Characterization of the Toll-like Receptor 7-agonist Imiquimod 3.75% As a New Surrogate Model of Itch

NCT03943407 | Withdrawn

• 1 other identifier: N-20190029
• Study Type: interventional
• Target: N/A
• Locations: 1 country
• Sites: 1

Brief Summary

The aim of this research project is to design a new model of human itch by application of Zyclara cream. Further, the aim is to characterize the model and to verify if the mechanism of action of imiquimod follows the histaminergic or non-histaminergic pathway by using the anti-histamine drug doxepin. The last goal is to evaluate the interaction between the activation of TLR7 receptor and the activation of TRPA1 and TRPM8 receptors, which are two of the most important receptors involved in the transduction of noxious stimuli, and to evaluate to which extent these three channel populations functionally overlap.

Conditions

Itch

Keywords

Imiquimod; Doxepin; Trans-cinnamaldehyde (CA); L-menthol; Histamine; Cowhage

Outcome Measures

Primary Outcomes (7)

• Superficial blood perfusion by by a Speckle contrast imager (FLPI, Moor Instruments, England).

  Two pictures will be taken: one with the sensor placed approximately 35 cm above the induction area and one with the sensor placed approximately 20 cm above the induction area.

  Change from baseline, to maximum 19 days after intervention

• Trans-epidermal Water Loss (TEWL)

  a 2x2 cm hollow probe with two small humidity gauges and two thermometers is placed lightly on the skin for 10-25 seconds. These establish a precise humidity gradient in a 2 cm vicinity of the skin, representative for the point-loss of water though the epidermis.

  Change from baseline, to maximum 19 days after intervention

• Neurogenic Inflammatory Response and Pigmentation

  treatment will be measured with a spectrometer designed for cutaneous use (ColorMeter, DSM II; Cortex Technology, Hadsund, Denmark).

  Change from baseline, to maximum 19 days after intervention

• Measuring Alloknesis

  Alloknesis is measured by using mildly pruritic, non-painful von Frey nylon filaments of a predetermined intensity (generally 5-30 miliNewton of force).

  Change from baseline, to maximum 19 days after intervention

• Thermal measurements (cold and warm detection thresholds, cold and heat pain thresholds)

  The tests for thermal sensation will all be conducted using a PATHWAY ATS (Medoc Ltd, Israel) thermal sensory testing device

  Change from baseline, to maximum 19 days after intervention

• Measurement of Pain to Supra-threshold Heat Stimuli

  The test will all be conducted using a PATHWAY ATS (Medoc Ltd, Israel) thermal sensory testing device

  Change from baseline, to maximum 19 days after intervention

• Measurement of Mechanical Detection Thresholds, Mechanical Pain Threshold and sensitivity

  These tests are conducted using a set of 20 different von Frey hairs (North Coast Medical, Gilroy, CA) with exerted forces ranging from .008g to 300g.

  Change from baseline, to maximum 19 days after intervention

Secondary Outcomes (2)

• Measurement of Itch rating by Computerized Visual Analog Scale Scoring

  Change from baseline, to maximum 19 days after intervention

• Measurement of pain rating by Computerized Visual Analog Scale Scoring

  Change from baseline, to maximum 19 days after intervention

Study Arms (4)

Zyclara/vehicle

EXPERIMENTAL

All subjects will be treated with Zyclara cream (Imiquimod 3.75%) and vehicle.

Drug: Zyclara 3.75 % Topical Cream

Zyclara/Doxepin

EXPERIMENTAL

All subjects will be treated with the topical antihistamine cream (Prudoxin, containing 5% doxepin hydrochloride, Healthpoint, San Antonio, TX) or a placebo cream. After removal, subjects will be treated with Zyclara cream

Drug: Zyclara 3.75 % Topical Cream; Drug: Prudoxin

Zyclara/Histamine/Cowage

EXPERIMENTAL

All subjects will be treated with Zyclara cream, vehicle cream, histamine and cowhage

Drug: Zyclara 3.75 % Topical Cream; Other: Histamine; Other: Cowhage

Zyclara/L-menthol/trans-cinnamaldehyde

EXPERIMENTAL

All subjects will be treated with Zyclara cream (Imiquimod 3.75%) and vehicle. After removal, subjects will be treated with L/menthol and trans-cinnamaldehyde

Drug: Zyclara 3.75 % Topical Cream; Other: L-menthol; Other: Trans-cinnamaldehyde (CA)

Interventions

Zyclara 3.75 % Topical Cream DRUG

The cream will be applied on 4x4 cm squared areas on the volar forearm. The cream will be left in place for 2h, 1 h or 30 min (sub-study 1) after which it will be removed. The technical and security procedures will be conducted in accordance with the manufacturer's instructions.

Zyclara/Doxepin; Zyclara/Histamine/Cowage; Zyclara/L-menthol/trans-cinnamaldehyde; Zyclara/vehicle

Prudoxin DRUG

The anti-histamine cream Prudoxin, containing 5% doxepin hydrochloride (1 g contains 50 mg of doxepin) (Healthpoint, San Antonio, TX) will be applied on the volar forearm. Two adhesive patches 4×4 cm (1mm thick, 3M foam adhesive tape, 3M, St. Paul, MN) each with a 3.5×3.5 cm center cut out (to deposit 1.2 grams of cream) will be each placed 3 cm distal and 3 cm proximal to the center of the volar aspect of each arm. Each patch will be covered with Tegaderm I.V., an occlusive, adhesive dressing (3M), for at least 1 h and 30 minutes.

