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Entacapone improves motor fluctuations in levodopa- treated Parkinson's disease patients.

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Entacapone Improves Motor Fluctuations in
Levodopa-Treated Parkinson’s
Disease Patients
Parkinson Study Group*
Motor fluctuations associated with levodopa therapy are common problems encountered in the long-term treatment of
Parkinson’s disease (PD). Entacapone, a peripherally acting, reversible inhibitor of catechol-0-methyltransferase, slows
the elimination of levodopa in humans by reducing the formation of 3-0-methyldopa. We conducted a placebocontrolled, double-blind, parallel-group, multicenter trial of entacapone in PD patients with motor fluctuations. Two
hundred five patients were randomized to receive either entacapone 200 mg or matching placebo with each dose of
levodopa and were followed for 24 weeks. The primary measure of efficacy was the change in percentage of “on” time
(relief of parkinsonism) while awake, as recorded by subjects at home in diaries completed at 30-minute intervals. At
baseline, patients averaged approximately 10 hours of “on” time per day while awake (60.5% “on” time), and entacapone
treatment increased the percent “on” time by 5.0 percentage points. The effect of entacapone was more prominent in
patients with a smaller percent “on” time (<55%) at baseline, and increased as the day wore on. Entacapone is effective
at increasing the duration of response to levodopa and at relieving parkinsonism in patients experiencing motor fluctuations and was well tolerated during the 24 weeks of treatment.
Parkinson Study Group. Entacapone improves motor fluctuations in levodopa-treated Parkinson’s
disease patients. Ann Neurol 1997;42:747-755
systemically inhibits C O M T but has a very limited
ability to enter the brain. COMT is responsible for
levodopa metabolism in both the gut and the liver
(first-pass metabolism) as well as in the systemic circulation. A peripheral COMT inhibitor could increase
absorption and decrease elimination of levodopa, and
thereby increase the plasma half-life after each levodopa
dose, and hence increase the area under the time-concentration curve for levodopa. Entacapone is rapidly
absorbed and eliminated with a time-to-maximum serum concentration and an elimination half-life of 1.6
to 3.4 hours [2]. Both acute and chronic administration of oral entacapone (200 mg), in conjunction with
carbidopa/levodopa, slow the elimination of levodopa,
without a significant change in the maximal serum
levodopa concentration (CmJ or time to achieve that
concentration (T,,), and reduce the plasma concentrations of 3-0-methyldopa (3-OMD) [3-51. Preliminary studies found that entacapone treatment was associated with an improvement in parkinsonian clinical
features [3-51.
W e hypothesized that by slowing the elimination of
levodopa, entacapone would benefit PD patients affected by the wearing-off phenomenon. T o test this hypothesis, we conducted a placebo-controlled, double-
Levodopa therapy is the most effective means of treating the signs and symptoms of Parkinson’s disease
(PD). Unfortunately, the effectiveness of levodopa deteriorates over time. Most patients with PD experience
a fluctuating response to levodopa within 5 years after
the initiation of therapy [l]. The most common motor
fluctuations associated with levodopa treatment are
the wearing-off phenomenon and dyskinesias. The
wearing-off phenomenon is characterized by the reemergence of parkinsonian symptoms before the next
scheduled dose of levodopa. Dyskinesias are typically
involuntary choreoathetoid movements usually present
in the middle of the dosing interval. Wearing-off fluctuations are associated with low plasma levels of levodopa, whereas dyskinesias can usually be linked to
higher plasma levels of levodopa. Although dyskinesias
are often well tolerated by patients, wearing-off of levodopa effectiveness is a major cause of disability in patients with advanced PD.
Entacapone is a selective, reversible inhibitor of
catechol-0-methyltransferase (COMT). COMT is a
widely distributed enzyme responsible for the 0methylation of levodopa, dopamine, and other catechols. 0-Methylated levodopa is not available as a
substrate for decarboxylation to dopamine. Entacapone
~
*A listing of authors is in the Appendix.
Received Mar 4, 1997, and in revised form Jun 4 and Jul 14, 1997.
Accepted for publication Jul 21, 1997.
Address correspondence to Dr Kieburtz, Department of Neurology,
University of Rochester, 601 Elmwood Ave, Box 673, Rochester,
NY 14642.
Copyright 0 1997 by the American Neurological Association 747
blind, parallel-group multicenter trial
PD patients with motor fluctuations.
of entacapone in
Materials and Methods
Organization
This multicenter trial was organized by the Parkinson Study
Group and sponsored primarily by Orion Pharma Pharmaceuticals (Espoo, Finland). The study was approved by the
institutional review boards at each of the 18 participating
centers. An independent safety monitoring committee periodically reviewed the safety of the study. The data were gathered, managed, and analyzed by the Parkinson Study Group.
