Repeat Immunoadsorption Post Covid ME/CFS

Study Overview
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Brief Summary
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The evidence for an autoimmune etiology in postinfectious myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) is growing. The investigators observed in a not yet published study that in ME/CFS triggered by COVID, similar to ME/CFS after other infections, there is a close correlation of ß2 adrenergic receptor (ß2R) autoantibodies with symptom severity. Immunoadsorption (IA) to remove autoantibodies has been used successfully in many autoantibody-mediated diseases. The investigators have already performed two proof of concept studies of IA in postinfectious ME/CFS with elevated ß2R antibodies, which resulted in improvement in most patients. This observational study aims to assess symptom outcome and functional ability in 20 patients with Post-COVID Syndrome (PCS) meeting ME/CFS diagnostic criteria with elevated ß2R antibodies undergoing antibody depletion by IA. The study will be conducted as a non-interventional observational study. IA with Miltenyi's TheraSorb® column in PCS will be performed in the approved use. Patients who have symptom improvement after the 1st IA will receive two additional IAs at 3 and 6 months, which will also be documented. The results of this observational study will provide the basis for a randomized controlled clinical trial (RCT) combining IA with B-cell depletion therapy preferentially with Obinutuzumab.

Detailed Description
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Studies indicate an overlap between post-COVID syndrome (PCS) and ME/CFS (Kedor et al., 2022). Post-infectious ME/CFS (ICD-10 code G93.3) is a complex and severely disabling disease with no approved treatment and thus, a very high medical need. Following an acute infection, patients suffer from severe central and muscle fatigue, chronic pain, cognitive impairment, and immune and autonomic dysfunction. The key symptom of ME/CFS is exertion intolerance with minor exertion resulting in symptom aggravation, also called post-exertional malaise (PEM), lasting until the next day up to weeks. Various pathogens are known to induce post-infectious ME/CFS, including the Epstein-Barr virus and SARS-CoV-2 (Sotzny, 2018). The investigators' ongoing Charité PA-COVID study (Berlin prospective COVID-19 patient cohort) and other reports show that SARS-CoV-2 triggers ME/CFS in a subset of mostly younger patients without preexisting comorbidities (Kedor et al., 2022). Due to the rapid increase of COVID-19 incidence worldwide, the prevalence of post-COVID-19 ME/CFS will likely be a substantial problem for health care and society. The evidence for an autoimmune etiology in post-infectious ME/CFS is growing (reviewed in Sotzny et al., 2018). Also, COVID-19 is a disease with a high risk for autoimmunity and developing ME/CFS due to the infection of many different cell types and the severity of immune activation. There is evidence from several studies from the investigators and other groups that natural regulatory autoantibodies targeting G protein-coupled receptors (GPCR) are involved in the pathogenesis of various autoimmune diseases. The investigators and others described enhanced levels and dysfunction of ß2R autoantibodies in ME/CFS and their correlation with the severity of key clinical symptoms (Freitag et al., 2021). The investigators' working hypothesis is that GPCR-specific autoantibodies with altered binding affinity or epitope specificity lead to immune dysregulation and autonomous dysfunction, and play a significant role in the pathomechanism of ME/CFS (Wirth et al., 2020). The investigators observed -- in a not yet published study -- a close correlation of ß2R antibodies with symptom severity in ME/CFS after COVID, similar to ME/CFS after other infections (Freitag et al., 2021). Two small proof-of-concept studies with immunoadsorption (IA) in patients with ME/CFS after other infections have shown improvements in symptoms in most patients (Scheibenbogen et al., 2018; Toelle et al., 2020). In this observational non-controlled trial, PCS ME/CFS patients who receive IA will be evaluated for clinical efficacy, a decrease in autoantibodies, and a change of biomarkers. IA with Miltenyi's TheraSorb® column will be performed in the approved use. Patients who have symptom improvement after the 1st IA will receive two additional IAs at 3 and 6 months, which will also be documented. Symptom severity will be assessed by online questionnaires and at repeated time points. Patients will be recruited for IA from the investigators' ongoing observational study with a follow-up of at least six months without disease improvement (Kedor et al., 2022). Patients have received a comprehensive diagnostic assessment to exclude other diseases, central nervous system, or organ comorbidity. ß2R autoantibodies in serum are determined by ELISA (Celltrend). Within four weeks prior to IA, patients will be assessed for eligibility for study participation by clinical investigation, laboratory analysis, and symptom questionnaires. The first ten patients will be treated end of August - mid of October and analyzed for efficacy until the beginning of December 2022 with a grant from the Weidenhammer-Zoebele foundation. The subsequent ten patients will be treated and analyzed with funding from the Federal Ministry of Education and Research(BMBF). These ten patients will also receive vessel diagnostics before (within four weeks) and four weeks after the first IA. In all 20 patients, blood will be collected the week before and four weeks after the first IA. All visits and treatments will take place in outpatient clinics. Antibody depletion in PCS using IA has yet to be investigated in a clinical trial. The results of this observational study will provide the basis for a RCT using IA and, in responders, consecutive B-cell depleting therapy with an anti-CD20 monoclonal antibody versus placebo.

