Efficacy and Safety of Lomitapide in Paediatric Patients With Homozygous Familial Hypercholesterolaemia (HoFH)

Phase III, Single Arm, Open Label, International, Multi Centre Study to Evaluate the Efficacy and Safety of Lomitapide in Paediatric Patients With Homozygous Familial Hypercholesterolaemia (HoFH) on Stable Lipid Lowering Therapy

This is a single arm, open label, multi centre phase III study to evaluate the efficacy and long term safety of lomitapide in paediatric patients with HoFH receiving stable lipid lowering therapy (LLT) (including lipoprotein apheresis (LA), when applicable) comprising of the following phases:

• Screening Period (starting at Week 12, i.e. ≤12 weeks prior to Baseline for up to 6 weeks)
• Stratified Enrolment and Start of Run in Period (starting at minimum at Week 6, i.e., 6 weeks prior to Baseline for a minimum of 6 weeks):
• Efficacy Phase (starting at Baseline, i.e. Day [D] 0 for 24 weeks±3 days
• Safety Phase (starting at Week 24±3 days for 80±1 weeks)

Study Overview

• Status: Completed
• Conditions: Homozygous Familial Hypercholesterolaemia (HoFH)
• Intervention / Treatment: Drug: Lomitapide

Detailed Description

Lomitapide has been approved for use in adult patients with HoFH in the European Union (EU) and European Economic Area (EEA), United States of America (USA), Israel, Argentina, Canada, Colombia, and Japan. This study is designed to determine if lomitapide is effective and can be safely administered to paediatric patients with HoFH. If the efficacy and safety so far observed in adults is confirmed in paediatric patients, the potential exists to significantly lower low-density lipoprotein cholesterol (LDL-C) levels in paediatric patients with HoFH. Furthermore, the lower LDL-C levels may reduce atherosclerosis progression and would be expected to benefit these paediatric patients with HoFH.

A single arm, non comparator design has been selected due to the rarity of the disease and because the evaluation of safety variables such as growth and sexual maturation requires longer term observation than would be feasible in the context of a placebo controlled study.

To mitigate the disadvantages of a single arm design, the study includes a Run in Period of at least 6 weeks during which current lipid lowering therapy (LLT) (including lipoprotein apheresis (LA), when applicable) will be stabilised to establish baseline levels allowing each patient to serve as his/her own control. Patients will also remain on stable LLT (including LA, when applicable) during the Efficacy Phase of the study through Week 24±3 days.

• Study Type: Interventional
• Enrollment (Actual): 46
• Phase: Phase 3

Contacts and Locations

Study Locations

• Germany
  • Cologne, Germany, 50937
    • University Hospital of Cologne
  • Hamburg, Germany, 20246
    • University Medical Center Hamburg-Eppendorf
  • Baden-Wurttemberg
    • Heidelberg, Baden-Wurttemberg, Germany, 69120
      • Universtiats-Kinderlinik Heidelberg
• Israel
  • Ramat Gan, Israel, 52621
    • Chaim Sheba Medical Center
• Italy
  • Roma, Italy, 00165
    • Bambino Gesù Children's Hospital,
  • Padua
    • Padua, Padua, Italy, 35128
      • U.O.C. Clinica Medica 1
• Saudi Arabia
  • Riyadh, Saudi Arabia
    • King Abdullah International Medical Research Centre (KAIMRC),
  • Riyadh, Saudi Arabia
    • King Faisal Specialist Hospital
• Spain
  • A Coruña, Spain, 15006
    • Hospital Abente y Lago
  • Valencia, Spain, 46010
    • Hospital Clinico Universitario of Valencia
  • Tarragona,
    • Reus, Tarragona,, Spain, 43204
      • Hospital Universitari Sant Joan
• Tunisia
  • Monastir, Tunisia, 5000
    • E.P.S. Fattouma Bourguiba Hospital

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 5 years to 17 years (Child)
• Accepts Healthy Volunteers: No

Description

Inclusion criteria

• Male and female patients aged 5 to ≤17 years with HoFH as defined by any of the following criteria recommended by the Consensus Panel on Familial Hypercholesterolaemia of the European Atherosclerosis Society (EAS) (Cuchel, Bruckert et al. 2014):

