on behalf of the BoTULS investigators. BoTULS: a multicentre randomised controlled trial to evaluate the clinical effectiveness and cost-effectiveness of treating upper limb spasticity due to stroke with botulinum toxin type A

Institute for Ageing and Health (Stroke Research Group), Newcastle University, Newcastle upon Tyne, UK.
Health technology assessment (Winchester, England) 05/2010; 14(26):1-113, iii-iv. DOI: 10.3310/hta14260
Source: PubMed


To compare the clinical effectiveness and cost-effectiveness of treating upper limb spasticity due to stroke with botulinum toxin type A plus an upper limb therapy programme with the upper limb therapy programme alone.
A multicentre open-label parallel-group randomised controlled trial and economic evaluation.
Twelve stroke services in the north of England, UK.
Three hundred and thirty-three adults with upper limb spasticity at the shoulder, elbow, wrist or hand and reduced upper limb function due to stroke more than 1 month previously.
The intervention group received botulinum toxin type A injection(s) plus a 4-week programme of upper limb therapy. The control group received the upper limb therapy programme alone. Participants were clinically reassessed at 3, 6 and 9 months to determine the need for repeat botulinum toxin type A injection(s) and/or therapy.
The primary outcome was upper limb function 1 month after study entry measured by the Action Research Arm Test (ARAT). A successful outcome was defined as: (1) a change of three or more points on the ARAT scale for a participant whose baseline ARAT score was between 0 and 3, (2) a change of six or more points on the ARAT scale for a participant whose baseline ARAT score was between 4 and 51, or (3) a final ARAT score of 57 for a participant whose baseline ARAT score was 52-56. Outcome assessments were undertaken at 1, 3 and 12 months by an assessor who was blinded to the study group allocation. Upper limb impairment and activity limitation were assessed by: Modified Ashworth Scale; Motricity Index; grip strength; ARAT; Nine-Hole Peg Test; upper limb basic functional activity questions and the Barthel Activities of Daily Living (ADL) Index. Stroke-related quality of life/participation restriction was measured using the Stroke Impact Scale, European Quality of Life-5 Dimensions (EQ-5D) and the Oxford Handicap Scale. Upper limb pain was assessed using numerical rating scales. Participant-selected upper limb goal achievement (1 month only) was measured using the Canadian Occupational Performance Measure. Adverse events were compared. Health-care and social services resource use was compared during the first 3 months postrandomisation. EQ-5D data were used to calculate the quality-adjusted life-years (QALYs) associated with intervention and control treatments, and the incremental cost per QALY gained of botulinum toxin type A plus therapy compared with therapy alone was estimated. The sensitivity of the base-case results to alternative assumptions was investigated, and cost-effectiveness acceptability curves, which summarise the evidence of botulinum toxin type A plus therapy being cost-effective for a range of societal willingness to pay for a QALY values, are presented.
