O
`
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`Novartis Pharmaceuticals Corporation
`East Hanover, New Jersey
`
`Clinical Development
`
`Compound/Project:
`
`Iloperidone/C|LO522A
`
`Study No: |LO522 2328
`
`A randomized, open-label, multicenter, 5-arm, safety study
`evaluating the effect of oral iloperidone at doses of 8 mg
`b.i.d., 12 mg b.i.d., and 24 mg q.d. on QTc interval duration in
`the presence and absence of metabolic inhibition, relative to
`other antipsychotics (ziprasidone 80 mg b.i.d, and quetiapine
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`Dr.MichaelLesem,Dr.'FhemasrShiev4tz,Dr.'Fram'Fran-
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` ':
`
`Decumentstatus:
`
`Final Reba
`
`C
`
`without the consent of NovartisPharmaceuticals Corporation
`
`VND7\_0265‘l 456
`
`Vanda Exhibit 2032 - Page 1
`
`
`
`S
`
`Novartis Pharmaceuticals Corporation
`East Hanover, New Jersey
`
`Clinical Development
`
`Compound/Project:
`
`Iloperidone/C|LO522A
`
`Study No: |LO522 2328
`
`A randomized, open-label, multicenter, 5-arm, safety study
`evaluating the effect of oral iloperidone at doses of 8 mg
`b.i.d., 12 mg b.i.d., and 24 mg q.d. on QTc interval duration in
`the presence and absence of metabolic inhibition, relative to
`other antipsychotics (ziprasidone 80 mg b.i.d, and quetiapine
`375 mg b.i.d., in the presence and absence of metabolic
`u
`u
`0‘-H -
`-
`‘Vi; “‘i3i‘i“i"
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`
`schizophrenia or schizoaffective disorder
`
`
`
`9
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`
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`-.--H- B,XHJ
`
`-
`
`type: wmasmw
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`
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`
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`
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`Dr.MichaelLesem,Dr.'FhemasrShiev4tz,Dr.'Fram'Fran-
`Jehnsenetal.
`
` ':
`
`Decumentstatus:
`
`Final Reba
`
`C
`
`without the consent of NovartisPharmaceuticals Corporation
`
`VND7\_0265‘l 456
`
`Vanda Exhibit 2032 - Page 1
`
`
`
`Novartis
`Clinical Stud Re ort
`
`Confidential
`
`Stud No.
`
`2
`Page
`lLO522 2328 abbreviated
`
`Table of contents
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`Clinical Study Report .
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`Ethics and Good Clinical Practice .
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`3.1 Overall study design .
`3.1.1 Pre-treatment phase .
`3.1.2 Treatment phase .
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`3.3.2 Inclusion and exclusion criteria .
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`15.2 Efiicacyassessments
`353 Safety assessmems
`3.5.41 Drug levels and .
`4 Protocol amend ih study C6FlEH:lCt .
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`4.2 Other changes In study conduct
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`5 Data management .
`51 Data collection
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`48
`
`VND7\_0265‘l 457
`
`Vanda Exhibit 2032 - Page 2
`
`
`
`Novartis
`Clinical Stud Re ort
`
`Confidential
`
`Stud No.
`
`3
`Page
`lLO522 2328 abbreviated
`
`6.1.2 Background and demographic characteristics .
`6.1.3 Study medication .
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`7.1 Patient disposition .
`7.2 Protocol deviations .
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`7.3 Groupings for analysis .
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`8 Medication .
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`8.1.3 Drug level and pharmacokinetic data .
`8.2 Concomitant medication .
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`9.2.1 Mean change In QTC from baseline to steady state at Tmax
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`9.3.2 Drug cem .
`19 Safety results .
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`9.2.3 Number of patients (%) with QTc values of > 500 msec at Tmax
`9.2.4 Additional analysis .
