Congenital Abnormalities, Dyslipidemias, Genetic Diseases, Inborn, Hypercholesterolemia, Hypercholesterolemia, Autosomal Dominant, Hyperlipidemias, Hyperlipoproteinemias, Hyperlipoproteinemia Type II, Infant, Newborn, Diseases, Lipid Metabolism Disorders, Lipid Metabolism, Inborn Errors, Metabolic Diseases, Metabolic Disorder, Metabolism, Inborn Errors
Conditions
Keywords
Apolipoprotein B, Homozygous Familial Hypercholesterolemia, LDL-receptor gene
Brief summary
The purpose of this study is to evaluate the safety and efficacy of mipomersen (ISIS 301012) in subjects with homozygous familial hypercholesterolemia on lipid-lowering therapy. This study consisted of a 26-week treatment period and a 24-week post-treatment follow-up period. Following treatment and Week 28 evaluations, participants could elect to enroll in an open-label extension study (301012-CS6; NCT00694109). Participants who were not eligible or elected not to enroll in the open-label extension study or who discontinued during the 28-week treatment period were followed in this study for 24 weeks from administration of the last dose of study drug.
Detailed description
Familial hypercholesterolemia (FH) is an autosomal dominant genetic disorder of lipoprotein metabolism characterized by markedly elevated low density lipoprotein (LDL), premature onset of atherosclerosis and development of xanthomata. Patients with homozygous familial hypercholesterolemia (HoFH) have a severe disease that presents in childhood with total cholesterol typically in the 650 to 1000 mg/dL range. This was a randomized, double-blind, placebo-controlled study, which consisted of a 4-week screening period, 26 weeks of treatment, and a 24-week post- treatment follow-up period (with the exception of patients who enrolled in the open-label extension study, Study 301012-CS6; NCT00694109). Eligible patients were randomized in a 2:1 ratio to receive 200 mg mipomersen or matching volume placebo subcutaneous (SC) injections weekly. Patients who weighed \<50 kg received a lower dose of 160 mg mipomersen or matching volume of placebo SC injections weekly. Patients were to have been on a stable (\>=12 weeks) regimen of allowed lipid-lowering therapies at screening, and were required to remain on the same dose and regimen throughout the study. Patients returned to the study center for clinical evaluation every other week during the first 4 weeks of treatment, once every 4 to 5 weeks for the remainder of the treatment period, and monthly during the post-treatment evaluation (follow-up) period. The primary endpoint assessment was at Week 28. Following treatment and Week 28 evaluations, eligible patients who tolerated the study drug could elect to enroll in the open-label extension study (Study 301012-CS6; NCT00694109). Patients who did not participate in the open-label extension study were required to return to the study center for clinical evaluation at least twice during the post-treatment follow-up period, including an end-of-study termination visit at the end of this 24-week period.
Interventions
DRUGmipomersen
200 mg mipomersen administered once a week for 26 weeks as a 1 mL subcutaneous injection. Subjects weighing less than 50 kg received a lower dose of 160 mg (0.8mL) mipomersen.
DRUGPlacebo
1 mL subcutaneous injection once a week for 26 weeks. Subjects weighing less than 50 kg received 0.8 mL subcutaneous injection.
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
12 Years to No maximum
Healthy volunteers
No
Inclusion criteria
* Diagnosis of Homozygous Familial Hypercholesterolemia (HoFH) * Stable lipid-lowering therapy for 12 weeks * Stable weight for 6 weeks * Stable low fat diet for 8 weeks
Exclusion criteria
* Significant health problems in the recent past including heart attack, stroke, blood disorders, cancer, or digestive problems
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Percent Change From Baseline in Low-density Lipoprotein Cholesterol (LDL-C) at Primary Efficacy Time Point | Baseline (the average of the screening and Day 1 pre-treatment assessments) and the Primary Efficacy Time point (PET) up to week 28 | 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. Baseline was defined as the average of the screening and Study Day 1 (pre-treatment) assessments. An assessment was not included in this calculation if it was associated with a non-fasting blood draw or was drawn more than 4 weeks prior to Study Day 1. If the Study Day 1 and screening LDL-C values were \>12% different (relative to the maximum value), then the screening value was not used, because the Study Day 1 value represents the best estimate of the patient's condition at the beginning of study drug administration. The PET was the post-baseline visit, for which LDL-C was assessed, closest to 14 days after the last dose of study drug. |
