ORIGINAL CONTRIBUTION
`
`Two 6-Week, Randomized, Double-Blind, Placebo-Controlled
`Studies of Ziprasidone in Outpatients With
`Bipolarl Depression
`
`Did Baseline Characteristics Impact Trial Outcome?
`
`llise Lombardi). MD. * Gary Sachs. MD.1‘i‘S/reela Kolluri. PhD.* Charlotte Kremer. MD. *
`and Runyong Yang. PhD"
`
`Abstract: Two randomized. double-blind. placebo-controlled. 6-wcek
`studies comparing Ziprasidone versus placebo for trmmient of bipo-
`lnr depression (BPD) failed to meet their primary study objectives.
`indicating that either Ziprasidone is inelTectivc in the treatment of BPD
`or the study failed
`Adult outpatients with bipolar I depressron wrth l7-item l-km'nlton
`Rating Scale for Depressirm total score more than 20 at screening and
`baseline received either Ziprasidone 40 to 80 rug/d. 120 to 160 nag/d. or
`placebo «study It. or Ziprasidone 40 m 160 mad or placebo (study 2).
`Primary cflicacy measure in both studies was change From baseline in
`Montgomery-Airbus Depression Rating Scale total scores at week 6
`(end of the study). Mixed-model repeated-measures methodology was
`used to analyze theprimaryell'rcuey measure in both studies. Secondary
`efficacy measures in both studies included Hamilton Rating Scale for
`Depression tour] score and Clinical Global Impression-Improvement
`score. Post hoc analyses were conducted for both studies to examine
`potential reasons for study failure. In both. Ziprasidone treatment groups
`failed to separate statrstrcally liom placebo for change fi-om baseline
`Montgomery-Asher}: Depression Rating Scale score at “wk 6. Response
`rates were 49%. 53%. and 46% for placebo. Ziprasidone 40 to 80 ring/d.
`arid 7ipr2tsidone 120 to I60 mgid. respectively Istudy I). and 51% and
`53% for placebo and zipmsidone 40 to 160 mg/d. respectively (study 2).
`Ziprasidone an to rm mg/rl did not show superiority over placebo
`at weds 6 in the treatment of BPD. Post hoc analyses revealed serious
`Inconsistencies in subject rating that may have limited the ability to detect
`a dilrcmrtre between drug and placebo response. Rating reliability warrants
`further investigation to improve clinical trial merhodolog in psychiatry.
`Key Words: bipolar depression. atypical antipsychotic. placebo
`response
`
`(J Clirr Pswhopharmaco/ 20|2:32: 470—478)
`
`Acute bipolar depression (BPDt is defined by a major de-
`pressive episode in a patient with bipolar disorder. Episodes
`of BPD share diagnostic criteria such as sadness. anxiety. guilt.
`anger. and sleep disturbances. with episodes of major depressive
`disorder (Diagnostic and Sratr'xlr'cal Manual ofMemal Disorders.
`Faun/1 Edition [DSM-fl'7). Despite the cross-sectional clinical
`similarities. BPD responds poorly to standard antidepressants as
`
`
`From ‘Pfizcr Inc. New York. NY; fMassuchusr-tts General llospilal. Boston;
`and illarvard University. Cambridge. MA.
`Received February 22. 2010; accepted uficr revision January 9. 2012.
`Reprints. llisc Lumbanlo. MD. Pfimr’lnc. 235 Etsl42nd St. New York. NY 10017
`(c-Inail iliwlomlxurlofiilpli/crxonr).
`This study was funded by l’ filer lnc. Editorial support was pmvidod by Annie
`\‘cild. PhD. of PAREXE]. and was funded by Pfi7er Inc.
`(‘ripyrighr C 2012 by Lippincntr Williams & Wilkins
`ISSN' 027l~0749
`DO]: Ill. 1097/1FPOb0l3e3lK25ccdeS
`
`monothempy or as an adjunct to mood stabilizers.' 5 Other class
`of medication have. however. demonstrated efficacy for BPD. ""5
`in 2003, Tohcn et a]5 reported that olanzapine and the
`combination of olanmpine and fluoxetine (OFC) were superior
`to placebo for treatment of BPD. and the US Food and Drug
`Administration granted approval to OFC in December 2003.
