The study included adults aged 18 - 64 years who underwent Dermapen 4 treatment to improve their facial skin symptoms. The following exclusion criteria were applied: a skin condition likely to affect the study outcome; use of a medicinal product (oral or topical), quasi-medicinal product (cosmetic product for medicinal use), or cosmetic product for skin-whitening or anti-wrinkle purposes within 1 month before the start of the study; a cosmetic procedure, such as laser therapy, phototherapy, or radiofrequency therapy, performed within 1 month before the start of the study; use of a cosmetic product containing an ingredient with a peeling effect; facial surgery or facial injection of Botulinum toxin or hyaluronic acid within 6 months before the start of the study; and judged by the investigator to be unsuitable for participation in the study.

The study had a randomized, evaluator-blinded, split-face (left vs. right) design. The test product was the DC, all ingredients of which conform to European Union regulation number 1223/200 for cosmetic products. The comparator product (CP) was white petrolatum (Propeto®; Daiichi Sankyo Healthcare, Tokyo, Japan), which conforms to the standards of the Japanese Pharmacopoeia.

After securing written consent, instrumental measurements were obtained at the study site for screening purposes. Dermapen 4 treatment was administered to the entire face by any of five dermatologists at their respective clinics within 7 days of obtaining these measurements. The device was set to a needle penetration depth of 1.5 - 1.75 mm and a needle speed of 120 revolutions per second, a depth chosen in accordance with the manufacturer’s recommendations for facial rejuvenation and to induce a reproducible, clinically meaningful level of erythema while remaining within the established safety range for microneedling. The participants were transferred to the study site within 2 h following the procedure, where the day 0 evaluation was carried out by a dermatologist. Participants were randomly assigned to receive DC on the left side of the face and the CP on the right side or vice versa using a randomization table that was generated using a random number generation program, ensuring an equal distribution of participants to each treatment group. The treatment consisted of application of the study product and the comparator product to the allocated sides of the face twice daily (morning and night) for 14 days. The amount of DC per application was 2 finger-tip units (1 g). The CP was applied in a thin layer to the allocated side of the face. The dermatologist assessing the treatment outcomes was blinded to which product was applied to which side of the face.

The participants attended the study site for evaluation at baseline and on days 2, 3, 5, 7, 14, and 28 post-procedure. Participants were instructed not to perform facial cleansing on the day of Dermapen 4 treatment and to use light makeup that could be removed with a facial cleanser for 3 days following treatment, with regular makeup allowed from day 4 onwards. The participants used only an approved facial wash (Toleriane Purifying Foaming Cleanser; La Roche Posay) and sunscreen (Uvidea XL; La Roche Posay) and were instructed not to use skin care products other than skin lotions which they usually use.

Erythema, edema/swelling, bleeding, crusting, and dryness/scaling were evaluated on a 5-point scale (0, none; 1, slight; 2, mild; 3, moderate; 4, severe), and the overall clinical evaluation was based on the total score for these variables. Post-inflammatory erythema and post-inflammatory hyperpigmentation were evaluated on day 28.

All instrumental measurements were obtained after face washing followed by acclimatization for at least 20 min in a room at constant temperature (20 ± 2˚C) and humidity (50 ± 5%). The sites for measurement were the fixed left and right cheeks. The water content of the stratum corneum was determined by measuring conductance of high-frequency current (µS) using a Skicon-200EX (Yayoi Co., Ltd, Tokyo, Japan). Five measurements were taken at each site, the highest and the lowest were discarded, and the mean of the remaining three measurements was calculated. Sebum content was determined by measuring once on each cheek using the Sebumeter SM 810 and transepidermal water loss was measured using the Tewameter TM300 (both from Courage + Khazaka Electronic GmbH, Cologne, Germany). Three measurements were taken at each site, and the mean value was calculated.

Erythema and pigmentation were evaluated on photographs using the VISIA Evolution 2 system (Canfield Scientific, Parsippany, NJ, USA).

