ELSEVI ER
`
`Ziprasidone 80 mg/ day and 160 mg/ day in the
`Acute Exacerbation of Schizophrenia and
`Schizoaffective Disorder: A 6-Week
`
`Placebo-Controlled Trial
`
`David G. Daniel, M.D., Dan L. Zimhrofi', M.D., Steven G. Potlcin, M.D., Karen R. Reeves, M.D.,
`Edmund P. Harrigan, M.D., Mani Lakshminarayanan, Ph.D., and the Ziprasidone Study Group
`
`
`
`in this double-blind study, patients with an acute
`exacerbation of schizophrenia or schizoafiective disorder
`were randomized to receive either zipraszdone 80 rag/day in =
`106) or 160 mg/day (n : 104) orplacebo (n : 92),for 6
`weeks. Both doses quiprasidone were statistically
`significantly more efective than placebo in improving the
`PANSS total, BPRS total, BPRS core items, CGl-S, and
`PANSS negative subscale scores (p < .05). Ziprasidone
`160 rag/day significantly improved depressive symptoms in
`patients with clinically signp‘icant depression at baseline
`(MADRS a 14, over-all mean 23.5) (p < .05) as compared
`with placebo. The percentage of patients experiencing
`adverse events was similar in each treatment group, and
`
`resultant discontinuation was rare. The mostfrequent
`adverse events associated with ziprasidone were generally
`mild dyspepsia, nausea, dizziness, and transient
`somnolence. Ziprasidone was shown to have a very low
`liabilityfor inducing movement disorders and weight gain.
`The results indicate that ziprasidone is fiective and well
`iolera ted in the treatment of the positive, negative, and
`depressive symptoms ofan acute exacerbation of
`schizophrenia or schizoafi’ective disorder.
`[Neuropsychophannaca logy 20:491—505, 1999]
`© 1999 American College ofNeuropsychopharmacology.
`Published by Elsevier Science Inc.
`
`KEY WORDS: Ziprasidone; Schizophrenia; Negative
`symptoms; Depression; Tolerahility; Antipsychotic
`
`Ziprasidone (5-[2-[4-(1,Z-Benzisothiazol-3—yl)piperazin—
`1-yl]ethyl]-6-chloroindolin-2-one hydrochloride hydrate)
`is a novel antipsychotic with high affinity for dopamine
`D2 and D3, serotonin 51-1sz SHTEC, and SHTID recep-
`tors and high affinity for the 5H1”m receptor, where it
`acts as a potent agonist (Seeger et al. 1995) (Table 1).
`
`From the Clinical Studies Ltd. ('DGD), Falls Church, Virginia;
`Lorna Linda Behavioral Medicine Center (DLZ), Rediands, Califor-
`nia; University of California (5GP), Irvine, California; Pfizer Central
`Research (KRR, EPH, ML), Groton, Connecticut.
`Address correspondence to: David C. Daniel, M.D., Clinical Stud-
`ies Ltd, 60661£esburg Pike, 6th Floor, Falls (Ii-lurch, VA 22041.
`Received March 16, 1998; revised August 14, 1998; accepted
`August 25, 1993.
`
`NEUROPSYCI-IOFI—IAMCOIMY 19994101.. 20, NO. 5
`© 1999 American College of Ne1.1ropay'chopharmacclog)»r
`Published by Elsevier Science Inc.
`655 Avenue of the Americas, New York, NY 10010
`
`Ziprasidone moderately inhibits SHT and norepineph—
`rine re—uptake into nerve terminals, has relatively mod-
`est aiiinity for histamine H1 and adrenergic a1 recep—
`tors, low affinity for dopamine D1 and as receptors, and
`negligible affinity for M1 receptors.
`In vitro hmctional dopamine receptor antagonism by
`ziprasidone has been demonstrated by concentration-
`dependent blockade of effects induced by a D2 agonist,
`quinpirole (inhibition of forskolin-stimulated adenylate
`cyclase) (Seeger et a1. 1995). After systemic administra-
`tion, ziprasidone produced relatively modest irmreases
`in dopamine metabolites as compared with haloperidol
`(Seeger et al. 1995). The inhibition by ziprasidone of the
`firing of dorsal raphe 5HI‘ neurons was antagonized by
`the selective 5HT1A antagonist WAY-100,635, as was the
`elevation of extracellular levels of dopamine in the me-
`
`1
`
`0893-133X/99/$-see front matter
`Pll 30893-133X(98)00090-6
`
`DEF-LURAS-OOOSBQB
`
`Exhibit 2038
`
`Slayback v. Sumitomo
`|PR2020-01053
`
`1
`
`Exhibit 2038
`Slayback v. Sumitomo
`IPR2020-01053
`
`

`

`492 DC. Daniel et al.
