Primary objectives • To characterize the histamine dose response on pruritus• To profile the response to intradermal histamine by:o Clinical measureso Biophysical measureso Imagingo Molecular and cellular responsesSecondary objective • Comparison to…
ID
Source
Brief title
Condition
- Epidermal and dermal conditions
Synonym
Research involving
Sponsors and support
Intervention
Outcome measures
Primary outcome
Tolerability / safety endpoints
• Monitoring adverse events
• Monitoring HR, BP and temperature
• Local tolerance (Visual Analog Scale (VAS) pruritus)
Pharmacodynamic endpoints
The injection sites will be monitored for a period of up to 180 min. Safety
assessments and non-invasive efficacy assessments (imaging) will be performed
at baseline, directly after histamine and saline administration after 10, 30
and 60 minutes.
Imaging measurements (Part A + Part C)
- Perfusion by Laser speckle contrast imaging (LSCI)
- Erythema by Antera 3D camera
- Wheal and flare by Antera 3D camera
- Wheal and flare by clinical evaluation (erythema grading scale)
- Erythema by colorimetry (DSM III)
Biochemical measurements
- Skin biopsies (Part C). Readout measures may comprise, but are not limited to:
o Immunohistochemistry:
- Eosinophils
- Monocytes/macrophages
- Mast cells
- IgE, IgG
o qPCR (exploratory):
- NAV 1.1 to 1.9 expression
Subject reported outcomes
Itch intensity is assessed on a horizontal bar from 0 to 100 representing the
visual analogue scale (VAS) in both parts following each provocation every
minute up to 15 minutes. After 15 minutes, itch will be assessed with a
frequency of 5 minutes up to 30 min after challenge. The burning sensation is
evaluated similarly.
Pain intensity is assessed on a 100 mm visual analogue scale (VAS) in both
parts following each provocation pre-dose, post-dose, after 10 and 30 minutes
of histamine challenge
Itch intensity is assessed on a horizontal bar from 0 to 100 representing the
visual analogue scale (VAS) in all three parts. After every histamine/NaCl
administration itch is assessed every minute up to 15 minutes. After 15
minutes, itch will be measured with a frequency of 5 minutes up to 30 min after
challenge. Additionally, itch will also be assessed after 45 min and 60 min of
challenge (only part A and part B).
Pain intensity is assessed on a 100 mm visual analogue scale (VAS) in each part
of the study. The intensity is measured pre-dose, post-dose, after 10, 30, 45
and 60 minutes of histamine challenge in Part A and B.
In case the subject still experiences substantial itch or pain at the end of a
round, the physician decides whether this is clinically relevant and provides
permission for next dosing/histamine challenge.
The following outcomes are included to evaluate itch sensitization with the
different histamine doses and the difference between HV and AD patients.
- Maximum itch / peak itch
- Time to maximum itch
- Time to complete itch subsidence
- AUCitch
Secondary outcome
N.a.
Background summary
In many dermatological diseases, pruritus (or itch will be used
interchangeably) is one of the impactful and burdensome symptoms patients face
every day. Although pruritus by itself is seen as a benign symptom, pruritus
can have adverse effects on the patients* wellbeing and daily life. In
addition, chronic itch is often accompanied by several unpleasant sensations
such as pain or a burning sensation. The mechanisms that underlie pruritus are
not well known and are compounded by the subjective nature of itch.
In dermatological conditions, itch is mainly caused by inflammation or skin
damage. Changes in barrier function of the skin can lead to itch by endogenous
mediators or exogenous allergens that come into contact with the skin.
The primary sensory nerve fibers that innervate the skin are categorized into
three groups based on the degree of myelination, diameter, and conduction
velocity. The thick myelinated Aβ fibers transmit tactile sensation, whereas
the thinly myelinated Aδ and unmyelinated C-fibers are mainly involved in the
conduction of thermal and pain/itch sensation. Itch is transmitted
predominately by these unmyelinated, slow conducting C-fibers. These fibers
extend to the dermo-epidermal junction with free endings penetrating into the
epidermis where sensation is detected. The cell bodies for these fibers are in
the dorsal root ganglia (DRG), just outside the spinal cord. From here, both
sensations involve secondary transmission neurons that ascend via the
contralateral spinothalamic tract to the thalamus (Garibyan et al 2013).
Pruritogens interact with receptors or ion channels on the nerve fibers. The
receptors that are often involved are G-protein coupled receptors (GPCR). GPCRs
detect and respond to a diverse range of ligands or stimuli and are the target
of many drugs. GPCRs that are relevant to itch respond to histamine,
prostaglandins, neuropeptides, and proteases. The ion channels that appear to
be primarily involved are members of the transient receptor potential (TRP)
family. As an example, TRPV1 detects capsaicin, the active ingredient in chili
peppers.
Various drugs with different mechanisms of action are currently in development.
These drugs have the potential to lead to targeted therapy of peripheral itch
independent of blocking inflammation. For clinical drug development efficient
and effective pruritus provoking challenge models in humans are needed. For
these purposes a variety of different compounds including cowhage, capsaicin
and histamine have been tested. Ample experience has been obtained with
histamine also being used as positive control of the skin prick test in allergy
testing sued routinely in clinical practice. However, hardly any
bioquantitative measurements have been performed to characterize the itch
response following histamine injection.
