Clinical Trial Results:
A Randomized, Double-Blind, Placebo-Controlled, Parallel-Group Study to Evaluate the Efficacy and Safety of Alirocumab in Patients with Heterozygous Familial Hypercholesterolemia Not Adequately Controlled with Their Lipid-Modifying Therapy
Summary
|
|
EudraCT number |
2012-001222-95 |
Trial protocol |
GB NL CZ |
Global end of trial date |
09 Jan 2015
|
Results information
|
|
Results version number |
v1 |
This version publication date |
18 Dec 2019
|
First version publication date |
07 Aug 2015
|
Other versions |
v2 |
Trial Information
Subject Disposition
Baseline Characteristics
End Points
Adverse Events
More Information
Subject Disposition
Baseline Characteristics
End Points
Adverse Events
More Information
|
|||
Trial identification
|
|||
Sponsor protocol code |
R727-CL-1112
|
||
Additional study identifiers
|
|||
ISRCTN number |
- | ||
US NCT number |
NCT01709500 | ||
WHO universal trial number (UTN) |
- | ||
Other trial identifiers |
Study Name: ODYSSEY FH II | ||
Sponsors
|
|||
Sponsor organisation name |
Regeneron Pharmaceuticals, Inc.
|
||
Sponsor organisation address |
777 Old Saw Mill River Rd., Tarrytown, United States, 10591
|
||
Public contact |
Clinical Trial Management, Regeneron Pharmaceuticals, Inc., clinicaltrials@regeneron.com
|
||
Scientific contact |
Clinical Trial Management, Regeneron Pharmaceuticals, Inc., clinicaltrials@regeneron.com
|
||
Paediatric regulatory details
|
|||
Is trial part of an agreed paediatric investigation plan (PIP) |
No
|
||
Does article 45 of REGULATION (EC) No 1901/2006 apply to this trial? |
No
|
||
Does article 46 of REGULATION (EC) No 1901/2006 apply to this trial? |
No
|
||
Results analysis stage
|
|||
Analysis stage |
Interim
|
||
Date of interim/final analysis |
10 Jun 2014
|
||
Is this the analysis of the primary completion data? |
Yes
|
||
Primary completion date |
13 May 2014
|
||
Global end of trial reached? |
Yes
|
||
Global end of trial date |
09 Jan 2015
|
||
Was the trial ended prematurely? |
No
|
||
General information about the trial
|
|||
Main objective of the trial |
Subjects entered into the 78 weeks double blind treatment period. The main objective of double blind treatment period was to demonstrate the reduction of low-density lipoprotein cholesterol (LDL-C) by alirocumab as add-on therapy to stable, maximally tolerated daily statin therapy with or without other Lipid Modifying Therapy (LMT) in comparison with placebo after 24 weeks of treatment in subjects with Heterozygous familial hypercholesterolemia (heFH).
All subjects who successfully completed the 78-week double-blind treatment period had the opportunity to participate in an open-label extension study, receiving alirocumab at entry into the open-label extension regardless of the study treatment they had received during the double-blind treatment period.
|
||
Protection of trial subjects |
This study was conducted in accordance with the ethical principles that have their origin in the Declaration of Helsinki and that are consistent with the International Conference on Harmonisation (ICH) guidelines for Good Clinical Practice (GCP) and applicable regulatory requirements.
|
||
Background therapy |
All subjects were on a maximally tolerated stable daily dose of statin (atorvastatin, rosuvastatin, or simvastatin) with or without other LMT throughout the duration of the study. | ||
Evidence for comparator |
- | ||
Actual start date of recruitment |
28 Nov 2012
|
||
Long term follow-up planned |
No
|
||
Independent data monitoring committee (IDMC) involvement? |
Yes
|
||
Population of trial subjects
|
|||
Number of subjects enrolled per country |
|||
Country: Number of subjects enrolled |
Norway: 49
|
||
Country: Number of subjects enrolled |
United Kingdom: 25
|
||
Country: Number of subjects enrolled |
Czech Republic: 75
|
||
Country: Number of subjects enrolled |
Netherlands: 100
|
||
Worldwide total number of subjects |
249
|
||
EEA total number of subjects |
249
|
||
Number of subjects enrolled per age group |
|||
In utero |
0
|
||
Preterm newborn - gestational age < 37 wk |
0
|
||
Newborns (0-27 days) |
0
|
||
Infants and toddlers (28 days-23 months) |
0
|
||
Children (2-11 years) |
0
|
||
Adolescents (12-17 years) |
0
|
||
Adults (18-64 years) |
198
|
||
From 65 to 84 years |
50
|
||
85 years and over |
1
|
|
||||||||||||||||||||||||||||||||||
Recruitment
|
||||||||||||||||||||||||||||||||||
Recruitment details |
The study was conducted at 26 sites in 4 countries. Overall, 322 subjects were screened between 28 Nov 2012 and 26 April 2013, 73 of whom were screen failures. | |||||||||||||||||||||||||||||||||
Pre-assignment
|
||||||||||||||||||||||||||||||||||
Screening details |
Randomization was stratified according to prior history of myocardial infarction or ischemic stroke, and intensity of statin treatment. Assignment to treatment arms was done centrally using an Interactive Voice/Web Response System in a 2:1 (alirocumab:placebo) ratio after confirmation of selection criteria. | |||||||||||||||||||||||||||||||||
Period 1
|
||||||||||||||||||||||||||||||||||
Period 1 title |
Up to primary completion (overall period)
|
|||||||||||||||||||||||||||||||||
Is this the baseline period? |
Yes | |||||||||||||||||||||||||||||||||
Allocation method |
Randomised - controlled
|
|||||||||||||||||||||||||||||||||
Blinding used |
Double blind | |||||||||||||||||||||||||||||||||
Roles blinded |
Subject, Investigator, Carer, Assessor | |||||||||||||||||||||||||||||||||
Arms
|
||||||||||||||||||||||||||||||||||
Are arms mutually exclusive |
Yes
|
|||||||||||||||||||||||||||||||||
Arm title
|
Alirocumab 75 mg/up to 150 mg | |||||||||||||||||||||||||||||||||
Arm description |
Alirocumab 75 mg every two weeks (Q2W) added to stable dose of statin with or without LMT for 78 weeks. Alirocumab dose up-titrated to 150 mg Q2W from Week 12 when LDL-C levels ≥70 mg/dL at Week 8. | |||||||||||||||||||||||||||||||||
Arm type |
Experimental | |||||||||||||||||||||||||||||||||
Investigational medicinal product name |
Alirocumab
|
|||||||||||||||||||||||||||||||||
Investigational medicinal product code |
REGN727/SAR236553
|
|||||||||||||||||||||||||||||||||
Other name |
||||||||||||||||||||||||||||||||||
Pharmaceutical forms |
Solution for injection
|
|||||||||||||||||||||||||||||||||
Routes of administration |
Subcutaneous use
|
|||||||||||||||||||||||||||||||||
Dosage and administration details |
Alirocumab administered as a subcutaneous (SC) injection of 1 mL into the abdomen, thigh, or outer area of the upper arm.
