dose.12 Investigator assessments revealed median duration of response to be 150 days (21.4 weeks) overall and 165 days (23.6 weeks) when treating moderate glabellar lines.12 Respective investigator and subject assessments showed that 61.9% and 66.7% maintained ≥1-grade improvements from baseline at day 150.12 However, subject numbers were small (n=30) and further studies are required to establish the influence of ABO dosing on longevity of aesthetic effect.12
The evolving evidence base for ABO may support individualized approaches to treatment, based on specific requirements (eg, facial anatomy, muscle activity pattern, muscle mass).13,14 The current study aimed to examine the impact of increasing dose on the efficacy, safety and durability of a single ABO treatment for the correction of moderate-to-severe glabellar lines.
The evolving evidence base for ABO may support individualized approaches to treatment, based on specific requirements (eg, facial anatomy, muscle activity pattern, muscle mass).13,14 The current study aimed to examine the impact of increasing dose on the efficacy, safety and durability of a single ABO treatment for the correction of moderate-to-severe glabellar lines.
MATERIALS AND METHODS
Study Design
A 36-week, Phase 2, multicenter, randomized, dose-ranging, double-blind, placebo-controlled study was conducted at 10 centers across the United States between November 2018 and July 2020 (NCT03736928). The study complied with the principles of the Declaration of Helsinki (1964) and subsequent amendments and the International Council for Harmonization of Technical Requirements for Pharmaceuticals for Human Use Good Clinical Practice (GCP). Subjects provided written informed consent. Ethical approval was obtained from relevant institutional review boards (IRBs).
Study Population
Males/females (aged 18–65 years) were included with moderateto- severe glabellar lines, assessed at maximum frown using the investigator live assessment (ILA) photographic scale and the subject self-assessment (SSA) static categorical scale. Both scales used a 4-point grading system: 0 (none), 1 (mild), 2 (moderate), and 3 (severe).
Subjects were excluded if they had received prior facial treatment with botulinum toxin (within 9 months), had a history of facial surgery or aesthetic procedures, or known allergy to any component of study product or to cow’s milk protein. Other exclusion criteria included history or presence of eyelid or eyebrow ptosis, amblyopia, cancerous/pre-cancerous lesions or radiation in the glabellar region, facial nerve palsy, and the presence of inflammation, active infection, or skin disorder near to or in the glabellar region. Women who were pregnant, planning a pregnancy, or breastfeeding could not enroll.
Study Treatment
Study vials containing ABO 300 U or placebo lyophilized powder were reconstituted with 1.5, 1.0, 0.75, or 0.60 mL of preservativefree NaCl 0.9% for injection, corresponding to four ABO doses: 50 U (10 U/0.05 mL injection), 75 U (15 U/0.05 mL injection), 100 U (20 U/0.05 mL injection), or 125 U (25 U/0.05 mL injection). At baseline (day 0), subjects were randomized (4:1) to receive either ABO or placebo, given as a 0.25 mL total volume (0.05 mL per injection site) at 5 pre-specified sites in the glabellar region; 2 in each corrugator muscle and 1 in the procerus muscle. Stepwise enrollment was applied for the two highest doses. Subjects were assessed post-treatment at day 2, week 1, and week 2, and then monthly at week 4 through week 36.
Primary Efficacy Endpoint
Primary endpoint was week 4 composite ≥2-grade responder rate. Responders were defined as those achieving a glabellar line severity score of 0 (none) or 1 (mild) and at least a 2-grade improvement from baseline at maximum frown on both the ILA and SSA scales concurrently.
Secondary Efficacy Endpoints
Secondary efficacy endpoints, evaluated at maximum frown during all post-treatment visits, comprised responder rate among subjects achieving a score of 0 (none) or 1 (mild) (assessed on ILA and SSA scales individually), and responder rate for subjects with ≥1-grade improvement from baseline (ILA scale only). Subject diary cards reported time to onset of treatment effect (days 1–7). Duration of response was assessed at maximum frown for those achieving scores of 0 (none) or 1 (mild) (ILA and SSA scales concomitantly) and reported as the time to loss of 0 (none) or 1 (mild) score and the time taken to return to baseline score/worse. Participants also completed the subject satisfaction questionnaire.
