Systematic review of prediction models in relapsing remitting multiple sclerosis

The natural history of relapsing remitting multiple sclerosis (RRMS) is variable and prediction of individual prognosis challenging. The inability to reliably predict prognosis at diagnosis has important implications for informed decision making especially in relation to disease modifying therapies. We conducted a systematic review in order to collate, describe and assess the methodological quality of published prediction models in RRMS. We searched Medline, Embase and Web of Science. Two reviewers independently screened abstracts and full text for eligibility and assessed risk of bias. Studies reporting development or validation of prediction models for RRMS in adults were included. Data collection was guided by the checklist for critical appraisal and data extraction for systematic reviews (CHARMS) and applicability and methodological quality assessment by the prediction model risk of bias assessment tool (PROBAST). 30 studies were included in the review. Applicability was assessed as high risk of concern in 27 studies. Risk of bias was assessed as high for all studies. The single most frequently included predictor was baseline EDSS (n = 11). T2 Lesion volume or number and brain atrophy were each retained in seven studies. Five studies included external validation and none included impact analysis. Although a number of prediction models for RRMS have been reported, most are at high risk of bias and lack external validation and impact analysis, restricting their application to routine clinical practice

Bostonia: The Boston University Alumni Magazine. Volume 12

Founded in 1900, Bostonia magazine is Boston University’s main alumni publication

Synthesis, characterisation and photochemistry of PtIV pyridyl azido acetato complexes

PtII azido complexes [Pt(bpy)(N3)2] (1), [Pt(phen)(N3)2] (2) and trans-[Pt(N3)2(py)2] (3) incorporating the bidentate diimine ligands 2,2′-bipyridine (bpy), 1,10-phenanthroline (phen) or the monodentate pyridine (py) respectively, have been synthesised from their chlorido precursors and characterised by X-ray crystallography; complex 3 shows significant deviation from square-planar geometry (N3–Pt–N3 angle 146.7°) as a result of steric congestion at the Pt centre. The novel PtIV complexes trans, cis-[Pt(bpy)(OAc)2(N3)2] (4), trans, cis-[Pt(phen)(OAc)2(N3)2] (5), trans, trans, trans-[Pt(OAc)2(N3)2(py)2] (6), were obtained from 1–3via oxidation with H2O2 in acetic acid followed by reaction of the intermediate with acetic anhydride. Complexes 4–6 exhibit interesting structural and photochemical properties that were studied by X-ray, NMR and UV-vis spectroscopy and TD-DFT (time-dependent density functional theory). These PtIV complexes exhibit greater absorption at longer wavelengths (ε = 9756 M−1 cm−1 at 315 nm for 4; ε = 796 M−1 cm−1 at 352 nm for 5; ε = 16900 M−1 cm−1 at 307 nm for 6, in aqueous solution) than previously reported PtIV azide complexes, due to the presence of aromatic amines, and 4–6 undergo photoactivation with both UVA (365 nm) and visible green light (514 nm). The UV-vis spectra of complexes 4–6 were calculated using TD-DFT; the nature of the transitions contributing to the UV-vis bands provide insight into the mechanism of production of the observed photoproducts. The UV-vis spectra of 1–3 were also simulated by computational methods and comparison between PtII and PtIV electronic and structural properties allowed further elucidation of the photochemistry of 4–6

Amiloride, fluoxetine or riluzole to reduce brain volume loss in secondary progressive multiple sclerosis: the MS-SMART four-arm RCT

