Healthy Participants
Conditions
Brief summary
Study aimed at comparing the pharmacodynamic profile (including duration of action) of three commercialized toxins by measuring the action potential of the injected muscle (extensor digitorum brevis)
Interventions
BIOLOGICALBotulinum toxin type A
Intramuscular Injection, concentration 300 units (U)
Sponsors
Ipsen
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
TRIPLE (Subject, Investigator, Outcomes Assessor)
Eligibility
Sex/Gender
MALE
Age
18 Years to 65 Years
Healthy volunteers
Yes
Inclusion criteria
* Participant must be between18 to 65 years of age inclusive, at the time of signing the informed consent * Participants who are overtly healthy as determined by medical evaluation including medical history, physical examination, laboratory tests, vital signs and cardiac monitoring * A body mass index (BMI) within the range 18 and 30 kg/m2 (inclusive).
Exclusion criteria
* Any medical condition that may put the participant at risk with exposure to BoNT, including diagnosed myasthenia gravis, Eaton-Lambert syndrome, amyotrophic lateral sclerosis, or any other disease that might interfere with neuromuscular function * Previous treatment with botulinum toxin (BoNT) (any serotype) during the past 6 months * Known hypersensitivity to any of the components of the Dysport/ Botox/ Xeomin formulation (which includes human serum albumin, lactose, sucrose) or allergy to cow's milk protein * Use of agents that could interfere with neuromuscular transmission, including calcium channel blockers, penicillamine, aminoglycosides, lincosamides, polymixins, magnesium sulphate, anticholinesterases, succinylcholine and quinidine
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Change From Baseline in Adjusted Mean (AM) Percentage (%) of CMAP Total Amplitude at Week 28 | Baseline (Day 1) and Week 28 | The CMAP procedure was performed on the injected foot by a neurophysiologist. Percentage relative to baseline was calculated as (value at Week 28 \[mean of the 3 measurements\]/baseline value) multiplied by (\*) 100. The adjusted mean was obtained from a mixed-effects model for repeated measures (MMRM) model with Fisher scoring. Baseline was defined as the last non-missing measurement taken prior to study drug administration. Baseline value used for this analysis was the average of 6 measurements, the 3 measurements at screening and the 3 measurements at baseline. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Percentage of Participants With Recovery of CMAP Total Amplitude | At Weeks 28 and 40 | The recovery was considered to be reached for all the visits occurring after the time to recovery, that is (i.e.) the first visit for which CMAP total amplitude returned to at least 85% of the baseline value. Percentage of participants with recovery of CMAP total amplitude was analyzed at Weeks 28 and 40. |
| Time to Onset of Action of Study Intervention | From Baseline (Day 1) up to Week 40 | Time to onset of action was defined as the first timepoint when EDB CMAP total amplitude was less or equal to 85% of the baseline value. |
| Change From Baseline in AM % of CMAP Total Amplitude at Week 40 | Baseline (Day 1) and Week 40 | The CMAP procedure was performed on the injected foot by a neurophysiologist. It was measured as percentage relative to baseline defined as CMAP at the corresponding visit (mean of the 3 measurements)/CMAP at baseline (mean of the 6 measurements)\*100. The adjusted mean was obtained from a MMRM model with Fisher scoring. Baseline was defined as the last non-missing measurement taken prior to study drug administration. Baseline value used for this analysis was the average of 6 measurements, the 3 measurements at screening and the 3 measurements at baseline. |
| Percentage of Maximal Inhibition (Maximal Effect) of CMAP Total Amplitude | Up to Week 40 | Maximal inhibition was defined as the maximal measured inhibition of CMAP total amplitude of stimulated EDB. |
| Number of Participants Who Achieved Maximal Effect of CMAP Total Amplitude | At Weeks 1, 4, 8 and 20 | Time to maximal effect was defined on an individual basis as the time between baseline and the timepoint of maximal inhibition of CMAP amplitude of stimulated EDB. Participants with maximal effect of CMAP total amplitude were reported. |
| Duration of Response | From Baseline (Day 1) up to Week 40 | Duration of response was calculated as time to recovery of CMAP total amplitude - time to onset. Time to recovery was defined as the first timepoint where EDB CMAP total amplitude returned to at least 85% of the baseline value. |
Countries
United Kingdom
Participant flow
Recruitment details
This Phase I, randomized, double-blind study was conducted in healthy adult male participants at a single investigational site in United Kingdom between 06 Jul 2021 and 08 Jun 2022. The purpose of this study was to compare the duration of action on compound muscle action potential (CMAP) of the extensor digitorum brevis (EDB) muscle injected with either Dysport 40 units (U), Botox 16 U or Xeomin 16 U.
