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Effect of lazabemide on the progression of disability in early Parkinson's disease.

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Effect of Lazabemide on the Progression of
Disability in Early Parkinson’s“Disease
The Parkinson Study Group
Lazabemide (Ro 19-6327) is a relatively short-acting, reversible, and selective type B monoamine oxidase inhibitor that
is not metabolized to amphetamines or other active compounds. We previously found lazabemide to be safe and well
tolerated at dosages of up to 400 mg/day during a 6-week study of 201 patients with early untreated Parkinson’s disease
(PD). We now assess whether or not lazabemide influences the progression of disability in untreated PD. Patients (N
= 321) were assigned by randomization to one of five treatment groups (placebo, 25 mg, 50 mg, 100 mg, or 200 mg/
day) and followed systematically for up to 1 year. The risk of reaching the primary end point (the onset of disability
sufficient to require levodopa therapy) was reduced by 51% for the patients who received lazabemide compared with
placebo-treated subjects. This effect was consistent among all dosages. The frequency of adverse experiences did not
differ among the treatment groups. At dosages ranging from 25 to 200 mglday, lazabemide was well tolerated and
delayed the need for levodopa in early, otherwise untreated PD. The magnitude and pattern of benefits were similar to
those observed after 1 year of deprenyl (selegiline) treatment in the DATATOP clinical trial.
The Parkinson Study Group. Effect of lazabemide on the progression of disability
in early Parkinson’s disease. Ann Neurol 1996;40:99- 107
Lazabemide (Ro 19-6327) is a relatively selective, reversible, competitive inhibitor of monoamine oxidase
type B (MAO-B) [l]. Both lazabemide and another
MAO-B inhibitor, deprenyl (selegiline), prevent 1methyl-4-phenyl- 1,2,3,6-tetrahydropyridine (MPTP)induced nigral damage in animal models of Parkinson’s
disease (PD) [2, 31. In controlled trials deprenyl delayed the onset of disability in patients with early, otherwise untreated PD [4-71. In contrast to deprenyl,
lazabemide is approximately 100-fold more selective
in inhibiting MAO-B compared with MAO-A, and is
not metabolized to potentially active compounds such
as I-methamphetamine and I-amphetamine [8].
Lazabemide is an effective inhibitor of both platelet
and brain MAO-B activity in PD patients. In singledose studies, there was a very high correlation between
the extent of platelet and brain MAO-B inhibition,
the latter assessed by L-[”C]deprenyl positron emission
tomography (PET) imaging [9]. In these single-dose
studies, a dose of 0.48 mg/kg was necessary for more
than 30% inhibition of brain MAO-B; however, in
studies with multiple doses (1-week, twice-daily dosing) a dosage of 0.40 mg/kg twice a day afforded the
same degree of continuous MAO-B inhibition [lo].
The MAO-B activity returned to baseline levels within
36 hours after the last dose. These short-term studies
indicated that a dosage of 50 mg/day will provide complete inhibition of MAO-B, but suggested that long-
term multiple doses may have greater cumulative
MAO-B inhibition.
In a 6-week, randomized, placebo-controlled, doubleblind trial of lazabemide in 201 patients with early
untreated PD, we found that dosages of 100 to 400
mg/day of lazabemide were well tolerated, although
there was a slightly increased frequency of insomnia
and laboratory test abnormalities (low hematocrit and
elevated serum alanine aminotransferase levels) associated with lazabemide at a dosage of 400 mg/day [I 11.
We also found lazabemide to be well tolerated at dosages of 100 to 400 mg/day in levodopa-treated PD
patients [ 121. Both lazabemide and deprenyl exerted
similarly mild ameliorative effects on the clinical features of PD after 4 weeks of administration [4, 111.
Prompted by these findings, we conducted a randomized, multicenter, placebo-controlled, double-blind
clinical trial over 1 year to determine the impact of
selected dosages of lazabemide on the progression of
disability in early, otherwise untreated PD, and to
further assess the long-term tolerability and safety of
Materials and Methods
This multicenter study, organized by the Parkinson Study
Group and sponsored by Hoffmann-La Roche (Nutley, NJ),
was reviewed and approved by the institutional review boards
See Appendix for full list of authors and affiliations.
Received Oct 20, 1995, and in revised form Feb 21, 1996. Accepted
for publication Feb 21, 1996.
Address correspondence to Dr Kieburtz, Department of Neurology,
University of Rochester Medical Center, 601 Elmwood Avenue,
Rochester, NY 14642.
Copyright 0 1996 by the American Neurological Association 99
at each of 18 participating centers. An independent safety
monitoring committee periodically reviewed the safety data
to ensure that disproportionate intolerance was not occurring
among the treatment groups.
