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Safety and Efficacy Study of Sebelipase Alfa in Participants With Lysosomal Acid Lipase Deficiency

The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been evaluated by the U.S. Federal Government. Read our disclaimer for details.
 
ClinicalTrials.gov Identifier: NCT02112994
Recruitment Status : Completed
First Posted : April 14, 2014
Results First Posted : January 15, 2019
Last Update Posted : December 4, 2019
Sponsor:
Information provided by (Responsible Party):
Alexion Pharmaceuticals

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).

Condition or disease Intervention/treatment Phase
Lysosomal Acid Lipase Deficiency Drug: Sebelipase Alfa Phase 2

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).

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Study Type : Interventional  (Clinical Trial)
Actual Enrollment : 31 participants
Intervention Model: Sequential Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Official Title: A Multi-Center, Open-Label Study of Sebelipase Alfa in Patients With Lysosomal Acid Lipase Deficiency
Actual Study Start Date : June 24, 2014
Actual Primary Completion Date : December 28, 2017
Actual Study Completion Date : December 28, 2017


Arm Intervention/treatment
Experimental: Sebelipase Alfa
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.
Drug: Sebelipase Alfa
IV infusion of sebelipase alfa
Other Name: SBC-102




Primary Outcome Measures :
  1. Participants Experiencing Severe Treatment-emergent Adverse Events (TEAEs) [ Time Frame: Screening, Week 144 ]
    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 :
  1. Percent Change In Serum Lipids From Baseline To Week 144 [ Time Frame: Baseline, 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.

  2. Participants Testing Positive For Anti-drug Antibodies (ADAs) [ Time Frame: Week 144 ]
    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.

  3. Percent Change In Body Mass Index (BMI)-For-Age Percentile From Baseline To Week 144 In Pediatric Participants [ Time Frame: Baseline, Week 144 ]
    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.

  4. Shift In Child-Pugh Status From Baseline To Week 144 [ Time Frame: Baseline, 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.



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Ages Eligible for Study:   8 Months and older   (Child, Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
Criteria

Key Inclusion Criteria:

  1. Participant was >8 months of age at the time of dosing.
  2. 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.
  3. 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
  4. 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:

  1. Participant had known causes of active liver disease other than LAL-D, which had not been adequately treated.
  2. Participant received a hematopoietic stem cell or liver transplant <2 years from the time of dosing.
  3. 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.

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT02112994


Locations
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United States, Illinois
Chicago, Illinois, United States, 60611
United States, Louisiana
Shreveport, Louisiana, United States, 71103
United States, Ohio
Cincinnati, Ohio, United States, 45229
Australia
Westmead, Australia, NSW 2145
Belgium
Brussels, Belgium, 1200
Brazil
Sao Paulo, Brazil, 04024-002
Canada, Nova Scotia
Halifax, Nova Scotia, Canada, B3H 1V7
Croatia
Zagreb, Croatia, 10000
Denmark
Copenhagen, Denmark, 2100
Germany
Freiburg, Germany, 79106
Italy
Padova, Italy, 35128
Mexico
Mexico City, Mexico, 06720
Netherlands
Amsterdam, Netherlands, 1105
Russian Federation
Moscow, Russian Federation, 117997
Spain
A Coruna, Spain, 15006
Barcelona, Spain, 08036
Madrid, Spain, 28046
Turkey
Balcali, Turkey, 01300
United Kingdom
Birmingham, United Kingdom, B4 6NH
Sponsors and Collaborators
Alexion Pharmaceuticals
  Study Documents (Full-Text)

Documents provided by Alexion Pharmaceuticals:
Study Protocol  [PDF] December 7, 2015
Statistical Analysis Plan  [PDF] November 17, 2016


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Responsible Party: Alexion Pharmaceuticals
ClinicalTrials.gov Identifier: NCT02112994    
Other Study ID Numbers: LAL-CL06
2011-004287-30 ( EudraCT Number )
First Posted: April 14, 2014    Key Record Dates
Results First Posted: January 15, 2019
Last Update Posted: December 4, 2019
Last Verified: November 2019

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Studies a U.S. FDA-regulated Drug Product: Yes
Studies a U.S. FDA-regulated Device Product: No
Keywords provided by Alexion Pharmaceuticals:
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
Additional relevant MeSH terms:
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Wolman Disease
Cholesterol Ester Storage Disease
Lipidoses
Lipid Metabolism, Inborn Errors
Metabolism, Inborn Errors
Genetic Diseases, Inborn
Lysosomal Storage Diseases
Infant, Newborn, Diseases
Lipid Metabolism Disorders
Metabolic Diseases