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

A Phase 2/3, Multicenter, Randomized, Double-blinded, Placebo-controlled, Repeat-dose Study to Evaluate the Efficacy, Safety, Pharmacodynamics, and Pharmacokinetics of Olipudase Alfa in Patients With Acid Sphingomyelinase Deficiency

Primary Objective:

The primary objective of this phase 2/3 study was to evaluate the efficacy of olipudase alfa (recombinant human acid sphingomyelinase) administered intravenously once every 2 weeks for 52 weeks in adult participants with acid sphingomyelinase deficiency (ASMD) by assessing changes in: 1) spleen volume as measured by abdominal magnetic resonance imaging (MRI) (and, for the United States [US] only, in association with participant perception related to spleen volume as measured by splenomegaly-related score [SRS]); and 2) infiltrative lung disease as measured by the pulmonary function test, diffusing capacity of the lung for carbon monoxide (DLCO).

Secondary Objectives:

• To confirm the safety of olipudase alfa administered intravenously once every 2 weeks for 52 weeks.
• To characterize the effect of olipudase alfa on the participant perception related to spleen volume as measured by the SRS after 52 weeks of study drug administration. (For the US, the effect of olipudase alfa on the SRS is part of the primary objective).

• To characterize the effect of olipudase alfa after 52 weeks of study drug administration on the following outcome measures assessed sequentially:

  • The effect of olipudase alfa on liver volume;
  • The effect of olipudase alfa on platelet count;
  • The effect of olipudase alfa on fatigue;
  • The effect of olipudase alfa on pain;
  • The effect of olipudase alfa on dyspnea.

Study Overview

• Status: Completed
• Conditions: Sphingomyelin Lipidosis
• Intervention / Treatment: Drug: placebo (saline); Drug: Olipudase alfa

Detailed Description

The planned total duration per participant was for at least 3 years and up to 5 years and 3 months. This included up to approximately two month of screening, 52 weeks of primary analysis period, up to 4 years and 3 months of extension treatment period, an end-of- study visit within 2 weeks of the last treatment, and a safety follow-up 30 to 37 days after the last treatment.

• Study Type: Interventional
• Enrollment (Actual): 36
• Phase: Phase 2; Phase 3

Expanded Access

Approved for sale to the public. See expanded access record.

Contacts and Locations

Study Locations

• Argentina
  • Córdoba, Argentina, X5004FHP
    • Investigational Site Number : 032001
• Australia
  • New South Wales
    • Westmead, New South Wales, Australia, 2145
      • Investigational Site Number : 036001
• Belgium
  • Leuven, Belgium, 3000
    • Investigational Site Number : 056001
• Brazil
  • Rio Grande Do Sul
    • Porto Alegre, Rio Grande Do Sul, Brazil, 90035 003
      • Hospital De Clinicas De Porto Alegre Site Number : 076001
• Bulgaria
  • Sofia, Bulgaria, 1431
    • Investigational Site Number : 100001
• Chile
  • Reg Metropolitana De Santiago
    • Santiago, Reg Metropolitana De Santiago, Chile, 753-0204
      • Investigational Site Number : 152001
• France
  • Paris, France, 75020
    • Investigational Site Number : 250001
• Germany
  • Mainz, Germany, 55131
    • Investigational Site Number : 276001
• Italy
  • Napoli, Italy, 80131
    • Investigational Site Number : 380002
  • Udine, Italy, 33100
    • Investigational Site Number : 380001
• Japan
  • Fukushima
    • Fukushima-shi, Fukushima, Japan, 960-1295
      • Investigational Site Number : 392001
• Netherlands
  • Amsterdam, Netherlands, 1105 AZ
    • Investigational Site Number : 528001
• Portugal
  • Porto, Portugal, 4099-001
    • Investigational Site Number : 620002
• Spain
  • Madrid, Spain, 28034
    • Investigational Site Number : 724001
• Tunisia
  • Tunis, Tunisia, 1007
    • Investigational Site Number : 788001
• Turkey
  • Ankara, Turkey, 06500
    • Investigational Site Number : 792002
  • Istanbul, Turkey, 34520
    • Investigational Site Number : 792004
  • Istanbul, Turkey, 34722
    • Investigational Site Number : 792003
  • Izmir, Turkey, 35040
    • Investigational Site Number : 792001
• United Kingdom
  • Birmingham, United Kingdom, B15 2GW
    • Investigational Site Number : 826002
  • London, City Of
    • London, London, City Of, United Kingdom, WC1N 3JZ
      • Investigational Site Number : 826001
• United States
  • California
    • San Francisco, California, United States, 94143
      • UCSF Medical Center Site Number : 840005
  • Georgia
    • Decatur, Georgia, United States, 30033
      • Emory University Site Number : 840003
  • New York
    • Bronx, New York, United States, 10467
      • Montefiore Medical Center Site Number : 840006

