toxins Article
Efficacy and Safety of Letibotulinum Toxin A for the Treatment of Dynamic Equinus Foot Deformity in Children with Cerebral Palsy: A Randomized Controlled Trial Hyun Jung Chang 1,† ID , Bo Young Hong 2,† and Jeong-Yi Kwon 6, * 1 2 3 4 5 6
* †
ID
, Sang-Jee Lee 3 , Soyoung Lee 4 , Joo Hyun Park 5
Department of Physical Medicine and Rehabilitation, Samsung Changwon Hospital, Sungkyunkwan University School of Medicine, Changwon 51353, South Korea; [email protected] Department of Rehabilitation Medicine, St. Vincent’s Hospital, College of Medicine, The Catholic University of Korea, Suwon 16247, South Korea; [email protected] Department of Rehabilitation Medicine, Daejeon St. Mary’s Hospital, College of Medicine, The Catholic University of Korea, Daejeon 34943, South Korea; [email protected] Department of Rehabilitation Medicine, Keimyung University, Dongsan Medical Center, Daegu 41931, South Korea; [email protected] Department of Rehabilitation Medicine, Seoul St. Mary’s Hospital, College of Medicine, The Catholic University of Korea, Seoul 06591, South Korea; [email protected] Department of Physical and Rehabilitation Medicine, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul 06351, South Korea Correspondence: [email protected]; Tel.: +82-2-3410-1030 These authors contributed to this work equally.
Academic Editors: Jianlong Lou and James D. Marks Received: 12 July 2017; Accepted: 16 August 2017; Published: 18 August 2017
Abstract: The objective of this clinical trial was to compare the efficacy and safety of letibotulinum toxin A and onabotulinum toxin A for improving dynamic equinus foot deformity in children with cerebral palsy (CP). In total, 144 children with spastic CP who had dynamic equinus foot deformity were assigned randomly to the Botulax group (injection of letibotulinum toxin A) or the Botox group (injection of onabotulinum toxin A). The Physician’s Rating Scale (PRS), ankle plantar flexor spasticity using the Modified Tardieu Scale, the Gross Motor Function Measure (GMFM)-88, and the GMFM-66 were completed before injection and at 6, 12, and 24 weeks after injection. The PRS responder rate was 60.27% in the Botulax group and 61.43% in the Botox group at 12 weeks after treatment, and the lower limit of the 95% confidence interval for the between-group difference in responder rates was −17.16%, higher than the non-inferiority margin of −24.00%. The clinical efficacy and the safety profiles of the groups did not significantly differ. The results suggest that injection of letibotulinum toxin A is as effective and safe as that of onabotulinum toxin A for the treatment of dynamic equinus foot deformity in children with spastic CP. Keywords: cerebral palsy; spasticity; botulinum toxin; letibotulinum toxin; onabotulinum toxin
1. Introduction Cerebral palsy (CP), which is characterized by movement and posture disorders caused by non-progressive lesions in the developing brain, is the most common developmental disorder associated with lifelong motor impairment and disability [1,2]. Spasticity is a major impairment in children with CP, affecting approximately two-thirds of this population [3]. Equinus is a common gait abnormality in children with CP, resulting from spasticity of the ankle plantar flexor [4]. Toxins 2017, 9, 252; doi:10.3390/toxins9080252
www.mdpi.com/journal/toxins
