Clinical Trials
Schizophrenia
The efficacy of oral ziprasidone in the treatment of schizophrenia was evaluated
in 5 placebo-controlled studies, 4 short-term (4- and 6-week) trials and one long-term
(52-week) trial. All trials were in inpatients, most of whom met DSM III-R criteria
for schizophrenia. Each study included two to three fixed doses of ziprasidone as
well as placebo. Four of the 5 trials were able to distinguish ziprasidone from
placebo; one short-term study did not. Although a single fixed-dose haloperidol
arm was included as a comparative treatment in one of the three short-term trials,
this single study was inadequate to provide a reliable and valid comparison of ziprasidone
and haloperidol.
Several instruments were used for assessing psychiatric signs and symptoms in these
studies. The Brief Psychiatric Rating Scale (BPRS) and the Positive and Negative
Syndrome Scale (PANSS) are both multi-item inventories of general psychopathology
usually used to evaluate the effects of drug treatment in schizophrenia. The BPRS
psychosis cluster (conceptual disorganization, hallucinatory behavior, suspiciousness,
and unusual thought content) is considered a particularly useful subset for assessing
actively psychotic schizophrenic patients. A second widely used assessment, the
Clinical Global Impression (CGI), reflects the impression of a skilled observer,
fully familiar with the manifestations of schizophrenia, about the overall clinical
state of the patient. In addition, the Scale for Assessing Negative Symptoms (SANS)
was employed for assessing negative symptoms in one trial.
The results of the oral ziprasidone trials in schizophrenia follow:
(1) In a 4-week, placebo-controlled trial (n=139) comparing 2 fixed doses of ziprasidone
(20 and 60 mg BID) with placebo, only the 60 mg BID dose was superior to placebo
on the BPRS total score and the CGI severity score. This higher dose group was not
superior to placebo on the BPRS psychosis cluster or on the SANS.
(2) In a 6-week, placebo-controlled trial (n=302) comparing 2 fixed doses of ziprasidone
(40 and 80 mg BID) with placebo, both dose groups were superior to placebo on the
BPRS total score, the BPRS psychosis cluster, the CGI severity score and the PANSS
total and negative subscale scores. Although 80 mg BID had a numerically greater
effect than 40 mg BID, the difference was not statistically significant.
(3) In a 6-week, placebo-controlled trial (n=419) comparing 3 fixed doses of ziprasidone
(20, 60, and 100 mg BID) with placebo, all three dose groups were superior to placebo
on the PANSS total score, the BPRS total score, the BPRS psychosis cluster, and
the CGI severity score. Only the 100 mg BID dose group was superior to placebo on
the PANSS negative subscale score. There was no clear evidence for a dose-response
relationship within the 20 mg BID to 100 mg BID dose range.
(4) In a 4-week, placebo-controlled trial (n=200) comparing 3 fixed doses of ziprasidone
(5, 20, and 40 mg BID), none of the dose groups was statistically superior to placebo
on any outcome of interest.
(5) A study was conducted in chronic, symptomatically stable schizophrenic inpatients
(n=294) randomized to 3 fixed doses of ziprasidone (20, 40, or 80 mg BID) or placebo
and followed for 52 weeks. Patients were observed for "impending psychotic relapse,"
defined as CGI-improvement score of ≥6 (much worse or very much worse) and/or scores
≥6 (moderately severe) on the hostility or uncooperativeness items of the PANSS
on two consecutive days. Ziprasidone was significantly superior to placebo in both
time to relapse and rate of relapse, with no significant difference between the
different dose groups.
There were insufficient data to examine population subsets based on age and race.
Examination of population subsets based on gender did not reveal any differential
responsiveness.
Bipolar Mania
The efficacy of ziprasidone in acute mania was established in 2 placebo-controlled,
double-blind, 3-week studies in patients meeting DSM-IV criteria for Bipolar I Disorder
with an acute manic or mixed episode with or without psychotic features.
Primary rating instruments used for assessing manic symptoms in these trials were:
(1) the Mania Rating Scale (MRS), which is derived from the Schedule for Affective
Disorders and Schizophrenia-Change Version (SADS-CB) with items grouped as the Manic
Syndrome subscale (elevated mood, less need for sleep, excessive energy, excessive
activity, grandiosity), the Behavior and Ideation subscale (irritability, motor
hyperactivity, accelerated speech, racing thoughts, poor judgment) and impaired
insight; and (2) the Clinical Global Impression – Severity of Illness Scale (CGI-S),
which was used to assess the clinical significance of treatment response.
The results of the oral ziprasidone trials in bipolar mania follow:
(1) In a 3-week placebo-controlled trial (n=210), the dose of ziprasidone was
40 mg BID on Day 1 and 80 mg BID on Day 2. Titration within the range of
40-80 mg BID (in 20 mg BID increments) was permitted for the duration of the study.
Ziprasidone was significantly more effective than placebo in reduction of the MRS
total score and the CGI-S score. The mean daily dose of ziprasidone in this study
was 132 mg.
(2) In a second 3-week placebo-controlled trial (n=205), the dose of ziprasidone
was 40 mg BID on Day 1. Titration within the range of 40-80 mg BID (in 20 mg BID
increments) was permitted for the duration of study (beginning on Day 2). Ziprasidone
was significantly more effective than placebo in reduction of the MRS total score
and the CGI-S score. The mean daily dose of ziprasidone in this study was 112 mg.
Acute Agitation in Schizophrenic Patients
The efficacy of intramuscular ziprasidone in the management of agitated schizophrenic
patients was established in two short-term, double-blind trials of schizophrenic
subjects who were considered by the investigators to be “acutely agitated” and in
need of IM antipsychotic medication. In addition, patients were required to have
a score of three or more on at least three of the following items of the PANSS:
anxiety, tension, hostility and excitement. Efficacy was evaluated by analysis of
the area under the curve (AUC) of the Behavioural Activity Rating Scale (BARS) and
Clinical Global Impression (CGI) severity rating. The BARS is a seven point scale
with scores ranging from 1 (difficult or unable to rouse) to 7 (violent, requires
restraint). Patients' scores on the BARS at baseline were mostly 5 (signs of overt
activity [physical or verbal], calms down with instructions) and as determined by
investigators, exhibited a degree of agitation that warranted intramuscular therapy.
There were few patients with a rating higher than 5 on the BARS, as the most severely
agitated patients were generally unable to provide informed consent for participation
in pre-marketing clinical trials.
Both studies compared higher doses of ziprasidone intramuscular with a 2 mg control
dose. In one study, the higher dose was 20 mg, which could be given up to four times
in the 24 hours of the study, at interdose intervals of no less than four hours.
In the other study, the higher dose was 10 mg, which could be given up to four times
in the 24 hours of the study, at interdose intervals of no less than two hours.
The results of the intramuscular ziprasidone trials follow:
(1) In a one-day, double-blind, randomized trial (n=79) involving doses of ziprasidone
intramuscular of 20 mg or 2 mg, up to QID, ziprasidone intramuscular 20 mg was statistically
superior to ziprasidone intramuscular 2 mg, as assessed by AUC of the BARS at 0
to four hours, and by CGI severity at four hours and study endpoint.
(2) In another one-day, double-blind, randomized trial (n=117) involving doses of
ziprasidone intramuscular of 10 mg or 2 mg, up to QID, ziprasidone intramuscular
10 mg was statistically superior to ziprasidone intramuscular 2 mg, as assessed
by AUC of the BARS at 0 to two hours, but not by CGI severity.