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(Stroke. 2000;31:2402.)
© 2000 American Heart Association, Inc.

Original Contributions

A Randomized, Double-Blind, Placebo-Controlled, Dose-Ranging Study to Compare the Efficacy and Safety of Three Doses of Botulinum Toxin Type A (Dysport) With Placebo in Upper Limb Spasticity After Stroke

A. M. O. Bakheit, MD, PhD; A. F. Thilmann, MD; A. B. Ward, MD; W. Poewe, MD; J. Wissel, MD; J. Muller, MD; R. Benecke, MD; C. Collin, MD; F. Muller, MD; C. D. Ward, MD C. Neumann, MD

From the Stroke Unit, Mount Gould Hospital, Plymouth, UK (A.M.O.B.); Department of Neurological Rehabilitation, Fachklinik Rhein/Ruhr, Essen-Kettwig, Germany (A.F.T.); North Staffordshire Rehabilitation Centre, Haywood Hospital, Stoke on Trent, UK (A.B.W.); Universitatsklinik fur Neurologie, Innsbruck, Austria (W.P., J.W., J.M.); Klinik fur Neurologie, Universitat Rostock, Rostock, Germany (R.B.); Department of Rehabilitation Medicine, Battle Hospital, Reading, UK (C.C); Neurologische Klinik Bad Aibling, Bad Aibling, Germany (F.M.); University of Nottingham Rehabilitation Unit, Derby City Hospital, Derby, UK (C.D.W.); and Abteilung Neurologie/Psychologie, Fachklinik Ichenhausen, Ichenhausen, Germany (C.N.).

Correspondence to Prof A.M.O. Bakheit, Stroke Unit, Mount Gould Hospital, Plymouth Pl4 7QD, UK.

	Abstract

Top Abstract Introduction Subjects and Methods Results Discussion References

 
Background and Purpose—We sought to define an effective and safe dose of botulinum toxin type A (Dysport) for the treatment of upper limb muscle spasticity due to stroke.

Methods—This was a prospective, randomized, double-blind, placebo-controlled, dose-ranging study. Patients received either a placebo or 1 of 3 doses of Dysport (500, 1000, 1500 U) into 5 muscles of the affected arm. Efficacy was assessed periodically by the Modified Ashworth Scale and a battery of functional outcome measures.

Results—Eighty-three patients were recruited, and 82 completed the study. The 4 study groups were comparable at baseline with respect to their demographic characteristics and severity of spasticity. All doses of Dysport studied showed a significant reduction from baseline of muscle tone compared with placebo. However, the effect on functional disability was not statistically significant and was best at a dose of 1000 U. There were no statistically significant differences between the groups in the incidence of adverse events.

Conclusions—The present study suggests that treatment with Dysport reduces muscle tone in patients with poststroke upper limb spasticity. Treatment was effective at doses of Dysport of 500, 1000, and 1500 U. The optimal dose for treatment of patients with residual voluntary movements in the upper limb appears to be 1000 U. Dysport is safe in the doses used in this study.

Key Words: botulinum toxins • muscle spasticity • stroke

	Introduction

Top Abstract Introduction Subjects and Methods Results Discussion References

 
Severe hypertonia of upper limb muscles is a common complication in patients with stroke. Only a very small minority (approximately 5%) of these patients regain useful function of the paralyzed arm,¹ and the prospects of recovery after the first 3 months of the stroke are usually negligible.² Although muscle weakness and loss of dexterity are important factors in the motor functional disability in these patients, the contribution of muscle spasticity is often quite significant. Spasticity may interfere with voluntary motor function in patients with residual muscle power.³ In addition, it frequently causes difficulties with activities of daily living, such as dressing and cleaning the palm of the clenched hand. In some patients the spasticity causes muscle pain or discomfort.

The current methods of treatment for muscle spasticity are unsatisfactory. Systemic antispasticity drugs are nonselective in their action and may cause functional loss, eg, inability to maintain sitting posture because of weakening of the trunk muscles. Paradoxically, in some patients these drugs reduce force in the normal muscles without having an effect on muscle spasticity.⁴ Furthermore, the value of the oral antispasticity drugs diminishes with prolonged use. Tolerance develops after a few months of treatment, and incremental increases in dosage are often required to maintain the initial clinical response. The high doses required often increase the incidence and severity of the adverse effects of these drugs.

