Post-stroke Spasticity of the Lower Limb
Conditions
Brief summary
The purpose of this study is to determine whether injections of Botulinum toxin type A into muscles of the leg are effective in treating patients with increased muscle tension/uncontrollable muscle stiffness (spasticity) after a stroke.
Interventions
Main period: One injection session of solution, prepared by reconstitution of powder with 0.9% Sodium Chloride (NaCl), 400 units, total volume 8.0 mL; Mode of administration: intramuscular injection.
DRUGPlacebo Comparator
Main period: one injection session of solution, prepared by reconstitution of powder with 0.9% NaCl, corresponding total placebo volume 8.0 mL; Mode of administration: intramuscular injection
Sponsors
Merz Pharmaceuticals GmbH
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 80 Years
Healthy volunteers
No
Inclusion criteria
* Age from 18-80 yrs * Lower limb spasticity * Time since stroke greater than 3 months * Need for 400 U Botulinum toxin type A
Exclusion criteria
* Body weight below 50kg * Fixed contractures of the lower limb * Generalized disorders of muscle activity like Myasthenia gravis that preclude use of Botulinum toxin type A * Infection at the injection site
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Change From Baseline in Ashworth Scale (AS) for Plantar Flexors at Week 4 | Baseline and Week 4 | The AS is a well known and commonly used scale in clinical trials with spasticity. It was considered to be the best clinical tool for measuring resistance to movement. It was used to categorize the severity of spasticity by judging resistance to passive movement. It is a 5-point scale that ranges from 0 (=no increase in tone) to 4 (=limb rigid in flexion or extension). |
| Co-primary Variable: Investigator's Global Assessment of Efficacy at Week 12 | Baseline to Week 12 | A 4-point Likert scale will be used with the ratings 1 = very good, 2 = good, 3 = moderate, and 4 = poor. Investigator's Global Assessment of Efficacy at Week 12 will be a co-primary outcome measure to fulfill post marketing commitments for U.S. regulatory authorities only. Elsewhere, it will be a secondary outcome measure. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Response Rate for Plantar Flexors at All Post-Baseline Visits for Subjects With an Improvement (Reduction) of at Least 1 Point From Baseline in the Ashworth Scale (AS) | Week 4, 8, and 12 | Response is defined as an improvement (reduction) of the plantar flexor Ashworth Score by at least one score point. The AS is a well known and commonly used scale in clinical trials with spasticity. It was considered to be the best clinical tool for measuring resistance to movement. It was used to categorize the severity of spasticity by judging resistance to passive movement. It is a 5-point scale that ranges from 0 (=no increase in tone) to 4 (=limb rigid in flexion or extension). |
| Ashworth Scale (AS) for Plantar Flexors at All Post-Baseline Visits | Baseline, Week 4, 8, and 12 | The AS is a well known and commonly used scale in clinical trials with spasticity. It was considered to be the best clinical tool for measuring resistance to movement. It was used to categorize the severity of spasticity by judging resistance to passive movement. It is a 5-point scale that ranges from 0 (=no increase in tone) to 4 (=limb rigid in flexion or extension). Here, 'n' specifies those subjects who were evaluated for this outcome measure at given time point. |
Countries
Canada, Czechia, France, Germany, Italy, Poland, Russia, Spain, United States
Participant flow
Recruitment details
A total of 331 individuals suffering from post-stroke lower-limb spasticity were screened and 290 were included in study at 51 sites. One ineligible subject was randomized to placebo but withdrawn from study prior to first treatment with study medication. For purpose of study analysis overall number of subjects enrolled is therefore considered 289.
Pre-assignment details
A total of 290 subjects were enrolled in study. One ineligible subject was randomized to placebo but withdrawn from study prior to first treatment with study medication. A total of 289 subjects were enrolled in main period. All of the 269 subjects who completed the main period of the study entered the open-label extension period.
Participants by arm
| Arm | Count |
|---|---|
| Main Period: IncobotulinumtoxinA (Xeomin) 400 Units IncobotulinumtoxinA (Xeomin, also known as NT 201 or Botulinum toxin type A (150 kiloDalton), free from complexing proteins) (active ingredient: Clostridium Botulinum neurotoxin Type A free from complexing proteins) powder for solution for injection.
