Clinical trial NCT05275751: Mechanisms of Human Heat Perception - Involvement of TRPA1, TRPV1 and TRPM3
Official title: Human Heat Sensation - a Single-group, Randomized, Placebo-controlled, Adaptive, Full-factorial Crossover Trial
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: EARLY_PHASE1
Conditions: Pain
Keywords: Psychophysics
Human physiology
Sensory neuron
TRP channels
Heat perception
Lead sponsor: Medical University of Vienna
Sponsor class: OTHER
First posted: 2022-03-11
Enrollment: 51
Sex: ALL
Minimum age (years): 18
Maximum age (years): 70
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: yes
Allocation: RANDOMIZED
Intervention model: SINGLE_GROUP
Intervention model description: Factorial: There are 4 treatments (TRPV1-, TRPA1-, TRPM3- and chloride channel inhibition). These will be applied in all possible combinations (16). Each healthy volunteer will receive 8 of these 16 combinations in a sequence defined by a Williams square (Hinkelmann, K., and Kempthorne, O. (2005). Design and Analysis of Experiments Vol. 2 - Advanced Experimental Design (Wiley))

Randomized: Volunteers will be randomly assigned to a pre-specified sequence.

Placebo-controlled: One of the 16 combinations includes none of the three treatments, i.e., can be regarded as placebo control.

Adaptive: Due to the complex study design, a priori assumptions about the distribution and correlation of data could not be made reliably. Therefore, after 16 volunteers, the responsible bio-statistician will simulate how much more patients are necessary to detect the a priori defined effect size with the until then observed data
Primary purpose: BASIC_SCIENCE

Brief summary: Animal studies suggest that the ion channels TRPV1, TRPA1 and TRPM3 are the relevant heat sensors. This study aims to validate these findings in humans.

Detailed description: Surprisingly, it is still not fully understood how humans perceive heat pain. There are several heat-sensitive ion channels whose manipulation in animals resulted in a more or less pronounced phenotype. However, complete blockade of heat sensation in animals has only recently been achieved. In triple knockout mice lacking TRPA1, TRPV1 and TRPM3, it was recently shown that only in the absence of all three receptors heat perception is largely abolished. Although the authors were unable to elucidate the underlying mechanism of this redundancy, the redundancy appears to have evolutionary value for protection against burns. In addition, recent evidence suggests that TRPV1 plays a role as a first-line defense against heat injury, i.e., that it encodes noninjurious heat injury in humans.

The goal of this study is to test whether the redundant functions of TRPV1, TRPA1 and TRPM3 observed in mice with respect to heat perception also apply to humans. More broadly, we want to understand which receptors enable humans to perceive heat pain. The study also aims to test if a chloride channel is involved in heat perception.

Design: Cross-over study with a Williams design group, 16 treatments incl. a placebo control.

Eligibility criteria: Inclusion Criteria:

* Age between 18 and 70 years
* Full legal capacity

To ensure an equal number of each sex in the study population, only volunteers of one sex will be included as soon as the number of subjects with the other sex has reached half of the calculated sample size.

Exclusion Criteria:

* Participant of another study, ongoing or within the last 4 weeks
* Medication intake (except contraception) or drug abuse
* Female subjects: Positive pregnancy test or breastfeeding
* Body temperature above 38°C, diagnostically verified
* Known allergic diseases, in particular asthmatic disorders and skin diseases, known allergic reactions to citrus fruits (but excluding food intolerances).
* Sensory deficit, skin disease or hematoma of unknown origin in physical examination of the test site
* Symptoms of a respiratory tract infection (Covid-19 related criterion)

Primary outcomes:
measure: HPI(50-52) - Heat pain inhibition in the range between 50°C and 52°C
timeFrame: Through study completion, on average 4 days.
Secondary outcomes:
measure: HPI - Heat pain inhibition
timeFrame: Through study completion, on average 4 days.
Other outcomes:
Locations:
city: Vienna
country: Austria
facility: Medical University of Vienna
Study officials:
affiliation: Medical University of Vienna
name: Michael JM Fischer, Professor MD
role: STUDY_CHAIR
References: