Treatment of acute cerebral infarction with a choline precursor in... double-blind placebo-controlled study.

Treatment of acute cerebral infarction with a choline precursor in a multicenter
double-blind placebo-controlled study.
Y Tazaki, F Sakai, E Otomo, T Kutsuzawa, M Kameyama, T Omae, M Fujishima and A Sakuma
Stroke. 1988;19:211-216
doi: 10.1161/01.STR.19.2.211
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211
Treatment of Acute Cerebral Infarction With a
Choline Precursor in a Multicenter
Double-Blind Placebo-Controlled Study
Yoshiaki Tazaki, MD, Fumihiko Sakai, MD, Eiichi Otomo, MD, Takashi Kutsuzawa, MD,
Masakuni Kameyama, MD, Teruo Omae, MD, Masatoshi Fujishima, MD,
and Akira Sakuma, PhD
A multicenter double-blind placebo-controlled study of cytidine 5'-diphosphocholine (CDP-choline)
was conducted to evaluate possible clinical benefits of the drug in patients with acute, moderate to
severe cerebral infarction. The patients included also suffered from moderate to mild disturbances
of consciousness, and all were admitted within 14 days of the ictus. Patients were allocated randomly
to treatment with either CDP-choline (1,000 mg/day i.v. once daily for 14 days) or with placebo
(physiological saline). One hundred thirty-three patients received CDP-choline treatment, and 139
received placebo. The group treated with CDP-choline showed significant improvements in level of
consciousness compared with the placebo-treated group, and CDP-choline was an entirely safe
treatment. (Stroke 1988; 19:211-216)
C
ytidine 5'-diphosphocholine (CDP-choline,
Nicholin, Takeda Chemical Industries, Ltd.,
Osaka, Japan) is a precursor essential for the
synthesis of phosphatidylcholine, one of the major
structural components of cell membranes that become
degraded to highly toxic substances, such as free fatty
acids and free radicals, during cerebral ischemia.1 In
animal models of brain ischemia, CDP-chol ine protects
the integrity of cell membranes by accelerating resynthesis of phospholipid.2"4 Administration of CDPcholine also attenuates the progression of ischemic cell
damage by suppressing the release of free fatty acids.3-6
Based on pharmacologic observations in animal
models, a multicenter double-blind placebo-controlled
trial was undertaken to evaluate critically any therapeutic efficacy as well as the safety of treatment with
CDP-choline among large numbers of patients with
well-established acute cerebral infarction.
Subjects and Methods
The prospective cooperative trial was conducted
according to an agreed-upon common protocol by staff
neurologists and neurosurgeons in 63 academic centers
throughout Japan from November 1982 to February
1985.
From the Department of Medicine, Kitasato University, Sagamihara (Y.T., F.S.), the Department of Medicine, Yokufukai
Geriatric Hospital, Tokyo (E.O.), the Department of Medicine,
Research Institute for Brain and Blood Vessels, Akita (T.K.), the
Department of Medicine, Kyoto University, Kyoto (M.K.), the
National Cardiovascular Center, Osaka (T.O.), the Department of
Medicine, Kyushu University, Fukuoka (M.F.), and the Medical
Research Institute, Tokyo Medical and Dental University, Tokyo
(A.S.), Japan.
Address for reprints: Yoshiaki Tazaki, MD, Professor and
Chairman, Department of Medicine, School of Medicine, Kitasato
University, 1-15-1, Kitasato, Sagamihara, Kanagawa-ken, Japan
(228).
Received March 2, 1987; accepted September 18, 1987.
A total of 272 patients aged 29-90 years suffering
from acute cerebral infarction were admitted to the
study. There were 183 men and 89 women. Criteria for
inclusion were 1) clinical evidence of cerebral infarction occurring within 14 days of admission to the study,
2) clinical diagnosis of cerebral infarction confirmed
by computed tomography (CT scanning) of the brain,
and 3) mild to moderate impairment of consciousness
indicated by the Japanese Coma Scale (JCS) developed
by Ohta et al7 (Table 1), which is an elaboration of the
Glasgow Coma Scale.8 Patients with total aphasia,
subarachnoid or intracerebral hemorrhage, or indications for neurosurgical intervention were excluded.
Prior to the study, consent was obtained from the
spouse or legal guardians.
