Aripiprazote
`BM‘§—3=37039./0PC—l4597
`
`Name of Sportsor./Coinpariy:
`.
`..
`Bristol-Myers Squrnl)
`
`Naine ofl7inished Product:
`
`Name of Aet.i've Ingredient:
`
`Individual Study Table Referring
`to the Dossier
`
`~ Acute Phase
`CNE
`Clinical Study Report
`
`or ,NaZiorzcii /l;',ziitoriz‘_§2 Use
`On] V ‘
`‘U
`
`.......................................................4
`
`SYNQPSES
`
`Clinical Study Report CNl38{l{i8
`
`'ll‘l'Il'LE OF STUDY: A ivlultieenter, Randoniizecl, Double-Blind Study of Aripipra::ole and llaloperidot
`in the i\Ilaintained Response to Treatment for an Acute l\/lanie Episode (Protocol
`l3800t3i)
`
`lNVES'l‘iGA"l"ORS AND S'l‘l.3'DY CENTERS: SeVenty—six investigators paiticipated in the conduct of
`this study (1 in Australia, 2 in Austria, 3 in Belgium, 2 in Brazil, 4 in Croatia, 2 in the Czech Republic, 3 in
`Estonia, 10 in France, 5 in Germany, 8 in ltaly, 2. in Latvia, 2 in Litliuania, 4 in Mexico, 8 in Poland, l in
`Poitngal,
`in Russia, 2 in South Africa, 3 in Spairi, and
`in the United Kingclorni.
`
`PUl3LICA"E'I(}NS:
`
`None
`
`STUDY l’ERI(}{3:
`
`Date tirst patient enrolled:
`
`'20-Nov-2€}(‘;tl
`
`Date last patient coniplered: Q8--.l2i.rt--?;[tt)'?.
`
`CLENECAL PHASE: Ill
`
`(}BJE{T'l‘iVES:
`
`Primary: The primary objective of this study was to compare the number of aripiprazote—treated patients
`with the nuinber of haloperidol~treated patients who continued on treatment and maintained response after
`12
`of study medication.
`
`to
`Secondary: The seeondaiy objectives were to compare the response rates at the end of Week 3,
`compare the numbers of patients maintained on treatment and responding at the end of Week l2 (in the
`subgroup of patients who continued in the study after Week 3), to assess the safety of ar‘ipiprazole and
`haloperidol in all patients, and to obtain data required for reirnhut'seinent filings.
`
`METHGBULOGY: This was a rnnhi,(:ent,er9 randoinized, double-blind study comparing" aripipra2'oie
`(15 to 3%) mg per day!) with hal peridol (ll) to l5 mg per day} in patients experiencing an acute rnanit:
`episode. After inforined consent was obtained, patients undeiwent a 1- to 7-day screening period (sereening
`could be extended to l4 days with perniission from l?tristol—Myers Squibb Company [Bl‘vlS"g). Patients met
`Diagnostic and Statistical l\/la,nnal of Mental Disorders, Fourth Edition t'l3SM—lV) criteria for Bipolar l
`Disorder and were experiencing an acute manic or niixed episode. Patients were excluded if they had
`i‘apid—cyelin_:=j; Bipolar I Disorder,
`
`treatment.
`Patients fulfilling en,ti'anee criteria were evenly raindorriizzed to at'ipipra::ole or hal peridol
`Patients could have entered this study While hospit.ali:zed or as outpatients, Patients assigned to aripi,prazoie
`started at a. dose of l5 rng daily. Patients assigned to halopetidoi started at it) rng daily. if patients had a
`Clinical Global lnipression-Bipolar Scale {CG}--Bl’ imaniail improvement Score of} or rnore at the end of
`Weeks 1 or
`aripiprazole could he increased to 30 rng daily and lialoperidol to 15 trig <laily. if the higher
`dose was not tolerated, the study medication could be decreased to the initial dose. if tl,e lo‘ rest dose of
`
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`
`_
`
`.
