Mechanisms of Human Heat Perception - Involvement of TRPA1, TRPV1 and TRPM3

NCT05275751 | Completed Early Phase 1

• 1 other identifier: EK Nr: 1152/2020
• Study Type: interventional
• Target: 51
• Locations: 1 country
• Sites: 1

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.

Conditions

Pain

Keywords

Psychophysics; Human physiology; Sensory neuron; TRP channels; Heat perception

Outcome Measures

Primary Outcomes (1)

• HPI(50-52) - Heat pain inhibition in the range between 50°C and 52°C

  'Heat pain inhibition between 50 and 52 °C', abbreviated HPI(50-52). A value of 0% would indicate that for a given injection there was no inhibition between 50 and 52 °C, i.e. that the injection was equal to a heated control injection without substance. In contrast, a value of 100% would indicate that there was complete inhibition and the injection was as indistinguishable from the injection at room temperature. Of note, pain is rated during the application of the test substances. There are 2 experimental days with injections, separated by a few days, resulting in a time frame of 4 days on average. The principle of AUC calculations from pain ratings during injections is described in Heber et al. 2020 (PMID: 32107360 DOI: 0.1097/j.pain.0000000000001848)

  Through study completion, on average 4 days.

Secondary Outcomes (1)

• HPI - Heat pain inhibition

  Through study completion, on average 4 days.

Study Arms (16)

Hot injection without TRP-channel inhibition

PLACEBO COMPARATOR

Pain induced by an increasingly hot intradermal injection up to 52°C over 2 minutes.

Drug: Placebo

Hot injection with TRPA1-inhibition

EXPERIMENTAL

Pain is induced by an increasingly hot intradermal injection up to 52°C over 2 minutes, while TRPA1 is blocked pharmacologically by an antagonist dissolved in the hot fluid (synthetic interstitial fluid). The antagonist(s) have sufficient concentration to reliably block the channel. The total dose is in the range of a microdose trial.

Drug: TRPA1-inhibitor

Hot injection with TRPV1-inhibition

EXPERIMENTAL

Pain is induced by an increasingly hot intradermal injection up to 52°C over 2 minutes, while TRPV1 is blocked pharmacologically by an antagonist dissolved in the hot fluid (synthetic interstitial fluid). The antagonist(s) have sufficient concentration to reliably block the channel. The total dose is in the range of a microdose trial.

Drug: TRPV1-inhibitor

Hot injection with TRPM3-inhibition

EXPERIMENTAL

Pain is induced by an increasingly hot intradermal injection up to 52°C over 2 minutes, while TRPM3 is blocked pharmacologically by an antagonist dissolved in the hot fluid (synthetic interstitial fluid). The antagonist(s) have sufficient concentration to reliably block the channel. The total dose is in the range of a microdose trial.

Drug: TRPM3-inhibitor

Hot injection with TRPA1- and TRPV1-inhibition

EXPERIMENTAL

Pain is induced by an increasingly hot intradermal injection up to 52°C over 2 minutes, while TRPA1 and TRPV1 are blocked pharmacologically by an antagonist dissolved in the hot fluid (synthetic interstitial fluid). The antagonist(s) have sufficient concentration to reliably block the channel. The total dose is in the range of a microdose trial.

Drug: TRPA1-inhibitor; Drug: TRPV1-inhibitor

Hot injection with TRPA1- and TRPM3-inhibition

EXPERIMENTAL

Pain is induced by an increasingly hot intradermal injection up to 52°C over 2 minutes, while TRPA1 and TRPM3 are blocked pharmacologically by an antagonist dissolved in the hot fluid (synthetic interstitial fluid). The antagonist(s) have sufficient concentration to reliably block the channel. The total dose is in the range of a microdose trial.

Drug: TRPA1-inhibitor; Drug: TRPM3-inhibitor

Hot injection with TRPM3- and TRPV1-inhibition

EXPERIMENTAL

Pain is induced by an increasingly hot intradermal injection up to 52°C over 2 minutes, while TRPM3 and TRPV1 are blocked pharmacologically by an antagonist dissolved in the hot fluid (synthetic interstitial fluid). The antagonist(s) have sufficient concentration to reliably block the channel. The total dose is in the range of a microdose trial.

Drug: TRPV1-inhibitor; Drug: TRPM3-inhibitor

Hot injection with TRPA1-, TRPV1 and TRPM3-inhibition

EXPERIMENTAL

Pain is induced by an increasingly hot intradermal injection up to 52°C over 2 minutes, while TRPA1, TRPV1 and TRPM3 are blocked pharmacologically by an antagonist dissolved in the hot fluid (synthetic interstitial fluid). The antagonist(s) have sufficient concentration to reliably block the channel. The total dose is in the range of a microdose trial.

