Efficacy and Safety of Adjunctive Oral Ziprasidone
`for Acute Treatment of Depression in Patients With Bipolar I Disorder:
`A Randomized, Double-Blind, Placebo-Controlled Trial
`
`Gary S. Sachs, MD; Kathleen S. Ice, PhD; Phillip B. Chappell, MBA, MD; Jeffrey H. Schwartz, PhD;
`Oksana G urtovaya, PhD; Douglas G. Vanderburg, MPH, MD; and Bryce Kasuba, MA, MBA
`
`ABSTRACT
`
`Objective: To assess efficacy and safety of adjunctrve
`7iprasidone in subjects with bipolar depression treated
`with lithium, larnotrlgine, or valproate.
`Method: 2.98 adult outpatients with bipolar I
`disorder (DSM-r‘Vcriteria) were random i7ed to
`receive ziprasidone. 20 80 mg twice a do , or placebo
`ts-rice a day for 6 weeks plus their preexrsting mood
`stabilirer. The primary efficacy variable was change
`in Montgomery Asberq Depression Rating Scale
`(MADRS) total scores from baseline to 6 weeks. The
`key secondary efficacy endpoint was c hange from
`baseline to week 6 in Clinical Global lmpressrons
`Severity (CG! -S) scores. Computer administered
`assessments for diagnostic confidence were included
`for quality control and to evaluate study perfonrance.
`The study was conducted between October 2007 and
`December 2008.
`
`Results: The mean 1-. SD darlv dose or aprasidone was
`89.8: 29.! reg. Least squares mean t standard error
`changes from baseline to week 6 on MADRS total
`score for ziprasidone and placebo treatment groups
`were
`13.2 .r 1.2 and -- i 2.9 -.r-. i], respectively, with
`a 2 sided P value of .792. There was no significant
`difterence on the key secondary variable (CGIv-Si.
`Acljunc rive zrprasidone was well tolerated. Poor
`quality ratings at baseline were associated with
`a trend for better improvement on placebo than
`7iprasidone, Arrong 43 placebo- treated subjects
`with poor baseline quality ratings, 29 (67.4%) had
`baseline MADRS scores >10 points higher on the
`cornpurer-administered assessment than the MADFS
`administered by the site based rater. The response
`favoring placebo over zrprasrdone observed in this
`subgroup suggests that poor signal detection in
`some clinical trials can be a consequence of”subject
`inflation‘ as well as 'rater inflation."
`
`Conclusions: Adjunctive ziprasidone treatment failed
`to separate from mood stabilizer alone on primary and
`secondary endpoints. Possible contributions to this
`result include enrollment. of a substantial number of
`subjects with low diagnostic confidence, low quality
`ratings on the MADRS. and overzealous reporting of
`symptoms by subjects.
`Trial Registration: clinical trialsgov Identifier:
`NCTOO4 83548
`
`[Clln Psychiatry 20l l;72( lO):I4l3—-l422
`50 Copyright 2011 Physicians Postgraduate Press. brc.
`
`
`Submitted: December 22, 2909; accepted August 2‘9, 3010.
`
`Onllne ahead nfpnnt: May 3, Jr) 3 ‘ (rlor. lil4088/K‘P09r7105974l.
`Corresponding author. Gary S, Sachs, MU Bipolar
`.‘mrc and
`Research Proqrurrr, Massachurcrtr GerierolHOrpflai 50 Standard
`St. 51h floo', Boston MA 02i i4 {Sachscmaozcom}.
`
`B ipolar l disorder is a common complex, chronic illness that is
`associated with considerable functional
`impairment.l This
`dynamic, pleomorphic disorder challenges researchers as well as cli-
`nicians and, as a consequence, relatively little high quality data are
`available to guide clinical practice. The management of depression in
`patients with bipolar l disorder remains an area of significant unmet
`need} In the Systematic Treatment Enhancement Program for Bipo-
`lar Disorder (STEP-8D). subjects with bipolar disorder experienced
`high rates of depressive relapse despite maintenance treatment with
`lithium. vulproate, or other US Food and Drug Administration (FDA) ~
`approved antimanic agents.1 In view of the unmet need for adjunctive
`treatments for patients suffering from bipolar depression despite pre—
`scribed maintenance treatment at dosages considered adequate, we
`undertook a study of adjunctive ziprasidone.
