Conditions: Bipolar I Disorder
Allocation: RANDOMIZED | Intervention model: PARALLEL
Enrollment: 417
Healthy volunteers: no

Brief summary:
The aim of this study is to investigate the efficacy, safety, and tolerability of iloperidone compared with placebo in treating acute manic or mixed episodes associated with Bipolar I Disorder.

Detailed description:

Arms:
arm 1: None arm 2: None

Interventions: intervention 1: Iloperidone intervention 2: Iloperidone Placebo
Intervention descriptions: intervention 1: Oral iloperidone intervention 2: Oral placebo

Protocol document:
Prot_SAP_000.pdf: 


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1. 
SYNOPSIS 
Name of Sponsor/Company:  Vanda Pharmaceuticals Inc. 
Name of Investigational Product:  iloperidone 
Name of Active Ingredient: iloperidone, VYV-683 
Title of Study: A multicenter, randomized, double-blind, placebo-controlled study to evaluate the 
efficacy and safety of iloperidone for 4 weeks in the treatment of patients with acute manic episodes 
associated with Bipolar I Disorder  
Study center(s): Approximately 50 sites across the U.S. and Europe  
Studied period (years):  
Estimated date first patient enrolled: March 2021 
Estimated date last patient completed (through the Short-Term 
Treatment Phase): May 2022 
Phase of development:  
Phase III 
Number of patients (planned): 400 (200 iloperidone and 200 placebo) 
Diagnosis and main criteria for inclusion:  
• 
Meet the Diagnostic and Statistical Manual of Mental Disorder, Fifth Edition (DSM-5) 
diagnosis of bipolar I disorder, manic or mixed type, as confirmed by the Structured 
Clinical Interview for Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition 
(SCID) manic or mixed type with or without psychotic symptoms 
• 
Men and women between the ages of 18-65 years inclusive 
• 
Had at least one prior documented manic or mixed episode (with or without psychotic 
symptoms) that required treatment prior to screening 
• 
Patients with Young Mania Rating Scale (YMRS) total score ≥ 20  
• 
Patients with ≥ 4 on at least 2 of 4 YMRS items (irritability, speech, content, 
disruptive/aggressive behavior) 
• 
Patients with Montgomery-Asberg Depression Rating Scale (MADRS) total score < 18 
• 
Voluntarily hospitalized for current manic episode 
Main Exclusion Criteria: 
• 
Patients with a DSM-5 diagnosis other than bipolar I disorder that was the primary focus 
of treatment within the previous six months 
• 
Patients experiencing a first manic episode or meeting criteria for rapid cycling  
Investigational product, dosage and mode of administration:  
Iloperidone will be provided as overencapsulated tablets containing either 1, 3, 6, 9, or 12 mg. 
Duration of treatment:   
Short Term Double-Blind Treatment Phase (4 weeks) 
Titration Period – 1 week 
Double-Blind Treatment Period – 3 weeks 


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Optional Open-Label Extension Phase (52 weeks) 
Open-label Titration  Period – 1 week 
Open-label Extension Period – 51 weeks  
Reference therapy, dosage and mode of administration:  
Placebo will be provided in size and appearance that are visually identical to those containing 
iloperidone. 
Primary Objective: 
To evaluate the efficacy of iloperidone monotherapy compared to placebo in the treatment of adult 
patients with bipolar I disorder experiencing an acute manic or mixed episode as measured by reduction 
in the Young Mania Rating Scale (YMRS) total score at Week 4 
Secondary Objective(s):  
• 
To evaluate the efficacy of iloperidone monotherapy compared to placebo in the treatment of 
adult patients diagnosed with bipolar I disorder experiencing an acute manic or mixed episode 
as measured by improvements in the Clinical Global Impression of Severity (CGI-S)  
• 
To evaluate the efficacy of iloperidone monotherapy compared to placebo in the treatment of 
adult patients diagnosed with bipolar I disorder experiencing an acute manic or mixed episode 
as measured by reduction in the Young Mania Rating Scale (YMRS) total score at each trial 
visit 
• 
To assess the rate of YMRS responders. A YMRS responder is defined as at least a 50% 
decrease from baseline in YMRS total score 
• 
To assess the efficacy of iloperidone monotherapy compared to placebo in improving clinical 
symptomatology in adult patients diagnosed with bipolar disorder, manic or mixed episodes 
after acute treatment as measured by CGI-C 
• 
To assess the efficacy of iloperidone monotherapy compared to placebo in improving clinical 
symptomatology in adult patients diagnosed with bipolar disorder, manic or mixed episodes 
after acute treatment as measured by MADRS 
• 
To assess the safety and tolerability of iloperidone compared to placebo in the treatment of 
adult patients in an acute manic or mixed episode of bipolar I disorder as measured by changes 
in vital signs and weight, laboratory analytes, electrocardiograms (ECGs), and the incidence 
and severity of TEAEs and extrapyramidal symptoms (EPS) using the Barnes Akathisia Scale, 
Simpson-Angus Scale, and the AIMS 
Exploratory Objective: 
• 
To conduct a whole genome association scan to identify potential markers of response and 
safety for a bipolar indication 
Open-label Extension (OLE) Objective: 
• 
To explore the long-term safety and tolerability of dosing with iloperidone over an additional 
52 weeks of treatment 