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`’L(L2_1 Seriousadverse events QSAEs7L
`10722 Other
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`VND7\_0265‘l 458
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`Vanda Exhibit 2032 - Page 3
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`
`
`Novartis
`Clinical Stud Re ort
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`Confidential
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`Stud No.
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`4
`Page
`lLO522 2328 abbreviated
`
`10.2.3 Evaluation of deaths and other serious or significant adverse
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`10.3.2 Frequency of abnormalities based on extended normal range .
`10.3.3 Frequency of abnormalities based on clinically notable criteria
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`11 Discussion and overall conclusions .
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`12 Reference list
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`89
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`VND7\_0265‘1 459
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`Vanda Exhibit 2032 - Page 4
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`
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`Novartis
`Clinical Stud Re ort
`
`Confidential
`
`Stud No.
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`5
`Page
`|LO522 2328 abbreviated
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`List of Text Figures
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`Figure 9-1 Mean QTC (Fridericia) change (95%C|) from baseline to steady state
`at TMAX* during Treatment Period 1 (Primary QTC population) .
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`Figure 9-2 Mean QTC (Fridericia) Change (95%C|) from baseline to steady
`state at TMAX* during Treatment Periods 1, 2, and 3 (Secondary QTC
`Population) .
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`Figure 10-1 Pulse (3-minute sitting) over time by treatment \ Safety population .
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`Figure 10-2 Mean systolic blood pressure over time by treatment \ Safety
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`VND7\_0265‘l 460
`
`Vanda Exhibit 2032 - Page 5
`
`
`
`Novartis
`Clinical Stud Re ort
`
`Confidential
`
`Stud No.
`
`6
`Page
`|LO522 2328 abbreviated
`
`List of Text Tables
`
`Table 3-1 Study Design (Pre-treatment phase) .
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`Table 3-2 Study Design (Treatment phase) .
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`Table 3-5 Dosing schedule for iloperidone .
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`Table 7-2 Number of patients in analysis populations by treatment group .
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`Table 9-1 Summary statistics of QTC change (95% CI) from baseline to steady
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`Table 9-2
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`Table 9-4 Averagea peak concentrations and ratios of average peak
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`Table 10-1 Number (%) of patients with AEs. overall and by body system
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`Table 10-2 Number (%) ''
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`VND7\_0265‘l 461
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`Vanda Exhibit 2032 - Page 6
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`Novartis
`Clinical Stud Re ort
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`Confidential
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`Stud No.
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`7
`Page
`lLO522 2328 abbreviated
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`Table 10-4 Patients with serious adverse events (SAEs) (Safety population). .
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`10.3.3 Frequency of abnormalities based on clinically notable criteria (also
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`10.4.2 Frequency of abnormalities based on clinically notable criteria (also
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`Table 10-7 Number (%) of patients with clinically notable values for sitting
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`Table 10-8 Number (%) of patients with clinically notable values for weight and
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`newly eccerring or
`Table 10-10 '
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`Vanda Exhibit 2032 - Page 7
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`Novartis
`Clinical Stud Re ort
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`Confidential
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`Stud No.
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`8
`Page
`lLO522 2328 abbreviated
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`Table of contents
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`Post-text supplement 1 (Criteria for clinically notable laboratory values,
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`Post-text supplement 2 (Patient narratives) .
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`2.2.1 Death .
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`2.2.3 Other clinically significant events .
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`2.3 Listing of patients for whom narratives are provided .
`24 Patient narratmes for deaths
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`2.7 Pafient narrafives wfih newly occurring or worsening ECG abnormalifies
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`3.5 Safety results 16) .
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`Post-text figures (PTF) .
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`Stud No.
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`9
`Page
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`Post-text tables (PTT) .
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`Post-text listings (PTL) .
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`Clinical Stud Re ort
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`Confidential
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`Stud No.
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`Page 10
`lLO522 2328 abbreviated
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`Table of contents
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`Appendix 1: Study information (Protocol and protocol amendments,
`information for patients and sample consent form, sample case report
`form) .
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`Table of Contents Appendix 1 .
