Summary

• Aripiprazole long-acting injection (ALAI) is commercially available in the United States as aripiprazole once-monthly (AOM) and aripiprazole lauroxil (AL). Results of a current literature search identified articles comparing INVEGA SUSTENNA to both products.
• Winter-van Rossum et al (2023)¹ conducted a randomized, open-label trial comparing all-cause discontinuations in adult patients with schizophrenia treated with AOM (N=127), oral aripiprazole (N=124), oral paliperidone (N=123) or INVEGA SUSTENNA (N=137) in 15 European countries and Israel (EULAST).
  • No significant benefit for long-acting injections (LAIs) vs oral treatments in time to all-cause discontinuation was identified when results were combined across treatment groups.
  • INVEGA SUSTENNA had the longest median time to all-cause discontinuation across all groups (256 days) and demonstrated significantly longer time to discontinuation vs oral paliperidone (136 days), whereas there was no difference between AOM (181 days) vs oral aripiprazole (224 days) in median time to all-cause discontinuation.
• de Filippis (2023)² conducted a head-to-head study comparing the effectiveness and tolerability of INVEGA SUSTENNA/INVEGA TRINZA and AOM in patients with schizophrenia.
  • No significant difference was observed between INVEGA SUSTENNA and AOM in Positive and Negative Syndrome Scale (PANSS) total score, quality of life (QoL) score, Personal and Social Performance (PSP) score, or cognitive tests.
  • No significant differences were observed between INVEGA SUSTENNA and AOM groups in triglyceride, total cholesterol, and prolactin (PL) levels.
• Bartoli et al (2022)³ conducted a prospective study evaluating the effectiveness and acceptability of INVEGA SUSTENNA with that of AOM in patients with schizophrenia spectrum disorder.
  • The rates of hospitalization during the 1-year follow-up in the INVEGA SUSTENNA vs AOM group were 32.0% vs 20.6% (odds ratio [OR], 1.59; 95% confidence interval [CI], 0.89-2.83; P=0.12).
  • The Brief Psychiatric Rating Scale (BPRS) score decreased over time in both INVEGA SUSTENNA and AOM groups, with greater effect in the INVEGA SUSTENNA group (time×treatment interaction, -5.18; P=0.02).
  • The rate of discontinuation at 1-year follow-up in the INVEGA SUSTENNA vs AOM group was 35.4% vs 44.1% (OR, 0.67; 95% CI, 0.35-1.27; P=0.23).
• Mason et al (2021)⁴ conducted a naturalistic, independent, 4-year mirror-image study comparing the real-world effectiveness of AOM with INVEGA SUSTENNA.
  • Overall, 37% vs 34% of patients receiving AOM vs INVEGA SUSTENNA discontinued therapy at the end of 2 years.
  • The most common reason for discontinuation was ineffectiveness (16.5%) in the AOM group and poor tolerability (14.5%) in the INVEGA SUSTENNA group.
  • The mean number of hospital admissions 2 years after the initiation of therapy was 0.2 vs 0.51 per patient (P=0.078) in the AOM vs INVEGA SUSTENNA group.
• Shymko et al (2021)⁵ conducted a naturalistic, longitudinal study to assess the
  long-term effects of AOM and INVEGA SUSTENNA on weight gain and metabolic parameters in young patients with early episode of psychosis.
  • Using 7% of body weight gain as the pathological threshold, 30% vs 26.9% of patients in the AOM vs INVEGA SUSTENNA group experienced clinically significant weight gain at 12 months, a difference that was nonsignificant (P=0.77).
  • A nonsignificant effect of time was observed on total cholesterol, high-density lipoprotein (HDL), and low-density lipoprotein (LDL) parameters as well as glucose and hemoglobin A1 (HbA1) levels (P=0.49).
  • Overall, triglycerides and PL levels were higher with INVEGA SUSTENNA vs AOM.
• Weiden et al (2020)⁶ conducted a 26-week, randomized, double-blind (DB), phase 3b study evaluating the efficacy and safety of AL (n=99) in patients hospitalized for acute exacerbation of schizophrenia followed by transition to outpatient care (ALPINE). INVEGA SUSTENNA (n=101) was included as an active control, but the study was not powered for direct comparisons between the randomized groups.
  • Within each treatment group, there was a statistically significant change in PANSS total score from baseline to week 4, with similar results achieved at weeks 9 and 25 (P<0.001, all within-group).
  • A post hoc analysis of the ALPINE study further characterized the safety and tolerability of treatment with AL and INVEGA SUSTENNA.⁷
• Cuomo et al (2018)⁸ conducted a head-to-head study of AOM vs INVEGA SUSTENNA comparing the impact of clinical status, substance craving, and QoL in patients with comorbid psychosis and substance use disorder.
  • Both groups showed statistically significant improvements in all outcomes. The mean difference (MD) in craving and QoL favored AOM over INVEGA SUSTENNA (P<0.00001 for visual analog scale for substance craving [VAScrav], QoL physical, QoL psychological, and QoL environment; P=0.000023 for QoL social relationships). Several study limitations were identified and discussed at the end of the trial analysis.
• Pae et al (2017)⁹ conducted an indirect treatment comparison (ITC) evaluating the relative efficacy and safety of AOM versus INVEGA SUSTENNA from short-term (≤16 weeks) randomized controlled schizophrenia trials.
  • The MD in the primary efficacy endpoint (mean change in PANSS total score) favored AOM (-6.4; 95% CI, -11.402 to -1.358) over INVEGA SUSTENNA.
  • There were no significant differences between AOM and INVEGA SUSTENNA with regard to overall early dropout rates (OR, 1.22; 95% CI, 0.737-2.03) or premature dropout rates due to treatment-associated AEs (OR, 0.902; 95% CI, 0.308-2.644). A significant difference in early dropouts was found
    between groups due to lack of efficacy, favoring AOM over INVEGA SUSTENNA (OR, 0.394; 95% CI, 0.185-0.841).
  • Several study limitations to the ITC were identified and are discussed at the end of the trial analysis.
• Results from an ITC (Cameron et al [2017]¹⁰) using network-meta-analysis (NMA) suggested that both AL (441 mg and 882 mg monthly) and INVEGA SUSTENNA (156 mg and 234 mg monthly) are effective for the treatment of adults experiencing an acute exacerbation of schizophrenia.¹⁰
• Naber et al (2015)¹¹ conducted a 28-week, randomized, open-label, rater-blinded, non-inferiority trial comparing the QoL and functioning of AOM versus once-monthly INVEGA SUSTENNA in adult patients with schizophrenia in Europe and North America (QUALIFY).
  • Patients were randomized to AOM 400 mg or INVEGA SUSTENNA 78-234 mg. At week 24, the mean doses were 387 mg for AOM and 172 mg for INVEGA SUSTENNA.
  • A change from baseline to week 28 on the Heinrichs-Carpenter Quality-of-Life Scale (QLS) total score served as the primary endpoint. The least squares mean (LSM) change in QLS total score from baseline to week 28 was 7.47 for AOM (n=136) and 2.80 for INVEGA SUSTENNA (n=132). Non-inferiority was established (LSM difference between treatments: 4.67 [95% CI, 0.32-9.02, P=0.036]).
  • A total of 16/144 (11.1%) AOM and 27/137 (19.7%) INVEGA SUSTENNA patients discontinued treatment due an AE. During the continuation phase, the most common (≥5% in either group) treatment-emergent adverse events (TEAEs) for AOM (n=119) and INVEGA SUSTENNA (n=109), respectively, were increased weight (10.1% vs 15.6%), psychotic disorder (2.5% vs 5.5%), and insomnia (2.5% vs 5.5%).
  • Several study limitations to treatment group selection, primary endpoint parameter, treatment dosing, and statistical analyses were identified and are discussed at the end of the trial analysis.
• A real-world retrospective study by Chen et al (2023)¹² of Texas Medicaid enrollees with schizophrenia treated with second-generation (SG)-LAI antipsychotics between 2015 and 2019 reported no significant difference in adherence to INVEGA SUSTENNA, AOM, AL 1-month, or 2-month.