Recruitment and Enrollment
Three hundred twenty-one eligible patients were enrolled in
the trial over 9 months between April 1992 and January
1993. As in the DATATOP trial [4],eligible patients included those who had idiopathic PD for less than 7 years
and who were in Hoehn and Yahr stage I or I1 of illness [13].
Patients were excluded if they (1) had atypical or secondary
parkinsonism; (2) had resting tremor scores higher than 3.0
on the Unified Parkinson's Disease Rating Scale (UPDRS)
[14];(3) were judged by the enrolling investigator to likely
require symptomatic treatment for I'D within a month after
randomization; (4) had unstable medical or psychiatric problems, a Mini-Mental State Examination [15] score of less
than 23, or a Hamilton Depression Rating Scale [16] score
higher than 15; (5) were taking any medication to treat PD
or any other medications that might affect the central nervous system and potentially confound the interpretation of
the results; or (6) were treated within 2 months of baseline
with a monoamine oxidase inhibitor or within 6 weeks of
baseline with levodopa or directly acting dopamine agonists.
The use of antidepressants, hypnotics, and amphetamines
was not permitted during the conduct of the study.
After informed consent was obtained, patients were randomly assigned at the baseline evaluation to one of five treatment groups: (1) lazabemide, 25 mg/day; (2) lazabemide, 50
mg/day; (3) lazabemide, 100 mglday; (4) lazabemide, 200
mg/day; or (5) matching placebo. The higher dosages had
previously been well tolerated in patients with untreated PD
[ I l l , and the lower dosages were thought to be minimally
effective. Within each experimental treatment group, patients were further assigned by randomization to receive active medication for either 52 or 54 weeks, followed respectively by placebo for either 4 or 2 weeks. This design
provided for a blinded, staggered withdrawal of lazabemide
and permitted a more objective assessment of the effects of
discontinuing experimental treatments. Based on the pharmacokinetic properties of this reversible MAO-B inhibitor,
the withdrawal periods were sufficiently long to expect complete elimination of lazabemide [ 101.
The randomization plan included stratification by investigator and blocking of treatment assignment to ensure that
each investigator had approximately the same number of patients assigned to each of the five treatment groups. Each of
the participating 18 investigators enrolled between 13 and
2 I patients. All patients, investigators, and coordinating staff
were kept unaware of treatment assignments.
Therapy and Follow-up
Patients orally took 12.5-mg, 25-mg, 50-mg, or 100-mg tablets of lazabemide or matching tablets of placebo (HoffmannLa Roche, Nutley, NJ) twice daily, approximately 12 hours
apart. Experimental treatments were started at the maintenance dose on the morning after the day of randomization.
100 Annals of Neurology
Vol 40
No 1 July 1996
Patients were reevaluated at 4 , 13, 26, 39, 52, 54, and 56
weeks after randomization. At each evaluation, the investigator was asked to judge if the patient had reached a level of
functional disability sufficient to warrant the initiation of
levodopa therapy. Additional clinical evaluations included
the UPDKS and its components [14] and measurements of
blood pressure, pulse, and weight. Patients were assessed for
adverse clinical experiences and also underwent a battery of
laboratory tests (Roche Biomedical Laboratories, Karitan,
NJ) including urinalysis, hematology (hemoglobin, hematocrit, mean cell volume, white blood cell count with differential, platelet count), and serum chemistry profiles (sodium,
potassium, chloride, biocarbonate, calcium, phosphorus, alanine aminotransferase, aspartate aminotransferase, lactate dehydrogenase, alkaline phosphatase, total protein, total bilirubin, glucose, creatinine, urea nitrogen, uric acid, cholesterol,
and triglycerides). Surveillance laboratory tests were also performed at weeks 8, 19, 32, and 45, and an electrocardiogram
was obtained at baseline and 4,26, and 52 weeks.
Monitoring of compliance was carried out at follow-up
evaluations by counting the number of unused tablets returned by the patient. Urinary testing for the presence of
amphetamine and methamphetamine was performed to help
detect the exclusionary use of deprenyl.
1he investigator, on the basis of a personal evaluation of
the patient, was permitted to discontinue experimental treatments for up to 7 days if the patient developed persistent
or recurrent adverse experiences judged to be of clinical significance. If the adverse experience abated, the full number
of tablets was resumed. Patients could be withdrawn from
the study if an adverse experience was judged to be severe
and persistent.
Primary Outcome Variable
The primary end point in the trial occurred if and when the
investigator determined, on the basis of a personal evaluation, that the patient had reached a level of functional disability sufficient to warrant initiation of levodopa therapy.
The primary end point could also occur at an interim unscheduled visit based on a personal evaluation of the patient
by the investigator. The primary outcome variable for the
trial was defined as the number of days from randomization
to the occurrence of the primary end point. If and when the
patient reached the end point, the evaluations for week 52
were performed, followed by completion of the blinded, staggered withdrawal of experimental treatment as described
above. If the patient reached the end point after the visit at
week 52, the evaluations for week 54 and week 56 were
performed as scheduled.