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`1.1 Protocol and protocol amendments .
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`1.3 Sample case report form .
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`Appendix 2: Study center information (List of |ECsl|RBs, information on
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`2.1 List of Independent Ethics Committees or Institutional Review Boards. .
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`2.2 Information on Investigators .
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`Appendix 3: Standardization and quality assurance (Laboratory quality
`assurance (QA) procedures, inter-laboratory standardization methods). .
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`3.1 Laboratory quality assurance (QA) procedures .
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`3.2 Inter-laboratory standardization methods .
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`Appendix 4: Publications (Publications reporting study results) .
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`Appendix 5: Statistics and randomization (Statistical methods,
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`Table of ContenIs.Appendix i
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`Appendix 6: Case Report Forms for Deaths, Serious Adverse Events,
`Adverse Event Withdrawals .
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`aeo on ens ppenix .
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`7.1 Selected patient listings .
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`7.2 US archival listings .
`‘ee--e : ‘eee-
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`tables, Other topics) .
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`Table of Contents Appendix 8 .
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`VNDA_0265‘l 465
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`Vanda Exhibit 2032 - Page 10
`
`
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`Novartis
`Clinical Stud Re ort
`
`Confidential
`
`Stud No.
`
`Page 11
`|LO522 2328 abbreviated
`
`8.1 Supplementary figures and tables .
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`8.2 Other topics .
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`VND7\_0265‘1 466
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`Vanda Exhibit 2032 - Page 11
`
`
`
`Novartis
`Clinical Stud Re ort
`
`Confidential
`
`Stud No.
`
`Page 12
`ILO522 2328 abbreviated
`
`Signatu res
`
`Authors:
`
`Bryan Campbell, Pharm.D.
`
`(Clinical Trial Leader)
`
`signature
`
`date
`
`Jane Xu, Ph.D.
`
`(Trial Statistician)
`
`signature
`
`date
`
`I certifv that this report accuratelv describes the conduct and the results of this clinical studv.
`
`Rec<;oZaninelli,MD
`
`VND7\_0265‘1 467
`
`Vanda Exhibit 2032 - Page 12
`
`
`
`Novartis
`Clinical Study Report
`
`Confidential
`
`Study No.
`
`Page 13
`ILO522 2328 (abbreviated)
`
`Study personnel
`
`Investigators and centers
`
`A list of all investigators and centers can be found in Appendix 2.2.
`
`Key Novartis personnel
`
`Clinical Program Leader
`
`Rocco Zaninelli, M.D.
`
`Clinical Trial Leader
`
`Bryan Campbell, Pharm.D.
`
`Trial Biostatistician
`
`Jane Xu, Ph.D.
`
`Medical Data Manager
`
`Stacy Sabo, B.S.
`
`Clinical Data Programmer
`
`Seth DeWacker, B.S.
`
`Clinical Research Physician
`
`Mila Etropolski, M.D.
`
`Medical Writer
`
`Christine Larsen, R.N., M.A.
`
`Laboratory analysis; Interactive
`Voice Response System (IVRS)
`
`Covance Central Laboratory Services, Inc.
`8211 SciCor Drive, Indianapolis, IA 46214 US
`& 210 Carnegie Center, Princeton, NJ 08540
`
`ECG database compflation
`
`eResearch Technology (eRT)
`(formerly Premier Research Worldwide, PRW)
`30 South T7th Street, Philadelphia, P7X TQTOB US
`
`VND7\_0265‘l 468
`
`Vanda Exhibit 2032 - Page 13
`
`
`
`Novartis
`Clinical Stud Re ort
`
`Confidential
`
`Stud No.
`
`Page 14
`ILO522 2328 abbreviated
`
`List of abbreviations
`
`0Ll,2
`
`alpha adrenergic receptor, subtypes 1 and 2
`
`SHT2, 2A, 6
`AE
`
`5-hydroxytryptamine (serotonin) receptor, subtypes 2, 2A, and 6
`Adverse event
`
`ALT
`
`a.m.
