Pooled Safety Analysis of IncobotulinumtoxinA in the Treatment of Neurological Disorders in Adults.

The pooled incidences of treatment-emergent adverse events (TEAEs) were examined by indication using the integrated clinical database of Merz-sponsored, placebo-controlled, or repeat-dose studies of incobotulinumtoxinA in adults with cervical dystonia, blepharospasm, limb spasticity, sialorrhea, or essential tremor of the upper limb. Overall incidences of TEAEs, serious TEAEs, TEAEs leading to discontinuation, fatal TEAEs, TEAEs of special interest (TEAESIs; indicating possible toxin spread), and treatment-related (TR) events were determined for incobotulinumtoxinA and placebo after a single injection and for repeated dose cycles of incobotulinumtoxinA. The most frequent events after a single dose of incobotulinumtoxinA are summarized. After a single cycle, incidences of overall TEAEs were similar between incobotulinumtoxinA and the placebo in most indications, although between-indication differences were observed. Few TEAEs led to incobotulinumtoxinA discontinuation; there were no fatal TEAEs with incobotulinumtoxinA. In general, repeated cycles did not increase the incidence of any event. The most frequent TR-TEAEs were indication-dependent, including dysphagia for indications affecting the head or neck. The TR-TEAESIs across all indications were most commonly muscular weakness, dysphagia and dry mouth. Overall, the results of this pooled analysis support and extend the favorable safety and tolerability profile of incobotulinumtoxinA for the treatment of adult neurological disorders established by individual clinical studies.

Spasticity-related pain in children/adolescents with cerebral palsy. Part 2: IncobotulinumtoxinA efficacy results from a pooled analysis.

PURPOSE: This pooled analysis of data from three Phase 3 studies investigated the effects of incobotulinumtoxinA on spasticity-related pain (SRP) in children/adolescents with uni-/bilateral cerebral palsy (CP). METHODS: Children/adolescents (ambulant and non-ambulant) were evaluated for SRP on increasingly difficult activities/tasks 4 weeks after each of four incobotulinumtoxinA injection cycles (ICs) using the Questionnaire on Pain caused by Spasticity (QPS; six modules specific to lower limb [LL] or upper limb [UL] spasticity and respondent type [child/adolescent, interviewer, or parent/caregiver]). IncobotulinumtoxinA doses were personalized, with all doses pooled for analysis. RESULTS: QPS key item responses were available from 331 and 155 children/adolescents with LL- and UL-spasticity, respectively, and 841/444 (LL/UL) of their parents/caregivers. IncobotulinumtoxinA efficacy was evident with the first IC. Efficacy was sustained and became more robust with further subsequent ICs. By Week 4 of the last (i.e. fourth) IC, 33.8-53.3% of children/adolescents reported complete SRP relief from their baseline pain for respective QPS items. Children/adolescents reported reductions in mean LL SRP intensity at levels that surpassed clinically meaningful thresholds. Similarly, parents/caregivers observed complete SRP relief and less frequent SRP with incobotulinumtoxinA. Similar results were found for UL SRP. CONCLUSION: These findings indicate that incobotulinumtoxinA could bring considerable benefit to children/adolescents with spasticity by reducing SRP, even during strenuous activities.

Safety Profile and Lack of Immunogenicity of IncobotulinumtoxinA in Pediatric Spasticity and Sialorrhea: A Pooled Analysis.

IncobotulinumtoxinA, a pure botulinumtoxinA formulation, is free of accessory proteins. This analysis provides pooled safety data from phase 3 trials of children/adolescents (2-17 years), investigating incobotulinumtoxinA for the treatment of spasticity associated with cerebral palsy (at doses ≤20 U/kg (max. 500 U) per injection cycle (IC) for ≤6 ICs; three trials) or sialorrhea associated with neurologic disorders (at total doses of 20-75 U per IC for ≤4 ICs; one trial) for ≤96 weeks. Safety endpoints included the incidences of different types of treatment-emergent adverse events (TEAEs) and immunogenicity. IncobotulinumtoxinA dose groups were combined. Of 1159 patients (mean age 7.3 years, 60.4% males) treated with incobotulinumtoxinA, 3.9% experienced treatment-related TEAEs, with the most common being injection site reactions (1.3%) (both indications), muscular weakness (0.7%) (spasticity), and dysphagia (0.2%) (sialorrhea). Two patients (0.2%) experienced a treatment-related treatment-emergent serious adverse event, and 0.3% discontinued the study due to treatment-related TEAEs. No botulinumtoxinA-naïve patients developed neutralizing antibodies (NAbs) after incobotulinumtoxinA. All children/adolescents with known pre-treatment status and testing positive for Nabs at final visit (n = 7) were previously treated with a botulinumtoxinA other than incobotulinumtoxinA. IncobotulinumtoxinA was shown to be safe, with very few treatment-related TEAEs in a large, diverse cohort of children/adolescents with chronic conditions requiring long-term treatment and was without new NAb formation in treatment-naïve patients.

