Back to resultsSafety, Tolerability, Efficacy, Pharmacokinetics, and Pharmacodynamics of Sebelipase Alfa in Children With Growth Failure Due to Lysosomal Acid Lipase Deficiency
Primary Purpose
Lysosomal Acid Lipase Deficiency, Wolman Disease
Status
Completed
Phase
Phase 2
Locations
International
Study Type
Interventional
Intervention
Sebelipase alfa (SBC-102)
Sponsored by
About this trial
This is an interventional treatment trial for Lysosomal Acid Lipase Deficiency focused on measuring LIPA, Wolman Disease, Wolman Phenotype, Acid Lipase Deficiency, Acid Cholesteryl Hydrolase, Acid Lipase Disease Deficiency, type 2, Cholesteryl Ester Storage Disease (CESD), Cholesteryl Ester Hydrolase Deficiency, Early Onset Lysosomal Acid Lipase Deficiency (Wolman Disease), LAL Deficiency, Late Onset Lysosomal Acid Lipase Deficiency (CESD), Wolman Disease (early onset LAL Deficiency), Related Disorders:, Non-alcoholic Fatty Liver Disease (NAFLD), Non-alcoholic Steatohepatitis (NASH), Alcoholic Liver Disease, Cryptogenic Cirrhosis, Niemann-Pick Disease (NPD) Type C, Chanarin Dorfman Syndrome
Eligibility Criteria
Inclusion Criteria:
- Participant's parent or legal guardian provided written informed consent/permission prior to any study procedures.
- Male or female child with documented decreased LAL activity relative to the normal range of the laboratory performing the assay or documented result of molecular genetic testing (2 mutations) confirming a diagnosis.
- Growth failure with onset before 6 months of age.
Exclusion Criteria:
- Clinically important concurrent disease or comorbidities.
- Had received an investigational product other than sebelipase alfa within 14 days prior to the first dose.
- Participant was older than 24 months of age.
- Myeloablative preparation, or other systemic pre-transplant conditioning, for hematopoietic stem cell or liver transplant.
- Previous hematopoietic stem cell or liver transplant.
- Known hypersensitivity to eggs.
Sites / Locations
Arms of the Study
Arm 1
Arm Type
Experimental
Arm Label
Open-Label Sebelipase Alfa
Arm Description
Participants received intravenous (IV) infusions of sebelipase alfa during the open-label treatment. Participants initially received 0.35 milligrams (mg)/kilogram (kg) qw and escalated to 1 mg/kg qw after demonstrating acceptable safety and tolerability during at least 2 infusions. One participant initiated treatment under a Temporary Use Authorization prior to enrollment, wherein the participant's dose was gradually escalated from 0.2 to 1 mg/kg over 4 weeks; the participant started the study at this dose. Participants on treatment for 96 weeks and on stable qw dosing for 24 weeks could be switched to an every other week (qow) dosing schedule. In the event of protocol-defined disease progression at any time during treatment, a participant could receive a dose increase from 1 to 3 mg/kg qw and, if necessary, a dose increase to 5 mg/kg qw with Safety Committee approval. Participants dosed qow who met dose-escalation criteria were reverted to qw dosing or escalated to 1 or 3 mg/kg qow.
Outcomes
Primary Outcome Measures
Percentage Of Participants In The Primary Efficacy Analysis Set (PES) Surviving To 12 Months Of Age
The primary efficacy endpoint was the percentage of participants (%) in the PES who survived to at least 12 months of age.
Secondary Outcome Measures
Percentage Of Participants Surviving Beyond 12 Months Of Age
The percentage of participants in the PES who survived to at least 18 months of age.
Median Age At Death
Participants in the PES who died during the study, including 3 participants who died after having received between 1 and 4 infusions of sebelipase alfa and 1 participant who died after approximately 40 weeks on treatment.
Change From Baseline To Months 12, 24, 36, 48, And 60 In Weight For Age (WFA) Percentiles
Baseline is defined as the last measurement prior to the first infusion of sebelipase alfa.
