Expert Opinion on Pharmacotherapy

ISSN: 1465-6566 (Print) 1744-7666 (Online) Journal homepage: http://www.tandfonline.com/loi/ieop20

Once-monthly injection of paliperidone palmitate

in patients with recently diagnosed and chronic
schizophrenia: a post-hoc comparison of efficacy
and safety

Tianmei Si, Jianmin Zhuo, Ibrahim Turkoz, Maju Mathews, Wilson Tan & Yu
Feng

To cite this article: Tianmei Si, Jianmin Zhuo, Ibrahim Turkoz, Maju Mathews, Wilson Tan & Yu
Feng (2017): Once-monthly injection of paliperidone palmitate in patients with recently diagnosed
and chronic schizophrenia: a post-hoc comparison of efficacy and safety, Expert Opinion on
Pharmacotherapy, DOI: 10.1080/14656566.2017.1401608

To link to this article: https://doi.org/10.1080/14656566.2017.1401608

Published online: 15 Nov 2017.

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 EXPERT OPINION ON PHARMACOTHERAPY, 2017
https://doi.org/10.1080/14656566.2017.1401608

ORIGINAL RESEARCH

Once-monthly injection of paliperidone palmitate in patients with recently

diagnosed and chronic schizophrenia: a post-hoc comparison of efficacy and safety
Tianmei Sia, Jianmin Zhuob, Ibrahim Turkozc, Maju Mathewsc, Wilson Tand and Yu Fengd
a
National Clinical Research Center for Mental Disorders (Peking University Sixth Hospital/Institute of Mental Health) and the Key Laboratory of
Mental Health, Ministry of Health, Beijing, People’s Republic of China; bJanssen Research and Development, Shanghai, People’s Republic of China;
c
Janssen Research and Development, LLC, Titusville, NJ, USA; dJanssen Pharmaceutical Companies of Johnson and Johnson, Singapore

ABSTRACT ARTICLE HISTORY

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Background: The use of long-acting injectable antipsychotics in recently diagnosed schizophrenia Received 17 May 2017
remains less explored. We evaluated the efficacy and safety of paliperidone palmitate once-monthly Accepted 2 November 2017
(PP1M) treatment in adult patients with recently diagnosed vs. chronic schizophrenia. KEYWORDS
Research design and methods: These post-hoc analyses included two multicenter studies. Study 1 Chronic schizophrenia;
(NCT01527305) enrolled recently diagnosed (≤5 years) and chronic (>5 years) patients; Study 2 clinical global impressions
(NCT01051531) enrolled recently diagnosed patients only. Recently diagnosed patients were further – severity (CGI-S);
sub-grouped into ≤2 years or 2–5 years. The primary efficacy endpoint was the change from baseline in long-acting injectable;
Positive and Negative Syndrome Scale (PANSS) total score. paliperidone palmitate;
Results: In Study 1, 41.5% patients had recent diagnosis (≤2 years: 56.8%; 2–5 years: 43.2%); 58.5% had positive and negative
chronic schizophrenia. In Study 2, 52.8% and 47.2% patients were grouped into ≤2 years and 2–5 years, syndrome scale (PANSS);
recently diagnosed
respectively. PANSS total score showed significantly greater improvement in patients with recently
schizophrenia
diagnosed vs. chronic schizophrenia. Similar results were obtained for PANSS responder rate, improve-
ments in PANSS, and CGI-S scores.
Conclusion: PP1M was efficacious in both recently diagnosed and chronic schizophrenia, with the
benefits being more pronounced in patients with recently diagnosed schizophrenia. This adds to
growing evidence recommending long-acting antipsychotic interventions at early stages of
schizophrenia.

1. Introduction adverse impact on socioeconomic status, educational engage-

ments [19,20], and quality of life [21].
The treatment of psychotic disorders during first few years of
Long-acting injectable (LAI) antipsychotics have a proven
their onset is critical in shaping long-term outcomes of
efficacy along with an improved adherence, and therefore,
patients with these disorders [1,2]. Treating schizophrenia
may provide an advantage over oral antipsychotics by redu-
with antipsychotic interventions during the early stages of
cing the relapse rate [22–24]. A large meta-analysis has also
the disease onset seems to be associated with improvement
demonstrated the superiority of LAIs in reducing the risk of
in treatment outcomes [3], especially when it is considered
hospitalizations [25]. Also, use of LAIs has been shown to be a
that the maximum clinical and psychosocial deterioration
more cost-effective approach compared to oral antipsychotics
occurs within the initial 5 years of disease onset [4,5].
in treatment of schizophrenia [8,26]. In real-world settings,
Besides exerting a positive effect on the long-term course of
however, LAIs are often reserved for the treatment of chronic
the illness [6,7], an intervention in the early stages of schizo-
schizophrenia [27,28]. Emerging data suggest that LAIs are
phrenia offers higher recovery rates at substantially lower
now increasingly being recommended for treating early or
personal and economic costs [8–10].
recently diagnosed schizophrenia, which not only improves
Although oral antipsychotics have traditionally been the
the adherence and responsiveness, but also reduces the
mainstay of schizophrenia treatment [11], patients are often
relapse risk, while improving the long-term functioning in
non-adherent to the treatment [12,13]. This might compro-
early stage or recently diagnosed schizophrenia [2,3,29–31].
mise the quality of therapeutic care during the early stages of
Paliperidone palmitate once monthly (PP1M) is a LAI
the disease [14–17], and increases the risk of relapse [18].
approved in the U.S.A., the European Union, and most of the
Frequent relapses in the early stages of the disease tend to
Asia-Pacific countries, for the treatment of adult patients with
have a long-lasting impact on the overall prognosis, which is
schizophrenia, with a well-established efficacy and safety pro-
further complicated by a progressive cognitive decline and an
file [32–38]. However, data on the efficacy and safety of PP1M,