`
`NEUROPSYCHDPHAWCOLOGY 1999-VOL. 2‘0, NO. 5
`
`In Vitro Receptor Binding Affinities and Neurotransmitter lie-Uptake Inhibition
`Table 1.
`by Ziprasidone, Olanzapine, Risperidone, and Haloperidol (Ki in 11M)“
`
`Receptor
`
`Ziprasidone
`
`Olanzapine
`
`Risperidone
`
`Haloperidol
`
`Neurotransmitter Receptor Binding
`
`D1
`D;
`Ba
`D4
`SET“
`5HT1A
`SHTZC
`SET“;
`a,
`o;
`H1
`Muscarinic M1
`
`525"
`5'
`7"
`32‘
`0.4"
`3"
`1“
`2'
`in
`260‘
`50'
`>1,(.l(1l0“a
`
`31"
`11"
`49‘
`27“1’
`4*
`>1,00[}°
`11"
`80!)"
`19"
`2.30"
`7”
`2"
`
`450"
`4"
`10"
`9‘
`0.5“
`210‘
`25"
`1'70"
`0.?“
`0.9‘l
`20"
`)10’0005
`
`210'
`0.7“
`2“
`3“
`45"
`1,100I
`>10,000'
`>10,000‘
`5-
`360’
`440‘
`;>1,500t
`
`Neurotransmitter lie-Uptake Blockade
`
`53‘
`48“
`
`“915,000“
`2,000‘1
`
`1,400“
`23,000d
`
`5HT reuptake
`NE reuptake
`‘Denotes Im.
`“Data from Seeger TS, Seymour PA, Sclunidt AW. Zorn SH, et at. I Pharmacoi Exp Ther. 1995;25:101—113.
`”Bymaster PP, Calligro DO, Falcons RD, et al. Neumpsyckopharmwlogy 1996; 14:87L96.
`‘Schotte A, et a]. Psychophanmoology 1996,- 124:57—73.
`flData on file. Pfizer Inc. 1997 provided by L Lebel and 5 20111.
`
`1,800“
`5,500”
`
`dial frontal cortex, establishing in vivo SI-I'Tm agonist
`activity (Reynolds et a1. 1997; Lu et al. 1997). Ziprasi—
`done also exhibited selectivity for prefrontal cortical vs.
`striatal dopamine release (Lu et al. 1997).
`The pharmacological properties of ziprasidone may
`be predictive of enhanced clinical efficacy and a favor-
`able tolerability profile, as compared with other agents,
`in the treatment of schizophrenia (Seeger et al. 1995;
`Tendon et al. 1997) (Table 1). These properties include a
`high ratio of 5HT2A to D2 receptor affinities (Meltzer,
`1995, for review; Meltzer et al. 1989, for review; Deutch
`et al. 1991; Matsubara et al. 1993; Stockmeier et a1. 1993)
`stimulation of SHTLA receptors (Sharma and Shapiro
`1996, for review; Newman-Tancredi et al. 1996; Neal-
`Beliveau et al. 1993). Blockade of 5HI'1D receptors and
`moderate affinity in blocking synaptic re—uptake of se-
`rotonin and norepinephrine distinguishes ziprasidone
`from conventional and other newer antipsychotics and
`have been assoeiated with the therapeutic effects of an-
`tidepressant agents (Rickels and Schweizer 1993; Briley
`and Moret 1993). Ziprasidone’s negligible affinity for
`muscarinic M1 receptors (Seeger et al. 1995) contrasts
`with clozapine and olanzapine (Moore et al. 1993; See—
`man and van Tot. 1993; Bymaster et al. 1996); its rela-
`tively modest affinity for :11 receptors contrasts with ris-
`peridone and sertindole (Seeger et al. 1995; Schotte et al.
`1996),- and its agonist properties at the 5HT1A receptor
`are in contrast to olanzapine, quefiapine (Reynolds et
`a]. 1997), risperidone (Seeger et al. 1995), sertindole and
`clozapine (Schotte et al. 1996).
`In behavioral pharmacology, assays with predictive
`value for antipsychotic action (Niemegeers and Jans-
`
`sen 1979), ziprasidone antagonized d-amphetamine-
`induced hyperactivity and apomorphine-mduced stereo-
`typy and inhibited conditioned avoidance (Seeger et al.
`1995). Ziprasidone also reversed both dopamine ago—
`nist— (apomorphine) and NNIDA antagonist- (ketamine)
`induced prepulse inhibition deficits (Brooks and Mans—
`bach 1997). In models considered to have predictive
`value for extrapyramidal side~effect liability (Niame—
`geers and Janssen 1979), the in vivo potency of ziprasi-
`done in blocking a 5H1"2A agonist—(quipazine) induced
`head twitches and amphetamine-induced locomotor ac-
`tivity each occurred at substantially lower doses than
`those needed to produce catalepsy (Seeger et al. 1995).
