CENTER FOR DRUG EVALUATION AND
`
`-
`
`RESEARCH
`
`APPLICA TION NUMBER:
`
`22-192
`
`STATISTICAL REVIEW! S2
`
`

`

`Office of Biostatistics
`
`US. Department of Health and Human Services
`Food and Drug Administration
`Center for Drug Evaluation and Research
`Office of Translational Sciences
`
`STATISTICAL REVIEW AND EVALUATION
`CLINICAL STUDIES
`
`NDA/Serial Number:
`
`22—192 / N000
`
`Drug Name:
`
`Ilopen'done
`
`Indicati0n(s):
`
`Treatment of Schizophrenia
`
`Applicant:
`
`Date(s):
`
`Vanda Pharmaceuticals
`
`‘
`
`Received: Sept 27, 2007;
`PDUFA Due Date: July 27, 2007
`
`Review Priority:
`
`Standard
`
`'
`
`Biometrics Division:
`
`Biometrics I, HFD—7 10
`
`Statistical Reviewers:
`
`Phillip Dinh, Ph.D.
`
`Concurring Reviewers:
`
`Peiling Yang, Ph.D.
`
`H.M. James Hung, PhrD.
`
`.
`
`Sue-Jane Wang, Ph.D.
`
`.
`
`.
`
`Medical Division:
`
`Division of Psychiatric Products, HFD-130
`
`Clinical Team:
`
`‘
`
`Michelle Chuen M.D., Medical Reviewer, RFD-130
`
`Ni Khin M.D., Medical Team Leader, HFD-130
`
`Project Manager:
`
`Kimberly Updegraff, M.S., R.Ph.', HFD-130
`
`Keywords: Clinical studies; NDA review; Pharmacogenomics; Subgroup analyses
`
`

`

`Table of Contents
`
`1. EXECUTIVE SUMMARY ......................................................................... ....... .
`
`CONCLUSIONS AND RECOMMENDATIONS
`.. 6
`
`BRIEF OVERVIEW OF CLINICAL STUDIES ..
`..6
`STATISTICAL ISSUES AND FINDINGS ............................................................................................................ 7
`
`1.1
`1.2
`1.3
`
`2.
`
`INTRODUCTION ..................................................
`
`......
`
`.........‘..................................................9
`
`3.
`
`2.1
`2.2
`
`OVERVIEW....................................'............................................................................................................... 9
`DATA SOURCES ............................ 9
`
`STATISTICAL EVALUATION
`
`...................................
`................................... 10
`
`EVALUATION OF EFFICACY
`3.1
`............................................................................ 10
`
`3.1.1 Study ILP3004ST..............
`10
`
`3.1.1.1 Objectives.............. IO
`
`3. 1.1.2 Study Design ................................
`. 10
`3.1.1.3 Eflicacy Endpoints and Analyses .
`. l 1
`
`3.1.1.4 Eflicacy Results........................
`. 11
`
`3.1.1.4.] Study Population ....................................................
`. ll
`
`3. 1. 1.4.2 Sponsor ’s Eflicacy Resultsfor Primary Endpoint ..
`. 13
`
`3.1. 1.4.3 Reviewer 's Results and Comments ............................................. 13
`
`.................. 14
`3.1.2 Study ILP3005ST....
`
`3.1.2.1 Objectives.............. 14
`
`3.1.2.2 Study Design ............................
`. 14
`
`3.1.2.3 Efiicacy Endpoints and Analyses.
`. 15
`
`3.1.2.4 Eflicacy Results........................
`. 16
`
`..
`3.1.24.] Study Population ..
`. 16
`
`3. 1.2. 4.2 Sponsor ’s Eflicacy Resultsfor Prim
`..... 17
`
`3.1.2.4.3 Sponsor’s Eflicacy Resultsfor the CNTF subgroup
`..... 18
`
`3.1.2.4.4 Reviewer ’3 Results and Comments .............................
`19
`
`3.1.3 Study VP-VYV-683-3101 .......................
`....22
`
`..... 22
`3.1.3.1 Objectives
`
`3.1.3.2 Study Design ................................. 23
`3.1.3.3 Eflicacy Endpoints and Analyses
`..... 23
`
`3.1.3.4 Efi'icacy Results............................. 24
`
`3. 1.3.4.1 Study Population ......................................................... 24
`3. 1. 3. 4.2 Sponsor is Eflicacy Resultsfor Primary Endpoint
`.
`..... 25
`
`3. 1. 3.4.3 Sponsor ’s Efi'icacy Resultsfor Key Secondary Endpom
`..... 25
`
`3.1.3.4.4 Sponsor ’3 Other Efiicacy Results .................................... 26
`
`..... 28
`3.1.3.4.5 Reviewer ’s Results and Comments ..
`
`3.1.4 Study 1LP3000ST.................................................................................................................................... 28
`3.1.5 Studies ILP3001, ILP3002, ILP3003 ..............................._...................................................................... 29
`3.2
`EVALUATION OF SAFETY ........................................................................................................................... 30
`
`4.
`
`FINDINGS IN SPECIAL/SUBGROUP POPULATIONS .........................................................................30
`
`GENDER,RACE AND AGE .......................................................................................................................... 30
`4.1
`Study 1LP3004ST............................................................................................................................. 30
`4.1.]
`..................................................................................................... 30
`Gender
`4.1.1.1
`
`..... 31
`4.1.1.2 Race.
`
`Age .............................. 31
`4.1.1.3
`
`Study ILP3005ST...
`4.1.2
`31
`
`Gender .................... 31
`4.1.2.1
`..... 32
`4.1.2.2
`Race
`
`Age ......................................... 32
`4.1.2.3
`
`4.1.3
`Study VP—VYV-683—3101.
`33
`
`Gender ................................... 33
`4.1.3.1
`Race» .............................................................................................................................................................. 33
`4.1.3.2
`
`Page 2 01°42
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`

