The VICTORY-S study is a multicenter, interventional, open-label, rater-blind, randomized comparison study. The study will be conducted at 17 sites in Japan between 2 February 2021 and 30 September 2025 (Table 1). The study will consist of two periods, a 6-week period of pharmacotherapy alone followed by a 24-week period of pharmacotherapy and NEAR combination treatment (Figure 1). Both patients and therapists will be aware of the group assignment (open-label study design). The allocation for each patient will be disclosed to the therapists, and the endpoint rater will be blinded. Eligible patients will be randomly assigned in a 1:1 ratio to either the lurasidone group (6-week lurasidone alone plus 24-week lurasidone and NEAR combination) or the paliperidone group (6-week paliperidone alone plus 24-week paliperidone and NEAR combination) using the minimization method, with balancing for age (≤39 years and ≥ 40 years), sex, and severity of cognitive impairment measured using the symbol coding task from the tablet-based BAC App (cutoff: 55 points). The cutoff for the BAC App symbol coding was determined by calculating the mean–one standard deviation of the symbol coding scores obtained when the Brief Assessment of Cognition in Schizophrenia Japanese version (BACS-J) was being developed (calculation: 67.4 points [mean] − 12.4 points [SD] = 55 points) (32). An electronic data capture system (HOPE eACReSS) managed by a central data center will be used for randomization.

The study protocol was approved by the Clinical Research Review Board of the National Center of Neurology and Psychiatry, National Research and Development Agency (CRB3200004), and written informed consent will be obtained from patients before enrollment. The study will be conducted in accordance with the principles of the Declaration of Helsinki and the Clinical Trials Act in Japan, and is registered under the identifier jRCTs031200338.¹

The following inclusion criteria must be met for enrollment in the study: Diagnostic and Statistical Manual of Mental Disorders (5th edition) criteria for schizophrenia; ability to provide in-person written informed consent; outpatient; aged 18–55 years at the time of informed consent; express a preference to switch antipsychotic drug and obtain agreement for this switch by the primary care physician; have presented no risk for self-harm or harming others in the 6 months prior to the date of informed consent; no acute illness requiring treatment; any chronic condition (e.g., hypertension) must be stable with treatment that has been continued for at least 1 month prior to participation; ability to participate in cognitive remediation sessions twice weekly (60–75 min per session); ability to undergo neuropsychological assessment (BAC App); chlorpromazine (CP) equivalent dose(s) of the prior antipsychotic drug(s) not more than 1,000 mg/day in the 30 days prior to the date of informed consent; and no change in the type of main agent of prior antipsychotic medication in the 30 days prior to the date of informed consent.

Exclusion criteria are as follows: a premorbid IQ of less than 70 on the Japanese Adult Reading Test-25 (33, 34); hearing or visual disability; non-native speaker of Japanese; currently receiving lurasidone, paliperidone, or clozapine; currently using three or more antipsychotic drugs; a history of treatment resistance, as evidenced by a failure to respond to at least two antipsychotic drugs when administered for at least 6 weeks at the dose specified on the package insert in the 12 months prior to the date of informed consent; receiving psychotropic drugs known to affect cognitive function, such as methamphetamine; administration of long-acting injections of antipsychotic drugs in the 6 weeks prior to the date of informed consent; a history of electroconvulsive therapy (ECT) in the 6 months prior to the date of informed consent or are expected to require ECT during participation in this study; a likelihood to attempt suicide during participation in this study; a history of intracranial disease or central nervous system disease (e.g., stroke, traumatic brain injury, epilepsy, Parkinson’s disease); a clinically significant abnormality in physical condition; a history of alcohol or drug abuse or addiction in the 6 months prior to the date of informed consent; pregnant or planning to become pregnant; breastfeeding; received cognitive remediation in the 6 months prior to the date of screening; any contraindication to lurasidone or paliperidone; and deemed ineligible for the study in the opinion of the investigator or subinvestigator.

