Efficacy, Safety, Pharmacodynamic, and Pharmacokinetics Study of Olipudase Alfa in Patients With Acid Sphingomyelinase Deficiency (ASCEND)

• ClinicalTrials.gov Identifier: NCT02004691
• Recruitment Status: Active, not recruiting
• First Posted: December 9, 2013
• Results First Posted: May 24, 2022
• Last Update Posted: May 24, 2022
• Sponsor: Genzyme, a Sanofi Company
• Information provided by (Responsible Party): Sanofi ( Genzyme, a Sanofi Company )

• Study Type: Interventional
• Study Design: Allocation: Randomized; Intervention Model: Parallel Assignment; Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor); Primary Purpose: Treatment
• Condition: Sphingomyelin Lipidosis
• Interventions: Drug: placebo (saline); Drug: GZ402665
• Enrollment: 36

Participant Flow

Recruitment Details	The study was conducted at 23 active centers in 17 countries. A total of 62 participants were screened between 18 December 2015 and 1 October 2018, out of which 36 participants were randomized.
Pre-assignment Details	A total of 18 participants each were randomized to the placebo and the olipudase alfa groups, respectively. Data reported based on date, 15 March 2021. Primary Analysis Period (PAP) is complete.

Arm/Group Title	Placebo	Olipudase Alfa
Arm/Group Description	Participants received intravenous (IV) infusion of placebo (matched to olipudase alfa) once every 2 weeks during the 52 weeks of primary analysis period (PAP). Participants who completed PAP entered in extension treatment period (ETP) and crossed over to olipudase alfa with a target maintenance dose of 3 milligram per kilogram (mg/kg) after dose escalation.	Participants received IV infusion of olipudase alfa once every 2 weeks during the 52 weeks of PAP. 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.
Period Title: PAP: Up to 52 Weeks
Started	18	18
Completed	17	18
Not Completed	1	0
Reason Not Completed
Poor compliance	1	0
Period Title: ETP: Ongoing From Week 52
Started	17	18
Completed	0	0
Not Completed	17	18
Reason Not Completed
Related to Coronavirus Disease (COVID-19)	1	0
Withdrawal by Subject	0	1
Other	0	1
Ongoing	16	16

Baseline Characteristics

Arm/Group Title		Placebo	Olipudase Alfa	Total Title
Arm/Group Description		Participants received intravenous (IV) infusion of placebo (matched to olipudase alfa) once every 2 weeks during the 52 weeks of primary analysis period (PAP). Participants who completed PAP entered in extension treatment period (ETP) and crossed over to olipudase alfa with a target maintenance dose of 3 milligram per kilogram (mg/kg) after dose escalation.	Participants received IV infusion of olipudase alfa once every 2 weeks during the 52 weeks of PAP. 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.	[Not Specified]
Overall Number of Baseline Participants		18	18	36
Baseline Analysis Population Description		Analysis was performed on modified intent-to-treat (mITT) population which included all randomized participants who had received at least 1 infusion (partial or total) and were analyzed according to the treatment arm allocated by randomization.
Age, Continuous; Mean (Standard Deviation); Unit of measure: Years
	Number Analyzed	18 participants	18 participants	36 participants
		33.46 (17.06)	36.17 (12.72)	34.81 (14.89)
Sex: Female, Male; Measure Type: Count of Participants; Unit of measure: Participants
	Number Analyzed	18 participants	18 participants	36 participants
	Female	13 72.2%	9 50.0%	22 61.1%
	Male	5 27.8%	9 50.0%	14 38.9%
Race/Ethnicity, Customized; Measure Type: Count of Participants; Unit of measure: Participants
	Number Analyzed	18 participants	18 participants	36 participants
	American Indian or Alaska Native	0 0.0%	0 0.0%	0 0.0%
	Asian	1 5.6%	1 5.6%	2 5.6%
	Black or African American	0 0.0%	0 0.0%	0 0.0%
	Native Hawaiian or Other Pacific Islander	0 0.0%	0 0.0%	0 0.0%
	White	16 88.9%	16 88.9%	32 88.9%
	More than one race	0 0.0%	0 0.0%	0 0.0%
	Unknown or Not Reported	0 0.0%	0 0.0%	0 0.0%
	Other	1 5.6%	1 5.6%	2 5.6%

Outcome Measures

1. Primary Outcome

Title	Percent Predicted (% Predicted) Hemoglobin (Hb) and Altitude-Adjusted Diffusing Capacity of the Lung for Carbon Monoxide (DLco) at Baseline
Description	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.
Time Frame	Baseline (Day 1)

Outcome Measure Data

Analysis Population Description

Analysis was performed on mITT population.

