ORIGINAL RESEARCH Evaluation of a New Formulation of Epoprostenol Sodium in Japanese Patients with Pulmonary Arterial Hypertension (EPITOME4) Yuichi Tamura • Tomohiko Ono • Keiichi Fukuda • Toru Satoh • Shigetake Sasayama To view enhanced content go to www.advancesintherapy.com Received: April 5, 2013 / Published online: May 8, 2013 Ó The Author(s) 2013. This article is published with open access at Springerlink.com ABSTRACT Introduction: Pulmonary arterial hypertension (PAH) is associated with poor prognosis despite significant recent advances in its treatment. An intravenous formulation of epoprostenol sodium containing glycine and mannitol (epoprostenol GM; GlaxoSmithKline, London, UK) is widely used to treat PAH. A new formulation of epoprostenol sodium containing arginine and sucrose excipients (epoprostenol AS; Actelion Pharmaceuticals Japan Ltd., Tokyo, Japan) shows better stability at room temperature after preparing diluted solutions. The primary objective of this study was to evaluate the safety and tolerability of switching from epoprostenol GM to epoprostenol AS in Japanese patients with PAH. The authors also evaluated the efficacy and treatment satisfaction after switching formulations. Methods: This was a two-site, open-label, single-arm, Phase 3b study. Eight adult Japanese PAH patients (seven females) treated with a stable dose of epoprostenol GM for C30 days were switched to epoprostenol AS and followed for 12 weeks. Outcomes included safety, changes from baseline to 12 weeks in pulmonary hemodynamic factors (pulmonary vascular resistance, mean pulmonary arterial pressure, and cardiac output), and treatment satisfaction, assessed using the Treatment Satisfaction Questionnaire for Medication (TSQM-9). Results: The mean (range) age and time since diagnosis of PAH were 48 (25–69) years and 6.2 (0.6–13.9) years, respectively. There were no Electronic supplementary material The online version of this article (doi:10.1007/s12325-013-0029-0) contains supplementary material, which is available to authorized users. Y. Tamura (&) Á T. Ono Á K. Fukuda Department of Cardiology, Keio University School of Medicine, 35 Shinanomachi Shinjuku-ku, Tokyo, Japan e-mail: [email protected]T. Satoh Department of Cardiology, Kyorin University School of Medicine, Tokyo, Japan S. Sasayama Kyoto University, Kyoto, Japan Enhanced content for Advances in Therapy articles is available on the journal web site: www.advancesintherapy.com 123 Adv Ther (2013) 30:459–471 DOI 10.1007/s12325-013-0029-0
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ORIGINAL RESEARCH
Evaluation of a New Formulation of EpoprostenolSodium in Japanese Patients with PulmonaryArterial Hypertension (EPITOME4)
Yuichi Tamura • Tomohiko Ono • Keiichi Fukuda •
Toru Satoh • Shigetake Sasayama
To view enhanced content go to www.advancesintherapy.comReceived: April 5, 2013 / Published online: May 8, 2013� The Author(s) 2013. This article is published with open access at Springerlink.com
ABSTRACT
Introduction: Pulmonary arterial hypertension
(PAH) is associated with poor prognosis despite
significant recent advances in its treatment. An
intravenous formulation of epoprostenol
sodium containing glycine and mannitol
(epoprostenol GM; GlaxoSmithKline, London,
UK) is widely used to treat PAH. A new
formulation of epoprostenol sodium
containing arginine and sucrose excipients
(epoprostenol AS; Actelion Pharmaceuticals
Japan Ltd., Tokyo, Japan) shows better stability
at room temperature after preparing diluted
solutions. The primary objective of this study
was to evaluate the safety and tolerability of
switching from epoprostenol GM to
epoprostenol AS in Japanese patients with
PAH. The authors also evaluated the efficacy
and treatment satisfaction after switching
formulations.
Methods: This was a two-site, open-label,
single-arm, Phase 3b study. Eight adult
Japanese PAH patients (seven females) treated
with a stable dose of epoprostenol GM
for C30 days were switched to epoprostenol AS
and followed for 12 weeks. Outcomes included
safety, changes from baseline to 12 weeks in
pulmonary hemodynamic factors (pulmonary
vascular resistance, mean pulmonary arterial
pressure, and cardiac output), and treatment
satisfaction, assessed using the Treatment
Satisfaction Questionnaire for Medication
(TSQM-9).
Results: The mean (range) age and time since
diagnosis of PAH were 48 (25–69) years and 6.2
(0.6–13.9) years, respectively. There were no
Electronic supplementary material The onlineversion of this article (doi:10.1007/s12325-013-0029-0)contains supplementary material, which is available toauthorized users.
