We performed a randomized, double-blind, placebo-controlled, multicenter phase IV study of oral PL extract (Anapsos) administered over 6 months. The study was performed in 9 hospitals in the Autonomous Community of Valencia, Spain (see the members of the Anapsos in Atopic Dermatitis Work Group in Appendix 1). Patients were randomized to receive PL extract or placebo at a ratio of 1:1. Randomization, with stratification per center, was performed electronically prior to initiation of the study. The study protocol (EudraCT 2008-006422-33) complied with the principles of the Declaration of Helsinki (2008) and was approved by the relevant clinical research ethics committees and the Spanish Agency for Medicines and Health Products. Parents or legal guardians and children older than 12 years gave their written consent to being included in the study.

Inclusion criteria were an age of between 2 and 17 years (inclusive) and a diagnosis of atopic dermatitis according to the Hanifin and Rajka criteria.12 Disease severity was evaluated using the Scoring Atopic Dermatitis (SCORAD) index.13 To be included in the study, patients had to have a SCORAD score of 20 to 40 (inclusive) and require or already be using topic corticosteroids to treat atopic dermatitis flares.

The main exclusion criteria were pregnancy or breastfeeding; current treatment with phototherapy for atopic dermatitis; treatment with PL extract, systemic corticosteroids, or other systemic or cytostatic immunosuppressants in the previous 2 months; treatment with systemic antimicrobials in the 4 days before the start of the study; fever; severe allergic disease; immunodeficiency disorders or cancer; contraindication for the use of any of the study drugs according to the summaries of product characteristics; known allergy to parabens; concomitant skin disease that could make it difficult to evaluate the atopic dermatitis or that required long-term use of topical corticosteroids; and participation in drug research studies in the 3 months before the start of the study. Women of childbearing age were required to use an effective birth control method if they were or became sexually active during the trial. The criteria for withdrawal was use of corticosteroids for more than 5 days in patients under the age of 10 years and for more than 7 days in patients aged between 10 and 17 years.

The patients received PL extract capsules (Anapsos 120 mg manufactured by Especialidades Farmacéuticas Centrum S.A) or similar placebo capsules produced by the same laboratory. Based on the recommendations of previous studies,14,15 the patients were divided into 3 treatment groups according to age (< 6 years, 6-12 years, and >12 years). Children aged less than 6 years received 2 capsules in a single dose at night (240 mg/day of PL extract or placebo); children aged 6 to 12 years received 3 capsules in 2 doses: 1 in the morning and 2 at night (360 mg/day); and children over 12 years received 4 capsules in 2 doses: 2 in the morning and 2 at night (480 mg/day).

Methylprednisolone aceponate 0.1% in emulsion was applied in a thin layer on affected areas to treat flares. Dry skin was treated symptomatically with moisturizing cream after showering or bathing. Patients who required systemic corticosteroids were administered deflazacort at a dosage of 0.25 to 1.5 mg/kg/d. Desloratadine was used to treat pruritus as it comes in tablet and liquid form and dosage could be adjusted to the ages of all the patients in the study. It is administered once daily and because it is a low-sedating antihistamine, it exerts a minimum effect on the sleep loss component of the SCORAD index. The following dosages were used: 2.5 mL of syrup (1.25 mg of desloratadine) once a day in children aged 2 to 5 years; 5 mL (2.5 mg) once a day in children aged 6 to 11 years; and 1 tablet (5 mg) once a day in children aged 12 or over.

Thirteen visits, to take place every 2 weeks after the start of treatment, were scheduled once patients had attended the inclusion visit and been assigned to treatment. To collect data on the use of medication, number of flares, and adverse events, the parents or carers were given a diary in which they were asked to note down in detail and objectively any information on the use of medication and the appearance of new health problems. Scheduled blood and urine tests were performed before and after the study. A pregnancy test was performed in patients of child-bearing age before and after the study and once a month for the duration of the study.

The primary outcome measure was the percentage of days on which topical corticosteroids were used in the 6 months in which patients received PL extract or placebo in addition to their standard treatment. Prespecified secondary outcome measures (based on systematically collected data) were changes in the SCORAD index and investigator's global assessment (IGA) 1, 2, 3, 4, 5, and 6 months after the start of treatment; time to first flare (time from randomization to appearance of a new flare); changes in the incidence of flares (based on mean number of flares reported for the 2 months before the baseline visit); and adverse events. A flare was defined as an exacerbation that could be quantified, following evaluation of the patient's diary, physical examination, and an interview with the patient or tutor, with an IGA score of 4 or more, or that required the use of topical corticosteroids for at least 3 days. A course of corticosteroids was defined as the use of corticosteroids according to the prescribed regimen for an interrupted period, regardless of the number of days.

