Critical appraisal of 3-monthly paliperidone depot injections in the treatment of schizophrenia

Figures & data

Figure 1 Literature search flow diagram.

Table 1 Summary of clinical studies

Study (authors, reference)	Aims	Design	Sample	Main findings
Berwaerts et al,^Citation26 2016	To evaluate the efficacy and safety of the 3-monthly injections of paliperidone palmitate (PP-3M) vs placebo in delaying time to relapse of schizophrenia symptoms	Randomized, multicenter trial; four phases: 3-week screening phase; flexible dose 1-week open label transition phase; 12-week open label maintenance phase; open ended double blind phase	506 patients enrolled, DSMIV-TR diagnosis of schizophrenia; 305 randomized to PP-3M (n=160) or placebo (n=145) in the double blind phase	Time to first relapse differed significantly, favoring PP-3M group over placebo During the double blind phase 62% of patients receiving PP-3M and 58% of those receiving placebo had at least one treatment-emergent adverse event (TEAE); TEAEs observed significantly more frequently among patients treated with PP-3M compared to placebo included: headache (9% vs 4%); weight increase (9% vs 3%); nasopharyngitis (6% vs 1%); and akathisia (4% vs 1%)
Ravenstijn et al,^Citation25 2015	Evaluation of pharmacokinetics, safety and, tolerability of PP-3M in patients affected by schizophrenia or schizoaffective disorder	Multicenter, randomized, open label, parallel-group, Phase 1 study	328 patients enrolled, affected by DSMIV-TR diagnosis of schizophrenia or schizoaffective disorder	Peak paliperidone plasma concentration achieved between 23 and 34 days; apparent half-life was 2–4 months; mean plasma AUC1 and Cmax appeared to be dose-proportional; relative bioavailability compared to paliperidone was 100%, independent of the dose and site of injection; headache and nasopharyngitis were the most common (>7%) TEAEs

Abbreviations: DSMIV-TR, Diagnostic and Statistical Manual of Mental Disorders 4th Edition, Text Revision; AUC₁, area under the curve; C_max, maximum serum concentration.

Table 2 Change from baseline mean scores of clinical and functioning scales in patients treated with PP-3M vs placebo*

Scales (mean, SD)	Placebo (n=145)	PP-3M (n=160)	P-value
PANSS total scorea
Baseline	54.3 (9.20)	54.8 (9.96)
Change from Baselineb	6.7 (14.40)	−0.5 (8.36)	<0.001
PANSS subscales scoresa
Positive subscale
Baseline	11.4 (2.99)	11.7 (3.20)
Change from Baselineb	2.7 (4.92)	−0.1 (2.84)	<0.001
Negative subscale
Baseline	16.2 (3.91)	16.4 (4.42)
Change from Baselineb	0.8 (3.76)	−0.1 (2.96)	0.013
General psychopathology subscale
Baseline	26.6 (4.92)	26.8 (4.98)
Change from Baselineb	3.2 (7.88)	−0.3 (4.77)	<.001
PANNS Marder standardized factor scoresa
Positive symptoms
Baseline	14.6 (3.71)	14.9 (3.72)
Change from Baselineb	2.5 (5.25)	−0.1 (2.74)	<0.001
Negative symptoms
Baseline	15.0 (3.70)	15.2 (4.28)
Change from Baselineb	0.4 (4.01)	−0.3 (3.21)	0.080
Disorganized thought
Baseline	13.8 (3.25)	13.8 (3.41)
Change from Baselineb	0.7 (3.38)	−0.2 (2.53)	0.005
Uncontrolled Hostility/excitement
Baseline	5.2 (1.77)	5.2 (1.80)
Change from Baselineb	1.7 (3.18)	−0-0 (1.89)	<0.001
Anxiety/depression
Baseline	5.7 (2.02)	5.8 (2.10)
Change from Baselineb	1.4 (3.28)	0.1 (2.34)	<0.001
CGI-S scorea
Baseline	2.8 (0.65)	2.7 (60.68)
Change from Baselineb	0.4 (0.87)	0.1 (0.60)	<0.001
PSP total scorea
Baseline	68.5 (8.93)	68.9 (9.34)
Change from Baselinec	−4.2 (9.70)	−0.5 (6.63)	<0.001

Notes:

* Based on analysis of covariance (ANCOVA) model with treatment (placebo, PP-3M) and country as factors and baseline value as a covariate.

a Explanation of scores: decrease in PANSS scores and CGI-S scores indicate improvement. Decrease in PSP scores indicate worsening.

b Placebo (n)=142; PP-3M (n)=159.

c Placebo (n)=142; PP-3M (n)=157. Reproduced with permission from JAMA Psychiatry. 2015. 72(8). doi:101001/jamapsychiatry.²⁶ Copyright ©2015 American Medical Association. All rights reserved.

Abbreviations: PP-3M, 3-monthly injections of paliperidone palmitate; PANSS, Positive and Negative Syndrome Scale; CGI-S, Clinical Global Impression-Severity Scale; PSP, Personal and Social Performance Scale; SD, standard deviation.