|
|||||||||||||||||||||||||||||||||
Arm title
|
Placebo | |||||||||||||||||||||||||||||||||
Arm description |
Placebo matched to alirocumab for 78-week treatment duration. | |||||||||||||||||||||||||||||||||
Arm type |
Placebo | |||||||||||||||||||||||||||||||||
Investigational medicinal product name |
Placebo
|
|||||||||||||||||||||||||||||||||
Investigational medicinal product code |
||||||||||||||||||||||||||||||||||
Other name |
||||||||||||||||||||||||||||||||||
Pharmaceutical forms |
Solution for injection
|
|||||||||||||||||||||||||||||||||
Routes of administration |
Subcutaneous use
|
|||||||||||||||||||||||||||||||||
Dosage and administration details |
Placebo matched to alirocumab administered as a SC injection of 1 mL into the abdomen, thigh, or outer area of the upper arm.
|
|||||||||||||||||||||||||||||||||
|
|
|||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Baseline characteristics reporting groups
|
|||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Reporting group title |
Alirocumab 75 mg/up to 150 mg
|
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Reporting group description |
Alirocumab 75 mg every two weeks (Q2W) added to stable dose of statin with or without LMT for 78 weeks. Alirocumab dose up-titrated to 150 mg Q2W from Week 12 when LDL-C levels ≥70 mg/dL at Week 8. | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Reporting group title |
Placebo
|
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Reporting group description |
Placebo matched to alirocumab for 78-week treatment duration. | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
|
|
|||
End points reporting groups
|
|||
Reporting group title |
Alirocumab 75 mg/up to 150 mg
|
||
Reporting group description |
Alirocumab 75 mg every two weeks (Q2W) added to stable dose of statin with or without LMT for 78 weeks. Alirocumab dose up-titrated to 150 mg Q2W from Week 12 when LDL-C levels ≥70 mg/dL at Week 8. | ||
Reporting group title |
Placebo
|
||
Reporting group description |
Placebo matched to alirocumab for 78-week treatment duration. |
|
|||||||||||||
End point title |
Percent Change From Baseline in Calculated LDL-C at Week 24 - Intent-to-Treat (ITT) Analysis | ||||||||||||
End point description |
Adjusted Least-squares (LS) means and standard errors at Week 24 were obtained from a mixed-effect model with repeated measures (MMRM) to account for missing data. All available post-baseline data from Week 4 to Week 52 regardless of status on- or off-treatment were used in the model (ITT analysis). ITT population: all randomized subjects with one baseline and at least one post-baseline calculated LDL-C value on- or off-treatment.
|
||||||||||||
End point type |
Primary
|
||||||||||||
End point timeframe |
From Baseline to Week 52
|
||||||||||||
|
|||||||||||||
Statistical analysis title |
Alirocumab 75 mg/up to 150 mg vs Placebo | ||||||||||||
Statistical analysis description |
Alirocumab group was compared to the placebo group using an appropriate contrast statement.
|
||||||||||||
Comparison groups |
Alirocumab 75 mg/up to 150 mg v Placebo
|
||||||||||||
Number of subjects included in analysis |
247
|
||||||||||||
Analysis specification |
Pre-specified
|
||||||||||||
Analysis type |
superiority | ||||||||||||
P-value |
< 0.0001 [1] | ||||||||||||
Method |
Mixed models analysis | ||||||||||||
Parameter type |
LS Mean Difference | ||||||||||||
Point estimate |
-51.4
|
||||||||||||
Confidence interval |
|||||||||||||
level |
95% | ||||||||||||
sides |
2-sided
|
||||||||||||
lower limit |
-58.1 | ||||||||||||
upper limit |
-44.8 | ||||||||||||
Notes [1] - Threshold for significance ≤ 0.05. |
|
|||||||||||||
End point title |
Percent Change From Baseline in Calculated LDL-C at Week 24 - On-Treatment Analysis | ||||||||||||
End point description |
Adjusted LS means and standard errors at Week 24 were obtained from MMRM model including available post-baseline on-treatment data from Week 4 to Week 52 (i.e. up to 21 days after last injection) (on-treatment analysis). Modified ITT (mITT) population: all randomized and treated subjects with one baseline and at least one post-baseline calculated LDL-C value on-treatment.
|
||||||||||||
End point type |
Secondary
|
||||||||||||
End point timeframe |
From Baseline to Week 52
|
||||||||||||
|
|||||||||||||
Statistical analysis title |
Alirocumab 75 mg/up to 150 mg vs Placebo | ||||||||||||
Statistical analysis description |
A hierarchical testing procedure was used to control type I error and handle multiple secondary endpoint analyses. Testing was then performed sequentially in the order the endpoints are reported. The hierarchical testing sequence continued only when previous endpoint was statistically significant at 5% level.
|
||||||||||||
Comparison groups |
Alirocumab 75 mg/up to 150 mg v Placebo
|
||||||||||||
Number of subjects included in analysis |
247
|
||||||||||||
Analysis specification |
Pre-specified
|
||||||||||||
Analysis type |
superiority | ||||||||||||
P-value |
< 0.0001 [2] | ||||||||||||
Method |
Mixed models analysis | ||||||||||||
Parameter type |
LS Mean Difference | ||||||||||||
Point estimate |
-52.2
|
||||||||||||
Confidence interval |
|||||||||||||
level |
95% | ||||||||||||
sides |
2-sided
|
||||||||||||
lower limit |
-58.7 | ||||||||||||
upper limit |
-45.6 | ||||||||||||
Notes [2] - Threshold for significance ≤ 0.05. |
|
|||||||||||||
End point title |
Percent Change From Baseline in Calculated LDL-C at Week 12 - ITT Analysis | ||||||||||||
End point description |
Adjusted LS means and standard errors at Week 12 from MMRM model including all available post-baseline data from Week 4 to Week 52 regardless of status on- or off-treatment (ITT analysis). ITT population.
|
||||||||||||
End point type |
Secondary
|
||||||||||||
End point timeframe |
From Baseline to Week 52
|
||||||||||||
|
|||||||||||||
Statistical analysis title |
Alirocumab 75 mg/up to 150 mg vs Placebo | ||||||||||||
Statistical analysis description |
Testing according to the hierarchical testing procedure (previous endpoints were statistically significant).