IncobotulinumtoxinA (400 Units): Main period: One injection session of solution, prepared by reconstitution of powder with 0.9% Sodium Chloride (NaCl), 400 units, total volume 8.0 mL; Mode of administration: intramuscular injection. | 144 |
| Main Period: Placebo Placebo to incobotulinumtoxinA (Xeomin) powder for solution for injection.
Placebo Comparator: Main period: one injection session of solution, prepared by reconstitution of powder with 0.9% NaCl, corresponding total placebo volume 8.0 mL; Mode of administration: intramuscular injection | 145 |
| Total | 289 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Main Period | Adverse Event | 6 | 1 |
| Main Period | Death | 0 | 1 |
| Main Period | Lack of Efficacy | 2 | 0 |
| Main Period | Predefined discontinuation criteria | 2 | 1 |
| Main Period | Withdrawal by Subject | 5 | 2 |
| Open-Label Extension Period | Adverse Event | 15 | 0 |
| Open-Label Extension Period | Death | 1 | 0 |
| Open-Label Extension Period | Lack of Efficacy | 5 | 0 |
| Open-Label Extension Period | Lost to Follow-up | 1 | 0 |
| Open-Label Extension Period | Non-compliance | 9 | 0 |
| Open-Label Extension Period | Predefined discontinuation criteria | 6 | 0 |
| Open-Label Extension Period | Withdrawal by Subject | 14 | 0 |
Baseline characteristics
| Characteristic | Main Period: IncobotulinumtoxinA (Xeomin) 400 Units | Main Period: Placebo | Total |
|---|---|---|---|
| Age, Continuous | 57.3 years STANDARD_DEVIATION 11.2 | 57.0 years STANDARD_DEVIATION 13 | 57.2 years STANDARD_DEVIATION 12.1 |
| Gender Female | 40 Participants | 55 Participants | 95 Participants |
| Gender Male | 104 Participants | 90 Participants | 194 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk |
|---|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — | — / — |
| other Total, other adverse events | 13 / 144 | 13 / 145 | 31 / 269 |
| serious Total, serious adverse events | 6 / 144 | 5 / 145 | 22 / 269 |
Outcome results
Primary
Change From Baseline in Ashworth Scale (AS) for Plantar Flexors at Week 4
The AS is a well known and commonly used scale in clinical trials with spasticity. It was considered to be the best clinical tool for measuring resistance to movement. It was used to categorize the severity of spasticity by judging resistance to passive movement. It is a 5-point scale that ranges from 0 (=no increase in tone) to 4 (=limb rigid in flexion or extension).
Time frame: Baseline and Week 4
Population: The Full Analysis Set (FAS) included subjects in the Safety Evaluation Set (SES) of the main period for whom the primary efficacy variable was available, whereby SES is the subset of all subjects who were exposed to IP in the main period at least once.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| IncobotulinumtoxinA (Xeomin) 400 Units | Change From Baseline in Ashworth Scale (AS) for Plantar Flexors at Week 4 | Baseline | 2.8 Units on a scale | Standard Deviation 0.7 |
| IncobotulinumtoxinA (Xeomin) 400 Units | Change From Baseline in Ashworth Scale (AS) for Plantar Flexors at Week 4 | Change at Week 4 | -0.4 Units on a scale | Standard Deviation 0.7 |
| Placebo | Change From Baseline in Ashworth Scale (AS) for Plantar Flexors at Week 4 | Baseline | 2.8 Units on a scale | Standard Deviation 0.7 |
| Placebo | Change From Baseline in Ashworth Scale (AS) for Plantar Flexors at Week 4 | Change at Week 4 | -0.4 Units on a scale | Standard Deviation 0.7 |
Comparison: The number of subjects included in the MMRM analysis was only 286 because a covariate was missing for 3 subjects.p-value: 0.77795% CI: [-0.1, 0.2]Mixed-Model Repeated Measures
Primary
Co-primary Variable: Investigator's Global Assessment of Efficacy at Week 12
A 4-point Likert scale will be used with the ratings 1 = very good, 2 = good, 3 = moderate, and 4 = poor. Investigator's Global Assessment of Efficacy at Week 12 will be a co-primary outcome measure to fulfill post marketing commitments for U.S. regulatory authorities only. Elsewhere, it will be a secondary outcome measure.
