Background
Methods
Study design
Study period I (SP I)
Study period II (SP II)
Study period III (SP III)
Assessments
Statistical methods
Results
Baseline and demographic characteristics
Characteristics | PBO | LY40 | LY80 | RIS | TOTAL | Overall p-Value |
---|---|---|---|---|---|---|
ITT Overall Population
| N = 295 | N = 292 | N = 280 | N = 142 | N = 1009 | |
Age, years, mean (SD) | 39.8 (11.4) | 39.6 (11.5) | 40.5 (11.5) | 40.3 (11.1) | 40.0 (11.5) | 0.771 |
Gender, male, n (%) | 181 (61.4) | 196 (67.1) | 183 (65.4) | 87 (61.3) | 647 (64.1) | 0.422 |
Ethnicity, n (%) | 0.612 | |||||
Hispanic or Latino | 13 (4.4) | 11 (3.8) | 15 (5.4) | 9 (6.3) | 48 (4.8) | |
Not Hispanic or Latino | 282 (95.6) | 281 (96.2) | 265 (94.6) | 133 (93.7) | 961 (95.2) | |
Race, n (%) | 0.899 | |||||
American Indian or Alaska Native | 1 (0.3) | 0 (0.0) | 1 (0.4) | 0 (0.0) | 2 (0.2) | |
Asian | 1 (0.3) | 2 (0.7) | 1 (0.4) | 0 (0.0) | 4 (0.4) | |
Black or African American | 102 (34.6) | 100 (34.2) | 94 (33.6) | 47 (33.1) | 343 (34.0) | |
Multiple | 6 (2.0) | 1 (0.3) | 6 (2.1) | 1 (0.7) | 14 (1.4) | |
Native Hawaiian or Other Pacific Islander | 2 (0.7) | 1 (0.3) | 1 (0.4) | 1 (0.7) | 5 (0.5) | |
White | 183 (62.0) | 188 (64.4) | 177 (63.2) | 93 (65.5) | 641 (63.6) | |
Weight (kg), mean (SD) | 81.4 (20.8) | 81.4 (20.4) | 83.3 (19.2) | 82.7 (21.9) | 82.1 (20.4) | 0.622 |
Duration of Lifetime Illness , years, mean (SD) | 14.5 (10.7) | 14.6 (10.7) | 15.6 (11.0) | 15.2 (10.4) | 14.9 (10.7) | 0.607 |
Number of Past Psychiatric Hospitalizations, mean (SD) | 8.0 (9.4) | 7.2 (7.3) | 8.2 (8.8) | 7.4 (5.7) | 7.8 (8.2) | 0.439 |
Simpson-Angus Total Score, mean (SD) | 0.5 (1.4) | 0.4 (1.2) | 0.5 (1.9) | 0.6 (1.7) | 1.5 (1.5) | 0.718 |
Barnes Akathisia Global Score, mean (SD) | 0.1 (0.5) | 0.1 (0.5) | 0.1 (0.4) | 0.1 (0.4) | 0.1 (0.5) | 0.799 |
AIMS 1–7 Total Score, mean (SD) | 0.4 (1.2) | 0.2 (1.1) | 0.6 (2.0) | 0.2 (1.0) | 0.4 (1.4) | 0.027 |
ᅟ | ||||||
Efficacy-Evaluable ITT Population
| N = 267 | N = 267 | N = 253 | N = 132 | N = 919 | |
PANSS Total Score, mean (SD) | 84.3 (14.8) | 83.7 (14.0) | 84.2 (14.5) | 84.0 (16.2) | 84.1 (14.7) | 0.971 |
Patient disposition
Analysis Population | PBO n (%) a
| LY40 n (%) a
| LY80 n (%) a
| RIS n (%) a
| Total n (%) a
|
---|---|---|---|---|---|
Randomized Patients | N = 295 | N = 293 | N = 282 | N = 143 | N = 1013 |
Completed
| 171 (58.0) | 143 (48.8) | 129 (45.7) | 96 (67.1) | 539 (53.2) |
ITT Patients in the Overall Population | 295 (100.0) | 292 (99.7) | 280 (99.3) | 142 (99.3) | 1009 (99.6) |
Completed
| 171 (58.0) | 143 (48.8) | 129 (45.7) | 96 (67.1) | 539 (53.2) |
