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Efficacy and Safety of Alirocumab Versus Usual Care on Top of Maximally Tolerated Statin Therapy in Patients With Type 2 Diabetes and Mixed Dyslipidemia (ODYSSEY DM-Dyslipidemia)

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ClinicalTrials.gov Identifier: NCT02642159
Recruitment Status : Completed
First Posted : December 30, 2015
Results First Posted : May 1, 2018
Last Update Posted : May 1, 2018
Sponsor:
Collaborator:
Regeneron Pharmaceuticals
Information provided by (Responsible Party):
Sanofi

Tracking Information
First Submitted Date  ICMJE December 24, 2015
First Posted Date  ICMJE December 30, 2015
Results First Submitted Date  ICMJE March 20, 2018
Results First Posted Date  ICMJE May 1, 2018
Last Update Posted Date May 1, 2018
Study Start Date  ICMJE March 15, 2016
Actual Primary Completion Date March 22, 2017   (Final data collection date for primary outcome measure)
Current Primary Outcome Measures  ICMJE
 (submitted: April 30, 2018)
  • Percent Change From Baseline in Non-HDL-C at Week 24: Overall Intent-to-treat (ITT) Analysis [ Time Frame: From Baseline to Week 24 ]
    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 8 to Week 24 regardless of status on- or off-treatment were used in the model (ITT analysis).
  • Percent Change From Baseline in Non-HDL-C at Week 24: ITT- Intent to Prescribe Fenofibrate Stratum [ 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 8 to Week 24 regardless of status on- or off-treatment in the intent to prescribe fenofibrate stratum. The usual care here corresponds to fenofibrate.
Original Primary Outcome Measures  ICMJE
 (submitted: December 24, 2015)
Percent change in non-HDL-C in the intent-to-treat (ITT) population [ Time Frame: From Baseline to Week 24 ]
Change History Complete list of historical versions of study NCT02642159 on ClinicalTrials.gov Archive Site
Current Secondary Outcome Measures  ICMJE
 (submitted: April 30, 2018)
  • Percent Change From Baseline in Measured Low-Density Lipoprotein Cholesterol (LDL-C) at Week 24: Overall ITT Analysis [ Time Frame: From Baseline to Week 24 ]
    Measured LDL-C values via beta quantification method. Adjusted LS means and standard errors at Week 24 from MMRM model including available post-baseline data from Week 8 to Week 24 regardless of status on- or off-treatment.
  • Percent Change From Baseline in Measured LDL-C at Week 24: ITT- Intent to Prescribe Fenofibrate Stratum [ Time Frame: From Baseline to Week 24 ]
    Measured LDL-C values via beta quantification method. Adjusted LS means and standard errors at Week 24 from MMRM model including available post-baseline data from Week 8 to Week 24 regardless of status on- or off-treatment in the intent to prescribe fenofibrate stratum. The usual care here corresponds to fenofibrate.
  • Percent Change From Baseline in Non-HDL-C at Week 12: Overall ITT Analysis [ Time Frame: From Baseline to Week 24 ]
    Adjusted LS means and standard errors at Week 12 from MMRM model including all available post-baseline data from Week 8 to Week 24 regardless of status on- or off-treatment.
  • Percent Change From Baseline in Non-HDL-C at Week 12: ITT- Intent to Prescribe Fenofibrate Stratum [ Time Frame: From Baseline to Week 24 ]
    Adjusted LS means and standard errors at Week 12 from MMRM model including all available post-baseline data from Week 8 to Week 24 regardless of status on- or off-treatment in the intent to prescribe fenofibrate stratum. The usual care here corresponds to fenofibrate.
  • Percent Change From Baseline in Measured LDL-C at Week 12: Overall ITT Analysis [ Time Frame: From Baseline to Week 24 ]
    Measured LDL-C values via beta quantification method. Adjusted LS means and standard errors at Week 12 from MMRM model including available post-baseline data from Week 8 to Week 24 regardless of status on- or off-treatment.
  • Percent Change From Baseline in Measured LDL-C at Week 12: ITT- Intent to Prescribe Fenofibrate Stratum [ Time Frame: From Baseline to Week 24 ]
    Measured LDL-C values via beta quantification method. Adjusted LS means and standard errors at Week 12 from MMRM model including available post-baseline data from Week 8 to Week 24 regardless of status on- or off-treatment in the intent to prescribe fenofibrate stratum. The usual care here corresponds to fenofibrate.
  • Percent Change From Baseline in Apolipoprotein B (Apo-B) at Week 24: Overall 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 8 to Week 24 regardless of status on- or off-treatment.
  • Percent Change From Baseline in Apo B at Week 24: ITT- Intent to Prescribe Fenofibrate Stratum [ 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 8 to Week 24 regardless of status on- or off-treatment in the intent to prescribe fenofibrate stratum. The usual care here corresponds to fenofibrate.
  • Percent Change From Baseline in Total Cholesterol (Total-C) at Week 24 : Overall 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 8 to Week 24 regardless of status on- or off-treatment.
