for established TCS designed to expand indications,16 eliminate alcohol and surfactants,17 improve penetration,20 ease dryness,21 and provide additional formulation options.23
Of these, 8 trials showed significant improvement in AD severity or symptoms in patients who received TCS compared with vehicle by end of treatment (Table 1, Figure 1). In one of the earliest trials captured within the limits of this search, lesion TSS was significantly improved by day 4 for clobetasol propionate compared with vehicle (P≤0.006), and remained significantly improved through end of treatment (day 43; P<0.001) (Table 1).22 In a phase 3 trial investigating the efficacy and safety of hydrocortisone butyrate cream, 0.1%, more hydrocortisone butyrate-treated patients exhibited Physician’s Global Assessment (PGA) success at day 29 (primary endpoint; PGA clear (0) or almost clear (1) with ≥2-grade reduction) compared with vehicle-treated patients (P<0.001) (Table 1, Figure 1).19
One trial explored the benefit of adding the antibiotic mupirocin to hydrocortisone butyrate cream, 0.1%.18 There was no difference in the primary efficacy endpoint (percentage improvement in signs and symptoms) between patients who received hydrocortisone butyrate + mupirocin and those who received hydrocortisone butyrate + vehicle at the end of treatment (day 28) (Table 1); however, differences were observed earlier in treatment (day 7).18
Topical Calcineurin Inhibitors
Tacrolimus
Four tacrolimus ointment publications fit the criteria for this analysis. Significant differences compared with vehicle were reported for the primary endpoint in each (Table 1).24-27
In a phase 2 trial of tacrolimus in patients aged 13-60 years, median decreases in TSS (erythema, edema, and pruritus) at week 3 (primary endpoint) were significantly different between each dosage of tacrolimus and vehicle (P<0.001 via Jonckheere test) (Table 1), with no differences among tacrolimus dosages.24 The efficacy of tacrolimus ointment was further explored in children.25 The primary efficacy endpoint, physician global evaluation (PGE) of clinical response on a scale of worse (<0%) to cleared (100%), was significantly improved for each dosage of tacrolimus compared with vehicle at the end of treatment (day 22; Table 1, Figure 1).25
Additional efficacy endpoints were explored in the remaining 2 tacrolimus trials. In the first trial, significantly more tacrolimustreated than vehicle-treated patients achieved the primary efficacy endpoint of Investigator’s Global AD Assessment (IGADA) clear or almost clear at week 6 (P<0.0001; Table 1; Figure 1).26 In the second trial, the mean number of flare-free treatment days and the time to first relapse were significantly longer in patients who received tacrolimus compared with vehicle (P=0.003 and 0.037, respectively) (Table 1).27
Pimecrolimus
Multiple studies have substantiated the efficacy of pimecrolimus cream based on primary efficacy endpoints of improvement in pruritus,28 decrease in EASI or local EASI,31-33 proportion of patients achieving IGA clear (0) or almost clear (1),31,34 reduction in the need for TCS,35,37,38 and proportion of patients who remained flare free.39 However, in other studies, significant differences were not reported for the primary efficacy endpoint (Table 1).29,30,36,40
In comparison with vehicle in trials of 3-4 weeks in duration, pimecrolimus treatment resulted in significantly more patients achieving IGA clear (0) or almost clear (1) (Table 1, Figure 1)31,32 and local EASI <2 for any lesion (Table 1)31 as well as greater changes in IGA score (secondary endpoint; P<0.001) (Figure 1)32 and EASI score (P<0.001) (Table 1).32 In identically designed, 6-week trials, 34.8% of pimecrolimus-treated patients achieved IGA clear (0) or almost clear (1) at day 43 (primary endpoint) compared with 18.4% of those treated with vehicle (P≤0.05) (Table 1, Figure 1).34
Another trial assessed the percentage of days that TCS was used. The primary endpoint was the percentage of days with TCS use.35 Secondary endpoints included the number of flares, time-to-first flare, proportion of patients with IGA mild or less (≤2) (Figure 1), and changes in EASI score and pruritus severity. By week 24, pimecrolimus-treated patients had significantly fewer days with TCS use than vehicle-treated patients (P<0.001) and a higher proportion of pimecrolimus-treated than vehicletreated patients had no TCS use (Table 1).35 Decrease in TCS use was also seen in several subsequent trials,37,38 including in patients with mild-to-moderate AD38,48 and pediatric patients.37 However, 1 study in patients with severe AD did not show a significant decrease in the mean percentage of days with TCS use for pimecrolimus compared with vehicle (Table 1).36 Unlike the other “TCS reduction†studies, this study had a screening phase in which all patients applied prednicarbate cream, 0.25%, twice daily for 7-21 days until flare was under control before enrollment in the double-blind portion of the study. After the study, it was determined that, although study centers enrolled patients with high severity scores according to Rajka and Langeland criteria, some patients did not have active disease, as shown by baseline IGA scores of almost clear (1) and mild (2)). When these patients were excluded in a post hoc analysis, there were significantly fewer days with TCS use in patients who received pimecrolimus than in those who received vehicle.36
In a 1-year study, significantly more pimecrolimus-treated versus vehicle-treated infants aged 3-23 months remained flarefree through month 6 (primary endpoint; P<0.001 Van Elteren test) and month 12 (Table 1), translating into longer flare-free
