Cervical Dystonia
Conditions
Brief summary
The purpose of the protocol is to evaluate the efficacy and safety of Dysport® using 2 mL dilution compared with placebo for the treatment of Cervical Dystonia.
Interventions
BIOLOGICALBotulinum toxin type A
Intramuscular injection, between 250 and 500 units (U)/vial using 2mL dilution, 1 cycle only
DRUGPlacebo
Up to 2mL
Sponsors
Ipsen
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
DOUBLE (Subject, Investigator)
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
* Primary diagnosis of Cervical Dystonia at least 9 months since onset and either previously untreated with botulinum toxin or currently treated with Botox at a total dosing range of 100-200 U and ≤60 U in the sternocleidomastoid muscle at the last injection cycle, and having had a satisfactory treatment response in the principal investigator's judgment during the last two sequential Botox treatment cycles. * TWSTRS total score≥ 20; TWSTRS-severity subscale score\> 10;
Exclusion criteria
* In apparent remission from Cervical Dystonia * Diagnosis of pure retrocollis or pure anterocollis * For non-naïve subjects, previous poor response to either of the last two Botox treatments * Known requirement of \<100U or \>200U of Botox injected into the neck muscles
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Change From Baseline in Toronto Western Spasmodic Torticollis Rating Scale (TWSTRS) Total Score at Week 4. | 4 weeks post-treatment | The change from baseline in the TWSTRS total score at Week 4 was determined for the subjects who received a single dose of Dysport® or placebo by intramuscular injection at the baseline visit (Day 1), and is expressed as weighted overall treatment difference. The TWSTRS is an assessment scale used to measure the impact of CD on subjects, and comprises 3 subscales: severity, disability and pain, each of which is scored independently. The total score from the 3 subscales gives the TWSTRS total score with a value from 0 to 85 (best to worst). The score was assessed by the investigator prior to study treatment at baseline and at all post-treatment visits. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Change From Baseline in Clinical Global Impression of Change (CGIC) in CD at Week 2. | 2 weeks post-treatment | The CGIC is an investigator-reported assessment of the global clinical change in CD since study treatment administration. The CGIC uses a seven-point Likert scale ranging from +3 (very much improved) to -3 (very much worse), and was assessed by the investigator at the Week 2 and Week 4 visits. |
| TWSTRS Responders at Week 2. | 2 weeks post-treatment | Treatment response was determined as the number of responders at Week 2 relative to the baseline TWSTRS total score. A treatment responder is defined as a subject who had at least a 30% reduction in the TWSTRS total score after treatment. This was calculated as (\[Week 2 score - baseline score\]/baseline score) \* 100. |
| Change From Baseline in CGIC in CD at Week 4. | 4 weeks post-treatment | The CGIC is an investigator-reported assessment of the global clinical change in CD since study treatment administration. The CGIC uses a seven-point Likert scale ranging from +3 (very much improved) to -3 (very much worse), and was assessed by the investigator at the Week 2 and Week 4 visits. |
| Change From Baseline in TWSTRS Total Score at Week 2. | 2 weeks post-treatment | The change from baseline in the TWSTRS total score at Week 2 was determined for the subjects who received a single dose of Dysport® or placebo by intramuscular injection at the baseline visit (Day 1), and is expressed as weighted overall treatment difference. The TWSTRS is an assessment scale used to measure the impact of CD on subjects, and comprises 3 subscales: severity, disability and pain, each of which is scored independently. The total score from the 3 subscales gives the TWSTRS total score with a value from 0 to 85 (best to worst). The score was assessed by the investigator prior to study treatment at baseline and at all post-treatment visits. |
| Change From Baseline in Cervical Dystonia Impact Profile-58 (CDIP-58) Total Score at Week 4. | 4 weeks post-treatment | The CDIP-58 scale is a subject-based rating scale measuring the health impact of CD measured in 8 health dimensions including head and neck symptoms, pain and discomfort, upper limb activities, walking, sleep, annoyance, mood and psychosocial functioning. Subscale scores were transformed to a common theoretical range of 0 (no impact) to 100 (most impact). Negative changes from the baseline total score indicate improvement in the impact of CD on health whereas postive changes indicate worsening. |
| Change From Baseline in CDIP-58 Total Score at Week 2. | 2 weeks post-treatment | The CDIP-58 scale is a subject-based rating scale measuring the health impact of CD measured in 8 health dimensions including head and neck symptoms, pain and discomfort, upper limb activities, walking, sleep, annoyance, mood and psychosocial functioning. Subscale scores were transformed to a common theoretical range of 0 (no impact) to 100 (most impact). Negative changes from the baseline total score indicate improvement in the impact of CD on health whereas postive changes indicate worsening. The hierarchical testing procedure would only be conducted if the previous secondary efficacy endpoint (change from baseline in CDIP-58 total score at Week 4) reached a statistically significant treatment effect. This secondary efficacy endpoint (change from baseline in CDIP-58 total score at Week 2) was performed to characterise the full clinical effect. |
| TWSTRS Responders at Week 4. | 4 weeks post-treatment | Treatment response was determined as the number of responders at Week 4 relative to the baseline TWSTRS total score. A treatment responder is defined as a subject who had at least a 30% reduction in the TWSTRS total score after treatment. This was calculated as (\[Week 4 score - baseline score\]/baseline score) \* 100. |
Countries
United States
Participant flow
Recruitment details
First subject enrolled: 7 January 2013; last subject completed: 9 January 2015. 46 investigational sites in the United States of America were planned, 43 sites were initiated and 38 sites enrolled adult subjects with cervical dystonia (CD).
