Trial Outcomes & Findings for Open Label Extension of ISIS 301012 (Mipomersen) to Treat Familial Hypercholesterolemia (NCT NCT00477594)

Last Updated: 2016-09-09

Results Overview

LDL cholesterol 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. For patients who were on placebo in the index study or who took their last dose of mipomersen ≥6 months prior to first dose in this study, Baseline is defined as the last measurement prior to first dose in this study. For participants who took their last dose of mipomersen less than 6 months before starting this study, Baseline is defined as the last measurement taken prior to receiving a first dose in the index study.

Recruitment status

COMPLETED

Study phase

PHASE2

Target enrollment

21 participants

Primary outcome timeframe

Baseline and Weeks 52 and 104

Results posted on

2016-09-09

Participant Flow

Patients who completed dosing in study 301012-CS8 (NCT00280995) or 301012-CS9 (NCT00281008) at a site in the U.S. with an acceptable safety profile, per Investigator judgment, were eligible to enroll in this study.

Patients who participated in Cohorts A, B, or C in study 301012-CS9 were randomized in a 1:1 ratio to mipomersen 200 mg once a week (QW) or 200 mg mipomersen every other week (QOW). Patients who participated in study 301012-CS8 or Cohort D of study 301012-CS9 received 200 mg mipomersen QW.

Participant milestones

Participant milestones
Measure	Mipomersen 200 mg Per Week Participants received 200 mg mipomersen once a week by subcutaneous injection, for up to 3 years.	Mipomersen 200 mg Every Other Week Participants received 200 mg mipomersen every other week by subcutaneous injection, for up to 3 years. Participants could receive mipomersen 200 mg once a week at the Investigator's discretion after the first 52 weeks of the treatment period.
Year 1 and Year 2 STARTED	16	5
Year 1 and Year 2 COMPLETED	7	1
Year 1 and Year 2 NOT COMPLETED	9	4
Year 3 STARTED	4	0
Year 3 COMPLETED	2	0
Year 3 NOT COMPLETED	2	0
Follow-up Period STARTED	16	5
Follow-up Period COMPLETED	13	4
Follow-up Period NOT COMPLETED	3	1

Reasons for withdrawal

Reasons for withdrawal
Measure	Mipomersen 200 mg Per Week Participants received 200 mg mipomersen once a week by subcutaneous injection, for up to 3 years.	Mipomersen 200 mg Every Other Week Participants received 200 mg mipomersen every other week by subcutaneous injection, for up to 3 years. Participants could receive mipomersen 200 mg once a week at the Investigator's discretion after the first 52 weeks of the treatment period.
Year 1 and Year 2 Adverse Event	4	2
Year 1 and Year 2 Physician Decision	2	1
Year 1 and Year 2 Withdrawal by Subject	2	1
Year 1 and Year 2 Other	1	0
Year 3 Adverse Event	1	0
Year 3 Withdrawal by Subject	1	0
Follow-up Period Withdrawal by Subject	2	1
Follow-up Period Other	1	0

Baseline Characteristics

Open Label Extension of ISIS 301012 (Mipomersen) to Treat Familial Hypercholesterolemia

Baseline characteristics by cohort

Baseline characteristics by cohort
Measure	Mipomersen 200 mg Per Week n=16 Participants Participants received 200 mg mipomersen once a week by subcutaneous injection, for up to 3 years.	Mipomersen 200 mg Every Other Week n=5 Participants Participants received 200 mg mipomersen every other week by subcutaneous injection, for up to 3 years. Participants could receive mipomersen 200 mg once a week at the Investigator's discretion after the first 52 weeks of the treatment period.	Total n=21 Participants Total of all reporting groups
Age, Continuous	47.1 years STANDARD_DEVIATION 11.6 • n=5 Participants	54.6 years STANDARD_DEVIATION 15.7 • n=7 Participants	48.9 years STANDARD_DEVIATION 12.7 • n=5 Participants
Sex: Female, Male Female	4 Participants n=5 Participants	2 Participants n=7 Participants	6 Participants n=5 Participants
Sex: Female, Male Male	12 Participants n=5 Participants	3 Participants n=7 Participants	15 Participants n=5 Participants
Race/Ethnicity, Customized Hispanic or Latino	1 participants n=5 Participants	0 participants n=7 Participants	1 participants n=5 Participants
Race/Ethnicity, Customized Not Hispanic or Latino	15 participants n=5 Participants	5 participants n=7 Participants	20 participants n=5 Participants
Race/Ethnicity, Customized White	14 participants n=5 Participants	5 participants n=7 Participants	19 participants n=5 Participants
Race/Ethnicity, Customized Other race	1 participants n=5 Participants	0 participants n=7 Participants	1 participants n=5 Participants
Race/Ethnicity, Customized Multiple	1 participants n=5 Participants	0 participants n=7 Participants	1 participants n=5 Participants
Body Mass Index (BMI)	28.9 kg/m^2 STANDARD_DEVIATION 5.60 • n=5 Participants	27.4 kg/m^2 STANDARD_DEVIATION 4.81 • n=7 Participants	28.6 kg/m^2 STANDARD_DEVIATION 5.34 • n=5 Participants
Metabolic syndrome No	8 participants n=5 Participants	3 participants n=7 Participants	11 participants n=5 Participants
Metabolic syndrome Yes	8 participants n=5 Participants	2 participants n=7 Participants	10 participants n=5 Participants
Tobacco Use Current	1 participants n=5 Participants	0 participants n=7 Participants	1 participants n=5 Participants
Tobacco Use Non-current	5 participants n=5 Participants	2 participants n=7 Participants	7 participants n=5 Participants
Tobacco Use Never	10 participants n=5 Participants	3 participants n=7 Participants	13 participants n=5 Participants
Alcohol use Current	13 participants n=5 Participants	3 participants n=7 Participants	16 participants n=5 Participants
Alcohol use Non-current	1 participants n=5 Participants	0 participants n=7 Participants	1 participants n=5 Participants
Alcohol use Never	2 participants n=5 Participants	2 participants n=7 Participants	4 participants n=5 Participants

PRIMARY outcome

Timeframe: Baseline and Weeks 52 and 104

Population: The Safety Set included all enrolled patients who received at least 1 injection of study drug. "N" indicates the number of participants with available data at the specified time point.