`Like other agents classified as atypical antipsychotics, zipmsidone
`is a dopamine D; and 5-HT; A antagonist and interacts with numerous
`other receptors. Ziprasidone shows agon ist activity at S—l le receptors
`and antagonist activity at 5-HTm and 5-HT”) receptors. The affinity
`of ziprasidone for 5-HTm receptors, and its scrotonin-norepinephrine
`reuptake inhibition, is comparable to that of the tricyclic antidepres—
`sant imipraminc. and provides a rationale for studying ziprasidone
`as an antidepressant.‘ Data from prior small. open studies suggest
`that ziprasiclone may reduce depressive symptoms associated with
`bipolar I disorder.5'7
`Only 2 treatments have FDA approval for treatment of bipolar
`depression: the atypical antipsychotics quetiapines and olanmpine
`fluoxctine combination9 have demonstrated more efficacy than
`placebo in reducing depressive symptoms in patients with bipolar l dis-
`order. However, both drugs are associated with undesirable metabolic
`effects such as weight gain and disturbances of glucose homeosta-
`sis.’°‘” Ziprasidone has a lower propensity for weight gain and other
`metabolic disturbances than olanzapinc or quctiapine.12
`Adjunctive treatment with standard antidepressant medications is
`the most commonly prescribed intervention for patients with bipolar
`depression.13 The STEP—ED showed no benefit, however, for adjunctive
`treatment with antidepressants (bupropion or paroxetine) compared
`to mood stabilizer plus placebo. To date. only one placebo-controlled
`study has succeeded in demonstrating the efficacy of any agent as an
`adjunct to lithium or valproate.” Although successful in an adjunct
`study” and commonly used for maintenance treatment for bipolar
`disorder, lamotrigine failed to separate from placebo in 5 of S bipolar
`depression monotherapy studies on primary outcome measure and
`4 of 5 studies on key secondary outcome measures.15 Another atypi-
`cal antipsychotic, aripiprazole. studied for bipolar depression. has also
`produced negative or failed results.16
`There are no double-blind data available to guide the care of
`depressed bipolar patients who have not responded to lithium, lamo-
`trigine. or valproate. As preliminary clinical studies have suggested that
`
`“geriatric sot? terrorists i’irs‘tfiititotiitt i’Wg-g ‘asrst It;
`
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`~.
`
`1
`
`Exhibit 2054
`Slayback v. Sumitomo
`|PR2020—O1053
`
`Exhibit 2054
`Slayback v. Sumitomo
`IPR2020-01053
`
`

`

`ziprasidone may have an antidepressant effect in subjects
`with bipolar disorder or with other psychiatric diagnoses,
`the present study was designed to investigate the efficacy
`and safety of ziprasidonc as add-on therapy in patients with
`bipolar l disorder who were treated with lithium. valproate.
`or lamotrigine. In view of the frequency at which bipolar
`depression studies have failed or produced negative results,
`we incorporated an innovative computer- based rating man-
`agement system into the study design.
`
`METHOD
`
`The study (clinicaltrialsgov registry: NC'I‘OO483548) was
`a randomized, double-blind. placebo-controlled, trial con-
`ducted at 78 centers located in Australia (4), lndia (6), and
`the United States (68). The protocol was approved by insti-
`tutional review boards or independent ethics committees at
`each center. and the trial was conducted in accordance with
`the Declaration of Helsinki. the International Conference
`
`on Harmonisation Good Clinical Practice widelines, and
`all appropriate local regulatory requirements.
`The primary aim of the study was to investigate the effl—
`cacy and safety of ziprasidone as add-on adjunctive therapy
`in the treatment of depression associated with bipolar l d isor—
`der. Secondary objectives included examination of the effects
`of ziprasidone on global Functioning and quality of life.
`
`Subjects
`Adult (2 I8 years old) outpatients of either sex were elir
`gible for the study if they had a primary diagnosis of bipolar
`l disorder. with the most recent episode depressed (296.5x),
`with or without rapid cycling, and without psychotic fea-
`tures, as defined in the Diagnostic and Statistical Manual of
`Mental Disorders, Fourth Edition (DSM-IV).‘7 The diagnosis
`was established by consensus between a certified sitebased
`rater using the Mini-International Neuropsychiatric lnter—
`View” and an independent expert employed by Concordant
`Raters Systems in Boston, Massachusetts; Philadelphia.
