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

Abstract

Summary 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 ...

Low-Frequency Repetitive Transcranial Magnetic Stimulation Over Contralesional Motor Cortex for Motor Recovery in Subacute Ischemic Stroke: A Randomized Sham-Controlled Trial

“…However, candidate drugs for motor recovery (eg, selective serotonin reuptake inhibitors, levodopa) did not result in significant effects in recent large clinical trials. 58,59 Finally, the various rehabilitation modalities could not be exactly counterbalanced between the groups from EOT to 1-month follow-up, although we investigated the dose of physical and occupational therapies based on patients' recall.…”

Principles and requirements for stroke recovery science

“…Evidence was challenged again in a recent, randomized, large controlled trial of a 6-week continuous dopamine treatment (100 mg levodopa+12.5 mg carbidopa) in addition to standard physical and occupational therapy within 6 weeks after the index event. 41 The results with respect to the relatively crude study endpoint “independent walking ability at 8 weeks” was negative, no surprise at all considering the mixture of stroke and deficit subtypes included in the study: almost 25% lacunar strokes, a variety of anterior circulation strokes, posterior circulation strokes, and even up to 17% of hemorrhages.…”

“…Such functions were, however, not investigated in the recent large randomized trials. In the dopamine trial (DARS) assessment was focused on walking ability 8 weeks after stroke, 41 and in the fluoxetine trial (FOCUS) gross functional outcome was measured by the modified Ranking Scale 6 months after stroke. 24 The latter endpoint is even more incomprehensible with respect to the prior FLAME trial, where the fluoxetine treatment effect was assessed and effective on arm and leg motor function measured with the Fugl-Meyer Motor Scale 3 months after the stroke.…”

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“…Several trials of dopamine agonists have reported that these agonists promote motor recovery after stroke [10]. The potential mechanisms of the dopamine-mediated improvement in motor recovery are the potentiation of drive and arousal in conditioned learning and the up-regulation of glutaminergic transmission, which modulates synaptic efficacy [32]. Nevertheless, the clinical effects of pharmacotherapy are limited in stroke patients with severe motor impairment because current motor rehabilitation strategies are focused on the reorganization of preserved motor networks after stroke [33].…”