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

PLoS One. 2013 Aug 1;8(8):e70019. doi: 10.1371/journal.pone.0070019. Print 2013.

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.

Publication types

  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, Non-P.H.S.

MeSH terms

  • Atrophy / complications
  • Biomarkers / blood
  • Biomarkers / cerebrospinal fluid
  • Brain / drug effects
  • Brain / metabolism
  • Brain / pathology
  • Clinical Trials, Phase II as Topic*
  • Disease Progression*
  • Female
  • Humans
  • Lamotrigine
  • Magnetic Resonance Imaging
  • Male
  • Middle Aged
  • Multiple Sclerosis / complications
  • Multiple Sclerosis / diagnosis
  • Multiple Sclerosis / drug therapy*
  • Multiple Sclerosis / metabolism*
  • Neurofilament Proteins / blood*
  • Neurofilament Proteins / cerebrospinal fluid*
  • Prognosis
  • Spinal Cord / drug effects
  • Spinal Cord / metabolism
  • Spinal Cord / pathology
  • Time Factors
  • Treatment Outcome
  • Triazines / therapeutic use*

Substances

  • Biomarkers
  • Neurofilament Proteins
  • Triazines
  • Lamotrigine

Grant support

This work was supported by National MS Society (USA) under the Promise 2010 initiative and the MS Society of Great Britain and Northern Ireland as part of exploratory analysis for the UK MS Clinical Trial Network. VL is supported by Italian Minister of Health grant for young researcher 2008. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.