Dosing
The majority of LY2140023-treated patients were taking the targeted dose (40 mg BID) at their final visit of the Study Period (approximate incidence of patients in each dose group at final visit: 14% patients at 20 mg BID; 62% patients at 40 mg BID; and 25% patients at 80 mg BID). The percentage of patients in the SOC group at their final visit of the Study Period receiving the minimum dose was 17%, the targeted dose was 46%, and the percentage receiving maximum dose was 38%. For each drug subgroup within the SOC group, the percentage of patients at their final visit of the study receiving the minimum, targeted, and maximum doses were: OLZ, 20%, 36%, 44%; RIS, 16%, 60%, 24%; and ARI: 14%, 48%, 39%, respectively.
Other safety measures
A total of 30 patients (LY2140023, n = 18; SOC, n = 12) experienced at least 1 serious adverse event (SAE) during the 24-week active-treatment phase of the study. The incidence of SAEs was not significantly different between groups. Reported SAEs included 3 deaths: 2 were in patients randomized to LY2140023, and 1 was in a patient who had not yet received any study drug. None of the 3 deaths was considered by investigators to be related to treatment with study drug or to protocol procedures.
One patient experienced 2 convulsions 1 day after discontinuing LY2140023 (approximately 3 weeks after randomization) and initiating treatment with intramuscular haloperidol; the convulsions were reported as possibly related to LY2140023 treatment. Another patient experienced a convulsion during the placebo lead-in phase; this convulsion was reported as possibly related to protocol procedure.
SAEs commonly reported (≥1% of LY2140023 patients) in the LY2140023 group were schizophrenia, psychotic disorder, agitation, insomnia, and pneumonia. Among patients in the SOC group, common SAEs were schizophrenia and psychotic disorder.
TEAEs reported at a statistically significantly higher rate among LY2140023-treated patients than among those on SOC included vomiting (P = .003), dyspepsia (P = .019), and agitation (P = .011) (Table
2). Among patients in the SOC group, akathisia (P = .019) and weight gain (P = .007) were reported at a significantly greater rate compared with the rate among those in the LY2140023 group.
Table 2
Treatment-emergent adverse events at incidence ≥5% in the LY2140023 group, or significantly different between groups
Patients with ≥ TEAE | 100 (76.9) | 94 (71.8) | .396 |
Insomnia | 20 (15.4) | 10 (7.6) | .054 |
Anxiety | 19 (14.6) | 10 (7.6) | .079 |
Headache | 16 (12.3) | 10 (7.6) | .222 |
Vomiting
|
15 (11.5)
|
3 (2.3)
|
.003*
|
Schizophrenia | 12 (9.2) | 11 (8.4) | .831 |
Agitation
|
11 (8.5)
|
2 (1.5)
|
.011*
|
Blood CPK increases | 10 (7.7) | 14 (10.7) | .521 |
Nausea | 10 (7.7) | 4 (3.1) | .108 |
Dyspepsia
|
8 (6.2)
|
1 (0.8)
|
.019*
|
Nasopharyngitis | 7 (5.4) | 3 (2.3) | .217 |
Akathisia
|
1 (0.8)
|
9 (6.9)
|
.019
*
|
Weight increased
|
0 (0.0)
|
8 (6.1)
|
.007*
|
Within-group comparisons revealed a significant reduction from baseline to last observation in fasting cholesterol (−0.30 mmol/L, P < .001), LDL cholesterol (−0.28 mmol/L, P < .001), and triglycerides (−0.11 mmol/L, P = .008) in patients treated with LY2140023, and a significant decrease in HDL cholesterol (−0.06 mmol/L, P = .004) in patients treated with SOC. There was a mean decrease in LDL cholesterol in the LY2140023 group that was significantly greater than the decrease observed in the SOC group (P = .031), and a decrease in the level of triglycerides in the LY2140023 group versus an increase in the SOC group (P = .008). The mean decrease (−0.06 mmol/L) in HDL cholesterol observed in the SOC group was significantly different from the slight increase (0.01 mmol/L) observed in the LY2140023 group (P = .018). A significant reduction from baseline was also observed for prolactin (−4.33 μg/L, P = .003) in the LY2140023 group, although prolactin changes did not differ between the groups (P = .062). There were no other clinically significant differences in mean laboratory values between treatment groups.
Within-group comparisons showed significant increases in weight at every visit for patients in the SOC group (maximum increase: 3.12 kg, P < .001), while LY2140023-treated patients had significant decreases in weight at Weeks 12, 16, and 24 (maximum decrease: -2.04 kg, P < .05). Pairwise comparisons revealed significant differences in mean weight change between LY2140023- and SOC-treated patients at every visit. Significantly more patients in the SOC group met potentially clinically significant (PCS) criteria of an increase in weight of at least 7% from baseline to endpoint (SOC, 21.4%, n = 28; LY2140023, 8.2%, n = 10; P = .004), while significantly more patients in the LY2140023 group met PCS criteria for decreased weight (SOC, 2.3%, n = 3; LY2140023, 14.8%, n = 18; P < .001).
Within-group comparisons showed a mean reduction from baseline in the Barnes Akathisia Scale global score for akathisia at most visits in the LY2140023 group (P < .05), while changes from baseline in the SOC group generally did not reach significance. Both treatment groups had statistically significant, within-group improvements on the Simpson-Angus Scale total score for parkinsonism at each visit (P < .001, most visits). There were few statistically significant differences observed from baseline to postbaseline visit in the Abnormal Involuntary Movement Scale total score for dyskinetic symptoms within either treatment group. Pairwise comparisons revealed few statistically significant differences between the LY2140023 and SOC treatment groups across these 3 extrapyramidal symptom measures (data not shown). The overall incidence of treatment-emergent parkinsonism (SOC, n = 14; LY2140023, n = 3; P = .011) and akathisia (SOC, n = 18; LY2140023, n = 6; P = .029) was significantly higher among patients treated with SOC than among patients in the LY2140023 group.
Comparisons of changes in electrocardiogram intervals and heart rate did not show significant differences between groups that were clinically significant.
There were no clinically significant differences in baseline EEG scores between groups and no clinically significant changes in postbaseline EEG scores. Abnormal epileptiform-like changes were not frequent or remarkably different between treatment arms (LY2140023, 0%; SOC, 3.4%).