Poll results: outcome measures and brain atrophy

“The headline result is that MSers rate a delay in disease progression the most important outcome measures in relation to DMTs.”

“The problem with disability progression in relatively short RRMS clinical trials is that the outcome measure is driven by relapses. Relapses change the EDSS in the short-term, which may not relate to long-term disability progression; I have said, on may occasions in the recent past, that the correlation between relapses and long-term outcome is very poor.”

“How do relapses drive short-term disability progression? This occurs because of the way we analyse disability progression using a statistical technique called the survival curve. For example, if you have an EDSS of 2.0 and have a relapse that increases your EDSS to 4.0, and your EDSS stays at this level for 4 months before you recover over the next 6 months back to an EDSS of 2.0, you will defined in the trial as having progressed, simply because your EDSS increased by more than 1.0 point for longer than 3 months. Despite having no effect on the average EDSS scores across a population of MSers in clinical trials many DMTs claim to have an impact on disability progression simply because of this effect; this scenario happens because more relapses occur in trial subjects on placebo than on active treatment.”

“This effect of relapses on the survival curve is a major confounder and is the reason why I believe that to claim that a particular drug has impact on disability progression it also need to impact on the average EDSS scores across the study and have an impact on objective MRI measures that we have linked to disease progression, for example brain atrophy. I am therefore very impressed that 38% of readers of this blog rated brain atrophy as the most important outcome measure for a DMT. I am not sure in myself that it should be rated this highly at this point in time, simply because we still have a lot for us to learn about its meaning and role in MS. Despite this brain atrophy does offer us a window into the brain and probably correlates with neuroprotective effects of DMTs. This is why DMTs that have a positive impact on brain atrophy are more-than-likely to have a positive impact on long-term disability progression, the outcome measure that is the most important to MSers.”

9 thoughts on “Poll results: outcome measures and brain atrophy”

  1. Prof. G do you think that some of the people who respond to these polls do not have MS, but instead are researchers who know a lot about MRI and other issues? The high result for brain atrophy could be explained by this.

  2. The pharma companies who have good atrophy outcomes with their DMT/DMTs will be using this to differentiate their drugs from others. So the message will soon become subject to marketing warfare with one group of companies promoting the value of brain atrophy as outcome measure and the other group of companies muddying the waters and stating that we can't interpret brain atrophy as it has yet to linked to a clinically meaningful outcome. I have been here before. This is what happened with neutralizing anti-interferon beta antibodies. May be we should get in before the marketeers and stake our claim? I think most people in the field think brain atrophy is an important negative outcome, slowing the rate of atrophy can only be a good thing! So I remain impressed with the results of this survey. May common sense rule the day.

    1. But I thought atrophy could be linked to EDSS? Also it should be linked to neurofilament levels because axon loss=less brain substance, right? Surely it you are slowly losing half of your brain cells it shows as disability, on what planet are some of the pharma guys living to think that an average MSer won't notice that this fact alone is 'a clinically meaningful outcome'? Just don't forget to include this survey in all of your slides and state that that's the MSers view of things, Prof. G.

  3. Atrophy linked to EDSS, yes it may be but EDSS is a measure of movement and some of this will depend on what goes on in the spinal cord which may be related but somewhat independent of brain atrophy. Atrophy may impact on cognitive outcome.ke In terms of neurofilament levels in the CNS tissues it probably will relate to nerve content but in fluids like CSF it is reflective of damage at a point in time.

  4. I was not aware of the survival curve used in statistical analysis before. How maddening. Long-term disability, atrophy etc are my biggest concern.

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