Acid Lipase Replacement Investigating Safety and Efficacy (ARISE) in Participants With Lysosomal Acid Lipase Deficiency (ARISE)

• ClinicalTrials.gov Identifier: NCT01757184
• Recruitment Status: Completed
• First Posted: December 28, 2012
• Results First Posted: April 18, 2016
• Last Update Posted: December 18, 2019
• Sponsor: Alexion Pharmaceuticals
• Information provided by (Responsible Party): Alexion Pharmaceuticals

Tracking Information

• First Submitted Date: December 17, 2012
• First Posted Date: December 28, 2012
• Results First Submitted Date: January 14, 2016
• Results First Posted Date: April 18, 2016
• Last Update Posted Date: December 18, 2019
• Actual Study Start Date: January 22, 2013
• Actual Primary Completion Date: May 30, 2014 (Final data collection date for primary outcome measure)

Current Primary Outcome Measures (submitted: December 16, 2019)

Percentage Of Participants Achieving Alanine Aminotransferase Normalization [ Time Frame: 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) ]

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.

• Original Primary Outcome Measures (submitted: December 27, 2012): Proportion of subjects who achieve ALT normalization (i.e., ALT below the age- and gender-specific upper limit of normal provided by the central laboratory performing the assay) relative to placebo [ Time Frame: 20 weeks ]

Current Secondary Outcome Measures (submitted: December 16, 2019)

• Percent Change From Baseline In Low-density Lipoprotein Cholesterol (LDL-C) [ Time Frame: 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). ]
  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.
• Percent Change From Baseline In Non-high Density Lipoprotein Cholesterol (Non-HDL-C) [ Time Frame: 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). ]
  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.
• Percentage Of Participants Achieving Aspartate Aminotransferase Normalization [ Time Frame: 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). ]
  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.
• Percent Change From Baseline In Triglycerides [ Time Frame: 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). ]
  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.
• Percent Change From Baseline In High-density Lipoprotein Cholesterol (HDL-C) [ Time Frame: 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). ]
  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.
• Percent Change From Baseline In Liver Fat Content [ Time Frame: 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). ]
  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.
• Participants With Improvement In Liver Histopathology (Decrease Of > 5% In Hepatic Steatosis Score) [ Time Frame: Double-blind Period: Baseline to the end of the Double-blind Period (Week 20). Open-label Period: Baseline up to Week 52. ]
  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.
• Percent Change From Baseline In Liver Volume [ Time Frame: 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). ]
  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.

Original Secondary Outcome Measures (submitted: December 27, 2012)

• Relative change in LDL cholesterol [ Time Frame: 20 weeks, 52 weeks and 78 weeks ]
• Relative change in non-HDL cholesterol [ Time Frame: 20 weeks, 52 weeks and 78 weeks ]
• Proportion of subjects with an abnormal baseline AST (i.e., >ULN) who achieve normalization of AST, based on age- and gender-specific normal ranges provided by the central laboratory performing this assay [ Time Frame: 20 weeks, 52 weeks and 78 weeks ]
• Relative change in triglycerides [ Time Frame: 20 weeks, 52 weeks and 78 weeks ]
• Relative change in HDL cholesterol [ Time Frame: 20 weeks, 52 weeks and 78 weeks ]
• In the subset of subjects where performed, relative change in liver fat content [ Time Frame: 20 weeks, 52 weeks and 78 weeks ]
• In the subset of subjects where performed, proportion of subjects who show improvement in liver histopathology [ Time Frame: 20 weeks, 52 weeks and 78 weeks ]
• In the subset of subjects where performed, relative change in liver volume [ Time Frame: 20 weeks, 52 weeks and 78 weeks ]
• Proportion of subjects who achieve ALT normalization (i.e., ALT below the age- and gender-specific upper limit of normal provided by the central laboratory performing the assay) [ Time Frame: 52 weeks and 78 weeks ]
• Incidence of Adverse Events, Serious Adverse Events, and Infusion Related Reactions [ Time Frame: 20 weeks, 52 weeks and 78 weeks ]
• Characterization of Anti-Drug Antibodies (ADAs), including seroconversion rate, time to seroconversion, ADA titer by time point, peak ADA titer, time to peak ADA titer, and tolerization [ Time Frame: 20 weeks, 52 weeks and 78 weeks ]
• Peak Plasma Concentration (Cmax) of sebelipase alfa [ Time Frame: Week 0, 22 weeks and 52 ]
• Time to maximum observed concentration (Tmax) of sebelipase alfa [ Time Frame: Week 0, 22 weeks and 52 weeks ]
• Area under the plasma concentration versus time curve (AUC) of sebelipase alfa [ Time Frame: Week 0, 22 weeks and 52 weeks ]
• Terminal elimination half-life (t1/2) of sebelipase alfa [ Time Frame: Week 0, 22 weeks and 52 weeks ]
• Clearance (CL) of sebelipase alfa [ Time Frame: Week 0, 22 weeks and 52 weeks ]
• Volume of distribution (Vd) of sebelipase alfa [ Time Frame: Week 0, 22 weeks and 52 weeks ]

• Current Other Pre-specified Outcome Measures: Not Provided
• Original Other Pre-specified Outcome Measures: Not Provided

Descriptive Information

• Brief Title: Acid Lipase Replacement Investigating Safety and Efficacy (ARISE) in Participants With Lysosomal Acid Lipase Deficiency
• Official Title: A Multicenter, Randomized, Placebo-controlled Study of SBC-102 in Patients With Lysosomal Acid Lipase Deficiency

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.

