Clinical Review
`Michelle M. Chuen, M.D.
`NDA #22-192
`Iloperidone
`
`The use of lorazepam (or if unavailable, another short-acting benzodiazepine) was permitted on a
`p.r.n. basis at doses of up to 6 mg/d p.o. for the first 2 weeks or up to 4 mg/d p.o. for the
`remainder ofthe study. Alternatively, up to 6 mg/d irn (up to 3 mg/im injection) could be
`administered throughout the entire study. Both the oral and im formulation could be administered
`for up to 3 consecutive days during: 1) the placebo run—in period; 2) the first 28 days of the initial
`double-blind phase (a lorazepam-free period of at least 1 day must have been instituted after any
`3-day treatment period with lorazepam during the first 28 days of the initial double-blind phase;
`and 3) no more than 1 day at a time for the remainder of the initial double-blind phase (Days 29-
`42).
`
`The use of sodium amytal was permitted on a p.r.n. basis at doses of 30-50 mg/im injection
`(up to 3 injections/d) for up to 6 consecutive days during the placebo run-in period and the 6-
`week initial double-blind phase of the study.
`
`Anticholinergic drugs for the treatment of extrapyramidal symptoms (EPS) were allowed during
`the placebo run-in period. However, EPS must have improved and anticholinergic medication
`discontinued for at least 24 h prior to the baseline day. Use of an anticholinergic drug on a p.r.n.
`basis for the treatment of extrapyramidal symptoms emerging during the active—treatment
`(double-blind) phase of the study was permitted. The Investigator reevaluated the need for
`anticholinergic medications on an ongoing basis. Benztropine could be initiated for
`extrapyramidal symptoms after randomization to active (double-blind) treatment and only after
`an assessment of EPS using the Extrapyramidal Symptom Rating Scale (ESRS) was completed.
`In case of severe EPS (e.g., acute dystonic reaction), the Investigator could treat the dystonia
`with a parenteral intramuscular injection of benztropine for immediate relief of symptoms, and
`then complete the ESRS assessment during a period when the effect of the medication was
`diminished, but prior to initiating treatment with oral benztropine.
`
`Beta-blockers were not allowed during the study for any indication. Diphenhydramine
`hydrochloride was excluded from use in the study for a psychiatric indication or extrapyramidal
`symptoms.
`
`With respect to the percentages of randomized patients43 using various concomitant medications
`during the study, there were no major differences between treatment groups (80% in 110 4-8 mg/d
`patients, 82% in 110 10—1 6 mg/d patients, 79% in Ris 4-8 mg/d patients, and 81% in placebo
`patients), and the most frequently used were lorazepam, zolpidem, and chloral hydrate. The
`sponsor did not provide information regarding patients identified as protocol violators because of
`prohibited medication use.
`
`'
`.
`Eflicacy Results
`Efficacy data displays may be found in Appendices 10.3.6 to 10.3.9 of Section 10.3.
`
`43 This information was not provided for ITT patients.
`
`108
`
`

