Clinical Trial Results:
A 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
Summary
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EudraCT number |
2011-005399-40 |
Trial protocol |
BE CZ ES IT NL Outside EU/EEA |
Global end of trial date |
31 Jan 2014
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Results information
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Results version number |
v1(current) |
This version publication date |
20 Jun 2016
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First version publication date |
03 Aug 2015
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Other versions |
Trial Information
Subject Disposition
Baseline Characteristics
End Points
Adverse Events
More Information
Subject Disposition
Baseline Characteristics
End Points
Adverse Events
More Information
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Trial identification
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Sponsor protocol code |
20110233
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Additional study identifiers
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ISRCTN number |
- | ||
US NCT number |
NCT01588496 | ||
WHO universal trial number (UTN) |
- | ||
Sponsors
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Sponsor organisation name |
Amgen, Inc.
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Sponsor organisation address |
One Amgen Center Drive, Thousand Oaks, CA, United States, 91320
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Public contact |
IHQ Medical Info-Clinical Trials, Amgen (EUROPE) GmbH, MedInfoInternational@amgen.com
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Scientific contact |
IHQ Medical Info-Clinical Trials, Amgen (EUROPE) GmbH, MedInfoInternational@amgen.com
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Paediatric regulatory details
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Is trial part of an agreed paediatric investigation plan (PIP) |
No
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Does article 45 of REGULATION (EC) No 1901/2006 apply to this trial? |
No
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Does article 46 of REGULATION (EC) No 1901/2006 apply to this trial? |
No
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Results analysis stage
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Analysis stage |
Final
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Date of interim/final analysis |
31 Jan 2014
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Is this the analysis of the primary completion data? |
No
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Global end of trial reached? |
Yes
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Global end of trial date |
31 Jan 2014
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Was the trial ended prematurely? |
No
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General information about the trial
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Main objective of the trial |
The primary objective was to characterize the effect of 12 weeks of evolocumab on percent change from baseline in low-density lipoprotein cholesterol (LDL-C) in subjects with homozygous familial hypercholesterolemia (HoFH).
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Protection of trial subjects |
This study was conducted in accordance with International Conference on Harmonisation (ICH) Good Clinical Practice (GCP) regulations and guidelines, and Food and Drug Administration (FDA) regulations, and guidelines set forth in 21 CFR Parts 11, 50, 54, 56, and 312.
All subjects provided written informed consent before undergoing any study-related procedures, including screening procedures.
The study protocol, amendments, and the informed consent form (ICF) were reviewed by the Institutional Review Boards (IRBs) and Independent Ethics Committees (IECs). No subjects were recruited into the study and no investigational product (IP) was shipped until the IRB/IEC gave written approval of the protocol and ICF and Amgen received copies of these approvals.
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Background therapy |
Subjects were permitted to remain on a stable dose of lipid-lowering medications throughout the study. | ||
Evidence for comparator |
- | ||
Actual start date of recruitment |
05 Apr 2012
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Long term follow-up planned |
No
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Independent data monitoring committee (IDMC) involvement? |
Yes
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Population of trial subjects
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Number of subjects enrolled per country |
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Country: Number of subjects enrolled |
Canada: 2
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Country: Number of subjects enrolled |
United States: 6
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Country: Number of subjects enrolled |
Belgium: 2
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Country: Number of subjects enrolled |
Czech Republic: 3
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Country: Number of subjects enrolled |
France: 2
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Country: Number of subjects enrolled |
Italy: 2
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Country: Number of subjects enrolled |
Lebanon: 1
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Country: Number of subjects enrolled |
Netherlands: 4
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Country: Number of subjects enrolled |
Spain: 3
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Country: Number of subjects enrolled |
South Africa: 33
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Worldwide total number of subjects |
58
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EEA total number of subjects |
16
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Number of subjects enrolled per age group |
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In utero |
0
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Preterm newborn - gestational age < 37 wk |
0
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Newborns (0-27 days) |
0
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Infants and toddlers (28 days-23 months) |
0
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Children (2-11 years) |
0
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Adolescents (12-17 years) |
11
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Adults (18-64 years) |
47
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From 65 to 84 years |
0
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85 years and over |
0
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Recruitment
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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 2012and the last participant enrolled on 08 November 2013. | ||||||||||||||||||||||||
Pre-assignment
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Screening details |
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). | ||||||||||||||||||||||||
Period 1
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Period 1 title |
Overall Study (overall period)
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Is this the baseline period? |
Yes | ||||||||||||||||||||||||
Allocation method |
Randomised - controlled
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Blinding used |
Double blind | ||||||||||||||||||||||||
Roles blinded |
Subject, Investigator | ||||||||||||||||||||||||
Blinding implementation details |
Part A was an open-label, single-arm, multicenter pilot study where all enrolled subjects received open-label evolocumab.
