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

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

Developing a User Interface for the iPAM Stroke Rehabilitation System

The increasing population of older people is leading to growing healthcare demands. Stroke is the commonest cause of severe disability in developed countries leaving one third of patients with long term disability. Rehabilitation is the cornerstone of recovery. Lack of rehabilitation manpower resources can limit recovery of limb function. However, technology can assist rehabilitation staff to deliver greater intensity of treatment. Robotic systems such as the iPAM robot can provide semi-automated arm exercises for people with complex impairments leading to loss of functional arm movement. Feedback to the patient about their performance, usability of the exercise "workspace" and motivating exercises are key aspects of the successful deployment of robotic systems within routine clinical use. We describe the development of the patient interface for the iPAM robotic system. Central to this development is user involvement (with rehabilitation professionals and people with stroke). Using user centred design methods which included use of questionnaires and one to one discussions, the user interface was changed from a simple screen showing a stick figure of the arm to a 3D scene with simplified indicators and feedback screens, providing feedback about performance and feedback about the quality of the movement. Patients were positive about the changes to the user interface, confirming that the feedback screens were clear, useful and motivating. The user interface can further be improved by adding more feedback about the quality of the movement