Clinical and E.xperimental Allergy, 1991, Volume 21. pages 77-83

ADONIS 0960217891000 t2X

Development and testing of a new measure of health status for clinical trials in rhinoconjunctivitis ELIZABETH F. JUNIPER and G. H. GUYATT* Departments of Clinical Epidemiology and Biostatistics and * Department of Medicine, McMaster University, Hamilton. Ontario, Canada Summary

The objective of this study was to develop and test a health-related quality of life questionnaire for clinical trials in rhinoconjunctivitis. The Rhinoconjunctivitis Quality of Life Questionnaire (RQLQ) was developed by asking patients to identify areas of their lives affected by rhinoconjunctivitis. The resultant RQLQ was tested for reproducibility, responsiveness and validity in a randomized, double-blind trial of regular versus 'as required" aqueous beclomethasone dipropionate (BDP) nasal spray in ragweed pollen-induced rhinoconjunctivitis. Eighty-tive patients from previous rhinoconjunctivitis studies participated in the developmental survey. Sixty ragweedsensitive patients, from previous trials and media notices, were enrolled in the clinical trial. Aqueous BDP (800 /(g) nasal spray was administered regularly or 'as required* throughout the ragweed pollen season. The survey revealed that, in addition to local symptoms of rhinoconjunctivitis. patients experienced impairment of quality of life through systemic symptoms, sleep disturbance, practical problems, activity limitations and emotional problems. The RQLQ includes 28 questions related to these dimensions. Repeated administration of the RQLQ demonstrated good reproducibility. During the clinical trial, the RQLQ proved responsive in its ability to distinguish between regular and 'as required' medication use. Validity was shown by moderate to strong relations between changes in symptom diary scores and changes in RQLQ scores. In conclusion the RQLQ is likely to prove useful as a measure of health-related quality of life in clinical trials in both rhinoconjunctivitis and rhinitis. Clinical and Experimental Allergy, Vol. 21, pp. 77-83. Submitted 6 June 1990; revised 13 August 1990; accepted 13 August 1990 Introduction Instruments to measure symptoms of rhinoconjunctivitis are used commonly in clinical trials in rhinoconjunctivitis [1,2]. However, these questionnaires do not address the overall impact of the symptoms on patients' day-to-day lives. In response to the need for a more sophisticated instrument for measuring health-related quality of life in clinical trials in rhinoconjunctivitis we developed Quality of Life Questionnaire (RQLQ). This was developed according to previously established principles [3], and methods [4] which have proved successful in the development of instruments for chronic lung disease [5]. chronic Correspondence: Prof, Elizabeth Juniper, Dept, of Clinical Epidemiology and Biostalistics. McMasler University Medical Centre. 1200 Main Street West. Hamilton, Ontario. Canada L8N 3Z5,

heart failure [6]., breast cancer chemotherapy [7] and inflammatory bowel disease [8]. In this paper we describe the developmental process for the RQLQ and present data regarding the reproducibility. responsiveness and validity of the questionnaire. Principles of questionnaire development The aim was to develop an evaluative instrument capable of measuring change over time within people [3]. The approach was guided by criteria which we deemed essential for the final questionnaire. (1) Both physical and emotional function should be measured. (2) Items must reflect areas of function which are important to patients with rhinoconjunctivitis, (3) Summary scores amenable to statistical analysis must be provided. 77

78

Elizabeth F. Juniper and G, H. Guyatt

(4) The questionnaire should be reproducible when the clinical state is stable. (5) The questionnaire should be responsive to clinically important changes, even if those changes are small. (6) The questionnaire should be valid, i.e. it actually measures subjective aspects of health status. (7) The questionnaire should be relatively short in order to optimize cost and efficiency.

Tabie 1. Item frequency and importance

Sleep Lack ofa good night's sleep Wake during the night Difficulty getting to sleep

74 75 79

2-5 2-4 2'!

