Summary

• A real-world study (TIME) in patients (18-40 years) recently diagnosed with schizophrenia within the past 5 years showed a significant improvement in functionality, high satisfaction with treatment, and a favorable safety profile in patients treated with INVEGA TRINZA. A high percentage of patients did not require hospitalization or emergency room visits during the study period.¹
• A post hoc analysis of the real-world REMISSIO study assessed the impact of patient age (younger patients <35 years vs older patients ≥35 years) and disease duration (≤3 years vs >3 years) on efficacy and safety outcomes in patients with stable schizophrenia who were switched from INVEGA SUSTENNA^® (paliperidone palmitate 1-month [PP1M]) to INVEGA TRINZA in a naturalistic clinical setting. The proportion of patients that achieved symptomatic remission was similar between those with disease duration ≤3 years and those with disease duration >3 years (57.8% and 56.5%, respectively). Functional remission was achieved by 45.4% of patients <35 years of age and by 36% of patients ≥35 years of age, with a similar pattern observed when analyzed by disease duration. INVEGA TRINZA had a favorable safety profile and was well tolerated among both age groups.²
• In a post hoc analysis of patients with schizophrenia with varying durations of illness, treatment with INVEGA SUSTENNA and INVEGA TRINZA was associated with greater improvement in symptom reduction and functional outcomes in patients with shorter duration of illness (≤5 years and 6-10 years) vs those with longer duration (>10 years).³
• In a post hoc analysis of patients with early illness schizophrenia (duration ≤5 years), treatment with INVEGA TRINZA significantly delayed time to relapse and maintained symptomatic control and patient functioning vs placebo.⁴

Clinical Data

Real-World Study (TIME Study)

Garcia-Portilla et al (2021)¹ conducted a multicenter, noninterventional, prospective, 1-year study in Spain to assess the impact of INVEGA TRINZA on functionality in patients recently diagnosed with schizophrenia.

Study Design/Methods

Patients included were 18-40 years with a diagnosis of schizophrenia (DSM-5 criteria) within the past five years and were treated with INVEGA TRINZA for ≥6 months.

The efficacy outcomes included change in the Personal and Social Performance (PSP) total score from baseline to 12 months, Clinical Global Impression Schizophrenia (CGI-SCH), Treatment Medication Satisfaction Questionnaire (MSQ), Abnormal Involuntary Movement Scale (AIMS), and an ad hoc 11-point numeric rating scale (NRS) for injection site pain and satisfaction with sexual functioning. Adverse events and hospitalization data were also evaluated.

Results

A total of 110 patients were included in the study. Patient characteristics included a mean age of 30 years (80.2% males and 19.8% females). The mean time since diagnosis was 31.2 months. At 12 months, a total of 80.2% of patients were on antipsychotic monotherapy with INVEGA TRINZA with an average dose of 384.2 mg.

Statistically significant differences were observed in the mean total PSP score and CGI-SCH score. See Table: Change in Mean Total PSP Score and CGI-SCH Score from Baseline to Month 12. According to the MSQ, 57 (56.5%) patients were “very satisfied” or “extremely satisfied” at baseline compared to 67 (66.4%) patients with treatment at month 12.

The AIMS and NRS for satisfaction with sexual functions mean scores were not significantly different from that observed at baseline (P>0.05); however, a statistically significant decrease was observed in mean NRS score for injection site pain from baseline to endpoint (3.1 vs 2.6; P=0.022). During the study, 94 (93.1%) patients did not require hospitalization, 6 (5.9%) patients were hospitalized once, 1 (1.0%) was hospitalized twice, and 90 (89.1%) did not require an emergency room visit.

A total of 17 (15.5%) patients reported at least 1 TEAE (sexual dysfunction, n=4; movement disorders, n=4; metabolic disorders, n=3; amenorrhea, n=2; galactorrhea, n =1; toxicity to various agents, n=1; sluggishness, n=1; psychiatric decompensation, n=1; suicide attempt, n=1; hypovolemic shock, n=1; and peripheral edema, n=1).

Retrospective Study

Segarra et al (2021)⁵ conducted a retrospective, observational, 12-month analysis in Spain to compare oral risperidone/paliperidone to INVEGA SUSTENNA or INVEGA TRINZA in patients with nonaffective first episode psychosis (FEP).

Study Design/Methods

Patients included were ≥18 years with a documented diagnosis of nonaffective FEP. Retrospective data were retrieved from the integrated electronic medical record system from the Basque Country Health Service (2014-2018).

Results

Of the 221 patients identified with FEP (both affective and nonaffective), 48 patients had nonaffective FEP with a diagnosis of schizophrenia and were treated with oral risperidone/paliperidone (n=16), INVEGA SUSTENNA (n=16), or INVEGA TRINZA (n=16). Patients treated with INVEGA TRINZA had received INVEGA SUSTENNA for at least 4 months and were clinically stable prior to transitioning to INVEGA TRINZA.

