Blepharospasm
Conditions
Brief summary
Patients received one injection with incobotulinumtoxinA (Xeomin) or placebo at baseline. Thereafter, all patients who entered the Open-Label Extension Period (OLEX) received up to five injection sessions of incobotulinumtoxinA (Xeomin) during the OLEX period.
Interventions
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, up to 50 Units per eye; Mode of administration: intramuscular injection
DRUGPlacebo
Placebo to incobotulinumtoxinA (Xeomin) powder for solution for injection dose (Main Period only): one injection session of solution, prepared by reconstitution of powder with 0.9% Sodium chloride (NaCl), placebo volume corresponding to up to 50 Units per eye; Mode of administration: intramuscular injection
Sponsors
Merz Pharmaceuticals GmbH
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
DOUBLE (Subject, Investigator)
Eligibility
Sex/Gender
ALL
Age
18 Years to 80 Years
Healthy volunteers
No
Inclusion criteria
Main Inclusion Criteria: * Male or female pretreated outpatients between ages 18 and 80 years (inclusive) * A clinical diagnosis of bilateral blepharospasm (BEB) characterized by spontaneous, spasmodic, intermittent or persistent involuntary contractions of the orbicular oculi muscles * A need for injection of Botulinum toxin (defined by a Jankovic Rating Scale (JRS) severity subscore \>= 2) * On a stable dose of other medications (if any) used for focal dystonia treatment (e.g. anticholinergics and benzodiazepines) for at least 3 months prior to and expected throughout the Main Period * Source documentation of the last two consecutive injection sessions with BOTOX® and a stable satisfactory therapeutic response directly prior to trial entry * At least 10 weeks must have been passed between the last injection with BOTOX® for BEB and Baseline Main
Exclusion criteria
* Atypical variant of BEB caused by inhibition of levator palpebrae muscle * Myotomy or denervation surgery in the affected muscles (e.g. peripheral denervation and/or spinal cord stimulation) * The previous two injections with BOTOX® with more than 50 Units per eye * Hypersensitivity to human serum albumin, sucrose, or Botulinum toxin A * Neuroleptic induced blepharospasm * Diagnosis of myasthenia gravis, Lambert-Eaton syndrome, amyotrophic lateral sclerosis, or any other significant neuromuscular disease which might interfere with the trial * Treatment with Botulinum toxins for any indication other than BEB within 4 months prior to Baseline and during the trial
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Jankovic Rating Scale (JRS) Change From Baseline in the JRS Severity Subscore at Week 6 After Injection (Assessed by a Blinded Independent Rater) | Baseline, week 6 | The Jankovic Rating Scale (JRS) is used for classification of the patient's individual symptoms of blepharospasm and for determination of the therapeutic efficacy of study medication. The JRS sumscore is the sum of the two components of the scale: * JRS-Severity score which ranges from 0 (=absence of severity) to 4 (=maximum severity) * JRS-Frequency score which ranges from 0 (=no frequency) to 4 (=maximum frequency) The change from baseline was calculated as the score at the corresponding visit minus the baseline score. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Jankovic Rating Scale (JRS) Change From Baseline in the JRS Severity Subscore at Week 6 After Injection (Assessed by Subject Diary) | Baseline, week 6 | The Jankovic Rating Scale (JRS) is used for classification of the patient's individual symptoms of blepharospasm and for determination of the therapeutic efficacy of study medication. The JRS sumscore is the sum of the two components of the scale: * JRS-Severity score which ranges from 0 (=absence of severity) to 4 (=maximum severity) * JRS-Frequency score which ranges from 0 (=no frequency) to 4 (=maximum frequency) The change from baseline was calculated as the score at the corresponding visit minus the baseline score. |
