What are minimal important changes for asthma measures in a clinical trial?

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1 Eur Respir J 1999; 14: 23±27 Prited i UK ± all rights reserved Copyright #ERS Jourals Ltd 1999 Europea Respiratory Joural ISSN What are miimal importat chages for asthma measures i a cliical trial? N.C. Sataello*, J. Zhag +, B. Seideberg +, T.F. Reiss +, B.L. Barber # What are miimal importat chages for asthma measures i a cliical trial? N.C. Sataello, J. Zhag, B. Seideberg, T.F. Reiss, B.L. Barber. #ERS Jourals Ltd ABSTRACT: I this study, the perceptios of asthmatics to chage i their disease was associated with observed chages i cliical asthma measures, i order to idetify the threshold where chages i cliical asthma measures are perceivable by patiets. The study icluded 281 asthmatic patiets, aged 18±63 yrs, i a radomized, placebo-cotrolled cliical trial of a leukotriee atagoist. Chages were related i: 1) asthma symptom scores; 2) ihaled b-agoist use; 3) forced expiratory volume i oe secod (FEV1); ad 4) peak expiratory flow (PEF) to a global questio that queried overall chage i asthma sice startig the study drug. Additioal aalyses examied differeces i the group reportig miimal improvemet by treatmet (active treatmet versus placebo), sex ad age groups. The average miimal patiet perceivable improvemet for each measure was: 1) poits for the symptom score o a scale of 0±6; 2) puffs.day -1 for ihaled b- agoist use; 3) 0.23 L for FEV1; ad 4) L.mi -1 for PEF. I geeral placebotreated patiets ad older patiets, who reported miimal improvemet, experieced less mea improvemet from baselie tha active-treated patiets ad youger patiets, who reported miimal improvemet. Determiig the miimal patiet perceivable improvemet value for a measure may be helpful to iterpret chages. However, iterpretatio should be carried out cautiously whe reportig a sigle value as a cliically importat chage. Eur Respir J 1999; 14: 23±27. *Merck Research Laboratories, West Poit, PA, USA. + Merck Research Laboratories, Rahway, NJ, USA. # Lilly ad Compay, Ic., Idiaapolis, IN, USA. Correspodece: N.C. Sataello PO Box 4, BL 1-7 West Poit PA USA Fax: Keywords: Asthma epidemiology methods questioaires Received: October Accepted after revisio Jauary Asthma is a chroic respiratory disease characterized histologically by airway iflammatio ad mucus hypersecretio, ad cliically by reversible airway obstructio ad specific patiet-reported symptoms [1]. I cliical trials, chages i asthma are measured by pulmoary fuctio tests, such as forced expiratory volume i oe secod (FEV1) ad peak expiratory flow (PEF), as well as by b-agoist ihaler use, ad validated symptom scales that capture patiet-reported symptoms [2]. While a cliical trial ca be powered to fid small differeces betwee treatmet groups o ay oe of these asthma measures, the meaig of these chages is ofte ukow. The questio is ofte asked: "Do differeces i asthma measures oted at the ed of the study matter to the patiets, that is are they cliically meaigful?". As a example, is a average of 1 or 2 puffs.day -1 decrease i b-agoist ihaler use or a icrease of 8 or 10% i FEV1 perceived by patiets? Oe method of providig cliical meaig is to relate chage i oe measure to a global measure of patietrated chage. For example, JAESCHKE et al. [3] related average chages i scores o a health-related quality-oflife (HRQoL) questioaire to patiets' global ratigs of chage i their disease withi a observatioal study eviromet. I this way, they provided meaig to chages i scores from baselie withi groups o a ewly developed HRQoL questioaire. I this study, the theoretical framework of JAESCHKE et al. [3] was utilized i order to provide cliical meaig to chages i asthma measures observed i a cliical trial. Specifically, the average score chages from baselie for: 1) a validated asthma daytime symptom scale; 2) b- agoist ihaler use; 3) FEV1; ad 4) PEF were related to patiet global ratigs of chage i asthma. However, ulike JAESCHKE et al. [3], ad others [4, 5], this study looked at chages from baselie for active treatmet ad placebo groups, ad sex ad age groups, i order to determie whether treatmet group assigmet, age ad sex ifluece patiet perceptio of chage. Subjects Methods Study participats were adult patiets, 18±65 yrs of age, with mild-to-moderate asthma symptoms who were evaluated i a cliical trial. Patiets were required to have: a history of typical, recurrig symptoms of asthma; FEV1 betwee 40±80% of predicted; ad evidece of reversibility of airway obstructio after ihaled b-agoist (at least 15% icrease i FEV1). Further, all patiets were required to be able to complete a daily symptom diary ad perform pulmoary fuctio tests (spirometry ad PEF) i a cosistet maer. Participats siged iformed cosets ad the study was approved by a Istitutioal Review Board.