  • Percent Change From Baseline in Total-C at Week 24: ITT- Intent to Prescribe Fenofibrate Stratum [ 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 8 to Week 24 regardless of status on- or off-treatment in the intent to prescribe fenofibrate stratum. The usual care here corresponds to fenofibrate.
  • Percent Change From Baseline in Lipoprotein(a) at Week 24 : Overall ITT Analysis [ Time Frame: From Baseline to Week 24 ]
    Adjusted means and standard errors at Week 24 were obtained from multiple imputation approach followed by robust regression model for handling of missing data. All available post-baseline data from Week 8 to Week 24 regardless of status on- or off-treatment were included in the imputation model.
  • Percent Change From Baseline in Lipoprotein(a) at Week 24: ITT- Intent to Prescribe Fenofibrate Stratum [ Time Frame: From Baseline to Week 24 ]
    Adjusted means and standard errors at Week 24 from multiple imputation approach followed by robust regression model including all available post-baseline data from Week 8 to Week 24 regardless of status on- or off-treatment in the intent to prescribe fenofibrate stratum. The usual care here corresponds to fenofibrate.
  • Percent Change From Baseline in Fasting Triglycerides at Week 24: Overall ITT Analysis [ Time Frame: From Baseline to Week 24 ]
    Adjusted means and standard errors at Week 24 from multiple imputation approach followed by robust regression model including all available post-baseline data from Week 8 to Week 24 regardless of status on- or off-treatment.
  • Percent Change From Baseline in Fasting Triglycerides at Week 24: ITT- Intent to Prescribe Fenofibrate Stratum [ Time Frame: From Baseline to Week 24 ]
    Adjusted means and standard errors at Week 24 from multiple imputation approach followed by robust regression model including all available post-baseline data from Week 8 to Week 24 regardless of status on- or off-treatment in the intent to prescribe fenofibrate stratum. The usual care here corresponds to fenofibrate.
  • Percent Change From Baseline in HDL-C at Week 24 : Overall 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 8 to Week 24 regardless of status on- or off-treatment.
  • Percent Change From Baseline in HDL-C at Week 24: ITT- Intent to Prescribe Fenofibrate Stratum [ 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 8 to Week 24 regardless of status on- or off-treatment in the intent to prescribe fenofibrate stratum. The usual care here corresponds to fenofibrate.
  • Percent Change From Baseline in LDL-C Particle Number at Week 24: Overall ITT Analysis [ Time Frame: From Baseline to Week 24 ]
    LDL-C particle number was calculated from lipid subfractions by nuclear magnetic resonance (NMR) spectroscopy. Adjusted LS means and standard errors at Week 24 from MMRM model including all available post-baseline data from Week 8 to Week 24 regardless of status on- or off-treatment.
  • Percent Change From Baseline in LDL-C Particle Number at Week 24: ITT- Intent to Prescribe Fenofibrate Stratum [ Time Frame: From Baseline to Week 24 ]
    LDL-C particle number was calculated from lipid subfractions by NMR spectroscopy. Adjusted LS means and standard errors at Week 24 from MMRM model including all available post-baseline data from Week 8 to Week 24 regardless of status on- or off-treatment in the intent to prescribe fenofibrate stratum. The usual care here corresponds to fenofibrate.
  • Absolute Change From Baseline in Hemoglobin A1c (HbA1c) at Week 12 and 24 : Overall ITT Analysis [ Time Frame: Baseline, Week 12 and 24 ]
    Absolute change = HbA1c value at specified week minus HbA1c value at baseline.
  • Absolute Change From Baseline in Fasting Plasma Glucose (FPG) at Week 12 and 24 : Overall ITT Analysis [ Time Frame: Baseline, Week 12 and 24 ]
    Absolute change = FPG value at specified week minus FPG value at baseline.
  • Absolute Change From Baseline in Number of Glucose-Lowering Treatments at Week 12 and 24 : Overall ITT Analysis [ Time Frame: Baseline, Week 12 and 24 ]
    Glucose lowering treatment was calculated for non-insulin treatments as one for each unique treatment received and for insulin treatment as one in total for all participants who have taken one or more treatments. Absolute change = number of glucose-lowering treatments at specified week minus baseline value.
Original Secondary Outcome Measures  ICMJE
 (submitted: December 24, 2015)
  • Percent change in measured LDL-C [ Time Frame: From Baseline to Week 24 ]
  • Percent change in non-HDL-C [ Time Frame: From baseline to Week 12 ]
  • Percent change in measured LDL-C [ Time Frame: From baseline to Week 12 ]
  • Percent change in Apo B [ Time Frame: From Baseline to Week 24 ]
  • Percent change in Total-C [ Time Frame: From Baseline to Week 24 ]
  • Percent change in Lp(a) [ Time Frame: From baseline to Week 24 ]
  • Percent change in TG [ Time Frame: From Baseline to Week 24 ]
  • Percent change in HDL-C [ Time Frame: From Baseline to Week 24 ]
  • Percent change in LDL-C particle number [ Time Frame: From Baseline to Week 24 ]
  • Number of patients with adverse events [ Time Frame: From baseline to Week 32 ]
Current Other Pre-specified Outcome Measures Not Provided
Original Other Pre-specified Outcome Measures Not Provided
 
