An Efficacy and Safety Study of Alirocumab in Children and Adolescents With Homozygous Familial Hypercholesterolemia

Study Overview
=================
Brief Summary
-----------------
Primary Objective: To evaluate the efficacy of alirocumab (75 or 150 milligrams [mg] depending on body weight [BW]), administered every 2 weeks (Q2W), on low-density lipoprotein cholesterol (LDL-C) levels at Week 12 of treatment in children and adolescents with homozygous familial hypercholesterolemia (hoFH) of 8 to 17 years of age on top of background treatments. Secondary Objectives: To evaluate the efficacy of alirocumab after 24 and 48 weeks of treatment on LDL-C levels. To evaluate the effects of alirocumab on other lipid parameters (eg, apolipoprotein B [Apo B], non-high density lipoprotein cholesterol [non-HDL-C], total cholesterol [Total-C], high density lipoprotein cholesterol [HDL-C], lipoprotein a [Lp (a)], triglycerides [TG], apolipoprotein A-1 [Apo A-1] levels) after 12, 24, and 48 weeks of treatment. To evaluate the safety and tolerability of alirocumab up to 48 weeks of treatment.

Detailed Description
-----------------
The study duration was up to 62 weeks, which included (if needed) a run-in period of up to 4 weeks, a screening period of up to 2 weeks, a treatment period of up to 48 weeks, and a follow-up of 8 weeks.

Official Title
-----------------
An Open-Label Study to Evaluate the Efficacy and Safety of Alirocumab in Children and Adolescents With Homozygous Familial Hypercholesterolemia

Conditions
-----------------
Hypercholesterolemia

Intervention / Treatment
-----------------
* Drug: Alirocumab SAR236553 (REGN727)
* Drug: Atorvastatin
* Drug: Simvastatin
* Drug: Fluvastatin
* Drug: Pravastatin
* Drug: Lovastatin
* Drug: Rosuvastatin
* Drug: Ezetimibe
* Drug: Cholestyramine
* Drug: Nicotinic acid
* Drug: Fenofibrate
* Drug: Omega-3 fatty acids


Participation Criteria
=================
Eligibility Criteria
-----------------
Inclusion criteria : Participants genetically diagnosed with hoFH. Participants treated with optimal dose of statin +/- other lipid modifying therapies (LMTs), or non-statin LMTs if statin-intolerant at stable dose(s) for at least 4 weeks. A signed informed consent indicating parental permission with or without participants assent. For participants on apheresis, currently undergoing stable LDL apheresis therapy prior to the screening visit (Week -2) and had initiated apheresis treatment for at least 6 months. Exclusion criteria: Participants with LDL-C <130 milligram per deciliter [mg/dL] (3.37 millimoles per liter [mmol/L]) obtained during the screening period after the participant had been on stable apheresis procedure or LMT (i.e., stable optimal dose of statin ± other stable LMTs, or stable non statin LMTs in statin-intolerant participants) treatment for at least 4 weeks. Participants with BW <25 kg. Participants aged 8 to 9 years not at Tanner Stage 1 and participants aged of 10 to 17 years not at least at Tanner Stage 2 in their development. Participants with uncontrolled Type 1 or 2 diabetes mellitus. Participants with known uncontrolled thyroid disease. Participants with uncontrolled hypertension. Participants who will receive statin de novo during the run-in period. Fasting triglycerides greater than (>) 350 mg/dL (3.95 mmol/L) at the screening visit. Severe renal impairment (i.e., estimated glomerular filtration rate <30 milliliter per minute/1.73 meter square) at the screening visit. Alanine aminotransferase or aspartate aminotransferase >2 * upper limit of normal (ULN) at the screening visit. Creatine phosphokinase >3 * ULN at the screening visit. The above information was not intended to contain all considerations relevant to a participants potential participation in a clinical trial.

Ages Eligible for Study
-----------------
Minimum Age: 8 Years
Maximum Age: 17 Years

