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    Time from diagnosis to death causing problems with clinical trials

    Good afternoon all

    Roger Leek kindly posted this in a Facebook group.

    https://www.facebook.com/ALSTherapyD...DEzNjY3NDk0Mw/

    And trying to find original let me to this, which is slightly different, more recent and more interesting;

    https://www.youtube.com/watch?v=P9CE...QbLxYv&index=1

    My takeaway from it is that some of us do not live long enough to be helpful to clinical trials, which therefore makes it difficult to work out what is causing it, which in turn means there are not enough of us living longer to help with clinical trials and so on :-(

    Best to all

    Andy
    Warmly


    Andy

    ​Diagnosed 03/2015. One sided limb onset (arm) sporadic ALS/MND. MND hitting - now 50% left arm and 90% right arm, plus other bits including left shoulder

    "Things turn out the best for people who make the best of the way things turn out"

    #2
    Thanks Andy.

    Two useful little videos.

    This problem of our very heterogeneous patient population and its relation to clinical trials was covered very well in the ALS Webinar on Tuesday that Ellie kindly flagged up. Still available I believe.

    https://www.als.net/als-webinars/register/05142019/

    Work is underway to find ways of stratifying the population to aid participant selection for trials.

    Another small step…..

    Doug

    Comment


      #3
      Oh the irony of it, eh Andy.....

      Random thoughts:

      I think that is why identifying so called subsets is important, but as to how to identify subsets, well, that seems to be beyond anyone for now!!!

      I am obviously in some sort of subset but have no apparent or obvious markers. If long survivors could be identified early on, they'd be good to throw into the mix of participants in clinical trials, in the hope some will live long enough to actually finish a trial. I am not sure how relevant trial results are @12, 24, 48 weeks are in the grand scheme of things???

      The Japanese trial result success of Edaravone is not being replicated in the general ALS population in the US. It's not Breaking News that Edaravone is thought to work only in a subset of people with ALS, which is why Europe is sceptical on its efficacy.

      Love Ellie.
      ​Diagnosed 03/2007. Sporadic Definite ALS/MND Limb Onset.
      Eye gaze user - No working limbs - No speech - Feeding tube - Overnight NIV.

      Comment


        #4
        Hi Ellie and Doug

        Thank you both - Ellie you have reminded me of my favourite irony joke, which is strangely current....

        "isn't it just a little ironic to see a group of pro-lifers throwing eggs at an abortion clinic?"

        I have to say I was a bit fed up when I wrote the original post because I felt that if I was right about my conclusion, the research community were blaming us for not being able to live longer.

        I had a session with my acupuncture practitioner this afternoon so I mentioned this to her and she quite understood my anger and in talking about it. I wondered whether the fix for this was either;

        a) concentrating on a diagnostic tool so that people get picked up earlier and therefore live long enough to take part in the trials

        b) find some way of testing drugs more quickly

        Clear that the ALS Therapy Development Institute understand this

        Warmly

        Andy
        Warmly


        Andy

        ​Diagnosed 03/2015. One sided limb onset (arm) sporadic ALS/MND. MND hitting - now 50% left arm and 90% right arm, plus other bits including left shoulder

        "Things turn out the best for people who make the best of the way things turn out"

        Comment


          #5
          Hi again

          And to add to that I'm told on facebook that I "make a very, very good point about trials and ALS/MND progress rate. "

          But to make matter even more difficult are two more additional factors.

          1) Time taken to achieve a diagnosis with a rapidly progressing disease is truly a major obstacle to find early stage volunteers

          2) But, conversely, so to is slow progress variants like PLS. Slow progression together with "plateauing" often seen, make almost impossible to detect the efficacy any innovative intervention might have. ( and hence the huge importance of the recently discovered P75 urine test. An easy test that responds promptly to changes/ progress or . . . lack of progress.)

          If someone proposes to launch a large scale, multi centre study, (phase 2 or phase3 trials) that for each volunteer participant lasts say, a year or more - but often also may require around a year follow up to validate any findings.

          To do all that meaningfully, researchers would need in excess of 300 people with MND to survive the full term of the study.

          That from an MND population - across UK of 3,000 to 5,000 per year - and median survival 14 months to 24 months is a tough ask.

          Researchers are however exploring potential 'short cuts' like precise matching age, sex, disease variant [? gene mutation], progression rates and 1:1 placebo control + P75 and other traditional progression measures.

          AI (Artificial Intelligence) is going to help, but even then, in all practical terms, it means almost ever single person with an MND diagnosis needs to volunteer!!

          Warmly

          Andy
          Warmly


          Andy

          ​Diagnosed 03/2015. One sided limb onset (arm) sporadic ALS/MND. MND hitting - now 50% left arm and 90% right arm, plus other bits including left shoulder

          "Things turn out the best for people who make the best of the way things turn out"

          Comment


            #6
            Hi,

            Does anyone have any idea whether staff at MND clinics routinely ask patients if they would be interested in volunteering for trials and/or studies?

