E.1 Medical condition or disease under investigation |
E.1.1 | Medical condition(s) being investigated |
Lysosomal Acid Lipase Deficiency |
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E.1.1.1 | Medical condition in easily understood language |
Insufficient lysosomal acid lipase activity leading to accumulation of fats in the human body. |
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E.1.1.2 | Therapeutic area | Diseases [C] - Congenital, Hereditary, and Neonatal Diseases and Abnormalities [C16] |
MedDRA Classification |
E.1.2 Medical condition or disease under investigation |
E.1.2 | Version | 19.0 |
E.1.2 | Level | HLT |
E.1.2 | Classification code | 10024579 |
E.1.2 | Term | Lysosomal storage disorders |
E.1.2 | System Organ Class | 100000004850 |
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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 demonstrate efficacy of Sebelipase alfa, relative to placebo, based on normalisation of ALT in patients with LALD. |
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E.2.2 | Secondary objectives of the trial |
(1) to demonstrate the efficacy of Sebelipase alfa, relative to placebo, based on the following parameters: decrease in LDL-c, decrease in non-high density lipoprotein cholesterol (HDL-c), normalization of aspartate aminotransferase (AST), decrease in triglycerides, increase in HDL-c, and, in the subset of subjects for whom the assessments are performed, decrease in liver fat content, improvement in hepatic histology, and decrease in liver volume; (2) to evaluate the safety, tolerability, and immunogenicity of Sebelipase alfa therapy; and (3) to further characterise the PK of Sebelipase alfa. |
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E.2.3 | Trial contains a sub-study | No |
E.3 | Principal inclusion criteria |
1. Subject and/or subject’s parent or legal guardian understand the full nature and purpose of the study, including possible risks and side effects, and is willing and able to comply with all compulsory study procedures (including liver biopsy and magnetic resonance imaging [MRI] assessments, as applicable) and provides informed consent/permission prior to any study procedures being performed. If the subject is <18 years of age, he/she is willing to provide assent where required per local regulations and if deemed able to do so. 2. Subject is ≥4 years of age on the date of informed consent. 3. Deficiency of lysosomal acid lipase (LAL) enzyme activity confirmed by dried blood spot (DBS) testing at screening, based on the definition of deficiency provided by the central laboratory performing the assay. 4. ALT ≥1.5x ULN (based on the age- and gender-specific normal ranges of the central laboratory performing the assay) on 2 consecutive screening ALT measurements obtained at least 1 week apart. 5. Female subjects of childbearing potential must (a) have negative serum pregnancy test at screening (b) cannot be breastfeeding, and (c) must agree to use a medically acceptable method of preventing conception from the screening visit until 4 weeks after the last dose of study drug administered under this protocol. A female of childbearing potential is defined as a menarchal female who has not had a hysterectomy, bilateral oophorectomy, or medically documented ovarian failure, and who is not postmenopausal. 6. Subjects receiving lipid-lowering therapies must be on a stable dose of the medication for at least 6 weeks prior to randomization and be willing to remain on a stable dose for at least the first 32 weeks of treatment in the study. 7. Subjects receiving medications for the treatment of non-alcoholic fatty liver disease (e.g., glitazones, high-dose vitamin E, metformin, ursodeoxycholic acid [UDCA]) must be on a stable dose for at least 16 weeks prior to randomization and be willing to remain on a stable dose for at least the first 32 weeks of treatment in the study. |
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E.4 | Principal exclusion criteria |
1. Severe hepatic dysfunction (Child-Pugh Class C). 2. Other medical conditions or comorbidities which, in the opinion of the Investigator, would interfere with study compliance or data interpretation, including but not restricted to severe intercurrent illness, known causes of active liver disease other than LALD (e.g., chronic viral hepatitis, autoimmune hepatitis, alcoholic liver disease, or physician concerns about excess alcohol consumption), human immunodeficiency virus (HIV), poorly-controlled diabetes, or cancers other than non-melanoma skin cancer. 3. Previous hematopoietic or liver transplant procedure. 4. Received treatment with high-dose corticosteroids (acute or chronic) within 26 weeks prior to randomization. (Note: Subjects receiving maintenance therapy with low-dose oral, intranasal, topical, or inhaled corticosteroids are considered eligible for the study.) 5. Participated in a study employing an investigational medicinal product within 30 days prior to randomization. 6. Known hypersensitivity to eggs. |
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E.5 End points |
E.5.1 | Primary end point(s) |
The primary efficacy outcome measure is the proportion of subjects who achieve ALT normalisation (i.e., ALT below the age-and gender-specific ULN provided by the central laboratory performing the assay) at the end of the double-blind treatment period (Week 20). |
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E.5.1.1 | Timepoint(s) of evaluation of this end point |
At the end of the double-blind treatment period (Week 20) |
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E.5.2 | Secondary end point(s) |
The secondary efficacy outcome measures include the following changes (or normalisation or improvement rates, as applicable) from baseline to the end of the double-blind treatment period: (1) Relative reduction in LDL-c (2) Relative reduction in non-HDL-c (3) The proportion of subjects with an abnormal baseline AST (i.e., > ULN) who achieve AST normalisation, based on age- and gender-specific normal ranges provided by the central laboratory performing this assay (4) Relative reduction in triglycerides (5) Relative increase in HDL-c And, in the subset of subjects for whom the assessments are performed: (6) Relative reduction in liver fat content (7) The proportion of subjects who show improvement in liver histopathology, and (8) Relative reduction in liver volume. |
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E.5.2.1 | Timepoint(s) of evaluation of this end point |
The following are all assessed at the end of the double-blind treatment period: (1) LDL-c (2) Non-HDL-c (3) AST normalisation (4) Triglycerides (5) HDL-c (6) Right lobe liver fat content (7) Liver histopathology (8) Liver volume |
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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 | No |
E.6.10 | Pharmacogenetic | Yes |
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 | Yes |
E.8.1.1 | Randomised | Yes |
E.8.1.2 | Open | No |
E.8.1.3 | Single blind | No |
E.8.1.4 | Double blind | Yes |
E.8.1.5 | Parallel group | Yes |
E.8.1.6 | Cross over | No |
E.8.1.7 | Other | Yes |
E.8.1.7.1 | Other trial design description |
20-wks double-blind treatment + an open-label extension of up to 130 wks + 104 wks of extension |
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E.8.2 | Comparator of controlled trial |
E.8.2.1 | Other medicinal product(s) | No |
E.8.2.2 | Placebo | Yes |
E.8.2.3 | Other | No |
E.8.2.4 | Number of treatment arms in the trial | 2 |
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 | 23 |
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 |
Argentina |
Australia |
Belgium |
Brazil |
Chile |
Croatia |
Cyprus |
Czech Republic |
Denmark |
France |
Germany |
Greece |
Israel |
Italy |
Japan |
Mexico |
Netherlands |
Poland |
Romania |
Russian Federation |
South Africa |
Spain |
Sweden |
Taiwan |
Turkey |
Ukraine |
United Kingdom |
United States |
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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
|
The LVLS will be a follow-up call at least 4 weeks after the last dose of study drug |
|
E.8.9 Initial estimate of the duration of the trial |
E.8.9.1 | In the Member State concerned years | 4 |
E.8.9.1 | In the Member State concerned months | 8 |
E.8.9.1 | In the Member State concerned days | 0 |
E.8.9.2 | In all countries concerned by the trial years | 5 |
E.8.9.2 | In all countries concerned by the trial months | 0 |
E.8.9.2 | In all countries concerned by the trial days | 0 |