Myalgia Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS)
Conditions
Brief summary
The efficacy and safety of rituximab on ME/CFS symptoms after administration to patients with myalgic encephalomyelitis/chronic fatigue syndrome will be compared in an exploratory, placebo-controlled, double-blind fashion. In the subsequent secondary evaluation period, subjects who received rituximab in the primary evaluation period will receive placebo, and the timing and duration of rituximab's effect will be explored throughout the entire evaluation period. Subjects who received placebo during the primary evaluation period will receive rituximab during the secondary evaluation period to explore changes in endpoints before and after switching from placebo to rituximab in the same subjects.
Detailed description
The efficacy and safety of rituximab (genetical recombination), a CD20 antibody, on ME/CFS symptoms after administration to patients with myalgic encephalomyelitis/chronic fatigue syndrome will be compared in an exploratory, placebo-controlled, double-blind fashion. In the subsequent secondary evaluation period, subjects who received rituximab in the primary evaluation period will receive placebo, and the timing and duration of rituximab's effect will be explored throughout the entire evaluation period. Subjects who received placebo during the primary evaluation period will receive rituximab during the secondary evaluation period to explore changes in endpoints before and after switching from placebo to rituximab in the same subjects.
Interventions
DRUGRituximab(Genetical Recombination)
Subjects will be assigned to the rituximab pre-treatment group or placebo pre-treatment group and will receive the study drug (rituximab actual or rituximab placebo) intravenously four times at weekly intervals during the first three weeks of the primary and secondary evaluation periods.
DRUGPlacebo
Subjects will be assigned to the rituximab pre-treatment group or placebo pre-treatment group and will receive the study drug (rituximab actual or rituximab placebo) intravenously four times at weekly intervals during the first three weeks of the primary and secondary evaluation periods.
Sponsors
National Center of Neurology and Psychiatry, Japan
Study design
Allocation
RANDOMIZED
Intervention model
CROSSOVER
Primary purpose
TREATMENT
Masking
QUADRUPLE (Subject, Caregiver, Investigator, Outcomes Assessor)
Eligibility
Sex/Gender
ALL
Age
18 Years to 65 Years
Healthy volunteers
No
Inclusion criteria
1. Patients diagnosed with ME/CFS who meet the Canadian criteria by a physician. 2. Patients with a severity score of 4 or higher on the Performance Status (PS) based ME/CFS severity classification by the Ministry of Health, Labour and Welfare Research Group 3. Patients who are between 18 and 65 years of age at the time of obtaining written consent 4. Patients who can be hospitalized (hospitalized from the day before administration and discharged the day after administration) at the time of the first dose of each of the primary and secondary evaluation periods 5. Patients whose written consent has been obtained
Exclusion criteria
1. Patients with a history of severe hypersensitivity or anaphylactic reactions to components of rituximab or products derived from mouse protein 2. Patients whose cardiopulmonary function is judged by the treating physician to be not maintained 3. Patients complaining of fatigue that does not meet the diagnostic criteria for ME/CFS 4. Patients found to have other medical conditions that may cause symptoms 5. Patients who are pregnant, lactating, or have a positive pregnancy test (serum human chorionic gonadotropin test) at the time of enrollment 6. Patients with coexisting or pre-existing malignant tumors (excluding basal cell carcinoma of the skin and cervical dysplasia) 7. Patients with coexisting or pre-existing severe immune system diseases (excluding autoimmune diseases such as thyroiditis and type 1 diabetes) 8. Patients with a history of systemic immunosuppressive therapy (e.g., immunoglobulin therapy, azathioprine, cyclosporine, mycophenolate mofetil, etc.) within 1 year, a history of receiving drugs such as monoclonal antibodies acting on the immune system (e.g., anti-CD20 