Pre-assignment details
This study consisted of a 14-day screening period, a double-blind period including treatment administration on Day 1, and follow-up period up to 40 weeks. A total of 45 male participants were randomized in a 1:1:1 ratio to receive treatment with Dysport 40 U, Botox 16 U or Xeomin 16 U respectively.
Participants by arm
| Arm | Count |
|---|---|
| Dysport 40 U Participants received a single IM injection of Dysport 40 U in the EDB muscle on Day 1. | 15 |
| Botox 16 U Participants received a single IM injection of Botox 16 U in the EDB muscle on Day 1. | 15 |
| Xeomin 16 U Participants received a single IM injection of Xeomin 16 U in the EDB muscle on Day 1. | 15 |
| Total | 45 |
Baseline characteristics
| Characteristic | Dysport 40 U | Botox 16 U | Xeomin 16 U | Total |
|---|---|---|---|---|
| Age, Continuous | 36.2 years STANDARD_DEVIATION 11.3 | 35.3 years STANDARD_DEVIATION 12.3 | 34.8 years STANDARD_DEVIATION 13.9 | 35.4 years STANDARD_DEVIATION 12.3 |
| Race and Ethnicity Not Collected | — | — | — | 0 Participants |
| Sex: Female, Male Female | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Sex: Female, Male Male | 15 Participants | 15 Participants | 15 Participants | 45 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk |
|---|---|---|---|
| deaths Total, all-cause mortality | 0 / 15 | 0 / 15 | 0 / 15 |
| other Total, other adverse events | 11 / 15 | 10 / 15 | 14 / 15 |
| serious Total, serious adverse events | 10 / 15 | 2 / 15 | 5 / 15 |
Outcome results
Primary
Change From Baseline in Adjusted Mean (AM) Percentage (%) of CMAP Total Amplitude at Week 28
The CMAP procedure was performed on the injected foot by a neurophysiologist. Percentage relative to baseline was calculated as (value at Week 28 \[mean of the 3 measurements\]/baseline value) multiplied by (\*) 100. The adjusted mean was obtained from a mixed-effects model for repeated measures (MMRM) model with Fisher scoring. Baseline was defined as the last non-missing measurement taken prior to study drug administration. Baseline value used for this analysis was the average of 6 measurements, the 3 measurements at screening and the 3 measurements at baseline.