2 24 N.C. SANTANELLO ET AL. Study desig The study was a blided, placebo-cotrolled, dose ragig cliical trial of a ivestigatioal compoud (three dose levels of the test compoud, leukotriee atagoist (motelukast) ad matchig placebo). It icluded a 2- week placebo ru-i period, a 3-week double-blid treatmet period ad a 1-week sigle-blid, wash-out period [6]. Patiets completed a validated daytime asthma symptom scale ad twice daily peak flow measuremets o a diary record. At a weekly cliic visit, patiets retured the diary cards, ad they performed pulmoary fuctio tests. At the ed of the treatmet period patiets assessed their perceptio of the chage i their asthma o a global questio. Measuremets The validated daytime symptom score [2] cosists of four questios to assess frequecy of symptoms, the extet to which symptoms were troublesome, frequecy of limitatio i usual activities ad how asthma symptoms affect this limitatio i activities. The scale was completed each eveig o the diary record. Additioally, patiets recorded their PEF ad the umber of puffs of ihaled b-agoist used (upo arisig i the morig ad at bedtime) o the diary record. At weekly cliic visits FEV1 was measured. The average of the four daily daytime symptom questios was computed as the daily asthma symptom score. The, weekly averages of the daily asthma scale scores were used as a overall daily score for the week. The rage for resposes to each questio was 0±6, where 0 idicated the least asthma symptomatology ad 6 the most. The chage i the asthma symptom scale score (possible rage: -6 idicatig improvemet to 6 idicatig worseig) was computed as the differece betwee the average daily score from the fial week of the placebo ru-i period to the fial week of the active treatmet period. The chage i average daily b-agoist ihaler use ad PEF was computed i a similar maer. The chage i FEV1 was computed as the differece from the baselie visit at the ed of the placebo ru-i period to the last active treatmet period study visit. The global questios of chage i asthma (oe give to the patiet, oe give to the ivestigator) asked the patiet or ivestigator to assess the chage i the patiet's asthma. These global assessmets were completed by the patiets ad ivestigators at the ed of the treatmet-period cliic visit while still blided to treatmet assigmet. Respose optios for the globals were preseted as seve-poit scales: very much better, moderately better, a little better, uchaged, a little worse, moderately worse, ad very much worse. Whe completig the global ratig, patiets were blided to the results of their pulmoary fuctio test (FEV1 ad forced vital capacity (FVC)), ad ivestigators were blided to the patiet-reported symptoms diary resposes ad the patiets' global assessmets of chage i their asthma. Lug fuctio was measured by stadardized pulmoary fuctio tests at weekly cliic visits. Statistical aalysis JAESCHKE et al. [3] related chages i score o a HRQoL questioaire to chages i a global ratig of disease. Similarly, the preset study related chages i the diary score, FEV1, averaged morig ad eveig PEF, ad b-agoist use to the patiets' global ratigs of chage i their asthma. For each category of the global, the average (ad quartiles) chage from baselie were calculated i each asthma measure (diary symptom score, FEV1, PEF ad b-agoist use). Ulike JAESCHKE et al. [3] ad others [4, 5], this study foud differeces i the magitude