Statistical Analysis
This study was designed to have approximately 0.90 power
to detect a significant association between the natural logarithm of the dose level and the probability of reaching the
end point, assuming that the true correlation between these
two variables was 0.20, using a two-sided test at the 5% level
of significance. The required sample size was calculated to
be 250 subjects, or 50 subjects per group.
Survival analysis techniques were used to examine the ef-
fect of lazabemide treatment on the primary outcome measure. These methods account for varying lengths of followup among the patients who reached the end point, those
who prematurely withdrew from the trial before reaching the
end point, and those who had not reached the end point as
of the week 52 evaluation. As prespecified, end points occurring after the week 52 visit were not included in the primary analysis but rather summarized separately. In accordance with the intention-to-treat principle [ 171, the primary
statistical analyses included all 321 patients who were randomly assigned to the five treatment groups. All p values
reported are two-sided.
The primary statistical analysis used the Cox proportional
hazards regression model [ 181, with the natural logarithm
of the dosage level as the independent variable and investigator as a stratification factor. For purposes of this analysis
the natural logarithm of zero was defined as zero, a definition
that was prespecified before data analysis. Treatment effects
were also examined by considering treatment as a five-level
nominal variable in the Cox model, and also by combining
the four active treatment groups and considering treatment
as a dichotomous variable (lazabemide vs placebo) in the
Cox model. Relative risks in the latter two models are
described in terms of the hazard ratio (i.e., the ratio of
the risk of reaching the end point per unit of time in an
active treatment group to the corresponding risk in the
placebo group).
Interactions between treatment (dichotomous variable)
and preselected baseline covariates, including investigator,
were examined individually by including the covariate and
the appropriate interaction term in the Cox model. Continuous covariates were dichotomized at or near their median
values for purposes of these analyses. Hazard ratios were estimated in the subgroups defined by these covariates, and their
consistency was examined across subgroups.
The assumption of proportionality of hazards was checked
with the use of time-dependent covariates [ 191. Hazard ratios
were estimated separately for the 0- to 26-week and 26- to
52-week time periods, and a test for equality of these hazard
ratios was performed. The analysis was repeated post hoc
comparing the hazard ratios during the 0- to 13-week and
13- to 52-week time periods.
The cumulative probabilities of reaching the end point
in each treatment group were estimated with the method
of Kaplan and Meier [20]. Analysis of variance, with
treatment group as the factor of interest and investigator
as a stratification factor, was used to compare the groups
regarding the following secondary response variables: changes
in UPDRS scores from baseline to weeks 4 and 13; changes
in UPDRS scores from baseline to week 52, with the last
available observation before drug withdrawal carried forward
for patients having follow-up of less than 52 weeks; annualized rates of change in UPDRS scores calculated between
baseline and the last available visit before and after withdrawal of medication (only for patients having at least 26
weeks of follow-up) [4];and 2- and 4-week changes in
UPDRS scores during the withdrawal period (weeks 5256).
Tests were used to compare the frequencies of
adverse experiences and laboratory abnormalities among the
treatment groups.
Comparability of Treatment Groups
No clinically significant differences were found at baseline among the five groups with respect to demographic and clinical variables (Table 1).
Primary End Point
Table 2 summarizes the status of patients, by treatment
group, by the week 52 visit according to those who
reached the primary end point, those who withdrew
from the study prior to reaching the end point, and
those who did not reach the end point (“surviving’
patients). Among the 47 subjects who withdrew from
the study before its planned conclusion at week 52,
there was no evidence that the withdrawal rate or reasons for withdrawal were related to dosage. The reasons
for withdrawal included 4 deaths, 19 other adverse experiences (headache, pneumonia, angina, seizure, insomnia, anxiety, hypertension, constipation, fatigue,
and depression), 18 refusing follow-up, and 6 protocol
violations o r administrative withdrawals.
Twenty-nine subjects in the placebo group (43.9%)
reached the end point, compared with 80 in the combined active treatment groups (31.4%, see Table 2).
Kaplan-Meier plots (Fig) of the probability of reaching
the end point for each treatment group revealed a consistent beneficial effect of lazabemide across all dosages.
This effect is quantified by the hazard ratios from the
Cox proportional hazards models, which are presented
in Table 3. Although the test for a linear trend in the
risk of reaching the end point by the natural logarithm
of the dosage was very sensitive to the treatment effect
( p 0.008), it is clear from the magnitudes of the
hazard ratios for the individual active treatment groups
that this relationship was not linear. Instead, the beneficial effect of lazabemide was remarkably consistent
across the four active treatment groups, with hazard
ratios ranging from 0.47 to 0.55. The hazard ratio for
the combined active treatment groups was 0.49 (95%
confidence limits, 0.32 and 0.77; p = 0.001).
