TESLA: Trial Evaluating PCSK9 Antibody in Subjects With LDL Receptor Abnormalities

• Sponsor: Amgen (Industry)
• Overall Status: Completed
• CT.gov ID: NCT01588496
• Collaborator: (none)
• Enrollment: 58
• Locations: 21
• Arms: 3
• Actual Duration (Months): 21.9
• Patients Per Site: 2.8
• Patients Per Site Per Month: 0.1

Study Details

Study Description

Brief Summary

A study to determine the safety, tolerability, and efficacy of evolocumab (AMG 145) in patients with homozygous familial hypercholesterolemia (HoFH).

Condition or Disease	Intervention/Treatment	Phase
Homozygous Familial Hypercholesterolemia	Biological: Evolocumab; Drug: Placebo	Phase 2/Phase 3

Detailed Description

Study Masking:

Part A: Open Label Part B: Double Blind

Study Design

• Study Type: Interventional
• Actual Enrollment: 58 participants
• Allocation: Randomized
• Intervention Model: Parallel Assignment
• Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
• Primary Purpose: Treatment
• Official Title: 2-part, Phase 2/3 Study to Assess the Safety, Tolerability and Efficacy of AMG 145 in Subjects With Homozygous Familial Hypercholesterolemia. Part A - Open-label, Single-arm, Multicenter Pilot Study to Evaluate Safety, Tolerability and Efficacy of AMG 145 in Subjects With Homozygous Familial Hypercholesterolemia. Part B - Double-blind, Randomized, Placebo-controlled, Multicenter Study to Evaluate Safety, Tolerability and Efficacy of AMG 145 in Subjects With Homozygous Familial Hypercholesterolemia
• Actual Study Start Date: Apr 5, 2012
• Actual Primary Completion Date: Jan 31, 2014
• Actual Study Completion Date: Jan 31, 2014

Arms and Interventions

Arm	Intervention/Treatment
Experimental: Part A: Evolocumab Participants received open-label evolocumab 420 mg subcutaneously once a month for 12 weeks.	Biological: Evolocumab; Administered by subcutaneous injection; Other Names: AMG 145 Repatha
Experimental: Part B: Evolocumab Participants received double-blind evolocumab 420 mg subcutaneously once a month for 12 weeks.	Biological: Evolocumab; Administered by subcutaneous injection; Other Names: AMG 145 Repatha
Placebo Comparator: Part B: Placebo Participants received double-blind placebo subcutaneously once a month for 12 weeks.	Drug: Placebo; Administered by subcutaneous injection

Outcome Measures

Primary Outcome Measures

1. Part A: Percent Change From Baseline in Low Density Lipoprotein Cholesterol (LDL-C) at Week 12 [Baseline and Week 12]

   LDL-C was quantified using the ultracentrifugation method.

2. Part B: Percent Change From Baseline in Low Density Lipoprotein Cholesterol (LDL-C) at Week 12 [Baseline and Week 12]

   LDL-C was quantified using the ultracentrifugation method.

Secondary Outcome Measures

1. Part A: Change From Baseline in LDL-C at Week 12 [Baseline and Week 12]

   LDL-C was quantified using the ultracentrifugation method.

2. Part A: Percent Change From Baseline in Non-High Density Lipoprotein Cholesterol (Non-HDL-C) at Week 12 [Baseline and Week 12]

3. Part A: Percent Change From Baseline in Apolipoprotein B at Week 12 [Baseline and Week 12]

4. Part A: Percent Change From Baseline in the Total Cholesterol/HDL-C Ratio at Week 12 [Baseline and Week 12]

5. Part A: Percent Change From Baseline in Apolipoprotein B/Apolipoprotein A1 Ratio at Week 12 [Baseline and Week 12]

6. Part A: Percentage of Participants With 15% or Greater Reduction in LDL-C From Baseline at Week 12 [Baseline and Week 12]

   LDL-C was quantified using the ultracentrifugation method.

7. Part A: Change From Baseline in Proprotein Convertase Subtilisin/Kexin Type 9 (PCSK9) at Week 12 [Baseline and Week 12]

8. Part B: Percent Change From Baseline in LDL-C at the Mean of Weeks 6 and 12 [Baseline and Weeks 6 and 12]

   LDL-C was quantified using the ultracentrifugation method.

