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| [ ...Back to search results ] | [ Print-friendly version ] |
| Dopamine Augmented Rehabilitation in Stroke |
| ISRCTN | ISRCTN99643613 |
| ClinicalTrials.gov identifier | |
| Public title | Dopamine Augmented Rehabilitation in Stroke |
| Scientific title | Does levodopa drug treatment in combination with routine UK National Health Service (NHS) occupational and physical therapy, delivered early after stroke within a stroke rehabilitation service, improve functional recovery including walking ability and arm function? A multicentre randomised double blind placebo-controlled trial |
| Acronym | DARS |
| Serial number at source | EME 08/43/61 |
| Study hypothesis |
As of 10/03/2010 this record has been extensively updated due to ethics committee approved changes to the protocol. All changes can be found under the relevant section with the above update date. At this time, the trial dates were also updated, the initial trial dates were as follows:
Initial anticipated start date: 20/09/2010 Initial anticipated end date: 20/03/2012 Current information as of 10/03/2010: Primary objectives: The proportion of participants walking as defined by a score of 7 or above on the Rivermead Mobility Index (RMI), in L-dopa and control group. Secondary outcomes: 1. Impact on physical functioning and mood at 8 weeks, 6 months and 12 months: 1.1. To compare the proportion of patients who are walking at 6 and 12 months post-randomisation in the two groups, as measured by a score of 7 or higher on the Rivermead Mobility Index 1.2. To compare activities of daily living and dependency (Barthel Index, Northwick Park Dependency Score, Nottingham Extended Activities of Daily Living Scale, ABILHAND) between groups, to compare psychological distress/mood between the two groups (General Health Questionnaire 12) 1.3. To compare carer burden between groups using the Caregiver Burden Scale 1.4. To investigate cost effectiveness of co-careldopa and conventional rehabilitation treatments (EQ-5D, Northwick Park Dependency Score to quantify care costs) 2. Investigate potential moderators and mediators of effect at 8 weeks, 6 months and 12 months: 2.1. To investigate whether baseline patient clinical characteristics and investigations (e.g. routine brain computed tomography [CT] scanning) help to predict those who might benefit from L-dopa augmented rehabilitation 2.2. To investigate whether key factors (e.g. fatigue [Fatigue Assessment Scale], concurrent musculoskeletal symptoms, signs and pain [using the MSK SSP manikin]) influence the short and long term effect of L-dopa on physical functioning Investigation of implementation within NHS: 1. To assess the adverse event profile associated with combination treatment (NHS stroke rehabilitation treatment linked with oral co-careldopa) 2. To investigate the practical implications of delivering this intervention within routine NHS acute and early community care of people with stroke 3. To assess acceptability of co-careldopa treatment to stroke patients (study drug adherence will be measured and a semi structured interview will be undertaken with participants at the week 8 assessment) Initial information at time of registration: Primary objectives: Measuring the effectiveness of L-dopa - does 6 weeks L-dopa treatment in combination with routine NHS physical therapy and occupational therapy treatment delivered to people with first stroke within a stroke service improve short term (8 weeks) and long term (6, 12 months) functional motor recovery? Secondary objectives: 1. Does L-dopa treatment in early stroke in combination with routine NHS physical therapy and occupational therapy treatment delivered within a stroke service improve extended activities of daily living and reduce carer burden? 