`
`AST
`
`Alanine aminotransferase, SGPT, glutamic pyruvic transaminase
`
`ante meridian (Latin: bcforc noon)
`
`Aspartate aminotransferase, SGOT, glutamic oxaloacetic transaminase
`
`[3—hCG
`
`Human chorionic gonadotropin (beta subunit)
`
`b.i.d.
`
`BMI
`
`BP
`
`b.p.m.
`
`BUN
`
`CGI—S
`
`CPK
`CR
`
`bis in die (Latin: twice a day)
`
`body mass index
`
`blood pressure
`
`beats per minute
`
`Blood urea nitrogen
`
`Severity of Illness scale of the Clinical Global Impression
`
`Creatine phosphokinase
`Clinical Research
`
`CRO
`
`CS&E
`
`CTL
`
`DAR
`BSMJV
`
`DNDP
`
`ECG
`
`eCH
`
`FDA
`
`Clinical ‘‘
`
`Clinical Trial/Study Leader
`
`_i _
`
`Division of Neuropharmacological Drug Products
`
`Electrocardiogram
`
`E=lectrorric*Case Report/Record Form
`
`Food and Drug Administration
`
`HbcAb v
`
`HbsAg
`HIV
`
`ICH
`
`IEC
`
`ILO
`IRB
`
`IVRS
`
`LDH
`
`Hepatitis B surface antigen
`H man imm n
`ii i n
`
`i
`
`Independent Ethics Committee
`
`Iloperidone
`
`Interactive Voice Response System
`
`Lactate dehvdrogenase
`
`NYHA
`
`New York Heart Association
`
`VND7\_0265‘1 469
`
`Vanda Exhibit 2032 - Page 14
`
`
`
`Novartis
`Clinical Stud Re ort
`
`Confidential
`
`Stud No.
`
`Page 15
`ILO522 2328 abbreviated
`
`PD
`PK
`
`p.m.
`
`p.o.
`
`p.r.n.
`
`q.d.
`
`QT
`
`QTc
`
`Phamiacodynamics
`Pharmacokinetics
`
`post meridian (Latin: after noon)
`
`per as (Latin: by mouth, orally)
`
`pro re nata (Latin: as needed)
`
`Quaque die (Latin: every day)
`
`the QT interval of the ECG Waveform
`
`Corrected QT value
`
`QTCF, QTCB
`
`Fridericia and Bazett corrections of QT duration
`
`QUET
`REB
`
`RIS
`SAE
`
`SC
`
`SGOT
`
`SGPT
`
`Quetiapine
`Research Ethics Board
`
`Risperidone
`Serious adverse event
`
`Study completion
`
`Serum glutamic-oxaloacetic transaminase (also AST, aspartate
`aminotransferase)
`
`Serum glutamic-pyruvic transaminase (also ALT, alanine
`aminotransferase)
`
`SOP procedure
`
`SSD 1, 2 ancF3
`
`Steady-State Day(s) l, 2 and 3
`
`Tum
`
`ULN
`US
`
`WHO
`
`The time at which maximum blood concentrations are reached
`
`Upper limit of normal range
`Unitedstates
`
`World Health Organization
`
`ZH’ Z
`
`VND7\_0265‘1 470
`
`Vanda Exhibit 2032 - Page 15
`
`
`
`Novartis
`Clinical Stud Re ort
`
`Confidential
`
`Stud No.
`
`Page 16
`ILO522 2328 abbreviated
`
`Study synopsis
`
`Name of finished product: To be determined
`
`Name of active ingredient:
`
`Iloperidone
`
`Title of study: A randomized, open-label, multicenter, 5-arm, safety study evaluating the effect of oral
`iloperidone at doses of 8 mg b.i.d., 12 mg b.i.d., and 24 mg q.d. on QTc interval duration in the
`presence and absence of metabolic inhibition, relative to other antipsychotics (ziprasidone 80 mg b.i.d,
`and quetiapine 375 mg b.i.d.,
`in the presence and absence of metabolic inhibition),
`in otherwise
`healthy patients diagnosed with schizophrenia or schizoaffective disorder
`
`Investigators: Dr. Mohammad Alam, Dr. Jeffrey Borenstein, Dr. David Brown, Dr. John Carman, Dr.
