A Digital Therapeutic Intervention for Negative Symptoms of Schizophrenia

Key Points

Questions

In adults with schizophrenia, can a digital therapeutic (CT-155) that delivers a treatment based on evidence-based psychosocial interventions engage patients and effectively and safely improve negative symptoms adjunctive to antipsychotic medication?

Findings

This randomized clinical trial of 457 individuals with negative symptoms of schizophrenia demonstrated that 16 weeks of CT-155 intervention reduced the primary outcome of negative symptom severity compared with digital control without major safety concerns.

Meaning

This study suggests that CT-155 is an effective and safe intervention for improving negative symptoms in adults with schizophrenia and represents a novel therapy option as an adjunct to pharmacologic treatment.

Abstract

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

This randomized clinical trial investigates the effectiveness and safety of CT-155, a smartphone-based digital therapeutic intervention, as an adjunct to pharmacotherapy for negative symptoms of schizophrenia.

Introduction

Negative symptoms of schizophrenia are a main contributor to poor outcomes and long-term disability.¹ Despite being a critical concern for patients,² there are no US Food and Drug Administration (FDA)–approved pharmacologic treatments specifically targeting negative symptoms.³ Among negative symptom dimensions, motivation and pleasure (MAP) symptoms (ie, anhedonia, avolition, asociality) are strongly linked with poor functional outcomes and quality of life.⁴ Consistent with this unmet need, global studies and, most recently, the FDA Patient-Focused Drug Development workshop have highlighted that people with schizophrenia and their caregivers want new treatments to address negative symptoms and improve their quality of life (eg, by improving motivation, enjoyment of daily activities, and making it easier to maintain relationships).^5,6,7,8,9

Although several neural and psychological processes underlying MAP negative symptoms have been identified,^10,11,12 pharmacologic interventions have been ineffective. In contrast, psychosocial treatments with core mechanisms such as goal setting, addressing defeatist beliefs, and reward processing^13,14,15 have shown small to moderate improvements in MAP symptoms.^16,17,18 However, psychosocial treatments remain difficult to access in routine care, as they are time intensive and require trained professionals.^19,20,21

Digital therapeutics are a novel treatment modality that, particularly when developed with patient involvement, may help reduce stigma or judgment^22,23 while offering flexibility and autonomy to integrate therapeutic techniques into daily routines.^24,25,26 People with schizophrenia generally use mobile devices at rates comparable to that of the overall population, although disparities remain.^27,28 Recent large-scale randomized clinical trials support the safe and effective delivery of technology-enabled adjunctive psychosocial therapies in schizophrenia predominantly on targeting positive symptoms.^29,30 Although early digital therapeutics designed to address negative symptoms have been reported by patients as meaningful, empowering, and aligned with their needs,^{31,32,33,34,35,36} there is a lack of rigorous confirmatory, controlled evidence for digital therapeutics specifically treating negative symptoms.

CT-155/BI 3972080 (CT-155) is an investigational digital therapeutic for people with MAP negative symptoms of schizophrenia.^37,38 Codesigned with patients,^39,40 CT-155 integrates multiple evidence-based psychosocial treatment components and, by targeting reward pathways, aims to enhance engagement in positive experiences and goal-directed behavior.^41,42,43 CT-155 was granted Breakthrough Device designation by the FDA in December 2023⁴⁴ based on early-phase, open-label studies.^37,39 To rigorously evaluate clinical effectiveness, a large phase 3, randomized clinical double-blind trial was conducted (CONVOKE).³⁸ The trial included a digital control app to account for nonspecific effects and tested the hypothesis that CT-155 would achieve greater reductions in MAP negative symptoms while maintaining safety and tolerability. We report the primary effectiveness, engagement, and safety findings from CONVOKE.

Methods

Trial Design and Oversight

CONVOKE was a phase 3, multicenter, double-blind, parallel-group, 16-week randomized clinical trial conducted between March 31, 2023, and June 20, 2025, across 66 clinical sites in the US (recruitment: March 2023–January 2025). The study evaluated the effectiveness and safety of CT-155 as an adjunct to standard-of-care antipsychotic medication in adults with MAP negative symptoms of schizophrenia and included a 2-week screening period, a 16-week active period, and a 4-week safety follow-up. The trial protocol is in Supplement 1 and the design is in eFigure 1 in Supplement 2. Further protocol details were previously published.³⁸ The protocol and informed consent were approved by the Advarra institutional review board. An independent data safety monitoring board reviewed safety events; technical issues reported by participants were assessed for potential adverse events (AEs) and forwarded to the data safety monitoring board. The trial followed Consolidated Standards of Reporting Trials (CONSORT) guidelines. Written informed consent from participants was obtained before enrollment.

