Summary

• Berwaerts et al (2015)¹ conducted a long-term, double-blind (DB), placebo-controlled (PBO-controlled), relapse-prevention study that showed INVEGA TRINZA was superior to placebo in delaying the time to first relapse in patients with schizophrenia. The study also found significant differences in favor of INVEGA TRINZA vs placebo in the mean change in Personal and Social Performance Scale (PSP) and Clinical Global Impression-Severity Scale (CGI-S) scores.
• Garcia-Portilla et al (2020)² conducted a real-world study of patients with schizophrenia who were adequately treated with INVEGA SUSTENNA^® (paliperidone palmitate 1-month) for at least 4 months and then converted to INVEGA TRINZA, which reported that personal and social functioning, as well as patient well-being, were maintained over the course of treatment with INVEGA TRINZA. A high level of physician and patient overall satisfaction was also maintained from baseline to endpoint.
• Di Lorenzo et al (2022)³ conducted an observational cohort study evaluating the effectiveness and quality of life (QoL) of INVEGA TRINZA compared with INVEGA SUSTENNA and haloperidol decanoate (HAL-D). No significant differences were seen among the 3 treatment groups in the mean scores of CGI-S, World Health Organization Quality of Life-26 Items (WHOQOL-BREF), and Global Assessment of Functioning (GAF).
• Garcia-Portilla et al (2022)⁴ conducted an observational, prospective study of recently diagnosed patients with schizophrenia that showed a significant difference in total PSP score (P<0.001) and a decrease in Clinical Global Impression-Schizophrenia (CGI-Sch) severity score (P<0.001).
• Barnett et al (2023)⁵ conducted a real-world, observational study evaluating the experience of switching from INVEGA SUSTENNA to INVEGA TRINZA in 46 patients with schizophrenia and schizoaffective disorders, which found that 93.5% of the patients reported that switching to INVEGA TRINZA was convenient with no disadvantages.

RATING SCALES

Clinical Context of the PSP Scale: A post hoc correlation analysis of nine clinical trials of paliperidone extended-release (ER) or paliperidone palmitate found that PSP scores correlate most strongly with the Clinical Global Impression (CGI), Positive and Negative Syndrome Scale (PANSS), and the Symptoms and Quality of Life in Schizophrenia Scale (P<0.0001).⁸ A second post hoc analysis found an association between change in functional status, as measured by the PSP, and change in PANSS, change in CGI, or a shorter duration of schizophrenia.⁹ According to an exploratory post hoc analysis of a relapse prevention clinical trial with paliperidone ER, a 10-point worsening in PSP score marks the threshold for a clinically meaningful decline in personal and social performance. A validation post hoc analysis of a relapse prevention clinical trial with paliperidone palmitate applied this 10-point decrement in PSP scores. The validation post hoc analysis found a 10-point worsening of PSP scores highly predictive of relapse.¹⁰

CLINICAL STUDIES

Randomized Clinical Trials

Berwaerts et al (2015)¹ conducted a long-term, DB, PBO-controlled, relapse-prevention study to evaluate the efficacy and safety of INVEGA TRINZA vs PBO in delaying time-to-relapse of schizophrenia symptoms in patients previously treated with INVEGA SUSTENNA for at least 4 months.

Study Design/Methods

• The study included 4 phases: a screening and oral tolerability testing phase of up to 3 weeks, a 17-week, open-label (OL) transition phase, a 12-week, OL maintenance phase, and a DB phase of variable length.
• During the transition phase, all patients except those who were receiving other long-acting injectable (LAI) antipsychotics or those who were receiving INVEGA SUSTENNA before entering the study received 4 months of INVEGA SUSTENNA treatment.
• During the maintenance phase, patients received a single dose of INVEGA TRINZA (273, 410, 546, or 819 mg; a 3.5-fold multiple of the final INVEGA SUSTENNA dose administered) in either the deltoid or gluteal muscle.
• During the DB phase, stabilized patients were randomized 1:1 to receive a fixed dose of INVEGA TRINZA (the same dose as during the maintenance phase) or PBO.
• The primary efficacy endpoint was the time to first relapse. Secondary endpoints included a comparison of PSP and CGI-S scores.

