Clinical trial NCT02817906
Conditions: Agitation in Dementia, Including Alzheimer's Disease
Sponsor: Intra-Cellular Therapies, Inc.
Start date: 2016-08-29; Completion date: 2019-01-30
Enrollment: 177 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
This is a randomized, double-blind, placebo-controlled study comparing the efficacy and safety of ITI-007 versus placebo administered orally once daily in the treatment of agitation in patients with dementia, including Alzheimer's disease.

Detailed description:

Arms: arm 1: 9 mg ITI-007 administered as a solid oral dose formulation once daily for 4 weeks. arm 2: Placebo administered as a visually-matched solid oral dose formulation once daily for 4 weeks
Interventions: intervention 1: ITI-007 intervention 2: Placebo
Intervention descriptions: intervention 1: None intervention 2: None

Protocol documents:
Prot_000.pdf: 
NCT02817906 
 
Study ID: ITI-007-201 
 
Title: A Randomized, Double-Blind, Placebo-Controlled, Multi-Center Study with an Open-Label 
Extension to Assess the Efficacy and Safety of ITI-007 in the Treatment of Agitation in Patients with 
Dementia, Including Alzheimer’s Disease 
 
Protocol Amendment 5.2 Date: 22 October 2018 


Intra-Cellular Therapies, Inc. 
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Clinical Study Protocol 
Protocol: ITI-007-201 
Protocol Amendment Version 5.2 
CLINICAL STUDY PROTOCOL 
ITI-007-201 
IND 127595 
A Randomized, Double-Blind, Placebo-Controlled, Multi-Center Study 
with an Open-Label Extension to Assess the Efficacy and Safety of ITI-007 
in the Treatment of Agitation in Patients with Dementia, Including 
Alzheimer’s Disease  
Confidential 






Intra-Cellular Therapies, Inc. 
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Clinical Study Protocol 
Protocol: ITI-007-201 
 
Protocol Amendment Version 5.2  
 
Declaration of Investigator 
I have read and understood all sections of the protocol entitled “A Randomized, Double-
Blind, Placebo-Controlled, Multi-Center Study with an Open-Label Extension to Assess the 
Efficacy and Safety of ITI-007 in the Treatment of Agitation in Patients with Dementia, 
Including Alzheimer’s disease” and the accompanying associated Investigator’s brochure 
issued. 
I agree to supervise all aspects of the protocol and to conduct the clinical investigation in 
accordance with the Final Protocol Version 5.2, dated 22 October 2018, the International 
Council for Harmonisation harmonised tripartite guideline E6(R1): Good Clinical Practice 
and all applicable government regulations.  I will not make changes to the protocol before 
consulting with ITI or implement protocol changes without independent ethics committee 
approval except to eliminate an immediate risk to patients.  I agree to administer study 
treatment only to patients under my personal supervision or the supervision of a 
subinvestigator. 
I will not supply the investigational drug to any person not authorized to receive it.  
Confidentiality will be protected.  Patient identity will not be disclosed to third parties or 
appear in any study reports or publications. 
I will not disclose information regarding this clinical investigation or publish results of the 
investigation without prior authorization from ITI. 
 
 
 
Signature of Principal Investigator 
 
Date 
 
 
 
Printed Name of Principal Investigator 
 
 
 
 


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Table of Contents 
Table of Contents .......................................................................................................................5 
List of Tables ..............................................................................................................................9 
List of Abbreviations................................................................................................................36 
1 
Introduction ......................................................................................................................38 
2 
Study Objectives...............................................................................................................43 
2.1 
Primary Objectives..................................................................................................43 
2.1.1 
Part A Primary Objective .........................................................................43 
 
 
2.2 
Secondary Objectives..............................................................................................43 
2.2.1 
Part A Secondary Objectives - Efficacy ...................................................43 
 
 
 
 
 
 
 
 
3 
Investigational Plan ..........................................................................................................46 
3.1 
Study Design ...........................................................................................................46 
3.1.1 
Part A Study Periods (up to Approximately 8 Weeks, Including 
Screening/Baseline) .................................................................................46 
 
 
3.1.3 
Rationale of Study Design .......................................................................48 
4 
Patient Selection and Withdrawal Criteria .......................................................................51 
4.1 
Selection of Study Population .................................................................................51 
4.1.1 
Part A Inclusion Criteria ..........................................................................51 
4.1.2 
Part A Exclusion Criteria .........................................................................53 
 
 
 
 
4.2 
Withdrawal of Patients from the Study ...................................................................59 
4.2.1 
Reasons for Withdrawal/Discontinuation ................................................59 
4.2.2 
Handling of Withdrawals .........................................................................60 
4.2.3 
Replacements ...........................................................................................61 


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5 
Study Treatments ..............................................................................................................62 
5.1 
Method of Assigning Patients to Treatment Groups ...............................................62 
5.2 
Treatments Administered ........................................................................................63 
5.3 
Identity of Investigational Product..........................................................................63 
5.3.1 
Investigational Product for Study Part A .................................................63 
 
 
5.4 
Management of Clinical Supplies ...........................................................................67 
5.4.1 
Study Drug Packaging and Storage .........................................................67 
5.4.2 
Test Article Accountability ......................................................................69 
5.5 
Overdose Management ...........................................................................................69 
 