186 178 166

Instrument deveiopment phase

Non-hay-fever symptoms Tired Fatigue Worn out Reduced productivity Poor concentration Thirst

79 77 71 71 66 60

2-3 2-3 2-4 1-9 20 2-2

181 179 173 132 130 130

83 83

30 29

252 238

Item selection Initially a list of 91 health-related items, considered of possible importance to patients with rhinoconjunctivitis, was constructed. The items were generated through the experience of the investigators., a review of general healthrelated quality of life measures [9,10] and unstructured interviews with patients with rhinoconjunctivitis. Item reduction

'

'

The purpose of this phase was to identify which of the 91 items are most important to patients with rhinoconjunctivitis and to construct the RQLQ. A questionnaire was sent to 89 patients with documented rhinoconjunctivitis who had participated previously in rhinoconjunctivitis clinical trials. Of these. 85 (96%) completed and returned the questionnaire. Patients were asked which of the 91 items were troublesome to them as a result of their rhinoconjunctivitis. They were then asked to indicate the importance of each of the identified items using a fourpoint scale from 1 = bothers me a little, to 4 = bothers me very much. The results of the item reduction process are presented in Table I. Associated with each item is the number of people who labelled the item as a problem, the mean importance associated with the item, and the product of the frequency and importance. The maximum possible score, if all 85 subjects chose an item and rated it 4 in importance, would be 340. The highest scores were related to nose and eye symptoms and the associated practical problems, Impairment of sleep, non-hay-fever symptoms, activity limitations, and emotional problems were also identified as frequent and important problems to these patients. Items selected for the final questionnaire were those most frequently identified by the patients and those labelled most important (Table I). Other criteria were adequate representation of both physical and emotional function and a minimum of three items per dimension. The fmal questionnaire, constructed on the basis of these results, contains 28 items; three items related to sleep, seven related to non-hay-fever symptoms, three to

Dimension (item)

Practical problems Need to blow nose repeatedly Need to ruh nose/eyes Inconvenience of having to earry tissues or handkerchief

Mean Frequency importanee Product

75

2-7

199

Nasal symptoms Stuffy/hlocked Sneezing Runny Itchy

83 85 83 81

32 31 30 28

269 262 248 226

Eye symptoms Itchy Watery Swollen Sore

84 81 74 74

32 29 26 2-3

266 234 193 171

78 73 73

2-4 2-4

2-2

184 177 160

61 67

20 19

125 125

Emotions Irritahle Frustrated Impatient Embarassed by nose/eye symptoms Restless

practical problems, four to nose symptoms, four to eye symptoms, three to activities, and four to emotional function. Overall quality of life is expressed as the mean of these seven domains. Due to a wide variety of lifestyles, activities in which patients experienced important limitations, varied greatly. Therefore, in the final questionnaire,, the activities are patient specific i.e. at the first administration of the RQLQ, the patient identifies three activities in which they arc limited by rhinoconjunctivitis and these activities remain specific for that patient throughout the clinical trial.

Measuring health slalus in rhinoconjum iiiiii.\

Reproducihility

2-0 r

Reproducibility was evaluated by administering the instrument on two occasions, 2 weeks apart, during a period of clinical stability. As fluctuating pollen counts can rapidly alter the clinical state, reproducibility was evaluated during the 3 weeks prior to the start of the ragweed pollen season when fungal spore and grass pollen counts are moderately stable. This meant that most patients were experiencing mild, fairly stable symptoms. The results, shown in Fig. I, demonstrated a close relationship between scores on the two administrations, with no significant change over time (intra-ciass correlation coefficient = 0'86). 0-5

1-0 Visit

2-0

Fig, !. Overall quality of life questionnaire scores measured on two occasions, 2 weeks apari. Intra-class correlation coefficient =0-86.