CONTACT Yu Feng yfeng23@its.jnj.com Janssen Pharmaceutical Companies of Johnson and Johnson, Singapore
Clinical Trial Registry: The study included post-hoc analyses of data from two studies – Study 1 (NCT01527305) and Study 2 (NCT01051531).
Previous presentations: Data in form of abstract have been accepted for presentation at Society of Biological Psychiatry’s (SOBP) 72nd Annual Scientific Program
and Convention, to be held in San Diego, California, from 18 to 20 May, 2017.
© 2017 Taylor & Francis
 2 T. SI ET AL.
when given in recently diagnosed schizophrenia, compared to
chronic schizophrenia in Asia-Pacific population, remain
scarce.
We conducted two separate post-hoc analyses of data from
two large, single-arm, open-label, multicenter studies to
explore the short-term and long-term efficacy and safety pro-
file of PP1M in patients with recently diagnosed and chronic
schizophrenia.
2. Patients and methods
2.1. Study population
These post-hoc analyses are based upon the data derived from
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two studies, PREVAIL (NCT01527305; Study 1) and SUSTAIN
(NCT01051531; Study 2), wherein patients with schizophrenia
received PP1M. The eligibility criteria, study design, and results
from PREVAIL and SUSTAIN have been previously published
[32,33].
Briefly, in Study 1, patients aged 18–65 years, diagnosed
with schizophrenia (as per Diagnostic and Statistical Manual of
Mental Disorders, [DSM-IV] criteria), presenting with acute
exacerbations within the preceding four weeks of hospitaliza-
tion were enrolled. The key exclusion criteria included primary
active DSM-IV Axis I diagnosis other than schizophrenia, DSM-
IV diagnosis of substance dependence (except for nicotine and
caffeine) within 6 months of screening, patients who received
clozapine, or LAI antipsychotics including paliperidone palmi-
tate within 1 month of the screening, and patients who were
at a significant risk of suicide.
In Study 2, patients aged 18–50 years, recently diagnosed
(≤5 years) with schizophrenia (DSM-IV criteria), having a pre-
vious unsatisfactory treatment with oral antipsychotic(s) were
enrolled. The key exclusion criteria included psychiatric diag-
nosis due to medication/substance abuse, or a general medi-
cal condition, treatment-resistance, DSM-IV diagnosis of
substance dependence within 6 months before study entry,
treatment with an LAI antipsychotic within three injection
cycles before baseline, or clozapine within 3 months before
screening, history of neuroleptic malignant syndrome, or tard-
ive dyskinesia. Women not using an acceptable method of
contraception unless postmenopausal for >1 year, surgically
sterile, or abstinent were also excluded.
2.2. Study design and drug administration
Study 1 was a 3-month, single-arm, open-label, prospective,
non-comparative, Phase IV study conducted between June
2012 and December 2013, across 27 centers in four Asian
countries (People’s Republic of China, Korea, Malaysia, and
Taiwan). Study 2 was a 18-month, single-arm, open-label,
multicenter, Phase IIIb study conducted between April 2010
and May 2013, across nine countries in the Asia-Pacific region
(Australia, People’s Republic of China, Hong Kong, Korea,
Malaysia, New Zealand, Philippines, Taiwan, and Thailand).
The duration of treatment was longer in Study 2, which
allowed long-term evaluation of the efficacy and safety of
PP1M. Both the studies had a screening phase of up to
seven days.
Oral antipsychotics were discontinued before initiating
PP1M treatment in both the studies. All patients received
initial intramuscular doses of paliperidone palmitate: 150 mg
equivalent (mg eq.) on day 1 and 100 mg eq. on day 8,
followed by once-monthly doses of either 75, 100, or 150 mg
eq. (Study 1) or 50, 75, 100, or 150 mg eq. (Study 2).
In both the post-hoc analyses, patients were stratified by
the time since diagnosis of schizophrenia. In Study 1, patients
having their diagnoses made within ≤5 years were categorized
as recently diagnosed, and those with >5 years were categor-
ized as patients with chronic schizophrenia. Study 2 had
patients with only recently diagnosed schizophrenia
(≤5 years). In both the studies, patients with recently diag-
nosed schizophrenia (≤5 years) were further sub-grouped into
those having their diagnosis made within ≤2 years (more
recently diagnosed) or within 2–5 years (less recently diag-
nosed). Though the stratification time points vary across dif-
ferent studies, cutoff of 2 and 5 years used in these post-hoc
analyses are the most commonly used and cited in literature
[39,40]. Secondly, we have used two different studies (Study 1
and Study 2) in post-hoc analyses and Study 2 has already
recruited patients with recent diagnosis of schizophrenia using
a 5 year cutoff. So, to ensure that both studies follow common
cutoff and are in sync with each other, it seems appropriate to
use 2 and 5 years cutoff. Also, using this cutoff (2 and 5 years)
provided us with enough sample size to determine clinically
meaningful differences between two groups/subgroups,
if any.
An institutional review board or ethics committee at
each study center approved the protocols of primary stu-
dies. Both studies were conducted in accordance with the
ethical principles that have their origin in the Declaration
of Helsinki and that are consistent with Good Clinical
Practices and applicable regulatory requirements. All
patients provided written informed consent prior to study
participation.
2.3. Study assessments
2.3.1. Efficacy
The primary efficacy measure for these post-hoc analyses
was the change in Positive and Negative Syndrome Scale
(PANSS) total score from baseline to the end point (Study
1: month 3; Study 2: month 18) in patients with recently
diagnosed (further divided into more recently [≤2 years]
and less recently diagnosed [2–5 years]) and chronic schi-
zophrenia. The secondary efficacy measures included
changes from baseline to the end point in terms of the
PANSS responder rate (defined as the percentage of
patients with at least a 30% reduction in the PANSS total
score from baseline), the changes in Clinical Global
Impression-Severity (CGI-S) overall score, clinically mean-
ingful change in the PANSS score (≥10 point reduction)
[41], and symptom remission (for Study 2 only).
Symptom remission was defined as none or mild core
symptoms for 6 months or more after the study treatment
was initiated, and was based on the following the PANSS
items: P1 delusions, P2 conceptual disorganization, P3 halluci-
natory behavior, N1 blunted affect, N4 passive/apathetic social
 EXPERT OPINION ON PHARMACOTHERAPY 3