During the pharmacotherapy alone period, 40 mg of lurasidone hydrochloride will be administered orally once daily after a meal. The dose will be adjusted as necessary depending on the age and symptoms of the patient; however, the dose should not exceed 80 mg/day. In the paliperidone group, patients will receive 6 mg of oral paliperidone once daily after breakfast. The dose will be adjusted as necessary, not to exceed 12 mg/day and using a daily dose increment of 3 mg with an interval of at least 5 days. In general, tapering of the prior antipsychotic medication (main agent) will be started simultaneously with the start of study drug treatment, initiating the switch from prior medication to study drug. Monitoring of the patient’s condition should be used as a guide for tapering the prior antipsychotic medication (main agent), which should be tapered and discontinued by Week 4. The study drug dose should remain unchanged during the first 4 to 6 weeks following treatment initiation. For drugs included as part of a patient’s prior antipsychotic treatment regimen other than the main agent, continuation of only one drug will be allowed during the study. The main agent is defined as an antipsychotic used at a dose greater than 50% of the daily CP equivalent. The dose should remain the same throughout the study and the drug must have been used for at least 30 days prior to the date of informed consent. The total antipsychotic dose, including the dose of the study drug, should not exceed a CP equivalent dose of 1,000 mg/day. The study drugs will be administered in accordance with the Japanese package insert. The dosage will be adjusted at the discretion of the attending physician within the range specified by the package insert.

Following the pharmacotherapy alone period, the NEAR combination treatment period will begin. NEAR will consist of cognitive task sessions lasting 45–60 min and bridging sessions lasting for 10 to 20 min. These sessions will be conducted twice weekly for 24 weeks. At least one of the practitioners at each site will have received training approved by the developer of NEAR, Alice Medalia (35). To ensure NEAR is being implemented correctly, on-site monitoring will be conducted for some sites using a fidelity scale. Regular supervision meetings will be held by the NEAR practitioners at each facility, either onsite or online. In this period, the dose of the study drug and other concomitant drugs will be maintained without change from the dose used during the pharmacotherapy alone period, but the dose of these drugs can be changed if the attending physician judges it necessary to do so.

Prohibited concomitant medications are as follows: as-needed but regular use of antipsychotic medications; adrenaline; strong inhibitors and inducers of cytochrome P450 3A4; and drugs that affect dopaminergic nerve activity, such as psychostimulants and prokinetic agents. Prohibited concomitant therapies are as follows: neuromodulation therapies such as ECT and repetitive transcranial magnetic stimulation therapy, any new psychotherapy other than NEAR, and psychosocial approaches that may affect cognitive function such as daycare and occupational therapy.

Restricted concomitant medications include antipsychotic drugs, psychotropic drugs, and antiparkinsonian drugs. Restrictions for antipsychotic drugs are as follows: antipsychotic drugs for treatment of adverse events (AEs) will be permitted on an as-needed basis up to three times weekly.

Psychotropic drugs are permitted under the following conditions. In general, psychotropic drugs (including antipsychotic drugs other than the main agent) that have been used for at least 30 days prior to the date of informed consent will be continued at the same dose during study participation. If any other psychotropic drug is used on an as-needed basis for treatment of AEs, lorazepam may be used up to 5 times weekly at a dose of ≤1 mg/day. Patients with insomnia may be treated up to 5 times weekly with zolpidem (≤10 mg/dose), eszopiclone (≤2 mg/dose), or zopiclone (≤10 mg/dose). However, none of these drugs should be used within the 12 h prior to cognitive function testing. Antiparkinsonian drugs may be used at an equivalent biperiden hydrochloride dose of ≤3 mg/day. Any concomitant therapy that has been used for at least 30 days prior to the date of informed consent may be continued at the same dosage during participation in the study.

The primary endpoint is the change from baseline in BAC App composite T-score at the end of the NEAR combination treatment period. BACS is a tool to assess both the composite and individual domain scores of cognitive function that are most frequently impaired and most strongly associated with outcomes in schizophrenia (36). The domains assessed include verbal memory, working memory, motor speed, attention, executive functions, and verbal fluency. BACS-J is the validated, Japanese version of BACS (37). The BAC App, which will be used in this study, is a tablet version of BACS/BACS-J (31).

