Keftab

By I. Hauke. Northwestern College, Iowa. 2019.

Outcomes were assessed using primarily Child Behavior Checklists for parents and teachers keftab 750mg with mastercard, and linear analogue scales of parent assessments of hyperactivity and tics discount keftab 125 mg otc, as compared with any time in the past. Based on the linear analogue assessments, clonidine was not significantly different to placebo. The assessment of tics, based on 4 scales, did not show a difference between placebo and clonidine. Multiple subgroup analyses of the checklists resulted in clonidine being superior to placebo on some subscale items. A poor quality systematic review Attention deficit hyperactivity disorder 62 of 200 Final Update 4 Report Drug Effectiveness Review Project included 11 studies of varying design. These studies did not meet inclusion criteria for this 156 review, and were inappropriately pooled regardless of their varying study designs. Two studies of extended-release clonidine have been published to date, with additional completed studies not published to date according to 157, 158 ClinicalTrials. The trials enrolled children with the hyperactive or combined subtype of ADHD with less than adequate response (ADHD-RS-IV scale score > 26 out of 54) to a stable dose of stimulant, and used the ADHD-RS-IV scale assessed by investigators as the primary outcome measure. Parent measurements on the Conners’ Parent Rating Scale and the Parent Global Assessment were secondary outcomes. In a fair-quality trial of 198 children randomized to flexible dose clonidine ER (0. Parent assessments found the group with clonidine XR to have better improvement in the Conners’ Parent Rating scale (– 40. Subgroup analysis by specific stimulants failed to show statistical significant benefits, most likely due to inadequate sample sizes (Type II error). In a fair-quality fixed-dose trial of 236 children, monotherapy clonidine ER 0. Week by week analysis indicated that the difference between drug (ether dose) and placebo started at week 2. Parent assessment using the Conners’ rating scale and the Parent Global Assessment also indicated a significant difference between changes in score at either dose compared with placebo, but actual scores were not reported. Guanfacine Immediate-release guanfacine compared with placebo. A small study of 24 children with ADHD, all of the mixed type, and a tic disorder studied the effects of immediate-release 159 guanfacine compared with placebo for 8 weeks. Slightly more than half of enrolled children had Tourette’s disorder (58. Teachers and investigators rated immediate-release guanfacine superior to placebo, while parent ratings did not. Teacher ratings resulted in a 37% decrease on the ADHD Rating Scale at 8 weeks, compared with an 8% drop with placebo group (P<0. Four fair-quality placebo-controlled trials 8-9 weeks in duration of 1341 children have been published with guanfacine XR. Two were monotherapy dose-ranging studies of 1 to 4 mg daily, included in the initial US Food and Drug Administration 160-162 documents reviewed, and another monotherapy study included only children aged 6-12 163 years with comorbid oppositional symptoms using a flexible dose of 1 to 4 mg daily. The fourth study assessing guanfacine XR as adjunctive therapy to stimulants was subsequently 164 submitted to the US Food and Drug Administration. Baseline mean ADHD-RS-IV scores (test results in score ranging from 0 to 54) were 37, 40, 37, and 42, respectively. Attention deficit hyperactivity disorder 63 of 200 Final Update 4 Report Drug Effectiveness Review Project In the dose-ranging studies, the placebo-adjusted change from baseline to endpoint in the ADHD-RS-IV score (primary outcome) was statistically significantly greater than placebo for all doses, although the absolute difference in score was not large (least squares mean difference –5. In both studies the largest difference in score change was with the 4 mg daily 160-162 dose (–9. For 2, 3, and 4 mg daily doses the difference compared with placebo was statistically significant starting at week 2. Revised Conners’ Parent and Conners’ Teacher Rating Scales also showed guanfacine XR superior to placebo in mean change from baseline to endpoint scores. Assessment of the duration of effect using these measures throughout the day showed all doses to have effect through 8 hours, but variable effects by dose and study at 12, 14, and 24 hours. Post-hoc analysis of weight-based dosing and outcome indicated a greater response with 0. A study of 217 children aged 6-12 years with comorbid ADHD and oppositional symptoms using flexible dosing (1-4 mg daily) over 8 weeks found that the mean least squares mean change on the ADHD-RS-IV scale was –23. The subscale scores on the CPRS-RS-L oppositional defiant subscale also improved more with guanfacine XR (–10. Slightly more patients were taking 3 mg daily, and only a few took 1 mg daily. As adjunctive therapy to stimulant therapy with suboptimal response (ADHD-RS-IV > 24 and CGI-S > 3 after at least 4 weeks treatment), guanfacine XR (given at night or in the morning) was found superior to placebo on the ADHD-RS-IV scale, least squares mean difference in Total score of ‒4. As a secondary outcome measure, response (defined as reduction of ADHD-RS-IV Total score of > 25% from baseline), the evening dosing of guanfacine XR was superior to placebo (83. Multiple subgroup and secondary analyses were conducted but are not presented here because they are comparisons to placebo.

