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

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

SummaryBackgroundVenous thromboembolism is a common, potentially avoidable cause of death and morbidity in patients in hospital, including those with stroke. In surgical patients, intermittent pneumatic compression (IPC) reduces the risk of deep vein thrombosis (DVT), but no reliable evidence exists about its effectiveness in patients who have had a stroke. We assessed the effectiveness of IPC to reduce the risk of DVT in patients who have had a stroke.MethodsThe CLOTS 3 trial is a multicentre parallel group randomised trial assessing IPC in immobile patients (ie, who cannot walk to the toilet without the help of another person) with acute stroke. We enrolled patients from day 0 to day 3 of admission and allocated them via a central randomisation system (ratio 1:1) to receive either IPC or no IPC. A technician who was masked to treatment allocation did a compression duplex ultrasound (CDU) of both legs at 7–10 days and, wherever practical, at 25–30 days after enrolment. Caregivers and patients were not masked to treatment assignment. Patients were followed up for 6 months to determine survival and later symptomatic venous thromboembolism. The primary outcome was a DVT in the proximal veins detected on a screening CDU or any symptomatic DVT in the proximal veins, confirmed on imaging, within 30 days of randomisation. Patients were analysed according to their treatment allocation. Trial registration: ISRCTN93529999.FindingsBetween Dec 8, 2008, and Sept 6, 2012, 2876 patients were enrolled in 94 centres in the UK. The included patients were broadly representative of immobile stroke patients admitted to hospital and had a median age of 76 years (IQR 67–84). The primary outcome occurred in 122 (8·5%) of 1438 patients allocated IPC and 174 (12·1%) of 1438 patients allocated no IPC; an absolute reduction in risk of 3·6% (95% CI 1·4–5·8). Excluding the 323 patients who died before any primary outcome and 41 without any screening CDU, the adjusted OR for the comparison of 122 of 1267 patients vs 174 of 1245 patients was 0·65 (95% CI 0·51–0·84; p=0·001). Deaths in the treatment period occurred in 156 (11%) patients allocated IPC and 189 (13%) patients allocated no IPC died within the 30 days of treatment period (p=0·057); skin breaks on the legs were reported in 44 (3%) patients allocated IPC and in 20 (1%) patients allocated no IPC (p=0·002); falls with injury were reported in 33 (2%) patients in the IPC group and in 24 (2%) patients in the no-IPC group (p=0·221).InterpretationIPC is an effective method of reducing the risk of DVT and possibly improving survival in a wide variety of patients who are immobile after stroke.FundingNational Institute of Health Research (NIHR) Health Technology Assessment (HTA) programme, UK; Chief Scientist Office of Scottish Government; Covidien (MA, USA).

BackgroundVenous thromboembolism (VTE) is a common cause of death and morbidity in stroke patients. There are few data concerning the effectiveness of intermittent pneumatic compression (IPC) in treating patients with stroke.ObjectivesTo establish whether or not the application of IPC to the legs of immobile stroke patients reduced their risk of deep vein thrombosis (DVT).DesignClots in Legs Or sTockings after Stroke (CLOTS) 3 was a multicentre, parallel-group, randomised controlled trial which allocated patients via a central randomisation system to IPC or no IPC. A technician blinded to treatment allocation performed compression duplex ultrasound (CDU) of both legs at 7–10 days and 25–30 days after enrolment. We followed up patients for 6 months to determine survival and later symptomatic VTE. Patients were analysed according to their treatment allocation.SettingWe enrolled 2876 patients in 94 UK hospitals between 8 December 2008 and 6 September 2012.ParticipantsInclusion criteria: patients admitted to hospital within 3 days of acute stroke and who were immobile on the day of admission (day 0) to day 3. Exclusion criteria: age InterventionsParticipants were allocated to routine care or routine care plus IPC for 30 days, or until earlier discharge or walking independently.Main outcome measuresThe primary outcome was DVT in popliteal or femoral veins, detected on a screening CDU, or any symptomatic DVT in the proximal veins, confirmed by imaging, within 30 days of randomisation. The secondary outcomes included death, any DVTs, symptomatic