INTRODUCTION • The development of upper facial lines can negatively influence self- perception and may have adverse psychological impacts1-3 • Subject satisfaction with aesthetic treatment reflects successful treatment outcomes, which consequently may be associated with improved self- esteem and body image1,2 • OnabotulinumtoxinA has been used effectively and safely to treat facial lines since the early 1990s4,5 • When treating forehead lines (FHL), concurrent treatment of glabellar lines (GL) is recommended to reduce the risk of eyebrow ptosis by maintaining a balance between eyebrow elevator muscles (primarily the frontalis muscle) and depressor muscles (including the procerus and corrugator muscles making up the glabellar complex)6 • The safety and efficacy of onabotulinumtoxinA for treating FHL with 20 U to the frontalis muscle and 20 U to the glabellar complex was evaluated in a 12-month, phase 3 study7 ─ The primary endpoint—proportion of subjects achieving ≥2-grade improvement from baseline on day 30 in investigator and subject Facial Wrinkle Scale with photonumeric guide (FWS) scores of FHL severity at maximum eyebrow elevation—was met (61.4% with onabotulinumtoxinA vs 0% with placebo; P<0.0001) OBJECTIVE • To present results from a 12-month, phase 3 study on the effects of onabotulinumtoxinA on patient-reported satisfaction and to assess impacts of treatment METHODS Patients • Neurotoxin-naive males and females aged ≥18 years with both: ─ Moderate to severe FHL at maximum eyebrow elevation (as assessed by both investigator and subject using the FWS on study day 1, before treatment) ─ Moderate to severe GL at maximum frown (as assessed by the investigator using the FWS on study day 1, before treatment) Study Design • This 12-month, phase 3 study was conducted at 9 sites in the United States, 5 in Canada, and 2 in Europe (Ireland) from October 2014 to April 2016 • The study comprised a 6-month double-blind, placebo-controlled, parallel- group treatment period (days 1–180) followed by a 6-month open-label treatment period (days 180–360) (Figure 1) • Eligible subjects were randomized (3:1) to receive a single treatment consisting of onabotulinumtoxinA 40 U (20 U in FHL and 20 U in GL) or placebo administered at 10 injection sites (Figure 2) ─ OnabotulinumtoxinA 4U or placebo was given in 0.1 mL at each injection site • Following the double-blind period, subjects could receive up to 2 open-label treatments with onabotulinumtoxinA using the same 10 injection sites, with ≥84 days between treatment cycles • Follow-up assessments were made at weeks 1 and 2 after each study treatment; all subjects also had follow-up visits every 30 days from study day 30 through day 360 Figure 1. Study Design W1 W2 D30 D60 D90 D120 D150 D180 D210 D240 D270 D300 D330 D360 Screening and randomization (3:1) Period 1–Double-Blind Treatment Period 2–Open-Label Treatment 40 U (20 U FHL + 20 U GL); N=300 40 U (20 U FHL + 20 U GL); N=400 Study Exit Pbo (Pbo FHL + Pbo GL); N=100 Screening, Randomization, and Treatment Follow-up Visit Follow-up/Criteria-Based Treatment Visit D, day; FHL, forehead lines; GL, glabellar lines; Pbo, placebo; W, week. Figure 2. Injection Sites for OnabotulinumtoxinA Treatment of FHL and GL Forehead Glabellar Patient-Reported Outcome (PRO) Measures • Subjects completed the Facial Line Satisfaction Questionnaire (FLSQ) and the 11-item Facial Line Outcomes Questionnaire (FLO-11) at baseline, on days 7, 14, and 30, then every 30 days through day 360 • Both PRO instruments were developed, validated, and implemented in accordance with US Food and Drug Administration guidance8,9 • The FLSQ (comprising 11 questions at baseline and 13 questions at follow-up) was designed to assess treatment satisfaction and appearance- related impacts associated with FHL and GL from the subject’s perspective ─ FLSQ Item 5 assesses subjects’ satisfaction with treatment of their facial lines ─ The Impact Domain measures appearance-related and emotional impacts of treatment, including appearance-related age, anger, tiredness, emotional unhappiness, and negative self-esteem • The FLO-11 assesses psychological and appearance-related impacts associated with FHL and GL from the subjects’ perspective ─ Item 4 evaluates whether subjects feel that they look older than their actual age Statistical Analysis • FLSQ Item 5 and Impact Domain and