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Efficacy and Safety of Alirocumab Versus Placebo on Top of Maximally Tolerated Lipid Lowering Therapy in Patients With Hypercholesterolemia Who Have Type 1 or Type 2 Diabetes and Are Treated With Insulin (ODYSSEY DM - Insulin)

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ClinicalTrials.gov Identifier: NCT02585778
Recruitment Status : Completed
First Posted : October 23, 2015
Results First Posted : May 17, 2018
Last Update Posted : May 17, 2018
Sponsor:
Collaborator:
Regeneron Pharmaceuticals
Information provided by (Responsible Party):
Sanofi

Brief Summary:

Primary Objectives:

  • To demonstrate the superiority of alirocumab in comparison with placebo in the reduction of calculated low-density lipoprotein cholesterol (LDL-C) in participants with diabetes treated with insulin and with hypercholesterolemia at high cardiovascular risk not adequately controlled on maximally tolerated LDL-C lowering therapy.
  • To evaluate the safety and tolerability of alirocumab in participants with diabetes treated with insulin.

Secondary Objective:

To demonstrate that alirocumab was superior in comparison to placebo in its effects on other lipid parameters (i.e., measured LDL-C, non-high-density lipoprotein cholesterol [non-HDL-C], apolipoprotein B [Apo B], total cholesterol [TC], lipoprotein a [Lp(a)], high density lipoprotein cholesterol [HDL-C], triglyceride [TG] levels, triglyceride rich lipoproteins [TGRL], apolipoprotein A-1 [Apo A-1], apolipoprotein C-III [Apo C-III], and LDL particle number and size).


Condition or disease Intervention/treatment Phase
Hypercholesterolaemia Drug: Alirocumab Drug: Placebo Drug: Lipid-Modifying Therapy (LMT) Drug: Antihyperglycemic Drug Phase 3

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.

Study Type : Interventional  (Clinical Trial)
Actual Enrollment : 517 participants
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Double (Participant, Investigator)
Primary Purpose: Treatment
Official Title: A Randomized, Double-Blind, Placebo-Controlled, Parallel Group Study to Evaluate the Efficacy and Safety of Alirocumab in Insulin Treated Patients With Type 1 or Type 2 Diabetes and With Hypercholesterolemia at High Cardiovascular Risk Not Adequately Controlled on Maximally Tolerated LDL-C Lowering Therapy
Actual Study Start Date : October 23, 2015
Actual Primary Completion Date : April 3, 2017
Actual Study Completion Date : April 3, 2017

Resource links provided by the National Library of Medicine


Arm Intervention/treatment
Experimental: Alirocumab 75 mg Q2W/Up to 150 mg Q2W
Alirocumab 75 mg subcutaneous (SC) injection every 2 weeks (Q2W) added to stable, maximally tolerated dose of statin therapy with or without other lipid-modifying therapy (LMT), insulin alone or with other antihyperglycemic drugs for 24 weeks. Alirocumab dose up-titrated to 150 mg Q2W from Week 12 when LDL-C levels ≥70 mg/dL (1.81 mmol/L) at Week 8.
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:
  • Praluent
  • SAR236553
  • REGN727

Drug: Lipid-Modifying Therapy (LMT)
Statins at stable, maximally tolerated dose with or without other LMT as clinically indicated.

Drug: Antihyperglycemic Drug
Insulin (injectable or inhaled) alone or with other antihyperglycemic drugs as clinically indicated.

Placebo Comparator: Placebo Q2W
Placebo (for alirocumab) SC injection Q2W added to stable, maximally tolerated dose of statin therapy with or without other LMT, insulin alone or with other antihyperglycemic drugs for 24 weeks.
Drug: Placebo
Solution for injection, one subcutaneous injection in the abdomen, thigh, or outer area of upper arm with a disposable auto-injector.

Drug: Lipid-Modifying Therapy (LMT)
Statins at stable, maximally tolerated dose with or without other LMT as clinically indicated.

Drug: Antihyperglycemic Drug
Insulin (injectable or inhaled) alone or with other antihyperglycemic drugs as clinically indicated.




Primary Outcome Measures :
  1. Percent Change From Baseline in Calculated LDL-C at Week 24 - 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 4 to Week 24 regardless of status on- or off-treatment were used in the model (ITT analysis).

  2. Percentage of Participants Who Experienced Treatment-Emergent Adverse Events (AEs) [ Time Frame: From Baseline up to 10 weeks after last study drug administration (maximum of 32 weeks) ]
    Reported adverse events are treatment-emergent adverse events that is AEs that developed/worsened during the 'treatment-emergent period' (the time from the first dose of study drug up to the last dose of study drug +70 days).


