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International Journal of Neuropsychopharmacology (2010), 13, 635647.

Copyright f CINP 2009


doi:10.1017/S1461145709990988

ARTICLE

Paliperidone palmitate, a potential long-acting


treatment for patients with schizophrenia.
Results of a randomized, double-blind,
placebo-controlled ecacy and safety study
Michelle Kramer1, Robert Litman2, David Hough1, Rosanne Lane1, Pilar Lim1, Yanning Liu1
and Marielle Eerdekens3
1

Johnson & Johnson Pharmaceutical Research and Development, L.L.C., Raritan, NJ, USA
Center for Behavioral Health, L.L.C., and Georgetown University Medical School, MD, USA
3
Johnson & Johnson Pharmaceutical Research & Development, Division of Janssen Pharmaceutica N.V., Beerse, Belgium
2

Abstract
We evaluated the ecacy and safety of the investigational long-acting injectable antipsychotic agent
paliperidone palmitate (PP) in the treatment of schizophrenia. Patients were randomized to receive gluteal
injections of placebo or PP (50 or 100 mg eq., xed doses), without oral supplementation, on days 1, 8, and
36 (9-wk, double-blind phase) in this phase 2b study. Patients (n=197, intent-to-treat analysis set) were
62 % men, mean (S.D.) age 39 (10) yr, with a baseline mean (S.D.) Positive and Negative Syndrome Scale
(PANSS) total score of 87.0 (12.5). Mean (S.D.) PANSS total scores showed signicant improvement at
endpoint (primary measure) for both the PP 50 mg eq. [x5.2 (21.5)] and PP 100 mg eq. [x7.8 (19.4)]
groups, vs. placebo [6.2 (18.3)] (pf0.001, each dose vs. placebo). This improvement was detected by day 8
and maintained to endpoint (pf0.011) for both doses. In the safety analysis set (n=247), fewer PP-treated
patients (2 %) discontinued for treatment-emergent adverse events vs. placebo-treated (10 %). Rates of
treatment-emergent extrapyramidal syndrome-related adverse events were comparable between active
treatment and placebo, with the exception of parkinsonism-related disorders (50 mg eq. 5 %, 100 mg eq.
8 %, placebo 1 %). Results of other safety measures suggest PP to be generally well-tolerated. Throughout
the study, investigators rated injection-site pain as absent (5671 %), mild (2439 %), moderate (212 %),
or severe (02 %). PP (50 and 100 mg eq. doses) administered as a gluteal intramuscular injection was
ecacious and generally tolerated in these patients with acute symptomatic schizophrenia.
Received 19 March 2009 ; Reviewed 26 May 2009 ; Revised 5 October 2009 ; Accepted 20 October 2009 ;
First published online 27 November 2009
Key words : Antipsychotics, clinical trial, long-acting injection, schizophrenia.

Introduction
Schizophrenia is a chronic disease, associated with
ongoing functional impairment and frequent recurrence of acute psychotic symptoms (Andreasen, 1995).
The prognosis and outcomes worsen with each

Address for correspondence : Dr M. Kramer, 3210 Merryeld Row,


San Diego, CA 92121, USA.
Tel. : 858 784-3203 Fax : 858 450-2090
Email : mkramer@its.jnj.com
Portions of this paper were presented at the United States Psychiatry
and Mental Health Congress, FL, USA, October 2007 ; and at the
Winter Workshop on Schizophrenia and Bipolar Disorders,
Montreux, Switzerland, February 2008.

successive relapse (Johnson et al. 1983 ; Kane, 2007 ;


Wyatt, 1991) and the chance of relapse increases with
poor treatment adherence, a frequent problem among
patients diagnosed with schizophrenia who are prescribed oral medications (Robinson et al. 1999).
Long-acting injectable antipsychotics oer the
opportunity for enhanced patient treatment adherence
and can simplify the medication regimen for patients
and caregivers (Kane, 2003 ; Keith & Kane, 2003 ;
Nasrallah, 2007). Injectable formulations release medication into the plasma on a continuous basis over
prolonged periods of time, diminishing the problems
typically associated with missed and inconsistent oral
dosing (Keith & Kane, 2003). The use of injectable

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M. Kramer et al.

long-acting medications also allows the clinician to


know if a dose is missed and the long half-life of these
agents allows time for rescheduling of an appointment
for the patient to receive the missed treatment. Finally,
if a recurrence of symptoms does occur, the clinician is
in a much better position to eliminate non-adherence
as a possible cause (Nasrallah, 2007).
Paliperidone palmitate (PP), an investigational
atypical antipsychotic, is the palmitate ester and injectable formulation of paliperidone. As an oral, extended-release formulation, paliperidone is approved
in the USA (INVEGATM ; Janssen, LP), European Union
(INVEGATM ; Janssen-Cilag) and many other countries
for both the acute and maintenance treatment of
schizophrenia (Davidson et al. 2007 ; Kane et al. 2007 ;
Kramer et al. 2007 ; Marder et al. 2007).
PP, an aqueous nanosuspension, was designed
to provide sustained plasma concentrations of the
pharmacologically active fraction, paliperidone : this
long-acting injectable formulation permits oncemonthly administration in patients. Following delivery into the muscle tissue, the undissolved PP particles
form an agglomerate at the injection site, dissolve
slowly due to low water solubility, and are then hydrolysed by esterases into paliperidone and palmitic acid.
After single gluteal injections of PP 25150 mg eq.,
plasma paliperidone concentrations increased slowly,
reached Cmax y23 wk after dosing, and declined
with a mean t1/2 of 2050 d. Based on early trial results,
initiation of therapy with two injections, administered
1 wk apart, is considered most appropriate to rapidly
achieve therapeutic plasma levels, steady-state, and
onset of ecacy, without the need for oral supplementation (Samtani, 2009).
This is an initial phase 2b study designed to evaluate the ecacy and safety of PP, compared to placebo,
in patients suering from schizophrenia.
Method
Patients
Men and women, aged 1865 yr, were enrolled provided they (1) had a diagnosis of schizophrenia
according to DSM-IV criteria for at least 1 yr, (2) had a
Positive and Negative Syndrome Scale (PANSS) total
score of 70120 (moderate to severe symptomatology ;
Leucht et al. 2005), inclusive, at screening, and 60120
inclusive, on day 1 before the start of double-blind
study drug, and (3) had a body mass index (BMI)
range of 1535 kg/m2. Patients were required to be
physically healthy, to be capable of performing study
requirements (e.g. evaluation of injection site) and to
have agreed to hospitalization for a minimum of 14 d.