`
`4
`
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`
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`
`V.
`
`OTSUKA EXHIBIT 2004
`
`Page 1 of 9
`
`IPR2017—OO287
`
`
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`Page 1 of 9
`
`OTSUKA EXHIBIT 2004
`ALKERMES v. OTSUKA
`IPR2017-00287
`
`

`

`Aripiprazole
`Blv,l‘x‘—3=37ll39./0PC—l4597
`
`~ Acute Phase
`CNE
`Clinical Study Report
`
`aripipraz le or haloperitlol was not tolerated, patients were diseontinnetl from the study. Patients with
`CGI--Bl’ (mania) Severity Score is 4 (‘rnoderately ill or Worse) or a Montgcsmery-Asberg l)epression llating
`Scale (MADRS) Score of 2 l8 at the end of Weel< 3 were diseontinued from the study. Patients who
`discontinued at or prior to the end of Weelc 3 due to lack of response or adverse events (Alis) received
`alternative treatment,
`
`At the eonolnsion of the initial ’3--w—:el< period, patients meeting eligihility eriteria tscsntinued in the same
`treatrnent groiip at the same dose level. The (lose of study me<lieation could not be inereased during this
`phase of the study, hut eoulcl he decreased from 30 to 15 mg daily for aripiprazole ancl irom l5 to ll} ing
`daily for haloperidol, ifneeessary for tolei'ability. lf these lowered doses of aripiprazole or haloperidol were
`not tolerated, patients were diseontinued from the study. Patients were evaluated at seheclnlecl treatment
`Visits.
`
`lE)(It‘(‘.EE‘:St)
`patients were disecsntinued froirt the study for any of the following reasons:
`During Weeks 4 to
`in the C/Gl—l3l’ (mania) Severity Score from previous assessment, which was eoiifiimed at two consecutive
`Visits; liospitalized for manic or <lepressive symptoms; req_uire<l an adclition to or inerease in psychotropic
`ineclieations; MADRS Score 2 l8; clicl not tolerate the study me<lieation at the lowest allowed dose; or
`required concomitant medication for symptomatic treatment of side effects.
`
`Patients who completed the l2-Weelc study and who met prespeeified eriteria could continue treatment in a
`l/-'l—Weel< double-hlincl Extension Phase. The results of the Extension Phase will he presented in as separate
`report. ln addition. quality of life and pharmaeoeeonomie results will be presented in
`separate report.
`
`Three hundred se 'enty-two patients were enrolled in the study and
`NUMBER OF PATEENTS:
`to tlonhle-vhliiitl
`treatment:
`l7'?.
`t'i49.6‘:'/5)
`to the halopericlol group and
`347 patients were X‘3.tlCl0ml?1€(l
`Ll’/'5 (50.4%) to the aripipraziole group. Tltere were 133 {$38,392:} men and 214
`Women between
`l8 and 68 years of age i'ar1d(snti;:/.ed to treatment. Of the 347 patients t'an<lomi2,ed to treatment, 344 were
`
`inelnclecl in tle fiafety Sample and 38 were in tl e Effiezttsy Sample. Two hunclred tVv’erttiy--riine (66.0%) and
`l (40. l 0./:3) (st tlte '3'~'l7 t'anclomi2,e<l patients completed Weeks I3 and
`oftlie study, respectively.
`
`BEAGN USES ANB MAIN CRITEREA FUR INCL LTSEON:
`
`DSl\~'l~lV’ diagnosis of Bipolar l Disorder,
`Weeks 1 to 3 ’l‘rentrnenl Phase: Patients must have had
`Manic or Mixed, and have been in ac ate relapse. Patients must also have had a Young Mania Rating Seale
`(Y~l‘vll{S} Seore 2 20.
`
`score of < 4 on the CGI-BF {mania} Severii)’
`‘weelés 4 to 12 Treatmetit Phase: Patients must have had
`Scale and a seore of <
`on the lVlADl{S at the end of Weelt 3.
