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Clinical Study In Infants With Rapidly Progressive 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. Identifier: NCT02193867
Recruitment Status : Terminated
First Posted : July 18, 2014
Results First Posted : November 18, 2019
Last Update Posted : November 18, 2019
Information provided by (Responsible Party):
Alexion Pharmaceuticals

Brief Summary:
This was an open-label, repeat-dose, study of sebelipase alfa in infants with rapidly progressive lysosomal acid lipase deficiency (LAL-D). Eligible participants received once-weekly infusions of sebelipase alfa for up to 3 years.

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

Detailed Description:

Lysosomal acid lipase deficiency is a rare autosomal recessive lipid storage disorder that is caused by a marked decrease or complete absence of the LAL enzyme, leading to the accumulation of lipids, predominately cholesteryl esters and triglycerides, in various tissues and cell types. In the liver, accumulation of lipids in hepatocytes and macrophages leads to hepatomegaly, fibrosis, cirrhosis, liver dysfunction, and hepatic failure. In the small intestine, lipid-laden macrophage accumulation in the lamina propria leads to profound malabsorption.

Lysosomal acid lipase deficiency presenting in infancy is an extremely rare form of the disease characterized by profound malabsorption, growth failure, and hepatic failure that is usually fatal within the first 6 months of life.

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Study Type : Interventional  (Clinical Trial)
Actual Enrollment : 10 participants
Allocation: N/A
Intervention Model: Single Group Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Official Title: A Phase 2, Open Label, Multicenter Study to Evaluate the Safety, Tolerability, Efficacy, and Pharmacokinetics of Sebelipase Alfa in Infants With Rapidly Progressive Lysosomal Acid Lipase Deficiency
Actual Study Start Date : June 6, 2014
Actual Primary Completion Date : October 30, 2018
Actual Study Completion Date : October 30, 2018

Arm Intervention/treatment
Experimental: Open-Label Sebelipase Alfa
All participants initiated once weekly (qw) intravenous (IV) infusions with sebelipase alfa at a dose of 1 milligram/kilogram (mg/kg) qw. A participant who met protocol defined dose escalation criteria at a dose of 1 mg/kg qw could be considered for a dose escalation to 3 mg/kg qw. If a participant continued to meet dose escalation criteria after at least 4 infusions at a dose of 3 mg/kg qw, the participant could be considered for a further dose escalation to 5 mg/kg qw. Under country-specific provisions (United Kingdom only), participants could be considered for a further dose escalation to 7.5 mg/kg qw if a thorough case review indicated that a participant continued to have evidence of disease progression at a dose of 5 mg/kg qw. All dose escalations were contingent upon acceptable safety and tolerability of preceding infusions and were undertaken by mutual agreement of the Investigator and Sponsor and after approval by an independent safety committee.
Drug: Sebelipase Alfa
Sebelipase alfa is a recombinant human lysosomal acid lipase. The investigational medicinal product is an enzyme replacement therapy intended for treatment of participants with LAL-D. Dosing occurred once weekly for up to 3 years.
Other Name: SBC-102

Primary Outcome Measures :
  1. Participants Experiencing Severe Treatment-emergent Adverse Events (TEAEs) [ Time Frame: Screening through Month 37 ]
    The number of participants experiencing severe TEAEs is presented for participants who received sebelipase alfa in this open-label study. Adverse events were obtained through spontaneous reporting or elicited by specific questioning or examination of the participant's parent or legal guardian. An adverse event was defined as any new untoward medical occurrence or worsening of a pre-existing medical condition in a participant, whether or not causally related to administration of study drug. Adverse event severity was graded by the Investigator as mild, moderate, or severe based on definitions developed from Clinical Data Interchange Standards Consortium Study Data Tabulation Model standard terminology v3.1.1. Adverse events reporting was from the date of informed consent until completion of the follow-up visit at approximately 30 days after the last dose of study drug. A summary of all serious and other nonserious AEs regardless of causality is located in the Reported AE module.

Secondary Outcome Measures :
  1. Percentage Of Participants Surviving To 12, 18, 24, And 36 Months Of Age [ Time Frame: Baseline through Month 12, Month 18, Month 24, and Month 36 ]
    The percentage of participants in the FAS who survived to 12, 18, 24, and 36 months of age. The exact confidence interval was calculated using the Clopper-Pearson method. Participants with unknown survival status at the age specified in the analysis were excluded. At 36 months, there were 2 participants who were alive and still on study who had not yet reached the age specified in the analysis. As such, these participants were excluded from the calculation of percent surviving.

  2. Median Age At Death [ Time Frame: Baseline through Month 36 ]
    Age at death for participants who died during the study. All deaths were assessed by the Investigator as unrelated to study drug.

  3. Change From Baseline In Percentiles For Weight For Age (WFA) At 12, 24, And 36 Months [ Time Frame: Baseline, Month 12, Month 24, and Month 36 ]
    This outcome measure evaluated the effects of sebelipase alfa on growth by measuring the changes from baseline in percentiles for WFA. Percentiles for WFA were summarized as observed values by visit. Baseline was defined as the last available assessment prior to the first infusion of sebelipase alfa.

