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[(Fa)19.8(ct)19.5(or)15.1(s)-386.8(k)0(n)20.8(o)0(w)20(n)-392.8(to)-376.7(pr)20.9(ed)19.7(ic)19.6(t)-392.9(o)0(r)-376.5(m)0(o)19.6(d)0(i)20.7(f)0(y)-382.3(a)0(s)19.9(t)0(h)20.7(m)0(a)-379(e)0(x)19.7(a)0(c)18.5(e)0(r)14(b)0(a)19.7(t)0(i)20.6(o)0(n)]TJ
-1.0137 -1.1174 TD
[(ri)15(sk)21(,)-326(b)0(a)13.9(s)0(e)19.9(d)-329.4(on)-319(co)19.7(ns)21(is)15.1(te)19.6(nt)-319.1(ev)19.7(id)20.7(en)19.7(ce)-321.3(fr)15.1(om)-320.2(th)20.7(e)-330.6(p)0(u)20.8(b)0(l)20.7(i)0(s)20.9(h)0(e)19.7(d)-329.4(li)14.8(te)19.6(ra)19.7(-)]TJ
0 -1.1116 TD
[(tu)15(re)19.7(,)-406.6(w)0(e)18.8(r)0(e)-400.7(e)0(x)19.7(a)0(m)18.5(i)0(n)20.7(e)0(d)-400.8(w)0(i)19.8(t)0(h)-394(t)0(h)15(e)-405.4(re)19.7(le)13.8(va)19.7(nt)-394(da)13.9(ta)-395.1(fr)20.9(om)-400.8(ea)18.5(ch)-400.8(tr)20.7(ia)19.6(l)]TJ
T*
[(ex)13.9(tr)20.7(ac)18.5(te)19.5(d)-340.9(a)0(n)19.7(d)-340.9(ch)13.9(ec)18.5(ke)19.7(d)-340.9(b)0(y)-330.5(t)0(w)19.8(o)-340.9(au)13.9(th)20.7(or)20.9(s)-340.7(\()0(S)15.3(D)-341.8(an)19.7(d)-340.9(B)0(G)18.9(\))0(.)-332.8(W)0(h)18.6(e)0(r)19.7(e)]TJ
0 -1.1174 TD
[(th)15(e)-244.2(r)0(e)19.7(q)0(u)20.8(i)0(s)20.9(i)0(t)14.8(e)-244.2(da)19.7(ta)-233.9(wa)18.8(s)-242.8(n)0(o)15.1(t)-243.1(av)19.7(ai)19.5(la)19.6(bl)20.7(e)-249.9(f)0(r)20.9(o)0(m)-233.8(a)0(t)-233.9(l)0(e)19.6(a)0(s)14.1(t)-243.1(a)-244.2(t)0(h)20.7(i)0(r)20.7(d)-248.8(of)-232.6(th)20.7(e)]TJ
0 -1.1116 TD
[(Co)14(ch)19.7(ra)19.7(ne)-325.9(st)20.9(ud)20.8(ie)19.6(s)-335(\()0(e)19.7(.)0(g)18.5(.)13.9(,)-337.5(b)0(a)19.7(s)0(e)19.9(l)0(i)20.6(n)0(e)-325.9(e)0(o)19.7(s)0(i)20.9(n)0(o)15.1(p)0(h)20.8(i)0(l)-319.2(l)0(e)13.8(v)0(e)19.7(l)0(s)20.9(\))-335.1(th)20.7(e)-336.3(c)0(o)19.7(r)0(r)20.9(e)0(-)]TJ
T*
[(sp)15.3(on)20.8(di)20.7(ng)-370.8(da)19.7(ta)-372.1(we)18.8(re)-371.9(no)20.8(t)-381.4(s)0(u)21(m)0(m)18.4(a)0(r)19.7(i)0(z)13.8(e)0(d)19.7(,)-377.8(gi)20.7(ve)19.7(n)-381.2(t)0(h)20.7(e)-382.4(di)20.7(f)15.3(cu)19.7(lt)20.6(y)-381.2(i)0(n)]TJ
0 -1.1174 TD
[(dr)15.1(aw)18.8(in)20.7(g)-323.6(a)0(n)19.7(y)-323.6(me)18.4(an)19.7(in)20.7(gf)20.9(ul)-313.4(co)13.9(nc)19.7(lu)20.7(si)20.9(on)20.8(s)-323.4(t)0(h)15(e)0(r)19.7(e)0(o)19.7(f)0(.)]TJ
/F12 1 Tf
8.9663 0 0 8.9663 59.7543 94.9606 Tm
[(Long-term)-335(uticasone/formoterol)-336.8(studies)]TJ
/F5 1 Tf
9.843 0 0 9.843 69.7323 78.5197 Tm
[(Both)-236(uticasone/formoterol)-242.3(studies)-239.1(were)-238(of)-238.3(an)-233.7(open-label,)]TJ
-1.0137 -1.1174 TD
[(long-term,)-620.7(multicentre)-616.3(design)-618.2(and)-615(enrolled)-616.1(two)-614.8(distinct)]TJ
0 -1.1116 TD
[(populations)-336(of)-336.2(patients.)]TJ
26.5234 67.9242 TD
[(Study)-483.5(1)]TJ
7.3823 0 0 6.5614 353.4802 729.5242 Tm
(\(30\))Tj
9.843 0 0 9.843 370.5448 725.1588 Tm
[(\(a)-487.1(follow-on)-483.3(study\))-490.3(assessed)-483.8(the)-488.4(long-term)]TJ
-6.065 -1.1174 TD
[(safety)-705.8(and)-707.1(efcacy)-703.3(of)-704.8(uticasone/formoterol)-714.6(250/10)]TJ
/F6 1 Tf
23.2404 0 TD
(l)Tj
/F5 1 Tf
.5472 0 TD
(g)Tj
-23.7876 -1.1116 TD
[(twice)-354.5(daily)-358.3(\(b.i.d.\))-355.7(over)-356.9(60)-353.5(weeks)-359.9(in)-353.7(280)-360.4(patients)-356.9(who)-355.5(had)]TJ
T*
[(completed)-464.1(an)-458.4(earlier)-466.4(12-week)-465.9(phase)-462.7(3)-456.1(trial)]TJ
7.3823 0 0 6.5614 491.244 696.6423 Tm
(\(34\))Tj
9.843 0 0 9.843 508.0818 692.277 Tm
[(within)-462.9(the)]TJ
-20.038 -1.1116 TD
[(previous)-292.1(24)-295.9(weeks.)-294.2(Patients)-299.2(had)-292.5(40%80%)-292.1(predicted)-295.9(FEV)]TJ
7.3823 0 0 6.5614 543.7983 679.6912 Tm
(1)Tj
9.843 0 0 9.843 547.4833 681.3352 Tm
(,)Tj
-24.041 -1.1174 TD
[(and)-240.6(were)-243.7(using)]TJ
/F10 1 Tf
6.2896 0 TD
()Tj
/F5 1 Tf
.5529 0 TD
(500)Tj
/F6 1 Tf
1.6646 0 TD
(l)Tj
/F5 1 Tf
.5529 0 TD
[(g)-243(uticasone)-244.8(or)-244.1(equivalent/day)-245.2([Study)]TJ
-9.06 -1.1116 TD
[(1:)-324.9(NCT00747318/EudraCT)-334(2008-002460-34;)-333.4(preceding)-330.3(12-)]TJ
T*
[(week)-335.9(trial:)-336.6(NCT00649025/EudraCT)-339.8(2007-005653-37].)]TJ
1.0137 -1.1174 TD
[(Key)-264.5(exclusion)-265.7(criteria)-271.8(for)-262.4(the)-269.5(parent)-262.5(study)-270.4(were:)-268(a)-261.4(history)]TJ
-1.0137 -1.1116 TD
[(of)-359.3(life-threatening)-374.2(asthma,)-364.9(hospitalization)-366.2(or)-365(intubation)-364(for)]TJ
T*
[(asthma)-326.9(within)-324.6(the)-327.1(past)-322.3(year,)-326.9(an)-325.9(emergency)-326.8(room)-328.1(\(ER\))-323.4(visit)]TJ
0 -1.1174 TD
[(for)-233.6(asthma)-240.5(or)-238.3(OCS)-241.2(for)-233.6(asthma)-240.5(in)-238.5(the)-235(preceding)-243.9(3)-231.5(months,)-241.6(the)]TJ
0 -1.1116 TD
[(use)-309.5(of)-313.2(omalizumab)-316.7(within)-318.9(6)-312.1(months)-313(or)-307.4(leukotriene)-321.2(receptor)]TJ
T*
[(antagonists)-273.6(within)-272.8(1)-271.8(week,)-270.2(and)-275.2(a)-267.2(smoking)-273.8(history)-272.7(within)-272.8(the)]TJ
T*
[(preceding)-318.8(12)-313.2(months.)-316.5(Asthma)-320.8(medications)-316.5(other)-317.8(than)-316.7(study)]TJ
0 -1.1174 TD
[(treatment)-239.6(were)-238(prohibited)-237.2(during)-237.1(the)-235(study)-235.8(and)-240.6(patients)-236(were)]TJ
0 -1.1116 TD
[(discontinued)-390.1(if)-388.2(they)-385.8(required)-391.3(systemic)-386.6(corticosteroid)-393.6(treat-)]TJ
T*
[(ment)-335.2(for)-331.5(an)-337.4(asthma)-332.6(exacerbation.)]TJ
1.0137 -1.1174 TD
[(In)-601.2(the)-609.4(parent)-608(study,)-602.1(patients)-610.3(received)-612.6(uticasone/for-)]TJ
-1.0137 -1.1116 TD
[(moterol)-586.3(250/10)]TJ
/F6 1 Tf
6.6582 0 TD
(l)Tj
/F5 1 Tf
.5529 0 TD
[(g)-588.6(b.i.d.)-583.9(\()]TJ
/F7 1 Tf
4.0376 0 TD
(N)Tj
/F10 1 Tf
.8352 0 TD
(=)Tj
/F5 1 Tf
.7142 0 TD
[(146\))-591.9(or)-583.9(uticasone)-590.4(250)]TJ
/F6 1 Tf
10.4423 0 TD
(l)Tj
/F5 1 Tf
.5472 0 TD
(g)Tj
-23.7876 -1.1116 TD
[(b.i.d.)-532.1(\()]TJ
/F7 1 Tf
2.8971 0 TD
(N)Tj
/F10 1 Tf
.8352 0 TD
(=)Tj
/F5 1 Tf
.72 0 TD
[(292\);)-535.5(392)-533.2(patients)-541.2(\(89.5%\))-535.2(completed)-539(and)-540.1(46)]TJ
-4.4522 -1.1174 TD
[(patients)-512.4(discontinued,)-508.8(of)-509(these,)-512.3(4)-507.9(patients)-512.4(\(1)-509(uticasone/)]TJ
0 -1.1116 TD
[(formoterol,)-443.2(3)-444.6(uticasone\))-441.7(discontinued)-447.7(due)-442.2(to)-440.1(asthma)-447.8(ex-)]TJ
T*
[(acerbations,)-411.9(and)-413.4(16)-411.1(\(1)-411.1(uticasone/formoterol)-420.9(and)-407.6(15)-411.1(uti-)]TJ
0 -1.1174 TD
[(casone\))-247.1(due)-246.4(to)-250(loss)-246.1(of)-244.1(asthma)-252(control.)-248.7(A)-243.9(total)-249(of)-249.8(280)-245.2(patients)]TJ