`These data suggest that there is good separation of the
`therapeutic efficacy of ziprasidone vs. the propensity to
`produce extrapyrarnidal side effects (Seeger et al. 1995).
`Ziprasidone was selected for clinical development,
`because its preclinical profile was considered predictive
`of antipsychotic efficacy, with modest anti-adrenergic
`and antihistaminergic and no anticholinergic sideeffect
`liability. Its high ratio of SHTZA to D2 antagonism, low
`potency to produce catalepsy, agonist effects at the
`SHTm receptor, reversal of ketamine disruption of
`prepulse irntiibition. preferential release of dopamine in
`the prefrontal cortex vs. the striatum, and blockade of
`synaptic re-uptake of 5HT and norepinephrine were
`considered favorable predictors of low liability for 1110-
`tor side effects and benefits in negative symptoms, cog-
`nition, and mood.
`In healthy volunteers, positron emission computed
`tomography (PET) studies confirmed that the occu-
`pancy by ziprasidone of 5HT2 receptors substantially
`
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`NEUROPSYCHOPHARMACOLOGY 1999-VOL. 20; N0. 5
`
`Ziprasidone in Scluzophrerua 493
`
`exceeded that of D; receptors (Fischman et al. 1996;
`Bench et al. 1993; Bench et al. 1996). In a 28-day clinical
`trial in which the majority of patients (84/90) had an
`acute exacerbation of schizophrenia or schizoaffectjve
`disorder, ziprasidone 160 mg/day reduced Brief Psy-
`chiatric Rating Scale (BPRS) total and core item scores
`and Clinical Global Impression of Severity (CGI-S)
`scores similarly to haloperidol 15 mg/day (Goff et a1.
`1998). In a second 28-day clinical trial, involving 139 pa-
`tients with an acute exacerbation of schizoplu‘enia or
`schizoaffective disorder, ziprasidone 120 mg/ day was
`significantly more effective than placebo in improving
`BPRS total, BPRS anxiety—depression cluster, BPRS an-
`ergia factor scores, and CGI—S (Keck et a1. 1998).
`In the present article, we report the results of a large,
`Phase III, randomized, placebo-controlled, parallel group,
`fixed dose study designed to evaluate the efficacy and
`safety of 6 weeks of treatment with ziprasidone (80 mg/
`day and 160 mg/ day) in patients with an acute exacer-
`bation of schizophrenia or schizoaffective disorder.
`
`METHODS
`
`Subjects
`
`Men or women aged over 18 years, with an acute exac-
`erbation of chronic or subchronic schizophrenia (2953(3)
`or schizoaffective disorder (295.x4) as defined in
`DSM-HI—R (American Psychiatric Association 1987)
`were eligible to enter. They were to have been hospital-
`ized within the previous 4 weeks and been diagnosed
`at least 6 months before the study. The patients were re»
`quired to have a total score 2 60 on the Positive and
`Negative Syndrome Scale (PANSS) (Kay et a1. 1989) and
`a score of at least 4 on two or more core items in the
`
`PANSS (conceptual disorganization, hallucinatory be-
`havior, suspiciousness, and unusual thought content)
`in the 24 hours before study treatment was started. In
`addition, the patients were required to have a score of 3
`(nfinimaily improved) or greater (worse) on the Clinical
`Global Impression Improvement Scale (CGI—I) (Na-
`tional Institutes of Mental Health 1976a) at baseline as
`compared with screening.
`Patients were excluded if they were resistant to neu-
`roleptic treatment (defined as failure to respond to two
`or more marketed antipsychotic agents given at an ade-
`quate dose for sufficient time), had been hospitalized
`for more than 4 weeks before screening, or had DSM-
`Ill-R-defined psychoactive substance abuse/depen-
`dence in the preceding 3 months. Also excluded Were
`those with mental retardation, an organic mental disor-
`der, previous brief reactive psychosis, those who had
`received long-acting intramuscular neuroleptic medica-
`tion within 4 weeks of the first day of double«blind
`treatment (unless blood level was below therapeutic
`level), and those judged by the investigator to be at im-
`minent risk of suicide or homicide.
`
`Patients were required to have normal electrocardio-
`grams (ECG, with the exception of abnormalities con-
`sidered by the investigator to be clinically unimportant)
`and normal laboratory test results (with the exception
`of minor deviations considered by the investigator to be
`clinically unimportant). Body weight was generally at
`least 80% of the lower limit of normal and no greater
`than 160% of the upper limit of normal according to sex,
`height, and frame (Metropolitan Life Insurance Com-
`pany 1993). Urine samples obtained during screening
`were required to be negative for all illicit drugs, except
`cannabinoids and benzodiazepines that were allowed
`based on the investigators' discretion. Patients were ex-
`cluded if they had received any investigational drug in
`the 4 weeks immediately preceding the baseline visit of
`the study, fluoxetine within 5 weeks of the first day of
`double-blind treatment, or phencyclidine during the 90
`days before admission. They were also excluded if they
`had a history of clinically significant or currently rele-
`vant illness, or if they had a history of hypersensitivity
`to, or malignant syndrome developing from, the ad-
`ministration of antipsychotic compounds.
