Safety, Tolerability, and Effect of Alirocumab in High Cardiovascular Risk Patients With Severe Hypercholesterolemia Not Adequately Controlled With Conventional Lipid-modifying Therapies (ODYSSEY APPRISE)

Study Overview
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Brief Summary
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Primary Objective: To provide participants with severe hypercholesterolemia at risk for subsequent cardiovascular (CV) events and not adequately controlled with currently available lipid-modifying therapy (LMT) access to alirocumab ahead of commercial availability and to document the overall safety and tolerability of alirocumab in this participant population. Secondary Objectives: To document the effect of alirocumab on low-density lipoprotein cholesterol (LDL-C) levels as well as non-high-density lipoprotein cholesterol (non-HDL-C), total cholesterol (total-C), high-density lipoprotein cholesterol (HDL-C), and triglyceride (TG) levels after 12 weeks of treatment. To document participant's acceptability of self-injection (Self Injection Assessment Questionnaire, SIAQ).

Detailed Description
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The study duration included a screening period of up to 3 weeks, a treatment period of a minimum of 12 weeks and up to a maximum of 120 weeks (30 months), and at least 2 weeks after the last study treatment injection.

Official Title
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A Multi-country, Multicenter, Single-arm, Open-label Study to Document the Safety, Tolerability and Effect of Alirocumab on Atherogenic Lipoproteins in High Cardio-vascular Risk Patients With Severe Hypercholesterolemia Not Adequately Controlled With Conventional Lipid-modifying Therapies

Conditions
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Hypercholesterolemia

Intervention / Treatment
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* Drug: ALIROCUMAB SAR236553 (REGN727)
* Drug: placebo (for injection training only)
* Drug: ezetimibe
* Drug: atorvastatin
* Drug: rosuvastatin
* Drug: simvastatin


