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

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.

Study Overview

• Status: Withdrawn
• Conditions: Itch
• Intervention / Treatment: Drug: Zyclara 3.75 % Topical Cream; Drug: Prudoxin; Other: Histamine; Other: Cowhage; Other: L-menthol; Other: Trans-cinnamaldehyde (CA)

• Study Type: Interventional
• Phase: Not Applicable

Contacts and Locations

Study Locations

• Denmark
  • Nordjylland
    • Aalborg, Nordjylland, Denmark, 9220
      • Aalborg University

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years to 60 years (ADULT)
• Accepts Healthy Volunteers: Yes
• Genders Eligible for Study: All

Description

Inclusion Criteria:

• Healthy men and women
• 18-60 years
• Speak and understand English

Exclusion Criteria:

• 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)

Study Plan

How is the study designed?

Design Details

• Primary Purpose: BASIC_SCIENCE
• Allocation: RANDOMIZED
• Interventional Model: PARALLEL
• Masking: SINGLE

Number of Arms

4

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
EXPERIMENTAL: Zyclara/vehicle; All subjects will be treated with Zyclara cream (Imiquimod 3.75%) and vehicle.	Drug: Zyclara 3.75 % Topical Cream; 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.
EXPERIMENTAL: Zyclara/Doxepin; 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; 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.; Drug: Prudoxin; 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.
EXPERIMENTAL: Zyclara/Histamine/Cowage; All subjects will be treated with Zyclara cream, vehicle cream, histamine and cowhage	Drug: Zyclara 3.75 % Topical Cream; 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.; Other: Histamine; 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.; Other: Cowhage; 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.
EXPERIMENTAL: Zyclara/L-menthol/trans-cinnamaldehyde; 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; 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.; Other: L-menthol; 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.; Other: Trans-cinnamaldehyde (CA); 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.

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
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 Outcome Measures

Outcome Measure	Measure Description	Time Frame
Measurement of Itch rating by Computerized Visual Analog Scale Scoring	We will ask the subjects to rate the sensation of itch on a VAS scale ranging from 0 to 10 where 0 indicates "no itch" and 10 indicates "worst itch imaginable"to 10 where 0 indicates "no itch" and 10 indicates "worst itch imaginable" and similarly for sensations of stinging/pricking and burning, both of which are frequently associated with the sensation of itch or pain.	Change from baseline, to maximum 19 days after intervention
Measurement of pain rating by Computerized Visual Analog Scale Scoring	the subjects will be asked to rate the sensation of pain on a VAS scale ranging from 0 to 10 where "0" is no pain and "10" is the worst pain.	Change from baseline, to maximum 19 days after intervention

Collaborators and Investigators

• Sponsor: Aalborg University

Study record dates

Study Major Dates

• Study Start (ANTICIPATED): November 1, 2019
• Primary Completion (ANTICIPATED): June 1, 2021
• Study Completion (ANTICIPATED): June 1, 2022

Study Registration Dates

• First Submitted: May 7, 2019
• First Submitted That Met QC Criteria: May 7, 2019
• First Posted (ACTUAL): May 9, 2019

Study Record Updates

• Last Update Posted (ACTUAL): January 15, 2021
• Last Update Submitted That Met QC Criteria: January 13, 2021
• Last Verified: January 1, 2021

More Information

Terms related to this study

• Keywords: Histamine; Imiquimod; L-menthol; Doxepin; Trans-cinnamaldehyde (CA); Cowhage
• Additional Relevant MeSH Terms: Physiological Effects of Drugs; Neurotransmitter Agents; Molecular Mechanisms of Pharmacological Action; Central Nervous System Depressants; Antineoplastic Agents; Immunologic Factors; Protective Agents; Antineoplastic Agents, Phytogenic; Dermatologic Agents; Psychotropic Drugs; Antidepressive Agents; Hypnotics and Sedatives; Adjuvants, Immunologic; Antidepressive Agents, Tricyclic; Sleep Aids, Pharmaceutical; Histamine Antagonists; Histamine Agents; Antipruritics; Interferon Inducers; Antimutagenic Agents; Histamine Agonists; Imiquimod; Doxepin; Menthol; Histamine; Cinnamaldehyde
• Other Study ID Numbers: N-20190029

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No