A Randomized Pragmatic Trial of Changing to and Stepping Down Fluticasone/Formoterol in Asthma.

BACKGROUND: Guidelines recommend reducing treatment in patients with well-controlled asthma after 3 months of stability. However, there is inadequate real-life data to guide physicians on therapy change in daily practice. OBJECTIVE: To assess asthma control after change to and step-down of fluticasone propionate/formoterol fumarate dihydrate (FP/FOR) in real-life patients. METHODS: In a randomized controlled, pragmatic, open-label trial, 225 well-controlled patients with asthma were randomized (1:2) to maintain high-dose fluticasone propionate/salmeterol xinafoate (FP/SAL, 1000/100 µg) or switch to FP/FOR (1000/40 µg) daily for 12 weeks (phase 1). One hundred sixteen patients stable on FP/FOR at week 12 were subsequently randomized (1:1) to maintain this therapy, or stepped down to FP/FOR (500/20 µg) daily for 12 weeks (phase 2). The primary end point was the 7-question Asthma Control Questionnaire (ACQ7) score. RESULTS: In phase 1, FP/FOR (1000/40 µg) (n = 126) was noninferior to FP/SAL (1000/100 µg) (n = 73) for ACQ7 (difference in means, -0.12; 95% CI, -0.32 to 0.09). In phase 2, FP/FOR (500/20 µg) (n = 52) was noninferior to FP/FOR (1000/40 µg) (n = 52) for ACQ7 (difference in means, 0.01; 95% CI, -0.20 to 0.22). There was no significant difference in exacerbation rate between the groups in either phase. However, 1 to 2 exacerbations in 12 months before phase 1 were associated with the occurrence of an exacerbation after step-down (P = .007). CONCLUSIONS: In patients with well-controlled asthma, a change from FP/SAL to FP/FOR did not compromise asthma control. Step-down of FP/FOR was well tolerated; however, in contrast to current guidelines, our data suggest caution in stepping down patients uncontrolled in the last 12 months. Larger step-down studies are required to confirm these findings.

Leukotriene antagonists as first-line or add-on asthma-controller therapy.

BACKGROUND: Most randomized trials of treatment for asthma study highly selected patients under idealized conditions. METHODS: We conducted two parallel, multicenter, pragmatic trials to evaluate the real-world effectiveness of a leukotriene-receptor antagonist (LTRA) as compared with either an inhaled glucocorticoid for first-line asthma-controller therapy or a long-acting beta(2)-agonist (LABA) as add-on therapy in patients already receiving inhaled glucocorticoid therapy. Eligible primary care patients 12 to 80 years of age had impaired asthma-related quality of life (Mini Asthma Quality of Life Questionnaire [MiniAQLQ] score ≤6) or inadequate asthma control (Asthma Control Questionnaire [ACQ] score ≥1). We randomly assigned patients to 2 years of open-label therapy, under the care of their usual physician, with LTRA (148 patients) or an inhaled glucocorticoid (158 patients) in the first-line controller therapy trial and LTRA (170 patients) or LABA (182 patients) added to an inhaled glucocorticoid in the add-on therapy trial. RESULTS: Mean MiniAQLQ scores increased by 0.8 to 1.0 point over a period of 2 years in both trials. At 2 months, differences in the MiniAQLQ scores between the two treatment groups met our definition of equivalence (95% confidence interval [CI] for an adjusted mean difference, -0.3 to 0.3). At 2 years, mean MiniAQLQ scores approached equivalence, with an adjusted mean difference between treatment groups of -0.11 (95% CI, -0.35 to 0.13) in the first-line controller therapy trial and of -0.11 (95% CI, -0.32 to 0.11) in the add-on therapy trial. Exacerbation rates and ACQ scores did not differ significantly between the two groups. CONCLUSIONS: Study results at 2 months suggest that LTRA was equivalent to an inhaled glucocorticoid as first-line controller therapy and to LABA as add-on therapy for diverse primary care patients. Equivalence was not proved at 2 years. The interpretation of results of pragmatic research may be limited by the crossover between treatment groups and lack of a placebo group. (Funded by the National Coordinating Centre for Health Technology Assessment U.K. and others; Controlled Clinical Trials number, ISRCTN99132811.).

