Bilateral Blepharospasm (BEB)
Conditions
Brief summary
This phase 3 study will serve to collect efficacy and safety data of two different doses of NT 201 in subjects suffering from Bilateral Blepharospasm (BEB) who are BTX treatment-naïve. In this study, BTX treatment-naïve subjects are defined as those who have not received BTX treatment within the last 12 months for the treatment of BEB. This definition aims to avoid bias by comparison of treatment effects in the subject's assessments. Furthermore, this study will substantiate the existing efficacy and safety database for the indication BEB.
Detailed description
Subjects to receive one injection with NT 201 or placebo at baseline of the placebo-controlled first cycle. Thereafter, all subjects entering the Open-Label Extension Period (OLEX) to receive a second injection of NT 201 (second injection cycle).
Interventions
DRUGPlacebo
Main Period: Placebo to IncobotulinumtoxinA (Xeomin), powder for solution for injection, prepared by reconstitution of powder with 0.9% Sodium Chloride (NaCl).
DRUGIncobulinumtoxinA (Xeomin), 25 Units
IncobotulinumtoxinA (active ingredient: Clostridium Botulinum neurotoxin Type A free from complexing proteins) powder for solution for injection, prepared by reconstitution of powder with 0.9% Sodium Chloride (NaCl). Main Period: 25 Units per eye.
DRUGIncobotulinumtoxinA (Xeomin), 12.5 Units
IncobotulinumtoxinA (active ingredient: Clostridium Botulinum neurotoxin Type A free from complexing proteins) powder for solution for injection, prepared by reconstitution of powder with 0.9% Sodium Chloride (NaCl). Main Period: 12.5 Units per eye.
DRUGIncobotulinumtoxinA (Xeomin), 35 Units
IncobotulinumtoxinA (active ingredient: Clostridium Botulinum neurotoxin Type A free from complexing proteins) powder for solution for injection, prepared by reconstitution of powder with 0.9% Sodium Chloride (NaCl). Open-Label Extension: up to 35 Units per eye.
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
* Male or female out-patients age ≥ 18 and ≤ 80 years. * A clinical diagnosis of bilateral BEB characterized by spontaneous, spasmodic, intermittent or persistent involuntary contractions of orbicular oculi muscles. * A need for injection of BTX defined as a Jankovic Rating Scale \[JRS\] severity subscore ≥ 2. * Treatment-naïve subject defined as at least 12 months without BTX of any serotype for the treatment of BEB before administration of IP.
Exclusion criteria
* Subject with any previous unsuccessful treatment with BTX of any serotype for the treatment of BEB. * Atypical variant of BEB (e.g., apraxia of the eyelid opening) caused by inhibition of levator palpebrae muscle. * Neuroleptic-induced blepharospasm. * Myotomy or denervation surgery in the affected muscles (e.g., peripheral denervation, spinal cord stimulation) and surgery in the upper face. * Generalized disorders of muscles activity (e.g., myasthenia gravis in particular ocularis, Lambert-Eaton-Syndrome, amyotrophic lateral sclerosis) or any other significant neuromuscular dysfunction which might interfere with the study.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Double-blind MP: Change From Baseline in JRS Severity Subscore at Day 43 (Visit 4) | Baseline, Day 43 (Visit 4) | JRS severity subscore was used to classify individual symptoms of blepharospasm and to determine therapeutic efficacy. JRS severity subscore ranges from 0 to 4, where 0: None; 1: increased blinking present with external stimuli; 2: Mild but spontaneous eyelid fluttering, definitely noticeable, possibly embarrassing, but not functionally disabling, 3: Moderate, very noticeable spasm of eyelids only, mildly incapacitating, 4: Severe, incapacitating spasm of eyelids and possibly other facial muscles. Values represent least square (LS) mean differences between baseline and visit 4 resulting from analysis of covariance (ANCOVA) with treatment group, pooled site, and gender as fixed factors and baseline JRS severity subscore and age as covariates and missings replaced using the last observation carried forward (LOCF) method. Negative values denote improvement, while positive values denote deterioration vs. baseline. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Double-blind MP: Change From Baseline in Blepharospasm Disability Index (BSDI) at Day 43 (Visit 4) | Baseline, Day 43 (Visit 4) | BSDI is a scale for assessment of impairment of specific activities of daily living caused by blepharospasm. BSDI consists of six items (driving a vehicle; reading; watching TV; shopping; getting about on foot (walking); doing everyday activities), each ranging from 0 (=no impairment) to 4 (=no longer possible due to illness). The BSDI total score is a mean score for non-missing items ranging from 0 to 4. It is calculated by adding scores of all applicable and answered items, and dividing the resulting sum by the number of items answered. Outcome values represent LS mean differences between baseline and visit 4 (visit 4 value minus baseline value) resulting from ANCOVA with treatment group, pooled site, gender as fixed factors and baseline BSDI total score, age as covariates. Missings were replaced by the LOCF method. Negative values denote an improvement, while positive values denote deterioration vs. baseline. |
| Double-blind MP: Patient Evaluation of Global Response (PEGR) at Final Visit (Day 43-Day 141) | Baseline, Final Visit (Day 43-Day 141) | PEGR scale is a descriptive subjective 9-point response self-rating scale ranging from complete abolishment of signs and symptoms (value=+4) down to very marked worsening (value=-4). Outcome values represent least square means at visit 4 resulting from an ANCOVA with treatment group, pooled site, gender as fixed factors and age as covariates. Missing were set to a zero effect (value=0). Positive values denote an improvement, while negative values denote deterioration. |
Countries
Greece, Malaysia, Sri Lanka
Participant flow
Pre-assignment details
A total of 68 participants were screened, 61 were enrolled and treated of which 55 completed the double-blind main period (MP). 39 participants from the double-blind MP entered the Open label Extension (OLEX) period and completed the study.