`Pennsylvania; or San Francisco, California. The expert was
`a psychiatrist or psychologist with clinical experience and
`research experience who reviewed details of prior manic
`or mixed episodes collected directly from the subject by
`the computer and who validated the subjects' eligibility for
`randomization, if at least I episode met full DSM—~IV cri-
`teria for mania or a mixed episode. The Bipolarity Index, a
`measure of diagnostic confidence.” was also used for cases
`in which it was not possible to confirm the diagnosis based
`on the computer assessment. In these cases, subjects were
`included only ifsufficient additional diagnostic information
`was obtained from the investigator (or designee) to estab-
`lish acceptable diagnostic confidence}0 The onset of the
`depressive episode was required to be between 2 weeks and
`6 months of screening. In addition. subjects were required to
`have a score ofat least 20 on the i7-item Hamilton Depres-
`sion Rating Scale (HDRS—l7)" and a score of S 12 on the
`Young Mania Rating Scale (YMRS)22 at both screening and
`randomization.
`
`Adjunctive Ziprasidone in Bipolar Depression
`
`I The frequent failure of randomized controlled studies
`to detect differences between study medication and
`placebo is a significant obstacle to drug development.
`
`I Although some studies include active comparators,this
`component alone does little to inform the field as to why
`randomized clinical trials often lack assay sensitivity.
`
`I Using data from tandem assessments made by site-
`based raters and computer-administered assessments,
`this report examined the impact of protocol-specific
`eligibility criteria, diagnostic confidence, and rating
`quality on signal detection. The results suggest that
`variability in study quality can lead to study failure and
`that future clinical trials could benefit from procedures
`that do not rely exclusively on assessments made by a
`single rater.
`
`o.
`5:('5 ,‘
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`
`{A
`
`Subjects were excluded from the study if they had any
`DSM-lV-TR Axis I or Axis ll disorder that was clinically
`unstable or required treatment or if they showed ultrafast
`rapid cycling (defined as 28 mood episodes during the 12
`months before screening). Other psychiatric exclusion cri-
`teria included a suicide attempt within the 3 months before
`screening or a score ofal least 4 on the suicide item of the
`Montgomery-Asberg Depression Rating Scale (MADRS),23
`DSM—lV-TR»~defined alcohol or psychoactive substance
`dependency within 6 months prior to screening or docu-
`mented abuse of such substances within 3 months before
`
`screening, electroconvulsive therapy (ECT) within 3 months
`before screening, a history of nonresponse to ECT, treatment
`with any psychotropic medication other than lithium, val-
`proate or lamotrigine within l week prior to screening, or
`depot neuroleptic treatment within the previous 6 months.
`in addition, subjects were excluded if they had clinically
`significant electrocardiogram (ECG) abnormalities, a his-
`tory of QT interval prolongation or any medical condition
`or treatment that could produce such prolongation, or sig-
`nificant medical conditions. including a history of seizures.
`cardiovascular disease. neuroleptic malignant syndrome. or
`tardive dyskinesia that did not respond to treatment. Women
`of childbearing potential were required to use appropriate
`contraceptive precautions during the study.
`Written informed consent was to be obtained before
`
`inclusion in the study. lo the case of illiterate subjects, the
`subject provided an alternative indication, such as a thumb-
`print, and an impartial witness was required to provide
`signed confirmation that the informed consent procedure
`had been appropriate.
`
`Study Design and Treatment
`Study subjects comprised (l) subjects already on a
`mood stabilizer at screening and (2) subjects initiated on a
`mood stabilizer at screening. in both cases, mood stabilizer
`treatment had to remain stable, as defined by the protocol
`
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`

`

`Adjunctive Ziprasidone in Bipolar Depression
`
`requirements for lamotrigine dose (100-200 mg/d) or blood
`concentrations of lithium or valproate (0.6—1.2 mEq/I. for
`lithium or 50—125 ug/ml. for valproate). and was to be main-
`tained for at least 4 weeks before randomimtion. Subjects
`whose mood stabilizer therapy had remained stable as per-
`protocol requirements for at least 4 weeks were randomized
`in a 1:1 ratio to receive adjunctive ziprasidone or placebo
`for 6 weeks.
`
`Randomization was performed using a unique identifica—
`tion number for each subject and was stratified according
`to the type of mood stabilizer therapy (lithium, valproate,
`or lamotrigine). An internet—ltelephone-based random-
`ization and drug management system was used to provide
`the identification number and to assign either ziprasidone
`or matching placebo capsules to each subject throughout
`the trial. Blinding was to be broken only in the event of an
`emergency that required knowledge of the treatment for
`subject safety. One formal interim analysis was to be per-
`formed whcn approximately 60% of the planned subjects
`had either completed the study or discontinued prematurely.