This report was written primarily by the Steering Committee
but with input from all authors. T h e sponsor did not control
the content or timing of the report.
Recruitment and Enrollment
A total of 205 eligible subjects were enrolled in our trial between April and December 1994. Patients who had idiopathic P D in (modified) Hoehn and Yahr [6] stage 1.5 to 4
(when in an “off‘ state), who were responsive to levodopa
treatment, who had motor fluctuations paralleling their levodopa dosing, and who were taking a stable regimen of four
to 10 daily doses of carbidopa/levodopa were considered eligible. Patients were excluded if they had atypical or secondary parkinsonism, pronounced dementia, or other significant
neurologic disease, major psychiatric disorders such as severe
depression, or clinically severe or unstable systemic illness.
Patients were allowed to continue with amantadine, anticholinergics, selegiline, or dopamine agonists at a constant dosage, in addition to their levodopa doses. Subjects were not
allowed to receive controlled-release carbidopallevodopa formulations. Subjects were excluded if treated within 6 months
with neuroleptic agents, or within 1 month with amethyldopa or reserpine. Concurrent treatment with apomorphine, or catechol-structured drugs such as adrenaline,
dopamine, dobutamine, and isoprenaline, was prohibited because these drugs are metabolized by 0-methylation.
Afrer informed consent was obtained, patients were required to maintain a stable dosage of carbidopa/levodopa for
a 4-week period before the baseline visit. At baseline, subjects
were randomly assigned to receive either placebo or entacapone. Within the entacapone treatment group, subjects were
further assigned by randomization to receive either 24 or 26
weeks of active medication, followed respectively by either 4
or 2 weeks of placebo. This design provided for a staggered,
blinded withdrawal of entacapone and permitted a more objective assessment of the effects of discontinuing experimental treatments. The subjects, investigators, and coordinating
staff remained unaware of the individual treatment assignments throughout the trial. The computer-generated randomization scheme included stratification (by center) and
blocking (block size = 4) to help ensure balance among the
treatment groups within each center.
after randomization and the maintenance entacapone dosage
was attained in the first day. During the first 8 weeks of
experimental treatment, the investigator adjusted the daily
carbidopa/levodopa intake up or down, vaiying dosage or
timing, to obtain an optimal clinical response. After the 8week dosage adjustment period, the carbidopa/levodopa dosage was intended to remain constant until the week 24 assessment unless clinical status mandated changes. A stable
levodopa dosage was maintained if possible during the 4week staggered withdrawal of study drug. Extra doses of carbidopa/levodopa were taken only in the case of exceptional
need. The use of such extra doses (booster doses) was systematically recorded by the patient. Other antiparkinsonian
medications were kept constant throughout the study.
Clinical assessments were performed at study visits conducted at baseline and at 2, 4, 8, 16, 24, 26, and 28 weeks
after randomization at baseline. At each visit, subjects were
assessed for adverse clinical experiences. An electrocardiogram (ECG) was performed at each visit, as well as a battery
of laboratory tests that included urinalysis, hematology, and
serum chemistry profiles. Clinical assessments, that occurred
during the “on” state at each visit, included vital signs, the
Unified Parkinson’s Disease Rating Scale (UPDRS) [7]and a
global evaluation of response to treatment. Subjects maintained a standardized home diary of their parkinsonian status
for the 3 days before each clinic visit. In completing the diaries, the subjects recorded whether they were “on,” “off,” or
asleep at half-hour intervals throughout the day. “On” was
defined as the subject being relatively free of parkinsonian
symptoms (eg, mobile or capable of moving with relative
ease and independence). “Off‘ was defined as the subject experiencing increased parkinsonian symptoms (eg, immobility
or incapability of moving with ease). Before enrollment in
the study, each subject and their site investigator completed
concurrent independent diary ratings during a 4-hour observation period in the clinic. This initial assessment confirmed
that subjects had motor fluctuations and was used to instruct
the subjects about proper diary completion. Subjects also recorded in the diary the timing and dosage of each levodopa
dose and any levodopa dose failures (no benefit from dose).
The diary was reviewed at each visit to assure accuracy and
completeness; however, the investigator was not allowed to
direct the subject how to classify any half-hour periods. T o
assess the impact of withdrawal of experimental treatments,
diaries were completed for the 2 days after the visits at weeks
24 and 26.