2. What are the practical implications of delivering this intervention during routine NHS management of people with stroke and what are the adverse events associated with combination treatment? 3. Is L-dopa in conjunction with rehabilitation treatment a cost-effective intervention for the NHS? 4. Is this additional treatment acceptable to stroke patients? 5. Do baseline patient clinical characteristics and investigations (e.g. routine brain computed tomography [CT] scanning) help us to predict those that might benefit from L-dopa augmented rehabilitation? Link to EME project website: http://www.eme.ac.uk/projectfiles/084361info.pdf Link to protocol: http://www.eme.ac.uk/projectfiles/084361protocol.pdf |
| Lay summary | |
| Ethics approval |
Added 09/03/2010:
North West 2 Research Ethics Committee (REC) - Liverpool Central, approved on the 11th February 2010 (ref: 10/H1005/6) |
| Study design | Multicentre prospective randomised double-blinded placebo-controlled trial |
| Countries of recruitment | United Kingdom |
| Disease/condition/study domain | Stroke |
| Participants - inclusion criteria |
Amended as of 23/03/2010:
Points 1 and 2 below have been amended to read as follows: 1. New clinically diagnosed ischaemic or haemorrhagic stroke (excluding subarachnoid haemorrhage) stroke in the 2 weeks prior to randomisation 2. Cannot walk 10 metres without assistance All other points remain the same. Current information as of 10/03/2010: 1. New clinically diagnosed ischaemic or haemorrhagic stroke 2. Cannot walk two metres 3. Expected to need ongoing rehabilitation treatment after randomisation 4. Aged 18 years or above, either sex 5. Able to give informed consent 6. Able to access continuity of rehabilitation treatment following discharge from hospital 7. Expected to comply with treatment schedule post-randomisation Initial information at time of registration: 1. New stroke in the previous 2 weeks 2. Aged 18 years or above, either sex 3. Able to give informed consent 4. Rivermead Mobility Index (RMI) score less than 7 (corresponds to No to the question "Can you walk 10 metres with an aid if necessary but with no standby help"). This provides a robust approach to defining participants for inclusion and would reflect the types of patients where this approach would be used if it was found to be effective. |
| Participants - exclusion criteria |
Current information as of 10/03/2010:
1. Not expected to survive 2 months following stroke 2. Diagnosis of Parkinson’s disease, dementia, severe systemic illness, severe psychosis or glaucoma 3. Known hypersensitivity to co-careldopa 4. Patients taking monoamine oxidase inhibitors, dopaminergic or sympathomimetic agents 5. Symptomatic postural hypotension 6. Need physical assistance of at least one person to walk prior to stroke due to pre-existing co-morbidities (e.g. heart failure, osteoarthritis) 7. Pregnancy/lactation or women of child bearing potential unwilling to use medically approved contraception whilst receiving treatment Initial information at time of registration: 1. Unlikely to survive for more than 1 month 2. Requiring palliative care as assessed by the treating physician 3. Parkinson's disease 4. Contraindications to L-dopa (such as glaucoma, cardiac arrhythmias, severe psychotic disorders, active peptic ulcer disease) 5. Symptomatic postural hypotension 6. Taking sympathomimetic agents 7. Unable to walk prior to stroke due to pre-existing co-morbidities (e.g. heart failure, osteoarthritis) |
| Anticipated start date | 20/10/2010 |
| Anticipated end date | 20/04/2012 |
| Status of trial | Completed |
| Patient information material | Not available in web format, please use the contact details below to request a patient information sheet |
| Target number of participants | 572 |
| Interventions |
572 people with stroke will be randomised to receive L-dopa and caridopa or placebo within 7 - 14 days post-stroke.
