key: cord-0028726-frsl8b1m
authors: Najarian, Dean; Sanga, Panna; Wang, Steven; Lim, Pilar; Singh, Arun; Robertson, Mary Jane; Cohen, Kristin; Schotte, Alain; Milz, Ruth; Venkatasubramanian, Raja; T’Jollyn, Huybrecht; Walling, David P; Galderisi, Silvana; Gopal, Srihari
title: A Randomized, Double-Blind, Multicenter, Noninferiority Study Comparing Paliperidone Palmitate 6-Month Versus the 3-Month Long-Acting Injectable in Patients With Schizophrenia
date: 2021-11-13
journal: Int J Neuropsychopharmacol
DOI: 10.1093/ijnp/pyab071
sha: 4268b29649a18939f3ce3c91af301bc80270e64d
doc_id: 28726
cord_uid: frsl8b1m

BACKGROUND: This double-blind (DB), randomized, parallel-group study was designed to evaluate efficacy and safety of paliperidone palmitate 6-month (PP6M) formulation relative to paliperidone palmitate 3-month (PP3M) formulation in patients with schizophrenia. METHODS: Following screening, patients entered an open-label (OL) maintenance phase and received 1 injection cycle of paliperidone palmitate 1-month (PP1M; 100 or 150 mg eq.) or PP3M (350 or 525 mg eq.). Clinically stable patients were randomized (2:1) to receive PP6M (700 or 1000 mg eq., gluteal injections) or PP3M (350 or 525 mg eq.) in a 12-month DB phase; 2 doses of PP6M (corresponding to doses of PP1M and PP3M) were chosen. RESULTS: Overall, 1036 patients were screened, 838 entered the OL phase, and 702 (mean age: 40.8 years) were randomized (PP6M: 478; PP3M: 224); 618 (88.0%) patients completed the DB phase (PP6M: 416 [87.0%]; PP3M: 202 [90.2%]). Relapse rates were PP6M, 7.5% (n = 36) and PP3M, 4.9% (n = 11). The Kaplan-Meier estimate of the difference (95% CI) between treatment groups (PP6M − PP3M) in the percentages of patients who remained relapse free was −2.9% (−6.8%, 1.1%), thus meeting noninferiority criteria (95% CI lower bound is larger than the pre-specified noninferiority margin of −10%). Secondary efficacy endpoints corroborated the primary analysis. Incidences of treatment-emergent adverse events were similar between PP6M (62.1%) and PP3M (58.5%). No new safety concerns emerged. CONCLUSIONS: The efficacy of a twice-yearly dosing regimen of PP6M was noninferior to that of PP3M in preventing relapse in patients with schizophrenia adequately treated with PP1M or PP3M. TRIAL REGISTRATION: Clinical Trials.gov identifier: NCT03345342

Long-acting injectable (LAI) antipsychotics encourage better treatment outcomes in patients with schizophrenia by offering numerous advantages, including infrequent dosing, stable plasma medication levels, and adherence transparency and provide clinicians, patients, and caregivers the opportunity to intervene before further symptomatic worsening occurs (Brissos et al., 2014; Correll et al., 2016) . LAI antipsychotics have shown superior efficacy to their oral equivalents in improving adherence, reducing hospitalizations and relapses in schizophrenia (Brissos et al., 2014; Marcus et al., 2015; Schreiner et al., 2015; Alphs et al., 2016; Correll et al., 2016; Greene et al., 2018) .

There is extensive clinical trial evidence for the use of paliperidone palmitate 1-month (PP1M) and paliperidone palmitate 3-month (PP3M) formulations for maintaining treatment continuity and preventing relapses and risk of hospitalizations in patients with schizophrenia (Gopal et al., , 2011 Hough et al., 2010; Berwaerts et al., 2015; Savitz et al., 2016; Di Lorenzo et al., 2018; Garcia-Portilla et al., 2020) . The evidence is further strengthened by findings from real-world studies (Emsley et al., 2018; Emond et al., 2019; Patel et al., 2020) . Both PP1M and PP3M have demonstrated efficacy in maintaining symptom and functional stability and acceptable safety and tolerability for long-term use in patients with schizophrenia (Attard et al., 2014; Bioque and Bernardo, 2018; Mathews et al., 2019) . LAIs with longer dosing durations could be more patient-centric as they enable fewer injections per year with sustained medication delivery, particularly useful for patients living in isolated areas who may have transportation limitations or healthcare access problems (Mace et al., 2019; Pietrini et al., 2019; Blackwood et al., 2020; Moreno et al., 2020) . To address this need, a paliperidone palmitate 6-month (PP6M) formulation was developed and is the first LAI with a substantially longer dosing interval of 6 months, enabling just 2 injections per year. The PP6M LAI is not intended for acutely symptomatic patients. Patients need to be stabilized on the shorter-acting equivalents (PP1M or PP3M) before transitioning to the longer-acting treatment with PP6M.

