Université d'Ottawa University of Ottawa

ControUd Trirl of Oril Glucoeortiroi& in Outpatients witb Acute COPD warbatioa

Who P m n t to the Ewrgency Departnient

A Ruidombcd, DoubbBUnd, PiacebControUed Püot Study

O Shan Ozvid AARON M.D.F.R.C.P

Thesis submitted to the School of Graduate Studies and Research

in partial fiMment of the rquirernents for the MSc degree in Epiderniology

Thesis supavisors:

Drs. Paul H M and Robert Dales

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1 would iike to express my gratitude to my W s supeniisors, Dn. Paul H e k t and Robert

Dales for th& induable inst~ction, guidance lad m e n i e n t throughout al1 phases of the

ddopment of the piiot study and the thesis. Thiinlo is dso due to Dr. George Wells who

provideci vaiuaôle advice concerthg a d y design and swistical anaiysis, and to Dr. Ian Stiel who

advisai me on how to seaire bding for the shidy.

M. Mary Lunau assisted me with the Emergency Department chart review and Ms.

Luenne Caicutt helped with logistical organization ofthe pilot shidy.

The mperation of the entire Ernergency Department madical staff of The Ottawa General

and Civic Hospitals was indispensable and was gnatly appreciated.

Finally, 1 am gratefùl to my mfe Karen for ali of the patience, good humour, and

encouragement which she has exhibiteci throughout the years of my postgraduate studies.

Ba&punh. In North Amerka, the p r d a i a of cbronic obstructive puimomy di- (COPD)

arnongst dddy patients is inCfClCSjIlg, and COPD uwda!ion is now a cornmon cause for

Emergency Department (ED) patient visits. ûva 900 patient visits were log@ at the ûttawa

Geaaa and CMC Hospital's Enmgclicy Depertmmts in 19% because of COPD exacerbation. F i -

two percent ofthese ED patient visits for COPD nsulted in a discharge home.

Although exacerbations of COPD occur commonly, the optimal therapy of this condition

ranamS udmown. Inhaled bro- ad d o t i c s have been proven to be effecive, however

the use of sysieniic gluaxdcoids for trcatmmt of COPD d t i o n ranaOu controvcfsial sincc

then is a lack of controIIed uials demonstrating theù efficacy . A review of 19% ED records suggests that 49% of COPD patients are being discharged fiom the ED with a p d p t i o n for orai

prednisone. Given this wide pmctiœ vuiation, it was felt that a state of clinical equipoise atists

which justifies the need for a randomized, double-blind, placebo-controlled trial exarnining whether

oral glucocorticoids should be used to treat patients with COPD cx~~cerbation who are dischargcd

home âom the ED. This theas wül report on the results of the pilot study which wss undertaken to

estabiish the feasibility of a larger, def'uiitive clinical trial.

Objectives: The primss, objective of the pilot study was to ensure that a larger cünical triai will bc

faible. Secondary objectives of the pilot study were: to assess the rate of patient relapse h order

to detennine whether this clinical variable coukl m e as the primary outcorne variable for the

definitive study, to ver@ the sample size cstimates for the îarger trial, to cvaluate patient r e f d rates

and trial reauitrnent, and to ver@ the enroîiment process and alow for pretesting of the data

collection and data -sis process.

Design: Randomioed, double-bünd, placebo-contrdled pilot trial. Patients who pnsented to the

Emergency Departments at The ûttawa General or Ottawa Civic Hospital with acute COPD

emœdwion wae randomized to trutmait with a 10 âay cuurse of prednisone or placebo prior to

hein$ disdiiuged home hm the ED. M patients rcccivcd 8 10 day course of oral uitibiotics and 30

days of inhalai bronchodilators.

éhkoms: The primary outcorne mkbIe was the percent irnprovement in for& expiratory volume

in oae secad (PEV,) ova tbe 10 &y mament paiod. Seoonbiy outcoaier included i m p m v ~ t s

in oxygamtion, improvana&~ in aibjective dyspma roorsr (d by The b d i m uxi

Tnnsitiod Dycpnca Indsxes), Ùnprovements in diraraspecific quility of life (usesred by the

CiiniicRespiraory DUeueIadar~onnaire),~iaasa10d30&pdadv~rs~eneot

ntes. Al1 ordcoaies wae d 10 dtys a i k domization, wi t i ~ the exception of patient nlapse

which wrc d at 10 ad 30 days ifta mdomivltion.

b u h k Atotal of67 rsfards to the study wim r d v d over the four rnonth piiot paiod, of these

twenty eligiie patients wae domized into the shidy. Nineteen patients suca~&Ny wmpleted

the study, &en in the placebo group anâ ught io the prednjsone group. Racniitment ntes were

appfoxbatdy Wh of that antiupated. Bucd on the d t s of the pilot data, s dculation of the

sample sk needed for the definitive dinid trial aiggested that 3-y rdapsc d d be used as the

primary outcorne variable if212 patients w a e to be awoild in the deMtive study.

Patients tnated with ptednisone in the pilot mdy improved their FEV, by a mean of 40.3 * 44.4% over the 10 âay rwssment pexiod comparai to a mean improvement of 13.9 23.8% in the

placebo-tnated patients v . 1 4 ) . The mean percent oxygen satwation in the ptednisone group

Uiaeassd by 1.6* 1.W in the pfednkmgroup cmpad to aO.18 î 2.8% increese in mean oxygen

saturation in the placebo group (~4.38). Patients reported simiiar Day 1 dyspnea scores on the

B d e Dyspnea Index, bowever by Day 10 the 'fûnctionai impainnent' and 'magnitude of effort'

components of the Transitional Dyspnea Index trended towrrds greater improvernents for the

prednisonatnated patients than for placebo-trcated prtients @ = 0.08 and p= 0.06 respectively).

OVaPU, the total Transitional Dyspnea Inda mean score was 2.44 points higher in the prednisone-

treated group, reflecfing a greater improvement in subjective seKreported dyspnei from Day 1 to

Day 10 in those treated with prednisone, however this improvement was not statisticaüy sisnifiant

(95% CI, - 1.36 to 6.24, fl. 19). Both treatment grcn~ps showed net uiiprovemetlt in disase-specific quality of We as Iissessed

by hpmvements in nie Chronic Reqirat~ry Di- Index Questionnaire scores measwed on Day

i and Day 10 of the triai. The pfddnisone-treatad group consistdy soored greater 10 &y improvemcnts t h the pllrrhrtreatcd groups across aü four domiiiis of tbe quaJity of üfe inâm however none of the differences between the two goups rmched statistidy signifiant levels.

iii

Patientrrlspsedatagratantetliuiapscted. Rdrpse0~~~ntdbyDaylOin45%

of pkdmmaW pitienfs ud 12% of prednisonetreated patiats @=O. 181, ud by Day 30 in 45%

of pLcebo ad 25% of pradniso~lbtrieated paîicnts (p10.63). ICaplaa-Muer airvivil curver did not

p 4.29). A logistic tegrdon mDdd ushg rislc of 30 day relapse as the outoome variable waa

corrihucted in ordato cittaiip to d i hr the infhrencc of suspecteci ciinidy significant covariates

on the treaûnent &'kt. The adjusted oâds ratio for the treaûmnt effèct was found to be 0.15,

h o w m this rpparais proteetivie &kt of steroid treaûnent was not statistidy si@cant ( 95% CI

of the odds ratio, 0.002- 13.70). The o v e d fiequency of sdf-reporteci dverse events was Smüar

in the two treatment groups.

Co~~~lrrsioonc In summary, the pilot study was complded successfiily and dernoll~tlllfed that a

larger, d e W k triel U f d e . Reiqse ~dapseed at a gr- nte than was acpeaed in the plardvr

group, and it was shown that the rate of 30aay relapse could be used as the primary outcome

variable for the definitive clinid triai. The pilot study involved a relatively s d number of patients,

and thedore did not have &tristical power to Shaw any ciiffixeme in results between the two groups.

Nevertheiess, the pilot data suggests a trend towards improved expiratory airflow, dyspnea scores,

dkw-speciûc quality of Wk, and relapse rates in the prednisonetreated patients compand to those

patienîs on placebo. Naturally, this trend could d y be r e v d in a larger study, and therefon a

larger trial wiü k needed in order to definitively establish whether prednisone is superior to placebo

for outpatient therapy of COPD exacerbation.

TABLE OF CONTENTS

Item Pa@

List of Tables .............................................................................................. Mü List of Figures ............................................................................................. x 1 . Introduction ..................................................................................... 1 2 . Background ...................................................................................

2.1 Definition of COPD ....................... ................................ 2.2 Epidemiology of COPD .................................................... 2.3 Natural History of COPD .................................................. 2.4 Etiology of COPD Exacerbations ....................................... 2.5 Aimay Inflammation in COPD ........................................... 2.6 Treatment of COPD Exacerbation ...................................... 2.7 Rationale for Use of G i u ~ ~ ~ ~ r t i c o i d s for COPD ................. 2.8 Potential Adverse Effects of Glucocorticoids in

Patients with COPD ........................................................... 2.8 1 Short-term Adverse Effects ................................... 2.82 Long-tenn Adverse Effècts ..................................

2.9 Glucocortioids for COPD Exacerbation-

Evidence f?om the Literatwe ............................................... 10 2.9 1 Giucocorticoids for Hospitaiized Patients ............... 11 2.92 Glucocorticoids for Ambulatory Patients ................. 12

2.10 Glucocorticoids for COPD Exocerbotion-

Clinid Guiddines .............................................................. 16 2.11Summary ............................................................................. 16

2.12 Rcsuits of the Emergency Department COPD Chrrt R e v i e ~ . 2.13 Codusiom Derived âom the Chrt Review .........................

................................................................................................ Objectives ............................................................................. Expaimtntal Mctbods

4.1 Saidy Design .......................................................................... 4.2 Patient Sdection .....................................................................

. 4.2 1 Inclusion Cnteria .......................................................

...................................................... 4.22 Exclusion Criteria 4.3 Treatment Protocols ................................................................

4.3 1 Expaimentai Manoeuvre ............................................ ................... 4.32 Otha Swdy Manoa~n~ .... ................