Number Of Participants With Stunting, Wasting, Or Underweight
The number of participants who met criteria for the following dichotomous indicators of under nutrition were reported. These indicators included the following:
Stunting was defined as at least 2 standard deviations below the median for length-for-age/height-for-age;
Wasting was defined as wasting at least 2 standard deviations below the median for weight-for-length/weight-for-height; and
Underweight was defined as at least 2 standard deviations below the median for WFA.
Change From Baseline To Months 12, 24, 36, 48, And 60 In Serum Transaminases (ALT And AST)
Change from Baseline to Months 12, 24, 36, 48, and 60 for alanine aminotransferase (ALT) and aspartate aminotransferase (AST).
Change From Baseline To Months 12, 24, 36, 48, And 60 In Serum Ferritin
The median change in serum ferritin from Baseline to Months 12, 24, 36, 48, and 60 is presented.
Number Of Participants Achieving And Maintaining Transfusion-free Hemoglobin Normalization [TFHN]
The number of participants achieving and maintaining TFHN are presented.
For TFHN to be achieved, the participant must a) have had 2 post-baseline measurements of hemoglobin at least 4 weeks apart that were both above the age-adjusted lower limit of normal; b) have had no known additional measurements of hemoglobin that were below the age-adjusted lower limit of normal during the (minimum) 4-week period; and c) have had no transfusions during the (minimum) 4-week period, and also no transfusions for 2 weeks prior to the first hemoglobin measurement in the (minimum) 4-week period.
For TFHN to be maintained, the participant must have been transfusion-free beginning at Week 6 and had all hemoglobin assessments above the lower limit of normal beginning in Week 8 and lasting at least 13 weeks.
Full Information
1. Study Identification
Unique Protocol Identification Number
NCT01371825
Brief Title
Safety, Tolerability, Efficacy, Pharmacokinetics, and Pharmacodynamics of Sebelipase Alfa in Children With Growth Failure Due to Lysosomal Acid Lipase Deficiency
Official Title
An Open Label, Multicenter, Dose Escalation Study to Evaluate the Safety, Tolerability, Efficacy, Pharmacokinetics, and Pharmacodynamics of SBC-102 (Sebelipase Alfa) in Children With Growth Failure Due to Lysosomal Acid Lipase Deficiency
Study Type
Interventional
2. Study Status
Record Verification Date
January 2019
Overall Recruitment Status
Completed
Study Start Date
May 4, 2011 (Actual)
Primary Completion Date
January 3, 2018 (Actual)
Study Completion Date
January 3, 2018 (Actual)
3. Sponsor/Collaborators
Responsible Party, by Official Title
Sponsor
Name of the Sponsor
Alexion
4. Oversight
Data Monitoring Committee
Yes
5. Study Description
Brief Summary
This was an open-label, repeat-dose, intra-participant dose-escalation study of SBC-102 (sebelipase alfa) in children with growth failure due to lysosomal acid lipase (LAL) Deficiency. Eligible participants received once-weekly (qw) infusions of sebelipase alfa for up to 5 years.
Detailed Description
LAL Deficiency is a rare autosomal-recessive lipid storage disorder that is caused by a marked decrease or almost complete absence of LAL, leading to the accumulation of lipids, predominately cholesteryl esters and triglycerides, in various tissues and cell types. In the liver, accumulation of lipids leads to hepatomegaly, liver dysfunction, and hepatic failure. Although a single disease, LAL Deficiency presents as a clinical continuum with 2 major phenotypes, Cholesteryl Ester Storage Disease (CESD) and Wolman Disease.
Early-onset LAL Deficiency (Wolman Disease) is extremely rare, with an estimated incidence of less than 2 lives per million. It is characterized by profound malabsorption, growth failure, and hepatic failure, and is usually fatal in the first year of life.
