Postgraduate Medicine: Volume 120: No.2

A Randomized, Double-Blind, Parallel-Group, Multicenter, Placebo-Controlled Study of the Safety and Efficacy of Extended-Release Guaifenesin/Pseudoephedrine Hydrochloride for Symptom Relief as an Adjunctive Therapy to Antibiotic Treatment of Acute Respiratory Infections

Craig LaForce, MD; Deborah A. Gentile, MD; and David P. Skoner, MD

Abstract:
Purpose: This study assessed the efficacy and safety of guaifenesin 600 mg and pseudoephedrine hydrochloride 60 mg extended-release bilayer tablets in providing relief of acute respiratory symptoms when used as an adjunct to antibiotics in patients with an acute respiratory infection (ARI).

Methods: Adult patients experiencing symptoms of ARI and meeting the physician's usual diagnostic criteria for oral antibiotic treatment were prescribed an antibiotic and randomized to adjunctive guaifenesin/pseudoephedrine hydrochloride or matching placebo twice daily for 7 days. Patients completed symptom diaries and treatment assessments twice daily and attended office visits on Days 4 and 8.

Results: The safety/intent-to-treat (ITT) population analysis included 601 patients (guaifenesin/pseudoephedrine, n = 303; placebo, n = 298). Mean symptom scores were lower with guaifenesin/pseudoephedrine from Day 3 for every symptom assessed, with statistically significant improvements in total symptom score from Day 3 (P = 0.026). The greatest effects of treatment with guaifenesin/pseudoephedrine were observed for nasal congestion and sinus headache. Time to overall relief was shorter with guaifenesin/pseudoephedrine (P = 0.038). Significantly more patients reported "the medication was helping during the day" on Day 2 with guaifenesin/pseudoephedrine (P = 0.002). Patient assessments of symptom relief showed a significant preference for guaifenesin/pseudoephedrine versus placebo (P = 0.021). Treatment with guaifenesin/pseudoephedrine was well tolerated. Insomnia (2.6%), nausea (2.3%), and headache (1.3%) were the most common treatment-related adverse effects.

Conclusions: As adjunctive therapy for symptom relief for patients taking antibiotics for ARIs, guaifenesin/pseudoephedrine shortened time to relief and improved bothersome respiratory symptoms better than placebo, with greatest effects seen for nasal congestion and sinus headache.

Introduction

Acute respiratory infections (ARIs) account for a significant proportion of visits to physicians and for about 75% of all prescriptions for antibiotics in the United States annually.1 Data show that ARI imposes a substantial economic burden, is associated with significant morbidity, and is one of the most common reasons for work and school absenteeism.2

Excessive mucus and congestion are frequent symptoms associated with ARI, and it is important that both symptoms be managed simultaneously.2-7 By thinning and loosening tenacious mucus, expectorants such as guaifenesin improve mucociliary clearance and facilitate productive cough. Expectorants are commonly found in over-the-counter cough suppressants in liquid or tablet form and are available in short-acting and extended-release formulations. They can be used in combination with decongestants and/or antitussives.3,4,8 Nasal congestion due to swelling of the mucosal lining can be treated with oral decongestants, such as pseudoephedrine hydrochloride. By producing nasal vasoconstriction of the mucosal capillaries, decongestants shrink swollen nasal mucous membranes, which reduces nasal congestion and increases the drainage of sinus secretions. 4,9 The combination of antibiotics, expectorants, and decongestants is quite common in the treatment of patients with ARI.10-12

This study (Protocol No. 2007-MUCD-001) was undertaken to assess the efficacy and safety of a fixed oral combination of an expectorant (guaifenesin 600 mg) and a nasal decongestant (pseudoephedrine hydrochloride 60 mg) in extended-release bilayer tablets, dosed as 2 oral tablets bid and compared with matching placebo for providing relief of respiratory symptoms when used as adjunctive therapy to antibiotics in patients with ARI. Specifically, the study aimed to assess whether the use of guaifenesin/pseudoephedrine may provide early symptomatic relief.

Materials and Methods

Study Design
This was a multicenter, randomized, double-blind, placebocontrolled, parallel-group study conducted at 30 clinical sites in the United States from January to May, 2007. Study participants were recruited from adult patients (18-75 years old) presenting with symptoms of ARI and satisfying the physician's usual diagnostic criteria for oral antibiotic treatment. Patients were also required to have a total symptom score of ≥10 based on a 0-to-3 severity rating of 10 symptoms (chest congestion, cough, thickened sputum/phlegm, runny nose, nasal congestion, sinus headache, facial pain/pressure/tenderness, post-nasal drip, sore throat, and breathlessness), with onset of symptoms within 7 days prior to entry. Pregnant women and patients with chronic, recurring respiratory signs and symptoms (diabetes, glaucoma, nasal polyps, asthma, or any other significant concomitant disease) and patients taking prior or concomitant medications for ARI (including antihistamines or bronchodilators) were excluded.