Drug: TRPA1-inhibitor; Drug: TRPV1-inhibitor; Drug: TRPM3-inhibitor

Hot injection with TRPA1-, TRPM3- and chloride channel inhibition

EXPERIMENTAL

Pain is induced by an increasingly hot intradermal injection up to 52°C over 2 minutes, while TRPA1, TRPM3 and a chloride channel are blocked pharmacologically by an antagonist dissolved in the hot fluid (synthetic interstitial fluid). The antagonist(s) have sufficient concentration to reliably block the channel. The total dose is in the range of a microdose trial.

Drug: TRPA1-inhibitor; Drug: TRPM3-inhibitor; Drug: Chloride-channel inhibitor

Hot injection with TRPV1-, TRPM3- and chloride channel inhibition

EXPERIMENTAL

Pain is induced by an increasingly hot intradermal injection up to 52°C over 2 minutes, while TRPV1, TRPM3 and a chloride channel are blocked pharmacologically by an antagonist dissolved in the hot fluid (synthetic interstitial fluid). The antagonist(s) have sufficient concentration to reliably block the channel. The total dose is in the range of a microdose trial.

Drug: TRPV1-inhibitor; Drug: TRPM3-inhibitor; Drug: Chloride-channel inhibitor

Hot injection with TRPA1- and chloride channel inhibition

EXPERIMENTAL

Pain is induced by an increasingly hot intradermal injection up to 52°C over 2 minutes, while TRPA1 and a chloride channel are blocked pharmacologically by an antagonist dissolved in the hot fluid (synthetic interstitial fluid). The antagonist(s) have sufficient concentration to reliably block the channel. The total dose is in the range of a microdose trial.

Drug: TRPA1-inhibitor; Drug: Chloride-channel inhibitor

Hot injection with TRPV1- and chloride channel inhibition

EXPERIMENTAL

Pain is induced by an increasingly hot intradermal injection up to 52°C over 2 minutes, while TRPV1 and a chloride channel are blocked pharmacologically by an antagonist dissolved in the hot fluid (synthetic interstitial fluid). The antagonist(s) have sufficient concentration to reliably block the channel. The total dose is in the range of a microdose trial.

Drug: TRPV1-inhibitor; Drug: Chloride-channel inhibitor

Hot injection with TRPV1-, TRPA1, TRPM3- and chloride channel inhibition

EXPERIMENTAL

Pain is induced by an increasingly hot intradermal injection up to 52°C over 2 minutes, while TRPV1, TRPA1, TRPM3 and a chloride channel are blocked pharmacologically by an antagonist dissolved in the hot fluid (synthetic interstitial fluid). The antagonist(s) have sufficient concentration to reliably block the channel. The total dose is in the range of a microdose trial.

Drug: TRPA1-inhibitor; Drug: TRPV1-inhibitor; Drug: TRPM3-inhibitor; Drug: Chloride-channel inhibitor

Hot injection with TRPM3- and chloride channel inhibition

EXPERIMENTAL

Pain is induced by an increasingly hot intradermal injection up to 52°C over 2 minutes, while TRPM3 and a chloride channel are blocked pharmacologically by an antagonist dissolved in the hot fluid (synthetic interstitial fluid). The antagonist(s) have sufficient concentration to reliably block the channel. The total dose is in the range of a microdose trial.

Drug: TRPM3-inhibitor; Drug: Chloride-channel inhibitor

Hot injection with TRPV1-, TRPA1, and chloride channel inhibition

EXPERIMENTAL

Pain is induced by an increasingly hot intradermal injection up to 52°C over 2 minutes, while TRPV1, TRPA1, and a chloride channel are blocked pharmacologically by an antagonist dissolved in the hot fluid (synthetic interstitial fluid). The antagonist(s) have sufficient concentration to reliably block the channel. The total dose is in the range of a microdose trial.

Drug: TRPA1-inhibitor; Drug: TRPV1-inhibitor; Drug: Chloride-channel inhibitor

Hot injection with chloride channel inhibition

EXPERIMENTAL

Pain is induced by an increasingly hot intradermal injection up to 52°C over 2 minutes, while a chloride channel is blocked pharmacologically by an antagonist dissolved in the hot fluid (synthetic interstitial fluid). The antagonist(s) have sufficient concentration to reliably block the channel. The total dose is in the range of a microdose trial.

