FormalPara Key Summary Points

Why carry out this study?

Idiopathic blepharospasm is a focal dystonia characterized by excessive involuntary contractions of the muscles surrounding the eye, and a local injection of botulinum neurotoxin type A (BoNT-A) is a highly effective and well-tolerated treatment

This double-blind placebo-controlled study with an open-label extension period (NCT01896895) aimed to assess the efficacy and safety of the BoNT-A incobotulinumtoxinA (Xeomin®, Merz Pharmaceuticals GmbH) in BoNT-naïve subjects with blepharospasm

What was learned from the study?

Subjects experienced improvement in blepharospasm with significant reduction versus placebo in the Jankovic Rating Scale severity subscore at week 6 (primary efficacy variable) in those who received incobotulinumtoxinA 50 U; this finding was supported by other efficacy variables, and sustained improvements were reported during the open-label extension period

Treatment was well tolerated, and low adverse event rates (22.2–42.1%) were observed throughout the entire study

This study offers new data to support treatment decisions and further demonstrates the favorable efficacy and safety of incobotulinumtoxinA in subjects with blepharospasm

Introduction

Idiopathic blepharospasm, also known as benign essential blepharospasm, is a focal dystonia characterized by excessive involuntary contractions of the muscles surrounding the eye [1]. It affects approximately 4–5 out of every 100,000 individuals [2, 3] and is more common in women [3, 4]. Previous treatments for blepharospasm have been either unsuccessful or intolerable [2, 5].

Botulinum neurotoxin type A (BoNT-A), given as a local injection, is a highly effective and well-tolerated treatment for blepharospasm [6,7,8,9]. IncobotulinumtoxinA (Xeomin®, Merz Pharmaceuticals GmbH, Frankfurt am Main, Germany) is a BoNT-A formulation free from complexing proteins [10, 11]. One American Academy of Neurology (AAN) Class I study (prospective, randomized, placebo-controlled clinical trial with masked outcome assessment) [12] currently supports the use of incobotulinumtoxinA for the treatment of blepharospasm [6, 13] and has demonstrated the superiority of incobotulinumtoxinA to placebo in subjects with blepharospasm pretreated with BoNT-A [6, 13]. A second, successful Class I study could qualify incobotulinumtoxinA for an AAN Level A recommendation, supporting its use for the treatment of blepharospasm [13]. Additionally, following the completion of the present study, the United States Food and Drug Administration (FDA) broadened the indication of incobotulinumtoxinA to include it as a first-line treatment for blepharospasm in adult subjects [11, 14].

The study described here is the second Class I study of incobotulinumtoxinA for the indication of blepharospasm and the first Class I study in subjects who have not received BoNT treatment for blepharospasm in the last 12 months (NCT01896895) [13]. Here, we report results that aimed to assess the efficacy and safety of two incobotulinumtoxinA doses versus placebo for the treatment of blepharospasm in BoNT-naïve subjects.

Methods

Study Design

This was a prospective, double-blind, placebo-controlled, randomized, parallel-group, multicenter study comprising a 6–20-week main period with a single injection cycle of incobotulinumtoxinA or placebo and a 6–20-week open-label extension period with a second injection cycle of incobotulinumtoxinA (Fig. 1a). In the main period, subjects were randomized (1:1:1) to receive a single intramuscular dose of 50 U total (25 U per eye), 25 U total (12.5 U per eye), or placebo at Visit 2. Randomization in the main period used a box system established by the sponsor. All vials were identical to maintain blinding, with the placebo vials containing human serum albumin and sucrose. The injection sites are shown in Fig. 1b. The injectors/assessors were physicians specialized in neurology, who underwent injection training.