4.33 Protocol for Dealing with Patients who Refapsed ........ ........................................................... 4.4 Memues of Cornpliana 27

................................................................. 4.5 Baseiine Assessrnent 27 ................................................................... 4.6 Outcorne Measures 27

4.6 1 Primary Outcorne Measure ............................. ... ...... 27 .................................................. 4.62 Secondary Outcornes 28

............................................. 4.7 Randornimion and StmiScation 31 ................................................................................... 4.8 Blinding 31

..................................................... 4.9 Sample Size Considerations 31 4.10 Sample Size Cddations ....................................................... 33 4.11 FinJ Analysis ...................................................................... 36

4.1 1.1 P ~ c i p a î Analysis of the Primary Outcorne Variable . 36 ......... 4.1 1.2 Analysis of the Seconrlary Outcorne Variables 38

4.1 2 Ethical Considerations ........................................................... 39 5 . Results ...................................................................................................... 40

5.1 Trial Profle ............................................ 40 5.2 P a t i a Characteristics .............................................................. 40

....................................... 5.3 Improvements in Airflow Obstruction 40

5.4 Improv~en& Oxygen Saturation .................................. 5.5 ANCOVA Mjustment for the Effcct of Stable FEV,

................................................ on Percent Change in FEV. 5.6 The Basciine and Transitionai Dyspnea Indexes .................. 5.7 The Cbronic Respiratory Index Questionnaire ............... ..... . 5.8 Relapse .............................................................................. 5.9 Logistic Regression Modei of 30 Day Relapse ..................... 5.10 Profile of Adverse EBects ..................................................

6 . Discussioa ............................................................................................ 6.1 Summrry ad Interpretation of the Results of

..................................................................... the Pilot Study ................... 6.2 Dctermination of the Primary Outcorne Variaôle

6.3 Verifidon of the Sample Size Estirnates for the

Largei Trial ......................................................................... 6.4 Nad for an Interim Analysis and OrganiZation of a

.................................................. Data Monitoring Committee

....................................... 6.5 Randornizstion and Data Collection 6.6 Ciasdication of Patients ........................................................ 6.7 Referral and Recniitment Rates .............................................

6.71 Pilot Sady R e f d Rates ........................................ 6.72 Measures to Improve Study R d t m e n t .................

7 Conclusion ............................................................................................. Appendices:

Appendix 1 . Patient C o m t ancl Infodon Form ......................................... Appendix II Doctor and Patient Information Letters ........................................

Appendix II . The Study Data Collection Fonn ............... .... ....................... Appendix Iü . The Badine and Transitionai Dyspwr Indexes ........................... Appendor IV . The Chronic Respiratory Discase Questio&e ................ .. ....

........................................................................................................... Re fer ences

List of Tables

Table P4e

1 . Glucocorticoids for COPD Exacdation Sunimery of Pubiished and Unpubüshed RandomW, ControUeû,

.............................................................................................. CMd Trials

2 . of COPD Admission and Relapse Rates ....................................

3 . Emergency Department Therapy for Patients Discharged FoUowing Acute COPD Exacerbation ..........................................................

4 . Summary of the Data CoUection Schedule ................................................

5 . Simulateci ANCOVA and Power Analysis of Treament Effect ...................... .. .................................................................

6 . BaseLine Characteristics of AU Patients Randornid to the Pilot Saidy .....................................................................................................

7 . Basehe Dyspnea Index Scores @ay 1) ......................................................

8 . Transitionai Dyspnea Index Scores (Day 10) ............................................

9 . Baseline CRQ Scores (Day 1) ......................................................................

vüi

................................................... 10 . Changes in CRQ Scores @ay 10 . Day 1)

1 1 . Ten and Thirty-Day Relapse Proportions in the Two ....................................................................................... TrCILtment Groups

12 . Unhdate Logistic Regmuion Mdels For 30 ................................................................................................ Day Relapse

.......................................................................... 14 . The Main Effects Model

15 . Summary: Impact of the Pilot Study on the Larger

Definitive Chical Triai ..................................................................................

List of Figures

1. Tbirty Day Relapse Rates Vs. Treatment Received

Ottawa General Hospital 19%. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . - . . . . . . . . . . .

2. Trial Profile ..............................................................................................

3. Absolute Change in FEV, From Day 1 to Day 10

Placebo and Prednisone-Treateâ Groups ... .. . . .. . . . .. . . . ... . . . . . . . . . . . . . . .. -. . . .. . . . . . -. -. . . . .

4. Percent Change in FEV, From Day 1 to Day 10

Placebo and Prednisoae-Treated Groups. .......... ..... .. .. ... ... ... . . ..... .... ...... . .. . . . .. ..

5. Distribution of m g e n Saturation Responses for

the Preûnisone and Placebtreated Groups ....................................................

6. Kaplan-Meier Sumival C w e Showing the Probability

of Ranainllig Relapse-Free for Patients Receiving Prednisone

and Those Receiving Placebo ................................................................ ... ..... .

7. Graphitai Representation of Power as a Function of

Sample Size for the Definitive Triai.. . ... ........ . -. . -. . . . -. . . . .. . . . ........ .. .. .. . .. .. . . ..-. . . . . -. . . . . .. . .

8. Power to Detect Absolute Diffaences

Total Sample of 2 12.. .. . . . . . . . . . . . . . . . . . . .. . . ................ .. . . . . . . . . . . . -. -. . . -. . .. . . . . . .+ - . . . . . . . . . . . . .. .

1.0 Introduction

and public heaith pmblem which results in hudreds of Emergency patient visits to

Ottawa-arca hospitais each year. The optirml tbenpy for acute COPD acacerbation ranaiao

unknown. Onl g l m m k d s a hquedy, but Uieoasistaidy, prescribed for COPD m o n ,

despite a lack of aimnt available evidence demonstrciting their efliicacy, and despite practicc

guidelines wtiich do not support the routine use of glucoc~rticoids for managing outpatient COPD

aacdmtiotl 42 . As a rcsuit, tbere is thedore a nacl to objedively determine whether outpatients with COPD apesbition b e d t h m tnshncat widi a course of oral ghcocortimidd fouowhg that

acute pmtation.

In orda to best answer tbis important clinid question a three-stciged plan ofresearch was

developed. nie p h of research bcgan with a litentwe ud chart review to document the adent of

the clinicai problem, and was foilowed by a pilot study which 1 designcd in wllaboration with

coiîeagues h m Tbe Division of Respiratocy Medicine. The pilot sîudy consisted of a randornized,

double-blind, pk&aantroUed, clinid trial of pfednisone for treatment of outpatients who present

to the Emagency Department with COPD exacerbation. The last stage of the research plan, which

is d y in prosrrss, Win consJt of the definitive, larger ciinid trial. This thesis WU describe the

process, and the results, of the pilot study whicb w u conducted fiom January 5 to May 4,1998.

The dcnmtion of clm,nic obstructive puimoaary disease has evolved considaably since The

BI.itish Medicai Resesrch Cound tint defined chtonic bronchitis in 1965 as a disease charactented

by "chroaic cough and sputum production for three months in two successive years in the absence

ofother diserisss recognised to cause sputum production."

Today, the deMion of COPD ha9 ban refined to dect its haümark characteristic of chronic

d o w obstniction. Airflow obstiuction rden to a diminished expiratoly flow of air through the

airways of the lung, and is objectively meesured by means of spirometry. The degree of airflow

obstruction is quantifiecl by detennining the forad expiratory volume in one second (the FEV,). in

relation to referenœ values.

In 1997 The British Thoracic Society dehed COPD as "a chronic, slowly progressive

disorder characteid by airflow obstniction that does not change markedly over several months.

Most of the lung finction impairment is fixed, although some reversibility can be produced by

bronchodilator (or o h ) therapy."' Accurding ta British guidelines a diagnosis of COPD in clinical

practice requires: "1) a history of chronic progressive symptoms (cough a d o r wheeze andlor

bdessriess) Md 2) objective evidence of airways obstruction that does not retum to normal with

treatrnent".

In contrast, The 1995 American Thoracic Society (ATS) definition of COPD is somewhat

different and hader to operationalize. The ATS definition States that "chronic obstructive pulmonary

disease is a disease state cfiaracterkd by the presence of chronic airfiow obstruction due to chro~c

bronchitis or emphysema or a combination of the two." ' Chronic bronchitis is ciinically defimd as the presence of chronic productive cough for 3

months in eadi oftwo successive years in a patient in whom other causes of chronic cou& have been

excludedl However, it sbwld be mted that the presence of chronic bronchitis does not n e c e s d y

si* the pnsaice of &wqa obstruction or a diagnosis of COPD. Patients with chronic bronchitis

who do not show spirometric evidence of airflow obstruction are not classified as having COPD

according to 1997 British, * or 1995 American Thodc Societies ddnitions.'

of tbe a h p x a c l i d to îhe taminal bmtlcbioles, rocompanied by dcsüuction of bronchiolar wrllq

without obvious &rosis.l In raûiây, moat pa!ients do not d a g o lung biopsy in order to maire a

diagnosis of emphyremi, so cliaicdiy patients are ususlly diagnoseci with cmphysema brsed on a

typical history of smoking, cbroiiic progressive dyspnea, ci~onic d o w obstruction, and cbest

radiograph andlor Ci' sari eviûetyx of anphysanatais lung destniction.' This highüghts a weakness

of the American da t ion , since technicaiiy it relies on prtbologic widence to d e a d@osis of

emphysemq whereas the British denaition allows for dinid aad physiologie aiteria for m a h g a

âiagnosis of COPD without requiring pathotogic evidenœ.

The M o w obstruction of COPD, unljkc that of asthme, is chronic, progressive, and is by

definition, largely irreversible.' Reversibility of ürtlow obstruction is deterxnined by testing the

patient's expiratory flow rate response to inheled bronchodilator. Classidy, patients with COPD.

unlike asthmatics, are said to be relatively unresponsive to bronchodilator (ie. relative percent

increase in FEV, of < 15%)', although several studies have show that patients with COPD cm

exhibit widely varying levels of revetsibiüty pst-bronchodilator making them difnailt to distinguish

fiom asthmatic patients based on this aiteria al~ne.~*

Patients wah asthma, wbse airflow obstruction and whose symptoms of breathlessness are

reversible, are not considerd to have COPD.' Often the most dicuit diagnostic problem is

distinguishing COPD âom the persistent airfîow limitation of chronic asthma in older subjects.