An alternative strategy in the management of muscle spasticity is chemical neurolysis with alcohol or phenol. However, nerve blocks and motor point injections in the upper limbs often cause skin sensory loss and dysesthesia, and their effect often diminishes with repeated treatment.⁵

In recent years, botulinum toxin type A (BtxA) has been shown to be an effective antispasticity agent.^{6 7 8} The use of BtxA for the relief of upper limb spasticity has several advantages. It is simple and can be performed as an outpatient procedure without anesthesia, and the toxin does not cause skin sensory loss or dysesthesia. However, the optimal dose of BtxA for the treatment of upper limb spasticity has not been established. To date only a single study has addressed this issue.⁸ Two preparations of BtxA are commercially available at present: Botox (Allergan, Inc) and Dysport (Ipsen Ltd). The potency of these drugs is not therapeutically equivalent. Simpson et al⁸ investigated the effects of different doses of Botox, but the findings of their study in relation to dose cannot be extrapolated to Dysport. The aim of the present study was to define an effective and safe dose of Dysport for the treatment of upper limb spasticity in stroke patients.

	Subjects and Methods

Top Abstract Introduction Subjects and Methods Results Discussion References

 
Study Design
This was an international, multicenter, prospective, randomized, double-blind, placebo-controlled study comparing the effect of 3 doses of Dysport (500, 1000, and 1500 U) with placebo. The study evaluated the efficacy and safety of Dysport in patients with upper limb spasticity who had suffered a stroke.

Patient Recruitment
Patients with hemiplegic stroke and severe or moderately severe muscle spasticity were recruited at least 3 months after the onset of the cerebrovascular event. They were included in the study if they had a muscle tone score of 2 on the Modified Ashworth Scale (MAS)⁹ in the wrist, elbow, and finger flexors. Those with muscle contractures of the upper limb joints were excluded (muscle contracture in this study was defined as severe restriction of the joint range of motion [ROM]on passive stretch). Other exclusion criteria were previous treatment with botulinum toxin, phenol or alcohol nerve blocks, or motor point injections for upper limb spasticity. De novo treatment with antispasticity drugs was not allowed. Stroke was defined according to the World Health Organization criteria.¹⁰ The possible effects of the etiology and site of the stroke, eg, thalamic versus cortical infarct, were not specifically addressed in this study.

Treatments
Patients were randomized to 1 of 4 study groups and received 1 of 3 doses of Dysport or placebo. Dysport was presented in powder form and was reconstituted in 2 mL of 0.9% sodium chloride solution to give 500, 1000, or 1500 U of Dysport. The placebo was identical to the active drug. The following muscles were injected: the biceps brachii, flexor digitorum profundus, flexor digitorum superficialis, flexor carpi ulnaris, and flexor carpi radialis. The injections were placed in the motor endplate zone with the use of anatomic landmarks, as in routine electromyography.¹¹ The dose of Dysport injected into each muscle is given in Table 1.

View this table: [in this window] [in a new window]   Table 1. Units of Dysport Injected at Each Site

Assessments
Patients were assessed before the injections and 2, 4, 8, 12, and 16 weeks afterward. Assessment was performed blind to randomization and, when possible, by 1 investigator in each participating center.

Outcome Measures
The efficacy of treatment was evaluated with the MAS.⁹ The joint ROM on voluntary extension of the elbow and wrist and on passive muscle stretch was measured with the use of a hand-held goniometer. The joint ROM in the fingers is difficult to measure accurately with goniometry. It was therefore assessed according to the following scale: hand closed, one quarter open, one half open, three quarters open, or fully open with active movement or passive muscle stretch. In addition, the severity of muscle pain was assessed on a 4-point scale (0=no pain, 1=mild pain, 2=moderate pain, 3=severe pain) at the shoulder, wrist, and fingers. The patient’s functional abilities were assessed with the Rivermead Motor Assessment (arm section) scale¹² and the Barthel Index of activities of daily living.¹³ Patients and caregivers were also asked to score the difficulties encountered in performing 3 functional activities that often result from upper limb spasticity. These were as follows: (1) being able to put the affected arm through the sleeve of a garment, (2) being able to open the hand of the affected limb for cleaning the palm, or (3) being able to open the hand of the affected limb for cutting the fingernails. The difficulty was graded as follows: no difficulty, little difficulty, moderate difficulty, a great deal of difficulty, or inability to perform the activity.