Efficacy and Safety of IncobotulinumtoxinA in the Treatment of Lower Limb Spasticity in Japanese Subjects.

Objective: To confirm the efficacy and safety of incobotulinumtoxinA (Xeomin®, Merz Pharmaceuticals GmbH; total dose 400 U) in Japanese subjects with lower limb (LL) poststroke spasticity using the Modified Ashworth Scale spasticity score for the plantar flexors (MAS-PF). Methods: This phase III study (Japic clinical study database No. CTI-153030, 7 October 2015) included a double-blind, 12-week main period (MP) in which 208 subjects were randomized to receive one injection cycle of incobotulinumtoxinA 400 U (n = 104) or placebo (n = 104) in the pes equinus muscles, and an open-label extension (OLEX) that enrolled 202 subjects who received three injection cycles, 10-14 weeks in duration (the last cycle was fixed at 12 weeks). Changes in MAS-PF for incobotulinumtoxinA vs. placebo from baseline to Week 4 of the MP and to the end-of-cycle visits in the OLEX were evaluated. Results: The area under the curve for the change in MAS-PF was statistically significantly greater with incobotulinumtoxinA vs. placebo in the MP (mean: -7.74 vs. -4.76; least squares mean: -8.40 vs. -5.81 [p = 0.0041]). In the OLEX, mean changes in MAS-PF from baseline to end-of-study showed continued improvement with repeated injections. No new safety concerns were observed with the incobotulinumtoxinA treatment. Its efficacy and safety were consistent regardless of the length of the injection cycle interval in the OLEX. Conclusion: This study demonstrated that incobotulinumtoxinA (total dose 400 U) is an effective and a well-tolerated treatment for LL spasticity in Japanese subjects using flexible injection intervals of 10-14 weeks.

Spasticity-related pain in children/adolescents with cerebral palsy. Part 1: Prevalence and clinical characteristics from a pooled analysis.

PURPOSE: A large prospective database from three Phase 3 studies allowed the study of spasticity-related pain (SRP) in pediatric cerebral palsy (CP). METHODS: Baseline (pretreatment) SRP data occurring during different activities in children/adolescents (aged 2-17 years, ambulant/nonambulant) with uni-/bilateral spastic CP was obtained using the Questionnaire on Pain caused by Spasticity (QPS; six modules specific to spasticity level [lower limb (LL) or upper limb (UL)] and type of respondent [child/adolescent, interviewer, or parent/caregiver]). RESULTS: At baseline, 331 children/adolescents with LL- and 155 with UL-spasticity completed at least one key item of their modules; LL/UL QPS modules of parent/caregivers were at least partially completed (key items) by 841/444 parents/caregivers. SRP with at least one activity at baseline was self-reported in 81.9% /69.7% (LLs/ULs) of children/adolescents with spasticity. Parents/caregivers observed LL/UL SRP behaviors in 85.9% /77.7% of their children, with multiple body regions affected. SRP negatively affected the great majority of the children in various ways. Child/adolescent-reported mean SRP intensity and parent/caregiver-observed mean SRP behavior frequencies were higher for LLs than ULs, and the level of SRP increased with more physically demanding activities. CONCLUSION: These data suggest SRP is more common and intense in pediatric CP than generally thought, emphasizing the need for effective, long-term pain management.

Safety and efficacy of repeat long-term incobotulinumtoxinA treatment for lower limb or combined upper/lower limb spasticity in children with cerebral palsy.

PURPOSE: The open-label phase 3 "Treatment with IncobotulinumtoxinA in Movement Open-Label" (TIMO) study investigated longer-term safety and efficacy of incobotulinumtoxin A in children/adolescents with cerebral palsy (CP). METHODS: Patients on standard treatment, with unilateral or bilateral lower limb (LL) or combined upper limb (UL)/LL spasticity received four incobotulinumtoxinA injection cycles (16 or 20 Units/kg bodyweight total [maximum 400 or 500 Units] per cycle depending on ambulatory status/clinical pattern treated), each followed by 12-16 weeks' observation. Treatment for pes equinus was mandatory; flexed knee or adducted thigh were options for unilateral treatment and/or ULs for unilateral/bilateral treatment. The primary endpoint was safety; changes in Ashworth Scale and Gross Motor Function Measure-66 scores, and Global Impression of Change Scale scores at week 4 of each injection cycle were also evaluated. RESULTS: IncobotulinumtoxinA (≤500 Units for ≤98 weeks) was safe, well-tolerated, and effective across all endpoints for multipattern treatment of LL and combined LL/UL spasticity in ambulant/nonambulant children/adolescents with CP. Treatment effects increased with each injection cycle. No new/unexpected safety concerns were identified. CONCLUSION: IncobotulinumtoxinA showed a good safety and tolerability profile, with efficacy over multiple clinical presentations. As an adjunct treatment, it offers an effective, individualized treatment option for pediatric CP-related spasticity.