Descriptive Information
Brief Title  ICMJE Efficacy and Safety of Alirocumab Versus Usual Care on Top of Maximally Tolerated Statin Therapy in Patients With Type 2 Diabetes and Mixed Dyslipidemia (ODYSSEY DM-Dyslipidemia)
Official Title  ICMJE A Randomized, Open-Label, Parallel Group Study to Evaluate the Efficacy and Safety of Alirocumab Versus Usual Care in Patients With Type 2 Diabetes and Mixed Dyslipidemia at High Cardiovascular Risk With Non-HDL-C Not Adequately Controlled With Maximally Tolerated Statin Therapy
Brief Summary

Primary Objective:

To demonstrate the superiority of alirocumab in comparison with usual care in the reduction of non-high-density lipoprotein cholesterol (non-HDL-C) in participants with type 2 diabetes and mixed dyslipidemia at high cardiovascular risk with non-HDL-C not adequately controlled with maximally tolerated statin therapy.

Secondary Objectives:

  • To demonstrate whether alirocumab is superior in comparison with usual care in its effects on other lipid parameters (ie, low-density lipoprotein cholesterol (LDL-C), apolipoprotein B (Apo B), total cholesterol (Total -C), lipoprotein a (Lp[a]), high-density lipoprotein cholesterol (HDL-C), triglycerides (TGs), triglyceride rich lipoproteins (TGRLs), apolipoprotein A-1 (Apo A-1), apolipoprotein C-III (Apo C-III), lipid subfractions by nuclear magnetic resonance (NMR) spectroscopy (ie, LDL-C particle size and LDL, very low-density lipoprotein [VLDL], HDL, and intermediate-density lipoprotein [IDL] particle number).
  • To assess changes in glycemic parameters with alirocumab vs. usual care treatment.
  • To demonstrate the safety and tolerability of alirocumab.
  • To evaluate treatment acceptance of alirocumab.
  • To evaluate proprotein convertase subtilisin kexin type 9 (PCSK9) concentrations and antibody development.
  • To demonstrate the superiority of alirocumab vs. fenofibrate on non-HDL-C and other lipid parameters (subgroup analysis).
Detailed Description

The maximum study duration was approximately 9 months per participant, including a 6 month treatment period, a screening period of up to 3 weeks, and an 8 week safety observation period.

For the purpose of scientific communication, a first-step analysis (both efficacy and safety) was performed at the Week 24 cut-off date. A second-step analysis was performed once all participants had completed the study to include a final update of the safety analysis.

