Dyslipidemias, Hypercholesterolemia, Hyperlipidemias, Lipid Metabolism Disorders, Metabolic Diseases, Metabolic Disorder
Conditions
Keywords
statin intolerant, hypercholesterolemia
Brief summary
The purpose of this study is to determine safety and efficacy of mipomersen (ISIS 301012) in the reduction of total cholesterol, low density lipoprotein cholesterol (LDL-C), and apolipoprotein B (apoB) in high risk subjects intolerant to statins.
Detailed description
In humans, apoB is the principal apolipoprotein of the atherogenic lipoproteins, comprising very low-density lipoprotein (VLDL), intermediate density lipoprotein (IDL) and low density lipoprotein (LDL). ApoB messenger ribonucleic acid (mRNA) is abundantly present in the liver. Within the endoplasmatic reticulum, apoB requires lipidation by microsomal triglyceride transfer protein, which allows apoB to be incorporated in the VLDL particle within the lumen of the endoplasmatic reticulum. Non-lipidated apoB is readily degraded via ubiquitination. Notably, apoB within the VLDL particle is obligatory for hepatic secretion of VLDL. ApoB remains present within the VLDL-metabolism pathway, from secretion to clearance of the end product LDL by the liver LDL receptor. As a consequence, apoB reliably reflects the total burden of atherogenic lipoproteins. Thus, apoB carries strong prognostic value for cardiovascular events, which exceeds the predictive value of LDL-C. Conversely, decreased levels of apoB (e.g. in familial hypobetalipoproteinemia) have been associated with reduced levels of atherosclerosis. These genetic observations have prompted interest in pharmacologic inhibition of apoB synthesis. Mipomersen (ISIS 301012) is an antisense drug targeted to human apoB, the principal apolipoprotein of LDL and its metabolic precursor, VLDL. Mipomersen (ISIS 301012) is complementary to the coding region of the mRNA for apoB, binding by Watson and Crick base pairing. The hybridization (binding) of mipomersen (ISIS 301012) to the cognate mRNA results in Ribonuclease (RNase) H-mediated degradation of the cognate mRNA, thus inhibiting translation of the apoB protein. This was a randomized, double-blind, placebo-controlled Phase 2 study to assess the safety and efficacy of mipomersen administration in high-risk statin-intolerant patients with hypercholesterolemia. This study consisted of a ≤3-week screening period, 26 weeks of treatment, and a 24-week post-treatment follow-up period. Eligible patients were randomized in a 2:1 ratio to receive mipomersen 200 mg or matching volume placebo subcutaneous (SC) injections weekly. Following the screening visit, eligible patients returned to the study center for clinical evaluation every week for study drug administration and assessments.
Interventions
DRUGmipomersen
DRUGplacebo
Sponsors
Ionis Pharmaceuticals, Inc.
Kastle Therapeutics, LLC
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
* Diagnosis of statin intolerance * Diagnosis of Coronary Artery Disease (CAD) * Diagnosis of hypercholesterolemia * Stable weight for \> 6 weeks
Exclusion criteria
* Significant health problems in the recent past (≤24 weeks) including heart attack, heart surgery, heart failure, uncontrolled hypothyroidism, blood disorders, digestive problems, disease of central nervous system, cancer, liver or renal disease
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Percent Change From Baseline in Low-density Lipoprotein Cholesterol (LDL-C) at the Primary Efficacy Time Point | Baseline (the average of the screening and Day 1 pre-treatment assessments) and the Primary Efficacy Time point (PET; Week 28 or the post-baseline visit closest to 14 days after the last dose). | LDL-C was measured in mg/dL. Samples were taken following an overnight fast. For patients with triglycerides \<400 mg/dL, LDL-C was obtained using Friedewald's calculation; and for patients with triglycerides ≥400 mg/dL, LDL-C was directly measured by the central laboratory using ultracentrifugation. The primary efficacy time point was the post-baseline visit closest to 14 days after the last dose of study treatment. |
| Low-density Lipoprotein Cholesterol at Baseline and the Primary Efficacy Time Point | Baseline (the average of the screening and Day 1 pre-treatment assessments) and the Primary Efficacy Time point (PET; Week 28 or the post-baseline visit closest to 14 days after the last dose). | The primary efficacy time point (PET) was the post-baseline visit closest to 14 days after the last dose of study treatment. |
| Summary of Participants With Adverse Events | Pre-treatment (prior to first dose), On-treatment (Day 1 to week 28), Post-treatment (Week 28-52) | The on-treatment time frame spanned the time during which the study drug was administered until the later of the primary efficacy time point and 14 days beyond the last study drug date. Adverse events (AEs) were considered related if assessed by the Investigator as possibly, probably or definitely related to study drug. Severity was assessed as: * Mild-symptom barely noticeable to the patient or do not make the patient uncomfortable; * Moderate-symptom makes the patient uncomfortable, affects performance of daily activities; * Severe-symptom causes the patient severe discomfort, may cause cessation of treatment with the study drug. Serious AEs (SAEs) are those that resulted in death, were life-threatening, required or prolonged inpatient hospitalization, resulted in persistent or significant disability/incapacity, congenital anomaly, or resulted in an important medical event that may have jeopardized the patient or required medical or surgical intervention. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Total Cholesterol at Baseline and at the Primary Efficacy Time Point | Baseline (the average of the screening and Day 1 pre-treatment assessments) and the Primary Efficacy Time point (PET; Week 28 or the post-baseline visit closest to 14 days after the last dose). | The primary efficacy time point (PET) was the post-baseline visit closest to 14 days after the last dose of study treatment. |
