Patient-reported outcomes to assess the efficacy of extended-release guaifenesin for the treatment of acute respiratory tract infection symptoms.

Respir Res. 2012 Dec 27;13:118.

Albrecht H, Vernon M, Solomon G.

H2A Associates, LLC, 3350 SW 27th Ave, Miami, FL 33133, USA. Helmut@H2A-Associates.com

Abstract

BACKGROUND: Guaifenesin is a component of medicines used to improve symptoms associated with upper respiratory tract infections. Patient-reported outcome instruments are valuable for evaluating symptom improvements; however, a validated tool to assess efficacy of mucoactive drugs does not exist. We compared the efficacy of extended-release guaifenesin with placebo for treatment of symptoms of upper respiratory tract infection using subjective efficacy assessments in a pilot study and confirmed precision of assessments in a validation study.

METHODS: The pilot study was a randomized, double-blind study where patients were dosed with either 1200 mg extended-release guaifenesin (n = 188) or placebo (n = 190), every 12 hours for 7 days. Efficacy was assessed using subjective measures including the Daily Cough and Phlegm Diary, the Spontaneous Symptom Severity Assessment and the Wisconsin Upper Respiratory Symptom Survey. End-of-study assessments were completed by patients and investigator. The validation study consisted of two phases. In Phase I, subjects completed interviews to gather evidence to support the content validity of the Daily Cough and Phlegm Diary, the Spontaneous Symptom Severity Assessment and Patient’s End-of-Treatment Assessment. Phase II examined the psychometric properties of assessments evaluated in Phase I of the validation study using data from the pilot study.

RESULTS: Subjective measures of efficacy at Day 4 showed the most prominent difference between treatment groups, in favor of guaifenesin. The 8-symptom related questions (SUM8) in the Daily Cough and Phlegm Diary, analyzed as a composite score appeared to be the strongest candidate endpoint for further evaluation. Results from the interviews in Phase I supported the content of the assessments which were validated during Phase II. Treatments were well tolerated.

CONCLUSIONS: Results from the clinical pilot and validation studies showed that the SUM8 diary scores were robust and reliable for use as efficacy endpoints in studies of mucoactive drugs.

TRIAL REGISTRATION: The study was registered with clinicaltrials.gov (NCT01046136).

PMID: 23270519

 

Supplement:

Expectorants, such as guaifenesin, are a component of many cough and cold medicines that are used to improve mucus clearance and relieve chest congestion associated with acute upper respiratory tract infections (URTIs) [1-4]. The mechanism of action of guaifenesin has been studied in vitro [5,6]. These experiments showed that guaifenesin affects the rheology (viscosity and elasticity) of mucus, leading to improved mucus clearance by the action of cilia in the airway epithelium (mucociliary transport) [5,6].

During the clinical development of an extended-release (ER), bilayer tablet formulation of guaifenesin (Mucinex®, Reckitt Benckiser, Parsippany, NJ, USA), it became apparent that there is no universally accepted, validated patient-reported outcome (PRO) instrument to assess the efficacy of expectorants or other mucoactive drugs. There are also a few challenges in assessing products to treat URTIs including the fact that URTI symptoms are highly subjective and current PROs used lack the precision to detect treatment effects from those occurring due to the natural resolution of symptoms [7]. There is also the placebo effect associated with cough studies, which has been well documented [8,9]. It is important from a regulatory perspective that any primary efficacy endpoints are clinically relevant and appropriately validated.

This manuscript describes the results of a pilot study where ER guaifenesin (two 600 mg tablets every 12 hours for 7 days) was compared with placebo for the treatment of symptoms of acute URTIs. Results were also reported from a validation study used to confirm the precision of PROs used in the pilot study. These studies aimed to identify and verify suitable clinical instruments for measuring the benefits of mucoactive treatments in patients with symptoms of acute URTIs. Sputum samples were obtained from treated patients to investigate changes in the physical properties of mucus (as objective outcome variables), but sampling and other methodological issues rendered the results inconclusive.