Although the distinction rnay be diflcidt, a history of heavy smoking, midace of emphysema

radiologically, and chronic hypoxemia favour the âiagnosis of COPD. In contrsst, onset in

childhood, atopy and marked improvement on spùometry with administration of bronchdiators

favour the âiagnosis of asthma.'

Dkth&h@ patients with asthma fiom those with COPD wül be important for the validity

of this shidy. Previous Large chicai trials have already established the efficacy of using steroids to

treat =te rsthma m o n , and have demonstrateû that Emergency Department patients 4 t h

acute rsthma mwhation treated with outpatient gluoacorticoids have rduced rdapse mes,

reduced use of bar-agoaist bronchodilators, and reduced hospitalisation rates." It would thus be

2.2 Epiri;cntiOlOg)r of COPD

COPD is a major oaire of morbidity anâ mortality in North Amaica. In 1985 in the United

States, COPD acc~unted for 5% of office visits to physicians and 13% of ho spi ta lido^.' In

Canaâa, COPD nmains a siemificnnt puôiic health burdai; more than 50,000 patients am admittcd

to hospitd every year for tnatment ofemphysam and chronic broncbitis, rind mmy more require

outpatient therapy for Bans of their dwase."

Am@& of morbidity data abstracted fiom the US National Health Interview S w y shows

that in 1985 the agdjusted prdence rate of COPD in persons aged 55 to 84 was 1 10 per 1,000

for males Md 120 per 1,000 for femrilesmiU2 This estimate may be somewhat infiateci however, siuce

the datri fepfe~tnts ~e~rcported pliovljencc of COPD, and h n ait& for the diagnosis of COPD

were not employed. Estimates of Cadian health-professional~sed COPD prdence mes,

derived from the 1994-95 National Health Swey, indiate a COPD pievalence rate of 47% in

persons aged 55-64, 5.4% in those 65-74 and 8.3% in persons 2 75.'' In 1985, accordhg to US

National Center for Health Statistics (NCHS) National Hospital Discharge Sunrey Data, the tige-

adjusted rate for hospital discharges for COPD was 14 per 1,000 and 10 per 1,000 for maks and

fernales respectively over age 55.11* " In Canada, the number of hospitel sepmtions with COPD as

the prllnary discharge diagnosis increased fiom 42,102 in 198 1-82 to 55,782 in 1993-94." Recent

trends suggest that disease prevaienct and hospital discharge rote is stable in men, but increasing

among womea, rd- a 40 year soQetai trad towards increaseû smoking among fernales.' In f k t

in Canada, the rate of age-specific hospital separations in women z 75 increased fiom 504 per

100,000 in 1981 to 1033 per 100,000 in 1994."

Mortality rates for COPD have been increasing. In 1991 COPD caused more than 85,500

deaths in the US, mkhg the disease the fourth leading cause of death in the country.' In the United

States, accordhg to death d c a t t Sormation compileci by the NCHS, the 1985 age-adjusfed

death rate fiom COPD amongst persons 55-84 years old w u 200 per 100,000 and 70 per 100,000

amongst males and f d e s rcspectively." in the US, age-adjusteci death rates for COPD rose 47?%

bawan 1979 and 1993,'. In cwdr. the totd numk of dcrths fkom COPD increased £rom 4438 in 1980 to 8583 in 1995. Age-qmific mortJity ntss runainai stable in aü groups except amon@

those aged 2 75 in which it increased from 2.5 per 1,000 in 1980 to 3.8 per 1,000 in 1995." The

importuice of COPD-associsteû mortality wiU ükely continue to increase given the aging popuiation

and the hervy srnoLing history of the aureat cohort.

Approxhately 90YI of al1 COPD patients bave a history of Although ntes of

cigarette smoking dtcihed amongst d e s in Cinada bom 1970 to 199016, ovaiill morbidiîy ad

morirlity b m COPD amtinuc to incrcasc due to the long laterrcy period before the devdopment of

clinid diSmse."

2.3 N&dHàisbq of COPD

COPD is a disease characttrized by duonic symptoms of COU& and breathicsmcss which

progrear over time. The &case, by debition, is ch.rnciedzed by chtonic, progressive Uaow

obstruction Reports on the MIunl hUtory of patients with COPD show acceferattd rates of decline

in hmg W o n In COPD patients who smolce, the f i , d expiratory volumes in one sccond (FEV,)

dedines by 50.75 mi per year le, versus an expected declhe in FEV, of 15-25 ml pa year in aga

matched controfs who do not have COPD. Patients with a d d COPD are at ri& of dying of their

disease; five year suNival rates for patients with an initial FEV, of less than 1 .O litre am 45 to 50

percent. '& ".

Individuals with COPD are prone to -te exacerbations of th& üiness. These acute

exacerbations of COPD are characterized ciinicaliy by symptoms of worsening dyspnea, cou&

sputum production and sputum pudence, as weU as by worsening of airflow It is

dficult to predict arpeaed exacerbation rates for individuai patients, however most patients with

COPD -ence one to faa aacdations per year? As aidow obstruction becornes more severe,

exllcerbations ofken ocair more fiequently. Age-adjusted US data suggests t h COPD

exacerbations iccount for an average 1.2 office visits and 0.1 to 0.23 h o s p i ~ o n s per year per

prevaient case.'

Acute acacerbaton of COPD can predict a poorer than expected patient outcorne. A recent

prospective cohort study of 1,016 patients who were admitted to hospital for acute COPD

m o n and who had an wtdaî PaC02 2 50 mm Hg, r m d c d that 11% of patients died durhg

the index hospital stay, and that 60 day and 2 year mortality was 2(W. and 49?% respecti~ely.~

A l t h g h dis study did not indude a contrd group, the reiatively high 2 year mortality nte sugpts

tbat rade COPD apoabrition with hypercarbh may be wwiated with a greater short-tam risL of

subsequent derth.

2.4 Biblogg of COPD ~ ~ l l s

Worsaing of pihmiary fundi011 during a COPD d î i o n is most commonly caused by

respiratory infedion, but can also occur seconâary to environmental triggers (e.g.. humidity.

pdlution, cxposurc to smoke or ocaipationa1 Mtants). car& dydbnction, or prognssion of the

dedying diseaseu Studies using Wal cuitures and serology have establishd that v i a and, to a

lesser extent, mycoplasana infèctions, are arrociaeû with approxiInaîely one third of acute

exacabatons of chronic br~ncbitis.~ Thnc bacterial pathogerrs, S~reptaroccrcs pmmmioe,

Hhernophilus influellzoe unàMwaxefIrr mkvrhalis, an âequently implicated in flans of COPD,

however these bacteria can be found in the upper respiratory tracts of healthy people, and are oftai

fwnd in the sputum of patients with COPD during periods of clinid quiescena, crs wel as during

periods of disease exacerbation." Deteminhg whether these bacteria are slmply commensals or

whetha they are respotlsl%le for clinid deterioration is therefon di£Ecult. However, severai clinicai

trials have supporteci the use ofantibiotics for treatment of COPD exacerbation, suggesting that in

some patients, bacterial infection of the airways may play a causai role in provoking COPD

exacerbation.

2.5 Ai- i n m i o n in COPD

Histologie and immunohistochemicat studies of the airways of patients with stable COPD have

revealed evidence of chronic infiammation. Lobar branchial biopsy specimens fiom patients with

COPD show infiltration of the airway wall with lymphocytes, and macrophages and increased

expression of marks of lymphocyte Recent studies have also shown that patients with

COPD have sigdcantly increased numks of CD3+ and CD8+ T-lymphocy~es in subepithelial

branchial biopsies as compared to control srnokm and non-srnoken." Similady, levels of the

in8animatorycyto~tumwne~0sisbdaud~.rrede~lltediatbespuhunofstable

COPD patients cornparcd to controls, aiggesting that COPD is assochaî with a dironic

inflammatory response within the airways? Ahhough it stems reasonable to assume thnt Urwry

inflammation plays a similar mle in the pathogenesis of worsening of airfiow obstruction seen during

acute exacerbations of COPD, there is to date suprisingly little data which exists characterizhg the

inflarnmatory responses seen in acute COPD exacerbation.

2.6 Treutment of COPD Exacerbaiion

Current Canadian, U.S., and European Thoracic Society guidelines recommend that

exacerbations of COPD be treated with appropriate supplemental oxygen therapy, plus

bronchodilator therapy with beta,-agonists and anticholinergic aerosols. '9 '* *' Antibiotics are usually prescribed since it has been show that they may be of help in resolving an acute exacerbation and

are valuable at decreasing the risk of fùrther deteri~ration.~' The most comprehensive study of

antibiotic therap y for COPD exacerbation showed that treatrnent wi th a broad-spectrum antibiotic

increased the 21 day successful recovery rate fiom 55% to 68% in the antibiotic-treated group (p

and release of inflammatory mediators, may thus have theoretic benefits in COPD exacerbation.j3

2.8 Potentiai Adverse Effects of Glucocorticoids in Patients with COPD

2.81 Short-term adverse effects:

A prospective randomized controlled trial evaluating the complication rate of a short course

of glucocorticoids (1-3 weeks) in patients with COPD has not been published. Albert et al reported

that the fkquency of side effects in COPD patients with acute respiratory failure treated with 3 days

of N methylprednisolone was similar to placebo." Unpublished results fiom the SCCOPE trial

(Systemic Corticosteroids in COPD Exa~erbations)'~, a trial using htravenous and oral steroids in

the treatrnent of hospitalized patients with COPD exacerbation, demonstrated that hyperglycemia

was the only short-terni side-effect seen more fkquently in the steroid-treated group.

However, short courses of glucocorticoids cm be associated with side effects which may be

important to patients with COPD exacerbation. Short courses of glucocorticoids can increase the

nsk of infection. The strongest evidence for this cornes fkom a meta-analysis of 71 controlled

clinical trials in which patients were randomized to treatment of their illness with steroids or

placebo? When al1 diagnostic groups were considered, systemic steroids were found to be

associated with a relative risk of 1.6 (95% CI, 1.3 to 1.9) of lethal and nonlethal idections. However

an increase in the incidence of infection was not seen in the subgroup of patients with puimonary

disease ( ~ 3 6 4 ) .

