Clinical trial NCT01364467
Conditions: Chronic Rhinitis
Sponsor: Virginia Commonwealth University
Start date: 2011-05-01; Completion date: 2018-03-05
Enrollment: 30 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
This is a 14-day, randomized, placebo-controlled, parallel group, masked clinical trial of oral guaifenesin for the therapy of Chronic Rhinitis (CRS) in 36 children between the ages of 7 and 18 years. The study investigates the effectiveness of guaifenesin in the relief of nasal symptoms in children with CRS using the sinonasal 5 survey (SN-5) in comparison to nasal airway volume, and biophysical properties of nasal secretion. The investigators hypothesize that Guaifenesin use over a period of 14 days improves subjective nasal complaints in pediatric patients with chronic rhinitis and nasal congestion, as measured by the SN-5 survey compared to use of placebo. There will be an observed improvement in nasal volume and cross-sectional area following use of guaifenesin, and nasal secretions will have more favorable mucociliary and sneeze clearability compared to use of placebo.

Detailed description:

Arms: arm 1: Placebo is provided by the sponsor and is identical in composition to the treatment only lacking active drug. arm 2: None
Interventions: intervention 1: Placebo intervention 2: Guaifenesin
Intervention descriptions: intervention 1: Children aged 7-11 years old will receive placebo 200 mg three times a day (TID), while children older than 12 will receive Placebo 400 mg TID. intervention 2: Children aged 7-11 years old will receive guaifenesin 200 mg TID, while children older than 12 will receive guaifenesin 400 mg TID.

Protocol documents:
Prot_000.pdf: 
 
 
Title: The Effect of Oral Guaifenesin on Pediatric Chronic Rhinitis: A Pilot Study 
 
NCT #: NCT01364467 
 
Document approval date: February 25, 2019 
 
Document Type: Protocol 
 
 
 


The Effect of Oral Guaifenesin on Pediatric Chronic Rhinitis: A Pilot Study 
 
 
 
Principal investigator: 
Kelley Dodson, MD 
Department of Otolaryngology – Head and Neck Surgery 
Virginia Commonwealth University 
Richmond, VA 23219 
 
Co-investigator:  
 
Bruce K. Rubin MEngr, MD, MBA, FRCPC 
Department of Pediatrics  
Virginia Commonwealth University   
 
 
Richmond, VA. 23219 
 
 
 
 


Introduction 
 
Rhinosinusitis accounts for over 2 billion dollars in over the counter medication sales1 
and is one of the most common infections in the United States.  In children, rhinosinusitis is 
estimated to account for 4.2% of all visits to pediatricians’ offices during the winter months, and 
17.3% of visits related to cough or cold symptoms2.  Many factors such as atopy, anatomic 
obstruction and immunodeficiency predispose patients to developing rhinitis.  Chronic 
rhinosinusitis (CRS), defined as a constellation of symptoms involving nasal congestion and 
obstruction, drainage, and thickened tenacious nasal secretions lasting for a period longer than 3 
months3, is an especially troubling entity in children. 
 
Therapies for chronic rhinitis are aimed at alleviating these symptoms and frequently 
include the use of antihistamines, decongestants, and topical nasal sprays.  Guaifenesin, a mucus 
expectorant derived from guaiac resin of the wood Guajacum officinale Linne4, has been used 
for many years in the treatment of both acute and chronic rhinitis in an over-the-counter 
preparation.  Other indications for its use include the treatment of cough and in cold formulations 
for adults and children.  The mechanism of guaifenesin’s action has been theorized to result from 
enhancement in mucus secretion from lower airway submucosal glands, with subsequent 
increase in total mucus volume and diminished mucus viscosity4.  A number of reports have 
shown subjective improvements in nasal symptom scores using guaifenesin5,6,7,8; however, to 
date no randomized, controlled studies have been conducted to show clear, objectively 
determined benefit in pediatric patients7.  We propose to investigate the effectiveness of 
guaifenesin in the relief of nasal symptoms in children with CRS using the sinonasal 5 survey 
(SN-5).  We will also measure nasal airway volume using acoustic rhinometry, and nasal 
secretion mucociliary clearability and dynamic viscoelasticity.  


