Immunoglobulin Deficiency a Treatable Cause of Fatigue in Patients With Multiple Sclerosis (MS)? (FatIgG)

Immunoglobulin Deficiency a Treatable Cause of Fatigue in Patients With Multiple Sclerosis (MS)? - A Prospective Observational Fatigue Trial

The investigators hypothesize that hypogammaglobulinemia (defined as IgG serum concentration <7.0g/L) is a treatable cause of fatigue in people with MS:

The primary objective is to prove the link between hypogammaglobulinemia and fatigue in patients with multiple sclerosis.

The secondary objective is to show that fatigue is mediated via frequent infections in people with MS and hypogammaglobulinemia.

Study Overview

• Status: Recruiting
• Conditions: Multiple Sclerosis; Fatigue; Hypogammaglobulinemia
• Intervention / Treatment: Diagnostic test: Laboratory test

Detailed Description

Multiple sclerosis (MS) is the most common cause of mental and physical disability in young adults affecting approximately 10'000-15'000 persons in Switzerland (incidence 16/100000; prevalence 190/100000). MS-fatigue affects at least 75% of the MS-patients (affected persons in Switzerland 7500-11250). MS-related fatigue has socioeconomic consequences leading to increased sick leaves and a higher probability of unemployment. Effective treatment strategies for MS-fatigue are missing, despite the appearance of more effective immunotherapies to treat autoimmune neuroinflammation and to control MS disease activity. The reason for the lack of therapeutic options is the unclear pathophysiological mechanism of fatigue with many non-MS associated influencing factors like thyroid dysfunction and anaemia.

Fatigue is also present in other inflammatory diseases, cancers and immunodeficiency syndromes. Regarding the latter patients with primary immunodeficiencies (PIDs) and common variable immunodeficiency (CVID) suffer from fatigue in 30 - 76%, which is more common than in the normal population. Studies investigating immunoglobulin replacement therapy in patients with CVID demonstrated a correlation between the frequency of infusions / s.c. applications and wear-off effect/fatigue.

Immunoglobulin deficiency seems to be much more common in people with autoimmune diseases. In MS reduced serum immunglobulin G (IgG) concentrations regardless of immunotherapy affect between 8 - 26% of the patients. Nonetheless consequences of IgG hypogammaglobulinemia in MS are partly unknown. However, based on the findings in patients with CVID, fatigue might be one of them. To close this knowledge gap prospective observational studies are needed.

• Study Type: Observational
• Enrollment (Estimated): 106

Contacts and Locations

• Study Contact: Name: Lara Diem, MD; Phone Number: 0041316327000; Email: larafrancesca.diem@insel.ch

Study Locations

• Switzerland
  • BE
    • Bern, BE, Switzerland, 3010
      • Recruiting
      • University Hospital of Bern Inselspital
      • Contact: Lara Diem, MD; Phone Number: 0041316327000; Email: larafrancesca.diem@insel.ch

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years to 65 years (Adult, Older Adult)
• Accepts Healthy Volunteers: No

• Sampling Method: Probability Sample

Study Population

Multiple Sclerosis Patients

Description

Inclusion Criteria:

• Diagnosis of Multiple Sclerosis following McDonald 2017-Criteria
• Age 18-65 years
• Stable MS disease at inclusion (definition: no clinical relapse, no MRI activity, stable disability within the last 12 months)
• Unchanged immunotherapy within the last 12 months
• Expanded Disability Status Scale (EDSS) level <4 points indicating fully ambulatory patients.
• Capability of written informed consent

Exclusion Criteria:

• Severe depression (definition: Beck Depression Index-II (BDI-II) ≥29 points) or other established psychiatric diagnosis
• Immunodeficiency other than hypogammaglobulinemia
• Immunglobulin replacement therapy or indication for immunoglobulin replacement therapy
• Severe Sleepiness (definition: Epworth-Sleepiness-Scale (ESS) >16 points)
• Fatigue aggravating factors such: liver/renal/thyroid dysfunction, substance abuse, medication (tranquilizers /antiepileptics/psychopharmaceuticals), chronic infectious disease (like hepatitis/HIV).
• Other neurodegenerative/autoimmune disease.
• Patients not able to give written consent
• Vulnerable patients such as children, pregnant women and prisoners

Study Plan

How is the study designed?

