Muscle Spasticity
Conditions
Brief summary
This study will evaluate the safety and efficacy of BOTOX® in the treatment of adult post-stroke lower limb spasticity.
Interventions
BIOLOGICALbotulinum toxin Type A
Double-Blind Study Phase (12 weeks): On Day 1, botulinum toxin Type A 300 U will be given by intramuscular injections into specified muscles of the lower limb, and an optional dose of 100 U may be injected into additional lower limb muscles. Open Label Study Phase: Up to 3 treatments with botulinum toxin Type A up to 400 U will be given by intramuscular injections to the lower limb approximately every 12 weeks over a 42 week period.
DRUGNormal Saline
Double-Blind Study Phase (12 weeks): On Day 1, normal saline (placebo) will be given by intramuscular injections into specified muscles of the lower limb, and optional injections may be administered into additional lower limb muscles.
Sponsors
Allergan
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
QUADRUPLE (Subject, Caregiver, Investigator, Outcomes Assessor)
Eligibility
Sex/Gender
ALL
Age
18 Years to 85 Years
Healthy volunteers
No
Inclusion criteria
* Diagnosis of post-stroke lower limb spasticity for at least 3 months * Minimum body weight of 50 kg * Never treated with botulinum toxin of any serotype for any reason, or if previously treated with botulinum toxin of any serotype, if previously treated for spasticity in the affected lower limb, must have been administered * 20 weeks before Day 1, or if previously treated for any other indication must have been administered ≥12 weeks prior to Day 1
Exclusion criteria
* Spasticity in the opposite leg that requires treatment * Casting of the study limb within 6 months or planned casting during the first 12 weeks of the study * Treatment modalities in the study limb including ultrasound, electrical nerve stimulation, electrical stimulation, acupuncture within 1 month of Day 1 or treatments planned during the study * Not able to perform 10 meter walking test independently with or without assistive device * Diagnosis of myasthenia gravis, Eaton-Lambert syndrome, or amyotrophic lateral sclerosis
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Change From Baseline in Modified Ashworth Scale-Bohannon (MAS-B) Score of Ankle Plantar Flexors Using a 6-Point Scale | Baseline, 6 Weeks | The MAS-B is a 6-point scale used to evaluate spasticity based on grading the resistance encountered in the ankle flexors by passively moving the ankle plantar flexor muscles through their range of motion. The score ranges from 0 (no increase in muscle tone) to 4 (affected part(s) rigid in flexion or extension). Scores are converted to a 0 to 5 grade. The average of the weeks 4 and 6 MAS-B ankle change from baseline is the primary end point. A negative number change from baseline indicates an improvement and a positive number change from baseline indicates a worsening. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Clinical Global Impression (CGI) of Overall Change by Physician Using a 9-Point Scale | Baseline, 6 weeks | The CGI is a 9-point scale evaluating change from baseline status by the Physician. Scores range from +4 (very marked improvement) to -4 (very marked worsening). The average of the weeks 4 and 6 CGI by Physician score is used as a secondary end point. Higher scores indicate a greater improvement from baseline. |
| Goal Attainment Scores on the 6-Point Physician-Assessed Goal Attainment Scale (GAS) | Week 8 | The physician-assessed GAS is an individualized, goal-oriented 6-point scale used to track functional improvement toward active and passive goals. GAS scoring ranged from -3 to 2 (-3 = worse than start; 0 = expected goal/attained the defined therapeutic goal; 2 = much more than expected/improvements clearly exceeded the defined therapeutic goal). Active and Passive Goal scores are presented. |
| Change From Baseline in Average Pain Score While Walking on the 11-Point Pain Scale | Baseline, Week 6 | The patient is asked to select a number that best describes his/her pain while walking on an 11-point scale from 0 = no pain to 10 = pain as bad as can be imagined. Patients are instructed to recall their average pain in the study limb during the 48-hour period prior to the visit. Patients with a baseline pain score \>0 are included in the analyses. |
| Change From Baseline in Modified Ashworth Scale-Bohannon (MAS-B) Score of Optional Muscles Using a 6-Point Scale | Baseline, Week 6 | The MAS-B is a 6-point scale used to evaluate spasticity based on grading the resistance encountered in the optional muscles by passively moving the muscles through their range of motion. Optional muscles treated include: Rectus Femoris, Flexor Digitorum Longus, Flexor Hallucis Longus, and Extensor Hallucis. The scores range from 0 (no increase in muscle tone) to 4 (affected part(s) rigid in flexion or extension). Scores are converted to a 0 to 5 grade. A negative number change from baseline indicates an improvement and a positive number change from baseline indicates a worsening. |