Monitoring of compliance was performed at follow-up
evaluations by counting the number of unused tablets returned by the subject. In addition, plasma concentrations of
3-OMD, which were expected to drop by approximately
30% with entacapone treatment, were determined at baseline
and at the 4-, 8-, 16-, 24-, 26-, and 28-week visits. To evaluate the success of the blind, subjects recorded their guesses
of individual treatment assignments at week 24.
Therapy and Follow-Up
Outcome Variables
The subjects took 200-mg tablets of entacapone or matching
tablets of placebo (Orion Pharma) orally with each dose of
their carbidopa/levodopa, up to a maximum of 10 doses per
day. Experimental treatments were started o n the morning
The primary outcome variable in this study was the percent
“on” time while awake, as determined from the home diaries
over the 3 days immediately preceding a scheduled visit.
Data from diaries containing fewer than 20 recorded hours
748 Annals of Neurology
Vol 42
No
5 November 1997
for a particular day were not used in the calculation of the
diary-derived outcome variables. Diary data were considered
to be completely missing at a particular visit only if all three
daily diaries contained fewer than 20 recorded hours. For the
visits used in the primary statistical analyses (weeks 0, 8, 16,
and 24), diary data were completely missing for only 3 of
771 subject visits (0.4%), excluding visits for subjects after
they were prematurely withdrawn from the study. Data from
weeks 2 and 4 were not included in the primary statistical
analyses because adjustments to the levodopa dosages were
permitted during this period.
Secondary outcome variables, also determined from the
home diaries, included the percent “on” time while awake in
the morning (before noon), afternoon (12 I’M to 6 PM), and
evening (after 6 PM), percent asleep time, total daily levodopa
dosage, number of levodopa doses per day, and number of
levodopa dose failures. Other outcome variables were the
UPDRS total score and the mental, motor, and Activities of
Daily Living (ADL) subscale scores, and the global evaluations.
Statistical Analysis
The primary statistical analysis used a repeated-measures
analysis of variance model to examine treatment effects over
time for the primary outcome variable. Factors in this model
included treatment group, subject (random effect), investigator, percent “on” time at baseline, and time (8, 16, and 24
weeks). An F test was performed for significance of the overall treatment effect, and a 95% confidence interval for the
overall treatment effect was computed by using this model.
Also, interactions between treatment and time, investigator,
and baseline percent “on” time were examined using F tests.
In cases where the interaction was found to be significant,
95% confidence intervals (CIS)for the treatment effects were
computed for subgroups (eg, separately for each time point),
after Bonferroni adjustment for multiple comparisons. All
analyses involving time used the Huynh-Feldt correction for
departures from the assumption of sphericity [8].
Analyses for continuous secondary outcome variables were
performed using the same methods as above for the primary
analyses. The total daily levodopa dosage was logtransformed for purposes of statistical analysis. Analyses for
categorical secondary outcome variables such as dose failures
tests
and the global evaluations were mainly descriptive.
were used to examine differences among the treatment
groups separately at each visit, after Bonferroni correction for
multiple comparisons.
The above analyses were performed according to the
intention-to-treat principle. If a subject was missing a response at a particular visit (week 8, 16, or 24), the last available observation for that subject was carried forward and imputed for that visit. Data from weeks 2 and 4 were not
included in this imputation process. To determine the impact of dropouts on these analyses, the analyses were repeated including only subjects who had complete data for
the response variable of interest. The results of the latter
analyses did not substantially differ from those of the
intention-to-treat analyses and, hence, are not reported here.
There were 23 subjects (11.2%) who dropped out of the
study prematurely (10 placebo and 13 entacapone), and im-
x2
putation of percent “on” time was required for only 52 of
820 subject visits (6.3%).
The change in percent “on” time during the staggered
withdrawal period was analyzed by examining mean changes
from the 3 days preceding the week 24 visit to 1 and 2 days
after the week 24 visit, and to 1 and 2 days after the week 26
visit. Subjects included in these analyses were those who began withdrawal of experimental medications at week 24 (the
entire placebo group and approximately one-half of the subjects in the entacapone group). Analysis of covariance models
were used with treatment group, center, and percent “on”
time for the 3 days preceding week 24 as the independent
variables.
For subjects who began withdrawal of experimental medications at week 24, mean changes in UPDRS scores berween
week 24 and weeks 26 and 28 were analyzed using analysis
of covariance models, with treatment group, investigator,
and week 24 score as the independent variables. For all subjects, mean changes in UPDRS scores during the first 2
weeks of drug withdrawal (week 24 to week 26, or week 26
to week 28, depending on when the subject began drug
withdrawal) were similarly analyzed.