of chage for the better ad worse global categories, ad therefore did ot combie categories ito oe measure of chage. Rather, the miimal patiet perceivable improvemet (MPPI) ad the miimal patiet perceivable deterioratio (MPPD) were examied. The MPPI ad MPPD describe the smallest average chage i a score that correspods to patiets perceivig improvemet or deterioratio. The impact of treatmet group, sex ad age o the MPPI was aalysed by comparig the MPPI for the placebo group versus the active treatmet groups, for males versus females, ad for patiets older tha the media age (33 yrs) versus those youger tha the media age. Similar categories could ot be used for the MPPD due to the small umbers reportig a deterioratio i the asthma measuremets. Although the focus of this study is o patiet perceivable chage, it was also of iterest to examie the associatio betwee the cliicia ad patiet perceptios of chage. Patiet ad cliicia ratigs were cross-tabulated otheglobalassessmetofchageiasthmatoassessthe level of agreemet i their ratigs. That is, the patiet global chage scores were compared to the cliicia global chage scores ad the sample measure weighted kappa [7] calculated to describe the closeess of their agreemet (usig quadratic weights). The study was desiged aprioriwith a sample size of 50 patiets per group to have 80% power to detect (a=0.05, two-tailed test) a mea differece betwee groups i FEV1 of 11% (per cet chage from baselie). The resultig over recruitmet to ~70 per group gave the study 80% power to detect a 9.3% differece i FEV1. The study was ot desiged specifically for the aalysis of miimal perceivable improvemet, as the umber of patiets who would fall ito each category could ot be kow prior to study completio. However, with 86 subjects i the miimally improved group, the stadard error for FEV1 chage from baselie would be Results A total of 281 patiets were erolled ito the study. Eight patiets discotiued prior to completig the study; therefore, complete data o 273 (97%) patiets is available for this report. The baselie characteristics for all patiets etered, are reported i table 1. Tables 2±6 preset the average chage i asthma measures for each category of patiet global ratig. The "A little better" provides the average MPPI ad the category "A little worse" provides the average MPPD. There were very few patiets i the

3 ASTHMA MEASURES IN A CLINICAL TRIAL 25 Table 1. ± Baselie characteristics by treatmet group Table 2. ± Average (quartiles) chages i symptom score by patiet global chage category Patiet-determied Placebo (=69) Active treatmet (=212) All (=281) Age yrs Mea Rage (18±63) (18±63) (18±63) Sex (%) Female 35 (51) 94 (44) 129 (46) Male 34 (49) 118 (56) 152 (54) Race (%) Caucasia 61 (88) 183 (86) 244 (87) Other 8 (12) 29 (14) 37 (13) FEV1 L.s -1 Mea SD Rage (1.04±4.28) (0.93±4.04) (0.93±4.28) Daily b-agoist puffs.day -1 Mea SD Rage (0.71±12.23) (0.77±14.57) (0.71±14.57) PEF L.mi -1 Mea SD Rage (212.9±577.9) 183.9±612.9 (183.9±612.9) FEV1: forced expiratory volume i oe secod; PEF: peak expiratory flow. Average (quartiles) chage from baselie i symptom score* Very much worse Moderately worse A little worse (-0.23±0.45) Uchaged (-0.20±0.38) A little better (MPPI) (-0.71±0.10) Moderately better (-0.90± -0.01) Very much better (-1.54± -0.13) MPPI: miimal patiet perceivable improvemet. *: symptom scale score rage 0±6, with 0=o symptoms, ad 