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

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

Study Type Interventional
Study Design Allocation: Randomized;   Intervention Model: Parallel Assignment;   Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor);   Primary Purpose: Treatment
Condition Lysosomal Acid Lipase Deficiency
Interventions Drug: Sebelipase Alfa
Drug: Placebo
Enrollment 66
Recruitment Details A total of 56 study centers located in 17 countries were initiated in this study. Participants were enrolled and treated at 41 centers in 16 countries, including 35 primary centers where participants initiated treatment and 6 qualified local medical centers where participants who were medically stable were transferred for long-term treatment.
Pre-assignment Details To assess eligibility, participants were screened for a period of up to 6 weeks prior to enrollment in the study. A total of 86 participants were screened. Six of these participants underwent rescreening (of which 2 were eligible for the study). In total, 66 participants were eligible for the study and 20 participants were screen failures.
Arm/Group Title Double-blind Sebelipase Alfa Double-blind Placebo Open-label Sebelipase Alfa/Sebelipase Alfa Open-label Placebo/Sebelipase Alfa
Hide Arm/Group Description Double-blind Period: Intravenous (IV) infusions of sebelipase alfa at a dose of 1 milligram/kilogram (mg/kg) administered every other week (qow). Double-blind Period: IV infusions of placebo administered qow. Participants who were randomized to receive sebelipase alfa during the Double-blind Period and also 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. 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.
Period Title: Double-blind Period
Started 36 30 0 0
Received at Least 1 Dose of Study Drug 36 30 0 0
Completed 35 30 0 0
Not Completed 1 0 0 0
Reason Not Completed
Adverse Event             1             0             0             0
Period Title: Open-label Period
Started 0 0 36 [1] 30
Received at Least 1 Dose of Study Drug 0 0 36 30
Completed 0 0 32 27
Not Completed 0 0 4 3
Reason Not Completed
Lost to Follow-up             0             0             2             0
Withdrawal by Subject             0             0             1             1
Discontinued by Sponsor             0             0             1             2
[1]
1 participant who did not complete Double-blind Period due to AE rechallenged for Open-label Period
Arm/Group Title Double-Blind Sebelipase Alfa Double-Blind Placebo Total
Hide Arm/Group Description Double-blind Period: IV infusions of sebelipase alfa at a dose of 1 mg/kg administered qow. Double-blind Period: IV infusions of placebo administered qow. Total of all reporting groups
Overall Number of Baseline Participants 36 30 66
Hide Baseline Analysis Population Description
All participants who received at least 1 dose (or any portion of a dose) of sebelipase alfa or placebo in the Double-blind Period.
Age, Continuous   [1] 
Mean (Standard Deviation)
Unit of measure:  Years
Number Analyzed 36 participants 30 participants 66 participants
16.9  (11.6) 15.2  (10.2) 16.1  (10.9)
[1]
Measure Description: Double-blind Period
Age, Continuous   [1] 
Mean (Standard Deviation)
Unit of measure:  Years
Number Analyzed 36 participants 30 participants 66 participants
17.39  (11.529) 15.70  (10.283) 16.62  (10.930)
[1]
Measure Description: Open-label Period
Sex: Female, Male  
Measure Type: Count of Participants
Unit of measure:  Participants
Number Analyzed 36 participants 30 participants 66 participants
Female
18
  50.0%
15
  50.0%
33
  50.0%
Male
18
  50.0%
15
  50.0%
33
  50.0%
Ethnicity (NIH/OMB)  
Measure Type: Count of Participants
Unit of measure:  Participants
Number Analyzed 36 participants 30 participants 66 participants
Hispanic or Latino
6
  16.7%
4
  13.3%
10
  15.2%
Not Hispanic or Latino
30
  83.3%
26
  86.7%
56
  84.8%
Unknown or Not Reported
0
   0.0%
0
   0.0%
0
   0.0%
Race (NIH/OMB)  
Measure Type: Count of Participants
Unit of measure:  Participants
Number Analyzed 36 participants 30 participants 66 participants
American Indian or Alaska Native
0
   0.0%
0
   0.0%
0
   0.0%
Asian
3
   8.3%
0
   0.0%
3
   4.5%
Native Hawaiian or Other Pacific Islander
0
   0.0%
0
   0.0%
0
   0.0%
Black or African American
1
   2.8%
0
   0.0%
1
   1.5%
White
27
  75.0%
28
  93.3%
55
  83.3%
More than one race
0
   0.0%
0
   0.0%
0
   0.0%
Unknown or Not Reported
5
  13.9%
2
   6.7%
7
  10.6%
1.Primary Outcome
Title Percentage Of Participants Achieving Alanine Aminotransferase Normalization
Hide Description 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.
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)
Hide Outcome Measure Data
Hide Analysis Population Description

Double-blind Period: All participants in the Full Analysis Set (defined as participants who received at least 1 dose [or any portion of a dose] of sebelipase alfa or placebo).

