Effects of intravenous immunoglobulin therapy in Japanese patients with polymyositis and dermatomyositis resistant to corticosteroids: a randomized double-blind placebo-controlled trial.

Abstract

High-dose intravenous immunoglobulin (IVIG) therapy has been effective in treating various autoimmune and systemic inflammatory diseases. Here, we assessed the efficacy and safety of IVIG therapy with polyethylene glycol-treated human IgG (drug code GB-0998) for patients with corticosteroid-refractory polymyositis (PM) and dermatomyositis (DM) by means of a randomized, double-blind, placebo-controlled study. We randomly assigned 26 subjects (16 PM and 10 DM) to receive either GB-0998 or placebo. Intragroup comparison in the GB-0998 group showed statistically significant improvements due to GB-0998 administration in the primary endpoint (manual muscle test score) and secondary endpoints (serum creatine kinase level and activities of daily living score). However, significant improvements were also found in the placebo group, and comparison of the GB-0998 group with the placebo group did not show any significant difference between the groups. We discuss possible reasons for the absence of a clear intergroup difference in efficacy. Nineteen adverse drug reactions were observed in 11 of 26 subjects (42.3%), of which 2 events (decreased muscle strength and increased serum creatine kinase) were assessed as serious; however, they are previously known events. These results indicate that GB-0998 can be safely used with the same precautions as other current IVIG therapy.

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ORIGINAL ARTICLE
Effects of intravenous immunoglobulin therapy in Japanese
patients with polymyositis and dermatomyositis resistant
to corticosteroids: a randomized double-blind placebo-controlled
trial
Nobuyuki Miyasaka•Masako Hara•Takao Koike•
Eizo Saito•Masahito Yamada•Yoshiya Tanaka•
Additional Members of the GB-0998 Study Group
Received: 13 July 2011/Accepted: 5 September 2011/Published online: 5 October 2011
? Japan College of Rheumatology 2011
Abstract
therapy has been effective in treating various autoimmune
and systemic inflammatory diseases. Here, we assessed the
efficacy and safety of IVIG therapy with polyethylene gly-
col-treated human IgG (drug code GB-0998) for patients
with corticosteroid-refractory polymyositis (PM) and der-
matomyositis (DM) by means of a randomized, double-
blind, placebo-controlled study. We randomly assigned 26
subjects (16 PM and 10 DM) to receive either GB-0998
or placebo. Intragroup comparison in the GB-0998
High-dose intravenous immunoglobulin (IVIG)
group showed statistically significant improvements due to
GB-0998 administration in the primary endpoint (manual
muscle test score) and secondary endpoints (serum creatine
kinase level and activities of daily living score). However,
significant improvements were also found in the placebo
group, and comparison of the GB-0998 group with the pla-
cebo group did not show any significant difference between
the groups. We discuss possible reasons for the absence of a
clear intergroup difference in efficacy. Nineteen adverse
drugreactionswereobservedin11of26subjects(42.3%),of
which 2 events (decreased muscle strength and increased
serum creatine kinase) were assessed as serious; however,
theyarepreviouslyknownevents.Theseresultsindicatethat
GB-0998 can be safely used with the same precautions as
other current IVIG therapy.
