Exploring Outcome Measures of disease progression in Secondary Progressive Multiple Sclerosis

Multiple sclerosis (MS) is a disabling and progressive neurological disease affecting more than 120,000 people in the UK and 2.5 million people worldwide. Most people diagnosed with relapsing-remitting MS (RRMS) experience a late phase of the disease characterised by gradual progression of impairment of neurological function, known as secondary progressive MS (SPMS). The underlying cause of disability accrual in SPMS is attributed to progressive neuro-axonal loss (neurodegeneration). Unlike RRMS, treatments for SPMS are lacking and research from clinical trials has provided only modest positive results. This thesis concerns my work on a multi-centre, multi-arm, placebo-controlled phase 2B clinical trial (MS-SMART, ClinicalTrials.gov NCT01910259) investigating neuroprotection in SPMS. Through this trial, I investigated: (1) cross-sectional relationships between clinical and radiological outcomes that characterise a well-defined UK SPMS population not on disease-modifying therapy; (2) whether amiloride, fluoxetine and riluzole – the three pre-identified putative neuroprotective drugs used in the MS-SMART trial – reduced the rate of MRI-derived brain atrophy compared to placebo; (3) whether spinal cord MRI measures - reflecting cord damage and atrophy - were predictors of long-term disease course in people with SPMS and could be reliably used as outcome measures in future phase 2 trials; and (4) whether optical coherence tomography (OCT) measures were predictors of long-term disease course in people with SPMS and had a role in the measurement of neuroaxonal loss in future phase 2 trials. I collected several measures of disability, which included the expanded disability status scale (EDSS), the symbol digit modalities test (SDMT), the multiple sclerosis functional composite (MSFC) and its sub-components (9-holep peg test, timed 25-foot walk, paced auditory serial addition test), and multiple sclerosis impact scale (MSIS-29v2). To characterise the trial cohort at baseline and identify the variables that could better explain the sample variance, I used some sophisticated statistical analyses (principal component analysis, LASSO regression analysis) which helped to deal with the multiplicity of the variables. I also looked at some of the MS symptoms onset and comorbidities and their relationships with disease severity using multivariate analyses. To investigate neuroprotection in the whole trial cohort, I measured MRI-derived percentage brain volume change, which is thought to reflect neuroaxonal integrity and disability. The percentage brain volume change was analysed with the SIENA method. As MS-related disability is also referable to spinal cord damage, which is seen in up to 90% of patients with MS, I investigated spinal cord MRI abnormalities in the UCL cohort. I measured the cervical cord lesion number and volume, and calculated cord cross-sectional area using the active surface model. Additionally, I measured the cross-sectional area using two different pipelines to improve reduceing variability and get more reliable results. Although MRI techniques are reliable and sensitive surrogate biomarkers of axonal pathology in MS, they are expensive, time consuming and not easily accessible. OCT is an emerging imaging technique that enables the measurement of the neural retina, whose layer thinning reflect axonal loss. In order to do so, I used a Heidelberg Spectralis OCT machine and measured the peripapillary retinal nerve fibre layer and the ganglion cell plus the inner plexiform layer thicknesses. Both participants from UCL and Edinburgh trial sites were included. From December 2014 to June 2016, I actively recruited 176 subjects at UCL. In total, 445 subjects were enrolled in the MS-SMART trial across the UK. The baseline analysis of the whole cohort showed that none of the clinical measures could explain the sample variance in isolation and that the SDMT – a measure of processing speed – emerged as the strongest explanatory component, although it could not explain more than 30% of the sample variance. The SDMT and the body mass index were the strongest predictor of whole brain volume. I also found that a history of optic neuritis at MS onset did not predict a better SPMS prognosis, while a history of hypertension was related to higher disease severity. The primary trial analysis findings were negative, meaning that there was no difference in terms of percentage brain volume change between any of the three active arms and the placebo. This suggested that amiloride, fluoxetine and riluzole had no neuroprotective effects. The annualised percentage brain volume change was -0.87%. In the fluoxetine arm, there was a significant pseudoatrophy at 24 weeks suggesting perhaps possible neuromodulation with some anti-inflammatory effects. Spinal cord atrophy occurred at a rate of -0.66% per year on average. Both spinal cord area and brain volume measures at baseline were significantly associated with EDSS at baseline and at 96 weeks. However, only spinal cord area at baseline, and not brain volume, seemed to predict confirmed disability progression at 96 weeks (OR= 0.94; 95% CI= 0.89 to 0.98, p= 0.01). The results from the two different spinal cord MRI analysis pipelines showed that head position into the scanner and lack of registration between baseline and follow-up would lead to substantial variability. However, when the sample size was larger, the two pipelines seemed to offer similar results. OCT measures showed significant mean annual thinning independent of age. Additionally, baseline OCT measures could significantly predict clinical changes as measured by the two most common clinical metrics (EDSS and MSFC) and with the MRI-derived percentage brain volume change at 96 weeks. There was no correlation between annualised atrophy rates of OCT measures and MRI percentage brain volume change or EDSS change. In summary, the cross-sectional analysis of the baseline characteristics of the trial cohort showed that the SDMT is an important clinical variable which correlates significantly with other clinical and MRI parameters. My study suggests that SDMT should be collected in all cross-sectional studies in SPMS. I found that multi-arm trials are feasible in a UK population of people with SPMS. None of the three drugs – amiloride, fluoxetine, and riluzole - had neuroprotective effects, suggesting that future trials in SPMS should focus on different agents with different mechanisms of action. The role of fluoxetine as an anti-inflammatory was questionable and might deserve more investigations in the future. I also found that the annual rates of brain volume and spinal cord atrophy were similar, although brain volume atrophy was slightly higher than spinal cord atrophy. However, both these measures were significantly associated with EDSS. Brain volume had the advantage of being associated with the timed 25-foot walk measure; whereas, spinal cord area had the advantage to predict confirmed disability progression at 96 weeks. OCT measures significantly decreased over time independently of patients’ age. Baseline OCT measures could predict EDSS changes and EDSS at 96 weeks, but the percentage change of OCT measures had no relation with EDSS changes, suggesting that the observation time of 96 weeks was insufficient to detect clinically meaningful OCT changes. In conclusion, analysing a large cohort of patients with SPMS enrolled in a phase 2B trial provided a large data set which served to explore outcome measures of disease progression. I found that none of the clinical, MRI or OCT variables was optimal, in isolation, to measure SPMS disability or progression. OCT and spinal cord MRI did not seem to provide better outcomes compared to MRI brain measures alone, implying that they could measure different aspects of the pathology underlying SPMS. My work suggests that investigation of composite outcome measures of multimodal variables might be the way forward to find more sensitive outcome measures for quantifying disability changes. Finally, my work also shows that multi-arm trials investigating different agents at the same time are feasible and advantageous in SPMS and should be replicated in MS and extended to other chronic neurological disorders

