Trial Outcomes & Findings for BOTOX® Treatment in Pediatric Lower Limb Spasticity (NCT NCT01603628)
NCT ID: NCT01603628
Last Updated: 2018-08-14
Results Overview
The MAS-B was used to evaluate spasticity based on grading the resistance encountered in the principal muscle group (elbow and wrist) by means of passively moving a limb through its range of motion at a study specified velocity. The resistance encountered to passive stretch was graded using a 6-point scale where: 0=no increase in muscle tone (best) to 4=affected part(s) rigid in flexion or extension (worst). For analysis purposes, the MAS-B was recoded as follows: 0=1, 1=1, 1+=2, 2=3, 3=4, 4=5. The scores at Weeks 4 and 6 were averaged. A Mixed Model Repeated Measures (MMRM) model was used for analysis. A negative change from Baseline indicates improvement.
Recruitment status
COMPLETED
Study phase
PHASE3
Target enrollment
384 participants
Primary outcome timeframe
Baseline (Day 1) to Weeks 4 and 6
Results posted on
2018-08-14
Participant Flow
Pediatric participants with lower limb spasticity were randomized 1:1:1 to one of three treatment groups: BOTOX® 4 or 8 U/kg (unit per kilogram) or placebo.
Participant milestones
| Measure |
BOTOX® 8 U/kg
Participants received intramuscular injections of BOTOX® (botulinum toxin Type A) 8 units (U) per kg of body weight (8 U/kg) into specified muscles of the lower limb on Day 1. Participants received weekly physical therapy (PT).
|
BOTOX® 4 U/kg
Participants received intramuscular injections of BOTOX® (botulinum toxin Type A) 4 U per kg of body weight (4 U/kg) into specified muscles of the lower limb on Day 1. Participants received weekly PT.
|
Placebo
Participants received intramuscular injections of normal saline (placebo) into specified muscles of the lower limb. Participants received weekly PT.
|
|---|---|---|---|
|
Overall Study
STARTED
|
128
|
126
|
130
|
|
Overall Study
Safety Population: Received Treatment
|
128
|
126
|
128
|
|
Overall Study
COMPLETED
|
125
|
123
|
128
|
|
Overall Study
NOT COMPLETED
|
3
|
3
|
2
|
Reasons for withdrawal
| Measure |
BOTOX® 8 U/kg
Participants received intramuscular injections of BOTOX® (botulinum toxin Type A) 8 units (U) per kg of body weight (8 U/kg) into specified muscles of the lower limb on Day 1. Participants received weekly physical therapy (PT).
|
BOTOX® 4 U/kg
Participants received intramuscular injections of BOTOX® (botulinum toxin Type A) 4 U per kg of body weight (4 U/kg) into specified muscles of the lower limb on Day 1. Participants received weekly PT.
|
Placebo
Participants received intramuscular injections of normal saline (placebo) into specified muscles of the lower limb. Participants received weekly PT.
|
|---|---|---|---|
|
Overall Study
Personal Reasons
|
1
|
1
|
2
|
|
Overall Study
Protocol Violation
|
1
|
1
|
0
|
|
Overall Study
Lost to Follow-up
|
0
|
1
|
0
|
|
Overall Study
Other Miscellaneous Reason
|
1
|
0
|
0
|
Baseline Characteristics
2 participants in the Placebo arm are not included in the analysis.
Baseline characteristics by cohort
| Measure |
BOTOX® 8 U/kg
n=128 Participants
Participants received intramuscular injections of BOTOX® (botulinum toxin Type A) 8 U per kg of body weight (8 U/kg) into specified muscles of the lower limb on Day 1. Participants received weekly physical therapy (PT).
|
BOTOX® 4 U/kg
n=126 Participants
Participants received intramuscular injections of BOTOX® (botulinum toxin Type A) 4 U per kg of body weight (4 U/kg) into specified muscles of the lower limb on Day 1. Participants received weekly PT.
|
Placebo
n=130 Participants
Participants received intramuscular injections of normal saline (placebo) into specified muscles of the lower limb. Participants received weekly PT.