Analyses of safety measures were mainly descriptive. Onesided Fisher’s exact tests were used to compare the treatment
groups regarding the proportion of subjects having particular
adverse experiences or abnormal laboratory test results. These
analyses were repeated excluding adverse experiences judged
to be of mild intensity. Repeated-measures analysis of variance models similar to those used in the primary analyses
were used to analyze changes in continuous laboratory test
results and vital signs over time. Compliance rates, the use of
concomitant medications, and the results of the blindedness
questionnaire were examined descriptively by treatment
group.
All statistical tests were performed at the 5% level of significance. All data were collected and methods of statistical
analysis were specified in advance of the revelation of individual subject treatment assignments.
Results
Comparability of Treatment Groups
The treatment groups were very similar at baseline
with regard to demographic and clinical variables (Table I). The only exception was that a somewhat higher
proportion of subjects had a history of taking a
controlled-release preparation of levodopa in the entacapone group than in the placebo group. Subjects averaged approximately 10 hours of “on” time per day
while awake (60.5% “on” time) on entry into the
study.
Tolerability o f Experimental Medications
Ten subjects in the placebo group and 13 subjects in
the entacapone group withdrew before completing the
trial. In the placebo group, 2 subjects withdrew because of worsening parkinsonism, 2 withdrew because
of increased dyskinesias, and 1 each withdrew for confusion, headache, and depression. Three subjects withdrew their consent for further participation (ie,
Parkinson Study Group: Entacapone in PD
749
Table 1. Subject Characteristics at Baseline
Table 2. Number of Patients with Clinical
Adverse Experiences
Entacapone
(n = 103)
Placebo
(n = 102)
62.7 (9.7)
Age (yr)
62.8
Male gender (Yo)
96.1
White (%)
Years since symptom onset 11.3 (6.4)
Years since onset of motor
4.5 (4.3)
fluctuations
Years of levodopa therapy
8.9 (6.0)
Total daily levodopa dos- 752.1 (434.7)
age (mglday)
Other anti-PD medica79.4
tions (Yo)
16.6
Amantadine (Yo)
Anticholinergics (%)
15.7
45.1
Selegiline (%)
18.6
Bromocriptine (Yo)
Pergolide (%)
35.3
40.2
History of CR levodopa
use (Yo)
60.9 (14.0)
Percent “ ~ n time
”
Percent asleep time
29.5 (6.2)
UPDRS scores
Total
35.6 (17.2)
Mental section
1.5 (1.7)
Motor section
22.6 (12.0)
ADL section
1 1.7 (6.7)
2.4 (0.6)
Modified HIY stage
79.1 (11.8)
S/E ADL scores
63.9 (8.0)
67.0
96.1
10.8 (4.9)
4.2 (3.0)
9.0 (4.7)
79 1.o (374.7)
88.4
16.5
11.7
53.4
14.6
36.9
55.3
60.1 (15.2)
29.0 (7.0)
35.1 (15.9)
1.3 (1.2)
22.0 (1 1.7)
11.9 (6.2)
2.4 (0.6)
79.8 (12.6)
Data are mean (SD) values unless othenviae indicated.
I‘D = Parkinson’s disease; CR = controlled release; UPDRS =
Unified Parlunson’s Disease Rating Scale; H/Y = Hoehn and Yahr;
SIE ADL = Schwab/England Activities of Daily Living.
dropped out of the study) for reasons other than adverse experiences. In the entacapone group, 2 subjects
withdrew because of worsening parkinsonism, 2 withdrew because of increased dyskinesias, and 1 each withdrew for psychosis, orthostatic hypotension, and shortness of breath. Six subjects withdrew consent for
further participation for reasons other than adverse experiences. Adverse events of any kind and at any time
were experienced by 95% of the placebo group and
97% of the entacapone group. The mean number of
adverse experiences per subject was higher in the entacapone group (6.6 -t 5.0; mean -t SD) than in the
placebo group (4.6 5 3.5). The most common clinical
adverse experiences are listed in Table 2. Dyskinesias,
nausea, and shortness of breath were reported more frequently in the entacapone group. Dyskinesias appeared
almost exclusively in the first 8 weeks of the trial (30 of
33 in the placebo group and 53 of 55 in the entacapone group) and resolved in about one-third of subjects (11 of 30 placebo group and 17 of 53 entacapone
group) during the first 8 weeks after modification of
levodopa dosage. Several entacapone-treated subjects
reported shortness of breath, although this appeared to
750 Annals of Neurology Vol 42
No 5
November 1997
Dyskinesia
Worsened PD
Urine abnormality
(discoloration)
Dizziness
Nausea
Falls
Constipation
Hallucination
Shortness of breath
Ataxia
Forgetfulness
Vomiting
Somnolence
Placebo
(n = 102)
Entacapone
(n = 103)
p
33
38
0
55
36
38
0.002
0.42
<0.000 1
14
5
10
5
4
1
1
0
0
0
24
16
16
14
10
8
7
5
5
5
0.06
0.01
0.15
0.03
0.09
0.02
0.03
0.03
0.03
0.03
P D = Parkinson’s disease.
