Magnetic Resonance Spectroscopy in Acid Sphingomyelinase Deficiency (MONACO)

The goal of this study is to assess the ability of MRI techniques to detect early stages of lipid accumulation in the liver of ASMD patients with the chronic visceral subtype compared to healthy subjects.

Participants will undergo an MRI with MR Spectroscopy (MRS) to measure lipid accumulation (steatosis) and MR Elastography (MRE) to measure liver stiffness (fibrosis).

Study Overview

• Status: Recruiting
• Conditions: Asmd, Visceral Type
• Intervention / Treatment: Diagnostic test: MR Spectroscopy (MRS); Diagnostic test: MR Elastography (MRE)

Detailed Description

Rationale: Acid sphingomyelinase deficiency (ASMD) is a rare lysosomal storage disorder caused by a deficiency of sphingomyelinase resulting in accumulation of the sphingolipid sphingomyelin (SM) in the liver, spleen and lungs. Accumulation of SM in the liver leads to liver fibrosis in a subset of ASMD patients. Enzyme replacement therapy (ERT, olipudase alfa, Sanofi Genzyme) is currently investigated in a phase 2/3 trial and recently received market authorization by the EMA and FDA. As ASMD is a slowly progressive disease, detection of early stages of SM storage in the liver might aid in identifying patients at risk for major complications who would benefit from therapy. Two magnetic resonance (MR) based techniques might be of interest: MR Spectroscopy (MRS) to measure lipid accumulation (steatosis) and MR Elastography (MRE) to measure liver stiffness (fibrosis).

Objective: To assess the ability of MRI techniques to detect early stages of lipid accumulation in the liver of ASMD patients with the chronic visceral subtype compared to healthy subjects.

Study design: Cross-sectional pilot study in which MRS and MRE measurements of ASMD patients will be compared to measurements in healthy subjects. All ASMD patients who participate will undergo an MRI during their yearly assessments. Patients eligible for therapy will also undergo an MRI after one year of treatment.

Study population: All adult patients with ASMD visiting the outpatient clinic for metabolic disorders of the Amsterdam UMC will be invited to participate. Participating ASMD patients will be matched to healthy controls based on age, sex and BMI in a ratio of 1:1.

Main study endpoint: Fat fraction in volume percentage (%) of liver tissue of ASMD patients measured with MRS compared to values of healthy subjects.

Nature and extent of the burden and risks associated with participation, benefit and group relatedness: The MRI procedure yields no risk: at most patients might feel uncomfortable lying in the tight space. Patients and healthy subjects will not directly benefit from participation in the study. The results of the study may improve clinical care in the future.

• Study Type: Interventional
• Enrollment (Estimated): 34
• Phase: Not Applicable

Contacts and Locations

• Study Contact: Name: Eline CB Eskes, MD; Phone Number: 0205669111; Email: e.c.eskes@amsterdamumc.nl

Study Locations

• Netherlands
  • Noord-Holland
    • Amsterdam, Noord-Holland, Netherlands, 1105 AZ
      • Recruiting
      • Amsterdam UMC
      • Contact: Eline CB Eskes, MD; Phone Number: 0205669111; Email: e.c.eskes@amsterdamumc.nl

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: Adult; Older Adult
• Accepts Healthy Volunteers: Yes

Description

Inclusion Criteria:

Patients:

• The patient has biochemically proven ASMD (preferably genetically confirmed)
• The patient is willing and able to provide written informed consent prior to the study-related procedure.
• The patient is ≥ 18 years of age

Healthy controls:

• The individual is willing and able to provide written informed consent prior to the study-related procedure
• The individual is ≥ 18 years of age
• General good health as determined by medical history

Exclusion Criteria:

Patients and healthy controls:

• Inability to adhere to the study protocol
• Inability to undergo an MRI procedure

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Diagnostic
• Allocation: Non-Randomized
• Interventional Model: Parallel Assignment
• Masking: None (Open Label)

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Other: Patients; Participants will undergo an MRI with MR Spectroscopy (MRS) and MR Elastography (MRE) measurements	Diagnostic test: MR Spectroscopy (MRS); MR Spectroscopy (MRS); Diagnostic test: MR Elastography (MRE); MR Elastography (MRE) with a device that induces shear waves in the body. This device is placed upon the abdomen of the subject and is hold in place by straps. The device will produce low-frequency vibrations (e.g. 30-60 Hz) which are not painful to the participant. A declaration of conformity and a safety document are provided in the study dossier.
Other: Healthy controls; Participants will undergo an MRI with MR Spectroscopy (MRS) and MR Elastography (MRE) measurements	Diagnostic test: MR Spectroscopy (MRS); MR Spectroscopy (MRS); Diagnostic test: MR Elastography (MRE); MR Elastography (MRE) with a device that induces shear waves in the body. This device is placed upon the abdomen of the subject and is hold in place by straps. The device will produce low-frequency vibrations (e.g. 30-60 Hz) which are not painful to the participant. A declaration of conformity and a safety document are provided in the study dossier.

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Fat fraction in volume percentage measured with MRS-PDFF	Fat fraction in volume percentage measured with MRS-PDFF of ASMD patients compared to age-, sex, and BMI-matched healthy subjects.	1 year

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Liver stiffness in kPa measured with MRE	Liver stiffness in kPa measured with MRE of ASMD patients compared to age-, sex, and BMI-matched healthy subjects.	1 year
Correlations between fat fraction and/or liver stiffness and liver parameters	Correlations between fat fraction and/or liver stiffness and liver parameters (i.e. liver stiffness measured with fibroscan, liver volume and plasma ALT and AST levels)	1 year
Correlations between fat fraction and/or liver stiffness and general disease parameters	Correlations between fat fraction and/or liver stiffness and general disease parameters (i.e. spleen volume, CO diffusion capacity, plasma LSM, LSM-509 and chitotriosidase levels)	1 year

Collaborators and Investigators

• Sponsor: Eline C. B. Eskes
• Investigators: Principal Investigator: Carla EM Hollak, prof dr, Academisch Medisch Centrum - Universiteit van Amsterdam (AMC-UvA); Study Director: xx xx xx, xx

Study record dates

Study Major Dates

• Study Start (Actual): May 5, 2023
• Primary Completion (Estimated): April 1, 2024
• Study Completion (Estimated): September 1, 2024

Study Registration Dates

• First Submitted: June 6, 2023
• First Submitted That Met QC Criteria: June 6, 2023
• First Posted (Actual): June 15, 2023

Study Record Updates

• Last Update Posted (Actual): June 15, 2023
• Last Update Submitted That Met QC Criteria: June 6, 2023
• Last Verified: June 1, 2023

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Metabolic Diseases; Brain Diseases; Central Nervous System Diseases; Nervous System Diseases; Lymphatic Diseases; Genetic Diseases, Inborn; Metabolism, Inborn Errors; Lysosomal Storage Diseases; Lipid Metabolism Disorders; Brain Diseases, Metabolic; Brain Diseases, Metabolic, Inborn; Sphingolipidoses; Lysosomal Storage Diseases, Nervous System; Lipidoses; Lipid Metabolism, Inborn Errors; Histiocytosis, Non-Langerhans-Cell; Histiocytosis; Niemann-Pick Diseases; Niemann-Pick Disease, Type A; Niemann-Pick Disease, Type C; Niemann-Pick Disease, Type B
• Other Study ID Numbers: 2022.0444

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: UNDECIDED
• IPD Plan Description: Research data will be submitted as articles to peer-reviewed journals. Also, an abstract of our research data reporting our findings will be submitted for presentations on scientific, public and/or patient organization meetings for (oral) presentation(s).

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No