Countries
Canada, Czechia, Germany, Hungary, Poland, Russia, South Korea, United Kingdom, United States
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| Botulinum Toxin Type A Double-Blind Study Phase (12 weeks): On Day 1, botulinum toxin Type A 300 U will be given by intramuscular injections into specified muscles of the lower limb, and an optional dose of 100 U may be injected into additional lower limb muscles. Open Label Study Phase: Up to 3 treatments with botulinum toxin Type A up to 400 U will be given by intramuscular injections to the lower limb approximately every 12 weeks over a 42 week period. | 233 |
| Normal Saline (Placebo) Followed by Botulinum Toxin Type A Double-Blind Study Phase (12 weeks): On Day 1, normal saline (placebo) will be given by intramuscular injections into specified muscles of the lower limb, and optional injections may be administered into additional lower limb muscles. Open Label Study Phase: Up to 3 treatments with botulinum toxin Type A up to 400 U will be given by intramuscular injections to the lower limb approximately every 12 weeks over a 42 week period. | 235 |
| Total | 468 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Overall Study | Adverse Event | 9 | 8 |
| Overall Study | Lost to Follow-up | 3 | 3 |
| Overall Study | Other Reasons | 5 | 3 |
| Overall Study | Personal Reasons | 10 | 11 |
| Overall Study | Protocol Violation | 2 | 1 |
Baseline characteristics
| Characteristic | Botulinum Toxin Type A | Normal Saline (Placebo) Followed by Botulinum Toxin Type A | Total |
|---|---|---|---|
| Age, Continuous | 56.0 Years STANDARD_DEVIATION 12.6 | 57.0 Years STANDARD_DEVIATION 11.88 | 56.5 Years STANDARD_DEVIATION 12.24 |
| Sex: Female, Male Female | 85 Participants | 80 Participants | 165 Participants |
| Sex: Female, Male Male | 148 Participants | 155 Participants | 303 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — |
| other Total, other adverse events | 0 / 231 | 0 / 233 |
| serious Total, serious adverse events | 10 / 231 | 9 / 233 |
Outcome results
Primary
Change From Baseline in Modified Ashworth Scale-Bohannon (MAS-B) Score of Ankle Plantar Flexors Using a 6-Point Scale
The MAS-B is a 6-point scale used to evaluate spasticity based on grading the resistance encountered in the ankle flexors by passively moving the ankle plantar flexor muscles through their range of motion. The score ranges from 0 (no increase in muscle tone) to 4 (affected part(s) rigid in flexion or extension). Scores are converted to a 0 to 5 grade. The average of the weeks 4 and 6 MAS-B ankle change from baseline is the primary end point. A negative number change from baseline indicates an improvement and a positive number change from baseline indicates a worsening.
Time frame: Baseline, 6 Weeks
Population: Intent-to-Treat: all randomized patients who were analyzed according to randomization assignment, regardless of treatment actually received
| Arm | Measure | Group | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|---|
| Botulinum Toxin Type A | Change From Baseline in Modified Ashworth Scale-Bohannon (MAS-B) Score of Ankle Plantar Flexors Using a 6-Point Scale | Baseline | 4.1 Scores on a Scale | Standard Deviation 0.27 |
| Botulinum Toxin Type A | Change From Baseline in Modified Ashworth Scale-Bohannon (MAS-B) Score of Ankle Plantar Flexors Using a 6-Point Scale | Change from Baseline at 6 weeks | -0.81 Scores on a Scale | Standard Deviation 0.874 |
| Normal Saline (Placebo) Followed by Botulinum Toxin Type A | Change From Baseline in Modified Ashworth Scale-Bohannon (MAS-B) Score of Ankle Plantar Flexors Using a 6-Point Scale | Baseline | 4.1 Scores on a Scale | Standard Deviation 0.25 |
| Normal Saline (Placebo) Followed by Botulinum Toxin Type A | Change From Baseline in Modified Ashworth Scale-Bohannon (MAS-B) Score of Ankle Plantar Flexors Using a 6-Point Scale | Change from Baseline at 6 weeks | -0.61 Scores on a Scale | Standard Deviation 0.835 |
Secondary
Change From Baseline in Average Pain Score While Walking on the 11-Point Pain Scale
The patient is asked to select a number that best describes his/her pain while walking on an 11-point scale from 0 = no pain to 10 = pain as bad as can be imagined. Patients are instructed to recall their average pain in the study limb during the 48-hour period prior to the visit. Patients with a baseline pain score \>0 are included in the analyses.