Fig. 1
figure 1

Study design (a) and incobotulinumtoxinA injection sites (b). a V1 (screening); V2 (injection): assessments included: JRS, BSDI; V3 (assessment): JRS, BSDI; V4 (assessment): antibody tests, JRS, BSDI; V5 (final visit of main period): antibody tests, JRS, BSDI, Investigator’s Global Assessment of Efficacy, PEGR. Subjects for whom a need for re-injection (JRS severity subscore ≥ 2) was confirmed during the main period were eligible for the open-label extension period. V6 (injection); V7 (assessment): antibody tests, JRS, BSDI; V8 (end of study): antibody tests, JRS, BSDI, Investigator’s Global Assessment of Efficacy, PEGR. Safety parameters and the use of concomitant medication were assessed at each visit throughout the study. b Volumes are specific to the main period. AC additional contact, BSDI Blepharospasm Disability Index, JRS Jankovic Rating Scale, PEGR Patient Evaluation of Global Response

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On the final visit of the main period (Visit 5), subjects were assessed for eligibility to enter the open-label extension period. The final day of the main period (6–20 weeks after injection) was defined as the first day of the open-label extension period. During the open-label extension period, subjects received treatment with incobotulinumtoxinA ≤ 70 U total (≤ 35 U per eye) on Visit 6 followed by 6–20 weeks of observation. The number of injection sites and the distribution of units during the open-label extension period were at the discretion of the investigator and depended on the degree of spasms in the affected muscles. The flexible dosing and re-injection interval (6–20 weeks) used in this study were intended to mirror clinical practice.

Permitted concomitant medications included non-steroidal anti-inflammatory drugs. Antidepressant medication (e.g., tricyclic antidepressants and serotonin reuptake inhibitors), opioid-analgesics, or oral medication used for the treatment of focal dystonia (e.g., anticholinergics, trihexyphenidyl, biperiden, benzatropine, profenamine, tiapride, and procyclidine) were permitted if subjects received stable doses beginning ≥ 3 months prior to screening that lasted throughout the main period. Centrally acting muscle relaxants (e.g., clonidine and tizanidine) were also permitted if subjects received stable doses ≥ 2 weeks prior to screening that lasted throughout the main period. Peripheral muscle relaxants, aminoglycoside antibiotics, and aminoquinolines were to be used with caution. Prohibited medications included BoNT of any other serotype, phenol/alcohol injections in the area of treatment, and parenterally administered drugs (prohibited during the main period only) that interfere with neuromuscular transmission (e.g., tubocurarine-type muscle relaxants).

The study was conducted at 12 sites in Greece, Malaysia, and Sri Lanka between 21 January 2014 and 10 November 2016 in accordance with Good Clinical Practice/International Conference on Harmonization guidelines and the Declaration of Helsinki. The study protocol, informed consent documents, and any other appropriate study-related documents were reviewed and approved by an independent ethics committee or institutional review board. All subjects provided written informed consent.

Study Population

Key Inclusion Criteria for the Main Period and Open-Label Extension Period

Male or female subjects (1) ≥ 18 to ≤ 80 years of age with (2) a clinical diagnosis of bilateral blepharospasm, characterized by spontaneous, spasmodic, intermittent, or persistent involuntary contractions of orbicular oculi muscles, and (3) a need for an injection of BoNT defined as a Jankovic Rating Scale (JRS) severity [15] subscore ≥ 2 were eligible for this study. Subjects were required to be (4) toxin-naïve, defined as ≥ 12 months without BoNT of any serotype for the treatment of blepharospasm, before the administration of incobotulinumtoxinA.

The main inclusion criterion for participation in the open-label extension period was a need for a BoNT injection, defined as a JRS severity subscore ≥ 2 (assessed at the final visit of the main period [Visit 5]).

Key Exclusion Criteria for the Main Period and Open-Label Extension Period

Subjects were excluded from this study for the following reasons: (1) any previous unsuccessful treatment with BoNT of any serotype for the treatment of blepharospasm; (2) an atypical variant of blepharospasm (e.g., variants associated with apraxia of the eyelid opening caused by inhibition of the levator palpebrae muscle); (3) neuroleptic-induced blepharospasm; myotomy or denervation surgery in the affected muscles (e.g., peripheral denervation and spinal cord stimulation) and surgery in the upper face; (4) generalized disorders of muscle activity (e.g., myasthenia gravis [in particular ocular myasthenia gravis], Lambert–Eaton syndrome, and amyotrophic lateral sclerosis) that may interfere with the evaluation of the drug effect or any other significant neuromuscular dysfunction that could have interfered with the study.