| LDL-C at Baseline and the Primary Efficacy Time Point (PET) | Baseline (the average of the screening and Day 1 pre-treatment assessments) and the Primary Efficacy Time point (PET) up to week 28 | The PET was the post-baseline visit, for which LDL-C was assessed, closest to 14 days after the last dose of study drug. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Percentage Change From Baseline in Total Cholesterol at Primary Efficacy Time Point (PET) | Baseline (the average of the screening and Day 1 pre-treatment assessments) and the Primary Efficacy Time point (PET) up to week 28 | Total cholesterol was measured in mg/dL. Samples were taken following an overnight fast. Baseline was defined as the average of the screening and Study Day 1 (pre-treatment) assessments. An assessment was not included in this calculation if it was associated with a non-fasting blood draw or was drawn more than 4 weeks prior to Study Day 1. The PET was the post-baseline visit, for which LDL-C was assessed, closest to 14 days after the last dose of study drug. |
| Total Cholesterol at Baseline and the Primary Efficacy Time Point (PET) | Baseline (the average of the screening and Day 1 pre-treatment assessments) and the Primary Efficacy Time point (PET) up to week 28 | The PET was the post-baseline visit, for which LDL-C was assessed, closest to 14 days after the last dose of study drug. |
| Percent Change From Baseline in Apolipoprotein B (Apo-B) at Primary Efficacy Time Point | Baseline (the average of the screening and Day 1 pre-treatment assessments) and the Primary Efficacy Time point (PET) up to week 28 | Apo-B was measured in mg/dL. Samples were taken following an overnight fast. Baseline was defined as the average of the screening and Study Day 1 (pre-treatment) assessments. An assessment was not included in this calculation if it was associated with a non-fasting blood draw or was drawn more than 4 weeks prior to Study Day 1. The PET was the post-baseline visit, for which LDL-C was assessed, closest to 14 days after the last dose of study drug. |
| Non-HDL-C at Baseline and the Primary Efficacy Time Point (PET) | Baseline (the average of the screening and Day 1 pre-treatment assessments) and the Primary Efficacy Time point (PET) up to week 28 | The PET was the post-baseline visit, for which LDL-C was assessed, closest to 14 days after the last dose of study drug. |
| Percentage Change From Baseline in Non-High-Density Lipoprotein Cholesterol (Non-HDL-C) at Primary Efficacy Time Point (PET) | Baseline (the average of the screening and Day 1 pre-treatment assessments) and the Primary Efficacy Time point (PET) up to week 28 | Non-HDL-C was measured in mg/dL. Samples were taken following an overnight fast. Baseline was defined as the average of the screening and Study Day 1 (pre-treatment) assessments. An assessment was not included in this calculation if it was associated with a non-fasting blood draw or was drawn more than 4 weeks prior to Study Day 1. The PET was the post-baseline visit, for which LDL-C was assessed, closest to 14 days after the last dose of study drug. |
| Apo-B at Baseline and the Primary Efficacy Time Point (PET) | Baseline (the average of the screening and Day 1 pre-treatment assessments) and the Primary Efficacy Time point (PET) up to week 28 ) | The PET was the post-baseline visit, for which LDL-C was assessed, closest to 14 days after the last dose of study drug. |
Other
| Measure | Time frame | Description |
|---|---|---|
| Percent Change From Baseline in Apolipoprotein A1 (Apo-A1) at Primary Efficacy Time Point (PET) | Baseline (the average of the screening and Day 1 pre-treatment assessments) and the Primary Efficacy Time point (PET) up to week 28 | Apo-A1 was measured in mg/dL. Samples were taken following an overnight fast. Baseline was defined as the average of the screening and Study Day 1 (pre-treatment) assessments. An assessment was not included in this calculation if it was associated with a non-fasting blood draw or was drawn more than 4 weeks prior to Study Day 1. The PET was the post-baseline visit, for which LDL-C was assessed, closest to 14 days after the last dose of study drug. |
| Apo-A1 at Baseline and the Primary Efficacy Time Point (PET) | Baseline (the average of the screening and Day 1 pre-treatment assessments) and the Primary Efficacy Time point (PET) up to week 28 | The PET was the post-baseline visit, for which LDL-C was assessed, closest to 14 days after the last dose of study drug. |
| Percentage Change From Baseline in Triglycerides at Primary Efficacy Time Point (PET) | Baseline (the average of the screening and Day 1 pre-treatment assessments) and the Primary Efficacy Time point (PET) up to week 28 | Triglycerides were measured in mg/dL. Samples were taken following an overnight fast. Baseline was defined as the average of the screening and Study Day 1 (pre-treatment) assessments. An assessment was not included in this calculation if it was associated with a non-fasting blood draw or was drawn more than 4 weeks prior to Study Day 1. The PET was the post-baseline visit, for which LDL-C was assessed, closest to 14 days after the last dose of study drug. |