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Since the first reports in the early 1990s, botulinum toxin type-A (BoNT-A) has been used for the management of spasticity in the lower limbs of children with CP [5,6]. BoNT-A injections decrease spasticity locally by interfering with cholinergic transmission at the neuromuscular junction [7]. BoNT-A has been established as an effective treatment for the management of spastic equinus, as it improves gait, goal attainment, and function [8]. Various BoNT-A products are used for the management of spasticity, including onabotulinum toxin A (Botox, Allergan Inc., Irvine, CA, USA), abobotulinum toxin A (Dysport, Ipsen Ltd., Slough, Berkshire, UK), letibotulinum toxin A (Botulax, Hugel Inc., Chuncheon, Korea), and incobotulinum toxin A (Xeomine, Merz Pharmaceutical, Frankfurt, Germany) [9–11]. Each BoNT-A product acts by a similar mechanism but has different components. Thus, it is possible that each product presents different levels of efficacy and safety. Letibotulinum toxin A is a novel neurotoxin from the C. botulinum CBFC26 strain that shows high toxicity in mice [12]. Also, its toxin and 16S rRNA sequences are completely homologous to those of the ATCC 3502 Hall A strain of onabotulinum toxin A. Letibotulinum toxin A has been subjected to additional processes, including enzyme-free purification steps such as protamine sulfate precipitation, to eliminate nucleic acids, and diethylaminoethanol-sepharose chromatography, which could theoretically improve the quality of the product. However, few studies have assessed the efficacy and safety of letibotulinum toxin A in the treatment of spasticity [12]. Also, there has been no report on the effectiveness of letibotulinum toxin A in the management of spasticity in children with CP. When newly formulated BoNT-A products are manufactured, clinical trials are needed to demonstrate the efficacy and safety for each indication. Generally, studies on the safety and efficacy of BoNT-A have been performed using a comparative design involving onabotulinum toxin A. We hypothesized that the efficacy and safety of letibotulinum toxin A were not inferior to those of onabotulinum toxin A. The objective of this clinical trial was to compare the efficacy of letibotulinum toxin A (Botulax) with that of onabotulinum toxin A (Botox) for improving dynamic equinus foot deformity among children with CP, and to record any adverse events in the two groups. 2. Results In total, 144 subjects participated in the study, with 73 subjects randomly assigned to the Botulax group (injected with letibotulinum toxin A) and 71 assigned to the Botox group (injected with onabotulinum toxin A) (Figure 1).
Figure 1. Flow diagram.
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There were 42 (57.5%) males in the Botulax group and 49 (70.0%) in the Botox group, and there was no statistically significant difference in the gender distribution of the groups. The mean age of subjects was 4.67 years in the Botulax group and 5.44 years in the Botox group; this constituted a statistically significant between-group difference (p = 0.0408; Table 1). Table 1. Baseline demographic and clinical data (FA set = 143 subjects). Baseline Characteristics Male/female, n (%) Age (years), mean (SD) 2–4 years, n 5–7 years, n 8–10 years, n Body weight (kg), mean (SD) Type, n (%) Right unilateral Left unilateral Bilateral Previous BoNT-A injection, n (%) Number of previous BoNT-A injectrion, median (min-max) PRS, median (min-max) GMFM-88
Botulax Group (N = 73)
Botox Group (N = 70)
42 (57.5)/31 (42.5) 4.7 (2.0) 37 28 8 18.98 (6.47)
49 (70.0)/21 (30.0) 5.4 (2.3) 26 31 13 20.01 (6.98)
18 (24.7) 6 (8.2) 49 (67.1) 48 (65.8)
17 (24.3) 7 (10.0) 46 (65.7) 47 (67.1)
0.8604
2 (1–6)
3 (1–7)
0.146
6 (2–13) 85.7 (13.9)
6 (3–12) 85.7 (13.7)
0.4800 0.7140
p-Value 0.1214 0.0408 * 0.2020
0.3406 0.9336
FA: Full Analysis, PRS: Physician’s Rating Scale, GMFM: Gross Motor Function Measure. * Statistically significant when compared between Botulax group and Botox group (p < 0.05).
