A Randomised Trial Evaluating the Effects of the TRPV1 Antagonist SB705498 on Pruritus Induced by Histamine, and Cowhage Challenge in Healthy Volunteers

<div><p>Background</p><p>Transient receptor potential vanilloid type 1 (TRPV1) is a non-selective cation channel widely expressed in skin tissues, and peripheral sensory nerve fibres. Activation of TRPV1 releases neuropeptides; the resulting neurogenic inflammation is believed to contribute to the development of pruritus. A TRPV1 antagonist has the potential to perform as an anti-pruritic agent. SB705498 is a TRPV1 antagonist that has demonstrated <i>in vitro</i> activity against cloned TRPV1 human receptors and when orally administered has demonstrated pharmacodynamic activity in animal models and clinical studies.</p><p>Objectives</p><p>To select a topical dose of SB705498 using the TRPV1 agonist capsaicin; to confirm engagement of the TRPV1 antagonistic action of SB705498 and assess whether the dose selected has an effect on itch induced by two challenge agents.</p><p>Methods</p><p>A clinical study was conducted in 16 healthy volunteers to assess the effects of 3 doses of SB705498 on skin flare induced by capsaicin. Subjects with a robust capsaicin response were chosen to determine if the selected topical formulation of SB705498 had an effect on challenge agent induced itch.</p><p>Results</p><p>Following capsaicin challenge the greatest average reduction in area of flare was seen for the 3% formulation. This dose was selected for further investigation. Itch intensity induced by two challenge agents (cowhage and histamine) was assessed on the Computerised Visual Analogue Scale. The difference in average itch intensity (Weighted Mean Over 15 Mins) between the 3% dose of SB705498 and placebo for the cowhage challenge was −0.64, whilst the histamine challenge showed on average a −4.65 point change.</p><p>Conclusions</p><p>The 3% topical formulation of SB705498 cream was clinically well tolerated and had target specific pharmacodynamic activity. However there were no clinically significant differences on pruritus induced by either challenge agent in comparison to placebo. SB705498 is unlikely to be of symptomatic benefit for histaminergic or non-histaminergic induced itch.</p><p>Trial Registration</p><p>ClinicalTrials.gov <a href="https://clinicaltrials.gov/ct2/show/NCT01673529?term=NCT01673529&rank=1" target="_blank">NCT01673529</a></p></div

Adjusted Means for Average Itch Intensity.

<p>Adjusted Means for Average Itch Intensity.</p

Mean profile plot of average itch intensity (weighted mean over 15 minutes).

<p>Mean profile plot of average itch intensity (weighted mean over 15 minutes).</p

Demographics and Baseline Characteristics.

<p>Demographics and Baseline Characteristics.</p

Geometric Mean Profile Plot of Area of Flare.

<p>Geometric Mean Profile Plot of Area of Flare.</p

Treatment Comparisons for Weighted Mean over Itch Period.

1<p>Posterior Probability the treatment difference is less than the stated number. This was calculated assuming non-informative priors.</p

Adjusted Means for Weighted Mean over Itch Period.

<p>Adjusted Means for Weighted Mean over Itch Period.</p

Treatment Comparison for Average Itch Intensity.

1<p>Posterior Probability the treatment difference is less than the stated number. This was calculated assuming non-informative priors.</p

Adjusted Geometric Means from Statistical Analysis of Area of flare.

<p>Adjusted Geometric Means from Statistical Analysis of Area of flare.</p

CONSORT diagram.

<p>CONSORT diagram.</p