The objective of this study is to deep phenotype CIndU (subtype SD and ColdU) and detect novel biomarkers for diagnosis and treatment response as well as establish methodologies for (non-) invasive monitoring of treatment effects in chronic…
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Source
Brief title
Condition
- Angioedema and urticaria
Synonym
Research involving
Sponsors and support
Intervention
Outcome measures
Primary outcome
Primary endpoints for the primary objectives:
• Blood-based biomarkers (including but not limited to abs. eosinophil counts,
abs. basophil counts, C-reactive protein, total serum IgE, D-dimer, complement
assessement, basophil activation test , IgG-anti-Fc*RI, cytokine profile
assessment)
• Skin punch biopsies:
o Histology
o Spatial metabolomics
o Tissue CyTOF
o Transcriptomics
Secondary outcome
• To evaluate biomarkers for disease-monitoring during standard of care
treatment with omalizumab and at follow-up;
• To evaluate the response of the biomarkers and disease characteristics to
standard of care treatment with omalizumab.
• To explore the variability of the selected biomarkers between patients and
within patients over time during and in relation to standard of care treatment
(omalizumab);
• To explore and determine the different endotypes of cold urticaria and
symptomatic dermographism.
Secondary endpoints:
• Provocations test: TempTest®, FricTest®
• Swab of healthy skin and (non-) lesional skin for microbiome
• Faecal microbiota
• Antera 3D multispectral imaging (3D skin morphology, erythema, haemoglobin
and melanin levels)
• Laser speckle contrast imaging (microcirculation)
• 2D photography
• ePRO ( Electronic patient reported outcomes): UAS7, UCT, DLQI, SDAS, SD-Qol,
Cold-UAS, Coldu-QOL
• Withing watch
• Skin barrier assessment by Nevisense
• Stratum corneum sampling with tape stripping
Background summary
Chronic inducible urticaria (CIndU) is a group of skin disorders defined by
recurrent itchy or burning wheals or angioedema that recur for more than six
weeks with a specific triggering factor. This is different from chronic
spontaneous urticaria which does not have a specific triggering factor. CIndU
is subclassified in nine subtypes with each having its own specific trigger.
These subtypes are further divided in physical urticarias (symptomatic
dermographism, cold urticaria, delayed pressure urticaria, solar urticaria,
heat urticaria, vibratory angioedema) or non-physical urticarias, i.e.,
cholinergic urticaria, aquagenic urticaria, and contact urticaria.
Symptomatic dermographism (SD) is the most prevalent subtype of the physical
urticarias. Its prevalence in Western populations is estimated to be between
1-5%. Following SD, cold urticaria (ColdU) is the next most common form, its
annual incidence is estimated to be 0.05%. In this study, patients with the
ColdU and symptomatic SD subtypes will be enrolled.
As of yet, disease diagnosis of SD and ColdU is mostly purely clinical
(clinical picture + patients* history), as there is a lack of objective
biomarkers. Currently only two objective tools are available for the diagnosis
of SD and ColdU, which are the FricTest and Temptest (both provocation tests).
In addition, there is a lack of objective biomarkers for the prediction of
treatment response and for the monitoring of treatment effects, as this is
nowadays only monitored by patient reported outcomes.
The objective of this study is to deep phenotype CIndU (subtype SD and ColdU)
and detect novel biomarkers for diagnosis and treatment 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 will consist 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 comparison with chronic
spontaneous urticaria (CSU) patients and matched healthy volunteers.
Study objective
The objective of this study is to deep phenotype CIndU (subtype SD and ColdU)
and detect novel biomarkers for diagnosis and treatment response as well as
establish methodologies for (non-) invasive monitoring of treatment effects in
chronic inducible urticaria.
The primary objectives are:
• To evaluate disease-related characteristics and biomarkers in patients with
CIndU compared to CSU patients and healthy volunteers;
• To evaluate the variability of the selected biomarkers between patients and
within patients over time during and in relation to standard of care treatment
(omalizumab);
• To evaluate and determine the different endotypes of cold urticaria and
symptomatic dermographism.
Study design
This is a two-part, observational study. In part A 10 healthy volunteers, 10
CSU patients,10 ColdU and 10 SD patients will be included. All patients will
visit the EMC Rotterdam or the UMC Utrecht for a screening visit and two short
visits (day 1 and day 15 (end of observational period)). All healthy
volunteers will visit CHDR for a screening and 2 short visit (day 1 and day 15
(end of study)).
Patients will continue the study with part B, in which standard of care
treatment with omalizumab will be administered every 4 weeks during a 12 week
treatment period. There will be 4 study visits in part B followed by one
follow-up visit.