In terms of spastic CP types, unilateral CP was reported in 24 (32.9%) subjects, and bilateral CP in 49 (67.1%) in the Botulax group; in the Botox group, unilateral CP was reported in 24 (34.3%), and bilateral CP was reported in 46 (65.7%). There was no statistically significant difference in the distribution of CP types between the two groups. For BoNT injection history, 48 subjects (65.8%) were injected with BoNT-A, and 25 subjects (34.25%) were de novo patients in the Botulax group. In the Botox group, 47 subjects (67.1%) had a history of BoNT-A injection, and 23 subjects (32.9%) had never been injected with BoNT before screening. In both groups, there was no subject with BoNT-B injection history, and there was no statistically significant between-group difference in the distribution of BoNT injection history. For subjects with BoNT-A injection history, there was no subject with a previous history of hypersensitivity to BoNT-A. The mean number of BoNT-A injection was 2.6 times in the Botulax group and 3.06 times in the Botox group, which showed no statistically significant difference between groups. The mean doses of botulinum toxin injected in each group were 100.0 ± 32.9 U in the Botulax group and 106.1 ± 39.4 U in the Botox group. There was no significant difference between the two groups (p = 0.497). 2.1. Physician’s Rating Scale (PRS) 2.1.1. Responder Rate The responder rate (proportion of subjects determined to be responders) was 60.27% (44/73 subjects) in the Botulax group and 61.43% (43/70 subjects) in the Botox group at 12 weeks after BoNT-A injection, and the lower limit of the 95% confidence interval (CI) for the difference in the responder rate (−1.15%) between the Botulax group and the Botox group was −17.16%, which was higher than the non-inferiority margin of −24.00% (Table 2) [13].
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Table 2. Responder rate in the Physician’s Rating Scale (PRS), n (%). Assessment Week
Botulax Group (N = 73)
Botox Group (N = 70)
p-Value
Post-injection 6 weeks Post-injection 12 weeks Post-injection 24 weeks
42 (58.9) 44 (60.3) 35 (48.0)
36 (51.4) 43 (61.4) 29 (41.4)
0.3688 0.8876 0.4334
2.1.2. Mean Score The mean PRS score in the Botulax group was 6.82 at baseline, 9.33 at week 6, 9.43 at week 12, and 8.88 at week 24; these figures were 6.85, 8.95, 9.25, and 8.89, respectively, in the Botox group, suggesting that the PRS score increased from the baseline to each time point in both groups, and the changes were statistically significant (p < 0.0001; Figure 2). There was no statistically significant difference between the two groups in terms of changes in the PRS scores at 6, 12, or 24 weeks after BoNT-A injection.
Figure 2. Changes in Physician’s Rating Scale (PRS). In both the Botulax group and Botox group, PRS score was significantly increased and maintained until 24 weeks after BoNT-A injection. The error bar indicates the standard deviation. * Statistically significant when compared between baseline data and post-injection data in the Botulax group; + Statistically significant when compared between baseline data and post-injection data in the Botox group.
2.2. Modified Tardieu Scale (MTS) The mean R1 of ankle dorsiflexion with knee extension were −14.19◦ at baseline, −6.24◦ at week 6, −5.83◦ at week 12, and −8.74◦ at week 24 in the Botulax group; these figures were −16.06◦ , −8.24◦ , −6.59◦ , and −9.14◦ , respectively, in the Botox group. And the mean R2 of ankle dorsiflexion with knee extension were 4.76◦ at baseline, 13.16◦ at week 6, 14.33◦ at week 12, and 9.87◦ at week 24 in the Botulax group; these figures were 4.48◦ , 11.96◦ , 12.19◦ , and 9.75◦ , respectively, in the Botox group, which demonstrated that the mean R1 and R2 of ankle dorsiflexion with knee extension changed in a positive direction from the baseline to 6, 12, and 24 weeks after BoNT-A injection in both groups. Although the within-group difference for each change was statistically significant (p < 0.0001), the between-group difference was not statistically significant (Figure 3).
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Figure 3. Changes in the Modified Tardieu Scale (MTS) of ankle dorsiflexion (DF) with knee flexion (KF) and knee extension (KE) states. In both the Botulax group and Botox group, ankle DF angles were significantly increased and maintained until 24 weeks after BoNT-A injection. The error bar indicates the standard deviation. * Statistically significant when compared between baseline data and post-injection data in the Botulax group; + Statistically significant when compared between baseline data and post-injection data in the Botox group.