6. Conditions and Keywords
Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study
Lysosomal Acid Lipase Deficiency, Wolman Disease
Keywords
LIPA, Wolman Disease, Wolman Phenotype, Acid Lipase Deficiency, Acid Cholesteryl Hydrolase, Acid Lipase Disease Deficiency, type 2, Cholesteryl Ester Storage Disease (CESD), Cholesteryl Ester Hydrolase Deficiency, Early Onset Lysosomal Acid Lipase Deficiency (Wolman Disease), LAL Deficiency, Late Onset Lysosomal Acid Lipase Deficiency (CESD), Wolman Disease (early onset LAL Deficiency), Related Disorders:, Non-alcoholic Fatty Liver Disease (NAFLD), Non-alcoholic Steatohepatitis (NASH), Alcoholic Liver Disease, Cryptogenic Cirrhosis, Niemann-Pick Disease (NPD) Type C, Chanarin Dorfman Syndrome
7. Study Design
Primary Purpose
Treatment
Study Phase
Phase 2, Phase 3
Interventional Study Model
Single Group Assignment
Masking
None (Open Label)
Allocation
N/A
Enrollment
9 (Actual)
8. Arms, Groups, and Interventions
Arm Title
Open-Label Sebelipase Alfa
Arm Type
Experimental
Arm Description
Participants received intravenous (IV) infusions of sebelipase alfa during the open-label treatment. Participants initially received 0.35 milligrams (mg)/kilogram (kg) qw and escalated to 1 mg/kg qw after demonstrating acceptable safety and tolerability during at least 2 infusions. One participant initiated treatment under a Temporary Use Authorization prior to enrollment, wherein the participant's dose was gradually escalated from 0.2 to 1 mg/kg over 4 weeks; the participant started the study at this dose. Participants on treatment for 96 weeks and on stable qw dosing for 24 weeks could be switched to an every other week (qow) dosing schedule. In the event of protocol-defined disease progression at any time during treatment, a participant could receive a dose increase from 1 to 3 mg/kg qw and, if necessary, a dose increase to 5 mg/kg qw with Safety Committee approval. Participants dosed qow who met dose-escalation criteria were reverted to qw dosing or escalated to 1 or 3 mg/kg qow.
Intervention Type
Drug
Intervention Name(s)
Sebelipase alfa (SBC-102)
Intervention Description
Sebelipase alfa is a recombinant human lysosomal acid lipase enzyme. The investigational medicinal product is an enzyme replacement therapy intended for treatment of participants with LAL Deficiency. Dosing occurred qw for up to 5 years.
Primary Outcome Measure Information:
Title
Percentage Of Participants In The Primary Efficacy Analysis Set (PES) Surviving To 12 Months Of Age
Description
The primary efficacy endpoint was the percentage of participants (%) in the PES who survived to at least 12 months of age.
Time Frame
Month 12
Secondary Outcome Measure Information:
Title
Percentage Of Participants Surviving Beyond 12 Months Of Age
Description
The percentage of participants in the PES who survived to at least 18 months of age.
Time Frame
Baseline to Month 18, Month 24, Month 36, Month 48, and Month 60
Title
Median Age At Death
Description
Participants in the PES who died during the study, including 3 participants who died after having received between 1 and 4 infusions of sebelipase alfa and 1 participant who died after approximately 40 weeks on treatment.
Time Frame
Baseline to Week 260
Title
Change From Baseline To Months 12, 24, 36, 48, And 60 In Weight For Age (WFA) Percentiles
Description
Baseline is defined as the last measurement prior to the first infusion of sebelipase alfa.
Time Frame
Baseline, Month 12, Month 24, Month 36, Month 48, and Month 60
Title
Number Of Participants With Stunting, Wasting, Or Underweight
Description
The number of participants who met criteria for the following dichotomous indicators of under nutrition were reported. These indicators included the following:
Stunting was defined as at least 2 standard deviations below the median for length-for-age/height-for-age;
Wasting was defined as wasting at least 2 standard deviations below the median for weight-for-length/weight-for-height; and
Underweight was defined as at least 2 standard deviations below the median for WFA.
