Efficacy and safety of co-careldopa as an add-on therapy to occupational and physical therapy in patients after stroke (DARS): a randomised, double-blind, placebo controlled trial

Background Dopamine is a key modulator of striatal function and learning and might improve motor recovery after stroke. Previous small trials of dopamine agonists after stroke provide equivocal evidence of effectiveness on improving motor recovery. We aimed to assess the safety and efficacy of co-careldopa plus routine occupational and physical therapy during early rehabilitation after stroke. Methods This double-blind, multicentre, randomised controlled trial of co-careldopa versus placebo in addition to routine NHS occupational and physical therapy was done at 51 UK NHS acute inpatient stroke rehabilitation services. We recruited patients with new or recurrent clinically diagnosed ischaemic or haemorrhagic (excluding subarachnoid haemorrhage) stroke 5–42 days before randomisation, who were unable to walk 10 m or more, had a score of less than 7 points on the Rivermead Mobility Index, were expected to need rehabilitation, and were able to access rehabilitation after discharge from hospital. Participants were assigned (1:1) using stratified random blocks to receive 6 weeks of oral co-careldopa or matched placebo in addition to routine NHS physiotherapy and occupational therapy. The initial two doses of co-careldopa were 62·5 mg (50 mg of levodopa and 12·5 mg of carbidopa) and the remaining doses were 125 mg (100 mg of levodopa and 25 mg of carbidopa). Participants were required to take a single oral tablet 45–60 min before physiotherapy or occupational therapy session. The primary outcome was ability to walk independently, defined as a Rivermead Mobility Index score of 7 or more, at 8 weeks. Primary and safety analyses were done in the intention-to-treat population. The trial is registered on the ISRCTN registry, number ISRCTN99643613.Findings Between May 30, 2011, and March 28, 2014, of 1574 patients found eligible, 593 (mean age 68·5 years) were randomly assigned to either the co-careldopa group (n=308) or to the placebo group (n=285), on an average 18 days after stroke onset. Primary outcome data were available for all 593 patients. We found no evidence that the ability to walk independently improved with co-careldopa (125 [41%] of 308 patients) compared with placebo (127 [45%] of 285 patients; odds ratio 0·78 [95% CI 0·53–1·15]) at 8 weeks. Mortality at 12 months did not differ between the two groups (22 [7%] vs 17 [6%]). Serious adverse events were largely similar between groups. Vomiting during therapy sessions, after taking the study drug, was the most frequent adverse event and was more frequent in the co-careldopa group than the placebo group (19 [6·2%] vs 9 [3·2%]).Interpretation Co-careldopa in addition to routine occupational and physical therapy does not seem to improve walking after stroke. Further research might identify subgroups of patients with stroke who could benefit from dopaminergic therapy at different doses or times after stroke with more intensive motor therap

Liver resection surgery compared with thermal ablation in high surgical risk patients with colorectal liver metastases: the LAVA international RCT.

