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    Over the rainbow

    Trials find pimecrolimus cream effective for atopic dermatitis in all ages

    A five-year-old girl in the Rainbow Study illustrates her image of herself before treatment for her eczema, at left; and after applying her medication, at right.
    Barcelona - In two Phase IV efficacy studies designed to evaluate pimecrolimus 1 percent cream (Elidel®, Novartis Pharmaceuticals Corp.) under "real world" conditions, treatment with pimecrolimus 1 percent cream for up to six months was found to be safe and effective in infants, children, and adults who were suffering from atopic dermatitis with all degrees of severity and who had received a wide variety of previous treatments. Moreover, in both trials, subjects reported improvements in quality of life and a high degree of cosmetic acceptability, according to clinical investigators Lyn C. Guenther, M.D., F.R.C.P.C., Professor of Dermatology at the University of Western Ontario in London, Ontario, Can., and Sheila Fallon Friedlander, M.D., Associate Clinical Professor of Dermatology at Children's Hospital & UCSD Medical Center in San Diego, Calif. Results of both trials were presented at the 12th Congress of the European Academy of Dermatology and Venereology in Barcelona.

    The trials were the Rainbow Study, a six-month, open-label, single-arm, multicenter Canadian study that enrolled 515 persons from 3 months to 80 years of age, and the NOBEL Study, a six-month, open-label, single-arm, multicenter, multinational study that enrolled 947 persons from 3 months to 81 years of age. Both trials were designed to assess the efficacy of pimecrolimus 1 percent cream based on the Investigator's Global Assessment (IGA) score for the whole body, the IGA score for the face, and measurement of pruritus severity in the 24 hours prior to assessment. Adverse events were assessed at each clinic visit by clinical examination and patient interviews.

    "Real life" treatment conditions Subjects in the Rainbow Study were given pimecrolimus 1 percent cream and instructed to use the cream continuously as long as signs and symptoms of atopic dermatitis persisted, and then to continue for three days after clearance of the rash. The study design in the NOBEL Study was similar. Because these studies were designed to evaluate pimecrolimus 1 percent cream under typical clinical conditions, as opposed to the more rigid conditions of a Phase III clinical trial, subjects were permitted to use other emollients or topical corticosteroids as needed. If signs and symptoms of AD recurred after clearance, subjects were instructed to resume treatment, with no need for a special clinic visit. However, subjects were advised to consult the investigator if a severe flare-up occurred.

    In the Rainbow Study, 416 subjects (80.8 percent) completing the six-month study. In the NOBEL Study, 797 (84.2 percent) completing the study. The mean age of subjects in the Rainbow Study was 20.9 (range: 0.3-80.2), with a slightly younger population (15.1; range: 0.3-81) in the NOBEL Study. The population in both studies was primarily Caucasian (72 percent in Rainbow, 78 percent in NOBEL) and female (56 percent in Rainbow, 53 percent in NOBEL). The majority of subjects in both studies had mild or moderate total body IGA severity scores at baseline (80 percent in Rainbow; 76.5 percent in NOBEL) and mild or moderate pruritus (68.5 percent in Rainbow, 69 percent in NOBEL) at baseline. Approximately half the subjects in both trials had mild or moderate facial IGA severity scores (50.1 percent in Rainbow, 45 percent in NOBEL) at baseline.

    Efficacy results Improvements in severity of pruritus were achieved within the first week, with 59.2 percent of subjects in Rainbow and 64 percent of subjects in NOBEL reporting absent or mild pruritus, compared to 32.8 percent and 35.6 percent at baseline, respectively.

    Overall, total-body IGA scores improved over the study period for patients in both studies. After 24 weeks, 64.9 percent of subjects in the Rainbow Study and 66.9 percent of subjects in the NOBEL Study had improved total body IGA scores, with clear or almost clear rating given to 38.8 percent and 47.2 percent of subjects in the two studies, respectively.