`Interest in atypical antipsychotic medication as treatment for
`BPD followed this success in the hopes that. as a class. atypical
`amipsychotics might be effective for the treatment of BPD} 7
`but results from clinical
`trials have been mixed. Whereas
`quetiapine“ and 0FC" have demonstrated efficacy for the
`treatment of BPD. bifeprunox and aripipmzole failed to dem-
`onstrate superiority to placebo in 2 recent clinical trials based
`on the change in Monrgomery-Asberg Depression Rating Scale
`(MADRS) score from baseline to the end of the study.“-" Studies
`of larnotrigine for BPD have also produced inconsistent results.l0
`Placebo response is a common problem in clinical trials for
`psychiatric disorders." in randomized trials for bipolar disorder.
`there has been a pronounced increase in placebo response during
`the last several years. ‘3 Some investigators have suggested that a
`component of the apparent placebo response may be attributable
`to a phenomenon referred to as baseline inflation. in which the
`biseline scores of subjects entering trial may be exaggerated so
`as to be above the threshold required for study entry.'1
`Ziprasidone is an atypical antipsychotic that.
`like most
`commonly prescribed antidepressants. inhibits the renptake of
`serotonin and norcpincphrinc. (liven that several small studies
`supported the use of Ziprasidone for BPD.” 1‘ the primary
`objective of the present studies was to compare the efficacy of
`Ziprasidone with placebo during a (5-week course of treatment
`in outpatients with bipolar l disorder. in an effort to mitigate
`baseline inflation of the primary efficacy measure. the l7-item
`Hamilton Rating Scale for Depression (HAM-D- l 7) was used
`to determine eligibility. and the MADRS was the primary
`measure of efficacy. Here. we describe the findings of the
`2 studies; in both. Ziprasidone failed to separate statistically
`from placebo for the change from baseline MADRS score at
`week 6. To better understand the outcome of the 2 present
`studies. we further examined the relationship between the
`HAM-D—l 7 and MADRS scores at screening and at baseline.
`The concurrent use of 2 rating scales allowed for evaluation
`of the reliability of illness severity ratings and may provide
`insights applicable to broader clinical trial methodology.
`
`MATERIALS AND METHODS
`
`Study Population
`Inclusion Criteria
`
`Subjects who met the following criteria were included in
`both studies: (1) men and women aged 18 years or older at the
`time of consent, with a primary diagnosis of bipolar l disorder.
`
`470 l ww.psychopharrnacology.com
`
`[oumal ofC/r'nical Psychophormaco/ogy - Volume 32, Number 4, August 2012
`
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`[oumal of CIWcal Psychopharmacology . Volume 32, Number 4, August 2012
`
`lerasldone In Bipolar I Depression
`
`most recent episode depressed with or without rapid cycling.
`and without psychotic features. as defined in the DSM—lV1721!
`Revision (296.5)() and confirmed by the Mini
`lntemational
`Neuropsychiatric Interview version 5.0.0. '7; (2) lifetime history
`of at least 1 bipolar manic or mixed-manic episode (the initial
`protocol required at least I lifetime hospitalization for a bipolar
`manic or mixed-manic episode: this requirement was dropped
`in May 2007);
`(3) HAM-D—l‘l
`total score more than 20 at
`screening and at baseline (HAM-D—l7 score was derived from
`the first 17 iten's of the HAM-D25”). obtained at least 3 days
`apart, and screening-to-baseline improvement in HAM-D-l7
`total score less than 25%; (4) Young Mania Rating Scale
`(YMRSW) score less than 12 at screening and at baseline.
`obtained at least 3 days apart; duration of the current bipolar
`l disorder depressive episode of more than 2 weeks and less
`than 6 months.
`
`Exclusion Criteria
`
`The following subjects were excluded from botli studies: (1)
`subjects diagnosed with schizophrenia or schizoafieetive disor-
`der, schizophrenifonn disorder. delusional disorder. or psychotic
`disorders not otherwise specified; (2) subjects who failed 3 or
`more adequate studies (more than 4 weeks at an adequate dose)
`of an antidepressant either as monotherapy or in combination
`therapy (with lithium or an anticonvulsant) in a previous de-
`pressive episode or within the current episode; (3) subjects with
`psychotic features associated with bipolar l depression within the
`index (ie. current) episode; (4) subjects with ultrafasr rapid cy-
`cling (defined as 8 or more mood episodes during the 12-month
`period preceding the screening visit); (5) subjects with YMRS
`score more than l6 at screening or at baseline were discontinued
`from the study and provided With appropriate treatment or re-
`ferral by the investigator; (6) subjects with a YMRS score greater
`than or equal to 16 at any postbaseline visit; (7) subjects with
`DSM-IV- Text Revision—defined alcohol or psychoactive sub-
`stance abuse in the 3-month period preceding the screening visit
`or significant risk of self-injurious/suicidal or violent/homicidal
`behavior; (8) subjects with a history of inadequate response to
`ziprasidone (at least 6 weeks’duration) for the treatment of BPD
`or a history of intolerance to zipmsidone; (9) subjects who had
`ever been discontinued from ziprasidone treatment because of
`lack of efi'icacy or significant adverse events (A55).