BACKGROUND: Although surgical resection has been considered the only curative option for colorectal liver metastases, thermal ablation has recently been suggested as an alternative curative treatment. There have been no adequately powered trials comparing surgery with thermal ablation. OBJECTIVES: Main objective - to compare the clinical effectiveness and cost-effectiveness of thermal ablation versus liver resection surgery in high surgical risk patients who would be eligible for liver resection. Pilot study objectives - to assess the feasibility of recruitment (through qualitative study), to assess the quality of ablations and liver resection surgery to determine acceptable standards for the main trial and to centrally review the reporting of computed tomography scan findings relating to ablation and outcomes and recurrence rate in both arms. DESIGN: A prospective, international (UK and the Netherlands), multicentre, open, pragmatic, parallel-group, randomised controlled non-inferiority trial with a 1-year internal pilot study. SETTING: Tertiary liver, pancreatic and gallbladder (hepatopancreatobiliary) centres in the UK and the Netherlands. PARTICIPANTS: Adults with a specialist multidisciplinary team diagnosis of colorectal liver metastases who are at high surgical risk because of their age, comorbidities or tumour burden and who would be suitable for liver resection or thermal ablation. INTERVENTIONS: Thermal ablation conducted as per local policy (but centres were encouraged to recruit within Cardiovascular and Interventional Radiological Society of Europe guidelines) versus surgical liver resection performed as per centre protocol. MAIN OUTCOME MEASURES: Pilot study - patients' and clinicians' acceptability of the trial to assist in optimisation of recruitment. Primary outcome - disease-free survival at 2 years post randomisation. Secondary outcomes - overall survival, timing and site of recurrence, additional therapy after treatment failure, quality of life, complications, length of hospital stay, costs, trial acceptability, and disease-free survival measured from end of intervention. It was planned that 5-year survival data would be documented through record linkage. Randomisation was performed by minimisation incorporating a random element, and this was a non-blinded study. RESULTS: In the pilot study over 1 year, a total of 366 patients with colorectal liver metastases were screened and 59 were considered eligible. Only nine participants were randomised. The trial was stopped early and none of the planned statistical analyses was performed. The key issues inhibiting recruitment included fewer than anticipated patients eligible for both treatments, misconceptions about the eligibility criteria for the trial, surgeons' preference for one of the treatments ('lack of clinical equipoise' among some of the surgeons in the centre) with unconscious bias towards surgery, patients' preference for one of the treatments, and lack of dedicated research nurses for the trial. CONCLUSIONS: Recruitment feasibility was not demonstrated during the pilot stage of the trial; therefore, the trial closed early. In future, comparisons involving two very different treatments may benefit from an initial feasibility study or a longer period of internal pilot study to resolve these difficulties. Sufficient time should be allowed to set up arrangements through National Institute for Health Research (NIHR) Research Networks. TRIAL REGISTRATION: Current Controlled Trials ISRCTN52040363. FUNDING: This project was funded by the NIHR Health Technology Assessment programme and will be published in full in Health Technology Assessment; Vol. 24, No. 21. See the NIHR Journals Library website for further project information

Safety and efficacy of co-careldopa as an add-on therapy to occupational and physical therapy in patients after stroke (DARS): a randomised, double-blind, placebo-controlled trial

Background Dopamine is a key modulator of striatal function and learning and might improve motor recovery after stroke. Previous small trials of dopamine agonists after stroke provide equivocal evidence of effectiveness on improving motor recovery. We aimed to assess the safety and efficacy of co-careldopa plus routine occupational and physical therapy during early rehabilitation after stroke. Methods This double-blind, multicentre, randomised controlled trial of co-careldopa versus placebo in addition to routine NHS occupational and physical therapy was done at 51 UK NHS acute inpatient stroke rehabilitation services. We recruited patients with new or recurrent clinically diagnosed ischaemic or haemorrhagic (excluding subarachnoid haemorrhage) stroke 5–42 days before randomisation, who were unable to walk 10 m or more, had a score of less than 7 points on the Rivermead Mobility Index, were expected to need rehabilitation, and were able to access rehabilitation after discharge from hospital. Participants were assigned (1:1) using stratified random blocks to receive 6 weeks of oral co-careldopa or matched placebo in addition to routine NHS physiotherapy and occupational therapy. The initial two doses of co-careldopa were 62·5 mg (50 mg of levodopa and 12·5 mg of carbidopa) and the remaining doses were 125 mg (100 mg of levodopa and 25 mg of carbidopa). Participants were required to take a single oral tablet 45–60 min before physiotherapy or occupational therapy session. The primary outcome was ability to walk independently, defined as a Rivermead Mobility Index score of 7 or more, at 8 weeks. Primary and safety analyses were done in the intention-to-treat population. The trial is registered on the ISRCTN registry, number ISRCTN99643613. Findings Between May 30, 2011, and March 28, 2014, of 1574 patients found eligible, 593 (mean age 68·5 years) were randomly assigned to either the co-careldopa group (n=308) or to the placebo group (n=285), on an average 18 days after stroke onset. Primary outcome data were available for all 593 patients. We found no evidence that the ability to walk independently improved with co-careldopa (125 [41%] of 308 patients) compared with placebo (127 [45%] of 285 patients; odds ratio 0·78 [95% CI 0·53–1·15]) at 8 weeks. Mortality at 12 months did not differ between the two groups (22 [7%] vs 17 [6%]). Serious adverse events were largely similar between groups. Vomiting during therapy sessions, after taking the study drug, was the most frequent adverse event and was more frequent in the co-careldopa group than the placebo group (19 [6·2%] vs 9 [3·2%]). Interpretation Co-careldopa in addition to routine occupational and physical therapy does not seem to improve walking after stroke. Further research might identify subgroups of patients with stroke who could benefit from dopaminergic therapy at different doses or times after stroke with more intensive motor therapy. Funding Medical Research Council

