Validating Immunological Markers Associated With Mental Fatigue in Graves' Disease

Graves Disease Clinical Trial

Official title:

Validating Immunological Markers in Blood and Cerebrospinal Fluid Associated With Mental Fatigue in Graves' Disease and Their Association With Functional Changes in Neuronal Activation

Clinical Trial Details — Status: Recruiting

Administrative data

• NCT number: NCT06081439
• Other study ID #: ImmunoGraves wp2
• Status: Recruiting
• Start date: September 12, 2019
• Est. completion date: December 20, 2025

Study information

• Verified date: September 2023
• Source: Vastra Gotaland Region
• Contact: Karin Tammelin, PhD student
• Phone: +46313427331
• Email: karin.tammelin[@]vgregion.se
• Is FDA regulated: No
• Study type: Observational

Clinical Trial Summary

Mental fatigue occurs in many diseases and the reasons are mostly unknown. The investigators hypothesize that remaining mental fatigue after restored euthyroidism in Graves' disease is an autoimmune complication. This is a confirmatory study of the biomarkers from ImmunoGraves WP1 in which immunological markers with possible association with mental fatigue in Graves' disease are explored.

In ImmunoGraves WP2, 310 patients with Graves' disease are assessed for symptoms of mental fatigue, quality of life, anxiety and depression, self-evaluated stress, coping strategies, personality traits, eye symptoms and background variables. Participants are examined in hyperthyroidism at inclusion, within three weeks from diagnosis, and in euthyroidism after 15 months. Serum and cerebrospinal fluid (in a subsample of participants) is collected at both visits and will be evaluated for the immunological markers identified in WP1 as well as for thyroid hormones, thyroid autoantibodies and biomarkers indicating organic and structural nerve damage. Significant predictors for mental fatigue will be identified by logistic regression.

To assess functional changes in the brain, magnetoencephalography will be performed in a subset of patients and in healthy controls at inclusion and after 15 to 18 months. Combined with magneto resonance imaging (MRI), magnetoencephalography gives information on neuronal activation during attention testing.

Recruitment information / eligibility

• Status: Recruiting
• Enrollment: 430
• Est. completion date: December 20, 2025
• Est. primary completion date: December 20, 2025
• Gender: All
• Age group: 18 Years to 72 Years

Eligibility

Inclusion Criteria:

• Recently diagnosed Graves' disease

• Positive thyroid stimulating hormone (TSH)-receptor antibodies (TRAb)

• Thyroid hormones above the upper reference limit

• Inclusion within three weeks after start of antithyroid drugs

Controls: Matched for gender and age

Exclusion Criteria:

• Person unable to follow protocol as with psychosis, dementia or not able to answer questionnaires in Swedish.

• Recidive of Graves' disease

• Pregnancy

Controls: -Thyroid disease

• Neurological disease

Related Conditions & MeSH terms

• Fatigue
• Graves Disease
• Mental Fatigue

Locations

Country	Name	City	State
Sweden	Endokrina Forskningsenheten, Sahlgrenska University Hospital	Gothenburg

Sponsors (1)