Arm/Group Title	Placebo	Olipudase Alfa
Arm/Group Description:	Participants received intravenous (IV) infusion of placebo (matched to olipudase alfa) once every 2 weeks during the 52 weeks of primary analysis period (PAP). Participants who completed PAP entered in extension treatment period (ETP) and crossed over to olipudase alfa with a target maintenance dose of 3 milligram per kilogram (mg/kg) after dose escalation.	Participants received IV infusion of olipudase alfa once every 2 weeks during the 52 weeks of PAP. 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.
Overall Number of Participants Analyzed	18	18
Mean (Standard Deviation); Unit of Measure: % Predicted DLco
	48.45 (10.76)	49.44 (10.99)

2. Primary Outcome

Title	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
Description	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.
Time Frame	Baseline, Week 52

Outcome Measure Data

Analysis Population Description

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

Arm/Group Title	Placebo	Olipudase Alfa
Arm/Group Description:	Participants received intravenous (IV) infusion of placebo (matched to olipudase alfa) once every 2 weeks during the 52 weeks of primary analysis period (PAP). Participants who completed PAP entered in extension treatment period (ETP) and crossed over to olipudase alfa with a target maintenance dose of 3 milligram per kilogram (mg/kg) after dose escalation.	Participants received IV infusion of olipudase alfa once every 2 weeks during the 52 weeks of PAP. 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.
Overall Number of Participants Analyzed	17	17
Least Squares Mean (Standard Error); Unit of Measure: percent change
	2.961 (3.3832)	21.968 (3.3362)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Placebo, Olipudase Alfa
	Comments	[Not Specified]
	Type of Statistical Test	Superiority
	Comments	[Not Specified]
Statistical Test of Hypothesis	P-Value	=0.0004
	Comments	Threshold for significance was 0.05.
	Method	Mixed model for repeated measures
	Comments	[Not Specified]
Method of Estimation	Estimation Parameter	Least Squares Mean Difference
	Estimated Value	19.008
	Confidence Interval	(2-Sided) 95%; 9.319 to 28.696
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 4.7576
	Estimation Comments	The 95% Confidence Interval (CI) and p-values were based on mixed model for repeated measures approach with Baseline Derived % Predicted DLco adjusted for Hb and pressure, age, treatment group, visit, and study visit by treatment group as covariates.

3. Primary Outcome

Title	Combination Spleen Endpoint: Component 1: Spleen Volume (in MN) at Baseline
Description	Spleen volume was assessed by abdominal magnetic resonance imaging (MRI) to quantitate the degree of splenomegaly in multiples of normal (MN).
Time Frame	Baseline (Day 1)

Outcome Measure Data

Analysis Population Description

Analysis was performed on mITT population.

Arm/Group Title	Placebo	Olipudase Alfa
Arm/Group Description:	Participants received intravenous (IV) infusion of placebo (matched to olipudase alfa) once every 2 weeks during the 52 weeks of primary analysis period (PAP). Participants who completed PAP entered in extension treatment period (ETP) and crossed over to olipudase alfa with a target maintenance dose of 3 milligram per kilogram (mg/kg) after dose escalation.	Participants received IV infusion of olipudase alfa once every 2 weeks during the 52 weeks of PAP. 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.
Overall Number of Participants Analyzed	18	18
Mean (Standard Deviation); Unit of Measure: multiples of normal (MN)
	11.21 (3.84)	11.69 (4.92)