| Blepharospasm Disability Index (BSDI) Change From Baseline in the BSDI at Week 6 After Injection | Baseline, week 6 | The Blepharospasm Disability Index is a scale for the assessment of impairment of specific activities of daily living caused by blepharospasm. The BSDI consists of six items (driving a vehicle; reading; watching TV; shopping; getting about on foot (walking); doing everyday activities), each ranges from 0 (=no impairment) to 4 (=no longer possible due to illness). The change from baseline was calculated as the score at the corresponding visit minus the baseline score. |
| Patient Evaluation of Global Response (PEGR) at Final Visit | Final visit (up to week 20 after injection of the Main Period) | The PEGR is a descriptive subjective 9-point response scale ranging from complete abolishment of signs and symptoms (value=+4) down to very marked worsening (value=-4). |
Countries
Canada, United States
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| incobotulinumtoxinA (Xeomin) incobotulinumtoxinA (Xeomin) (active ingredient: Clostridium Botulinum neurotoxin Type A free from complexing proteins) powder for solution for injection | 75 |
| Placebo Placebo to incobotulinumtoxinA (Xeomin) powder for solution for injection Dose (Main Period only): one injection session of solution, prepared by reconstitution of powder with 0.9% NaCl;Mode of administration: intramuscular injection | 34 |
| Total | 109 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Main Period - 6 to 20 Weeks | Consent Withdrawn | 1 | 0 |
| Main Period - 6 to 20 Weeks | Dosing Error At Visit 2 (Baseline) | 0 | 1 |
| Main Period - 6 to 20 Weeks | Lost to Follow-up | 0 | 1 |
| Main Period - 6 to 20 Weeks | Withdrawal Criteria Occurred | 4 | 0 |
| Open-Label Ext. Period - up to 68 Weeks | Consent Withdrawn | 6 | 0 |
| Open-Label Ext. Period - up to 68 Weeks | Injection in Wrong Muscle | 1 | 0 |
| Open-Label Ext. Period - up to 68 Weeks | Lack of Efficacy | 4 | 0 |
| Open-Label Ext. Period - up to 68 Weeks | Lost to Follow-up | 2 | 0 |
| Open-Label Ext. Period - up to 68 Weeks | OLEX Drug Given at Baseline | 1 | 0 |
| Open-Label Ext. Period - up to 68 Weeks | Subject Received Botox Injection | 1 | 0 |
| Open-Label Ext. Period - up to 68 Weeks | Subjects Needed Further Injection | 1 | 0 |
| Open-Label Ext. Period - up to 68 Weeks | Withdrawal Criteria Occurred | 4 | 0 |
Baseline characteristics
| Characteristic | incobotulinumtoxinA (Xeomin) | Placebo | Total |
|---|---|---|---|
| Age Continuous | 61.5 years STANDARD_DEVIATION 11 | 62.6 years STANDARD_DEVIATION 8.7 | 61.9 years STANDARD_DEVIATION 10.3 |
| Sex: Female, Male Female | 49 Participants | 22 Participants | 71 Participants |
| Sex: Female, Male Male | 26 Participants | 12 Participants | 38 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — |
| other Total, other adverse events | 45 / 74 | 13 / 34 |
| serious Total, serious adverse events | 0 / 74 | 1 / 34 |
Outcome results
Primary
Jankovic Rating Scale (JRS) Change From Baseline in the JRS Severity Subscore at Week 6 After Injection (Assessed by a Blinded Independent Rater)
The Jankovic Rating Scale (JRS) is used for classification of the patient's individual symptoms of blepharospasm and for determination of the therapeutic efficacy of study medication. The JRS sumscore is the sum of the two components of the scale: * JRS-Severity score which ranges from 0 (=absence of severity) to 4 (=maximum severity) * JRS-Frequency score which ranges from 0 (=no frequency) to 4 (=maximum frequency) The change from baseline was calculated as the score at the corresponding visit minus the baseline score.
