NIHRDataInsights/HRCSData huggingface dataset:
Title: A randomised placebo-controlled study examining the role of anti-IgE in severe recalcitrant paediatric atopic eczema
Funder: Department of Health (England)

Abstract: Research design: A double blind randomised placebo-controlled study comparing anti-IgE to placebo in children with severe eczema.Study population: Inclusion criteria: a)6-19 years old b)Severe eczema: objective SCORAD(SCORing Atopic Dermatitis a validated eczema score>40 c)Intolerance or failure of systemic therapy d)total IgE>300kU/l e) clinical history that allergic exposures cause worsening eczema f)IgE mediated allergic disease. The exclusion criteria are: a)inability to comply with the regime b)significant underlying condition uncontrolled infection c)hypersensitivity to anti-IgE injections e)recent CTIMP Planned interventions: Therapy in the treatment arm will comprise anti-IgE (Xolair/omalizumab) injections. The placebo arm will receive matching placebo injections. Proposed outcome measures/assessment and follow up: Primary: 1. Eczema severity at 16 weeks determined by SCORAD Secondary: 1. Systemic prednisolone dosage by drug history 2. Quality of life: by questionnaire a)Patient-oriented Eczema Measure(POEM) b)Children’s Dermatology Quality of Life Index(CDLQI) 3. Eczema severity during & after therapy: by SCORAD transepidermal water loss photos 4. Coexisting allergic disease: spirometry exhaled nitric oxide measurements questionnaire(PADQLQ) 5. Side effects and safety: by blood tests for cortisol glucose and HbA1c levels urinary glucose monitoring pubertal staging growth monitoring bone density monitoring ophthalmology review and frequency of AEs reported. 6.Eczema exacerbations and infections. 7. Effect on specific IgE and skin tests. Secondary outcome measures will be assessed at baseline 2-4 weekly during treatment at the end of treatment and at the 26 36 and 48 week post treatment reviews.Proposed sample size: 62 patients 31 each in the treatment and placebo arms would enable us to detect a clinically meaningful difference of 33% relative reduction in the SCORAD(by 40% from 45 to 27 points in the treatment group and by 10% from 45 to 40.5 points in the placebo group) between the treatment arms assuming a standard deviation of 15 a significance level of 5% and 90% power and 15% drop out rate. Statistical analysis: We will use analysis of covariance to to compare the change in SCORAD in the two groups(primary outcome). The analysis of covariance or conditional logistic regression will be used to assess the effect on systemic steroid dose safety and side effects. Analyses will be conducted according to the intention to treat. Project timetables: In place : Research Ethics Committee(REC) and MHRA approvals functioning clinical trial facilities. 0-6 months: Finalising details with Novartis staff recruitment protocol publication and amendments for REC and MHRA. 6-24 months: patient recruitment and run-in. 6-30 months: patients undergoing treatment. 12-30 months: end of treatment and assessments. 12.5-36 months: post treatment reviews. 36-39 months: data analysis and draft paper.


Research activity codes: 6.1 PHARMACEUTICALS
Health categories: SKIN
Title: High-speed multi-channel 3-D Optical Coherence Tomography studies of the biomechanics of skin friction.
Funder: Engineering and Physical Sciences Research Council

Abstract: The health of the skin has profound effects on both our physical and psychological well-being. Enormous academic and commercial effort is devoted to optimising the health and appearance of skin. The barrier function of skin has been widely studied, but less well studied is its role in providing enough friction to allow us to grip and manipulate objects. Excessive friction can produce undesirable skin conditions such as chaffing and irritation in many scenarios such as wearing a respiration face mask or the skin being in contact with a damp surface. Conversely reduction of skin friction can occur in old age and compound the difficulties experienced by the older population when gripping and manipulating objects. Many potential determinants of friction have been studied, including applied load, skin deformation, skin mechanical properties and surface textures and materials, but the sub-surface behaviour and skin strain has not been investigated as rigorously. Most of these parameters have been investigated statically and although it is known that they will change when the contact is dynamic no quantitative data is available for using in computer models of skin. The aim in this work will be to develop new imaging techniques to allow sub-surface observation of how skin behaves when it is sliding against an object and what influences this the most, for example, skin moisture, applied load, sliding speed etc. The contact area between skin and object will also studied in greater detail than before as this has a major effect on friction and as yet no techniques exist for characterising this in a moving contact. The objectives of the work will initially focus on developing the equipment and techniques needed to observe the surface and sub-surface behaviour. These will then be combined with skin testing apparatus to allow the measurements of friction etc. to be taken in parallel with the sub-surface images. The information from the tests and the techniques themselves will then be applied in three practical case studies to ensure real world impact for the work. The first will involve working with Philips on studying facial masks used by sleep apnea sufferers. Test data will help improve computer models of the contact between facial skin and a mask. The second will be carried out with Unilever and focus on characterising the effects of skin creams and cleansers. The final case study will be on using the new non-invasive imaging technique in clinical studies carried out by dermatologists at The University of Sheffield to replace tape-stripping methods currently used to study skin damage.