Results

• INVEGA TRINZA significantly delayed the time to first relapse compared to PBO (P<0.001).
• Mean OL baseline PSP and CGI-S scores were 58.7 (standard deviation [SD], 12.13) and 3.8 (SD, 0.89), respectively.
  • In the INVEGA TRINZA arm, mean DB baseline PSP and CGI-S scores were 68.8
    (SD, 9.27) and 2.7 (SD, 0.67), respectively.
  • In the PBO arm, mean DB baseline PSP and CGI-S scores were 68.6 (SD, 9.01) and 2.8 (SD, 0.65), respectively.
  • Significant differences were seen in favor of INVEGA TRINZA vs PBO in mean change in PSP scores (-0.5 [SD, 6.63] vs -4.2 [SD, 9.70]) and CGI-S scores (0.1 [SD, 0.60] vs 0.4 [SD, 0.87]) from DB baseline to endpoint (P<0.001).
• PSP scores by category (poor, variable, good) are summarized in Table: PSP Scores by Category During Double-Blind Phase.

Post-hoc Analysis

Savitz et al (2017)¹¹ conducted a post hoc analysis of a randomized, DB, parallel-group, multicenter, noninferiority study of INVEGA TRINZA and INVEGA SUSTENNA¹² to assess symptomatic and functional remission. Functional remission (defined as PSP score >70) during the last 6 months of DB treatment (with no excursions) was assessed based upon 4 domains of behavior: 1) socially useful activities, 2) personal/social relationships, 3) self-care, and 4) disturbing and aggressive behavior. During the last 6 months of the DB phase, functional remission was achieved and maintained in 27.3% of INVEGA TRINZA patients and 30.1% of INVEGA SUSTENNA patients.

Observational Studies

Garcia-Portilla et al (2020)² conducted a prospective, single-arm, OL, 52-week realworld study of patients with clinically stable schizophrenia who transitioned from treatment with INVEGA SUSTENNA to INVEGA TRINZA to assess the percentage of patients who achieved symptomatic remission (SR).

Study Design/Methods

• 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.
• The treatment duration for INVEGA TRINZA was from day 1 to day 360, with the last injection at day 270 (±14 days).
• The primary outcome (at last observation carried forward [LOCF]) was the percentage of patients who achieved SR, defined as a score ≤3 on 8 PANSS items (P1, P2, P3, N1, N4, N6, G5, and G9) maintained for ≥6 months.
• Secondary outcomes included achievement of SR at months 6, 9, and 12, maintenance of SR, changes in PANSS total and subscores, PANSS Marder factors, CGI-S, Clinical Global Impression of Change (CGI-C), and adverse events.

Results

Efficacy

• The modified intent-to-treat (mITT) population included 305 patients (mean age 36.5 years, two-thirds being male). A total of 291 (95.4%) patients completed the study.
• The distribution among patients of the last INVEGA SUSTENNA dose before conversion to INVEGA TRINZA was: 78 mg (8.9%), 117 mg (24.3%), 156 mg (37.4%), and 234 mg (29.5%). Most patients received INVEGA SUSTENNA treatment for over 6 months and were on INVEGA SUSTENNA monotherapy before conversion to INVEGA TRINZA.
• At the LOCF endpoint, SR was achieved by 172/303 (56.8%; 95% confidence interval [CI], 51.0-62.4) patients. The median time to SR was 247 days (95% CI, 189-275).
  • Achievement of SR at LOCF was higher in patients with >6 months of previous treatment with INVEGA SUSTENNA compared to those with 4 to 6 months of treatment (58.3% vs 50.9%, respectively).
• From baseline to LOCF endpoint, the mean PANSS total score decreased from 52.4 to 49.4, indicating a mean change of -3.1 (95% CI, -4.1 to -2.0) and maintained efficacy with INVEGA TRINZA (P<0.0001).
  • Among these patients, 142 (46.9%) patients met the PANSS severity criterion at baseline and all time points during the treatment period.
• The patients who achieved SR at baseline (58.1%) and remained stable from month 6 to month 12 was over 85%. The mean CGI-S score remained stable, from 3.2 at baseline to 3.0 at LOCF endpoint, with the percentage of patients considered moderate-to-severely ill decreased from baseline to LOCF endpoint (35.4% vs 25.7%, respectively).

