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David Lopes Neto Federal  University   of  Amazonas Manaus-Amazonas- Brazil

Principles and Practice of
ppcp, Clinical Research

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Randomized   Trial   of   the   Effect   of   Drug   Presentation   on   Asthma   Outcomes  The American  Lung   Association   Asthma   Clinical   Research  Centers  INTRODUCTION

Information   that   enhances   expectations   about   drug   effectiveness  improves  the  response  to  placebos for  pain .  Although   asthma   often  improves  with  placebo, it  is   not   known   whether   the  response  to  placebo  or   active   treatment   can   be   augmented   by   increasing   expectation   of   benefit .  OBJECTIVE: To   assess   the   effect   of   manipulating   expectations   regarding   drug   efficacy   on   physiological   and   patient-reported  responses  to   an   active   drug  ( montelukast )  or  placebo. HYPOTHESIS: The  effects   of   increased   expectation   would   be   different  in  an   active   treatment   group   compared   to  a placebo  group   and   that   physiological   outcome   measures   would   be   less   susceptible   to   the   effects   of   expectation   than   subjective   measures .

Princi les and Practice of
ppcR Clin{cal Research

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STUDY DESIGN: 2 × 2  factorial   study   with   an   additional   group  for a total  of  5  groups . THE TWO MAIN FACTORS:  Study   drug  ( montelukast  versus placebo)  and   treatment   presentation  (neutral versus  increased   expectation ); Additional   group :  usual  care . SAMPLING: Participants   at   each  center  were   randomly   assigned   with   equal   odds   of   allocation   to   one   of   the  5  treatments  (Figure 1).

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Randomization : It  was   stratified   by   clinical  center  and   used  a  permuted   block  design  with   variable   block   sizes . The  factorial  design  allowed   us   to   evaluate   the   effect   of   the   treatment   presentation   on   the  placebo response, as  well  as  on   the  response  to   montelukast . After  a 2-week  run -in  period  for  baseline  data  collection ,  participants   took   the   study   drug  for 4  weeks .

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STUDY VISITS: Occurred   every  2  weeks .  A  concurrent   group   of   asthmatics   treated   with  usual  care   who   were   randomized   to   receive  no  study   treatment   was   studied   to  determine  whether  placebo capsules  had   an   effect   beyond   enrollment  in a  research   study .

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STUDY LOCATION: 20 centers  from   the  American  Lung   Association   Asthma   Clinical   Research  Centers  (ALA-ACRC)  conducted   the   study   from   December  2003  to   December  2005 . The ALA-ACRC  Coordination  Center  collected   and   analyzed   the  data. ETHICAL ASPECTS: The  trial   was   sponsored   by   the  American  Lung   Association   and  NIH.  All  centers  obtained   and   maintained  IRB  approval   throughout   the   study .  The  study   was   registered   at   ClinicalTrials.gov , NCT00148408  under   the   acronym   Trial   of   Asthma   Patient   Education  (TAPE).

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PARTICIPANTS:  Eligible   participants   had   inadequately   controlled   asthma . Inclusion   criteria : Non- smokers   aged  15  or  over, History   of   physician-diagnosed   asthma   with  regular use  of   asthma   medication  in  the   previous   year , Postbronchodilator  FEV1 ≥ 75%  predicted  22  and   one   or  more  indicators   of   poor   asthma   control  [ Asthma   Control   Questionnaire  (ACQ) 23 ≥ 1.5, use  of  beta- agonists  for  asthma   symptoms  ≥ 2 times a  week ,  or   awakening   nightly  ≥  once  /  week ]. Participants   taking   or   having   an   intolerance   to   montelukast   or   participants   with   other   serious   health   problems   were   excluded . Participants   signed   an   informed   consent   approved   by   the  IRB. No  mistakes   were   employed  in  conducting   the   trial . The  informed   consent   document   stated , “The  purpose   of   this   research   study   is   to   investigate   how   educational  approaches  and   drug   presentation   can   affect   the  response  to   montelukast   and  placebo ( an   inactive   drug ) in  individuals   with   asthma . You  are  being   invited   to   participate  in  this   research   study   because   you   have   asthma   that  causes  symptoms   with   your   current   treatment .