`
`TEE’? ?R{3E}UC"l', l}(}SE ANB MGDE OF ADMlNlS"l'RA"E'l0N, BATCH NUMBERS: Aripiprazole
`l5~mg tablet, one or two tablets daily, atlrninistered orally, hatch numbers 99H93AOl5A and 99L77A0l5.
`
`BURATEGN {BF TREATMENT:
`
`l'2 weeks.
`
`AND MGl)E OF ABMlNilS'l'RA'l'l0N, BATCEE NUMBERS:
`REFERENCE ’l‘}lERAl‘Y,
`I-laloperidol 5--mg (32i,pSlllt)S, two or three eapsules daily, atlministeretl orally, bateli numbers ll)'?.924--0:3 ancl
`Ll(l292l)-03; plaeebo capsules for haloperitlol,
`two or three eapsules claily, administered orally, batelt
`numbers lllIZ924--02 and ll)IZ9'?.t:)-'02; placebo tahlets for aripiprazole, one or two tahlets daily, a.<lministere<l
`orally, liateh nnniher 99K 77l’l)U€}B.
`
`Page 2 of 9
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`

`Aripiprazole
`Blv,lS—3=37ll39.«’0PC—l4597
`
`CRITERIA FGR EVALlJATl{)N:
`
`~ Acute Phase
`CNl
`Clinical Study Report
`
`Eflleaey: The primary efficacy measure was the number ofpatients who completed Weelt l2 and were in
`response at the end of \ feel: 12 (at least 50?/o inlpr Ventent fioni baseline Y-l\~'lRS). l3fficaey rating scales
`completed during this study included the Y~l‘vlRS, l\'lADl{S, the Positive and Negative Syndrome Seale
`(PANSSL), and the CC<l-Bl’.
`
`Safety: Safety assessments included medical review of All reports (including intercurrent illness), Vital
`sign measurements, eleetroeardiogams (l3C(_}s), body weight, concomitant medications, and results of
`physical examination and Clinical laboratory
`lixtrapyraniidal syndrome (l3l3S) rating
`completed
`during this study were the Sirnpson~Angus Scale (SAS), Abnormal lnvoluntary lvloyement Scale (All‘vlS),
`and Barnes Akathisia Rating Scale.
`
`of 306 patients (153 per treatment group) was
`STATTSTECAL ME'l‘H(}lJS: The planned sample
`estimated to yield 90% power to detect a treatment difference of 54% of patients completing the study in
`the aripiprazole group versus 35% of patients completing the study in the haloperidol group, assuming a
`two—sided test at the 0.05 level. The estimated percentages of patients completing the study were derived
`from an estimated response rate at end of Week 3 of 60% in the aripiprazole group versus 50% in the
`haloperidol group, and the estimated nuniher of patients who either dropped out after end of Week 3 or
`were not in response at end of Weelt
`(10% in the aripiprazole group and 30% in the haloperidol group).
`
`The Safety Sample ineluded patients who received at least one dose of study medication as indicated on the
`dosing record. The Effeaey Sample included patients in the Safety Sample who had at least one eflicaey
`evaluation (ie, evaluable patients) who reeeived at least one dose ofstudy niedieation.
`
`clelined as the proportion ofpatients who
`The primary efficacy endpoint was the response rate at Week
`eoinpleted the l2—weel< phase (as stated on the Week l2 end~of~stncly form) and who had at least a 50%
`improvement from haseline in the Y—l‘vlRS Total Score. Patients who discontinued from the study (luring
`the l'Z—weel< phase and patients Without a Week— '12 Y—lv,lRS Total Score were considered non~respondet's.
`The priniary outeorne rneasure was analyzed within the franieworlr of the CoehranvMantel Haenszel
`(Clvlll) test, eontrolling for treatment, and was perforinecl on the Safety Sample. Relative risk (RR) versus
`
`haloperidol, l3—V'alues, and 9.