Efficacy Assessments

Primary Efficacy Variable

The primary efficacy variable in this study was the change from baseline in JRS severity subscore at week 6 (Visit 4) of the main period. The JRS severity subscore was rated on a scale comprising five severity categories ranging from 0 (no spasms) to 4 (severe spasms) [15, 16]. Using other scales as comparators, a change in the JRS severity subscore of ≥ 1 point is regarded as clinically meaningful [15, 17].

Secondary Efficacy Variables

The secondary efficacy variables were the change from baseline in Blepharospasm Disability Index (BSDI) score at week 6 of the main period and Patient Evaluation of Global Response (PEGR) at the final visit of the main period (Visit 5). The BSDI score, a disease-specific disability self-assessment scale, includes six items with a 5-point rating [16]. A clinically meaningful treatment effect was assumed with an improvement of ≥ 0.7 points on the BSDI [15, 16]. PEGR is a subjective 9-point self-rating scale to rate the effect of the last injection [18]. A PEGR score of 2 corresponds to the answer “moderate improvement,” and a PEGR score of 1 corresponds to the answer “slight improvement.”

Tertiary Efficacy Variables

Tertiary efficacy variables included the change in the JRS severity subscore, JRS frequency subscore, JRS sumscore, BSDI score over the main period (Visit 2 to Visits 3 and 5) and over the open-label extension period (Visit 2 to Visit 8; Visit 6 to Visits 7 and 8), and change in PEGR over the open-label extension period (Visit 8). The JRS frequency subscore was calculated from five frequency subscore rating categories, each of which was rated on a scale from 0 (no spasms) to 4 (persistent eye closure) [19]. The JRS sumscores were calculated from the results of the JRS severity and frequency subscores of respective visits. Investigator’s Global Assessment of Efficacy at the final visit of the main period (Visit 5) and the final visit of the open-label extension period (Visit 8) was also evaluated. Investigator’s Global Assessment of Efficacy is a subjective estimation made by the investigator on a 5-point rating scale ranging from a score of 1, corresponding to the answer “very good,” to a score of 5, corresponding to the answer “very poor.” Other tertiary variables, including the time to onset, duration, and time to the waning of incobotulinumtoxinA effect, are reported separately.

Safety Assessments

Incidence of adverse events (AEs), including AEs related to treatment, AEs of special interest (AESIs), serious adverse events (SAEs), and AEs leading to discontinuation, were monitored during both the main period and open-label extension period. AESIs were defined as AEs that occurred after treatment that were thought to indicate possible toxin spread. Vital signs, clinical chemistry, hematology, coagulation, and anti-BoNT-A antibodies were also assessed.

Statistical Analysis

All main period efficacy analyses were performed on the main period full analysis set (FAS-MP; all subjects treated in the main period who received study medication and for whom a baseline JRS severity subscore was available). All open-label extension period analyses were performed on the FAS-EP, defined as all subjects of the open-label extension period who received study medication and for whom a JRS severity subscore at Visit 5 was available. Study sites were pooled by country for analysis. Safety analyses were performed on the main period or open-label safety evaluation set (all subjects who received ≥ 1 dose of study medication during the main period or open-label-extension period, respectively).

