Olanzapine Versus Placebo in the Treatment of Acute Mania
`
`Mauricio Tohen, M.D., Dr.P.H., Todd M. Sanger, Ph.D., Susan L. McElroy, M.D.,
`Gary D. Tollefson, M.D., Ph.D., K.N. Roy Chengappa, M.D., David G. Daniel, M.D.,
`Frederick Petty, M.D., Ph.D., Franca Centorrino, M.D., Richard Wang, M.D., Ph.D.,
`Starr L. Grundy, B.Sc.Pharm., Michael G. Greaney, M.S., Thomas G. Jacobs, M.A.S.,
`Stacy R. David, Ph.D., Verna Toma, B.S., and The Olanzapine HGEH Study Group
`
`Objective: The primary intent of this study was to compare the efficacy and safety of
`olanzapine and placebo in the treatment of acute mania. Method: The design involved a
`random-assignment, double-blind, placebo-controlled parallel group study of 3 weeks’ du-
`ration. After a 2- to 4-day screening period, qualified patients were assigned to either olan-
`zapine (N=70) or placebo (N=69). Patients began double-blind therapy with either olanza-
`pine, 10 mg, or placebo given once per day. After the first day of treatment, the daily dose
`could be adjusted upward or downward, as clinically indicated, by one capsule (olanzapine,
`5 mg/day) within the allowed range of one to four capsules. The primary efficacy measure
`in the protocol was defined as a change from baseline to endpoint in total score on the
`Young Mania Rating Scale. Clinical response was defined a priori as a decrease of 50% or
`more from baseline in Young Mania Rating Scale total score. Results: The olanzapine
`group experienced significantly greater mean improvement in Young Mania Rating Scale
`total score than the placebo group. On the basis of the clinical response criteria, signifi-
`cantly more olanzapine-treated patients (48.6%) responded than those assigned to pla-
`cebo (24.2%). Somnolence, dizziness, dry mouth, and weight gain occurred significantly
`more often with olanzapine. There were no statistically significant differences between the
`olanzapine-treated and placebo-treated patients with respect to measures of parkin-
`sonism, akathisia, and dyskinesias. No discontinuations of treatment due to adverse
`events occurred in the olanzapine treatment group. Conclusions: The results from this
`study suggest that compared with placebo, olanzapine has superior efficacy for the symp-
`toms of acute mania.
`(Am J Psychiatry 1999; 156:702–709)
`
`(cid:66)(cid:105)(cid:112)(cid:111)(cid:108)(cid:97)(cid:114)(cid:32)(cid:100)(cid:105)(cid:115)(cid:111)(cid:114)(cid:100)(cid:101)(cid:114)(cid:32)(cid:40)(cid:109)(cid:97)(cid:110)(cid:105)(cid:99)(cid:45)(cid:100)(cid:101)(cid:112)(cid:114)(cid:101)(cid:115)(cid:115)(cid:105)(cid:118)(cid:101)(cid:32)(cid:105)(cid:108)(cid:108)(cid:110)(cid:101)(cid:115)(cid:115)(cid:41)(cid:32)(cid:105)(cid:115)(cid:32)(cid:97)
`
`(cid:99)(cid:104)(cid:114)(cid:111)(cid:110)(cid:105)(cid:99)(cid:32)(cid:101)(cid:112)(cid:105)(cid:115)(cid:111)(cid:100)(cid:105)(cid:99)(cid:32)(cid:100)(cid:105)(cid:115)(cid:111)(cid:114)(cid:100)(cid:101)(cid:114)(cid:32)(cid:119)(cid:105)(cid:116)(cid:104)(cid:32)(cid:97)(cid:32)(cid:108)(cid:105)(cid:102)(cid:101)(cid:116)(cid:105)(cid:109)(cid:101)(cid:32)(cid:112)(cid:114)(cid:101)(cid:118)(cid:97)(cid:108)(cid:101)(cid:110)(cid:99)(cid:101)
`between 0.8% and 1.6% (1–3). Over the past several
`decades, substantial progress has been made in the
`pharmacologic treatment of the manic phase of bipo-
`
`Received May 12, 1998; revision received Sept. 30, 1998;
`accepted Nov. 20, 1998. From the Lilly Research Laboratories, Eli
`Lilly and Co.; the Department of Psychiatry, Harvard Medical
`School, McLean Hospital, Belmont, Mass.; the Department of Psy-
`chiatry, University of Cincinnati College of Medicine; the Stanley
`Center for Treatment of Bipolar Disorders, Western Psychiatric
`Institute and Clinic, University of Pittsburgh Medical Center; the
`Washington Clinical Research Center, Neuro-Psychiatric Services,
`Falls Church, Va.; the VA Medical Center, Dallas; and Milwaukee
`Psychiatric Hospital. Address reprint requests to Dr. Tohen, Lilly
`Research Laboratories, Lilly Corporate Center, Drop Code 0538,
`Indianapolis, IN 46285.
`Supported by Eli Lilly and Co.
`The authors thank all nursing personnel involved in this clinical
`study for their patience and dedication.
`
`lar disorder. Numerous authorities and treatment
`guidelines presently recognize that three individual
`agents—lithium, valproate, and carbamazepine (typi-
`cally referred to as mood stabilizers)—and one class
`of agents—the conventional antipsychotics—have
`proven efficacy in the short-term treatment of acute
`mania (4–10).
`However, it is also well recognized that a substantial
`proportion of patients with mania fail to respond ade-
`quately to these agents, whether they are used alone or
`in various combinations, or are unable to tolerate them
`(9, 10). Moreover, all of these agents are characterized
`by safety concerns that necessitate regular monitoring
`(e.g., renal and thyroid toxicity with lithium and tar-
`dive dyskinesia and neuroleptic malignant syndrome
`with typical antipsychotics). Novel medical treatments
`for the manic phase of bipolar disorder are therefore
`needed.