9. Part B: Percent Change From Baseline in Apolipoprotein B at Week 12 [Baseline and Week 12]

10. Part B: Percent Change From Baseline in Apolipoprotein B at the Mean of Weeks 6 and 12 [Baseline and Weeks 6 and 12]

11. Part B: Percent Change From Baseline in Lipoprotein (a) at Week 12 [Baseline and Week 12]

12. Part B: Percent Change From Baseline in Lipoprotein (a) at the Mean of Weeks 6 and 12 [Baseline and Weeks 6 and 12]

Eligibility Criteria

Criteria

• Ages Eligible for Study: 12 Years to 80 Years
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

Inclusion Criteria:

• Males and females ≥ 12 to ≤ 80 years of age

• Diagnosis of homozygous familial hypercholesterolemia

• Stable lipid-lowering therapies for at least 4 weeks

• LDL cholesterol ≥ 130 mg/dl (3.4 mmol/L)

• Triglyceride ≤ 400 mg/dL (4.5 mmol/L)

• Bodyweight of ≥ 40 kg at screening.

Exclusion Criteria:

• LDL or plasma apheresis within 8 weeks prior to randomization

• New York Heart Association (NYHA) class III or IV or last known left ventricular ejection fraction < 30%

• Myocardial infarction, unstable angina, percutaneous coronary intervention (PCI), coronary artery bypass graft (CABG) or stroke within 3 months of randomization

• Planned cardiac surgery or revascularization

• Uncontrolled cardiac arrhythmia

• Uncontrolled hypertension

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	Research Site	New York	New York	United States	10032
2	Research Site	Cincinnati	Ohio	United States	45227
3	Research Site	Bruxelles		Belgium	1200
4	Research Site	La Louvière		Belgium	7100
5	Research Site	London	Ontario	Canada	N6A 5K8
6	Research Site	Chicoutimi	Quebec	Canada	G7H 7K9
7	Research Site	Brno		Czechia	656 91
8	Research Site	Hradec Kralove		Czechia	500 05
9	Research Site	Uherske Hradiste		Czechia	686 01
10	Research Site	Dijon		France	21000
11	Research Site	Paris Cedex 13		France	75651
12	Research Site	New Territories		Hong Kong
13	Research Site	Pisa		Italy	56124
14	Research Site	Beirut		Lebanon	0000
15	Research Site	Amsterdam		Netherlands	1105 AZ
16	Research Site	Christchurch		New Zealand	8011
17	Research Site	Johannesburg	Gauteng	South Africa	2193
18	Research Site	Observatory	Western Cape	South Africa	7925
19	Research Site	Cordoba	Andalucía	Spain	14004
20	Research Site	Lugo	Galicia	Spain	27003
21	Research Site	Madrid		Spain	28040

Sponsors and Collaborators

• Amgen

Investigators

• Study Director: MD, Amgen

Study Documents (Full-Text)

None provided.

More Information

Additional Information:

• AmgenTrials clinical trials website

Publications

• Kasichayanula S, Grover A, Emery MG, Gibbs MA, Somaratne R, Wasserman SM, Gibbs JP. Clinical Pharmacokinetics and Pharmacodynamics of Evolocumab, a PCSK9 Inhibitor. Clin Pharmacokinet. 2018 Jul;57(7):769-779. doi: 10.1007/s40262-017-0620-7. Review.

• Responsible Party: Amgen
• ClinicalTrials.gov Identifier: NCT01588496
• Other Study ID Numbers: 20110233; 2011-005399-40
• First Posted: May 1, 2012
• Last Update Posted: Nov 29, 2018
• Last Verified: Nov 1, 2018

• Keywords provided by Amgen: hypercholesterolemia; familial hypercholesterolemia; homozygous familial hypercholesterolemia
• Additional relevant MeSH terms: Hyperlipoproteinemia Type II; Hypercholesterolemia; Evolocumab

Study Results

Participant Flow

Recruitment Details	Male and female adults and adolescents ages ≥ 12 to ≤ 65 years (≥ 12 to ≤ 80 years in Part B) with a diagnosis of homozygous familial hypercholesterolemia (HoFH) were eligible for this study. The first participant enrolled on 05 April 2012 and the last participant enrolled on 08 November 2013.
Pre-assignment Detail	Part A was an open-label, single-arm, multicenter pilot study. Part B was a double-blind, randomized, placebo-controlled, multicenter study with expanded enrollment. In Part B participants were randomized in a 1:2 allocation stratified on the basis of screening low-density lipoprotein cholesterol (LDL-C) (< 420 mg/dL vs ≥ 420 mg/dL).

