Upper Limb Spasticity
Conditions
Keywords
ULS, JUNIPER, DAXI for injection, Botulinum toxin
Brief summary
This is a randomized, Double-Blind, Placebo-Controlled, Parallel Group, Dose-Ranging, trial to Evaluate the Efficacy and Safety of DaxibotulinumtoxinA for Injection for the Treatment of Upper Limb Spasticity in Adults After Stroke or Traumatic Brain Injury. The study will be conducted in the U.S.A., approximately 128 adult subjects from approximately 30 study centers will be randomly assigned (1:1:1:1) to one of four treatment groups. The study consists of a 21-day screening period, a treatment visit and follow-up visits. The protocol was amended and the study was completed with fewer subjects than described in the initial protocol due to impact of COVID-19 on enrollment.
Detailed description
Subjects will be randomly assigned to DAXI for Injection 250 U, DAXI for Injection 375 U, DAXI for Injection 500 U, or placebo group, respectively. Eligible subjects will have ULS characterized by a primary aggregate posture
Interventions
BIOLOGICALDAXI for injection 250 U
DaxibotulinumtoxinA for injection is a sterile, white to off-white lyophilized product containing the active ingredient, daxibotulinumtoxinA, and inactive ingredients to be reconstituted with sterile, non-preserved, 0.9% sodium chloride solution saline
BIOLOGICALDAXI for injection 375 U
DaxibotulinumtoxinA for injection is a sterile, white to off-white lyophilized product containing the active ingredient, daxibotulinumtoxinA, and inactive ingredients to be reconstituted with sterile, non-preserved, 0.9% sodium chloride solution saline.
BIOLOGICALDAXI for injection 500 U
DaxibotulinumtoxinA for injection is a sterile, white to off-white lyophilized product containing the active ingredient, daxibotulinumtoxinA, and inactive ingredients to be reconstituted with sterile, non-preserved, 0.9% sodium chloride solution saline
OTHERPlacebo
Placebo is a sterile lyophilized product consisting of inactive ingredients without the neurotoxin to be reconstituted with sterile, non-preserved 0.9% sodium chloride solution.
Sponsors
Revance Therapeutics, Inc.
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
QUADRUPLE (Subject, Caregiver, Investigator, Outcomes Assessor)
Masking description
Double Blinded. The subject, Sponsor, and study site research personnel will be blinded to the identity of the subject's assigned treatment.
Intervention model description
Eligible subjects will be randomized (1:1:1:1) to one of four treatment groups: Group 1: DAXI 250 U (N=32); Group 2: DAXI 375 U (N=32); Group 3: DAXI 500 U (N=32); Group 4: Placebo (N=32).
Eligibility
Sex/Gender
ALL
Age
18 Years to 75 Years
Healthy volunteers
No
Inclusion criteria
* 18 to 75 years of age * Written informed consent including authorization to release health information * Focal upper limb spasticity (ULS) after a stroke (as defined by WHO criteria) or traumatic brain injury (TBI), last stroke or TBI \> 24 weeks prior to Screening * ULS with the primary aggregate posture * Moderate to severe ULS with a MAS score ≥ 2 at the elbow, wrist, and finger flexors * Moderate to severe functional disability (Disability Assessment Score \[DAS\] score ≥2) on the principal target of treatment * Has sufficient cognitive and communication ability to be able to give informed consent
Exclusion criteria
* Upper limb spasticity attributable to an etiology other than stroke or TBI. * Bilateral upper limb paresis or quadriplegia. * Initiated in physiotherapy of the upper extremities ≤ 30 days prior to Screening or planned to start physiotherapy of the upper extremities during the course of the study. * Previous or planned treatment of the spastic upper limb with phenol, alcohol injection, or surgery * Profound muscular atrophy or fixed contracture leading to marked limitation on range of motion * Prior treatment with intrathecal baclofen * Any neuromuscular neurologic conditions (amyotrophic lateral sclerosis, Lambert- Eaton, myasthenia gravis)
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Change From Baseline at Week 6 on the Modified Ashworth Scale (MAS) in the Suprahypertonic Muscle Group (SMG) Score | Week 6 | Mean change from baseline at Week 6 in muscle tone measured with the Modified Ashworth Scale (MAS) in the Suprahypertonic Muscle Group (SMG) in one of the following: elbow, wrist, or finger flexors. Score range: 0 (Normal tone, no in tone) to 4 (Affected part{s} rigid in flexion or extension). |