Pre-assignment details
150 subjects were screened; 16 subjects failed screening. 134 subjects were enrolled (signed informed consent) and were randomised with a 2:1 ratio of Dysport®:placebo. Randomisation was also stratified for subjects who were Botulinum toxin type A (BoNT-A) treatment naive or non-naive at baseline.
Participants by arm
| Arm | Count |
|---|---|
| Dysport® Subjects were randomised to receive a single intramuscular injected dose of study medication, Dysport® 500 U/vial using a 2 mL dilution scheme. The dose of Dysport® was between 250 U and 500 U divided among a minimum of two clinically indicated muscles. Dysport® contains the neurotoxin Clostridium botulinum type A toxin-hemagglutinin complex (abobotulinumtoxinA). | 89 |
| Placebo Subjects were randomised to receive a single dose of placebo by intramuscular injection. The placebo was provided in glass vials indistinguishable from the Dysport® vials. The placebo contained only the excipients used in Dysport® without the toxin, provided as a white lyophilised powder for reconstitution with the same storage and preparation conditions as for Dysport®. | 45 |
| Total Title | 134 |
| Total | 268 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Overall Study | Adverse Event | 1 | 0 |
| Overall Study | Entered into open label extension study | 25 | 22 |
| Overall Study | Lost to Follow-up | 2 | 0 |
| Overall Study | Sponsor decision | 1 | 0 |
| Overall Study | Subject decision | 2 | 2 |
| Overall Study | Withdrawal by Subject | 1 | 0 |
Baseline characteristics
| Characteristic | Dysport® | Placebo | Total Title |
|---|---|---|---|
| Age, Customized 18-24 years | 0 participants | 0 participants | 0 participants |
| Age, Customized 25-34 years | 2 participants | 2 participants | 4 participants |
| Age, Customized 35-44 years | 9 participants | 4 participants | 13 participants |
| Age, Customized 45-54 years | 26 participants | 14 participants | 40 participants |
| Age, Customized 55-64 years | 26 participants | 12 participants | 38 participants |
| Age, Customized 65-74 years | 22 participants | 11 participants | 33 participants |
| Age, Customized >75 years | 4 participants | 2 participants | 6 participants |
| Sex: Female, Male Female | 59 Participants | 28 Participants | 87 Participants |
| Sex: Female, Male Male | 30 Participants | 17 Participants | 47 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — |
| other Total, other adverse events | 35 / 88 | 10 / 45 |
| serious Total, serious adverse events | 4 / 88 | 1 / 45 |
Outcome results
Primary
Change From Baseline in Toronto Western Spasmodic Torticollis Rating Scale (TWSTRS) Total Score at Week 4.
The change from baseline in the TWSTRS total score at Week 4 was determined for the subjects who received a single dose of Dysport® or placebo by intramuscular injection at the baseline visit (Day 1), and is expressed as weighted overall treatment difference. The TWSTRS is an assessment scale used to measure the impact of CD on subjects, and comprises 3 subscales: severity, disability and pain, each of which is scored independently. The total score from the 3 subscales gives the TWSTRS total score with a value from 0 to 85 (best to worst). The score was assessed by the investigator prior to study treatment at baseline and at all post-treatment visits.