Validation of a parent-proxy quality of life questionnaire for paediatric chronic cough (PC-QOL).

BACKGROUND: Quality of life (QOL) measures are an important patient-relevant outcome measure for clinical studies. Currently there is no fully validated cough-specific QOL measure for paediatrics. The objective of this study was to validate a cough-specific QOL questionnaire for paediatric use. METHOD: 43 children (28 males, 15 females; median age 29 months, IQR 20-41 months) newly referred for chronic cough participated. One parent of each child completed the 27-item Parent Cough-Specific QOL questionnaire (PC-QOL), and the generic child (Pediatric QOL Inventory 4.0 (PedsQL)) and parent QOL questionnaires (SF-12) and two cough-related measures (visual analogue score and verbal category descriptive score) on two occasions separated by 2-3 weeks. Cough counts were also objectively measured on both occasions. RESULTS: Internal consistency for both the domains and total PC-QOL at both test times was excellent (Cronbach alpha range 0.70-0.97). Evidence for repeatability and criterion validity was established, with significant correlations over time and significant relationships with the cough measures. The PC-QOL was sensitive to change across the test times and these changes were significantly related to changes in cough measures (PC-QOL with: verbal category descriptive score, r(s)=-0.37, p=0.016; visual analogue score, r(s)=-0.47, p=0.003). Significant correlations of the difference scores for the social domain of the PC-QOL and the domain and total scores of the PedsQL were also noted (r(s)=0.46, p=0.034). CONCLUSION: The PC-QOL is a reliable and valid outcome measure that assesses QOL related to childhood cough at a given time point and measures changes in cough-specific QOL over time.

Cost effectiveness of leukotriene receptor antagonists versus inhaled corticosteroids for initial asthma controller therapy: a pragmatic trial.

BACKGROUND: Information is lacking on the relative effectiveness and cost effectiveness--in a primary-care setting--of leukotriene receptor antagonists (LTRAs) as an alternative to inhaled corticosteroids (ICS) for initial asthma controller therapy. OBJECTIVE: To compare the cost effectiveness of LTRAs versus ICS for patients initiating asthma controller therapy. METHODS: An economic evaluation was conducted alongside a 2-year, pragmatic, randomized controlled trial set in 53 primary-care practices in the UK. Patients aged 12-80 years with asthma and symptoms requiring regular anti-inflammatory therapy (n = 326) were randomly assigned to LTRAs (n = 162) or ICS (n = 164). The main outcome measures were the incremental costs per point improvement in the Mini Asthma Quality of Life Questionnaire, per point improvement in the Asthma Control Questionnaire and per QALY gained from the UK NHS and societal perspectives. RESULTS: Over 2 years, resource use was similar between the two treatment groups, but the cost to society per patient was significantly higher for the LTRA group, at pounds sterling 711 versus pounds sterling 433 for the ICS group (adjusted difference pounds sterling 204; 95% CI 74, 308) [year 2005 values]. Cost differences were driven primarily by differences in prescription drug costs, particularly study drug costs. There was a nonsignificant (imputed, adjusted) difference between treatment groups, favouring ICS, in QALYs gained at 2 years of -0.073 (95% CI -0.143, 0.010). Therapy with LTRAs was, on average, a dominated strategy, and, at a threshold for willingness to pay of pounds sterling 30,000 per QALY gained, the probability of LTRAs being cost effective compared with ICS was approximately 3% from both societal and NHS perspectives. CONCLUSIONS: There is a very low probability of LTRAs being cost effective in the UK, at 2005 values, compared with ICS for initial asthma controller therapy. TRIAL REGISTRATION: UK National Research Register N0547145240; Controlled Clinical Trials ISRCTN99132811.

Cost effectiveness of leukotriene receptor antagonists versus long-acting beta-2 agonists as add-on therapy to inhaled corticosteroids for asthma: a pragmatic trial.

