Eligible participants were 18 years or older, fluent in written and spoken English, and had a primary diagnosis of schizophrenia as defined in the DSM-5 (Diagnostic and Statistical Manual of Mental Disorders [Fifth Edition]) for ≥6 months prior to the screening visit. Participants were required to have been on a stable dose of antipsychotic medications for ≥12 weeks prior to randomization, to have obtained an average score of ≥2 (moderate to severe) in at least 2 of the 3 Clinical Assessment Interview for Negative Symptoms Motivation and Pleasure subscale (CAINS-MAP) domains (Social, Work or Recreational) at both the screening visit and at baseline, and to be the sole user of a smartphone. Individuals were excluded if they had a DSM-5 diagnosis for schizophreniform or schizoaffective disorder, or were receiving or had received psychotherapy. Full eligibility criteria are presented in Multimedia Appendix 1.

This study was conducted in accordance with the Declaration of Helsinki and the Good Clinical Practice Guidelines. The study protocol was approved by the Institutional Review Boards prior to study initiation. Institutional Review Board services were provided by Advarra (registration number Pro00065686). All participants were asked to provide written informed consent prior to starting the study and were informed that their participation was voluntary. All information collected during the study was considered confidential and was only used in accordance with the protocol, and participants were assigned a unique identifier by the sponsor at screening. Participants were offered up to US $45-US $200 and US $25-US $136 per in-person and remote visit, respectively, based on study center locality. While participants were compensated for their time attending site visits, they were not compensated for completing daily in-app activities. An independent Data Safety Monitoring Board reviewed safety events throughout the study period.

CT-155 is an investigational smartphone-based DTx being developed for use as an adjunct to standard-of-care antipsychotic medications in adults with negative symptoms of schizophrenia. CT-155 was designed based on the underlying principles of face-to-face treatment to provide maximal support to people living with schizophrenia [83-86]. By integrating multiple components of evidence-based psychosocial therapeutic techniques in a patient-centered manner, CT-155 aims to address the dual challenge of accessibility and psychosocial therapy use for people with negative symptoms living with schizophrenia.

The components of CT-155 are designed to address defeatist beliefs and lack of motivation. Defeatist beliefs are a mediating variable between cognitive impairment, negative symptomatology, and poor functioning in schizophrenia [49], while a lack of motivation reduces an individual’s ability to successfully overcome the challenges of daily living with schizophrenia [87,88]. CT-155 components included the setting of goals appropriate to the patients’ current level of functioning (adaptive goal setting) [89,90] to promote real-world engagement (behavioral activation) [43,44], while targeting defeatist performance beliefs (cognitive restructuring) [47,49,72] and delivering therapeutic interventions to facilitate successful goal attainment (social skills training [33,41,48,50], positive affect training [45,46], distress tolerance skills [91]). These core components are intended to remediate dysfunctions in reward pathways, which contribute to reduced internal representations of behavioral goals and drive motivational impairments central to ENS [92-94]. In particular, targeted behavioral activation strategies followed by cognitive restructuring promote engagement in goal-directed behaviors, while also creating and maintaining associations between effort and positive affect in relation to those behaviors [42,95,96]. A selection of screenshots from the CT-155 study app are presented in Figures 3 and 4.

CT-155 design and development were informed by an iterative patient-centered approach from 156 people living with schizophrenia. For example, the mood check-in feature was refined based on feedback from individuals with lived experience. Initially designed as a simple, single-screen daily prompt, it evolved into a dynamic tool offering tailored feedback and coping strategies aligned with users’ reported mood. Feedback also informed how therapeutic content was structured, the tone and pacing of the app’s narrative, and improvements in usability and overall user flow. Further details are available in Figure S1 in Multimedia Appendix 1 and have been described by Snipes et al [81] and Goenjian et al [74].