4. Primary Outcome

Title	Combination Spleen Endpoint: Component 1: Percent Change From Baseline in Spleen Volume (in MN) at Week 52
Description	Spleen volume was assessed by abdominal MRI to quantitate the degree of splenomegaly in MN.
Time Frame	Baseline, Week 52

Outcome Measure Data

Analysis Population Description

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

Arm/Group Title	Placebo	Olipudase Alfa
Arm/Group Description:	Participants received intravenous (IV) infusion of placebo (matched to olipudase alfa) once every 2 weeks during the 52 weeks of primary analysis period (PAP). Participants who completed PAP entered in extension treatment period (ETP) and crossed over to olipudase alfa with a target maintenance dose of 3 milligram per kilogram (mg/kg) after dose escalation.	Participants received IV infusion of olipudase alfa once every 2 weeks during the 52 weeks of PAP. 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.
Overall Number of Participants Analyzed	17	18
Least Squares Mean (Standard Error); Unit of Measure: percent change
	0.481 (2.5002)	-39.446 (2.4294)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Placebo, Olipudase Alfa
	Comments	[Not Specified]
	Type of Statistical Test	Superiority
	Comments	[Not Specified]
Statistical Test of Hypothesis	P-Value	<.0001
	Comments	Threshold for significance was 0.05.
	Method	Mixed model for repeated measures
	Comments	[Not Specified]
Method of Estimation	Estimation Parameter	Least Squares Mean Difference
	Estimated Value	-39.927
	Confidence Interval	(2-Sided) 95%; -47.051 to -32.803
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 3.4957
	Estimation Comments	The 95% CI and p-values were based on a mixed model for repeated measures approach with Baseline Spleen Volume (MN), Baseline age, treatment group, study visit, and study visit by treatment group interaction as covariates.

5. Primary Outcome

Title	Combination Spleen Endpoint (Primary for US Only): Component 2: Splenomegaly-Related Score (SRS) at Baseline
Description	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.
Time Frame	Baseline (Day 1)

Outcome Measure Data

Analysis Population Description

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

Arm/Group Title	Placebo	Olipudase Alfa
Arm/Group Description:	Participants received intravenous (IV) infusion of placebo (matched to olipudase alfa) once every 2 weeks during the 52 weeks of primary analysis period (PAP). Participants who completed PAP entered in extension treatment period (ETP) and crossed over to olipudase alfa with a target maintenance dose of 3 milligram per kilogram (mg/kg) after dose escalation.	Participants received IV infusion of olipudase alfa once every 2 weeks during the 52 weeks of PAP. 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.
Overall Number of Participants Analyzed	17	18
Mean (Standard Deviation); Unit of Measure: score on a scale
	28.05 (10.56)	24.55 (11.13)

6. Primary Outcome

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

Outcome Measure Data

Analysis Population Description

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

Arm/Group Title	Placebo	Olipudase Alfa
Arm/Group Description:	Participants received intravenous (IV) infusion of placebo (matched to olipudase alfa) once every 2 weeks during the 52 weeks of primary analysis period (PAP). Participants who completed PAP entered in extension treatment period (ETP) and crossed over to olipudase alfa with a target maintenance dose of 3 milligram per kilogram (mg/kg) after dose escalation.	Participants received IV infusion of olipudase alfa once every 2 weeks during the 52 weeks of PAP. 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.
Overall Number of Participants Analyzed	17	17
Least Squares Mean (Standard Error); Unit of Measure: score on a scale
	-9.281 (2.4165)	-7.664 (2.3481)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Placebo, Olipudase Alfa
	Comments	[Not Specified]
	Type of Statistical Test	Superiority
	Comments	[Not Specified]
Statistical Test of Hypothesis	P-Value	=0.6364
	Comments	Threshold for significance was 0.15.
	Method	Mixed model for repeated measures
	Comments	[Not Specified]
Method of Estimation	Estimation Parameter	Least Squares Mean Difference
	Estimated Value	1.618
	Confidence Interval	(2-Sided) 95%; -5.302 to 8.538
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 3.3877
	Estimation Comments	The 95% CI and p-values are based on a mixed model for repeated measures approach with Baseline Splenomegaly Related Score, Baseline age, treatment group, study visit, and study visit by treatment group interaction as covariates.