Sexes Eligible for Study
-----------------
All

Accepts Healthy Volunteers
-----------------
No

Study Plan
=================
How is the study designed?
-----------------

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 with BW less than (<) 50 kilograms (kg) received subcutaneous (SC) injection of alirocumab 75 mg Q2W for 48 weeks. Alirocumab dose was up-titrated to 150 mg Q2W from Week 12 in case of increase in BW with BW greater than or equal to [>=] 50 kg. Participants with BW >=50 kg received SC injection of alirocumab 150 mg Q2W for 48 weeks. | Drug: Alirocumab SAR236553 (REGN727)<br>* Pharmaceutical form: solution for injection in pre-filled syringe, Route of administration: subcutaneous (SC)<br>Drug: Atorvastatin<br>* Pharmaceutical form: tablet, Route of administration: oral<br>Drug: Simvastatin<br>* Pharmaceutical form: tablet, Route of administration: oral<br>Drug: Fluvastatin<br>* Pharmaceutical form: capsule, Route of administration: oral<br>Drug: Pravastatin<br>* Pharmaceutical form: tablet, Route of administration: oral<br>Drug: Lovastatin<br>* Pharmaceutical form: tablet, Route of administration: oral<br>Drug: Rosuvastatin<br>* Pharmaceutical form: tablet, Route of administration: oral<br>Drug: Ezetimibe<br>* Pharmaceutical form: tablet, Route of administration: oral<br>Drug: Cholestyramine<br>* Pharmaceutical form: oral suspension, Route of administration: oral<br>Drug: Nicotinic acid<br>* Pharmaceutical form: tablet, Route of administration: oral<br>Drug: Fenofibrate<br>* Pharmaceutical form: tablet, Route of administration: oral<br>Drug: Omega-3 fatty acids<br>* Pharmaceutical form: capsule, Route of administration: oral<br>|