Arm/Group Title	Part A: Evolocumab	Part B: Placebo	Part B: Evolocumab
Arm/Group Description	Participants received open-label evolocumab 420 mg subcutaneously (SC) once a month (QM) for 12 weeks.	Participants received double-blind placebo subcutaneously once a month for 12 weeks.	Participants received double-blind evolocumab 420 mg subcutaneously once a month for 12 weeks.
Period Title: Overall Study
STARTED	8	17	33
Received Treatment	8	16	33
COMPLETED	8	16	33
NOT COMPLETED	0	1	0

Baseline Characteristics

Arm/Group Title	Part A: Evolocumab	Part B: Placebo	Part B: Evolocumab	Total
Arm/Group Description	Participants received open-label evolocumab 420 mg subcutaneously (SC) once a month (QM) for 12 weeks.	Participants received double-blind placebo subcutaneously once a month for 12 weeks.	Participants received double-blind evolocumab 420 mg subcutaneously once a month for 12 weeks.	Total of all reporting groups
Overall Participants	8	17	33	58
Age (years) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [years]	34.3 (12.4)	32.8 (13.7)	30.3 (12.4)	31.6 (12.7)
Sex: Female, Male (Count of Participants)
Female	2 25%	8 47.1%	16 48.5%	26 44.8%
Male	6 75%	9 52.9%	17 51.5%	32 55.2%
Race/Ethnicity, Customized (participants) [Number]
American Indian or Alaska Native	0 0%	0 0%	0 0%	0 0%
Asian	0 0%	1 5.9%	1 3%	2 3.4%
Black or African American	0 0%	0 0%	0 0%	0 0%
Native Hawaiian or Other Pacific Islander	0 0%	0 0%	0 0%	0 0%
White	8 100%	16 94.1%	29 87.9%	53 91.4%
Other	0 0%	0 0%	3 9.1%	3 5.2%
Race/Ethnicity, Customized (participants) [Number]
Hispanic or Latino	0 0%	0 0%	1 3%	1 1.7%
Not Hispanic or Latino	8 100%	17 100%	32 97%	57 98.3%
Stratification Factor: Low-Density Lipoprotein Cholesterol (LDL-C) Level (participants) [Number]
< 420 mg/dL	0 0%	11 64.7%	21 63.6%	32 55.2%
≥ 420 mg/dL	0 0%	6 35.3%	12 36.4%	18 31%
Missing	8 100%	0 0%	0 0%	8 13.8%
LDL-C Concentration (mg/dL) [Mean (Standard Deviation) ]
Part A	441.7 (113.3)	NA (NA)	NA (NA)	441.7 (113.3)
Part B	NA (NA)	335.8 (146.0)	356.0 (134.5)	349.4 (137.2)
Non-High-Density Lipoprotein Cholesterol (non-HDL-C) Concentration (mg/dL) [Mean (Standard Deviation) ]
Part A	470.6 (117.8)	NA (NA)	NA (NA)	470.6 (117.8)
Part B	NA (NA)	358.9 (149.1)	374.9 (136.9)	369.7 (139.6)
Apolipoprotein B Concentration (mg/dL) [Mean (Standard Deviation) ]
Part A	269.1 (53.0)	NA (NA)	NA (NA)	269.1 (53.0)
Part B	NA (NA)	208.6 (79.5)	208.3 (68.4)	208.4 (71.4)
Total Cholesterol/HDL-C Ratio (ratio) [Mean (Standard Deviation) ]
Part A	15.988 (5.107)	NA (NA)	NA (NA)	15.988 (5.107)
Part B	NA (NA)	12.101 (6.619)	11.972 (6.387)	12.014 (6.395)
Apolipoprotein B/Apolipoprotein A1 Ratio (ratio) [Mean (Standard Deviation) ]
Part A	2.800 (0.729)	NA (NA)	NA (NA)	2.800 (0.729)
Part B	NA (NA)	2.053 (0.967)	2.098 (1.046)	2.084 (1.011)
Lipoprotein(a) Concentration (nmol/L) [Median (Inter-Quartile Range) ]
Part A	246.5	NA	NA	246.5
Part B	NA	127.5	76.0	100.5
Proprotein Convertase Subtilisin/Kexin Type 9 (PCSK9) Concentration (ng/mL) [Mean (Standard Deviation) ]
Part A	598.6 (121.1)	NA (NA)	NA (NA)	598.6 (121.1)
Part B	NA (NA)	674.2 (180.0)	640.3 (207.5)	651.4 (197.7)

