| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
| Homozygous familial hypercholesterolemia (HoFH). |
|
| E.1.1.1 | Medical condition in easily understood language |
| Homozygous familial hypercholesterolemia (HoFH), a genetic condition resulting in extremely high levels of cholesterol. |
|
| E.1.1.2 | Therapeutic area | Diseases [C] - Nutritional and Metabolic Diseases [C18] |
| MedDRA Classification |
| E.1.2 Medical condition or disease under investigation |
| E.1.2 | Version | 18.1 |
| E.1.2 | Level | LLT |
| E.1.2 | Classification code | 10057080 |
| E.1.2 | Term | Homozygous familial hypercholesterolemia |
| E.1.2 | System Organ Class | 100000004850 |
|
| E.1.3 | Condition being studied is a rare disease | Yes |
| E.2 Objective of the trial |
| E.2.1 | Main objective of the trial |
| To evaluate the efficacy of lomitapide as defined by the mean percent change in LDL-C (low density lipoprotein cholesterol) at the maximum tolerated dose at Week 24 compared to baseline when added to stable lipid-lowering therapy (including LDL apheresis when applicable) in pediatric and adolescent patients (≥5 to <18 years of age) with HoFH. |
|
| E.2.2 | Secondary objectives of the trial |
The secondary objectives are to evaluate the efficacy, safety, and pharmacokinetics of lomitapide in pediatric patients with HoFH.
|
|
| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal inclusion criteria |
1. Male or female aged ≥5 and<18 years with diagnosed functional HoFH by at least one of the following criteria.
a) Documented functional mutation(s) in both LDL-R alleles or alleles known to affect LDL-R functionality (e.g., apo B defective mutations),
b) Skin fibroblast LDL-R activity <20% normal,
c) Untreated TC >500 mg/dL (13.0 mmol/L) AND TG <300 mg/dL (3.4 mmol/L) with both parents having documented untreated TC >250 mg/dL (6.5 mmol/L),
d) Average fasting LDL-C >300 mg/dL (7.8 mmol/L) on maximally
tolerated lipid-lowering therapy as decided by the treating physician with both parents having documented untreated TC >250 mg/dL (6.5 mmol/L).
2. Baseline LDL-C >160 mg/dL (4.1 mmol/L) on background therapy and no documented CVD or baseline LDL-C >130 mg/dL (3.4 mmol/L) on background therapy for patients with established CVD (defined as aortic valve disease and/or coronary atherosclerosis).
3. Parent/guardian is able to provide written informed consent for patient (according to local legal requirements) prior to any trial procedures.
4. Patient must provide informed assent or informed consent according to local legal requirements and must understand the trial procedures and that he or she can withdraw from the study at any time.
5. Patient must weigh at least 15 kg and be at or above the 10th percentile in BMI and at least 10th percentile in height for age and gender based on the CDC growth charts.
6. Patient and parent/guardian understand and agree that lipid-lowering therapy, including LDL apheresis, must be stable for at least 12 weeks prior to Day 1 of treatment and remain stable through the Week 24 visit of the study.
7. Patient must be in stable physical and mental health at Screening.
8. Patient/guardian must agree to be compliant with a low-fat diet supplying <20% of energy (calories) from fat, starting at the beginning of the Run-in Period and continuing until completion in the trial.
9. Patient/guardian must agree to be compliant with the dietary supplement regimen starting at Week 2 of the Run-in Period and continuing until completion in the trial.
10. All female patients of potential child-bearing age and who have attained menarche must have a negative pregnancy test at Screening and during the study.
11. Potentially sexually active female patients who are of childbearing age must either be sexually abstinent or follow two acceptable methods of contraception including one highly effective and one effective method (i.e., the use of a hormonal contraceptive in addition to the use of a barrier method plus spermicide) during the study and for 4 weeks after the last dose of study medication. Patients taking estrogen-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.
- Highly effective methods of contraception include: hormonal contraceptives (e.g., combined oral contraceptives, patch, vaginal ring, injectables, and implants); intrauterine device (IUD) or intrauterine system (IUS); vasectomy or tubal ligation.
- Effective methods of contraception include: barrier method (e.g., male condom, female condom, cervical cap with spermicide, diaphragm with spermicide, contraceptive sponge). |
|
| E.4 | Principal exclusion criteria |
1. Other forms of primary hyperlipoproteinemia and secondary causes of hypercholesterolemia (e.g., nephrotic syndrome, hypothyroidism).
2. Abnormal liver function test (LFT) at Screening (aspartate aminotransferase [AST] or alanine aminotransferase [ALT] >1.5 times the upper limit of normal [× ULN] and/or total bilirubin >1.5 × ULN in the absence of Gilbert’s syndrome, or alkaline phosphatase [ALP] >1.5 × ULN based on appropriate age and gender normal values).
3. Moderate or severe hepatic impairment or active liver disease.
4. Serum creatine phosphokinase (CPK) level >2 × ULN.
5. Chronic renal insufficiency with glomerular filtration rate (GFR) <70 mL/min calculated using the Schwartz formula.
6. History of drug abuse within the last 3 years or habitual alcohol consumption (defined as >1 ounce [28 grams] of liquor or 4 ounce glass [113 grams] of wine, or the equivalent, 3 or more times per week).
7. New York Heart Association (NYHA) Class III or IV congestive heart failure.
8. Uncontrolled hypertension (defined as mean systolic or diastolic blood pressure >95% of the ULN for age and sex) despite medical therapy.
