Safety, Tolerability and Efficacy of Evolocumab (AMG 145) in Children With Inherited Elevated Low-density Lipoprotein Cholesterol (Familial Hypercholesterolemia) (HAUSER-OLE)

Open-label, Single-Arm, Multicenter Study to Evaluate the Safety, Tolerability and Efficacy of Evolocumab for LDL-C Reduction, as Add-on to Diet and Lipid-lowering Therapy, in Pediatric Subjects From 10 to 17 Years of Age With Heterozygous Familial Hypercholesterolemia (HeFH) or Homozygous Familial Hypercholesterolemia (HoFH)

The main purpose of this study is to describe the safety and tolerability of 80 weeks of subcutaneous (SC) evolocumab when added to standard of care in children 10 to 17 years of age with familial hypercholesterolemia.

Study Overview

• Status: Completed
• Conditions: Familial Hypercholesterolemia
• Intervention / Treatment: Biological: Evolocumab

• Study Type: Interventional
• Enrollment (Actual): 163
• Phase: Phase 3

Contacts and Locations

Study Locations

• Australia
  • New South Wales
    • Camperdown, New South Wales, Australia, 2050
      • Research Site
• Austria
  • Feldkirch, Austria, 6800
    • Research Site
  • Salzburg, Austria, 5020
    • Research Site
  • Wien, Austria, 1090
    • Research Site
• Belgium
  • Gent, Belgium, 9000
    • Research Site
  • La Louvière, Belgium, 7100
    • Research Site
  • Leuven, Belgium, 3000
    • Research Site
• Brazil
  • São Paulo, Brazil, 05403-000
    • Research Site
  • São Paulo, Brazil, 04040-000
    • Research Site
  • Ceará
    • Fortaleza, Ceará, Brazil, 60430-270
      • Research Site
  • Distrito Federal
    • Brasília, Distrito Federal, Brazil, 71625-175
      • Research Site
• Canada
  • Quebec, Canada, G1V 4W2
    • Research Site
  • Quebec
    • Chicoutimi, Quebec, Canada, G7H 5H6
      • Research Site
    • Chicoutimi, Quebec, Canada, G7H 7K9
      • Research Site
• Colombia
  • Atlántico
    • Barranquilla, Atlántico, Colombia, 080020
      • Research Site
  • Santander
    • Bucaramanga, Santander, Colombia, 81004
      • Research Site
• Czechia
  • Svitavy, Czechia, 568 25
    • Research Site
• Greece
  • Athens, Greece, 17674
    • Research Site
  • Thessaloniki, Greece, 54642
    • Research Site
• Hungary
  • Budapest, Hungary, 1094
    • Research Site
• Italy
  • Palermo, Italy, 90127
    • Research Site
  • Pisa, Italy, 56124
    • Research Site
  • Roma, Italy, 00161
    • Research Site
  • Roma, Italy, 00165
    • Research Site
  • Torino, Italy, 10126
    • Research Site
• Malaysia
  • Kelantan
    • Kota Bharu, Kelantan, Malaysia, 16150
      • Research Site
• Netherlands
  • Amsterdam, Netherlands, 1066 EC
    • Research Site
• Norway
  • Bergen, Norway, 5021
    • Research Site
  • Oslo, Norway, 0586
    • Research Site
• Poland
  • Gdansk, Poland, 80-952
    • Research Site
• Portugal
  • Guimaraes, Portugal, 4835-044
    • Research Site
• Russian Federation
  • Saint Petersburg, Russian Federation, 191025
    • Research Site
• Slovenia
  • Ljubljana, Slovenia, 1000
    • Research Site
• South Africa
  • Gauteng
    • Parktown, Gauteng, South Africa, 2193
      • Research Site
  • Western Cape
    • Parow, Western Cape, South Africa, 7505
      • Research Site
• Spain
  • Andalucía
    • Cordoba, Andalucía, Spain, 14004
      • Research Site
  • Galicia
    • A Coruña, Galicia, Spain, 15001
      • Research Site
    • Lugo, Galicia, Spain, 27003
      • Research Site
• Switzerland
  • Geneva 14, Switzerland, 1211
    • Research Site
  • Reinach, Switzerland, 4153
    • Research Site
• Turkey
  • Ankara, Turkey, 06500
    • Research Site
  • Izmir, Turkey, 35100
    • Research Site
• United Kingdom
  • Birmingham, United Kingdom, B4 6NH
    • Research Site
• United States
  • New York
    • Bronx, New York, United States, 10467
      • Research Site
  • Ohio
    • Cincinnati, Ohio, United States, 45227
      • Research Site
  • Tennessee
    • Nashville, Tennessee, United States, 37212
      • Research Site