Time frame: 4 weeks post-treatment
Population: The modified ITT population consisted of all randomised subjects with both a baseline and a Week 4 post-treatment TWSTRS total score assessment.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Dysport® | Change From Baseline in Toronto Western Spasmodic Torticollis Rating Scale (TWSTRS) Total Score at Week 4. | Baseline (Day 1) Pre-treatment | 42.5 units on a scale | Standard Deviation 10.4 |
| Dysport® | Change From Baseline in Toronto Western Spasmodic Torticollis Rating Scale (TWSTRS) Total Score at Week 4. | Week 4 Post-treatment | 31.7 units on a scale | Standard Deviation 15.29 |
| Placebo | Change From Baseline in Toronto Western Spasmodic Torticollis Rating Scale (TWSTRS) Total Score at Week 4. | Baseline (Day 1) Pre-treatment | 42.4 units on a scale | Standard Deviation 10.63 |
| Placebo | Change From Baseline in Toronto Western Spasmodic Torticollis Rating Scale (TWSTRS) Total Score at Week 4. | Week 4 Post-treatment | 39.9 units on a scale | Standard Deviation 12.46 |
Comparison: The superiority of Dysport® to placebo was tested at a two-tailed 5% level by using a stratified analysis of covariance (ANCOVA) with baseline TWSTRS total score as covariate and stratified by the randomisation stratification factor (BoNT-A naïve versus BoNT-A non-naïve).p-value: <0.00195% CI: [-12.17, -4.47]t-test, 2 sided
Secondary
Change From Baseline in CDIP-58 Total Score at Week 2.
The CDIP-58 scale is a subject-based rating scale measuring the health impact of CD measured in 8 health dimensions including head and neck symptoms, pain and discomfort, upper limb activities, walking, sleep, annoyance, mood and psychosocial functioning. Subscale scores were transformed to a common theoretical range of 0 (no impact) to 100 (most impact). Negative changes from the baseline total score indicate improvement in the impact of CD on health whereas postive changes indicate worsening. The hierarchical testing procedure would only be conducted if the previous secondary efficacy endpoint (change from baseline in CDIP-58 total score at Week 4) reached a statistically significant treatment effect. This secondary efficacy endpoint (change from baseline in CDIP-58 total score at Week 2) was performed to characterise the full clinical effect.
Time frame: 2 weeks post-treatment
Population: The ITT population consisted of all randomised subjects. Only subjects with data available at the point of testing are reported. A total of 8 subjects (6 from the Dysport® arm and 2 from the Placebo arm) had missing values for CDIP-58.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Dysport® | Change From Baseline in CDIP-58 Total Score at Week 2. | -5.8 units on a scale | Standard Deviation 13.96 |
| Placebo | Change From Baseline in CDIP-58 Total Score at Week 2. | -4.3 units on a scale | Standard Deviation 14.49 |
Comparison: The superiority of Dysport® to placebo on CDIP-58 was tested at a two-tailed 5% level by using an ANOVA with treatment and randomisation stratification factor as main effects.p-value: =0.583ANOVA
Secondary
Change From Baseline in Cervical Dystonia Impact Profile-58 (CDIP-58) Total Score at Week 4.
The CDIP-58 scale is a subject-based rating scale measuring the health impact of CD measured in 8 health dimensions including head and neck symptoms, pain and discomfort, upper limb activities, walking, sleep, annoyance, mood and psychosocial functioning. Subscale scores were transformed to a common theoretical range of 0 (no impact) to 100 (most impact). Negative changes from the baseline total score indicate improvement in the impact of CD on health whereas postive changes indicate worsening.
Time frame: 4 weeks post-treatment
Population: The ITT population consisted of all randomised subjects. Only subjects with data available at the point of testing are reported. A total of 8 subjects (7 from the Dysport® arm and 1 from the Placebo arm) had missing values for CDIP-58.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Dysport® | Change From Baseline in Cervical Dystonia Impact Profile-58 (CDIP-58) Total Score at Week 4. | -8.5 units on a scale | Standard Deviation 14.26 |
| Placebo | Change From Baseline in Cervical Dystonia Impact Profile-58 (CDIP-58) Total Score at Week 4. | -4.7 units on a scale | Standard Deviation 16.18 |
Comparison: The superiority of Dysport® to placebo on CDIP-58 was tested at a two-tailed 5% level by using an ANOVA with treatment and randomisation stratification factor as main effects.p-value: =0.174ANOVA
Secondary
Change From Baseline in CGIC in CD at Week 4.
The CGIC is an investigator-reported assessment of the global clinical change in CD since study treatment administration. The CGIC uses a seven-point Likert scale ranging from +3 (very much improved) to -3 (very much worse), and was assessed by the investigator at the Week 2 and Week 4 visits.
Time frame: 4 weeks post-treatment
Population: The ITT population consisted of all randomised subjects. Only subjects with data available at the point of testing are reported. A total of 3 subjects (all from the Dysport® arm) had missing values for CGIC.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Dysport® | Change From Baseline in CGIC in CD at Week 4. | 1.2 units on a scale | Standard Deviation 1.5 |
| Placebo | Change From Baseline in CGIC in CD at Week 4. | 0.1 units on a scale | Standard Deviation 1.27 |
Comparison: The superiority of Dysport® to placebo on CGIC of CD was tested at a two-tailed 5% level by using an ANOVA with treatment and randomisation stratification factor as main effects.p-value: <0.001ANOVA
Secondary
Change From Baseline in Clinical Global Impression of Change (CGIC) in CD at Week 2.