The 28 items in the RQLQ were serially pre-tested to clarify issues of wording and item presentation. A summary of the questionnaire is included in Appendix I. An interviewer assists patients to identify the three activities in which they are limited by their rhinoconjunctivitis. subsequently the questionnaire can be self-administered. We found that initial administration of the RQLQ (including an explanation, instructions and identification of patient-specific activities) takes a maximum of 15 min, and usually between 5 and 10 min. Follow-up administration takes a maximum of 10 min and usually less than 8 min.

Testing the RQLQ for reproducibility, responsiveness and validity Evaluation of the RQLQ measurement properties took place within a randomized, double-blind clinical trial of regular versus "as required' use of aqueous beclomethasone dipropionate (BDP) nasal spray in ragweed-pollen induced rhinoconjunctivitis. Details of the study design, patient recruitment, and primary outcomes are presented in a separate report [II]. In brief, 60 patients with documented ragweed-potlen induced rhinoconjunctivitis were randomized. Thirty received 200/jg BDP nasal spray twice daily starting I week before the ragweed pollen season and continuing until it finished, and 30 received 400 /ig BDP daily, to be taken as required in response to symptoms. Double-blindness was maintained by use of a double-dummy design.

Responsiveness During the clinical trial, which encompassed the entire ragweed pollen season, patients completed a daily symptom diary which monitored sneezing, stufTy, runny and itchy nose and eye symptoms. The RQLQ was administered during the first week of the ragweed pollen season when pollen counts were still fairly low and patients experiencing only mild symptoms. It was repeated at the height of the ragweed pollen season and again during the last week of the study when the pollen counts had decreased and symptoms were resolving. Figure 2 shows conventional nose and eye symptom scores from the daily diary for the week before each administration of the RQLQ. Figures 3 and 4 show the response in each of the seven domains of the RQLQ and the overall quality of life scores at these times. For both the diary symptoms and the quality of life outcomes, higher scores represent a deterioration. It is evident from these figures that both nose and eye symptoms and the RQLQ domains reflect mild symptoms and impairment of quality of life at the beginning of the ragweed pollen season with no evidence of any difference between the two treatment groups. With the exception of a deterioration in eye symptoms at the height of the season, the group on regular BDP nasal spray remained minimally symptomatic throughout the irial. In contrast, the "as required' group showed substantial deterioration in both nose and eye symptoms, measured by both the daily diary and the RQLQ. At the end of the study, when airborne pollen counts had fallen, although both groups had improved, the "as required" group remained more symptomatic. Unpaired r-tests comparing the two groups were conducted for each of the three observation periods, the resulting P-values, difTerences in mean scores and confidence intervals, representing the responsiveness of each measure, are presented in Table 2. The results demonstrate that nasal symptom and non-hay-fever symptom

79

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Elizabeth F. Juniper and G. H. Guyatt

1-0 (o)

(b)

0-8

S 0-8 u V)

E

0-6

I 06 E D C

a

I 0-2 Dunng

Pr«

Post

During

Fig. 2. Mean ± s.e.m. daily nasal (a) and (b) eye symptom scores recorded by the subjects in their diaries during the first, middle and last week of the ragweed pollen season, (o) 'as required" nasal spray: (•) regular nasal spray.

(b)

Pre

During

Post

(d)

Pre

Durlnq

Posr

Pre

domains of the RQLQ, as well as the overall score, are comparable in their responsiveness to the daily diary. Most other domains, while somewhat less responsive, nevertheless reach conventional levels of statistical significance.

Validity The following data from the trial support the validity of the RQLQ. (1) In the'as required'arm of the trial, function deterior-

During

PosI

Fig. 3. Quality of life questionnaire scores (mean + s.e.m.) for sleep disturbance (a). non-haylever symptoms (h), practical problems (c) and nasal symptoms (d), for the first, middle and last weeks of the ragweed pollen season. (O) 'as 'required' nasal spray; (•) regular nasal spray.

ated as pollen counts rose, and improved as pollen counts fell. (2) Most RQLQ dimensions showed changes in parallel with the nasal symptoms diary. The eye symptom dimensions showed equal deterioration in both groups during the hay fever season, and these changes were similar to those seen in the eye symptoms diary. It is biologically sensible that steroid inhaled through the nose should ameliorate nasal symptoms but have no appreciable impact on eye symptoms. (3) We examined correlations between changes in six RQLQ dimensions (sleep, non-hay-fever symptoms.