Multiple sclerosis: changes in microarchitecture of white matter tracts after training with a video game balance board

Purpose: To determine if high-intensity, task-oriented, visual feedback training with a video game balance board (Nintendo Wii) induces significant changes in diffusion-tensor imaging (DTI) parameters of cerebellar connections and other supratentorial associative bundles and if these changes are related to clinical improvement in patients with multiple sclerosis.Conclusion: Despite the low statistical power (35%) due to the small sample size, the results showed that training with the balance board system modified the microstructure of superior cerebellar peduncles. The clinical improvement observed after training might be mediated by enhanced myelinationrelated processes, suggesting that high-intensity, taskoriented exercises could induce favorable microstructural changes in the brains of patients with multiple sclerosis.Materials and Methods: The protocol was approved by local ethical committee; each participant provided written informed consent. In this 24-week, randomized, two-period crossover pilot study, 27 patients underwent static posturography and brain magnetic resonance (MR) imaging at study entry, after the first 12-week period, and at study termination. Thirteen patients started a 12-week training program followed by a 12-week period without any intervention, while 14 patients received the intervention in reverse order. Fifteen healthy subjects also underwent MR imaging once and underwent static posturography. Virtual dissection of white matter tracts was performed with streamline tractography; values of DTI parameters were then obtained for each dissected tract. Repeated measures analyses of variance were performed to evaluate whether DTI parameters significantly changed after intervention, with false discovery rate correction for multiple hypothesis testing.Results: There were relevant differences between patients and healthy control subjects in postural sway and DTI parameters (P <.05). Significant main effects of time by group interaction for fractional anisotropy and radial diffusivity of the left and right superior cerebellar peduncles were found (F2,23 range, 5.555-3.450; P = .036-.088 after false discovery rate correction). These changes correlated with objective measures of balance improvement detected at static posturography (r = 20.381 to 0.401, P < .05). However, both clinical and DTI changes did not persist beyond 12 weeks after training

