseline in ApoC-III, TC, LDL-C, HDL-C, Non-HDL-C, VLDL-C, ApoB, and ApoA-I at the Primary Analysis Time Point | ApoA-1 | 5 percent change |
| Cohort A: ISIS 678354: 10 mg Q4W | Percent Change From Baseline in ApoC-III, TC, LDL-C, HDL-C, Non-HDL-C, VLDL-C, ApoB, and ApoA-I at the Primary Analysis Time Point | Non-HDL-C | -6 percent change |
| Cohort A: ISIS 678354: 10 mg Q4W | Percent Change From Baseline in ApoC-III, TC, LDL-C, HDL-C, Non-HDL-C, VLDL-C, ApoB, and ApoA-I at the Primary Analysis Time Point | ApoB | 0 percent change |
| Cohort C: ISIS 678354: 15 mg Q2W | Percent Change From Baseline in ApoC-III, TC, LDL-C, HDL-C, Non-HDL-C, VLDL-C, ApoB, and ApoA-I at the Primary Analysis Time Point | ApoB | -17 percent change |
| Cohort C: ISIS 678354: 15 mg Q2W | Percent Change From Baseline in ApoC-III, TC, LDL-C, HDL-C, Non-HDL-C, VLDL-C, ApoB, and ApoA-I at the Primary Analysis Time Point | ApoA-1 | 14 percent change |
| Cohort C: ISIS 678354: 15 mg Q2W | Percent Change From Baseline in ApoC-III, TC, LDL-C, HDL-C, Non-HDL-C, VLDL-C, ApoB, and ApoA-I at the Primary Analysis Time Point | HDL-C | 33 percent change |
| Cohort C: ISIS 678354: 15 mg Q2W | Percent Change From Baseline in ApoC-III, TC, LDL-C, HDL-C, Non-HDL-C, VLDL-C, ApoB, and ApoA-I at the Primary Analysis Time Point | VLDL-C | -54 percent change |
| Cohort C: ISIS 678354: 15 mg Q2W | Percent Change From Baseline in ApoC-III, TC, LDL-C, HDL-C, Non-HDL-C, VLDL-C, ApoB, and ApoA-I at the Primary Analysis Time Point | LDL-C | 2 percent change |
| Cohort C: ISIS 678354: 15 mg Q2W | Percent Change From Baseline in ApoC-III, TC, LDL-C, HDL-C, Non-HDL-C, VLDL-C, ApoB, and ApoA-I at the Primary Analysis Time Point | TC | -12 percent change |
| Cohort C: ISIS 678354: 15 mg Q2W | Percent Change From Baseline in ApoC-III, TC, LDL-C, HDL-C, Non-HDL-C, VLDL-C, ApoB, and ApoA-I at the Primary Analysis Time Point | Apo-C III | -68 percent change |
| Cohort C: ISIS 678354: 15 mg Q2W | Percent Change From Baseline in ApoC-III, TC, LDL-C, HDL-C, Non-HDL-C, VLDL-C, ApoB, and ApoA-I at the Primary Analysis Time Point | Non-HDL-C | -24 percent change |
| Cohort D: ISIS 678354: 10 mg QW | Percent Change From Baseline in ApoC-III, TC, LDL-C, HDL-C, Non-HDL-C, VLDL-C, ApoB, and ApoA-I at the Primary Analysis Time Point | TC | -3 percent change |
| Cohort D: ISIS 678354: 10 mg QW | Percent Change From Baseline in ApoC-III, TC, LDL-C, HDL-C, Non-HDL-C, VLDL-C, ApoB, and ApoA-I at the Primary Analysis Time Point | LDL-C | 27 percent change |
| Cohort D: ISIS 678354: 10 mg QW | Percent Change From Baseline in ApoC-III, TC, LDL-C, HDL-C, Non-HDL-C, VLDL-C, ApoB, and ApoA-I at the Primary Analysis Time Point | HDL-C | 40 percent change |
| Cohort D: ISIS 678354: 10 mg QW | Percent Change From Baseline in ApoC-III, TC, LDL-C, HDL-C, Non-HDL-C, VLDL-C, ApoB, and ApoA-I at the Primary Analysis Time Point | Non-HDL-C | -15 percent change |
