OnabotulinumtoxinA (Botox) in the Treatment of Crow’s Feet Lines in Japanese Subjects

This 13-month, phase 3, multicenter, double-blind, randomized, parallel-group study comprised 2 treatment periods: a 6-month placebo-controlled treatment period followed by a 7-month open-label period. Two doses of onabotulinumtoxinA (24 and 12 U) were evaluated for the treatment of moderate to severe CFL. These doses were compared with placebo in treatment period 1 (up to day 180), which consisted of an initial treatment (day 1) followed by up to 1 additional treatment. In treatment period 2 (starting on study day 180), all subjects received either onabotulinumtoxinA 24 U or onabotulinumtoxinA 12 U (up to 3 re-treatments) to assess the safety and efficacy of repeated treatments through the end of the study (day 390). All subjects could receive up to 5 total treatments based on meeting re-treatment criteria. The onabotulinumtoxinA 24 and 12 U doses were administered in a double-blind manner throughout the study.

Eligible subjects were randomized at the day 1 visit to 1 of the following 4 treatment groups in a 2:2:1:1 ratio for treatment periods 1 and 2: onabotulinumtoxinA 24 U/onabotulinumtoxinA 24 U, onabotulinumtoxinA 12 U/onabotulinumtoxinA 12 U, placebo/onabotulinumtoxinA 24 U, or placebo/onabotulinumtoxinA 12 U. Subjects were assigned a randomization number (not disclosed to the study center), and randomization was stratified by baseline CFL severity at maximum smile. The study drug was packaged and labeled with kit numbers; each kit contained 1 vial of study drug. An interactive voice or web response system designed by Allergan Data Management provided a specific kit number for each subject, and the study center administered treatment. The same procedure was followed during subsequent study visits. During treatment period 2, subjects who received onabotulinumtoxinA in period 1 continued to receive the same treatment dose, and subjects who received placebo in period 1 received either onabotulinumtoxinA 24 U or onabotulinumtoxinA 12 U, as determined on randomization at day 1. Each treatment comprised a total of 6 intramuscular injections in the lateral aspect of the orbicularis oculi (3 injections per side; 0.1 mL per injection site). Two alternative treatment patterns (Fig. 1) were available to the investigators, who selected a pattern based on the subject’s pattern of CFL and on their own clinical judgment.

Each subject could receive up to 5 treatments over the 13-month study period, based on re-treatment criteria (1 initial treatment and up to 1 additional treatment in period 1; up to 3 additional treatments in period 2). Re-treatment was permitted if subjects met all of the following criteria: bilateral CFL of at least moderate severity at maximum smile, as measured by the investigator using the FWS-A; a negative pregnancy test; and at least 3 months since the last treatment (no earlier than 84 days); no treatment was allowed after the day 360 visit.

Eligible subjects were Japanese males and nonpregnant females aged 20–64 years, with bilaterally symmetrical moderate to severe CFL at maximum smile, as measured by the investigator using the FWS-A. Subjects with previous cosmetic treatments or surgical procedures at the treatment sites were excluded. Other key exclusion criteria included eyebrow or eyelid ptosis and eyelid hooding or other skin laxity likely to interfere with onabotulinumtoxinA treatment or CFL assessments.

This study was conducted in compliance with the International Council for Harmonisation guidelines and Japanese Good Clinical Practice guidelines, as well as applicable US Food and Drug Administration guidelines. All subjects provided written informed consent prior to study participation.

Subjects attended up to 24 visits (depending on the number of treatments received). Visits included randomization/treatment (day 1); follow-up (at weeks 1 and 2 following each treatment); monthly from months 1 through 12; and upon exit (month 13 or early discontinuation). Differences in duration of response between subjects resulted in differences in the timing to re-treatment eligibility; accordingly, the study design allowed treatment/re-treatment intervals of various potential duration (Table 1). On treatment days, all measurements were taken prior to treatment.

The primary efficacy measure was the proportion of investigator-assessed responders at day 30 after initial treatment, with responders defined as subjects achieving CFL severity of none or mild severity at maximum smile on the FWS-A (0 = none, 1 = mild, 2 = moderate, and 3 = severe). Additional efficacy endpoints based on the investigator-assessed FWS-A included the following: the proportion of subjects achieving at least a 1-grade improvement in CFL severity at maximum smile and at rest (responders) at day 30; the duration of effect, defined as the median time until loss of efficacy (from responder to nonresponder in treatment period 1 for day 30 responders), using the following FWS-A responder definitions: CFL severity of none or mild at maximum smile, at least a 1-grade improvement in CFL severity at maximum smile, and ≥1-grade improvement in CFL severity at rest; and responder analyses at time points other than day 30 of treatment period 1.