Qu alityassessmentofplacebo-controlledtrialsinpatientsw ith PAR Class Control Au th or cheap 375mg keftab otc, naïv e grou p Year buy keftab 750 mg lowest price, patients standard Cou ntry Ex clu sioncriteria Ru n-in/w ash ou t only ofcare Fu nding Relev ance Ch ervinsky Historyof ph ysica lfinding s of na sa lpa th olog y;recentna sa l 7-14da yba seline no yes Alta na P h a rm a yes 2007 biopsy;na sa ltra u m a ;na sa lsu rg ery;a troph icrh initis;rh initis period US m edica m enntosa ;a ctivea sth m a requ iring trea tm entwith corticosteroids orbeta a g onists,known h ypersentivitityto corticosteroids;h istoryof RTIwith in 14da ys of screening visitordevelopm entof respira toryinfection du ring ba seline; u sefo a ntibiotics with in 14da ys of screening visit Meltzer Abnorm a lfinding s inclu ding na sa lpolyps a ndna sa ltra ct 7-14da yba seline no yes Alta na P h a rm a yes 2007 m a lform a tions;rh initis m edica m entosa ;evidenceof a n RTI period US orsig nifica ntm edica ldisorderoth erth a n ARwith in 14da ys of screening ;positivetestforh ep B,h ep CorHIV;a ctive a sth m a requ iring trea tm entwith inh a ledorsystem itc corticosteroids orrou tineu seof beta a g onists;u seof proh ibitedm edica tions du ring wa sh ou tperiods Rosenblu t Anym edica lcondition th a tcou ldinterferewith sa fety 7-14da yba seline no yes Gla xoSm ith KlineR&D yes Mu lticou ntry eva lu a tions,inclu ding severena sa lobstru ction,recentna sa l period 2007 septa lorfa cia lsu rg ery;a sth m a ;rh initis m edica m entosa ; recentRTI;sinu sitis;ca ndida infection of th enoseor oroph a rynx;g la u com a ;ca ta ra cts;ocu la rh erpes sim plex; h istoryof a drena linsu fficiencyora bnorm a lECGorclinica l la btest;INSwith in 4weeks of screening ;corticosteroids with in 6m onth s of screening ;oth erm edica tions th a tcou ld a ffectAR. Da h l pa tients wh o su fferedfrom a sth m a a ndARbeca u seof NR no yes Gla xoSm ith KlineR&D yes 2005 a llerg ens oth erth a n pollen;th osereceiving ch ronic Denm a rk trea tem entwith a ntia sth m a m edica tion ora ny im m u nosu ppressa nts a nd/orim m u noth era pyoverth ela st3 yea rs NCS Page 279 of 357 Final Report Update 1 Drug Effectiveness Review Project Ev idenceTable6a. Qu alityassessmentofplacebo-controlledtrialsinpatientsw ith PAR Au th or, Eligibility Year, Allocationconcealment Grou pssimilar criteria Ou tcomeassessors Patient Cou ntry Randomizationadeq u ate? Gu revich notclea r notclea r yes yes yes yes 2005 USA Mu rph y notclea r notclea r yes yes yes yes 2006 USA Stelm a ch notclea r notclea r yes yes yes yes 2005 Bra zil NCS Page 280 of 357 Final Report Update 1 Drug Effectiveness Review Project Ev idenceTable6a. Qu alityassessmentofplacebo-controlledtrialsinpatientsw ith PAR Reportingof attrition, Nu mber Au th or, crossov ers, Post- screened/ Year, adh erence, Losstofollow -u p: Intention-to-treat randomization eligible/ Cou ntry andcontamination differential/h igh (ITT)analysis ex clu sions Qu alityRating enrolled Gu revich y/y/n/n no yes no fa ir NR/NR/26 2005 USA Mu rph y y/n/n/n no u nclea r no fa ir 407/229/229 2006 USA Stelm a ch y/n/y/n no no yes fa ir NR/NR/74 2005 Bra zil NCS Page 281 of 357 Final Report Update 1 Drug Effectiveness Review Project Ev idenceTable6a. Qu alityassessmentofplacebo-controlledtrialsinpatientsw ith PAR Class Control Au th or, naïv e grou p Year, patients standard Cou ntry Ex clu sioncriteria Ru n-in/w ash ou t only ofcare Fu