PCRS on Schizophrenia and Schizoaffective Disorders

CenExel is proud to highlight the poster presented at the annual CNS Summit, November 2019, in Boca Raton FL.

ABSTRACT

Introduction: The Placebo-Control Reminder Script (PCRS) was first reported at CNS Summit 2018 as being empirically validated to significantly manage the placebo effect among depressed subjects. The current investigation replicated that methodology to determine if the PCRS has a similar impact on subjects with Schizophrenia/Schizoaffective Disorder.

Method: Schizophrenia/Schizoaffective depressed adult patients from multiple sites were randomized to two groups. The Intervention Group (IG) subjects were read the PCRS before completing the Beck Depression Inventory-II (BDI-II). The script reviews key causes of the placebo effect, Including participant expectations. Control Group (CG) subjects were not read the PCRS. Depression, and not psychosis, was the dependent variable due to scale psychometrics and assessment duration. Adverse Events were collected to assess nocebo effect. Subjects were informed of the 50% chance being assigned placebo or active drug, yet all 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: IG and CG subjects did not differ in baseline characteristics, including BDI-II scores. IG subjects reported significantly (p=0.002) higher BDI-II scores at the primary endpoint (IG M=22.000, SD=5.17 vs. CG M=17.17, SD=5.63). Four subjects (8.7%) reported adverse events, all were in the CG group (p=.05).

Conclusion: While more subjects need to be enrolled in the current investigation to confirm these findings, preliminary data suggest the PCRS continues to reduce the placebo and the nocebo effects among subjects with psychotic disorders. Future investigation recommendations will be discussed.

INTRODUCTION

• As the magnitude of the placebo effect persists within psychosis clinical trials (Chen et al., 2010; Kemp et al., 2010), implementing strategies to manage this effect should similarly persist. Various methodological approaches 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 procedure); however, the authors of this poster know of only one subject-targeted intervention, the Placebo-Control Reminder Script (PCRS), which has been empirically validated to reduce this phenomenon (Cohen et al., 2018). The paucity of scientifically substantiated participant-focused procedures is surprising given the obvious, direct role study subjects have in producing the placebo effect.
• It was at CNS Summit 2018 where Cohen and his colleagues reported that the PCRS was found to significantly control for the placebo effect among subjects experiencing a major depressive episode (MDE), as compared to subjects who were not administered this intervention. The PCRS is an easy to administer tool (a script) which is read to all subjects at all study visits reminding, and subsequently educating, study participants about the commonly cited subject-producing causes of the high placebo rate within our clinical trial industry (e.g., Alphs et al., 2012; Weber et al., 2005) or what we term Placebo Response Factors (PRFs):
  • 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
• The current investigation replicated the Cohen et al. methodology to explore if the PCRS had a similar impact in managing the placebo effect on subjects with Schizophrenia and Schizoaffective Disorder. It also assessed if the PCRS might help reduce the nocebo effect. This is crucial for the industry as approximately 25% of clinical trial subjects, including those in Phase I studies, experience a nocebo effect which leads to subject early withdrawal and perhaps unnecessarily halting a compound’s research program (Barsky et al., 2002; Cohen, 2012; Faase & Petrie, 2013; Preston et al., 2000; Webster et al., 2017; Wells, 2012). The present study is currently enrolling subjects, but has enough participants to communicate preliminary valid and reliable results at a provisional perspective.