DOSAGE STRENGTH INFORMATION

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

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

Aripiprazole Once-monthly

Winter-van Rossum et al (2023)¹ conducted a randomized, open-label trial comparing all-cause discontinuations in adult patients with schizophrenia treated with AOM (N=127), oral aripiprazole (N=124), oral paliperidone (N=123) or INVEGA SUSTENNA (N=137) in 15 European countries and Israel (EULAST).

Study Design/Methods

Inpatients and outpatients recruited were at least 6 months and no more than 7 years since the start of illness (defined as first contact with a healthcare provider in relation to psychotic symptoms) at randomization to the 4 treatment groups. Randomization was stratified by duration of illness (6 months to 3 years vs 4-7 years) and country. Flexible dosing was allowed throughout the trial. Concomitant medications, including psychotropic drugs and augmentation with another antipsychotic beyond visit 4, were allowed up to a prespecified threshold. Patients were assessed at monthly visits and blood draws were taken quarterly to assess adherence to study medication. Patients were treated for up to 19 months.

Results

Patients in the intent-to-treat (ITT) sample did not differ significantly across multiple baseline variables.

Efficacy

Data was combined across treatment groups to assess the primary endpoint of all-cause discontinuations for oral vs LAI treatment. Time to all-cause discontinuation did not differ between the combined oral and LAI treatment groups (median, 175 days [95% CI, 122-228] vs 200 days [131-269]). Discontinuations were subcategorized by cause as related to efficacy, safety issues, or other concerns, and no significant difference was observed for efficacy or safety, and a difference between orals and LAIs in the other category (hazard ratio, 1.51; 95% CI, 1.15-1.98; P=0.0034) was shown with a significantly longer use of medication in the LAI group vs orals group (P=0.0029).