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 10 years to 17 years (Child)
• Accepts Healthy Volunteers: No

Description

Inclusion Criteria:

Heterozygous Familial Hypercholesterolemia (HeFH):

-Completed Study 20120123 (NCT02392559) while still on assigned investigational product and did not experience a treatment-related serious adverse event

Homozygous Familial Hypercholesterolemia (HoFH):

• Male or female, ≥ 10 to ≤ 17 years of age at time of enrollment
• Diagnosis of HoFH
• On a low-fat diet and receiving background lipid-lowering therapy
• Lipid-lowering therapy unchanged for ≥ 4 weeks prior to LDL-C screening; fibrates must be stable for at least 6 weeks prior to screening.
• Fasting LDL-C at screening ≥ 130 mg/dL (3.4 mmol/L)
• Fasting triglycerides ≤ 400 mg/dL (4.5 mmol/L)

Exclusion Criteria:

-Currently receiving treatment in another investigational device or drug study, or less than 30 days since ending treatment on another investigational device or drug study(s); except Study 20120123

HoFH:

• Moderate to severe renal dysfunction
• Active liver disease or hepatic dysfunction,
• Creatine kinase > 3 times the upper limit of normal (ULN) at screening

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: N/A
• Interventional Model: Single Group Assignment
• Masking: None (Open Label)

Number of Arms

1

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Evolocumab; Participants receive 420 mg evolocumab administered by subcutaneous injection every 4 weeks (QM) for up to 80 weeks.	Biological: Evolocumab; Administered by subcutaneous injection; Other Names: AMG 145; Repatha®

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Number of Participants With Treatment-emergent Adverse Events (TEAEs)	An adverse event is defined as any untoward medical occurrence in a clinical trial participant, not necessarily having a causal relationship with study treatment. A serious AE is as an AE that met at least 1 of the following criteria: fatal;; life threatening;; required in-patient hospitalization or prolongation of existing hospitalization;; resulted in persistent or significant disability/incapacity;; congenital anomaly/birth defect;; other medically important serious event. AEs were graded for severity using the National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events (CTCAE) version 4.0: Grade 1: Mild; asymptomatic or mild symptoms; Grade 2: Moderate; minimal, local or noninvasive intervention indicated; Grade 3: Severe or medically significant but not immediately life-threatening; hospitalization or prolongation of hospitalization indicated; Grade 4: Life-threatening consequences; urgent intervention indicated; Grade 5: Death related to AE.	From first dose of evolocumab in this study up to and including 30 days after the last dose or up to the end of study date, whichever was earlier; up to 80 weeks.