be a heterogeneous complaint. For about one-half of
these subjects shortness of breath was an “off phenomenon, but for others it was a brief complaint associated with a respiratory infection. Forgetfulness was
reported primarily by subjects who also had hallucinations or vivid dreaming. Also, 38 subjects in the entacapone group noticed discoloration of their urine (a
known property of this and related compounds) compared with no subjects in the placebo group.
There were no differences in vital signs, laboratory
test values, or ECG values between the treatment
groups.
Primary Outcome Variable
The mean percent “on” time was significantly higher at
weeks 8, 16, and 24 for the entacapone group compared with the placebo group (Fig 1). The overall
treatment effect was 5.0 percentage points (95% CI,
1.7 to 8.3; p = 0.003) or approximately 1 hr/day, and
this effect was consistent across time (weeks 8, 16, and
24). There was no evidence of a differential effect of
entacapone among the 18 participating cencers; however, there was evidence of an interaction between
treatment and percent “on” time at study entry ( p =
0.0002). This interaction is described in Table 3,
which shows that the effect of entacapone treatmenr
was particularly prominent among subjects who had a
smaller percent “on” time (<55%) at baseline. There
was also evidence that the effect of enracapone on percent “on” time depended on the time of day (see Table
3), with benefit increasing as the day wore on.
The average 3-OMD level for subjects who received
entacapone declined from 6.5 pg/ml at baseline to 2.8
pg/ml at week 24, compared with an increase from 6.0
to 6.3 pg/ml in the placebo group. The adjusted mean
3-OMD level was 57.8% lower in the entacapone
71
T
70
69
66
67
E
F
66
6
I
564
e
L?63
I
62
61
I
60
59
58
-2
0
2
4
6
8
10
12
16
14
Weeks After Randomization
......
Placebo
-Entacapone
Table 3. Effects of Entacapone Treatment on Percent “On”
Time by Baseline Status and Time of Daya
Baseline
Status (percent
“on” time)
<55
55-70
2 70
Time of day
Morning
Afternoon
Evening
Treatment Effectb
(Change in
Percent “On”
Time)
98.3% CI
p
10.3
3.7
-0.9
3.2, 17.4
-3.4, 10.7
-8.5, 6.6
0.0006
0.21
0.76
-2.2, 6.7
-0.8, 8.5
1.7, 13.4
0.23
0.05
0.002
2.2
3.9
7.6
“Positive values indicate a beneficial effect of entacapone relative to
placebo.
For baseline status, treatment effects are estimated by using a
repeated-measures analysis of variance model including treatment,
center, baseline percent “on” time, and the interaction between
treatment and baseline percent “on” time as between-subject factors.
For time of day, treatment effects are estimated by using three separate repeated-measures analysis of variance models including treatment, center, and baseline percent “on” time as between-subject factors. Three separate dependent variables were used (percent “on”
time in the morning, afternoon, and evening).
CI = confidence interval. (The confidence coefficient of 98.3% includes a Bonferroni adjustment for the three subgroup comparisons.
The significance level for each test is 0.017.)
group than in the placebo group (95% CI, 53.7-61.5;
p < O.OOOl), using the repeated-measures analysis of
variance model. Analyses also revealed no substantive
relationship between changes from baseline in 3-OMD
18
2o
22
24
26
Fig 1. Percentage of awake time
spent in the “on” condition by week
during the trial. Patients began
stagered withdrawal of experimental medications after week 24. The
lines connect the mean responses at
each visit, and the error bars represent one standard error from the
mean. The time points are when
percent “on”time was assessed.
levels and changes from baseline in percent “on” time
among subjects assigned to receive entacapone treatment.