0 -1.1116 TD
[(continued)-335(into)-333(the)-332.9(follow-on)-339.3(study)-333.7(\(i.e.)-334(Study)-333.8(1\).)]TJ
1.0137 -1.1116 TD
[(Study)-328(2)]TJ
7.3823 0 0 6.5614 351.8928 444.5857 Tm
(\(31\))Tj
9.843 0 0 9.843 367.4834 440.2204 Tm
[(evaluated)-331.6(the)-327.1(long-term)-335(safety)-331.4(of)-324.7(uticasone/)]TJ
-5.7539 -1.1116 TD
[(formoterol)-244(100/10)]TJ
/F6 1 Tf
7.4819 0 TD
(l)Tj
/F5 1 Tf
.5529 0 TD
[(g)-243(o)0(r)-244.1(250/10)]TJ
/F6 1 Tf
4.769 0 TD
(l)Tj
/F5 1 Tf
.5529 0 TD
[(g)-243(b.i.d.)-244.1(in)-238.5(472)-245.2(patients)-247.5(with)]TJ
-13.3568 -1.1174 TD
[(40%85%)-441.8(predicted)-451.4(FEV)]TJ
7.3823 0 0 6.5614 415.9558 416.6361 Tm
(1)Tj
9.843 0 0 9.843 424.0062 418.2802 Tm
[(and)-448(using)]TJ
/F10 1 Tf
4.5041 0 TD
()Tj
/F5 1 Tf
.5529 0 TD
(500)Tj
/F6 1 Tf
1.6646 0 TD
(l)Tj
/F5 1 Tf
.5529 0 TD
[(g/day)-444.5(utica-)]TJ
-18.7709 -1.1116 TD
[(sone)-264.6(or)-267.1(equivalent)-274.1(\(allocation)-269.5(to)-267.3(uticasone/formoterol)-276.9(dose)]TJ
T*
[(group)-610.2(was)-609.9(dependent)-612.5(upon)-603.4(the)-609.4(patients)-617.2(pre-study)-610(ICS)]TJ
0 -1.1174 TD
[(dose\).)-493.7(Key)-494.9(exclusion)-501.9(criteria)-496.4(and)-494(prohibited)-496.4(concomitant)]TJ
0 -1.1116 TD
[(medications)-247.4(were)-249.5(very)-247.4(similar)-246.4(to)-244.2(Study)-247.4(1;)-244.2(however,)-250.5(in)-244.2(Study)]TJ
T*
[(2)-548.3(patients)-552.7(could)-548.2(only)-551.7(enter)-549.3(the)-551.8(study)-552.6(with)-546.9(uncontrolled)]TJ
0 -1.1174 TD
[(asthma)-424.8(and)-430.7(concomitant)-426.2(antimuscarinics)-431.4(were)-428(not)-423.9(speci-)]TJ
0 -1.1116 TD
[(cally)-405.5(precluded.)-414.4(As)-406.1(in)-411.3(Study)-402.9(1,)-407.7(the)-407.8(use)-413.2(of)-405.3(systemic)-409.7(corti-)]TJ
T*
[(costeroids)-272.4(for)-273.9(worsening)-276.8(asthma)-275(led)-275.3(to)-267.3(discontinua)-8.9(tion)-269.6(from)]TJ
T*
[(the)-321.4(study.)-319.9(The)-322.4(rst)-320.9(80)-324.7(patients)-322.4(in)-319.1(each)-324.7(dose)-322.2(group)-322.3(received)]TJ
0 -1.1174 TD
[(treatment)-389.4(for)-383.4(12)-388.1(months.)-385.6(Subsequent)-387.5(patients)-385.7(were)-393.5(treated)]TJ
0 -1.1116 TD
[(for)-331.5(6)-335.2(months)-336.1(\(NCT00394121/EudraCT)-335.1(2005-003518)-6.3(-14\).)]TJ
1.0137 -1.1116 TD
[(For)-389(the)-396.3(main)-392.8(analysis,)-394.6(patients)-397.2(in)-394(Studies)-394.7(1)-392.8(and)-390.4(2)-392.7(were)]TJ
-1.0137 -1.1174 TD
[(considered)-365.7(to)-365.2(have)-363.8(an)-366.2()50.8(OCS)-369(exacerbation)43()-363.9(i)0(f)-365.2(they)-362.8(had)-367.3(an)]TJ
0 -1.1116 TD
[(asthma)-476.6(exacerbation)-480(that)-472.4(was)-477.4(treated)-478(with)-472.1(an)-475.7(oral,)-475.6(intra-)]TJ
T*
[(muscular,)-361.3(or)-365(intravenous)-365.8(corticosteroid)-364.8(for)-360.3(asthma:)-368.4(this)-361.6(al-)]TJ
0 -1.1174 TD
[(lowed)-503(a)-503.3(like-for-like)-506.6(comparison)-504.1(with)-500.9(OCS)-506.1(exacerbation)]TJ
0 -1.1116 TD
[(frequency)-330.1(as)-331.5(reported)-333.7(in)-324.9(the)-332.9(three)-330.5(Cochrane)-330.1(meta-analyses.)]TJ
T*
[(A)-577.9(second)-579(denition)-581.5(of)-572.4()45(respiratory)-579.9(exacerbations)42.1()-577(was)]TJ
0 -1.1174 TD
[(employed)-306.2(as)-302.7(a)-307.5(sensitivity)-307.3(analysis:)-311.7(patients)-305.1(were)-307.1(deemed)-310.8(to)]TJ
0 -1.1116 TD
[(have)-496.3(a)-491.8(respiratory)-504(exacerbation)-497.3(if)-497.6(they)-495.3(received)-497.4(an)-498.7(oral,)]TJ
T*
[(intramuscular,)-437.3(or)-428.4(intravenous)-440.7(corticosteroid)-433.9(for)-435.2(any)-430.7(respi-)]TJ
T*
[(ratory)-560.8(illness.)-565.2(This)-558.5(denition)-564.2(was)-563.8(primarily)-565.6(intended)-564.3(to)]TJ
0 -1.1174 TD
[(identify)-425(potentially)-435.6(miscoded)-427(OCS)-425.5(exacerbati)-11.3(ons.)-427(Patients)]TJ
0 -1.1116 TD
[(captured)-484.7(by)-486(either)-487.2(denition)-489.4(who)-488(required)-483.5(hospital)-488.2(man-)]TJ
T*
[(agement)-335.1(were)-335.9(identied.)]TJ
/F12 1 Tf
8.9663 0 0 8.9663 310.8472 116.8441 Tm
[(Compliance)-336.2(with)-330.2(ethics)]TJ
/F5 1 Tf
9.843 0 0 9.843 320.8251 100.4031 Tm
[(Study)-333.8(1)-329.4(and)-338.5(Study)-333.8(2)-335.2(were)-335.9(conducted)-336.1(in)-336.4(accordance)-340.5(with)]TJ
-1.0137 -1.1116 TD
[(the)-275.3(Declaration)-282.9(of)-278.6(Helsinki)-276(and)-280.9(International)-283.2(Conference)-281.6(on)]TJ
0 -1.1174 TD
[(Harmonisation)-324.2(Good)-316.3(Clinical)-323.7(Practice)-324.5(guidelines,)-322.2(and)-321.2(were)]TJ
0 -1.1116 TD
[(approved)-241.5(by)-238.3(the)-240.7(relevant)-242.9(independent)-240.5(ethics)-245.1(committees.)-245.2(All)]TJ
T*
[(patients)-333.9(provided)-338.4(written)-332.6(informed)-339.6(consent.)]TJ
/F3 1 Tf
8.9663 0 0 8.9663 59.7543 749.7069 Tm
[(FLUTICASONE/FORMOTEROL:)-345.7(LOW)-332.6(RATE)-338(OF)-331.2(EXACERBATIONS)-21721(347)]TJ
ET
endstream
endobj
67 0 obj
<>stream
/GS1 gs
BT
/F12 1 Tf
8.9663 0 0 8.9663 62.022 725.7825 Tm
0 0 0 rg
0 Tc
0 Tw
[(Other)-333.7(ICS)-333(and)-335.7(LABA)-333.3(combination)-335(therapies)]TJ
/F5 1 Tf
9.843 0 0 9.843 72 709.3416 Tm
.0115 Tc
[(Dat)4.5(a)-342.1(on)-335.2(th)4.6(e)-342.1(i)-1.2(n)4.6(c)-2.3(i)4.5(d)-1.1(ence)-342.1(o)4.6(f)-340.9(OCS)-340.8(e)3.5(xacerbati)4.5(on)4.6(s)-340.7(w)-2(i)4.5(t)-1.2(h)-335.2(o)-1.1(th)4.6(er)]TJ
-1.0137 -1.1116 TD
.0119 Tc
[(co)5(mb)5(in)5(at)4.9(io)5(ns)-449.8(of)-449.9(an)-455.7(I)5.1(C)-1.7(S)-449.8(a)3.9(nd)-450(LABA)-450.8(wer)5.1(e)-451.1(ob)5(tained)-450(fr)5.1(om)]TJ
0 -1.1174 TD
.0132 Tc
[(th)6.3(re)5.2(e)-409.5(r)6.4(ec)5.2(en)6.3(t)-402.7(C)-.4(oc)5.2(hr)6.4(an)6.3(e)-403.8(r).6(ev)]TJ
11.0356 0 TD
.0108 Tc
[(iews)-404.8(\(Ducharme)-411.9(e)2.8(t)-405.1(a)-3(l)3.8(.)1.6(;)]TJ
7.3823 0 0 6.5614 266.57 691.8234 Tm
.014 Tc
(\(22\))Tj
9.843 0 0 9.843 283.2944 687.4014 Tm
.0131 Tc
[(La)5.1(s-)]TJ
-22.4801 -1.1116 TD
.0107 Tc
[(serso)3.8(n)-416.6(et)-416.7(al)3.7(.;)]TJ
7.3823 0 0 6.5614 116.1071 680.825 Tm
.014 Tc
(\(32\))Tj
9.843 0 0 9.843 132.8881 676.4597 Tm
.0136 Tc
[(Ch)6.7(auh)6.7(a)-.2(n)-408(a)-.2(n)6.7(d)-413.7(Du)6.7(ch)6.7(ar)6.8(me)]TJ
7.3823 0 0 6.5614 233.2913 680.825 Tm
.0209 Tc
[(\(3)20.9(3\))]TJ
9.843 0 0 9.843 246.0472 676.4597 Tm
.0078 Tc
[(\),)-421.8(se)-6(le)-6(cted)-419.5(a)-6(s)]TJ
-18.696 -1.1116 TD
.0118 Tc