Research activity codes: 4.1 DISCOVERY AND PRECLINICAL TESTING OF MARKERS AND TECHNOLOGIES;4.2 EVALUATION OF MARKERS AND TECHNOLOGIES
Health categories: SKIN
Title: Capillary Bed Bioreactor: Improved Estimation Of Dermal Bioavailability
Funder: Engineering and Physical Sciences Research Council

Abstract: Historically, animal testing has been used to support risk assessment for a variety of toxicological endpoints related to_x000D_ cosmetic ingredients, including the local lymph node assay (LLNA) to assess the sensitization potential and potency of a_x000D_ chemical. However, in recent years, there has been a continuous drive to reduce the level of animal testing undertaken to_x000D_ support risk assessments for new cosmetic products, and a move towards a mechanistic understanding of human_x000D_ exposure. Consequently, the development of mechanistic/biologically relevant in vitro, in chemico or in silico models for_x000D_ predicting the sensitising potential and/or potency of new chemicals is necessary to generate data leading to increased_x000D_ confidence in predictions of in vivo scenarios. The chemical and biological events driving the induction of human skin_x000D_ sensitisation are now well understood and companies such as Unilever use this information in non-animal models to test_x000D_ the safety of new compounds. Discs of ex vivo skin (from cosmetic surgery procedures) are mounted in diffusion cells and_x000D_ the permeation of a test item through the skin is monitored over time. While this has proved to be an adequate model, it_x000D_ does not truly represent living skin. At present, little is known regarding chemical clearance via dermal capillaries, and this_x000D_ is a gap in our mechanistic understanding of the bioavailability of a topically applied chemical in the elicitation of skin_x000D_ sensitisation. The proposed capillary bed bioreactor (CBB) better replicates the in vivo environment of the skin and its_x000D_ blood supply by providing a bed of pseudovascularisation in the form of hollow fibre membranes. Therefore it should more_x000D_ accurately predict permeation of chemicals through the skin, and provide data that more closely resembles that of the in_x000D_ vivo scenario. The new bioreactor will be more physiologically accurate than the current model and can therefore_x000D_ potentially refine inputs to our mechanistic models for skin sensitisation, to give us more accurate predictions of adverse_x000D_ outcomes. This in turn will give greater confidence in our ability to risk assess new ingredients in the future without the_x000D_ requirement for animal testing.


Research activity codes: 2.2 FACTORS RELATING TO PHYSICAL ENVIRONMENT
Health categories: SKIN
Title: Investigating the functions and therapeutic potential for Eph receptors and ephrins during wound repair and inflammation
Funder: Medical Research Council

Abstract: Wound healing is an evolutionary conserved process that enables all multicellular organisms to survive traumas. The repair process is generally efficient but there are many occasions when it fails or is too exuberant which leads, at one extreme, to chronic non-healing wounds or, at the other, to fibrosis and scarring. In this project we aim to investigate the role(s) of Eph receptors and their ephrin ligands in the normal process of skin wound healing and how these may be perturbed in chronic non-healing wounds and potentially modulated in order to improve tissue repair. Microarray comparison of the repair transcriptomes of PU.1 null mice, where inflammatory cells are absent, versus those of wild type sibs, reveals both inflammation-dependent and independent wound healing genes (Cooper et al, Genome Biol 2005). This study highlighted how several members of the Eph family of receptors are dramatically up and down regulated with different timecourses post wounding. These receptors, which form the largest family of tyrosine kinase receptors in the mammalian genome, are already well established as regulators of cell migration during embryonic development and cancer, but have not yet been investigated in the context of skin repair. Led by this microarray result, our subsequent PCR and immunohistochemical studies in mice confirm that several of the Ephs and their ephrin ligands might be key regulators of migration in the various wound cell lineages, with particular receptor/ligand pairings being restricted to specific cell lineages, thus offering opportunities to therapeutically modulate some cell lineages while not disturbing others. We propose a systematic survey of these receptors and their ligands, and the activity states of receptors, during the various phases of the repair response, and we will test function using tissue specific knockout mouse strategies complemented by pharmacological and cell co-culture studies. In particular, we will be looking for Eph/ephrin pairings that may drive epidermal migration and stopping/fusing, wound angiogenesis, and/or the wound inflammatory response and its fibrotic consequences. Through a recently initiated collaboration with Prof Harding, who has a wound healing clinic in Cardiff, we will also examine how the Eph/ephrin signature we see in the healthy, acute wound repair process is disrupted in patients with chronic wound healing conditions, with a view to therapeutically modulating particular Eph/ephrin signals to enhance aspects of the repair process that have gone awry in such wounds.


