Summary

• Noninferiority between INVEGA TRINZA and INVEGA SUSTENNA (1-month paliperidone palmitate) was established in a long-term, double-blind (DB), randomized, controlled trial. The median time-to-relapse was not estimable in either group due to the low rate of relapse. Comparable safety and tolerability profiles for INVEGA SUSTENNA and INVEGA TRINZA were observed over the 48-week DB phase of the trial.¹
  • An analysis of the noninferiority trial demonstrated that both symptomatic and functional remission were achieved in a similar proportion of patients treated with INVEGA TRINZA and INVEGA SUSTENNA.²
  • Patients who received INVEGA SUSTENNA and INVEGA TRINZA showed similar improvement in negative symptoms in a post-hoc analysis of a noninferiority study.³
• In an analysis comparing relapse risk following discontinuation of treatment, patients who withdrew from treatment with INVEGA TRINZA demonstrated longer time to relapse versus those who discontinued treatment with INVEGA SUSTENNA and oral paliperidone.⁴
• A real-world observational study reported the effectiveness and effect on quality of life (QOL) after 1-year treatment with INVEGA TRINZA vs other long-acting injectables (LAIs). There was no statistically significant difference in urgent psychiatric consultations, number or length of hospitalizations, and WHOQOL-BREF, Clinical Global Impressions-Severity (CGI-S) and Global Assessment of Functioning (GAF) scores between the treatment groups. Adverse events were reported more frequently in patients in the INVEGA TRINZA and INVEGA SUSTENNA groups (41.7%), with weight gain reported significantly more frequently (P=0.022).⁵
• A real-world retrospective study of Texas Medicaid enrollees with schizophrenia and with ≥1 claims for treatment with second-generation (SG)-LAI antipsychotics between 2015 and 2019 reported significantly higher adherence rate for INVEGA TRINZA compared to other SG-LAIs (P≤0.01), including INVEGA SUSTENNA, risperidone 4-week, aripiprazole once-monthly (AOM), aripiprazole lauroxil (AL) 1-month, and 2-month.⁶

DOSAGE STRENGTH INFORMATION

Doses of paliperidone palmitate extended-release injectable suspension may be expressed in milligram equivalents of paliperidone (active moiety) or milligrams of paliperidone palmitate. Dosage information in this response has been converted to mg of paliperidone palmitate to reflect the commercially available INVEGA SUSTENNA and INVEGA TRINZA dosage strengths. The conversion factor from mg eq. to mg is 1.56.

• INVEGA SUSTENNA doses expressed as 25, 50, 75, 100, and 150 mg eq. are equal to 39, 78, 117, 156, and 234 mg of paliperidone palmitate, respectively.
• INVEGA TRINZA doses expressed as 175, 263, 350, and 525 mg eq. are equal to 273, 410, 546, and 819 mg of paliperidone palmitate, respectively.

CLINICAL STUDIEs

Randomized Controlled Studies

Savitz et al (2016)¹ conducted a randomized, DB, parallel-group, multicenter, noninferiority study of INVEGA TRINZA and INVEGA SUSTENNA. The primary endpoint was the percentage of patients who remained relapse-free at the end of the 48-week DB phase.

Study Design/Methods

The study consisted of 4 phases: a 3-week screening phase, a 17-week, open-label (OL) stabilization phase, a 48-week DB phase, and a follow-up phase.

The study included patients between the ages of 18-70 years diagnosed with schizophrenia (Diagnostic and Statistical Manual of Mental Disorders, 4th Edition [DSM-IV]) and a Positive and Negative Syndrome Scale (PANSS) score between 70-120 who had worsening schizophrenia symptoms and discontinued other antipsychotics due to insufficient efficacy, safety or tolerability issues with current treatment, or those with a preference for injectable medications.

During the OL phase, 1429 patients received INVEGA SUSTENNA in the following doses:

• Day 1: 234 mg (deltoid administration)
• Day 8: 156 mg (deltoid administration)
• Weeks 5 and 9: flexible dosing between 78-234 mg (deltoid or gluteal administration); the week 13 dose was the same as week 9

Patients who were clinically stable after completing the OL phase were randomized (1:1) into the DB phase. Patients in the DB phase received fixed doses of INVEGA SUSTENNA (78, 117, 156 or 234 mg; n=512) or INVEGA TRINZA (273, 410, 546, 819 mg; n=504) in the deltoid or gluteal muscle. In the INVEGA SUSTENNA group, injections occurred every 4 weeks and in the INVEGA TRINZA group placebo injections were given monthly when active therapy was not administered.

