Short Repeated Nickel Exposures

Study Overview
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Brief Summary
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The former Nickel Directive was introduced in EU in 1994 limiting the release of nickel from items intended for prolonged contact with skin. The nickel regulation entered into full force in 2001 and became a part of REACH (the EU chemicals regulation) in 2009. Since then the prevalence of nickel allergy has declined in some countries, but not in others, following the implementation. Young individuals still become allergic to nickel (2, 3) and a high prevalence of nickel allergy, exceeding 10%, is seen among young women (below 30 years) in the general population. The EU nickel regulation has been changing over time. The present limits of nickel release for metallic items intended for direct and prolonged contact with the skin is <0.5 μg/cm2/week and <0.2 μg/cm2/week for any post assemblies inserted into pierced holes. In 2014, EU defined prolonged contact with the skin as: at least 30 minutes on one or more occasions within two weeks for items with continuous skin contact, or to at least 10 minutes on three or more occasions within two weeks (7). The overall objective is to evaluate how well the EU nickel regulation protects individuals against developing nickel dermatitis. More specifically we will: Study the penetration of nickel in normal and irritated skin after short repeated skin exposure under controlled temperature in nickel sensitized patients and in healthy controls Reveal the potential of short repeated nickel skin exposure on normal and irritated skin to elicit dermatitis, during controlled climate factors in nickel sensitized patients and controls using the time restrictions of the definition of prolonged skin contact in the nickel regulation.

Official Title
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Evaluation of the Clinical Implication of Short Repeated Nickel Exposures

Conditions
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Allergic Contact Dermatitis Due to Nickel

Intervention / Treatment
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* Other: Experimental stimulation with nickel discs


Participation Criteria
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Eligibility Criteria
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For patients with nickel allergy: Inclusion Criteria: Positive patch test to nickel sulphate 5% pet. according to European society of contact dermatitis(ESCD) guidelines within the last 5 years at the Department of Dermatology and Allergy, Gentofte Hospital. Age 18-75 years. Exclusion Criteria: Active eczema in test areas Generalized eczema Scar tissue in test areas. Pregnancy or breast feeding Treatment with topical corticosteroids or other immune-suppressants on/near test areas within four weeks prior to study start Systemic immunomodulatory* treatment within 4 weeks prior to study start UV exposure of test areas within three weeks prior to study start Participation in other clinical studies within four weeks prior to study start Unable to cooperate or communicate with the investigators *Systemic immunomodulatory treatment is drugs taken orally or by injection that modify the response of the immune system by increasing (immunostimulators) or decreasing (immunosuppressives) the production of serum antibodies For Healthy volunteers: Inclusion Criteria: Negative patch test result to nickel sulphate 5% pet. according to ESCD guidelines (48) at the Department of Dermatology and Allergy, Gentofte Hospital Age 18-75 years. Exclusion Criteria: History of contact allergy Generalized eczema Scar tissue in test areas. Pregnancy or breast feeding Treatment with topical corticosteroids or other immune-suppressants on/near test areas within four weeks prior to study start Systemic immunomodulatory treatment within four weeks prior to study start UV exposure of test areas within three weeks prior to study start Participation in other clinical studies within four weeks prior to study start Unable to cooperate or communicate with the investigators

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 75 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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Accepts Healthy Volunteers

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Prevention
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Patients with nickel allergy<br>Experimental stimulation with nickel discs | Other: Experimental stimulation with nickel discs<br>* All participants will be exposed to 8 metal discs, 3 cm in diameter, 4 on each arm, placed on the volar side of the forearms (figure 1). Three of the metallic discs consists of >99 wt.% nickel one consist of >99wt.% Aluminium.The latter is used as a negative control. The discs will be applied under occlusion and with initial pressure and friction. One metallic disc with nickel, and one with aluminium, will be randomized for the earlobes on the patients with nickel allergy<br>|
| Experimental: Persons without nickel allergy<br>Experimental stimulation with nickel discs | Other: Experimental stimulation with nickel discs<br>* All participants will be exposed to 8 metal discs, 3 cm in diameter, 4 on each arm, placed on the volar side of the forearms (figure 1). Three of the metallic discs consists of >99 wt.% nickel one consist of >99wt.% Aluminium.The latter is used as a negative control. The discs will be applied under occlusion and with initial pressure and friction. One metallic disc with nickel, and one with aluminium, will be randomized for the earlobes on the patients with nickel allergy<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Clinical evaluation of development of dermatitis after stimulation over time | Development of dermatitis after stimulation with nickel discs as a change from baseline skin assessment. The criteria developed by the International Contact Dermatitis Research Group (ICDRG), later modified by Hindsén and Bruze will be used for assessment | 24 hours and 78 hours post stimulation with nickel discs | 
| Change of baseline blood flow over time after stimulation | measure blood flow with laser doppler technique as a surrogate for inflammation on skin following stimulation with nickel discs over time | 24 hours and 78 hours post stimulation with nickel discs | 
| Nickel skin penetration at different time points after stimulation | by using the tape stripping technique we will measure the deposition of nickel and the penetration of nickel in the stratum corneum following stimulation | Immediate deposition and penetration, 24 hours and 78 hours post stimulation of nickel discs |