Efficacy and Safety Evaluation of Alirocumab in Patients With Heterozygous Familial Hypercholesterolemia or High Cardiovascular Risk Patients With Hypercholesterolemia on Lipid Modifying Therapy (ODYSSEY JAPAN)

Study Overview
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Brief Summary
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Primary Objective: To demonstrate the reduction of low-density lipoprotein cholesterol (LDL-C) by alirocumab as add-on therapy to stable daily statin therapy with or without other lipid modifying therapy in comparison with placebo after 24 weeks of treatment in heterozygous familial hypercholesterolemia (HeFH) or high cardiovascular risk participants with hypercholesterolemia. Secondary Objectives: To evaluate the effect of alirocumab in comparison with placebo on LDL-C after 12 weeks of treatment. To evaluate the effect of alirocumab on other lipid parameters. To evaluate the long-term effect of alirocumab in comparison with placebo on LDL-C after 52 weeks of treatment. To evaluate the safety and tolerability of alirocumab. To evaluate the development of anti-alirocumab antibodies. To evaluate the pharmacokinetics of alirocumab.

Detailed Description
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Total duration per participant of approximately 63 weeks (14 months) (screening: 3 weeks, double-blind treatment period: 52 weeks, and follow-up period: 8 weeks).

Official Title
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A Randomized, Double-blind, Placebo-controlled, Parallel Group, Multicenter Study to Evaluate the Efficacy and Safety of Alirocumab in Heterozygous Familial Hypercholesterolemia or High Cardiovascular Risk Patients With Hypercholesterolemia Not Adequately Controlled With Their Lipid Modifying Therapy

Conditions
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Hypercholesterolemia

Intervention / Treatment
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* Drug: Placebo (for alirocumab)
* Drug: Alirocumab
* Drug: Lipid-Modifying Therapy (LMT)


Participation Criteria
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Eligibility Criteria
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Inclusion criteria: Participants with heterozygous familial hypercholesterolemia or non-familial hypercholesterolemia who were not adequately controlled with a stable daily dose of statin with or without other lipid modifying therapy, at stable dose prior to the screening visit (Week -3). Exclusion criteria: LDL-C <100 mg/dL (<2.59 mmol/L) at the screening visit in participants with heterozygous familial hypercholesterolemia or in participants with non-familial hypercholesterolemia who had a history of documented coronary heart disease as described in Japan Atherosclerosis Society (JAS) Guidelines for Prevention of Atherosclerotic Cardiovascular Diseases 2012. LDL-C <120 mg/dL (<3.10 mmol/L) at the screening visit in participants with non-familial hypercholesterolemia who had a history of documented diseases or other risk factors as categorized in primary prevention category III as described in JAS Guidelines for Prevention of Atherosclerotic Cardiovascular Diseases 2012. Not on a stable daily dose of lipid modifying therapy (including statin) within 4 weeks prior to the screening visit or between screening and randomization visits. Age <20 years at the screening visit. The above information is not intended to contain all considerations relevant to a participants' potential participation in a clinical trial.

