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PARIS, FRANCE -- September 22, 2006 -- The second generation
antipsychotic ziprasidone has comparable efficacy to the
current gold standard, clozapine, while showing improved
tolerability and metabolic safety, for patients with schizophrenia
who are refractory or intolerant, or both, to antipsychotic
treatment.
Study coordinator Fabio Romeo, MD, medical advisor, CNS
Team, Medical Affairs, Medical Department, Pfizer Italia,
Rome, Italy, presented this 18-week, equivalence (non-inferiority),
randomised, double-blind, parallel-group study on behalf
of the MOZART Study Group.
Among schizophrenic patients, about 20% to 30% do not respond
adequately to their current treatment due to inefficacy
or tolerability problems, represents a major public health
issue, said Dr. Romeo here on September 18th at the 19th
Congress of the European College of Neuropsychopharmacology
(ECNP).
Dr. Romeo and colleagues therefore designed a study to
compare the efficacy of ziprasidone versus that of clozapine
for treatment of patients with treatment-resistant schizophrenia.
A secondary objective was to compare the tolerability and
safety of clozapine and ziprasidone.
The key inclusion criteria were adults (>/=18 years
old; female patients had to be non-fertile or on approved
contraception).
Patients had a Diagnostic and Statistical Manual of Mental
Disorders, Revision IV (DSM-IV) diagnosis of schizophrenia,
with a documented history of refractory or intolerant antipsychotic
treatment, specifically defined as: refractory, lack of
adequate therapeutic response after >/=3 adequate (>/=6
week) trials in the previous 5 years; intolerant, unable
to achieve adequate therapeutic doses due to severe or persistent
side effects of a therapeutic dose. The patients also had
a Clinical Global Impression of Severity (CGI-S) >/=4,
and a Positive and Negative Syndrome Scale (PANSS) total
>/=80.
The main exclusion criteria were for clozapine or ziprasidone
treatment within the previous 3 months, along with a range
of clinical exclusions.
For drug dosing, Dr. Romeo stressed, "The dosing in
this trial was quite high, which is important for ziprasidone,
as it was about 140 mg/day." A starting dose of clozapine
25 mg/day was titrated up 25 mg/day to 300 mg/day for 1
week from day 10, with flexible dosing thereafter between
250 and 600 mg/day. The ziprasidone starting dose was 80
mg/day, increased to 120 mg/day from days 4 to 10, with
flexible dosing thereafter between 80 and 160 mg/day.
In all, 73 patients were randomised to clozapine and 73
to ziprasidone. There were no significant differences in
their clinical characteristics, including (clozapine vs
ziprasidone). Patients were 38.3 and 41.6 years, respectively;
67.1% and 71.2% were male, respectively.
The study used an analysis of covariance (ANCOVA) model.
The 4 most common antipsychotic treatments previously received
were: haloperidol (24.0% vs 24.6%); olanzapine (19.3% vs
18.1%); risperidone (18.8% vs 17.5%); and quetiapine (10.9%
vs 7.0%).
Both groups had significant reductions from baseline in
PANSS total score at the study end of day 11, the study's
primary outcome, in the intention-to-treat population as
last observation carried forward. The benefits of ziprasidone
fell entirely within the prespecified +/=13.5 limit (95%
unilateral confidence interval [CI] 6.45 and bilateral 95%
CI -6.42 to 7.59). Thus, ziprasidone was shown to be clinically
equivalent to clozapine.
Similarly, significant and equivalent improvements versus
baseline were seen for clozapine and ziprasidone for the
full PANSS subscales considered: positive, -7.0 versus -6.0;
negative, -6.1 versus -7.6; and general psychopathology,
-11.4 versus -11.3, respectively.
Clozapine and ziprasidone showed significant reductions
from baseline for CGI-S scores, from day 18 for clozapine
and day 11 for ziprasidone, to study endpoint, and significant
improvements from baseline in depressive symptoms, according
to decrease in Calgary Depression Scale for Schizophrenia
(clozapine, 2.1; ziprasidone, 3.1, P < .001).
The most frequently reported treatment-related adverse
events generally favoured ziprasidone. Specific analyses
were made for movement disorders in particular, for clozapine
versus ziprasidone, where greater and more significant improvements
from baseline were seen for ziprasidone: Simpson-Angus Scale
(P < .001), Barnes Akathisia Scale (P < .05); Abnormal
Involuntary Movement Scale (P < .001).
Ziprasidone-treated patients had no electrocardiogram abnormalities,
significantly more favourable lipid profiles, and significant
reduction in weight compared with clozapine. Clozapine was
also associated with significant increase over baseline
in fasting glucose levels.
Dr. Romeo stressed the need to use agents like ziprasidone
at the right doses. "If ziprasidone is used at these
doses, it is as effective as clozapine in this very difficult
to treat subgroup of patients, while it also showed better
tolerability and safety," he said.
This study was supported by funding from Pfizer Italia.
[Presentation title: Comparative Efficacy and Safety of
Ziprasidone and Clozapine in Treatment-Refractory Schizophrenic
Patients: Results of a Randomised, Double-Blind, 18-Week
Trial. Abstract P.3.a.019]
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