Efficacy, Safety, Pharmacodynamic, and Pharmacokinetics S... | NCT02004691

NCT02004691

ID	Type	Description
U1111-1142-5963	Registry Identifier	ICTRP
DFI12712	Other Identifier	Sanofi Identifier
2015-000371-26	EudraCT Number

Status Module

Description Module

Arms/Interventions Module

Arm Groups

Label	Type	Description	Intervention Names
Placebo	Placebo Comparator	Placebo (saline) administered intravenously once every 2 weeks during the 52 weeks of the primary analysis period for patients randomized to placebo.	Drug: placebo (saline)
Olipudase alfa	Experimental	Olipudase alfa dose (3 mg/kg body weight) in saline administered intravenously once every 2 weeks during the 52 weeks of the primary analysis period for patients randomized to olipudase alfa, and during the extension treatment period for all patients.	Drug: Olipudase alfa

Interventions

Name	Type	Description	Arm Group Labels	Other Names
placebo (saline)	Drug	Pharmaceutical form: solution administered once every two weeks during the 52 weeks of the primary analysis period for participants randomized to placebo. Route of administration: intravenous infusion

Outcomes Module

Primary Outcomes

Measure	Description	Time Frame
Percent Predicted (% Predicted) Hemoglobin (Hb) and Altitude-Adjusted Diffusing Capacity of the Lung for Carbon Monoxide (DLco) at Baseline	Percent predicted Hb and Altitude-adjusted DLco was calculated as: 100*Adjusted DLco/Predicted DLco in unit of mL CO/min/mmHg where, adjusted DLco = Observed DLco (in mL CO/min/mmHg) times Hemoglobin-adjusted factor times Altitude-adjustment factor.	Baseline (Day 1)
Percent Change From Baseline in Percent Predicted (% Predicted) Hemoglobin (Hb) and Altitude-Adjusted Diffusing Capacity of the Lung for Carbon Monoxide (DLco) at Week 52	Percent predicted Hb and Altitude-adjusted DLco was calculated as: 100*Adjusted DLco/Predicted DLco in unit of mL CO/min/mmHg where, adjusted DLco = Observed DLco (in mL CO/min/mmHg) times Hemoglobin-adjusted factor times Altitude-adjustment factor.	Baseline, Week 52
Combination Spleen Endpoint: Component 1: Spleen Volume (in MN) at Baseline	Spleen volume was assessed by abdominal magnetic resonance imaging (MRI) to quantitate the degree of splenomegaly in multiples of normal (MN).	Baseline (Day 1)
Combination Spleen Endpoint: Component 1: Percent Change From Baseline in Spleen Volume (in MN) at Week 52	Spleen volume was assessed by abdominal MRI to quantitate the degree of splenomegaly in MN.	Baseline, Week 52
Combination Spleen Endpoint (Primary for US Only): Component 2: Splenomegaly-Related Score (SRS) at Baseline	The SRS rates 5 items: abdominal pain, abdominal discomfort, early satiety, dissatisfaction with abdominal body image, and difficulty to bend down using a numerical rating scale of 0 (absent) to 10 (worst imaginable). The total score of SRS ranges from 0 to 50, with higher scores (50) indicated worst imaginable rating. It was pre-specified as secondary endpoint for countries outside of US.

Secondary Outcomes

Measure	Description	Time Frame
Number of Participants With Treatment-Emergent Adverse Events (TEAEs) and Treatment-Emergent Serious Adverse Events (TESAEs) up to Week 52	An AE was defined as any untoward medical occurrence in a participant or clinical investigation participant administered with a pharmaceutical product and which does not necessarily have to have a causal relationship with this treatment. TESAEs was defined as any untoward medical occurrence that at any dose: resulted in death, was life-threatening, required inpatient hospitalization or prolongation of existing hospitalization, resulted in persistent or significant disability/incapacity, was a congenital anomaly/birth defect, was a medically important event. Reported AEs are treatment-emergent AEs that developed, worsened or became serious during the treatment period.

Eligibility Module

Eligibility Criteria

Inclusion criteria :

The participant was willing and able to provide signed written informed consent.
The participant was male or female aged 18 years or older.
The participant had documented deficiency of acid sphingomyelinase as measured in peripheral leukocytes, cultured fibroblasts, or lymphocytes; and a clinical diagnosis consistent with Niemann-Pick disease type B (NPD B).
The participant had diffuse capacity of the lung for carbon monoxide less than or equal to (<=)70% of the predicted normal value.
The participant had a spleen volume greater than or equal to (>=)6 multiples of normal (MN) measured by MRI; participant who have had partial splenectomy was allowed if the procedure was performed >=1 year before screening/baseline and the residual spleen volume was >=6 MN.
The participant had an SRS >=5.
Female participants of childbearing potential must have had a negative serum pregnancy test for beta-human chorionic gonadotropin (β-HCG).
Female participants of childbearing potential and male participants were willing to practice true abstinence in line with their preferred and usual lifestyle, or use 2 acceptable effective methods of contraception for up to 15 days following their last dose of study drug.