Duration and onset of effect of incobotulinumtoxinA for the treatment of blepharospasm in botulinum toxin-naïve subjects.

OBJECTIVE: Blepharospasm is a focal dystonia whereby excessive eyelid muscle contractions cause involuntary eye closure. Botulinum neurotoxin type A (BoNT-A) injections are an approved treatment. This randomized placebo-controlled trial (NCT01896895; EudraCT number 2012-004821-26) assessed the efficacy, safety, and treatment effect duration of incobotulinumtoxinA (Xeomin, Merz Pharmaceuticals GmbH), a BoNT-A formulation without complexing proteins, in BoNT-A-naïve adults with blepharospasm. METHODS: Subjects received incobotulinumtoxinA 50 U, 25 U (total dose) or placebo during a main study period (MP; 6-20 weeks). Patients needing a second injection received incobotulinumtoxinA ≤70 U in an open-label extension period (EP; 6-20 weeks). Treatment effect durations were time from first injection to EP injection or final MP visit and from EP injection to end-of-study visit. Times to effect onset and to waning of effect (MP) were time from injection to first subject-assessed onset effect and time from injection to subject-reported waning of effect, respectively. RESULTS: Of 61 subjects, 39 entered the EP. During the MP, median duration of treatment effect was longer with incobotulinumtoxinA 50 U (20 weeks) versus incobotulinumtoxinA 25 U (11 weeks) or placebo (6 weeks). Median duration of treatment effect was 20 weeks during the EP. Median time to effect onset was 5, 7, and 14 days with 50 U, 25 U, and placebo, respectively (p = .022 for 50 U versus placebo). Median time to waning of treatment effect was comparable between groups. CONCLUSION: Subjects reported an effect onset from 5 days after injection lasting up to 20 weeks (maximum observation period). Data indicate that incobotulinumtoxinA re-treatment of blepharospasm may not be required at fixed 12-week intervals and provide evidence for a patient-tailored approach.

PLAIN LANGUAGE SUMMARYBlepharospasm is a condition in which involuntary contractions of the eyelid muscles cause the eye to close. The condition can be treated with botulinum neurotoxin type A (BoNT-A) injections. This study assessed the duration of effect and time to onset of effect for the BoNT-A formulation incobotulinumtoxinA (Xeomin, Merz Pharmaceuticals GmbH) in adults with blepharospasm. Subjects received a single injection of one of two doses of incobotulinumtoxinA (total dose 25 or 50 U) or placebo and received a second injection of incobotulinumtoxinA only (total dose ≤70 U; the second injection was not compared with placebo) if needed 6­20 weeks after the first injection. After the first injection, the median (mid-point of values from all subjects) duration of treatment effect was longer with the higher incobotulinumtoxinA dose (20 weeks) than with the lower dose (11 weeks) and was longer with both incobotulinumtoxinA doses than with placebo (6 weeks). After the second incobotulinumtoxinA injection, the median duration of treatment effect was 20 weeks. The time to onset of effect was quicker with both incobotulinumtoxinA doses (5 and 7 days for the higher and lower doses, respectively) than with placebo (14 days) and the difference was statistically significant for the higher incobotulinumtoxinA dose compared with placebo. The time to waning of treatment effect was similar for the two incobotulinumtoxinA doses and placebo. This study shows that incobotulinumtoxinA is an effective treatment for blepharospasm, with a fast onset of action. In addition, the effects of one injection can last for up to 20 weeks.

IncobotulinumtoxinA for the treatment of lower-limb spasticity in children and adolescents with cerebral palsy: A phase 3 study.

