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)
试验速览
- 阶段
- 2 期
- 状态
- 尚未招募
- 入组人数
- 38
- 试验地点
- 1
- 主要终点
- Improvement in Physical Function (PF) as measured by the Short Form 36 Health Survey Questionnaire (SF-36) comparing Inebilizumab with placebo
研究概览
简要总结
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.
详细描述
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.
研究设计
- 研究类型
- Interventional
- 分配方式
- Randomized
- 干预模型
- Parallel
- 主要目的
- Treatment
- 盲法
- Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
盲法说明
Double-blind
入排标准
- 年龄范围
- 18 Years 至 65 Years（Adult, Older Adult）
- 性别
- All
- 接受健康志愿者
- 否
入选标准
- •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):
- •Confirmed post-menopausal state, defined as amenorrhea for at least 12 months, or
- •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%)
排除标准
- •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
结局指标
主要结局
Improvement in Physical Function (PF) as measured by the Short Form 36 Health Survey Questionnaire (SF-36) comparing Inebilizumab with placebo
时间窗: 9 months (36 weeks) after first IMP administration
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).
次要结局
- Difference in responder rate in Physical Function (PF) as measured by the Short Form 36 Health Survey Questionnaire (SF-36) comparing Inebilizumab with placebo(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(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(9 months (36 weeks) after first IMP administration)
- Improvement in symptoms of ME/CFS as measured by Canadian Consensus Criteria (CCC) Symptom Score(9 months (36 weeks) after first IMP administration)
- Improvement in functional disability as measured by the Bell Disability Scale(9 months (36 weeks) after first IMP administration)
- Improvement in symptoms of autonomic dysfunction as measured by the Composite Autonomic Symptom Score (COMPASS-31)(9 months (36 weeks) after first IMP administration)
- Improvement in fatigue as measured by the Fatigue Severity Score (FSS)(9 months (36 weeks) after first IMP administration)
- Improvement in post exertional malaise (PEM) frequency, strength and severity as measured by the PEM questionnaire(9 months (36 weeks) after first IMP administration)
- Improvement in muscle fatigue measured by the repetitive hand grip strength test (HGS)(9 months (36 weeks) after first IMP administration)
- Improvement in cognitive function measured by the Symbol Digit Modalities Test (SDMT)(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).(1 day, 15 days, 3 months, 6 months, and 9 months (36 weeks) after first IMP administration)
研究者
Judith Bellmann-Strobl
Senior physician
Charite University, Berlin, Germany