6=maximum symptoms. Table 3. ± Average miimal patiet perceivable improvemet (MPPI) values i symptom score, forced expiratory volume i oe secod (FEV1), peak expiratory flow (PEF), ad b-agoist use by treatmet, sex ad age groups Average MPPI from baselie for asthma measures Subgroups MPPI Diary scale score FEV1 L PEF L.mi -1 b-agoist use puffs.day -1 Active treatmet Placebo treatmet Male Female Older tha media age* Youger tha media age *: media age=33 yrs for all patiets erolled. "Moderately worse" ad "Very much worse" categories. Therefore, little cofidece is placed o the average chages i the asthma measures associated with these two categories. Table 2 reports the average chage i the asthma symptom score for each category of patiet global ratig. The MPPI was ad the MPPD was 0.19 for all treatmet groups combied. The average MPPI differed by treatmet groups (table 3). For the active treatmet groups combied the MPPI was -0.37, whereas the MPPI for the placebo group was The MPPI for males (-0.29) ad females (-0.33) was similar. Usig the media age (33 yrs) to divide the patiets ito two groups (older versus youger) the average MPPI for the older group was smaller (MPPI= -0.19) tha the youger group (MPPI= -0.41). I geeral, for the measures of airflow (FEV1 ad PEF), the average chages were i the expected directio (tables 4 ad 5); that is, as patiets reported improvemet or deterioratio i their asthma the average chage i airflow measures icreased or decreased, respectively. The MPPI for FEV1 was 0.23 L (10.38% chage from baselie) for all treatmet groups combied. The active treatmet groups combied showed a MPPI for FEV1 of 0.25 L compared to 0.18 L for placebo group. Males (0.25 L) ad females (0.22 L) showed a similar MPPI for FEV1, whereas, cosistet with what was foud for the asthma symptom score, older patiets had a lower MPPI for FEV1 (0.17 L) tha youger patiets (0.28 L) (table 3). Furthermore, the values for chage i FEV1 were cosistet across patiets i the MPPI group with differet baselie FEV1 values (the correlatio betwee the chage i FEV1 ad baselie FEV1 values i the MPPI group was early zero). The MPPI for PEF was 18.8 L.mi -1 (or 5.39%) for all treatmet groups combied. Agai, the placebo group had a lower MPPI (7.2 L.mi -1 ) tha the active treatmet group (22.1 L.mi -1 ), as show i table 3. The MPPI for males ad females were similar (19.0 L.mi -1 versus 18.6 L.mi -1, respectively). There were o apparet differeces i average MPPI values betwee older (19.4 L.mi -1 ) ad youger subjects (18.3 L.mi -1 ). As expected, daily b-agoist ihaler use icreased as patiets reported a deterioratio i their asthma ad decreased as patiets reported a improvemet i their asthma (table 6). The MPPI for b-agoist ihaler use was puffs.day -1 for all treatmet groups combied, puffs.day -1 for placebo ad puffs.day -1 for active treatmet groups. There were differeces observed for the MPPI use of b-agoist ihaler betwee males ad females (-0.67 ad puffs.day -1, respectively) ad betwee Table 4. ± Average (quartiles) chages i forced expiratory volume i oe secod (FEV1) by patiet global chage category Patiet determied Average (quartiles) chage from baselie i FEV1 L Very much worse Moderately worse A little worse (-0.10±0.26) Uchaged (-0.12±0.34) A little better (MPPI) (0.01±0.48) Moderately better (-0.14±0.55) Very much better (0.10±0.63) MPPI: miimal patiet perceivable improvemet.