BACKGROUND: Information is lacking on the relative effectiveness and cost effectiveness--in a real-life primary-care setting--of leukotriene receptor antagonists (LTRAs) and long-acting beta2 adrenergic receptor agonists (beta2 agonists) as add-on therapy for patients whose asthma symptoms are not controlled on low-dose inhaled corticosteroids (ICS). OBJECTIVE: To estimate the cost effectiveness of LTRAs compared with long-acting beta2 agonists as add-on therapy for patients whose asthma symptoms are not controlled on low-dose ICS. METHODS: An economic evaluation was conducted alongside a 2-year, pragmatic, randomized controlled trial set in 53 primary-care practices in the UK. Patients aged 12-80 years with asthma insufficiently controlled with ICS (n = 361) were randomly assigned to add-on LTRAs (n = 176) or long-acting beta2 agonists (n = 185). The main outcome measures were the incremental cost per point improvement in the Mini Asthma Quality of Life Questionnaire (MiniAQLQ), per point improvement in the Asthma Control Questionnaire (ACQ) and per QALY gained from perspectives of the UK NHS and society. RESULTS: Over 2 years, the societal cost per patient receiving LTRAs was pounds sterling 1157 versus pounds sterling 952 for long-acting beta2 agonists, a (significant, adjusted) increase of pounds sterling 214 (95% CI 2, 411) [year 2005 values]. Patients receiving LTRAs experienced a non-significant incremental gain of 0.009 QALYs (95% CI -0.077, 0.103). The incremental cost per QALY gained from the societal (NHS) perspective was pounds sterling 22,589 (pounds sterling 11,919). Uncertainty around this point estimate suggested that, given a maximum willingness to pay of pounds sterling 30,000 per QALY gained, the probability that LTRAs are a cost-effective alternative to long-acting beta2 agonists as add-on therapy was approximately 52% from both societal and NHS perspectives. CONCLUSIONS: On balance, these results marginally favour the repositioning of LTRAs as a cost-effective alternative to long-acting beta2 agonists as add-on therapy to ICS for asthma. However, there is much uncertainty surrounding the incremental cost effectiveness because of similarity of clinical benefit and broad confidence intervals for differences in healthcare costs. TRIAL REGISTRATION: UK National Research Register N0547145240; Controlled Clinical Trials ISRCTN99132811.

Modification, translation and adaptation of questionnaires: should copyright laws be observed?

This commentary is intended to start a discussion about whether people should be allowed to modify, translate, adapt or sell copyrighted questionnaires without the permission of the developer (copyright-holder).

Patients may respond differently to paper and electronic versions of the same questionnaires.

AIM: To adapt the Asthma Quality of Life Questionnaire (AQLQ(S)), the Asthma Control Questionnaire (ACQ) and the Rhinoconjunctivitis Quality of Life Questionnaire (RQLQ(S)) for a personal digital assistant (Palm TX) and to examine the validity of the electronic versions by comparing them with the original paper versions. METHODS: 84 adults with asthma and 32 with rhinitis were randomised to complete either the paper or the electronic version first. After 2h, they completed the other version. RESULTS: 68 asthma and 27 rhinitis patients provided analysable data. For the AQLQ(S) and RQLQ(S) differences between paper and electronic were significant. Concordance between paper and electronic, evaluated using an intraclass correlation coefficient were: AQLQ=0.92, ACQ=0.90 and RQLQ=0.85. Concordance for the individual domains of the AQLQ and RQLQ ranged from 0.52 to 0.94. These levels of concordance did not reach the a priori defined requirement for validity. CONCLUSIONS: The significant bias between paper and electronic versions and only modest concordance provides evidence that patients may respond differently to questionnaires in different formats and show that different formats must not be used interchangeably.

What is the burden of chronic cough for families?