Participants

CONVOKE enrolled adults aged 18 years or older with a primary schizophrenia diagnosis present for 6 months or more before screening. Participants were receiving a stable dose of antipsychotic medication(s) for 12 weeks or more before randomization, with no restrictions on antipsychotic class. Participants had a mean score of 2 or more (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 screening and baseline, and were the sole user of a smartphone with regular internet access. Individuals treated with more than 2 antipsychotic medications (including >2 dosage forms), currently or in the last 3 months receiving psychotherapy or cognitive remediation, or with a current Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition (DSM-5) diagnosis other than schizophrenia were excluded. Individuals with prominent positive symptoms based on prespecified Positive and Negative Syndrome Scale (PANSS) item thresholds were excluded. Full eligibility criteria have been published.³⁸ Per the FDA directive on diversity in clinical trials, having representation proportional to disease burden is important; race and ethnicity (American Indian or Alaska Native, Asian, Black or African American, Hispanic or Latino, White, and multiple or other races and ethnicities [other was a single category that participants could select and was not specified further]) were self-reported using prespecified options and captured electronically by study staff.

Study Blinding and Randomization

CONVOKE included 2 arms: CT-155 (investigational treatment) and a digital control. To maintain blinding, the arms were presented as digital therapeutic A and digital therapeutic B. Participants were informed that both digital therapeutics may or may not be effective, and that the clinical study was comparing effectiveness.³⁸ Eligible participants were centrally randomized 1:1 to either CT-155 or the digital control using interactive web response system–generated personal identification number (PIN) codes to direct allocation.³⁸ All participants downloaded and installed the same study app, and at the baseline visit site staff used the PIN code to deliver either CT-155 or the digital control, ensuring a uniform setup experience and maintaining face validity across arms. Investigators, raters, and primary study staff remained fully blinded to treatment assignment throughout the study. Although site staff could help participants with technical difficulties during the routine site visits, their interaction did not extend to any engagement-specific coaching.

Study Arms

Digital Intervention (CT-155)

CT-155 is a digital therapeutic designed to remediate deficits in reward pathways linked with impairments in goal-directed behavior and motivation. This is accomplished by using a patient-centered adaptive goal-setting approach^45,46 to promote engagement (behavioral activation)^47,48 while targeting defeatist beliefs (cognitive restructuring)^14,35,49 and delivering other therapeutic interventions to facilitate successful goal attainment (social skills training,^50,51,52,53 positive affect training,^54,55 and distress tolerance skills⁵⁶). See the eMethods in Supplement 2 and the study protocol³⁸ (Supplement 1) for a detailed description of CT-155.

Digital Control

The digital control app was designed to engage participants daily, matching the frequency of CT-155 use, via disease-relevant educational lessons. Its components were intended to deliver an engaging experience without therapeutic benefit, therefore requiring less time per day than CT-155, with participants expected to spend only a few minutes daily using the digital control app.

Procedures

At screening, the Mini International Neuropsychiatric Interview (MINI)⁵⁷ was administered to confirm DSM-5 schizophrenia diagnoses and evaluate comorbidities. The CAINS was administered by centralized blinded raters, with eligibility for MAP negative symptoms confirmed at screening using the CAINS-MAP subscale. The PANSS was administered at screening; prespecified PANSS item thresholds were applied to exclude individuals with prominent positive symptoms. Eligible participants proceeded to baseline assessment and randomization. The Columbia–Suicide Severity Rating Scale (C-SSRS) was administered at baseline to assess lifetime history of suicidal ideation and behavior and at each subsequent visit to evaluate suicidality since the previous visit. The CAINS and PANSS were administered in full at screening, baseline, week 8, and week 16. The full schedule of procedures has been published.³⁸

Clinical Outcomes

Effectiveness Outcomes

The prespecified primary effectiveness end point was change from baseline to week 16 in CAINS-MAP. CAINS is a second-generation, semistructured, clinician-rated instrument designed to comprehensively assess negative symptoms of schizophrenia with improved construct specificity relative to first-generation scales,^58,59 comprising 2 subscales: Motivation and Pleasure (MAP) and Expression (EXP). The CAINS-MAP subscale specifically measures motivation, desire, and frequency of engagement in functionally relevant social and recreational behaviors.^60,61 CAINS items are scored on a 5-point scale (total score range, 0-52), with higher scores reflecting greater negative symptom severity (see the eMethods in Supplement 2 for additional details).

Secondary end points included change from baseline at week 8 in MAP negative symptoms (CAINS-MAP assessment), and at weeks 8 and 16 in expressive negative symptoms (CAINS-EXP assessment), positive symptoms (PANSS assessment; total score range, 30-210, with higher scores reflecting more severe symptoms),⁶² and Patient Global Impression–Improvement (PGI-I; a single-item, 7-point Likert scale where patients rate the change in their overall clinical condition since starting treatment; scores range from 1 [very much improved] to 7 [very much worse]). Change from baseline at weeks 8 and 16 in CAINS-MAP subdomains and item-level scores as well as CAINS total score (MAP + EXP) were included as post hoc exploratory end points. Other exploratory end points beyond engagement metrics are not reported here. The full list of end points is summarized in the CONVOKE protocol.³⁸

Engagement and Adherence Outcomes

Participants’ day-to-day engagement with CT-155 and the digital control was measured passively within each app. Prespecified engagement metrics included number of days the app was used and number of days with 1 or more app session of 60 seconds or more. Adherent days were defined as the number of days with 1 or more daily activity completed. Overall retention across the study (ie, last day of study app engagement) and mean daily time spent using the study app were also evaluated.

Safety Assessments

Safety was comprehensively assessed over the 20-week study period. AEs were systematically recorded and characterized by frequency, severity, seriousness, and relationship to study treatment; discontinuations due to AEs and serious AEs were also documented. Suicidal ideation and behavior were monitored throughout using the C-SSRS.⁶³

Sample Size

CONVOKE was powered to detect a standardized effect size of 0.35 on the primary end point with 90% power, assuming a significance level of P < .05 (2-sided test). Allowing for 20% attrition, randomization of 432 participants was planned (~216 per arm).

Statistical Analysis

Unless otherwise specified, all analyses described in this section were prespecified in the statistical analysis plan) (Supplement 1) that was finalized prior to database lock and unblinding. All baseline demographic and clinical characteristic, effectiveness, and engagement analyses were performed using the intention-to-treat (ITT) set, which included all randomized participants, regardless of successful activation or use of the study app. Seven participants were randomized twice. Only the first randomization was included in the ITT set for double-randomized participants. There was no overlap in treatment periods for those randomized twice. The per-protocol (PP) set included all randomized participants who completed the 16-week active period with an adherence level of 60% or more and who did not have a major protocol deviation that could affect the calculation of the primary end point. The PP set was included to evaluate effectiveness in the high-adherence population compared with those with all levels of adherence in the ITT set. Safety was analyzed in the safety set, defined as all randomized participants who signed consent, activated either CT-155 or the digital control, and completed at least 1 available daily activity during the active period. Retention was assessed with Kaplan-Meier analysis, where the time to event was the last recorded day of app use.⁶⁴ In addition, the retention analysis was also conducted using the last day of app use where the participant was adherent.

The primary end point was analyzed using a single mixed-model repeated measures approach that included participants from the ITT set with baseline measures and at least 1 postbaseline measure. The dependent variable was change from baseline (to week 8 and week 16); fixed effects are described in the eMethods in Supplement 2. To assess the effect of missing data, a prespecified sensitivity analysis included repeating the above model on the ITT set with multiple imputations under the missing at random assumption and tipping point analysis to account for missing not at random. Secondary continuous end points were analyzed using a similar mixed-model repeated measures approach. Statistical significance of the primary end point was assessed using a two-sided α of .05. All sensitivity and subgroup analyses, including secondary and exploratory end points, were not controlled for multiplicity. Further details are provided in the eMethods in Supplement 2. All statistical analyses were performed using SAS software, version 9.4 or higher (SAS Institute Inc).

Results

Participants

In total, 1205 individuals were screened and 464 randomization events occurred; 7 participants were randomized twice, but only their first randomization was included in the ITT set. The final sample (ITT) included 457 participants randomized to CT-155 (n = 227) or the digital control (n = 230) (Figure 1). A total of 53 of 227 participants (23.3%) in the CT-155 group and 51 of 230 (22.2%) in the digital control group discontinued early, most commonly due to loss to follow-up and consent withdrawal.

Figure 1. CONSORT Flow Diagram for the CONVOKE Trial.

^aOf the 7 participants randomized twice, 5 (3 from the CT-155 arm and 2 from the digital control arm) were exposed to their second allocated study app, completed at least 1 available daily activity, and were included in the safety analysis. The resulting safety set (n = 459) therefore exceeded the intention-to-treat set (n = 457).

^bParticipants with major protocol deviations were discontinued from treatment and excluded from the per-protocol set, but all remained in both the intention-to-treat and safety sets and were analyzed according to their randomized assignment.

^cThe intention-to-treat set includes all randomized participants, based on the assigned intervention in the randomization and recorded in the database, regardless of successful activation or use of the study app.

AE indicates adverse event; CONSORT, Consolidated Standards of Reporting Trials; SAE, serious adverse event.

