Sunday, 12 February 2017

Measuring Progression...Does it bode well for the future?

Kuhle J, Nourbakhsh B, Grant D, Morant S, Barro C, Yaldizli Ö, Pelletier D, Giovannoni G, Waubant E, Gnanapavan S.Serum neurofilament is associated with progression of brain atrophy and disability in early MS. Neurology.  pii: 10.1212/WNL.0000000000003653.

OBJECTIVE:To investigate a potential effect of riluzole on serum neurofilaments (Nf) compared to placebo and the relationship between longitudinal clinical and MRI outcomes and serum Nf levels.
METHODS:Serum samples were obtained from participants enrolled in a randomized double-blind trial of neuroprotection with riluzole vs placebo as an add-on to weekly interferon-β (IFN-β)-1a IM initiated 3 months after randomization. Nf measurements were performed by ELISA and electrochemiluminescence immunoassay.
RESULTS:Longitudinal serum samples were available from 22 riluzole and 20 placebo participants over 24 months. There was no observed treatment effect with riluzole. Nf light chain (NfL) levels decreased over time (p = 0.007 at 24 months), whereas the Nf heavy chain was unchanged (p = 0.997). Changes in NfL were correlated with EDSS change (p = 0.009) and neuropsychological outcomes. Brain volume decreased more rapidly in patients with high baseline NfL (p = 0.05 at 12 months and p = 0.008 at 24 months) and this relationship became stronger at 24 months (p = 0.024 for interaction). Higher and increasing NfL predicted higher number of gadolinium-enhancing lesions (p < 0.001 for both).
CONCLUSIONS:Our findings support the potential value of serum NfL as a marker of neuroaxonal injury in early multiple sclerosis. Its reduction over time could represent regression to the mean, or a possible treatment effect of IFN-β-1a. The association with whole brain atrophy and the formation of acute white matter lesions has relevant implications to use serum NfL as a noninvasive biomarker of the overall consequences of brain damage and ongoing disease activity.

This is some work by NeuroDocG, but she won't report on it because she thinks she will be accussed of blowing her own trumpet.  So modest:-)

So, I do it. 

I would have to say this paper is disappointing :-)

So NDG should blow her own trumpet because she knows best what it means. 

Furthermore NDG would not pick the points I am about to discuss as a highlight or should I say Lowlight of the work.

Does it tell us that beta interferon saves nerves.

However, why is it disappointing, it is disappointing because it implies that riluzole is a drug that won't work to stop nerve loss. 

Riluzole is a drug that is a sodium channel blocker and a glutamate receptor blocker, so it should be neuroprotective, and block neurofilament release. This study implies that it does not do anything over and above what beta interferon may or may not do. 
This is because with time the neurofilament levels went down. 

Is this a treatment effect? or was it because people entered the trial when they were worse? 

But it says that if you have evidence of disease activity such as lesions then this is associated with damage as we would expect for the inflammatory penumbra.

So the claim that metabolites of tryptophan is the first biomarker of disease worsening, if a bit of a porkie pie. This is yet more evidence that neurofilament can pick up stuff.

However, what NDG would not say is that this study suggests that MS SMART may not be so smart, as this study suggests that it may not work in the secondary progressive trial.

MS SMART is a trial of 3 drugs against one placebo. The original aim was to replace the losers with new drugs in an adaptive design but has the process picked Donkeys and not Racehorses? 

We have no idea what fluoxetine does and how it may work....but it's prozac and an serotonin re-uptake inhibitor and so should at least make people less depressed, but a Dutch trial has failed to show it modifies progressive study since MS SMART started. 

More recently my favourite horse of the trio was reported to failed to inhibit optic neuritis and perhaps made myelination worse. The failing in optic neuritis should have been predicted because drug was started too late to be really useful. But the potential affect on myelination and the extra weeing that this drug may cause, could be disappointing.

We won't have too long to find out as MS SMART is now finishing.

So will MS SMART produce anything? 

I hope it does. The biology is there to support some value 

It will be disappointing if it doesn't. 

But if it doesn't,  

What would it say about the meta analysis to find the neuroprotective drugs? 
(Using Bog-standard EAE experiments to determine Neuroprotective (or repair drugs) is probably a waste of time). 
There is is masive publication bias for positive results and the data is often done in such a way as to make understanding the result in-intelligable. To find neuroprotectives I would look in the stroke and neurodegenerative disease literature.

What would it say about trial design? 
(Neuros killing off basic science ideas again)

or is the idea? 

Oh course I am playing Devil's Advocate...and there are explanations, why the big-SMART-three have not produced the goods in the studies I mentioned.

I'll get a good telling off by NDG next week:-)

3 comments:

  1. Lol, my answer to your semi-justified rant is that the test doesn't lie, it's biology plain and simple. That's not me touting my own trumpet, but 10 years + worth of evidence pointing to the same!

    ReplyDelete
    Replies
    1. :-)

      There you go...isn't it better when the author does their papers...

      Maybe the problem is with ProfG. 5-6 papers a week and he would not have time to post on anything else:-).

      A Blog and Tweet...one way to skew altmetrics :-)

      Delete
  2. This may explain why a small percentage of pwMS does not pass into the Secondarily Progressive stage of MS. So does GA, right?
    But why do the vast majority go to SPMS, because beta INF would lose neuroprotective efficacy?
    What are the most appropriate drugs as neuroprotective in the scientific literature?

    ReplyDelete

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