Back to resultsSafety and Efficacy Study of Sebelipase Alfa in Participants With Lysosomal Acid Lipase Deficiency
Primary Purpose
Lysosomal Acid Lipase Deficiency
Status
Completed
Phase
Phase 2
Locations
International
Study Type
Interventional
Intervention
Sebelipase Alfa
Sponsored by
About this trial
This is an interventional treatment trial for Lysosomal Acid Lipase Deficiency focused on measuring Enzyme Replacement Therapy (ERT), Lysosomal Storage Disease, Late Onset Lysosomal Acid Lipase (LAL) Deficiency, Acid cholesteryl ester hydrolase deficiency, type 2, Acid lipase disease, Cholesterol ester hydrolase deficiency, LAL Deficiency, LIPA Deficiency, Wolman disease, Additional relevant MeSH terms:, Cholesterol Ester Storage Disease, Metabolic Diseases, Lipidoses, Lipid Metabolism, Inborn Errors, Metabolism, Inborn Errors, Genetic Diseases, Inborn, Lysosomal Storage Diseases, Lipid Metabolism Disorders, Infant, Newborn, Diseases
Eligibility Criteria
Key Inclusion Criteria:
- Participant was >8 months of age at the time of dosing.
- Confirmation of LAL-D diagnosis as determined by the central laboratory or, for participants with prior hematopoietic stem cell transplant or liver transplant, historical enzyme activity or molecular genetic testing confirming a diagnosis of LAL-D.
Participants >8 months but <4 years of age at Screening had at least 1 of the following documented clinical manifestations of LAL-D:
- Dyslipidemia
- Elevated transaminases
- Impaired growth
- Suspected malabsorption
- Other clinical manifestation of LAL-D
Participants ≥4 years of age at Screening had at least 1 of the following documented clinical manifestations of LAL-D:
- Evidence of advanced liver disease
- Histologically confirmed disease recurrence in participants with past liver or hematopoietic transplant
- Persistent dyslipidemia
- Suspected malabsorption
- Other clinical manifestation of LAL-D
Key Exclusion Criteria:
- Participant had known causes of active liver disease other than LAL-D, which had not been adequately treated.
- Participant received a hematopoietic stem cell or liver transplant <2 years from the time of dosing.
- Participant with co-morbidities other than complications due to LAL-D, which were irreversible or associated with a high mortality risk within 6 months or would interfere with study compliance or data interpretation.
Sites / Locations
Arms of the Study
Arm 1
Arm Type
Experimental
Arm Label
Sebelipase Alfa
Arm Description
Pediatric and adult participants initiated IV treatment with sebelipase alfa at a dose of 1 mg/kg qow. Participants were considered for a dose adjustment at the discretion of the Investigator and in consultation with the Sponsor. Dose escalation to 3 mg/kg qow was considered if pre-defined dose-escalation criteria were met. If these criteria continued to be met, a subsequent dose escalation to 3 mg/kg every week (qw) was considered. Dose decreases as low as 0.35 mg/kg qow were permitted based upon evidence of intolerance to sebelipase alfa treatment. Participants who completed the 96-week treatment period were permitted to continue receiving sebelipase alfa in an expanded treatment period for up to 48 weeks, pending local drug availability and study participation status.
Outcomes
Primary Outcome Measures
Participants Experiencing Severe Treatment-emergent Adverse Events (TEAEs)
The number of participants experiencing severe TEAEs is presented for participants who received sebelipase alfa in this open-label study. Adverse events (AEs) information was obtained at each scheduled contact with the participant (or participant's parent or legal guardian). An AE was defined as any untoward medical occurrence that did not require a causal relationship with study drug administration. An AE could have been any unfavorable and unintended sign, symptom, or disease temporally associated with the use of the study drug, whether or not considered related to the study drug. Pre-existing conditions that worsened in severity during the study were reported as AEs. A summary of all serious and other non-serious AEs regardless of causality is located in the Reported AE module. Severity assessed using Clinical Data Interchange Standards Consortium Study Data Tabulation Model standard terminology v3.1.1. Data presented only according to age group, not dose of study drug received.
Secondary Outcome Measures
Percent Change In Serum Lipids From Baseline To Week 144
The effect of sebelipase alfa on lipid metabolism was evaluated by measuring the change from baseline to Week 144 in 4 serum lipids: low-density lipoprotein cholesterol (LDL-C); high-density lipoprotein cholesterol (HDL-C); non-HDL-C; triglycerides. Blood samples for these clinical laboratory tests were collected at scheduled time points and analyzed by a central laboratory.