`in addition. subjects were required to have discontinued
`use of previous psychotropic agents (including anticonvulsants)
`for a minimum of l week; lithium for a minimum of 2 weeks;
`monoamine oxidase inhibitors. fluoxetine. or the OFC for a
`minimum of 4 weeks; and any depot neuroleptic agent for a
`minimum of 6 months before being randomized into the study.
`Women of childbearing age agreed to use birth control. All
`subjects provided written informed consent.
`
`Study Design
`Studies 1 and 2 were 6-week. randomized. double-blind.
`multicenter. flexible—dose. placebo-controlled studies conducted
`in the United States evaluating the efi'icacy and safety of oral
`ziprasidone in outpatient stibjects aged 18 years and older with
`bipolar l disorder The first study recruited participants from
`56 of 70 investigational sites in 25 states. whereas the second
`recruited at 45 sites from a total of 48 sites in 22 states. Fifieen
`states contributed to both trials.
`
`Study 1 (A1281136, July 2005-February 2008)
`Subjects were randomly assigned to a zipiasidone fixed-
`flexible dosing group (20—40 mg twice daily |bid| or 60—80 mg
`bid) or placebo in a l:l:l ratio as follows:
`
`- Ziprasidone low-dose (40—80 mg/d): subjects started dosing
`at 20 mg bid on days 1 to 6, their flexible dosing started on day
`7 (2040 mg bid [20 mg bid or 40 mg bid at the discretion of
`the investigator“ for the remainder of the 6-week study.
`. Ziprasidone high-dose (120-160 org/d): subjects started at
`20 mg bid on days I to 2. then 40 mg bid on days 3 to 4. then
`()0 mg bid on days 5 to 6. then flexible dosing started on day 7
`(60—80 mg bid I60 mg bid or 80 mg bid at the discretion of
`the investigated) for the remainder of the 6-week study.
`' Placebo: subjects were given placebo with the same flexible
`dosing schedule as ziprasidonc for the entire 6-week study.
`
`Study 2 (A128H39, February 2006—March 2008)
`Subjects were randomly assigned to a zipntsidone flexible-
`dose treatment group or placebo in a lzl ratio as follows:
`- Zipmsidone flexible-disc treatment group: subjects were
`started at 20 mg bid fixed dose on days 1 and 2. 40 mg bid on
`days 3 to 6. and flexible dosing starting on day 7 (ie. 20—80 mg
`bid. adjustable by 20 mg bid at each visit) for the remainder
`of the 6-week study.
`- Placebo: subjects were given placebo with the same flexible
`dosing schedule as ziprasidonc for the entire 6-week study.
`
`Concomitant Medication
`For agitation or intolerable anxiety. lomzepani up to 2 ing/d
`was allowed during the screening period and the first 2 weeks
`of double-blind treatment up to 4 days per week. For insomnia.
`nonbenzodiazepine sleep agents (all approved agents. eg, zol—
`pideni up to lo tug/d. eszopiclone tip to 3 trig/d. 7aleplon up to
`20 mgid. or rumelteon up to 8 rug/d) were allowed during the
`screening period and the first 2 weeks of double-blind treat-
`ment up to 4 days per week and for the remainder of the study
`up to 2 days per week. Benzrropine (up to 6 mg/d) for extra-
`pyramidal symptoms and proptanolol (up to I20 mg/d) for
`akarhisia were allowed only on an its-needed basis and not on
`a continuous daily basis prophylactically to treat extrapyramidal
`symptoms/akathisia. These medications were not allowed within
`the l2 hours before cognitive testing. All other psychoactive
`medications were prohibited during the subject’s participation
`in the study.