| HDL-C at Baseline and the Primary Efficacy Time Point (PET) | Baseline (the average of the screening and Day 1 pre-treatment assessments) and the Primary Efficacy Time point (PET) up to week 28 | The PET was the post-baseline visit, for which LDL-C was assessed, closest to 14 days after the last dose of study drug. |
| Percentage Change From Baseline in High-Density Lipoprotein Cholesterol (HDL-C) at Primary Efficacy Time Point (PET) | Baseline (the average of the screening and Day 1 pre-treatment assessments) and the Primary Efficacy Time point (PET) up to week 28 | HDL-C was measured in mg/dL. Samples were taken following an overnight fast. Baseline was defined as the average of the screening and Study Day 1 (pre-treatment) assessments. An assessment was not included in this calculation if it was associated with a non-fasting blood draw or was drawn more than 4 weeks prior to Study Day 1. The PET was the post-baseline visit, for which LDL-C was assessed, closest to 14 days after the last dose of study drug. |
| Triglycerides at Baseline and the Primary Efficacy Time Point (PET) | Baseline (the average of the screening and Day 1 pre-treatment assessments) and the Primary Efficacy Time point (PET) up to week 28 | The PET was the post-baseline visit, for which LDL-C was assessed, closest to 14 days after the last dose of study drug. |
| Percentage Change From Baseline in Lipoprotein(a) at Primary Efficacy Time Point (PET) | Baseline (the average of the screening and Day 1 pre-treatment assessments) and the Primary Efficacy Time point (PET) up to week 28 | Lipoprotein(a) was measured in mg/dL. Samples were taken following an overnight fast. Baseline was defined as the average of the screening and Study Day 1 (pre-treatment) assessments. An assessment was not included in this calculation if it was associated with a non-fasting blood draw or was drawn more than 4 weeks prior to Study Day 1. The PET was the post-baseline visit, for which LDL-C was assessed, closest to 14 days after the last dose of study drug. |
| Lipoprotein(a) at Baseline and the Primary Efficacy Time Point (PET) | Baseline (the average of the screening and Day 1 pre-treatment assessments) and the Primary Efficacy Time point (PET) up to week 28 | The PET was the post-baseline visit, for which LDL-C was assessed, closest to 14 days after the last dose of study drug. |
| Percentage Change From Baseline in Very-Low-Density Lipoprotein Cholesterol (VLDL-C) at Primary Efficacy Time Point (PET) | Baseline (the average of the screening and Day 1 pre-treatment assessments) and the Primary Efficacy Time point (PET) up to week 28 | VLDL-C was measured in mg/dL. Samples were taken following an overnight fast. Baseline was defined as the average of the screening and Study Day 1 (pre-treatment) assessments. An assessment was not included in this calculation if it was associated with a non-fasting blood draw or was drawn more than 4 weeks prior to Study Day 1. The PET was the post-baseline visit, for which LDL-C was assessed, closest to 14 days after the last dose of study drug. |
| VLDL-C at Baseline and the Primary Efficacy Time Point (PET) | Baseline (the average of the screening and Day 1 pre-treatment assessments) and the Primary Efficacy Time point (PET) up to week 28 | The PET was the post-baseline visit, for which LDL-C was assessed, closest to 14 days after the last dose of study drug. |
| Change From Baseline in Ratio of Low-density Lipoprotein Cholesterol (LDL-C) to High-density Lipoprotein Cholesterol (HDL-C) at Primary Efficacy Time Point (PET) | Baseline (the average of the screening and Day 1 pre-treatment assessments) and the Primary Efficacy Time point (PET) up to week 28 | LDL-C and HDL-C were measured in mg/dL. Samples were taken following an overnight fast. Baseline was defined as the average of the screening and Study Day 1 (pre-treatment) assessments. An assessment was not included in this calculation if it was associated with a non-fasting blood draw or was drawn more than 4 weeks prior to Study Day 1. The PET was the post-baseline visit, for which LDL-C was assessed, closest to 14 days after the last dose of study drug. |
| Ratio of LDL-C to HDL-C at Baseline and the Primary Efficacy Time Point (PET) | Baseline (the average of the screening and Day 1 pre-treatment assessments) and the Primary Efficacy Time point (PET) up to week 28 | The PET was the post-baseline visit, for which LDL-C was assessed, closest to 14 days after the last dose of study drug. |
Countries
Brazil, Canada, Singapore, South Africa, Taiwan, United Kingdom, United States
Participant flow
Pre-assignment details
Sixty-one patients were screened and fifty-one randomized. Eligible patients were randomized in a 2:1 ratio to receive 200 mg mipomersen or matching volume placebo subcutaneous (SC) injections weekly.