Outcome measures

Outcome measures
Measure	Mipomersen 200 mg Per Week n=16 Participants Participants received 200 mg mipomersen once a week by subcutaneous injection, for up to 3 years.	Mipomersen 200 mg Every Other Week n=5 Participants Participants received 200 mg mipomersen every other week by subcutaneous injection, for up to 3 years. Participants could receive mipomersen 200 mg once a week at the Investigator's discretion after the first 52 weeks of the treatment period.
Percent Change From Baseline in Low-density Lipoprotein Cholesterol (LDL-C) Week 52 [N=13, 4]	-16.2 percentage of baseline Interval -41.8 to -7.8	-2.6 percentage of baseline Interval -10.2 to 14.8
Percent Change From Baseline in Low-density Lipoprotein Cholesterol (LDL-C) Week 104 [N=7, 1]	-32.4 percentage of baseline Interval -38.8 to -16.6	30.6 percentage of baseline Interval 30.6 to 30.6
Percent Change From Baseline in Low-density Lipoprotein Cholesterol (LDL-C) Week 104/Early Termination [N=16, 5]	-13.8 percentage of baseline Interval -31.4 to -3.0	9.5 percentage of baseline Interval 3.4 to 11.5

PRIMARY outcome

Timeframe: Baseline and Weeks 52 and 104.

Population: The Safety Set included all enrolled patients who received at least 1 injection of study drug. "N" indicates the number of participants with available data at the specified time point.

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. For patients who were on placebo in the index study or who took their last dose of mipomersen ≥6 months prior to first dose in this study, Baseline is defined as the last measurement prior to first dose in this study. For participants who took their last dose of mipomersen less than 6 months before starting this study, Baseline is defined as the last measurement taken prior to receiving a first dose in the index study.

Outcome measures

Outcome measures
Measure	Mipomersen 200 mg Per Week n=16 Participants Participants received 200 mg mipomersen once a week by subcutaneous injection, for up to 3 years.	Mipomersen 200 mg Every Other Week n=5 Participants Participants received 200 mg mipomersen every other week by subcutaneous injection, for up to 3 years. Participants could receive mipomersen 200 mg once a week at the Investigator's discretion after the first 52 weeks of the treatment period.
Low-density Lipoprotein Cholesterol (LDL-C) Over Time Baseline [N=16, 5]	177 mg/dL Interval 134.0 to 205.0	131 mg/dL Interval 124.0 to 147.0
Low-density Lipoprotein Cholesterol (LDL-C) Over Time Week 52 [N=13, 4]	145 mg/dL Interval 106.0 to 173.0	127 mg/dL Interval 124.0 to 139.0
Low-density Lipoprotein Cholesterol (LDL-C) Over Time Week 104 [N=7, 1]	121 mg/dL Interval 82.0 to 156.0	162 mg/dL Interval 162.0 to 162.0
Low-density Lipoprotein Cholesterol (LDL-C) Over Time Week 104/Early Termination [N=16, 5}	144 mg/dL Interval 116.0 to 213.0	161 mg/dL Interval 146.0 to 162.0

SECONDARY outcome

Timeframe: Baseline and Weeks 52 and 104

Population: The Safety Set included all enrolled patients who received at least 1 injection of study drug. "N" indicates the number of participants with available data at the specified time point.

Apolipoprotein B was measured in mg/dL. Samples were taken following an overnight fast. For patients who were on placebo in the index study or who took their last dose of mipomersen ≥6 months prior to first dose in this study, Baseline is defined as the last measurement prior to first dose in this study. For participants who took their last dose of mipomersen less than 6 months before starting this study, Baseline is defined as the last measurement taken prior to receiving a first dose in the index study.

Outcome measures

Outcome measures
Measure	Mipomersen 200 mg Per Week n=16 Participants Participants received 200 mg mipomersen once a week by subcutaneous injection, for up to 3 years.	Mipomersen 200 mg Every Other Week n=5 Participants Participants received 200 mg mipomersen every other week by subcutaneous injection, for up to 3 years. Participants could receive mipomersen 200 mg once a week at the Investigator's discretion after the first 52 weeks of the treatment period.
Percent Change From Baseline in Apolipoprotein B Week 52 [N=13, 4]	-25.9 percentage of baseline Interval -39.1 to -11.0	-7.3 percentage of baseline Interval -19.7 to 7.7
Percent Change From Baseline in Apolipoprotein B Week 104 [N=7, 1]	-27.2 percentage of baseline Interval -39.7 to -22.4	20.8 percentage of baseline Interval 20.8 to 20.8
Percent Change From Baseline in Apolipoprotein B Week 104/Early Termination [N=16, 5]	-15.8 percentage of baseline Interval -26.2 to -3.5	-3.7 percentage of baseline Interval -14.9 to -1.6

SECONDARY outcome

Timeframe: Baseline and Weeks 52 and 104.

Population: The Safety Set included all enrolled patients who received at least 1 injection of study drug. "N" indicates the number of participants with available data at the specified time point.

For patients who were on placebo in the index study or who took their last dose of mipomersen ≥6 months prior to first dose in this study, Baseline is defined as the last measurement prior to first dose in this study. For participants who took their last dose of mipomersen less than 6 months before starting this study, Baseline is defined as the last measurement taken prior to receiving a first dose in the index study.