`

`4.1.3.3 Age ........................................................... 34
`OTHER SUBGROUPS.............. 34
`
`Study ILP3004ST............... 34
`U.S.A. versus non-USA............................................................................ 34
`
`Study ILP3005ST.............................................................................. 34
`
`U.S.A. versus non-USA.....
`...... 34
`
`4.2
`4.2.1
`4.2.1.1
`4.2.2
`4.2.2. I
`
`Study VP-VYV-683-3I01 ................................................................................................................. 35
`4.2.3.
`s. ' SUMMARY AND CONCLUSIONS.........................................................................................................35
`
`5.1
`5.2
`
`STATISTICAL ISSUES AND COLLECTIVE EVIDENCE .................................................................................... 35
`CONCLUSIONS AND RECOMMENDATIONS .................................................................................................. 36
`
`6. APPENDIX...................................................................................................................................................... 38
`
`6.1
`6.2
`6.3
`
`STUDY ILP3000ST ...................... ........................................................._..................................................... 38
`STUDY ILP3004ST...........40
`
`
`
`STUDY ILP3OOSST ................................................................................................................................41
`
`Page 3 of 42
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`

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`LIST OF TABLES
`
`Table 1. Dosing schedule for the 6—week initial double-blind phase ....................................................................... 10
`Table 2. Study ILP3004ST: disposition of patients ................................................................................................. 12
`Table 3. Study ILP3004ST: demographic and baseline disease characteristics (randomized sample) .................... 12
`Table 4. Study ILP3004ST: sponsor’s primary efficacy results: change from endpoint to baseline in BPRS total
`score (LOCF) in the MITT sample ........................................................................................................................... 13
`Table 5. Study ILP3004ST: reviewar’s primary efficacy results: change from endpoint to baseline in BPRS total
`score (LOCF) (excluding schizoaffective patients); MITT sample .......................................................................... 13
`Table 6. Study ILP3004ST: Adjusted mean change from baseline up to end of week 6 in the BPRS total score
`(LOCF) (excluding schizoaffective patients); MITT sample ................................................................................... 14
`Table 7. Study ILP3OOSST: disposition of patients ................................................................................................. 16
`Table 8. Study ILP3OOSST: demographic and baseline disease characteristics (randomized sample) .................... 17
`Table 9. Study ILP3OOSST: sponsor’s primary efficacy results: change from endpoint to baseline in BPRS total
`score (LOCF) in the MITT sample ........................................................................................................................... 17
`Table 10. Study ILP3OOSST: Sponsor’s Efficacy Results by genetic subgroups: Change from baseline at. Week 6:
`ANCOVA (LOCF) analysis (PG Population)........................................................................................................... 18
`Table 11. Study ILP3OOSST: Reviewer’s Efficacy Results by genetic subgroups: Change from baseline at Week
`6. ANCOVA (LOCF) analysis (PG Population) ...................................................................................................... 19
`Table 12. Study ILP3OOSST: Reviewer’5 Efficacy Results by genetic subgroups: Change from baseline at Week
`6. ANCOVA (LOCF) analysis (PG Population-Schizophrenia sample) .................................................................. 19
`Table 13. Study ILP3OOSST: reviewer’ s primary efficacy results: change from endpoint to baseline'in BPRS total
`score (LOCF) (excluding schizoaffective patients); MITT sample .......................................................................... 20
`Table 14. Study ILP3OOSST: Adjusted mean change from baseline up to end of week 6 in the BPRS total score
`(LOCF) (excluding schizoaffective patients); MITT sample ................................................................................... 20
`Table 15. Study lLP3OOSST: reviewer’s efficacy results: change from endpoint to baseline in BPRS total score
`(0C) (excluding schizoaffective patients); MITT sample ........................................................................................ 20
`Table 16. Study ILPSOOSST: reviewer’s MMRM results: change from endpoint to baseline in BPRS total score
`(0C) (excluding schizoaffective patients); MITT sample ........................................................................................ 21
`Table 17. Study ILP3OOSST: reviewer’s efficacy results: change from endpoint to baseline in PANSS total score
`(LOCF) (excluding schizoaffective patients); MITT sample ................................................................................... 21
`Table 18. Study lLP3OOSST: reviewer’s efficacy results: change from endpoint to baseline in BPRS total score
`(LOCF) (excluding schizoaffective patients); MITT sample; Pre- versus Post-dose modification .......................... 22
`Table 19. Study VP-VYV-683-3101: disposition of patients (randomized sample) ............................................... 24
`Table 20. Study VP~V Y V—683—3101: demographic and baseline disease characteristics (randomized sample) ..... 25
`Table 21. Study VP-V Y V-683-3101: Sponsor’s Primary Efficacy Results: Change from Baseline in PANSS total
`score in the MITT sample............................................................................................................................ ............. 25