The present study was an active-controlled, non-inferiority study to evaluate the efficacy of PP6M relative to PP3M in preventing relapses and assess the safety and pharmacokinetics (PK) of PP6M in clinically stabilized patients with schizophrenia.

The study protocol and amendments were approved by an independent ethics committee or institutional review board (See list of institutional review boards and independent ethics committees in the online supplement). The trial was conducted in compliance with the ethical principles of the Declaration of Helsinki, Good Clinical Practices, and applicable regulatory requirements. All patients provided written informed consent before study participation.

Eligible patients were between 18 and 70 years of age, had a Diagnostic and Statistical Manual of Mental Disorders, 5th edition (DSM-5) diagnosis of schizophrenia for ≥6 months before screening, and had a Positive and Negative Syndrome Scale (PANSS) total score of <70 points at screening. Patients were receiving treatment with paliperidone palmitate (PP1M [100 or 150 mg eq.] or PP3M [350 or 525 mg eq.], with dose timing that fits the current study schedule), injectable risperidone microspheres, or any oral antipsychotic (except clozapine), which in the opinion of the investigator could have been discontinued during screening (except for PP1M/PP3M).

Patients who met any of the following criteria were excluded from the study: active primary DSM-5 diagnosis other than schizophrenia; receiving any form of involuntary treatment (e.g., involuntary psychiatric hospitalization); attempted suicide within 12 months before screening and was at imminent risk of suicide or violent behavior, as clinically assessed by the investigator; DSM-5 diagnosis of moderate or severe substance use disorder (except for nicotine or caffeine) within 6 months of screening; history of neuroleptic malignant syndrome, tardive dyskinesia, or clinically significant and unstable medical illness; history of treatment-resistant schizophrenia (i.e., failure to respond to 2 adequate trials of different antipsychotic medications with adequate doses); or intolerability or severe reactions to moderate or higher doses of antipsychotic medications. Please see supplementary Methods for details on entry criteria.

Patients were recruited from various sites, and the recruitment method was dependent on the regulations of the respective independent ethics committee or institutional review board and meeting eligibility criteria. Acutely ill patients were excluded, and the recruitment was at the discretion of the investigators.

This study (NCT03345342) was a double-blind (DB), randomized, active-controlled, parallel-group multicenter study conducted between November 2017 and May 2020 at 121 research sites in 20 countries.

The study had 3 phases: (1) a screening phase (up to 28 days), (2) an open-label (OL) maintenance phase (duration of 1 or 3 months depending on treatment received [1 injection cycle of PP1M/ PP3M]), and (3) DB phase (12 months) (Figure 1 ). Patients who entered the study on an oral antipsychotic, injectable risperidone microspheres, or PP1M previously initiated but not stabilized at

Medications for schizophrenia in the form of injections that are long-lasting, known as long-acting injectable (LAI) antipsychotics, are more beneficial compared with oral pills in preventing the risk of relapse. Currently available LAIs can be received every 2 weeks up to once every 3 months, and there is a need for LAIs that are longer lasting, especially for patients with serious adherence issues and those living in isolated areas with healthcare access problems. Paliperidone palmitate 6-month (PP6M) is the first LAI that can be administered once every 6 months, enabling just 2 injections per year for patients who have been adequately treated on the 1-monthly or 3-monthly LAIs of paliperidone palmitate. In this phase 3 clinical study, the efficacy of PP6M was noninferior or comparable with the 3-monthly equivalent formulation (PP3M) for prevention of relapses, and there were no new safety concerns. study entry were eligible to participate in an OL transition phase just prior to the OL maintenance phase to initiate and/or continue treatment with PP1M for up to 4 months. Patients on PP1M or PP3M OL maintenance treatment could be randomized to DB treatment with equivalent doses of PP6M or PP3M.

Patients could have entered the study screening phase on PP1M (100 or 150 mg eq.), PP3M (350 or 525 mg eq.), injectable risperidone microspheres (50 mg), or oral antipsychotics (at any dosage with a reason to change, such as problems with efficacy, safety or tolerability, or a preference for a LAI) as prior medications. Patients without documented tolerability to any oral or injectable risperidone or paliperidone formulations received paliperidone extendedrelease/prolonged-release 6-mg tablets or risperidone 3 mg/d for 4-6 consecutive days during screening. Patients previously treated with oral antipsychotics, injectable risperidone microspheres, or a moderate or higher dose of PP1M but without previous stabilization (defined as ≥3 monthly injections, with the last 2 doses being the same dose strength) received additional doses of PP1M during the conditional OL transition phase ( Figure 1 ).

