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Trial details imported from ClinicalTrials.gov
For full trial details, please see the original record at
https://clinicaltrials.gov/ct2/show/NCT01757184
Registration number
NCT01757184
Ethics application status
Date submitted
17/12/2012
Date registered
28/12/2012
Date last updated
29/12/2020
Titles & IDs
Public title
Acid Lipase Replacement Investigating Safety and Efficacy (ARISE) in Participants With Lysosomal Acid Lipase Deficiency
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Scientific title
A Multicenter, Randomized, Placebo-controlled Study of SBC-102 in Patients With Lysosomal Acid Lipase Deficiency
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Secondary ID [1]
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LAL-CL02
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Universal Trial Number (UTN)
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Trial acronym
ARISE
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Linked study record
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Health condition
Health condition(s) or problem(s) studied:
Lysosomal Acid Lipase Deficiency
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Condition category
Condition code
Human Genetics and Inherited Disorders
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Other human genetics and inherited disorders
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Metabolic and Endocrine
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Metabolic disorders
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Metabolic and Endocrine
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Other metabolic disorders
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Intervention/exposure
Study type
Interventional
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Description of intervention(s) / exposure
Treatment: Drugs - Sebelipase Alfa
Treatment: Drugs - Placebo
Experimental: Double-blind Sebelipase Alfa - Double-blind Period: IV infusions of sebelipase alfa at a dose of 1 mg/kg administered qow for 20 weeks.
Placebo Comparator: Double-blind Placebo - Double-blind Period: IV infusions of matched placebo administered qow for 20 weeks.
Experimental: Open-label Sebelipase Alfa/Sebelipase Alfa - Participants who were randomized to receive sebelipase alfa during the Double-blind Period and received sebelipase alfa in the Open-label Period. All participants received sebelipase alfa at a dose of 1 mg/kg qow, irrespective of treatment received in the Double-blind Period. Dose modifications were permitted during the Open-label Period.
Experimental: Open-label Placebo/Sebelipase Alfa - Participants who were randomized to receive placebo during the Double-blind Period and received sebelipase alfa in the Open-label Period. All participants received sebelipase alfa at a dose of 1 mg/kg qow, irrespective of treatment received in the Double-blind Period. Dose modifications were permitted during the Open-label Period.
Treatment: Drugs: Sebelipase Alfa
IV infusions of sebelipase alfa
Treatment: Drugs: Placebo
IV infusions of matched placebo
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Intervention code [1]
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Treatment: Drugs
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Comparator / control treatment
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Control group
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Outcomes
Primary outcome [1]
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Percentage Of Participants Achieving Alanine Aminotransferase Normalization
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Assessment method [1]
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Alanine aminotransferase (ALT) normalization was defined as an abnormal baseline value (ALT > the age- and gender-specific upper limit of normal [ULN] provided by the central laboratory performing the assay) that becomes normal (< ULN). Alanine aminotransferase normalization was evaluated at the end of the Double-blind Period (the last double-blind assessment) and at the end of the Open-label Period (last open-label assessment). Baseline for the Open-label Period was defined relative to the first infusion of sebelipase alfa, which occurred at Week 0 for participants in the sebelipase alfa/sebelipase alfa group and Week 22 for participants in the placebo/sebelipase alfa group. The last open-label assessment varied by participant, depending on whether a participant completed treatment through Week 256 or discontinued prior to this timepoint to transition out of clinical study settings.
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Timepoint [1]
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Double-blind Period: Baseline to the end of the Double-blind Period (Week 20). Open-label Period: Baseline to the last Open-label assessment (up to Week 256)
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Secondary outcome [1]
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Percent Change From Baseline In Low-density Lipoprotein Cholesterol (LDL-C)
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Assessment method [1]
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Relative reduction (percentage change from baseline) in LDL-C, as assessed by laboratory measurements was evaluated at the end of the Double-blind Period and at the end of the Open-label Period. Baseline for the Open-label Period was defined relative to the first infusion of sebelipase alfa, which occurred at Week 0 for participants in the sebelipase alfa/sebelipase alfa group and Week 22 for participants in the placebo/sebelipase alfa group. The last open-label assessment varied by participant, depending on whether a participant completed treatment through Week 256 or discontinued prior to this timepoint to transition out of clinical study settings.
