A Randomized, Placebo-Controlled Study of High-Dose Baclofen in Alcohol-Dependent Patients-The ALPADIR Study.

AIMS: Alcohol dependence is a major public health issue with a need for new pharmacological treatments. The ALPADIR study assessed the efficacy and safety of baclofen at the target dose of 180 mg/day for the maintenance of abstinence and the reduction in alcohol consumption in alcohol-dependent patients. METHODS: Three hundred and twenty adult patients (158 baclofen and 162 placebo) were randomized after alcohol detoxification. After a 7-week titration, the maintenance dose was provided for 17 weeks, then progressively decreased over 2 weeks before stopping. RESULTS: The percentage of abstinent patients during 20 consecutive weeks (primary endpoint) was low (baclofen: 11.9%; placebo: 10.5%) and not significantly different between groups (OR 1.20; 95%CI: 0.58 to 2.50; P = 0.618). A reduction in alcohol consumption was observed from month 1 in both groups, but the difference of 10.9 g/day at month 6 between groups, in favour of baclofen, was not statistically significant (P = 0.095). In a subgroup of patients with high drinking risk level at baseline, the reduction was greater with a difference at month 6 of 15.6 g/day between groups in favour of baclofen (P = 0.089). The craving assessed with Obsessive-Compulsive Drinking Scale significantly decreased in the baclofen group (P = 0.017). No major safety concern was observed. CONCLUSIONS: This study did not demonstrate the superiority of baclofen in the maintenance of abstinence at the target dose of 180 mg/day. A tendency towards a reduction in alcohol consumption and a significantly decreased craving were observed in favour of baclofen. SHORT SUMMARY: Baclofen was assessed versus placebo for maintenance of abstinence and reduction in alcohol consumption in alcohol-dependent patients. This study did not demonstrate the superiority of baclofen in the maintenance of abstinence. A tendency towards a reduction in alcohol consumption and a significantly decreased craving were observed in favour of baclofen.

Upper limb international spasticity study: rationale and protocol for a large, international, multicentre prospective cohort study investigating management and goal attainment following treatment with botulinum toxin A in real-life clinical practice.

OBJECTIVES: This article provides an overview of the Upper Limb International Spasticity (ULIS) programme, which aims to develop a common core dataset for evaluation of real-life practice and outcomes in the treatment of upper-limb spasticity with botulinum toxin A (BoNT-A). Here we present the study protocol for ULIS-II, a large, international cohort study, to describe the rationale and steps to ensure the validity of goal attainment scaling (GAS) as the primary outcome measure. METHODS AND ANALYSIS DESIGN: An international, multicentre, observational, prospective, before-and-after study, conducted at 84 centres in 22 countries across three continents. PARTICIPANTS: 468 adults presenting with poststroke upper limb spasticity in whom a decision had already been made to inject BoNT-A (5-12 consecutive participants recruited per centre). INTERVENTIONS: Physicians were free to choose targeted muscles, BoNT-A preparation, injected doses/technique and timing of follow-up in accordance with their usual practice and the goals for treatment. PRIMARY OUTCOME MEASURE: GAS. SECONDARY OUTCOMES: Measurements of spasticity, standardised outcome measures and global benefits. Steps to ensure validity included: (1) targeted training of all investigators in the use of GAS; (2) within-study validation of goal statements and (3) establishment of an electronic case report form with an in-built tracking facility for separation of baseline/follow-up data. ANALYSIS: Efficacy population: all participants who had (1) BoNT-A injection and (2) subsequent assessment of GAS. Primary efficacy variable: percentage (95% CI) achievement of the primary goal from GAS following one BoNT-A injection cycle. ETHICS AND DISSEMINATION: This non-interventional study is conducted in compliance with guidelines for good pharmacoepidemiology practices. Appropriate ethical approvals were obtained according to local regulations. ULIS-II will provide important information regarding treatment and outcomes from BoNT-A in real-life upper limb spasticity management. The results will be published separately. REGISTRATION: ClinicalTrials.gov identifier: NCT01020500.

Factors influencing response to Botulinum toxin type A in patients with idiopathic cervical dystonia: results from an international observational study.