Outcome measures

Outcome measures
Measure	Mipomersen 200 mg Per Week n=16 Participants Participants received 200 mg mipomersen once a week by subcutaneous injection, for up to 3 years.	Mipomersen 200 mg Every Other Week n=5 Participants Participants received 200 mg mipomersen every other week by subcutaneous injection, for up to 3 years. Participants could receive mipomersen 200 mg once a week at the Investigator's discretion after the first 52 weeks of the treatment period.
Apolipoprotein B Over Time Baseline [N=16, 5]	148 mg/dL Interval 127.0 to 181.0	124 mg/dL Interval 109.0 to 154.0
Apolipoprotein B Over Time Week 52 [N=13, 4]	136 mg/dL Interval 102.0 to 146.0	110 mg/dL Interval 104.0 to 123.0
Apolipoprotein B Over Time Week 104 [N=7, 1]	110 mg/dL Interval 73.0 to 146.0	128 mg/dL Interval 128.0 to 128.0
Apolipoprotein B Over Time Week 104/Early Termination [N=16, 5]	132 mg/dL Interval 104.0 to 175.0	128 mg/dL Interval 122.0 to 131.0

SECONDARY outcome

Timeframe: Baseline and Weeks 52 and 104.

Population: The Safety Set included all enrolled patients who received at least 1 injection of study drug. "N" indicates the number of participants with available data at the specified time point.

Total cholesterol was measured in mg/dL. Samples were taken following an overnight fast.

Outcome measures

Outcome measures
Measure	Mipomersen 200 mg Per Week n=16 Participants Participants received 200 mg mipomersen once a week by subcutaneous injection, for up to 3 years.	Mipomersen 200 mg Every Other Week n=5 Participants Participants received 200 mg mipomersen every other week by subcutaneous injection, for up to 3 years. Participants could receive mipomersen 200 mg once a week at the Investigator's discretion after the first 52 weeks of the treatment period.
Percent Change From Baseline in Total Cholesterol Week 104/Early Termination [N=16, 5]	-11.2 percentage of baseline Interval -24.2 to -2.4	-1.5 percentage of baseline Interval -1.7 to 2.6
Percent Change From Baseline in Total Cholesterol Week 52 [N=13, 4]	-10.5 percentage of baseline Interval -26.8 to -6.4	-6.5 percentage of baseline Interval -13.4 to 8.6
Percent Change From Baseline in Total Cholesterol Week 104 [N=7, 1]	-25.3 percentage of baseline Interval -29.2 to -18.0	-1.5 percentage of baseline Interval -1.5 to -1.5

SECONDARY outcome

Timeframe: Baseline and Weeks 52 and 104.

Population: The Safety Set included all enrolled patients who received at least 1 injection of study drug. "N" indicates the number of participants with available data at the specified time point.

Outcome measures

Outcome measures
Measure	Mipomersen 200 mg Per Week n=16 Participants Participants received 200 mg mipomersen once a week by subcutaneous injection, for up to 3 years.	Mipomersen 200 mg Every Other Week n=5 Participants Participants received 200 mg mipomersen every other week by subcutaneous injection, for up to 3 years. Participants could receive mipomersen 200 mg once a week at the Investigator's discretion after the first 52 weeks of the treatment period.
Total Cholesterol Over Time Baseline [N=16, 5]	251 mg/dL Interval 206.0 to 293.0	233 mg/dL Interval 199.0 to 235.0
Total Cholesterol Over Time Week 104/Early Termination [N=16, 5]	209 mg/dL Interval 193.0 to 297.0	231 mg/dL Interval 199.0 to 239.0
Total Cholesterol Over Time Week 52 [N=13, 4]	216 mg/dL Interval 173.0 to 245.0	203 mg/dL Interval 192.0 to 220.0
Total Cholesterol Over Time Week 104 [N=7, 1]	209 mg/dL Interval 143.0 to 209.0	196 mg/dL Interval 196.0 to 196.0

SECONDARY outcome

Timeframe: Baseline and Weeks 52 and 104.

Population: The Safety Set included all enrolled patients who received at least 1 injection of study drug. "N" indicates the number of participants with available data at the specified time point.

Non-high-density lipoprotein cholesterol was measured in mg/dL. Samples were taken following an overnight fast.

Outcome measures

Outcome measures
Measure	Mipomersen 200 mg Per Week n=16 Participants Participants received 200 mg mipomersen once a week by subcutaneous injection, for up to 3 years.	Mipomersen 200 mg Every Other Week n=5 Participants Participants received 200 mg mipomersen every other week by subcutaneous injection, for up to 3 years. Participants could receive mipomersen 200 mg once a week at the Investigator's discretion after the first 52 weeks of the treatment period.
Percent Change From Baseline in Non-High-Density Lipoprotein Cholesterol Week 104 [N=7, 1]	-34.3 percentage of baseline Interval -37.9 to -21.6	17.2 percentage of baseline Interval 17.2 to 17.2
Percent Change From Baseline in Non-High-Density Lipoprotein Cholesterol Week 52 [N=13, 4]	-24.7 percentage of baseline Interval -40.5 to -12.6	-6.7 percentage of baseline Interval -15.0 to 9.5
Percent Change From Baseline in Non-High-Density Lipoprotein Cholesterol Week 104/Early Termination [N=16, 5]	-16.5 percentage of baseline Interval -31.2 to -6.6	3.7 percentage of baseline Interval -3.0 to 14.1

SECONDARY outcome

Timeframe: Baseline and Weeks 52 and 104.

Population: The Safety Set included all enrolled patients who received at least 1 injection of study drug. "N" indicates the number of participants with available data at the specified time point.

Outcome measures

Outcome measures
Measure	Mipomersen 200 mg Per Week n=16 Participants Participants received 200 mg mipomersen once a week by subcutaneous injection, for up to 3 years.	Mipomersen 200 mg Every Other Week n=5 Participants Participants received 200 mg mipomersen every other week by subcutaneous injection, for up to 3 years. Participants could receive mipomersen 200 mg once a week at the Investigator's discretion after the first 52 weeks of the treatment period.
Non-High-Density Lipoprotein Cholesterol Over Time Baseline [N=16, 5]	206 mg/dL Interval 167.0 to 253.0	151 mg/dL Interval 149.0 to 203.0
Non-High-Density Lipoprotein Cholesterol Over Time Week 52 [N=13, 4]	167 mg/dL Interval 134.0 to 208.0	150 mg/dL Interval 140.0 to 164.0
Non-High-Density Lipoprotein Cholesterol Over Time Week 104 [N=7, 1]	161 mg/dL Interval 95.0 to 174.0	177 mg/dL Interval 177.0 to 177.0
Non-High-Density Lipoprotein Cholesterol Over Time Week 104/Early Termination [N=16, 5]	164 mg/dL Interval 151.0 to 255.0	177 mg/dL Interval 170.0 to 197.0

SECONDARY outcome

Timeframe: 2 years

Population: Safety set

AEs were considered as related if assessed by the Investigator as possibly, probably or definitely related to study drug. The severity of each event was assessed using the following categories: Mild (symptom(s) barely noticeable to the patient or do not make the patient uncomfortable); Moderate (symptom(s) of a sufficient severity to make the patient uncomfortable, performance of daily activities is influenced) or Severe (symptom(s) of a sufficient severity to cause 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 to prevent one of the outcomes listed above.