Participants by arm
| Arm | Count |
|---|---|
| Placebo Participants received placebo as a subcutaneous injection once a week for 26 weeks | 17 |
| Mipomersen Participants received mipomersen 200 mg as a subcutaneous injection once a week for 26 weeks. | 34 |
| Total | 51 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Follow-up Period | Other | 0 | 1 |
| Follow-up Period | Protocol Violation | 0 | 1 |
| Follow-up Period | Withdrawal by Subject | 1 | 3 |
| Treatment Period | Adverse Event | 0 | 4 |
| Treatment Period | Physician Decision | 0 | 1 |
| Treatment Period | Withdrawal by Subject | 0 | 1 |
Baseline characteristics
| Characteristic | Placebo | Mipomersen | Total |
|---|---|---|---|
| Age, Continuous | 33.0 years STANDARD_DEVIATION 14.1 | 30.4 years STANDARD_DEVIATION 11.5 | 31.3 years STANDARD_DEVIATION 12.4 |
| Alcohol Use Current | 6 participants | 14 participants | 20 participants |
| Alcohol Use Never | 8 participants | 17 participants | 25 participants |
| Alcohol Use Non-current | 3 participants | 3 participants | 6 participants |
| Body Mass Index | 26.32 kg/m^2 STANDARD_DEVIATION 4.41 | 25.97 kg/m^2 STANDARD_DEVIATION 5.81 | 26.08 kg/m^2 STANDARD_DEVIATION 5.34 |
| Fasting hemoglobin A1c | 5.47 percentage of total hemoglobin STANDARD_DEVIATION 0.22 | 5.34 percentage of total hemoglobin STANDARD_DEVIATION 0.37 | 5.38 percentage of total hemoglobin STANDARD_DEVIATION 0.33 |
| Fasting serum insulin | 9.72 microIU/mL STANDARD_DEVIATION 5.98 | 11.54 microIU/mL STANDARD_DEVIATION 14.78 | 10.93 microIU/mL STANDARD_DEVIATION 12.51 |
| Metabolic syndrome No | 16 participants | 27 participants | 43 participants |
| Metabolic syndrome Yes | 1 participants | 7 participants | 8 participants |
| Race/Ethnicity, Customized Asian | 3 participants | 8 participants | 11 participants |
| Race/Ethnicity, Customized Black | 1 participants | 1 participants | 2 participants |
| Race/Ethnicity, Customized Hispanic or Latino | 1 participants | 5 participants | 6 participants |
| Race/Ethnicity, Customized Not Hispanic or Latino | 16 participants | 29 participants | 45 participants |
| Race/Ethnicity, Customized White | 13 participants | 25 participants | 38 participants |
| Sex: Female, Male Female | 10 Participants | 19 Participants | 29 Participants |
| Sex: Female, Male Male | 7 Participants | 15 Participants | 22 Participants |
| Tobacco Use Current | 3 participants | 7 participants | 10 participants |
| Tobacco Use Never | 11 participants | 23 participants | 34 participants |
| Tobacco Use Non-current | 3 participants | 4 participants | 7 participants |
| Waist/hip ratio | 0.83 ratio STANDARD_DEVIATION 0.07 | 0.85 ratio STANDARD_DEVIATION 0.06 | 0.84 ratio STANDARD_DEVIATION 0.07 |
| Weight <50 kg | 2 participants | 4 participants | 6 participants |
| Weight >=50 kg | 15 participants | 30 participants | 45 participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — |
| other Total, other adverse events | 13 / 17 | 30 / 34 |
| serious Total, serious adverse events | 1 / 17 | 2 / 34 |
Outcome results
Primary
LDL-C at Baseline and the Primary Efficacy Time Point (PET)
The PET was the post-baseline visit, for which LDL-C was assessed, closest to 14 days after the last dose of study drug.
Time frame: Baseline (the average of the screening and Day 1 pre-treatment assessments) and the Primary Efficacy Time point (PET) up to week 28
Population: Full analysis set
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Placebo | LDL-C at Baseline and the Primary Efficacy Time Point (PET) | Baseline | 400.2 mg/dL | Standard Deviation 141.5 |
| Placebo | LDL-C at Baseline and the Primary Efficacy Time Point (PET) | PET | 388.2 mg/dL | Standard Deviation 150.5 |
| Mipomersen | LDL-C at Baseline and the Primary Efficacy Time Point (PET) | Baseline | 438.9 mg/dL | Standard Deviation 138.6 |
| Mipomersen | LDL-C at Baseline and the Primary Efficacy Time Point (PET) | PET | 326.2 mg/dL | Standard Deviation 121.3 |
Primary
Percent Change From Baseline in Low-density Lipoprotein Cholesterol (LDL-C) at 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. Baseline was defined as the average of the screening and Study Day 1 (pre-treatment) assessments. An assessment was not included in this calculation if it was associated with a non-fasting blood draw or was drawn more than 4 weeks prior to Study Day 1. If the Study Day 1 and screening LDL-C values were \>12% different (relative to the maximum value), then the screening value was not used, because the Study Day 1 value represents the best estimate of the patient's condition at the beginning of study drug administration. The PET was the post-baseline visit, for which LDL-C was assessed, closest to 14 days after the last dose of study drug.
Time frame: Baseline (the average of the screening and Day 1 pre-treatment assessments) and the Primary Efficacy Time point (PET) up to week 28
Population: Full analysis set (FAS). The FAS, which represents the practically-feasible intent-to-treat (ITT) population as delineated in ICH Guideline E9, consists of treated participants with a valid baseline and at least one post-baseline LDL-C measure.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Placebo | Percent Change From Baseline in Low-density Lipoprotein Cholesterol (LDL-C) at Primary Efficacy Time Point | -3.31 percentage of baseline | Standard Deviation 17.06 |
| Mipomersen | Percent Change From Baseline in Low-density Lipoprotein Cholesterol (LDL-C) at Primary Efficacy Time Point | -24.66 percentage of baseline | Standard Deviation 19.85 |
Comparison: Based upon prior clinical study experience with mipomersen, it was estimated that the standard deviation of the percent change in LDL-C is approximately 22%. With 15 patients in the control group and 30 patients in the mipomersen-treated group, this study would have at least 80% power to detect a 20 percentage point difference between the 2 treatment groups. Fifty-one patients were enrolled to allow for patient withdrawals and potential exclusions from analysis sets.p-value: <0.001t-test, 2 sided
Secondary
Apo-B at Baseline and the Primary Efficacy Time Point (PET)
The PET was the post-baseline visit, for which LDL-C was assessed, closest to 14 days after the last dose of study drug.
