Subject accountability and baseline characteristics
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due to redness and dryness; three subjects in the tretinoin regimen group and two in the NPP regimen group were withdrawn due to noncompliance.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.). shows the demographics and baseline values of the two balanced groups.
Demographics and baseline values of key parameters
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; ). 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 .
Fig 2 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 (more ...)
(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, ). The change from baseline of relevant efficacy self-assessment questions at 4 and 8 weeks is shown in . 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.
Fig 4 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: (more ...)
Relevant efficacy assessment questions from the self-assessment questionnaire (change from baseline; full study population)
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 (). 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).
Fig 5 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; (more ...)
After 2 weeks of treatment, both product regimen groups exhibited a significant increase in erythema from baseline (). 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.
Fig 6 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 (more ...)
At 2, 4, 6 and 8 weeks, the tretinoin regimen group showed significantly more skin dryness from baseline (). 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 (). 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.
Changes in stratum corneum protein analytes
Cohort 24-week results
Of the 50 subjects (n=25 in each group) who continued on treatment for an additional 16 weeks, 48 (25, tretinoin regimen; 23, NPP regimen) completed the entire 24 weeks. As seen in , after 8 weeks treatment the mean improvements in the two cohorts were not significantly different by either expert visual grading of the REAL images or by image analysis of the VISIA CR images. The mean cohort responses were not consistent with those determined in the full study population, as the mean tretinoin response was higher in the cohort than in the full population, while for the NPP cohort the mean response was lower. This is likely to be attributable to the self-selection of the cohort subjects, which was made prior to the start of treatment. Wrinkle severity at enrolment, however, was not significantly different between the cohorts, nor was it significantly different between the cohorts and the full populations. For both regimens, the appearance of facial fine lines and wrinkles continued to improve from 8 to 24 weeks as measured by both visual grading and image analysis (P<0·01 for both). Consistent with the 8-week results for the cohort, after 24 weeks of treatment there were no significant differences between the NPP regimen and the tretinoin regimen by either measure (P=0·74, P=0·77, respectively). There was a statistically significant difference in change in TEWL between the two groups at 8 and 24 weeks (P<0·01, ). After 24 weeks of treatment, the stratum corneum barrier was not different from baseline in the tretinoin regimen group (P=0·47) but was significantly improved in the NPP regimen group (P<0·01).
After 16 and 24 weeks of treatment, the subset of the NPP regimen group exhibited a nonsignificant decrease from baseline in erythema and dryness (P>0·21, data not shown). After 16 weeks of treatment, erythema in the subset of the tretinoin regimen group was not different from baseline, but at 24 weeks of treatment there was a significant decrease in erythema. Skin dryness in the tretinoin regimen cohort was not significantly different from baseline after 16 and 24 weeks of treatment.
In general, subjects in both groups continued to notice an improvement in their skin from baseline based on the self-assessment questionnaire (data not shown). In addition, the NPP regimen subjects did not report any significant irritation after 16 and 24 weeks of treatment; the tretinoin regimen subjects did report significant peeling and flaking at 16 weeks but no significant irritation after 24 weeks (data not shown).
After 8 weeks, protein analyte changes in the cohort were consistent with those in the full population (). After 24 weeks, protein changes in both cohorts generally improved relative to 8 weeks. None the less, soluble protein levels remained significantly higher than baseline in the tretinoin regimen group and significantly lower than baseline in the NPP regimen group. Levels of HSA were similar to baseline in the tretinoin regimen group (P=0·59) but significantly reduced relative to baseline in the NPP regimen group. Involucrin levels remained not significantly different from baseline following 24 weeks use of the NPP regimen; however, levels of involucrin in the tretinoin regimen group decreased between 8 and 24 weeks, which is consistent with the TEWL and irritation data showing accommodation to tretinoin treatment with longer term use. Overall, the NPP regimen group had significantly lower levels of soluble protein, HSA and involucrin and significantly higher levels of keratins 1, 10 and 11 than the tretinoin regimen group at 24 weeks.