9. In the judgment of the PI, precocious or delayed puberty or endocrine disorder that would affect growth (e.g., hypothyroidism, premature adrenarche).
10. History of non-skin malignancy (with the exception of treated basal cell or squamous cell cancer or noninvasive cervical cancer in situ) or other cancers occurring within the past 3 years.
11. History of inflammatory bowel disease or other malabsorption syndrome or a history of bowel resection, gastric bypass, or other weight loss surgical procedure.
12. Use of mipomersen within 6 months of Screening
13. Any medical condition for which the life expectancy is predicted to be less than 5 years.
14. Any patient who is unable to avoid treatment with strong or moderate cytochrome P450 3A4 (CYP3A4) inhibitors, or other drugs contraindicated for use with lomitapide during the study.
15. Participation in an interventional clinical study within 6 weeks for a statin therapy or within 6 months for any other unapproved therapy. |
|
| E.5 End points |
| E.5.1 | Primary end point(s) |
| The mean percent change in LDL-C from Baseline at Week 24. |
|
| E.5.1.1 | Timepoint(s) of evaluation of this end point |
| From Baseline at Week 24. |
|
| E.5.2 | Secondary end point(s) |
Secondary Efficacy Endpoints:
The mean percent change from Baseline at Week 24 for the following lipid parameters:
- TC
- Non-HDL-C
- HDL-C
- TG
- VLDL-C
- Lp(a)
- Apo B
- Apo A-1
The mean percent change from Baseline at all other time points through Week 104 for the following lipid parameters :
- LDL-C
- TC
- Non-HDL-C
- HDL-C
- TG
- VLDL-C
- Lp(a)
- Apo B
- Apo A-1
Changes in lipid-lowering therapy and LDL apheresis from Week 24
through Week 104.
Number (percent) of patients achieving goal at Week 24 and at any
time on study (LDL-C of <100 mg/dL [2.6 mmol/L] for patients without documented CVD at Baseline; LDL-C of <70 mg/dL [1.8 mmol/L] for patients with documented CVD at Baseline).
Safety evaluations and endpoints to be evaluated in this study through Year 2/End of Treatment include:
1. AEs
2. Physical examinations including growth and sexual maturation assessments and a genitourinary examination per the PI’s judgment
3. Weight, height, and BMI
4. Vital signs
5. Bone health
a. X-rays of the wrist to assess bone health and bone age
b. Assessed indirectly using growth to track age-appropriate progress, and measurement of 25-hydroxyvitamin D and total and uncarboxylated osteocalcin levels (as a reflection of vitamin K levels)
6. 12-Lead safety ECG (read locally)
7. PFTs
8. Tanner staging
9. Hepatic fat content (percent) as measured by MRI; if MRI is contraindicated, another method of imaging will be performed (e.g., CT or ultrasound scan)
10. Laboratory tests including the following:
a. Liver function tests including: ALT, AST, ALP, total bilirubin, gamma-glutamyl transferase (GGT), and serum albumin
b. Creatinine phosphokinase (CPK)
c. Serum levels of fat-soluble vitamins
d. Serum levels of EFAs
e. Sex hormones (serum testosterone, serum estradiol) for patients assessed at Tanner Stage 2 or higher
f. Pituitary-adrenal hormones (TSH, FSH, LH, ACTH, and AM cortisol) for patients assessed at Tanner Stage 2 or higher
g. Serum lipase
h. Standard hematology (including complete blood count [CBC]) and clinical chemistry panels (including comprehensive metabolic panel and fasting lipid panel)
i. Urinalysis
Pharmacokinetic Endpoint:
Steady-state PK at Weeks 4, 8, 12, and 20
Exploratory Endpoints include:
- Resolution and/or regression of pre-existing tendon and cutaneous xanthomas at Weeks 56, 104 and at the End of Treatment, as compared to Baseline.
- Change from Baseline in mean CIMT using ultrasound scan at Week 56, and Week 104.
Palatability Endpoints:
- Palatability will be assessed using a 5-point facial hedonic scale and will be used to predict acceptance by establishing preference into categories of like and dislike in children for the study medication. |
|
| E.5.2.1 | Timepoint(s) of evaluation of this end point |
| Various through year 2; see details above for each 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 | Yes |
| E.6.4 | Safety | Yes |
| E.6.5 | Efficacy | Yes |
| E.6.6 | Pharmacokinetic | Yes |
| E.6.7 | Pharmacodynamic | Yes |
| E.6.8 | Bioequivalence | No |
| E.6.9 | Dose response | Yes |
| 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 | Information not present in EudraCT |
| E.8.1.2 | Open | Information not present in EudraCT |
| 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 | Information not present in EudraCT |
| E.8.1.6 | Cross over | Information not present in EudraCT |
| E.8.1.7 | Other | Information not present in EudraCT |
| E.8.2 | Comparator of controlled trial |
| E.8.2.1 | Other medicinal product(s) | Information not present in EudraCT |
| E.8.2.2 | Placebo | Information not present in EudraCT |
| E.8.2.3 | Other | Information not present in EudraCT |
| 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 | 10 |
| 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 |
| Austria |
| Canada |
| Germany |
| Greece |
| Israel |
| Italy |
| Turkey |
|
| 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
|
|
| 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 | 3 |
| E.8.9.1 | In the Member State concerned days | 0 |
| 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 | 3 |
| E.8.9.2 | In all countries concerned by the trial days | 0 |
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