Dopamine Augmented Rehabilitation in Stroke (DARS): a multicentre double-blind, randomised controlled trial of co-careldopa compared with placebo, in addition to routine NHS occupational and physical therapy, delivered early after stroke on functional recovery

BACKGROUND: Dopamine is a key modulator of striatal function and learning, and may improve motor recovery after stroke. Seven small trials of dopamine agonists after stroke have provided equivocal evidence of the clinical effectiveness of dopamine agonists in improving motor recovery. DESIGN: Dopamine Augmented Rehabilitation in Stroke was a multicentre, randomised, double-blind, placebo-controlled trial with stroke patients randomised to receive 6 weeks of co-careldopa (Sinemet®, Merck Sharp & Dohme Ltd) or placebo in combination with occupational and physical rehabilitation. METHODS: The primary outcome measure was the proportion of patients walking independently at 8 weeks [Rivermead Mobility Index (RMI) score of ≥ 7 points and ‘yes’ to item 7 on the RMI]. Secondary outcome measures assessed physical functioning, pain, cognition, mood, fatigue and carer burden at 8 weeks, 6 months and 12 months. RESULTS: Between May 2011 and March 2014, 593 patients (mean age 68.5 years) and 165 carers (mean age 59.7 years) were recruited from stroke rehabilitation units; 308 patients were randomised to co-careldopa and 285 to placebo at a median of 15 days following stroke onset. The study drug was to be taken 45–60 minutes before therapy, which included motor activities (mean 23.2 and 24.8 sessions in the co-careldopa and placebo groups, respectively). The mean number of investigational medicinal product doses taken was 20.6 in the co-careldopa group and 22.4 in the placebo group. Ability to walk independently was not improved at 8 weeks [40.6% (co-careldopa) vs. 44.6% (placebo); odds ratio 0.78, 95% confidence interval (CI) 0.53 to 1.15], 6 months [51.6% (co-careldopa) vs. 53.3% (placebo)] or 12 months [51.6% (co-careldopa) vs. 56.8% (placebo)]. There were no significant differences for Barthel Index, Nottingham Extended Activities of Daily Living, ABILHAND Manual Ability Measure or Modified Rankin Scale, pain or fatigue at any time point. Montreal Cognitive Assessment scores did not significantly differ; the majority of participants had cognitive impairment at baseline, which improved during 12 months’ follow-up. No difference was observed in General Health Questionnaire 12-item version scores between groups at 8 weeks and 12 months but, at 6 months, those in the co-careldopa group reported significantly better general health [mean difference (MD) –1.33, 95% CI –2.57 to –0.10]. Mortality at 12 months was not significantly different. Carers in the placebo group reported significantly greater burden at 6 months (MD 5.05, 95% CI 0.10 to 10.01) and 12 months (MD 7.52, 95% CI 1.87 to 13.18). CONCLUSION: Co-careldopa in addition to routine NHS occupational and physical therapy is not clinically effective or cost-effective in improving walking, physical functioning, mood or cognition following stroke. We recommend further research to develop imaging and clinical markers that would allow identification of promising drug therapies that would enhance motor therapy in improving walking ability and arm function. Further research is needed to compare strategies of giving drug therapy intermittently immediately prior to therapy sessions or as continuous background daily administration. LIMITATIONS: In total, 10.3% of patients were lost to follow-up at 8 weeks and < 10% of patients met the strict per-protocol definition. Despite this, the findings are robust and generalisable to patients with limited mobility in the first few weeks after stroke. TRIAL REGISTRATION: Current Controlled Trials ISRCTN99643613. FUNDING: This project was funded by the Efficacy and Mechanism Evaluation programme, a Medical Research Council and National Institute for Health Research partnership

The DARS (Dopamine Augmented Rehabilitation in Stroke) trial: protocol for a randomised controlled trial of Co-careldopa treatment in addition to routine NHS occupational and physical therapy after stroke