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Percent Change From Baseline to Week 80 in Low-density Lipoprotein Cholesterol (LDL-C) in HeFH Participants	For HeFH participants baseline was defined as the baseline value of the parent study 20120123.	Baseline and week 80
Percent Change From Baseline to Week 80 in Low-density Lipoprotein Cholesterol (LDL-C) in HoFH Participants	For HoFH participants baseline was defined as the baseline value in this study (20120124).	Baseline and week 80
Percent Change From Baseline to Week 80 in Non-HDL-C in HeFH Participants	For HeFH participants baseline was defined as the baseline value of the parent study 20120123.	Baseline and week 80
Percent Change From Baseline to Week 80 in Non-HDL-C in HoFH Participants	For HoFH participants baseline was defined as the baseline value in this study (20120124).	Baseline and week 80
Percent Change From Baseline to Week 80 in Apolipoprotein B in HeFH Participants	For HeFH participants baseline was defined as the baseline value in the parent study 20120123.	Baseline and week 80
Percent Change From Baseline to Week 80 in Apolipoprotein B in HoFH Participants	For HoFH participants baseline was defined as the baseline value in this study (20120124).	Baseline and week 80
Percent Change From Baseline to Week 80 in Total Cholesterol/HDL-C Ratio in HeFH Participants	For HeFH participants baseline was defined as the baseline value in the parent study 20120123.	Baseline and week 80
Percent Change From Baseline to Week 80 in Total Cholesterol/HDL-C Ratio in HoFH Participants	For HoFH participants baseline was defined as the baseline value in this study (20120124).	Baseline and week 80
Percent Change From Baseline to Week 80 in Apolipoprotein B / Apolipoprotein A1 Ratio in HeFH Participants	For HeFH participants baseline was defined as the baseline value in the parent study 20120123.	Baseline and week 80
Percent Change From Baseline to Week 80 in Apolipoprotein B/Apolipoprotein A1 Ratio in HoFH Participants	For HoFH participants baseline was defined as the baseline value in this study (20120124).	Baseline and week 80
Change From Baseline to Week 80 in LDL-C in HeFH Participants	For HeFH participants baseline was defined as the baseline value of the parent study 20120123.	Baseline and week 80
Change From Baseline to Week 80 in LDL-C in HoFH Participants	For HoFH participants baseline was defined as the baseline value in this study (20120124).	Baseline and week 80
Change From Baseline to Week 80 in Estradiol Levels	For HeFH participants baseline was defined as the baseline value in the parent study 20120123. For HoFH participants baseline was defined as the baseline value in this study (20120124).	Baseline and week 80
Change From Baseline to Week 80 in Testosterone Levels	For HeFH participants baseline was defined as the baseline value in the parent study 20120123. For HoFH participants baseline was defined as the baseline value in this study (20120124).	Baseline and week 80
Change From Baseline to Week 80 in Follicle Stimulating Hormone (FSH) Levels	For HeFH participants baseline was defined as the baseline value in the parent study 20120123. For HoFH participants baseline was defined as the baseline value in this study (20120124).	Baseline and week 80
Change From Baseline to Week 80 in Luteinizing Hormone (LH) Levels	For HeFH participants baseline was defined as the baseline value in the parent study 20120123. For HoFH participants baseline was defined as the baseline value in this study (20120124).	Baseline and week 80
Change From Baseline to Week 80 in Adenocorticotropic Hormone (ACTH) Levels	For HeFH participants baseline was defined as the baseline value in the parent study 20120123. For HoFH participants baseline was defined as the baseline value in this study (20120124).	Baseline and week 80
Change From Baseline to Week 80 in Dehydroepiandrosterone Sulfate (DHEA-S) Levels	For HeFH participants baseline was defined as the baseline value in the parent study 20120123. For HoFH participants baseline was defined as the baseline value in this study (20120124).	Baseline and week 80
Change From Baseline to Week 80 in Cortisol Levels	For HeFH participants baseline was defined as the baseline value in the parent study 20120123. For HoFH participants baseline was defined as the baseline value in this study (20120124).	Baseline and week 80
Number of Participants With Liver Function Test Abnormalities at Week 80	Liver function tests included alanine aminotransferase (ALT) levels, aspartate aminotransferase (AST) levels and total bilirubin levels.	Week 80
Number of Participants With Abnormalities in Levels of Creatine Kinase (CK) at Week 80	The number of participants with levels of creatine kinase greater than 5 times the upper limit of normal (ULN) and greater than 10 times the ULN, measured by the central laboratory.	Week 80
Change From Baseline to Week 80 in Carotid Intima-media Thickness (cIMT)	Carotid intima-media thickness measures the thickness of the intima and media, the inner two layers of the carotid artery, and is used to determine the extent of plaque buildup in the walls of the arteries (atherosclerosis) supplying blood to the head. CIMT was measured by ultrasonography and analyzed at a core laboratory. The largest values measured in the left common carotid artery (LCCA) and the right common carotid artery (RCCA) are averaged in this analysis.	Baseline and week 80
Change From Baseline in Height at Weeks 24, 48, and 80		Baseline and weeks 24, 48, and 80
Change From Baseline in Weight at Weeks 24, 48, and 80		Baseline and weeks 24, 48, and 80
Number of Participants With Change in Tanner Staging From Baseline to Week 80	Pubertal growth and sexual maturity was assessed separately for males and females using the 5 Tanner stages where stage 1 = prepubertal and stage 5 = mature. The number of participants with any change in Tanner Stage from baseline is reported.	Baseline and week 80

