Formation of neutralizing antibodies in patients receiving botulinum toxin type a for treatment of poststroke spasticity: A pooled-data analysis of three clinical trials

Abstract

Objective: The purpose of this study was to investigate the incidence of neutralizing antibody (NAb) formation in patients with poststroke spasticity treated with a specific formulation of botulinum toxin type A (BoNTA). Methods: Data from 3 previous clinical trials of BoNTA in patients with upper and/or lower limb spasticity were pooled and evaluated. Study 1 was a randomized, double-blind, placebo-controlled, multicenter trial of BoNTA in patients aged ≥21 years who had experienced a stroke >6 months before the initiation of the study. Study 2 was an open-label extension of study 1. Study 3 was a randomized, double-blind, multicenter trial of a specific BoNTA formulation in patients aged ≥ 21 years who had experienced a stroke ≥6 weeks before study entry. Patients with a fixed contracture of the studied limb were excluded from participation in studies 1 and 2. Serum samples were obtained from each patient before each BoNTA treatment and at the end of each study. The mouse protection assay (MPA) was used for detection of NAbs to BoNTA in serum. Results: A total of 235 individual patients with post-stroke spasticity were enrolled in the 3 trials, including 126, 111 (all of whom participated in study 1), and 109 in studies 1, 2, and 3, respectively. Study 1 had an equal (50.0%) distribution of male and female patients (63/63). The distribution of male and female patients was 56 (50.5%) and 55 (49.5%), respectively, in study 2, and 55 (50.5%) and 54 (49.5), respectively, in study 3. The mean (SD) ages of patients in studies 1, 2, and 3 were 61.4 (13.8), 61.5 (14.1), and 58.5 (13.9) years, respectively. The MPA was used for detection of NAbs to BoNTA in the serum samples of 191 patients, including 64 from study 1, 111 from study 2 (55 of these patients were placebo recipients and 56 received their first BoNTA injection in study 1), and 72 (a sample was not obtained for 1 patient who had not received an injection) from study 3. The median number of BoNTA treatments received by these patients was 2 (range, 1–4 treatments) over a period lasting from 12 to 42 weeks. The mean dose of BoNTA was 241 U (range, 100–400 U), with a maximum dose of 960 U in any 1 patient. NAbs to BoNTA were detected in the serum sample of 1/191 (0.5%) patient who had participated in studies 1 and 2. Based on muscle-tone scores (3 and 4 for wrist and fingers, respectively) on a 5-point Ashworth Scale (0 = none to 4 = severe), the patient did not appear to exhibit a clinical response to BoNTA at any time during the studies. Conclusion: Formation of NAbs was rare (1/191) in this group of adults with poststroke spasticity from three 12- to 42-week clinical trials who received ≥1 treatment with a specific BoNTA formulation at doses ranging from 100 to 400 U.