Clinical trial NCT05955885: Effect of Over-the-counter NSAIDS on Cough Reflex Sensitivity in Patients with Upper Respiratory Tract Infections
Official title: Effect of Over-the-counter Non-steroidal Anti-inflammatory Treatments on Cough Reflex Sensitivity in Subjects with Upper Respiratory Tract Infection
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: EARLY_PHASE1
Conditions: Cough
Upper Respiratory Tract Infections
Keywords: Cough
Cough sensitivity
Urge to cough
Respiratory tract infection
Non-steroidal anti-inflammatory drug
Mechanism of disease
Lead sponsor: University of Melbourne
Sponsor class: OTHER
Collaborators: name: Reckitt Benckiser LLC
First posted: 2023-07-21
Enrollment: 101
Sex: ALL
Minimum age (years): 18
Maximum age (years): 70
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: yes
Allocation: RANDOMIZED
Intervention model: PARALLEL
Intervention model description: 120 participants will be randomised into four study arms, i.e. treatment with:

1. flurbiprofen lozenge
2. placebo lozenge
3. flurbiprofen spray
4. low dose flurbiprofen spray

Regardless of which arm they are assigned to, each participant will undergo cough challenge testing to test cough sensitivity, fill out quality of life questionnaires, and have their nasal fluid, saliva and pharyngeal fluid sampled for inflammatory markers before and after the intervention.
Primary purpose: BASIC_SCIENCE

Brief summary: The goal of this mechanism of disease study is to investigate the effect of flurbiprofen, a non-steroidal anti-inflammatory drug (NSAID), on the cough hypersensitivity associated with upper respiratory tract infections (URTI).

The main questions it aims to answer are:

* Q1: Does a single treatment with an approved therapeutic dose of flurbiprofen, an NSAID that prevents the production of prostaglandins, acutely reduce objective measures of cough hypersensitivity in participants with URTI?
* Q2: Is the effect of flurbiprofen on cough hypersensitivity in URTI related to participant subjective ratings of acute cough severity?
* Q3: Is the effect of flurbiprofen on cough hypersensitivity in URTI related to the levels of prostaglandins or other inflammatory markers measurable in upper airway secretions?

Participants will be asked to undergo cough challenge testing, complete quality of life questionnaires, and have their nasal fluid, saliva and pharyngeal secretions sampled before and after a single treatment with flurbiprofen in the form of a lozenge or spray. Participants in the comparator arms of the study will instead receive a placebo lozenge or low dose flurbiprofen spray.

Detailed description: People with an Upper Respiratory Tract Infection (URTI), for example the common cold, often exhibit heightened sensitivity to stimuli that cause coughing. This heightened sensitivity is thought to contribute to the short-term excessive coughing that accompanies the infection. What causes the heightened sensitivity is not known but may involve inflammation in the throat.

HYPOTHESIS: The investigators hypothesise that in URTI prostaglandins may lead to cough hypersensitivity by either a direct or indirect action on cough nerve fibre endings in the larynx, lowering their activation threshold to cough stimuli.

OVERALL AIM: This study aims to investigate this hypothesis by assessing whether a single treatment with flurbiprofen, an existing over the counter anti-inflammatory drug (NSAID) medication contained in some 'cold and flu remedies' and used to relieve sore throat in URTI, reduces heightened cough sensitivity through a reduction in throat inflammation. The investigators will recruit 120 otherwise healthy male and female adults experiencing an URTI with acute cough for laboratory assessments lasting 5-6 hours.

OBJECTIVES: The primary objective is to assess whether flurbiprofen, in commercially available lozenge or spray formulations, reduces an individual's sensitivity to a cough evoking stimulus by assessing participant responsiveness to inhaled capsaicin. Capsaicin is the naturally occurring 'hot' component of chilli peppers and commonly used to investigate the cough reflex in humans.

The secondary objectives are to assess the effect of flurbiprofen on:

A. subjective measures of cough and urge-to-cough using questionnaires that assess Patient Reported Outcomes (PROs); and, B. the levels of chemical mediators of inflammation present in nasal secretions and saliva, to investigate flurbiprofen's potential mechanism of action.

