Safety and Efficacy of NT 201 (IncobotulinumtoxinA [Xeomin]) in the Treatment of Glabellar Frown Lines

Study Overview
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Brief Summary
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The study objective was to investigate the safety and efficacy of incobotulinumtoxinA (Xeomin) during repeat dose treatment of glabellar frown lines. 801 participants with moderate to severe glabellar frown lines at maximum frown who completed participation in one of the studies in this program, i.e. MRZ 60201-0520/1, MRZ 60201-0527/1, MRZ 60201-0724/1, or MRZ 60201-0741/1 were eligible to participate in this repeat-dose study.

Detailed Description
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This was a prospective, multicenter, open-label, non-control group design Phase 3 clinical study. Approximately 880 participants who were to complete former studies in this program (370 participants from studies MRZ 60201-0520/1 (8) and MRZ 60201-0527/1 (8) as well as approximately 510 participants from studies MRZ 60201-0724/1 (10) and MRZ 60201-0741/1) (11) were expected to enroll in this study in 26 centers in the United States, Canada and Germany. Participants with moderate to severe glabellar frown lines at maximum frown who completed participation in one of these four feeder studies in the frown line program were eligible to participate in this repeated dose study. Each participant received a dose of 20 units incobotulinumtoxinA (Xeomin) intramuscular injection on Visit 1 (Day 0 of Cycle 1). Re-injections with 20 U NT 201 could be performed on Day 0 of a subsequent cycle for up to 8 cycles (one cycle >= 85 days). Intervals between treatments were at least three months or 12 weeks, i.e., >= 85 days. For a new treatment cycle to start, the participant had to request a re-injection. The investigator then had to assess if the glabellar frown lines had relapsed to 'moderate' or 'severe'. In this case, a new injection could be administered. The treatment duration per participant was 24 months and up to eight cycles for participants enrolled from studies MRZ 60201-0520/1 and MRZ 60201-0527/1 and 6 months and up to two cycles for participants enrolled from studies MRZ 60201-0724/1 and MRZ 60201-0741/1, respectively. Participants enrolled from studies MRZ 60201-0520/1 and MRZ 60201-0527/1 participated at least one year in the study whereas participants enrolled from studies MRZ 60201-0724/1 and MRZ 60201-0741/1 participated for six months and up to two cycles.

Official Title
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A Prospective, Open-label, Multicenter, Repeat-dose Trial to Investigate the Safety and Efficacy of NT 201, Free of Complexing Proteins, in the Treatment of Glabellar Frown Lines

Conditions
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Glabellar Lines

Intervention / Treatment
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* Drug: IncobotulinumtoxinA (Xeomin) (20 units)


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Participants with 'moderate' or 'severe' glabellar frown lines at maximum frown at the beginning of each treatment cycle (as assessed by the investigator according to FWS) , stable medical condition; Completion of one former study in the Merz NT 201 glabellar program Exclusion Criteria: Participants with preexisting neuromuscular diseases (e.g. myasthenia gravis, Lambert-Eaton syndrome) putting the participant at risk, History of Facial Nerve Palsy, Previous treatment with Botulinum Toxin in the glabellar area during the last 12 months, Previous treatment with biodegradable fillers or other procedures (e.g. chemical peeling, photo rejuvenation) in the glabellar area during the last 12 months, Previous insertion of permanent material in the glabellar area; Planned treatment with Botulinum toxin of any serotype in any body region during the study period, Any other planned facial aesthetic procedure in the glabellar area during the trial period; Any surgery in the glabellar area including surgical removal of the corrugator, procerus or depressor supercili muscles or a combination of these or scars in the glabellar area, Inability to substantially lessen glabellar frown lines even by physically spreading apart, Marked facial asymmetry or ptosis of eyelid and/or eyebrow; Any infection in the area of the injection sites.