BACKGROUND: The burden of children's chronic cough to parents is largely unknown. The objectives of this study were as follows: (1) to determine the burden of chronic cough using a purposely designed questionnaire, and (2) to evaluate psychological (child's anxiety and parental emotional distress) and other influences on the reported burden of cough. METHODS: Parents of children newly referred for chronic cough completed three questionnaires (Spence anxiety scale; depression, anxiety, and stress 21-item scale [DASS]; and burden of cough questionnaire) at enrollment. The last 79 parents also completed these questionnaires at follow-up. RESULTS: Median age of the 190 children recruited was 2.6 years. The number of medical consultations for coughing illness in the last 12 months was high: > 80% of children had > or = 5 doctor visits and 53% had > 10 visits. At presentation, burden scores correlated to parental DASS scores when their child was coughing. Stress was the largest contributor to parents' emotional distress. Parental anxiety and depression scores were within published norms. Scores on all three DASS subscales reduced significantly when the children ceased coughing. At follow-up, the reduction in burden scores was significantly higher in the "ceased coughing" group (n = 49) compared to the "still coughing" group (n = 32). CONCLUSIONS: Chronic cough in children is associated with a high burden of recurrent doctor visits, parental stress, and worries that resolve when cough ceases. Parents of children with chronic cough did not have above-average anxiety or depression levels. This study highlights the need to improve the management of children with chronic cough, including clinicians being cognizant of the emotional distress of the parents.

Development of a parent-proxy quality-of-life chronic cough-specific questionnaire: clinical impact vs psychometric evaluations.

BACKGROUND: Chronic cough affects at least 7% of children, and the impact of this on families is significant. Although adult cough-specific quality-of-life (QOL) instruments have been shown to be a useful cough outcome measure, no suitable cough-specific QOL for parents of children with chronic cough exists. This article compares two methods of item reduction (clinical impact and psychometric) and reports on the statistical properties of both QOL instruments. METHOD: One hundred seventy children (97 boys and 73 girls; median age, 4 years; interquartile range, 3 to 7.25 years) and one of their parents participated. A preliminary 50-item parent cough-specific QOL (PC-QOL) questionnaire was developed from conversations with parents of children with chronic cough (ie, cough for > 3 weeks). Parents also completed generic QOL questionnaires (eg, Pediatric Quality of Life Inventory, version 4.0 [PedsQL4.0] and the 12-item Short Form Health Survey, version 2 [SF-12v2]). RESULTS: The clinical impact and psychometric method of item reduction resulted in 27-item and 26-item PC-QOL questionnaires, respectively, with approximately 50% of items overlapping. Internal consistency among the final items from both methods was excellent. Some evidence for concurrent and criterion validity of both methods was established as significant correlations were found between subscales of the PC-QOL questionnaire and the scales of the SF-12v2 and PedsQL4.0 scores. The PC-QOL questionnaire derived from both methods was sensitive to change following an intervention. CONCLUSION: Chronic cough significantly impacts on the QOL of both parents and children. Although the PC-QOL questionnaires derived from a clinical impact method and from a psychometric method contained different items, both versions were shown to be internally consistent and valid. Further testing is required to compare both final versions to objective and subjective cough measures.

Assessing asthma control.

Guidelines for the treatment of asthma have identified that the primary goal of management is achieving good asthma control, thus reducing the risk of exacerbations. Research has shown, however, that the accuracy with which clinicians can estimate the adequacy of control may not be very good. Nor are clinicians accurate in estimating change in asthma control between clinic visits. Simple questionnaires to measure asthma control are now available, and can be used to evaluate the adequacy of control and to monitor whether levels of control change between assessments. This article discusses selection of a questionnaire, interpretation of data obtained, and methods of administration.

Identifying 'well-controlled' and 'not well-controlled' asthma using the Asthma Control Questionnaire.

The 7-item Asthma Control Questionnaire (ACQ) has been validated to measure the goals of asthma management as defined by international guidelines (minimisation of day- and night-time symptoms, activity limitation, beta(2)-agonist use and bronchoconstriction). Responses are given on a 7-point scale and the overall score is the mean of the responses (0=totally controlled, 6=severely uncontrolled). The aim of this analysis was to determine the cut-point on the ACQ that best differentiates between 'well-controlled' and 'not well-controlled' for (a) clinical practice (low risk of missing 'not well-controlled') and (b) clinical trials (low risk of including 'well-controlled'). All 1323 patients who provided data sets at week 12 in the Gaining Optimal Asthma Control (GOAL) clinical trial were included in the analysis. The gold standard for 'well-controlled' was a composite based on the GINA/NIH guidelines and derived from data collected in the clinical trial diaries and clinic records. The analysis showed that the crossover point between 'well-controlled' and 'not well-controlled' is close to 1.00 on the ACQ. However, to be confident that a patient has well-controlled asthma, the optimal cut-point is 0.75 (negative predictive value=0.85). To be confident that the patient has inadequately controlled asthma, the optimal cut-point is 1.50 (positive predictive value=0.88). In conclusion, knowledge of these cut-points will enhance practising clinicians ability to identify patients whose asthma requires additional treatment, enable investigators to enroll poorly controlled patients into studies and for both clinicians and investigators to evaluate whether treatment goals are being achieved.