The aim of this study is to characterize the dose-pruritogenic response upon
intradermal histamine injection in healthy volunteers and patients with atopic
dermatitis. This setup will create a challenge model that temporarily induces
skin itch which enables future application as proof-of-pharmacology or drug
profiling in drug developmental programs. As histamine is known as low potent
pruritogenic agent the study will also enroll atopic dermatitis patients where
lesional site will be evaluated to study the difference in pruritus response in
patients. With the application oral antihistamine, the reversal of a fixed
histamine-dose effect can be investigated in both populations.
Study objective
Primary objectives
• To characterize the histamine dose response on pruritus
• To profile the response to intradermal histamine by:
o Clinical measures
o Biophysical measures
o Imaging
o Molecular and cellular responses
Secondary objective
• Comparison to itch induction in healthy volunteers and patients with atopic
dermatitis
• To assess safety and tolerability of intradermal histamine challenge
Study design
This is a randomized, single-blind, saline-controlled, dose-finding, study to
characterize the pruritus and immune response to intradermal histamine in
healthy volunteers and patients with atopic dermatitis.
The study is divided into three parts: in part A, the optimal dose of histamine
is explored in healthy volunteers and in atopic dermatitis patients to enhance
the characterization of the pruritus challenge. Part B will be carried out to
explore itch response by administration of histamine dihydrochloride via
intradermal injection and skin prick test. In these two parts the optimal
administration method and dose will be determined. In part C, oral
antihistamine is used as a positive control to assess reversal of the
histamine-induced pruritus challenge.
Intervention
Investigational product: Histamine dihydrochloride
Non-investigational product: Cetirizine 10 mg
or placebo
Study burden and risks
The overall aim of this study is to characterize a model for pruritus upon
intradermal histamine injection in healthy volunteers and patients with atopic
dermatitis. In addition, the reversal effect of histamine challenge will be
examined by applying systemic antihistamine. No medical benefit can be expected
from this study for the participating subjects.
Chudoji Awatacho 93 .
Shimogyo-ku, Kyoto 600-8815
JP
Chudoji Awatacho 93 .
Shimogyo-ku, Kyoto 600-8815
JP
Listed location countries
Age
Inclusion criteria
All participants
1. Body mass index (BMI) between 18 and 30 kg/m2, inclusive, and with a minimum
weight of 50 kg;
2. Fitzpatrick skin type I-II (Caucasian);
3. All subjects must use effective contraception for the duration of the study;
4. Able and willing to give written informed consent and to comply with the
study restrictions.
Healthy volunteers
5. Healthy male subjects, 18 to 45 years of age, inclusive. Healthy status is
defined by absence of evidence of any active or chronic disease following a
detailed medical and surgical history, a complete physical examination
including vital signs, 12-lead ECG, hematology, blood chemistry, blood serology
and urinalysis;
AD patients
6. Male and female subjects with mild to moderate AD (IGA 2 or 3) 18 to 65
years of age,
inclusive. The health status is verified by absence of evidence of any
clinically significant
active or uncontrolled chronic disease other than AD following a detailed
medical history and
a complete physical examination including vital signs, 12-lead ECG, hematology,
blood chemistry, blood serology and urinalysis;
7. Diagnosed with AD according to the Hanifin & Rajka diagnostic criteria;
8. Suitable target of the affected skin defined as an eczema lesion of at least
1% BSA for each lesions (volar forearms and/or preferably upper back, total 3
lesions)
9. IGA 2 or 3
10. VAS itch of <=30 at screening and prior to first administration of target
lesions
Exclusion criteria
All participants
1. Diseases associated with immune system impairment, including auto-immune
diseases, HIV and transplantation patients;
2. History of pathological scar formation (keloid, hypertrophic scar);
3. Excessive sun exposure or a tanning booth within 3 weeks of enrollment
4. Participation in an investigational drug or device study within 3 months
prior to screening or more than 4 times a year;
5. Loss or donation of blood over 500 mL within three months prior to
screening. Or the donation of plasma within 14 days prior to screening;
6. Current smoker and/or regular user of other nicotine-containing products
(e.g., patches);
7. History of or current drug or substance abuse considered significant by the
PI (or medically qualified designee), including a positive urine drug screen.
8. Use of antihistamines within 3 weeks prior to start of the study;
9. Subjects who show skin reaction to Skin marker;
10. Subject has a body temperature of >=38.0 °C at any visit.
Healthy volunteers
11. Subjects suffering from chronic itch defined as presence of pruritic
symptoms lasting more than 6 weeks;
12. Have known history of atopy;
13. Have any current and / or recurrent pathologically, clinically significant
skin condition at the treatment area (i.e. atopic dermatitis);
AD patients
14. Requirement of immunosuppressive or immunomodulatory medication within 30
days prior to enrollment or planned to use during the course of the study;
15. Pregnant, a positive pregnancy test, intending to become pregnant, or
breastfeeding.;
Design
Recruitment
Medical products/devices used
Followed up by the following (possibly more current) registration
No registrations found.
Other (possibly less up-to-date) registrations in this register
In other registers
| Register | ID |
|---|---|
| EudraCT | EUCTR2019-004261-40-NL |
| CCMO | NL71946.056.19 |