antibody products including rituximab), or a history of comorbidities requiring treatment with immunosuppressive drugs Patients with comorbidities requiring treatment with immunosuppressive agents (excluding treatment with low-dose steroids of 5 mg /day or less) 9. Patients who have started alternative medicine (reference: acupuncture, moxibustion, and Japanese warm therapy) within 12 weeks prior to the start of treatment with the investigational drug. 10. Patients with severe endogenous (primary) depression 11. Patients with a neutrophil count \<1.5\*103/microliter and platelet count \<10.0\*104/microliter on blood test 12. Patients with impaired renal function (serum creatinine level \> 1.5 times the upper limit of the reference value at the institution) 13. Patients with impaired hepatic function (serum bilirubin, Aspartate Aminotransferase (AST), Alanine Aminotransferase (ALT) levels exceeding 1.5 times the upper limit of the reference value of the institution) 14. Patients infected with Human Immunodeficiency Virus (HIV) 15. Patients who test positive for at least one of Hepatitis B surface (HBs) antigen, HBs antibody, Hepatitis B core (HBc) antibody, or Hepatitis C virus (HCV) antibody. However, patients who meet the following conditions (1) and (2) may be registered. (i) Patients who are positive for HBs or HBc antibodies and whose HBV-DNA quantification is confirmed to be negative (less than detection sensitivity) and for whom appropriate monitoring, etc. can be conducted in accordance with the Guidelines for Hepatitis B Treatment edited by the Japan Society of Hepatology. (ii) For patients with positive HCV antibody, when HCV-RNA quantification is negative (less than detection sensitivity) 16. Patients who do not have the ability to comply with the study protocol 17. Patients who have participated in other clinical trials or clinical studies (except for observational studies without intervention) within 16 weeks prior to obtaining consent 18. Other patients who are judged by the investigator or subinvestigator (hereinafter referred to as investigator) to be inappropriate to participate in this clinical trial.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Improvement rate | From Baseline to the end of treatment at 24 weeks | Percentage of cases in which the severity score of ME/CFS based on PS by the MHLW research group improved by 1 or more compared to that before the start of study drug administration (week 0) |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| The amount of change in the severity score of ME/CFS based on PS by the MHLW Research Group at each assessment point from that before the start of treatment with the investigational drug (week 0) | At 4-week intervals from Baseline up to Week 48 | — |
| Proportion of awake time spent in supine position (%),Proportion of awake time spent in sitting position (%) | At 4-week intervals from Baseline up to Week 48 | Changes in proportions will be aggregated. |
| Duration of standing and activity (hours) | At 4-week intervals from Baseline up to Week 48 | Changes in time will be aggregated. |
| Fatigue during rest and lying position | At 4-week intervals from Baseline up to Week 48 | Patients will be asked to report the level of fatigue they feel even while lying down, and changes in their fatigue levels will be aggregated. |
| Records on exertion and Post-Exertional Malaise (PEM) | At 4-week intervals from Baseline up to Week 48 | Patients will be asked to describe the specific activities they perform and the exhaustion they experience afterward, and a summary table will be created. |
| Assessment of fatigue during physical activity | At 4-week intervals from Baseline up to Week 48 | Patients will be asked to report the level of fatigue they experience during physical activity in daily life, and changes in fatigue levels will be aggregated. |
| Evaluation based on Fatigue Score | At 2-week intervals from Baseline up to Week 48 | Patients will be asked to complete the Fatigue Score questionnaire, and changes in the score will be aggregated. |
| SF-36 | At 12-week intervals from Baseline up to Week 48 | Changes in scores obtained from the SF-36 questionnaire will be assessed to evaluate patients' quality of life. |
