Summary

• Cognitive endpoints were not included in the pivotal schizophrenia^1-6 or schizoaffective trials⁷ for INVEGA SUSTENNA.
  • During the long-term, double-blind, placebo-controlled, randomized-withdrawal study in patients with schizoaffective disorder, 1 patient receiving INVEGA SUSTENNA discontinued treatment due to a cognitive disorder treatment-emergent adverse event.
• The methodology of a phase 4 US clinical trial assessing cognitive outcomes in patients receiving INVEGA SUSTENNA vs oral risperidone (NCT01451736) is described below. Results on cognitive outcomes of this study are not yet available, and therefore, no clinical data can be provided at this time.
• A post hoc analysis of the DREaM (Disease Recovery Evaluation and Modification) trial compared disease progression and modification following treatment with INVEGA SUSTENNA or INVEGA TRINZA (paliperidone palmitate [PP] 1-month or 3-month) formulation vs oral antipsychotics (OAPs) in patients with recent-onset schizophrenia or schizophreniform disorder. Cognitive performance improved significantly during part II of the study (PP, P<0.05; OAP, P<0.001) and remained stable during part III (PP, P=0.821; OAP, P=0.375). In part III, the dispersion remained stable in the PP group, and neurocognitive performance was significantly variable in the OAP group (P<0.01).⁸
• A post hoc analysis of 2 studies compared RLAI (NCT00330551) and INVEGA SUSTENNA or INVEGA TRINZA (NCT02431702) with OAPs for the management of schizophrenia within 2 years of the first episode. Intracortical myelin (ICM) volume at baseline and speed of processing (SoP) were significantly correlated for up to 12 months of treatment in both trials.⁹
• A 49-week, randomized, multicenter, active-controlled, open-label (OL) study conducted in China in patients with schizophrenia with aggressive tendencies assessed cognitive function differences after treatment with INVEGA SUSTENNA vs OAPs using the Repeatable Battery for the Assessment of Neuropsychological Status (RBANS) score. The results indicated no significant differences between the treatment groups in RBANS total scores with respect to time, treatment, or the interaction between time and treatment (P>0.05). Nevertheless, the INVEGA SUSTENNA group demonstrated a significant improvement in immediate memory subscores (P<0.001) compared to the OAP group, and both groups showed significant improvements in language subscores from baseline by the end of the study (P<0.05).¹⁰
• In an observational, OL, longitudinal study, an improvement was observed in 6 of 10 cognitive functioning tests in patients with schizophrenia upon switching to INVEGA SUSTENNA from risperidone.¹¹
• A 6-month, OL study in Japanese patients with non-acute schizophrenia or schizophreniform disorder found no significant between-group differences in any of the Brief Assessment of Cognition in Schizophrenia (BACS) z-scores with the exception of the attention and processing speed score, which showed greater improvement for INVEGA SUSTENNA compared to risperidone long-acting injection (RLAI; 0.62 vs 0.32; P=0.039). Limitations that may have affected results: small patient population (INVEGA SUSTENNA, n=10; RLAI, n=11), OL study design, lack of multipletesting corrections, use of concomitant anticholinergic agents (RLAI, n=1; INVEGA SUSTENNA, n=0), and drug blood level at the time of cognitive evaluation.¹²
• A real-world observational study reported improvement in cognition in patients with schizophrenia treated with different LAIs, including INVEGA SUSTENNA.¹³

CLINICAL STUDIES

Phase 4 Clinical Trials

NCT01451736 is a 12-month, OL study to determine the clinical and cognitive effects of INVEGA SUSTENNA vs risperidone, at optimal doses, in patients with firstepisode schizophrenia. The overall composite score from the Measurement and Treatment Research to Improve Cognition in Schizophrenia (MATRICS) Consensus Cognitive Battery (MCCB) will serve as the primary cognitive outcome measurement. In addition, to identify the domains in which treatment effects occurred, the cognitive domain scores from the MCCB will be assessed as a secondary measure.

DREaM Study

Williamson et al (2022)⁸ conducted a post hoc analysis of the DREaM trial (NCT02431702), a prospective, delayed-start, matched-control, double-randomized, OL, flexible-dose, multicenter study, to compare disease progression and modification following treatment with INVEGA SUSTENNA or INVEGA TRINZA formulation vs OAPs in patients with recent-onset schizophrenia or schizophreniform disorder. This post hoc analysis examined the extent of dispersion of neurocognitive performance on MCCB relative to changes in the mean MCCB performance.