Part B was a double-blind, randomized, placebo-controlled, multicenter study with expanded enrollment that was initiated after effective LDL-C reduction (defined as an average reduction in LDL-C of ≥ 15% at week 12) was demonstrated in Part A.
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Arms
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Are arms mutually exclusive |
Yes
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Arm title
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Part A: Evolocumab | ||||||||||||||||||||||||
Arm description |
Participants received open-label evolocumab 420 mg subcutaneously (SC) once a month (QM) for 12 weeks. | ||||||||||||||||||||||||
Arm type |
Experimental | ||||||||||||||||||||||||
Investigational medicinal product name |
Evolocumab
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Investigational medicinal product code |
AMG 145
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Other name |
Repatha
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Pharmaceutical forms |
Solution for injection
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Routes of administration |
Subcutaneous use
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Dosage and administration details |
Administered by subcutaneous injection
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Arm title
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Part B: Evolocumab | ||||||||||||||||||||||||
Arm description |
Participants received double-blind evolocumab 420 mg subcutaneously once a month for 12 weeks. | ||||||||||||||||||||||||
Arm type |
Experimental | ||||||||||||||||||||||||
Investigational medicinal product name |
Evolocumab
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Investigational medicinal product code |
AMG 145
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Other name |
Repatha
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Pharmaceutical forms |
Solution for injection, Solution for injection in pre-filled pen
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Routes of administration |
Subcutaneous use
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Dosage and administration details |
Administered by subcutaneous injection
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Arm title
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Part B: Placebo | ||||||||||||||||||||||||
Arm description |
Participants received double-blind placebo subcutaneously once a month for 12 weeks. | ||||||||||||||||||||||||
Arm type |
Experimental | ||||||||||||||||||||||||
Investigational medicinal product name |
Placebo
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Investigational medicinal product code |
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Other name |
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Pharmaceutical forms |
Solution for injection, Solution for injection in pre-filled pen
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Routes of administration |
Subcutaneous use
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Dosage and administration details |
Administered by subcutaneous injection
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Baseline characteristics reporting groups
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Reporting group title |
Part A: Evolocumab
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Reporting group description |
Participants received open-label evolocumab 420 mg subcutaneously (SC) once a month (QM) for 12 weeks. | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Reporting group title |
Part B: Placebo
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Reporting group description |
Participants received double-blind placebo subcutaneously once a month for 12 weeks. | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Reporting group title |
Part B: Evolocumab
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Reporting group description |
Participants received double-blind evolocumab 420 mg subcutaneously once a month for 12 weeks. | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
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End points reporting groups
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Reporting group title |
Part A: Evolocumab
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Reporting group description |
Participants received open-label evolocumab 420 mg subcutaneously (SC) once a month (QM) for 12 weeks. | ||
Reporting group title |
Part B: Evolocumab
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Reporting group description |
Participants received double-blind evolocumab 420 mg subcutaneously once a month for 12 weeks. | ||
Reporting group title |
Part B: Placebo
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Reporting group description |
Participants received double-blind placebo subcutaneously once a month for 12 weeks. |
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End point title |
Part A: Percent Change From Baseline in Low Density Lipoprotein Cholesterol (LDL-C) at Week 12 [1] [2] | ||||||||
End point description |
LDL-C was quantified using the ultracentrifugation method.
All endpoints are analyzed in the full analysis set.
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End point type |
Primary
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End point timeframe |
Baseline and Week 12
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Notes [1] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point. Justification: Part A provided an estimate of the LDL-C reduction in this particular population and was used to guide the decision to initiate Part B; formal hypothesis testing was performed only in Part B. [2] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period. Justification: This endpoint pertains to subjects in Part A only |
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No statistical analyses for this end point |
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End point title |
Part B: Percent Change From Baseline in Low Density Lipoprotein Cholesterol (LDL-C) at Week 12 [3] | ||||||||||||
End point description |
LDL-C was quantified using the ultracentrifugation method.
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End point type |
Primary
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End point timeframe |
Baseline and Week 12
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Notes [3] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period. Justification: This endpoint pertains to subjects in Part B only |
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Statistical analysis title |
Statistical Analysis | ||||||||||||
Statistical analysis description |
LDL-C lowering was analyzed by comparing evolocumab and placebo. Statistical analysis was 2-sided with a significance level of 0.05.
