Combination Therapy for Atopic Dermatitis

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)

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.

Study Overview

• Status: Completed
• Conditions: Atopic Dermatitis
• Intervention / Treatment: Drug: pimecrolimus; Drug: Combination of pimecrolimus and fluticasone

Detailed Description

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.

• Study Type: Interventional
• Enrollment (Actual): 90
• Phase: Phase 4

Contacts and Locations

Study Locations

• United States
  • Colorado
    • Denver, Colorado, United States, 80206
      • National Jewish Research Medical Center
  • Illinois
    • Chicago, Illinois, United States, 60611
      • Northwestern University School Of Medicine
  • Texas
    • Houston, Texas, United States, 77030
      • University of Texas at Houston Medical School

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 7 months to 63 years (Child, Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

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

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Double

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Placebo Comparator: placebo; Placebo cream	Drug: pimecrolimus; apply daily with fluticasone cream for flares
Active Comparator: pimecrolimus cream	Drug: pimecrolimus; apply daily with fluticasone cream for flares; Drug: Combination of pimecrolimus and fluticasone; Pimecrolimus cream twice a day and fluticasone cream once a day; Other Names: fluticasone; Pimecrolimus cream

What is the study measuring?

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

Collaborators and Investigators

• Sponsor: Children's Hospital of Philadelphia
• Collaborators: Novartis Pharmaceuticals
• Investigators: Principal Investigator: Jonathan M Spergel, MD, PhD, Children's Hospital of Philadelphia

Publications and helpful links

General Publications

• Hanifin JM, Thurston M, Omoto M, Cherill R, Tofte SJ, Graeber M. The eczema area and severity index (EASI): assessment of reliability in atopic dermatitis. EASI Evaluator Group. Exp Dermatol. 2001 Feb;10(1):11-8. doi: 10.1034/j.1600-0625.2001.100102.x.
• Spergel J, Hultsch T. Pimecrolimus cream 1% and fluticasone propionate cream 0.05% versus fluticasone propionate cream 0.05% for the treatment of flares of atopic dermatitis. 28th Annual Hawaii Dermatology Seminar, 2004
• Leung DY, Boguniewicz M, Howell MD, Nomura I, Hamid QA. New insights into atopic dermatitis. J Clin Invest. 2004 Mar;113(5):651-7. doi: 10.1172/JCI21060.
• Grassberger M, Baumruker T, Enz A, Hiestand P, Hultsch T, Kalthoff F, Schuler W, Schulz M, Werner FJ, Winiski A, Wolff B, Zenke G. A novel anti-inflammatory drug, SDZ ASM 981, for the treatment of skin diseases: in vitro pharmacology. Br J Dermatol. 1999 Aug;141(2):264-73. doi: 10.1046/j.1365-2133.1999.02974.x.
• Eichenfield LF, Lucky AW, Boguniewicz M, Langley RG, Cherill R, Marshall K. 1% pimecrolimus cream for atopic dermatitis. Arch Dermatol. 2003 Oct;139(10):1369-70; author reply 1370-1. doi: 10.1001/archderm.139.10.1369. No abstract available.
• Wahn U, Bos JD, Goodfield M, Caputo R, Papp K, Manjra A, Dobozy A, Paul C, Molloy S, Hultsch T, Graeber M, Cherill R, de Prost Y; Flare Reduction in Eczema with Elidel (Children) Multicenter Investigator Study Group. Efficacy and safety of pimecrolimus cream in the long-term management of atopic dermatitis in children. Pediatrics. 2002 Jul;110(1 Pt 1):e2. doi: 10.1542/peds.110.1.e2.
• Lee MJ, Pyszczynski N, Jusko WJ. Combined inhibition effects of tacrolimus and methylprednisolone on in vitro human lymphocyte proliferation. Immunopharmacol Immunotoxicol. 1995 May;17(2):335-45. doi: 10.3109/08923979509019755.

Study record dates

Study Major Dates

• Study Start: October 1, 2004
• Primary Completion (Actual): June 1, 2005
• Study Completion (Actual): June 1, 2005

Study Registration Dates

• First Submitted: July 5, 2005
• First Submitted That Met QC Criteria: July 5, 2005
• First Posted (Estimate): July 13, 2005

Study Record Updates

• Last Update Posted (Estimate): July 27, 2010
• Last Update Submitted That Met QC Criteria: July 23, 2010
• Last Verified: July 1, 2010

More Information

Terms related to this study

• Keywords: THerapy for acute moderate to severe flares
• Additional Relevant MeSH Terms: Skin Diseases; Immune System Diseases; Hypersensitivity, Immediate; Genetic Diseases, Inborn; Skin Diseases, Genetic; Hypersensitivity; Skin Diseases, Eczematous; Dermatitis; Eczema; Dermatitis, Atopic; Physiological Effects of Drugs; Molecular Mechanisms of Pharmacological Action; Autonomic Agents; Peripheral Nervous System Agents; Enzyme Inhibitors; Analgesics; Sensory System Agents; Anti-Inflammatory Agents, Non-Steroidal; Analgesics, Non-Narcotic; Anti-Inflammatory Agents; Antirheumatic Agents; Immunosuppressive Agents; Immunologic Factors; Dermatologic Agents; Bronchodilator Agents; Anti-Asthmatic Agents; Respiratory System Agents; Anti-Allergic Agents; Calcineurin Inhibitors; Fluticasone; Xhance; Tacrolimus; Pimecrolimus
• Other Study ID Numbers: 2004-10-3975