Collaborators and Investigators

• Sponsor: Amgen
• Investigators: Study Director: MD, Amgen

Publications and helpful links

General Publications

• Santos RD, Ruzza A, Hovingh GK, Stefanutti C, Mach F, Descamps OS, Bergeron J, Wang B, Bartuli A, Buonuomo PS, Greber-Platzer S, Luirink I, Bhatia AK, Raal FJ, Kastelein JJP, Wiegman A, Gaudet D. Paediatric patients with heterozygous familial hypercholesterolaemia treated with evolocumab for 80 weeks (HAUSER-OLE): a single-arm, multicentre, open-label extension of HAUSER-RCT. Lancet Diabetes Endocrinol. 2022 Oct;10(10):732-740. doi: 10.1016/S2213-8587(22)00221-2. Epub 2022 Sep 5.
• Santos RD, Ruzza A, Wang B, Maruff P, Schembri A, Bhatia AK, Mach F, Bergeron J, Gaudet I, St Pierre J, Kastelein JJP, Kees Hovingh G, Wiegman A, Gaudet D, Raal FJ. Evolocumab in paediatric heterozygous familial hypercholesterolaemia: cognitive function during 80 weeks of open-label extension treatment. Eur J Prev Cardiol. 2023 Oct 19:zwad332. doi: 10.1093/eurjpc/zwad332. Online ahead of print.

Helpful Links

• AmgenTrials clinical trials website

Study record dates

Study Major Dates

• Study Start (Actual): September 10, 2016
• Primary Completion (Actual): June 1, 2021
• Study Completion (Actual): June 1, 2021

Study Registration Dates

• First Submitted: October 22, 2015
• First Submitted That Met QC Criteria: December 4, 2015
• First Posted (Estimated): December 9, 2015

Study Record Updates

• Last Update Posted (Actual): February 21, 2024
• Last Update Submitted That Met QC Criteria: February 15, 2024
• Last Verified: February 1, 2024

More Information

Terms related to this study

• Keywords: Elevated Cholesterol; Pediatric; Hypercholesterolemia; High Cholesterol; Paediatric; Heterozygous Familial Hypercholesterolemia; Homozygous Familial Hypercholesterolemia; Repatha; evolocumab; PCSK9 mutations; Severe Familial Hypercholesterolemia
• Additional Relevant MeSH Terms: Metabolic Diseases; Genetic Diseases, Inborn; Metabolism, Inborn Errors; Lipid Metabolism Disorders; Hyperlipidemias; Dyslipidemias; Lipid Metabolism, Inborn Errors; Hyperlipoproteinemias; Hypercholesterolemia; Hyperlipoproteinemia Type II; Homozygous Familial Hypercholesterolemia; Molecular Mechanisms of Pharmacological Action; Enzyme Inhibitors; Antimetabolites; Protease Inhibitors; Anticholesteremic Agents; Hypolipidemic Agents; Lipid Regulating Agents; Serine Proteinase Inhibitors; PCSK9 Inhibitors; Evolocumab
• Other Study ID Numbers: 20120124; 2015-002276-25 (EudraCT Number)

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: YES
• IPD Plan Description: De-identified individual patient data for variables necessary to address the specific research question in an approved data sharing request
• IPD Sharing Time Frame: Data sharing requests relating to this study will be considered beginning 18 months after the study has ended and either 1) the product and indication (or other new use) have been granted marketing authorization in both the US and Europe or 2) clinical development for the product and/or indication discontinues and the data will not be submitted to regulatory authorities. There is no end date for eligibility to submit a data sharing request for this study.
• IPD Sharing Access Criteria: Qualified researchers may submit a request containing the research objectives, the Amgen product(s) and Amgen study/studies in scope, endpoints/outcomes of interest, statistical analysis plan, data requirements, publication plan, and qualifications of the researcher(s). In general, Amgen does not grant external requests for individual patient data for the purpose of re-evaluating safety and efficacy issues already addressed in the product labelling. Requests are reviewed by a committee of internal advisors, and if not approved, may be further arbitrated by a Data Sharing Independent Review Panel. Upon approval, information necessary to address the research question will be provided under the terms of a data sharing agreement. This may include anonymized individual patient data and/or available supporting documents, containing fragments of analysis code where provided in analysis specifications. Further details are available at the link below.
• IPD Sharing Supporting Information Type: STUDY_PROTOCOL; SAP; ICF; CSR