`Table 22. Study VP-VYV—683~3101: Reviewer’s Primary Efficacy Results by genetic subgroups: Change from
`Baseline in PANSS total score in the MITT sample................................................................................................. 26
`Table 23 Study VP—VYV—683-3101: Sponsor’s Efficacy Results: Change from Baseline1n BPRS total score in
`the MITT sample ...................................................................................................................................................... 26
`Table 24. Study VP—VYV—683-3101: Adjusted mean change from baseline up to end of week 61n the PANSS total
`score, MMRM analysis; MITT sample..................................................................................................................... 27
`Table 25. Study VP-VYV-683-3101: Sponsor’s Primary Efficacy Sensitivity Analysis: Change from Baseline in
`PANSS total score in the MITT sample (LOCF).......- ............................................................................................... 27
`Table 26. Study VP-VYV-683—3101: Reviewer’s Efficacy Results by genetic subgroups: Change from Baseline
`in PANSS total score in the MITT sample (LOCF) ................................................................................................. 27
`Table 27. Study VP—VYV-683-3101: Sponsor’s Primary Efficacy Sensitivity Analysis: Change from Baseline in
`PANSS total score in the OC sample........................................................................................................................ 28
`Table 28. Study VP-VYV-683—3101: Reviewer’s Primary Efficacy Results: Change from Baseline in PANSS
`total score in the MI'IT sample (Site #032 excluded) ............................................................................................... 28
`Table 29. Study ILP3004ST: reviewer’s primary efficacy results by gender: change from endpoint to baseline in
`BPRS total score (LOCF) (excluding schizoaffective patients); MITT sample ....................................................... 31
`
`Page 4 of 42
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`Table 30. Study ILP3004ST: reviewer’s primary efficacy results by race: change from endpoint to baseline in
`BPRS total score (LOCF) (excluding schizoaffective patients); MITT sample ....................................................... 31
`Table 31. Study ILP3OOSST: reviewer’ 5 primary efficacy results by gender: change from endpoint to baseline in
`BPRS total score (LOCF) (excluding schizoaffective patients); MITT sample ....................................................... 32
`Table 32. Study ILP3OOSST: reviewer’s primary efficacy results by gender: change from endpoint to baseline in
`BPRS total score (LOCF) (excluding schizoaffective patients); MITT sample ....................................................... 32
`Table 33. Study VP-VYV—683-3101: Reviewer’s Primary Efficacy Results by Gender: Change from Baseline in
`PANSS total score in the MITT sample ................................................................................................................... 33
`Table 34. Study VP-VYV-683-3101: Reviewer’ 5 Primary Efficacy Results by Race: Change from Baseline in
`PANSS total score in the MITT sample ................................................................................................................... 33
`Table 35. Study ILP3004ST: reviewer’ s primary efficacy results by region: change from endpoint to baseline1n
`BPRS total score (LOCF) (excluding schizoaffective patients); MITT sample ....................................................... 34
`Table 36. Study ILP3005ST: reviewer’s primary efficacy results by region: change from endpoint to baseline in
`BPRS total score (LOCF) (excluding schizoaffective patients); MITT sample ........................................................35
`
`Table 37. Study ILPSOOOST: disposition of patients ...............................................................................
`Table 38. Study ILP3000ST: demographic and baseline disease characteristics (randomized sample) .................. 38
`Table 39 Study ILPBOOOST: sponsor’s primary efficacy results: change from endpoint to baseline1n PANSS total
`score (LOCF)1n the MITT sample ........................................................................................................................... 39
`Table 40. Study ILP3000ST: change from endpoint to baselineIn PANSS total score (LOCF)1n the MITT sample
`(excluding schizoaffective patients) ......................................................................................................................... 39
`Table 41. Study ILP3004$T: disposition of patients (excluding schizoaffective patients) .....................................40
`Table 42. Study ILP30043T: demographic and baseline disease characteristics (randomized sample) (excluding
`schizoaffective patients) ...........................................................................................................................................40
`Table 43. Study ILP3OOSST: disposition of patients (randomized schizophrenia subsample) ................................ 41
`Table 44. Study ILP3005 ST: demographic and baseline disease characteristics (randomized schizophrenia
`subsample) ................................................................................................................................................................41
`Table 45. Study ILP3OOSST: reviewer’s efficacy results: change fiom endpoint to baseline in BPRS total score
`(LOCF) (excluding schizoaffective patients); MITT sample, risperidone—referenced..............................................41
`Table 46. Study ILP3005ST: demographic and baseline disease characteristics (MITT schizophrenia subsample
`stratified by the date of treatment arms modification) .............................................................................................. 42
`
`Page 5 of 42
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`