Research activity codes: 1.1 NORMAL BIOLOGICAL DEVELOPMENT AND FUNCTIONING;2.1 BIOLOGICAL AND ENDOGENOUS FACTORS
Health categories: SKIN
Title: Innovative gel aid for administering tablets to stroke and other dysphagic patients
Funder: Medical Research Council

Abstract: At least 110,000 people suffer a stroke each year in the UK, with an NHS cost of #2.8 billion. More than half of such patients experience swallowing difficulties which may render oral medication administration extremely difficult and unpleasant. This has also led to the dangerous practice of tablet crushing which may seriously compromise the absorption process, particularly for controlled release medications, as well as increasing risks associated with fragment aspiration and nasogastric tube blockage. We have invented a gel system into which the tablet may be inserted immediately prior to administration to aid the swallowing process. The gel is inexpensive, composed of safe components and is simple to manufacture reproducibly; our market research has established that such an intervention is desired by patients, carer groups and clinicians. A small scale trial has been performed. We request support for further developmental and early evaluation studies so as to bring the prototype to the stage of full clinical trials. We also argue that in the slightly longer term the invention may be generally applicable to patients with swallowing difficulties, particularly the elderly, and hence may prove to be an invaluable device for a significant patient population.


Research activity codes: 4.2 EVALUATION OF MARKERS AND TECHNOLOGIES
Health categories: SKIN
Title: Development of an image-based high throughput screening platform in full thickness skin
Funder: Biotechnology and Biological Sciences Research Council

Abstract: The drug discovery field has been revolutionised by the ability to perform high-throughput screening (HTS) in cell-based assays; however, the single, population-averaged readouts from monolayer cells often do not translate into tissue- or animal-based assays. We propose here to perform HTS in full thickness human skin by combining novel, state-of-the-art skin culture and imaging techniques. We have recently developed an ex vivo full thickness skin culture system capable of maintaining the physiological complexity, metabolic activity, and structural integrity of all the skin compartments (i.e. epidermis and dermis). To date, much of the development of the culture system has been performed in circular devices with a 15-18 mm diameter; however, we have shown that devices with diameters as small as 3 mm allow reproducible and consistent results up to five days when evaluated with our standard criteria (e.g., response to small molecule stimuli and wound healing). We propose to transform our explant system into a standard 384-well format to allow automated plate and liquid handling, as well as automated high content screening (HCS) confocal fluorescence imaging. To evaluate the expression of specific disease-related proteins we propose to optimise an antibody labelling and tissue clearing protocol for skin to facilitate on-plate whole-mount volumetric confocal imaging. Once the platform is in place, we propose to perform a proof-of-principle screen of ~2,000 compounds to demonstrate the capabilities of the platform.


Research activity codes: 2.5 RESEARCH DESIGN AND METHODOLOGIES (AETIOLOGY)
Health categories: SKIN
Title: Clinical, genetic and immune determinants of drug immunogenicity in psoriasis
Funder: British Skin Foundation

Abstract: Management of psoriasis has been transformed by biologics. However, 30% of patients stop these drugs due to ineffectiveness within 3 years. A major cause of loss of response to treatment is drug immunogenicity, but this is poorly understood and has been identified by the BAD (British Association of Dermatologists) as a research priority. Aim 1: Develop and validate a drug immunogenicity risk prediction score by integrating clinical and genetic determinants A case-control design within the BADBIR (BAD Biologics Intervention Register) Bioresource will compare 800 patients with detectable anti-drug antibodies (ADA) to 1200 patients with undetectable ADA, taking first-line anti-TNF inhibitor adalimumab as the exemplar drug. Impact of clinical variables on drug immunogenicity will be modelled, and genetic variables will be identified via a genome-wide association study with human leukocyte antigen imputation. Clinical and genetic variables will be integrated into a risk prediction score. This will be validated in psoriasis, then tested in patients on a different biologic (ustekinumab), and in rheumatoid arthritis (RA)/inflammatory bowel disease (IBD). Aim 2: Investigate early B cell mechanisms underlying development of drug immunogenicity by using a tailored immune marker panel Mass cytometry (CyTOF) will be used to study immune phenotypes pre- and post-biologic initiation, in patients with detectable ADA compared to those with undetectable ADA. Standard flow cytometry will be used to replicate resulting candidate markers before testing them in RA and IBD. Identifying psoriasis patients at increased risk of drug immunogenicity would allow us to take steps to minimize this risk, thus reducing loss of response to treatment. This may have wide applicability to diverse conditions treated with biologics. Fundamentally, we may uncover mechanistic insights into the development of drug immunogenicity, as well as predictors of antibody responses in humans per se.


