Zeus HSCT trial is like Buses…Wait and two or is it three arrive at the same time.

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Some of you tell us that we, AKA Prof G, don’t design and do enough investigator-led (non pharma) trials. But anyone who knows ProfG and thinks or says such a thing, I am sorry to say is a fool.

OK, we have to hold our hands up and say yes we have been slow at writing some trials up…but we are not the only ones. I accept part of the blame for this, the Canbex trial was written over a year ago, but we were gagged.

As you know ProfG has been on more company advisory boards than you can shake a stick at and has been involved in virtually every major drug development led by pharma. He knows that pharma has the resource to do the study in a timely manner. Importantly, by working with pharma, it gives people in our care the opportunity to try new drugs before they become freely available. If you don’t want to volunteer you don’t have to.

We know that doing investigator-led studies, with limited infrastructure, as investigator led trials are always under resourced, and hard work. Couple this with doing other clinical trials and it makes it more difficult.

Our investigator led trials clinical trials try to innovate and serve pwMS who do not get options such as Chariot-MS that is aimed at people who are excluded from treatment due to their advanced disease. With success the current treatment paradigm changes. Without success at least we tried.

It is not that we can’t do these things, but it is that we do not have the bandwidth to do so many studies. We have burnt out some of our excellent nurses because of the work load. Drop us a few million quid and we can do a lot more. Otherwise you have to accept us for what we are…..no not A-holes, although I am sure some people think this…. but an idea factory:-).

This blog is like the gift that keeps giving, as we put our ideas out in the public domain for others to say “Thanks very much”.

ProfG is a juggler and spends his day thinking. I and other members of the lab often walk behind him trying to catch some of the balls. Some we may let fall because they are not balls, but turkeys, but many will drop to the ground unless other people come along and catch them. We know we can’t do everything and we do what we do. Therefore, it is better that others do the trials than they don’t get done.

There are loads of ideas that we take no credit for. Ideas are ten a penny and people can have the same idea at the same time. Is it arrogant to suggest this?

ProfG suggested we need a trial comparing early highly-effective treatment verses the escalation route. This was an idea many years ago maybe he should be ProgG. It turned into a James Lind Alliance top ten questions for the MS Society. However we can’t do it because our neuros essentially do not use CRAB drugs. This is because we do not believe that they are good enough. It is a crying shame that we get so many referrals from neuros to treat with the more-effective agents, because they do not have the infrastructutre or the desire to use them and a lot of time has passed from diagnosis. We are left to pick up the pieces.

Some years ago ProfG also proposed the Zeus trial (Click Here to see the design) of doing head to head with Haemapoeitic stem cell therapy (HSCT) verses alemtuzumab, which was the most highly affective agent at the time. Although we have set up a HSCT clinic, we are not known as being HSCT experts, so maybe let other people run the show.

Although I may get told off for mentioning this now because there has been no fanfare, suggesting that it is not ready to go live yet, but if it’s on the internet it is out there and you can’t take it back. But did you know that people listened and this study was apparently funded in the UK by the National Institute for Health Research in the United Kingdom and should have started in Jan 2019.

Maybe it wasnt anything to do with us, cos we were only saying something obvious, but neuros are still doing monotherapy trials so maybe it is not that obvious. Maybe profG and some neuros got chatting. Maybe by reading the Zeus post the funders thought the idea wasn’t bad and so when they get the grant application to do the work they are already receptive. Who knows? Maybe profG does, but I’m a mushroom in the dark.

Anyway here is the funding announcement online.

EME Project:16/126/26 – STAR-MS: Autologous Stem Cell Transplantation versus Alemtuzumab or Ocrelizumab in Relapsing Remitting Multiple Sclerosis.

AIMS: 1. To determine whether autologous haematopoietic stem cell transplantation (aHSCT) has superior clinical efficacy to Alemtuzumab
with acceptable safety profile in patients with relapsing remitting multiple sclerosis (RRMS) who continued to relapse on first line Disease
Modifying Therapy (DMT)

2. To advance understanding of mechanisms of action of aHSCT by hypothesis-driven laboratory studies.

Why would ProfG ever want to run this, this is not ours main expertise or interest. There are an number of excellent sites and Prof John Snowden from Sheffield South Yorkshire is one of them and is the lead and gets the credit for doing the study. This is done with co-investigators Peniket A, Silber E, Kazmi M, Nicholas R, De Silva T, Beecher C, Paioannou D, Coles A, Venneri , Sharrack B, Young C, Giovannoni G, scolding N, Ciccarelli O, Muraro P, Walters S. Hopefully it allows the investigators a chance to visit Gods own Country.

There has been no announcement that I am aware of, probably because the temporary withdrawal of alemtuzumab caused a rethink. ProfG would have to comment on this. The machinery of the NIHR is so slow as ProfK will testify as his trial was given the go ahead ages ago and he is still waiting for the NIHR to sign on the dotted line and for it all to be wrapped up. It is in set-up. The study aims to recruit 198 pwMS from 19 sites across the UK. Participants in the study will be randomly allocated to receive either aHSCT or treatment with a highly effective DMT (Alemtuzumab or Ocrelizumab).  I don’t know why cladribine is not in the mix.