PURPOSE: Investigate the efficacy and safety of multipattern incobotulinumtoxinA injections in children/adolescents with lower-limb cerebral palsy (CP)-related spasticity. METHODS: Phase 3 double-blind study in children/adolescents (Gross Motor Function Classification System - Expanded and Revised I-V) with unilateral or bilateral spastic CP and Ashworth Scale (AS) plantar flexor (PF) scores ⩾ 2 randomized (1:1:2) to incobotulinumtoxinA (4, 12, 16 U/kg, maximum 100, 300, 400 U, respectively) for two 12- to 36-week injection cycles. Two clinical patterns were treated. Pes equinus (bilateral or unilateral) was mandatory; if unilateral, treatment included flexed knee or adducted thigh. ENDPOINTS: Primary: AS-PF change from baseline to 4 weeks; Coprimary: investigator-rated Global Impression of Change Scale (GICS)-PF at 4 weeks; Secondary: investigator's, patient's, and parent's/caregiver's GICS, Gross Motor Function Measure-66 (GMFM-66). RESULTS: Among 311 patients, AS-PF and AS scores in all treated clinical patterns improved from baseline to 4-weeks post-injection and cumulatively across injection cycles. GICS-PF and GICS scores confirmed global spasticity improvements. GMFM-66 scores indicated better motor function. No significant differences between doses were evident. Treatment was well-tolerated, with no unexpected treatment-related adverse events or neutralising antibody development. CONCLUSION: Children/adolescents with lower-limb spasticity experienced multipattern benefits from incobotulinumtoxinA, which was safe and well-tolerated in doses up to 16 U/kg, maximum 400 U.

Sustained efficacy of incobotulinumtoxina repeated injections for upper-limb post-stroke spasticity: A post hoc analysis.

OBJECTIVE: This post hoc analysis assessed the impact of repeated incobotulinumtoxinA injections on muscle tone, disability, and caregiver burden in adults with upper-limb post-stroke spasticity. DESIGN: Data from the double-blind, placebo-controlled main period and three open-label extension cycles of two Phase 3, randomized, multicentre trials were pooled. METHODS: Subjects received incobotulinumtoxinA 400 Units at 12-week intervals (±3 days) (study 3001, NCT01392300) or ≤ 400 Units at ≥12-week intervals based on clinical need (study 0410, NCT00432666). Ashworth Scale (AS) arm sumscore (sum of elbow, wrist, finger and thumb flexor, and forearm pronator AS scores), Disability Assessment Scale (DAS), and Carer Burden Scale (CBS) scores were assessed. RESULTS: Among 465 subjects, from study baseline to 4 weeks post-injection, mean (standard deviation) AS arm sumscore improved continuously: main period, -3.23 (2.55) (placebo, -1.49 (2.09)); extension cycles 1, 2, and 3, -4.38 (2.85), -4.87 (3.05), and -5.03 (3.02), respectively. DAS principal target domain responder rate increased from 47.4% in the main period (placebo 27.2%) to 66.6% in extension cycle 3. Significant improvements in CBS scores 4 weeks post-injection accompanied improved functional disability in all cycles. CONCLUSION: IncobotulinumtoxinA conferred sustained improvements in muscle tone, disability, and caregiver burden in subjects with upper-limb post-stroke spasticity.

IncobotulinumtoxinA for upper- and lower-limb spasticity in Japanese patients.

Introduction: The safety and tolerability of incobotulinumtoxinA 400 U for upper- and lower-limb post-stroke spasticity was assessed in a small cohort of Japanese patients during the open-label lead-in tolerability periods (LITP) of two phase 3 studies (CTI-153029 and CTI-153030; Japan Pharmaceutical Information Centre).Methods: Adult patients received a single incobotulinumtoxinA injection session (total dose of 400 U) in the upper (J-PURE) or lower limb (J-PLUS). Adverse events (AEs) were assessed at 1, 4, 8 and 12 weeks post-injection during the 12 week follow-up.Results: The LITP of J-PURE and J-PLUS included 11 patients each. Mild/moderate AEs were reported by 5/11 (45.5%) and 8/11 (72.7%) patients in J-PURE and J-PLUS, respectively. No serious AEs were reported. Non-serious, transient AEs of special interest reported by two patients in J-PURE comprised muscular weakness and eyelid ptosis. No patient discontinued due to AEs.Conclusion: Preliminary results in this small population suggest that incobotulinumtoxinA 400 U is well tolerated for treating upper- or lower-limb post-stroke spasticity in Japanese patients.

Efficacy and safety of incobotulinumtoxinA in post-stroke upper-limb spasticity in Japanese subjects: results from a randomized, double-blind, placebo-controlled study (J-PURE).