Among the 457 participants, the mean (SD) age was 45.8 (12.5) years; 277 (60.6%) were male and 180 (39.4%) were female; and 5 (1.1%) were American Indian or Alaska Native, 9 (2.0%) were Asian, 244 (53.4%) were Black or African American, 127 (27.8%) were Hispanic or Latino, 181 (39.6%) were White, and 18 (3.9%) were multiple or other races and ethnicities (Table 1). At baseline, the mean (SD) CAINS-MAP total score was 26.3 (6.0) and PANSS positive score was 15.1 (3.9). Baseline demographics and clinical characteristics were balanced across study arms (Table 1; eTable 1 in Supplement 2). Similar characteristics were observed in the ITT and PP sets (eTable 2 and eTable 3 in Supplement 2).

Table 1. Participant Baseline Demographics and Characteristics (ITT Set).

Characteristic	CT-155 (n = 227)	Digital control (n = 230)a	Overall (N = 457)a
Demographics
Age, mean (SD), y	46.2 (12.4)	45.3 (12.5)	45.8 (12.5)
Sex, No. (%)
Male	142 (62.6)	135 (58.7)	277 (60.6)
Female	85 (37.4)	95 (41.3)	180 (39.4)
Race, No. (%)
American Indian or Alaska Native	2 (0.9)	3 (1.3)	5 (1.1)
Asian	5 (2.2)	4 (1.7)	9 (2.0)
Black or African American	125 (55.1)	119 (51.7)	244 (53.4)
White	88 (38.8)	93 (40.4)	181 (39.6)
Multiple or otherb	7 (3.1)	11 (4.8)	18 (3.9)
Ethnicity, No. (%)
Hispanic or Latino	62 (27.3)	65 (28.3)	127 (27.8)
Not Hispanic or Latino	165 (72.7)	161 (70.0)	326 (71.3)
Living or housing status, No. (%)
Living with othersc	46 (20.3)	44 (19.1)	90 (19.7)
Living with familyd	110 (48.5)	118 (51.3)	228 (49.9)
Living on own	71 (31.3)	68 (29.6)	139 (30.4)
Employment
Employed	35 (15.4)	30 (13.0)	65 (14.2)
In school	3 (1.3)	2 (0.9)	5 (1.1)
Occasional	5 (2.2)	1 (0.4)	6 (1.3)
Unemployed	175 (77.1)	192 (83.5)	367 (80.3)
Volunteer work or retired	9 (4.0)	5 (2.2)	14 (3.1)
Clinical characteristics
Baseline assessments, mean (SD)
CAINS-MAP total score	26.0 (6.1)	26.6 (6.0)	26.3 (6.0)
CAINS-EXP total score	7.4 (3.9)	7.1 (3.9)	7.3 (3.9)
PANSS positive subscale score	15.0 (4.0)	15.2 (3.9)	15.1 (3.9)
Time since diagnosis, median (IQR), y	15.3 (6.7-28.4)	14.5 (7.0-24.4)	14.8 (6.9-26.1)
Time since diagnosis, No. (%)
≤5 y	39 (17.2)	38 (16.5)	77 (16.8)
>5-10 y	38 (16.7)	40 (17.4)	78 (17.1)
>10 y	150 (66.1)	152 (66.1)	302 (66.1)
No. of antipsychotics used at baseline, No. (%)
1	193 (85.0)	209 (90.9)	402 (88.0)
2	33 (14.5)	21 (9.1)	54 (11.8)
Class of antipsychotics at baseline, No. (%)
First generatione	19 (8.4)	19 (8.3)	38 (8.3)
Second generationf	207 (91.2)	211 (91.7)	418 (91.5)

Abbreviations: CAINS-EXP, Clinical Assessment Interview for Negative Symptoms, Expression subscale; CAINS-MAP, Clinical Assessment Interview for Negative Symptoms, Motivation and Pleasure subscale; ITT, intention-to-treat; PANSS, Positive and Negative Syndrome Scale.

^a Four participants did not report ethnicity.

^b Other was a single category that participants could select and was not specified further.

^c Includes those living with others (not family or spouse or partner); living in care, hospital, or institution; and living in group home, supported housing, or assisted living.

^d Includes those living with their family or spouse or partner.

^e Includes patients who took first-generation antipsychotics regardless of whether they also took second-generation antipsychotics.

^f Includes patients who took only second-generation antipsychotics.

