Randomized trial of the effect of drug presentation on asthma outcomes: The American Lung Association Asthma Clinical Research Centers

Division of Pulmonary and Critical Care Medicine, Department of Medicine, the Johns Hopkins University School of Medicine, Baltimore, Md 21224, USA.
The Journal of allergy and clinical immunology (Impact Factor: 11.48). 08/2009; 124(3):436-44, 444e1-8. DOI: 10.1016/j.jaci.2009.05.041
Source: PubMed


Information that enhances expectations about drug effectiveness improves the response to placebos for pain. Although asthma symptoms often improve with placebo, it is not known whether the response to placebo or active treatment can be augmented by increasing expectation of benefit.
The study objective was to determine whether response to placebo or a leukotriene antagonist (montelukast) can be augmented by messages that increase expectation of benefit.
A randomized 20-center controlled trial enrolled 601 asthmatic patients with poor symptom control who were assigned to one of 5 study groups. Participants were randomly assigned to one of 4 treatment groups in a factorial design (ie, placebo with enhanced messages, placebo with neutral messages, montelukast with enhanced messages, or montelukast with neutral messages) or to usual care. Assignment to study drug was double masked, assignment to message content was single masked, and usual care was not masked. The enhanced message aimed to increase expectation of benefit from the drug. The primary outcome was mean change in daily peak flow over 4 weeks. Secondary outcomes included lung function and asthma symptom control.
Peak flow and other lung function measures were not improved in participants assigned to the enhanced message groups versus the neutral messages groups for either montelukast or placebo; no differences were noted between the neutral placebo and usual care groups. Placebo-treated participants had improved asthma control with the enhanced message but not montelukast-treated participants; the neutral placebo group did have improved asthma control compared with the usual care group after adjusting for baseline difference. Headaches were more common in participants provided messages that mentioned headache as a montelukast side effect.
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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    • "Several studies have given first hints that framing information may be an effective approach to improve patient outcomes (O'Connor, Pennie, & Dales, 1996; Wise et al., 2009). However, experimental research on the effects of informed consent procedures on patient outcome is lacking. "
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    ABSTRACT: Objective: Informing patients about medical treatments and their possible side effects is ethically and legally obligatory but may trigger negative expectations and nocebo-related side effects. This pilot study aims to investigate the effect of different informed consent procedures on treatment expectations for adjuvant breast cancer treatments (Study 1: endocrine therapy; Study 2: chemotherapy). Method: Using an experimental 2-factorial design, healthy women were informed about endocrine therapy (n = 60) or chemotherapy (n = 64) within a hypothetical scenario. Information was framed with or without treatment benefit information and delivered in a personalized or standardized interaction. Primary outcomes were necessity-concern beliefs about the treatment and side-effect expectations, secondary outcomes were decisional conflicts. Results: In Study 1, side-effect expectations (ηp2 = .08) and decisional conflicts (ηp2 = .07) were lower when framed treatment information was given. Providing personalized information resulted in more functional necessity-concern beliefs (ηp2 = .06) and lower decisional conflicts (ηp2 = .07). Personalizing and framing of information resulted in more functional necessity-concern beliefs (ηp2 = .10) and lower decisional conflicts. In Study 2, necessity-concern beliefs were more functional with framing (ηp2 = .06). Participants in the personalized groups reported lower decisional conflicts (ηp2 = .06). No differences in side-effect expectations were revealed. Conclusions: This is the first study to provide evidence for optimized treatment expectations through altered informed consent strategies. The results emphasize that framing and personalizing informed consent can positively influence treatment expectations and reduce decisional conflicts. However, generalizations are impaired by the study's pilot character. The potential to prevent nocebo responses in clinical practice should be analyzed.
    Health Psychology 02/2015; DOI:10.1037/hea0000217 · 3.59 Impact Factor
    • "Physiologically this could occur if there is an overlap in some component of the pain reduction pathways for the mind– body effect and the specific effect of the active medication. In this subadditive state [1] [13] [26] [27], the overall group response and ratio of placebo to active medication group responses can change based on the degree of overlap (Fig. 4b). If there is also a maximal total benefit possible from the active medication treatment, the differences between groups would be as diagrammed in Fig. 4c. "
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    ABSTRACT: The degree of variability in the patient baseline 7-day diary of pain ratings has been hypothesized to have a potential effect on the assay sensitivity of randomized clinical trials of pain therapies. To address this question, we obtained clinical trial data from the Food and Drug Administration (FDA) through the Analgesic, Anesthetic, and Addiction Clinical Trial Translations, Innovations, Opportunities, and Networks (ACTTION) public-private partnership, and harmonized patient level data from 12 clinical trials (4 gabapentin and 8 pregabalin) in postherpetic neuralgia (PHN) and painful diabetic peripheral neuropathy (DPN). Models were developed using exploratory logistic regression to examine the interaction between available baseline factors and treatment (placebo vs. active-medication) in predicting patient response to therapy (i.e., >30% improvement). Our analysis demonstrated an increased likelihood of response in the placebo-treated group for patients with a higher standard deviation in the baseline 7-day diary without affecting the likelihood of a response in the active-medication treated group, confirming our hypothesis. In addition, there was a small but significant age-by-treatment interaction in the PHN model, and small weight-by-treatment interaction in the DPN model. The patient's sex, baseline pain level, and the study protocol only had an effect on the likelihood of response overall. Our results suggest the possibility that at least in some disease processes excluding patients with a highly variable baseline 7-day diary has the potential to improve the assay sensitivity of these analgesic clinical trials, although reductions of external validity must be considered when increasing the homogeneity of the investigated sample.