nding Relev ance Gu revich neg a tiveskin testresponseto a yea r-rou nda llerg en; 1-week ru n-in with no yes Astra Zeneca yes 2005 sea sona la llerg ies;sleep a pnea ;na sa lpolyps;devia ted sa linena sa lspra y USA septu m ;a topicdisea ses oth erth a n AR;non-AR;obesity; onceda ily ch ronicobstru ctivepu lm ona rydisea se;recentu ppera nd 1week wa sh ou t lowera irwa yinfection;u seof ora lorna sa lsteroids with in between stu dya rm s 30d;a nd/oru seof Beta bolckers,tricyclica ntidepressa nts or oth erm edica tions th a ta reknown to a ffectsleep,rh initis a nd da ilyperform a nce Mu rph y a nysig nifica ntch ronicdisea se;a nydisea seorcondition th a tnone no yes Astra Zeneca yes 2006 m ig h ta ffectg rowth ;ch rom osom ea berrra tion;skeleta l USA a bnorm a lities th a ta ffecth eig h t;evidenceof na sa lpolyps; stru ctu ra la bnorm a litites of th enoseca u sing na sa l obstru ction;a clinica llyreleva nta bnora m lityin th eph ysicla exa m ina tion resu lts;a h istoryof su bsta ncea bu se,nenta l illness orreta rda tion;g la u com a orca ta ra a cts,a n a sth m a dia g nosis th a trequ iredtrea tm entwith ora lorinh a led steroids orleu kotrienem odifiers;trea tm entwith ora l, injecta ble,orinh a ledcorticosteroids with in 60dof visit1; insu fficientARsym ptom s to requ ireda ilyth era py;a h istory orevidenceof a bnorm a lg rowth ;a known g esta tiona la g e less th a n 35weeks;g rowth velocitybelowth eth irdpercentile a tth eendof th e6-m onth ba selineperiod;ora nyu seof m edica tion th a tcou lda ffectg rowth Stelm a ch im m u noth era pyorh ospita liza tion du eto a n a sth m a 2-week ru n-in with for3 yes m edica tions a nd yes 2005 exa cerba tion du ring th epreviou s 6m onth s,u seof ora l, pla cebo. Only m onth s pla cebo su ppliedby Bra zil injectedorinh a ledcorticosteroids,no respira toryinfection sa lbu ta m ola nd priorto Fa rm a la b-Ch iesi co. Placebo -co ntro lledtrialsinchildrenwithPAR Autho r Year Co untry Studydesign TrialName Setting Eligibilitycriteria Interventio ns Run-in/washo utperio d Da y Ra nd om ized , Pa tients a ged 6yea rs a nd old er, Intra na sa lb ud esonid e,200 2weeks/NR 1990 d oub le-b lind ,p a ra llel, with p erennia lrhinitis fora tlea st m ea n gra m s twic e d a ilyvs p la c eb o-c ontrolled 2yea rs,c urrentlyrec eiving no p la c eb o trea tm entforrhinitis S tud yp eriod :4weeks Exc lusion:Pregna nc y, tub erc ulosis,resp ira toryinfec tion, a d d itiona ld isea se,ora sthm a req uiring trea tm entwith c ortic osteroid s Fokkens Ra nd om ized , Child ren a ged 6-16yea rs with b ud esonid e a q ueous na sa l NR/NR 2002 d oub le-b lind ,p la c eb o- p erennia la llergic rhinitis fora t sp ra y,128m c g onc e d a ilyvs c ontrolled ,p a ra llel, lea st1yea r,need fortrea tm entof p la c eb o m ultic enter na sa lsym p tom s,m od era te to S tud yp eriod :6weeks severe sym p tom sc ore for b loc ked nose a nd a tlea sta m ild sc ore forrunnynose orsneezing on 4of7d a ys ofrun-in p eriod NCS Page 283 of 357 Final Report Update 1 Drug Effectiveness Review Project EvidenceTable7. Placebo -co ntro lledtrialsinchildrenwithPAR Autho r Year Metho do fo utco me Age Numberscreened/ Co untry Allo wedo thermedicatio ns/assessmentandtimingo fGender Otherpo pulatio n eligible/ TrialName interventio ns assessment Ethnicity characteristics enro lled Da y terfena d ine,up to two Na sa lsym p tom s 28. Placebo -co ntro lledtrialsinchildrenwithPAR Autho r Year Number Co