Engagement and Adherence

Retention analyses showed that most participants remained active users of CT-155 or the digital control until the end of the goal attainment phase at week 15 (CT-155: 70.4% [160 of 227]; digital control: 76.5% [176 of 230]) (Figure 2A). Analyses using the last adherent day in app showed similar retention (eFigure 2 in Supplement 2). Regarding daily app engagement, participants used CT-155 on a median of 76 of 112 days (67.9%) and the digital control on a median of 92 of 112 days (82.1%) (eTable 4 in Supplement 2). Participants in the CT-155 arm were adherent on a median of 75 of 112 days (67.0%), and those in the digital control arm were adherent on a median of 91 of 112 days (81.3%). Median daily study app exposure, measured as time spent using the app, was 6 minutes (IQR, 3-8.5 minutes) with CT-155 vs 2 minutes (IQR, 1-3 minutes) for the digital control (eFigure 3 in Supplement 2).

Figure 2. Line Graphs of the Engagement With CT-155 and Digital Control and Primary End Point (Intention-to-Treat [ITT] Set) and Change From Baseline to Week 16 in Clinical Assessment Interview for Negative Symptoms, Motivation and Pleasure Subscale (CAINS-MAP), Subdomain Scores (ITT Set).

A, Participant engagement over the 16-week active period, consisting of a 3-week orientation phase, a 12-week goal attainment phase, and a 1-week consolidation phase. Dashed vertical lines mark phase transitions. See the eMethods in Supplement 2 for further details on these phases. The number at risk represents the number of participants who have not yet experienced the event of interest (ie, disengagement with the study app). B, The primary analysis of change from baseline to week 16 in CAINS-MAP total score analyzed using a mixed-model repeated measures (MMRM) approach. The primary analysis included all participants from the ITT set who had at least 1 postbaseline CAINS-MAP change from baseline assessment available. This included 196 participants in the CT-155 group and 204 participants in the digital control group. C, Change from baseline to week 16 in CAINS-MAP Social subdomain analyzed using an MMRM approach. D, Change from baseline to week 16 in CAINS-MAP Recreational subdomain analyzed using an MMRM approach. E, Change from baseline to week 16 in CAINS-MAP Vocational subdomain analyzed using an MMRM approach.

All trajectories shown reflect model-based estimates from the single MMRM approach using the full ITT population; per-visit counts shown below the x-axis indicate only the number of participants with observed data at that visit. LS indicates least-squares.

^aP < .01.

^bP < .001.

^cP < .05.

^dP > .05.

Primary Effectiveness End Point: MAP Negative Symptoms

A significant improvement in MAP negative symptoms was observed with CT-155 as measured by CAINS-MAP score from baseline to week 16. The least-squares mean (SE) change from baseline to week 16 in CAINS-MAP score was −6.8 (0.5) in the CT-155 group (n = 196) compared with −4.2 (0.5) for the digital control (n = 204), yielding a between-group difference of −2.6 (95% CI, −4.0 to −1.2) (Figure 2B, Table 2), which corresponds to a Cohen d of −0.36 (95% CI, –0.56 to –0.17).

Table 2. Tabulated Primary and Secondary Effectiveness End Points (ITT Set).

Outcome	CT-155			Digital control			Treatment difference LS mean (SE) [95% CI]	P value	Cohen d effect size (95% CI)
	Mean (SD)	Mean (SD) change from baseline	No.	Mean (SD)	Mean (SD) change from baseline	No.
CAINS-MAP score
Baseline	26.0 (6.1)	NA	227	26.6 (6.0)	NA	230	NA	NA	NA
Week 8	20.9 (7.6)	−5.3 (6.4)	196	23.8 (8.0)	−2.8 (6.1)	204	−2.5 (0.6) [−3.8 to −1.3]	<.001	−0.39 (−0.59 to −0.21)
Week 16 (primary end point)	19.5 (7.8)	−6.7 (7.4)	180	22.5 (8.3)	−4.3 (6.7)	184	−2.6 (0.7) [−4.0 to −1.2]	<.001	−0.36 (−0.56 to −0.17)
CAINS-EXP score
Baseline	7.4 (3.9)	NA	227	7.1 (3.9)	NA	230	NA	NA	NA
Week 8	6.2 (3.9)	−1.1 (4.1)	196	6.7 (3.8)	−0.4 (3.7)	204	−0.6 (0.3) [−1.3 to <0.1]	.07	−0.15 (−0.32 to 0.01)
Week 16	6.1 (3.7)	−1.3 (4.1)	180	6.4 (3.9)	−0.8 (4.0)	184	−0.5 (0.4) [−1.2 to 0.2]	.20	−0.12 (−0.29 to 0.06)
PANSS positive subscale score
Baseline	15.0 (4.0)	NA	227	15.2 (3.9)	NA	230	NA	NA	NA
Week 8	14.6 (4.3)	−0.3 (3.3)	193	14.6 (4.2)	−0.5 (2.9)	204	0.2 (0.3) [−0.4 to 0.7]	.59	0.07 (−0.14 to 0.24)
Week 16	14.1 (4.2)	−0.8 (3.6)	181	13.9 (4.1)	−0.8 (3.4)	182	0.1 (0.3) [−0.6 to 0.8]	.79	0.03 (−0.16 to 0.21)

