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

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ClinicalTrials.gov Identifier: NCT03943407
Recruitment Status : Withdrawn (The Imiquimod 3.75% was ineffective)
First Posted : May 9, 2019
Last Update Posted : January 15, 2021
Sponsor:
Information provided by (Responsible Party):
Silvia Lo Vecchio, Aalborg University

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.

Condition or disease Intervention/treatment Phase
Itch Drug: Zyclara 3.75 % Topical Cream Drug: Prudoxin Other: Histamine Other: Cowhage Other: L-menthol Other: Trans-cinnamaldehyde (CA) Not Applicable

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Study Type : Interventional  (Clinical Trial)
Actual Enrollment : 0 participants
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Single (Participant)
Primary Purpose: Basic Science
Official Title: Characterization of the Toll-like Receptor 7-agonist Imiquimod 3.75% as a New Surrogate Model of Itch
Estimated Study Start Date : November 2019
Estimated Primary Completion Date : June 2021
Estimated Study Completion Date : June 2022

Resource links provided by the National Library of Medicine

MedlinePlus related topics: Itching
Drug Information available for: Imiquimod

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.




Primary Outcome Measures :
  1. Superficial blood perfusion by by a Speckle contrast imager (FLPI, Moor Instruments, England). [ Time Frame: Change from baseline, to maximum 19 days after intervention ]
    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.

  2. Trans-epidermal Water Loss (TEWL) [ Time Frame: Change from baseline, to maximum 19 days after intervention ]
    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.

  3. Neurogenic Inflammatory Response and Pigmentation [ Time Frame: Change from baseline, to maximum 19 days after intervention ]
    treatment will be measured with a spectrometer designed for cutaneous use (ColorMeter, DSM II; Cortex Technology, Hadsund, Denmark).

  4. Measuring Alloknesis [ Time Frame: Change from baseline, to maximum 19 days after intervention ]
    Alloknesis is measured by using mildly pruritic, non-painful von Frey nylon filaments of a predetermined intensity (generally 5-30 miliNewton of force).

  5. Thermal measurements (cold and warm detection thresholds, cold and heat pain thresholds) [ Time Frame: Change from baseline, to maximum 19 days after intervention ]
    The tests for thermal sensation will all be conducted using a PATHWAY ATS (Medoc Ltd, Israel) thermal sensory testing device

  6. Measurement of Pain to Supra-threshold Heat Stimuli [ Time Frame: Change from baseline, to maximum 19 days after intervention ]
    The test will all be conducted using a PATHWAY ATS (Medoc Ltd, Israel) thermal sensory testing device

  7. Measurement of Mechanical Detection Thresholds, Mechanical Pain Threshold and sensitivity [ Time Frame: Change from baseline, to maximum 19 days after intervention ]
    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.


Secondary Outcome Measures :
  1. Measurement of Itch rating by Computerized Visual Analog Scale Scoring [ Time Frame: Change from baseline, to maximum 19 days after intervention ]
    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.

  2. Measurement of pain rating by Computerized Visual Analog Scale Scoring [ Time Frame: Change from baseline, to maximum 19 days after intervention ]
    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.



Information from the National Library of Medicine

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Ages Eligible for Study:   18 Years to 60 Years   (Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   Yes
Criteria

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)

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT03943407


Locations
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Denmark
Aalborg University
Aalborg, Nordjylland, Denmark, 9220
Sponsors and Collaborators
Aalborg University
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Responsible Party: Silvia Lo Vecchio, Principal Investigator, Aalborg University
ClinicalTrials.gov Identifier: NCT03943407    
Other Study ID Numbers: N-20190029
First Posted: May 9, 2019    Key Record Dates
Last Update Posted: January 15, 2021
Last Verified: January 2021

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Studies a U.S. FDA-regulated Drug Product: No
Studies a U.S. FDA-regulated Device Product: No
Keywords provided by Silvia Lo Vecchio, Aalborg University:
Imiquimod
Doxepin
Trans-cinnamaldehyde (CA)
L-menthol
Histamine
Cowhage
Additional relevant MeSH terms:
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Imiquimod
Cinnamic aldehyde
Doxepin
Menthol
Histamine
Antipruritics
Dermatologic Agents
Histamine Agonists
Histamine Agents
Neurotransmitter Agents
Molecular Mechanisms of Pharmacological Action
Physiological Effects of Drugs
Adjuvants, Immunologic
Immunologic Factors
Antineoplastic Agents
Interferon Inducers
Antineoplastic Agents, Phytogenic
Antimutagenic Agents
Protective Agents
Sleep Aids, Pharmaceutical
Hypnotics and Sedatives
Central Nervous System Depressants
Antidepressive Agents, Tricyclic
Antidepressive Agents
Psychotropic Drugs
Histamine Antagonists