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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 .

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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).

Consort Diagram

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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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METHODS Drug Presentation

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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METHODS Statistical Analysis

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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METHODS Statistical Analysis

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 .

Thank you very much !

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