The present study aimed to further evaluate efficacy and safety
of treatment of moderate to severe GL using an injection volume
of 0.1 mL with the currently approved 50-U-dose of aboBoNT-A,
in a large US study population, following reconstitution of the
300-U-vial with a total reconstitution of 3.0 mL per vial.
MATERIALS AND METHODS
Study Design
This was a Phase III, randomized, double-blind study conducted at 12 US centers between June 2019 and April 2020 (clinicaltrials. gov registration number NCT03960957). Subjects were treated on day 0 with aboBoNT-A 50 U or placebo, and then followed up at day 2, week 2, and monthly from month 1 to month 6.
The primary objective was to evaluate efficacy of aboBoNT-A versus placebo based on the month 1, composite 2-grade response at maximum frown, defined as a GL severity score of 0 or 1 and a ≥2-grade improvement from baseline concurrently on both the Investigator’s Live Assessment (ILA) and the Subject’s Self-Assessment (SSA) scales. Secondary and exploratory objectives included further assessment of efficacy, subject satisfaction, other subject-reported outcomes and safety.
The study was conducted in accordance with the Declaration of Helsinki, the International Council for Harmonization Consolidated Guideline on Good Clinical Practice and local regulatory requirements, after approval from institutional review boards.
Subjects
Male and female subjects aged 18–64 years, with moderate-tosevere (Grade 2 or 3) GL at maximum frown, as assessed by ILA and SSA, who provided written informed consent were eligible for enrolment. Exclusion criteria included: facial treatment with botulinum toxin in the past 6 months; absorbable (temporary) or non-absorbable (permanent) material inserted in the glabellar region; any facial surgery or aesthetic or other procedures which could interfere with study evaluations; known hypersensitivity to any component of the study product; allergy to cow’s milk protein; breastfeeding or planned pregnancy for females during the study; history or presence of eyelid or eyebrow ptosis, amblyopia, cancerous or pre-cancerous lesions in or near the glabellar region, or facial nerve palsy; presence of inflammation, active infection or skin disorder in or near the glabellar region; use of medications that affect neuromuscular transmission; and conditions that might interfere with neuromuscular function.
Subjects had to abstain from facial aesthetic procedures and any planned facial surgery or eye surgery during the study.
Treatment
Treatment with aboBoNT-A or placebo was randomized 3:1, stratified by study center. AboBoNT-A, commercially available Dysport, was provided as a lyophilized powder in single-use 300-U-vials. Placebo vials contained excipients identical in appearance to aboBoNT-A powder. Before injection, each vial was reconstituted with 3.0 mL sterile preservative-free 0.9% NaCl USP for injection. A total volume of 0.5 mL reconstituted aboBoNT-A (50 U) or placebo was injected in the glabellar area, divided into five aliquots of 0.1 mL (10 U). One injection was placed in the procerus muscle, and two into each corrugator muscle.
Efficacy Assessments
GL severity was evaluated at maximum frown and at rest by investigators, using the validated 4-grade photographic ILA scale ranging from ‘none’ (Grade 0), ‘mild’ (Grade 1), ‘moderate’ (Grade 2) to ‘severe’ (Grade 3). GL severity was also graded at maximum frown by subjects, using the 4-grade categorical SSA scale ranging from ‘no wrinkles’ (Grade 0), ‘mild wrinkles’ (Grade 1), ‘moderate wrinkles’ (Grade 2), to ‘severe wrinkles’ (Grade 3).
The primary endpoint was the composite 2-grade GL response at maximum frown at month 1, which is defined above.
Other GL severity endpoints included ILA response at maximum frown and at rest, defined as achievement of a 0 or 1 score, or defined as a ≥1-grade improvement from baseline. Similar definitions were used to assess SSA response at maximum frown.
Time to loss of a score of 0 or 1 (ie, return to a score of 2 or 3) and time to return to baseline scores were calculated based on concurrent evaluations on both ILA and SSA at maximum frown. Subject-reported time to onset of response, was assessed using a 7-day subject diary.
Subjects responded ‘yes’ or ‘no’ to the question ‘Since being injected, have you noticed an improvement in the appearance of your glabellar lines (lines between your eyebrows)?’
Aesthetic improvement of GL at maximum frown was rated by the subjects using the 7-graded Global aesthetic improvement scale (GAIS) from ‘very much worse’ to ‘very much improved’. Other subject-reported outcomes included a subject satisfaction questionnaire consisting of 10 questions, capturing satisfaction with appearance and treatment outcome, and three validated FACE-Q® scales: Appraisal of Lines Between the Eyebrows, comprising 7 questions relating to how bothered the subject was by their GL, rated on a 4-point scale from ‘not at all’ (1) to ‘extremely’ (4),4 Psychological Function, comprising 10 items, rated on a 4-point scale from ‘definitely disagree’ (1) to ‘definitely agree’ (4),5 and Subject-perceived Age Visual Analog Scale (VAS) capturing how old the subject thinks that they look compared to their actual age (±15 years).6
This was a Phase III, randomized, double-blind study conducted at 12 US centers between June 2019 and April 2020 (clinicaltrials. gov registration number NCT03960957). Subjects were treated on day 0 with aboBoNT-A 50 U or placebo, and then followed up at day 2, week 2, and monthly from month 1 to month 6.