Measuring health status In rhinoconjunctivitis

81

1-50 1-25 I'OO 0-75

0-50 0-25 During

Pre

Post

Pre

During

Post

Pta

During

Post

1-50 (d) 1-25

Fig. 4. Overall quality of life questionnaire scores (a) and scores (mean±s.e.m.) for eye symptoms (b), activities (c) and emotions (d), for the first, middle and last weeks of the ragweed pollen season. (O) 'as required' nasal spray; {•) regular nasal spray.

0-8 -

I'OO

0-6 -

0-75

0-4 -

0-50

0-2 -

0-25

During

Post

Table 2. Differences between treatment groups Pre-season Omcome measure

Mid-season

95%CI

Post-season

6

95%CI

P

95%CI

P

Diary Nasal symptoms Eye symptoms

009 - 0 08

±0-21 ±018

024 047

0 36 -017

±0 24 ±0-26

0007 027

022 - 0 04

±0-17 ±016

0 017 065

Quality of life Questionnaire Sleep Non-hay-fever symptoms Practical problems Nasal symptoms Eye symptoms Activities Emotions Overall quality of life

-003 -0-05 0-29 034 00 0-16 0-25 016

±0'42 ±0'47 ±0-39 ±0 40 ±042 ±0 43 ±042 ±0-42

0-54 056 Oil Oil 1 00 0-27 0 16 0-26

0-34 070 046 0-85 -014 036 056 0-57

±0 43 ±0 41 ±0-41 ±0 46 ±0 46 ±0 39 ±032 ±039

0097 0003 0-032 0 001 0 61 0-060 0022 0009

032 038 030 041 0 01 0-32 0-28 033

±0-31 ±0-33 ±0 26 ±018 ±031 ±0 43 ±028 ±0-31

0-041 0029 0-030 0-006 095 0-094 0-050 0-037

* Difference between ihc means of the two treatment groups. t Probability of a type 1 error (one-sided).

practical problems, nasal symptoms, activities and emotions) which we anticipated should be moderately (coefficient 0-3-0-5) or strongly (coefficient >0-5) related to changes in diary nasal symptoms. We also examined the correlation between changes between the eye symptoms diary score and the eye symptoms

RQLQ dimension, which we felt should be greater than 0-5 to support the validity of this RQLQ dimension fully. The correlations between change in diary nasal symptoms and the six relevant RQLQ dimensions are: sleep:

82

Elizabeth F. Juniper and G. H. Guyatt

r = 0 41; non-hay-fever symptoms: r = 0 31; practical problems: r = O-55; nasal symptoms: /• = 0 54; activities: r^O 49; and emotions: r = 0 59. The correlation between change in eye symptoms and change in RQLQ eye symptoms was r = O-56. \ Discussion A number of points about our process of selection and reduction of items for the RQLQ are worthy of note. First, the very high response rate among those asked to participate suggests the results should be generally applicable. Secondly, although the issues of greatest concern to patients wilh rhinoconjunclivitis are the symptoms which are traditionally measured, in almost all patients the condition has a deleterious impact on a number of aspects of their lives. Almost all patients experience important degrees of systemic symptoms, impairment of sleep, limitation of activities, and emotional distress as a result of their rhinoconjunctivitis. Any attempt to measure the full impact of the condition, or its treatment, must consider ihese other factors. The results of the current study provide considerable support for the reproducibility. responsiveness and validity of the RQLQ. The treatment efTect (in tenns of symptom diff'erence between the two groups) was. in comparison lo other studies [12]. small. Nevertheless, statistically significant differences between groups were detected in most RQLQ domains. It is striking that despite the relatively small effects on nasal symptoms, differences in areas such as sleep, limitation in activity, and emotional function were detectable. These results emphasi/e the important deleterious effects that even relatively minor illnesses can have on quality of life, and the importance of measuring these effects. Support for the validity of the RQLQ can be found in the moderate to strong relation between changes in symptom diary scores and changes in qtieslionnaire scores. Issues in item presentation include lime specification and response option selection. Time specification refers to the fad that patients are asked lo think about how they have been feeling over a well-defined lime period; up to now, we have used I week, but this could be modified depending on ihe study. The crucial issue in selecting response options for an evaluative instrument (one designed to measure change over time) is ensuring item responsiveness: we have chosen a seven-point scale to ensure that relatively fine gradations of change will be detected [13,14]. The results reported here require confirmation in the hands of other investigators. Nevertheless, we believe the RQLQ is ready for use in other clinical trials in rhinocotijunctivitis in which investigators wish to determine