Participants Testing Positive For Anti-drug Antibodies (ADAs)
The impact of ADAs on the safety and immunogenicity of sebelipase alfa was evaluated by testing for ADAs in participants who received sebelipase alfa in this open-label study. Blood samples for assessment were collected prior to study infusions at Week 2, Week 4, Week 8, Week 12, and every 12 weeks thereafter. Participants testing positive for ADAs were also tested for the presence of neutralizing antibodies that inhibited sebelipase alfa enzyme activity and/or cellular uptake. Any participant experiencing a moderate or severe infusion-associated reaction (IAR) was to have an additional assessment of ADAs at the next study visit (prior to study drug infusion); these participants were to also have serum samples collected at 1 to 2 hours after IAR onset and at the next study visit (prior to study drug infusion) for analysis of serum tryptase. The count of participants who became ADA positive and who tested positive for neutralizing antibodies are presented.
Percent Change In Body Mass Index (BMI)-For-Age Percentile From Baseline To Week 144 In Pediatric Participants
To evaluate the effects of sebelipase alfa on growth parameters in pediatric participants (≤18 years old) presenting with evidence of growth delay, the percent change in the anthropometric parameter of BMI-for-age percentile from Baseline to Week 144 is reported. Anthropometric parameters were plotted on standard growth curves. When possible, historical data on growth parameters was also incorporated into the analyses. Percentiles and Z-scores for BMI-for-age were determined using standard growth charts appropriate to a participant's age on the date of the assessment: the World Health Organization standard growth chart for participants ≤2 years of age and the Centers for Disease Control standard growth chart for participants >2 years of age.
Shift In Child-Pugh Status From Baseline To Week 144
In order to evaluate the effects of sebelipase alfa on liver function, the number of participants with a shift in Child-Pugh status from Baseline to Week 144 is reported. The status is based on the Child-Pugh score, which is used in clinical practice to assess prognosis in individuals with chronic liver disease. Laboratory data were used in derivation of the score by summing individual scores (scored 1-3, with 3 indicating most severe) from clinical laboratory test results and physical examinations, including total serum bilirubin, serum albumin, prothrombin time, ascites, and hepatic encephalopathy. The total score was used to determine the Child-Pugh status, reported as Class A (score of 5 or 6), Class B (score of 7 to 9), or Class C (score of 10 to 15). Higher scores and higher categories represented a worse outcome. Data reported as 1 of 2 types of shifts in class: No Change from Baseline; Decline from Baseline.
Full Information
1. Study Identification
Unique Protocol Identification Number
NCT02112994
Brief Title
Safety and Efficacy Study of Sebelipase Alfa in Participants With Lysosomal Acid Lipase Deficiency
Official Title
A Multi-Center, Open-Label Study of Sebelipase Alfa in Patients With Lysosomal Acid Lipase Deficiency
Study Type
Interventional
2. Study Status
Record Verification Date
November 2019
Overall Recruitment Status
Completed
Study Start Date
June 24, 2014 (Actual)
Primary Completion Date
December 28, 2017 (Actual)
Study Completion Date
December 28, 2017 (Actual)
3. Sponsor/Collaborators
Responsible Party, by Official Title
Sponsor
Name of the Sponsor
Alexion
4. Oversight
Studies a U.S. FDA-regulated Drug Product
Yes
Studies a U.S. FDA-regulated Device Product
No
Data Monitoring Committee
Yes
5. Study Description
Brief Summary
This study evaluated the safety and efficacy of sebelipase alfa in a broad population of participants with lysosomal acid lipase deficiency (LAL-D).
Detailed Description
The primary objective of this study was to evaluate the safety of intravenous (IV) infusions of sebelipase alfa in a more broad population of LAL-D participants than previously studied. Such participants may have been excluded from enrollment in other studies of LAL-D because of age, disease progression, previous treatment by hematopoietic stem cell or liver transplantation, less common disease manifestations, or disease characteristics that would preclude participation in a placebo-controlled study. This open-label study included infants >8 months, children, and adults. At least 4 participants in the study were to be between the age of 2 and 4 years. Eligible participants received sebelipase alfa at a dose of 1 milligram/kilogram (mg/kg) every other week (qow).
