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Study of Alirocumab (REGN727/SAR236553) in Patients With Primary Hypercholesterolemia and Moderate, High, or Very High Cardiovascular (CV) Risk, Who Are Intolerant to Statins (ODYSSEY ALTERNATIVE)

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ClinicalTrials.gov Identifier: NCT01709513
Recruitment Status : Completed
First Posted : October 18, 2012
Results First Posted : August 28, 2015
Last Update Posted : August 28, 2017
Sponsor:
Collaborator:
Sanofi
Information provided by (Responsible Party):
Regeneron Pharmaceuticals

Tracking Information
First Submitted Date  ICMJE October 8, 2012
First Posted Date  ICMJE October 18, 2012
Results First Submitted Date  ICMJE July 29, 2015
Results First Posted Date  ICMJE August 28, 2015
Last Update Posted Date August 28, 2017
Actual Study Start Date  ICMJE September 2012
Actual Primary Completion Date May 2014   (Final data collection date for primary outcome measure)
Current Primary Outcome Measures  ICMJE
 (submitted: July 29, 2015)
Percent Change From Baseline in Calculated LDL-C at Week 24 - Intent--To-Treat (ITT) Analysis [ Time Frame: From Baseline to Week 24 ]
Calculated LDL-C values were obtained from Friedewald formula. 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 24 regardless of status on- or off-treatment were used in the model (ITT analysis).
Original Primary Outcome Measures  ICMJE
 (submitted: October 16, 2012)
Percent change in calculated LDL-C to wk 24 [ Time Frame: Baseline to Wk 24 ]
The primary efficacy endpoint is the percent change in calculated low-density lipoprotein-cholesterol (LDL-C) from baseline to week 24
Change History
Current Secondary Outcome Measures  ICMJE
 (submitted: May 25, 2016)
  • Percent Change From Baseline in Calculated LDL-C at Week 24 - On--Treatment Analysis [ Time Frame: From Baseline to Week 24 ]
    Calculated LDL-C values were obtained from Friedewald formula. 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 24 (i.e. up to 21 days after last injection or 3 days after the last capsule, whichever came first) (on-treatment analysis).
  • Percent Change From Baseline in Calculated LDL--C at Week 12 -- ITT Analysis [ Time Frame: From Baseline to Week 12 ]
    Calculated LDL-C values were obtained from Friedewald formula. Adjusted LS means and standard errors at Week 12 from MMRM model including all available post-baseline data from Week 4 to Week 24 regardless of status on- or off-treatment.
  • Percent Change From Baseline in Calculated LDL-C at Week 12 - On--Treatment Analysis [ Time Frame: From Baseline to Week 12 ]
    Calculated LDL-C values were obtained from Friedewald formula. 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 24 (i.e. up to 21 days after last injection or 3 days after the last capsule, whichever came first) (on-treatment analysis).
  • Percent Change From Baseline in Apolipoprotein (Apo) B at Week 24 -- ITT Analysis [ Time Frame: From Baseline to Week 24 ]
    Adjusted LS means and standard errors at Week 24 from MMRM model including all available post--baseline data from Week 4 to Week 24 regardless of status on- or off-treatment.
  • Percent Change From Baseline in Apo B at Week 24 -- On--Treatment Analysis [ Time Frame: From Baseline to Week 24 ]
    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 24 (i.e. up to 21 days after last injection or 3 days after the last capsule, whichever came first).
  • Percent Change From Baseline in Non--High Density Lipoprotein Cholesterol (Non-HDL-C) at Week 24 -- ITT Analysis [ Time Frame: From Baseline to Week 24 ]
    Adjusted LS means and standard errors at Week 24 from MMRM model including all available post-baseline data from Week 4 to Week 24 regardless of status on- or off-treatment.
  • Percent Change From Baseline in Non--HDL-C at Week 24 -- On--Treatment Analysis [ Time Frame: From Baseline to Week 24 ]
    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 24 (i.e. up to 21 days after last injection or 3 days after the last capsule, whichever came first).
  • Percent Change From Baseline in Total Cholesterol (Total--C) at Week 24 - ITT Analysis [ Time Frame: From Baseline to Week 24 ]
    Adjusted LS means and standard errors at Week 24 from MMRM model including all available post-baseline data from Week 4 to Week 24 regardless of status on- or off-treatment.
  • Percent Change From Baseline in Apo B at Week 12 -- ITT Analysis [ Time Frame: From Baseline to Week 12 ]
    Adjusted LS means and standard errors at Week 12 from MMRM model including all available post-baseline data from Week 4 to Week 24 regardless of status on- or off-treatment.
  • Percent Change From Baseline in Non-HDL-C at Week 12 - ITT Analysis [ Time Frame: From Baseline to Week 12 ]
    Adjusted LS means and standard errors at Week 12 from MMRM model including all available post-baseline data from Week 4 to Week 24 regardless of status on- or off-treatment.
  • Percent Change From Baseline in Total-C at Week 12 - ITT Analysis [ Time Frame: From Baseline to Week 12 ]
    Adjusted LS means and standard errors at Week 12 from MMRM model including all available post-baseline data from Week 4 to Week 24 regardless of status on- or off-treatment.
