Subject baseline demographics, disposition, and dosing
Subjects in the recently diagnosed subgroup were younger than the chronically ill subgroup at study entry, with an older age at the time of diagnosis of schizophrenia, and with a lower weight and body mass index (). There was a higher percentage of Caucasians and a lower percentage of smokers in the recently diagnosed subgroup than in the chronically ill subgroup. The mean years of illness was 2.9 ± 1.5 (range 1.0–5.0) in the recently diagnosed subgroup and 16.2 ± 8.1 (range 6.0–47.0) in the chronically ill subgroup. The subgroups were similar with respect to sex (male 60.2% and 58.0%, respectively), mean total Positive and Negative Syndrome Scale score (70.7 and 73.3, P = 0.0811, respectively), and Clinical Global Impressions Scale scores (not ill to moderate in 87.0% and 81.8%, respectively). Completion rates were generally similar between the subgroups during each study phase (). Among subjects receiving paliperidone palmitate who entered the double-blind relapse prevention phase, the time to relapse was not significantly different between the recently diagnosed and chronically ill subgroups (P = 0.0999, log-rank test).
Transition baseline demographics and characteristics that differed between subgroups
The mean monthly dose was similar in each subgroup (approximately 109 mg [69.9 mg eq]), with a mean duration of exposure of 333.9 ± 271.9 days in the recently diagnosed subgroup and 308.7 ± 278.3 days in the chronically ill subgroup. During the study, 42.1% of those in the recently diagnosed subgroup received benzodiazepines and 10.2% received medications for extrapyramidal symptoms, respectively. In the chronically ill subgroup, rates were 46.4% for benzodiazepines and 17.0% for medications used to treat extrapyramidal symptoms.
Reported adverse events
During the month following the first injection, 31.5% (68 of 216) of recently diagnosed and 42.7% (183 of 429) of subjects in the chronically ill subgroup reported an adverse event (). In general, incidence rates, RR, and 95% CI suggested that adverse events were less likely in the recently diagnosed subgroup than in the chronically ill subgroup at each time interval.
Subjects with at least one adverse event in the recently diagnosed and chronically ill subgroups (from time since first injection to specified time point)
In the month following the first injection, no adverse events were reported at a margin of ≥2% in more of the recently diagnosed subjects than in those with chronic illness (). Insomnia, worsening of schizophrenia, and agitation were reported at a margin of ≥2% in more of the chronically ill subjects than in recently diagnosed subjects. These differences in incidence were not considered potentially significant based upon the 95% CI. Nasopharyngitis was reported by more subjects with chronic illness than by those in the recently diagnosed subgroup of subjects at months 6 (4.9% versus 1.4%; RR 0.28; 95% CI 0.086–0.941 respectively), 9 (5.6% versus 1.9%; RR 0.33; 95% CI 0.116–0.942), and 12 (6.1% versus 2.3%; RR 0.38; 95% CI 0.149–0.981), and endpoint (7.2% versus 2.8%; RR 0.38; 95% CI 0.163–0.907); the 95% CI did not include 1 and were considered potentially significant. Influenza (2.8% versus 0.7%; RR 3.97; 95% CI 1.003–15.730) and amenorrhea (3.2% versus 0.9%; RR 3.48; 95% CI 1.029–11.744) were reported by more subjects in the recently diagnosed subgroup at endpoint. Given that the 95% CI did not include 1, these events were also considered potentially significantly different between subgroups.
Percentage, relative risk (recently diagnosed versus chronic illness), and 95% confidence intervals of adverse events reported by a margin of ≥2% in recently diagnosed or chronically ill subgroups.
In the recently diagnosed subgroup, sedation was reported by none, one, or two subjects at each time point (0.0%–0.93%), with somnolence reported by one or two subjects at each time point (0.46%–0.93%), and five subjects at endpoint (2.31%). In the chronically ill subgroup, sedation was reported by two subjects at each time point (0.47%), with somnolence reported by 1–5 subjects at each time point (0.23%–1.17%).
