Disrupt the Status Quo

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Barts-MS rose-tinted-odometer: ★★★★★ (seeing turquoise; creative turquoise Friday)

She was 42 years of age and had had MS for 16 years. After a relapse in 2016, she was switched from interferon-beta to fingolimod. Despite being NEDA-2 ( no relapses or focal MRI activity) since starting fingolimod her disability has worsened with her EDSS going from 4.5 (walking unaided for more than 300m) to 6.0 (needing a walking stick to walk 100m). Clearly, fingolimod is doing what it should do, i.e. keeping relapse and MRI activity at bay. What can we add-on to fingolimod to stop worsening disability? 

To answer this question we need to tackle smouldering MS in a creative way; one way is to use the so-called “Simon 2-stage, single-centre, phase 2, single-arm futility trial”. The Simon design comes from oncology and allows multiple treatment regimens to be compared. The idea is to screen treatments using an initial futility study and if you pass this phase you can then stop for futility but you don’t stop if there is evidence for an overwhelming effect on the outcome. A non-futile treatment can be taken forward for further testing in a phase 2b study. 

The Simon 2-stage design provides initial evidence supporting or opposing a specific treatment, which then requires confirmation. I can see us using this trial design to test the long list of potential repurposed add-on treatments we  have to tackle smouldering MS. I see no reason why we can’t use this trial design in a factorial way to test combination therapies, i.e. to build  a MS-MDT sandwich. 

The study below uses the Simon 2-stage design to test oral domperidone, an anti-nausea drug, in SPMS. The hypothesis was that the increase in the hormone prolactin-induced as a side-effect of domperidone would stimulate remyelination, which will improve or at least slowdown disability progression. Sadly it didn’t but it shows that this route is feasible.

I wonder if we could set up a ‘disruptive Simon-stage-2 trial platform’ for pwMS to run their own trials of over-the-counter medications and/or supplements. The platform will screen patients online and assess trial eligibility using PROMs (patient-related outcomes) and then randomise them to different treatment arms. The trial platform will then follow them up via smartphones using the futility design. The primary and secondary outcomes will all be self-monitored using smartphone technology. Wouldn’t it be cool if patients with progressive MS took control of their own trials and generated the evidence to support taking some of the supplements or medication a lot of pwMS take anyway; an example could be alpha-lipoic acid. 

You may remember that Patients Like-Me did something similar with lithium in motor neuron disease a few years ago. The article by Paul Wicks ‘Patient Study Thyself’ highlighted below explains the process and is really asking people with disease to disrupt the status quo. I would urge you to go for it!  

Koch et al. Repurposing Domperidone in Secondary Progressive Multiple Sclerosis: A Simon 2-Stage Phase 2 Futility Trial. Neurology. 2021 May 4;96(18):e2313-e2322.

Objective: To assess whether treatment with the generic drug domperidone can reduce the progression of disability in secondary progressive multiple sclerosis (SPMS), we conducted a phase 2 futility trial following the Simon 2-stage design.

Methods: We enrolled patients in an open-label, Simon 2-stage, single-center, phase 2, single-arm futility trial at the Calgary Multiple Sclerosis Clinic if they met the following criteria: age of 18 to 60 years, SPMS, screening Expanded Disability Status Scale score of 4.0 to 6.5, and screening timed 25-ft walk (T25FW) of ≥9 seconds. Patients received domperidone 10 mg 4 times daily for 1 year. The primary outcome was worsening of disability, defined as worsening of the T25FW performance by ≥20% at 12 months compared to baseline. This trial is registered with ClinicalTrials.gov (NCT02308137).

Results: Between February 13, 2015, and January 3, 2020, 110 patients were screened, 81 received treatment, and 64 completed follow-up, of whom 62 were analyzed. The study did not meet its primary endpoint: 22 of 62 (35%) patients experienced significant worsening of disability, which is close to the expected proportion of 40% and above the predefined futility threshold. Patients with higher prolactin levels during the study had a significantly lower risk of disability progression, which may warrant further investigation. Domperidone treatment was reasonably well tolerated, but adverse events occurred in 84% and serious adverse events in 15% of patients.

