Functional standing frame programme early after severe sub-acute stroke (SPIRES): a randomised controlled feasibility trial.

BACKGROUND: Early mobilisation (> 24 h post-stroke) is recommended for people with stroke. However, there is a paucity of evidence about how to implement early mobilisation for people who have had a severe stroke. Prolonged standing and task-specific training (sit-to-stand repetitions) have separately been evaluated in the literature; however, these functionally linked tasks have not been evaluated in combination for people with severe sub-acute stroke. METHODS: The objective was to determine the feasibility of conducting a randomised controlled trial (RCT) of a functional standing frame programme compared with usual physiotherapy for people with severe sub-acute stroke. An assessor-blinded feasibility RCT with nested qualitative component (interviews and focus group) and process evaluation was adopted. Participants were aged ≥ 18 years with new diagnosis of severe sub-acute stroke (modified Rankin Scale (mRS) 4/5) from four Stroke Rehabilitation Units across South West England. Participants were randomised to receive either: (1) functional standing frame programme (30 min. standing plus sit-to-stand repetitions) plus 15 min of usual physiotherapy daily (intervention); (2) usual physiotherapy (45 min) daily (control). Both programmes were protocolised to be undertaken a minimum of five sessions per week for 3 weeks. Feasibility indicators included process, resource, management, and safety. Adherence, fidelity, and acceptability of the trial and intervention were evaluated using data recorded by therapists, observation of intervention and control sessions, interviews and one focus group. Patient measures of motor impairment, activities/participation, and quality of life were carried out by blinded assessors at baseline, 3, 15, 29, and 55 weeks post-randomisation. RESULTS: Forty-five participants (51-96 years; 42% male, mRS 4 = 80% 5 = 20%) were randomised (n = 22 to intervention). Twenty-seven (60%) participants were followed-up at all time points. Twelve participants (27%) died during the trial; no deaths were related to the trial. Adherence to the minimum number of sessions was low: none of the participants completed all 21 sessions, and only 8 participants (18%) across both groups completed ≥ 15 sessions, over the 3 weeks; 39% intervention; 51% control sessions were completed; mean session duration 39 min (SD 19) control, 37 min intervention (SD 11). Intervention group: mean standing time 13 min (SD 9); mean sit-to-stand repetitions/session 5 (SD 4). Interviews were conducted with 10 participants, four relatives and six physiotherapists. Five physiotherapists attended a focus group. CONCLUSIONS: The majority of progression criteria for this feasibility trial were met. However, adherence to the interventions was unacceptably low. This aspect of the trial design needs to be addressed prior to moving to a definitive RCT of this standing frame intervention in people with severe sub-acute stroke. Solutions have been identified to address these concerns. TRIAL REGISTRATION: International Standard Randomised Controlled Trial Number ISRCTN15412695 . Registration 19 December 2016.

The Use of Tranexamic Acid to Reduce the Need for Nasal Packing in Epistaxis (NoPAC): Randomized Controlled Trial.

STUDY OBJECTIVE: Epistaxis is a common emergency department (ED) presentation and, if simple first aid measures fail, can lead to a need for anterior nasal packing. Tranexamic acid is an agent that contributes to blood clot stability. The aim of this study is to investigate the effectiveness of topical intranasal tranexamic acid in adult patients presenting to the ED with persistent epistaxis, and whether it reduces the need for anterior nasal packing. METHODS: From May 5, 2017, to March 31, 2019, a double-blind, placebo-controlled, multicenter, 1:1, randomized controlled trial was conducted across 26 EDs in the United Kingdom. Participants with spontaneous epistaxis, persisting after simple first aid and the application of a topical vasoconstrictor, were randomly allocated to receive topical tranexamic acid or placebo. The primary outcome was the need for anterior nasal packing of any kind during the index ED attendance. Secondary outcome measures included hospital admission, need for blood transfusion, recurrent epistaxis, and any thrombotic events requiring any hospital reattendance within 1 week. RESULTS: The study sample consisted of 496 participants with spontaneous epistaxis, persisting after simple first aid and application of a topical vasoconstrictor. In total, 211 participants (42.5%) received anterior nasal packing during the index ED attendance, including 111 of 254 (43.7%) in the tranexamic acid group versus 100 of 242 (41.3%) in the placebo group. The difference was not statistically significant (odds ratio 1.107; 95% confidence interval 0.769 to 1.594; P=.59). Furthermore, there were no statistically significant differences between tranexamic acid and placebo for any of the secondary outcome measures. CONCLUSION: In patients presenting to an ED with atraumatic epistaxis that is uncontrolled with simple first aid measures, topical tranexamic acid applied in the bleeding nostril on a cotton wool dental roll is no more effective than placebo at controlling bleeding and reducing the need for anterior nasal packing.