No clinically or statistically significant interactions
were found between treatment and dichoromized baseline variables, including age, gender, years since onset
of symptoms, previous deprenyl use, previous levodopa
use, UPDRS scores, Hoehn and Yahr stage, Hamilton
Depression Rating Scale score, and Mini-Mental State
Examination score. Also, no statistically significant differences in treatment effect were found among the 18
investigators. The assumption of proportionality of
hazards appeared to be reasonable, with hazard ratios
being very similar for the 0- to 26-week and 26- to 52week observation periods. A post hoc analysis showed a
trend for the benefit of lazabemide treatment to be
more prominent during the first 3 months (0-13-week
hazard ratio of 0.40; 13-52-week hazard ratio of 0.54,
Parkinson Study Group: Lazabemide in Early PD
Table I . Patient Characteristics at Baseline”
Dosage (mg/day)
No. of subjects
62.5 t 10.8
65.9 2 7.4
64.0 2 7.7
1.9 2 1.3
62.5 i 9.8
60.5 ir 10.1
2.0 i 1.5
64.2 % 11.1
62.4 _t 11.3
1.8 ir 1.5
65.8 t 9.5
63.8 ? 9.5
1.9 ? 1.5
20.8 t 8.1
0.9 _f 1.1
14.4 t 6.2
5.4 ir 3.3
2.3 _t 2.9
28.9 5 1.6
Age (yr)
60.7 F 10.9
1.7 t 1.4
Male gender (Yo)
Age at onset (yr)
Years since symptom onset
Prior deprenyl use (Yo)
Prior levodopa use (Yo)
UPDRS scores
Activities of daily living
Hoehn/Yahr stage I (%)
Hamilton Depression Rating Scale
Mini-Mental State Examination
-+ 9.3
i 0.8
t- 7.5
? 3.1
C 1.9
2 1.6
F 11.0
t 1.0
-+ 8.1
t 3.6
2 1.8
t 1.5
i 10.9
i 1.2
t 8.5
2 3.1
t 2.9
i 1.3
? 10.0
i 0.9
2 7.6
2 3.6
i 1.1
‘Values are presented as mean ? SD, unless otherwise indicated
UPDKS = Unified Parkinson’s Disease Rating Scale.
Table 2. Status of Patients by the Week 52 Ksit
Dosage (mg/day)
Reached the end pointa
29 (43.9)
20 (33.3)
19 (28.4)
21 (32.8)
20 (31.3)
109 (34.0%)
Withdrew before week 52
Did not reach the end point
32 1
'values in parentheses are percentages for each treatment group.
for the combined active treatment groups); however,
this difference was not statistically significant ( p =
Seventeen patients reached the end point after the
week 52 visit; 15 of them reached the end point after
withdrawal from active treatment (N = 2 for 25 mg;
N = 4 for 50 mg; N = 5 for 100 mg; N = 4 for
200 mg). The remaining 2 patients were still receiving
active treatment (N = 1 for 50 mg, N = 1 for 200
mg) when they reached the end point. None of the
patients assigned to the placebo group reached end
point during the withdrawal period.
Seconda y Response Variables
Table 4 shows the average changes from baseline to
week 52 visit for the five groups on the UPDRS (total
score and the mental, motor, and activities of daily
living components); the last available observation before drug withdrawal was used to calculate the change
102 Annals of Neurology
Vol 40
No 1 July 1996
for patients having follow-up for less than 52 weeks.
There were no statistically significant differences between the individual treatment groups regarding these
changes; however, in nearly all patients the average
changes for the active treatment groups were less than
that for the placebo group. The average change in total
UPDRS score for the combined active treatment group
(N = 253) was approximately 2 points less than that
for the placebo group (N = 66): -6.1 (8.4) [mean
(SD)] versus -8.1 (8.5),p = 0.06. Similar results were
seen for the annualized rates of change calculated between baseline and the last evaluation before drug
When medication was withdrawn, UPDRS scores
tended to decline in the active treatment groups and
remain stable in the placebo group (Table 5), but no
statistically significant differences occurred among the
groups. In general, the effects of withdrawal were similar over the 2-week and 4-week periods.
25 mgiday
50 mg/day
100 rnglday
200 rng/day
Weeks After Randomization
Cumulative probabiliv of reaching the primary end point
(Kaplan-Meier estimate), according to treatment group.
Table 3. Cox Proportional Hazards Modelsa
Model 1
Log (dosage)
Model 2
25 mg
50 mg
100 mg
200 mg
Model 3
Hazard Ratio
p Value
(0.77, 0.96)
(0.26, 0.90)
(0.26, 0.86)
(0.31, 0.98)
(0.26, 0.84)
(0.32, 0.77)
’Model 1: linear regression on log dosage (primary analysis); model
2: treatment as a five-level nominal variable; model 3: treatment as
a dichotomous variable. See text for derails.