7. Secondary Outcome

Title	Percent Change From Baseline in Liver Volume (in MN) at Week 52
Description	Liver volume was assessed by abdominal MRI in MN.
Time Frame	Baseline, Week 52

Outcome Measure Data

Analysis Population Description

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

Arm/Group Title	Placebo	Olipudase Alfa
Arm/Group Description:	Participants received intravenous (IV) infusion of placebo (matched to olipudase alfa) once every 2 weeks during the 52 weeks of primary analysis period (PAP). Participants who completed PAP entered in extension treatment period (ETP) and crossed over to olipudase alfa with a target maintenance dose of 3 milligram per kilogram (mg/kg) after dose escalation.	Participants received IV infusion of olipudase alfa once every 2 weeks during the 52 weeks of PAP. 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.
Overall Number of Participants Analyzed	17	18
Least Squares Mean (Standard Error); Unit of Measure: percent change
	-1.468 (2.5409)	-28.064 (2.4899)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Placebo, Olipudase Alfa
	Comments	A hierarchical testing procedure was used to control the overall type I error. Testing was then performed sequentially in an order the outcome measure were reported and continued when previous endpoint was statistically significant at two-sided 0.05.
	Type of Statistical Test	Superiority
	Comments	[Not Specified]
Statistical Test of Hypothesis	P-Value	<.0001
	Comments	Threshold for significance was 0.05.
	Method	Mixed model for repeated measures
	Comments	[Not Specified]
Method of Estimation	Estimation Parameter	Least Squares Mean Difference
	Estimated Value	-26.596
	Confidence Interval	(2-Sided) 95%; -33.911 to -19.281
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 3.5862
	Estimation Comments	The 95% CI and p-values are based on a mixed model for repeated measures approach with Baseline Liver Volume (MN), Baseline age, treatment group, study visit, and study visit by treatment group interaction as covariates.

8. Secondary Outcome

Title	Percent Change From Baseline in Platelet Counts at Week 52
Description	[Not Specified]
Time Frame	Baseline, Week 52

Outcome Measure Data

Analysis Population Description

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

Arm/Group Title	Placebo	Olipudase Alfa
Arm/Group Description:	Participants received intravenous (IV) infusion of placebo (matched to olipudase alfa) once every 2 weeks during the 52 weeks of primary analysis period (PAP). Participants who completed PAP entered in extension treatment period (ETP) and crossed over to olipudase alfa with a target maintenance dose of 3 milligram per kilogram (mg/kg) after dose escalation.	Participants received IV infusion of olipudase alfa once every 2 weeks during the 52 weeks of PAP. 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.
Overall Number of Participants Analyzed	16	18
Least Squares Mean (Standard Error); Unit of Measure: percent change
	2.490 (4.1923)	16.822 (3.9596)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Placebo, Olipudase Alfa
	Comments	A hierarchical testing procedure was used to control the overall type I error. Testing was then performed sequentially in an order the outcome measure were reported and continued when previous endpoint was statistically significant at two-sided 0.05.
	Type of Statistical Test	Superiority
	Comments	[Not Specified]
Statistical Test of Hypothesis	P-Value	=0.0185
	Comments	Threshold for significance was 0.05.
	Method	Mixed model for repeated measures
	Comments	[Not Specified]
Method of Estimation	Estimation Parameter	Least Squares Mean Difference
	Estimated Value	14.332
	Confidence Interval	(2-Sided) 95%; 2.564 to 26.099
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 5.7822
	Estimation Comments	The 95% CI and p-values are based on a mixed model for repeated measures approach with Baseline Platelets, Baseline age, treatment group, study visit, and study visit by treatment group interaction as covariates.