|
||||||||||||
Comparison groups |
Alirocumab 75 mg/up to 150 mg v Placebo
|
||||||||||||
Number of subjects included in analysis |
247
|
||||||||||||
Analysis specification |
Pre-specified
|
||||||||||||
Analysis type |
superiority | ||||||||||||
P-value |
< 0.0001 [3] | ||||||||||||
Method |
Mixed models analysis | ||||||||||||
Parameter type |
LS Mean Difference | ||||||||||||
Point estimate |
-48.4
|
||||||||||||
Confidence interval |
|||||||||||||
level |
95% | ||||||||||||
sides |
2-sided
|
||||||||||||
lower limit |
-54.7 | ||||||||||||
upper limit |
-42.2 | ||||||||||||
Notes [3] - Threshold for significance ≤ 0.05. |
|
|||||||||||||
End point title |
Percent Change From Baseline in Calculated LDL-C at Week 12 - On-Treatment Analysis | ||||||||||||
End point description |
Adjusted LS means and standard errors at Week 12 were obtained from MMRM model including available post-baseline on-treatment data from Week 4 to Week 52 (i.e. up to 21 days after last injection) (on-treatment analysis). mITT population.
|
||||||||||||
End point type |
Secondary
|
||||||||||||
End point timeframe |
From Baseline to Week 52
|
||||||||||||
|
|||||||||||||
Statistical analysis title |
Alirocumab 75 mg /up to 150 mg vs Placebo | ||||||||||||
Statistical analysis description |
Testing according to the hierarchical testing procedure (previous endpoints were statistically significant).
|
||||||||||||
Comparison groups |
Alirocumab 75 mg/up to 150 mg v Placebo
|
||||||||||||
Number of subjects included in analysis |
247
|
||||||||||||
Analysis specification |
Pre-specified
|
||||||||||||
Analysis type |
superiority | ||||||||||||
P-value |
< 0.0001 [4] | ||||||||||||
Method |
Mixed models analysis | ||||||||||||
Parameter type |
LS Mean Difference | ||||||||||||
Point estimate |
-48.8
|
||||||||||||
Confidence interval |
|||||||||||||
level |
95% | ||||||||||||
sides |
2-sided
|
||||||||||||
lower limit |
-55 | ||||||||||||
upper limit |
-42.5 | ||||||||||||
Notes [4] - Threshold for significance ≤ 0.05. |
|
|||||||||||||
End point title |
Percent Change From Baseline in Apolipoprotein (Apo) B at Week 24 - ITT Analysis | ||||||||||||
End point description |
Adjusted LS means and standard errors at Week 24 from MMRM model including all available post-baseline data from Week 4 to Week 52 regardless of status on- or off-treatment. Subjects analyzed: subjects of the ITT population with one baseline and at least one post-baseline Apo B value on- or off-treatment.
|
||||||||||||
End point type |
Secondary
|
||||||||||||
End point timeframe |
From Baseline to Week 52
|
||||||||||||
|
|||||||||||||
Statistical analysis title |
Alirocumab 75 mg/up to 150 mg vs Placebo | ||||||||||||
Statistical analysis description |
Testing according to the hierarchical testing procedure (previous endpoints were statistically significant).
|
||||||||||||
Comparison groups |
Alirocumab 75 mg/up to 150 mg v Placebo
|
||||||||||||
Number of subjects included in analysis |
244
|
||||||||||||
Analysis specification |
Pre-specified
|
||||||||||||
Analysis type |
superiority | ||||||||||||
P-value |
< 0.0001 [5] | ||||||||||||
Method |
Mixed models analysis | ||||||||||||
Parameter type |
LS Mean Difference | ||||||||||||
Point estimate |
-39.3
|
||||||||||||
Confidence interval |
|||||||||||||
level |
95% | ||||||||||||
sides |
2-sided
|
||||||||||||
lower limit |
-44.1 | ||||||||||||
upper limit |
-34.5 | ||||||||||||
Notes [5] - Threshold for significance ≤ 0.05. |
|
|||||||||||||
End point title |
Percent Change From Baseline in Apo B at Week 24 - On-Treatment Analysis | ||||||||||||
End point description |
Adjusted LS means and standard errors at Week 24 were obtained from MMRM model including available post-baseline on-treatment data from Week 4 to Week 52 (i.e. up to 21 days after last injection). Subjects analyzed: subjects of the mITT population with one baseline and at least one post-baseline Apo B value on-treatment.
|
||||||||||||
End point type |
Secondary
|
||||||||||||
End point timeframe |
From Baseline to Week 52
|
||||||||||||
|
|||||||||||||
Statistical analysis title |
Alirocumab 75 mg/up to 150 mg vs Placebo | ||||||||||||
Statistical analysis description |
Testing according to the hierarchical testing procedure (previous endpoints were statistically significant).
|
||||||||||||
Comparison groups |
Alirocumab 75 mg/up to 150 mg v Placebo
|
||||||||||||
Number of subjects included in analysis |
242
|
||||||||||||
Analysis specification |
Pre-specified
|
||||||||||||
Analysis type |
superiority | ||||||||||||
P-value |
< 0.0001 [6] | ||||||||||||
Method |
Mixed models analysis | ||||||||||||
Parameter type |
LS Mean Difference | ||||||||||||
Point estimate |
-39.8
|
||||||||||||
Confidence interval |
|||||||||||||
level |
95% | ||||||||||||
sides |
2-sided
|
||||||||||||
lower limit |
-44.5 | ||||||||||||
upper limit |
-35.1 | ||||||||||||
Notes [6] - Threshold for significance ≤ 0.05. |
|
|||||||||||||
End point title |
Percent Change From Baseline in Non-High-Density Lipoprotein Cholesterol (non-HDL-C) at Week 24 - ITT Analysis | ||||||||||||
End point description |
Adjusted LS means and standard errors at Week 24 from MMRM model including all available post-baseline data from Week 4 to Week 52 regardless of status on- or off-treatment. Subjects analyzed: subjects of the ITT population with one baseline and at least one post-baseline non-HDL-C value on- or off-treatment.
|
||||||||||||
End point type |
Secondary
|
||||||||||||
End point timeframe |
From Baseline to Week 52
|
||||||||||||
|
|||||||||||||
Statistical analysis title |
Alirocumab 75 mg/up to 150 mg vs Placebo | ||||||||||||
Statistical analysis description |
Testing according to the hierarchical testing procedure (previous endpoints were statistically significant).