Time frame: Baseline (the average of the screening and Day 1 pre-treatment assessments) and the Primary Efficacy Time point (PET) up to week 28 )
Population: Full analysis set
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Placebo | Apo-B at Baseline and the Primary Efficacy Time Point (PET) | Baseline | 259.2 mg/dL | Standard Deviation 84.4 |
| Placebo | Apo-B at Baseline and the Primary Efficacy Time Point (PET) | PET | 252.6 mg/dL | Standard Deviation 85 |
| Mipomersen | Apo-B at Baseline and the Primary Efficacy Time Point (PET) | Baseline | 283.1 mg/dL | Standard Deviation 78.4 |
| Mipomersen | Apo-B at Baseline and the Primary Efficacy Time Point (PET) | PET | 205.4 mg/dL | Standard Deviation 70 |
Secondary
Non-HDL-C at Baseline and the Primary Efficacy Time Point (PET)
The PET was the post-baseline visit, for which LDL-C was assessed, closest to 14 days after the last dose of study drug.
Time frame: Baseline (the average of the screening and Day 1 pre-treatment assessments) and the Primary Efficacy Time point (PET) up to week 28
Population: Full analysis set
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Placebo | Non-HDL-C at Baseline and the Primary Efficacy Time Point (PET) | PET | 409.1 mg/dL | Standard Deviation 156.6 |
| Placebo | Non-HDL-C at Baseline and the Primary Efficacy Time Point (PET) | Baseline | 418.9 mg/dL | Standard Deviation 144.5 |
| Mipomersen | Non-HDL-C at Baseline and the Primary Efficacy Time Point (PET) | Baseline | 464.3 mg/dL | Standard Deviation 145.4 |
| Mipomersen | Non-HDL-C at Baseline and the Primary Efficacy Time Point (PET) | PET | 345.8 mg/dL | Standard Deviation 126.6 |
Secondary
Percentage Change From Baseline in Non-High-Density Lipoprotein Cholesterol (Non-HDL-C) at Primary Efficacy Time Point (PET)
Non-HDL-C was measured in mg/dL. Samples were taken following an overnight fast. Baseline was defined as the average of the screening and Study Day 1 (pre-treatment) assessments. An assessment was not included in this calculation if it was associated with a non-fasting blood draw or was drawn more than 4 weeks prior to Study Day 1. The PET was the post-baseline visit, for which LDL-C was assessed, closest to 14 days after the last dose of study drug.
Time frame: Baseline (the average of the screening and Day 1 pre-treatment assessments) and the Primary Efficacy Time point (PET) up to week 28
Population: Full analysis set
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Placebo | Percentage Change From Baseline in Non-High-Density Lipoprotein Cholesterol (Non-HDL-C) at Primary Efficacy Time Point (PET) | -2.90 percentage of baseline | Standard Deviation 16.32 |
| Mipomersen | Percentage Change From Baseline in Non-High-Density Lipoprotein Cholesterol (Non-HDL-C) at Primary Efficacy Time Point (PET) | -24.50 percentage of baseline | Standard Deviation 19.17 |
p-value: <0.001t-test, 2 sided
Secondary
Percentage Change From Baseline in Total Cholesterol at Primary Efficacy Time Point (PET)
Total cholesterol was measured in mg/dL. Samples were taken following an overnight fast. Baseline was defined as the average of the screening and Study Day 1 (pre-treatment) assessments. An assessment was not included in this calculation if it was associated with a non-fasting blood draw or was drawn more than 4 weeks prior to Study Day 1. The PET was the post-baseline visit, for which LDL-C was assessed, closest to 14 days after the last dose of study drug.
Time frame: Baseline (the average of the screening and Day 1 pre-treatment assessments) and the Primary Efficacy Time point (PET) up to week 28
Population: Full analysis set
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Placebo | Percentage Change From Baseline in Total Cholesterol at Primary Efficacy Time Point (PET) | -1.98 percentage of baseline | Standard Deviation 14.82 |
| Mipomersen | Percentage Change From Baseline in Total Cholesterol at Primary Efficacy Time Point (PET) | -21.20 percentage of baseline | Standard Deviation 17.69 |
p-value: <0.001t-test, 2 sided
Secondary
Percent Change From Baseline in Apolipoprotein B (Apo-B) at Primary Efficacy Time Point
Apo-B was measured in mg/dL. Samples were taken following an overnight fast. Baseline was defined as the average of the screening and Study Day 1 (pre-treatment) assessments. An assessment was not included in this calculation if it was associated with a non-fasting blood draw or was drawn more than 4 weeks prior to Study Day 1. The PET was the post-baseline visit, for which LDL-C was assessed, closest to 14 days after the last dose of study drug.
