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Effect of Over-the-counter NSAIDS on Cough Reflex Sensitivity in Patients With Upper Respiratory Tract Infections

Primary Purpose

Cough, Upper Respiratory Tract Infections

Status

Recruiting

Phase

Early Phase 1

Locations

Australia

Study Type

Interventional

Intervention

Flurbiprofen Oral Lozenge

Difflam

Flurbiprofen 8.75 MG

About this trial

This is an interventional basic science trial for Cough focused on measuring Cough, Cough sensitivity, Urge to cough, Respiratory tract infection, Non-steroidal anti-inflammatory drug, Mechanism of disease

Eligibility Criteria

18 Years - 70 Years (Adult, Older Adult)All SexesAccepts Healthy Volunteers

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.

Sites / Locations

University of MelbourneRecruiting

Arms of the Study

Arm 1

Arm 2

Arm 3

Arm 4

Arm Type

Experimental

Placebo Comparator

Experimental

Other

Arm Label

Flurbiprofen Oral Lozenge

Placebo lozenge

Flurbiprofen 8.75 MG

Low dose flurbiprofen spray

Arm Description

30 participants will be asked to suck one (1) flurbiprofen 8.75 mg honey and lemon lozenge (tradename: Strepfen) until dissolved.

30 participants will be asked to suck one (1) non-medicated Difflam Soothing Drops + Immune Support Honey & Lemon flavour lozenge until dissolved.

30 participants will be asked to perform three (3) oral actuations (2.91 mg per actuation) of flurbiprofen 8.75mg spray.

30 participants will be asked to perform one (1) oral actuation of flurbiprofen 8.75 mg spray, equivalent to a 2.91mg dosage. This will serve a a low dose control as there is no placebo spray available.

Outcomes

Primary Outcome Measures

Change in objective measures of cough sensitivity

Participants' cough sensitivity thresholds will be measured by inhaled cough challenge testing. This involves participants inhaling single breaths of increasing concentrations of a tussigenic stimulus (capsaicin; (active component of hot chili peppers) as well as saline control to determine threshold doses that elicit an urge to cough, two coughs (C2) and five coughs (C5). The principal endpoint is measured as the change in capsaicin concentration needed to elicit cough responses and the unit of measure is micromolar.

Secondary Outcome Measures

Change in Cold Symptoms Questionnaire (CSQ) score

Participants will be asked to self-report on their cold symptom severity using the Cold Symptoms Questionnaire. Each item requires rating on a 10-point Likert scale from 1 to 10. A higher score indicates a worse outcome. The principal endpoint is measured as the change in Cold Symptoms Questionnaire score and the unit of measure is points.

Change in levels of inflammatory markers in nasal fluid samples

Samples of nasal fluid will be taken from participants and levels of inflammatory markers such as prostaglandins will be measured using liquid chromatography-mass spectroscopy. The principle endpoint is measured as change in levels and the unit of measure is points. A higher score indicates a better outcome.

Change in levels of inflammatory markers in saliva samples

Samples of saliva will be taken from participants and levels of inflammatory markers such as prostaglandins will be measured using liquid chromatography-mass spectroscopy. The principle endpoint is measured as change in levels and the unit of measure is points. A higher score indicates a better outcome.

Change in levels of inflammatory markers in pharyngeal lavage samples

Samples of pharyngeal fluid and tissue will be collected from a lavage and levels of inflammatory markers such as prostaglandins will be measured using liquid chromatography-mass spectroscopy. The principle endpoint is measured as change in levels and the unit of measure is points. A higher score indicates a better outcome.

Patients' Global Impression of Change score

Participants will self-report on their overall impression of whether the intervention they received resulted in any perceivable changes in their coughing/urge-to-cough. This questionnaire contains mixed items, including items that require rating of degree of change of symptoms on a 10 point Likert scale. The principal endpoint is the score for each item and the unit of measure is points.A higher score indicates a worse outocme.