Exclusion criteria:

The participant had received an investigational drug within 30 days before study enrollment.
The participant had a medical condition, including significant intercurrent illness; significant cardiac disease (e.g., clinically significant arrhythmia, moderate or severe pulmonary hypertension or clinically significant valve dysfunction, or less than or equal to (<=)40% left ventricular ejection fraction by echocardiogram); active hepatitis B or hepatitis C, or infection with human immunodeficiency virus (HIV); malignancy diagnosed within the past 5 years (other than non-melanoma skin cancer), or any other serious medical condition that might have precluded participation in the study.
The participant had a platelet count less than (<)60,000/microliters based on the average of 2 samples.
The participant had an international normalized ratio (INR) greater than (>)1.5.
The participant had alanine aminotransferase (ALT) or aspartate aminotransferase (AST) >250 IU/L or total bilirubin >1.5 mg/dL (except for participant with Gilbert's syndrome).
The participant had a major organ transplant (eg, bone marrow or liver).
The participant was scheduled during the study for in-patient hospitalization including elective surgery and excluding the liver biopsies required per protocol.
The participant, in the opinion of the investigator, was unable to adhere to the requirements of the study.
The participant was unwilling or unable to abstain from the use of alcohol for 1 day before and 3 days after each study drug infusion. Testing for blood alcohol levels was not required.
The participant was unwilling or unable to avoid 10 days before and 3 days after the protocol scheduled liver biopsies the use of medications or herbal supplements that were potentially hepatotoxic (e.g., 3-hydroxy-3-methyl glutaryl coenzyme A reductase inhibitors, erythromycin, valproic acid, anti-depressants, kava, echinacea) and/or might have caused or prolonged bleeding (e.g., anti-coagulants, ibuprofen, aspirin, garlic supplements, ginkgo, ginseng).
The participant required medications that might have decreased olipudase alfa activity (e.g., fluoxetine, chlorpromazine, tricyclic antidepressants [e.g., imipramine, or desipramine]).
The participant required use of invasive ventilatory support.
The participant required use of noninvasive ventilator support while awake for longer than 12 hours daily.
The participant was breast-feeding.

The above information was not intended to contain all considerations relevant to a participant's potential participation in a clinical trial.

Name	Affiliation	Role
Clinical Sciences & Operations	Sanofi	Study Director

Facility	Status	City	State	ZIP	Country	Contacts
UCSF Medical Center Site Number : 840005		San Francisco	California	94143	United States
Emory University Site Number : 840003

PubMed Identifier	Type	Citation	Retractions
38042851	Derived	Wasserstein MP, Lachmann R, Hollak C, Barbato A, Gallagher RC, Giugliani R, Guelbert NB, Hennermann JB, Ikezoe T, Lidove O, Mabe P, Mengel E, Scarpa M, Senates E, Tchan M, Villarrubia J, Thurberg BL, Yarramaneni A, Armstrong NM, Kim Y, Kumar M. Continued improvement in disease manifestations of acid sphingomyelinase deficiency for adults with up to 2 years of olipudase alfa treatment: open-label extension of the ASCEND trial. Orphanet J Rare Dis. 2023 Dec 2;18(1):378. doi: 10.1186/s13023-023-02983-0.

Results Section

Participant Flow Module

Arm/Group Information

ID	Title	Description
FG000	Placebo	Participants received intravenous (IV) infusion of placebo (matched to olipudase alfa) once every 2 weeks up to Week 52. Participants who completed PAP entered in ETP and crossed over to olipudase alfa with a target maintenance dose of 3 mg/kg after dose escalation which was administered IV once every 2 weeks up to Year 5.
FG001

Baseline Characteristics Module

Outcome Measures Module

Adverse Events Module

More Info Module

Type	Includes Protocol	Includes SAP	Includes ICF	Document Label	Document Date	Document Uploaded Date	Document File Name
Prot	Yes	No	No	Study Protocol	Nov 1, 2022	Oct 16, 2024

Arm/Group Information

ID	Title	Description
BG000	Placebo	Participants received IV infusion of placebo (matched to olipudase alfa) once every 2 weeks up to Week 52. Participants who completed PAP entered in ETP and crossed over to olipudase alfa with a target maintenance dose of 3 mg/kg after dose escalation which was administered IV once every 2 weeks up to Year 5.
BG001	Olipudase Alfa	Participants received IV infusion of olipudase alfa once every 2 weeks up to Week 52. Each participant underwent a dose escalation according to the following paradigm: 0.1, 0.3, 0.3, 0.6, 0.6, 1.0, 2.0, 3.0, 3.0 mg/kg. Three (3) mg/kg was the target maintenance dose, which was maintained for the remaining duration of 52 weeks of PAP. Participants who completed PAP entered in ETP and continued the same treatment in ETP up to Year 5.
BG002	Total Title

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

Percent Predicted (% Predicted) Hemoglobin (Hb) and Altitude-Adjusted Diffusing Capacity of the Lung for Carbon Monoxide (DLco) at Baseline

Percent predicted Hb and Altitude-adjusted DLco was calculated as: 100*Adjusted DLco/Predicted DLco in unit of mL CO/min/mmHg where, adjusted DLco = Observed DLco (in mL CO/min/mmHg) times Hemoglobin-adjusted factor times Altitude-adjustment factor.