withdrawal, N6 lack of spontaneity and conversation flow, G5

Less recently diagnosed

mannerisms and posturing, and G9 unusual thought con-

64.4 (19.33)
tent [42].

151 (61.89)

161 (65.98)
(2–5 years)

24.8 (5.44)
29.4 (7.89)

92 (37.70)
(n = 244)

3.4 (0.87)
1 (0.41)
18–56
2.3.2. Safety

Study 2 (N = 517)
In Study 1, safety assessments included treatment-emergent
adverse events (TEAEs) as reported by study subject and/or
caregiver, concomitant use of psychotropic medications, clin-

More recently diagnosed

ical laboratory tests, physical examinations, vital sign measure-
ments, and 12-lead electrocardiograms [32]. In Study 2, the

63.8 (18.98)
128 (46.89)
145 (53.11)

178 (65.20)
(≤2 years)
(n = 273)

0.7 (0.59)
assessments included TEAEs, clinical laboratory tests, vital sign

24 (4.83)
28 (7.92)
18–50
measurements, physical examinations, and movement disor-

-
der evaluation using Extrapyramidal Symptom Rating Scale-
Abbreviated scale, and Clinical Global Impression of
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Movement Severity scale [33,43,44].

These post-hoc analyses focused on TEAEs. The adverse

Less recently diagnosed

events (AEs) of interest included extrapyramidal symptoms
(EPS), prolactin, and glucose-related AEs.

91.8 (15.15)
33.2 (11.51)
(2–5 years)

23.6 (4.92)
14 (36.84)
20 (52.63)

21 (55.26)

3.5 (0.86)
4 (10.53)
(n = 38)

19–61
2.3.3. Statistical analysis
These post-hoc analyses included the patients in the intent-to-
treat (ITT) analyses data set in both studies, i.e. all the patients

≤5 years
who received at least one injection of PP1M during the treat-
ment period, regardless of their adherence to the protocol.

More recently diagnosed

The actual values and change from baseline in the efficacy
parameters were summarized using last observation carried

89.7 (13.23)
22.5 (3.90)
(≤2 years)

35 (13.88)

0.4 (0.54)
(n = 50)

19 (38)
20 (40)
11 (22)

24 (48)
18–64
Study 1 (N = 212)
forward (LOCF) data. The differences in the primary/secondary
efficacy parameters within the groups were analyzed using a
paired t-test with 95% confidence intervals (CIs). The change

BMI: body mass index; ITT: intent-to-treat; PANSS: Positive and Negative Syndrome Scale; SD: standard deviation.
from baseline to the end point between the patients with
recently diagnosed versus chronic schizophrenia, and patients
with more recently versus less recently diagnosed schizophre-

89.5 (19.49)
23.9 (4.12)
12.6 (7.13)
39.2 (10.6)
(>5 years)

21 (16.94)

63 (50.81)
(n = 124)

10 (8.06)
Chronic

93 (75)
nia were compared using the analysis of covariance (ANCOVA)
21–61

model with group as a factor, and baseline score as a

covariate.
SAS (V.9.1.3; SAS Institute, Cary, North Carolina, USA) was
Overall
Recently diagnosed

used for the statistical analyses.