Patients were excluded if they had a DSM-IV Axis I


diagnosis other than schizophrenia, including a DSMIV Axis I diagnosis of substance dependence (except
nicotine or caeine) within 3 months prior to screening ; were considered at signicant risk for suicidal or
aggressive behaviour ; or had a previous lack (within
12 months) of response to two adequate trials of antipsychotic treatment (dened as a minimum of 4-wk
treatment at a therapeutic dose). In addition, patients
were excluded for : medical conditions that could potentially alter the absorption, metabolism, or excretion
of the study medication ; relevant history of signicant
or unstable medical illness (other than schizophrenia) ;
known allergic reactions to risperidone or paliperidone ; use of a depot antipsychotic or uoxetine or
monoamine oxidase inhibitors (MAOIs) within 1
month, clozapine therapy within 3 months, long-acting risperidone within 100 d, or PP within 10 months
prior to screening ; exposure to experimental treatment
within 30 d of screening. Women were excluded
if pregnant, nursing, or planning to become pregnant
during the trial.
Prohibited concomitant medications included psychotropics (including over-the-counter and nutritional
medications), anticonvulsants or mood stabilizers
and MAOIs. Oral benztropine or biperiden (or equivalent agents) were permitted for the treatment of extrapyramidal system (EPS) symptoms, but all other
anti-EPS therapies were prohibited. Lorazepam was
permitted during the rst week for agitation, anxiety,
or sleep diculties, but was tapered and discontinued
by day 8. Antidepressants (excluding uoxetine or
MAOIs) were allowed if the dose was stable for at least
3 months before screening. Limited supportive psychotherapy and psychoeducational programmes were
also permitted.
This study was conducted in accordance with the
ethical principles that have their origin in the Declaration of Helsinki and that are consistent with Good
Clinical Practice and applicable regulatory requirements. After receiving a complete description of the
study, all patients signed a study informed consent
document.
Study design, randomization, and blinding
Johnson & Johnson Pharmaceutical Research &
Development, L.L.C., funded this study, which was
conducted in three phases over y11 wk. The study
phases included : (1) screening (up to 5 d, including a
3-d washout of disallowed psychotropic medications) ;
(2) a run-in phase (7 d) during which eligible patients
were hospitalized and within each centre sequentially

Paliperidone palmitate in schizophrenia


assigned one of four open-label once-daily morning
doses of oral paliperidone [either of two formulations :
paliperidone ER (6 mg, 12 mg) or paliperidone immediate release (2 mg, 4 mg)] ; and (3) a double-blind
treatment phase (64 d) during which eligible patients
were randomized 1 : 1 : 1 [via a sponsor-prepared
computer-generated randomization and stratication
scheme, with treatment assignment by an interactive
voice-response system (IVRS)] to receive either
PP 50 mg eq., PP 100 mg eq., or placebo, without oral
supplementation. Patients were hospitalized for a
minimum of 14 d, starting at the run-in phase, and
could be discharged from the hospital after the second
injection of study drug on day 8 if the investigator
determined there was no signicant risk of suicidal or
violent behaviour and if the patients Clinical Global
Impression of Severity (CGI-S) score was 4 (moderately ill) or less.
A placebo arm was included to establish the true
(attributable) ecacy and safety prole of the study
drug. A meta-analysis of successfully marketed antipsychotics (i.e. thought to be eective) from the Food
and Drug Administration database showed that y25 %
of studies failed to distinguish active medication from
placebo (Laughren, 2001). Observed placebo response
rates in psychopharmacology studies vary from 20 %
to 70 %. Additionally, the absence of evidence for excess risk of suicide in placebo-treated patients compared to drug-treated patients in schizophrenia trials
argues for the acceptability of including a placebo arm
(Laughren, 2001).
Patients received a total of three separate injections,
each injection administered intramuscularly in alternate gluteal muscles. The rst two injections were
administered 1 wk apart as single doses on day 1 and
day 8 (together comprising the initial dosage regimen),
followed 4 wk later by a single intramuscular injection
on day 36. Doses of PP were selected to achieve a
projected range of 7080 % brain D2 receptor occupancy (Karlsson et al. 2006). Patients were hospitalized
during the oral paliperidone run-in and during the
rst 7 d of the double-blind treatment phase. The oral
run-in phase was designed to evaluate the safety and
tolerability of switching from oral to injectable formulations of paliperidone in a typical clinical situation and to allow pharmacokinetic (PK) comparisons
across the formulations.
Doses of PP can be expressed both in terms of
milligram equivalents (mg eq.) of the pharmacologically active fraction, paliperidone, and in milligrams
of PP. Thus, the doses expressed as PP 50 and
100 mg eq., equate to 78 and 156 mg, respectively,
of PP.