|
Total
n=384 Participants
Total of all reporting groups
|
|---|---|---|---|---|
|
Age, Continuous
|
6.7 years
STANDARD_DEVIATION 3.90 • n=128 Participants
|
6.4 years
STANDARD_DEVIATION 3.58 • n=126 Participants
|
6.6 years
STANDARD_DEVIATION 3.89 • n=130 Participants
|
6.6 years
STANDARD_DEVIATION 3.79 • n=384 Participants
|
|
Sex: Female, Male
Female
|
57 Participants
n=128 Participants
|
58 Participants
n=126 Participants
|
62 Participants
n=130 Participants
|
177 Participants
n=384 Participants
|
|
Sex: Female, Male
Male
|
71 Participants
n=128 Participants
|
68 Participants
n=126 Participants
|
68 Participants
n=130 Participants
|
207 Participants
n=384 Participants
|
|
Race/Ethnicity, Customized
White
|
77 Participants
n=128 Participants
|
76 Participants
n=126 Participants
|
80 Participants
n=130 Participants
|
233 Participants
n=384 Participants
|
|
Race/Ethnicity, Customized
Black
|
2 Participants
n=128 Participants
|
3 Participants
n=126 Participants
|
4 Participants
n=130 Participants
|
9 Participants
n=384 Participants
|
|
Race/Ethnicity, Customized
Asian
|
42 Participants
n=128 Participants
|
35 Participants
n=126 Participants
|
38 Participants
n=130 Participants
|
115 Participants
n=384 Participants
|
|
Race/Ethnicity, Customized
Hispanic
|
7 Participants
n=128 Participants
|
10 Participants
n=126 Participants
|
6 Participants
n=130 Participants
|
23 Participants
n=384 Participants
|
|
Race/Ethnicity, Customized
Other Not Specified
|
0 Participants
n=128 Participants
|
1 Participants
n=126 Participants
|
3 Participants
n=130 Participants
|
4 Participants
n=384 Participants
|
|
Modified Ashworth Scale-Bohannon (MAS-B) Ankle Score with Knee Extended
|
3.5 score on a scale
STANDARD_DEVIATION 0.52 • n=128 Participants • 2 participants in the Placebo arm are not included in the analysis.
|
3.5 score on a scale
STANDARD_DEVIATION 0.53 • n=126 Participants • 2 participants in the Placebo arm are not included in the analysis.
|
3.5 score on a scale
STANDARD_DEVIATION 0.50 • n=128 Participants • 2 participants in the Placebo arm are not included in the analysis.
|
3.5 score on a scale
STANDARD_DEVIATION 0.52 • n=382 Participants • 2 participants in the Placebo arm are not included in the analysis.
|
PRIMARY outcome
Timeframe: Baseline (Day 1) to Weeks 4 and 6Population: Participants from the mITT population, all randomized participants with a valid MAS-B baseline ankle score with knee extended and at least one post-baseline measurement at Weeks 2, 4, or 6 for the MAS-B of the ankle score with knee extended and the CGI by physician, with data available for analysis.
The MAS-B was used to evaluate spasticity based on grading the resistance encountered in the principal muscle group (elbow and wrist) by means of passively moving a limb through its range of motion at a study specified velocity. The resistance encountered to passive stretch was graded using a 6-point scale where: 0=no increase in muscle tone (best) to 4=affected part(s) rigid in flexion or extension (worst). For analysis purposes, the MAS-B was recoded as follows: 0=1, 1=1, 1+=2, 2=3, 3=4, 4=5. The scores at Weeks 4 and 6 were averaged. A Mixed Model Repeated Measures (MMRM) model was used for analysis. A negative change from Baseline indicates improvement.
Outcome measures
| Measure |
BOTOX® 8 U/kg
n=123 Participants
Participants received intramuscular injections of BOTOX® (botulinum toxin Type A) 8 U per kg of body weight (8 U/kg) into specified muscles of the lower limb on Day 1. Participants received weekly physical therapy (PT).
|
BOTOX® 4 U/kg
n=119 Participants
Participants received intramuscular injections of BOTOX® (botulinum toxin Type A) 4 U per kg of body weight (4 U/kg) into specified muscles of the lower limb on Day 1. Participants received weekly PT.
|
Placebo
n=125 Participants
Participants received intramuscular injections of normal saline (placebo) into specified muscles of the lower limb. Participants received weekly PT.
|
|---|---|---|---|
|
Average Change From Baseline in Modified Ashworth Scale-Bohannon (MAS-B) Ankle Score With Knee Extended at Weeks 4 and 6
|
-1.06 score on a scale
Standard Error 0.071
|
-1.01 score on a scale
Standard Error 0.072
|
-0.80 score on a scale
Standard Error 0.071
|
PRIMARY outcome
Timeframe: Weeks 4 and 6Population: Participants from the mITT population, all randomized participants with a valid MAS-B baseline ankle score with knee extended and at least one post-baseline measurement at Weeks 2, 4, or 6 for the MAS-B of the ankle score with knee extended and the CGI by physician, with data available for analysis.