 
5.5.2 
Medication Errors ....................................................................................69 
5.5.3 
Treatment of Medication Errors ...............................................................70 
5.6 
Blinding ..................................................................................................................70 
5.6.1 
Breaking the Blind ...................................................................................70 
5.7 
Treatment Compliance ............................................................................................71 
5.8 
Prior and Concomitant Therapy ..............................................................................71 
6 
Study Assessments and Procedures ..................................................................................74 
6.1 
Screening Assessments and Procedures ..................................................................80 
6.1.1 
Informed Consent ....................................................................................80 
6.1.2 
Medical History and Other Information ..................................................80 
6.1.3 
Modified Physical and Neurological Examination ..................................81 
6.1.4 
Electrocardiogram Assessments ..............................................................81 
6.1.5 
Vital Sign Measurements .........................................................................82 
6.1.6 
Hepatitis Screening ..................................................................................83 
6.1.7 
HIV Screening .........................................................................................83 
6.1.8 
Drug and Alcohol Screening ....................................................................83 
6.1.9 
Laboratory Assessments ..........................................................................84 
6.1.10 
Dementia Diagnosis .................................................................................84 
6.1.11 
Mini Mental State Examination ...............................................................84 
6.1.12 
Columbia Suicide Severity Rating Scale .................................................84 
6.1.13 
Neuropsychiatric Inventory Clinician ......................................................85 
6.1.14 
Clinical Global Impression scale for Severity of Illness .........................86 


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6.1.15 
Caregiver Daily Diary (Part A only) ........................................................86 
6.1.16 
Actigraphy (Part A only) ..........................................................................86 
6.1.17 
Eligibility Adjudication (Part A only) ......................................................87 
6.2 
Efficacy Assessments and Procedures ....................................................................87 
6.2.1 
CMAI-C ...................................................................................................87 
6.2.2 
Clinical Global Impressions ....................................................................88 
6.2.3 
Neuropsychiatric Inventory Clinician ......................................................88 
6.2.4 
Caregiver Daily Diary (Part A only) ........................................................88 
6.2.5 
Actigraphy (Part A only) ..........................................................................89 
6.3 
Safety and Tolerability Assessments .......................................................................89 
6.3.1 
Adverse Events ........................................................................................89 
6.3.1.1 
Definition of Adverse Event ....................................................................89 
6.3.1.2 
Definition of Serious Adverse Event .......................................................90 
6.3.1.3 
Nonserious Adverse Event .......................................................................91 
6.3.1.4 
Definition of Relationship to Study Drug ................................................91 
6.3.1.5 
Definition of Intensity ..............................................................................93 
6.3.1.6 
Period of Observation for Adverse Events ..............................................93 
6.3.1.7 
Documenting, Reporting, and Eliciting Adverse Events .........................94 
6.3.1.8 
Notification About Serious or Unexpected Adverse Events ....................94 
6.3.1.9 
Exceptions ................................................................................................95 
6.3.1.10 Follow-Up of Adverse Events .................................................................96 
6.3.2 
Safety Assessments ..................................................................................96 
6.3.2.1 
C-SSRS ....................................................................................................96 
6.3.2.2 
MMSE ......................................................................................................96 
6.3.2.3 
Abnormal Involuntary Movement Scale..................................................96 
6.3.2.4 
Barnes Akathisia Rating Scale .................................................................97 
6.3.2.5 
Simpson-Angus Scale ..............................................................................97 
6.3.2.6 
Vital Sign Measurements .........................................................................97 
6.3.2.7 
ECG Assessments ....................................................................................98 
6.3.2.8 
Modified Physical and Neurological Examination ..................................98 
6.4 
Safety Monitoring Committee ................................................................................98 
6.5 
Laboratory Analyses ...............................................................................................98 
 
 
 
 


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6.8 
Pregnancy ..............................................................................................................101 
7 
Statistical and Analytical Plan ........................................................................................103 
7.1 
Analysis Endpoints ...............................................................................................103 
7.1.1 
Primary Efficacy Endpoints – Part A .....................................................103 
7.1.2 
Secondary 
 Efficacy Endpoints – Parts A 
 ..........103 
7.1.2.1 
Key Secondary Efficacy Endpoint – Part A ...........................................103 
 
 
 
 
 
 
 
 
 
 
7.2 
Sample Size Calculations ......................................................................................105 
7.3 
Analysis Sets .........................................................................................................106 
7.4 
Description of Subgroups to be Analyzed ............................................................107 
7.5 
Statistical Analysis Methodology .........................................................................107 
7.5.1 
Patient Disposition, Analysis of Demographics and Other Baseline 
Characteristics ........................................................................................108 
7.5.2 
Analysis of Primary and Key Secondary Efficacy Endpoints – Part A .108 
7.5.3 
Sensitivity Analyses of Primary Efficacy Endpoint – Part A ................ 110 
 
 
 
 
 
 
 
 
7.5.8 
Interim Analyses – Part A ...................................................................... 113 
7.6 
Data Quality Assurance......................................................................................... 113 
7.6.1 
Data Management .................................................................................. 113 
8 
Ethics .............................................................................................................................. 115 
8.1 
Independent Ethics Committee or Institutional Review Board ............................ 115 
8.2 
Ethical Conduct of the Study ................................................................................ 115 
8.3 
Patient Information and Consent .......................................................................... 115 


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9 
Investigator’s Obligations .............................................................................................. 117 
9.1 
Confidentiality ...................................................................................................... 117 
9.2 
Financial Disclosure and Obligations ................................................................... 117 
9.3 
Investigator Documentation .................................................................................. 118 
9.4 
Study Conduct ....................................................................................................... 118 
9.5 
Adherence to Protocol .......................................................................................... 118 
9.6 
Adverse Events and Study Report Requirements ................................................. 119 
9.7 
Investigator’s Final Report ................................................................................... 119 
9.8 
Records Retention ................................................................................................. 119 
9.9 
Publications ........................................................................................................... 119 
10 Study Management .........................................................................................................120 
10.1 Monitoring ............................................................................................................120 
10.1.1 
External Data Monitoring Committee ...................................................120 
10.1.2 
Monitoring of the Study .........................................................................120 
10.1.3 
Inspection of Records ............................................................................120 
10.2 Management of Protocol Amendments and Deviations........................................120 
10.2.1 
Modification of the Protocol ..................................................................120 
10.2.2 
Protocol Deviations ...............................................................................121 
10.3 Study Termination .................................................................................................121 
10.4 Final Report ..........................................................................................................121 
11 Reference List.................................................................................................................123 
 