`
`Efficacy, Safety, and Post Hoc Analyses
`Ett'Ieacy
`The primary efiicacy measure in both studies was the
`change in MADRS total score” from baseline to week 6 (end
`of the study). Response on the MADRS scale was defined as
`a 50% or greater reduction from baseline in the MADRS to-
`tal score. Secondary efficacy measures included baseline and
`postbaseline measurement of the range ofdepressive symptoms
`(using HAM-D score). anxiety (HAM-A score). mania (using
`YMRS). global clinical severity. and global improvement of
`symptoms (via Clinical Global impression [CGI] of Severity
`and CGI of Improvement scores. respectively): global assess-
`ment of functioning; change in quality of life. enjoyment. or
`satisfaction; (mmpalional/psychosocial impact of symptoms;
`and cognition.
`
`Safety
`Safety and tolerability assessments included AEs. vital
`signs. laboratory tests. senun prolactin. and weight. Movement
`disorder symptoms were measured using the Simpson-Angus
`Scale (SAS);l the Barnes Akathisia Smile (BAS)?2 and the
`Abnormal Involuntary Movement Scale (AIMS),
`
`33' 201.? Lippinmtt Williaim & Wilkins
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`
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`2
`
`

`

`Lomban'lo et a!
`
`[oumal ofC/Inlcal Psychopharmacology 0 Volume 32, Number 4, August 2012
`
`Post Hoc Analyses
`Post ltoc analyses were performed for both studies to ob-
`tain a better understanding ofpotential reasons for snrdy failure
`such as high placebo response and rating inconsistencies Spe-
`cifically. comparisons were made between the MADRS scores
`and llAM-D-l7 scores at baseline and between MADRS actual
`scores and predicted MADRS scores (ie. MADRS scores derived
`from I IAM-D scores using the fonnula developer] by Zimmerman
`et 3F“). Subgroup analyses to study the influence of baseline
`illness severity (as measured by the MADRS score) were also
`performed
`
`Statlstlcal Analysls
`The safety population for both studies included all ran-
`domized srtbjects who were administered at least
`1 dose of
`double-blind study medication. The intent—to-treat (lTl') pop»
`ulation for both studies included all subjects included in the
`safety population and for whom at least I postbaseline primary
`efficacy evaluation was obtained. The primary efi’icacy analysis
`in both studies used the ITT population
`
`Efficacy
`Similar mixed-model repeated-measm'cs (MMRM) analy-
`ses were used for the primary efficacy evaluation in both studies.
`The primary comparisons of interest in both studies were the
`mean changes from brseline to week 6 in MADRS score between
`ziprasidone and placebo. In study I. the specific tremment com-
`parisons of interest were zipmsidone 120 to 160 mg/d versus
`placebo and ziprasidone 40 and 80 mg/d versus placebo. The
`primary analysis was based on the ITT population using ob-
`served cases (0C5) data. The Hochberg procedure for adjusting
`for multiple treatment comparisons was used only for the change
`from baseline MADRS score [at each time point) in the MMRM
`analysis only. The MMRM model in both studies included fixed
`categorical efi'ects of treatment. rapid cycling. center. visit. pre-
`vious hospitalization status (with or without previous bipolar
`manic or united-manic episode hospitalization). and treatment-by-
`visit interaction. as well as fixed continuous efl‘ect of baseline
`MMRS total score in the model. The subject effect was included
`as a random effect. The restricted maximum likelihood estima-
`tion method was used for the MMRM analysis with a sandwich
`estimator of the variance-covariance matrix of the fixed-efi'octs
`parameters. An unstructured variance-covariance matrix was used.
`The assumptions of the MMRM amlyses were evaluated. In ad-
`dition. changes from baseline in MADRS total score at each visit
`week (last observation carried forward [LOCF] at week 6 arid 0C
`data at each visit week) were analyzed with an analysis of co-
`variance (ANCOVA) model that included the following model
`terms: treatment. rapid cycling. center. previous hospitalization
`status. and baseline score as a covariate.
`For the secondary efficacy evaluations in both studies. the
`MMRM model described above for the MADRS total score was
`applied to the change from baseline in CGl of severity and CGI
`of improvement scores. Change from baseline in HAM-D47
`at each visit week was analyzed rising the ANCOVA model
`described above for the MADRS total score.
