Evaluate the Efficacy and Safety of Evinacumab in Pediatric Patients With Homozygous Familial Hypercholesterolemia

Study Overview
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Brief Summary
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The primary objective for Part A of the study is to assess the pharmacokinetics (PK) of evinacumab in pediatric patients with homozygous familial hypercholesterolemia (HoFH). The primary objective for Part B of the study is to demonstrate a reduction of low-density lipoprotein cholesterol (LDL-C) by evinacumab in pediatric (5 to 11 years of age) patients with HoFH. The secondary objective for Part A of the study is to evaluate the safety and tolerability of evinacumab administered intravenous (IV) in pediatric patients with HoFH. The secondary objectives for Part B of the study are: To evaluate the effect of evinacumab on other lipid parameters (ie, apolipoprotein B (Apo B), non-high-density lipoprotein cholesterol (non-HDL-C), total cholesterol (TC), lipoprotein a [Lp(a)]) in pediatric patients with HoFH To evaluate the safety and tolerability of evinacumab administered IV in pediatric patients with HoFH To assess the PK of evinacumab in pediatric patients with HoFH To assess the immunogenicity of evinacumab in pediatric patients with HoFH over time To evaluate patient efficacy by mutation status

Detailed Description
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Part A is Phase 1b Part B is Phase 3

Official Title
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A Three-Part, Single-Arm, Open-Label Study to Evaluate the Efficacy, Safety, and Pharmacokinetics of Evinacumab in Pediatric Patients With Homozygous Familial Hypercholesterolemia

Conditions
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Homozygous Familial Hypercholesterolemia

Intervention / Treatment
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* Drug: Evinacumab


Participation Criteria
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Eligibility Criteria
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Key Inclusion Criteria: Diagnosis of functional HoFH by either genetic or clinical criteria as defined in the protocol LDL-C >130 mg/dL at the screening visit Body weight ≥15 kg Receiving stable maximally tolerated therapy*at the screening visit *Maximally tolerated therapy could include a daily statin. Willing and able to comply with clinic visits and study-related procedures Parent(s) or legal guardian(s) must provide the signed informed consent form (ICF). Patients ≥5 years of age (or above age determined by the IRB/EC and in accordance with the local regulations and requirements) must also provide informed assent forms (IAFs) to enroll in the study, and sign and date a separate IAF or ICF signed by the parent(s)/legal guardian(s) (as appropriate based on local regulations and requirements) Key Exclusion Criteria: Background pharmacologic LMT, nutraceuticals or over-the-counter (OTC) therapies known to affect lipids, at a dose/regimen that has not been stable for at least 4 weeks (8 weeks for PCSK9 inhibitors) before the screening visit and patient is unwilling to enter the run-in period For patients entering Part A, unable to temporarily discontinue apheresis from the baseline visit through the week 4 visit Receiving lipid apheresis, a setting (if applicable) and schedule that has not been stable for approximately 8 weeks before the screening visit or an apheresis schedule that is not anticipated to be stable over the duration of the treatment period (48 weeks). Plasmapheresis within 8 weeks of the screening visit, or plans to undergo plasmapheresis during Part A or Part B Presence of any clinically significant uncontrolled endocrine disease known to influence serum lipids or lipoproteins Newly diagnosed (within 3 months prior to randomization visit) diabetes mellitus or poorly controlled diabetes as defined in the protocol Note: Other protocol-defined criteria apply

