RADICHOL II: Efficacy and Safety Study of ISIS 301012 (Mipomersen) as Add-on in Familial Hypercholesterolemic Patients With Coronary Artery Disease

• Sponsor: Kastle Therapeutics, LLC (Industry)
• Overall Status: Completed
• CT.gov ID: NCT00706849
• Collaborator: Ionis Pharmaceuticals, Inc. (Industry)
• Enrollment: 124
• Locations: 48
• Arms: 2
• Duration (Months): 22
• Patients Per Site: 2.6
• Patients Per Site Per Month: 0.1

Study Details

Study Description

Brief Summary

The purpose of this study is to determine whether mipomersen safely and effectively lowers low-density lipoprotein cholesterol (LDL-C) in patients with Heterozygous Familial Hypercholesterolemia (HeFH) and coronary artery disease (CAD) who are already on a stable dose of other lipid-lowering agents (including maximally tolerated statin therapy).

Condition or Disease	Intervention/Treatment	Phase
Heterozygous Familial Hypercholesterolemia; Coronary Artery Disease	Drug: mipomersen sodium; Drug: placebo	Phase 3

Detailed Description

Familial hypercholesterolemia (FH) is an autosomal dominant genetic disorder of lipoprotein metabolism characterized by markedly elevated LDL-C, premature onset of atherosclerosis and development of xanthomata. Patients with heterozygous familial hypercholesterolemia typically have total plasma cholesterol between 350 to 550 mg/dL and disease onset in their third and fourth decade.

Mipomersen (ISIS 301012) is an antisense drug that reduces a protein in the liver cells called apolipoprotein B (apo-B). Apo-B plays a role in producing low density lipoprotein cholesterol (the "bad" cholesterol) and moving it from the liver to one's bloodstream. High LDL-C is an independent risk factor for the development of coronary heart disease (CHD) or other diseases of blood vessels. It has been shown that lowering LDL-C reduces the risk of heart attacks and other major adverse cardiovascular events.

This study consisted of a 26-week treatment period 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]). The treatment period spanned the time during which the study treatment was administered until the later of the primary efficacy time point (PET) or 14 days beyond the last day of study drug administration. The post-treatment follow-up period began the day after completion of the treatment period and ended on the day of the patient's last contact date within the study.

Following treatment and Week 28 evaluations, eligible patients who tolerated study drug could elect to enroll in an open-label extension study (301012-CS6). Patients who were not eligible for or who elected not to enroll in the open-label extension study and patients who discontinued during the 26-week treatment period were followed in this study for an additional 24 weeks from administration of the last dose of study drug.

Study Design

• Study Type: Interventional
• Actual Enrollment: 124 participants
• Allocation: Randomized
• Intervention Model: Parallel Assignment
• Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
• Primary Purpose: Treatment
• Official Title: A Randomized, Double-Blind, Placebo-Controlled Study to Assess Efficacy and Safety of ISIS 301012 as Add-on Therapy in Heterozygous Familial Hypercholesterolemia Subjects With Coronary Artery Disease
• Study Start Date: Jul 1, 2008
• Actual Primary Completion Date: Dec 1, 2009
• Actual Study Completion Date: May 1, 2010

Arms and Interventions

Arm	Intervention/Treatment
Experimental: Mipomersen Participants received mipomersen 200 mg as a subcutaneous injection once a week for 26 weeks.	Drug: mipomersen sodium; 200 mg /mL; Other Names: ISIS 301012 Kynamro™
Placebo Comparator: Placebo Participants received a placebo subcutaneous injection once a week for 26 weeks.	Drug: placebo; 1 mL matching placebo

Outcome Measures

Primary Outcome Measures

1. 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 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. The primary efficacy time point was the post-baseline visit closest to 14 days after the last dose of study treatment.

2. LDL 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.

Secondary Outcome Measures

1. 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.

2. 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.

3. 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.

4. 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.

5. 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.

6. 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.

Other Outcome Measures

1. 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.

2. 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.

3. 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.

4. 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.

5. 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 (VLDL) 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.

6. Very Low Density Lipoprotein 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.

7. Percent Change From Baseline in the Ratio of LDL Cholesterol to HDL 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 at Baseline and the post-baseline visit closest to 14 days after the last dose of study treatment.

8. Ratio of LDL Cholesterol to HDL 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.

9. 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.

10. 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.

11. 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.

12. 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.

Eligibility Criteria

Criteria

• Ages Eligible for Study: 18 Years and Older
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

Inclusion Criteria:

• Diagnosis of Heterozygous Familial Hypercholesterolemia (HeFH)

• Diagnosis of Coronary Artery Disease (CAD)

• Stable lipid-lowering therapy for 12 weeks

• On maximally tolerated statin therapy with at least 1 statin at a dose greater than zero, per Investigator judgment

• Stable low-fat diet for 8 weeks

• Stable weight for 6 weeks

Exclusion Criteria:

• Significant health problems in recent past including heart attack, stroke, coronary syndrome, unstable angina, heart failure, significant arrhythmia, orthostatic hypotension, uncontrolled hypertension, blood disorders, liver disease, cancer, or digestive problems