Zyclara/Doxepin

Histamine OTHER

To deliver histamine, standard allergy skin prick test (SPT) lancets are applied. The lancets have a 1 mm shouldered tip adapt to introduce a small amount of test substance extremely locally and approximately at the dermo-epidermal junction. . A small drop of histamine dihydrochloride (1%, in saline) will be applied to a previously determined area on the volar forearm followed by a prick through the drop.

Zyclara/Histamine/Cowage

Cowhage OTHER

Cowhage spicules are 1-2 mm in length and have diameter of 1-3 um at their tip. The active substance delivered (mucunain) has been calculated to be in the nanogram range. The insertion of cowhage spicule(s) rapidly and consistently produces itch with no or very little flare reaction. This insertion is conducted by forceps using a stereo-microscope, and 30-35 spicules are gently rubbed into a 1 cm diameter skin area.

Zyclara/Histamine/Cowage

L-menthol OTHER

L-menthol (≥99.9%, TRPM8 agonist; (Sigma Aldrich, Broendby, Denmark) is dissolved in 96% ethanol at concentrations of 40%(w/v) L-menthol. A 1 mL aliquot is dispensed onto a 3 × 3 cm cotton pad and placed on a 6 × 6 cm sheet of medical tape. In between the cotton pad and the medical tape, a layer of parafilm will be added to avoid evaporation. This configuration was subsequently applied for 1 h.

Zyclara/L-menthol/trans-cinnamaldehyde

Trans-cinnamaldehyde (CA) OTHER

CA will be obtained from Sigma Aldrich (Brøndby, Denmark) and dissolved in 90% ethanol at a concentration of 10% (vol/vol) CA. One ml aliquot of CA is dispensed onto a 3x3 cm cotton pad and placed on a 5x5 cm sheet of medical tape. Between the cotton pad and the tape, a layer of plastic film will be added to inhibit the evaporation of the solutions. This configuration will be applied for 1 h.

Zyclara/L-menthol/trans-cinnamaldehyde

Eligibility Criteria

• Age: 18 Years - 60 Years
• Sex: all
• Healthy Volunteers: Yes
• Age Groups: Adult (18-64)

You may qualify if:

• Healthy men and women
• years
• Speak and understand English

You may not qualify if:

• Pregnancy or lactation
• Drug addiction defined as any use of cannabis, opioids or other drugs
• Previous or current neurologic, musculoskeletal or mental illnesses
• Lack of ability to cooperate
• Current use of medications that may affect the trial
• Skin diseases
• Consumption of alcohol or painkillers 24 hours before the study days and between these
• Acute or chronic pain
• Participation in other trials within 1 week of study entry (4 weeks in the case of pharmaceutical trials)

Sponsors & Collaborators

• Aalborg University: lead

Study Sites (1)

Aalborg University

Aalborg, North Denmark, 9220, Denmark

Location

MeSH Terms

Conditions

Pruritus

Interventions

Imiquimod; Doxepin; Histamine; Menthol; cinnamaldehyde

Condition Hierarchy (Ancestors)

Skin Diseases; Skin and Connective Tissue Diseases; Skin Manifestations; Signs and Symptoms; Pathological Conditions, Signs and Symptoms

Intervention Hierarchy (Ancestors)

Aminoquinolines; Quinolines; Heterocyclic Compounds, 2-Ring; Heterocyclic Compounds, Fused-Ring; Heterocyclic Compounds; Oxepins; Ethers, Cyclic; Ethers; Organic Chemicals; Dibenzoxepins; Heterocyclic Compounds, 3-Ring; Biogenic Monoamines; Biogenic Amines; Amines; Ethylamines; Imidazoles; Azoles; Heterocyclic Compounds, 1-Ring; Autacoids; Inflammation Mediators; Biological Factors; Cyclohexanols; Hexanols; Fatty Alcohols; Alcohols; Cyclohexane Monoterpenes; Cyclohexanes; Cycloparaffins; Hydrocarbons, Alicyclic; Hydrocarbons, Cyclic; Hydrocarbons; Monoterpenes; Terpenes; Lipids

Study Design

• Study Type: interventional
• Phase: not applicable
• Allocation: RANDOMIZED
• Masking: SINGLE
• Who Masked: PARTICIPANT
• Purpose: BASIC SCIENCE
• Intervention Model: PARALLEL
• Sponsor Type: OTHER
• Responsible Party: PRINCIPAL INVESTIGATOR
• PI Title: Principal Investigator

Study Record Dates

• First Submitted: May 7, 2019
• First Posted: May 9, 2019
• Study Start: November 1, 2019
• Primary Completion: June 1, 2021
• Study Completion: June 1, 2022
• Last Updated: November 22, 2024

Record last verified: 2021-01

Data Sharing

• IPD Sharing: Will not share

Locations

DK (1)