4 26 N.C. SANTANELLO ET AL. Table 5. ± Average (quartiles) chages i peak expiratory flow (PEF) by patiet global chage category Patiet determied Average (quartiles) chage from baselie i PEF L.mi -1 Very much worse Moderately worse A little worse (-31.8± -0.8) Uchaged (-9.8±19.8) A little better (MPPI) (0.7±36.9) Moderately better (0.4±43.3) Very much better (12.9±55.2) MPPI: miimal patiet perceivable improvemet. older ad youger patiets (-0.54 ad puffs.day -1, respectively) (table 3). The weighted kappa statistic describig the agreemet betwee patiet ad ivestigator global resposes was 0.66 (95% cofidece iterval 0.57±0.73). The MPPI values for each of the four asthma measures were relatively similar to the miimum ivestigator-perceived improvemet. Whe the patiet ad ivestigator disagreed, the patiet more ofte tha ot rated themselves as more improved tha the ivestigator perceived them to be. Discussio Previous research determied at what poit asthmatics begi to perceive deterioratio i their lug fuctio [8± 10]. The aalysis preseted i this study determied the level at which a populatio of asthmatics i a cliical trial perceived chage, improvemet or deterioratio, i lug fuctio ad other asthma measures after treatmet. The cliical meaig was determied by relatig chages i four measures of asthma (FEV1, PEF, b-agoist use ad a asthma symptoms score) to patiets' perceptio of chage i their asthma. This approach has bee used previously i quality-of-life research to describe the amout of chage i a quality-of-life measure that is cliically meaigful to a group of patiets withi a study [3±5, 11, 12]. The preset study foud that the distributio of average MPPI ad MPPD scores for chages i symptom score, FEV1, PEF ad ihaled b-agoist use were ot symmetric. That is, the average MPPI chage value differed from the average MPPD value for each asthma measure i distace from the "uchaged" category. Therefore, the MPPI ad MPPD were ot combied ito oe measure of chage. This fidig differs from that reported by others [3±5] who Table 6. ± Average (quartiles) chages i b-agoist ihaler use by patiet global chage category Patiet determied Average (quartiles) chage from baselie i b-agoist use puffs.day -1 Very much worse Moderately worse A little worse (-1.21±2.33) Uchaged (-0.67±0.56) A little better (MPPI) (-1.67±0.28) Moderately better (-2.07± -0.50) Very much better (-3.10± -0.88) MPPI: miimal patiet perceivable improvemet. looked at miimal chages from baselie withi a observatioal study desig where the chage was symmetrical (improvemet ad deterioratio had approximately equal magitude). The preset study foud that there were differeces i the cliically importat improvemets for all four asthma measures betwee treatmet ad age groups. Patiets i the placebo group who rated themselves as miimally improved teded to have experieced less improvemet i the four measures tha the active treatmet group. Likewise, older patiets, o average, eeded less improvemet i asthma measures to report improvemet tha youger patiets. For the four asthma measures, oly puffs of b- agoist differed slightly i miimal improvemet usig the sex groups (males who reported miimal improvemet experieced o average a lesser decrease i puffs tha females who reported miimal improvemet). However due to sample size limitatios the authors were uable to test for statistical differeces ad, therefore, differeces betwee groups may be due to chace aloe. Differeces i MPPI values for differet levels of severity were ot examied, sice the MPPI value for chage i FEV1 did ot systematically vary from baselie FEV1 (the lie describig the relatioship betwee baselie FEV1 ad chage i FEV1 i the MPPI group was close to zero). Previous studies examied miimally importat chages from baselie for quality-of-life measures i prospective observatioal studies [3±5]. Withi these studies oly the chage from baselie i a asthma cohort who reported chage o a global questio was calculated. This chage from baselie was termed the miimal importat differece (MID). The MID has bee used as a way to determie whether the differece observed betwee treatmet groups is cliically importat [3±5, 12, 13]. However, the methodology uderlyig the calculatio of the MID is based o chage from baselie i a observatioal cohort of asthmatics who report chage o a global basis, ad, as such, caot examie whether there are differeces i values for what are perceived as importat betwee treatmet groups. Usig blided cliical trial data for the preset aalyses, it was foud that the chage from baselie for the placebo group who rated themselves as miimally improved was less tha that see i the active treatmet group who rated themselves as miimally improved for each asthma measure. These fidigs