Several subject-reported outcomes were also assessed. The subject’s global assessment of change in CFL (SGA-CFL) was evaluated on a 7-point scale ranging from 1 (very much improved) to 7 (very much worse). On the self-perception of age (SPA), subjects reported if they perceived themselves as looking their current age, older than their current age, or younger than their current age. Subjects’ perception of the effect of their facial lines on their appearance was assessed using specific items from the 11-item Facial Line Outcomes (FLO-11) Questionnaire including the psychological impact items 2 (“look older”), 5 (“look less attractive”), and 8 (“look tired”). Responses were based on a scale wherein 0 indicates “not at all” and 10 indicates “very much”; responders were subjects achieving at least a 2-point improvement for items 2 and 5 and at least a 3-point improvement for item 8. Subject Assessment of Satisfaction with Appearance was based on a 5-point scale (1 = very unsatisfied; 5 = very satisfied), and a responders were defined as subjects who rated their satisfaction as improved (ie, from neutral or worse at baseline to very satisfied or satisfied after treatment). Satisfaction with treatment was assessed by the Facial Line Satisfaction Questionnaire (FLSQ) overall satisfaction item. Responses were based on a 5-point Likert scale ranging from −2 (very dissatisfied) to +2 (very satisfied); responders were subjects who were “mostly” or “very” satisfied. Finally, subjects’ perception of onset of effect was assessed by asking subjects at weeks 1 and 2 if they noticed an improvement in CFL appearance; those who answered yes were asked when (in number of days) the improvement was first noticed.

Safety measures were adverse events (AEs), vital sign measurements (pulse rate, respiratory rate, and blood pressure), physical examination, urine pregnancy test for female subjects of childbearing potential, and neurologic assessments (focused symptoms questionnaire and focused neurologic examination).

Analyses were performed on the intent-to-treat population (all subjects who were randomized) and safety population (all subjects who received ≥1 injection of study drug). The last observation carried forward method was used for imputation of missing values through day 90 of each treatment. Between-group baseline and demographic comparisons were performed using the Kruskal–Wallis test. For the FWS-A, FLO-11, satisfaction with treatment (FLSQ), and satisfaction with appearance, the comparison of the proportion of responders was performed using the Cochran–Mantel–Haenszel test stratified by baseline CFL severity at maximum smile. The median time to onset of improvement in CFL as reported by subjects at weeks 1 and 2 during each treatment period was estimated using the Kaplan–Meier survival method.

Of the 305 subjects screened, 300 were enrolled and were randomized (Fig. 2). The majority of subjects completed the study (89.3%). Demographic characteristics between treatment groups were similar (Table 2). Mean (range) age was 49.7 (25–64) years; 56.3% of subjects were younger than 50 years of age, and the majority of subjects (74.7%) were female. At baseline, CFL mean severity score at maximum smile was moderate in 49.0% of subjects and severe in 51.0% of subjects. No statistically significant differences in subject-reported measures were noted between groups at baseline.

For the primary endpoint, responder rates at day 30 of treatment period 1 were significantly greater (P < 0.001) in the onabotulinumtoxinA 24 and 12 U groups than in the placebo group (Fig. 3). Differences between the onabotulinumtoxinA 24 and 12 U groups were not statistically significant. The proportion of responders was significantly greater (P ≤ 0.001) in the onabotulinumtoxinA 24 and 12 U groups compared with the placebo group at all other time points through day 90 in the treatment period 1 (Fig. 4). During the non-placebo-controlled period (treatments 3, 4, and 5), the proportion of responders was similar to that observed during the placebo-controlled treatments. For all treatments (1–5), the proportion of responders in the onabotulinumtoxinA 24 U group was generally greater compared with the onabotulinumtoxinA 12 U group.

