Biomarker report from the phase II lamotrigine trial in secondary progressive MS - neurofilament as a surrogate of disease progression

Abstract

Objective: Lamotrigine trial in SPMS was a randomised control trial to assess whether partial blockade of sodium channels has a neuroprotective effect. The current study was an additional study to investigate the value of neurofilament (NfH) and other biomarkers in predicting prognosis and/or response to treatment.

Methods: SPMS patients who attended the NHNN or the Royal Free Hospital, UK, eligible for inclusion were invited to participate in the biomarker study. Primary outcome was whether lamotrigine would significantly reduce detectable serum NfH at 0-12, 12-24 and 0-24 months compared to placebo. Other serum/plasma and CSF biomarkers were also explored.

Results: Treatment effect by comparing absolute changes in NfH between the lamotrigine and placebo group showed no difference, however based on serum lamotrigine adherence there was significant decline in NfH (NfH 12-24 months p=0.043, Nfh 0-24 months p=0.023). Serum NfH correlated with disability: walking times, 9-HPT (non-dominant hand), PASAT, z-score, MSIS-29 (psychological) and EDSS and MRI cerebral atrophy and MTR. Other biomarkers explored in this study were not found to be significantly associated, aside from that of plasma osteopontin.

Conclusions: The relations between NfH and clinical scores of disability and MRI measures of atrophy and disease burden support NfH being a potential surrogate endpoint complementing MRI in neuroprotective trials and sample sizes for such trials are presented here. We did not observe a reduction in NfH levels between the Lamotrigine and placebo arms, however, the reduction in serum NfH levels based on lamotrigine adherence points to a possible neuroprotective effect of lamotrigine on axonal degeneration.

Figure 1. A diagrammatic representation of patient follow up and investigations.

CSF sampling was performed at 6 and 18 m in 9 subjects and 12 m in 14 subjects.

Figure 2. The relationship between serum biomarkers NfH, NOx, GFAP, BDNF, NGF and clinical (MSFC, EDSS, MSIS-29) as well as MRI measures are presented in tabular form and as forest plots.

a) 25-foot walk (secs); b) 9-hole peg test, dominant had (secs); c) 9-hole peg test, non-dominant hand (secs); d) Paced Auditory Serial Addition Test (PASAT); e) Z-score; f) Expanded Disability Status Scale (EDSS); g) Multiple Sclerosis Impact Scale (MSIS-29) physical; h) MSIS-29 psychological; i) Magnetization Transfer Ratio (MTR) white matter; j) MTR grey matter; k) MTR whole brain; l) MRI Central Cerebral Volume (MRICCV); m) T1 volume; n) T2 volume.

Figure 3. Survival curves of walking times and 9-hole peg test times (dominant and non-dominant hand) are plotted according to absent, below median or above median NfH levels.

Figure 4. Power curves for determining sample size for changes percentage change in NfH levels.