Placebo-controlled clinical trial of incobotulinumtoxinA for sialorrhea in children : sIPEXI

BACKGROUND AND OBJECTIVES: To investigate the efficacy and safety of repeated injections of incobotulinumtoxinA (incoBoNT/A) for treatment of chronic sialorrhea (drooling) associated with neurologic disorders (e.g., cerebral palsy, traumatic brain injury) or intellectual disability in children and adolescents in a prospective phase III study (SIPEXI [Sialorrhea Pediatric Xeomin Investigation]). METHODS: The study enrolled 2- to 17-year-old patients with sialorrhea due to neurologic disorders or intellectual disability. Patients received body weight–dependent doses of incoBoNT/A (20–75 U). A main period with 1 injection cycle (placebo-controlled, double-blind, 6- to 17-year-olds) was followed by an open-label extension with up to 3 further cycles. An additional cohort of 2- to 5-year-olds received active treatment throughout the study. Coprimary endpoints were the change in unstimulated salivary flow rate (uSFR) from baseline to week 4 and the carers' Global Impression of Change Scale (GICS) rating at week 4. Adverse events were recorded. RESULTS: In the main period, 220 patients aged 6–17 years were randomized and treated (148 patients in incoBoNT/A group, 72 patients in placebo group). A total of 35 patients aged 2–5 years received incoBoNT/A (no placebo). A total of 214 patients aged 6–17 years and 33 patients aged 2–5 years continued treatment in the open-label extension period. For the 6- to 17-year-olds, a significant difference between incoBoNT/A and placebo was seen in mean uSFR decrease (difference −0.06 g/min; p = 0.0012) and the carers' GICS rating (difference 0.28 points; p = 0.032) at week 4, in favor of active treatment. The secondary endpoints consistently supported these results. A sustained benefit was observed during the extension. Incidences of adverse events were comparable between incoBoNT/A and placebo and did not increase notably with repeated injections. The most common adverse events were respiratory infections. Efficacy and safety were also favorable in the uncontrolled cohort of 2- to 5-year-olds. DISCUSSION: Both co–primary efficacy endpoints were reached and superiority of incoBoNT/A over placebo was confirmed. IncoBoNT/A (up to 75 U, up to 4 cycles) is an effective and well-tolerated treatment for sialorrhea associated with neurologic disorders in children. TRIAL REGISTRATION INFORMATION: Clinicaltrials.gov: NCT02270736 (clinicaltrials.gov/ct2/show/results/NCT02270736); EU Clinical Trials Register: 2013-004532-30 (clinicaltrialsregister.eu/ctr-search/search?query=2013-004532-30). CLASSIFICATION OF EVIDENCE: This study provides Class I evidence that injection of incobotulinumtoxinA decreases drooling in children aged 6 to 17 years with neurologic disorders

Post hoc analysis of the improvement in shoulder spasticity and safety observed following treatment with incobotulinumtoxina

International audienceObjective: The Titration study in lOWer and uppERlimb spasticity (TOWER) study (NCT01603459), evaluated incobotulinumtoxinA for upper- and lower-limb spasticity. This post hoc analysis assessed shoulder spasticity in patients who received injections into the shoulder. Methods: Subjects received 3 injection cycles with escalating incobotulinumtoxinA doses on the same side (400, 600, 600.800 U; = 600 U per limb including optional shoulder dose, planned range 100.250 U). Joint function was assessed with the Ashworth Scale shoulder sumscore (AS-SSS) in subjects treated in the shoulder vs those who were not. Safety was assessed in subjects treated in the shoulder, and in those who had upper-limb treatment without shoulder treatment. Results: The proportion of subjects receiving shoulder treatment increased with escalating dose at each cycle (n = 84/140 (60.0%) by cycle 3; mean (standard deviation (SD)) shoulder dose 118.4 U (SD 60.2)). From baseline to 4-weeks post-injection, mean AS-SSS improved by -1.1 (SD 1.9), -1.7 (SD 1.8) and -1.7 (1.8) in cycles 1, 2 and 3, respectively, in subjects treated in the shoulder, and -0.5 (SD 1.3), -0.8 (SD 1.6) and -0.9 (SD 1.4) in subjects who were not. A significant dose effect on AS-SSS was observed in cycle 3 (p = 0.0081). No unexpected safety concerns were reported. Conclusion: The results demonstrate an improvement in shoulder spasticity and safety following incobotulinumtoxinA treatment

Efficacy of incobotulinumtoxinA for the treatment of adult lower-limb post-stroke spasticity, including pes equinovarus