`The Data Safety Monitoring Committee had the option to
`recommend stopping the study early for efficacy (nominal
`P value 5.0076. 2-sided) or for futility (nominal P value
`2.5099. 2-sided).
`Subjects were instructed to take all study medication
`with food. The starting dose of ziprasidone was 40 mg in
`the evening on the day of randomimtion, followed by 40 mg
`twice daily on the second day (ie. 80 mg total daily dose).
`Thereafter, subjects were titrated twice daily with total daily
`doses in the range of 40—160 mg. depending on symptoms
`and tolerability. Compliance was assessed by pill counts. and
`blood levels of lithium and valproate were monitored via
`samples taken at screening, baseline, and week 6, or at the
`early termination visit to ensure the subject met the required
`therapeutic blood level specified in the protocol.
`All other psychotropic medications were withdrawn at
`least 7 days or 4 half-lives (whichever was longer) before
`randomization. Lorazepam, or an alternative short-acting
`benzodiazepine, could be given at doses of up to 2 mg/d for
`up to 4 days per week during screening and the first 2 weeks
`of the double-blind treatment period to treat agitation or
`anxiety. Regulatory agency—approved nonbenzodiazepinc
`medications could be used to treat sleep disturbances for
`up to 4 days per week until the end of the second week
`of double-blind treatment and for up to 2 days per week
`thereafter. The benzodiazepines and sleep agents were not
`to be given on the same day and were not to be used within
`24 hours of efficacy assessments. Benztropine (S 6 mg/d)
`or an equivalent agent could be used to treat extrapyrami-
`dal symptoms. Propranolol (S 120 mg/d) could be used to
`treat akathisia.
`
`Assessments
`
`Efficacy assessments were made at baseline (randomiza-
`tion) and at weekly intervals thereafter. The primary efficacy
`endpoint was the change from baseline to week 6 in the
`MADRS total score. The key secondary efficacy endpoint
`
`was the change from baseline to week 6 in the Clinical Global
`lmpressionsSeverity scale (CGI-S)Z4 score. Additional sec—
`ondary efficacy endpoints included change from baseline in
`Hamilton Anxiety RatingSc-ale (ll/\RS)25 total score; change
`from baseline in YMRS total score; change from baseline
`in Global Assessment of Functioning (GAF) scale17 score;
`change from baseline in Sheehan Disability Scalez" total
`score; and change from baseline in Quality of Life Enjoy--
`ment and Satisfaction Scale (QvLES—Q)27 total score.
`Only qualified raters who met educational and experience
`requirements participated in the trial. Prior to the start of the
`trial, rater training was conducted on-line and at an inves-
`tigators’ meeting for all participating centers. The MADRS
`data at each study visit were monitored using a remote site
`management system developed by Concordant Rater Sys-
`tems, the vendor responsible for rater training and remote
`site management. Raters completed the training program
`and then received “provisional certification": “full certifica~
`tion" was granted on raters demonstrating proficiency with
`concordance between site-based ratings and computer rat-
`ings within the acceptable concordance range over the first
`3-6 actual subject ratings. Raters not meeting proficiency re-
`quirements were not allowed to enroll additional subjects.
`Each site was provided with a laptop computer with
`the remote site management software (Concordant Rater
`Systems). The MADRS item scores as determined by the
`site-based ratings were entered on the laptop. In addition,
`(without assistance or input from the site rater), the subject
`completed an interactive interview on the computer, which
`selected a sequence of questions as necessary to map the
`subject’s responses to the MADRS anchor points for each
`scale item. A computergenerated score was assigned based
`on the subject’s input. Prior studies have demonstrated that
`site-based ratings and computer-administered MADRS are
`highly correlated.”
`ltem ratings scores on which the site-based ratings and
`computer scores differed by no more than l point were
`considered to be concordant. Concordant Rater Systems
`contacted raters by telephone to discuss the potential causes
`for discordant ratings, if the total score differential was 26
`points or more than 2 items with a differential of 2 3 points.
`No further action was taken with raters who provided
`supporting information for their ratings; however, raters
`with unresolved discordance received remediation on use
`
`of appropriate probes and/or scoring conventions for the
`MADRS. In all cases, site-based raters were instructed not
`to change their original scores.
