A型ボツリヌス毒素製剤（Botulinum Toxin Type A）の脳卒中後の上肢痙縮に対する臨床評価―プラセボ対照二重盲検群間比較試験ならびにオープンラベル反復投与試験

Efficacy and Safety of Botulinum Toxin Type A in treating Upper Limb Spasticity in Post-stroke Patients : A Multicenter, Double-blind, Placebo-controlled Trial followed by an Open-label Trial

要旨　【目的】脳卒中後の上肢痙縮患者を対象にA型ボツリヌス毒素製剤（botulinum toxin type A：BTXA）単回投与時の有効性をプラセボを対照として検証し，反復投与した際の有効性および安全性を評価した．【方法】上肢痙縮患者109例にBTXA低用量（120～150単位），高用量（200～240単位）またはプラセボを手関節，手指関節，母指関節（母指に痙縮が認められた場合）の対象筋に1回筋注し，投与12週以降は再投与基準を満たした被験者にBTXA 200～240単位を最大3回反復投与し48週まで観察を行った．【結果】手関節のModified Ashworth Scale（MAS）の投与前からの変化量に基づく曲線下面積の平均値の差はBTXA高用量群とプラセボ群間で-6.830であり，プラセボ群に対して有意な減少が認められた（p＜0.001，t検定）．反復投与によりMASは更なる改善を示した．副作用発現頻度はBTXA群，プラセボ群間で著明な差は認められず，反復投与においても副作用発現率の増加は認められなかった．【結論】BTXAは初回投与から上肢痙縮を改善し，長期的に有効で安全な治療法に成り得ると考えられた．

Abstract　Objective : To evaluate the efficacy and safety of botulinum toxin type A (BTXA) in Japanese patients with post-stroke upper limb spasticity in a multicenter, randomized, double-blind, single dose, placebo-controlled study (double-blind phase) followed by an open-label, multiple dose extension (open-label phase). Methods : One hundred and nine patients with upper limb spasticity were randomized to receive a single treatment with either a lower dose (120-150 Units ; U), higher dose (200-240U) BTXA or placebo into upper limb muscles in the double-blind phase. These treatments were administered to improve wrist and finger flexion for all patients and thumb flexion in patients with thumb spasticity. Patients who met the re-injection criteria received up to 3 repeated treatments of BTXA (200-240U) into their upper limb muscles with at least 12 weeks between treatments in the open-label phase through 48 weeks. Results : In the double-blind phase there was significant improvement from baseline spasticity on the Modified Ashworth Scale (MAS) wrist score between the higher dose BTXA and placebo groups, with a mean difference in the area under the curve (AUC) of -6.830 (p＜0.001, t test). The MAS wrist score further decreased from baseline in all repeat treatment cycles of BTXA in the open-label phase. No clinically relevant difference was noted in the frequency of treatment-related adverse events between BTXA-treated and placebo-treated patients during the study period. Conclusions : BTXA injections reduced spasticity in the upper limb muscles from the first treatment with continued long-term efficacy. Our results suggest that BTXA injections are safe and effective for the long-term treatment of post-stroke upper limb spasticity.