Open-Label Period: All participants in the Extension Set (defined as participants who received at least 1 dose [or any portion of a dose] of sebelipase alfa).

Arm/Group Title Double-blind Sebelipase Alfa Double-blind Placebo Open-label Sebelipase Alfa/Sebelipase Alfa Open-label Placebo/Sebelipase Alfa
Hide Arm/Group Description:
Double-blind Period: IV infusions of sebelipase alfa at a dose of 1 mg/kg administered qow.
Double-blind Period: IV infusions of placebo administered qow.
Participants who were randomized to receive sebelipase alfa during the Double-blind Period and also 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.
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.
Overall Number of Participants Analyzed 36 30 36 30
Measure Type: Number
Unit of Measure: percentage of participants
31 7 56 37
Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection Double-blind Sebelipase Alfa, Double-blind Placebo
Comments A sample size of 50 randomized participants (approximately 25 participants per treatment group) provided 97% power to detect a statistically significant difference between sebelipase alfa and placebo, using Fisher's exact test at α=0.05.
Type of Statistical Test Superiority
Comments [Not Specified]
Statistical Test of Hypothesis P-Value 0.0271
Comments [Not Specified]
Method Fisher Exact
Comments Fisher's exact test at α=0.05.
2.Secondary Outcome
Title Percent Change From Baseline In Low-density Lipoprotein Cholesterol (LDL-C)
Hide Description 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.
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).
Hide Outcome Measure Data
Hide Analysis Population Description

Double-blind Period: All participants in the Full Analysis Set (defined as participants who received at least 1 dose [or any portion of a dose] of sebelipase alfa or placebo).

Open-Label Period: All participants in the Extension Set (defined as participants who received at least 1 dose [or any portion of a dose] of sebelipase alfa).

Arm/Group Title Double-blind Sebelipase Alfa Double-blind Placebo Open-label Sebelipase Alfa/Sebelipase Alfa Open-label Placebo/Sebelipase Alfa
Hide Arm/Group Description:
Double-blind Period: IV infusions of sebelipase alfa at a dose of 1 mg/kg administered qow.
Double-blind Period: IV infusions of placebo administered qow.
Participants who were randomized to receive sebelipase alfa during the Double-blind Period and also 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.
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.
Overall Number of Participants Analyzed 36 30 36 30
Mean (Standard Deviation)
Unit of Measure: percent change
-28.42  (22.304) -6.25  (13.015) -19.74  (33.262) -18.09  (33.685)
Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection Double-blind Sebelipase Alfa, Double-blind Placebo
Comments [Not Specified]
Type of Statistical Test Superiority
Comments [Not Specified]
Statistical Test of Hypothesis P-Value <0.0001
Comments [Not Specified]
Method Wilcoxon (Mann-Whitney)
Comments [Not Specified]
3.Secondary Outcome
Title Percent Change From Baseline In Non-high Density Lipoprotein Cholesterol (Non-HDL-C)
Hide Description 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.
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).
Hide Outcome Measure Data
Hide Analysis Population Description

Double-blind Period: All participants in the Full Analysis Set (defined as participants who received at least 1 dose [or any portion of a dose] of sebelipase alfa or placebo).

Open-Label Period: All participants in the Extension Set (defined as participants who received at least 1 dose [or any portion of a dose] of sebelipase alfa).

Arm/Group Title Double-Blind Sebelipase Alfa Double-Blind Placebo Open-Label Sebelipase Alfa/Sebelipase Alfa Open-Label Placebo/Sebelipase Alfa
Hide Arm/Group Description:
Double-blind Period: IV infusions of sebelipase alfa at a dose of 1 mg/kg administered qow.
Double-blind Period: IV infusions of placebo administered qow.
Participants who were randomized to receive sebelipase alfa during the Double-blind Period and also 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.
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.
Overall Number of Participants Analyzed 36 30 36 30
Mean (Standard Deviation)
Unit of Measure: percent change
-27.97  (18.612) -6.94  (10.922) -19.75  (26.875) -18.34  (29.177)
Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection Double-Blind Sebelipase Alfa, Double-Blind Placebo
Comments [Not Specified]
Type of Statistical Test Superiority
Comments [Not Specified]
Statistical Test of Hypothesis P-Value <0.0001
Comments [Not Specified]
Method Wilcoxon (Mann-Whitney)
Comments [Not Specified]
4.Secondary Outcome
Title Percentage Of Participants Achieving Aspartate Aminotransferase Normalization
Hide Description

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.

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).
Hide Outcome Measure Data
Hide Analysis Population Description

Double-blind Period: All participants in the Full Analysis Set (defined as participants who received at least 1 dose [or any portion of a dose] of sebelipase alfa or placebo).

Open-Label Period: All participants in the Extension Set (defined as participants who received at least 1 dose [or any portion of a dose] of sebelipase alfa).

