Clinical trial NCT06007768: Autoimmune and Inflammatory Response Biomarkers in Fabry Disease
Official title: Autoimmune and Inflammatory Response Biomarkers in Fabry Disease
Study type: OBSERVATIONAL
Overall status: COMPLETED
Conditions: Fabry Disease
Keywords: Fabry Disease
Immune response
Biomarkers
Quality of life
Inflammation
Lead sponsor: Fundacion para la Investigacion Biomedica del Hospital Universitario Ramon y Cajal
Sponsor class: OTHER
Collaborators: name: Fundación Mutua Madrileña
First posted: 2023-08-23
Enrollment: 32
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: yes
Observational model: CASE_CONTROL
Time perspective: CROSS_SECTIONAL
Sampling method: NON_PROBABILITY_SAMPLE
Study population: Population of consecutive patients with Fabry Disease (FD) under follow-up in the Internal Medicine Department of the Hospital Universitario Ramon y Cajal.

In addition, a Control group of subjects without Fabry disease will be included, among those who come to donate blood at the Hospital Universitario Ramón y Cajal.

Controls will be matched for age (± 5 years) and sex with FD patients.

Brief summary: The goal of this observational study is to understand the immune response in Fabry disease (FD). We want to find out how the immune response is related to the severity of FD and how it affects patients' quality of life and pain.

Main Questions the Study Aims to Answer:

* How are immune response markers linked to the health of FD patients?
* How is the immune response different between FD patients and healthy individuals?

Participants:

We will include 20 patients who have FD and are older than 18, and do not have other autoimmune or autoinflammatory diseases. We'll also include a comparison group of the same size who don't have FD, but are similar in age and sex to the FD group.

Participants with Fabry disease will be asked about their medical history and complete questionnaires. We will measure their vital signs and collect blood samples to study immune response markers. We'll also look at specific biomarkers related to FD.

Healthy participants will do similar tasks for comparison.

Comparison: Researchers will compare the immune response markers and other measurements between FD patients and healthy individuals to understand the differences and similarities.

Duration: The study will take place over 18 months to gather comprehensive information.

Detailed description: Rationale: The immune response could play a relevant role in the pathophysiological mechanisms of Fabry disease (FD), although the relationship between the activated immune pathways and the clinical expression of the disease needs to be clarified. Knowledge of the immune response in FD could help to better understand the progression of the disease, identifying new biomarkers potentially useful in the clinical follow-up of these patients.

Study design: Observational cross-sectional study with a control group. Study subjects: Target group: patients with Fabry disease, older than 18 years and without autoimmune or autoinflammatory diseases. Control group: subjects without Fabry disease matched for age (± 5 years) and sex.

Sample size: n=40 (20 patients with Fabry disease + 20 controls).

Objectives:

1. To study the relationship between immune response biomarkers and the clinical status of the patient, as measured by the MSSI scale (Mainz Severity Score Index) or by markers of target organ damage (clinical, biochemical and imaging parameters).
2. To characterize the immune response profile by circulating biomarkers of subjects with Fabry disease (FD) compared to healthy subjects.
3. To compare circulating biomarker values with those measured in PBMC (Peripheral Blood Mononuclear Cells) culture supernatant from patients with FD.
4. To evaluate the relationship between biomarkers of the immune response and the concentration of specific Fabry disease markers (Lyso-Gb3).
5. To evaluate the association between immune response biomarkers and quality of life and neuropathic pain in FD patients.

Variables: Demographics, vital signs, anthropometric data, FD medical history, questionnaires, clinical biochemical variables, biochemical markers of autoimmunity, specific markers of FD (Lyso-Gb3), immune response markers and markers of target organ damage.

Duration: 18 months

Eligibility criteria: For the Fabry Disease (FD) group:

Inclusion Criteria:

* Age ≥ 18 years.
* Diagnosis of Fabry disease (enzymatic or genetic).
* Having signed the informed consent, after having received all the information concerning the study.

Exclusion Criteria:

* Autoimmune or autoinflammatory disease or patients with transplanted organs (corneal transplant excluded) and under additional immunosuppressive treatment.
* Acute cardiovascular event or major surgery in the 90 days prior to inclusion in the study.
* Serious intercurrent diseases such as HIV, COVID-19, cancer under active treatment, severe anemia, severe hepatic, respiratory or renal failure, or other pathologies that, at the investigator's discretion, could interfere with the objectives of the study.

For the Control group:

• Participants must not meet any of the exclusion criteria applied to the target (FD) population and must sign, prior to inclusion, the informed consent form after having received all the information concerning the study.