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Overall Design: This will be a multicenter, randomized, double-blind, placebo-controlled, parallel-
group study. The study has two phases: the Pre-Randomization Phase and the Short-Term Treatment 
Phase and is followed by an optional third phase, the Open-Label Extension (OLE) Phase. The Pre-
Randomization Phase includes the Screening visit and the Baseline visit. The Short-Term Treatment 
Phase includes two periods: (1) the Titration Period and (2) the Double-Blind Treatment Period. The 
optional OLE Phase also includes two periods: (1) the OLE Titration Period and (2) the OLE 
Maintenance Period.  
The Pre-Randomization Phase begins with the screening visit (Day -7 to -1) during which an 
informed consent will be obtained from potential patients and their eligibility will be initially 
assessed. The Screening Visit (Day -7 to -1) and Baseline Visit (Day 0) will be separated by a 
maximum of 1 week. Patients meeting all entry criteria for enrollment into the study will enter the 
Short-Term Treatment Phase. During this Phase, patients will undergo a 7-day Titration Period where 
iloperidone or placebo will be titrated to 24 mg/day total daily dose given as a bid regimen (12 mg 
bid) utilizing a fixed titration regiment, whereby the doses will be increased to 
2→6→12→18→24→24→24 mg/day (bid doses of 1, 3, 6, 9, 12, 12, and 12 mg). The target dose for 
CYP2D6 poor metabolizers is 12mg/d (6 mg bid) utilizing a fixed titration regiment, whereby the 
doses will be increased to 2→6→12→12→12→12→12 mg/day (bid doses of 1, 3, 6, 6, 6, 6, and 6 
mg). Patients will discontinue current antipsychotic treatment prior to the first day of the Titration 
Period (Day 1-7). Patients will remain in-patient during this period to ensure compliance with dosing.  
Subjects continuing to meet the criteria for randomization will be eligible to proceed to the Double-
Blind Treatment Period. During this period, patients will be randomized 1:1 to either iloperidone or 
placebo, stratified by country. Subjects will remain in this period for up to 3 weeks. 
 
Subjects who complete the Double-Blind Treatment Period will be eligible to participate in the optional 
OLE Phase. Eligible subjects will enter the 7-day OLE Titration Period where iloperidone will be 
titrated to 24 mg/day total daily dose given as a bid regimen (12 mg bid). The target dose for CYP2D6 
poor metabolizers is 12mg/d (6 mg bid). Subjects will then enter the OLE Maintenance Period in which 
subjects will be treated with iloperidone for up to 52 weeks. 
Criteria for evaluation:  
Mean baseline-to-endpoint change in total score using following parameters: 
Efficacy:  
• 
Young Mania Rating Scale (YMRS)  
• 
Overall and mania severity of illness for Clinical Global Impression of Severity (CGI-S) 
• 
Clinical Global Impression of Change (CGI-C) 
• 
Montgomery-Asberg Depression Rating Scale (MADRS) 
Safety:  
• 
Adverse Events (AEs) and proportion of patients withdrawing due to AEs  
• 
EPS scale scores as measured by Simpson-Angus Scale (SAS), Abnormal Involuntary 
Movement Scale (AIMS), and Barnes Akathisia Rating Scale (BARS)  
• 
Metabolic risk factors, clinical chemistry, hematology, vital signs, and weight 
• 
Columbia Suicide-Severity Rating Scale (C-SSRS) 
• 
CYP2D6 genotyping  
• 
12-lead electrocardiograms (ECG) 
Statistical methods: 


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If not otherwise specified, statistical significance is defined as p ≤ 0.05 and is two-tailed when 
appropriate. Data base lock will occur after 4-week ST double-blind period. The primary efficacy 
variable is the change from baseline in the YMRS total score.  


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11. 
STATISTICAL PLAN 
11.1. 
Sample Size and Accrual 
Based on a two-sided t-test with the 5% significant level, the planned sample size of 200 subjects  
per arm (a total of 400 subjects) provides around 90% power to detect a mean difference of 3.6 
in YMRS (change from baseline at week 4) assuming a standard deviation of 11 in each 
treatment group. 
11.2. 
Statistical Methods 
This section describes the planned statistical analyses in general terms. A complete description of 
the methodology will be specified in a statistical analysis plan (SAP), which will be finalized 
prior to unblinding. Any changes in the statistical methods described in this protocol that occur 
prior to unblinding will be documented in the statistical analysis plan and will not require a 
protocol amendment.  
 