`

`1.
`
`EXECUTIVE SUMMARY
`
`1.1 Conclusions and Recommendations
`
`The sponsor submitted four short-term studies and three long-term studies to seek claims
`for efficacy and safety of iloperidone in the treatment of adult schizophrenia. Efficacy for
`the schizophrenia subsample was demonstrated fiom two studies: ILP3005ST and VP—
`VYV—683—3 101. The efficacy in study ILP3005ST was demonstrated by the change fiom
`baseline to Week 6 in the Brief Psychiatric Rating Scale (BPRS) total score. The efficacy
`in study VP-VYV-683-3101 was demonstrated by the change from baseline to Week 4 in
`the Positive and Negative Syndrome Scale (PANSS) total score.
`.
`
`In study ILPSOOSST, the PANSS total score, PANSS positive subscale, PANSS negative
`subscale, CGI severity scale, and CGI improvement scale were not pie-specified. They
`only serve exploratory purposes and do not support labeling claims.
`
`In study VP-VYV-683—3 101, the BPRS total score, PANSS positive subscale, PANSS
`negative subscale, CGI severity scale, and CGI improvement scale were not pre-specified.
`They do not support labeling claims.
`
`Study ILP3000ST was considered negative based on the primary hypothesis. All labeling
`efficacy claims with respect to this study were not justified.
`
`The findings based on the genetic subgroup that the treatment benefit was enhanced among
`patients carrying the CNTF FS63Ter (—/—) genotype were suggestive, but not conclusive to
`support labeling claims.
`
`The long—term non—inferiority claim based on studies ILP3001, ILP3002, and ILP3003 did
`not have a regulatory merit given the designs and analyses of these studies.
`
`1.2 Brief Overview of Clinical Studies
`
`.
`
`Study ILP3000ST was a randomized, double-blind, placebo—controlled, parallel-group,
`multi-center, United States study. The study investigated three doses: iloperidone 4
`mg/day, 8 mg/day, and 12 mg/day. The study also included haloperidol (15 mg/day) for
`assay sensitivity. The duration of the double-blind phase was 42 days. Six hundreds and
`twenty one subjects between‘the age of 18 and 68 were randomized. The primary efficacy
`variable was the change from baseline to Day 42 in the PANSS total score. The primary
`hypothesis was the combined 8 mg/day and 12 mg/day against placebo.
`
`Study ILP3004ST was a randomized, double-blind, placebo-controlled, parallel—group,
`multi-center, international study. The duration of the double—blind phase was 42 days. Six
`hundreds and sixteen subjects from the age of 17 to 67 were randomized to either
`iloperidone 4-8 mg/day, ilopen'done 10-16 mg/day, risperidone 4-8 mg/day, or placebo.
`The primary efficacy variable was the change from baseline to Day 42 in the BPRS total
`score.
`
`Page 6 of 42
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`