No significant difference was observed in all-cause discontinuation when the treatment groups were evaluated independently. When comparing the same compound between its oral and LAI formulation, no difference was observed between oral aripiprazole and AOM (median, 224 days; 95% CI, 129-319 and median, 181 days; 95% CI, 123-239). Time to all-cause discontinuation was significantly longer in the INVEGA SUSTENNA vs oral paliperidone group (median, 256 days; 95% CI, 118-394 vs median, 136 days; 95% CI, 88-185; P=0.0255), although this effect was not maintained after applying a Bonferroni correction for multiple testing.

Safety

There were no significant differences in the incidence of safety and tolerability events across multiple domains, with the exception of PL levels. Post hoc pairwise comparisons identified a significant difference in PL levels between the aripiprazole and paliperidone groups, with the paliperidone groups (oral and LAI) showing a higher rate of PL levels than the prespecified range.

Correspondence Letters

Lancet Psychiatry published 3 letters to the editor that questioned the conclusions reached by Winter-van Rossum et al. based on the EULAST data, which stated, “that there is no reason to prescribe LAIs instead of oral antipsychotics if the goal is to prevent discontinuation of antipsychotic medication in daily clinical practice.” Price & Price and Kane et al., both stated that random assignment in the EULAST study to an oral or LAI, irrespective of physician or patient choice, may have enhanced the overall discontinuation rates and Tiihonen further highlighted that randomized clinical trials are inherently biased for compliant patients, which together reduce the generalizability of EULAST to daily clinical practice. Additionally, these letters pointed out that a closer evaluation of reasons for discontinuation and the analysis time-point might lead to a different conclusion or no difference.^13-15 Fleischhacker, Winter-van Rossum, and Kahn replied to these letters and acknowledged certain limitations of the EULAST study design, offering to reevaluate different time points throughout the study and to reconsider specific discontinuation criteria using a sensitivity analysis.¹⁶

de Filippis et al (2023)² conducted a head-to-head study comparing the effectiveness and tolerability of INVEGA SUSTENNA/INVEGA TRINZA (n=17) and AOM (n=29) in patients with schizophrenia in a real-world setting over a 15-month follow-up. Patients initially received treatment with oral aripiprazole or paliperidone, and then as an LAI (INVEGA SUSTENNA, 156-234 mg; INVEGA TRINZA, 546-819 mg; or AOM,
300-400 mg). Patients with an adequate response after 12 months of treatment with INVEGA SUSTENNA were switched to INVEGA TRINZA.

Results

Baseline Characteristics

A total of 17 patients received INVEGA SUSTENNA, of whom 4 switched to INVEGA TRINZA, and 29 patients received AOM. The mean age in the INVEGA SUSTENNA vs AOM group was 43.1 vs 42.5 years. Mean baseline PANSS total score was not significantly different between the INVEGA SUSTENNA (96.6) and AOM (84.5) groups.

Efficacy

Overall, 16.4% of patients dropped out from the study, and 83.6% of patients had a complete response. Although there were significant within-group improvements from baseline to 15 months, no significant differences were observed between INVEGA SUSTENNA and AOM in PANSS total score (P=0.498; positive subscale, P=0.923; negative subscale, P=0.525; and general subscale, P=0.301), QoL total score (P=0.307), PSP score (P=0.783), Stroop Color and Word Test (SCWT; P=0.064), ReyOsterrieth Complex Figure Test (RCFT) accuracy (P=0.145), RCFT recall (P=0.623), RCFT order (P=0.331), RCFT style (P=0.172), RCFT Central Coherence Index (CCI) (P=0.231), and RCFT organizational strategies (OS; P=0.450).

Clinical and Metabolic Parameters

No significant differences were observed between INVEGA SUSTENNA and AOM group in triglyceride, total cholesterol, PL, neutrophil, platelet, and thyroid stimulating hormone (TSH) levels.

Bartoli et al (2022)³ conducted a prospective study evaluating the effectiveness and acceptability of INVEGA SUSTENNA with that of AOM in patients with schizophrenia spectrum disorder in a real-world setting using the 1-year follow-up data from the ‘Servizi Territoriali Associati per la Ricerca’ (STAR - Community Services Associated for Research) Network Depot Study.

Study Design/Methods

A subgroup of adult patients with schizophrenia spectrum disorder and other psychotic disorders who were started on INVEGA SUSTENNA or AOM and not on any other LAI during the previous 3 months was included. Patients were treated with AOM 400 mg (300 mg in case of tolerability issues) or flexible doses of INVEGA SUSTENNA ranging between 78 and 234 mg. Effectiveness was assessed using the BPRS scores and hospitalization rates during follow-up, whereas acceptability was assessed based on the rates of all-cause treatment discontinuation.

Results

Baseline Characteristics

A total of 195 patients were included in the study, of whom 117 received INVEGA SUSTENNA and 78 received AOM. The baseline characteristics of patients are described in Table: Select Baseline and Clinical Characteristics.