`The same procedure was applied to the YMRS data
`at screening and baseline and to the HDRS-l7 data at
`screening. Rater quality scores were categorized as better
`quality, lower quality, and poor quality ifthe absolute value of
`the difference between the computer- and site—based ratings
`was 5 5. >5 5 l0. or > ID, respectively. The poor quality ratings
`were designated rater inflation if the site-based ratings score
`was > 10 points higher than the computer score and subject
`inflation when the computer score was > 10 points higher
`than the site-based ratings score. Confidence in the lifetime
`
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`

`diagnosis of bipolar I disorder was assessed with the Bipo-
`larity Index.” This scale quantifies the procefi suggested
`by Robins and (Suze30 for validating psychiatric diagnosis
`by scoring 5 illness domains (episode characteristics. age at
`onset, response to treatment, course of illness, and family
`history) on a 0—20 scale, on which higher scores are given
`to characteristics most associated with the Kraepelinian
`conception of bipolar disorder. Prior psychometric studies
`indicate that acceptable confidence for bipolar l disorder
`lifetime diagnosis corresponds to scores above 60 or having
`at least 3 domains scored l5 or higher.”
`Safety and tolerability were assessed by recording of
`adverse events, physical examination, and measurement of
`vital signs, 12 dead ECG, and clinical laboratory evaluation.
`Extrapyramidal symptoms, akathisia. and dyskinesia were
`assessed by means oftlie Simpson-A ngus Scale,“ the Barnes
`Akathisia Scale,32 and the Abnormal Involuntary Movement
`Scale (AIMS).33
`
`Statistical Analysis
`Statistical analyses were performed on the intent—to-
`treat (ITT) population, which consisted of all subjects who
`were randomized. received at least I close of double-blind
`
`medication, and had at least 1 postbaseline primary effi-
`cacy assessment. In addition, the primary and key secondary
`efficacy endpoints were analyzed in the per—protocol popu-
`lation, which included all subjects in the lTT population
`with no major protocol violations.
`The primary efficacy variable, the mean change in
`MADRS scores from baseline to week 6, was analyzed
`using a mixed model repeated measures (MMRM) analysis
`with fixed categorical effects of treatment, country, type of
`mood stabilizer, visit and treatment-by-visit interaction, and
`a fixed, continuous effect of baseline MADRS score; subject
`effect was included as a random effect. The mixed model
`
`repeated measures analysis used the restricted maximum
`likelihood estimation method,with a sandwich estimator of
`variance—covariance matrix of the fixed effects parameters.
`The analysis was performed using the SAS PROC MIXED
`procedure (SAS Institute Inc, Cary, North Carolina). [in
`unstructured variance-covariance matrix was used in the
`
`REPEATED statement. Supplemental analyses of the pri-
`mary endpoint included analysis of covariance (ANCOVA)
`of the change in MADRS scores from baseline to week 6,
`with missing data imputed using last observation carried
`forward (LOCF) principle; ANCOVA of change from base-
`line in MADRS scores at week 6 on observed cases only,
`the primary analysis using log-transformed total MADRS
`score; and a pattern mixture. mixed model repeated mea-
`sures analysis of change from baseline in MADRS scores.
`The change in CGl-S score from baseline to week 6 was
`analyzed by mixed model repeated measures as described
`above. and supplementary analyses were performed by
`ANCOVA on both LOCF and observed cases data. Adjusted
`for the interim analysis, the P value threshold for the pri-
`mary analysis was .0476. For change from baseline in total
`score for I-lARS and YMRS, ANCOVA similar to that for the
`
`Adjunetive Ziprasidone in Bipolar Depression
`
`primary endpoint was conducted at each postbaseline col-
`lection time point on the basis of both LOCF and observed
`cases. For change from baseline in scores for GAP, Sheehan
`Disability Scale, Q-LES-Q, Simpson-Angus Scale, Barnes
`Akathisia Scale, and AIMS. ANCOVA similar to that for
`the primary endpoint was conducted on the basis of the
`observed cases.
`
`The sample size calculation was performed with EAST 4
`software (Cytel Inc, Cambridge, Massachusetts) to account
`for a prcplanned interim analysis, when approximately 60%
`ofthe planned number of subjects had either completed the
`study or discontinued prematurely. it was calculated that a
`sample size of 141 subjects per group (282 in total) would
`provide 85% power to detect a treatment difference in the
`mean change in MADRS scores from baseline to week 6 of
`4.0 points, with a standard deviation of l 1.0. using a 2-sided
`test at a significance level of .05.