Keywords
muscle test (MMT) ? Polymyositis (PM) ? Dermatomyositis
(DM) ? Randomized, double-blind, placebo-controlled
study
Intravenous immunoglobulin (IVIG) ? Manual
Introduction
Polymyositis (PM) and dermatomyositis (DM) are diffuse
inflammatory myopathies of unknown etiology, causing
decreased strength in the limb proximal group muscles,
cervical muscles, and pharyngeal muscles, and have been
designated as targets for disease treatment research by the
Japanese Ministry of Health, Labor, and Welfare. Oral
corticosteroids are the first-line treatment for patients with
PM and DM, and they produce good response in approxi-
mately 80% of patients [1]. For patients showing either no
response or incomplete response, other therapies such as
methylprednisolone pulse therapy and/or concomitant
N. Miyasaka (&)
Department of Medicine and Rheumatology, Graduate School,
Tokyo Medical and Dental University, 1-5-45 Yushima,
Bunkyo-ku, Tokyo 113-8519, Japan
e-mail: miya.rheu@tmd.ac.jp
M. Hara
Institute of Rheumatology, Tokyo Women’s Medical University,
10-22 Kawadacho, Shinjuku-ku, Tokyo 162-0054, Japan
T. Koike
Department of Medicine II, Graduate School of Medicine,
Hokkaido University, N15W7 Kita-ku, Sapporo 060-8638, Japan
E. Saito
Fourth Department of Internal Medicine, Toho University
School of Medicine, 2-17-6 Ohashi, Meguro-ku,
Tokyo 153-8515, Japan
M. Yamada
Department of Neurology and Neurobiology of Aging,
Kanazawa University Graduate School of Medical Science,
13-1 Takara-machi, Kanazawa 920-8641, Japan
Y. Tanaka
First Department of Internal Medicine, School of Medicine,
University of Occupational and Environmental Health, Japan,
1-1 Iseigaoka, Yahatanishi-ku, Kitakyushu 807-8555, Japan
123
Mod Rheumatol (2012) 22:382–393
DOI 10.1007/s10165-011-0534-4

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immunosuppressive drug therapy are empirically used, but
are not always effective [2]. In addition, long-term and/
or high-dose administration of corticosteroids and/or
immunosuppressive drugs may cause severe side-effects,
such as infection, and therefore new therapies are
required.
Here, we present the results of a double-blind, placebo-
controlled, crossover study designed to evaluate the efficacy
and safety of polyethylene glycol-treated human IgG (GB-
0998) in patients with corticosteroid-resistant PM or DM.
Patients and methods
Study design
This randomized, double-blind, placebo-controlled, cross-
over trial was performed in 47 medical institutions in
Japan. The study protocol was approved by the Institutional
Review Board of each participating institution, and the
trial was carried out in accordance with the Declaration
of Helsinki and Good Clinical Practice. Patients gave
written informed consent prior to registration for this study.
This trial is registered with ClinicalTrials.gov, number
NCT00335985.
The trial began with a 6-week run-in period, during
which corticosteroid resistance was confirmed. Patients
who had given informed consent, and had been confirmed
to be resistant to corticosteroid treatment during the run-in
period, were randomly allocated to receive GB-0998
(Benesis Corporation, Osaka, Japan), a polyethylene gly-
col-treated human normal immunoglobulin, followed by an
indistinguishable placebo (GB-0998 group), or the same
two treatments in the reverse order (placebo group), as
shown in Fig. 1. GB-0998 at a dose of 400 mg (8 mL)/kg/
day or the placebo was administered by intravenous infu-
sion once daily for 5 consecutive days, in a double-blind
manner. After an assessment duration of 8 weeks from the
start of administration (the first period), subjects receiving
the active drug were switched to receive the placebo in the
second period, whereas those receiving the placebo in
the first period were switched to receive the active drug in
the second period. The assessment duration in the second
period was 8 weeks, and there was an additional 4-week
observation period (follow-up period) after the second
period. Because of the seriousness of the disease, the sec-
ond period was included in the study design to enable all
subjects in the study to receive GB-0998. For ethical rea-
sons, patients who did not show disease alleviation within
4 weeks after the start of the first period, rendering con-
tinuation of the study difficult, were given an early tran-
sition to the second period; i.e., these subjects were
transferred to the second period without continuing in the
first period for the full 8 weeks. For this reason, the pri-
mary evaluation was of efficacy in the first period.
Increases in corticosteroid and immunosuppressant
doses, including methylprednisolone pulse therapy, were
not allowed during the period from acquisition of informed
consent until completion or termination of the study.
Decreases in the dose were allowed when side-effects were
elicited by corticosteroid or immunosuppressant during the
period prior to the start of test drug administration, and
were also allowed depending on the patients’ medical
condition following the administration of the test drug.