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Timepoint [1]
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Double-blind Period: Baseline to the end of the Double-blind Period (Week 20). Open-label Period: Baseline to the last Open-label assessment (up to Week 256).
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Secondary outcome [2]
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Percent Change From Baseline In Non-high Density Lipoprotein Cholesterol (Non-HDL-C)
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Assessment method [2]
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Relative reduction (percent change from baseline) in non-HDL-C, as assessed by laboratory measurements, was evaluated at the end of the Double-blind Period and the Open-label Period. Baseline for the Open-label Period was defined relative to the first infusion of sebelipase alfa, which occurred at Week 0 for participants in the sebelipase alfa/sebelipase alfa group and Week 22 for participants in the placebo/sebelipase alfa group. The last open-label assessment varied by participant, depending on whether a participant completed treatment through Week 256 or discontinued prior to this timepoint to transition out of clinical study settings.
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Timepoint [2]
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Double-blind Period: Baseline to the end of the Double-blind Period (Week 20). Open-label Period: Baseline to the last Open-label assessment (up to Week 256).
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Secondary outcome [3]
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Percentage Of Participants Achieving Aspartate Aminotransferase Normalization
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Assessment method [3]
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Aspartate aminotransferase (AST) normalization was defined as an abnormal baseline value (AST > the age- and gender-specific ULN provided by the central laboratory performing the assay) that becomes normal (< ULN). AST normalization was evaluated at the end of the Double-blind Period (the last Double-blind assessment) and at the end of the Open-label Period (last open-label assessment).
Baseline for the Open-label Period was defined relative to the first infusion of sebelipase alfa, which occurred at Week 0 for participants in the sebelipase alfa/sebelipase alfa group and Week 22 for participants in the placebo/sebelipase alfa group. The last open-label assessment varied by participant, depending on whether a participant completed treatment through Week 256 or discontinued prior to this timepoint to transition out of clinical study settings.
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Timepoint [3]
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Double-blind Period: Baseline to the end of the Double-blind Period (Week 20). Open-label Period: Baseline to the last Open-label assessment (up to Week 256).
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Secondary outcome [4]
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Percent Change From Baseline In Triglycerides
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Assessment method [4]
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Relative reduction (percent change from baseline) in triglycerides, as assessed by laboratory measurements, was evaluated at the end of the Double-blind Period and the Open-label Period. Baseline for the Open-label Period was defined relative to the first infusion of sebelipase alfa, which occurred at Week 0 for participants in the sebelipase alfa/sebelipase alfa group and Week 22 for participants in the placebo/sebelipase alfa group. The last open-label assessment varied by participant, depending on whether a participant completed treatment through Week 256 or discontinued prior to this timepoint to transition out of clinical study settings.
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Timepoint [4]
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Double-blind Period: Baseline to the end of the Double-blind Period (Week 20). Open-label Period: Baseline to the last Open-label assessment (up to Week 256).
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Secondary outcome [5]
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Percent Change From Baseline In High-density Lipoprotein Cholesterol (HDL-C)
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Assessment method [5]
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Relative increase (percent change from baseline) in HDL-C, assessed by laboratory measurements, was evaluated at the end of the Double-blind Period and the Open-label Period. Baseline for the Open-label Period was defined relative to the first infusion of sebelipase alfa, which occurred at Week 0 for participants in the sebelipase alfa/sebelipase alfa group and Week 22 for participants in the placebo/sebelipase alfa group. The last open-label assessment varied by participant, depending on whether a participant completed treatment through Week 256 or discontinued prior to this timepoint to transition out of clinical study settings.
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Timepoint [5]
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Double-blind Period: Baseline to the end of the Double-blind Period (Week 20). Open-label Period: Baseline to the last Open-label assessment (up to Week 256).
