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J. Brady Scott, MSc, RRT-ACCS Assistant Professor Department of Respiratory Care Rush University Chicago, Illinois.

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Presentation on theme: "J. Brady Scott, MSc, RRT-ACCS Assistant Professor Department of Respiratory Care Rush University Chicago, Illinois."— Presentation transcript:

1 J. Brady Scott, MSc, RRT-ACCS Assistant Professor Department of Respiratory Care Rush University Chicago, Illinois

2 Author’s Conflicts of Interest The author disclosed no conflicts of interest Research sponsor – The sponsor had full access to data – The sponsor had no part in data analysis or in writing the manuscript – Study was funded by investigator-initiated research grant from Reckitt Benckiser Pharmaceuticals, Bristol, United Kingdom Mucinex®

3 Background Guaifenesin (GGE) is an over-the-counter (OTC) expectorant – FDA approved as OTC expectorant – $135 million annual sales in the United States Used to loosen phlegm and thin bronchial secretions to produce a more effective cough – Studied both as expectorant and cough suppressant – Studies have failed to show consistent benefit

4 What is the research question? Do two 600 mg extended-release GGE tablets (Mucinex) or matching-placebo given twice daily for 7 days to subjects with an acute respiratory tract infection (common cold): – Improve the volume or properties of sputum? – Affect subjective symptoms and symptom- associated quality of life?

5 Significance FDA increasing pressure on drug companies to demonstrate usefulness and safety of OTC medications Lack of data suggesting that GGE is effective GGE is FDA approved as an OTC expectorant medication – $135 million in annual sales/U.S. market

6 Methods 8-day, multi-center, double-blind, randomized placebo-controlled trial Compared the administration of: – Two 600 mg GGE tablets every 12 hours for 7 days – Placebo every 12 hours for 7 days Institutional review board approved at each site – Consent was obtained from each subject prior to enrollment

7 Subjects Inclusion Criteria – 12 years of age or older – Acute respiratory tract infection for 5 days or less – Productive cough beginning within 72 hours of the first dose of study medication – At least 2 of 3 target symptoms Cough Thickened mucus Chest congestion – If female, a negative pregnancy test – Likely to comply with study requirements Exclusion Criteria – Respiratory symptoms due to chronic disease, such as: Cystic fibrosis COPD Asthma Allergic rhinitus – Had been febrile (>101.7°F) in the previous 7 days – Physical/psychiatric disorders that may interfere with adherence or study outcomes – If already taking prescription or OTC cough or cold medications

8 Randomization Randomization done by sequential number assignment Both GGE and placebo packaged in identical blister packs – No identifying markers other than the protocol and randomization numbers

9 Sputum Collection Collected on days 1, 3, 4, and 8 in clinic For days 1, 3, & 4: – Sputa collected immediately before drug – Also collected 3 and 6 hours after drug administration For day 8: – Only a baseline sample was collected Separated from saliva and debris Stored at -80°C until analysis

10 Sputum Collection 24-hr home collections were done on days 1, 2, 4, and 5 – Stored in home refrigerators – Returned to clinics on days 2 and 8  then frozen at -80°C Samples not analyzed – Watery and degraded – Saliva contaminated – Contained food particles or debris – Missing or illegible labels

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12 Rheology What is Rheology? – Noun: a science dealing with the deformation and flow of matter; also : the ability to flow or be deformed Used to evaluate if GGE improves the properties of sputum that play a role in the effectiveness of sputum clearance Each sample evaluated for dynamic rheology using a rheometer (AR1500ex, TA Instruments, New Castle, Delaware) http://www.merriam-webster.com/dictionary/rheology

13 Interfacial Tension What is interfacial tension? – Noun: surface tension at the surface separating two non-miscible liquids Used to evaluate properties that may effect ease/difficulty of sputum clearance by cough http://www.thefreedictionary.com/interfacial+tension

14 Mucus Hydration and Volume Used to determine if GGE works as an expectorant – Increase in volume of mucus or fluid produced? Total weight and hydration (% solid material) of the two 24 hour samples – Calculated by measuring wet weight, freeze- drying, and determining ratio of solid-to-wet weight to obtain the percent solids

15 Statistical Analysis Sample size determination was based on previous studies of sputum properties Study goal of enrollment (375 subjects) and data collection (300 subjects) were not met – 378 enrolled – 295 subjects completed full protocol – Post-hoc power analysis; confirmed study sample size was adequate to detect important changes in properties and volume of sputum

16 Statistical Analysis JMP 9.0 or StatView 5.0 used for statistical output Significance defined as P <.05 Subject demographics and sputum – Descriptive statistics: Describes the sample Reported as – Means, medians, modes – Number (N), percentages, standard deviations

17 Results

18 Statistical Analysis – Inferential statistics: Used to infer information about a target population Student’s t-test – Compare the means of two samples – Most common parametric statistic ANOVA – Compare the means of more than two samples Chi-square test for proportions – Determines if observed data fits an expected set – Frequently used non-parametric statistic

19 Results Mucus Hydration and Volume – No significant difference between GGE and placebo in either first or second collection (Figure 4)

20 Statistical Analysis Rheology/interfacial tension – Analyzed using two-way ANOVA ANOVA: Analysis of variance – Compares the means of 2 or more groups – Parametric statistical test

21 Results Rheology – No significant differences between GGE and placebo (Figure 1)

22 Results Rheology – No significant differences between GGE and placebo (Figure 2)

23 Results Interfacial Tension – No significant differences between GGE and placebo (Figure 3)

24 Discussion What does this all mean? No significant changes in sputum properties Unlikely to be a mucolytic Unlikely to improve cough clearance Unlikely to have expectorant properties GuaifenesinPlacebo V.

25 Limitations Limitations: – Inadequate dose? Consistent with current dosing recommendations – Sample attrition? – Acute respiratory tract infection diagnosis? Clinically versus microbiological testing

26 Discussion How may this impact practice? – Will we recommend GGE for the treatment of symptoms associated with acute upper respiratory tract infections?

27 Editorial by Dr. O’Connell Nice review of mucus properties – Elasticity – Viscosity Lists compounds alleged to be beneficial on mucus or its secretion – Expectorants  hypertonic saline – Mucolytics  N-acetylcysteine – Mucokinetics  albuterol – Mucoregulators  glucocorticosteroids Commends the FDA’s efforts to increase evidence of efficacy for new OTC medications

28 Conclusion Author’s conclude: GGE given at recommended dose is not effective at changing sputum properties versus placebo Interesting Points– Take home message – Placebo effect reported in up to 85% in studies of cough therapy – This may explain any perceived benefits for GGE

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