Time frame: Baseline (the average of the screening and Day 1 pre-treatment assessments) and the Primary Efficacy Time point (PET) up to week 28
Population: Full analysis set
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Placebo | Percent Change From Baseline in Apolipoprotein B (Apo-B) at Primary Efficacy Time Point | -2.54 percentage of baseline | Standard Deviation 12.56 |
| Mipomersen | Percent Change From Baseline in Apolipoprotein B (Apo-B) at Primary Efficacy Time Point | -26.77 percentage of baseline | Standard Deviation 17.04 |
p-value: <0.001t-test, 2 sided
Secondary
Total Cholesterol at Baseline and the Primary Efficacy Time Point (PET)
The PET was the post-baseline visit, for which LDL-C was assessed, closest to 14 days after the last dose of study drug.
Time frame: Baseline (the average of the screening and Day 1 pre-treatment assessments) and the Primary Efficacy Time point (PET) up to week 28
Population: Full analysis set
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Placebo | Total Cholesterol at Baseline and the Primary Efficacy Time Point (PET) | Baseline | 460.5 mg/dL | Standard Deviation 132 |
| Placebo | Total Cholesterol at Baseline and the Primary Efficacy Time Point (PET) | PET | 452.1 mg/dL | Standard Deviation 144.6 |
| Mipomersen | Total Cholesterol at Baseline and the Primary Efficacy Time Point (PET) | Baseline | 502.4 mg/dL | Standard Deviation 144.5 |
| Mipomersen | Total Cholesterol at Baseline and the Primary Efficacy Time Point (PET) | PET | 389.7 mg/dL | Standard Deviation 125.3 |
Other Pre-specified
Apo-A1 at Baseline and the Primary Efficacy Time Point (PET)
The PET was the post-baseline visit, for which LDL-C was assessed, closest to 14 days after the last dose of study drug.
Time frame: Baseline (the average of the screening and Day 1 pre-treatment assessments) and the Primary Efficacy Time point (PET) up to week 28
Population: Full analysis set
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Placebo | Apo-A1 at Baseline and the Primary Efficacy Time Point (PET) | Baseline | 118.6 mg/dL | Standard Deviation 33 |
| Placebo | Apo-A1 at Baseline and the Primary Efficacy Time Point (PET) | PET | 124.5 mg/dL | Standard Deviation 34.9 |
| Mipomersen | Apo-A1 at Baseline and the Primary Efficacy Time Point (PET) | Baseline | 111.5 mg/dL | Standard Deviation 27.9 |
| Mipomersen | Apo-A1 at Baseline and the Primary Efficacy Time Point (PET) | PET | 118.8 mg/dL | Standard Deviation 20.5 |
Other Pre-specified
Change From Baseline in Ratio of Low-density Lipoprotein Cholesterol (LDL-C) to High-density Lipoprotein Cholesterol (HDL-C) at Primary Efficacy Time Point (PET)
LDL-C and HDL-C were measured in mg/dL. Samples were taken following an overnight fast. Baseline was defined as the average of the screening and Study Day 1 (pre-treatment) assessments. An assessment was not included in this calculation if it was associated with a non-fasting blood draw or was drawn more than 4 weeks prior to Study Day 1. The PET was the post-baseline visit, for which LDL-C was assessed, closest to 14 days after the last dose of study drug.
Time frame: Baseline (the average of the screening and Day 1 pre-treatment assessments) and the Primary Efficacy Time point (PET) up to week 28
Population: Full analysis set
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Placebo | Change From Baseline in Ratio of Low-density Lipoprotein Cholesterol (LDL-C) to High-density Lipoprotein Cholesterol (HDL-C) at Primary Efficacy Time Point (PET) | -6.22 percentage of baseline | Standard Deviation 18.81 |
| Mipomersen | Change From Baseline in Ratio of Low-density Lipoprotein Cholesterol (LDL-C) to High-density Lipoprotein Cholesterol (HDL-C) at Primary Efficacy Time Point (PET) | -34.32 percentage of baseline | Standard Deviation 21 |
p-value: <0.001t-test, 2 sided
Other Pre-specified
HDL-C at Baseline and the Primary Efficacy Time Point (PET)
The PET was the post-baseline visit, for which LDL-C was assessed, closest to 14 days after the last dose of study drug.
Time frame: Baseline (the average of the screening and Day 1 pre-treatment assessments) and the Primary Efficacy Time point (PET) up to week 28
Population: Full analysis set
| Arm | Measure | Group | Value (MEDIAN) |
|---|---|---|---|
| Placebo | HDL-C at Baseline and the Primary Efficacy Time Point (PET) | Baseline | 38 mg/dL |
| Placebo | HDL-C at Baseline and the Primary Efficacy Time Point (PET) | PET | 43 mg/dL |
| Mipomersen | HDL-C at Baseline and the Primary Efficacy Time Point (PET) | Baseline | 35 mg/dL |
| Mipomersen | HDL-C at Baseline and the Primary Efficacy Time Point (PET) | PET | 43 mg/dL |
Other Pre-specified
Lipoprotein(a) at Baseline and the Primary Efficacy Time Point (PET)
The PET was the post-baseline visit, for which LDL-C was assessed, closest to 14 days after the last dose of study drug.