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Comparison groups |
Part B: Placebo v Part B: Evolocumab
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Number of subjects included in analysis |
49
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Analysis specification |
Pre-specified
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Analysis type |
superiority | ||||||||||||
P-value |
< 0.001 [4] | ||||||||||||
Method |
Repeated measures linear effects model | ||||||||||||
Parameter type |
LS Mean Treatment Difference | ||||||||||||
Point estimate |
-30.93
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Confidence interval |
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level |
95% | ||||||||||||
sides |
2-sided
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lower limit |
-43.86 | ||||||||||||
upper limit |
-18 | ||||||||||||
Variability estimate |
Standard error of the mean
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Dispersion value |
6.42
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Notes [4] - Model includes treatment group, baseline LDL-C level (< 420 mg/dL vs ≥ 420 mg/dL), scheduled visit, and the interaction of treatment with scheduled visit. Multiplicity adjusted p-value is significant if less than the familywise error rate of 0.05. |
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End point title |
Part A: Change From Baseline in LDL-C at Week 12 [5] | ||||||||
End point description |
LDL-C was quantified using the ultracentrifugation method.
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End point type |
Secondary
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End point timeframe |
Baseline and Week 12
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Notes [5] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period. Justification: This endpoint pertains to subjects in Part A only |
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No statistical analyses for this end point |
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End point title |
Part A: Percent Change From Baseline in Non-High Density Lipoprotein Cholesterol (non-HDL-C) at Week 12 [6] | ||||||||
End point description |
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End point type |
Secondary
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End point timeframe |
Baseline and Week 12
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Notes [6] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period. Justification: This endpoint pertains to subjects in Part A only |
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No statistical analyses for this end point |
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End point title |
Part A: Percent Change From Baseline in Apolipoprotein B at Week 12 [7] | ||||||||
End point description |
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End point type |
Secondary
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End point timeframe |
Baseline and Week 12
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Notes [7] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period. Justification: This endpoint pertains to subjects in Part A only |
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No statistical analyses for this end point |
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End point title |
Part A: Percent Change From Baseline in the Total Cholesterol/HDL-C Ratio at Week 12 [8] | ||||||||
End point description |
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End point type |
Secondary
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End point timeframe |
Baseline and Week 12
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Notes [8] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period. Justification: This endpoint pertains to subjects in Part A only |
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No statistical analyses for this end point |
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End point title |
Part A: Percent Change From Baseline in Apolipoprotein B/Apolipoprotein A1 Ratio at Week 12 [9] | ||||||||
End point description |
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End point type |
Secondary
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End point timeframe |
Baseline and Week 12
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Notes [9] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period. Justification: This endpoint pertains to subjects in Part A only |
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No statistical analyses for this end point |
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End point title |
Part A: Percentage of Participants With 15% or Greater Reduction in LDL-C From Baseline at Week 12 [10] | ||||||||
End point description |
LDL-C was quantified using the ultracentrifugation method.
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End point type |
Secondary
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End point timeframe |
Baseline and Week 12
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Notes [10] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period. Justification: This endpoint pertains to subjects in Part A only |
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No statistical analyses for this end point |
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End point title |
Part A: Change From Baseline in Proprotein Convertase Subtilisin/Kexin Type 9 (PCSK9) at Week 12 [11] | ||||||||
End point description |
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End point type |
Secondary
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End point timeframe |
Baseline and Week 12
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Notes [11] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period. Justification: This endpoint pertains to subjects in Part A only |
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No statistical analyses for this end point |
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End point title |
Part B: Mean Percent Change From Baseline in LDL-C at Weeks 6 and 12 [12] | ||||||||||||
End point description |
LDL-C was quantified using the ultracentrifugation method.