|
||||||||||||
Comparison groups |
Alirocumab 75 mg/up to 150 mg v Placebo
|
||||||||||||
Number of subjects included in analysis |
247
|
||||||||||||
Analysis specification |
Pre-specified
|
||||||||||||
Analysis type |
superiority | ||||||||||||
P-value |
< 0.0001 [7] | ||||||||||||
Method |
Mixed models analysis | ||||||||||||
Parameter type |
LS Mean Difference | ||||||||||||
Point estimate |
-45.7
|
||||||||||||
Confidence interval |
|||||||||||||
level |
95% | ||||||||||||
sides |
2-sided
|
||||||||||||
lower limit |
-51.8 | ||||||||||||
upper limit |
-39.7 | ||||||||||||
Notes [7] - Threshold for significance ≤ 0.05. |
|
|||||||||||||
End point title |
Percent Change From Baseline in Non-HDL-C at Week 24 - On-Treatment Analysis | ||||||||||||
End point description |
Adjusted LS means and standard errors at Week 24 from MMRM model including available post-baseline on-treatment data from Week 4 to Week 52 (i.e. up to 21 days after last injection). Subjects analyzed: subjects of the mITT population with one baseline and at least one post-baseline non-HDL-C value on-treatment.
|
||||||||||||
End point type |
Secondary
|
||||||||||||
End point timeframe |
From Baseline to Week 52
|
||||||||||||
|
|||||||||||||
Statistical analysis title |
Alirocumab 75 mg/up to 150 mg vs Placebo | ||||||||||||
Statistical analysis description |
Testing according to the hierarchical testing procedure (previous endpoints were statistically significant).
|
||||||||||||
Comparison groups |
Alirocumab 75 mg/up to 150 mg v Placebo
|
||||||||||||
Number of subjects included in analysis |
247
|
||||||||||||
Analysis specification |
Pre-specified
|
||||||||||||
Analysis type |
superiority | ||||||||||||
P-value |
< 0.0001 [8] | ||||||||||||
Method |
Mixed models analysis | ||||||||||||
Parameter type |
LS Mean Difference | ||||||||||||
Point estimate |
-46.4
|
||||||||||||
Confidence interval |
|||||||||||||
level |
95% | ||||||||||||
sides |
2-sided
|
||||||||||||
lower limit |
-52.3 | ||||||||||||
upper limit |
-40.4 | ||||||||||||
Notes [8] - Threshold for significance ≤ 0.05. |
|
|||||||||||||
End point title |
Percent Change From Baseline in Total Cholesterol (Total-C) at Week 24 - ITT Analysis | ||||||||||||
End point description |
Adjusted LS means and standard errors at Week 24 from MMRM model including all available post-baseline data from Week 4 to Week 52 regardless of status on- or off-treatment. Subjects analyzed: subjects of the ITT population with one baseline and at least one post-baseline Total-C value on- or off-treatment.
|
||||||||||||
End point type |
Secondary
|
||||||||||||
End point timeframe |
From Baseline to Week 52
|
||||||||||||
|
|||||||||||||
Statistical analysis title |
Alirocumab 75 mg/up to 150 mg vs Placebo | ||||||||||||
Statistical analysis description |
Testing according to the hierarchical testing procedure (previous endpoints were statistically significant).
|
||||||||||||
Comparison groups |
Alirocumab 75 mg/up to 150 mg v Placebo
|
||||||||||||
Number of subjects included in analysis |
247
|
||||||||||||
Analysis specification |
Pre-specified
|
||||||||||||
Analysis type |
superiority | ||||||||||||
P-value |
< 0.0001 [9] | ||||||||||||
Method |
Mixed models analysis | ||||||||||||
Parameter type |
LS Mean difference | ||||||||||||
Point estimate |
-32.8
|
||||||||||||
Confidence interval |
|||||||||||||
level |
95% | ||||||||||||
sides |
2-sided
|
||||||||||||
lower limit |
-37.4 | ||||||||||||
upper limit |
-28.1 | ||||||||||||
Notes [9] - Threshold for significance ≤ 0.05. |
|
|||||||||||||
End point title |
Percent Change From Baseline in Apo B at Week 12 - ITT Analysis | ||||||||||||
End point description |
Adjusted LS means and standard errors at Week 12 from MMRM model including all available post-baseline data from Week 4 to Week 52 regardless of status on- or off-treatment. Apo B ITT population.
|
||||||||||||
End point type |
Secondary
|
||||||||||||
End point timeframe |
From Baseline to Week 52
|
||||||||||||
|
|||||||||||||
Statistical analysis title |
Alirocumab 75 mg/up to 150 mg vs Placebo | ||||||||||||
Statistical analysis description |
Testing according to the hierarchical testing procedure (previous endpoints were statistically significant).
|
||||||||||||
Comparison groups |
Alirocumab 75 mg/up to 150 mg v Placebo
|
||||||||||||
Number of subjects included in analysis |
244
|
||||||||||||
Analysis specification |
Pre-specified
|
||||||||||||
Analysis type |
superiority | ||||||||||||
P-value |
< 0.0001 [10] | ||||||||||||
Method |
Mixed models analysis | ||||||||||||
Parameter type |
LS Mean Difference | ||||||||||||
Point estimate |
-34.5
|
||||||||||||
Confidence interval |
|||||||||||||
level |
95% | ||||||||||||
sides |
2-sided
|
||||||||||||
lower limit |
-39.2 | ||||||||||||
upper limit |
-29.8 | ||||||||||||
Notes [10] - Threshold for significance ≤ 0.05. |
|
|||||||||||||
End point title |
Percent Change From Baseline in Non-HDL-C at Week 12 - ITT Analysis | ||||||||||||
End point description |
Adjusted LS means and standard errors at Week 12 from MMRM model including all available post-baseline data from Week 4 to Week 52 regardless of status on- or off-treatment. Non-HDL-C ITT population.
|
||||||||||||
End point type |
Secondary
|
||||||||||||
End point timeframe |
From Baseline to Week 52
|
||||||||||||
|
|||||||||||||
Statistical analysis title |
Alirocumab 75 mg/up to 150 mg vs Placebo | ||||||||||||
Statistical analysis description |
Testing according to the hierarchical testing procedure (previous endpoints were statistically significant).