| Percent Change From Baseline in Apolipoprotein B at the Primary Efficacy Time Point | Baseline (the average of the screening and Day 1 pre-treatment assessments) and the Primary Efficacy Time point (PET; Week 28 or the post-baseline visit closest to 14 days after the last dose). | Apolipoprotein B was measured in mg/dL. Samples were taken following an overnight fast. The primary efficacy time point was the post-baseline visit closest to 14 days after the last dose of study treatment. |
| Non-High-Density Lipoprotein Cholesterol at Baseline and at the Primary Efficacy Time Point | Baseline (the average of the screening and Day 1 pre-treatment assessments) and the Primary Efficacy Time point (PET; Week 28 or the post-baseline visit closest to 14 days after the last dose). | The primary efficacy time point (PET) was the post-baseline visit closest to 14 days after the last dose of study treatment. |
| Percent Change From Baseline in Non-High-Density Lipoprotein Cholesterol at the Primary Efficacy Time Point | Baseline (the average of the screening and Day 1 pre-treatment assessments) and the Primary Efficacy Time point (PET; Week 28 or the post-baseline visit closest to 14 days after the last dose). | Non-high-density lipoprotein cholesterol was measured in mg/dL. Samples were taken following an overnight fast. The primary efficacy time point was the post-baseline visit closest to 14 days after the last dose of study treatment. |
| Apolipoprotein B at Baseline and at the Primary Efficacy Time Point | Baseline (the average of the screening and Day 1 pre-treatment assessments) and the Primary Efficacy Time point (PET; Week 28 or the post-baseline visit closest to 14 days after the last dose). | The primary efficacy time point (PET) was the post-baseline visit closest to 14 days after the last dose of study treatment. |
| Percent Change From Baseline in Total Cholesterol at the Primary Efficacy Time Point | Baseline (the average of the screening and Day 1 pre-treatment assessments) and the Primary Efficacy Time point (PET; Week 28 or the post-baseline visit closest to 14 days after the last dose). | Total cholesterol was measured in mg/dL. Samples were taken following an overnight fast. The primary efficacy time point was the post-baseline visit closest to 14 days after the last dose of study treatment. |
Other
| Measure | Time frame | Description |
|---|---|---|
| Apolipoprotein A1 at Baseline and at the Primary Efficacy Time Point | Baseline (the average of the screening and Day 1 pre-treatment assessments) and the Primary Efficacy Time point (PET; Week 28 or the post-baseline visit closest to 14 days after the last dose). | The primary efficacy time point (PET) was the post-baseline visit closest to 14 days after the last dose of study treatment. |
| Percent Change From Baseline in Triglycerides at the Primary Efficacy Time Point | Baseline (the average of the screening and Day 1 pre-treatment assessments) and the Primary Efficacy Time point (PET; Week 28 or the post-baseline visit closest to 14 days after the last dose). | Triglycerides were measured in mg/dL. Samples were taken following an overnight fast. The primary efficacy time point was the post-baseline visit closest to 14 days after the last dose of study treatment. |
| High-Density Lipoprotein Cholesterol at Baseline and at the Primary Efficacy Time Point | Baseline (the average of the screening and Day 1 pre-treatment assessments) and the Primary Efficacy Time point (PET; Week 28 or the post-baseline visit closest to 14 days after the last dose). | The primary efficacy time point (PET) was the post-baseline visit closest to 14 days after the last dose of study treatment. |
| Percent Change From Baseline in High-Density Lipoprotein Cholesterol at the Primary Efficacy Time Point | Baseline (the average of the screening and Day 1 pre-treatment assessments) and the Primary Efficacy Time point (PET; Week 28 or the post-baseline visit closest to 14 days after the last dose). | High-density lipoprotein cholesterol (HDL-C) was measured in mg/dL. Samples were taken following an overnight fast. The primary efficacy time point was the post-baseline visit closest to 14 days after the last dose of study treatment. |
| Triglycerides at Baseline and at the Primary Efficacy Time Point | Baseline (the average of the screening and Day 1 pre-treatment assessments) and the Primary Efficacy Time point (PET; Week 28 or the post-baseline visit closest to 14 days after the last dose). | The primary efficacy time point (PET) was the post-baseline visit closest to 14 days after the last dose of study treatment. |
| Percent Change From Baseline in Lipoprotein (a) at the Primary Efficacy Time Point | Baseline (the average of the screening and Day 1 pre-treatment assessments) and the Primary Efficacy Time point (PET; Week 28 or the post-baseline visit closest to 14 days after the last dose). | Lipoprotein (a) was measured in mg/dL. Samples were taken following an overnight fast. The primary efficacy time point was the post-baseline visit closest to 14 days after the last dose of study treatment. |