`The Cochran-ManteI-Haenszel test stratified by study center
`and rapid cycling strata was used in both studies to compare re-
`sponse rats between zipmsidone and placebo. where response
`based on the MADRS scales was defined as a more than 50%
`reduction from the baseline MADRS total score.
`
`Safety
`Standard safety summaries of ABS. vital signs. laboratory
`tests, serum prolactin. and weight were generated. Analysis of the
`
`change from baseline to the end of the study in SAS total score.
`BAS global clinical assessment of akathisia. Al MS total score.
`AIMS global severity score. and AIMS incapacitation score wzn‘.
`performed using the same ANCOVA model described above in
`the analysis of the MADRS total score.
`
`Post Hoc Analyses
`Additional post hoc analyses were conducted for both studies
`to outline possible reasons for study failure. These included:
`( I) Comparison of the distribution of MADRS total scores and
`HAM-D-l7 scores at baseline using graphical displays of
`MADRS total scores and the HAM-D-l 7 scores at baseline
`with the inclusion cutoff highlighted for both scales.
`(2) Analysis comparing the actual and predicted (ie. derived from
`llAM-D-I7) MADRS total scores at both baseline and the end
`ofthe study (using LOC Fdata) were performed as a measure of
`rating reliability. Specifically, predicted MADRS total scores
`were calculated from the HAM-D-l7 total scores using the
`formula developed by Zimmerman et al23 (as MADRSPM‘M,
`total score - L43 x HAM-D47 total score l 0.87). A swn~
`mary of the divergence (calculated for each subject as actual
`MADRS total soon: - predicted MADRS total score) was
`reported at baseline and at the end of the study.
`(3) To study the influence ofbaseline illness severity. the primary
`MMRM efficacy analysis was repeated within subgroups
`based on baseline MADRS score categories. The mucx‘ol eli-
`gihility criterion called fora score ofleast 20 on the llAM-D-l 7
`at baseline, which conesponds to a predicted MADRS score
`greater than 29.5. Hence. the subgroups eligible [2295)
`versus ineligible «29.5) were created for this analysis. Of
`note is that. as the conversion calculation gave a cutofi‘ score
`of 29.5. and it is not possible for MADRS score to be other
`than an integer. the criterion of 29 or less was used.
`(4) To characterize placebo response by site. graphic)! displays
`showing placebo resporse rates at the end of the study for
`each site (for sites with at least 10 subjects enrolled) are
`presented.
`
`RESULTS
`01‘treated subjects, a total of l 02 (61.8%) of I65. 9] (53.2%)
`of 171. and 111 (66.1%) ofl68 subjects in the ziprasidone 40- to
`80-mg/d group. ziprasidone 120- to lliO-mg/d group. and placebo
`group. respectively. completed study 1. For study 2. of the treated
`subjects a total of 1 l2 (60.5%) of 185 and 134 (68.4%) of I96
`7jprasidone and placebo subjects. respectively. were completers.
`The overall mean daily dose of zipmsidone for study 1 “as I 13.1
`(127.2) mg/d for the higher dose group and 53.9 (ti 5.3) mg/d for
`the lower dose group; for study 2. the overall mean daily dose of
`a‘pmsidone was 83.9 (:29.6) mg/d. Of the treated subjects. the
`proportion of study entrants hospitalized for mania did not dif-
`fer significantly between groups in study 1 (range. 825%—84.8%)
`and in study 2 (range. 80.6%—SSA%). In study I . hen7mlia7epine
`(lomzepam) usage was reported by 10.9%. 8.2%. and 8.9% in the
`40- to 80-mg/d. 120- to léO-mg/d and placebo groups. respec-
`tively. in study 2. benzodiazrepine usage was reported by 10.3%
`and 6.6% in the ziprasidone and placebo groups. respectively.
`
`Primary Efficacy Analysis
`The primary efi‘icacy analysis (MMRM) indicated that
`both the high- and lowdose ziprasidone groups in study I and
`the ziprasidone group in study 2 failed to demonstrate statistical
`superiority over placebo in change from baseline MADRS score
`at week 6 (Fig. 1). In both studies, the results from the ANCOVA
`
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`[oumal of CIWcaI Psychopharmacology 0 Volume 32, Mimber 4, August 2012
`
`Zipraridone In Bipolar I Depression
`
`ziprasidone high- and low-dose groups, respectively, and -10.6
`(0.95) (n ~~ 153) in the placebo group. in study 2, the LS mean
`(SE) for change from baseline to the end of the study (0C) were
`—6.9 (1.4) (n = 168) and -7.1 (1.3)(n = 181) in the ziprasidone
`and placebo groups. respectively. Response rates based on the
`HAM-D-l7 total score (response defined as 250% reduction
`front baseline llAM-D-l7 total score) also showed no signif-
`icant difference between ziprasidone and placebo groups in
`both studies (nominal P > 0.05 for all comparisons between
`ziprasidone and placebo).