`

`Clinical Review
`Michelle M. Chuen, M.D.
`NDA #22-192
`
`Iloperidone
`
`For the entire ITT population (including schizoaffective patients), for the BPRS mean change
`from baseline analysis, the differences were not statistically significant for the 110 4-8 mg/d
`group from Week 4 and on, for the 110 10—16 mg/d group from Week 3 and on, and for the Ris 4-
`8 mg/d group from Week 1 and on in the LOCF analysis. The OC analysis was consistent with
`the LOCF analysis for the Ris 4-8 mg/d group, but not for the 110 4-8 mg/d and 110 10-16 mg/d
`groups. For the 110 4-8 mg/d group, the differences were not significant at any time point and for
`the Ho 10-16 mg/d group, the differences were significant at Weeks 3 and 4 only.
`
`For the ITT population excluding schizoaffective patients, for the BPRS mean change from
`baseline analysis, the differences were not statistically significant for either the 110 4-8 mg/d
`group or the 110 10-16 mg/d group at any time point in the LOCF analysis. For the Ris 4-8 mg/d
`group, the differences were significant at all time points at the p S 0.05 level.
`
`Conclusions
`
`The results of Study 3004 do not provide evidence of the efficacy of iloperidone at flexible doses
`of 10 to 16 mg/d given twice daily (primary treatment comparison) in the treatment of
`schizophrenia versus placebo over 42 days of treatment. Moreover, risperidone 4-8 mg/d was
`found to be superior to placebo. '
`
`Study 3005
`
`Investigators/Sites
`Sixty seven (67) investigators conducted this study at 65 sites in North America (32 in the U.S.
`and 7 in Canada), Africa (1 in South Africa), Asia (3 in Israel), and Europe (5 in Poland, 6 in
`Hungary, 7 in Germany, 6 in Croatia). Investigators and sites are listed in Appendix 10.3.10 in
`Section 10.3 extracted from the sponsor’s submission.
`
`Objectives
`By protocol, the objective of this trial was to determine the efficacy and safety of two
`nonoverlapping dose ranges of iloperidone (12 or 16 mg/d and 20 or 24 mg/d) and risperidone (6 or
`8 mg/d) compared with placebo, administered on a twice—daily (b.i.d.) basis over 42 days in
`schizophrenic or schizoaffective patients.
`
`Patient Sample
`Important inclusion criteria were:
`
`0
`0
`
`0
`
`0
`
`age 18 to 65 years, inclusive
`male, surgically sterilized female, postmenopausal female, or non—pregnant female of
`childbearing potential who agreed not to attempt to get pregnant and to use contraception
`diagnosed with schizophrenia according to DSM-IV criteria. This included DSM-IV
`diagnosis of schizophrenia (i.e., 295) with suffixes 10 (disorganized), 30 (paranoid), 70
`(schizoaffective), or 90 (undifferentiated) .
`had PANSS Total (PANSS—T) score of at least 60 at screening and baseline. Prior to
`baseline evaluation and during placebo run-in, the Investigator examined the patient. If
`
`109
`
`

`

`Clinical Review
`Michelle M. Chuen, M.D.
`NBA #22- l 92
`Doperidone
`
`clinically relevant improvement compared with screening was detected, the placebo run-
`in period was extended until the patient’s psychiatric status returned back to a level
`comparable with screening. If this improvement persisted for 7 additional days (i.e., total
`' of 10 days of placebo run-in), the patient was not allowed to enter the study and a re-
`evaluation of the patient’s psychiatric diagnosis was performed
`had a rating of at least "4" ("moderate") on at least 3 of the following 5 symptoms on the
`PANSS Positive Syndrome: delusions, conceptual disorganization, hallucinatory
`behavior, grandiosity and suspiciousness/persecution
`was in need of psychiatric treatment
`had vital signs measurements within normal ranges, defined for healthy adults as supine
`blood pressure in the range of 100-160 mm Hg systolic and 60-95 mm Hg diastolic, with
`a supine radial pulse of 60-100 beats per minute (bpm)
`was to have no medical contraindication fOr oral treatment with iloperidone or
`risperidone, as confirmed by medical history, physical examination, electrocardiogram
`(ECG), and clinical laboratory tests, which were within the normal range, or, if abnormal,
`judged not to be clinically significant
`
`The following were relevant exclusion criteria:
`
`met the DSM-IV criteria for schizophreniforrn disorder (295.40)
`had any other primary psychiatric diagnosis (Axis I) or comorbid diagnosis (Axis II),
`according to DSM—IV criteria
`had diagnosis or history suggestive of chemical dependence, according to DSM-IV
`criteria, or toxic psychosis in the preceding 6 months, or a clinical presentation possibly
`confounded by the use of recreational drugs or alcohol
`was mentally retarded (moderate to severe), in a comatose state, or with significant brain
`trauma
`
`had a history of suicide attempt within the last year, or, in the opinion of the Investigator,
`were currently at imminent risk of suicide
`suffered from significant physical illness in the 4—week period preceding baseline
`had other medical conditions that could be expected to progress, recur, or change to such
`an extent that they may put the patient at special risk or bias the assessment of the clinical
`and the mental status of the patient to a significant degree
`had a current diagnosis or recent past history of epilepsy, major head trauma, or
`progressive neurological disease (other than tardive dyskinesia or drug-induced
`extrapyramidal side-effects)
`had past history of priapism treated with surgical intervention.
`was known to have hypersensitivity to drugs chemically related to benzisoxazoles or
`butyrophenones
`received, during the 30 days immediately prior to screening, any drug known to cause
`major organ system toxicity (e.g., chloramphenicol or tamoxifen)
`‘
`received any mood stabilizers during the 30 days preceding baseline, unless the patient
`was documented to have a plasma concentration below the limit of quantification.
`received electroshock (ECT) therapy in the 3 months preceding baseline
`1 1 0
`
`

