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)

Study Overview
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Brief Summary
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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
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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.

Official Title
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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

Conditions
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Dyslipidemia

Intervention / Treatment
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* Drug: Alirocumab
* Drug: Statins
* Drug: Ezetimibe
* Drug: Fenofibrate
* Drug: Nicotinic acid
* Drug: Omega-3 fatty acids
* Drug: Antihyperglycemic Drug


Participation Criteria
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Eligibility Criteria
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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.

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Alirocumab 75 mg Q2W/Up to 150 mg Q2W<br>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. | Drug: Alirocumab<br>* Solution for injection, one subcutaneous injection in the abdomen, thigh, or outer area of upper arm with a disposable auto-injector.<br>* Other names: Praluent;Drug: Statins<br>* Statins at stable dose without other LMT as clinically indicated.<br>Drug: Antihyperglycemic Drug<br>* Insulin (injectable or inhaled) or other antihyperglycemic drugs as clinically indicated.<br>|
| Active Comparator: Usual Care<br>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. | Drug: Statins<br>* Statins at stable dose without other LMT as clinically indicated.<br>Drug: Ezetimibe<br>* Pharmaceutical form: tablet Route of administration: oral<br>Drug: Fenofibrate<br>* Pharmaceutical form: tablet Route of administration: oral<br>Drug: Nicotinic acid<br>* Pharmaceutical form: tablet Route of administration: oral<br>Drug: Omega-3 fatty acids<br>* Pharmaceutical form: tablet Route of administration: oral<br>Drug: Antihyperglycemic Drug<br>* Insulin (injectable or inhaled) or other antihyperglycemic drugs as clinically indicated.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Percent Change From Baseline in Non-HDL-C at Week 24: Overall Intent-to-treat (ITT) Analysis | 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). | From Baseline to Week 24 | 
| Percent Change From Baseline in Non-HDL-C at Week 24: ITT- Intent to Prescribe Fenofibrate Stratum | 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. | From Baseline to Week 24 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Percent Change From Baseline in Measured Low-Density Lipoprotein Cholesterol (LDL-C) at Week 24: Overall ITT Analysis | 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. | From Baseline to Week 24 | 
| Percent Change From Baseline in Measured LDL-C at Week 24: ITT- Intent to Prescribe Fenofibrate Stratum | 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. | From Baseline to Week 24 | 
| Percent Change From Baseline in Non-HDL-C at Week 12: Overall ITT Analysis | 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. | From Baseline to Week 24 | 
| Percent Change From Baseline in Non-HDL-C at Week 12: ITT- Intent to Prescribe Fenofibrate Stratum | 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. | From Baseline to Week 24 | 
| Percent Change From Baseline in Measured LDL-C at Week 12: Overall ITT Analysis | 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. | From Baseline to Week 24 | 
| Percent Change From Baseline in Measured LDL-C at Week 12: ITT- Intent to Prescribe Fenofibrate Stratum | 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. | From Baseline to Week 24 | 
| Percent Change From Baseline in Apolipoprotein B (Apo-B) at Week 24: Overall ITT Analysis | 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. | From Baseline to Week 24 | 
| Percent Change From Baseline in Apo B at Week 24: ITT- Intent to Prescribe Fenofibrate Stratum | 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. | From Baseline to Week 24 | 
| Percent Change From Baseline in Total Cholesterol (Total-C) at Week 24 : Overall ITT Analysis | 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. | From Baseline to Week 24 | 
| Percent Change From Baseline in Total-C at Week 24: ITT- Intent to Prescribe Fenofibrate Stratum | 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. | From Baseline to Week 24 | 
| Percent Change From Baseline in Lipoprotein(a) at Week 24 : Overall ITT Analysis | 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. | From Baseline to Week 24 | 
| Percent Change From Baseline in Lipoprotein(a) at Week 24: ITT- Intent to Prescribe Fenofibrate Stratum | 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. | From Baseline to Week 24 | 
| Percent Change From Baseline in Fasting Triglycerides at Week 24: Overall ITT Analysis | 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. | From Baseline to Week 24 | 
| Percent Change From Baseline in Fasting Triglycerides at Week 24: ITT- Intent to Prescribe Fenofibrate Stratum | 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. | From Baseline to Week 24 | 
| Percent Change From Baseline in HDL-C at Week 24 : Overall ITT Analysis | 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. | From Baseline to Week 24 | 
| Percent Change From Baseline in HDL-C at Week 24: ITT- Intent to Prescribe Fenofibrate Stratum | 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. | From Baseline to Week 24 | 
| Percent Change From Baseline in LDL-C Particle Number at Week 24: Overall ITT Analysis | 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. | From Baseline to Week 24 | 
| Percent Change From Baseline in LDL-C Particle Number at Week 24: ITT- Intent to Prescribe Fenofibrate Stratum | 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. | From Baseline to Week 24 | 
| Absolute Change From Baseline in Hemoglobin A1c (HbA1c) at Week 12 and 24 : Overall ITT Analysis | Absolute change = HbA1c value at specified week minus HbA1c value at baseline. | Baseline, Week 12 and 24 | 
| Absolute Change From Baseline in Fasting Plasma Glucose (FPG) at Week 12 and 24 : Overall ITT Analysis | Absolute change = FPG value at specified week minus FPG value at baseline. | Baseline, Week 12 and 24 | 
| Absolute Change From Baseline in Number of Glucose-Lowering Treatments at Week 12 and 24 : Overall ITT Analysis | 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. | Baseline, Week 12 and 24 |