Secondary Outcome Measures :
  1. Percent Change From Baseline in Calculated LDL-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).

  2. Percent Change From Baseline in Measured LDL-C at Week 24 - 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 4 to Week 24 regardless of status on- or off-treatment.

  3. Percent Change From Baseline in Calculated LDL-C at Week 12 - ITT Analysis [ Time Frame: From Baseline to Week 24 ]
    Adjusted LS means and standard errors at Week 12 from MMRM model including available post-baseline data from Week 4 to Week 24 regardless of status on- or off-treatment.

  4. Percent Change From Baseline in Measured LDL-C at Week 12 - 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 4 to Week 24 regardless of status on- or off-treatment.

  5. 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.

  6. Percent Change From Baseline in Apolipoprotein B (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.

  7. 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.

  8. 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 from multiple imputation approach model including available post-baseline data from Week 4 to Week 24 (i.e. up to 21 days after last injection).

  9. Percentage of Participants Reaching Calculated LDL-C <50 mg/dL (1.3 mmol/L) at Week 24 - On-Treatment Analysis [ Time Frame: Up to Week 24 ]
    Adjusted percentages at Week 24 from last observation carried forward (LOCF) approach (for T1DM participants) and multiple imputation approach model (for T2DM participants) including available post-baseline data from Week 4 to Week 24 (i.e. up to 21 days after last injection). The maximum likelihood estimate did not exist as response rate was zero in a treatment group of T1DM participants.

  10. Percentage of Participants Reaching Calculated Non-HDL-C <100 mg/dL at Week 24 - On-Treatment Analysis [ Time Frame: Up to Week 24 ]
    Adjusted percentages at Week 24 from multiple imputation approach model including available post-baseline data from Week 4 to Week 24 (i.e. up to 21 days after last injection).

  11. Percentage of Participants Reaching Calculated Non-HDL-C <80 mg/dL at Week 24 - On-Treatment Analysis [ Time Frame: Up to Week 24 ]
    Adjusted percentages at Week 24 from multiple imputation approach including available post-baseline on-treatment data from Week 4 to Week 24 (i.e. up to 21 days after last injection).

  12. Percent Change From Baseline in Lipoprotein(a) at Week 24 - ITT Analysis [ Time Frame: From Baseline to Week 24 ]
    Adjusted means and standard errors at Week 24 were obtained from multiple imputation approach for handling of missing data followed by robust regression model. All available post-baseline data from Week 4 to Week 24 regardless of status on- or off-treatment were included in the imputation model.

  13. 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.

  14. Percent Change From Baseline in Fasting Triglycerides at Week 24 - ITT Analysis [ Time Frame: From Baseline to Week 24 ]
    Adjusted means and standard errors at Week 24 from multiple imputation approach for handling of missing data followed by robust regression model including all available post-baseline data from Week 4 to Week 24 regardless of status on- or off-treatment.

  15. Percent Change From Baseline in LDL-C Particle Number at Week 24 - 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 4 to Week 24 regardless of status on- or off-treatment.

  16. Percent Change From Baseline in LDL-C Particle Size at Week 24 - ITT Analysis [ Time Frame: From Baseline to Week 24 ]
    LDL-C particle size was calculated from lipid subfractions by NMR spectroscopy. Adjusted LS means and standard errors at Week 24 from MMRM model including available post-baseline data from Week 4 to Week 24 regardless of status on- or off-treatment.

  17. Absolute Change From Baseline in Glycosylated Hemoglobin (HbA1c) at Weeks 12 and 24 - ITT Analysis [ Time Frame: Baseline, Weeks 12 and 24 ]
    Absolute change = HbA1c value at specified weeks minus HbA1c value at baseline.

  18. Absolute Change From Baseline in HbA1c at Weeks 12 and 24 - On-Treatment Analysis [ Time Frame: Baseline, Weeks 12 and 24 ]
    Absolute change = HbA1c value at specified weeks minus HbA1c value at baseline.

  19. Absolute Change From Baseline in Fasting Plasma Glucose (FPG) at Weeks 12 and 24 - ITT Analysis [ Time Frame: Baseline, Weeks 12 and 24 ]
    Absolute change = FPG value at specified weeks minus FPG value at baseline.

  20. Absolute Change From Baseline in FPG at Weeks 12 and 24 - On-Treatment Analysis [ Time Frame: Baseline, Weeks 12 and 24 ]
    Absolute change = FPG value at specified weeks minus FPG value at baseline.