Research activity codes: 5.1 PHARMACEUTICALS
Health categories: SKIN
Title: A brief school-based intervention to reduce sunburn in adolescence: A feasibility study
Funder: Chief Scientist Office, Scotland

Abstract: The sun can be harmful. If children/adolescents get sunburnt five or more times, they are twice as likely to get skin cancer as an adult. The sun can also be beneficial. It is a source of vitamin D which is essential for healthy bones. In this study, 15/16 year olds will have a lesson on sun safety, home-based exercises and receive text messages over the summer holidays to encourage safer behaviour. We will measure skin colour on their forearms before and after the summer holiday to see if they got sunburnt and ask them about sun protection behaviours.


Research activity codes: 3.1 PRIMARY PREVENTION INTERVENTIONS TO MODIFY BEHAVIOURS OR PROMOTE WELL-BEING
Health categories: SKIN
Title: Evaluation of the early efficacy of intravenously administered allogeneic mesenchymal stromal cells on itching in adults with Epidermolysis Bullosa Pruriginosa
Funder: DEBRA

Abstract: We have previously undertaken clinical trials (EBSTEM and ADSTEM) of intravenous allogeneic mesenchymal stromal cells (MSCs) in children and adults with recessive dystrophic epidermolysis bullosa (RDEB). In those studies we noted that, in most subjects, the MSCs had a positive impact in reducing itch, with improvements persisting for several months post-MSCs. Itch is a major symptom for many people living with EB, none more so than those individuals with the itchy variant of dystrophic EB known as EB pruriginosa (EBP). The cause of the itch in EBP is unknown and current treatments are not particularly effective. This clinical trial will evaluate whether intravenous allogeneic MSCs can also benefit people with EBP. We plan to undertake a phase II clinical trial in which three intravenous injections of allogeneic MSCs (1-2 x 106 cells/kg for each infusion) are given at day 0, week 4 and week 8. We will then evaluate whether the symptoms of itch change pre- and post-MSCs using the Leuven Itch Scale (LIS; previously validated for use in EB), which assesses itch across six different categories; duration, frequency, intensity, distress, consequences and body surface area. Skin biopsies and blood samples will also be studied for changes in gene, protein and cytokine expression to assess how MSCs may lead to a reduction in itch. The goal is to improve understanding about (a) what causes itch in EBP, (b) whether systemic administration of allogeneic MSCs is helpful therapeutically for EBP and, (c) how do those MSCs work in reducing pruritus in EBP.


Research activity codes: 6.2 CELLULAR AND GENE THERAPIES
Health categories: SKIN
Title: Natural History and Clinical Endpoints Study in EB
Funder: DEBRA

Abstract: Our proposed study will start by examining what has already been published on the natural history of EB and the complications (skin and other organs) that can occur, focussing on recessive dystrophic EB (RDEB). In the second and major part of the study, we will examine and record data on a large series of RDEB patients (approximately 120) who are seen at the adult and paediatric EB centres in London. This data will provide insight into the natural course of RDEB over time, and also identify which clinical features are meaningful as endpoints for clinical trials of new EB therapies.


Research activity codes: 2.4 SURVEILLANCE AND DISTRIBUTION
Health categories: SKIN
Title: MRC/UCB ADI 2018
Funder: Medical Research Council

Abstract: CD1a is highly expressed by Langerhans cells of the skin, and presents lipid antigens to T cells. We have recently shown that such lipid-specific CD1a-reactive T cells contribute to skin inflammation in the settings of allergy, atopic dermatitis and psoriasis (Bourgeois et al J Exp Med 2015; Cheung et al J Exp Med 2016; Jarrett et al Science TM 2016); and it is likely that CD1a is involved in inflammation in other skin diseases. Recently, it has been shown in a transgenic model that anti-CD1a therapy can reduce both dermatitis and psoriasiform inflammation, providing evidence that targeting this pathway may offer therapeutic benefit. Given the highly localised expression of CD1a in the skin, this potential approach is likely to be associated with minimal systemic risks. The aim of the proposal is to develop anti-CD1a antibodies for future therapeutic use, and accompanying patient stratification. We have produced highly purified recombinant CD1a, which can be used for immunisation, and have control antigens of CD1b and CD1c for subsequent specificity analysis. We have primary and immortal cell lines expressing native CD1a, together with relevant controls. We will test the efficacy and specificity of developed antibodies in our existing functional T cell assays using samples from blood and skin of patients with disease and controls. Furthermore, we have significant experience of early clinical trials for novel therapeutics for inflammatory skin disease, and so have access to relevant patient populations should translation progress. In summary, there is considerable evidence that CD1a represents a novel therapeutic target for different forms of inflammatory skin disease, and there are locally established reagents and downstream functional assays and patient samples with which to define early go/no-go signals.


Research activity codes: 5.1 PHARMACEUTICALS
Health categories: SKIN