Effectiveness

The rates of hospitalization during the 1-year follow-up in the INVEGA SUSTENNA vs AOM group were 32.0% vs 20.6% (OR, 1.59; 95% CI, 0.89-2.83; P=0.12). The BPRS score decreased over time in both INVEGA SUSTENNA and AOM groups, with a greater effect in the INVEGA SUSTENNA group (time×treatment interaction, -5.18; P=0.02). After the adjustment of the BPRS score in the ITT population, the mean change score did not differ significantly between the INVEGA SUSTENNA and AOM groups (P=0.90).

Acceptability

The rates of discontinuation in the 1-year follow-up in the INVEGA SUSTENNA vs AOM group were 35.4% vs 44.1% (OR, 0.67; 95% CI, 0.35-1.27; P=0.23).

Mason et al (2021)⁴ conducted a naturalistic, independent, 4-year mirror-image study comparing the real-world effectiveness of AOM with that of INVEGA SUSTENNA.

Results

Baseline Characteristics

A total of 148 patients were identified for initiating AOM between May 2014 and March 2018, of whom 109 were included in the study. Among 109 patients in the AOM group, 71 (65%) had schizophrenia and 38 (35%) had schizoaffective disorder, bipolar affective disorder, or other diagnoses. The INVEGA SUSTENNA group included 173 patients, of whom 120 of 173 (69%) had schizophrenia and 53 of 173 (31%) had other diagnoses. The pertinent baseline characteristics are presented in Table: Select Patient Demographics and Baseline Characteristics.

Discontinuation Rates

In patients who received AOM vs INVEGA SUSTENNA, discontinuation of treatment at the end of 2 years was reported in 37% vs 34% of patients in the total population and 38% vs 31% of patients with schizophrenia. Among all patients, the most common reason for discontinuation was ineffectiveness (16.5%) in the AOM group and poor tolerability (14.5%) in the INVEGA SUSTENNA group. In patients with schizophrenia, the most common reason for discontinuation was nonadherence and ineffectiveness (15.5%) in the AOM group and poor tolerability (11%) in the INVEGA SUSTENNA group.

Hospitalization Rates

In patients who received AOM vs INVEGA SUSTENNA, the mean number of hospital admissions 2 years prior to initiation of therapy was 1.26 vs 1.16 per patient (P=0.004) in all patients and 0.9 vs 1.0 per patient (P=0.426) in the schizophrenia group. The length of admission was 81.45 vs 61.76 days (P=0.000) in all patients and 64.0 vs 51.44 days (P=0.058) in patients with schizophrenia.

In patients who received AOM vs INVEGA SUSTENNA, the mean number of hospital admissions 2 years after initiation of therapy was 0.2 vs 0.51 per patient (P=0.078) in all patients and 0.15 vs 0.43 per patient (P=0.143) in the schizophrenia group. The length of admission was 10.26 vs 20.91 days (P=0.666) in all patients and 7.74 vs 19.27 days (P=0.724) in patients with schizophrenia.

Shymko et al (2021)⁵ conducted a naturalistic, longitudinal study to assess the
long-term effects of AOM and INVEGA SUSTENNA on weight gain and metabolic parameters in young patients with early episode of psychosis.

Results

Baseline Characteristics

A total of 59 patients were included in the study, of whom 33 received AOM and 26 received INVEGA SUSTENNA. In the AOM vs INVEGA SUSTENNA group, 30.3% vs 38.5% had a first episode of psychosis, 24.2% vs 26.9% had schizophrenia, 9.1% vs 11.5% had schizoaffective disorder, 21.2% vs 7.7% had psychosis not otherwise specified (NOS), and 15.4% vs 15.4% had drug-induced psychosis. The mean age of patients was 20.5 vs 21.6 years, and the dose range was 300-400 vs 78-234 mg. The mean duration of LAI medication was 13 months.

Weight and Body Mass Index

Using 7% of body weight gain as the pathological threshold, 30% vs 26.9% of patients in the AOM vs INVEGA SUSTENNA group experienced clinically significant weight gain at 12 months, a difference that was nonsignificant (P=0.77). The results of weight gain and body mass index (BMI) from baseline to 12 months are described in Table: Weight Gain and BMI.

Metabolic Parameter

A significant increase in total cholesterol, HDL, and LDL parameters as well as glucose and HbA1 levels (P=0.49) was not observed over a period of time in either group. The results of major metabolic parameters are found in Table: Metabolic Parameters.

Cuomo et al (2018)⁸ conducted a head-to-head study of AOM (N=50) vs INVEGA SUSTENNA (N=51) comparing the impact of clinical status, substance craving, and QoL in initially hospitalized adult patients with comorbid psychosis and substance use disorder. Patients who were stabilized prior to discharge were randomized to receive AOM 400 mg intramuscularly (IM) once-monthly or 156 mg INVEGA SUSTENNA once-monthly for one year.

Results

Baseline Characteristics

Patients in the INVEGA SUSTENNA vs AOM group were older (mean age: 36.92 years vs 26.69 years, respectively; P=0.001) and had more diagnoses of schizophrenia spectrum disorders vs bipolar disorders (50/1 vs 40/10, respectively; P=0.003). However, AOM patients had a stronger craving for substances at baseline (VAScrav: 8.94 vs 8.20; P=0.019).