Randomisation groups were well matched at baseline. There was no significant difference between the groups for the primary outcome of improved arm function at 1 month. This was achieved by 30/154 (19.5%) in the control group and 42/167 (25.1%) in the intervention group (p = 0.232). The relative risk of having a 'successful treatment' in the intervention group compared with the control group was 1.3 [95% confidence interval (CI) 0.9 to 2.0]. No significant differences in improved arm function were seen at 3 or 12 months. In terms of secondary outcomes, muscle tone/spasticity at the elbow was decreased in the intervention group compared with the control group at 1 month. The median change in the Modified Ashworth Scale was - 1 in the intervention group compared with zero in the control group (p < 0.001). No difference in spasticity was seen at 3 or 12 months. Participants treated with botulinum toxin type A showed improvement in upper limb muscle strength at 3 months. The mean change in strength from baseline (upper limb component of the Motricity Index) was 3.5 (95% CI 0.1 to 6.8) points greater in the intervention group compared with the control group. No differences were seen at 1 or 12 months. Participants in the intervention group were more likely to be able to undertake specific basic functional activities, e.g. dress a sleeve, clean the palm and open the hand for cutting fingernails. At 1 month, 109/144 (75.7%) of the intervention group and 79/125 (63.2%) of the control group had improved by at least one point on a five-point Likert scale for at least one of these tasks (p = 0.033). At 3 months the corresponding proportions were 102/142 (71.8%) of the intervention group and 71/122 (58.2%) of the control group (p = 0.027). Improvement was sustained at 12 months for opening the hand for cleaning the palm and opening the hand for cutting the nails but not for other activities. Pain rating improved by two points on a 10-point severity rating scale in the intervention group compared with zero points in the control group (p = 0.004) at 12 months, but no significant differences were seen at 1 or 3 months. There were a number of occasions when there were statistically significant differences in favour of the intervention group; however, these differences were small and of uncertain clinical relevance. These differences were: 3 months - upper limb function (change in ARAT score from baseline), pain (EQ-5D) and participation restriction (Oxford Handicap Scale); 12 months - anxiety/depression (EQ-5D) and participation restriction (Oxford Handicap Scale). No differences in grip strength, dexterity or the Barthel ADL Index were found at any time point. There were no differences between the groups for achievement of patient-selected goals. There was a higher incidence of general malaise/flu-like/cold symptoms in participants treated with botulinum toxin type A with a relative risk of 7.6 (95% CI 1.8 to 32.3). Only one serious adverse event (dysphagia) was potentially related to botulinum toxin type A. Time since stroke and severity of initial upper limb function were preplanned subgroup analyses. There was no significant difference in either subgroup for achievement of ARAT 'success' following treatment with botulinum toxin type A. The base-case incremental cost-effectiveness ratio was 93,500 pounds per QALY gained and estimation of the cost-effectiveness acceptability curve for botulinum toxin type A plus the upper limb therapy programme indicated that there was only a 0.36 probability of it being cost-effective at a threshold ceiling ratio of 20,000 pounds per QALY.
The addition of botulinum toxin type A to an upper limb therapy programme to treat spasticity due to stroke did not enhance improvement in upper limb function when assessed by the prespecified primary outcome measure at 1 month. However, improvements were seen in muscle tone at 1 month, upper limb strength at 3 months, upper limb functional activities related to undertaking specific basic functional tasks at 1, 3 and 12 months, and upper limb pain at 12 months. Botulinum toxin was well tolerated and side effects were minor. The addition of botulinum toxin type A to an upper limb therapy programme for the treatment of upper limb spasticity due to stroke was not estimated to be cost-effective at levels of willingness to pay for a QALY set by NHS decision-makers.
ISRCTN78533119; EudraCT 2004-002427-40; CTA 17136/0230/001.

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    • "However, more detailed analyses of the initial cost of the treatment are lacking. A recent prospective study in England compared the cost of BoNTA treatment for the upper limb with that of classical rehabilitation in 150 adult patients [10] and found no difference in cost-effectiveness at 3 months. The methods used to evaluate costs were not clearly described but appeared to be global. "
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    ABSTRACT: Intramuscular injection of botulinum toxin (BoNTA) is one of the primary treatments for focal spasticity. This treatment is considered costly and the level of reimbursement by health insurance has been decreasing in many countries for several years. The aim of this study was to determine the real cost of treating spasticity with BoNTA and to compare this with the level of reimbursement by the national health insurance in France in 2008 and with a new fee, specific to the injection of BoNTA in ambulatory services. A single-center, retrospective study using the 2008 database from a French secondary-care day-hospital unit (treating spasticity in adults with sequelae of stroke, multiple sclerosis or traumatic brain injuries). The level of reimbursement by the French ministry of health for BoNTA treatment for adults with spasticity constituted the "calculated cost" and corresponded to the hospital's "budget". The "real cost" (incurred by the hospital) included the sum of staffing and material costs as well as the number of toxin vials used. The calculated costs for 2009 and 2013 were based on the levels of reimbursement during those years. The difference between real and calculated cost for 2009 and 2013 was estimated considering that the real cost of 2008 was stable. In 2008, 364 patients received BoNTA, resulting in 870 day-hospital admissions. The calculated cost was 459,056€/year and the real cost was 567,438€/year (equivalent to 4.27€/day/patient). The total budget deficit (hospital income minus hospital costs) was 108,383€. The deficit was estimated at 222,892€ in 2009 and 241,188€ in 2013. The daily cost of BoNTA treatment for spasticity is reasonable; however, because of the level of reimbursement by the national health insurance in France, the treatment is costly for French hospitals. Copyright © 2015 Elsevier Masson SAS. All rights reserved.