`Women were either of nonchildbearing potential,
`had been using an oral or injectable contraceptive for at
`least 1 month before entry into the study, and agreed to
`continuing using it or another reliable barrier method
`of contraception during the study. The study was ap-
`proved by appropriate institutional review boards at
`each site. Before initiation of any study-related proce—
`dure, written informed consent was obtained from all
`patients who were competent to give it. In the case of
`patients who were not competent to give informed con—
`sent, a pre—existing legal representative consented on
`their behalf.
`
`Study Design
`
`This randomized, double—blind, fixed-dose, placebo—
`controlled, parallel-group, multicenter clinical trial was
`carried out at 34 sites; 32 in the United States and two in
`Canada. Patients who met the study entry criteria en-
`tered a mandatory, single-blind placebo washout pe-
`riod lasting 3 to 7 days. During this washout period,
`any pre-existing neuroleptic or antidepressant treat-
`ment was discontinued. Sedative, anxiolytic, or hyp-
`notic treatments (except lorazepam) were also discon-
`tinued or substituted with an appropriate dose of
`lorazepam. Anticholinergic and B-adrenoceptor antago-
`nist treatment were also withdrawn by reducing the
`daily dose by one-third each day during the washout
`period. After washout, patients who still met the study
`entry criteria were randomized to receive orally either
`ziprasidone 80 mg/day (given 40 mg BID), ziprasidone
`160 mg/ day (given 80 mg BID), or placebo for 6 weeks.
`Patients randomized to receive ziprasidone 160 mg/
`day received 80 mg/day for the first 2 days of the
`study, and then received the full dose for the remainder
`
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`494 DC. Daniel et al.
`
`NEUROPSYCHOPHAWCOLOGY 1999-VOL. 2‘0, NO. 5
`
`of the study. Patients were to remain in hospital for the
`first 14 days of the study. Concomitant lorazeparn (for
`insomnia or agitation), benztropine (for extrapyramidal
`symptoms), and a B-adrenoceptor antagonists (for
`akathisia) were allowed if required during the study
`but were not administered prophylactically.
`
`Efficacy Assessments
`
`The following efficacy variables were used to evaluate
`the efficacy of ziprasidone: PAN55 total score (the sum
`of all 30 items); the PANSS negative subscale score (the
`sum of the seven negative items on PANSS); the CG!-
`severity (CGI-S) score, ranging from 1 (normal) to 7
`(most severely ill) (National Institutes of Mental Health
`1976b), and the CGI—I score. The BPRS (BPRSd) total
`score was derived from the PANSS, as was the BPRSd
`core items score (the sum of items P2, conceptual disor-
`ganization, P6, suspiciousness, P3, hallucinatory behav-
`ior, and G9, unusual thought content). Responder rates
`based on the PANSS total score (defined as a 230% de-
`crease from baseline to last observation) and the CGI-I
`score (defined as a score of 1, very much improved, or
`2, much improved at the last observation) were also de-
`termined. The Montgomery-Asberg Depression Rating
`Scale MADRS) Montgomery and Asberg, 1979) total
`score (the sum of all 10 items) was also measured. Dis-
`continuations because of insufficient clinical response
`and adverse events were recorded.
`
`Efficacy variables, with the exception of MADRS,
`were measured at baseline (Day 0), and weekly for 6
`weeks or on early termination (within 24 hours of receiv-
`ing the last dose). For CGI—l, the baseline value was
`based on the comparison with screening, and subsequent
`weekly assessments were based on comparisons with
`baseline. The MADRS total score was assessed at base-
`
`line and at weeks 1, 2, 3, and 6, or on early termination.
`
`Safety and Tolerability Assessments
`
`All adverse events volunteered and observed during
`the study or within 6 days of the last day of treatment
`were recorded using the COSTART dictionary, together
`with their date of onset, duration, concurrent therapy,
`the investigator’s assessment of severity, and the possi-
`ble causative relationship to study drug, and whether a
`change in dose or withdrawal of treatment was re-
`quired. All serious adverse events were recorded.
`Safety assessments were performed at regular inter-
`vals or within 24 hours of early termination. Movement
`disorders were assessed using the Ill-item Simpson—
`Angus Rating scale (Simpson and Angus, 1970), to mea-
`sure extrapyramidal symptoms (0 = normal to 4 2
`most severe), the Barnes Akathisia scale (Barnes 1989)
`to evaluate akattusia (D = normal to 5 = most severe),
`and the Abnormal Involuntary Movement Scale (AIMS)
`
`(0 = normal to 4 = most severe) (National Institutes of
`Mental Health 1976c) to evaluate tardive dyskinesia.