“ p value for test of equality of the five hazard ratios.
The annualized rates of change for patients who
completed at least 26 weeks of follow-up, calculated
between baseline and the Iasr evaluation after drug
withdrawal, did not differ significantly among the five
groups (Table 6). Similar results were also observed
when patients who did and those who did not reach
the end point were considered separately.
The short-term effects of lazabemide after 4 and 13
weeks, compared with baseline, were small and, in general, not statistically significant (Table 7). Some improvement was detected on the total UPDRS score in
the 50-mg group, after Bonferroni adjustment for multiple comparisons.
Adverse Experiences and Tolerability of
Experimental Medications
The occurrence of clinical adverse experiences and abnormal laboratory results was distributed uniformly
among all treatment groups. The most common adverse experiences were headache (49/321 subjects),
nausea (26), upper respiratory infections (27), “flulike” symptoms (21), light-headedness (1 8). insomnia
(18), dizziness (18), constipation (16), and fatigue
(16). There was no statistically significant difference in
the frequency of these events among the treatment
groups. The numbers of patients experiencing one or
more clinical adverse experiences, of any kind, in each
of the groups were as follows: placebo group = 38
(58%), 25-mg group = 36 (60%), 50-mg group = 46
(69%), 100-mg group = 40 (63%), and 200-mg group
= 44 (69%). Four deaths occurred during the study:
one in the placebo group (sudden cardiac death), 1 in
the 100-mg group (ruptured abdominal aneurysm),
and two in the 200-mg group (motor vehicle accident,
postoperative cardiac arrest). Two additional patients
died within a month of study participation: 1 in the
placebo group (myocardial infarction) and 1 in the 25mg group (respiratory failure). None of the deaths were
thought to be related to experimental treatment.
There were no differences among the treatment
groups regarding changes in any of the laboratory tests
or vital signs at any visit, including during the withdrawal of treatment. There was no difference in the
frequency of electrocardiogram abnormalities among
the treatment groups. One subject in the 100-mglday
group had a transient and self-limited elevation of serum aspartate aminotransferase to five times the upper
limit of normal, and 1 patient in the ZOO-mgiday
group had a similar elevation to three times the upper
limit of normal.
The overall compliance of study medications was
not different among treatment groups, ranging between 92 and 97%. No exclusionary use of deprenyl
(“drop-in”) was detected by testing of urine for amphetamines.
Parkinson Study Group: Lazabemide in Early PD
Table 4. Changes in UPDRS Scores fiom Baseline to Week 52"
Dosage (rng/day)
(n = 66)
T o t a l UPDRS
Mental UPDRS
M o t o r UPDRS
25 (n
50 ( n
100 (n
-5.3 (8.3)
-0.3 (1.2)
-3.4 (6.2)
-1.5 (3.2)
200 (n
'The last available observation before drug withdrawal was used for the week 52 visit for patients having less than 52-week follow-up. Values
are presented as mean (SD), where negative values indicate a worsening.
UPDRS = Unified Parkinson's Disease Rating Scale; ADL = activities of daily living.
Table 5. Chunges in Total UPDRS Scores During Drug WithdrawaP
Dosage (rng/day)
A. All patients during first 2 weeks of withdrawal
2 wk
n = 44
n = 49
n = 50
-1.9 (6.8)
-0.2 (4.8)
n = 51
-0.0 (7.5)
n = 47
0.9 (5.0)
B. Patients having 4 weeks of withdrawal
2 wk
4 wk
0.7 (4.6)
0.0 (5.1)
-0.8 (7.2)
-3.5 (6.5)
n = 19
n = 23
0.4 (7.8)
-0.5 (7.7)
-0.7 (6.3)
-0.9 (6.0)
= 25
0.3 (5.8)
-0.4 (6.3)
-1.3 (5.1)
"Values are presented as mean (SD), where negative values indicate a worsening.
UPDRS = Unified Parkinson's Disease Rating Scale.
Table 6 Annualized Rates of Chunge in UPDRS Scores fiom Baseline to AJter Drug WithdrawaP
Dosage (mglday)
T o t a l UPDRS
Mental UPDRS
M o t o r UPDRS
-8.7 (10.5)
-0.3 (1.2)
-5.5 (7.4)
-2.9 (3.7)
25 ( n
50 (n
100 ( n
200 (n
-6.5 (8.2)
-0.1 (0.7)
-4.7 (6.8)
- 1.7 (2.4)
'Includes patients who completed at least 26 weeks of follow-up. Values are presented as mean (SD), where negative values indicate a
Unified Parkinson's Disease Rating Scale; ADL = activities of daily living.