Patients
Patients with corticosteroid-resistant PM/DM (Japanese
people, resident in Japan) who were aged 16–75 years and
fulfilled the diagnostic criteria of Bohan and Peter [3] for
‘‘definite’’ PM/DM were considered eligible to participate
in this study. Among them, those that met one of the
following criteria with respect to their history of cortico-
steroid therapy were enrolled for this study after obtaining
their informed consent:
1. Had
(C50 mg/day or C1 mg/kg/day for 1 month or more),
startingbetween6 weeksand1 yearpriortoacquisition
of informed consent, and continued until the day of
acquisition of informed consent.
In receipt of C50 mg/day or C1 mg/kg/day of cortico-
steroids on the day of acquisition of informed consent.
Hadreceivedtwo or
pulse therapies within 6 weeks before the acquisition
of informed consent, and receiving C30 mg/day or
C0.6 mg/kg/day of corticosteroid on the day of
acquisition of informed consent.
receivedhigh-dose corticosteroid therapy
2.
3.moremethylprednisolone
Patients with manual muscle test (MMT) scores of B80
points (normal score 90 points), assessed after having
obtained their informed consent, and with twice the stan-
dard upper limit value of serum creatine kinase (CK) or
more were tentatively enrolled, and followed for 6 weeks
(run-in period). The patients who did not show any
Fig. 1 Outline of study design. GB-0998 (active drug) was admin-
istered to the GB-0998 group in the first period and to the placebo
group in the second period. Differences between before and after the
8-week first period in the GB-0998 group were assessed in the
primary analysis
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improvement in MMT scores and serum CK levels during
these 6 weeks were formally registered, and received the
investigational drug.
Patients excluded from participation in this study were
those with malignant tumors; acute interstitial pneumonia
including acute exacerbation of chronic phase; severe mus-
cular atrophy for a long period; severe infectious disease;
severehepaticdisorderorsevererenaldisorder;thosewhohad
aprevioushistoryofshockorhypersensitivitytothetestdrug;
those who had a history of cerebral infarction or ischemic
heart disease, or had symptom of these diseases; those who
hadahistoryofIgAdeficiencydiagnosed;pregnant,lactating,
and possibly pregnant patients; patients who wanted to
become pregnant; and those who had been administered
immunoglobulin within 6 weeks of obtaining consent.
Efficacy assessment
Since muscle weakness is the most common symptom of
PM/DM, changes in MMT scores were used as the primary
endpoint, because the therapeutic effect could be assessed
by observing the degree to which muscular strength was
restored. MMT was scored on the following 18 muscles:
the right and left of each of the following: deltoid, biceps
brachii, brachioradialis, triceps brachii, iliopsoas, gluteus
maximus, quadriceps femoris, and hamstring muscle; and
the flexor and extensor muscles of the neck area. Each
muscle was scored 0–5, with a healthy state thus being a
score of 90 [4, 5]. In order to achieve consistency of
evaluation, in principle, a single assessor evaluated the
MMT for all patients throughout the study.
The secondary efficacy endpoints were serum CK level
and the activities of daily living (ADL) score. Serum CK
measurements and other clinical laboratory tests were
carried out at a central laboratory, at Mitsubishi Chemical
Medience Corporation (Tokyo, Japan). The upper limits of
the normal serum CK range were taken as 270 and 150 IU/
L for males and females, respectively. The ADL score was
based on the following 15 actions, with each action being
scored 0–3, and the normal total score being 45: raising
arms, taking off outer clothes, turning on water tap,
combing hair, fastening buttons, getting out of bed, lifting
up feet, standing up from chair, climbing stairs, walking on
flat surface, turning over in bed, holding up head, sitting
down on bed, having conversation, and swallowing [4, 5].
In addition to the above endpoints, we considered the
time (number of days) to discharge from hospital during
the first period. Furthermore, two additional parameters
evaluated were dysphagia, which was graded as none, mild,
or severe by each attending physician, and the occurrence
or nonoccurrence of early transition to the second period.