`

`Study ILPBOOSST was a randomized, double-blind, placebo-controlled, parallel-group,
`multi—center, international study. Two dose groups of iloperidone were investigated: 12-16
`mg/day and 20-24 mg/day. The study also included risperidone 6-8 mg/day for assay
`sensitivity. The initial randomization scheme was a 2: 1 :1 ratio (iloperidone 12-16 mg/day,
`risperidone 6—8 mg/day, and placebo, respectively). The decision to include the high dose
`group (iloperidone 20-24 mg/day) occurred after the initiation of the study and was
`depended on the outcome of study ILP3004ST. With the addition of the iloperidone 20-24
`mg/d, patients were randomized in a ratio of 1:2: 1 :1 to iloperidone 12—16 mg/day,
`iloperidone 20-24 mg/day, risperidone, or placebo, respectively. Subjects in the study were
`between 18 and 65 years old. Seven hundreds and six (706) subjects were randomized.
`The primary efficacy variablewas the change from baseline to Day 42 in the BPRS total
`score.
`-
`
`Study VP-VYV-683—3 101 was a randomized, double-blind, placebo-controlled, parallel-
`group, multi—center study. Six hundreds and six subjects (606) between the age of 18 and
`65 from India and the United States were randomized. The randomized ratio was 2:121 to
`iloperidone 24 mg/day, ziprasidone 160 mg/day, or placebo, respectively. The double-blind
`phase lasted for four weeks. The primary endpoint was the change from baseline to Week 4
`in the PANSS total score.
`'
`
`Studies ILP3001, ILP3002, ILP3003 were randomized, multi-center, double-blind, active-
`controlled, flexible dose studies. Subjects were randomized in a 3:1 ratio to receive either
`iloperidone 4-16 mg/day or haloperidol 5-20 mg/day. The duration of the study was 52
`weeks. The primary hypothesis Was the non-inferiority of iloperidone versus haloperidol in
`the time to relapse based on a pooled analysis of these three studies.
`'
`
`Study ILP3000ST was deemed negative from a regulatory perspective. Studies ILP3001,
`ILP3002, ILP3003 had serious flaws in the design that made the interpretation difficult.
`Except study VP-VYV-683-3101, all above-mentioned studies included both schizophrenia
`and schizoaffective patients. Because the indication sought is schizophrenia, this review
`will focus on the schizophrenia efficacy evaluation of studies ILP3004ST, ILP3OOSST, and
`VP-V Y V-683~3101.
`
`1.3 Statistical Issues and Findings
`
`The sponsor submitted four short—term studies and three long-term studies. Except study
`VP-V Y V-683-3101, all studies included both schizophrenia and schizoaffective patients.
`The sponsor claimed all four studies demonstrated at least one positive dose against
`placebo. However, based on the primary hypotheses, only one study was positive for the
`schizophrenia and schizoaffective population: Study ILP3004ST.
`
`On the other hand, when considering the schizophrenia sample only, study ILP3004ST was
`no longer positive. Instead, studies ILP3005 ST and VP—VYV-683-3101‘ were positive.
`
`Study VP-V Y V—683-3 101 evaluated the dose 24 mg/day. Study ILP3OOSST evaluated two
`dose groups: 12-16 mg/day and 20-24 mg/day. Although both dose groups showed
`
`Page 7 of 42
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`