Arm/Group Title Double-Blind Sebelipase Alfa Double-Blind Placebo Open-Label Sebelipase Alfa/Sebelipase Alfa Open-Label Placebo/Sebelipase Alfa
Hide Arm/Group Description:
Double-blind Period: IV infusions of sebelipase alfa at a dose of 1 mg/kg administered qow.
Double-blind Period: IV infusions of placebo administered qow.
Participants who were randomized to receive sebelipase alfa during the Double-blind Period and also 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.
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.
Overall Number of Participants Analyzed 36 29 36 29
Measure Type: Number
Unit of Measure: percentage of participants
42 3 69 62
Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection Double-Blind Sebelipase Alfa, Double-Blind Placebo
Comments [Not Specified]
Type of Statistical Test Superiority
Comments [Not Specified]
Statistical Test of Hypothesis P-Value 0.0003
Comments [Not Specified]
Method Fisher Exact
Comments [Not Specified]
5.Secondary Outcome
Title Percent Change From Baseline In Triglycerides
Hide Description 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.
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).
Hide Outcome Measure Data
Hide Analysis Population Description

Double-blind Period: All participants in the Full Analysis Set (defined as participants who received at least 1 dose [or any portion of a dose] of sebelipase alfa or placebo).

Open-Label Period: All participants in the Extension Set (defined as participants who received at least 1 dose [or any portion of a dose] of sebelipase alfa).

Arm/Group Title Double-Blind Sebelipase Alfa Double-Blind Placebo Open-Label Sebelipase Alfa/Sebelipase Alfa Open-Label Placebo/Sebelipase Alfa
Hide Arm/Group Description:
Double-blind Period: IV infusions of sebelipase alfa at a dose of 1 mg/kg administered qow.
Double-blind Period: IV infusions of placebo administered qow.
Participants who were randomized to receive sebelipase alfa during the Double-blind Period and also 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.
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.
Overall Number of Participants Analyzed 36 30 36 30
Mean (Standard Deviation)
Unit of Measure: percent change
-25.45  (29.411) -11.14  (28.827) -11.87  (34.580) -19.63  (27.066)
Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection Double-Blind Sebelipase Alfa, Double-Blind Placebo
Comments [Not Specified]
Type of Statistical Test Superiority
Comments [Not Specified]
Statistical Test of Hypothesis P-Value 0.0375
Comments [Not Specified]
Method Wilcoxon (Mann-Whitney)
Comments [Not Specified]
6.Secondary Outcome
Title Percent Change From Baseline In High-density Lipoprotein Cholesterol (HDL-C)
Hide Description 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.
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).
Hide Outcome Measure Data
Hide Analysis Population Description

Double-blind Period: All participants in the Full Analysis Set (defined as participants who received at least 1 dose [or any portion of a dose] of sebelipase alfa or placebo).

Open-Label Period: All participants in the Extension Set (defined as participants who received at least 1 dose [or any portion of a dose] of sebelipase alfa).

Arm/Group Title Double-Blind Sebelipase Alfa Double-Blind Placebo Open-Label Sebelipase Alfa/Sebelipase Alfa Open-Label Placebo/Sebelipase Alfa
Hide Arm/Group Description:
Double-blind Period: IV infusions of sebelipase alfa at a dose of 1 mg/kg administered qow.
Double-blind Period: IV infusions of placebo administered qow.
Participants who were randomized to receive sebelipase alfa during the Double-blind Period and also 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.
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.
Overall Number of Participants Analyzed 36 30 36 30
Mean (Standard Deviation)
Unit of Measure: percent change
19.57  (16.833) -0.29  (12.360) 31.65  (28.971) 34.78  (29.927)
Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection Double-Blind Sebelipase Alfa, Double-Blind Placebo
Comments [Not Specified]
Type of Statistical Test Superiority
Comments [Not Specified]
Statistical Test of Hypothesis P-Value <0.0001
Comments [Not Specified]
Method Wilcoxon (Mann-Whitney)
Comments [Not Specified]
7.Secondary Outcome
Title Percent Change From Baseline In Liver Fat Content
Hide Description 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.
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).
Hide Outcome Measure Data
Hide Analysis Population Description

Double-blind Period: All participants in the Full Analysis Set (defined as participants who received at least 1 dose [or any portion of a dose] of sebelipase alfa or placebo).

Open-Label Period: All participants in the Extension Set (defined as participants who received at least 1 dose [or any portion of a dose] of sebelipase alfa).