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Secondary outcome [6]
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Percent Change From Baseline In Liver Fat Content
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Assessment method [6]
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Decrease in liver fat content, as assessed by magnetic resonance imaging (MRI), was evaluated in participants for whom imaging was performed. Baseline for the Open-label Period was defined relative to the first infusion of sebelipase alfa, which occurred at Week 0 for participants in the sebelipase alfa/sebelipase alfa group and Week 22 for participants in the placebo/sebelipase alfa group. The last open-label assessment varied by participant, depending on whether a participant completed treatment through Week 256 or discontinued prior to this timepoint to transition out of clinical study settings.
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Timepoint [6]
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Double-blind Period: Baseline to the end of the Double-blind Period (Week 20). Open-label Period: Baseline to the last Open-label assessment (up to Week 256).
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Secondary outcome [7]
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Participants With Improvement In Liver Histopathology (Decrease Of > 5% In Hepatic Steatosis Score)
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Assessment method [7]
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The number of participants who had an improvement in hepatic histopathology (defined as a decrease of > 5% in hepatic steatosis score, assessed by morphometry), as determined by blinded central pathologist review, in the participants for whom liver biopsy was performed. Baseline for the Open-label Period was defined relative to the first infusion of sebelipase alfa, which occurred at Week 0 for participants in the sebelipase alfa/sebelipase alfa group and Week 22 for participants in the placebo/sebelipase alfa group.
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Timepoint [7]
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Double-blind Period: Baseline to the end of the Double-blind Period (Week 20). Open-label Period: Baseline up to Week 52.
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Secondary outcome [8]
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Percent Change From Baseline In Liver Volume
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Assessment method [8]
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Relative reduction (percent change from baseline) in liver volume, as assessed by MRI, was evaluated in participants for whom imaging was performed. Baseline for the Open-label Period was defined relative to the first infusion of sebelipase alfa, which occurred at Week 0 for participants in the sebelipase alfa/sebelipase alfa group and Week 22 for participants in the placebo/sebelipase alfa group. The last open-label assessment varied by participant, depending on whether a participant completed treatment through Week 256 or discontinued prior to this timepoint to transition out of clinical study settings.
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Timepoint [8]
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Double-blind Period: Baseline to the end of the Double-blind Period (Week 20). Open-label Period: Baseline to the last Open-label assessment (up to Week 256).
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Eligibility
Key inclusion criteria
- Participant and/or participant's parent or legal guardian provided informed consent.
- Participant was = 4 years of age on the date of informed consent.
- Deficiency of LAL enzyme activity confirmed by dried blood spot testing at screening.
- Alanine aminotransferase = 1.5x upper limit of normal on 2 consecutive screening
measurements obtained at least 1 week apart.
- Female participants of childbearing potential must not have been pregnant or
breastfeeding and must have agreed to use a medically acceptable method of preventing
contraception from screening until 4 weeks after the last dose of study drug.
- Participant receiving lipid-lowering therapies must have been on a stable dose of the
medication for at least 6 weeks prior to randomization and was willing to remain on a
stable dose for at least the first 32 weeks of treatment in the study.
- Participant receiving medications for the treatment of nonalcoholic fatty liver
disease must have been on a stable dose for at least 16 weeks prior to randomization
and was willing to remain on a stable dose for at least the first 32 weeks of
treatment in the study.
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Minimum age
4
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Maximum age
No limit
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Sex
Both males and females
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Can healthy volunteers participate?
No
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Key exclusion criteria
- Severe hepatic dysfunction (Child-Pugh Class C).
- Other medical conditions or comorbidities, which, in the opinion of the Investigator,
would have interfered with study compliance or data interpretation.
- Previous hematopoietic or liver transplant procedure.
- Received treatment with high-dose corticosteroids (acute or chronic) within 26 weeks.
(Note: Participants receiving maintenance therapy with low-dose oral, intranasal,
topical, or inhaled corticosteroids were considered eligible for the study).
- Known hypersensitivity to eggs.
- Participated in a study employing an investigational medicinal product within 4 weeks
prior to randomization.
