Of the 97 tretinoin regimen subjects and 99 NPP regimen subjects who started the study, 93 and 97 subjects, respectively, completed the study. One subject in the tretinoin regimen group withdrew due to redness and dryness; three subjects in the tretinoin regimen group and two in the NPP regimen group were withdrawn due to noncompliance. Five subjects (three in the tretinoin regimen group; two in the NPP regimen group) were excluded from the REAL image analysis due to image quality issues (facial expressions, etc.). Table 2 shows the demographics and baseline values of the two balanced groups.

Eight‐week results

After 8 weeks of treatment, the appearance of facial fine lines and wrinkles improved in both groups as measured by expert visual grading of the REAL images (P = 0·05, tretinoin regimen; P < 0·01, NPP regimen). The NPP regimen gave significantly greater improvement than the tretinoin regimen (P < 0·01; Fig. 2). A significantly higher percentage of subjects on the NPP regimen (58%) was judged to look better after 8 weeks of treatment, defined as being given the minimum positive grade of +1 on each side of their face by at least two of the three graders, compared with the tretinoin regimen (41%, P = 0·03). Also, a significantly higher percentage of subjects on the NPP regimen responded substantially to treatment (mean grade ≥ 2) as compared with the tretinoin regimen (28% vs. 13%, P = 0·02). For perspective, a +2 grade would indicate visible improvement in at least one to three small lines and/or 15–25% of areas of crepiness or cross‐hatching. Examples of subjects showing substantial responses to each treatment regimen are shown in Figure 3.

Figure 2 Open in figure viewer PowerPoint Improvement in the appearance of periorbital wrinkles for the full study population and 24‐week cohort. Changes were determined by expert visual comparison of subject images before and after treatment, using a ± eight‐point scale. Error bars represent SEM. Entire population at 8 weeks: n = 90 in the tretinoin regimen group; n = 95 in the niacinamide/peptide/retinyl propionate (NPP) regimen group. Cohort at 8 weeks: n = 25 in each group. Cohort at 24 weeks: n = 25 in the tretinoin regimen group; n = 23 in the NPP regimen group.

Figure 3 Open in figure viewer PowerPoint (a) Niacinamide/peptide/retinyl propionate regimen before and after 8 weeks of treatment. (b) Tretinoin regimen before and after 8 weeks of treatment.

As determined by analysis of the VISIA CR images, both product regimens also significantly reduced periorbital wrinkle area fraction at week 8 relative to baseline (P < 0·01 for both). The mean percentage reduction from baseline in wrinkle area fraction was greater for the NPP regimen group vs. the tretinoin regimen group (17% vs. 11%, P = 0·06, Fig. 4). The change from baseline of relevant efficacy self‐assessment questions at 4 and 8 weeks is shown in Table 3. Both groups noticed significant improvement from baseline in overall skin appearance, fine lines and wrinkles, and eye lines and wrinkles at both time points. After 4 weeks, subjects in the NPP regimen group noticed a significant improvement from baseline in overall skin feel and uneven skin texture, and both groups noticed a significant improvement in these assessments at 8 weeks. By 8 weeks, both groups noticed improvement from baseline in deep wrinkles. The self‐assessed improvements in overall skin appearance, overall skin feel, and eye lines and wrinkles were significantly greater for the NPP regimen group than for the tretinoin group after both 4 and 8 weeks, and for uneven skin texture after 4 weeks.

Figure 4 Open in figure viewer PowerPoint Reductions in wrinkle area (as a fraction of the facial area of interest) for the full study population and 24‐week cohort. Wrinkle area was determined by computer image analysis. Error bars indicate 95% confidence interval. Entire population at 8 weeks: n = 92 in the tretinoin regimen group; n = 95 in the niacinamide/peptide/retinyl propionate (NPP) regimen group. Cohort at 8 weeks: n = 25 in the tretinoin regimen group; n = 24 in the NPP regimen group. Cohort at 24 weeks: n = 25 in the tretinoin regimen group; n = 22 in the NPP regimen group.