`
`702
`
`Am J Psychiatry 156:5, May 1999
`
`1
`
`Exhibit 2139
`Slayback v. Sumitomo
`IPR2020-01053
`
`

`

`(cid:84)(cid:104)(cid:101)(cid:32)(cid:115)(cid:117)(cid:99)(cid:99)(cid:101)(cid:115)(cid:115)(cid:32)(cid:111)(cid:102)(cid:32)(cid:116)(cid:104)(cid:101)(cid:32)(cid:110)(cid:111)(cid:118)(cid:101)(cid:108)(cid:32)(cid:97)(cid:110)(cid:116)(cid:105)(cid:112)(cid:115)(cid:121)(cid:99)(cid:104)(cid:111)(cid:116)(cid:105)(cid:99)(cid:32)(cid:97)(cid:103)(cid:101)(cid:110)(cid:116)(cid:32)(cid:99)(cid:108)(cid:111)(cid:122)(cid:97)(cid:45)
`(cid:112)(cid:105)(cid:110)(cid:101)(cid:32)(cid:102)(cid:111)(cid:114)(cid:32)(cid:116)(cid:114)(cid:101)(cid:97)(cid:116)(cid:109)(cid:101)(cid:110)(cid:116)(cid:45)(cid:114)(cid:101)(cid:115)(cid:105)(cid:115)(cid:116)(cid:97)(cid:110)(cid:116)(cid:32)(cid:115)(cid:99)(cid:104)(cid:105)(cid:122)(cid:111)(cid:112)(cid:104)(cid:114)(cid:101)(cid:110)(cid:105)(cid:97)(cid:32)(cid:104)(cid:97)(cid:115)(cid:32)(cid:114)(cid:101)(cid:115)(cid:117)(cid:108)(cid:116)(cid:101)(cid:100)
`(cid:105)(cid:110)(cid:32)(cid:105)(cid:116)(cid:115)(cid:32)(cid:117)(cid:115)(cid:101)(cid:32)(cid:102)(cid:111)(cid:114)(cid:32)(cid:98)(cid:105)(cid:112)(cid:111)(cid:108)(cid:97)(cid:114)(cid:32)(cid:112)(cid:97)(cid:116)(cid:105)(cid:101)(cid:110)(cid:116)(cid:115)(cid:32)(cid:117)(cid:110)(cid:114)(cid:101)(cid:115)(cid:112)(cid:111)(cid:110)(cid:115)(cid:105)(cid:118)(cid:101)(cid:32)(cid:116)(cid:111)(cid:32)(cid:116)(cid:104)(cid:101)(cid:32)(cid:117)(cid:115)(cid:117)(cid:97)(cid:108)
`treatment strategies (11–15). However, caution must
`be applied in interpreting these data, since the numbers
`of patients evaluated in controlled trials were small.
`Nonetheless, clozapine appears to benefit patients with
`rapid-cycling illness and those who do not respond to
`standard treatment. On the other hand, the use of clo-
`zapine in bipolar illness is limited by the relatively high
`incidence of agranulocytosis (annual rate=0.8%),
`which is tenfold higher than the rate for traditional
`antipsychotic agents (16). Furthermore, clozapine has
`other troublesome side effects (e.g., excessive saliva-
`tion and sedation) that are likely to limit its use in bi-
`polar patients. Another recently released antipsychotic
`agent, risperidone, has also been studied in open-label
`designs, with some studies suggesting a favorable re-
`sponse when it is combined with mood-stabilizing
`agents (17, 18). Accordingly, there continues to be a
`medical need for controlled studies to identify novel
`pharmacologic agents for use in bipolar disorder.
`Olanzapine, a recently introduced novel antipsy-
`chotic, demonstrates a pharmacologic profile that
`most closely resembles that of clozapine (19). In a se-
`ries of double-blind controlled trials in patients with
`schizophrenia and schizoaffective disorder, olanzapine
`appeared superior to the conventional antipsychotic
`haloperidol on measures of overall psychotic symp-
`toms, negative symptoms, comorbid mood symptoms,
`and quality of life (20–25). Recent reports of open-la-
`bel studies suggest that olanzapine may be efficacious
`in patients with bipolar disorder (26–28), including
`those with manic or mixed symptoms inadequately re-
`sponsive to lithium, anticonvulsants, and typical anti-
`psychotics. Thus, on the basis of these reports and the
`findings of mood stabilization with olanzapine among
`both depressed schizophrenic patients (20) and schizo-
`affective bipolar patients (29), we decided to study
`olanzapine’s efficacy in the treatment of acute manic
`and mixed episodes in bipolar I disorder with and
`without psychotic features. We report on a double-
`blind study that included 139 patients and was con-
`ducted in the United States at 16 study sites between
`October 1996 and August 1997.
