HARC was first approved in the EU in 2009, where it is registered as Restylane Volyme. Depending on the area to be treated and the tissue support, HARC is designed for deep injections into the supraperiosteal zone or subcutis to augment the volume of facial tissues.8 It is intended to be used for correction of facial volume and is an optimal gel for restoring a soft contour and natural looking volume. This gel has previously been investigated for full-face correction of volume loss in an open-label study with 18 months follow-up9 and also in another open-label study to assess performance and tolerance of the product in patients with cheek volume loss.10
The purpose of this study was to evaluate effectiveness and safety of treatment with HARC for cheek augmentation and correction of midface contour deficiencies compared to a comparator product (Juvéderm Voluma XC), hereafter referred to as Control. Also, the choice of needle or cannula for midface injections depends on the physician’s experience and preference, and in order to investigate both options, a second study group was included to assess HARC when used with a small blunt-tip cannula or a needle.
The purpose of this study was to evaluate effectiveness and safety of treatment with HARC for cheek augmentation and correction of midface contour deficiencies compared to a comparator product (Juvéderm Voluma XC), hereafter referred to as Control. Also, the choice of needle or cannula for midface injections depends on the physician’s experience and preference, and in order to investigate both options, a second study group was included to assess HARC when used with a small blunt-tip cannula or a needle.
MATERIALS AND METHODS
Subjects and Treatment
This was a randomized, evaluator-blinded, parallel-group, comparator-controlled, multi-center study (NCT03700047). Group A subjects were randomized 2:1 to treatment with HARC or Control, with all treatments administered using the co-packed 27G needle. Group B subjects were treated with HARC using a randomized split-face design (1:1 right:left) where one cheek was treated using a small blunt tip cannula and the other cheek using the co-packed 27G needle. Eligible subjects were over the age of 21 and had mild to substantial loss of midface fullness (Medicis Midface Volume Scale [MMVS] score 2-4)11 on each side of the face. Each cheek in a single subject could differ 1 grade on the MMVS. At least 15% of the subjects were to have a Fitzpatrick Skin Type (FST) IV–VI, with at least 10% having FST V–VI. Subjects provided a written informed consent for participation in the study. Main exclusion criteria included known or previous allergies/hypersensitivity to injectable hyaluronic acid (HA) gel, gram-positive bacterial proteins or lidocaine. Subjects were treated according to their randomization with a sufficient amount to achieve optimal correction of the midface defined as at least 1-grade improvement from baseline on the MMVS, and the best correction that could be achieved according to treating investigator and subject. Touch-up was allowed after 4 weeks if determined as necessary. The volume was recommended not to exceed 6 mL per treatment session (maximum total injection volume including touch-up: 12 mL). Study product was injected into the midface at the supraperiosteal to subcutaneous layer inferior to the maxillary prominence, superior to the plane of nasal alae, including the area from the lateral canthus to the medial canthus and lateral to the nose on the subject’s right and left sides.
Study Assessments
Primary study objective was to demonstrate non-inferiority of HARC versus the Control in cheek augmentation. Blinded evaluators used the MMVS to compare change from baseline in midface fullness at 12 weeks after the last injection. Other assessments included 1) effectiveness of HARC in cheek augmentation, based on blinded evaluation of MMVS responder rate (at least 1-grade improvement on both sides of the face); 2) aesthetic improvement of overall appearance based on the Global Aesthetic Improvement Scale (GAIS) defined as at least improved, determined by subject and treating investigator separately; 3) subject satisfaction using the FACE-Q™ Satisfaction with Outcome and FACE-Q Satisfaction with Cheeks questionnaires, from which the overall Rasch transformed score was determined; 4) change from baseline in cheek volume using digital 3D photography and 5) improvement in cheek augmentation determined by an independent photographic reviewer using random, blinded pairings of baseline and post-treatment photographs. Safety assessments included adverse events collected throughout the study, and pre-defined symptoms including bruising, redness, tenderness, swelling, pain, and itching recorded in a subject diary for 4 weeks following each injection. Follow-up visits to the clinic were made 12, 24, 36, and 48 weeks since last injection.