are cosistet with those expected based o a aalysis i a study by NORMAN et al. [14] comparig "retrospective" chage (chage observed i a cohort who report chage o a global basis) with "treatmet" iduced chage (chage observed as a result of a applied treatmet). It might easily be accepted that there would be differeces i the MPPI betwee older ad youger patiets as was foud i this study. Differet age groups (older or youger patiets) might be more sesitive to smaller chages i asthma measures to defie improvemet or deterioratio. CONNOLLY et al. [8] showed that elderly asthmatic patiets were less aware of brochocostrictio tha youger patiets. However, i the preset study, it had bee assumed that o large differeces would be foud betwee the treatmet groups i the amout of chage i a measure perceived as miimal improvemet, sice the data were collected i a blided, placebo-cotrolled, radomized cliical trial. A possible explaatio for the differeces foud betwee treatmet groups may be that

5 ASTHMA MEASURES IN A CLINICAL TRIAL 27 withi a blided, placebo-cotrolled, radomized cliical trial, all patiets geerally expect to improve. Therefore, the blided placebo group might be more sesitive to smaller improvemets i cliical asthma measures ad rate themselves as improved more easily, eve without evidece of greater chage i asthma measures. Additioally, there may be a threshold rage of effect, such that although may patiets fell ito the rage, the active treatmet group resposes are distributed more towards the top of the threshold rage ad the placebo group more towards the bottom, as evideced by the differece i average chages. The patiet ad ivestigator miimal improvemet was comparable i magitude for each asthma measure. This fidig was expected sice the weighted kappa of 0.66 idicated relatively strog agreemet betwee patiets' ad cliicia's global ratigs. There are limitatios to the use of this method i providig cliical meaig to chages i cliical measures. Although the average chages i the asthma measures showed a orderly progressio i the expected directio with the categories of chage i the global ratigs, cosiderable variability existed amog idividuals. Oe explaatio for this is that idividual patiets perceive symptoms differetly ad hece also perceive the magitude of chage i their asthma differetly whe aswerig the global chage [8±10]. Aother reaso is that global ratigs do ot represet a "gold stadard" for assessmet of chage i these measures, but rather provide directio ad magitude of average effects. This is cosistet with the authors' previous research where it was demostrated that the value for miimal improvemet differed based o the type of global questio asked [15]. With these limitatios i mid, it the becomes clear that the miimal patiet perceivable chage for a measure defied from cliical trial data should ot be used by a cliicia to defie cliical improvemet or deterioratio i the care of a idividual patiet. Rather, the results of this study might provide a basis for iterpretig the cliical meaig of average chages i asthma measures reported withi cliical trials. I summary, statistically sigificat differeces from placebo may ot be sufficiet to demostrate cliical improvemet or deterioratio, if the cliical meaig of the differece is ot uderstood [12]. The method of relatig chage i cliical measures to patiets' overall ratig of chage i their disease may be useful to provide a estimate of what level of chage from baselie or differece betwee treatmet groups i a measure is cliically relevat to patiets. However, this aalysis of a blided, placebo-cotrolled, radomized cliical trial demostrated that what patiets perceive as miimally cliically relevat may differ by treatmet group ad age. Therefore, while a level of miimal chage i a measure that is defied as cliically relevat by this method might be useful, cautio is advised agaist settig a uiversal bechmark of what is a importat chage for a measure based o this method for may reasos [14], icludig possible differeces betwee treatmet groups ad other demographic groups. Based o the preset fidigs, further research appears warrated to determie whether miimal improved values for measures vary for other treatmets ad other types of patiet populatios. Ackowledgemets. The authors would like to thak Z. Zhao for assistace i the statistical aalyses. Refereces 1. Busse WW, Reed CE. Asthma: defiitio ad pathogeesis. I: Middleto E, Reed CE, Ellis EF, Adkiso HF, Yugiger JW, eds. Allergy: Priciples ad Practice. 3rd Ed. St. Louis, CV Mosby 1988; p Sataello NC, Barber BL, Friedma B, Reiss TF, Zhag J. Measuremet characteristics of two asthma symptom diaries validated i two separate cliical trials. 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