#AttackMS

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AttackMS was conceived on the 29th of Nov 2017 over a beer or two (or was it Elderflower?) at the Lago Maggiore.

Prof Jeremy Hobart (Plymouth), ProfG and I sat down on the eve of the annual meeting of the European Charcot Foundation in Baveno, and I said something along the lines of: “Why don’t we treat MS with highly effective disease modifying treatment (HE-DMT) at first presentation, which means potentially even *before* the McDonald criteria of MS (free download available here) are fulfilled? A: Mostly because of diagnostic uncertainty. However, if we can be ≥80% certain at first presentation that MS is the diagnosis, the main reasons not to treat with HE-DMT are (i) long term effects of the treatment on the immune system in case the diagnosis does not turn out to be MS and (ii) potentially detrimental effects of the HE-DMT on one of the possible differential diagnoses. So what about using N a t a l i z u m a b ?”

We ordered another beer (or was it Elderflower?).

However, waking up next morning we knew that – bar preventing MS altogether (and aren’t we all excited about the latest news about EBV?) – AttackMS may provide the most promising risk/benefit compromise here and now to explore whether intervention with HE-DMT within 14 days of symptom onset is feasible and can facilitate brain lesion repair (remyelination).

We discussed the concepts underpinning AttackMS with people who were recently diagnosed with MS. Their feedback was very positive, and I’m delighted that Rachel and John have joined the team as PPI members.

Key question then was, which biomarker should we use as the primary outcome, and after some toing and froing about serum neurofilament light chain level we decided that lesion MRI magnetization transfer ratio (MTR) it would be. MTR has been in use for some time in phase II MS trials of myelin repair, most recently in the Bexarotene study. Vanity strikes when I tell you our investigation of the pathological correlates of MTR in MS (main correlate: myelin) remains my highest cited paper…

Funding was obviously also needed, and we were fortunate that Biogen, the maker of natalizumab (Tysabri®), awarded the amount required to undertake the study, which is now due to start recruitment, under the sponsorship of QMUL, from March/April, i.e. in 2-3 months.

Please be aware AttackMS is NOT OPEN FOR RECRUITMENT YET. WE WILL KEEP YOU UPDATED!

The slides give an overview of the study. Recruitment will be challenging, and we’ll undertake plenty of awareness activities, mainly among acute physicians and neurologists involved in acute medical care in and around London, though essentially anybody up to age 45 in the UK presenting within 14 days of symptom onset and an MRI suggestive of demyelination has a chance to join AttackMS. They just need an acute referral to one of our three trial sites Chelsea & Westminster (PI: Dr Victoria Singh-Curry), St George’s (PI: Dr Waqar Rashid) and The Royal London (PI: ProfK).

AttackMS_overview_20220129

Disclaimer: The opinions expressed here are those of the author and nobody else.

CoI: I am the CI of AttackMS, which is an investigator initiated and led study sponsored by Queen Mary University of London, and funded by Biogen.

@KlausSchmierer

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18 comments

  • Nice work

    But

    “14 days of symptom onset”

    Most diagnostics takes months in your experience as a a clinician did you treat a patient within that time frame?

    Thanks

    • Good point. One of our aims is “To provide evidence for the feasibility of rapid recruitment in the NHS”, so you’re right that’s one of the challenges we’ve set ourselves. Having said that, in the Phenytoin optic neuritis study we achieved a mean time between onset and randomisation of 8 days, and Moorfields is one of our collaborators (https://www.thelancet.com/action/showPdf?pii=S1474-4422%2816%2900004-1). It will be very important to collaborate with our colleagues in A&E & stroke medicine; I expect that recruitment will primarily come through those pathways (and ophthalmology).

      • Thanks for reply

        I remember my own case was 1 week just to scheduled mri and about 2 or maybe 3 week to get the result

  • Love the sound of this! Much more hopeful for those still to become ill. Hopefully will increase awareness of the diagnose quickly and treat aggressively early mantra among the medics more generally too. Would be good to have a pathway for GPs to get people seen early also?

    • Thanks Rebecca, and quite right we were thinking of making GPs aware, the only issue I’m mindful that they are inundated with research requests, and the situation that somebody with first symptoms pitching within 14 day rather slim. We’ll take your suggestion on board though, and think again.