Analysis was performed on mITT population.

Posted

Mean

Standard Deviation

% Predicted DLco

Baseline (Day 1)

ID	Title	Description
OG000	Placebo	Participants received IV infusion of placebo (matched to olipudase alfa) once every 2 weeks up to Week 52. Participants who completed PAP entered in ETP and crossed over to olipudase alfa with a target maintenance dose of 3 mg/kg after dose escalation which was administered IV once every 2 weeks up to Year 5.
OG001	Olipudase Alfa	Participants received IV infusion of olipudase alfa once every 2 weeks up to Week 52. Each participant underwent a dose escalation according to the following paradigm: 0.1, 0.3, 0.3, 0.6, 0.6, 1.0, 2.0, 3.0, 3.0 mg/kg. Three (3) mg/kg was the target maintenance dose, which was maintained for the remaining duration of 52 weeks of PAP. Participants who completed PAP entered in ETP and continued the same treatment in ETP up to Year 5.

Units	Counts
Participants	OG00018 OG00118

Title

Denominators

Categories

Title	Measurements
	OG00048.45± 10.76 OG00149.44± 10.99

Primary

Percent Change From Baseline in Percent Predicted (% Predicted) Hemoglobin (Hb) and Altitude-Adjusted Diffusing Capacity of the Lung for Carbon Monoxide (DLco) at Week 52

Analysis was performed on mITT population. Here, overall number of participants analyzed = participants evaluable for this outcome measure.

Posted

Least Squares Mean

Standard Error

percent change

Baseline, Week 52

ID	Title	Description
OG000	Placebo	Participants received IV infusion of placebo (matched to olipudase alfa) once every 2 weeks up to Week 52. Participants who completed PAP entered in ETP and crossed over to olipudase alfa with a target maintenance dose of 3 mg/kg after dose escalation which was administered IV once every 2 weeks up to Year 5.
OG001	Olipudase Alfa	Participants received IV infusion of olipudase alfa once every 2 weeks up to Week 52. Each participant underwent a dose escalation according to the following paradigm: 0.1, 0.3, 0.3, 0.6, 0.6, 1.0, 2.0, 3.0, 3.0 mg/kg. Three (3) mg/kg was the target maintenance dose, which was maintained for the remaining duration of 52 weeks of PAP. Participants who completed PAP entered in ETP and continued the same treatment in ETP up to Year 5.

Primary

Combination Spleen Endpoint: Component 1: Spleen Volume (in MN) at Baseline

Spleen volume was assessed by abdominal magnetic resonance imaging (MRI) to quantitate the degree of splenomegaly in multiples of normal (MN).

Analysis was performed on mITT population.

Posted

Mean

Standard Deviation

multiples of normal (MN)

Baseline (Day 1)

ID	Title	Description
OG000	Placebo	Participants received IV infusion of placebo (matched to olipudase alfa) once every 2 weeks up to Week 52. Participants who completed PAP entered in ETP and crossed over to olipudase alfa with a target maintenance dose of 3 mg/kg after dose escalation which was administered IV once every 2 weeks up to Year 5.
OG001	Olipudase Alfa	Participants received IV infusion of olipudase alfa once every 2 weeks up to Week 52. Each participant underwent a dose escalation according to the following paradigm: 0.1, 0.3, 0.3, 0.6, 0.6, 1.0, 2.0, 3.0, 3.0 mg/kg. Three (3) mg/kg was the target maintenance dose, which was maintained for the remaining duration of 52 weeks of PAP. Participants who completed PAP entered in ETP and continued the same treatment in ETP up to Year 5.

Units	Counts

Primary

Combination Spleen Endpoint: Component 1: Percent Change From Baseline in Spleen Volume (in MN) at Week 52

Spleen volume was assessed by abdominal MRI to quantitate the degree of splenomegaly in MN.

Analysis was performed on mITT population. Here, overall number of participants analyzed = participants evaluable for this outcome measure.

Posted

Least Squares Mean

Standard Error

percent change

Baseline, Week 52

ID	Title	Description
OG000	Placebo	Participants received IV infusion of placebo (matched to olipudase alfa) once every 2 weeks up to Week 52. Participants who completed PAP entered in ETP and crossed over to olipudase alfa with a target maintenance dose of 3 mg/kg after dose escalation which was administered IV once every 2 weeks up to Year 5.
OG001	Olipudase Alfa	Participants received IV infusion of olipudase alfa once every 2 weeks up to Week 52. Each participant underwent a dose escalation according to the following paradigm: 0.1, 0.3, 0.3, 0.6, 0.6, 1.0, 2.0, 3.0, 3.0 mg/kg. Three (3) mg/kg was the target maintenance dose, which was maintained for the remaining duration of 52 weeks of PAP. Participants who completed PAP entered in ETP and continued the same treatment in ETP up to Year 5.