Ages Eligible for Study
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Minimum Age: 20 Years
Maximum Age: 80 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: Quadruple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Placebo Comparator: Placebo Q2W<br>Placebo (for alirocumab) every two weeks (Q2W) added to stable lipid-modifying therapy (LMT). | Drug: Placebo (for alirocumab)<br>* Solution for injection, one subcutaneous injection in the abdomen, thigh, or outer area of upper arm with an auto-injector.<br>Drug: Lipid-Modifying Therapy (LMT)<br>* Statin (pravastatin, simvastatin, fluvastatin, atorvastatin, pitavastatin, rosuvastatin) at stable dose with or without other LMT as clinically indicated.<br>|
| Experimental: Alirocumab 75 mg/Up to 150 mg Q2W<br>Alirocumab 75 mg Q2W added to stable LMT for 52 weeks. Alirocumab dose up-titrated to 150 mg from Week 12 when LDL-C levels above pre-specified threshold at Week 8 as defined in Japan Atherosclerosis Society (JAS) Guidelines for Prevention of Atherosclerotic Cardiovascular Diseases 2012 i.e. ≥100 mg/dL (2.59 mmol/L) in heFH participants or in non-familial hypercholesterolemia (non-FH) participants who had a history of documented coronary heart disease (CHD) ≥120 mg/dL (3.10 mmol/L) in non-FH participants who had a history of documented diseases or other risk factors as categorized in primary prevention category III | Drug: Alirocumab<br>* Solution for injection, one subcutaneous injection in the abdomen, thigh, or outer area of upper arm with an auto-injector.<br>* Other names: Praluent;Drug: Lipid-Modifying Therapy (LMT)<br>* Statin (pravastatin, simvastatin, fluvastatin, atorvastatin, pitavastatin, rosuvastatin) at stable dose with or without other LMT 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 Calculated LDL-C at Week 24 - 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 4 to Week 24 regardless of status on- or off-treatment were used in the model (ITT analysis). | From Baseline to Week 24 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Percent Change From Baseline in Calculated LDL-C at Week 24 - On-Treatment Analysis | 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) (on-treatment analysis). | From Baseline to Week 24 | 
| Percent Change From Baseline in Calculated LDL-C at Week 12 - ITT Analysis | 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. | From Baseline to Week 24 | 
| Percent Change From Baseline in Calculated LDL-C at Week 12 - On-treatment Analysis | Adjusted LS means and standard errors at Week 12 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). | From Baseline to Week 24 | 
| Percent Change From Baseline in Apolipoprotein (Apo) B at Week 24 - ITT Analysis | 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. | From baseline to Week 24 | 
| Percent Change From Baseline in Apo B at Week 24 - On-Treatment Analysis | 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). | From Baseline to Week 24 | 
| Percent Change From Baseline in Non-High Density Lipoprotein Cholesterol (Non-HDL-C) at Week 24 - ITT Analysis | 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. | From Baseline to Week 24 | 
| Percent Change From Baseline in Non-HDL-C at Week 24 - On-Treatment Analysis | Adjusted LS means and standard errors at Week 24 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). | From Baseline to Week 24 | 
| Percent Change From Baseline in Total Cholesterol (Total-C) at Week 24 - ITT Analysis | 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. | From Baseline to Week 24 | 
| Percent Change From Baseline in Apo B at Week 12 - ITT Analysis | 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. | From Baseline to Week 24 | 
| Percent Change From Baseline in Non-HDL-C at Week 12 - ITT Analysis | 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. | From Baseline to Week 24 | 
| Percent Change From Baseline in Total-C at Week 12 - ITT Analysis | 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. | From Baseline to Week 24 | 
| Percentage of Participants Reaching Calculated LDL-C Goal at Week 24 - ITT Analysis | Calculated LDL-C goal was defined as: <100 mg/dL (2.59 mmol/L) for heFH or non-FH participants who had a history of documented congestive heart disease (CHD), or <120 mg/dL (3.10 mmol/L) for non-FH participants who had a history of documented diseases (ischemic stroke, peripheral artery disease, chronic kidney disease or diabetes) or other risk factors as defined in JAS Guidelines for Prevention of Atherosclerotic Cardiovascular Diseases 2012. Adjusted percentages at Week 24 were obtained from 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 imputation model. | Up to Week 24 | 
| Percentage of Participants Reaching Calculated LDL-C Goal at Week 24 - On-Treatment Analysis | Adjusted percentages at Week 24 were from 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). | Up to Week 24 | 
| Percent Change From Baseline in Lipoprotein (a) at Week 24 - ITT Analysis | Adjusted means and standard errors at Week 24 from a multiple imputation approach followed by robust regression 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. | From Baseline to Week 24 | 
| Percent Change From Baseline in Fasting Triglycerides at Week 24 - 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 4 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 Analysis | 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. | From Baseline to Week 24 | 
| Percent Change From Baseline in Apo A1 at Week 24 - ITT Analysis | 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. | From Baseline to Week 24 | 
| Percent Change From Baseline in Lipoprotein (a) at Week 12 - ITT Analysis | Adjusted means and standard errors at Week 12 from multiple imputation approach followed by robust regression model including all available post-baseline data from Week 4 to Week 24 regardless of status on-or off-treatment. | From Baseline to Week 24 | 
| Percent Change From Baseline in Fasting Triglycerides at Week 12 - ITT Analysis | Adjusted means and standard errors at Week 12 from multiple imputation approach followed by robust regression model including all available post-baseline data from Week 4 to Week 24 regardless of status on-or off-treatment. | From Baseline to Week 24 | 
| Percent Change From Baseline in HDL-C at Week 12 - ITT Analysis | 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. | From Baseline to Week 24 | 
| Percent Change From Baseline in Apo A1 at Week 12 - ITT Analysis | 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. | From Baseline to Week 24 |