Abbreviations: CAINS-EXP, Clinical Assessment Interview for Negative Symptoms, Expressive Symptoms subscale; CAINS-MAP, Clinical Assessment Interview for Negative Symptoms, Motivation and Pleasure subscale; ITT, intention-to-treat; LS, least-squares; NA, not applicable; PANSS, Positive and Negative Syndrome Scale.

The robustness of the primary end point was confirmed through tipping-point and missing at random multiple imputation (n = 457) sensitivity analyses (eTable 5 in Supplement 2) and supportive analyses adjusting for site as a random effect and of the PP set (eFigure 4 in Supplement 2). Improvement in MAP negative symptoms was observed across the spectrum of participants’ baseline MAP negative symptom severity (eTable 6 in Supplement 2). Prespecified subgroup analyses showed comparable effect sizes across race and ethnicity and educational level subgroups (eFigure 5 in Supplement 2). Furthermore, post hoc analyses showed that improvement in the CAINS-MAP score at week 16 was primarily driven by the Social (between-group difference, −1.44 [95% CI, −2.17 to −0.70]; P = .001; Cohen d −0.38) and Recreational subdomains (−1.31 [−1.97 to −0.65]; P < .001; Cohen d −0.36; Figure 2C and 2D; eTable 7 in Supplement 2). No significant difference in change from baseline compared with digital control was observed in the Vocational subscale score at week 16 (between-group difference, 0.06 [95% CI, −0.33 to 0.45]; P = .76). Corresponding item-level analyses for each subdomain are presented in eFigure 6 and eTable 7 in Supplement 2. Finally, post hoc analysis of the CAINS total score (MAP + EXP) also favored CT-155 at both week 8 and week 16, showing improvement in overall negative symptoms (eTable 8 in Supplement 2).

Secondary Effectiveness Outcomes

A significant improvement in MAP negative symptoms was evident by week 8 (Cohen d −0.39 [95% CI, −0.59 to −0.21]; P < .001), with a between-group difference of −2.5 (95% CI, −3.8 to −1.3; Table 2). Change in positive symptom severity (assessed using the PANSS positive subscale) at week 16 was not significantly different between arms (least-squares mean difference: 0.1; 95% CI, −0.6 to 0.8; P = .79; Table 2; eFigure 7 in Supplement 2). Participants in the CT-155 group reported an improvement in negative symptoms as assessed by the PGI-I (lower values indicate better outcome; scores range from 1 [very much improved] to 7 [very much worse]) at week 8 (Cohen d, −0.28; P = .02). However, statistical significance was not maintained at week 16 (Cohen d, −0.17; P = .07). There was no significant difference between groups for change in expressive negative symptoms (CAINS-EXP) at week 16 (mean difference, −0.5 [95% CI, −1.16 to 0.24]; P = .20; Table 2).

Safety

Serious AEs were reported in 3 of 228 participants (1.3%) receiving CT-155 and 5 of 231 participants (2.2%) receiving digital control (Table 3). None were deemed related to study treatment. AEs were reported in 19 of 228 participants (8.3%) in the CT-155 group compared with 31 of 231 (13.4%) in the digital control group. Treatment-emergent AEs (TEAE) were reported in 18 of 228 participants (7.9%) in the CT-155 group and 27 of 231 (11.7%) in the digital control group (Table 3; eTable 9 in Supplement 2). No TEAEs led to discontinuation in the CT-155 group. In the digital control group, 2 of 231 participants (0.9%) discontinued due to TEAEs (tibia fracture and suicidal ideation). One participant in the CT-155 group and 1 in the digital control group reported a TEAE related to study treatment (CT-155 group: psychotic symptoms; digital control group: irritability). Over the 20-week observation period, there was no meaningful emergence of or increase in suicidal ideation or behavior within either group (eTable 10 in Supplement 2).

Table 3. Summary of AEs (Safety Set)^a.

