Menthol for Dyspnea Relief in Health and COPD

Study Overview
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Brief Summary
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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.

Detailed Description
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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).

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

Conditions
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Dyspnea, Chronic Obstructive Pulmonary Disease

Intervention / Treatment
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* Other: Menthol inhalation
* Other: Strawberry scent


Participation Criteria
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Eligibility Criteria
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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

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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Accepts Healthy Volunteers

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Crossover Assignment
Masking: Single


Arms and Interventions

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

What is the study measuring?
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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 | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Menthol