Combination Therapy for Atopic Dermatitis

• Sponsor: Children's Hospital of Philadelphia (Other)
• Overall Status: Completed
• CT.gov ID: NCT00119158
• Collaborator: Novartis Pharmaceuticals (Industry)
• Enrollment: 90
• Locations: 3
• Arms: 2
• Duration (Months): 8
• Patients Per Site: 30
• Patients Per Site Per Month: 3.8

Study Details

Study Description

Brief Summary

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.

Condition or Disease	Intervention/Treatment	Phase
Atopic Dermatitis	Drug: Combination of pimecrolimus and fluticasone; Drug: pimecrolimus	Phase 4

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 Design

• Study Type: Interventional
• Actual Enrollment: 90 participants
• Allocation: Randomized
• Intervention Model: Parallel Assignment
• Masking: Double (Participant, Investigator)
• Primary Purpose: Treatment
• Official Title: 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)
• Study Start Date: Oct 1, 2004
• Actual Primary Completion Date: Jun 1, 2005
• Actual Study Completion Date: Jun 1, 2005

Arms and Interventions

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

Outcome Measures

Primary Outcome Measures

1. Change From Baseline in the m-EASI (Eczema Area Severity Index) Score. [up to 15 days]

   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

Secondary Outcome Measures

1. The Time to Clearance of the Disease [assessed up to 30 days following drug application]

   The time to clearance of eczema measured in days

2. The Time to the First Day When m-EASI is Scored by the Investigator as 2 or Less [up to one week]

   Time to partial clearance of the localized eczema lesion assessed by the investigator is measured in days

3. The Percentage of Target Areas Reaching a l-IGA (Localized Investigator Global Assessment (l-IGA) or 0 or 1) [up to 15 days]

   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

4. The Percentage of Target Areas Improved (i.e., Decrease in Localized Investigator Global Assessmet (l-IGA) Score From Baseline) [up to 15 days]

   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).

5. The Percentage of Target Areas Reaching a m-EASI (Modifed-Eczema Area Severity Index) Score of 2 or Less [up to one week]

   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

6. Change From Baseline in Patients' Self Assessment of Disease Severity (PSA) of Target Areas [30 days]

   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

Eligibility Criteria

Criteria

• Ages Eligible for Study: 2 Years to 65 Years
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

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

• 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

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	National Jewish Research Medical Center	Denver	Colorado	United States	80206
2	Northwestern University School of Medicine	Chicago	Illinois	United States	60611
3	University of Texas at Houston Medical School	Houston	Texas	United States	77030

Sponsors and Collaborators

• Children's Hospital of Philadelphia
• Novartis Pharmaceuticals

Investigators

• Principal Investigator: Jonathan M Spergel, MD, PhD, Children's Hospital of Philadelphia

Study Documents (Full-Text)

None provided.

More Information

Publications

• 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.
• 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.
• 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.
• 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.
• Leung DY, Boguniewicz M, Howell MD, Nomura I, Hamid QA. New insights into atopic dermatitis. J Clin Invest. 2004 Mar;113(5):651-7. Review.
• 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
• 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.

• ClinicalTrials.gov Identifier: NCT00119158
• Other Study ID Numbers: 2004-10-3975
• First Posted: Jul 13, 2005
• Last Update Posted: Jul 27, 2010
• Last Verified: Jul 1, 2010

• Keywords provided by , ,: THerapy for acute moderate to severe flares
• Additional relevant MeSH terms: Dermatitis, Atopic; Dermatitis; Eczema; Fluticasone; Xhance; Pimecrolimus; Tacrolimus

Study Results

Participant Flow

Recruitment Details	Medical clinics at academic centers
Pre-assignment Detail	Patients are self controls. Equivalent areas of eczema were compared

Arm/Group Title	Active Therapy	Placebo Arm
Arm/Group Description	Patients had equivalent eczema on each side of the body. One side of the body was treated with 1% pimecrolimus cream twice a day and fluticasone cream once a day. The opposite side of the body was treated with placebo cream twice a day and fluticasone cream once a day	Patients had equivalent eczema on each side of the body. One side of the body was treated with 1% pimecrolimus cream twice a day and fluticasone cream once a day. The opposite side of the body was treated with placebo cream twice a day and fluticasone cream once a day
Period Title: Active Treatment
STARTED	45	45
COMPLETED	45	45
NOT COMPLETED	0	0
Period Title: Active Treatment
STARTED	45	45
COMPLETED	45	45
NOT COMPLETED	0	0