Results

During the OL phase, the study enrolled 55% males, and the mean age of all participants was 38 years with a mean total PANSS score of 85.7. Baseline and demographic characteristics were similar between the INVEGA TRINZA and INVEGA SUSTENNA groups during the DB phase. Overall, 83% of patients completed the DB phase of the trial, including those who experienced relapse. The rate of relapse was similar between INVEGA TRINZA (n=37, 8%) and INVEGA SUSTENNA (n=45, 9%). The estimated Kaplan-Meier difference between INVEGA TRINZA and INVEGA SUSTENNA and was found to be 1.2% (95% confidence interval [CI]: -2.7%, 5.1%) demonstrating that INVEGA TRINZA was noninferior to INVEGA SUSTENNA based on the pre-defined criteria. See Figure: Time-to-Relapse During the Double-blind Phase (Based on per-Protocol Analysis, n=948).

The median time-to-relapse was not estimable for INVEGA TRINZA or INVEGA SUSTENNA due to a low incidence of relapse. In the DB phase, the hazard ratio for relapse for switching from INVEGA SUSTENNA to INVEGA TRINZA vs remaining on INVEGA SUSTENNA was 0.87 (95% CI: 0.56, 1.34).

An increase of ≥25% in the total PANSS score (5% of patients in both INVEGA TRINZA and INVEGA SUSTENNA groups), and psychiatric hospitalizations (3% in INVEGA TRINZA; 4% in INVEGA SUSTENNA) were the most common reasons for relapse.

The secondary endpoints also improved from DB baseline to endpoint in both groups. The endpoints included PANSS total score change from baseline INVEGA TRINZA vs INVEGA SUSTENNA (-3.5 vs -4.3 [95% CI: -0.61, 2.34]), CGI-S change from baseline (-0.1 vs -0.1 [95% CI: -0.05, 0.13]), Personal and Social Performance scale (PSP) score change from baseline (1.3 vs 1.9 [95% CI: -1.73, 0.64]). The DB 6-month symptomatic remission status (defined by Andreasen remission criteria) was 58% (282/483) and 59% (303/512) for INVEGA TRINZA and INVEGA SUSTENNA, respectively (relative risk 0.98; 95% CI 0.89, 1.08).

Pharmacokinetics

The paliperidone plasma concentration-time profiles for the corresponding INVEGA SUSTENNA and INVEGA TRINZA doses (78 vs 273 mg, 117 vs 410 mg, 156 vs 546 mg, and 234 vs 819 mg) completely overlapped from beginning of the DB period (day 120) until the end of the DB period (day 456).

Safety

During the DB phase, a similar percentage of patients in the INVEGA TRINZA and INVEGA SUSTENNA groups experienced treatment-emergent adverse events (TEAEs; 68% vs 66%). The most common TEAEs (≥5% of patients) during the DB phase for INVEGA TRINZA vs INVEGA SUSTENNA were weight increase (21% for both groups), nasopharyngitis (7% vs 6%), anxiety (5% in both groups), headache (4% vs 5%) and insomnia (3% vs 5%). The extrapyramidal symptom-related TEAEs (≥ 2%) observed in INVEGA TRINZA vs INVEGA SUSTENNA were akathisia (4% vs 3%), tremor (2% vs 1%), and musculoskeletal stiffness (1% vs 2%). The most common TEAEs leading to drug withdrawal in INVEGA TRINZA vs INVEGA SUSTENNA were akathisia (0.2% vs 0.4%), anxiety (0.4% vs 0.0%), and galactorrhea (0.2% vs 0.4%).

Najarian et al (2022)⁸ conducted a phase 3, randomized, DB, active-controlled, interventional, parallel-group, multicenter, noninferiority study (N=702) to evaluate the efficacy and safety of INVEGA HAFYERA for the treatment of schizophrenia in adult patients who had previously been stabilized on either INVEGA SUSTENNA for ≥4 months or INVEGA TRINZA for ≥1 injection cycle of 3 months. In the intent-to-treat (ITT) analysis at the end of the 12-month DB phase, INVEGA HAFYERA demonstrated noninferiority to INVEGA TRINZA on the primary endpoint of time to first relapse. A relapse event occurred in 7.5% of patients in the INVEGA HAFYERA treatment group and 4.9% in the INVEGA TRINZA treatment group. The safety profile of INVEGA HAFYERA was generally consistent with previous studies of INVEGA SUSTENNA and INVEGA TRINZA.

