Clinical Study In Infants With Rapidly Progressive Lysoso... | NCT02193867

Clinical Study In Infants With Rapidly Progressive Lysoso... | NCT02193867 | Trialant

Arms/Interventions Module

Arm Groups

Label	Type	Description	Intervention Names
Open-Label Sebelipase Alfa	Experimental	All participants initiated once weekly (qw) intravenous (IV) infusions with sebelipase alfa at a dose of 1 milligram/kilogram (mg/kg) qw. A participant who met protocol defined dose escalation criteria at a dose of 1 mg/kg qw could be considered for a dose escalation to 3 mg/kg qw. If a participant continued to meet dose escalation criteria after at least 4 infusions at a dose of 3 mg/kg qw, the participant could be considered for a further dose escalation to 5 mg/kg qw. Under country-specific provisions (United Kingdom only), participants could be considered for a further dose escalation to 7.5 mg/kg qw if a thorough case review indicated that a participant continued to have evidence of disease progression at a dose of 5 mg/kg qw. All dose escalations were contingent upon acceptable safety and tolerability of preceding infusions and were undertaken by mutual agreement of the Investigator and Sponsor and after approval by an independent safety committee.	Drug: Sebelipase Alfa

Interventions

Name	Type	Description	Arm Group Labels	Other Names
Sebelipase Alfa	Drug	Sebelipase alfa is a recombinant human lysosomal acid lipase. The investigational medicinal product is an enzyme replacement therapy intended for treatment of participants with LAL-D. Dosing occurred once weekly for up to 3 years.

Outcomes Module

Primary Outcomes

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

Secondary Outcomes

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

References Module

Citations

PubMed Identifier	Type	Citation	Retractions
23348766	Background	Balwani M, Breen C, Enns GM, Deegan PB, Honzik T, Jones S, Kane JP, Malinova V, Sharma R, Stock EO, Valayannopoulos V, Wraith JE, Burg J, Eckert S, Schneider E, Quinn AG. Clinical effect and safety profile of recombinant human lysosomal acid lipase in patients with cholesteryl ester storage disease. Hepatology. 2013 Sep;58(3):950-7. doi: 10.1002/hep.26289. Epub 2013 Mar 28.
26312827

Arm/Group Information

ID	Title	Description
FG000	Open-Label Sebelipase Alfa	All participants initiated once weekly (qw) intravenous (IV) infusions with sebelipase alfa at a dose of 1 milligram/kilogram (mg/kg) qw. A participant who met protocol defined dose escalation criteria at a dose of 1 mg/kg qw could be considered for a dose escalation to 3 mg/kg qw. If a participant continued to meet dose escalation criteria after at least 4 infusions at a dose of 3 mg/kg qw, the participant could be considered for a further dose escalation to 5 mg/kg qw. Under country-specific provisions (UK only), participants could be considered for a further dose escalation to 7.5 mg/kg qw if a thorough case review indicated that a participant continued to have evidence of disease progression at a dose of 5 mg/kg qw. All dose escalations were contingent upon acceptable safety and tolerability of preceding infusions and were undertaken by mutual agreement of the Investigator and Sponsor and after approval by an independent safety committee.

Periods

Title

Milestones

Reasons Not Completed

Overall Study

Type	Comment	Milestone Data
STARTED		FG00010 subjects
Received At Least 1 Dose Of Study Drug	Full Analysis Set (FAS)	FG00010 subjects
Completed 18 Months Of Treatment	Treatment was to be at least 18 months; participants could continue treatment for up to 3 years	FG0008 subjects
COMPLETED	All participants continued to receive commercial therapy after study completion/Sponsor termination	FG0006 subjects
NOT COMPLETED		FG0004 subjects

Type	Comment	Reasons
Death		FG0002 subjects
Sponsor Study Termination		FG0002 subjects

Baseline Characteristics Module

Arm/Group Information

ID	Title	Description
BG000	Open-Label Sebelipase Alfa	All participants initiated qw IV infusions with sebelipase alfa at a dose of 1 mg/kg qw. A participant who met protocol defined dose escalation criteria at a dose of 1 mg/kg qw could be considered for a dose escalation to 3 mg/kg qw. If a participant continued to meet dose escalation criteria after at least 4 infusions at a dose of 3 mg/kg qw, the participant could be considered for a further dose escalation to 5 mg/kg qw. Under country-specific provisions (UK only), participants could be considered for a further dose escalation to 7.5 mg/kg qw if a thorough case review indicated that a participant continued to have evidence of disease progression at a dose of 5 mg/kg qw. All dose escalations were contingent upon acceptable safety and tolerability of preceding infusions and were undertaken by mutual agreement of the Investigator and Sponsor and after approval by an independent safety committee.