637

Ecacy measures
The primary ecacy assessment was the mean change
in PANSS total score (Kay et al. 1987) from baseline
(day 1) to endpoint (day 64) during the double-blind
phase for each PP dose and placebo. Secondary ecacy measures included : onset of eect (the rst
PANSS assessment at which there was a statistically
signicant dierence in PANSS total score between
active drug and placebo that was then maintained for
the remainder of the study), treatment response (dened as at least 30 % improvement in PANSS total
score from baseline to endpoint), and change from
baseline to endpoint in the PANSS subscale scores
(Lindenmayer et al. 1994 ; Marder et al. 1997) and CGI-S
scores.
Safety and tolerability measures
Safety assessments included reports of treatmentemergent adverse events (TEAEs) (using the Medical
Dictionary for Regulatory Activities, v. 8.0), clinical
laboratory tests, vital sign measurements, body
weight, physical examinations, 12-lead ECGs, movement disorder rating scales [Simpson Angus Scale
(Simpson & Angus, 1970), Barnes Akathisia Rating
Scale (Barnes, 1989), and Abnormal Involuntary
Movement Scale (Guy, 1976)] and serum prolactin
values. Study personnel evaluated the injection site
for induration, redness, pain, and swelling and the
patient assessed the degree of pain at the injection site.
QTc interval was corrected for heart rate using a
linear-derived correction factor (QTcLD) (Sagie et al.
1992).
PK assessments
Blood samples were taken for PK analysis on days x7,
x1, 1, 8, 15, 18, 22, 29, 36, 43, 50, 57, and 64. Plasma
concentrations and PK parameters of patients enrolled
at the six sites that did not appropriately use the IVRS
were not included in the calculations for the descriptive analyses and graphical summaries.
On study days when the study drug was administered, the pre-dose PK blood sample was collected
y10 min before study drug administration. The plasma concentrations of paliperidone were determined
using a validated liquid chromatography coupled to a
tandem mass spectrometry method, with a target limit
of quantication of 0.2 ng/ml.
Statistical analyses
This study was designed to have 90 % power to detect
a dierence of at least 10 points on the change from

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M. Kramer et al.

baseline to endpoint in PANSS total score between


placebo and either of the PP dose groups, with a
signicance level set at 0.10 (two-sided) and at least
70 patients per treatment group. A standard deviation
of y20 was assumed. An a-level of 0.10 was chosen in
consideration of the limited drug supply available at
the time this phase 2 study was initiated. However,
this a-level allowed selection of a sample size that was
considered sucient to meet the primary study objectives.
An analysis of covariance (ANCOVA) model with
factors for treatment, analysis centre and oral runin treatment and with baseline PANSS total score as
a covariate, was used to compare the change from
baseline to endpoint for each active treatment group
to placebo with no adjustments for multiplicity.
Estimated least-square means of the dierence between each PP group and placebo, with corresponding
p values and 90 % condence intervals, were produced
for the change from baseline to endpoint in PANSS
total score and factor scores. A similar ANCOVA
model was used for a post-hoc analysis of percentage
change in PANSS total score. The percentage change
was calculated to take into account the minimum
PANSS total score. For CGI-S, a similar ANCOVA
model was used with ranked data. Responder-rate
data were analysed using the CochranMantelHaenszel procedure, controlling for analysis centre. The last-observation-carried-forward (LOCF)
approach was used for the primary analysis of the
data. In addition, an analysis using the repeatedmeasures mixed-eects model was performed. Statistical analyses were performed using SAS version 9.1
(SAS Institute Inc., USA).
Descriptive statistics were provided to evaluate adverse events and changes from baseline in EPS rating
scale scores, laboratory assessments, and vital signs.
For ECG parameters and body weight an ANCOVA
model with factors for treatment, analysis centre, and
baseline value as a covariate was used to compare the
change from baseline to endpoint for each active
treatment group with placebo.
Populations assessed
All ecacy analyses from the double-blind phase used
the intent-to-treat (ITT) analysis set, which included
all randomized patients who received at least one dose
of double-blind medication and had at least one valid
post-baseline ecacy measurement. Patients from six
sites (three in USA, three in India) did not receive
double-blind medication according to the randomization schedule, as a result of incorrect use of IVRS. This

error primarily resulted in omission of the second call,


which was to provide additional dosing instructions
for patients randomized to double-blind treatments.
Although those patients who were assigned to placebo
received the correct dosing, those assigned to PP did
not and the actual dose received could not be conrmed. All patients from these six sites (n=49) were
prospectively excluded from the primary ITT analysis.
Evaluable patients from this group (n=46) were similarly divided among treatment groups and included in
conrmatory analyses.
Safety summaries used data from all randomized
patients who had taken at least one dose of study
treatment and provided post-baseline safety data. This
included patients from the six sites that did not follow
correct randomization assignments.

Results
Patient population
A total of 266 patients met eligibility requirements for
this study, which was conducted from October 2003 to
July 2004 at 30 centres in the USA, Russia, Bulgaria,
Poland, Ukraine, and India (see Appendix). Most
(93 %) of the patients who entered the oral run-in period continued into the double-blind period. Of those
who did not (n=19), four (2 %) withdrew due to adverse events (Fig. 1). Of the 247 patients randomized,
125 (51 %) completed the 64-d double-blind period.
Twice as many patients in the PP groups [50 mg eq.
(n=47, 59 %) ; 100 mg eq. (n=51, 61 %)] completed the
study compared to placebo-treated patients (n=27
[32 %]) (Fig. 1).
A total of 197 (80 %) patients formed the ITT analysis set used for ecacy assessments, and 247 (100 %)
contributed to the safety assessments. The ITT analysis
set was predominately white (81 %) and male (62 %).
The mean age was 39 yr (S.D.=10.3 yr). Most patients
(88 %) were diagnosed with paranoid schizophrenia,
75 % of patients previously used antipsychotics in
the 30 d before the study, and 67 % had three or more
prior hospitalizations for psychosis. Baseline demographics, including psychiatric history, did not dier
signicantly among treatment groups in the ITT
analysis set (Table 1) or between the ITT and safety
analysis sets. Patients with at least a 15-point
improvement in PANSS total score during the
oral run-in phase were distributed similarly across
double-blind phase treatment groups (Table 1). In addition, the mean PANSS total scores at baseline were
similar for each double-blind treatment group
(Table 1).

