Clash of the Titans: the HILO study


Barts-MS rose-tinted-odometer: ★★★ (I am seeing blue and Spanish yellow today) 
Roche blue (#0066CC) & Novartis Spanish Yellow (#F7B516)

Yes, I really do think that intrathecal (within the meninges that cover the brain and spinal cord) or CNS resident B-cells and plasma cells are pathogenic in MS. In other words, the cytokine or chemicals B-cells and plasma cells produce, in particular their antibodies, are what is driving some of the pathologies of smouldering MS. The evidence to support this hypothesis is well rehearsed on this blog and is the reason why we are testing high-dose ocrelizumab (more CNS penetrant) vs. standard-dose ocrelizumab (less CNS penetrant) against each other in two head-2-head studies. It is also the reason we are testing cladribine’s (CLADRIPLAS and CLAD-B) and ixazomib’s (SIZOMUS) effects in intrathecal B and plasma cell markers. Yes, I really do think we need to scrub the CNS clean of B-cells, plasma cells and their products, in particular the oligoclonal IgG bands. 

I am therefore proposing a new study; the HIgh-dose versus LOw-dose anti-CD20 study or HILO Study. 

In this study, I propose testing high-dose or double-dose ocrelizumab vs. standard or intermediate-dose ocrelizumab vs. low-dose ofatumumab against each other over two years and measure their impact on end-organ damage markers (slowly expanding lesions and brain volume loss) and on CSF markers of B-cell, plasma cell and microglial activity. The latter will include free kappa and lambda immunoglobulin light chains, OCBs, soluble CD14, etc. This will answer at least from a biomarker question whether or not we need CNS penetration of anti-CD20 monoclonal antibodies to target this component of smouldering MS. The following would also answer the question of whether or not you as a person with MS would want to be treated with high-dose or low-dose anti-CD20 therapy? 

Would you want to be randomised into this study?

This study would be a clash of the titans; Roche vs. Novartis. Who would win? It really is not that important as Novartis is a major shareholder in Roche and hence when Roche makes a profit so does Novartis. The real winners will be people with MS, the data will allow them to make an informed decision about whether or not they want to go beyond NEIDA (no evident inflammatory disease activity) and be on a treatment that tackles the smouldering B-cell and plasma-cell driven processes within their brains and spinal cords. 


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General Disclaimer: Please note that the opinions expressed here are those of Professor Giovannoni and do not necessarily reflect the positions of the Barts and The London School of Medicine and Dentistry nor Barts Health NHS Trust and are not meant to be interpreted as personal clinical advice. 

About the author

Prof G

Professor of Neurology, Barts & The London. MS & Preventive Neurology thinker, blogger, runner, vegetable gardener, husband, father, cook and wine & food lover.


  • What is the upper age limit? As it’s usually 65, I assume that’s to exclude older pwMS, either on the grounds of safety (Pharma being risk averse) or because OpwMS don’t usually experience highly active MS. Are there other reasons?

    • Neither Roche nor Novartis will fund this study; it is not their interest to go head-2-head. Best to share the market between them 🙁

      • When shareholders decide what scientists should research, it are the patients who lose.
        That’s not how things should go in science, and especially not in medical science.

        Is there still a way to sign up for this study?
        And aren’t there other ways to finance these kinda things, in the Netherlands a aHSCT comparison with alemtuzumab didn’t get enough money from the government to start. So two MS foundations paid the remaining part.

        There are always ways

        • Maybe but would this really be the best use of the MS society’s money? Prof G has already got his double- and triple-dose Ocrevus trial. We’re going to find out whether high-dose anti-CD20 is better than intermediate-dose, do we really care all that much about how it compares to low-dose?

  • Where can we find the trials for CLADRIPLAS and CLAD-B on clinical ( asking for a friend ) ?

    • They are not on as they are no CTIMPs (Clinical Trials of an Investigational Medicinal Products), but local single-centre biomarker studies.

  • It should be done at least we get knowledge. The only question is: there are a lot of trials ongoing and some of them may already hold the answer too many ous the questions. Wouldn’t this be redundant? In the meantime one can start building up the trial anyway.
    Another question: if there are so many trials ongoing where will you get enough patients? 😉

  • I would love to sign up for this trial if possible, as not receiving any treatment for smouldering MS does distress me. Please keep us all posted

  • Isn’t this what BTKi are going to achieve. If BTKi fails however will the drug companies then move to trials for higher does anti-cd20.

    Also doesn’t cladrabine achieve this effect anyway, the effect that a higher dose anti-cd20 would bring.

  • Would such studies be necessary given the ongoing DODO study? Would they prove something different from DODO?

  • Why can you not dose this by patient weight / targeted blood concentrations in patients? I weigh a lot more than many beautiful people with MS (not excess adipose either…I am just, well, large).

  • We need to be looking at cause then cure surely ?!
    Treatments after the event and studies to help line the pockets of drug companies mean ultimately that the patients suffer and loose out; just becoming a lab rat and cash cow

  • Thank you for posting your thoughts on this blog. This is an interesting proposal and going beyond the usual endpoints is needed. What would be likely exclusion criteria for this trial? Could pwMS with normal OCB participate? And perhaps a bit more technical: have you performed any power calculation for this trial? What would be a meaningful difference between the tree arms on the primary and secondary outcomes?

By Prof G



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