Objective: To test the effectiveness and long term safety of cannabinoids in multiple sclerosis (MS), in a follow up to the main Cannabinoids in Multiple Sclerosis (CAMS) study. Methods: In total, 630 patients with stable MS with muscle spasticity from 33 UK centres were randomised to receive oral D 9 -tetrahydrocannabinol (D 9 -THC), cannabis extract, or placebo in the main 15 week CAMS study. The primary outcome was change in the Ashworth spasticity scale. Secondary outcomes were the Rivermead Mobility Index, timed 10 metre walk, UK Neurological Disability Score, postal Barthel Index, General Health Questionnaire-30, and a series of nine category rating scales. Following the main study, patients were invited to continue medication, double blinded, for up to12 months in the follow up study reported here. Results: Intention to treat analysis of data from the 80% of patients followed up for 12 months showed evidence of a small treatment effect on muscle spasticity as measured by change in Ashworth score from baseline to 12 months (D 9 -THC mean reduction 1?82 (n = 154, 95% confidence interval (CI) 0.53 to 3.12), cannabis extract 0.10 (n = 172, 95% CI 20.99 to 1.19), placebo 20.23 (n = 176, 95% CI 21.41 to 0.94); p = 0.04 unadjusted for ambulatory status and centre, p = 0.01 adjusted). There was suggestive evidence for treatment effects of D 9 -THC on some aspects of disability. There were no major safety concerns. Overall, patients felt that these drugs were helpful in treating their disease. Conclusions: These data provide limited evidence for a longer term treatment effect of cannabinoids. A long term placebo controlled study is now needed to establish whether cannabinoids may have a role beyond symptom amelioration in MS.

Spasticity is most commonly defined as an inappropriate, velocity dependent, increase in muscle tonic stretch reflexes, due to the amplified reactivity of motor segments to sensory input. It forms one component of the upper motor neuron syndrome and often leads to muscle stiffness and disability. Spasticity can, therefore, be measured through electrophysiological, biomechanical and clinical evaluation, the last most commonly using the Ashworth scale. None of these techniques incorporate the patient experience of spasticity, nor how it affects people's daily lives. Consequently, we set out to construct a rating scale to quantify the perspectives of the impact of spasticity on people with multiple sclerosis. Qualitative methods (in-depth patient interviews and focus groups, expert opinion and literature review) were used to develop a conceptual framework of spasticity impact, and to generate a pool of items with the potential to convert this framework into a rating scale with multiple dimensions. This item pool was administered, in the form of a questionnaire, to a sample of people with multiple sclerosis and spasticity. Guided by Rasch analysis, we constructed and validated a rating scale for each component of the conceptual framework. Decisions regarding item selection were based on the integration and assimilation of seven specific analyses including clinical meaning, ordering of thresholds, fit statistics and differential item functioning. The qualitative phase (17 patient interviews, 3 focus groups) generated 144 potential scale items and a conceptual model with eight components addressing symptoms (muscle stiffness, pain and discomfort and muscle spasms,), physical impact (activities of daily living, walking and body movements) and psychosocial impact (emotional health, social functioning). The first postal survey was sent to 272 people with multiple sclerosis and had a response rate of 88%. Findings supported the development of scales for each component but demonstrated that five item response options were too many. The 144-item questionnaire, reformatted with four-item response options, was administered with four validating instruments to an independent sample of 259 people with multiple sclerosis (response rate 78%). From the responses, an 88-item instrument with eight subscales was developed that satisfied criteria for reliable and valid measurement. Correlations with other measures were consistent with predictions. The 88-item Multiple Sclerosis Spasticity Scale (MSSS-88) is a reliable and valid, patient-based, interval-level measure of the impact of spasticity in multiple sclerosis. It has the potential to advance outcomes measurement in clinical trials and clinical practice, and provides a new perspective in the clinical evaluation of spasticity.