To ensure the homogeneity and consistency of the clinical evaluations, two dermatologists who were not otherwise involved in treatment or the initial skin assessments evaluated each study participant’s skin, using photographs taken with the VISIA system. The evaluating dermatologists were blinded to treatment allocation and the initial assessments made by the treating physicians.

NRS scores for pain and pruritus

Participants evaluated their pain and pruritus using a numerical rating scale (NRS). Pain was evaluated for each cheek on an 11-point scale, with 0 being no pain and 10 being the worst pain imaginable. Pruritus was evaluated for each cheek on an 11-point scale, with 0 being no itching and 10 being the worst pruritus imaginable.

Responses to a questionnaire

The participants evaluated whether their skin was better on the left or right side of the face at each visit to the study site between days 2 and 14. The usability of each study product was evaluated by rating of the ease of application to the skin, ease of blending into the skin, absence of irritation, and overall smoothness of application on a 5-point scale (good, somewhat good, neutral, somewhat bad, bad). Willingness to use the product was evaluated by surveying which product the participant preferred, whether the participant would like to use the product after the next cosmetic procedure, and whether the participant would like to continue using the product as part of their daily skin care routine. The product evaluation questionnaire was administered on day 14. The results for product usability, willingness to use the product, and evaluation of skin condition were analyzed and are presented as percentages.

Safety was evaluated from the time at which consent was obtained until the end of the observation period. Any symptoms detected were recorded as adverse events. The type and severity of adverse events, number of cases, and number of occurrences were recorded and analyzed.

The full analysis set comprised all participants who were enrolled in the study and commenced treatment with the study products. The safety analysis set comprised all participants but excluded any who did not use the study products at any time following enrollment or for whom no safety data were obtained. The statistical analysis was performed using JMP statistical software (version 17; JMP Statistical Discovery LLC, Cary, NC, USA). Where data from after the start of the study were missing, they were treated as missing data and excluded from the parameters for calculation without imputation. For the analysis, the mean and standard deviation of the DC side and that of the CP side were calculated for each observation period. The two sides were compared using the paired t-test.

The number of days until the erythema score decreased to 2 (the level at which it was considered that erythema would have no effect on day-to-day living) was compared between the treatment groups using the Kaplan-Meier method. Changes in the distribution of erythema and bleeding severity scores over time were analyzed. This included examining the percentage of participants with each severity score (from 0 to 4) at the different time points (i.e., days 0, 2, 3, 5, 7, 14 and 28) and comparing these percentages between the two treatment groups. The time course of resolution of erythema was investigated in participants judged to have severe erythema (score 4) on day 0.

Thirty-three subjects (30 female, 3 male) were enrolled. Three subjects discontinued before allocation to treatment (one did not meet the selection criteria, one did not attend the clinic on the day of Dermapen 4 treatment, and one experienced an unrelated adverse event). A further subject withdrew consent. The remaining 29 subjects (27 female, 2 male) were included in the analysis. The study population had a mean age of 40.7 ± 11.9 years. On day 0, the mean erythema score was 3.2 ± 0.7 for both the DC side and the CP side, and the mean NRS scores were 2.4 ± 2.0 for pain and 0.6 ± 1.2 for pruritus on both sides.

The score for erythema was lower on the DC side than on the CP side on day 2 (1.9 ± 0.7 vs 2.1 ± 0.8), day 3 (1.3 ± 0.7 vs 1.4 ± 0.9), and day 14 (0.1 ± 0.3 vs 0.2 ± 0.5). The score for bleeding was lower on the DC side on day 2 (1.3 ± 0.9 vs 1.4 ± 1.1). The dryness/scaling score was slightly higher on the DC side on days 3 and 5. The overall clinical evaluation score was slightly lower on the DC side on day 2. No significant difference in edema/swelling or crusting was observed between the sides throughout the observation period.

Figure 1. Number of days until erythema score reduced to 2. Average number of days (mean ± SD); DC side: 2.63 ± 0.25, CP side: 3.68 ± 0.57, p = 0.0687, Log-rank.