90.6 (14.04)
34.2 (12.87)
(≤5 years)

33 (37.50)
40 (45.45)
15 (17.05)

45 (51.14)
23 (4.39)
(n = 88)

1.8 (1.7)
18–64

3. Results
N: total number of patients; n, number of patients in specified category.

3.1. Patient demographics and baseline characteristics

Table 1. Demographic and baseline characteristics (ITT population).

The demographic and baseline characteristics of patients are

Mean time since first diagnosis of schizophrenia, years (SD)

presented in Table 1. In Study 1, 88 out of 212 (41.5%) patients

had a recent diagnosis of schizophrenia (≤5 years), and 124 out
of 212 (58.5%) patients had chronic schizophrenia (>5 years). In
≤5 years group, 50 out of 88 (56.80%) patients had a more
recent diagnosis (≤2 years ago), and 38 out of 88 (43.20%)
patients had a less recent diagnosis (within 2–5 years). Overall,
Baseline PANSS total score, mean (SD)

18 out of 88 (20.45%) patients with recently diagnosed schizo-

phrenia, and 42 out of 124 (33.87%) patients with chronic
schizophrenia discontinued the study. In recently diagnosed
group (≤5 years), 13 out of 50 (26%) and 5 out of 38 (13.16%)
Mean BMI, kg/m2 (SD)
Mean age, years (SD)

patients with more recently and less recently diagnosed schizo-

Age range in years
Age groups, n (%)

phrenia, respectively, discontinued the study.

Gender, n (%)

In Study 2, 273 out of 517 (52.80%) patients had a more

18–25 years
26–50 years
>50 years

recent diagnosis (≤2 years), and 244 out of 517 (47.20%)

patients had a less recent diagnosis (2–5 years). Overall, 114
Men

out of 273 (41.76%) patients with more recently diagnosed

 4 T. SI ET AL.
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Figure 1. Change in PANSS total score (least squares mean) from baseline to endpoint (LOCF) in ITT population.
A: ≤5 years vs. >5 years (Study 1), B: ≤2 years vs. 2–5 years (Study 1), C: ≤2 years vs. 2–5 years (Study 2). *Compared with baseline, p < 0.0001 (for within group difference). p-value
between groups is for change from baseline to end point in LS mean score. Values in bracket represents 95% confidence intervals. p-values for within group difference are based on a
paired t-test. LOCF, last observation carried forward; PANSS, Positive and Negative Syndrome Scale

schizophrenia, and 100 out of 244 (40.98%) patients with less younger, and leaner versus patients with chronic schizophre-
recently diagnosed schizophrenia discontinued the study. nia. For patients with more recently or less recently diagnosed
In both the studies, the majority of the patients were schizophrenia also, the demographic and baseline character-
26–50 years of age. Patients with a recent diagnosis were istics followed a similar trend (Table 1).

Figure 2. PANSS responder rates (at least 30%) at each time point (LOCF) in ITT population.
*significant difference, p = 0.0224ITT: intent-to-treat; LOCF, last observation carried forward; PANSS, Positive and Negative Syndrome Scale
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3.2. Primary efficacy outcome
3.2.1. Change in PANSS total score from baseline to the
end point
In Study 1, a significant and clinically meaningful reduction in
the PANSS total score from baseline to the end point was
observed for patients with recently diagnosed schizophrenia
as well as with chronic schizophrenia. The improvement in the
PANSS total score from baseline to the end point was signifi-
cantly greater in patients with recently diagnosed versus those
with chronic schizophrenia (Figure 1). Further, the subgroup
analysis in patients with recently diagnosed schizophrenia also
showed a significant change in the mean PANSS total score
from baseline to the end point in both, more recently and less
recently diagnosed schizophrenia subgroups. There was no
significant difference between these two further refined
subgroups.
In Study 2, a significant change in the mean PANSS total
score from baseline to the end point was observed, both for
the patients with more recently diagnosed and less recently
diagnosed schizophrenia. There was no statistical difference
between the two groups (Figure 1).
3.3. Secondary efficacy outcomes
3.3.1. PANSS responder rates
In Study 1, the percentage of responders in both, recently
diagnosed and chronic schizophrenia groups, increased at
each visit (Figure 2). The benefit was significantly greater for
the patients with recently diagnosed versus chronic schizo-
phrenia at the end point but was comparable between the
patients with more recently and less recently diagnosed schi-
zophrenia at all the time points evaluated.
In Study 2, a greater number of patients with more recently
diagnosed schizophrenia achieved responder status. However,
this benefit was not significantly different versus patients with
less recently diagnosed schizophrenia (Figure 2).
3.3.2. Change in CGI-S score from baseline to the end
point
In Study 1, the improvement in the mean CGI-S scores from
baseline to the end point was significant in patients with
recently diagnosed as well as those with chronic schizophrenia
(Table 2). Also, improvement was significantly greater in
patients with recently diagnosed schizophrenia compared to
EXPERT OPINION ON PHARMACOTHERAPY 5
those with chronic schizophrenia. The improvement was also
significant in both patients with more recently and less
recently diagnosed schizophrenia but remained similar
between the two subgroups.
In Study 2, the improvement in mean CGI-S score was
significant within each group. Further, the improvement was
significantly greater in patients with more recently diagnosed
versus those with less recently diagnosed schizophrenia
(Table 2).
3.3.3. CGI-S categorical summary
The CGI-S categorical scores showed improvement for all the
patients evaluated. Most of the patients had moderate to
severe disease at baseline. Compared to baseline, fewer
patients were found to be severely ill at the end point in
both studies (Figure 3). There was no significant difference in
the CGI-S categorical scores between the patients with
recently diagnosed versus chronic (Study 1, p = 0.0849), or
more recently versus less recently diagnosed schizophrenia
(Study 1, p = 0.2989; Study 2, p = 0.5176) in either study.
3.3.4. Meaningful change in PANSS (≥10 point reduction)
In Study 1, a significantly greater proportion of patients with
recently diagnosed schizophrenia had a ≥10 point reduction in
the PANSS scores compared to those with chronic schizophre-
nia at any time point during treatment. However, the sub-
group analysis of patients having their diagnosis made within
≤5 years revealed that though the proportion of patients
achieving ≥10 point reduction in PANSS scores was greater
in more recently versus less recently diagnosed schizophrenia,
the difference was not significant at the end point (Table 3).
In Study 2, the proportion of patients with meaningful
improvement in the PANSS score was greater in more recently
diagnosed versus less recently diagnosed group at any given
time point, but this did not differ significantly between the
two groups at the end point (Table 3).
3.3.5. PANSS symptom remission (Study 2)
At day 188, day 368, and day 548, a greater proportion of
patients achieved symptom remission in both more and less
recently diagnosed groups than those who failed to achieve
the remission. However, when compared between the groups,
the proportion of patients achieving symptom remission was
numerically greater in more recently diagnosed group than
 6 T. SI ET AL.