Events related to extrapyramidal symptoms
Extrapyramidal symptom-related adverse event rates included parkinsonism, hyperkinesia, dystonia, tremor, and dyskinesia. Rates of any extrapyramidal symptom-related events were numerically lower in the recently diagnosed subgroup at each period assessed (through months 1, 3, 6, 9, and 12 and open-label extension). Rates ranged from 2.3% to 9.3% in the recently diagnosed subgroup and from 5.8% to 12.6% in the chronically ill subgroup (). Rates of individual extrapyramidal symptom-related events and their specific preferred terms are summarized in . Among the specific preferred terms, nonspecific extrapyramidal disorder was reported by more recently diagnosed subjects (4.6%) than by chronically ill subjects (2.3%), and akathisia was reported by more chronically ill subjects (3.3%) than recently diagnosed subjects (1.9%).
Percentage of Subjects with Any EPS-Related Event* from First Injection to Specified Timepoint, in Recently Diagnosed and Chronic Illness Subjects.
Extrapyramidal symptom-related adverse events from first injection through open-label extension phase, in recently diagnosed and chronically ill subgroups
Logistic regression models showed that none of the baseline characteristics that differed between the subgroups was associated with risk of extrapyramidal symptom-related events (ie, age, P = 0.7057; weight, P = 0.8921; body mass index, P = 0.9823; age at diagnosis of schizophrenia, P = 0.7727; current smoking status, P = 0.3507; and race [black, P = 0.0950; other, P = 0.1602]).
Weight changes (least squares mean ± standard error) at endpoint were 2.6 ± 0.9 kg in the recently diagnosed subgroup and 3.4 ± 0.7 kg in the chronically ill subgroup (P = 0.42; least squares mean difference 0.8 ± 0.99, 95% CI: −1.15–2.75). Observed scores at each time point were evaluated using repeated-measures analysis of covariance. Average changes from baseline to endpoint between groups were similar (between-group comparison, P = 0.4342); this finding did not differ throughout the trial (group-by-visit interaction, P = 0.9520). Linear regression models assessing the impact of baseline differences did not reveal any potential associations (ie, age, P = 0.5117; weight, P = 0.1504; body mass index, P = 0.6557; age at schizophrenia diagnosis, P = 0.9309; current smoking status, P = 0.1172; and race, [black, P = 0.5444; other, P = 0.3842]).
Rates of glucose-related adverse events were 5.1% (22 of 429) in the chronically ill subjects and 2.8% (6 of 216) in recently diagnosed subjects, with “blood glucose increased” being the most frequent (4.0% versus 1.9%, ). In logistic regression models, age (P < 0.0001; odds ratio [OR] 1.087; 95% CI 1.047–1.129) had a significant association with incidence of glucose-related adverse events (one-year increase in age is associated with an 8.7% increase in odds of experiencing “blood glucose increased”), whereas body mass index (P = 0.0516; OR 1.057; 95% CI 1.000–1.118) and age at diagnosis of schizophrenia (P = 0.0578; OR 1.040; 95% CI 0.999–1.082) showed trends towards significance. Other baseline characteristics had no impact (ie, weight, P = 0.4310; current smoking status, P = 0.6082; and race [black, P = 0.1737; other, P = 0.0810]).
Glucose-related events from the first injection through open-label extension phasea
Mean glucose levels at open-label endpoint were not significantly different between the groups (least squares mean difference −0.1, 95% CI −0.61–0.32, P = 0.5436). Regression models showed that age (P = 0.0126, regression coefficient 0.025 ± 0.010) and age at diagnosis of schizophrenia (P = 0.0021, regression coefficient 0.042 ± 0.014) were associated with changes at endpoint.
Prolactin levels increased in both sexes in both subgroups. Mean prolactin values were consistently higher in recently diagnosed female subjects compared with chronically ill female subjects (). Potentially prolactin-related adverse events were reported by 7.9% of recently diagnosed subjects compared with 3.5% of chronically ill subjects through endpoint (). The most commonly reported events were amenorrhea (7 [3.2%] and 4 [0.9%], respectively) and galactorrhea (2 [0.9%] and 6 [1.4%], respectively).
Mean prolactin levels at transition baseline and open-label endpoint by sex in the recently diagnosed and chronically ill subgroups
Potentially prolactin-related events from first injection through open-label extension phasea