| COMPASS31 | At 12-week intervals from Baseline up to Week 48 | Changes in scores obtained from the COMPASS31 questionnaire will be assessed to evaluate patients' autonomic symptoms. |
| Pittsburgh Sleep Quality Index (PSQI) | At 12-week intervals from Baseline up to Week 48 | Changes in scores obtained from the PSQI questionnaire will be assessed to evaluate patients' sleep quality. |
| Pain intensity | At 12-week intervals from Baseline up to Week 48 | Pain intensity will be assessed using the Visual Analogue Scale (VAS) |
| Grip strength | At 12-week intervals from Baseline up to Week 48 | Patients' grip strength will be measured, and changes in the measurements will be aggregated. |
| Analysis of the gut microbiota | At 24-week intervals from Baseline up to Week 48 | samples collected from patients will be analyzed, and the composition of the gut microbiota will be aggregated. |
| Brain imaging evaluation (Magnetic Resonance Imaging (MRI) of the head, Single Photon Emission Computed Tomography (SPECT) of cerebral blood flow) | At 24-week intervals from Baseline up to Week 48 | Findings from imaging will be aggregated. |
| Percentage of patients whose MHLW-PS-based ME/CFS severity score improved by 1 or more at each evaluation point (improvement rate) compared to that before the start of treatment with the investigational drug (week 0). | At 4-week intervals from Baseline up to Week 48 | — |
| Immune biomarker analysis (anti-autonomic receptor antibody analysis) | At 24-week intervals from Baseline up to Week 48 | Quantify the level of anti-autonomic receptor antibodies will be measured, and changes in their levels will be aggregated. |
| Immune biomarker analysis (immune cell subfractionation analysis) | At 24-week intervals from Baseline up to Week 48 | The subsets of immune cells will be measured, and changes in the levels will be aggregated. |
| Metabolome analysis | At Baseline | A detailed characterization of the patients' metabolome at baseline will be conducted. |
| Adverse events | From Baseline up to Week 48 | The number of adverse events will be aggregated. |
| Vital signs (body temperature) | Assessments will be conducted at baseline and at Weeks 1, 2, 3, 4, 8, 12, 24, 25, 26, 27, 28, 32, 36, and 48 | Summary statistics of vital signs will be calculated to monitor changes over time. |
| Vital signs (blood pressure) | Assessments will be conducted at baseline and at Weeks 1, 2, 3, 4, 8, 12, 24, 25, 26, 27, 28, 32, 36, and 48 | Summary statistics of vital signs will be calculated to monitor changes over time. |
| Vital signs (pulse rate) | Assessments will be conducted at baseline and at Weeks 1, 2, 3, 4, 8, 12, 24, 25, 26, 27, 28, 32, 36, and 48 | Summary statistics of vital signs will be calculated to monitor changes over time. |
| Serum immunoglobulins (IgG) | At 4-week intervals from Baseline up to Week 48 | Summary statistics of serum immunoglobulins will be calculated to monitor changes over time. |
| Serum immunoglobulins (IgM) | At 4-week intervals from Baseline up to Week 48 | Summary statistics of serum immunoglobulins will be calculated to monitor changes over time. |
| Serum immunoglobulins (IgA) | At 4-week intervals from Baseline up to Week 48 | Summary statistics of serum immunoglobulins will be calculated to monitor changes over time. |
| Rituximab concentration of the blood plasma | Assessments will be conducted at baseline and at Weeks 1, 2, 3, 4, 12, 24, 25, 26, 27, 28, 36, and 48 | Rituximab concentration of the blood plasma |
| Blood drug concentration Anti-Drug Antibody (ADA) | Assessments will be conducted at baseline and at Weeks 4, 12, 24, 28, 36, and 48. | Summary statistics of ADA will be calculated to monitor changes over time. |
| B cells (CD19/CD20 positive cells) and T cells (CD3/CD4/CD8 positive cells) | Assessments will be conducted at baseline and at Weeks 1, 12, 24, 25, 36, and 48. | Summary statistics of B cells and T cells will be calculated to monitor changes over time. |
| Immune biomarker analysis (qPCR) | At 24-week intervals from Baseline up to Week 48 | qPCR will be measured, and changes in their levels will be aggregated. |
Countries
Japan
Contacts
Primary ContactTakami Ishizuka, PhD
Outcome results
None listed