In the OL maintenance phase, all patients received only 1 dose of PP1M (100 or 150 mg eq.) or PP3M (350 or 525 mg eq.), which was either matched (PP1M to PP1M, or PP3M to PP3M) or converted (PP1M to PP3M) to an equivalent of the dose last received in the OL transition phase or prior to enrollment ( Figure  1 ). To ensure adequate numbers of PP1M-and PP3M-treated patients were switched to PP6M when randomized, some patients (after appropriate treatment with PP1M) were switched to PP3M on entry to the OL maintenance phase (until approximately onehalf of the total maintenance phase sample was treated with PP3M) because low enrollment of patients previously treated with PP3M was anticipated. Injections of PP1M or PP3M during the OL phase were deltoid or gluteal in accordance with the prescribing information. In the DB phase, patients were randomized to PP6M or PP3M (2:1, respectively). Patients in the PP3M group who received OL PP1M doses (100 or 150 mg eq.) were assigned to DB PP3M doses (350 or 525 mg eq., respectively), and those on OL PP3M doses (350 or 525 mg eq.) continued at the same DB dose level ( Figure 1 ). Patients in the PP6M group were transitioned to PP6M doses corresponding to the prescribed doses of PP1M (100 mg eq. or 150 mg eq.) and PP3M (350 mg eq. or 525 mg eq.) (supplementary Table 1 ). Patients who received "moderate" doses of OL PP1M (100 mg eq.) or PP3M (350 mg eq.) received the "moderate" dose of PP6M (700 mg eq.) in the DB phase, and those on the "high" doses of OL PP1M (150 mg eq.) or PP3M (525 mg eq.) received the "high" dose of PP6M (1000 mg eq.) in the DB phase. Injections (PP6M and PP3M) were administered dorsogluteally due to the larger volume of PP6M. paliperidone palmitate 3-month formulation; PP6M, paliperidone palmitate 6-month formulation. a Patients in PP6M group received 2 placebo injections. b Before prerandomization (approximately one-half of the total maintenance phase sample was treated with PP3M) criteria are met. c After pre-randomization criteria are met. d One patient entered the OL transition phase, withdrew, then re-screened again and entered the DB phase. e Among 838 patients who entered the OL phase, 71 withdrew during OL transition phase and 767 entered the OL maintenance phase.

Randomization was based on a computer-generated randomization schedule, balanced using randomly permuted blocks, and stratified by study site and moderate or high dose in the maintenance phase. To maintain the blinding, patients treated with PP6M received injections of placebo at the 3-month time points between their 6-month doses. The placebo was 20% Intralipid ® (200 mg/mL) injectable emulsion and matched the appearance of the active treatment. Therefore, the 12-month DB phase included a total of 4 injections at 3-month intervals, irrespective of treatment group. Due to differences in syringe sizes for PP6M vs PP3M, the study drug administrator was unblinded and not allowed to perform any other study-related procedures or communicate patient-related information with study-site personnel to ensure integrity of the blind.

See supplementary Methods.

The primary endpoint was time to relapse during the DB phase. This noninferiority primary endpoint was based on the difference in the Kaplan-Meier 12-month estimate of survival (i.e., percentage of patients remaining relapse free) between PP6M and PP3M. The relapse criteria were identical to those used in previous clinical studies of PP3M and PP1M (Berwaerts et al., 2015; Savitz et al., 2016) . Relapse was defined as ≥1 of the following: (1) psychiatric hospitalization due to exacerbation of schizophrenia symptoms (involuntary or voluntary admission);

(2) 25% increase (for patients with PANSS scores >40 at randomization) or 10-point increase (for patients with PANSS scores ≤40 at randomization) in PANSS total score from randomization for 2 consecutive assessments between 3 to 7 days; (3) deliberate selfinjury resulting in suicide or exhibited violent behavior resulting in clinically significant injury; (4) aggressive behavior, suicidal or homicidal ideation; (5) PANSS items scores ≥5 (if PANSS items was ≤3 at randomization); or ≥6 (PANSS items was 4 at randomization) after randomization for 2 consecutive assessments between 3 to 7 days on any of the following items: P1 (delusions), P2 (conceptual disorganization), P3 (hallucinatory behavior), P6 (suspiciousness/persecution), P7 (hostility), and G8 (uncooperativeness). The date of relapse was the date of the first assessment for symptoms of relapse (not the date of confirmation).

Secondary efficacy endpoints included changes from baseline during the 12 months of the DB phase in the following scales: PANSS total score and subscale scores (Kay et al., 1987) , Clinical Global Impression-Severity (CGI-S) (Busner and Targum, 2007) , and Personal and Social Performance (PSP) scale (Morosini et al., 2000) . Additionally, the proportion of patients during the DB phase who met criteria for symptomatic remission (defined as having a score ≤3 on all of the following 8 PANSS items: P1, P2, P3, N1, N4, N6, G5, and G9 for the last 6 months of DB treatment, with 1 excursion allowed) was summarized (Andreasen et al., 2005) .

Safety was assessed by treatment-emergent adverse events (TEAEs), 12-lead electrocardiograms, vital signs, clinical laboratory tests, and injection-site evaluations. Extrapyramidal symptoms (EPS) were assessed by the Simpson-Angus Scale, Barnes Akathisia Rating Scale, and Abnormal Involuntary Movement Scale. Suicidal ideation and behavior were assessed using Columbia Suicide Severity Rating Scale.