Participants by arm
| Arm | Count |
|---|---|
| Double-blind MP: Placebo Participants received 1.0 mL placebo matched to the volume of incobotulinumtoxinA doses per injection session via intramuscular injections into orbicular oculi muscles on Day 1 in the double-blind MP. | 20 |
| Double-blind MP: IncobotulinumtoxinA 25 Units Participants received 1.0 mL of incobotulinumtoxinA containing 25 units per injection session (12.5 units per eye) via intramuscular injections into orbicular oculi muscles on Day 1 in the double-blind MP. | 22 |
| Double-blind MP: IncobotulinumtoxinA 50 Units Participants received 1.0 mL of incobotulinumtoxinA containing 50 units per injection session (25 units per eye) via intramuscular injections into orbicular oculi muscles on Day 1 in the double-blind MP. | 19 |
| Total | 61 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 | FG002 | FG003 |
|---|---|---|---|---|---|
| Double-blind MP | Lost to Follow-up | 1 | 0 | 1 | 0 |
| Double-blind MP | Physician Decision | 0 | 0 | 1 | 0 |
| Double-blind MP | Withdrawal by Subject | 0 | 2 | 1 | 0 |
Baseline characteristics
| Characteristic | Double-blind MP: Placebo | Double-blind MP: IncobotulinumtoxinA 25 Units | Double-blind MP: IncobotulinumtoxinA 50 Units | Total |
|---|---|---|---|---|
| Age, Categorical <=18 years | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Age, Categorical >=65 years | 3 Participants | 9 Participants | 5 Participants | 17 Participants |
| Age, Categorical Between 18 and 65 years | 17 Participants | 13 Participants | 14 Participants | 44 Participants |
| Age, Continuous | 55.4 years STANDARD_DEVIATION 12.01 | 55.8 years STANDARD_DEVIATION 15.7 | 53.5 years STANDARD_DEVIATION 13.82 | 55.0 years STANDARD_DEVIATION 13.79 |
| Region of Enrollment Greece | 4 participants | 6 participants | 4 participants | 14 participants |
| Region of Enrollment Malaysia | 6 participants | 6 participants | 5 participants | 17 participants |
| Region of Enrollment Sri Lanka | 10 participants | 10 participants | 10 participants | 30 participants |
| Sex: Female, Male Female | 12 Participants | 11 Participants | 13 Participants | 36 Participants |
| Sex: Female, Male Male | 8 Participants | 11 Participants | 6 Participants | 25 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 / 20 | 0 / 22 | 0 / 19 | 0 / 39 |
| other Total, other adverse events | 6 / 20 | 7 / 22 | 7 / 19 | 4 / 39 |
| serious Total, serious adverse events | 0 / 20 | 2 / 22 | 1 / 19 | 0 / 39 |
Outcome results
Primary
Double-blind MP: Change From Baseline in JRS Severity Subscore at Day 43 (Visit 4)
JRS severity subscore was used to classify individual symptoms of blepharospasm and to determine therapeutic efficacy. JRS severity subscore ranges from 0 to 4, where 0: None; 1: increased blinking present with external stimuli; 2: Mild but spontaneous eyelid fluttering, definitely noticeable, possibly embarrassing, but not functionally disabling, 3: Moderate, very noticeable spasm of eyelids only, mildly incapacitating, 4: Severe, incapacitating spasm of eyelids and possibly other facial muscles. Values represent least square (LS) mean differences between baseline and visit 4 resulting from analysis of covariance (ANCOVA) with treatment group, pooled site, and gender as fixed factors and baseline JRS severity subscore and age as covariates and missings replaced using the last observation carried forward (LOCF) method. Negative values denote improvement, while positive values denote deterioration vs. baseline.