Outcome Measures

1. Primary Outcome

Title	Part A: Percent Change From Baseline in Low Density Lipoprotein Cholesterol (LDL-C) at Week 12
Description	LDL-C was quantified using the ultracentrifugation method.
Time Frame	Baseline and Week 12

Outcome Measure Data

Analysis Population Description

Part A full analysis set (all enrolled participants who received at least 1 dose of evolocumab)

Arm/Group Title	Part A: Evolocumab
Arm/Group Description	Participants received open-label evolocumab 420 mg subcutaneously (SC) once a month (QM) for 12 weeks.
Measure Participants	8
Mean (Standard Error) [percent change]	-16.5 (6.7)

2. Secondary Outcome

Title	Part A: Change From Baseline in LDL-C at Week 12
Description	LDL-C was quantified using the ultracentrifugation method.
Time Frame	Baseline and Week 12

Outcome Measure Data

Analysis Population Description

Part A full analysis set

Arm/Group Title	Part A: Evolocumab
Arm/Group Description	Participants received open-label evolocumab 420 mg subcutaneously (SC) once a month (QM) for 12 weeks.
Measure Participants	8
Mean (Standard Error) [mg/dL]	-70.6 (32.3)

3. Secondary Outcome

Title	Part A: Percent Change From Baseline in Non-High Density Lipoprotein Cholesterol (Non-HDL-C) at Week 12
Time Frame	Baseline and Week 12

Outcome Measure Data

Analysis Population Description

Part A full analysis set

Arm/Group Title	Part A: Evolocumab
Arm/Group Description	Participants received open-label evolocumab 420 mg subcutaneously (SC) once a month (QM) for 12 weeks.
Measure Participants	8
Mean (Standard Error) [percent change]	-16.6 (6.5)

4. Secondary Outcome

Title	Part A: Percent Change From Baseline in Apolipoprotein B at Week 12
Time Frame	Baseline and Week 12

Outcome Measure Data

Analysis Population Description

Part A full analysis set

Arm/Group Title	Part A: Evolocumab
Arm/Group Description	Participants received open-label evolocumab 420 mg subcutaneously (SC) once a month (QM) for 12 weeks.
Measure Participants	8
Mean (Standard Error) [percent change]	-14.9 (5.0)

5. Secondary Outcome

Title	Part A: Percent Change From Baseline in the Total Cholesterol/HDL-C Ratio at Week 12
Time Frame	Baseline and Week 12

Outcome Measure Data

Analysis Population Description

Part A full analysis set

Arm/Group Title	Part A: Evolocumab
Arm/Group Description	Participants received open-label evolocumab 420 mg subcutaneously (SC) once a month (QM) for 12 weeks.
Measure Participants	8
Mean (Standard Error) [percent change]	-18.319 (6.058)

6. Secondary Outcome

Title	Part A: Percent Change From Baseline in Apolipoprotein B/Apolipoprotein A1 Ratio at Week 12
Time Frame	Baseline and Week 12

Outcome Measure Data

Analysis Population Description

Part A full analysis set

Arm/Group Title	Part A: Evolocumab
Arm/Group Description	Participants received open-label evolocumab 420 mg subcutaneously (SC) once a month (QM) for 12 weeks.
Measure Participants	8
Mean (Standard Error) [percent change]	-15.65 (4.690)

7. Secondary Outcome

Title	Part A: Percentage of Participants With 15% or Greater Reduction in LDL-C From Baseline at Week 12
Description	LDL-C was quantified using the ultracentrifugation method.
Time Frame	Baseline and Week 12