Baseline Characteristics

Arm/Group Title	Active Therapy	Placebo Arm	Total
Arm/Group Description	Patients had equivalent eczema on each side of the body. One side of the body was treated with 1% pimecrolimus cream twice a day and fluticasone cream once a day. The opposite side of the body was treated with placebo cream twice a day and fluticasone cream once a day	Patients had equivalent eczema on each side of the body. One side of the body was treated with 1% pimecrolimus cream twice a day and fluticasone cream once a day. The opposite side of the body was treated with placebo cream twice a day and fluticasone cream once a day	Total of all reporting groups
Overall Participants	45	45	90
Age (Count of Participants)
<=18 years	22 48.9%	22 48.9%	44 48.9%
Between 18 and 65 years	23 51.1%	23 51.1%	46 51.1%
>=65 years	0 0%	0 0%	0 0%
Age (years) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [years]	16.2 (17.4)	16.2 (17.4)	16.2 (17.4)
Sex: Female, Male (Count of Participants)
Female	27 60%	27 60%	54 60%
Male	18 40%	18 40%	36 40%
Region of Enrollment (participants) [Number]
United States	45 100%	45 100%	90 100%

Outcome Measures

1. Primary Outcome

Title	Change From Baseline in the m-EASI (Eczema Area Severity Index) Score.
Description	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
Time Frame	up to 15 days

Outcome Measure Data

Analysis Population Description

Analysis was per protocol, last observation carried forward

Arm/Group Title	Active Therapy	Placebo Arm
Arm/Group Description	Patients had equivalent eczema on each side of the body. One side of the body was treated with 1% pimecrolimus cream twice a day and fluticasone cream once a day. The opposite side of the body was treated with placebo cream twice a day and fluticasone cream once a day	Patients had equivalent eczema on each side of the body. One side of the body was treated with 1% pimecrolimus cream twice a day and fluticasone cream once a day. The opposite side of the body was treated with placebo cream twice a day and fluticasone cream once a day
Measure Participants	45	45
Mean (Standard Deviation) [units of a 0-12 scale]	5.04 (2.7)	4.77 (2.4)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Active Therapy
	Comments
	Type of Statistical Test	Non-Inferiority or Equivalence
	Comments	modified EASI (eczema area severity index) was considered equivalent if p value was greater than >0.05
Statistical Test of Hypothesis	p-Value	<0.05
	Comments
	Method	t-test, 2 sided
	Comments

2. Secondary Outcome

Title	The Time to Clearance of the Disease
Description	The time to clearance of eczema measured in days
Time Frame	assessed up to 30 days following drug application

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Active Therapy	Placebo Arm
Arm/Group Description	Patients had equivalent eczema on each side of the body. One side of the body was treated with 1% pimecrolimus cream twice a day and fluticasone cream once a day. The opposite side of the body was treated with placebo cream twice a day and fluticasone cream once a day	Patients had equivalent eczema on each side of the body. One side of the body was treated with 1% pimecrolimus cream twice a day and fluticasone cream once a day. The opposite side of the body was treated with placebo cream twice a day and fluticasone cream once a day
Measure Participants	45	45
Mean (Standard Error) [days]	9.22 (4.5)	7.88 (3.88)

3. Secondary Outcome

Title	The Time to the First Day When m-EASI is Scored by the Investigator as 2 or Less
Description	Time to partial clearance of the localized eczema lesion assessed by the investigator is measured in days
Time Frame	up to one week

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title

Arm/Group Description

4. Secondary Outcome

Title	The Percentage of Target Areas Reaching a l-IGA (Localized Investigator Global Assessment (l-IGA) or 0 or 1)
Description	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
Time Frame	up to 15 days

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title

Arm/Group Description

5. Secondary Outcome

Title	The Percentage of Target Areas Improved (i.e., Decrease in Localized Investigator Global Assessmet (l-IGA) Score From Baseline)
Description	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).
Time Frame	up to 15 days

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title

Arm/Group Description

6. Secondary Outcome

Title	The Percentage of Target Areas Reaching a m-EASI (Modifed-Eczema Area Severity Index) Score of 2 or Less
Description	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
Time Frame	up to one week

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title

Arm/Group Description

7. Secondary Outcome

Title	Change From Baseline in Patients' Self Assessment of Disease Severity (PSA) of Target Areas
Description	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
Time Frame	30 days

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title

Arm/Group Description

Adverse Events

Time Frame	2 weeks
Arm/Group Title	Active Therapy		Placebo Arm
Arm/Group Description	Patients had equivalent eczema on each side of the body. One side of the body was treated with 1% pimecrolimus cream twice a day and fluticasone cream once a day. The opposite side of the body was treated with placebo cream twice a day and fluticasone cream once a day		Patients had equivalent eczema on each side of the body. One side of the body was treated with 1% pimecrolimus cream twice a day and fluticasone cream once a day. The opposite side of the body was treated with placebo cream twice a day and fluticasone cream once a day
All Cause Mortality
	Active Therapy		Placebo Arm
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	/ (NaN)		/ (NaN)
Serious Adverse Events
	Active Therapy		Placebo Arm
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	0/45 (0%)		0/45 (0%)
Other (Not Including Serious) Adverse Events
	Active Therapy		Placebo Arm
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	0/45 (0%)		0/45 (0%)

Limitations/Caveats

[Not Specified]

More Information

Certain Agreements

Principal Investigators are NOT employed by the organization sponsoring the study.

There is NOT an agreement between Principal Investigators and the Sponsor (or its agents) that restricts the PI's rights to discuss or publish trial results after the trial is completed.