6. Conditions and Keywords
Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study
Lysosomal Acid Lipase Deficiency
Keywords
Enzyme Replacement Therapy (ERT), Lysosomal Storage Disease, Late Onset Lysosomal Acid Lipase (LAL) Deficiency, Acid cholesteryl ester hydrolase deficiency, type 2, Acid lipase disease, Cholesterol ester hydrolase deficiency, LAL Deficiency, LIPA Deficiency, Wolman disease, Additional relevant MeSH terms:, Cholesterol Ester Storage Disease, Metabolic Diseases, Lipidoses, Lipid Metabolism, Inborn Errors, Metabolism, Inborn Errors, Genetic Diseases, Inborn, Lysosomal Storage Diseases, Lipid Metabolism Disorders, Infant, Newborn, Diseases
7. Study Design
Primary Purpose
Treatment
Study Phase
Phase 2
Interventional Study Model
Sequential Assignment
Masking
None (Open Label)
Enrollment
31 (Actual)
8. Arms, Groups, and Interventions
Arm Title
Sebelipase Alfa
Arm Type
Experimental
Arm Description
Pediatric and adult participants initiated IV treatment with sebelipase alfa at a dose of 1 mg/kg qow. Participants were considered for a dose adjustment at the discretion of the Investigator and in consultation with the Sponsor. Dose escalation to 3 mg/kg qow was considered if pre-defined dose-escalation criteria were met. If these criteria continued to be met, a subsequent dose escalation to 3 mg/kg every week (qw) was considered. Dose decreases as low as 0.35 mg/kg qow were permitted based upon evidence of intolerance to sebelipase alfa treatment. Participants who completed the 96-week treatment period were permitted to continue receiving sebelipase alfa in an expanded treatment period for up to 48 weeks, pending local drug availability and study participation status.
Intervention Type
Drug
Intervention Name(s)
Sebelipase Alfa
Other Intervention Name(s)
SBC-102
Intervention Description
IV infusion of sebelipase alfa
Primary Outcome Measure Information:
Title
Participants Experiencing Severe Treatment-emergent Adverse Events (TEAEs)
Description
The number of participants experiencing severe TEAEs is presented for participants who received sebelipase alfa in this open-label study. Adverse events (AEs) information was obtained at each scheduled contact with the participant (or participant's parent or legal guardian). An AE was defined as any untoward medical occurrence that did not require a causal relationship with study drug administration. An AE could have been any unfavorable and unintended sign, symptom, or disease temporally associated with the use of the study drug, whether or not considered related to the study drug. Pre-existing conditions that worsened in severity during the study were reported as AEs. A summary of all serious and other non-serious AEs regardless of causality is located in the Reported AE module. Severity assessed using Clinical Data Interchange Standards Consortium Study Data Tabulation Model standard terminology v3.1.1. Data presented only according to age group, not dose of study drug received.
Time Frame
Screening, Week 144
Secondary Outcome Measure Information:
Title
Percent Change In Serum Lipids From Baseline To Week 144
Description
The effect of sebelipase alfa on lipid metabolism was evaluated by measuring the change from baseline to Week 144 in 4 serum lipids: low-density lipoprotein cholesterol (LDL-C); high-density lipoprotein cholesterol (HDL-C); non-HDL-C; triglycerides. Blood samples for these clinical laboratory tests were collected at scheduled time points and analyzed by a central laboratory.
Time Frame
Baseline, Week 144
Title
Participants Testing Positive For Anti-drug Antibodies (ADAs)
Description
The impact of ADAs on the safety and immunogenicity of sebelipase alfa was evaluated by testing for ADAs in participants who received sebelipase alfa in this open-label study. Blood samples for assessment were collected prior to study infusions at Week 2, Week 4, Week 8, Week 12, and every 12 weeks thereafter. Participants testing positive for ADAs were also tested for the presence of neutralizing antibodies that inhibited sebelipase alfa enzyme activity and/or cellular uptake. Any participant experiencing a moderate or severe infusion-associated reaction (IAR) was to have an additional assessment of ADAs at the next study visit (prior to study drug infusion); these participants were to also have serum samples collected at 1 to 2 hours after IAR onset and at the next study visit (prior to study drug infusion) for analysis of serum tryptase. The count of participants who became ADA positive and who tested positive for neutralizing antibodies are presented.
Time Frame
Week 144
Title
Percent Change In Body Mass Index (BMI)-For-Age Percentile From Baseline To Week 144 In Pediatric Participants
Description
To evaluate the effects of sebelipase alfa on growth parameters in pediatric participants (≤18 years old) presenting with evidence of growth delay, the percent change in the anthropometric parameter of BMI-for-age percentile from Baseline to Week 144 is reported. Anthropometric parameters were plotted on standard growth curves. When possible, historical data on growth parameters was also incorporated into the analyses. Percentiles and Z-scores for BMI-for-age were determined using standard growth charts appropriate to a participant's age on the date of the assessment: the World Health Organization standard growth chart for participants ≤2 years of age and the Centers for Disease Control standard growth chart for participants >2 years of age.