|
||||||||||||
Comparison groups |
Alirocumab 75 mg/up to 150 mg v Placebo
|
||||||||||||
Number of subjects included in analysis |
247
|
||||||||||||
Analysis specification |
Pre-specified
|
||||||||||||
Analysis type |
superiority | ||||||||||||
P-value |
< 0.0001 [11] | ||||||||||||
Method |
Mixed models analysis | ||||||||||||
Parameter type |
LS Mean Difference | ||||||||||||
Point estimate |
-42
|
||||||||||||
Confidence interval |
|||||||||||||
level |
95% | ||||||||||||
sides |
2-sided
|
||||||||||||
lower limit |
-47.8 | ||||||||||||
upper limit |
-36.2 | ||||||||||||
Notes [11] - Threshold for significance ≤ 0.05. |
|
|||||||||||||
End point title |
Percent Change From Baseline in Total-C at Week 12 - ITT Analysis | ||||||||||||
End point description |
Adjusted LS means and standard errors at Week 12 from MMRM model including all available post-baseline data from Week 4 to Week 52 regardless of status on- or off-treatment. Total-C ITT population.
|
||||||||||||
End point type |
Secondary
|
||||||||||||
End point timeframe |
From Baseline to Week 52
|
||||||||||||
|
|||||||||||||
Statistical analysis title |
Alirocumab 75 mg/up to 150 mg vs Placebo | ||||||||||||
Statistical analysis description |
Testing according to the hierarchical testing procedure (previous endpoints were statistically significant).
|
||||||||||||
Comparison groups |
Alirocumab 75 mg/up to 150 mg v Placebo
|
||||||||||||
Number of subjects included in analysis |
247
|
||||||||||||
Analysis specification |
Pre-specified
|
||||||||||||
Analysis type |
superiority | ||||||||||||
P-value |
< 0.0001 [12] | ||||||||||||
Method |
Mixed models analysis | ||||||||||||
Parameter type |
LS Mean Difference | ||||||||||||
Point estimate |
-29.9
|
||||||||||||
Confidence interval |
|||||||||||||
level |
95% | ||||||||||||
sides |
2-sided
|
||||||||||||
lower limit |
-34.5 | ||||||||||||
upper limit |
-25.4 | ||||||||||||
Notes [12] - Threshold for significance ≤ 0.05. |
|
|||||||||||||
End point title |
Percent Change From Baseline in Calculated LDL-C at Week 52 - ITT Analysis | ||||||||||||
End point description |
Adjusted LS means and standard errors at Week 52 from MMRM model including all available post-baseline data from Week 4 to Week 52 regardless of status on- or off-treatment. ITT population.
|
||||||||||||
End point type |
Secondary
|
||||||||||||
End point timeframe |
From Baseline to Week 52
|
||||||||||||
|
|||||||||||||
Statistical analysis title |
Alirocumab 75 mg/up to 150 mg vs Placebo | ||||||||||||
Statistical analysis description |
Testing according to the hierarchical testing procedure (previous endpoints were statistically significant).
|
||||||||||||
Comparison groups |
Alirocumab 75 mg/up to 150 mg v Placebo
|
||||||||||||
Number of subjects included in analysis |
247
|
||||||||||||
Analysis specification |
Pre-specified
|
||||||||||||
Analysis type |
superiority | ||||||||||||
P-value |
< 0.0001 [13] | ||||||||||||
Method |
Mixed models analysis | ||||||||||||
Parameter type |
LS Mean Difference | ||||||||||||
Point estimate |
-58.8
|
||||||||||||
Confidence interval |
|||||||||||||
level |
95% | ||||||||||||
sides |
2-sided
|
||||||||||||
lower limit |
-66.8 | ||||||||||||
upper limit |
-50.8 | ||||||||||||
Notes [13] - Threshold for significance ≤ 0.05. |
|
|||||||||||||
End point title |
Percentage of Very High CV Risk Subjects Reaching Calculated LDL-C <70 mg/dL (1.81 mmol/L) or High CV Risk Subjects Reaching Calculated LDL-C <100 mg/dL (2.59 mmol/L) at Week 24 - ITT Analysis | ||||||||||||
End point description |
Adjusted percentages at Week 24 were obtained from a multiple imputation approach model for handling of missing data. All available post-baseline data from Week 4 to Week 52 regardless of status on- or off-treatment were included in the imputation model (ITT analysis). ITT population.
|
||||||||||||
End point type |
Secondary
|
||||||||||||
End point timeframe |
Up to Week 52
|
||||||||||||
|
|||||||||||||
Statistical analysis title |
Alirocumab 75 mg/up to 150 mg vs Placebo | ||||||||||||
Statistical analysis description |
Testing according to the hierarchical testing procedure (previous endpoints were statistically significant). Statistical analysis used a multiple imputation approach followed by a Logistic regression model.
|
||||||||||||
Comparison groups |
Alirocumab 75 mg/up to 150 mg v Placebo
|
||||||||||||
Number of subjects included in analysis |
247
|
||||||||||||
Analysis specification |
Pre-specified
|
||||||||||||
Analysis type |
superiority | ||||||||||||
P-value |
< 0.0001 [14] | ||||||||||||
Method |
Regression, Logistic | ||||||||||||
Parameter type |
Odds ratio (OR) | ||||||||||||
Point estimate |
52.2
|
||||||||||||
Confidence interval |
|||||||||||||
level |
95% | ||||||||||||
sides |
2-sided
|
||||||||||||
lower limit |
20.9 | ||||||||||||
upper limit |
130 | ||||||||||||
Notes [14] - Threshold for significance ≤ 0.05 |
|
|||||||||||||
End point title |
Percentage of Very High CV Risk Subjects Reaching Calculated LDL-C <70 mg/dL (1.81 mmol/L) or High CV Risk Subjects Reaching Calculated LDL-C <100 mg/dL (2.59 mmol/L) at Week 24 - On-Treatment Analysis | ||||||||||||
End point description |
Adjusted percentages at Week 24 were obtained from a multiple imputation approach model including available post-baseline on-treatment data from Week 4 to Week 52 (i.e. up to 21 days after last injection) (on-treatment analysis). mITT population.
|
||||||||||||
End point type |
Secondary
|
||||||||||||
End point timeframe |
Up to Week 52
|
||||||||||||
|
|||||||||||||
Statistical analysis title |
Alirocumab 75 mg/up to 150 mg vs Placebo | ||||||||||||
Statistical analysis description |
Testing according to the hierarchical testing procedure (previous endpoints were statistically significant). Statistical analysis used a multiple imputation approach followed by a Logistic regression model.