Outcome measures

Outcome measures
Measure	Mipomersen 200 mg Per Week n=16 Participants Participants received 200 mg mipomersen once a week by subcutaneous injection, for up to 3 years.	Mipomersen 200 mg Every Other Week n=5 Participants Participants received 200 mg mipomersen every other week by subcutaneous injection, for up to 3 years. Participants could receive mipomersen 200 mg once a week at the Investigator's discretion after the first 52 weeks of the treatment period.
Number of Participants With Treatment-Emergent Adverse Events (AEs) Any adverse event	16 participants	5 participants
Number of Participants With Treatment-Emergent Adverse Events (AEs) Treatment-related adverse event	16 participants	5 participants
Number of Participants With Treatment-Emergent Adverse Events (AEs) Mild adverse event	5 participants	2 participants
Number of Participants With Treatment-Emergent Adverse Events (AEs) Moderate adverse event	8 participants	3 participants
Number of Participants With Treatment-Emergent Adverse Events (AEs) Severe adverse event	3 participants	0 participants
Number of Participants With Treatment-Emergent Adverse Events (AEs) Serious adverse event	4 participants	2 participants
Number of Participants With Treatment-Emergent Adverse Events (AEs) Adverse event leading to treatment discontinuation	4 participants	2 participants

SECONDARY outcome

Timeframe: Baseline and Week 104 or the Early Termination visit for participants who did not complete 2 years of treatment.

Population: Safety set.

Outcome measures

Outcome measures
Measure	Mipomersen 200 mg Per Week n=16 Participants Participants received 200 mg mipomersen once a week by subcutaneous injection, for up to 3 years.	Mipomersen 200 mg Every Other Week n=5 Participants Participants received 200 mg mipomersen every other week by subcutaneous injection, for up to 3 years. Participants could receive mipomersen 200 mg once a week at the Investigator's discretion after the first 52 weeks of the treatment period.
Percent Change From Baseline in Clinical Chemistry Parameters Bilirubin, Total	34.79 percentage of baseline Standard Deviation 57.97	0.48 percentage of baseline Standard Deviation 10.96
Percent Change From Baseline in Clinical Chemistry Parameters Blood Urea Nitrogen (BUN)	6.08 percentage of baseline Standard Deviation 22.90	-11.06 percentage of baseline Standard Deviation 16.56
Percent Change From Baseline in Clinical Chemistry Parameters Alanine aminotransferase (ALT)	63.73 percentage of baseline Standard Deviation 112.98	29.96 percentage of baseline Standard Deviation 80.01
Percent Change From Baseline in Clinical Chemistry Parameters Aspartate aminotransferase (AST)	48.73 percentage of baseline Standard Deviation 86.00	3.53 percentage of baseline Standard Deviation 39.14
Percent Change From Baseline in Clinical Chemistry Parameters Bilirubin, Indirect	13.81 percentage of baseline Standard Deviation 20.56	12.50 percentage of baseline Standard Deviation 29.86
Percent Change From Baseline in Clinical Chemistry Parameters Creatine Kinase	-17.24 percentage of baseline Standard Deviation 36.85	40.95 percentage of baseline Standard Deviation 149.95
Percent Change From Baseline in Clinical Chemistry Parameters Creatinine	-9.94 percentage of baseline Standard Deviation 12.54	-9.84 percentage of baseline Standard Deviation 14.05
Percent Change From Baseline in Clinical Chemistry Parameters Glomerular Filtration Rate (GFR)	16.20 percentage of baseline Standard Deviation 24.56	15.49 percentage of baseline Standard Deviation 21.58

SECONDARY outcome

Timeframe: Baseline and Week 104 or the Early Termination visit for participants who did not complete 2 years of treatment

Population: Safety set

Outcome measures

Outcome measures
Measure	Mipomersen 200 mg Per Week n=16 Participants Participants received 200 mg mipomersen once a week by subcutaneous injection, for up to 3 years.	Mipomersen 200 mg Every Other Week n=5 Participants Participants received 200 mg mipomersen every other week by subcutaneous injection, for up to 3 years. Participants could receive mipomersen 200 mg once a week at the Investigator's discretion after the first 52 weeks of the treatment period.
Percent Change From Baseline in Hematology Parameters Hematocrit	-0.04 percentage of baseline Standard Deviation 8.69	-5.24 percentage of baseline Standard Deviation 3.69
Percent Change From Baseline in Hematology Parameters Hemoglobin	0.90 percentage of baseline Standard Deviation 7.61	-4.24 percentage of baseline Standard Deviation 4.44
Percent Change From Baseline in Hematology Parameters Leukocytes	-0.80 percentage of baseline Standard Deviation 31.95	-5.99 percentage of baseline Standard Deviation 43.17
Percent Change From Baseline in Hematology Parameters Platelets	-8.55 percentage of baseline Standard Deviation 11.88	-1.36 percentage of baseline Standard Deviation 12.31

SECONDARY outcome

Timeframe: Baseline and Week 104 or the Early Termination visit for participants who did not complete 2 years of treatment.

