PCRS on Subjects with Major Depression​

CenExel is proud to highlight the poster presented at the Annual CNS Summit Meeting,​ November 2018, Boca Raton, FL.​

​ABSTRACT

Introduction: This investigation is the first known that empirically explores if educating subjects about key causes of the placebo effect significantly reduce placebo and nocebo effects. The key causes are Placebo Response Factors (PRFs), which include participant expectations of benefit, poor placebo understanding, misconception of expected interactions with site staff, and subject role uncertainty.

Methods: In this Institutional Review Board approved, US multicenter, single-blind, all placebo investigation, moderate to severe depressed patients aged 18-65 were randomized to the Control Group (CG) or Intervention Group (IG). IG subjects were read the Placebo-Control Reminder Script (PCRS) which reviewed the PRFs before the primary efficacy scale (self-reported Beck Depression Inventory-II) administration. CG subjects were not read the PCRS. Adverse Events were also collected to assess side effects. Subjects were informed of the 50% chance of being assigned placebo or active drug, yet all subjects received placebo. Given this deception, subjects were provided a Debriefing Form at the end of the study revealing the investigation’s true intent and procedures.

Results and Conclusions: This study is currently enrolling subjects with a requirement of 80 completers, powering the study to detect at least a small effect size (d≥.2). Results will be provided to the CNS Summit Poster Program Committee by middle October 2018. Ideally this proposed poster will be accepted regardless of its findings because the final data outcomes have crucial implications for placebo-controlled clinical trials (e.g., complexities of the placebo and nocebo effects would be discussed if the results indicated insignificant IG and CG separation).​

INTRODUCTION

• The high rate of placebo effect, which is approximately 50% within major depressive disorder (MDD) double-blind, randomized, placebo-controlled trials (RCTs) (Khan et al., 2017), has been found to only be increasing over time (Kemp et al., 2010).​
• While various methodological strategies have been implemented or recommended to reduce the placebo effect (e.g., centralized ratings, remote rater monitoring, data surveillance before subject is randomized, subject duration of current illness exacerbation, and different lead-in phase procedures), no subject targeted interventions aimed at reducing the placebo or nocebo effect were found by the authors of this study to have been empirically investigated. ​
• There is general consensus (e.g., Alphs et al., 2012; Weber et al., 2005) about the subject-producing causes of the high placebo rate or what we term Placebo Response Factors (PRFs), including: ​
  • Lack of subject understanding of the placebo​
  • Subject expectations of benefit​
  • Subject misconception of expected interactions with research site staff​
  • Subject uncertainty of his/her role in the trial ​
• While Hassman et al. (2017a, 2017b) found that subjects can enhance their understanding about PRFs compared to study participants who were not educated about the factors, no research could be found that explored if such an understanding reduces the placebo or nocebo effect. ​
• The current study is the first that these authors are aware of that examines whether a Placebo-Control Reminder Script (PCRS; see Figure 1), which reviews the PRFs and read to subjects with major depression, decreases their response to placebo and reporting of side effects (i.e., lessens the nocebo effect). 

METHODS

• This study implemented a US multicenter (one site in the East and the other in the West Coast), randomized, single-blind, all placebo design aimed to mirror the methodologies typically used in MDD clinical trials, such as implementing conventional inclusion and exclusion criteria, multiple study visits, and evaluation of Adverse Events (AEs) and Serious Adverse Events (SAEs).​
• Also similar to other MDD trials, subjects were informed via the Informed Consent Form they have a 50 percent chance of receiving active medication or a placebo. However, as part of the methodology of the current study, all participants received placebo. ​
• Deception was necessary to assess for the placebo and nocebo effects and all subjects received a Debriefing Form at the end of their participation which revealed the true intent and procedures of the study.​
• The placebo was used as the Investigational Product (IP) because it allowed for specific measurement of the PCRS (the independent variable) to either decrease depression symptoms (the dependent variable) which would entail a placebo effect occurred, or help control for the placebo effect.​
• The Beck Depression Inventory-II (BDI-II; Beck et al., 1996) was used as the primary efficacy scale to assess depressive symptoms. Using this self-report scale was necessary given the single-blind design of the current study. ​
• Subjects digested the IP (total two white capsules at the Screening Visit and Visit 2) at their respective research site rather than at home each day of the week in order to ensure compliance and illuminate the risk that many clinical trials experience regarding study drug adherence at home (Shiovitz et al., 2016). To help rectify (equalize) the expectation by subjects of taking medication at home each day and further mirror clinical trial procedures, subjects were informed the two active medication capsules were developed to be sufficient to treat their depressive symptoms.​