The difference in the change in the JRS severity subscore between the treatment groups was analyzed using an analysis of covariance (ANCOVA) approach (α = 0.05, two-sided) with treatment group, country, and gender as fixed factors and baseline JRS severity subscore and age as covariates. A hierarchical test procedure was used, starting with a comparison of the incobotulinumtoxinA 50 U dose group versus placebo. When statistically significant differences were found between the incobotulinumtoxinA 50 U and placebo groups, a second step of the hierarchical test was performed that tested the incobotulinumtoxinA 25 U group versus the placebo group. The secondary efficacy variables were analyzed descriptively based on the FAS-MP. An ANCOVA with treatment group, country, and gender as factors and baseline score and age as covariates was applied for the comparison of the placebo and active treatments of BSDI. For PEGR, an ANCOVA with treatment group, country, and gender as factors and age as a covariate was applied. For open-label extension period analyses, a paired, two-sided t-test was used to determine statistically significant differences from the baseline values (of both the main period and open-label extension period). All hypotheses were tested by two-sided tests at a significance level of 5%. In case of missing data, the last observation carried forward (LOCF) strategy (including baseline, if there was no post-injection value) was applied in the analyses of JRS severity subscore, JRS frequency subscore, JRS sumscore, and BSDI. For the analysis of PEGR, missing values were set to zero. Due to the large sample size, it was justified to assume that the data were normally distributed for the use of these parametric tests. Post-hoc non-parametric tests (Wilcoxon rank-sum tests to support ANCOVA results and Wilcoxon signed-rank tests to support t-test results; both Wilcoxon tests were two-sided) were also carried out to confirm the results of the parametric tests.

A sample size of 20 subjects per group was considered sufficient to provide 80% power to show the superiority of the incobotulinumtoxinA 50 U group compared with placebo, based on a two-sided t-test at a significance level of 5%. This assumes a clinically relevant difference for the incobotulinumtoxinA 50 U group of 1.0 point versus placebo in the mean change from baseline in the JRS severity subscore, with a common standard deviation (SD) of ~ 1.1. A lower power for the comparison of the incobotulinumtoxinA 25 U group versus placebo (second step of the hierarchical test procedure) had to be considered.

Results

Subjects

A total of 68 subjects were screened, and 61 were randomized in the main period (FAS-MP; n = 20 in the placebo group, n = 22 in the incobotulinumtoxinA 25 U group, and n = 19 in the incobotulinumtoxinA 50 U group) (Fig. 2). The majority of subjects were female (59.0%) and of Asian race (77.0%). The mean (SD) age was 55.0 (13.8) years old. Overall, demographic data were comparable among the treatment groups in the main period (Table 1). Of the 55 subjects completing the main period, 39 entered the open-label extension period: 16 subjects from the placebo group (main period), 14 subjects from the incobotulinumtoxinA 25 U group (main period), and 9 subjects from the incobotulinumtoxinA 50 U group (main period) changed to the open-label extension period dosing regimen of incobotulinumtoxinA ≤ 70 U (Fig. 2). Of the 16 subjects who did not enter the open-label extension period, 14 were not eligible as they did not require a re-injection. Two subjects had other reasons not to enter (unrelated AE and personal decision to withdraw).

Fig. 2
figure 2

Subject disposition flow diagram—main period (a) and extension period (b)

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Table 1 Summary of subject demographics—main period (FAS-MP) and open-label extension period (FAS-EP)
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Overall, demographic data for subjects in the open-label extension period were generally comparable between the original main period treatment groups (Table 1). Doses of incobotulinumtoxinA were also similar between groups during the open-label extension period (mean [SD]: placebo (main period) → ≤ 70 U (open-label extension period) group, 49.4 U [2.5]; incobotulinumtoxinA 25 U (main period) → ≤ 70 U (open-label extension period) group, 49.3 U [6.2]; incobotulinumtoxinA 50 U (main period) → ≤ 70 U (open-label extension period) group, 50.0 U [0.0]). No subject had documentation of previous treatment with BoNT-A.

Efficacy

Primary Efficacy Variable

At week 6 of the main period, treatment with incobotulinumtoxinA 50 U resulted in statistically significant improvements from baseline in the primary efficacy variable, the JRS severity subscore, compared with placebo (ANCOVA, least squares mean [LSM] difference − 1.2, 95% confidence interval [CI] [− 1.9, − 0.6]; p = 0.0004; Fig. 3). The change in JRS severity subscore from baseline was improved with incobotulinumtoxinA 25 U versus placebo, although this change was not statistically significant (ANCOVA, LSM difference − 0.5, 95% CI [− 1.1, 1.2]; p = 0.1452).