`

`Clinical Review
`Michelle M. Chuen, M.D.
`NDA #22-192
`Iloperidone
`
`o
`
`0
`
`0
`
`0
`0
`
`0
`
`likely to require continuous treatment with any other psychotropic drug, including
`antidepressants or mood stabilizers, during the study
`required treatment with anticholinergic drugs during at least the 24 h prior to baseline
`evaluations (i.e., baseline day and the day before baseline) Note: Use of an
`anticholinergic drug on a p.r.n. basis for the treatment of extrapyramidal symptoms
`emerging at any other time during the study was permitted
`experienced neuroleptic malignant syndrome (rigidity/rigor, hyperpyrexia, and creatinine
`phosphokinase [CPK] level >2 times upper limit of normal)
`received clozapine within 60 days prior to screening
`whose psychotic symptoms failed to improve (based upon the Investigator’s opinion)
`following sufficient exposure to a therapeutic dose of any antipsychotic treatment over
`the prior 2 years
`was previously randomized to treatment in this study or in other studies with _iloperidone
`
`Design
`This was a prospective, randomized, double—blind, placebo- and risperidone-controlled,
`multicenter study. This study has three phases: pre—randomization, short-term double-blind (6-
`week), and long-term open-label (46-week).
`
`The dosing schedule for the pre-randomization and short-term double-blind phases are
`summarized in the table below, extracted from the sponsor’s submission.
`
`Pre-randomization phase
`Day -30 to -3
`Day -2 to 0‘l
`Screening
`Single blind placebo mn-
`in eriod bid dosin-
`Placebo
`
`
`Short—(em double-blind phase (bid dosing)
`Day 1 to 7
`Day 8 to 42
`
`Fixed titration period (mgid)
`Flexible maintenance
`period (mgld)
`llo low: 12b or 16
`
`
`
`Ilo low: 2—>4—\8->12
`
`
`
`
`
`
`
`
`
`
`.
`
`llo high:2—>4—>8—+12—>
`16—)20
`
`110 high: 20“ or 24
`
`
`llo=iloperidone; Ris=risperidone; Pbo=placebo
`’ Placebo run-in period lasted a minimum of 3 days; the last day of placebo run-in period was baseline
`(Day 0)
`b Titration target dose
`
`Ris: 2—)4—96
`
`RIS: 6b or 8
`
`Patients who consented to participate in the study agreed to be hospitalized for at least 10 days
`(i.e., during the placebo run-in period and the titration period of the initial double-blind phase)
`and at any other time throughout the study, if medically indicated. The decision to discharge
`patients was based on the Investigator’s clinical judgment and the following discharge criteria:
`__ toleration of study medication
`_ lack of worsening
`
`lll
`
`

`

`Clinical Review
`Michelle M. Chuen, M.D.
`NDA #22-192
`lloperidone
`
`_ absence of unmanageable behavior
`‘
`_ lack of suicidal tendency
`_ likelihood of compliance with the protocol, especially dosing
`_ availability of a responsible caregiver
`
`Patients were instructed to take all study medication (3 tablets and 1 capsule) in the morning and
`evening, at approximately 8 AM and 6 PM, respectively. Study medication was to be taken with
`food.
`
`Initially patients were randomized to one of three treatment groups in a 2:.l:1 ratio (iloperidone
`12-16 mg/d, risperidone, and placebo, respectively). When it was determined that patients might
`benefit from iloperidone doses >16 mg/d (based on the outcome of Study 3004), randomization
`to iloperidone 20-24 mg/d (10 to 12 mg bid) was initiated afler approximately one-half of the
`anticipated enrollment was completed. From that point on, patients were randomized in a ratio
`of 12:1 :1 to receive treatment with iloperidone 12-16 mg/d, iloperidone 20—24 mg/d,
`risperidone, or placebo to balance the treatment arms.
`
`For the iloperidone 12-16 mg/d group, the dosage was increased every other day until the target
`dosage of 12 mg/d was reached on Day 7. For the 20-24 mg/d group, daily dosage increases
`were made up of 12 mg/d (Days 4 and 5). Thereafter, the dosage was increased every day until
`the target dose of 20 mg/d was reached on Day 7.
`-
`
`The target dose during titration was the lower of the dosages (Level A) in each treatment group.
`The investigator was given the option of increasing the dosage to a higher maintenance dose
`(Level B) in order to explore additional benefit. Thus, if randomized to iloperidone 12 mg/d
`(Level A), the dosage could be increased to 16 mg/d (Level B); if randomized to iloperidone 20
`mg/d iloperidone (Level A), an increase to 24 mg/d (Level B) was allowed, and if randomized to
`risperidone, an increase from 6 to 8 mg/d was permitted.
`
`Patients who completed 42 days of double-blind treatment were eligible to participate in the
`long-term open-label phase of the study. The following description of the open-label phase is
`based on the sponsor’s protocol. The long-term open-label phase consisted of a blinded fixed
`titration period followed by an open label maintenance flexible dosing period. The fixed titration
`period lasted for 7 days (Days 43 to Day 49), and the flexible maintenance dosing period lasted from
`Day 50 (Week 8) through Day 364 (Week 52).
`
`An overview of study design including the prerandomization, short-term double-blind and long-
`term open-label phases of the study is provided in the table below, extracted from the sponsor’s
`submission.
`
`112
`
`