Simvastatin as a neuroprotective treatment for Parkinson's disease (PD STAT): protocol for a double-blind, randomised, placebo-controlled futility study.

INTRODUCTION: Parkinson's disease (PD) is a progressive neurodegenerative condition affecting approximately 185,000 people in the UK. No drug has been proven to slow disease progression. Epidemiological and pre-clinical data support simvastatin, a widely used cholesterol-lowering drug with a well-established safety profile, having neuroprotective properties. The aim of this study (Simvastatin as a neuroprotective treatment for PD (PD STAT)) is to determine whether simvastatin has the potential to slow PD progression. The study is part of the International Linked Clinical Trials initiative coordinated by The Cure Parkinson's Trust. This paper describes the protocol for the PD STAT study. METHODS AND ANALYSIS: PD STAT is a double-blind, randomised, placebo-controlled, multi-centre, parallel group, futility trial in patients with PD of mild-moderate severity. 235 participants have been recruited and randomly allocated in a 1:1 ratio to receive either oral simvastatin or matched placebo. Treatment involves a 1-month low-dose phase (40 mg daily), followed by a 23-month high-dose phase (80 mg daily) and ends with a 2-month washout period. Participants are reviewed at clinic visits at 1 month, 6, 12, 18, 24 and 26 months post-baseline, with interim telephone follow-up to monitor for adverse events.The primary outcome is the change in the Movement Disorder Society Unified Parkinson's Disease Rating Scale part III motor subscale score in the practically defined OFF medication state (OFF state) between baseline and 24 months. Primary analysis will be on a modified intention to treat basis and will include only those participants who progress to the high-dose phase of the study. ETHICS AND DISSEMINATION: The protocol has been approved by the North East-Newcastle and North Tyneside 2 Research Ethics Committee. The results will be disseminated via research articles in peer-reviewed journals and presentations at local, national and international scientific meetings, as well as disseminated via patient groups, websites and networks. A summary of the study findings will be posted to participants at the end of the study. TRIAL REGISTRATION: ISRCTN16108482 (prospectively registered); EudraCT 2015-000148-40; ClinicalTrials.gov NCT02787590; Pre-results.

A self-management programme to reduce falls and improve safe mobility in people with secondary progressive MS: the BRiMS feasibility RCT.

BACKGROUND: Balance, mobility impairments and falls are common problems for people with multiple sclerosis (MS). Our ongoing research has led to the development of Balance Right in MS (BRiMS), a 13-week home- and group-based exercise and education programme intended to improve balance and encourage safer mobility. OBJECTIVE: This feasibility trial aimed to obtain the necessary data and operational experience to finalise the planning of a future definitive multicentre randomised controlled trial. DESIGN: Randomised controlled feasibility trial. Participants were block randomised 1 : 1. Researcher-blinded assessments were scheduled at baseline and at 15 and 27 weeks post randomisation. As is appropriate in a feasibility trial, statistical analyses were descriptive rather than involving formal/inferential comparisons. The qualitative elements utilised template analysis as the chosen analytical framework. SETTING: Four sites across the UK. PARTICIPANTS: Eligibility criteria included having a diagnosis of secondary progressive MS, an Expanded Disability Status Scale (EDSS) score of between ≥ 4.0 and ≤ 7.0 points and a self-report of two or more falls in the preceding 6 months. INTERVENTIONS: Intervention - manualised 13-week education and exercise programme (BRiMS) plus usual care. Comparator - usual care alone. MAIN OUTCOME MEASURES: Trial feasibility, proposed outcomes for the definitive trial (including impact of MS, mobility, quality of life and falls), feasibility of the BRiMS programme (via process evaluation) and economic data. RESULTS: A total of 56 participants (mean age 59.7 years, standard deviation 9.7 years; 66% female; median EDSS score of 6.0 points, interquartile range 6.0-6.5 points) were recruited in 5 months; 30 were block randomised to the intervention group. The demographic and clinical data were broadly comparable at baseline; however, the intervention group scored worse on the majority of baseline outcome measures. Eleven participants (19.6%) withdrew or were lost to follow-up. Worsening of MS-related symptoms unrelated to the trial was the most common reason (n = 5) for withdrawal. Potential primary and secondary outcomes and economic data had completion rates of > 98% for all those assessed. However, the overall return rate for the patient-reported falls diary was 62%. After adjusting for baseline score, the differences between the groups (intervention compared with usual care) at week 27 for the potential primary outcomes were MS Walking Scale (12-item) version 2 -7.7 [95% confidence interval (CI) -17.2 to 1.8], MS Impact Scale (29-item) version 2 (MSIS-29vs2) physical 0.6 (95% CI -7.8 to 9) and MSIS-29vs2 psychological -0.4 (95% CI -9.9 to 9) (negative score indicates improvement). After the removal of one outlier, a total of 715 falls were self-reported over the 27-week trial period, with substantial variation between individuals (range 0-93 falls). Of these 715 falls, 101 (14%) were reported as injurious. Qualitative feedback indicated that trial processes and participant burden were acceptable, and participants highlighted physical and behavioural changes that they perceived to result from undertaking BRiMS. Engagement varied, influenced by a range of condition- and context-related factors. Suggestions to improve the utility and accessibility of BRiMS were highlighted. CONCLUSIONS: The results suggest that the trial procedures are feasible and acceptable, and retention, programme engagement and outcome completion rates were sufficient to satisfy the a priori progression criteria. Challenges were experienced in some areas of data collection, such as completion of daily diaries. FUTURE WORK: Further development of BRiMS is required to address logistical issues and enhance user-satisfaction and adherence. Following this, a definitive trial to assess the clinical effectiveness and cost-effectiveness of the BRiMS intervention is warranted. TRIAL REGISTRATION: Current Controlled Trials ISRCTN13587999. 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. 23, No. 27. See the NIHR Journals Library website for further project information.