|
||||||||||||
Comparison groups |
Alirocumab 75 mg/up to 150 mg v Placebo
|
||||||||||||
Number of subjects included in analysis |
247
|
||||||||||||
Analysis specification |
Pre-specified
|
||||||||||||
Analysis type |
superiority | ||||||||||||
P-value |
< 0.0001 [15] | ||||||||||||
Method |
Regression, Logistic | ||||||||||||
Parameter type |
Odds ratio (OR) | ||||||||||||
Point estimate |
53.3
|
||||||||||||
Confidence interval |
|||||||||||||
level |
95% | ||||||||||||
sides |
2-sided
|
||||||||||||
lower limit |
21.4 | ||||||||||||
upper limit |
132.6 | ||||||||||||
Notes [15] - Threshold for significance ≤ 0.05. |
|
|||||||||||||
End point title |
Percentage of Subjects Reaching Calculated LDL-C <70 mg/dL (1.81 mmol/L) at Week 24 - ITT Analysis | ||||||||||||
End point description |
Adjusted percentages at Week 24 were obtained from a multiple imputation approach model for handling of missing data. All available post-baseline data from Week 4 to Week 52 regardless of status on- or off-treatment were included in the imputation model (ITT analysis). ITT population.
|
||||||||||||
End point type |
Secondary
|
||||||||||||
End point timeframe |
Up to Week 52
|
||||||||||||
|
|||||||||||||
Statistical analysis title |
Alirocumab 75 mg/up to 150 mg vs Placebo | ||||||||||||
Statistical analysis description |
Testing according to the hierarchical testing procedure (previous endpoints were statistically significant). Statistical analysis used a multiple imputation approach followed by a Logistic regression model.
|
||||||||||||
Comparison groups |
Alirocumab 75 mg/up to 150 mg v Placebo
|
||||||||||||
Number of subjects included in analysis |
247
|
||||||||||||
Analysis specification |
Pre-specified
|
||||||||||||
Analysis type |
superiority | ||||||||||||
P-value |
< 0.0001 [16] | ||||||||||||
Method |
Regression, Logistic | ||||||||||||
Parameter type |
Odds ratio (OR) | ||||||||||||
Point estimate |
239.7
|
||||||||||||
Confidence interval |
|||||||||||||
level |
95% | ||||||||||||
sides |
2-sided
|
||||||||||||
lower limit |
31.6 | ||||||||||||
upper limit |
1820.3 | ||||||||||||
Notes [16] - Threshold for significance ≤ 0.05. |
|
|||||||||||||
End point title |
Percentage of Subjects Reaching Calculated LDL-C <70 mg/dL (1.81 mmol/L) at Week 24 - On-Treatment Analysis | ||||||||||||
End point description |
Adjusted percentages at Week 24 were obtained from a multiple imputation approach model including available post-baseline on-treatment data from Week 4 to Week 52 (i.e. up to 21 days after last injection) (on-treatment analysis). mITT population.
|
||||||||||||
End point type |
Secondary
|
||||||||||||
End point timeframe |
Up to Week 52
|
||||||||||||
|
|||||||||||||
Statistical analysis title |
Alirocumab 75 mg/up to 150 mg vs Placebo | ||||||||||||
Statistical analysis description |
Testing according to the hierarchical testing procedure (previous endpoints were statistically significant). Statistical analysis used a multiple imputation approach followed by a Logistic regression model.
|
||||||||||||
Comparison groups |
Alirocumab 75 mg/up to 150 mg v Placebo
|
||||||||||||
Number of subjects included in analysis |
247
|
||||||||||||
Analysis specification |
Pre-specified
|
||||||||||||
Analysis type |
superiority | ||||||||||||
P-value |
< 0.0001 [17] | ||||||||||||
Method |
Regression, Logistic | ||||||||||||
Parameter type |
Odds ratio (OR) | ||||||||||||
Point estimate |
240.6
|
||||||||||||
Confidence interval |
|||||||||||||
level |
95% | ||||||||||||
sides |
2-sided
|
||||||||||||
lower limit |
31.4 | ||||||||||||
upper limit |
1841.7 | ||||||||||||
Notes [17] - Threshold for significance ≤ 0.05. |
|
|||||||||||||
End point title |
Percent Change From Baseline in Lipoprotein (a) at Week 24 - ITT Analysis | ||||||||||||
End point description |
Adjusted means and standard errors at Week 24 from from a multiple imputation approach model including all available post-baseline data from Week 4 to Week 52 regardless of status on- or off-treatment. Subjects analyzed: subjects of the ITT population.
|
||||||||||||
End point type |
Secondary
|
||||||||||||
End point timeframe |
From Baseline to Week 52
|
||||||||||||
|
|||||||||||||
Statistical analysis title |
Alirocumab 75 mg/up to 150 mg vs Placebo | ||||||||||||
Statistical analysis description |
Testing according to the hierarchical testing procedure (previous endpoints were statistically significant). Statistical analysis used a multiple imputation approach followed by a robust regression model.
|
||||||||||||
Comparison groups |
Alirocumab 75 mg/up to 150 mg v Placebo
|
||||||||||||
Number of subjects included in analysis |
247
|
||||||||||||
Analysis specification |
Pre-specified
|
||||||||||||
Analysis type |
superiority | ||||||||||||
P-value |
< 0.0001 [18] | ||||||||||||
Method |
Regression, Robust | ||||||||||||
Parameter type |
Adjusted Mean Difference | ||||||||||||
Point estimate |
-20.3
|
||||||||||||
Confidence interval |
|||||||||||||
level |
95% | ||||||||||||
sides |
2-sided
|
||||||||||||
lower limit |
-26.4 | ||||||||||||
upper limit |
-14.2 | ||||||||||||
Notes [18] - Threshold for significance ≤ 0.05. |
|
|||||||||||||
End point title |
Percent Change From Baseline in HDL-C at Week 24 - ITT Analysis | ||||||||||||
End point description |
Adjusted LS means and standard errors at Week 24 from MMRM model including all available post-baseline data from Week 4 to Week 52 regardless of status on- or off-treatment. Subjects analyzed: subjects of the ITT population with one baseline and at least one post-baseline HDL-C value on- or off-treatment.
|
||||||||||||
End point type |
Secondary
|
||||||||||||
End point timeframe |
From Baseline to Week 52
|
||||||||||||
|
|||||||||||||
Statistical analysis title |
Alirocumab 75 mg/up to 150 mg vs Placebo | ||||||||||||
Statistical analysis description |
Testing according to the hierarchical testing procedure (previous endpoints were statistically significant).