Experimental intervention: L-dopa 100 mg (as co-careldopa in conjunction with carbidopa [25 mg]) will be given to patients as a single oral tablet 45 - 60 minutes before physical or occupational therapy sessions (section 5.1) focused on motor skills (e.g. walking, dressing) or 45 - 60 minutes before training at the perceptual/motor task. The peak effect is 0.5 to 2 hours after an oral dose and plasma half-life is 1 to 3 hours. This dose and timing of the medication reflects current evidence on use of L-dopa in this context. Study drug will be administered not more than twice during any day (if the patient is having more than two physical or occupational therapy sessions). L-dopa/placebo augmented rehabilitation treatment will be continued for six weeks (less if the patient is clinically deemed not to require further rehabilitation treatment). The use of intermittent single doses for short periods is anticipated to result in a low rate of adverse effects such as dyskinesias. Nausea is a recognised side effect of L-dopa. Postural hypotension is a recognised side effect of the study drug. We will measure blood pressure in all participants at baseline assessment (those receiving active and placebo IMP) and at any time if patients experience falls or symptoms of postural hypotension. The blister packs will be packaged so that the first two doses of those randomised to receive active drug will be half dose (i.e. 62.5 Co-caredopa) to reduce the risk of early adverse effects and reflecting clinical practice (in the large multicentre trial). Treatment will be stopped if a patient has symptomatic postural hypotension. As the patients will be started on study medication in hospital we will be able to closely observe patients for presence of adverse medication related events. We anticipate adverse effects which require L-dopa to be stopped on clinical grounds occurring in approx 10% patients. For the multicentre study assuming a maximum of 2 sessions of physiotherapy or occupational therapy per day for 30 days over 6 weeks, each individual will have a maximum of 60 active or placebo tablets over study period. Control intervention: Placebo tablet that is identical in preparation to the study drug but without the active medication. The placebo will be given to patients as a single oral tablet 45 - 60 minutes before rehabilitation treatment. Safety and treatment stopping rules will be as per active intervention. We will outsource production of trial medication with supply in blister packs. The placebo will have the same appearance and packaging as active drug (Bilcare Ltd). Routine physical and occupational therapy will be administered to all patients in both groups. All treatments recorded using a standardised recording sheet. |
| Primary outcome measure(s) | The proportion of participants walking as defined by a score of 7 or above on the Rivermead Mobility Index (RMI), in the L-dopa and control intervention groups. This is a robust unambiguous clinical cut off indicator of L-dopa effect as it defines clearly the proportion of those walking at least 10 metres without assistance from another person, in the active and control groups at the primary end point (8 weeks) and the secondary end points (6, 12 months). The RMI has been validated and extensively used in clinical studies. |
| Secondary outcome measure(s) |
Current information as of 10/03/2010:
1. Barthel Index - a widely used and validated scale, scored from 0 - 20, that measures self care dependency in stroke 2. Northwick Park Nursing Dependency measure, a validated method of capturing physical dependency from which care costs can be estimated 3. Nottingham Extended Activities of Daily Living Scale (validated and sensitive to change, used to measure instrumental activities of daily living such as outdoor mobility and household tasks) 4. General Health Questionnaire 12, a widely used questionnaire to measure depression in clinical trials 5. Caregiver Burden Index (we anticipate that improved physical recovery would reduce carers strain, this is a validated measure of carer strain and has been used in stroke clinical trials) 6. EQ-5D (a widely used measure of health status for economic evaluation) 7. A standardised proforma will be developed to capture the patient and therapists perspective of the use of L-dopa as part of the rehabilitation treatment (including issues relating to adherence to timing of L-dopa treatment as well as the type of rehabilitation treatment given 8. Modified Rankin Scale will be used so that results form this study can be related to other clinical trials (see National Stroke Trials database initiative) 9. Changes on the RMI can also capture changes in posture and movement. The RMI has 15 items that measure the ability of patients to make postural adjustments (e.g. move in bed), transfer (e.g. between bed to chair, chair to toilet) and walk (indoors and outdoors) and it scored from 0 - 15. We will analyse RMI change score which, as an indicator of the effect of L-dopa on overall posture and movement of patients undergoing stroke rehabilitation 10. Baseline routinely collected clinical data will be used to allow Edinburgh case mix adjuster to be completed and ensure that the the baseline clinical characteristics are comparable across the active and control groups. Data on concomitant medication will be recorded. We will also collect data on lesion location identified from routinely undertaken Brain CT scans at time of admission to stroke unit. All people with acute stroke should have a CT Brain scan on admission to identify presence of intracranial hemorrhage (National Stroke Strategy, RCP Stroke guidelines). Therefore we anticipate that this data would be available for the majority of patients recruited to the study. We will develop and trial the use of a standardised proforma to collect the data on lesion location as part of the baseline assessment. 