Our clinical trial showed that lazabemide, at dosages
ranging from 25 to 200 mglday, delayed the onset of
disability associated with early, otherwise untreated
PD. Although we had not expected that all dosages
would be similarly beneficial, the effects appeared to
be uniform across all active treatment groups throughout the study. The benefits of lazabemide on the primary end point of disability were independent of patients' baseline characteristics and appeared to be
relatively consistent throughout the study.
There was some evidence of a mild improvement in
parkinsonian features with the initiation of lazabemide
104 Annals of Neurology Vol 40
No 1
July 1996
and slight worsening after its withdrawal, as evidenced
by the number of patients in the active treatment arms
requiring levodopa treatment during the period of lazabemide withdrawal and the trend in patients in the
active treatment arms toward worsening of UPDRS
scores during lazabemide withdrawal.
This study was designed to determine whether or
not lazabemide delays the onset of disability sufficient
to warrant levodopa therapy in early I'D. Although the
study clearly demonstrated that lazabemide was effective in this regard, the limitations of clinical trial design
precluded our ability to define the mechanism underlying the effect, and especially whether or not lazabemide
Table 7.Changes in UPDRS Scores fiom Baseline to 4 and 13 Weeks"
Dosage (mglday)
4 wk
13 wk
Mental UPDRS
4 wk
13 wk
4 wk
13 wk
4 wk
13 wk
-0.9 t 5.9
-1.5 2 5.9
1.0 2 4.9
0.3 2 6.7
1.6 2 5.5b
2.0 t 5.3b
-0.2 2 5.4
0.0 t 5.8
0.4 t 4.0
-0.4 t- 5.4
-0.2 t 0.9
-0.2 2 1.0
0.1 t 1.1
0.2 t 1 . 0 b
0.1 ? 1.1
0.1 t 0.8
0.0 5 1.0
0.0 t 0.8
-0.1 t 1.0
-0.7 2 4.5
-0.9 t 4.5
0.6 2 3.6
0.1 t 5.2
0.8 2 4.4
1.2 5 4.0
0.0 2 4.0
0.0 t 4.4
0.1 t 3.5
-0.1 2 4.5
-0.1 ? 2.2
-0.3 2 2.2
0.3 2 1.9
0.1 t 2.4
0.6 t 1.7
0.6 t 2.4
-0.3 t 1.7
-0.1 t 2.1
0.4 5 1.6
-0.2 t 1.7
'Values presented are mean 2 SD. Negative numbers indicate a worsening.
bp < 0.05 for comparison with placebo group, after Bonferroni adjustment for multiple comparisons. See text for details.
UPDRS = Unified Parkinson's Disease Rating Scale; ADL = activities of daily living.
slows the underlying progression of the disease. Moreover, the mild antiparkinsonian effect of lazabemide
confounds the ability to distinguish between symptomatic (short-term clinical benefit) and more enduring
neuroprotective effects. Changes in UPDRS scores between the baseline and final (after drug withdrawal)
visits could have been used as a surrogate index of disease progression; however, nearly half of the patients
in our trial either reached the end point or withdrew
from the study before the final visit. Therefore, our
analyses of annualized rates of change between the
baseline and final visits cannot adequately clarify the
mechanism. An alternative design of following all
patients for a fixed period of time (e.g., 52 weeks),
withdrawing all antiparkinsonian medications (e.g.,
levodopa, deprenyl), and then reassessing would be
complicated by the problem of dropouts and the need
for a sufficiently long drug withdrawal period to ensure
a valid assessment of the patient in a truly unmedicated
state. For example, the 2-month withdrawal period for
deprenyl in the DL4TATOP study may not have been
sufficiently long to entirely eliminate the pharmacological effects of this drug [21], but longer periods entirely
off the drug may be unrealistic for patients requiring
symptomatic amelioration of their illness.
The magnitude of the effect of lazabemide in delaying the need for levodopa therapy and its short-term
impact on the clinical features of PD were similar to
those observed with deprenyl (selegiline) treatment in
the DATATOP trial [4].All lazabemide dosages were
equally effective in this regard. These results are somewhat surprising, especially for the 25-mg/day group,
which in previous lazabemide studies utilizing "C-selegiline PET imaging in PD patients [lo] afforded only
partial (about 80%) continuous inhibition of MAO-B
activity. It is possible that less than complete continuous inhibition of MAO-B is sufficient for benefit, and
more prolonged administration of lazabemide (i.e., > 1
week) may result in more extensive inhibition of
MAO-B. Alternatively, the observed benefits may not
be directly related to the extent of MAO-B inhibition.
Recent work by Tatton and Greenwood [22] suggests
that the MAO-B inhibitor deprenyl may have an impact on cell death and recovery, independent of the
inhibition of MAO-B. It is not known whether or not
lazabemide exerts similar effects.