The CGIC is an investigator-reported assessment of the global clinical change in CD since study treatment administration. The CGIC uses a seven-point Likert scale ranging from +3 (very much improved) to -3 (very much worse), and was assessed by the investigator at the Week 2 and Week 4 visits.
Time frame: 2 weeks post-treatment
Population: The ITT population consisted of all randomised subjects. Only subjects with data available at the point of testing are reported. A total of 4 subjects (3 from the Dysport® arm and 1 from the Placebo arm) had missing values for CGIC.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Dysport® | Change From Baseline in Clinical Global Impression of Change (CGIC) in CD at Week 2. | 1.2 units on a scale | Standard Deviation 1.32 |
| Placebo | Change From Baseline in Clinical Global Impression of Change (CGIC) in CD at Week 2. | -0.0 units on a scale | Standard Deviation 1.07 |
Comparison: The superiority of Dysport® to placebo on CGIC of CD was tested at a two-tailed 5% level by using an analysis of variance (ANOVA) with treatment and randomisation stratification factor as main effects.p-value: <0.001ANOVA
Secondary
Change From Baseline in TWSTRS Total Score at Week 2.
The change from baseline in the TWSTRS total score at Week 2 was determined for the subjects who received a single dose of Dysport® or placebo by intramuscular injection at the baseline visit (Day 1), and is expressed as weighted overall treatment difference. The TWSTRS is an assessment scale used to measure the impact of CD on subjects, and comprises 3 subscales: severity, disability and pain, each of which is scored independently. The total score from the 3 subscales gives the TWSTRS total score with a value from 0 to 85 (best to worst). The score was assessed by the investigator prior to study treatment at baseline and at all post-treatment visits.
Time frame: 2 weeks post-treatment
Population: The ITT population consisted of all randomised subjects.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Dysport® | Change From Baseline in TWSTRS Total Score at Week 2. | Baseline (Day 1) pre-treatment | 42.1 units on a scale | Standard Deviation 10.77 |
| Dysport® | Change From Baseline in TWSTRS Total Score at Week 2. | Week 2 post-treatment | 34.5 units on a scale | Standard Deviation 14.54 |
| Placebo | Change From Baseline in TWSTRS Total Score at Week 2. | Baseline (Day 1) pre-treatment | 42.4 units on a scale | Standard Deviation 10.63 |
| Placebo | Change From Baseline in TWSTRS Total Score at Week 2. | Week 2 post-treatment | 39.8 units on a scale | Standard Deviation 12.72 |
Comparison: The superiority of Dysport® to placebo was tested at a two-tailed 5% level by using a stratified ANCOVA with baseline TWSTRS total score as covariate and stratified by the randomisation stratification factor (BoNT-A naïve versus BoNT-A non-naïve).p-value: =0.00195% CI: [-8.67, -2.14]t-test, 2 sided
Secondary
TWSTRS Responders at Week 2.
Treatment response was determined as the number of responders at Week 2 relative to the baseline TWSTRS total score. A treatment responder is defined as a subject who had at least a 30% reduction in the TWSTRS total score after treatment. This was calculated as (\[Week 2 score - baseline score\]/baseline score) \* 100.
Time frame: 2 weeks post-treatment
Population: The ITT population consisted of all randomised subjects.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Dysport® | TWSTRS Responders at Week 2. | 27.9 percentage of participants |
| Placebo | TWSTRS Responders at Week 2. | 11.4 percentage of participants |
Comparison: The superiorty of Dysport® to placebo on treatment response was tested at a two-tailed 5% level by using a Mantel-Haenszel chi-squared test stratified by the randomisation factor.p-value: =0.033Mantel-Haenszel chi-squared test
Secondary
TWSTRS Responders at Week 4.
Treatment response was determined as the number of responders at Week 4 relative to the baseline TWSTRS total score. A treatment responder is defined as a subject who had at least a 30% reduction in the TWSTRS total score after treatment. This was calculated as (\[Week 4 score - baseline score\]/baseline score) \* 100.
Time frame: 4 weeks post-treatment
Population: The ITT population consisted of all randomised subjects.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Dysport® | TWSTRS Responders at Week 4. | 41.9 percentage of participants |
| Placebo | TWSTRS Responders at Week 4. | 11.1 percentage of participants |
Comparison: The superiorty of Dysport® to placebo on treatment response was tested at a two-tailed 5% level by using a Mantel-Haenszel chi-squared test stratified by the randomisation factor.p-value: <0.001Mantel-Haenszel chi-squared test