[(th)4.9(ey)-306.1(were)-307.2(the)-307.2(m)3.7(ost)-306.2(r)-.8(ecent)4.8(,)-308.4(rel)4.8(e)-2(v)4.9(a)-2(n)4.9(t)-312(met)4.8(a)-2(-)5(a)-2(naly)4.9(ses)-311.6(o)-.8(f)-306()-.6(x)4.9(e)-2(d)]TJ
0 -1.1174 TD
.011 Tc
[(do)4.1(se)-452(ICS/LABA)-457.5(combi)4(n)-1.6(ati)4(o)-1.6(n)-450.9(t)-1.7(herapy)-450.9(in)-450.9(as)4.3(thma)-452(that)-456.8(i)4(n)-1.6(-)]TJ
0 -1.1116 TD
.0132 Tc
[(cl)6.2(ud)6.3(ed)-391.1(s)6.5(p).6(e)5.2(c)-.6(i)6.5(c)-392.2(a)-.6(n)6.3(a)-.6(l)6.2(y).6(s)6.5(e)-.6(s)-390.9(o)6.3(f)-391(O)-.3(C)5.3(S)-390.9(ex)6.3(ace)5.2(rb)6.3(at)6.2(io)6.3(ns.)-387.6(F).8(r)6.4(o).6(m)-392.3(t)6.2(he)]TJ
T*
.0069 Tc
[(C)-6.7(o)0(c)-6.9(h)0(r)-5.7(a)-1.1(n)-5.7(e)-387(r)-5.7(e)-1.1(v)-5.7(i)-.1(e)-6.9(w)-.8(s)-391.4(w)-.8(e)-387(f)-5.7(oc)-6.9(us)-5.5(e)-6.9(d)-385.9(on)-5.7(ly)-391.6(on)-385.9(s)-5.5(t)-5.8(ud)-5.7(ie)-6.9(s)-385.7(o)-5.7(f)-385.8(p)0(a)-6.9(t)-.1(i)-5.8(e)-6.9(nt)-5.8(s)]TJ
T*
.0138 Tc
[(ag)6.9(ed)]TJ
/F10 1 Tf
2.206 0 TD
0 Tc
()Tj
/F5 1 Tf
.5644 0 TD
.0124 Tc
[(12)-265.2(year)5.6(s)-270.7(a)-1.4(n)5.5(d)-270.9(o)5.5(n)-.2(ly)-265.2(on)-265.2(stu)5.5(d)-.2(i)5.4(e)-1.4(s)-270.7(o)5.5(f)]TJ
/F10 1 Tf
13.1091 0 TD
0 Tc
(>)Tj
/F5 1 Tf
.5645 0 TD
.0074 Tc
[(16)-275.9(we)-6.4(ek)-5.2(s)-275.7(t).4(o)-275.9(e)-.6(n)-5.2(s)-5(ur)-5.2(e)]TJ
-16.444 -1.1174 TD
.0129 Tc
[(co)6(mp)6(ar)6.1(ab)6(il)5.9(ity)-328(wi)5.9(th)-333.8(t)5.9(h).3(e)-329.2().4(ut)5.9(icas)6.2(one/f)6.1(or)6.1(mo)6(ter)6.1(o).3(l)-328.2(s).5(tu)6(di)5.9(es.)-330.4(T)4.9(he)]TJ
0 -1.1116 TD
.0132 Tc
[(pr)6.4(im)5.1(ar)6.4(y)-563.9(o)6.3(ut)6.2(co)6.3(me)-559.3(me)5.2(as)6.5(ur)6.4(e)-565(i)6.2(n)-563.9(a)5.2(ll)-558.2(th)6.3(re)5.2(e)-565(C)5.3(oc)5.2(hr)6.4(an)6.3(e)-565(m)5.1(et)6.2(a-)]TJ
T*
[(an)6.3(al)6.2(ys)6.5(es)-500.3(wa)5.2(s)-506.1(t)6.2(he)-501.7(nu)6.3(mb)6.3(er)-500.5(of)-500.5(p)6.3(a)-.6(ti)6.2(en)6.3(ts)-500.3(wi)6.2(th)-500.5(on)6.3(e)-501.7(o).6(r)-500.5(m)-.6(o)6.3(r).6(e)]TJ
0 -1.1174 TD
.0122 Tc
[(ex)5.3(acer)5.4(batio)5.3(ns)-305.5(r)5.4(e)-1.6(q)5.3(u)-.4(ir)5.4(in)5.3(g)-305.7(oral)-305.8(s)-.2(t)5.2(e)]TJ
13.0918 0 TD
.0114 Tc
[(r)4.6(o)-1.2(id)4.5(s)-306.3(\()-1.2(i)4.4(.)-3.5(e.,)-308.8(t)4.4(he)-307.6(i)4.4(n)-1.2(ci)4.4(dence)-307.6(o)-1.2(f)]TJ
-13.0918 -1.1116 TD
.0118 Tc
[(OCS)-334.7(e)3.8(xacerb)4.9(at)4.8(ion)4.9(s)-.6(\))5(.)]TJ
1.0137 -1.1116 TD
0 Tc
[(The)-449.2(meta-analysis)-457.9(by)-451.5(Lasserson)-450.6(et)-452.7(al.)]TJ
7.3823 0 0 6.5614 229.8897 560.2959 Tm
(\(32\))Tj
9.843 0 0 9.843 246.6708 555.9305 Tm
[(estimated)-452.6(the)]TJ
-18.7594 -1.1174 TD
[(relative)-692.3(effects)-696.5(of)-687.6(xed-dose)-691.5(single-inhaler)-693.1(uticasone/)]TJ
0 -1.1116 TD
[(salmeterol)-407.6(and)-396.1(budesonide/formoterol)-408.2(in)-399.7(ve)-401.7(head-to-head)]TJ
T*
[(long-term)-628.8(studie)-7.8(s.)-626.4(OCS)-627.1(exacerbations)-636.5(were)-629.6(reported)-633.2(in)]TJ
0 -1.1174 TD
[(four)-401.8(of)-405.3(the)-402(ve)-407.5(studies)-400.4(\(Aalbers)-409.3(et)-400.9(al.,)]TJ
7.3823 0 0 6.5614 221.8393 516.4723 Tm
(\(35\))Tj
9.843 0 0 9.843 238.1102 512.0503 Tm
[(Busse)-404.7(et)-406.7(al.,)]TJ
7.3823 0 0 6.5614 288.7936 516.4723 Tm
(\(36\))Tj
9.843 0 0 9.843 62.022 501.1085 Tm
[(COMPASS)-333.5([Kuna)-335.8(et)-331.8(al.],)]TJ
7.3823 0 0 6.5614 164.6929 505.4739 Tm
(\(37\))Tj
9.843 0 0 9.843 180.2834 501.1085 Tm
[(EXCEL)-333.5([Dahl)-335.9(et)-331.8(al.])]TJ
7.3823 0 0 6.5614 264.4156 505.4739 Tm
(\(38\))Tj
9.843 0 0 9.843 276.7747 501.1085 Tm
[(\).)-327(The)]TJ
-21.8178 -1.1116 TD
[(four)-540(studies)-538.6(included)-541.3(4949)-534.3(patients,)-538.9(and)-540.1(each)-537.8(compared)]TJ
T*
[(regular)-413.3(maintenance)-416.8(treatment)-418.2(with)-408.7(budesonide/formoterol)]TJ
0 -1.1174 TD
(400/12)Tj
/F6 1 Tf
2.949 0 TD
(l)Tj
/F5 1 Tf
.5529 0 TD
[(g)-484.9(b.i.d.)-480.3(with)-489.3(uticasone/salmeterol)-492.3(250/50)]TJ
/F6 1 Tf
18.0106 0 TD
(l)Tj
/F5 1 Tf
.5529 0 TD
(g/day)Tj
-22.0654 -1.1116 TD
[(\(Table)-286.7(1\).)-282.1(Notably,)-278.4(the)-286.8(Lasserson)-283.5(studies)-285.2(were)-284(of)-278.6(somewhat)]TJ
T*
[(shorter)-573.2(duration)-574.7(\(24)-573.5(or)-578.1(28)-572.4(weeks\))-574(than)-575.9(the)-569(uticasone/)]TJ
0 -1.1174 TD
[(formoterol)-336.1(studies)-337(\(26/52)-335(weeks)-336.8(or)-330.5(60)-336.3(weeks\).)]TJ
1.0137 -1.1116 TD
[(The)-299.4(meta-analysis)-308.2(by)-295.9(Ducha)-8.7(rme)-299.4(et)-297.2(al.)]TJ
7.3823 0 0 6.5614 224.2204 428.7684 Tm
(\(22\))Tj
9.843 0 0 9.843 239.5275 424.403 Tm
[(compared)-301.5(xed)]TJ
-18.0336 -1.1116 TD
[(dose)-448.9(ICS)-447.6(plus)-442.1(LABA)-451.9(versus)-445.1(the)-448.1(same)-451.3(xed)-443.1(dose)-448.9(of)-445.7(ICS)]TJ
0 -1.1174 TD
[(alone)-463(in)-457.3(patients)-466.3(with)-460.5(asthma)-459.4(insufciently)-466(controlled)-463(on)]TJ
0 -1.1116 TD
[(ICS)-280.6(monotherapy.)-278.4(Five)-276.2(long-term)-283.2(studies)-279.4(\(duration)-276.2(24)-278.7(to)-278.8(52)]TJ
T*
[(weeks\))-528(from)-523.9(this)-522.8(Cochrane)-525.9(review)-522.5(\(Pauwels)-524.4(et)-527.6(al.)-519.5([FA-)]TJ
T*
(CET],)Tj
7.3823 0 0 6.5614 86.4566 374.0031 Tm
(\(16\))Tj
9.843 0 0 9.843 103.5212 369.6377 Tm
[(OByrne)-483(et)-481.5(al.)-479.2([OPTIMA],)]TJ
7.3823 0 0 6.5614 215.6031 374.0031 Tm
(\(18\))Tj
9.843 0 0 9.843 232.6676 369.6377 Tm
[(Aubier)-486.8(et)-481.5(al.,)]TJ
7.3823 0 0 6.5614 288.7936 374.0031 Tm
(\(39\))Tj
9.843 0 0 9.843 62.022 358.6393 Tm
[(Fitzgerald)-354.5(et)-349.1(al.,)]TJ
7.3823 0 0 6.5614 128.2393 363.0046 Tm
(\(40\))Tj
9.843 0 0 9.843 144 358.6393 Tm
[(and)-350(van)-344.3(der)-350(Molen)-353.3(et)-343.3(al.)]TJ
7.3823 0 0 6.5614 244.7432 363.0046 Tm
(\(41\))Tj
9.843 0 0 9.843 257.1023 358.6393 Tm
[(\))-346.6(including)]TJ
-19.8191 -1.1116 TD
[(1615)-545.8(patients,)-550.4(reported)-546.9(OCS)-546.5(exacerbati)-11.3(ons)-544.5(and)-545.9(are)-547(pre-)]TJ
T*
[(sented)-377.5(here.)-378.8(The)-374.3(studies)-377.4(all)-373.3(involved)-378.9(separate)-382(inhaler)-373.1(IC)14.1(S/)]TJ
0 -1.1174 TD
[(LA)18.8(BA)-292.1(co)13.9(m)15(b)0(i)14.9(n)0(a)19.7(t)0(i)20.6(o)0(n)20.8(s)-306.2(\()21(ut)20.7(ic)19.6(as)19.9(on)15.1(e)]TJ
/F10 1 Tf
13.472 0 TD
(+)Tj
/F5 1 Tf
.8524 0 TD
[(sa)19.9(lm)19.5(et)19.5(er)14(ol)20.7(,)-302.9(b)0(u)20.8(d)0(e)19.7(s)0(o)21(n)0(i)20.7(d)0(e)]TJ
/F10 1 Tf
9.4171 0 TD
(+)Tj
/F5 1 Tf
-23.7415 -1.1116 TD
[(formoterol,)-414.4(beclometasone)]TJ
/F10 1 Tf
11.3293 0 TD
(+)Tj
/F5 1 Tf
.9619 0 TD
[(formoterol,)-414.4(and)-407.6(unisolide)]TJ
/F10 1 Tf
