Menthol for Dyspnea Relief in Health and COPD (MENTHODYSC)

Effectiveness and Mechanisms of Menthol Inhalation for the Relief of Dyspnea in Health and COPD

Menthol inhalation (MI) is a novel and promising treatment option for acute relief of dyspnea, however, the underlying ventilatory and/or neural related mechanisms for this relief in symptoms remain unknown. The overall aim of this research project is to systematically examine the mechanisms of dyspnea relief from MI in healthy individuals and those with COPD.

Study Overview

• Status: Recruiting
• Conditions: Chronic Obstructive Pulmonary Disease; Dyspnea
• Intervention / Treatment: Other: Menthol inhalation; Other: Strawberry scent

Detailed Description

The project is structured in 4 work packages (WP), each including a different sample of healthy volunteers (WP1, 2) or patients with COPD (WP3, 4), respectively with a 1:1 female/male ratio in each WP. Each WP will be single-blind, placebo-controlled cross-over trial to investigate the effects of MI compared to placebo in healthy volunteers during resistive loaded breathing (WP1), in healthy volunteers during cycling exercise (WP2), in people with COPD who have dyspnea at rest (WP3), and in people with COPD during cycling exercise (WP4).

• Study Type: Interventional
• Enrollment (Anticipated): 120
• Phase: Not Applicable

Contacts and Locations

• Study Contact: Name: Daniel Langer; Phone Number: +32 16 37 64 97; Email: daniel.langer@kuleuven.be

Study Locations

• Belgium
  • Leuven, Belgium, 3000
    • Recruiting
    • University Hospital Leuven
    • Principal Investigator: Daniel Langer
    • Sub-Investigator: Andreas von Leuopoldt
    • Principal Investigator: Wim Janssens

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: Yes
• Genders Eligible for Study: All

Description

Inclusion Criteria:

• Age: 18 years of age or older
• Able to speak, read, and write Dutch or English
• Normal pulmonary function: forced expiratory volume in 1 second (FEV1) to forced vital capacity ratio>0.70; FEV1≥80%predicted (WP1 and 2 only)
• Non-smoker or former smokers (smoke-free ≥12 months prior to enrolment) (WP1 and 2 only)
• Clinically stable COPD (based on clinical judgment of the study physician that have not had exacerbations requiring escalation of medical therapy (i.e., short course of oral corticosteroids or antibiotics) within the preceding 14 days (WP3 and 4 only)

Exclusion Criteria:

• Contraindication to exercise testing (e.g., significant cardiovascular, musculoskeletal, neurological disease; see Table 4 from ERS/ATS consensus statement)
• Significant pulmonary or extra-pulmonary disease that, based on clinical assessment, could influence dyspnea and/or impair exercise capacity (with the exception of COPD in WP3 and 4)
• Body mass index <18.5 or >35 kg/m2
• An ulcer or tumor in the esophagus, a nasal septum deviation, or recent nasopharyngeal surgery
• Severe facial trauma including cribriform plate disruption (bone separating brain from nasal cavity)
• Allergies to latex and sensitivities to local anesthetics
• Inability to give informed consent, including those with significant cognitive impairment
• Alcohol consumption within 12 hours of study visit
• Current smoker*
• History of early menopause (age <45 years)
• Pregnancy or desire to become pregnant while in trial

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Crossover Assignment
• Masking: Single

Number of Arms

9

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: WP 1a; Menthol inhalation during resistive loaded breathing trials in healthy participants.	Other: Menthol inhalation; 300 milligrams of L-menthol will be deposited on to a cellulose swab and secured inside the lower portion of a sealed facemask.
Placebo Comparator: WP 1b; Strawberry scent during resistive loaded breathing trials in healthy participants.	Other: Strawberry scent; 600 microliters of 100% natural strawberry flavoring will be deposited onto on to a cellulose swab and secured inside the lower portion of a sealed facemask.
Experimental: WP 2a; Menthol inhalation during cycle exercise in healthy participants.	Other: Menthol inhalation; 300 milligrams of L-menthol will be deposited on to a cellulose swab and secured inside the lower portion of a sealed facemask.
Placebo Comparator: WP 2b; Strawberry scent during cycle exercise in healthy participants.	Other: Strawberry scent; 600 microliters of 100% natural strawberry flavoring will be deposited onto on to a cellulose swab and secured inside the lower portion of a sealed facemask.
Experimental: WP 3a; Menthol inhalation during resting breathing in dyspneic COPD participants.	Other: Menthol inhalation; 300 milligrams of L-menthol will be deposited on to a cellulose swab and secured inside the lower portion of a sealed facemask.
Placebo Comparator: WP 3b; Strawberry scent during resting breathing in dyspneic COPD participants.	Other: Strawberry scent; 600 microliters of 100% natural strawberry flavoring will be deposited onto on to a cellulose swab and secured inside the lower portion of a sealed facemask.
No Intervention: WP 3c; Resting breathing in dyspneic COPD participants.
Experimental: WP 4a; Menthol inhalation during cycle exercise in COPD participants.	Other: Menthol inhalation; 300 milligrams of L-menthol will be deposited on to a cellulose swab and secured inside the lower portion of a sealed facemask.
Placebo Comparator: WP 4b; Strawberry scent during cycle exercise in COPD participants.	Other: Strawberry scent; 600 microliters of 100% natural strawberry flavoring will be deposited onto on to a cellulose swab and secured inside the lower portion of a sealed facemask.