`

`statistical signficance against placebo based on the priar analysis, evidence for the high
`dose group (20-24 mg/day) appeared stronger than for the dose group 12-16 mg/day. The
`dose group 20-24 mg/day seemed to have a larger numerical treatment difference against
`placebo than the dose group 12-16 mg/day. Though study ILP3005ST was not designed to
`control (risperidone) to iloperidone, numerical evidence suggested that
`the active control resulted in a larger treatment effect than the low dose group (see
`Appendix, Table 45). In addition, in study ILP3004ST, the dose group 10-16 mg/day did
`not separate from placebo.
`
`compare the active
`
`several limtations. Currently, the Division
`
`The thee long-term studies were active control, non-inferior studies. These studies faced
`of Psychiatr does not consider a non-inerior,
`active-controlled study as an appropriate design for the schizophrenia indication.
`Originally, the study was planed for an analysis of change from baseline to endpoint in the
`P ANSS total score. However, durg the interactions with the European Medicines
`Evaluation Agency, the analysis was changed to a tie to recurence of
`schizophrenia/schizoaffective symptoms. The analysis population wàs also amended to
`reflect the new efficacy endpoint. The effcacy evaluations were based on the pooled data
`from studies ILP3001, ILP3002, and ILP3003. More importantly, only patients who
`responded at Day 42 were included in the analysis population of the long-term-
`maintenance. Thus the randomization may be compromised. Furermore, the poolig of
`studies for effcacy evaluation is not the curent standard practice of the Division of
`Psychiatr. In addition, these studies did not include a placebo ar that made the
`the long-term
`
`inteTJretation difficulty for ths indication. For these reasons, the value of
`
`effcacy claim is dimshed.
`
`Several secondar endpoints (BPRS, P ANSS positive subscale, P ANSS negative subscale,
`CGI Improvement, CGI-Severity) were claimed. However, they were not pre-specified and
`thus can only serve as exploratory findings.
`
`The findings on the CNTF FS63Ter subgroup were suggestive, but not conclusive to
`support labeling claims for the following reasons: 1) in study VP-VY-683-3101, the
`findings suggested a greater treatment effect in the CNTF (-) subgroup; however, in the
`CNTF (+) subgroup, the treatment benefit appeared vanished; 2) in study ILP3005ST, an
`exploratory analysis was performed on the CNTF genotye subgroup, the findings in study
`ILP3005ST were not consistent with the findings in study VP- VY -683-3101: numerical
`improvements were seen in both CNTF subgroups; 3) an analysis based on study
`ILP3005STwas post-hoc. Thus, the findings on study VP-VYV-683-3101 regarding the
`CNTF subgroup have not been replicated.
`
`Study ILP3005ST was an international study. The numerical treatment effects observed for
`the two iloperidone dose groups were marginal for the United States (U.S.) patients and
`the treatment effects seen in the non-U.S. patients. However, study
`VP-VY-683-3101 was a predomiant U.S. study and it was positive.
`
`were about one-fift of
`
`Page 8 of42
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`

