Homozygous familial hypercholesterolaemia (HoFH). A rare and life-threatening inherited disorder of lipid metabolism with an estimated prevalence of 1 per 160,000 to 300,000 in the European population. MedDRA version: 20.0 Level: LLT Classification code 10057100 Term: Homozygous familial hypercholesterolaemia System Organ Class: 100000004850
Conditions
Interventions
Trade Name: Lojuxta 5 mg hard capsules
Pharmaceutical Form: Capsule, hard
INN or Proposed INN: LOMITAPIDE
CAS Number: 182431-12-5
Concentration unit: mg milligram(s)
Concentration type: equal
Concent
Sponsors
Amryt Pharmaceuticals DAC
Eligibility
Sex/Gender
All
Inclusion criteria
Inclusion criteria: 1. 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): a. 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 b. 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 2. Baseline LDL C on LLT (maximum concentration [Cmax ] immediately prior to LA, if applicable) a. >160 mg/dL (4.1 mmol/L, no documented cardiovascular disease [CVD]) or b. >130 mg/dL (3.4 mmol/L, established CVD defined as aortic valve disease and/or coronary atherosclerosis) 3. 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 4. 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 5. Patient and/or his/her legal representative must be able and willing to follow study procedures and instructions, particularly that a. 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) b. The patient must be compliant with both the low fat diet supplying =65 years) no F.1.3.1 Number of subjects for this age range
Exclusion criteria
Exclusion criteria: 1. Other forms of primary hyperlipoproteinaemia and secondary causes of hypercholesterolaemia (e.g., nephrotic syndrome, hypothyroidism) 2. Contraindications for the use of lomitapide according to section 4.3 of the 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 3. 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]) 4. Serum CK >2 x ULN 5. Chronic renal insufficiency with glomerular filtration rate (GFR) 1 ounce [28 g] of liquor or 4 ounce glass [113 g] of wine, or the equivalent, =3 times per week) 10. Life expectancy predicted to be <5 years 11. History of a non skin malignancy (with the exception of cervical cancer in situ) within 3 years prior to enrolment 12. 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 13. Patient is related to Sponsor or an Investigator of this Clinical Trial 14. Pregnant or nursing women
Design outcomes
Primary
| Measure | Time frame |
|---|---|
| Main Objective: 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) at Week 24±3 days (W24) compared to baseline when added to stable lipid-lowering therapy (LLT, including lipoprotein apheresis [LA] where applicable) in paediatric patients (5 to =17 years of age) with HoFH. ;Secondary Objective: To evaluate the efficacy by: •% change from baseline in lipid parameters at W24 and at other time-points to W104 •change in LLT and LA from W24-104 •% patients achieving EAS target LDL-C of <135 mg/dL (3.5 mmol/L) at W24 and during the study To evaluate safety: •Incidence AEs, abnormal physical and lab findings •Effect on growth, bone health and age •Potential effects on maturation, reproductive development, gonadotropins & pituitary adrenal axis variables •Hepatic fat accumulation To evaluate the PK by sparse blood sampling Exploratory objectives: •Change in mean CIMT and flow FMD and resolution/regression of xanthomas (W56+W104) •Change of lipid parameters (W24) Palatability Objective: •a 5 point facial hedonic scale, in terms of overall liking. •with either food media if taken on apple sauce or mashed banana •a 3 point scale of interpretation of the child’s reaction & assessment of ease of admin. of IMP & dietary supplements •timing of reaction relative to dosing;Primary end point(s): Percent change from Baseline in LDL-C at Week 24±3 days;Timepoint(s) of evaluation of this end point: Week 24±3 days compared to Baseline | — |
Secondary
| Measure | Time frame |
|---|---|
| Secondary end point(s): Secondary endpoints: • Percent change from Baseline at Week 24±3 days for the following lipid parameters: TC, Non-HDL-C, VLDL-C, TG, Lp(a), and apo B. • 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. • Total number and percent of patients with a change from Baseline 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. Safety endpoints: Safety evaluations and endpoints from Baseline through Week 104±1 week include: • Incidence of AEs overall and by severity and relatedness. • Physical examinations including regular measurements of height, weight, and BMI. • Sexual maturation (Tanner staging): - In patients with Tanner Stage =2: Changes from Baseline in sex hormones (serum testosterone and serum oestradiol). • 12-Lead safety ECG (read locally), standard of care echocardiography (if available), vital signs and blood pressure. • PFT. • Laboratory tests: - Standard haematology (complete blood count [CBC]) and clinical chemistry panels. - Liver function tests: Alanine transaminase (ALT), aspartate transaminase (AST), gamma-glutamyl transferase (GGT), alkaline phosphatase (AP), total bilirubin, and serum albumin. - High-density lipoprotein cholesterol (HDL-C) and apolipoprotein A-I (apo A-I). - Creatinine kinase (CK). - Serum lipase. - Serum levels of essential fatty acids (EFA): Linoleic acid, alpha linoleic acid (ALA), eicosapentaenoic acid (EPA), docosahexaenoic acid (DHA), arachidonic acid (AA), and eicosatrienoic acid. - Serum concentrations of fat-soluble vitamins: Vitamin A (retinol), vitamin E (alpha tocopherol), ratio of vitamin E to total lipids (total cholesterol plus fasting triglycerides), and vitamin D | — |
Countries
Germany, Israel, Italy, Saudi Arabia, Spain, Tunisia
Contacts
Public ContactHead of Clinical Development
Amryt Pharmaceuticals DAC
Outcome results
None listed