An Explorative Psoriasis Biomarker Study

Study Overview
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Brief Summary
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Plaque psoriasis may be an ideal model disease to explore potential therapeutic effects of immunosuppressive agents, given the easy accessibility of inflammatory lesions. In this study, the applicability of a systems dermatology approach is investigated in order to better assess the efficacy of psoriasis treatments at an early clinical stage. Up to this point, the clinical manifestation and regression of psoriasis is not yet sufficiently characterized with a multimodal state-of-the-art evaluation tool. The in-house developed 'DermaToolbox' enables the determination and subsequent integration of different diseaserelated biomarkers, including clinical, biophysical, molecular, cellular, and imaging markers as well as patient reported outcomes

Detailed Description
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Psoriasis is a common skin disorder affecting up to an estimated 3% of the world's population. The most prevalent form of psoriasis, called psoriasis vulgaris or plaque psoriasis, is characterized by the presence of sharply demarcated erythematous plaques covered with white scales. These lesions can occur all over the body, but are most often seen on the extensor surface of the joints, nether regions and on the scalp. Patients can experience excessive itch, pain and sometimes bleeding of the lesions. Moreover, the visual appearance of psoriatic lesions can severely impact the patients psychological state and quality of life. An abundancy of different factors contributes to the pathogenesis of psoriasis. However, aberrant inflammatory reactions in the skin are thought to be the underlying cause. Excessive infiltration of immune cells in the skin and their interactions with cutaneous resident cells results in the hyper proliferation of keratinocytes and subsequent thickening of the epidermis. Indeed, more and more immunosuppressive biologicals targeting specific components of the immune system, like tumor necrosis factor alpha (TNFα), interleukin (IL-)17 and IL-23, have shown excellent efficacy in treating psoriasis Plaque psoriasis may be an ideal model disease to explore potential therapeutic effects of immunosuppressive agents, given the easy accessibility of inflammatory lesions and the good willingness of patients to participate in clinical studies. In this study, the applicability of a systems dermatology approach is investigated in order to better assess the efficacy of psoriasis treatments at an early clinical stage. Up to this point, the clinical manifestation and regression of psoriasis is not yet sufficiently characterized with a multimodal state-of-the-art evaluation tool. The in-house developed 'DermaToolbox' enables the determination and subsequent integration of different disease-related biomarkers, including clinical, biophysical, molecular, cellular, and imaging markers as well as patient-reported outcomes

Official Title
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An Exploratory, Single-center, Double-blinded, Healthy Volunteer Controlled Study to Characterize Psoriasis Patients and Explore Novel Biomarkers for the Treatment Response of Psoriasis With a Multimodal Patient Profiling Approach.

Conditions
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Psoriasis Vulgaris

Intervention / Treatment
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* Drug: Guselkumab
* Drug: Placebos