Y. Tamura (&) � T. Ono � K. FukudaDepartment of Cardiology, Keio UniversitySchool of Medicine, 35 Shinanomachi Shinjuku-ku,Tokyo, Japane-mail: [email protected]
T. SatohDepartment of Cardiology, Kyorin UniversitySchool of Medicine, Tokyo, Japan
following a disaster, it is likely that frozen gel
packs would not be available, which may be a
life-threatening issue for patients with PAH. The
authors speculate that epoprostenol AS, which
is stable for a longer time at room temperature
than the GM formulation, could be valuable for
continuing medical treatment during
emergencies, and may have a positive impact
on the quality of medical care, although
additional examination of epoprostenol AS use
is required in situations where the temperature
exceeds 30 �C. Further studies are needed to
evaluate the impact of higher environmental
temperatures on the safety/tolerability and
efficacy of this formulation, and to accumulate
evidence supporting its clinical use.
Some limitations of this study warrant
mention. Firstly, the sample size was small,
which may prevent detection of small
differences in hemodynamic factors or
infrequent adverse events. Secondly, as the study
was conducted inanopen-labelmannerwithouta
control group (e.g., of patients continuing
epoprostenol GM during the 12-week treatment
phase), it is possible that a study effect or patient
bias contributed to the observed improvements in
treatment satisfaction.
CONCLUSION
In conclusion, the present study showed that
switching to a new formulation of epoprostenol
was associated with an improvement in
convenience in relation to treatment
satisfaction, without unexpected adverse
Table 5 Changes in WHO FC from baseline to week 12
WHO FC
Baseline Week 12
I II III IV
N N [N] [N] [N] [N]
8 I 1 1 – – –
II 5 – 5 – –
III 2 – – 2 –
IV 0 – – – 0
FC functional class, WHO World Health Organization
Fig. 1 NT-proBNP concentration measured at baselineand at week 12. P = 0.5781 at the 5% level (Wilcoxonsigned rank sum test) NT-proBNP N-terminal prohor-mone of brain natriuretic peptide
Adv Ther (2013) 30:459–471 469
123
events or deteriorations in pulmonary
hemodynamic factors. Prospective studies in a
larger group of patients are needed to confirm
the safety of this formulation in long-term
clinical use. Epoprostenol AS was approved in
February 2013 in Japan as a generic drug with
the same potency and effectiveness as the
originally approved drug, epoprostenol GM. As
intravenous epoprostenol sodium therapy may
result in high medical costs, the introduction of
cheaper generic drugs may help to reduce
medical expenditure for treating PAH.
ACKNOWLEDGMENTS
The study and article processing charges were
funded and supported by Actelion
Pharmaceuticals Japan Ltd. The authors would
like to thank Nicholas D. Smith, PhD, an
employee of Edanz, for editorial support in the
preparation of this manuscript, which was
funded by Actelion Pharmaceuticals Japan Ltd.
Dr Yuichi Tamura is the guarantor for this
article, and takes responsibility for the integrity
of the work as a whole.
Conflict of interest. Yuichi Tamura declares
no conflict of interest. Tomohiko Ono declares
no conflict of interest. Keiichi Fukuda declares
no conflict of interest. Toru Satoh declares no
conflict of interest. Shigetake Sasayama declares
no conflict of interest.
Compliance with Ethics Guidelines. All
procedures followed were in accordance with
the ethical standards of the responsible
committee on human experimentation
(institutional and national) and with the
Helsinki Declaration of 1975, as revised in
2000. Informed consent was obtained from all
patients included in the study.Tab
le6
Cha
nges
intr
eatm
ent
sati
sfac
tion
from
base
line
to12
wee
ksaf
ter
swit
chin
gep
opro
sten
olfo
rmul
atio
ns
TSQ
M-9
dom
ain
Bas
elin
e(n
58)
12w
eeks
ofad
min
istr
atio
n(n
58)
Act
ual
scal
eA
ctua
lsc
ale
Cha
nges
from
base
line
Mea
n–
SDM
edia
n[M
in,
Max
]M
ean
–SD
Med
ian
[Min
,M
ax]
Mea
n–
SDM
edia
n[M
in,
Max
]P
valu
ea
Eff
ecti
vene
ss56
.25
±7.
5558
.4[4
4.4,
66.7
]58
.31
±14
.55
61.1
[33.
3,72
.2]
2.06
±10
.68
0.0
[-11
.1,2
2.2]
0.90
63
Con
veni
ence
51.4
0±
10.1
955
.6[3
3.3,
61.1
]58
.33
±12
.96
61.1
[33.
3,72
.2]
6.93
±5.
735.
6[0
.0,1
6.6]
0.03
13
Glo
bal
sati
sfac
tion
54.0
1±
31.3
060
.5[-
8.3,
91.7
]54
.19
±25
.94
52.8
[22.
2,93
.1]
0.18
±23
.09
1.4
[-40
.2,3
0.5]
0.71
88
SDst
anda
rdde
viat
ion,
TSQ
M-9
Tre
atm
ent
Sati
sfac
tion
Que
stio
nnai
refo
rM
edic
atio
na
Pva
lue
base
dup
onW
ilcox
onsi
gned
rank
sum
test
470 Adv Ther (2013) 30:459–471
123
Open Access. This article is distributed
under the terms of the Creative Commons
Attribution Noncommercial License which
permits any noncommercial use, distribution,
and reproduction in any medium, provided the
original author(s) and the source are credited.
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