`
`METHOD
`
`(cid:80)(cid:97)(cid:116)(cid:105)(cid:101)(cid:110)(cid:116)(cid:115)(cid:32)(cid:98)(cid:101)(cid:116)(cid:119)(cid:101)(cid:101)(cid:110)(cid:32)(cid:116)(cid:104)(cid:101)(cid:32)(cid:97)(cid:103)(cid:101)(cid:115)(cid:32)(cid:111)(cid:102)(cid:32)(cid:49)(cid:56)(cid:32)(cid:97)(cid:110)(cid:100)(cid:32)(cid:54)(cid:53)(cid:32)(cid:121)(cid:101)(cid:97)(cid:114)(cid:115)(cid:32)(cid:119)(cid:101)(cid:114)(cid:101)(cid:32)(cid:101)(cid:110)(cid:114)(cid:111)(cid:108)(cid:108)(cid:101)(cid:100)(cid:32)(cid:105)(cid:110)(cid:32)(cid:116)(cid:104)(cid:101)
`(cid:115)(cid:116)(cid:117)(cid:100)(cid:121)(cid:46)(cid:32)(cid:65)(cid:108)(cid:108)(cid:32)(cid:115)(cid:116)(cid:117)(cid:100)(cid:121)(cid:32)(cid:115)(cid:117)(cid:98)(cid:106)(cid:101)(cid:99)(cid:116)(cid:115)(cid:32)(cid:109)(cid:101)(cid:116)(cid:32)(cid:116)(cid:104)(cid:101)(cid:32)(cid:68)(cid:83)(cid:77)(cid:45)(cid:73)(cid:86)(cid:32)(cid:99)(cid:114)(cid:105)(cid:116)(cid:101)(cid:114)(cid:105)(cid:97)(cid:32)(cid:102)(cid:111)(cid:114)(cid:32)(cid:98)(cid:105)(cid:112)(cid:111)(cid:108)(cid:97)(cid:114)(cid:32)(cid:100)(cid:105)(cid:115)(cid:111)(cid:114)(cid:45)
`(cid:100)(cid:101)(cid:114)(cid:44)(cid:32)(cid:101)(cid:105)(cid:116)(cid:104)(cid:101)(cid:114)(cid:32)(cid:109)(cid:97)(cid:110)(cid:105)(cid:99)(cid:32)(cid:111)(cid:114)(cid:32)(cid:109)(cid:105)(cid:120)(cid:101)(cid:100)(cid:32)(cid:101)(cid:112)(cid:105)(cid:115)(cid:111)(cid:100)(cid:101)(cid:32)(cid:40)(cid:119)(cid:105)(cid:116)(cid:104)(cid:32)(cid:111)(cid:114)(cid:32)(cid:119)(cid:105)(cid:116)(cid:104)(cid:111)(cid:117)(cid:116)(cid:32)(cid:112)(cid:115)(cid:121)(cid:99)(cid:104)(cid:111)(cid:116)(cid:105)(cid:99)(cid:32)(cid:102)(cid:101)(cid:97)(cid:45)
`(cid:116)(cid:117)(cid:114)(cid:101)(cid:115)(cid:41)(cid:44)(cid:32)(cid:111)(cid:110)(cid:32)(cid:116)(cid:104)(cid:101)(cid:32)(cid:98)(cid:97)(cid:115)(cid:105)(cid:115)(cid:32)(cid:111)(cid:102)(cid:32)(cid:116)(cid:104)(cid:101)(cid:32)(cid:83)(cid:116)(cid:114)(cid:117)(cid:99)(cid:116)(cid:117)(cid:114)(cid:101)(cid:100)(cid:32)(cid:67)(cid:108)(cid:105)(cid:110)(cid:105)(cid:99)(cid:97)(cid:108)(cid:32)(cid:73)(cid:110)(cid:116)(cid:101)(cid:114)(cid:118)(cid:105)(cid:101)(cid:119)(cid:32)(cid:102)(cid:111)(cid:114)(cid:32)(cid:68)(cid:83)(cid:77)(cid:45)(cid:73)(cid:73)(cid:73)(cid:45)
`R (SCID) (30). Manic or mixed episodes were of at least 2 weeks’
`duration. A minimum total score of 20 on the Young Mania Rating
`Scale (31) was required. Patients were excluded if any of the follow-
`ing criteria were met: serious, unstable illness such that hospitaliza-
`tion was anticipated within 3 months or death was anticipated
`within 3 years; DSM-IV-defined substance dependence (except nico-
`tine or caffeine) within the past 3 months; and serious risk of suicide.
`The study was fully explained to each patient, and written informed
`consent was obtained before their participation in the study.
`
`TOHEN, SANGER, MCELROY, ET AL.
`
`Olanzapine
`Group
`(N=70)
`%
`61.4
`
`N
`43
`
`p
`(Fisher’s
`exact
`test)
`0.002
`
`TABLE 1. Disposition of Patients With Bipolar Disorder Treated
`With Olanzapine or Placebo
`Placebo
`Group
`(N=69)
`%
`34.8
`
`N
`24
`
`Variable
`Completed treatment
`Reason treatment
`was discontinued
`Adverse event
`Lack of efficacy
`Other
`
`2
`33
`10
`
`2.9
`47.8
`14.5
`
`0
`20
`7
`
`0.0
`28.6
`10.0
`
`0.25
`0.02
`0.45
`
`This was a randomized, double-blind, placebo-controlled parallel
`group study. Severity of illness and psychopathology was measured
`by the following rating scales: the Young Mania Rating Scale (31),
`the 21-item Hamilton Depression Rating Scale (32), the Positive and
`Negative Syndrome Scale (33), and the Clinical Global Impression
`(CGI), Bipolar Version (34). Quality of life was assessed with the
`Medical Outcomes Study 36-item Short-Form Health Survey (SF-36)
`(35, 36). Change from baseline to endpoint in total score on the
`Young Mania Rating Scale was the primary efficacy measure. Inter-
`rater reliability assessments with the Young Mania Rating Scale were
`conducted before the study began by measuring the correlation of
`each rater’s scoring with the groupwise median score for each item.
`The correlation coefficients ranged between 0.76 and 0.99, with a
`median of 0.94. Extrapyramidal symptoms were assessed with the
`Simpson-Angus Rating Scale (37), the Barnes Akathisia Scale (38),
`and the Abnormal Involuntary Movement Scale (39).
`After a 2- to 4-day washout period of all medications except ben-
`zodiazepines, qualified patients were randomly assigned to one of
`two treatment groups, olanzapine or placebo, in a 1:1 ratio. Seventy
`patients were assigned to olanzapine and 69 to placebo. To ensure pa-
`tient safety, a minimum of 1 week of hospitalization was required.
`After 1 week, patients with a CGI, Bipolar Version, severity of mania
`score of 3 or lower and a reduction of 50% or more in Young Mania
`Rating Scale total score could be discharged, if clinically appropriate.
`Double-blind acute therapy lasted for 3 weeks. Patients began
`double-blind therapy with either olanzapine, 10 mg (two 5-mg tab-
`lets), or placebo (two placebo tablets), given once per day, preferably
`in the evening. After the first day of treatment, the daily dose could
`be adjusted upward or downward, as clinically indicated, by 5-mg
`increments/decrements within the allowed dosage range of 5–20 mg/
`day. Decreases in dosage because of adverse events could occur at
`any time by any number of one-tablet (5-mg) decrements (at the in-
`vestigator’s discretion), to a minimum of one tablet per day.