`

`2.
`
`INTRODUCTION
`
`2.1 Overview
`
`This review provides a statistical evaluation of iloperidone in the treatment of
`schizophrenia.
`
`According to the sponsor, iloperidone is a new chemical entity belonging to the chemical
`class of piperidinyl-benzisoxazole derivatives. The clinical development of iloperidone
`was initiated by Hoechst Marion Roussel (HMR) in 1990. Norvatis Pharmaceuticals
`licensed iloperidone in 1998 and continued its development program. In 2004, Vanda
`Pharmaceuticals Inc. licensed iloperidone and continued its clinical development program.
`This submission contains clinical studies from all three sponsors.
`
`Schizophrenia is a common disorder affecting approximately 1% of the population. The
`characteristics of the illness include both the positive symptoms (for example,
`hallucinations and delusions) and negative symptoms (for example, apathy, blunted affect
`and social withdrawal) as well as Cognitive impairment (for example, attention deficit,
`learning and memory). The illness is also lethal with an estimate of more than 10% of
`patients with schizophrenia completing suicide in their lifetime. The costs of schizophrenia
`in terms of care and} lost of productivity place a high social and financial burden on the
`patient, family, and community. -
`
`According to the sponsor, none of the currently available treatment for schizophrenia is
`curative and there remains a significant unmet medical need. It is estimated that
`approximately 75% of the patients discontinue their medication within 18—month period for
`both lack of efficacy and side effects. The most common and worrisome side effects of the
`available antipsychotics‘are weight gain, diabetes, extrapyramidal symptoms, prolactin
`elevation, sedation, and QT prolongation.
`
`In this application, the sponsor submitted four short—term studies and three long term
`studies in order to demonstrate the efficacy and safety of iloperidone in the treatment of
`schizophrenic adult patients. The four short—term phase III studies were ILP3000ST,
`ILP3004ST, ILP3005 ST, and VP—VYY—683-3 101. The three long-term studies were
`ILP3001, ILP3002, and ILP3003.
`
`Except study VP-VYY—683-3101, all studies mentioned above included both schizophrenia
`and schizoaffective patients. Because the indication for this application is schizophrenia,
`this review will differentiate the schizophrenia samples and the (schizophrenia +
`schizoaffective) samples.
`
`2.2 Data Sources
`
`The sponsor’s submitted data are stored in the following directory of the CDER’s electronic
`document room:
`
`\\Cdsesub1\evsprod\NDA022192\0000.
`
`Page 9 of 42
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`