Safety

• At least one treatment-emergent adverse event (TEAE) was reported in 161 (53.1%) patients in the mITT population.
• The most common TEAEs (≥3%) were weight increase (8.6%), injection site pain (5.9%), viral upper respiratory infection (3.6%), insomnia (3.6%) schizophrenia (3.3%), and weight decrease (3.3%). No deaths were reported during the study period.
• Eighteen (5.9%) patients reported a serious TEAE, 7 (2.6%) reported a severe TEAE and 4 (1.3%) patients discontinued the study due to TEAEs.
• Possible prolactin-related TEAEs were reported by 14 (4.6%) patients and included menstrual disturbance, sexual or erectile dysfunction, galactorrhea, and hyperprolactinemia.
• Increased weight (>7% from baseline) was observed in 10.4%, 11.6%, and 9.3% of patients with baseline body mass index <25 kg/m², 25 to <30 kg/m², and ≥30 kg/m², respectively.

Di Lorenzo et al (2022)³ conducted an observational cohort study to assess the effectiveness and QoL of INVEGA TRINZA compared with INVEGA SUSTENNA and HAL-D.

Study Design/Methods

• Data was collected from all outpatient community Mental Health Centers (MHCs) of the Department of Mental Health and Pathological Addictions of AUSL-Modena in Italy from  June 1, 2019 to October 28, 2020.
• The study included patients aged >18 years who were diagnosed with schizophrenia spectrum disorders and treated with HAL-D, INVEGA SUSTENNA, or INVEGA TRINZA for ≥6 months.
• During the 1-year treatment period, the study compared the number of psychiatric hospitalizations, urgent psychiatric consultations, adverse events, and increase in weight (change in body mass index [BMI]) in the HAL-D, INVEGA SUSTENNA, and INVEGA TRINZA treatment groups. WHOQOL-BREF, GAF, and CGI-S scores were evaluated at 6 and 12 months of treatment.

Results

• Overall, 90 patients were included in the study (male, n=58; mean age, 52.4 years). A total of 73 patients completed the study (HAL-D, n=34; INVEGA SUSTENNA, n=17; INVEGA TRINZA, n=22).
• Results pertaining to the number of hospitalizations, psychiatric consultations, adverse events, and BMI at 1-year follow-up are presented in Table: Hospitalization, Psychiatric Consultation, Adverse Events, and BMI.

• Mean scores of CGI-S and GAF did not show any statistically significant differences among the 3 treatment groups.
• No statistically significant difference was observed in the total scale and 4 domain WHOQOL-BREF score in the 3 treatment groups.
  • According to the 2-item WHOQOL-BREF score, among patients receiving LAIs, 69% reported QoL as “very good” or “good”, 3% reported their QoL as “very bad” or “bad”, 71% were “satisfied” or “very satisfied” with their health status, and 13% were dissatisfied or “very dissatisfied”.
• The proportion of patients reporting better QoL and health satisfaction significantly increased in all 3 treatment groups after 12 months vs 6 months of treatment (P=0.000 and P=0.006, respectively).

Garcia-Portilla et al (2022)⁴ conducted a real-world, prospective, observational study in Spain from April 2018 to July 2019 to evaluate the impact of INVEGA TRINZA on the functionality of patients recently diagnosed with schizophrenia.

Study Design/Methods

• Adult patients diagnosed with schizophrenia within 5 years of the study and treated with INVEGA TRINZA for at least 6 months before the study were included.
• Assessments at the baseline, 6-, and 12-month were made using the PSP scale, the CGI-Sch scale, the Medication Satisfaction Questionnaire (MSQ), the Involvement Evaluation Questionnaire (IEQ), the Abnormal Involuntary Movement Scale (AIMS), and ad-hoc scales (1-11) for injection site pain and sexual function.