Paliperidone palmitate in schizophrenia

639

Screening and washout


Screen failures: n=39
Failed to meet eligibility criteria
Eligibility criteria met
(n=266)

Open-label run-in phase (day-7)


Sequential assignment to 1 of 4 treatments

Paliperidone ER
6 mg p.o. q.d
(n=75)

Dropouts
Pali ER groups: n=9
6 mg
Adverse event: 0
Other:
2

Paliperidone ER
12 mg p.o. q.d
(n=71)

12 mg
2
5

Paliperidone IR
2 mg p.o. q.d
(n=65)

Eligible (n=247)
PANSS total score of 60 to 120
Randomization

Paliperidone IR
4 mg p.o. q.d
(n=55)

Dropouts
Pali IR groups: n=10
2 mg
Adverse event: 1
Other:
4

4 mg
1
4

Double-blind treatment period

Placebo i.m. (n=84)


Days 1, 8, and 36

Dropouts
Placebo group: n=57
Patient choice:
8
Lost to follow-up: 2
Adverse event:
8
Lack efficacy:
36
Other:
3

Paliperidone palmitate
50 mg eq. i.m. (n=79)
Days 1, 8, and 36

Paliperidone palmitate
100 mg eq. i.m. (n=84)
Days 1, 8, and 36

Study completion (day 64)


(n=125)

Dropouts
Paliperidone palmitate groups: n=65
50 mg 100 mg
4
11
Patient choice:
Lost to follow-up: 1
4
3
2
Adverse event:
23
14
Lack efficacy:
1
2
Other:

Fig. 1. Study ow and patient disposition. Patients from six sites (n=49) were excluded from the ITT analyses, but are
included here in patient accounting as they were part of the all randomized set. The strengths expressed as PP 50 and 100 mg eq.
equate to 78 mg and 156 mg, respectively, of paliperidone palmitate.

Dosing
Approximately 93 % (n=247) of the patients who entered the oral run-in phase continued into the doubleblind phase. In terms of drug exposure, 95 % (n=254)
of patients in the oral run-in phase received oral paliperidone (as an extended-release or immediate-release
formulation) for at least 7 d, at which time apparent
steady state is achieved. Approximately 66 % (n=107)
of PP-treated patients received all three injections,
compared to 42 % (n=35) of placebo-treated patients.
Ecacy
Both doses of PP produced signicant dierences
(pf0.001, Table 2) in the mean change in PANSS total

score from baseline to endpoint (the primary


measure), compared to placebo. Inclusion of patient
data from the six excluded sites produced similar results. These dierences were signicant by day 8 for
each palmitate group, compared to placebo, and were
maintained to the end of the double-blind period
(pf0.011) (Fig. 2). Results of the mixed-eects model
analysis were consistent with the primary analysis :
both PP 50 and 100 mg eq. separated from placebo
(pf0.002). PP treatment also resulted in signicant
improvement in the ve PANSS factor scores and 30 %
responder rates (Table 2). A post-hoc analysis of percentage improvement in PANSS total scores also
showed both PP 50 and 100 mg eq. separated from
placebo (pf0.001) (Table 2). Similarly, CGI-S scores

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M. Kramer et al.

Table 1. Patient characteristics of intent-to-treat analysis set

Demographics
Age, yr (S.D.)
Sex, n ( %)
Men
Race, n ( %)
White
Black
Other
BMI, mean kg/m2 (S.D.)
BMI category, n ( %)
Normal <25
Overweight 25 to <30
Obese o30
Symptom severity and disease characteristics
Patients with at least 15-point reduction in
PANSS total score during oral run-in, n ( %)
PANSS total score, mean (S.D.) [range]
PANSS subscale scores
Positive symptoms, mean (S.D.)
Negative symptoms, mean (S.D.)
Anxiety/depression, mean (S.D.)
Disorganized thoughts, mean (S.D.)
Uncontrolled hostility/excitement, mean (S.D.)
CGI-S, n ( %)
Mild
Moderate
Marked
Severe
Age at diagnosis of schizophrenia, yr mean (S.D.)c
Antipsychotic usage
Patients reporting prior antipsychotic use, n ( %)
Prior antipsychotics used by at least 10 % of patients
in any treatment group
Haloperidol
Risperidone
Chlorpromazine
Diazepam
Lorazepam
Olanzapine
Trihexyphenidyl

Placebo
(n=66)

PPa 50 mg eq.
(78 mg) (n=63)

PPa 100 mg eq.


(156 mg) (n=68)

40 (10.5)

40 (9.8)

37 (10.4)

39 (59)

41 (65)

42 (62)

54 (82)
11 (17)
1 (2)
26 (4.9)

50 (79)
9 (14)
4 (6)
26 (4.9)

55 (81)
13 (19)
0
25 (4.6)

36 (55)
14 (21)
16 (24)

33 (52)
15 (24)
15 (24)

40 (59)
16 (24)
12 (18)

15 (23)

10 (16)

14 (21)

87.8 (13.90) [55b118]

88.0 (12.39) [64120]

85.2 (11.09) [66118]

24.1 (5.64)
23.6 (4.70)
9.3 (2.58)
22.3 (4.24)
8.7 (3.26)

24.3 (4.98)
23.3 (4.88)
9.7 (2.72)
22.6 (4.52)
8.1 (2.35)

23.9 (5.06)
22.3 (4.42)
9.4 (2.54)
21.5 (3.16)
81 (2.74)

6 (9)
26 (39)
28 (42)
6 (9)
28 (9.4)

3 (5)
27 (43)
27 (43)
6 (10)
27 (8.7)

6 (9)
32 (47)
26 (38)
4 (6)
25 (7.2)

49 (74)

47 (75)

51 (75)