  1. Genetic confirmation of 2 mutant alleles at the LDL receptor (LDLR), apo B, Proprotein convertase subtilisin/kexin type 9 (PCSK9), or LDL receptor adapter protein 1 (LDLRAP1) gene locus OR
  2. An untreated LDL C >500 mg/dL (13 mmol/L) or treated LDL C ≥300 mg/dL (8 mmol/L ) together with either Cutaneous or tendon xanthoma before age 10 years or Untreated LDL C levels consistent with heterozygous FH in both parents

• Baseline LDL C on LLT (maximum concentration [Cmax] immediately prior to LA, if applicable)

  1. >160 mg/dL (4.1 mmol/L, no documented cardiovascular disease [CVD]) or
  2. >130 mg/dL (3.4 mmol/L, established CVD defined as aortic valve disease and/or coronary atherosclerosis)
• Body weight ≥15 kg or body mass index (BMI) and height both >10th percentile according to World Health Organization (WHO) Growth Charts for Boys and Girls 5 to 19 Years of Age
• Patient and/or his/her legal representative has/have been informed, has/have read and understood the patient information/informed consent form, and has/have given written informed assent/consent

• Patient and/or his/her legal representative must be able and willing to follow study procedures and instructions, particularly that

  1. LLT (including LA, when applicable) must be stable for at least 6 weeks prior to Baseline (Run in Period) and remain stable through Week 24±3 days (end of Efficacy Phase)
  2. The patient must be compliant with both the low fat diet supplying <20% of energy (calories) from fat or <30 g fat, whichever is the lesser amount starting at the beginning of the Run in Period and the dietary supplement regimen starting at Week 2 of the Run in Period, both continuing until completion of the study
• Postmenarchal female adolescents must be willing to use an effective form of birth control with failure rates <1% per year (e.g., implant, injectable, combined oral contraceptive, intrauterine contraceptive device, sexual abstinence, vasectomy or vasectomised partner) during participation in the study (and at least 4 weeks thereafter). Patients taking oestrogen based oral contraceptives should be advised about possible loss of effectiveness due to diarrhea and/or vomiting. Additional contraceptive measures should be used for 7 days after resolution of symptoms.
• Patient must be in stable physical and mental health at screening

Exclusion criteria

• Other forms of primary hyperlipoproteinaemia and secondary causes of hypercholesterolaemia (e.g., nephrotic syndrome, hypothyroidism)
• Contraindications for the use of lomitapide according to section 4.3 of the European Medicines Agency (EMA) Summary of Product Characteristics (SmPC), such as hypersensitivity to the active substance or to any of the excipients listed in Section 6.1 of the SmPC, known significant or chronic inflammatory bowel disease or malabsorption
• Moderate (Child Pugh B) or severe hepatic impairment (Child Pugh C), active liver disease and/or abnormal liver function tests at screening (AST or ALT >1.5 x upper limit of normal (ULN) and/or total bilirubin >1.5 x ULN in the absence of Gilbert's syndrome or AP >1.5 x ULN [based on appropriate age and gender normal values])
• Serum CK >2 x ULN
• Chronic renal insufficiency with glomerular filtration rate (GFR) <70 mL/min/1.73 m2 calculated using the Schwartz formula
• Uncontrolled hypertension (defined as mean systolic and/or diastolic blood pressure ≥95% of normal for age and sex) despite medical therapy
• New York Heart Association (NYHA) Class III or IV congestive heart failure
• Precocious/delayed puberty or endocrine disorder affecting growth (e.g., hypothyroidism, premature adrenarche)
• History of drug abuse within the last 3 years or habitual alcohol consumption (defined as >1 ounce [28 g] of liquor or 4 ounce glass [113 g] of wine, or the equivalent, ≥3 times per week)
• Life expectancy predicted to be <5 years
• History of a non skin malignancy (with the exception of cervical cancer in situ) within 3 years prior to enrolment
• Treatment with any Investigational Medicinal Product (IMP) within 6 months or 5 times the terminal half life of the corresponding IMP, whichever is longer, before the screening visit
• Patient is a dependent of the sponsor, of the investigational team or his/her immediate family
• Pregnant or nursing women