Secondary Outcome Variables
Table 4 shows the effects of entacapone treatment on
UPDRS scores. The UPDRS evaluation was done in
the “on” state an average 1.5 hours after a levodopa
dose, and this interval was the same for both treatment
groups and throughout the trial. Overall, entacapone
had a nominally significant beneficial effect on the total score ( p = 0.05), reflected mainly in the motor
( p = 0.08) and ADL ( p = 0.06) subscales. The effect
of entacapone on these scores tended to increase over
time. At week 24, subjects treated with entacapone had
improved in total UPDRS score by an average of 3.5
points relative to placebo-treated subjects (98.3% CI,
0.5-6.5; Bonferroni-adjusted p = 0.018), representing
an approximately 10% improvement. There was no effect of entacapone treatment on the mental subscale
score of the UPDRS.
Entacapone treatment also had a slight but nominally statistically significant overall effect on percent
asleep time, increasing it by 1.1 percentage points (or
15 minutes per day) on average (95% CI, 0.0-2.2;
p = 0.05). The average total daily levodopa dosage was
12% (-100 mg/day) lower in the entacapone group
than in the placebo group (95% CI, 4-19%; p =
0.003; Fig 2), with most of the decrease in dosage
coming during the first 4 weeks of entacapone treatment. The results of the investigators’ global evaluations of the patients at baseline and at week 24 are
presented in Table 5. The distribution of responses was
Parkinson Study Group: Entacapone in PD
751
Table 4. Effects of Entdcapone Treatment on UPDRS Scores"
Variable
Treatment
Effectb
CI
P
2.1
0.8
2.1
3.5
0.0, 4.3
-2.2, 3.9
-0.9, 5.1
0.5, 6.5
0.05
0.50
0.10
0.006
I .4
0.4
1.5
2.4
-0.2,
-2.0,
-0.9,
-0.0,
3.1
2.8
3.9
4.8
0.08
0.69
0.14
0.02
0.8
0.5
0.8
1.1
-0.0,
-0.6,
-0.3,
-0.1,
1.6
1.7
2.0
2.2
0.06
0.30
0.09
0.03
0.1
0.2
0.1
0.2
-0.1,
-0.3,
-0.4,
-0.2,
0.4
0.6
0.5
0.6
0.36
0.36
0.76
0.30
in the entacapone group and in the negative direction
in the placebo group ( p = 0.002). Results were similar
for the patients' self-reported global evaluations. There
were no statistically significant differences among the
groups regarding changes in the number of levodopa
doses per day or the number of dose failures.
Total UPDRS
Overall
Week 8
Week 16
Week 24
Mocor UPDRS
Overall
Week 8
Week 16
Week 24
ADL UPDRS
Overall
Week 8
Week 16
Week 24
Mental UPDRS
Overall
Week 8
Week 16
Week 24
Effects of the Withdrawal of Experimental
Medications
The results in Tables 6 and 7 demonstrate that the
beneficial effects of entacapone, as measured by percent
"on" time and UPDRS scores, were completely and
rapidly lost on its withdrawal. In addition, 3-OMD
values quickly returned to baseline levels in subjects
withdrawn from entacapone treatment.
Compliance and Blindness
Overall compliance, as measured by pill counts, averaged 93.6% in the placebo group and 94.9% in the
entacapone group and varied little over time. Compliance was also measured by whether 3-OMD levels decreased by 30%, a cutoff set before the start of the
study that was expected to be achieved by subjects receiving entacapone treatment and not achieved by subjects receiving placebo. Compliance was greater than
95% in the placebo group and greater than 94% in the
entacapone group at weeks 8, 16, and 24 according to
this criterion.
Subjects guessed correctly their trearment assignments significantly better than by chance ( p <
0.0001); 71% of those assigned to receive placebo
guessed their assignment correctly, and 60% of those
"Positive values indicate a beneficial effect of entacapone relative to
placebo.
Treatment effects are estimated by using a repeated-measures analysis of variance model including trearment, center, and baseline
UPDRS score as between-subject factors.
UPDRS = Unified Parkinson's Disease Rating Scale; CI = confidence interval. (The confidence coefficient is 95% for the overall
effect and is 98.3Yo (Bonferroni adjustment) for the three individual
time points. The significance level for each test for the individual
time points is 0.017.)
similar among the two groups at baseline, but at week
24 the distribution was shifted in the positive direction
732-
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7.04
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14
I
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Weeks Afler Randomization
-.....
752 Annals of Neurology Vol 42
Placebo
- Entacapone
No 5
November 1997
log o f the total daily levodopa dos26
age at each visit and the error bars
represent one standard error from
the mean.