Category, No. (%)	CT-155 (n = 228)		Digital control (n = 231)
	Events, No.	Participants, No. (%)	Events, No.	Participants, No. (%)
Any AE	29	19 (8.3)	39	31 (13.4)
Any serious AE	3	3 (1.3)	6	5 (2.2)
Any serious AE related to study treatment	0	0	0	0
Any TEAE	26	18 (7.9)	35	27 (11.7)
Mild	15	11 (4.8)	16	16 (6.9)
Moderate	10	9 (3.9)	17	11 (4.8)
Severe	1	1 (0.4)	2	2 (0.9)
Any serious TEAE	2	2 (0.9)	6	5 (2.2)
Any serious TEAE related to study treatment	0	0	0	0
Any TEAE leading to study discontinuation	0	0	2	2 (0.9)

Abbreviations: AE, adverse event; TEAE, treatment-emergent adverse event.

^a The safety set was defined as all randomized participants who signed the consent form, activated the study app, and completed at least 1 available daily activity in the study app during the active period. Of the 7 participants randomized twice, 5 were exposed to their second allocated study app, completed at least 1 available daily activity, and were included in the safety analysis. Three participants in the intention-to-treat set did not complete a daily activity and were excluded from the safety set. The resulting safety set (n = 459) therefore exceeded the intention-to-treat set (n = 457). The treatment periods for those randomized did not overlap.

Discussion

CONVOKE is the first confirmatory phase 3 study to demonstrate improvement in MAP negative symptoms using an investigational digital therapeutic. CT-155 was associated with a significant improvement in MAP negative symptoms vs digital control at week 16. Participant retention and daily engagement were high and CT-155 was well tolerated with no safety concerns. Participants in the study were broadly representative of adults with schizophrenia in the US.^{65,66,67,68,69} These findings support CT-155 as a potential adjunctive therapy for patients for an indication of negative symptoms of schizophrenia with a high unmet need for FDA-approved pharmacologic treatments specifically targeting negative symptoms.

The observed treatment effect (Cohen d = 0.36) was consistent across sensitivity analyses. CAINS reflects an updated conceptualization of MAP negative symptoms and provides a more detailed assessment of subjective negative symptoms than older scales.^60,61 Post hoc analyses showed that the effect of CT-155 was primarily concentrated in the Social and Recreational CAINS-MAP subdomains, with between-group differences of −1.44 points for the Social subdomain and −1.31 points for the Recreational subdomain (Figure 2B; eTable 8 in Supplement 2). As each CAINS-MAP anchor (a standardized, operationalized descriptor attached to each point on the MAP subdomain’s 0-4 rating scale) represents a distinct level of MAP, a shift of 1 point per item reflects tangible behavioral changes, indicating improvement in functionally relevant behaviors.¹¹ Changes in the Vocational subdomain were modest and similar in both arms at week 16. Although a separation was observed at week 8, it was not maintained and should be interpreted cautiously given the exploratory nature of these analyses. Meaningful change in work or school functioning typically depends on structural factors that are unlikely to change within 16 weeks.

Although the overall effect size was small to moderate, it is broadly comparable with those reported for in-person psychotherapy.⁷⁰ Benchmarking against negative symptom trials evaluating pharmacologic approaches is difficult, as no prior phase 3 study has shown confirmatory efficacy for negative symptoms as a primary end point. The effect size observed here is, overall, comparable with those in trials of antipsychotic and antidepressant medications for psychiatric conditions.^70,71 However, effect size comparisons should be interpreted cautiously, as these estimates were derived from different comparators, populations, outcome measures, and study designs used here. CT-155 was tested as an adjunctive treatment to antipsychotic medication, and no safety concerns emerged. Thus, CT-155 introduces an integrated and patient-centered adjunctive digital approach that targets the MAP-related drivers of negative symptoms, while providing ease of access and scalable digital modality. PANSS positive subscale scores did not change, indicating that CT-155’s effects on MAP negative symptoms were not secondary to positive symptom improvement.^50,60

Contemporary models identify MAP as a central and clinically consequential aspect of negative symptoms in schizophrenia.^72,73 Moving away from older unidimensional models by explicitly highlighting MAP deficits as core components of the overall construct rather than a distinct clinical entity may facilitate new therapeutic approaches. In line with these updated contemporary models, CAINS offers a thorough assessment of negative symptoms that not only considers the frequency of functionally relevant goal-directed social and recreational behaviors but also the desire to engage in those activities, and how important an individual finds them.^60,61 CAINS therefore captures subjective internal experiences, such as joy, pleasure, interest, and intimacy, that reflect the experiential challenges most relevant to the individual. Consistent with these models and the intended specificity of CT-155, improvement on CAINS-MAP can therefore be reasonably interpreted as meaningful change within the broader negative symptom domain, even if expressive features do not change. The post hoc exploratory analysis of total CAINS favored CT-155, highlighting the significance of the change in MAP negative symptoms on the overall negative symptom domain. Complementing CAINS-MAP outcomes, the patient-reported PGI-I showed significant improvement at week 8, although changes were not significant at week 16.