BACKGROUND: Upper-limb spasticity frequently occurs after stroke and there is a clinical need for more effective therapies. The Phase III J-PURE study assessed the efficacy and safety of incobotulinumtoxinA up to 400 U for post-stroke upper-limb spasticity in Japan. METHODS: In the 12-week main period (MP) of this double-blind, placebo-controlled study, Japanese subjects with upper-limb spasticity received one injection cycle of incobotulinumtoxinA 400 U, 250 U, or matching placebo. Eligible subjects enrolled in an open-label extension (OLEX) period of three injection cycles of incobotulinumtoxinA 400 U (32-40 weeks). The primary objective was to establish the efficacy of a single incobotulinumtoxinA injection using the Modified Ashworth Scale (MAS) wrist score. Secondary efficacy outcomes and safety were also assessed. RESULTS: Among 100 treated subjects, AUCs for incobotulinumtoxinA 400 and 250 U were significantly different versus placebo (p = 0.0014 and p = 0.0031, respectively) for change from baseline in MAS wrist score to the end of the MP, with similar results from baseline to week 4. IncobotulinumtoxinA 400 U was superior versus placebo across other spasticity patterns and at most study visits. Improvements were maintained throughout the OLEX period. Disability Assessment Scale and Investigator's Clinical Global Impression scores improved significantly for incobotulinumtoxinA 400 U versus placebo from baseline to week 4 (p = 0.0067 and p < 0.0001, respectively). IncobotulinumtoxinA was well tolerated up to 52 weeks, with no unexpected adverse events. CONCLUSION: IncobotulinumtoxinA reduced (pathologically) increased muscle tone, improved functionality and was well tolerated in Japanese subjects with post-stroke upper-limb spasticity.

Duration of Treatment Effect Using IncobotulinumtoxinA for Upper-limb Spasticity: A Post-hoc Analysis.

The efficacy and safety of incobotulinumtoxinA ≤400 U was demonstrated in subjects with post-stroke upper-limb spasticity in a randomized, double-blind Phase 3 study with an open-label extension (OLEX; EudraCT number 2005-003951-11, NCT00432666). We report a post-hoc analysis of the duration of the treatment effect. Subjects completing the placebo-controlled main period (single injection cycle with 12-20-week observation) entered the OLEX and received a maximum of five further treatments (maximum duration 69 weeks) with incobotulinumtoxinA ≤400 U at flexible intervals with a minimum duration of 12 weeks, based on clinical need. Intervals between two consecutive incobotulinumtoxinA injections, excluding treatment intervals prior to the end-of-study visit, were evaluated. Of 437 incobotulinumtoxinA treatment intervals, 415 received by 136 subjects were included in the post-hoc analysis. More than half (52.3%; 217/415) of all incobotulinumtoxinA reinjections were administered at Week ≥14, 31.1% (129/415) at Week ≥16, 19.0% (79/415) at Week ≥18, and 11.6% (48/415) at Week ≥20. The duration of effect may vary and can exceed 20 weeks or more, which was observed in at least one injection cycle in 29.4% (40/136) subjects over the course of their treatment. Data show that incobotulinumtoxinA retreatment for upper-limb spasticity may not be required at 12-week intervals and provides evidence for flexible treatment intervals beyond this time frame.

IncobotulinumtoxinA Treatment in Upper-Limb Poststroke Spasticity in the Open-Label Extension Period of PURE: Efficacy in Passive Function, Caregiver Burden, and Quality of Life.

BACKGROUND: Poststroke spasticity affects motor function and the ability to perform activities of daily living, with the potential to affect quality of life (QoL) and increase caregiver burden. OBJECTIVE: To investigate the effect of repeated incobotulinumtoxinA treatment on spasticity-associated functional disability, caregiver burden, and QoL in the 36-week open-label extension of the phase 3 PURE study (NCT01392300). DESIGN: Open-label extension period of a prospective, double-blind, placebo-controlled, randomized, multicenter study. SETTING: Forty-six investigation sites in seven countries (Czech Republic, Germany, Hungary, India, Poland, Russia, United States). PARTICIPANTS: Adults, aged 18-80 years, ≥12 months since last botulinum neurotoxin injection or entirely toxin naïve, with median poststroke upper-limb spasticity of >2 years' duration. METHODS: Participants who completed the 12-week, double-blind main period could enter the open-label extension and receive up to three additional incobotulinumtoxinA treatments (fixed total dose 400 U at 12-week intervals) into the affected muscles of one upper limb. MAIN OUTCOME MEASURES: Functional disability (Disability Assessment Scale; DAS), caregiver burden (Carer Burden Scale), and quality of life (QoL; EuroQol [EQ] 5-dimensions three-level [EQ-5D-3L]). RESULTS: The open-label extension included 296 treated patients. Mean DAS score for the principal target domain improved significantly from the main period baseline to the end-of-study visit (P < .0001). Carer Burden Scale scores also significantly improved from the main period baseline to the end-of-study visit (P < .05 for all caregiving activities except "applying a splint"). At the end-of-study visit, versus the main period baseline, 19.7%-33.3% of patients experienced improvements for each parameter on the EQ-5D-3L, except "mobility," with significant improvement in EQ-5D visual analog scale scores (P < .001). CONCLUSIONS: Repeated incobotulinumtoxinA treatments at 12-week intervals in participants with chronic poststroke upper-limb spasticity resulted in significant improvements in QoL, as well as significant reductions in upper-limb functional disability and caregiver burden.