| Lipoprotein (a) at Baseline and at the Primary Efficacy Time Point | Baseline (the average of the screening and Day 1 pre-treatment assessments) and the Primary Efficacy Time point (PET; Week 28 or the post-baseline visit closest to 14 days after the last dose). | The primary efficacy time point (PET) was the post-baseline visit closest to 14 days after the last dose of study treatment. |
| Percent Change From Baseline in Very Low Density Lipoprotein Cholesterol at the Primary Efficacy Time Point | Baseline (the average of the screening and Day 1 pre-treatment assessments) and the Primary Efficacy Time point (PET; Week 28 or the post-baseline visit closest to 14 days after the last dose). | Very low density lipoprotein cholesterol was measured in mg/dL. Samples were taken following an overnight fast. The primary efficacy time point was the post-baseline visit closest to 14 days after the last dose of study treatment. |
| Very Low Density Lipoprotein Cholesterol at Baseline and at the Primary Efficacy Time Point | Baseline (the average of the screening and Day 1 pre-treatment assessments) and the Primary Efficacy Time point (PET; Week 28 or the post-baseline visit closest to 14 days after the last dose). | The primary efficacy time point (PET) was the post-baseline visit closest to 14 days after the last dose of study treatment. |
| Percent Change From Baseline in the Ratio of Low-Density Lipoprotein Cholesterol to High-Density Lipoprotein Cholesterol at the Primary Efficacy Time Point | Baseline (the average of the screening and Day 1 pre-treatment assessments) and the Primary Efficacy Time point (PET; Week 28 or the post-baseline visit closest to 14 days after the last dose). | The ratio of low-density lipoprotein (LDL) cholesterol to high-density lipoprotein (HDL) cholesterol was measured in mg/dL. Samples were taken following an overnight fast. The primary efficacy time point was the post-baseline visit closest to 14 days after the last dose of study treatment. |
| Ratio of Low-Density Lipoprotein Cholesterol to High-Density Lipoprotein Cholesterol at Baseline and at the Primary Efficacy Time Point | Baseline (the average of the screening and Day 1 pre-treatment assessments) and the Primary Efficacy Time point (PET; Week 28 or the post-baseline visit closest to 14 days after the last dose). | The primary efficacy time point (PET) was the post-baseline visit closest to 14 days after the last dose of study treatment. |
| Percent Change From Baseline in Apolipoprotein A1 at the Primary Efficacy Time Point | Baseline (the average of the screening and Day 1 pre-treatment assessments) and the Primary Efficacy Time point (PET; Week 28 or the post-baseline visit closest to 14 days after the last dose). | Apolipoprotein A1 was measured in mg/dL. Samples were taken following an overnight fast. The primary efficacy time point was the post-baseline visit closest to 14 days after the last dose of study treatment. |
Countries
Netherlands
Participant flow
Pre-assignment details
42 patients were screened, 34 participants were randomized, and 33 participants were treated: 21 participants to mipomersen and 12 participants to placebo.
Participants by arm
| Arm | Count |
|---|---|
| Placebo 1 mL placebo saline, weekly subcutaneous injections for 26 weeks | 12 |
| Mipomersen 200 mg (1 mL) of mipomersen, weekly subcutaneous injections for 26 weeks | 21 |
| Total | 33 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Treatment Period | Adverse Event | 2 | 4 |
| Treatment Period | Ineligibility | 0 | 1 |
Baseline characteristics
| Characteristic | Placebo | Mipomersen | Total |
|---|---|---|---|
| Age, Continuous | 51.7 years STANDARD_DEVIATION 8.7 | 55.6 years STANDARD_DEVIATION 6.8 | 54.2 years STANDARD_DEVIATION 7.6 |
| Alcohol use Current | 8 participants | 16 participants | 24 participants |
| Alcohol use Never | 2 participants | 2 participants | 4 participants |
| Alcohol use Non-current | 2 participants | 3 participants | 5 participants |
| Body Mass Index (BMI) | 26.06 kg/m^2 STANDARD_DEVIATION 2.49 | 26.46 kg/m^2 STANDARD_DEVIATION 3.25 | 26.31 kg/m^2 STANDARD_DEVIATION 2.96 |
| Ethnicity (NIH/OMB) Hispanic or Latino | 0 Participants | 0 Participants | 0 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 12 Participants | 21 Participants | 33 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants | 0 Participants |
| Metabolic syndrome No | 4 participants | 12 participants | 16 participants |
| Metabolic syndrome Yes | 8 participants | 9 participants | 17 participants |
| Race/Ethnicity, Customized Black | 0 participants | 1 participants | 1 participants |
| Race/Ethnicity, Customized White | 12 participants | 20 participants | 32 participants |
| Sex: Female, Male Female | 8 Participants | 10 Participants | 18 Participants |
| Sex: Female, Male Male | 4 Participants | 11 Participants | 15 Participants |
| Tobacco Use Current | 2 participants | 6 participants | 8 participants |
| Tobacco Use Never | 5 participants | 6 participants | 11 participants |
| Tobacco Use Non-current | 5 participants | 9 participants | 14 participants |
| Waist/hip Ratio | 0.92 ratio STANDARD_DEVIATION 0.09 | 0.93 ratio STANDARD_DEVIATION 0.08 | 0.93 ratio STANDARD_DEVIATION 0.08 |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — |
| other Total, other adverse events | 12 / 12 | 21 / 21 |
| serious Total, serious adverse events | 1 / 12 | 0 / 21 |
Outcome results
Primary
Low-density Lipoprotein Cholesterol at Baseline and the Primary Efficacy Time Point
The primary efficacy time point (PET) was the post-baseline visit closest to 14 days after the last dose of study treatment.
Time frame: Baseline (the average of the screening and Day 1 pre-treatment assessments) and the Primary Efficacy Time point (PET; Week 28 or the post-baseline visit closest to 14 days after the last dose).
