Deep Phenotyping of CIndU

The objective of this study is to deep phenotype CIndU (subtype SD and ColdU) and detect novel biomarkers for diagnosis andtreatment response as well as establish methodologies for (non-) invasive monitoring of treatment effects in chronic inducible urticaria.

For this purpose, a study with a multi-modal approach will be performed for in-depth characterization of SD and ColdU. The study willconsist of 2 parts: in part A the biology of disease will be investigated, and in part B the response of the biomarkers to real-world treatment with omalizumab will be monitored (part B). The former to characterize objectively measured disease characteristics and mechanisms underlying its development, the latter to monitor response of the disease and its characteristics to standard of care treatment once in four weeks. The study focusses on cellular, molecular, biophysical, imaging and microbiome analyses in comparisonwith chronic spontaneous urticaria (CSU) patients and matched healthy volunteers.

Inclusion criteria

Healthy volunteers

• Male and female subjects between 18-69 years of age; in general, stable good health as per judgement of the investigator based upon the results of a medical history, physical examination and vital signs.
• No clinically significant skin disease in the research area
• No history of hypertrophic scarring or keloid.
• Willing to give written informed consent and willing and able to comply with the study protocol.
• Negative TempTest and FricTest at screening.
• Participant is willing to refrain from extensively washing (including bathing, swimming, showering and excessive sweating) the skin 12 hours before study visit 1.

Eligible patients:

• Male and female subjects aged ≥18 years
• Diagnosis of SD, ColdU or CSU (moderate to severe according to international guidelines (Zuberbier et al, 2022)) for ≥3 months and symptomatic disease despite treatment with H1 antihistamines (up to fourfold the approved dose).
• Patients currently on an antihistamine (up to fourfold the approved dose) must be on a stable dose for at least 2 weeks prior to day 1 and must maintain the same stable dose throughout the treatment period. Patients are according to the stepped care model eligible to start treatment with omalizumab
• Willing to give written informed consent and willing and able to comply with the study protocol.
• Positive provocation test:

• For ColdU patients: developing a wheal at the test site within 10 min after using TempTest® at any temperature at both screening and Baseline. Alternatively, patients with a negative TempTest® may also be included if they have a positive ice cube test;
• For SD patients: developing a wheal at the test site within 10 min after using FricTest® with ≥ 3mm at both screening and Baseline.
• For CSU patients: negative TempTest® and FricTest® at screening
• Participant is willing to refrain from extensively washing (including bathing, swimming, showering and excessive sweating) the skin 12 hours prior to Day 1 and EOS.
• Female participants of reproductive potential must agree to use contraception from screening until EOS.

Exclusion criteria

• Significant, uncontrolled or unstable disease in any organ system as per judgment of the investigator (regardless of association with the immunosuppressing disorder/therapy), including but not limited to: psychiatric, neurologic, cardiovascular, pulmonary, gastrointestinal, hepatic, renal, endocrine, hematologic or respiratory disease.
• History of immunological abnormality (e.g., immune suppression) that may interfere with study objectives, in the opinion of the investigator.
• Loss or donation of blood over 500 mL within three months prior to screening.
• Positive hepatitis B surface antigen (HbsAg), hepatitis C antibody (HCV ab), or human immunodeficiency virus antibody (HIB ab) at screening
• Known infection requiring (topical or oral) antibiotic therapy within 56 days prior to Day 1.
• The use of systemic antibiotic therapy for >2 months the past 12 months.
• The use of any oral/systemic medication (e.g. immunomodulatory, immunosuppressive) within 28 days prior to Day 1, if the investigator judges that it may interfere with the study objectives.
• Treatment with omalizumab within 5 half lives (120 days) prior to Day 1
• Pregnant, a positive pregnancy test, intending to become pregnant, or breastfeeding.
• Have any current and/or recurrent clinically significant or subject reported skin condition other than the CInDU/CSU wherefore subject is included in the study.
• Evidence of current drug or alcohol abuse.
• History of regular alcohol consumption within 12 months of the trial defined as an average weekly intake of >21 alcoholic drinks/week for men or >14 alcoholic drinks/week for women (i.e., 1 drink is equivalent to 150 mL of wine or 360 mL of beer or 45 mL of hard liquor)

Healthy volunteers

• Participation in an investigational drug study within 3 months prior to screening or more than 4 times a year.

Eligible patients

• For CIndU patients: active CSU or other forms of CIndU besides ColdU or SD that may interfere with study assessments. For CSU patients: presence of active CIndU disease that may interfere with study assessments.
• Urticarial or angioedema symptoms such as urticarial vasculitis, erythema multiforme, cutaneous mastocytosis (urticaria pigmentosa) and hereditary or acquired angioedema (eg, due to C1 inhibitor deficiency).
• Active, pruritic skin condition in addition to CIndU (CIndU patients) or CSU (CSU patients).
• Routine doses of the following medications within 30 days prior to Day 1: Systemic or cutaneous (topical) corticosteroids (prescription or over the counter), hydroxychloroquine, methotrexate, cyclosporine, or cyclophosphamide.
• Intravenous (IV) immunoglobulin G (IVIG), or plasmapheresis within 30 days prior to screening.
• Regular (daily/every other day) doxepin (oral) use within 6 weeks prior to Day 1.
• Any H2 antihistamine use within 7 days prior to Day 1.
• Any leukotriene receptor antagonist (LTRA) (montelukast or zafirlukast) within 7 days prior to Day 1.
• Patients with current malignancy, history of malignancy, or currently under work-up for suspected malignancy except non-melanoma skin cancer that has been treated or excised and is considered resolved.
• Hypersensitivity to omalizumab or any component of the formulation.
• History of anaphylactic shock.
• Evidence of parasitic infection.