Efficacy of three neuroprotective drugs in secondary progressive multiple sclerosis (MS-SMART): a phase 2b, multiarm, double-blind, randomised placebo-controlled trial.

BACKGROUND: Neurodegeneration is the pathological substrate that causes major disability in secondary progressive multiple sclerosis. A synthesis of preclinical and clinical research identified three neuroprotective drugs acting on different axonal pathobiologies. We aimed to test the efficacy of these drugs in an efficient manner with respect to time, cost, and patient resource. METHODS: We did a phase 2b, multiarm, parallel group, double-blind, randomised placebo-controlled trial at 13 clinical neuroscience centres in the UK. We recruited patients (aged 25-65 years) with secondary progressive multiple sclerosis who were not on disease-modifying treatment and who had an Expanded Disability Status Scale (EDSS) score of 4·0-6·5. Participants were randomly assigned (1:1:1:1) at baseline, by a research nurse using a centralised web-based service, to receive twice-daily oral treatment of either amiloride 5 mg, fluoxetine 20 mg, riluzole 50 mg, or placebo for 96 weeks. The randomisation procedure included minimisation based on sex, age, EDSS score at randomisation, and trial site. Capsules were identical in appearance to achieve masking. Patients, investigators, and MRI readers were unaware of treatment allocation. The primary outcome measure was volumetric MRI percentage brain volume change (PBVC) from baseline to 96 weeks, analysed using multiple regression, adjusting for baseline normalised brain volume and minimisation criteria. The primary analysis was a complete-case analysis based on the intention-to-treat population (all patients with data at week 96). This trial is registered with ClinicalTrials.gov, NCT01910259. FINDINGS: Between Jan 29, 2015, and June 22, 2016, 445 patients were randomly allocated amiloride (n=111), fluoxetine (n=111), riluzole (n=111), or placebo (n=112). The primary analysis included 393 patients who were allocated amiloride (n=99), fluoxetine (n=96), riluzole (n=99), and placebo (n=99). No difference was noted between any active treatment and placebo in PBVC (amiloride vs placebo, 0·0% [95% CI -0·4 to 0·5; p=0·99]; fluoxetine vs placebo -0·1% [-0·5 to 0·3; p=0·86]; riluzole vs placebo -0·1% [-0·6 to 0·3; p=0·77]). No emergent safety issues were reported. The incidence of serious adverse events was low and similar across study groups (ten [9%] patients in the amiloride group, seven [6%] in the fluoxetine group, 12 [11%] in the riluzole group, and 13 [12%] in the placebo group). The most common serious adverse events were infections and infestations. Three patients died during the study, from causes judged unrelated to active treatment; one patient assigned amiloride died from metastatic lung cancer, one patient assigned riluzole died from ischaemic heart disease and coronary artery thrombosis, and one patient assigned fluoxetine had a sudden death (primary cause) with multiple sclerosis and obesity listed as secondary causes. INTERPRETATION: The absence of evidence for neuroprotection in this adequately powered trial indicates that exclusively targeting these aspects of axonal pathobiology in patients with secondary progressive multiple sclerosis is insufficient to mitigate neuroaxonal loss. These findings argue for investigation of different mechanistic targets and future consideration of combination treatment trials. This trial provides a template for future simultaneous testing of multiple disease-modifying medicines in neurological medicine. FUNDING: Efficacy and Mechanism Evaluation (EME) Programme, an MRC and NIHR partnership, UK Multiple Sclerosis Society, and US National Multiple Sclerosis Society.

Psychometric properties of the PHQ-9 depression scale in people with multiple sclerosis: A systematic review.

BACKGROUND: Depression affects approximately 25% of people with MS (pwMS) at any given time. It is however under recognised in clinical practice, in part due to a lack of uptake for brief assessment tools and uncertainty about their psychometric properties. The 9-item Patient Health Questionnaire (PHQ-9) is an attractive candidate for this role. OBJECTIVE: To synthesise published findings on the psychometric properties of the 9-item Patient Health Questionnaire (PHQ-9) when applied to people with multiple sclerosis (pwMS). DATA SOURCES: PubMed, Medline and ISI Web of Science databases, supplemented by hand-searching of references from all eligible sources. STUDY ELIGIBILITY CRITERIA: Primary literature written in English and published following peer-review with a primary aim to evaluate the performance of the PHQ-9 in pwMS. OUTCOME MEASURES: Psychometric performance with respect to appropriateness, reliability, validity, responsiveness, precision, interpretability, acceptability, and feasibility. RESULTS: Seven relevant studies were identified, these were of high quality and included 5080 participants from all MS disease-course groups. Strong evidence was found supporting the validity of the PHQ-9 as a unidimensional measure of depression. Used as a screening tool for major depressive disorder (MDD) with a cut-point of 11, sensitivity was 95% sensitivity and specificity 88.3% (PPV 51.4%, NPV 48.6%). Alternative scoring systems that may address the issue of overlap between somatic features of depression and features of MS per se are being developed, although their utility remains unclear. However data on reliability was limited, and no specific evidence was available on test-retest reliability, responsiveness, acceptability, or feasibility. CONCLUSIONS: The PHQ-9 represents a suitable tool to screen for MDD in pwMS. However use as a diagnostic tool cannot currently be recommended, and the potential value for monitoring depressive symptoms cannot be established without further evidence on test-retest reliability, responsiveness, acceptability, and feasibility. REGISTRATION: PROSPERO register ID: CRD42017067814.

Autologous mesenchymal stem cells for the treatment of secondary progressive multiple sclerosis: an open-label phase 2a proof-of-concept study.