9. Secondary Outcome

Title	Change From Baseline in Fatigue Severity as Measured by Brief Fatigue Inventory (BFI)-Item 3 Scale Score at Week 52
Description	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.
Time Frame	Baseline, Week 52

Outcome Measure Data

Analysis Population Description

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

Arm/Group Title	Placebo	Olipudase Alfa
Arm/Group Description:	Participants received intravenous (IV) infusion of placebo (matched to olipudase alfa) once every 2 weeks during the 52 weeks of primary analysis period (PAP). Participants who completed PAP entered in extension treatment period (ETP) and crossed over to olipudase alfa with a target maintenance dose of 3 milligram per kilogram (mg/kg) after dose escalation.	Participants received IV infusion of olipudase alfa once every 2 weeks during the 52 weeks of PAP. 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.
Overall Number of Participants Analyzed	17	17
Least Squares Mean (Standard Error); Unit of Measure: score on a scale
	-1.806 (0.5272)	-1.862 (0.5129)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Placebo, Olipudase Alfa
	Comments	A hierarchical testing procedure was used to control the overall type I error. Testing was then performed sequentially in an order the outcome measure were reported and continued when previous endpoint was statistically significant at two-sided 0.05.
	Type of Statistical Test	Superiority
	Comments	[Not Specified]
Statistical Test of Hypothesis	P-Value	=0.9400
	Comments	Threshold for significance was 0.05.
	Method	Mixed model for repeated measures
	Comments	[Not Specified]
Method of Estimation	Estimation Parameter	Least Squares Mean Difference
	Estimated Value	-0.056
	Confidence Interval	(2-Sided) 95%; -1.566 to 1.454
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 0.7384
	Estimation Comments	The 95% CI and p-values are based on a mixed model for repeated measures approach with Baseline BFI item 3 (Worst Fatigue), Baseline age, treatment group, study visit, and study visit by treatment group interaction as covariates.

10. Secondary Outcome

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

Outcome Measure Data

Analysis Population Description

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

Arm/Group Title	Placebo	Olipudase Alfa
Arm/Group Description:	Participants received intravenous (IV) infusion of placebo (matched to olipudase alfa) once every 2 weeks during the 52 weeks of primary analysis period (PAP). Participants who completed PAP entered in extension treatment period (ETP) and crossed over to olipudase alfa with a target maintenance dose of 3 milligram per kilogram (mg/kg) after dose escalation.	Participants received IV infusion of olipudase alfa once every 2 weeks during the 52 weeks of PAP. 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.
Overall Number of Participants Analyzed	17	17
Least Squares Mean (Standard Error); Unit of Measure: score on a scale
	-2.293 (0.5899)	-1.404 (0.5742)

11. Secondary Outcome

Title	Change From Baseline in Dyspnea Severity as Measured by Functional Assessment of Chronic Illness Therapy (FACIT) Dyspnea Scale at Week 52
Description	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.
Time Frame	Baseline, Week 52

Outcome Measure Data

Analysis Population Description

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

Arm/Group Title	Placebo	Olipudase Alfa
Arm/Group Description:	Participants received intravenous (IV) infusion of placebo (matched to olipudase alfa) once every 2 weeks during the 52 weeks of primary analysis period (PAP). Participants who completed PAP entered in extension treatment period (ETP) and crossed over to olipudase alfa with a target maintenance dose of 3 milligram per kilogram (mg/kg) after dose escalation.	Participants received IV infusion of olipudase alfa once every 2 weeks during the 52 weeks of PAP. 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.
Overall Number of Participants Analyzed	11	16
Least Squares Mean (Standard Error); Unit of Measure: score on a scale
	-6.769 (1.9132)	-5.862 (1.6918)