International audienceBackground: Lower-limb spasticity can impair ambulation and gait, impacting quality of life.Objectives: This ancillary analysis of the TOWER study (NCT01603459) assessed the efficacy of incobotulinumtoxinA for lower-limb post-stroke spasticity including pes equinovarus.Methods: Participants received escalating incobotulinumtoxinA doses (400-800U) across 3 injection cycles. Changes were compared for those treated in the lower limb (with/without upper-limb treatment) or the upper limb only or for participants treated or untreated for pes equinovarus. Outcome measures were those used in the seminal study: resistance to passive movement scale (REPAS), Ashworth Scale (AS), functional ambulation and lower-limb goal attainment.Results: Among 132/155 (85%) participants with post-stroke spasticity, in cycles 1, 2 and 3, 99, 119 and 121 participants received lower-limb treatment with mean (SD) total limb incobotulinumtoxinA doses of 189.2 (99.2), 257.1 (115.0) and 321.3 (129.2) U, respectively. Of these, 80, 105 and 107, respectively, were treated for pes equinovarus. The mean (SD) improvement in REPAS lower-limb score was greater with treatment in the lower limb versus the upper limb only: -1.6 (2.1) versus-0.4 (1.4); -1.9 (1.9) versus -0.6 (1.6); -2.2 (2.2) versus -1.0 (0.0) (P=0.0005, P=0.0133 and P=0.3581; analysis of covariance [ANCOVA], between-group differences) in cycles 1, 2 and 3, respectively. For all cycles, the mean improvement in ankle joint AS score from injection to 4 weeks post-treatment was greater for participants treated versus not treated for pes equinovarus, with a significant between-group difference in cycle 1 (P=0.0099; ANCOVA). At the end of cycle 3, 42% of participants walked independently and 63% achieved 2 of 2 lower-limb treatment goals (baseline 23% and 34%, respectively).Conclusions: This study supports the efficacy of incobotulinumtoxinA for treatment of pes equinovarus and other patterns of lower-limb post-stroke spasticity

Quality of life in subjects with upper- And lower-limb spasticity treated with incobotulinumtoxinA

International audienceBackground: We evaluated quality of life among subjects with upper- and lower-limb spasticity who received escalating doses of incobotulinumtoxinA (total body doses up to 800 U) in the prospective, single-arm, dose-titration TOWER study. Methods: In this exploratory trial, subjects (N = 155; 18-80 years of age) with upper- and lower-limb spasticity due to cerebral causes who were deemed to require total body doses of up to 800 U incobotulinumtoxinA received three consecutive injection cycles of incobotulinumtoxinA (400, 600, and up to 800 U), each with 12 to 16 weeks' follow-up. QoL was assessed using the EuroQol 5-dimensions questionnaire, three-level (EQ-5D), before and 4 weeks post-injection in each injection cycle and at the end of injection cycle 3. Results: The mean EQ-5D visual analog scale scores of 155 participants continuously improved from study baseline to 4 weeks post-injection in all injection cycles (mean [standard deviation] change 6.7 [14.1], 9.6 [16.3], and 8.6 [17.0] for injection cycles 1, 2, and 3, respectively; p < 0.0001 for all, paired sample t-test). In general, among those with a change in the EQ-5D rating of their condition, the proportion of subjects with 'improvement' was greater than that with 'worsening' for individual EQ-5D dimensions across all injection cycles. At the end of injection cycle 3, the proportion of subjects rating their condition as 'normal' increased from study baseline for all dimensions, and there was a ≥ 46% reduction in the proportion of subjects with a rating of 'severe impairment'. Conclusion: These preliminary results suggest that escalating incobotulinumtoxinA doses up to 800 U are associated with improvement in quality of life ratings in subjects with multifocal upper- and lower-limb spasticity, and form a basis for future comparator studies. Trial registration: ClinicalTrials.gov, NCT01603459. Date of registration: May 22, 2012

Safety and efficacy of incobotulinumtoxinA doses up to 800 U in limb spasticity

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Safety and efficacy of incobotulinumtoxinA doses up to 800 U in limb spasticity: The TOWER study

OBJECTIVE: To evaluate safety (primary objective) and efficacy of increasing doses (400 U up to 800 U) of incobotulinumtoxinA (Xeomin, Merz Pharmaceuticals GmbH) for patients with limb spasticity. METHODS: In this prospective, single-arm, dose-titration study (NCT01603459), patients (18-80 years) with spasticity due to cerebral causes, who were clinically deemed to require total doses of 800 U incobotulinumtoxinA, received 3 consecutive injection cycles (ICs) with 400 U, 600 U, and 600-800 U incobotulinumtoxinA, respectively, each followed by 12-16 weeks' observation. Outcomes included adverse events (AEs), antibody testing, Resistance to Passive Movement Scale (REPAS; based on the Ashworth Scale), and Goal Attainment Scale. RESULTS: In total, 155 patients were enrolled. IncobotulinumtoxinA dose escalation did not lead to an increased incidence of treatment-related AEs (IC1: 4.5%; IC2: 5.3%; IC3: 2.9%). No treatment-related serious AEs occurred. The most frequent AEs overall were falls (7.7%), nasopharyngitis, arthralgia, and diarrhea (6.5% each). Five patients (3.2%) discontinued due to AEs. No patient developed secondary nonresponse due to neutralizing antibodies. Mean (SD) REPAS score improvements from each injection to 4 weeks postinjection increased throughout the study (IC1: -4.6 [3.9]; IC2: -5.9 [4.2]; IC3: -7.1 [4.8]; p < 0.0001 for all). The proportion of patients achieving 653 (of 4) treatment goals also increased (IC1: 25.2%; IC2: 50.7%; IC3: 68.6%). CONCLUSION: Escalating incobotulinumtoxinA doses (400 U up to 800 U) did not compromise safety or tolerability, enabled treatment in a greater number of muscles/spasticity patterns, and was associated with increased treatment efficacy, improved muscle tone, and goal attainment. CLINICALTRIALSGOV IDENTIFIER: NCT01603459. CLASSIFICATION OF EVIDENCE: This study provides Class IV evidence that, for patients with limb spasticity, escalating incobotulinumtoxinA doses (400 U up to 800 U) increases treatment efficacy without compromising safety or tolerability