PurposeTo investigate the effect of Tai Chi exercise on postural balance among people with dementia (PWD) and the feasibility of a definitive trial on falls prevention.Patients and methodsDyads, comprising community-dwelling PWD and their informal carer (N=85), were randomised to usual care (n=43) or usual care plus weekly Tai Chi classes and home practice for 20 weeks (n=42). The primary outcome was the timed up and go test. All outcomes for PWD and their carers were assessed six months post-baseline, except for falls, which were collected prospectively over the six-month follow-up period.ResultsFor PWD, there was no significant difference at follow-up on the timed up and go test (mean difference [MD] = 0.82, 95% confidence interval [CI] = −2.17, 3.81). At follow-up, PWD in the Tai Chi group had significantly higher quality of life (MD = 0.051, 95% CI = 0.002, 0.100, standardised effect size [ES] = 0.51) and a significantly lower rate of falls (rate ratio = 0.35, 95% CI =0.15, 0.81), which was no longer significant when an outlier was removed. Carers in the Tai Chi group at follow-up were significantly worse on the timed up and go test (MD = 1.83, 95% CI = 0.12, 3.53, ES = 0.61). The remaining secondary outcomes were not significant. No serious adverse events were related to participation in Tai Chi.ConclusionWith refinement, this Tai Chi intervention has potential to reduce the incidence of falls and improve quality of life among community-dwelling PWD [Trial registration: NCT02864056].

BackgroundThere is a need for greater understanding of the impact of multiple sclerosis (MS) from the perspective of individuals with the condition. The South West Impact of MS Project (SWIMS) has been designed to improve understanding of disease impact using a patient-centred approach. The purpose is to (1) develop improved measurement instruments for clinical trials, (2) evaluate longitudinal performance of a variety of patient-reported outcome measures, (3) develop prognostic predictors for use in individualising drug treatment for patients, particularly early on in the disease course.MethodsThis is a patient-centred, prospective, longitudinal study of multiple sclerosis and clinically isolated syndrome (CIS) in south west England. The study area comprises two counties with a population of approximately 1.7 million and an estimated 1,800 cases of MS. Self-completion questionnaires are administered to participants every six months (for people with MS) or 12 months (CIS). Here we present descriptive statistics of the baseline data provided by 967 participants with MS.ResultsSeventy-five percent of those approached consented to participate. The male:female ratio was 1.00:3.01 (n = 967). Average (standard deviation) age at time of entry to SWIMS was 51.6 (11.5) years (n = 961) and median (interquartile range) time since first symptom was 13.3 (6.8 to 24.5) years (n = 934). Fatigue was the most commonly reported symptom, with 80% of participants experiencing fatigue at baseline. Although medication use for symptom control was common, there was little evidence of effectiveness, particularly for fatigue. Nineteen percent of participants were unable to classify their subtype of MS. When patient-reported subtype was compared to neurologist assessment for a sample of participants (n = 396), agreement in disease sub-type was achieved in 63% of cases. There were 836 relapses, reported by 931 participants, in the twelve months prior to baseline. Twenty-three percent of the relapsing-remitting group and 12% of the total sample were receiving disease-modifying therapy at baseline.ConclusionsDemographics of this sample were similar to published data for the UK. Overall, the results broadly reflect clinical experience in confirming high symptom prevalence, with relatively little complete symptom relief. Participants often had difficulty in defining MS relapses and their own MS type.

