AbobotulinumtoxinA Versus OnabotulinumtoxinA in Adults with Upper Limb Spasticity: A Randomized, Double-Blind, Crossover Study Protocol.

INTRODUCTION: The safety and efficacy of both abobotulinumtoxinA and onabotulinumtoxinA for upper limb spasticity are well established, but head-to-head comparisons are lacking. METHODS: DIRECTION is an international, randomized, double-blind, crossover study comparing the safety and efficacy of abobotulinumtoxinA with onabotulinumtoxinA in the management of upper limb spasticity at doses at or near maximum recommended in product labelling. Participants (18-75 years) will be randomized (1:1) to either one cycle of abobotulinumtoxinA (900U) followed by onabotulinumtoxinA (360U) or vice versa. To maintain blinding, a fixed volume (3.6 ml) will be injected into the target upper limb muscles (four wrist and finger flexors and biceps brachii). The second treatment cycle will begin at Week 12 if retreatment criteria are fulfilled, and if not, they will be reassessed every 4 weeks until they meet retreatment parameters. PLANNED OUTCOMES: The primary hypothesis is that there is comparable safety between products; non-inferiority will be tested based on treatment-emergent adverse event (TEAE) rates from injection to Week 12. A secondary hypothesis is that abobotulinumtoxinA has longer duration of effect than onabotulinumtoxinA. This hypothesis will be tested with secondary efficacy endpoints, including injection cycle duration, Modified Ashworth Scale, Disability Assessment Scale and Physician Global Assessment. TRIAL REGISTRATION: EudraCT ( http://eudract.ema.europa.eu ): 2021-000161-32 and Clinicaltrials.gov ( http://clinicaltrials.gov ): NCT04936542. Overview of the study protocol by the principal investigator (MP4 185265 KB).

Safety and Stability of Pulmonary Function in Patients with Decreased Respiratory Function Treated for Spasticity with OnabotulinumtoxinA.

Two randomized, placebo-controlled studies evaluated the pulmonary function safety of onabotulinumtoxinA (onabotA) for treatment of upper and/or lower limb spasticity. Patients with stable baseline respiratory status received one or two treatments with placebo, 240 U, or 360 U of onabotA. Pulmonary function tests, adverse events, and efficacy were measured at least every 6 weeks for 18 weeks (Study 1) or 30 weeks (Study 2). Study 1 enrolled 109 patients (n = 36-37/group) and Study 2 enrolled 155 patients (n = 48-54/group). Mean baseline forced vital capacity (FVC) was 76-78% of predicted per group in Study 1 and 71% of predicted per group in Study 2. In Study 1, change from baseline FVC values were significantly (p < 0.05) decreased vs. placebo at weeks 3 (240 U -57 mL vs. placebo +110 mL) and 12 (360 U -6 mL vs. +167 mL placebo). In Study 2, change from baseline FVC values were significantly decreased in the 360 U group vs. placebo at weeks 6 (-78 mL vs. +49 mL placebo), 13 (-60 mL vs. +119 mL placebo), 18 (-128 mL vs. +80 mL placebo), and 24 (-82 mL vs. +149 mL placebo). Individual pulmonary function-related adverse events were not correlated with PFT decreases. The most frequent pulmonary-related adverse events were nasopharyngitis (Study 1) and upper respiratory tract infection (Study 2). Ashworth scores were significantly improved at multiple time points in both studies. Injection of onabotA for spasticity in patients with decreased pulmonary function, at single and repeated doses of up to 360 U, was associated with small but statistically significant decreases in FVC or forced expiratory volume 1 s (FEV1) (>12% and 200 mL) that were subclinical and not correlated with any adverse clinical pulmonary events.

Dose-Dependent Effects of AbobotulinumtoxinA (Dysport) on Spasticity and Active Movements in Adults With Upper Limb Spasticity: Secondary Analysis of a Phase 3 Study.

BACKGROUND: AbobotulinumtoxinA has beneficial effects on spasticity and active movements in hemiparetic adults with upper limb spasticity (ULS). However, evidence-based information on optimal dosing for clinical use is limited. OBJECTIVE: To describe joint-specific dose effects of abobotulinumtoxinA in adults with ULS. DESIGN: Secondary analysis of a phase 3 study (NCT01313299). SETTING: Multicenter, international, double-blind, placebo-controlled clinical trial. PARTICIPANTS: A total of 243 adults with ULS >6 months after stroke or traumatic brain injury, aged 52.8 (13.5) years and 64.3% male, randomized 1:1:1 to receive a single-injection cycle of placebo or abobotulinumtoxinA 500 U or 1000 U (total dose). METHODS: The overall effects of injected doses were assessed in the primary analysis, which showed improvement of angles of catch in finger, wrist, and elbow flexors and of active range of motion against these muscle groups. This secondary analysis was performed at each of the possible doses received by finger, wrist, and elbow flexors to establish possible dose effects. MAIN OUTCOME MEASURES: Angle of arrest (XV1) and angle of catch (XV3) were assessed with the Tardieu Scale, and active range of motion (XA). RESULTS: At each muscle group level (finger, wrist, and elbow flexors) improvements in all outcome measures assessed (XV1, XV3, XA) were observed. In each muscle group, increases in abobotulinumtoxinA dose were associated with greater improvements in XV3 and XA, suggesting a dose-dependent effect. CONCLUSIONS: Previous clinical trials have established the clinical efficacy of abobotulinumtoxinA by total dose only. The wide range of abobotulinumtoxinA doses per muscle groups used in this study allowed observation of dose-dependent improvements in spasticity and active movement. This information provides a basis for future abobotulinumtoxinA dosing recommendations for health care professionals based on treatment objectives and quantitative assessment of spasticity and active range of motion at individual joints. LEVEL OF EVIDENCE: I.