Population: Safety set

Outcome measures

Outcome measures
Measure	Mipomersen 200 mg Per Week n=16 Participants Participants received 200 mg mipomersen once a week by subcutaneous injection, for up to 3 years.	Mipomersen 200 mg Every Other Week n=5 Participants Participants received 200 mg mipomersen every other week by subcutaneous injection, for up to 3 years. Participants could receive mipomersen 200 mg once a week at the Investigator's discretion after the first 52 weeks of the treatment period.
Percent Change From Baseline in Blood Pressure Systolic Blood Pressure	6.99 percentage of baseline Standard Deviation 12.33	2.35 percentage of baseline Standard Deviation 12.54
Percent Change From Baseline in Blood Pressure Diastolic Blood Pressure	-0.88 percentage of baseline Standard Deviation 11.31	10.67 percentage of baseline Standard Deviation 15.35

SECONDARY outcome

Timeframe: Baseline and Week 104 or the Early Termination visit for participants who did not complete 2 years of treatment.

Population: Safety set

Outcome measures

Outcome measures
Measure	Mipomersen 200 mg Per Week n=16 Participants Participants received 200 mg mipomersen once a week by subcutaneous injection, for up to 3 years.	Mipomersen 200 mg Every Other Week n=5 Participants Participants received 200 mg mipomersen every other week by subcutaneous injection, for up to 3 years. Participants could receive mipomersen 200 mg once a week at the Investigator's discretion after the first 52 weeks of the treatment period.
Percent Change From Baseline in Pulse Rate	4.89 percentage of baseline Standard Deviation 14.41	6.28 percentage of baseline Standard Deviation 17.45

SECONDARY outcome

Timeframe: Baseline and Week 104 or the Early Termination visit for participants who did not complete 2 years of treatment.

Population: Safety set

Outcome measures

Outcome measures
Measure	Mipomersen 200 mg Per Week n=16 Participants Participants received 200 mg mipomersen once a week by subcutaneous injection, for up to 3 years.	Mipomersen 200 mg Every Other Week n=5 Participants Participants received 200 mg mipomersen every other week by subcutaneous injection, for up to 3 years. Participants could receive mipomersen 200 mg once a week at the Investigator's discretion after the first 52 weeks of the treatment period.
Percent Change From Baseline in Respiratory Rate	0.87 percentage of baseline Standard Deviation 10.57	-4.44 percentage of baseline Standard Deviation 13.30

OTHER_PRE_SPECIFIED outcome

Timeframe: Baseline and Weeks 52 and 104.

Population: The Safety Set included all enrolled patients who received at least 1 injection of study drug. "N" indicates the number of participants with available data at the specified time point.

Triglycerides were measured in mg/dL. Samples were taken following an overnight fast.

Outcome measures

Outcome measures
Measure	Mipomersen 200 mg Per Week n=16 Participants Participants received 200 mg mipomersen once a week by subcutaneous injection, for up to 3 years.	Mipomersen 200 mg Every Other Week n=5 Participants Participants received 200 mg mipomersen every other week by subcutaneous injection, for up to 3 years. Participants could receive mipomersen 200 mg once a week at the Investigator's discretion after the first 52 weeks of the treatment period.
Percent Change From Baseline in Triglycerides Week 52 [N=13, 4]	-30.2 percentage of baseline Interval -36.3 to -26.7	-27.0 percentage of baseline Interval -43.0 to -3.1
Percent Change From Baseline in Triglycerides Week 104 [N=7, 1]	-46.8 percentage of baseline Interval -58.2 to -30.2	-44.8 percentage of baseline Interval -44.8 to -44.8
Percent Change From Baseline in Triglycerides Week 104/Early Termination [N=16, 5]	-34.3 percentage of baseline Interval -42.9 to 2.2	-34.7 percentage of baseline Interval -36.1 to 9.0

OTHER_PRE_SPECIFIED outcome

Timeframe: Baseline and Weeks 52 and 104.

Population: The Safety Set included all enrolled patients who received at least 1 injection of study drug. "N" indicates the number of participants with available data at the specified time point.

Outcome measures

Outcome measures
Measure	Mipomersen 200 mg Per Week n=16 Participants Participants received 200 mg mipomersen once a week by subcutaneous injection, for up to 3 years.	Mipomersen 200 mg Every Other Week n=5 Participants Participants received 200 mg mipomersen every other week by subcutaneous injection, for up to 3 years. Participants could receive mipomersen 200 mg once a week at the Investigator's discretion after the first 52 weeks of the treatment period.
Triglycerides Over Time Baseline [N=16, 5]	167 mg/dL Interval 96.0 to 254.0	134 mg/dL Interval 92.0 to 199.0
Triglycerides Over Time Week 52 [N=13, 4]	102 mg/dL Interval 67.0 to 150.0	90 mg/dL Interval 80.0 to 123.0
Triglycerides Over Time Week 104 [N=7, 1]	77 mg/dL Interval 67.0 to 113.0	74 mg/dL Interval 74.0 to 74.0
Triglycerides Over Time Week 104/Early Termination [N=16, 5]	98 mg/dL Interval 76.0 to 180.0	122 mg/dL Interval 97.0 to 130.0

OTHER_PRE_SPECIFIED outcome

Timeframe: Baseline and Weeks 52 and 104.

Population: The Safety Set included all enrolled patients who received at least 1 injection of study drug. "N" indicates the number of participants with available data at the specified time point.

Lipoprotein(a) was measured in mg/dL. Samples were taken following an overnight fast.

Outcome measures

Outcome measures
Measure	Mipomersen 200 mg Per Week n=16 Participants Participants received 200 mg mipomersen once a week by subcutaneous injection, for up to 3 years.	Mipomersen 200 mg Every Other Week n=5 Participants Participants received 200 mg mipomersen every other week by subcutaneous injection, for up to 3 years. Participants could receive mipomersen 200 mg once a week at the Investigator's discretion after the first 52 weeks of the treatment period.
Percent Change From Baseline in Lipoprotein(a) Week 52 [N=13, 4]	-20.2 percentage of baseline Interval -34.3 to -4.7	0.0 percentage of baseline Interval -27.3 to 0.0
Percent Change From Baseline in Lipoprotein(a) Week 104 [N=7, 1]	-30.7 percentage of baseline Interval -32.7 to -24.1	0.0 percentage of baseline Interval 0.0 to 0.0
Percent Change From Baseline in Lipoprotein(a) Week 104/Early Termination [N=16, 5]	-18.2 percentage of baseline Interval -31.0 to 0.0	-20.0 percentage of baseline Interval -25.0 to 0.0

OTHER_PRE_SPECIFIED outcome

Timeframe: Baseline and Weeks 52 and 104.