  4. Number Of Participants With Stunting, Wasting, Or Underweight At Baseline, 12, 24, And 36 Months [ Time Frame: Baseline to Month 12, Month 24, and Month 36 ]

    The number of participants who met criteria for the following 3 dichotomous indicators of under nutrition were reported. These indicators included the following:

    1. Stunting was defined as at least 2 standard deviations below the median for length-for-age/height-for-age.
    2. Wasting was defined as wasting at least 2 standard deviations below the median for weight-for-length/weight-for-height.
    3. Underweight was defined as at least 2 standard deviations below the median for WFA.

  5. Change From Baseline In Serum Transaminases (ALT And AST) At Month 12, 24, And 36 [ Time Frame: Baseline, Month 12, Month 24, and Month 36 ]
    This outcome measure evaluated the effects of sebelipase alfa on liver function by measuring the change from baseline in alanine aminotransferase (ALT) and aspartate aminotransferase (AST) at months 12, 24, and 36. Results are reported in units/liter (U/L).

  6. Change From Baseline In Serum Ferritin At Month 12, 24, And 36 [ Time Frame: Baseline, Month 12, Month 24, and Month 36 ]
    The median change in the inflammatory marker serum ferritin from Baseline to Months 12, 24, and 36 is presented. The number of participants analyzed reflects only those from the FAS who had both a baseline value and a value at the indicated timepoint (Months 12, 24, and 36). Results are reported in micrograms (ug)/L.

  7. Number Of Participants Achieving And Maintaining Transfusion-free Hemoglobin Normalization (TFHN) [ Time Frame: Baseline through Month 36 ]

    The number of participants achieving and maintaining TFHN are presented. For TFHN to be achieved, the participant had to meet the following criteria:

    1. Two post baseline measurements of hemoglobin, at least 4 weeks apart, were above the age-adjusted lower limit of normal (LLN);
    2. No known additional measurements of hemoglobin were below the age-adjusted LLN during the (minimum) 4 week period;
    3. No transfusions were administered to the participant during the (minimum) 4 week period, or for 2 weeks prior to the first hemoglobin measurement in the (minimum) 4 week period. If all 3 criteria were met, a participant was considered to have achieved TFHN on the date of the first hemoglobin assessment in the 4 week period. A participant was considered to have maintained TFHN if he/she was transfusion free at Week 6 and had no abnormally low hemoglobin levels (levels below the age adjusted LLN) beginning at Week 8 of the study and continuing for at least 13 weeks (3 months).

Information from the National Library of Medicine

Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the contacts provided below. For general information, Learn About Clinical Studies.

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Ages Eligible for Study:   up to 8 Months   (Child)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No

Inclusion Criteria:

  1. Participant's parent or legal guardian (if applicable) consent to participation in the study
  2. Confirmation of documented decreased LAL activity relative to the normal range of the lab performing the assay or confirmation of LAL-D diagnosis as determined by a Sponsor-approved central laboratory
  3. Substantial clinical concerns, in the opinion of Investigator and Sponsor, of rapid disease progression requiring urgent medical intervention including, but not restricted to the following:

    • Marked abdominal distension and hepatomegaly
    • Failure to thrive
    • Disturbance of coagulation
    • Severe anemia
    • Sibling with rapidly progressive course of LAL-D

Exclusion Criteria:

  1. Clinically important concurrent disease
  2. Participant was > 8 months of age at the time of first dosing
  3. Participant received an investigational medicinal product other than sebelipase alfa within 14 days prior to the first dose of sebelipase alfa in this study
  4. Myeloablative preparation, or other systemic pre-transplant conditioning, for hematopoietic stem cell or liver transplantation
  5. Previous hematopoietic stem cell or liver transplant
  6. Known hypersensitivity to eggs

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 identifier (NCT number): NCT02193867

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United States, Arizona
Phoenix, Arizona, United States, 85016
Kuopio, Finland
Naples, Italy
United Kingdom
Birmingham, United Kingdom
Manchester, United Kingdom
Sponsors and Collaborators
Alexion Pharmaceuticals
  Study Documents (Full-Text)

Documents provided by Alexion Pharmaceuticals:
Study Protocol  [PDF] December 8, 2015
Statistical Analysis Plan  [PDF] July 31, 2018

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Responsible Party: Alexion Pharmaceuticals Identifier: NCT02193867    
Other Study ID Numbers: LAL-CL08
First Posted: July 18, 2014    Key Record Dates
Results First Posted: November 18, 2019
Last Update Posted: November 18, 2019
Last Verified: October 2019
Keywords provided by Alexion Pharmaceuticals:
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
Additional relevant MeSH terms:
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Wolman Disease
Cholesterol Ester Storage Disease
Lipid Metabolism, Inborn Errors
Metabolism, Inborn Errors
Genetic Diseases, Inborn
Lysosomal Storage Diseases
Infant, Newborn, Diseases
Lipid Metabolism Disorders
Metabolic Diseases