less recently diagnosed group, but this difference was not

n, number of patients; ap-value for within group difference are based on a paired t-test; bANCOVA model was used and p-value shown is between groups for change from baseline to end point in LS (least squares) mean score.
Less recently diagnosed

−0.83, −0.47; <.0001

significant (day 188: 183 out of 267 [68.54%] vs. 150 out of
240 [62.50%], p = 0.1527; day 368: 191 out of 267 [71.54%] vs.

(2–5 years)

3.4 (1.12)

2.7 (1.35)
−0.6 (1.40)
149 out of 240 [62.08%], p = 0.0238; and day 548: 185 out of

244

242
267 [69.29%] vs. 154 out of 240 [64.17%], p = 0.2212).

3.3.6. Safety outcomes

Study 2

0.0353
In Study 1, 61 out of 88 (69.3%) patients with recently diag-
nosed and 78 out of 124 (62.9%) patients with chronic schizo-
More recently diagnosed

−1.04, −0.73; <.0001

phrenia had at least one TEAE, while 7 out of 88 (8%) and 7
3.4 (1.10)

2.5 (1.22)
−0.9 (1.30)
out of 124 (5.6%) patients had at least one serious TEAE,
(≤2 years)

ANCOVA: analysis of covariance; CGI-S: Clinical Global Impression Severity; CI: confidence interval; ITT: intent-to-treat; LOCF: last observation carried forward; SD: standard deviation.
272

272 respectively. In all, 5 out of 88 (5.7%) patients with recently

diagnosed and 8 out of 124 (6.5%) patients with chronic
schizophrenia discontinued the study due to TEAEs. EPS-
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related AEs were reported by 18 out of 88 (20.5%) and 19

out of 124 (15.3%) patients with recently diagnosed and
chronic schizophrenia, respectively. Prolactin-related events
Less recently diagnosed

−2.09, −1.21; <.0001

were noted in 9 out of 88 (10.2%) of recently diagnosed

(2–5 years)

4.9 (0.73)

3.3 (1.22)
−1.6 (1.32)

patients and 20 out of 124 (16.1%) patients with chronic

38

37

schizophrenia. Glucose-related events were observed in

patients with chronic schizophrenia only (1 out of 124, 0.8%).
No deaths were reported in any of the groups.
In the recently diagnosed subgroup, 36 out of 50 (72%)
≤5 years

0.3877

patients with more recently diagnosed and 25 out of 38

More recently diagnosed

(65.8%) patients with less recently diagnosed schizophrenia

−2.30, −1.62; <.0001

had at least one TEAE; serious TEAEs were reported in 5 out

5.1 (0.68)

3.1 (1.10)
(≤2 years)

of 50 (10%) and 2 out of 38 (5.3%) patients, respectively.

−2 (1.19)
50

49

Treatment was discontinued due to TEAEs by 4 out of 50

(8%) patients with more recently diagnosed and 1 out of 38
(2.6%) patients with less recently diagnosed schizophrenia.
Study 1

EPS-related AEs occurred in 13 out of 50 (26%) and 5 out of

38 (13.2%) patients with more recently diagnosed and less
−1.39, −0.91; <.0001

recently diagnosed schizophrenia, respectively; while prolac-

tin-related events occurred in 5 out of 50 (10%) and 4 out of
4.8 (0.85)

3.7 (1.32)
−1.1 (1.32)
(>5 years)
Chronic

38 (10.5%) patients in each of these subgroups, respectively.