Background: Neuroprotective drugs are needed to slow or prevent neurodegeneration and disability accrual in secondary progressive multiple sclerosis. Amiloride, fluoxetine and riluzole are repurposed drugs with potential neuroprotective effects. Objectives: To assess whether or not amiloride, fluoxetine and riluzole can reduce the rate of brain volume loss in people with secondary progressive multiple sclerosis over 96 weeks. The secondary objectives that were assessed were feasibility of a multiarm trial design approach, evaluation of anti-inflammatory effects, clinician- and patient-reported efficacy and three mechanistic substudies. Design: A multicentre, multiarm, randomised, double-blind, placebo-controlled, parallel-group Phase IIb trial with follow-up at 4, 8, 12, 24, 36, 48, 72 and 96 weeks. Patients, investigators (including magnetic resonance imaging analysts), and treating and independent assessing neurologists were blinded to the treatment allocation. The target sample size was 440 patients. Setting: Thirteen UK clinical neuroscience centres. Participants: Participants were aged 25–65 years, had secondary progressive multiple sclerosis with evidence of disease progression independent of relapses in the previous 2 years, and had an Expanded Disability Status Scale score of 4.0–6.5. Patients were ineligible if they could not have a magnetic resonance imaging scan; had a relapse or steroids in the previous 3 months; or had epilepsy, depression, bipolar disorder, glaucoma, bleeding disorders or significant organ comorbidities. Exclusion criteria were concurrent disease-modified treatments, immunosuppressants or selective serotonin reuptake inhibitors. Interventions: Participants received amiloride (5 mg), fluoxetine (20 mg), riluzole (50 mg) or placebo (randomised 1 : 1 : 1 : 1) twice daily. Main outcome measures: The primary end point was magnetic resonance imaging-derived percentage brain volume change at 96 weeks. Secondary end points were new/enlarging T2 lesions, pseudoatrophy, and clinician- and patient-reported measures (including the Expanded Disability Status Scale, Multiple Sclerosis Functional Composite, Symbol Digit Modalities Test, low-contrast letter visual acuity, Multiple Sclerosis Impact Scale 29 items, version 2, Multiple Sclerosis Walking Scale, version 2, and questionnaires addressing pain and fatigue). The exploratory end points included measures of persistent new T1 hypointensities and grey matter volume changes. The substudies were advanced magnetic resonance imaging, optical coherence tomography and cerebrospinal fluid analyses. Results: Between December 2014 and June 2016, 445 patients were randomised (analysed) to amiloride [n = 111 (99)], fluoxetine [n = 111 (96)], riluzole [n = 111 (99)] or placebo [n = 112 (99)]. A total of 206 randomised patients consented to the advanced magnetic resonance imaging substudy, 260 consented to the optical coherence tomography substudy and 70 consented to the cerebrospinal fluid substudy. No significant difference was seen between the active drugs and placebo in percentage brain volume change at week 96 as follows (where negative values mean more atrophy than placebo): amiloride minus placebo 0.0% (Dunnett-adjusted 95% confidence interval –0.4% to 0.5%), fluoxetine minus placebo –0.1% (Dunnett-adjusted 95% confidence interval –0.5% to 0.3%); riluzole minus placebo –0.1% (Dunnett-adjusted 95% confidence interval –0.6% to 0.3%). There was good adherence to study drugs. The proportion of patients experiencing adverse events was similar in the treatment and placebo groups. There were no emergent safety issues. Limitations: There was a lower than expected uptake in the cerebrospinal fluid substudy. Conclusions: A multiarm Phase II paradigm is efficient in determining which neuroprotective agents to take through to Phase III trials. Amiloride, fluoxetine and riluzole were not effective in reducing the brain atrophy rate in people with secondary progressive multiple sclerosis. Mechanistic pathobiological insight was gained. Future work: To use the information gained from the Multiple Sclerosis-Secondary Progressive Multi-Arm Randomisation Trial (MS-SMART) to inform future trial design as new candidate agents are identified. Trial registration: Current Controlled Trials ISRCTN28440672, NCT01910259 and EudraCT 2012-005394-31. Funding: This project was funded by the Efficacy and Mechanism Evaluation (EME) programme, a Medical Research Council and National Institute for Health Research (NIHR) partnership. This will be published in full in Efficacy and Mechanism Evaluation; Vol. 7, No. 3. See the NIHR Journals Library website for further project information. This trial also received funding from the UK MS Society and the US National Multiple Sclerosis Society

