| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
| 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. |
|
| E.1.1.1 | Medical condition in easily understood language |
| A condition that runs in families (homozygous familial hypercholesterolaemia or HoFH), which leads to the patient having very high cholesterol from a very early age. |
|
| E.1.1.2 | Therapeutic area | Body processes [G] - Metabolic Phenomena [G03] |
| MedDRA Classification |
| E.1.2 Medical condition or disease under investigation |
| E.1.2 | Version | 20.0 |
| E.1.2 | Level | LLT |
| E.1.2 | Classification code | 10057100 |
| E.1.2 | Term | Homozygous familial hypercholesterolaemia |
| E.1.2 | System Organ Class | 100000004850 |
|
| E.1.3 | Condition being studied is a rare disease | No |
| E.2 Objective of the trial |
| E.2.1 | Main objective of the trial |
| 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. |
|
| E.2.2 | Secondary objectives of the trial |
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 |
|
| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal 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 <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 (and during the LTE of this study, when applicable)
6. 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.
7. Patient must be in stable physical and mental health at screening |
|
| E.4 | Principal 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) <70 mL/min/1.73 m2 calculated using the Schwartz formula
6. Uncontrolled hypertension (defined as mean systolic and/or diastolic blood pressure ≥95% of normal for age and sex) despite medical therapy
7. New York Heart Association (NYHA) Class III or IV congestive heart failure
8. Precocious/delayed puberty or endocrine disorder affecting growth (e.g., hypothyroidism, premature adrenarche)
9. 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)
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 |
|
| E.5 End points |
| E.5.1 | Primary end point(s) |
| Percent change from Baseline in LDL-C at Week 24±3 days |
|
| E.5.1.1 | Timepoint(s) of evaluation of this end point |
| Week 24±3 days compared to Baseline |
|
| E.5.2 | 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
(25-hydroxy-D). Levels of vitamin K will be assessed indirectly by measuring total and
uncarboxylated levels of serum osteocalcin. (Bone health will be assessed indirectly using growth
to track age-appropriate progress, and measurement of 25-hydroxy-D as well as total and
uncarboxylated osteocalcin levels.).
− Pituitary-adrenal hormone levels (thyroid stimulating hormone [TSH], follicle stimulating hormone
[FSH], luteinising hormone [LH], adrenocorticotrophic hormone [ACTH], and morning serum
cortisol).
− Urinalysis.
• Lipid accumulation in the liver as measured by NMR imaging or echography (i.e., ultrasound scan)
at Baseline and at Week 24±3 days, Week 56±3 days, and at Week 104±1 week (Week 108 for
patients who opt not to participate in the LTE of this study or who are ineligible). All patients will
undergo NMR imaging unless it is contraindicated or not feasible (e.g., due to the need for sedation
or general anaesthesia in very young or anxious patients). In this case, ultrasound scans will be
used at the discretion of the investigator.
Exploratory endpoints:
• Percent change from Baseline at Week 56±3 days and Week 104±1 week in CIMT and FMD.
• Total number and percent of patients with resolution and/or regression of pre-existing xanthomas at
Week 56±3 days and at Week 104±1 week.
• Changes from Baseline through Week 24±3 days in cholesterol and triglyceride content of VLDL,
IDL, LDL and HDL, particle number and size of VLDL, LDL, and HDL as well as particle number of
their respective lipoprotein subclasses (large, medium, and small) as assessed based on 2D NMR
(Liposcale® Test) of PK samples at Week 4±3 days, Week 8±3 days, Week 12±3 days,
Week 16±3 days, Week 20±3 days and at Week 24±3 days.
Palatability endpoints:
• Total number and percent of patients for each response of palatability:
− Able to swallow capsule (including food media responses if used).
− Palatability rating (using a 5-point facial hedonic scale).
− Parent/guardian interpretation of child’s reaction/facial expression (using a 3-point scale).
− Parent/guardian experience problems in giving medication to child because they refuse to take
or throw up immediately after taking.
− Parent/guardian experience problems in giving dietary supplement to child because they refuse
to take or throw up immediately after taking.
Pharmacokinetic endpoints:
• The PK data from this study will be incorporated into an existing population PK model in adult
HoFH patients. |
|
| E.5.2.1 | Timepoint(s) of evaluation of this end point |
| As specified for each secondary endpoint |
|
| E.6 and E.7 Scope of the trial |
| E.6 | Scope of the trial |
| E.6.1 | Diagnosis | No |
| E.6.2 | Prophylaxis | No |
| E.6.3 | Therapy | No |
| E.6.4 | Safety | Yes |
| E.6.5 | Efficacy | Yes |
| E.6.6 | Pharmacokinetic | Yes |
| E.6.7 | Pharmacodynamic | No |
| E.6.8 | Bioequivalence | No |
| E.6.9 | Dose response | No |
| E.6.10 | Pharmacogenetic | No |
| E.6.11 | Pharmacogenomic | No |
| E.6.12 | Pharmacoeconomic | No |
| E.6.13 | Others | No |
| E.7 | Trial type and phase |
| E.7.1 | Human pharmacology (Phase I) | No |
| E.7.1.1 | First administration to humans | No |
| E.7.1.2 | Bioequivalence study | No |
| E.7.1.3 | Other | No |
| E.7.1.3.1 | Other trial type description | |
| E.7.2 | Therapeutic exploratory (Phase II) | No |
| E.7.3 | Therapeutic confirmatory (Phase III) | Yes |
| E.7.4 | Therapeutic use (Phase IV) | No |
| E.8 Design of the trial |
| E.8.1 | Controlled | No |
| E.8.1.1 | Randomised | No |
| E.8.1.2 | Open | Yes |
| E.8.1.3 | Single blind | Information not present in EudraCT |
| E.8.1.4 | Double blind | Information not present in EudraCT |
| E.8.1.5 | Parallel group | No |
| E.8.1.6 | Cross over | No |
| E.8.1.7 | Other | Yes |
| E.8.1.7.1 | Other trial design description |
|
| E.8.2 | Comparator of controlled trial |
| E.8.2.1 | Other medicinal product(s) | No |
| E.8.2.2 | Placebo | No |
| E.8.2.3 | Other | No |
| E.8.3 |
The trial involves single site in the Member State concerned
| No |
| E.8.4 | The trial involves multiple sites in the Member State concerned | Yes |
| E.8.4.1 | Number of sites anticipated in Member State concerned | 4 |
| E.8.5 | The trial involves multiple Member States | Yes |
| E.8.5.1 | Number of sites anticipated in the EEA | 8 |
| E.8.6 Trial involving sites outside the EEA |
| E.8.6.1 | Trial being conducted both within and outside the EEA | Yes |
| E.8.6.2 | Trial being conducted completely outside of the EEA | No |
| E.8.6.3 | If E.8.6.1 or E.8.6.2 are Yes, specify the regions in which trial sites are planned |
| Israel |
| Saudi Arabia |
| Tunisia |
| Spain |
| Germany |
| Italy |
|
| E.8.7 | Trial has a data monitoring committee | Yes |
| E.8.8 |
Definition of the end of the trial and justification where it is not the last
visit of the last subject undergoing the trial
|
| Completion of the last visit or last assessment for the last subject. |
|
| E.8.9 Initial estimate of the duration of the trial |
| E.8.9.1 | In the Member State concerned years | 3 |
| E.8.9.1 | In the Member State concerned months | 2 |
| E.8.9.1 | In the Member State concerned days | |
| E.8.9.2 | In all countries concerned by the trial years | 3 |
| E.8.9.2 | In all countries concerned by the trial months | 2 |
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