CD19-B Cell Depletion in PAIS-ME/CFS Patients (PIONEER_PAIS)

Prospective, Randomized, Double-blind, Placebo-controlled Phase 2b Trial Evaluating the Efficacy and Safety of the Anti-CD19 Monoclonal Antibody Inebilizumab Compared With Placebo in Patients With Post-acute Infection Syndromes Fulfilling ME/CFS Criteria (PIONEER)

Post-acute infection syndromes (PAIS) are long-lasting health problems that can develop after an infection. They include post-COVID-19 syndrome and similar illnesses following other infections. Some people with PAIS develop myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS), a serious and disabling illness that can greatly limit everyday activities. People with ME/CFS may experience severe fatigue, reduced physical and mental function, pain, sleep problems, and problems with the regulation of heart rate and blood pressure. A key feature is post-exertional malaise (PEM), in which symptoms become worse after physical or mental activity. The biological causes of PAIS and ME/CFS are not fully understood, and there is currently no established treatment that targets the underlying disease process.

Research suggests that changes in the immune system may contribute to PAIS and ME/CFS in some patients. In particular, B cells (a type of immune cell) and autoantibodies (antibodies that react with the body's own structures) may play a role. Previous studies of immunoadsorption, a procedure that removes antibodies from the blood, have shown improvements in some patients with ME/CFS. These findings support further investigation of treatments that target B cells in selected patients.

The PIONEER_PAIS study will investigate whether inebilizumab can improve physical function in adults with PAIS who meet the diagnostic criteria for ME/CFS. The study includes a selected group of patients with evidence of autoantibodies and immune activation who previously improved after immunoadsorption but later experienced worsening of their symptoms. Inebilizumab is a monoclonal antibody that targets CD19, a protein found on B cells, and leads to the depletion of these cells.

Participants will be randomly assigned to receive either inebilizumab or placebo (saline solution) as an infusion into a vein. Inebilizumab will be given at a dose of 300 mg on Day 1, Day 15, and Week 24. The study is double-blind, meaning that neither the participants nor the study team assessing them will know which treatment they receive.

The main research question is whether treatment with inebilizumab leads to a greater improvement in physical function (PF) than placebo. PF will be measured using the PF scale of the SF-36 health questionnaire, comparing the change from the start of the study to Month 9 (Week 36).

The study will also examine other aspects of health and daily functioning, including fatigue, post-exertional malaise, pain and headache, disability, symptoms related to the autonomic nervous system, muscle strength and fatigability, heart rate and blood pressure responses during standing, daily step count, and cognitive function. Adverse events will be monitored to assess the safety of the treatment. In addition, the study includes biomarker research focusing on B cells, autoantibodies, and other markers in the blood.

This research aims to explore biological characteristics that may be associated with response to treatment and may help inform future studies of B-cell-targeted treatment in PAIS and ME/CFS.

Study Overview

• Status: Not yet recruiting
• Conditions: Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS); Post-acute Infectious Syndrome (PAIS); Post-COVID 19 Condition (PCC or Long COVID)
• Intervention / Treatment: Drug: Inebilizumab; Drug: Placebo

Detailed Description

Post-acute infection syndromes (PAIS) comprise persistent health problems that develop following an acute infection. The term encompasses post-COVID-19 condition (PCS) as well as post-infectious syndromes associated with other infectious triggers. A subset of patients with PAIS fulfils the Canadian Consensus Criteria (CCC) for myalgic encephalomyelitis/ chronic fatigue syndrome (ME/CFS), a chronic and disabling condition characterized by impaired physical and cognitive function and a range of other symptoms. Post-exertional malaise (PEM), defined by worsening of symptoms following physical or cognitive exertion, is a central feature of ME/CFS.

Despite the substantial clinical burden associated with PAIS and ME/CFS, their underlying pathophysiological mechanisms remain incompletely understood, and no established treatment targeting the underlying disease process is available. Increasing evidence supports the hypothesis that immune dysregulation contributes to disease mechanisms in at least a subset of affected patients. Proposed mechanisms include B-cell dysregulation, autoimmune responses, and the production of autoantibodies, including autoantibodies directed against G-protein-coupled receptors. Associations between such autoantibodies, symptom severity, autonomic dysfunction, disability, and alterations of the central nervous system have been reported.

