Transcript PowerPoint Slides

J. Brady Scott, MSc, RRT-ACCS
Assistant Professor
Department of Respiratory Care
Rush University
Chicago, Illinois
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®
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
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 symptomassociated quality of life?
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
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
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
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
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
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
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
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
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, freezedrying, and determining ratio of solid-to-wet
weight to obtain the percent solids
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
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
Results
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
Results
• Mucus Hydration and Volume
– No significant difference between GGE and placebo in either first or second
collection (Figure 4)
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
Results
• Rheology
– No significant differences between GGE and placebo (Figure 1)
Results
• Rheology
– No significant differences between GGE and placebo (Figure 2)
Results
• Interfacial Tension
– No significant differences between GGE and placebo (Figure 3)
Discussion
• What does this all mean?
Guaifenesin




V.
Placebo
No significant changes in sputum properties
Unlikely to be a mucolytic
Unlikely to improve cough clearance
Unlikely to have expectorant properties
Limitations
• Limitations:
– Inadequate dose?
• Consistent with current dosing recommendations
– Sample attrition?
– Acute respiratory tract infection diagnosis?
• Clinically versus microbiological testing
Discussion
• How may this impact practice?
– Will we recommend GGE for the treatment of
symptoms associated with acute upper respiratory
tract infections?
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
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