Table 5. Distributions of Responses on the Investigator; Global Evaluation of the Patient at Baseline and at Week 24
Very
Poorly
Poorly
Rather
Poorly
Not Well,
Not Poorly
Rather
Well
Well
Well
1
0
2
3
11
14
42
35
32
29
13
18
1
4
1
1
4
7
28
9
30
30
26
33
7
24
3
2
very
Baseline
Placebo
Entacapone
Week 24
Placebo
Entacapone
The investigator was asked to rate how the patient had been doing in terms of his or her Parkinson’s disease during the week preceding the visit.
Table 7. Changes in UPDRS Scores after the First Two
Weeks of Drug Withdrawal
Table 6. Changes in Percent “On”Time after Week 24
During the Staggered Drug- Withdrawal Period
Week 24
Day 1
Day 2
Average”
Placebo
(n = 90)
Entacapone
(n = 43)
P
0.8 (14.1)
0.3 (12.9)
0.5 (11.9)
-8.3 (16.5)
-6.3 (14.1)
-7.3 (13.7)
0.003
0.02
0.003
Data are mean (SD) values, where negative values indicate a worsening.
Total UPDRS
Motor UPDRS
Placebo
(n = 91)
Entacapone
(n = 90)
p
0.0 (7.8)
-0.1 (6.6)
-4.2 (9.2)
-3.0 (8.0)
0.004
0.030
Data are mean (SD) values, where negative values indicare a worsening.
UPDRS = Unified Parkinson’s Disease Rating Scale.
“Average of the changes over days 1 and 2 after the week 24 visit.
assigned to receive entacapone guessed their assignment
correctly. Subjects were also asked to indicate the primary reason for their guess of treatment assignment.
Of the 85 subjects who guessed that they had received
placebo, 77 (90.6%) reported the primary reason as
lack of improvement in symptoms. Of the 72 subjects
who guessed that they had received entacapone, 58
(80.6%) reported the primary reason as improvement
in symptoms. However, within each group (guessed
placebo and guessed entacapone), these reasons (lack of
improvement and improvement in symptoms, respectively) were not associated with the actual treatment
assignment.
ment were both significant statistically and relevant
clinically.
There was an increased frequency of dyskinesias and
nausea in the entacapone-treated group, consistent
with enhanced dopaminergic activity. In general, these
side effects were mild and did not lead to withdrawal
from the study. Adverse effects were encountered most
frequently in the initial 8 weeks of the trial and often
subsided after adjustment of levodopa dosage. Nausea,
dizziness, and urine discoloration were associated with
entacapone treatment and have also been reported in
association with tolcapone treatment [ 1 11. Diarrhea
was not a common problem for entacapone-treated patients, in contrast to the experience with tolcapone
Discussion
[9, 121.
This study demonstrates that entacapone is effective in
increasing “on” time in levodopa-treated PD patients
experiencing motor fluctuations. Entacapone-treated
subjects had about an hour increase in “on” time per
day and reduced their levodopa dosage by about 100
mg. In general, entacapone was well tolerated and not
associated with serious adverse experiences. Previous
experience with entacapone has also supported its efficacy as an extender of levodopa benefits [3-51. The
magnitude of benefit from entacapone was similar to
the improvements observed with another COMT inhibitor, tolcapone, which also may exert some central
action [9, 101. Because both the primary data from the
diaries and the global impression scales were completed
by the subjects themselves, the improvements observed
provide evidence that the benefits of entacapone treat-
Although most subjects were taking adjunctive antiparkinson medications (including pergolide, bromocriptine, selegiline, amantadine, and anticholinergics), the addition of entacapone enhanced the
duration of the benefits from levodopa. Subjects were
not permitted to use sustained-release levodopa preparations that can also extend the elimination profile of
levodopa, and additional trials are in progress to assess
the effect of entacapone in patients receiving these
preparations. Strictly speaking, our results may not apply to patients taking sustained-release levodopa preparations; however, switching from regular levodopa to
sustained-release levodopa preparations does not increase “on” time in PD patients with motor fluctuations [13, 141. In contrast, the addition of a dopamine
agonist (bromocriptine [ 151, pergolide [ 161, carbergo-
Parkinson Study Group: Entacapone in PD
753
line [17]) or selegiline [18] t o levodopa can improve
“on” time by 10% o r more. W e found that entacapone
increased “on” time by about 5%, even i n subjects already receiving dopamine agonists a n d selegiline as adjuncts to levodopa; b u t our study does not provide a
direct comparison with these other therapies. In addition, the total UPDRS scores i n the “on” (relatively
free from parkinsonism disability) state were improved
with entacapone treatment compared with placebo
treatment. This suggests that entacapone may n o t only
extend the duration o f levodopa benefit b u t may also
enhance its maximal antiparkinsonian effect.