Population: Full analysis set
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Placebo | Low-density Lipoprotein Cholesterol at Baseline and the Primary Efficacy Time Point | Baseline | 243.7 mg/dL | Standard Deviation 65.6 |
| Placebo | Low-density Lipoprotein Cholesterol at Baseline and the Primary Efficacy Time Point | Primary efficacy time point | 236.3 mg/dL | Standard Deviation 52.8 |
| Mipomersen | Low-density Lipoprotein Cholesterol at Baseline and the Primary Efficacy Time Point | Baseline | 241.9 mg/dL | Standard Deviation 90.8 |
| Mipomersen | Low-density Lipoprotein Cholesterol at Baseline and the Primary Efficacy Time Point | Primary efficacy time point | 128.3 mg/dL | Standard Deviation 74.2 |
Primary
Percent Change From Baseline in Low-density Lipoprotein Cholesterol (LDL-C) at the Primary Efficacy Time Point
LDL-C was measured in mg/dL. Samples were taken following an overnight fast. For patients with triglycerides \<400 mg/dL, LDL-C was obtained using Friedewald's calculation; and for patients with triglycerides ≥400 mg/dL, LDL-C was directly measured by the central laboratory using ultracentrifugation. The primary efficacy time point was the post-baseline visit closest to 14 days after the last dose of study treatment.
Time frame: Baseline (the average of the screening and Day 1 pre-treatment assessments) and the Primary Efficacy Time point (PET; Week 28 or the post-baseline visit closest to 14 days after the last dose).
Population: The Full Analysis Set, which consisted of all randomized patients who received at least 1 injection of study drug (mipomersen or placebo) and with a valid baseline and at least 1 post-baseline LDL-C measurement.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Placebo | Percent Change From Baseline in Low-density Lipoprotein Cholesterol (LDL-C) at the Primary Efficacy Time Point | -2.0 percentage of baseline | Standard Deviation 8.4 |
| Mipomersen | Percent Change From Baseline in Low-density Lipoprotein Cholesterol (LDL-C) at the Primary Efficacy Time Point | -47.3 percentage of baseline | Standard Deviation 18.43 |
Comparison: It was estimated that the standard deviation of the percent change in LDL-C was 20%. A sample size of 30 patients was planned for this study: 20 patients in the mipomersen group and 10 patients in the placebo group. A 2-sided t-test with an alpha level of 0.05 was expected to provide ≥90% power to detect a 30% difference in LDL-C percent reduction between the 2 groups (35% reduction for the mipomersen group and 5% reduction for the placebo group).p-value: <0.001t-test, 2 sided
Primary
Summary of Participants With Adverse Events
The on-treatment time frame spanned the time during which the study drug was administered until the later of the primary efficacy time point and 14 days beyond the last study drug date. Adverse events (AEs) were considered related if assessed by the Investigator as possibly, probably or definitely related to study drug. Severity was assessed as: * Mild-symptom barely noticeable to the patient or do not make the patient uncomfortable; * Moderate-symptom makes the patient uncomfortable, affects performance of daily activities; * Severe-symptom causes the patient severe discomfort, may cause cessation of treatment with the study drug. Serious AEs (SAEs) are those that resulted in death, were life-threatening, required or prolonged inpatient hospitalization, resulted in persistent or significant disability/incapacity, congenital anomaly, or resulted in an important medical event that may have jeopardized the patient or required medical or surgical intervention.
Time frame: Pre-treatment (prior to first dose), On-treatment (Day 1 to week 28), Post-treatment (Week 28-52)
Population: Safety set of all randomized participants who received at least one injection of study drug.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Placebo | Summary of Participants With Adverse Events | On-treatment SAEs-related | 1 participants |
| Placebo | Summary of Participants With Adverse Events | On-treatment SAEs-leading to trt discontinuation | 1 participants |
| Placebo | Summary of Participants With Adverse Events | On-treatment AEs | 12 participants |
| Placebo | Summary of Participants With Adverse Events | Deaths | 0 participants |
| Placebo | Summary of Participants With Adverse Events | On-treatment AEs-leading to trt discontinuation | 2 participants |
| Placebo | Summary of Participants With Adverse Events | On-treatment SAEs-moderate | 0 participants |
| Placebo | Summary of Participants With Adverse Events | On-treatment Serious Adverse Events (SAEs) | 1 participants |
| Placebo | Summary of Participants With Adverse Events | On-treatment AEs-moderate | 5 participants |
| Placebo | Summary of Participants With Adverse Events | Pre-treatment adverse events (AEs) | 3 participants |
| Placebo | Summary of Participants With Adverse Events | On-treatment AEs-related | 12 participants |
| Placebo | Summary of Participants With Adverse Events | Post-treatment AEs | 9 participants |
| Placebo | Summary of Participants With Adverse Events | On-treatment SAEs-severe | 1 participants |
| Placebo | Summary of Participants With Adverse Events | On-treatment AEs-severe | 1 participants |
| Placebo | Summary of Participants With Adverse Events | On-treatment AEs-mild | 6 participants |
| Placebo | Summary of Participants With Adverse Events | On-treatment SAEs-mild | 0 participants |
| Mipomersen | Summary of Participants With Adverse Events | On-treatment SAEs-related | 0 participants |
| Mipomersen | Summary of Participants With Adverse Events | On-treatment SAEs-moderate | 0 participants |
| Mipomersen | Summary of Participants With Adverse Events | On-treatment SAEs-severe | 0 participants |
| Mipomersen | Summary of Participants With Adverse Events | On-treatment SAEs-leading to trt discontinuation | 0 participants |
| Mipomersen | Summary of Participants With Adverse Events | Deaths | 0 participants |
| Mipomersen | Summary of Participants With Adverse Events | On-treatment Serious Adverse Events (SAEs) | 0 participants |
| Mipomersen | Summary of Participants With Adverse Events | On-treatment AEs-related | 21 participants |
| Mipomersen | Summary of Participants With Adverse Events | On-treatment AEs-leading to trt discontinuation | 4 participants |
| Mipomersen | Summary of Participants With Adverse Events | Post-treatment AEs | 20 participants |
| Mipomersen | Summary of Participants With Adverse Events | On-treatment AEs | 21 participants |
| Mipomersen | Summary of Participants With Adverse Events | On-treatment SAEs-mild | 0 participants |
| Mipomersen | Summary of Participants With Adverse Events | On-treatment AEs-mild | 5 participants |
| Mipomersen | Summary of Participants With Adverse Events | Pre-treatment adverse events (AEs) | 7 participants |
| Mipomersen | Summary of Participants With Adverse Events | On-treatment AEs-moderate | 16 participants |
| Mipomersen | Summary of Participants With Adverse Events | On-treatment AEs-severe | 0 participants |
Secondary
Apolipoprotein B at Baseline and at the Primary Efficacy Time Point
The primary efficacy time point (PET) was the post-baseline visit closest to 14 days after the last dose of study treatment.
