Combination Therapy for Atopic Dermatitis

Study Overview
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Brief Summary
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Atopic dermatitis is a chronic relapsing disease with acute flares. The standard therapy is to treat acute flares using topical medications. The two most common classes of topical medications for atopic dermatitis (AD) are topical corticosteroids and topical calcineurin inhibitors. Pimecrolimus and topical corticosteroids exert their activity by different mechanisms, there may be a synergistic effect of the combination therapy. Therefore, a combination therapy may provide a faster resolution of severe skin lesions and consequently reduce the duration of the topical corticosteroid treatment. Another benefit of the combination therapy maybe the use of a lower potency corticosteroid to achieve the same degree of clearance. The hypothesis of this trial is that the combination of the two agents will lead to faster clearance than the single agent of topical corticosteroids.

Detailed Description
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This trial is a double-blind controlled trial of fluticasone cream daily and pimecrolimus cream BID versus fluticasone cream daily and placebo cream BID for the treatment of acute flares of atopic dermatitis. While pimecrolimus cream 1% has been proven to be effective in mild and moderate Atopic dermatitis (AD), there is a need for a fast control of severe skin lesions. On the other hand, reducing the duration of the topical corticosteroid treatment is a reasonable approach to minimize the occurrence of adverse effects. Because pimecrolimus and topical corticosteroids exert their activity by different mechanisms, there may be a synergistic effect of the combination therapy. Therefore, a combination therapy may provide a faster resolution of severe skin lesions and consequently reduce the duration of the topical corticosteroid treatment. Another benefit of the combination therapy maybe the use of a lower potency corticosteroid to achieve the same degree of clearance. In vitro data have demonstrated that a combination of steroids and tacrolimus has synergistic effects on in vitro human lymphocyte proliferation. In addition, it has previously been reported, in a pilot investigation in two subjects, that a combination regimen of pimecrolimus 1% twice a day and fluticasone propionate cream 0.05% once daily was superior to fluticasone propionate cream 0.05% once daily in the acute treatment of atopic dermatitis (AD). This study is conducted to validate these findings in a larger number of patients.

Official Title
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An Exploratory Double-blind, Randomized, Vehicle-controlled, Paired Study to Evaluate the Efficacy and Safety of Concomitant Use of Elidel Cream 1% and Cutivate Cream 0.05% in Patients With Severe Lesions of Atopic Dermatitis (AD)

Conditions
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Atopic Dermatitis

Intervention / Treatment
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* Drug: Combination of pimecrolimus and fluticasone
* Drug: pimecrolimus


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Age 2 to 65 years Clinical diagnosis of (Atopic Dermatitis) AD according to the American Academy of Dermatology (AAD) Consensus Conference (2001) At least two lesions of AD on symmetrical part of the body (same location for each side of the body), of severe intensity (m-EASI is at least 7 on each site, with erythema of at least 3 (severe) and papulation/infiltration of at least 3 (severe)) and similar severity (m-EASI does not differ from more than 2 points on both sides) Signed written informed consent Willingness and ability to comply with the study requirements Female is able to enter and participate in this study if she is of: Non-childbearing potential (i.e., physiologically incapable of becoming pregnant) or Childbearing potential, has a negative pregnancy test (urine) at the screen visit and agrees to an adequate method of birth control throughout the study (which may, at the investigator's discretion, include abstinence) Exclusion Criteria: History of immune deficiencies or history of malignant disease Patients with moderate to severe lichenification at the target areas (i.e. score 2 or 3) Active cutaneous bacterial, viral or fungal infections in target areas History of other skin disorders, including Netherton syndrome, that could interfere with the evaluations Use of any topical treatment known or suspected to have an effect on atopic dermatitis within one week prior to the screen visit (except for calcineurin inhibitors, for which the washout is 2 weeks) Use of any systemic treatment (including phototherapy) known or suspected to have an effect on AD within four weeks prior to the screen visit [(patients on a stable and low dose of inhaled steroids, on a stable dose of anti histamines, on stable dose of leukotriene antagonists, or receiving occasional short-acting b2-agonists for the treatment of asthma and topical corticosteroids (nasal spray) for the treatment of allergic rhinitis may participate). High-dose inhaled corticosteroids (> 440 mcg of fluticasone a day) and anti-IgE products are not permitted]. Known sensitivity to pimecrolimus or vehicle (placebo) or fluticasone propionate cream or any of their ingredients Patients with severe medical condition(s) that in the view of the investigator prohibits participation in the study Use of any other investigational agent in the last 30 days

Ages Eligible for Study
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Minimum Age: 2 Years
Maximum Age: 65 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Double


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Placebo Comparator: placebo<br>Placebo cream | Drug: pimecrolimus<br>* apply daily with fluticasone cream for flares<br>|
| Active Comparator: pimecrolimus cream<br> | Drug: Combination of pimecrolimus and fluticasone<br>* Pimecrolimus cream twice a day and fluticasone cream once a day<br>* Other names: fluticasone;Drug: pimecrolimus<br>* apply daily with fluticasone cream for flares<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change From Baseline in the m-EASI (Eczema Area Severity Index) Score. | Eczema Area severity index (EASI) is a composition of scores based on area of eczema involved, (0 = mild to 3 = severe) for four separate Atopic Dermatitis (AD) symptoms: erythema,infiltration ⁄population, excoriation and ichenification. Total score 0-12 | up to 15 days | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| The Time to Clearance of the Disease | The time to clearance of eczema measured in days | assessed up to 30 days following drug application | 
| The Time to the First Day When m-EASI is Scored by the Investigator as 2 or Less | Time to partial clearance of the localized eczema lesion assessed by the investigator is measured in days | up to one week | 
| The Percentage of Target Areas Reaching a l-IGA (Localized Investigator Global Assessment (l-IGA) or 0 or 1) | The Investigator Global Assessment (IGA) and l-IGA were graded on a scale of 0-4 (0 = clear, 1 = almost clear, 2 = mild disease, 3 = moderate disease, 4 = severe). The percentage of eczema lesions from the total population that reach almost clear | up to 15 days | 
| The Percentage of Target Areas Improved (i.e., Decrease in Localized Investigator Global Assessmet (l-IGA) Score From Baseline) | The percentage of eczema areas that show improvement in l-IGA score. The l-IGA were graded on a scale of 0-4 (0 = clear, 1 = almost clear, 2 = mild disease, 3 = moderate disease, 4 = severe disease). | up to 15 days | 
| The Percentage of Target Areas Reaching a m-EASI (Modifed-Eczema Area Severity Index) Score of 2 or Less | The EASI is a measure of Atopic Dermatitis (AD) severity. A m-EASI score (0-12) was also calculated as the sum of severity (0 = mild to 3 = severe) for four separate AD symptoms: erythema, infiltration ⁄population, excoriation and lichenification. The percentage of participants whose eczema reaches almost clear | up to one week | 
| Change From Baseline in Patients' Self Assessment of Disease Severity (PSA) of Target Areas | The patient or caregiver assessment of eczema severity (PSA) was recorded daily in a diary using a 0-4 scale similar to that of the IGA.(0 = clear, 1 = almost clear, 2 = mild disease, 3 = moderate disease,4 = severe disease). Difference in value of PSA from baseline to end of study | 30 days | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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THerapy for acute moderate to severe flares