`The Simpson—Angus Rating scale incorporated a new
`item 7, head rotation, in place of the original item 7,
`head dropping. The Simpson-Angus Rating and Barnes
`Akathisia assessments were conducted at baseline and
`at weeks 1, 3, and 6. The AIMS was assessed at base-
`line and at week 6. Concomitant use of benztropine,
`B—adrenoceptor antagonists, and lorazepam was re-
`corded.
`
`Vital signs, including blood pressure (sitting and
`standing) and pulse rate, were measured weekly. A 12-
`lead ECG was done at baseline and at weeks 2 and 6.
`
`Patients were weighed at baseline and at week 6. Clini-
`cal laboratory tests, including routine hematology, se
`rum chemistry, urinalysis with microscopic evaluation,
`and liver function tests, were done at baseline and at
`weeks 1, 3, and 6.
`
`Serum Ziprasidone Concentrations
`
`Venous blood samples were collected for the determi-
`nation of serum ziprasidone concentrations before ad-
`ministration of the morning dose of study drug at
`weeks 1, 2, and 6 (and, in some cases, week 3). Samples
`were analyzed using a validated high-pressure liquid
`chromatography (HPLC) assay with solid phase extrac-
`tion and detection by ultraviolet absorption UsniszeVVski
`et al. 1995).
`
`Statistical Analysis
`
`It was estimated that approximately 100 patients per
`group would be required to detect a difference of five
`points between the placebo group and a ziprasidone
`treatment group in the mean change from baseline in
`the BPRSd total score with at least 80% power and a
`comparison-wise error rate of 0.05 (two-sided).
`The primary statistical analysis used for all efficacy
`variables was an intention-to—treat (I'I'I') analysis with
`the last observation being carried forward (LOCF). All
`patients with a baseline assessment and at least one
`postbaseline assessment were included in the HT LOCF
`analysis. MADRS scores were calculated for the entire
`I'IT cohort, for the subset of patients with baseline
`MADRS scores 2314, and for patients with a primary di-
`agnosis of schizoaffective disorder.
`Mean baseline to endpoint changes were compared
`between the placebo group and each of the ziprasidone
`groups. Estimates of treatment effects were based on
`least-squares means derived from an analysis of covari-
`ance (ANCOVA) model, with the measured value as
`the dependent variable and the baseline value as the co-
`variate, with fixed terms for the study centers and treat—
`ment. Comparisons between treatments were estimated
`using least—squares means from a type 1]] sum of
`
`DEF-LURAS-0005899
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`NEUROPSYCHOPHARMACOLOGY 1999-VOL. 20; N0. 5
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`Ziprasidone in Sclfizophrerua 495
`
`squares analysis of PROC GLM of SAS®. Confidence in-
`tervals and p-values were derived from a Student’s
`t-test. Responder rate p-values and confidence intervals
`for the PANSS total score and the CGI—I score and were
`
`obtained using normal approximation to binomial, with
`correction for continuity.
`All statistical tests performed were two-sided, and
`values of test statistics were considered significant if
`p < .05. No adjustments for multiple comparisons were
`made to significance levels.
`Descriptive statistics Were used to compare features
`of the history of illness, baseline characteristics, the inci-
`dence of adverse events and laboratory test abnormali-
`ties, discontinuations because of insufficient clinical
`response, and concomitant use of benztropine, B—adrend
`ceptor antagonists, and lorazepam among treatment
`groups. Serum ziprasidone concentrations were sum-
`marized as means and standard deviations, but no for-
`mal hypothesis testing was performed.
`
`RESULTS
`
`Clinical Characteristics
`
`A total of 440 patients were screened. Of these, 302 (215
`men and 87 women) were randomized and received at
`least one dose of double-blind treatment. Baseline pa-
`tient characteristics and illness characteristics were gen-
`erally similar across treatment groups (Table 2). Psychi-
`atric illness history was highly variable within each
`group, but mean values for each attribute were gener-
`ally consistent across the treatment groups (Table 2).
`One exception was the duration of the last psychiatric
`hospitalization, where the mean value in the ziprasi—
`done 160 mg/day group was considerably greater than
`those in the other two groups. This was mainly attribut-
`able to two patients whose previous psychiatric hospi~
`talizations lasted 900 and 1300 days, respectively. Al-
`most all patients had received anlipsychofic treatment
`in the previous 12 months.
`The mean baseline PANSS total and negative sub-
`scale scores, BPRSd total and core items scores, as well
`as the CGI—S scores, indicate that all three treatment
`groups had moderately severe levels of over-all psycho-
`pathology, positive symptoms, and negative symptoms
`(Table 2). Furthermore, over 50% of patients in each
`treatment group had clinically significant depression at
`baseline (MADRS score .33 14) (Table 3).