Short-term steroid use is also associated with acute psychiatnc side-effects. A prospective

study of 676 patients treated with short-term steroids for a variety of illnesses showed that 3.1 %

developed acute psychosis or inappropriate euphona. 37 Finally, atrophy and myopathy of skeletal

and respiratory muscles are well-known side-effects which may occur with short term administration

of glucocorticoids. Short courses of supra therapeutic doses of glucocorticoids in rats and hamsters

have been shown to cause reduction in diaphragm weight and atrophy of type IIb diaphragmatic

muscle fibres.38*

2.82 Long-tenn adverse effects:

A clinical study involving 21 consecutive patients admitted to hospital with acute

exacerbations of COPD or asthma has suggested that patients who have been treated with nwnerous

courses of systemic steroid are more at risk for generalized and respiratory muscle weakness than

those patients who have not received steroids. A multiple regression analysis of the relationship

between maximal inspiratory muscle strength (Pimax) and quadriceps force (QF) and steroid dose

in these patients, showed that the average daily dose of steroids used over the previous 6 month

period independently accounted for 32% of the variance in Pimax and for 5 1% of the variance of

QF? This potential contribution of steroids to reduced respiratory muscle strength in COPD

patients is of great clinical significance since respiratory muscle f'unction of many patients with

COPD is already compromised due to hyperinflation, malnutrition, and detraining. Any additional

steroid-induced reduction of respiratory muscle force could theoretically cause M e r respiratory

c~mpromise.~ l

Finally, epidemiological data exists which suggests that long-terni use of glucocorticoids in

patients with COPD may be hannfûl. When data fiom the Swedish Long-Term Home Oxygen

Registry were analysed using multivariate regression analysis models to determine predictors of

survival in COPD patients, oral steroid usage showed no tendency to improve swival in men and

steroid use was associated with an increased mortality rate in women with COPD (relative risk of

death 2.13; 95% CI, 1.38 to 3.29)." Similar studies fiom The Netherlands assessing the

independent contribution of corticosteroids on mortality using a Cox proportional hazards mode1 and

adjusting for age, FEV,, smoking and sex, has shown that the chronic use of oral steroids was

associated with increased risk of mortality (RR =1.33, p=0.002)."

2.9 Glucocorticoid9 for COPD Exucerbation- Evidence fron, the Literuture

A MEDLINE search of the published literature was undertaken to look for trials which

exarnined the use of oral or parenteral steroids for acute management of COPD exacerbation. The

search ternis used were the following: (exp lung diseases, obstructive or chronic bronchitis tw. or

emphysema tw.) and (exp steroids or prednisone.tw.). The reference lists of retrieved studies were

manually searched in order to try to find M e r studies. Three published clinical trials, as well as

one study published in abstract fiom only were found. Preliminary data h m two unpublished trials

recently presented at an international meeting are also summarized below. A summary of the

retrieved clinical trials is found in table 1.

2.91 G f u ~ ~ ~ ~ r t i ~ ~ i à s for LospUalized patients:

Albert et ai studied 44 patients admitted to hospital with COPD exacerbation and randomized

them to either methylprednisolone 0.5 mgkg every 6 hours for 72 hours, or to p l a ~ e b o . ~ They

found that 12 of 22 steroid treated patients had prebronchodilator FEV, increases of 40% or more

at the end of 72 hours of therapy compared to. 3 of 2 1 placebo treated patients @+.O 1 ). They did

not h d a difference in oxygenation, and mortality and hospital duration time were not assessed.

A large trial, which has not yet been published, was recently presented at the 1998 Amencan

Thoracic Society annual meeting.'' The SCCOPE ûial was a multicenter, placebo-controlled study

which randomized patients admitted to hospital with COPD exacerbation to treatment with placebo,

or to treatment with 3 days intravenous methylprednisolone and then either 2 weeks or 8 weeks of

oral prednisone. Al1 patients received antibiotics and inhaled bmnchodilators. The trial's primary

endpoint was treatment failure within 6 months of entry (a composite outcome defined as death,

intubation, readmission for COPD, or need for pharmacologie intensification of treatment). The

study was designed as an equivalence trial and actually required 1200 patients to show a 25%

difference in failure rates between the two groups. Unfominately the trial only enrolled 27 1 patients.

The study showed that the 30 day and 90 day failure rate was 10% higher in the placebo group as

compared to the active group. However, at 6 months the two groups had identical failure rates.

Mean hospital stay was slightly lower in the steroid-treated groups (8.4 vs. 9.7 days, p=0.03). FEV,

was significanily greater on days 2 and 3 in the steroid-treated groups, however this efFect was lost

by 14 days (although it shouid be noted that the analysis was by intention-to-treat and a significant

proportion of patients had crossed over from placebo to open-label prednisone by day 14).

Another recent trial, published in abstract fom only, randomized 57 hospitalised COPD

patients to treatment with 30 rng/day of prednisolone for 14 days or placebo.* Seven patients

withdrew due to treatment failure, 2 in the steroid-treated group and 5 in the placebo-treated group.

Lung function was marginally better in the steroid-treated goup at discharge from hospital; FEV,

was 42% predicted in the treatment group compared to 34% predicted in control group, however

statistical tests were lacking. The rate of M e r exacerbations afier discharge fiom hospital was

similar in both groups. The authon concluded that steroids were associated with fewer dropouts but

did not prevent M e r exacerbations after discharge and were therefore of little benefit. However,

it is âifficult to judge the valiâity of this conciusion in the absence of a more complete presentation

of the study data.

A similar trial, published only in abstract fonn randomized 30 inpatients with acute COPD

exacerbation to therapy with either steroids or placebo for an 1 1 day course? The authors observed

a statistically significant improvement in pulmonary fûnction in both groups, however there was no

additional improvement in the pulmonary fùnction of the steroid-treated group over that of the

placebo-treated group afler one month of follow-up. The authors concluded that steroids were of

little benefit.

2.92 Glucocorticoids for ambulatory patients:

Emerrnan et al studied patients with acute COPD exacerbation in the- emergency

department." They randomized 96 patients to 100 mg of methyl-prednisolone or placebo within 30

minutes of arriva1 to the ED. They did not hd a significant treatment effect. Change in FEV, was

similar at 4.5 hours in both groups (37% improvement in the steroid treated group compareâ to 43%

improvement in the control group), and there was no difference in percent of patients admitted to

hospital(33% vs. 30%), or the number who relapsed within 24 hours (1 0% vs. 1 5%). It should be

noted however, that this trial studied the acute effects of therapy over only 4.5 hours following only

one dose of systemic steroids. Therefore inferences from this study may be limited, since the

duration of therapy and follow-up may have been too bnef to discem a treatment effect.

The only longitudinal trial studying steroid use in outpatients with COPD exacerbation was

performed by Thompson et al!' Twenty-seven outpatients with COPD exacerbation were recmited

fiom the emergency department and f?om outpatient clinics. Patients were randomized to receive a

9 day taper of prednisone (60 mg, 40 mg, then 20 mglday each for 3 days). Unfortunately, because

of the small numbers of patients randomized, the baseline characteristics of the prednisone and the

placebo groups were somewhat different, and suggest that the placebo treated group may have been

more chronically il1 before entering the trial (the placebo group had a baseline FEV,, before

exacerbation of 1.15 0.49 litres compared to 1.59 * 0.67 litres in the prednisone-treated group). This may have biased the resuits in favour of the prednisone-treated group, since obviously the

prednisone-treated group had more potential for improvement back to their higher previous baseline

status. Results from this small trial showed Chat patients in the prednisone-treated group had a

significant improvement in FEV, on day 10 but not day 3 of the trial. Overall, patients in the

prednisone-treated group hproved their FEVl by 0.05 litres per day VS. 0.00 litres per day for

control patients (p4.006). Prednisone treated patients also had a more rapid improvement in arterial

oxygenation , but no significant change in dyspnea scale scores when compared to placebo-treated

patients. Eight of the 14 placebo treated patients required hospital admission or open-label

prednisone compared to none of the 13 actively-treated patients (p4.002).

In addition to data fiom these three clinical trials, several retrospective studies have been

published suggesting a possible benefit to glucocorticoids for COPD exacerbation. Murata and

colleagues conducted a retrospective review of 352 patients with COPD exacerbation who were

treated and released fiom the emergency department." Thirty-two percent of ED visits resulted in

relapse, defined as an unscheduled revisit to the ED within 14 days of treatment. A multiple logistic

regression mode1 comparing visits that resulted in relapse versus those that did not showed that

patients who had visits which resulted in relapse had lower entry and discharge FEV,'s, required

greater number of treatments with nebulized bronchodilators in the ED, had more fiequent use of

parenteral adrenergic h g s , and had less fiequent use of oral prednisone on discharge. The same

investigators have also published a retrospective case-control study of 30 COPD patients with a

history of multiple relapsed9 They compared 45 emergency department visits in which steroids

were prescnbed to an equal nurnber of matched visits in which they were withheld and found that

the 48 hour relapse rate for steroid-treated visits was 9% compared to 3 3% for the non-steroid treated

visits (~~0.005).

ble 1.

Glucocorticoids for COPD Exacerbation

Summary of Published and Unoublished Randomized. Controlled. m a l Trials;

- --- - - - --

Author, year n Patient Treatment Protocol Outcome Results Author's Commen ts

( refertnce) Population Measures Conclusions

lben, 1980 '4 44 Inpatients IV methyl- FEV,. Control group: mean FEV, Stcroids improvcd Clinical outcornes not

prcdnisolonc x 72 PaO,. improved 20%. airflow more than asstsstd.

hours or placebo Sttroid group: mean FEV, placebo

improved 40% (p

-- -

Author, year n Patient Treatment Protocol Outcome Results Author's Comments

( reference) Population Measures Conclusions

Rostom, 1994 '5 30 Inpatients IV methyl- FEV,. No improvement of FEV, in Steroids of no bencfit Many patients lost to

prednisolone x 72 steroid group compared to follow-up, data is

hours followtd by 1 1 controls. incomplete.

days of oral

prendnisone, or

placebo

Emcrman, 1989& 96 Emtrgency IV methyl- FEVl at 4.5 Control group: 43% Steroids of no bmcfit Duration of therapy and

Deparanent prednisolonc 125 hours. improvement in FEV, . F/U may have k n too patients mg. x 1 dose No, of patients Steroid group: 37% bdef to disceru treamcnt

admitted. improvernent in FEV,. (p = NS), t ffect.