Relationship between prolactin plasma levels and white matter volume in women with multiple sclerosis

BACKGROUND: The role of prolactin (PRL) on tissue injury and repair mechanisms in multiple sclerosis (MS) remains unclear. The aim of this work was to investigate the relationship between PRL plasma levels and brain damage as measured by magnetic resonance imaging (MRI). METHODS: We employed a chemiluminescence immunoassay for measuring plasma levels of PRL. We used a 1.5 T scanner to acquire images and Jim 4.0 and SIENAX software to analyse them. RESULTS: We included 106 women with relapsing remitting (RR) MS and stable disease in the last two months. There was no difference in PRL plasma levels between patients with and without gadolinium enhancement on MRI. PRL plasma levels correlated with white matter volume (WMV) (rho = 0.284, p = 0.014) but not with grey matter volume (GMV). Moreover, PRL levels predicted changes in WMV (Beta: 984, p = 0.034). CONCLUSIONS: Our data of a positive association between PRL serum levels and WMV support the role of PRL in promoting myelin repair as documented in animal models of demyelination. The lack of an increase of PRL in the presence of gadolinium enhancement, contrasts with the view considering this hormone as an immune-stimulating and detrimental factor in the inflammatory process associated with MS

Oral contraceptives combined with interferon β in multiple sclerosis

Objective: To test the effect of oral contraceptives (OCs) in combination with interferon b (IFN-b) on disease activity in patients with relapsing-remitting multiple sclerosis (RRMS). Methods: One hundred fifty women with RRMS were randomized in a 1:1:1 ratio to receive IFNb-1a subcutaneously (SC) only (group 1), IFN-b-1a SC plus ethinylstradiol 20 mg and desogestrel 150 mg (group 2), or IFN-b-1a SC plus ethinylestradiol 40 mg and desogestrel 125 mg (group 3). The primary endpoint was the cumulative number of combined unique active (CUA) lesions on brain MRI at week 96. Secondary endpoints included MRI and clinical and safety measures. Results: The estimated number of cumulative CUA lesions at week 96 was 0.98 (95% confidence interval [CI] 0.81–1.14) in group 1, 0.84 (95% CI 0.66–1.02) in group 2, and 0.72 (95% CI 0.53–0.91) in group 3, with a decrease of 14.1% (p 5 0.24) and 26.5% (p 5 0.04) when comparing group 1 with groups 2 and 3, respectively. The number of patients with no gadoliniumenhancing lesions was greater in group 3 than in group 1 (p 5 0.03). No significant differences were detected in other secondary endpoints. IFN-b or OC discontinuations were equally distributed across groups. Conclusions: Our results translate the observations derived from experimental models to patients, supporting the anti-inflammatory effects of OCs with high-dose estrogens, and suggest possible directions for future research

Differentiating Multiple Sclerosis From AQP4-Neuromyelitis Optica Spectrum Disorder and MOG-Antibody Disease With Imaging