Full Information

NCT ID

NCT05955885

First Posted

July 11, 2023

Last Updated

July 23, 2023

Sponsor

University of Melbourne

Collaborators

Reckitt Benckiser LLC

1. Study Identification

Unique Protocol Identification Number

NCT05955885

Brief Title

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

2. Study Status

Record Verification Date

July 2023

Overall Recruitment Status

Recruiting

Study Start Date

July 1, 2023 (Actual)

Primary Completion Date

July 1, 2024 (Anticipated)

Study Completion Date

July 1, 2024 (Anticipated)

3. Sponsor/Collaborators

Responsible Party, by Official Title

Principal Investigator

Name of the Sponsor

University of Melbourne

Collaborators

Reckitt Benckiser LLC

4. Oversight

Studies a U.S. FDA-regulated Drug Product

Studies a U.S. FDA-regulated Device Product

Product Manufactured in and Exported from the U.S.

Data Monitoring Committee

5. Study Description

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.

6. Conditions and Keywords

Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study

Cough, Upper Respiratory Tract Infections

Keywords

Cough, Cough sensitivity, Urge to cough, Respiratory tract infection, Non-steroidal anti-inflammatory drug, Mechanism of disease

7. Study Design

Primary Purpose

Basic Science

Study Phase

Early Phase 1

Interventional Study Model

Parallel Assignment

Model Description

120 participants will be randomised into four study arms, i.e. treatment with: flurbiprofen lozenge placebo lozenge flurbiprofen spray 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.

Masking

Participant

Masking Description

The study will involve one-way blinding. Participants will be made aware prior to consenting that they will receive either flurbiprofen or a control intervention during the initial briefing and screening communications. However, they will not be told if the intervention they receive will contain flurbiprofen, a low dose of flurbiprofen, or no flurbiprofen. Blinding of the researchers to the identity of the treatment is difficult to achieve in practice given the physical characteristics of the interventions. Regardless of this, the researchers don't have any subjective role in quantifying the endpoint measures (patient-reported outcomes and cough sensitivity), minimising the risk of influencing the findings. For these reasons, the pragmatic approach of single blinding of the experiment is appropriate, acknowledging that this experiment is not designed to be a true clinical trial.

Allocation

Randomized

Enrollment

120 (Anticipated)

8. Arms, Groups, and Interventions

Arm Title

Flurbiprofen Oral Lozenge

Arm Type

Experimental

Arm Description

30 participants will be asked to suck one (1) flurbiprofen 8.75 mg honey and lemon lozenge (tradename: Strepfen) until dissolved.

Arm Title

Placebo lozenge

Arm Type

Placebo Comparator

Arm Description

30 participants will be asked to suck one (1) non-medicated Difflam Soothing Drops + Immune Support Honey & Lemon flavour lozenge until dissolved.

Arm Title

Flurbiprofen 8.75 MG

Arm Type

Experimental

Arm Description

30 participants will be asked to perform three (3) oral actuations (2.91 mg per actuation) of flurbiprofen 8.75mg spray.

Arm Title

Low dose flurbiprofen spray

Arm Type

Other

Arm Description

Intervention Type

Drug

Intervention Name(s)

Flurbiprofen Oral Lozenge

Other Intervention Name(s)

Strepfen Intensive Lozenge - Honey and Lemon Flavour

Intervention Description

This commercially available, over-the-counter lozenge manufactured by Reckitt Benckiser contains flurbiprofen as the active ingredient and is registered for the short-term treatment of sore throat associated with upper respiratory tract infections in people over the age of 12 years.

Intervention Type

Drug

Intervention Name(s)

Difflam

Other Intervention Name(s)

Difflam Soothing Drops + Immune Support Honey & Lemon Flavour

Intervention Description

This is a non-medicated, control lozenge that is the same flavour as the experimental lozenge that is marketed to help soothe dry, tickly throats while supporting the body's immune health.