 
 
 
 
List of Tables 
 
 
 
 




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Protocol Synopsis 
Protocol Number: 
ITI-007-201 
Title: 
A Randomized, Double-Blind, Placebo-Controlled, Multi-Center 
Study with an Open-Label Extension to Assess the Efficacy and 
Safety of ITI-007 in the Treatment of Agitation in Patients with 
Dementia, Including Alzheimer’s Disease 
Sponsor: 
Intra-Cellular Therapies, Inc. (ITI) 
Study Phase: 
Phase 3 
Study Sites: 
Up to approximately 60 study sites in 1 country (United States) 
Indication: 
Agitation in Patients with Dementia 
Rationale: 
Intra-Cellular Therapies, Inc. is developing ITI-007, a new 
chemical entity, for the treatment of symptoms of agitation, 
including aggression, in patients with dementia, including 
Alzheimer’s disease (AD). 
Dementia can be caused by a variety of conditions, the most 
common of which is AD.  Typically patients develop signs of 
cognitive decline, including diminished capacity for 
concentration, calculation, language, comprehension, and 
memory.  The behavioral disorders that commonly accompany 
this disease remain largely untreated by currently approved 
drugs.  These behavioral disturbances include agitation, 
aggression, depression, apathy, delusions, hallucinations, and 
disrupted sleep/wake cycles.  These symptoms have serious 
consequences for the patients and caregivers, leading to more 
rapid deterioration in patient health and increased burden of 
care. 
ITI-007 represents a novel, small molecule therapeutic agent 
designed specifically to combine in a dose-dependent manner 
potent serotonin 5-HT2A receptor antagonism with 
mesolimbic/mesocortical selective modulation of 
phosphoprotein pathways downstream of dopamine receptors 
together with serotonin reuptake inhibition.  As a dopamine 
receptor protein phosphorylation modulator, ITI-007 has dual 
properties, acting as a post-synaptic antagonist and as a 
pre-synaptic partial agonist at dopamine D2 receptors in vivo 
with mesolimbic/mesocortical selectivity.  ITI-007 also 
indirectly (i.e., through D1 receptor partial agonism) modulates 


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glutamatergic activity by increasing the phosphorylation of the 
NR2B subunit or GluN2B subunit of N-methyl-D-aspartate 
(NMDA) channels in extrastriatal dopamine-rich brain regions 
(e.g., nucleus accumbens).  ITI-007 has been tested in a number 
of animal models that predict antipsychotic efficacy without 
movement disorders, antidepressant efficacy, and improved 
sleep.  The in vitro and in vivo activities of ITI-007 support the 
development of low doses of this compound for the treatment of 
agitation and other behavioral disturbances associated with 
dementia and higher doses for the treatment of schizophrenia, 
bipolar depression, and other psychiatric and neurological 
indications. 
To date, over 2,400 people have been exposed to doses ranging 
from 1 mg to 140 mg ITI-007 administered for up to 42 days.  In 
all trials completed to date, ITI-007 has been well tolerated with 
a safety profile similar to placebo.  The safety, tolerability, and 
appropriate pharmacokinetic (PK) profile of ITI-007 were 
demonstrated in a Phase 1/2 randomized, double-blind, placebo-
controlled, multiple ascending dose clinical study in healthy 
geriatric subjects and patients with dementia, including 
Alzheimer’s disease.  
The available data support the development of ITI-007 for the 
treatment of agitation in patients with dementia. 
Objectives Part A 
(Double-blind, placebo-
controlled phase): 
Primary Objective 
The primary objective of Part A of this study is to compare the 
efficacy, measured as change from baseline to Day 29 in the 
Cohen-Mansfield Agitation Inventory – Community version 
(CMAI-C) symptoms related to aggressive behavior, 
non-aggressive agitated behavior and/or verbally agitated 
behavior, for 9 mg ITI-007 administered orally once daily in the 
evening (QPM) to that of placebo in patients with dementia.   
Key Secondary Efficacy Objective 
Key secondary objective of Part A of this study is to compare the 
efficacy of 9 mg ITI-007 administered orally QPM to that of 
placebo in relation to the difference in the change from baseline 
to Day 29 in the Clinical Global Impression scale for Severity 
(CGI-S) of illness (e.g., CGI-S of Agitation and/or CGI-S of 
Aggression). 








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3. Is a male or female, > 55 years of age at the time of 
screening; 
4. Has a clinical diagnosis of probable AD according to the 
National Institute on Aging- Alzheimer's Association 
(NIA-AA) guidelines (McKhann, 2011; Appendix A); 
5, Has an MMSE score of 8 to 26 (inclusive) at screening; 
6. Has clinically significant symptom(s) of agitation 
secondary to probable AD, consistent with the 
International Psychogeriatric Association consensus 
definition (see Appendix B); 
7. At screening, according to NPI-C, has verbally agitated 
behavior, physically agitated nonaggressive behavior, or 
physical aggressive behavior occurring at least several 
times a week defined as ratings of frequency scores on 
items comprising the domains of Agitation and/or 
Aggression i.e., at least one behavior occurring at a 
frequency of 3 (several times a week but less than every 
day) or 4 (once or more per day), or at least two behaviors 
occurring at a frequency of 2 (about once per week), or at 
least three behaviors occurring at a frequency of 1 (less 
than once per week).  This will be assessed over the past 4 
weeks before screening; 
8. At baseline according to the CMAI-C, has agitation 
and/or aggressive behavior as measured by any of the 
items in the Factor Composite occurring at least several 
times a week, i.e., at least one behavior occurring at a 
frequency of 4, or two behaviors occurring at a frequency 
of 3, or three behaviors occurring at a frequency of 2, at 
baseline (as assessed over the past 2 weeks before 
baseline); 