Time frame: Baseline (the average of the screening and Day 1 pre-treatment assessments) and the Primary Efficacy Time point (PET) up to week 28
Population: Full analysis set
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Placebo | Lipoprotein(a) at Baseline and the Primary Efficacy Time Point (PET) | Baseline | 66.3 mg/dL | Standard Deviation 53.1 |
| Placebo | Lipoprotein(a) at Baseline and the Primary Efficacy Time Point (PET) | PET | 61.6 mg/dL | Standard Deviation 52.6 |
| Mipomersen | Lipoprotein(a) at Baseline and the Primary Efficacy Time Point (PET) | Baseline | 64.3 mg/dL | Standard Deviation 41 |
| Mipomersen | Lipoprotein(a) at Baseline and the Primary Efficacy Time Point (PET) | PET | 43.8 mg/dL | Standard Deviation 32.1 |
Other Pre-specified
Percentage Change From Baseline in High-Density Lipoprotein Cholesterol (HDL-C) at Primary Efficacy Time Point (PET)
HDL-C was measured in mg/dL. Samples were taken following an overnight fast. Baseline was defined as the average of the screening and Study Day 1 (pre-treatment) assessments. An assessment was not included in this calculation if it was associated with a non-fasting blood draw or was drawn more than 4 weeks prior to Study Day 1. The PET was the post-baseline visit, for which LDL-C was assessed, closest to 14 days after the last dose of study drug.
Time frame: Baseline (the average of the screening and Day 1 pre-treatment assessments) and the Primary Efficacy Time point (PET) up to week 28
Population: Full analysis set
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Placebo | Percentage Change From Baseline in High-Density Lipoprotein Cholesterol (HDL-C) at Primary Efficacy Time Point (PET) | 4.1 percentage of baseline |
| Mipomersen | Percentage Change From Baseline in High-Density Lipoprotein Cholesterol (HDL-C) at Primary Efficacy Time Point (PET) | 14.8 percentage of baseline |
p-value: 0.035Wilcoxon rank sum test
Other Pre-specified
Percentage Change From Baseline in Lipoprotein(a) at Primary Efficacy Time Point (PET)
Lipoprotein(a) was measured in mg/dL. Samples were taken following an overnight fast. Baseline was defined as the average of the screening and Study Day 1 (pre-treatment) assessments. An assessment was not included in this calculation if it was associated with a non-fasting blood draw or was drawn more than 4 weeks prior to Study Day 1. The PET was the post-baseline visit, for which LDL-C was assessed, closest to 14 days after the last dose of study drug.
Time frame: Baseline (the average of the screening and Day 1 pre-treatment assessments) and the Primary Efficacy Time point (PET) up to week 28
Population: Full analysis set
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Placebo | Percentage Change From Baseline in Lipoprotein(a) at Primary Efficacy Time Point (PET) | -7.87 percentage of baseline | Standard Deviation 21.87 |
| Mipomersen | Percentage Change From Baseline in Lipoprotein(a) at Primary Efficacy Time Point (PET) | -31.10 percentage of baseline | Standard Deviation 23.02 |
p-value: 0.001t-test, 2 sided
Other Pre-specified
Percentage Change From Baseline in Triglycerides at Primary Efficacy Time Point (PET)
Triglycerides were measured in mg/dL. Samples were taken following an overnight fast. Baseline was defined as the average of the screening and Study Day 1 (pre-treatment) assessments. An assessment was not included in this calculation if it was associated with a non-fasting blood draw or was drawn more than 4 weeks prior to Study Day 1. The PET was the post-baseline visit, for which LDL-C was assessed, closest to 14 days after the last dose of study drug.
Time frame: Baseline (the average of the screening and Day 1 pre-treatment assessments) and the Primary Efficacy Time point (PET) up to week 28
Population: Full analysis set
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Placebo | Percentage Change From Baseline in Triglycerides at Primary Efficacy Time Point (PET) | 0.9 percentage of baseline |
| Mipomersen | Percentage Change From Baseline in Triglycerides at Primary Efficacy Time Point (PET) | -17.5 percentage of baseline |
p-value: 0.013Wilcoxon rank sum test
Other Pre-specified
Percentage Change From Baseline in Very-Low-Density Lipoprotein Cholesterol (VLDL-C) at Primary Efficacy Time Point (PET)
VLDL-C was measured in mg/dL. Samples were taken following an overnight fast. Baseline was defined as the average of the screening and Study Day 1 (pre-treatment) assessments. An assessment was not included in this calculation if it was associated with a non-fasting blood draw or was drawn more than 4 weeks prior to Study Day 1. The PET was the post-baseline visit, for which LDL-C was assessed, closest to 14 days after the last dose of study drug.