Ages Eligible for Study
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Minimum Age: 5 Years
Maximum Age: 11 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: Evinacumab<br>Part A: Single intravenous (IV) dose Part B: IV dose every 4 weeks (Q4W) until week 20 Part C: IV dose Q4W | Drug: Evinacumab<br>* Part A: Single IV dose Part B & C: IV dose Q4W<br>* Other names: Evkeeza™;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Part A: Maximum Observed Serum Concentration (Cmax) of Evinacumab | Cmax was obtained directly from the plasma concentration versus time curve. | At day 12 | 
| Part A: Area Under the Serum Concentration-Time Curve From Time Zero to the Time of the Last Measurable Concentration (AUClast) of Evinacumab | AUClast was defined as area under the serum concentration time-curve from zero to the last measured concentration. | Pre-dose at Week 0; End of infusion at Week 0.006, 1, 2, 4, 8 and 12 | 
| Part A: Terminal Half-Life (t1/2) of Evinacumab | T1/2 was defined as the time required for the plasma concentration of drug to decrease 50 percent in the final stage of its elimination. | Pre-dose at Week 0; End of infusion at Week 0.006, 1, 2, 4, 8 and 12 | 
| Part B: Percent Change in Calculated Low-Density Lipoprotein Cholesterol (LDL-C) From Baseline to Week 24 | Percent change was calculated as 100 multiplied by (calculated LDL-C value at Week 24 minus calculated LDL-C value at baseline) divided by calculated LDL-C value at baseline. | Baseline to Week 24 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Part A and Part B: Number of Participants With Treatment-Emergent Adverse Events (TEAEs) | Any untoward medical occurrence in a participant who received investigational medicinal product (IMP) was considered an AE without regard to possibility of causal relationship with this treatment. A serious adverse event (SAE) was defined as any untoward medical occurrence that resulted in any of the following outcomes: death, life-threatening, required initial or prolonged in-patient hospitalization, persistent or significant disability/incapacity, congenital anomaly/birth defect, or considered as medically important event. TEAE was defined as AE starting/worsening after first intake of study drug. TEAE included participants with both serious and non-serious AEs. | Part A: up to Week 24; Part B: up to Week 48 | 
| Part B: Percent Change in Apolipoprotein B (Apo B) From Baseline to Week 24 | Percent change in Apo B from baseline to Week 24 was reported. | Baseline to Week 24 | 
| Part B: Percent Change in Non-High-Density Lipoprotein Cholesterol (Non-HDL-C) From Baseline to Week 24 | Percent change in Non-HDL-C from baseline to Week 24 was reported. | Baseline to Week 24 | 
| Part B: Percent Change in Total Cholesterol (TC) From Baseline to Week 24 | Percent change in TC from baseline to Week 24 was reported. | Baseline to Week 24 | 
| Part B: Percentage of Participants With ≥50 Percent (%) Reduction in Calculated Low-Density Lipoprotein Cholesterol (LDL-C) at Week 24 | Percentage of participants who achieved reduction in calculated LDL-C ≥ 50% at Week 24 was reported. | Week 24 | 
| Part B: Percent Change in Calculated Low-Density Lipoprotein Cholesterol (LDL-C) From Baseline to Week 24 in Participants Who Have Negative/Negative and Null/Null Mutations | Participants with HoFH was classified based on the phenotype of the Low-density lipoprotein receptor (LDLR) mutation(s), ranging from defective mutations (where the LDLR retains some LDL-binding functionality) to null or negative mutations where no functioning LDLR was expressed. Participants who have LDLR activity <15% are considered null and participants whose LDLR activity was impaired but >15% are LDLR defective. Percent change in calculated LDL-C from baseline to Week 24 in participants who have negative/negative and null/null mutations was reported. | Baseline to Week 24 | 
| Part B: Percent Change in Lipoprotein A (Lp[a]) From Baseline to Week 24 | Percent change in Lp(a) from baseline to Week 24 was reported. | Baseline to Week 24 | 
| Part B: Absolute Change in Low-density Lipoprotein Cholesterol (LDL-C) From Baseline at Week 24 | Absolute change in LDL-C from baseline at Week 24 was reported | Baseline, Week 24 | 
| Part B: Serum Concentration of Total Evinacumab | Serum concentration of total evinacumab was reported. Pre-dose samples at week 0 were assayed and the reported value is based on actual measurement. | Pre-dose at Weeks 0, 4, 8, 12; End of infusion at Weeks 0.006, 4.006, 8.006, 12.006 and 24 | 
| Part B: Maximum Serum Concentration at Steady State (Cmax,ss) of Evinacumab | Maximum serum concentration (Cmax,ss) steady state following drug administration. | Post-dose on Days 1, 29, 57, 85 and 169 | 
| Part B: Area Under the Serum Concentration-time Curve at Steady State (AUCtau.ss) of Evinacumab | AUCtau.ss was defined as area under the serum concentration-time curve at steady state of evinacumab | Post-dose on Days 1, 29, 57, 85 and 169 | 
| Part B: Minimum Serum Concentration at Steady State (Ctrough.ss) of Evinacumab | Ctrough.ss was defined as minimum serum concentration at steady state of evinacumab | Post-dose on Days 1, 29, 57, 85 and 169 | 
| Part B: Percent Change in Calculated Low-Density Lipoprotein Cholesterol (LDL-C) From Baseline to Week 24 in Participants Who Have by Null/Null vs. Non-null/Null and Negative/Negative vs.Non-negative/Negative Mutations |  | Baseline to Week 24 | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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HoFH