Sample Size Determination-Sample size calculation for the DB phase was based on the primary endpoint, which was also tested for noninferiority. The study was designed to have a minimum of 80% power to demonstrate an 85% survival rate (percentage of patients remaining relapse free at 12 months) in the PP3M group based on 1-sided significance level of 2.5%. A total 549 patients were expected to be randomized (2:1, PP6M:PP3M) to demonstrate with 80% power that PP6M is no worse than PP3M by a noninferiority margin of −10% for the percentage of patients remaining relapse free at 12 months assuming efficacy similar as observed in previous studies of PP3M (rationale for the 10% noninferiority margin is described previously; Savitz et al., 2016) . The study design assumed discontinuation rates of 20% and 40% during the transition and maintenance for patients who entered the study with or without previous PP1M or PP3M stability, respectively, and a dropout rate of 10% during the DB phase. Given these assumptions for discontinuation, the study targeted approximately 840 patients to enter the transition or maintenance phase. Statistical Analyses-Plasma concentrations of paliperidone and paliperidone palmitate and the derived PK parameters were summarized descriptively for the PK data analysis set. Efficacy and safety during the OL phase were summarized for the OL intent-to-treat (ITT-OL) set (all patients who received ≥1 dose of OL study drug, including transition and maintenance phases). The primary efficacy analysis included all randomized patients who received ≥1 dose of treatment (PP3M or PP6M) during the DB phase (ITT-DB analysis set). Analyses involving changes from the DB baseline were provided for both observed case and last observation carried forward data. The ITT-DB set was used for all secondary efficacy endpoints. An additional analysis with the per-protocol analysis set (all patients who were randomized in the DB-phase received ≥1 dose of DB treatment and did not have any major protocol violations) was performed to evaluate consistency of results for the primary endpoint. Safety analysis during the DB phase was conducted using the DB safety analysis set (DB safety; same as the ITT-DB).

The null hypotheses to be tested using a 1-sided α = 0.025 level were as follows: H0: p 6 -p 3 ≤−δ vs H1: p 6 -p 3 >−δ; where p 3 referred to the percentage of patients who remained relapse free at 12 months for the PP3M groups and p 6 referred to the percentage of patients who remained relapse free at 12 months for the PP6M group. The Kaplan-Meier method was used to estimate the 12-month cumulative estimate of survival. Standard error (SE) estimates were based on Greenwood's formula. Noninferiority of PP6M to PP3M was to be concluded if the lower limit of the 2-sided 95% confidence interval (CI) of the difference in the relapse-free rates between PP6M and PP3M exceeded −10%. Hazard ratios (HR) along with 95% CI were estimated using the Cox proportional hazards model with treatment as the only factor to compare treatment effects on the time to relapse of schizophrenia symptoms. The change from baseline (DB) at each visit in PANSS total and subscale scores and CGI-S and PSP scores during the DB phase was analyzed using an ANCOVA model with factors for treatment and country and baseline score as a covariate. Estimates of treatment effects as least square mean difference (PP6M − PP3M) and the accompanying 95% CI were presented. The proportion of patients achieving symptomatic remission in the DB phase was calculated using the Cochran-Mantel-Haenszel test controlling for country.

Of the 838 patients enrolled and dosed in the OL phases, 702 (83.8%) completed the OL phases and were randomized (PP6M, n = 478; PP3M, n = 224) in the DB phase ( Figure 1 ). All 702 patients were included in the ITT-DB set. Withdrawal by patient (57/ 

The demographics and baseline (OL) psychiatric characteristics of patients in the PP6M and PP3M groups in the DB phase were generally similar (Table 1) . Overall demographics and baseline characteristics of dropouts/not randomized were similar to those randomized in the DB phase. Patients (n = 702) were a mean age of 40.8 (range, 18-69) years and were mostly men (68.4%), White (74.2%), non-Hispanic (84.6%), and ≤50 years of age (79.6%). The PP6M and PP3M treatment groups were matched in terms of baseline severity of illness as measured by the PANSS, CGI-S, and PSP scores and age at first diagnosis. Duration of psychiatric hospitalization was numerically longer in the PP6M group ( 

At DB phase entry, the proportion of patients on prior psychotropic medication was similar between the PP3M and PP6M group (supplementary Table 2 ). Before study entry, 701/702 (99.9%) patients received psychotropic medications. Atypical antipsychotics (61.0%) were most commonly used, 18.4% of patients received benzodiazepines, and 14.2% were on anti-EPS medications.

During the DB phase, the concomitant use of benzodiazepines (23.6% vs 21.0%), anti-EPS medications such as anticholinergic medications (15.5% vs 12.9%), antihistamines (6.1% vs 8.5%), and beta-blockers (propranolol: 2.1% vs 1.8%; metoprolol: 1.3% vs 1.8%) were similar between PP6M and PP3M groups (supplementary Table 3 ). A total of 415/702 (59.1%) patients received concomitant medications other than benzodiazepines during the DB phase (PP6M: 60.5% vs PP3M: 56.3%), the common ones being acetaminophen (9.7%), metformin (8.3%), and biperiden (7.7%).