People with secondary progressive multiple sclerosis (SPMS) often have problems with walking and balance, which lead them to fall. Undertaking exercise and learning about falls prevention could help reduce injury risk and improve mobility. We developed a mobility, balance and falls programme called Balance Right in MS (BRiMS). Before testing its effectiveness in a large-scale trial, we needed to conduct a small-scale version of the trial. We asked people with SPMS who had balance and mobility problems to be assigned by chance to undertake the BRiMS programme plus their usual care, or to continue with usual care only. Questionnaires were used to ask people about their mobility, falls and quality of life, and we measured their balance and activity levels. We interviewed participants about BRiMS and being in the trial, and collected information about costs. Fifty-six people entered the trial from three areas of the south-west and from Ayrshire. At completion of the study we were able to review 44 people. The key measures were completed by 98% of those we assessed, but only around half (62%) of the diaries detailing falls were returned. As this was a feasibility trial, the numbers were too small for us to look at differences between the groups. Participants liked the BRiMS programme; some did a lot of exercise and learning activities, but most did not manage the amount we asked them to do. People reported feeling a little overwhelmed by the educational content of BRiMS, and that this should be reduced in future. They told us that they felt that their balance had improved and that they fell less frequently after the BRiMS programme. Our assessment of the trial methods we used showed that it would be possible to conduct a full-scale trial using this design, but that we need to adapt the BRiMS programme further to make it more user-friendly.

Standing Practice In Rehabilitation Early after Stroke (SPIRES): a functional standing frame programme (prolonged standing and repeated sit to stand) to improve function and quality of life and reduce neuromuscular impairment in people with severe sub-acute stroke-a protocol for a feasibility randomised controlled trial.

BACKGROUND: The most common physical deficit caused by a stroke is muscle weakness which limits a person's mobility. Mobility encompasses activities necessary for daily functioning: getting in and out bed, on/off toilet, sitting, standing and walking. These activities are significantly affected in people with severe stroke who typically spend most of their time in bed or a chair and are immobile. Immobility is primarily caused by neurological damage but exacerbated by secondary changes in musculoskeletal and cardiorespiratory systems. These secondary changes can theoretically be prevented or minimised by early mobilisation, in this case standing up early post-stroke.Standing up early post-stroke has been identified as an important priority for people who have suffered a severe stroke. However, trials of prolonged passive standing have not demonstrated any functional improvements. Conversely, task-specific training such as repeated sit-to-stand has demonstrated positive functional benefits. This feasibility trial combines prolonged standing and task-specific strength training with the aim of determining whether this novel combination of physiotherapy interventions is feasible for people with severe stroke as well as the overall feasibility of delivering the trial. METHODS/DESIGN: This is a pragmatic multi-centre parallel single-blinded two-armed feasibility randomised controlled trial. Fifty people with a diagnosis of severe stroke will be randomly allocated to either the functional standing frame programme or usual physiotherapy. All patient participants will be assessed at baseline and followed up at 3 weeks, then 3, 6 and 12 months post-randomisation. Trial objectives are to determine the feasibility according to the following indicators:: (i) Process: recruitment and retention rate, ability to consent, eligibility criteria, willingness/ability of physiotherapists to recruit, willingness of patients to be randomised, and acceptability of the intervention; (ii) Resource: burden and potential costs; (iii) Management: treatment fidelity, participant adherence, acceptability and completeness of outcome measures, impact and management or orthostatic hypotension; and (iv) Safety: number and nature of adverse and serious adverse events. DISCUSSION: The functional standing frame programme addresses a key concern for people who have suffered a severe stroke. However, several uncertainties exist which need to be understood prior to progressing to a full-scale trial, including acceptability and tolerance of the functional standing frame programme intervention and practicality of the trial procedures. This feasibility trial will provide important insights to resolve these uncertainties. TRIAL REGISTRATION: International Standard Randomised Controlled Trial Number ISRCTN15412695. Registration on 19 December 2016.