`

`Clinical Review
`Michelle M. Chuen, M.D.
`NDA #22— 1 92
`Iloperidone
`
`Da -2 to 0‘
`Single blind
`placebo run-in
`
`Long-term open-lathe! phase
`
`
`
`
`_
`
`
`
`_I__
`
`Prerandomization phase
`
`Ba -30 to -3
`
`
`
`
`
`
`Short-term double-blind phase
`. .d. dosin
`hid. dosin-
`Ba 43 to 49
`D-
`t to 7
`De 8 to 42
`Ba 50 to 364
`Fixed titration
`Fiexflnle
`Flexmle
`Fixed titration period
`
`
`period (mgid)
`maintenance
`maintenance
`
`
`
`period {mg!d)
`period (mgl'd)
`
`
`
`ILO low: 244—)8412
`lLO iow: 12 or 16
`lLD low 8
`
`1L0: 4.1,
`cm, 12m,
`lLO high:
`1L0 high: 20' or 24
`lLO high a
`
`
`16.70 or 241;)
`2—>4-a&-nz—>15—>20
`
`
`
`Abbreviations: P=placebo; lLO=iEoperidone; RIS=risperidone; mgid=rniliigramslday2 b.i.d.=twice daily; q.d.=once daily
`8 The piecebo run-in period wiil last at least 3 days. The last day of placebo run-in period wilt be basetine (Day 0).
`b Titration target dose
`
`During the fixed-dose period of the open label phase, all patients received treatment with
`iloperidone and all dosing switched from twice to once daily. Patients who received iloperidone
`during the short-term double-blind phase continued to receive iloperidone at a fixed dose of 8
`mg/d (dose level M), given q.d.
`
`Patients who received either placebo or risperidone during the short—term double-blind phase
`were switched to iloperidone and their medication were titrated using a fixed titration schedule.
`These patients achieved their target dose of 8 mg/d (dose level M) on Study Day 47. All patients
`remained at dose level M through Study Day 49.
`
`Patients were switched to open-label treatment on Day 50, the first day of the long-term
`maintenance period.
`
`The long-term open-label phase will not be discussed further in this section, due to lack of a
`placebo control.
`
`The PANSS was administered at screening, baseline, Day 7, Day 14, Day 21, Day 28, Day 35,
`and Day 42 or at study completion. When patients were hospitalized (i.e., during the placebo
`run-in period and the titration period), study assessments were done on the days indicated in the
`evaluation schedule. When the patients left the hospital and returned for weekly visits (i.e.,
`during the maintenance period), a window of 3 days was allowed for flexibility in scheduling
`visits.
`
`Efficacy Assessments
`The protocol-defined primary efficacy variable was the 18-item PANSS-derived BPRS. No key
`secondary variables were identified.
`
`Eflicacy Analysis
`The intent-to-treat (ITT) patients were those who:
`0
`were randomized
`
`-
`
`received at least one dose of double-blind study medication
`
`113
`
`