The mean R1 of ankle dorsiflexion with knee flexion were −4.12◦ at baseline, 2.09◦ at week 6, at week 12, and −0.08◦ at week 24 in the Botulax group; in Botox group, these values were −4.76◦ , −0.08◦ , 3.08◦ , and 0.24◦ , respectively. Also, the mean R2 of ankle dorsiflexion with knee flexion were 14.31◦ at baseline, 19.40◦ at week 6, 20.21◦ at week 12, and 18.15◦ at week 24 in the Botulax group; in Botox group, these values were 15.19◦ , 20.01◦ , 20.71◦ , and 17.73◦ , respectively. These alterations showed that the mean R1 and R2 of ankle dorsiflexion with knee flexion changed in a positive direction from baseline to each time point in both groups. Although the within-group difference for each change was statistically significant (p < 0.001), the between-group difference was not statistically significant (Figure 3). 1.34◦
2.3. Gross Motor Function Measure (GMFM) The means of the GMFM-88 and GMFM-66 increased from baseline to each time point in both groups. Although the within-group difference for each change was statistically significant (all p < 0.0001), the between-group difference was not statistically significant (Table 3).
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Table 3. Changes in Gross Motor Function Measure (GMFM). Botulax Group (N = 73) GMFM
±SD
Mean
Within-Group Difference p-Value
Botox Group (N = 70)
±SD
Mean
Within-Group Difference p-Value
Between-Group Difference p-Value
GMFM-88 Pre-injection (Baseline) Post-injection 6 weeks Post-injection 12 weeks Post-injection 24 weeks Change (Week 6) Change (Week 12) Change (Week 24)
85.71 86.78 87.53 88.39 1.07 1.82 2.68
±13.90 ±13.22 ±12.83 ±12.36 ±2.37 ±3.20 ±4.23
Pre-injection (Baseline) Post-injection 6 weeks Post-injection 12 weeks Post-injection 24 weeks Change (Week 6) Change (Week 12) Change (Week 24)
70.50 71.53 72.45 73.66 1.04 1.95 3.16
±13.47 ±13.58 ±13.37 ±13.55 ±3.01 ±3.45 ±3.52
Efficacy and Safety of Letibotulinum Toxin A for the Treatment of Dynamic Equinus Foot Deformity in Children with Cerebral Palsy: A Randomized Controlled Trial Hyun Jung Chang 1,† ID , Bo Young Hong 2,† and Jeong-Yi Kwon 6, * 1 2 3 4 5 6
* †
ID
, Sang-Jee Lee 3 , Soyoung Lee 4 , Joo Hyun Park 5
Department of Physical Medicine and Rehabilitation, Samsung Changwon Hospital, Sungkyunkwan University School of Medicine, Changwon 51353, South Korea; [email protected] Department of Rehabilitation Medicine, St. Vincent’s Hospital, College of Medicine, The Catholic University of Korea, Suwon 16247, South Korea; [email protected] Department of Rehabilitation Medicine, Daejeon St. Mary’s Hospital, College of Medicine, The Catholic University of Korea, Daejeon 34943, South Korea; [email protected] Department of Rehabilitation Medicine, Keimyung University, Dongsan Medical Center, Daegu 41931, South Korea; [email protected] Department of Rehabilitation Medicine, Seoul St. Mary’s Hospital, College of Medicine, The Catholic University of Korea, Seoul 06591, South Korea; [email protected] Department of Physical and Rehabilitation Medicine, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul 06351, South Korea Correspondence: [email protected]; Tel.: +82-2-3410-1030 These authors contributed to this work equally.