`Use of concomitant medications was limited to lorazepam, up to 4
`mg/day, if necessary, to alleviate severe agitation during the first 7
`days of therapy; then, during the next 3 days, 2 mg/day could be used.
`Also, benztropine, up to a maximum dose of 2 mg/day, could be used
`for treatment-emergent extrapyramidal symptoms. The prophylactic
`use of benztropine for extrapyramidal symptoms was not allowed.
`A total of 139 patients were enrolled in the study; 70 were ran-
`domly assigned to olanzapine and 69 to placebo. The treatment
`groups did not significantly differ with respect to baseline patient
`characteristics or severity of illness ratings. Patients were generally in
`their late 30s (mean age=39.5 years, SD=11.0), the majority (72.7%)
`were Caucasian, and half (51.8%) were male. The majority of the pa-
`tients (82.7%) were experiencing a manic episode, while the rest
`(17.3%) were experiencing a mixed episode. Overall, 53.2% dis-
`played psychotic features. Of those with psychotic symptoms, 85.1%
`displayed mood-congruent psychotic features. A DSM-IV-defined
`rapid-cycling course was present in 32.4% of the patients. Compari-
`sons of the treatment groups at baseline on efficacy variables demon-
`strated no evidence of any statistically significant differences.
`All statistical analyses were done on an intent-to-treat basis; that
`is, data on all randomly assigned patients were included in the anal-
`ysis. Patients’ data were included in the analysis of change if they
`had both a baseline and a postbaseline observation. For the analysis
`of baseline efficacy and extrapyramidal symptom scores, only the
`patients with a baseline and a postbaseline observation were included,
`
`Am J Psychiatry 156:5, May 1999
`
`703
`
`2
`
`

`

`OLANZAPINE IN TREATMENT OF ACUTE MANIA
`
`TABLE 2. Endpoint Change in Severity of Illness Scores (Last Observation Carried Forward) of Patients With Bipolar Disorder
`Treated With Olanzapine or Placebo
`
`Measure
`Young Mania Rating Scale
`total score
`Hamilton 21-item depression
`scale total score
`Positive and Negative Syn-
`drome Scale
`Total symptom score
`Positive symptom score
`Negative symptom score
`Clinical Global Impression,
`Bipolar Version
`Severity of mania rating
`Severity of depression rating
`Severity of overall bipolar
`0.15
`1, 108
`2.10
`1.39
`–0.89
`0.88
`4.46
`70
`1.30
`–0.59
`0.83
`4.68
`66
`illness rating
`a Changes from baseline means were analyzed with an F test from an ANOVA model with treatment, investigator, and interaction. No sta-
`tistically significant differences were observed between baseline values of the two groups for any measure.
`
`Olanzapine Group (N=70)
`Change From
`Baseline
`Mean
`SD
`
`Baseline
`Mean
`SD
`
`Analysisa
`df
`
`p
`
`F
`
`28.66
`
`6.71
`
`–10.26
`
`13.43
`
`5.64
`
`1, 108
`
`0.02
`
`12.58
`
`7.15
`
`–2.90
`
`6.74
`
`0.03
`
`1, 106
`
`0.87
`
`71.04
`20.90
`13.51
`
`18.74
`6.59
`5.45
`
`–11.06
`–4.67
`–0.90
`
`16.98
`6.57
`4.26
`
`5.64
`4.30
`0.72
`
`1, 106
`1, 106
`1, 106
`
`0.02
`0.04
`0.40
`
`4.51
`1.71
`
`0.86
`0.97
`
`–1.07
`0.06
`
`1.60
`1.17
`
`5.69
`2.17
`
`1, 108
`1, 108
`
`0.02
`0.14
`
`Placebo Group (N=69)
`Change From
`Baseline
`Mean
`SD
`
`Baseline
`Mean
`SD
`
`27.65
`
`6.46
`
`–4.88
`
`11.64
`
`13.98
`
`6.69
`
`–3.00
`
`6.00
`
`70.97
`20.72
`13.94
`
`21.04
`7.01
`5.69
`
`–3.09
`–2.00
`–0.19
`
`18.37
`7.10
`4.23
`
`4.62
`2.11
`
`0.87
`1.29
`
`–0.48
`–0.30
`
`1.37
`1.15
`
`N
`
`70
`
`69
`
`70
`70
`70
`
`70
`70
`
`N
`
`66
`
`65
`
`64
`64
`64
`
`66
`66
`
`FIGURE 1. Change in Total Scores on the Young Mania Rating
`Scale of Patients With Bipolar Disorder Treated With Olanza-
`pine or Placeboa
`
`a There was no significant difference in the treatment advantage of
`olanzapine and placebo for patients with and without psychotic
`features (therapy-by-subgroup: F=0.02, df=1, 106, p=0.88).
`b N=33 for the placebo group; N=38 for the olanzapine group. Mean
`baseline score=29.0 for the placebo group; mean baseline score=
`29.6 for the olanzapine group. Within strata, F=2.32, df=1, 56, p=
`0.13.
`c N=33 for the placebo group; N=32 for the olanzapine group. Mean
`baseline score=26.3 for the placebo group; mean baseline score=
`27.6 for the olanzapine group. Within strata, F=3.73, df=1, 52, p<
`0.06.