Multiple sclerosis; Neuromyelitis optica; ImagingEsclerosis múltiple; Neuromielitis óptica; ImágenesEsclerosi múltiple; Neuromielitis òptica; ImatgesBackground and Objectives Relapsing-remitting multiple sclerosis (RRMS), aquaporin-4 antibody–positive neuromyelitis optica spectrum disorder (AQP4-NMOSD), and myelin oligodendrocyte glycoprotein antibody–associated disease (MOGAD) may have overlapping clinical features. There is an unmet need for imaging markers that differentiate between them when serologic testing is unavailable or ambiguous. We assessed whether imaging characteristics typical of MS discriminate RRMS from AQP4-NMOSD and MOGAD, alone and in combination. Methods Adult, nonacute patients with RRMS, APQ4-NMOSD, and MOGAD and healthy controls were prospectively recruited at the National Hospital for Neurology and Neurosurgery (London, United Kingdom) and the Walton Centre (Liverpool, United Kingdom) between 2014 and 2019. They underwent conventional and advanced brain, cord, and optic nerve MRI and optical coherence tomography (OCT). Results A total of 91 consecutive patients (31 RRMS, 30 APQ4-NMOSD, and 30 MOGAD) and 34 healthy controls were recruited. The most accurate measures differentiating RRMS from AQP4-NMOSD were the proportion of lesions with the central vein sign (CVS) (84% vs 33%, accuracy/specificity/sensitivity: 91/88/93%, p < 0.001), followed by cortical lesions (median: 2 [range: 1–14] vs 1 [0–1], accuracy/specificity/sensitivity: 84/90/77%, p = 0.002) and white matter lesions (mean: 39.07 [±25.8] vs 9.5 [±14], accuracy/specificity/sensitivity: 78/84/73%, p = 0.001). The combination of higher proportion of CVS, cortical lesions, and optic nerve magnetization transfer ratio reached the highest accuracy in distinguishing RRMS from AQP4-NMOSD (accuracy/specificity/sensitivity: 95/92/97%, p < 0.001). The most accurate measures favoring RRMS over MOGAD were white matter lesions (39.07 [±25.8] vs 1 [±2.3], accuracy/specificity/sensitivity: 94/94/93%, p = 0.006), followed by cortical lesions (2 [1–14] vs 1 [0–1], accuracy/specificity/sensitivity: 84/97/71%, p = 0.004), and retinal nerve fiber layer thickness (RNFL) (mean: 87.54 [±13.83] vs 75.54 [±20.33], accuracy/specificity/sensitivity: 80/79/81%, p = 0.009). Higher cortical lesion number combined with higher RNFL thickness best differentiated RRMS from MOGAD (accuracy/specificity/sensitivity: 84/92/77%, p < 0.001). Discussion Cortical lesions, CVS, and optic nerve markers achieve a high accuracy in distinguishing RRMS from APQ4-NMOSD and MOGAD. This information may be useful in clinical practice, especially outside the acute phase and when serologic testing is ambiguous or not promptly available. Classification of Evidence This study provides Class II evidence that selected conventional and advanced brain, cord, and optic nerve MRI and OCT markers distinguish adult patients with RRMS from AQP4-NMOSD and MOGAD.The study was funded by the UK MS Society (Grant No.: 917-09) and the National Institute for Health and Care Re- search (RP-2017-08-ST2-004)

Spatial patterns of brain lesions assessed through covariance estimations of lesional voxels in multiple Sclerosis: The SPACE-MS technique