`

`Clinical Review
`Michelle M. Chuen, M.D.
`NDA #22-192
`Iloperidone
`
`o
`
`from whom at least one efficacy measurement was obtained while on study medication
`
`The primary outcome measure was the change from baseline to endpoint or early termination in
`the lS—item BPRS extracted from the Positive and Negative Syndrome Scale (PANSS). In order
`to control for multiplicity in the analyses of efficacy, the primary comparison was between the
`iloperidone 12 to 16 mg range and placebo. Ifthis test was significant at alpha=0.05, the
`subsequent pairwise comparisons of iloperidone 20 to 24 mg dose range to placebo would be
`considered significant at the 0.05 level. If the comparison of 12 to 16 mg range to placebo was not
`significant, comparison of the 20 to 24 mg range to placebo would not be considered significant
`regardless of the nominal significance level. A two-way analysis of covariance (ANCOVA)
`model was used for the analysis of treatment main effect ofcontinuous variables. The terms in
`the model include treatment, center, baseline (as covariate), and the treatment-by—baseline term.
`An additional analysis was performed for the exploration of treatment—by-center interaction by
`adding this interaction term to the above ANCOVA model. If a treatment-by—center interaction was
`detected, the interaction will be explored in an ad-hoc manner. Categorical variables were analyzed
`using Cochran-Mantel-Haenszel (CMI-I) test blocking on centers.
`
`The primary efficacy analysis was the analysis of the primary variable using the ANCOVA
`model based on the LOCF data set of the short—term double-blind phase. The analysis to explore
`treatment-by—center interaction was performed on the LOCF data set. Significant treatment-by-
`center interactions were investigated.
`
`Of note, the last protocol amendment 2/14/01 and the last patient completed the study on
`3/15/01. The undersigned reviewer reviewed the protocol amendments and determined that they
`were not likely to have a significant impact on the efficacy results.
`
`Baseline Demographics
`The table below displays the demographic characteristics of the randomized patient sample
`(excluding schizoaffective patients)44 by treatment group. _ No patient under age 18 or over age
`65 participated in this study. There were no major differences among the 4 treatment groups
`with respect to age, gender, or race.
`
`44 This information was not provided for the ITT population.
`114
`
`

`

`Clinical Review
`Michelle M. Chuen, M.D.
`NDA #22- 192
`
`Iloperidone
`
`TABLE 10.1.4 : STUDY 3005 BASELINE DEMOGRAPHICS AND DISEASE
`CHARACTERISTICS, RANDOMIZED POPULATION45
`
`110 12-16 mg/d
`N: 188
`
`110 20-24 mg/d Risp 6-8 mg/d
`N= 114
`N= 126
`
`Placebo
`
`N=120
`
`Total
`
`N= 548
`
`39.0 (11.4)
`
`36.1 (10.9)
`
`40.0 (10.7)
`
`38.0
`
`36.0
`
`39.5
`
`38.4
`(10.4)
`38.0
`
`38.5
`
`(11.0)
`38.0
`
`18 — 65
`
`19 — 65
`
`18 — 64
`
`18—64
`
`18—65
`
`120 (63.8)
`
`84 (73.7)
`
`78 (61.9)
`
`75 (62.5)
`
`357
`
`
`
`Age (W) n
`
`Mean (SD)
`
`Median
`
`Min — Max
`
`Sex — n (%)
`Male
`
`Female
`
`Race — n (%)
`
`Caucasian
`
`Black
`
`Other
`
`Baseline BPRS-total
`score
`
`N M
`
`ean (SD)
`Median
`
`Min — Max
`
`68 (36.2)
`
`30 (26.3)
`
`48 (38.1)
`
`45 (37.5)
`
`129 (68.6)
`
`79 (69.3)
`
`97 (77.0)
`
`53 (28.2)
`
`27 (23.7)
`
`21 (16.7)
`
`6(- 3.2)
`
`8( 7.0)
`
`8( 6.3)
`
`82
`
`(68.3)
`30
`
`(25.0)
`8 (
`6.7)
`
`(65.2)
`191
`
`(34.8)
`
`387 (70.6)
`
`131
`
`(23.9)
`30 (
`5.5)
`
`”186
`
`113
`
`123
`
`120
`
`542
`
`54.6 (7.5)
`54.5
`
`55.3 (8.5)
`55.0
`
`55.7 (8.6)
`55.0
`
`55.3 (8.6)
`55.0
`
`55.2 (8.2)
`55
`
`39 — 79
`
`39 — 85
`
`38 — 92
`
`35 — 90-
`
`35 — 92
`
`Source: Dr. Phillip Dinh, Statistical Reviewer
`
`Baseline Severity ofIllness
`For the randomized patients (excluding schizoaffective patients), treatment groups had no major
`differences with respect to mean baseline BPRS total score46 (mean scores of 54.6 in 110 12—16
`mg/d patients, 55.3 in 110 20-24 mg/d patients, 55.7 in Risp 6-8 mg/d patients, and 55.3 in
`placebo patients).
`
`45 This information was not provided for the ITT population.
`46 This information was not provided for the ITT population.
`115
`
`