Population: The Safety Set included all enrolled patients who received at least 1 injection of study drug. "N" indicates the number of participants with available data at the specified time point.

Outcome measures

Outcome measures
Measure	Mipomersen 200 mg Per Week n=16 Participants Participants received 200 mg mipomersen once a week by subcutaneous injection, for up to 3 years.	Mipomersen 200 mg Every Other Week n=5 Participants Participants received 200 mg mipomersen every other week by subcutaneous injection, for up to 3 years. Participants could receive mipomersen 200 mg once a week at the Investigator's discretion after the first 52 weeks of the treatment period.
Lipoprotein(a) Over Time Baseline [N=16, 5]	50 mg/dL Interval 15.0 to 98.0	5 mg/dL Interval 3.0 to 11.0
Lipoprotein(a) Over Time Week 52 [N=13, 4]	54 mg/dL Interval 23.0 to 75.0	4 mg/dL Interval 3.0 to 5.0
Lipoprotein(a) Over Time Week 104 [N=7, 1]	49 mg/dL Interval 33.0 to 79.0	3 mg/dL Interval 3.0 to 3.0
Lipoprotein(a) Over Time Week 104/Early Termination [N=16, 5]	47 mg/dL Interval 24.0 to 71.0	4 mg/dL Interval 3.0 to 4.0

OTHER_PRE_SPECIFIED outcome

Timeframe: Baseline and Weeks 52 and 104.

Population: The Safety Set included all enrolled patients who received at least 1 injection of study drug. "N" indicates the number of participants with available data at the specified time point.

Very-Low-Density Lipoprotein (VLDL) Cholesterol was measured in mg/dL. Samples were taken following an overnight fast.

Outcome measures

Outcome measures
Measure	Mipomersen 200 mg Per Week n=16 Participants Participants received 200 mg mipomersen once a week by subcutaneous injection, for up to 3 years.	Mipomersen 200 mg Every Other Week n=5 Participants Participants received 200 mg mipomersen every other week by subcutaneous injection, for up to 3 years. Participants could receive mipomersen 200 mg once a week at the Investigator's discretion after the first 52 weeks of the treatment period.
Percent Change From Baseline in Very-Low-Density Lipoprotein (VLDL) Cholesterol Week 52 [N=13, 4]	-31.6 percentage of baseline Interval -37.1 to -25.0	-25.9 percentage of baseline Interval -43.6 to -2.8
Percent Change From Baseline in Very-Low-Density Lipoprotein (VLDL) Cholesterol Week 104 [N=7, 1]	-48.6 percentage of baseline Interval -58.3 to -31.6	-44.4 percentage of baseline Interval -44.4 to -44.4
Percent Change From Baseline in Very-Low-Density Lipoprotein (VLDL) Cholesterol Week 104/Early Termination [N=16, 5]	-34.0 percentage of baseline Interval -44.0 to 2.8	-35.0 percentage of baseline Interval -35.7 to 5.6

OTHER_PRE_SPECIFIED outcome

Timeframe: Baseline and Weeks 52 and 104.

Population: The Safety Set included all enrolled patients who received at least 1 injection of study drug. "N" indicates the number of participants with available data at the specified time point.

Outcome measures

Outcome measures
Measure	Mipomersen 200 mg Per Week n=16 Participants Participants received 200 mg mipomersen once a week by subcutaneous injection, for up to 3 years.	Mipomersen 200 mg Every Other Week n=5 Participants Participants received 200 mg mipomersen every other week by subcutaneous injection, for up to 3 years. Participants could receive mipomersen 200 mg once a week at the Investigator's discretion after the first 52 weeks of the treatment period.
Very-Low-Density Lipoprotein (VLDL) Cholesterol Over Time Baseline [N=16, 5]	34 mg/dL Interval 19.0 to 51.0	27 mg/dL Interval 18.0 to 40.0
Very-Low-Density Lipoprotein (VLDL) Cholesterol Over Time Week 52 [N=13, 4]	20 mg/dL Interval 13.0 to 30.0	18 mg/dL Interval 16.0 to 25.0
Very-Low-Density Lipoprotein (VLDL) Cholesterol Over Time Week 104 [N=7, 1]	15 mg/dL Interval 13.0 to 23.0	15 mg/dL Interval 15.0 to 15.0
Very-Low-Density Lipoprotein (VLDL) Cholesterol Over Time Week 104/Early Termination [N=16, 5]	20 mg/dL Interval 15.0 to 36.0	24 mg/dL Interval 19.0 to 26.0

OTHER_PRE_SPECIFIED outcome

Timeframe: Baseline and Weeks 52 and 104.

Population: The Safety Set included all enrolled patients who received at least 1 injection of study drug. "N" indicates the number of participants with available data at the specified time point.

Outcome measures

Outcome measures
Measure	Mipomersen 200 mg Per Week n=16 Participants Participants received 200 mg mipomersen once a week by subcutaneous injection, for up to 3 years.	Mipomersen 200 mg Every Other Week n=5 Participants Participants received 200 mg mipomersen every other week by subcutaneous injection, for up to 3 years. Participants could receive mipomersen 200 mg once a week at the Investigator's discretion after the first 52 weeks of the treatment period.
Percent Change From Baseline in Ratio of Low-density Lipoprotein Cholesterol to High-density Lipoprotein Cholesterol Week 52 [N=13, 4]	-33.5 percentage of baseline Interval -43.6 to -25.8	2.6 percentage of baseline Interval -11.8 to 10.2
Percent Change From Baseline in Ratio of Low-density Lipoprotein Cholesterol to High-density Lipoprotein Cholesterol Week 104 [N=7, 1]	-41.2 percentage of baseline Interval -57.8 to -34.6	230.1 percentage of baseline Interval 230.1 to 230.1
Percent Change From Baseline in Ratio of Low-density Lipoprotein Cholesterol to High-density Lipoprotein Cholesterol Week 104/Early Termination [N=16, 5]	-24.9 percentage of baseline Interval -38.2 to -18.5	15.2 percentage of baseline Interval 3.1 to 35.7

OTHER_PRE_SPECIFIED outcome

Timeframe: Baseline and Weeks 52 and 104.