Fig. 3
figure 3

Changes in JRS severity subscore in the main period (FAS-MP, LOCF) and extension period (FAS-EP, LOCF). JRS severity subscore range: 0 (no spasms) to 4 (severe spasms). aData are LSM change from baseline; p values refer to incobotulinumtoxinA treatment versus placebo using ANCOVA. bData are mean change from baseline; *p < 0.05; **p < 0.01; ***p < 0.0001 versus baseline using paired, two-tailed t tests; mean total dose during the extension period was close to 50 U for all treatment groups (range 30–60 U). ANCOVA analysis of covariance, EP extension period, FAS full analysis set, JRS Jankovic Rating Scale, LOCF last observation carried forward, LSM least squares mean, MP main period

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Secondary Efficacy Variables

Improvements were observed for both incobotulinumtoxinA groups versus placebo for the change from baseline in BSDI score at week 6 (Fig. 4). The LSM change from baseline was − 0.4 in the placebo group, − 0.5 in the incobotulinumtoxinA 25 U group, and − 0.7 in the incobotulinumtoxinA 50 U group. The LSM difference between the incobotulinumtoxinA 50 U group and the placebo group was − 0.3 (ANCOVA; p = 0.2392) and − 0.1 (ANCOVA; p = 0.5830) between the incobotulinumtoxinA 25 U group and placebo group. Slight improvements in BSDI score were observed from the main period baseline to the end of the study, from the open-label extension period baseline to week 6, and from the open-label extension period baseline to the end of the study (Fig. 4).

Fig. 4
figure 4

Mean change in BSDI score during the main period (FAS-MP, LOCF) and extension period (FAS-EP, LOCF). BSDI score range: from 0 (no impairment) to 4 (activity no longer possible). aData are LSM change from baseline; p values refer to incobotulinumtoxinA treatment versus placebo using ANCOVA. bData are mean change from baseline; **p < 0.01 versus baseline using paired, two-tailed t tests; mean total dose during the extension period was close to 50 U for all treatment groups (range 30–60 U). ANCOVA analysis of covariance, BSDI Blepharospasm Disability Index, EP extension period, FAS full analysis set, LOCF last observation carried forward, LSM least squares mean, MP main period

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Subjects in both incobotulinumtoxinA groups showed greater improvements in the PEGR score at Visit 5 of the main period, compared with placebo. The LSM was 1.3 in the placebo group, 1.8 in the incobotulinumtoxinA 25 U group, and 2.2 in the incobotulinumtoxinA 50 U group (Fig. 5). The LSM difference between the incobotulinumtoxinA 50 U group and the placebo group was 0.9 (ANCOVA; p = 0.0546). The LSM difference between the incobotulinumtoxinA 25 U group and the placebo group was 0.5 (ANCOVA; p = 0.2416).

Fig. 5
figure 5

Mean PEGR score at the end of the main period (FAS-MP) and extension period (FAS-EP). PEGR score range: from − 4 (very marked worsening) to 4 (complete abolishment of signs and symptoms). A PEGR score of + 2 corresponds to the answer “moderate improvement,” and a PEGR score of + 1 corresponds to the answer “slight improvement.” Missing data of this variable were set to a zero effect (value = 0). aData are LSM change from baseline; p values refer to incobotulinumtoxinA treatment versus placebo using ANCOVA. bData are mean change from baseline; mean total incobotulinumtoxinA dose during the extension period was close to 50 U for all treatment groups (range: 30–60 U). ANCOVA analysis of covariance, EP extension period, FAS full analysis set, LSM least squares mean, MP main period, PEGR Patient Evaluation of Global Response

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During the open-label extension period, the mean (± SD) PEGR score ranged from 1.9 ± 1.98 in the incobotulinumtoxinA 25 U (main period) → ≤ 70 U (open-label extension period) group to 2.4 ± 1.13 in the incobotulinumtoxinA 50 U (main period) → ≤ 70 U (open-label extension period) group. The overall mean (± SD) PEGR score for the open-label extension period was 2.2 ± 1.61, with a score of + 2 corresponding to “moderate improvement” (Fig. 5).

