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

NCT05955885 | Completed Early Phase 1

• 1 other identifier: 25925
• Study Type: interventional
• Target: 101
• Locations: 1 country
• Sites: 1

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.

Conditions

Cough; Upper Respiratory Tract Infections

Keywords

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

Outcome Measures

Primary Outcomes (1)

• 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.

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

Secondary Outcomes (5)

• Change in Cold Symptoms Questionnaire (CSQ) score

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

• Change in levels of inflammatory markers in nasal fluid samples

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

• Change in levels of inflammatory markers in saliva samples

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

• Change in levels of inflammatory markers in pharyngeal lavage samples

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

• Patients' Global Impression of Change score

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

Other Outcomes (3)

• Leicester Cough Questionnaire - Acute score

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

• Optional: Acute Cough Scale (ACS) score

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

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

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

Study Arms (4)

Flurbiprofen Oral Lozenge

EXPERIMENTAL

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

Drug: Flurbiprofen Oral Lozenge

Placebo lozenge

PLACEBO COMPARATOR

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

Drug: Difflam

Flurbiprofen 8.75 MG

EXPERIMENTAL

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

Drug: Flurbiprofen 8.75 MG

Low dose flurbiprofen spray

OTHER

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.

Drug: Flurbiprofen 8.75 MG

Interventions

Flurbiprofen Oral Lozenge DRUG

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.

Also known as: Strepfen Intensive Lozenge - Honey and Lemon Flavour

Flurbiprofen Oral Lozenge

Difflam DRUG

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.

Also known as: Difflam Soothing Drops + Immune Support Honey & Lemon Flavour

Placebo lozenge

Flurbiprofen 8.75 MG DRUG

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.

Also known as: Strepfen Intensive Oromucosal Spray; Strepsils Intensive Oromucosal Spray

Flurbiprofen 8.75 MG; Low dose flurbiprofen spray

Eligibility Criteria

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

You may qualify if:

• 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.

You may not qualify if:

• 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.

Sponsors & Collaborators

• University of Melbourne: lead
• Reckitt Benckiser LLC: collaborator

Study Sites (1)

University of Melbourne

Carlton, Victoria, 3010, Australia

Location

Related Publications (8)

• 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.

  PMID: 30763726 BACKGROUND

• 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.

  PMID: 31100512 BACKGROUND

• 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.

  PMID: 25383204 BACKGROUND

• 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.

  PMID: 28137663 BACKGROUND

• 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.

  PMID: 22890476 BACKGROUND

• 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.

  PMID: 33029351 BACKGROUND

• 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.

  PMID: 12011823 BACKGROUND

• 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.

  PMID: 24231654 BACKGROUND

MeSH Terms

Conditions

Cough; Respiratory Tract Infections

Interventions

Benzydamine; Flurbiprofen

Condition Hierarchy (Ancestors)

Respiration Disorders; Respiratory Tract Diseases; Signs and Symptoms, Respiratory; Signs and Symptoms; Pathological Conditions, Signs and Symptoms; Infections

Intervention Hierarchy (Ancestors)

Indazoles; Pyrazoles; Azoles; Heterocyclic Compounds, 1-Ring; Heterocyclic Compounds; Heterocyclic Compounds, 2-Ring; Heterocyclic Compounds, Fused-Ring; Propionates; Acids, Acyclic; Carboxylic Acids; Organic Chemicals; Biphenyl Compounds; Benzene Derivatives; Hydrocarbons, Aromatic; Hydrocarbons, Cyclic; Hydrocarbons

Study Officials

• Stuart Mazzone, PhD

  University of Melbourne

  PRINCIPAL INVESTIGATOR

Study Design

• Study Type: interventional
• Phase: early phase 1
• Allocation: RANDOMIZED
• Masking: SINGLE
• Who Masked: PARTICIPANT
• Masking Details: 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.
• Purpose: BASIC SCIENCE
• Intervention Model: PARALLEL
• Sponsor Type: OTHER
• Responsible Party: PRINCIPAL INVESTIGATOR
• PI Title: Professor in Neuroscience

Model Details: 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.

Study Record Dates

• First Submitted: July 11, 2023
• First Posted: July 21, 2023
• Study Start: July 1, 2023
• Primary Completion: July 1, 2024
• Study Completion: July 1, 2024
• Last Updated: December 6, 2024

Record last verified: 2024-12

Data Sharing

• IPD Sharing: Will not share

Locations

AU (1)