`

`Clinical Review
`Michelle M. Chuen, MD.
`NDA #22—192
`Iloperidone
`
`Patient Disposition
`Seven hundred six (706) patients (including schizoaffective patients) were randomized in this
`study. Of these patients, 697 received at least one dose of double-blind study medication and
`had at least one subsequent safety evaluation during Days 1-42. These patients comprised the
`safety population. 47 Six hundred seventy one (671) patients comprised the ITT sample (230 110
`12-16 mg/d patients, 141 I10 20-24 mg/d patients, 148 Ris 6—8 mg/d patients, and 152 placebo
`patients). Five hundred twenty one (521) patients comprised the ITT sample excluding
`schizoaffective patients (178 110 12-16 mg/d patients, 111 110 20-24 mg/d patients, 119 Ris 6-8
`mg/d patients, and 113 placebo patients).
`'
`
`The numbers of ITT patients (including schizoaffective patients) in-study over time are displayed
`in Appendix 10.3.12 in Section 10.3. At Day 42, 57% (131/230) of 110 12-16 mg/d patients, 61%
`(86/141) of 110 20-24 mg/dpatients, 76% (112/148) of Ris 6-8 mg/d patients, and 55% (84/152)
`of placebo patients completed the study. Of note, the number of patients completing the study
`based on the sponsor’s data displayed in Appendix 10.3.12 (obtained from Post-test Table 9.1-2
`on page 592 of 36408 of the sponsor’s CSR for Study 3005) is not consistent with the data
`contained in Table 7-2 on page 62 of 36408 of the sponsor’s CSR for Study 3005.
`
`For the ITT population excluding schizoaffective patients, at Day 42, 57% (102/178) of 110 12—16
`mg/d patients, 65% (72/111) of 110 20—24 mg/d patients, 77% (92/119) of Ris 6-8 mg/d patients,
`and 53% (60/113) placebo patients completed the study.
`
`Based on the randomized population (excluding schizoaffective patients),48 overall dropout rates
`were high, but were lowest in the Ris 6-8 mg/d group [47% (88/188) of 110 12-16 mg/d patients,
`37% (42/114) of 110 20-24 mg/d patients, 28% (35/126) of Ris 6-8 mg/d patients, and 48%
`(57/120) of placebo patients]. Based on the randomized population (excluding schizoaffective
`patients), dropout rates due to unsatisfactory therapeutic effect was lowest in the risperidone
`group [27% (51/188) of 110 12-16 mg/d patients, 19% (22/114) Ilo 20-24 mg/d patients, 8%
`(10/126) Ris 6—8 mg/d patients, and 31% (37/120) placebo patients].
`
`Dosing Information
`Dosing information is displayed in the following table.
`
`47 Ofnote, all patients who received at least one dose of double-blind study medication also had at least one
`subsequent safety evaluation.
`48 This information was not provided for the safety population.
`116
`
`