`

`3.
`
`STATISTICAL EVALUATION
`
`3.1 Evaluation of Efficacy
`3.1.1
`Study ILP3004ST
`
`3.1.1.1 Objecfz'ves
`
`Primafl: The objective of the initial double-blind phase (6 weeks) was to evaluate
`the efficacy and safety of two non-overlapping dose ranges of iloperidone (4-8
`mg/d, administered as 2-4 mg twice daily, and 10—16 mg/d, administered as 5-8
`mg twice daily) and risperidone 4-8 mg/d (administered as 2-4 mg twice daily)
`compared with placebo, over 42 days in patients with an acute or subacute
`exacerbation of schizophrenia or schizoaffective disorder.
`
`Secondag: Secondary objectives of the study include:
`- To evaluate the effects of iloperidone on neurocognitive function
`- To measure the impact of iloperidone on resource utilization
`-
`To explore the relationship of certain genotypes and treatment effect
`
`3.1.1.2 Study Design
`
`This was a prospective, international, randomized, double-blind, parallel—group,
`multi-center study with three phases: pre—randomization, initial double-blind, and
`long-term double-blind. The pre-randomization phase consisted of a screening
`period and a placebo run-in period. The placebo run-in period lasted 3 days. For
`patients who showed clinical improvement compared to screening, the placebo
`run-in phase was extended (up to an additional 7 days) until the patient’s
`psychiatric status returned back to a level comparable to that at screening. The
`initial 6—week double-blind phase consisted of titration (days 1-7) and
`maintenance periods (days 8-42). In the titration period, subjects were titrated to
`the target dose. In the maintenance period, flexible dosing regimens were
`administered within the target dose ranges. The treatment arms were iloperidone
`4-8 mg/d, iloperidone 10-16 mg/d, risperidone 4-8 mg/d, and placebo. The dosing
`schedule is summarized in Table 1.
`
`Table 1. Dosing schedule for the 6—week initial double-blind phase
`
`5mg!!!
`
`
`Titration
`target dose
`
`(m9)
`Titration period
`
`
`
`Flexlble maintenance dosing period (Days 8-42)
`Datho42
`4/Aor
`20f
`GIBor
`30r
`8/0
`4
`
`P=placebo
`
`1DIAot
`12IB or
`16/0
`
`5m
`Bot
`5
`
`50!
`60:
`8
`
`(Source: lLP3004st-Iegacy Report; Table 3-3, page 30)
`
`Page 10 of 42
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`

`Subjects between 18-65 years old were enrOlled from June 1999 to May 2000.
`Eligible patients were those who met the Diagnostic and Statistical Manual of
`Mental Disorders, 4111 Edition (DSM-IV) of schizophrenia with suffixes 10
`(disorganized), 30 (paranoid), 70 (schizoaffective), or 90 (undifferentiated); had a
`total PANSS score of at least 60 at screening and baseline; had a PANSS item
`score of at least 4 (“moderate”) on at least 3 of the following 5 symptoms:
`.
`delusions, conceptual disorganization, hallucinatory behavior, grandiosity, and
`suspiciousness/persecution. Originally, the primary efficacy variable was the
`PANSS total score. Under protocol amendment 2 (November, 1999), the primary
`efficacy variable was revised to the 18-item PANSS-derived BPRS score.
`Primary efficacy was assessed at screening, baseline, and on Days 7, 14, 21, 28,
`35, and 42 or the last visit before discontinuation.
`
`It was determined that 150 patients per arm were needed for an 80% power and
`with a two-sided alpha = 0.05 to detect a 4-point difference in the BPRS total
`score, with a standard deviation of 12 (source: protocol amendment 2).
`
`3.1.1.3 Efiicacy Endpoints and Analyses
`
`Primm endpoint and analysis: The primary endpoint was the change from
`baseline to Day 42 (or premature discontinuation) on the 18—item PANSS-derived
`BPRS score. The primary analysis model was an analysis of covariance
`(ANCOVA) with terms for treatment, center, baseline (as covariate), and the
`treatment-by-baseline interaction. Missing values were imputed by the Last-
`Observation—Carried—Forward (LOCF) method. To control for multiplicity in the
`analysis, a sequential testing procedure was employed. First, a comparison was
`carried out between the 10—16 mg/d group and the placebo group. If this test was
`significant at the 0.05 level, a subsequent pairwise comparison of the iloperidone
`4-8 mg/d group with placebo would be tested at the 0.05 level (source: protocol
`amendment 2).
`
`3.1.1.4 Eflicacy Results
`
`3.1.1.4.] Study Population
`S