Table 3. Relevant efficacy assessment questions from the self‐assessment questionnaire (change from baseline; full study population) Question Week 4 Week 8 Tretinoin regimen NPP regimen Tretinoin regimen NPP regimen Overall skin appearance 0·287* 1·211*† 1·296* 1·792*† Overall skin feel −0·150 1·360*† 0·759* 1·889*† Fine lines/wrinkles −0·625* −0·899* −1·110* −1·466* Eye lines/wrinkles −0·651* −1·206*† −1·337* −1·975*† Deep wrinkles −0·233 −0·218 −0·562* −0·563* Uneven skin texture 0·300 −0·528*† −0·506* −0·810*

After 8 weeks of treatment, the stratum corneum barrier in the tretinoin regimen group was significantly compromised, with TEWL increasing by 5·9 g m−2 h−1 from baseline (Fig. 5). TEWL values in the NPP regimen group remained essentially unchanged from baseline. There was a significant difference in change in TEWL between the two groups at 8 weeks (P < 0·01).

Figure 5 Open in figure viewer PowerPoint Changes in facial skin transepidermal water loss (TEWL) for the full study population and 24‐week cohort. At 8 weeks, n = 91 for the full population tretinoin group and n = 97 for the full population niacinamide/peptide/retinyl propionate (NPP) regimen group; n = 25 for both cohorts. At 24 weeks, n = 25 for the tretinoin regimen cohort and n = 23 for the NPP regimen cohort.

After 2 weeks of treatment, both product regimen groups exhibited a significant increase in erythema from baseline (Fig. 6). After 4 weeks of treatment, erythema continued to be significantly increased in the tretinoin regimen group and was significantly higher compared with the NPP regimen group (P = 0·01). Erythema in the NPP regimen group was lower at 4, 6 and 8 weeks compared with 2 weeks and was no longer statistically significantly different from baseline. At 6 and 8 weeks, erythema did decrease in the tretinoin regimen but remained significantly higher than at baseline.

Figure 6 Open in figure viewer PowerPoint Erythema and skin dryness during the initial 8 weeks of treatment (full study population). Both erythema and clinical dryness were determined on a 0–6 scale. For the tretinoin regimen, n = 95 (week 2), n = 94 (week 4) and n = 93 (weeks 6 and 8). For the niacinamide/peptide/retinyl propionate (NPP) regimen, n = 99 (week 2) and n = 97 (weeks 4, 6 and 8).

At 2, 4, 6 and 8 weeks, the tretinoin regimen group showed significantly more skin dryness from baseline (Fig. 6). There was no significant change from baseline in skin dryness in the NPP regimen group at 2, 4, 6 and 8 weeks. In addition, the skin of subjects in the tretinoin regimen group was significantly drier than the skin of subjects in the NPP regimen group at 2, 4, 6 and 8 weeks (P < 0·01 for all).

The results of the subjects’ self‐assessments of product tolerability were consistent with the expert erythema and dryness results (data not shown). Compared with the NPP regimen group, after 2 weeks of treatment significantly more subjects in the tretinoin regimen group experienced itchiness, redness/rash and peeling/flaking, which is consistent with known side‐effects of tretinoin.4 Symptoms continued in the tretinoin regimen group for the entire 8‐week study with a peak between 4 and 6 weeks. Subjects in the NPP regimen group who reported any irritation at any time point generally reported experiencing it only a ‘slight amount’.

There were significant differences between the product regimens for each of the four stratum corneum protein analytes after 8 weeks of treatment (Table 4). Soluble protein, HSA and involucrin levels were significantly increased from baseline in the tretinoin regimen group. In contrast, in the NPP regimen group, soluble protein and HSA decreased from baseline, and involucrin was essentially unchanged from baseline. Keratins 1, 10 and 11 significantly decreased in the tretinoin regimen group but were significantly increased in the NPP regimen group.