Symptom-based questionnaire for differentiating COPD and asthma.

BACKGROUND: Many patients with obstructive lung disease (OLD) carry an inaccurate diagnostic label. Symptom-based questionnaires could identify persons likely to need spirometry. OBJECTIVES: We prospectively tested questions derived from a comprehensive literature review and an international Delphi panel to help identify chronic OLD (COPD) in persons with prior evidence of OLD. METHODS: Subjects were recruited via random mailing to primary-care practices in Aberdeen, Scotland, and Denver, Colorado. Persons aged 40 and older reporting any prior diagnosis of OLD or any respiratory medications in the past year were enrolled. Participants answered 54 questions covering demographics and symptoms and underwent spirometry with reversibility testing. A study diagnosis of COPD was defined by fixed airway obstruction as measured by post-bronchodilator FEV(1)/FVC <0.70. We examined ability of individual questions in a multivariate framework to discriminate between persons with and without the study diagnosis of COPD. RESULTS: 597 persons completed all investigations and proceeded to analysis. The list of 54 questions yielded 52 items for analyses, which was reduced to 19 items for entry into a multivariate regression model. Nine items had significant relationships with the study diagnosis of COPD, including increased age, pack-years, worsening cough, breathing-related disability or hospitalization, worsening dyspnea, phlegm quantity, cold going to the chest, and receipt of treatment for breathing. Individual items yielded odds ratios ranging from 0.33 to 20.7. This questionnaire demonstrated a sensitivity of 72.0 and a specificity of 82.7. CONCLUSIONS: A short, symptom-based questionnaire identifies persons more likely to have COPD among persons with prior evidence of OLD.

Symptom-based questionnaire for identifying COPD in smokers.

BACKGROUND: Symptom-based questionnaires may enhance chronic obstructive pulmonary disease (COPD) screening in primary care. OBJECTIVES: We prospectively tested questions to help identify COPD among smokers without prior history of lung disease. METHODS: Subjects were recruited via random mailing to primary care practices in Aberdeen, UK, and Denver, Colo., USA. Current and former smokers aged 40 or older with no prior respiratory diagnosis and no respiratory medications in the past year were enrolled. Participants answered questions covering demographics and symptoms and then underwent spirometry with reversibility testing. A study diagnosis of COPD was defined as fixed airway obstruction as measured by post-bronchodilator FEV(1)/FVC <0.70. We examined the ability of individual questions in a multivariate framework to correctly discriminate between persons with and without COPD. RESULTS: 818 subjects completed all investigations and proceeded to analysis. The list of 54 questions yielded 52 items for analysis, which was reduced to 17 items for entry into multivariate regression. Eight items had significant relationships with the study diagnosis of COPD, including age, pack-years, body mass index, weather-affected cough, phlegm without a cold, morning phlegm, wheeze frequency, and history of any allergies. Individual items yielded odds ratios ranging from 0.23 to 12. This questionnaire demonstrated a sensitivity of 80.4 and specificity of 72.0. CONCLUSIONS: A simple patient self-administered questionnaire can be used to identify patients with a high likelihood of having COPD, for whom spirometric testing is particularly important. Implementation of this questionnaire could enhance the efficiency and diagnostic accuracy of current screening efforts.

Modification of the asthma quality of life questionnaire (standardised) for patients 12 years and older.