The proportion of responders defined as those achieving at least a 1-grade improvement in severity at maximum smile was significantly greater (P < 0.001) in the onabotulinumtoxinA 24 and 12 U groups (80.8 and 75.8%, respectively) compared with the placebo group (17.5%) at day 30. Differences between each onabotulinumtoxinA group and the placebo group were significant at all time points for treatments 1 and 2 (through day 90; P ≤ 0.001) (Fig. 5a). Similarly, at day 30 of treatment period 1, among the 274 subjects with at least mild static CFL at baseline, a greater proportion of subjects achieved at least a 1-grade improvement in CFL severity at rest with onabotulinumtoxinA 24 U (61.6%) and onabotulinumtoxinA 12 U (43.6%) compared with placebo (17.3%; P < 0.001, both comparisons) (Fig. 5b). Differences were significant (P ≤ 0.003) at all time points in treatment period 1 (up to 90 days). For treatment period 2, the proportion of responders in the onabotulinumtoxinA groups was similar to that observed during the placebo-controlled treatment (period 1), both at maximum smile and at rest. Responder rates were numerically higher in the onabotulinumtoxinA 24 U group than in the 12 U group, but differences were not statistically significant at any time point across treatments.

Representative photographs of 2 subjects at baseline and at the end of treatment period 1 are shown in Fig. 6. Both female subjects had severe CFL at baseline that improved to mild at 30 days after treatment with onabotulinumtoxinA 24 U or 12 U.

Repeated treatment with onabotulinumtoxinA 24 and 12 U in the CFL areas (up to 5 treatments over 13 months) was safe and well tolerated. Over the entire study, a greater proportion of subjects who received onabotulinumtoxinA (47.0% [71/151] for 24 U; 59.4% [85/143] for 12 U) experienced 1 or more treatment-emergent AEs (TEAEs) compared with subjects who received placebo (35.1% [34/97]), likely owing to the greater exposure to onabotulinumtoxinA (up to 5 treatments) compared with placebo (up to 2 treatments). The proportion of subjects experiencing TEAEs was comparable between all treatment groups during the placebo-controlled period 1 (25.2% [38/151] for 24 U; 29.4% [42/143] for 12 U; 22.7% [22/97] for placebo).

The most common TEAEs (incidence ≥1%) across all treatment groups are displayed in Table 4. All TEAEs reported during the study were mild or moderate in severity. Treatment-related AEs occurred in 13 subjects (4.0% [6/151] with onabotulinumtoxinA 24 U, 2.8% [4/143] with onabotulinumtoxinA 12 U, and 3.1% [3/97] with placebo). The most frequently reported treatment-related AEs were malaise (n = 2, 24 U and placebo), headache (n = 2, placebo), and sensory disturbance (n = 2, 12 U and placebo); all other treatment-related AEs occurred in 1 onabotulinumtoxinA subject each (abnormal sensation in eye, eyelid edema, eyelid pain, eyelid ptosis, abdominal pain upper, thirst, injection site pain, injection site warmth, injection site pruritus, dysphoria, brow ptosis, skin tightening); some subjects experienced more than 1 treatment-related AE. All treatment-related AEs were mild in severity.

Four subjects (1 with onabotulinumtoxinA 24 U; 2 with onabotulinumtoxinA 12 U; 1 with placebo) experienced events that were identified as possible spread of toxin: blurred vision (1 subject each with onabotulinumtoxinA 12 U and placebo); eyelid ptosis (1 subject with onabotulinumtoxinA 24 U); and muscular weakness (1 subject with onabotulinumtoxinA 12 U). Safety adjudication of each event determined that the events of blurred vision and eyelid ptosis in onabotulinumtoxinA subjects were local events consistent with the known pharmacology of onabotulinumtoxinA, while the events of blurred vision (with placebo) and muscle weakness (with onabotulinumtoxinA 12 U) did not represent the distant spread of toxin.

Two subjects were discontinued from the study after receiving onabotulinumtoxinA 24 U because of TEAEs considered unrelated to study drug (back pain and angina pectoris). No subject died during the study. Seven subjects experienced a serious TEAE (2.0% [3/151] with onabotulinumtoxinA 24 U, 2.1% [3/143] with onabotulinumtoxinA 12 U, and 1.0% [1/97] with placebo). None of the serious TEAEs were considered to be related to the study drug by the investigators. No clinically meaningful findings were reported from the neurologic assessment. All subjects were negative for neutralizing antibodies at baseline and at the end of the study.