Time to onset and time to resolution of extrapyramidal symptoms in patients with exacerbated schizophrenia treated with 3-monthly vs once-monthly paliperidone palmitate

Figures & data

Figure 1 Study design.

Abbreviations: DB, double-blind; OL, open-label; mg eq., milligram equivalent; PP1M, once-monthly paliperidone palmitate; PP3M, 3-monthly paliperidone palmitate.

Table 1 Overall incidence of EPS-related TEAEs (ITT [OL] analysis set and safety analysis set [DB])

	OL phase, n (%)	DB phase, n (%)
	PP1M (n=1,429)	PP3M (n=504)	PP1M (n=512)
Overall incidence of EPS-related TEAEs	180 (12.6)	42 (8.3)	38 (7.4)
Hyperkinesia	92 (6.4)	22 (4.4)	16 (3.1)
Parkinsonism	68 (4.8)	16 (3.2)	17 (3.3)
Tremor	22 (1.5)	9 (1.8)	3 (0.6)
Dyskinesia	16 (1.1)	4 (0.8)	3 (0.6)
Dystonia	7 (0.5)	0	4 (0.8)

Notes: Predefined EPS-related TEAEs using MedDRA preferred terms: hyperkinesia: akathisia, hyperkinesia, periodic limb movement disorder, restless legs syndrome, restlessness; parkinsonism: stiffness, akinesia, hypokinesia, nuchal rigidity, parkinsonian gait, parkinsonian rest tremor, parkinsonism, muscle rigidity, muscle tightness, glabellar reflex abnormal, on and off phenomenon, Parkinson’s disease, parkinsonian crisis, extrapyramidal disorder, masked facies; tremor: tremor, essential tremor, intention tremor; dyskinesia: dyskinesia, muscle contractions involuntary, movement disorder, muscle twitching, athetosis, chorea, choreoathetosis, tardive dyskinesia, myoclonus, protrusion tongue, rabbit syndrome, buccoglossal syndrome; dystonia: oculogyration, oculogyric crisis, trismus, tongue spasm, tongue paralysis, cervical spasm, emprosthotonus, myotonia, pleurothotonus, risus sardonicus, muscle spasms, blepharospasm, dystonia, opisthotonus, torticollis, facial spasm, muscle contracture.

Abbreviations: DB, double-blind; EPS, extrapyramidal symptom; ITT, intent-to-treat; MedDRA, Medical Dictionary for Regulatory Activities; OL, open-label; PP1M, once-monthly paliperidone palmitate; PP3M, 3-monthly paliperidone palmitate; TEAE, treatment-emergent adverse event.

Table 2 Median (range) of TTO and TTR of EPS-related TEAEs (ITT [OL] analysis set and safety analysis set [DB])

	OL phase	DB phase
	PP1M (n=1,429)	PP3M (n=504)	PP1M (n=512)
TTOa (days)
All EPS-related TEAEs, n	180	42	38
Median TTO (range)	17.0 (1, 120)	115.0 (1, 323)	98.5 (1, 322)
Dyskinesia, n	16	4	3
Median TTO (range)	19.5 (3, 103)	106.5 (29, 254)	155.0 (1, 166)
Dystonia, n	7	0	4
Median TTO (range)	10.0 (3, 118)	NC	177.0 (8, 214)
Hyperkinesia	92	22	16
Median TTO (range)	16.0 (1, 99)	147.0 (2, 323)	98.5 (1, 322)
Parkinsonism	68	16	17
Median TTO (range)	17.5 (1, 120)	112.5 (27, 246)	87.0 (21, 242)
Tremor	22	9	3
Median TTO (range)	21.0 (1, 118)	61.0 (1, 253)	21.0 (1, 144)
TTRa (days)
All EPS-related TEAEs, n	180	42	38
Median TTR (range)	36.5 (1, 127)	91.0 (1, 336)	85.5 (1, 337)
Dyskinesia, n	16	4	3
Median TTR (range)	47.5 (5, 122)	92.0 (1, 182)	123.0 (99, 176)
Dystonia, n	7	0	4
Median TTR (range)	15.0 (1, 115)	NC	122.5 (42, 205)
Hyperkinesia, n	92	22	16
Median TTR (range)	34.5 (1, 127)	141.0 (1, 336)	61.5 (3, 337)
Parkinsonism, n	68	16	17
Median TTR (range)	34.0 (1, 120)	87.5 (7, 309)	54.0 (1, 278)
Tremor, n	22	9	3
Median TTR (range)	35.5 (1, 117)	78.0 (11, 277)	54.0 (37, 330)

Notes:

a Median time based on Kaplan–Meier estimate. For patients who had >1 event for a specific EPS-related TEAE, only the event for that specific EPS-related TEAE with the earliest onset was included in the TTO analysis. For patients who had >1 event for a specified group of EPS-related TEAEs, only the event for that specified EPS-related TEAE with longest TTR was included in the TTR analysis.