The active period for CT-155 comprised 3 structured but personalized phases within the app: 3-week orientation phase, 12-week goal attainment phase, and 1-week consolidation phase. The orientation phase included lessons to set expectations and encourage daily adherence, provide schizophrenia-specific psychoeducation, and help build an effective therapeutic alliance (also referred to as a digital working alliance [81]), which is important for engagement with DTx. The goal attainment phase included adaptive goal setting, social skills training, and cognitive restructuring. The consolidation phase included guided reflection on, and celebration of progress, and establishment of a plan for continued application of skills learned over the course of the study in daily life. Lessons and activities were delivered through brief, daily interactive modules designed to be completed in under 10 minutes. These included a combination of text-based explanations, short exercises, and reflection prompts tailored to each phase. Participants also completed daily check-ins and were encouraged to access content regularly. The app included SMS and push notifications to prompt check-in completion and encourage daily lesson engagement. Two prior exploratory studies using earlier versions of CT-155 (CT-155 beta) demonstrated initial feasibility in engaging people living with schizophrenia and an associated reduction in ENS severity following 7 weeks of use [74,81].

The digital control app served as a comparator that controlled for common elements of a digital app (eg, receipt of notifications, on-demand access), daily engagement, and face validity [78,97]. It was designed to be reasonably equivalent to the active treatment in terms of daily engagement and face validity. For example, the user interface was similar (Figure 3 depicts the identical log-in screens of the CT-155 app and the digital control app), and the experience included SMS text messages, push reminders, daily check-ins, and daily activities. This design aimed to promote frequent use of the app and ensure that any differences in outcomes could be attributed to the therapeutic content, rather than to nonspecific effects of digital engagement. The digital control app also included elements of the disease-specific educational components of CT-155. The educational components were designed to increase knowledge about schizophrenia without encouraging behavior change or providing other therapeutic benefits.

In line with FDA current best practices and terminology in medical device clinical research, improvement in clinical outcomes is herein referred to as effectiveness (rather than efficacy) [98].

End points included clinician-reported and patient-reported assessments. The primary effectiveness end point was change from baseline to Week 16 in ENS severity, as assessed by CAINS-MAP (Table 1). CAINS is a 13-item interview-based, clinician-administered assessment that consists of 2 subscales covering the 5 domains of negative symptoms: Motivation and Pleasure (referred to as “MAP”; ie, avolition, anhedonia, and asociality), and Expressivity (referred to as “EXP”; ie, blunted affect, alogia). CAINS items are scored on a 5-point scale, with lower scores indicating lower negative symptom severity [99]. CAINS is a second-generation negative symptoms scale that was developed to reflect updated conceptualizations of negative symptoms, as recommended by the National Institute of Mental Health and the Measurement and Treatment Research to Improve Cognition in Schizophrenia initiative [99,100]. CAINS offers a more detailed assessment of negative symptoms than older scales such as the Positive and Negative Syndrome Scale (PANSS) and assesses internal experiences (eg, joy, pleasure, interest, and intimacy) rather than just behavior to focus on experiential deficits important to the individual [101,102]. CAINS was administered by a centralized rater team. Raters were trained consistently with didactic training and posttests, and video scoring exercises; interrater reliability was measured every 6 months.

Other study end points included change from baseline to Week 8 in ENS severity (assessed by CAINS-MAP), and change from baseline to Weeks 8 and 16 in expressive negative symptoms (assessed by CAINS Expressivity subscale [CAINS-EXP]), positive symptoms (PANSS), social functioning (Personal and Social Performance Scale), self-reported defeatist beliefs (Dysfunctional Attitudes Scale), Patient Global Impression of Improvement Scale, Clinical Global Impressions-Severity, and quality of life (Schizophrenia Quality of Life Scale – Revision 4). PANSS consists of 3 subscales (positive, negative, and general psychopathology) containing a total of 30 symptom constructs. For each symptom construct, severity is rated on a 7-point scale, with a score of 1 indicating the absence of symptoms and a score of 7 indicating extremely severe symptoms [99]. Further assessment details are described in Table 1.