Debt Counselling for Depression in Primary Care: an adaptive randomised controlled pilot trial (DeCoDer study).

BACKGROUND: Depression and debt are common in the UK. Debt Counselling for Depression in Primary Care: an adaptive randomised controlled pilot trial (DeCoDer) aimed to assess the clinical effectiveness and cost-effectiveness of the addition of a primary care debt counselling advice service to usual care for patients with depression and debt. However, the study was terminated early during the internal pilot trial phase because of recruitment delays. This report describes the rationale, methods and findings of the pilot study, and implications for future research. OBJECTIVES: The overarching aim of the internal pilot was to identify and resolve problems, thereby assessing the feasibility of the main trial. The specific objectives were to confirm methods for practice recruitment and the ability to recruit patients via the proposed approaches; to determine the acceptability of the study interventions and outcome measures; to assess contamination; to confirm the randomisation method for main trial and the level of participant attrition; and to check the robustness of data collection systems. DESIGN: An adaptive, parallel, two-group multicentre randomised controlled pilot trial with a nested mixed-methods process and economic evaluation. Both individual- and cluster (general practice)-level were was used in the pilot phase to assign participants to intervention or control groups. SETTING: General practices in England and Wales. PARTICIPANTS: Individuals were included who were aged ≥ 18 years, scored ≥ 14 on the Beck Depression Inventory II and self-identified as having debt worries. The main exclusion criteria were being actively suicidal or psychotic and/or severely depressed and unresponsive to treatment; having a severe addiction to alcohol/illicit drugs; being unable/unwilling to give written informed consent; currently participating in other research including follow-up phases; having received Citizens Advice Bureau (CAB) debt advice in the past year; and not wanting debt advice via a general practice. INTERVENTIONS: The participants in the intervention group were given debt advice provided by the CAB and shared biopsychosocial assessment, in addition to treatment as usual (TAU) and two debt advice leaflets. The participants in the control group were given advice leaflets provided by the general practitioner and TAU only. MAIN OUTCOME MEASURES: (1) Outcomes of the pilot trial - the proportion of eligible patients who consented, the number of participants recruited compared with target, assessment of contamination, and assessment of patient satisfaction with intervention and outcome measures. (2) Participant outcomes - primary - Beck Depression Inventory II; secondary - psychological well-being, health and social care utilisation, service satisfaction, substance misuse, record of priority/non-priority debts, life events and difficulties, and explanatory measures. Outcomes were assessed at baseline (pre-randomisation) and at 4 months post randomisation. Other data sources - qualitative interviews were conducted with participants, clinicians and CAB advisors. RESULTS: Of the 238 expressions of interest screened, 61 participants (26%) were recruited and randomised (32 in the intervention group and 29 in the control group). All participants provided baseline outcomes and 52 provided the primary outcome at 4 months' follow-up (14.7% dropout). Seventeen participants allocated to the intervention saw a CAB advisor. Descriptive statistics are reported for participants with complete outcomes at baseline and 4 months' follow-up. Our qualitative findings suggest that the relationship between debt and depression is complex, and the impact of each on the other is compounded by other psychological, social and contextual influences. CONCLUSIONS: As a result of low recruitment, this trial was terminated at the internal pilot phase and was too small for inferential statistical analysis. We recommend ways to reduce this risk when conducting complex trials among vulnerable populations recruited in community settings. These cover trial design, the design and delivery of interventions, recruitment strategies and support for sites. TRIAL REGISTRATION: Current Controlled Trials ISRCTN79705874. 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. 21, No. 35. See the NIHR Journals Library website for further project information. Mark Gabbay and Adele Ring are part-funded by NIHR Collaborations for Leadership in Applied Health Research and Care (CLAHRC) North West Coast and Richard Byng and Rod S Taylor, Vashti Berry and Elizabeth Shaw part-funded by NIHR CLAHRC South West Peninsula.

A preconsultation web-based tool to generate an agenda for discussion in diabetes outpatient clinics to improve patient outcomes (DIAT): a feasibility study.