Tertiary Efficacy Variables

Over the open-label extension period, sustained improvements from baseline in JRS severity subscore were seen with incobotulinumtoxinA ≤ 70 U, with the greatest improvements seen in the incobotulinumtoxinA 50 U (main period) → ≤ 70 U (open-label extension period) group over the complete study (Fig. 3).

During the main period, treatment with incobotulinumtoxinA 50 U resulted in improvements from baseline in JRS frequency subscore at weeks 3 and 6 compared to placebo (ANCOVA, LSM difference − 1.2; p < 0.0001 for both time points; see Table S1 in the electronic supplementary material). Treatment with incobotulinumtoxinA 25 U resulted in improvements from baseline in JRS frequency subscore at weeks 3 and 6 compared to placebo (p = 0.1464 and 0.0853, respectively; Table S1). During the open-label extension period, the mean changes in JRS frequency subscore from main period baseline were similar between groups (see Table S2 in the electronic supplementary material).

JRS sumscores at weeks 3 and 6 were improved during the main period after treatment with incobotulinumtoxinA 50 U compared to placebo (ANCOVA, LSM difference − 2.4; p = 0.0001 and − 2.5; p < 0.0001, respectively; Table S1). Treatment with incobotulinumtoxinA 25 U resulted in improvements from baseline in JRS sumscore at weeks 3 and 6 compared to placebo (p = 0.1396 and 0.1016, respectively; Table S1). During the open-label extension period, the mean change in JRS sumscore from the main period baseline to the end of the study was similar between groups (Table S2).

At the end of the main period, the percentages of subjects for whom the scores of “very good” or “good” were documented on the Investigator’s Global Assessment of Efficacy were lowest in the placebo group (n = 20; 5.0% very good and 35.0% good), higher in the incobotulinumtoxinA 25 U group (n = 22; 18.2% very good and 45.5% good), and highest in the incobotulinumtoxinA 50 U group (n = 19; 36.8% very good and 31.6% good). At the end of the open-label extension period, subjects in the placebo (main period) → incobotulinumtoxinA ≤ 70 U (open-label extension period), incobotulinumtoxinA 25 U (main period) → incobotulinumtoxinA ≤ 70 U (open-label extension period), and incobotulinumtoxinA 50 U (main period) → incobotulinumtoxinA ≤ 70 U (open-label extension period) groups achieved “very good” or “good” scores at rates of 75.0% (12/16), 71.4% (10/14), and 66.7% (6/9), respectively.

Results of post hoc non-parametric tests mirrored those of the parametric tests described above for all efficacy variables.

Safety

AEs in the main period and the open-label extension period are reported in Table 2 and in Table S3 in the electronic supplementary material. The majority of all events were mild to moderate in severity. Overall, 36.6% (15/41) and 28.2% (11/39) of subjects experienced any AE during the main period and open-label extension period, respectively.

Table 2 Summary of adverse events—main period (SES-MP) and open-label extension period (SES-EP)
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Nine subjects (22.0%) experienced treatment-related AEs during the main period, which were reported as AESIs in 6 subjects (eyelid ptosis in 5 incobotulinumtoxinA-treated subjects and eyelid function disorder in 1 incobotulinumtoxinA-treated subject and 1 placebo subject). In the incobotulinumtoxinA groups, only eyelid ptosis was reported in ≥ 1 subject during the main period, and this occurred in 2 subjects (9.1%) in the incobotulinumtoxinA 25 U group and 3 subjects (15.8%) in the incobotulinumtoxinA 50 U group. Two subjects (9.1%) in the incobotulinumtoxinA 25 U group had SAEs (goiter [moderate] and acute myocardial infarction [moderate]) and 1 subject (5.3%) in the incobotulinumtoxinA 50 U group had an SAE (atrioventricular block [severe]). The subject experiencing the SAE of goiter discontinued the study; however, none of the SAEs were considered related to treatment. One subject who presented with a borderline anti-BoNT-A neutralizing antibody assay result at screening tested positive at the end-of-study visit, but this subject still responded to treatment.