`eonfclenee intervals (C/ls) for the relative risk were presented. The same
`a,na.ljv"”lis was performed on the QC data set. A sensitivity analysis was performed, similar to the primary
`analysis but with adjustment for the current episode (tnanie, mixed).
`
`The secondary outtzorne measures \ 'ere the response rate at Week 3 and the response rate at Week l2. in tle
`subgroup of patients who had a CGT--BF (mania) Severity Score <1 4 and a ,lV,lAT)REl Total Score < l8 at
`Week
`Secondary measures were analyzied with the same methods as those used for the primary tmtrrome
`measure.
`
`A.
`tlefitietl as the proportion of patients who completed Week .3
`l2),
`(‘Weel~;
`Remission rate at Week
`(Week
`with a Y--.=‘vlR.“3 Total Score <
`wa,s analyzed within the :h‘ameWork of the ClV,ll‘l, test,
`tsontrolling for treatmerttj and was performed on the Safety Sample. Relative rislt:
`rersus haloperidol_.
`}‘’-values, and 95% Cls :h)r the relative rislt: were presented. The same analysis was performed on tle OC
`data set.
`
`Time to discontinuation and time to diseontinuation due to laclt of efficacy were evaluated using the
`log-rank test to eonlpare suiyival distributions. The parameter estimates and 95% Cl for the hazard ratio
`\ 'ere obtained from the Cox regression model, with treatrnent as eovariate. The Safety Sample was used for
`these analyses.
`
`Other eflieacy analyses included the mean change from baseline to each speeitied visit in the Y-MRS Total
`Score, the mean changes from baseline in the Cfil-Bl’ Severity of lllness (mania, depressions and overall)
`Scores, the mean change from baseline in the PAN Total Score, the mean change fioni baseline in the
`1~\;l\l Cognitive Suhscale Score, the mean ehange from baseline in the FANSS ltlostility Suhscale Score,
`
`Page 3 of 9
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`

`Aripiprazole
`BMS—337tl39.«’()PC—l4597
`
`~ Acute Phase
`CNl
`Clinical Study Report
`
`and the mean change from baseline in the MADRS Total Score. The analysis niodel included the baseline
`measure as covaiiate and treainient as main effect. Baseline scores for these efficacy variables and mean
`C01-Bl‘ change frorn preceding phase (rnania, depression, and overall) scores were evaluated by analysis
`of Variance (ANUK/’A)=, with trealrnent as main e tect. These analyses were applied to tle Efficacy Sample,
`and performed on the last observation carried ih)iWard (LOCl7) and observed cases (QC) data sets.
`
`Other efficacy measures analyzed within the framework ol‘ the Clvlli test were the proportion of patients
`with a MADRS Total Score 2 18 (evaluated at all time points), lime to discontinuation for lack cl‘ efficacy,
`and proportion of patients with at least "/'l)‘:'/ii irnprovemenl. from haseline in Y--MRS Total Score at Weelr: 3.
`These analyses were applied to the l?.fl‘ica<:y Sample, and perforrned on the LOCl7 and QC data sets,
`
`All analyses carried out on the QC data set were considered secondary.
`
`EFlTlCACԤ:' RESULTS:
`
`Priniary Ellicacy Endpoint: The analysis of the primary efticacy endpoint, the number of patients who
`continued on treatment and maintained response after 12‘:
`of study medication, showed that patients
`in the aripiprazole goup had
`statistically significantly (P < 0.001) greater response rate (49.7%) than
`patients in the haloperidol group (28.4%) at Week 12, and the relative risk was L75 in favor of
`aripiprazole.
`
`Secondary Efficacy Endpoints: For the secondary eftieaey measure, response rate at the end of Week 3,
`the aripiprazole group showed greater‘ response (5l).§9“'/ts)
`than the haloperidol group (42.6%), but the
`comparison was not statistically significant (P = U. l'26). There was 8' statistically significantly (F = ’l.:')/-'l8,‘;
`greater proportion of patients in the aripiprazole group (68.8%) conipared with the halopericlol group
`(54.6%) who were in response (for the suh group of patients who continued in the study after Week 3 with a
`CGl~Bl’ lnianial
`ilevcrity of lllness Score <4 and at IVTADRS Score <1 18 at Week 3, and who were in
`response at the end of Week 12).