Post-Hoc Analyses of the INVEGA TRINZA vs INVEGA SUSTENNA Noninferiority Trial

Gopal et al (2020)³ conducted a post-hoc analysis of the noninferiority study trial to assess improvement in negative symptoms in patients treated with INVEGA TRINZA compared to INVEGA SUSTENNA. The PANSS total score, subscale scores (PANSS negative and PANSS positive subscales), and 5 PANSS Marder factor scores (evaluated based on positive symptoms, negative symptoms, disorganized thoughts, uncontrolled hostility/excitement, and anxiety/depression) were calculated every 4 weeks between DB baseline and DB endpoint. Severe negative symptoms were based on the PANSS subscales and the PANSS Marder factor scores and were classified as severe if a patient displayed a baseline negative factor score of >25.

Following stabilization with INVEGA SUSTENNA, at DB baseline the negative symptoms factor was 16.2 and the negative subscale score was 17.3; negative subscale scores were comparable between INVEGA SUSTENNA and INVEGA TRINZA (17.4 vs 17.3, respectively) and both declined over time. From OL endpoint to DB endpoint, the negative symptom factor significantly declined to 14.9 (P<0.0001) in all patients treated with INVEGA SUSTENNA and INVEGA TRINZA.

Mean negative subscale scores at DB endpoint were 15.9 for INVEGA SUSTENNA and 15.8 for INVEGA TRINZA groups. The mean change in negative subscale score from DB baseline to endpoint was significant and comparable between INVEGA SUSTENNA and INVEGA TRINZA (-1.4 for both; P<0.0001). At DB endpoint, the mean negative symptoms factors were similar in the severe and less severe patient groups (16.1 vs 13.3, respectively).

Russu et al (2019)⁹ conducted an analysis of the noninferiority trial using pharmacokinetic-pharmacodynamic modeling to evaluate the relationship between the time course of paliperidone plasma concentrations and the risk of relapse of schizophrenia symptoms. Among 1002 patients randomized to receive INVEGA TRINZA or INVEGA SUSTENNA in the DB phase of the noninferiority trial, risk of relapse decreased with increasing paliperidone concentrations for both INVEGA TRINZA and INVEGA SUSTENNA. Model-based simulations demonstrated that both INVEGA TRINZA and INVEGA SUSTENNA were associated with similar relapse rates over time, confirming comparable efficacy in relapse prevention.

Savitz et al (2017)² conducted a post-hoc analysis of the noninferiority trial¹ to assess symptomatic and functional remission. Symptomatic remission was assessed according to Andreasen’s criteria (score of ≤3 on 8 individual PANSS items) for the last 6 months of DB treatment (with no excursions). 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, symptomatic remission was achieved by 50.3% of the 483 patients in the INVEGA TRINZA group and 50.8% of the 512 patients in the INVEGA SUSTENNA group. Functional remission was achieved and maintained during the same period of time in 27.3% of INVEGA TRINZA and 30.1% of INVEGA SUSTENNA patients. Both symptomatic and functional remission were achieved during the last 6 months of the DB period (defined as symptomatic remission with 1 excursion allowed and PSP >70 with no excursions) in 25.1% of INVEGA TRINZA and 26.6% of INVEGA SUSTENNA patients. Most patients who entered the DB phase in remission maintained their remission status throughout the DB phase.

Post-Hoc Analysis - Time to Relapse Comparison of Oral Paliperidone, INVEGA SUSTENNA, and INVEGA TRINZA

Weiden et al (2017)⁴ compared the effect of 3 different formulations of paliperidone (oral paliperidone, INVEGA SUSTENNA, INVEGA TRINZA) on times to relapse following medication discontinuation. Using final analysis datasets from 3 similarly designed, multicenter, DB, placebo-controlled, randomized-withdrawal studies in patients with schizophrenia, the median times to relapse were compared from the treatment-withdrawal arms of each study. Among 449 patients (oral paliperidone [n=101], INVEGA SUSTENNA [n=203], INVEGA TRINZA [n=145]) who were withdrawn from treatment, the post-withdrawal median days to relapse were: 58 days for oral paliperidone, 172 days for INVEGA SUSTENNA, and 395 days for INVEGA TRINZA. The risk of relapse was 56% lower for patients discontinuing INVEGA SUSTENNA versus those discontinuing oral paliperidone, 79% lower for patients discontinuing INVEGA TRINZA versus those discontinuing oral paliperidone, and 52% lower for patients discontinuing INVEGA TRINZA versus those discontinuing INVEGA SUSTENNA (P<0.001 for all comparisons).