Arm/Group Title Double-Blind Sebelipase Alfa Double-Blind Placebo Open-Label Sebelipase Alfa/Sebelipase Alfa Open-Label Placebo/Sebelipase Alfa
Hide Arm/Group Description:
Double-blind Period: IV infusions of sebelipase alfa at a dose of 1 mg/kg administered qow.
Double-blind Period: IV infusions of placebo administered qow.
Participants who were randomized to receive sebelipase alfa during the Double-blind Period and also 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.
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.
Overall Number of Participants Analyzed 32 25 35 25
Mean (Standard Deviation)
Unit of Measure: percent change
-31.98  (26.763) -4.21  (15.559) -9.89  (32.892) -0.93  (37.233)
Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection Double-Blind Sebelipase Alfa, Double-Blind Placebo
Comments [Not Specified]
Type of Statistical Test Superiority
Comments [Not Specified]
Statistical Test of Hypothesis P-Value <0.0001
Comments [Not Specified]
Method Wilcoxon (Mann-Whitney)
Comments [Not Specified]
8.Secondary Outcome
Title Participants With Improvement In Liver Histopathology (Decrease Of > 5% In Hepatic Steatosis Score)
Hide Description 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.
Time Frame Double-blind Period: Baseline to the end of the Double-blind Period (Week 20). Open-label Period: Baseline up to Week 52.
Hide Outcome Measure Data
Hide Analysis Population Description

Double-blind Period: All participants in the Full Analysis Set (defined as participants who received at least 1 dose [or any portion of a dose] of sebelipase alfa or placebo).

Open-Label Period: All participants in the Extension Set (defined as participants who received at least 1 dose [or any portion of a dose] of sebelipase alfa).

Arm/Group Title Double-Blind Sebelipase Alfa Double-Blind Placebo Open-Label Sebelipase Alfa/Sebelipase Alfa Open-Label Placebo/Sebelipase Alfa
Hide Arm/Group Description:
Double-blind Period: IV infusions of sebelipase alfa at a dose of 1 mg/kg administered qow.
Double-blind Period: IV infusions of placebo administered qow.
Participants who were randomized to receive sebelipase alfa during the Double-blind Period and also 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.
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.
Overall Number of Participants Analyzed 16 10 12 6
Measure Type: Number
Unit of Measure: participants
10 4 7 4
Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection Double-Blind Sebelipase Alfa, Double-Blind Placebo
Comments [Not Specified]
Type of Statistical Test Superiority
Comments [Not Specified]
Statistical Test of Hypothesis P-Value 0.4216
Comments [Not Specified]
Method Fisher Exact
Comments [Not Specified]
9.Secondary Outcome
Title Percent Change From Baseline In Liver Volume
Hide Description 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.
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).
Hide Outcome Measure Data
Hide Analysis Population Description

Double-blind Period: All participants in the Full Analysis Set (defined as participants who received at least 1 dose [or any portion of a dose] of sebelipase alfa or placebo).

Open-Label Period: All participants in the Extension Set (defined as participants who received at least 1 dose [or any portion of a dose] of sebelipase alfa).

Arm/Group Title Double-Blind Sebelipase Alfa Double-Blind Placebo Open-Label Sebelipase Alfa/Sebelipase Alfa Open-Label Placebo/Sebelipase Alfa
Hide Arm/Group Description:
Double-blind Period: IV infusions of sebelipase alfa at a dose of 1 mg/kg administered qow.
Double-blind Period: IV infusions of placebo administered qow.
Participants who were randomized to receive sebelipase alfa during the Double-blind Period and also 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.
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.
Overall Number of Participants Analyzed 33 27 36 27
Mean (Standard Deviation)
Unit of Measure: percent change
-10.28  (10.510) -2.66  (10.107) -24.04  (15.792) -21.55  (11.727)
Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection Double-Blind Sebelipase Alfa, Double-Blind Placebo
Comments [Not Specified]
Type of Statistical Test Superiority
Comments [Not Specified]
Statistical Test of Hypothesis P-Value 0.0068
Comments [Not Specified]
Method Wilcoxon (Mann-Whitney)
Comments [Not Specified]
Time Frame In the Double-blind Period, adverse events were assessed on or after the first infusion of study drug until Week 20. In the Open-label Period, adverse events were assessed after the first infusion of study drug on Week 22 up to Follow-up call (4 weeks [+ 7 days] after the last infusion of sebelipase alfa).
Adverse Event Reporting Description Adverse events were obtained through spontaneous reporting or were elicited by specific questioning of the participant or the participant's parent or legal guardian.
 
