of hyaluronic acid products within 12 months prior to randomization.
Treatment
Patients were randomized (1:1) to receive CaHA (+) treatment in the jawline area with either needle (27 gauge, ¾") or cannula (27 gauge, 1.6") at baseline. The injection method assigned at baseline was maintained if patients received a touch-up and/or re-treatment. The injection techniques used were a combination of linear-threading/tunneling, serial puncture and fanning, and linear-threading/tunneling. In all three treated anatomical locations (ie, angle/ramus, mid-body, and anterior), injection at multiple depths was allowed (ie, subdermal and/or supraperiosteal). The maximum volume of CaHA (+) per jawline side was limited to 3 mL during initial treatment and no more than 1.5 mL per jawline side during touch-up. At retreatment, the maximum volume of CaHA (+) per jawline side was limited to 3 mL.
Outcomes
Primary effectiveness was assessed on the MJAS by blinded raters. The 5-point MJAS ranges from grade 0 (a continuous jawline contour and no loss of volume) to grade 4 (an extreme loss of jawline contour and loss of jawline volume). Prior to study initiation, the MJAS was validated in a live setting (ie, 2 sessions, 3-weeks apart) by board-certified facial plastic surgeons and dermatologists who rated male and female volunteers with varying jawline severities, Fitzpatrick skin types, and ages. All raters exceeded the minimum weighted Kappa point estimate of 0.70 or greater for the intra- and inter-rater reliability, demonstrating the reliability of the MJAS. All blinded raters were qualified using the same criteria as used for MJAS validation before rating study patients.
The primary effectiveness endpoint was the comparison of responder rates between the treatment group and the untreated control group at week 12, according to the MJAS, as assessed live by the blinded rater. Treatment response was defined as a 1-point or greater improvement on both jawlines compared to baseline. Secondary and other endpoint assessments at week 12 included: FACE-Q Satisfaction with Lower Face and Jawline; patient and treating investigator ratings on the Global Aesthetic Improvement Scale (GAIS); independent panel review (IPR) responder rates according to the MJAS as assessed by three blinded raters in photographs (response defined as 1-point or greater improvement on both jawlines by at least 2 raters), and FACE-Q Patient-perceived Age Visual Analogue Scale (VAS). Retention of treatment response was also assessed at 48 weeks post-treatment.
Safety assessments included investigator-reported adverse events (AEs) over a 60-week period and patient-reported common treatment responses (CTRs) recorded in an electronic diary for 28 days after each treatment session.
Statistical Analysis
Two hypothesis tests for the primary endpoint were performed in sequential order: 1) a binomial test was used to demonstrate at least 50% of treated patients were responders (H01: Ptreatment ≤50% vs H11: Ptreatment >50%), and 2) the Fisher's exact test was used to compare the treatment group with the control group (H02: Ptreatment ≤ Pcontrol vs H12: Ptreatment > Pcontrol). Each hypothesis test was a onesided test, at a significance level of 0.025. Secondary and other endpoints, as well as safety, were descriptively summarized. Additionally, subgroup analysis by sex and Fitzpatrick skin types were performed. The SAS software package (SAS Institute, Cary, NC, USA) was used.
Treatment
Patients were randomized (1:1) to receive CaHA (+) treatment in the jawline area with either needle (27 gauge, ¾") or cannula (27 gauge, 1.6") at baseline. The injection method assigned at baseline was maintained if patients received a touch-up and/or re-treatment. The injection techniques used were a combination of linear-threading/tunneling, serial puncture and fanning, and linear-threading/tunneling. In all three treated anatomical locations (ie, angle/ramus, mid-body, and anterior), injection at multiple depths was allowed (ie, subdermal and/or supraperiosteal). The maximum volume of CaHA (+) per jawline side was limited to 3 mL during initial treatment and no more than 1.5 mL per jawline side during touch-up. At retreatment, the maximum volume of CaHA (+) per jawline side was limited to 3 mL.
Outcomes
Primary effectiveness was assessed on the MJAS by blinded raters. The 5-point MJAS ranges from grade 0 (a continuous jawline contour and no loss of volume) to grade 4 (an extreme loss of jawline contour and loss of jawline volume). Prior to study initiation, the MJAS was validated in a live setting (ie, 2 sessions, 3-weeks apart) by board-certified facial plastic surgeons and dermatologists who rated male and female volunteers with varying jawline severities, Fitzpatrick skin types, and ages. All raters exceeded the minimum weighted Kappa point estimate of 0.70 or greater for the intra- and inter-rater reliability, demonstrating the reliability of the MJAS. All blinded raters were qualified using the same criteria as used for MJAS validation before rating study patients.