Detailed Description

Lysosomal acid lipase deficiency (LAL-D) is a genetic disease characterized by abnormal lipid accumulation in many parts of the body due to a marked decrease in activity of the enzyme lysosomal acid lipase (LAL).

The LAL-D disease spectrum ranges from a presentation in infants that is rapidly progressive to a presentation that occurs in childhood, adolescence, or less frequently, in adulthood in which the rate of disease progression is more variable. Irrespective of where a patient is on the disease spectrum, LAL-D is associated with significant burden of disease and a shortened life expectancy in some patients.

The non-infantile onset form of the disease, also known as CESD, occurs in both children and adults and is an under-appreciated cause of fatty liver with prominent microvesicular steatosis, fibrosis, and cirrhosis. Although the natural history of the disease has not been well studied, serious complications are frequently described, including early death, liver transplantation, or cardiovascular accidents. Other complications include premature atherosclerosis (hardening of arteries) associated with high levels of total cholesterol and low-density lipoprotein (LDL) cholesterol, often called the "bad" cholesterol. The levels of triglycerides can also be high and the levels of high-density lipoprotein (HDL) cholesterol (the "good" cholesterol) are typically low.

In the past, treatments mainly focused on control of the lipid abnormalities through diet and the use of lipid-lowering medications, which only address some aspects of the disease, while progression to fibrosis and cirrhosis may still occur. In preclinical studies and clinical studies in participants with LAL-D, treatment with SBC-102 (sebelipase alfa, Kanuma®) has been shown to produce improvements in markers of liver damage and in the lipid abnormalities. The purpose of this study was to examine the effects of using SBC-102 to treat LAL-D through a placebo-controlled, randomized, double-blinded study in children and adults.

This multicenter, randomized, double-blind, placebo-controlled study involving 66 participants evaluated the safety and efficacy of enzyme-replacement therapy with sebelipase alfa (administered intravenously at a dose of 1 mg/kg of body weight qow). The study included a 20-week placebo-controlled period followed by open-label treatment periods for all participants. The primary end-point was normalization of the alanine aminotransferase level. Secondary end-points included additional disease-related efficacy and safety assessments.

Final study results have not been published in a peer-reviewed journal.

• Study Type: Interventional
• Study Phase: Phase 3
• Study Design: Allocation: Randomized; Intervention Model: Parallel Assignment; Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor); Primary Purpose: Treatment
• Condition: Lysosomal Acid Lipase Deficiency

Intervention

• Drug: Sebelipase Alfa
  IV infusions of sebelipase alfa
  Other Name: SBC-102
• Drug: Placebo
  IV infusions of matched placebo

Study Arms

• 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.
  Intervention: Drug: Sebelipase Alfa
• Placebo Comparator: Double-blind Placebo
  Double-blind Period: IV infusions of matched placebo administered qow for 20 weeks.
  Intervention: Drug: Placebo
• 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.
  Intervention: Drug: Sebelipase Alfa
• 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.
  Intervention: Drug: Sebelipase Alfa

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, Barić I, Burrow TA, Camarena Grande C, Coker M, Consuelo-Sánchez 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.
• Valayannopoulos V, Malinova V, Honzík T, Balwani M, Breen C, Deegan PB, Enns GM, Jones SA, Kane JP, Stock EO, Tripuraneni R, Eckert S, Schneider E, Hamilton G, Middleton MS, Sirlin C, Kessler B, Bourdon C, Boyadjiev SA, Sharma R, Twelves C, Whitley CB, Quinn AG. Sebelipase alfa over 52 weeks reduces serum transaminases, liver volume and improves serum lipids in patients with lysosomal acid lipase deficiency. J Hepatol. 2014 Nov;61(5):1135-42. doi: 10.1016/j.jhep.2014.06.022. Epub 2014 Jun 30.

Recruitment Information

• Recruitment Status: Completed
• Actual Enrollment (submitted: June 24, 2014): 66
• Original Estimated Enrollment (submitted: December 27, 2012): 50
• Actual Study Completion Date: December 11, 2018
• Actual Primary Completion Date: May 30, 2014 (Final data collection date for primary outcome measure)

Eligibility Criteria

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.

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.

Sex/Gender

• Sexes Eligible for Study: All

• Ages: 4 Years and older (Child, Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Contacts: Contact information is only displayed when the study is recruiting subjects
• Listed Location Countries: Argentina, Australia, Croatia, Czechia, France, Germany, Italy, Japan, Mexico, Poland, Russian Federation, Spain, Turkey, United Kingdom, United States
• Removed Location Countries: Brazil, Canada, Czech Republic, Greece, Israel

Administrative Information

• NCT Number: NCT01757184
• Other Study ID Numbers: LAL-CL02
• Has Data Monitoring Committee: Yes
• U.S. FDA-regulated Product: Not Provided
• IPD Sharing Statement: Not Provided
• Responsible Party: Alexion Pharmaceuticals
• Study Sponsor: Alexion Pharmaceuticals
• Collaborators: Not Provided

Investigators

• Study Director: Florian Abel, MD; Alexion Pharmaceuticals

• PRS Account: Alexion Pharmaceuticals
• Verification Date: December 2019