Results

• Of the 110 patients included, 101 (91.8%) completed the study (male, 80.2%; mean [SD] age, 30.0 [6.1] years), and 44.6% were first-episode patients currently in full or partial remission.
• Before initiation on INVEGA TRINZA, patients were treated with a mean (SD) final dose of 116.6 (34.0) mg INVEGA SUSTENNA over a mean (SD) treatment length of 22.1 (18.7) months.
• Patients received a mean (SD) dose of 402.9 (119.7) mg INVEGA TRINZA over a mean (SD) treatment length of 24.0 (6.8) months. Seventy (69.3%) patients were maintained with INVEGA TRINZA as antipsychotic monotherapy throughout the study.  
• Concomitant psychotropics included benzodiazepines (35.6%), antidepressants (23.8%), anticholinergics (5.9%), and mood stabilizers (11.9%).
• The total PSP mean score significantly increased from the baseline at both follow-ups (baseline to 6-month difference [95% CI], 3.6 [1.6-5.5]; P<0.001 and baseline to 12-month difference, 6.2 [4.2-8.3]; P<0.001).
• The overall CGI-Sch mean score significantly decreased from the baseline at 12 months (baseline to 12-month difference [95% CI], -0.6 [-0.8 to -0.4]; P<0.001).
• During the treatment period, 1 (1.0%) patient was hospitalized twice and 6 (5.9%) patients once; the majority of patients (93.1%) did not require psychiatric hospitalization.
• In patient satisfaction (evaluated by the MSQ), patients who reported ‘extremely’ or ‘very’ satisfied with the treatment were 56.5% at the baseline, 55.4% at 6 months, and 66.4% at 12 months. No significant change was reported in caregiver burden evaluated by the IEQ.
• Of the 110 patients evaluated for safety, 17 (15.5%) reported at least one adverse event. Overall, 20 adverse events were reported, including 4 serious adverse events, all evaluated as unrelated to INVEGA TRINZA, and patients recovered without interruptions of INVEGA TRINZA.
• The AIMS analysis indicated no change throughout the study period. At 12 months, most patients (83.5%; 81/97) reported no abnormal movements (severity category ‘none’).
• No significant change in weight or sexual functioning was noted from the baseline at 12 months. A significant reduction in injection site pain was reported at 12 months vs the baseline from a mean (SD) of 3.1 (2.6) at baseline to 2.6 (2.3) at 12 months on an 11-point scale (P=0.022).

Barnett et al (2023)⁵ conducted a cross-sectional, multicenter, real-world, observational study in London from April to June 2020 in patients primarily diagnosed with schizophrenia to evaluate their experience of switching from INVEGA SUSTENNA to INVEGA TRINZA.

Study Design/Methods

• Patients who consented to participate in the study were already receiving INVEGA TRINZA under the care of secondary mental health services, and demonstrated adequate mental capacity. INVEGA TRINZA was initiated as part of an independent prescribing decision without any change to the standard of care.
• All demographical and clinical information, including the number of hospitalizations 1 year before and after initiation of INVEGA TRINZA, compliance (number of injections in 1 year), and discontinuation rate at 1 year, were obtained from the electronic clinical records system.
• The experience of switching from INVEGA SUSTENNA to INVEGA TRINZA was recorded via a 4-part questionnaire co-developed by 2 psychiatrists that included satisfaction, feeling of safety during the COVID-19 pandemic, advantages, and disadvantages.

Results

• Forty-six patients were included (male, n=31; average age, 48.5 years; age range, 23-78 years).
• Patients were diagnosed with schizophrenia (84.8%) or schizoaffective disorder (15.2%). INVEGA TRINZA is not indicated for use with schizoaffective disorder in the United States.
• Patients were treated for 47.0 months (mean treatment length) with INVEGA SUSTENNA before switching to INVEGA TRINZA.
• Patients requiring hospitalizations decreased 1 year after treatment with INVEGA TRINZA vs 1 year before the switch (6.5% [n=3] vs 19.6% [n=9]).
• Forty-five (97.8%) patients completed 1 year of treatment with INVEGA TRINZA with 100% compliance; 1 (2.2%) patient discontinued after receiving 2 doses of INVEGA TRINZA due to worsening of symptoms.
• Regarding feeling satisfaction after switching to INVEGA TRINZA, 32 (69.6%) patients responded, “strongly agreed”; 9 (19.6%), “agreed”; 3 (6.5%), “neither agreed nor disagreed”; and 2 (4.3%), “disagreed”. None reported “strongly disagreed”.
• Among the list of advantages of switching to INVEGA TRINZA, 43 (93.5%) patients selected, convenience; 27 (58.7%), improved quality of life; 18 (39.1%), decreased stigma; 13 (28.3%), better compliance; and 10 (21.7%), improved side effects. Three (6.5%) patients reported not experiencing any advantages.
• Regarding the disadvantages of switching to INVEGA TRINZA, 43 (93.5%) patients reported experiencing no disadvantages, 2 (4.3%) reported worsening/new side effects, and 1 (2.2%) reported worsening of symptoms.

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 10 May 2024.