Units	Counts
Participants	BG000

Title	Description	Population Description	Parameter Type	Dispersion Type	Unit of Measure	Calculate Percentage	Denominator Units Selected	Denominators	Classes
Age, Continuous			Mean

Outcome Measures Module

Outcome Measures

Type	Title	Description	Population Description	Reporting Status	Anticipated Posting Date	Parameter Type	Dispersion Type	Unit of Measure	Calculate Percentage	Time Frame	Units Analyzed	Denominator Units Selected	Arm/Group Information	Denominators	Classes	Analyses
Primary	Participants Experiencing Severe Treatment-emergent Adverse Events (TEAEs)	The number of participants experiencing severe TEAEs is presented for participants who received sebelipase alfa in this open-label study. Adverse events were obtained through spontaneous reporting or elicited by specific questioning or examination of the participant's parent or legal guardian. An adverse event was defined as any new untoward medical occurrence or worsening of a pre-existing medical condition in a participant, whether or not causally related to administration of study drug. Adverse event severity was graded by the Investigator as mild, moderate, or severe based on definitions developed from Clinical Data Interchange Standards Consortium Study Data Tabulation Model standard terminology v3.1.1. Adverse events reporting was from the date of informed consent until completion of the follow-up visit at approximately 30 days after the last dose of study drug. A summary of all serious and other nonserious AEs regardless of causality is located in the Reported AE module.	FAS: All participants who received any amount of sebelipase alfa (1.0, 3.0, 5.0, or 7.5 mg/kg qw) during the study and where applicable, met end point criteria.	Posted		Count of Participants		Participants		Screening through Month 37

Adverse Events Module

Arm/Groups

ID	Title	Description	Deaths (Affected)	Deaths (At Risk)	Serious Events (Affected)	Serious Events (At Risk)	Other Events (Affected)	Other Events (At Risk)
EG000	Sebelipase Alfa: 1.0 mg/kg qw	This reporting group is based on the FAS and includes AEs with onset during the administration of IV treatment of sebelipase alfa at a dose of 1.0 mg/kg qw. All 10 participants in the FAS received sebelipase alfa at a dose of 1.0 mg/kg qw.

Term	Organ System	Source Vocabulary	Assessment Type	Notes	Statistical Information
Abdominal lymphadenopathy	Blood and lymphatic system disorders	MedDRA 21.0	Systematic Assessment

Term	Organ System	Source Vocabulary	Assessment Type	Notes	Statistical Information
Vomiting	Gastrointestinal disorders	MedDRA 21.0	Systematic Assessment

More Info Module

Certain Agreements

Title	Organization	Phone	Extension	Email
Alexion Pharmaceuticals Inc.	Alexion Pharmaceuticals Inc.	855-752-2356		clinicaltrials@alexion.com

Uploaded Document Information

Type	Includes Protocol	Includes SAP	Includes ICF	Document Label	Document Date	Document Uploaded Date	Document File Name
Prot	Yes	No	No	Study Protocol	Dec 8, 2015	Jun 24, 2019	Prot_000.pdf
SAP	No	Yes	No	Statistical Analysis Plan	Jul 31, 2018	Jun 24, 2019	SAP_001.pdf

Condition Browse Module

MeSH Terms

ID	Term
D015223	Wolman Disease
D015217	Cholesterol Ester Storage Disease
D065626	Non-alcoholic Fatty Liver Disease
D008108	Liver Diseases, Alcoholic
C562577	Cirrhosis, Cryptogenic
D009542	Niemann-Pick Diseases
C536560	Chanarin-Dorfman Syndrome

ID	Term
D008064	Lipidoses
D008052	Lipid Metabolism, Inborn Errors
D008661	Metabolism, Inborn Errors
D030342	Genetic Diseases, Inborn