Design of Clinical Trial
After establishing the diagnosis by clinical signs and
symptoms and confirming by CT scan of the brain,
eligible patients were randomly assigned to treatment
with 1,000 mg CDP-choline i.v. daily for 14 days
(CDP-choline) or physiological saline (placebo) by a
central coordinator of the study who was also blinded
to the treatment assigned. Suitable provisions were
made so that CDP-choline could not be distinguished
from the placebo. Those carrying out the clinical
assessments in the study were also blinded to the
treatment assigned. The code was maintained confidential by the central coordinator until the end of the
study, when the code was broken for data analysis.
Active drug was prepared in 20-ml ampules containing
1,000 mg CDP-choline. Placebo was likewise prepared
in identical 20-ml ampules containing only physiological saline. Both active drug and placebo were diluted
with 500 ml physiological saline or 5% dextrose in
sterile water and were administered by intravenous drip
once daily for 14 days.
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212
Stroke
TABLE 1. Method for Grading Levels of Impaired Consciousness According to Japanese Coma Scale7
Grade
0
1
1-1
1-2
1-3
II
II-1
D-2
II-3
HI
III-l
IH-2
DI-3
Description
Patient fully alert
Patient spontaneously awake but
Obtunded or confused
Disoriented to time, place, and person
Unable to state name and date of birth
Patient may be aroused, but falls into drowsy state after
cessation of stimulation
Easily aroused by spoken words
Aroused by loud voice or shaking the shoulders
Aroused only by repeated stimuli
Patient cannot be aroused by painful stimuli
Responds by movement to avoid stimulus
Responds with minimal movement such as decerebrate and
decorticate posturing
Does not respond except for respiratory changes
Japanese Coma Scale, 7 originally reported in Japanese, translated into English by present authors. R and I might be added to
grading to indicate restlessness and incontinence of urine and feces.
Examples: III-1R, JJ-3RI, etc.
There were no restrictions on the use of concurrent
drugs if they were thought to be indicated, but any
additional medications prescribed were recorded in
detail.
Methods of Assessment
Complete neurologic and medical assessments were
performed for each patient six times throughout the
trial, immediately before treatment and during treatment on Days 1 , 2 , 3 , 7 , and 14. Final assessment was
obtained on Day 14, or at the end point of treatment
(Table 2).
Major components of the neurologic assessments
were graded changes in the level of consciousness or
in mentation. It was shown from preliminary trials' that
graded changes in consciousness provide the most
reliable indexes of neurologic improvement or worsening during treatment. The level of consciousness was
assessed in 10 grades according to the JCS. Scoring of
neurologic status also included assessments of speech
and dysarthria, motor strength, reflex testing, and
sensory examination.
The global improvement rating (GIR) was also used
to assess the neurologic status to determine whether
individual signs had improved from pretreatment
conditions. GIR was assessed as six categories based
on changes in the level of consciousness, individual
neurologic signs, and the patient's general condition:
markedly improved, improved, slightly improved,
unchanged, worse, and severely deteriorated.
General medical examinations were performed at
each assessment, and factors analyzed included blood
pressure, pulse rate, respiratory rate, and body temperature. Analysis of the brain CT findings included
location, nature, and size of each lesion plus the
presence of any mass effect such as displacement of
midline structures. Laboratory tests included complete
blood count, liver function tests (SGOT, SGPT, alkaline phosphatase, LDH), renal function test (BUN,
creatinine), and urinalysis. These were determined
before and during treatment.
Vol 19, No 2, February 1988
The overall safety rating (OSR) was assessed on the
basis of whether side effects developed as judged by
results of laboratory examinations or by adverse
clinical reactions.
The global usefulness rating (GUR) summarized the
efficacy and safety and assessed the risk-benefit ratio
of the drug treatment. GUR was assessed in six grades
by coding the physicians' evaluations based on both
GIR and OSR and was used at each evaluation.
Overall assessment included GIR and GUR.
Review and Analysis of Data
Data on five patients were excluded from statistical
analysis before the randomization code was broken
because they developed exclusion criteria during treatment (Table 2); 267 patients were included. There were
12 patients whose JCS level of consciousness was IU-2
or D3-3 and nine who suffered a stroke, probably 2-3
weeks before admission; these 21 patients were included in the statistical analysis based on the judgment
of the study committee that these possible slight
deviations from provisions of the study protocol were
acceptable. Data were analyzed using the MannWhitney U test and %2 test > and a 5% level of
significance was used. GIR was analyzed separately on
Days 1, 2, 3, 7, and 14. Final assessments were also
analyzed. Data from patients who completed the full
program of 14 doses plus data from patients who died
or were withdrawn for other reasons and therefore
received fewer than 14 doses (Table 2) were also
analyzed. The average number of doses before withdrawal was 8 ± 2 for the CDP-choline group and 7 ±
2 for the placebo group.