Real-world Observational Studies

Di Lorenzo et al (2022)⁵ conducted a real-world observational cohort study between June 2019 and October 2020 in an Italian outpatient mental health center, comparing the effectiveness and effect on QOL after 1-year of treatment with INVEGA TRINZA vs INVEGA SUSTENNA and haloperidol decanoate (HAL-D) in patients diagnosed with schizophrenia spectrum disorders.

Study Design/Methods

Adult patients with schizophrenia spectrum disorders and on LAI therapy for at least 6 months were included in the study. In the 1-year treatment period, the following outcomes were evaluated:

• Number of urgent psychiatric consultations and number and length of psychiatric hospitalizations
• Adverse events and increases in weight (indicated by change in body mass index)
• Discontinuations
• QOL assessment at 6 and 12 months (assessed by the World Health Organization quality of life-26 items [World Health Organization Quality of Life Scale Brief Version, WHOQOL-BREF])
• Severity of disease at 6 and 12 months (assessed by the CGI-S scale)
• Physician’s assessment of global functioning (assessed by the GAF scale)

Results

• Overall, 90 patients (INVEGA TRINZA, n=26; INVEGA SUSTENNA, n=27; and HAL-D, n=37) were evaluated, of whom 12 (13.3%) discontinued treatment after 6 months.
• Approximately 85% of patients treated with HAL-D were being treated with concomitant oral psychiatric medication (including oral antipsychotics) at 6 and 12 months. This was significantly higher than the proportion of patients in the INVEGA TRINZA (65% and 50%) and INVEGA SUSTENNA (50% and 41%) arms at 6 and 12 months, respectively.
• Mean dosages administered during the treatment period included the following: INVEGA TRINZA, 293.27 mg (standard deviation [SD], 130.61); INVEGA SUSTENNA, 85.29 mg (SD, 36.51); and HAL-D, 112.5 mg (SD, 54.79).
• At 12 months, no statistically significant differences in urgent psychiatric consultations and number or length of hospitalizations were reported between the treatment groups.
• Side effects were reported in 49.3% of patients in all treatment groups, with significant difference between groups (P=0.001).
  • Adverse events were reported more frequently in patients in the INVEGA TRINZA and INVEGA SUSTENNA groups (41.7%).
  • Weight gain was reported significantly more frequently in the INVEGA TRINZA and INVEGA SUSTENNA groups (P=0.022).
• No significant differences in scores on the total scale and the 4 domains of WHOQOL-BREF (physical health, psychological conditions, social relations, and environment) were reported between treatment groups.
  • Significantly more patients reported better perception of QOL and health satisfaction (HS) at 12 months vs 6 months after treatment with LAIs (QOL: P=0.000, Pearson chi-square test=36.6; HS: P=0.006, Pearson chi-square test=33.85).
• No statistically significant difference between the treatments was found on CGI-S and GAF scores; however, across all the treatments, patients showed significant improvement in GAF scores at 12 months vs 6 months (P=0.01; t-test=-2.44).

Limitations

• The sample size was small due to the recent availability of INVEGA TRINZA.
• The three treatment groups had significantly different lengths of treatment durations, with patients on INVEGA TRINZA having the shortest time on treatment.
• The observation period was short.

Chen et al (2023)⁶ conducted a retrospective cohort study using data from the Texas Medicaid database between 2015 and 2019 to evaluate the adherence to SG-LAI antipsychotics, including INVEGA TRINZA, INVEGA SUSTENNA, AL 1-month, AL 2-month, risperidone 4-week, and AOM, in adult patients (age range, 18-63 years, N=4,422) with schizophrenia and with ≥1 claims for treatment with SG-LAIs. Medication adherence was evaluated by the proportion of days covered (PDC) during the 12-month follow-up (adherence was defined by PDC≥0.8).

Baseline demographic and clinical characteristics were similar across all treatment groups. The mean PDC was highest for INVEGA TRINZA (0.91±0.20), followed by AL 2-month (0.69±0.34), risperidone 4-week (0.64±0.34), AOM (0.63±0.33), INVEGA SUSTENNA (0.62±0.33), and AL 1-month (0.57±0.33). The adherence rate for INVEGA TRINZA was 86.9%; AL 2-month, 60.2%; risperidone 4-week, 44.8%; AOM, 44.3%; INVEGA SUSTENNA, 41.3%; and AL 1-month, 33.4%. The adherence rate for INVEGA TRINZA was significantly higher than the other SG-LAIs (P≤0.01).

LITERATURE SEARCH

A literature search of MEDLINE^®, EMBASE^®, BIOSIS Previews^®, DERWENT Drug File (and/or other resources, including internal/external databases) pertaining to this topic was conducted on 23 October 2024.