Safety, Effectiveness, and Pharmacokinetics of Crisaborole in Infants Aged 3 to < 24 Months with Mild-to-Moderate Atopic Dermatitis: A Phase IV Open-Label Study (CrisADe CARE 1)

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 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 [10], mild (2) or moderate (3) AD per ISGA [6], 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.

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 [0] or almost clear [1] 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 [13]; 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 (C_max) at day 8, time to reach maximum observed plasma concentration (T_max) at day 8, and area under the plasma concentration-time profile for the dosing interval (AUC_tau) 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 C_max 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.

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 C_max and AUC_tau 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 [14]. For the propylene glycol analysis, unplanned postbaseline visits were excluded.

A total of 137 patients (non-PK cohort, n = 116; PK cohort, n = 21) from the United States (n = 112; 81.8%), Australia (n = 15; 10.9%), and Canada (n = 10; 7.3%) were evaluated in the study from January 16, 2018 (first patient first visit), to April 12, 2019 (last patient last visit). In total, nine patients (6.6%) discontinued treatment. Among these, four (2.9%) discontinued treatment because of a TEAE. Other reasons for discontinuing treatment were lack of efficacy (n = 1; 0.7%), lost to follow-up (n = 1; 0.7%), and withdrawal by parent or guardian (n = 3; 2.2%) (Supplemental Fig. 1 in ESM).

Patient demographics and baseline disease characteristics are summarized in Table 1. Overall, the median age was 13 months with median ISGA of 3.0 and mean %BSA of 28.1. One patient with severe AD (ISGA 4) was enrolled in and completed the trial but was considered a protocol deviation due to the severe baseline ISGA. Generally, baseline characteristics were similar between the patients included in the non-PK cohort and the PK cohort; however, %BSA involvement and disease severity (per ISGA and EASI scores) were greater in the PK cohort, consistent with inclusion criteria. A total of 22 patients (16.1%) had a medical history that included at least one other atopic condition, such as asthma, food allergies, and/or allergic/seasonal rhinitis. Approximately half of patients (n = 72; 52.6%) had used topical corticosteroids prior to entering the study, and two patients (1.5%) had used TCIs. Overall, 126 patients (92%) were considered adherent to the treatment regimen (received 80–120% of the expected number of doses).

In the overall study population (N = 137), all-cause TEAEs were reported for 88 (64.2%) patients; 98.9% of which were rated as mild or moderate. Treatment-related AEs were reported for 22 patients (16.1%). Four (2.9%) patients discontinued treatment because of a TEAE and remained in the study, including one patient who experienced a serious TEAE of ‘febrile convulsion’ (not related to treatment). The other three patients who discontinued treatment because of a TEAE were one patient with ‘dermatitis infected’ (not related to treatment), one patient with ‘application site pain’ (treatment-related), and one patient with ‘application site discomfort’ (treatment-related). The most frequently reported (≥ 5%) all-cause TEAEs were ‘pyrexia’ (9.5%), ‘upper respiratory tract infection’ (7.3%), ‘diarrhea’ (7.3%), ‘dermatitis atopic’ (6.6%), ‘dermatitis diaper’ (6.6%), and ‘cough’ (5.1%) (Table 2). The most frequently reported (≥ 2.5%) treatment-related treatment area AEs were ‘application site pain’ (n = 5; 3.6%), ‘application site discomfort’ (n = 4; 2.9%), and ‘erythema’ (n = 4; 2.9%) (Table 3). Treatment-related ‘application site pain’ or ‘application site discomfort’ (occurring in nine patients with no overlap between each AE term) were reported on the face for four patients, on the leg for four patients, on the arm for three patients, on the chest for two patients, on the back for one patient, on the neck for one patient, and on the abdomen for one patient. (Note: each patient could report more than one body location for ‘application site pain’ or ‘application site discomfort’ AEs.) Patients with an ‘application site erythema’ AE did not overlap with any patients with an ‘erythema’ AE. No safety signals were identified in clinical laboratory findings, weight, height, electrocardiograms, or vital signs (data not shown).

In the overall study population, 20.0% of patients achieved ISGA success at day 8 (first postbaseline assessment) and 30.2% achieved ISGA success at day 29 (Fig. 1). In addition, 40.7% of patients achieved ISGA of clear or almost clear at day 8 and 47.3% achieved ISGA of clear or almost clear at day 29 (Fig. 1). Mean (standard error [SE]) EASI score decreased from 11.8 (0.72) at baseline to 5.0 (0.50) for a mean percentage change (SE) from baseline of − 57.5% (3.27) at day 29 (Fig. 2). Mean (SE) %BSA was reduced from 28.1 (1.88) at baseline to 12.4 (1.18) for a mean change (SE) from baseline of − 15.2 (1.51) at day 29 (Supplemental Fig. 2 in ESM). Mean (SE) POEM total score improved from 14.8 (0.52) at baseline to 6.1 (0.48) for a mean change (SE) from baseline of − 8.5 (0.5) at day 29 (Fig. 3). When POEM total score was analyzed by domain, mean changes from baseline ranged from approximately − 1 to − 2 across subscales at day 29, including improvements in itching and sleep loss (Fig. 4).

Eighteen patients were evaluated for PK parameters, and all had quantifiable concentrations of crisaborole (Table 4) and the inactive metabolites (data on file). Based on nonlinear regression analysis, which accounts for dose differences (due to differences in %BSA) and age differences (accounting for the difference in clearance of crisaborole), crisaborole exposure was comparable with that in patients aged ≥ 2 years observed in previous studies [14‐16].

A majority of the patients had measurable concentrations of propylene glycol at screening covering a wide range (0–30,000 ng/mL) (Supplemental Table 2 in ESM). After treatment with crisaborole, propylene glycol concentrations were still measurable and had a similarly wide range (0–44,000 ng/mL). Based on the wide overlapping ranges observed between screening and end of treatment visits and examination of individual patient profiles, no systematic trend for increased propylene glycol plasma concentrations following treatment with crisaborole was identified. In addition, no propylene glycol toxicity effects were identified, including no changes in electrocardiogram, clinical laboratory, or vital sign parameters.