Lead Sponsor	Collaborator
Vastra Gotaland Region

Country where clinical trial is conducted

Sweden, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	Identifying the immunological markers in blood at inclusion that significantly increases the risk for mental fatigue at follow up.	Immunological markers in blood identified in the on-going study ImmunoGraves Wp1 are analysed between participants who at follow up have 10.5 points or more at the Mental Fatigue Scale and participants who have less than 10.5 points at the Mental Fatigue Scale. Higher scores at the Mental Fatigue Scale means more brain fatigue.	Blood drawn at inclusion. Mental Fatigue Scale completed by participants at follow-up 15 months after inclusion.
Secondary	Levels of the previously identified immunological markers in serum at inclusion compared between participants who at follow up have high scores at the Mental Fatigue Scale and participants who at follow up have low scores at the Mental Fatigue Scale	Immunological markers identified in the on-going study ImmunoGraves Wp1 are compared between participants who at follow up have 10.5 points or more at the Mental Fatigue Scale and participants who have less than 10.5 points at the Mental Fatigue Scale.Higher scores at the Mental Fatigue Scale means more brain fatigue.	Blood drawn at inclusion. Mental Fatigue Scale completed by participants at follow-up 15 months after inclusion.
Secondary	Levels of the previously identified immunological markers in cerebrospinal fluid at inclusion compared between patients with high and low scores at the Mental Fatigue Score at follow-up	Immunological markers identified in the on-going study ImmunoGraves Wp1 are compared between participants who at follow up have 10.5 points or more at the Mental Fatigue Scale and participants who have less than 10.5 points at the Mental Fatigue Scale.Higher scores at the Mental Fatigue Scale means more brain fatigue.	Cerebrospinal fluid drawn at inclusion. Mental Fatigue Scale completed by participants at follow-up 15 months after inclusion
Secondary	Levels of the previously identified immunological markers in serum at follow up compared between patients with high and low scores at the Mental Fatigue Scale at follow-up and to healthy controls	Immunological markers identified in the on-going study ImmunoGraves Wp1 are compared between participants who at follow-up have 10.5 points or more at the Mental Fatigue Scale and participants who have less than 10.5 points at the Mental Fatigue Scale. Higher scores at the Mental Fatigue Scale means more brain fatigue.	Blood drawn and Mental Fatigue Scale completed by participants at follow-up 15 months after inclusion.
Secondary	Levels of the previously identified immunological markers in cerebrospinal fluid at follow up compared between patients with high and low scores at the Mental Fatigue Scale at follow-up	Immunological markers identified in the on-going study ImmunoGraves Wp1 are compared between participants who at follow-up have 10.5 points or more at the Mental Fatigue Scale and participants who have less than 10.5 points at the Mental Fatigue Scale. Higher scores at the Mental Fatigue Scale means more brain fatigue.	Cerebrospinal fluid drawn and Mental Fatigue Scale completed by participants at follow-up 15 months after inclusion.
Secondary	Levels of thyroid hormones at inclusion compared in patients with high and low scores at the Mental Fatigue Scale at follow-up	Levels of thyroid hormones, analysed with the standard method of the laboratory at Sahlgrenska University Hospital, compared between participants who at follow-up have 10.5 points or more at the Mental Fatigue Scale and participants who have less than 10.5 points at the Mental Fatigue Scale. Higher scores at the Mental Fatigue Scale means more brain fatigue.	Blood drawn at inclusion. Mental Fatigue Scale completed by participants at follow-up 15 months after inclusion.
Secondary	Levels of thyroid hormones at inclusion compared in patients with high and low scores at the Mental Fatigue Scale at inclusion	Levels of thyroid hormones, analysed with the standard method of the laboratory at Sahlgrenska University Hospital, compared between participants who at inclusion have 10.5 points or more at the Mental Fatigue Scale and participants who have less than 10.5 points at the Mental Fatigue Scale. Higher scores at the Mental Fatigue Scale means more brain fatigue.	Blood drawn at inclusion. Mental Fatigue Scale completed by participants at inclusion.
Secondary	Levels of thyroid antibodies at inclusion compared in patients with high and low scores at the Mental Fatigue Scale at follow-up	Levels of thyroid autoantibodies, analysed with the standard method of the laboratory at Sahlgrenska University Hospital, compared between participants who at follow-up have 10.5 points or more at the Mental Fatigue Scale and participants who have less than 10.5 points at the Mental Fatigue Scale.Higher scores at the Mental Fatigue Scale means more brain fatigue.	Blood drawn at inclusion. Mental Fatigue Scale completed by participants at follow-up 15 months after inclusion.