Patient Populations
Table 3 shows the distribution of major background
factors in the 267 patients included in the statistical
analysis. The level of consciousness expressed by JCS
was I in 55% of the patients, II in 39%, and III in 6%.
Thus, most patients had mild to moderate impairment
TABLE 2. Exclusion and Withdrawal of Patients Entered Into
Study of Efficacy and Usefulness of CDP-Choline
CDP-choline
Total patients
Excluded from analysis of efficacy
and usefulness
133
1
2
136
18
131
17
Side effects
Complications
Transferred to other hospital
Switched to other therapy
Death
Poor drug compliance
CDP-choline, cytidine 5'-diphosphocholine.
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3
2
0
Duration of disease > 3 weeks
Did not complete 14 doses
139
2
Fully conscious
Included in analysis of efficacy
and usefulness
Placebo
1
1
1
1
3
3
6
3
3
0
11
2
Tazaki el al
CDP-Choline in Acute Stroke
213
TABLE 3. Demographic Data Among Patients Admitted to
Study of Efficacy and Usefulness of CDP-Choline
Patients with cerebral infarction
Factor
CDPcholine Placebo
Total
(n=131) (n=136) (n = 267)
Sex
Male
Female
Age (yr)
29-39
40-49
50-59
60-69
70-79
80-90
Diagnosis
Cerebral thrombosis
Cerebral embolism
Hemorrhagic infarction
Indeterminate
Strokes before study
0
87
44
93
43
180
5
7
19
30
48
1
6
11
35
87
22
4
16
35
60
20
72
28
13
18
84
30
14
8
156
58
27
65
108
42
26
68
63
131
1
36
34
70
2
8
2
17
20
28
2
4
17
34
15
28
36
22
16
11
3
15
30
3-5
Unknown
Duration of disease (days from onset of stroke to start of treatment)
1
2
3-4
5-7
8-10
11-14
15-19
Pretreatment level of consciousness
1-1
1-2
1-3
II-l
D-2
II-3
III-l
26
54
37
24
13
17
4
73
13
36
19
15
30
18
8
65
46
35
56
27
21
10
5
2
29
27
20
26
9
4
6
in-2
2
3
m-3
1
1
46
29
28
7
CDP-choline, cytidine 5'-diphosphocholine.
of consciousness. CT scans showed lesions of the
middle cerebral artery in 70% of the patients. Approximately 30% of the lesions were in the cortical branches
and approximately 30% involved the perforating
branches, while approximately 30% involved both. CT
evidence of cerebral atrophy was seen in 146 of the 267
cases and was equally divided between the CDPcholine and placebo groups.
Six patients in the CDP-choline group and 11 in the
placebo group died during the 14-day interval. The
immediate causes of death in the CDP-choline group
were refractory cerebral edema and transtentorial
herniation (n = 3), progressive basilar artery thrombosis (n= 1), refractory epileptic seizures (n= 1), and
acute myocardial infarction ( n = l ) . In the placebo
group, six died due to cerebral edema and five due to
cardiopulmonary disease.
These background data were compared between
groups. There was no significant difference in any
factor analyzed.
Results
Figures 1 and 2 summarize changes in the level of
consciousness and GIR for the CDP-choline and
placebo groups. Improvements in level of consciousness did not differ between groups on Days 1, 2, or 3
but were significantly improved for the CDP-choline
group on Days 7 and 14. The rates of improvement were
calculated at the final assessment: 5 1 % for the CDPcholine group compared with 33% in the placebo
group. The difference was significant.
Differences in GIR between the groups became
larger as treatment progressed. On Days 2, 7, and 14,
GIR of the CDP-choline group was significantly better
than that of the placebo group. Improvement was noted
in 32% (42 of 131) and 18% (24 of 131) on Day 7 and
54% (68 of 125) and 29% (36 of 125) on Day 14 for
the CDP-choline and placebo groups, respectively.
Rates of improvement at the final assessment were 52%
for patients receiving CDP-choline and 26% for those
receiving placebo.
Stratified analysis was conducted on results obtained
at the final GIR assessment (Figure 2). Rates of
improvement calculated as the number of patients
improving were consistently higher for all factors
analyzed among the CDP-choline group. However,
among cases with CT evidence of any mass effect
there were no differences in the rates of improvement between the groups. As shown in Figure 2,
the higher improvement rate in the CDP-choline
compared with the placebo group was not influenced
by differences in age or in duration of illness before
treatment.