The CGI of overall change (improvement or worsening) was assessed by the physician considering the participant's clinical condition and severity of side effects using a 9-point scale where: -4=very marked worsening to +4=very marked improvement. The scores at Weeks 4 and 6 were averaged. A Mixed Model Repeated Measures (MMRM) model was used for analysis.
Outcome measures
| Measure |
BOTOX® 8 U/kg
n=123 Participants
Participants received intramuscular injections of BOTOX® (botulinum toxin Type A) 8 U per kg of body weight (8 U/kg) into specified muscles of the lower limb on Day 1. Participants received weekly physical therapy (PT).
|
BOTOX® 4 U/kg
n=118 Participants
Participants received intramuscular injections of BOTOX® (botulinum toxin Type A) 4 U per kg of body weight (4 U/kg) into specified muscles of the lower limb on Day 1. Participants received weekly PT.
|
Placebo
n=124 Participants
Participants received intramuscular injections of normal saline (placebo) into specified muscles of the lower limb. Participants received weekly PT.
|
|---|---|---|---|
|
Average Clinical Global Impression (CGI) of Overall Change by Physician at Weeks 4 and 6
|
1.65 score on a scale
Standard Error 0.090
|
1.49 score on a scale
Standard Error 0.091
|
1.36 score on a scale
Standard Error 0.089
|
SECONDARY outcome
Timeframe: Weeks 8 and 12Population: Participants from the mITT population, all randomized participants with a valid MAS-B baseline ankle score with knee extended and at least one post-baseline measurement at Weeks 2, 4, or 6 for the MAS-B of the ankle score with knee extended and the CGI by physician, with data available for analysis at the given time-point.
Two functional goals, one active and one passive, were selected by the participant and family in consultation with the physician investigator and/or treating physical therapist relative to the lower limb impairment due to spasticity. The physician assessed the achievement of the goals using a 6-point scale: where -3=worse than start to +2=much more than expected: improvements clearly exceed the defined therapeutic goal. An Analysis of Covariance (ANCOVA) model was used for analysis.
Outcome measures
| Measure |
BOTOX® 8 U/kg
n=127 Participants
Participants received intramuscular injections of BOTOX® (botulinum toxin Type A) 8 U per kg of body weight (8 U/kg) into specified muscles of the lower limb on Day 1. Participants received weekly physical therapy (PT).
|
BOTOX® 4 U/kg
n=125 Participants
Participants received intramuscular injections of BOTOX® (botulinum toxin Type A) 4 U per kg of body weight (4 U/kg) into specified muscles of the lower limb on Day 1. Participants received weekly PT.
|
Placebo
n=129 Participants
Participants received intramuscular injections of normal saline (placebo) into specified muscles of the lower limb. Participants received weekly PT.
|
|---|---|---|---|
|
Goal Attainment Score (GAS) as Assessed by Physician Using a 6-Point Scale
Week 12, Passive Goal
|
0.40 score on a scale
Standard Error 0.114
|
0.27 score on a scale
Standard Error 0.114
|
0.00 score on a scale
Standard Error 0.112
|
|
Goal Attainment Score (GAS) as Assessed by Physician Using a 6-Point Scale
Week 8, Active Goal
|
0.10 score on a scale
Standard Error 0.108
|
-0.03 score on a scale
Standard Error 0.108
|
-0.31 score on a scale
Standard Error 0.105
|
|
Goal Attainment Score (GAS) as Assessed by Physician Using a 6-Point Scale
Week 8, Passive Goal
|
0.19 score on a scale
Standard Error 0.115
|
0.18 score on a scale
Standard Error 0.114
|
-0.26 score on a scale
Standard Error 0.111
|
|
Goal Attainment Score (GAS) as Assessed by Physician Using a 6-Point Scale
Week 12, Active Goal
|
0.37 score on a scale
Standard Error 0.112
|
0.09 score on a scale
Standard Error 0.113
|
-0.12 score on a scale
Standard Error 0.111
|
SECONDARY outcome
Timeframe: Baseline (Day 1) to Weeks 2, 4, 6, 8 and 12Population: Participants from the mITT population, all randomized participants with a valid MAS-B baseline ankle score with knee extended and at least one post-baseline measurement at Weeks 2, 4, or 6 for the MAS-B of the ankle score with knee extended and the CGI by physician, with data available for analysis at the given time-point.