11.4503 0 TD
(+)Tj
/F5 1 Tf
-23.7415 -1.1116 TD
[(formoterol\);)-499.7(Aubier)-492.6(et)-498.8(al.)-490.7(also)-495.1(evalu)-8(ated)-490.7(a)-497.6(single-inhaler)]TJ
0 -1.1174 TD
[(ICS/LABA)-768.3(\(uticasone/salmeterol\))-770.9(\(Table)-764.7(1\).)-765.9(OByrne)]TJ
0 -1.1116 TD
[(et)-516.1(al.)]TJ
7.3823 0 0 6.5614 83.9055 286.2991 Tm
(\(18\))Tj
9.843 0 0 9.843 101.2535 281.9338 Tm
[(and)-517.1(Pauwels)-517.5(et)-510.3(al.)]TJ
7.3823 0 0 6.5614 180.2834 286.2991 Tm
(\(16\))Tj
9.843 0 0 9.843 197.6881 281.9338 Tm
[(both)-511.4(evaluated)-521.7(two)-511.2(dose)]TJ
-13.783 -1.1116 TD
[(levels)-337.3(in)-330.6(their)-335.2(respective)-338.2(studies.)]TJ
1.0137 -1.1174 TD
[(Chauhan)-281.8(and)-286.7(Ducharmes)-287.1(meta-analysis)]TJ
7.3823 0 0 6.5614 232.1574 264.4157 Tm
(\(33\))Tj
9.843 0 0 9.843 247.2944 259.9936 Tm
[(compared)-284.2(the)]TJ
-18.8227 -1.1116 TD
[(addition)-430.8(of)-428.4(a)-422.7(LABA)-434.6(versus)-427.8(that)-426.3(of)-428.4(a)-428.5(leukotriene)-430.7(receptor)]TJ
T*
[(agonist)-550.4(to)-549.5(the)-546(treatment)-556.4(regimen)-547(of)-549.3(asthmatics)-551.4(who)-551.3(re-)]TJ
T*
[(mained)-338.6(symptomatic)-339.6(despite)-338.4(regular)-338.4(ICS.)-341.6(There)-337.3(were)-335.9(three)]TJ
0 -1.1174 TD
[(long-term)-680.6(studies)-676.9(summarized)-685(in)-676.2(this)-678.4(review)-678(\(Bjermer)]TJ
0 -1.1116 TD
[(et)-464.3(al.,)]TJ
7.3823 0 0 6.5614 85.8897 209.5937 Tm
(\(42\))Tj
9.843 0 0 9.843 102.7842 205.2283 Tm
[(Ilowite)-465.1(et)-464.3(al.,)]TJ
7.3823 0 0 6.5614 159.1936 209.5937 Tm
(\(43\))Tj
9.843 0 0 9.843 176.0881 205.2283 Tm
[(and)-465.2(Price)-468.5(et)-464.3(al.)]TJ
7.3823 0 0 6.5614 241.1716 209.5937 Tm
(\(44\))Tj
9.843 0 0 9.843 253.474 205.2283 Tm
[(\),)-465.3(including)]TJ
-19.4505 -1.1116 TD
[(1655)-436.4(patients)-443.3(overall,)-439.9(which)-439.6(reported)-437.4(OCS)-442.8(exacerbations.)]TJ
0 -1.1174 TD
[(The)-362.8(studies)-365.8(by)-359.3(Bjermer)-363.7(et)-360.6(al.)]TJ
7.3823 0 0 6.5614 181.5873 187.6535 Tm
(\(42\))Tj
9.843 0 0 9.843 197.4614 183.2881 Tm
[(and)-361.6(Ilowite)-367.2(et)-360.6(al.)]TJ
7.3823 0 0 6.5614 267.1936 187.6535 Tm
(\(43\))Tj
9.843 0 0 9.843 283.0676 183.2881 Tm
(used)Tj
-22.4571 -1.1116 TD
[(separate)-606.6(inhaler)-609.3(ICS/LABA)-607(combinations)-610.2(\(uticasone)]TJ
/F10 1 Tf
23.7415 0 TD
(+)Tj
/F5 1 Tf
-23.7415 -1.1116 TD
[(salmeterol\),)-452.4(whilst)-451.2(the)-448.1(study)-448.9(by)-445.7(Price)-451.3(et)-447(al.)]TJ
7.3823 0 0 6.5614 244.2897 165.7701 Tm
(\(44\))Tj
9.843 0 0 9.843 261.0141 161.4047 Tm
[(allowed)-454.7(a)]TJ
-20.2166 -1.1174 TD
[(range)-284.3(of)-278.6(separate)-284.1(or)-278.6(single)-284.3(inhaler)-281(ICS/LABA)-284.5(combinations)]TJ
0 -1.1116 TD
[(\(beclometasone,)-411.8(budesonide)-404.9(or)-405.3(uticasone)]TJ
/F10 1 Tf
17.9127 0 TD
(+)Tj
/F5 1 Tf
.9561 0 TD
[(salmeterol)-407.6(or)]TJ
-18.8688 -1.1116 TD
[(formoterol)-474.4(or)-474.5(budesonide/formoterol)-483.1(or)-474.5(uticasone/salme-)]TJ
0 -1.1174 TD
[(terol\))-336.3(\(Table)-338.5(1\).)]TJ
1.0137 -1.1116 TD
[(Key)-506.4(entry)-507.9(criteria)-513.7(for)-504.3(the)-505.7(studies)-509.8(described)-508.6(above)-508.9(are)]TJ
-1.0137 -1.1116 TD
[(summarized)-368.2(in)-359.4(Table)-360.5(2)-364(and)-361.6(were)-358.9(broadly)-366.1(comparable)-362.6(with)]TJ
T*
[(patients)-340.7(requirement)-339.6(for)-331.5(step-up)-337.1(to)-336.4(ICS/LABA)-342.1(ascertained)]TJ
0 -1.1174 TD
[(in)-434.3(all)-436.7(but)-435.4(one)-436.4(case)-439.7(\(FACET\).)-435.7(Only)-437.4(the)-436.6(COMPASS)-437.1(study)]TJ
0 -1.1116 TD
[(specically)-437.3(recruited)-434.1(patients)-431.8(with)-431.8(a)-428.5(history)-428.2(of)-434.1(recent)-430.7(ex-)]TJ
25.504 67.2964 TD
[(acerb)-9(ations)-445.6(\()]TJ
/F10 1 Tf
5.3565 0 TD
()Tj
/F5 1 Tf
.9964 0 TD
[(1)-438.8(i)0(n)-445.8(the)-448.1(previous)-447.6(112)-442.1(months\).)-444.3(All)-447.9(other)]TJ
-6.353 -1.1174 TD
[(studie)-7.8(s)-432.9(excluded)-444.4(patients)-437.5(with)-437.5(a)-440(recent)-442.2(history)-439.7(of)-434.1(exacer-)]TJ
0 -1.1116 TD
[(bations,)-507.7(although)-505.6(the)-499.9(exact)-510.2(criteria)-502.2(varied)-504.4(from)-506.7(study)-500.8(to)]TJ
T*
[(study.)-354.5(Studies)-348.6(1)-352.4(and)-350(2)-352.4(and)-350(the)-350.2(EXCEL)-350.8(study)-351(excluded)-352.3(pa-)]TJ
T*
[(tients)-370.8(with)-362.6(exacerbations)-371.5(in)-365.2(the)-367.5(preceding)-364.8(3)-364(months,)-368.3(while)]TJ
0 -1.1174 TD
[(Aalbe)-8.8(rs)-243.9(et)-239.6(al.,)-246.5(Busse)-243.5(et)-245.4(al.,)-246.5(COMPASS,)-244.7(van)-246.4(der)-246.3(Molen)-243.9(et)-245.4(al.,)]TJ
0 -1.1116 TD
[(Bjermer)-358(et)-349.1(al.,)-350.2(and)-350(Ilowite)-355.7(et)-349.1(al.)-352.5(all)-350.3(excluded)-352.3(patients)-356.9(with)]TJ
T*
[(exacerbati)-11.3(ons)-331.4(within)-336.2(1)-329.4(month)-335.2(of)-336.2(study)-333.7(entry.)]TJ
1.0137 -1.1174 TD
[(In)-249.8(the)-252.3(FACET)-251.6(study)-247.3(only)-246.4(very)-253.2(frequent)-253.1(exacerbators)-255.1(\(3)-244.1(or)]TJ
-1.0137 -1.1116 TD
[(more)-266(courses)-268.8(of)-261.4(OCS)-264.2(or)-261.3(hospitalization)-268.3(due)-263.7(to)-261.5(asthma)-263.5(in)-267.3(the)]TJ
T*
[(6)-300.6(months)-307.3(before)-302.6(study)-299.2(entry\))-301.6(were)-307.1(excluded.)-303.9(Patients)-304.9(in)-301.8(the)]TJ
0 -1.1174 TD
[(study)-443.2(by)-439.9(Price)-439.7(et)-441.2(al.,)-442.3(were)-439.5(excluded)-444.4(if)-440(they)-443.4(were)-439.5(experi-)]TJ
0 -1.1116 TD
[(encin)-8(g)-364(a)0(n)-366.2(acute)-372(asthma)-367.2(exacerbati)-11.3(on)-365.1(or)-365(had)-367.3(used)-368.2(systemic)]TJ
T*
[(corticostero)-11.1(ids)-487.1(within)-491.7(2)-490.7(weeks)-498.1(of)-491.7(study)-489.3(entry.)-494(Fitzgerald)]TJ
T*
[(et)-452.7(al.)-444.7(excluded)-450.2(patients)-449.1(who)-447.7(had)-448(had)-448(an)-446.9(exacerbation)-451.2(re-)]TJ
0 -1.1174 TD
[(quirin)-6.8(g)-352.4(a)0(n)-354.7(emergency)-355.6(room)-356.9(visit)-357(within)-353.5(3)-352.4(months)-359.1(of)-353.5(study)]TJ
0 -1.1116 TD
[(entry.)-361.5(The)-357(studies)-360.1(reported)-362.5(by)-353.5(Aubier)-360.1(et)-360.6(al.)-358.3(and)-355.8(the)-361.7(OPTI-)]TJ
T*
[(MA)-424.4(study)-425.9(did)-423.9(not)-418.1(specify)-430.4(any)-419.2(inclusion/exclusion)-428(criteria)]TJ
0 -1.1174 TD
[(regarding)-559.5(prior)-558.5(asthma)-557.3(exacerbations)-561.6(or)-555.1(recent)-557.4(systemic)]TJ
0 -1.1116 TD