Academic Editors: Jianlong Lou and James D. Marks Received: 12 July 2017; Accepted: 16 August 2017; Published: 18 August 2017
Abstract: The objective of this clinical trial was to compare the efficacy and safety of letibotulinum toxin A and onabotulinum toxin A for improving dynamic equinus foot deformity in children with cerebral palsy (CP). In total, 144 children with spastic CP who had dynamic equinus foot deformity were assigned randomly to the Botulax group (injection of letibotulinum toxin A) or the Botox group (injection of onabotulinum toxin A). The Physician’s Rating Scale (PRS), ankle plantar flexor spasticity using the Modified Tardieu Scale, the Gross Motor Function Measure (GMFM)-88, and the GMFM-66 were completed before injection and at 6, 12, and 24 weeks after injection. The PRS responder rate was 60.27% in the Botulax group and 61.43% in the Botox group at 12 weeks after treatment, and the lower limit of the 95% confidence interval for the between-group difference in responder rates was −17.16%, higher than the non-inferiority margin of −24.00%. The clinical efficacy and the safety profiles of the groups did not significantly differ. The results suggest that injection of letibotulinum toxin A is as effective and safe as that of onabotulinum toxin A for the treatment of dynamic equinus foot deformity in children with spastic CP. Keywords: cerebral palsy; spasticity; botulinum toxin; letibotulinum toxin; onabotulinum toxin
1. Introduction Cerebral palsy (CP), which is characterized by movement and posture disorders caused by non-progressive lesions in the developing brain, is the most common developmental disorder associated with lifelong motor impairment and disability [1,2]. Spasticity is a major impairment in children with CP, affecting approximately two-thirds of this population [3]. Equinus is a common gait abnormality in children with CP, resulting from spasticity of the ankle plantar flexor [4]. Toxins 2017, 9, 252; doi:10.3390/toxins9080252
www.mdpi.com/journal/toxins
Toxins 2017, 9, 252
2 of 11
Since the first reports in the early 1990s, botulinum toxin type-A (BoNT-A) has been used for the management of spasticity in the lower limbs of children with CP [5,6]. BoNT-A injections decrease spasticity locally by interfering with cholinergic transmission at the neuromuscular junction [7]. BoNT-A has been established as an effective treatment for the management of spastic equinus, as it improves gait, goal attainment, and function [8]. Various BoNT-A products are used for the management of spasticity, including onabotulinum toxin A (Botox, Allergan Inc., Irvine, CA, USA), abobotulinum toxin A (Dysport, Ipsen Ltd., Slough, Berkshire, UK), letibotulinum toxin A (Botulax, Hugel Inc., Chuncheon, Korea), and incobotulinum toxin A (Xeomine, Merz Pharmaceutical, Frankfurt, Germany) [9–11]. Each BoNT-A product acts by a similar mechanism but has different components. Thus, it is possible that each product presents different levels of efficacy and safety. Letibotulinum toxin A is a novel neurotoxin from the C. botulinum CBFC26 strain that shows high toxicity in mice [12]. Also, its toxin and 16S rRNA sequences are completely homologous to those of the ATCC 3502 Hall A strain of onabotulinum toxin A. Letibotulinum toxin A has been subjected to additional processes, including enzyme-free purification steps such as protamine sulfate precipitation, to eliminate nucleic acids, and diethylaminoethanol-sepharose chromatography, which could theoretically improve the quality of the product. However, few studies have assessed the efficacy and safety of letibotulinum toxin A in the treatment of spasticity [12]. Also, there has been no report on the effectiveness of letibotulinum toxin A in the management of spasticity in children with CP. When newly formulated BoNT-A products are manufactured, clinical trials are needed to demonstrate the efficacy and safety for each indication. Generally, studies on the safety and efficacy of BoNT-A have been performed using a comparative design involving onabotulinum toxin A. We hypothesized that the efficacy and safety of letibotulinum toxin A were not inferior to those of onabotulinum toxin A. The objective of this clinical trial was to compare the efficacy of letibotulinum toxin A (Botulax) with that of onabotulinum toxin A (Botox) for improving dynamic equinus foot deformity among children with CP, and to record any adverse events in the two groups. 2. Results In total, 144 subjects participated in the study, with 73 subjects randomly assigned to the Botulax group (injected with letibotulinum toxin A) and 71 assigned to the Botox group (injected with onabotulinum toxin A) (Figure 1).
Figure 1. Flow diagram.
