Ruben van Eijk

Check out the findings of our review exploring the use of digital devices for monitoring physical behaviour in #MND jmir.org/2025/1/e68479 @profcjmcdermott @DrEstherHobson @alysgriffiths_ @Fred_Steyn @LiamKnox92 @rpavaneijk @DeirdreMurray6a @EmmaHTole @GladysOP1 @HoldomCory

P A van Eijk et al. report that a trimetazidine trial for ALS showed it was safe and well-tolerated. It reduced oxidative stress markers and resting energy expenditure, suggesting potential for further study. Read at:buff.ly/HNd3No6 @rpavaneijk @Fred_Steyn @AmmarAlChalab

Our study on the safety and tolerability of Trimetazidine in #ALS @braincomms Trimetazidine reduced oxidative stress markers and energy expenditure, warranting a follow up study. @rpavaneijk @Fred_Steyn @AmmarAlChalabi academic.oup.com/braincomms/adv…

⁉️ ¿Te perdiste el VIII Encuentro Internacional de la #ELA en España? Un evento científico organizado por la #frAreces y la @FundacionLuzon Recuerda que puedes verlo cuando quieras en nuestro canal 🖥️: · youtube.com/live/a-TSyp-Df… (ESP) · youtube.com/live/mLFVsSX13… (ENG)

POTW 5: Patient Ranked Order of Function (PROOF) as a modified interpretation of the ALSFRS-R. An emerging alternative approach to optimize the detection of individualized function to predict survival and other outcomes in ALS. @UMCUtrecht @rpavaneijk doi.org/10.1212/WNL.00…

Amyotrophic lateral sclerosis established as a multistep process across phenotypes | Multistep process has been established across #ALS; the number of steps to develop disease is different across clinical presentations @rpavaneijk⁩ ⁦@WolfVucic⁩ pubmed.ncbi.nlm.nih.gov/39475283/

@Jeanc9orf72 I think for early stage trials/phase 2 it is indeed not the best strategy to use a crude thing as the FRS, but at some point we need to show a drug also has clinical meaning, then # of motor unit is not sufficient and we need clinical outcomes including the FRS, QoL, survival

@rpavaneijk Why would we ever use such a crude thing as alsfrs (which provides only suspect approvals in America and Canada) when this knowledge of motor loss prior to functional impairment was documented in the 70s?

To put a finer point on this- disease progression and functional decline are not on a 1:1 basis.

@Jeanc9orf72 There are some papers that provide some insight, for example that about half of the motor neurons are lost before you even notice functional limitations. Quite interesting area to develop novel noninvasive outcomes for trials. Here is one example paper nature.com/articles/s4159…

@rpavaneijk I think when considering weakness, the latter three are nearly instant, whereas we are ignorant of the timing of the first. I guess with the exception of sod1 a5v als where it appears to be about a 6-12 month process.

@Jeanc9orf72 So yes, I agree with you that disease progression is not 1:1 related to functional decline. There are many steps leading up to ALSFRS-R loss, which maybe captured earlier by other endpoints (muscle streng, motor unit estimates, wet biomarkers?)

@Jeanc9orf72 I like the Nagi model to outline the concept (example below). There will be motor neuron loss (e.g., CMAP scan) before it leads to muscle strength loss (e.g., HHD), which will lead eventually to loss in function (e.g., ALSFRS-R), finally followed by reduction in QoL.

In the latest DEI blog, authors Weemering and @rpavaneijk discuss barriers to inclusive clinical trial participation for neurodegenerative diseases and potentially modifiable factors to increase underrepresented patient populations. bit.ly/4d5msB1 #NeuroTwitter

@Jeanc9orf72 Just to provide an opposing view - not necessarily mine - is that HIV was effectively treated by combining treatments that on their own have modest effects. By combining them together one may have a synergistic effect. In that view, it could make sense to go for modest effects.

#9 how is this controversial- Who needs another drug that patients nor clinicians can discern someone is actually taking vs throwing it away. Now that’s not to say if you are shooting for the fences and hit a single it shouldn’t be reckoned with.

@BlockAntonious @alsadvocacy My main worry with suboptimal control arms in trials is that we comprise our own decision making, for example initiating more futile phase 3 trials or end up with debatable market applications with global disagreement … this may only delay a treatment further

@BlockAntonious @alsadvocacy I get your reasoning and completely agree on the urgency. I am not saying old data is useless, I only don’t think we are there yet to get fully rid of current placebo arms for the reasons above. Likely a hybrid solution - mixing placebo data - is most promising and efficient

The pendulum swings in ALS Land. There is always a big Q: How do you get inclusion criteria that give you healthy enough people on the therapy & at the same time give a placebo group that drops off. Criteria are as much about selecting the control group as the treatment group.

@BlockAntonious @alsadvocacy So some placebo treatment is needed as long as we don’t have hugely effective treatments. We can think about strategies, however, how to re-use some old placebo data and mix that with current placebo data, so current patients have a higher change on active treatments. 3/3

@BlockAntonious @alsadvocacy These small differences influence the disease trajectory. This would be a small problem if we expect huge treatment effects, but for ALS we expect relatively small gains (e.g. 20 – 25% slowing). These small effects can become quickly twisted if we use imprecise control data 2/3

@alsadvocacy Good points! An additional thought for registration trials may be to consider how representative the included population is for all people living with ALS/MND. If we are too selective, how sure are we that the drug benefits the 'average' patient (and is safe) outside the trial?

Finally, we extended our online calculator to illustrate the comparisons used by PROOF with various sets of preferences and integration with the Combined Assessment of Function and Survival (CAFS). The calculator is open-source and can be found here: tricals.shinyapps.io/PROOF/ 5/5

We also evaluated the prognostic impact of incorporating patient preferences, showing that patient-reported preferences can be safely incorporated and does not weaken the association between function and overall survival. 4/5

Happy to share that our new #openaccess paper has been published in the @GreenJournal: Cultivating Patient Preferences in ALS Clinical Trials: Reliability and Prognostic Value of the Patient-Ranked Order of Function (PROOF). 1/5 neurology.org/doi/10.1212/WN…