| Physician Global Impression of Change (PGIC) Score | Week 6 | Mean score on the Physician Global Impression of Change (PGIC) score at week 6. The PGIC is a single-item, 9-point scale that measures the physician's impression of improvement following treatment. Score range: -4 (Markedly worse) to +4 (Markedly improved). |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Muscle Tone Improvement Responder Rate | Weeks 6 and 12 | Percentage of subjects who improve by a full point on the Modified Ashworth Scale (MAS) in the Suprahypertonic Muscle Group (SMG). Score range: 0 (Normal tone, no increase in tone) to 4 (Affected part(s) rigid in flexion or extension) |
| Physician Global Impression of Change (PGIC) Responder Rate | Weeks 6 and 12 | Percentage of subjects with improvement (i.e., a score of 1 to 4) on the Physician Global Impression of Change (PGIC). The PGIC is a single-item, 9-point scale that measures the physician's impression of improvement following treatment. Score range: -4 (Markedly worse) to +4 (Markedly improved). Scores of 1 or more indicate improvement following treatment. |
| Change From Baseline at Weeks 6 and 12 on the Disability Assessment Scale (DAS) Functional Impairment | Weeks 6 and 12 | Change from Baseline at Weeks 6 and 12 in functional impairment as measured by the Disability Assessment Scale (DAS) for the principal treatment target (PTT). DAS score range: 0 (No disability) to 3 (Severe disability - normal activities limited). |
| Duration of Effect | Up to 36 weeks | Duration of effect is defined as time from injection (in weeks) until loss of muscle tone improvement in the SMG, as indicated by a reduction from baseline in MAS score of \< 1-point and PGIC score is ≤ 0. |
Countries
United States
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| DAXI 250 U DAXI for injection for the treatment of Upper Limb Spasticity (ULS) in Adults with 250 U | 22 |
| DAXI 375 U DAXI for injection for the treatment of Upper Limb Spasticity (ULS) in Adults with 375 U | 19 |
| DAXI 500 U DAXI for injection for the treatment of Upper Limb Spasticity (ULS) in Adults with 500 U | 18 |
| Placebo Placebo group | 24 |
| Total | 83 |
Baseline characteristics
| Characteristic | DAXI 250 U | DAXI 375 U | DAXI 500 U | Placebo | Total |
|---|---|---|---|---|---|
| Age, Customized <= 50 years | 10 Participants | 6 Participants | 5 Participants | 7 Participants | 28 Participants |
| Age, Customized > 50 years | 12 Participants | 13 Participants | 13 Participants | 17 Participants | 55 Participants |
| Race/Ethnicity, Customized American Indian or Alaska Native | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race/Ethnicity, Customized Asian | 1 Participants | 1 Participants | 0 Participants | 0 Participants | 2 Participants |
| Race/Ethnicity, Customized Black | 4 Participants | 6 Participants | 3 Participants | 10 Participants | 23 Participants |
| Race/Ethnicity, Customized Native Hawaiian or Other Pacific Islander | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race/Ethnicity, Customized Not provided | 0 Participants | 0 Participants | 1 Participants | 0 Participants | 1 Participants |
| Race/Ethnicity, Customized Other | 0 Participants | 1 Participants | 0 Participants | 0 Participants | 1 Participants |
| Race/Ethnicity, Customized White | 17 Participants | 11 Participants | 14 Participants | 14 Participants | 56 Participants |
| Sex: Female, Male Female | 7 Participants | 10 Participants | 5 Participants | 12 Participants | 34 Participants |
| Sex: Female, Male Male | 15 Participants | 9 Participants | 13 Participants | 12 Participants | 49 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk | EG003 affected / at risk |
|---|---|---|---|---|
| deaths Total, all-cause mortality | 0 / 22 | 0 / 19 | 0 / 18 | 0 / 24 |
| other Total, other adverse events | 4 / 22 | 12 / 19 | 6 / 18 | 4 / 24 |
| serious Total, serious adverse events | 2 / 22 | 0 / 19 | 1 / 18 | 2 / 24 |
Outcome results
Primary
Change From Baseline at Week 6 on the Modified Ashworth Scale (MAS) in the Suprahypertonic Muscle Group (SMG) Score
Mean change from baseline at Week 6 in muscle tone measured with the Modified Ashworth Scale (MAS) in the Suprahypertonic Muscle Group (SMG) in one of the following: elbow, wrist, or finger flexors. Score range: 0 (Normal tone, no in tone) to 4 (Affected part{s} rigid in flexion or extension).