Population: The Safety Set included all enrolled patients who received at least 1 injection of study drug. "N" indicates the number of participants with available data at the specified time point.

Outcome measures

Outcome measures
Measure	Mipomersen 200 mg Per Week n=16 Participants Participants received 200 mg mipomersen once a week by subcutaneous injection, for up to 3 years.	Mipomersen 200 mg Every Other Week n=5 Participants Participants received 200 mg mipomersen every other week by subcutaneous injection, for up to 3 years. Participants could receive mipomersen 200 mg once a week at the Investigator's discretion after the first 52 weeks of the treatment period.
Ratio of Low-density Lipoprotein Cholesterol to High-density Lipoprotein Cholesterol Over Time Baseline [N=16, 5]	4 ratio Interval 3.0 to 6.0	3 ratio Interval 2.0 to 4.0
Ratio of Low-density Lipoprotein Cholesterol to High-density Lipoprotein Cholesterol Over Time Week 52 [N=13, 4]	3 ratio Interval 2.0 to 4.0	3 ratio Interval 2.0 to 3.0
Ratio of Low-density Lipoprotein Cholesterol to High-density Lipoprotein Cholesterol Over Time Week 104 [N=7, 1]	3 ratio Interval 2.0 to 4.0	9 ratio Interval 9.0 to 9.0
Ratio of Low-density Lipoprotein Cholesterol to High-density Lipoprotein Cholesterol Over Time Week 104/Early Termination [N=16, 5]	3 ratio Interval 2.0 to 4.0	5 ratio Interval 2.0 to 5.0

OTHER_PRE_SPECIFIED outcome

Timeframe: Baseline and Weeks 52 and 104.

Population: The Safety Set included all enrolled patients who received at least 1 injection of study drug. "N" indicates the number of participants with available data at the specified time point.

Apolipoprotein A1 was measured in mg/dL. Samples were taken following an overnight fast.

Outcome measures

Outcome measures
Measure	Mipomersen 200 mg Per Week n=16 Participants Participants received 200 mg mipomersen once a week by subcutaneous injection, for up to 3 years.	Mipomersen 200 mg Every Other Week n=5 Participants Participants received 200 mg mipomersen every other week by subcutaneous injection, for up to 3 years. Participants could receive mipomersen 200 mg once a week at the Investigator's discretion after the first 52 weeks of the treatment period.
Percent Change From Baseline in Apolipoprotein A1 Week 52 [N=13, 4]	4.6 percentage of baseline Interval -4.3 to 11.2	7.4 percentage of baseline Interval -5.3 to 17.0
Percent Change From Baseline in Apolipoprotein A1 Week 104 [N=7, 1]	5.9 percentage of baseline Interval -2.7 to 7.6	-55.1 percentage of baseline Interval -55.1 to -55.1
Percent Change From Baseline in Apolipoprotein A1 Week 104/Early Termination [N=16, 5]	6.3 percentage of baseline Interval -0.7 to 9.5	-7.9 percentage of baseline Interval -11.8 to -3.4

OTHER_PRE_SPECIFIED outcome

Timeframe: Baseline and Weeks 52 and 104.

Population: The Safety Set included all enrolled patients who received at least 1 injection of study drug. "N" indicates the number of participants with available data at the specified time point.

Outcome measures

Outcome measures
Measure	Mipomersen 200 mg Per Week n=16 Participants Participants received 200 mg mipomersen once a week by subcutaneous injection, for up to 3 years.	Mipomersen 200 mg Every Other Week n=5 Participants Participants received 200 mg mipomersen every other week by subcutaneous injection, for up to 3 years. Participants could receive mipomersen 200 mg once a week at the Investigator's discretion after the first 52 weeks of the treatment period.
Apolipoprotein A1 Over Time Baseline [N=16, 5]	132 mg/dL Interval 120.0 to 149.0	149 mg/dL Interval 147.0 to 178.0
Apolipoprotein A1 Over Time Week 52 [N=13, 4]	139 mg/dL Interval 123.0 to 160.0	159 mg/dL Interval 144.0 to 178.0
Apolipoprotein A1 Over Time Week 104 [N=7, 1]	142 mg/dL Interval 113.0 to 155.0	66 mg/dL Interval 66.0 to 66.0
Apolipoprotein A1 Over Time Week 104/Early Termination [N=16, 5]	141 mg/dL Interval 129.0 to 153.0	144 mg/dL Interval 126.0 to 164.0

OTHER_PRE_SPECIFIED outcome

Timeframe: Baseline and Weeks 52 and 104.

Population: The Safety Set included all enrolled patients who received at least 1 injection of study drug. "N" indicates the number of participants with available data at the specified time point.

High-Density Lipoprotein (HDL) Cholesterol was measured in mg/dL. Samples were taken following an overnight fast.