OBJECTIVE: To test the feasibility of running a randomised controlled trial of a preconsultation web-based intervention (Presenting Asking Checking Expressing (PACE-D)) to improve the quality of care and clinical outcomes in patients with diabetes. DESIGN AND SETTING: A feasibility study (with randomisation) conducted at outpatient diabetes clinics at two secondary care hospitals in Devon, UK. PARTICIPANTS: People with diabetes (type 1 and type 2) attending secondary care general diabetes outpatient clinics. INTERVENTION: The PACE-D, a web-based tool adapted for patients with diabetes to use before their consultation to generate an agenda of topics to discuss with their diabetologist. OUTCOMES: The percentage of eligible patients who were recruited and the percentage of participants for whom routine glycosylated haemoglobin (HbA1c) data (the putative primary outcome) could be extracted from medical notes and who completed secondary outcome assessments via questionnaire at follow-up were reported. RESULTS: In contrast with the planned recruitment of 120 participants, only 71 participants were randomised during the 7-month recruitment period. This comprised 18.7% (95% CI 14.9% to 23.0%) of those who were eligible. Mean (SD) age of the participants was 56.5 (12.4) years and 66.2% had type 1 diabetes. Thirty-eight patients were randomised to the intervention arm and 33 to the control arm. HbA1c data were available for only 73% (95% CI 61% to 83%) of participants at the 6 months follow-up. The questionnaire-based data were collected for 66% (95% CI 54% to 77%) of the participants at 6 months follow-up. Participants reported that the PACE-D tool was easy to use. CONCLUSIONS: A randomised controlled trial of the preconsultation web-based intervention as set out in our current protocol is not feasible without significant modification to improve recruitment and follow-up of participants. The study also provides insights into the feasibility and challenges of conducting complex intervention trials in everyday clinical practice. TRIAL REGISTRATION: ISRCTN75070242.

Western medical acupuncture in a group setting for knee osteoarthritis: results of a pilot randomised controlled trial.

BACKGROUND: Evidence suggests acupuncture may be effective for treating the symptoms of knee osteoarthritis. Offering this in a group setting may offer cost savings. The aim of this study was to establish the feasibility of a definitive trial to assess the clinical and cost-effectiveness of Western medical acupuncture given in groups, or given individually, for adults with severe knee pain attributable to osteoarthritis. METHODS: A pilot randomised controlled trial (RCT) was conducted. Participants were recruited from seven general practices in Plymouth, Devon. Acupuncture was provided, at a dosage that increased up to and including electroacupuncture if no pain relief was reported, by one experienced acupuncturist in a community clinic. Potentially eligible adults aged at least 45 years with knee osteoarthritis were identified from practice registers, screened and randomised to either: (1) standardised advice and exercise booklet alone ('standard'); (2) booklet plus group acupuncture ('group'); and (3) booklet plus individual acupuncture ('individual'). Both acupuncture arms received up to ten treatments over 12 weeks. Recruitment, retention and data completion rates were recorded, and participants completed questionnaires on acceptability. We collected pain, stiffness and function data (using the Western Ontario McMaster Universities Osteoarthritis Index; WOMAC) and general health (EQ-5D) and economic measures at baseline and 14 weeks post-randomisation. RESULTS: We screened 149 people and randomised 60 (40 %), 20 per arm. The overall 14 week follow-up rate was 77 %, but only 70 % in the 'standard' group; 4.1 % of data points were missing. The study was acceptable to participants. Changes in WOMAC pain score (intention to treat complete case analysis) from baseline to 14 week follow-up were: 'standard', 0.4 (95 % confidence interval (CI) -1.4, 2.2, n = 14); 'group' -3.2 (95 % CI -5.1, -1.4, n = 17); 'individual' -2.4 (95 % CI -4.1, -0.7, n = 15). CONCLUSIONS: A definitive three-arm trial is feasible. Further follow-up reminders, minimum data collection and incentives should be considered to improve participant retention in the follow-up processes in the standardised advice and exercise booklet arm. TRIAL REGISTRATION: ISRCTN05305406.

Postural modification to the standard Valsalva manoeuvre for emergency treatment of supraventricular tachycardias (REVERT): a randomised controlled trial.