Safety Endpoints
Treatment-emergent adverse events (TEAEs) were reported. Blood samples were taken at baseline (prior to treatment) and at week 36 or in cases of early termination from the study and were tested for the presence of neutralizing antibodies against ABO. '
Statistical Analysis
Statistical analyses were performed using the SAS® system (Version 9.4) and compared responder rate data at all study visits from ABO-treated groups against placebo group data, with P values calculated using Fisher’s Exact Tests and exact confidence intervals using the Chan and Zhang method. The study was not powered to examine statistical differences in efficacy between ABO doses. Confidence intervals (CI) were 2-tailed and constructed at a confidence level of 95%. Primary and secondary efficacy variables were analyzed using the intent-to-treat (ITT) population; all subjects randomized and treated with study product. Kaplan-Meier methods were used to evaluate time to onset and duration of treatment effect. The safety population was identical to the ITT population.
A 36-week, Phase 2, multicenter, randomized, dose-ranging, double-blind, placebo-controlled study was conducted at 10 centers across the United States between November 2018 and July 2020 (NCT03736928). The study complied with the principles of the Declaration of Helsinki (1964) and subsequent amendments and the International Council for Harmonization of Technical Requirements for Pharmaceuticals for Human Use Good Clinical Practice (GCP). Subjects provided written informed consent. Ethical approval was obtained from relevant institutional review boards (IRBs).
Study Population
Males/females (aged 18–65 years) were included with moderateto- severe glabellar lines, assessed at maximum frown using the investigator live assessment (ILA) photographic scale and the subject self-assessment (SSA) static categorical scale. Both scales used a 4-point grading system: 0 (none), 1 (mild), 2 (moderate), and 3 (severe).
Subjects were excluded if they had received prior facial treatment with botulinum toxin (within 9 months), had a history of facial surgery or aesthetic procedures, or known allergy to any component of study product or to cow’s milk protein. Other exclusion criteria included history or presence of eyelid or eyebrow ptosis, amblyopia, cancerous/pre-cancerous lesions or radiation in the glabellar region, facial nerve palsy, and the presence of inflammation, active infection, or skin disorder near to or in the glabellar region. Women who were pregnant, planning a pregnancy, or breastfeeding could not enroll.
Study Treatment
Study vials containing ABO 300 U or placebo lyophilized powder were reconstituted with 1.5, 1.0, 0.75, or 0.60 mL of preservativefree NaCl 0.9% for injection, corresponding to four ABO doses: 50 U (10 U/0.05 mL injection), 75 U (15 U/0.05 mL injection), 100 U (20 U/0.05 mL injection), or 125 U (25 U/0.05 mL injection). At baseline (day 0), subjects were randomized (4:1) to receive either ABO or placebo, given as a 0.25 mL total volume (0.05 mL per injection site) at 5 pre-specified sites in the glabellar region; 2 in each corrugator muscle and 1 in the procerus muscle. Stepwise enrollment was applied for the two highest doses. Subjects were assessed post-treatment at day 2, week 1, and week 2, and then monthly at week 4 through week 36.
Primary Efficacy Endpoint
Primary endpoint was week 4 composite ≥2-grade responder rate. Responders were defined as those achieving a glabellar line severity score of 0 (none) or 1 (mild) and at least a 2-grade improvement from baseline at maximum frown on both the ILA and SSA scales concurrently.
Secondary Efficacy Endpoints
Secondary efficacy endpoints, evaluated at maximum frown during all post-treatment visits, comprised responder rate among subjects achieving a score of 0 (none) or 1 (mild) (assessed on ILA and SSA scales individually), and responder rate for subjects with ≥1-grade improvement from baseline (ILA scale only). Subject diary cards reported time to onset of treatment effect (days 1–7). Duration of response was assessed at maximum frown for those achieving scores of 0 (none) or 1 (mild) (ILA and SSA scales concomitantly) and reported as the time to loss of 0 (none) or 1 (mild) score and the time taken to return to baseline score/worse. Participants also completed the subject satisfaction questionnaire.
Safety Endpoints
Treatment-emergent adverse events (TEAEs) were reported. Blood samples were taken at baseline (prior to treatment) and at week 36 or in cases of early termination from the study and were tested for the presence of neutralizing antibodies against ABO. '
Statistical Analysis
Statistical analyses were performed using the SAS® system (Version 9.4) and compared responder rate data at all study visits from ABO-treated groups against placebo group data, with P values calculated using Fisher’s Exact Tests and exact confidence intervals using the Chan and Zhang method. The study was not powered to examine statistical differences in efficacy between ABO doses. Confidence intervals (CI) were 2-tailed and constructed at a confidence level of 95%. Primary and secondary efficacy variables were analyzed using the intent-to-treat (ITT) population; all subjects randomized and treated with study product. Kaplan-Meier methods were used to evaluate time to onset and duration of treatment effect. The safety population was identical to the ITT population.