Conclusions: Domperidone treatment could not reject futility in reducing disability progression in SPMS. The Simon 2-stage trial model may be a useful model for phase 2 studies in progressive MS.

Trial registration information: ClinicalTrials.gov Identifier: NCT02308137.

Classification of evidence: This study provides Class III evidence that in individuals with SPMS participating in a futility trial, domperidone treatment could not reject futility in reducing disability progression at 12 months.

Paul Wicks. Patient, study thyself. BMC Medicine volume 16, Article number: 217 (2018).

The past 15 years have seen the emergence of a new paradigm in medical research, namely of people living with medical conditions (whether patients, parents, or caregivers) using digital tools to conduct N-of-1 trials and scientifically grounded research on themselves, whilst using the Internet to form communities of like-minded individuals willing to self-experiment. Prominent examples can be found in amyotrophic lateral sclerosis/motor neurone disease (the ‘lithium study’ on PatientsLikeMe), Parkinson’s disease (‘digital patient’ Sara Riggare), and diabetes (the ‘open artificial pancreas’ of the #WeAreNotWaiting movement). Through transparency, data sharing, open source code, and publication in the peer-reviewed scientific literature, such activities conform to expected scientific conventions. However, other conventions, such as ethical oversight, regulation, professionalization, and the ability to translate this new form of relatively biased data into generalizable decisions, remain challenged. While critics worry such participant-led research merely muddies the waters of high-quality medical research and exposes patients to new harms, the potential is there to enroll millions of active minds in unravelling the wicked problems of complex medical disorders that degrade the human health span.

Conflicts of Interest

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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.

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.

28 comments

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  • I am a patient at the Calgary Multiple Sclerosis Clinic. I can attest that my neurologist is very progressive and was supportive of my desire to do an IRT soon after diagnosis (and fought with my insurance company when they initially tried to deny me coverage). He even told me that he is a fan of this blog and that he recommends it to his patients.

  • I would think this is a very appealing research methodology for us patients. I know it would be something I would sign up for. It implies a trust in the patient that we are not always afforded.

    • Re: “It implies a trust in the patient that we are not always afforded.”

      Sad, but true. Why shouldn’t we trust our patients? We expect them to trust us. Isn’t the doctor-patient or patient-doctor relationship based on mutual trust?

  • People did this with hsct for ms. But instead of learning/following their examples.
    You put yourself above listening/considering their experiences. Just in 2020 you
    threatened to ban people for mentioning hsct and called them trolls..Now
    you refer to it as a potential cure.

    “We do post your comments, but we are about to stop posting your comments on the grounds that you promote/advertise HSCT and that you are a troll.”
    “I agree. I have been reading about how social memes stick and by not giving memes a platform or a soapbox is one way of reducing their stickiness.”
    https://multiple-sclerosis-research.org/2020/01/premature-ageing/

    Guess something can go from a social meme in 2020 to now a potential cure in one year.
    Have you considered politics after you retire..?

    No..hsct is not a cure one of Burts rr patients failed after 11 years of remission….this
    tells us that any one drug or supplement is going to be like a drop in the bucket…unless
    it directly acts on EBV.

    • Re: “Guess something can go from a social meme in 2020 to now a potential cure in one year.
      Have you considered politics after you retire..?”

      Some of the AHSCT units abroad advertise and taking money from vulnerable people. However, when you look at their protocols and doses of cyclophosphamide used it is not HSCT. This is why we need we have to moderate comments.

      Not sure you can run trials yourself with HSCT. Somebody has to do the procedure.

      • “Not sure you can run trials yourself with HSCT. Somebody has to do the procedure.”

        You can with help. Know someone who had oncologist friend give him
        the CYC doses to put him into neutropenia. Then he just recovered with out stem cell rescue. He was still in remission couple years later.

      • “Some of the AHSCT units abroad advertise and taking money from vulnerable people. However, when you look at their protocols and doses of cyclophosphamide used it is not HSCT.”

        You can’t just make accusations…without info. Which clinics..?
        What doses of CYC are used..?