Relapse rates. No difference in relapse or

admission rates betwetn thc two

groups.

Thornpson, 1996 " 27 Outpatients- Nine days of tapering FEV,. Conîrol group: FEV, improvcd Steroids improve airflow Groups unbalanccd with

clinics and oral prednisone Failure rate. 0.00 Lld. Failure rate 8/14. obstruction and prevent respect to baselhc

ED Dyspnea scale, Steraid group: FEV , improved trtatment failwes charactcristics, mal1 0.05 Wd (p=0.006), numbtr of patients

Failure rate 011 3. randomized.

2.10 G- for COPD 4!xadhhn- awcal GY*

Current American Thoncic Society GuiAdincli for cve of @am with COPD state that "corticostwiâsxan k useful ifthere h an ;isthmatic compoamt in a patient who dembnstmtcs

responsivcntss to Ma-agoaist thmpy, although tbat h limited informafion supporthg the use of

intnvenous rad oral staoids in the m e n n e n t of COPD cxacctbatioll~."~

Cumnt British Thoracic Society Guiddines state thaî for trrrtmmt of amte COPD

exacerbations "W corticosteroi& may be prtscll'bed in some cases. These shodd not be used

uniess: the prtimt h rilruuïy on orai wrticosiaoids; &ere is a previoudy d~cumeated respoase to

o d c m b s t d Q ; rirflow obstniction to respoad to an inamse in broncbodilator dosage; this

is the first prescntation of airflow obstruction." The guideLines conclude by stating "therc is a necd

for further research into the place of oral corticosteroids in the conta of an raite exacerbation of

COPDw . l6

2.1 1 Suinnuiip

COPD acacabaton npresents an important ciinid and public health problem. The optimal

treatment of aate COPD exacerbation remaiflS unknown. Although experimental data strongly

supports the use of oral gluco«>rtiwids for treathg outpatient exacerbations of rsthma, the data is

weak to aupport the same trecitment in the COPD population. The ridrs and benefits of short courses

of prednisone are unclear for COPD a d nimnt available evidaia is inConc1usive. There is therefore

a n d to objecrivdy study tbis issue and detenaine whether patients who present to the Emergsncy

Depatmiait with COPD mcdation shaild be dischiuged home on oral prednisom. A randoniizcd,

d d d - phabcoirtroIIed dinicai trial is warranted and offas a unique opportunity to answer

this Unportant clinid question.

made for COPD etaddm to the ûttawa OeMJ and C i Hospital m m c y in

1996. Datawasrcassedthtough t b e O C H ~ a q E P l S Databue and throu~T&eOOH EmeqeaylXdwgeCodjngDatabgse. DatawascdledtdonthemimbaofEDvisits,disposition

of tbe patient fdowhg eadi visit, lad nLpse rates. Red& rn aumrarirrd bdow, ad are ptesented

in Tables 2 and 3.

Table 2 depicts a summary of 19% COPDdaîeû admission, discharge and relapse rates for

The ûttawa Gavnl and Civic Hospitais. In 1996, The Ottawa G a d Hospitai recorded 368 ED

vUits f a COPD m o n . Of these visits, 187 (5 1%) r d t e d iu U i s i o n to hospitrl rad 18 1

(490h) resdtnsutttd in disdrvge h m the Department. Excluding repeat visits, 142 individuai

patients at OGH were dkhargad fhm the ED in 1996. At The Ottawa Civic Hospital 546 ED visits

were recorded; 252 (46%) r d t e d in admission to hospital and 294 (54%) r d t e d in discharge

fiom the ED. Excluding qxat nsits, 2 16 individual patients at OCH were discharged fiom the ED

in 1996.

Relapse rates, defineci as a repeat visit to the same Emergency Department for symptoms of

COPD exaddon , an outlined in table 2. Ofthe 475 ED visits that resuheâ in discharge âom both

hospitais, 12.W d t e d in a rdapse w i t h 10 days, and 18.9Lh resuited in relapse within 30 days.

Tabk 3 depicts data rebieved fiom a more d d e d d y s i s ofthe charts of the 142 patients

who wae dischargai home fiom the W H ED in 1996. Data h m these patient charts wu coUected

in orda to deterrnine Emergency Deparment therapy of the patients' COPD exacerbation. Patient

characteristics were also abstracted ftom the entire chart in order to determine whether the patient

would meet the criteria for trial eiigibility.

One hwdrrd and thirty4ght of 142 charts were retrieved (97.2%)- four patients had charts

which had gone misshg from Medicd Records d data on these patients w u not adable. 70 of

138 patients (5 1%) haci had recentîy p l a d on pradnisone or had d v e d a prescription for

prednisone on d k h g e fhm the Emwpcy Depvtmcnt. 54 of 138 patients (39%) hd bœn

recently placeci on mtiiiotics or had raceiveci a prescription for mtibiotics on discharge fkom the

Emergency Department.

F i p 1 depicta r flow diagram of 3ûday rdapse events W. artmeDt tdccived. ûftbore

patients who dapd witbin 30 days of thir Virit to the Emergmq oaly 3% were

p r r s a a s d ~ u p o a ~ ~ ~ m ( o r ~ i I r r r d y b e a a p c e a c i i i p ~ n e b s f o r e

pnseptation to The Emergw Depcvrment). In contrast, 51% of those patients who did not

a 3-y relapse were p d ô a i , or were already taking, pdnisonc on dischuge âom

nie ED, (x2 = 1.13, p = 0.29). Finally, a feasibility miew wrr da taken to detamiae that a d u e n t naumba of @%le

patiarts would be avaüabk at the two ho~pitrlr in orda to support the definitive hger study. Tbe

charts of 138 of the 142 COPD patients who wae dischargexi fiom The OGH ED in 19% wac

aiulymd (Eair cbsrrr wae unadable h m Medical Records) in orda to detamine the proportion

of patients wbo would fit the digiiiiüity aiteria for the proposed clinical triai. In total, 41 of 138

patients (30%) definitely met aii study eligiiility criteria and an a d d i t i d 19 of 138 patients (14%)

werepiged to possiiiy Wii shdy digibii aiteria according to information contaimû in the chart.

Assuming the COPD patients who present to the OGH ED are similar to those who present to the

OCH ED, then approximately 35% of the 358 individual patients who presented to both hospitals

with COPD araCabation in 1996 would have been etigible for the trial. B d on this estimate, 125

efigible patients would have b a n adable in 1996 for potentiai recniitment into the triai.

1) A diderit nmikr of patients with amte COPD e m d a t b n shaild be aniable for the definitive

shidy .

2) niae appeius to be a wide practia variation c o n d g the veatment of COPD exacerbation in

the ED- only 49% of ED patients were prescribed staoids on discharge. Given this wide practice

variation, a statc of ciinid equipoise exists *ch cthiully justifies the necd for the pilot study and

definitive trial.

3) Relapse is M y ammon and can save u an objective clinicai outame variable.

RESULTS OF THE 1996 EMERGENCY DEPARTMENT COPD RECORDS REVIEW:

Table 2: Summvy of COPD Admission and Rates:

HorpiW lYEDVWb UAdmbrioiu #Dischargea 18d.y 30 diy

for COPD for COPD home relapserate rdipcerrtc

Both 914 439 (48%) 475 (52%) 12.00/0 18.9%

* 18 1 discharges /l42 wüviduai patients ** 294 discharges / 216 individual patients

Table 3: Ernergeacy Departmart Therapy for Patients Discharged Fdowing Acute COPD

Exacerbation.

T h i r t y d a y r s l i p r c a t e s v s . ~ & e d

Ottriwa Gaieral Hospital 1996.

142 COPD patient8 diichargcd in 1996

23 patients relapaed within 30 days

1 19 patienta did not relapse

unknown (9% (5 2%) (5 1%) (47%)

2 therapy unknown

(2%)

This thesis Win describe the pmess, and the r&s, of the pilot study wbich 1 designed

in wiib d l c q ~ ~ ftoai The Ottawa Hoqbl, Division of Respiratory Medicine, and

wbich wrs canductcd from January 5 to May 4, 1998. This pilot study was a rsndonnzed,

placebocon~olled cünid triai, and was designed to k a pdude to a larger, debitive, clinid

trial. The dehitive ciinid trial wdi attanpt to rscatlrin whctha o d gluoocorticoids are effectm at t r d n g anite aP#rbition ofchronic obstrucrM pibnoaiiry direare in patients discharged fkom

Spteifi Objd~~l~yics u f t k Hlbt Su&:

Pn'rmvy Objcc~l~vc:

The primiiry objective of the pilot study was to ensure that a larger cihical triai wül be

feasible.

The specific secondary objectives of the pilot study were:

1) To cissess the proportion of patients who relapse in the two treatment groups, in order

to ddamine whetba thU clinicai variabie d d serve as the p h m y outcorne variable for

the definitive study.

2) To verify the sample size estimates for the larger trial.

3) To d u a t c patient r e f d rat- and triai recruitment.

4) To verify the emoUmcnt proass- did the iacIusion/exciusion aiteria Jlow for the

intendeci group of patients to be entacd into the study?

5) To aUow for prc-testing of the ditr coildcfion d data anaiysW procas.

Ine h e e mcrjoy objectîws of thc definithe clinical bicil will & :

1) To detaalnc whether r 10 dry anux of o d glucocorticoids wüi improve airflow obstruction

in paîients with raite mmrbtion of chronic obsüuctive puimomy diseue (COPD) who are

discharged from The Emergency Dqwtment.

