|E.1 Medical condition or disease under investigation
|Medical condition(s) being investigated
|Lysosomal Acid Lipase Deficiency (LALD)
|Medical condition in easily understood language
|Insufficient lysosomal acid lipase activity leading to accumulation of fats in the human body.
|Diseases [C] - Congenital, Hereditary, and Neonatal Diseases and Abnormalities [C16]
|E.1.2 Medical condition or disease under investigation
|Lysosomal storage disorders
|System Organ Class
|Condition being studied is a rare disease
|E.2 Objective of the trial
|Main objective of the trial
|The primary objective of this study is to evaluate the safety of sebelipase alfa in a broad population of patients with LALD than previously studied.
|Secondary objectives of the trial
|The secondary objectives of this study are (1) to evaluate effects of sebelipase alfa relative to Baseline assessment of lipid metabolism and liver function (including histopathology); (2) to evaluate the effects of sebelipase alfa on additional clinical parameters of LALD including those not previously well characterized in the literature, and (3) to evaluate the effects of sebelipase alfa on growth parameters in pediatric patients presenting with evidence of growth delay.
|Trial contains a sub-study
|Principal inclusion criteria
|1. Subject will be > 8 months of age at the time of dosing.
2. Subject or subject's parent or legal guardian consents to participation in the study. If the subject is of minor age, he/she is willing to provide assent where required per local regulations, and if deemed able to do so.
3. Confirmation of LALD diagnosis as determined by the central lab; a subject who received a liver or hematopoietic stem cell transplant who does not show evidence of LAL enzyme deficiency by DBS due to the effects of transplantation must have either:
a. Molecular genetic testing which confirms mutations in both alleles of the LIPA gene; OR
b. Appropriately documented historical result of an enzyme test prior to hematopoietic or liver transplantation.
4. Subjects > 8 months but < 4 years of age at Screening will have at
least 1 of the following documented clinical manifestations of LALD:
a. Dyslipidemia (defined as Screening LDL-C > 130 mg/dL; TG > 200
b. Elevated transaminases (ALT ≥1.5x ULN);
c. Impaired growth as defined as:
i. WFA or SFA less than the age- and gender-appropriate 5th percentile on a standard WHO (subjects ≤ 24 months of age) or CDC (subjects > 24 months and < 4 years of age) WFA or SFA chart for at least 3 months prior to study entry; OR
ii. Poor weight gain as evidenced by calculated weight percentile
decreasing across 2 major percentile (99th, 97th, 95th, 90th, 75th, 50th, 25th, 10th, 5th, 3rd, and 1st) lines on a standard WHO (subjects ≤24 months of age) or CDC subjects > 24 months and <4 years of age) WFA chart over a period of 6 months prior to study entry;
d. Suspected malabsorption with:
i. Persistent unexplained gastrointestinal symptoms such as nausea,
diarrhea, abdominal pain, and bloating; OR
ii. Unexplained anemia, or other abnormalities suggestive of
iii. Documented small intestinal disease involvement on a small bowel biopsy performed within 1 year of Screening
e. Other clinical manifestation of LALD in the opinion of the investigator and in consultation with the Sponsor.
5. Subjects ≥ 4 years of age at Screening will have at least 1 of the
following documented clinical manifestations of LALD:
a. Evidence of advanced liver disease at Screening accompanied by:
i. Clinically significant portal hypertension as defined by a hepatic
venous pressure gradient (HVPG) greater than or equal to 10 mmHg; OR
ii. Documented esophageal varices at Screening.
b. Disease recurrence in subjects with past liver or hematopoietic
c. Persistent dyslipidemia (defined as LDL-C > 130mg/dL, triglycerides > 200mg/dL, or HDL-C <40mg/dL in males, and
< 50mg/dL in females) that has persisted despite 3 or more months of treatment with one or more lipid-lowering therapies such as statins, cholesterol absorption inhibitors (ezetimibe), combination therapies
(single-pill; ezetimibe/simvastatin, niacin/simvastatin), fibrates
(fenofibrate, gemfibrozil, fenofibric acid), niacin or bile acid
sequestrants (cholestyramine, colestipol, colesevelam);
d. Suspected malabsorption based on the following manifestations:
i. Documented small intestinal involvement by small bowel biopsy
performed within 1 year of Screening; AND
ii. Unexplained iron deficiency, osteopenia, weight loss or chronic
iii. Impaired growth in pediatric subjects defined as:
1. WFA or SFA less than the age- and gender-appropriate 5th percentileon a standard CDC WFA chart for at least 6 months prior to study entry;
2. Poor weight gain as evidenced by calculated weight percentile
decreasing across 2 major percentile lines on a standard CDC WFA chart over a period of 6 months prior to study entry;
e. Other clinical manifestation of LAL Deficiency in the opinion of the investigator and in consultation with the Sponsor .
6. Male and female subjects of childbearing potential must agree to use a highly reliable method of birth control from the screening visit through 4 weeks after the last dose of study drug.
7. Women of childbearing potential must have a negative serum
pregnancy test prior to entering the study.
8. Subjects receiving lipid-lowering therapies must be on a stable dose of the medication or stable apheresis regimen for at least 4 weeks prior to treatment and be willing to remain on a stable dose for at least the first 12 weeks of treatment in the study.
9. Subjects receiving medications for the treatment of nonalcoholic fatty liver disease must be on a stable dose for at least 4 weeks prior to treatment and be willing to remain on a stable dose for at least the first 12 weeks of treatment in the study.
|Principal exclusion criteria
|1. Subject meets eligibility criteria for another interventional study of sebelipase alfa in LALD that is open for enrollment in the region where the subject will receive treatment.