In this pilot study we will test the hypothesis that: 
 
1) Guaifenesin use over a period of 14 days improves subjective nasal complaints in pediatric 
patients with chronic rhinitis and nasal congestion, as measured by the SN-5 survey compared to 
use of placebo. 
2) There will be an observed improvement in nasal volume and cross-sectional area following 
use of guaifenesin, measured objectively using acoustic rhinometry compared to use of placebo. 
3) Following treatment with guaifenesin, nasal secretions will have more favorable mucociliary 
and sneeze clearability compared to use of placebo.  
4.) Children that respond and those that do not respond to guaifenesin therapy will show 
significant differences in mucus characteristics and mucociliary clearance.  
 
Materials and Methods  
Study Design 
This is a 14-day, randomized, placebo-controlled, parallel group, masked clinical trial of 
oral guaifenesin for the therapy of CRS in 36 children between the ages of 7 and 18 years. A 2:1 
ratio of subjects on active medication to placebo will be used. Before starting the study, this 
study will be approved by the Virginia Commonwealth University Institutional Review Board 
for human research.  Study subjects will be assigned a unique coded identifier and all 
information will be entered into an Excel database in a password-protected computer, to which 
only the investigators have access.  There is minimal risk to the child in acoustic rhinometry 
measurements, collecting nasal secretions, and completing the SN-5 surveys.   
 


Subject Recruitment 
 
We will enroll 36 subjects from the pediatric otolaryngology clinic at the Virginia 
Commonwealth University Medical Center in a 2:1 ratio of active medication to placebo. The 
subjects will be between the ages of 7 and 18 years at the time of the study.  They will be 
identified during routine clinical evaluation for CRS as defined as chronic rhinitis and nasal 
stuffiness of at least 3 months duration.  Informed consent will be obtained from the subject’s 
parent or legal guardian and assent will be obtained from the study subjects.  Given our clinic 
volume we anticipate that it will take 12 months to complete subject enrollment. 
 
Children with immunodeficiency, cystic fibrosis, acute or subacute symptoms, signs of 
bacterial infection, and/or those who are unable to cooperate with testing will be excluded.  
Children with documented use of the study medication in the month before evaluation and during 
period of symptoms will also be excluded. 
 
Parents of the subjects will complete the SN-5 questionnaire as described below, at initial 
evaluation and again during a lead-in phase three days later to ensure stability of symptoms.  
Patients with an improved score will be excluded. 
 
  
The Sinus and Nasal Quality of Life Survey (SN-5) 
The Sinus and Nasal Quality of Life Survey (SN-5) is a validated and reliable 
questionnaire designed to score five areas of impact from sinonasal dysfunction (SN-5) in 
patients 1 year to 18 years of age9,10.  Parents assess the impact of infection on nasal symptoms, 
emotion, and activity on a scale of worsening symptoms scored 1 through 7 to provide a 
quantifiable score capable of comparing both disease severity and the impact of interventions on 
subjective complaints. It has been shown as a responsive measure of health-related quality of life 


for children with persistent sinonasal symptoms, suitable for use in outcomes studies and routine 
clinical care.  Kay et al showed SN-5 test-retest reliability with an R value of 0.709.  Terrell et all 
demonstrated that the SN-5 correlated to disease severity as measured by the Lung-MacKay CT 
scan score11.   
 
Acoustic rhinometry 
 
Acoustic rhinometry is used to measure cross-sectional volume of the nasal cavity 
allowing the calculation of nasal volume.  Audible reflected sound waves are painlessly 
introduced through nasal adaptors into the nasal passages allowing the production of area-
distance graphs.  As the acoustic rhinometer is calibrated to a standard nose, accurate results can 
be obtained with good test-retest reliability12,13. 
 
Analysis of nasal secretions  
Secretion collection 
 
Collection and analysis of nasal secretions will be performed under direct vision at the 
time of rhinologic assessment.  These will be collected using the Jun-Tymp-Tap (Xomed, 
Jacksonville, FL) as previously described14. 
 