Time Frame
Baseline, Week 144
Title
Shift In Child-Pugh Status From Baseline To Week 144
Description
In order to evaluate the effects of sebelipase alfa on liver function, the number of participants with a shift in Child-Pugh status from Baseline to Week 144 is reported. The status is based on the Child-Pugh score, which is used in clinical practice to assess prognosis in individuals with chronic liver disease. Laboratory data were used in derivation of the score by summing individual scores (scored 1-3, with 3 indicating most severe) from clinical laboratory test results and physical examinations, including total serum bilirubin, serum albumin, prothrombin time, ascites, and hepatic encephalopathy. The total score was used to determine the Child-Pugh status, reported as Class A (score of 5 or 6), Class B (score of 7 to 9), or Class C (score of 10 to 15). Higher scores and higher categories represented a worse outcome. Data reported as 1 of 2 types of shifts in class: No Change from Baseline; Decline from Baseline.
Time Frame
Baseline, Week 144
10. Eligibility
Sex
All
Minimum Age & Unit of Time
8 Months
Accepts Healthy Volunteers
No
Eligibility Criteria
Key Inclusion Criteria:
Participant was >8 months of age at the time of dosing.
Confirmation of LAL-D diagnosis as determined by the central laboratory or, for participants with prior hematopoietic stem cell transplant or liver transplant, historical enzyme activity or molecular genetic testing confirming a diagnosis of LAL-D.
Participants >8 months but <4 years of age at Screening had at least 1 of the following documented clinical manifestations of LAL-D:
Dyslipidemia
Elevated transaminases
Impaired growth
Suspected malabsorption
Other clinical manifestation of LAL-D
Participants ≥4 years of age at Screening had at least 1 of the following documented clinical manifestations of LAL-D:
Evidence of advanced liver disease
Histologically confirmed disease recurrence in participants with past liver or hematopoietic transplant
Persistent dyslipidemia
Suspected malabsorption
Other clinical manifestation of LAL-D
Key Exclusion Criteria:
Participant had known causes of active liver disease other than LAL-D, which had not been adequately treated.
Participant received a hematopoietic stem cell or liver transplant <2 years from the time of dosing.
Participant with co-morbidities other than complications due to LAL-D, which were irreversible or associated with a high mortality risk within 6 months or would interfere with study compliance or data interpretation.
Facility Information:
City
Chicago
State/Province
Illinois
ZIP/Postal Code
60611
Country
United States
City
Shreveport
State/Province
Louisiana
ZIP/Postal Code
71103
Country
United States
City
Cincinnati
State/Province
Ohio
ZIP/Postal Code
45229
Country
United States
City
Westmead
ZIP/Postal Code
NSW 2145
Country
Australia
City
Brussels
ZIP/Postal Code
1200
Country
Belgium
City
Sao Paulo
ZIP/Postal Code
04024-002
Country
Brazil
City
Halifax
State/Province
Nova Scotia
ZIP/Postal Code
B3H 1V7
Country
Canada
City
Zagreb
ZIP/Postal Code
10000
Country
Croatia
City
Copenhagen
ZIP/Postal Code
2100
Country
Denmark
City
Freiburg
ZIP/Postal Code
79106
Country
Germany
City
Padova
ZIP/Postal Code
35128
Country
Italy
City
Mexico City
ZIP/Postal Code
06720
Country
Mexico
City
Amsterdam
ZIP/Postal Code
1105
Country
Netherlands
City
Moscow
ZIP/Postal Code
117997
Country
Russian Federation
City
A Coruna
ZIP/Postal Code
15006
Country
Spain
City
Barcelona
ZIP/Postal Code
08036
Country
Spain
City
Madrid
ZIP/Postal Code
28046
Country
Spain
City
Balcali
ZIP/Postal Code
01300
Country
Turkey
City
Birmingham
ZIP/Postal Code
B4 6NH
Country
United Kingdom
12. IPD Sharing Statement
Citations:
PubMed Identifier
35442238
Citation
Burton BK, Sanchez AC, Kostyleva M, Martins AM, Marulkar S, Abel F, Baric I. Long-Term Sebelipase Alfa Treatment in Children and Adults With Lysosomal Acid Lipase Deficiency. J Pediatr Gastroenterol Nutr. 2022 Jun 1;74(6):757-764. doi: 10.1097/MPG.0000000000003452. Epub 2022 Apr 19.
Results Reference
derived
Learn more about this trial
Safety and Efficacy Study of Sebelipase Alfa in Participants With Lysosomal Acid Lipase Deficiency
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