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Complement Activation in the Lysosomal Storage Disorders (CATALYST)

The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been evaluated by the U.S. Federal Government. Know the risks and potential benefits of clinical studies and talk to your health care provider before participating. Read our disclaimer for details.
 
ClinicalTrials.gov Identifier: NCT04189601
Recruitment Status : Not yet recruiting
First Posted : December 6, 2019
Last Update Posted : December 6, 2019
Sponsor:
Collaborator:
Sanofi
Information provided by (Responsible Party):
Melbourne Health

Brief Summary:
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.

Condition or disease Intervention/treatment
Fabry Disease Gaucher Disease Niemann-Pick Disease, Type C Lysosomal Storage Diseases 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.

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Study Type : Observational
Estimated Enrollment : 140 participants
Observational Model: Case-Control
Time Perspective: Cross-Sectional
Official Title: Complement Activation in the Lysosomal Storage Disorders
Estimated Study Start Date : February 28, 2020
Estimated Primary Completion Date : February 26, 2021
Estimated Study Completion Date : April 30, 2021


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




Primary Outcome Measures :
  1. Change in soluble C5b-9 [ Time Frame: At baseline ]
    Difference in sC5b-9 between Subjects and Controls at a single timepoint up to 8 months


Secondary Outcome Measures :
  1. Other complement biomarkers [ Time Frame: Difference in C3a and C5a between Subjects and Controls at a single timepoint up to 8 months ]
    Serum C3a and C5a



Information from the National Library of Medicine

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Ages Eligible for Study:   17 Years to 70 Years   (Child, Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   Yes
Sampling Method:   Probability Sample
Study Population
Consenting patients with FD, GD or NPC, and age and sex-matched controls
Criteria

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.

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT04189601


Contacts
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Contact: Thomas D Barbour, MBBS +61 3 9342 9003 tom.barbour@mh.org.au
Contact: Gloria Sepe gloria.sepe@mh.org.au

Locations
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Australia, Victoria
The Royal Melbourne Hospital
Melbourne, Victoria, Australia, 3050
Contact: Thomas D Barbour, MBBS    +61 3 9342 9003    tom.barbour@mh.org.au   
Contact: Gloria Sepe       gloria.sepe@mh.org.au   
Sub-Investigator: Kathy Nicholls, MBBS         
Sub-Investigator: Jeff Szer, MBBS         
Sub-Investigator: Mark Walterfang, MBBS         
Sub-Investigator: Steve Holt, MBBS         
Sponsors and Collaborators
Melbourne Health
Sanofi
Investigators
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Principal Investigator: Thomas D Barbour, MBBS Melbourne Health

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Responsible Party: Melbourne Health
ClinicalTrials.gov Identifier: NCT04189601    
Other Study ID Numbers: Royal_Melbourne
First Posted: December 6, 2019    Key Record Dates
Last Update Posted: December 6, 2019
Last Verified: December 2019
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD: No
Plan Description: No IPD sharing

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Studies a U.S. FDA-regulated Drug Product: No
Studies a U.S. FDA-regulated Device Product: No
Keywords provided by Melbourne Health:
complement
Additional relevant MeSH terms:
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Fabry Disease
Gaucher Disease
Pick Disease of the Brain
Niemann-Pick Diseases
Niemann-Pick Disease, Type A
Niemann-Pick Disease, Type C
Lysosomal Storage Diseases
Sphingolipidoses
Lysosomal Storage Diseases, Nervous System
Brain Diseases, Metabolic, Inborn
Brain Diseases, Metabolic
Brain Diseases
Central Nervous System Diseases
Nervous System Diseases
Cerebral Small Vessel Diseases
Cerebrovascular Disorders
Vascular Diseases
Cardiovascular Diseases
Genetic Diseases, X-Linked
Genetic Diseases, Inborn
Metabolism, Inborn Errors
Lipidoses
Lipid Metabolism, Inborn Errors
Metabolic Diseases
Lipid Metabolism Disorders
Frontotemporal Dementia
Frontotemporal Lobar Degeneration
Dementia
Neurocognitive Disorders
Mental Disorders