[(corticostero)-11.1(id)-330.6(use.)]TJ
1.0137 -1.1116 TD
[(There)-320(was)-316.2(some)-317.6(variation)-317.9(in)-319.1(baseline)-317.6(ICS)-315.2(doses:)-318.5(the)-321.4(two)]TJ
-1.0137 -1.1174 TD
[(uticasone/)-9.9(formoterol)-520.4(studies,)-524.8(the)-523(COMPASS)-523.5(study,)-521.5(and)]TJ
0 -1.1116 TD
[(those)-398.3(of)-399.6(Aalbers)-396.7(et)-400.9(al.)-392.8(and)-396.1(Busse)-399(et)-395.2(al.)-398.6(imposed)-401.7(an)-395(upper)]TJ
T*
[(limit)-439.2(for)-441(enrolment)-439.9(of)-434.1(500600)]TJ
/F6 1 Tf
13.3971 0 TD
(l)Tj
/F5 1 Tf
.5529 0 TD
[(g)-438.8(uticasone)-440.6(propionate-)]TJ
-13.95 -1.1174 TD
[(equivalents)-263.5(\(FP-e\)/day.)-264.2(In)-261.3(the)-258(OPTIMA)-263.7(study,)-256.5(patients)-264.8(were)]TJ
0 -1.1116 TD
[(ICS-naive)-272.4(or)-272.9(on)-267.1(a)-267.2(low)-269.2(dose)-270.3(of)]TJ
/F10 1 Tf
12.3891 0 TD
()Tj
/F5 1 Tf
.5529 0 TD
(200)Tj
/F6 1 Tf
1.6703 0 TD
(l)Tj
/F5 1 Tf
.5529 0 TD
[(g)-266(FP-e/day.)-273.5(Somewhat)]TJ
-15.1653 -1.1116 TD
[(higher)-439.8(screening)-445.3(doses)-438.3(of)-434.1(up)-439.9(to)-440.1(800)-435.3(to)-434.3(1000)]TJ
/F6 1 Tf
19.1913 0 TD
(l)Tj
/F5 1 Tf
.5529 0 TD
[(g)-433.1(FP-e/day)]TJ
-19.7443 -1.1116 TD
[(were)-341.6(permitted)-336.4(in)-330.6(the)-332.9(remaining)-336.2(studies)-337(\(Table)-338.5(2\).)]TJ
1.0137 -1.1174 TD
[(Patients)-466.2(in)-463.1(most)-460.6(studies)-463.8(had)-459.5(uncontrolled)-465.2(symptoms)-460.3(at)]TJ
-1.0137 -1.1116 TD
[(baseline,)-309.5(dened)-308.3(as)-308.4(the)-304.1(use)-309.5(of)-307.4(rescue)-309.4(medication)-309.9(and/or)-307.4(the)]TJ
T*
[(presence)-600.7(of)-589.7(asthma)-591.8(symptoms)-592.7(during)-594.2(the)-586.3(run-in)-594.2(period)]TJ
0 -1.1174 TD
[(\(Tabl)-8(e)-255.7(2\).)-253.3(The)-253.3(exceptions)-262.2(were)-255.2(uticasone/formoterol)-265.4(Study)]TJ
0 -1.1116 TD
[(1,)-252.2(which)-249.6(mandated)-255.6(uncontrolled)-252.1(symptoms)-252.9(at)-251.2(the)-252.3(start)-254.4(of)-249.8(the)]TJ
T*
[(previous)-315.1(12-week)-310.4(double-blind)-308.5(study,)-308.4(but)-308.7(not)-308.7(at)-308.8(the)-309.9(start)-306.2(of)]TJ
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[(the)-332.9(60)-330.5(week)-335.9(extension)-334.9(study,)-331.4(and)-332.8(the)-332.9(FACET)-332.2(study,)-331.4(which)]TJ
0 -1.1116 TD
[(requir)-7.8(ed)-331.7(that)-334.1(randomized)-338.4(patients)-333.9(had)-338.5(stable)-331.5(asthma.)]TJ
1.0137 -1.1116 TD
[(Following)-362.4(enrollment,)-369.7(only)-355.9(two)-367.2(of)-359.3(the)-361.7(studies)-365.9(mandated)]TJ
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[(treatment)-372.1(with)-362.6(oral)-362.8(steroids)-366.9(for)-366.1(specic)-362.3(exacerbation)-370.6(crite-)]TJ
0 -1.1174 TD
[(ria:)-483.8(the)-482.7(FACET)-481.9(study)-483.5(in)-480.4(case)-480(of)-480.2(a)]TJ
/F10 1 Tf
15.5397 0 TD
(>)Tj
/F5 1 Tf
.5529 0 TD
[(30%)-482.4(decrease)-486.7(from)]TJ
-16.0926 -1.1116 TD
[(baseline)-288.8(peak)-277.4(expiratory)-284.2(ow)-280.5(rate)-283.3(\(PEFR\))-284.9(for)-279.7(2)-277.6(consecutive)]TJ
T*
[(days)-299.1(\(as)-298(well)-300.4(as)-296.9(if)-296(deemed)-299.3(necessary)-296.4(by)-295.9(the)-298.3(investigator)-298.1(for)]TJ
0 -1.1174 TD
[(clinical)-427.5(need\))-428.3(and)-424.9(van)-419.2(der)-424.9(Molen)-428.2(et)-423.9(al.,)-419.3(where)-429.1(PEFR)-426.8(de-)]TJ
0 -1.1116 TD
[(creased)-340.4(by)]TJ
/F10 1 Tf
4.6826 0 TD
(>)Tj
/F5 1 Tf
.5472 0 TD
[(20%)-338.4(from)-333.9(baseline)-334.9(for)-331.5(2)-335.2(consecutive)-339.4(days.)]TJ
-4.2161 -1.1116 TD
[(Studies)-244.9(1)-243(and)-246.4(2)-243(were)-243.7(conducted)-249.7(across)-244.7(different)-248.6(territories)]TJ
-1.0137 -1.1174 TD
[(\(Study)-455.8(1;)-445.8(Central,)-458.2(South)-449(and)-453.7(North)-450(America)-456.9(and)-448(Eastern)]TJ
0 -1.1116 TD
[(Europe:)-557.3(Study)-558.4(2;)-555.3(Eastern)-558.3(and)-551.6(Western)-559.4(Europe\).)-560.6(Of)-556(the)]TJ
T*
[(Cochrane)-439.5(studies,)-438.4(eight)-433.1(were)-439.5(performed)-439.6(in)-434.3(Europe)-435.2(and/or)]TJ
0 -1.1174 TD
[(North)-375.1(America)-382(\(one)-374.2(study)-374.1(also)-374.1(included)-374.3(Israel\),)-381.9(whilst)-376.3(the)]TJ
0 -1.1116 TD
[(countries)-421.2(in)-411.3(which)-416.6(four)-413.3(studies)-411.9(were)-416.5(undertaken)-417.8(were)-416.5(not)]TJ
T*
[(specied)-340.4(\(Table)-338.5(1\).)]TJ
/F12 1 Tf
8.9663 0 0 8.9663 313.0582 166.2236 Tm
[(Data)-337.7(analysis)]TJ
/F5 1 Tf
9.843 0 0 9.843 323.0361 149.7826 Tm
[(The)-316.7(incidence)-325.9(of)-313.2(OCS)-321.8(exacerbations)-319.7(\(main)-319(analysis\))-323.1(and)]TJ
-1.0137 -1.1116 TD
[(respiratory)-348.5(exacerbations)-354.2(\(sensitivity)-342.9(analysis\))-351.9(for)-343.1(the)-344.4(uti-)]TJ
T*
[(casone/formotero)-12(l)-496.6(studies)-504.1(was)-500.5(calculated)-506.8(by)-497.5(dividing)-504.5(the)]TJ
0 -1.1174 TD
[(number)-354.6(of)-353.5(patients)-351.2(with)-351.1(at)-354.8(least)-353.5(one)-350.1(exacerbation)-353.3(event)-353.5(by)]TJ
0 -1.1116 TD
[(the)-471.1(total)-473.6(number)-469.8(of)-474.5(patients)-472.1(in)-468.9(the)-471.1(studies,)-473(and)-471(the)-471.1(95%)]TJ
T*
[(condence)-313.9(interval)-305.2(\(CI\))-304.8(was)-310.4(calculated.)-308.6(A)-307.2(similar)-309.8(approach)]TJ
0 -1.1174 TD
[(was)-425.6(used)-420.1(to)-422.8(calculate)-425.1(the)-419.3(pooled)-422.6(incidence)-423.8(of)-422.6(OCS)-419.7(exac-)]TJ
0 -1.1116 TD
[(erbations)-375.1(for)-371.9(xed-dose)-374.7(uticasone/salmeterol)-377.1(and)-373.1(budeso-)]TJ
T*
[(nide/s)-7.8(almeterol)-585.2(for)-585(the)-586.3(studies)-590.5(included)-587.4(from)-581.5(Lasserson)]TJ
/F3 1 Tf
8.9663 0 0 8.9663 62.022 749.6502 Tm
(348)Tj
48.7749 0 TD
[(PAPI)-331(ET)-338.7(AL.)]TJ
ET
endstream
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487.332 56.693 .22675 702.198 re
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110.891 56.693 .28346 702.198 re
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BT
/F11 1 Tf
0 9.845 -9.845 -0 66.8409 255.685 Tm
0 Tc
0 Tw
(Table)Tj
/F5 1 Tf
3.0002 0 TD
(1.)Tj
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1.2496 0 TD
[(Summary)-337.8(of)-331.2(the)-338.1(Studies)-330.2(Included)-338.1(in)-331.6(the)-332.4(Pooled)-333.5(Analysis)]TJ
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-24.4623 -3.8697 TD
(Study)Tj
9.7953 1.0135 TD
(Randomized)Tj
.0518 -1.0135 TD
[(patients)-337.7(\(N\))-2652.9(Blinding)]TJ