11.2.1. 
General 
Statistical analyses will be performed using two-sided tests at alpha level of 0.05.   
 
Data will be summarized by treatment group (and by visit when applicable), with respect to 
demographic and baseline characteristics, efficacy variables, and safety variables. 
 
Summary statistics will include the mean, N, standard deviation, median, minimum, and 
maximum values for continuous variables, and frequencies and percentages for categorical 
variables. 
 
For the analyses of change from baseline, only patients with a baseline and at least one post-
baseline measure will be included in the analysis. Unless otherwise specified, baseline is defined 
as the latest non-missing observation across all the visits in the screening phase, before the active 
study drug begins. Endpoint will be the latest non-missing observation across all the post-
baseline visits in the treatment phase. 
 
Low enrolling sites will be pooled for analysis and the pooling algorithm will be determined 
prior to breaking the blind.  The goal of pooling low enrolling sites is to have a sufficient number 
of patients per treatment group within a site for the analysis models.  Unless otherwise specified, 
the pooled sites will only be used in the analyses where the site has an effect.  The actual sites 
rather than the pooled sites will be specified in the data listings. 
 
Details of the model and the analyses will be specified in the SAP.  All statistical analyses will 
be performed using SAS®, Version 9.1.3 or higher. 
11.2.2. 
Patient Populations for Analysis 
The following analysis populations will be defined for this study: 


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Intent-to-Treat: will include any patient randomized into the study that receives a dose of 
study drug and that has completed at least one post-baseline efficacy measurement while on 
study medication;   
Safety: Any patient randomized into the study that receives a dose of study drug; 
Per-Protocol: Any patient who is randomized and receives the protocol required study drug 
exposure and required protocol processing.   
Efficacy analyses will be performed on the Intent-to-Treat population and the Per-Protocol 
population.  Safety summaries will be based on Safety set.  Patient characteristics will be 
presented for all patients randomized. 
11.2.3. 
Patient Disposition 
Study completion and reasons for discontinuation for all randomized patients in the treatment 
phase will be summarized for each treatment group.    Discontinuations by reason will be 
tabulated for each treatment group. 
As needed, time to discontinuation due to adverse events, lack of efficacy and for any reason 
may be analyzed using Kaplan-Meier survival techniques; the log-rank test may be used for 
group comparison. 
11.2.4. 
Demography and Other Baseline Data 
Demographic data and patient characteristics at screening/baseline will be listed and summarized 
by treatment group for all randomized patients using descriptive statistics. 
Past and current medical history will be summarized by treatment group using the system organ 
class (SOC) as coded using the Medical Dictionary for Regulatory Activities (MedDRA) coding 
dictionary.  
Past medical conditions will be defined as an onset date prior to randomization (Visit 2) and 
resolved (not on-going) as of Visit 2.  Current medical conditions, defined as an onset date on or 
after the date of randomization (Visit 2) or an onset date prior to randomization (Visit 2) and 
unresolved (on-going) as of Visit 2, will be reported separately, but similarly to the past medical 
conditions.  If both a past and a current (on-going) medical condition record are indicated for a 
condition, the condition will be presented under current medical conditions only. 
11.2.5. 
Study Medication 
The number of subjects at each visit will be summarized by treatment group.  
The compliance to study medication, as recorded in the CRF, will also be summarized by 
treatment group. The proportion of subjects who are significantly noncompliant in the double-
blind phase will be summarized by treatment groups. 
11.2.6. 
Prior/Concomitant Therapy 
Any medications or therapy present before the first dose of study medication (Visit 2) will be 
considered as prior medications.  Concomitant medications (medications present while on study 
medication) will be recorded throughout the study and at early discontinuation.  These 
medications will be coded using the WHO-drug dictionary.  The number of subjects from the 


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Safety Population using prior or concomitant medications will be categorized by the WHO-drug 
category and preferred term, and presented for each treatment group.  In any given category (e.g., 
drug category) a subject will be counted only once. 
 
11.3. 
Efficacy Data Analysis 
11.3.1. 
Primary Outcome  
The primary efficacy outcome measure is the change from baseline in the Young Mania Rating 
Scale (YMRS) total score at Week 4. The primary statistical method will be mixed effect model 
repeat measurement (MMRM). A detailed description of the primary analysis model, and other 
supportive analyses will be included in the SAP.  
As stated previously, any changes in the statistical methods that occur prior to database lock will 
be documented in the SAP and will not require a protocol amendment. 
 
11.3.2. 
Secondary Outcomes 
The other secondary efficacy outcomes include: 
• Responder  
• CGI-S 
• CGI-C 
• MADRS 
These outcomes will be analyzed similarly as the primary outcome. The categorical endpoints 
will be analyzed by a Cochran-Mantel-Haenszel test with adjusting for sites.  
 