Participation Criteria
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Eligibility Criteria
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Inclusion criteria: Either A, B, C, D, or E below and not adequately controlled with a maximally tolerated dose of statin with or without other LMTs, all at stable doses for at least 4 weeks prior to the screening visit (Week-3): A. Participants suffering from heterozygous familial hypercholesterolemia (heFH) with LDL-C concentrations greater than or equal to (>=)160 mg/dL (4.14 millimoles per liter [mmol/L]) despite treatment. B. Participants suffering from heFH with LDL-C concentrations >=130 mg/dL (3.36 mmol/L) despite treatment and two or more CV risk factors among this list: LDL-C greater than (>) 250 milligrams per deciliter (mg/dL) (6.46 mmol/L) at the time of the familial hypercholesterolemia (FH) diagnosis (before treatment). Family history of premature-onset coronary heart disease (CHD; first-degree male relative with onset before age 55 years; first-degree female relative with onset before age 65 years). Metabolic syndrome. HDL-C less than (<) 40 mg/dL (1.03 mmol/L). Hypertension (blood pressure >140/90 mmHg or drug treatment). Lipoprotein a (Lp[a]) >=50 mg/dL (1.78 µmol/L). Tendon xanthoma. C. Participants suffering from heFH with LDL-C concentrations >=130 mg/dL (3.36 mmol/L) despite treatment and one of the following characteristics: Established CHD or other cardiovascular disease (CVD; history of acute myocardial infarction, ischemic stroke, peripheral arterial disease, coronary or peripheral arterial revascularization, stable or unstable angina, transient ischemic attack, carotid artery stenosis >=50 percent (%), or aortic abdominal aneurysm). Drug-treated type 2 diabetes mellitus or type 1 with target organ damage. Family history of first- or second-degree relative with very premature onset CHD (first- or second-degree male relative with onset before age 45; first- or second-degree female relative with onset before age 55). D. Non-FH participants suffering from established CHD or other CVD (history of acute myocardial infarction (MI), ischemic stroke, peripheral arterial disease, coronary or peripheral arterial revascularization, stable or unstable angina, transient ischemic attack, carotid artery stenosis >=50%, or aortic abdominal aneurysm) and with LDL-C concentrations >=130 mg/dL (3.36 mmol/L). E. Participants suffering from progressive CVD (coronary artery disease, or peripheral arterial occlusive disease or cerebrovascular disease as documented clinically or by imaging techniques, with a subsequent CV event [acute MI, ischemic stroke, ischemia-driven revascularization, unstable angina, transient ischemic attack] occurring despite stable doses of maximally tolerated LMT) with LDL-C concentrations >=100 mg/dL (2.59 mmol/L). Exclusion criteria: Not on a stable dose of LMT (including statin) for at least 4 weeks prior to the screening visit (Week -3) and from screening to enrollment. Use of a fibrate other than fenofibrate within 4 weeks of the screening visit (Week-3) or between screening and enrollment. Daily doses above atorvastatin 80 mg, rosuvastatin 40 mg, or simvastatin 40 mg (except for participants on simvastatin 80 mg for more than one year, who were eligible). Use of statin other than simvastatin, atorvastatin, or rosuvastatin prior to the screening visit (Week-3) or between screening and enrollment, except when there was a documented reason for intolerance to the above mentioned potent statins (in which case the use of a different statin was allowed). Fasting serum TG >400 mg/dL (>4.52 mmol/L) at the screening visit (Week -3). Uncontrolled hypertension (>180 mmHg systolic and/or >110 mmHg diastolic at randomization visit). New York Heart Association Class III or IV congestive heart failure persisting despite treatment. History of hemorrhagic stroke. Liver transaminases >3 times the upper limit of normal. Laboratory evidence of current hepatitis B or C infection. Creatine kinase >3 times the upper limit of normal. Estimated glomerular filtration rate <30 mL/min/1.73 m^2. Pregnant or breastfeeding woman or with childbearing potential without appropriate contraception. Male participant with a female partner of childbearing potential not protected by a highly-effective method(s) of birth control. Participants eligible for enrollment into an ongoing clinical study of alirocumab conducted at the same investigational site. Hypersensitivity to alirocumab or any of the excipients. 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
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Alirocumab<br>Participants received Alirocumab 150 milligram (mg) subcutaneously (SC) once every two weeks (Q2W) or 75 mg SC Q2W added to stable LMT up to a maximum of 120 weeks. Alirocumab dose was either up-titrated from 75 to 150 mg Q2W or down-titrated from 150 to 75 mg Q2W, based on Investigator judgment and treatment response. | Drug: ALIROCUMAB SAR236553 (REGN727)<br>* Pharmaceutical form:solution Route of administration: subcutaneous<br>* Other names: Praluent®;Drug: placebo (for injection training only)<br>* Pharmaceutical form:solution Route of administration: subcutaneous<br>Drug: ezetimibe<br>* Pharmaceutical form:capsule Route of administration: oral<br>Drug: atorvastatin<br>* Pharmaceutical form:tablet Route of administration: oral<br>Drug: rosuvastatin<br>* Pharmaceutical form:tablet Route of administration: oral<br>Drug: simvastatin<br>* Pharmaceutical form:tablet Route of administration: oral<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Percentage of Participants With Treatment Emergent Adverse Events (TEAEs) | Adverse Event (AE) was defined as any untoward medical occurrence in a participant or clinical investigation participant administered a pharmaceutical product and which does not necessarily have to have a causal relationship with this treatment. Treatment-emergent AEs (TEAEs) were defined as AEs that that developed or worsened or became serious during the TEAE period (time from the first injection of study drug up to the day of the last injection of study drug + 14 days). A Serious Adverse Event (SAE) was any untoward medical occurrence that at any dose: resulted in death, was life-threatening, required inpatient hospitalization or prolongation of existing hospitalization, resulted in persistent or significant disability/incapacity, was a congenital anomaly/birth defect, was a medically important event. | From first injection of investigational medicinal product (IMP) up to 2 weeks after last dose of study drug (Week 120) | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Percent Change From Baseline in Calculated Low Density Lipoprotein Cholesterol (LDL-C) at Week 12 | Calculated LDL-C values were obtained using the Friedewald formula. Calculated LDL-C in mg/dL from Friedewald formula (LDL cholesterol = Total cholesterol - HDL cholesterol - [Triglyceride/5]). Baseline value was defined as the last observation before the first dose of the treatment. | Baseline, Week 12 | 
| Percentage of Participants Reaching Calculated LDL-C <100 mg/dL (2.59 mmol/L) at Week 12 | LDL-Cholesterol was calculated using the Friedewald formula. Percentage of participants who reached calculated LDL-C <100 mg/dL (2.59 mmol/L) at week 12 were reported. | At Week 12 | 
| Percentage of Participants Reaching Calculated LDL-C <70 mg/dL (1.81 mmol/L) at Week 12 | LDL-Cholesterol was calculated using the Friedewald formula. Percentage of participants who reached calculated LDL-C <70 mg/dL (1.81 mmol/L) at week 12 were reported. | At Week 12 | 
| Percentage of Participants Reaching Calculated LDL-C <70 mg/dL (1.81 mmol/L) and/or >=50% Reduction From Baseline in LDL-C at Week 12 | LDL-Cholesterol was calculated using the Friedewald formula. Percentage of participants who reached LDL-C <70 mg/dL at Week 12 and/or >=50% reduction from baseline in LDL-C at Week 12 are reported. | At Week 12 | 
| Percent Change From Baseline in Non-High Density Lipoprotein Cholesterol (Non-HDL-C) at Week 12 | Baseline value was defined as the last observation before the first dose of the treatment. | Baseline, Week 12 | 
| Percent Change From Baseline in Total Cholesterol (Total-C) at Week 12 | Baseline value was defined as the last observation before the first dose of the treatment. | Baseline, Week 12 | 
| Percent Change From Baseline in High Density Lipoprotein Cholesterol at Week 12 | Baseline value was defined as the last observation before the first dose of the treatment. | Baseline, Week 12 | 
| Percent Change From Baseline in Triglycerides at Week 12 | Baseline value was defined as the last observation before the first dose of the treatment. | Baseline, Week 12 | 
| Assessment of Participant's Acceptability of Self-Injection Using Self Injection Assessment Questionnaire (SIAQ): Feeling About Injections, Self Confidence, Satisfaction With Self-Injections | Pre-SIAQ: self-completed before first self-injection & Post-SIAQ: self-completed after self-injection. Pre-SIAQ consisted of 7 items grouped into 3 domains:feelings about injections,self-confidence & satisfaction with self-injection. Post-SIAQ consisted of 21 items grouped into 6 domains:feelings about injections,self-image,self-confidence,injection-site reactions,ease of use & satisfaction with self-injection. Participants rated each item on 5-point (or 6-point) semantic Likert-type scale, where lower numbers indicate a worse experience. Item scores were transformed to obtain a score ranging from 0 (worst experience) to 10 (best experience). Transformed scores for items contributing to a domain were then averaged into a domain score. Each domain score ranges from 0 (worst experience) to 10 (best experience), higher score=better acceptability. Domain scores common to the Pre & Post SIAQ were analyzed on participants belonging to Pre & Post-SIAQ population and are reported. | Baseline (Pre-SIAQ), Week 4, Week 8, Week 12, Week 24, Week 48, Week 72, Week 96 | 
| Assessment of Participant's Acceptability of Self-Injection Using Self Injection Assessment Questionnaire (SIAQ): Self Image, Injection-Site Reactions, Ease of Use | SIAQ: contained 2 modules: Pre-SIAQ and Post-SIAQ. Post-SIAQ: self-completed after self-injection. Post-SIAQ consisted of 21 items grouped into 6 domains: feelings about injections, self-image, self-confidence, injection-site reactions, ease of use & satisfaction with self-injection. Participants rated each item on 5-point (or 6-point) semantic Likert-type scale, where lower numbers indicated a worse experience. Item scores were transformed to obtain a score ranging from 0 (worst experience) to 10 (best experience) for each item. Transformed scores for items contributing to a domain were then averaged into a domain score. Each domain score ranges from 0 (worst experience) to 10 (best experience), higher score=better acceptability. Domain scores which are not in common with Pre-SIAQ were analyzed on the Post-SIAQ population and are reported here. | Week 4, Week 8, Week 12, Week 24, Week 48, Week 72, Week 96 |