The magnitude of benefit over the 16-week study period was also analyzed, as described in Sample Size and Statistical Analysis.

The safety of Dysport was assessed by recording the reported adverse events. In addition, the presence or absence of swallowing difficulties was confirmed with a timed swallowing test. Patients were asked to drink 150 mL of tap water as quickly as possible. A swallowing speed of <10 mL/s and symptoms of coughing or choking during the test were considered evidence of dysphagia.¹⁴ Inquiries about adverse events of treatment and examination for dysphagia were made at each assessment visit.

Sample Size and Statistical Analysis
The best change from baseline in the MAS at week 4 in either the elbow, wrist, or finger joints was chosen as the primary efficacy outcome measure. The sample size was calculated to give 80% to 90% power (=0.05, 2-tailed test) to detect a difference between the groups in posttreatment MAS scores of 1, assuming the SD of the posttreatment scores was 1. This gives a total sample size of 80 patients (20 patients per group).

The data of the intention-to-treat population were analyzed by logistic regression analysis, with the study center and baseline of MAS included as terms in the model. Comparisons were made between each dose of Dysport and placebo. When appropriate in the secondary efficacy analysis, changes from baseline at week 4 were analyzed with logistic regression, while the magnitude of benefit was examined with an area under the curve analysis. The area under the curve was derived by the trapezoidal method. ANOVA was used on the values obtained under the curve, and a model consisting of treatment, adjusted for center effects, was fitted to the data.

	Results

Top Abstract Introduction Subjects and Methods Results Discussion References

 
Nine principal investigators in 11 West European centers took part in the study. A total of 83 patients were recruited and randomized into the following groups: placebo, n=20; Dysport 500, n=22; Dysport 1000, n=22; Dysport 1500, n=19. One patient in the placebo group withdrew from the study, leaving data on 82 patients for the final analysis. The demographic data and disease characteristics of all the study groups were similar at baseline (Table 2). The study groups were also well matched with respect to treatment with antispasticity drugs at study entry and during the trial.

View this table: [in this window] [in a new window]   Table 2. Demographic Characteristics and Details of Stroke at Baseline

Efficacy
All 3 doses of Dysport resulted in statistically significant reduction in the MAS score in any joint at week 4 compared with placebo (Table 3). Analysis of the magnitude of benefit also showed that the MAS was significantly reduced in the hemiparetic arm for all Dysport doses over the 16-week follow-up period in the elbow and wrist areas and also for the fingers in the 1000 U Dysport group (Table 4). Similar results were observed in patients with complete weakness of the affected limb (data not shown). The number of patients who had an improvement of the MAS in all 3 joints was significantly higher in the Dysport groups than in the placebo group (P<0.02).

View this table: [in this window] [in a new window]   Table 3. Summary of Best Change at Week 4 From Baseline in the MAS and Odds Ratio for Improvement in MAS for Each Dysport Group Compared With Placebo

View this table: [in this window] [in a new window]   Table 4. Analysis of Magnitude of Benefits (Measured With MAS) in Affected Arm

Table 5 summarizes the results of the secondary outcome measures. All study groups had an increase in the ROM at the elbow, wrist, and fingers. However, the differences between the groups were not statistically significant. Similarly, there were no statistically significant differences between the study groups in the scores of pain, the Rivermead Motor Assessment Scale, or the Barthel Index for activities of daily living. Not surprisingly, 15.8% of patients who received 1500 U of Dysport and had residual muscle strength in the affected limb lost their ability to extend their fingers voluntarily.

View this table: [in this window] [in a new window]   Table 5. Change in Active and Passive Joint ROM, Pain Scores, and Functional Assessment at Week 4

Patients and their caregivers made a subjective evaluation of the effects of treatment on the ease (or difficulty) of extending the elbow to put the affected arm into a garment sleeve or to open the hand for cleaning the palm or for cutting the fingernails. However, formal statistical analysis was not performed on the data because of the small sample size. As shown in Table 6, more patients in the Dysport study groups showed improvement at 4 weeks compared with the placebo group, and this seemed to correlate with the dose of Dysport given.