ID	Term
C000603932	Sebelipase alfa

Race/Ethnicity, Customized

Count of Participants

Participants

Title

Denominators

Categories

Race/Ethnicity

Title	Measurements
American Indian or Alaska Native	BG0001
Asian	BG0006
White	BG0001
Egyptian	BG0001
Turkish Kurdish	BG0001

ID	Title	Description
OG000	Open-Label Sebelipase Alfa	All participants initiated qw IV infusions with sebelipase alfa at a dose of 1 mg/kg qw. A participant who met protocol defined dose escalation criteria at a dose of 1 mg/kg qw could be considered for a dose escalation to 3 mg/kg qw. If a participant continued to meet dose escalation criteria after at least 4 infusions at a dose of 3 mg/kg qw, the participant could be considered for a further dose escalation to 5 mg/kg qw. Under country-specific provisions (UK only), participants could be considered for a further dose escalation to 7.5 mg/kg qw if a thorough case review indicated that a participant continued to have evidence of disease progression at a dose of 5 mg/kg qw. All dose escalations were contingent upon acceptable safety and tolerability of preceding infusions and were undertaken by mutual agreement of the Investigator and Sponsor and after approval by an independent safety committee.

Secondary

Percentage Of Participants Surviving To 12, 18, 24, And 36 Months Of Age

The percentage of participants in the FAS who survived to 12, 18, 24, and 36 months of age. The exact confidence interval was calculated using the Clopper-Pearson method. Participants with unknown survival status at the age specified in the analysis were excluded. At 36 months, there were 2 participants who were alive and still on study who had not yet reached the age specified in the analysis. As such, these participants were excluded from the calculation of percent surviving.

FAS: All participants who received any amount of sebelipase alfa (1.0, 3.0, 5.0, or 7.5 mg/kg qw) during the study and where applicable, met end point criteria.

Posted

Number

95% Confidence Interval

percentage of participants

Baseline through Month 12, Month 18, Month 24, and Month 36

ID	Title	Description
OG000	Open-Label Sebelipase Alfa	All participants initiated qw IV infusions with sebelipase alfa at a dose of 1 mg/kg qw. A participant who met protocol defined dose escalation criteria at a dose of 1 mg/kg qw could be considered for a dose escalation to 3 mg/kg qw. If a participant continued to meet dose escalation criteria after at least 4 infusions at a dose of 3 mg/kg qw, the participant could be considered for a further dose escalation to 5 mg/kg qw. Under country-specific provisions (UK only), participants could be considered for a further dose escalation to 7.5 mg/kg qw if a thorough case review indicated that a participant continued to have evidence of disease progression at a dose of 5 mg/kg qw. All dose escalations were contingent upon acceptable safety and tolerability of preceding infusions and were undertaken by mutual agreement of the Investigator and Sponsor and after approval by an independent safety committee.

Units	Counts
Participants	OG00010

Title

Denominators

Categories

Month 12

- ParticipantsOG00010

Title	Measurements
	OG00090(55.5 to 99.7)

Month 18

- ParticipantsOG000

Secondary

Median Age At Death

Age at death for participants who died during the study. All deaths were assessed by the Investigator as unrelated to study drug.

FAS: All participants who received any amount of sebelipase alfa (1.0, 3.0, 5.0, or 7.5 mg/kg qw) during the study and where applicable, met end point criteria.

Posted

Median

Full Range

months

Baseline through Month 36

ID	Title	Description
OG000	Open-Label Sebelipase Alfa	All participants initiated qw IV infusions with sebelipase alfa at a dose of 1 mg/kg qw. A participant who met protocol defined dose escalation criteria at a dose of 1 mg/kg qw could be considered for a dose escalation to 3 mg/kg qw. If a participant continued to meet dose escalation criteria after at least 4 infusions at a dose of 3 mg/kg qw, the participant could be considered for a further dose escalation to 5 mg/kg qw. Under country-specific provisions (UK only), participants could be considered for a further dose escalation to 7.5 mg/kg qw if a thorough case review indicated that a participant continued to have evidence of disease progression at a dose of 5 mg/kg qw. All dose escalations were contingent upon acceptable safety and tolerability of preceding infusions and were undertaken by mutual agreement of the Investigator and Sponsor and after approval by an independent safety committee.