DVTs, pulmonary emboli, skin breaks on the legs, falls with injury or fractures and duration of IPC use occurring within 30 days of randomisation and survival, symptomatic VTE, disability (as measured by the Oxford Handicap Scale), quality of life (as measured by the European Quality of Life-5 Dimensions 3 Level questionnaire) and length of initial hospital stay measured 6 months after randomisation.ResultsWe allocated 1438 patients to IPC and 1438 to no IPC. The primary outcome occurred in 122 (8.5%) of 1438 patients allocated to IPC and 174 (12.1%) of 1438 patients allocated to no IPC, giving an absolute reduction in risk of 3.6% [95% confidence interval (CI) 1.4% to 5.8%] and a relative risk reduction of 0.69 (95% CI 0.55 to 0.86). After excluding 323 patients who died prior to any primary outcome and 41 who had no screening CDU, the primary outcome occurred in 122 of 1267 IPC participants compared with 174 of 1245 no-IPC participants, giving an adjusted odds ratio of 0.65 (95% CI 0.51 to 0.84;p = 0.001). Secondary outcomes in IPC compared with no-IPC participants were death in the treatment period in 156 (10.8%) versus 189 (13.1%) (p = 0.058); skin breaks in 44 (3.1%) versus 20 (1.4%) (p = 0.002); and falls with injury in 33 (2.3%) versus 24 (1.7%) (p = 0.221). Among patients treated with IPC, there was a statistically significant improvement in survival to 6 months (hazard ratio 0.86, 95% CI 0.73 to 0.99;p = 0.042), but no improvement in disability. The direct cost of preventing a DVT was £1282 per event (95% CI £785 to £3077).ConclusionsIPC is an effective and inexpensive method of reducing the risk of DVT and improving survival in immobile stroke patients.Future researchFurther research should test whether or not IPC improves survival in other groups of high-risk hospitalised medical patients. In addition, research into methods to improve adherence to IPC might increase the benefits of IPC in stroke patients.Trial registrationCurrent Controlled Trials ISRCTN93529999.FundingThe start-up phase of the trial (December 2008–March 2010) was funded by the Chief Scientist Office of the Scottish Government (reference number CZH/4/417). The main phase of the trial was funded by the National Institute for Health Research Health Technology Assessment programme (reference number 08/14/03). Covidien Ltd (Mansfield, MA, USA) lent its Kendall SCD™ Express sequential compression system controllers to the 105 centres involved in the trial and donated supplies of its sleeves. It also provided logistical help in keeping our centres supplied with sleeves and training materials relevant to the use of their devices. Recruitment and follow-up were supported by the National Institute for Health Research-funded UK Stroke Research Network and by the Scottish Stroke Research Network, which was supported by NHS Research Scotland.

BACKGROUND: Deep vein thrombosis (DVT) is an important complication of stroke, but the evidence to support commonly used prophylactic strategies is conflicting. OBJECTIVES: To describe the incidence, extent, associated clinical features and evolution of DVT after stroke. PATIENTS/METHODS: The CLOTS trials 1 and 2 together randomized 5632 immobile stroke patients in 135 hospitals in nine countries. We screened patients for asymptomatic DVT with compression duplex ultrasound (CDU) at about 7-10 days and again at about 25-30 days after enrollment. RESULTS: Six hundred and forty-one (11.4%) of 5632 patients had DVT detected on the first CDU scan at a median of 8 days (interquartile range [IQR] 7-10 days) after enrollment, and an additional 176 (3.1%) had a DVT on the second CDU scan at a median of 28 days (IQR 26-30 days). Of the 817 with DVTs, 289 (35%) were symptomatic and 39 (5%) had pulmonary embolism (PE) confirmed by imaging. Six hundred and seventy-six (83%) were unilateral, 141 (17%) were bilateral, 322 (39%) were limited to calf veins, 172 (21%) were popliteal, and 323 (40%) were femoral. Among the 542 patients with DVT and a weak leg, the DVT affected the weaker leg in 396 (73%), the stronger leg in 59 (11%), and was bilateral in 87 (16%). Among the 318 patients with a DVT detected on the first CDU scan who had a second scan, the DVT regressed in 148 (47%), stayed the same in 140 (44%), and progressed in only 30 (9%). CONCLUSIONS: Although most DVTs develop within the first week, some develop later, and some early DVTs progress. Any prophylaxis needs to be started early but ideally continued for at least 4 weeks.

