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 Exclusion 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

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)

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

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 V. 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
Guaifenesin
Placebo V.

25. Limitations Limitations: Inadequate dose? Sample attrition?
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

29. Questions/Comments

30. Thank you!