Facial skin revitalization with CPM®-HA20G: an effective and safe early intervention treatment.

BACKGROUND: Hyaluronic acid (HA) fillers are popular for the treatment of signs of facial skin aging. OBJECTIVE: The objective of this study was to confirm the performance and safety of a new cohesive polydensified matrix HA filler ([CPM®-HA20G, Belotero Revive®, lidocaine-free], Merz Pharmaceuticals GmbH, Frankfurt, Germany) for the treatment of early signs of facial skin aging by use of biophysical measurements as well as subject and investigator satisfaction. METHODS: Twenty-five healthy female subjects with signs of facial skin aging were enrolled in this open-label, rater-blinded, observational post-market clinical follow-up study, and received 20 micropuncture treatments of 50 µL CPM®-HA20G each into the lower cheek area at three injection visits 4 weeks apart. Objective biophysical assessments were conducted to demonstrate effects on viscoelastic properties of the skin, surface roughness, tone and radiance, and hydration, at baseline and at all follow-up visits up to 36 weeks. RESULTS: CPM®-HA20G significantly increased gross elasticity of the skin (at weeks 9 and 12), skin firmness (up to week 24), skin tone and radiance and skin hydration (all up to 36 weeks). Significant reduction of skin fatigue (up to 9 weeks), skin roughness (up to 28 weeks), and redness (up to 36 weeks) was also observed. Subjects and blinded investigator were highly satisfied with the treatment outcomes. The treating investigator reported a high level of satisfaction with the ease of injection and the clinical performance of the device. Moreover, data demonstrated a good safety profile of the device. CONCLUSION: CPM®-HA20G is considered to be an effective and safe HA injectable for skin revitalization in patients suffering from signs of skin aging and loss of skin elasticity. It seems to be a perfect early intervention approach in patients that do not need volumizing treatment and a combination approach in older patients with more pronounced aging.

IncobotulinumtoxinA Efficacy and Safety in Adults with Upper-Limb Spasticity Following Stroke: Results from the Open-Label Extension Period of a Phase 3 Study.

INTRODUCTION: The objective of the study was to investigate the efficacy and safety of repeated incobotulinumtoxinA injections for the treatment of upper-limb post-stroke spasticity in adults. METHODS: Adults 18-80 years of age with post-stroke upper-limb spasticity who completed the 12-week randomized, double-blind, placebo-controlled main period (MP) of a phase 3 trial (NCT01392300) were eligible to enrol in the 36-week open-label extension period (OLEX). The OLEX included three treatment cycles at fixed 12-week injection intervals; subjects were injected with 400 U incobotulinumtoxinA into the affected upper limb. Efficacy assessments included evaluation of muscle tone using the Ashworth Scale (AS) and the Global Impression of Change Scale (GICS) assessed by the investigator, subject, and caregiver. The incidence of adverse events (AEs) was monitored throughout the OLEX. RESULTS: A total of 296 of 299 subjects (99.0%) who completed the MP received incobotulinumtoxinA in the OLEX, and 248 subjects completed the 36-week OLEX. The proportion of subjects with at least a 1-point improvement in AS score from each incobotulinumtoxinA treatment to the respective 4-week post-injection visit ranged by cycle from 52.3% to 59.2% for wrist flexors, 49.1% to 52.3% for elbow flexors, 59.8% to 64.5% for finger flexors, 35.5% to 41.2% for thumb flexors, and 37.4% to 39.9% for forearm pronators (P < 0.0001 for all). Over 90% of subjects were assessed by the investigator to be at least minimally improved (4 weeks post-injection) on the GICS during each injection cycle; 61.0% in the 1st cycle, 58.2% in the 2nd cycle, and 57.4% in the 3rd cycle were considered much improved or very much improved on the GICS. Three percent of subjects (9/296) reported treatment-related AEs; the most frequently reported were pain in the extremity (n = 2, 0.7%) and constipation (n = 2, 0.7%). Serious AEs were reported by 22 subjects (7.4%); however, none were considered treatment-related. CONCLUSIONS: Repeated injections of incobotulinumtoxinA for the treatment of post-stroke upper-limb spasticity led to significant improvements in muscle tone and investigator's global impression of change. Treatment was well tolerated, with no serious treatment-related AEs. FUNDING: Merz Pharmaceuticals GmbH.