Participant engagement with CT‑155 and digital control were measured passively by the smartphone as a result of participants’ day-to-day app use and completion of in-app activities. These included the number of days the app was used, the number of days with at least 1 app session ≥60 seconds, and the number of days with at least 1 daily activity completed. Daily activities in CT-155 included completing lessons, completing check-ins, practicing skills, or completing steps to attain goals. Daily activities in the digital control included completing lessons or completing check-ins. Participants were considered adherent during the study if they completed at least 1 daily activity for at least 67 of the 112 days of the active period (≈60%). The schedule of assessments is presented in Table 2.

Safety end points included the frequency and severity of adverse events (AEs) and serious AEs, including those related to the worsening of positive or negative schizophrenia symptoms. The incidence of suicidality, as identified via the Columbia-Suicide Severity Rating Scale was also assessed.

Using a 2-sample t test approach and assuming a type I error rate of 5% (2-sided), 173 participants per arm were required to achieve 90% power to detect an effect size of Cohen d of 0.35. Assuming 20% early termination, a total of 432 participants was calculated as being needed before being randomized to the study in a 1:1 ratio (approximately 216 in each arm). The assumed effect size (Cohen d=0.35) was informed by an earlier exploratory study of a related version of the digital therapeutic [74], early research studies with psychosocial interventions targeting negative symptoms [72,114,115], and moderate effect sizes seen in broader confirmatory trials in schizophrenia and major depressive disorder [116,117].

The treatment of negative symptoms is a critical unmet need for people living with schizophrenia. Evidence-based DTx have demonstrated the potential to provide a scalable new patient-centered treatment option to enhance existing care for individuals with schizophrenia [63,74,81]. However, well-designed randomized clinical trials are essential to rigorously evaluate the effectiveness and safety of DTx, and to generate the evidence required for FDA regulatory approval. We summarized the clinical trial protocol for the CONVOKE study, the largest phase 3, randomized, controlled, double-blind trial conducted to date to assess the effectiveness and safety of a DTx in schizophrenia. CT-155 is an investigational adjunctive treatment for negative symptoms in people living with schizophrenia who are on standard-of-care antipsychotic medication.

The CONVOKE protocol included study design elements that strengthen study rigor. First, CONVOKE will evaluate the potential of CT-155 to reduce participants’ ENS of schizophrenia using the CAINS-MAP assessment. CAINS is a second-generation negative symptom scale recommended by experts as a more detailed measure of negative symptoms compared with the older PANSS assessment, capturing both experiential (CAINS-MAP) and expressive (CAINS-EXP) symptoms [99,100,128]. Compared with PANSS, CAINS demonstrates better construct validity and coverage of negative symptoms domains, better psychometric properties, and more sensitivity in detecting treatment-related changes [99,101,102,129]. Furthermore, CAINS-MAP was administered by central raters, an approach that has a significantly lower placebo affect than using site-based raters [130]. Second, the CONVOKE protocol was developed in the context of a conventional phase 3 registrational study, by including design aspects such as a blind-to-hypothesis and a digital control arm. The digital control app for CT-155 was designed to control for unintended therapeutic benefit that may arise from nonspecific factors (eg, self-monitoring, treatment expectations), referred to as a placebo response in pharmaceutical trials. To our knowledge, CONVOKE is the first DTx study in participants with negative symptoms of schizophrenia to include such a digital control. The blind-to-hypothesis approach requires the digital control app being masked as an active therapeutic by closely mirroring it in terms of design, delivery, participant engagement, and the duration of the intervention. Thus, the risk of unmasking and disengagement for those assigned to the digital control is expected to be reduced. However, it is important to examine whether the blind-to-hypothesis approach functioned as intended, and this could be investigated by comparing participant engagement between the 2 study arms.

Finally, in keeping with the FDA’s patient-focused drug development initiative, CT-155 development was informed by a patient-centered design approach that considered the needs of those living with schizophrenia [31]. Feedback was captured from peer support specialists with lived experience of schizophrenia and patient panel participants with a diagnosis of schizophrenia, to iteratively improve CT-155. This patient-centric approach also supports establishing the digital working alliance and optimizes participant experience by creating an interactive, empathic, knowledgeable, and personally meaningful content within the CT-155 app that is critical for treatment outcome. These robust study design elements lay the groundwork for strengthening study rigor and ultimately improving confidence in the effectiveness of CT-155.