`
`(Ether Key Efficacy Endpoints: At Weel< l2, the proportion of patients in remission (Y—MRS Total Score
`< l3) was statistically significantly higher (P < tliltll) in the aripiprazole group (50%) than in the
`haloperidol group ('Z7%). For time to discontinuation for any reason, the treatment coniparison showed a
`highly statistically signiticant result (p <4 0.()€ll)
`in favor ofaripiprazole, For the niean ehange from baseline
`in Y-l\<lRS Total Score for the LOCF data set, none of the clifferences l)ClW’t)Sfi the groups at any time )oint
`was statistically significant, and the largest ditference was l.7l points at Week 12 nunierically in favor of
`aripiprazole (P = 0.226).
`
`tl e treatment
`Other additional efficacy endpoints were analyzed. For lime to discontinuation due to AE,
`cornparison showed a highly statistically significant result {P < Q.l)0l) in favor of aripi,prazole. For nine to
`discontinnation, due to lack of efficacy (P
`=I),=l)4 E) and the proportion of patients who discontinued due to
`lack of efficacy (P <?l').€l(l
`l), results were statistically significantly in favor of haloperidol. The only other
`additional etlicaey analysis showing statistically signiticant treatnient differences was the l_.OCF analysis
`of ehange from baseline in the CGl—l?lP Severity of illness (overall) Score. The results from Week 6 to
`Week
`(P = €l.0l 9) favored aripiprazole, There were no differences between the groups on the MADRS
`Total Score, the proportion of patients with h/lAl3RS scores
`l8 at Week l3, the proportion of patients
`with at least 70% irnproyement from baseline in “{—MRS at Week 3, the CGl~Bl’ Severity oflllness (mania
`and depression) Scores, the CGl—Bl’ Change from Preceding Phase (mania, depression, and overall) Scores,
`and the
`Total Score, Cognitive Suhscale Score, and Hostility Suhscale Score.
`
`Page 4 of 9
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`

`Aripiprzazole
`BMS—3=37039.«’0PC—14597
`
`~ Acute Phase
`CNE
`Clinical Study Report
`
`Suminary 9%‘ Priinary Eflffieaey Resaits at El‘§{l}§®§§i‘i, Safety Saingiie
`
`Variabie
`
`PRU§’,"L§RY EFFECACY ENBPOENTE
`
`H‘ E
`
`
`
`------------H N
`
`Number
`
`s)fresp0ncEa—:rs at ‘«V<::~:}<; LL .“32a.f:—:ty Sampie
`
`48 (38.~"§)
`
`87 (~"¥9.7)
`
`RR (95% C1 on RR)C
`
`Pwaiue
`
`I-‘r0:IQc:s)E CN I3 8 GD 8
`
`RR Aripiprazzs) Ee.:‘H310p e Eidol
`Ei
`
`1.75
`
`.33,
`
`<: 0.001
`
`Analysis: CWH anaiysis and RR unsiratified.
`
`A responder was 2: patient W130 had at least a 50% decrease {Tum baseline on the ‘f~MRS Total Score and
`who did not discomitiue 3:01‘ before Week 1
`
`U
`
`L‘
`
`A RR greater than 1 favors aiipipmzole.
`
`Page 5 of 9
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`33f‘:f‘C37C5 E
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`Aripiprzazole
`Blv,lS—3=37039.«’0PC—l4597
`
`~ Acute Plizase
`CNE
`Clinical Study Report
`
`Snininary of Secondary anti Other Efficasty Results
`
`
`
`}1ale;.:ei"ide3l
`
`IIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIII-0
`
`
`
`Proportion (9%)) of responders at Week 3,21 Safety Sample
`RR (95% Cl on RR)b
`P~Value
`
`72/l 69 (42.6)
`89/175 (50.9)
`(0.95, 1.50)
`0.126
`
`I-‘ropcsrtion (9/6) of resp<an<lers a1:'\?Ve:—:l~: E2 in atlas: subset ofpatients who
`completed Week 3, with a CGLBP ifmania) severity seore <; 4 and 3
`MADRS score <
`at Week 3,0 Safety Sample
`RR (95% Cl on RR) b
`P—Value
`
`.