Background: Stroke has a huge impact, leaving more than a third of affected people with lasting disability and rehabilitation remains a cornerstone treatment in the National Health Service (NHS). Recovery of mobility and arm function post-stroke occurs through re-learning to use the affected body parts and/or learning to compensate with the lesser affected side. Promising evidence suggests that the addition of Co-careldopa to physical therapy and occupational therapy may improve the recovery of arm and leg movement and lead to improved function. Methods/design: Dopamine Augmented Rehabilitation in Stroke (DARS) is a multi-centre double-blind, randomised, placebo, controlled clinical trial of Co-careldopa in addition to routine NHS occupational therapy and physical therapy as part of early stroke rehabilitation. Participants will be randomised on a 1:1 basis to either Co-careldopa or placebo. The primary objective of the trial is to determine whether the addition of six weeks of Co-careldopa treatment to rehabilitation therapy can improve the proportion of patients who can walk independently eight weeks post-randomisation. Discussion: The DARS trial will provide evidence as to whether Co-careldopa, in addition to routine NHS occupational and physical therapy, leads to a greater recovery of motor function, a reduction in carer dependency and advance rehabilitation treatments for people with stroke. Trial registration: ISRCTN99643613 assigned on 4 December 2009

Effect of rituximab on a salivary gland ultrasound score in primary Sjögren’s syndrome: results of the TRACTISS randomised double-blind multicentre substudy

Objectives To compare the effects of rituximab versus placebo on salivary gland ultrasound (SGUS) in primary Sjögren’s syndrome (PSS) in a multicentre, multiobserver phase III trial substudy. Methods Subjects consenting to SGUS were randomised to rituximab or placebo given at weeks 0, 2, 24 and 26, and scanned at baseline and weeks 16 and 48. Sonographers completed a 0–11 total ultrasound score (TUS) comprising domains of echogenicity, homogeneity, glandular definition, glands involved and hypoechoic foci size. Baseline-adjusted TUS values were analysed over time, modelling change from baseline at each time point. For each TUS domain, we fitted a repeated-measures logistic regression model to model the odds of a response in the rituximab arm (≥1-point improvement) as a function of the baseline score, age category, disease duration and time point. Results 52 patients (n=26 rituximab and n=26 placebo) from nine centres completed baseline and one or more follow-up visits. Estimated between-group differences (rituximab-placebo) in baseline-adjusted TUS were −1.2 (95% CI −2.1 to −0.3; P=0.0099) and −1.2 (95% CI −2.0 to −0.5; P=0.0023) at weeks 16 and 48. Glandular definition improved in the rituximab arm with an OR of 6.8 (95% CI 1.1 to 43.0; P=0.043) at week 16 and 10.3 (95% CI 1.0 to 105.9; P=0.050) at week 48. Conclusions We demonstrated statistically significant improvement in TUS after rituximab compared with placebo. This encourages further research into both B cell depletion therapies in PSS and SGUS as an imaging biomarker

Kinetics of acid-mediated disassembly of the b-subunit pentamer of escherichia-coli heat-labile enterotoxin - molecular-basis of ph stability

The B-subunit pentamer of Escherichia coli heat-labile enterotoxin (EtxB) is highly stable, maintaining its quaternary structure in a range of conditions that would normally be expected to cause protein denaturation, In this paper the structural stability of EtxB has been studied as a function of pH by electrophoretic, immunochemical, and spectroscopic techniques, Disassembly of the cyclic pentameric structure of human EtxB occurs only below pH 2. As determined by changes in intrinsic fluorescence this process follows first-order kinetics, with the rate constant for disassembly being proportional to the square of the H+ ion concentration, and with an activation energy of 155 kJ mol(-1). A C-terminal deletion mutant, hEtxB214, similarly shows first-order kinetics for disassembly but with a higher pH threshold, resulting in disassembly being seen at pH 3.4 and below. These findings are consistent with the rate-limiting step for disassembly of human EtxB being the simultaneous disruption of two interfaces by protonation of two C-terminal carboxylates. By comparison, disassembly of the B-subunit of cholera toxin (CtxB), a protein which shows 80% sequence identity with EtxB, exhibits a much lower stability to acid conditions; with disassembly of CtxB occurring below pH 3.9, with an activation energy of 81 kJ mol(-1). Reasons for the observed differences in acid stability are discussed, and the implications of these findings to the development of oral vaccines using EtxB and CtxB are considered