periods (P<0.001 via log-rank test), fewer flares per year (1.0 vs 2.2, P<0.001 via Van Elteren test), and greater proportions of patients with no TCS use (63.7% vs 34.8%).39 This reduction in risk of flare was observed regardless of baseline disease severity, including for patients with severe AD.39 Likewise, the proportion of patients achieving IGA clear (0) or almost clear (1) was significantly greater for pimecrolimus versus vehicle at day 8 (44.6% vs 8.7%; P<0.001) and continuing through month 6 (52.9% vs 37.0%, P<0.03); at month 12, differences remained numerically, but not statistically, greater (53.9% vs 47.8%, P>0.05).39 Differences in EASI score and proportion of patients achieving pruritus score of none (0) or mild (1) were also significantly greater for pimecrolimus versus vehicle at day 43 and beyond.39
The Study of the Atopic March (SAM) was a long-term study of pimecrolimus compared with vehicle in patients aged 3-18 months with IGA ≥2 newly diagnosed with AD.40 The trial was designed as a 3-year double-blind, dose-escalation study followed by 3 years of open-label pimecrolimus. Coprimary endpoints included proportion of disease-free days (ie, with no TCS use) and longest duration of remission. The study was prematurely halted after a mean follow-up of 2.8 years after the double-blind phase at the recommendation of the independent study monitoring committee based on protocol-specified criteria.40 TCS could be used for flares; during the first 14 weeks, its use was governed by the investigator, whereas after 14 weeks, TCS could be initiated at the discretion of the caregiver. There was a significant difference between pimecrolimus and vehicle groups in the proportion days with no TCS use at week 14 (P<0.001), but this difference decreased in subsequent weeks and there was no difference at the end of the doubleblind phase (week 158) (Table 1).40 Similar trends were observed for the secondary endpoint of proportion of patients achieving IGA clear (0) or almost clear (1) (Figure 1).40 It was concluded that, although the SAM trial replicated the short-term efficacy previously observed with pimecrolimus compared with vehicle, the high discontinuation rate (48%) and empowerment of caregivers to initiate rescue TCS could have impacted the ability to identify the efficacy of pimecrolimus long-term.40
A randomized, double-blind, parallel-group trial was conducted to investigate the efficacy of pimecrolimus in patients with TCSinsensitive AD, defined as a <35% reduction in EASI after at least 12 days treatment with twice-daily prednicarbate cream, 0.25% (Table 1).33 The difference in the primary endpoint (decrease in EASI score) between the pimecrolimus and vehicle arms was only significant at week 3 (P=0.043) (Table 1), with large standard deviations and substantial differences between mean and median values, indicating that there was significant variability in patient response.33 Treatment success, defined as IGA clear (0) or almost clear (1), was achieved by 11% of pimecrolimustreated patients and zero vehicle-treated patients (Figure 1).33 Change in lesion-specific IGA scores, pruritus scores, and patient assessment of AD were comparable between the pimecrolimus and vehicle arms.33 To evaluate whether TCI plus TCS has a synergistic effect, an exploratory randomized, vehicle-controlled intrapatient comparison trial was conducted to evaluate the efficacy of pimecrolimus twice daily + fluticasone propionate cream, 0.05%, once daily compared with vehicle twice daily + fluticasone propionate cream, 0.05%, once daily in patients with severe AD.30 Secondary efficacy endpoints included IGA score (Figure 1), local IGA score, and patient/caregiver assessment of eczema severity. At end of treatment, there was no statistically significant difference in change from baseline in modified EASI score at week 2 (primary endpoint, P=0.262) (Table 1).30 There were also no differences in secondary efficacy endpoints— proportion of patients achieving global or local IGA clear (0) or almost clear (1).30 Post hoc analyses to explore variables such as age, study site, sex, baseline EASI score, right versus left side, or lesion site found no differences that could predict response.30
The Study of the Atopic March (SAM) was a long-term study of pimecrolimus compared with vehicle in patients aged 3-18 months with IGA ≥2 newly diagnosed with AD.40 The trial was designed as a 3-year double-blind, dose-escalation study followed by 3 years of open-label pimecrolimus. Coprimary endpoints included proportion of disease-free days (ie, with no TCS use) and longest duration of remission. The study was prematurely halted after a mean follow-up of 2.8 years after the double-blind phase at the recommendation of the independent study monitoring committee based on protocol-specified criteria.40 TCS could be used for flares; during the first 14 weeks, its use was governed by the investigator, whereas after 14 weeks, TCS could be initiated at the discretion of the caregiver. There was a significant difference between pimecrolimus and vehicle groups in the proportion days with no TCS use at week 14 (P<0.001), but this difference decreased in subsequent weeks and there was no difference at the end of the doubleblind phase (week 158) (Table 1).40 Similar trends were observed for the secondary endpoint of proportion of patients achieving IGA clear (0) or almost clear (1) (Figure 1).40 It was concluded that, although the SAM trial replicated the short-term efficacy previously observed with pimecrolimus compared with vehicle, the high discontinuation rate (48%) and empowerment of caregivers to initiate rescue TCS could have impacted the ability to identify the efficacy of pimecrolimus long-term.40