The adverse effects of lazabemide were generally
mild and clinically inconsequential (not serious). There
were rare increases in serum levels of aspartate aminotransferase, which we previously observed in smaller
and briefer trials with lazabemide [9, 101. We found
no increased frequency in electrocardiographic abnormalities attributable to lazabemide [ 4 ] ,
Lazabemide may be an effective alternative treatment
in early untreated P D in light of its selectivity for
MAO-B, reversibility, lack of active metabolites, and
similar efficacy to deprenyl. A direct comparison of deprenyl and lazabemide in patients with early untreated
PD would be necessary to adequately determine the
relative efficacy and tolerability of these MAO-B inhibitors. The mechanisms accounting for the beneficial affects of lazabemide in early PD remain unclear. Based
on our observations in this and previous studies [I 1,
121, lazabemide at dosages of 25 to 200 mg/day is
effective and well tolerated in patients with early, otherwise untreated PD.
The Parkinson Study Group authors of this study are
as follows:
Parkinson Study Group: Lazabemide in Early PD
Steering Committee
Karl Kieburtz, M D (Medical Director), Michael McDermott, PhD (Chief Biostatistician), Ira Shoulson,
M D (Principal Investigator), University of Rochester,
Rochester, NY; Stanley Fahn, M D (Co-Principal Investigator), Columbia-Presbyterian Medical Center,
New York, NY; Mitchell Brin, MD, Mt. Sinai Medical Center, New York, NY; Christopher Goetz, MD,
Rush-PresbyteriadSt. Luke’s Medical Center, Chicago, IL; Anthony Lang, MD, The Toronto Hospital,
Toronto, Ontario, Canada; C. Warren Olanow, MD,
University of South Florida, Tampa, FL.
Participating Investigators and Coordinators
Peter LeWitt, MD, Kathie Mistura, RN, Sinai Hospital, Detroit, MI; Cheryl Waters, MD, Mickie Welsh,
RN, DNS, University of Southern California, Los
Angeles, CA; Robert Rodnitzky, MD, Judith Dobson,
RN, University of Iowa, Iowa City, IA;Oksana Suchowersky, MD, Pat Argatoff, RN, University of
Calgary Medical Center, Calgary, Alberta, Canada;
Caroline Tanner, MD, Paula Lewis, RN, Parkinson’s
Institute, Sunnyvale, CA; Ray Watts, MD, Becky
Bryan, RN, Emory University School of Medicine,
Atlanta, GA; Cynthia Comella, MD, Jean A. Jaglin,
RN, Rush-PresbyterianiSt. Luke’s, Chicago, IL; Cliff
Shults, MD, Deborah Fontaine, RN, University of
California, San Diego, La Jolla, CA; Susan B. Bressman, MD, Carol Moskowitz, RN, Columbia-Presbyterian Medical Center, New York, NY; Howard I. Hurtig, MD, Kathy Shallow, BA, The Graduate Hospital
and the University of Pennsylvania, Philadelphia, PA;
Jean Hubble, MD, Ruth Barter, RN, University of
Kansas, Kansas City, KS; James P.Bennett, MD, PhD,
Elke Rost-Ruffner, RN, University of Virginia, Charlottesville, VA; Joel s. Perlmutter, MD, Lori McGeeMinnich, RN, Washington University, St. Louis, MO;
Robert Hauser, MD, Lisa Gauger, BA, University of
South Florida, Tampa, FL; Ali H. Rajput, MD, Ann
Sutton, RN, University of Saskatchewan, Saskatoon,
Saskatchewan, Canada; Kimberly Trinidad, MD, Irenita Flynn Gardiner, RN, University of Rochester,
Rochester, NY; Carlos Singer, MD, Carol Sheldon,
RN, University of Miami, Miami, FL; J. Stephen Fink,
MD, PhD, Marsha Tennis, RN, Massachusetts General Hospital, Boston, MA.
Biostatistics and Coordination Centers Staff
Deborah Baker (secretary), Keith Bourgeois, BS (analyst-programmer), Cynthia Casaceli, MBA (analystprogrammer), Kathy Claude, MS (information analyst), Charlyne Hickey, RN, MS (nurse clinician),
Ruth Nobel (secretary), David Oakes, PhD (b’lostatistician), Constance Orme, BA (information analyst),
Rita M. Pelusio, MSEd (program manager), Sandra
Plumb, BS (lead programmer), Alice Rudolph, PhD
106 Annals of Neurology
Vol 40
No 1 July 1996
(senior study coordinator), Heidi Randolph (data control clerk), Jenny Sotack (data control clerk), Arthur
Watts, BA (analyst-programmer).
Sa$q Monitoring Committee
Pierre N. Tariot, MD, Chair, Rochester, NY;Lawrence I.
Golbe, MD, UMDNJ Robert Wood Johnson Medical School, New Brunswick, NJ; J. Phil Miller, AB,
Washington University Medical School, St. Louis,
MO; W. Jackson Hall, PhD, University of Rochester,
Rochester, NY; Robert Herndon, MD, Good Samaritan Hospital, Portland, OR.