View this table: [in this window] [in a new window]   Table 6. Percentage of Patients in Each Study Group Who Were Able to Perform the Activity Without Difficulty or With Ease at Baseline and in Week 4 (Caregiver Rating)

Safety
Adverse events were reported by 33 patients in the 4 treatment groups, ie, 40.2% of the study population. No fatal, life-threatening, or incapacitating adverse events relating to the study medication were reported or observed. Overall, 8 of 19 patients (42.1%) reported adverse events in the placebo group, compared with 13 of 22 (59.1%), 4 of 22 (18.2%), and 8 of 19 (42.1%) in each of the 500, 1000, and 1500 U Dysport groups, respectively. The most frequently reported adverse events during the study were epileptic seizures (n=5), accidental injury (n=5), and urinary and respiratory tract infections (n=6), but these were not considered related to the study medication. Other common adverse events that were probably due to the study medication were skin rashes and flulike symptoms. These occurred in 6 and 3 patients, respectively. There were no statistically significant differences in the incidence of any of the adverse events between the study groups. The results of the timed swallow test were also similar.

	Discussion

Top Abstract Introduction Subjects and Methods Results Discussion References

 
The present study demonstrated that treatment with Dysport reduces muscle tone in patients with poststroke upper limb spasticity and confirmed the findings of previously reported open-label studies.^{6 15 16} Treatment was effective and safe at doses of 500, 1000, and 1500 U. The optimal dose of Dysport for the treatment of patients with residual voluntary movement in the upper limb appears to be 1000 U. At a dose of 1500 U, the range of active movement was sometimes reduced, probably because of excessive weakening of these muscles. The findings of a previous study using Botox (Allergan Inc) in doses of 75, 150, and 300 U were similar to the present study, assuming a Dysport/Botox dose conversion ratio of 3:1. In this dose ratio, the 2 products appear to have the same therapeutic equivalence.¹⁷

Although the 3 doses of Dysport that were evaluated in this study resulted in significant reduction in muscle spasticity, their overall effect on the global disability scores was minimal. This is hardly surprising because the global assessment scales used have a low level of sensitivity. The Rivermead Motor Assessment is a hierarchical scale, and once a patient has reached a level at which he/she cannot perform the test activity, the assessment is discontinued. The Barthel Index includes mobility and continence items that are unlikely to be affected by localized treatment of upper limb muscle spasticity. In a similar study,⁸ other investigators did not observe a measurable improvement on global functional outcome measures, such as the Functional Independence Measure. This suggests that individualized goal-attainment scales, eg, ability to put the spastic arm through a garment sleeve, are more relevant outcome measures in studies of this nature. On further analysis of the effects of Dysport, we found that patients with the greatest difficulties or who were unable to put their arm through a sleeve or open their clenched hand for cleaning or cutting fingernails showed the greatest improvement. This suggests that individualized goal-attainment scales are more sensitive measures of functional change in this patient population. Another explanation for the poor functional improvement would be the choice of muscles injected. In this study we used a standard protocol for all patients. An individualized approach based on the distribution of spasticity in the individual patient would have given a more accurate indication of the effects of treatment on functional disability.

Although spasticity is frequently associated with muscle pain, this symptom was not a prominent feature in our study population. It is therefore not possible to make conclusions from the findings of this study regarding the effects of BtxA on muscle pain or painful muscle spasms.

	Acknowledgments

 
The study was sponsored by Ipsen Limited, Maidenhead, Berkshire, UK, who also designed the study in consultation with the senior authors and was responsible for the recruitment of the researchers and monitoring of the data collection. The statistical analysis of the study data was performed by Hartington Statistics and Data Management Limited, London, UK. The sponsors were not involved in the data interpretation or the writing of the manuscript. None of the authors were employees or paid consultants of Ipsen Ltd. The following clinicians contributed to the data collection: I. Al-Khawaja, J. Durner, A.G. Hatfield, W.A. Holden, S.H. Jawad, C. KoKo, R. Marks, J. Sawyer, R. Singha, K. Stefan, J.W. Symons, J.A. Wall, and K. Wohlfarth.

Received June 8, 2000; revision received June 29, 2000; accepted June 29, 2000.

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This Article Abstract Full Text (PDF) Alert me when this article is cited Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Request Permissions Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Bakheit, A. M. O. Articles by Neumann, C. Search for Related Content PubMed PubMed Citation Articles by Bakheit, A. M. O. Articles by Neumann, C. Related Collections Rehabilitation, Stroke Other Stroke Treatment - Medical