Efficacy-Evaluable ITT Patients in the Overall Population | 267 (90.5) | 267 (91.1) | 253 (89.7) | 132 (92.3) | 919 (90.7) |
Completed
| 154 (52.2) | 136 (46.4) | 116 (41.1) | 90 (62.9) | 496 (49.0) |
ITT Patients in the Predefined Subpopulation | 211 (71.5) | 210 (71.7) | 195 (69.1) | 98 (68.5) | 714 (70.5) |
Completed
| 120 (40.7) | 107 (36.5) | 83 (29.4) | 65 (45.5) | 375 (37.0) |
Efficacy-Evaluable ITT Patients in the Predefined Subpopulation | 195 (66.1) | 189 (64.5) | 176 (62.4) | 93 (65.0) | 653 (64.5) |
Completed
| 111 (37.6) | 101 (34.5) | 73 (25.9) | 61 (42.7) | 346 (34.2) |
p-value | |||||||||
---|---|---|---|---|---|---|---|---|---|
Variable | PBO N = 295 n (%) | LY40 N = 292 n (%) | LY80 N = 280 n (%) | RIS N = 142 n (%) | Total N = 1009 n (%) | Overall | LY40 vs. PBO | LY80 vs. PBO | RIS vs. PBO |
Completed
| 171 (58.0) | 143 (49.0) | 129 (46.1) | 96 (67.6) | 539 (53.4) | <.001 | 0.032 | 0.005 | 0.059 |
Discontinued
| |||||||||
Adverse Event-Physician Decision | 24 (8.1) | 18 (6.2) | 29 (10.4) | 10 (7.0) | 81 (8.0) | 0.322 | 0.424 | 0.389 | 0.849 |
Adverse Event-Subject Decision | 9 (3.1) | 6 (2.1) | 7 (2.5) | 2 (1.4) | 24 (2.4) | 0.770 | 0.603 | 0.802 | 0.515 |
Entry Criteria Not Met | 1 (0.3) | 1 (0.3) | 0 (0.0) | 0 (0.0) | 2 (0.2) | >.999 | >.999 | >.999 | >.999 |
Lost to follow up | 9 (3.1) | 4 (1.4) | 6 (2.1) | 3 (2.1) | 22 (2.2) | 0.576 | 0.262 | 0.604 | 0.759 |
Perceived Lack of Efficacy-Physician Decision | 39 (13.2) | 56 (19.2) | 57 (20.4) | 7 (4.9) | 159 (15.8) | <.001 | 0.057 | 0.025 | 0.007 |
Perceived Lack of Efficacy-Subject Decision | 9 (3.1) | 14 (4.8) | 12 (4.3) | 3 (2.1) | 38 (3.8) | 0.499 | 0.296 | 0.508 | 0.759 |
Protocol Violation | 5 (1.7) | 10 (3.4) | 7 (2.5) | 3 (2.1) | 25 (2.5) | 0.616 | 0.202 | 0.568 | 0.718 |
Scheduling Conflict | 1 (0.3) | 1 (0.3) | 0 (0.0) | 0(0.0) | 2 (0.2) | >.999 | >.999 | >.999 | >.999 |
Sponsor Decision | 1 (0.3) | 1 (0.3) | 1 (0.4) | 0 (0.0) | 3 (0.3) | >.999 | >.999 | >.999 | >.999 |
Subject Decision-Consent Withdrawn | 26 (8.8) | 33 (11.3) | 30 (10.7) | 18 (12.7) | 107 (10.6) | 0.596 | 0.339 | 0.483 | 0.235 |
Subject is Moving or has Moved | 0 (0.0) | 4 (1.4) | 1 (0.4) | 0 (0.0) | 5 (0.5) | 0.082 | 0.061 | 0.487 | |
Transportation Issues | 0 (0.0) | 1 (0.3) | 1 (0.4) | 0 (0.0) | 2 (0.2) | 0.668 | 0.497 | 0.487 |
Efficacy measures
Primary objective
Population | Treatment | N | LS Mean change | LS Mean change vs. placebo [1-Sided p-value] | Significance level (α, 1-sided) | Result of significance test (S/NS) |
---|---|---|---|---|---|---|
Overall population
| PBO | 253 | −7.9 | |||
RIS | 124 | −16.6 | −8.7 [<.001]* | 0.05* | Validity: S | |