Time frame: Baseline (Day 1) and Week 28
Population: The Pharmacodynamic (PD) analysis set consisted of all participants from the randomized set who received the appropriate dose of study treatment and had CMAP recorded for baseline and at least 1 post-baseline assessment.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Dysport 40 U | Change From Baseline in Adjusted Mean (AM) Percentage (%) of CMAP Total Amplitude at Week 28 | 73.62 % of AM of CMAP total amplitude | Standard Error 5.26 |
| Botox 16 U | Change From Baseline in Adjusted Mean (AM) Percentage (%) of CMAP Total Amplitude at Week 28 | 74.78 % of AM of CMAP total amplitude | Standard Error 5.26 |
| Xeomin 16 U | Change From Baseline in Adjusted Mean (AM) Percentage (%) of CMAP Total Amplitude at Week 28 | 84.23 % of AM of CMAP total amplitude | Standard Error 5.25 |
Comparison: The adjusted mean, standard error (SE) and 95% confidence interval (CI) of the adjusted mean as well as difference in % relative to baseline and p-value were obtained from a MMRM with Fisher scoring with treatment, time (corresponding to all study visits when CMAP was measured), treatment by time interaction and baseline CMAP amplitude as factors and an unstructured variance covariance matrix.p-value: 0.876995% CI: [-16.25, 13.93]MMRM model
Comparison: The adjusted mean, SE and 95% CI of the adjusted mean as well as difference in % relative to baseline and p-value were obtained from a MMRM with Fisher scoring with treatment, time (corresponding to all study visits when CMAP was measured), treatment by time interaction and baseline CMAP amplitude as factors and an unstructured variance covariance matrix.p-value: 0.16295% CI: [-25.69, 4.47]MMRM model
Secondary
Change From Baseline in AM % of CMAP Total Amplitude at Week 40
The CMAP procedure was performed on the injected foot by a neurophysiologist. It was measured as percentage relative to baseline defined as CMAP at the corresponding visit (mean of the 3 measurements)/CMAP at baseline (mean of the 6 measurements)\*100. The adjusted mean was obtained from a MMRM model with Fisher scoring. Baseline was defined as the last non-missing measurement taken prior to study drug administration. Baseline value used for this analysis was the average of 6 measurements, the 3 measurements at screening and the 3 measurements at baseline.
Time frame: Baseline (Day 1) and Week 40
Population: The PD analysis set consisted of all participants from the randomized set who received the appropriate dose of study treatment and had CMAP recorded for baseline and at least 1 post-baseline assessment.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Dysport 40 U | Change From Baseline in AM % of CMAP Total Amplitude at Week 40 | 77.10 % of AM of CMAP total amplitude | Standard Error 5.09 |
| Botox 16 U | Change From Baseline in AM % of CMAP Total Amplitude at Week 40 | 81.83 % of AM of CMAP total amplitude | Standard Error 5.1 |
| Xeomin 16 U | Change From Baseline in AM % of CMAP Total Amplitude at Week 40 | 92.01 % of AM of CMAP total amplitude | Standard Error 5.09 |
Secondary
Duration of Response
Duration of response was calculated as time to recovery of CMAP total amplitude - time to onset. Time to recovery was defined as the first timepoint where EDB CMAP total amplitude returned to at least 85% of the baseline value.
Time frame: From Baseline (Day 1) up to Week 40
Population: The PD analysis set consisted of all participants from the randomized set who received the appropriate dose of study treatment and had CMAP recorded for baseline and at least 1 post-baseline assessment. Only those participants who showed recovery before the end of the study were analyzed.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Dysport 40 U | Duration of Response | 18.29 weeks |
| Botox 16 U | Duration of Response | 10.86 weeks |
| Xeomin 16 U | Duration of Response | 17.07 weeks |
Secondary
Number of Participants Who Achieved Maximal Effect of CMAP Total Amplitude
Time to maximal effect was defined on an individual basis as the time between baseline and the timepoint of maximal inhibition of CMAP amplitude of stimulated EDB. Participants with maximal effect of CMAP total amplitude were reported.
Time frame: At Weeks 1, 4, 8 and 20
Population: The PD analysis set consisted of all participants from the randomized set who received the appropriate dose of study treatment and had CMAP recorded for baseline and at least 1 post-baseline assessment.