• Receiving apheresis treatment or last apheresis treatment within 8 weeks

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1		La Jolla	California	United States	92093
2		Los Angeles	California	United States	90048
3		Mission Viejo	California	United States	92691
4		Newport Beach	California	United States	92260
5		Santa Ana	California	United States	92705
6		Thousand Oaks	California	United States	91360
7		Bridgeport	Connecticut	United States	06606
8		Melbourne	Florida	United States	32901
9		Pensacola	Florida	United States	32514
10		Chicago	Illinois	United States	60610
11		Naperville	Illinois	United States	60540
12		Kansas City	Kansas	United States	66160
13		Biddeford	Maine	United States	04005
14		Scarborough	Maine	United States	04074
15		Boston	Massachusetts	United States	02114
16		Ann Arbor	Michigan	United States	48109-5853
17		St. Louis	Missouri	United States	63110
18		Las Vegas	Nevada	United States	89144
19		Concord	New Hampshire	United States	03301
20		New York	New York	United States	10032
21	The Rogosin Institute Comprehensive Lipid Control Center	New York	New York	United States	10065
22		Charlotte	North Carolina	United States	28204
23		Charlotte	North Carolina	United States	28211
24		Durham	North Carolina	United States	27710
25		Cincinnati	Ohio	United States	45212
26	ResEvo, LLC	Cuyahoga Falls	Ohio	United States	44223
27		Franklin	Ohio	United States	45005
28		Oklahoma City	Oklahoma	United States	73120
29		Portland	Oregon	United States	97239
30		Nashville	Tennessee	United States	37232
31		Dallas	Texas	United States	75220
32		Dallas	Texas	United States	75226
33		Grapevine	Texas	United States	76051
34		Houston	Texas	United States	77093
35		San Antonio	Texas	United States	78229
36		Salt Lake City	Utah	United States	84108
37		Seattle	Washington	United States	98104
38		Calgary	Alberta	Canada	T2E 7C5
39		Vancouver	British Columbia	Canada	V6Z 1Y6
40		Winnipeg	Manitoba	Canada	R3A 1R9
41		London	Ontario	Canada	N6A 5K8
42		Toronto	Ontario	Canada	M5C 2T2
43		Toronto	Ontario	Canada	M5G 2C4
44		Chicoutimi	Quebec	Canada	G7H 5H6
45		Montreal	Quebec	Canada	H1T 1C8
46		Montreal	Quebec	Canada	H2W 1R7
47		Sherbrooke	Quebec	Canada	J1H 5N4
48		St. Foy	Quebec	Canada	G1V 4M6

Sponsors and Collaborators

• Kastle Therapeutics, LLC
• Ionis Pharmaceuticals, Inc.

Investigators

• Study Director: Medical Monitor, Genzyme, a Sanofi Company

Study Documents (Full-Text)

None provided.

More Information

Publications

None provided.

• Responsible Party: Kastle Therapeutics, LLC
• ClinicalTrials.gov Identifier: NCT00706849
• Other Study ID Numbers: 301012-CS7
• First Posted: Jun 30, 2008
• Last Update Posted: Sep 9, 2016
• Last Verified: Aug 1, 2016

• Keywords provided by Kastle Therapeutics, LLC: familial hypercholesterolemia
• Additional relevant MeSH terms: Coronary Artery Disease; Myocardial Ischemia; Coronary Disease; Hyperlipoproteinemia Type II; Hypercholesterolemia; Mipomersen

Study Results

Participant Flow

Pre-assignment Detail	Two hundred and twenty-five patients were screened and 124 participants were randomized on Day 1 in a 2:1 ratio to receive mipomersen or placebo once a week for 26 weeks.

Arm/Group Title	Placebo	Mipomersen
Arm/Group Description	Participants received a placebo subcutaneous injection once a week for 26 weeks.	Participants received mipomersen 200 mg as a subcutaneous injection once a week for 26 weeks.
Period Title: Treatment Period
STARTED	41	83
Full Analysis Set	41	82
COMPLETED	41	73
NOT COMPLETED	0	10
Period Title: Treatment Period
STARTED	3	28
COMPLETED	3	25
NOT COMPLETED	0	3

Baseline Characteristics

Arm/Group Title	Placebo	Mipomersen	Total
Arm/Group Description	Participants received a placebo subcutaneous injection once a week for 26 weeks.	Participants received mipomersen 200 mg as a subcutaneous injection once a week for 26 weeks.	Total of all reporting groups
Overall Participants	41	83	124
Age (years) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [years]	55.9 (9.3)	56.2 (9.7)	56.1 (9.5)
Sex: Female, Male (Count of Participants)
Female	13 31.7%	33 39.8%	46 37.1%
Male	28 68.3%	50 60.2%	78 62.9%
Race/Ethnicity, Customized (participants) [Number]
Hispanic or Latino	2 4.9%	2 2.4%	4 3.2%
Not Hispanic or Latino	39 95.1%	81 97.6%	120 96.8%
Race/Ethnicity, Customized (participants) [Number]
White	38 92.7%	81 97.6%	119 96%
Black	1 2.4%	2 2.4%	3 2.4%
Other race	2 4.9%	0 0%	2 1.6%
Body Mass Index (BMI) (kg/m^2) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [kg/m^2]	30.25 (3.79)	28.66 (4.23)	29.18 (4.14)
Waist/hip ratio (ratio) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [ratio]	0.95 (0.07)	0.93 (0.08)	0.93 (0.08)
Metabolic syndrome (participants) [Number]
No	30 73.2%	48 57.8%	78 62.9%
Yes	11 26.8%	35 42.2%	46 37.1%
Tobacco use (participants) [Number]
Current	4 9.8%	13 15.7%	17 13.7%
non-current	17 41.5%	32 38.6%	49 39.5%
Never	20 48.8%	38 45.8%	58 46.8%
Alcohol use (participants) [Number]
Current	31 75.6%	64 77.1%	95 76.6%
Non-current	7 17.1%	10 12%	17 13.7%
Never	3 7.3%	9 10.8%	12 9.7%

Outcome Measures

1. Primary Outcome

Title	Percent Change From Baseline in Low-density Lipoprotein Cholesterol (LDL-C) at the Primary Efficacy Time Point
Description	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. 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).

Outcome Measure Data

Analysis Population Description

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/Group Title	Placebo	Mipomersen
Arm/Group Description	Participants received a placebo subcutaneous injection once a week for 26 weeks.	Participants received mipomersen 200 mg as a subcutaneous injection once a week for 26 weeks.
Measure Participants	41	82
Mean (Standard Deviation) [percentage of Baseline]	5.17 (18.02)	-28.02 (26.99)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Placebo, Mipomersen
	Comments	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 20 patients in the control group and 40 patients in the mipomersen-treated group, this study would have at least 90% power to detect a 20% difference between the 2 treatment groups.
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	<0.001
	Comments	Statistical significance was concluded if p ≤ 0.05.
	Method	t-test, 2 sided
	Comments

2. Primary Outcome

Title	LDL Cholesterol at Baseline and at the Primary Efficacy Time Point
Description	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).