`
`(cid:116)(cid:111)(cid:32)(cid:98)(cid:101)(cid:32)(cid:99)(cid:111)(cid:110)(cid:115)(cid:105)(cid:115)(cid:116)(cid:101)(cid:110)(cid:116)(cid:32)(cid:119)(cid:105)(cid:116)(cid:104)(cid:32)(cid:116)(cid:104)(cid:101)(cid:32)(cid:97)(cid:110)(cid:97)(cid:108)(cid:121)(cid:115)(cid:105)(cid:115)(cid:32)(cid:111)(cid:102)(cid:32)(cid:99)(cid:104)(cid:97)(cid:110)(cid:103)(cid:101)(cid:32)(cid:102)(cid:114)(cid:111)(cid:109)(cid:32)(cid:98)(cid:97)(cid:115)(cid:101)(cid:108)(cid:105)(cid:110)(cid:101)(cid:46)(cid:32)(cid:65)(cid:108)(cid:108)(cid:32)(cid:112)(cid:97)(cid:116)(cid:105)(cid:101)(cid:110)(cid:116)(cid:115)
`(cid:114)(cid:97)(cid:110)(cid:100)(cid:111)(cid:109)(cid:108)(cid:121)(cid:32)(cid:97)(cid:115)(cid:115)(cid:105)(cid:103)(cid:110)(cid:101)(cid:100)(cid:32)(cid:116)(cid:111)(cid:32)(cid:100)(cid:111)(cid:117)(cid:98)(cid:108)(cid:101)(cid:45)(cid:98)(cid:108)(cid:105)(cid:110)(cid:100)(cid:32)(cid:116)(cid:104)(cid:101)(cid:114)(cid:97)(cid:112)(cid:121)(cid:32)(cid:119)(cid:101)(cid:114)(cid:101)(cid:32)(cid:105)(cid:110)(cid:99)(cid:108)(cid:117)(cid:100)(cid:101)(cid:100)(cid:32)(cid:105)(cid:110)(cid:32)(cid:116)(cid:104)(cid:101)(cid:32)(cid:97)(cid:110)(cid:97)(cid:108)(cid:45)
`(cid:121)(cid:115)(cid:105)(cid:115)(cid:32)(cid:111)(cid:102)(cid:32)(cid:98)(cid:97)(cid:115)(cid:101)(cid:108)(cid:105)(cid:110)(cid:101)(cid:32)(cid:112)(cid:97)(cid:116)(cid:105)(cid:101)(cid:110)(cid:116)(cid:32)(cid:97)(cid:110)(cid:100)(cid:32)(cid:105)(cid:108)(cid:108)(cid:110)(cid:101)(cid:115)(cid:115)(cid:32)(cid:99)(cid:104)(cid:97)(cid:114)(cid:97)(cid:99)(cid:116)(cid:101)(cid:114)(cid:105)(cid:115)(cid:116)(cid:105)(cid:99)(cid:115)(cid:32)(cid:97)(cid:115)(cid:32)(cid:119)(cid:101)(cid:108)(cid:108)(cid:32)(cid:97)(cid:115)(cid:32)(cid:116)(cid:104)(cid:101)(cid:32)(cid:97)(cid:110)(cid:97)(cid:108)(cid:121)(cid:45)
`(cid:115)(cid:105)(cid:115)(cid:32)(cid:111)(cid:102)(cid:32)(cid:116)(cid:104)(cid:101)(cid:32)(cid:105)(cid:110)(cid:99)(cid:105)(cid:100)(cid:101)(cid:110)(cid:99)(cid:101)(cid:32)(cid:111)(cid:102)(cid:32)(cid:116)(cid:114)(cid:101)(cid:97)(cid:116)(cid:109)(cid:101)(cid:110)(cid:116)(cid:45)(cid:101)(cid:109)(cid:101)(cid:114)(cid:103)(cid:101)(cid:110)(cid:116)(cid:32)(cid:97)(cid:100)(cid:118)(cid:101)(cid:114)(cid:115)(cid:101)(cid:32)(cid:101)(cid:118)(cid:101)(cid:110)(cid:116)(cid:115)(cid:46)(cid:32)(cid:84)(cid:111)(cid:116)(cid:97)(cid:108)(cid:32)(cid:115)(cid:99)(cid:111)(cid:114)(cid:101)(cid:115)
`(cid:102)(cid:114)(cid:111)(cid:109)(cid:32)(cid:114)(cid:97)(cid:116)(cid:105)(cid:110)(cid:103)(cid:32)(cid:115)(cid:99)(cid:97)(cid:108)(cid:101)(cid:115)(cid:32)(cid:119)(cid:101)(cid:114)(cid:101)(cid:32)(cid:100)(cid:101)(cid:114)(cid:105)(cid:118)(cid:101)(cid:100)(cid:32)(cid:102)(cid:114)(cid:111)(cid:109)(cid:32)(cid:116)(cid:104)(cid:101)(cid:32)(cid:105)(cid:110)(cid:100)(cid:105)(cid:118)(cid:105)(cid:100)(cid:117)(cid:97)(cid:108)(cid:32)(cid:105)(cid:116)(cid:101)(cid:109)(cid:115)(cid:59)(cid:32)(cid:105)(cid:102)(cid:32)(cid:97)(cid:110)(cid:121)(cid:32)(cid:115)(cid:105)(cid:110)(cid:103)(cid:108)(cid:101)
`(cid:105)(cid:116)(cid:101)(cid:109)(cid:32)(cid:119)(cid:97)(cid:115)(cid:32)(cid:109)(cid:105)(cid:115)(cid:115)(cid:105)(cid:110)(cid:103)(cid:44)(cid:32)(cid:116)(cid:104)(cid:101)(cid:32)(cid:116)(cid:111)(cid:116)(cid:97)(cid:108)(cid:32)(cid:115)(cid:99)(cid:111)(cid:114)(cid:101)(cid:32)(cid:119)(cid:97)(cid:115)(cid:32)(cid:116)(cid:114)(cid:101)(cid:97)(cid:116)(cid:101)(cid:100)(cid:32)(cid:97)(cid:115)(cid:32)(cid:109)(cid:105)(cid:115)(cid:115)(cid:105)(cid:110)(cid:103)(cid:46)