OBJECTIVES: Real-life data on response to Botulinum toxin A (BoNT-A) in cervical dystonia (CD) are sparse. An expert group of neurologists was convened with the overall aim of developing a definition of treatment response, which could be applied in a non-interventional study of BoNT-A-treated subjects with CD. DESIGN: International, multicentre, prospective, observational study of a single injection cycle of BoNT-A as part of normal clinical practice. SETTING: 38 centres across Australia, Belgium, Czech Republic, France, Germany, The Netherlands, Portugal, Russia and the UK. PARTICIPANTS: 404 adult subjects with idiopathic CD. Most subjects were women, aged 41-60 years and had previously received BoNT-A. OUTCOME MEASURES: Patients were classified as responders if they met all the following four criteria: magnitude of effect (≥25% improvement Toronto Western Spasmodic Torticollis Rating Scale), duration of effect (≥12-week interval between the BoNT-A injection day and subject-reported waning of treatment effect), tolerability (absence of severe related adverse event) and subject's positive Clinical Global Improvement (CGI). RESULTS: High rates of response were observed for magnitude of effect (73.6%), tolerability (97.5%) and subject's clinical global improvement (69.8%). The subjective duration of effect criterion was achieved by 49.3% of subjects; 28.6% of subjects achieved the responder definition. Factors most strongly associated with response were age (<40 years; OR 3.9, p<0.05) and absence of baseline head tremor (OR 1.5; not significant). CONCLUSIONS: Three of four criteria were met by most patients. The proposed multidimensional definition of response appears to be practical for routine practice. Unrealistically high patient expectation and subjectivity may influence the perception of a quick waning of effect, but highlights that this aspect may be a hurdle to response in some patients. CLINICAL REGISTRATION NUMBER: (NCT00833196; ClinicalTrials.gov).

Classification of posture in poststroke upper limb spasticity: a potential decision tool for botulinum toxin A treatment?

A significant percentage of patients suffering from a stroke involving motor-relevant central nervous system regions will develop a spastic movement disorder. Hyperactivity of different muscle combinations forces the limbs affected into abnormal postures or movement patterns. As muscular hyperactivity can effectively and safely be treated with botulinum toxin type A (BoNT-A), we present a classification of spastic arm movement patterns to support BoNT-A therapy of arm spasticity. A few characteristic patterns can be distinguished that may be relevant for BoNT-A treatment. On the basis of a differentiated posture and arm movement analysis, five characteristic arm spasticity patterns (ASP I-V) were defined with respect to the position of the shoulder, elbow, forearm, and wrist joints. These patterns were verified using data from a worldwide noninterventional Upper Limb International Survey. By clinical observation, spastic arm postures in 94% of 665 poststroke patients could be assigned to one of these five ASPs. The most frequent pattern of arm spasticity was ASP III (41.8%) with internal rotation and adduction of the shoulder and flexion at the elbow coupled with a neutral positioning of the forearm and wrist, not the typical Wernicke-Mann position. These five different arm position patterns (ASP I-V) form the foundation of a common terminology and facilitate quick and understandable exchange of information with other physicians. Furthermore, utilization of these patterns may improve the dosing, goal setting, and outcome of the BoNT-A treatment of arm spasticity.

Botulinum toxin injection for hypertonicity of the upper extremity within 12 weeks after stroke: a randomized controlled trial.

BACKGROUND: Botulinum neurotoxin type A (BoNT-A) reduces upper-extremity poststroke spasticity when given 6 or more months after stroke. Effects on functional use of the arm and hand are less apparent. OBJECTIVE: To determine the effect and safety of very early use of BoNT-A for patients with upper-limb spasticity. METHODS: The Asia Botulinum Toxin-A Clinical Trial DESIGN: ed for Early Post-stroke Spasticity (ABCDE-S; NCT00234546) was a multicenter, randomized, placebo-controlled trial conducted in patients recruited within 2 -12 weeks of first-ever stroke. Participants with a Modified Ashworth Scale (MAS) score of 1+ or above received BoNT-A (Dysport) 500 U or placebo to one or more wrist and elbow mover muscles, plus unstructured rehabilitation. The primary outcome was the MAS score in the most affected joint 4 weeks after first injection. Follow-up was 24 weeks. RESULTS: A total of 163 patients were enrolled and assigned to placebo (n = 83) or BoNT-A (n = 80). Mean time since stroke was about 7 weeks. At 4 weeks postinjection, BoNT-A significantly improved MAS scores. Treatment effect-size estimates increased with higher baseline MAS scores from 0.45 (Q1) to 0.70 (Q3). MAS scores for all secondary end points improved with BoNT-A versus placebo at all time points (P < .0001, all visits). The Functional Motor Assessment Scale did not reveal clinically significant differences. No group differences in adverse events were found. Interpretation. BoNT-A 500 U can provide a sustained reduction in poststroke upper-limb spasticity when combined with rehabilitation in Asian patients who have mild-to-moderate hypertonicity and voluntary movement, within 2 -12 weeks of stroke. Functional use of the arm and hand was not affected.

Survey of practices employed by neurologists for the definition and management of secondary non-response to botulinum toxin in cervical dystonia.