The MTS measured the difference between slow and fast range of motion (R2-R1) and respective change from baseline to each posttreatment office visit. The MTS of the ankle was used to determine the passive range of movement at different movement velocities, V1 (as slow as possible) and V3 (as fast as possible) with the relative difference between a slow and fast velocity passive stretch determining the dynamic component of the muscle contracture for the joint. The investigator measured 2 joint angles by goniometer: the R1 angle which is the angle of catch after a fast velocity (V3) stretch and the R2 angle defined as the passive joint range of movement following a slow velocity (V1) stretch. The R2-R1 value indicated the level of the dynamic component of spasticity in the joint. The difference between R2 and R1 range of motion and respective change from baseline to each posttreatment office visit on the MTS was derived. An Analysis of Covariance (ANCOVA) model was used for analysis.
Outcome measures
| Measure |
BOTOX® 8 U/kg
n=127 Participants
Participants received intramuscular injections of BOTOX® (botulinum toxin Type A) 8 U per kg of body weight (8 U/kg) into specified muscles of the lower limb on Day 1. Participants received weekly physical therapy (PT).
|
BOTOX® 4 U/kg
n=125 Participants
Participants received intramuscular injections of BOTOX® (botulinum toxin Type A) 4 U per kg of body weight (4 U/kg) into specified muscles of the lower limb on Day 1. Participants received weekly PT.
|
Placebo
n=129 Participants
Participants received intramuscular injections of normal saline (placebo) into specified muscles of the lower limb. Participants received weekly PT.
|
|---|---|---|---|
|
Change From Baseline in Severity of Spasticity of the Ankle With Knee Extended and Knee Flexed (R2-R1) Calculated Using the Modified Tardieu Scale (MTS)
Change from Baseline to Week 2
|
-4.44 degrees
Standard Error 1.023
|
-5.69 degrees
Standard Error 1.024
|
-2.44 degrees
Standard Error 1.0101
|
|
Change From Baseline in Severity of Spasticity of the Ankle With Knee Extended and Knee Flexed (R2-R1) Calculated Using the Modified Tardieu Scale (MTS)
Change from Baseline to Week 4
|
-6.11 degrees
Standard Error 1.134
|
-6.80 degrees
Standard Error 1.135
|
-4.69 degrees
Standard Error 1.121
|
|
Change From Baseline in Severity of Spasticity of the Ankle With Knee Extended and Knee Flexed (R2-R1) Calculated Using the Modified Tardieu Scale (MTS)
Change from Baseline to Week 6
|
-6.65 degrees
Standard Error 1.029
|
-7.23 degrees
Standard Error 1.049
|
-3.32 degrees
Standard Error 1.029
|
|
Change From Baseline in Severity of Spasticity of the Ankle With Knee Extended and Knee Flexed (R2-R1) Calculated Using the Modified Tardieu Scale (MTS)
Change from Baseline to Week 8
|
-5.42 degrees
Standard Error 1.317
|
-5.82 degrees
Standard Error 1.308
|
-3.36 degrees
Standard Error 1.291
|
|
Change From Baseline in Severity of Spasticity of the Ankle With Knee Extended and Knee Flexed (R2-R1) Calculated Using the Modified Tardieu Scale (MTS)
Change from Baseline to Week 12
|
-4.59 degrees
Standard Error 1.070
|
-3.07 degrees
Standard Error 1.074
|
-1.98 degrees
Standard Error 1.057
|
Adverse Events
BOTOX® 8 U/kg
Serious events: 0 serious events
Other events: 24 other events
Deaths: 0 deaths
BOTOX® 4 U/kg
Serious events: 3 serious events
Other events: 26 other events
Deaths: 0 deaths
Placebo
Serious events: 4 serious events
Other events: 35 other events
Deaths: 0 deaths
Serious adverse events
| Measure |
BOTOX® 8 U/kg
n=128 participants at risk
Participants received intramuscular injections of BOTOX® (botulinum toxin Type A) 8 U per kg of body weight (8 U/kg) into specified muscles of the lower limb on Day 1. Participants received weekly physical therapy (PT).