18 (27)
8 (12)
7 (11)
9 (14)
3 (5)
6 (9)
9 (14)

15 (24)
10 (16)
10 (16)
7 (11)
11 (17)
6 (10)
3 (5)

18 (26)
15 (22)
14 (21)
10 (15)
4 (6)
6 (9)
5 (7)

PP, Paliperidone palmitate ; BMI, Body mass index ; PANSS, Positive and Negative Syndrome Scale ; CGI-S, Clinical Global
Impression of Severity scale.
a
The strength is expressed both in terms of milligram equivalents (mg eq.) of paliperidone, the pharmacologically active
fraction, and in milligrams of PP.
b
One patient had a baseline score of 55, below the lower limit of 60 that was allowed per protocol.
c
n=65 for placebo ; n=62 for PP 50 mg eq. groups.

showed symptom improvement at endpoint : 50 %


of placebo-treated patients had a rating of marked,
severe, or extremely severe, compared to 37 % for

PP 50 mg eq. and 32 % for PP 100 mg eq. Both dose


groups were statistically superior to placebo (pf0.004)
in reducing CGI-S scores.

Paliperidone palmitate in schizophrenia

641

Table 2. Ecacy measures (intent-to-treat analysis set)


Placebo
(n=66)
PANSS total scores, mean (S.D.)
Endpoint
Change from baseline
Percentage change from baseline (S.D.)
PANSS factor scores, mean (S.D.)
Positive symptoms
Change from baseline
Negative symptoms
Change from baseline
Anxiety/depression
Change from baseline
Disorganized thoughts
Change from baseline
Uncontrolled hostility/excitement
Change from baseline
CGI-S Scale, n ( %) by category at endpoint
Not ill/very mild/mild
Moderate
Marked
Severe/extremely severe
Responder rate (change in PANSS total score
from baseline to endpoint), n ( %)
At least 30 % improvement
Less than 30 % improvement

PPa 50 mg eq.
(78 mg) (n=63)

PPa 100 mg eq.


(156 mg) (n=68)

94.0 (24.84)
6.2 (18.25)
10.1 (31.34)

82.8 (24.48)
x5.2 (21.52) p=0.001
x9.4 (35.99), p=0.001

77.5 (21.42)
x7.8 (19.40) p<0.001
x13.9 (36.47), p<0.001

1.7 (5.32)

x2.0 (6.81), p=0.001

x2.9 (6.86), p<0.001

0.3 (5.03)

x1.9 (5.12), p=0.010

x2.6 (4.47), p<0.001

1.1 (2.98)

x0.6 (3.52), p=0.002

x0.5 (2.90), p<0.001

0.8 (4.89)

x1.5 (5.64), p=0.012

x2.1 (4.64), p<0.001

2.1 (4.37)

0.8 (4.26), p=0.080

0.4 (3.95), p=0.006

7 (11)
26 (39)
15 (23)
18 (27)

19 (30)
21 (33)
12 (19)
11 (17)

27 (40)
19 (28)
19 (28)
3 (4)

9 (14)
57 (86)

21 (33)
42 (67), p=0.007

25 (37)
43 (63), p=0.002

PP, Paliperidone palmitate ; PANSS, Positive and Negative Syndrome Scale ; CGI-S, Clinical Global Impression of Severity scale.
Treatment with PP resulted in signicant dierences in all ecacy measures compared to placebo. Percentage change in PANSS
total score was calculated as : 100rchange/(baseline PANSS total score 30).
a
The strength is expressed both in terms of milligram equivalents (mg eq.) of paliperidone, the pharmacologically active
fraction, and in milligrams of PP.

Safety evaluations
The overall incidence of TEAEs was similar in dose
groups [safety analysis set (n=247) : 64 % for placebotreated patients, 65 % for PP 50 mg eq.-treated patients, and 60 % for PP 100 mg eq.-treated patients].
Discontinuation due to TEAEs occurred more frequently in the placebo group (10 %, n=8) compared to
either PP group [50 mg eq. (3 %, n=2), 100 mg eq.
(2 %, n=2)]. Psychiatric disorders (7 %, n=6), accounted for the majority of the discontinuations in the
placebo group, with most of these classied as psychotic disorder (5 %, n=4). Insomnia, schizophrenia,
and extrapyramidal disorder were the only TEAEs
that occurred more frequently (i.e. o5 % dierence) in
any of the PP-treated groups than placebo (Fig. 3).
One patient receiving 4 mg paliperidone IR during
the oral run-in phase reported akathisia 3 d before

receiving double-blind phase medication (assigned to


PP 50 mg eq.). Consequently, this adverse event was
not classied as treatment-emergent in terms of PP. Of
the four patients (2 %) in the combined PP group who
discontinued due to TEAEs, three discontinued due to
schizophrenia and one for pyelocystitis.
Parkinsonism-related adverse events (extrapyramidal disorder, drooling, and hypertonia) were
the most common EPS-related adverse events and occurred more frequently in the PP groups [100 mg eq.
(8 %, n=7), 50 mg eq. (5 %, n=4)] than placebo (1 %,
n=1). All other EPS-related events occurred at similar,
low rates across groups and none were severe in intensity. Movement disorder rating scales did not show
any statistically signicant or clinically relevant differences between the PP and placebo groups.
However, the percentage of patients receiving antiEPS medications was higher in the PP 100 mg eq.

M. Kramer et al.

Least squares mean change from baseline (S.E.)

642

Placebo
PP 50 mg eq.
PP 100 mg eq.

10

Insomnia
Headache
Schizophrenia
Agitation
Sedation
Psychotic disorder
Nasopharyngitis
Extrapyramidal disorder
Constipation
Anxiety
Somnolence
Restlessness
Myalgia
Hypertonia
Asthenia
Irritability
Hypertension
Diarrhoea
Vomiting
Pruritus

*
10

*
*

15

22

29

*
36

Placebo (n=84)
PP 50 mg eq. (n=79)
PP 100 mg eq. (n=84)

43

50

57

END

Days

Fig. 2. Change in PANSS total score over time (LOCF).