OnabotulinumtoxinA for Lower Limb Spasticity: Guidance From a Delphi Panel Approach.

BACKGROUND: OnabotulinumtoxinA is approved for the treatment of upper and lower limb spasticity in adults. Guidance on common postures and onabotulinumtoxinA injection paradigms for upper limb spasticity has been developed via a Delphi Panel; however, similar guidance for lower limb spasticity has not been established. OBJECTIVE: To define a clinically recommended treatment paradigm for the use of onabotulinumtoxinA for each common posture among patients with poststroke lower limb spasticity (PSLLS) and to identify the most common PSLLS aggregate postures. DESIGN: Clinical experts provided insight regarding onabotulinumtoxinA treatment for PSLLS using an adaptation of the Delphi consensus process. SETTING: Delphi panel. PARTICIPANTS: Ten expert clinicians in neurology and physical medicine and rehabilitation who treat PSLLS. METHODS: A minimum of 2 rounds of anonymous voting occurred for each recommendation until consensus was reached (≥66% agreement). The first round was conducted via a survey; the second round was an in-person meeting. MAIN OUTCOME MEASUREMENTS: Reached consensus on muscle selection for injection, overall and per-muscle dose of onabotulinumtoxinA, number of injection sites/muscle, onabotulinumtoxinA dilution, and use of localization techniques. The most common PSLLS postures were reviewed. Recommendations were tailored toward injectors with less experience. RESULTS: Consensus was reached on targeted subsets of muscles for each posture. Doses ranged from 20 to 150 U for individual muscles and 50 to 300 U for limb postures. OnabotulinumtoxinA dilution 50 U/mL (2:1 ratio) was considered most appropriate but varied based on muscles selected (range, 2:1-4:1). Experts agreed that localization techniques for muscle identification during injection for all postures would be useful. For suboptimal response to injection, all panel members would increase the dose, and the majority (89%) would increase the number of treated muscles. The panel identified 3 common aggregating lower limb postures: (1) equinovarus foot and flexed toes; (2) extended knee and plantar flexed foot/ankle; and (3) plantar flexed foot/ankle and flexed toes. The recommended starting doses for each aggregate posture were 400 U, 400 U, and 300 U, respectively. CONCLUSION: The modified Delphi panel process provided consensus on common muscles and corresponding onabotulinumtoxinA treatment paradigms for postures associated with PSLLS that can be used for guidance in optimizing care delivery. LEVEL OF EVIDENCE: V.

OnabotulinumtoxinA Injection for Poststroke Upper-Limb Spasticity: Guidance for Early Injectors From a Delphi Panel Process.

BACKGROUND: OnabotulinumtoxinA reduces muscle hypertonia associated with poststroke spasticity (PSS). PSS manifests as several common postures. OBJECTIVE: To define treatment paradigms for PSS upper-limb common postures. DESIGN: Modified Delphi method. SETTING: Expert panel. PARTICIPANTS: Ten injectors experienced in the treatment and clinical research of PSS (physiatrists and neurologists) were invited to participate in the Delphi panel. METHODS: The Delphi panel reviewed an electronic worksheet with PSS upper-limb postures to define onabotulinumtoxinA treatment paradigms (Round 1). During Round 2, panel members discussed in person Round 1 results and voted until consensus (≥66% agreement). Recommendations were geared toward those with new or early injection experience. MAIN OUTCOME MEASUREMENTS: Expert consensus on onabotulinumtoxinA treatment parameters for PSS including muscles to inject, dose per muscle and posture, and treatment adjustments for suboptimal response. RESULTS: For each posture, consensus was reached on targeted subsets of muscles. Doses ranged for individual muscles (10-100 U) and total doses per posture (50-200 U). An onabotulinumtoxinA dilution 50 U/mL (2:1 dilution ratio) was considered most appropriate; dilution ratios of 1:1 to 4:1 may be appropriate in some circumstances. The majority (89%) of panel members would increase the dose and/or the number of muscles treated for a suboptimal response to onabotulinumtoxinA. The panel identified 3 common aggregate upper-limb postures: (1) adducted shoulder + flexed elbow + pronated forearm + flexed wrist + clenched fist; (2) flexed elbow + pronated forearm + flexed wrist + clenched fist; and (3) flexed wrist + clenched fist. The recommended starting dose per aggregate was 300 U, 300 U, and 200 U, with a total maximum dose of 400 U, 400 U, and 300 U, respectively. Localization guidance techniques were considered essential for all postures. CONCLUSIONS: Consensus on common muscles and onabotulinumtoxinA treatment paradigms for postures associated with upper-limb PSS was achieved via a modified Delphi method. The purpose of this analysis is to educate early onabotulinumtoxinA injectors rather than provide an evidence-based review. LEVEL OF EVIDENCE: V.

Heterotopic ossification complicating prolonged intubation: case report and review of the literature.

BACKGROUND: Within the past decade several reports have been published concerning heterotopic ossification (HO) in adult respiratory distress syndrome patients subjected to prolonged mechanical ventilation. The knee has been the most common site of involvement, which tends to differentiate this entity of HO from those previously described. METHOD: Case report and literature review. FINDINGS: HO associated with prolonged intubation differs in clinical presentation from HO seen in spinal cord injury (SCI) and other trauma. Use of neuromuscular blockade does not appear to explain this risk. An unidentified humoral response mechanism may underlie the development of HO in these cases. Certain individuals may be genetically predisposed to develop HO. CONCLUSION: Increased awareness of this relatively new entity may assist early diagnosis, medical treatment, and eventually direct rehabilitation. Investigation of the pathogenesis of different types of HO may provide clues to the prevention and treatment of HO in individuals with SCI and other central nervous system trauma.