FLO-11 Item 4 were included as key secondary efficacy endpoints as they reflect each subject’s perception of treatment effects and drive retreatment decisions ─ Proportion of subjects mostly or very satisfied on FLSQ Item 5 (primary time point: day 60) ─ Proportion of responders on FLSQ Impact Domain, defined by ≥20-point improvement from baseline (primary time point: day 30) ─ Proportion of responders on FLO-11 Item 4, defined by a ≥3-point improvement from baseline (primary time point: day 30) • These PROs were evaluated in the intent-to-treat (ITT) population, comprising all randomized subjects • Between-group comparisons were conducted using the Cochran-Mantel- Haenszel test, stratified by study site, with statistical significance achieved at P≤0.05 RESULTS Subjects • The ITT population comprised 391 subjects, including 290 in the onabotulinumtoxinA group and 101 in the placebo group • The majority of subjects completed the study (n=333; 85.2%); discontinuations were mostly for personal reasons (n=39; 10.0%) or being lost to follow-up (n=15; 3.8%) ─ Overall, 349 subjects (89.3%) received a second treatment cycle and 225 subjects (57.5%) received a third treatment cycle during the open-label period • Demographics and baseline characteristics were similar between treatment groups (Table 1) Table 1. Subject Demographics and Baseline Characteristics (ITT population) Parameter Onabotulinum- toxinA (n=290) Placebo (n=101) Age, mean, years 44.5 42.4 Range 18–77 22–64 Female, n (%) 249 (85.9) 87 (86.1) Caucasian, n (%) 260 (89.7) 87 (86.1) FHL severity at maximum eyebrow elevation, subject FWS rating, n (%) Moderate 138 (47.6) 48 (47.5) Severe 152 (52.4) 53 (52.5) GL severity at maximum frown, investigator FWS rating,* n (%) Moderate 85 (29.3) 39 (38.6) Severe 205 (70.7) 61 (60.4) FLO-11 Item 4 score,† mean (range) 5.9 (0–10) 5.6 (0–10) FLSQ Impact Domain score,‡ mean (range) 55.3 (0–100) 52.0 (0–100) *One subject in the placebo group had a rating of mild. †FLO-11 Item 4 scored on a scale from 0 (“not at all”) to 10 (“very much”). ‡ FLSQ Impact Domain scored from 0–100, with higher scores indicating facial lines have greater negative impact on the subject. FHL, forehead lines; FLO-11, 11-item facial line outcomes questionnaire; FLSQ, facial line satisfaction questionnaire; FWS, facial wrinkle scale; GL, glabellar lines; ITT, intent-to-treat. FLSQ Item 5 • The proportion of subjects who were mostly or very satisfied with study treatment was significantly greater with onabotulinumtoxinA than placebo on day 30 (88.9% vs 3.0%; P<0.0001) and at the primary time point for this measure on day 60 (90.3% vs 1.0%; P<0.0001) • Subject satisfaction with treatment remained significantly higher with onabotulinumtoxinA than placebo at all time points through the end of the double-blind treatment period (ie, day 180; P<0.0001) (Figure 3) • During the open-label period, subject satisfaction was maintained with repeated onabotulinumtoxinA treatment, including in subjects initially allocated to placebo Figure 3. Subjects Mostly or Very Satisfied on FLSQ Item 5 Over the 12-Month Study 0 10 20 30 40 50 60 70 80 90 100 Day 7 Day 14 Day 30 Day 60 Day 90 Day 120 Day 150 Day 180 M o s t ly S a t is fi e d o r V e r y S a t is f ie d ( % ) Visit Day OnabotulinumtoxinA (n=289) Placebo (n=99, cycle 1) → onabotulinumtoxinA Period 1 Period 2 * * * * * * * * Day 7 Day 14 Day 30 Day 60 Day 90 Day 7 Day 14 Day 30 Day 60 Day 90 Cycle 3: Open-labelCycle 2: Open-labelCycle 1: Double-blind *P<0.0001 for onabotulinumtoxinA vs placebo. FLSQ Impact Domain • The responder rate on the FLSQ Impact Domain was significantly greater with onabotulinumtoxinA than placebo on day 30 (73.9% vs 18.9%; P<0.0001) • The FLSQ Impact Domain responder rate remained significantly higher with onabotulinumtoxinA than placebo at all time points through day 180 (P≤0.0007) (Figure 4) • During the open-label treatment period, FLSQ Impact Domain responder rates were generally maintained with repeated onabotulinumtoxinA treatment Figure 4. Responders Achieving ≥20-Point Improvement From Baseline on FLSQ Impact Domain Over the 12-Month Study (subjects with baseline scores ≥20) R e s p o n d e r s o n F L S Q I m p a c t D o m a in ( % ) Visit Day OnabotulinumtoxinA (n=268) Placebo (n=9 , cycle 1) → onabotulinumtoxinA Period 1 Period 2 * * * * * * * † 0 10 20 30 40 50 60 70 80 90 100 