`
`Study Therapy
`
`The median duration (range) of treatment was 36 (2—
`45), 40 (1—46), and 42 (2—46) days for patients in the pla-
`cebo, ziprasidone 80 rag/day, and ziprasidone 160 mg]
`day groups, respectively. The percentage of patients
`
`discontinuing because of an insufficient clinical re-
`sponse was lower in the ziprasidone 160 mg/ day (15%)
`and ziprasidone 80 mg/day groups (25%) than in the
`placebo group (35%). Although infrequent, discontinu-
`ations because of adverse events occurred more often in
`
`the ziprasidone 160 mg/day group than the other two
`groups in which they were similar (Table 4). No patient
`discontinued as a result of a laboratory test abnormal-
`ity. The percentage of patients who discontinued for
`other reasons (protocol violation,
`lost
`to follow-up,
`withdraw consent, failure to meet randomization cri-
`teria, or other unspecified reasons) was 15, 23, and 13%
`in the placebo, ziprasidone 80 mg/day, and ziprasidone
`160 nag/day groups, respectively. The majority of pa-
`tients in each the placebo (92%), ziprasidone 80 mg/ day
`(81%), and ziprasidone 160 rag/day (87%) groups took
`lorazepam at some time during the study. In all three
`groups,
`the percentage of patients who required
`lorazepam was greatest in the first week and decreased
`throughout the study.
`
`Efficacy Analysis
`
`Both doses of ziprasidone were statistically signifi-
`cantly more effective than placebo in treating psychosis
`as measured by reduction between baseline and 6
`weeks (endpoint) in all assessments of global, positive,
`and negative symptoms (p <:
`.05) (Figure l). The effi-
`cacy of ziprasidone was also evident when the re—
`sponses to treatment were expressed as the percentage
`of patients classified as responders (Figure 2). The per-
`centage of patients classified as PANSS responders was
`significantly greater than placebo (17.6%) in the ziprasi—
`done 160 mg/day group (31.1%, p < .05) and numeri-
`cally greater in ziprasidone 80 mg/ day group, (28.8%
`p = .09). Similarly, the percentage of patients classified
`as CGI-I responders was significantly greater than pla—
`cebo (26.1%) in the ziprasidone 160 mg/day group
`(42.7%, p < .05) and numerically greater in ziprasidone
`80 mg/day group (32.7%, p = .39).
`In the all patient group, ziprasidone had no signifi-
`cant effect on MADRS scores (Table 3). However, in pa-
`tients with clinically significant depressive symptoms
`at baseline (baseline MADRS a 14; over-all mean 23.5),
`ziprasidone 160 mg!day produced a statistically signif-
`icant reduction in MADRS scores as compared with
`placebo (31.3% vs. 12.6%) (p < .05) (Figure 3). In the
`small subset of patients with schizoaffective disorder,
`the severity of depressive symptoms at baseline was
`less than in the subset with baseline MADRS ? 14, and
`ziprasidone 80 mg/day and 160 mg/day were associ-
`ated with numerically, but statistically, nonsigrfificantly
`greater improvements (18.5 and 30.0%, respectively) in
`depressive symptoms than placebo (11.9%).
`In addition to the analysis of mean baseline to end-
`point changes, the time course for symptom improved
`
`DEF-LURAS-0005900
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`5
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`

`496 DC. Daniel et a1.
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`NEUROPSYCHOPHARNMCOLOGY 1999—v0L. 20, NO. 5
`
`Table 2. Baseline Demographic and Illness History Characteristics and
`Psychopathology Scores
`
`Characteristichariable
`
`Men (‘16)
`Women (95:)
`Mean age (years) (range)
`Men
`Women
`Race
`White
`Black
`Oriental
`Other
`Mean weight (kg) (range)
`Men
`Women
`Primary diagnosis
`Disarganized schizophrenia (%)‘
`Catatonic schizophrenia (9..)1
`Paranoid schizophrenia (94)“
`Undifferentiated scl'iizoplu'erfia (%)“
`Schizoafiective disorder (96)”
`Illness history
`Mean age at onset of first psychiatric
`hospitalization (years) (so)c
`Mean time since onset first
`
`Placebo
`(n = 92)
`
`63 (68%)
`29 (32%)
`37.2 (1564)
`35.? (18—63)
`40.4 (18—64)
`
`56
`24
`2
`10
`
`Ziprasidone
`80 mghiay
`(n = 106)
`
`75 (71%)
`31 (29%)
`36.8 (1%7)
`35.6 (19—65)
`39.6 (19-65)
`
`77
`19
`2
`8
`
`Ziprasidone
`160 mgfday
`(n = 104)
`
`7'? (74%)
`27 (26%)
`35.8 (18435)
`34.6 (18—58)
`39.1 (24—65)
`
`73
`1'7
`3
`11
`
`82.4 (51—122)
`73.1 (49413)
`
`78.6 (49-12?)