13.5614 2.027 TD
(Treatment)Tj
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(duration)Tj
.1958 -1.0135 TD
[(\(weeks\))-7658.6(Treatment)]TJ
25.7983 1.0135 TD
[(Countries)-333.6(in)-336.2(which)]TJ
.5874 -1.0135 TD
[(study)-334.4(performed)]TJ
13.6017 2.027 TD
[(Visit)-334.7(frequency)]TJ
-.357 -1.0135 TD
[(during)-334.2(treatment)]TJ
2.1134 -1.0135 TD
(period)Tj
-65.6762 -1.8946 TD
[(FP/FORM)-336.1(studies)]TJ
/F5 1 Tf
0 -1.0135 TD
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0 7.3837 -6.5625 -0 129.2031 61.6252 Tm
(a)Tj
0 9.845 -9.845 -0 133.5685 170.0787 Tm
[(280)-3020.4(Open-label)-4471.7(60)-2852.5(FP/FORM)-337.4(250/10)]TJ
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24.7905 0 TD
(l)Tj
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[(g)-335(MDI)-332.8(b.i.d.)-3739(Argentina,)-338.3(Mexico,)-335.1(Peru,)]TJ
9.8701 -1.0135 TD
[(Romania,)-331.7(Ukraine,)-336.1(USA)]TJ
15.9224 1.0135 TD
[(Every)-335.5(12)-330.2(weeks)]TJ
-62.6472 -2.0212 TD
(2)Tj
0 7.3837 -6.5625 -0 149.1023 61.6252 Tm
(b)Tj
0 9.845 -9.845 -0 153.4677 170.0787 Tm
[(472)-3020.4(Open-label)-3055.1(26)-330.2(or)-336(52)]TJ
0 7.3837 -6.5625 -0 149.1023 322.9227 Tm
(c)Tj
0 9.845 -9.845 -0 153.4677 340.3842 Tm
[(FP/FORM)-337.4(100/10)]TJ
/F6 1 Tf
7.4919 0 TD
(l)Tj
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[(g)-335(MDI)-332.8(b.i.d.)-335.7(or)]TJ
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(250/10)Tj
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2.9484 0 TD
(l)Tj
/F5 1 Tf
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[(g)-335(MDI)-332.9(b.i.d.)]TJ
12.4212 1.0135 TD
[(Germany,)-337.1(Hungary,)-334.8(Poland,)]TJ
.9962 -1.0135 TD
[(Romania,)-331.7(United)-336.5(Kingdom)]TJ
15.9224 1.0135 TD
[(Every)-335.5(4)-335(weeks)]TJ
/F7 1 Tf
-62.6472 -2.3322 TD
[(Lasserson)-337.4(et)-331.6(al.)-333.8(\(32\))-332.2(Cochrane)-339.3(review)-332.9(of)-336.1(single)-335.5(inhaler)-336.5(FP/SAL)-331.9(versus)-336(single)-335.5(inhaler)-336.5(BUD/FORM)]TJ
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0 -1.0077 TD
[(Aalbers,)-335.9(2004)-332.2(\(35\))-3821.9(215)]TJ
11.5171 -1.0135 TD
(219)Tj
4.5205 1.0135 TD
[(Open-label)-4471.7(28)-2852.5(BUD/FORM)-335.7(400/12)]TJ
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21.2663 0 TD
(l)Tj
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[(g)-335(TBH)-334.2(b.i.d.)]TJ
-8.0504 -1.0135 TD
[(FP/SAL)-335.8(250/50)]TJ
/F6 1 Tf
6.5532 0 TD
(l)Tj
/F5 1 Tf
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[(g)-335(DSK)-332.7(b.i.d.)]TJ
8.8163 1.0135 TD
[(Denmark,)-337.1(Finland,)-334.1(Germany,)-337.1(Norway,)]TJ
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[(Sweden,)-334.8(Netherlands)]TJ
15.9224 1.0135 TD
(NR)Tj
-62.6472 -2.027 TD
[(Busse,)-332.6(2008)-338(\(36\))-4547.5(422)]TJ
11.5171 -1.0077 TD
(404)Tj
4.5205 1.0077 TD
[(Open-label)-4471.7(28)-2852.5(BUD/FORM)-335.7(400/12)]TJ
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[(g)-335(MDI)-332.8(b.i.d.)]TJ
-8.0504 -1.0077 TD
[(FP/SAL)-335.8(250/50)]TJ
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[(g)-335(DSK)-332.7(b.i.d.)]TJ
8.8163 1.0077 TD
[(USA)-14930.6(Months)-335(1,)-332.6(4)-335(and)-332.4(7)]TJ
-45.7286 -2.0212 TD
[(COMPASS)-332.3(\(37\))]TJ
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[(\(Kuna)-335.2(2007\))]TJ
10.279 1.0135 TD
(1099)Tj
0 -1.0135 TD
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4.7681 1.0135 TD
[(Double-blind)-3584.7(24)-2852.5(BUD/FORM)-335.7(400/12)]TJ
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[(g)-335(TBH)-334.2(b.i.d.)]TJ
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[(g)-335(MDI)-332.8(b.i.d.)]TJ
8.8163 1.0135 TD
[(16)-336(countries)-333.9(\(countries)-340.7(not)-331.4(specied\))-1722.5(Every)-335.5(8)-335(weeks)]TJ
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[(EXCEL)-332.7(\(38\))]TJ
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[(\(Dahl,)-333(2006\))]TJ
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[(g)-335(TBH)-334.2(b.i.d.)]TJ
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[(FP/SAL)-335.8(250/50)]TJ
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[(g)-335(DSK)-332.7(b.i.d.)]TJ
8.8163 1.0077 TD
[(18)-336(countries)-333.9(\(countries)-340.7(not)-331.4(specied\))-1722.5(Weeks)-337.5(4,)-332.6(8,)-332.6(16)-330.2(and)]TJ
17.9091 -1.0077 TD
(24)Tj
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[(Ducharme)-334.2(et)-337.3(al)-330.4(\(22\))-338(Cochrane)-333.6(review)-338.7(of)-330.4(addition)-336.7(of)-330.4(LABA)-335.5(to)-336.2(ICS)-332.2(versus)-336(same)-334(dose)-339(of)-330.4(ICS)]TJ
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[(Aubier,)-334(1999)-332.2(\(39\))]TJ
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[(167)-3020.4(Double-blind)-3584.7(28)-2852.5(FP/SAL)-335.8(500/50)]TJ
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27.7159 -1.0077 TD
[(20)-336(and)-332.4(28)]TJ
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[(Two)-333.2(inhalers)-6177.8(171)-3020.4(Double-blind)-3584.7(28)-2852.5(FP)-335.6(500)-331.2(DSK)]TJ
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[(SAL)-333(50)]TJ
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[(gD)275.6(P)276.6(I)0(o)270.7(r)]TJ
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[(FORM)-338.4(1)2.1(2)]TJ
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8.108 1.0135 TD
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[(Canada)-13911.6(Months)-335(1,)-332.6(3,)-332.6(5)-335(and)-332.4(6)]TJ
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[(OPTIMA)-337.6(\(18\))-332.2(Low)]TJ
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10.5266 1.0135 TD
[(323)-3020.4(Double-blind)-3584.7(52)-2852.5(BUD)-333.8(100)]TJ
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21.4045 0 TD
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[(g)-329.2(TBH)]TJ
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[(FORM)-334.7(4.5)]TJ
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[(TBH)-334.2(b.i.d.)]TJ
15.9224 1.0135 TD
[(17)-336(countries)-333.9(\(countries)-340.7(not)-331.4(specied\))-1722.5(9)-335(visits)-334.4(over)-333.4(1)-335(year)]TJ
-45.7286 -2.027 TD
[(\(OByrne,)-336.8(2001\))]TJ
.9905 -1.0077 TD
[(High)-333.2(dose)-333.2(ICS)]TJ
10.5266 1.0077 TD