Mean change from baseline in PANSS total scores is
shown, by treatment group, for each time-point assessed.
Intent-to-treat analysis set, which excludes patients from
six sites. * pf0.011 (LOCF analysis) paliperidone palmitate
(PP) group vs. placebo. Results for the repeated-measures
mixed-eects model were consistent with the LOCF
analysis : PP 50 mg eq. vs. placebo (p=0.0016) ;
PP 100 mg eq. vs. placebo (p<0.0003). The strengths
expressed as PP 50 and 100 mg eq. equate to 78 mg and
156 mg, respectively, of PP.

group (21 %, n=18)] than in the PP 50 mg eq. (10 %,


n=8)] or placebo (7 %, n=6) groups. There were no
reports of tardive dyskinesia.
Serious TEAEs occurred in 19 patients during the
double-blind phase ; six (7 %) received placebo and 13
(8 %) received PP. Psychotic disorder or schizophrenia
(exacerbation of symptoms) was reported for most
(n=15) of these patients : ve patients treated with
placebo, seven treated with PP 50 mg eq., and three
treated with PP 100 mg eq. One case of elevated
hepatic enzymes was reported in the placebo group.
Additionally, in the PP groups, depression and suicidal
ideation (n=1 ; 50 mg eq. group), psychomotor agitation (n=1 ; 100 mg eq. group), and syncope (n=1 ;
100 mg eq. group) were reported.
Median prolactin levels increased, more so in
women than men, during the run-in phase, during
which all patients were treated with oral paliperidone.
Prolactin values decreased, relative to the increased
baseline values, by endpoint of the double-blind
treatment. However, the median values remained elevated for the PP treatment groups compared to median pre-dose treatment values (Table 3). Prolactin
levels decreased to pretreatment values for placebotreated patients. The incidence of potentially prolactin-related adverse events was low : one case of

10 12 14 16 18 20 22 24
Percent

Fig. 3. Treatment-emergent adverse events occurring in at


least 3 % of patients in any group. Paliperidone palmitate
(PP) (50 mg eq.) overlaps placebo for extrapyramidal
disorder rates ; PP 100 mg eq. overlaps placebo for myalgia
and asthenia rates ; PP 100 mg eq. overlaps PP 50 mg eq.
for hypertension rates. The strengths expressed as
PP 50 and 100 mg eq. equate to 78 mg and 156 mg,
respectively, of PP.

erectile disorder in a man (PP 50 mg eq.) and two


cases of galactorrhoea in women (one in each of the
PP 50 and 100 mg eq. groups). The woman treated with
50 mg eq. PP also reported amenorrhoea, as did one
placebo-treated woman. There were no other clinically
relevant treatment-related changes in any evaluated
laboratory value, including lipids and glucose
(Table 3).
Treatment with PP was associated with signicant
mean increases in body weight and BMI from baseline
to endpoint for both the 100 mg eq. group (pf0.001
both measures ; last observation available during the
double-blind phase) and the 50 mg eq. group (p=
0.036 for BMI ; p=0.059 for weight ; last observation
available during double-blind phase) compared to
placebo (Table 3). The percentage of patients with
a >7 % increase in weight was low, with 68 % of
patients in that category for the two PP dose groups
vs. 4 % for placebo-treated patients. Weight increase
was reported as a TEAE for three patients : one in the
placebo group and two in the PP 50 mg eq. group.
Incidences of increased heart rate were higher for
PP-treated patients than placebo, as were incidences
of orthostatic hypotension (Table 3). None of the incidences of orthostatic hypotension, dened by vital
sign measurements, were reported as an adverse
event. No case was symptomatic, except possibly for
one PP 50 mg eq.-treated patient who reported nausea
on the same day. There were no clinically relevant
changes in QTcLD (i.e. o450 ms) reported for PPtreated patients and none had an increase in QTcLD

Paliperidone palmitate in schizophrenia

643

Table 3. Results for key clinical laboratory and safety measures (safety analysis set)

Measure
Orthostatic hypotensionb
Total no. patients with orthostatic hypotension
Increase in pulse rate >15 and decrease
in systolic blood pressure >20
Increase in pulse rate >15 and decrease in
diastolic blood pressure >10
Heart rate
Abnormally high (o100 bpm)
Abnormally low (f50 bpm)
Glucose (n, %)
Abnormally high (>16.7 mmol/l)
Abnormally low (<2.2 mmol/l)
Weight (kg)
Mean change (S.D.)
Decrease o7 % change (n, %)
Increase o7 % change (n, %)
Body mass index (kg/m2)
Mean change (S.D.)
Prolactin, median (range), (ng/ml)
Males
Pre-dose ; oral run-in (day x7)
Baseline double-blind
Endpoint double-blind
Females
Pre-dose ; oral run-in (day x7)
Baseline double-blind
Endpoint double-blind
Cholesterol, median (range), (mmol/l)
Baseline
Endpoint
Triglycerides, median (range), (mmol/l)
Baseline
Endpoint

Placebo
(n=84)

PPa 50 mg eq.
(78 mg) (n=79)

PPa 100 mg eq.