Time frame: Baseline, week 6
Population: Intention to treat population: all participants randomized were included in the primary efficacy analysis; Last Observation Carried Forward (LOCF) imputation technique used for missing values
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| incobotulinumtoxinA (Xeomin) | Jankovic Rating Scale (JRS) Change From Baseline in the JRS Severity Subscore at Week 6 After Injection (Assessed by a Blinded Independent Rater) | -0.8 Points on a scale | Standard Error 0.13 |
| Placebo | Jankovic Rating Scale (JRS) Change From Baseline in the JRS Severity Subscore at Week 6 After Injection (Assessed by a Blinded Independent Rater) | 0.2 Points on a scale | Standard Error 0.18 |
Comparison: The null hypothesis in the analysis of covariance (ANCOVA) model was the absence of difference in the change from baseline in the JRS severity subscore between incobotulinumtoxinA (Xeomin) and placebo. The ANCOVA model was performed 2-sided (type-I error=5 percent) and change from baseline in the JRS Severity subscore assessed by a blinded Independent Rater as dependent variable. The independent variables were treatment, baseline JRS Severity subscore, gender, age, dose group, and pooled center.p-value: <0.00195% CI: [-1.4, -0.5]ANCOVA
Secondary
Blepharospasm Disability Index (BSDI) Change From Baseline in the BSDI at Week 6 After Injection
The Blepharospasm Disability Index is a scale for the assessment of impairment of specific activities of daily living caused by blepharospasm. The BSDI consists of six items (driving a vehicle; reading; watching TV; shopping; getting about on foot (walking); doing everyday activities), each ranges from 0 (=no impairment) to 4 (=no longer possible due to illness). The change from baseline was calculated as the score at the corresponding visit minus the baseline score.
Time frame: Baseline, week 6
Population: Intention to treat population by using the Last Observation Carried Forward (LOCF) imputation technique for missing values
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| incobotulinumtoxinA (Xeomin) | Blepharospasm Disability Index (BSDI) Change From Baseline in the BSDI at Week 6 After Injection | -0.4 Points on a scale | Standard Deviation 0.69 |
| Placebo | Blepharospasm Disability Index (BSDI) Change From Baseline in the BSDI at Week 6 After Injection | 0.11 Points on a scale | Standard Deviation 0.67 |
Secondary
Jankovic Rating Scale (JRS) Change From Baseline in the JRS Severity Subscore at Week 6 After Injection (Assessed by Subject Diary)
The Jankovic Rating Scale (JRS) is used for classification of the patient's individual symptoms of blepharospasm and for determination of the therapeutic efficacy of study medication. The JRS sumscore is the sum of the two components of the scale: * JRS-Severity score which ranges from 0 (=absence of severity) to 4 (=maximum severity) * JRS-Frequency score which ranges from 0 (=no frequency) to 4 (=maximum frequency) The change from baseline was calculated as the score at the corresponding visit minus the baseline score.
Time frame: Baseline, week 6
Population: Intention to treat population by using the Last Observation Carried Forward (LOCF) imputation technique for missing values
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| incobotulinumtoxinA (Xeomin) | Jankovic Rating Scale (JRS) Change From Baseline in the JRS Severity Subscore at Week 6 After Injection (Assessed by Subject Diary) | -0.75 Points on a scale | Standard Deviation 1.24 |
| Placebo | Jankovic Rating Scale (JRS) Change From Baseline in the JRS Severity Subscore at Week 6 After Injection (Assessed by Subject Diary) | 0.16 Points on a scale | Standard Deviation 1.07 |
Secondary
Patient Evaluation of Global Response (PEGR) at Final Visit
The PEGR is a descriptive subjective 9-point response scale ranging from complete abolishment of signs and symptoms (value=+4) down to very marked worsening (value=-4).
Time frame: Final visit (up to week 20 after injection of the Main Period)
Population: Intention to treat population with missing values imputed by no effect.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| incobotulinumtoxinA (Xeomin) | Patient Evaluation of Global Response (PEGR) at Final Visit | 1.3 Points on a scale | Standard Deviation 2.09 |
| Placebo | Patient Evaluation of Global Response (PEGR) at Final Visit | -0.6 Points on a scale | Standard Deviation 2.16 |