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: Yes

Description

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.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Quadruple

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Placebo Comparator: Placebo; 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); 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
Experimental: Olipudase alfa; 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; Pharmaceutical form: Powder for concentrate for solution for infusion administered once every two weeks during the 52 weeks of the primary analysis period for participants randomized to olipudase alfa, and during the extension treatment period for all participants. Route of administration: intravenous infusion; Other Names: GZ402665, Xenpozyme™

What is the study measuring?

Primary Outcome Measures

Outcome Measure	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.	Baseline (Day 1)
Combination Spleen Endpoint (Primary for US Only): Component 2: Change From Baseline in Splenomegaly-Related Score (SRS) at Week 52	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.	Baseline, Week 52

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Percent Change From Baseline in Liver Volume (in MN) at Week 52	Liver volume was assessed by abdominal MRI in MN.	Baseline, Week 52
Percent Change From Baseline in Platelet Counts at Week 52		Baseline, Week 52
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.	Baseline, Week 52
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.	Baseline, Week 52
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.	Baseline, Week 52
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.	From the first infusion of investigational medicinal product (IMP) up to 52 weeks
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.	From the first infusion of IMP up to 52 weeks
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.	From Baseline (Day 1) up to 52 weeks
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.	Baseline (Day 1) and Week 52

Collaborators and Investigators

• Sponsor: Genzyme, a Sanofi Company
• Investigators: Study Director: Clinical Sciences & Operations, Sanofi

Publications and helpful links

Helpful Links

• A randomized, placebo-controlled clinical trial evaluating olipudase alfa enzyme replacement therapy for chronic acid sphingomyelinase deficiency (ASMD) in adults: One-year results, Genetics in Medicine, 2022,ISSN 1098-3600

Study record dates

Study Major Dates

• Study Start (Actual): December 18, 2015
• Primary Completion (Actual): March 15, 2021
• Study Completion (Actual): October 19, 2023

Study Registration Dates

• First Submitted: November 26, 2013
• First Submitted That Met QC Criteria: December 4, 2013
• First Posted (Estimated): December 9, 2013

Study Record Updates

• Last Update Posted (Actual): November 7, 2024
• Last Update Submitted That Met QC Criteria: October 16, 2024
• Last Verified: October 1, 2024

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Brain Diseases; Central Nervous System Diseases; Nervous System Diseases; Metabolism, Inborn Errors; Genetic Diseases, Inborn; Metabolic Diseases; Lymphatic Diseases; Lipid Metabolism Disorders; Lysosomal Storage Diseases; Brain Diseases, Metabolic, Inborn; Brain Diseases, Metabolic; Lipid Metabolism, Inborn Errors; Lysosomal Storage Diseases, Nervous System; Histiocytosis, Non-Langerhans-Cell; Histiocytosis; Sphingolipidoses; Niemann-Pick Diseases; Niemann-Pick Disease, Type A; Niemann-Pick Disease, Type C; Lipidoses
• Other Study ID Numbers: DFI12712 (Other Identifier: Sanofi Identifier); 2015-000371-26 (EudraCT Number); U1111-1142-5963 (Registry Identifier: ICTRP)

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: YES
• IPD Plan Description: Qualified researchers may request access to patient level data and related study documents including the clinical study report, study protocol with any amendments, blank case report form, statistical analysis plan, and dataset specifications. Patient level data will be anonymized and study documents will be redacted to protect the privacy of trial participants. Further details on Sanofi's data sharing criteria, eligible studies, and process for requesting access can be found at: https://vivli.org.

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: Yes
• Studies a U.S. FDA-regulated device product: No
• product manufactured in and exported from the U.S.: No