A total of 106/838 (12.6%) patients underwent oral tolerability testing, and none reported tolerability concerns. Of the 568 patients treated in the OL transition phase, 272 (47.9%) received 5 injections of PP1M and 217 (38.2%) received 4 injections; 458 (80.6%) patients received PP1M for ≥91 days. Of the 767 patients treated in the OL maintenance phase, 362 patients received PP1M (100 mg eq., n = 175; 150 mg eq., n = 187) and 405 received PP3M (350 mg eq. n = 193; 525 mg eq., n = 212). In the DB phase, the mean (SD) duration of exposure was 329.8 (86.97) days in the PP6M group and 336.4 (80.89) days in the PP3M group. The mean (SD) dose of PP6M was 855.6 (150.05) mg eq. and the mean (SD) dose of PP3M was 442.2 (87.57) mg eq. Overall, 86.4% of patients in the PP6M group received 2 and 84.8% in the PP3M group received 4 active injections.

In the DB phase for all treatments and administered dosages, mean C max was achieved around 1 month after each dose ( Figure  2 ). After achieving mean C max , concentrations gradually declined for the remainder of the dosing cycle. Patients who received PP6M had approximately 20%-25% lower trough concentrations (dose normalized C trough ) compared with patients who received PP3M. In the DB phase, mean peak paliperidone concentrations (dose normalized C max ) after PP6M dosing was slightly higher (1.4-to 1.5-fold) than after PP3M dosing, and mean total paliperidone exposure (dose normalized AUC 6month ) was comparable after PP3M and PP6M dosing (see supplementary Results for more details).

Thirty-six (7.5%) patients in the PP6M group and 11 (4.9%) in the PP3M group experienced a relapse event during the DB phase (ITT-DB). The Kaplan-Meier estimate of the difference (95% CI) between the treatment groups (PP6M − PP3M) in the percentages of patients who remained relapse free was −2.9% (−6.8%, 1.1%). Thus, PP6M was noninferior to PP3M based on the lower bound of the 95% CI being larger than the pre-specified noninferiority margin of −10% (Figure 3) . Analysis using the per-protocol set corroborated the ITT-DB analysis, with the lower bound of 95% CI of Kaplan-Meier estimate of treatment difference being larger than the pre-specified noninferiority margin of −10% (supplementary Figure 1 ). Thus, PP6M was declared noninferior to PP3M for the primary efficacy endpoint. The median time to relapse (the time at which the cumulative survival function equals 0.5 [or 50%]) was not estimable for either the PP6M or PP3M groups due to the low number of relapses during the DB phase (Table 2; Figure 3 ). The most common reasons for relapses were an increase of ≥25% in PANSS total score (PP6M: 16 [3.3%]; PP3M: 5 [2.2%]), PANSS item (P1, P2, P3, P6, P7, G8) score of ≥5 after randomization (PP6M: 13 [2.7%]; PP3M: 5 [2.2%]), and psychiatric hospitalizations (PP6M: 11 [2.3%]; PP3M: 6 [2.7%]). The ratio (95% CI) of the instantaneous risk of relapse for a patient who received PP6M treatment vs the risk for a patient who received PP3M in the DB phase was 1.57 (0.80, 3.08).

Results for the secondary endpoints corroborated the primary efficacy analysis, indicating comparable improvements in PANSS total, subscale and Marder factor scores, and CGI-S and PSP scores between PP6M and PP3M groups from DB baseline to DB endpoint (Table 3; supplementary Figures 2 and 3) . Changes in CGI-S and PSP scores indicated persistence of clinical stability over the 12-month DB period. The percentage of patients with ≥20% improvement from DB baseline to DB endpoint in PANSS total scores was numerically higher in the PP6M (38.9%) compared with PP3M (32.1%); similar percentage of patients in the PP6M and PP3M treatment groups showed an improvement of ≥30% and ≥40% in PANSS total score (Table 3 ). More than 60% of patients in both treatment groups (PP6M: 66.3%; PP3M: 70.1%) achieved symptomatic remission during the DB phase.

A total of 341 of 838 patients (40.7%) had ≥1 TEAE in the OL phase; 23 (2.7%) patients had ≥1 serious TEAE, 31 (3.7%) had TEAEs leading to withdrawal of the study drug, and 1 (0.1%) death (due to completed suicide) was reported in the OL phase (Table 4 ).