| Cohort D: ISIS 678354: 10 mg QW | Percent Change From Baseline in ApoC-III, TC, LDL-C, HDL-C, Non-HDL-C, VLDL-C, ApoB, and ApoA-I at the Primary Analysis Time Point | VLDL-C | -59 percent change |
| Cohort D: ISIS 678354: 10 mg QW | Percent Change From Baseline in ApoC-III, TC, LDL-C, HDL-C, Non-HDL-C, VLDL-C, ApoB, and ApoA-I at the Primary Analysis Time Point | ApoA-1 | 18 percent change |
| Cohort D: ISIS 678354: 10 mg QW | Percent Change From Baseline in ApoC-III, TC, LDL-C, HDL-C, Non-HDL-C, VLDL-C, ApoB, and ApoA-I at the Primary Analysis Time Point | Apo-C III | -73 percent change |
| Cohort D: ISIS 678354: 10 mg QW | Percent Change From Baseline in ApoC-III, TC, LDL-C, HDL-C, Non-HDL-C, VLDL-C, ApoB, and ApoA-I at the Primary Analysis Time Point | ApoB | -7 percent change |
| Cohort B: ISIS 678354: 50 mg Q4W | Percent Change From Baseline in ApoC-III, TC, LDL-C, HDL-C, Non-HDL-C, VLDL-C, ApoB, and ApoA-I at the Primary Analysis Time Point | HDL-C | 29 percent change |
| Cohort B: ISIS 678354: 50 mg Q4W | Percent Change From Baseline in ApoC-III, TC, LDL-C, HDL-C, Non-HDL-C, VLDL-C, ApoB, and ApoA-I at the Primary Analysis Time Point | ApoA-1 | 14 percent change |
| Cohort B: ISIS 678354: 50 mg Q4W | Percent Change From Baseline in ApoC-III, TC, LDL-C, HDL-C, Non-HDL-C, VLDL-C, ApoB, and ApoA-I at the Primary Analysis Time Point | LDL-C | 10 percent change |
| Cohort B: ISIS 678354: 50 mg Q4W | Percent Change From Baseline in ApoC-III, TC, LDL-C, HDL-C, Non-HDL-C, VLDL-C, ApoB, and ApoA-I at the Primary Analysis Time Point | ApoB | -12 percent change |
| Cohort B: ISIS 678354: 50 mg Q4W | Percent Change From Baseline in ApoC-III, TC, LDL-C, HDL-C, Non-HDL-C, VLDL-C, ApoB, and ApoA-I at the Primary Analysis Time Point | Apo-C III | -74 percent change |
| Cohort B: ISIS 678354: 50 mg Q4W | Percent Change From Baseline in ApoC-III, TC, LDL-C, HDL-C, Non-HDL-C, VLDL-C, ApoB, and ApoA-I at the Primary Analysis Time Point | VLDL-C | -60 percent change |
| Cohort B: ISIS 678354: 50 mg Q4W | Percent Change From Baseline in ApoC-III, TC, LDL-C, HDL-C, Non-HDL-C, VLDL-C, ApoB, and ApoA-I at the Primary Analysis Time Point | TC | -8 percent change |
| Cohort B: ISIS 678354: 50 mg Q4W | Percent Change From Baseline in ApoC-III, TC, LDL-C, HDL-C, Non-HDL-C, VLDL-C, ApoB, and ApoA-I at the Primary Analysis Time Point | Non-HDL-C | -19 percent change |
Comparison: HDL-Cp-value: <0.000195% CI: [28, 57]ANCOVA
Comparison: ApoC IIIp-value: 0.012395% CI: [-47, -8]ANCOVA
Comparison: Apo-C IIIp-value: <0.000195% CI: [-76, -58]ANCOVA
Comparison: Apo-C IIIp-value: <0.000195% CI: [-80, -65]ANCOVA
Comparison: Apo-C IIIp-value: <0.000195% CI: [-80, -66]ANCOVA
Comparison: TCp-value: 0.56895% CI: [-11, 7]ANCOVA
Comparison: TCp-value: 0.00895% CI: [-19, -3]ANCOVA
Comparison: TCp-value: 0.447695% CI: [-12, 6]ANCOVA
Comparison: TCp-value: 0.060695% CI: [-16, 0]ANCOVA
Comparison: LDL-Cp-value: 0.450995% CI: [-10, 26]ANCOVA
Comparison: LDL-Cp-value: 0.674695% CI: [-12, 23]ANCOVA
Comparison: LDL-Cp-value: 0.003295% CI: [9, 53]ANCOVA