Time frame: Baseline (the average of the screening and Day 1 pre-treatment assessments) and the Primary Efficacy Time point (PET) up to week 28
Population: Full analysis set
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Placebo | Percentage Change From Baseline in Very-Low-Density Lipoprotein Cholesterol (VLDL-C) at Primary Efficacy Time Point (PET) | 2.3 percentage of baseline |
| Mipomersen | Percentage Change From Baseline in Very-Low-Density Lipoprotein Cholesterol (VLDL-C) at Primary Efficacy Time Point (PET) | -17.3 percentage of baseline |
p-value: 0.009Wilcoxon rank sum test
Other Pre-specified
Percent Change From Baseline in Apolipoprotein A1 (Apo-A1) at Primary Efficacy Time Point (PET)
Apo-A1 was measured in mg/dL. Samples were taken following an overnight fast. Baseline was defined as the average of the screening and Study Day 1 (pre-treatment) assessments. An assessment was not included in this calculation if it was associated with a non-fasting blood draw or was drawn more than 4 weeks prior to Study Day 1. The PET was the post-baseline visit, for which LDL-C was assessed, closest to 14 days after the last dose of study drug.
Time frame: Baseline (the average of the screening and Day 1 pre-treatment assessments) and the Primary Efficacy Time point (PET) up to week 28
Population: Full analysis set
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Placebo | Percent Change From Baseline in Apolipoprotein A1 (Apo-A1) at Primary Efficacy Time Point (PET) | 5.35 percentage of baseline | Standard Deviation 10.63 |
| Mipomersen | Percent Change From Baseline in Apolipoprotein A1 (Apo-A1) at Primary Efficacy Time Point (PET) | 9.27 percentage of baseline | Standard Deviation 17.59 |
p-value: 0.328t-test, 2 sided
Other Pre-specified
Ratio of LDL-C to HDL-C at Baseline and the Primary Efficacy Time Point (PET)
The PET was the post-baseline visit, for which LDL-C was assessed, closest to 14 days after the last dose of study drug.
Time frame: Baseline (the average of the screening and Day 1 pre-treatment assessments) and the Primary Efficacy Time point (PET) up to week 28
Population: Full analysis set
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Placebo | Ratio of LDL-C to HDL-C at Baseline and the Primary Efficacy Time Point (PET) | Baseline | 12.14 ratio | Standard Deviation 7.675 |
| Placebo | Ratio of LDL-C to HDL-C at Baseline and the Primary Efficacy Time Point (PET) | PET | 11.37 ratio | Standard Deviation 7.095 |
| Mipomersen | Ratio of LDL-C to HDL-C at Baseline and the Primary Efficacy Time Point (PET) | Baseline | 13.02 ratio | Standard Deviation 6.115 |
| Mipomersen | Ratio of LDL-C to HDL-C at Baseline and the Primary Efficacy Time Point (PET) | PET | 8.13 ratio | Standard Deviation 3.921 |
Other Pre-specified
Triglycerides at Baseline and the Primary Efficacy Time Point (PET)
The PET was the post-baseline visit, for which LDL-C was assessed, closest to 14 days after the last dose of study drug.
Time frame: Baseline (the average of the screening and Day 1 pre-treatment assessments) and the Primary Efficacy Time point (PET) up to week 28
Population: Full analysis set
| Arm | Measure | Group | Value (MEDIAN) |
|---|---|---|---|
| Placebo | Triglycerides at Baseline and the Primary Efficacy Time Point (PET) | Baseline | 92 mg/dL |
| Placebo | Triglycerides at Baseline and the Primary Efficacy Time Point (PET) | PET | 85 mg/dL |
| Mipomersen | Triglycerides at Baseline and the Primary Efficacy Time Point (PET) | Baseline | 91 mg/dL |
| Mipomersen | Triglycerides at Baseline and the Primary Efficacy Time Point (PET) | PET | 76 mg/dL |
Other Pre-specified
VLDL-C at Baseline and the Primary Efficacy Time Point (PET)
The PET was the post-baseline visit, for which LDL-C was assessed, closest to 14 days after the last dose of study drug.
Time frame: Baseline (the average of the screening and Day 1 pre-treatment assessments) and the Primary Efficacy Time point (PET) up to week 28
Population: Full analysis set
| Arm | Measure | Group | Value (MEDIAN) |
|---|---|---|---|
| Placebo | VLDL-C at Baseline and the Primary Efficacy Time Point (PET) | Baseline | 18 mg/dL |
| Placebo | VLDL-C at Baseline and the Primary Efficacy Time Point (PET) | PET | 17 mg/dL |
| Mipomersen | VLDL-C at Baseline and the Primary Efficacy Time Point (PET) | Baseline | 18 mg/dL |
| Mipomersen | VLDL-C at Baseline and the Primary Efficacy Time Point (PET) | PET | 15 mg/dL |