Primary

Combination Spleen Endpoint (Primary for US Only): Component 2: Splenomegaly-Related Score (SRS) at Baseline

The SRS rates 5 items: abdominal pain, abdominal discomfort, early satiety, dissatisfaction with abdominal body image, and difficulty to bend down using a numerical rating scale of 0 (absent) to 10 (worst imaginable). The total score of SRS ranges from 0 to 50, with higher scores (50) indicated worst imaginable rating. It was pre-specified as secondary endpoint for countries outside of US.

Analysis was performed on mITT population. Here, overall number of participants analyzed = participants evaluable for this outcome measure.

Posted

Mean

Standard Deviation

score on a scale

Baseline (Day 1)

ID	Title	Description
OG000	Placebo	Participants received IV infusion of placebo (matched to olipudase alfa) once every 2 weeks up to Week 52. Participants who completed PAP entered in ETP and crossed over to olipudase alfa with a target maintenance dose of 3 mg/kg after dose escalation which was administered IV once every 2 weeks up to Year 5.
OG001	Olipudase Alfa	Participants received IV infusion of olipudase alfa once every 2 weeks up to Week 52. Each participant underwent a dose escalation according to the following paradigm: 0.1, 0.3, 0.3, 0.6, 0.6, 1.0, 2.0, 3.0, 3.0 mg/kg. Three (3) mg/kg was the target maintenance dose, which was maintained for the remaining duration of 52 weeks of PAP. Participants who completed PAP entered in ETP and continued the same treatment in ETP up to Year 5.

Primary

Combination Spleen Endpoint (Primary for US Only): Component 2: Change From Baseline in Splenomegaly-Related Score (SRS) at Week 52

Analysis was performed on mITT population. Here, overall number of participants analyzed = participants evaluable for this outcome measure.

Posted

Least Squares Mean

Standard Error

score on a scale

Baseline, Week 52

ID	Title	Description
OG000	Placebo	Participants received IV infusion of placebo (matched to olipudase alfa) once every 2 weeks up to Week 52. Participants who completed PAP entered in ETP and crossed over to olipudase alfa with a target maintenance dose of 3 mg/kg after dose escalation which was administered IV once every 2 weeks up to Year 5.
OG001	Olipudase Alfa	Participants received IV infusion of olipudase alfa once every 2 weeks up to Week 52. Each participant underwent a dose escalation according to the following paradigm: 0.1, 0.3, 0.3, 0.6, 0.6, 1.0, 2.0, 3.0, 3.0 mg/kg. Three (3) mg/kg was the target maintenance dose, which was maintained for the remaining duration of 52 weeks of PAP. Participants who completed PAP entered in ETP and continued the same treatment in ETP up to Year 5.

Secondary

Number of Participants With Treatment-Emergent Adverse Events (TEAEs) and Treatment-Emergent Serious Adverse Events (TESAEs) up to Week 52

An AE was defined as any untoward medical occurrence in a participant or clinical investigation participant administered with a pharmaceutical product and which does not necessarily have to have a causal relationship with this treatment. TESAEs was defined as any untoward medical occurrence that at any dose: resulted in death, was life-threatening, required inpatient hospitalization or prolongation of existing hospitalization, resulted in persistent or significant disability/incapacity, was a congenital anomaly/birth defect, was a medically important event. Reported AEs are treatment-emergent AEs that developed, worsened or became serious during the treatment period.

The safety population was a subset of the randomized population and included randomized participants who received at least 1 infusion (partial or total).

Posted

Count of Participants

Participants

From the first infusion of investigational medicinal product (IMP) up to 52 weeks

ID	Title	Description
OG000	Placebo	Participants received IV infusion of placebo (matched to olipudase alfa) once every 2 weeks up to Week 52. Participants who completed PAP entered in ETP and crossed over to olipudase alfa with a target maintenance dose of 3 mg/kg after dose escalation which was administered IV once every 2 weeks up to Year 5.
OG001	Olipudase Alfa

Secondary

Number of Participants With Adverse Events of Special Interest (AESIs) up to Week 52

An AESI was defined as an AE (serious or nonserious) of scientific and medical concern specific to sponsor's product or program, for which ongoing monitoring and rapid communication by investigator to sponsor was appropriate. AESIs included any pregnancy, symptomatic overdose, dose-limiting toxicities (DLTs) as defined in protocol and infusion associated reactions (IARs). Protocol-defined IARs were AEs that occurred during the infusion or within up to 24 hours after the start of infusion and were considered as related or possibly related to the study treatment by the investigator or the sponsor. Events occurring greater than or equal to (>=) 24 hours after the start of an infusion might have been judged an IAR at the discretion of the investigator or sponsor. Algorithm-defined IARs were all AEs that started between the start of infusion and the end of infusion plus 24 hours, irrespective of the perceived relation with study treatment.

The safety population was a subset of the randomized population and included randomized participants who received at least 1 infusion (partial or total).