Hofiann-La Roche
Ernest Dorflinger, MD, David Myl, Marlene Modi,
PhD, Leigh Oarsley, Kisook Yoo, PhD, Elie Eliahou,
Ghazwan Shimoun, PharmD, Gina Colletta, Judy
Siege1 (Nutley, NJ), Simon Pedder, PhD, Connie Dupuis, RN, MA (Missisauga, Ontario, Canada).
Presented in part at the American Academy of Neurology, Seattle,
WA, May 10, 1995.
1. Da Prada M, Kettler R, Keller HH, et al. From moclobemide
to Ro 19-6327 and Ro 41-1049: the development of a new
class of reversible, selective MAO-A and MAO-B inhibitors.
J Neural Transm 1990;29(suppl):279-292
2. Cohen G, Pasik P, Cohen B, et al. Pargyline and deprenyl
prevent the neurotoxicity of MPTP in monkeys. Eur J Pharmacol 1984;106:209-210
3. Reinhard F Jr, Carmichael SW, Daniels AJ. Mechanisms of
toxicity and cellular resistance to 1-methyl-4-phenyl-l,2,3,6tetrahydropyridine and 1-methyl-4-phenylpyridinium in adrenomedullary chromaffin cell cultures. J Neurochem 1990;55:
4. Parkinson Study Group. Effects of tocopherol and deprenyl
on the progression of disability in early Parkinson’s disease.
N Engl J Med 1993;328:176-183
5. Teravainen H. Selegiline in Parkinson’s disease. Acta Neurol
Scand 1990;81:333-336
6. Allain H, Cougnard J, Neukrich H-C, the FSMT members.
Selegiline in de novo parkinsonian patients: the French Selegiline Multicenter Trial (FSMT). Acta Neurol Scand Suppl
1991 ;136:73-78
7. Myllyla W, Sotaniemi KA, Vuorinen JA, Heinonen EH. Selegiline as initial treatment in de novo parkinsonian patients.
Neurology 1992;42:339-343
8. DaPrada M, Kettler R, Keller HH, Burkard WP. Ro 19-6327,
a reversible, highly selective inhibitor of type B monoamine
oxidase, completely devoid of tyramine-potentiating effects:
comparison with selegiline. In: Dahlstrom A, ed. Progress in
catecholamine research. Part B: central aspects. New York:
Alan R Liss, 1988:359-363
9 Bench CJ, Price GW, Larnmerrsma AA, et al. Measurement of
human cerebral monoamine oxidase type B (MAO-B) activity
with positron emission tomography (PET): a dose ranging
study with the reversible inhibitor Ro 19-6327. Eur J Clin
Pharmacol 199 1 9 0 :169% 173
10 Fowler JS, Bolkow ND, Logan J, et al. Monoamine oxidase B
( M A 0 B) inhibitor therapy in Parkinson’s disease: the degree
and reversibiliry of human brain MA0 B inhibition by Ro 196327. Neurology 1993;43:1984-1992
Parkinson Study Group. A controlled trial of lazabemide (Ro
19-6327) in untreated Parkinson’s disease. Ann Neurol 1993;
Parkinson Study Group. A controlled trial of lazabernide (Ro
19-6327) in levodopa-treated Parkinson’s disease. Arch Neurol
Hoehn MM, Yahr MD. Parkinsonism: onset, progression and
mortality. Neurology 1967; 17:427-442
Lang AE,Fahn S. Assessment of Parkinson’s disease. In: Munsat TL, ed. Quantification of neurologic deficit. Boston: Buttenvorths, 1989285-309
Folstein MF, Folstein SE, McHugh P. Mini-Mental State: a
practical method for grading the cognitive state of patients for
the clinician. J Psychiatr Res 1975;12:189-198
Hamilton M. A rating scale for depression. J Neurol Neurosurg
Psychiatiy 1960;23:56-62
17. Cox DR. Regression models and life-tables. J R Stat SOC[B]
18. Peto R, Pike MC, Armitage P, et al. Design and analysis of
randomized clinical trials requiring prolonged observation of
each patient. I. Introduction and design. Br J Cancer 1976;
19. Kalbfleisch JD, Prentice RL. The statistical analysis of failure
time data. New York: Wiley, 1980
20. Kaplan EL, Meier P. Nonparametric estimation from incomplete observations. J Am Stat Assoc 1958;53:457-481
21. Parkinson Study Group. Cerebrospinal fluid homovanillic acid
in the DATATOP study on Parkinson’s disease. Arch Neurol
22. Tatton WG, Greenwood CE. Rescue of dying neurons: a new
action for deprenyi in MPTP parkinsonism. J Neurosci Res
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