Outcome Measure Data

Analysis Population Description

Full Analysis Set

Arm/Group Title	Placebo	Mipomersen
Arm/Group Description	Participants received a placebo subcutaneous injection once a week for 26 weeks.	Participants received mipomersen 200 mg as a subcutaneous injection once a week for 26 weeks.
Measure Participants	41	82
Baseline	142.9 (51.6)	152.9 (48.7)
Primary efficacy time point	146.4 (43.4)	103.9 (33.0)

3. Secondary Outcome

Title	Percent Change From Baseline in Apolipoprotein B at the Primary Efficacy Time Point
Description	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).

Outcome Measure Data

Analysis Population Description

Full Analysis Set

Arm/Group Title	Placebo	Mipomersen
Arm/Group Description	Participants received a placebo subcutaneous injection once a week for 26 weeks.	Participants received mipomersen 200 mg as a subcutaneous injection once a week for 26 weeks.
Measure Participants	41	82
Mean (Standard Deviation) [percentage of baseline]	7.02 (16.52)	-26.31 (22.16)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Placebo, Mipomersen
	Comments
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	<0.001
	Comments	Inflation of type 1 error was controlled by specifying a small number of secondary parameters and a sequential inferential approach in which inferential conclusions about each successive parameter required statistical significance of the prior one.
	Method	t-test, 2 sided
	Comments

4. Secondary Outcome

Title	Apolipoprotein B at Baseline and at the Primary Efficacy Time Point
Description	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).

Outcome Measure Data

Analysis Population Description

Full Analysis Set

Arm/Group Title	Placebo	Mipomersen
Arm/Group Description	Participants received a placebo subcutaneous injection once a week for 26 weeks.	Participants received mipomersen 200 mg as a subcutaneous injection once a week for 26 weeks.
Measure Participants	41	82
Baseline	126.8 (33.2)	132.8 (33.9)
Primary efficacy time point	133.8 (32.6)	95.0 (29.7)

5. Secondary Outcome

Title	Percent Change From Baseline in Total Cholesterol at the Primary Efficacy Time Point
Description	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).

Outcome Measure Data

Analysis Population Description

Full Analysis Set

Arm/Group Title	Placebo	Mipomersen
Arm/Group Description	Participants received a placebo subcutaneous injection once a week for 26 weeks.	Participants received mipomersen 200 mg as a subcutaneous injection once a week for 26 weeks.
Measure Participants	41	82
Mean (Standard Deviation) [percentage of baseline]	3.85 (12.84)	-19.43 (19.25)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Placebo, Mipomersen
	Comments
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	<0.001
	Comments	Inflation of type 1 error was controlled by specifying a small number of secondary parameters and a sequential inferential approach in which inferential conclusions about each successive parameter required statistical significance of the prior one.
	Method	t-test, 2 sided
	Comments

6. Secondary Outcome

Title	Total Cholesterol at Baseline and at the Primary Efficacy Time Point
Description	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).

Outcome Measure Data

Analysis Population Description

Full Analysis Set

Arm/Group Title	Placebo	Mipomersen
Arm/Group Description	Participants received a placebo subcutaneous injection once a week for 26 weeks.	Participants received mipomersen 200 mg as a subcutaneous injection once a week for 26 weeks.
Measure Participants	41	82
Baseline	213.4 (54.6)	225.3 (51.5)
Primary efficacy time point	219.0 (49.0)	176.0 (35.9)

7. Secondary Outcome

Title	Percent Change From Baseline in Non-High-Density Lipoprotein Cholesterol at the Primary Efficacy Time Point
Description	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).

Outcome Measure Data

Analysis Population Description

Full Analysis Set

Arm/Group Title	Placebo	Mipomersen
Arm/Group Description	Participants received a placebo subcutaneous injection once a week for 26 weeks.	Participants received mipomersen 200 mg as a subcutaneous injection once a week for 26 weeks.
Measure Participants	41	82
Mean (Standard Deviation) [percentage of baseline]	3.74 (16.04)	-25.05 (25.71)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Placebo, Mipomersen
	Comments
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	<0.001
	Comments	Inflation of type 1 error was controlled by specifying a small number of secondary parameters and a sequential inferential approach in which inferential conclusions about each successive parameter required statistical significance of the prior one.
	Method	t-test, 2 sided
	Comments

8. Secondary Outcome

Title	Non-High-Density Lipoprotein Cholesterol at Baseline and at the Primary Efficacy Time Point
Description	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).

Outcome Measure Data

Analysis Population Description

Full Analysis Set

Arm/Group Title	Placebo	Mipomersen
Arm/Group Description	Participants received a placebo subcutaneous injection once a week for 26 weeks.	Participants received mipomersen 200 mg as a subcutaneous injection once a week for 26 weeks.
Measure Participants	41	82
Baseline	165.3 (54.5)	175.5 (51.1)
Primary efficacy time point	168.2 (47.5)	125.2 (37.8)

9. Other Pre-specified Outcome

Title	Percent Change From Baseline in Triglycerides at the Primary Efficacy Time Point
Description	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).

Outcome Measure Data

Analysis Population Description

Full Analysis Set

Arm/Group Title	Placebo	Mipomersen
Arm/Group Description	Participants received a placebo subcutaneous injection once a week for 26 weeks.	Participants received mipomersen 200 mg as a subcutaneous injection once a week for 26 weeks.
Measure Participants	41	82
Median (Inter-Quartile Range) [percentage of baseline]	0.5 (20.77)	-14.3 (43.76)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Placebo, Mipomersen
	Comments
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.042
	Comments	No adjustments were made for tertiary parameters.
	Method	Wilcoxon (Mann-Whitney)
	Comments

10. Other Pre-specified Outcome

Title	Triglycerides at Baseline and at the Primary Efficacy Time Point
Description	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).

