Verasci (United States)

Complementing randomized controlled trials, real-world evidence (RWE) from observational analyses can extend clinical insights in oncology. While healthcare stakeholders have published rigorous RWE frameworks and resources, a multidisciplinary think tank was established to further advance acceptance and use of RWE in treatment decision-making, with the focus on breast cancer (while recognizing relevance in oncology more broadly). Members discussed perceptions of RWE from a clinical perspective, across domains of data, methodology, and mindset, and “calls-to-action” for stakeholders. Agreement was reached on a primary “call-to-action,” to develop clinically-relevant, patient-informed, real-world endpoints, and secondary “calls-to-action”: establish a multidisciplinary consensus forum; publish examples of unique RWE value; build upon existing frameworks and resources; and tailor an approach for exhibiting utility to guideline bodies.

BackgroundMitigating rating inconsistency can improve measurement fidelity and detection of treatment response. MethodsThe International Society for CNS Clinical Trials and Methodology convened an expert Working Group that developed consistency checks for ratings of the Hamilton Anxiety Rating Scale (HAM-A) and Clinical Global Impression of Severity of anxiety (CGIS) that are widely used in studies of mood and anxiety disorders. Flags were applied to 40,349 HAM-A administrations from 15 clinical trials and to Monte Carlo-simulated data as a proxy for applying flags under conditions of inconsistency. ResultsThirty-three flags were derived these included logical consistency checks and statistical outlier-response pattern checks. Twenty-percent of the HAM-A administrations had at least one logical scoring inconsistency flag, 4 % had two or more. Twenty-six percent of the administrations had at least one statistical outlier flag and 11 % had two or more. Overall, 35 % of administrations had at least one flag of any type, 19 % had one and 16 % had 2 or more. Most of administrations in the Monte Carlo- simulated data raised multiple flags. LimitationsFlagged ratings may represent less-common presentations of administrations done correctly. Conclusions-Application of flags to clinical ratings may aid in detecting imprecise measurement. Flags can be used for monitoring of raters during an ongoing trial and as part of post-trial evaluation. Appling flags may improve reliability and validity of trial data.

Criteria for treatment-resistant depression (TRD) and partially responsive depression (PRD) as subtypes of major depressive disorder (MDD) are not unequivocally defined. In the present document we used a Delphi-method-based consensus approach to define TRD and PRD and to serve as operational criteria for future clinical studies, especially if conducted for regulatory purposes. We reviewed the literature and brought together a group of international experts (including clinicians, academics, researchers, employees of pharmaceutical companies, regulatory bodies representatives, and one person with lived experience) to evaluate the state-of-the-art and main controversies regarding the current classification. We then provided recommendations on how to design clinical trials, and on how to guide research in unmet needs and knowledge gaps. This report will feed into one of the main objectives of the EUropean Patient-cEntric clinicAl tRial pLatforms, Innovative Medicines Initiative (EU-PEARL, IMI) MDD project, to design a protocol for platform trials of new medications for TRD/PRD.

AimAttenuated psychosis syndrome (APS), a condition for further study in the Diagnostic and Statistical Manual of Mental Disorders‐5, comprises psychotic symptoms that are qualitatively similar to those observed in schizophrenia but are less severe. Patients with APS are at high risk of converting to first‐episode psychosis (FEP). As evidence for effective pharmacological interventions in APS is limited, novel treatments may provide symptomatic relief and delay/prevent psychotic conversion. This trial aims to investigate the efficacy, safety, and tolerability of BI 409306, a potent and selective phosphodiesterase‐9 inhibitor, versus placebo in APS. Novel biomarkers of psychosis are being investigated.MethodsIn this Phase II, multinational, double‐blind, parallel‐group trial, randomized (1:1) patients will receive BI 409306 50 mg or placebo twice daily for 52 weeks. Patients (n = 300) will be enrolled to determine time to remission of APS, time to FEP, change in everyday functional capacity (Schizophrenia Cognition Rating Scale), and change from baseline in Brief Assessment of Cognition composite score and Positive and Negative Syndrome Scale scores. Potential biomarkers of psychosis under investigation include functional measures of brain activity and automated speech analyses. Safety is being assessed throughout.ConclusionsThis trial will determine whether BI 409306 is superior to placebo in achieving sustainable remission of APS and improvements in cognition and functional capacity. These advances may provide evidence‐based treatment options for symptomatic relief in APS. Furthermore, the study will assess the effect of BI 409306 on psychotic conversion and explore the identification of patients at risk for conversion using novel biomarkers.