Safety analyses will determine whether CT-155 has a low safety risk and can be tolerated by participants, an important study design component for a prescription DTx to be made available under FDA regulation. CT-155 is expected to be well tolerated, as demonstrated in the 2 single-arm clinical learning studies [74,81]. In contrast to pharmacotherapy, DTx do not involve the administration of pharmaceutical compounds and are therefore not associated with side effects as frequently present for pharmaceuticals and may be considered minimal risk [131,132]. However, it is still important to assess the safety of a DTx throughout the study (eg, monitoring hospital admissions, referrals to crisis care, and suicidal ideation) [75,133-137]. The 4-week posttreatment follow-up was specifically designed to assess short-term safety and tolerability after treatment concluded, and was intended to monitor for adverse events, potential withdrawal effects, or other posttreatment concerns. To extend observation beyond the initial study and provide further insights into maintenance of effect and safety, there was an opportunity for some participants to enroll into an open-label extension study (NCT06067984) [113].

Although the protocol had strengths by utilizing a conventional phase 3 clinical study design, there were potential limitations that may have introduced selection bias that could limit the external validity and generalizability of findings. First, participants were required to be on a stable dose of antipsychotic medication (≤2 antipsychotics) for at least 12 weeks. This was intended to ensure stability and reduce the likelihood of symptom fluctuations which could impact engagement with digital intervention. However, this may have also excluded individuals with recent diagnoses or those who had started antipsychotics within the last 12 weeks. These groups may have different treatment needs, and future studies will be important to assess the potential benefits of this intervention in more acutely unwell or treatment-initiating populations.

To address broader generalizability beyond a confirmatory phase 3 trial population, there is an ongoing prospective cohort study (ENSPIRUS) that aims to assess the effectiveness and safety of CT-155 in a broader population (eg, no exclusion criteria for those who recently engaged in psychotherapy; NCT06791122) [138].

Second, participants were required to own a smartphone, with consistent internet access, and have stable housing. While necessary for evaluating a digital intervention, these criteria may introduce some selection bias towards participants with greater digital literacy, greater socioeconomic stability, or higher overall functioning which could limit the external validity and generalizability of findings to the broader population of people with schizophrenia. The requirement for smartphone ownership aimed to reduce nonspecific effects related to unfamiliarity with digital devices and to avoid variability in engagement that could arise if participants were using loaned devices rather than their own. Although smartphone ownership is increasingly common across all socioeconomic groups, including among individuals with serious mental illness, disparities in digital literacy, data affordability, and reliable internet access may still limit broad generalizability across the target population [64,65,139]. Future studies should consider hybrid models that include loaning smartphones to further access the impact of accessibility and inclusiveness.

Finally, as no correction for multiple comparisons was applied across secondary end points or subgroup analyses, there is an increased risk of type I error; thus, these findings should be interpreted with caution and considered supportive of the study’s primary objective.

This manuscript describes the methodological design for CONVOKE, the largest robust pivotal clinical trial evaluating the effectiveness and safety of a DTx as an adjunct to standard-of-care antipsychotic medication for negative symptoms in people living with schizophrenia. CT-155 development was informed by a patient-centered design approach. The CONVOKE study design included the centrally rated CAINS with its CAINS-MAP subdomain as the primary end point, blind-to-hypothesis, and used digital control arm. The treatment of negative symptoms has been a critical unmet need for people living with schizophrenia and the results of this study may shift the treatment paradigm for them. If the pivotal trial data show a significant difference between CT-155 and the digital control, CT-155 would offer an accessible, evidence-based psychosocial treatment delivered through smartphones in a patient-centered manner to augment standard-of-care for people with negative symptoms of schizophrenia.