|
||||||||||||
Comparison groups |
Alirocumab 75 mg/up to 150 mg v Placebo
|
||||||||||||
Number of subjects included in analysis |
247
|
||||||||||||
Analysis specification |
Pre-specified
|
||||||||||||
Analysis type |
superiority | ||||||||||||
P-value |
= 0.0009 [19] | ||||||||||||
Method |
Mixed models analysis | ||||||||||||
Parameter type |
LS Mean Difference | ||||||||||||
Point estimate |
6.8
|
||||||||||||
Confidence interval |
|||||||||||||
level |
95% | ||||||||||||
sides |
2-sided
|
||||||||||||
lower limit |
2.8 | ||||||||||||
upper limit |
10.7 | ||||||||||||
Notes [19] - Threshold for significance ≤ 0.05. |
|
|||||||||||||
End point title |
Percent Change From Baseline in Fasting Triglycerides at Week 24 - ITT Analysis | ||||||||||||
End point description |
Adjusted means and standard errors at Week 24 from a multiple imputation approach model including all available post-baseline data from Week 4 to Week 52 regardless of status on- or off-treatment. Subjects analyzed: subjects of the ITT population.
|
||||||||||||
End point type |
Secondary
|
||||||||||||
End point timeframe |
From Baseline to Week 52
|
||||||||||||
|
|||||||||||||
Statistical analysis title |
Alirocumab 75 mg/up to 150 mg vs Placebo | ||||||||||||
Statistical analysis description |
Testing according to the hierarchical testing procedure (previous endpoints were statistically significant). Statistical analysis used a multiple imputation approach followed by a robust regression model.
|
||||||||||||
Comparison groups |
Alirocumab 75 mg/up to 150 mg v Placebo
|
||||||||||||
Number of subjects included in analysis |
247
|
||||||||||||
Analysis specification |
Pre-specified
|
||||||||||||
Analysis type |
superiority | ||||||||||||
P-value |
= 0.0012 [20] | ||||||||||||
Method |
Regression, Robust | ||||||||||||
Parameter type |
Adjusted Mean Difference | ||||||||||||
Point estimate |
-10.9
|
||||||||||||
Confidence interval |
|||||||||||||
level |
95% | ||||||||||||
sides |
2-sided
|
||||||||||||
lower limit |
-17.5 | ||||||||||||
upper limit |
-4.3 | ||||||||||||
Notes [20] - Threshold for significance ≤ 0.05. |
|
|||||||||||||
End point title |
Percent Change From Baseline in Apo A-1 at Week 24 - ITT Analysis | ||||||||||||
End point description |
Adjusted LS means and standard errors at Week 24 from MMRM model including all available post-baseline data from Week 4 to Week 52 regardless of status on- or off-treatment. ITT population: all randomized and treated subjects with one baseline and at least one post-baseline Apo A-1 value on- or off-treatment.
|
||||||||||||
End point type |
Secondary
|
||||||||||||
End point timeframe |
From Baseline to Week 52
|
||||||||||||
|
|||||||||||||
Statistical analysis title |
Alirocumab 75 mg/up to 150 mg vs Placebo | ||||||||||||
Statistical analysis description |
Testing according to the hierarchical testing procedure (previous endpoints were statistically significant).
|
||||||||||||
Comparison groups |
Alirocumab 75 mg/up to 150 mg v Placebo
|
||||||||||||
Number of subjects included in analysis |
244
|
||||||||||||
Analysis specification |
Pre-specified
|
||||||||||||
Analysis type |
superiority | ||||||||||||
P-value |
= 0.0062 [21] | ||||||||||||
Method |
Mixed models analysis | ||||||||||||
Parameter type |
LS Mean Difference | ||||||||||||
Point estimate |
4.4
|
||||||||||||
Confidence interval |
|||||||||||||
level |
95% | ||||||||||||
sides |
2-sided
|
||||||||||||
lower limit |
1.3 | ||||||||||||
upper limit |
7.5 | ||||||||||||
Notes [21] - Threshold for significance ≤ 0.05. |
|
|||||||||||||
End point title |
Percent Change From Baseline in Lipoprotein (a) at Week 12 - ITT Analysis | ||||||||||||
End point description |
Adjusted means and standard errors at Week 12 from from a multiple imputation approach model including all available post-baseline data from Week 4 to Week 52 regardless of status on- or off-treatment. Lipoprotein (a) ITT population.
|
||||||||||||
End point type |
Secondary
|
||||||||||||
End point timeframe |
From Baseline to Week 52
|
||||||||||||
|
|||||||||||||
Statistical analysis title |
Alirocumab 75 mg/up to 150 mg vs Placebo | ||||||||||||
Statistical analysis description |
Testing according to the hierarchical testing procedure (previous endpoints were statistically significant). Statistical analysis used a multiple imputation approach followed by a robust regression model.
|
||||||||||||
Comparison groups |
Alirocumab 75 mg/up to 150 mg v Placebo
|
||||||||||||
Number of subjects included in analysis |
247
|
||||||||||||
Analysis specification |
Pre-specified
|
||||||||||||
Analysis type |
superiority | ||||||||||||
P-value |
< 0.0001 [22] | ||||||||||||
Method |
Regression, Robust | ||||||||||||
Parameter type |
Adjusted Mean Difference | ||||||||||||
Point estimate |
-19.1
|
||||||||||||
Confidence interval |
|||||||||||||
level |
95% | ||||||||||||
sides |
2-sided
|
||||||||||||
lower limit |
-25 | ||||||||||||
upper limit |
-13.1 | ||||||||||||
Notes [22] - Threshold for significance ≤ 0.05. |
|
|||||||||||||
End point title |
Percent Change From Baseline in HDL-C at Week 12 - ITT Analysis | ||||||||||||
End point description |
Adjusted LS means and standard errors at Week 12 from MMRM model including all available post-baseline data from Week 4 to Week 52 regardless of status on- or off-treatment. HDL-C ITT population.
|
||||||||||||
End point type |
Secondary
|
||||||||||||
End point timeframe |
From Baseline to Week 52
|
||||||||||||
|
|||||||||||||
Statistical analysis title |
Alirocumab 75 mg/up to 150 mg vs Placebo | ||||||||||||
Statistical analysis description |
Testing according to the hierarchical testing procedure (previous endpoints were statistically significant).
|
||||||||||||
Comparison groups |
Alirocumab 75 mg/up to 150 mg v Placebo
|
||||||||||||
Number of subjects included in analysis |
247
|
||||||||||||
Analysis specification |
Pre-specified
|
||||||||||||
Analysis type |
superiority | ||||||||||||
P-value |
= 0.0147 [23] | ||||||||||||
Method |
Mixed models analysis | ||||||||||||
Parameter type |
LS Mean Difference | ||||||||||||
Point estimate |
4.3
|
||||||||||||
Confidence interval |
|||||||||||||
level |
95% | ||||||||||||
sides |
2-sided
|
||||||||||||
lower limit |
0.9 | ||||||||||||
upper limit |
7.8 | ||||||||||||
Notes [23] - Threshold for significance ≤ 0.05. |
|
|||||||||||||
End point title |
Percent Change From Baseline in Fasting Triglycerides at Week 12 - ITT Analysis | ||||||||||||
End point description |
Adjusted means and standard errors at Week 12 from from a multiple imputation approach model including all available post-baseline data from Week 4 to Week 52 regardless of status on- or off-treatment. Fasting Triglycerides ITT population.
