CrisADe CARE 1 was a multicenter, open-label, single-arm, phase IV study designed to evaluate the safety, efficacy, and PK of crisaborole in infants aged 3 to < 24 months with mild-to-moderate AD. The institutional review board at each study site approved the study protocol, and written informed consent was provided by parents or legal guardians. The study was conducted in accordance with the protocol, local legal and regulatory requirements, and the general principles set forth in the International Ethical Guidelines for Biomedical Research Involving Human Subjects, International Conference on Harmonisation Guideline for Good Clinical Practice, and the Declaration of Helsinki.
Patients and Treatment
Patients were recruited from 30 study sites across three countries (United States, Canada, and Australia). Enrolled patients were aged 3 to < 24 months with a diagnosis of AD per Hanifin and Rajka criteria , mild (2) or moderate (3) AD per ISGA , and a percentage of treatable body surface area (%BSA) ≥ 5, excluding the scalp. Patients were excluded if they had received systemic corticosteroids or immunosuppressive agents within 28 days of the first dose of study drug; used high- or medium-potency topical corticosteroids, topical calcineurin inhibitors (TCIs), topical antibiotics, light therapy, antibacterial soaps (for bathing), bleach baths, or topical sodium hypochlorite-based products on treatable AD lesions within 7 days of the first dose of study drug; used systemic antihistamines or low-potency topical corticosteroids within 3 days of the first dose of study drug; or used emollients, topical antihistamines, or topical hydrocortisone < 1% on treatable AD lesions within 8 h of the first dose of study drug. Patients in the PK cohort (of whom at least three patients were to be aged 3 to < 9 months) were required to have moderate AD per ISGA with a treatable %BSA ≥ 35, excluding the scalp, at baseline and have adequate venous access. Patients were excluded from the PK cohort if they had lesions on the extremities (i.e., below wrists or ankles) or within 2 cm of the mouth to prevent inadvertent ingestion of crisaborole.
Open-label crisaborole was applied twice daily to all AD-affected areas of the body throughout the 28-day duration of the study, even if the AD lesions resolved. Patients in the PK cohort had twice daily visits on days 1 through the morning of day 8 for application of investigational product at the site. Caregivers were instructed to avoid applying crisaborole to mucous membranes and the scalp to avoid potential patient dissatisfaction with ointment application to scalp hair. In the PK cohort, application to the hands, feet, and perioral areas was also avoided to prevent inadvertent ingestion of crisaborole. Crisaborole could also be applied to any new treatable AD-involved areas that appeared outside of these areas following baseline (day 1) after consultation with the investigator at the next visit. Therapies not permitted during the study were systemic corticosteroids, antihistamines, leukotriene receptor antagonists, and immunosuppressants. Additionally, topical agents, such as low-to-high-potency topical corticosteroids, TCIs, topical antihistamines, topical antibiotics, topical sodium hypochlorite-based products, antibacterial soaps, bleach baths, diaper rash creams, lotions, ointments, and powders, and light therapy, were not permitted. Use of bland emollients was permitted to manage dry skin in areas surrounding but not on or overlapping with treatable AD-involved areas or on AD-involved areas where crisaborole was not applied.
For the non-PK cohort, treatment adherence was recorded by site staff for the day 1 morning dose and by parent/guardian at home in a dosing diary for subsequent doses. For the PK cohort, the day 1 morning dose through the day 8 morning dose were recorded by site staff, while all subsequent doses were recorded by parent/guardian at home in the dosing diary. Patients were considered adherent to treatment if 80–120% of the expected number of doses were received.
Study Outcomes and Assessments
Site visits occurred at screening, baseline (day 1), day 8, day 15, day 22 (telephone visit), and day 29 during the treatment period, and telephone follow-up visits occurred at days 36 and 57.
Primary endpoints were the incidence of treatment-emergent adverse events (TEAEs), which were assessed at all study visits and follow-up visits; clinically significant changes in vital signs, such as temperature, blood pressure, pulse, and respiratory rate (assessed at screening, baseline, day 8, day 15, and day 29); height, weight, and physical examination (assessed at baseline and day 29); electrocardiography (assessed at baseline, day 8, and day 29); and laboratory assessments, including metabolic panels, serum chemistry, and hematology panels (assessed at screening and day 29, and also at day 8 for the PK cohort). Blood pressure, electrocardiography, and cardiovascular and neurologic physical examination were included to monitor for potential cardiovascular and neurologic effects of propylene glycol. The investigator recorded all directly observed TEAEs and all TEAEs spontaneously reported by the patient’s parent/legal guardian. Each patient’s parent/legal guardian was to be questioned about the occurrence of AEs in a non-leading manner. Verbatim AE terms reported by the investigator were coded to Medical Dictionary for Regulatory Activities (MedDRA) preferred terms.
Exploratory efficacy endpoints included the proportion of patients who achieved ISGA success (defined as clear  or almost clear  with ≥ 2-grade improvement from baseline; ISGA was assessed at day 8, day 15, and day 29), proportion of patients who achieved ISGA clear or almost clear, percentage change from baseline in Eczema Area and Severity Index (EASI [11, 12]; assessed at days 15 and 29), change from baseline in %BSA (assessed at days 15 and 29), and change from baseline in Patient-Oriented Eczema Measure (POEM proxy version ; assessed at days 8, 15, and 29). Efficacy outcome measures are further described in Supplemental Table 1 (in Electronic Supplementary Material [ESM]).
Exploratory PK endpoints for crisaborole were maximum observed plasma concentration (Cmax) at day 8, time to reach maximum observed plasma concentration (Tmax) at day 8, and area under the plasma concentration-time profile for the dosing interval (AUCtau) at day 8. PK parameters of crisaborole and its metabolites were assessed for the patients in the PK cohort using blood samples collected before the day 8 morning dose, 3 h after the day 8 morning dose, and 12 h after the day 8 morning dose. A 3-h sample time was chosen for Cmax based on previous data obtained from patients with AD and healthy volunteers (data on file). In addition, plasma concentrations of propylene glycol were assessed for all patients at screening and day 29 (12 h after the last dose). For patients in the PK cohort, propylene glycol concentrations were also assessed before the day 8 morning dose. Plasma samples were analyzed using validated analytical methods.
Study Statistical Considerations
All safety, efficacy, PK, and propylene glycol concentration data were summarized using descriptive statistics. The 95% CIs for binary endpoints were obtained by Clopper–Pearson exact method. A target of 125 enrolled patients was chosen to ensure that approximately 100 patients completed the study, assuming a 20% dropout rate. The sample size was determined by clinical judgment based on experience with other clinical studies of the investigational product. Statistical power was not calculated because there was no comparator group within the trial. A sample size of 16 patients was selected for the PK cohort to provide 96.0% overall power for 90% one-sided CIs for Cmax and AUCtau on day 8 to be less than the previously observed 85th percentiles of 166 ng/mL and 1281 ng h/mL, respectively, under maximum-use conditions in patients aged 2–17 years . For the propylene glycol analysis, unplanned postbaseline visits were excluded.