`

`Clinical Review
`Michelle M. Chuen, MD.
`NDA #22-192
`Iloperidone
`
`TABLE 10.1.5: PRESCRIBED DOSAGE (MG/D) SUMMARY STATISTICS FOR ALL
`RANDOMIZED PATIENTS, BY TREATMENT, DAYS 8-42 (STUDY 3005)
`Exposure
`110 12-16 mg
`110 20-24 mg
`R15
`
`
` week N Mean. RD N Mean SD R Mean SD 11 Mean SD
`
`
`
`
`
`
`2
`206 13.80 2.01
`127 21.42 2.42
`145
`6.76 1.13
`138
`0.00 0.00
`3
`170 14.09 2.20
`107 21.69 2.87
`134
`6.92 1.04
`121
`0.00 0.00
`4
`154 14.38 2.21
`98 $.27 1.97
`124
`7.05 1.01
`103
`0.00 0.00
`5
`141 14.48 1.94
`92 22.11 2.26
`119
`7.05
`1.04
`93
`0.00 0.00
`6
`135' 14.42 2.06
`87 22.17 2.10
`114
`7.09 1.06
`88
`0.00 0.00
` Rates:
`1. Based on patient' a weekly mean dose, whereby daily data for each patient: was aggregated over successive 7——day (weekly)
`intervals after baseline.
`2.1118 Drug Administration Record (DAR)
`for: the lat uaek of the short-can double-blind phase (titration period)
`did not capture the patienc'a daily dose, since this vary a fmd- titration period
`
`Concomitant Medications
`
`All comorbid illnesses were treated in accordance with prevailing medical practice.
`
`Medications with known central nervous system effects that were likely to interfere with study
`assessments (e.g., antidepressants, anxiolytics, mood stabilizers, sedative/hypnotics, or
`psychostimulants) were prohibited during the study.
`
`0
`
`Antipsychotic treatment taken prior to study enrollment were discontinued according to the
`following criteria:
`0
`patients who had not recently received treatment with a neuroleptic had a placebo run-in
`period of 3 days
`patients who had recently received treatment with an oral neuroleptic had a placebo run—in
`period of 3 days, or longer, if appropriate.
`Patients who were being treated with a depot neuroleptic had to complete their entire
`treatment cycle prior to beginning the 3-day placebo run-in
`0 Patients who showed clinical improvement during the placebo run-in period had an extension
`of this period up to a maximum of 14 days. Patients were randomized only after reaching a
`psychiatric status comparable to screening.
`
`0
`
`Patients who received allowed medication for insomnia, agitation, or severe restlessness prior to
`baseline were permitted to enter the study.
`
`The following concomitant medications were permitted for the placebo run—in period and the
`short-term double-blind phase of the study for the treatment of insomnia:
`- Chloral hydrate (pm, 500 mg p.o., up to 2000 mg/d total); or
`0 Zolpidem (pm, 5-10 mg/d p.o.). In countries where zolpidem was not available, another short
`half—life hypnotic was acceptable.
`
`No study evaluation was permitted until at least 4 hours after the administration of either of the
`above medications.
`
`Only two concomitant medications were allowed for the treatment of agitation or severe
`restlessness under the guidelines outlined in the protocol: chloral hydrate or lorazepam.
`
`117
`
`

`

`Clinical Review
`Michelle M. Chuen, M.D.
`NDA #22-192
`
`Iloperidone
`
`The use of chloral hydrate was permitted on a p.r.n. basis at doses of 500 mg orally (up to 2000
`mg/d total) during the placebo run-in period and the initial double-blind phase of the study.
`
`The use of lorazepam (or if unavailable, another short-acting benzodiazepine) was permitted on a
`p.r.n. basis at doses of up to 6 mg/d p.o. for the first 2 weeks or up to 4 mg/d p.o. for the
`remainder of the study. Alternatively, up to 6 mg/d im (up to 3 mg/im injection) may have been
`administered throughout the entire study. In countries where lorazepam IV/im was not
`available, another injectable short half-life benzodiazepine was acceptable. Both the oral and im
`formulation were allowed in 3-day consecutive periods. At the end of each 3-day period the
`patient was evaluated for a decrease or discontinuation of the dose of lorazepam.
`'
`
`No study evaluation was permitted until at least 4 hours after the administration of either of the
`above medications.
`
`Anticholinergic drugs for the treatment of extrapyramidal symptoms (EPS) were allowed during
`the placebo run-in period. However, BPS must have improved and anticholinergic medication
`discontinued for at least 24 h prior to the baseline day. Use of an anticholinergic drug on a p.r.n.
`basis for the treatment of extrapyramidal symptoms emerging during the active-treatment phase
`of the study was permitted. The Investigator reevaluated the need for anticholinergic medications
`on an ongoing basis. Benztropine was the only medication allowed for the treatment of
`’
`extrapyramidal symptoms emerging after randomization to active treatment (double-blind phase)
`and only after an assessment of EPS using the Extrapyramidal Symptom Rating Scale (ESRS)
`was completed. In case of severe EPS (e.g., acute dystonic reaction), the Investigator was
`permitted to treat the dystonia with a parenteral intramuscular injection of benztropine for
`immediate relief of symptoms, then complete the ESRS assessment during a period when the
`effect of the medication was diminished, but prior to initiating treatment with oral benztropine
`mesylate.
`
`Beta-blockers were not permitted during the study for any indication. Diphenhydramine
`hydrochloride was excluded from use in the study for a psychiatric indication or extrapyramidal
`symptoms.
`
`With respect to the percentages of randomized patients49 using various concomitant medications
`during the study, there were no major differences between treatment groups (66% in 110 12-16
`mg/d patients, 67% in 110 20—24 mg/d patients, 73% in Risp 6-8 mg/d patients, and 69% in
`placebo patients), and the most frequently used were lorazepam, paracetamol, zolpidem, and
`chloral hydrate. Five (1%) patients in the iloperidone group, 3 (2%) patients in the risperidone
`group, and 1 patient in the placebo group were withdrawn from the study prematurely due to
`protocol deviations. The sponsor did not provide information regarding patients identified as
`protocol violators because of prohibited medication use.
`
`49 This information was not provided for ITT patients.
`
`118
`
`