Time frame: Baseline (the average of the screening and Day 1 pre-treatment assessments) and the Primary Efficacy Time point (PET; Week 28 or the post-baseline visit closest to 14 days after the last dose).
Population: Full analysis set
| Arm | Measure | Group | Value (MEDIAN) | Dispersion |
|---|---|---|---|---|
| Placebo | Apolipoprotein B at Baseline and at the Primary Efficacy Time Point | Baseline | 180 mg/dL | Inter-Quartile Range 65.6 |
| Placebo | Apolipoprotein B at Baseline and at the Primary Efficacy Time Point | Primary efficacy time point | 173 mg/dL | Inter-Quartile Range 52.8 |
| Mipomersen | Apolipoprotein B at Baseline and at the Primary Efficacy Time Point | Baseline | 177 mg/dL | Inter-Quartile Range 90.8 |
| Mipomersen | Apolipoprotein B at Baseline and at the Primary Efficacy Time Point | Primary efficacy time point | 96 mg/dL | Inter-Quartile Range 74.2 |
Secondary
Non-High-Density Lipoprotein Cholesterol at Baseline and at the Primary Efficacy Time Point
The primary efficacy time point (PET) was the post-baseline visit closest to 14 days after the last dose of study treatment.
Time frame: Baseline (the average of the screening and Day 1 pre-treatment assessments) and the Primary Efficacy Time point (PET; Week 28 or the post-baseline visit closest to 14 days after the last dose).
Population: Full analysis set
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Placebo | Non-High-Density Lipoprotein Cholesterol at Baseline and at the Primary Efficacy Time Point | Baseline | 273.5 mg/dL | Standard Deviation 65.3 |
| Placebo | Non-High-Density Lipoprotein Cholesterol at Baseline and at the Primary Efficacy Time Point | Primary efficacy time point | 266.0 mg/dL | Standard Deviation 53 |
| Mipomersen | Non-High-Density Lipoprotein Cholesterol at Baseline and at the Primary Efficacy Time Point | Baseline | 270.1 mg/dL | Standard Deviation 92.9 |
| Mipomersen | Non-High-Density Lipoprotein Cholesterol at Baseline and at the Primary Efficacy Time Point | Primary efficacy time point | 147.7 mg/dL | Standard Deviation 81.1 |
Secondary
Percent Change From Baseline in Apolipoprotein B at the Primary Efficacy Time Point
Apolipoprotein B was measured in mg/dL. Samples were taken following an overnight fast. The primary efficacy time point was the post-baseline visit closest to 14 days after the last dose of study treatment.
Time frame: Baseline (the average of the screening and Day 1 pre-treatment assessments) and the Primary Efficacy Time point (PET; Week 28 or the post-baseline visit closest to 14 days after the last dose).
Population: The Full Analysis Set, which consisted of all randomized patients who received at least 1 injection of study drug (mipomersen or placebo) and with a valid baseline and at least 1 post-baseline LDL-C measurement.
| Arm | Measure | Value (MEDIAN) | Dispersion |
|---|---|---|---|
| Placebo | Percent Change From Baseline in Apolipoprotein B at the Primary Efficacy Time Point | -4.0 percentage of baseline | Inter-Quartile Range 8.4 |
| Mipomersen | Percent Change From Baseline in Apolipoprotein B at the Primary Efficacy Time Point | -45.8 percentage of baseline | Inter-Quartile Range 18.43 |
p-value: <0.001Wilcoxon signed rank sum
Secondary
Percent Change From Baseline in Non-High-Density Lipoprotein Cholesterol at the Primary Efficacy Time Point
Non-high-density lipoprotein cholesterol was measured in mg/dL. Samples were taken following an overnight fast. The primary efficacy time point was the post-baseline visit closest to 14 days after the last dose of study treatment.
Time frame: Baseline (the average of the screening and Day 1 pre-treatment assessments) and the Primary Efficacy Time point (PET; Week 28 or the post-baseline visit closest to 14 days after the last dose).
