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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

Tracking Information
First Submitted Date  ICMJE March 20, 2014
First Posted Date  ICMJE April 14, 2014
Results First Submitted Date  ICMJE December 26, 2018
Results First Posted Date  ICMJE January 15, 2019
Last Update Posted Date December 4, 2019
Actual Study Start Date  ICMJE June 24, 2014
Actual Primary Completion Date December 28, 2017   (Final data collection date for primary outcome measure)
Current Primary Outcome Measures  ICMJE
 (submitted: December 26, 2018)
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.
Original Primary Outcome Measures  ICMJE
 (submitted: April 9, 2014)
The safety of sebelipase alfa in a more broad population of patients with LALD than have been previously studied. [ Time Frame: 30 days after last study drug infusion (up to 96 weeks) ]
  • Incidence of adverse events (AEs), SAEs, and infusion-related reactions (IRRs);
  • Changes from Baseline in 12-lead electrocardiograms (ECGs) and clinical laboratory tests;
  • 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);
  • Functional and overall development in patients ≤ 6 years of age will be assessed, as determined by Denver II scores.
Change History
Current Secondary Outcome Measures  ICMJE
 (submitted: December 26, 2018)
  • 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.
  • 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.
  • 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.
  • 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.
Original Secondary Outcome Measures  ICMJE
 (submitted: April 9, 2014)
  • The effect of sebelipase alfa on lipid metabolism. [ Time Frame: Baseline to end of treatment period (up to 96 weeks) ]
    • Decrease in LDL-C;
    • Decrease in non-HDL-C;
    • Decrease in triglycerides;
    • Increase in HDL-C
  • The effect of sebelipase alfa on growth parameters in pediatric patients presenting with evidence of growth delay. [ Time Frame: Baseline to end of treatment period (up to 96 weeks) ]
  • The effect of sebelipase alfa on PK parameters. [ Time Frame: Week 0, Week 24, Week 48 ]
    PK parameters include: Cmax, time to maximum concentration, area under the serum concentration vs. time curve from time zero to the last measurable time point, area under the serum concentration vs. time curve from time zero to infinity, terminal elimination half-life, serum clearance, and apparent volume of distribution.
  • The effect of sebelipase alfa on liver function (including histopathology). [ Time Frame: Baseline to end of treatment period (up to 96 weeks) ]
    • Decrease in Child-Pugh status for patients with Child-Pugh class C or B at Baseline;
    • Decreased United Kingdom Model for End-Stage Liver Disease (UK-ELD) score;
    • Improvement in liver histopathology.
Current Other Pre-specified Outcome Measures Not Provided
Original Other Pre-specified Outcome Measures Not Provided
 
Descriptive Information
Brief Title  ICMJE Safety and Efficacy Study of Sebelipase Alfa in Participants With Lysosomal Acid Lipase Deficiency
Official Title  ICMJE A Multi-Center, Open-Label Study of Sebelipase Alfa in Patients With Lysosomal Acid Lipase Deficiency
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).
Study Type  ICMJE Interventional
Study Phase  ICMJE Phase 2
Study Design  ICMJE Intervention Model: Sequential Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Condition  ICMJE Lysosomal Acid Lipase Deficiency
Intervention  ICMJE Drug: Sebelipase Alfa
IV infusion of sebelipase alfa
Other Name: SBC-102
Study Arms  ICMJE 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.
Intervention: Drug: Sebelipase Alfa
Publications * Not Provided

*   Includes publications given by the data provider as well as publications identified by ClinicalTrials.gov Identifier (NCT Number) in Medline.
 
Recruitment Information
Recruitment Status  ICMJE Completed
Actual Enrollment  ICMJE
 (submitted: December 22, 2016)
31
Original Estimated Enrollment  ICMJE
 (submitted: April 9, 2014)
20
Actual Study Completion Date  ICMJE December 28, 2017
Actual Primary Completion Date December 28, 2017   (Final data collection date for primary outcome measure)
Eligibility Criteria  ICMJE

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.
Sex/Gender  ICMJE
Sexes Eligible for Study: All
Ages  ICMJE 8 Months and older   (Child, Adult, Older Adult)
Accepts Healthy Volunteers  ICMJE No
Contacts  ICMJE Contact information is only displayed when the study is recruiting subjects
Listed Location Countries  ICMJE Australia,   Belgium,   Brazil,   Canada,   Croatia,   Denmark,   Germany,   Italy,   Mexico,   Netherlands,   Russian Federation,   Spain,   Turkey,   United Kingdom,   United States
Removed Location Countries  
 
Administrative Information
NCT Number  ICMJE NCT02112994
Other Study ID Numbers  ICMJE LAL-CL06
2011-004287-30 ( EudraCT Number )
Has Data Monitoring Committee Yes
U.S. FDA-regulated Product
Studies a U.S. FDA-regulated Drug Product: Yes
Studies a U.S. FDA-regulated Device Product: No
IPD Sharing Statement  ICMJE Not Provided
Responsible Party Alexion Pharmaceuticals
Study Sponsor  ICMJE Alexion Pharmaceuticals
Collaborators  ICMJE Not Provided
Investigators  ICMJE Not Provided
PRS Account Alexion Pharmaceuticals
Verification Date November 2019

ICMJE     Data element required by the International Committee of Medical Journal Editors and the World Health Organization ICTRP