Units	Counts
Participants	OG0002

Title

Denominators

Categories

Title	Measurements
	OG0009.33(4.9 to 13.8)

Secondary

Change From Baseline In Percentiles For Weight For Age (WFA) At 12, 24, And 36 Months

This outcome measure evaluated the effects of sebelipase alfa on growth by measuring the changes from baseline in percentiles for WFA. Percentiles for WFA were summarized as observed values by visit. Baseline was defined as the last available assessment prior to the first infusion of sebelipase alfa.

FAS: All participants who received any amount of sebelipase alfa (1.0, 3.0, 5.0, or 7.5 mg/kg qw) during the study and where applicable, met end point criteria.

Posted

Median

Full Range

percentile

Baseline, Month 12, Month 24, and Month 36

ID	Title	Description
OG000	Open-Label Sebelipase Alfa	All participants initiated qw IV infusions with sebelipase alfa at a dose of 1 mg/kg qw. A participant who met protocol defined dose escalation criteria at a dose of 1 mg/kg qw could be considered for a dose escalation to 3 mg/kg qw. If a participant continued to meet dose escalation criteria after at least 4 infusions at a dose of 3 mg/kg qw, the participant could be considered for a further dose escalation to 5 mg/kg qw. Under country-specific provisions (UK only), participants could be considered for a further dose escalation to 7.5 mg/kg qw if a thorough case review indicated that a participant continued to have evidence of disease progression at a dose of 5 mg/kg qw. All dose escalations were contingent upon acceptable safety and tolerability of preceding infusions and were undertaken by mutual agreement of the Investigator and Sponsor and after approval by an independent safety committee.

Units	Counts
Participants	OG0009

Title

Denominators

Categories

Month 12

- ParticipantsOG0008

Title	Measurements
	OG00027.760(1.34 to 67.58)

Month 24

- ParticipantsOG000

Secondary

Number Of Participants With Stunting, Wasting, Or Underweight At Baseline, 12, 24, And 36 Months

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

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

FAS: All participants who received any amount of sebelipase alfa (1.0, 3.0, 5.0, or 7.5 mg/kg qw) during the study and where applicable, met end point criteria.

Posted

Count of Participants

Participants

Baseline to Month 12, Month 24, and Month 36

ID	Title	Description
OG000	Open-Label Sebelipase Alfa	All participants initiated qw IV infusions with sebelipase alfa at a dose of 1 mg/kg qw. A participant who met protocol defined dose escalation criteria at a dose of 1 mg/kg qw could be considered for a dose escalation to 3 mg/kg qw. If a participant continued to meet dose escalation criteria after at least 4 infusions at a dose of 3 mg/kg qw, the participant could be considered for a further dose escalation to 5 mg/kg qw. Under country-specific provisions (UK only), participants could be considered for a further dose escalation to 7.5 mg/kg qw if a thorough case review indicated that a participant continued to have evidence of disease progression at a dose of 5 mg/kg qw. All dose escalations were contingent upon acceptable safety and tolerability of preceding infusions and were undertaken by mutual agreement of the Investigator and Sponsor and after approval by an independent safety committee.

Units	Counts
Participants	OG00010

Title

Denominators

Categories

Stunting, Baseline

- ParticipantsOG0009

Title	Measurements
	OG0004

Stunting, Month 12

- ParticipantsOG000

Secondary

Change From Baseline In Serum Transaminases (ALT And AST) At Month 12, 24, And 36

This outcome measure evaluated the effects of sebelipase alfa on liver function by measuring the change from baseline in alanine aminotransferase (ALT) and aspartate aminotransferase (AST) at months 12, 24, and 36. Results are reported in units/liter (U/L).

FAS: All participants who received any amount of sebelipase alfa (1.0, 3.0, 5.0, or 7.5 mg/kg qw) during the study and where applicable, met end point criteria.