untry withdrawn/ Metho do fadverseeffects TrialName lo stto fu/analyzedOutco mes assessment Da y NR/NR/51 Mea n c ha nge in sym p tom sc ores from b a seline to 4 La b ora torytests,p a tient 1990 weeks;p -va lue=Bvs p la c eb o: self-rep ortofa d verse events Bloc ked nose: Allergic rhinitis:B:-0. Placebo -co ntro lledtrialsinchildrenwithPAR Autho r Year To talwithdrawals; Co untry Adverseeffects withdrawalsdueto adverse TrialName repo rted events Co mments Da y Noseb leed : NR;NR 1990 Child ren:B:0vs p la c eb o:1 Ad ults:B:4vs p la c eb o:1 S neezing a ftersp ra y: Child ren:B:3vs p la c eb o:2 Ad ults:B:1vs p la c eb o:1 Na sa lirrita tion: Child ren:B:5vs p la c eb o:2 Ad ults:B:4vs p la c eb o:3 Nose d ryness: Child ren:B:1vs p la c eb o:2 Ad ults:B:1vs p la c eb o:1 Coughing: Child ren:B:1vs p la c eb o:3 Ad ults:B:4vp la c eb o:0 H ea d a c he: Child ren:B:7vs p la c eb o:8 Ad ults:B:8vs p la c eb o:5 Fokkens No ofa d verse events rep orted :B:75vs 0;0 2002 p la c eb o:73 Mostfreq uenta d verse events: p ha ryngitis:B:9vs p la c eb o:7 resp ira toryinfec tion:B:7vs p la c eb o:7 vira linfec tion:B;&vs p la c eb o:6 c oughing:B:7vs p la c eb o:4 b lood -tinged sec retion/nose b leed s:B:4vs p la c eb o:6 NCS Page 286 of 357 Final Report Update 1 Drug Effectiveness Review Project EvidenceTable7. Placebo -co ntro lledtrialsinchildrenwithPAR Autho r Year Co untry Studydesign TrialName Setting Eligibilitycriteria Interventio ns Run-in/washo utperio d H ill Ra nd om ized ,d oub le- Child ren a ged 7-17yea rs,c hronic Intra na sa lb ec lom etha sone NR/NR 1978 b lind ,c ross-over,p la c eb o-m outh-b rea thers with gross d ip rop iona te,300m g/d a yvs c ontrolled hyp ertrop yofna sa lm uc osa a nd p la c eb o single-c enter exc essive rhinorrhea ,fa iling to S tud yp eriod :NR resp ond to a ntihista m ines a nd a d rengic d rugs Na ya k Doub le-b lind ,p la c eb o- Child ren a ged 6-12yea rs with tria m inolone a c etonid e a q ueous NR/NR 1998 c ontrolled a llergic rhinitis,m a les a nd na sa lsp ra y220g onc e d a ilyvs m ultic enter p rem ena rc hea lfem a les 440g onc e d a ily Exc lusion:c linic a llyrelelva nt S tud yp eriod :6weeks d evia tion from norm a lm ed ic a lor la b p a ra m eters,intolera nc e to c ortic osteroid thera p y,a ny m ed ic a lc ond ition c a p a b le of a ltering p ha rm okineti NCS Page 287 of 357 Final Report Update 1 Drug Effectiveness Review Project EvidenceTable7. Placebo -co ntro lledtrialsinchildrenwithPAR Autho r Year Metho do fo utco me Age Numberscreened/ Co untry Allo wedo thermedicatio ns/assessmentandtimingo fGender Otherpo pulatio n eligible/ TrialName interventio ns assessment Ethnicity characteristics enro lled H ill No d rugs used forrhinitis Da ilysym p tom d ia ryresults 7-17yea rs Assoc ia ted rec urrenta sthm a :12/22 NR/NR/22 1978 a llowed d uring stud yp eriod rec ord ed a tc linic visits 50% Fem a le Evid enc e ofm a rked system ic a llergy Ethnic ityNR to house d ustm ite a nd /orrye gra ss Na ya k NR/NR Ad renoc ortic a lfunc tion 9. Placebo -co ntro lledtrialsinchildrenwithPAR Autho r Year Number Co untry withdrawn/ Metho do fadverseeffects TrialName lo stto fu/analyzedOutco mes assessment H ill 0/0/22 Num b erofc hild ren with resp onse: Pa tientd a ilysym p tom d ia ry 1978 Na sa lsym p tom s: Im p roved sc ore:19 Unc ha nged sc ore:0 W orse sc ore:3 Na sa lsigns: Im p roved sc ore:15 Unc ha nged sc ore:7 W orse sc ore:0 Eye sym p tom s: Im p