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria Healthy volunteers Eligible healthy volunteers must meet all of the following inclusion criteria at screening: Male or non-pregnant female subjects, 18 to 75 years of age (inclusive); Healthy as defined by the absence of any uncontrolled active or uncontrolled chronic disease following a medical and surgical history, documentation of general symptoms, and a symptom-directed physical examination including vital signs; Willing to give written informed consent and willing and able to comply with the study protocol; Psoriasis patients Eligible psoriasis patients must meet all of the following inclusion criteria at screening: Male or non-pregnant female subjects, 18 to 75 years of age (inclusive); Diagnosed with plaque psoriasis at least 6 months prior to study participation Willing to discontinue any psoriasis therapy other than emollients. Having mild (PASI ≥1 and ≤ 5) or moderate-to-severe (PASI ≥ 10) plaque psoriasis; Currently not using psoriasis medication and ≥ 2 plaques suitable for repeated biopsies and target lesion assessments. At least one of these lesions must be located on the extremities, preferably on the elbow or knee, with a minimal target lesion score between 6 and 9. Or, when currently using psoriasis medication and insufficient lesional skin is present, willing to discontinue treatment awaiting rescreening (see also exclusion criteria 3 for psoriatic patients); Willing to give written informed consent and willing and able to comply with the study protocol; Exclusion Criteria Eligible healthy volunteers must meet none of the following exclusion criteria at screening: History or symptoms of any uncontrolled, significant disease including (but not limited to), neurological, psychiatric, endocrine, cardiovascular, respiratory, gastrointestinal, hepatic, or renal disorder that may interfere with the study objectives, in the opinion of the Investigator; History of immunological abnormality (e.g., immune suppression, severe allergy or anaphylaxis) that may interfere with study objectives, in the opinion of the Investigator; Known infection requiring antibiotic therapy within the last three months prior to the study; Immunosuppressive or immunomodulatory treatment within 30 days prior to the study; Body mass index (BMI) ≤ 18.0 or ≥ 40.0 kg/m2; Participation in an investigational drug study within 3 months prior to screening or more than 4 times a year; Previous participation in an investigational drug study involving the dosing of an investigational compound targeting an immune pathway within one year prior to screening; Loss or donation of blood over 500 mL within three months prior to screening; The use of any medication or vitamin/mineral/herbal/dietary supplement within less than 5 half-lives prior to study participation, if the Investigator judges that it may interfere with the study objectives. The use of paracetamol (up to 4 g/day) is allowed; History of alcohol consumption exceeding 5 standard drinks per day on average within 3 months of screening. Alcohol consumption will be prohibited from at least 12 hours preceding each study visit; Any other condition that could interfere with the conduct of the study or the study objectives, in the opinion of the Investigator. Psoriasis patients Eligible psoriasis patients must meet none of the following exclusion criteria at screening: Having primarily erythrodermic, pustular or guttate psoriasis; Having medication-induced psoriasis; Having previously failed on anti-IL23 therapy; Having received treatments for psoriasis within the following intervals prior to the start of the study: < 2 weeks for topical treatment, e.g. retinoids, corticosteroids, vitamin D analogs < 4 weeks for phototherapy, e.g. PUVA, PDT < 4 weeks for non-biologic systemic treatment, e.g. retinoids, methotrexate, cyclosporine, fumaric acid esters < 4 weeks for etanercept < 8 weeks for adalimumab < 3 months for anti-IL17, anti-IL12(/23) and anti-IL23 treatments History or symptoms of any significant uncontrolled disease including (but not limited to), neurological, psychiatric, endocrine, cardiovascular, respiratory, gastrointestinal, hepatic, or renal disorder that may interfere with the study objectives, in the opinion of the Investigator, excluding psoriasis and conditions that are related to psoriasis; History of immunological abnormality (e.g., immune suppression, severe allergy or anaphylaxis) that may interfere with study objectives, in the opinion of the Investigator; Known infection requiring antibiotic therapy within the last 3 months prior to the study, including latent tuberculosis; Systemic immunosuppressive or immunomodulatory treatment within 30 days prior to the study; Body mass index (BMI) ≤ 18.0 or ≥ 40.0 kg/m2; Participation in an investigational drug study within 3 months prior to screening or more than 4 times a year; Loss or donation of blood over 500 mL within three months prior to screening; The use of any medication or vitamin/mineral/herbal/dietary supplement within less than 5 half-lives prior to study participation, if the Investigator judges that it may interfere with the study objectives. The use of paracetamol (up to 4 g/day) is allowed; History of alcohol consumption exceeding 5 standard drinks per day on average within 3 months of screening. Alcohol consumption will be prohibited from at least 12 hours preceding each study visit; Any other condition that could interfere with the conduct of the study or the study objectives, in the opinion of the Investigator.

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: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Interventional Model Description: This is an observational and interventional study in up to 40 patients with chronic plaque psoriasis and 10 healthy volunteers (observational only).
Masking: Triple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Guselkumab<br>Guselkumab 100 mg/ml in prefilled syringe, subcutaneous injection, administered on day 0, 28 and 84. | Drug: Guselkumab<br>* 100 mg guselkumab administered subcutaneously<br>|
| Placebo Comparator: Placebo<br>Sodiumchloride 0,9% solution for injection, subcutaneous injection, administered on day 0, 28 and 84. | Drug: Placebos<br>* Sodiumchloride 0,9% solution for injection<br>|
| No Intervention: Healthy volunteers<br>Healthy volunteer cohort (observational) | |