`(cid:65)(cid:110)(cid:97)(cid:108)(cid:121)(cid:115)(cid:105)(cid:115)(cid:32)(cid:111)(cid:102)(cid:32)(cid:118)(cid:97)(cid:114)(cid:105)(cid:97)(cid:110)(cid:99)(cid:101)(cid:32)(cid:40)(cid:65)(cid:78)(cid:79)(cid:86)(cid:65)(cid:41)(cid:32)(cid:119)(cid:97)(cid:115)(cid:32)(cid:117)(cid:115)(cid:101)(cid:100)(cid:32)(cid:116)(cid:111)(cid:32)(cid:101)(cid:118)(cid:97)(cid:108)(cid:117)(cid:97)(cid:116)(cid:101)(cid:32)(cid:116)(cid:104)(cid:101)(cid:32)(cid:99)(cid:111)(cid:110)(cid:116)(cid:105)(cid:110)(cid:117)(cid:45)
`(cid:111)(cid:117)(cid:115)(cid:32)(cid:101)(cid:102)(cid:102)(cid:105)(cid:99)(cid:97)(cid:99)(cid:121)(cid:32)(cid:97)(cid:110)(cid:100)(cid:32)(cid:115)(cid:97)(cid:102)(cid:101)(cid:116)(cid:121)(cid:32)(cid:118)(cid:97)(cid:114)(cid:105)(cid:97)(cid:98)(cid:108)(cid:101)(cid:115)(cid:59)(cid:32)(cid:116)(cid:104)(cid:101)(cid:32)(cid:109)(cid:111)(cid:100)(cid:101)(cid:108)(cid:115)(cid:32)(cid:105)(cid:110)(cid:99)(cid:108)(cid:117)(cid:100)(cid:101)(cid:100)(cid:32)(cid:116)(cid:104)(cid:101)(cid:32)(cid:116)(cid:101)(cid:114)(cid:109)(cid:115)(cid:32)(cid:102)(cid:111)(cid:114)
`(cid:116)(cid:114)(cid:101)(cid:97)(cid:116)(cid:109)(cid:101)(cid:110)(cid:116)(cid:44)(cid:32)(cid:105)(cid:110)(cid:118)(cid:101)(cid:115)(cid:116)(cid:105)(cid:103)(cid:97)(cid:116)(cid:111)(cid:114)(cid:44)(cid:32)(cid:97)(cid:110)(cid:100)(cid:32)(cid:116)(cid:114)(cid:101)(cid:97)(cid:116)(cid:109)(cid:101)(cid:110)(cid:116)(cid:45)(cid:98)(cid:121)(cid:45)(cid:105)(cid:110)(cid:118)(cid:101)(cid:115)(cid:116)(cid:105)(cid:103)(cid:97)(cid:116)(cid:111)(cid:114)(cid:32)(cid:105)(cid:110)(cid:116)(cid:101)(cid:114)(cid:97)(cid:99)(cid:116)(cid:105)(cid:111)(cid:110)(cid:46)
`(cid:68)(cid:97)(cid:116)(cid:97)(cid:32)(cid:119)(cid:101)(cid:114)(cid:101)(cid:32)(cid:112)(cid:111)(cid:111)(cid:108)(cid:101)(cid:100)(cid:32)(cid:102)(cid:114)(cid:111)(cid:109)(cid:32)(cid:105)(cid:110)(cid:118)(cid:101)(cid:115)(cid:116)(cid:105)(cid:103)(cid:97)(cid:116)(cid:111)(cid:114)(cid:115)(cid:32)(cid:119)(cid:104)(cid:111)(cid:32)(cid:100)(cid:105)(cid:100)(cid:32)(cid:110)(cid:111)(cid:116)(cid:32)(cid:104)(cid:97)(cid:118)(cid:101)(cid:32)(cid:97)(cid:116)(cid:32)(cid:108)(cid:101)(cid:97)(cid:115)(cid:116)(cid:32)(cid:116)(cid:119)(cid:111)
`patients per treatment. Fisher’s exact test, two-tailed, was used to an-
`alyze treatment effects for categorical efficacy and safety variables.
`For selected efficacy variables, weekly changes from baseline were
`
`analyzed. The protocol established the primary efficacy analysis as
`the mean change from baseline to endpoint (last observation carried
`forward) in Young Mania Rating Scale total score.
`All cited p values were two-tailed, with a significance level of 0.05
`as specified in the protocol. SAS (40) was used for all analyses.
`
`RESULTS
`
`(cid:84)(cid:104)(cid:101)(cid:32)(cid:100)(cid:105)(cid:115)(cid:112)(cid:111)(cid:115)(cid:105)(cid:116)(cid:105)(cid:111)(cid:110)(cid:32)(cid:111)(cid:102)(cid:32)(cid:116)(cid:104)(cid:101)(cid:32)(cid:115)(cid:116)(cid:117)(cid:100)(cid:121)(cid:32)(cid:103)(cid:114)(cid:111)(cid:117)(cid:112)(cid:32)(cid:100)(cid:117)(cid:114)(cid:105)(cid:110)(cid:103)(cid:32)(cid:116)(cid:104)(cid:101)(cid:32)(cid:97)(cid:99)(cid:117)(cid:116)(cid:101)
`(cid:112)(cid:104)(cid:97)(cid:115)(cid:101)(cid:32)(cid:111)(cid:102)(cid:32)(cid:116)(cid:104)(cid:101)(cid:32)(cid:116)(cid:114)(cid:105)(cid:97)(cid:108)(cid:32)(cid:105)(cid:115)(cid:32)(cid:115)(cid:104)(cid:111)(cid:119)(cid:110)(cid:32)(cid:105)(cid:110)(cid:32)(cid:116)(cid:97)(cid:98)(cid:108)(cid:101)(cid:32)(cid:49)(cid:46)(cid:32)(cid:65)(cid:108)(cid:109)(cid:111)(cid:115)(cid:116)(cid:32)(cid:116)(cid:119)(cid:105)(cid:99)(cid:101)(cid:32)(cid:97)(cid:115)