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DRUG TREATMENT The  active   treatment   was   montelukast  10 mg  orally   ( Singulair ®, Merck &  Co .  Whitehouse   Station , N.J.).  Tablets   were  over- encapsulated   to   be   indistinguishable   from  placebo .  All   drugs   supplies   were   purchased   by   the  ALA-ACRC.  Participants   and   research  staff  were   masked   to   drug   treatment   assignment .  Participants   assigned   to  usual  care   did   not   receive   study   drug   and   their   assignment   was   unmasked .

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The  presentation   of   treatments   to   the   participants   was   made   with   enhanced   messages   to   increase   the   expected   benefit   or   with  neutral  messages   about   the   benefit   of   the   treatment . Participants   assigned   to  usual  care   did   not   receive   an   introduction ;  they   received   an  NIH  booklet   on   asthma   control . 24  Presentation   occurred   soon   after   randomization   and   after   two   weeks .  Clinical  center staff  were   not   masked  for  the   presentation   assignment . The  drug   presentation   had  3  components : a  scripted   message , a  computer   presentation   and   the   appearance   of   the  capsules. The  research   coordinator   gave  a  scripted   description   of   the   treatment . The  enhanced   expectation  script  emphasized   the   benefits   of   treatment   and   the   likelihood   of   improvement  in  asthma   symptoms ;  the  neutral  presentation   expressed   uncertainty   about   the   improvement .

Participants   watched   an   interactive   computer-based   educational   presentation   at   randomization   and   after  2  weeks . The  computer   presentations   provided   education   on   basic   asthma  self- care ,  including   information   on   asthma   pathophysiology , self- monitoring , trigger  prevention ,  peak   flow   monitoring ,  and   an   asthma   action   plan  for  both   groups . The  program   consisted   of  16  to  21  screens , some  with   interactive   and   animated   features ,  and  a  narration . The  interactive   presentations   took   about  10  to  20 minutes  to   be   seen   at   the   participants '  own   pace . Each   message   group   saw  2  presentations . The  first   was   viewed   at   the   randomization   visit   after   baseline  data  collection ;  the   second   presentation   expanded   and   reinforced   the   first   presentation   and   was   seen   at   the   week  2  visit   after   the   end   of  data  collection .

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VISIT SCHEDULE Each   participant   had  four  visits   scheduled  over  six   weeks .  The  first   visit   was  for  enrollment ,  and   the   second   was  for  the   collection   of   baseline  data,  randomization   of   eligible   participants ,  distribution   of   drugs ,  and   the   first   educational   session .  Participants   were   assigned   randomly   to  a  study   group   at   the  time  of   the   second   visit ,  with  prior  concealment   of   treatment   assignment  via  an  online  randomization  system.  At  the   third   visit , 2  weeks   after   randomization ,  there   was   an   additional   educational   session   and   collection   of  interim data;  the   fourth   visit , 4  weeks   after   randomization ,  was  for data  collection   and   return   of   unused   drugs .  Participants   were   instructed   to   record   morning   peak   flow ,  asthma   medication  use,  urgent   care  for  asthma ,  and   asthma   symptoms   on   diary   cards   each   day ;  one   diary   card   was   used  per  week .

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OUTCOME MEASURES  The  primary   outcome   measure   was   change  in  morning   peak-expiratory-flow  (PEF)  from   baseline .  Other   measures   included   spirometry ,  the   Asthma   Control   Questionnaire  (ACQ),23  the   Asthma   Quality   of  Life Questionnaire ,26  and   the   Asthma   Symptom   Utility  Index  (ASUI), 27  and   the   Knowledge ,  Attitude ,  and  Self- Efficacy   Asthma   Questionnaire   KASE-AQ.28  Participants   also   completed  a  questionnaire   on   their   perceptions   of   asthma   treatment   that   included  four  Likert-scale   questions   about   the   efficacy   of   montelukast  in  treating   asthma .