124

121
Table 2. Change in mean CGI-S score from baseline to end point (LOCF) in ITT population.

No glucose-related AEs were recorded in any subgroup.

In Study 2, 227 out of 273 (83.2%) patients with more
recently diagnosed schizophrenia and 201 out of 244 (82.4%)
Overall

0.0008

patients with less recently diagnosed schizophrenia reported

−2.09, −1.56; <.0001

at least one TEAE; 31 out of 273 (11.4%) and 44 out of 244

Recently diagnosed

(18%), respectively, had a serious TEAE. Two patients (2 out of

3.2 (1.15)
−1.8 (1.25)
(≤5 years)

5 (0.70)

273; 0.7%) died in more recently diagnosed subgroup – one

88

86

committed suicide and other died of pulmonary embolism.

Both deaths were considered unrelated to the study drug.
There were no deaths in less recently diagnosed subgroup.
Overall, 34 out of 273 (12.5%) patients with more recently
Change from baseline to end point, mean (SD)

diagnosed and 32 out of 244 (13.1%) patients with less

recently diagnosed schizophrenia discontinued the study due
to TEAEs. EPS-related AEs occurred in 97 out of 273 (35.5%)
and 66 out of 244 (27%) patients with more recently diag-
95% CI of mean change; p-valuea

nosed and less recently diagnosed schizophrenia, respectively.

While prolactin-related events were reported in 40 out of 273
p-Valueb between groups

(14.7%) patients with more recently diagnosed schizophrenia

and 22 out of 244 (9%) patients with less recently diagnosed
Mean score (SD)

Mean score (SD)

schizophrenia, glucose-related events occurred only in

patients with less recently diagnosed schizophrenia (3 out of
End point

244, 1.2%).
Baseline

TEAEs reported in ≥5% of patients in both studies are

n

summarized in Table 4.
 EXPERT OPINION ON PHARMACOTHERAPY 7
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Figure 3. CGI-S categorical proportion of patients by category at baseline and endpoint (LOCF) in Study 1 (3A) and Study 2 (3B) (ITT population).
CGI-S, Clinical Global Impression Severity; ITT, Intent-to-treat; LOCF, last observation carried forward

4. Discussion psychiatric illness were often more responsive to the treat-

ment [2,30,31].
These post-hoc analyses were conducted to compare the
Similar results were noted for other efficacy outcomes
efficacy and safety of PP1M in patients with recently (less
including PANSS responder rate, meaningful change in the
and more recently) diagnosed schizophrenia and chronic schi-
PANSS, and CGI-S scores, where patients with recently diag-
zophrenia from two previous multicenter studies [32,33]. The
nosed versus chronic schizophrenia achieved significantly
results demonstrated that PP1M is efficacious in treating not
greater benefit, along with a significant benefit within each
only chronic schizophrenia, but also potentially offers a similar
subgroup. As for PANSS total score, treatment benefit did not
to better efficacy in patients with recently diagnosed schizo-
differ between the patients with more recently and less
phrenia. Similar results have been noted previously [3].
recently diagnosed schizophrenia at end of study. In fact, no
The treatment benefit with PP1M in terms of reduction in
significant differences were observed between the patients
the PANSS total score from baseline to the end point was
with more recently (≤2 years) versus less recently diagnosed
significant in both, patients with recently diagnosed and
schizophrenia (2–5 years) for any parameter except for CGI-S
chronic schizophrenia, and the benefit was significantly
scores in Study 2. This indicates that the patients in the early
greater in the patients with recently diagnosed versus chronic
stages of schizophrenia, possibly within the first 5 years of
schizophrenia. The treatment benefit was however, compar-
diagnosis, are highly responsive to PP1M treatment, and this
able for all the patients with diagnosis made within 5 years, i.e.
efficacy is sustained during the chronic stage of schizophrenia.
more recent diagnosis (≤2 years) and less recent diagnosis (2–
However, since improvement in CGI-S score was significantly
5 years). The data add to the growing body of evidence
greater in patients with more recently diagnosed schizophre-
supporting the efficacy of PP1M in patients with recently
nia versus less recently diagnosed schizophrenia (Study 2
diagnosed schizophrenia [8,33,45–47]. These findings are also
only), there is a possibility that the current sample size did
aligned to the prior reports, where patients early in their
not yield enough power for other outcome variables in these
 8 T. SI ET AL.

post-hoc analyses. Also, impact of some unknown confoun-

All values are presented as n/N*100 (%), where n is the number of patients achieving the clinical significant improvement and N is total number of patients in the group at a particular time point; p-values for group difference
recently diagnosed
ders could not be ruled out in masking the difference between
the two groups and further studies are warranted. The data

128 (53.33)
162 (67.78)

139 (57.92)
101 (42.08)

140 (58.33)
100 (41.67)

112 (46.67)
(2–5 years)

77 (32.22)
add to the growing pool of evidence that supports recom-

240
239

240

240
mending LAIs for the treatment of recently diagnosed schizo-
phrenia (i.e. within 5 years of diagnosis), in addition to their
Less

therapeutic use in chronic schizophrenia [30,48].