Time frame: Baseline to Week 12
Population: The Full Analysis Set (FAS) included subjects in the Safety Evaluation Set (SES) of the main period for whom the primary efficacy variable was available, whereby SES is the subset of all subjects who were exposed to IP in the main period at least once.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| IncobotulinumtoxinA (Xeomin) 400 Units | Co-primary Variable: Investigator's Global Assessment of Efficacy at Week 12 | Moderate | 22.2 Percentage of Participants |
| IncobotulinumtoxinA (Xeomin) 400 Units | Co-primary Variable: Investigator's Global Assessment of Efficacy at Week 12 | Very good | 3.5 Percentage of Participants |
| IncobotulinumtoxinA (Xeomin) 400 Units | Co-primary Variable: Investigator's Global Assessment of Efficacy at Week 12 | Poor | 45.8 Percentage of Participants |
| IncobotulinumtoxinA (Xeomin) 400 Units | Co-primary Variable: Investigator's Global Assessment of Efficacy at Week 12 | Good | 28.5 Percentage of Participants |
| Placebo | Co-primary Variable: Investigator's Global Assessment of Efficacy at Week 12 | Poor | 45.5 Percentage of Participants |
| Placebo | Co-primary Variable: Investigator's Global Assessment of Efficacy at Week 12 | Very good | 4.8 Percentage of Participants |
| Placebo | Co-primary Variable: Investigator's Global Assessment of Efficacy at Week 12 | Moderate | 26.9 Percentage of Participants |
| Placebo | Co-primary Variable: Investigator's Global Assessment of Efficacy at Week 12 | Good | 22.8 Percentage of Participants |
Comparison: The statistical analysis provided was for all categories of this outcome measure.p-value: 0.804Wilcoxon's Rank-Sum Test
Secondary
Ashworth Scale (AS) for Plantar Flexors at All Post-Baseline Visits
The AS is a well known and commonly used scale in clinical trials with spasticity. It was considered to be the best clinical tool for measuring resistance to movement. It was used to categorize the severity of spasticity by judging resistance to passive movement. It is a 5-point scale that ranges from 0 (=no increase in tone) to 4 (=limb rigid in flexion or extension). Here, 'n' specifies those subjects who were evaluated for this outcome measure at given time point.
Time frame: Baseline, Week 4, 8, and 12
Population: The Full Analysis Set (FAS) included subjects in the Safety Evaluation Set (SES) of the main period for whom the primary efficacy variable was available, whereby SES is the subset of all subjects who were exposed to IP in the main period at least once.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| IncobotulinumtoxinA (Xeomin) 400 Units | Ashworth Scale (AS) for Plantar Flexors at All Post-Baseline Visits | Baseline (n=144, 145) | 2.8 Units on a scale | Standard Deviation 0.7 |
| IncobotulinumtoxinA (Xeomin) 400 Units | Ashworth Scale (AS) for Plantar Flexors at All Post-Baseline Visits | Week 4 (n= 142, 144) | 2.4 Units on a scale | Standard Deviation 0.9 |
| IncobotulinumtoxinA (Xeomin) 400 Units | Ashworth Scale (AS) for Plantar Flexors at All Post-Baseline Visits | Week 8 (n=140, 142) | 2.4 Units on a scale | Standard Deviation 0.9 |
| IncobotulinumtoxinA (Xeomin) 400 Units | Ashworth Scale (AS) for Plantar Flexors at All Post-Baseline Visits | Week 12 (n= 135, 141) | 2.7 Units on a scale | Standard Deviation 0.8 |
| Placebo | Ashworth Scale (AS) for Plantar Flexors at All Post-Baseline Visits | Week 12 (n= 135, 141) | 2.7 Units on a scale | Standard Deviation 0.7 |
| Placebo | Ashworth Scale (AS) for Plantar Flexors at All Post-Baseline Visits | Baseline (n=144, 145) | 2.8 Units on a scale | Standard Deviation 0.7 |