In the DB phase, TEAEs were reported in a comparable percentage of patients in the PP6M (297/478 [62.1%]) and PP3M (131/224 [58.5%]) groups. The most common TEAEs (≥5% in either group) were increased weight, injection-site pain, headache, upper respiratory tract infections, and nasopharyngitis. Most TEAEs were mild or moderate in severity. In total, 24/478 (5.0%) patients in the PP6M group and 15/224 (6.7%) in the PP3M group experienced serious TEAEs that were mostly related to worsening of psychiatric symptoms; schizophrenia was the most frequent (PP6M: 1.7%; PP3M: 0.4%). Overall, 16/478 (3.3%) patients in the PP6M group and 6/224 (2.7%) in the PP3M group discontinued the DB phase due to TEAEs that were mostly psychiatric in nature, with schizophrenia (PP6M: 8 [1.7%]; PP3M: 1 [0.4%]) being the most common. Three deaths (PP6M: n = 1 [cause not specified]; PP3M: n = 2 [pulmonary embolism and sudden death, unknown cause, n = 1 each]) were reported in the DB phase; investigators considered these deaths as not related to study medication. were generally similar between the treatment groups (PP6M vs PP3M). There were no reported TEAEs for neuroleptic malignant syndrome or post-injection delirium/sedation syndrome during the study.

Prolactin-related TEAEs also occurred in a similar percentage of patients (PP6M: 18/478 [3.8%]; PP3M: 7/224 [3.1%]). The magnitude of change in mean (SD) levels of serum prolactin from OL or DB baseline to DB endpoint was greater in patients from the PP3M vs the PP6M group (Table 5) . Median prolactin levels in men remained relatively stable throughout the OL and DB phases, whereas women showed an increase from OL baseline to DB baseline (continued to week 3 in the DB phase and remained relatively stable through month 6) ( Figure 4) . Incidences of TEAEs of weight gain in the DB phase were also similar between the groups: PP6M, 44/478 (9.2%) vs PP3M, 18/224 (8.0%). Injection site-related TEAEs were reported in 59/478 (12.3%) patients in the PP6M group and 11/224 (4.9%) in the PP3M group. Injection site pain was the most frequently reported TEAE in the PP6M (37 [7.7%]) and PP3M (9 [4.0%]) groups, and all other TEAEs including induration, redness, and swelling occurred in <2% of patients in both groups. Induration, redness, and swelling at the injection site, as noted by investigator evaluation, were observed in ≤6% of patients in both treatment groups and were mostly mild in severity. Reduction in mean (SD) value of injection site pain was observed in local tolerability assessments by patients using a visual analog scale from DB baseline to endpoint (Table 5) .

This multicenter, randomized, DB relapse prevention study demonstrated the noninferiority of PP6M at 700 and 1000 mg eq. doses in patients with schizophrenia, suggesting comparable efficacy with its 3-monthly equivalent formulation (PP3M) for patients who remained relapse free at the end of the 12-month DB phase. There were no appreciable differences in efficacy or safety when transitioning directly from PP1M or PP3M to PP6M. The safety profiles of PP6M and PP3M were largely similar aside from higher injection site pain with PP6M, which could be attributable to the larger injection volume.

The rate of relapse during the DB phase was low in both PP6M (7.5%) and PP3M (4.9%) groups, and a high proportion of patients remained relapse free and completed the 12-month DB phase (PP6M: 79.5%; PP3M: 85.3%). Results for the secondary efficacy analysis were supportive of the primary analysis. Overall, the type and incidence of TEAEs were comparable between PP6M and PP3M groups in the DB phase and consistent with the known profile of paliperidone palmitate Kramer et al., 2010; Gopal et al., 2011; Berwaerts et al., 2015; Savitz et al., 2016) . None of the TEAEs related to injection site, potentially prolactin-related, weight gain or diabetes mellitus and hyperglycemia-were reported as serious or resulted in treatment discontinuation during the OL or DB phase. Investigator evaluations of swelling, redness, and induration were similar across treatment groups, and patient assessment of injection site pain showed reduction from DB baseline to endpoint for both treatments, suggesting good tolerability and acceptance of the dorsogluteal injections.

Two doses of PP6M (moderate: 700 mg eq.; high: 1000 mg eq.) that resulted in a range of paliperidone plasma exposures similar to simulated exposures obtained with the most commonly prescribed monthly doses of PP1M (100 and 150 mg eq.), 3-monthly doses of PP3M (350 and 525 mg eq.), and corresponding doses of once-daily paliperidone ER (8 [dose used for comparing moderate-dose level] and 12 mg) were selected for assessment (data on file). Dose-normalized total exposure over a 6-month period (2 PP3M administrations vs 1 PP6M administration) were comparable between dose levels for both products. Overall, administration of PP6M once every 6 months, at doses of 700 and 1000 mg. eq., resulted in a range of paliperidone exposures that overlapped with the range of exposures obtained with corresponding doses of PP3M. Relapses were observed throughout dosing cycle and did not appear to be clustered near the end of dosing cycle for both treatments, implying that the comparably lower PP6M C trough is likely not the key determinant of relapse.