Outcome Measure Data

Analysis Population Description

Part A full analysis set

Arm/Group Title	Part A: Evolocumab
Arm/Group Description	Participants received open-label evolocumab 420 mg subcutaneously (SC) once a month (QM) for 12 weeks.
Measure Participants	8
Number [percentage of participants]	50.0 625%

8. Secondary Outcome

Title	Part A: Change From Baseline in Proprotein Convertase Subtilisin/Kexin Type 9 (PCSK9) at Week 12
Time Frame	Baseline and Week 12

Outcome Measure Data

Analysis Population Description

Part A full analysis set

Arm/Group Title	Part A: Evolocumab
Arm/Group Description	Participants received open-label evolocumab 420 mg subcutaneously (SC) once a month (QM) for 12 weeks.
Measure Participants	8
Mean (Standard Error) [ng/mL]	-151.3 (81.7)

9. Secondary Outcome

Title	Part B: Percent Change From Baseline in LDL-C at the Mean of Weeks 6 and 12
Description	LDL-C was quantified using the ultracentrifugation method.
Time Frame	Baseline and Weeks 6 and 12

Outcome Measure Data

Analysis Population Description

Part B full analysis set

Arm/Group Title	Part B: Placebo	Part B: Evolocumab
Arm/Group Description	Participants received double-blind placebo subcutaneously once a month for 12 weeks.	Participants received double-blind evolocumab 420 mg subcutaneously once a month for 12 weeks.
Measure Participants	16	33
Least Squares Mean (Standard Error) [percent change]	4.22 (4.56)	-25.56 (3.28)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Part A: Evolocumab, Part B: Evolocumab
	Comments
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	<0.001
	Comments	Multiplicity adjusted p-value is significant if less than the familywise error rate of 0.05.
	Method	Repeated measures linear effects model
	Comments	Model includes treatment group, baseline LDL-C level (< 420 vs ≥ 420 mg/dL), scheduled visit and the interaction of treatment with scheduled visit.
Method of Estimation	Estimation Parameter	LS Mean Treatment Difference
	Estimated Value	-29.78
	Confidence Interval	(2-Sided) 95%; -40.94 to -18.62
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 5.54
	Estimation Comments	Placebo is the reference

10. Secondary Outcome

Title	Part B: Percent Change From Baseline in Apolipoprotein B at Week 12
Time Frame	Baseline and Week 12

Outcome Measure Data

Analysis Population Description

Part B full analysis set

Arm/Group Title	Part B: Placebo	Part B: Evolocumab
Arm/Group Description	Participants received double-blind placebo subcutaneously once a month for 12 weeks.	Participants received double-blind evolocumab 420 mg subcutaneously once a month for 12 weeks.
Measure Participants	16	33
Least Squares Mean (Standard Error) [percent change]	3.97 (4.74)	-19.17 (3.46)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Part A: Evolocumab, Part B: Evolocumab
	Comments
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	<0.001
	Comments	Multiplicity adjusted p-value is significant if less than the familywise error rate of 0.05.
	Method	Repeated measures linear effects model
	Comments	Model includes treatment group, baseline LDL-C level (< 420 vs ≥ 420 mg/dL), scheduled visit and the interaction of treatment with scheduled visit.
Method of Estimation	Estimation Parameter	LS Mean Treatment Difference
	Estimated Value	-23.14
	Confidence Interval	(2-Sided) 95%; -34.83 to -11.45
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 5.81
	Estimation Comments	Placebo is the reference

11. Secondary Outcome

Title	Part B: Percent Change From Baseline in Apolipoprotein B at the Mean of Weeks 6 and 12
Time Frame	Baseline and Weeks 6 and 12

Outcome Measure Data

Analysis Population Description

Part B full analysis set

Arm/Group Title	Part B: Placebo	Part B: Evolocumab
Arm/Group Description	Participants received double-blind placebo subcutaneously once a month for 12 weeks.	Participants received double-blind evolocumab 420 mg subcutaneously once a month for 12 weeks.
Measure Participants	16	33
Least Squares Mean (Standard Error) [percent change]	2.65 (4.42)	-20.24 (3.18)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Part A: Evolocumab, Part B: Evolocumab
	Comments
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	<0.001
	Comments	Multiplicity adjusted p-value is significant if less than the familywise error rate of 0.05.
	Method	Repeated measures linear effects model
	Comments	Model includes treatment group, baseline LDL-C level (< 420 vs ≥ 420 mg/dL), scheduled visit and the interaction of treatment with scheduled visit.
Method of Estimation	Estimation Parameter	LS Mean Treatment Difference
	Estimated Value	-22.89
	Confidence Interval	(2-Sided) 95%; -33.72 to -12.05
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 5.38
	Estimation Comments	Placebo is the reference