Time frame: Baseline, Week 6
Population: Intent-to-Treat: all randomized patients who were analyzed according to randomization assignment, regardless of treatment actually received
| Arm | Measure | Group | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|---|
| Botulinum Toxin Type A | Change From Baseline in Average Pain Score While Walking on the 11-Point Pain Scale | Baseline | 4.5 Scores on a Scale | Standard Deviation 1.95 |
| Botulinum Toxin Type A | Change From Baseline in Average Pain Score While Walking on the 11-Point Pain Scale | Change from Baseline at Week 6 (N=175, 158) | -0.8 Scores on a Scale | Standard Deviation 2.3 |
| Normal Saline (Placebo) Followed by Botulinum Toxin Type A | Change From Baseline in Average Pain Score While Walking on the 11-Point Pain Scale | Baseline | 4.5 Scores on a Scale | Standard Deviation 2.13 |
| Normal Saline (Placebo) Followed by Botulinum Toxin Type A | Change From Baseline in Average Pain Score While Walking on the 11-Point Pain Scale | Change from Baseline at Week 6 (N=175, 158) | -1.1 Scores on a Scale | Standard Deviation 2.38 |
Secondary
Change From Baseline in Modified Ashworth Scale-Bohannon (MAS-B) Score of Optional Muscles Using a 6-Point Scale
The MAS-B is a 6-point scale used to evaluate spasticity based on grading the resistance encountered in the optional muscles by passively moving the muscles through their range of motion. Optional muscles treated include: Rectus Femoris, Flexor Digitorum Longus, Flexor Hallucis Longus, and Extensor Hallucis. The scores range from 0 (no increase in muscle tone) to 4 (affected part(s) rigid in flexion or extension). Scores are converted to a 0 to 5 grade. A negative number change from baseline indicates an improvement and a positive number change from baseline indicates a worsening.
Time frame: Baseline, Week 6
Population: Intent-to-Treat: all randomized patients who were analyzed according to randomization assignment, regardless of treatment actually received
| Arm | Measure | Group | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|---|
| Botulinum Toxin Type A | Change From Baseline in Modified Ashworth Scale-Bohannon (MAS-B) Score of Optional Muscles Using a 6-Point Scale | Baseline Rectus Femoris (N=25, 25) | 3.3 Scores on a Scale | Standard Deviation 0.58 |
| Botulinum Toxin Type A | Change From Baseline in Modified Ashworth Scale-Bohannon (MAS-B) Score of Optional Muscles Using a 6-Point Scale | Chng from BL at Wk6 in Rectus Femoris (N=24,25) | -0.9 Scores on a Scale | Standard Deviation 0.87 |
| Botulinum Toxin Type A | Change From Baseline in Modified Ashworth Scale-Bohannon (MAS-B) Score of Optional Muscles Using a 6-Point Scale | Baseline Flexor Digitorum Longus (N=86,88) | 3.3 Scores on a Scale | Standard Deviation 0.76 |
| Botulinum Toxin Type A | Change From Baseline in Modified Ashworth Scale-Bohannon (MAS-B) Score of Optional Muscles Using a 6-Point Scale | Chng from BL at Wk6 in Digitorum Longus (N=85,84) | -0.9 Scores on a Scale | Standard Deviation 1.11 |
| Botulinum Toxin Type A | Change From Baseline in Modified Ashworth Scale-Bohannon (MAS-B) Score of Optional Muscles Using a 6-Point Scale | Baseline Flexor Hallucis Longus (N=73,67) | 3.1 Scores on a Scale | Standard Deviation 0.81 |
| Botulinum Toxin Type A | Change From Baseline in Modified Ashworth Scale-Bohannon (MAS-B) Score of Optional Muscles Using a 6-Point Scale | Chng frm BL at Wk6 Flexor Hallucis Longus(N=72,66) | -1.0 Scores on a Scale | Standard Deviation 1.3 |
| Botulinum Toxin Type A | Change From Baseline in Modified Ashworth Scale-Bohannon (MAS-B) Score of Optional Muscles Using a 6-Point Scale | Baseline Extensor Hallucis (N=23,13) | 3.6 Scores on a Scale | Standard Deviation 0.49 |
| Botulinum Toxin Type A | Change From Baseline in Modified Ashworth Scale-Bohannon (MAS-B) Score of Optional Muscles Using a 6-Point Scale | Chng from BL at Wk6 in Extensor Hallucis (N=23,13) | -1.3 Scores on a Scale | Standard Deviation 1.22 |
| Normal Saline (Placebo) Followed by Botulinum Toxin Type A | Change From Baseline in Modified Ashworth Scale-Bohannon (MAS-B) Score of Optional Muscles Using a 6-Point Scale | Chng from BL at Wk6 in Extensor Hallucis (N=23,13) | -1.3 Scores on a Scale | Standard Deviation 1.09 |