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End point type |
Secondary
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End point timeframe |
Baseline and Weeks 6 and 12
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Notes [12] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period. Justification: This endpoint pertains to subjects in Part B only |
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Statistical analysis title |
Statistical Analysis | ||||||||||||
Comparison groups |
Part B: Placebo v Part B: Evolocumab
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Number of subjects included in analysis |
49
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Analysis specification |
Pre-specified
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Analysis type |
superiority | ||||||||||||
P-value |
< 0.001 [13] | ||||||||||||
Method |
Repeated measures linear effects model | ||||||||||||
Parameter type |
LS Mean Treatment Difference | ||||||||||||
Point estimate |
-29.78
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Confidence interval |
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level |
95% | ||||||||||||
sides |
2-sided
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lower limit |
-40.94 | ||||||||||||
upper limit |
-18.62 | ||||||||||||
Variability estimate |
Standard error of the mean
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Dispersion value |
5.54
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Notes [13] - Model includes treatment group, baseline LDL-C level (< 420 mg/dL vs ≥ 420 mg/dL), scheduled visit, and the interaction of treatment with scheduled visit. Multiplicity adjusted p-value is significant if less than the familywise error rate of 0.05. |
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End point title |
Part B: Percent Change From Baseline in Apolipoprotein B at Week 12 [14] | ||||||||||||
End point description |
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End point type |
Secondary
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End point timeframe |
Baseline and Week 12
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Notes [14] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period. Justification: This endpoint pertains to subjects in Part B only |
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Statistical analysis title |
Statistical Analysis | ||||||||||||
Comparison groups |
Part B: Placebo v Part B: Evolocumab
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Number of subjects included in analysis |
49
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Analysis specification |
Pre-specified
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Analysis type |
superiority | ||||||||||||
P-value |
< 0.001 [15] | ||||||||||||
Method |
Repeated measures linear effects model | ||||||||||||
Parameter type |
LS Mean Treatment Difference | ||||||||||||
Point estimate |
-23.14
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Confidence interval |
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level |
95% | ||||||||||||
sides |
2-sided
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lower limit |
-34.83 | ||||||||||||
upper limit |
-11.45 | ||||||||||||
Variability estimate |
Standard error of the mean
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Dispersion value |
5.81
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Notes [15] - Model includes treatment group, baseline LDL-C level (< 420 mg/dL vs ≥ 420 mg/dL), scheduled visit, and the interaction of treatment with scheduled visit. Multiplicity adjusted p-value is significant if less than the familywise error rate of 0.05. |
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End point title |
Part B: Mean Percent Change From Baseline in Apolipoprotein B at Weeks 6 and 12 [16] | ||||||||||||
End point description |
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End point type |
Secondary
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End point timeframe |
Baseline and Weeks 6 and 12
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Notes [16] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period. Justification: This endpoint pertains to subjects in Part B only |
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Statistical analysis title |
Statistical Analysis | ||||||||||||
Comparison groups |
Part B: Placebo v Part B: Evolocumab
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Number of subjects included in analysis |
49
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Analysis specification |
Pre-specified
|
||||||||||||
Analysis type |
superiority | ||||||||||||
P-value |
< 0.001 [17] | ||||||||||||
Method |
Repeated measures linear effects model | ||||||||||||
Parameter type |
LS Mean Treatment Difference | ||||||||||||
Point estimate |
-22.89
|
||||||||||||
Confidence interval |
|||||||||||||
level |
95% | ||||||||||||
sides |
2-sided
|
||||||||||||
lower limit |
-33.72 | ||||||||||||
upper limit |
-12.05 | ||||||||||||
Variability estimate |
Standard error of the mean
|
||||||||||||
Dispersion value |
5.38
|
||||||||||||
Notes [17] - Model includes treatment group, baseline LDL-C level (< 420 mg/dL vs ≥ 420 mg/dL), scheduled visit, and the interaction of treatment with scheduled visit. Multiplicity adjusted p-value is significant if less than the familywise error rate of 0.05. |
|
|||||||||||||
End point title |
Part B: Percent Change From Baseline in Lipoprotein (a) at Week 12 [18] | ||||||||||||
End point description |
|||||||||||||
End point type |
Secondary
|
||||||||||||
End point timeframe |
Baseline and Week 12
|
||||||||||||
Notes [18] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period. Justification: This endpoint pertains to subjects in Part B only |
|||||||||||||
|
|||||||||||||
Statistical analysis title |
Statistical Analysis | ||||||||||||
Comparison groups |
Part B: Placebo v Part B: Evolocumab
|
||||||||||||
Number of subjects included in analysis |
49
|
||||||||||||
Analysis specification |
Pre-specified
|
||||||||||||