METHOD: The investigators will test the hypothesis by measuring in participants their cough thresholds, subjective experiences with cough and urge-to-cough, and levels of airway prostaglandins and other inflammatory mediators, before and after a single treatment of flurbiprofen, which blocks the production of prostaglandins.

Eligibility criteria: Inclusion Criteria:

* An onset of any 2 URTI symptoms in past 3-5 days, such as a sore throat, fever, coughing, coughing up phlegm, sneezing, and runny nose;
* A current cough or urge-to-cough rated at least 5 in severity and/or ranking cough as subject's most bothersome symptom on Cold Symptoms Questionnaire (CSQ);
* A feeling of sickness interfering with their daily life, rated as at least mildly;
* A cough consistent with acute cough - i.e., cough onset with URTI and not ongoing, chronic cough;
* Written informed consent and a willingness and ability to comply with the study protocol.

Exclusion Criteria:

* A pre-existing chronic lung disease (asthma, COPD, chronic bronchitis etc), to exclude these as causes for cough;
* The use of inhaled or systemic steroids / broncho-active medication, ACE inhibitors, oral or inhaled antihistamines, opiates, gabapentin, tricyclic antidepressants (current or within the past 3 months), as these will alter airway inflammatory profiles and/ or cough sensitivity;
* A current cigarette or marijuana smoker/vaper, recreational drug user, or have given up smoking/vaping within the last 12 months, or a former smoker with greater than 20 pack-years, alter airway inflammatory profiles and/ or cough sensitivity;
* Pre-existing chronic cough (cough persisting for more than 8 weeks): unexplained chronic cough (UCC) or refractory chronic cough (RCC) associated with or without a pre-existing condition (GERD, rhinitis, etc), as we are studying acute cough;
* Prior experience of an allergic or bad reaction to capsaicin or chilli (which is rare);
* Prior experience an allergic or bad reaction to a non-steroidal anti-inflammatory drug (NSAID) such as ibuprofen;
* Ongoing or history of stomach ulcer, impaired kidney or liver function, or heart failure;
* Pregnancy, lactation or actively trying to become pregnant;
* Currently taking other products with flurbiprofen, aspirin or other anti-inflammatory medicines;
* Evidence of COVID-19 positivity, either during the COVID Rapid Antigen Test administered on the day of assessment or have informed us that they have become positive in the 24-48 hours after the testing session (i.e., participants who were likely positive during assessment but under the detection threshold);
* Participants who cannot provide informed voluntary consent.

Primary outcomes:
measure: Change in objective measures of cough sensitivity
timeFrame: Cough challenge testing will be performed at baseline and 3 hours after intervention.
Secondary outcomes:
measure: Change in Cold Symptoms Questionnaire (CSQ) score
timeFrame: Participant self-reports using the Cold Symptoms Questionnaire at baseline and every 30 min after invention until 3 hours has elapsed.
measure: Change in levels of inflammatory markers in nasal fluid samples
timeFrame: Nasal fluid samples will be taken at baseline and at 3 hours post-intervention.
measure: Change in levels of inflammatory markers in saliva samples
timeFrame: Saliva samples will be taken at baseline and at 3 hours post-intervention.
measure: Change in levels of inflammatory markers in pharyngeal lavage samples
timeFrame: Pharyngeal lavage samples will be taken at baseline and at 3 hours post-intervention.
measure: Patients' Global Impression of Change score
timeFrame: Participants self-report using the Patients' Global Impression of Change score at 3 hours post-intervention.
Other outcomes:
measure: Leicester Cough Questionnaire - Acute score
timeFrame: Participants self-report using the Leicester Cough Questionnaire at baseline.
measure: Optional: Acute Cough Scale (ACS) score
timeFrame: Participants self-report using the Acute Cough Scale at baseline.
measure: Optional: 8-item Quality of Life General (QGEN-8) survey
timeFrame: Participants self-report using the 8-item Quality of Life General survey at baseline.
Locations:
city: Carlton
country: Australia
facility: University of Melbourne
state: Victoria
Study officials:
affiliation: University of Melbourne
name: Stuart Mazzone, PhD
role: PRINCIPAL_INVESTIGATOR
References:
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