Patients were prescribed an antibiotic and randomized to adjunctive treatment with 2 guaifenesin 600 mg and pseudoephedrine hydrochloride 60 mg extended-release bilayer tablets (Mucinex D®, Reckitt Benckiser Inc., Parsippany, NJ) or matching placebo tablets twice daily (morning and evening) for 7 days. Patients started adjunctive therapy at approximately 6:00 PM on Day 1 and recorded symptom ratings and other outcome measures on home-use diaries twice daily at the time of study medication dosing. Patients returned to the physician's office for diary and medication review and symptom assessment on Days 4 and 8.

This study was performed in accordance with the Declaration of Helsinki and the International Conference of Harmonization and Good Clinical Practice guidelines. Approval was obtained from the IRB Quorum Review Inc., and written informed consent was obtained from all patients prior to study entry.

Efficacy Evaluations

Acute respiratory infection symptom severity was assessed at baseline (Day 1), at each subsequent office visit, and morning and evening in patient home-use diaries. The severity of chest congestion, cough, thickened sputum/phlegm, runny nose, nasal congestion, sinus headache, facial pain/pressure/tenderness, post-nasal drip, sore throat, and breathlessness were rated on a scale of 0 to 3 for each symptom (0 = none, 1 = mild, 2 = moderate, and 3 = severe). Every morning, patients rated symptoms of cough and sleep disturbance due to respiratory infection on a scale of 0 to 4 (0 = not bothersome at all, 1 = somewhat bothersome, 2 = moderately bothersome, 3 = very bothersome, and 4 = extremely bothersome). Every evening, patients rated how they felt compared with baseline (worse, the same, better, much better, all better), their ability to perform their normal daily activities (yes or no), and whether the medication was helping during the day (yes or no).

Patients and investigators performed a global assessment of treatment efficacy on Day 8 or at the end of treatment. Patients provided an overall rating of treatment efficacy for symptom relief (0 = not effective at all, 1 = somewhat effective, 2 = moderately effective, 3 = very effective, and 4 = extremely effective) and investigators indicated whether they would recommend the study medication for future use as adjunctive therapy with antibiotics for treatment of symptoms associated with ARI (yes or no).

Safety and Tolerability Assessments

Adverse events (AEs) were recorded and assessed throughout the study period. The relationship of AEs to the study medication was assessed by the investigator.

Statistical Analysis

The target sample size was 300 patients in each treatment arm to provide at least 80% power to detect a clinically significant difference of 20% between treatments in mean total symptom score. The primary analysis of efficacy and safety was performed in the intent-to-treat (ITT) population of patients who received at least 1 dose of study medication. Supportive efficacy analyses were undertaken in 5 additional populations comprising patients who completed the treatment regimen and did not deviate significantly from protocol requirements through to the sixth diary entry on the morning of Day 4 (Early Diary [ED] population), the second office visit on Days 3-5 (Visit 2 [V2] population), the final diary entry on the morning of Day 8 (Final Diary [FD] population), the final visit on Days 7-9 (Final Visit [FV] population), or their final office visit (Global Assessment [GA] population).

Ordinal and binary efficacy ratings (including all diary and office symptom assessments) were compared between treatment groups using the Cochran-Mantel-Haenszel row mean score test, adjusting for investigator. Exploratory repeated measures analyses and nonparametric ordinal logistic analysis were also performed on the individual symptom scores. In addition, the sum of scores and the most bothersome symptom were computed and analyzed by time point. Time to significant relief (defined as a 2-grade reduction in symptom score in patients with moderate or severe symptoms at baseline, sustained throughout the remainder of the study) was calculated for each symptom and compared between treatments using Kaplan-Meier survival analysis (log rank and Wilcoxon tests). Kaplan-Meier methods were also used for analysis of time to overall relief (the first diary time point at which no symptom was scored worse than "mild"); the time to complete relief (the first diary time point at which no symptom was scored worse than "none"); the time from Visit 1 to the first diary time point indicating the patient felt "better," "much better," and "all better;" the time from Visit 1 to the first day on which the patient was able to return to normal routine activities, including only those patients who reported being unable to perform normal routine activities at Visit 1; the time from Visit 1 to the first diary time point indicating that the "medication was helping;" the time to overall relief of the most bothersome symptom; and the time to complete relief of the most bothersome symptom.