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9. In the opinion of the investigator, has frequent agitation 
that is clinically significant and warrants treatment with a 
pharmacological agent; 
10. Has a CGI-S of Agitation or CGI-S of Aggression score of 
≥ 4 (moderately ill) at screening and baseline; 
11. Is maintained on a stable dose of any allowed standard of 
care medications for at least 3 months prior to Day 1 
(baseline) [unless a shorter duration is reviewed and 
approved by the medical monitor] and for the duration of 
study participation.  This includes stable doses of 
cholinesterase inhibitors and memantine; 
12. Has a body mass index (BMI) between 19.0 and 38.0 
kg/m2, inclusive, and a minimum body weight of 46 kg at 
screening; 
13. Has a score of ≤ 4 on a modified Hachinski Ischemia 
Scale; 
14. Has normal serum B12 and folate levels (patients with 
abnormally low serum B12 and folate levels at screening 
can be re-screened following supplementation). 
 
 
Exclusion Criteria - Part A: 
1. Is bedridden; 
2. Is, in the opinion of the investigator, unable to comply 
with study procedures; 
3. Has clinical symptoms suggestive of other neurological 
disease such as evidence of infection, tumor, infarction, or 
other focal (e.g., subdural hematoma) or generalized 
lesions (e.g., hydrocephalus) that could account for the 
subject’s dementia;   
[Note: if magnetic resonance imaging (MRI) or computed 
tomography (CT) scan of the head is available within the 
last 12 months, it should be negative]; 


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4. Has, in the opinion of the investigator, and/or as assessed 
by the C-SSRS at screening (suicidal ideation of type 4 or 
5 on the C-SSRS within 6 months prior to screening or 
any suicidal behavior in the last 2 years prior to screening, 
as indicated by any “yes” answers on the suicidal 
behavior section of the C-SSRS), a significant risk for 
suicidal behavior during the course of their participation 
in the study or is considered to be an imminent danger to 
themselves or others; 
5. Has any clinically significant systemic illness or unstable 
or severe medical condition(s) that could put the patient at 
risk during the study, interfere with outcome measures, or 
affect compliance with the protocol procedures, such as: 
a. History of myocardial infarction within 3 months 
prior to screening, unstable or severe cardiovascular 
disease including uncontrolled angina or congestive 
heart failure with symptoms at rest within 2 years 
before enrollment or history of a clinically significant 
cardiac arrhythmia including antipsychotic drug-
induced QTc prolongation; 
b. Endocrine-related disease (including insulin-
requiring diabetes or poorly controlled diabetes as 
judged by the investigator; uncorrected 
hypothyroidism within the last 2 years)  
[Note: if on thyroid replacement medication, dose 
should be stable for at least 3 months prior to 
screening and remain stable during trial participation, 
unless a shorter duration is reviewed and approved by 
the medical monitor]; 
c. Uncontrolled hypertension (systolic blood pressure > 
180 mmHg or diastolic blood pressure > 110 
mmHg); 
d. History of clinically significant liver disease, 
coagulopathy or Vitamin K deficiency within the last 
2 years prior to screening; 
e. History of clinically significant renal disease;  


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f. Clinically significant obstructive pulmonary disease 
or asthma; 
g. Clinically significant and unstable gastrointestinal 
disorder; 
h. Documented and confirmed clinically significant 
neurological or psychiatric disease (e.g., Parkinson’s 
disease, multi-infarct dementia, Huntington’s disease, 
normal pressure hydrocephalus [based upon clinical 
judgment], brain tumor, progressive supranuclear 
palsy, seizure disorder including epilepsy, subdural 
hematoma, schizophrenia, major depressive disorder, 
significant anxiety and/or phobic disorder(s), 
multiple sclerosis, arteriovenous malformation or 
history of significant head trauma and/or subdural 
hematoma followed by persistent neurologic deficits 
or known structural abnormalities, substance-induced 
persisting dementia, dementia due to multiple 
etiologies or dementia not otherwise specified) [Note: 
with the exception of rapid eye movement (REM) 
sleep behavior disorder, sleep disorders are allowed, 
but should be carefully documented, including but 
not limited to insomnia (sleep induction and/or sleep 
maintenance insomnia), periodic limb movements of 
sleep, and sleep apnea as determined by the STOP-
bang questionnaire]; 
i. Malignancy (including any malignancy and/or 
chemotherapy within the 2 years prior to screening; 
malignancy more than 2 years prior to screening must 
have been local and without metastasis and/or 
recurrence, and if treated with chemotherapy, without 
nervous system complications; some malignancies, 
such as basal cell carcinoma, may not preclude 
participation and will be individually reviewed); 
j. Metabolic, psychiatric or other condition that might 
be detrimental to the patient if he or she participates 
in the study in the opinion of the investigator;  
6. Has abnormal laboratory values or clinical findings at 
screening that are judged clinically significant by the 
investigator (one re-test is allowed to confirm 
reproducibility of results; results must be available prior 