`
`Safety and Tolerability
`In study 1. the most frequently reported treatment-emergent
`AEs (all causalities) in the higher dose ziprasidone group (at
`twice the rate of placebo) were somnolence ( 17.5%) and sedation
`( 1 1.7%). [n the lower dose ziprasidone group. the most fiequently
`reported AE was somnolence (15.2%). In study 2. among sub-
`jects randomized to the ziprasidone group. the 3 most frequently
`reported AEs were somnolence (13.5%). sedation (11.9%). and
`headache (11.4%) compared with nausea and headache (each
`107%) and diarrhea (7.7%) for subjects in the placeim group. In
`both studies. mean changes in vital sign values. body mass index.
`weight and waist circtunference were similar among treatment
`groups. Clinically significant weight gain or loss was not cont-
`monly observed. Vital signs among the treatment groups did not
`change appreciably front baseline to the end of the smdy.
`For both studies. changes from baseline across treatment
`groups and across movement scales were very small and not
`clinically relevant. although some differences did reach statis-
`tical significance. In srudy 1. significant changes from baseline
`were observed at the end ofthe study for the comparison between
`the zipmsidone higher dose trwtment group and placebo group
`for SAS total score (nominal P v 0.0277). In study 2. the LS
`mean change (SE) from baseline to the end of the study in SAS
`total score was —0.07 (0.08) and -0.23 (0.07) in the ziprasidone
`and placebo groups. respectively: this difference was significant
`(nominal P = 0.0174). The LS man change (SE) from baseline
`to the end of the study in BAS total score was 0.08 (0.17) and
`-0.37 (0.16) in the ziprasidone and placebo groups. respec-
`tively; this difference was significant (nominal P — 0.0033). The
`LS mean change (SE) from baseline to the end of the study
`in ALMS total score was 0.01 (0.09) and -0.00 (0.08) in the
`ziprasidone and placebo groups. respectively; this difi‘erence was
`not significant (nominal P : 0.8399).
`
`Post Hoc Analyses
`Results of the post hoc analyses conducted for both studies
`to examine potential reasons for study failure are described below.
`
`D'stributiun ol' HAM-D47 and MADRS
`Scores at Emeline
`In both studies. baseline llAM-D-l7 scam detemtined
`subject inclusion. but a distribution of these scores does not fully
`correspond to baseline MADRS scores—a similar measure of
`depression and the primary efi'icacy measure in both studies.
`Figures 2 and 3 illustrate the distribution of actual HAM-D47
`and MADRS scores. respectively. at baseline. Whereas HAM-D-
`17 scores show the inclusion of appropriate study subjects.
`MADRS scores suggest the inclusion of many individuals with
`depression oflesser severitythan “as required by study inclusion
`criteria.
`The actual baseline MADRS scores of 29 or less show
`that most of the subjects in both studies (52.9% of486 in study 1
`and 50.5% of 370 in study 2) had scores below the threshold
`considered to be the minimal severity threshold required for
`
`analyses of week 6 data (both LOCF and 0C data) were generally
`consistent with the prilnary MMRM analysis results.
`
`Secondary Efficacy Analysis
`In butlt studies. MADRS response rates (250% improve-
`ment from baseline MADRS scores) were similar to placebo.
`ranging from 46% to 53% of subjects (Table I). In study 1. re-
`sponse rates at the end of the study for subjects indicated by the
`MADRS scores were 52.5%. 45.8% and 49.4% for lower dose
`ziprasidone. higher dose ziprasidone. and placebo. respectively.
`In study 2. response rates at the end of the study were 52.8%
`for ziprasidone subjects and 51.1% for placebo subjects. The
`ziprasidone groups did not demonstrate a statistically significant
`difierence over placebo in response rates in either study
`Results of the ANCOVA analysis ofthe secondary efiicacy
`end point. change from baseline in the HAM-D—l'l total score.