roved sc ore:13 Unc ha nged sc ore:4 W orse sc ore:5 Na ya k 1/0/79 Mea n d ifferenc es in p la sm a c ortisollevels b etween Pa tientrep ort 1998 b a seline a tweek 6: 0hrs: T AA220g:-1. Placebo -co ntro lledtrialsinchildrenwithPAR Autho r Year To talwithdrawals; Co untry Adverseeffects withdrawalsdueto adverse TrialName repo rted events Co mments H ill None rep orted 0;0 1978 Na ya k Perc enta ge ofp a tients rep orting a d verse 0;0 1998 events: T AA220g/d :54% T AA440g/d :42% Pla c eb o:35% NCS Page 290 of 357 Final Report Update 1 Drug Effectiveness Review Project EvidenceTable7. Placebo -co ntro lledtrialsinchildrenwithPAR Autho r Year Co untry Studydesign TrialName Setting Eligibilitycriteria Interventio ns Run-in/washo utperio d Neum a n Doub le-b lind , Child ren a ged 9-18yea rs, b ec lom etha sone d ip rop iona te NR/NR 1978 c rossover with p erennia la llergic rhinitis a nd 50g inha led in ea c h nostril,4 d a ilysym p tom s ofsneezing, tim es d a ily rhinorrhoea a nd na sa lob struc tion S tud yp eriod :6weeks fora tlea st5yea rs Nga m p ha ib oon Ra nd om ized d oub le- Child ren a ged 5-11yea rs with m od flutic a sone p rop iona te 100m c g NR/2week wa shoutb etween 1997 b lind ,single d ose, vs p la c eb o trea tm ents T ha ila nd p la c eb o-c ontrolled , S tud yp eriod :4weeks,with 2 p a ra llel weeks a d d itiona lfollowup m ultic enter S a rsfield Ra nd om ized , Child ren with p erennia l Na sa lflunisolid e vs p la c eb o NR/NR 1979 d oub le-b lind ,c rossover a rthritis S tud yp eriod :2m onths stud y T hen 17p a tients resp ond ing wellwith fluc isolid e c ontinued trea tm entfora d d itiona l6m onth, op en p eriod NCS Page 291 of 357 Final Report Update 1 Drug Effectiveness Review Project EvidenceTable7. Placebo -co ntro lledtrialsinchildrenwithPAR Autho r Year Metho do fo utco me Age Numberscreened/ Co untry Allo wedo thermedicatio ns/assessmentandtimingo fGender Otherpo pulatio n eligible/ TrialName interventio ns assessment Ethnicity characteristics enro lled Neum a n NR Da ilyd ia ryc a rd s, 13. Placebo -co ntro lledtrialsinchildrenwithPAR Autho r Year Number Co untry withdrawn/ Metho do fadverseeffects TrialName lo stto fu/analyzedOutco mes assessment Neum a n NR/NR/NR Mea n d a ilyna sa lsym p tom sc ores: Pa tientoutc om e,self-rep ort 1978 W eek 1:BD:1. Placebo -co ntro lledtrialsinchildrenwithPAR Autho r Year To talwithdrawals; Co untry Adverseeffects withdrawalsdueto adverse TrialName repo rted events Co mments Neum a n None Rep orted NR;NR 1978 Nga m p ha ib oon None rep orted 0;0 1997 T ha ila nd S a rsfield Mostc om m on a d verse events rep orted : 1;1 1979 tra nsientna sa lstinging After6m onth op en-p eriod ,m ea surem ents of0900b lood c ortisolc onc entra tions found no effec t. NCS Page 294 of 357 Final Report Update 1 Drug Effectiveness Review Project EvidenceTable7. Placebo -co ntro lledtrialsinchildrenwithPAR Autho r Year Co untry Studydesign TrialName Setting Eligibilitycriteria Interventio ns Run-in/washo utperio d S hore Ra nd om ized ,d oub le- Child ren a ged 4-12yea rs, Intra na sa lb ec lom etha sone vs NR/3week wa shoutb etween 1976 b lind ,p la c eb o-c ontrolled ,with p erennia la llergic rhinitis for p la c eb o trea tm ents c ross-over over1yea r,fa ilure to resp ond to S tud yp eriod :4m onths single-c enter sod ium c rom oglyc a te insuffla tion a nd hyp osensitiza tion, p retrea tm entob serva tion a tstud y c linic fora tlea st6m onths, sym