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to the baseline visit and must have returned to non-
clinically significant range). Absolute value exclusions 
are listed in item 6b and 6c below:  
a. Thyroid stimulating hormone (TSH) outside of the 
normal limits and clinically significant as determined 
by the investigator.  Free thyroxine (T4) levels may 
be measured if TSH level is high.  Patient will be 
excluded if Free T4 level is judged clinically 
significant by investigator; 
b. 12-lead ECG (in a supine position at rest at screening 
or baseline visit; note: baseline ECG measures for 
determining inclusion into the study are based on the 
investigator/site read ECG data, though the database 
will reflect centrally read ECG data) mean of 
triplicate QTcF > 500 ms (independent from sex) 
and/or heart rate (HR) ≤50 beats per minute. Bundle 
branch blocks deemed clinically significant by 
investigator will be excluded. [Note: If it is the 
opinion of the investigator that a lower HR is 
physiological in a well-fit subject or due to stable 
concomitant medications, this will be reviewed and 
approved by the medical monitor on a case by case 
basis]; 
c. Alanine transaminase (ALT), aspartate transaminase 
(AST), or creatine phosphokinase values > 3 times 
the upper limit of normal (ULN); 
d. Any other clinically significant abnormal laboratory 
result at the time of the screening as determined by 
the investigator. 
7. Is a female of childbearing potential as determined by the 
investigator; 
8. Has a history of neuroleptic malignant syndrome induced 
by any antipsychotic medication; 
9. Has a history of human immunodeficiency virus (HIV) 
infection or demonstration of HIV antibodies; 




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investigational product with a central nervous 
system indication; 
b. Any strong or moderate CYP450 3A4 inhibitor or 
inducer within 7 days (or 5 half-lives, whichever is 
greater) prior to the baseline visit;  
c. Certain drugs with known psychotropic properties or 
any non-psychotropic drugs with known or potential 
significant central nervous system effects within 5 
half-lives before the baseline visit unless noted 
below to be discontinued by the baseline with taper, 
if appropriate (see Section 5.8), including:  
i. Anxiolytics (except lorazepam as 
described in Table 5-7) 
ii. Sedative hypnotics  
iii. Central opioid agonists/antagonists 
including tramadol (Ultram). Except: 
following review by medical monitor for 
treatment of stable condition on case by 
case basis  
iv. Antipsychotics may be tapered and must 
be discontinued by the baseline visit  
v. Methotrexate 
vi. Any known 5-HT2A receptor antagonist or 
inverse agonist including but not limited 
to mianserin, mirtazapine, nefazodone, 
cyproheptadine, pimavanserin, or 
fluvoxamine 
vii. Immunosuppressants 
viii. St. John’s Wort must be discontinued by 
the baseline visit  
[Notes: Anticonvulsants, mood stabilizers, 
and antidepressants (such as SSRI or 
SNRI) may be allowed, but the dose 
should be stable for at least 3 months 
prior to screening and remain stable 
during trial participation, unless a shorter 
duration is reviewed and approved by the 
medical monitor.  Dietary supplements, 


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medical foods, or pharmaceuticals used 
specifically for the treatment of dementia, 
agitation, or sleep, containing omega3 
fatty acids, melatonin, kava kava, Vitamin 
B12, folate, or valerian root may be 
allowed, but the dose should be stable for 
at least 3 months prior to screening and 
remain stable during trial participation, 
unless a shorter duration is reviewed and 
approved by the medical monitor.  
Multivitamin as daily supplement is 
allowed.  All stable psychotropic 
medications or supplements require 
review and approval by the medical 
monitor.]; 
16. Is unable to be safely discontinued from current above-
mentioned psychotropic medications; 
17. Is unable to swallow oral medication; 
18. Is judged by the investigator to be inappropriate for the 
study; 
19. Is an immediate family (i.e., spouse, parent, child, or 
sibling, whether biological or legally adopted) of the 
investigator, ITI or CROs conducting the study. 
 
 
 
  
 
 
 
 
 
 
 
 
























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Date of Protocol: 
22 October 2018  
 


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List of Abbreviations 
Abbreviation 
Definition 
AD 
Alzheimer’s disease 
AE 
adverse event 
AIMS 
Abnormal Involuntary Movement Scale 
ALT 
alanine aminotransferase 
ANCOVA 
analysis of covariance 
AST 
aspartate aminotransferase 
BARS 
Barnes Akathisia Rating Scale 
BMI 
body mass index 
CFR 
Code of Federal Regulations 
CGI-S 
Clinical Global Impression for Severity scale 
CI 
confidence interval 
CMAI-C 
Cohen-Mansfield Agitation Inventory – Community version 
CMH 
Cochran-Mantel-Haenszel 
CP 
Conditional power 
CRO 
contract research organization 
C-SSRS 
Columbia Suicide Severity Rating Scale 
D2 
dopamine 2  
DMC 
Data Monitoring Committee 
DNA 
Deoxyribonucleic acid 
DSM-5 
Diagnostic and Statistical Manual, 5th Edition 
ECG 
Electrocardiogram 
eCRF 
electronic case report form  
EDC 
electronic data capture 
FAS 
full analysis set 
FDA 
Food and Drug Administration 
GCP 
Good Clinical Practice 
HbA1c 
glycated hemoglobin A1c 
HIV 
human immunodeficiency virus 
HR 
Heart rate 
IA 
Interim analysis 
ICF 
informed consent form 


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Abbreviation 
Definition 
ICH 
International Council for Harmonisation 
IRB 
Institutional Review Board 
ITI 
Intra-Cellular Therapies, Inc. 
IVRS 
interactive voice response system 
IWRS 
interactive web response system 
LDL 
low-density lipoprotein 
LOCF 
last observation carried forward 
MAR 
missing at random 
MedDRA 
Medical Dictionary for Regulatory Activities 
MI 
multiple imputation 
MMRM 
mixed-model–repeated measures  
MMSE 
Mini Mental State Examination 
MNAR 
missing not at random 
MRI 
Magnetic Resonance Imaging 
NIA-AA 
National Institute on Aging – Alzheimer’s Association 
NPI-C 
Neuropsychiatric Inventory Clinician 
nTST 
Nocturnal Total Sleep Time 
RNA 
Ribonucleic acid 
PET 
positron emission tomography 
PK 
Pharmacokinetic 
PMM 
pattern-mixture model 
PPS 
per-protocol set 
QTcF 
corrected QT interval using the Fridericia formula 
SAE 
serious adverse event 
SA 
safety analysis  
SAP 
statistical analysis plan 
SAS 
Simpson Angus Scale 
SERT 
serotonin transporter 
TEAE 
treatment-emergent adverse event  
TSH 
Thyroid stimulating hormone 
ULN 
upper limit of normal 