Between-group comparisons were also made of
GUR. The rate of efficacy of treatment between groups
was also calculated as the number of patients in whom
the treatment was efficacious. This rating was also
better (47%) in the CDP-choline compared with the
placebo group (24%).
Complications occurred in 4 patients (1.0%) in the
CDP-choline group (hepatic dysfunction, n = 3; renal
dysfunction, n= 1) and in 11 patients (8.1%) in the
placebo group (hepatic dysfunction, n = 4; skin rash,
n = 3; hot flashes, n = l ; restlessness, n=\; anemia,
n — 1; renal dysfunction, n = 1). No serious side effects
were related to treatment with CDP-choline in any
patient with cerebral infarction.
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Stroke Vol 19, No 2, February 1988
214
An air si s
T real ment
w i th
No. of
patients on
U-test
20
i
CDP-choline
Improvement in
Level of
consiousnes a
i
60
•
i
80
.
i
100
.
i
Global
• mprovement
rating
CDP-choline
13 1
Placebo
1 36
Global
51 %
CDP- cholinc
1 31
Markedly
improved
Highly
use ful
P < 0. 0 1
33 %
52%
P < 0.0 1
P < 0. 0 1
26%
47%
P<0.01
fulfipsn
ra I ing
Moderately
i m proved"
or better
P<0.05
13 6
or
40
.
13 1
Placebo
usr
test
Cumulative rate of
i mprovement
Placebo
1 36
Moderately
Slightly
improved ___ improved
or
[ • •1 o r
Fairly
Slightly
useful
useful
P < 0. 0 1
24%
No
change
•
Hardly
useful
Worse
I °
r
I Slightly
undesi rable
Severely
de te riora ted
or
Very
undesirable
FIGURE 1. Changes in level of consciousness and overall assessment of all patients who completed full program (1,000 mg cytidine
5'-diphosphocholine i.v. once a day for 14 days) and all withdrawn patients (those who receivedfewer than 14 doses) for whom data
could be analyzed.
Discussion
A number of different pharmacologic approaches
to the treatment of cerebral ischemia have been proposed from knowledge gained from animal models
of the pathophysiology of acute stroke. Despite
these encouraging results from experimental studies,
there has been little objective evidence from controlled clinical trials that drugs are efficacious during the acute stages of cerebral hemorrhage or
infarction.10-'2
Our study is the first large-scale double-blind clinical
trial to critically compare the effects of CDP-choline
with placebo among patients with cerebral infarction.
There were significant improvements in level of consciousness among patients receiving CDP-choline
compared with those receiving placebo. GIR and GUR
quantified overall clinical improvement among treatment groups and were helpful in assessing the effectiveness of CDP-choline in this double-blind trial. A
moderate to severe acute stroke is difficult to quantify
objectively, making evaluation of treatment difficult.
Our evaluation system combines several assessment
scales that appear to be sufficient to disclose the clinical
effectiveness of proposed medical treatments. The
number of patients included in our study was greater
than in any other reported double-blind clinical trial of
drug treatment of cerebral infarction, and our study
appears to fulfill all the requirements recommended by
Spence and Donner.13
Baseline clinical data on admission, including the
CT scan features of the brain lesions, were not different
for any factor analyzed between CDP-choline and
placebo groups. Homogeneity of patient populations
between groups is an important requirement for valid
clinical trials and can be accomplished only with large
numbers of patients.
Differences in response to CDP-choline among
patients with cerebral infarction were revealed by
stratified analysis comparing their locations (according
to distribution in both cortical and perforating
branches) and the presence of any mass effect. These
analyses indicate that CDP-choline is effective in
patients with moderate to mild cerebral infarction and
produces more rapid recovery than no treatment.
CDP-choline was less effective in patients with larger
cerebral infarctions, particularly if they showed a mass
effect. CDP-choline treatment showed little or no
benefit in such patients critically ill from cerebral
edema. This suggests some limitations of CDP-choline
used alone and that its usefulness might be enhanced
by combining it with appropriate treatment of cerebral
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Tazaki et al
CDP-Chollne in Acute Stroke
215
edema, such as combined with the use of glycerol.12
Precise mechanisms for the beneficial pharmacologic actions of CDP-choline in ischemia of
the brain have yet to become fully established. Results
of the present clinical trial, however, suggest that
CDP-choline enhances recovery of reversible tissue
damage and prevents aggravation of postischemic
changes.