Background There is modest evidence that exercise referral schemes increase physical activity in inactive individuals with chronic health conditions. There is a need to identify additional ways to improve the effects of exercise referral schemes on long-term physical activity. Objectives To determine if adding the e-coachER intervention to exercise referral schemes is more clinically effective and cost-effective in increasing physical activity after 1 year than usual exercise referral schemes. Design A pragmatic, multicentre, two-arm randomised controlled trial, with a mixed-methods process evaluation and health economic analysis. Participants were allocated in a 1 : 1 ratio to either exercise referral schemes plus e-coachER (intervention) or exercise referral schemes alone (control). Setting Patients were referred to exercise referral schemes in Plymouth, Birmingham and Glasgow. Participants There were 450 participants aged 16–74 years, with a body mass index of 30–40 kg/m2, with hypertension, prediabetes, type 2 diabetes, lower limb osteoarthritis or a current/recent history of treatment for depression, who were also inactive, contactable via e-mail and internet users. Intervention e-coachER was designed to augment exercise referral schemes. Participants received a pedometer and fridge magnet with physical activity recording sheets, and a user guide to access the web-based support in the form of seven ‘steps to health’. e-coachER aimed to build the use of behavioural skills (e.g. self-monitoring) while strengthening favourable beliefs in the importance of physical activity, competence, autonomy in physical activity choices and relatedness. All participants were referred to a standard exercise referral scheme. Primary outcome measure Minutes of moderate and vigorous physical activity in ≥ 10-minute bouts measured by an accelerometer over 1 week at 12 months, worn ≥ 16 hours per day for ≥ 4 days including ≥ 1 weekend day. Secondary outcomes Other accelerometer-derived physical activity measures, self-reported physical activity, exercise referral scheme attendance and EuroQol-5 Dimensions, five-level version, and Hospital Anxiety and Depression Scale scores were collected at 4 and 12 months post randomisation. Results Participants had a mean body mass index of 32.6 (standard deviation) 4.4 kg/m2, were referred primarily for weight loss and were mostly confident self-rated information technology users. Primary outcome analysis involving those with usable data showed a weak indicative effect in favour of the intervention group (n = 108) compared with the control group (n = 124); 11.8 weekly minutes of moderate and vigorous physical activity (95% confidence interval –2.1 to 26.0 minutes; p = 0.10). Sixty-four per cent of intervention participants logged on at least once; they gave generally positive feedback on the web-based support. The intervention had no effect on other physical activity outcomes, exercise referral scheme attendance (78% in the control group vs. 75% in the intervention group) or EuroQol-5 Dimensions, five-level version, or Hospital Anxiety and Depression Scale scores, but did enhance a number of process outcomes (i.e. confidence, importance and competence) compared with the control group at 4 months, but not at 12 months. At 12 months, the intervention group incurred an additional mean cost of £439 (95% confidence interval –£182 to £1060) compared with the control group, but generated more quality-adjusted life-years (mean 0.026, 95% confidence interval 0.013 to 0.040), with an incremental cost-effectiveness ratio of an additional £16,885 per quality-adjusted life-year. Limitations A significant proportion (46%) of participants were not included in the primary analysis because of study withdrawal and insufficient device wear-time, so the results must be interpreted with caution. The regression model fit for the primary outcome was poor because of the considerable proportion of participants [142/243 (58%)] who recorded no instances of ≥ 10-minute bouts of moderate and vigorous physical activity at 12 months post randomisation. Future work The design and rigorous evaluation of cost-effective and scalable ways to increase exercise referral scheme uptake and maintenance of moderate and vigorous physical activity are needed among patients with chronic conditions. Conclusions Adding e-coachER to usual exercise referral schemes had only a weak indicative effect on long-term rigorously defined, objectively assessed moderate and vigorous physical activity. The provision of the e-coachER support package led to an additional cost and has a 63% probability of being cost-effective based on the UK threshold of £30,000 per quality-adjusted life-year. The intervention did improve some process outcomes as specified in our logic model. Trial registration Current Controlled Trials ISRCTN15644451. Funding This project was funded by the National Institute for Health Research (NIHR) Health Technology Assessment programme and will be published in full in Health Technology Assessment; Vol. 24, No. 63. See the NIHR Journals Library website for further project information.

The measures were broadly comparable in detecting mobility changes in this community sample. These correlations highlight that in selection of measures, one should also consider the discrete mobility dimension that the intervention intends to impact.

BackgroundFalls are a public health issue for the older adult population and more so for people with dementia (PWD). Compared with their cognitively intact peers, PWD are at higher risk of falls and injurious falls. This randomised controlled trial aims to test the clinical and cost effectiveness of Tai Chi to improve postural balance among community-dwelling PWD and to assess the feasibility of conducting a larger definitive trial to reduce the incidence of falls among PWD.MethodsA 3-centre parallel group randomised controlled trial with embedded process evaluation. One hundred and fifty community-dwelling dyads of a person with dementia and their informal carer will be recruited and assessed at baseline and at six-month follow-up. Dyads will be randomised in a 1:1 ratio to either usual care or usual care plus a Tai Chi intervention for 20 weeks. The Tai Chi intervention will consist of weekly classes (45 min’ Tai Chi plus up to 45 min for informal discussion, with up to 10 dyads per class) and home-based exercises (20 min per day to be facilitated by the carer). Home practice of Tai Chi will be supported by the use of behaviour change techniques with the Tai Chi instructor at a home visit in week 3–4 of the intervention (action planning, coping planning, self-monitoring, and alarm clock reminder) and at the end of each class (feedback on home practice). The primary outcome is dynamic balance measured using the Timed Up and Go test, coinciding with the end of the 20-week intervention phase for participants in the Tai Chi arm. Secondary outcomes for PWD include functional balance, static balance, fear of falling, global cognitive functioning, visual-spatial cognitive functioning, quality of life, and falls. Secondary outcomes for carers include dynamic balance, static balance, quality of life, costs, and carer burden.DiscussionThis trial is the first in the UK to test the effectiveness of Tai Chi to improve balance among PWD. The trial will inform a future study that will be the first in the world to use Tai Chi in a trial to prevent falls among PWD.Trial registrationNCT02864056.