[(315)-3020.4(Double-blind)-3584.7(52)-2852.5(BUD)-333.8(200)]TJ
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21.4045 0 TD
(l)Tj
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[(g)-329.2(TBH)]TJ
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3.1614 0 TD
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[(FORM)-334.7(4.5)]TJ
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4.5723 0 TD
(l)Tj
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-12.8416 -1.0077 TD
[(TBH)-334.2(b.i.d.)]TJ
-29.8062 -1.0135 TD
[(FACET)-337.2(\(16\))-332.2(Low)]TJ
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10.5266 1.0135 TD
[(210)-3020.4(Double-blind)-3584.7(52)-2852.5(BUD)-333.8(100)]TJ
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21.4045 0 TD
(l)Tj
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[(g)-329.2(TBH)]TJ
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3.1614 0 TD
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0 9.845 -9.845 -0 368.6739 426.1038 Tm
[(FORM)-334.7(12)]TJ
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4.3247 0 TD
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(g)Tj
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[(TBH)-334.2(b.i.d.)]TJ
15.9224 1.0135 TD
[(Belgium,)-336.5(Canada,)-336.3(the)-338.3(Netherlands,)]TJ
.9962 -1.0135 TD
[(Israel,)-334.1(Italy,)-338.1(Luxembourg,)-333.5(Norway,)]TJ
T*
[(Spain,)-332(United)-336.5(Kingdom)]TJ
15.9224 2.027 TD
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[(Week)-333.5(2)-333.5(a)-.7(nd)-333.5(Months)]TJ
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[(1,)-272.8(2,)-272.8(3,)-272.8(6,)-272.8(9,)-267.1(an)-10.3(d)-265.7(1).2(2)]TJ
-63.6377 -1.0135 TD
0 Tc
[(\(Pauwels,)-336.8(1997\))]TJ
.9905 -1.0077 TD
[(High)-333.2(dose)-333.2(ICS)]TJ
10.5266 1.0077 TD
[(215)-3020.4(Double-blind)-3584.7(52)-2852.5(BUD)-333.8(400)]TJ
/F6 1 Tf
21.4045 0 TD
(l)Tj
/F5 1 Tf
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[(g)-329.2(TBH)]TJ
/F10 1 Tf
3.1614 0 TD
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[(FORM)-334.7(12)]TJ
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4.3247 0 TD
(l)Tj
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(g)Tj
-12.5939 -1.0077 TD
[(TBH)-334.2(b.i.d.)]TJ
-29.8062 -1.0135 TD
[(van)-303.6(der)-303.6(Molen,)-304.2(1997)]TJ
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(\(41\))Tj
10.5266 1.0135 TD
[(125)-3020.4(Double-blind)-3584.7(24)-2852.5(ICS)-268.7(\(usual)-266.2(dose\))-270.8(DPI)-268.5(or)-266.9(MDI)]TJ
/F10 1 Tf
29.4434 0 TD
(+)Tj
/F5 1 Tf
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(FORM)Tj
-11.972 -1.0135 TD
(24)Tj
/F6 1 Tf
1.169 0 TD
(l)Tj
/F5 1 Tf
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[(g)-329.2(TBH)-340(b.i.d.)]TJ
14.2006 1.0135 TD
[(The)-339.3(Netherlands,)-335.5(Canada)-6586.7(Weeks)-337.5(4,)-332.6(12)-330.2(and)-338.1(24)]TJ
/F7 1 Tf
-45.7286 -2.3265 TD
[(Chauhan)-330.4(and)-337(Ducharme)-334.2(\(33\))-338(Cochrane)-333.6(review)-338.7(of)-330.4(addition)-336.7(to)-330.4(ICS)-338(of)-330.4(LABAs)-336.3(versus)-336(anti-leukotrienes)]TJ
/F5 1 Tf
0 -1.0135 TD
[(Bjermer,)-337.5(2003)-332.2(\(42\))-3643.4(743)-3020.4(Double-blind)-3584.7(48)-2852.5(FP)-249.2(100)]TJ
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31.8332 0 TD
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[(20)-295.7(pack/years;)]TJ
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[(from)-333.9(Ducharme)-336.9(et)-337.6(al.)-335.2(and)-332.8(Chauhan)-333.6(and)-338.5(Ducharme.)]TJ
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T*
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T*
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T*
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[(\(35)-10.1(37,39,44\))]TJ
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[(94%)-545.8(in)]TJ
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[(Aubiers)-402.4(and)-401.9(Aalbers)-403.5(studies,)-398.1(whilst)]TJ
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[(93%)-401.8(of)-393.8(subjects)-402.7(in)]TJ
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T*
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ET
62.022 523.275 490.167 .22675 re
f
62.022 68.372 490.167 .22675 re
f
62.022 494.646 490.167 .22681 re
f
BT
/F11 1 Tf
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(Table)Tj
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3.0002 0 TD
(3.)Tj
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[(Baseline)-338.1(Characteristics)-333.4(of)-337(Patients)-331.2(by)-335.8(Study)]TJ
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[(\(%)-279.4(male:female\))-3184.8(Ethnicity)]TJ
18.0818 1.0077 TD
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(1)Tj
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[(%)-289.9(predicted)-1803.5(Reversibility)-284.1(\(%\))]TJ
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[(FP/FORM)-336.1(studies)]TJ
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[(1)-15376.3(4)0(3)-4833.4(35:65)-4024.6(White)-336.9(74.6%)]TJ
27.9923 -1.0077 TD
[(Black)-336.7(2.1%)]TJ
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[(Asian)-335.2(0.4%)]TJ
T*
[(Hispanic)-281.9(19.6%)]TJ
T*
[(Other)-335.4(3.2%)]TJ
10.1811 4.0483 TD
[(67)-6491.9(NR)]TJ
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[(2)-15376.3(4)0(2)-4833.4(46:54)-4024.6(White)-336.9(98.9%)]TJ
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T*
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[(73)-6687.6(28)]TJ
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[(Lasserson)-337.5(et)-331.6(al)-336.2(\(32\))-332.2(Cochrane)-339.3(review)-332.9(of)-336.2(single)-335.5(inhaler)-330.8(FP/SAL)-337.7(versus)-336(single)-335.5(inhaler)-336.5(BUD/FORM)]TJ
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[(Aalbers,)-335.9(2004)-332.2(\(35\))-338(BUD/FORM)]TJ
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[(46)-4833.4(45:55)-4024.6(NR)-8774.1(84)-6491.9(NR)]TJ
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[(46)-4833.4(49:51)-4024.6(NR)-8774.1(85)-6491.9(NR)]TJ
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[(Busse,)-338.4(2008)-332.2(\(36\))-332.2(BUD/FORM)]TJ
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[(39)-4833.4(34:66)-4024.6(White)-336.9(82.0%)]TJ