2. Subject has known causes of active liver disease other than LALD
which have not been adequately treated
3. Subject is unable or unwilling to comply with study procedures.
4. Subject received a hematopoietic stem cell or liver transplant < 2
years from the time of dosing.
5. Females who are nursing or pregnant.
6. Subject with co-morbidities other than complications due to LALD
which, in the opinion of the Investigator and in consultation with the Sponsor, are irreversible or associated with a high mortality risk within 6 months, or would interfere with study compliance or data interpretation.
7. Exposure to any investigational product within 30 days of Screening for a small molecule and 60 days of Screening for a biologic.
8. Known hypersensitivity to eggs.
|E.5 End points
|Primary end point(s)
|Safety endpoints will include the incidence of adverse events (AEs),
SAEs, and infusion-associated reactions (IARs); changes from Baseline in 12-lead electrocardiograms (ECGs) and clinical laboratory tests (hematology, serum chemistry [including lipid panel], and urinalysis); changes in vital signs during and after infusion, relative to pre-infusion values; physical examination findings; use of concomitant medications/therapies; characterization of anti-drug antibodies (ADAs) including ADA titer by time point, peak ADA titer, and time to peak ADA
titer. The effect of ADAs on the safety of sebelipase alfa will also be
explored, in particular, the relationship between ADA-positive subjects and the incidence of IARs. Functional and overall development in subjects ≤ 6 years of age will be assessed, as determined by Denver II scores.
|Timepoint(s) of evaluation of this end point
|Screening will occur within 45 days.Eligible patients will receive intravenous infusions of sebelipase alfa for up to 96 weeks, an expanded treatment period of a maximum of up to 48 weeks. All patients will receive a starting dose of 1 mg•kg-1 qow. Dose increases (up to 3 mg•kg-1 qw) will be permitted during the treatment period. The follow up period will be 4 weeks from the last infusion of sebelipase alfa.
|Secondary end point(s)
|Secondary outcome measures include the following changes or percent change from Baseline to the end of the treatment period: (1) decrease in Alanine Aminotransferase (ALT); (2) decrease in Aspartate Aminotransferase (AST); (3) decrease in LDL-C; (4) decrease in non-HDL-C; (5) increase in HDL-C; (6) decrease in triglyceride, (7) decrease in Child-Pugh status, (8) decrease in United Kingdom Model for End-Stage Liver Disease (UKELD) score. In the subset of subjects for whom these assessments are
performed: (9) improvement in hepatic histology; (10) decrease in liver and spleen volume by MRI; and (11) decrease in liver fat fraction by MRI. The effect of sebelipase alfa on growth parameters in pediatric subjects with manifestations of impaired growth will be measured.
Additional clinical, biochemical and hematological abnormalities will also be evaluated, including (1) total and conjugated bilirubin, (2) gamma glutamyltransferase (GGT), (3) markers of macrophage activation, (4) high-sensitivity C-reactive protein, (4) hemoglobin level, and (5) platelet count.
Exploratory measures of additional clinical manifestations of LALD not previously well characterized in the literature will include changes in functional assessments outcomes.
PK parameters (in subjects for whom these assessments are performed) will be reported, as the data permit, and may include serum clearance and apparent volume of distribution estimates along with secondary parameters of area under the concentration-time curve, maximum observed concentration, time to maximum observed concentration, and terminal elimination half-life (t1/2). The effect of ADAs on sebelipase alfa PK will also be explored.
PK analysis will be discussed in the statistical analysis plan (SAP).
Health-Related Quality of Life Exploratory HRQOL measures will include changes from Baseline in scores for the Functional Assessment of Chronic Illness Therapy-Fatigue scale, Chronic Liver Disease Questionnaire, or Pediatric Quality of Life Inventory (PedsQL™) Generic Core Scales, as appropriate to the age of the subject.
Pharmacodynamics Exploratory disease-related biomarkers, which may be identified based on emerging information from the Sebelipase alfa development program and scientific literature, will be analyzed by changes or percent changes over time.
|Timepoint(s) of evaluation of this end point
|Screening will occur within 45 days.Eligible patients will receive intravenous infusions of sebelipase alfa for up to 96 weeks. All patients will receive a starting dose of 1 mg·kg-1 qow. Dose increases (up to 3 mg·kg-1 qw) will be permitted during the treatment period. The follow-up period will be at least 4 weeks from the last infusion of sebelipase alfa.
|E.6 and E.7 Scope of the trial
|Scope of the trial
|Trial type and phase
|Human pharmacology (Phase I)
|First administration to humans
|Other trial type description
|Therapeutic exploratory (Phase II)
|Therapeutic confirmatory (Phase III)
|Therapeutic use (Phase IV)
|E.8 Design of the trial
| Comparator of controlled trial
|Other medicinal product(s)
|Number of treatment arms in the trial
The trial involves single site in the Member State concerned
| The trial involves multiple sites in the Member State concerned
|The trial involves multiple Member States
|Number of sites anticipated in the EEA
|E.8.6 Trial involving sites outside the EEA
|Trial being conducted both within and outside the EEA
|Trial being conducted completely outside of the EEA
|If E.8.6.1 or E.8.6.2 are Yes, specify the regions in which trial sites are planned
|Trial has a data monitoring committee
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
|In the Member State concerned years
|In the Member State concerned months
|In the Member State concerned days
|In all countries concerned by the trial years
|In all countries concerned by the trial months