Graduated compression stockings are widely used for deep venous thrombosis (DVT) prophylaxis. Although below-knee stockings are used more often than thigh-length stockings, no reliable evidence indicates that they are as effective as thigh-length stockings.To compare the effectiveness of thigh-length stockings with that of below-knee stockings for preventing proximal DVT in immobile, hospitalized patients with stroke.Parallel-group trial with centralized randomization (minimization within centers) to ensure allocation concealment. The ultrasonographers who looked for DVT were blinded, but the patients and caregivers were not. (Controlled-trials.com registration number: ISRCTN28163533)112 hospitals in 9 countries.3114 immobile patients hospitalized with acute stroke between January 2002 and May 2009.1552 patients received thigh-length stockings and 1562 patients received below-knee stockings to wear while they were in the hospital.Ultrasonographers performed compression duplex ultrasonography in 1406 patients (96% of survivors) in each treatment group between 7 and 10 days after enrollment. They performed a second scan in 643 patients in the thigh-length stockings group and 639 in the below-knee stockings group at about 25 to 30 days. The primary outcome was symptomatic or asymptomatic DVT in the popliteal or femoral veins, detected on either scan.Patients were retained in their assigned group for all analyses. The primary outcome occurred in 98 patients (6.3%) who received thigh-length stockings and 138 (8.8%) who received below-knee stockings (absolute difference, 2.5 percentage points [95% CI, 0.7 to 4.4 percentage points]; P = 0.008), an odds reduction of 31% (CI, 9% to 47%). Seventy-five percent of patients in both groups wore the stockings for 30 days or until they were discharged, died, or regained mobility. Skin breaks occurred in 61 patients who received thigh-length stockings (3.9%) and 45 (2.9%) who received below-knee stockings.Blinding was incomplete, 2 scans were not obtained for all enrolled patients, and the trial was stopped before the target accrual was reached.Proximal DVT occurs more often in patients with stroke who wear below-knee stockings than in those who wear thigh-length stockings.Medical Research Council of the United Kingdom, Chief Scientist Office of the Scottish Government, and Chest Heart and Stroke Scotland.

