Back to resultsEfficacy and Safety of Lomitapide in Paediatric Patients With Homozygous Familial Hypercholesterolaemia (HoFH)
Primary Purpose
Homozygous Familial Hypercholesterolaemia (HoFH)
Status
Active
Phase
Phase 3
Locations
International
Study Type
Interventional
Intervention
Lomitapide
Sponsored by
About this trial
This is an interventional treatment trial for Homozygous Familial Hypercholesterolaemia (HoFH)
Eligibility Criteria
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 EAS (Cuchel, Bruckert et al. 2014):
- 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
- 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)
- >160 mg/dL (4.1 mmol/L, no documented cardiovascular disease [CVD]) or
- >130 mg/dL (3.4 mmol/L, established CVD defined as aortic valve disease and/or coronary atherosclerosis)
- Body weight ≥15 kg or 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
- 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)
- 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
Sites / Locations
- Universtiats-Kinderlinik Heidelberg
- University Hospital of Cologne
- University Medical Center Hamburg-Eppendorf
- Chaim Sheba Medical Center
- U.O.C. Clinica Medica 1
- Bambino Gesù Children's Hospital,
- King Abdullah International Medical Research Centre (KAIMRC),
- King Faisal Specialist Hospital
- Hospital Universitari Sant Joan
- Hospital Abente y Lago
- Hospital Clinico Universitario of Valencia
- E.P.S. Fattouma Bourguiba Hospital
Arms of the Study
Arm 1
Arm 2
Arm 3
Arm Type
Other
Other
Other
Arm Label
Age 5-10 years
Age11-15years
16 to ≤17 years
Arm Description
Age 5-10 years Lomitapide dosing will commence with 2mg at week 1 for 8 Weeks,then increase to 5mg 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
Lomitapide dosing will commence with 2mg at week 1 for 4 Weeks, then increase to 5mg Week 4±3 days, 10 mg at Week 8±3 days,20mgs at week, 12±3 days to the maximum allowable dose of 40 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
Lomitapide dosing will commence with 5mg at week 1 for 4 Weeks, then increase to 10mg Week 4±3 days,20 mg at Week 8±3 days,40mgs at week, 12±3 days to the maximum allowable dose of 60 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
Outcomes
Primary Outcome Measures
Efficacy endpoint Percent change in LDL C
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)
Safety endpoints AE reporting
Incidence, severity, and relatedness of AEs
Secondary Outcome Measures
Percent change from Baseline at Week 24±3 days for the following lipid parameters: TC, Non HDL C, VLDL C, TG, Lp(a), and apoB
Percent change from Baseline at all other time points through Week 104±1 week for the following lipid parameters: LDL C, TC, Non HDL C, VLDL C, TG, Lp(a), and apo B
• Change in LLT and LA from Week 24±3 days through Week 104±1 week
• Total number and percent of patients achieving the EAS recommended target LDL C of <135 mg/dL (3.5 mmol/L) in paediatric HoFH patients at Week 24±3 days and at any time on study
Full Information
1. Study Identification
Unique Protocol Identification Number
NCT04681170
Brief Title
Efficacy and Safety of Lomitapide in Paediatric Patients With Homozygous Familial Hypercholesterolaemia (HoFH)
Official Title
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
Study Type
Interventional
2. Study Status
Record Verification Date
April 2023
Overall Recruitment Status
Active, not recruiting
Study Start Date
December 14, 2020 (Actual)
Primary Completion Date
October 16, 2022 (Actual)
Study Completion Date
April 30, 2024 (Anticipated)
3. Sponsor/Collaborators
Responsible Party, by Official Title
Sponsor
Name of the Sponsor
Amryt Pharma
4. Oversight
Studies a U.S. FDA-regulated Drug Product
No
Studies a U.S. FDA-regulated Device Product
No
Data Monitoring Committee
Yes
5. Study Description
Brief Summary
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 LLT (including 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)
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 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 LLT (including 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.