p tom a tic a tsc reening, ra d iologic a lstud ies exc lud ing a b norm a lities c a using ob struc tion,ina d eq ua te p revious resp onse to trea tm ent S torm s Ra nd om ized ,d oub le- Pa tients a ged 12-65yea rs,with tria m c inolone a c etonid e na sa l NR/NR 1991 b lind ,p la c eb o-c ontrolled ,p erennia la llergic rhinitis fora t sp ra y,110g vs 220g vs 440g p a ra llel lea st2yea rs,p oorresp onse to onc e d a ilyvs p la c eb o Multi-c enter a ntihista m ines a nd /or S tud yp eriod :12weeks d ec ongesta nts or im m unothera p y,p ostive skin p ric k testfora tlea sta llergin Exc lusion:p regna nc yorla c ta tion, use ofna sa lc rom olyn T od d Ra nd om ized , Child ren with p erennia l fluisolid e na sa lsp ra y50g three NR/NR 1983 d oub le-b lind ,c ross-over rhinitis tim es d a ily,vs p la c eb o S tud yp eriod :8weeks NCS Page 295 of 357 Final Report Update 1 Drug Effectiveness Review Project EvidenceTable7. Placebo -co ntro lledtrialsinchildrenwithPAR Autho r Year Metho do fo utco me Age Numberscreened/ Co untry Allo wedo thermedicatio ns/assessmentandtimingo fGender Otherpo pulatio n eligible/ TrialName interventio ns assessment Ethnicity characteristics enro lled S hore Pa tients a llowed to Da ilysym p tom d ia ry 8yea rs Allergyto gra ss extra c t:36% NR/NR/46 1976 c ontinue usua la ntihista m ine results rec ord ed a tc linic 78. Placebo -co ntro lledtrialsinchildrenwithPAR Autho r Year Number Co untry withdrawn/ Metho do fadverseeffects TrialName lo stto fu/analyzedOutco mes assessment S hore 2/0/44 Results rec ord c a rd s ofb ec lom eta sone: Pa tientd a ilysym p tom d ia ry 1976 S uc c ess:38(86%) Fa ilure:6 S torm s 0/0/305 Mea n Cha nges from Ba seline in S ym p tom s S c ores: Pa tientoutc om e,self-rep ort 1991 W eek 6: Na sa lS tuffiness:110m c g:-0. T od d NR/NR/64 Cha nges in sym p tom a tolgyfrom b a seline to 8weeks- Ind irec tq uestionning a t 1983 p -va lue ofd ifferenc e b etween trea tm enta nd p la c eb o: c linic visits S neezing:p =0. Placebo -co ntro lledtrialsinchildrenwithPAR Autho r Year To talwithdrawals; Co untry Adverseeffects withdrawalsdueto adverse TrialName repo rted events Co mments S hore None rep orted 2;0 1976 S torm s Ad verse events rep orted : 0;0 1991 H ea d a c he:T 200:16% vs T 400:18% vs T 800:21% vs p la c eb o:18% Up p erresp ira toryinfec tion:T 200:4% vs T 400:5% vs T 800:7% vs p la c eb o:13% Ep ista xis:T 200:3% vs T 400:3% vs T 800: 4% vs p la c eb o:9% T hroa td isc om fort:T 200:1% T od d Na sa lirrita tion:F:12vs p la c eb o:10 NR;NR 1983 Eyes running:F:3vs p la c eb o:1 Nose b leed :F:1vs p la c eb o:1 Itc h:F:2vs p la c eb o:0 Na usea :F:1vs p la c eb o:0 H ea d a c he:F:2vs p a c eb o:2 S leep y:F:0vs p la c eb o:1 Ra sh:F:0vs p la c eb o:1 NCS Page 298 of 357 Final Report Update 1 Drug Effectiveness Review Project Ev id enc eTable8. Qualityassessm entofplac ebo-c ontrolled trials in c h ild ren with PAR InternalValidity R eporting of attrition, Auth or, Alloc ation Elig ibility Outc om e c rossov ers, Year, R and om ization c onc ealm ent Groups sim ilar c riteria assessors Careprov id er Patient ad h erenc e,and Country ad equate? Qualityassessm entofplac ebo-c ontrolled trials in c h ild ren with PAR ExternalValidity Auth or, Loss to follow- Intention-to- Post- Num bersc reened / Year, up: treat(ITT) rand om ization Quality elig ible/ Country d ifferential/h ig h analysis exc lusions rating enrolled Exc lusion c riteria R