        All the clinics doing non-myelo hsct all use the same amounts of CYC
        And Sweden has apparently switched from myelo to non-myelo
        because it’s been found to be beneficial and it causes less brain atrophy.
        Myeloablative came out of cancer and BMT but it’s not relevant to ms as
        all you need to eliminate in ms is auto reactive t cells and b cells. Ther
        is no benefit to destroying bone marrow in ms unlike other conditions
        where it’s necessary.

        Dr. Burt learned non-myelo from Prof. Slavin in Israel…and far as I know
        that’s where it started and since then all the clinics use same CYC amounts.
        For instance both Russia and Mexico…use the exact same amount. And they
        have treated the vast majority over 2,500 of patients.

        And these clinics don’t just take in all patients…they turn away those who they feel won’t benefit. Sad when people post “2 years earlier they would have taken me..but now I progressed past the point where they’re willing to treat.”

    • Re: HSCT being a cure.

      I have been talking about HSCT/Alemtuzumab being a potential cure for over a decade; not sure why you are fixated on 2020. I actually gave a talk in 1999 when I did due diligence on BMT and it mentions a cure.

      • “I have been talking about HSCT/Alemtuzumab being a potential cure for over a decade; not sure why you are fixated on 2020.”

        Because in 2020 on the premature ageing post you posted……..”I am sure Luis won’t mind being blocked. In fact, we could do it on the grounds of no advertising as he is one of the main HSCT proponents on the blog.”

        Implying hsct proponents should be blocked…If you were pro hsct in
        2000…no idea why you didn’t open the clinic when you had the chance to
        in 2000….So many from u.k. have gone to Mexico that there is no room
        for more pins on their map. Had you opened up the hsct clinic none of
        them would have had to travel so far and spend so much to seek treatment.

      • I actually gave a talk in 1999 when I did due diligence on BMT and it mentions a cure.

        At the end of the day adoption of any treatment is a slow process and is data driven. The data has to be good quality. The reality at the moment is the quality of HSCT data as a broad treatment for MS is simply not good enough, in particular its relative efficacy and risk-benefit profile relative to other DMTs, to result in high adoption rates. This is why we are trying to get funding to do a comparative clinical trial.

        This is your coment from 2018

        Do you thinks that in 1999 when you gave your speech the data was good quality?

        You did mention a cure? In 1999?

        Because after 19 years (2018) the data was still not good enough

        But in 1999 you mention the word cure

        I am getting a bit confused

        🙂

    • Re: Trolls

      Definition: A person who posts remarks or comments onto internet forums or message boards in an attempt to get someone to comment negatively to it and to redirect attention onto themself or issue they represent.

      This definition speaks for itself.

  • I would definitely be interested in such a study. Empowering pwMS to make a difference both for themselves and others would be a very positive move all round.
    It would be useful to know a selection of drugs that are considered of sufficient promise to be worth trying before starting. I know each neurologist would have their own opinion on this but it could save previous time and help an individual’s research.

  • Why do progression trials always seam exclude people with RRMS?

    I know secondary and primary progressive MS are where the needs are, progression wise.

    However if progression is slowed while in the RRMS stage, would this not possibly slow the time to conversion to SPMS.

  • why dont you be the one to disrupt the status quo ? go to the correct people at the nhs that are out of our reach with a petition filled out by your readers and the zealots and petition them to get hsct and alumtuzumab as a first line therapy ? get national news coverage and support from the ms charity’s! we would support you the whole way!

  • why dont you be the one to disrupt the status quo ? go to the correct people at the nhs that are out of our reach with a petition filled out by your readers and the zealots and petition them to get hsct and alumtuzumab as a first line therapy ? get national news coverage and support from the ms charity’s! we would support you the whole way

    • Was wondering the same thing ever since Prof. G tweeted praise for a double-blind randomized psilocybin trial that was run by lay people. It’s possible. I note that generic versions of Combivir and Tenofovir can be purchased online, albeit from sources of unknown reliability in India etc. I’m going to ask my neurologist (here in the States) if he’d be willing to prescribe one or the other. If not, I might just roll the dice…