Outcome Measure Data

Analysis Population Description

Full Analysis Set

Arm/Group Title	Placebo	Mipomersen
Arm/Group Description	Participants received a placebo subcutaneous injection once a week for 26 weeks.	Participants received mipomersen 200 mg as a subcutaneous injection once a week for 26 weeks.
Measure Participants	41	82
Baseline	100 (53.3)	107 (39.6)
Primary efficacy time point	101 (42.5)	89 (70.1)

11. Other Pre-specified Outcome

Title	Percent Change From Baseline in Lipoprotein (a) at the Primary Efficacy Time Point
Description	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).

Outcome Measure Data

Analysis Population Description

Full Analysis Set

Arm/Group Title	Placebo	Mipomersen
Arm/Group Description	Participants received a placebo subcutaneous injection once a week for 26 weeks.	Participants received mipomersen 200 mg as a subcutaneous injection once a week for 26 weeks.
Measure Participants	41	82
Median (Inter-Quartile Range) [percentage of baseline]	0.0 (15.10)	-21.1 (24.22)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Placebo, Mipomersen
	Comments
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	<0.001
	Comments	No adjustments were made for tertiary parameters.
	Method	Wilcoxon (Mann-Whitney)
	Comments

12. Other Pre-specified Outcome

Title	Lipoprotein (a) at Baseline and at the Primary Efficacy Time Point
Description	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).

Outcome Measure Data

Analysis Population Description

Full Analysis Set

Arm/Group Title	Placebo	Mipomersen
Arm/Group Description	Participants received a placebo subcutaneous injection once a week for 26 weeks.	Participants received mipomersen 200 mg as a subcutaneous injection once a week for 26 weeks.
Measure Participants	41	82
Baseline	53 (56.2)	45 (64.6)
Primary efficacy time point	51 (53.5)	35 (55.3)

13. Other Pre-specified Outcome

Title	Percent Change From Baseline in Very Low Density Lipoprotein Cholesterol at the Primary Efficacy Time Point
Description	Very low density lipoprotein (VLDL) 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).

Outcome Measure Data

Analysis Population Description

Full Analysis Set

Arm/Group Title	Placebo	Mipomersen
Arm/Group Description	Participants received a placebo subcutaneous injection once a week for 26 weeks.	Participants received mipomersen 200 mg as a subcutaneous injection once a week for 26 weeks.
Measure Participants	41	82
Median (Inter-Quartile Range) [percentage of baseline]	0.0 (20.11)	-13.8 (45.70)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Placebo, Mipomersen
	Comments
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.023
	Comments	No adjustments were made for tertiary parameters.
	Method	Wilcoxon (Mann-Whitney)
	Comments

14. Other Pre-specified Outcome

Title	Very Low Density Lipoprotein at Baseline and at the Primary Efficacy Time Point
Description	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).

Outcome Measure Data

Analysis Population Description

Full Analysis Set

Arm/Group Title	Placebo	Mipomersen
Arm/Group Description	Participants received a placebo subcutaneous injection once a week for 26 weeks.	Participants received mipomersen 200 mg as a subcutaneous injection once a week for 26 weeks.
Measure Participants	41	82
Baseline	20 (9.5)	21 (7.9)
Primary efficacy time point	20 (8.5)	18 (14.6)

15. Other Pre-specified Outcome

Title	Percent Change From Baseline in the Ratio of LDL Cholesterol to HDL Cholesterol at the Primary Efficacy Time Point
Description	The ratio of low-density lipoprotein (LDL) cholesterol to high-density lipoprotein (HDL) cholesterol was measured at Baseline and 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).

Outcome Measure Data

Analysis Population Description

Full Analysis Set

Arm/Group Title	Placebo	Mipomersen
Arm/Group Description	Participants received a placebo subcutaneous injection once a week for 26 weeks.	Participants received mipomersen 200 mg as a subcutaneous injection once a week for 26 weeks.
Measure Participants	41	82
Median (Inter-Quartile Range) [percentage of baseline]	-2.8 (19.38)	-29.2 (29.99)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Placebo, Mipomersen
	Comments
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	<0.001
	Comments	No adjustments were made for tertiary parameters.
	Method	Wilcoxon (Mann-Whitney)
	Comments

16. Other Pre-specified Outcome

Title	Ratio of LDL Cholesterol to HDL Cholesterol at Baseline and at the Primary Efficacy Time Point
Description	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).

Outcome Measure Data

Analysis Population Description

Full Analysis Set

Arm/Group Title	Placebo	Mipomersen
Arm/Group Description	Participants received a placebo subcutaneous injection once a week for 26 weeks.	Participants received mipomersen 200 mg as a subcutaneous injection once a week for 26 weeks.
Measure Participants	41	82
Baseline	2.72 (1.495)	2.99 (1.353)
Primary efficacy time point	2.95 (1.337)	2.09 (1.034)

17. Other Pre-specified Outcome

Title	Percent Change From Baseline in Apolipoprotein A1 at the Primary Efficacy Time Point
Description	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).

Outcome Measure Data

Analysis Population Description

Full Analysis Set

Arm/Group Title	Placebo	Mipomersen
Arm/Group Description	Participants received a placebo subcutaneous injection once a week for 26 weeks.	Participants received mipomersen 200 mg as a subcutaneous injection once a week for 26 weeks.
Measure Participants	41	82
Mean (Standard Deviation) [percentage of baseline]	3.71 (8.70)	-2.44 (14.22)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Placebo, Mipomersen
	Comments
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.004
	Comments	No adjustments were made for tertiary parameters.
	Method	t-test, 2 sided
	Comments

18. Other Pre-specified Outcome

Title	Apolipoprotein A1 at Baseline and at the Primary Efficacy Time Point
Description	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).