The safety endpoint was the occurrence or nonoccur-
rence of adverse events.
Target number of subjects
The number of patients meeting the criteria for inclusion in
this study is very small. It was therefore considered that,
with a study duration of 3 years, the number of subjects
who could be enrolled would be limited to 20. Therefore,
from the viewpoint of the feasibility of carrying out the
study, the target number of subjects was set at 10 per group
(a total of 20 subjects).
Statistical analysis
As described above, the number of target patients for this
studywasverysmall,anditwasnotpracticallypossibletoset
the target number of subjects sufficiently high to permit a
clear demonstration of the superiority of GB-0998 over
placebo. Therefore, the primary analysis consisted of an in-
tragroupcomparison inthe GB-0998group,usingthe paired
t test, of changes in MMT score, serum CK level, and ADL
score between before initiation of study drug administration
and after administration for 8 weeks in the first period.
An intergroup comparison between the GB-0998 and
placebo groups was also carried out as a subsidiary anal-
ysis. For this analysis, descriptive statistics were calculated
separately for the two groups, with respect to the changes
in MMT score, serum CK level, and ADL score between
before initiation of administration during the first period
and after administration for 8 weeks. The serum CK levels
were widely scattered, depending upon the severity of
disease in each subject, and logarithmic transformation was
therefore carried out for efficacy evaluation in relation to
change in serum CK level. Then, using the mean changes
in these parameters, the point-estimation value and 95%
confidence interval were calculated for the difference
between the GB-0998 and placebo groups.
In addition, the Kaplan–Meier method was used to
compare the time (number of days) until improvement of
the MMT score in the GB-0998 and placebo groups. On the
basis of a report by Dalakas et al. [6], the time at which
‘‘improvement’’ was taken to have occurred was the first
time point when the MMT score was increased by 5 or
more (and subsequently maintained at the higher level)
during the period from before initiation of administration
during the first period until transition to the second period.
The median value of the time was calculated for each
group, and the log-rank test was applied.
For the serum CK level, the Kaplan–Meier method was
used to compare the time (number of days) until normali-
zation in the GB-0998 and placebo groups. The event taken
to constitute ‘‘normalization’’ was the serum CK reaching a
level below the upper limit of the normal range for the first
time during the period from before initiation of adminis-
tration during the first period until transition to the second
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period. The median values for the groups were calculated,
and the generalized Wilcoxon test was applied.
With respect to parameters other than the primary and
secondary endpoints, the Kaplan–Meier method was used
to compare the time (number of days) until first discharge
from hospital during the first period. The median value was
calculated for each of the groups.
Several supplementary analyses were also carried out, as
follows. For MMT score, the percentage of subjects
showing improvement was calculated for each group. In
addition, for each of the individual muscles evaluated, an
intergroup comparison using the paired t test was carried
out for the change during the first period. For ADL score,
the paired t test was used for intergroup comparison of the
change in each evaluated individual action during the first
period. In addition, the change in dysphagia during the first
period was calculated, and the Fisher direct probability test
was used for intergroup comparison of the elimination or
nonelimination of dysphagia. Numbers of subjects under-
going early transition to the second period were also
compared in the two groups.
Efficacy was assessed using the last observation carried
forward (LOCF) approach at 8 weeks after the start of
administration in the first period, when premature discon-
tinuation occurred in the first 8-week period, or when the
second period was started before the scheduled end of the
first period. Similarly, when premature discontinuation
occurred in the second 8-week period, the efficacy after
8 weeks for the second period was assessed using the
LOCF approach.
Results
Background of subjects
Of 63 subjects who gave informed consent to participate in
the study, corticosteroid resistance was confirmed in 26 (12
in the GB-0998 group and 14 in the placebo group). Study
drug administration and evaluation of safety and efficacy
were carried out with these subjects (Fig. 2).