| Normal Saline (Placebo) Followed by Botulinum Toxin Type A | Change From Baseline in Modified Ashworth Scale-Bohannon (MAS-B) Score of Optional Muscles Using a 6-Point Scale | Baseline Rectus Femoris (N=25, 25) | 3.2 Scores on a Scale | Standard Deviation 0.59 |
| Normal Saline (Placebo) Followed by Botulinum Toxin Type A | Change From Baseline in Modified Ashworth Scale-Bohannon (MAS-B) Score of Optional Muscles Using a 6-Point Scale | Baseline Flexor Hallucis Longus (N=73,67) | 3.2 Scores on a Scale | Standard Deviation 0.83 |
| Normal Saline (Placebo) Followed by Botulinum Toxin Type A | Change From Baseline in Modified Ashworth Scale-Bohannon (MAS-B) Score of Optional Muscles Using a 6-Point Scale | Chng from BL at Wk6 in Rectus Femoris (N=24,25) | -1.0 Scores on a Scale | Standard Deviation 1.14 |
| Normal Saline (Placebo) Followed by Botulinum Toxin Type A | Change From Baseline in Modified Ashworth Scale-Bohannon (MAS-B) Score of Optional Muscles Using a 6-Point Scale | Baseline Extensor Hallucis (N=23,13) | 3.6 Scores on a Scale | Standard Deviation 0.51 |
| Normal Saline (Placebo) Followed by Botulinum Toxin Type A | Change From Baseline in Modified Ashworth Scale-Bohannon (MAS-B) Score of Optional Muscles Using a 6-Point Scale | Baseline Flexor Digitorum Longus (N=86,88) | 3.4 Scores on a Scale | Standard Deviation 0.7 |
| Normal Saline (Placebo) Followed by Botulinum Toxin Type A | Change From Baseline in Modified Ashworth Scale-Bohannon (MAS-B) Score of Optional Muscles Using a 6-Point Scale | Chng frm BL at Wk6 Flexor Hallucis Longus(N=72,66) | -0.6 Scores on a Scale | Standard Deviation 1.2 |
| Normal Saline (Placebo) Followed by Botulinum Toxin Type A | Change From Baseline in Modified Ashworth Scale-Bohannon (MAS-B) Score of Optional Muscles Using a 6-Point Scale | Chng from BL at Wk6 in Digitorum Longus (N=85,84) | -0.8 Scores on a Scale | Standard Deviation 1.22 |
Secondary
Clinical Global Impression (CGI) of Overall Change by Physician Using a 9-Point Scale
The CGI is a 9-point scale evaluating change from baseline status by the Physician. Scores range from +4 (very marked improvement) to -4 (very marked worsening). The average of the weeks 4 and 6 CGI by Physician score is used as a secondary end point. Higher scores indicate a greater improvement from baseline.
Time frame: Baseline, 6 weeks
Population: Intent-to-Treat: all randomized patients who were analyzed according to randomization assignment, regardless of treatment actually received
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| Botulinum Toxin Type A | Clinical Global Impression (CGI) of Overall Change by Physician Using a 9-Point Scale | 0.86 Scores on a Scale | Standard Deviation 0.953 |
| Normal Saline (Placebo) Followed by Botulinum Toxin Type A | Clinical Global Impression (CGI) of Overall Change by Physician Using a 9-Point Scale | 0.65 Scores on a Scale | Standard Deviation 0.902 |
Secondary
Goal Attainment Scores on the 6-Point Physician-Assessed Goal Attainment Scale (GAS)
The physician-assessed GAS is an individualized, goal-oriented 6-point scale used to track functional improvement toward active and passive goals. GAS scoring ranged from -3 to 2 (-3 = worse than start; 0 = expected goal/attained the defined therapeutic goal; 2 = much more than expected/improvements clearly exceeded the defined therapeutic goal). Active and Passive Goal scores are presented.
Time frame: Week 8
Population: Intent-to-Treat: all randomized patients who were analyzed according to randomization assignment, regardless of treatment actually received
| Arm | Measure | Group | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|---|
| Botulinum Toxin Type A | Goal Attainment Scores on the 6-Point Physician-Assessed Goal Attainment Scale (GAS) | Active Goals (N=226, 228) | -0.8 Scores on a Scale | Standard Deviation 1.34 |
| Botulinum Toxin Type A | Goal Attainment Scores on the 6-Point Physician-Assessed Goal Attainment Scale (GAS) | Passive Goals--use (N=214, 217) | -0.5 Scores on a Scale | Standard Deviation 1.42 |
| Normal Saline (Placebo) Followed by Botulinum Toxin Type A | Goal Attainment Scores on the 6-Point Physician-Assessed Goal Attainment Scale (GAS) | Active Goals (N=226, 228) | -1.0 Scores on a Scale | Standard Deviation 1.33 |
| Normal Saline (Placebo) Followed by Botulinum Toxin Type A | Goal Attainment Scores on the 6-Point Physician-Assessed Goal Attainment Scale (GAS) | Passive Goals--use (N=214, 217) | -0.8 Scores on a Scale | Standard Deviation 1.33 |