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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
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M. Kramer et al.
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.
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).
639
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
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
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
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M. Kramer et al.
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)
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)
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.
641
PPa 50 mg eq.
(78 mg) (n=63)
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)
0.3 (5.03)
1.1 (2.98)
0.8 (4.89)
2.1 (4.37)
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
M. Kramer et al.
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
10 12 14 16 18 20 22 24
Percent
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)
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)
M. Kramer et al.
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
645
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M. Kramer et al.
647