Secondary	Levels of thyroid antibodies at inclusion compared in patients with high and low scores at the Mental Fatigue Scale at inclusion	Levels of thyroid autoantibodies, analysed with the standard method of the laboratory at Sahlgrenska University Hospital, compared between participants who have 10.5 points or more at the Mental Fatigue Scale and participants who have less than 10.5 points at the Mental Fatigue Scale at inclusion. Higher scores at the Mental Fatigue Scale means more brain fatigue.	Blood drawn at inclusion. Mental Fatigue Scale completed by participants at inclusion.
Secondary	Levels of thyroid antibodies at follow-up compared in patients with high and low scores at the Mental Fatigue Scale at follow-up.	Levels of thyroid autoantibodies, analysed with the standard method of the laboratory at Sahlgrenska University Hospital, compared between participants who at follow-up have 10.5 points or more at the Mental Fatigue Scale and participants who have less than 10.5 points at the Mental Fatigue Scale.Higher scores at the Mental Fatigue Scale means more brain fatigue.	Blood drawn and Mental Fatigue Scale completed by participants at follow-up 15 months after inclusion.
Secondary	Levels of biomarkers indicating organic and structural nerve damage at inclusion in patients with high and low scores at the Mental Fatigue Scale at follow-up	Levels of biomarkers indicating organic and structural nerve damage, analysed with the standard method of the laboratory at Sahlgrenska University Hospital, compared between participants who at follow-up have 10.5 points or more at the Mental Fatigue Scale and participants who have less than 10.5 points at the Mental Fatigue Scale. Higher scores at the Mental Fatigue Scale means more brain fatigue.	Blood and, in a subgroup, cerebrospinal fluid drawn at inclusion. Mental Fatigue Scale completed by participants at follow-up 15 months after inclusion.
Secondary	Levels of biomarkers indicating organic and structural nerve damage at inclusion in patients with high and low scores at the Mental Fatigue Scale at inclusion	Levels of biomarkers indicating organic and structural nerve damage, analysed with the standard method of the laboratory at Sahlgrenska University Hospital, compared between participants who at inclusion have 10.5 points or more at the Mental Fatigue Scale and participants who have less than 10.5 points at the Mental Fatigue Scale. Higher scores at the Mental Fatigue Scale means more brain fatigue.	Blood and, in a subgroup, cerebrospinal fluid, drawn at inclusion. Mental Fatigue Scale completed by participants at inclusion.
Secondary	Levels of biomarkers indicating organic and structural nerve damage at follow-up in patients with high and low scores at the Mental Fatigue Scale at follow-up	Levels of biomarkers indicating organic and structural nerve damage, analysed with the standard method of the laboratory at Sahlgrenska University Hospital, compared between participants who at follow up have 10.5 points or more at the Mental Fatigue Scale and participants who have less than 10.5 points at the Mental Fatigue Scale.Higher scores at the Mental Fatigue Scale means more brain fatigue.	Blood and, in a subgroup, cerebrospinal fluid, drawn at follow-up after 15 months. Mental Fatigue Scale completed by participants at follow-up 15 months after inclusion.
Secondary	Prevalence of endocrine ophthalmopathy at inclusion compared between patients with high and low scores at the Mental Fatigue Scale at follow-up	Endocrine ophthalmopathy defined as Clinical Activity Score of 3/7 or more, compared between participants who at follow up have 10.5 points or more at the Mental Fatigue Scale and participants who have less than 10.5 points at the Mental Fatigue Scale. Higher scores at the Mental Fatigue Scale means more brain fatigue.; Higher scores at the Clinical Activity Score means more serious endocrine ophthalmopathy.	Patients examined at inclusion, Mental Fatigue Scale completed by participants at follow-up 15 months after inclusion.
Secondary	Prevalence of endocrine ophthalmopathy at follow-up compared between patients with high and low scores at the Mental Fatigue Scale at follow-up	Endocrine ophthalmopathy defined as Clinical Activity Score of 3/7 or more, compared between participants who at follow-up have 10.5 points or more at the Mental Fatigue Scale and participants who have less than 10.5 points at the Mental Fatigue Scale. Higher scores at the Mental Fatigue Scale means more brain fatigue. Higher scores at the Clinical Activity Score means more serious endocrine ophthalmopathy.	Patients examined and Mental Fatigue Scale completed by participants at follow-up 15 months after inclusion.
Secondary	Scores at the Mental Fatigue Scale at inclusion compared between patients with Graves' with and without mental fatigue at follow-up and to healthy controls	Scores at the Mental Fatigue Scale at inclusion compared between participants who at follow-up have 10.5 points or more at the Mental Fatigue Scale and participants who have less than 10.5 points at the Mental Fatigue Scale. Higher scores at the Mental Fatigue Scale means more brain fatigue.	Mental Fatigue Scale completed by participants at inclusion and follow-up at 15 months after inclusion, by controls at inclusion.