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Non-Randomized
• Interventional Model: Parallel Assignment
• Masking: None (Open Label)

Number of Arms

3

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Other: Age 5-10 years; Lomitapide dosing commenced with 2mg at week 1 for 8 Weeks,then increased to 5mg at Week 8±3 days, 10 mg at Week 12±3 days to the maximum allowable dose of 20 mg by Week 16±3 days or the MTD by Week 20±3 days based upon acceptable safety and tolerability criteria in addition to LDL C values.	Drug: Lomitapide; 2mg,5mg, 10mg and 20mg capsules
Other: Age 11-15 years; Lomitapide dosing commenced with 2mg at week 1 for 4 Weeks, then increased to 5mg at Week 4±3 days, 10 mg at Week 8±3 days, 20mg at Week 12±3 days to the maximum allowable dose of 40mg by Week 16±3 days or the MTD by Week 20±3 days based upon acceptable safety and tolerability criteria in addition to LDL C values.	Drug: Lomitapide; 2mg,5mg, 10mg and 20mg capsules
Other: Age 16 to ≤17 years; Lomitapide dosing commenced with 5mg at week 1 for 4 Weeks, then increased to 10mg at Week 4±3 days, 20 mg at Week 8±3 days, 40mg at Week 12±3 days to the maximum allowable dose of 60mg by Week 16±3 days or the MTD by Week 20±3 days based upon acceptable safety and tolerability criteria in addition to LDL C values.	Drug: Lomitapide; 2mg,5mg, 10mg and 20mg capsules

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Efficacy Endpoint: Percent Change in Low-density Lipoprotein Cholesterol (LDL C) at Week 24 Compared to Baseline	To evaluate the efficacy of lomitapide, as defined by the percent change in low density lipoprotein cholesterol (LDL C) at the maximum tolerated dose (MTD)	Baseline through Week 24

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Efficacy Endpoint: Percent Change From Baseline at Week 24 for Various Lipid Parameters	To evaluate the efficacy of lomitapide, as defined by the percent change of the following lipid parameters at the maximum tolerated dose (MTD): Non-high-density lipoprotein cholesterol (Non-HDL-C); Total cholesterol (TC); Very-low-density lipoprotein cholesterol (VLDL-C); Apolipoprotein B (Apo B); TG (Triglycerides)	Baseline through Week 24
Efficacy Endpoint: Percent Change From Baseline at Week 24 for Lp(a)	To evaluate the efficacy of lomitapide, as defined by the percent change in Lp(a) at the maximum tolerated dose (MTD)	Baseline through Week 24
Percent Change From Baseline at All Other Time Points Through Week 104 for LDL-C	To evaluate the efficacy of lomitapide, as defined by the percent change in LDL-C at the maximum tolerated dose (MTD)	Baseline through Week 104
Percent Change From Baseline at All Other Time Points Through Week 104 for Non-HDL-C	To evaluate the efficacy of lomitapide, as defined by the percent change in Non-HDL-C at the maximum tolerated dose (MTD)	Baseline through Week 104
Percent Change From Baseline at All Other Time Points Through Week 104 for TC	To evaluate the efficacy of lomitapide, as defined by the percent change in TC at the maximum tolerated dose (MTD)	Baseline through Week 104
Percent Change From Baseline at All Other Time Points Through Week 104 for VLDL-C	To evaluate the efficacy of lomitapide, as defined by the percent change in VLDL-C at the maximum tolerated dose (MTD)	Baseline through Week 104
Percent Change From Baseline at All Other Time Points Through Week 104 for Apo B	To evaluate the efficacy of lomitapide, as defined by the percent change in apo B at the maximum tolerated dose (MTD)	Baseline through Week 104
Percent Change From Baseline at All Other Time Points Through Week 104 for TG	To evaluate the efficacy of lomitapide, as defined by the percent change in TG at the maximum tolerated dose (MTD)	Baseline through Week 104
Percent Change From Baseline at All Other Time Points Through Week 104 for Lipoprotein(a) (Lp(a))	To evaluate the efficacy of lomitapide, as defined by the percent change in Lp(a) at the maximum tolerated dose (MTD)	Baseline through Week 104
Percent Change in TC/HDL-C Ratio From Baseline at All Other Time Points to Week 104	To evaluate the efficacy of lomitapide, as defined by the percent change in TC/HDL-C ratio at the maximum tolerated dose (MTD)	Baseline through Week 104
Percent Change in HDL-C From Baseline at All Other Time Points to Week 104	To evaluate the efficacy of lomitapide, as defined by the percent change in HDL-C at the maximum tolerated dose (MTD)	Baseline through Week 104 week
Change in LLT From Week 28 Through Week 104	To evaluate the efficacy of lomitapide, as defined by the change in background lipid lowering therapy	Week 28 through Week 104
Change in LA From Week 28 Through Week 104	To evaluate the efficacy of lomitapide, as defined by the change in lipoprotein apheresis	Week 28 through Week 104
Number and Percentage of Patients Achieving European Atherosclerosis Society (EAS) Recommended Target (2013) of LDL-C at Any Timepoint Between Baseline and Week 24	To evaluate the efficacy of lomitapide, as defined by the number and percentage of patients achieving EAS recommended target (2013) of LDL-C	Baseline through Week 24
Number and Percentage of Patients Achieving EAS Recommended Target (2013) of LDL-C at Any Time in the Study	To evaluate the efficacy of lomitapide, as defined by the number and percentage of patients achieving EAS recommended target (2013) of LDL-C	Baseline through Week 104