Drug: Chloride-channel inhibitor

Interventions

TRPA1-inhibitor DRUG

Pharmacological inhibition of TRPA1 during intradermal injection of hot synthetic interstitial fluid

Also known as: Specific antagonist of the TRPA1 channel

Hot injection with TRPA1- and TRPM3-inhibition; Hot injection with TRPA1- and TRPV1-inhibition; Hot injection with TRPA1- and chloride channel inhibition; Hot injection with TRPA1-, TRPM3- and chloride channel inhibition; Hot injection with TRPA1-, TRPV1 and TRPM3-inhibition; Hot injection with TRPA1-inhibition; Hot injection with TRPV1-, TRPA1, TRPM3- and chloride channel inhibition; Hot injection with TRPV1-, TRPA1, and chloride channel inhibition

TRPV1-inhibitor DRUG

Pharmacological inhibition of TRPV1 during intradermal injection of hot synthetic interstitial fluid

Also known as: Specific antagonist of the TRPV1 channel

Hot injection with TRPA1- and TRPV1-inhibition; Hot injection with TRPA1-, TRPV1 and TRPM3-inhibition; Hot injection with TRPM3- and TRPV1-inhibition; Hot injection with TRPV1- and chloride channel inhibition; Hot injection with TRPV1-, TRPA1, TRPM3- and chloride channel inhibition; Hot injection with TRPV1-, TRPA1, and chloride channel inhibition; Hot injection with TRPV1-, TRPM3- and chloride channel inhibition; Hot injection with TRPV1-inhibition

TRPM3-inhibitor DRUG

Pharmacological inhibition of TRPM3 during intradermal injection of hot synthetic interstitial fluid

Also known as: Specific antagonist of the TRPM3 channel

Hot injection with TRPA1- and TRPM3-inhibition; Hot injection with TRPA1-, TRPM3- and chloride channel inhibition; Hot injection with TRPA1-, TRPV1 and TRPM3-inhibition; Hot injection with TRPM3- and TRPV1-inhibition; Hot injection with TRPM3- and chloride channel inhibition; Hot injection with TRPM3-inhibition; Hot injection with TRPV1-, TRPA1, TRPM3- and chloride channel inhibition; Hot injection with TRPV1-, TRPM3- and chloride channel inhibition

Placebo DRUG

No pharmacological intervention

Also known as: No antagonist

Hot injection without TRP-channel inhibition

Chloride-channel inhibitor DRUG

Pharmacological inhibition of a chloride channel during intradermal injection of hot synthetic interstitial fluid

Also known as: Specific inhibitor of a chloride channel

Hot injection with TRPA1- and chloride channel inhibition; Hot injection with TRPA1-, TRPM3- and chloride channel inhibition; Hot injection with TRPM3- and chloride channel inhibition; Hot injection with TRPV1- and chloride channel inhibition; Hot injection with TRPV1-, TRPA1, TRPM3- and chloride channel inhibition; Hot injection with TRPV1-, TRPA1, and chloride channel inhibition; Hot injection with TRPV1-, TRPM3- and chloride channel inhibition; Hot injection with chloride channel inhibition

Eligibility Criteria

• Age: 18 Years - 70 Years
• Sex: all
• Healthy Volunteers: Yes
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• 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.

You may not qualify if:

• 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)

Sponsors & Collaborators

• Medical University of Vienna: lead

Study Sites (1)

Medical University of Vienna

Vienna, 1090, Austria

Location

MeSH Terms

Conditions

Pain

Condition Hierarchy (Ancestors)

Neurologic Manifestations; Signs and Symptoms; Pathological Conditions, Signs and Symptoms

Study Officials

• Michael JM Fischer, Professor MD

  Medical University of Vienna

  STUDY CHAIR

Study Design

• Study Type: interventional
• Phase: early phase 1
• Allocation: RANDOMIZED
• Masking: TRIPLE
• Who Masked: PARTICIPANT, CARE PROVIDER, OUTCOMES ASSESSOR
• Purpose: BASIC SCIENCE
• Intervention Model: SINGLE GROUP
• Sponsor Type: OTHER
• Responsible Party: PRINCIPAL INVESTIGATOR
• PI Title: Principal Investigator

Model Details: 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

Study Record Dates

• First Submitted: February 22, 2022
• First Posted: March 11, 2022
• Study Start: June 13, 2022
• Primary Completion: November 30, 2022
• Study Completion: November 30, 2022
• Last Updated: March 17, 2023

Record last verified: 2023-03

Data Sharing

• IPD Sharing: Will share
• Shared Documents: STUDY PROTOCOL, ANALYTIC CODE
• Time Frame: As soon as the study is published.
• Access Criteria: Access will be granted to other researchers as well as clinicians.

Locations

AU (1)