Secondary	Self-evaluated quality of life in relation to ophthalmopathy compared between patients with Graves' with and without mental fatigue at follow-up, and to healthy controls.	Evaluated by the validated questionnaire the Graves' Ophthalmopathy Quality of Life Questionnaire (GO QoL). Scores are compared between participants who at follow-up have 10.5 points or more at the Mental Fatigue Scale and participants who have less than 10.5 points at the Mental Fatigue Scale. Higher scores at the Mental Fatigue Scale means more brain fatigue. Higher scores at the Graves' Ophthalmopathy Quality of Life Questionnaire means better quality of life.	Graves' Ophthalmopathy Quality of Life Questionnaire and Mental Fatigue Scale completed by participants at inclusion and follow-up at 15 months after inclusion, by controls at inclusion.
Secondary	Self-evaluated quality of life in relation to thyroid symptoms will be compared between patients with Graves' with and without mental fatigue at follow-up, and to healthy controls.	Evaluated by the validated questionnaire Thyroid-specific Patient-Reported Outcome short-form (ThyPro 39). Scores are compared between participants who at follow-up have 10.5 points or more at the Mental Fatigue Scale and participants who have less than 10.5 points at the Mental Fatigue Scale. Higher scores at the Mental Fatigue Scale means more brain fatigue.Higher scores at the Thyroid-specific Patient-Reported Outcome short-form means worse quality of life.	Thyroid-specific Patient-Reported Outcome short-form and Mental Fatigue Scale completed by participants at inclusion and follow-up 15 months after inclusion, by controls at inclusion.
Secondary	Self-evaluated quality of life and well-being will be compared between patients with Graves' with and without mental fatigue at follow-up and to healthy controls	Evaluated by the validated questionnaire Psychological General Well Being index (PGWB). Scores are compared between participants who at follow-up have 10.5 points or more at the Mental Fatigue Scale and participants who have less than 10.5 points at the Mental Fatigue Scale. Higher scores at the Mental Fatigue Scale means more brain fatigue. Higher scores at the Psychological General Well Being means higher quality of life.	Psychological General Well Being indexed Mental Fatigue Scale completed by participants at inclusion and follow-up 15 months after inclusion, by controls at inclusion.
Secondary	Self-evaluated symptoms of anxiety and depression compared between patients with Graves' with and without mental fatigue at follow-up and to healthy controls	Evaluated by the validated questionnaire the Comprehensive Psychopathological Rating Scale (CPRS). Scores are compared between participants who at follow-up have 10.5 points or more at the Mental Fatigue Scale and participants who have less than 10.5 points at the Mental Fatigue Scale. Higher scores at the Mental Fatigue Scale means more brain fatigue. Higher scores at the Comprehensive Psychopathological Rating Scale mean more symptoms of anxiety and depression.	Comprehensive Psychopathological Rating Scale and Mental Fatigue Scale completed by participants at inclusion and follow-up 15 months after inclusion, by controls at inclusion.
Secondary	Self-evaluated stress compared between patients with Graves' with and without mental fatigue at follow-up and to healthy controls	Evaluated by the validated questionnaire Perceived Stress Scale (PSS-14). Scores are compared between participants who at follow-up have 10.5 points or more at the Mental Fatigue Scale and participants who have less than 10.5 points at the Mental Fatigue Scale. Higher scores at the Perceived Stress Scale mean more symptoms of stress.	Perceived Stress Scale and Mental Fatigue Scale completed by participants at inclusion and follow up 15 months after inclusion, by controls at inclusion.
Secondary	Coping strategies will be compared between patients with Graves' with and without mental fatigue at follow-up, and to healthy controls	Evaluated by the validated questionnaire Brief cope. Coping strategies are compared between participants who at follow-up have 10.5 points or more at the Mental Fatigue Scale and participants who have less than 10.5 points at the Mental Fatigue Scale.	Brief cope and Mental Fatigue Scale completed by participants at inclusion and follow up 15 months after inclusion, by controls at inclusion.
Secondary	Optimistic self-beliefs to cope with difficulties in life will be compared between patients with Graves' with and without mental fatigue at follow-up and to healthy controls.	Evaluated by the validated questionnaire General Self-Efficacy. Scores are compared between participants who at follow-up have 10.5 points or more at the Mental Fatigue Scale and participants who have less than 10.5 points at the Mental Fatigue Scale. Higher scores at the General Self-Efficacy questionnaire means higher optimistic self-beliefs.	General self efficacy and Mental Fatigue Scale completed by participants at inclusion and follow-up 15 months after inclusion, by controls at inclusion.
Secondary	Personality traits will be compared between patients with Graves' with and without mental fatigue at follow-up, and to healthy controls	Evaluated by the validated questionnaire NEO Five-Factor Inventory-3 (NEO-FFI-3). Personality traits are compared between participants who at follow-up have 10.5 points or more at the Mental Fatigue Scale and participants who have less than 10.5 points at the Mental Fatigue Scale.	NEO Five-Factor Inventory-3 and Mental Fatigue Scale completed by participants at inclusion and follow-up 15 months after inclusion, by controls at inclusion.
Secondary	Observations of hippocampal neuronal activation during attention testing in hyperthyroidism and in healthy controls.	Magnetoencephalography will be performed in a subset of patients and in healthy controls. Combined with magneto resonance imaging (MRI), magnetoencephalography gives information on neuronal activation by measuring alfa- and theta-band oscillations during attention testing.	Magnetoencephalography will be performed in patients and in controls at inclusion.
Secondary	Observations of neuronal activation during attention testing in patients with Graves' disease at follow-up and in healthy controls.	Magnetoencephalography will be performed in a subset of patients and in healthy controls. Combined with magneto resonance imaging (MRI), magnetoencephalography gives information on neuronal activation by measuring alfa- and theta-band oscillations during attention testing.	Magnetoencephalography will be performed in patients at follow-up 15 months after inclusion, in controls at inclusion.
Secondary	Observations of neuronal activation during attention testing at follow-up compared between patients with and without mental fatigue and in healthy controls.	Magnetoencephalography will be performed in a subset of patients and in healthy controls. Combined with magneto resonance imaging (MRI), magnetoencephalography gives information on neuronal activation by measuring alfa- and theta-band oscillations during attention testing. The alfa- and theta-band oscillations will be compared between participants who at follow-up have 10.5 points or more at the Mental Fatigue Scale and participants who have less than 10.5 points at the Mental Fatigue Scale.	Magnetoencephalography will be performed in patients after 15 months, in controls at inclusion. Mental Fatigue Scale will be completed by patients at follow-up 15 months after inclusion, by controls at inclusion.
Secondary	Immunological markers from Primary Outcome will be compared in patients with changed hippocampal neuronal activation compared to controls, and in controls.	Magnetoencephalography will be performed in a subset of patients and in healthy controls. Combined with magneto resonance imaging (MRI), magnetoencephalography gives information on neuronal activation by measuring alfa- and theta-band oscillations during attention testing. Immunological markers identified in the on-going study ImmunoGraves wp1 and in Primary Outcome.	Magnetoencephalography will be performed in patients at inclusion and after 15 month, in controls at inclusion. Blood and cerebrospinal fluid will be drawn at inclusion.
Secondary	Immunological markers from Primary Outcome will be compared in patients without changed hippocampal neuronal activation compared to controls, and in controls.	Magnetoencephalography will be performed in a subset of patients and in healthy controls. Combined with magneto resonance imaging (MRI), magnetoencephalography gives information on neuronal activation by measuring alfa- and theta-band oscillations during attention testing. Immunological markers identified in the on-going study ImmunoGraves wp1 and in Primary Outcome.	Magnetoencephalography will be performed in patients at inclusion and after 15 months, in controls at inclusion. Blood and cerebrospinal fluid will be drawn at inclusion.
Secondary	Biomarkers indicating organic and structural nerve damage will be compared in patients without changed hippocampal neuronal activation compared to controls, and in controls.	Magnetoencephalography will be performed in a subset of patients and in healthy controls. Combined with magneto resonance imaging (MRI), magnetoencephalography gives information on neuronal activation by measuring alfa- and theta-band oscillations during attention testing. Biomarkers indicating organic and structural nerve damage analysed with the standard method of the laboratory at Sahlgrenska University Hospital.	Magnetoencephalography will be performed in patients at inclusion and at follow-up 15 months after inclusion, in controls at inclusion. Blood and cerebrospinal fluid will be drawn at inclusion.
Secondary	Thyroid autoantibodies will be compared in patients with changed hippocampal neuronal activation compared to controls, and in controls.	Magnetoencephalography will be performed in a subset of patients and in healthy controls. Combined with magneto resonance imaging (MRI), magnetoencephalography gives information on neuronal activation by measuring alfa- and theta-band oscillations during attention testing. Thyroid autoantibodies analysed with the standard method of the laboratory at Sahlgrenska University Hospital.	Magnetoencephalography will be performed in patients at inclusion and after 15 months, in controls at inclusion. Blood and cerebrospinal fluid will be drawn at inclusion.
Secondary	Thyroid autoantibodies will be compared in patients without changed hippocampal neuronal activation compared to controls, and in controls.	Magnetoencephalography will be performed in a subset of patients and in healthy controls. Combined with magneto resonance imaging (MRI), magnetoencephalography gives information on neuronal activation by measuring alfa- and theta-band oscillations during attention testing. Thyroid autoantibodies analysed with the standard method of the laboratory at Sahlgrenska University Hospital.	Magnetoencephalography will be performed in patients at inclusion and after 15 months, in controls at inclusion. Blood and cerebrospinal fluid will be drawn at inclusion.