un-in/wash out Day No Ye s No Fair NR/NR/107adults Pre gnancy,tube rculosis,re spiratory 2-w e e k base line pe riod 1990 andchildre n infe ction,additional nasal dise ase or w he re patie nts asthm are quiringtre atm e ntw ith re corde dsym ptom s corticoste roids andre ce ive donly te rfe nadine (60m gup to tw o table ts pe rday Fok k ens No Ye s No Fair NR/NR/202 Pollle n alle rgyin se ason,uppe r 1-w e e k base line pe riod 2002 re spiratoryinfe ction w ithin 2w k s in w hiche fficacy be fore scre e ning,rhinitis variable s w e re m e dicam e ntosaorstructural m e asure dtw ice daily abnorm alitie s sym ptom atice e nough to cause significantnasal obstruction, unstable asthm a,im m unothe rapynot on constantm ainte nance dose ,any othe rsignificantdise ase s,syste m ic corticoste roidthe rapyw ithin 2 m onths,e x te nsive application of topical cutane ous ste roids,topical nasal ste roids w ithin one m onth be fore scre e ning,othe rm e dication possiblyinte rfe ring:antihistam ine s w ithin 3days,crom oglycate w ithin 2 w k s,aste m izole w ithin 1m onth be fore scre e ning Hill No Ye s No Fair NR/NR/22 None re porte d No 1978 NCS Page 300 of 357 Final Report Update 1 Drug Effectiveness Review Project Ev id enc eTable8. Qualityassessm entofplac ebo-c ontrolled trials in c h ild ren with PAR Class Control Auth or, naïv e g roup Year, patients stand ard of Country only c are Fund ing R elev anc e Day No N/A One authoris from Ye s 1990 ABDraco,Lund, Sw e de n Fok k ens No N/A Financial support Ye s 2002 from AstraZe ne ca R&D,LundSw e de n Hill No N/A NR Ye s 1978 NCS Page 301 of 357 Final Report Update 1 Drug Effectiveness Review Project Ev id enc eTable8. Qualityassessm entofplac ebo-c ontrolled trials in c h ild ren with PAR InternalValidity R eporting of attrition, Auth or, Alloc ation Elig ibility Outc om e c rossov ers, Year, R and om ization c onc ealm ent Groups sim ilar c riteria assessors Careprov id er Patient ad h erenc e,and Country ad equate? Qualityassessm entofplac ebo-c ontrolled trials in c h ild ren with PAR ExternalValidity Auth or, Loss to follow- Intention-to- Post- Num bersc reened / Year, up: treat(ITT) rand om ization Quality elig ible/ Country d ifferential/h ig h analysis exc lusions rating enrolled Exc lusion c riteria R un-in/wash out Nayak no ye s no fair NR/NR/80 Anyclinicallyre le vantde viation from no 1998 norm al m e dical orlaboratory USA param e te rs,an intole rance to corticoste roidthe rapy,anym e dical condition capable ofalthe ringthe pharm acok intics ofthe drup,acute infe tiors sinusitis,unde rlyingnasal pathologyre sultingin occlusion ofa nostril,visible e vide nce offungal infe ctionn ofthe nose ,throat,or m outh,oran initial m orningplasm a cortisol le ve l outside the range of5to 20m cg/dl. Also patie nts tre ate dw ithsyste m ic corticoste roids w ithin 90d,oral corticoste roids form ore than 10d w ithin the pastye ar,orifthe y participate din anyinve stigational drugstudyw ithin 60doranypre vious studyw ithtriam cinolone aque sous nasal spray. Neum an no notcle ar no poor NR/NR/30 NR no 1978 Israel NCS Page 303 of 357 Final Report Update 1 Drug Effectiveness Review Project Ev id enc eTable8. Qualityassessm entofplac ebo-c ontrolled trials in c h ild ren with PAR Class Control Auth or, naïv e g roup Year, patients stand ard of Country only c are Fund ing R elev anc e Nayak no ye s Supporte din partby ye s 1998 Rhone -Poule ncrore USA Pharace uticals,Inc.