|
BOTOX® 4 U/kg
n=126 participants at risk
Participants received intramuscular injections of BOTOX® (botulinum toxin Type A) 4 U per kg of body weight (4 U/kg) into specified muscles of the lower limb on Day 1. Participants received weekly PT.
|
Placebo
n=128 participants at risk
Participants received intramuscular injections of normal saline (placebo) into specified muscles of the lower limb. Participants received weekly PT.
|
|---|---|---|---|
|
Cardiac disorders
Extrasystoles
|
0.00%
0/128 • Baseline (Day 1) to the end of study (Week 12)
The Safety Population, all treated participants based on the treatment received, was used to determine the number of participants at risk for Serious Adverse Events and Adverse Events.
|
0.79%
1/126 • Baseline (Day 1) to the end of study (Week 12)
The Safety Population, all treated participants based on the treatment received, was used to determine the number of participants at risk for Serious Adverse Events and Adverse Events.
|
0.00%
0/128 • Baseline (Day 1) to the end of study (Week 12)
The Safety Population, all treated participants based on the treatment received, was used to determine the number of participants at risk for Serious Adverse Events and Adverse Events.
|
|
Cardiac disorders
Tachycardia
|
0.00%
0/128 • Baseline (Day 1) to the end of study (Week 12)
The Safety Population, all treated participants based on the treatment received, was used to determine the number of participants at risk for Serious Adverse Events and Adverse Events.
|
0.79%
1/126 • Baseline (Day 1) to the end of study (Week 12)
The Safety Population, all treated participants based on the treatment received, was used to determine the number of participants at risk for Serious Adverse Events and Adverse Events.
|
0.00%
0/128 • Baseline (Day 1) to the end of study (Week 12)
The Safety Population, all treated participants based on the treatment received, was used to determine the number of participants at risk for Serious Adverse Events and Adverse Events.
|
|
Infections and infestations
Gastoeneteritis
|
0.00%
0/128 • Baseline (Day 1) to the end of study (Week 12)
The Safety Population, all treated participants based on the treatment received, was used to determine the number of participants at risk for Serious Adverse Events and Adverse Events.
|
0.00%
0/126 • Baseline (Day 1) to the end of study (Week 12)
The Safety Population, all treated participants based on the treatment received, was used to determine the number of participants at risk for Serious Adverse Events and Adverse Events.
|
0.78%
1/128 • Baseline (Day 1) to the end of study (Week 12)
The Safety Population, all treated participants based on the treatment received, was used to determine the number of participants at risk for Serious Adverse Events and Adverse Events.
|
|
Nervous system disorders
Seizure
|
0.00%
0/128 • Baseline (Day 1) to the end of study (Week 12)
The Safety Population, all treated participants based on the treatment received, was used to determine the number of participants at risk for Serious Adverse Events and Adverse Events.
|
0.79%
1/126 • Baseline (Day 1) to the end of study (Week 12)
The Safety Population, all treated participants based on the treatment received, was used to determine the number of participants at risk for Serious Adverse Events and Adverse Events.
|
1.6%
2/128 • Baseline (Day 1) to the end of study (Week 12)
The Safety Population, all treated participants based on the treatment received, was used to determine the number of participants at risk for Serious Adverse Events and Adverse Events.
|
|
Nervous system disorders
Radicular Pain
|
0.00%
0/128 • Baseline (Day 1) to the end of study (Week 12)
The Safety Population, all treated participants based on the treatment received, was used to determine the number of participants at risk for Serious Adverse Events and Adverse Events.
|
0.00%
0/126 • Baseline (Day 1) to the end of study (Week 12)
The Safety Population, all treated participants based on the treatment received, was used to determine the number of participants at risk for Serious Adverse Events and Adverse Events.