Outcome Measure Data

Analysis Population Description

Full Analysis Set

Arm/Group Title	Placebo	Mipomersen
Arm/Group Description	Participants received a placebo subcutaneous injection once a week for 26 weeks.	Participants received mipomersen 200 mg as a subcutaneous injection once a week for 26 weeks.
Measure Participants	41	82
Baseline	146.1 (24.9)	150.7 (28.1)
Primary efficacy time point	151.5 (29.1)	145.4 (27.9)

19. Other Pre-specified Outcome

Title	Percent Change From Baseline in High-Density Lipoprotein Cholesterol at the Primary Efficacy Time Point
Description	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).

Outcome Measure Data

Analysis Population Description

Full Analysis Set

Arm/Group Title	Placebo	Mipomersen
Arm/Group Description	Participants received a placebo subcutaneous injection once a week for 26 weeks.	Participants received mipomersen 200 mg as a subcutaneous injection once a week for 26 weeks.
Measure Participants	41	82
Median (Inter-Quartile Range) [percentage of baseline]	5.8 (9.57)	2.5 (18.04)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Placebo, Mipomersen
	Comments
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.207
	Comments	No adjustments were made for tertiary parameters.
	Method	Wilcoxon (Mann-Whitney)
	Comments

20. Other Pre-specified Outcome

Title	High-Density Lipoprotein Cholesterol at Baseline and at the Primary Efficacy Time Point
Description	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).

Outcome Measure Data

Analysis Population Description

Full Analysis Set

Arm/Group Title	Placebo	Mipomersen
Arm/Group Description	Participants received a placebo subcutaneous injection once a week for 26 weeks.	Participants received mipomersen 200 mg as a subcutaneous injection once a week for 26 weeks.
Measure Participants	41	82
Baseline	48 (11.1)	47 (13.6)
Primary efficacy time point	51 (13.5)	48 (15.6)