BACKGROUND: The Valsalva manoeuvre is an internationally recommended treatment for supraventricular tachycardia, but cardioversion is rare in practice (5-20%), necessitating the use of other treatments including adenosine, which patients often find unpleasant. We assessed whether a postural modification to the Valsalva manoeuvre could improve its effectiveness. METHODS: We did a randomised controlled, parallel-group trial at emergency departments in England. We randomly allocated adults presenting with supraventricular tachycardia (excluding atrial fibrillation and flutter) in a 1:1 ratio to undergo a modified Valsalva manoeuvre (done semi-recumbent with supine repositioning and passive leg raise immediately after the Valsalva strain), or a standard semi-recumbent Valsalva manoeuvre. A 40 mm Hg pressure, 15 s standardised strain was used in both groups. Randomisation, stratified by centre, was done centrally and independently, with allocation with serially numbered, opaque, sealed, tamper-evident envelopes. Patients and treating clinicians were not masked to allocation. The primary outcome was return to sinus rhythm at 1 min after intervention, determined by the treating clinician and electrocardiogram and confirmed by an investigator masked to treatment allocation. This study is registered with Current Controlled Trials (ISRCTN67937027). FINDINGS: We enrolled 433 participants between Jan 11, 2013, and Dec 29, 2014. Excluding second attendance by five participants, 214 participants in each group were included in the intention-to-treat analysis. 37 (17%) of 214 participants assigned to standard Valsalva manoeuvre achieved sinus rhythm compared with 93 (43%) of 214 in the modified Valsalva manoeuvre group (adjusted odds ratio 3·7 (95% CI 2·3-5·8; p<0·0001). We recorded no serious adverse events. INTERPRETATION: In patients with supraventricular tachycardia, a modified Valsalva manoeuvre with leg elevation and supine positioning at the end of the strain should be considered as a routine first treatment, and can be taught to patients. FUNDING: National Institute for Health Research.

The Cannabinoid Use in Progressive Inflammatory brain Disease (CUPID) trial: a randomised double-blind placebo-controlled parallel-group multicentre trial and economic evaluation of cannabinoids to slow progression in multiple sclerosis.

BACKGROUND: The Cannabinoid Use in Progressive Inflammatory brain Disease (CUPID) trial aimed to determine whether or not oral Δ(9)-tetrahydrocannabinol (Δ(9)-THC) slowed the course of progressive multiple sclerosis (MS); evaluate safety of cannabinoid administration; and, improve methods for testing treatments in progressive MS. OBJECTIVES: There were three objectives in the CUPID study: (1) to evaluate whether or not Δ(9)-THC could slow the course of progressive MS; (2) to assess the long-term safety of Δ(9)-THC; and (3) to explore newer ways of conducting clinical trials in progressive MS. DESIGN: The CUPID trial was a randomised, double-blind, placebo-controlled, parallel-group, multicentre trial. Patients were randomised in a 2 : 1 ratio to Δ(9)-THC or placebo. Randomisation was balanced according to Expanded Disability Status Scale (EDSS) score, study site and disease type. Analyses were by intention to treat, following a pre-specified statistical analysis plan. A cranial magnetic resonance imaging (MRI) substudy, Rasch measurement theory (RMT) analyses and an economic evaluation were undertaken. SETTING: Twenty-seven UK sites. PARTICIPANTS: Adults aged 18-65 years with primary or secondary progressive MS, 1-year evidence of disease progression and baseline EDSS 4.0-6.5. INTERVENTIONS: Oral Δ(9)-THC (maximum 28 mg/day) or matching placebo. ASSESSMENT VISITS: Three and 6 months, and then 6-monthly up to 36 or 42 months. MAIN OUTCOME MEASURES: Primary outcomes were time to EDSS progression, and change in Multiple Sclerosis Impact Scale-29 version 2 (MSIS-29v2) 20-point physical subscale (MSIS-29phys) score. Various secondary patient- and clinician-reported outcomes and MRI outcomes were assessed. RMT analyses examined performance of MS-specific rating scales as measurement instruments and tested for a symptomatic or disease-modifying treatment effect. Economic evaluation estimated mean incremental costs and quality-adjusted life-years (QALYs). RESULTS: Effectiveness - recruitment targets were achieved. Of the 498 randomised patients (332 to active and 166 to placebo), 493 (329 active and 164 placebo) were analysed. PRIMARY OUTCOMES: no significant treatment effect; hazard ratio EDSS score progression (active : placebo) 0.92 [95% confidence interval (CI) 0.68 to 1.23]; and estimated between-group difference in MSIS-29phys score (active-placebo) -0.9 points (95% CI -2.0 to 0.2 points). Secondary clinical and MRI outcomes: no significant treatment effects. Safety - at least one serious adverse event: 35% and 28% of active and placebo patients, respectively. RMT analyses - scale evaluation: MSIS-29 version 2, MS Walking Scale-12 version 2 and MS Spasticity Scale-88 were robust measurement instruments. There was no clear symptomatic or disease-modifying treatment effect. Economic evaluation - estimated mean incremental cost to NHS over usual care, over 3 years £27,443.20 per patient. No between-group difference in QALYs. CONCLUSIONS: The CUPID trial failed to demonstrate a significant treatment effect in primary or secondary outcomes. There were no major safety concerns, but unwanted side effects seemed to affect compliance. Participants were more disabled than in previous studies and deteriorated less than expected, possibly reducing our ability to detect treatment effects. RMT analyses supported performance of MS-specific rating scales as measures, enabled group- and individual person-level examination of treatment effects, but did not influence study inferences. The intervention had significant additional costs with no improvement in health outcomes; therefore, it was dominated by usual care and not cost-effective. Future work should focus on determining further factors to predict clinical deterioration, to inform the development of new studies, and modifying treatments in order to minimise side effects and improve study compliance. The absence of disease-modifying treatments in progressive MS warrants further studies of the cannabinoid pathway in potential neuroprotection. TRIAL REGISTRATION: Current Controlled Trials ISRCTN62942668. FUNDING: The National Institute for Health Research Health Technology Assessment programme, the Medical Research Council Efficacy and Mechanism Evaluation programme, Multiple Sclerosis Society and Multiple Sclerosis Trust. The report will be published in full in Health Technology Assessment; Vol. 19, No. 12. See the NIHR Journals Library website for further project information.