Study burden and risks
Omalizumab treatment:
Omalizumab is an humanized ant-IgE monoclonal antibody with a positive
benefit/risk ratio for the use in chronic urticaria (CSU and CIndU). A detailed
explanation of the potential issues of concern is therefore not included as the
EMA assessment report for omalizumab suffices.
Study procedures:
Biopsies with a size of four millimeter in diameter are taken in order to
assess histology, immunohistochemistry and perform imaging mass cytometry
analysis from one biopsy. Biopsies of this small size generally do not need
stitching in order to heal. Biopsy can possibly leave a lasting mark on the
skin, therefore healthy subjects with a history of hypertrophic scarring or
keloid will be excluded. The biopsy are performed at day 1 (for patients and
healthy volunteers) and at EOS for patients. Results from these time points
will provide a comprehensive overview on how disease characteristics and
biomarkers of lesional skin will change when treatment effects are apparent
compared to non-responding skin. Healthy volunteers will only undergo a single
biopsy and blister at day 1 as they will only participate in the observational
part.
In summary, the risk to participate in the trial can be assessed as acceptable.
Zernikedreef 8
Leiden 2333CL
NL
Zernikedreef 8
Leiden 2333CL
NL
Listed location countries
Age
Inclusion criteria
Healthy volunteers must meet all of the following inclusion criteria:
1. 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.
2. No clinically significant skin disease in the research area
3. No history of hypertrophic scarring or keloid.
4. Willing to give written informed consent and willing and able to comply with
the study protocol.
5. Body mass index (BMI) > 18.0 and < 35 kg/m2.
6. Negative TempTest and FricTest at screening.
7. 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 must meet all of the following inclusion criteria at
screening:
8. Male and female subjects between 18-69 years old
9. 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).
10. 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.
11. Body mass index (BMI) > 18.0 and < 35.0 kg/m2.
12. Willing to give written informed consent and willing and able to comply
with the study protocol.
13. Positive provocation test:
a) For ColdU patients: developing a wheal at the test site within 10 min after
using TempTest® at any temperature at both screening and Baseline;
b) For SD patients: developing a wheal at the test site within 10 min after
using FricTest® with >= 3mm at both screening and Baseline.
14. For CSU patients: negative TempTest® and FricTest® at screening
15. 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.
16. Female participants of reproductive potential must agree to use
contraception from screening until EOS.
Exclusion criteria
General for all subjects to be enrolled:
1. 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.
2. History of immunological abnormality (e.g., immune suppression) that may
interfere with study objectives, in the opinion of the investigator.
3. Loss or donation of blood over 500 mL within three months prior to
screening.
4. Positive hepatitis B surface antigen (HbsAg), hepatitis C antibody (HCV ab),
or human immunodeficiency virus antibody (HIB ab) at screening (healthy
volunteers only)
5. Known infection requiring (topical or oral) antibiotic therapy within 56
days prior to Day 1.
6. The use of systemic antibiotic therapy for >2 months the past 12 months.
7. 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.
8. Treatment with omalizumab within 5 half lives (120 days) prior to Day 1.
9. Pregnant, a positive pregnancy test, intending to become pregnant, or
breastfeeding.
10. 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.
11. Evidence of current drug or alcohol abuse.
12. 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).
Eligible healthy volunteers must not meet the following exclusion criterion at
screening:
13. Participation in an investigational drug study within 3 months prior to
screening or more than 4 times a year.
Eligible patients must meet none of the following exclusion criteria at
screening:
14. 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.
15. 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).
16. Active, pruritic skin condition in addition to CIndU (CIndU patients) or
CSU (CSU patients).
17. 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.
18. Intravenous (IV) immunoglobulin G (IVIG), or plasmapheresis within 30 days
prior to screening.
19. Regular (daily/every other day) doxepin (oral) use within 6 weeks prior to
Day 1.
20. Any H2 antihistamine use within 7 days prior to screening.
21. Any leukotriene receptor antagonist (LTRA) (montelukast or zafirlukast)
within 7 days prior to Day 1.
22. 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.
23. Hypersensitivity to omalizumab or any component of the formulation.
24. History of anaphylactic shock.
25. Evidence of parasitic infection.
Design
Recruitment
Medical products/devices used
metc-ldd@lumc.nl
metc-ldd@lumc.nl
Followed up by the following (possibly more current) registration
No registrations found.
Other (possibly less up-to-date) registrations in this register
No registrations found.
In other registers
| Register | ID |
|---|---|
| CCMO | NL84908.058.23 |