Posted

Median

Full Range

U/L

Baseline, Month 12, Month 24, and Month 36

ID	Title	Description
OG000	Open-Label Sebelipase Alfa	All participants initiated qw IV infusions with sebelipase alfa at a dose of 1 mg/kg qw. A participant who met protocol defined dose escalation criteria at a dose of 1 mg/kg qw could be considered for a dose escalation to 3 mg/kg qw. If a participant continued to meet dose escalation criteria after at least 4 infusions at a dose of 3 mg/kg qw, the participant could be considered for a further dose escalation to 5 mg/kg qw. Under country-specific provisions (UK only), participants could be considered for a further dose escalation to 7.5 mg/kg qw if a thorough case review indicated that a participant continued to have evidence of disease progression at a dose of 5 mg/kg qw. All dose escalations were contingent upon acceptable safety and tolerability of preceding infusions and were undertaken by mutual agreement of the Investigator and Sponsor and after approval by an independent safety committee.

Units	Counts
Participants	OG00010

Title

Denominators

Categories

ALT: Month 12

- ParticipantsOG0007

Title	Measurements
	OG0000(-175 to 66)

ALT: Month 24

- ParticipantsOG000

Secondary

Change From Baseline In Serum Ferritin At Month 12, 24, And 36

The median change in the inflammatory marker serum ferritin from Baseline to Months 12, 24, and 36 is presented. The number of participants analyzed reflects only those from the FAS who had both a baseline value and a value at the indicated timepoint (Months 12, 24, and 36). Results are reported in micrograms (ug)/L.

FAS: All participants who received any amount of sebelipase alfa (1.0, 3.0, 5.0, or 7.5 mg/kg qw) during the study and where applicable, met end point criteria.

Posted

Median

Full Range

ug/L

Baseline, Month 12, Month 24, and Month 36

ID	Title	Description
OG000	Open-Label Sebelipase Alfa	All participants initiated qw IV infusions with sebelipase alfa at a dose of 1 mg/kg qw. A participant who met protocol defined dose escalation criteria at a dose of 1 mg/kg qw could be considered for a dose escalation to 3 mg/kg qw. If a participant continued to meet dose escalation criteria after at least 4 infusions at a dose of 3 mg/kg qw, the participant could be considered for a further dose escalation to 5 mg/kg qw. Under country-specific provisions (UK only), participants could be considered for a further dose escalation to 7.5 mg/kg qw if a thorough case review indicated that a participant continued to have evidence of disease progression at a dose of 5 mg/kg qw. All dose escalations were contingent upon acceptable safety and tolerability of preceding infusions and were undertaken by mutual agreement of the Investigator and Sponsor and after approval by an independent safety committee.

Units	Counts
Participants	OG0002

Title

Denominators

Categories

Month 12

- ParticipantsOG0001

Title	Measurements
	OG000-2957.00(-2957.0 to -2957.0)

Month 24

- ParticipantsOG000

Secondary

Number Of Participants Achieving And Maintaining Transfusion-free Hemoglobin Normalization (TFHN)

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

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

FAS: All participants who received any amount of sebelipase alfa (1.0, 3.0, 5.0, or 7.5 mg/kg qw) during the study and where applicable, met end point criteria.

Posted

Count of Participants

Participants

Baseline through Month 36

ID	Title	Description
OG000	Open-Label Sebelipase Alfa	All participants initiated qw IV infusions with sebelipase alfa at a dose of 1 mg/kg qw. A participant who met protocol defined dose escalation criteria at a dose of 1 mg/kg qw could be considered for a dose escalation to 3 mg/kg qw. If a participant continued to meet dose escalation criteria after at least 4 infusions at a dose of 3 mg/kg qw, the participant could be considered for a further dose escalation to 5 mg/kg qw. Under country-specific provisions (UK only), participants could be considered for a further dose escalation to 7.5 mg/kg qw if a thorough case review indicated that a participant continued to have evidence of disease progression at a dose of 5 mg/kg qw. All dose escalations were contingent upon acceptable safety and tolerability of preceding infusions and were undertaken by mutual agreement of the Investigator and Sponsor and after approval by an independent safety committee.

Units	Counts
Participants	OG00010

Title

Denominators

Categories

Achieved TFHN

Title	Measurements
	OG0007

Maintained TFHN

Title	Measurements
	OG0000

Facility	Status	City	State	ZIP	Country	Contacts
		Phoenix	Arizona	85016	United States