Population: The Full Analysis Set, which consisted of all randomized patients who received at least 1 injection of study drug (mipomersen or placebo) and with a valid baseline and at least 1 post-baseline LDL-C measurement.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Placebo | Percent Change From Baseline in Non-High-Density Lipoprotein Cholesterol at the Primary Efficacy Time Point | -1.9 percentage of baseline | Standard Deviation 7.06 |
| Mipomersen | Percent Change From Baseline in Non-High-Density Lipoprotein Cholesterol at the Primary Efficacy Time Point | -45.6 percentage of baseline | Standard Deviation 18.22 |
p-value: <0.001t-test, 2 sided
Secondary
Percent Change From Baseline in Total Cholesterol at the Primary Efficacy Time Point
Total cholesterol was measured in mg/dL. Samples were taken following an overnight fast. The primary efficacy time point was the post-baseline visit closest to 14 days after the last dose of study treatment.
Time frame: Baseline (the average of the screening and Day 1 pre-treatment assessments) and the Primary Efficacy Time point (PET; Week 28 or the post-baseline visit closest to 14 days after the last dose).
Population: The Full Analysis Set, which consisted of all randomized patients who received at least 1 injection of study drug (mipomersen or placebo) and with a valid baseline and at least 1 post-baseline LDL-C measurement.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Placebo | Percent Change From Baseline in Total Cholesterol at the Primary Efficacy Time Point | -1.7 percentage of baseline | Standard Deviation 6.46 |
| Mipomersen | Percent Change From Baseline in Total Cholesterol at the Primary Efficacy Time Point | -36.9 percentage of baseline | Standard Deviation 14.66 |
p-value: <0.001t-test, 2 sided
Secondary
Total Cholesterol at Baseline and at the Primary Efficacy Time Point
The primary efficacy time point (PET) was the post-baseline visit closest to 14 days after the last dose of study treatment.
Time frame: Baseline (the average of the screening and Day 1 pre-treatment assessments) and the Primary Efficacy Time point (PET; Week 28 or the post-baseline visit closest to 14 days after the last dose).
Population: Full analysis set
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Placebo | Total Cholesterol at Baseline and at the Primary Efficacy Time Point | Baseline | 322.3 mg/dL | Standard Deviation 66.2 |
| Placebo | Total Cholesterol at Baseline and at the Primary Efficacy Time Point | Primary efficacy time point | 314.5 mg/dL | Standard Deviation 53 |
| Mipomersen | Total Cholesterol at Baseline and at the Primary Efficacy Time Point | Baseline | 318.9 mg/dL | Standard Deviation 91.8 |
| Mipomersen | Total Cholesterol at Baseline and at the Primary Efficacy Time Point | Primary efficacy time point | 200.1 mg/dL | Standard Deviation 77.6 |
Other Pre-specified
Apolipoprotein A1 at Baseline and at the Primary Efficacy Time Point
The primary efficacy time point (PET) was the post-baseline visit closest to 14 days after the last dose of study treatment.
Time frame: Baseline (the average of the screening and Day 1 pre-treatment assessments) and the Primary Efficacy Time point (PET; Week 28 or the post-baseline visit closest to 14 days after the last dose).
Population: Full analysis set
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Placebo | Apolipoprotein A1 at Baseline and at the Primary Efficacy Time Point | Baseline | 150.0 mg/dL | Standard Deviation 24.8 |
| Placebo | Apolipoprotein A1 at Baseline and at the Primary Efficacy Time Point | Primary efficacy time point | 148.9 mg/dL | Standard Deviation 33.2 |
| Mipomersen | Apolipoprotein A1 at Baseline and at the Primary Efficacy Time Point | Baseline | 150.3 mg/dL | Standard Deviation 25.6 |
| Mipomersen | Apolipoprotein A1 at Baseline and at the Primary Efficacy Time Point | Primary efficacy time point | 149.1 mg/dL | Standard Deviation 24 |
Other Pre-specified
High-Density Lipoprotein Cholesterol at Baseline and at the Primary Efficacy Time Point
The primary efficacy time point (PET) was the post-baseline visit closest to 14 days after the last dose of study treatment.
Time frame: Baseline (the average of the screening and Day 1 pre-treatment assessments) and the Primary Efficacy Time point (PET; Week 28 or the post-baseline visit closest to 14 days after the last dose).
Population: Full analysis set
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Placebo | High-Density Lipoprotein Cholesterol at Baseline and at the Primary Efficacy Time Point | Baseline | 48.8 mg/dL | Standard Deviation 12.4 |
| Placebo | High-Density Lipoprotein Cholesterol at Baseline and at the Primary Efficacy Time Point | Primary efficacy time point | 48.5 mg/dL | Standard Deviation 16.9 |
| Mipomersen | High-Density Lipoprotein Cholesterol at Baseline and at the Primary Efficacy Time Point | Baseline | 48.8 mg/dL | Standard Deviation 9.9 |
| Mipomersen | High-Density Lipoprotein Cholesterol at Baseline and at the Primary Efficacy Time Point | Primary efficacy time point | 52.4 mg/dL | Standard Deviation 12.4 |
Other Pre-specified
Lipoprotein (a) at Baseline and at the Primary Efficacy Time Point
The primary efficacy time point (PET) was the post-baseline visit closest to 14 days after the last dose of study treatment.
Time frame: Baseline (the average of the screening and Day 1 pre-treatment assessments) and the Primary Efficacy Time point (PET; Week 28 or the post-baseline visit closest to 14 days after the last dose).