During the open-label extension period, five subjects (12.8%) experienced treatment-related AEs (2 in the placebo [main period] → incobotulinumtoxinA ≤ 70 U [open-label extension period] group and 3 in the incobotulinumtoxinA 25 U [main period] → incobotulinumtoxinA ≤ 70 U [open-label extension period] group), three of whom experienced AESIs (eyelid ptosis in 2 subjects who had received incobotulinumtoxinA 25 U during the main period and eyelid function disorder in 1 subject who had received placebo during the main period). No subjects in the incobotulinumtoxinA 50 U [main period] → incobotulinumtoxinA ≤ 70 U [open-label extension period] group reported treatment-related AEs during the open-label extension period. No SAEs were reported in any of the groups, and no deaths were reported throughout the study.

Discussion

The results of this Phase 3 study confirmed the efficacy and safety of incobotulinumtoxinA at a dose of 50 U for the treatment of blepharospasm in toxin-naïve subjects. During the main period of the study, treatment with incobotulinumtoxinA 50 U led to clinically meaningful (≥ 1 point [15]), statistically significant improvements from baseline versus placebo in JRS severity subscore (indicating reduction in spasms) at week 6 (LSM difference: − 1.2, p = 0.0004). Statistically significant improvements were also reported in the JRS frequency subscore and JRS sumscore in patients treated with incobotulinumtoxinA 50 U versus placebo. Numerically greater improvements were observed for both incobotulinumtoxinA groups versus placebo for the change from baseline in BSDI score (indicating reduced disability; ≥ 0.7 points considered clinically meaningful [15]) and PEGR score (indicating effect of the last injection) compared with placebo.

Furthermore, a higher percentage of patients treated with incobotulinumtoxinA 50 U scored “very good” or “good” on the Investigator’s Global Assessment of Efficacy versus those treated with placebo (68.4% versus 40%). Sustained improvements in JRS severity subscore, JRS frequency subscore, JRS sumscore, PEGR score, BSDI score, and Investigator’s Global Assessment of Efficacy were observed at week 6 and/or the final visit of the open-label extension period. This study is the second AAN Class I study to demonstrate the superiority of incobotulinumtoxinA over placebo for the treatment of blepharospasm. As such, incobotulinumtoxinA would be the first BoNT formulation to fulfill the AAN criteria for a Level A recommendation in this indication [12, 13].

The current efficacy results are in line with results from a previous Class I, single-dose trial of incobotulinumtoxinA (≤ 50 U per eye) for the treatment of blepharospasm in subjects pretreated with BoNT [6]. Results indicated a similar improvement in JRS severity subscore of 1.0 with incobotulinumtoxinA versus placebo after 6 weeks [6]. Similarly, during a flexible, multiple-dose study of subjects also pretreated with onabotulinumtoxinA, incobotulinumtoxinA (≤ 50 U per eye) improved the mean JRS severity score by approximately 1.6, 6 weeks after each treatment [7]. Statistically significant differences in improvement of JRS severity subscore at week 6 were reported between the incobotulinumtoxinA 50 U and placebo groups in the current study. Differences between improvements in JRS severity subscore for incobotulinumtoxinA 25 U and placebo groups were not statistically significant, possibly because of a relatively pronounced placebo effect in this toxin-naïve population (− 0.6 score change from baseline in the placebo group) and also because 25 U was used in this study to cover the lower end of the effective dose range. Numerical improvements were also seen for the secondary efficacy variables of BSDI and PEGR scores for incobotulinumtoxinA versus placebo. The smaller sample sizes compared to a previous incobotulinumtoxinA study [6] and the pronounced placebo effect may explain why these changes did not reach statistical significance. Results from the open-label extension period generally support the efficacy findings from the main period of this study. Furthermore, 14 subjects were not eligible to enter the open-label extension period as they did not require re-injection, suggesting it is possible that their previous incobotulinumtoxinA injection was still having an effect after 20 weeks.

