treatments were allowed at monthly intervals (Treatments 2, 3, and 4). Follow up visits were conducted at months 7, 9, and 12 (taking place 3, 5, and 8 months after the fourth treatment session, respectively). Each vial containing sterile, freeze-dried, injectable PLLA-SCA (150 mg) was reconstituted in SWFI (8 mL) and 1 mL lidocaine hydrochloride (2%) was added immediately prior to injection. PLLA-SCA solution (9 mL maximum) was administered sub-dermally into each cheek using a 25 G needle. The treated area was defined according to the superior, medial, inferior, and lateral anatomical cheek borders. The superior border comprised the area from the topmost part of the tragus to top of alar crease. The medial border encompassed the top of the alar crease, along the nasolabial fold to the inferior border of the mandibular ramus. The inferior border ran from the medial border at the mandibular ramus to the angle of mandibular ramus and the lateral border comprised the area from the angle of the mandibular ramus to the top of the tragus.
Effectiveness Endpoints
The primary effectiveness endpoint was the responder rate based on a blinded evaluator assessment of GCWS at rest at month 12 after baseline. A responder was defined as a subject with 1-grade or greater GCWS improvement from baseline in both cheeks concurrently.
Secondary and exploratory endpoints included responder rate for GCWS at rest at months 7 and 9, and responder rate for GCWS dynamic at months 7, 9, and 12 (blinded evaluator assessments). Treating investigators assessed the combined improvement on both sides of the face using the 7-point Global Aesthetic Improvement Scale (GAIS: very much improved, much improved, improved, no change, worse, much worse, very much worse) at all visits for the PLLA-SCA group and at months 7, 9, and 12 for the control group. GAIS responders scored very much improved, much improved, or improved from baseline. Treating investigators also assessed the change from baseline regarding skin radiance, tightness, and jawline contour at months 7, 9, and 12.
PLLA-SCA recipients completed the subject satisfaction questionnaire at all visits, following treatment. Participants rated overall treatment results using a 5-grade scale: excellent, very good, good, satisfactory, or not satisfied. Subjects also indicated the extent to which they agreed with statements relating to the effectiveness of treatment using a 5-grade scale: strongly agree, agree, neither agree nor disagree, disagree, strongly disagree. The satisfaction with cheeks FACE-Q questionnaire examined subject-assessed outcomes regarding the change in symmetry, smoothness, attractiveness, contour, and youthful fullness. Subjects indicated their level of satisfaction with treatment outcomes using a 4-grade scale: very satisfied, somewhat satisfied, somewhat dissatisfied, very dissatisfied. The control group completed the satisfaction with cheeks FACE-Q questionnaire at months 7, 9, and 12. FACE-Q responses were converted to Rasch-transformed total scores. Subject diaries recorded the time to return to social engagement for 28 days after each treatment.
Safety Endpoints
Adverse events (AEs) were reported by the treating investigator throughout the study and included any abnormal findings from an evaluation of cheek firmness, symmetry, function, mass formation and palpability, cheek sensation, and visual function performed at all study visits. Subject diary cards were used to collect expected post-treatment symptoms (for 28 days after each treatment).
Statistical Analysis
All statistical analyses used the SAS software. Confidence intervals (CIs) were 2-tailed and at a level of 95%. The intention-to-treat (ITT) and safety populations comprised all randomized subjects. Effectiveness analyses examined the ITT population. The per-protocol (PP) population comprised all ITT subjects completing baseline and month 12 visits without deviations considered likely to impact the primary effectiveness outcome. The primary endpoint analysis used Fisher's exact test with multiple imputations of missing data instead of baseline observation carried forward (defined in the study protocol) to manage the increased risk of premature study discontinuation or missed month 12 visits during the COVID-19 pandemic. Month 12 responder rate CIs used multiple imputations, but sensitivity analysis of the primary and secondary endpoints used the planned Clopper-Pearson intervals.
RESULTS
Study Population
Baseline demographics and characteristics are presented in Table 1. Overall, 149 subjects were included in the study, with 97 randomized to the PLLA-SCA group and 52 to the control group. Most subjects were female (96.6%), White (90.6%), and not of Hispanic/Latino origin (91.9%). Mean age was 60.7 (range: 41-89) years and subjects were typically aged greater than or equal to 55 years (77.9%). All subjects had moderate or severe cheek wrinkles at baseline (blinded evaluator GCWS at rest assessments). Additional PLLA-SCA treatments were required at months 1, 2, and 3 for 95 (97.9%), 86 (88.7%), and 67 (69.1%) subjects, respectively. Injection volumes for each treatment are shown in Table 2.
Effectiveness Outcomes
Figure 2 shows the GCWS at rest responder rate at months 7, 9, and 12 (live blinded evaluator assessment). Concerning the primary endpoint, the GCWS at rest responder rate was significantly higher in the PLLA-SCA group (70.7% estimated; 71.6% observed cases), compared with the control group (25.9% estimated; 26.1% observed cases) at month 12 (P<0.0001 for both comparisons). GCWS responder rate was also significantly