Primary outcomes:
measure: High-sensitivity C-reactive protein (hsCRP)
timeFrame: Day 1 (one cross-sectional examination only)
measure: Tumor necrosis factor (TNF)
timeFrame: Day 1 (one cross-sectional examination only)
measure: Interleukin 6 (IL-6)
timeFrame: Day 1 (one cross-sectional examination only)
measure: Interferon gamma (IFN-γ)
timeFrame: Day 1 (one cross-sectional examination only)
measure: Vascular cell adhesion protein 1 (VCAM-1)
timeFrame: Day 1 (one cross-sectional examination only)
Secondary outcomes:
measure: Globotriaosylsphingosine (Lyso-Gb3)
timeFrame: Day 1 (one cross-sectional examination only)
measure: Brain natriuretic peptide (BNP)
timeFrame: Day 1 (one cross-sectional examination only)
measure: N-terminal prohormone of brain natriuretic peptide (NT-proBNP)
timeFrame: Day 1 (one cross-sectional examination only)
measure: Cystatin C
timeFrame: Day 1 (one cross-sectional examination only)
measure: EuroQol Health-Related Quality of Life (EQ-5D-5L)
timeFrame: Day 1 (one cross-sectional examination only)
measure: 11-point numerical rating scale (NRS-11) score of neuropathic pain
timeFrame: Day 1 (one cross-sectional examination only)
measure: Mainz Severity Score Index (MSSI)
timeFrame: Day 1 (one cross-sectional examination only)
Other outcomes:
Locations:
city: Madrid
country: Spain
facility: Hospital Universitario Ramón y Cajal
Study officials:
affiliation: Hospital Universitario Ramon y Cajal
name: Monica A Lopez Rodriguez, MD PhD
role: PRINCIPAL_INVESTIGATOR
References:
citation: Rozenfeld P, Feriozzi S. Contribution of inflammatory pathways to Fabry disease pathogenesis. Mol Genet Metab. 2017 Nov;122(3):19-27. doi: 10.1016/j.ymgme.2017.09.004. Epub 2017 Sep 13.
citation: De Francesco PN, Mucci JM, Ceci R, Fossati CA, Rozenfeld PA. Fabry disease peripheral blood immune cells release inflammatory cytokines: role of globotriaosylceramide. Mol Genet Metab. 2013 May;109(1):93-9. doi: 10.1016/j.ymgme.2013.02.003. Epub 2013 Feb 13.
citation: Mauhin W, Lidove O, Masat E, Mingozzi F, Mariampillai K, Ziza JM, Benveniste O. Innate and Adaptive Immune Response in Fabry Disease. JIMD Rep. 2015;22:1-10. doi: 10.1007/8904_2014_371. Epub 2015 Feb 18.
citation: Ge W, Li D, Gao Y, Cao X. The Roles of Lysosomes in Inflammation and Autoimmune Diseases. Int Rev Immunol. 2015;34(5):415-31. doi: 10.3109/08830185.2014.936587. Epub 2014 Jul 30.
citation: Simonetta I, Tuttolomondo A, Daidone M, Pinto A. Biomarkers in Anderson-Fabry Disease. Int J Mol Sci. 2020 Oct 29;21(21):8080. doi: 10.3390/ijms21218080.
citation: Loso J, Lund N, Avanesov M, Muschol N, Lezius S, Cordts K, Schwedhelm E, Patten M. Serum Biomarkers of Endothelial Dysfunction in Fabry Associated Cardiomyopathy. Front Cardiovasc Med. 2018 Aug 15;5:108. doi: 10.3389/fcvm.2018.00108. eCollection 2018.
citation: Shen JS, Meng XL, Moore DF, Quirk JM, Shayman JA, Schiffmann R, Kaneski CR. Globotriaosylceramide induces oxidative stress and up-regulates cell adhesion molecule expression in Fabry disease endothelial cells. Mol Genet Metab. 2008 Nov;95(3):163-8. doi: 10.1016/j.ymgme.2008.06.016. Epub 2008 Aug 15.
citation: Weidemann F, Beer M, Kralewski M, Siwy J, Kampmann C. Early detection of organ involvement in Fabry disease by biomarker assessment in conjunction with LGE cardiac MRI: results from the SOPHIA study. Mol Genet Metab. 2019 Feb;126(2):169-182. doi: 10.1016/j.ymgme.2018.11.005. Epub 2018 Nov 12.
citation: Chimenti C, Scopelliti F, Vulpis E, Tafani M, Villanova L, Verardo R, De Paulis R, Russo MA, Frustaci A. Increased oxidative stress contributes to cardiomyocyte dysfunction and death in patients with Fabry disease cardiomyopathy. Hum Pathol. 2015 Nov;46(11):1760-8. doi: 10.1016/j.humpath.2015.07.017. Epub 2015 Aug 4.
citation: Yogasundaram H, Nikhanj A, Putko BN, Boutin M, Jain-Ghai S, Khan A, Auray-Blais C, West ML, Oudit GY. Elevated Inflammatory Plasma Biomarkers in Patients With Fabry Disease: A Critical Link to Heart Failure With Preserved Ejection Fraction. J Am Heart Assoc. 2018 Nov 6;7(21):e009098. doi: 10.1161/JAHA.118.009098.
citation: Chen KH, Chien Y, Wang KL, Leu HB, Hsiao CY, Lai YH, Wang CY, Chang YL, Lin SJ, Niu DM, Chiou SH, Yu WC. Evaluation of Proinflammatory Prognostic Biomarkers for Fabry Cardiomyopathy With Enzyme Replacement Therapy. Can J Cardiol. 2016 Oct;32(10):1221.e1-1221.e9. doi: 10.1016/j.cjca.2015.10.033. Epub 2015 Nov 10.