Background: Although typically an aggressive disease some patients with Mantle Cell Lymphoma (MCL) follow an indolent course and may not benefit from immediate therapy. Several studies evaluating watch-and-wait (W&W) strategies in MCL show no detriment to patient survival and international guidelines acknowledge the strategy's suitability for a minority of patients. Differences in pathogenetic mechanisms have provided insight into variable clinical behaviour, but there is little clinical evidence to inform patient suitability for W&W. The MCL Biobank Observational Study is a prospective study designed to distinguish indolent from aggressive forms of MCL. Tissue samples and baseline characteristics are collected at enrolment. The study has recruited over 550 patients across the UK and remains open to recruitment. Method: This analysis includes 315 patients from 58 centers in the United Kingdom enrolled between January 2015 and March 2018. All new MCL diagnoses compatible with WHO diagnostic criteria were eligible. Patients were enrolled within 90 days of diagnosis and prior to receiving therapy. Baseline data was recorded including investigator decision to start systemic therapy or enter W&W. Clinical updates were provided at 6 month intervals and patients were followed-up for a minimum of 12 months. Standard statistical methods were used to examine which factors were associated with initial disease management and those remaining on W&W long-term. Time to treatment was measured from date of diagnosis until date of first treatment, patients who had not commenced treatment were censored at the last date of follow-up. Results: Median age of all patients was 71 (range 32-92), 68.9% were male, 53.5% were MIPI high risk and median follow up 26 months. At baseline 67.3% of patients received upfront systemic therapy, 4.1% received localized radiotherapy, 1.0% were palliated and 27.6% were on W&W 90 days beyond diagnosis. Estimated 2-year OS of the whole population was 77.5%. Patients on initial W&W tended to be older than those treated early (median 73 yrs vs. 71 yrs), had similar performance score (ECOG>1 OR 1.16, p=0.68) and no significant difference in WBC (WBC>15 OR 0.55, p=0.07). Although high risk MIPI was equally prevalent between the groups (OR 1.3, p=0.31) it was notable that no patient under 75 years was high risk in the observation group. Presence of measurable disease on CT discriminated between the two groups (OR 0.23, p=<0.001), but 71% of W&W had measurable disease indicating most were not the leukemic subtype. Markers of higher cell turnover, raised LDH and Ki67≥30%, were significantly less common in W&W patients (OR 0.32, p=<0.001; OR 0.3, p=0.001). 40% of women were put on W&W compared to 22% of men (OR 2.6, p=<0.001). Of 87 patients followed on W&W 73.5% remained on observation at 1 year and 50.6% at 2 years, with median follow up 2.4 years. Univariate analysis revealed few baseline characteristics to be predictive for prolonged period of observation, in part relating to the low patient numbers, but key observations are displayed in figure 1. Patients with Ki67≥30% were less likely to remain on observation (HR 2.39, p=0.03), as were patients over 80 years old (HR 3.67, p=0.007), and those MIPI high risk compared to low risk (3.56, p=0.02). Conclusion: This study demonstrates the high prevalence of W&W in UK clinical practice and it provides reassurance to clinicians that half remain on observation beyond 2 yrs. LDH level and Ki67 status reflect the biological nature of disease and it is therefore not unexpected that lower levels predict for a more indolent course. However, with Ki67≥30 in 25% of patients observed beyond 2 years these measures alone are not sufficient to decide treatment. The tendency for older patients to be observed likely reflects a less aggressive clinical approach in patients with co-morbidities, and not the underlying biology. This explains the tendency for shortened observation period in older patients. The high prevalence of female patients in W&W is a striking observation that alludes to pathophysiological differences between the sexes that warrants further investigation. Although the study highlights clinicians are increasingly at ease adopting W&W in MCL, it also demonstrates the need for better predictive markers of indolent disease. This study aims to achieve this with analysis of the collected tissue samples. Disclosures Crosbie: Janssen: Honoraria. Rule:Sunesis: Consultancy, Honoraria; TG Therapeutics: Consultancy, Honoraria; Napp: Consultancy; Kite: Consultancy; Gilead: Consultancy, Honoraria; Pharmacyclics: Consultancy, Honoraria; Celgene: Consultancy, Honoraria; Astra-Zeneca: Consultancy, Honoraria; Roche: Consultancy, Honoraria, Research Funding; Janssen: Consultancy, Honoraria, Research Funding.