Official Title
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Observational Study of Repeat Immunoadsorption (RIA) in Post Covid ME/CFS Patients With Elevated ß2 Adrenergic Receptor Autoantibodies

Conditions
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Post-COVID ME/CFS

Intervention / Treatment
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* Device: IA with TheraSorb ® column


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Consenting patients aged 18-65 years with a diagnosis of Post-COVID ME/CFS according to the Canadian Consensus Criteria (CCC) or fulfilling CCC with exertion intolerance with symptom worsening (post exertional malaise = PEM) duration of less than 14 hours (thus fulfilling Institute of Medicine criteria) Evidence of COVID infection at disease onset (PCR) or N-IgG Detection of autoantibodies (elevated ß2 receptor adrenergic autoantibodies) Immunoadsorption with the TheraSorb® column for 5 days Health insurance Exclusion Criteria: Lack of willingness to store pseudonymized disease data as part of the study Pregnancy Other illnesses that do not allow the diagnosis of PCS to be made with certainty (e.g., heart failure, lung disease, severe depression, cancer) Acute infection (COVID, HIV, hepatitis) Severe fatigue disease with bedriddenness

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 65 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Arms and Interventions

| Intervention/Treatment |
| --- |
|Device: IA with TheraSorb ® column|IA cycle is 5 days, repeat cycles will be given to responders at months 3 and 6|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Improvement in Physical Function (PF) as measured by the Short Form 36 Health Survey Questionnaire (SF-36) | The Short Form 36 Health Survey (SF-36) is an established and widely used health-related quality of life measure. The Physical Function (PF) domain asks patients to report limitations on ten mobility activities, such as walking specified distances, carrying groceries, and bathing or dressing. Scores are weighted and transformed into a scale ranging from 0 (greatest possible health restrictions, i.e., severe disability) to 100 (no health restrictions). An intra-patient change of 10 points in SF-36-PF from baseline to week four is considered clinically meaningful. | 4 weeks after first IA | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Efficacy of repeat immunoadsorptions (IA) on Physical Function (PF) as measured by the Short Form 36 Health Survey Questionnaire (SF-36) | Patients who have meaningful improvements in PF after the first IA, will receive two additional IAs at 3 and 6 months. Enhanced efficacy of repeat IAs on PF as measured by the SF-36 will be documented and assessed. | 3 - 6 months after first IA | 
| Response duration of repeat immunoadsorptions (IA) on Physical Function (PF) as measured by the Short Form 36 Health Survey Questionnaire (SF-36) | Additive effect of repeat IA to increase response duration after each IA cycle. Response duration assessed by SF-36 PF (> 10 points). | 3 - 6 months after first IA | 
| Improvement in ability to work in daily hours | Number of patients with an intra-patient change in his/her/their ability to work in daily hours from 6 months before first IA to 12 months after last IA. | 12 months after last IA | 