2) To compare tbe fhquc~lcy of 10 dry ad 30 day relapse events in patients rccciving oral

gluoocorticoids cornparcd to controls rfta the tmtmaii of w t e COPD auCabiton in the

Em=%=Y - 0

3) To compare rates of patientlcc~lfc~ed outcornes, including improvements in subjective dyspnea

scores and irnprovemaits in disease-specific q d t y of life measured at day 10 following an

Emergency Department visit.

nie pVwy aitanne variable of the definitive triai win be either percent improvement in

akfiow obstruction (objective 1 above) or relapse rate (objective 2 above). The choice of primary

outcome variable w i l depend on the results of the pilot study.

41 wgal

niispbr~wasaMdomurd,daiblabüad,p~ntroUadclinicalüiai. Patients

were randomized to artmeat with oral prednisonc or to treatrnent with identidy kbelled

pleoebo apsules. nie shdy was nm out of The Emergency Departmm of The ûttawa Gaiarl

and Ottawa CMC Hospitais lad recruited patients &om January 5,1998 to May 4, 1998. Data

coMecfion was completed on June 4,1998.

4.2 PafUnii3&&11

4.21 Inclusina C&&

Inclusion criteria wae chosen to wnform to wrent ATS definitions of COPD. The

aiteria were also dected to ensure that the shidy population was refledjve of those patients in

the ED who are ordinarily identifid and diagnosed as having COPD exacerbation.

Patients were considerd to fiilfill the diagnosis of COPD if they met the foliowing criteria:

1) Patients with a previais dirignosis of dironic bronchitis, ernphysema or COPD estabiished

by th& physician In the e ~ i r that the patient had not been previously labelleci as havhg

COPD, hdshe was di eligible for the study if the tnating emergency department

physQM felt that the clinical history was complti'blc with a diagnosis of COPD, and not

asthma.

Chicil history n e c a a q to support a new diagnosis of COPD:

a) Patient must have a history of cbroaic shortness of breath or chronic cough with sputum

production.

b) Symptorns should be constant Md chonic and wt fluctuate on a day-today basis.

2) Patients must have had evidence of airflow obstruction on prescatrtion at the emergency

deputmcnt. d e h d as an FEV, r 7P? of p d d e d and a FEV, 1 FVC d o r 703C.

3) Patients mut have cbronic Mow obstniction, defincd as an FEV, s 7W of predided

and a FE& 1 FVC Rbjo s 7Wh. The FEV, ad FVC d fk tbis aitaion wrr takm h m spirometry d t s otmhd at r t h e of ciinid staôiüty eitba before,

or1 moathi&rtheanqaxyroomvirit.

4) Patiam anirr be 1 35 y e ~ old.

5) Patients must bave a minimum history of 15 padc-ycars smoking.

6) Patients mus& be an acute uadmtion of COPD and must mtet at lcast one of the foUowing tbree clinid criteria for acute COPD exacdwion as defiaed by

Anbisena: hmasd chronic baseline dyspnea , increased sputum volume or hmasai sputum punilencc. The above cornplaints hid to have n d t a t e d the cmctgency

department visit.

Patients excluded were those with:

Signifiant reversible aidow obstruction in the ernergency rwm: Signifiant reversible

akfiow obshuction was defined as at Ieast a r 200/r and a 22ûû ml irnprovernent in FEV,

fiom bwiine after inhalation of bronchodilator.

Physician diagnosed rpthme, cczema, ;iuagic rhinitis or nasal polyposis.

Use of oral or injectable corticosteroi& (but not inhaled steroids) during the month

preceâing trial aitry.

History of chronic lune disease ot&er than COPD. Patients with a bistory of

broncbiectads, cystic fibrosis, and interstitial lung disuise were excluded. P a b t s with

lung cancer were excluded, unless the cancer has ban complete1y resected with no

evidence of residual di-.

Pneunonia or congestive hem faüure on anergency room CXR.

Patients not able to paform an FEV, rrsessmsnt.

Patients with h w n adverse d o n or intoleru~ce to systemic steroids.

Patients with severe uncontroUed dllbeia mdüau (emet.gc~~cy ioom b l d sugar > 15

nimolli), sevae mul (Cr > 200, or cm âhlyis), hcprtic (ôiopsy proven cinhosis or chronic

bepatitis), or cadac Mwe (echocsrdiogmrnd0~~lle~1ted paâe ï l I or IV le& vatriEUllV

d y s 8 m e r i a i r a d y m p a m i t i c ~ ~ ~ N Y H A ~ ~ o r T V ) , p a t i ~ 1 1 ~ w i t h o ~ o ~

&isirointeStinalbl-.

9) Iaiibüay to provide inforneci consent or wmply with the study protocol duc to cognitive

impairment, ianguagc barri@, or distance > 100 Hometres fiom the study centre.

10) Patients admitted to hospitai.

1 1) Patient has ptCViOUSly participateci in the shrdy.

4.31 eig,m'mcnlOl M-m:

Eiigible patients wae d o d y rllocated to receive ather:

Oral pmdnisone, 40 mg cspaiks to takc once M y for 10 days, or

placebo capsuies identicai in taste and appeamnce, to be Eaken daily for 10 days.

Uedications were preparad by one centrai pharmacy and labeîled only with a saidy nwnbef so as

to easure concealmerit of docation.

This dose and duration of administration of prednisone was chosen ôaseâ on previous

stucïies in astbmatics which demonstrateci that a 10 âay course of 40 mg/day of preânisone was

as d e and was as effective as a taperllig prednisone coune in achieving relief of ainlow

obstruction and prevention of asthmatic rela~se.~"

4.32 Oiher adj, manueuncc

1) A standsrdized emergency department pmtocoI and order sheet for treatment of COPD

exacerbation was distnbuted - the order sbeets specified that patients should not receive intravenous or oral giucocorticoids in the anergaicy department. AU other decisions regarding

treatment and care of the patients were left to the treating emergency physician.

2) Both groups of patients were placed on an antibiotic. Patients were prescribed

trimethoprim-~ethoxaso1c (septra) 2 tablets twice daily for 10 days, or in the event of a

sulfa allergy, they received doxycyciine 100 mg twice daiiy for 10 days.

3) Both groups of patients were provideû with inhaled salbutamol and inhaled

ipratropium m e t d dose inhalers. Education concerning use of the M e r s wss provided to

al patients and inhalation technique was verified. Patients were adnsed to use ipratropium 3

p u 5 fair times diUly and sslkitrund 2 pifn f i timeJ M y for the duration of the triai period

of 30 days.

4) Those patic~ns taking hbdd corticosteroi& d o r thsophyhe preparatiom More

aiteMg the trial were advised to continue on these &CIltiom.

4.33 mwud fw dciibiiy MW padirnlr wko *se& The patient's EMily doctor wu notifiai by fix the patieat eritaed the sîudy.

Patients who d e an umcheddcd nsl to the anergmcy d e p t t m t or to the famiiy doctor

on or More &y 10 bcccpise of seKreported woneniag of dyspnea wcrc considemi to have

relapsed ad wae cbdïed treatment Wwes. In tbe case of treabnat Mures, the

physician tredng the patient w u advised to take the patient 08 the study medication, ad to

treatthepitYntwithopatJawlprsdmaone. ~waes&nbystudypersonneioathesime

day of their reiapse, or u soon as possible thmafk, anâ they wera asked to c~mplete the

saidy m-ts which hd kea scheduied for dry 10.

Cornpliance with the trial medication and antibiotic reg- w u ursessed through

patient questionnaire and pi11 counts. Patients were asked to retm u n u d pus and pül

containers on study day 10 to ver@ cornpliance with the drug regimen. Udortunately, there

is no wrnrnercially available assay to monitor for blood levels of prednisone, and Urnefore

laboratory testhg for cornpliance was not feasible.

4.5 Bascüne Assessment

Recorded infiormation for al patients on admission into the trial inciuded: age, gaider,

height, weipis WC ongin, past medicai history, duntion of COPD, srnohg history, aimnt

medication use, aliergies, md reani respiratory symptoms. M o u s pulmonary function tests

were rlso d e d favailable. A CXR, brsdine rnd podm&xWor spirometry, and pulse

oximetry was obtahed on ail patients as part of routine tmergency room care.

4.6 Outcome M i =

4.61 t i r m y y outCome nteasum

The primery outcome me8SUre was improvement in airflow obstruction. This w u

determined by assessin8 the percent change in the postbronchodilator FEV, at study day 10

h m the postbronehodilator FEV, oôtaiaed before discharge from the cmetgency department.

FEV, was chosen as the primiary outwme variable 9na it is a direct, sensitive,

r m m e of the u n d m physioIogic abnocmality'. FE& is an objective rneasurement ad k

bishly reprOdcIc~'ble.~~ l percent change in FE& h9 prcviously bcen shown in the diaicd

trials of Albert Y and Thompson " to k a sensitive mcuun of improvmmt in airfiow obstruction in a simikr patient popdation.

AIthough -t in FEV, hs b c~~feiated with cbangm h patients' of

dyspner and quality of üfé a a, we chose not to use dyspatr iadac or @ty of He as the

Pimuy autcome variables, since patient reporting ofqwlity of afe anâ dyspnea Y aeccssuily

subjective, ad patient scores on these questionnaires mry ûe affkctcd by the douad l l i g

effécts of steroids on mood and a€Fect, inclepcndcnt of the dects of stcroid on the acaul

dimue pmcess.

In the event that we wae unable to oôtain spirometric meJlQUles on dry 10, then

in the sitting position rccording to esâablisbtd Amaican Tboncic Society aiteria.'' A

minimum of two forcd flow-volume loops of g d quJity wae obtained. If the FEV, and

FVC dues wen not within 1W of one amthet, an additionai rneasuramt was taken. The

flow-volume loop with the ôest FEV, and FVC wu, used.

4 62 S c c o ~ ouikomes

Secondary outcornes were asssed at day IO, with the exception of relapse mes which were

assesscd a! 10 days and 30 days der dornization. Secondary outcornes inciudcd:

1) The absolute change in postbronchodilator FEV, on study day 10 complrcd to day 1.

2) Absdute improvuncnt in oxygenation measund by pulse oximetry done on room Ur,

or if the patient was on home oxygm, O- wu performeû on the patient's usurl oxygen

prescription.