METHODS

• This IRB approved 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 psychosis indication clinical trials, such as implementing conventional inclusion and exclusion criteria (see Inclusion and Exclusion Table), multiple study visits, and the evaluation of Adverse Events (AEs) and Serious Adverse Events (SAEs).
• Also similar to other trials, subjects were informed via the Informed Consent Form that they have a 50% chance of receiving active medication or a placebo. However, as part of the purposeful 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 the study to measure the extent to which the PCRS (the independent variable; see Figure 1) could maintain depressive symptoms (the dependent variable). If there was a decrease in depression, this would indicate a placebo effect occurred, whereas the relative maintenance of depressive sxs would demonstrate that the PCRS helped control for the placebo effect. The PCRS takes about 2 minutes to read and answer subject questions.
• 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. Depression, as opposed to psychotic symptoms, was selected as the dependent variable because only two widely used self-reported scales assess psychosis (the Brief Symptom Inventory and Symptom Checklist 90 Revised), but only do so validly and reliably by evaluating other general mental health factors (e.g., hostility, obsessive-compulsiveness, phobic anxiety, and somatization) not relevant to the purposes of the current study with the potential to confound our primary study objectives. Moreover, using either of the scales would add significant duration and possible frustration on behalf of the subjects when completing the primary efficacy scale.
• Subjects digested the IP (total two white blinded placebo capsules at the Screening Visit and Visit 2) at the site rather than at home each day of the week in order to 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, subjects were informed the two active medication capsules were developed to sufficiently treat depressive symptoms.

RESULTS

• Forty-six completed subjects were included in the analysis, with 23 participants each randomly assigned to the IG and CG. Table 1 lists the subjects’ demographics by group.
• The IG and CG subjects did not differ in any of the baseline characteristics, including BDI-II scores (IG M= 24.09, SD=2.39 vs. CG M= 24.48, SD=3.36, p=.651) and diagnosis of either Schizophrenia or Schizoaffective Disorder (all p>.05) – see Table 1 .
• The above results were consistent across the two research site locations as well as the Schizophrenia and Schizoaffective Disorders.
• As hypothesized:
  1. Figure 3: illustrates the results from a repeated measures two-way analysis of variance (ANOVA) whereby there was a significant time by group interaction (p=0.002) of the IG subjects showing significantly higher BDI-II scores at Visit 3 compared to CG participants (IG M=22.00, SD= 5.17 vs. CG M=17.17, SD=5.63). This mean decrease of approximately 5-points may be statistically meaningful for randomized placebo-controlled studies because achieving signal detection from placebo can be a matter of only a few point differences (such as exactly 5) in the primary efficacy scale (Mallinckrodt et al., 2010; Mancini et al., 2014).
  2. Figure 4: A Mann-Whitney analysis indicated 4 subjects (8.7%) reported adverse events, all were in the CG group (p=.054). No group reported an SAE.
  3. Figure 5: A Chi-Squared test revealed that perceived improvement in sadness/depression was significantly more common in CG subjects (IG 17.4% vs. CG 52.2%, p=.013) and the opposite among the IG.
• Figure 6: A Chi-Squared test indicated no difference in belief about receiving real medication (IG 30.4% vs. CG 47.8%, p= .227), but data trended toward the hypothesis and perhaps the greater sample size will yield the expected results.
• The above results were consistent across the two research site locations as well as the Schizophrenia and Schizoaffective Disorders.

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CONCLUSIONS

PLACEBO EFFECT:

• The results of the current investigation indicate that subjects with a primary psychotic disorder experiencing a MDE had significantly less improvement in depressive symptoms after receiving an inert substance if they were read the PCRS as compared to subjects being given the same inert substance but who were not administered the PCRS. While it appears the PCRS profoundly helped control for the placebo effect, the authors are not commercializing its use. Rather, we assert the script’s impact stems from its content and methodological administration.
• Also as expected, subjects who received education about the PRFs (i.e., were read the PCRS) were significantly more likely to selfreport (perceive) either staying the same regarding their depressive symptoms or that their symptoms worsened, as opposed to subjects who were not educated about these factors. These data findings are not surprising given that the subjects who were not read the PCRS had a significantly higher placebo response – i.e., they reported less depressive symptoms (improving) after receiving the inert substance at each study visit.
• The accumulation of the above study findings, as well as those from Cohen et al.’s (2019) investigation of the PCRS among subjects experiencing a MDE, illustrates a positive trend toward suggesting that the placebo effect may be optimally managed when study subjects are systemically informed / reminded throughout their participation of the PRFs. The current study results become even more applicable to psychosis clinical trials considering that the PCRS is quite manageable to implement within the methodology of such clinical trials – it has a short administration time (approximately 2-3 minutes total), is easy to understand for subjects of various racial, educational, and diagnostic background, and is streamlined procedurally. Moreover, the PCRS findings indicate that the effect size of studies using this tool may be enhanced given the PCRS’ potential to decrease variability and placebo as well as nocebo responses.
• Indeed the PCRS has been seamlessly implemented in placebo-controlled clinical trials and with positive results. Noven Pharmaceuticals conducted a Phase 3, 6-week acute inpatient Schizophrenia trial which showed statistically significant separation of their HP-3070 (Asenapine patch) from placebo, resulting in FDA approval. Noven fortunately shared the unblinded data post study completion with Hassman Research Institute (HRI), which administered the PCRS to their participant cohort. HRI was the highest US study enroller and 4th highest globally. While HRI’s data could not be analyzed for significance given the low n, the site’s 15.3 average point difference (see Figure 7) between HP-3070 and placebo at week six suggests that the PCRS may be a contributing factor to the site’s data and that the active medication group was not negatively impacted by the PCRS (see below Study Limitations Section). To confirm this in placebocontrolled trials, it would be ideal for future studies to include a PCRS and non-PCRS group or have an accumulation of such trials using the PCRS or similar script with showing significant separation between the study compound and placebo.
• The current data indicated there was no significant differences between those subjects who were read the PCRS or not read the PCRS regarding their belief of what type of medication (active as opposed to placebo) they received. This was surprising given that the results showed that the IG subjects remained more depressed and, moreover, believed their depressive symptoms either stayed the same or worsened – so why would these subjects also not report suspecting that they were randomized to placebo? It would be difficult to presume that the IG subjects were not aware of what a placebo is since the PCRS diligently explains this and these participants remained depressed. This study did not evaluate the reasons subjects had for believing which drug they were randomly assigned, and perhaps future studies assessing this subjective data may derive a rationale for this finding.

NOCEBO EFFECT:

• The nocebo effect can mistakenly cease the crucial continuation of a research program as well as stop thousands of patients from taking their needed medications – for example, there have been reports of patients ceasing vital medication because research studies reported side effects, but later analysis of those investigations found a large proportion of the reported adverse events were due to the nocebo effect (Brazil, 2018). As such, identifying interventions that may help control for this phenomenon cannot be underemphasized. The current study’s results indicate that the PCRS may be a sound strategy for minimizing subjects from unwittingly reporting side effects.

STUDY LIMITATIONS:

• The results of this study are provisional, as the analysis did not include the required 80 protocol-required subjects.
• Although the goal was to duplicate typical clinical trials, the current investigation was not identical to such studies insofar as (a) the IP was provided to subjects once a week as opposed to every day, (b) there were three total visits rather than the more common 6-8 study visits, (c) the study compensation was $20 per visit and not the more typical $75 and, subsequently, it is unsure if subjects would have reported depressive symptoms differently with higher compensation, (d) it is unsure if the results of the dependent variable (depressive symptoms) transfer to psychotic symptoms, and (e) while the above Noven data begins to address this matter, there was no active drug arm in the current investigation which was aimed to reduce MDD symptoms and, therefore, it is unknown how the PCRS would have impacted these assigned subjects’ reporting of depressive symptoms (i.e., would the PCRS influence active medication subjects’ reporting of depressive symptoms?). These factors may have impacted the current study results and should be addressed in future studies, in which replication would serve to increase confidence in its findings.

Cohen, EA,¹ Hassman, H,¹ Walling, DP,² Wyka, K,³ Grindell, VM,² Glass, SJ,¹ Ball, RB,¹ Styczynski, J,¹ Lobb, JM,¹ Hazzard-Randolph, D,¹ Joseph, AV,¹ and Ereshefsky, L^1,4

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