However, in the interim between that announcement and now the trial name has been adopted by the MRI crowd. They have the “Single Test to ARive at Multiple Sclerosis (STAR-MS) to determine if a central vein sign detected using FLAIR* = FLAIR-STAR can predict MS. Importantly the Americans and one of the STAR-MS team have pipped them to the post to essentially exactly the same trial of HSCT. This is called is called BEAT-MS and this is now recruiting and if you are eligible and are willing to have HSCT verses the best available this may be your opportunity. One site Cleveland Clinic is up and running

Best Available Therapy Versus Autologous Hematopoetic Stem Cell Transplant for Multiple Sclerosis (BEAT-MS) (BEAT-MS) has been put on NCT04047628 . This is funded by the National Institute of Allergy and Infectious Diseases (NIAID) which part of the National Institute of Health (NIH). This is done by the Immune Tolerance Network (ITN) and the Blood and Marrow Transplant Clinical Trials Network .

This is a multi-center prospective rater-masked (blinded) randomized controlled trial of 156 participants, comparing the treatment strategy of Autologous Hematopoietic Stem Cell Transplantation (AHSCT) to the treatment strategy of Best Available Therapy (BAT) for treatment-resistant relapsing multiple sclerosis (MS). Participants will be randomized at a 1 to 1 (1:1) ratio.

The question is what does BAT mean…in the Burt trials they did HSCT verses MS drug and the fact that some people got beta interferon or copaxone says something was wrong. If you are willing to take the risk of HSCT and you end up getting GA then this would be a problem, as you know the chances are that it is going to be abit rubbish. However, in this trial BAT is: natalizumab; alemtuzumab; ocrelizumab, or rituximab. Again not cladribine….maybe another bit of the antiG mobement. I suspect if the STAR-MS trial starts, ocrelizumab will be the main comparitor. In the US the trial is myoablative so you are replacing the immune system

The chairs are Prof Cohen (cleveland clinic), Georges (Washington state) and Paolo Muraro from London and is being done in 21 sites (20 in USA and 1 in UK).

I am sure this is interesting news to people, but it shows you that the community of neuros are not running frightened of the power of HSCT, but they are embracing this and putting it to the test in a scientific fashion.

However, for the HSCT zealots out there and you know who you are, please don’t comment unless it is something constructive and relevant.

Who will get there first? Do we need two trials? However, having two will help on validating the results. The immune tolerance network is behind the US study and provides an infrastructure of immunology thatbI suspect will be lacking in the UK version as the NIHR will be driving the costs down. However it is not two but three because but we have another potential trial .

RCT Comparing Autologous Hematopoietic Stem Cell Transplantation Versus Alemtuzumab in MS (RAM-MS). NCT03477500 in Finland aiming to look at 100 people

At the end of this if we don’t see that ablative HSCT is more effective I will be surprised. Why say that well it obvious that you are using a bigger sledge hammer to crack the nut and the nut stays cracked with a bigger hammer. Importantly the current data points in that direction.

Maybe the plus point of these studies is that we will see if alemtuzumab (T + B) is really superior to ocrelizumab (mainly B) as it is a head to head study. I guess the problem will be is whether enough people will select alemtuzumab over ocrelizumab , it is unlikely there will be enough rituximab use to show that ocrelizumab shows no more advantage. Therefore sadly it will be a head to head of HSCT verses ocrelizumab and so it will be T &B that wins for the wrong reasons. Hopefully it will be started soon enough so we can see the influence on atrophy that profG thinks exists.

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MouseDoctor

9 comments

  • Well I know of at least one neuro who is very scared and seems completely oblivious about HSCT, I SO wish we could have a conversation about HSCT with my partners neurologist without him looking at us as though we are naive idiots and basically making it clear that HSCT will not be discussed.

    In respect of the trial – any trial has to be good. Although I don’t understand why people with PPMS are not involved as it has been proved time and time again that HSCT can stop progression for PPMS.

    When is someone going to stand Up and shout to get some help for the many many people who are struggling daily with PPMS who have NO treatment options available in the UK (unless you ‘tick’ all the boxes!)These people are getting worse sometimes daily and nothing is being done to help them.

    • You have option to get another neuro. But they will have guidelines about when and if someone is eligible. You may not fit the criteria.

    • As for the issue to poms this is another question and another trial.

      Nothing is being done, that is not the case there is alot going.on behind the scenes.

    • … it has been proved time and time again that HSCT can stop progression for PPMS …

      Not sure this is correct; can you please direct us to the evidence? Peer-reviewed evidence please, not anecdote. I suspect your claim is one of the many false facts being promoted by the HSCT community.

      • The NHS is all the evidence I need, this treatment is being carried out on the NHS on people with PPMS. I don’t think the NHS would be carrying out such an expensive treatment if they had not done the research and have the evidence.

  • Laura Robb sent a comment that MS drugs don’t work.
    There are lots of trial data that show some efficacy.
    I said constructive comments please.
    Spammed today

  • I hope these various trials yield results quickly so that more patients can benefit from a proven best treatment. I don’t understand why the Cleveland trial is using a myelo-ablative protocol though, when Dr Burt’s MIST trial already shows that non-myelo is equally effective and has a better safety profile

  • The RAM-MS trial is well under way. I think they have treated 30-40 people already. Nonmyeloablative HSCT against the most efficiatious DMTs. I think it is a collaborative project led by clinicians in Bergen, Norway with Swedish and other European clinics taking part. I wish them the best of luck!!

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