Biomarker Report from the Phase II Lamotrigine Trial in Secondary Progressive MS - Neurofilament as a Surrogate of Disease Progression

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 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.

<p>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.</p

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.

<p>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.</p

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

<p>Power curves for determining sample size for changes percentage change in NfH levels.</p

Summary characteristics of subjects in the study according to randomisation, serum adherence and tablet compliance (p>0.05).

<p>Three samples were present in each sub-group corresponding to time points 0–12–24 months *, and of the 120 subjects who participated in the biomarker study there were 19 drop-outs ^†.</p

A diagrammatic representation of patient follow up and investigations.

<p>CSF sampling was performed at 6 and 18 m in 9 subjects and 12 m in 14 subjects.</p

Lamotrigine for neuroprotection in secondary progressive multiple sclerosis: a randomised, double-blind, placebo-controlled, parallel-group trial.

BACKGROUND: Partial blockade of voltage-gated sodium channels is neuroprotective in experimental models of inflammatory demyelinating disease. In this phase 2 trial, we aimed to assess whether the sodium-channel blocker lamotrigine is also neuroprotective in patients with secondary progressive multiple sclerosis. METHODS: Patients with secondary progressive multiple sclerosis who attended the National Hospital for Neurology and Neurosurgery or the Royal Free Hospital, London, UK, were eligible for inclusion in this double-blind, parallel-group trial. Patients were randomly assigned via a website by minimisation to receive lamotrigine (target dose 400 mg/day) or placebo for 2 years. Treating physicians, evaluating physicians, and patients were masked to treatment allocation. The primary outcome was the rate of change of partial (central) cerebral volume over 24 months. All patients who were randomly assigned were included in the primary analysis. This trial is registered with ClinicalTrials.gov, NCT00257855. FINDINGS: 120 patients were randomly assigned to treatment (87 women and 33 men): 61 to lamotrigine and 59 to placebo. 108 patients were analysed for the primary endpoint: 52 in the lamotrigine group and 56 in the placebo group. The mean change in partial (central) cerebral volume per year was -3.18 mL (SD -1.25) in the lamotrigine group and -2.48 mL (-0.97) in the placebo group (difference -0.71 mL, 95% CI -2.56 to 1.15; p=0.40). However, in an exploratory modelling analysis, lamotrigine treatment seemed to be associated with greater partial (central) cerebral volume loss than was placebo in the first year (p=0.04), and volume increased partially after treatment stopped (p=0.04). Lamotrigine treatment reduced the deterioration of the timed 25-foot walk (p=0.02) but did not affect other secondary clinical outcome measures. Rash and dose-related deterioration of gait and balance were experienced more by patients in the lamotrigine group than the placebo group. INTERPRETATION: The effect of lamotrigine on cerebral volume of patients with secondary progressive multiple sclerosis did not differ from that of placebo over 24 months, but lamotrigine seemed to cause early volume loss that reversed partially on discontinuation of treatment. Future trials of neuroprotection in multiple sclerosis should include investigation of complex early volume changes in different compartments of the CNS, effects unrelated to neurodegeneration, and targeting of earlier and more inflammatory disease. FUNDING: Multiple Sclerosis Society of Great Britain and Northern Ireland

Feminist Theory, Feminist Psychology: A Bibliography Of Epistemology, Critical Analysis, And Applications

A selection of recent (post-1980) works on feminist theory and method, this bibliography includes literature from psychology and other social sciences, feminist studies, and philosophy of science. The first of its four sections concerns epistemology and metatheory. The second lists works that offer reformulations or critical analyses of key concepts in gender studies; many of these are grounded in social constructionist and feminist standpoint epistemologies. The third section cites writings that illustrate the potential of new epistemological stances or exemplify new ways of working. The last section lists related bibliographies. (232 entries.