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Difference in respiratory-related evoked potentials (RREP) with menthol vs. strawberry.	RREPs will be measured using an electroencephalogram (EEG) sensor cap connected to a high-density 129 channel EEG system during breathing trials and exercise tests. Inspiration will briefly be interrupted for 150 milliseconds every two to six breaths by activation of the occluder, which induces the RREP in the EEG signal.	1 week

Other Outcome Measures

Outcome Measure	Measure Description	Time Frame
Difference in diaphragmatic electromyography with menthol vs. strawberry.	Diaphragmatic electromyography will be measured using a multi-pair electrode catheter during breathing trials and exercise tests. and used as an index of neural respiratory drive.	1 week
Difference in dyspnea with menthol vs. strawberry.	Dyspnea ratings will be measured using the Borg 0-10 category ratio scale and will be assessed at the end of each 5-minute breathing trial (WP1 and 3) and at baseline, every minutes during, and at peak of each cycle exercise test (WP2 and 4). 0 represents no dyspnea at all and then 10 the most maximal dyspnea ever experienced or could be imagined experiencing.	1 week
Difference in the rate of perceived inspiratory airflow	Participants will be asked: "In which of the two conditions did your airflow feel easier when breathing in?" at the end of each study visit.	1 week
Perception of a cooling sensation	Participants will be asked: "In which of the two conditions did you feel a fresh or cooling sensation when breathing in?" at the end of each study visit.	1 week
Difference in activation of extra-diaphragmatic inspiratory muscles with menthol vs. strawberry.	Activation of extra-diaphragmatic inspiratory muscles will be measured using bipolar surface electrodes during breathing trials and exercise testing.	1 week
Difference in the cardiorespiratory responses to exercise with menthol vs. strawberry.	Cardiorespiratory responses to exercise will be measured on a breath-by-breath basis using a commercially available cardiopulmonary testing system during exercise testing.	1 week
Difference in respiratory pressures with menthol vs. strawberry	Respiratory pressures will be measured using esophageal and gastric balloons during breathing trials and exercise testing.	1 week
Difference in leg discomfort ratings with menthol vs. strawberry.	Leg discomfort will be measured using the Borg 0-10 category ratio scale at baseline, every minute during, and at peak of each cycle exercise test (WP2 and 4). 0 represents no leg discomfort at all and then 10 the most maximal leg discomfort ever experienced or could be imagined experiencing.	1 week
Difference in exercise endurance time with menthol vs. strawberry.	Exercise endurance time will be measured during submaximal constant load cycle exercise testing (WP 2 and 4).	1 week
Difference in the reasons for stopping exercise with menthol vs. strawberry.	Participants will be asked to give their reasons for stopping (e.g., "breathing discomfort," "leg discomfort," "a combination of breathing and leg discomfort," or "other") and attributing a percentage to each of breathing discomfort and leg discomfort to total 100 (WP 2 and 4).	1 week
Difference in ratings of affective state on the dimensions of valence and arousal with menthol vs. strawberry.	Dimensions of valence and arousal will be measured using the 9-point SAM scale at the end of each breathing trial (WP 1 and 3) and at peak exercise (WP 2 and 4).	1 week

Collaborators and Investigators

• Sponsor: KU Leuven
• Investigators: Principal Investigator: Daniel Langer, KU Leuven

Study record dates

Study Major Dates

• Study Start (Actual): January 1, 2023
• Primary Completion (Anticipated): December 31, 2026
• Study Completion (Anticipated): June 30, 2027

Study Registration Dates

• First Submitted: February 7, 2023
• First Submitted That Met QC Criteria: March 14, 2023
• First Posted (Actual): March 27, 2023

Study Record Updates

• Last Update Posted (Actual): March 27, 2023
• Last Update Submitted That Met QC Criteria: March 14, 2023
• Last Verified: March 1, 2023

More Information

Terms related to this study

• Keywords: Menthol
• Additional Relevant MeSH Terms: Respiratory Tract Diseases; Respiration Disorders; Lung Diseases; Signs and Symptoms, Respiratory; Lung Diseases, Obstructive; Pulmonary Disease, Chronic Obstructive; Dyspnea; Dermatologic Agents; Antipruritics; Menthol
• Other Study ID Numbers: S66762

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: NO

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No