Anisotropy; Lesion spatial distribution; Multiple sclerosisAnisotropia; Distribució espacial de la lesió; Esclerosi múltipleAnisotropía; Distribución espacial de la lesión; Esclerosis múltiplePredicting disability in progressive multiple sclerosis (MS) is extremely challenging. Although there is some evidence that the spatial distribution of white matter (WM) lesions may play a role in disability accumulation, the lack of well-established quantitative metrics that characterise these aspects of MS pathology makes it difficult to assess their relevance for clinical progression. This study introduces a novel approach, called SPACE-MS, to quantitatively characterise spatial distributional features of brain MS lesions, so that these can be assessed as predictors of disability accumulation. In SPACE-MS, the covariance matrix of the spatial positions of each patient’s lesional voxels is computed and its eigenvalues extracted. These are combined to derive rotationally-invariant metrics known to be common and robust descriptors of ellipsoid shape such as anisotropy, planarity and sphericity. Additionally, SPACE-MS metrics include a neuraxis caudality index, which we defined for the whole-brain lesion mask as well as for the most caudal brain lesion. These indicate how distant from the supplementary motor cortex (along the neuraxis) the whole-brain mask or the most caudal brain lesions are. We applied SPACE-MS to data from 515 patients involved in three studies: the MS-SMART (NCT01910259) and MS-STAT1 (NCT00647348) secondary progressive MS trials, and an observational study of primary and secondary progressive MS. Patients were assessed on motor and cognitive disability scales and underwent structural brain MRI (1.5/3.0 T), at baseline and after 2 years. The MRI protocol included 3DT1-weighted (1x1x1mm3) and 2DT2-weighted (1x1x3mm3) anatomical imaging. WM lesions were semiautomatically segmented on the T2-weighted scans, deriving whole-brain lesion masks. After co-registering the masks to the T1 images, SPACE-MS metrics were calculated and analysed through a series of multiple linear regression models, which were built to assess the ability of spatial distributional metrics to explain concurrent and future disability after adjusting for confounders. Patients whose WM lesions laid more caudally along the neuraxis or were more isotropically distributed in the brain (i.e. with whole-brain lesion masks displaying a high sphericity index) at baseline had greater motor and/or cognitive disability at baseline and over time, independently of brain lesion load and atrophy measures. In conclusion, here we introduced the SPACE-MS approach, which we showed is able to capture clinically relevant spatial distributional features of MS lesions independently of the sheer amount of lesions and brain tissue loss. Location of lesions in lower parts of the brain, where neurite density is particularly high, such as in the cerebellum and brainstem, and greater spatial spreading of lesions (i.e. more isotropic whole-brain lesion masks), possibly reflecting a higher number of WM tracts involved, are associated with clinical deterioration in progressive MS. The usefulness of the SPACE-MS approach, here demonstrated in MS, may be explored in other conditions also characterised by the presence of brain WM lesions.Carmen Tur is currently being funded by a Junior Leader La Caixa Fellowship. The project that gave rise to these results received the support of a fellowship from ”la Caixa” Foundation (ID 100010434). The fellowship code is LCF/BQ/PI20/11760008. She has also received the 2021 Merck’s Award for the Investigation in MS, awarded by the Merck Foundation. In 2015, she received an ECTRIMS Post-doctoral Research Fellowship and has received funding from the UK MS Society. She has also received honoraria from Roche and Novartis. Francesco Grussu has received funding under the European Union’s Horizon 2020 research and innovation programme under grant agreement No. 634541, from the Engineering and Physical Sciences Research Council (EPSRC EP/R006032/1, M020533/1) and Rosetrees Trust (UK), and is now supported by PREdICT (a study funded by AstraZeneca in Spain). Ferran Prados was supported by the Guarantors of Brain and the National Institute for Health Research, University College London Hospitals Biomedical Research Centre. Rosa Cortese is supported by the ECTRIMS-MAGNIMS fellowships programme. Alberto Calvi is supported by ECTRIMS-MAGNIMS fellowship (2018), Guarantors of Brain “Entry” clinical fellowship (2019) and the UK MS Society PhD studentship (2020). Declan Chard is a consultant for Biogen and Hoffmann-La Roche. In the last 3 years, he has received research funding from the International Progressive MS Alliance, the UK MS Society, and the National Institute for Health Research (NIHR) University College London Hospitals (UCLH) Biomedical Research Centre. Jeremy Chataway, in the last three years, has received support from the Efficacy and Evaluation (EME) Programme, a Medical Research Council (MRC) and National Institute for Health Research (NIHR) partnership and the Health Technology Assessment (HTA) Programme (NIHR), the UK MS Society, the US National MS Society and the Rosetrees Trust. He is supported in part by the National Institute for Health Research, University College London Hospitals, Biomedical Research Centre, London, UK. He has been a local principal investigator for a trial in MS funded by the Canadian MS society. A local principal investigator for commercial trials funded by: Actelion, Biogen, Novartis and Roche; has received an investigator grant from Novartis; and has taken part in advisory boards/consultancy for Azadyne, Biogen, Celgene, Janssen, MedDay, Merck, Novartis and Roche. Alan J Thompson acknowledges grant support from the National Institute for Health Research HTA and BRC, and has received honoraria for consultancy from Eisai and Abbvie (paid to Institution), support for travel for consultancy from the International Progressive MS Alliance and National MS Society (USA), and receives an honorarium from SAGE Publishers as Editor-in-Chief of Multiple Sclerosis Journal. Olga Ciccarelli is supported by the National Institute for Health Research, University College London Hospitals Biomedical Research Centre. OC also receives research grant support from the MS Society of Great Britain and Northern Ireland, and the NIHR UCLH Biomedical Research Centre. She is an Associate Editor for Neurology, for which he receives an honorarium. Claudia A.M. Gandini Wheeler-Kingshott has received research grants (principal investigator and co-applicant) from the UK MS Society (#77), Wings for Life (#169111), BRC (#BRC704/CAP/CGW), UCL Global Challenges Research Fund (GCRF), MRC (#MR/S026088/1), Ataxia UK. CGWK is a shareholder in Queen Square Analytics Ltd