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1 Introduction 
Dementia is a group of symptoms that affect mnemonic processes such as memory and 
reasoning.  The World Health Organization estimates that 35.6 million people around the 
world are living with various forms of dementia.  Dementia can be caused by a variety of 
conditions, the most common of which is Alzheimer’s disease (AD).  Alzheimer's disease is a 
progressive neurodegenerative disease, currently affecting 25 million worldwide.  According 
to the 2014-2015 Alzheimer’s Disease Progress Report published by the National Institute of 
Aging (NIA), as many as 5.1 million people over the age of 64 in the United States suffer 
from AD (www.nia.nih.gov/alzheimers).  Typically patients first develop mild signs of 
cognitive decline, including diminished capacity for concentration, calculation, language, 
comprehension, and memory.  Behavioral disorders that commonly accompany this disease 
remain largely untreated by currently approved drugs.  These behavioral disturbances include 
agitation, aggression, depression, apathy, delusions, hallucinations, and disrupted sleep/wake 
cycles.  These symptoms have serious consequences for the patients and caregivers, leading 
to more rapid deterioration in patient health.  It has been estimated that up to 80% of patients 
with dementia exhibit behavioral disturbances during the course of the disease. 
The NIA refers to dementia, including AD, as a growing public health crisis with a major 
impact on our economy and costs of care continuing to rise with the aging of our population.  
Behavioral disturbances in patients with dementia, including agitation, remains a 
significantly underserved medical need, with no Food and Drug Administration 
(FDA)-approved treatment options available.  Treatment guidelines updated in 2014, 
recommends cautious (off-label) use of low doses of antipsychotics for the treatment of 
agitation and psychosis associated with dementia, given limited efficacy and severe adverse 
events (AEs) associated with these drugs (Rabins, 2014). 
The Alzheimer’s Association has raised concern over dementia-related behaviors in a 2015 
statement (http://www.alz.org/about_us_statements.asp) in which it is recognized that such 
behaviors can be associated with serious clinical implications.  Agitation, particularly 
physical aggression, can create an unsafe environment for the patient with dementia as well 
as for the caregiver.  It is noted that failing to address the agitation may cause greater harm 
than the currently available medication options.  There is clearly a need for treatments that 
can reduce the behavioral disturbances associated with dementia, including agitation and 
aggression, with decreased risk for motor side effects and with a favorable safety profile. 


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Intra-Cellular Therapies, Inc. (ITI) is developing ITI-007, a new chemical entity, for the 
treatment of symptoms of agitation in patients with dementia.  ITI-007 is currently in Phase 3 
clinical development in the United States for the treatment of schizophrenia and bipolar 
depression. 
ITI-007 is a novel small molecule therapeutic agent designed specifically to combine, in a 
dose-dependent manner, potent serotonin 5-HT2A receptor antagonism with both 
mesolimbic/mesocortical selective modulation of phosphoprotein pathways downstream of 
dopamine receptors and serotonin reuptake inhibition (Snyder, 2015).  As a dopamine 
receptor protein phosphorylation modulator, ITI-007 has dual properties, acting as a 
post-synaptic antagonist and as a pre-synaptic partial agonist at dopamine 2 (D2) receptors in 
vivo, with mesolimbic/mesocortical selectivity.  ITI-007 also indirectly modulates 
glutamatergic activity by increasing the phosphorylation of the NR2B, or GluN2B, subunit of 
N-methyl-D-aspartate channels in extrastriatal dopamine-rich brain regions (e.g., nucleus 
accumbens), likely downstream from dopamine 1 (D1) receptor activation.  ITI-007 has been 
tested in a number of animal models that predict antipsychotic efficacy and reduced agitation 
without movement disorders, antidepressant efficacy, and improved sleep.  The in vitro and 
in vivo activities of ITI-007 support the development of low doses of this compound for the 
treatment of agitation and other behavioral disturbances associated with dementia and higher 
doses for the treatment of schizophrenia and bipolar depression and other psychiatric and 
neurological indications. 
The 5-HT2A receptor antagonism by ITI-007 is predicted to reduce aggression, increase deep 
slow-wave sleep and improve sleep maintenance.  The D2 receptor modulation by ITI-007 is 
predicted to reduce irritability, agitation and aggression, and to improve sleep maintenance.  
In addition to a primary reduction in agitation and aggression, improved sleep maintenance 
by ITI-007 should translate to reduced nighttime agitation and reduced dementia-specific 
sleep-related behavioral disturbances, such as nighttime wandering and waking during the 
night thinking it is daytime.  Serotonin reuptake inhibition by ITI-007 is predicted to reduce 
anxiety and depression.  The D1 receptor activation and indirect glutamatergic 
neurotransmission by ITI-007 is predicted to improve cognitive function.  With its first-in-
class pharmacological profile via all of these pharmacological pathways, ITI-007 is predicted 
to reduce the behavioral disturbances associated with dementia, including agitation, 
aggression, sleep-related behavioral disturbances, anxiety and depression, and to improve 
cognition. 


