Ideas are ten a penny, but when they are all about doing a same duff trial…it’s alot of pennies wasted, infections and dashed hope


We have trialled intravenous rituximab in PPMS and it failed, but indicated that people with active lesions could respond and this was shown with ocrelizumab. So another trial has been done in SPMS and it should be positive if you load the trial with people with active disease….and put enough people in it. But in a trial of 36-38 people a group with one of them Glatiramer acetate there just wasn’t a big enough difference to say it worked. Some would call it a Trend but when the ocrelizumab trial had 244 people in the placebo arm, it makes you wonder was this study doomed…or is glatiramer acetate just great.

Rituximab and glatiramer-acetate in secondary-progressive multiple sclerosis: A randomized-clinical trial.Cheshmavar M, Mirmosayyeb O, Badihian N, Badihian S, Shaygannejad V.Acta Neurol Scand. 2020 Sep 8. doi: 10.1111/ane.13344. Online ahead of print.

Background: Treatment options for secondary progressive multiple sclerosis (SPMS) are limitedly investigated. We aimed to compare the efficacy of rituximab (RTX) and Glatiramer acetate (GA) in SPMS patients.

Method: This open, randomized-clinical trial was conducted on 84 SPMS patients, assigned to receive RTX or GA for 12 months. In RTX group patients received 1g intravenous RTX primarily and then every 6-months. In GA group patients received 40mg of GA 3-times/week subcutaneously. We measured EDSS as the primary outcome, and neuroimaging findings, relapse rate (RR) and side-effects, as the secondary outcomes.

Results: Seventy-three patients completed the study (37 and 36 in RTX and GA groups, respectively). The mean EDSS increased from 3.05±1.01 to 4.14±0.91 in RTX group (p<0.001) and from 3.22±1.20 to 4.60±0.67 in GA group (p<0.001). No statistically significant difference was observed in EDSS between two groups (F(1, 67)=3.377; p=0.071). The number of active lesions in brain and cervical spine decreased with no difference between groups (p>0.05). Also, RR decreased in both groups without significant difference between them (F(1, 67)=0.390; p=0.534). Non-serious complications were observed in both groups.

Conclusion: Neither RTX nor GA affect EDSS in SPMS patients. They are equally effective in the relapse control of these patients.

In relapsing disease it works when delivered by infusion but when delivered by the intrathecal route (into the space in the spine) rituximab failed to deplete B cells in the brain but went out into the blood and depleted the B cells . Some one said the flow from the spinal cord is down and out, so maybe we have to put it in the top and put it in the brain. Guess what? It failed too. However, I am not sure what the question was.

Intrathecal treatment trial of rituximab in progressive MS: results after a 2-year extension.Bergman J, Burman J, Bergenheim T, Svenningsson A.J Neurol. 2020 Sep 8. doi: 10.1007/s00415-020-10210-0. Online ahead of print.

Objectives: To evaluate the effect of intrathecally (IT) delivered rituximab as a therapeutic intervention for progressive multiple sclerosis (PMS) during a 3-year follow-up period.

Methods: Participants of a 1-year open-label phase 1b study of IT delivered rituximab to patients with PMS were offered extended treatment with follow-up for an additional 2 years. During the extension phase, treatment with 25 mg rituximab was administered every 6 months via a subcutaneous Ommaya reservoir connected to the right frontal horn with a ventricular catheter.

Results: Mild to moderate vertigo and nausea occurred in 4 out of 14 participants as temporary adverse events associated with IT rituximab infusion. During the entire 3-year period, two cases of low-virulent bacterial meningitis occurred, which were successfully treated. Walking speed deteriorated significantly during the study.

Conclusions: IT administration of rituximab via a ventricular catheter was well tolerated. Considering the meningitis cases, the risk of infection was not negligible. The continued loss of walking speed indicates that IT rituximab was not able to stop disease progression.

Classification of evidence: This study provides class IV evidence that intraventricularly administered rituximab in progressive MS is associated with a risk for bacterial meningitis and does not halt disease progression.

Eu clinical trial register: EudraCT; 2008-002626-11 and 2012-000721-53.

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  • I had asked this question in a previous comments section but no response so will ask again here…what if my anecdotal I.T. rituxan works because of CNS complement depletion, not B or T cell depletion? I’m not sure it depletes the “right” form of complement. Which has been outed as a possible driver of ms disease? Would frequent repeated I.T. doses consistently keep complement depleted allowing for brain to heal and ms to go into true temporary remission until things rebuilt to damaging levels again?

    • But IT rituxmab doesnt work for the majority so it is a not starter. If it works, it it B cell depletion is it complement then C1q binds to antibody unless the alternative complement cascade is activated and then it is C3. Coplement is important in macrophage activity and antibody against C5 is being used in some conditions. I dont think repeated IT is much of a goer but you will argue baclofen is administered this way. Why not use cobra venon if you want to deplete complement?

      However what you are saying is a hyothesis you have to put it to the test to discount it

      • Cobra venom… nature is surprising. I think there a few small molecules without bothering cobras.

        What about administering anti-cd20 both peripherally and IT? The higher concentration in the periphery could slow down the efflux from the CNS increasing central effect.

      • I don’t think I’ve seen any trials using the protocol I follow. I am given rituxan iv and it on the same day and this is repeated for a total of 4 weekly infusion/injections over one month. This might be crucial if the blurbs about it rituxan and complement I’ve read are correct. Complement would be depleted from ~day 1 to ~day 25. If abnormal complement activity is cause of ongoing inflammation that damages CNS, it might be stopped long enough for healing and temporary disease halt?? I’m not sure it’s the relevant suspect complement though. Not sure of much actually.

        What are cobra venom side effects at required dose? I might be persuaded to try it if CNS complement depletion proves effective and it’s less expensive than rituxan. 😀

  • Maybe i am missing something

    In this study csf b cells are depleted by 100% with Ocrelizumab

    Results: Baseline CSF B cells, T cells and CCL19 levels were indistinguishable between patients with PPMS and RMS, while CSF NfL (p=0.012) and CXCL13 (p=0.020) were decreased in patients with PPMS. PPMS CSF B cells (n=15; median percent change, −100 [IQR −100, −91.4]; p<0.001) and T cells (n=17; −63.69 [IQR −80.5, −12.9]; p=0.051) were reduced at 52 weeks post-treatment. Neither CSF NfL nor sNfL were decreased at 52 weeks overall (n=28; IQR −51.1, 51.6 and IQR −30.1, 22.5, respectively); however, NfL trended lower in 7 patients with PPMS with baseline T1 gadolinium–enhancing lesions vs those without. CSF CXCL13 levels were reduced in patients with PPMS following OCR treatment but did not achieve significance (n=28; IQR −59.1, 0; p=0.084).

    • Yes you are mssing something..its called time…The CSF was collected at baseline and 52 weeks, the effect of the antibody will be within a day or two and stoping MRI lessions within 2 weeks and disease activity within 8 weeks and you find no cells 1 year later…I call this therapy, shut the disease down and the cell numbers would drop.

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