Day 7 Day 14 Day 30 Day 60 Day 90 Day 120 Day 150 Day 180 Day 7 Day 14 Day 30 Day 60 Day 90 Day 7 Day 14 Day 30 Day 60 Day 90 Cycle 3: Open-labelCycle 2: Open-labelCycle 1: Double-blind *P<0.0001; †P=0.0007 for both onabotulinumtoxinA groups vs placebo. FLO-11 Item 4 • The responder rate on the FLO-11 Item 4 (looking older than actual age) was significantly greater with onabotulinumtoxinA than placebo on day 30 (77.2% vs 11.2%; P<0.0001) • The FLO-11 Item 4 responder rate remained significantly higher with onabotulinumtoxinA than placebo at all time points through day 180 (P≤0.0002) (Figure 5) • Like the other PRO measures, the FLO-11 responder rate was generally maintained with repeated onabotulinumtoxinA treatment during the open-label period Figure 5. Responders Achieving ≥3-Point Improvement From Baseline on FLO-11 Item 4 Over the 12-Month Study (subjects with baseline score ≥3) R e s p o n d e r s o n F L O - 1 1 I t e m 4 ( % ) Visit Day OnabotulinumtoxinA (n=246) Placebo (n= 9, cycle 1) → onabotulinumtoxinA 0 10 20 30 40 50 60 70 80 90 100 Day 7 Day 14 Day 30 Day 60 Day 90 Day 120 Day 150 Day 180 Day 7 Day 14 Day 30 Day 60 Day 90 Day 7 Day 14 Day 30 Day 60 Day 90 Period 1 Period 2 * * * * * * * † Cycle 3: Open-labelCycle 2: Open-labelCycle 1: Double-blind *P<0.0001; †P=0.0002 for onabotulinumtoxinA vs placebo. CONCLUSIONS • Subjects were highly satisfied with onabotulinumtoxinA treatment of FHL and GL, and reported significant improvements in appearance-related and emotional impacts of their facial lines • These PRO improvements were sustained for ≥6 months after a single treatment cycle and, thereafter, were maintained with repeated onabotulinumtoxinA treatment REFERENCES 1. Finn CJ, et al. Dermatol Surg. 2003;29(5):450-5. 2. Cox SE, Finn JC. Int Ophthalmol Clin. 2005;45(3):13-24. 3. Gupta MA, Gilchrest BA. Dermatol Clin. 2005;23(4):643-8. 4. Carruthers JD, Carruthers JA. J Dermatol Surg Oncol. 1992;18(1):17-21. 5. Carruthers J, et al. Dermatol Surg. 2015;41(6):702-11. 6. Lorenc ZP, et al. Aesthet Surg J. 2013;33(1 Suppl):35S-40S. 7. Fagien S, et al. Presented at: International Master Course on Aging Sciences; February 1-3, 2017; Paris, France. 8. Pompilus F, et al. J Cosmet Dermatol. 2015;14(4):274-85. 9. Yaworsky A, et al. J Cosmet Dermatol. 2014;13(4):297-306. ACKNOWLEDGMENTS This study was sponsored by Allergan plc, Dublin, Ireland. Medical writing and editorial assistance was provided to the authors by Peloton Advantage, Parsippany, NJ, USA, and was funded by Allergan plc. All authors met the ICMJE authorship criteria. Neither honoraria nor other form of payments were made for authorship. FINANCIAL DISCLOSURES S Dayan has received research support or speaking/consultant fees from Allergan plc, Galderma, Merz Aesthetics, and Valeant. P Ogilvie serves as an investigator for Allergan plc. AZ Rivkin serves as a consultant and investigator for Allergan plc and Merz Aesthetics. SG Yoelin serves as a consultant and investigator for Allergan plc. JK Garcia is an employee of Allergan plc and may own stock/options in the company. IL Ferrusi was an employee of Allergan plc at the time of the study. OnabotulinumtoxinA for Treatment of Moderate to Severe Horizontal Frontalis Lines and Glabellar Lines From the Subject’s Perspective: Patient-Reported Satisfaction and Impact Outcomes From a Phase 3 Double-Blind Study Steven Dayan, MD1; Patricia Ogilvie, MD, PhD2; Alexander Z. Rivkin, MD3; Steven G. Yoelin, MD4; Julie K. Garcia, PhD5; Ilia L. Ferrusi, PhD5 1DeNova Research, Chicago, IL; 2SkinConcept, Munich, Germany; 3David Geffen School of Medicine, UCLA, Los Angeles, CA; 4Medical Associates Inc., Newport Beach, CA; 5Allergan plc, Irvine, CA Scan to obtain PDF of poster To obtain a PDF of this poster: Scan the QR code OR Visit www.allergancongressposters.com/935984 Charges may apply. No personal information is stored. To view a video of the MOA of Botox-C, scan the QR code, then click on the “narrated poster” button. When prompted, enter the password BotoxMOA123. Note that the password is case sensitive. Enter a valid e-mail to send this QR code or click to download. Please ensure that qrcode@allergancongressposters.com has been added to your safe senders list or spam filter. Fall Clinical Dermatology Conference, Las Vegas, October 12-15, 2017 FC17PosterAllerganDayanOnabotulinumtoxinAHorizontalFrontalisLines.pdf