Abbreviations: AE, adverse event; DB, double-blind; EPS, extrapyramidal symptom; ITT, intent-to-treat; NC, non calculable; OL, open-label; PP1M, once-monthly paliperidone palmitate; PP3M, 3-monthly paliperidone palmitate; TEAE, treatment-emergent AE; TTO, time to onset; TTR, time to resolution.

Table 3 TTO and TTR of EPS-related TEAEs by dose (50/75, 100, and 150 mg eq.; ITT [OL] analysis set and safety analysis set [DB])

	OL phase			DB phase
	PP1M (n=1,429)			PP3M (n=504)			PP1M (n=512)
	50/75 mg eq. (n=157)	100 mg eq. (n=577)	150 mg eq. (n=695)	50/75 mg eq. (n=65)	100 mg eq. (n=200)	150 mg eq. (n=239)	50/75 mg eq. (n=61)	100 mg eq. (n=217)	150 mg eq. (n=234)
TTOa (days)
All EPS-related TEAEs, n	39	71	70	8	13	21	5	15	18
Median TTO (range)	22.0 (1–83)	16.0 (1–118)	16.0 (1–120)	118.5 (28–254)	112.0 (1–246)	125.0 (9–323)	4.0 (1–218)	113.0 (1–254)	124.5 (1–322)
Dyskinesia, n	6	7	3	1	2	1	2	1	0
Median TTO (range)	26.5 (3–83)	11.0 (3–103)	50.0 (9–65)	254.0	43.0 (29–57)	156.0	78.0 (1–155)	166.0	NC
Dystonia, n	2	4	1	0	0	0	0	2	2
Median TTO (range)	12.5 (10–15)	10.0 (3–118)	6.0	NC	NC	NC	NC	88.0 (8–168)	200.0 (186–214)
Hyperkinesia, n	22	33	37	6	5	11	1	6	9
Median TTO (range)	24.5 (1–69)	10.0 (1–97)	16.0 (1–99)	118.5 (28–254)	162.0 (2–173)	147.0 (9–323)	4.0	135.0 (1–254)	92.0 (1–322)
Parkinsonism, n	8	30	30	2	7	7	2	7	8
Median TTO (range)	8.0 (1–65)	24.5 (1–112)	16.5 (1–120)	59.0	113.0 (64–246)	117.0 (27–204)	139.0 (60–218)	71.0 (37–225)	115.5 (21–242)
Tremor, n	6	8	8	2	3	4	1	0	2
Median TTO (range)	25.0 (1–63)	11.0 (1–118)	31.5 (2–93)	157.0 (61–253)	112.0 (1–121)	36.0 (31–204)	1.0	NC	82.5 (21–144)
TTRa (days)
All EPS-related TEAEs, n	39	71	70	8	13	21	5	15	18
Median TTR (range)	46.0 (1–117)	26.0 (1–119)	39.5 (1–127)	83.0 (1–310)	90.0 (16–336)	117.0 (2–328)	123.0 (15–330)	145.0 (3–268)	54.0 (1–337)
Dyskinesia, n	6	7	3	1	2	1	2	1	0
Median TTR (range)	46.5 (5–85)	26.0 (5–78)	71.0 (55–112)	1.0	92.0 (38–146)	182.0	111.0 (99–123)	176.0	NC
Dystonia, n	2	4	1	0	0	0	0	2	2
Median TTR (range)	42.0 (1–83)	61.5 (3–115)	15.0	NC	NC	NC	NC	153.0 (101–205)	93.0 (42–144)
Hyperkinesia, n	22	33	37	6	5	11	1	6	9
Median TTR (range)	34.5 (5–103)	25.0 (1–119)	38.0 (2–127)	120.0 (1–310)	160.0 (16–336)	138.0 (2–328)	109.0	43.5 (3–198)	69.0 (15–337)
Parkinsonism, n	8	30	30	2	7	7	2	7	8
Median TTR (range)	71.0 (4–117)	27.0 (1–117)	46.0 (2–120)	169.0 (59–279)	90.0 (36–231)	50.0 (7–309)	146.5 (15–278)	157.0 (25–268)	35.0 (1–120)
Tremor, n	6	8	8	2	3	4	1	0	2
Median TTR (range)	38.5 (1–113)	47.5 (2–117)	31.5 (1–59)	185.0 (93–277)	49.0 (30–90)	61.5 (11–152)	330.0	NC	45.5 (37–54)

Notes:

a Median time based on Kaplan–Meier estimate. For patients who had more than one event for a specific EPS-related TEAE, only the event for that specific EPS-related TEAE with the earliest onset was included in the TTO analysis.