What is the study measuring?
-----------------
Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Percent Change From Baseline in Low-Density Lipoprotein Cholesterol (LDL-C) at Week 12: Intent-to-Treat (ITT) Analysis | Adjusted least square (LS) means and standard errors were obtained from the mixed model analysis with repeated measures (MMRM) to account for missing data using all available post-baseline data from Week 4 to Week 48 regardless of status on- or off-treatment used in the model (ITT analysis). | Baseline to Week 12 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Percent Change From Baseline in Low-Density Lipoprotein Cholesterol at Week 12: On-treatment Analysis | Adjusted LS means and standard errors were obtained from the MMRM model to account for missing data using all available post-baseline on-treatment data from Week 4 to Week 48 (on-treatment Analysis). | Baseline to Week 12 | 
| Percent Change From Baseline in Low-Density Lipoprotein Cholesterol at Weeks 24 and 48: ITT Analysis/On-treatment Analysis | Adjusted LS means and standard errors were obtained from the MMRM model to account for missing data using all available post-baseline data from Week 4 to Week 48 regardless of status on- or off-treatment used in the model (ITT analysis). Although separate analyses of all available data (ITT analysis) and only data collected within a defined time window (On-treatment analysis) were planned, if all values used in the ITT approach were within the on-treatment time window, the on-treatment analysis would be identical to the ITT analysis, thus the results would be identical and a single outcome measure presenting the results for both types of analysis would be provided. | Baseline to Weeks 24 and 48 | 
| Percent Change From Baseline in Apolipoprotein (Apo) B at Weeks 12, 24 and 48: ITT Analysis/On-treatment Analysis | Adjusted LS means and standard errors were obtained from the MMRM model to account for missing data using all available post-baseline data from Week 4 to Week 48 regardless of status on- or off-treatment used in the model (ITT analysis). Although separate analyses of all available data (ITT analysis) and only data collected within a defined time window (On-treatment analysis) were planned, if all values used in the ITT approach were within the on-treatment time window, the on-treatment analysis would be identical to the ITT analysis, thus the results would be identical and a single outcome measure presenting the results for both types of analysis would be provided. | Baseline to Weeks 12, 24 and 48 | 
| Percent Change From Baseline in Non-High Density Lipoprotein Cholesterol (Non-HDL-C) at Weeks 12, 24 and 48 - ITT Analysis/On-treatment Analysis | Adjusted LS means and standard errors were obtained from the MMRM model to account for missing data using all available post-baseline data from Week 4 to Week 48 regardless of status on- or off-treatment used in the model (ITT analysis). Although separate analyses of all available data (ITT analysis) and only data collected within a defined time window (On-treatment analysis) were planned, if all values used in the ITT approach were within the on-treatment time window, the on-treatment analysis would be identical to the ITT analysis, thus the results would be identical and a single outcome measure presenting the results for both types of analysis would be provided. | Baseline to Weeks 12, 24 and 48 | 
| Percent Change From Baseline in Total Cholesterol (Total-C) at Weeks 12, 24 and 48: ITT Analysis/On-treatment Analysis | Adjusted LS means and standard errors were obtained from the MMRM model to account for missing data using all available post-baseline data from Weeks 4 to Week 48 regardless of status on- or off-treatment used in the model (ITT analysis). Although separate analyses of all available data (ITT analysis) and only data collected within a defined time window (On-treatment analysis) were planned, if all values used in the ITT approach were within the on-treatment time window, the on-treatment analysis would be identical to the ITT analysis, thus the results would be identical and a single outcome measure presenting the results for both types of analysis would be provided. | Baseline to Weeks 12, 24 and 48 | 
| Percent Change From Baseline in Lipoprotein a (Lp) (a) at Weeks 12, 24 and 48: ITT Analysis/On-treatment Analysis | Adjusted means and standard errors were obtained from a multiple imputation approach followed by a robust regression model including all available post-baseline data from Week 4 to Week 48 regardless of status on-or off-treatment used in the model (ITT analysis). Although separate analyses of all available data (ITT analysis) and only data collected within a defined time window (On-treatment analysis) were planned, if all values used in the ITT approach were within the on-treatment time window, the on-treatment analysis would be identical to the ITT analysis, thus the results would be identical and a single outcome measure presenting the results for both types of analysis would be provided. | Baseline to Weeks 12, 24 and 48 | 
| Percent Change From Baseline in High Density Lipoprotein Cholesterol (HDL-C) at Weeks 12, 24 and 48: ITT Analysis/On-treatment Analysis | Adjusted LS means and standard errors were obtained from the MMRM model to account for missing data using all available post-baseline data from Weeks 4 to Week 48 regardless of status on- or off-treatment used in the model (ITT analysis). Although separate analyses of all available data (ITT analysis) and only data collected within a defined time window (On-treatment analysis) were planned, if all values used in the ITT approach were within the on-treatment time window, the on-treatment analysis would be identical to the ITT analysis, thus the results would be identical and a single outcome measure presenting the results for both types of analysis would be provided. | Baseline to Weeks 12, 24 and 48 | 
| Percent Change From Baseline in Fasting Triglycerides (TG) at Weeks 12, 24 and 48: ITT Analysis/On-treatment Analysis | Adjusted means and standard errors were obtained from a multiple imputation approach followed by a robust regression model including all available post-baseline data from Week 4 to Week 48 regardless of status on- or off-treatment used in the model (ITT analysis). Although separate analyses of all available data (ITT analysis) and only data collected within a defined time window (On-treatment analysis) were planned, if all values used in the ITT approach were within the on-treatment time window, the on-treatment analysis would be identical to the ITT analysis, thus the results would be identical and a single outcome measure presenting the results for both types of analysis would be provided. | Baseline to Weeks 12, 24 and 48 | 
| Percent Change From Baseline in Apolipoprotein A1 (Apo A1) at Weeks 12, 24 and 48: ITT Analysis/On-treatment Analysis | Adjusted LS means and standard errors were obtained from the MMRM model to account for missing data using all available post-baseline data from Week 4 to 48 regardless of status on- or off-treatment used in the model (ITT analysis). Although separate analyses of all available data (ITT analysis) and only data collected within a defined time window (On-treatment analysis) were planned, if all values used in the ITT approach were within the on-treatment time window, the on-treatment analysis would be identical to the ITT analysis, thus the results would be identical and a single outcome measure presenting the results for both types of analysis would be provided. | Baseline to Weeks 12, 24 and 48 | 
| Percentage of Participants Reporting >=15 Percent (%) Reduction in LDL-C Level at Weeks 12, 24 and 48: ITT Analysis/On-treatment Analysis | Adjusted Percentage were obtained from a multiple imputation approach for handling of missing data including all available post-baseline data from Week 4 to Week 48 regardless of status on- or off-treatment used in the model (ITT analysis). Although separate analyses of all available data (ITT analysis) and only data collected within a defined time window (On-treatment analysis) were planned, if all values used in the ITT approach were within the on-treatment time window, the on-treatment analysis would be identical to the ITT analysis, thus the results would be identical and a single outcome measure presenting the results for both types of analysis would be provided. | Baseline to Weeks 12, 24 and 48 | 
| Absolute Change From Baseline in LDL-C Level at Weeks 12, 24 and 48: ITT Analysis/On-treatment Analysis | Adjusted LS means and standard errors were obtained from the MMRM model to account for missing data using all available post-baseline data from Week 4 to Week 48 regardless of status on- or off-treatment used in the model (ITT analysis). Although separate analyses of all available data (ITT analysis) and only data collected within a defined time window (On-treatment analysis) were planned, if all values used in the ITT approach were within the on-treatment time window, the on-treatment analysis would be identical to the ITT analysis, thus the results would be identical and a single outcome measure presenting the results for both types of analysis would be provided. | Baseline to Weeks 12, 24 and 48 | 
| Number of Participants With Tanner Staging at Baseline, Weeks 12, 24 and 48 | Tanner stage defines physical measurements of development in children and adolescent based on external primary and secondary sex characteristics. Participants were evaluated for pubic hair distribution, breast development (only females) and genital development (only males), and classified in 3 categories as: Prepubescent (defined as a person just before start of the development of adult sexual characteristics), Pubescent (defined as a person at or approaching the age of puberty), Postpubescent (sexually mature or a person who has completed puberty). | Baseline, Weeks 12, 24 and 48 | 

 Terms related to the study
=================
Keywords Provided by Centre Hospitalier Valida
-----------------
Pediatrics, Homozygous Familial Hypercholesterolemia, Alirocumab, PCSK9 inhibitor, Low-density Lipoprotein Cholesterol (LDL-C)