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Study design
Purpose of the study
Treatment
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Allocation to intervention
Randomised controlled trial
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Procedure for enrolling a subject and allocating the treatment (allocation concealment procedures)
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Methods used to generate the sequence in which subjects will be randomised (sequence generation)
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Masking / blinding
Blinded (masking used)
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Who is / are masked / blinded?
The people receiving the treatment/s
The people administering the treatment/s
The people assessing the outcomes
The people analysing the results/data
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Intervention assignment
Parallel
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Other design features
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Phase
Phase 3
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Type of endpoint/s
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Statistical methods / analysis
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Recruitment
Recruitment status
Completed
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Data analysis
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Reason for early stopping/withdrawal
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Other reasons
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Date of first participant enrolment
Anticipated
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Actual
22/01/2013
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Date of last participant enrolment
Anticipated
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Actual
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Date of last data collection
Anticipated
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Actual
11/12/2018
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Sample size
Target
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Accrual to date
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Final
66
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Recruitment in Australia
Recruitment state(s)
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Recruitment hospital [1]
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- Brisbane
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Recruitment hospital [2]
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- New Lambton
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Recruitment hospital [3]
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- Parkville
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- Perth
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Recruitment postcode(s) [1]
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- Brisbane
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Recruitment postcode(s) [2]
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- New Lambton
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Recruitment postcode(s) [3]
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- Parkville
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Recruitment postcode(s) [4]
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- Perth
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Recruitment outside Australia
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United States of America
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Arizona
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California
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Delaware
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Zagreb
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Olomouc
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Paris
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France
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Vandoeuvre les Nancy
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Freiburg
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Mainz
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Padova
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Tottori
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Mexico City
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Warsaw
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Russian Federation
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Moscow
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Elche
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Madrid
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Oviedo
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Ankara
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Izmir
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Cambridge
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London
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United Kingdom
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Plymouth
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Funding & Sponsors
Primary sponsor type
Commercial sector/Industry
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Name
Alexion Pharmaceuticals, Inc.
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Ethics approval
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Summary
Brief summary
This Phase 3 study evaluated the efficacy and safety of 1 milligram/kilogram (mg/kg)
intravenous (IV) infusions of SBC-102 (sebelipase alfa) administered every other week (qow)
in participants with late onset lysosomal acid lipase deficiency (LAL-D) (cholesteryl ester
storage disease [CESD]).
Late-onset LAL-D is an underappreciated cause of cirrhosis, liver failure and dyslipidemia.
There is currently no standard treatment for LAL-D other than supportive care. Enzyme
replacement therapy may be a potential new treatment option for LAL-D participants.
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Trial website
https://clinicaltrials.gov/ct2/show/NCT01757184
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Trial related presentations / publications
Wilson DP, Friedman M, Marulkar S, Hamby T, Bruckert E. Sebelipase alfa improves atherogenic biomarkers in adults and children with lysosomal acid lipase deficiency. J Clin Lipidol. 2018 May-Jun;12(3):604-614. doi: 10.1016/j.jacl.2018.02.020. Epub 2018 Mar 9.
Burton BK, Balwani M, Feillet F, Baric I, Burrow TA, Camarena Grande C, Coker M, Consuelo-Sanchez A, Deegan P, Di Rocco M, Enns GM, Erbe R, Ezgu F, Ficicioglu C, Furuya KN, Kane J, Laukaitis C, Mengel E, Neilan EG, Nightingale S, Peters H, Scarpa M, Schwab KO, Smolka V, Valayannopoulos V, Wood M, Goodman Z, Yang Y, Eckert S, Rojas-Caro S, Quinn AG. A Phase 3 Trial of Sebelipase Alfa in Lysosomal Acid Lipase Deficiency. N Engl J Med. 2015 Sep 10;373(11):1010-20. doi: 10.1056/NEJMoa1501365.
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Public notes
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Contacts
Principal investigator
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Florian Abel, MD
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Address
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Alexion Pharmaceuticals, Inc.
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Summary Results
For IPD and results data, please see
https://clinicaltrials.gov/ct2/show/NCT01757184
Download to PDF