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

NCT02004691 | Completed Phase 2 Results DMC FDA Drug

• 3 other identifiers: DFI12712U1111-1142-59632015-000371-26
• Study Type: interventional
• Target: 36
• Locations: 16 countries
• Sites: 23

Brief Summary

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.

Conditions

Sphingomyelin Lipidosis

Outcome Measures

Primary Outcomes (6)

• 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 Outcomes (9)

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

  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

  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

  From Baseline (Day 1) up to 52 weeks

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

  Baseline (Day 1) and Week 52

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

  Baseline, Week 52

Study Arms (2)

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

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

Placebo

Olipudase alfa DRUG

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

Also known as: GZ402665, Xenpozyme™

Olipudase alfa

Eligibility Criteria

• Age: 18 Years+
• Sex: all
• Healthy Volunteers: Yes
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• 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.

You may not qualify if:

• 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.

Sponsors & Collaborators

• Genzyme, a Sanofi Company: lead

Study Sites (24)

UCSF Medical Center Site Number : 840005

San Francisco, California, 94143, United States

Location

Emory University Site Number : 840003

Decatur, Georgia, 30033, United States

Location

Montefiore Medical Center Site Number : 840006

The Bronx, New York, 10467, United States

Location

Investigational Site Number : 032001

Córdoba, X5004FHP, Argentina

Location

Investigational Site Number : 036001

Westmead, New South Wales, 2145, Australia

Location

Investigational Site Number : 056001

Leuven, 3000, Belgium

Location

Hospital De Clinicas De Porto Alegre Site Number : 076001

Porto Alegre, Rio Grande do Sul, 90035 003, Brazil

Location

Investigational Site Number : 100001

Sofia, 1431, Bulgaria

Location

Investigational Site Number : 152001

Santiago, Reg Metropolitana de Santiago, 753-0204, Chile

Location

Investigational Site Number : 250001

Paris, 75020, France

Location

Investigational Site Number : 276001

Mainz, 55131, Germany

Location

Investigational Site Number : 380002

Napoli, 80131, Italy

Location

Investigational Site Number : 380001

Udine, 33100, Italy

Location

Investigational Site Number : 392001

Fukushima, Fukushima, 960-1295, Japan

Location

Investigational Site Number : 528001

Amsterdam, 1105 AZ, Netherlands

Location

Investigational Site Number : 620002

Porto, 4099-001, Portugal

Location

Investigational Site Number : 724001

Madrid, 28034, Spain

Location

Investigational Site Number : 788001

Tunis, 1007, Tunisia

Location

Investigational Site Number : 792002

Ankara, 06500, Turkey (Türkiye)

Location

Investigational Site Number : 792004

Istanbul, 34520, Turkey (Türkiye)

Location

Investigational Site Number : 792003

Istanbul, 34722, Turkey (Türkiye)

Location

Investigational Site Number : 792001

Izmir, 35040, Turkey (Türkiye)

Location

Investigational Site Number : 826001

London, London, City of, WC1N 3JZ, United Kingdom

Location

Investigational Site Number : 826002

Birmingham, B15 2GW, United Kingdom

Location

Related Publications (1)

• 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.

  PMID: 38042851 DERIVED

MeSH Terms

Conditions

Niemann-Pick Disease, Type A

Interventions

Sodium Chloride; olipudase alfa

Condition Hierarchy (Ancestors)

Niemann-Pick Diseases; Sphingolipidoses; Lysosomal Storage Diseases, Nervous System; Brain Diseases, Metabolic, Inborn; Brain Diseases, Metabolic; Brain Diseases; Central Nervous System Diseases; Nervous System Diseases; Histiocytosis, Non-Langerhans-Cell; Histiocytosis; Lymphatic Diseases; Hemic and Lymphatic Diseases; Metabolism, Inborn Errors; Genetic Diseases, Inborn; Congenital, Hereditary, and Neonatal Diseases and Abnormalities; Lipidoses; Lipid Metabolism, Inborn Errors; Lysosomal Storage Diseases; Metabolic Diseases; Nutritional and Metabolic Diseases; Lipid Metabolism Disorders

Intervention Hierarchy (Ancestors)

Chlorides; Hydrochloric Acid; Chlorine Compounds; Inorganic Chemicals; Sodium Compounds

Results Point of Contact

• Title: Trial Transparency Team
• Organization: Sanofi-Aventis Recherche & Développement

Contact-US@sanofi.com

800-633-1610

Study Officials

• Clinical Sciences & Operations

  Sanofi

  STUDY DIRECTOR

Publication Agreements

• PI is Sponsor Employee: No
• Restriction Type: OTHER
• Restrictive Agreement: Yes

Study Design

• Study Type: interventional
• Phase: phase 2
• Allocation: RANDOMIZED
• Masking: QUADRUPLE
• Who Masked: PARTICIPANT, CARE PROVIDER, INVESTIGATOR, OUTCOMES ASSESSOR
• Purpose: TREATMENT
• Intervention Model: PARALLEL
• Sponsor Type: INDUSTRY
• Responsible Party: SPONSOR
• Expanded Access: Yes

Study Record Dates

• First Submitted: November 26, 2013
• First Posted: December 9, 2013
• Study Start: December 18, 2015
• Primary Completion: March 15, 2021
• Study Completion: October 19, 2023
• Last Updated: November 7, 2024
• Results First Posted: May 24, 2022

Record last verified: 2024-10

Data Sharing

• IPD Sharing: Will share

Locations

IT (2); JP (1); PT (1); AR (1); CL (1); ES (1); DE (1); NL (1); BE (1); BU (1); US (3); TU (4); AU (1); BR (1); GB (2); FR (1)