RESULTS

• There were 25 subjects within each of the Intervention and Control Groups (N = 50) and a Friedman rank sum test indicated no statistical differences by age/gender between these groups. ​
• After testing for normality, a repeated measures one-way analysis of variance (ANOVA) was calculated (see Table 1), indicating there was a significant difference, F(2, 41) = 700, p < .001, between the Intervention Group and the Controls, such that the Intervention Group subjects were significantly better able to identify the factors (i.e., their role) associated with reducing a placebo response after watching the video as compared to the Control Group participants.​
• Figure 2 illustrates the ANOVA based statistically significant mean differences between the Pre-Test and Post-Test Intervention and Control Group subjects (respectively [with Standard Deviations], 32.04 [4.14], 88.64 [8.96], 31.76 [3.49], 30.80 [2.18]).​
• A Wilcoxon signed rank test indicated significant differences between the Pre-Test and Post-Test Intervention Group (V=325, p<.001), suggesting again that the video intervention helped subjects learn the appropriate placebo response factors, whereas the Control Group subjects showed no statistical difference between their Pre-Test and Post-Test (V=77.50, p=.101).​
• After a Friedman rank sum test was conducted, ꭕ2(3) = 49.62, p < .001 (indicating the differences in the median values of the Intervention and Control Group Pre- and Post-Tests were statistically significant), a pairwise comparison was examined between each variable level to further explore the potential impact of having subjects watch the placebo response video. Figure 3 shows the significant differences between the pairwise comparisons, indicating that subjects learned more about the four placebo response factors as a result of the intervention (i.e., watching the video).​

CONCLUSIONS

• Theories abound regarding the ways in which subjects contribute to the placebo effect – notably the commonly cited factors of: their interactions with site staff, expectations of benefit, lack of subject understanding of the placebo, and subject uncertainty of his/her role in the trial.​
• To our knowledge, the current study is the only one which empirically examines how subjects initially are naïve about the above key subject-centered placebo contributing factors and how they may best be educated to enhance their awareness about these factors.​
• The results of the study indicated that subjects were less than clear about the factors which are commonly cited as contributing to the placebo effect in clinical trials and that a brief (7-minute) psychoeducational video focused on these factors significantly increased subjects’ understanding of these crucial issues. ​
• Given that the placebo response factors are centered around subject expectations during a clinical trial, the current results add to the literature concerning the role in which expectations have in generating a placebo effect. For example, Lidtsone et al.’s (2010) seminal publication found that the strength of PD subject expectations for improvement (even though all subjects were blindly given a placebo) predicted increased dopamine release (i.e., reward circuitry) in the ventral striatum and subjects also reported feeling better. The current study results indicate that indeed subject expectations can be managed/harnessed through a brief video regarding the placebo effect in clinical trials. ​
• The limitations of the current investigation include: (a) the study does not address whether subjects’ increased knowledge about the placebo effect key factors translates to greater drug-placebo separation; (b) It is unknown if subjects remember the placebo response key factors throughout their participation in trials (although some sites have begun to read a script explaining these factors to each study subject per study visit which should extend their understanding throughout the trial); and (c) it is unknown if subjects in this current study who were participating in different indication clinical trials (e.g., CNS vs Medical) were more likely to learn the key factors. Future studies should address these matters.​
• The results of the study are even more vital considering that subjects came to the clinic agreeing to participate specifically for a placebo-controlled clinical trial (e.g., many subjects were prescreened over the phone by an experienced clinician and were carefully informed about the details of a placebo-controlled trial). Given that many patients come into research sites with this understanding, it is RECOMMENDED that research sites or sponsors implement a video or similar method (e.g., script read to subjects by raters) to ensure subjects at the outset of their participation clearly understand their role and the explicit expectations of participating in a placebo-controlled study which are intended to reduce their potential biased symptom reporting.​

​Elan A. Cohen, Ph.D.¹, Howard A. Hassman, DO¹, David P. Walling, Ph.D.² , Steven Hoover, Ph.D.², Katarzyna Wyka, Ph.D.³ , Roberta R. Ball, DO¹, Ashok V. Joseph, MD¹, Jaclyn M. Lobb, MS,¹ Dakota Hazzard-Randolph, MS¹, and Larry Ereshefsky, Pharm.D., BCPP^1,2,4

¹CenExel Hassman Research Institute ²CenExel Collaborative Neuroscience Network ³The City University of New York, Graduate School of Public Health and Health Policy ⁴Retired Professor, The University of Texas