Objectives: To determine whether routine oral nutritional supplementation of a normal hospital diet improves outcome after stroke (Trial 1); whether early tube feeding improves the outcomes of dysphagic stroke patients (Trial 2); and if tube feeding via a percutaneous endoscopic gastrostomy (PEG) results in better outcomes than that via a nasogastric tube (NG) (Trial 3). Design: The Feed Or Ordinary Diet (FOOD) trial was a family of three pragmatic, randomised controlled trials (RCTs). They shared facilities for randomisation, data collection, follow-up and coordination. Patients could be co-enrolled in more than one of these trials. Setting: Patients were enrolled in 131 hospitals in 18 countries. Participants: A total of 5033 patients who had been admitted to hospital with a recent stroke were enrolled in the trials between November 1996 and July 2003. Interventions: In Trial 1, patients who could swallow within the first 30 days of admission were allocated to normal hospital diet versus normal hospital diet plus oral nutritional supplements (equivalent to 360 ml of 1.5 kcal/ml, 20 g of protein per day) until hospital discharge. In Trial 2, dysphagic patients enrolled within 7 days of admission were allocated to early enteral tube feeding versus avoid any enteral tube feeding for at least 1 week. In Trial 3, dysphagic patients were allocated within 30 days of admission to receive enteral tube feeding via PEG versus NG. Main outcome measures: Survival and the modified Rankin scale (MRS), a measure of functional outcome (grade 0 indicating no symptoms and grade 5 indicating severe disability, requiring help day and night). The primary outcomes were measured 6 months after enrollment, blind to treatment allocation, by the patient or their proxy completing a postal or telephone questionnaire. Results: In Trial 1, 4023 patients were enrolled by 125 hospitals in 15 countries. Only 314 (7.8%) patients were judged undernourished at baseline. Vital status and MRS at the end of the trial were known for 4012 (99.7%) and 4004 (99.5%), respectively. Of the 2007 allocated normal hospital diet, 253 (12.6%) died, 918 (45.7%) were alive with poor outcome (MRS 3-5) and 823 (41.1%) had a good outcome (MRS 0-2). Of the 2016 allocated oral supplements, 241 (12.0%) died, 953 (47.3%) were alive with poor outcome and 813 (40.4%) had a good outcome. The supplemented diet was associated with an absolute reduction in risk of death of 0.7% (95% CI -1.4 to 2.7; p = 0.5) and a 0.7% (95% CI -2.3 to 3.8, p = 0.6) increased risk of death or poor outcome. In Trial 2, a total of 859 patients were enrolled by 83 hospitals in 15 countries. MRS at the end of the trial was known for 858 (99.9%). At follow-up, of 429 allocated early tube feeding, 182 (42.4%) died, 157 (36.6%) were alive with poor outcome (MRS 4-5) and 90 (21.0%) had a good outcome (MRS 0-3). Of 430 allocated avoid tube feeding 207 (48.1%) died, 137 (31.9%) were alive with poor outcome and 85 (19.8%) had a good outcome. Early tube feeding was associated with an absolute reduction in risk of death of 5.8% (95% CI -0.8 to 12.5; p = 0.09) and a reduction in death or poor outcome of 1.2% (95% CI -4.2 to 6.6; p = 0.7). In Trial 3, 321 patients were enrolled by 47 hospitals in 11 countries. Of 162 allocated PEG, 79 (48.8%) died, 65 (40.1%) were alive with poor outcome and 18 (11.1%) had good outcome. Of 159 allocated NG, 76 (47.8%) died, 53 (33.3%) were alive with poor outcome and 30 (18.9%) had good outcome. PEG was associated with an increase in absolute risk of death of 1.0% (95% CI -10.0 to 11.9; p = 0.9) and an increased risk of death or poor outcome of 7.8% (95% CI 0.0 to 15.5; p = 0.05). Conclusions: The results of Trial 1 would be compatible with oral supplementation being associated with a 1-2% absolute benefit or harm, but do not support routine supplementation of hospital diet for unselected stroke patients who are predominantly well nourished on admission. In Trial 2, the data suggest that a policy of early tube feeding may substantially reduce the risk of dying after stroke and it is very unlikely that the alternative policy of avoiding early tube feeding would significantly improve survival. Improved survival may be at the expense of increasing the proportion surviving with poor outcome. These data might usefully inform the difficult discussions about whether or not to feed a patient with a severe stroke. In Trial 3, the data suggest that in the first 2-3 weeks after acute stroke, better functional outcomes result from feeding via NG tube than PEG tube, although there was no major difference in survival. These data do not support a policy of early initiation of PEG feeding in dysphagic stroke patients. Future research might be focused on making NG tube feeding safer and more effective, also studies need to confirm the increased risk of gastrointestinal haemorrhage associated with tube feeding and, if confirmed, establish whether any interventions might reduce this risk. Future work might also aim to establish why worse functional outcomes occurred in PEG-fed patients because patients with prolonged dysphagia or intolerance of an NG tube are inevitably fed via a PEG tube.