Efficacy

Both groups showed statistically significant improvements in Clinical Global Impressions (CGIs) at the 1-year endpoint (P<0.00001 for both groups), craving intensity (P<0.0001 for both groups), and in all QoL domains (physical, psychological, social, and environment). The MD in craving and QoL favored AOM over INVEGA SUSTENNA (P<0.00001 for VAScrav, QoL physical, QoL psychological, and QoL environment; P=0.000023 for QoL social relationships). The authors stated that while they do not know the exact reason why QoL outcomes favored AOM over INVEGA SUSTENNA, they hypothesized that AOM's action as a partial agonist at the dopaminergic D_2/3 receptors may be responsible.

Safety

Two patients in the AOM group developed akathisia. In the INVEGA SUSTENNA group, galactorrhea (n=5), hyperprolactinemia (n=4), and increased substance craving (n=2) were the most common side effects. There were no side effects leading to drug discontinuation in either group.

Limitations

• Open study design may limit validity of the data.
• Wide assessment times prevented control of effect of the 2 LAIs on the course of psychoses.
• CGI-S is not a refined tool for measuring severity and did not allow for parametric analyses.
  • BPRS may have been more suitable for providing stronger data on clinical change as it has been tested in patients with dual diagnosis problems.
• Using the visual analog scale (VAS) to measure craving day before could have exposed patients to recall bias.

There was no clear-cut superiority of one LAI antipsychotic over the other, but only a clear difference favoring AOM on QoL indicating the need for further head-to-head comparisons with more homogeneous groups at baseline and using more assessment scales to confirm these results.

Naber et al (2015)¹¹ conducted a 28-week, randomized, open-label, rater-blinded, noninferiority trial comparing the QoL and functioning of AOM versus INVEGA SUSTENNA in adult patients with schizophrenia in Europe and North America (QUALIFY).

Study Design/Methods

Stable patients needing a change from current oral antipsychotic treatment due to a poor response, unsatisfactory adherence, or lack of tolerability were included in the study. Patients were required to have a Clinical Global Impression-Severity (CGI-S) scale score ≥3 and ≤5 at screening and baseline and treatment with an oral antipsychotic for 3 months prior to screening. Patients experiencing an acute exacerbation of symptoms, hospitalization >3 months at screening visit, were a significant risk to themselves or others, refractory to antipsychotic treatment, or those with a failure to respond to/responding only to clozapine therapy were excluded from the study.

Patients entered 3 phases following randomization:

• 3-week oral conversion: aripiprazole (5 to 30 mg/day) or paliperidone (3 to 12 mg/day)
• 5-week LAI initiation:
  • AOM: oral aripiprazole (10 to 30 mg/day) for 1 week; AOM 400 mg on day 28 with an additional 2 weeks of oral aripiprazole (10 to 20 mg/day)
  • INVEGA SUSTENNA: 234 mg on day 21, oral paliperidone discontinued; 156 mg on day 28
• 20-week continuation: 5 injections of AOM 400 mg (reduction to 300 mg based on patient tolerability was permitted) or INVEGA SUSTENNA 78-234 mg

A change from baseline to week 28 on the QLS total score served as the primary effectiveness endpoint. Secondary endpoints included changes in the Investigator’s Assessment Questionnaire (IAQ) and CGI-S. QUALIFY was designed as a non-inferiority study allowing for subsequent superiority testing if the noninferiority criterion was met
(prespecified noninferiority margin for change from baseline in QLS score was -5.0).

Results

A total of 148 and 147 patients were randomized to AOM (mean age, 42.6 years, 70.8% >35 years) and INVEGA SUSTENNA (mean age, 41.2 years; 72.3% >35 years), respectively. Approximately 60% of patients from both treatment groups were male and 70% were white. At week 24, the mean doses of AOM and INVEGA SUSTENNA were 387 mg and 172 mg, respectively.

Effectiveness

The LSM change in QLS total score from baseline to week 28 was 7.47 for AOM (n=136) and 2.80 for INVEGA SUSTENNA (n, 132). Non-inferiority was established (LSM difference between treatments: 4.67 [95% CI, 0.32-9.02; P=0.036]). Significant improvements in LSM QLS total scores for AOM versus INVEGA SUSTENNA were observed from week 8 onwards. Significant improvements in CGI-S and IAQ scores were also observed for AOM versus INVEGA SUSTENNA. Secondary exploratory analyses found significant LSM treatment differences at week 28 favoring AOM versus INVEGA SUSTENNA in patients ≤35 years of age based on the QLS total score (P=0.037), CGI-S (P=0.026) and IAQ (P=0.048). No statistically significant differences between the 2 groups were observed in patients >35 years of age which represented >70% of the patient population. For all secondary analyses, P values were nominal and were not corrected for multiple comparisons.