0.5329
0.8130

0.1152

0.0449
Despite potential benefits, there is still a general reluc-
tance in the early introduction of LAIs in the treatment of
More recently diagnosed

schizophrenia [2], from patients’ as well as physicians’ per-

135 (50.56)
132 (49.44)
177 (66.79)

136 (50.94)
131 (49.06)

132 (49.44)
135 (50.56)
spective. While patients may not be comfortable with inject-
Study 2

(≤2 years)

88 (33.21)
265

267

267

267
able preparations owing to injection site pain, perceived
stigma, and higher treatment cost associated with LAIs
[49], physicians may be reluctant due to various reasons
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ranging from lack of explicit evidence for LAIs superiority

over oral antipsychotics in terms of efficacy and adherence
to practical issues in their use like invasive nature, dose
n (%)
n (%)

n (%)
n (%)

n (%)
n (%)

n (%)
n (%)
selection, pharmacokinetics, side effects associated with
Reduction <10,

Reduction <10,

Reduction <10,
Reduction ≥10,

Reduction <10,
Reduction ≥10,

Reduction ≥10,

Reduction ≥10,

LAIs, and lack of institutional structure and trained staff

Day 548, N
Day 188, N

Day 368, N

[50–54]. Nevertheless, considering results from the current

Day 38, N

p-Value

p-Value

p-Value

p-Value

study and available literature [55], LAIs could be considered

as an important and valuable treatment option to be insti-
tuted early in the course of the disease for patients with
schizophrenia.
Less recently diagnosed

The incidence of TEAEs/possibly drug-related TEAEs and

(2–5 years)

EPS-related AEs was higher in patients with recently diag-

31 (81.58)
27 (71.05)
11 (28.95)

19 (50.00)
19 (50.00)

29 (76.32)
9 (23.68)

7 (18.42)

nosed versus chronic schizophrenia, and also in patients

38

38

38

38

with more recently diagnosed versus less recently diag-

nosed schizophrenia. Fewer patients with recently diag-
nosed versus chronic schizophrenia discontinued from the
≤5 years

0.5744
0.4857

0.0875

0.3658

study, suggesting a better adherence with an early treat-

ITT: intent-to-treat; LOCF: last observation carried forward; PANSS: Positive and Negative Syndrome Scale.

ment by PP1M. This is consistent with the studies demon-

More recently diagnosed

strating increased treatment adherence with use of LAIs in

(≤2 years)

43 (86.00)
32 (64.00)
18 (36.00)

16 (32.00)
34 (68.00)

42 (84.00)

early stages of schizophrenia [2,8,50]. However, within the

8 (16.00)

7 (14.00)
50

50

50

50

recently diagnosed group, the incidence of treatment dis-

continuations was higher in patients with more recently
diagnosed schizophrenia compared to those with less
Study 1

are based on chi-square test or Fisher’s test when the cell counts are less than 5.

recently diagnosed schizophrenia in both the post-hoc

Table 3. Ten point improvement in PANSS total score (LOCF) in ITT populationa.

analyses.
There were few study limitations. The primary studies were
(>5 years)

36 (29.51)
86 (70.49)
99 (82.50)
21 (17.50)

69 (56.56)
53 (43.44)

40 (32.79)
82 (67.21)
Chronic

122
120

122

122

not designed to compare subgroups and hence there were no

power calculations for these post-hoc analyses and did not
consider the impact of other confounders. We also identified
unblinded treatment, lack of a comparator group in primary
Recently diagnosed (≤5 years)

studies, and short duration of Study 1 as limitations to study

Overall

0.0100

0.0164

0.0303

0.0224

design. Further, the data from two studies could not be

59 (67.05)
29 (32.95)

35 (39.77)
53 (60.23)

17 (19.32)
71 (80.68)

14 (15.91)
74 (84.09)

pooled since populations and assessment time points were

88

88

88

88

different in both the studies. Additionally, the severity of

patients also differed substantially in two studies. Also, better
improvement in patients with recently diagnosed schizophre-
nia could have been due to early stage of the disease, and
could also be attributed to PP1M treatment. However, we
could not evaluate this in the current analyses. Any compar-
<10, n (%)
≥10, n (%)

<10, n (%)
≥10, n (%)

<10, n (%)
≥10, n (%)

<10, n (%)
≥10, n (%)

isons between different interventions (e.g. oral antipsychotics

vs. LAI treatment) in patients with recently diagnosed schizo-
phrenia could not be made either. Additionally, there could be
Reduction
Reduction

Reduction
Reduction

Reduction
Reduction

Reduction
Reduction
Day 36, N

Day 92, N
Day 4, N

Day 8, N

a possible bias due to adherence, which is generally high in

p-Value
p-Value

p-Value

p-Value

the controlled clinical trials, while this could vary largely in a

real-world scenario.
a
 EXPERT OPINION ON PHARMACOTHERAPY 9

Table 4. Treatment-emergent adverse events (ITT population).