The remarkably high and growing placebo response rates in clinical trials for CNS indications, such as depression and schizophrenia, constitute a major challenge for the drug development enterprise. Despite extensive literature on participant expectancies and other potent psychosocial factors that perpetuate placebo response, no empirically validated participant-focused strategies to mitigate this phenomenon have been available. This study evaluated the efficacy of the Placebo-Control Reminder Script (PCRS), a brief interactive procedure that educates participants about factors known to cause placebo response, which was administered prior to the primary outcome assessments to subjects with major depressive or psychotic disorders who had at least moderate depression. Participants were informed they would participate in a 2-week randomized clinical trial with a 50% chance of receiving either an experimental antidepressant medication or placebo. In actuality, all participants received placebo. Participants randomly assigned to receive the PCRS (n = 70) reported significantly smaller reductions (i.e., less placebo response) in depression than those who did not receive the PCRS (n = 67). The magnitude of this effect was medium (Cohen’s d = 0.40) and was not significantly impacted by diagnostic status. The number of adverse events (i.e., nocebo effect) was also lower in the PCRS group, particularly in the first week of the study. These findings suggest that briefly educating participants about placebo response factors can help mitigate the large placebo response rates that are increasingly seen in failed CNS drug development programs.

Recovery from an eating disorder (ED) may be defined differently by different stakeholders. We set out to understand the definition of ED recovery from the perspective of patients, their parents, and clinicians. We recruited patients with EDs (n = 24, ages 12-23 years) representing different diagnoses (anorexia nervosa n = 17, bulimia nervosa n = 4, binge-ED n = 2, avoidant/restrictive food intake disorder n = 1), along with their parents (n = 20), dietitians (n = 11), therapists (n = 14), and primary care providers (n = 9) from three sites: Boston Children's Hospital, University of Michigan C. S. Mott Children's Hospital, and Penn State Hershey Children's Hospital. In-depth, semi-structured, qualitative interviews explored participants' definitions of recovery. Interviews were analyzed using inductive data-driven thematic analysis. Statistical analyses followed to examine the distribution within each theme by respondent type. Qualitative analysis resulted in the emergence of four overarching themes of ED recovery: (a) psychological well-being, (b) eating-related behaviors/attitudes, (c) physical markers, and (d) self-acceptance of body image. Endorsement of themes two and four did not significantly differ between patients, parents, and clinicians. Clinicians were significantly more likely to endorse theme one (χ2 = 9.90, df = 2, p = .007, φc = 0.356) and theme three (χ2 = 6.42, df = 2, p = .04, φc = 0.287) than patients and parents. Our study demonstrates overwhelming support for psychological markers as indicators of ED recovery by all three groups. Clinicians should remain open to additional markers of recovery such as body acceptance and eating-related behaviors/emotions that may be of critical importance to patients and their caregivers.

The Mini International Neuropsychiatric Interview, version 6, module K (MINI6-Mod-K) is a diagnostic tool to confirm schizophrenia; whereas the Positive and Negative Syndrome Scale in Schizophrenia (PANSS) is a scale to assess psychotic symptoms severity. The objective of this study was to cross-validate the diagnostic questions (categorical) from the Arabic MINI6-Mod-K with the corresponding items’ scores (dimensional) from Arabic PANSS. Arab subjects (N = 101) were recruited from the Psychiatry Hospital in Qatar. MINI6-Mod-K was used to confirm schizophrenia diagnosis, and PANSS was administered to assess psychopathology by an independent rater. The most common symptoms according to MINI6-Mod-K were the delusions and hallucinations but the PANSS items scores ≥2.5 captured more positive responses on all the diagnostic features of schizophrenia. The cut-off PANSS scores that significantly distinguished between the presence or absence of schizophrenia features on MINI6-Mod-K were mostly between 2.5 and 3.5. Multivariate linear regression showed that negative symptoms and disorganized/catatonic behaviors independently contributed to the PANSS score on positive symptoms subscale. However, none of the symptom questions in the MINI6-Mod-K were significant predictors of the PANSS negative score. Our results showed that there is very good cross-validation between the diagnostic questions of Arabic MINI6-Mod-K and the corresponding positive cut-off scores in Arabic PANSS.