Randomised Evaluation of modified Valsalva Effectiveness in Re-entrant Tachycardias (REVERT) study.

INTRODUCTION: The Valsalva manoeuvre (VM) is a recommended first-line physical treatment for patients with re-entrant supraventricular tachycardia (SVT), but is often ineffective in standard practice. A failed VM is typically followed by treatment with intravenous adenosine, which patients often find unpleasant. VM effectiveness might be improved by a modification to posture which exaggerates the manoeuvre's vagal response and reduces the need for further emergency treatment. METHODS AND ANALYSIS: This is a multicentre randomised controlled clinical trial in 10 UK emergency departments (EDs). It compares a standard VM with a modified VM incorporating leg elevation and a supine posture after a standardised strain in stable adult patients presenting to the ED with SVT. The primary outcome measure is return to sinus rhythm on a 12-lead ECG. Secondary outcome measures include the need for treatment with adenosine or other antiarrhythmic treatments and the time patients spend in the ED. We plan to recruit approximately 372 patients, with 80% power to demonstrate an absolute improvement in cardioversion rate of 12%. An improvement of this magnitude through the use of a modified VM would be of significant benefit to patients and healthcare providers, and justify a change to standard practice. ETHICS AND DISSEMINATION: The study has been approved by the South West-Exeter Research Ethics Committee (REC reference 12/SW/0281). The trial will be published in an international peer reviewed journal. Study findings will be sent to the European and International resuscitation councils to inform future revisions of arrhythmia management guidelines. RESULTS: The trial will also be disseminated at international conferences and to patients through the Arrhythmia Alliance, a patient support charity. REGISTRATION: The study is registered with Current Controlled Trials (ISRCTN67937027) and has been adopted by the National Institute for Health Research (NIHR) Clinical Research Network.

A pilot randomised controlled trial of a preconsultation web-based intervention to improve the care quality and clinical outcomes of diabetes outpatients (DIAT).

INTRODUCTION: Diabetes is a chronic condition associated with many long-term complications. People with diabetes need to actively manage their condition, which can be complex. In consultations with healthcare professionals, patients receive advice about their diabetes but do not always discuss things which concern them, perhaps because of the perceived limited time or embarrassment. We want to test a 'preconsultation' intervention in which the patient is supported by a healthcare assistant to complete a web-based intervention aimed at producing an agenda to help them identify important areas for discussion in the consultation. Use of this agenda may enable the patient to play a more active role in that consultation and consequently become more confident, and hence more successful, in managing their condition. METHODS AND ANALYSIS: In this pilot randomised controlled trial, 120 people with diabetes will be randomised with equal allocation to receive the intervention or usual clinical care. The primary outcome is reduction in glycosylated haemoglobin(HbA1c). Secondary outcomes are patient-reported communication, enablement, self-care activity, diabetes-dependent quality of life, empowerment, satisfaction, health-related quality of life and resource use. The aim of the pilot study was to estimate parameters to inform the design of the definitive trial. Follow-up on quantitative outcomes will be at 3 and 6 months. A nested qualitative study will collect data on the patients' experiences of producing an agenda. Resource use data and medication use will also be collected via a review of medical records for a sample of participants. ETHICS AND DISSEMINATION: Approval was granted by the NHS Research Ethics Committee North West-Preston (13/NW/0123). Dissemination will include publication of quantitative and qualitative findings, and experience of public involvement in peer-reviewed journals. Results will also be disseminated to trial participants via workshops led by lay coapplicants. TRIAL REGISTRATION: ISRCTN75070242.

Effect of dronabinol on progression in progressive multiple sclerosis (CUPID): a randomised, placebo-controlled trial.