`

`Clinical Review
`Michelle M. Chuen, M.D.
`NDA #22-192
`Iloperidone
`
`Efi‘icacy Results
`Efficacy data displays may be found in Appendices 10.3.11 to 10.3.16 of Section 10.3.
`
`For the BPRS mean change from baseline analysis (excluding schizoaffective patients),
`compared with placebo, the differences were statistically significant for risperidone from Week 1
`onward, for the Ilo 12-16 mg/d group from Week 3 onward, and for the 110 20-24 mg/d group
`from Week 3 onward in the LOCF analysis. The OC analysis at Week 6 was consistent with the
`LOCF analysis. The OC analysis by week was not available.
`
`When stratified by entering date of the iloperidone 20—24 mg/d group (since this dose group was
`added midway through enrollment), the results were roughly comparable.
`
`Conclusions
`
`The results of Study 3005 provide evidence that suggests efficacy of iloperidone at flexible doses
`of 12 to 16 mg/d and 20 to 24 mg/d given twice daily in the treatment of schizophrenia versus
`placebo over 42 days of treatment. However, risperidone 6-8 mg/d had a larger effect size50 and
`appeared to have an earlier onset of action than both the iloperidone dose groups (12-16 mg/d
`and 20-24 mg/d).
`
`Study 3101
`
`Investigators/Sites
`Forty one investigators conducted this study at 35 sites in the US. and 9 sites in India. Of note,
`on 11/9/05, the sponsor modified participating sites from US, Mexico, Canada and Singapore to
`US. and India. Investigators and sites are listed in Appendix 10.3.17 in Section 10.3 extracted
`from the sponsor’s submission.
`
`Objectives
`According to the original protocol submitted on 8/2/05, the objective of this trial was to 1)
`evaluate the efficacy of a 24 mg/day iloperidone dose compared to placebo, administered b.i.d.
`over 28 days to schizophrenic patients and 2) to assess the efficacy of a 24 mg/d (12 mg bid.)
`iloperidone dose in schizophrenic patients lacking the CNTF FS63Ter mutation versus patients
`who harbor the mutation.
`
`In a 9/16/05 protocol amendment, the study objectives were revised to allow for a step-down
`approach in which the second primary objective would only be evaluated if significance was
`attained on the first primary objective of the study. In addition, the second primary objective
`was changed to “to assess the efficacy of treatment of iloperidone on patients with schizophrenia
`
`5° The larger effect size in the risperidone group appears to be statistically significant for the 12-16 mg/d dose group
`and not for the 20-24 mg/d dose group in a post-hoe analysis. However, the study was not designed to compare
`active control to iloperidone and this finding is difficult to interpret.
`119
`
`

`

`Clinical Review
`Michelle M. Chuen, MD.
`NDA #22-192
`Iloperidone
`
`lacking the CNTF FS63Ter polymorphism compared with all patients with schizophrenia treated
`with placebo.”
`
`In an 8/4/06 protocol amendment, the step-down primary objective was modified to reflect an
`analysis in which comparisons are made among the same subpopulation of patients (i.e., patients
`in the genetic subgroup receiving iloperidone with those in the same genetic subgroup receiving
`placebo). Thus, the step—down objective was changed to read “to assess the efficacy of a 24 mg/d
`(12 mg bid.) iloperidone dose in patients with schizophrenia lacking the CNTF F563Ter
`polymorphism compared with patients with schizophrenia treated with placebo lacking the
`CNTF FS63Ter polymorphism.”
`
`Of note, the last patient completed the study on 9/26/06.
`
`Patient Sample
`Important inclusion criteria were:
`0
`age 18 to 65 years, inclusive. Patients older than 65 years were considered on a case-by-
`case basis.
`
`0
`
`«-
`
`0
`
`0
`
`0
`0
`
`0
`0
`
`male, surgically sterilized female, postmenopausal female, or non-pregnant female of
`childbearing potential who agreed not to attempt to get pregnant and to use contraception
`BMI >18 and <35