LY80 | 229 | −7.1 | 0.8 [0.698] | 0.01 | Step 1: NS | |
LY40 | 251 | −9.4 | −1.5 [0.154] | 0.01 | Step 2: NS | |
Predefined subpopulation
| PBO | 184 | −7.2 | |||
RIS | 87 | −16.3 | −9.1 [<.001]* | 0.05* | Validity: S | |
LY80 | 160 | −6.4 | 0.8 [0.659] | 0.0025 | Step 1: NS | |
LY40 | 178 | −10.5 | −3.3 [0.033] | 0.0025 | Step 2: NS |
Other efficacy measures
Sensitivity analyses
Pharmacokinetic analyses and results
Safety measures
p-value | |||||||||
---|---|---|---|---|---|---|---|---|---|
Preferred term | PBO N = 295 n (%) | LY40 N = 292 n (%) | LY80 N = 280 n (%) | RIS N = 142 n (%) | Total N = 1009 n (%) | Overall | LY40 vs. PBO | LY80 vs. PBO | RIS vs. PBO |
Patients with > = 1 TEAE
| 177 (60.0) | 159 (54.5) | 176 (62.9) | 82 (57.7) | 594 (58.9) | 0.220 | 0.183 | 0.494 | 0.678 |
Headache | 27 (9.2) | 20 (6.8) | 21 (7.5) | 11 (7.7) | 79 (7.8) | 0.770 | 0.362 | 0.547 | 0.719 |
Schizophrenia | 23 (7.8) | 14 (4.8) | 16 (5.7) | 5 (3.5) | 58 (5.7) | 0.284 | 0.174 | 0.407 | 0.098 |
Nausea | 14 (4.7) | 22 (7.5) | 16 (5.7) | 5 (3.5) | 57 (5.6) | 0.338 | 0.172 | 0.708 | 0.627 |
Insomnia | 21 (7.1) | 10 (3.4) | 15 (5.4) | 10 (7.0) | 56 (5.6) | 0.188 | 0.064 | 0.396 | >.999 |
Blood CK increased | 15 (5.1) | 12 (4.1) | 17 (6.1) | 4 (2.8) | 48 (4.8) | 0.485 | 0.694 | 0.717 | 0.327 |
Anxiety | 9 (3.1) | 11 (3.8) | 12 (4.3) | 5 (3.5) | 37 (3.7) | 0.887 | 0.657 | 0.508 | 0.778 |
Vomiting | 6 (2.0) | 11 (3.8) | 13 (4.6) | 5 (3.5) | 35 (3.5) | 0.350 | 0.229 | 0.102 | 0.347 |
Dyspepsia | 5 (1.7) | 7 (2.4) | 11 (3.9) | 8 (5.6) | 31 (3.1) | 0.105 | 0.575 | 0.130 | 0.033* |
Constipation | 8 (2.7) | 7 (2.4) | 7 (2.5) | 5 (3.5) | 27 (2.7) | 0.900 | >.999 | >.999 | 0.765 |
Psychotic disorder | 7 (2.4) | 6 (2.1) | 10 (3.6) | 2 (1.4) | 25 (2.5) | 0.594 | >.999 | 0.465 | 0.724 |
Agitation | 3 (1.0) | 8 (2.7) | 10 (3.6) | 1 (0.7) | 22 (2.2) | 0.102 | 0.141 | 0.050* | >.999 |
Weight increased | 2 (0.7) | 4 (1.4) | 1 (0.4) | 5 (3.5) | 12 (1.2) | 0.049* | 0.449 | >.999 | 0.039* |
Restlessness | 5 (1.7) | 1 (0.3) | 0 (0.0) | 4 (2.8) | 10 (1.0) | 0.008* | 0.216 | 0.062 | 0.481 |
Extrapyramidal disorder | 3 (1.0) | 0 (0.0) | 6 (2.1) | 0 (0.0) | 9 (0.9) | 0.029* | 0.249 | 0.329 | 0.554 |
Dysmenorrhoea | 0 (0.0 | 5 (5.2) | 0 (0.0) | 1 (1.8) | 6 (1.7) | 0.006* | 0.019* | 0.325 | |
Sinusitis | 0 (0.0) | 5 (1.7) | 0 (0.0) | 1 (0.7) | 6 (0.6) | 0.013* | 0.030* | 0.325 | |
Asthenia | 2 (0.7) | 0 (0.0) | 0 (0.0) | 4 (2.8) | 6 (0.6) | 0.002* | 0.499 | 0.499 | 0.091 |
Fatigue | 1 (0.3) | 0 (0.0) | 1 (0.4) | 3 (2.1) | 5 (0.5) | 0.031* | >.999 | >.999 | 0.103 |
Hyperhidrosis | 0 (0.0) | 0 (0.0) | 1 (0.4) | 2 (1.4) | 3 (0.3) | 0.019* | 0.487 | 0.105 |