Getting rid of MRI as an outcome measure in trials may be feasible


Blood neurofilament light as a potential endpoint in Phase 2 studies in MS


To assess whether neurofilament light chain (NfL) could serve as an informative endpoint in Phase 2 studies in patients with relapsing–remitting multiple sclerosis (RRMS) and estimate the sample size requirements with NfL as the primary endpoint.


Using data from the Phase 3 FREEDOMS study, we evaluated correlation of NfL at Month 6 with 2‐year outcomes: relapses, confirmed disability worsening (CDW), new or enlarging T2 lesions (active lesions), and brain volume loss (BVL). We compared the proportion of treatment effect (PTE) on 2‐year relapses and BVL explained by 6‐month log‐transformed NfL levels with the PTE explained by the number of active lesions over 6 months. We estimated sample size requirements for different treatment effects.Results

At Month 6, blood NfL levels (pg/mL, median [range]) were lower in the fingolimod arm (fingolimod (n = 132) 18 [8–247]; placebo (n = 114) 26 [8–159], P < 0.001). NfL at 6 months correlated with number of relapses (r = 0.25, P < 0.001 [This comment is rubbish and r=0.25 is meaningless as far as correlation goes OK it is statistically different but so what!], 6‐month CDW (hazard ratio 1.83, P = 0.012), active lesions (r = 0.46, P < 0.001 [ditto]), and BVL (r = −0.41, P < 0.001 [ditto]) at Month‐24. The PTE (95% CI) on 24‐month relapses and BVL explained by 6‐month NfL was 25% (8–60%) and 60% (32–132%), and by 6‐month active lesions was 28% (11–66%) and 45% (18–115%), respectively. Assuming a 20–40% treatment‐related reduction in NfL levels, 143‐28 patients per arm will be required.

“See what I mean about r=0.46 being meaningless. You have a high neurofilament level, how many T2 active lesions do you have? At the individual level it impossible to guess what is the outcome


Blood NfL may qualify as an informative and easy‐to‐measure endpoint for future Phase 2 clinical studies that captures both inflammatory‐ and non-inflammatory‐driven neuroaxonal injury in RRMS.

This study looked at data from fingolimod phase III trial to address if measuring neurofilament could be an outcome in a phase II trial. at the moment we are using imaging outcomes.Using neurofilament measurements one can pick-up disease activity. There is no doubt it can pick up inflammatory-driven neuroaxonal loss, but how good it is for measuring progressive neurodegeneration is not totally clear. The authors suggest this is non-inflammatory, this is not likely as progressive neurodegeneration is inflammatory, it is just a different type of inflammation.

As for the correlations made, I wish this level of correlation was binned as being uninterpretable. This is why we have so many MRI studies that really mean nothing in terms of prediction. Sure it helps neuros get a feel for what may occur down the line but as a prediction of an individual’s journey it will not cut the mustard. By accepting such this, we do not strive to get better and perhaps progress with MRI has not been as good as one would like.

This used blood neurofilament levels. It is suggested to correlated with levels in CSF, maybe NDG or ProfG will give an opinion on whether blood levels are good enough for “prime-time” use.

Update. The correlation is not good.

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  • “This used blood neurofilament levels. It is suggested to correlated with levels in CSF”

    Aparently in RRms not in PPms

    In RRMS, serum and plasma levels of NfL serve well as surrogates for CSF NfL and may be useful surrogates of
    MRI disease activity. PPMS CSF NfL levels may be a useful surrogate of MRI activity, however peripheral levels
    of NfL in PPMS may not serve well as a surrogate for CSF NfL levels

    NfL Levels in CSF, Serum, and Plasma of RRMS and PPMS Patients in a Cross-sectional
    UCSF Cohort

    AAN 2019

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