3) The poporrion of patients Wb0 rdapse within 10 ud 30 dry+ rdrpse wu defined, as paCbiiparnetd)uaiimdisdukdWatoaphys9ui'so~ora~tothe~cllcy

department kcruw of a patient's perception of worsening dyspnea.

4) Improvement in subjective dyspacr score as d ôy The Mahler Badine rad Truuitiod Dyspma Indexes. 5s T h W e r inciex ïs a two-part, intenimua-idministd

dyspnea iada tht ntes dyspnea rccordhg to th= crtegories: iùnctionai impainnait,

mgnitu& of tasic, rad mgnitude of &ort. The h.adinc idex @DI) Y usai to rate

the~~~aityof~~~~aita~epoinSintimedthetriingtiondylp~ind~Oursd~

u s e a s ~ a O m t h a b a s d l l i e . Atbaseüiie,dyspneain&oftl ira~on~~~ntedon

a 5 p o i a t c a l e â o m O ( r e v a e ) t o 4 ( ~ ) . ~foruchofthethrescategoriesare adûedtoEormabasdiaetocjdyspaer~(~û-12). Thetnnsitiondyspneaindar(TDI)

is useû to rate changes in each of the thrœ utegories using a 7-point d e f?om -3 (major

detaioration) to +3 (major improvement). Ratmgs form the transition index csn be added to

fom a dyspna transition total score (range, -9 to +9).

Interobasmr cigrranait for the baJdine index has ban obscfvd at Wh, whüe the

agreement for the tnnation index was W A . ~ A cornlition of r = 0.60 @ 4l.001) was

rrportsd betweai the basdine totai score ad the 12 minute wak test, anâ the transition totaî

score has km signiiicz~lltly correlatecl with the cbange in 12 minite wallc (r = 0.33, p < 0.05).

TheBDIhasJsokaiscaito comktestroi lglywidiotha~ofdyspnea(the MRC and

Oxygen Cost Diagram), (r = 0.53 - 0.83). and moderately with the FEV, (r = 0.43)." 5 ) Improvement in disease-specific quaiity of life as rssessod by the Chronic Respiratory

Disease Index Questionnaire (CRQ)? The CRQ evaiuates fm aspects of quality of We in

p a t i e r r t s w a h ~ ~ ~ : dyspnea, &igue, etnotionai oaslon, and mastery. Each domain includes fiiur to mm items, d each item U scored on a d e of t to 7 (1- extmnely

short of breath to 7- not at ali short of breath). This questionnaire has been demonstrated in

the COPD population to be reiiabie, vaîïd, and responsive to change. " " In previous clinid trials evaluating dmg trament protocois, changes in the CRQ correiated with changes in

spirometric values, acacise paforrnance, Md subjective ratings of hprovement by both the

patients ud phy9cians. " CmeMons improvd fûrther when patients wae given information abcut tbeir pmiiais C~CS~OI ISC~, and the dwdopers of the CRQ recommcnd providing pa!ients

with feedback on th& previous responses whai they r e p t the test more than one the.*

6) Adverse e f f i rates uwvA at 10 days by patient questionnaire.

Table 4: Summary of the Data Coiiection Schaduie:

Pd- with wte COPD arroerbition wac rneaed by the v c l l c y depuimnt

p ~ a d i f ~ ~ w a e ~ t ~ o d ~ y p e r s o d w h o r u i e a x d t h c patient rad determincd ifthe patient fiilfiud digibüity aiteria. Study pasonad wae on cali

by page systan 24 hain a day, sevm days a wak in a rotathg oabin-five cill scbeduie. The

priaapai inveatgator (rnyseif) wu on continuous s a m d ull to handle quaies Born the study

employees or patients. Atta informed consent was obtained Born digib1e patients

randocnidon was pafonncd. 'Ibe randoniiution process aonsisted of a computer-generated

random iisthg of tbe two treatmcnt aîiocafiolls blockd by groups of four and sbritifid by

emergency dqwîmmt. Randomization was tbrough central allocafion of r domiauion

~ e a n d w a s coordiaiitedbythcOttawiGasaJHosptilWumrcyRcstirJiDepPrtmait.

Physichm and nscardi M w e n unaware of die treatmsnt docation prior to randomization. 4.8 Blinùïng

The sbdy was doubleblinded. Medidons wae pnpared by one central pharmacy and

labellecl only with a study number so as to ensure concealment of allocation. The prednisone

and placebo were packaged in capsule form and had identicel taste and appearance.

49~kiR1ZLÇolLSCICCrafiOns

Patients were r d t e d for the pilot study over a four month peiod. AU consecutive

patients randornized over the four month pilot period were included in the study . Twenty patients wen randomind fiom Jan. 5 1998 to April5 1998.

Befm die pilot was pedonned a totai of 124 patients (62 per group) were estimated to be requireû for the larga cünicai trial. This sampk was caiailated to provide a power of

8% to d e t a a 2W difference ôetween improvement in FEV, in the placebo and matment

groups, with a probabii oftype 1 error (two-taüd aiph) of 5%.

A 20 % âi fkace in i m p m m in FEV, wss choseri as the s d e s t difference having

dinicd importance hiai on Americm and Camdian lhoraQc Society recommendatiom stating

tbat a 2O?h mip0VmWiit in FEV, in cbronic COPD patients is a sisnificant bnprovement w&kh

iustifies bng-tenn staoid use in these patients In addition, 1 conductecl a ~umy of 10

4.19 ScuiipIc rjzC c&nWns

The sunple size e s t h m was basai upon the foiiowhg ~ t i o ~ :

Theaitcoiaemeisunuced topiantheraidywasthe~b~geinFEVl rtDay 1Ofirom

~ . T b s ~ ~ , r n d b M n b r d ~ n w a e ~ ~ o m d r c a b o m t h e s t u d y

by Thompron et ai. to be 0.90 * 0.26 litres. At Day 10, placebo patients wae assumeû to improve by 15% h m basdine and prednisone patients by 35% for a hypothesbd a h b i

cllnicaiiy important diffttcact of 20%. As patients improved, both groups were asamad to

have a large straQrd devhiion of0.49 at Day 10 as per Thompson's study.

kpanaw a conrkSion of .8 ktmai Badine d Day 10 FEVl measms, the standard

deviation of the change âom baseiine wu aimami to be 0.32. In a prdiminiry estimate, a

ample of 104 patients (52 pa groupa) were needed to detect a 2VA improvement (ie. an

absolute miprowmnt of 0.18 litres ) bastd on the twdded t-test for two independent groups

with an 8û% power and a 5% fàlsapositive rate; using the formula

where ZN = total sample size

Ze= 1 .% (standard nonnal deviate for a two-tailed a = 0.05)

Z04.84 (standard normal deviate for P = 0.20) O = standard deviation around the mean of the outcorne measurernent. The

standard deviation is estmiated at .32 ütres

b = A 2W differetlce between improvement in FEV, in the placebo and prednisoae

groups on Day 10 of tbe triai. A 2W diftierenct comsponds to an absolute greater

improvemcnt in FEV, of O. 18 litres in the ueatment group fiom badine, as compared to the

placeôo group. Substituthg the values of the wiow parametas hto the fonnula yields

'Ibtis, lO4prtia1tsuenseded to6daUW.dinaaicebetweenUnptovemeat inFEV,

in the placebo rad pdnbone groups 4 t h r two-tadeci a = 0.05 and W h powa. S W c d

FEV, chta wae thm andysd using an ANCOVA modd to ver@ the adequacy of the plannad

sample size for the large clinid triai:

prednisone and piacebo) rnd ucluunait (i.~. BUdjllt ud Day 10). fwr oohorts wcre

ge11Cr(lfed. The sinnilitcd FEVl changes wae subjcctad to an acllilysis of cowisnce

(ANCOVA) mode1 hcluding the foiiowing arplanaîory mors: treatrnent, centre, baPdine

FEVl and by centre interaction. For snipücity, we llssumed FEVl change c o d a i d

with baseîine leveI with equal slope between the two treatment groups. Imbalance between

cenins at baseline was chancterized according to the mean levd difference equal to O, .25 of

baseJine dandard deviation, .S SD, 1 SD Md 1.5 SD (whae the baseîine standard deviation wes

0.26). Test of ûeatmmt &kt in the ANCOVA mode1 w u then subjected to a power anaiysis.

Table 5 sunnaentd the rrsubs the simiiirrni ANCOVA (pva&es of various effects) Md of the

power analysis of treatment effect.

Table 5: S i ANCOVA ad Powa hdysb of Tnrtmait E&ct

rEntrc 2N haru W mut Difft~cooc Signifiant RxA ame" FEIV,"

Numba (N)@ -A

A- an rimition rate of 2Wh, a total of 124 patients (104 + (.20 104)), are needed for the study.

4 D l l . l P n ' ~ r i l ~ s U of tkpn'ntoly O U l C O m e ~

The fiaril uulygs wiü be p d o d on an " M o n to trcata basis. Us@ uiir appmach,

patients wül be inchcied in the d y s i s accorcüug to tbe group to which thy were d o m i d .

Tbosepatiest~whorrlapsewitbindieQst 10dayrofthe~winhnnthcpost-koncbodürtorFEV,

vaiue dont on the day of relapse oountui as the Day 10 Mhie for puposes of the adysis W. endpoint llIISlysY, with the hst observation canieû forward).

The principal d y s i s of the dinerem between the petcent improvement in

poBtbroadiodilator FEV, m the plicebo ancl pradnisanc p u p s fiom day 1 to dry 10 of the trial wüi

be rssessed ushg patamdric proCCdures (Mependent t tests) iiiitUUy. Student's t-test with eqwû

Varwces wÿl be usai foc these analyses if the p-vJue of Leverie's test for homo8dty of wiaace

k graata that O. 10, otherwise Students t-test with unequai wiances wüi ôe used. Howcver, if the

Kolmogorov-SnWwrv test of d t y suggests that the data is not normally disbibuted (p < 0. IO),

a nonparametric test (Wdcoxon Rank Sum) wiii also be monned.