During the pilot study, efficacy was assessed using subjective PROs, including the Daily Cough and Phlegm Diary (DCPD) (Days 1–8 [or end of study]), the Spontaneous Symptom Severity Assessment (SSSA) (Days 1, 3, 4, 8 [or end of study]) and the Wisconsin Upper Respiratory Symptom Survey (WURSS-21) (Days 1, 3, 4, 8 [or end of study]). The 11-item DCPD consisted of an eight-question diary symptom subscale and three social function questions where participants rated daily changes in their symptoms. For the SSSA, participants rated the severity of chest congestion, mucus thickness, and coughing. The WURSS-21 was used to assess disease-specific changes in quality of life parameters during the study. This tool was included as it is a validated PRO for the assessment of quality of life changes in colds. End-of-study assessments were also completed by patients and the investigator. Regarding the statistical methods, all efficacy endpoints were exploratory and given equal consideration. Due to the exploratory nature of the study no multiplicity adjustments were made and this study was not sized or intended to achieve statistically significant results across the board.

The validation study consisted of two phases. In Phase I, subjects completed interviews to gather evidence to support the content validity of the DCPD, the SSSA, and Patient’s End-of-Treatment Assessment. Phase II examined the psychometric properties of assessments evaluated in Phase I of the validation study using data from the pilot study.

The pilot study confirmed that treatment with ER guaifenesin was well tolerated in accordance with previously reported safety data [10] and post-marketing surveillance. 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 (Table 1 and Table 2, respectively).

Table 1: Summary of DCPD between-treatment comparisons (mITT population) Hannah Chatfield-table 1

DCPD: Daily Cough and Phlegm Diary;   mITT: modified intent-to-treat. p<0.05: statistically significant difference between treatment groups; p<0.10: viewed as a trend towards a significant difference between treatment groups. Note: p-values are from an ordinal logistic regression model with predictors: treatment group, center, and baseline.

 

Table 2: Summary of SSSA between-treatment comparisons (mITT population)Hannah Chatfield-table 2

SSSA:   Spontaneous Symptom Severity Assessment; mITT: modified intent-to-treat.   p<0.05: statistically significant difference between treatment groups;   p<0.10: viewed as a trend towards a significant difference between   treatment groups. Note: p-values are from Wilcoxon rank sum tests comparing   treatments. Results for Hour 0 on Days 3 and 4 and for Day 8 are treatment   comparisons based on within-subject changes from Baseline (Day 1). Results   for Hour 3 on Days 3 and 4 are treatment comparisons based on within-subject   changes from Hour 0 of the same day.

 

 

Post-hoc analyses of the data indicated that the most effective way to discriminate between the ER guaifenesin and placebo treatments was to use a composite sub-score of the questions in the DCPD; the ‘SUM8’ which is limited to questions 1, 2, 4, 5, 8, 9, 10, and 11 (Table 1). The validation study results 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 that were calculated. However, it was also noted that during interviews in the validation study, 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.

The SUM8 was also determined to be a comprehensive measure that evaluates the role of phlegm (mucus) in the symptomatology of URTIs, as six of the questions included phlegm. As ER guaifenesin is an expectorant that improves the rheology and clearance of excess respiratory tract mucus, this comprehensive measure of phlegm may be ideal for evaluating treatment effects.

It was calculated 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). However, 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.

Overall, this study determined that the SUM8 diary scores were robust and suitably reliable for use as efficacy endpoints in studies of expectorants such as guaifenesin for the symptoms of URTIs.

 

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Acknowledgements: Both the pilot and validation studies were funded by Reckitt Benckiser. Medical writing assistance was provided by Elements Communications Ltd,

Westerham, UK, supported by Reckitt Benckiser.

 

Contact:
Helmut H. Albrecht, MD, MS, FFPM
President
H2A Associates, LLC
3350 SW 27th Ave
Ste 2203
Miami
FL 33133, USA
Helmut@H2A-Associates.com

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