Open [Tokyo, Japan] Study of the Efficacy and Safety for Rituximab in Myalgia Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS)

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 Start (Actual)
2025-04-09
Primary Completion (Estimated)
2026-09-30
Study Completion (Estimated)
2027-10-31
Enrollment (Estimated)
30

Recruiting at National Center of Neurology and Psychiatry (NCNP)

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.

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

Primary outcome
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 Outcomes

• 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).
• 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)
• Proportion of awake time spent in supine position (%),Proportion of awake time spent in sitting position (%)
• Duration of standing and activity (hours)
• 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.
• Patients will be asked to describe the specific activities they perform and the exhaustion they experience afterward, and a summary table will be created.
• 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
• SF-36
• COMPASS31
• Pittsburgh Sleep Quality Index (PSQI)
• Pain intensity
• Grip strength
• Analysis of the gut microbiota
• Brain imaging evaluation (Magnetic Resonance Imaging (MRI) of the head, Single Photon Emission Computed Tomography (SPECT) of cerebral blood flow)
• Immune biomarker analysis (qPCR)
• Immune biomarker analysis (anti-autonomic receptor antibody analysis)
• Immune biomarker analysis (immune cell subfractionation analysis)
• Metabolome analysis
• Adverse events
• Vital signs (body temperature)
• Vital signs (pulse rate)
• Serum immunoglobulins (IgG)
• Serum immunoglobulins (IgA)
• Serum immunoglobulins (IgM)
• Rituximab concentration of the blood plasma
• Blood drug concentration Anti-Drug Antibody (ADA)
• B cells (CD19/CD20 positive cells) and T cells (CD3/CD4/CD8 positive cells)

Link (ClinicalTrials.gov)

 

Nice to see these objective markers of improvement, but hopefully it's based on an actimeter and not self-report.

The primary outcome is "Performance Status". I found a website that has the score descriptions:

Another auto-translated Japanese source talking about this score.

 

Please could you remove the quotes from the secondary outcomes to make them easier to reference? The formatting is nicer with them, but it’s a hassle to copy and past on a phone when there are so many

 

Sure thing, done.

 

Thank you very much!

 

I’m not sure what the point of doing a Rituximab trial is given the big one found null results.
But lots of the secondary outcomes look real interesting.

 

I guess cost plays a role if there's no support by a manufacturer.

But yes, a more efficient CD20 drug or also CD19 like Scheibenbogen is aiming for would be more sensible I guess.

 

The question is why they should be starting an 'exploratory' study with 30? patients at this stage when a formal phase 3 with over 100 was negative.

 

I don't think we know of any situation where you get no result with rituximab and a result with another anti-CD20 or anti-CD19.

The ethical problem I see here is that people sometimes die of complications of rituximab and we have quite good evidence that it does not help. More powerful drugs are even more likely to have adverse outcomes I suspect.

I wonder who is funding this, since the drug companies are unlikely to and the cost is unlikely to be under $1M. My worry is that the patients may be.

 

The primary outcome measure is odd:
It is toe be measured "From Baseline to the end of treatment at 24 weeks"

You do not treat people for 24 weeks with rituximab. You treat them over a one to two week period.
And if there is going to be benefit it is likely to occur only after 12 or more weeks and may reverse by 24 weeks in some cases.

I don't get the impression that the investigators know much about B cell depletion.

 

Is it bad that it’s a crossover? That ruins the possibility of long term follow up of the placebo group.

I wonder how they will measure this.

I don’t like the emphasis on «exhaustion».

I wonder why they are not using FUNCAP?

 

The primary outcome scale seems to be very top heavy in terms of functioning for ME/CFS patients.

A 6 is probably mild, but 7 is anything above completely bedridden.

The 50 % bedridden threshold for 8 also does not make any sense because I can’t think of many non-mild patients that don’t have to lie down for at least 50 % of the day due to OI.

 

これは無意味だ！

 

I think by 24 weeks they just mean duration of monitoring and the drug is only administered for the first three weeks. I added the intervention description to the first post and here:

 

The researcher that has the contact info has published on Duchenne muscular dystrophy and MS:
https://www.researchgate.net/scientific-contributions/Takami-Ishizuka-2243762218

 

Well for CD19 (as you know) it at least targets additional stages of B cells.

I thought I remembered Scheibenbogen talking about more efficient CD20 drugs, but I may be wrong. Other than that, nobody ever tried IgG reducers like Efgartigimod, another avenue.

Regarding Rituximab, I found this CAR-T study very interesting.
Possibly shedding light on Rituximab's "lack of efficiency", evidenced by lymph node biopsy:
https://ard.bmj.com/content/early/2024/09/11/ard-2024-226142

 

How can they get institutional approval if there already was a negative phase 3?

 

I don’t think it’s necessarily top heavy. It’s just massively oversimplified. And really isn’t suited to show nuanced QOL changes.
9 is bedridden (v severe)
8 is probably most housebound people (severe-moderate?)
7 sounds like moderate-mild ME/CFS
6 is probably most mild people

 

A press release from the research group says this (translated):

https://www.ncnp.go.jp/topics/detail.php?@uid=3rwyGfErGEkjguFa
(Shared by my Japanese partner, could never have found this myself)

Seems a dubious argument.