Effect on cognition of estroprogestins combined with Interferon beta in multiple sclerosis: analysis of secondary outcomes from a randomized controlled trial

Introduction Cognitive impairment is a disabling symptom in multiple sclerosis (MS). While its management remains challenging, beneficial effects on cognition of interferon beta (IFN-β) have been reported and a positive effect from estroprogestins has been hypothesised, suggesting that the combination of the two medications in women with MS could offer a promising treatment strategy. Objectives We investigated whether a combination of estroprogestins and IFN-β can improve cognition in women with MS. Methods Women with relapsing-remitting (RR) MS were randomly assigned (1:1:1) to receive subcutaneous IFN-β-1a (Rebif®, Merck Serono, Geneva, Switzerland) 44 mcg three times a week (tiw) (group 1), subcutaneous IFN-β-1a 44 mcg tiw plus ethinyl estradiol 20 mcg and desogestrel 150 mcg (Mercilon®, MSD Italia SRL, Rome, Italy) (group 2) or subcutaneous IFN-β-1a 44 mcg tiw plus ethinyl estradiol 40 mcg and desogestrel 125 mcg (Gracial®, Organon Italia S.p.A., Rome, Italy) (group 3) in a randomised controlled trial, for which we report the analysis of secondary outcomes. At baseline and at 24 months, all patients underwent magnetic resonance imaging (MRI) and a comprehensive cognitive assessment, including Rao’s Brief Repeatable Battery (RBRB) and questionnaires for depression, fatigue and quality of life. Failure in at least two of the RBRB tests defined ‘cognitive impairment’. Results At baseline, there was no difference in the proportion of cognitively impaired patients. At month 24, the proportion of patients with cognitive impairment was lower in group 3 (34.8%) than in group 1 (47.6%) (p = 0.03). The risk of developing cognitive impairment over 24 months was lower in group 3 (p = 0.02). Mood and fatigue scores were comparable across the groups over time at both time points. However, at month 24, group 3 showed worsening on the sexual function subscale of the 54-item MS quality-of-life questionnaire (p = 0.03). Conclusions This study suggests that the combination of high-dose estroprogestins and IFN-β may have positive effects on cognition. However, the effect of this treatment on sexual function requires caution to be exercised

Efficacy of Fluoxetine, Riluzole and Amiloride in treating neuropathic pain associated with secondary progressive multiple sclerosis. Pre-specified analysis of the MS-SMART double-blind randomised placebo-controlled trial

BACKGROUND: Evidence-based treatment of pain in people with MS presents a major unmet need. OBJECTIVE: We aimed to establish if use of Fluoxetine, Riluzole or Amiloride improved neuropathic pain outcomes in comparison to placebo, in adults with secondary progressive MS participating in a trial of these putative neuroprotectants. METHODS: In pre-specified secondary analyses of the MS SMART phase-2b double-blind randomised controlled trial (NCT01910259), we analyzed reports of neuropathic pain, overall pain, and pain interference. Multivariate analyses included adjustment for baseline pain severity. Additionally, we explored associations of pain severity with clinical and MRI brain imaging variables. RESULTS: 445 Participants were recruited from 13 UK neuroscience centres. We found no statistically significant benefit of active intervention on any rating of neuropathic pain, or pain overall. Compared to placebo, adjusted mean difference in pain intensity was 0.38 (positive values favouring placebo, 95%CI -0.30 to 1.07, p = 0.27) for Amiloride; 0.52 (-0.17 to 1.22, p = 0.14) for Fluoxetine; and 0.40 (-0.30 to 1.10, p = 0.26) for Riluzole. Pain severity was positively correlated with depressive symptoms (Spearman correlation 0.19, 95%CI 0.10-0.28) and fatigue (Rho 0.30, 95%CI 0.20-0.39). CONCLUSION: Use of Fluoxetine, Riluzole or Amiloride was not associated with improvement in neuropathic pain symptoms, in comparison to placebo