the eff"ects of their intervention on aspects of health status of direct relevance to patients. Acknowledgments We would like to thank the patients who participated in these studies, Maria Vivieros for help in data collection, Jenny Whyte for data management support and Debbie Maddock for her help in the preparation of the manuscript. This study was supported in part by Glaxo Canada Inc. G.H.G. is a career scientist of the Ontario Ministry of Health. References 1 Juniper EF, Carlier A, Trebilcock AL, Frith PA. Dolovich J, Hargreave FE. Effects of oxatomide compared with cblorpbeniramine in allergic rhinoconjunclivitis. Clin Allergy 1981; 1L6I-6. 2 Wibl J-A, Petersen BN. Petersen LN. Gundersen G, Bresson K. Mygind N. Effect of the nonsedative HI receptor antagonist, astemizole. in perennial allergic and nonallergic rhinitis. J Allergy Clin Immunol 1985; 75:720-7. 3 Kirshner B. Guyatt GH. A methodologic framework for assessing health indices. J Cbron Dis 1985; 38:27 36. 4 Guyatt GH. Bombardier C. Tugwell PX. Measuring disease-specific quality of life in clinical trials. Can Med Assoc J 1986; 134;889-95. 5 Guyatt GH, Berman LB. Townsend M. Pugsley SO, Chambers LW. A measure of quality of life for clinical trials in chronic lung disease. Thorax 1987; 42:773-8. 6 Guyatt GH. Nogradi S, Halcrow S, et al. Development and testing of a new measure ofhealtb status for clinical trials in heart failure. J Gen Int Med 1989; 4:101 7. 7 Levine MN. Guyatt GH. Gent M. ct al. Quality of life in stage II breast cancer: an instrument for clinical trials. J Clin Oncol 1988; 6:1798-810. 8 Guyatt GH. Mitchell A. Irving EJ. et al. A new measure of health status for clinical trials in inflammatory bowel disease. Gastroentcrology 1989; 96:804-10. 9 Brook RH. Ware JE. Davics-Avcry A. el al. Overview of validity and ihe index of well-being. Health Services Res 1976: 11:478-507. 10 Bergner M. Bobbitt RA. Carter WB. Giison BS. Tbe sickness impact profile: development and final revision of a bealtb status measure. Med Care 1981; 19:787-805. 11 Juniper EF. Vivieros M. O'Byrne PM. Guyalt GH. Aqueous beclometbasone diproprionate nasal spray: regular versus "as required' use in tbe treatment of seasonal allergic rhinitis. J Allergy Clin Immunol. 1990: 86:3-6. 12 Juniper EF. Kline PA. Ramsdale EH. Hargreave FE. Comparison of efficacy and side etTects of aqueous steroid nasal spray (budesonide) and allergen-injection therapy (Pollinex-R) in the treatment of seasonal allergic rhinitis. J Allergy Clin Immunol I990;85:606-l 1. 13 Guyatt GH. Townsend M. Berman LB. Keller JL. A

Measuring health status in rhinoconjunctivitis

comparison of iikert and visual analogue scales for measuring cbange in function. J Chron Dis 1987:40:1129-33. 14 Jaeschke R. Singer J. Guyatt GH. A comparison of seven point and visual analogue scales: data from a randomized trial. Controlled Clinical Trials 1990; 11:43-51.