In the event that the two treatment groups appear to be imbalanced at baseline with respect

to a major badine covuiate, aich as stable FEV, or Day 1 FEV,, then an analysis of covariance

mode1 4 t h the imbalanced variable as the covariate wiU be conducted. The adysis of cuvariance

wül be done ifthe stable FEV, is imbaland betweca the two groups sincc bigha stable FEVL)s in

one group compared to the otha couid bias the results in tiivour of thaî group. In theory, patients

in the group with high stable FEVI)s d d have more m m for improvement bidr to their becdine

iung fiuiction rnd d d therefore show proportionately greater changes in % improvement in FEV,

from day 1 to day 10. The anaiysis of covariance wül thus sewe to adjust for the possible

confoundiag &ed of diffaait subie FEV, or Doy 1 FE&, distnhtions in the two treatment gmups.

Tbe ANCOVA mU k pafonned as per methods dcsaiibtd by Kleinbaum a al? Fint. the two sbajght line nlgesaon equations of percent change in FEV, on the covariate wül be genented.

T h e t w o s t r a i ~ ü a e s w ü l b e c o m p M I S u s i ~ a p u t i r l F t c s t f ~ r p u i l l ~ ~ t h e m o d d Y = ~ ~

+ ~ l X + ~ + ~ x Z + ~ , w t i a e ~ b a A i n i m y M n i b l e i d ~ t i f y i n s t b c treatmentgroup(0ifplaccb0, 1 if trea!ment) and with the n d hypothesis for the test for paraiielism Ho: P, = O. Afta the

nr t t A- o f a l n n d a r ~ , O Y ~ C O ~ C Absolute changes in FE& and oxygen Saniration for the two tmûment lgoups wül be

camparsd us@ piinmetric procebres (idependent t tests) initiallys or with noqmamtdc mctbods

ifdie daîa is mt normaiiy distributad. Diaamces in scores of the Tnnsitiod Dyspnca Indexes in

the two graips, ad diffhnces fiom day 1 to day 10 in the scores of the four cbmpoaaits of the

C W Respintory Questonnaire, wili be compareû u s i ~ independent t tests. Relapse rates at 10

and 30 days wül be comparai ushg Fisba's exact cbi-quart tests.

ofal the outcorne variables d for thb study, the wt«wie variable wbich is arguably

the most coiroi9y imptant is tbe pm9orim of ppoiems who arpaiaia a 30-day rolipsc. A logistic

regesdon d e l will be developed using the pilot with 3ûday relapse as the dependent

variable. The logistic regrcssion will be done in an rttempt to a d j ~ for the influase of suspected

climcaliy asiiifiaint coviniites on the tmtmmt &kt. Variables which wül be assesed for potaitiil inchision m the mode1 wiN k those that arc wnsidered: 1) ciinidy Unportant variables that could

potaii;ahr ducllcc tbe outame; d o r 2) variables which are maldistributad in the two trcatmc11t

groups at baseline.

The sdection of variables for the logistic mode1 wül begh with a univariate uialysis of t ich

variable. nie indepadent variables will then be screened for inclusion into the final modd by adding

each variable individuaiiy to the basic logistic m d containhg the constant tenn and the vuUbk

'treatment'. Any vahable which appears to apprearbly change the btta d c i e n t for the variable

'treatment' wül be consided to be a possible confoundct rad wiü be rdained in the d. In

addition, uiy relevant variable wbidi h w s a signifiant nLtionship with the treatment variaôlt

~ b y a ~ n t i o t e s t f w t i i e ~ p < O . l O ) w ü l b e r M . Usingthisapproachafiniil

logistic modd wdî be gaiartcd and an adjusted od& d o for the tr-t &dct wül k obtwid.

S u ~ v a i aaalysU w i l be uwd to compue number of days to reiapse in the two trtafmmt

gmups. ~~ smhd auves wül be oonstnicred to dcscn'be time to relapse and the ames wiN be oompared ushg the log-nnlt test stritisiic.

Allp values will be reportcd as two-sided. AU data wül be presu~ted as iileuu * stindsrd deviatiom unltss othembe sta!Cd. Od& d o s win be rrported with 95% confidc~lcc intemis.

Ali analyses wül be pdonacd with SPSS software (n3 vemion mimba 8.0.

health problan. Tbas L nimntly no oonvkhq &dam tbt t rdqg aitpotid COPD aracabrition with oorticostcroi& provides MY sipifiant M t to patiw Wb0 are rlrsidy ô c i q

trcated with stradrrd thaipy of antibiotics and broacbodilatom. the uaoatYnty mgadhg tnihnaitappnmhmthispopihtioaddietditive~ofclllncrlWin thisfield, Ibeiieve

that a state of ciinid quipise &sts which cthicaîly justifies the nced for a trial.

A S & i Data Monitoring Conmittee wiii k m e d for the luga trial for the putpose of

irdaimPialysi,rndpossiôleeariytanmgtionofthetrnl. A s a b i r i b a s a f k t y ~ t h o s e p a t i ~

who compLm of worsaiing dyspnea during the fust 10 days of the trial win k withcûawn fiom the

Jaidy, and th& physician WU k o f f i the option of placing the patient on opai-labd preQUone.

This will e n m that assignment to the placebo um will not k bazardous to the patient. Ethical

approvai for the plot rad the îarger study was granted fiom the Ottawa G e n d and Civic Hospitals

Research Ethics Cornmittees.

i l W P C g k

SBdy-mm patients wae r e f d to the study d* the four month pilot phase, oftberc,

23 patients fhltibd digibüity criteria for admission h o the triai (Fiw 2). Tweniy ofthe eligiiiile

23 pathts wae amllcd inio tbe trial, tbrce pcticiu &sui c a m t . Nieen of twmty completad

the 3o.dry study. Oae patient in the prcdnisone-treated grwp withârew affer 3 days on the advice

of ber W y physician and rrfiised fûrther attenipts at foliow-up. Complete chta was thdore

available for 1 1 patients in the placebo group rad 8 patients in the prednisone group.

Thae wae two protocol violations reiated to irnpmper ~ ~ l ~ o h c n t of patients iado the pilot

study. ûne patiait (Who died 6 drys rffa enrollmeat) was dialysisdependant and shodd have beai

excludeci bpsed ai aekision critaia 118, and the second patient was discovered on day 10 of the trial

to have been on pndiiisone 21 days More triai entry whem be brought in his old piîl bottles to the

study imestigaton. Both patients were retained in the intention-to-treat dys i s .

5.2 P&nt . Age, sex, smoking history, presenting symptoms, and mean study Day 1 FEV, were

comparable ktween groups (Table 6). Becaw of the smpll numbers of patients enroUed in the püot

study tbae wae imbiknco wah rrspect to rncan stable FEV,, history of ooronary iirtery diseasc, and

use of inhaled stsroids b a n the two groups (Table 6).

$3 InilproocHcnrrnb in A ÿ l a u Obstm&n

Figure 3 depicts tk aûsolute changes in FEV, âom day 1 to day 10 for the placebo and

prednisone-treated patients. The mem improverneat in FEV, was 0.15 * .27 Litres for the placebo- treated group uwl0.26 * -25 litres for the prednisone-treated group. The data were not nonnally disvibuted (KoImogorov-Smimov (KS) test p=.M for placebo group and r . 2 0 for predaisone

group) and the &ta were thttefore anaiyscd using the Wdcoxon rank-sum test. The mean absolute

improvement in FEV, was not si@cantly Mema b a n the two groups @=0.20). The percent change in FEV, h m base& K. (Dry 10 FEV, - Day 1 FEV,) 1 Day 1 FEV,,

is depicteû in F i p 4. Phcebtrortad patiam improvd th& FEV, by r mean of 13.9 * 23.8% over the 10 dry paiod comparai to an improvcment of 4.3 * 44.4% in the prednisone-treated

group. K S t e s t r n W a o r m a ü ( y w e r e ~ d ~ p = 0 . 1 1 rnd0.12forthetworrspedivs~ps),

d d i t i w u e ~ ~ ~ û o t h p M m a r i c u d ~ ~ ) n - p ; r n m C r r i c ~ . Ltvcae'stsrtfor

eqdty of lmimccs was SiSmfiCant p= 0.05, rnd M o r t the two groups wae a!mlmed to bave

w q u d w l i i e c s f o r t h ~ o f t h e ~ t e s t . T h e m e r n p a a n t i m p m ~ i n F E V ,

was not aigniûcrntly ktweea the two ~pwips Çdepenâent t-tem amunhg umqud

wirnces pt 0.16, Wilcoxon rank-aun tert p= 0.14).

Figure 5 dcpîcts the distriion of oxygc11 situntion responses for the prednisonc and

placebo-treatd groups. The mean cbange in orna sanuation (Day 10 - Day 1) wu rliehdy, kit of the Qghc patients tnated wiui prednisoae improd tbeir oxygm saturation ove the 10 day period

comparedto6ofthe 11 pb#boarritedpa!ic~lfs. nieph#bolpoup siK,weda0.18t2.8%inctease

in mean oxygen saturation cumpared to a 1.6 1.PA increase in mean oxygen saniration in the

prednisone group (Wiicoxon p = 0.38).

Figure 2: Trial Profiie

1 67 patients refemd to the study during pilot phase

1 23 patients fûlfillcd eligibility critena 1 1 _ 1 3 patients refiscd 1

I consent I

20 patients randomized

I l rcceived

I l completed trial

44 patients excluded due to failurt to meet eligibility

cntcna

( 9 received 1 I prednisone 1 ,-,

Table 6: Badine Charaderistics of AU Patients Randomhd to the Hot Sady:

Mcin rtrbk FEVfIFVC (Va) SD 53 14% 43 9%

MM dudy day 1 FEV, (L) * SD 0.82 .27 0.85 .30

Mcin rtridy dry 1 F E V W C (Y.) f SD 47 10% 45 10%

COPD m d c a t h we ~~ 5 (4%) 8 (8%) IpntroQim 7 (6w s (%%) Aatibiotics 5 (45%) 2 (2%) TbWhyline 1 (9% 2 (2%) Home oxyw 1 O (0%)

Figure 3 : Absolute Cbange in FEV, From Day 1 to Day 10

Piacebo a d Prednisanc-Treatd Gmups:

Placebo-treated group (n = 1 1 ) : mean change = .15 2.27 litres

Prednisone-treated group (n = 8) : mean chan