Intervention Type

Drug

Intervention Name(s)

Flurbiprofen 8.75 MG

Other Intervention Name(s)

Strepfen Intensive Oromucosal Spray; Strepsils Intensive Oromucosal Spray

Intervention Description

This commercially available, over-the-counter spray manufactured by Reckitt Benckiser contains flurbiprofen as the active ingredient and is registered for the short-term treatment of sore throat associated with upper respiratory tract infections in people over the age of 12 years. It requires 3 actuations of the spray to deliver the full 8.75 dose. Here, a low dose control can be delivered by only performing 1 actuation of the spray.

Primary Outcome Measure Information:

Title

Change in objective measures of cough sensitivity

Description

Time Frame

Cough challenge testing will be performed at baseline and 3 hours after intervention.

Secondary Outcome Measure Information:

Title

Change in Cold Symptoms Questionnaire (CSQ) score

Description

Time Frame

Participant self-reports using the Cold Symptoms Questionnaire at baseline and every 30 min after invention until 3 hours has elapsed.

Title

Change in levels of inflammatory markers in nasal fluid samples

Description

Time Frame

Nasal fluid samples will be taken at baseline and at 3 hours post-intervention.

Title

Change in levels of inflammatory markers in saliva samples

Description

Time Frame

Saliva samples will be taken at baseline and at 3 hours post-intervention.

Title

Change in levels of inflammatory markers in pharyngeal lavage samples

Description

Time Frame

Pharyngeal lavage samples will be taken at baseline and at 3 hours post-intervention.

Title

Patients' Global Impression of Change score

Description

Time Frame

Participants self-report using the Patients' Global Impression of Change score at 3 hours post-intervention.

Other Pre-specified Outcome Measures:

Title

Leicester Cough Questionnaire - Acute score

Description

Participants will be asked to self-report on the impact of cough on their quality of life to enable a measurement of how severe their cough is at baseline. Each item requires a rating on a 7-point Likert scale from 1 to 7 and is related to the impact of cough in one of three domains (physical, psychological social). The Leicester Cough Questionnaire is scored by averaging the ratings in each domain and then adding the average domain scores (range 3-21). A higher score indicates a better outcome. The principal endpoint is measured as the overall Leicester Cough Questionnaire score and the unit of measure is points.

Time Frame

Participants self-report using the Leicester Cough Questionnaire at baseline.

Title

Optional: Acute Cough Scale (ACS) score

Description

Inclusion of this scale is exploratory and participants may choose to do it. It is new, alternative scale to a Visual Analogue Scale that enables the respondent to describe their cough in a more detailed fashion through 13 items that capture specific dimensions of cough and using a 6 point Likert scale from 0 to 5 with cues given at each grade. The principle endpoint is measured as total score and the unit of measure is points. A higher score indicates a greater severity of cough and disturbance to daily well-being, i.e. worse outcome.

Time Frame

Participants self-report using the Acute Cough Scale at baseline.

Title

Optional: 8-item Quality of Life General (QGEN-8) survey

Description

Inclusion of this scale is exploratory and participants may choose to do it. It is new survey that condenses the numerous items measuring functional health and well-being in other, lengthy health-related quality of life surveys into an 8-item survey that reduces the time and effort burden on survey respondents. It also extends the measurement range to reduce ceiling effects commonly noted in the functioning and feeling domains. The principle endpoint is measured as total score and the unit of measure is points. A higher score indicates a greater quality of life.

Time Frame

Participants self-report using the 8-item Quality of Life General survey at baseline.