Other Outcome Measures

Outcome Measure	Measure Description	Time Frame
Percent Change of Body Mass Index (BMI)	To evaluate the efficacy of lomitapide, as defined by the percent change of BMI	Baseline through Week 104
Lipid Accumulation in the Liver Over Time Measured by Nuclear Magnetic Resonance (NMR) at Baseline and at Week 24, Week 56 and at Week 104	To evaluate the safety of lomitapide, as defined by lipid accumulation in the liver as measured by nuclear magnetic resonance (NMR)	Baseline through Week 104
Lipid Accumulation in the Liver Over Time Measured by Ultrasound at Baseline and at Week 24, Week 56 and at Week 104	To evaluate the safety of lomitapide, as defined by lipid accumulation in the liver as measured by ultrasound	Baseline through Week 104

Collaborators and Investigators

• Sponsor: Amryt Pharma

Publications and helpful links

General Publications

• Masana L, Zambon A, Schmitt CP, Taylan C, Driemeyer J, Cohen H, Buonuomo PS, Alashwal A, Al-Dubayee M, Kholaif N, Diaz-Diaz JL, Maatouk F, Martinez-Hervas S, Mangal B, Lowe S, Cunningham T. Lomitapide for the treatment of paediatric patients with homozygous familial hypercholesterolaemia (APH-19): results from the efficacy phase of an open-label, multicentre, phase 3 study. Lancet Diabetes Endocrinol. 2024 Dec;12(12):880-889. doi: 10.1016/S2213-8587(24)00233-X. Epub 2024 Oct 16.

Study record dates

Study Major Dates

• Study Start (Actual): December 14, 2020
• Primary Completion (Actual): October 16, 2022
• Study Completion (Actual): June 6, 2024

Study Registration Dates

• First Submitted: December 7, 2020
• First Submitted That Met QC Criteria: December 18, 2020
• First Posted (Actual): December 23, 2020

Study Record Updates

• Last Update Posted (Estimated): August 27, 2025
• Last Update Submitted That Met QC Criteria: August 8, 2025
• Last Verified: June 1, 2025

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Metabolism, Inborn Errors; Genetic Diseases, Inborn; Metabolic Diseases; Hyperlipidemias; Dyslipidemias; Lipid Metabolism Disorders; Lipid Metabolism, Inborn Errors; Hyperlipoproteinemias; Congenital, Hereditary, and Neonatal Diseases and Abnormalities; Nutritional and Metabolic Diseases; Hyperlipoproteinemia Type II; Homozygous Familial Hypercholesterolemia; BMS201038
• Other Study ID Numbers: APH-19

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: NO

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No