12. Secondary Outcome

Title	Part B: Percent Change From Baseline in Lipoprotein (a) at Week 12
Time Frame	Baseline and Week 12

Outcome Measure Data

Analysis Population Description

Part B full anlaysis set

Arm/Group Title	Part B: Placebo	Part B: Evolocumab
Arm/Group Description	Participants received double-blind placebo subcutaneously once a month for 12 weeks.	Participants received double-blind evolocumab 420 mg subcutaneously once a month for 12 weeks.
Measure Participants	16	33
Least Squares Mean (Standard Error) [percent change]	2.43 (5.49)	-9.40 (4.07)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Part A: Evolocumab, Part B: Evolocumab
	Comments
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.088
	Comments	Multiplicity adjusted p-value is significant if less than the familywise error rate of 0.05.
	Method	Repeated measures linear effects model
	Comments	Model includes treatment group, baseline LDL-C level (< 420 vs ≥ 420 mg/dL), scheduled visit and the interaction of treatment with scheduled visit.
Method of Estimation	Estimation Parameter	LS Mean Treatment Difference
	Estimated Value	-11.83
	Confidence Interval	(2-Sided) 95%; -25.48 to 1.82
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 6.77
	Estimation Comments	Placebo is the reference

13. Secondary Outcome

Title	Part B: Percent Change From Baseline in Lipoprotein (a) at the Mean of Weeks 6 and 12
Time Frame	Baseline and Weeks 6 and 12

Outcome Measure Data

Analysis Population Description

Part B full analysis set

Arm/Group Title	Part B: Placebo	Part B: Evolocumab
Arm/Group Description	Participants received double-blind placebo subcutaneously once a month for 12 weeks.	Participants received double-blind evolocumab 420 mg subcutaneously once a month for 12 weeks.
Measure Participants	16	33
Least Squares Mean (Standard Error) [percent change]	-1.43 (4.78)	-12.71 (3.53)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Part A: Evolocumab, Part B: Evolocumab
	Comments
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.088
	Comments	Multiplicity adjusted p-value is significant if less than the familywise error rate of 0.05.
	Method	Repeated measures linear effects
	Comments	Model includes treatment group, baseline LDL-C level (< 420 vs ≥ 420 mg/dL), scheduled visit and the interaction of treatment with scheduled visit.
Method of Estimation	Estimation Parameter	LS Mean Treatment Difference
	Estimated Value	-11.27
	Confidence Interval	(2-Sided) 95%; -23.11 to 0.56
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 5.86
	Estimation Comments	Placebo is the reference

14. Primary Outcome

Title	Part B: Percent Change From Baseline in Low Density Lipoprotein Cholesterol (LDL-C) at Week 12
Description	LDL-C was quantified using the ultracentrifugation method.
Time Frame	Baseline and Week 12

Outcome Measure Data

Analysis Population Description

Part B full analysis set (all enrolled participants who received at least 1 dose of investigational product)

Arm/Group Title	Part B: Placebo	Part B: Evolocumab
Arm/Group Description	Participants received double-blind placebo subcutaneously once a month for 12 weeks.	Participants received double-blind evolocumab 420 mg subcutaneously once a month for 12 weeks.
Measure Participants	16	33
Least Squares Mean (Standard Error) [percent change]	7.88 (5.26)	-23.05 (3.78)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Part A: Evolocumab, Part B: Evolocumab
	Comments	LDL-C lowering was analyzed by comparing evolocumab and placebo. Statistical analysis was 2-sided with a significance level of 0.05.
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	<0.001
	Comments	Multiplicity adjusted p-value is significant if less than the familywise error rate of 0.05.
	Method	Repeated measures linear effects model
	Comments	Model includes treatment group, baseline LDL-C level (< 420 vs ≥ 420 mg/dL), scheduled visit and the interaction of treatment with scheduled visit.
Method of Estimation	Estimation Parameter	LS Mean Treatment Difference
	Estimated Value	-30.93
	Confidence Interval	(2-Sided) 95%; -43.86 to -18.00
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 6.42
	Estimation Comments	Placebo is the reference