The number and percentage of patients who reported AEs were tabulated by treatment group with regard to frequency, severity, and relationship to study medication. All statistical analyses were performed using SAS® statistical software (Version 9.13). Statistical significance was tested at the 2-sided 5% level.

Results

Patient Population
Patient disposition by treatment group and the different efficacy populations analyzed are summarized in Table 1. A total of 605 patients were enrolled and randomized to study treatment (305 in the guaifenesin/pseudoephedrine group and 300 in the placebo group).

The 2 study groups were well matched with regard to patient demographic and clinical characteristics at baseline (Table 2). The majority of study participants were female (62.9%), white (91.3%), and non-Hispanic (91.8%), and the mean age was 39.7 ± 13.5 years. Sinusitis and bronchitis were the most frequent diagnoses (51.8% and 32.2%, respectively). The most bothersome symptoms at baseline were cough (21.3%), nasal congestion (19.0%), sore throat (15.5%), and sinus headache (13.0%). In all, 43.6% of study participants were unable to sustain normal daily activities, such as attending work or school.

Baseline demographic characteristics for the 5 supportive efficacy populations did not differ significantly from those in the Safety/ITT population. Overall compliance with study medication was good. The mean number of doses taken was 13.2 in the guaifenesin/pseudoephedrine group and 13.5 in the placebo group.

Efficacy
The mean total symptom score at baseline was 16.6 with guaifenesin/pseudoephedrine and 16.9 with placebo. At the investigator assessment on Day 8, the mean scores had decreased to 4.4 and 5.3 in the 2 groups, respectively, and this difference was statistically significant in favor of guaifenesin/pseudoephedrine (P = 0.015). The mean total symptom scores derived from the patient diaries were significantly lower with guaifenesin/pseudoephedrine than with placebo from Day 3 (P = 0.026) onward.







The mean score for the most bothersome symptom was 2.7 in both groups at baseline and decreased to 0.7 and 0.8 with guaifenesin/pseudoephedrine and placebo, respectively, at the investigator assessment on Day 8. The percentage of patients rating their most bothersome symptom as "severe" decreased from 73.3% and 74.5% with guaifenesin/pseudoephedrine and placebo, respectively, at baseline, to 5.9% and 7.0% at Visit 3. The mean score for the most bothersome symptom based on the patient diary assessments was lower with guaifenesin/pseudoephedrine than with placebo from the evening of Day 2 onward, but the difference between the 2 groups attained statistical significance only on the morning of Day 5 (P = 0.015).

The mean individual symptom scores tended to be lower with guaifenesin/pseudoephedrine than with placebo at the investigator assessments and from Day 3 through to Day 8 in the diary assessments. The greatest effects of treatment with guaifenesin/pseudoephedrine were observed for nasal congestion and sinus headache. The difference in mean symptom score was statistically significant in favor of guaifenesin/pseudoephedrine for nasal congestion at both the Day 4 and Day 8 investigator assessments (P = 0.01 and 0.004, respectively), and for all patient diary assessments from Day 3 (P < 0.05) onward. For sinus headache, the difference in mean symptom score was statistically significant for most patient diary assessments from Day 2 (P = 0.05) onward. Results of the analyses of mean total symptom scores, most bothersome symptom scores, and individual symptom scores in the ED, V2, FD, and FV populations supported those in the ITT population. Statistically significant differences in the mean symptom score for nasal congestion were observed between the 2 study groups starting from Day 3 in the ED and FD populations and from the Day 4 investigator assessment in the V2 and FV populations (P values ranging from P = 0.035 to P = 0.005).

The median time to overall relief of symptoms (no symptom worse than "mild") was 2.75 days with guaifenesin/pseudoephedrine and 3.25 days with placebo. The difference between these data was significant as analyzed by the Wilcoxon test (P = 0.038) and was close to significance by the log rank test (P = 0.056). Further analysis of time to significant relief of symptoms was undertaken for the 2 symptoms for which greatest effects were observed. The median time to achieving significant relief (a 2-grade reduction from baseline score sustained throughout the study) was significantly shorter with guaifenesin/pseudoephedrine than with placebo for both nasal congestion (4.75 vs 5.75 days [log rank test, P = 0.015; Wilcoxon test, P = 0.012]) and sinus headache (3.25 vs 4.75 days [log rank test, P = 0.041; Wilcoxon test, P = 0.022]) (Figure 1). Results of the patients' global assessment showed the mean rating for relief of symptoms at the end of the study to be significantly better with guaifenesin/pseudoephedrine (P = 0.021) in the ITT population (Table 3). A larger proportion of patients with guaifenesin/pseudoephedrine than with placebo indicated that the treatment was helpful during the day at all time points assessed, with the difference between treatments attaining statistical significance on Day 2 (67.9% vs 55.2% in the 2 groups respectively; P = 0.002) and Day 6 (79.7% vs 71.3% respectively; P = 0.02). Results of the same analysis in the ED and FD populations were supportive of these ITT findings. Investigator global assessments also favored guaifenesin/pseudoephedrine, with 82.2% of investigators in the guaifenesin/pseudoephedrine group recommending study medication for future use as adjunctive therapy to antibiotics for relief of symptoms associated with ARI compared with 75.0% in the placebo group (P = 0.048).







