Repeat Immunoadsorption Post Covid ME/CFS

NCT ID: NCT05629988

Last Updated: 2025-05-31

Basic Information

• Recruitment Status: COMPLETED
• Total Enrollment: 20 participants
• Study Classification: OBSERVATIONAL
• Study Start Date: 2022-08-28
• Study Completion Date: 2025-03-31

Brief Summary

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

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.

Conditions

Post-COVID ME/CFS

Study Design

• Observational Model Type: COHORT
• Study Time Perspective: PROSPECTIVE

Interventions

IA with TheraSorb ® column

IA cycle is 5 days, repeat cycles will be given to responders at months 3 and 6

Intervention Type: DEVICE

Eligibility Criteria

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

• Minimum Eligible Age: 18 Years
• Maximum Eligible Age: 65 Years
• Eligible Sex: ALL
• Accepts Healthy Volunteers: No

Sponsors

Charite University, Berlin, Germany

OTHER

Sponsor Role: lead

Responsible Party

Carmen Scheibenbogen

Director of the Institute for Medical Immunology

Responsibility Role: PRINCIPAL_INVESTIGATOR

Locations

Charité - Universitätsmedizin Berlin

Berlin, State of Berlin, Germany

Countries

Germany

References

Kedor C, Freitag H, Meyer-Arndt L, Wittke K, Hanitsch LG, Zoller T, Steinbeis F, Haffke M, Rudolf G, Heidecker B, Bobbert T, Spranger J, Volk HD, Skurk C, Konietschke F, Paul F, Behrends U, Bellmann-Strobl J, Scheibenbogen C. A prospective observational study of post-COVID-19 chronic fatigue syndrome following the first pandemic wave in Germany and biomarkers associated with symptom severity. Nat Commun. 2022 Aug 30;13(1):5104. doi: 10.1038/s41467-022-32507-6.

Reference Type: BACKGROUND

PMID: 36042189 (View on PubMed)

Sotzny F, Blanco J, Capelli E, Castro-Marrero J, Steiner S, Murovska M, Scheibenbogen C; European Network on ME/CFS (EUROMENE). Myalgic Encephalomyelitis/Chronic Fatigue Syndrome - Evidence for an autoimmune disease. Autoimmun Rev. 2018 Jun;17(6):601-609. doi: 10.1016/j.autrev.2018.01.009. Epub 2018 Apr 7.

Reference Type: BACKGROUND

PMID: 29635081 (View on PubMed)

Freitag H, Szklarski M, Lorenz S, Sotzny F, Bauer S, Philippe A, Kedor C, Grabowski P, Lange T, Riemekasten G, Heidecke H, Scheibenbogen C. Autoantibodies to Vasoregulative G-Protein-Coupled Receptors Correlate with Symptom Severity, Autonomic Dysfunction and Disability in Myalgic Encephalomyelitis/Chronic Fatigue Syndrome. J Clin Med. 2021 Aug 19;10(16):3675. doi: 10.3390/jcm10163675.

Reference Type: BACKGROUND

PMID: 34441971 (View on PubMed)

Scheibenbogen C, Loebel M, Freitag H, Krueger A, Bauer S, Antelmann M, Doehner W, Scherbakov N, Heidecke H, Reinke P, Volk HD, Grabowski P. Immunoadsorption to remove ss2 adrenergic receptor antibodies in Chronic Fatigue Syndrome CFS/ME. PLoS One. 2018 Mar 15;13(3):e0193672. doi: 10.1371/journal.pone.0193672. eCollection 2018.

Reference Type: BACKGROUND

PMID: 29543914 (View on PubMed)

Tolle M, Freitag H, Antelmann M, Hartwig J, Schuchardt M, van der Giet M, Eckardt KU, Grabowski P, Scheibenbogen C. Myalgic Encephalomyelitis/Chronic Fatigue Syndrome: Efficacy of Repeat Immunoadsorption. J Clin Med. 2020 Jul 30;9(8):2443. doi: 10.3390/jcm9082443.

Reference Type: BACKGROUND

PMID: 32751659 (View on PubMed)

Stein E, Heindrich C, Wittke K, Kedor C, Kim L, Freitag H, Kruger A, Tolle M, Scheibenbogen C. Observational Study of Repeat Immunoadsorption (RIA) in Post-COVID ME/CFS Patients with Elevated ss2-Adrenergic Receptor Autoantibodies-An Interim Report. J Clin Med. 2023 Oct 9;12(19):6428. doi: 10.3390/jcm12196428.

Reference Type: DERIVED

PMID: 37835071 (View on PubMed)

Other Identifiers

01EP2201

Identifier Type: OTHER_GRANT

Identifier Source: secondary_id

IAINPCS

Identifier Type: -

Identifier Source: org_study_id