Physiological Study to Determine the Allergic Skin Activity After Different Skin Preparation
Condition: Birch Pollen Allergy
MeSH terms: Rhinitis, Allergic, Seasonal
Study type: Interventional
Phase: Phase 1

Summary: 
      The objectives of this monocentric investigator initiated exploratory clinical trial is to
      optimize allergen delivery across the epidermal barrier. The cornified outer epidermal layers
      represent the main barrier towards entry into the viable epidermal layers. In the latter we
      aim to target the allergen for uptake by professional antigen presenting cells, called
      Langerhans cells. At the same time as little allergen as possible should be delivered to the
      dermis. The latter contains a high density of sensitized mast cells eliciting local reactions
      and also a high density of blood vessels which could lead to systemic distribution of
      allergen and therefore to systemic allergic reactions.

      In birch pollen allergic individuals we will compare different methods of preparing the skin
      before application of the allergen. We will subsequently apply titrated allergen doses to the
      prepared skin areas to determine at which dose we start observing mast cell degranulation
      manifesting as hives.

      This will allow for determination of the maximal tolerated allergen dose for each skin
      preparation method.

      The skin preparation methods compared will be:

        -  Single pricking with prick lancet (Entaco LTD., Redditch, Worcestershire, UK,
           distributed by Stallergenes®).

        -  Tape stripping with conventional adhesive Tape (Tesa-film®).

        -  Microchanneling with Micro Needle Patch (Micro Skin System, 3M®). The methods are
           strongly connected to routine diagnostics of allergies with low risk associated.

      The clinical trial protocol has been submitted to the local Ethics Committee.

      This comparison of skin preparation methods and the determination of the maximal tolerated
      allergen dose will help us to further improve epicutaneous allergen immunotherapy, which has
      the potential to make allergen specific immunotherapy not only considerably shorter and
      safer, but also more convenient for patients. Skin preparation by microneedle patches is
      significantly less painful than conventional injection and can be self administered. This
      should help improve the acceptance of allergen specific immunotherapy, as well as treatment
      compliance.
    

Detailed description: 
      BACKGROUND INFORMATION The prevalence of allergic diseases has been continuously increasing,
      reaching a prevalence of up to 30% in industrialized countries. In Switzerland, about 2
      million people are affected by IgE-mediated allergies as reported by the Swiss Center for
      Allergy, Skin and Asthma and the Swiss Society for Allergology and Immunology (SSAI). By
      subcutaneous injections of gradually increasing allergen doses, conventional subcutaneous SIT
      (SCIT) is found to reduce the inappropriate T-helper (Th) 2 responses and IgE production. Due
      to the risk of systemic allergic side effects, the typical therapy duration of 3-5 years and
      the requirement of 50-80 injections, patient acceptance of SCIT is low and less than 5% of
      allergy patients choose to undergo SCIT. A recently rediscovered route of allergen
      administration is via the epidermis in a procedure called epicutaneous immunotherapy (EPIT).

      The skin is an attractive administration route for immunotherapy being both easily accessible
      as well as playing an important role in the immune system consisting of keratinocytes,
      Langerhans cells (LC), dermal dendritic cells (DC). A major challenge in EPIT is to overcome
      the physiological barrier function of the skin. In order to deliver the allergen to the
      immunological effector cells in the skin, the allergen must be transported through the
      outermost keratinized layer of the epidermis, called the stratum corneum. The stratum corneum
      is 10-20μm thick and impermeable for molecules greater than 500 Da. Proteins, such as
      allergens, do not passively permeate across the skin and therefore enhancement strategies are
      needed to enable this transfer. Advances in microtechnology might contribute to improve the
      situation by allowing for the miniaturization of mechanics and structures. As the stratum
      corneum is only 10-20μm thick, it has been proposed by Henry et al., that microneedles as
      small as a few tens to a few hundreds of microns, could be used to penetrate the stratum
      corneum.

      Such new methods of overcoming the skin barrier raise the question of the influence of
      different types of skin injury patterns on the allergic skin reactivity. Namely, how
      important is the role of the exposed area (microneedles), the depth of injury (skin pricking)
      and the keratinocyte activation. This physiological question is in the focus of this study.

      PRODUCTS In order to investigate the physiological reactions concerning different skin
      conditions and allergen exposition the following products/techniques have been chosen for the
      purpose of inducing different skin conditions in a reproducible way.

      Prick lancet:

      For the pricking skin preparation, sterile prick lancets for 1mm point skin testing will be
      used: prick lancet, produced by Entaco LTD., Redditch, Worcestershire, UK and distributed by
      Stallergenes®. They are used for allergy diagnostics in daily routine.

      Adhesive tape:

      For the tape stripping skin preparation a conventional tape will be used (Tesafilm®).

      Microneedle array:

      To induce a large number of microchannels with a maximal depth of 150μm into the cornea
      layer,the solid Microstructured Transdermal System (sMTS) by 3M® will be used. This system is
      a small patch of 351 tiny needles, which is on the market in the US and is intended for
      preparing the skin for transdermal application of topical dermatology products.

      Epicutaneous allergen solution:

      For the epicutaneous administration four ten-fold serial dilutions (10 HEP, 1 HEP, 0.1 HEP
      and 0.01HEP/ml) of registered allergen extracts of birch pollen (Betula verrucosa)
      (Soluprick®, ALK-Abelló A/S, Hørsholm, Denmark) will be used as in everyday allergy
      diagnostic practice. Histamine as positive control will be used at 10 mg/ml and a solution
      containing only the excipients will serve as negative control.

      This is an open-label physiological investigation of the allergic skin reactivity to
      epicutaneous allergen exposition in allergic patients comparing different methods of skin
      preparation. The focus of the study is on the skin preparation and not on the specific
      allergen or allergy, but for reasons of homogeneity a single allergic disease, birch pollen
      allergy was chosen as the basis for the testing. In order to evaluate the effects of the
      different skin preparation techniques an intra-individual comparison of the skin reactivity
      in terms of the immediate phase I reaction to serial dilutions of birch pollen extracts was
      chosen. The serial dilution approach allows a dose dependent effect evaluation and
      determination of the mean allergen concentration yielding similar skin reactions - thus
      differences will be explained mainly by the different skin preparation allowing a
      quantitative comparison of these techniques.

      HYPOTHESIS We will determine which of the three different skin preparation techniques uses
      higher protein concentration of allergen preparation (Ch10) eliciting a wheal area of the
      same size as histamine 10 mg/ml will be calculated.

      The Null hypothesis therefore would be:

      Ch10 is not significantly different between the three skin preparation techniques.
    

Intervention name(s): prick lancet; Tape stripping; Microneedle
Intervention type(s): Other; Other; Other
Intervention description(s): For the pricking skin preparation, sterile prick lancets for 1mm point skin testing will be used. They are used for allergy diagnostics in daily routine.; For the tape stripping in the skin preparation test conventional self adhesive tape by Tesafilm® is used.; To induce a large number of microchannels with a maximal depth of 150µm into the cornea layer a small patch of 351 tiny needles is used, which is on the market in the US and is intended for preparing the skin for transdermal application of topical dermatology products.
Other intervention name(s): Prick Lancet; Worcestershire, UK; distr. by Stallergenes®.; Tesafilm; solid Microstructured Transdermal System (sMTS) by 3M®
Intervention model: Single Group Assignment
Masking: None (Open Label)
Primary purpose: Treatment