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There were 42 (57.5%) males in the Botulax group and 49 (70.0%) in the Botox group, and there was no statistically significant difference in the gender distribution of the groups. The mean age of subjects was 4.67 years in the Botulax group and 5.44 years in the Botox group; this constituted a statistically significant between-group difference (p = 0.0408; Table 1). Table 1. Baseline demographic and clinical data (FA set = 143 subjects). Baseline Characteristics Male/female, n (%) Age (years), mean (SD) 2–4 years, n 5–7 years, n 8–10 years, n Body weight (kg), mean (SD) Type, n (%) Right unilateral Left unilateral Bilateral Previous BoNT-A injection, n (%) Number of previous BoNT-A injectrion, median (min-max) PRS, median (min-max) GMFM-88
Botulax Group (N = 73)
Botox Group (N = 70)
42 (57.5)/31 (42.5) 4.7 (2.0) 37 28 8 18.98 (6.47)
49 (70.0)/21 (30.0) 5.4 (2.3) 26 31 13 20.01 (6.98)
18 (24.7) 6 (8.2) 49 (67.1) 48 (65.8)
17 (24.3) 7 (10.0) 46 (65.7) 47 (67.1)
0.8604
2 (1–6)
3 (1–7)
0.146
6 (2–13) 85.7 (13.9)
6 (3–12) 85.7 (13.7)
0.4800 0.7140
p-Value 0.1214 0.0408 * 0.2020
0.3406 0.9336
FA: Full Analysis, PRS: Physician’s Rating Scale, GMFM: Gross Motor Function Measure. * Statistically significant when compared between Botulax group and Botox group (p < 0.05).
In terms of spastic CP types, unilateral CP was reported in 24 (32.9%) subjects, and bilateral CP in 49 (67.1%) in the Botulax group; in the Botox group, unilateral CP was reported in 24 (34.3%), and bilateral CP was reported in 46 (65.7%). There was no statistically significant difference in the distribution of CP types between the two groups. For BoNT injection history, 48 subjects (65.8%) were injected with BoNT-A, and 25 subjects (34.25%) were de novo patients in the Botulax group. In the Botox group, 47 subjects (67.1%) had a history of BoNT-A injection, and 23 subjects (32.9%) had never been injected with BoNT before screening. In both groups, there was no subject with BoNT-B injection history, and there was no statistically significant between-group difference in the distribution of BoNT injection history. For subjects with BoNT-A injection history, there was no subject with a previous history of hypersensitivity to BoNT-A. The mean number of BoNT-A injection was 2.6 times in the Botulax group and 3.06 times in the Botox group, which showed no statistically significant difference between groups. The mean doses of botulinum toxin injected in each group were 100.0 ± 32.9 U in the Botulax group and 106.1 ± 39.4 U in the Botox group. There was no significant difference between the two groups (p = 0.497). 2.1. Physician’s Rating Scale (PRS) 2.1.1. Responder Rate The responder rate (proportion of subjects determined to be responders) was 60.27% (44/73 subjects) in the Botulax group and 61.43% (43/70 subjects) in the Botox group at 12 weeks after BoNT-A injection, and the lower limit of the 95% confidence interval (CI) for the difference in the responder rate (−1.15%) between the Botulax group and the Botox group was −17.16%, which was higher than the non-inferiority margin of −24.00% (Table 2) [13].
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Table 2. Responder rate in the Physician’s Rating Scale (PRS), n (%). Assessment Week
Botulax Group (N = 73)
Botox Group (N = 70)
p-Value
Post-injection 6 weeks Post-injection 12 weeks Post-injection 24 weeks
42 (58.9) 44 (60.3) 35 (48.0)
36 (51.4) 43 (61.4) 29 (41.4)
0.3688 0.8876 0.4334
2.1.2. Mean Score The mean PRS score in the Botulax group was 6.82 at baseline, 9.33 at week 6, 9.43 at week 12, and 8.88 at week 24; these figures were 6.85, 8.95, 9.25, and 8.89, respectively, in the Botox group, suggesting that the PRS score increased from the baseline to each time point in both groups, and the changes were statistically significant (p < 0.0001; Figure 2). There was no statistically significant difference between the two groups in terms of changes in the PRS scores at 6, 12, or 24 weeks after BoNT-A injection.