  21. Absolute Change From Baseline in Total Daily Insulin Dose at Weeks 12 and 24 - ITT Analysis [ Time Frame: Baseline, Weeks 12 and 24 ]
    Absolute change = total daily insulin dose at specified weeks minus baseline value.

  22. Absolute Change From Baseline in Total Daily Insulin Dose at Weeks 12 and 24 - On-Treatment Analysis [ Time Frame: Baseline, Weeks 12 and 24 ]
    Absolute change = total daily insulin dose at specified weeks minus baseline value.

  23. Absolute Change From Baseline in Insulin Daily Dose/Kg at Weeks 12 and 24 - ITT Analysis [ Time Frame: Baseline, Weeks 12 and 24 ]
    Absolute change = daily insulin dose/kg at specified weeks minus baseline value.

  24. Absolute Change From Baseline in Insulin Daily Dose/Kg at Weeks 12 and 24 - On-Treatment Analysis [ Time Frame: Baseline, Weeks 12 and 24 ]
    Absolute change = daily insulin dose/kg at specified weeks minus baseline value.

  25. Absolute Change From Baseline in Number of Glucose-Lowering Treatments at Weeks 12 and 24 - ITT Analysis [ Time Frame: Baseline, Weeks 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 weeks minus baseline value.

  26. Absolute Change From Baseline in Number of Glucose-Lowering Treatments at Weeks 12 and 24 - On-Treatment Analysis [ Time Frame: Baseline, Weeks 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 weeks minus baseline value.



Information from the National Library of Medicine

Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the contacts provided below. For general information, Learn About Clinical Studies.


Ages Eligible for Study:   18 Years and older   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
Criteria

Inclusion criteria:

  • Participants diagnosed with Type 1 or Type 2 diabetes at least one year prior to the screening visit (Week -3).
  • Signed written informed consent
  • Participants with type 1 or type 2 diabetes treated with insulin whose LDL-C levels were not adequately controlled with maximally tolerated lipid-modifying therapy
  • LDL-C of 70 mg/dL or greater
  • 18 years of age or more
  • Glycosylated hemoglobin (HbA1c) less than 10%
  • History of cardiovascular disease (including coronary heart disease [CHD] and/or CHD risk equivalents) and/or at least one additional cardiovascular risk factor

Exclusion criteria:

  • Not on a stable dose of statin or other lipid modifying therapy for at least 4 weeks prior to screening or from screening to randomization, unless statin intolerant
  • Triglycerides >400 mg/dL
  • Estimated glomerular filtration rate (eGFR) <15 mL/min/1.73 m² according to the Modification of Diet in Renal Disease (MDRD) equation
  • Currently received or planned to receive renal replacement therapy (for example, hemodialysis)
  • Change in weight of more than 5 kilograms within the prior 2 months
  • Not on a stable dose/regimen of insulin or other antidiabetic drugs for the past 3 months or planned to intensify insulin regimen during the study
  • Not treated with insulin for at least 6 months
  • Planned to start new lipid modifying therapy or change dose of current lipid modifying therapy during the study
  • Body mass index (BMI) >45 kg/m² or planned to undergo bariatric surgery, weight loss program, or initiate weight loss drugs during the study
  • History of recent decompensation of diabetes within the prior 2 months (for example, diabetic ketoacidosis)

The above information was not intended to contain all considerations relevant to a participant's potential participation in a clinical trial.


Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT02585778


  Show 110 Study Locations
Sponsors and Collaborators
Sanofi
Regeneron Pharmaceuticals
Investigators
Study Director: Clinical Sciences & Operations Sanofi
  Study Documents (Full-Text)

Documents provided by Sanofi:
Study Protocol  [PDF] July 8, 2015
Statistical Analysis Plan  [PDF] March 6, 2017


Publications automatically indexed to this study by ClinicalTrials.gov Identifier (NCT Number):
Responsible Party: Sanofi
ClinicalTrials.gov Identifier: NCT02585778     History of Changes
Other Study ID Numbers: LPS14355
2015-000799-92 ( EudraCT Number )
U1111-1172-4772 ( Other Identifier: UTN )
First Posted: October 23, 2015    Key Record Dates
Results First Posted: May 17, 2018
Last Update Posted: May 17, 2018
Last Verified: April 2018

Additional relevant MeSH terms:
Hypercholesterolemia
Hyperlipidemias
Dyslipidemias
Lipid Metabolism Disorders
Metabolic Diseases
Insulin, Globin Zinc
Insulin
Hypoglycemic Agents
Antibodies, Monoclonal
Physiological Effects of Drugs
Immunologic Factors