Complement Activation in the Lysosomal Storage Disorders (CATALYST)

The lysosomal storage disorders (LSDs) are monogenic disorders associated with inflammation affecting multiple organs, and early death. Few treatments are available that can modify the disease course, and there is an urgent need to identify new steps in pathogenesis that can be targeted therapeutically. The complement system is novel and highly plausible as a primary driver of inflammation and cellular injury in the LSDs. This study assesses the complement activation state in patients with Fabry disease (FD), Gaucher disease (GD) and Niemann-Pick disease, type C (NPC), with comparison to healthy controls. This has the potential for immense clinical benefit through targeted complement inhibition across the full spectrum of lysosomal storage disorders, in which key pathophysiological processes including the inflammatory response to lysosomally 'stored' materials are shared.

Study Overview

• Status: Withdrawn
• Conditions: Lysosomal Storage Diseases; Fabry Disease; Niemann-Pick Disease, Type C; Gaucher Disease
• Intervention / Treatment: Diagnostic test: Complement measurements

Detailed Description

This is a single-centre, cross-sectional observational study in patients >16 years of age diagnosed with FD, GD or NPC. The research hypotheses of this study are:

1. That complement is excessively activated, including at the specifically complement C5 level, in patients with the lysosomal storage disorders FD, GD and NPC.
2. That complement activation drives tissue injury in the LSDs via downstream effector mechanisms including membrane attach complex (MAC/C5b-9)-mediated cytotoxicity and C5aR-mediated inflammation.

The study aims to show enhanced complement activation, including at the C5 level, in patients with FD, GD and NPC compared to healthy controls.

The research assays for this study include the primary outcome measure of plasma soluble C5b-9 (sC6b-9) levels measured using ELISA. This assay measures the degree to which ongoing C5 activation Is occurring in vivo based on sensitive detection in plasma of the key activation product C5b-9. The assay would be expected to show elevated plasma sC5b-9 levels in patients with the glycosphingolipidoses compared to disease-free controls, as was previously demonstrated in patient cohorts of atypical haemolytic uraemia syndrome (aHUS) and C3 glomerulopathy (C3G). Additional complement activation products will be assessed as secondary endpoints including plasma C3a and C5a levels by ELISA, and intracellular leukocyte C5a concentration as a marker of systemic C5a generation and C5aR1 expression.

• Study Type: Observational

Contacts and Locations

Study Locations

• Australia
  • Victoria
    • Melbourne, Victoria, Australia, 3050
      • The Royal Melbourne Hospital

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 15 years to 68 years (Child, Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

• Sampling Method: Probability Sample

Study Population

Consenting patients with FD, GD or NPC, and age and sex-matched controls

Description

Inclusion Criteria:

• All consenting patients with a prior diagnosis of FD, GD or NPC will be included in the study. Control participants will be healthy volunteers.

Exclusion Criteria:

• Patients who are unable to provide consent or to perform a blood or urine test will be excluded.

Study Plan

How is the study designed?

Design Details

• Observational Models: Case-Control
• Time Perspectives: Cross-Sectional

Number of groups / cohorts

2

Cohorts and Interventions

Group / Cohort	Intervention / Treatment
Study subjects; Patients with Fabry disease, Gaucher disease, or Niemann-Pick disease, type D	Diagnostic test: Complement measurements; Blood and urine tests to assess the complement activation state
Controls; Age- and sex-matched to Study subjects	Diagnostic test: Complement measurements; Blood and urine tests to assess the complement activation state

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Change in soluble C5b-9	Difference in sC5b-9 between Subjects and Controls at a single timepoint up to 8 months	At baseline

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Other complement biomarkers	Serum C3a and C5a	Difference in C3a and C5a between Subjects and Controls at a single timepoint up to 8 months

Collaborators and Investigators

• Sponsor: Melbourne Health
• Collaborators: Sanofi
• Investigators: Principal Investigator: Thomas D Barbour, MBBS, Melbourne Health

Study record dates

Study Major Dates

• Study Start (Anticipated): September 30, 2020
• Primary Completion (Anticipated): February 26, 2021
• Study Completion (Anticipated): April 30, 2021

Study Registration Dates

• First Submitted: December 1, 2019
• First Submitted That Met QC Criteria: December 4, 2019
• First Posted (Actual): December 6, 2019

Study Record Updates

• Last Update Posted (Actual): June 7, 2021
• Last Update Submitted That Met QC Criteria: June 2, 2021
• Last Verified: May 1, 2021

More Information

Terms related to this study

• Keywords: complement
• Additional Relevant MeSH Terms: Mental Disorders; Cardiovascular Diseases; Vascular Diseases; Metabolic Diseases; Cerebrovascular Disorders; Brain Diseases; Central Nervous System Diseases; Nervous System Diseases; Lymphatic Diseases; Neurocognitive Disorders; Genetic Diseases, Inborn; Genetic Diseases, X-Linked; Metabolism, Inborn Errors; Lipid Metabolism Disorders; Dementia; Brain Diseases, Metabolic; Brain Diseases, Metabolic, Inborn; Sphingolipidoses; Lysosomal Storage Diseases, Nervous System; Cerebral Small Vessel Diseases; Lipidoses; Lipid Metabolism, Inborn Errors; Frontotemporal Lobar Degeneration; Histiocytosis, Non-Langerhans-Cell; Histiocytosis; Frontotemporal Dementia; Fabry Disease; Pick Disease of the Brain; Lysosomal Storage Diseases; Niemann-Pick Diseases; Niemann-Pick Disease, Type A; Niemann-Pick Disease, Type C; Gaucher Disease; Physiological Effects of Drugs; Immunologic Factors; Complement System Proteins
• Other Study ID Numbers: Royal_Melbourne

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: No
• IPD Plan Description: No IPD sharing

Drug and device information, study documents

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