The mean number of days until the erythema score decreased to 2 was 2.63 ± 0.25 for the DC side and 3.68 ± 0.57 for the CP side (p = 0.0687, log-rank test) (Figure 1). The percentage change in the erythema severity score (moderate + severe) was 82.8% on the DC side and 86.2% on the CP side on day 0, 17.2% and 31.0%, respectively, on day 2, and 3.7% and 11.1% on day 3 (Figure 2). The percentage change in the bleeding severity score (moderate + severe) was 58.6% on the DC side and 65.5% on the CP side on day 0, 10.3% and 20.7%, respectively, on day 2, and 0% and 0% on day 3 (Figure 3). The time course in cases with severe erythema (score 4) on day 0 is shown in Figure 4(A) and that for bleeding in Figure 4(B). The erythema scores were lower on the DC side than on the CP side until day 5. The bleeding scores were lower on the DC side on day 2. Scores for dryness/scaling were higher on the DC side on days 2, 3, and 5. Photographs of a typical case are shown in Figure 5.

Figure 2.Percentage by erythema severity score.

Figure 3.Percentage by bleeding severity score.

Figure 4.Time course of cases with severe erythema (erythema score 4) at 0 d. (A) Erythema score; (B) bleeding score.

Figure 5.Case photos (VISIA).

Post-inflammatory erythema involving the entire face was observed in 2 cases, on the DC side only in 1 case and on the CP side only in 1 case. There were no cases of post-inflammatory hyperpigmentation on either side.

Water content in the stratum corneum was greater on the DC side than on the CP side until day 7 and was significantly higher on day 2 (114.9 µS vs 98. 2 µS; p < 0.05) and day 5 (119.8 µS vs 103.8 µS; p < 0.05). The sebum content was significantly higher on the CP side from day 2 to day 7 (p < 0.05). Transepidermal water loss was less on the CP side than on the DC side until day 7 and significantly less on day 2 (5.5 g/[m²∙h] vs 4.6 g/[m²∙h]; p < 0.05) and day 5 (5.9 g/[m²∙h] vs 5.2 g/[m²∙h]; p < 0.05).

No significant differences in changes in erythema or pigmentation were found between the two sides.

There were no noticeable differences between the VISIA photographic evaluation by blinded investigators and the clinical evaluation by the treating physicians.

The NRS scores for pain were lower on the DC side than on the CP side on days 2, 3, and 5 but the differences were not significant. There were no significant differences in the NRS scores for pruritus between the sides.

The percentages of participants who responded “good” or “somewhat good” to the questionnaire item regarding overall smoothness of application were 75.8% on the DC side and 37.9% on the CP side (Figure 6). In response to the question “Which was the best product for shortening downtime?”, 72.4% checked the DC side and 20.7% checked the CP side (Figure 7(A)). In response to the question “Would you like to use it for downtime symptoms after your next cosmetic procedure?”, 72.4% checked the DC side and 17.2% checked the CP side (Figure 7(B)). In response to the question “Would you like to continue using the product as part of your daily skin care routine?”, 69.0% expressed a desire to continue using the DC (Fig. 7C). In response to the survey question “Which skin condition is better, left or right?”, 37.9%, 37.0%, and 32.0%, considered the DC side to be better and 10.3%, 22.2%, and 4.0% considered the CP side to be better on days 2, 3, and 5 respectively (Figure 8).

Figure 6.Product survey percentage. Overall smoothness of application.

Figure 7.Product survey percentage. (A) Which was the best product to shortening downtime? (B) Would you like to use it for downtime symptoms after your next cosmetic procedure? (C) Would you like to continue using the product as part of your daily skin care routine? n = 29.

Figure 8.Skin condition survey percentage. Which skin condition is better, left or right?

Eight adverse events occurred in eight participants during the study period but were not related to either of the study products. The adverse events were fever (five cases, mild, recovered), tinnitus (one case, moderate, recovered), eczema (one case, mild, recovered), and hyperlipidemia (one case, moderate, unresolved).