A randomized, double-blind, parallel-group trial was conducted to investigate the efficacy of pimecrolimus in patients with TCSinsensitive AD, defined as a <35% reduction in EASI after at least 12 days treatment with twice-daily prednicarbate cream, 0.25% (Table 1).33 The difference in the primary endpoint (decrease in EASI score) between the pimecrolimus and vehicle arms was only significant at week 3 (P=0.043) (Table 1), with large standard deviations and substantial differences between mean and median values, indicating that there was significant variability in patient response.33 Treatment success, defined as IGA clear (0) or almost clear (1), was achieved by 11% of pimecrolimustreated patients and zero vehicle-treated patients (Figure 1).33 Change in lesion-specific IGA scores, pruritus scores, and patient assessment of AD were comparable between the pimecrolimus and vehicle arms.33 To evaluate whether TCI plus TCS has a synergistic effect, an exploratory randomized, vehicle-controlled intrapatient comparison trial was conducted to evaluate the efficacy of pimecrolimus twice daily + fluticasone propionate cream, 0.05%, once daily compared with vehicle twice daily + fluticasone propionate cream, 0.05%, once daily in patients with severe AD.30 Secondary efficacy endpoints included IGA score (Figure 1), local IGA score, and patient/caregiver assessment of eczema severity. At end of treatment, there was no statistically significant difference in change from baseline in modified EASI score at week 2 (primary endpoint, P=0.262) (Table 1).30 There were also no differences in secondary efficacy endpoints— proportion of patients achieving global or local IGA clear (0) or almost clear (1).30 Post hoc analyses to explore variables such as age, study site, sex, baseline EASI score, right versus left side, or lesion site found no differences that could predict response.30
SAFETY OF TOPICAL TREATMENTS
Phosphodiesterase 4 Inhibitors
In the phase 3 crisaborole trials, the most frequently reported TRAE was application site pain (burning or stinging), which was reported for 4.4% of crisaborole-treated patients and 1.2% of vehicle-treated patients (Table 2); most patients (77.6%) experienced resolution within 1 day of onset.10 No treatmentrelated serious AEs (SAEs) were reported. In the long-term (48 weeks), open-label safety extension trial (N=517), no new safety signals were identified, and no evidence of skin atrophy or telangiectasia were reported.49
In the phase 2a intrapatient comparison crisaborole trial, AEs were reported for 44% of patients, and TRAEs were reported for 12% of patients (Table 1).11 These TRAEs included application site events such as erythema, irritation, pain, and pruritus (Table 2).11 There was no evidence of severe AEs or SAEs.11
Topical Corticosteroids
The occurrence of local AEs with TCS is well known, but the true incidence is poorly characterized because of the lack of clinical trials performed to modern standards and because many trials do not report the incidence of TEAEs.7,8,50 Systemic absorption of TCS also has the potential to lead to systemic AEs, such as hypothalamic-pituitary-adrenal axis suppression7 and decreased serum cortisol (Table 2). To reduce the risk for systemic absorption of TCS, treatment guidelines include cautions for use with occlusive wrappings, coverage of a high percentage of the body, and prolonged use, especially in small children and infants and on sensitive skin areas (eg, facial skin).7,8 Additional concerns include TCS addiction and steroid withdrawal syndrome, which are most often associated with
In the phase 3 crisaborole trials, the most frequently reported TRAE was application site pain (burning or stinging), which was reported for 4.4% of crisaborole-treated patients and 1.2% of vehicle-treated patients (Table 2); most patients (77.6%) experienced resolution within 1 day of onset.10 No treatmentrelated serious AEs (SAEs) were reported. In the long-term (48 weeks), open-label safety extension trial (N=517), no new safety signals were identified, and no evidence of skin atrophy or telangiectasia were reported.49
In the phase 2a intrapatient comparison crisaborole trial, AEs were reported for 44% of patients, and TRAEs were reported for 12% of patients (Table 1).11 These TRAEs included application site events such as erythema, irritation, pain, and pruritus (Table 2).11 There was no evidence of severe AEs or SAEs.11
Topical Corticosteroids
The occurrence of local AEs with TCS is well known, but the true incidence is poorly characterized because of the lack of clinical trials performed to modern standards and because many trials do not report the incidence of TEAEs.7,8,50 Systemic absorption of TCS also has the potential to lead to systemic AEs, such as hypothalamic-pituitary-adrenal axis suppression7 and decreased serum cortisol (Table 2). To reduce the risk for systemic absorption of TCS, treatment guidelines include cautions for use with occlusive wrappings, coverage of a high percentage of the body, and prolonged use, especially in small children and infants and on sensitive skin areas (eg, facial skin).7,8 Additional concerns include TCS addiction and steroid withdrawal syndrome, which are most often associated with