  • Percentage of Very High CV Risk Participants Reaching Calculated LDL-C <70 mg/dL (1.81 mmol/L) or Moderate or High CV Risk Participants Reaching Calculated LDL-C <100 mg/dL (2.59 mmol/L) at Week 24 - ITT Analysis [ Time Frame: Up to Week 24 ]
    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 24 regardless of status on- or off-treatment were included in the imputation model (ITT analysis).
  • Percentage of Very High CV Risk Participants Reaching Calculated LDL-C <70 mg/dL (1.81 mmol/L) or Moderate or High CV Risk Participants Reaching Calculated LDL-C <100 mg/dL (2.59 mmol/L) at Week 24 - On-Treatment Analysis [ Time Frame: Up to Week 24 ]
    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 24 i.e. up to 21 days after last injection or 3 days after the last capsule, whichever came first (on-treatment analysis).
  • Percentage of Participants Reaching Calculated LDL-C <70 mg/dL (1.81 mmol/L) at Week 24 - ITT Analysis [ Time Frame: Up to Week 24 ]
    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 24 regardless of status on- or off-treatment were included in the imputation model (ITT analysis).
  • Percentage of Participants Reaching Calculated LDL-C <70 mg/dL (1.81 mmol/L) at Week 24 - On-Treatment Analysis [ Time Frame: Up to Week 24 ]
    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 24 i.e. up to 21 days after last injection or 3 days after the last capsule, whichever came first (on-treatment analysis).
  • Percent Change From Baseline in Lipoprotein(a) at Week 24 - ITT Analysis [ Time Frame: From Baseline to Week 24 ]
    Combined Estimate for Adjusted Mean (Standard Error) at Week 24 from multiple imputation followed by robust regression including all available post-baseline data from Week 4 to Week 24 regardless of status on or off-treatment.
  • Percent Change From Baseline in HDL-C at Week 24 - ITT Analysis [ Time Frame: From Baseline to Week 24 ]
    Adjusted LS means and standard errors at Week 24 from MMRM model including all available post-baseline data from Week 4 to Week 24 regardless of status on- or off-treatment.
  • Percent Change From Baseline in Fasting Triglycerides at Week 24 - ITT Analysis [ Time Frame: From Baseline to Week 24 ]
    Combined Estimate for Adjusted Mean (Standard Error) at Week 24 from multiple imputation followed by robust regression including all available post-baseline data from Week 4 to Week 24 regardless of status on or off-treatment.
  • Percent Change From Baseline in Apo A-1 at Week 24 - ITT Analysis [ Time Frame: From Baseline to Week 24 ]
    Adjusted LS means and standard errors at Week 24 from MMRM model including all available post-baseline data from Week 4 to Week 24 regardless of status on- or off-treatment.
  • Percent Change From Baseline in Lipoprotein(a) at Week 12 -- ITT Analysis [ Time Frame: From Baseline to Week 12 ]
    Combined Estimate for Adjusted Mean (Standard Error) at Week 24 from multiple imputation followed by robust regression including all available post-baseline data from Week 4 to Week 24 regardless of status on or off-treatment.
  • Percent Change in HDL-C From Baseline to Week 12 -- ITT Analysis [ Time Frame: From Baseline to Week 12 ]
    Least-squares (LS) means and standard errors (SE) taken from MMRM (mixed-effect model with repeated measures) analysis
  • Percent Change in Fasting Triglycerides From Baseline to Week 12 -- ITT Analysis [ Time Frame: From Baseline to Week 12 ]
    Combined Estimate for Adjusted Mean (Standard Error) at Week 24 from multiple imputation followed by robust regression including all available post-baseline data from Week 4 to Week 24 regardless of status on or off-treatment.
  • Percent Change From Baseline in Apo A--1 at Week 12 -- ITT Analysis [ Time Frame: From Baseline to Week 12 ]
    Least squares (LS) means and standard errors (SE) taken from MMRM (mixed effect model with repeated measures) analysis.
Original Secondary Outcome Measures  ICMJE
 (submitted: October 16, 2012)
  • Percent change in calculated LDL-C to wk 12 [ Time Frame: Baseline to WK 12 ]
    The effect of REGN727 (SAR236553) on LDL-C in comparison with placebo from baseline to other time points
  • Percent change in ApoB, non-HDL-C, total-C, HDL-C, Lp(a), TG, and Apo A-1 to time points up to wk 24 [ Time Frame: Baseline to Wk 24 ]
    The change in ApoB, non-HDL-C, total-C, HDL-C, Lp(a), TG, and Apo A-1 from baseline to time points up to wk 24.
  • Proportion of patients reaching LDL-C less than 70 mg/dL [ Time Frame: At Wk 24 ]
    The proportion of patients reaching LDL-C less than 70 mg/dL at week 24
Current Other Pre-specified Outcome Measures
 (submitted: May 25, 2016)
  • Percentage of Participants Who Experienced Skeletal Muscle-related Adverse Event (AE) [ Time Frame: From Baseline up to Week 24 ]
    Skeletal muscle-related adverse events were a predefined category including myalgia, muscle spasms, muscular weakness, musculoskeletal stiffness and muscle fatigue. Events that developed during treatment emergent adverse events period (the time from the first double-blindstudy treatment [injection or capsules, whichever came first] up to the day of the last double-blind injection + 70 days ) are reported.
  • Percent Change From Baseline in Calculated LDL-C at Week 24 Versus Atorvastatin - Raw Data Description - Intent-To-Treat (ITT) Analysis [ Time Frame: From Baseline up to Week 24 ]
Original Other Pre-specified Outcome Measures Not Provided
 