Posted

Count of Participants

Participants

From the first infusion of IMP up to 52 weeks

ID	Title	Description
OG000	Placebo	Participants received IV infusion of placebo (matched to olipudase alfa) once every 2 weeks up to Week 52. Participants who completed PAP entered in ETP and crossed over to olipudase alfa with a target maintenance dose of 3 mg/kg after dose escalation which was administered IV once every 2 weeks up to Year 5.

Secondary

Number of Participants With Potentially Clinically Significant Abnormalities (PCSA) in Liver Function Tests up to Week 52

PCSA criteria: Alanine aminotransferase (ALT) and aspartate aminotransferase (AST): >3 x upper limit of normal (ULN), >5 x ULN, >10 x ULN and >20 x ULN. Alkaline phosphatase (ALP) > 1.5 x ULN. Total bilirubin >1.5 x ULN and >2 x ULN. ALT and total bilirubin: ALT > 3 x ULN and total bilirubin > 2 x ULN. Baseline was defined as the last non-missing value prior to the first infusion of study treatment.

The safety population was a subset of the randomized population and included randomized participants who received at least 1 infusion (partial or total).

Posted

Count of Participants

Participants

From Baseline (Day 1) up to 52 weeks

ID	Title	Description
OG000	Placebo	Participants received IV infusion of placebo (matched to olipudase alfa) once every 2 weeks up to Week 52. Participants who completed PAP entered in ETP and crossed over to olipudase alfa with a target maintenance dose of 3 mg/kg after dose escalation which was administered IV once every 2 weeks up to Year 5.
OG001	Olipudase Alfa	Participants received IV infusion of olipudase alfa once every 2 weeks up to Week 52. Each participant underwent a dose escalation according to the following paradigm: 0.1, 0.3, 0.3, 0.6, 0.6, 1.0, 2.0, 3.0, 3.0 mg/kg. Three (3) mg/kg was the target maintenance dose, which was maintained for the remaining duration of 52 weeks of PAP. Participants who completed PAP entered in ETP and continued the same treatment in ETP up to Year 5.

Secondary

Number of Participants Who Developed Anti-Drug Antibodies (ADA) to Olipudase Alfa up to Week 52

Number of participants with treatment-emergent ADA are presented. Baseline was defined as the last non-missing value prior to the first infusion of study treatment.

The safety population was a subset of the randomized population and included randomized participants who received at least 1 infusion (partial or total).

Posted

Count of Participants

Participants

Baseline (Day 1) and Week 52

ID	Title	Description
OG000	Placebo	Participants received IV infusion of placebo (matched to olipudase alfa) once every 2 weeks up to Week 52. Participants who completed PAP entered in ETP and crossed over to olipudase alfa with a target maintenance dose of 3 mg/kg after dose escalation which was administered IV once every 2 weeks up to Year 5.
OG001	Olipudase Alfa	Participants received IV infusion of olipudase alfa once every 2 weeks up to Week 52. Each participant underwent a dose escalation according to the following paradigm: 0.1, 0.3, 0.3, 0.6, 0.6, 1.0, 2.0, 3.0, 3.0 mg/kg. Three (3) mg/kg was the target maintenance dose, which was maintained for the remaining duration of 52 weeks of PAP. Participants who completed PAP entered in ETP and continued the same treatment in ETP up to Year 5.

Secondary

Percent Change From Baseline in Liver Volume (in MN) at Week 52

Liver volume was assessed by abdominal MRI in MN.

Analysis was performed on mITT population. Here, overall number of participants analyzed = participants evaluable for this outcome measure.

Posted

Least Squares Mean

Standard Error

percent change

Baseline, Week 52

ID	Title	Description
OG000	Placebo	Participants received IV infusion of placebo (matched to olipudase alfa) once every 2 weeks up to Week 52. Participants who completed PAP entered in ETP and crossed over to olipudase alfa with a target maintenance dose of 3 mg/kg after dose escalation which was administered IV once every 2 weeks up to Year 5.
OG001	Olipudase Alfa	Participants received IV infusion of olipudase alfa once every 2 weeks up to Week 52. Each participant underwent a dose escalation according to the following paradigm: 0.1, 0.3, 0.3, 0.6, 0.6, 1.0, 2.0, 3.0, 3.0 mg/kg. Three (3) mg/kg was the target maintenance dose, which was maintained for the remaining duration of 52 weeks of PAP. Participants who completed PAP entered in ETP and continued the same treatment in ETP up to Year 5.

Units	Counts

Secondary

Percent Change From Baseline in Platelet Counts at Week 52

Analysis was performed on mITT population. Here, overall number of participants analyzed = participants evaluable for this outcome measure.

Posted

Least Squares Mean

Standard Error

percent change

Baseline, Week 52

ID	Title	Description
OG000	Placebo	Participants received IV infusion of placebo (matched to olipudase alfa) once every 2 weeks up to Week 52. Participants who completed PAP entered in ETP and crossed over to olipudase alfa with a target maintenance dose of 3 mg/kg after dose escalation which was administered IV once every 2 weeks up to Year 5.
OG001	Olipudase Alfa	Participants received IV infusion of olipudase alfa once every 2 weeks up to Week 52. Each participant underwent a dose escalation according to the following paradigm: 0.1, 0.3, 0.3, 0.6, 0.6, 1.0, 2.0, 3.0, 3.0 mg/kg. Three (3) mg/kg was the target maintenance dose, which was maintained for the remaining duration of 52 weeks of PAP. Participants who completed PAP entered in ETP and continued the same treatment in ETP up to Year 5.