Time Frame
Baseline to Month 12, Month 24, Month 36, Month 48, and Month 60
Title
Change From Baseline To Months 12, 24, 36, 48, And 60 In Serum Transaminases (ALT And AST)
Description
Change from Baseline to Months 12, 24, 36, 48, and 60 for alanine aminotransferase (ALT) and aspartate aminotransferase (AST).
Time Frame
Baseline, Month 12, Month 24, Month 36, Month 48, and Month 60
Title
Change From Baseline To Months 12, 24, 36, 48, And 60 In Serum Ferritin
Description
The median change in serum ferritin from Baseline to Months 12, 24, 36, 48, and 60 is presented.
Time Frame
Baseline, Month 12, Month 24, Month 36, Month 48, and Month 60
Title
Number Of Participants Achieving And Maintaining Transfusion-free Hemoglobin Normalization [TFHN]
Description
The number of participants achieving and maintaining TFHN are presented.
For TFHN to be achieved, the participant must a) have had 2 post-baseline measurements of hemoglobin at least 4 weeks apart that were both above the age-adjusted lower limit of normal; b) have had no known additional measurements of hemoglobin that were below the age-adjusted lower limit of normal during the (minimum) 4-week period; and c) have had no transfusions during the (minimum) 4-week period, and also no transfusions for 2 weeks prior to the first hemoglobin measurement in the (minimum) 4-week period.
For TFHN to be maintained, the participant must have been transfusion-free beginning at Week 6 and had all hemoglobin assessments above the lower limit of normal beginning in Week 8 and lasting at least 13 weeks.
Time Frame
Baseline to Month 60
10. Eligibility
Sex
All
Maximum Age & Unit of Time
24 Months
Accepts Healthy Volunteers
No
Eligibility Criteria
Inclusion Criteria:
Participant's parent or legal guardian provided written informed consent/permission prior to any study procedures.
Male or female child with documented decreased LAL activity relative to the normal range of the laboratory performing the assay or documented result of molecular genetic testing (2 mutations) confirming a diagnosis.
Growth failure with onset before 6 months of age.
Exclusion Criteria:
Clinically important concurrent disease or comorbidities.
Had received an investigational product other than sebelipase alfa within 14 days prior to the first dose.
Participant was older than 24 months of age.
Myeloablative preparation, or other systemic pre-transplant conditioning, for hematopoietic stem cell or liver transplant.
Previous hematopoietic stem cell or liver transplant.
Known hypersensitivity to eggs.
Facility Information:
City
Irvine
State/Province
California
ZIP/Postal Code
92697
Country
United States
City
Cairo
ZIP/Postal Code
11771
Country
Egypt
City
Grenoble
ZIP/Postal Code
38700
Country
France
City
Paris
ZIP/Postal Code
75015
Country
France
City
Dublin
ZIP/Postal Code
1
Country
Ireland
City
London
ZIP/Postal Code
SE1 7EH
Country
United Kingdom
City
Manchester
ZIP/Postal Code
M13 9WL
Country
United Kingdom
12. IPD Sharing Statement
Plan to Share IPD
Undecided
Citations:
PubMed Identifier
28179030
Citation
Jones SA, Rojas-Caro S, Quinn AG, Friedman M, Marulkar S, Ezgu F, Zaki O, Gargus JJ, Hughes J, Plantaz D, Vara R, Eckert S, Arnoux JB, Brassier A, Le Quan Sang KH, Valayannopoulos V. Survival in infants treated with sebelipase Alfa for lysosomal acid lipase deficiency: an open-label, multicenter, dose-escalation study. Orphanet J Rare Dis. 2017 Feb 8;12(1):25. doi: 10.1186/s13023-017-0587-3.
Results Reference
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Safety, Tolerability, Efficacy, Pharmacokinetics, and Pharmacodynamics of Sebelipase Alfa in Children With Growth Failure Due to Lysosomal Acid Lipase Deficiency
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