`Ram Gopalan, Dr. Michael Lesem, Dr. Rick Mofsen, Dr. Steven Potkin, Dr. Sheldon Preskorn, Dr.
`Thomas Shiovitz, Dr. Tram Tran-Johnson, Dr. Craig Wronski
`
`Study center(s): 12 centers in the US enrolled patients
`
`Pub|ication(s): No publications have been written/are planned at this time.
`
`Study period: First patient enrolled: 27-Nov-01
`
`Last patient completed: 03-May-02
`
`Development phase: Ila
`
`Objectives: The primary objective of this study was to characterize the effect of iloperidone (at 8 mg
`b.i.d. and 12 mg b.i.d.) on the duration of the QTc interval in patients diagnosed with schizophrenia or
`schizoaffective disorder.
`
`The secondary objectives of this study were:
`
`- ---- -- ---- e
`2
`dose,
`
`0
`
`0
`
`to evaluate the effect of floperidone on QTc interval duration in the presence of inhfbflors of
`1
`o'o- so - " - .'oo
`
`to evaluate the concentration—effect relationship of iloperidone and its primary metabolite (PS8), on
`QTc interval duration,
`
`= =:-e=--
`-- ---
`= =--e.-
`9 g-I9 e g e_g Anrnenrn
`' 5.9!‘: e_:,eI: gne _e: can:
`'o- col‘ Av
`-no -o
`on ' out. on
`
`,9, :9 09-Jan-2002,
`
`
`
`This study had 2 phases:
`
`1) Pre-treatment Phase. consisting of a Screening Period (Day -30 to -12). a Taper Period (Day -12 to
`-5), and a Washout/Baseline Period (Day -4 to 0). Patients were randomized in a ratio of 1:1:1:1:1 to
`receive iloperidone 8 mg b.i.d.,
`iloperidone 12 mg b.i.d,
`iloperidone 24 mg q.d., ziprasidone 80 mg
`b.i.d., or quetiapine 375 mg b.i.d. Randomization was stratified based on gender in order to assure
`equal distribution of males and females in each treatment arm. Basefine ECGs were conducted over 3
`days (‘Day -2, 1, 0).
`
`2) Treatment Phase, consisting of 3 treatment periods: Treatment Period 1 (dose titration and steady
`state without metabolic inhibition), Treatment Period 2 (addition of
`1 metabolic inhibitor), and
`Treatment Period 3 (addition of a second metabolic inhibitor to the iloperidone groups). During
`Treatment Period 1, patients followed fixed dosing regimens to achieve the target dosage of their
`
`VND73t_0265‘1 471
`
`Vanda Exhibit 2032 - Page 16
`
`
`
`
`
`
`
`;
`:
`I
`ZQOQFEQO
`251
`'
`.0‘ 01.1:
`.
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`0 -.on-
`
`m of uetiaine' zirasidone sulied as Geodon® was formulated as a casule containin 20 40
`80, or 80 mg of ziprasidone. Batch numbers and National Drug Code (NDC) numbers for the reference
`therapies were as follows:
`
`Product
`.o-
`III
`' o-our
`
`.!Tl!IT In 49?
`'
`II! tablets
`
`Ziprasfilone 20 mg capsules
`(HOTKDTD
`Zprasfione 40 mg capsules
`O414K01 E
`Ziprasidone 60 mg capsules
`O891KOOD, 1132KO1A
`Ziprasidone 80 mg capsules
`|_E”.,
`2..
`
`,
`
`U019-31370-60
`0049-3980-60
`0049-3990-60
`
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