Time frame: Baseline, Day 43 (Visit 4)
Population: FAS was subset of participants in the SES of the double-blind MP for whom at least a baseline value of the JRS severity subscore was available.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) |
|---|---|---|
| Double-blind MP: Placebo | Double-blind MP: Change From Baseline in JRS Severity Subscore at Day 43 (Visit 4) | -0.6 score on a scale |
| Double-blind MP: IncobotulinumtoxinA 25 Units | Double-blind MP: Change From Baseline in JRS Severity Subscore at Day 43 (Visit 4) | -1.0 score on a scale |
| Double-blind MP: IncobotulinumtoxinA 50 Units | Double-blind MP: Change From Baseline in JRS Severity Subscore at Day 43 (Visit 4) | -1.8 score on a scale |
Comparison: The difference in change of JRS severity subscore between treatment groups was analyzed by an ANCOVA according to a hierarchical test procedure. First step of hierarchy is hypothesis of superiority of 50 unit dose group NT 201 compared to placebo. This was tested confirmatory (α=0.05, 2-sided) by an ANCOVA with treatment group, pooled site, and gender as fixed factors and baseline JRS severity subscore and age as covariates based on LS means comparison. Missing values were imputed by LOCF.p-value: =0.000495% CI: [-1.9, -0.6]ANCOVA
Comparison: The difference in change of JRS severity subscore between treatment groups was analyzed by an ANCOVA according to a hierarchical test procedure. Second step of hierarchy is hypothesis of superiority of 25 unit dose group NT 201 compared to placebo. This was tested confirmatory (α=0.05, 2-sided) by an ANCOVA with treatment group, pooled site, and gender as fixed factors and baseline JRS severity subscore and age as covariates based on LS means comparison. Missing values were imputed by LOCF.p-value: =0.145295% CI: [-1.1, 0.2]ANCOVA
Secondary
Double-blind MP: Change From Baseline in Blepharospasm Disability Index (BSDI) at Day 43 (Visit 4)
BSDI is a scale for assessment of impairment of specific activities of daily living caused by blepharospasm. BSDI consists of six items (driving a vehicle; reading; watching TV; shopping; getting about on foot (walking); doing everyday activities), each ranging from 0 (=no impairment) to 4 (=no longer possible due to illness). The BSDI total score is a mean score for non-missing items ranging from 0 to 4. It is calculated by adding scores of all applicable and answered items, and dividing the resulting sum by the number of items answered. Outcome values represent LS mean differences between baseline and visit 4 (visit 4 value minus baseline value) resulting from ANCOVA with treatment group, pooled site, gender as fixed factors and baseline BSDI total score, age as covariates. Missings were replaced by the LOCF method. Negative values denote an improvement, while positive values denote deterioration vs. baseline.
Time frame: Baseline, Day 43 (Visit 4)
Population: FAS was subset of participants in the SES of the double-blind MP for whom at least a baseline value of the JRS severity subscore was available.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) |
|---|---|---|
| Double-blind MP: Placebo | Double-blind MP: Change From Baseline in Blepharospasm Disability Index (BSDI) at Day 43 (Visit 4) | -0.4 score on a scale |
| Double-blind MP: IncobotulinumtoxinA 25 Units | Double-blind MP: Change From Baseline in Blepharospasm Disability Index (BSDI) at Day 43 (Visit 4) | -0.5 score on a scale |
| Double-blind MP: IncobotulinumtoxinA 50 Units | Double-blind MP: Change From Baseline in Blepharospasm Disability Index (BSDI) at Day 43 (Visit 4) | -0.7 score on a scale |
Secondary
Double-blind MP: Patient Evaluation of Global Response (PEGR) at Final Visit (Day 43-Day 141)
PEGR scale is a descriptive subjective 9-point response self-rating scale ranging from complete abolishment of signs and symptoms (value=+4) down to very marked worsening (value=-4). Outcome values represent least square means at visit 4 resulting from an ANCOVA with treatment group, pooled site, gender as fixed factors and age as covariates. Missing were set to a zero effect (value=0). Positive values denote an improvement, while negative values denote deterioration.
Time frame: Baseline, Final Visit (Day 43-Day 141)
Population: FAS was subset of participants in the SES of the double-blind MP for whom at least a baseline value of the JRS severity subscore was available.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) |
|---|---|---|
| Double-blind MP: Placebo | Double-blind MP: Patient Evaluation of Global Response (PEGR) at Final Visit (Day 43-Day 141) | 1.3 score on a scale |
| Double-blind MP: IncobotulinumtoxinA 25 Units | Double-blind MP: Patient Evaluation of Global Response (PEGR) at Final Visit (Day 43-Day 141) | 1.8 score on a scale |
| Double-blind MP: IncobotulinumtoxinA 50 Units | Double-blind MP: Patient Evaluation of Global Response (PEGR) at Final Visit (Day 43-Day 141) | 2.2 score on a scale |