Units	Counts
Participants

Secondary

Change From Baseline in Fatigue Severity as Measured by Brief Fatigue Inventory (BFI)-Item 3 Scale Score at Week 52

The BFI is a 9-item, validated, self-administered questionnaire that was originally developed to assess fatigue severity. The 9-items were measured on a 0-10 scale, with 0 being 'does not interfere' and 10 being 'completely interferes.' BFI - Item 3 asks participants to "Please rate your fatigue (weariness, tiredness) by circling the one number that best describes your worst level of fatigue during the past 24 hours. Numerical rating scale ranges from 0 (no fatigue) to 10 (worst imaginable fatigue). Higher global scores were associated with more severe fatigue.

Analysis was performed on mITT population. Here, overall number of participants analyzed = participants evaluable for this outcome measure.

Posted

Least Squares Mean

Standard Error

score on a scale

Baseline, Week 52

ID	Title	Description
OG000	Placebo	Participants received IV infusion of placebo (matched to olipudase alfa) once every 2 weeks up to Week 52. Participants who completed PAP entered in ETP and crossed over to olipudase alfa with a target maintenance dose of 3 mg/kg after dose escalation which was administered IV once every 2 weeks up to Year 5.
OG001	Olipudase Alfa	Participants received IV infusion of olipudase alfa once every 2 weeks up to Week 52. Each participant underwent a dose escalation according to the following paradigm: 0.1, 0.3, 0.3, 0.6, 0.6, 1.0, 2.0, 3.0, 3.0 mg/kg. Three (3) mg/kg was the target maintenance dose, which was maintained for the remaining duration of 52 weeks of PAP. Participants who completed PAP entered in ETP and continued the same treatment in ETP up to Year 5.

Secondary

Change From Baseline in Pain Severity as Measured by Brief Pain Inventory-Short Form (BPI-SF)-Item 3 Scale Score at Week 52

The BPI-SF is a validated, self-administered questionnaire designed to measure a participant's perceived level of pain. The BPI-SF consisted of 15 items that use a numeric rating scale to assess pain severity and pain interference in the past 24 hours and the past week. For BPI-SF Item 3 asks participants to "Please rate your pain by marking the box beside the number that best describes your pain at its worst in the past 24 hours." The numeric rating scale ranged from 0 (no pain) to 10 (worst imaginable pain), where higher scores indicate greater intensity of pain.

Analysis was performed on mITT population. Here, overall number of participants analyzed = participants evaluable for this outcome measure.

Posted

Least Squares Mean

Standard Error

score on a scale

Baseline, Week 52

ID	Title	Description
OG000	Placebo	Participants received IV infusion of placebo (matched to olipudase alfa) once every 2 weeks up to Week 52. Participants who completed PAP entered in ETP and crossed over to olipudase alfa with a target maintenance dose of 3 mg/kg after dose escalation which was administered IV once every 2 weeks up to Year 5.
OG001	Olipudase Alfa	Participants received IV infusion of olipudase alfa once every 2 weeks up to Week 52. Each participant underwent a dose escalation according to the following paradigm: 0.1, 0.3, 0.3, 0.6, 0.6, 1.0, 2.0, 3.0, 3.0 mg/kg. Three (3) mg/kg was the target maintenance dose, which was maintained for the remaining duration of 52 weeks of PAP. Participants who completed PAP entered in ETP and continued the same treatment in ETP up to Year 5.

Secondary

Change From Baseline in Dyspnea Severity as Measured by Functional Assessment of Chronic Illness Therapy (FACIT) Dyspnea Scale at Week 52

FACIT-Dyspnea is a 20 Item assessment that is split into two 10-item sections. The first 10-item section asks participants about the severity of their shortness of breath during various activities. The second 10-item section asks participants to rate the difficulty due to shortness of breath associated with the same activities that were referenced in the first section. For the dyspnea severity items, score range from 0=no shortness of breath; 1=mildly short of breath; 2=moderately short of breath; 3=severely short of breath. For the functional limitation items, score range from no difficult = 0, A little difficult = 1, some difficult = 2, and much difficulty =3. A raw score was calculated as: sum of individual item scores * 10/number of items answered. Raw scores were then converted to scale scores using the table included in the FACIT Dyspnea Scale Short Form Scoring Guideline. FACIT dyspnea scale score ranged between 27.7 to 75.9. Higher score represented high levels of dyspnea.

Analysis was performed on mITT population. Here, overall number of participants analyzed = participants evaluable for this outcome measure.