BACKGROUND: Laboratory evidence has shown that cannabinoids might have a neuroprotective action. We investigated whether oral dronabinol (Δ(9)-tetrahydrocannabinol) might slow the course of progressive multiple sclerosis. METHODS: In this multicentre, parallel, randomised, double-blind, placebo-controlled study, we recruited patients aged 18-65 years with primary or secondary progressive multiple sclerosis from 27 UK neurology or rehabilitation departments. Patients were randomly assigned (2:1) to receive dronabinol or placebo for 36 months; randomisation was by stochastic minimisation, using a computer-generated randomisation sequence, balanced according to expanded disability status scale (EDSS) score, centre, and disease type. Maximum dose was 28 mg per day, titrated against bodyweight and adverse effects. Primary outcomes were EDSS score progression (masked assessor, time to progression of ≥1 point from a baseline score of 4·0-5·0 or ≥0·5 points from a baseline score of ≥5·5, confirmed after 6 months) and change from baseline in the physical impact subscale of the 29-item multiple sclerosis impact scale (MSIS-29-PHYS). All patients who received at least one dose of study drug were included in the intention-to-treat analyses. This trial is registered as an International Standard Randomised Controlled Trial (ISRCTN 62942668). FINDINGS: Of the 498 patients randomly assigned to a treatment group, 329 received at least one dose of dronabinol and 164 received at least one dose of placebo (five did not receive the allocated intervention). 145 patients in the dronabinol group had EDSS score progression (0·24 first progression events per patient-year; crude rate) compared with 73 in the placebo group (0·23 first progression events per patient-year; crude rate); HR for prespecified primary analysis was 0·92 (95% CI 0·68-1·23; p=0·57). Mean yearly change in MSIS-29-PHYS score was 0·62 points (SD 3·29) in the dronabinol group versus 1·03 points (3·74) in the placebo group. Primary analysis with a multilevel model gave an estimated between-group difference (dronabinol-placebo) of -0·9 points (95% CI -2·0 to 0·2). We noted no serious safety concerns (114 [35%] patients in the dronabinol group had at least one serious adverse event, compared with 46 [28%] in the placebo group). INTERPRETATION: Our results show that dronabinol has no overall effect on the progression of multiple sclerosis in the progressive phase. The findings have implications for the design of future studies of progressive multiple sclerosis, because lower than expected progression rates might have affected our ability to detect clinical change. FUNDING: UK Medical Research Council, National Institute for Health Research Efficacy and Mechanism Evaluation programme, Multiple Sclerosis Society, and Multiple Sclerosis Trust.

Patient-orientated longitudinal study of multiple sclerosis in south west England (The South West Impact of Multiple Sclerosis Project, SWIMS) 1: protocol and baseline characteristics of cohort.

BACKGROUND: There 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. METHODS: This 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. RESULTS: Seventy-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. CONCLUSIONS: Demographics 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.

Cannabinoids for treatment of spasticity and other symptoms related to multiple sclerosis (CAMS study): multicentre randomised placebo-controlled trial.

BACKGROUND: Multiple sclerosis is associated with muscle stiffness, spasms, pain, and tremor. Much anecdotal evidence suggests that cannabinoids could help these symptoms. Our aim was to test the notion that cannabinoids have a beneficial effect on spasticity and other symptoms related to multiple sclerosis. METHODS: We did a randomised, placebo-controlled trial, to which we enrolled 667 patients with stable multiple sclerosis and muscle spasticity. 630 participants were treated at 33 UK centres with oral cannabis extract (n=211), Delta9-tetrahydrocannabinol (Delta9-THC; n=206), or placebo (n=213). Trial duration was 15 weeks. Our primary outcome measure was change in overall spasticity scores, using the Ashworth scale. Analysis was by intention to treat. FINDINGS: 611 of 630 patients were followed up for the primary endpoint. We noted no treatment effect of cannabinoids on the primary outcome (p=0.40). The estimated difference in mean reduction in total Ashworth score for participants taking cannabis extract compared with placebo was 0.32 (95% CI -1.04 to 1.67), and for those taking Delta9-THC versus placebo it was 0.94 (-0.44 to 2.31). There was evidence of a treatment effect on patient-reported spasticity and pain (p=0.003), with improvement in spasticity reported in 61% (n=121, 95% CI 54.6-68.2), 60% (n=108, 52.5-66.8), and 46% (n=91, 39.0-52.9) of participants on cannabis extract, Delta9-THC, and placebo, respectively. INTERPRETATION: Treatment with cannabinoids did not have a beneficial effect on spasticity when assessed with the Ashworth scale. However, though there was a degree of unmasking among the patients in the active treatment groups, objective improvement in mobility and patients' opinion of an improvement in pain suggest cannabinoids might be clinically useful.