| Arm | Measure | Group | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| Dysport 40 U | Number of Participants Who Achieved Maximal Effect of CMAP Total Amplitude | Week 1 | 11 Participants |
| Dysport 40 U | Number of Participants Who Achieved Maximal Effect of CMAP Total Amplitude | Week 4 | 2 Participants |
| Dysport 40 U | Number of Participants Who Achieved Maximal Effect of CMAP Total Amplitude | Week 8 | 1 Participants |
| Dysport 40 U | Number of Participants Who Achieved Maximal Effect of CMAP Total Amplitude | Week 20 | 1 Participants |
| Botox 16 U | Number of Participants Who Achieved Maximal Effect of CMAP Total Amplitude | Week 20 | 0 Participants |
| Botox 16 U | Number of Participants Who Achieved Maximal Effect of CMAP Total Amplitude | Week 1 | 13 Participants |
| Botox 16 U | Number of Participants Who Achieved Maximal Effect of CMAP Total Amplitude | Week 8 | 1 Participants |
| Botox 16 U | Number of Participants Who Achieved Maximal Effect of CMAP Total Amplitude | Week 4 | 1 Participants |
| Xeomin 16 U | Number of Participants Who Achieved Maximal Effect of CMAP Total Amplitude | Week 20 | 0 Participants |
| Xeomin 16 U | Number of Participants Who Achieved Maximal Effect of CMAP Total Amplitude | Week 4 | 4 Participants |
| Xeomin 16 U | Number of Participants Who Achieved Maximal Effect of CMAP Total Amplitude | Week 8 | 0 Participants |
| Xeomin 16 U | Number of Participants Who Achieved Maximal Effect of CMAP Total Amplitude | Week 1 | 11 Participants |
Secondary
Percentage of Maximal Inhibition (Maximal Effect) of CMAP Total Amplitude
Maximal inhibition was defined as the maximal measured inhibition of CMAP total amplitude of stimulated EDB.
Time frame: Up to Week 40
Population: The PD analysis set consisted of all participants from the randomized set who received the appropriate dose of study treatment and had CMAP recorded for baseline and at least 1 post-baseline assessment.
| Arm | Measure | Value (MEAN) |
|---|---|---|
| Dysport 40 U | Percentage of Maximal Inhibition (Maximal Effect) of CMAP Total Amplitude | 39.79 percentage of inhibition |
| Botox 16 U | Percentage of Maximal Inhibition (Maximal Effect) of CMAP Total Amplitude | 38.55 percentage of inhibition |
| Xeomin 16 U | Percentage of Maximal Inhibition (Maximal Effect) of CMAP Total Amplitude | 44.99 percentage of inhibition |
Secondary
Percentage of Participants With Recovery of CMAP Total Amplitude
The recovery was considered to be reached for all the visits occurring after the time to recovery, that is (i.e.) the first visit for which CMAP total amplitude returned to at least 85% of the baseline value. Percentage of participants with recovery of CMAP total amplitude was analyzed at Weeks 28 and 40.
Time frame: At Weeks 28 and 40
Population: The PD analysis set consisted of all participants from the randomized set who received the appropriate dose of study treatment and had CMAP recorded for baseline and at least 1 post-baseline assessment. Only those participants who showed recovery at Weeks 28 and 40 were analyzed.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Dysport 40 U | Percentage of Participants With Recovery of CMAP Total Amplitude | Week 28 | 33.3 percentage of participants |
| Dysport 40 U | Percentage of Participants With Recovery of CMAP Total Amplitude | Week 40 | 33.3 percentage of participants |
| Botox 16 U | Percentage of Participants With Recovery of CMAP Total Amplitude | Week 28 | 26.7 percentage of participants |
| Botox 16 U | Percentage of Participants With Recovery of CMAP Total Amplitude | Week 40 | 33.3 percentage of participants |
| Xeomin 16 U | Percentage of Participants With Recovery of CMAP Total Amplitude | Week 28 | 53.3 percentage of participants |
| Xeomin 16 U | Percentage of Participants With Recovery of CMAP Total Amplitude | Week 40 | 66.7 percentage of participants |
Secondary
Time to Onset of Action of Study Intervention
Time to onset of action was defined as the first timepoint when EDB CMAP total amplitude was less or equal to 85% of the baseline value.
Time frame: From Baseline (Day 1) up to Week 40
Population: The PD analysis set consisted of all participants from the randomized set who received the appropriate dose of study treatment and had CMAP recorded for baseline and at least 1 post-baseline assessment.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Dysport 40 U | Time to Onset of Action of Study Intervention | 1.00 weeks |
| Botox 16 U | Time to Onset of Action of Study Intervention | 1.00 weeks |
| Xeomin 16 U | Time to Onset of Action of Study Intervention | 1.00 weeks |