The scientific rationale for PIONEER is further supported by previous therapeutic studies targeting antibodies or B cells. Immunoadsorption, which reduces circulating immunoglobulins, has been associated with clinical improvement in subsets of patients with ME/CFS and elevated β2-adrenergic receptor autoantibodies. Previous studies of B-cell depletion with rituximab have produced mixed results: responses were observed in earlier studies, whereas efficacy was not confirmed in a subsequent multicenter trial. These findings, together with the heterogeneity of ME/CFS, provide a rationale for evaluating B-cell-targeted therapy in a more specifically characterized population selected for features consistent with autoantibody-associated or B-cell-mediated disease.

PIONEER evaluates inebilizumab, a humanized monoclonal antibody directed against CD19. Binding of inebilizumab to CD19-positive B cells results in their depletion. In contrast to therapies directed against CD20, CD19 targeting affects a broader range of B-cell subsets, including early B cells and plasmablasts. Inebilizumab is approved for the treatment of aquaporin-4 immunoglobulin G antibody-positive neuromyelitis optica spectrum disorder (NMOSD). However, it has not previously been investigated as a treatment for PAIS-associated ME/CFS.

PIONEER is a prospective, randomized, double-blind, placebo-controlled, parallel-group Phase 2b trial designed to assess the efficacy and safety of inebilizumab in a selected subgroup of adults with PAIS-associated ME/CFS. The trial plans to randomize 38 participants to treatment with either inebilizumab or saline placebo. Inebilizumab is administered intravenously at a dose of 300 mg on Day 1, Day 15, and Week 24. The dose and administration schedule are based on the established dosing regimen for NMOSD. The placebo-controlled and double-blind design is intended to allow an unbiased comparison of treatment effects and safety outcomes.

The study population is selected to address the hypothesis that B-cell depletion may be beneficial in a subgroup of patients with evidence consistent with autoantibody-associated or B-cell-mediated disease. Participants must have PAIS and meet the CCC for ME/CFS, including PEM lasting more than 14 hours. They must have evidence of elevated β2-adrenergic receptor autoantibodies and a pro-inflammatory immune cell status. In addition, participants must previously have received immunoadsorption in an immunoadsorption study at least 6 months before inclusion in PIONEER and have shown a documented clinical response, defined as an increase of at least 10 points in SF-36-PF at Week 8, followed by subsequent worsening of at least 10 points persisting for at least 3 months. This selection approach is intended to investigate the effect of CD19-targeted B-cell depletion in a clinically and immunologically characterized population.

The primary objective is to determine whether inebilizumab improves physical function compared with placebo. The primary endpoint is the intra-participant change in SF-36-PF score from baseline to Month 9 (Week 36), comparing the mean change between the inebilizumab and placebo groups.

Secondary efficacy assessments evaluate both the magnitude and breadth of potential treatment effects. A responder analysis will compare the proportion of participants achieving an increase of at least 20 points in SF-36-PF from baseline to Week 36. Further assessments examine changes in other SF-36 domains and improvement in other patient reported outcome measures (Bell disability score, CCC symptom score, COMPASS-31, Fatigue severity scale, PEM etc.). Objective and activity-related assessments complement the patient-reported outcomes and include: i) repetitive hand-grip testing to evaluate changes in hand-grip force, fatigability, and recovery, ii) NASA 10-minute Lean Test to assess changes in blood pressure and heart rate regulation during passive standing, and iii) daily step count as a measure of activity in everyday life. Safety is evaluated through the occurrence of adverse events, serious adverse events, and suspected unexpected serious adverse reactions.

A comprehensive biomarker program accompanies the clinical trial. The analyses focus on B cells, autoantibodies, and soluble markers and are intended to explore biological characteristics associated with response to anti-CD19 treatment. By combining a randomized, double-blind, placebo-controlled clinical evaluation with biomarker analyses, PIONEER is designed to examine both the clinical effects of CD19-targeted B-cell depletion and biological characteristics that may be associated with treatment response.

The resulting clinical and biomarker data are intended to provide a basis for the design of subsequent confirmatory studies and for further evaluation of biomarkers that may help characterize treatment response in autoimmune-associated post-infectious ME/CFS.

