Astrid Scheschonka

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 ≥3 (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. ClinicalTrials.gov 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.

Poster 65: Efficacy of IncobotulinumtoxinA in the Treatment of Shoulder Spasticity

hemiparetic subjects who received abobotulinumtoxinA (Dysport , aboBoNT-A) in both UL and LL simultaneously. Design: Phase-III, open-label (OL) study (NCT01251367). Setting: 52 centres;11 countries worldwide. Participants: Eligible subjects previously completed double-blind (DB) placebo-controlled study (NCT01249404). Interventions: DB: aboBoNT-A 1000U or 1500U in LL for one treatment cycle (TC). OL: repeated injections (up to 4 TC) performed over max18 months. Subjects received aboBoNT-A 1500U in LL for TC1/TC2; from TC3 subjects could receive up to 500U in UL, providing total aboBoNTA dose did not exceed 1500U. Main Outcome Measures: Ten-meter comfortable barefoot walking speed. Results: Of 352 subjects, 63 received co-injection in LL+UL at both TC3/TC4, and 64 received injection in LL only. Mean (SD) aboBoNT-A doses in LL at TC3 and TC4 were 1380U (210) and 1360U (220), respectively, in subjects injected in LL only, and 1000U (50) and 1000U (50), respectively, for subjects injected in LL+UL. At baseline, tenmeter comfortable barefoot walking speed (mean [SD]) was similar in subjects injected in LL+UL (0.42 [0.20]) and LL only (0.42 [0.20]). At TC3 Wk4, both subgroups had improvements from baseline (mean change [SD]: LL+UL: 0.063 [0.131]; LL only: 0.078 [0.114]), which further improved to TC4 Wk4 ( LL+UL: 0.086 [0.166]; LL only: 0.086 [0.123]). Conclusions: In subjects with spastic paresis requiring concurrent treatment of UL and LL, it was possible to split 1500U total dose of aboBoNT-A between both extremities while still improving walking speed similarly to that observed in subjects injected in lower extremities only. This provides important information for the treatment of LL and UL simultaneously with aboBoNT-A in adult patients with hemiparesis. Level of Evidence: Level I

Poster 371 Escalating Doses of IncobotulinumtoxinA (400-800U) Are Well Tolerated and Lead to Increasing Improvements in Disability Due to Multifocal Upper- and Lower-Limb Spasticity.

Disclosures: J€ org Wissel: Speakers bureau Allergan, Ipsen, Merz, Medtronic Objective: To assess the safety and efficacy of escalating incobotulinumtoxinA (Xeomin, Merz Pharmaceuticals GmbH) doses (400-800U) in patients with spasticity. Design: Prospective dose-escalation study (NCT01603459). Setting: 30 study sites worldwide. Participants: 155 adults (18-80 years) with spasticity due to cerebral causes deemed to require total body doses of incobotulinumtoxinA 800U. Interventions: 3 injection cycles (ICs) with escalating incobotulinumtoxinA doses (400U, 600U and 600-800U, respectively), each followed by 12-16-week observations. Main Outcome Measures: Ashworth Scale (AS) responder rate ( 1point improvement 4 weeks post-injection), Disability Assessment Scale (DAS), Functional Ambulatory Classification (FAC), Investigators Global Efficacy Assessment (IGEA), adverse events (AEs) and antibody testing. Results: Escalation of the total incobotulinumtoxinA dose enabled physicians to treat an increasing number of spasticity patterns in each patient. AS responses were achieved in 364/608 (59.9%) patterns treated in IC1 (155 patients), 431/743 (58.0%) patterns in IC2 (152 patients) and 537/811 (66.2%) patterns in IC3 (140 patients). There was increased reporting of “no”/“slight” disability for the principal target domain (DAS score 0 or 1) after each IC (baseline: 0.7%; study end: 42.9%). The proportion of ambulator-independent patients (FAC level 5) also improved throughout the study (baseline: 24.5%; study end: 40.6%). The proportion of “good”/“very good” IGEA assessments increased with escalating doses (IC1: 55.5%; IC2: 72.4%; IC3: 89.3%). Importantly, dose escalation did not increase the incidence of AEs (IC1: 36.1%; IC2: 37.5%; IC3: 25.7%) or treatment-related AEs (IC1: 4.5%; IC2: 5.3%; IC3: 2.9%). There were no treatment-related serious AEs or cases of clinical non-responsiveness due to antibodies. Conclusions: Increasing incobotulinumtoxinA doses (400-800U) allowed the effective treatment of a rising number of spasticity patterns for each patient while maintaining safety and tolerability. This enhanced efficacy was confirmed by improved muscle tone, favorable investigator global assessments, reduced upper-limb disability and greater ambulator independence. Level of Evidence: Level II