The mean age (years) in the oral risperidone/paliperidone, INVEGA SUSTENNA, and INVEGA TRINZA group was 39.8, 29.6, and 35.8, respectively, with a duration of untreated psychosis (weeks) of 16.4, 17.5, and 15.8, respectively.

A significant reduction in mean Positive and Negative Syndrome Scale (PANSS) total score from baseline was observed in the oral risperidone/paliperidone, INVEGA SUSTENNA, and INVEGA TRINZA groups (all, P<0.001). See Table: Change in Mean PANSS Total Score from Baseline to Endpoint. At endpoint, patients in the INVEGA TRINZA group demonstrated significant improvements in CGI-S and CGI-I scores compared to those in the oral group (P=0.004) and INVEGA SUSTENNA group (P<0.001).

Adverse events were reported in 12 patients. The most common treatment-emergent adverse events were sedation (42%), sexual dysfunction (40%), and weight gain (25%). Weight gain was reported by more patients in the INVEGA SUSTENNA group (33%) than those in the oral risperidone/paliperidone group (25%) or INVEGA TRINZA group (12.5%).

Post Hoc Analysis of Real-World REMISSIO Study

Pungor et al (2020)² conducted a post hoc subgroup analysis of the REMISSIO study, evaluating efficacy and safety outcomes according to patient age (younger patients <35 years vs older patients ≥35 years) and disease duration (≤3 years vs >3 years) in patients with stable schizophrenia who were switched from INVEGA SUSTENNA to INVEGA TRINZA in a naturalistic clinical setting.

Study Design/Methods

Details of the real-world study are provided by Garcia-Portilla et al (2020)⁶. Briefly, the study included:

• Patients (aged 18-50 years) with schizophrenia who were likely to benefit from a switch to INVEGA TRINZA and had been adequately treated with INVEGA SUSTENNA for at least 4 months (with the last 2 doses being the same), and then transitioned to INVEGA TRINZA
• Two phases: a screening phase and a 52-week, open-label, flexible-dose INVEGA TRINZA treatment phase

In the present analysis, the primary efficacy endpoint was the proportion of patients achieving symptomatic remission. Secondary efficacy endpoints included time to symptomatic remission and change from baseline in PANSS total score and CGI-S and Clinical Global Impression of Change (CGI-C) scores.

Results

A total of 305 patients were included in the subgroup analysis (younger group, n=123; older group, n=182; ≤3 years disease duration, n=72; >3 years duration, n=233). The mean duration of exposure, dose, and distribution of INVEGA TRINZA were similar between the age and disease duration groups. The mean age of the younger group was 28.5 years compared to 41.9 years in the older group. Disease duration at baseline was also lower in the younger group vs the older group (mean time from schizophrenia diagnosis: 5.4 years vs 11.9 years, respectively).

At the last observation carried forward (LOCF) endpoint, total symptomatic remission was achieved by 60.7% of younger patients (95% confidence interval [CI]: 51.4-69.4%) and 54.1% of older patients (95% CI: 46.6-61.6%). According to disease duration, a similar proportion of patients achieved symptomatic remission in the ≤3 years and >3 years groups (57.8% and 56.5%, respectively). Median time to symptomatic remission was numerically shorter for the younger group compared to the older age group (189 days vs 273 days, respectively) and the ≤3 years group compared to the >3 years group (190.5 days vs 268 days, respectively); however, this was not statistically significant. Mean PANSS total score change from baseline in the younger and older group was -2.2 (95% CI: -3.7 to -0.8) and -3.6 (95% CI: -5.1 to -2.2), respectively, and in the ≤3 years and >3 years groups was -2.8 (95% CI: -4.9 to -0.7) and -3.2 (95% CI: -4.3 to -2.0), respectively. Mean CGI-S scores at baseline and LOCF were similar in both age groups. The proportion of patients with CGI-C score indicating improvement was slightly higher in the younger group compared to the older group (70.4% vs 66.1%, respectively) and in the ≤3 years group compared to the >3 years group (71.9% vs 66.7%, respectively).  

Safety data was similar between both age groups and disease duration groups. A summary of TEAEs that occurred in the modified intention-to-treat population is presented in Table: A Summary of TEAEs in the mITT Population.

Post Hoc Analysis of Non-Inferiority Study

Brown et al (2019)³ conducted a post hoc analysis of a randomized, double-blind, parallel-group, noninferiority study to evaluate the effect of INVEGA SUSTENNA and INVEGA TRINZA on symptom severity and functional remission in patients with schizophrenia with varying durations of disease.

Study Design/Methods

Details of the noninferiority study are provided by Savitz et al (2016).⁷ Briefly, the study included:

• Adults (18-70 years) with schizophrenia for ≥1 year with worsening symptoms before screening
• Three phases: a screening phase; a flexible-dose, 17-week, open-label phase with INVEGA SUSTENNA treatment; and a double-blind, 48-week, controlled phase during which subjects were randomized to fixed doses of INVEGA SUSTENNA or INVEGA TRINZA

In the present analysis, the PANSS score was used to determine symptom severity and the PSP score was used to evaluate functional status. Data from the noninferiority study were pooled to assess symptom severity and functional status based on duration of illness (≤5 years, 6-10 years, and >10 years since diagnosis).