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The  planned   enrollment   of  120  participants  per  group   had  98%  power   to   detect  a  difference   of  30 L/min  between   the  neutral versus  enhanced   presentation   with  a  two-sided   type   I   error   of  0.025.  The  power   to   detect  a similar  difference   between   the   effect   of   presentation   on  placebo  and   the   effect   of   presentation   on   active   drug  (i.e.  an   interaction   effect   between   factorial   components )  was   estimated   by  Monte Carlo  simulation   to   be  0.83,  but   was   highly   sensitive   to   the   assumptions   regarding   the   effect   of   presentation   on   the  placebo  group .  Because   montelukast   is   known   to   be  superior  to  placebo, 30  comparison   of   montelukast   to  placebo  was   not   an   aim   of   the   trial .  Power for  the   comparison   of  usual  care  versus neutral placebo  was  76%  with  a  two -  sided   type   I   error  rate  of  0.025.

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Continuous   outcomes   measures   were   analyzed  as  change   from   baseline   values   assessed   during   the   initial   two-week   run -in  period .  Categorical   event   type   outcomes   were   evaluated  as  the   percent   of   participants   experiencing   the   event .  Statistical   analysis   of   the   outcomes   was   performed   based   on   treatment   assignment  ( intention-to-treat )  using  a linear  regression   or   logistic   model   with   robust   estimates   of   variance  (GEE)  and   adjusted  for  visit  (2  or  4  weeks  post  randomization )  and   clinic . Post hoc sub  group   analyses   were   performed  for  groups   based   on   lung   function  ( bronchodilator  response  and   percent   predicted  FEV1)  and  ACQ score  at   baseline .  Analyses   were   performed   with  SAS V8

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The  trial   enrolled   participants   between   December  2003  and   December  2005.  A total  of  601  participants   were   randomized   to   the   five   study   groups   arms   at  20  academic   clinical  centers;  clinics   enrolled   from  11  to  56  patients   with  a  median   of  27.  Participants   were   recruited   from   the   clinic   patient   populations   and  local  advertisements ;  There   was   heterogenity   among  sites for  several   baseline   characteristics .  Of   the  601  enrolled   participants , 480  were   randomly   assigned   to   the   factorial   component   of   the   trial :  treatment   with  placebo  or   montelukast   and   enhanced   or  standard  messages   about   treatment   and  121  were   assigned   to  usual  care . Most   participants   were   females ,  and   about   one-third   African-Americans .  Overall,  the   characteristics   of   the   population   were   balanced   among   the   groups   with   the   exception   that  more  women   were  in  the   montelukast-enhanced   presentation   group .  By  design,  participants   had   poor   asthma   control  as  shown   by   an   elevated  ACQ score34  frequent  use  of  beta- agonists   to   control   asthma   symptoms ,  or   frequent   nocturnal   awakenings   due   to   asthma .  The  mean   pre-bronchodilator  FEV1  was   at   the   lower  range  of  normal; 27%  of   participants   demonstrated   bronchodilator   reversibility   of  12%  or   greater   and  33%  had  a  pre-bronchodilator  FEV1.that  was  80%  or   less   of   predicted   at   baseline ..

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-  This   study   showed   that   messages   enhancing   the   expectation   of   benefit   from  a  drug  for  asthma  do  not   affect   lung   function   but   can   augment   the  placebo  effect   on   asthma   symptoms .  Because   we   could   not   induce  a  change  in response  to   montelukast   treatment   with   increased   expectancy ,  such   messages   could   mask   the   demonstration   of   benefit  in  any   clinical   trial   of   an   effective   treatment .  Although  it  is   unlikely   that   investigators   would   present  a  message  as  optimistic  as  we   did  in  this   trial , more  subtle   messages   may   be   delivered   by   researchers ,  consumer   advertising , internet  or   news  media.  The  results  show  that   the   way   that  a placebo  is   administered  for  asthma ,  and   messages   enhancing   expectation   of   effectiveness ,  can   influence   the   symptomatic  response  of   patients   despite  a  lack   of   efficacy  for  lung   function .

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Optimistic   drug   presentation   augments   the  placebo  effect  for  patient-reported   outcomes  ( asthma   control ),  but   not   lung   function .  However ,  the   effect   of   montelukast   was   not   enhanced   by   optimistic   messages   regarding   treatment   effectiveness .

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