`
`Rating Quality Data Analysis
`After completion of the efficacy analysis. the study spon -
`sor sent unblinded treatment assignments to Concordant
`Rater Systems and matched with the rater quality data files.
`The files were reviewed for accuracy, and analyses were car-
`ried out using Stuta version I 1.0 statistical software.
`The analysis plan compared key results from the efficacy
`analysis to those derived from the Rater Quality data set
`and evaluated a list of a priori competing hypotheses. These
`involved comparing results from prespecified subgroups
`defined by variables derived from computer-administered
`scales.
`
`Quality ratings were defined based on the absolute value
`of the difference between the computer. and site—based rat-
`ings scores on the MADRS: better quality (difference 5 5).
`low quality (absolute value of difference from 5—10), or
`poor quality (difference > 10). Baseline MADRS ratings in
`which the site-based ratings score was > 10 higher than the
`computer scored were classified as indicating likely rater
`inflation. Baseline MADRS ratings in which the site—based
`ratings score was > 10 lower than the computer scored were
`classified as indicating likely subject inflation.
`
`RESULTS
`
`Between October 2007 and December 2008, 792 subjects
`were screened, of whom 298 were randomized and 294 (147
`in each group) received treatment (Figure 1). Of the 294
`who received treatment, 102 subjects discontinued treat-
`ment, mainly due to adverse events and protocol violat ions.
`Thus, 192 subjects (88 in the ziprasidone group, Kit} in the
`placebo group) completed the study (Figure l). The sample
`characteristics are summarized in Table l.
`
`Interim Analysis
`The interim analysis was performed on 168 subjects
`(84 subjects in each treatment group; 59.6% of the planned
`final sample size). At the interim analysis, the least squares
`mean 1 standard error (SE) changes from baseline to week
`
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`

`

`Adjunctive Ziprasidone in Bipolar Depression
`
`
`
`Figure 1. Study Profile
`
`
`
`
`
`
`
`
`
`43(29_flu)l)1sconllnuations
`i
`
`5
`14 (9.5%) Myers: events
`2 (1.4961 ubordtoiyebnormaltie: :
`B (SAW ad: cfefiucy
`I (4.8%) Protozoivnlmions
`12 (8.2"! Other reasons
`
`Ziprasidonc (n
`
`1'17)
`
`Placcbo (n H7)
`
`53 (39.5)
`21905115)
`
`56 1.13.1)
`91 (51.9)
`
`l16(78.9)
`1902.9)
`7 (-1.8)
`513.4)
`10.41. 11.1(18—6'1)
`8-1.3 1. 21.4 (450—156.!)
`168.2 ‘: 10.1 (1380-1881))
`16.2 (1107-50.?)
`
`111 (75.5)
`20(135)
`11 (75)
`513.1)
`10.1.1 11.9(18—66)
`89.91 232145.147”)
`108.0110.0{l39.7-195,0)
`16.6 (0.1 45.2)
`
`
`Tablo 1. Basollno Characteristics
`Characteristic
`Sex. n (‘36)
`Male
`Female
`Race. n (91:)
`White
`Black
`Asian
`Other
`Age. mean .t SD (range), y
`Weight. mam 1 SD (range). kg
`Height. mean :51) (range). cm
`Tim: since first diagnosis ofbipolar l disorder.
`mean (range). y
`Duration of current. episode. mean (range), (1
`No. of episodes in previous 12 mo. mean (range)
`Suicidal idealion in prewous I! mo. n (96)
`History of suicide attempt in pmvious 12 months. 11 (1‘61)
`Mood stabilizer. n“
`Lithium
`Valpruule
`Lamotrigine
`‘Oue subject in the ziprasidone group did not receive a mood stabilizer during the double-blind period and was
`therefore excluded from the analysis.
`
`76.2 (15—251)
`2.7 (0—20)
`41001.4)
`6 (1.1)
`
`53
`52
`:11
`
`82.9 (16—207)
`2.3 (0—10)
`45131.5)
`4 [2.8)
`
`5-1
`52
`41
`
`6 on the MADRS for the ziprasidone and placebo treatment
`groups were —1 1.3 (2.18) and -13.3 (2.06), respectively, with
`a 2-sided Pvalue of .2690 favoring placebo.
`Enrollment in the study was faster than expected. and the
`results of the interim analysis were not available until enroll—
`ment was almost completed. On the basis of the results of
`the interim analysis, the Data Safety Monitoring Committee
`recommended that, due to study futility, already random-
`ized subjects could complete the study but that no further
`subjects should enter the trial. Enrollment was complctcd
`before this recommendation was implemented.