    • Was wondering the same thing ever since Prof. G tweeted praise for a double-blind randomized psilocybin trial that was run by lay people. It’s possible. I note that generic versions of Combivir and Tenofovir can be purchased online, albeit from sources of unknown reliability in India etc. I’m going to ask my neurologist (here in the States) if he’d be willing to prescribe one or the other. If not, I might just roll the dice…

  • I am a bit confused maybe. I assumed that neurologists would fill some sort of database with patients records including additional drugs and supplement. If so I think lipoic acid is so widespread that one could have positive and negative controls in the database. I think data are there or could just simply be there to be used. We could start with that.
    Concerning progression I think that we lack markers for progression: no access to sNFL, BVL is not measured routinely and other indicators are sensitive only in the long run and could be biased by the absence of blinding. I think it is critical that these simple trials are supported by the neurologists community at least on doing the clinical evaluations. This reconnects with the previous party of my comment… it would be much simpler to use what is already in place to record. What is lacking is a platform to share and assign people to treatments.
    I am taking lipoic acid and would love to know if it makes sense to take it and I would be happy to participate.
    I also think that paracetamol (acetaminophene) could prevent progression lowering body temperature and thus reducing excitotoxic stress due to signal transport by demyelinated axons, lower temperature means better transport thus lower energy requirement. The question is how much to take? How to monitor for liver damage? You need a doctor to do this…

    • Re: “I am a bit confused maybe. ”

      No with PatientsLikeMe they run their own cloud-based database separate from their official healthcare database.

  • We hear about open label trials, what about open source trials. This will sound extremely fishy and biased but what if you could post the study you want to do online and people can sign up. For example, prof G wants to do the EBV study and every EBV post gets dozens of replies.

    What if you could structure your study and people participate online, get the drugs on their own, do a number of tests similar to the bloodspot and submit the results. Obviously it will be more than that as MRIs seem to be a cornerstone of any MS study. But all in all, could really expedite the process.

    But I doubt anyone will approve of this. Then again, reading the posts about people doing a fasting-mimicking keto diet and taking metformin, clemastine and that acid thingy.

    • As with all research it has to be done well so that the results are robust and if possible definitive. This will then allow registration trials to be done, data submitted to the regulators and hope for the regulators to approve a therapy or therapeutic procedure, e.g. AHSCT. The reason this has to be done in this way is to make sure the payers reimburse or cover the cost of the treatments.

  • You’re the Greatest 😎🙏🏼
    This is a study worth doing on a large scale.
    I’m ready.
    I think part of the problem with modern day living is we’re too portable.
    In the old days your neurologist was The neurologist and You were their patient for life.
    The good thing was the Doctor Really got to see you, like chapters in a book.
    Noticing subtle changes.
    Patients and families have to Improvise their own care plan, schedule, meds, appointments.
    The Doctors do their high level thinking. Patient & Family on a parallel track to the Doctor-clinic track.
    I really want my use of Copaxone/Glatopa into my 60’s documented. I want to tell you I think it’s a pretty easy regimen For Me. I do my own self assessment as an old Neuro Nurse. I give these to my Doctors.
    I have to be careful in case I get “one of those”. You know, they speak first, with authority and Uber intellect.
    It’s helpful with these doctors to tease them with facts and let them draw the conclusion. Even if all that comes from such a study is a vitamin or salve that even Helps a little, it is worth the work. Teaching patients and family to self-assess, evaluate, plan, report is a good exercise. You can even graph it out. What helps, what doesn’t, what You do , what you can’t. Makes the most out of that 15 minute clinic visit that we wait all year for to hear, “No change, see you next year”.

  • I don’t see that fingolimod is keeping her MS at bay if she is deteriorating …what is the evidence for that ?

      • “I don’t see that fingolimod is keeping her MS at bay if she is deteriorating

        She is clearly only few years from wheelchair…even with no relapse or lesions. Had she had hsct at edss 2-3…might have stopped the progression.
        Burt says in people spms w/no lesions…50% stopped progression for 5 years.

        “You stop the fingolimod and her MS will rebound.”

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