• Study Type: Interventional
• Enrollment (Estimated): 38
• Phase: Phase 2

Contacts and Locations

• Study Contact: Name: Judith Bellmann-Strobl, MD; Phone Number: +49 30 450 540258; Email: judith.bellmann-strobl@charite.de

Study Locations

• Germany
  • Berlin, Germany, 10117
    • Charité - Universitätsmedizin Berlin
    • Contact: Judith Bellmann-Strobl, MD; Phone Number: +49 30 450 540660; Email: judith.bellmann-strobl@charite.de
    • Principal Investigator: Judith Bellmann-Strobl, MD

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: Adult; Older Adult
• Accepts Healthy Volunteers: No

Description

Inclusion Criteria:

• Male/female/diverse adults who are 18-65 years old at time of enrollment
• Subject is able and willing to give informed consent
• Signed informed consent prior to initiation of any trial related measure
• Diagnosis of PAIS as defined by WHO for PCS, wi th other infectious triggers
• Diagnosis of ME/CFS according to CCC criteria with PEM > 14 hours = PAIS/CFS
• Detection of autoantibodies (elevated ß2R adrenergic AAB) prior to immunoadsorption or prior to inclusion to PIONEER
• Pre-treatment with immunoadsorption in the immunoadsorption studies at least 6 months before study inclusion
• Documented clinical response to immunoadsorption (minimum increase in SF-36 PF of 10 points at week 8) followed by consecutive worsening of symptoms (minimum decrease in SF-36 PF of 10 points for at least 3 months)
• Evidence of activated pro inflammatory immune cell status
• Bell score at screening visit: 30-60
• Normal thyroid function or sufficiently medicated dysfunction

• For women of childbearing potential (WOCBP):

  1. Confirmed post-menopausal state, defined as amenorrhea for at least 12 months, or
  2. If being of childbearing potential: Negative highly sensitive urine or serum pregnancy test before randomization, and practicing a highly effective birth control method (failure rate of less than 1%)

Exclusion Criteria:

• Contraindication against IMP or AMP
• Hypersensitivity to the active substance or any of the other ingredients
• Vaccination less or up to 4 weeks before first visit
• Immunomodulative therapy < 3 month before screening visit
• Concomitant and previous use of IMP
• Known SARS-CoV-2 or other infection related organ damage/comorbidity
• Pre-infection history of chronic fatigue syndrome or other fatigue syndromes that are due to associated diseases (e.g., cancer, autoimmune diseases [patients with a preexcisting Hashimoto thyroiditis and/or fibromyalgia without fatigue syndromes can be included])
• Serious infections, including active or latent and chronic infections such as tuberculosis, HIV, Lues, hepatitis B and C
• Immune- and immunoglobulin-deficiency or severely immunocompromised condition
• Any other severe or unstable medical conditions (immune, cardiovascular, respiratory, endocrine, gastrointestinal, hematological, neurological, psychiatric, systemic) or any other condition deemed by the Investigator to pose unacceptable risk, interfere with IP evaluation, or confound study results.
• At screening : aspartate transaminase (AST) > 2.5 × upper limit of normal (ULN), alanine transaminase (ALT) > 2.5 × ULN, total bilirubin > 1.5 × ULN (unless due to Gilbert's syndrome), platelet count < 75,000/µL, hemoglobin < 8 g/dL, eGFR<30 mL/min/1.73 m², total immunoglobulin < 900 mg/dL, absolute neutrophil count < 1200 cells/µL, CD4 T lymphocyte count < 300 cells/µL
• Concomitant diseases or health constellations causing general physical weakness or fatigue, like: i) renal insufficiency with eGR< 15 or diyalsis, ii) impaired liver function with elevated liver enzymes a) Aspartate aminotransferase (AST) and b) Alanin-Aminotransferase (ALT), both >35 U/l for women or > 50 U/l for men, iii) anemia with low hemoglobin-concentrations <13,0 g/dL for males and <12,0 g/dL for females, and iv) adipositas grades II or higher (BMI: ≥ 35 kg/m 2) at screening
• Subject is pregnant or breastfeeding
• Subject is institutionalized by order of court or public authority
• Subject who might be dependent on the sponsor, the investigator, or the trial site
• Participation in another clinical trial with a medical device or an investigational medicinal product within 3 Months or 5 half-lives (whichever is longer) before screening visit