| Improvement in physical and mental fatigue as measured by the Chalder Fatigue Scale | The Chalder Fatigue Scale measures the extent and severity of tiredness and has been used in multiple randomized trials of behavioral interventions in patients with ME/CFS. Each of the 11 items is answered on a 4-point scale with an overall score ranging from 0 (asymptomatic) to 33 (maximum symptomology). Intra-patient change in physical and mental fatigue from baseline to follow-up points will be documented as indexed by the Chalder Fatigue Scale. | 4 weeks after first IA; 6 and 12 months after last IA | 
| Improvement in fatigue as measured by the Fatigue Severity Score (FSS) | The Fatigue Severity Scale (FSS) is a 9-item scale that measures the severity of fatigue and its effect on a person's activities and lifestyle. Answers are scored on a seven-point scale (1 = strongly disagree; 7 = strongly agree). Thus, the minimum score is 9 (no fatigue), and the highest is 63 (heavy fatigue). Intra-patient change in fatigue severity from baseline to follow-up points will be documented as indexed by the FSS. | 4 weeks after first IA; 6 and 12 months after last IA | 
| Improvement in symptoms of myalgic encephalomyelitis (ME)/ chronic fatigue syndrome (CFS) as measured by Canadian Consensus Criteria (CCC) Symptom Score | The Canadian Consensus Criteria (CCC) Symptom Score quantifies ME/CFS symptoms. Its score ranges from 1 (no symptoms) to 10 (extreme symptoms). Intra-patient change in ME/CFS symptoms from baseline to follow-up points will be documented as indexed by the CCC Symptom Score. | 4 weeks after first IA; 6 and 12 months after last IA | 
| Improvement in symptoms of autonomic dysfunction as measured by the Composite Autonomic Symptom Score (COMPASS-31) | The Composite Autonomic Symptom Score (COMPASS-31) is a refined, internally consistent, and markedly abbreviated quantitative measure of autonomic symptoms. It is based on the original Autonomic Symptom Profile (ASP) and COMPASS, applies a much-simplified scoring algorithm, and is suitable for widespread use in autonomic research and practice. It evaluates six domains of autonomic function: orthostatic intolerance, vasomotor, secretomotor, gastrointestinal, bladder, and pupillomotor domains. The score ranges from 0 (no symptoms) to 100 (strong autonomic dysfunction). Intra-patient change in autonomic dysfunction from baseline to follow-up points will be documented as indexed by the COMPASS-31. | 4 weeks after first IA; 6 and 12 months after last IA | 
| Improvement in hand grip strength | Intra-patient change in hand grip strength from baseline to follow-up points assessed using the Handgrip-Muscle-Fatigue Test | 4 weeks after first IA; 6 and 12 months after last IA | 
| Improvement of vascular regulation as indexed by the reactive hyperemia index (RHI) assessed using Endopat. | Intra-patient change in endothelial cell function from baseline to follow-up points assessed using Endopat | 6 and 12 months after last IA | 
| Improvement in symptoms of orthostatic intolerance assessed using the Passive Standing Test | Intra-patient change in orthostatic intolerance from baseline to follow-up points assessed using the Passive Standing Test. | 4 weeks after first IA; 6 and 12 months after last IA | 
| Decrease in ß2R autoantibodies and soluble biomarkers of disease | Intra-patient change in ß2R autoantibodies and soluble biomarkers of disease from baseline to follow-up points assessed | 4 weeks after first IA; 6 and 12 months after last IA | 
| Verification of tolerability | Number of patients tolerating the IA treatment. | 4 weeks after last IA | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Post-COVID Syndrome, Long COVID, Chronic Fatigue Syndrome