BACKGROUND: The age limit for some adult asthma clinical trials has recently been lowered to 12 years. In this study we have made minor modifications to the standardised version of the adult Asthma Quality of Life Questionnaire (AQLQ(S)) to make it valid for patients 12 years and older (AQLQ12+). METHODS: We have used two clinical trial databases, in which the AQLQ12+ was used, to compare the measurement properties of the questionnaire in patients 12-17 years and patients 18 years and older. A total of 2433 patients (12-75 years), with current asthma and with data that could be evaluated both at randomisation and end of treatment, were included. RESULTS: The analysis showed that internal consistency, responsiveness and correlations with other clinical indices were very similar in patients 12-17 years and patients 18 years and older. CONCLUSION: The measurement properties of the AQLQ12+ are similar in adolescents and adults and therefore the instrument is valid for use in adult studies which include children 12 years and older.

Health-related quality of life in preschool children with wheezing and dyspnea: preliminary results from a random general population sample.

Respiratory symptoms have a high prevalence among preschool children (5-20%). This study evaluated the impact of parent-reported respiratory symptoms on health-related quality of life (HRQOL) using the TNO-AZL Preschool Children Quality of Life (TAPQOL) questionnaire. A random general population sample of 500 parents of 3-46-month old children was mailed a questionnaire containing the TAPQOL and questions on the prevalence of respiratory symptoms. The impact of respiratory symptoms on HRQOL was analysed using the Mann-Whitney test and linear regression analysis. Response rate was 83%. The prevalence of combined "wheezing and dyspnea" during the past 4 weeks was 10%. For the sleeping, appetite, lung problems, skin problems, communication, and positive mood TAPQOL scales, HRQOL was significantly lower in the subgroup with "wheezing and dyspnea" (n = 41) than in the subgroup without symptoms (n = 321); large effect sizes were observed for lung problems (2.06) and sleeping (0.80). In multivariate analysis, adjusted for age and gender of the child, "wheezing and dyspnea" were associated with the scales sleeping, appetite, lung problems, communication, and positive mood (p < 0.05). In conclusion, decreases in HRQOL among preschoolers with parent-reported respiratory symptoms are measurable with the TAPQOL. We recommend studying the impact of doctor-diagnosed respiratory symptoms on HRQOL in future studies.

Concordance between supervised and postal administration of the Mini Asthma Quality of Life Questionnaire (MiniAQLQ) and Asthma Control Questionnaire (ACQ) was very high.

BACKGROUND AND OBJECTIVE: There is increasing international interest in using patient-based outcome measures to evaluate interventions. We compared responses to postal administration of Mini Asthma Quality of Life Questionnaire (MiniAQLQ) and Asthma Control Questionnaire (ACQ) with the gold standard of supervised self-completion. STUDY DESIGN AND SETTING: Validation study involving 96 adults, recruited from U.K. general practice, sent the postal questionnaires with an instruction sheet 1 week before supervised self-completion. Responses for those whose quality of life (n=56) or asthma control (n=61) had 'not changed' between postal and supervised completions were compared using paired-sample t-tests, Pearson's correlation coefficient (r), and intraclass correlation coefficient (ICC). RESULTS: For the MiniAQLQ, overall mean scores were similar in both groups: Postal=5.14 (SD=1.42) vs. Supervised=5.17 (SD=1.39), with mean difference of -0.03 (95% CI=-0.14, 0.08; P=.59), with a high degree of correlation (r=.96, P<.001) and concordance (ICC=0.96; 95% CI=0.93, 0.98; P<.001). For the ACQ, overall mean scores (with SD) were also similar in both groups: Postal=1.24 (SD=1.09) vs. Supervised=1.26 (SD=1.10), with mean difference of -0.02 (95% CI=-0.12, 0.08; P=.74), with good correlation (r=.94, P<.01) and concordance (ICC=0.94; 95% CI=0.90, 0.96; P<.01). CONCLUSIONS: Correlation and concordance between supervised and postal administration of the MiniAQLQ and ACQ are very high. Users may confidently choose the mode of administration most appropriate to their needs.

Measurement properties and interpretation of three shortened versions of the asthma control questionnaire.