Safety

A total of 16/144 (11.1%) AOM and 27/137 (19.7%) INVEGA SUSTENNA patients discontinued treatment due to AEs. During the continuation phase, the most common (≥5% in either group) TEAEs for AOM (n=119) and INVEGA SUSTENNA (n=109), respectively, were: increased weight (10.1% vs 15.6%), psychotic disorder (2.5% vs 5.5%), and insomnia (2.5% vs 5.5%). Extrapyramidal symptoms (EPS)-related TEAEs, including akathisia, were low, occurring <5% in both groups. Mean change in body weight from baseline to week 28 was 0.2 kg for AOM (n=100) and 1.4 kg for INVEGA SUSTENNA (n=83). Clinically significant weight gain (≥7% from baseline) was observed in 11.1% and 14.6% of AOM and INVEGA SUSTENNA patients, respectively.¹¹ The number of patients reporting sexual dysfunction at week 28 was 37.9% with AOM vs 63.1% with INVEGA SUSTENNA.¹⁸

Limitations

• The authors note that measurement of QoL as assessed by the change in
  Heinrichs-Carpenter QLS is not a traditional measure of treatment efficacy but may be relevant to patient populations in a real-world setting. They note that the LSM difference from baseline to week 28 in QLS total scores between AOM and INVEGA SUSTENNA (4.67) is close to the minimal clinically important difference of 5.3 points defined by Falissard, et al.¹⁹
• The design of the study required patients to be stabilized on an oral antipsychotic (either aripiprazole or oral paliperidone) prior to entering the long-acting injectable phase. However, this is not necessary when starting INVEGA SUSTENNA if there is prior exposure to risperidone or paliperidone.
• While all patients in the AOM treatment group were started on the maximum dose of 400 mg, with a dose reduction to 300 mg permitted for tolerability reasons, the INVEGA SUSTENNA treatment arms received flexible dosing (78-234 mg), possibly impacting the change in QLS for each product.
• This was not a blinded study, consequently, the authors stated that the patients' knowledge of treatment assignment and willingness to take LAI may have biased the reporting. Additionally, raters were blinded for QLS and IAQ but not for CGI-S.
• The study population was highly selected with significant inclusion and exclusion criteria limiting the generalization of results to a broad population of patients with schizophrenia.
• The authors concluded that patients ≤35 years of age may benefit from initiation with AOM versus INVEGA SUSTENNA based on results from a subgroup analysis which showed significant between-group differences with regard to QLS total score, CGI-S and IAQ changes (AOM, n=40; INVEGA SUSTENNA, n=37). Results from the larger subgroup of patients (>35 years of age), which represented >70% of the patient population, did not show statistically significant differences between AOM and INVEGA SUSTENNA. These analyses lacked statistical power, were not covariate-adjusted, and were considered exploratory.

Cost-Effectiveness Analysis

Sapin et al (2016)^20,21 conducted a cost-effectiveness comparison of AOM vs INVEGA SUSTENNA in patients participating in the QUALIFY trial¹¹. A health economic assessment (HEA) questionnaire was utilized to collect healthcare resource utilization across the 28-week study and was administered at the final visit. Total cost outcomes were estimated from an analysis of covariance model. Covariates included treatment as fixed effects and cost incurred during the 6 months before study entry and study drug exposure time. The additional cost of 1 unit of health outcome (point on the QLS or CGI-S scale) gained by a treatment vs the alternative was estimated via incremental cost-effectiveness ratios.

Results

HEA data was evaluated for 125 AOM patients (mean dose: 388 mg) and 122 INVEGA SUSTENNA patients (mean dose: 178 mg; most received 156- or 234-mg doses). Total direct costs were significantly lower for AOM vs INVEGA SUSTENNA ($8,908 vs $9,675; P=0.005), with drug treatment costs as the key component ($7,967 vs $8,706; P<0.001). Other cost components associated with care delivered by healthcare professionals and inpatient and outpatient providers did not significantly differ between treatment groups. Cost-effectiveness analyses over the 28-week period, utilizing QLS and CGI-S scores, showed that AOM demonstrated greater effectiveness at lower costs compared to INVEGA SUSTENNA.

Limitations

• The limitations of the QUALIFY trial¹¹ need to be considered when evaluating the results of this cost-effectiveness analysis.
• The HEA questionnaire was administered only once, at the end of the trial (week 28), and is likely impacted by the ability to recall what health resources were actually utilized during the trial.
• The data sources and methods for calculating treatment costs are unclear.
• Health resource utilization costs were based upon data from mixed clinical environments (Centers for Medicare & Medicaid Services and Veteran's Administration) and therefore do not accurately portray the cost of either environment.
• Results are not generalizable to the overall United States (US) schizophrenia population. The analyses included only stable patients evaluated over a relatively short period of time (28 weeks), with an unknown percentage of US patients identified in the study population.

Indirect Treatment Comparison

Pae et al (2017)⁹ conducted an ITC evaluating the relative efficacy and safety of AOM versus INVEGA SUSTENNA from short-term (≤16 weeks) randomized controlled schizophrenia trials. The mean change in PANSS total score served as the primary efficacy measure for treatment comparison. Studies were excluded if the primary outcome was the prevention of relapse. A meta-analysis of each drug vs placebo was first carried out to find MDs. These MDs were utilized for the ITC, which assumes that the placebo groups were similar. However, there was no comparison of placebo groups.

