DISCUSSION
pain, psychiatric disorders, EPS-related TEAEs, schizophrenia, deaths
DISEASE, RECURRENCE, INJECTION SITE REACTION
In this 2-year OLE study in participants with schizophrenia who had remained relapse free in the DB study and who either transitioned from PP3M to PP6M (PP3M/PP6M) or maintained the 6-month formulation (PP6M/PP6M), PP6M demonstrated long-term efficacy and safety.The clinical improvements observed during the DB study were maintained in the OLE, as demonstrated by stable scores on PANSS, CGI-S, and PSP scales over the 2-year period with very few cases of relapses (3.9%). These efficacy results were generally consistent across the PP3M/PP6M and PP6M/PP6M subgroups. When efficacy parameters were examined from baseline to endpoint of the OLE as well as from DB study baseline to OLE endpoint, PP6M demonstrated an increased efficacy in the maintenance treatment of participants with schizophrenia (supplementary The study completion rate (86.5%) observed in this 2-year OLE was comparable with those observed in the 1-year DB study (completion rate: PP6M, 87.0%; PP3M, 90.2%). However, the relapse rate (3.9%) in the OLE was lower than those observed in the DB study (relapse rate: PP6M, 7.5%; PP3M, 4.9%) (The follow-up frequency in the current study was every 3 months. In routine clinical practice, the frequency of patient visits should be based on clinician’s judgement and not the frequency of injection interval. In this OLE study with PP6M (administered at doses of 700 or 1000 mg eq.), no new safety signals were identified and no deaths were reported. Overall, the safety of PP6M was consistent with the known profile of paliperidone palmitate (Low rates (4.5%) of serious TEAEs were observed across all groups. The serious TEAEs reported were mainly psychiatric disorders and were indicative of worsening of the underlying disease. Incidence of EPS-related TEAEs was also low (2.2%) in this study.As expected, prolactin levels in females were higher than males. However, there were also substantial fluctuations observed in prolactin values in females, which increased the mean value. However, none of the TEAEs related to prolactin levels were considered serious by investigators. The higher proportion of males in the study may have had a confounding effect on prolactin reporting (Although the volume of PP6M doses was 3.5 or 5 mL, which requires gluteal muscle administration, the incidence of injection site reaction was low (3.9%). This was confirmed by the low mean score on participant-reported Visual Analog Scale for injection site pain during the study. No clinically meaningful changes in vital signs and laboratory analytes were noted from OLE baseline to endpoint. Injection site evaluation over time showed that all the assessed parameters were either absent or mild for most participants, except for one.The safety and efficacy data described in this study support the use of LAIs in schizophrenia treatment. To date, PP6M has the longest dosing duration of current antipsychotic agents, and it is available to participants who have demonstrated adequate treatment with the PP1M or PP3M. Evidence suggests the longer the half-life of the antipsychotic used in the treatment, the longer the patient’s time to relapse after stopping the medication. In a study comparing oral paliperidone with PP1M and PP3M, recurrence was observed on average 58 days after oral paliperidone discontinuation, 172 days after PP1M discontinuation, and 395 days after PP3M discontinuation (As this was a single-arm study, the absence of a control arm/reference group was a potential limitation. Data were collected in local laboratories and electrocardiogram was not standardized, which would be characteristic of real-world conditions rather than as part of the typical phase 3 clinical study. Moreover, in this study, only relapse-free participants with schizophrenia who had completed the previous DB study were included, which may not fully represent the target population, thus limiting the generalizability of results. Finally, since the extension study was limited to 6 participating countries from a more expansive randomized DB study, data may have been affected by confounding demographic factors.The twice-a-year administration of PP6M in this OLE showed continued efficacy with no new safety concerns over 2 years. The study had a high completion rate, and the results were consistent with the known profile of paliperidone palmitate products.