Of these, 8 trials showed significant improvement in AD severity or symptoms in patients who received TCS compared with vehicle by end of treatment (Table 1, Figure 1). In one of the earliest trials captured within the limits of this search, lesion TSS was significantly improved by day 4 for clobetasol propionate compared with vehicle (P≤0.006), and remained significantly improved through end of treatment (day 43; P<0.001) (Table 1).22 In a phase 3 trial investigating the efficacy and safety of hydrocortisone butyrate cream, 0.1%, more hydrocortisone butyrate-treated patients exhibited Physician’s Global Assessment (PGA) success at day 29 (primary endpoint; PGA clear (0) or almost clear (1) with ≥2-grade reduction) compared with vehicle-treated patients (P<0.001) (Table 1, Figure 1).19
One trial explored the benefit of adding the antibiotic mupirocin to hydrocortisone butyrate cream, 0.1%.18 There was no difference in the primary efficacy endpoint (percentage improvement in signs and symptoms) between patients who received hydrocortisone butyrate + mupirocin and those who received hydrocortisone butyrate + vehicle at the end of treatment (day 28) (Table 1); however, differences were observed earlier in treatment (day 7).18
Topical Calcineurin Inhibitors
Tacrolimus
Four tacrolimus ointment publications fit the criteria for this analysis. Significant differences compared with vehicle were reported for the primary endpoint in each (Table 1).24-27
In a phase 2 trial of tacrolimus in patients aged 13-60 years, median decreases in TSS (erythema, edema, and pruritus) at week 3 (primary endpoint) were significantly different between each dosage of tacrolimus and vehicle (P<0.001 via Jonckheere test) (Table 1), with no differences among tacrolimus dosages.24 The efficacy of tacrolimus ointment was further explored in children.25 The primary efficacy endpoint, physician global evaluation (PGE) of clinical response on a scale of worse (<0%) to cleared (100%), was significantly improved for each dosage of tacrolimus compared with vehicle at the end of treatment (day 22; Table 1, Figure 1).25
Additional efficacy endpoints were explored in the remaining 2 tacrolimus trials. In the first trial, significantly more tacrolimustreated than vehicle-treated patients achieved the primary efficacy endpoint of Investigator’s Global AD Assessment (IGADA) clear or almost clear at week 6 (P<0.0001; Table 1; Figure 1).26 In the second trial, the mean number of flare-free treatment days and the time to first relapse were significantly longer in patients who received tacrolimus compared with vehicle (P=0.003 and 0.037, respectively) (Table 1).27
Pimecrolimus
Multiple studies have substantiated the efficacy of pimecrolimus cream based on primary efficacy endpoints of improvement in pruritus,28 decrease in EASI or local EASI,31-33 proportion of patients achieving IGA clear (0) or almost clear (1),31,34 reduction in the need for TCS,35,37,38 and proportion of patients who remained flare free.39 However, in other studies, significant differences were not reported for the primary efficacy endpoint (Table 1).29,30,36,40
In comparison with vehicle in trials of 3-4 weeks in duration, pimecrolimus treatment resulted in significantly more patients achieving IGA clear (0) or almost clear (1) (Table 1, Figure 1)31,32 and local EASI <2 for any lesion (Table 1)31 as well as greater changes in IGA score (secondary endpoint; P<0.001) (Figure 1)32 and EASI score (P<0.001) (Table 1).32 In identically designed, 6-week trials, 34.8% of pimecrolimus-treated patients achieved IGA clear (0) or almost clear (1) at day 43 (primary endpoint) compared with 18.4% of those treated with vehicle (P≤0.05) (Table 1, Figure 1).34
Another trial assessed the percentage of days that TCS was used. The primary endpoint was the percentage of days with TCS use.35 Secondary endpoints included the number of flares, time-to-first flare, proportion of patients with IGA mild or less (≤2) (Figure 1), and changes in EASI score and pruritus severity. By week 24, pimecrolimus-treated patients had significantly fewer days with TCS use than vehicle-treated patients (P<0.001) and a higher proportion of pimecrolimus-treated than vehicletreated patients had no TCS use (Table 1).35 Decrease in TCS use was also seen in several subsequent trials,37,38 including in patients with mild-to-moderate AD38,48 and pediatric patients.37 However, 1 study in patients with severe AD did not show a significant decrease in the mean percentage of days with TCS use for pimecrolimus compared with vehicle (Table 1).36 Unlike the other “TCS reduction†studies, this study had a screening phase in which all patients applied prednicarbate cream, 0.25%, twice daily for 7-21 days until flare was under control before enrollment in the double-blind portion of the study. After the study, it was determined that, although study centers enrolled patients with high severity scores according to Rajka and Langeland criteria, some patients did not have active disease, as shown by baseline IGA scores of almost clear (1) and mild (2)). When these patients were excluded in a post hoc analysis, there were significantly fewer days with TCS use in patients who received pimecrolimus than in those who received vehicle.36
In a 1-year study, significantly more pimecrolimus-treated versus vehicle-treated infants aged 3-23 months remained flarefree through month 6 (primary endpoint; P<0.001 Van Elteren test) and month 12 (Table 1), translating into longer flare-free