Analysis type |
superiority | ||||||||||||
P-value |
= 0.088 [19] | ||||||||||||
Method |
Repeated measures linear effects model | ||||||||||||
Parameter type |
LS Mean Treatment Difference | ||||||||||||
Point estimate |
-11.83
|
||||||||||||
Confidence interval |
|||||||||||||
level |
95% | ||||||||||||
sides |
2-sided
|
||||||||||||
lower limit |
-25.48 | ||||||||||||
upper limit |
1.82 | ||||||||||||
Variability estimate |
Standard error of the mean
|
||||||||||||
Dispersion value |
6.77
|
||||||||||||
Notes [19] - Model includes treatment group, baseline LDL-C level (< 420 mg/dL vs ≥ 420 mg/dL), scheduled visit, and the interaction of treatment with scheduled visit. Multiplicity adjusted p-value is significant if less than the familywise error rate of 0.05. |
|
|||||||||||||
End point title |
Part B: Mean Percent Change From Baseline in Lipoprotein (a) at Weeks 6 and 12 [20] | ||||||||||||
End point description |
|||||||||||||
End point type |
Secondary
|
||||||||||||
End point timeframe |
Baseline and Weeks 6 and 12
|
||||||||||||
Notes [20] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period. Justification: This endpoint pertains to subjects in Part B only |
|||||||||||||
|
|||||||||||||
Statistical analysis title |
Statistical Analysis | ||||||||||||
Comparison groups |
Part B: Placebo v Part B: Evolocumab
|
||||||||||||
Number of subjects included in analysis |
49
|
||||||||||||
Analysis specification |
Pre-specified
|
||||||||||||
Analysis type |
superiority | ||||||||||||
P-value |
= 0.088 [21] | ||||||||||||
Method |
Repeated measures linear effects | ||||||||||||
Parameter type |
LS Mean Treatment Difference | ||||||||||||
Point estimate |
-11.27
|
||||||||||||
Confidence interval |
|||||||||||||
level |
95% | ||||||||||||
sides |
2-sided
|
||||||||||||
lower limit |
-23.11 | ||||||||||||
upper limit |
0.56 | ||||||||||||
Variability estimate |
Standard error of the mean
|
||||||||||||
Dispersion value |
5.86
|
||||||||||||
Notes [21] - Model includes treatment group, baseline LDL-C level (< 420 mg/dL vs ≥ 420 mg/dL), scheduled visit, and the interaction of treatment with scheduled visit. Multiplicity adjusted p-value is significant if less than the familywise error rate of 0.05. |
|
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Adverse events information
|
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Timeframe for reporting adverse events |
From the first dose of study drug until 28 days after the last dose (12 weeks).
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Assessment type |
Systematic | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Dictionary used for adverse event reporting
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Dictionary name |
MedDRA | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Dictionary version |
17.0
|
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Reporting groups
|
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Reporting group title |
Part A: Evolocumab
|
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Reporting group description |
Participants received open-label evolocumab 420 mg subcutaneously (SC) once a month (QM) for 12 weeks. | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Reporting group title |
Part B: Evolocumab
|
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Reporting group description |
Participants received double-blind evolocumab 420 mg subcutaneously once a month for 12 weeks. | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Reporting group title |
Part B: Placebo
|
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Reporting group description |
Participants received double-blind placebo subcutaneously once a month for 12 weeks. | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
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Frequency threshold for reporting non-serious adverse events: 5% | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
|
|
|||
Substantial protocol amendments (globally) |
|||
Were there any global substantial amendments to the protocol? Yes | |||
Date |
Amendment |
||
06 Apr 2012 |
- added optional visits for weeks 2 and 10, since more frequent visits would help mitigate against the risk of missing a detectable therapeutic effect
- clarified that only phase 3 was blinded
- added additional information about the analysis between the phases of the study
- changed the sample size in phase 2
- updated safety reporting language |
||
24 May 2013 |
- clarified that phase 2 was successfully completed and updated the primary, secondary and tertiary endpoints for phase 3 based on phase 2 data
- added co-primary and co-secondary efficacy endpoints to include changes from baseline at the mean of weeks 6 and 12 and at the mean of weeks 8 and 12 for the lipid parameters (see Amendment 3 below for subsequent changes to these endpoints)
- added treatment response (≥ 15% reduction in LDL-C at week 12) as an exploratory endpoint in phase 3
- added the LDLR Defective Analysis Set in phase 3
- added multiplicity adjustment methods
- updated safety reporting language
- allowed additional flexibility for specific visits
- expanded age limit to include ≥ 12 to ≤ 80 years
- added an exclusion criterion for lomitapide use
- updated the list of participating countries
- added new evolocumab formulation and autoinjector/pen (AI/pen) language
- introduced the simplified terminology of monthly dosing (QM)
- implemented minor editorial clarifications and corrections |
||
12 Nov 2013 |
- removed the use of co-primary and co-secondary endpoints
- made percent change in LDL-C from baseline to week 12 the primary endpoint
- removed changes from baseline at the mean of weeks 8 and 12 from all endpoints, but kept changes from baseline to the mean of weeks 6 and 12 as secondary and exploratory endpoints |
||
Interruptions (globally) |
|||
Were there any global interruptions to the trial? No | |||
Limitations and caveats |
|||
Limitations of the trial such as small numbers of subjects analysed or technical problems leading to unreliable data. | |||
None reported |