Study Type  ICMJE Interventional
Study Phase  ICMJE Phase 4
Study Design  ICMJE Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Condition  ICMJE Dyslipidemia
Intervention  ICMJE
  • Drug: Alirocumab
    Solution for injection, one subcutaneous injection in the abdomen, thigh, or outer area of upper arm with a disposable auto-injector.
    Other Names:
    • SAR236553
    • REGN727
    • Praluent
  • Drug: Statins
    Statins at stable dose without other LMT as clinically indicated.
  • Drug: Ezetimibe
    Pharmaceutical form: tablet Route of administration: oral
  • Drug: Fenofibrate
    Pharmaceutical form: tablet Route of administration: oral
  • Drug: Nicotinic acid
    Pharmaceutical form: tablet Route of administration: oral
  • Drug: Omega-3 fatty acids
    Pharmaceutical form: tablet Route of administration: oral
  • Drug: Antihyperglycemic Drug
    Insulin (injectable or inhaled) or other antihyperglycemic drugs as clinically indicated.
Study Arms  ICMJE
  • Experimental: Alirocumab 75 mg Q2W/Up to 150 mg Q2W
    Alirocumab 75 mg subcutaneous (SC) injection every 2 weeks (Q2W) added to insulin or other antihyperglycemic drugs, stable maximally tolerated dose of statin therapy without other lipid modifying therapy (LMT) for 24 weeks. Alirocumab dose up-titrated to 150 mg Q2W from Week 12 when non-high-density lipoprotein cholesterol (non-HDL-C) levels >=100 mg/dL (2.59 mmol/L) at Week 8.
    Interventions:
    • Drug: Alirocumab
    • Drug: Statins
    • Drug: Antihyperglycemic Drug
  • Active Comparator: Usual Care
    Participants on usual care continued on insulin or other antihyperglycemic drugs, stable maximally tolerated dose of statin therapy without additional LMT or with either ezetimibe, fenofibrate, omega-3 fatty acids or nicotinic acid as per Investigator's judgment for 24 weeks.
    Interventions:
    • Drug: Statins
    • Drug: Ezetimibe
    • Drug: Fenofibrate
    • Drug: Nicotinic acid
    • Drug: Omega-3 fatty acids
    • Drug: Antihyperglycemic Drug
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: November 17, 2016)
413
Original Estimated Enrollment  ICMJE
 (submitted: December 24, 2015)
420
Actual Study Completion Date  ICMJE May 15, 2017
Actual Primary Completion Date March 22, 2017   (Final data collection date for primary outcome measure)
Eligibility Criteria  ICMJE

Inclusion criteria:

  • Participants with type 2 diabetes and mixed dyslipidemia whose non-HDL-C was not adequately controlled with a stable, maximum dose/regimen of statin that was tolerated by the participant.
  • 18 years of age or more.
  • Documented history of atherosclerotic cardiovascular disease (ASCVD) or at least one additional cardiovascular risk factor.
  • Non-HDL-C of 100 mg/dL or greater.
  • Triglycerides greater than or equal to 150 mg/dL and less than 500 mg/dL.
  • Stable anti-hyperglycemic agents for at least 3 months prior to the screening visit and between screening and randomization (including stable insulin dose defined as no variation more than 30% in daily insulin dose within the preceding 3 months, as judged by the Investigator).
  • No change in weight of more than 5 kg within the prior 3 months.
  • On stable dose of medications that are known to influence weight and/or lipids within the last 3 months.

Exclusion criteria:

  • Use of any lipid modifying therapies other than statins within the last 4 weeks (eg, ezetimibe, fenofibrate, nicotinic acid, omega-3 fatty acids, etc.) or use of over the counter products/nutraceuticals known to impact lipids (eg, red yeast rice) within the last 4 weeks.
  • Currently drinking more than 2 standard alcoholic drinks per day.
  • Body Mass Index (BMI) >45 kg/m² or currently enrolled in a weight loss program and still in active phase of weight loss.
  • Glycosylated hemoglobin (HbA1c) 9% or greater.

The above information was not intended to contain all considerations relevant to a participant's potential participation in a 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 Australia,   Brazil,   Finland,   Germany,   Israel,   Italy,   Kuwait,   Lebanon,   Norway,   Sweden,   Switzerland,   Turkey,   United Arab Emirates,   United Kingdom,   United States
Removed Location Countries  
 
Administrative Information
NCT Number  ICMJE NCT02642159
Other Study ID Numbers  ICMJE LPS14354
2015-001934-19 ( EudraCT Number )
U1111-1172-5262 ( Other Identifier: UTN )
Has Data Monitoring Committee No
U.S. FDA-regulated Product Not Provided
IPD Sharing Statement  ICMJE Not Provided
Responsible Party Sanofi
Study Sponsor  ICMJE Sanofi
Collaborators  ICMJE Regeneron Pharmaceuticals
Investigators  ICMJE
Study Director: Clinical Sciences & Operations Sanofi
PRS Account Sanofi
Verification Date March 2018

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