Secondary non-response (SNR) to botulinum toxin (BoNT) in cervical dystonia (CD) lacks a universal definition. We conducted a retrospective survey to develop a definition based on clinicians' practice. Fifty-seven neurologists completed a 17-item questionnaire. In defining SNR, insufficiently improved posture was considered to be more relevant (98% of physicians) than insufficiently improved pain (86%). The most frequently used diagnostic test for SNR was the frontalis test (68%); antibody testing was performed by only 13% of physicians. Three consecutive unsuccessful injection cycles were considered the most appropriate indicator of SNR (55% of physicians). Physicians reported that 5.9% (median) of patients treated in 2008 became secondary non-responders to BoNT-A. The most common strategy for SNR was optimization of physiotherapy, considered by 98% of the physicians. On the basis of our findings, SNR can be defined as insufficiently improved posture after ≥3 unsuccessful injection cycles in CD patients previously achieving satisfactory results.

The profile of patients and current practice of treatment of upper limb muscle spasticity with botulinum toxin type A: an international survey.

To document the current practice in relation with the treatment of patients with upper limb spasticity with botulinum toxin type A to inform future research in this area. We designed an international, cross-sectional, noninterventional survey of current practice. Nine hundred and seventy-four patients from 122 investigational centres in 31 countries were studied. Most patients were over 40 years old and had a stroke. Improvement of active function was the most frequent treatment goal in the first 3 months after the onset of upper limb spasticity, but was less common than passive function in the chronic stage. Pain relief was a common goal in both the stages. As a rule, clinicians intended to assess the effectiveness of treatment with impairment level scales. Functional outcome measures seem to be rarely used in clinical practice. The use of these measures should be encouraged to assess whether the reduction in muscle tone translates into functional benefit to patients and their caregivers.

Botulinum toxin A in the treatment of glabellar lines: scheduling the next injection.

BACKGROUND: A single intramuscular treatment with botulinum toxin A (BoNT-A) into the facial muscles underlying glabellar rhytids has been shown to effectively attenuate or totally erase these lines for at least 3 months. OBJECTIVE: We sought to evaluate the optimal time for a second injection of BoNT-A (Dysport, Ipsen). METHODS: One hundred patients with moderate to severe glabellar rhytids at rest were randomized to a first, double-blind injection of 50 U of BoNT-A (n = 50) divided into 5 intramuscular sites, or placebo (n = 50). At monthly intervals between Month 3 and Month 6, the patient and the investigator consensually decided to repeat the injection with open-label BoNT-A in both groups. The main outcome was the time between the first and second injections. Responder ratings (mild or no glabellar lines) after the first and second injections, patient satisfaction, and safety were also assessed. RESULTS: At Months 3 and 4 after the first injection, the cumulative percentage of patients having a second injection was lower in the BoNT-A group compared to the placebo group, with a significant difference at Month 4. Following the first double-blind injection, responder rates were significantly higher in BoNT-A group (up to 75%) compared to placebo up to Month 4, and a large majority of patients were significantly satisfied with the BoNT-A treatment at Month 4 (75% satisfied and completely satisfied versus 9.1% with placebo) and Month 5 (86.7% versus 0%, respectively). Headache was the most frequent adverse event in the BoNT-A group (10% versus 6% in the placebo group). No blepharoptosis was reported. CONCLUSIONS: The effectiveness of 50 U of BoNT-A was confirmed for the treatment of glabellar lines. A second injection was sought within 3 to 4 months by most patients and investigators. Both injections were safe.

A multicenter, randomized, double-blind, placebo-controlled study of efficacy and safety of 3 doses of botulinum toxin A in the treatment of glabellar lines.

BACKGROUND: Botulinum toxin A (BTX-A) is used to treat glabellar lines but the rigorous demonstration of its efficacy in a well-designed study had never been reported. OBJECTIVE: This study was designed to evaluate the efficacy and the safety of 3 doses of BTX-A in the treatment of glabellar lines. METHODS: A total of 119 patients with moderate to severe glabellar lines at rest were treated with 25, 50, or 75 U of BTX-A (Dysport, Ipsen) or placebo divided into 5 intramuscular glabellar sites. Outcome measures included evaluations of glabellar lines by independent experts from blinded standardized photographs at rest 1 month after treatment, physician evaluations, and patient assessments during a 6-month period. RESULTS: A significant efficacy was reported for the 3 BTX-A groups for at least 3 months after injection (at least P <.015). Investigator and patient evaluations suggested that 50 U was the optimal dose. BTX-A was well tolerated. No blepharoptosis was reported. An evaluation in blinded conditions by independent experts was necessary because the results were overestimated by the investigators. CONCLUSION: BTX-A is an effective and safe treatment for glabellar lines.