Continuous quantitative variables were reported as means (SD), categorical variables as numbers and percentages, and time to first flare as a median and range. All the data were analyzed using intention-to-treat analysis (all patients included in the study) and per-protocol analysis (all those who completed follow-up). The last observation carried forward method was used for patients who did not complete follow-up. The percentage of days on which topical corticosteroids or antihistamines were used was calculated as the number of days on which treatment was used divided by the total number of days the study lasted. The PL extract and placebo groups were compared using the Wilcoxon test, with statistical significance set at 5%. Bonferroni adjustment was used for multiple comparisons. Sample size was calculated using data from previous studies of adults with a similar diagnosis and moderate disease in which the placebo group used topical corticosteroids for a mean of 37.2% (34.6%) of days (6-month study period).16,17 Assuming thus a 60% reduction in the days topical corticosteroids would be used in the group treated with PL extract and an estimated loss to follow-up of 20%, we calculated that we would need 53 patients per group to detect statistically significant differences for a power of 80%.

In total, 105 patients (69 girls) were included in the study. Ninety-three patients (89%) completed the 6 months of treatment and the number of withdrawals was similar in the PL extract group and the placebo group. Fifty-two patients were assigned to the PL extract group and 53 to the placebo group (Fig. 1). The mean SCORAD score was 31 (95% CI, 30-32). The IGA was classified as mild to moderate in 97% of cases. The mean age of the patients was 8 (4) years (range, 2-17 years), the mean weight was 33.2 (18.8) kg, and the mean axillary temperature was 36.1 (0.6) °C. All the patients met the Hanifin and Rajka diagnostic criteria and most of them met the 4 major criteria. Eighty-eight percent of patients were using topical corticosteroids at the time of the baseline visit. There were no significant differences in demographic characteristics, clinical variables related to atopic dermatitis, or clinical course between the patients in the PL extract group and those in the placebo group (Table 1).

Figure 1.

Flow diagram showing treatment allocation and follow-up.

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Topical corticosteroids were used on 11% (12%) of the days in the study period by the patients in the PL extract group and on 12% (11%) of the days by those in the placebo group (P=.2) (Table 2). Table 2 also shows a lower use of topical corticosteroids in the PL extract group for all the other variables analyzed but the differences with the placebo group were not significant in any of the cases. Fig. 2, in turn, shows a lower percentage of patients requiring topical corticosteroids and a lower mean number of courses of treatment in the PL extract group over the course of the study, but again, the differences with the placebo group were not statistically significant.

Figure 2.

A, Percentage of patients who required treament with topical corticosteroids during the study. B, Number of courses of treatment required.

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Fig. 2 also shows a progressive reduction in topical corticosteroid use over the 6 months in both groups. In the placebo group, the changes with respect to the previous month were not significant for any of the months analyzed. In the PL group, however, there was a relevant and significant reduction in the second month compared to the first (median of 13.8 days in the first month vs 7.2 days in the second, P=.012) and in the fifth month compared to the fourth (median of 3 days in the fourth month vs 6 days in the fifth, P=.012).

On comparing the use of topical steroids each month with that recorded in the first month (by percentage of days), a reduction of 36% was observed in the fifth month for the PL extract group; the corresponding reduction in the placebo group was 9% (P=.02).

No significant variations in results were seen when the data were adjusted for season.

Antihistamine and systemic corticosteroid use was evaluated using the same approach as that described for topical corticosteroids. The percentage of days on which the patients took desloratadine over the 6 months was significantly lower in the PL extract group (mean, 14% [19%]; median, 4.5% [range, 0%-66.5%]) than in the placebo group (mean, 21% [22%]; median, 13.6% [range, 0%-86.4% (P=.038). On analyzing the percentage of days on which desloratadine was used by month, a nonsignificant reduction was seen in the first month and a significant reduction in months 4, 5, and 6 (Fig. 3A). The overall proportion of patients who required oral antihistamines was also lower in the PL extract group than in the placebo group. This difference was apparent after the first month of treatment but it became statistically significant after the third month (fourth, fifth, and sixth months) (Fig. 3B).

Figure 3.

Use of oral antihistamines during the 6 months of the study. A, Mean percentage of days on which the patients in the Polypodium leucotomos extract and the placebo group took oral antihistamines. B, Percentage of patients who took oral antihistamines every month. * P<.05 on comparing data from the same month between groups.

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No significant between-group differences were observed for the use of systemic corticosteroids (9.6% in the PL extract group vs 13% in the placebo group).

Fig. 4 shows the changes in the SCORAD index and the number of flares each month. The changes in the overall SCORAD index and the 3 subscores (extent, intensity, and pruritus and sleep loss) were similar in both groups. Fewer flares (total number of flares and flares recorded at each visit) were reported in the PL extract group but the differences with the placebo group were slight and statistically insignificant in all cases. There were also no significant differences between the groups in the time to the first flare (median of 0.5 months in both groups) or in the progressive reduction in disease severity assessed using the IGA. In total, 463 adverse events were recorded over the study period: 218 in the PL extract group and 223 in the placebo group. In both groups, most of the events were classified as mild. Moderate adverse events were more common in the placebo group (14 patients) than in the PL extract group (7 patients) (Table 3). Only 1 patient, receiving placebo, experienced a severe adverse event (diarrhea with dehydration).

Figure 4.

A, Changes in atopic dermatitis extent, severity, and symptoms (SCORAD index) over the 6 months of the study. B, Mean Number of flares recorded at each monthly visit. Columns show the median and range for each group and month. SCORAD indicates Scoring Atopic Dermatitis index.

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