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Potent 5-HT2A receptor antagonism combined with modest dopamine receptor modulation is 
predicted to be especially effective in reducing agitation and aggression.  The 5-HT2A 
receptor plays a particularly important role in the control of aggression in humans and in 
animals.  In animal models, 5-HT2A receptor antagonists attenuate aggressive behaviors and 
5-HT2A receptor agonists promote aggressive behavior (Sakaue, 2002; Higgins, 2003; 
Winstanley, 2004).  Aggression has been shown to be directly correlated with platelet 5-HT2A 
receptor binding in personality disordered patients, but not in healthy controls 
(Coccaro, 1991).  In a postmortem study of human brain, 5-HT2A receptor expression in 
prefrontal cortical areas was directly correlated with lifetime aggression history in those who 
committed suicide compared to those who died by other means (Oquendo, 2006).  
Aggression also is related to various human genetic polymorphisms of the 5-HT2A receptor 
(Giegling, 2006; Nomura, 2006; Bjork, 2002).  Further, 5-HT2A receptor availability in the 
orbitofrontal cortex has been directly correlated with a clinical measure of aggression 
(Rosell, 2010).  These findings are consistent with a model in which orbitofrontal 5-HT2A 
receptors modulate aggression, and therefore, antagonism of 5-HT2A receptors represents an 
attractive therapeutic target for controlling these kinds of behaviors.   
While useful in treating some of the behavioral disturbances seen in patients with dementia, 
5-HT2A receptor blockade, as described above, may not be sufficient to alleviate the full 
range of behavioral disturbances experienced by patients with dementia.  The other beneficial 
drug target interactions possessed by ITI-007 may be required to treat the full spectrum of 
behavioral symptoms in these patients.  The addition of dopamine receptor modulation may 
be particularly useful in treating agitation and psychotic symptoms.  It has been recognized 
that excessive dopamine neurotransmission can cause increases in agitation and psychosis 
(Engelborghs, 2008).  Moreover, serotonin reuptake inhibition by ITI-007, the mechanism of 
action of the most current antidepressant drugs, may be useful in elevating mood in these 
patients. 
Importantly, ITI-007 lacks potent off-target interactions that have been associated with side 
effects for other antipsychotic drugs used off-label for the treatment of agitation associated 
with dementia.  For example, ITI-007 shows relatively weak affinity for 5-HT2C and no 
measurable affinity for H1 or muscarinic cholinergic receptors, which predict favorable body 
weight and metabolic profile responses to the extent that these receptors mediate such effects 
(Snyder, 2015).  Additional details of the pharmacologic profile of ITI-007 can be found in 
the most recent version of the Investigator’s brochure.  


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In animal models, ITI-007 demonstrated antipsychotic-like efficacy in a rat conditioned 
avoidance assay and antidepressant-like activity in a rat resident-intruder/social defeat model 
of chronic social stress (Snyder, 2015).  These data suggest that ITI-007 will reduce agitation 
and psychosis and improve mood.  
Human brain receptor target engagement was confirmed in healthy male volunteers in the 
ITI-007-003 PET Phase 1 clinical trial (Davis, 2015).  Positron emission tomography was 
used to determine dopamine D2 receptor, serotonin transporter (SERT), and serotonin 5-HT2A 
receptor occupancy in the brain at various times following single dose oral ITI-007 
administration.  ITI-007 rapidly penetrated the brain, showed long-lasting and dose-related 
occupancy, and was safe and generally well-tolerated.  Cortical 5-HT2A receptors were shown 
to be fully occupied at 10 mg ITI-007 (>85% occupancy), while this dose was associated 
with an average of 12% striatal D2 receptor occupancy.  A dose of 40 mg ITI-007 achieved up 
to 39% striatal D2 receptor occupancy (average of 29%) and up to 31% striatal SERT 
occupancy (average of 22%).  Together, these data confirm a central mechanism for ITI-007 
at dopaminergic and serotonergic brain targets.  Projecting occupancy to higher doses based 
on plasma levels, it was estimated that a dose of 60 mg ITI-007 should achieve 
approximately 50% striatal D2 receptor occupancy and similar or slightly less SERT 
occupancy.  Additional clinical studies have demonstrated that 60 mg ITI-007, a dose that 
exhibited antipsychotic efficacy in randomized, placebo-controlled trials (ITI-007-005 and 
ITI-007-301), was associated an average of approximately 40% striatal D2 receptor 
occupancy in patients with schizophrenia (ITI-007-008).  This is lower than the D2 receptor 
occupancy associated with antipsychotic efficacy of most other antipsychotic drugs and 
likely contributes to the improved motoric tolerability, similar to placebo for ITI-007. 
The low dose strategy of 9 mg ITI-007 for the treatment of agitation in patients with 
dementia is estimated to be associated with approximately 10% striatal D2 receptor 
occupancy and full cortical 5-HT2A receptor occupancy. 
To date, over 2,400 people have been exposed to doses ranging from 1 mg to 140 mg ITI-007 
administered for up to 42 days.  In all trials completed to date, ITI-007 has been well 
tolerated with a safety profile similar to placebo.  
ITI has demonstrated the safety, tolerability and appropriate pharmacokinetic (PK) profile of 
ITI-007 in a Phase 1/2 randomized, double-blind, placebo-controlled, multiple ascending 
dose clinical study in healthy geriatric subjects and patients with dementia.  This was a 


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single-center, randomized, double-blind, placebo-controlled, multiple oral dose escalation 
study.  In Part A, doses of ITI–007 (7.5, 15, and 30 mg) were escalated in separate sequential 
groups of healthy geriatric subjects.  Part B of the study evaluated 9 mg ITI-007 in a group of 
geriatric patients with dementia who were maintained on their standard-of-care medications 
for dementia.  In both parts, study subjects received ITI–007 or placebo at least once daily for 
7 days with a meal.  Safety and tolerability were assessed, blood samples for PK analysis 
were collected, and pharmacodynamic measures were explored.  In both parts, ITI-007 was 
safe and well tolerated with PK exposures in the range of those expected based on PK 
profiles in younger healthy adult subjects.  There was no suggestion of any adverse 
interaction with the standard-of-care medications in the dementia cohort.  Exploratory 
assessments indicated improvements in cognitive function with ITI-007. 
The available data support the development of ITI-007 for the treatment of agitation, 
including aggression, in patients with dementia.   