(156 mg) (n=84)

n=84
3 (4)
3 (4)

n=79
5 (6)
3 (4)

n=84
9 (11)
7 (8)

3 (4)

4 (5)

n=79
6 (8)
4 (5)
n=80
0
0
n=73
x0.3 (2.99)
3 (4)
3 (4)
n=73
x0.1 (1.00)

n=78
17 (22)
5 (6)
n=79
1 (1)
1 (1)
n=74
0.7 (2.71)
2 (3)
6 (8)
n=74
0.3 (0.94)

n=82
10 (12)
4 (5)
n=82
0
0
n=72
1.4 (3.49)
1 (1)
4 (6)
n=72
0.5 (1.15)

n=53c
7.0 (132)
29.0 (359)
6.0 (233)
n=29c
15.0 (4242)
92.0 (29269)
8.0 (3180)
n=84d
4.8 (38)
4.7 (28)
n=84d
1.5 (16)
1.6 (04)

n=56c
6.5 (135)
27.0 (292)
18.0 (654)
n=22c
12.0 (341)
94.5 (31587)
33.5 (11769)
n=79
4.6 (37)
4.4 (38)
n=79
1.5 (15)
1.3 (15)

n=54c
7.0 (265)
33.0 (375)
30.0 (993)
n=29c
20.0 (2120)
124.0 (13457)
66.5 (9228)
n=84e
4.5 (37)
4.4 (37)
n=84e
1.3 (17)
1.4 (15)

PP, Paliperidone palmitate.


a
The strength is expressed both in terms of milligram equivalents (mg eq.) of paliperidone, the pharmacologically active
fraction, and in milligrams of PP.
b
Dened as a decrease in systolic (>20 mmHg) or diastolic (>10 mmHg) blood pressure with an increase in pulse rate of
>15 beats per min, after standing for at least 2 min.
c
Number of patients at day x7 oral run-in. Patient numbers varied by up to two patients at endpoint.
d
Four patients did not have endpoint values.
e
Two patients did not have endpoint values.

>60 ms at any time-point during the study. In general,


pairwise comparisons of the mean changes from average pre-dose value between each PP group and
placebo were not dierent for any of the ECG parameters measured in this study.
Injection site tolerability was good overall. Throughout the study investigator-rated local injection-site
pain was similar between PP and placebo treatment

groups and generally absent or mild : absent (5671 %),


mild (2439 %), moderate (212 %), or severe (02 %).
Induration and swelling appeared in f10 % of
patients in any group, but appeared to be more frequent in PP-treated patients. Redness was largely
rated as absent or mild across groups. PP 100 mg eq.
was associated with more redness for the rst injection, but the incidence of redness was similar across

M. Kramer et al.

Median plasma concentration (ng/ml)

644

PP 100 mg eq.

35

PP 50 mg eq.

30
25
20
15
10
5
1

15

22

29
36
43
Time (days)

50

57

64

71

Fig. 4. Linear plasma concentrations over time during the


double-blind phase (pharmacokinetic analysis set).
The strengths expressed as PP 50 and 100 mg eq. equate
to 78 mg and 156 mg, respectively, of paliperidone
palmitate (PP).

PP groups for the subsequent two injections, although


higher than placebo.
PK ndings
For all treatments in the oral run-in period, apparent
steady-state was achieved within 7 d after starting
the oral run-in phase. In the 7-d period following
the rst intramuscular injection of PP, the median
plasma concentrations of paliperidone gradually
decreased from 18.9 ng/ml (pre-dose day 1) to
7.59 ng/ml (pre-dose day 8) for the PP 50 mg eq.
group, and from 28.7 ng/ml (pre-dose day 1) to
8.24 ng/ml (pre-dose day 8) for the PP 100 mg eq.
group. Following the third intramuscular injection
of PP (on day 36), plasma concentrations of paliperidone slowly increased to reach a maximum about 4 d
after each injection. Thereafter, plasma concentrations
of paliperidone decreased gradually over 2027 d
(Fig. 4).
Discussion
This phase 2b study was an initial study to assess the
ecacy and safety of PP, an investigational atypical
antipsychotic formulated as a long-acting injectable
aqueous nanosuspension. Administered as an intramuscular injection into gluteal muscle (and not
requiring oral supplementation), PP improved
symptom control in this population of patients with
schizophrenia. Mean change in PANSS total scores at
endpoint, 4 wk after the last injection, demonstrated
signicant (pf0.001) reductions for both PP dose
groups compared to placebo. At least 19 % more PPtreated patients achieved treatment response (i.e.

patients achieved at least a 30 % improvement in


PANSS total score), compared to placebo, and the
dierence was signicant for both PP dose groups.
Both groups were also signicantly dierent on the
post-hoc analysis of percentage change in PANSS total
scores. In addition, all secondary ecacy measures
assessed, including CGI-S scores, showed signicant
changes vs. placebo, consistent with improvement in
patients treated with PP. Onset of eect was early,
with both doses showing statistical separation from
placebo within 8 d of the rst injection, and was
maintained throughout the 2-month double-blind
period.
PP was generally tolerated systemically. The incidence of TEAEs was similar between PP- and placebotreated groups. The rate of discontinuations as a
result of TEAEs was lower in patients treated with
PP (2 %), compared to placebo (10 %). EPS-related
adverse events were infrequent, and all were mild or
moderate in severity. However, Parkinsonism-related
adverse events did occur more frequently in the PP
treatment groups (7 % overall) compared to placebo
(1 %). More patients in the PP 100 mg eq. group used
antiparkinson medication than patients in either the
PP 50 mg eq. or placebo groups, which were similar
in this respect. There were no reports of tardive
dyskinesia.
Mean body weight increases, which were signicant compared to placebo, were detected in both PP
dose groups (y1 kg at endpoint). A 44.5 kg increase
was reported over a 10-wk treatment period for olanzapine and clozapine (Allison et al. 1999). Consistent
with previously published information (Davidson et al.
2007 ; Kane et al. 2007 ; Marder et al. 2007), prolactin
levels increased during the oral run-in phase, in which
all patients were treated with paliperidone ER. While
they decreased for all groups during the double-blind
phase, and decreased to normal for placebo-treated
patients, mean prolactin levels remained above the
upper limit of normal for PP-treated patients. The
rates of potentially prolactin-related adverse events
were low, consistent with other studies to date (Hough
et al. in press). However, it should be noted that
assessing sexual dysfunction via spontaneous reports
can result in underreporting.
There was no worsening noted in other metabolic
parameters, including lipids and glucose.
Cardiovascular tolerability of PP administration
appeared to be good overall, although the study
was not powered to assess safety. No patient receiving
PP experienced QTcLD prolongation or a QTcLD
>450 ms during the study. PP treatment was associated with higher incidences of abnormally high