6. Conditions and Keywords
Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study
Homozygous Familial Hypercholesterolaemia (HoFH)
7. Study Design
Primary Purpose
Treatment
Study Phase
Phase 3
Interventional Study Model
Parallel Assignment
Masking
None (Open Label)
Allocation
Non-Randomized
Enrollment
46 (Actual)
8. Arms, Groups, and Interventions
Arm Title
Age 5-10 years
Arm Type
Other
Arm Description
Age 5-10 years Lomitapide dosing will commence with 2mg at week 1 for 8 Weeks,then increase to 5mg 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
Arm Title
Age11-15years
Arm Type
Other
Arm Description
Lomitapide dosing will commence with 2mg at week 1 for 4 Weeks, then increase to 5mg Week 4±3 days, 10 mg at Week 8±3 days,20mgs at week, 12±3 days to the maximum allowable dose of 40 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
Arm Title
16 to ≤17 years
Arm Type
Other
Arm Description
Lomitapide dosing will commence with 5mg at week 1 for 4 Weeks, then increase to 10mg Week 4±3 days,20 mg at Week 8±3 days,40mgs at week, 12±3 days to the maximum allowable dose of 60 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
Intervention Type
Drug
Intervention Name(s)
Lomitapide
Intervention Description
2mg,5mg, 10mg and 20mg capsules
Primary Outcome Measure Information:
Title
Efficacy endpoint Percent change in LDL C
Description
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)
Time Frame
Baseline through Week 104±1 week
Title
Safety endpoints AE reporting
Description
Incidence, severity, and relatedness of AEs
Time Frame
Baseline through Week 104±1 week
Secondary Outcome Measure Information:
Title
Percent change from Baseline at Week 24±3 days for the following lipid parameters: TC, Non HDL C, VLDL C, TG, Lp(a), and apoB
Time Frame
Baseline through Week 104±1 week
Title
Percent change from Baseline at all other time points through Week 104±1 week for the following lipid parameters: LDL C, TC, Non HDL C, VLDL C, TG, Lp(a), and apo B
Time Frame
Baseline through Week 104±1 week
Title
• Change in LLT and LA from Week 24±3 days through Week 104±1 week
Time Frame
Baseline through Week 104±1 week
Title
• Total number and percent of patients achieving the EAS recommended target LDL C of <135 mg/dL (3.5 mmol/L) in paediatric HoFH patients at Week 24±3 days and at any time on study
Time Frame
Baseline through Week 104±1 week
10. Eligibility
Sex
All
Minimum Age & Unit of Time
5 Years
Maximum Age & Unit of Time
17 Years
Accepts Healthy Volunteers
No
Eligibility Criteria
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 EAS (Cuchel, Bruckert et al. 2014):
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
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)
>160 mg/dL (4.1 mmol/L, no documented cardiovascular disease [CVD]) or
>130 mg/dL (3.4 mmol/L, established CVD defined as aortic valve disease and/or coronary atherosclerosis)
Body weight ≥15 kg or 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
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)
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
Facility Information:
Facility Name
Universtiats-Kinderlinik Heidelberg
City
Heidelberg
State/Province
Baden-Wurttemberg
ZIP/Postal Code
69120
Country
Germany
Facility Name
University Hospital of Cologne
City
Cologne
ZIP/Postal Code
50937
Country
Germany
Facility Name
University Medical Center Hamburg-Eppendorf
City
Hamburg
ZIP/Postal Code
20246
Country
Germany
Facility Name
Chaim Sheba Medical Center
City
Ramat Gan,
ZIP/Postal Code
52621
Country
Israel
Facility Name
U.O.C. Clinica Medica 1
City
Padova
State/Province
Padua
ZIP/Postal Code
35128
Country
Italy
Facility Name
Bambino Gesù Children's Hospital,
City
Roma
ZIP/Postal Code
00165
Country
Italy
Facility Name
King Abdullah International Medical Research Centre (KAIMRC),
City
Riyadh
Country
Saudi Arabia
Facility Name
King Faisal Specialist Hospital
City
Riyadh
Country
Saudi Arabia
Facility Name
Hospital Universitari Sant Joan
City
Reus
State/Province
Tarragona,
ZIP/Postal Code
43204
Country
Spain
Facility Name
Hospital Abente y Lago
City
A Coruña
ZIP/Postal Code
15006
Country
Spain
Facility Name
Hospital Clinico Universitario of Valencia
City
Valencia
ZIP/Postal Code
46010
Country
Spain
Facility Name
E.P.S. Fattouma Bourguiba Hospital
City
Monastir,
ZIP/Postal Code
5000
Country
Tunisia
12. IPD Sharing Statement
Plan to Share IPD
No
Learn more about this trial
Efficacy and Safety of Lomitapide in Paediatric Patients With Homozygous Familial Hypercholesterolaemia (HoFH)
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