The Asthma Control Questionnaire (ACQ) measures the adequacy of asthma treatment as identified by international guidelines. It consists of seven items (5 x symptoms, rescue bronchodilator use and FEV1% of predicted normal). A validation study suggested that in clinical studies measurement of FEV1 and bronchodilator use may not be needed but this has never formally been tested in a clinical trial. The aims of this analysis were (1) to examine the measurement properties of three shortened versions of the ACQ (symptoms alone, symptoms plus FEV1 and symptoms plus short-acting beta2-agonist) and (2) to determine whether using the shortened versions would alter the results of a clinical trial. In the randomised trial, 552 adults completed the ACQ at baseline and after 13 and 26 weeks of treatment. The analysis showed that the measurement properties of all four versions of the ACQ are very similar. Agreement between the original ACQ and the reduced versions was high (intraclass correlation coefficients: 0.94-0.99). Mean differences between the ACQ and the shortened versions were less than 0.04 (on the 7-point scale). Clinical trial results using the four versions were almost identical with the mean treatment difference ranging from -0.09 (P=0.17), to -0.13 (P=0.07). For interpretability, the minimal important difference for all four versions was close to 0.5. In conclusion, these three shortened versions of the ACQ can be used in large clinical trials without loss of validity or change in interpretation.

Clinical outcomes and adverse effect monitoring in allergic rhinitis.

The subjective recording in diary cards of symptoms of itch, sneeze, nose running, and blockage, with the use of a rating scale to indicate the level of severity, is usual for clinical trials in allergic rhinitis. The primary outcome measure is usually a composite score that enables a single total symptoms score endpoint. It is appreciated, however, that rhinitis has a greater effect on the individual than is reflected purely by the recording of anterior nasal symptoms. Nasal obstruction is troublesome and may lead to sleep disturbance in addition to impaired daytime concentration and daytime sleepiness. These impairments affect school and work performance. Individuals with rhinitis find it socially embarrassing to be seen sneezing, sniffing, or blowing their nose. To capture these and other aspects of the disease-specific health-related quality of life, questionnaires such as the Rhinoconjunctivitis Quality of Life Questionnaire have been developed and validated for clinical trial use. The adoption of health-related quality of life questionnaires into clinical trials broadens the information obtained regarding the effect of the therapeutic intervention and helps focus on issues relevant to the individual patient. It must be appreciated that it is not only the disease that may adversely affect health-related quality of life; administered therapy, although intended to be beneficial, may also cause health impairment. Adverse-event monitoring is thus essential in clinical trials. The first-generation H 1 -histamines, because of their effect on central H 1 -receptors, are classically associated with central nervous system (CNS) effects such as sedation. Although this is not always perceived by the patient, it is clearly evident with objective performance testing, and positron emission tomography scanning has directly demonstrated the central H 1 -receptor occupancy. The second-generation H 1 -antihistamines have reduced central H 1 -receptor occupancy and considerably reduced or absent CNS sedative effects. Therefore, the CNS effects are entirely avoidable, and the first-generation H 1 -antihistamines should no longer be used in the management of allergic rhinitis. The considerably rarer but potentially very serious cardiac arrhythmogenic effects of H 1 -antihistamines are appreciated to be molecule-specific rather than class-specific. The in vitro screening of new compounds to eliminate the further development of those with cardiotoxicity ideally will lead to this adverse effect being historic. The incorporation of electrocardiogram recording in clinical trials provides direct information relating to prolongation of QT interval corrected for heart rate. Although administered at low doses, intranasal steroids still have the potential for systemic absorption and adverse consequences. However, it is appreciated that meaningful differences exist in the bioavailability of different steroid molecules, and although a small but statistically significant effect on growth in children has been identified with the long-term use of intranasal beclomethasone when administered twice daily for 1 year, this is not evident with all intranasal steroids. In addition, twice-daily intranasal steroid administration may have more effect--from the endocrinologic perspective--than once-daily administration in the morning, which coincides better with the natural diurnal variation in cortisol. Thus, once-daily intranasal steroid administration is preferable, and when used in studies in children, measurement of height change during the study period is an important outcome variable together with other indices of systemic steroid bioavailability (eg, tests of hypothalamic-pituitary-adrenal axis function). These considerations have even greater relevance if children are concurrently also receiving inhaled steroids for asthma, because the total steroid load will be greater.