Descriptive Information
Brief Title  ICMJE Study of Alirocumab (REGN727/SAR236553) in Patients With Primary Hypercholesterolemia and Moderate, High, or Very High Cardiovascular (CV) Risk, Who Are Intolerant to Statins (ODYSSEY ALTERNATIVE)
Official Title  ICMJE A Randomized, Double-Blind, Double-Dummy, Active-Controlled Study to Evaluate the Efficacy and Safety of REGN727/SAR236553 in Patients With Primary Hypercholesterolemia Who Are Intolerant to Statins
Brief Summary This is a randomized, double-blind, double-dummy, active-controlled, parallel-group, multi-national, multi-center study to compare alirocumab (REGN727/SAR236553) versus ezetimibe in participants with primary hypercholesterolemia and moderate, high, or very high CV risk, who are intolerant to statins. An atorvastatin arm is added to determine that the population selected in the study is a truly statin intolerant population by assessing skeletal muscle-related adverse events.
Detailed Description Not Provided
Study Type  ICMJE Interventional
Study Phase  ICMJE Phase 3
Study Design  ICMJE Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
Primary Purpose: Treatment
Condition  ICMJE Hypercholesterolemia
Intervention  ICMJE
  • Drug: Atorvastatin
    Atorvastatin over-encapsulated tablets.
  • Drug: Ezetimibe
    Ezetimibe over-encapsulated tablet.
    Other Name: Zetia
  • Drug: Alirocumab
    Alirocumab SC injection of 1 mL into the abdomen, thigh, or outer area of the upper arm.
    Other Name: REGN727/SAR236553
  • Drug: Placebo
    Placebo for alirocumab, ezitimibe and atorvastatin.
Study Arms  ICMJE
  • Atorvastatin (statin rechallenge arm)
    Atorvastatin 20 mg over-encapsulated tablets orally once daily (QD) for 24 weeks and placebo (for alirocumab) subcutaneous (SC) injection every two weeks (Q2W) for 24 weeks added to stable lipid-modifying therapy (LMT).
    Interventions:
    • Drug: Atorvastatin
    • Drug: Placebo
  • Active Comparator: Ezetimibe
    Ezetimibe 10 mg over-encapsulated tablets orally QD for 24 weeks and placebo (for alirocumab) SC injection Q2W for 24 weeks added to stable LMT.
    Interventions:
    • Drug: Ezetimibe
    • Drug: Placebo
  • Experimental: Alirocumab 75 mg/ up to 150 mg
    Alirocumab 75 mg SC injection Q2W for 24 weeks and placebo (for atorvastatin/ezetimibe) over-encapsulated tablets orally QD for 24 weeks added to stable LMT. Alirocumab dose up-titrated to 150 mg Q2W from Week 12 when LDL-C levels ≥70 mg/dL (1.81 mmol/L) or ≥100 mg/dL (2.59 mmol/L) at Week 8, based on cardiovascular risk.
    Interventions:
    • Drug: Alirocumab
    • Drug: Placebo
Publications *