Study Design/Methods

The study consists of 3 parts as follows:

• Part I (2 months oral run-in phase): Patients were randomized to receive oral paliperidone extended-release or oral risperidone.
• Part II (9 months disease progression phase): Patients were randomized to receive PP or OAPs.
• Part III (9 months disease modification phase): Patients receiving OAP in part I were rerandomized to either the OAP/OAP or OAP/PP group. Patients receiving PP in part II remained on PP.
• An extended disease progression (EDP) analysis (starting from months 0 to 18) compared patients taking PP/PP vs OAP/OAP.

MCCB assessments were conducted on day 29 of part I, day 1 of randomization (baseline) of part II, day 260 after randomization of part II and start of part III, and day 520 after randomization of part III.

Results

The mean age of patients in the PP (n=49) vs OAP (n=63) group was 23.7 vs 23.0 years. Cognitive performance improved in both groups (P<0.05) during the EDP phase. Least squares mean (LSM) of MCCB neurocognitive composite score in the PP vs OAP group, respectively, was 30.1 vs 29.5 on day 1, and in PP/PP vs OAP/OAP group, respectively, was 33.2 vs 33.4 on day 260, and 32.4 vs 33.1 on day 520. Cognitive performance improved significantly during part II (PP, P<0.05; OAP, P<0.001) and remained stable during part III (PP, P=0.821; OAP, P=0.375). Rates of change in the mean neurocognitive T-scores were not significantly different for both treatment groups (P=0.548).

LSM in dispersion MCCB neurocognitive composite subtests in the PP vs OAP group, respectively, was 9.7 vs 9.1 on day 1, and in PP/PP vs OAP/OAP groups, respectively, was 9.4 vs 8.7 on day 260, and 9.5 vs 9.8 on day 520. In part II, the dispersion for both treatment groups was not statistically significant. In part III, the dispersion remained stable in the PP group, and neurocognitive performance was significantly variable in the OAP group (P<0.01).

Nuechterlein et al (2020)⁹ conducted a post hoc analysis of 2 randomized controlled trials to compare RLAI (NCT00330551) and INVEGA SUSTENNA or INVEGA TRINZA (NCT02431702) with OAPs for the management of schizophrenia within 2 years of the first episode. The analysis examined the correlation between ICM volume and SoP using MCCB.

Magnetic resonance imaging (MRI) and MCCB data of 22 patients from risperidone trial and 64 patients from the DREaM trial were available. In both trials, the ICM volume at baseline and SoP were significantly correlated for up to 12 months of treatment.

Open-label Studies

Wang et al (2024)¹⁰ conducted a 49-week, prospective, randomized, active-controlled, OL, rater-blinded, multicenter study in China between November 2017 and June 2020 to evaluate the impact of INVEGA SUSTENNA vs OAPs on violent behavior in 134 patients (mean age, 39.1 years; male, 52.2%) with schizophrenia.

Study Design/Methods

Patients were randomized to receive either OAPs (n=67; risperidone, aripiprazole, ziprasidone, olanzapine, quetiapine, and amisulpride) or INVEGA SUSTENNA (n=67; on-label initiation followed by once-monthly injections of flexible dosing range of 117 to 234 mg [deltoid IM or gluteal IM]). The RBANS score was used to evaluate cognitive function at baseline, 25, and 49 weeks.

Results

Of the 134 patients, 104 (77.6%) completed the study (INVEGA SUSTENNA group, n=59; OAP group, n=45). The duration of maintenance treatment was significantly longer in the INVEGA SUSTENNA group vs the OAP group (44.9 [95% CI, 42.2-47.6] weeks vs 37.1 [95% CI, 38.5-43.6] weeks; P=0.002). No significant differences were reported in RBANS total score in relation to time, treatment, or interaction between time and treatment in either group (P>0.05). Nevertheless, the INVEGA SUSTENNA group demonstrated significant improvement in immediate memory sub-scores vs the OAP group (P<0.001), although the effect was not significant from the baseline. Additionally, both groups showed significant improvement in language sub-scores from the baseline to the end of week 49 (P<0.05), but the between-group comparison was not significant (P=0.224).

Tost et al (2023)¹¹ conducted an observational, OL, longitudinal study evaluating the impact of switching from risperidone to INVEGA SUSTENNA on social and cognitive functioning in patients with schizophrenia.