Posted

Least Squares Mean

Standard Error

score on a scale

Baseline, Week 52

ID	Title	Description
OG000	Placebo	Participants received IV infusion of placebo (matched to olipudase alfa) once every 2 weeks up to Week 52. Participants who completed PAP entered in ETP and crossed over to olipudase alfa with a target maintenance dose of 3 mg/kg after dose escalation which was administered IV once every 2 weeks up to Year 5.

Arm/Groups

ID	Title	Description	Deaths (At Risk)	Serious Events (Affected)	Serious Events (At Risk)	Other Events (Affected)	Other Events (At Risk)
EG000	PAP: Placebo	Subjects received IV infusion of placebo (matched to olipudase alfa) once every 2 weeks up to Week 52.	18	4	18	13	18
EG001	PAP: Olipudase Alfa	Subjects received IV infusion of olipudase alfa once every 2 weeks up to Week 52. Each subject underwent a dose escalation according to the following paradigm: 0.1, 0.3, 0.3, 0.6, 0.6, 1.0, 2.0, 3.0,3.0 mg/kg. Three (3) mg/kg was the target maintenance dose, which was maintained for the remaining duration of 52 weeks of PAP.	18	3	18	17	18
EG002	ETP: Placebo/Olipudase Alfa	Subjects who completed PAP entered in ETP and crossed over to olipudase alfa with a target maintenance dose of 3 mg/kg after dose escalation which was administered IV once every 2 weeks up to Year 5.	17	6	17	9	17
EG003	ETP: Olipudase Alfa/Olipudase Alfa	Subjects who completed PAP entered in ETP and continued the same treatment in ETP up to Year 5.	18	5	18	12	18

Serious Adverse Events

Term	Organ System	Source Vocabulary	Assessment Type	Statistical Information
Anaemia	Blood and lymphatic system disorders	MedDra 26.0	Systematic Assessment	EG0001 events1 affected18 at risk EG0010 events0 affected18 at risk EG0020 events0 affected17 at risk EG0030 events0 affected18 at risk
Angina Pectoris	Cardiac disorders	MedDra 26.0	Systematic Assessment	EG0000 events0 affected18 at risk EG0010 events0 affected18 at risk EG0021 events1 affected17 at risk EG003
Extrasystoles	Cardiac disorders	MedDra 26.0	Systematic Assessment	EG0000 events0 affected18 at risk EG0010 events0 affected18 at risk EG0021 events1 affected17 at risk EG003
Inguinal Hernia	Gastrointestinal disorders	MedDra 26.0	Systematic Assessment	EG0000 events0 affected18 at risk EG0010 events0 affected18 at risk EG0021 events1 affected17 at risk EG003
Non-Cardiac Chest Pain	General disorders	MedDra 26.0	Systematic Assessment	EG0000 events0 affected18 at risk EG0010 events0 affected18 at risk EG0021 events1 affected17 at risk EG003
Pyrexia	General disorders	MedDra 26.0	Systematic Assessment	EG0000 events0 affected18 at risk EG0010 events0 affected18 at risk EG0021 events1 affected17 at risk EG003
Cholecystitis Acute	Hepatobiliary disorders	MedDra 26.0	Systematic Assessment	EG0000 events0 affected18 at risk EG0010 events0 affected18 at risk EG0020 events0 affected17 at risk EG003
Hepatic Haemorrhage	Hepatobiliary disorders	MedDra 26.0	Systematic Assessment	EG0001 events1 affected18 at risk EG0011 events1 affected18 at risk EG0020 events0 affected17 at risk EG003
Appendicitis	Infections and infestations	MedDra 26.0	Systematic Assessment	EG0001 events1 affected18 at risk EG0010 events0 affected18 at risk EG0020 events0 affected17 at risk EG003
Covid-19	Infections and infestations	MedDra 26.0	Systematic Assessment	EG0000 events0 affected18 at risk EG0010 events0 affected18 at risk EG0020 events0 affected17 at risk EG003
Cellulitis	Infections and infestations	MedDra 26.0	Systematic Assessment	EG0000 events0 affected18 at risk EG0011 events1 affected18 at risk EG0020 events0 affected17 at risk EG003
Gastritis Viral	Infections and infestations	MedDra 26.0	Systematic Assessment	EG0000 events0 affected18 at risk EG0011 events1 affected18 at risk EG0020 events0 affected17 at risk EG003
Liver Abscess	Infections and infestations	MedDra 26.0	Systematic Assessment	EG0001 events1 affected18 at risk EG0010 events0 affected18 at risk EG0020 events0 affected17 at risk EG003
Peritonitis	Infections and infestations	MedDra 26.0	Systematic Assessment	EG0001 events1 affected18 at risk EG0010 events0 affected18 at risk EG0020 events0 affected17 at risk EG003
Pneumonia	Infections and infestations	MedDra 26.0	Systematic Assessment	EG0000 events0 affected18 at risk EG0010 events0 affected18 at risk EG0020 events0 affected17 at risk EG003
Urinary Tract Infection	Infections and infestations	MedDra 26.0	Systematic Assessment	EG0000 events0 affected18 at risk EG0010 events0 affected18 at risk EG0021 events1 affected17 at risk EG003
Lower Limb Fracture	Injury, poisoning and procedural complications	MedDra 26.0	Systematic Assessment	EG0000 events0 affected18 at risk EG0011 events1 affected18 at risk EG0020 events0 affected17 at risk EG003
Hepatocellular Carcinoma	Neoplasms benign, malignant and unspecified (incl cysts and polyps)	MedDra 26.0	Systematic Assessment	EG0000 events0 affected18 at risk EG0010 events0 affected18 at risk EG0021 events1 affected17 at risk EG003
Loss Of Consciousness	Nervous system disorders	MedDra 26.0	Systematic Assessment	EG0000 events0 affected18 at risk EG0010 events0 affected18 at risk EG0022 events2 affected17 at risk EG003
Syncope	Nervous system disorders	MedDra 26.0	Systematic Assessment	EG0001 events1 affected18 at risk EG0010 events0 affected18 at risk EG0021 events1 affected17 at risk EG003
Transient Ischaemic Attack	Nervous system disorders	MedDra 26.0	Systematic Assessment	EG0000 events0 affected18 at risk EG0011 events1 affected18 at risk EG0020 events0 affected17 at risk EG003
Epistaxis	Respiratory, thoracic and mediastinal disorders	MedDra 26.0	Systematic Assessment	EG0003 events1 affected18 at risk EG0010 events0 affected18 at risk EG0020 events0 affected17 at risk EG003
Pleural Effusion	Respiratory, thoracic and mediastinal disorders	MedDra 26.0	Systematic Assessment	EG0001 events1 affected18 at risk EG0010 events0 affected18 at risk EG0020 events0 affected17 at risk EG003
Pneumothorax	Respiratory, thoracic and mediastinal disorders	MedDra 26.0	Systematic Assessment	EG0000 events0 affected18 at risk EG0010 events0 affected18 at risk EG0022 events1 affected17 at risk EG003
Aortic Dilatation	Vascular disorders	MedDra 26.0	Systematic Assessment	EG0000 events0 affected18 at risk EG0010 events0 affected18 at risk EG0020 events0 affected17 at risk EG003
Phlebitis Superficial	Vascular disorders	MedDra 26.0	Systematic Assessment	EG0000 events0 affected18 at risk EG0010 events0 affected18 at risk EG0021 events1 affected17 at risk EG003
Shock Haemorrhagic	Vascular disorders	MedDra 26.0	Systematic Assessment	EG0001 events1 affected18 at risk EG0010 events0 affected18 at risk EG0020 events0 affected17 at risk EG003