Statistical Analyses
Statistical analyses were performed using the SAS® system version 9.4. All effectiveness variables were analyzed based on the Intention-to-Treat (ITT) population (all subjects who were randomized), and the basis for safety analyses was the safety population (all subjects who were injected at least once). For Group A, the primary effectiveness analysis of change from baseline in MMVS at week 12 was a test of non-inferiority of HARRC to Control. Difference (across sides) between treatments means (Control – HARC), and the corresponding 2-sided 95% confidence interval (CI) were calculated and used for assessing non-inferiority, which was demonstrated if the upper limit of the CI was below the pre-determined margin of 0.5. For Group B, the primary effectiveness analysis was a test of non-inferiority of HARC using cannula to needle. The change from baseline in MMVS for the treatment using cannula and needle was analyzed by calculating the two-sided 95% CI around the mean paired difference (cannula – needle) at week 12. Noninferiority was established if the upper limit of the CI was below the non-inferiority margin of 0.5 units. Robustness of the results of Group A and Group B primary endpoints was investigated across FST skin type. Other endpoints for effectiveness (MMVS responders, GAIS, subject satisfaction, independent photographic review, and cheek volume from 3D photography) were analyzed descriptively. Safety endpoints for Group A and Group B were analyzed descriptively and presented separately. Group B results were summarized separately for the needle and cannula sides of the face.
This was a randomized, evaluator-blinded, parallel-group, comparator-controlled, multi-center study (NCT03700047). Group A subjects were randomized 2:1 to treatment with HARC or Control, with all treatments administered using the co-packed 27G needle. Group B subjects were treated with HARC using a randomized split-face design (1:1 right:left) where one cheek was treated using a small blunt tip cannula and the other cheek using the co-packed 27G needle. Eligible subjects were over the age of 21 and had mild to substantial loss of midface fullness (Medicis Midface Volume Scale [MMVS] score 2-4)11 on each side of the face. Each cheek in a single subject could differ 1 grade on the MMVS. At least 15% of the subjects were to have a Fitzpatrick Skin Type (FST) IV–VI, with at least 10% having FST V–VI. Subjects provided a written informed consent for participation in the study. Main exclusion criteria included known or previous allergies/hypersensitivity to injectable hyaluronic acid (HA) gel, gram-positive bacterial proteins or lidocaine. Subjects were treated according to their randomization with a sufficient amount to achieve optimal correction of the midface defined as at least 1-grade improvement from baseline on the MMVS, and the best correction that could be achieved according to treating investigator and subject. Touch-up was allowed after 4 weeks if determined as necessary. The volume was recommended not to exceed 6 mL per treatment session (maximum total injection volume including touch-up: 12 mL). Study product was injected into the midface at the supraperiosteal to subcutaneous layer inferior to the maxillary prominence, superior to the plane of nasal alae, including the area from the lateral canthus to the medial canthus and lateral to the nose on the subject’s right and left sides.
Study Assessments
Primary study objective was to demonstrate non-inferiority of HARC versus the Control in cheek augmentation. Blinded evaluators used the MMVS to compare change from baseline in midface fullness at 12 weeks after the last injection. Other assessments included 1) effectiveness of HARC in cheek augmentation, based on blinded evaluation of MMVS responder rate (at least 1-grade improvement on both sides of the face); 2) aesthetic improvement of overall appearance based on the Global Aesthetic Improvement Scale (GAIS) defined as at least improved, determined by subject and treating investigator separately; 3) subject satisfaction using the FACE-Q™ Satisfaction with Outcome and FACE-Q Satisfaction with Cheeks questionnaires, from which the overall Rasch transformed score was determined; 4) change from baseline in cheek volume using digital 3D photography and 5) improvement in cheek augmentation determined by an independent photographic reviewer using random, blinded pairings of baseline and post-treatment photographs. Safety assessments included adverse events collected throughout the study, and pre-defined symptoms including bruising, redness, tenderness, swelling, pain, and itching recorded in a subject diary for 4 weeks following each injection. Follow-up visits to the clinic were made 12, 24, 36, and 48 weeks since last injection.
Statistical Analyses
Statistical analyses were performed using the SAS® system version 9.4. All effectiveness variables were analyzed based on the Intention-to-Treat (ITT) population (all subjects who were randomized), and the basis for safety analyses was the safety population (all subjects who were injected at least once). For Group A, the primary effectiveness analysis of change from baseline in MMVS at week 12 was a test of non-inferiority of HARRC to Control. Difference (across sides) between treatments means (Control – HARC), and the corresponding 2-sided 95% confidence interval (CI) were calculated and used for assessing non-inferiority, which was demonstrated if the upper limit of the CI was below the pre-determined margin of 0.5. For Group B, the primary effectiveness analysis was a test of non-inferiority of HARC using cannula to needle. The change from baseline in MMVS for the treatment using cannula and needle was analyzed by calculating the two-sided 95% CI around the mean paired difference (cannula – needle) at week 12. Noninferiority was established if the upper limit of the CI was below the non-inferiority margin of 0.5 units. Robustness of the results of Group A and Group B primary endpoints was investigated across FST skin type. Other endpoints for effectiveness (MMVS responders, GAIS, subject satisfaction, independent photographic review, and cheek volume from 3D photography) were analyzed descriptively. Safety endpoints for Group A and Group B were analyzed descriptively and presented separately. Group B results were summarized separately for the needle and cannula sides of the face.