Comparison: LDL-Cp-value: 0.199695% CI: [-6, 32]ANCOVA
Comparison: HDL-Cp-value: 0.037395% CI: [1, 24]ANCOVA
Comparison: HDL-Cp-value: <0.000195% CI: [21, 49]ANCOVA
Comparison: HDL-Cp-value: <0.000195% CI: [18, 44]ANCOVA
Comparison: Non-HDL-Cp-value: 0.282695% CI: [-18, 6]ANCOVA
Comparison: Non-HDL-Cp-value: <0.000195% CI: [-34, -14]ANCOVA
Comparison: Non-HDL-Cp-value: 0.011895% CI: [-26, -4]ANCOVA
Comparison: Non-HDL-Cp-value: 0.000995% CI: [-29, -9]ANCOVA
Comparison: VLDL-Cp-value: 0.008695% CI: [-34, -6]ANCOVA
Comparison: VLDL-Cp-value: <0.000195% CI: [-60, -44]ANCOVA
Comparison: VLDL-Cp-value: <0.000195% CI: [-64, -50]ANCOVA
Comparison: VLDL-Cp-value: <0.000195% CI: [-66, -52]ANCOVA
Comparison: ApoBp-value: 0.680195% CI: [-7, 13]ANCOVA
Comparison: ApoBp-value: 0.000795% CI: [-24, -7]ANCOVA
Comparison: ApoBp-value: 0.318395% CI: [-14, 5]ANCOVA
Comparison: ApoBp-value: 0.02495% CI: [-19, -1]ANCOVA
Comparison: ApoA-Ip-value: 0.093695% CI: [-1, 11]ANCOVA
Comparison: ApoA-Ip-value: <0.000195% CI: [8, 21]ANCOVA
Comparison: ApoA-Ip-value: <0.000195% CI: [11, 25]ANCOVA
Comparison: ApoA-Ip-value: <0.000195% CI: [7, 20]ANCOVA
Secondary
Time to Reach Maximum Plasma Concentration (Tmax) of ISIS 678354
Time frame: Predose, 1, 2, 4, 8, 24 hours post the first dose (Day 1), Week 21 (for Cohorts A and B) and Week 25 (for Cohorts C and D)
Population: PK subgroup: Subset of participants who were randomized, received \>= 1 dose of ISIS 678354, had \>= 1 evaluable concentration result post first dose and had additional PK sampling after dose administration on Day 1 and Week 21 (Cohorts A and B) or Week 25 (Cohorts C and D). 'Number analyzed' = participants evaluable for this outcome measure at specified time points.
| Arm | Measure | Group | Value (MEDIAN) |
|---|---|---|---|
| Pooled Placebo | Time to Reach Maximum Plasma Concentration (Tmax) of ISIS 678354 | Day 1 | 1.08 hours (h) |
| Pooled Placebo | Time to Reach Maximum Plasma Concentration (Tmax) of ISIS 678354 | Week 21 (for Cohorts A and B) and Week 25 (for Cohorts C and D) | 2.00 hours (h) |
| Cohort A: ISIS 678354: 10 mg Q4W | Time to Reach Maximum Plasma Concentration (Tmax) of ISIS 678354 | Week 21 (for Cohorts A and B) and Week 25 (for Cohorts C and D) | 2.08 hours (h) |
| Cohort A: ISIS 678354: 10 mg Q4W | Time to Reach Maximum Plasma Concentration (Tmax) of ISIS 678354 | Day 1 | 2.00 hours (h) |
| Cohort C: ISIS 678354: 15 mg Q2W | Time to Reach Maximum Plasma Concentration (Tmax) of ISIS 678354 | Day 1 | 3.03 hours (h) |
| Cohort C: ISIS 678354: 15 mg Q2W | Time to Reach Maximum Plasma Concentration (Tmax) of ISIS 678354 | Week 21 (for Cohorts A and B) and Week 25 (for Cohorts C and D) | 2.50 hours (h) |
| Cohort D: ISIS 678354: 10 mg QW | Time to Reach Maximum Plasma Concentration (Tmax) of ISIS 678354 | Day 1 | 1.50 hours (h) |
| Cohort D: ISIS 678354: 10 mg QW | Time to Reach Maximum Plasma Concentration (Tmax) of ISIS 678354 | Week 21 (for Cohorts A and B) and Week 25 (for Cohorts C and D) | 4.04 hours (h) |