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Quadruple

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Active Comparator: Inebilizumab (Uplizna®); Tested IMP: Inebilizumab (Uplizna®), an anti-CD19 monoclonal antibody. Authorization status: Not authorized for the targeted indication; inebilizumab is authorized for the treatment of neuromyelitis optica spectrum disorder (NMOSD) in adults who are AQP4-IgG seropositive. Inebilizumab used in this trial is a commercially available medicinal product manufactured by Amgen Europe B.V., with marketing authorization number EU/1/21/1602/001. Administration: The treatment period comprises three intravenous administrations of 300 mg inebilizumab: on Day 1, Day 15, and after 6 months, followed by a 3-months follow-up period. Each infusion will be preceded by methylprednisolone 125 mg and dimetindene maleate 4 mg administered intravenously in 100 ml of 0.9% sodium chloride solution, and paracetamol 500 mg administered orally, to reduce the risk of infusion-related reactions (premedication). The dosing regimen follows the authorized regimen for AQP4-IgG-seropositive NMOSD.	Drug: Inebilizumab; The treatment period comprises three intravenous administrations of 300 mg inebilizumab: on Day 1, Day 15, and after 6 months, followed by a 3-months follow-up period. Each infusion will be preceded by a premediaction (methylprednisolone 125 mg, dimetindene maleate 4 mg, and paracetamol 500 mg) to reduce the risk of infusion-related reactions.; Other Names: Anti-CD19 monoclonal antibody
Placebo Comparator: Placebo; Comparator IMP: Saline solution (0.9% sodium chloride solution) for intravenous infusion. Authorization status: Saline solution is routinely used in clinical practice; it is used as a placebo comparator in this trial and has no expected therapeutic effect on PAIS or ME/CFS. Administration: The treatment period comprises three intravenous placebo administrations: on Day 1, Day 15, and after 6 months, followed by a 3-month follow-up period. To maintain blinding, each placebo infusion is preceded by the same premedication as the inebilizumab infusion: methylprednisolone 125 mg and dimetindene maleate 4 mg administered intravenously in 100 ml of 0.9% sodium chloride solution, and paracetamol 500 mg administered orally.	Drug: Placebo; The treatment period comprises three intravenous placebo administrations: on Day 1, Day 15, and after 6 months, followed by a 3-month follow-up period. To maintain blinding, each placebo infusion is preceded by the same premedication (methylprednisolone 125 mg, dimetindene maleate 4 mg, and paracetamol 500 mg) as the inebilizumab infusion.; Other Names: Saline solution (0.9% sodium chloride solution)

What is the study measuring?

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) comparing Inebilizumab with placebo	The SF-36 is an established and widely used measure of health-related quality of life. The PF domain assesses limitations in ten activities related to mobility and self-care, such as walking specified distances, carrying groceries, bathing, and dressing. Scores are weighted and transformed to a scale ranging from 0 (severe functional limitations) to 100 (no functional limitations). The intra-patient change in SF-36 PF will be assessed from baseline to month 9 (week 36).	9 months (36 weeks) after first IMP administration