Safety of IncobotulinumtoxinA in the Treatment of Facial Lines: Results From a Pooled Analysis of Randomized, Prospective, Controlled Clinical Studies.

BACKGROUND: The safety and efficacy of incobotulinumtoxinA in aesthetics has been established in multiple studies. Although individual studies have been reported, a combined assessment of incobotulinumtoxinA safety across studies is not available. OBJECTIVE: To assess the frequency of adverse events (AEs) across prospective incobotulinumtoxinA studies in aesthetics. MATERIALS AND METHODS: Safety data were assessed from 9 placebo-controlled or active-controlled single-dose studies on glabellar frown lines (GFL), crow's feet (CF), and upper facial lines (UFL). Analyses by treatment cycle included 4 repeat-dose studies on GFL and UFL. RESULTS: One thousand three hundred seventy-seven subjects received incobotulinumtoxinA (GFL, n = 1,189; CF, n = 83; UFL, n = 105) in single-dose studies (placebo-controlled studies: incobotulinumtoxinA, n = 866; placebo, n = 395). Over 1,000 subjects received incobotulinumtoxinA in repeat-dose studies (GFL, n = 880; UFL, n = 290). In placebo-controlled single-dose studies, incidences of treatment-related AEs ranged from 5.4% (GFL) to 22.9% (UFL). The most frequent treatment-related AE in single-dose studies was headache (GFL, 4.8%; UFL, 11.4%). In repeat-dose studies, incidence of AEs was highest during cycle 1 (GFL, 8.9%; UFL, 17.2%) and decreased across treatment cycles. No serious treatment-related AEs were observed. CONCLUSION: Results confirm the favorable safety and tolerability of incobotulinumtoxinA. The frequency of treatment-related AEs was low and may decrease with subsequent treatments.

Randomized, placebo-controlled trial of incobotulinumtoxina for upper-limb post-stroke spasticity.

INTRODUCTION: Efficacy and safety of incobotulinumtoxinA in post-stroke upper-limb spasticity were studied. METHODS: Subjects randomized 2:1 to incobotulinumtoxinA (fixed dose 400 U) or placebo, with fixed doses for the primary target clinical pattern (PTCP; flexed elbow, 200 U; flexed wrist, 150 U; clenched fist, 100 U). Doses for non-primary patterns were flexible within predefined ranges. RESULTS: At week 4, incobotulinumtoxinA led to larger improvements in PTCP Ashworth scale (AS) scores than placebo [least-squares mean change ± standard error: -0.9 ± 0.06 (n = 171) vs. -0.5 ± 0.08 (n = 88); P < 0.001], and more subjects were PTCP AS responders (≥1-point improvement) with incobotulinumtoxinA (69.6%) than with placebo (37.5%; P < 0.001). Investigator's Global Impression of Change confirmed superiority of incobotulinumtoxinA vs. placebo (P = 0.003). IncobotulinumtoxinA was associated with functional improvements, as demonstrated in responder rates for Disability Assessment Scale principal target at week 4 (P = 0.007). Adverse events were mainly mild/moderate, and were reported by 22.4% (incobotulinumtoxinA) and 16.8% (placebo) of subjects. CONCLUSIONS: IncobotulinumtoxinA significantly improved upper-limb spasticity and associated disability, and was well-tolerated.

IncobotulinumtoxinA (Xeomin®) injected for blepharospasm or cervical dystonia according to patient needs is well tolerated.

Typically, botulinum toxin injections for blepharospasm or cervical dystonia (CD) are administered at approximately 3-month intervals, reflecting concerns that shorter intervals might increase the risk of adverse events (AEs) and development of neutralizing antibodies. These post-hoc analyses investigated flexible incobotulinumtoxinA (Xeomin®) injection intervals (6-20 weeks) in patients with blepharospasm or CD. Patients received up to 6 injections at intervals ≥ 6 weeks, as determined by physician assessment upon patient request. The blepharospasm study permitted flexible doses (≤ 50 U/eye). The CD study employed fixed dosing using incobotulinumtoxinA 120 U, 240 U, or placebo for the first treatment followed by subsequent randomization to 120 U or 240 U for the extension period. Standard safety assessments were performed. Intervals <12 weeks were employed in 207 of 461 (44.9%) treatment cycles for blepharospasm and in 369 of 821 (44.9%) treatment cycles for CD. The most frequent AEs were eyelid ptosis and dry eyes in patients treated for blepharospasm, and dysphagia and neck pain in patients with CD. AE frequency and severity were similar for intervals <12 weeks and ≥ 12 weeks in both studies. In conclusion, repeated incobotulinumtoxinA injections employing flexible intervals (6-20 weeks) per patients' needs were well tolerated. No additional safety concerns were observed with <12-week intervals compared with ≥ 12-week intervals.