Study Design/Methods

Thirty-eight patients with a diagnosis of schizophrenia who received risperidone monotherapy (oral or LAI) with stable antipsychotic medications without changes in dosing in the last 2 months were included. Clinical assessments were conducted at baseline (before switching), 3 months after switching, and 6 months after switching. Cognitive assessment was conducted at each visit using MCCB.

Results

An improvement was observed in 6 of 10 cognitive functioning tests, mainly in cognitive tasks dealing with processing speed, working memory, visual memory, reasoning and problem solving, and attention and vigilance. Longitudinal changes in cognitive outcomes are described in Table: Cognitive Outcomes.

Takekita et al (2016)¹² conducted a 6-month, OL, randomized, controlled trial comparing the effects of flexibly-dosed INVEGA SUSTENNA vs RLAI on cognition in Japanese patients diagnosed with non-acute phase schizophrenia or schizophreniform disorder (Positive and Negative Syndrome Scale [PANSS] ≤120).

Study Design/Methods

Thirty patients having received RLAI for ≥2 months were randomized to continued treatment with RLAI (n=16), administered via gluteal intramuscular (IM) injection every 2 weeks, or be switched to INVEGA SUSTENNA (n=14), at a starting dose equivalent to twice the RLAI dose, administered via deltoid or gluteal IM injection every 4 weeks. The dose was adjusted based upon clinical status with a maximum dose of 50 mg every 2 weeks for RLAI and 234 mg every 4 weeks for INVEGA SUSTENNA.

Results

The final analysis was based upon completers and included 10 INVEGA SUSTENNA (mean age, 43.5 years) and 11 RLAI (mean age, 46.4 years) patients. At 6 months, no significant between group differences were observed in any of the BACS z-scores with the exception of the attention and processing speed score which showed greater improvement for INVEGA SUSTENNA compared to RLAI (0.62 vs 0.32; P=0.039). Limitations which may have affected results: small patient population, OL study design, lack of multipletesting corrections, use of concomitant anticholinergic agents (RLAI, n=1; INVEGA SUSTENNA, n=0), and drug blood level at time of cognitive evaluation.

Real-world Study

de Filippis et al (2023)¹³ conducted a 15-month, real-world, observational study between July 2016 and October 2020 in Italy, evaluating the effectiveness, safety, tolerability, and adherence of patients with schizophrenia to aripiprazole long-acting injectable (Ari-LAI) and INVEGA SUSTENNA or INVEGA TRINZA.

Study Design/Methods

Fifty-five adult patients with a diagnosis of schizophrenia who were stabilized on oral aripiprazole or paliperidone were included. Overall, 34 patients were initiated on Ari-LAI and 21 on INVEGA SUSTENNA, of whom 5 and 4, respectively, dropped out from treatment in the observation phase. Forty-six patients completed the study: 29 patients in the Ari-LAI group and 17 patients in the PP group (INVEGA SUSTENNA, 13 patients; INVEGA TRINZA, 4 patients, who switched to INVEGA TRINZA from INVEGA SUSTENNA in the last 3 months of the 15-month treatment period). Clinical assessments were conducted at baseline and at 3, 12, and 15 months. Cognitive assessments were conducted at all time points using the Stroop Color and Word Test (SCWT) and the Rey-Osterrieth Complex Figure Test (RCFT).

Results

Significant improvements in cognitive assessments were reported with longer treatment time with LAI, irrespective of the LAI type, as assessed by the SCWT score and components of the RCFT, including the percentage of recall and organizational strategies. Results for the PP1M group include the patients who transitioned to INVEGA TRINZA during the study period, as well as those who continued on INVEGA SUSTENNA. Longitudinal changes in cognitive outcomes are described in Table: Cognitive Outcomes.

Case Report

Suzuki et al (2017)¹⁴ reported the case of a 24-year-old female with a 6-year history of paranoid schizophrenia who experienced mild cognitive dysfunction as assessed by the BACS (Japanese language version) following treatment with INVEGA SUSTENNA 78 mg every 4 weeks. Eight months after the dosing interval was extended from every 4 weeks to every 6 weeks, verbal memory, working memory, motor speed, verbal fluency, attention and processing speed and composite score improved while PANSS total score remained unchanged.

LITERATURE SEARCH

A literature search of Ovid MEDLINE^®, Embase^®, BIOSIS Previews^®, and Derwent Drug File databases (and/or other resources, including internal/external databases) pertaining to this topic was conducted on 18 October 2024.