10. Eligibility

Sex

All

Minimum Age & Unit of Time

18 Years

Maximum Age & Unit of Time

70 Years

Accepts Healthy Volunteers

Eligibility Criteria

Central Contact Person:

First Name & Middle Initial & Last Name or Official Title & Degree

Stuart Mazzone, PhD

Phone

+61383446457

stuart.mazzone@unimelb.edu.au

First Name & Middle Initial & Last Name or Official Title & Degree

Tara Bautista, PhD

Phone

+61383448900

tara.bautista@unimelb.edu.au

Overall Study Officials:

First Name & Middle Initial & Last Name & Degree

Stuart Mazzone, PhD

Organizational Affiliation

University of Melbourne

Official's Role

Principal Investigator

Facility Information:

Facility Name

University of Melbourne

City

Carlton

State/Province

Victoria

ZIP/Postal Code

3010

Country

Australia

Individual Site Status

Recruiting

Facility Contact:

First Name & Middle Initial & Last Name & Degree

Stuart Mazzone, PhD

Phone

0383446457

stuart.mazzone@unimelb.edu.au

First Name & Middle Initial & Last Name & Degree

Tara Bautista, PhD

tara.bautista@unimelb.edu.au

12. IPD Sharing Statement

Plan to Share IPD

Citations:

PubMed Identifier

30763726

Citation

Mazzone SB, Farrell MJ. Heterogeneity of cough neurobiology: Clinical implications. Pulm Pharmacol Ther. 2019 Apr;55:62-66. doi: 10.1016/j.pupt.2019.02.002. Epub 2019 Feb 11.

Results Reference

background

PubMed Identifier

31100512

Citation

Farrell MJ, Mazzone SB. Are neural pathways processing airway inputs sensitized in patients with cough hypersensitivity? Pulm Pharmacol Ther. 2019 Aug;57:101806. doi: 10.1016/j.pupt.2019.101806. Epub 2019 May 15.

Results Reference

background

PubMed Identifier

25383204

Citation

Dicpinigaitis PV. Effect of viral upper respiratory tract infection on cough reflex sensitivity. J Thorac Dis. 2014 Oct;6(Suppl 7):S708-11. doi: 10.3978/j.issn.2072-1439.2013.12.02.

Results Reference

background

PubMed Identifier

28137663

Citation

Driessen AK, McGovern AE, Narula M, Yang SK, Keller JA, Farrell MJ, Mazzone SB. Central mechanisms of airway sensation and cough hypersensitivity. Pulm Pharmacol Ther. 2017 Dec;47:9-15. doi: 10.1016/j.pupt.2017.01.010. Epub 2017 Jan 27.

Results Reference

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PubMed Identifier

22890476

Citation

Renner B, Mueller CA, Shephard A. Environmental and non-infectious factors in the aetiology of pharyngitis (sore throat). Inflamm Res. 2012 Oct;61(10):1041-52. doi: 10.1007/s00011-012-0540-9. Epub 2012 Aug 14.

Results Reference

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PubMed Identifier

33029351

Citation

Lambkin-Williams R, Mann A, Shephard A. Inhibition of viral and bacterial trigger-stimulated prostaglandin E2 by a throat lozenge containing flurbiprofen: An in vitro study using a human respiratory epithelial cell line. SAGE Open Med. 2020 Sep 24;8:2050312120960568. doi: 10.1177/2050312120960568. eCollection 2020.

Results Reference

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PubMed Identifier

12011823

Citation

Schachtel BP, Homan HD, Gibb IA, Christian J. Demonstration of dose response of flurbiprofen lozenges with the sore throat pain model. Clin Pharmacol Ther. 2002 May;71(5):375-80. doi: 10.1067/mcp.2002.124079.

Results Reference

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PubMed Identifier

24231654

Citation

Schachtel B, Aspley S, Shephard A, Shea T, Smith G, Sanner K, Savino L, Rezuke J, Schachtel E. Onset of action of a lozenge containing flurbiprofen 8.75 mg: a randomized, double-blind, placebo-controlled trial with a new method for measuring onset of analgesic activity. Pain. 2014 Feb;155(2):422-428. doi: 10.1016/j.pain.2013.11.001. Epub 2013 Nov 12.

Results Reference

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Effect of Over-the-counter NSAIDS on Cough Reflex Sensitivity in Patients With Upper Respiratory Tract Infections

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