`
`Efficacy
`Table 2 describes changes in efficacy rating scores. At
`baseline, there were no significant differences between the
`
`groups on any efficacy measure. The mean :81) daily dose
`ofziprasidone was 89.82: 29.1 mg.
`There was no significant difference on the primary out-
`come variable, the key secondary variable (CG l-S). or most
`of the other secondary measures, including YMRS. MARS,
`and Q—LES—Q. There was, however, a significant difference
`favoring ziprasidone over placebo on the GAF scale and the
`Sheehan Disability Scale.
`The least squares mean 1 SE change from baseline at week
`6 in MADRS total score for ziprasidonc~ and placebo-treated
`subjects was -l 3.2. i 1.2 and —12.9 i H . respectively (Table
`2), corresponding to a least squares mean 1 SE treatment
`difference of —O.3o:t 1.37 (95% Cl, -3.07 to 2.34) that was
`not statistically significant (P=.792l ). The results of the
`per-protocol analysis (1": .3989) and the sensitivity analysis
`
`
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`
`Adjunctive Ziprasidone in Bipolar Depression
`
`Table 2. Changes in Efficagx Rating Scores
`
`Ziprasklone
`(n : 1:15)
`
`Placebo
`(n = 1415)
`
`P
`Trealmcnt Difference.
`1.5 Mean: SF. (95%(11) Value
`
`30.0.1. 5.5
`— 13.2.1. 12
`
`28.8: 6.1
`- 12.9.1. [.1
`
`-0.‘l; 1:1 (-3.1 to 2.3)
`
`.7921
`
`Scale
`MADRSa
`Baseline score, mean 1 SD
`Change from basclinc to wcclt 6. LS mean .LSF.
`(XiI-S'
`Easclinc score, meanLSD
`Change from baseline to week 6.15 mean 15F.
`YMRS"
`Baseline score. mean .1. SD
`Change from baseline to week 6.13 mean tSF
`HARS“
`Emeline score. mean 7: SD
`Change from b.|se1ine to week 6.LS mean LSE
`GM"
`Hoseline score. mean .2 SD
`Change from baseline to week 6.1.5 mean :SE
`Sheehan Disability Scale‘
`Baseline score. mean at 50
`Change from baseline to week 6. LS mean 1 SE
`Q-IJ‘ZS-Q‘
`Baseline score. mean -.1. SD
`Change from baseline to wch 6.1.5 mean t SE
`‘Mixed model repeated measures.
`hLast observation tamed forward.
`“Observed «uses.
`Abbmiations CGl-S Clinical Global lmprcssions—Sm-crity scolc;GA1’ Global Assessment of functioning:
`HARS: Hmnillun Anxiety Rating Scale; LS: least sqrnrcs‘. MADRS =Montgomery-Asberg Depression Rating
`Scale: Q‘1.1’.S-Q = Quality of Life. Enjoyment. and Satisfaction Smle: SE : stzanIrd error; YMRS: Young
`Marlin Rating Scale.
`
`4.4.1.05
`4.4.10.2
`
`6.8.1 3.1
`~- (1.81 1.1
`
`20.1 :t 62
`-8.6;t 1.4
`
`52.4 .0. 7.5
`16.82 2.1
`
`18.11 7.1
`77.4.1. 2
`
`4.41.0.7
`—l.4 .t 0.2
`
`7.1 J. 3.0
`~ 1.0: 1.0
`
`19.9 t 7.0
`—9.ZJ. 1.3
`
`52.1 3.16.9
`12.5: 23
`
`16.9 1 7.3
`7 2.8!. 2.1
`
`0.11.0.2(-0.3 100.11)
`
`.7223
`
`0.210.? (-1.1 to 1.5)
`
`.7647
`
`0.6109 (-1.1 to 2.3)
`
`.4770
`
`1.2: 1.7 (1.0 to 7.5)
`
`.0108
`
`4.6:. M (~72 to - 1.9)
`
`.001
`
`411.713. 152
`12.1 14.6
`
`43.2 1 16.6
`10.6;t-15
`
`1.5 1 2.5 (-3.5 to 6.5)
`
`.5519
`
`
`
`figure 2. (A) Least Squares Mean Change in Montgomery-Asberg Depression Rating Scale (MADBS) Scores (last
`observation carried forward) and (B) Correlation Between Site-Based Rater and Computer-Administered MADRS
`Scores Over the Course of the Study
`
`A. Change in MADRS Score
`
`8. Correlation Between Site-Based Rater and
`Computer-Mmhistered MADRS Scores
`
`O leutidone
`O Placebo
`
`1'0
`
`0
`3‘
`5
`5 —2
`c
`
`-4.