Arm/Group Title Double-blind Sebelipase Alfa Double-blind Placebo Open-label Sebelipase Alfa/Sebelipase Alfa Open-label Placebo/Sebelipase Alfa
Hide Arm/Group Description Double-blind Period: IV infusions of sebelipase alfa at a dose of 1 mg/kg administered qow. Double-blind Period: IV infusions of placebo administered qow. Participants who were randomized to receive sebelipase alfa during the Double-blind Period and also 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. 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.
All-Cause Mortality
Double-blind Sebelipase Alfa Double-blind Placebo Open-label Sebelipase Alfa/Sebelipase Alfa Open-label Placebo/Sebelipase Alfa
Affected / at Risk (%) Affected / at Risk (%) Affected / at Risk (%) Affected / at Risk (%)
Total   0/36 (0.00%)   0/30 (0.00%)   0/36 (0.00%)   0/30 (0.00%) 
Hide Serious Adverse Events
Double-blind Sebelipase Alfa Double-blind Placebo Open-label Sebelipase Alfa/Sebelipase Alfa Open-label Placebo/Sebelipase Alfa
Affected / at Risk (%) Affected / at Risk (%) Affected / at Risk (%) Affected / at Risk (%)
Total   2/36 (5.56%)   1/30 (3.33%)   6/36 (16.67%)   5/30 (16.67%) 
Eye disorders         
Eyelid oedema  1  0/36 (0.00%)  0/30 (0.00%)  0/36 (0.00%)  1/30 (3.33%) 
Gastrointestinal disorders         
Gastritis  1  1/36 (2.78%)  0/30 (0.00%)  0/36 (0.00%)  1/30 (3.33%) 
Gastrointestinal haemorrhage  1  0/36 (0.00%)  0/30 (0.00%)  1/36 (2.78%)  1/30 (3.33%) 
General disorders         
Chest discomfort  1  0/36 (0.00%)  0/30 (0.00%)  0/36 (0.00%)  1/30 (3.33%) 
Infections and infestations         
Appendicitis  1  0/36 (0.00%)  0/30 (0.00%)  0/36 (0.00%)  1/30 (3.33%) 
Gastroenteritis  1  0/36 (0.00%)  0/30 (0.00%)  0/36 (0.00%)  1/30 (3.33%) 
Influenza  1  0/36 (0.00%)  0/30 (0.00%)  1/36 (2.78%)  0/30 (0.00%) 
Peritonitis  1  0/36 (0.00%)  0/30 (0.00%)  0/36 (0.00%)  1/30 (3.33%) 
Injury, poisoning and procedural complications         
Infusion-related reaction  1  1/36 (2.78%)  0/30 (0.00%)  0/36 (0.00%)  0/30 (0.00%) 
Post procedural haemorrhage  1  0/36 (0.00%)  0/30 (0.00%)  2/36 (5.56%)  0/30 (0.00%) 
Procedural pain  1 [1]  0/36 (0.00%)  0/30 (0.00%)  1/36 (2.78%)  0/30 (0.00%) 
Road traffic accident  1  0/36 (0.00%)  1/30 (3.33%)  0/36 (0.00%)  0/30 (0.00%) 
Musculoskeletal and connective tissue disorders         
Musculoskeletal pain  1  0/36 (0.00%)  0/30 (0.00%)  0/36 (0.00%)  1/30 (3.33%) 
Patellofemoral pain syndrome  1  0/36 (0.00%)  0/30 (0.00%)  1/36 (2.78%)  0/30 (0.00%) 
Plantar fasciitis  1  0/36 (0.00%)  0/30 (0.00%)  1/36 (2.78%)  0/30 (0.00%) 
Neoplasms benign, malignant and unspecified (incl cysts and polyps)         
Hepatic cancer  1  0/36 (0.00%)  0/30 (0.00%)  1/36 (2.78%)  0/30 (0.00%) 
Metastases to lung  1  0/36 (0.00%)  0/30 (0.00%)  1/36 (2.78%)  0/30 (0.00%) 
Nervous system disorders         
Epilepsy  1  0/36 (0.00%)  0/30 (0.00%)  0/36 (0.00%)  1/30 (3.33%) 
Hepatic encephalopathy  1  0/36 (0.00%)  0/30 (0.00%)  1/36 (2.78%)  0/30 (0.00%) 
Respiratory, thoracic and mediastinal disorders         
Dyspnoea  1  0/36 (0.00%)  0/30 (0.00%)  0/36 (0.00%)  1/30 (3.33%) 
Sleep apnoea syndrome  1  0/36 (0.00%)  0/30 (0.00%)  1/36 (2.78%)  0/30 (0.00%) 
Skin and subcutaneous tissue disorders         
Pruritus  1  0/36 (0.00%)  0/30 (0.00%)  0/36 (0.00%)  1/30 (3.33%) 
Urticaria  1  0/36 (0.00%)  0/30 (0.00%)  0/36 (0.00%)  1/30 (3.33%) 