To date, the PP6M LAI has the longest available dosing interval of 6 months and is intended for use in stable patients with schizophrenia who have been adequately treated with PP1M and PP3M. Its widespread use will require a paradigm shift in how clinicians and patients place oral antipsychotics and LAIs in the management of schizophrenia. Longer-term treatment planning will be required. Evidence supporting patient-centric care also indicates that long-term treatment continuation in schizophrenia improves when treatment injections are less frequent or have longer dosing intervals (Citrome, 2017; Pietrini et al., 2019) . Fewer injections are associated with less social stigma, which is a barrier in patients with severe mental illness (da Silva et al., 2020) . The twice-yearly dosing regimen of PP6M represents a significant advancement over existing treatments for the management of a chronic illness such as schizophrenia. The use of PP6M would allow patients with limited access to healthcare (due to geographic or economic constraints) to have more consistent medication coverage. Real-world data from specific groups of clinical interest such as homeless patients who often have infrequent contact with outreach workers, patients with recent-onset schizophrenia who have high relapse rates within 5 years after initial recovery, or patients with a history of incarceration or self-harm could provide useful insights on Based on Kaplan-Meier product limit estimates.

the potential benefits of treatment with PP6M in these patients (Robinson et al., 1999; Morken et al., 2008; Sajatovic et al., 2013) . Studies investigating LAIs in adults with first-episode schizophrenia have shown favorable neuropathological changes along with early symptom improvement and reduced risk of relapse (Taylor and Ng, 2013; Stevens et al., 2016) . A recent guideline also recommended LAI use in stabilized adult patients after first episode and in early-phase patients to maintain treatment continuity (floridabhcenter.org, 2020). In accordance with a recent clinical guideline issued by Serious Mental Illness (SMI) Adviser (an initiative from the American Psychiatric Association and the Substance Abuse and Mental Health Services Administration), the use of LAIs such as PP6M can be of great value to ensure medication continuation while minimizing interpersonal contact and hospital visits (Moreno et al., 2020; SMI-Adviser, 2020) . However, the 6-month dosing interval of PP6M does not dictate the frequency of clinical visits, which can be decided mutually by the patient and clinician. The present study was adequately powered to assess efficacy using a noninferiority approach. The noninferiority margin of −10% (different from the PP3M study: −15%) was selected based on the efficacy results of a phase 3 non-inferiority study comparing PP3M to PP1M (Berwaerts et al., 2015; Savitz et al., 2016) and on advice from experts and health authorities and endorsed by the Committee for Medicinal Products for Human Use. The eligibility criteria for the present study were similar to the PP3M studies and designed to give a representative patient population likely to be treated with PP6M in clinical practice (Berwaerts et al., 2015; Savitz et al., 2016) . Notably, at study entry (OL baseline), the criterion for PANSS total score (<70 indicating clinical stability) was different from the previous PP3M studies (between 70 and 120, not indicating clinical stability, although a PANSS <70 score was the criteria for DB entry). Several study limitations should be noted. The noninferiority design was based on the principle of enrichment, that is, criteria of clinical stability were applied prior to entry into the DB phase; thus, the results may not reflect true efficacy for prevention of relapses in the overall population. However, the criterion of clinical stability was fundamental to the study design, and PP6M is not intended for use in acutely ill patients with schizophrenia. Furthermore, an OL long-term study (NCT04072575) with more real-world features is currently ongoing and will provide additional insight on the relapse prevention efficacy of PP6M. Also, the absence of a placebo group further limits interpretation of findings, and it is unknown how these findings compare with oral antipsychotics. The fixed doses evaluated during the DB phase were not directly informative of any changes in the dose of PP6M that could occur during long-term treatment in clinical practice or directly inform the dose response of PP6M for use as maintenance therapy, as patients were not randomly assigned to distinct dose levels of PP6M. Notably, patients in the PP6M group received injections every 3 months to maintain the blinding (2 active, 2 placebo injections), thus limiting the interpretation on injection site ratings, patient preference, caregiver Assessment of local tolerability by the patient using a visual analog scale (VAS) (within 30 mins of injection) presented as a 100-mm horizontal line on which the patient's pain intensity is represented by a point between the "no pain at all" (0) and "unbearably painful" (100).

burden, etc., that are directly related to different dosing intervals between the 2 formulations. The use of placebo injections could also introduce a potential placebo effect in the PP6M group, which is an inherent limitation of most randomized controlled trials.

The primary efficacy analysis of this clinical trial confirmed that the efficacy (measured by percentage of patients who remained relapse free) of PP6M (700 or 1000 mg eq.) was noninferior to PP3M (350 or 525 mg eq.) in clinically stable patients with schizophrenia adequately treated with PP1M for ≥4 months or PP3M for ≥1 injection cycle. Safety findings for PP6M were consistent with the known profile of paliperidone palmitate, and no new signals specific for PP6M emerged. There were no appreciable differences in efficacy or safety when transitioning directly from PP1M or PP3M to PP6M. Thus, PP6M offers the longest LAI dosing interval available to date and, along with PP1M and PP3M, provides flexible dosing regimens for a patient-centric approach in the management of schizophrenia. An OL extension study is currently underway to assess the long-term safety and tolerability of PP6M.