`showed no significant difference between ziprasidone and pla-
`cebo in both studies (unadjusted P > 0.05 for all comparisons
`between zipmsidone and placebo). In study 1. the least squares
`(LS) mean (SE) for change from baseline to the end of the study
`(0C) were - 10.5 (0.9) (n = 151). —ll.5 (0.95) (n = 150) in the
`
` ' "' Ziptesim (120-100 mgt'd)
`
`“*~ Ziptuiidone (to-so mom)
`
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`2 44-;
`464;
`—1a--‘
`FIGURE 1. Primary efficacy analysisa comparing ziprasidone
`versus placebo (intent-to-treat [HT] population, observed cases).
`aThe mixed-model repeatedmeasures (MMRM) with model
`terms: treatment, rapid cycling, (enter, visit, previous
`hospitalization status, treatment by visit interaction, and
`baseline as covariate. ”P < 0.05. ‘Baseline Montgomery-“berg
`Depression Rating Scale (MADRS) scores were 27.1
`(ziprasidone 120—160 mg/d), 28.7 (ziprasidone 40—80 mg/d),
`and 28.9 (placebo). dBaseline MADRS scores were 28.6
`(zipras'done 40-160 mg/d) and 28.2 (placebo).
`Week 6 results represent the primary efficacy analysis.
`
`CA 201.? Lippinmrr [VII/farm & Wilkins
`
`ww.psychopharmacology.com I 473
`
`Copyrigwt © 2012 Lippinoott Vialliams 8: Wlkins. Unauthorized reproduction of this article is prohibited.
`
`4
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`

`

`Lomban‘lo er a!
`
`[oumal ofC/Inlcal Psychopharmatology 0 Volume 32, Number 4, August 201 2
`
`TABLE I. Results From Clinical Studies of Atypical Antipsychotics for the Treatment of Bipolar I Depression
`
`Change in MA DRS Score at Last
`
`Discontinuation Rate
`(Discontinued/Randomized), %
`
`Response' $
`Rate, %
`a
`LS Mean (SE)
`
`Duration, wk
`6
`
`49
`53
`46
`
`51
`53
`
`45
`60
`58
`
`36
`58
`58
`
`30
`56
`39
`
`3‘)
`43
`
`162
`158
`166
`
`190
`180
`
`161
`155
`151
`
`169
`172
`170
`
`355
`82
`351
`
`177
`162
`
`~13.3 (1.0)
`-14.8 (0.97)
`~13.8 (1.0)
`
`-13.2 (0.9)
`-14.9 (1.0)
`
`-11.9 (0.99)
`—l6.9 (0.99)
`-l6.0 (1.01)
`
`-10.3
`‘16.4
`-l6.7
`
`-l 1.9 (0.8)
`-18.5 (1.3)
`-15.0 (0.7)
`
`- 10.6
`-l 1.9
`
`‘1 1.5
`‘12.}
`
`Study
`Study 1
`Placebo
`Ziprasidonc 40—80 mg/d
`Ziprnsidonc I20 160 mg/d
`Study 2
`Placebo
`Zipmsidone 40—160 ngd
`'lhasc at a], 20067
`Placebo
`Quetiapine 300 mg/d
`Quetiapine 600 mg/d
`Calabrese et a1, 20056
`Placebo
`Quctiapine 300 nig/d
`Ouctiapinc 600 mg/d
`’l'ohe-n et a13
`Placebo
`Olanmpine/fluoxctine
`Olanrapirie
`"(base cl all (study ”"15
`Placebo
`Aripipraaolc
`Nurse et al (study 2?,”
`176
`44
`56/188 (29.8)
`Placebo
`175
`45
`77/137 (41.2)
`Aripipnimlc
`‘50% decrease in Montgomery-Ashcrg Depression Rating Scale (MADRS) soon: li‘om baseline. SE data mining when unmailablc.
`LS indicates least sqmres; SE, standard error.
`
`57/174 (32.8)
`63/ 176 (35.8)
`80/186 (43.0)
`
`62/200 (31.0)
`73/192 (38.0)
`
`58/168 (34.5)
`71/172 (41.3)
`79/169 (46.7)
`
`74/181 (40.9)
`60/181 (33.1)
`82/180 (45.5)
`
`232/377 (61.5)
`31/86 (36.0)
`191/370 (51.6)
`
`66/188 (35.1)
`87/186 (46.8)
`
`6
`
`8
`
`x
`
`8
`
`8
`
`8
`
`study enrollment. Furthermore. 12 ( 3%. study 1) and 19 (5%.