CDP-choline has been shown, in experimental
cerebral ischemia, to increase the synthesis of phosphatidylcholine and to prevent the release of free
fatty acids through its anti-phospholipase A activity,
particularly if arachidonic acid is released.314 It
also has been shown that CDP-choline is capable of
removing accumulated free fatty acids by stimulating
resynthesis of phospholipids.6 Metabolic turnover of
membrane phospholipid is a rapid process.13 It
has been shown recently that if CDP-choline is administered during reperfusion in a rat model of
cerebral ischemia, it is immediately used for membrane
lipid resynthesis.16 This suggests that CDP-choline
rapidly restores structural integrity of cell membranes
impaired by cerebral ischemia. Studies in animal
models of cerebral ischemia also indicate that CDPcholine increases synaptosomal phosphorylation,17 restores mitochondrial dysfunction," andreduceslactate
production."
The present clinical study was designed to examine
the possible efficacy of CDP-choline treatment
judged by improvement of disturbances of consciousness in acute stroke. It was not intended to evaluate
further long-term clinical outcomes. However, followup assessment has been made 18 months after
stroke in the 267 patients with cerebral infarction
who participated in our trial. Between-group comparisons were made for later fatal strokes and cardiopulmonary deaths using the survival analysis model.
As judged by this analysis, the prognosis appears
better in CDP-choline-treated cerebral infarction than
in the placebo-treated group. Such follow-up observations are encouraging and provide rationale for
further long-term investigations of the role of CDPcholine in the medical treatment of acute cerebral
infarction.
No. of
Factor
/
Age(years)
Diagnosis
Duration of
illness (Days
after onset of the
present attack)
Pretreatment
level of
consciousness
Cortical
branch or
perforating
branch
Sice of lesion
of infarction
Mass e f f e c t
Breakdown of
mass effecta
Analysis
patlenta on
/
CDPcholine
Placebo
81-59
60-69
70-90
Cerebral thrombosis
Cerebral embolisms
Hemorrhagic infarction
81
80
70
72
28
18
21
86
80
84
80
14
1-2
8-7
8-17
48
58
80
41
61
84
Cumulative rate of
improvementC/i)
X teat
U-teat ("moderately
lmprovtdnor
better)
a so 40 to Kin
\
SJ .
J
/
1
0
.
• Q
W ' &
N. S.
P < 0. 0 1
P < 0 06
N.S.
P<0.01
P < 0.06
P<0.tl
N. 8 .
N. S.
P < 0.0 1
N. S.
N. S.
N. 8 .
P < 0.0 1
N.S.
N. S.
P< 00 1
P < 0 06
FIGURE 2.
Stratified analysis of
data according to final global
76
48
7
70
56
10
Cortical branch
Perforating branch
Cortical and perforating branches
42
89
88
40
48
44
SmalKlesa than 1.5cm
in diameter )
Medium
Large (branchlg area)
Absent
Present
Compression of ventricles
Absent
Present
Shift of Mjdlme Structures
Absent
Present
Cerebral herniation
Deformation of basal
cisterns
Absent
Marked and mild
Enlargement of
inferior horns of
lateral ventricle
Absent
Marked or mild
29
27
46
48
70
58
58
49
78
67
88
45
86
49
104
24
108
81
1 12
16
118
16
105
28
120
18
1
n
IB
P<0.01
N. S.
P<006
P < 00 1
N. S.
N. S.
N.S.
P<001
N. S.
1' < 0.0 6
1' < 0 0 1
N.S.
N. S.
P < 0 06
P<006
P<00S
PC 0 0 6
P< 0.0 6
P < 0.0 1
P < 0.0 1
N. S.
N. S.
P<001
N. S.
P< 0 0 1
N. S.
t _^°
P<001
N. S.
P C 0.0 1
N. S.
9
P<001
N. S.
PC 00 1
N. S.
P<001
N.S.
P < 0. 0 1
N. S.
\
f
w
o
#
o
r
~^*
v
•
•
r $ .
\
^
c^
improvement ratings. • , Physiological saline (placebo); o, cytidine 5' -diphosphocholine (CDPcholine); N.S.,
not significant.
Mass effect, presence of any compression of ventricles, shift of
midline structures, deformity of
basal cisterns, or enlargement of
inferior horns of lateral ventricle.
Downloaded from http://stroke.ahajournals.org/ by guest on June 9, 2014
216
Stroke
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KEY WORDS • placebos • cerebrovascular disorders
choline precursors (cytidine diphosphate choline)
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