T h e introduction of entacapone treatment led within
I m o n t h to an improvement in parkinsonian features,
despite a concomitant reduction in levodopa dosage.
Withdrawal of entacapone led within 1 day to a worsening of parkinsonian features, demonstrating that the
benefits of treatment were sustained over 6 months a n d
were rapidly reversible. O u r analyses of blindness indicated that subjects could correctly guess their actual
treatment assignment more frequently than by chance,
b u t that such correct guesses were based on the subject’s perception of clinical improvement, rather than
on side effects o r other characteristics such as urine
discoloration.
Our analyses also indicate that patients with the
greatest a m o u n t of “off‘ time are those who are most
likely to benefit from entacapone. T h i s is reassuring in
that it implies that entacapone treatment will be useful
in patients with a large a m o u n t of “off’ time, not just
in patients with mild motor fluctuations. In addition,
the maximal benefits in improving “on” time appear to
be in the afternoon and evening, which are typically
the most difficult time periods for patients with the
wearing off phenomenon.
Entacapone is generally well tolerated a n d effective
in subjects with motor fluctuations; hence, this COMT
inhibitor appears to be a useful adjunct in extending
the benefit of each levodopa dose a n d ameliorating the
signs a n d symptoms of PD.
Appendiv
The following members of the Parkinson Study Group
(PSG) participated in this study and authorized this report:
Steering Committee: Karl Kieburtz, Medical Director
(Rochester, NY); Ira Shoulson, Principal Investigator (Rochester, NY); Stanley Fahn, Co-Principal Investigator (New
York, NY); Michael McDermott, Chief Biostatistician
(Rochester, NY); William Koller (Kansas City, KS), Peter
LeWitt (West Bloomfield, MI), and John Nutt (Portland,
OR).
Investigators and Coordinators: Matthias Kurth and Melanie Brewer (Phoenix, AZ); Mark Lew, Mickie Welsh, and
Cheryl Waters (Los Angles, CA); James Bennett and Elke
Rost-Ruffner (Charlottesville, VA); Andrew Feigin, Irenita
Gardiner, and Roger Kurlan (Rochester, NY); John Hammerstad and Claudia Stone (Portland, OR); Joseph Jankovic
754 Annals of Neurology
Vol 42
No 5
November 1997
and Jenny Beach (Houston, TX); James Tetrud and Kristopher Kelker (Sunnyvale, CA); David G. Standaert, John H.
Growdon, Marsha Tennis, and Karin Graefe (Boston, MA);
Margery H. Mark and Sandra J. Kelly (New Brunswick, NJ);
Rajesh Pahwa, Desni McGuire, and Jean Hubble (Kansas
City, KS); Stewart A. Factor and Diane L. Brown (Albany,
NY); Paul Tuite, Elspeth Sime, and Anthony E. Lang (Toronto, Ontario); Paul Greene and Hal Winfield (New York,
NY); George Paulson, Kim Zoog, and Carolyn Weeks (Columbus, OH); Cliff Shults and Deborah Fontaine (San Diego, CA); Jorge L. Juncos and Colleen Wood (Atlanta, GA);
Kathleen Shannon and Jean A. Jaglin (Chicago, IL); Joseph
Tornabene, Margaret C. Lannon, Robin Davies, and Joe
Friedman (Providence, RI).
Monitoring Committee: Pierre N. Tariot, Chair (Rochester,
NY); W. Jackson Hall (Rochester, NY); Robert Herndon
(Portland, OR); Ronald F. Pfeiffer (Memphis, TN).
Coordination and Biostatistics Centers (Rochester, NU: Sandra Plumb, Coordinator; Cynthia Casaceli, Database Management; Heidi Randolph, Haidy Behman, Joe Connorton,
Denni Day, Alice Rudolph, Rita Pelusio, Barry Guthrie,
Kathy Claude, Constance Orme, Deborah Baker, Ruth Nobel, Carrie Irvine, and Arthur Watts.
Orion Pharma Pharmaceuticals (Sponsor): Ariel Gordin,
Project Director; Helena Heikkinen, Project Manager; and
Heli Rita, Statistician.
This study was supported primarily by Orion Pharma Pharmaceuticals (Espoo, Finland) and by the NIH-supported General Clinical
Research Centers at the University of Rochester (MO1-RR00044)
and Massachusetts General Hospital (MO1-RROlO66) and a Natiotial Parkinson Foundation Center of Excellence at the University
of Rochester.
Presented in part at the meeting of the American Neurological Association, Miami, FL, October 1996.
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Parkinson Study Group: Entacapone in
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