Outcome measures

Outcome measures
Measure	Mipomersen 200 mg Per Week n=16 Participants Participants received 200 mg mipomersen once a week by subcutaneous injection, for up to 3 years.	Mipomersen 200 mg Every Other Week n=5 Participants Participants received 200 mg mipomersen every other week by subcutaneous injection, for up to 3 years. Participants could receive mipomersen 200 mg once a week at the Investigator's discretion after the first 52 weeks of the treatment period.
Percent Change From Baseline in High-Density Lipoprotein Cholesterol Week 52 [N=13, 4]	12.8 percentage of baseline Interval 6.4 to 32.4	6.8 percentage of baseline Interval -4.9 to 12.0
Percent Change From Baseline in High-Density Lipoprotein Cholesterol Week 104 [N=7, 1]	14.9 percentage of baseline Interval 6.1 to 43.8	-60.4 percentage of baseline Interval -60.4 to -60.4
Percent Change From Baseline in High-Density Lipoprotein Cholesterol Week 104/Early Termination [N=16, 5]	15.3 percentage of baseline Interval 4.9 to 26.9	-17.9 percentage of baseline Interval -19.6 to 6.3

OTHER_PRE_SPECIFIED outcome

Timeframe: Baseline and Weeks 52 and 104.

Population: The Safety Set included all enrolled patients who received at least 1 injection of study drug. "N" indicates the number of participants with available data at the specified time point.

Outcome measures

Outcome measures
Measure	Mipomersen 200 mg Per Week n=16 Participants Participants received 200 mg mipomersen once a week by subcutaneous injection, for up to 3 years.	Mipomersen 200 mg Every Other Week n=5 Participants Participants received 200 mg mipomersen every other week by subcutaneous injection, for up to 3 years. Participants could receive mipomersen 200 mg once a week at the Investigator's discretion after the first 52 weeks of the treatment period.
High-Density Lipoprotein Cholesterol Over Time Baseline [N=16, 5]	40 mg/dL Interval 33.0 to 46.0	52 mg/dL Interval 48.0 to 56.0
High-Density Lipoprotein Cholesterol Over Time Week 52 [N=13, 4]	46 mg/dL Interval 41.0 to 50.0	54 mg/dL Interval 43.0 to 66.0
High-Density Lipoprotein Cholesterol Over Time Week 104 [N=7, 1]	47 mg/dL Interval 35.0 to 48.0	19 mg/dL Interval 19.0 to 19.0
High-Density Lipoprotein Cholesterol Over Time Week 104/Early Termination [N=16, 5]	47 mg/dL Interval 40.0 to 50.0	45 mg/dL Interval 34.0 to 58.0

Adverse Events

Mipomersen 200 mg Per Week

Serious events: 4 serious events

Other events: 16 other events

Deaths: 0 deaths

Mipomersen 200 mg Every Other Week

Serious events: 3 serious events

Other events: 5 other events

Deaths: 0 deaths

Serious adverse events

Serious adverse events
Measure	Mipomersen 200 mg Per Week n=16 participants at risk Participants received 200 mg mipomersen once a week by subcutaneous injection, for up to 3 years.	Mipomersen 200 mg Every Other Week n=5 participants at risk Participants received 200 mg mipomersen every other week by subcutaneous injection, for up to 3 years. Participants could receive mipomersen 200 mg once a week at the Investigator's discretion after the first 52 weeks of the treatment period.
Cardiac disorders Angina pectoris	0.00% 0/16 • Up to 3 years. In the event a single participant has experienced both a serious and a non-serious form of the same adverse event term, the individual has been included in the numerator ("number of affected participants") of both adverse event tables.	20.0% 1/5 • Up to 3 years. In the event a single participant has experienced both a serious and a non-serious form of the same adverse event term, the individual has been included in the numerator ("number of affected participants") of both adverse event tables.
Cardiac disorders Coronary artery disease	0.00% 0/16 • Up to 3 years. In the event a single participant has experienced both a serious and a non-serious form of the same adverse event term, the individual has been included in the numerator ("number of affected participants") of both adverse event tables.	40.0% 2/5 • Up to 3 years. In the event a single participant has experienced both a serious and a non-serious form of the same adverse event term, the individual has been included in the numerator ("number of affected participants") of both adverse event tables.
Gastrointestinal disorders Inguinal hernia	6.2% 1/16 • Up to 3 years. In the event a single participant has experienced both a serious and a non-serious form of the same adverse event term, the individual has been included in the numerator ("number of affected participants") of both adverse event tables.	0.00% 0/5 • Up to 3 years. In the event a single participant has experienced both a serious and a non-serious form of the same adverse event term, the individual has been included in the numerator ("number of affected participants") of both adverse event tables.
General disorders Non-cardiac chest pain	6.2% 1/16 • Up to 3 years. In the event a single participant has experienced both a serious and a non-serious form of the same adverse event term, the individual has been included in the numerator ("number of affected participants") of both adverse event tables.	0.00% 0/5 • Up to 3 years. In the event a single participant has experienced both a serious and a non-serious form of the same adverse event term, the individual has been included in the numerator ("number of affected participants") of both adverse event tables.
Investigations Alanine aminotransferase increased	6.2% 1/16 • Up to 3 years. In the event a single participant has experienced both a serious and a non-serious form of the same adverse event term, the individual has been included in the numerator ("number of affected participants") of both adverse event tables.	0.00% 0/5 • Up to 3 years. In the event a single participant has experienced both a serious and a non-serious form of the same adverse event term, the individual has been included in the numerator ("number of affected participants") of both adverse event tables.
Neoplasms benign, malignant and unspecified (incl cysts and polyps) Malignant melanoma in situ	6.2% 1/16 • Up to 3 years. In the event a single participant has experienced both a serious and a non-serious form of the same adverse event term, the individual has been included in the numerator ("number of affected participants") of both adverse event tables.	0.00% 0/5 • Up to 3 years. In the event a single participant has experienced both a serious and a non-serious form of the same adverse event term, the individual has been included in the numerator ("number of affected participants") of both adverse event tables.

Other adverse events

Additional Information

Genzyme Medical Information

Genzyme Corporation

Phone: 617-252-7832

Results disclosure agreements

Principal investigator is a sponsor employee After the multicenter publication or 12 months after completion of the study the PI may publish the results of his/her data from the study. The PI shall provide the sponsor with an advance copy at least 60 days prior to planned submission and the Sponsor shall have 60 days to review (contracts have variable timeframes; maximum times are stated here). The sponsor may request the deletion of any confidential information, or a delay in submission for an additional period not to exceed 90 days.
Publication restrictions are in place

Restriction type: OTHER