|
0.78%
1/128 • Baseline (Day 1) to the end of study (Week 12)
The Safety Population, all treated participants based on the treatment received, was used to determine the number of participants at risk for Serious Adverse Events and Adverse Events.
|
|
Respiratory, thoracic and mediastinal disorders
Tonsillar hypertrophy
|
0.00%
0/128 • Baseline (Day 1) to the end of study (Week 12)
The Safety Population, all treated participants based on the treatment received, was used to determine the number of participants at risk for Serious Adverse Events and Adverse Events.
|
0.79%
1/126 • Baseline (Day 1) to the end of study (Week 12)
The Safety Population, all treated participants based on the treatment received, was used to determine the number of participants at risk for Serious Adverse Events and Adverse Events.
|
0.00%
0/128 • Baseline (Day 1) to the end of study (Week 12)
The Safety Population, all treated participants based on the treatment received, was used to determine the number of participants at risk for Serious Adverse Events and Adverse Events.
|
Other adverse events
| Measure |
BOTOX® 8 U/kg
n=128 participants at risk
Participants received intramuscular injections of BOTOX® (botulinum toxin Type A) 8 U per kg of body weight (8 U/kg) into specified muscles of the lower limb on Day 1. Participants received weekly physical therapy (PT).
|
BOTOX® 4 U/kg
n=126 participants at risk
Participants received intramuscular injections of BOTOX® (botulinum toxin Type A) 4 U per kg of body weight (4 U/kg) into specified muscles of the lower limb on Day 1. Participants received weekly PT.
|
Placebo
n=128 participants at risk
Participants received intramuscular injections of normal saline (placebo) into specified muscles of the lower limb. Participants received weekly PT.
|
|---|---|---|---|
|
General disorders
Pyrexia
|
3.9%
5/128 • Baseline (Day 1) to the end of study (Week 12)
The Safety Population, all treated participants based on the treatment received, was used to determine the number of participants at risk for Serious Adverse Events and Adverse Events.
|
6.3%
8/126 • Baseline (Day 1) to the end of study (Week 12)
The Safety Population, all treated participants based on the treatment received, was used to determine the number of participants at risk for Serious Adverse Events and Adverse Events.
|
5.5%
7/128 • Baseline (Day 1) to the end of study (Week 12)
The Safety Population, all treated participants based on the treatment received, was used to determine the number of participants at risk for Serious Adverse Events and Adverse Events.
|
|
Infections and infestations
Viral upper respiratory tract infection
|
9.4%
12/128 • Baseline (Day 1) to the end of study (Week 12)
The Safety Population, all treated participants based on the treatment received, was used to determine the number of participants at risk for Serious Adverse Events and Adverse Events.
|
11.1%
14/126 • Baseline (Day 1) to the end of study (Week 12)
The Safety Population, all treated participants based on the treatment received, was used to determine the number of participants at risk for Serious Adverse Events and Adverse Events.
|
17.2%
22/128 • Baseline (Day 1) to the end of study (Week 12)
The Safety Population, all treated participants based on the treatment received, was used to determine the number of participants at risk for Serious Adverse Events and Adverse Events.
|
|
Infections and infestations
Upper respiratory tract infection
|
6.2%
8/128 • Baseline (Day 1) to the end of study (Week 12)
The Safety Population, all treated participants based on the treatment received, was used to determine the number of participants at risk for Serious Adverse Events and Adverse Events.
|
7.9%
10/126 • Baseline (Day 1) to the end of study (Week 12)
The Safety Population, all treated participants based on the treatment received, was used to determine the number of participants at risk for Serious Adverse Events and Adverse Events.
|
7.0%
9/128 • Baseline (Day 1) to the end of study (Week 12)
The Safety Population, all treated participants based on the treatment received, was used to determine the number of participants at risk for Serious Adverse Events and Adverse Events.
|
Additional Information
Results disclosure agreements
- Principal investigator is a sponsor employee A disclosure restriction on the PI is that the sponsor can review results communications prior to public release and can embargo communications regarding trial results for a period that is less than or equal to 90 days from the time submitted to the sponsor for review. The sponsor cannot require changes to the communication and cannot extend the embargo.
- Publication restrictions are in place
Restriction type: OTHER