A battery of strength tests for evidence-based classification in Para swimming

This study examined the validity of isometric strength tests for evidence-based classification in Para swimming. Thirty non-disabled participants and forty-two Para swimmers with physical impairment completed an isometric strength test battery designed to explain activity limitation in the freestyle discipline. Measures pertaining to dominant and non-dominant limb strength and symmetry were derived from four strength tests that were found to be reliable in a cohort of non-disabled participants (ICC = 0.85–0.97; CV = 6.4–9.1%). Para swimmers had lower scores in strength tests compared with non-disabled participants (d = 0.14–1.00) and the strength test battery successfully classified 95% of Para swimmers with physical impairment using random forest algorithm. Most of the strength measures had low to moderate correlations (r = 0.32 to 0.53; p ≤ 0.05) with maximal freestyle swim speed in Para swimmers. Although, fewer correlations were found when Para swimmers with hypertonia or impaired muscle power were analysed independently, highlighting the impairment-specific nature of activity limitation in Para swimming. Collectively, the strength test battery has utility in Para swimming classification to infer loss of strength in Para swimmers, guide minimum eligibility criteria, and to define the impact that strength impairment has on Para swimming performance

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

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

Safety and efficacy of bexarotene in patients with relapsing-remitting multiple sclerosis (CCMR One): a randomised, double-blind, placebo-controlled, parallel-group, phase 2a study

Background: Progressive disability in multiple sclerosis occurs because CNS axons degenerate as a late consequence of demyelination. In animals, retinoic acid receptor RXR-gamma agonists promote remyelination. We aimed to assess the safety and efficacy of a non-selective retinoid X receptor agonist in promoting remyelination in people with multiple sclerosis. Methods: This randomised, double-blind, placebo-controlled, parallel-group, phase 2a trial (CCMR One) recruited patients with relapsing-remitting multiple sclerosis from two centres in the UK. Eligible participants were aged 18–50 years and had been receiving dimethyl fumarate for at least 6 months. Via a web-based system run by an independent statistician, participants were randomly assigned (1:1), by probability-weighted minimisation using four binary factors, to receive 300 mg/m2 of body surface area per day of oral bexarotene or oral placebo for 6 months. Participants, investigators, and outcome assessors were masked to treatment allocation. MRI scans were done at baseline and at 6 months. The primary safety outcome was the number of adverse events and withdrawals attributable to bexarotene. The primary efficacy outcome was the patient-level change in mean lesional magnetisation transfer ratio between baseline and month 6 for lesions that had a baseline magnetisation transfer ratio less than the within-patient median. We analysed the primary safety outcome in the safety population, which comprised participants who received at least one dose of their allocated treatment. We analysed the primary efficacy outcome in the intention-to-treat population, which comprised all patients who completed the study. This study is registered in the ISRCTN Registry, 14265371, and has been completed. Findings: Between Jan 17, 2017, and May 17, 2019, 52 participants were randomly assigned to receive either bexarotene (n=26) or placebo (n=26). Participants who received bexarotene had a higher mean number of adverse events (6·12 [SD 3·09]; 159 events in total) than did participants who received placebo (1·63 [SD 1·50]; 39 events in total). All bexarotene-treated participants had at least one adverse event, which included central hypothyroidism (n=26 vs none on placebo), hypertriglyceridaemia (n=24 vs none on placebo), rash (n=13 vs one on placebo), and neutropenia (n=10 vs none on placebo). Five (19%) participants on bexarotene and two (8%) on placebo discontinued the study drug due to adverse events. One episode of cholecystitis in a placebo-treated participant was the only serious adverse event. The change in mean lesional magnetisation transfer ratio was not different between the bexarotene group (0·25 percentage units [pu; SD 0·98]) and the placebo group (0·09 pu [0·84]; adjusted bexarotene–placebo difference 0·16 pu, 95% CI –0·39 to 0·71; p=0·55). Interpretation: We do not recommend the use of bexarotene to treat patients with multiple sclerosis because of its poor tolerability and negative primary efficacy outcome. However, statistically significant effects were seen in some exploratory MRI and electrophysiological analyses, suggesting that other retinoid X receptor agonists might have small biological effects that could be investigated in further studies. Funding: Multiple Sclerosis Society of the United Kingdom

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).RIGHTS : This article is licensed under the BioMed Central licence at http://www.biomedcentral.com/about/license which is similar to the 'Creative Commons Attribution Licence'. In brief you may : copy, distribute, and display the work; make derivative works; or make commercial use of the work - under the following conditions: the original author must be given credit; for any reuse or distribution, it must be made clear to others what the license terms of this work are