Expectorants are an important and widely used component of treatment for relief of the symptoms of acute URTIs. Currently the main assessments used to assess mucoactive therapies include quality of life questionnaires
[14, 15]; however, there is a need for a universally accepted, sensitive, clinically relevant and appropriately validated PRO measure for use as the primary efficacy outcome measure in future clinical trials in this field.
The clinical pilot study reported here is unique in the field of guaifenesin research and was conducted to assess the efficacy and safety of ER guaifenesin compared with placebo in patients with productive cough due to an acute URTI. In addition, together with the validation study, the research was conducted to support the selection of primary endpoints for future clinical studies of mucoactive compounds.
The subjective measures of efficacy in this study showed the most prominent difference between groups at Day 4 but there were also some improvements at earlier time points. In agreement with the mode of action of ER guaifenesin and current labeling in the USA, the most significant symptom improvements were seen with cough and several discomforts associated with excess and tenacious mucus.
The rating of effects on mucus in the SSSA showed a strong trend throughout the course of treatment but did not quite meet statistical significance at the p < 0.05 level. Nevertheless, the consistency of the signal over the course of treatment supports the concept of a steady effect of ER guaifenesin on airway mucus; this is the mechanism by which guaifenesin improves mucus-related symptoms as reported in questions 2, 5 and 8 of the DCPD.
The DCPD includes 8-symptom related questions (SUM8) and three functional items that focus on phlegm and cough. Due to the fact that excess and tenacious airway mucus during URTIs is one of the triggers for cough, it also seems to be consistent that ER guaifenesin was associated with improvements in cough symptoms on Day 4 (p = 0.0293). This signal weakened and lost statistical significance towards Day 8 (p = 0.1158), which can be explained by the overall improvement of other cough triggers and disease dynamics of URTIs over time.
In this study the WURSS-21 score decreased at a similar rate and showed statistically significant between-day comparisons for both treatment groups. However, the WURSS-21 is a quality of life questionnaire designed to assess the negative impact of the many symptoms of the common cold
 rather than the symptomatic effects specific to mucus; therefore, it does not highlight the specific improvements associated with expectorant treatment. This suggests that this tool may not be suitable for future studies of guaifenesin.
For the Patient’s End-of-Treatment Assessment of outcomes there was no statistically significant difference between treatment groups; however, it did show a trend favoring ER guaifenesin and the difference between treatments (9.6%) comes close to a meaningful therapeutic effect. The lack of a statistically significant difference between the treatment groups may have been due to a relatively small sample size and large placebo effect.
The Investigator’s (HCP) End-of-Study Assessment significantly favored ER guaifenesin over placebo; although this outcome is not likely to be an appropriate primary measure of treatment efficacy it may be helpful in confirming some of the improvement in symptoms and could be considered as a secondary endpoint in future studies.
The clinical pilot study confirmed that treatment with ER guaifenesin was well tolerated in accordance with the well-documented safety profile and post-marketing surveillance of an over-the-counter ER, bilayer formulation of guaifenesin.
Based on the overall results from the pilot study, the most promising tools for discriminating symptomatic improvements between the active treatment and placebo were found to be symptom self-assessments by the patient, i.e. the DCPD and the SSSA with peak separation at Days 4 and 5. Additional post hoc analyses of the data indicated that the best way to discriminate between the active and placebo treatments is to use a composite sub-score of the questions in the DCPD; the ‘SUM8’, limited to the symptoms questions numbered 1, 2, 4, 5, 8, 9, 10, and 11, seemed best suited to capture the effects of the treatment.
Results from the validation study provided further evidence that SUM8 is likely to be a sensitive and precise measure for evaluating changes in URTI respiratory symptoms over time with an expectorant treatment, demonstrated by the reliability and validity estimates. The SUM8 scale demonstrated sensitivity to detect changes over time with patient ratings of efficacy. During interviews some minor inconsistencies in the interpretation of the terminology were found, therefore, future studies could provide patients with training and/or a glossary that further defines any potentially ambiguous terms.
It was determined that the SUM8 is a comprehensive symptom measure that evaluates aspects of phlegm experience, with six items dedicated to this concept. As ER guaifenesin is an expectorant that improves the rheology and clearance of respiratory tract mucus, this comprehensive measure of phlegm may be optimal for precisely evaluating treatment effects.
Results suggest that from the patient’s perspective, a clinically meaningful change in the SUM8 might be approximately 4.58 points. This score represents an intra-individual Minimally Important Difference (MID). A limitation of this analysis was that, due to the population being studied and the natural disease progression of URTIs, study design, and available measures, it was not possible to adequately evaluate test–retest reliability estimates.