Vascular disorders         
Hyperaemia  1  0/36 (0.00%)  0/30 (0.00%)  0/36 (0.00%)  1/30 (3.33%) 
1
Term from vocabulary, MedDRA (15.1)
Indicates events were collected by systematic assessment
[1]
Procedural pain after liver biopsy unrelated to study drug.
Hide Other (Not Including Serious) Adverse Events
Frequency Threshold for Reporting Other Adverse Events 5%
Double-blind Sebelipase Alfa Double-blind Placebo Open-label Sebelipase Alfa/Sebelipase Alfa Open-label Placebo/Sebelipase Alfa
Affected / at Risk (%) Affected / at Risk (%) Affected / at Risk (%) Affected / at Risk (%)
Total   31/36 (86.11%)   28/30 (93.33%)   35/36 (97.22%)   29/30 (96.67%) 
Blood and lymphatic system disorders         
Anaemia  1  0/36 (0.00%)  0/30 (0.00%)  2/36 (5.56%)  1/30 (3.33%) 
Eosinophilia  1  0/36 (0.00%)  0/30 (0.00%)  1/36 (2.78%)  2/30 (6.67%) 
Cardiac disorders         
Arrhythmia  1  0/36 (0.00%)  2/30 (6.67%)  0/36 (0.00%)  0/30 (0.00%) 
Ear and labyrinth disorders         
Ear pain  1  0/36 (0.00%)  0/30 (0.00%)  1/36 (2.78%)  2/30 (6.67%) 
Gastrointestinal disorders         
Diarrhoea  1  6/36 (16.67%)  5/30 (16.67%)  7/36 (19.44%)  11/30 (36.67%) 
Abdominal pain  1  3/36 (8.33%)  1/30 (3.33%)  7/36 (19.44%)  9/30 (30.00%) 
Constipation  1  3/36 (8.33%)  1/30 (3.33%)  4/36 (11.11%)  4/30 (13.33%) 
Nausea  1  3/36 (8.33%)  2/30 (6.67%)  5/36 (13.89%)  3/30 (10.00%) 
Vomiting  1  3/36 (8.33%)  3/30 (10.00%)  9/36 (25.00%)  7/30 (23.33%) 
Abdominal pain upper  1  2/36 (5.56%)  2/30 (6.67%)  10/36 (27.78%)  3/30 (10.00%) 
Odynophagia  1  0/36 (0.00%)  1/30 (3.33%)  2/36 (5.56%)  2/30 (6.67%) 
Toothache  1  0/36 (0.00%)  0/30 (0.00%)  1/36 (2.78%)  2/30 (6.67%) 
Abdominal discomfort  1  0/36 (0.00%)  1/30 (3.33%)  1/36 (2.78%)  2/30 (6.67%) 
Gastrooesophageal reflux disease  1  1/36 (2.78%)  0/30 (0.00%)  1/36 (2.78%)  2/30 (6.67%) 
Eructation  1  0/36 (0.00%)  0/30 (0.00%)  0/36 (0.00%)  2/30 (6.67%) 
Gingival bleeding  1  0/36 (0.00%)  0/30 (0.00%)  0/36 (0.00%)  2/30 (6.67%) 
Gastritis  1  1/36 (2.78%)  0/30 (0.00%)  2/36 (5.56%)  0/30 (0.00%) 
General disorders         
Pyrexia  1  7/36 (19.44%)  6/30 (20.00%)  15/36 (41.67%)  9/30 (30.00%) 
Asthenia  1  3/36 (8.33%)  1/30 (3.33%)  1/36 (2.78%)  0/30 (0.00%) 
Fatigue  1  0/36 (0.00%)  2/30 (6.67%)  3/36 (8.33%)  3/30 (10.00%) 
Vaccination site pain  1  0/36 (0.00%)  2/30 (6.67%)  0/36 (0.00%)  0/30 (0.00%) 
Chest pain  1  1/36 (2.78%)  0/30 (0.00%)  1/36 (2.78%)  4/30 (13.33%) 
Malaise  1  0/36 (0.00%)  1/30 (3.33%)  2/36 (5.56%)  2/30 (6.67%) 
Immune system disorders         
Seasonal allergy  1  0/36 (0.00%)  0/30 (0.00%)  4/36 (11.11%)  2/30 (6.67%) 
Infections and infestations         
Upper respiratory tract infection  1  6/36 (16.67%)  6/30 (20.00%)  10/36 (27.78%)  5/30 (16.67%) 
Nasopharyngitis  1  4/36 (11.11%)  3/30 (10.00%)  17/36 (47.22%)  14/30 (46.67%) 
Rhinitis  1  2/36 (5.56%)  3/30 (10.00%)  4/36 (11.11%)  9/30 (30.00%) 
Sinusitis  1  2/36 (5.56%)  0/30 (0.00%)  4/36 (11.11%)  0/30 (0.00%) 
Tonsillitis  1  2/36 (5.56%)  4/30 (13.33%)  4/36 (11.11%)  3/30 (10.00%) 
Pharyngitis  1  0/36 (0.00%)  5/30 (16.67%)  6/36 (16.67%)  5/30 (16.67%) 
Respiratory tract infection viral  1  0/36 (0.00%)  2/30 (6.67%)  0/36 (0.00%)  4/30 (13.33%) 
Varicella  1  0/36 (0.00%)  2/30 (6.67%)  1/36 (2.78%)  0/30 (0.00%) 