|
||||||||||||
End point type |
Secondary
|
||||||||||||
End point timeframe |
From Baseline to Week 52
|
||||||||||||
|
|||||||||||||
Statistical analysis title |
Alirocumab 75 mg/up to 150 mg vs Placebo | ||||||||||||
Statistical analysis description |
Testing according to the hierarchical testing procedure (previous endpoints were statistically significant). Statistical analysis used a multiple imputation approach followed by a robust regression model.
|
||||||||||||
Comparison groups |
Alirocumab 75 mg/up to 150 mg v Placebo
|
||||||||||||
Number of subjects included in analysis |
247
|
||||||||||||
Analysis specification |
Pre-specified
|
||||||||||||
Analysis type |
superiority | ||||||||||||
P-value |
= 0.024 [24] | ||||||||||||
Method |
Regression, Robust | ||||||||||||
Parameter type |
Adjusted Mean Difference | ||||||||||||
Point estimate |
-8.6
|
||||||||||||
Confidence interval |
|||||||||||||
level |
95% | ||||||||||||
sides |
2-sided
|
||||||||||||
lower limit |
-16.1 | ||||||||||||
upper limit |
-1.1 | ||||||||||||
Notes [24] - Threshold for significance ≤ 0.05. |
|
|||||||||||||
End point title |
Percent Change From Baseline in Apo A-1 at Week 12 - ITT Analysis | ||||||||||||
End point description |
Adjusted LS means and standard errors at Week 12 from MMRM model including all available post-baseline data from Week 4 to Week 52 regardless of status on- or off-treatment. Apo A-1 ITT population.
|
||||||||||||
End point type |
Secondary
|
||||||||||||
End point timeframe |
From Baseline to Week 52
|
||||||||||||
|
|||||||||||||
Statistical analysis title |
Alirocumab 75 mg/up to 150 mg vs Placebo | ||||||||||||
Statistical analysis description |
Testing according to the hierarchical testing procedure (previous endpoints were statistically significant).
|
||||||||||||
Comparison groups |
Alirocumab 75 mg/up to 150 mg v Placebo
|
||||||||||||
Number of subjects included in analysis |
244
|
||||||||||||
Analysis specification |
Pre-specified
|
||||||||||||
Analysis type |
superiority | ||||||||||||
P-value |
= 0.1475 [25] | ||||||||||||
Method |
Mixed models analysis | ||||||||||||
Parameter type |
LS Mean Difference | ||||||||||||
Point estimate |
2.3
|
||||||||||||
Confidence interval |
|||||||||||||
level |
95% | ||||||||||||
sides |
2-sided
|
||||||||||||
lower limit |
-0.8 | ||||||||||||
upper limit |
5.5 | ||||||||||||
Notes [25] - Threshold for significance ≤ 0.05. |
|
|||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Adverse events information
|
|||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Timeframe for reporting adverse events |
From Baseline up to Week 52
|
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Adverse event reporting additional description |
Treatment emergent adverse events that developed during treatment emergent adverse events period (the time from the first dose of study drug to the last dose of study drug + 70 days (10 weeks) are reported.
|
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Assessment type |
Systematic | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Dictionary used for adverse event reporting
|
|||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Dictionary name |
MedDRA | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Dictionary version |
17.0
|
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Reporting groups
|
|||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Reporting group title |
Alirocumab 75 mg/up to 150 mg
|
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Reporting group description |
Alirocumab 75 mg Q2W added to stable dose of statin with or without LMT for 78 weeks. Alirocumab dose up-titrated to 150 mg Q2W from Week 12 when LDL-C levels ≥70 mg/dL at Week 8. | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Reporting group title |
Placebo
|
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Reporting group description |
Placebo matched to alirocumab for 78 week treatment duration. | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
|
|||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
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 |
||
13 Feb 2013 |
The purpose of this amendment was to: - Change an exclusion criterion from HbA1c >8.5% to HbA1c >9%. - Clarify that repeat testing was allowed for eligibility with respect to Thyroid-stimulating hormone (TSH) laboratory results. - Clarify fulfillment of applicable local regulatory requirements through the Informed consent form (ICF) or a local protocol addendum in women of childbearing potential and add a definition for the duration of required contraception use after discontinuation of the study drug. - Add contingency language to ensure the continuity of study drug treatment without interruption (in the event the manufacturer faced any performance or supply issues of the auto-injector). - Widen some visit windows to allow more scheduling flexibility, and make the visit window for the end of double-blind treatment visit (visit 12, week 78) narrower. - Clarify that reporting of Adverse event of special interests (AESIs) that require accelerated reporting was to be done within 24 hours of the site’s learning of the event. - Add neurologic and ophthalmologic events that require additional examinations/procedures and/or referral to a specialist as reportable AESIs that require accelerated reporting. - Define neurologic and ophthalmologic events that did not require additional examinations/procedures and/or referral to a specialist as AESIs that did not require accelerated reporting. - Remove hospitalization for unanticipated coronary revascularization from the list of Clinical events committee (CEC) adjudication categories, and add that all coronary revascularizations was to be submitted to the CEC. - Make miscellaneous administrative corrections and clarifications. |
||
09 Apr 2014 |
The purpose of this amendment was to: - Modify the primary efficacy analysis population to the ITT population for the primary and secondary efficacy endpoints, which included assessments both on study treatment and off study treatment through the analysis period. - MMRM was to be used for the primary endpoint and for other continuous secondary endpoints anticipated to have normally distributed data. - For continuous endpoints expected to have non-normally distributed data, the robust regression method was to be used to test the treatment group differences and missing data was to be handled using multiple imputation approach. - For binary endpoints, logistic regression method was be used to test the treatment group differences and missing data was to be handled using multiple imputation approach. - Primary and key secondary endpoints was to also be analyzed in the mITT population to assess the drug effect during the study treatment period (on-treatment approach). - The list of key and other secondary efficacy endpoints and estimands (ITT estimand or on-treatment estimand) were adjusted. - Update language on CV events to be reported to the CEC for adjudication, and to clarify cerebrovascular events. - Clarify that LDL-C measured and calculated was to be performed at weeks 0 and 24. - Update language on collection of partner pregnancy, per the ODYSSEY program. - Update categorization of AEs (update language on how to record injection site reactions that were not related to study drug). - Make minor corrections/clarifications. |
||
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 |