11. The ABILHAND questionnaire is a Rasch derived person-centred measure of the manual ability in everyday bimanual tasks in people with chronic stroke 12. Musculoskeletal symptoms/signs & Pain Manikin (MSK-SSP Manikin) as both stroke and musuloskeletal pain are a common cause of disability, this will be used to ascertain the long term impact of stroke interventions 13. Fatigue Assessment Scale - used to measure post stroke fatigue in stroke patients All measured at baseline (pre-randomisation), and 6 and 12 months post-randomisation. Initial information at time of registration: 1. Barthel Index - a widely used and validated scale, scored from 0 - 20, that measures self care dependency in stroke 2. Motor Activity Log-28 (AOU) scale, a validated scale that has been used successfully to measure functional upper limb activities in the context of clinical trials in people with stroke (e.g. the impact of constraint therapy) 3. Northwick Park Nursing Dependency measure, a validated method of capturing physical dependency from which care costs can be estimated 4. Nottingham Extended Activities of Daily Living Scale (validated and sensitive to change, used to measure instrumental activities of daily living such as outdoor mobility and household tasks) 5. General Health Questionnaire 28, a widely used questionnaire to measure depression in clinical trials 6. Caregiver Burden Index (we anticipate that improved physical recovery would reduce carers strain, this is a validated measure of carer strain and has been used in stroke clinical trials) 7. EQ-5D (a widely used measure of health status for economic evaluation) 8. A standardised proforma will be developed to capture the patient and therapists perspective of the use of L-dopa as part of the rehabilitation treatment (including issues relating to adherence to timing of L-dopa treatment as well as the type of rehabilitation treatment given 9. Modified Rankin Scale will be used so that results form this study can be related to other clinical trials (see National Stroke Trials database initiative) 10. Changes on the RMI can also capture changes in posture and movement. The RMI has 15 items that measure the ability of patients to make postural adjustments (e.g. move in bed), transfer (e.g. between bed to chair, chair to toilet) and walk (indoors and outdoors) and it scored from 0 - 15. We will analyse RMI change score which, as an indicator of the effect of L-dopa on overall posture and movement of patients undergoing stroke rehabilitation 11. Baseline routinely collected clinical data will be used to allow Edinburgh case mix adjuster to be completed and ensure that the the baseline clinical characteristics are comparable across the active and control groups. Data on concomitant medication will be recorded. We will also collect data on lesion location identified from routinely undertaken Brain CT scans at time of admission to stroke unit. All people with acute stroke should have a CT Brain scan on admission to identify presence of intracranial hemorrhage (National Stroke Strategy, RCP Stroke guidelines). Therefore we anticipate that this data would be available for the majority of patients recruited to the study. We will develop and trial the use of a standardised proforma to collect the data on lesion location as part of the baseline assessment. All measured at baseline (pre-randomisation), and 6 and 12 months post-randomisation. |
| Sources of funding | Medical Research Council (MRC)/National Institutes of Health Research (NIHR) (UK) - Efficacy and Mechanism Evaluation (EME) Programme (ref: EME 08/43/61) |
| Trial website | |
| Publications | |
| Contact name | Prof Bipin Bhakta |
| Address |
Academic Department of Rehabilitation Medicine
Faculty of Medicine and Health University of Leeds Level D, Martin Wing Leeds General Infirmary |
| City/town | Leeds |
| Zip/Postcode | LS1 3EX |
| Country | United Kingdom |
| Sponsor | University of Leeds (UK) |
| Address |
c/o Clare Skinner
Faculty of Medicine and Health Room 110, Level 10 Worsley Building |
| City/town | Leeds |
| Zip/Postcode | LS2 9NL |
| Country | United Kingdom |
| Sponsor website: | http://www.leeds.ac.uk/ |
| Date applied | 07/09/2009 |
| Last edited | 24/06/2010 |
| Date ISRCTN assigned | 04/12/2009 |
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| © 2012 ISRCTN unless otherwise stated. | |
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