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Clinical trial information and results are updated daily from ClinicalTrials.gov. The latest data update was conducted on 01/20/2021.

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

Clinicaltrials.gov identifier NCT03943407

Recruitment Status Not yet recruiting

First Posted May 9, 2019

Last update posted September 3, 2019

Study Description

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:Itch
  • Intervention/Treatment: Drug: Zyclara 3.75 % Topical Cream
    Drug: Prudoxin
    Other: Histamine
    Other: Cowhage
    Other: L-menthol
    Other: Trans-cinnamaldehyde (CA)
  • Phase: N/A
Detailed Description

The pathogenesis of itch in psoriasis is unclear. A recent study found that there is no correlation between the severity of the disease and the intensity of the pruritus in patients with psoriasis. Imiquimod (IMQ)-treated mice represent a useful model to examine the neuronal mechanisms underlying itch and its sensitization in psoriasis. Zyclara cream is most commonly used for topical treatment of external genital warts, actinic keratosis and superficial basal cell carcinoma. Its active component, imiquimod, is a TLR7/8 agonist that induces a potent anti-viral response characterized by the production of type I interferons (IFN), proinflammatory cytokines, and chemokines. Its clinical use has highlighted common local side effects including erythema, swelling, scabbing and itching of the skin, and it has subsequently been tested in rodents as a potential model of psoriasis.Based on these considerations, 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. Doxepin hydrochloride (HCl) is one of a class of agents known as dibenzoxipine tricyclic compounds used for the treatment of clinical depression. Doxepin has also been found to have very potent H1 and H2 histamine receptor blocking properties. Recent studies have also shown an emerging role of Toll-like receptors in the control of pain and itch. Toll-like receptors (TLRs) are germline-encoded pattern-recognition receptors expressed in both non-neuronal and neuronal cell types in the central nervous system (CNS) and contribute to both infectious and non-infectious disorders in the CNS. Considering that the involvement of TRP channels in itch pathway has been demonstrated, 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, will be evaluated together with the evaluation of to which extent these three channel populations functionally overlap.

Study Design
  • Study Type: Interventional
  • Estimated Enrollment: 80 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: September 2019
  • Estimated Primary Completion Date: June 2021
  • Estimated Study Completion Date: June 2022
Arms and interventions
Arm Intervention/treatment
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.
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.
Outcome Measures
  • Primary Outcome Measures: 1. 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
  • 2. 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.
  • 3. 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.
  • 4. 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).
  • 5. 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).
  • 6. 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
  • 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.
Eligibility Criteria
  • Ages Eligible for Study: 18 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)

Contacts and Locations
Contacts
Locations

Denmark, Nordjylland
Aalborg University
Aalborg

Sponsors and Collaborators

Aalborg University

More Information
  • Responsible Party: Aalborg University
  • ClinicalTrials.gov Identifier: NCT03943407 History of Changes
  • Other Study ID Numbers: N-20190029
  • First Posted: May 9, 2019 Key Record Dates
  • Last Update Posted: September 3, 2019
  • Last Verified: August 2019
  • Studies a U.S. FDA-regulated Drug Product: No
  • Studies a U.S. FDA-regulated Device Product: No
  • Keywords provided by Aalborg University: Imiquimod
    Doxepin
    Trans-cinnamaldehyde (CA)
    L-menthol
    Histamine
    Cowhage