Monday, 17 March 2014

First UK NEDA Meeting

More on our trial to test treat-2-target of NEDA. #MSBlog #MSResearch #ClinicSpeak

"Klaus Schmierer in our group hosted the first UK NEDA (no evident disease activity meeting) last week (14 & 15th March 2014). The aim of the meeting was to discuss the initiatives in the UK to address the problems we are having of treating-2-target of NEDA under the current NICE guidelines and NHS England policy. All the attendees were very supportive of the concept of T2T-NEDA and trying to move things forward. Five initiatives were highlighted during the meeting to address the problems we are having treating MSers in the UK; these were:

1. The OPTIMISE Study - this is an initiative that is being led by Professor Paul Matthews at Imperial College. Paul was unsuccessful in getting the MRC grant last year. However, has secured money to get the complex database, and register, that will underpin this project funded. The database and register will underpin our efforts to T2T-NEDA.

2. The STRAT-MS study - this is a new grant application to the MRC to fund a stratified medicine initiative help define responders and non-responders to DMTs early on. It is being led by Professor Siddharthan Chandran in Edinburgh.

3. The CLARIMS Study - this study is being led by Dr Klaus Schmierer and will compare two induction therapies early in the course of MS; alemtuzumab vs. subcutaneous cladribine. This is low risk trial in that we already know that alemtuzumab and cladribine are effective. The study is testing two dose of cladribine and will be assessing whether or not cladribine is as effective as alemtuzumab. Based on the CLARITY, CLARITY extension and ORACLE data I am predicting that there will be little to choose between these agents. 

4. The T2-NEDA Study to is a pragmatic clinical trial to assess whether MSers managed actively with MRI monitoring will do better than MSers managed according to current NHS England and NICE guidelines. This study is being led by Professor Nikos Evangelou in Nottingham. As you know neurologists in the UK are handcuffed by these guidelines, which are very prescriptive and don’t allow switching or escalation of treatment using MRI. MSers have to fail on their therapy clinically, and sometimes badly, to access more effective therapies. At present MSers with smouldering MS are left to accrue end-organ damage on lower efficacy medication because we can’t escalate their treatment. The trial below will address this issue. It is a pragmatic clinical trial to see if MSers manage using a standard care pathway do worse than those managed more actively with a treat-2-target of no evident disease activity (NEDA). The latter algorithm will allow a single shot at a lower-tier efficacy drug before being escalated to a highly-efficacy therapy and will incorporate MRI monitoring. The current standard care pathway allows cycling on the lower tier and only escalation based on clinical criteria as per our current guidelines. The picture below sketches out the trial. Please note this has to be a randomised trial so that we can minimise any biases. On my recent trip to Australia, the Australians thought this study was unethical as they already monitor MSers actively and T2T of NEDA. The question is do you think this trial is ethical and would you be willing to participate in it? We are suggesting that it lasts 5 years, with an interim analysis at 3 years. The outcome at 3 years will be time to confirmed disability progression and at 5 years time to EDSS 3.5 or 4.0. We are still debating the latter and it will depend on the power calculations. We are using the time to EDSS of 3.5 or 4.0 as a surrogate to time to onset of SPMS. The latter will be controversial.

We are planning to produce a paper from the meeting and will almost be certainly be holding a follow-up meeting next year on the subject.”




11 comments:

  1. Great post. I like the way different neuros across the UK are leading different aspects. I do find it frustrating that the current guidelines are so restrictive and potentially damaging to MSers. I was on a Campath trial and now have an annual clinic appointment in Cambridge and an MRI every 18 months. Dr C always says that if there is any evidence of disease activity (he mentioned NEDA) then i would be given the option of another round of Alemtuzumab. It's 8 years since my second Campath infusion. So sad that others with MS don't have the choice. Who are the regulators and what are there motives for not allowing patients the option of getting treatments to limit the damage to their? Also i've been EDSS 3.5 since the end of my second Campath infusion (i had aggressive MS). I don't consider myself SPMS.

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    1. That's great to know. Glad Alemtuzumab is working for you and your EDSS is stable. Long may it continue.
      Hopefully many others will be given the chance. It's been approved by the EMA but not by the FDA (at least yet).

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  2. In a previos post the measure of IL-1beta in CSF was a marker of glial cell activation that may have been a better prognostic indicator for progression. Why is MRI/clinical exam not paired with CSF evaluation to better test for NEDA? Even in early MS the absence of CSF nfl and ILs point toward NEDA.

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    1. Re: ".... IL-1beta in CSF .... Why is MRI/clinical exam not paired with CSF evaluation to better test for NEDA? ....

      There is a reluctance to do frequent and repeated lumbar punctures. Therefore these bio-markers need validation. But I agree with you; we should include CSF biomarkers in the definition of NEDA.

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  3. Why is Klaus using cladribine? It will never see the light of day?

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    1. Re: "Why is Klaus using cladribine? It will never see the light of day?"

      Why not? Cladribine has a very good efficacy profile and its safety profile is no worse than some of the other DMTs. What we need is long-term safety and that will take years to accrue.

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  4. Prof G why is the NEDA trial raising ethical issues?

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    1. Re: "..why is the NEDA trial raising ethical issues?"

      Simply because in countries that don't have rationed healthcare and MSers have access to all DMTs as first-line therapies the neurologists are practicing T2T-NEDA. Therefore they feel any trial that disadvantages one group of subjects will be unethical. However, in the UK we are not allowed to escalate or switch treatment based on MRI monitoring therefore there is equipoise. All we will be doing is comparing standard clinical practice with rapid switching/escalation to achieve suppression of inflammatory disease activity. Any bets on which group will do better? Smoldering MS is a real issue and we in the UK have our hands tied behind our backs when it comes to treating this form of the disease.

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  5. Klaus Schmierer has left a new comment on your post "First UK NEDA Meeting":

    Why to pessimistic? Cladribine is a licensed treatment for hairy cell leukaemia, as is alemtuzumab for various types of lymphoma, and relapsing MS. Cladribine only 'didn't see the light of day' (ie. didn't obtain a license) because one manufacturer decided to withdraw their efforts after EMA rejection. The data so far suggest cladribine's efficacy is on a level with alemtuzumab, and it's probably safer and more convenient. But more data is needed, therefore the trial.

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  6. Is the decision of NICE to forbid treatment choice based on MRI solely to do with cost? Can't we definitely say that MRI + clinical assessment gives a more complete picture than clinical symptoms alone?

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    1. Re: "Is the decision of NICE to forbid treatment choice based on MRI solely to do with cost?"

      Partly, they tend to focus on class 1 evidence and not post-marketing data. However, they need to relook at this issue; MRI monitoring may be cost effective if it is delaying disease progression and the onset of secondary progression.

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