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

Homozygous Familial Hypercholesterolemia Clinical Trial

Official title:

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

Clinical Trial Details — Status: Completed

Administrative data

• NCT number: NCT04233918
• Other study ID #: R1500-CL-17100
• Secondary ID: 2019-001931-30
• Status: Completed
• Phase: Phase 3
• Start date: June 29, 2020
• Est. completion date: May 30, 2023

Study information

• Verified date: June 2023
• Source: Regeneron Pharmaceuticals
• Contact: n/a
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial Summary

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

Description:

Part A is Phase 1b Part B is Phase 3

Recruitment information / eligibility

• Status: Completed
• Enrollment: 20
• Est. completion date: May 30, 2023
• Est. primary completion date: January 31, 2022
• Accepts healthy volunteers: No
• Gender: All
• Age group: 5 Years to 11 Years

Eligibility

Key Inclusion Criteria:

1. Diagnosis of functional HoFH by either genetic or clinical criteria as defined in the protocol

2. LDL-C >130 mg/dL at the screening visit

3. Body weight =15 kg

4. Receiving stable maximally tolerated therapy*at the screening visit *Maximally tolerated therapy could include a daily statin.

5. Willing and able to comply with clinic visits and study-related procedures

6. 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:

1. 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

2. For patients entering Part A, unable to temporarily discontinue apheresis from the baseline visit through the week 4 visit

3. 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).

4. Plasmapheresis within 8 weeks of the screening visit, or plans to undergo plasmapheresis during Part A or Part B

5. Presence of any clinically significant uncontrolled endocrine disease known to influence serum lipids or lipoproteins

6. 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

Related Conditions & MeSH terms

• Homozygous Familial Hypercholesterolemia
• Hypercholesterolemia
• Hyperlipoproteinemia Type II

Intervention

Drug:
• Evinacumab
Part A: Single IV dose Part B & C: IV dose Q4W

Locations

Country	Name	City	State
Australia	Regeneron Research Center	Westmead	New South Wales
Austria	Regeneron Research Site	Vienna
Netherlands	Regeneron Research Site	Amsterdam
Taiwan	Regeneron Research Center	Taipei
Ukraine	Regeneron Research Site	Kyiv
United States	Regeneron Research Site	Boca Raton	Florida
United States	Regeneron Research Center	Boston	Massachusetts
United States	Regeneron Research Site	Kansas City	Kansas
United States	Regeneron Research Center	Philadelphia	Pennsylvania
United States	Regeneron Research Center	Salt Lake City	Utah
United States	Regeneron Research Site	Wilmington	Delaware

Sponsors (1)

Lead Sponsor	Collaborator
Regeneron Pharmaceuticals

Countries where clinical trial is conducted

United States,  Australia,  Austria,  Netherlands,  Taiwan,  Ukraine, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	Part A: Maximum Observed Serum Concentration (Cmax) of Evinacumab	Cmax was obtained directly from the plasma concentration versus time curve.	At day 12
Primary	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
Primary	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
Primary	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	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
Secondary	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
Secondary	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
Secondary	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
Secondary	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
Secondary	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
Secondary	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
Secondary	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
Secondary	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
Secondary	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
Secondary	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
Secondary	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
Secondary	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