Results

Baseline Characteristics

A total of 5 studies were selected and included 1,310 patients (see Table: Indirect Treatment Comparison - Clinical Trial Characteristics).

Efficacy

The MD in the primary efficacy endpoint (mean change in PANSS total score) favored AOM (-6.4; 95% CI, -11.402 to -1.358) over INVEGA SUSTENNA.

Early Dropouts

There were no significant differences between AOM and INVEGA SUSTENNA with regard to overall early dropout rates (OR, 1.22; 95% CI, 0.737-2.03) or premature dropout rates due to treatment-associated AEs (OR, 0.902; 95% CI, 0.308-2.644). A significant difference in early dropouts was found between groups due to lack of efficacy, favoring AOM over INVEGA SUSTENNA (OR, 0.394; 95% CI, 0.185-0.841).

Limitations

• The authors note that findings from ITCs cannot supersede those from direct comparisons and should be taken into consideration to avoid misinterpretation of results with respect to clinical implications.
  • ITC methodology included only one treatment arm from each of the INVEGA SUSTENNA studies, even though INVEGA SUSTENNA had multiple dosage strengths available for maintenance dosing in those trials.
• ITC also assumes the placebo arms to be the same – no comparison of the placebo groups was included.⁹
  • However, baseline PANSS scores in the placebo arm were higher in the AOM trial compared to the INVEGA SUSTENNA trials, 104.0 (11) vs 89.0 (13.5); MD, -15.0; P<0.001. A greater symptomatic improvement as measured by change in PANSS total score was observed with placebo in the AOM trial compared to placebo in the INVEGA SUSTENNA trials (AOM, -11.7 [20.7]; INVEGA SUSTENNA, -2.2 [22.0]; P<0.001).²⁷
• The number of randomized controlled trials and participants was too small to draw meaningful conclusions for clinical practice (1 AOM study vs 4 INVEGA SUSTENNA studies).
  • The ITC did not include 2 of the 4 INVEGA SUSTENNA studies that were consistent with the authors objective and inclusion criteria (Pandina 2010²⁸; Kramer 2010²⁹).²⁷
• Two of the included INVEGA SUSTENNA studies (Gopal 2010²⁴; Nasrallah 2010²⁵) did not utilize the recommended initiation regimen (day 1: 234 mg IM; day 8: 156 mg IM, both in the deltoid muscle) which likely contributed to an underestimation of efficacy and early dropout due to lack of efficacy.²⁷
• Only a post hoc subgroup analysis of Pandina 2010²⁸ (the main pivotal study in which 1 treatment arm used the recommended initiation regimen), in markedly to severely ill patients, was included in the meta-analysis.
• There was considerable heterogeneity in terms of study population characteristics, particularly in regard to baseline symptom severity, which may have favored AOM over INVEGA SUSTENNA.^9,27
  • Baseline PANSS scores were higher in the AOM trial, 103 vs an average of 90.3 (range, 85.7-94.5) for INVEGA SUSTENNA. Though both fall under the marked psychopathology range, however, it is easier to see a larger decrease in a higher vs lower score.
  • One of the INVEGA SUSTENNA studies was only conducted in Asia where diagnosis and symptom assessment may not be generalizable to other populations.

aripiprazole Lauroxil

ALPINE Study

Weiden et al (2020)⁶ conducted a 26-week, randomized, DB, active-controlled, phase 3b study evaluating the efficacy and safety of AL and INVEGA SUSTENNA in patients hospitalized for acute exacerbation of schizophrenia followed by transition to outpatient care (ALPINE).

Study Design/Methods

The study consisted of a 1-week screening phase followed by an initial 2-week, inpatient, DB phase, and an outpatient continuation phase through week 25.

Patients were randomized to AL (AL NanoCrystal Dispersion plus a single 30 mg dose of oral aripiprazole on day 1 followed by AL 1,064 mg IM gluteal on day 8 and every 8 weeks) or INVEGA SUSTENNA (INVEGA SUSTENNA 234 mg on day 1 and INVEGA SUSTENNA 156 mg on day 8, both IM deltoid, followed by 156 mg IM gluteal every 4 weeks). The study did not allow for flexible dosing of INVEGA SUSTENNA.

The primary endpoint was change in PANSS total score from baseline to week 4 within treatment groups. Secondary endpoints included within-group change in PANSS total score from baseline to week 9 and week 25, as well as, between-group comparisons at weeks 4, 9, and 25.

The study included INVEGA SUSTENNA as an active control and was not powered to test between-group differences between AL and INVEGA SUSTENNA.

Results

A total of 200 patients were randomized to receive AL (n=99) or INVEGA SUSTENNA (n=101). The completion rates for the 4-week acute phase were 79.8% for the AL group and 74.3% for the INVEGA SUSTENNA group. At week 25, the completion rates for the AL group and the INVEGA SUSTENNA group were 56.6% and 42.6%, respectively.