            When I received my diagnosis I was an in-patient and had already offered myself as a guinea pig for student doctors and student nurses. It was a natural progression to offer myself for any studies/trials. The research team did all their necessary tests while I was still an in-patient. Now they automatically ask me if I would like to take part, if they have any others that I might be a 'fit' for.

            The research team also go to the MND clinic to see if they can sign people up.

            I'm just wondering if clinics need to be more proactive in their recruiting?
            Dina

            Trying to keep positive, but not always managing.

            Comment


              #7
              Hi Dina

              You raise an important point.

              In my experience of the researchers at the MND clinic at the John Radcliffe Hospital in Oxford – yes, they are proactive. I was asked on diagnosis if I would take part in various studies and have done so for the past couple of years.

              One of the reasons I was banging on recently about everybody should sign up on the MND register was because this is the place where researchers can find potential subjects if they don’t come across them at clinics.

              Well done for being a guinea pig!

              Doug

              Comment


                #8
                Biomarkers

                Hi Andy

                Yes, it can be difficult for researchers to assemble cohorts for trials – see my reply to Dina above. My view is we should help them to help maybe not us but future generations of MND patients.

                The P75 test is attractive because it’s easy to collect and analyse samples. And there is some evidence

                https://www.nature.com/articles/s41598-017-05430-w.pdf

                https://n.neurology.org/content/neur.../1137.full.pdf

                that it correlates with progression. However, from the published data, I think the correlation with the ALSFRS-R is weak. Nevertheless, it’s yet another potentially useful biomarker.

                There’s a very good recent review paper on biomarkers:

                https://www.ncbi.nlm.nih.gov/pmc/art...r-10-00191.pdf

                from the folks in Queensland that recognises the multifactorial nature of the problem.

                On a separate topic, I’m just hoping I’ll live long enough to learn the outcome of the IC14 monoclonal antibody study at the hospital there.

                Doug

                Comment


                  #9
                  Mick was diagnosed last July in Preston. He only sees the Respiratory department. When he had his Rig done in january a lady came and asked him to be part of a study, he agreed. She asked when he was next at clinic to see a nurse, we said mid March. She said 2 weeks before due to come she would send out paperwork for us to complete a diary of everything that he had eaten, we heard nothing!

                  Comment


                    #10
                    Hi Doug,

                    I am happy to be a guinea pig - there may as well be something useful that comes from having MND.
                    Dina

                    Trying to keep positive, but not always managing.

                    Comment


                      #11
                      Biomarkers

                      Another very comprehensive review of biomarkers - including imaging studies - has recently been published by the SITraN team at Sheffield.

                      https://www.frontiersin.org/articles...019.00291/full

                      Doug

                      Comment


                        #12
                        Good morning Doug

                        Originally posted by Doug Carpenter View Post
                        Another very comprehensive review of biomarkers - including imaging studies - has recently been published by the SITraN team at Sheffield
                        Thank you - as you say, really good summary.

                        Key line seems to be "Despite excellent attempts in each field, single useful biomarkers of ALS are as of yet out of reach"

                        What we do have is markers that allow some segmentation of those diagnosed for research study - e.g. the breathing test that has led me to be accepted for the for the REFALS trial, which is looking at the effects of oral levosimendan on the respiratory function in patients with ALS.

                        Mind you, I was on the edge of that as its almost 4 years since I saw the first signs of MND and they are not accepting people who were showing signs more than 4 years ago.

                        So I guess there is progress but with the caveats about selecting folk clinical trials above.

                        Warmly

                        Andy
                        Warmly


                        Andy

                        ​Diagnosed 03/2015. One sided limb onset (arm) sporadic ALS/MND. MND hitting - now 50% left arm and 90% right arm, plus other bits including left shoulder

                        "Things turn out the best for people who make the best of the way things turn out"

                        Comment


                          #13
                          Thanks for posting that Doug.


                          Originally posted by nunhead_man View Post

                          Key line seems to be "Despite excellent attempts in each field, single useful biomarkers of ALS are as of yet out of reach"
                          And with every failed attempt to find even one valid biomarker, it look as if MND is more of a syndrome...
                          ​Diagnosed 03/2007. Sporadic Definite ALS/MND Limb Onset.
                          Eye gaze user - No working limbs - No speech - Feeding tube - Overnight NIV.

                          Comment


                            #14
                            Quite right, Ellie.

                            I’m sure there are some mechanisms that will be found to be common across several types of MND – and possibly other neurodegenerative diseases. But as far as initial triggers are concerned, for example, I expect many different ones to emerge and different disease pathways found that will need to be explored.

                            Researchers face a daunting task!

                            Doug

                            Comment


                              #15
                              One point made in the webinar was that ALSFRS-R is somewhat subjective so a better indicator would eliminate subjective bias.

                              I hadn’t realised before the webinar just how many genes are implicated in inherited MND

                              Comment

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