Adverse Events

Time Frame	Adverse Events (AEs) were collected from time from the first infusion of investigational medicinal product to the time just prior to first infusion in extension treatment period i.e. up to 52 weeks of PAP regardless of seriousness or relationship to investigational product.
Adverse Event Reporting Description	Reported AEs are treatment emergent AEs i.e. AEs that developed/worsened during the treatment epoch for PAP (defined as the time from the first infusion of investigational medicinal product to the time just prior to first infusion in extension treatment period (ETP) if the participant had an infusion in ETP or to last date the data are available if the participant had no infusion in ETP i.e. up to Week 52). Analysis was performed on safety population.
Arm/Group Title	Placebo		Olipudase Alfa
Arm/Group Description	Participants received intravenous (IV) infusion of placebo (matched to olipudase alfa) once every 2 weeks during the 52 weeks of primary analysis period (PAP). Participants who completed PAP entered in extension treatment period (ETP) and crossed over to olipudase alfa with a target maintenance dose of 3 milligram per kilogram (mg/kg) after dose escalation.		Participants received IV infusion of olipudase alfa once every 2 weeks during the 52 weeks of PAP. 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.
All-Cause Mortality
	Placebo		Olipudase Alfa
	Affected / at Risk (%)		Affected / at Risk (%)
Total	0/18 (0.00%)		0/18 (0.00%)
Serious Adverse Events
	Placebo		Olipudase Alfa
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	4/18 (22.22%)		3/18 (16.67%)
Blood and lymphatic system disorders
Anaemia † 1	1/18 (5.56%)	1	0/18 (0.00%)	0
Hepatobiliary disorders
Hepatic Haemorrhage † 1	1/18 (5.56%)	1	1/18 (5.56%)	1
Infections and infestations
Appendicitis † 1	1/18 (5.56%)	1	0/18 (0.00%)	0
Cellulitis † 1	0/18 (0.00%)	0	1/18 (5.56%)	1
Gastritis Viral † 1	0/18 (0.00%)	0	1/18 (5.56%)	1
Liver Abscess † 1	1/18 (5.56%)	1	0/18 (0.00%)	0
Peritonitis † 1	1/18 (5.56%)	1	0/18 (0.00%)	0
Injury, poisoning and procedural complications
Lower Limb Fracture † 1	0/18 (0.00%)	0	1/18 (5.56%)	1
Nervous system disorders
Syncope † 1	1/18 (5.56%)	1	0/18 (0.00%)	0
Transient Ischaemic Attack † 1	0/18 (0.00%)	0	1/18 (5.56%)	1
Respiratory, thoracic and mediastinal disorders
Epistaxis † 1	1/18 (5.56%)	3	0/18 (0.00%)	0
Pleural Effusion † 1	1/18 (5.56%)	1	0/18 (0.00%)	0
Vascular disorders
Shock Haemorrhagic † 1	1/18 (5.56%)	1	0/18 (0.00%)	0
1 Term from vocabulary, MedDRA23.1; † Indicates events were collected by systematic assessment
Other (Not Including Serious) Adverse Events
Frequency Threshold for Reporting Other Adverse Events	2%
	Placebo		Olipudase Alfa
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	13/18 (72.22%)		17/18 (94.44%)
Infections and infestations
Nasopharyngitis † 1	6/18 (33.33%)	8	8/18 (44.44%)	18
Upper Respiratory Tract Infection † 1	4/18 (22.22%)	6	6/18 (33.33%)	8
Musculoskeletal and connective tissue disorders
Arthralgia † 1	3/18 (16.67%)	3	4/18 (22.22%)	10
Nervous system disorders
Headache † 1	8/18 (44.44%)	32	12/18 (66.67%)	64
Respiratory, thoracic and mediastinal disorders
Cough † 1	2/18 (11.11%)	3	5/18 (27.78%)	5
1 Term from vocabulary, MedDRA23.1; † Indicates events were collected by systematic assessment

Limitations and Caveats

[Not Specified]

More Information

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.

The Sponsor supports publication of clinical trial results but may request that investigators temporarily delay or alter publications in order to protect proprietary information. The Sponsor may also require that the results of multicenter studies be published only in their entirety and not as individual site data.

Results Point of Contact

• Name/Title: Trial Transparency Team
• Organization: Sanofi-Aventis Recherche & Développement
• Phone: 800-633-1610 ext 6#
• EMail: Contact-US@sanofi.com

• Responsible Party: Sanofi ( Genzyme, a Sanofi Company )
• ClinicalTrials.gov Identifier: NCT02004691
• Other Study ID Numbers: DFI12712; 2015-000371-26 ( EudraCT Number ); U1111-1142-5963 ( Other Identifier: UTN )
• First Submitted: November 26, 2013
• First Posted: December 9, 2013
• Results First Submitted: April 27, 2022
• Results First Posted: May 24, 2022
• Last Update Posted: May 24, 2022