The comparable engagement across arms indicates that the added benefit observed with CT-155 was not attributable to engagement alone but driven by the therapeutic content of CT-155. The slight improvement compared with baseline in the digital control arm may reflect nonspecific placebo effects, commonly seen in psychiatric clinical trials.

Participants spent more time using CT-155, which is consistent with the design of CT-155 vs the digital control, with CT-155 providing therapeutic content. In total, participants using CT-155 experienced almost 45 minutes of weekly therapy, a level that is difficult to achieve in standard care.^19,20,21 Participants used the app without financial incentives for daily use, suggesting perceived value and successful integration into daily routines. This engagement is consistent with CT-155’s patient-centric design, including adaptive goal-setting, and aligns with self-determination theory, which links sustained engagement with support for autonomy, competence, and relatedness.⁷⁴

CT-155 was well tolerated, with no treatment-related concerns identified. Premature discontinuation rates were similar between groups, and no CT-155 participants (vs 2 control participants) discontinued due to AEs or serious AEs. All serious AEs were deemed unrelated to treatment. There was no increase in positive symptoms, and only a small number of suicidal ideation or behavior cases were reported during the study. These findings support the favorable safety profile of CT-155 in this population.

Limitations

The study findings should be viewed in the context of several limitations that may restrict generalizability. These include requirements for stable antipsychotic treatment and exclusion of individuals who had received a new diagnosis of schizophrenia or were initiating treatment, those with milder presentations of negative symptoms, and individuals receiving or with a recent history of psychotherapy or cognitive remediation. The requirement for smartphone ownership, internet access, and stable housing may have introduced selection bias toward participants with greater digital literacy and socioeconomic stability. Engagement results should be interpreted in the context of routine study contact at clinical sites, although no engagement-enhancing or therapeutic support was provided. Future real-world studies are required to assess the effect of CT-155 in a broader population.

Conclusions

Results from this randomized clinical trial demonstrate that CT-155, an investigational digital therapeutic, is an effective and well-tolerated intervention in adults with schizophrenia. Codesigned with patients and leveraging evidence-based psychosocial strategies, CT-155 showed high engagement among individuals with negative symptoms who are typically difficult to engage. CT-155 is scalable, potentially more accessible than traditional therapy, and, to our knowledge, the first investigational digital therapeutic shown to improve MAP negative symptoms of schizophrenia. CT-155 may represent a scalable, accessible option for improving schizophrenia negative symptoms.

Supplement 1.

Trial Protocol and Statistical Analysis Plan

Supplement 2.

eMethods.

eTable 1. Participant Baseline Assessments for Additional Secondary End Points (ITT Set)

eTable 2. Participant Baseline Demographics by the ITT Set and PP Set

eTable 3. Participant Baseline Demographics by Participants Who Terminated Early and Those Who Completed the Study (ITT Set)

eTable 4. Key Engagement Metrics (ITT Set)

eTable 5. Sensitivity Analysis of the Primary End Point Using MAR Multiple Imputation and Tipping Point Methods (ITT Set)

eTable 6. Descriptive Summary of CAINS-MAP by Visit Stratified by Baseline CAINS-MAP Quartiles (ITT Set)

eTable 7. Post Hoc Analysis of Change From Baseline to Week 16 in CAINS-MAP Social, Recreational, and Vocational Subdomain and Items Using MMRM (ITT Set)

eTable 8. Post Hoc Analysis of Change From Baseline at Week 8 and Week 16 in CAINS Total (MAP + EXP) Score (ITT Set)

eTable 9. Treatment-Emergent Adverse Events

eTable 10. Incidence of Suicidal Ideation and Behavior (Safety Set)

eFigure 1. CONVOKE Study Design

eFigure 2. Retention Analysis of App Engagement (ITT Set)

eFigure 3. Average Daily Exposure in the Study App Across the 2 Study Arms

eFigure 4. (A) Supportive Analysis of the Primary End Point Using MMRM, Adjusting for Site as a Random Effect on the ITT Set; (B) Supportive Analysis of the Primary End Point Using MMRM, Conducted on the PP Set

eFigure 5. Forest Plot Showing Change From Baseline at Week 16 in CAINS-MAP by Subgroup (ITT Set)

eFigure 6. Post Hoc Analysis of Change From Baseline to Week 16 in (A) CAINS-MAP Social Subdomain items, (B) CAINS-MAP Recreational Subdomain Items, and (C) CAINS-MAP Vocational Subdomain Items Using MMRM (ITT Set)

eFigure 7. Change From Baseline to Week 16 in PANSS Positive Subscale Score (ITT Set)

eReferences.

Supplement 3.

Data Sharing Statement