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T*
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[(79)-6491.9(NR)]TJ
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[(39)-4833.4(43:57)-4024.6(White)-336.9(84.0%)]TJ
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[(78)-6491.9(NR)]TJ
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[(COMPASS)-338.1(\(37\))-332.2(BUD/FORM)]TJ
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[(38)-4833.4(41:59)-4024.6(NR)-8774.1(73)-6687.6(25)]TJ
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[(\(Dahl,)-333(2006\))-333.2(FP/SAL)]TJ
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[(47)-4833.4(41:59)-4024.6(NR)-8774.1(79)-6687.6(24)]TJ
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[(46)-4833.4(44:56)-4024.6(NR)-8774.1(79)-6687.6(20)]TJ
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[(Ducharme)-340(et)-331.6(al)-336.2(\(22\))-332.2(Cochrane)-333.6(review)-338.7(of)-336.2(ICS/LABA)-334.9(free)-334.5(combinations)]TJ
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[(Aubier,)-305.2(1999)-303.4(\(39\))-309.2(Single)-306.7(inhaler)]TJ
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[(46)-4833.4(57:43)-4024.6(NR)-8774.1(73)-6687.6(16)]TJ
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[(48)-4833.4(50:50)-4024.6(NR)-8774.1(73)-6687.6(18)]TJ
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[(\(OByrne,)-336.8(2001\))-333.2(High)-333.2(dose)-333.2(ICS)]TJ
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[(37)-4833.4(45:55)-4024.6(NR)-8774.1(86)-6491.9(NR)]TJ
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[(37)-4833.4(41:59)-4024.6(NR)-8774.1(87)-6491.9(NR)]TJ
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[(FACET)-337.2(\(16\))-332.2(Low)-333.2(dose)-339(ICS)]TJ
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[(\(Pauwels,)-336.8(1997\))-333.2(High)-333.2(dose)-333.2(ICS)]TJ
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[(41)-4833.4(50:50)-4024.6(NR)-8774.1(76)-6491.9(NR)]TJ
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[(42)-4833.4(47:53)-4024.6(NR)-8774.1(76)-6491.9(NR)]TJ
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[(van)-332.4(der)-338.1(Molen,)-333(1997)-332.2(\(41\))-5284.5(41)-4833.4(49:51)-4024.6(NR)-8774.1(68)-6687.6(25)]TJ
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27.9923 -1.0135 TD
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T*
[(Asian)-335.2(7.4%)]TJ
T*
[(Other)-335.4(14.7%)]TJ
10.1811 3.0405 TD
[(73)-6687.6(19)]TJ
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[(Ilowite,)-335.3(2004)-332.2(\(43\))-8451.7(38)-4833.4(37:63)-4024.6(White)-336.9(85.6%)]TJ
27.9923 -1.0135 TD
[(Black)-336.7(7.7%)]TJ
T*
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10.1811 2.027 TD
[(74)-6687.6(19)]TJ
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[(NR)-6297.9(NR)]TJ
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(352)Tj
48.7749 0 TD
[(PAPI)-331(ET)-338.7(AL.)]TJ
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[(Fluticasone/formoterol)-278.1(was)-275.8(associated)-280.5(with)-270.5(a)-273(similar,)-272.9(low)]TJ
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[(incidence)-331.6(of)-330.5(OCS)-327.6(exacerbations)-331.2(in)-324.9(both)-327.1(studies)-331.3(\(Fig.)-324.6(1)-323.6(and)]TJ
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T*
[(0.2,)-343.1(3.3%,)]TJ
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(n/N)Tj
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18.6557 8.9045 TD
(3.7%,)Tj
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(n/N)Tj
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T*
[(therapy)-332.7(was)-339.2(2.1%)-330.3(\(95%)-333.7(CI:)-338.5(1.1,)-331.6(3.2%,)]TJ
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T*
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/Im1 Do
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BT
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[(FIG.)-296.4(1.)]TJ
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[(Ducharme)-358.9(et)-354.6(al.,)]TJ
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(\(33\))Tj
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[(BDP,)-353.5(beclometasone;)]TJ
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59.754 113.329 490.167 .28348 re
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301.89 199.616 248.031 .22681 re
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BT
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[(ICS/LABA)-340.7(combination)]TJ
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[(OCS)-333(exacerbation)-339.2(rate)]TJ
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[(n/)5.6(N)]TJ
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(Fluticasone/formoterol)Tj
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(a)Tj
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(Fluticasone/formoterol)Tj
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(b)Tj
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[(22)-330.2(/)-335.2(752)-5041.7(2.9)-7957.9(1.7,)-331.2(4.1)]TJ
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[(Fluticasone/salmeterol)-341.6([Lasserson,)-338.7(2011)-332.2(\(32\)])-5919(239)-331.2(/)-335.2(2516)-5042.7(9.5)-7957.9(8.4,)-331.2(10.6)]TJ
T*
[(Budesonide/formoterol)-343.7([Lasserson,)-333(2011)-332.2(\(32\)])-5711.7(257)-331.2(/)-335.2(2433)-4541.7(10.6)-7958.9(9.3,)-331.2(11.8)]TJ
T*
[(ICS/LABA)-341(combinations)-332.4([Ducharme,)-340.3(2010)-332.2(\(22\)])-4542.7(258)-331.2(/)-335.2(1615)-4541.7(16.0)-7457.9(14.2,)-332.2(17.8)]TJ
0 -1.0077 TD
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8.7511 0 0 8.7511 67.748 101.537 Tm
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[(Ducharme,)-338.6(2014.)]TJ
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(a)Tj
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[(intramuscular,)-304.3(or)-294.2(intravenous)-294.9(corticosteroid\);)]TJ
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(b)Tj
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/F3 1 Tf
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[(FLUTICASONE/FORMOTEROL:)-345.7(LOW)-332.6(RATE)-338(OF)-331.2(EXACERBATIONS)-21721(353)]TJ
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