Population: Full analysis set
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Placebo | Lipoprotein (a) at Baseline and at the Primary Efficacy Time Point | Baseline | 37.3 mg/dL | Standard Deviation 76.3 |
| Placebo | Lipoprotein (a) at Baseline and at the Primary Efficacy Time Point | Primary efficacy time point | 41.3 mg/dL | Standard Deviation 90.1 |
| Mipomersen | Lipoprotein (a) at Baseline and at the Primary Efficacy Time Point | Baseline | 53.5 mg/dL | Standard Deviation 45.8 |
| Mipomersen | Lipoprotein (a) at Baseline and at the Primary Efficacy Time Point | Primary efficacy time point | 42.3 mg/dL | Standard Deviation 48.2 |
Other Pre-specified
Percent Change From Baseline in Apolipoprotein A1 at the Primary Efficacy Time Point
Apolipoprotein A1 was measured in mg/dL. Samples were taken following an overnight fast. The primary efficacy time point was the post-baseline visit closest to 14 days after the last dose of study treatment.
Time frame: Baseline (the average of the screening and Day 1 pre-treatment assessments) and the Primary Efficacy Time point (PET; Week 28 or the post-baseline visit closest to 14 days after the last dose).
Population: The Full Analysis Set, which consisted of all randomized patients who received at least 1 injection of study drug (mipomersen or placebo) and with a valid baseline and at least 1 post-baseline LDL-C measurement.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Placebo | Percent Change From Baseline in Apolipoprotein A1 at the Primary Efficacy Time Point | -1.2 percentage of baseline | Standard Deviation 11.11 |
| Mipomersen | Percent Change From Baseline in Apolipoprotein A1 at the Primary Efficacy Time Point | -0.0 percentage of baseline | Standard Deviation 12.45 |
p-value: 0.784t-test, 2 sided
Other Pre-specified
Percent Change From Baseline in High-Density Lipoprotein Cholesterol at the Primary Efficacy Time Point
High-density lipoprotein cholesterol (HDL-C) was measured in mg/dL. Samples were taken following an overnight fast. The primary efficacy time point was the post-baseline visit closest to 14 days after the last dose of study treatment.
Time frame: Baseline (the average of the screening and Day 1 pre-treatment assessments) and the Primary Efficacy Time point (PET; Week 28 or the post-baseline visit closest to 14 days after the last dose).
Population: The Full Analysis Set, which consisted of all randomized patients who received at least 1 injection of study drug (mipomersen or placebo) and with a valid baseline and at least 1 post-baseline LDL-C measurement.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Placebo | Percent Change From Baseline in High-Density Lipoprotein Cholesterol at the Primary Efficacy Time Point | -2.3 percentage of baseline | Standard Deviation 12.72 |
| Mipomersen | Percent Change From Baseline in High-Density Lipoprotein Cholesterol at the Primary Efficacy Time Point | 8.1 percentage of baseline | Standard Deviation 17.15 |
p-value: 0.079t-test, 2 sided
Other Pre-specified
Percent Change From Baseline in Lipoprotein (a) at the Primary Efficacy Time Point
Lipoprotein (a) was measured in mg/dL. Samples were taken following an overnight fast. The primary efficacy time point was the post-baseline visit closest to 14 days after the last dose of study treatment.
Time frame: Baseline (the average of the screening and Day 1 pre-treatment assessments) and the Primary Efficacy Time point (PET; Week 28 or the post-baseline visit closest to 14 days after the last dose).
Population: The Full Analysis Set, which consisted of all randomized patients who received at least 1 injection of study drug (mipomersen or placebo) and with a valid baseline and at least 1 post-baseline LDL-C measurement.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Placebo | Percent Change From Baseline in Lipoprotein (a) at the Primary Efficacy Time Point | 0.0 percentage of baseline | Standard Deviation 8.65 |
| Mipomersen | Percent Change From Baseline in Lipoprotein (a) at the Primary Efficacy Time Point | -27.1 percentage of baseline | Standard Deviation 31.19 |
p-value: <0.001t-test, 2 sided
Other Pre-specified
Percent Change From Baseline in the Ratio of Low-Density Lipoprotein Cholesterol to High-Density Lipoprotein Cholesterol at the Primary Efficacy Time Point
The ratio of low-density lipoprotein (LDL) cholesterol to high-density lipoprotein (HDL) cholesterol was measured in mg/dL. Samples were taken following an overnight fast. The primary efficacy time point was the post-baseline visit closest to 14 days after the last dose of study treatment.
Time frame: Baseline (the average of the screening and Day 1 pre-treatment assessments) and the Primary Efficacy Time point (PET; Week 28 or the post-baseline visit closest to 14 days after the last dose).
Population: The Full Analysis Set, which consisted of all randomized patients who received at least 1 injection of study drug (mipomersen or placebo) and with a valid baseline and at least 1 post-baseline LDL-C measurement.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Placebo | Percent Change From Baseline in the Ratio of Low-Density Lipoprotein Cholesterol to High-Density Lipoprotein Cholesterol at the Primary Efficacy Time Point | 1.4 percentage of baseline | Standard Deviation 12.84 |
| Mipomersen | Percent Change From Baseline in the Ratio of Low-Density Lipoprotein Cholesterol to High-Density Lipoprotein Cholesterol at the Primary Efficacy Time Point | -49.2 percentage of baseline | Standard Deviation 22.16 |
p-value: <0.001t-test, 2 sided
Other Pre-specified
Percent Change From Baseline in Triglycerides at the Primary Efficacy Time Point
Triglycerides were measured in mg/dL. Samples were taken following an overnight fast. The primary efficacy time point was the post-baseline visit closest to 14 days after the last dose of study treatment.
Time frame: Baseline (the average of the screening and Day 1 pre-treatment assessments) and the Primary Efficacy Time point (PET; Week 28 or the post-baseline visit closest to 14 days after the last dose).