Mucociliary clearability 
 
A mature leopard frog (Rana pipiens) is pithed and rapidly decapitated.  The lower jaw is 
then disarticulated and the palate removed by cutting through from the junction of the posterior 
pharynx and esophagus out to the skin of the back.  The excised palate is placed on a piece of 
gauze saturated with amphibian Ringer’s solution and the palate is allowed to rest in a 


refrigerator at 4°C for 12 hours to deplete of mucus.  The palate is then placed in a Plexiglas box 
with a fitted top where humidity is maintained at 95-100% and temperature is kept at 24°C.  The 
palate is focused under a microscope so that a 5 mm micrometer scale runs between the optic 
bulges to the opening of the esophagus.  The movement of a 4µL mucus specimen is timed as the 
trailing edge moves across a 3 mm segment.  Three measurements of mucu transport rate are 
taken to minimize variability15. 
 
Dynamic viscoelasticity 
 
Dynamic viscoelasticity measures the strain response of mucus to an applied stress.  
Because mucus is subjected to both low stress (ciliary beat) and high stress (sneeze) conditions, 
we measure the strain developed in response to a dynamic stress.  Viscosity (loss modulus) is the 
loss of energy from a rheologic probe (stress) moving through a substance and thus the resistance 
to flow.  Elasticity (storage modulus) is the recoil energy transmitted back to the probe.  
Viscoelasticity is a property of non-Newtonian fluids (gels).  In the AR1500ex rheometer (TA 
Instruments, New Castle, DE), a parallel plate geometry is used to assess the dynamic frequency 
range of stress-strain of a 20µL nasal mucus sample over driving frequencies of 1 to 100 rad/sec.  
The viscosity G” and the elasticity G’ of the specimen are determined from these curves after 
non-destructive creep transformation. Rheologic data can also be presented using vectorial 
notation as tangent δ which is the ratio of viscosity to elasticity and G*, the vector sum of 
viscosity and elasticity (mechanical impedance).  The viscoelastic properties of a gel can be 
plotted using Cartesian coordinates (G’, G”) or vector notation (G*, δ)16. 
 


Study Protocol  
After informed consent is obtained, a medical history will be obtained, including 
demographic data of personal or family history of allergies, asthma, nasal or sinus disease, 
exposure to tobacco smoke, prior medication history and other associated conditions. A head and 
neck physical examination will be performed, including a thorough rhinoscopic examination. We 
will determine nasal patency both by direct visualization and scoring and by acoustic rhinometry 
pretreatment and at post treatment follow-up, using the mean of three consecutive measurements.   
Secretions will be collected from the middle meatus pre and post treatment using the Jun-Tym-
Tap.  The SN-5 questionnaire will be completed at two baseline visits and after completion of the 
study.  
 
The subject will be given a 14- day course of either guaifenesin or matched placebo to be 
taken orally three times daily according to following age-matched dosages: children aged 7-11 
years old will receive guaifenesin 200 mg TID, while children older than 12 will receive 
guaifenesin 400 mg TID.  Randomization of medication use will be carried out by a study 
participant not involved in the direct care of the patient.  A 2:1 ratio of subjects on active 
medication to placebo will be used.  After two weeks, the subject will return for data collection 
including nasal examination, SN-5, acoustic rhinometry, and collection of nasal secretions.  
Subjects that do not return for their follow up visit will be contacted to schedule repeat 
examination.   
 
 
Data Analysis 
Power calculation 


 
The primary outcome variable will be changes in the SN-5 questionnaire score.  It has 
been reported that the mean score in children with CRS is 3.8 with a standard deviation of 1.0 
and a temporal effect size of standard therapy equal to 0.8811.  Thus assuming a normal 
distribution of results, using a paired 2-tail test to evaluate pre and post treatment outcome with 
an α error probability of 0.05 and a β (power) to detect a change of 0.88 at 80%, the critical t is 
2.1788 yielding a sample size of 13 subjects per group17. 
 
We will also compare pre and post treatment nasal patency scores based upon subjective 
direct visualization score of % obstruction by a single investigator and objective mean acoustic 
rhinometry values, and pre- and post treatment mucus biophysical properties.  Collected data will 
be used to evaluate the outcome measures most predictive of therapeutic response.  We will 
compare responders to non-responders to see if there are factors in the history, physical 
examination, demographics (e.g. tobacco smoke exposure), or baseline measurement that predict 
response to guaifenesin.  These pilot data will be used to develop a focused controlled 
prospective study of children and adults most likely to respond to oral guaifenesin.  
 