Optimising recruitment in clinical trials for progressive multiple sclerosis: observational analysis from the MS-SMART and MS-STAT2 randomised controlled trials

BACKGROUND: Slower than planned recruitment is a major factor contributing to the delay or failure of randomised controlled trials to report on time. There is a limited evidence base regarding the optimisation of recruitment strategies. Here we performed an observational review of our experience in recruitment for two large randomised controlled trials for people with secondary progressive multiple sclerosis. We aimed to explicitly determine those factors which can facilitate trial recruitment in progressive neurodegenerative disease. METHODS: Recruitment data from the sequential MS-SMART [NCT01910259] and MS-STAT2 [NCT03387670] UK randomised controlled trials was reviewed from the largest recruiting site, University College London (UCL). The trial population was similar which allowed comparison over the two recruitment periods of 2015-2016 and 2018-2021. This included sources of referral, progress through stages of recruitment, reasons for participant ineligibility and the impact of publicity events upon recruitment. RESULTS: In MS-SMART, 18% of patients contacted were enrolled, compared to 27% for MS-STAT2. Online registration of interest portals provided the greatest number of referrals (76% in MS-SMART, and 51% in MS-STAT2), with publicity in national media outlets producing a demonstrable increase in the number of potential participants. The introduction of an online self-screening questionnaire for MS-STAT2 resulted in 67% of potential participants (3080 of 4605) automatically determining their own ineligibility. In both studies, however, around 60% of those directly telephoned to discuss the study were not eligible, with difficulties related to travel to trial visits, or excluded medication, being the most common issues. Eighty-four percent of those deemed potentially eligible following telephone calls were enrolled in the MS-STAT2 study, compared to only 55% for MS-SMART. CONCLUSIONS: Through a detailed review of recruiting participants at the largest centre into two large randomised controlled trials with similar entry criteria, we have identified a number of approaches that may improve recruitment efficiency. We highlight here the importance of mandatory online self-screening questionnaires, a coordinated publicity campaign, and simple interventions such as eligibility checklists and appointment reminders. Recruitment approaches should be further assessed through a studies within a trial (SWAT) design. TRIAL REGISTRATION: MS-SMART: NCT01910259 ; registered July 2013 and MS-STAT2: NCT03387670 ; registered Jan 2018

Fully automated segmentation of the cervical cord from T1-weighted MRI using PropSeg: Application to multiple sclerosis.

Spinal cord (SC) atrophy, i.e. a reduction in the SC cross-sectional area (CSA) over time, can be measured by means of image segmentation using magnetic resonance imaging (MRI). However, segmentation methods have been limited by factors relating to reproducibility or sensitivity to change. The purpose of this study was to evaluate a fully automated SC segmentation method (PropSeg), and compare this to a semi-automated active surface (AS) method, in healthy controls (HC) and people with multiple sclerosis (MS). MRI data from 120 people were retrospectively analysed; 26 HC, 21 with clinically isolated syndrome, 26 relapsing remitting MS, 26 primary and 21 secondary progressive MS. MRI data from 40 people returning after one year were also analysed. CSA measurements were obtained within the cervical SC. Reproducibility of the measurements was assessed using the intraclass correlation coefficient (ICC). A comparison between mean CSA changes obtained with the two methods over time was performed using multivariate structural equation regression models. Associations between CSA measures and clinical scores were investigated using linear regression models. Compared to the AS method, the reproducibility of CSA measurements obtained with PropSeg was high, both in patients and in HC, with ICC > 0.98 in all cases. There was no significant difference between PropSeg and AS in terms of detecting change over time. Furthermore, PropSeg provided measures that correlated with physical disability, similar to the AS method. PropSeg is a time-efficient and reliable segmentation method, which requires no manual intervention, and may facilitate large multi-centre neuroprotective trials in progressive MS