Population: The Full Analysis Set, which consisted of all randomized patients who received at least 1 injection of study drug (mipomersen or placebo) and with a valid baseline and at least 1 post-baseline LDL-C measurement.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Placebo | Percent Change From Baseline in Triglycerides at the Primary Efficacy Time Point | 5.0 percentage of baseline | Standard Deviation 26.81 |
| Mipomersen | Percent Change From Baseline in Triglycerides at the Primary Efficacy Time Point | -27.0 percentage of baseline | Standard Deviation 30.21 |
p-value: 0.005t-test, 2 sided
Other Pre-specified
Percent Change From Baseline in Very Low Density Lipoprotein Cholesterol at the Primary Efficacy Time Point
Very low density lipoprotein cholesterol was measured in mg/dL. Samples were taken following an overnight fast. The primary efficacy time point was the post-baseline visit closest to 14 days after the last dose of study treatment.
Time frame: Baseline (the average of the screening and Day 1 pre-treatment assessments) and the Primary Efficacy Time point (PET; Week 28 or the post-baseline visit closest to 14 days after the last dose).
Population: The Full Analysis Set, which consisted of all randomized patients who received at least 1 injection of study drug (mipomersen or placebo) and with a valid baseline and at least 1 post-baseline LDL-C measurement.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Placebo | Percent Change From Baseline in Very Low Density Lipoprotein Cholesterol at the Primary Efficacy Time Point | 4.6 percentage of baseline | Standard Deviation 26.53 |
| Mipomersen | Percent Change From Baseline in Very Low Density Lipoprotein Cholesterol at the Primary Efficacy Time Point | -27.1 percentage of baseline | Standard Deviation 30.79 |
p-value: 0.006t-test, 2 sided
Other Pre-specified
Ratio of Low-Density Lipoprotein Cholesterol to High-Density Lipoprotein Cholesterol at Baseline and at the Primary Efficacy Time Point
The primary efficacy time point (PET) was the post-baseline visit closest to 14 days after the last dose of study treatment.
Time frame: Baseline (the average of the screening and Day 1 pre-treatment assessments) and the Primary Efficacy Time point (PET; Week 28 or the post-baseline visit closest to 14 days after the last dose).
Population: Full analysis set
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Placebo | Ratio of Low-Density Lipoprotein Cholesterol to High-Density Lipoprotein Cholesterol at Baseline and at the Primary Efficacy Time Point | Baseline | 5.3 ratio | Standard Deviation 2.18 |
| Placebo | Ratio of Low-Density Lipoprotein Cholesterol to High-Density Lipoprotein Cholesterol at Baseline and at the Primary Efficacy Time Point | Primary efficacy time point | 5.4 ratio | Standard Deviation 2.27 |
| Mipomersen | Ratio of Low-Density Lipoprotein Cholesterol to High-Density Lipoprotein Cholesterol at Baseline and at the Primary Efficacy Time Point | Baseline | 5.2 ratio | Standard Deviation 2.38 |
| Mipomersen | Ratio of Low-Density Lipoprotein Cholesterol to High-Density Lipoprotein Cholesterol at Baseline and at the Primary Efficacy Time Point | Primary efficacy time point | 2.7 ratio | Standard Deviation 2.21 |
Other Pre-specified
Triglycerides at Baseline and at the Primary Efficacy Time Point
The primary efficacy time point (PET) was the post-baseline visit closest to 14 days after the last dose of study treatment.
Time frame: Baseline (the average of the screening and Day 1 pre-treatment assessments) and the Primary Efficacy Time point (PET; Week 28 or the post-baseline visit closest to 14 days after the last dose).
Population: Full analysis set
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Placebo | Triglycerides at Baseline and at the Primary Efficacy Time Point | Baseline | 149.0 mg/dL | Standard Deviation 63.9 |
| Placebo | Triglycerides at Baseline and at the Primary Efficacy Time Point | Primary efficacy time point | 149.3 mg/dL | Standard Deviation 62.4 |
| Mipomersen | Triglycerides at Baseline and at the Primary Efficacy Time Point | Baseline | 141.4 mg/dL | Standard Deviation 50.9 |
| Mipomersen | Triglycerides at Baseline and at the Primary Efficacy Time Point | Primary efficacy time point | 97.3 mg/dL | Standard Deviation 47.3 |
Other Pre-specified
Very Low Density Lipoprotein Cholesterol at Baseline and at the Primary Efficacy Time Point
The primary efficacy time point (PET) was the post-baseline visit closest to 14 days after the last dose of study treatment.
Time frame: Baseline (the average of the screening and Day 1 pre-treatment assessments) and the Primary Efficacy Time point (PET; Week 28 or the post-baseline visit closest to 14 days after the last dose).
Population: Full analysis set
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Placebo | Very Low Density Lipoprotein Cholesterol at Baseline and at the Primary Efficacy Time Point | Baseline | 29.8 mg/dL | Standard Deviation 12.7 |
| Placebo | Very Low Density Lipoprotein Cholesterol at Baseline and at the Primary Efficacy Time Point | Primary efficacy time point | 29.8 mg/dL | Standard Deviation 12.5 |
| Mipomersen | Very Low Density Lipoprotein Cholesterol at Baseline and at the Primary Efficacy Time Point | Baseline | 28.3 mg/dL | Standard Deviation 10.2 |
| Mipomersen | Very Low Density Lipoprotein Cholesterol at Baseline and at the Primary Efficacy Time Point | Primary efficacy time point | 19.4 mg/dL | Standard Deviation 9.5 |