    Full-text · Article · Jul 2015 · Annals of physical and rehabilitation medicine
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    • "All the subjects that entered in the study protocol completed the study. To compare the BoNT-A effect in the two groups with different injection techniques, changes in MAS were analyzed before BoNT-A treatment (t 0 ) and after one month (t 1 ), considering a reduction of at least 1 point of score as efficacy of treatment , similar to other studies on spasticity measurement [1] [21]. Moreover , FPR was also evaluated before BoNT-A treatment (t 0 ) and after one month (t 1 ). "
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    ABSTRACT: Background Botulinum toxin type A is a first-line treatment for post-stroke focal spasticity, and the accuracy in delivering the toxin to the target muscles may influence the treatment outcome. Our aim was to compare the reduction of spasticity and the related finger position at rest improvement in post-stroke patients treated with botulinum toxin type A in upper limb muscles using ultrasound guidance and manual needle placement. Methods In a randomized clinical trial, two groups of 15 stroke patients were treated with botulinum toxin type A injections in the wrist and finger flexor muscles of the affected upper limb using ultrasound guidance or manual needle placement. The Modified Ashworth Scale and the finger position at rest were measured at baseline and one month after toxin injections. Results After one month of follow-up from toxin injections, the Modified Ashworth Scale and finger position at rest significantly improved in both treatment groups, although these clinical outcomes were significantly better in patients treated under ultrasound guidance than in patients injected using manual needle placement. Conclusion Ultrasound guidance for botulinum toxin type A injections could improve clinical outcome measures better than manual needle placement in post-stroke patients with spasticity.
    Full-text · Article · Sep 2014 · Journal of the Neurological Sciences
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    • "The cost of rehabilitation and management of problematic spasticity and related complications (pain, contracture, etc.) can be extraordinarily high [27] and “cost-benefit” research of pharmacological treatments often use standard clinical assessment tools such as the MAS [28,29] as outcomes measurements. Furthermore, according to Pandyan et al. [8] all randomized clinical trials on stroke therapy published between October 1989 and October 2004 used the MAS as a primary outcome measure. "
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    ABSTRACT: Background Spasticity is a prevalent chronic condition among persons with upper motor neuron syndrome that significantly impacts function and can be costly to treat. Clinical assessment is most often performed with passive stretch-reflex tests and graded on a scale, such as the Modified Ashworth Scale (MAS). However, these scales are limited in sensitivity and are highly subjective. This paper shows that a simple wearable sensor system (angle sensor and 2-channel EMG) worn during a stretch-reflex assessment can be used to more objectively quantify spasticity in a clinical setting. Methods A wearable sensor system consisting of a fibre-optic goniometer and 2-channel electromyography (EMG) was used to capture data during administration of the passive stretch-reflex test for elbow flexor and extensor spasticity. A kinematic model of unrestricted passive joint motion was used to extract metrics from the kinematic and EMG data to represent the intensity of the involuntary reflex. Relationships between the biometric results and clinical measures (MAS, isometric muscle strength and passive range of motion) were explored. Results Preliminary results based on nine patients with varying degrees of flexor and extensor spasticity showed that kinematic and EMG derived metrics were strongly correlated with one another, were correlated positively (and significantly) with clinical MAS, and negatively correlated (though mostly non-significant) with isometric muscle strength. Conclusions We conclude that a wearable sensor system used in conjunction with a simple kinematic model can capture clinically relevant features of elbow spasticity during stretch-reflex testing in a clinical environment.
    Full-text · Article · Jun 2013 · Journal of NeuroEngineering and Rehabilitation
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