Table 3 Treatment-emergent adverse events 5% in any treatment group

	Panel A		Panel B		Panel C		Panel D
	Period 1 N=72	Period 2 N=66	Period 1 N=128	Period 2 N=120	Period 1 N=25	Period 2 N=24	Period 1 N=100	Period 2 N=98
Patients with at least 1 TEAEs	27 (37.5)	49 (74.2)	40 (31.2)	99 (82.5)	5 (20)	18 (75)	15 (15)	61 (62.2)
Nasopharyngitis	1 (1.4)	9 (13.6)	–	15 (12.5)	–	–	–	10 (10.2)
Headache	4 (5.6)	9 (13.6)	6 (4.7)	14 (11.7)	2 (8.0)	4 (16.7)	2 (2.0)	7 (7.1)
Weight increased	1 (1.4)	2 (3.0)	2 (1.6)	9 (7.5)	–	–	2 (2.0)	5 (5.1)
Back pain	–	–	–	8 (6.7)	–	2 (8.3)	1 (1.0)	6 (6.1)
Anxiety	2 (2.8)	2 (3.0)	4 (3.1)	12 (10.0)	–	–	–	–
Tootache	1 (1.4)	4 (6.1)	1 (0.8)	9 (7.5)	–	–	–	4 (4.1)
Psychotic disorder	–	3 (4.5)	–	6 (5.0)	–	–	–	4 (4.1)
Diarrhea	1 (1.4)	3 (4.5)	2 (1.6)	9 (7.5)	–	–	–	–
Insomnia	4 (5.6)	3 (4.5)	1 (0.8)	9 (7.5)	–	–	–	–
Depression	–	3 (4.5)	–	6 (5.0)	–	–	–	2 (2.0)
Tachycardia	1 (1.4)	2 (3.0)	–	7 (5.8)	–	–	–	2 (2.0)
Abdominal pain	–	2 (3.0)	1 (0.8)	8 (6.7)	–	–	–	–
Weight loss	–	–	–	7 (5.8)	–	–	–	–
Upper Respiratory Tract infections	–	–	–	3 (2.5)	–	6 (25.0)	–	–
Schizophrenia	–	–	1 (0.8)	6 (5.0)	–	–	–	–
Vomiting	–	–	–	–	–	2 (8.3)	–	–
Warmness injection site	–	–	–	–	–	2 (8.3)	–	–
Diabetes mellitus	–	–	–	–	–	2 (8.3)	–	–

Notes: Data shown as n (%), treatment emergent adverse events. Phase 2: Panel A, 300 mg eq PP-3M, im (gluteal); panel B, 75, 150 or 450 mg eq PP-3M, im (gluteal) or 300 or 450 mg eq PP-3M, im (deltoid); panel C, 150 mg eq PP-3M, im (gluteal); panel D, 175 mg eq (deltoid), 350 mg eq (gluteal), or 525 mg eqPP-3M, im (deltoid). During period 1 patients (all panels) received a single dose intramuscular injection of 1 mg paliperidone IR (immediate release) solution; during period 2 patients (all panels) received a single dose intramuscular injection of PP-3M. Reproduced from Ravenstijn P, Remmerie B, Savitz A, et al. Pharmacokinetics, safety, and tolerability of paliperidone palmitate 3-month formulation in patients with schizophrenia: A phase-1, single-dose, randomized, open-label study. J Clin Pharmacol. 2016;56(3):330–339,²⁵ John Wiley and Sons. Copyright ©2015.

Abbreviations: PP-3M, 3-monthly injections of paliperidone palmitate; TEAEs, treatment-emergent adverse events.

Table 4 Summary of TEAEs reported during the Double-Blind Phase in the Safety Analysis Seta

Variable	Placebo (N=145) N (%)	3mo Paliperidone Palmitate N=160 N (%)
Patients with TEAEs	84 (58)	99 (62)
Possibly drug-related TEAE	27 (19)	54 (34)
TEAE leading to drug withdrawal	1 (1)	0
Patients with ≥1 serious TEAE	15 (10)	4 (3)
TEAEs reported in ≥2% of patients in either group
Headache	6 (4)	14 (9)
Anxiety	16 (11)	13 (8)
Insomnia	17 (12)	11 (7)
Nasopharyngitis	2 (1)	9 (6)
Upper Respiratory Tract infections	3 (2)	6 (4)
Cough	3 (2)	5 (3)
Urinary tract infections	2 (1)	6 (4)
Influenza	3 (2)	3 (2)
Schizophrenia	15 (10)	2 (1)
Weight decreased	11 (8)	2 (1)
Agitation	3 (2)	2 (1)
Decreased appetite	3 (2)	1 (1)
Irritability	3 (2)	1 (1)
Suicidal ideation	3 (2)	0
EPS-related TEAEs	5 (3)	13 (8)
Akathisia	1 (1)	7 (4)
Diabetes mellitus and hyperglicemia-related TEAEs	8 (6)	4 (3)
Blood glucose level increased	3 (2)	3 (2)
Hyperglicemia	4 (3)	0
Weight gain-related TEAEs	5 (3)	15 (9)
Weight increased	5 (3)	14 (9)
Injection site-related TEAEs	0	6 (4)
Prolactin-related TEAEs	0	1 (1)
Amenorrhea	0	1 (2)b

Notes:

a The TEAEs reported herein occurred in the double-phase; if a patient developed a TEAE during the open-label phase (either transition or maintenance) and the TEAE did not worsen during the double-blind phase, it would not be captured.

b Sample size was 42 women. Reproduced from JAMA Psychiatry. 2015. 72(8), doi:101001/jamapsychiatry.2015.0241,²⁶ Copyright ©2015 American Medical Association. All rights reserved.

Abbreviations: EPS, extrapyramidal symptoms; TEAEs, treatment-emergent adverse events.

BewaertsJLiuYGopalSEfficacy and Safety of the 3-Month Formulation of Paliperidone Palmitate vs Placebo for Relapse Prevention of Schizophrenia: A Randomized Clinical TrialJAMA Psychiatry201572883083925820612

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RavenstijnPRemmerieBSavitzAPharmacokinetics, safety, and tolerability of paliperidone palmitate 3-month formulation in patients with schizophrenia: A phase-1, single-dose, randomized, open-label studyJ Clin Pharmacol201656333033926189570

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