Adverse Events

Time Frame	Up to Week 28 (2 weeks after last dose)
Adverse Event Reporting Description	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.
Arm/Group Title	Placebo		Mipomersen
Arm/Group Description	Participants received a placebo subcutaneous injection once a week for 26 weeks.		Participants received mipomersen 200 mg as a subcutaneous injection once a week for 26 weeks.
All Cause Mortality
	Placebo		Mipomersen
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	/ (NaN)		/ (NaN)
Serious Adverse Events
	Placebo		Mipomersen
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	2/41 (4.9%)		6/83 (7.2%)
Cardiac disorders
Acute myocardial infarction	0/41 (0%)		1/83 (1.2%)
Angina pectoris	0/41 (0%)		1/83 (1.2%)
Coronary artery disease	1/41 (2.4%)		0/83 (0%)
Supraventricular tachycardia	1/41 (2.4%)		0/83 (0%)
General disorders
Chest pain	0/41 (0%)		1/83 (1.2%)
Non-cardiac chest pain	0/41 (0%)		1/83 (1.2%)
Neoplasms benign, malignant and unspecified (incl cysts and polyps)
Basal cell carcinoma	0/41 (0%)		1/83 (1.2%)
Respiratory, thoracic and mediastinal disorders
Pulmonary embolism	0/41 (0%)		1/83 (1.2%)
Other (Not Including Serious) Adverse Events
	Placebo		Mipomersen
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	38/41 (92.7%)		83/83 (100%)
Blood and lymphatic system disorders
Anaemia	0/41 (0%)		1/83 (1.2%)
Lymphadenopathy	1/41 (2.4%)		1/83 (1.2%)
Cardiac disorders
Angina pectoris	0/41 (0%)		2/83 (2.4%)
Coronary artery disease	0/41 (0%)		1/83 (1.2%)
Myocardial ischaemia	1/41 (2.4%)		1/83 (1.2%)
Palpitations	0/41 (0%)		2/83 (2.4%)
Sinus bradycardia	1/41 (2.4%)		0/83 (0%)
Ear and labyrinth disorders
Ear pain	1/41 (2.4%)		0/83 (0%)
Tinnitus	1/41 (2.4%)		0/83 (0%)
Vertigo	1/41 (2.4%)		1/83 (1.2%)
Eye disorders
Cataract	0/41 (0%)		1/83 (1.2%)
Conjunctivitis	0/41 (0%)		1/83 (1.2%)
Dry eye	0/41 (0%)		1/83 (1.2%)
Eye irritation	0/41 (0%)		1/83 (1.2%)
Eyelid cyst	0/41 (0%)		1/83 (1.2%)
Presbyopia	1/41 (2.4%)		0/83 (0%)
Gastrointestinal disorders
Abdominal distension	1/41 (2.4%)		1/83 (1.2%)
Abdominal pain	1/41 (2.4%)		2/83 (2.4%)
Abdominal pain lower	1/41 (2.4%)		0/83 (0%)
Abdominal pain upper	1/41 (2.4%)		6/83 (7.2%)
Bezoar	0/41 (0%)		1/83 (1.2%)
Constipation	3/41 (7.3%)		4/83 (4.8%)
Dental caries	2/41 (4.9%)		0/83 (0%)
Diarrhoea	5/41 (12.2%)		9/83 (10.8%)
Diverticulum	1/41 (2.4%)		1/83 (1.2%)
Dry mouth	0/41 (0%)		1/83 (1.2%)
Dyspepsia	0/41 (0%)		3/83 (3.6%)
Dysphagia	0/41 (0%)		1/83 (1.2%)
Gastric polyps	0/41 (0%)		1/83 (1.2%)
Gastric ulcer	0/41 (0%)		1/83 (1.2%)
Gastritis	0/41 (0%)		1/83 (1.2%)
Gastrooesophageal reflux disease	0/41 (0%)		1/83 (1.2%)
Haematochezia	1/41 (2.4%)		0/83 (0%)
Haemorrhoids	1/41 (2.4%)		0/83 (0%)
Hiatus hernia	0/41 (0%)		1/83 (1.2%)
Hypoaesthesia oral	0/41 (0%)		1/83 (1.2%)
Irritable bowel syndrome	1/41 (2.4%)		0/83 (0%)
Lip pain	0/41 (0%)		1/83 (1.2%)
Lip swelling	0/41 (0%)		1/83 (1.2%)
Mouth ulceration	1/41 (2.4%)		0/83 (0%)
Nausea	6/41 (14.6%)		14/83 (16.9%)
Oesophageal dilatation	0/41 (0%)		1/83 (1.2%)
Paraesthesia oral	0/41 (0%)		1/83 (1.2%)
Periodontal disease	0/41 (0%)		1/83 (1.2%)
Retching	0/41 (0%)		1/83 (1.2%)
Tooth disorder	1/41 (2.4%)		0/83 (0%)
Toothache	0/41 (0%)		1/83 (1.2%)
Vomiting	0/41 (0%)		5/83 (6%)
General disorders
Adverse drug reaction	0/41 (0%)		1/83 (1.2%)
Asthenia	2/41 (4.9%)		1/83 (1.2%)
Chills	1/41 (2.4%)		6/83 (7.2%)
Cyst	1/41 (2.4%)		0/83 (0%)
Discomfort	1/41 (2.4%)		1/83 (1.2%)
Facial pain	0/41 (0%)		1/83 (1.2%)
Fatigue	4/41 (9.8%)		22/83 (26.5%)
Feeling jittery	0/41 (0%)		1/83 (1.2%)
Influenza like illness	3/41 (7.3%)		15/83 (18.1%)
Injection site discolouration	1/41 (2.4%)		13/83 (15.7%)
Injection site discomfort	0/41 (0%)		10/83 (12%)
Injection site eczema	0/41 (0%)		1/83 (1.2%)
Injection site erythema	3/41 (7.3%)		56/83 (67.5%)
Injection site haematoma	9/41 (22%)		45/83 (54.2%)
Injection site haemorrhage	1/41 (2.4%)		9/83 (10.8%)
Injection site induration	0/41 (0%)		11/83 (13.3%)
Injection site inflammation	0/41 (0%)		3/83 (3.6%)
Injection site lymphadenopathy	0/41 (0%)		1/83 (1.2%)
Injection site macule	0/41 (0%)		3/83 (3.6%)
Injection site nodule	0/41 (0%)		8/83 (9.6%)
Injection site oedema	0/41 (0%)		6/83 (7.2%)
Injection site pain	8/41 (19.5%)		54/83 (65.1%)
Injection site papule	0/41 (0%)		5/83 (6%)
Injection site paraesthesia	0/41 (0%)		2/83 (2.4%)
Injection site pruritus	2/41 (4.9%)		23/83 (27.7%)
Injection site rash	0/41 (0%)		11/83 (13.3%)
Injection site reaction	1/41 (2.4%)		5/83 (6%)