`(cid:109)(cid:97)(cid:110)(cid:121)(cid:32)(cid:111)(cid:108)(cid:97)(cid:110)(cid:122)(cid:97)(cid:112)(cid:105)(cid:110)(cid:101)(cid:45)(cid:116)(cid:114)(cid:101)(cid:97)(cid:116)(cid:101)(cid:100)(cid:32)(cid:112)(cid:97)(cid:116)(cid:105)(cid:101)(cid:110)(cid:116)(cid:115)(cid:32)(cid:97)(cid:115)(cid:32)(cid:112)(cid:108)(cid:97)(cid:99)(cid:101)(cid:98)(cid:111)(cid:45)(cid:116)(cid:114)(cid:101)(cid:97)(cid:116)(cid:101)(cid:100)
`(cid:112)(cid:97)(cid:116)(cid:105)(cid:101)(cid:110)(cid:116)(cid:115)(cid:32)(cid:99)(cid:111)(cid:109)(cid:112)(cid:108)(cid:101)(cid:116)(cid:101)(cid:100)(cid:32)(cid:116)(cid:104)(cid:101)(cid:32)(cid:97)(cid:99)(cid:117)(cid:116)(cid:101)(cid:32)(cid:112)(cid:104)(cid:97)(cid:115)(cid:101)(cid:32)(cid:111)(cid:102)(cid:32)(cid:116)(cid:104)(cid:101)(cid:32)(cid:115)(cid:116)(cid:117)(cid:100)(cid:121)(cid:46)(cid:32)(cid:78)(cid:101)(cid:97)(cid:114)(cid:108)(cid:121)
`(cid:111)(cid:110)(cid:101)(cid:32)(cid:105)(cid:110)(cid:32)(cid:116)(cid:119)(cid:111)(cid:32)(cid:112)(cid:97)(cid:116)(cid:105)(cid:101)(cid:110)(cid:116)(cid:115)(cid:32)(cid:114)(cid:101)(cid:99)(cid:101)(cid:105)(cid:118)(cid:105)(cid:110)(cid:103)(cid:32)(cid:112)(cid:108)(cid:97)(cid:99)(cid:101)(cid:98)(cid:111)(cid:32)(cid:104)(cid:97)(cid:100)(cid:32)(cid:116)(cid:111)(cid:32)(cid:100)(cid:105)(cid:115)(cid:99)(cid:111)(cid:110)(cid:45)
`(cid:116)(cid:105)(cid:110)(cid:117)(cid:101)(cid:32)(cid:98)(cid:101)(cid:99)(cid:97)(cid:117)(cid:115)(cid:101)(cid:32)(cid:111)(cid:102)(cid:32)(cid:108)(cid:97)(cid:99)(cid:107)(cid:32)(cid:111)(cid:102)(cid:32)(cid:101)(cid:102)(cid:102)(cid:105)(cid:99)(cid:97)(cid:99)(cid:121)(cid:44)(cid:32)(cid:99)(cid:111)(cid:109)(cid:112)(cid:97)(cid:114)(cid:101)(cid:100)(cid:32)(cid:116)(cid:111)(cid:32)(cid:111)(cid:110)(cid:101)(cid:32)(cid:105)(cid:110)
`(cid:102)(cid:111)(cid:117)(cid:114)(cid:32)(cid:111)(cid:108)(cid:97)(cid:110)(cid:122)(cid:97)(cid:112)(cid:105)(cid:110)(cid:101)(cid:45)(cid:116)(cid:114)(cid:101)(cid:97)(cid:116)(cid:101)(cid:100)(cid:32)(cid:112)(cid:97)(cid:116)(cid:105)(cid:101)(cid:110)(cid:116)(cid:115)(cid:46)
`(cid:84)(cid:104)(cid:101)(cid:32)(cid:109)(cid:101)(cid:97)(cid:110)(cid:32)(cid:109)(cid:111)(cid:100)(cid:97)(cid:108)(cid:32)(cid:97)(cid:110)(cid:100)(cid:32)(cid:109)(cid:101)(cid:100)(cid:105)(cid:97)(cid:110)(cid:32)(cid:109)(cid:111)(cid:100)(cid:97)(cid:108)(cid:32)(cid:100)(cid:111)(cid:115)(cid:101)(cid:115)(cid:32)(cid:111)(cid:102)(cid:32)(cid:111)(cid:108)(cid:97)(cid:110)(cid:122)(cid:97)(cid:45)
`(cid:112)(cid:105)(cid:110)(cid:101)(cid:32)(cid:119)(cid:101)(cid:114)(cid:101)(cid:32)(cid:49)(cid:52)(cid:46)(cid:57)(cid:32)(cid:109)(cid:103)(cid:47)(cid:100)(cid:97)(cid:121)(cid:32)(cid:40)(cid:83)(cid:68)(cid:61)(cid:53)(cid:46)(cid:48)(cid:41)(cid:32)(cid:97)(cid:110)(cid:100)(cid:32)(cid:49)(cid:53)(cid:32)(cid:109)(cid:103)(cid:47)(cid:100)(cid:97)(cid:121)(cid:44)(cid:32)(cid:114)(cid:101)(cid:45)
`(cid:115)(cid:112)(cid:101)(cid:99)(cid:116)(cid:105)(cid:118)(cid:101)(cid:108)(cid:121)(cid:46)(cid:32)(cid:84)(cid:104)(cid:101)(cid:32)(cid:109)(cid:111)(cid:100)(cid:97)(cid:108)(cid:32)(cid:100)(cid:111)(cid:115)(cid:101)(cid:32)(cid:119)(cid:97)(cid:115)(cid:32)(cid:100)(cid:101)(cid:102)(cid:105)(cid:110)(cid:101)(cid:100)(cid:32)(cid:97)(cid:115)(cid:32)(cid:116)(cid:104)(cid:101)(cid:32)(cid:100)(cid:97)(cid:105)(cid:108)(cid:121)