11.4. 
Safety Evaluation 
The primary assessment of safety will be based on the frequency of treatment-emergent adverse 
events (TEAEs), serious adverse events (SAEs) and on the frequency of clinically notable 
abnormal vital signs, electrocardiograms (ECGs) and laboratory values. Other safety evaluations 
include changes in vital signs, changes in clinical laboratory evaluations, and changes in ECGs, 
extra pyramidal symptoms (EPS) using the Barnes Akathisia Scale, Simpson-Angus Scale and 
the AIMS, physical exam findings during treatment, and suicide ideation (C-SSRS) and behavior 
events. 
11.4.1.1. Adverse Events  
Adverse events will be recorded throughout the study and at early discontinuation. Adverse 
events and medical conditions will be coded using the Medical Dictionary for Regulatory 
Activities (MedDRA) coding dictionary.  Treatment-emergent adverse events will be defined as 
those events, which are newly occurring or worsening from baseline.  In all cases only treatment 
emergent adverse events will be summarized.  


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Treatment-emergent adverse events will be summarized within each treatment group by primary 
system organ class and preferred term. (NOTE: In any given category [e.g. body system] a 
patient will only be counted once.) The incidence rates of TEAEs will be analyzed as described 
in the SAP.  Similar displays will be provided for SAE and prior (conditions ending prior to the 
first dose of study medication) and current (conditions present while on study medication) 
medical conditions. 
Adverse events will further be categorized by severity, relationship to study medication, and 
action taken. Other information collected will be listed, as appropriate. Any event starting more 
than 3 days after the final dose of study medication will be excluded from the above tables and 
only listed, unless the event caused discontinuation. 
The proportions of patients experiencing SAEs and AEs resulting in discontinuation from the 
study will be summarized by treatment groups. 
11.4.1.2. Laboratory Data 
Clinical Laboratory Data 
The summary statistics of raw data (hematology and chemistry) and change from baseline values 
will be presented, as well as shift tables from baseline to post-baseline values using normal 
ranges.  For urinalysis parameters, the number and percentage of patients falling under each 
category of the test will be presented. 
Clinical laboratory data will be summarized for each treatment group by presenting the 
proportions of patients with clinically notable abnormalities (Appendix 17.2). 
Clinically notable values will be identified according to the criteria identified in the FDA's 
"Supplementary Suggestions for Preparing an Integrated Summary of Safety Information in an 
Original NDA Submission and for Organizing Information in Periodic Safety Updates" (Revised 
2-APR-87) provided by the FDA Division of Neuropharmacological Drug Products (DNDP).  
Differences in incidence rates between the treatment groups will be tested as described in the 
SAP. 
11.4.1.3. Vital Signs 
Data from vital signs and body measurements will be listed, clinically notable values 
(Appendix 17.3) will be flagged, and any other information collected will be listed. Data will 
also be summarized by treatment group using mean change from baseline and proportions of 
patients with values outside the normal range, and values that were clinically notable. 
11.4.1.4. Electrocardiogram (ECG) 
Results from the ECG will be listed for each patient. These data will also be summarized for 
each treatment group by presenting patients with newly occurring or worsening ECG 
abnormalities. 
11.4.1.5. Extrapyramidal Symptoms (EPS) 
The observed value and change from baseline in AIMS, BAS and SAS will be tabulated by 
treatment and analyzed by ANCOVA.  In addition, categorical responses, such as “worsened”, 


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“unchanged” and “improved” may be derived from the AIMS, BAS or SAS scores and be 
compared between the two treatments.  Details of the analysis will be provided in the SAP. 
11.4.1.6. Columbia-Suicide Severity Rating Scale (C-SSRS) 
Results from the C-SSRS will be listed for each patient.  These data will also be summarized by 
treatment group and for suicidal ideation events, suicidal behaviors and completed suicides. In 
particular, for each of the following suicide related events, the number and percent of patients 
with the event will be enumerated by treatment group: completed suicide, nonfatal suicide 
attempt, interrupted attempt, aborted attempt, preparatory acts or behavior, active suicidal 
ideation with specific plan and intent, active suicidal ideation with some intent to act without 
specific plan, active suicidal ideation with any methods (no plan) without intent to act, non-
specific active suicidal thoughts, and wish to be dead.  Details of the analysis will be provided in 
the SAP. 
11.5. 
Subgroup Analysis 
The subgroup analysis (such as, sex, age, baseline illness severity etc.) for efficacy variables and 
safety variables may be conducted as described in the SAP. 
11.6. 
Deviations in Analysis from Statistical Plan and Other Issues 
 
During the analysis and reporting process, any deviations from the statistical plan designed for 
this protocol will be described and justified in the final report.