Other Adverse Events

Term	Organ System	Source Vocabulary	Assessment Type	Statistical Information
Covid-19	Infections and infestations	MedDra 26.0	Systematic Assessment	EG0000 events0 affected18 at risk EG0010 events0 affected18 at risk EG0028 events7 affected17 at risk EG0039 events8 affected18 at risk
Nasopharyngitis	Infections and infestations	MedDra 26.0	Systematic Assessment	EG0008 events6 affected18 at risk EG00118 events8 affected18 at risk EG00210 events5 affected17 at risk EG003
Upper Respiratory Tract Infection	Infections and infestations	MedDra 26.0	Systematic Assessment	EG0006 events4 affected18 at risk EG0018 events6 affected18 at risk EG0027 events3 affected17 at risk EG003
Arthralgia	Musculoskeletal and connective tissue disorders	MedDra 26.0	Systematic Assessment	EG0003 events3 affected18 at risk EG00110 events4 affected18 at risk EG0025 events3 affected17 at risk EG003
Headache	Nervous system disorders	MedDra 26.0	Systematic Assessment	EG00032 events8 affected18 at risk EG00164 events12 affected18 at risk EG00248 events4 affected17 at risk EG003
Cough	Respiratory, thoracic and mediastinal disorders	MedDra 26.0	Systematic Assessment	EG0003 events2 affected18 at risk EG0015 events5 affected18 at risk EG0022 events1 affected17 at risk EG003

ID	Term
D009542	Niemann-Pick Diseases
D013106	Sphingolipidoses
D020140	Lysosomal Storage Diseases, Nervous System
D020739	Brain Diseases, Metabolic, Inborn
D001928	Brain Diseases, Metabolic
D001927	Brain Diseases
D002493	Central Nervous System Diseases
D009422	Nervous System Diseases
D015616	Histiocytosis, Non-Langerhans-Cell
D015614	Histiocytosis
D008206	Lymphatic Diseases
D006425	Hemic and Lymphatic Diseases
D008661	Metabolism, Inborn Errors
D030342	Genetic Diseases, Inborn
D009358	Congenital, Hereditary, and Neonatal Diseases and Abnormalities
D008064	Lipidoses
D008052	Lipid Metabolism, Inborn Errors
D016464	Lysosomal Storage Diseases
D008659	Metabolic Diseases
D009750	Nutritional and Metabolic Diseases
D052439	Lipid Metabolism Disorders

ID	Term
D002712	Chlorides
D006851	Hydrochloric Acid
D017606	Chlorine Compounds
D007287	Inorganic Chemicals
D017670	Sodium Compounds