*   Includes publications given by the data provider as well as publications identified by ClinicalTrials.gov Identifier (NCT Number) in Medline.
 
Recruitment Information
Recruitment Status  ICMJE Completed
Actual Enrollment  ICMJE
 (submitted: October 7, 2013)
314
Original Estimated Enrollment  ICMJE
 (submitted: October 16, 2012)
250
Actual Study Completion Date  ICMJE May 2017
Actual Primary Completion Date May 2014   (Final data collection date for primary outcome measure)
Eligibility Criteria  ICMJE

Inclusion:

  1. Patients with primary hypercholesterolemia [Heterozygous Familial Hypercholesterolemia (heFH) or non-FH] with moderate, high or very high CV risk and a history of statin intolerance
  2. Provide signed informed consent

Exclusion:

  1. Calculated serum LDL-C <70 mg/dL (1.81 mmol/L) and very high CV risk at the screening visit
  2. Calculated serum LDL-C <100 mg/dL (2.59 mmol/L) and high or moderate CV risk at the screening visit
  3. A 10-year fatal cardiovascular disease risk score <1% at the screening visit

(The inclusion/ exclusion criteria provided above is not intended to contain all considerations relevant to a patient's potential participation in this clinical trial).

Sex/Gender  ICMJE
Sexes Eligible for Study: All
Ages  ICMJE 18 Years and older   (Adult, Older Adult)
Accepts Healthy Volunteers  ICMJE No
Contacts  ICMJE Contact information is only displayed when the study is recruiting subjects
Listed Location Countries  ICMJE Austria,   Canada,   France,   Israel,   Italy,   Norway,   United Kingdom,   United States
Removed Location Countries Germany,   Netherlands
 
Administrative Information
NCT Number  ICMJE NCT01709513
Other Study ID Numbers  ICMJE R727-CL-1119
Has Data Monitoring Committee Yes
U.S. FDA-regulated Product Not Provided
IPD Sharing Statement  ICMJE Not Provided
Responsible Party Regeneron Pharmaceuticals
Study Sponsor  ICMJE Regeneron Pharmaceuticals
Collaborators  ICMJE Sanofi
Investigators  ICMJE
Study Director: Clinical Trial Management Regeneron Pharmaceuticals
PRS Account Regeneron Pharmaceuticals
Verification Date July 2017

ICMJE     Data element required by the International Committee of Medical Journal Editors and the World Health Organization ICTRP