| Placebo | Ashworth Scale (AS) for Plantar Flexors at All Post-Baseline Visits | Week 8 (n=140, 142) | 2.5 Units on a scale | Standard Deviation 0.7 |
| Placebo | Ashworth Scale (AS) for Plantar Flexors at All Post-Baseline Visits | Week 4 (n= 142, 144) | 2.4 Units on a scale | Standard Deviation 0.8 |
Secondary
Response Rate for Plantar Flexors at All Post-Baseline Visits for Subjects With an Improvement (Reduction) of at Least 1 Point From Baseline in the Ashworth Scale (AS)
Response is defined as an improvement (reduction) of the plantar flexor Ashworth Score by at least one score point. The AS is a well known and commonly used scale in clinical trials with spasticity. It was considered to be the best clinical tool for measuring resistance to movement. It was used to categorize the severity of spasticity by judging resistance to passive movement. It is a 5-point scale that ranges from 0 (=no increase in tone) to 4 (=limb rigid in flexion or extension).
Time frame: Week 4, 8, and 12
Population: The FAS included subjects in SES of main period for whom primary efficacy variable was available, whereby SES is subset of all subjects who were exposed to IP in main period at least once. Here, N(Number of Participants Analyzed) and n signifies those participants who were evaluable for this outcome measure and at given time point respectively.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| IncobotulinumtoxinA (Xeomin) 400 Units | Response Rate for Plantar Flexors at All Post-Baseline Visits for Subjects With an Improvement (Reduction) of at Least 1 Point From Baseline in the Ashworth Scale (AS) | Week 4 (n=142, 144) | 37.3 Percentage of Participants |
| IncobotulinumtoxinA (Xeomin) 400 Units | Response Rate for Plantar Flexors at All Post-Baseline Visits for Subjects With an Improvement (Reduction) of at Least 1 Point From Baseline in the Ashworth Scale (AS) | Week 8 (n=140, 142) | 39.3 Percentage of Participants |
| IncobotulinumtoxinA (Xeomin) 400 Units | Response Rate for Plantar Flexors at All Post-Baseline Visits for Subjects With an Improvement (Reduction) of at Least 1 Point From Baseline in the Ashworth Scale (AS) | Week 12 (n=135, 141) | 20 Percentage of Participants |
| Placebo | Response Rate for Plantar Flexors at All Post-Baseline Visits for Subjects With an Improvement (Reduction) of at Least 1 Point From Baseline in the Ashworth Scale (AS) | Week 4 (n=142, 144) | 35.4 Percentage of Participants |
| Placebo | Response Rate for Plantar Flexors at All Post-Baseline Visits for Subjects With an Improvement (Reduction) of at Least 1 Point From Baseline in the Ashworth Scale (AS) | Week 8 (n=140, 142) | 33.8 Percentage of Participants |
| Placebo | Response Rate for Plantar Flexors at All Post-Baseline Visits for Subjects With an Improvement (Reduction) of at Least 1 Point From Baseline in the Ashworth Scale (AS) | Week 12 (n=135, 141) | 17 Percentage of Participants |
Comparison: Week 4. Number of subjects included in analysis was three less than the observed cases because of a missing covariate for the logistic regression analysis, that is, n=283 for week 4.p-value: 0.84595% CI: [0.63, 1.74]Regression, Logistic
Comparison: Week 8. Number of subjects included in analysis was three less than the observed cases because of a missing covariate for the logistic regression analysis, that is, n=279 for week 8.p-value: 0.43795% CI: [0.73, 2.04]Regression, Logistic
Comparison: Week 12. Number of subjects included in analysis was three less than the observed cases because of a missing covariate for the logistic regression analysis, that is, n=273 for week 12.p-value: 0.69895% CI: [0.59, 2.21]Regression, Logistic