Efficacy

Within each treatment group, there was a statistically significant change in PANSS total score from baseline to week 4, with similar results achieved at weeks 9 and 25 (P<0.001, all within-group).

Secondary analyses demonstrated that there were no statistically significant differences between AL and INVEGA SUSTENNA in change from baseline in PANSS total scores at weeks 4, 9, and 25. This study was not powered to formally test between-group differences.

Safety

Safety profiles for AL and INVEGA SUSTENNA were consistent with previous studies. The most frequent AEs (≥5%) were injection site pain, increased weight, akathisia, headache, and schizophrenia in the AL group, and injection site pain, increased weight, akathisia, headache, dystonia, and somnolence in the INVEGA SUSTENNA group.

Limitations

• The design of the study was not powered for a direct comparison between AL and INVEGA SUSTENNA.
• The authors note that the rates of successful transition and continuation of LAI after discharge may be higher than routine clinical care.
• Results limit generalizability to the hospitalized schizophrenia population starting LAIs.
• The study did not allow for flexible dosing and used one dose (156 mg) out of 5 available doses of INVEGA SUSTENNA.

Post Hoc Analysis of the ALPINE Study

Citrome et al (2024)⁷ conducted a post hoc analysis of the ALPINE study to evaluate the safety and tolerability of AL and INVEGA SUSTENNA.

Results

• AEs of interest reported in both treatment groups were injection site reactions, motor AEs, sedation and daytime sleepiness, hypotension, PL, body weight change, and suicidal ideation/behavior. For details on the AEs of interest and discontinuations through week 25 see Table: Adverse Events of Interest.
• Injection site pain on Day 1 was reported in 10.1% of patients in the AL group and 18.8% of patients in the INVEGA SUSTENNA group; injection site pain decreased by the next injections. For the occurrence rate of injection site-related AEs see Table: Injection Site-Related Adverse Events.
• In both groups, akathisia was the most frequently reported motor-related AE. The median time to onset of akathisia was 3.5 days (range: 2-15 days) in the AL group and 7.5 days (range: 1 to 22 days) in the INVEGA SUSTENNA group.
• In the AL vs the INVEGA SUSTENNA groups, the median change from baseline in PL concentration for male patients was -4.60 ng/mL vs 21.2 mg/mL, and for female patients was -3.55 ng/mL vs 80.4 ng/mL.
  • In the AL group, none of the 70 male patients with postbaseline PL assessments had PL concentrations >1×upper limit of normal (ULN) or >100 ng/mL; 1 of 22 female patients with postbaseline PL assessments had PL concentrations >1×ULN, but none had PL concentrations >2×ULN or >150 ng/mL.
  • In the INVEGA SUSTENNA group, of the 73 male patients with postbaseline PL assessments, PL concentrations were >1×ULN in 80.8%; >2×ULN in 38.4%; and >3×ULN in 13.7%, none had concentrations >100 ng/mL. Of the 25 female patients with postbaseline assessments, PL concentrations were >1×ULN in 96%; >2×ULN in 88%; and >3×ULN in 52%; 8% had concentrations >150 ng/mL.

Indirect Treatment Comparison

Cameron et al (2017)¹⁰ conducted an ITC using the NMA method to compare the efficacy and tolerability of AL versus INVEGA SUSTENNA for the treatment of acute exacerbations of schizophrenia. Studies with a similar design to the AL pivotal trial by Meltzer et al.³⁰ were included in the analysis. For INVEGA SUSTENNA studies, the authors excluded the 39 mg and 78 mg dose groups as they were considered subtherapeutic for acutely ill patients and may bias the efficacy comparison in favor of AL. The change from baseline in PANSS total score served as the primary outcome parameter. Secondary outcomes included occurrences of weight gain >7% from baseline, akathisia, EPS, and TEAEs.

Results

Baseline Characteristics

A total of 4 studies met eligibility criteria and included 1,589 patients (AL, n=400; INVEGA SUSTENNA, n=576; placebo, n=613). Pertinent baseline characteristics are found in Table: Indirect Treatment Comparison – Clinical Trial Characteristics.

Efficacy

All active treatment regimens (AL, 441 mg and 882 mg; INVEGA SUSTENNA, 156 mg and 234 mg) were associated with decreases in PANSS total scores from baseline to endpoint versus placebo. Between-group comparisons were associated with summary estimates of a magnitude near 0. When adjusting for the differences in baseline PANSS total scores, only minor shifts in the summary estimates were observed for all comparisons.

Safety

No differences in weight gain, TEAEs, akathisia, or EPS were observed between active treatment groups.

Aripiprazole Once-monthly and aripiprazole Lauroxil

Chen et al (2023)¹² conducted a retrospective cohort study using data from the Texas Medicaid database between 2015 to 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 for AL 2-month was 0.69±0.34; AOM, 0.63±0.33; INVEGA SUSTENNA, 0.62±0.33; and AL 1-month, 0.57±0.33; the mean PDC was highest for INVEGA TRINZA (0.91±0.20). The adherence rate for AL 2-month was 60.2%; 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 (86.9%, P≤0.01).

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 09 May 2024.