Injection site recall reaction	0/41 (0%)		15/83 (18.1%)
Injection site swelling	0/41 (0%)		13/83 (15.7%)
Injection site urticaria	0/41 (0%)		3/83 (3.6%)
Injection site vesicles	0/41 (0%)		2/83 (2.4%)
Injection site warmth	0/41 (0%)		12/83 (14.5%)
Injury associated with device	0/41 (0%)		1/83 (1.2%)
Irritability	0/41 (0%)		2/83 (2.4%)
Local swelling	0/41 (0%)		1/83 (1.2%)
Localised oedema	0/41 (0%)		1/83 (1.2%)
Malaise	1/41 (2.4%)		0/83 (0%)
Non-cardiac chest pain	0/41 (0%)		2/83 (2.4%)
Oedema peripheral	1/41 (2.4%)		7/83 (8.4%)
Pain	3/41 (7.3%)		5/83 (6%)
Pyrexia	0/41 (0%)		10/83 (12%)
Tenderness	0/41 (0%)		1/83 (1.2%)
Vessel puncture site haematoma	0/41 (0%)		1/83 (1.2%)
Hepatobiliary disorders
Hepatic cyst	0/41 (0%)		1/83 (1.2%)
Hepatic lesion	1/41 (2.4%)		0/83 (0%)
Hepatic steatosis	0/41 (0%)		5/83 (6%)
Hepatomegaly	0/41 (0%)		1/83 (1.2%)
Infections and infestations
Abscess oral	1/41 (2.4%)		0/83 (0%)
Asymptomatic bacteriuria	0/41 (0%)		1/83 (1.2%)
Bronchitis	1/41 (2.4%)		0/83 (0%)
Ear infection	1/41 (2.4%)		0/83 (0%)
Eye infection	1/41 (2.4%)		0/83 (0%)
Eye infection viral	1/41 (2.4%)		0/83 (0%)
Furuncle	1/41 (2.4%)		0/83 (0%)
Gastrointestinal infection	1/41 (2.4%)		0/83 (0%)
Gastrointestinal viral infection	0/41 (0%)		2/83 (2.4%)
H1N1 influenza	0/41 (0%)		1/83 (1.2%)
Influenza	2/41 (4.9%)		5/83 (6%)
Kidney infection	0/41 (0%)		2/83 (2.4%)
Laryngitis	1/41 (2.4%)		0/83 (0%)
Localised infection	0/41 (0%)		1/83 (1.2%)
Lower respiratory tract infection	0/41 (0%)		1/83 (1.2%)
Lyme disease	1/41 (2.4%)		0/83 (0%)
Nasopharyngitis	3/41 (7.3%)		9/83 (10.8%)
Pneumonia	0/41 (0%)		1/83 (1.2%)
Respiratory tract infection	1/41 (2.4%)		0/83 (0%)
Rhinitis	0/41 (0%)		1/83 (1.2%)
Sinusitis	4/41 (9.8%)		1/83 (1.2%)
Upper respiratory tract infection	3/41 (7.3%)		4/83 (4.8%)
Urinary tract infection	4/41 (9.8%)		6/83 (7.2%)
Vaginal infection	0/41 (0%)		1/83 (1.2%)
Viral upper respiratory tract infection	0/41 (0%)		1/83 (1.2%)
Vulvovaginal mycotic infection	1/41 (2.4%)		0/83 (0%)
Injury, poisoning and procedural complications
Animal bite	1/41 (2.4%)		0/83 (0%)
Arthropod bite	1/41 (2.4%)		0/83 (0%)
Arthropod sting	1/41 (2.4%)		0/83 (0%)
Brain contusion	0/41 (0%)		1/83 (1.2%)
Contusion	1/41 (2.4%)		5/83 (6%)
Epicondylitis	0/41 (0%)		1/83 (1.2%)
Face injury	0/41 (0%)		1/83 (1.2%)
Fall	0/41 (0%)		1/83 (1.2%)
Injury	0/41 (0%)		1/83 (1.2%)
Joint sprain	1/41 (2.4%)		0/83 (0%)
Muscle injury	1/41 (2.4%)		0/83 (0%)
Muscle strain	1/41 (2.4%)		1/83 (1.2%)
Post procedural haematoma	0/41 (0%)		1/83 (1.2%)
Procedural pain	1/41 (2.4%)		1/83 (1.2%)
Road traffic accident	1/41 (2.4%)		0/83 (0%)
Scratch	0/41 (0%)		1/83 (1.2%)
Skin laceration	1/41 (2.4%)		0/83 (0%)
Sunburn	1/41 (2.4%)		0/83 (0%)
Thermal burn	0/41 (0%)		1/83 (1.2%)
Tooth fracture	0/41 (0%)		1/83 (1.2%)
Investigations
Alanine aminotransferase increased	0/41 (0%)		6/83 (7.2%)
Aspartate aminotransferase increased	1/41 (2.4%)		3/83 (3.6%)
Bacterial test positive	0/41 (0%)		1/83 (1.2%)
Blood creatine phosphokinase increased	2/41 (4.9%)		0/83 (0%)
Blood pressure increased	1/41 (2.4%)		0/83 (0%)
Body temperature increased	0/41 (0%)		2/83 (2.4%)
Carotid bruit	1/41 (2.4%)		1/83 (1.2%)
Computerised tomogram abdomen abnormal	0/41 (0%)		1/83 (1.2%)
Electrocardiogram T wave inversion	0/41 (0%)		1/83 (1.2%)
Epstein-Barr virus antibody positive	0/41 (0%)		1/83 (1.2%)
Haematocrit decreased	0/41 (0%)		1/83 (1.2%)
Haemoglobin decreased	0/41 (0%)		1/83 (1.2%)
Hepatic enzyme increased	0/41 (0%)		4/83 (4.8%)
Herpes simplex serology positive	0/41 (0%)		1/83 (1.2%)
International normalised ratio increased	0/41 (0%)		2/83 (2.4%)
Liver function test abnormal	1/41 (2.4%)		5/83 (6%)
Multiple gated acquisition scan abnormal	0/41 (0%)		1/83 (1.2%)
Nitrite urine present	0/41 (0%)		1/83 (1.2%)
Nuclear magnetic resonance imaging abnormal	0/41 (0%)		1/83 (1.2%)
Platelet count decreased	0/41 (0%)		2/83 (2.4%)
Protein urine present	0/41 (0%)		1/83 (1.2%)
Pulse abnormal	0/41 (0%)		1/83 (1.2%)
Red blood cells urine positive	0/41 (0%)		1/83 (1.2%)
Transaminases increased	0/41 (0%)		2/83 (2.4%)
Urine leukocyte esterase positive	0/41 (0%)		1/83 (1.2%)
Weight decreased	1/41 (2.4%)		1/83 (1.2%)
Weight increased	1/41 (2.4%)		1/83 (1.2%)
White blood cells urine positive	1/41 (2.4%)		1/83 (1.2%)
Metabolism and nutrition disorders
Decreased appetite	3/41 (7.3%)		2/83 (2.4%)
Dehydration	0/41 (0%)		1/83 (1.2%)
Vitamin B12 deficiency	0/41 (0%)		1/83 (1.2%)