Respiratory tract infection  1  0/36 (0.00%)  0/30 (0.00%)  3/36 (8.33%)  5/30 (16.67%) 
Gastroenteritis  1  1/36 (2.78%)  0/30 (0.00%)  5/36 (13.89%)  7/30 (23.33%) 
Bronchitis  1  0/36 (0.00%)  1/30 (3.33%)  2/36 (5.56%)  3/30 (10.00%) 
Influenza  1  0/36 (0.00%)  1/30 (3.33%)  3/36 (8.33%)  1/30 (3.33%) 
Urinary tract infection  1  0/36 (0.00%)  0/30 (0.00%)  2/36 (5.56%)  2/30 (6.67%) 
Conjunctivitis  1  0/36 (0.00%)  0/30 (0.00%)  1/36 (2.78%)  3/30 (10.00%) 
Oral herpes  1  1/36 (2.78%)  0/30 (0.00%)  1/36 (2.78%)  3/30 (10.00%) 
Vulvovaginitis  1 [1]  0/18 (0.00%)  0/15 (0.00%)  1/18 (5.56%)  2/15 (13.33%) 
Otitis media  1  0/36 (0.00%)  0/30 (0.00%)  3/36 (8.33%)  0/30 (0.00%) 
Viral infection  1  0/36 (0.00%)  1/30 (3.33%)  0/36 (0.00%)  3/30 (10.00%) 
Gastroenteritis viral  1  0/36 (0.00%)  0/30 (0.00%)  0/36 (0.00%)  2/30 (6.67%) 
Gastrointestinal infection  1  1/36 (2.78%)  0/30 (0.00%)  0/36 (0.00%)  2/30 (6.67%) 
Ear infection  1  0/36 (0.00%)  0/30 (0.00%)  2/36 (5.56%)  0/30 (0.00%) 
Rotavirus infection  1  0/36 (0.00%)  0/30 (0.00%)  0/36 (0.00%)  2/30 (6.67%) 
Injury, poisoning and procedural complications         
Procedural Pain  1 [2]  1/36 (2.78%)  3/30 (10.00%)  0/36 (0.00%)  1/30 (3.33%) 
Ligament sprain  1  1/36 (2.78%)  1/30 (3.33%)  4/36 (11.11%)  3/30 (10.00%) 
Contusion  1  0/36 (0.00%)  0/30 (0.00%)  5/36 (13.89%)  2/30 (6.67%) 
Skin abrasion  1  0/36 (0.00%)  0/30 (0.00%)  4/36 (11.11%)  1/30 (3.33%) 
Arthropod bite  1  0/36 (0.00%)  0/30 (0.00%)  2/36 (5.56%)  2/30 (6.67%) 
Laceration  1  0/36 (0.00%)  1/30 (3.33%)  2/36 (5.56%)  2/30 (6.67%) 
Thermal burn  1  0/36 (0.00%)  0/30 (0.00%)  2/36 (5.56%)  2/30 (6.67%) 
Joint injury  1  0/36 (0.00%)  0/30 (0.00%)  2/36 (5.56%)  0/30 (0.00%) 
Sunburn  1  0/36 (0.00%)  0/30 (0.00%)  2/36 (5.56%)  0/30 (0.00%) 
Investigations         
Body temperature increased  1  2/36 (5.56%)  1/30 (3.33%)  0/36 (0.00%)  2/30 (6.67%) 
Blood cholesterol increased  1  0/36 (0.00%)  0/30 (0.00%)  2/36 (5.56%)  0/30 (0.00%) 
Blood pressure increased  1  0/36 (0.00%)  0/30 (0.00%)  2/36 (5.56%)  0/30 (0.00%) 
Cardiac murmur  1  0/36 (0.00%)  0/30 (0.00%)  2/36 (5.56%)  0/30 (0.00%) 
Eosinophil count increased  1  0/36 (0.00%)  0/30 (0.00%)  0/36 (0.00%)  2/30 (6.67%) 
Metabolism and nutrition disorders         
Vitamin D deficiency  1  0/36 (0.00%)  0/30 (0.00%)  8/36 (22.22%)  4/30 (13.33%) 
Iron deficiency  1  0/36 (0.00%)  0/30 (0.00%)  3/36 (8.33%)  2/30 (6.67%) 
Musculoskeletal and connective tissue disorders         
Arthralgia  1  2/36 (5.56%)  1/30 (3.33%)  3/36 (8.33%)  4/30 (13.33%) 
Musculoskeletal pain  1  1/36 (2.78%)  0/30 (0.00%)  3/36 (8.33%)  2/30 (6.67%) 
Back pain  1  0/36 (0.00%)  0/30 (0.00%)  2/36 (5.56%)  1/30 (3.33%) 
Tendonitis  1  0/36 (0.00%)  0/30 (0.00%)  2/36 (5.56%)  2/30 (6.67%) 
Pain in extremity  1  1/36 (2.78%)  0/30 (0.00%)  3/36 (8.33%)  0/30 (0.00%) 
Myalgia  1  0/36 (0.00%)  1/30 (3.33%)  0/36 (0.00%)  3/30 (10.00%) 
Neck pain  1  0/36 (0.00%)  0/30 (0.00%)  0/36 (0.00%)  2/30 (6.67%) 
Osteoporosis  1  0/36 (0.00%)  0/30 (0.00%)  2/36 (5.56%)  0/30 (0.00%) 
Nervous system disorders         
Headache  1  10/36 (27.78%)  6/30 (20.00%)  19/36 (52.78%)  12/30 (40.00%) 
Syncope  1  2/36 (5.56%)  0/30 (0.00%)  1/36 (2.78%)  1/30 (3.33%) 
Dizziness  1  0/36 (0.00%)  1/30 (3.33%)  6/36 (16.67%)  3/30 (10.00%) 
Somnolence  1  1/36 (2.78%)  1/30 (3.33%)  1/36 (2.78%)  2/30 (6.67%) 