Time frame: Week 6
Population: Intent to treat population
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| DAXI 250 U | Change From Baseline at Week 6 on the Modified Ashworth Scale (MAS) in the Suprahypertonic Muscle Group (SMG) Score | -0.9 score on a scale | Standard Error 0.25 |
| DAXI 375 U | Change From Baseline at Week 6 on the Modified Ashworth Scale (MAS) in the Suprahypertonic Muscle Group (SMG) Score | -1.0 score on a scale | Standard Error 0.26 |
| DAXI 500 U | Change From Baseline at Week 6 on the Modified Ashworth Scale (MAS) in the Suprahypertonic Muscle Group (SMG) Score | -1.5 score on a scale | Standard Error 0.27 |
| Placebo | Change From Baseline at Week 6 on the Modified Ashworth Scale (MAS) in the Suprahypertonic Muscle Group (SMG) Score | -0.8 score on a scale | Standard Error 0.26 |
p-value: 0.7645ANCOVA
p-value: 0.5509ANCOVA
p-value: 0.0488ANCOVA
Primary
Physician Global Impression of Change (PGIC) Score
Mean score on the Physician Global Impression of Change (PGIC) score at week 6. The PGIC is a single-item, 9-point scale that measures the physician's impression of improvement following treatment. Score range: -4 (Markedly worse) to +4 (Markedly improved).
Time frame: Week 6
Population: Intent to treat population
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| DAXI 250 U | Physician Global Impression of Change (PGIC) Score | 1.5 score on a scale | Standard Error 0.29 |
| DAXI 375 U | Physician Global Impression of Change (PGIC) Score | 1.7 score on a scale | Standard Error 0.3 |
| DAXI 500 U | Physician Global Impression of Change (PGIC) Score | 1.7 score on a scale | Standard Error 0.32 |
| Placebo | Physician Global Impression of Change (PGIC) Score | 1.2 score on a scale | Standard Error 0.28 |
p-value: 0.3698ANCOVA
p-value: 0.1972ANCOVA
p-value: 0.2037ANCOVA
Secondary
Change From Baseline at Weeks 6 and 12 on the Disability Assessment Scale (DAS) Functional Impairment
Change from Baseline at Weeks 6 and 12 in functional impairment as measured by the Disability Assessment Scale (DAS) for the principal treatment target (PTT). DAS score range: 0 (No disability) to 3 (Severe disability - normal activities limited).
Time frame: Weeks 6 and 12
Population: Intent to treat population
| Arm | Measure | Group | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|---|
| DAXI 250 U | Change From Baseline at Weeks 6 and 12 on the Disability Assessment Scale (DAS) Functional Impairment | Week 6 | -0.9 score on a scale | Standard Error 0.19 |
| DAXI 250 U | Change From Baseline at Weeks 6 and 12 on the Disability Assessment Scale (DAS) Functional Impairment | Week 12 | -0.7 score on a scale | Standard Error 0.21 |
| DAXI 375 U | Change From Baseline at Weeks 6 and 12 on the Disability Assessment Scale (DAS) Functional Impairment | Week 6 | -1.2 score on a scale | Standard Error 0.19 |
| DAXI 375 U | Change From Baseline at Weeks 6 and 12 on the Disability Assessment Scale (DAS) Functional Impairment | Week 12 | -1.0 score on a scale | Standard Error 0.22 |
| DAXI 500 U | Change From Baseline at Weeks 6 and 12 on the Disability Assessment Scale (DAS) Functional Impairment | Week 12 | -0.5 score on a scale | Standard Error 0.21 |
| DAXI 500 U | Change From Baseline at Weeks 6 and 12 on the Disability Assessment Scale (DAS) Functional Impairment | Week 6 | -0.7 score on a scale | Standard Error 0.21 |
| Placebo | Change From Baseline at Weeks 6 and 12 on the Disability Assessment Scale (DAS) Functional Impairment | Week 6 | -0.50 score on a scale | Standard Error 0.2 |
| Placebo | Change From Baseline at Weeks 6 and 12 on the Disability Assessment Scale (DAS) Functional Impairment | Week 12 | -0.8 score on a scale | Standard Error 0.23 |
Secondary
Duration of Effect
Duration of effect is defined as time from injection (in weeks) until loss of muscle tone improvement in the SMG, as indicated by a reduction from baseline in MAS score of \< 1-point and PGIC score is ≤ 0.