Musculoskeletal and connective tissue disorders
Arthralgia	4/41 (9.8%)		6/83 (7.2%)
Axillary mass	1/41 (2.4%)		0/83 (0%)
Back pain	4/41 (9.8%)		7/83 (8.4%)
Bursitis	1/41 (2.4%)		0/83 (0%)
Dupuytren's contracture	0/41 (0%)		1/83 (1.2%)
Exostosis	0/41 (0%)		1/83 (1.2%)
Groin pain	1/41 (2.4%)		1/83 (1.2%)
Joint effusion	0/41 (0%)		1/83 (1.2%)
Joint range of motion decreased	0/41 (0%)		1/83 (1.2%)
Joint warmth	0/41 (0%)		1/83 (1.2%)
Muscle fatigue	0/41 (0%)		1/83 (1.2%)
Muscle spasms	0/41 (0%)		1/83 (1.2%)
Muscular weakness	0/41 (0%)		1/83 (1.2%)
Musculoskeletal discomfort	1/41 (2.4%)		0/83 (0%)
Musculoskeletal pain	1/41 (2.4%)		3/83 (3.6%)
Musculoskeletal stiffness	0/41 (0%)		1/83 (1.2%)
Myalgia	4/41 (9.8%)		8/83 (9.6%)
Neck pain	1/41 (2.4%)		0/83 (0%)
Osteoarthritis	0/41 (0%)		1/83 (1.2%)
Osteopenia	1/41 (2.4%)		0/83 (0%)
Pain in extremity	3/41 (7.3%)		4/83 (4.8%)
Pain in jaw	0/41 (0%)		1/83 (1.2%)
Sensation of heaviness	0/41 (0%)		1/83 (1.2%)
Spinal osteoarthritis	0/41 (0%)		1/83 (1.2%)
Spondylitis	0/41 (0%)		1/83 (1.2%)
Neoplasms benign, malignant and unspecified (incl cysts and polyps)
Basal cell carcinoma	0/41 (0%)		1/83 (1.2%)
Lipoma	0/41 (0%)		2/83 (2.4%)
Morton's neuroma	0/41 (0%)		1/83 (1.2%)
Nervous system disorders
Amnesia	1/41 (2.4%)		0/83 (0%)
Burning sensation	0/41 (0%)		1/83 (1.2%)
Carotid artery stenosis	1/41 (2.4%)		0/83 (0%)
Carpal tunnel syndrome	1/41 (2.4%)		0/83 (0%)
Disturbance in attention	0/41 (0%)		1/83 (1.2%)
Dizziness	4/41 (9.8%)		4/83 (4.8%)
Dizziness postural	0/41 (0%)		2/83 (2.4%)
Dysgeusia	0/41 (0%)		1/83 (1.2%)
Headache	7/41 (17.1%)		15/83 (18.1%)
Hyperaesthesia	1/41 (2.4%)		0/83 (0%)
Hypoaesthesia	1/41 (2.4%)		0/83 (0%)
Lethargy	0/41 (0%)		2/83 (2.4%)
Migraine with aura	0/41 (0%)		1/83 (1.2%)
Paraesthesia	0/41 (0%)		4/83 (4.8%)
Sciatica	0/41 (0%)		2/83 (2.4%)
Sinus headache	0/41 (0%)		1/83 (1.2%)
Psychiatric disorders
Anxiety	2/41 (4.9%)		3/83 (3.6%)
Claustrophobia	0/41 (0%)		1/83 (1.2%)
Insomnia	1/41 (2.4%)		2/83 (2.4%)
Libido decreased	0/41 (0%)		1/83 (1.2%)
Panic attack	0/41 (0%)		1/83 (1.2%)
Stress	0/41 (0%)		1/83 (1.2%)
Renal and urinary disorders
Albuminuria	0/41 (0%)		1/83 (1.2%)
Chromaturia	0/41 (0%)		1/83 (1.2%)
Dysuria	0/41 (0%)		1/83 (1.2%)
Haematuria	0/41 (0%)		1/83 (1.2%)
Micturition urgency	0/41 (0%)		1/83 (1.2%)
Pollakiuria	0/41 (0%)		2/83 (2.4%)
Proteinuria	0/41 (0%)		3/83 (3.6%)
Stress urinary incontinence	0/41 (0%)		1/83 (1.2%)
Urge incontinence	0/41 (0%)		1/83 (1.2%)
Reproductive system and breast disorders
Menstruation delayed	1/41 (2.4%)		0/83 (0%)
Prostatitis	1/41 (2.4%)		0/83 (0%)
Prostatomegaly	1/41 (2.4%)		0/83 (0%)
Respiratory, thoracic and mediastinal disorders
Cough	2/41 (4.9%)		9/83 (10.8%)
Dyspnoea	0/41 (0%)		2/83 (2.4%)
Dyspnoea exertional	1/41 (2.4%)		0/83 (0%)
Nasal congestion	1/41 (2.4%)		2/83 (2.4%)
Nasal polyps	1/41 (2.4%)		0/83 (0%)
Oropharyngeal pain	1/41 (2.4%)		7/83 (8.4%)
Paranasal sinus hypersecretion	0/41 (0%)		1/83 (1.2%)
Postnasal drip	0/41 (0%)		1/83 (1.2%)
Productive cough	1/41 (2.4%)		2/83 (2.4%)
Pulmonary congestion	1/41 (2.4%)		0/83 (0%)
Rhinitis allergic	1/41 (2.4%)		0/83 (0%)
Rhinorrhoea	1/41 (2.4%)		3/83 (3.6%)
Sinus congestion	0/41 (0%)		2/83 (2.4%)
Sinus disorder	0/41 (0%)		1/83 (1.2%)
Upper respiratory tract congestion	1/41 (2.4%)		1/83 (1.2%)
Skin and subcutaneous tissue disorders
Actinic keratosis	1/41 (2.4%)		0/83 (0%)
Cold sweat	0/41 (0%)		1/83 (1.2%)
Dermatitis	0/41 (0%)		1/83 (1.2%)
Dermatitis contact	1/41 (2.4%)		0/83 (0%)
Dry skin	0/41 (0%)		1/83 (1.2%)
Ecchymosis	0/41 (0%)		2/83 (2.4%)
Eczema	0/41 (0%)		1/83 (1.2%)
Erythema	0/41 (0%)		1/83 (1.2%)
Hyperhidrosis	1/41 (2.4%)		1/83 (1.2%)
Hypoaesthesia facial	0/41 (0%)		1/83 (1.2%)
Pruritus	2/41 (4.9%)		2/83 (2.4%)
Pruritus generalised	0/41 (0%)		2/83 (2.4%)
Rash	4/41 (9.8%)		2/83 (2.4%)
Rash maculo-papular	0/41 (0%)		1/83 (1.2%)
Scab	0/41 (0%)		1/83 (1.2%)
Skin induration	0/41 (0%)		1/83 (1.2%)
Skin lesion	1/41 (2.4%)		0/83 (0%)
Skin plaque	0/41 (0%)		1/83 (1.2%)
Urticaria	0/41 (0%)		1/83 (1.2%)
Vascular disorders
Aortic aneurysm	0/41 (0%)		1/83 (1.2%)
Flushing	1/41 (2.4%)		1/83 (1.2%)
Hot flush	0/41 (0%)		3/83 (3.6%)
Hypertension	1/41 (2.4%)		2/83 (2.4%)
Hypotension	0/41 (0%)		1/83 (1.2%)
Infarction	0/41 (0%)		1/83 (1.2%)

Limitations/Caveats

[Not Specified]

More Information

Certain Agreements

Principal Investigators are NOT employed by the organization sponsoring the study.

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.