They compared esomeprazole 80 81 82 with omeprazole 750 mg keftab for sale, rabeprazole generic keftab 250 mg otc, or pantoprazole. The 3 studies used different outcome measures, but all found esomeprazole to be similar in efficacy to the compared drug (Evidence Table 3). A fourth head-to-head trial (lansoprazole compared with omeprazole) included patients with erosive and nonerosive gastroesophageal reflux disease but did not separate results by these 83 patient populations. Three identically designed 4-week trials comparing omeprazole 20 mg and esomeprazole 20 mg and 40 mg were conducted simultaneously and were described in 1 80 publication. There was no difference in the resolution of heartburn at 14 days (secondary outcome) or 28 days (primary outcome) between patients taking omeprazole 20 mg or esomeprazole 20 mg or 40 mg. At 2 weeks, proportions of patients with resolution ranged from 35% to 44%, and at 4 weeks ranged from 57% to 70%. Results for adequate control of symptoms were similar, with no significant differences between drugs. A head-to-head trial comparing pantoprazole 20 mg with esomeprazole 20 mg measured 84 time to first and sustained relief of symptoms. This trial was designed to test for noninferiority of pantoprazole compared with esomeprazole. The noninferiority margin was set at –2 days for the primary outcome of time to first symptom relief (that is, a lower boundary of the 95% confidence interval greater than 2 days would indicate noninferiority). Symptom assessment was based on patient report using a validated questionnaire (ReQuest). The questionnaire includes items on the 7 dimensions of gastroesophageal reflux disease symptoms (general well-being, acid complaints, upper abdominal/stomach complaints, lower abdominal/digestive complaints, nausea, sleep disturbances, and other complaints). Results showed that pantoprazole was not inferior to esomeprazole for first and sustained relief of symptoms. A 4-week trial comparing rabeprazole 10 mg with esomeprazole 20 mg was conducted in 81 134 patients in Singapore. The primary outcome was time to first 24-hour period without Proton pump inhibitors Page 35 of 121 Final Report Update 5 Drug Effectiveness Review Project symptoms of heartburn or regurgitation. There was no difference between groups on this endpoint (for heartburn, 8. There was also no significant difference between groups on secondary outcomes, including complete and satisfactory relief of heartburn symptoms at weeks 1 and 4, and symptom severity score in the first 5 days. A good-quality Cochrane systematic review of literature through 2003 addressed the efficacy of proton pump inhibitors, H2 receptor antagonists, and prokinetics in adults with 85 endoscopically verified nonerosive or empirically treated symptoms of reflux disease. This review was not designed to compare the efficacy of different proton pump inhibitors. The primary efficacy outcome of the review was heartburn remission, defined as mild heartburn on no more than 1 day per week. Proton pump inhibitors were superior to placebo for heartburn remission and overall symptom improvement. Proton pump inhibitors also were more effective than H2 receptor antagonists for heartburn remission in empirically treated patients (pooled relative risk 0. However, only 3 trials compared proton pump inhibitors with H2 receptor antagonists in nonerosive gastroesophageal reflux disease. Another systematic review evaluated the efficacy of proton pump inhibitors for resolution 86 of heartburn in patients with nonerosive gastroesophageal reflux disease. This review searched literature through 2002, including the US Food and Drug Administration website. In patients with nonerosive gastroesophageal reflux disease, the risk difference in comparisons with placebo for resolution of heartburn at 4 weeks was 25% (95% CI 18 to 31). The review does not provide evidence about comparative efficacy of different proton pump inhibitors in patients with nonerosive gastroesophageal reflux disease. Table 10 shows rates of heartburn remission rates and complete symptom relief 85 calculated from data provided in the Cochrane review. Similar proportions of patients experienced heartburn resolution or complete symptom relief across the drugs. Proton pump inhibitors Page 36 of 121 Final Report Update 5 Drug Effectiveness Review Project Table 10. Percent patients with resolution of heartburn at 4 weeks from Cochrane 40 review Endoscopically verified nonerosive gastroesophageal Presumptive treatment of reflux disease symptoms Number Number Drug, dose of trials %, range of trials %, range Esomeprazole 20 mg 2 61% to 62% Esomeprazole 40 mg 2 57% to 71% Esomeprazole 40 mg 1 84% Omeprazole 10 mg or 20 mg 1 75% Omeprazole 10 mg or 20 mg 4 56% to 95% Omeprazole 20 mg 5 58% to 84% 4 60% to 70% Omeprazole 40 mg 1 95% Pantoprazole 20 mg 1 81% Pantoprazole 40 mg 1 57% 1 66% Rabeprazole 10 mg or 20 mg 1 98% 87 88 We identified 1 additional placebo-controlled and 1 active-control (ranitidine) trial published since this review (Evidence Table 3). In a fair-quality trial of empiric treatment of patients with symptoms of gastroesophageal reflux disease, more patients taking pantoprazole 20 mg than ranitidine 300 mg were free of gastroesophageal reflux disease symptoms (heartburn, 88 acid eructation, and pain on swallowing) at 4 weeks (68% compared with 43%). In a fair- to poor-quality, 8-week, placebo-controlled trial of patients with endoscopically verified nonerosive gastroesophageal reflux disease whose primary symptom was upper abdominal discomfort, patients taking lansoprazole 15 mg had fewer days with upper abdominal discomfort and reduced 87 severity of average daily pain. Patients whose predominant symptom was heartburn were not included. It is not clear what proportion of patients was analyzed; patients were excluded from analysis for a specific endpoint if there were no data available for that endpoint. Prevention of relapse We identified only 1 head-to-head trial of maintenance treatment in patients with nonerosive 89 gastroesophageal reflux disease.