Safety and Tolerability

The mean number of days of exposure to study medication was 7.6 in the guaifenesin/pseudoephedrine group and 7.8 in the placebo group. Treatment with guaifenesin/pseudoephedrine was well tolerated, with most AEs of mild or moderate intensity (Table 4). The most frequently reported treatment-related AEs occurring in ≥1% of patients in any treatment group (Safety/ITT population) were insomnia (2.6%) and nausea (2.3%) with guaifenesin/pseudoephedrine, and insomnia (1.7%) and headache (1.7%) with placebo. The most common AE leading to treatment discontinuation was insomnia, reported by 7 patients with guaifenesin/pseudoephedrine and 2 patients with placebo. No serious AEs or deaths were reported in either group during the study.

Discussion

Results of this large, randomized, double-blind, placebocontrolled study show guaifenesin/pseudoephedrine to be



effective as an adjunct to antibiotic therapy in the relief of symptoms associated with ARI, significantly shortening time to relief of bothersome respiratory symptoms compared with placebo, with greatest effects seen for nasal congestion and sinus headache. The health care practitioner's office setting and home-use diary assessments were intended to simulate the typical naturalistic patient-care setting for ARI treatment, with symptomatic outcomes measured by patient self-assessment. Multiple efficacy analyses were performed, with results in the 5 per-protocol populations supporting those of the primary analysis in the ITT population.

Guaifenesin/pseudoephedrine was not found to have a statistically significant difference from placebo for some of the individual symptoms analyzed. Other studies have also documented a large placebo effect in studies of symptomatic relief for ARI.13 However, both patient and investigator global assessments of symptom relief in this study showed statistically significant differences in favor of guaifenesin/pseudoephedrine versus placebo. Global assessments are considered to provide a more complete evaluation of overall treatment effectiveness for conditions involving multiple and variable symptoms.

Guaifenesin/pseudoephedrine was found to be well tolerated and there were no unexpected safety findings in the study. Adverse events were generally of a mild or moderate severity, and most were not considered to be related to study medication. The most frequently reported treatmentrelated AEs were insomnia and nausea with guaifenesin/pseudoephedrine and insomnia and headache with placebo. In conclusion, when used as adjunctive therapy to antibiotics in patients with ARI, guaifenesin/pseudoephedrine shortened time to relief and improved bothersome respiratory symptoms better than placebo, with greatest effects seen for nasal congestion and sinus headache. Both patient and investigator global assessments of symptom relief showed a significant preference for guaifenesin/pseudoephedrine. As an adjunct to an antibiotic treatment regimen, guaifenesin/pseudoephedrine can play an important role in relief of symptoms associated with ARI.

Acknowledgments

The following investigators participated in this study: J. Adler, MD; M. Archuleta, MD; A. Bartkowiak, MD; M. Basista, MD; D. Britt, MD; J.J. Champlin, MD; M.J. Devine, III, MD; G.P. Erdy, MD; B. Feldman, DO; G. Flippo, MD; D. Gentile, MD; V. Hershberger, MD; H.A. Hidalgo, Jr., MD; W.J. Keating, MD; J. Kirstein, MD; S. Koch, MD; C. LaForce, MD; C. Levin, MD; R. Lorraine, MD; D. Minnick, MD; J. Mullen, DO; D. Pampe, MD; J.H. Peniston, DO; K. Pierce, MD; M. Ponse, DO; A. Puopolo, MD; M. Raikhel, MD; W. Saway, MD; D. Skoner, MD; J.C. Stringer, MD; S. Szewczak, DO.
This study was funded by Reckitt Benckiser Inc. The authors thank José Luis Traverso, MD, PhD, of Complete Medical Communications who provided medical writing support, funded by Reckitt Benckiser, Inc.

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