Study 1 Study 2
Recently More recently Less recently More recently Less recently
diagnosed Chronic diagnosed diagnosed diagnosed diagnosed
(≤5 years) (>5 years) (≤2 years) (2–5 years) (≤2 years) (2–5 years)
N = 88 N = 124 N = 50 N = 38 N = 273 N = 244
Possibly drug-related TEAEs, n (%)a 41 (46.6) 53 (42.7) 24 (48) 17 (44.7) 188 (68.9) 161 (66)
Probably drug-related serious TEAEs, 1 (1.1) 3 (2.4) 1 (2) 0 17 (6.2) 24 (9.8)
n (%)a
Number of TEAEs, n (%)b 54 (61.4) 63 (50.8) 36 (72) 25 (65.8) 208 (76.2) 179 (73.4)
TEAEs in ≥5% of patients, n (%)
Injection site pain 2 (2.3) 7 (5.6) - 2 (5.3) 49 (17.9) 48 (19.7)
Akathisia 3 (3.4) 7 (5.6) - - 42 (15.4) 28 (11.5)
Blood prolactin increased 5 (5.7) 13 (10.5) 2 (4) 3 (7.9) - -
Diarrhea 5 (5.7) - 2 (4) 3 (7.9) - -
Insomnia 6 (6.8) 11 (8.9) 3 (6) 3 (7.9) 43 (15.8) 36 (14.8)
Tremor 6 (6.8) 5 (4) 3 (6) 3 (7.9) 19 (7) 14 (5.7)
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Upper respiratory tract infection 8 (9.1) - 3 (6) 5 (13.2) 25 (9.2) 21 (8.6)

Weight increased 7 (8) 9 (7.3) 4 (8) 3 (7.9) 24 (8.8) 15 (6.1)
Constipation 7 (8) 12 (9.7) 5 (10) 2 (5.3) - -
Nasopharyngitis 13 (14.8) 5 (4) 8 (16) 5 (13.2) - -
Injection site erythema - - - 2 (5.3) - -
Dyspepsia - - - 2 (5.3) - -
Agitation - - 1 (2) 2 (5.3) - -
Headache - - 1 (2) 2 (5.3) 29 (10.6) 30 (12.3)
Anxiety - - 2 (4) 2 (5.3) 15 (5.5) 14 (5.7)
Extrapyramidal disorder - - 3 (6) - - -
Hepatic function abnormal - - 3 (6) 1 (2.6) - -
Hyperprolactinemia - - 3 (6) - - -
Rash - - 3 (6) - - -
Sinus bradycardia - - 3 (6) 1 (2.6) - -
Vision blurred - - 3 (6) - - -
Parkinsonism - - 4 (8) - - -
Schizophrenia - - - - 12 (4.4) 21 (8.6)
Dizziness - - - - 20 (7.3) 17 (7)
Somnolence - - - - 17 (6.2) 10 (4.1)
Nausea - - - - 18 (6.6) 16 (6.6)
Psychotic disorder - - - - 17 (6.2) 25 (10.2)
Restlessness - - - - 19 (7) 7 (2.9)
Abnormal weight gain - - - - 30 (11) 21 (8.6)
N: total number of patients; n: number of patients experiencing specific TEAE; aTEAEs in overall population (study drug relationship of possible, probable, and very
likely were included in this category); btotal number of TEAEs in at least 2% patients.
ITT: intent-to-treat; TEAEs: treatment-emergent adverse event.

5. Conclusion Declaration of interest

In conclusion, PP1M significantly improved symptoms in
patients with schizophrenia. This was evident in both patients
with recently diagnosed and chronic schizophrenia with a
more pronounced effect in patients in early stages of their
illness. The results of these post-hoc analyses further supports
the use of antipsychotic intervention in the initial years of
schizophrenia, an approach that is increasingly being accepted
as a basic and critical tenet for improving the disease course
and outcome(s).
Acknowledgments
T Si has been a consultant and/or advisor to or has received honoraria
and grant from Xian, Janssen, Pfizer, Lundbeck and Otsuka. Y Feng is
an employee of Janssen Pharmaceutical Companies of Johnson and
Johnson, Singapore. J Zhuo is an employee of Janssen Research &
Development, Shanghai, People’s Republic of China. I Turkoz is an
employee of Janssen Research & Development, Titusville, NJ, USA. M
Mathews is an employee of Janssen Research & Development, Titusville,
NJ, USA. W Tan is an employee of Janssen Pharmaceutical Companies
of Johnson and Johnson, Singapore. Writing assistance, provided by
Ramandeep Singh, Tata Consultancy Services, was utilized in the pro-
duction of this manuscript and funded by Janssen Asia Pacific. The
authors have no other relevant affiliations or financial involvement with
any organization or entity with a financial interest in or financial con-
flict with the subject matter or materials discussed in the manuscript
apart from those disclosed.

The authors thank Dr. Ellen Baum (Janssen Research and Development,
LLC) for additional editorial assistance in the preparation of this
manuscript.
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