BACKGROUND: More than half of patients with multiple sclerosis have progressive disease characterised by accumulating disability. The absence of treatments for progressive multiple sclerosis represents a major unmet clinical need. On the basis of evidence that mesenchymal stem cells have a beneficial effect in acute and chronic animal models of multiple sclerosis, we aimed to assess the safety and efficacy of these cells as a potential neuroprotective treatment for secondary progressive multiple sclerosis. METHODS: Patients with secondary progressive multiple sclerosis involving the visual pathways (expanded disability status score 5·5-6·5) were recruited from the East Anglia and north London regions of the UK. Participants received intravenous infusion of autologous bone-marrow-derived mesenchymal stem cells in this open-label study. Our primary objective was to assess feasibility and safety; we compared adverse events from up to 20 months before treatment until up to 10 months after the infusion. As a secondary objective, we chose efficacy outcomes to assess the anterior visual pathway as a model of wider disease. Masked endpoint analyses was used for electrophysiological and selected imaging outcomes. We used piecewise linear mixed models to assess the change in gradients over time at the point of intervention. This trial is registered with ClinicalTrials.gov, number NCT00395200. FINDINGS: We isolated, expanded, characterised, and administered mesenchymal stem cells in ten patients. The mean dose was 1·6×10(6) cells per kg bodyweight (range 1·1-2·0). One patient developed a transient rash shortly after treatment; two patients had self-limiting bacterial infections 3-4 weeks after treatment. We did not identify any serious adverse events. We noted improvement after treatment in visual acuity (difference in monthly rates of change -0·02 logMAR units, 95% CI -0·03 to -0·01; p=0·003) and visual evoked response latency (-1·33 ms, -2·44 to -0·21; p=0·020), with an increase in optic nerve area (difference in monthly rates of change 0·13 mm(2), 0·04 to 0·22; p=0·006). We did not identify any significant effects on colour vision, visual fields, macular volume, retinal nerve fibre layer thickness, or optic nerve magnetisation transfer ratio. INTERPRETATION: Autologous mesenchymal stem cells were safely given to patients with secondary progressive multiple sclerosis in our study. The evidence of structural, functional, and physiological improvement after treatment in some visual endpoints is suggestive of neuroprotection. FUNDING: Medical Research Council, Multiple Sclerosis Society of Great Britain and Northern Ireland, Evelyn Trust, NHS National Institute for Health Research, Cambridge and UCLH Biomedical Research Centres, Wellcome Trust, Raymond and Beverly Sackler Foundation, and Sir David and Isobel Walker Trust.

The mesenchymal stem cells in multiple sclerosis (MSCIMS) trial protocol and baseline cohort characteristics: an open-label pre-test: post-test study with blinded outcome assessments.

BACKGROUND: No treatments are currently available that slow, stop, or reverse disease progression in established multiple sclerosis (MS). The Mesenchymal Stem Cells in Multiple Sclerosis (MSCIMS) trial tests the safety and feasibility of treatment with a candidate cell-based therapy, and will inform the wider challenge of designing early phase clinical trials to evaluate putative neuroprotective therapies in progressive MS. Illustrated by the MSCIMS trial protocol, we describe a novel methodology based on detailed assessment of the anterior visual pathway as a model of wider disease processes--the "sentinel lesion approach". METHODS/DESIGN: MSCIMS is a phase IIA study of autologous mesenchymal stem cells (MSCs) in secondary progressive MS. A pre-test : post-test design is used with healthy controls providing normative data for inter-session variability. Complementary eligibility criteria and outcomes are used to select participants with disease affecting the anterior visual pathway. RESULTS: Ten participants with MS and eight healthy controls were recruited between October 2008 and March 2009. Mesenchymal stem cells were successfully isolated, expanded and characterised in vitro for all participants in the treatment arm. CONCLUSIONS: In addition to determining the safety and feasibility of the intervention and informing design of future studies to address efficacy, MSCIMS adopts a novel strategy for testing neuroprotective agents in MS--the sentinel lesion approach--serving as proof of principle for its future wider applicability. TRIAL REGISTRATION: ClinicalTrials.gov (NCT00395200).

Procedural confidence in hospital based practitioners: implications for the training and practice of doctors at all grades.

BACKGROUND: Medical doctors routinely undertake a number of practical procedures and these should be performed competently. The UK Postgraduate Medical Education and Training Board (PMETB) curriculum lists the procedures trainees should be competent in. We aimed to describe medical practitioner's confidence in their procedural skills, and to define which practical procedures are important in current medical practice. METHODS: A cross sectional observational study was performed measuring procedural confidence in 181 hospital practitioners at all grades from 2 centres in East Anglia, England. RESULTS: Both trainees and consultants provide significant service provision. SpR level doctors perform the widest range and the highest median number of procedures per year. Most consultants perform few if any procedures, however some perform a narrow range at high volume. Cumulative confidence for the procedures tested peaks in the SpR grade. Five key procedures (central line insertion, lumbar puncture, pleural aspiration, ascitic aspiration, and intercostal drain insertion) are the most commonly performed, are seen as important generic skills, and correspond to the total number of procedures for which confidence can be maintained. Key determinants of confidence are gender, number of procedures performed in the previous year and total number of procedures performed. CONCLUSION: The highest volume of service requirement is for six procedures. The procedural confidence is dependent upon gender, number of procedures performed in the previous year and total number of procedures performed. This has implications for those designing the training curriculum and with regards the move to shorten the duration of training.