`-,
`.
`I
`42/77 (44 6}
`
`,
`.
`H
`.
`,
`77/} 19 (63 3,
`
`(ll .00, L58)
`0.048
`
`{}'l"}iER EFFICACY ENlJ?(}lNTS
`
`Propcsrtion (9/6) of patients in remission at Week
`RR
`CI on RR)b
`F-Vztlue
`
`Safety Sample
`
`37/175 (50)
`45/169 '37,)
`(1.41, 2.47)
`< 0001
`
`Time to discontinuation (for any reason), Safety Sample
`
`N =
`
`N = 175
`
`Hazard Ratio (Haloperidol/'AripiprazolV‘ 95% Cl)
`
`P-Value
`
`1.94 ('1.-497, 3.57)
`
`<1 0.00]
`
`Y-MR,S.,€ Efficacy Sample
`
`lvlezan Baseline (SE)
`
`N =
`
`= 17"
`
`31.39 (0.57)
`
`3 .07 (0.55)
`
`~ 13.22
`-l 9.93
`Mean Change at Week
`Vi -71 {"4499 1-95)
`Treatment Differeneef at W 12 (95% Cl)
`0/226
`P~Value
`
`Protocol Cl\ 38008
`
`RR : Aripipr:azole.«’Halopeiidoi
`
`4 A responder was 2: patient who had at least 21 50% decrease liom baseline on the Y-MRS "i‘ota,l Score and
`who did not discontinue at or before Week 3. Every patient in the Safety Sample who was not 21
`responder was considered 21 non-responder and was included in the analysis.
`
`A RR greater than I
`
`f2iVs)rs aripiprazioie,
`
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`

`

`~ Acute Phase
`CNE
`Aripiprazole
`Clinical Study Report
`BMS—3=37039.«’0PC—l4597
`F,
`p
`.
`_
`c
`p.
`A responder was a patient who had at least a 30% decrease from baseline on the Y--=.‘vlR::> Total Score and
`who did not distsoutlriue at or before Week
`Every patient in the subset of the Safety Sample Who was
`not a responder was considered a non-responder and was included in the analysis.
`
`A patient with remission in a specific stucly Week was a patient with an Y—l\~’lRS Total Score <
`did not discontinue in, or prior to, that study Week.
`
`who
`
`LOCF data
`
`Difference T aripiprazole ~ haloperidol. A negative difference favors aripiprazole.
`
`SAFETY RESULTS: Two hundred sixty (75.59-/0} of the 344 patients in the Safety’ Sample reported at
`least one Ali:
`(86.7%) ofthe lfafsi patients in the haloperidoi group and 12 (64.8%) ofthe l75 patients
`in the aiipiprazole group. The most frequently occurring
`(2 l0% incidence) for the haloperidol group
`were extrapyrainidal syhdronie, akathisia, depression, headache, and tremor. For the aiipiprazole goup, the
`most frequently occurring ABS (2 l()% incidence) were insornnia, akathisia, depression, and headache. The
`incider te of weight gain was low in both groups (haloperidoi 2.4%; aripiprazole l.l%).
`
`One patient (lied tfeardiac arrest) prior to randomization to treatment. Eighteen patients experienced an
`during the stuciy or Within 30 days of discontinuing horn the study:
`patients in the haloperidoi group
`and 6 patients in the aripiprazole
`ln general,
`were related to the patients underlying disease.