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Difference in responder rate in Physical Function (PF) as measured by the Short Form 36 Health Survey Questionnaire (SF-36) comparing Inebilizumab with placebo	Occurrence of responders in patients that receive Vericiguat compared with placebo. Responders are defined as an intra-patient 20-point increase in SF-36-PF from baseline to month 9 (week 36).	9 months (36 weeks) after first IMP administration
Improvement in other sub-domains of the Short Form 36 Health Survey Questionnaire (SF-36) comparing Inebilizumab with placebo	The intra-patient change in other SF-36 subdomains will be assessed from baseline to month 9 (week 36).	9 months (36 weeks) after first IMP administration
Improvement in severity of muscle pain and headache as measured by the Canadian Consensus Criteria (CCC) Symptom Score	The CCC Symptom Score quantifies ME/CFS symptoms. Its score ranges from 1 (no symptoms) to 10 (extreme symptoms). The intra-patient change in muscle pain and headache will be assessed from baseline to month 9 (week 36).	9 months (36 weeks) after first IMP administration
Improvement in symptoms of ME/CFS as measured by Canadian Consensus Criteria (CCC) Symptom Score	The intra-patient change in ME/CFS symptoms will be assessed from baseline to month 9 (week 36) as indexed by the CCC Symptom Score.	9 months (36 weeks) after first IMP administration
Improvement in functional disability as measured by the Bell Disability Scale	The Bell Disability Scale is a standard assessment tool used to evaluate functional ability in adults with ME/CFS. It comprises 11 statements describing the patient's functional status, including symptom severity at rest and during activity, overall activity level, and the ability to work, travel, and perform self-care activities. Scores range from 0 (bedridden) to 100 (no symptoms and fully functional). The intra-patient change in Bell score will be assessed from baseline to month 9 (week 36).	9 months (36 weeks) after first IMP administration
Improvement in symptoms of autonomic dysfunction as measured by the Composite Autonomic Symptom Score (COMPASS-31)	The 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). The intra-patient change in autonomic dysfunction will be assessed from baseline to month 9 (week 36).	9 months (36 weeks) after first IMP administration
Improvement in fatigue as measured by the Fatigue Severity Score (FSS)	The 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). The intra-patient change in fatigue severity will be assessed from baseline to month 9 (week 36).	9 months (36 weeks) after first IMP administration
Improvement in post exertional malaise (PEM) frequency, strength and severity as measured by the PEM questionnaire	The PEM questionnaire determines frequency (from 0 to 20 points, higher scores equate to greater frequency), severity (from 0 to 20 points, higher scores equate to greater severity), and length (from 0 to 6 points, higher scores equate to longer duration) of PEM. The intra-patient change in PEM score will be assessed from baseline to month 9 (week 36).	9 months (36 weeks) after first IMP administration
Improvement in muscle fatigue measured by the repetitive hand grip strength test (HGS)	The intra-patient change in hand grip force (maximum, mean), fatigue ratio and recovery rate will be assessed from baseline to month 9 (week 36).	9 months (36 weeks) after first IMP administration
Improvement in cognitive function measured by the Symbol Digit Modalities Test (SDMT)	The Symbol Digit Modalities Test (SDMT) is a screening instrument commonly used to assess neurological dysfunction. It detects cognitive impairment as well as changes in cognitive functioning over time and in response to treatment. The scores range between 0 and 110 (higher scores equate to greater cognitive functioning). The intra-patient change in cognitive score will be assessed from baseline to month 9 (week 36).	9 months (36 weeks) after first IMP administration
Difference in the occurrence of occurring Adverse Events (AE) and Serious Adverse Events (SAE) comparing Inebilizumab with placebo (IMP safety).	Occurrence of IMP side and adverse effects, assessed with AE, SAE and SUSAR reports.	1 day, 15 days, 3 months, 6 months, and 9 months (36 weeks) after first IMP administration

Collaborators and Investigators

• Sponsor: Charite University, Berlin, Germany
• Investigators: Principal Investigator: Judith Bellmann-Strobl, MD, Charité - Universitätsmedizin Berlin, Berlin, Germany 10117

Study record dates

Study Major Dates

• Study Start (Estimated): December 1, 2026
• Primary Completion (Estimated): February 1, 2029
• Study Completion (Estimated): March 1, 2029

Study Registration Dates

• First Submitted: July 21, 2026
• First Submitted That Met QC Criteria: July 21, 2026
• First Posted (Actual): July 24, 2026

Study Record Updates

• Last Update Posted (Actual): July 24, 2026
• Last Update Submitted That Met QC Criteria: July 21, 2026
• Last Verified: July 1, 2026

More Information

Terms related to this study

• Keywords: Fatigue; Long COVID; ME/CFS; PAIS
• Additional Relevant MeSH Terms: Neuroinflammatory Diseases; Post-Infectious Disorders; COVID-19; Musculoskeletal Diseases; Nervous System Diseases; Muscular Diseases; Pathologic Processes; Encephalomyelitis; Neuromuscular Diseases; Chronic Disease; Disease Attributes; Genetic Diseases, Inborn; Respiratory Tract Infections; Infections; RNA Virus Infections; Virus Diseases; Respiratory Tract Diseases; Lung Diseases; Hematologic Diseases; Pneumonia, Viral; Pneumonia; Coronavirus Infections; Coronaviridae Infections; Nidovirales Infections; Blood Coagulation Disorders; Hemorrhagic Disorders; Genetic Diseases, X-Linked; Blood Coagulation Disorders, Inherited; Coagulation Protein Disorders; Congenital, Hereditary, and Neonatal Diseases and Abnormalities; Pathological Conditions, Signs and Symptoms; Signs and Symptoms; Hemic and Lymphatic Diseases; Post-Acute COVID-19 Syndrome; Fatigue Syndrome, Chronic; Fatigue; Hemophilia B; Pharmaceutical Preparations; Inorganic Chemicals; Chlorine Compounds; Crystalloid Solutions; Isotonic Solutions; Solutions; Sodium Compounds; Chlorides; Hydrochloric Acid; Saline Solution; Sodium Chloride; inebilizumab
• Other Study ID Numbers: PIONEER_PAIS

Drug and device information, study documents

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