Figure 2. Changes in Physician’s Rating Scale (PRS). In both the Botulax group and Botox group, PRS score was significantly increased and maintained until 24 weeks after BoNT-A injection. The error bar indicates the standard deviation. * Statistically significant when compared between baseline data and post-injection data in the Botulax group; + Statistically significant when compared between baseline data and post-injection data in the Botox group.
2.2. Modified Tardieu Scale (MTS) The mean R1 of ankle dorsiflexion with knee extension were −14.19◦ at baseline, −6.24◦ at week 6, −5.83◦ at week 12, and −8.74◦ at week 24 in the Botulax group; these figures were −16.06◦ , −8.24◦ , −6.59◦ , and −9.14◦ , respectively, in the Botox group. And the mean R2 of ankle dorsiflexion with knee extension were 4.76◦ at baseline, 13.16◦ at week 6, 14.33◦ at week 12, and 9.87◦ at week 24 in the Botulax group; these figures were 4.48◦ , 11.96◦ , 12.19◦ , and 9.75◦ , respectively, in the Botox group, which demonstrated that the mean R1 and R2 of ankle dorsiflexion with knee extension changed in a positive direction from the baseline to 6, 12, and 24 weeks after BoNT-A injection in both groups. Although the within-group difference for each change was statistically significant (p < 0.0001), the between-group difference was not statistically significant (Figure 3).
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Figure 3. Changes in the Modified Tardieu Scale (MTS) of ankle dorsiflexion (DF) with knee flexion (KF) and knee extension (KE) states. In both the Botulax group and Botox group, ankle DF angles were significantly increased and maintained until 24 weeks after BoNT-A injection. The error bar indicates the standard deviation. * Statistically significant when compared between baseline data and post-injection data in the Botulax group; + Statistically significant when compared between baseline data and post-injection data in the Botox group.
The mean R1 of ankle dorsiflexion with knee flexion were −4.12◦ at baseline, 2.09◦ at week 6, at week 12, and −0.08◦ at week 24 in the Botulax group; in Botox group, these values were −4.76◦ , −0.08◦ , 3.08◦ , and 0.24◦ , respectively. Also, the mean R2 of ankle dorsiflexion with knee flexion were 14.31◦ at baseline, 19.40◦ at week 6, 20.21◦ at week 12, and 18.15◦ at week 24 in the Botulax group; in Botox group, these values were 15.19◦ , 20.01◦ , 20.71◦ , and 17.73◦ , respectively. These alterations showed that the mean R1 and R2 of ankle dorsiflexion with knee flexion changed in a positive direction from baseline to each time point in both groups. Although the within-group difference for each change was statistically significant (p < 0.001), the between-group difference was not statistically significant (Figure 3). 1.34◦
2.3. Gross Motor Function Measure (GMFM) The means of the GMFM-88 and GMFM-66 increased from baseline to each time point in both groups. Although the within-group difference for each change was statistically significant (all p < 0.0001), the between-group difference was not statistically significant (Table 3).
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Table 3. Changes in Gross Motor Function Measure (GMFM). Botulax Group (N = 73) GMFM
±SD
Mean
Within-Group Difference p-Value
Botox Group (N = 70)
±SD
Mean
Within-Group Difference p-Value
Between-Group Difference p-Value
GMFM-88 Pre-injection (Baseline) Post-injection 6 weeks Post-injection 12 weeks Post-injection 24 weeks Change (Week 6) Change (Week 12) Change (Week 24)
85.71 86.78 87.53 88.39 1.07 1.82 2.68
±13.90 ±13.22 ±12.83 ±12.36 ±2.37 ±3.20 ±4.23
Pre-injection (Baseline) Post-injection 6 weeks Post-injection 12 weeks Post-injection 24 weeks Change (Week 6) Change (Week 12) Change (Week 24)
70.50 71.53 72.45 73.66 1.04 1.95 3.16
±13.47 ±13.58 ±13.37 ±13.55 ±3.01 ±3.45 ±3.52