`One patient (f‘i38(l08--7-281) in the halopericiol group experienced an SAE of liver damage considered
`possibly related to study rnedicatioh. More patients discontinued treatnient because of Alis frorn the
`haloperidoi group (49.1%) compared with the aripiprazole group (18.9%), and one patient
`in the
`haloperidoi group hecarne pregnant during the study.
`
`was higher in the haloperidoi group (62.7%) than in the
`incidence of l3l’S-related
`The overall
`aripiprazole group (24.0“/(3)., with the incidence of EPS nearly four times greater in the haloperidol group
`(35.5%) eornpared with the aripiprazole group (9.1%), and the incidence ol‘ akathisia two times greater in
`the haloperidol group (23.1%) compared with the aripiprazoie group (1 l.4%). Although irnprovernent was
`not dernonstratetl at endpoint {Weelsi l2) LOCF on any of the l3PS-ratirtg scales for either treatrnent group,
`significantly srnaller increases were shown for the aripiprazoie group compared with the halopericiol group.
`For all
`three scales.
`the (lil‘ferences in the means at endpoint between the groups were statist,ica.lly
`significant and favored aripiprazole. Results of the EPS rating scales are presented in the following table:
`
`Page 7 of 9
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`

`Aripiprzazole
`BMS—3=37039.«’0PC—14597
`
`~ Acute Plizase
`CNl
`Ciinicai Study Report
`
`E}’E§ Rating Scaies: Mean Change frnnt Bzaseiine to Endpnint {‘Week E2), L{}{I.7}?‘
`Beta Set, Safety Snnrple
`
`Varinbie
`
`SAS Total Score
`
`Mean Baseline Scorea
`
`i\/i(‘.EE31 Chzirige at Endpoint (‘Week 12)
`Difference at Endpoint (Week 12)}; (95% Cl‘;
`P-vveine
`
`AEYVES Total Score
`
`Meat: Baseline Scorec
`
`lviezan Change at Endpoint {Week 12)
`Diffei‘ei1ee zit Endpoint {Week 12)}? (95%. Cl)
`P~\/‘aiue
`
`Barnes Akathisia Rating Scale
`
`=.‘viea31 Baseline Scorea
`
`Meat: Change at Endpoint (Week 12.)
`Difference at Endpoint €Weel~: 12)?) (95% Cl)
`F ~Vaiue
`
`Protocol CN 3 8908
`.,
`.
`.
`, ,.
`.
`3»
`,
`.
`IN at baseline: haioperidol = £639; arrprprazoie = l /4.
`
`Haloperidoi
`
`N 1 use
`
`1=l),7.'3
`
`5.70
`
`Aripiprnzoie
`
`= l73
`
`10.94
`
`1.02
`
`4.69 (f-5.S8;—3.5(l)
`<1 0.€=l)l
`
`"QI7 ("i1~93;'U-25)
`0.002
`
`3.48 (0.74; 43.23)
`< 0 . 001
`
`= 154
`
`(3. E3
`
`0.81
`
`N = 160
`
`0.13
`
`8.80
`
`= 167
`
`0.22
`
`0.14
`
`T l’/'3
`
`0.17
`
`0.32
`
`Arrprprazole — naloperidoi: a negative ditterenee tavors arrpiprazole over haioperidol.
`
`C
`
`at baseline:
`
`iiaioperidoi = léiil; aripiprazoie = 173.
`
`A review of AES potentizaliy related to czardiovascuiar etiology provided no signiti-cant findings. One
`aripiprazole patient experienced an Ali ofproionged QT iiitewai, wliich occurred one day after tlie patient
`received their fast dose of study rnedication and resoived the sarne day. The event was considered by the
`investigator to be possibly related to treatment. Nine patients had potentiaiiy clinically significant increased
`QT intervals wlien Bazett"s correction factor was applied:
`four (2.7%) patients in tlie naloperidoi group
`and five (3.0?/9) patients in the aripiprazoie group. When the I\'europhai“niacoiogieai Division correction
`factor was used, none of the Vaines was ecnsidered potentially clinieaily sigrrilieam. No patient
`
`disecntinued from the study because of an abnornmi QTC Value.