The primary objective was to evaluate efficacy of aboBoNT-A versus placebo based on the month 1, composite 2-grade response at maximum frown, defined as a GL severity score of 0 or 1 and a ≥2-grade improvement from baseline concurrently on both the Investigator’s Live Assessment (ILA) and the Subject’s Self-Assessment (SSA) scales. Secondary and exploratory objectives included further assessment of efficacy, subject satisfaction, other subject-reported outcomes and safety.
The study was conducted in accordance with the Declaration of Helsinki, the International Council for Harmonization Consolidated Guideline on Good Clinical Practice and local regulatory requirements, after approval from institutional review boards.
Subjects
Male and female subjects aged 18–64 years, with moderate-tosevere (Grade 2 or 3) GL at maximum frown, as assessed by ILA and SSA, who provided written informed consent were eligible for enrolment. Exclusion criteria included: facial treatment with botulinum toxin in the past 6 months; absorbable (temporary) or non-absorbable (permanent) material inserted in the glabellar region; any facial surgery or aesthetic or other procedures which could interfere with study evaluations; known hypersensitivity to any component of the study product; allergy to cow’s milk protein; breastfeeding or planned pregnancy for females during the study; history or presence of eyelid or eyebrow ptosis, amblyopia, cancerous or pre-cancerous lesions in or near the glabellar region, or facial nerve palsy; presence of inflammation, active infection or skin disorder in or near the glabellar region; use of medications that affect neuromuscular transmission; and conditions that might interfere with neuromuscular function.
Subjects had to abstain from facial aesthetic procedures and any planned facial surgery or eye surgery during the study.
Treatment
Treatment with aboBoNT-A or placebo was randomized 3:1, stratified by study center. AboBoNT-A, commercially available Dysport, was provided as a lyophilized powder in single-use 300-U-vials. Placebo vials contained excipients identical in appearance to aboBoNT-A powder. Before injection, each vial was reconstituted with 3.0 mL sterile preservative-free 0.9% NaCl USP for injection. A total volume of 0.5 mL reconstituted aboBoNT-A (50 U) or placebo was injected in the glabellar area, divided into five aliquots of 0.1 mL (10 U). One injection was placed in the procerus muscle, and two into each corrugator muscle.
Efficacy Assessments
GL severity was evaluated at maximum frown and at rest by investigators, using the validated 4-grade photographic ILA scale ranging from ‘none’ (Grade 0), ‘mild’ (Grade 1), ‘moderate’ (Grade 2) to ‘severe’ (Grade 3). GL severity was also graded at maximum frown by subjects, using the 4-grade categorical SSA scale ranging from ‘no wrinkles’ (Grade 0), ‘mild wrinkles’ (Grade 1), ‘moderate wrinkles’ (Grade 2), to ‘severe wrinkles’ (Grade 3).
The primary endpoint was the composite 2-grade GL response at maximum frown at month 1, which is defined above.
Other GL severity endpoints included ILA response at maximum frown and at rest, defined as achievement of a 0 or 1 score, or defined as a ≥1-grade improvement from baseline. Similar definitions were used to assess SSA response at maximum frown.
Time to loss of a score of 0 or 1 (ie, return to a score of 2 or 3) and time to return to baseline scores were calculated based on concurrent evaluations on both ILA and SSA at maximum frown. Subject-reported time to onset of response, was assessed using a 7-day subject diary.
Subjects responded ‘yes’ or ‘no’ to the question ‘Since being injected, have you noticed an improvement in the appearance of your glabellar lines (lines between your eyebrows)?’
Aesthetic improvement of GL at maximum frown was rated by the subjects using the 7-graded Global aesthetic improvement scale (GAIS) from ‘very much worse’ to ‘very much improved’. Other subject-reported outcomes included a subject satisfaction questionnaire consisting of 10 questions, capturing satisfaction with appearance and treatment outcome, and three validated FACE-Q® scales: Appraisal of Lines Between the Eyebrows, comprising 7 questions relating to how bothered the subject was by their GL, rated on a 4-point scale from ‘not at all’ (1) to ‘extremely’ (4),4 Psychological Function, comprising 10 items, rated on a 4-point scale from ‘definitely disagree’ (1) to ‘definitely agree’ (4),5 and Subject-perceived Age Visual Analog Scale (VAS) capturing how old the subject thinks that they look compared to their actual age (±15 years).6
