A Digital Therapeutic Intervention for Negative Symptoms of Schizophrenia: A Randomized Clinical Trial.

IMPORTANCE

Negative symptoms of schizophrenia are a major contributor to poor outcomes, yet no US Food and Drug Administration-approved pharmacotherapies are specifically indicated for their treatment. In particular, motivation and pleasure negative symptoms are especially burdensome for patients. Psychosocial interventions can be effective, but access barriers and challenges in sustaining engagement limit their impact. Digital therapeutics are a novel modality that can deliver patient-centered interventions. CT-155/BI 3972080 (CT-155), an investigational smartphone-based digital therapeutic integrating evidence-based psychosocial strategies, is designed to address negative symptoms of schizophrenia adjunctive to pharmacotherapy.

OBJECTIVE

To evaluate the effectiveness and safety of CT-155 as an adjunct to pharmacotherapy for negative symptoms of schizophrenia.

DESIGN, SETTING, AND

PARTICIPANTS

CONVOKE was a phase 3, multicenter, double-blind, parallel-group, randomized clinical trial conducted between March 31, 2023, and June 20, 2025, at 66 clinical sites in the US among adults with negative symptoms of schizophrenia who were receiving up to 2 antipsychotic medications.

INTERVENTIONS: Participants were randomized 1:1 to CT-155 or a digital control for 16 weeks.

MAIN OUTCOMES AND MEASURES: The primary end point was change from baseline to week 16 in Clinical Assessment Interview for Negative Symptoms, Motivation and Pleasure subscale (CAINS-MAP) score. Secondary end points included change from baseline to week 16 in Positive and Negative Syndrome Scale positive subscale scores. All baseline demographic and clinical characteristic, effectiveness, and engagement analyses were performed using the intention-to-treat set.

RESULTS

Overall, 457 participants were randomized (227 to CT-155 and 230 to digital control; mean [SD] age, 45.8 [12.5] years; 277 male [60.6%]). Retention analyses showed that most participants stayed active in CT-155 (70.4%; [160 of 227]) or digital control (76.5% [176 of 230]) through the end of week 15. At week 16, CT-155 significantly reduced mean (SE) CAINS-MAP total score vs digital control (CT-155 [n = 196], -6.8 (0.5); digital control [n = 204], -4.2 (0.5); least-squares difference, -2.6 [95% CI, -4.0 to -1.2]; P < .001; Cohen d, -0.36 [95% CI, -0.56 to -0.17]). During the 16-week intervention and 4-week follow-up, serious adverse events occurred in 3 of 228 participants (1.3%) receiving CT-155 and 5 of 231 (2.2%) receiving digital control; none were treatment related.

CONCLUSIONS AND RELEVANCE: In this randomized clinical trial, CT-155 improved motivation and pleasure negative symptoms with a small-to-moderate effect size comparable with psychosocial interventions and pharmacologic treatment in psychiatry and was well tolerated and safe, thus representing a novel adjunctive therapy for schizophrenia. CT-155 may represent a scalable, accessible option for improving schizophrenia negative symptoms.

TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT05838625.