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: IncobotulinumtoxinA (Xeomin) (20 units)<br>IncobotulinumtoxinA (Xeomin), also known as 'NT 201' or 'Botulinum toxin type A (150 kD), free from complexing proteins' (active ingredient: Clostridium Botulinum neurotoxin type A free from complexing proteins) powder for solution for injection; dose: one injection session of solution, prepared by reconstitution of powder with 0.9% sodium chloride (NaCl), 20 units, total volume 0.5 mL, mode of administration: intramuscular injection | Drug: IncobotulinumtoxinA (Xeomin) (20 units)<br>* Injection of a total of 20 Units incobotulinumtoxinA (Xeomin) on day one of each of up to eight cycles, reconstituted in a total injection volume of 0.5 mL administered in five equal parts of 0.1 mL to five predefined points of the glabellar area.<br>* Other names: IncobotulinumtoxinA (Xeomin), also known as 'NT 201' or 'Botulinum toxin type A (150 kD), free from complexing proteins (20 units);|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Incidence of Adverse Events (AEs) |  | Baseline up to Month 30 | 
| Incidence of Adverse Events of Special Interest (AESI) |  | Baseline up to Month 30 | 
| Percentage of Responders at Maximum Frown as Assessed by the Investigator According to Facial Wrinkle Scale (FWS) | FWS was used to assess the severity of glabellar frown lines at maximum frown by the investigator. The 4-point scale depicted as: 0 = none, 1 = mild, 2 = moderate and 3 = severe. Responders on the FWS were defined as participants with glabellar line severity of none (0) or mild (1). | At evaluation visit (30 days after injection) and at last control visit (85 days after last injection) in each treatment cycle from Cycle 1 to Cycle 8 (each cycle length >=85 days) | 
| Percentage of Responders at Rest as Assessed by the Investigator According to FWS | FWS was used to assess the severity of glabellar frown lines at rest by the investigator. The 4-point scale depicted as: 0 = none, 1 = mild, 2 = moderate and 3 = severe. Responders on the FWS were defined as participants with glabellar line severity of none (0) or mild (1). Responders on the FWS were defined as participants with glabellar line severity of none (0) or mild (1). | At evaluation visit (30 days after injection) and at last control visit (85 days after last injection) in each treatment cycle from Cycle 1 to Cycle 8 (each cycle length >=85 days) | 
| Percentage of Responders at Maximum Frown by Participant's Assessment on the 4-point Scale | Participant's assessment of the glabellar frown lines at maximum frown on the 4-point scale was done by asking participant the following question in local language: How would you judge the potency of frown muscle action by comparison to sample photos at this visit? The possible rating responses were: 0 = no muscle action at all, 1 = some even slight muscle action possible, 2 = moderately strong muscle action possible, 3 = strong muscle action possible which may cause local pallor. Responders were participants with at least 1-point improvement compared to Day 0 whereas improvement was expressed by lowering of the numerical score. | At evaluation visit (30 days after injection) and at last control visit (85 days after last injection) in each treatment cycle from Cycle 1 to Cycle 8 (each cycle length >=85 days) | 
| Percentage of Responders at Rest by Participant's Assessment on the 4-point Scale | Participant's assessment of the glabellar frown lines at rest on the 4-point scale was done by asking participant the following question in local language: How would you judge the degree of your glabellar lines by comparison to sample photos at this visit? The possible rating responses were: 0 = no visible vertical line(s) at all, 1 = slightly visible vertical line(s), 2 = moderate vertical line(s) with depression, and 3 = deep vertical line(s) and depression which cannot be effaced by spreading. Responders were participants with at least 1-point improvement compared to Day 0 whereas improvement was expressed by lowering of the numerical score. | At evaluation visit (30 days after injection) and at last control visit (85 days after last injection) in each treatment cycle from Cycle 1 to Cycle 8 (each cycle length >=85 days) | 
| Degree of Glabellar Lines as Assessed by the Participant on the 6-point Likert Type Scale at Maximum Frown | Number of participants are reported categorized in grades based on the assessment of the glabellar frown lines at maximum frown on the 6-point Likert scale. Participant's assessment of the glabellar frown lines at maximum frown on the 6-point Likert type scale was done by asking participant the following question in local language: How would you judge the potency of frown muscle action at this visit? The possible rating responses were given on a categorical scale of 6 grades between the grades 0 = none at all and 5 = very deep, with higher score reflecting higher potency. | At evaluation visit (30 days after injection); and at last control visit (85 days after last injection) in each treatment cycle from Cycle 1 to Cycle 8 (each cycle length >=85 days) | 
| Degree of Glabellar Lines as Assessed by the Participant on the 6-point Likert Type Scale at Rest | Number of participants are reported categorized in grades based on the assessment of the glabellar frown lines at rest on the 6-point Likert scale. Participant's assessment of the glabellar frown lines at rest on the 6-point Likert type scale was done by asking participant the following question in local language: How would you judge the degree of your glabellar lines at this visit? The possible rating responses were given on a categorical scale of 6 grades between the grades 0 = none at all and 5 = very deep, with higher scores reflecting higher degree of glabellar lines. | At evaluation visit (30 days after injection); and at last control visit (85 days after last injection) in each treatment cycle from Cycle 1 to Cycle 8 (each cycle length >=85 days) | 
| Time to Onset of Treatment Effect | Onset of treatment effect was analyzed using number of participants with corresponding onset of treatment effect, stratified by cycles. | From injection visit up to date of onset of treatment effect in each treatment cycle from Cycle 1 to Cycle 8 (each cycle length >=85 days) |