Study of the Efficacy and Safety for Rituximab in Myalgia Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS)

An Exploratory, Placebo-controlled, Double-blind, Phase II Study of the Efficacy and Safety for Rituximab (Genetical Recombination) in Myalgia Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS)

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.

Study Overview

• Status: Recruiting
• Conditions: Myalgia Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS)
• Intervention / Treatment: Drug: Rituximab(Genetical Recombination); Drug: Placebo

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.

• Study Type: Interventional
• Enrollment (Estimated): 30
• Phase: Phase 2

Contacts and Locations

• Study Contact: Name: Takami Ishizuka, PhD; Phone Number: +081-42-341-2711; Email: tmc-crso@ncnp.go.jp

Study Locations

• Japan
  • Tokyo
    • Kodaira, Tokyo, Japan, 187-8551
      • Recruiting
      • National Center of Neurology and Psychiatry
      • Contact: Takami Ishizuka, PhD; Phone Number: +81-42-341-2711; Email: tmc-crso@ncnp.go.jp
      • Contact: Tomoko Okamoto, MD

Participation Criteria

Eligibility Criteria

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

Description

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.

Study Plan

How is the study designed?

Design Details

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

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Placebo Comparator: Placebo	Drug: Placebo; 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.
Active Comparator: Rituximab(Genetical Recombination)	Drug: Rituximab(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.

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Improvement rate	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)	From Baseline to the end of treatment at 24 weeks

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
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
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 (%)	Changes in proportions will be aggregated.	At 4-week intervals from Baseline up to Week 48
Duration of standing and activity (hours)	Changes in time will be aggregated.	At 4-week intervals from Baseline up to Week 48
Fatigue during rest and lying position	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.	At 4-week intervals from Baseline up to Week 48
Records on exertion and Post-Exertional Malaise (PEM)	Patients will be asked to describe the specific activities they perform and the exhaustion they experience afterward, and a summary table will be created.	At 4-week intervals from Baseline up to Week 48
Assessment of fatigue during physical activity	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.	At 4-week intervals from Baseline up to Week 48
Evaluation based on Fatigue Score	Patients will be asked to complete the Fatigue Score questionnaire, and changes in the score will be aggregated.	At 2-week intervals from Baseline up to Week 48
SF-36	Changes in scores obtained from the SF-36 questionnaire will be assessed to evaluate patients' quality of life.	At 12-week intervals from Baseline up to Week 48
COMPASS31	Changes in scores obtained from the COMPASS31 questionnaire will be assessed to evaluate patients' autonomic symptoms.	At 12-week intervals from Baseline up to Week 48
Pittsburgh Sleep Quality Index (PSQI)	Changes in scores obtained from the PSQI questionnaire will be assessed to evaluate patients' sleep quality.	At 12-week intervals from Baseline up to Week 48
Pain intensity	Pain intensity will be assessed using the Visual Analogue Scale (VAS)	At 12-week intervals from Baseline up to Week 48
Grip strength	Patients' grip strength will be measured, and changes in the measurements will be aggregated.	At 12-week intervals from Baseline up to Week 48
Analysis of the gut microbiota	samples collected from patients will be analyzed, and the composition of the gut microbiota will be aggregated.	At 24-week intervals from Baseline up to Week 48
Brain imaging evaluation (Magnetic Resonance Imaging (MRI) of the head, Single Photon Emission Computed Tomography (SPECT) of cerebral blood flow)	Findings from imaging will be aggregated.	At 24-week intervals from Baseline up to Week 48
Immune biomarker analysis (qPCR)	qPCR will be measured, and changes in their levels will be aggregated.	At 24-week intervals from Baseline up to Week 48
Immune biomarker analysis (anti-autonomic receptor antibody analysis)	Quantify the level of anti-autonomic receptor antibodies will be measured, and changes in their levels will be aggregated.	At 24-week intervals from Baseline up to Week 48
Immune biomarker analysis (immune cell subfractionation analysis)	The subsets of immune cells will be measured, and changes in the levels will be aggregated.	At 24-week intervals from Baseline up to Week 48
Metabolome analysis	A detailed characterization of the patients' metabolome at baseline will be conducted.	At Baseline
Adverse events	The number of adverse events will be aggregated.	From Baseline up to Week 48
Vital signs (body temperature)	Summary statistics of vital signs will be calculated to monitor changes over time.	Assessments will be conducted at baseline and at Weeks 1, 2, 3, 4, 8, 12, 24, 25, 26, 27, 28, 32, 36, and 48
Vital signs (blood pressure)	Summary statistics of vital signs will be calculated to monitor changes over time.	Assessments will be conducted at baseline and at Weeks 1, 2, 3, 4, 8, 12, 24, 25, 26, 27, 28, 32, 36, and 48
Vital signs (pulse rate)	Summary statistics of vital signs will be calculated to monitor changes over time.	Assessments will be conducted at baseline and at Weeks 1, 2, 3, 4, 8, 12, 24, 25, 26, 27, 28, 32, 36, and 48
Serum immunoglobulins (IgG)	Summary statistics of serum immunoglobulins will be calculated to monitor changes over time.	At 4-week intervals from Baseline up to Week 48
Serum immunoglobulins (IgM)	Summary statistics of serum immunoglobulins will be calculated to monitor changes over time.	At 4-week intervals from Baseline up to Week 48
Serum immunoglobulins (IgA)	Summary statistics of serum immunoglobulins will be calculated to monitor changes over time.	At 4-week intervals from Baseline up to Week 48
Rituximab concentration of the blood plasma	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
Blood drug concentration Anti-Drug Antibody (ADA)	Summary statistics of ADA will be calculated to monitor changes over time.	Assessments will be conducted at baseline and at Weeks 4, 12, 24, 28, 36, and 48.
B cells (CD19/CD20 positive cells) and T cells (CD3/CD4/CD8 positive cells)	Summary statistics of B cells and T cells will be calculated to monitor changes over time.	Assessments will be conducted at baseline and at Weeks 1, 12, 24, 25, 36, and 48.

Collaborators and Investigators

• Sponsor: National Center of Neurology and Psychiatry, Japan
• Investigators: Principal Investigator: Tomoko Okamoto, MD, National Center of Neurology and Psychiatry

Study record dates

Study Major Dates

• Study Start (Actual): April 9, 2025
• Primary Completion (Estimated): September 30, 2026
• Study Completion (Estimated): October 31, 2027

Study Registration Dates

• First Submitted: April 9, 2025
• First Submitted That Met QC Criteria: April 23, 2025
• First Posted (Actual): April 30, 2025

Study Record Updates

• Last Update Posted (Actual): April 30, 2025
• Last Update Submitted That Met QC Criteria: April 23, 2025
• Last Verified: April 1, 2025

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Neuroinflammatory Diseases; Pain; Neurologic Manifestations; Musculoskeletal Diseases; Central Nervous System Diseases; Nervous System Diseases; Muscular Diseases; Pathologic Processes; Neuromuscular Diseases; Chronic Disease; Disease Attributes; Infections; Disease; Musculoskeletal Pain; Central Nervous System Infections; Fatigue Syndrome, Chronic; Syndrome; Fatigue; Myalgia; Encephalomyelitis; Antineoplastic Agents, Immunological; Antineoplastic Agents; Immunologic Factors; Physiological Effects of Drugs; Antirheumatic Agents; Rituximab
• Other Study ID Numbers: IDEC-C2B8-MC

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: NO

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No
• product manufactured in and exported from the U.S.: No