`study 2) subjects at baseline would be considered in remission
`3‘ baseline according ‘0 their MAPRS 509755 (MADRS scores
`512‘). At the time of last observation. 98_ (20%) and 54 ( 15%)
`“bled? had MADRS “0‘35 0M 0" loss 1“ study 1_ and 5“de 1
`respectively. including 28 and 12 SlIhJCCIS. respectively. With an
`MADRS score 0‘“).
`Comparison of Actual and Predicted MADRS Score at
`Both Baseline and at the End of the Study
`.
`'. .
`.
`.
`.
`d.
`The mean (‘50) and linediian (Tug? “68:1;an of“:
`ivcrgence
`tween actua an prc I“:
`A
`scores 0 '
`served at baseline were _7'90 (* 5'52) and -8'09 {-28'63‘
`13.54). and -8.63(16.18)and -8.32(—34.34. 7.1). forstiidies
`l and 2. respectively In a quarter of subjects.
`the predicted
`MADRS score was more than II and 123 points greater than
`the actual MADRS score in studies I and 2. respectively. In 10%
`of subjects. the denved MADRS score was more than 15 and
`16.6 points greater than the actual MADRS score in studies 1 and
`2. respectively. At the end of the study. the mean and median
`divergences were markedly less than at baseline. at 4.67 (t 4.99)
`and -4.3 (23.33. 9.84) for study I. and -4.29 (i 5.69) and
`-4.31 (-22.04. 21.11) for study 2. [n a quarter of the subjects.
`the predicted MADRS score was more than 7.8 (study I) and
`7.9 (study 2) points greater than the actual MADRS score; in
`10% of subjects, the predicted MADRS score was more than
`1 1.3 (study I) and 12.1 (study 2) points greater than the actual
`MADRS score.
`
`Influence of Baseline Illness Severlty
`Results of the primary efficacy MMRM analysis repeated
`for each of the 2 subgroups (ineligible vs eligible based on
`baseline MADRS total scores (29.5 and 2295) are presented in
`Table 2. Not unexpectedly. subjects with lower baseline MADRS
`scores experienced less change duringthe course ofthe study than
`subjects with higher MADRS scores. Results in the 2 subgroups
`brsed on baseline MADRS scores were oousrstent With the re-
`sults from [he ‘3er effim I n 1“ [analysrs. m mdy 1‘ the
`placebo response rate in the ineligible group was greater than the
`proportion in the eligible group (57.1% vs 41.0%); in study 2.
`however. the placebo response rate in the eligible group was
`greater than that in the ineligible group (54.8% vs 47.4%). For
`both studies. there were no meaningful difi'erenccsl
`the
`.
`.
`‘
`.
`.
`.
`.
`.
`response rates for ztprasidone subjects in the ineligible group
`versus the eligible group.
`Placebo Response
`Among the 21 sites in study 1 that had at least 10 sub-
`jects, placebo response rates greater than 40% were observed in
`14 sites (66.7%); and among the 15 sites in study 2 that had at
`least 10 subjects, placebo response rates greater than 40% were
`observed in 13 sites (86.7%) (Fig. 4. A and B).
`
`DISCUSSION
`Randomized clinical trials can generate positive or negative
`results or they can fail to provide meaningful results. Positive
`
`474 I vwvw.psychopharrnacology.com
`
`if! 2013 ijpinmrr Williams & Wilkins
`
`Copyrigwt © 2012 Lippinoott Vialliams 8: Wlkins. Unauthorized reproduction of this article is prohibited.
`
`5
`
`

`

`[oumal of Clinical Psychopharmacology 0 Volume 32, Number 4, August 2012
`
`lerasidone In Bipolar I Depression
`
`Suidyi
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`
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`
`results require a statistically signifimnt difi'erence between the
`test conditions Negative results refer to outcomes in which the
`test dmg is not significantly different from placebo in a study
`with demonstrated assay sensitivity (eg. results indicating that a
`comparator drug of known or established benefit is significantly
`
`more efiective than placebo but the test drug is not). A failed
`study may be declared in the absence of assay sensitivity leg.
`when both the test drug and the comparator failed to separate
`from placebo). In the absence ofa known active comparator. it is
`not possible to distinguish between