    Pain 05/2014; 155(8). DOI:10.1016/j.pain.2014.05.009 · 5.21 Impact Factor
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    • "The use of a placebo inhaler for asthma symptoms resulted in subjective improvement, similar to the active drug [23]. In agreement with our findings, asthma treatment with enhanced expectations seems more powerful for placebo groups [24]. "
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    ABSTRACT: Studies suggest that expectations powerfully shape clinical outcomes. For subjective outcomes in adequately blinded trials, health improvements are substantial and largely explained by non-specific factors.The objective of this study was to investigate if unblinding in randomized controlled trials (RCTs) is associated with enhanced placebo effects for intervention groups and nocebo effects for placebo groups. For these effects, a secondary objective was to explore potential moderating factors. We included RCTs that investigated the efficacy of phosphodiesterase-5 (PDE-5) inhibitors for male erectile dysfunction by comparing one PDE-5 inhibitor to placebo. In addition, to be included studies must have reported scores for change from baseline, or baseline and final International Index of Erectile Functioning-Erectile Functioning domain score (IIEF-EF), and be published in either English, French, Dutch, or German.We searched for both published and unpublished relevant trials using PUBMED, EMBASE, the Cochrane Central Register of Controlled Trials, a clinical trials register ( and the Food and Drug Administration clinical reviews through March 2012.We evaluated the blinding status of trials with the Cochrane Risk of Bias Tool, using the domains of allocation sequence concealment, blinding of participants, healthcare providers and outcome assessors. Across these four domains, studies that scored low risk of bias were judged to be adequately blinded and studies that scored unclear or high risk of bias were judged to be inadequately blinded. We included 110 studies (205 journal publications and 2 unpublished sources) that involved 23,877 participants; 93 (85%), 51 (46%), 93 (85%) and 93 (85%) studies were assessed with an unclear risk of bias for allocation concealment, blinding of participant, blinding of caregiver and blinding of outcome assessor, respectively. None of the studies reported testing of blinding.None of the 205 journal publications provided sufficient details to assess allocation concealment, blinding of participants, caregivers and outcome assessors. After contacting authors for additional information, we judged five studies to be adequately (n = 1,202) and 16 to be inadequately (n = 3,006) blinded. The IIEF-EF score for placebo groups in adequately blinded trials versus inadequately blinded trials was 1.92 points (95% CI, 0.64 to 3.20) versus 1.56 (95% CI, 0.93 to 2.20), respectively. The IIEF-EF score for intervention groups in adequately blinded trials versus inadequately blinded trials was 9.40 (95% CI, 6.96 to 11.83) versus 8.33 (95% CI, 7.29 to 9.37), respectively. In a secondary analysis, prior experience with the drug affected the scores; in placebo groups with participants naive to the intervention the score was 2.89 (95% CI, 2.33 to 3.45) versus -0.11 (95% CI, -2.06 to 1.84) with participants having prior experience. In the intervention groups, these scores were 7.99 (95% CI, 6.85 to 9.14) versus 8.33 (95% CI, 7.51 to 9.16), respectively.Unblinding lowered placebo scores (creating a nocebo effect) by 19% (0.33 points; 95% CI, -0.96 to 1.62). Unblinding lowered intervention scores by 11% (1.0; 95% CI, -1.35 to 3.47). The results provided no conclusive evidence for nocebo or enhanced placebo effects. Patients taking a PDE-5 inhibitor for the first time experience a larger placebo effect that accounts for 35% of the total effect. Given the overall poor reporting of blinding in clinical trial reports and the small number of trials that could be rated as adequately or inadequately blinded, we could not draw any robust conclusions about the existence or absence of nocebo and enhanced placebo effects. A large placebo effect was found for patients taking PDE-5 inhibitors for the first time. It was not clear if previous exposure to the drug impacted trial blinding.We found clear evidence that studies assessing a subjective continuous outcome fail to report on measures taken to secure double blinding. Although we observed a trend for the presence of a nocebo effect, there was insufficient evidence to quantify its impact on expectations. RCTs with patients with no prior experience with PDE-5 inhibitors reported larger placebo effects and possibly these studies were better blinded. Future research should further investigate the factors that contribute to blinding and their impact on health outcomes in randomized trials of subjectively assessed conditions. This research is part of a PhD project and has no external funding. The authors have no competing interests to declare (
    Systematic Reviews 02/2014; 3(1):14. DOI:10.1186/2046-4053-3-14
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