NAME: DATE; (Visit l^dentify 3 activities that have been limited by nose/eye symptoms during the previous week.) Please score every item: (Yellow Card) How troubled have you been by each of these sleep problems during tbe last week as a result of your nose/eye symptoms? 0 0 0

EYE SYMPTOMS (Yellow Card) How troubled bave you been by each of these symptoms during tbe last week? (a) (b) (c) (d)

Itcby eyes Watery eyes Sore eyes Swollen eyes

0 0 0 0

I I I I

2 3 4 2 3 4 2 3 4 2 3 4

5 5 5 5

6 6 6 6

ACTIVITIES (Yellow Card) How troubled bave you been by each of these activities during the last week as a result of your nose/eye symptoms?

Appendix 1. Rhinoconjunctivitis quality of life questionnaire

(a) Difficulty getting to sleep . . . . (b) Wake up during the night. . . . (c) Lack of a good night's sleep. .

83

3 4 3 4 3 4

5 6 5 6 5 6

(a) Activity 1 (b) Activity 2 (c) Activity 3

0 0 0

I 2 3 4 I 2 3 4 1 2 3 4

5 6 5 6 5 6

EMOTIONAL (Green Card) How often during the last week have you been troubled by these emotions as a result of your nose/eye symptoms? (a) (b) (c) (d)

Frustrated Impatient or restless Irritable Embarrased by your symptoms

0 0 0 0

1 I 1 1

2 3 4 2 3 4 2 3 4 2 3 4

5 5 5 5

6 6 6 6

NON-HA YFEVER SYMPTOMS (Yellow Card) How troubled have you been by these symptoms during the last week as a result of your nose/eye symptoms? (a) (b) (c) (d) (e) (f) (g)

Fatigue Tbirst Reduced productivity Tiredness Poor concentration Headache Worn out

0 0 0 0 0 0 0

1 1 1 I I 1 1

2 3 4 2 3 4 2 3 4 2 3 4 2 3 4 2 3 4 2 3 4

5 5 5 5 5 5 5

6 6 6 6 6 6 6

PRACTICAL PROBLEMS (Yellow Card) How troubled have you been by each of these problems during the last week as a result of your nose/eye symptoms? (a) Inconvenience of having to carry tissues or handkerchief 0 (b) Need to rub nose/eyes 0 (c) Need to blow your nose repeatedly 0

I I I

2 2 2

3 4 3 4 3 4

0 0 0 0

1 I I I

2

3 4 2 3 4 2 3 4 2 3 4

(6) (5) (4) (3) (2) (1) (0)

Extremely troubled Very troubled Quite a bit troubled Moderately troubled Somewhat troubled Hardly troubled at all Not troubled

GREEN CARD

5 6

Please indicate how often during the last week you have been troubled by eaeh of these items as a result of your nose/eye symptoms. Please use tbe following scale:

How troubled have you been by each of these symptoms during tbe last week? StuiTy/blocked nose Runny nose Sneezing Itchy nose

Please indicate bow mueh you have been troubled by each item, during the last week, as a result of your nose/eye symptoms. Please use the following scale:

5 6 5 6

NASAL SYMPTOMS (Yellow Card)

(a) (b) (c) (d)

YELLOW CARD

5 5 5 5

6 6 6 6

(0) (1) (2) (3) (4) (5) (6)

All of the time Most of the time A good part of the time Some of the time A small part of the time Hardly any time at all None of the time

Development and testing of a new measure of health status for clinical trials in rhinoconjunctivitis.

The objective of this study was to develop and test a health-related quality of life questionnaire for clinical trials in rhinoconjunctivitis. The Rhi...
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