Paliperidone palmitate in schizophrenia


heart rate (17 % combined PP vs. 8 % placebo) and
orthostatic hypotension (9 % combined vs. 4 % placebo)
as based on vital sign measurements. None of the incidences of orthostatic hypertension were reported as
an adverse event and incidences of tachycardia as an
adverse event were low (<2 %).
The aqueous nanosuspension formulation also resulted in good tolerability around the injection site.
Investigators rated injection-site pain and redness predominately as absent or mild throughout the study.
These are positive attributes for an injectable formulation of an atypical antipsychotic and similar to results seen for risperidone LAI, another aqueous-based
injectable atypical antipsychotic (Lindenmayer et al.
2005). Oil-based injectable formulations of conventional (typical) antipsychotics have been associated
with injection-site pain and skin reactions (Hamann
et al. 1990). Furthermore, the severity of pain can aect
patient attitudes towards treatment (Bloch et al. 2001).
Because this was the rst double-blind, placebocontrolled clinical study of PP, patient enrolment
was limited to a modest sample size. In addition, this
9-wk study was relatively short and did not include
an active comparator. Thus, conclusions regarding
ecacy of PP compared to other antipsychotics,
including oral paliperidone, should not be drawn.
Finally, discontinuations rates were high in this study.
However, it is worth noting that the LOCF and repeated-measures mixed-eects model analyses, which
each handle drop-outs dierently, yielded consistent
results.
As with any clinical trial, the data are from a select
patient population and results may not be fully generalizable. In fact, data from subsequent clinical
and PK studies indicate that treatment initiation of
PP using a 150 mg eq. dose in the deltoid muscle
results in more consistent achievement of eective
therapeutic levels across patients (Pandina et al. 2009 ;
Samtani et al. 2009). Subsequent injections can be administered in either the gluteal or deltoid site (Hough
et al. 2009).
This study included a 7-d oral run-in period that
assessed the pharmacokinetics of two dierent formulations of paliperidone : an immediate release and
an extended release (currently marketed). It is anticipated some clinicians may treat patients with an oral
formulation for several days before initiation of PP.
Treatment with the dierent oral formulations improved PANSS total scores during the run-in period.
However, patients with an improvement in PANSS
total scores during run-in were equally distributed
across the three treatment groups and additionally,
mean PANSS total scores were similar across

645

treatment groups at double-blind baseline. A nal


consideration is that this study used the LOCF
approach for the primary ecacy parameter.
Adherence issues with a daily oral regimen, frequently leading to repeated symptomatic relapses,
continue to be a major problem in patients with
schizophrenia taking oral antipsychotics (Byerly et al.
2005 ; Keith et al. 2004). Long-acting injectable antipsychotics may oer multiple advantages for patients
with schizophrenia including improved assurance
that patients have more continuous blood levels of an
atypical antipsychotic. With the use of long-acting injectable formulations, missed injections can be easily
detected and acted upon. There are very few options
currently available among injectable formulations of
atypical antipsychotics. PP demonstrated ecacy
in quickly reducing the severity of symptoms and
maintaining symptom control over a 2-month period.
It was generally tolerated in this study.
Appendix. Main investigators from the 30 sites
that enrolled patients
Bulgaria : Loris Sayan, M.D. ; Stefan Todorov, M.D. ;
Todor Tolev, M.D. ; Lubomir Jivkov, M.D. India : M. K
Desphande, M.D. ; Shubhangi R. Parkar, M.D. ; R.
Sathianathan, M.D. Poland : Slawomir Dziadkiewicz,
M.D. ; Mieczyslaw Janiszewski, M.D. ; Masiak Marek,
M.D. ; Zbigniew Wawrzyniak, M.D. Russia : Mikhail
Ivanov, M.D. ; Margarita Morozova, M.D., Ph.D. ;
Nikolay Neznanov, M.D. ; Galina Panteleyeva, M.D. ;
Mikhail Popov, M.D. ; Antoly Smulevich, M.D. ;
Vladimir Tochilov, M.D. Ukraine : Valeryy Bitensky,
M.D. ; Vladislav Demchenko, M.D. ; Svetlana Moroz,
M.D., Ph.D. ; Ludmila Yuryeva, M.D.. USA : Daniel D.
Anderson, M.D. ; Carlos Collin, M.D. ; David Howard
Flaherty, D.O. ; Henry T. Haye, M.D. ; Robert E.
Litman, M.D. ; Rakesh Ranjan, M.D. ; David Sack,
M.D. ; Martin Schuster, M.D.
Acknowledgements
The authors thank Dr Wendy P. Battisti of Johnson
& Johnson Pharmaceutical Research & Development,
L.L.C. for writing and editorial assistance. [This
study is registered at ClinicalTrials.gov (www.
clinicaltrials.gov) corresponding to NCT number :
NCT00074477.]
Statement of Interest
Johnson & Johnson Pharmaceutical Research &
Development, L.L.C., Raritan, New Jersey funded this
study and was principally responsible for its design

646

M. Kramer et al.

and conduct. Dr Litman was a principal investigator


for this study and has received research support
from Johnson & Johnson Pharmaceutical Research &
Development, L.L.C. Drs Kramer, Lane, Lim, and
Hough were employees by Johnson & Johnson
Pharmaceutical Research & Development, L.L.C. during this study. Dr Eerdekens was employed by
Johnson & Johnson Pharmaceutical Research & Development, Division of Janssen Pharmaceutica, N.V.
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