Time frame: Up to 36 weeks
Population: Intent to treat population
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| DAXI 250 U | Duration of Effect | NA weeks |
| DAXI 375 U | Duration of Effect | 24.0 weeks |
| DAXI 500 U | Duration of Effect | 24.7 weeks |
| Placebo | Duration of Effect | 8.4 weeks |
Secondary
Muscle Tone Improvement Responder Rate
Percentage of subjects who improve by a full point on the Modified Ashworth Scale (MAS) in the Suprahypertonic Muscle Group (SMG). Score range: 0 (Normal tone, no increase in tone) to 4 (Affected part(s) rigid in flexion or extension)
Time frame: Weeks 6 and 12
Population: Intent to treat population
| Arm | Measure | Group | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| DAXI 250 U | Muscle Tone Improvement Responder Rate | Week 6 | 13 Participants |
| DAXI 250 U | Muscle Tone Improvement Responder Rate | Week 12 | 9 Participants |
| DAXI 375 U | Muscle Tone Improvement Responder Rate | Week 12 | 7 Participants |
| DAXI 375 U | Muscle Tone Improvement Responder Rate | Week 6 | 11 Participants |
| DAXI 500 U | Muscle Tone Improvement Responder Rate | Week 6 | 11 Participants |
| DAXI 500 U | Muscle Tone Improvement Responder Rate | Week 12 | 9 Participants |
| Placebo | Muscle Tone Improvement Responder Rate | Week 6 | 8 Participants |
| Placebo | Muscle Tone Improvement Responder Rate | Week 12 | 6 Participants |
Secondary
Physician Global Impression of Change (PGIC) Responder Rate
Percentage of subjects with improvement (i.e., a score of 1 to 4) on the Physician Global Impression of Change (PGIC). The PGIC is a single-item, 9-point scale that measures the physician's impression of improvement following treatment. Score range: -4 (Markedly worse) to +4 (Markedly improved). Scores of 1 or more indicate improvement following treatment.
Time frame: Weeks 6 and 12
Population: Intent to treat population
| Arm | Measure | Group | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| DAXI 250 U | Physician Global Impression of Change (PGIC) Responder Rate | Week 6 | 17 Participants |
| DAXI 250 U | Physician Global Impression of Change (PGIC) Responder Rate | Week 12 | 15 Participants |
| DAXI 375 U | Physician Global Impression of Change (PGIC) Responder Rate | Week 6 | 16 Participants |
| DAXI 375 U | Physician Global Impression of Change (PGIC) Responder Rate | Week 12 | 17 Participants |
| DAXI 500 U | Physician Global Impression of Change (PGIC) Responder Rate | Week 12 | 13 Participants |
| DAXI 500 U | Physician Global Impression of Change (PGIC) Responder Rate | Week 6 | 14 Participants |
| Placebo | Physician Global Impression of Change (PGIC) Responder Rate | Week 12 | 13 Participants |
| Placebo | Physician Global Impression of Change (PGIC) Responder Rate | Week 6 | 15 Participants |
Post Hoc
Change From Baseline at Week 4 in the Physician Global Impression of Change (PGIC) Score
Change from Baseline at Week 4 in the Physician Global Impression of Change (PGIC). Score range: -4 (Markedly worse) to +4 (Markedly improved).
Time frame: Week 4
Population: Intent to treat population
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| DAXI 250 U | Change From Baseline at Week 4 in the Physician Global Impression of Change (PGIC) Score | 1.5 score on a scale | Standard Error 0.24 |
| DAXI 375 U | Change From Baseline at Week 4 in the Physician Global Impression of Change (PGIC) Score | 1.7 score on a scale | Standard Error 0.24 |
| DAXI 500 U | Change From Baseline at Week 4 in the Physician Global Impression of Change (PGIC) Score | 1.8 score on a scale | Standard Error 0.26 |
| Placebo | Change From Baseline at Week 4 in the Physician Global Impression of Change (PGIC) Score | 0.9 score on a scale | Standard Error 0.23 |
p-value: 0.0562ANCOVA
p-value: 0.015ANCOVA
p-value: 0.0092ANCOVA
Post Hoc
Change From Baseline at Week 4 in the Suprahypertonic Muscle Group (SMG) Score
Mean change from baseline at Week 4 in muscle tone measured with the Modified Ashworth Scale (MAS) in the Suprahypertonic Muscle Group (SMG) in one of the following: elbow, wrist, or finger flexors. Score range: 0 (Normal tone, no in tone) to 4 (Affected part{s} rigid in flexion or extension).
Time frame: Week 4
Population: Intent to treat population
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| DAXI 250 U | Change From Baseline at Week 4 in the Suprahypertonic Muscle Group (SMG) Score | -0.9 score on a scale | Standard Error 0.22 |
| DAXI 375 U | Change From Baseline at Week 4 in the Suprahypertonic Muscle Group (SMG) Score | -0.9 score on a scale | Standard Error 0.23 |
| DAXI 500 U | Change From Baseline at Week 4 in the Suprahypertonic Muscle Group (SMG) Score | -1.8 score on a scale | Standard Error 0.24 |
| Placebo | Change From Baseline at Week 4 in the Suprahypertonic Muscle Group (SMG) Score | -0.6 score on a scale | Standard Error 0.22 |
p-value: 0.4324ANCOVA
p-value: 0.3893ANCOVA
p-value: 0.0002ANCOVA