Psychiatric disorders         
Anxiety  1  2/36 (5.56%)  0/30 (0.00%)  2/36 (5.56%)  1/30 (3.33%) 
Autism spectrum disorder  1  0/36 (0.00%)  0/30 (0.00%)  2/36 (5.56%)  0/30 (0.00%) 
Sleep disorder  1  0/36 (0.00%)  0/30 (0.00%)  0/36 (0.00%)  2/30 (6.67%) 
Reproductive system and breast disorders         
Dysmenorrhoea  1 [1]  0/18 (0.00%)  1/15 (6.67%)  3/18 (16.67%)  4/15 (26.67%) 
Respiratory, thoracic and mediastinal disorders         
Oropharyngeal pain  1  6/36 (16.67%)  1/30 (3.33%)  5/36 (13.89%)  6/30 (20.00%) 
Epistaxis  1  4/36 (11.11%)  6/30 (20.00%)  5/36 (13.89%)  5/30 (16.67%) 
Cough  1  3/36 (8.33%)  3/30 (10.00%)  12/36 (33.33%)  9/30 (30.00%) 
Rhinorrhoea  1  2/36 (5.56%)  1/30 (3.33%)  8/36 (22.22%)  5/30 (16.67%) 
Asthma  1  1/36 (2.78%)  0/30 (0.00%)  2/36 (5.56%)  3/30 (10.00%) 
Rhinitis allergic  1  1/36 (2.78%)  0/30 (0.00%)  4/36 (11.11%)  5/30 (16.67%) 
Nasal congestion  1  0/36 (0.00%)  1/30 (3.33%)  5/36 (13.89%)  0/30 (0.00%) 
Productive cough  1  1/36 (2.78%)  0/30 (0.00%)  0/36 (0.00%)  2/30 (6.67%) 
Skin and subcutaneous tissue disorders         
Rash  1  1/36 (2.78%)  3/30 (10.00%)  2/36 (5.56%)  4/30 (13.33%) 
Urticaria  1  0/36 (0.00%)  0/30 (0.00%)  3/36 (8.33%)  4/30 (13.33%) 
Dermatitis allergic  1  0/36 (0.00%)  0/30 (0.00%)  0/36 (0.00%)  6/30 (20.00%) 
Ecchymosis  1  1/36 (2.78%)  0/30 (0.00%)  1/36 (2.78%)  2/30 (6.67%) 
Dermatitis atopic  1  0/36 (0.00%)  0/30 (0.00%)  1/36 (2.78%)  2/30 (6.67%) 
Eczema  1  0/36 (0.00%)  0/30 (0.00%)  1/36 (2.78%)  2/30 (6.67%) 
Pruritus  1  1/36 (2.78%)  0/30 (0.00%)  0/36 (0.00%)  3/30 (10.00%) 
Dermatitis  1  0/36 (0.00%)  0/30 (0.00%)  2/36 (5.56%)  0/30 (0.00%) 
Vascular disorders         
Hypertension  1  1/36 (2.78%)  0/30 (0.00%)  2/36 (5.56%)  0/30 (0.00%) 
1
Term from vocabulary, MedDRA (15.1)
Indicates events were collected by systematic assessment
[1]
Adverse event occurring in female participants only.
[2]
Procedural pain after liver biopsy deemed by the Investigator to be unrelated to study drug.
Certain Agreements
Principal Investigators are NOT employed by the organization sponsoring the study.
There IS an agreement between Principal Investigators and the Sponsor (or its agents) that restricts the PI's rights to discuss or publish trial results after the trial is completed.

Institution and/or Principal Investigator may publish or make an individual oral or written presentation of publication of study results either 1) after Alexion publishes the study data or 2) 18 months after the completion of the study, whichever comes first.

Alexion reserves the right to review and comment on a communication at least 30 days prior to submission with a provision to extend the review for an additional 60 days where information is relevant to a patent application.

Results Point of Contact
Layout table for Results Point of Contact information
Name/Title: Alexion Pharmaceuticals, Inc.
Organization: Alexion Pharmaceuticals, Inc.
Phone: 855-752-2356
EMail: clinicaltrials@alexion.com
Layout table for additonal information
Responsible Party: Alexion Pharmaceuticals
ClinicalTrials.gov Identifier: NCT01757184    
Other Study ID Numbers: LAL-CL02
First Submitted: December 17, 2012
First Posted: December 28, 2012
Results First Submitted: January 14, 2016
Results First Posted: April 18, 2016
Last Update Posted: December 18, 2019