      • Rebecca’s suggestion is a good one. In reality GPs see all those unlucky enough to present with ‘mild’ (ie sensory and non-disabling) first symptoms and referrals can take ages. Trial offers GPs an alternative fast neurology referral for possible MS.

          • No thank you! It’s a fantastic study!
            As is Chariot, the double dose Ocrelizumab thing and Sizomus too. What an amazing research centre! Thanks a million to everyone involved 🙂

  • I’m guessing that for most of us, the first MS symptoms don’t require a 999 call (like a heart attack). My first attack affected my right hand and funny sensations down right side. I thought it would sort itself out, but after three weeks went to the GP. GP (I don’t blame) thought it was a virus or a trapped nerve. After 2 more GP visits I was referred to a neuro (I had private health care) and diagnosed over two weeks (after an MRI). From start of first symptom to diagnosis it took c.8 weeks for a diagnosis which is pretty quick compared to some.

    I’m guessing AttackMS will mainly deal with those who have very severe initial symptoms and go to A&E.

    Why did you not consider treatment with an IRT rather than Natalizumab?

    • Thanks. This trial will try help turning MS into a much more acutely managed condition. From the protocol: “Should pre-diagnostic treatment … prove successful, the development of ‘hyperacute MS units’ (HAMSU), in analogy with hyper-acute stroke units (HASU) is conceivable. There is, thus, transformative potential in AttackMS”. We are aware this is a steep challenge since it targets the culture of how things are currently being done, and you are correct being diagnosed within 8 weeks is still a very good result. The reason we are using natalizumab is manifold; it’s a well known compound, most MS teams will put it right to the top among the highest efficacy drugs (in line with the trial evidence), and the short term adverse risk is low. An IRT is a long term commitment – once the drug has been given, there is no shortcut removing it or its effects (that being said, the ORACLE study was something to marvel at: https://pubmed.ncbi.nlm.nih.gov/24502830/). Natalizumab acts rapidly, but it also leaves the body within a few weeks; in extreme circumstances removal can even be expedited by plasma exchange. This is preferable in a situation where (i) some diagnostic uncertainty may persist and (ii) people facing the reality of having (or very likely having) MS for the first time may not be ready to commit, there and then, to a long term treatment strategy. Another extract from the protocol: “At the week 12 visit, the options for DMT after the end of AttackMS will be discussed by the trial team with each participant. The decision of which DMT the participant will start taking, will depend on their individual eligibility according to the NHS England commissioning rules. We have received confirmation from … NHS England, that all participants will be able to receive Tysabri® on the NHS after the end of trial, provided their responsible clinician supports such treatment.”

  • Prof K, you are confirming what I have experienced many times – that some of life’s best ideas come when sitting in a beautiful place in the company of friends. And yes, with a glass of something.

  • All the best for Attack MS
    It’s a great idea

    Now one concern, a worst case scenario:
    As some people have said already, you will mainly get patients whose first symptoms are severe enough that they get to A&E or a neuro.
    The more typical first symptom is so mild that people just let it pass or they go to a GP.
    In fact, people with dramatic “first symptoms” may have a history of milder stuff that was ignored.
    So you will recruit patients at “first presentation of serious symptoms”. You may not get any patients truly at first presentation.

    • Good points, and we will have to rely on the inquisitive skills of the sites, all of which are MS experts, to rule out that peoples’ MS has already been lingering on for a while. Another stop/go to avoid this issue is the presence/absence of chronic lesions on T1 weighted MRI. If you have more than one of these so-called “black holes” in the brain, you won’t be eligible for the trial.

  • I remember having a conversation/ heated debate with a neurology consultant approx 8 years ago. Can a MS relapse ever require acute or urgent care?
    No was their answer, well I don’t agree. I think if the brainstem is involved, that can have severe nasty symptoms.
    Your study seems like it’s going in the right direction.

  • The drug can work rapidly, that’s great. My questions are:
    1) If natalizumab is given when someone is having a relapse, can it reduce the severity of that relapse?Similar in some ways to workng like steroids.
    2) Could the patient experience a rebound relapse, even after a low number of natalizumab infusions? Such as two infusions.

    • I am not a clinician but natalizumab works very quickly but not sure if it can reverse a relapse, I suspect it hasnt been treid I dont know the literature the aim of attack MS is to stop the next attack from occurring.
      No drug is 100% and rebound or disease breakthrough can occur with any treatment but you can always ask if the attck would be more severe without treatemnt

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