Supplementary data are available at International Journal of Neuropsychopharmacology (IJNPPY) online. 

A pragmatic analysis comparing once-monthly paliperidone palmitate versus daily oral antipsychotic treatment in patients with schizophrenia

Remission in schizophrenia: proposed criteria and rationale for consensus

Paliperidone palmitate long-acting injection-prospective year-long follow-up of use in clinical practice

Efficacy and safety of the 3-month formulation of paliperidone palmitate vs placebo for relapse prevention of schizophrenia: a randomized clinical trial

The current data on the 3-month paliperidone palmitate formulation for the treatment of schizophrenia

Patients' preference for long-acting injectable versus oral antipsychotics in schizophrenia: results from the Patient-Reported Medication Preference Questionnaire

The role of long-acting injectable antipsychotics in schizophrenia: a critical appraisal

The clinical global impressions scale: applying a research tool in clinical practice

Long-acting injectable antipsychotics update: lengthening the dosing interval and expanding the diagnostic indications

The use of long-acting injectable antipsychotics in schizophrenia: evaluating the evidence

The impact of mental illness stigma on psychiatric emergencies

Clinical improvement, relapse and treatment adherence with paliperidone palmitate 1-month formulation: 1-year treatment in a naturalistic outpatient setting

Adherence, healthcare resource utilization, and costs in medicaid beneficiaries with schizophrenia transitioning from once-monthly to onceevery-3-months paliperidone palmitate

Real-world data on paliperidone palmitate for the treatment of schizophrenia and other psychotic disorders: a systematic review of randomized and nonrandomized studies

Symptomatic and functional outcomes after treatment with paliperidone palmitate 3-month formulation for 52 weeks in patients with clinically stable schizophrenia

Efficacy and safety of paliperidone palmitate in adult patients with acutely symptomatic schizophrenia: a randomized, double-blind, placebo-controlled, dose-response study

A 52-week open-label study of the safety and tolerability of paliperidone palmitate in patients with schizophrenia

Medication adherence and discontinuation of long-acting injectable versus oral antipsychotics in patients with schizophrenia or bipolar disorder

Paliperidone palmitate maintenance treatment in delaying the time-to-relapse in patients with schizophrenia: a randomized, double-blind, placebo-controlled study

The positive and negative syndrome scale (PANSS) for schizophrenia

Paliperidone palmitate, a potential long-acting treatment for patients with schizophrenia. Results of a randomized, double-blind, placebo-controlled efficacy and safety study

Positive views on antipsychotic long-acting injections: results of a survey of community patients prescribed antipsychotics

Antipsychotic adherence and rehospitalization in schizophrenia patients receiving oral versus long-acting injectable antipsychotics following hospital discharge

Clinical relevance of paliperidone palmitate 3-monthly in treating schizophrenia

How mental health care should change as a consequence of the COVID-19 pandemic

Non-adherence to antipsychotic medication, relapse and rehospitalisation in recent-onset schizophrenia

Development, reliability and acceptability of a new version of the DSM-IV Social and Occupational Functioning Assessment Scale (SOFAS) to assess routine social functioning

Real-world analysis of switching patients with schizophrenia from oral risperidone or oral paliperidone to once-monthly paliperidone palmitate

The modern perspective for long-acting injectables antipsychotics in the patient-centered care of schizophrenia

Predictors of relapse following response from a first episode of schizophrenia or schizoaffective disorder

Prospective trial of customized adherence enhancement plus long-acting injectable antipsychotic medication in homeless or recently homeless individuals with schizophrenia or schizoaffective disorder

Efficacy and safety of paliperidone palmitate 3-month formulation for patients with schizophrenia: a randomized, multicenter, double-blind, noninferiority study

Paliperidone palmitate versus oral antipsychotics in recently diagnosed schizophrenia

Serious Mental Illness Adviser. What are clinical considerations for giving LAIs during the COVID-19 public health emergency? American Psychiatric Association

Clinical benefits and impact of early use of long-acting injectable antipsychotics for schizophrenia

Should long-acting (depot) antipsychotics be used in early schizophrenia? A systematic review

We acknowledge Priya Ganpathy, MPharm CMPP (SIRO Clinpharm Pvt. Ltd., India), for medical writing assistance and Ellen Baum, PhD (Janssen Global Services, LLC) for additional editorial support. We also thank the study patients and investigators for their support. from AbbVie, Acadia, Alkermes, Allergan, Avanir, Boehringer Ingelheim, CoMentis, Intra-Cellular Therapies, Janssen, Johnson & Johnson PRD, Lundbeck, Lupin, Novartis, Noven, Omeros, Otsuka, Pfizer, Roche, Sunovion, Takeda, and Zogenix and personal fees from Janssen and Otsuka. Prof. Galderisi has consulted with or served on advisory boards for Innova Pharma-Recordati Group, Janssen, Gedeon Richter-Recordati, and Angelini and also reports fees as speaker in Congresses and Webinars for Angelini, Janssen, and Recordati.