    More striking improvements were noted for the face. Most subjects who showed improvement in facial IGA scores (78.1 percent in the Rainbow Study and 76.7 percent in the NOBEL Study) actually had ratings of clear or almost clear after 24 weeks (72.6 percent in the Rainbow Study and 73.6 percent in the NOBEL Study).

    Adverse events reported in either study with >5 percent frequency were nasopharyngitis (12.7 percent NOBEL; 8 percent, Rainbow), upper respiratory tract infection (10 percent, NOBEL; 5.4 percent, Rainbow), cough (7.2 percent, NOBEL), headache (7.2 percent, NOBEL), burning sensation at the application site (7 percent, NOBEL; 8.2 percent, Rainbow), pyrexia (6.5 percent, NOBEL; 6.4 percent, Rainbow), and asthma (5.2 percent, NOBEL). Only one severe adverse event in the Rainbow study and two in the NOBEL study were suspected to be related to study medication; in all three cases, the events resolved.

    In response to the baseline questionnaire concerning steroid usage and attitudes towards steroids, two-thirds or more of the subjects in both studies expressed concerns about using steroids. "Patients and their parents are concerned about potential adverse events associated with steroid use, particularly thinning of the skin, and non-specific long-term effects," said Dr. Guenther. "Also, they are concerned that they might become immune to the steroid effects."

    Quality of life improves Subject evaluations of quality of life (QOL) at baseline and on therapy were important features of both studies for the age groups in which validated QOL questionnaires are available because atopic dermatitis can have such a devastating effect on patients and their families. "The itching can be intractable and keep the child and family up at night," said Dr. Guenther, one of the investigators in the Rainbow Study. "Sleepless nights result in fatigue, irritability, and loss of concentration."

    Rainbow Study participants or their parents were asked to complete the adult or pediatric version of the Quality of Life Index - Atopic Dermatitis questionnaire at baseline and at months two and six. Significant improvement in quality of life was seen in all age groups in the Rainbow Study.

    Subjects in both studies were asked to assess the cosmetic acceptability of pimecrolimus cream. At week eight, the majority of participants in both studies rated pimecrolimus 1 percent cream as "very good" or "excellent" regarding spreadability (88 percent, Rainbow; 74 percent, NOBEL), ease of rub-in (82 percent, Rainbow; 70 percent, NOBEL), ease of application (89 percent, Rainbow; 75 percent, NOBEL), and non-sticky feel (83 percent, Rainbow; 69 percent, NOBEL). "Most patients hate ointments because they are so greasy," said Dr. Friedlander. "They preferred Elidel because of its cream base."

    The rainbow returns It is well known that skin diseases such as atopic dermatitis can have a negative psychosocial impact, perhaps especially so in children and adolescents. "Children with atopic dermatitis often scratch to the point of bleeding. This can result in clothing stains, embarrassment and shunning by other children," said Dr. Guenther.

    Drawings from a five-year-old girl who participated in the Rainbow Study illustrate this point well, with the child's image of herself showing a remarkable metamorphosis when her skin condition is controlled. One sketch shows the child as an itchy, frowning, blue-faced caterpillar. As the child explained, the caterpillar feels crabby from the pain: its many arms are not enough to scratch its skin so that the itching stops. The next sketch shows how the child feels when topical cream medication controls her eczema: a smiling little girl playing in the sunshine, under a colorful rainbow, engaged in her favorite activity of catching butterflies with her friends.

    Real-world acceptance In the "real world" conditions of both studies, pimecrolimus 1 percent cream appeared effective, safe and generally well-tolerated and was rated highly by study participants in terms of cosmetic acceptability. "Many patients with significant atopic dermatitis will benefit from use of both topical corticosteroids and topical immunomodulators for control of their disease," Dr. Friedlander said.

    "Although the optimal combination and treatment plan have yet to be defined, we should remember that therapeutic regimens should be modified according to patient preference and response."

    Drs. Guenther and Friedlander have both served as paid consultants and clinical investigators for various pharmaceutical companies including Novartis, maker of Elidel® (pimecrolimus 1 percent cream).

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