Design Details

• Observational Models: Cohort
• Time Perspectives: Prospective

Number of groups / cohorts

2

Cohorts and Interventions

Group / Cohort	Intervention / Treatment
MS patients with IgG deficiency (serum IgG-concentration <7g/L).	Diagnostic test: Laboratory test; Frequency of fatigue (defined as Fatigue Scala for Motor and Cognitive Function (FSMC) total ≥ 43 points) in MS patients with IgG-deficiency; Other Names: Fatigue Score
MS patients with normal IgG serum concentration (serum IgG-concentration ≥7g/L).	Diagnostic test: Laboratory test; Frequency of fatigue (defined as Fatigue Scala for Motor and Cognitive Function (FSMC) total ≥ 43 points) in MS patients with IgG-deficiency; Other Names: Fatigue Score

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Number of patients with fatigue and hypogammaglobulinemia	The primary endpoint will be measured as frequency (%) of fatigue (defined as Fatigue Scala for Motor and Cognitive Function (FSMC) total ≥ 43 points) in MS patients with IgG-deficiency (IgG serum concentration <7.0 g/L) compared to those with normal IgG-serum concentration (≥ 7.0 g/L). The FSMC is an assessment of MS-related cognitive and motor fatigue. A Likert-type 5-point scale (ranging from 'does not apply at all' to 'applies completely') produces a score between 1 and 5 for each scored question. Thus minimum value is 20 (no fatigue at all) and maximum value is 100 (severest grade of fatigue) FSMC Sum Score: ≥ 43 points mild fatigue, ≥ 53 points moderate fatigue, ≥ 63 severe fatigue	1.5 years
Number of patients with fatigue without hypogammaglobulinemia	The primary endpoint will be measured as frequency (%) of fatigue (defined as Fatigue Scala for Motor and Cognitive Function (FSMC) total ≥ 43 points) in MS patients with IgG-deficiency (IgG serum concentration <7.0 g/L) compared to those with normal IgG-serum concentration (≥ 7.0 g/L). The FSMC is an assessment of MS-related cognitive and motor fatigue. A Likert-type 5-point scale (ranging from 'does not apply at all' to 'applies completely') produces a score between 1 and 5 for each scored question. Thus minimum value is 20 (no fatigue at all) and maximum value is 100 (severest grade of fatigue) FSMC Sum Score: ≥ 43 points mild fatigue, ≥ 53 points moderate fatigue, ≥ 63 severe fatigue	1.5 years

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Fatigue and infections	As secondary endpoint the frequency of infections (infection/months) in MS patients will be measured and compared between those with (IgG serum concentration <7.0 g/L) and without hypogammaglobulinemia (IgG serum concentration ≥ 7.0 g/L). Furthermore, the mediation of fatigue by "frequency of infections*" will be detailed in the cohort of MS patients with hypogammaglobulinemia. *A telephone interview with 6 questions about the frequency of infections will take place once a month.	1.5 years

Collaborators and Investigators

• Sponsor: Insel Gruppe AG, University Hospital Bern
• Investigators: Principal Investigator: Lara Diem, MD, Inselspital University Hospital of Bern

Study record dates

Study Major Dates

• Study Start (Actual): July 1, 2022
• Primary Completion (Estimated): December 30, 2026
• Study Completion (Estimated): December 30, 2026

Study Registration Dates

• First Submitted: April 19, 2022
• First Submitted That Met QC Criteria: April 27, 2022
• First Posted (Actual): May 3, 2022

Study Record Updates

• Last Update Posted (Actual): December 19, 2023
• Last Update Submitted That Met QC Criteria: December 12, 2023
• Last Verified: December 1, 2023

More Information

Terms related to this study

• Keywords: Fatigue; Hypogammaglobulinemia
• Additional Relevant MeSH Terms: Pathologic Processes; Nervous System Diseases; Immunologic Deficiency Syndromes; Immune System Diseases; Lymphoproliferative Disorders; Lymphatic Diseases; Demyelinating Autoimmune Diseases, CNS; Autoimmune Diseases of the Nervous System; Demyelinating Diseases; Autoimmune Diseases; Hematologic Diseases; Blood Protein Disorders; Multiple Sclerosis; Sclerosis; Fatigue; Agammaglobulinemia
• Other Study ID Numbers: 2021-02372

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: NO

Drug and device information, study documents

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