`(cid:100)(cid:111)(cid:115)(cid:101)(cid:32)(cid:109)(cid:111)(cid:115)(cid:116)(cid:32)(cid:111)(cid:102)(cid:116)(cid:101)(cid:110)(cid:32)(cid:116)(cid:97)(cid:107)(cid:101)(cid:110)(cid:46)
`(cid:84)(cid:104)(cid:101)(cid:114)(cid:101)(cid:32)(cid:119)(cid:101)(cid:114)(cid:101)(cid:32)(cid:110)(cid:111)(cid:32)(cid:115)(cid:116)(cid:97)(cid:116)(cid:105)(cid:115)(cid:116)(cid:105)(cid:99)(cid:97)(cid:108)(cid:108)(cid:121)(cid:32)(cid:115)(cid:105)(cid:103)(cid:110)(cid:105)(cid:102)(cid:105)(cid:99)(cid:97)(cid:110)(cid:116)(cid:32)(cid:100)(cid:105)(cid:102)(cid:102)(cid:101)(cid:114)(cid:101)(cid:110)(cid:99)(cid:101)(cid:115)(cid:32)(cid:98)(cid:101)(cid:45)
`(cid:116)(cid:119)(cid:101)(cid:101)(cid:110)(cid:32)(cid:116)(cid:104)(cid:101)(cid:32)(cid:116)(cid:119)(cid:111)(cid:32)(cid:116)(cid:114)(cid:101)(cid:97)(cid:116)(cid:109)(cid:101)(cid:110)(cid:116)(cid:32)(cid:103)(cid:114)(cid:111)(cid:117)(cid:112)(cid:115)(cid:32)(cid:105)(cid:110)(cid:32)(cid:116)(cid:104)(cid:101)(cid:32)(cid:110)(cid:117)(cid:109)(cid:98)(cid:101)(cid:114)(cid:32)(cid:111)(cid:102)(cid:32)(cid:112)(cid:97)(cid:45)
`(cid:116)(cid:105)(cid:101)(cid:110)(cid:116)(cid:115)(cid:32)(cid:119)(cid:104)(cid:111)(cid:32)(cid:117)(cid:115)(cid:101)(cid:100)(cid:32)(cid:97)(cid:110)(cid:116)(cid:105)(cid:99)(cid:104)(cid:111)(cid:108)(cid:105)(cid:110)(cid:101)(cid:114)(cid:103)(cid:105)(cid:99)(cid:32)(cid:109)(cid:101)(cid:100)(cid:105)(cid:99)(cid:97)(cid:116)(cid:105)(cid:111)(cid:110)(cid:44)(cid:32)(cid:98)(cid:101)(cid:110)(cid:122)(cid:111)(cid:100)(cid:105)(cid:97)(cid:122)(cid:45)
`(cid:101)(cid:112)(cid:105)(cid:110)(cid:101)(cid:115)(cid:44)(cid:32)(cid:111)(cid:114)(cid:32)(cid:97)(cid:110)(cid:121)(cid:32)(cid:111)(cid:116)(cid:104)(cid:101)(cid:114)(cid:32)(cid:99)(cid:111)(cid:110)(cid:99)(cid:111)(cid:109)(cid:105)(cid:116)(cid:97)(cid:110)(cid:116)(cid:32)(cid:109)(cid:101)(cid:100)(cid:105)(cid:99)(cid:97)(cid:116)(cid:105)(cid:111)(cid:110)(cid:115)(cid:32)(cid:100)(cid:117)(cid:114)(cid:105)(cid:110)(cid:103)
`(cid:116)(cid:104)(cid:101)(cid:32)(cid:115)(cid:116)(cid:117)(cid:100)(cid:121)(cid:46)(cid:32)(cid:79)(cid:102)(cid:32)(cid:97)(cid:108)(cid:108)(cid:32)(cid:112)(cid:97)(cid:116)(cid:105)(cid:101)(cid:110)(cid:116)(cid:115)(cid:44)(cid:32)(cid:56)(cid:54)(cid:46)(cid:51)(cid:37)(cid:32)(cid:40)(cid:78)(cid:61)(cid:49)(cid:50)(cid:48)(cid:41)(cid:32)(cid:116)(cid:111)(cid:111)(cid:107)(cid:32)(cid:97)(cid:116)(cid:32)(cid:108)(cid:101)(cid:97)(cid:115)(cid:116)
`(cid:111)(cid:110)(cid:101)(cid:32)(cid:100)(cid:111)(cid:115)(cid:101)(cid:32)(cid:111)(cid:102)(cid:32)(cid:97)(cid:32)(cid:98)(cid:101)(cid:110)(cid:122)(cid:111)(cid:100)(cid:105)(cid:97)(cid:122)(cid:101)(cid:112)(cid:105)(cid:110)(cid:101)(cid:44)(cid:32)(cid:97)(cid:110)(cid:100)(cid:32)(cid:57)(cid:46)(cid:52)(cid:37)(cid:32)(cid:40)(cid:78)(cid:61)(cid:49)(cid:51)(cid:41)(cid:32)(cid:116)(cid:111)(cid:111)(cid:107)
`(cid:97)(cid:116)(cid:32)(cid:108)(cid:101)(cid:97)(cid:115)(cid:116)(cid:32)(cid:111)(cid:110)(cid:101)(cid:32)(cid:100)(cid:111)(cid:115)(cid:101)(cid:32)(cid:111)(cid:102)(cid:32)(cid:97)(cid:110)(cid:32)(cid:97)(cid:110)(cid:116)(cid:105)(cid:99)(cid:104)(cid:111)(cid:108)(cid:105)(cid:110)(cid:101)(cid:114)(cid:103)(cid:105)(cid:99)(cid:32)(cid:109)(cid:101)(cid:100)(cid:105)(cid:99)(cid:97)(cid:116)(cid:105)(cid:111)(cid:110)(cid:46)(cid:32)(cid:79)(cid:102)
`(cid:116)(cid:104)(cid:101)(cid:32)(cid:112)(cid:97)(cid:116)(cid:105)(cid:101)(cid:110)(cid:116)(cid:115)(cid:32)(cid:114)(cid:101)(cid:99)(cid:101)(cid:105)(cid:118)(cid:105)(cid:110)(cid:103)(cid:32)(cid:98)(cid:101)(cid:110)(cid:122)(cid:11