This current study also confirmed the favorable safety and tolerability profile of incobotulinumtoxinA in toxin-naïve subjects with blepharospasm, with no new or unexpected safety concerns identified. The safety findings were similar to previous studies and were in line with the known safety profile of incobotulinumtoxinA [6,7,8, 19, 20]. Only eyelid ptosis was reported in ≥ 1 subject in both active treatment groups. This incidence of eyelid ptosis was relatively low, was to be expected as a recent treatment guideline lists ptosis as one of the most commonly reported AEs after BoNT injections [13], and was comparable to that observed in the similar clinical trial in a pretreated population published by Jankovic et al. [6].

It is important to note that nocebo responses (AEs experienced by subjects receiving placebo treatment) [21] were frequent in this study (6 of 20 subjects [30%] receiving placebo in the main period reported AEs following injection). It has previously been shown that nocebo phenomena are prevalent within clinical trials aiming to treat a variety of diseases and that they can be associated with a subject’s expectation that any medication will have negative side effects [21,22,23]. Therefore, the rates of AEs experienced by both subjects receiving placebo and those receiving incobotulinumtoxinA preparations may be overestimated because of subjects’ presumptions. The subjects’ predilections may also explain the notable placebo effect in this study, where subjects expected a positive effect from any medication, even if it was a placebo treatment.

In the present study, only one subject had borderline and positive anti-BoNT-A antibody assay results. This subject presented with borderline antibody assay results at screening. Although only BoNT-naïve subjects were enrolled in this study, toxin-naïve was defined as ≥ 12 months without BoNT treatment for blepharospasm before administration of treatment. Thus, it is possible that this subject developed BoNT-A neutralizing antibodies as a result of previous foodborne botulism or had previous undocumented treatment with BoNT. Regardless, this subject still responded to treatment.

Previous studies have suggested that there is no statistically significant difference in efficacy for treating blepharospasm between onabotulinumtoxinA (Botox) and incobotulinumtoxinA (Xeomin) [8, 19, 20]. IncobotulinumtoxinA is a high-purity preparation without complexing proteins [24] and therefore may carry less risk of immunogenicity associated with its use compared to other BoNT preparations. Therefore, incobotulinumtoxinA may be suitable for longer-term and first-line use. Indeed, the FDA has recently broadened the indication for incobotulinumtoxinA to be a first-line treatment for blepharospasm [11, 14].

Strengths of this study include its robust, state-of-the-art, flexible dosing, and re-injection design and the use of standardized outcome measures. This is the first study of incobotulinumtoxinA treatment for blepharospasm performed in toxin-naïve (≥ 12 months without BoNT treatment for blepharospasm) subjects. Thus, this study provided first-time insight into the efficacy of incobotulinumtoxinA in subjects who were previously unable to receive first-line incobotulinumtoxinA treatment for blepharospasm in the USA [11]. Approximately 90% of subjects completed the study, with no subject citing “lack of efficacy” as a reason for discontinuation. All 39 subjects who entered the open-label extension period completed the study. Also, the study population appeared to be representative and similar to populations included in other BoNT studies, with more women than men and similar subject age [4, 6,7,8, 19].

A potential limitation of the study was that the main period and open-label extension period were both relatively short (6–20 weeks) with only one injection cycle during each period and a sample size that was slightly smaller than in similar studies [6, 7]. The smaller sample size may limit the robustness of findings from the open-label extension period. As such, results should be interpreted with caution. However, this study was adequately powered to detect a statistically significant difference between the placebo and incobotulinumtoxinA 50 U groups in the JRS severity subscore (primary efficacy variable) during the placebo-controlled main period.

In summary, this Class I, prospective, multi-center Phase 3 study in toxin-naïve subjects with blepharospasm confirms the efficacy of incobotulinumtoxinA 50 U in adults who had not had prior treatment with another BoNT-A preparation such as onabotulinumtoxinA within ≥ 12 months. This study offers new data to support treatment decisions and further demonstrates the efficacy and safety of incobotulinumtoxinA for subjects with blepharospasm. With two positive placebo-controlled Class I studies, incobotulinumtoxinA is the first BoNT that could fulfill the AAN criteria for a Level A recommendation for the treatment of blepharospasm [6, 12, 13].