Satisfaction with botulinum toxin treatment in post-stroke spasticity: results from two cross-sectional surveys (patients and physicians).

OBJECTIVE: To characterize patient and physician satisfaction with current standard-of-care botulinum toxin treatment regimens for symptom control in patients with post-stroke spasticity using structured interviews with patients and physicians. RESEARCH DESIGN AND METHODS: Two cross-sectional surveys were conducted in Canada, France, Germany, and the US. The patient survey included patients with post-stroke spasticity who had undergone at least two botulinum toxin A injection cycles. Information on patients' current and prior botulinum toxin treatment cycles and quality of life was collected. The physician survey included physicians treating post-stroke spasticity with botulinum toxins and collected information regarding physician satisfaction with botulinum toxin treatment for post-stroke spasticity. RESULTS: Of 79 participating patients with post-stroke spasticity, 61 (77%) received treatment with onabotulinumtoxinA, 15 (19%) with abobotulinumtoxinA, and three (4%) with incobotulinumtoxinA. Overall, 40.5% of patients were very satisfied, 48.1% were somewhat satisfied, and 11.4% were not at all satisfied with botulinum toxin treatment. Patient satisfaction was lowest just before injection and highest at the time of peak effect. The mean injection interval was 13.7 (SD = 3.5) weeks; however, 43.4% of patients expressed a preference for intervals of ≤ 10 weeks. Most of the 105 participating physicians' were moderately (57.7%) or very (36.5%) satisfied with botulinum toxin treatment. However, physicians estimated that 16.2% of their patients with post-stroke spasticity could benefit from shorter injection intervals, and that 24.6% of patients could benefit from higher doses than those permitted by current country directives. STUDY LIMITATIONS: Patients' responses were based on subjective recollections and physicians' responses were based on general impressions. CONCLUSIONS: These surveys indicate that patients' and physicians' satisfaction with botulinum toxin therapy for post-stroke spasticity is overall very good. However, patients' satisfaction over the treatment cycle varied with onset, peak, and trough of treatment effects and patients and physicians expressed a need for treatment individualization.

A randomized, double-blind study of repeated incobotulinumtoxinA (Xeomin(®)) in cervical dystonia.

IncobotulinumtoxinA (Xeomin(®), NT 201), a preparation without accessory (complexing) proteins, has shown comparable efficacy and safety to onabotulinumtoxinA in treating cervical dystonia (CD). This study evaluated the efficacy and safety of repeated incobotulinumtoxinA injections in subjects with CD. Following a ≤20-week placebo-controlled, randomized, double-blind, single-dose main period, subjects could enter a ≤68-week prospective, randomized, double-blind, repeated-dose, flexible-interval (minimum 6 weeks) extension period with 240 U or 120 U of incobotulinumtoxinA (≤5 injections). Outcome measures included the Toronto Western Spasmodic Torticollis Rating Scale (TWSTRS) and adverse events (AEs). Of 219 subjects completing the main period, 214 were randomized in the extension period to receive incobotulinumtoxinA 240 U (n = 111) or 120 U (n = 103); 169 subjects completed the extension period, with 90 receiving five injection sessions. Both doses of incobotulinumtoxinA provided statistically significant and clinically relevant improvements in mean TWSTRS-Total, -Severity, -Disability, and -Pain scores, from each injection session to respective 4-week follow-up visits. The most frequently reported AE was dysphagia (240 U: 23.4 %; 120 U: 12.6 %), which did not result in any study withdrawals. There was no impact of injection interval on the incidence of AEs (post hoc analysis). A major limitation of this study was the fixed dose design requested by regulatory authorities, which does not reflect clinical practice. However, repeated incobotulinumtoxinA injections (240 or 120 U; flexible intervals) provided sustained efficacy and were well tolerated, with no unexpected safety risks following repeated injections. The incidence of AEs was similar in subjects requiring repeated injections at shorter intervals (≤12 weeks) compared with those treated using longer intervals (>12 weeks).