The primary effectiveness endpoint was the comparison of responder rates between the treatment group and the untreated control group at week 12, according to the MJAS, as assessed live by the blinded rater. Treatment response was defined as a 1-point or greater improvement on both jawlines compared to baseline. Secondary and other endpoint assessments at week 12 included: FACE-Q Satisfaction with Lower Face and Jawline; patient and treating investigator ratings on the Global Aesthetic Improvement Scale (GAIS); independent panel review (IPR) responder rates according to the MJAS as assessed by three blinded raters in photographs (response defined as 1-point or greater improvement on both jawlines by at least 2 raters), and FACE-Q Patient-perceived Age Visual Analogue Scale (VAS). Retention of treatment response was also assessed at 48 weeks post-treatment.
Safety assessments included investigator-reported adverse events (AEs) over a 60-week period and patient-reported common treatment responses (CTRs) recorded in an electronic diary for 28 days after each treatment session.
Statistical Analysis
Two hypothesis tests for the primary endpoint were performed in sequential order: 1) a binomial test was used to demonstrate at least 50% of treated patients were responders (H01: Ptreatment ≤50% vs H11: Ptreatment >50%), and 2) the Fisher's exact test was used to compare the treatment group with the control group (H02: Ptreatment ≤ Pcontrol vs H12: Ptreatment > Pcontrol). Each hypothesis test was a onesided test, at a significance level of 0.025. Secondary and other endpoints, as well as safety, were descriptively summarized. Additionally, subgroup analysis by sex and Fitzpatrick skin types were performed. The SAS software package (SAS Institute, Cary, NC, USA) was used.
RESULTS
Patients
A total of 219 patients were screened with 180 patients being enrolled and randomized (123 to treatment and 57 to control/ delayed treatment; Figure 2) including patients of all Fitzpatrick skin types, both males and females, and patients of various ages and races. The majority (81.1%) of patients were female, self-identified as White (80.6%) and mean (SD) age was 55.3 (7.1) years (Table 1). Regarding Fitzpatrick skin type categories, 60.6% of patients had skin types I, II, or III, and 39.4% had skin types IV, V, or VI. For baseline severity MJAS scores, 55% of patients had a score of 2 (moderate) and 45% had a score of 3 (severe); all patients had the same baseline score on both sides of their jawlines.
Treatment
A total of 175/180 randomized patients received treatment (Figure 2) with either needle (88/175 patients) or cannula (87/175 patients). The median injection volume for each side of the jawline was 1.80 mL. Among patients receiving a touch-up (132/175, 75.4%), the median volume injected was 1.10 mL in the right jawline and 1.25 mL in the left jawline. In treatment-group patients eligible for re-treatment at week 48 (76/122, 62.3%), median re-treatment injection volumes were 1.40 mL for the right jawline and 1.50 mL for the left jawline. No patient was injected with more than 3 mL of CaHA (+) per jawline per treatment session. No clinically significant trends were identified when considering the volume injected during each injection cycle or between the treatment and delayed-treatment groups.
The most commonly used injection techniques were serial puncture when injecting with a needle and linear-threading/ tunneling when injecting with a cannula. The most common injection depth was subdermal and patients were frequently injected at multiple depths. The median number of injection points per jawline was 3 for all three treatment sessions, with a higher number of injection points when a needle was used, as expected.
A total of 219 patients were screened with 180 patients being enrolled and randomized (123 to treatment and 57 to control/ delayed treatment; Figure 2) including patients of all Fitzpatrick skin types, both males and females, and patients of various ages and races. The majority (81.1%) of patients were female, self-identified as White (80.6%) and mean (SD) age was 55.3 (7.1) years (Table 1). Regarding Fitzpatrick skin type categories, 60.6% of patients had skin types I, II, or III, and 39.4% had skin types IV, V, or VI. For baseline severity MJAS scores, 55% of patients had a score of 2 (moderate) and 45% had a score of 3 (severe); all patients had the same baseline score on both sides of their jawlines.
Treatment
A total of 175/180 randomized patients received treatment (Figure 2) with either needle (88/175 patients) or cannula (87/175 patients). The median injection volume for each side of the jawline was 1.80 mL. Among patients receiving a touch-up (132/175, 75.4%), the median volume injected was 1.10 mL in the right jawline and 1.25 mL in the left jawline. In treatment-group patients eligible for re-treatment at week 48 (76/122, 62.3%), median re-treatment injection volumes were 1.40 mL for the right jawline and 1.50 mL for the left jawline. No patient was injected with more than 3 mL of CaHA (+) per jawline per treatment session. No clinically significant trends were identified when considering the volume injected during each injection cycle or between the treatment and delayed-treatment groups.
The most commonly used injection techniques were serial puncture when injecting with a needle and linear-threading/ tunneling when injecting with a cannula. The most common injection depth was subdermal and patients were frequently injected at multiple depths. The median number of injection points per jawline was 3 for all three treatment sessions, with a higher number of injection points when a needle was used, as expected.