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Psoriasis Area and Severity Index (PASI) Assessment | Psoriasis Area and Severity Index (PASI) combines the assessment of the severity of lesions and the area affected into a single score in the range 0 (no disease) to 72 (maximal disease). | from day -14 to day 168 | 
| Physicians Global Assesment (PGA) Assessment | Physicians Global Assesment (PGA) is a 4-point scale ranging from 0 (no disease) to 4 (maximal disease). | from day -14 to day 168 | 
| Percentage body surface affected (%BSA) Assessment | Percentage body surface affected (%BSA) is the area of lesional skin as a percentage of the total body surface | from day -14 to day 168 | 
| digital PASI | Digital Psoriasis Area and Severity Index (dPASI) calculated from standardized total body photography | from day -14 to day 168 | 
| Erythema measurement of the skin | Redness of the skin will be determined using a colorimeter | from day -14 to day 168 | 
| Multispectral imaging | The redness and superficial morphology of (non-)lesional skin sites will be determined using a multispectral imaging system | from day -14 to day 168 | 
| Laser Speckle Contrast imaging | The cutaneous microcirculation of (non-)lesional skin sites will be monitored over a 30 second timespan with a laser speckle contrast imager | from day -14 to day 168 | 
| Thermography | Body surface temperature of (non-)lesional skin will be determined using a thermal imaging infrared camera | from day -14 to day 168 | 
| Patient reported outcomes | Patients will be asked to report on their condition through an NRS scale (0 (better)- 10 (worse)) for sleeplessness, itch and quality of life. Additionally, patients image their lesions on a daily basis using a mobile device. | from day -14 to day 168 | 
| Activity Tracking Heartrate | Subjects are requested to wear a smartwatch at all times which heart rate (beats per minute) | from day -14 to day 168 | 
| Activity Tracking Steps | Subjects are requested to wear a smartwatch at all times which register steps (amount of steps taken) | from day -14 to day 168 | 
| Activity Tracking Sleep | Subjects are requested to wear a smartwatch at all times which register sleep (hrs, minutes, seconds of rest) | from day -14 to day 168 | 
| Cells/ml; Circulating immune cell subsets | Blood be drawn during using a venipuncture during visits and analyzed for the presence of immune cells (e.g. CD4+ and CD8+ T-Cells) using flow cytometry | from day -14 to day 168 | 
| Circulating protein biomarkers | Blood be drawn during using a venipuncture during visits and analyzed for the presence of various chemokines and cytokines (e.g. CCL20, CCL17, CXCL8) | from day -14 to day 168 | 
| Anti-drug antibodies | The occurrence of antibodies directed against guselkumab will be monitored during the treatment period (ng/ml) | from day 0 to day 168 | 
| Blister immune cell subsets | Blisters will be induced on the non-lesional skin and the blister exudate aspirated. Blister exudate will be analyzed for the presence of immune cells (e.g. CD4+ and CD8+ T-Cells) using flow cytometry | from day 0 to day 112 | 
| Blister protein biomarkers | Blisters will be induced on the non-lesional skin and blister fluid aspirated. Blister fluid will be analyzed for the presence of various chemokines and cytokines (e.g. CCL20, CCL17, CXCL8) (ng/ml) | from day 0 to day 112 | 
| Immunohistochemistry of biopsies | Biopsies will be sectioned and stained for the determination of the epidermal homeostasis (proliferation, differentiation and thickness) and infiltration of cellular immune subsets (e.g. presence of CD4 and CD8). | day 0 to day 112 | 
| Transcriptome of biopsies | Biopsies will be analyzed with an untargeted next-generation sequencing approach. | day 0 to day 112 | 
| Cutaneous microbiome | The microbiome is collected by swabbing. The abundance of bacteria is thereafter determined using next-generation sequencing. | from day -14 to day 112 | 
| Fecal microbiome | The bacterial composition of stool samples is determined using next-generation sequencing. | from day 0 to day 112 | 
| Skin surface biomarkers | Superficial protein biomarkers are samples using a FibroTx Patch. Afterwards, these patches are extracted and the presence of protein biomarkers (e.g. HBD-3) determined using ELISA. | from day -14 to day 112 | 
| Lipidomics of the stratum corneum | Tape stripping will be performed on (non-)lesional skin and lipids are subsequently extracted from the tape and analyzed using Liquid Chromatogrpahy-Mass Spectormetry. (ng/cm2) | from day -14 to day 112 | 
| Skin barrier function | The trans epidermal water loss of (non-)lesional skin will be determined as function of the inside-out barrier function of the skin. (g/m2/h) | from day -14 to day 168 | 
| Patient genotyping | A whole blood sample will be used to scan for common mutations in genes implicated in psoriasis using next-generation sequencing. | day -14 | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Psoriasis, Biomarker, Guselkumab