Table 1 presents the backgrounds of these subjects,
separately for each of the two groups. In the GB-0998 group
there were 6 subjects with PM and 6 with DM, while in the
placebo group, there were 10 with PM and 4 with DM.
Results of principal analyses: intragroup comparison
during the first period
With respect to the principal analyses of the primary and
secondary endpoints, Table 2 presents the changes in effi-
cacy endpoints between before initiation of study drug
administration, and after administration for 8 weeks during
the first period.
The MMT score was the primary endpoint, and the
mean (±standard deviation, SD) of the change in this score
in the GB-0998 group during the first period was
11.8 ± 8.0, this change being statistically significant
according to the paired t test (p = 0.0004). In terms of
classification by disease type, the mean scores in subjects
with PM and DM were 12.2 ± 11.0 and 11.3 ± 4.5,
respectively; thus, no marked difference was found
between PM and DM subjects.
Serum CK level and the ADL score were the secondary
endpoints. The mean (±SD) of the change in serum CK
level was -1.1633 ± 1.4123 Ln (IU/L) (paired t test,
p = 0.0157), and the mean (±SD) of the change in the
ADL score was 7.3 ± 6.6 (paired t test, p = 0.0029). The
changes in both these parameters were statistically
significant.
Statistically significant increases during the first period
were also found in the intragroup comparison in the
placebo group. The mean change in MMT score was
9.9 ± 8.3 (paired t test, p = 0.0007), the mean change in
serum CK level was -1.2662 ± 0.8900 Ln (IU/L) (paired
t test, p = 0.0001), and the mean change in ADL score was
4.0 ± 5.8 (paired t test, p = 0.0237).
Results of subsidiary analyses: intergroup analyses
Changes during the first period
The results for intergroup comparison of MMT score,
serum CK level, and ADL score during the first period are
presented in Table 2.
Fig. 2 Flow diagram of patients participating in this trial. In this
study, a total of 26 subjects received GB-0998. Asterisk Premature
discontinuation occurred after the sixth week of the first period
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Table 1 Patients’ characteristics
CharacteristicGB-0998 group (n = 12) Placebo group (n = 14) Total (n = 26)
Gender, n (%)
Male 1 (8.3)5 (35.7)6 (23.1)
Female11 (91.7) 9 (64.3)20 (76.9)
Age (years)
Mean 50.648.1 49.3
Standard deviation13.1 12.112.4
Minimum value 273027
Median 49.050.5 49.0
Maximum value 6968 69
Diagnosis, cases (%)
Polymyositis 6 (50.0)10 (71.4)16 (61.5)
Dermatomyositis 6 (50.0) 4 (28.6) 10 (38.5)
Disease period, cases (%)
\6 months
C6 months and\1 year
C1 year
5 (41.7) 3 (21.4)8 (30.8)
0 (0.0) 4 (28.6) 4 (15.4)
7 (58.3)7 (50.0) 14 (53.8)
Interstitial pulmonary disease, cases (%)
Absence 6 (50.0) 11 (78.6)17 (65.4)
Presence 6 (50.0)3 (21.4)9 (34.6)
Daily dose of corticosteroid at formal registration (mg)
Mean34.79 40.7137.98
Standard deviation14.56 14.6914.65
Minimum value10 7.5 7.5
Median35.0047.50 42.50
Maximum value 605560
Therapeutic history with immunosuppressant, cases (%)
Absence 5 (41.7)7 (50.0)12 (46.2)
Presence7 (58.3) 7 (50.0)14 (53.8)
Manual muscle test score at formal registration (points)
0–50213
51–60437
61–7048 12
71–80224
Mean ± SD 61.8 ± 10.664.7 ± 9.0–
Minimum value 424342
Maximum value777777
Activities of daily living score at formal registration (points)
0–15325
16–20314
21–25011
26–30202
31–35257
36–40235
41–45022
Not done000
Mean ± SD (points)23.8 ± 11.130.2 ± 10.3–
Minimum value4 114
Maximum value 40 45 45
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