`72.0 (%101)
`
`72.9 (57—137)
`68.6(51P111)
`
`3 (3%)
`1 (1%)
`45 (49%)
`24 (26%)
`19 (21%)
`
`4 (3%)
`1 (1%)
`53 (50%)
`25 (23%)
`24 (23%)
`
`3 (3%)
`1 (1%)
`43 (42%)
`31 (32%)
`25 (24%)
`
`22.3 (7.3)
`
`22.8 (8.1)
`
`21.3 (6.6)
`
`14.7 (8.9)
`
`133 (9.1)
`
`8.7 (9.6)
`
`13.6 (9.0)
`
`12.8 (9.9)
`
`8.7 (9.4)
`
`14.4 (9.9)
`
`11.4 (9.4)
`
`8.4 (10.3)
`
`psychiatric illness (years) (9-D)c
`Mean time since first psychiatric
`hospitalization (years) (soy
`Mean number of previous psychiatric
`hospitalizations (SD)‘
`Mean total duration of all previous
`psychiatric hospitalizations
`months)"
`Mean time since last hospitalization
`(days) (SD)
`Mean duration of last psychiatric
`hospitalization (days) (SD)c
`Antipsychofic use in the previous 12
`months (”/0 of patients)
`Mean (SD) Psychopafllology scores
`95.3 (22.7)
`932 (22.1)
`923 (223)
`PANSS total score
`55.0 (12.4)
`56.5 (12.5)
`5.1 (12.6)
`13?de total score
`16.6 (3.3)
`16.9 (3.6)
`16.4 (3.8)
`BPRSd core itemsE score
`4.8 (0.8)
`4.8 (0.7)
`4.86.1.8)
`CGI-s score
`
`
`24.9 (7.1)PANSS negative subscale’ score 24.3 (7.7) 25.4 (7.3)
`
`Abbreviation SD = standard deviation.
`“All patients had a chmnic course except for one with subchronic disorganized schizophrenia in the ziprasi-
`done 80 rug/day group; and one with subchronic cataimu‘c schizophrerfia, three with paranoid subchrunio
`schizophrenia, and one with subchronic undifferentiated schizophrenia in the ziprasidone 160 trig/day group.
`I’Patientri were depmsive type except 13, 9, and 12 in the placebo, ziprasidone 81} mgr'day and ziprasidone
`160 mg/ day groups, respectively, who were bipolar type.
`‘l-Iistorlcal data were not available for 1-18 patients in each group depending on the variable.
`“Historical data were not available [or 3?, 39, and 39 patients in the placebo, ziprasidone 30 mgl‘day, and
`ziprasidone 160 mg/day groups, respectively.
`‘BPRSd core items were concePtual disorganization, suspiciousness, hallucinatory belmvior, and unusual
`thought content.
`Negative subscale items were blunted affect, emotional withdrawal, poor rapport, passive/apafliettc so-
`cial withdrawal, difficulty in abstract kinking, lack of spontaneity and flow conversion, and stereotyped
`thinking.
`
`9.7 (12.2)
`
`8.4 (14.2)
`
`9.6 (18.9)
`
`594.4 (982.7)
`
`854.2 (1507.2)
`
`767.4 (1406.1)
`
`34.1 (52.7)
`
`26.9 (32.1)
`
`21.4 (184.6)
`
`35 (92%)
`
`94 (39%)
`
`94 (90%)
`
`DEF- LU HAS-000 5901
`
`6
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`

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`NEUROPSYCHOPHARMACOLOGY 1999-VOL. 20; N0. 5
`
`Ziprasidone in Schizophrenia 497
`
`Table 3. Mean (SD) Baseline MADRS Total Scores and Changes at 6 Weeks in All
`Patients, Schizoaffective Patients, and Patients With Baseline MADRS Scores 2 14
` (TIT LOCF)
`
`Placebo
`
`n=89
`17.4 (9.2)
`71.3 (9.1)
`n = 19
`1.5.1 (8.4)
`—1.3(s2)
`n=54
`23.1 (6.6)
`—2.9 (9.5)
`
`Ziprasidone
`SI] mgfday
`
`Ziprasidone
`160 mgiday
`
`n=100
`17.0 (9.3)
`71.8 (8.8)
`n = 20
`20.0 (7.6)
`—3.7 (12.7)
`:1 =56
`23.4 (7.2)
`—3.1 (9.3)
`
`n=100
`16.9 (9.8)
`73.1 (9.6)
`n = 24
`18.0 (9.9)
`—5.4 (8.1)
`n =56
`24.0 (7.1)
`-7.5 (8.3)”
`
`Allpafients
`Baseline
`Change at week 6
`Schizoaffective patients
`Baseline
`Change at week 6
`Patientswithbaselinescore?”
`Baseline
`Change at week 6
`Abbreviation; SD = standard deviation.
`‘p < .05 vs. placebo.
