A randomized Phase II trial evaluating efficacy, safety, and tolerability of oral BI 409306 in attenuated psychosis syndrome: Design and rationale

Abstract

Aim Attenuated 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. Methods In 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. Conclusions This 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.

Development of the PSYCHS: Positive SYmptoms and Diagnostic Criteria for the CAARMS Harmonized with the SIPS

“…Meeting time was spent reviewing the literature, comparing item content between SIPS version 5.6.1 (Keefe et al, 2021; Walsh, 2021) and CAARMS 2015 (Yung et al, 2015), ensuring that all attenuated positive symptom content in both instruments was captured in the PSYCHS by verbatim interviewer inquiries, reformulating the joint item content into new and distinct items (Table 1 Content comparison across SIPS, CAARMS, and PSYCHS items), ensuring the consistency of measurement concepts across items, harmonizing scaling, ensuring that the harmonized scale anchors for each item were distinct, ordered, and graded according to similar intervals within each measurement concept, and crafting interviewer and scoring instructions. All decisions were made by consensus, and minutes were taken by SAW.…”

Development of the PSYCHS: Positive SYmptoms and Diagnostic Criteria for the CAARMS Harmonized with the SIPS

“…Meeting time was spent reviewing the literature, comparing item content between SIPS version 5.6.1 (Keefe et al, 2021;Walsh, 2021) and CAARMS 2015 (Yung et al, 2015), ensuring that all attenuated positive symptom content in both instruments was captured in the PSYCHS by verbatim interviewer inquiries, reformulating the joint item content into new and distinct items (Table 1), ensuring the consistency of measurement concepts across items, harmonizing scaling, ensuring that the harmonized scale anchors for each item were distinct, ordered, and graded according to similar intervals within each measurement concept, and crafting interviewer and scoring instructions. All decisions were made by consensus, and minutes were taken by SAW.…”

Progress and Pitfalls in Developing Agents to Treat Neurocognitive Deficits Associated with Schizophrenia

“…Earlier, the PDE9 inhibitor BI 409306 failed to improve cognitive function in schizophrenia patients in a phase II trial [ 280 ]. Despite this negative result, a new, industry-sponsored, proof-of-concept trial has been set up to investigate the change in everyday functional capacity and cognition in patients with attenuated psychosis syndrome treated with BI 409306 versus a placebo (NCT03230097) [ 281 ].…”