`-5
`
`g
`E
`a.
`,
`'8
`E
`g? —10
`' ~12-
`fi
`§
`5 -14
`
`0.9
`
`~
`5 0.8
`z
`1‘
`3 0.7
`
`os-
`
`OS
`
`Baseline Will WkZ Wk} WIM WkS Wk6
`
`
`
`11978
`.
`Last
`Baseline Whl sz Wk3 W1” WkS Wko
`Uxervation
`
`limepoint
`
`limepoint
`
`wcrc consistent with this result. Figure 2A shows change in
`MADRS score with time.
`
`Rater Quality
`Results from 1 or more computer-administered scales
`were available for 282 subjects at 66 of the 78 sites partici-
`pating in the triaL Results from at least 1 postran domization
`visit were available for 265 subjects (placebo, n = 137; zipra-
`sidone, n= 128). Overall, the rater quality data produced
`results (Table 3) similar to the overall results of the effi-
`cacy analysis. The meaniSD Bipolarity Index score was
`
`71.71 10.1. The correlation between site—based rater and
`
`computer-administered MADRS scores improved consis-
`tently over the course ofstudy visits (Figure EB).
`None of the subgroup analyses based on the computer
`assessments found statistically significant differences be-
`tween adjunctivc placebo versus ndjunctivc ziprasidonc.
`The computer assessments. however, suggest that many
`subjects were enrolled who did not meet protocol-specified
`eligibility criteria. On the basis ofthe computer assessments,
`about 30% of all participants failed to meet severity criteria
`(computer‘administcrcd HDRS score <20 criteria n =22
`
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`

`

`Adjunctive Ziprasidone in Bipolar Depression
`
`
`
`11.1 (11.0)
`—10.3(12.7)
`
`11
`
`137
`137
`
`115
`llS
`2:
`22
`
`-- 11.4 (11.2)
`-11.4(12.3)
`
`1o.9111.1)
`11.21123)
`413111.15)
`712.5(l2.2
`
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`Site-based rater
`(.omputer
`Baseline HDllStmie 20
`Eligible
`-10.7(11.1)
`She-based rater
`10.31125)
`Computer
`Not eligible
`43.01105)
`Site-based rater
`710.7035]
`Computer
`Baseline YMRSQmP<Ssymptomsot‘mania
`Eligible
`1231112)
`“4
`ll.5(l0.9)
`Sitebnsed rater
`42.51127)
`1”
`41'0“”)
`NOC'ZE's’i’Lf'
`778 (10.7)
`23
`79.0 (11.7)
`Site-based mter
`—-6218.6)
`23
`4.2010)
`Computer
`Diagnostic confidence-(Bipolaritv Index mean score -7l.7)
`Above mom
`Silt-based mlcr
`B Ic‘ompu'“
`9 0W “19611
`Site-based rater
`Com uter
`1
`
`11 Difference
`
`128
`128
`
`108
`108
`20
`20
`
`l04
`10“
`211
`24
`
`56
`56
`72
`72
`
`10.3
`+1.1
`
`+0.20
`10.94
`+1.3
`1 LS
`
`10.8
`”'6
`, 1.2
`-~1.0
`
`+1.2
`'2-2
`0
`+0.2
`
`>30
`>48
`
`>39
`> .57
`>.72
`>66
`
`>450
`>34
`> .7
`2.74
`
`>.67
`)5"
`>33
`>.92
`
`and/or met criteria tor vat-current mixed
`Table 3. Impact of Eligibility Criteria Based on Computer Assessments:
`episode (3 clinically Sigmticant symptoms
`Comparison of Last Observation Carried Forward Site-Based Rater and
`on computer—administered YMRS, n = 23).
`Computer-Achinistered Montgomery-Asberg Depression Rating Scale (MADRS)
`SEW—w— Only 89 (33.6%) of the 265 subjects met
`_&_w the eligibility requirements based on the
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`Lilian e l‘nm
`PValue.
`.
`.
`-
`.
`BaselingeMADRS.
`BaselinfMA‘DRS.
`2-Sidcd
`computer ratings. The computer ratings
`Mean (SD)
`M