Secondary endpoints include the change from baseline at the end of the NEAR combination treatment period in the Positive and Negative Syndrome Scale (PANSS) (38, 39), Brief Negative Symptom Scale (BNSS) (40, 41), Montgomery Åsberg Depression Rating Scale (MADRS) (42), BAC App subscale T-score, University of California San Diego Performance-based Skills Assessment-Brief (UPSA-B) (43, 44), Specific Levels of Functioning Scale (SLOF) (45, 46), Schizophrenia Quality of Life Scale (47, 48), EQ-5D-5L (49–51), Work Productivity and Activity Impairment Questionnaire (52), and Defeatist Performance Belief (53–55). Change from baseline to the end of the pharmacotherapy alone period and change from the end of the pharmacotherapy alone period to the end of the NEAR combination treatment period in each of these scale scores will also be included as secondary endpoints. Additional endpoints will include the proportion of patients who successfully switch from their prior antipsychotic treatment to the study drugs, the proportion of patients who discontinue the study treatments, the total number of NEAR sessions performed as part of the study treatment, and the proportion of patients who discontinue NEAR. All study raters will have received training in the use of PANSS, BNSS, MADRS, SLOF, UPSA-B, and BACS-J, as well as operational training for the BAC App (VeraSci).

Safety endpoints will include AEs, change in Drug-Induced Extrapyramidal Symptoms Scale (DIEPSS) from baseline and the pharmacotherapy alone period to the NEAR combination treatment period (56, 57), change in DIEPSS from baseline to the pharmacotherapy alone period, vital signs, height, body weight, and laboratory tests.

Assuming the standardized group difference of 0.5 based on the effect size (0.82 and 0.32) of previous studies (20, 27, 29, 30), the mixed models for repeated measures (MMRM) requires 64 patients for each group to achieve 80% power to detect a group difference of 0.5 at a two-sided significance level of 0.05 (58). With the anticipation that some patients would fail to switch from their prior antipsychotic drug to the study treatment, a dropout rate of 25% was assumed (27). Based on the above, the target sample size of this study was determined to be 170 patients (85 per group).

The efficacy and safety analyses will be based on the full analysis set, which will include all patients who are randomly allocated, undergo treatment, and are evaluated at least once. The per-protocol set will also be analyzed. Two-sided p-values will be presented; p < 0.05 will be considered statistically significant.

The primary endpoint, change from baseline to end of the NEAR combination treatment period in BAC App composite T-score, will be analyzed using the MMRM to estimate the difference between the groups. Covariates will be allocated group, time point, interaction term of the allocated group and time point, and baseline score. For all other scores of change, the repeated measures will be analyzed using the MMRM, and one-point measures will be analyzed using the linear models.

As a secondary analysis of changes from the end of the pharmacotherapy alone period, MMRM with the inverse probability weighting method will be used to adjust the imbalance between the groups caused by dropouts during the pharmacotherapy alone period. Weights will be estimated using logistic regression with explanatory variables that will be selected from treatment group, patient characteristics, baseline scale scores, occurrence of serious adverse effects, and their interaction terms.

The proportion of patients who complete the switch to the study drug, discontinue the pharmacotherapy alone period, and discontinue the NEAR combination treatment period will be compared between treatment groups using Fisher’s exact test. The number of NEAR sessions completed will be compared between treatment groups using the Wilcoxon test. Subgroup analyses will be performed by baseline BAC App composite T-score, age, sex, duration of disease, and baseline BAC App symbol coding score. Missing data will not be imputed.

AEs will be coded by System Organ Class and Preferred Term per the Medical Dictionary for Regulatory Activities, version J.25.1 or higher. The frequency and proportion of patients reporting AEs will be summarized by time point and group.

All statistical analyses will be conducted using SAS version 9.4 or higher (SAS Institute Inc., Cary, NC, USA) or R version 3.6 or higher.