References 
1.) Lau J, Zucker D, et al. Diagnosis and treatment of acute bacterial rhinosinusitis.  
Evidence Report/Technology Assessment No. 9 (Contract 290970019 to the New 
England Medical Center). Rockville, MD: Agency for Health Care Policy and Research; 
March 1999. 
2.) Aitken M, Taylor JA. Prevalence of clinical sinusitis in young children followed up by 
primary care pediatricians. Archives of Pediatric and Adolescent Medicine 1998;152:244-
248. 


3.) Bailey BJ and JT Johnson.  Head & Neck Surgery – Otolaryngology: Fourth Edition.  
Lippincott Williams & Wilkins. 2006:vol 1, 405-416. 
4.) Dicpinigaitis PV, Gayle YE. Effect of guaifenesin on cough reflex sensitivity.Chest 
2003;124;2178-2181. 
5.) Houtmeyers E, Gosselink R, Gayan-Ramirez G, Decramer M. Effects of drugs on mucus 
clearance. European Respiratory Journal 1999;14:452-467. 
6.) Rosen EJ, Calhoun KH. Alterations of nasal mucociliary clearance in association with 
HIV infection and the effect of guaifenesin therapy.  The Laryngoscope 2005;115:27-30. 
7.) Storms W, Farrar JR.  Guaifenesin in rhinitis.  Current Allergy and Asthma Reports 
2009;9:101-106 
8.) Storms W, Kaliner MA, Javidi M, Farrar JR, Efessiou CS.  A real world open-label 
multicenter single group study to evaluate patients’ reactions to mucinex (single entity 
long-acting guaifenesin). Journal of Allergy and Clinical Immunology 2007;119:S229. 
9.) Kay DJ, Rosenfeld RM.  Quality of life for children with persistent sinonasal symptoms.  
Otolaryngology Head and Neck Surgery 2003;128:17-26. 
10.) 
Rudnick EF, Mitchell RB. Long-term improvements in quality-of-life after 
surgical therapy for pediatric sinonaal disease. Otolaryngology Head and Neck Surgery 
2007;6:873-877. 
11.) 
Terrell AM, Ramadan HH. Correlations between SN-5 and computed tomography 
in children with chronic rhinosinusitis. Laryngoscope 2009;119:1394-1398. 
12.) 
Corey, JP. Acoustic rhinometry: should we be using it?  Current Opinion in 
Otolaryngology & Head and Neck Surgery 2006;14:29-34. 


13.) 
Clement PAR, Gordts F.  Consensus report on acoustic rhinometry and 
rhinomanometry.  Rhinology 2005;43:169-179. 
14.) 
Rubin BK, Druce H, Ramirez OE, Palmer R. The effect of clarithromycin on 
mucus properties in healthy subjects and in patients with acute purulent rhinitis. Am J 
Respir Crit Care Med 1997;115:2018-23 
15.) 
Rubin BK, Ramirez O, King M. Mucus-depleted frog palate as a model for the 
study of mucociliary clearance. Journal of Applied Physiology 1990;69:424-429. 
16.) 
King M, and Rubin BK. Mucus rheology, Relationship with Transport. Chapter 7 
in Airway secretion: Physiologic Bases for the Control of Mucus Hypersecretion. Ed. T. 
Takishima. Marcel Dekker, Inc. New York. 1994 pp. 283-314. 
 
17.) 
Erdfelder, E., Faul, F., & Buchner, A. (1996). GPOWER: A general power 
analysis program. Behavior Research Methods, Instruments, & Computers, 28, 1-11. 

SAP_001.pdf: 
 
 
Title: The Effect of Oral Guaifenesin on Pediatric Chronic Rhinitis: A Pilot Study 
 
NCT #: NCT01364467 
 
Document approval date: February 25, 2019 
 
Document Type: Statistical Analysis Plan 
 
 
 


Statistical Analysis 
Data were logged into Excel spreadsheets and analyzed by StatView 5.0 (SAS, 
Cary, NC). Subject demographic were compared among groups using the t test 
for continuous variables and the chi squared test for proportions. Significance 
was defined as P<0.05.