`
`There were differences between the groups in laboratory abnormaiities, witli more than twice the number of
`patients in the litaloperidoi group (94 patients) experiencing a potentiaily elinicaiiy significant resnit
`
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`

`Aripiprazoie
`BMS—3=37039.«’0PC—14597
`
`~ Acute Phase
`CNE
`Clinical Study Report
`
`compared with the aiipiprazoie group (40 patients). This ditferenee was primarily due to an increased rate
`of elevated proiactin ieveis reported in the haioperidoi group (59.2%) eoinpareti with the aripiprazoie group
`(14.7%). Resuits ofproiaetin ieveis showed 2: mean increase from haseiine to endpoint (;Weei~:
`LUCY}
`for the naioperidoi, group (47.7%) ng./mL) and a mean decrease hon) hasehne to endpoint, for the aripiprazioie
`group (i13.'~'i_i rig/niL). ‘Tie difference in the mean change from baseline to endpoint hetween the groups was
`statisticaiiy sigriificant, (P <‘ C).Q€)1). The only other result of note was a slightly higher rate of elevated CPK
`in the aripiprazoie group (55%) compared with the naioperido} group (3,4%)=, No patient in the ar'ipipr'azoie
`group disctnitinued from the study because of a laboratory abnorrnaiitiy, but two patients in the haioperido}
`group discontinued hecanse of an abnorriianty: one patient discontinued because of increased AST and
`[DH ieveis and one patient discontinued because ofan elevated CPK ievei.
`
`There were no tiitferenees hetween the groups in vitai sign or ECG a.hnorrna.iities, and no patient
`tiiscontineued horn the study due to either of these ahn,orrnaTities,
`
`There was no st,atisticaiiy significant ciiiferenee in mean change in weight horn baseline to '\."eei~:
`hetx 'een the h&,iOpt31”i(i<;5i- and aripiprazoie-treated patients.
`
`C{}NCLUSi(}NS:
`
`it
`
`9
`
`0
`
`0
`
`8
`
`Aripiprazoie was found to be superior to haioperidoi on the primary efficacy endpoint, number of
`patients on treatment and in response at Week 12, thus, demonstrating the efficacy of aripiprazoie,
`observed during acute therapy, in the continuation treatment ofrnania for up to 12‘: Weeks.
`
`There was a greater proportion of aripipra:/zoie~treated patients than haioperidoi-treated patients in
`remission at Week 12. Additionally,
`the aripiprazoie group had higher coinpietion rates than the
`haioperidoi group in this s,tu<iy.
`
`Ar‘ipipr‘a2o}e was safe and better tolerated than haioperidoi. The incidence of Afls was tower in tie
`aripiprazzoie group, and the proportion of patients with
`and who discontinued due to ABS ' re ‘e
`tower in the ar'ipipr'azoie group than in the haioperidoi group,
`
`The rate. of TSPS--reiateci ABS was higher in the haioperidoi group than ti e ar'ipipra2:oie group, and was
`ciirectiy related to the increased rates of EPS and akathisia evident in the haioperidoi group
`
`The incidence of elevated proiaetin that was of potential clinical significance was higher in the
`haioperidoi group than the aripiprazoie group, and the mean change from haseiine in proiaetin ievei for
`the haioperidoi group increased while it decreased for the aripiprazoie group with a statistically
`signiticant difference be ween the two groups in favor ofaripiprazoie.
`
`#2 Differences between the groups were not observed for Vitai Sign or ECG (including QTC)
`abnormalities, and no patient discontinued the triai because of either of these ahnorinaiities. There was
`no evidence ofincreased cardiac liability with aripiprazoie treatment.
`
`9
`
`The number ofpatients with significant Weight gain was siniiiar between the two treatment groups.
`
`QATE OF REPGRT:
`
`28—Api‘—'Z()€}3
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`Page 9 of 9
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`Lo (_I\J :) F) O [J] .4 (‘N U1
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`ON
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