Results

Of the 1427 patients included in the 17-week, open-label phase, 379/532 (71.2%) patients in the ≤5-year group, 235/337 (69.7%) in the 6-10-year group, and 380/558 (68.1%) in the >10-year group entered the double-blind phase. In the open-label and double-blind phases, the mean age of subjects was 31.5 years, 35.7-36.3 years, and 46.6-47.4 years in the ≤5-year, 6-10 year, and >10-year groups, respectively. In the 2-year period before study initiation, patients in the ≤5-year group had significantly more hospitalizations for psychosis compared with those in the >10-year group (P<0.001).

The incidence of relapse and all-cause discontinuation was similar across the ≤5-year, 6-10-year, and >10-year groups; relapse: 8%, 7%, and 10%, respectively; all-cause discontinuation: 26%, 23%, and 27%, respectively. While PANSS and PSP scores improved significantly in all subgroups from baseline to open-label endpoint and then continued to improve until the end of the double-blind phase, greater improvement was observed in patients with shorter duration of illness (≤5 years and 6-10 years) vs those with longer disease duration (>10 years). Additionally, functional remission (defined as PSP >70) was achieved by more patients in the ≤5-year and 6-10-year groups than those in the >10-year group during the open-label and double-blind phases. Functional remission starting from week 13 (open-label) and during the double-blind phase for ≥6 months was achieved by 26.4 % of patients in the ≤5-year group, 30.2% in the 6-10-year group, and 18.6% in the >10-year group.

The most commonly reported adverse event (≥5%) was increased weight during the double-blind phase in all groups (13.3%-29.2%). Weight gain was reported by more patients in the ≤5-year group (29% INVEGA SUSTENNA, 28% INVEGA TRINZA) than those in the 6-10-year group (16% INVEGA SUSTENNA, 23% INVEGA TRINZA) and >10-year group (16% INVEGA SUSTENNA, 13% INVEGA TRINZA).

Post Hoc Analysis of Relapse-Prevention Study

Bell Lynum et al (2018)⁴ conducted a post hoc analysis of a double-blind, randomized, placebo-controlled, relapse-prevention study to evaluate the efficacy and safety of INVEGA TRINZA in a subpopulation of patients with early illness schizophrenia.

Study Design/Methods

Details of the relapse-prevention study are provided by Berwaerts et al (2015).⁸ Briefly, the study included:

• Adults (aged 18-70 years) with schizophrenia for ≥1 year before screening
• Four phases: a 3-week screening phase; a flexible-dose, 17-week, open-label transition phase with INVEGA SUSTENNA treatment; a 12-week, open-label maintenance phase with one dose of INVEGA TRINZA; and a placebo-controlled, double-blind phase of variable duration

The present analysis focused on patients in this study with early illness schizophrenia, defined as those who were diagnosed with schizophrenia for ≤5 years before study enrollment. The primary efficacy variable for the post hoc analysis was time to first relapse in the double-blind phase.

Results

From the open-label phase (n=506), a total of 305 patients entered the double-blind phase: 160 patients were randomized to INVEGA TRINZA (n=62 [38.8%] with early illness) and 145 to placebo (n=57 [39.3%] with early illness). Among the early illness subgroup, 5 (8.1%) patients in the INVEGA TRINZA group and 12 (21.1%) patients in the placebo group experienced a relapse during the double-blind phase. The median time to relapse could not be estimated in each treatment group due to the low incidence of relapse (<50% of patients relapsed in each group). There was a significant delay in time to relapse with INVEGA TRINZA treatment vs placebo (P=0.027). Additionally, the risk of relapse was 3.08-fold higher (95% CI: 1.08-8.80; P=0.035) for patients who were randomized to placebo than for those who continued treatment with INVEGA TRINZA in the double-blind phase. PANSS total, CGI-S, and PSP scores were maintained during treatment with INVEGA TRINZA, but significantly worsened with placebo.

The most common treatment-emergent adverse events (≥2%) reported among the early illness subgroup that occurred more frequently with INVEGA TRINZA than with placebo in the double-blind phase included: weight increased (12.9% vs 3.5%), anxiety (9.7% vs 8.8%), nasopharyngitis (8.1% vs 3.5%), headache (8.1% vs 1.8%), urinary tract infection (6.5% vs 0.0%), and akathisia (3.2% vs 0.0%), respectively. Eight patients in the double-blind phase experienced 3 serious adverse events, which included paranoid-type schizophrenia (n=1) in the INVEGA TRINZA group and schizophrenia (n=6) and cellulitis (n=1) in the placebo group. No deaths were reported during the double-blind phase.

Literature Search

A literature search of MEDLINE^®, EMBASE^®, BIOSIS Previews^®, and DERWENT Drug File (and/or other resources, including internal/external databases) pertaining to this topic was conducted on 13 May 2024.