`
`ment was also investigated. At week 1, both the 80 mg/
`day and 160 mg/ day doses of ziprasidone produced re-
`ductions from baseline in mean PANSS total, BPRSd to-
`tal, BPRSd core items, CGI-S, and PANSS negative sub-
`scale scores that were statistically significantly greater
`than placebo (p < .05, Figure 4).With few exceptions,
`firrtber statistically significant improvement compared
`to placebo was observed at each subsequent weekly as
`sessment in both ziprasidone treatment groups.
`
`Safety—Adverse Events
`
`A total of 264 out of the 302 patients (87%) who received
`at least one dose of double—blind medication experi-
`enced an adverse event (Table 4). The over-all incidence
`of adverse events associated with ziprasidone was simi-
`lar to placebo. The majority of treament—emergent ad-
`verse events were of mild or moderate severity. Al-
`though infrequent, discontinuations because of adverse
`
`Table 4. Summary of Treatment-Emergent Adverse Evmis and Those Occurring in?lo%
`of Patients in Any Treatment Group
`
`Placebo
`(It = 92)
`
`Ziprasidone
`80 mglday
`(n = 106)
`
`Ziprasidone
`160 myday
`[II = 104)
`
`79 (86%)
`
`10 (11%)
`
`92 (87%)
`
`8 (8%)
`
`93 (89%)
`
`8 (8%)
`
`Total patients with
`adverse events (%)
`Patients with severe
`adverse events (%J
`Patients discontinued
`
`due to adverse events (‘14:)
`1 (1.1%)
`2 (1.8%)
`S (7.11%)
`Adverse event
`10 (10%)
`6 (6%)
`8 (9%)
`Pain
`32 (31%)
`18 (17%)
`30 (33%)
`Headache
`10 (10%)
`3 (3%)
`5 (5%)
`Abdominal pain
`6 (6%)
`12 (11%)
`1.4 (15%)
`Vomiting
`16 (14%)
`10 (9%)
`B (9%)
`Dyspepsia
`7 (7%)
`15 (14%)
`8 (9%)
`Nausea
`13 (13%)
`4 (4%)
`4 (4%)
`Dry mouth
`14 (14%)
`7 (i’%)
`13 (14%)
`Constipation
`18 (17%)
`10 (9%)
`8 (9%)
`Dizziness
`9 (9%)
`10 (10%)
`10 (11%)
`Agitation
`12 (12%)
`13 (12%)
`13 (14%)
`Insomnia
`20 (19%)
`20 (19%)
`5 (5%)
`Somnolence
`
`Akathisa 13 (13%) 6 (7%) 15 (14%)
`
`
`
`Adverse events occurring during treatment or within 6 days of the last day of treatment Patients with mul-
`tiple occurrences of the same adverse event were counted once only. laboratory test abnormalities are ex-
`cluded.
`
`DEF-LU RAS-OOO 5902
`
`7
`
`

`

`498 DC. Daniel et al.
`
`NEURDPSYCHOPI-LKRMACULOGY 1999-VOL. 20, N0. 5
`
`I Placebo
`El Ziprasioona so mgmay
`I Ziprasidona 160 mglday
`woos vs placebo
`
`30—
`
`10
`
`
`
`lmprovernent("M
`
`‘
`
`All patients
`
`Schizoafiectwe
`psiiams
`
`Patients with
`baseline MADFIS
`214
`
`Figure 3. Percentage improvement from baseline at 6
`weeks in mean MADRS total score in all patients, panel-its
`with schizoaffective disorder and in patients with baseline
`MADRS 2 14 (l'l'l'LOCF).
`
`reported adverse events associated with ziprasidone
`were somnolence, dizziness, dyspepsia, and nausea
`(Table 4). Dry mouth occurred with higher frequency in
`the ziprasidone 160 mg/day group than the other two
`groups, but constipation was no more frequent than
`with placebo. Insomnia was less frequent with ziprasi-
`done 80 mg/day and 160 mg/day (12.3 and 11.5%, re-
`spectively)
`than placebo (14.1%). Tachycardia and
`orthostatic hypotension were very infrequent with
`ziprasidone (2 and 1% in both groups, respectively).
`There were no reports of increased body weight as an
`adverse event, and only two patients in the ziprasidone
`80 mg/ day group reported an increase in appetite. No-
`table was the extremely low incidence of dystonia with
`ziprasidone 160 mg/day (3.8%) relative to placebo
`(2.2%). Although the incidence of akathisia was higher
`with ziprasidone than placebo, this was not dose re-
`lated. The reported incidence of extrapyramidal syn-
`drome (EPS) was 1, 2, and 7% in the placebo, ziprasi-
`done 80 mg/day, and ziprasidone 160 mg/day groups,
`respectively. Severe EPS occurred in only one patient
`(160 nag/day group). There was only one report each of
`male sexual dysfunction and im