Abbreviations: DB, double-blind; EPS, extrapyramidal symptom; ITT, intent-to-treat; NC, non calculable; OL, open-label; PP1M, once-monthly paliperidone palmitate; PP3M, 3-monthly paliperidone palmitate; TEAE, treatment-emergent adverse event; TTO, time to onset; TTR, time to resolution.

Table 4 TTO and TTR of EPS-related TEAEs by age (18–25, 26–50, >50 years; ITT [OL] analysis set and safety analysis set [DB])

	OL phase			DB phase
	PP1M (n=1,429)			PP3M (n=504)			PP1M (n=512)
	18–25 years (n=220)	26–50 years (n=947)	>50 years (n=262)	18–25 years (n=74)	26–50 years (n=326)	>50 years (n=104)	18–25 years (n=87)	26–50 years (n=328)	>50 years (n=97)
TTOa (days)
All EPS-related TEAEs, n	37	110	33	5	24	13	4	22	12
Median TTO (range)	18.0 (1–120)	14.5 (1–118)	22.0 (1–112)	117.0 (44–147)	113.0 (1–323)	113.0 (9–253)	65.0 (4–322)	128.5 (1–305)	70.0 (1–254)
Dyskinesia, n	3	10	3	0	3	1	1	2	0
Median TTO (range)	17.0 (10–83)	11.5 (3–103)	36.0 (22–50)	NC	156.0 (57–254)	29.0	155.0	83.5 (1–166)	NC
Dystonia, n	1	5	1	0	0	0	0	2	2
Median TTO (range)	12.0	10.0 (3–118)	6.0	NC	NC	NC	NC	200.0 (186–214)	88.0 (8–168)
Hyperkinesia, n	16	60	16	3	14	5	4	7	5
Median TTO (range)	17.5 (1–99)	14.0 (1–97)	17.5 (1–62)	147.0 (44–147)	164.5 (2–323)	125.0 (9–164)	65.0 (4–322)	113.0 (1–305)	92.0 (1–254)
Parkinsonism, n	18	36	14	2	8	6	0	11	6
Median TTO (range)	14.5 (1–120)	14.0 (1–79)	33.5 (1–112)	114.5 (112–117)	113.0 (59–204)	100.5 (27–246)	NC	71.0 (37–242)	113.5 (21–218)
Tremor, n	4	12	6	1	6	2	0	1	2
Median TTO (range)	21.0 (16–32)	19.0 (1–118)	24.5 (1–58)	112.0	50.5 (1–204)	142.5 (32–253)	NC	144.0	11.0 (1–21)
TTRa (days)
All EPS-related TEAEs, n	37	110	33	5	24	13	4	22	12
Median TTR (range)	39.0 (1–119)	35.5 (1–127)	31.0 (3–113)	90.0 (7–191)	66.0 (1–336)	138.0 (26–328)	56.5 (15–109)	98.5 (1–337)	93.5 (3–336)
Dyskinesia, n	3	10	3	0	3	1	1	2	0
Median TTR (range)	38.0 (5–78)	47.5 (5–112)	71.0 (43–85)	NC	38.0 (1–182)	146.0	99.0	149.5 (123–176)	NC
Dystonia, n	1	5	1	0	0	0	0	2	2
Median TTR (range)	110.0	13.0 (1–115)	15.0	NC	NC	NC	NC	93.0 (42–144)	153.0 (101–205)
Hyperkinesia, n	16	60	16	3	14	5	4	7	5
Median TTR (range)	74.0 (5–119)	30.5 (1–127)	26.5 (3–105)	191.0 (16–191)	95.0 (1–336)	167.0 (26–328)	56.5 (15–109)	54.0 (22–337)	72.0 (3–336)
Parkinsonism, n	18	36	14	2	8	6	0	11	6
Median TTR (range)	45.0 (1–117)	47.0 (1–120)	28.0 (7–113)	48.5 (7–90)	117.5 (36–279)	88.5 (29–309)	NC	85.0 (1–278)	38.5 (15–199)
Tremor, n	4	12	6	1	6	2	0	1	2
Median TTR (range)	28.0 (2–89)	18.0 (1–117)	58.0 (18–113)	90.0	47.0 (11–277)	122.5 (93–152)	NC	54.0	183.5 (37–330)

Notes:

a Median time based on Kaplan–Meier estimate. For patients who had more than one event for a specific EPS-related TEAE, only the event for that specific EPS-related AE with the earliest onset was included in the TTO analysis.

Abbreviations: DB, double-blind; EPS, extrapyramidal symptom; ITT, intent-to-treat; NC, non calculable; OL, open-label; PP1M, once-monthly paliperidone palmitate; PP3M, 3-monthly paliperidone palmitate; TEAE, treatment-emergent adverse event; TTO, time to onset; TTR, time to resolution.