Adverse Events

Time Frame	12 weeks
Adverse Event Reporting Description	Other Adverse Events summarizes the non-serious occurrences of adverse events that exceed the indicated frequency threshold. MedDRA 16.0 was used to code adverse events in Part A; MedDRA 16.1 was used to code adverse events in Part B.
Arm/Group Title	Part A: OL Evolocumab		Part B: DB Placebo		Part B: DB Evolocumab
Arm/Group Description	Participants received open-label (OL) evolocumab 420 mg subcutaneously once a month for 12 weeks.		Participants received double-blind (DB) placebo subcutaneously once a month for 12 weeks.		Participants received double-blind evolocumab 420 mg subcutaneously once a month for 12 weeks.
All Cause Mortality
	Part A: OL Evolocumab		Part B: DB Placebo		Part B: DB Evolocumab
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	/ (NaN)		/ (NaN)		/ (NaN)
Serious Adverse Events
	Part A: OL Evolocumab		Part B: DB Placebo		Part B: DB Evolocumab
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	0/8 (0%)		0/16 (0%)		0/33 (0%)
Other (Not Including Serious) Adverse Events
	Part A: OL Evolocumab		Part B: DB Placebo		Part B: DB Evolocumab
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	4/8 (50%)		10/16 (62.5%)		11/33 (33.3%)
Cardiac disorders
Palpitations	0/8 (0%)		1/16 (6.3%)		0/33 (0%)
Gastrointestinal disorders
Abdominal pain	0/8 (0%)		1/16 (6.3%)		1/33 (3%)
Abdominal pain upper	0/8 (0%)		1/16 (6.3%)		0/33 (0%)
Dyspepsia	1/8 (12.5%)		0/16 (0%)		0/33 (0%)
Nausea	0/8 (0%)		2/16 (12.5%)		0/33 (0%)
General disorders
Chest pain	0/8 (0%)		1/16 (6.3%)		1/33 (3%)
Fatigue	0/8 (0%)		1/16 (6.3%)		0/33 (0%)
Injection site pain	0/8 (0%)		1/16 (6.3%)		0/33 (0%)
Medical device site reaction	0/8 (0%)		1/16 (6.3%)		0/33 (0%)
Pain	1/8 (12.5%)		0/16 (0%)		0/33 (0%)
Infections and infestations
Bronchitis	1/8 (12.5%)		0/16 (0%)		0/33 (0%)
Gastroenteritis	0/8 (0%)		0/16 (0%)		2/33 (6.1%)
Influenza	0/8 (0%)		0/16 (0%)		3/33 (9.1%)
Nasopharyngitis	0/8 (0%)		0/16 (0%)		2/33 (6.1%)
Upper respiratory tract infection	0/8 (0%)		1/16 (6.3%)		3/33 (9.1%)
Investigations
Blood creatine phosphokinase increased	0/8 (0%)		1/16 (6.3%)		0/33 (0%)
Weight decreased	0/8 (0%)		1/16 (6.3%)		0/33 (0%)
Musculoskeletal and connective tissue disorders
Back pain	0/8 (0%)		1/16 (6.3%)		0/33 (0%)
Nervous system disorders
Dizziness	0/8 (0%)		1/16 (6.3%)		0/33 (0%)
Headache	0/8 (0%)		1/16 (6.3%)		0/33 (0%)
Presyncope	0/8 (0%)		1/16 (6.3%)		0/33 (0%)
Reproductive system and breast disorders
Dysmenorrhoea	0/8 (0%)		1/16 (6.3%)		1/33 (3%)
Respiratory, thoracic and mediastinal disorders
Rhinitis allergic	1/8 (12.5%)		0/16 (0%)		0/33 (0%)

Limitations/Caveats

[Not Specified]

More Information

Certain Agreements

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

The Clinical Trial Agreement generally does not restrict an investigator's discussion of trial results after completion. The Agreement permits Amgen a limited period of time to review material discussing trial results (typically up to 45 days and possible extension). Amgen may remove confidential information, but authors have final control and approval of publication content. For multicenter studies, the investigator agrees not to publish any results before the first multi-center publication.