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2 Study Objectives 
2.1 Primary Objectives 
2.1.1 Part A Primary Objective 
The primary objective of Part A of this study is to compare the efficacy, measured as change 
from baseline to Day 29 in the Cohen-Mansfield Agitation Inventory – Community version 
(CMAI-C) symptoms related to aggressive behavior, non-aggressive agitated behavior and/or 
verbally agitated behavior, for 9 mg ITI-007 administered orally once daily in the evening 
(QPM) to that of placebo in patients with dementia.   
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
2.2 Secondary Objectives  
2.2.1 Part A Secondary Objectives - Efficacy 
Key Secondary Efficacy Objective 


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The key secondary objective of Part A of this study is to compare the efficacy of 9 mg ITI-
007 administered orally QPM to that of placebo in relation to the difference in the change 
from baseline to Day 29 in the Clinical Global Impression scale for Severity (CGI-S) of 
illness (e.g., CGI-S of Agitation and/or CGI-S of Aggression). 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


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3 Investigational Plan 
3.1 Study Design 
The study will be conducted in two parts, Part A 
  Part A is a randomized, double-
blind, placebo-controlled study comparing the efficacy and safety of ITI-007 versus placebo 
administered orally once daily in the treatment of agitation in patients with dementia, 
including Alzheimer’s disease.
 
  This study will be conducted at up to 
approximately 60 sites in 1 country (United States). 
3.1.1 Part A Study Periods (up to Approximately 8 Weeks, Including 
Screening/Baseline) 
Part A is an adaptive two-stage design with a single interim analysis and a final analysis.  An 
interim analysis (IA) will be performed after a pre-specified number of patients have 
completed the 28-day treatment period, and will be reviewed by an independent data 
monitoring committee (DMC).  The IA will be used to reassess the assumptions of variability 
and effect size, and correcting the sample size if needed.  The interim data may be used for a 
decision to terminate the study due to superior efficacy or futility, at the discretion of the 
Sponsor. 
Part A of the study consists of the following periods: screening/baseline period, on-treatment 
period, and safety follow-up period.   
Screening/Baseline Period (up to 2 Weeks)  
Potential patients will be evaluated during the screening period lasting up to 2 weeks, starting 
with a screening visit (Visit 1).  In an effort to retain patients and reduce caregiver burden, 
every effort should be made to schedule the baseline visit (Visit 2) for randomization and to 
start study drug within 1 week of screening, but up to 2 weeks are allowed for flexibility of 
scheduling and to ensure that prohibited medications are tapered and/or sufficiently washed 
out. Extension to the screening period may be approved by the Sponsor or representative in 
extenuating circumstances related to the patient or caregiver. 
After obtaining written informed consent, diagnostic interviews and modified physical 
examinations (including height and weight) will be conducted; vital signs (3-positional blood 
pressure and pulse rate, respiration rate and oral body temperature) and 12-lead ECGs will be 
assessed; and blood samples for laboratory assessments (hematology, serum chemistry, HIV 


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and Hepatitis) will be collected.  Suicidal ideation and behavior will be assessed by the C-
SSRS.  Patients considered potentially eligible for participation will be required to 
discontinue prohibited medications.  Patients on excluded medications, including long-acting 
medications, that cannot be washed out safely, including any taper that might be appropriate, 
should be considered not eligible for the study.   
Adjudication of patient eligibility and caregiver suitability will be administered by remote, 
independent expert raters and/or medical monitor(s) in conjunction with the sponsor.  
At baseline (Visit 2), patients who continue to meet all eligibility criteria will be randomized 
equally (1:1) to one of the two treatment arms for the double-blind on-treatment period, 
stratified by the MMSE score at screening.  Patients will be randomized to 9 mg ITI-007 or 
matching placebo.  Patients may receive the investigational product for a period of up to 
4 weeks during the on-treatment period. 
On-Treatment Period (4 Weeks)  
Patients will take their first dose of study drug the evening of their baseline randomization 
visit (Visit 2).  A single dose will be taken each day in the evening during the on-treatment 
period.  
Following randomization, study visits will be conducted at Day 15 (Visit 4) and Day 29 
(Visit 6).  Interim ‘visits’ will be conducted by phone on Day 8 (Visit 3) and Day 22 (Visit 5) 
to check on patient status, adverse events and any change in medication.  
The on-treatment period will be a total of 4 weeks.   
At the end of the on-treatment period, patients can be restarted on prior medications or be 
started on other medications 
as deemed appropriate by the investigator 
following all study procedures at the end of the last treatment visit at Day 29 (Visit 6); any 
and all post-study treatment medications should be recorded. 
Safety Follow-up Period (2 Weeks) 
a safety follow-up visit (Visit 7) will occur at 
Week 6, approximately 2 weeks following the last dose of study drug.  If possible, patients 
who withdraw prematurely will be seen in the research clinic for an early termination visit 
(within 1 week of early termination, where possible) 2 weeks following withdrawal for a 


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safety follow-up.  The final safety follow-up, for both completed patients and following early 
termination visits, will be completed as a study clinic visit.  
At any time during the study, a visit to the research clinic can be conducted as an 
unscheduled visit to address any safety concerns.   
 
 
 
 
 
 
 
  
 
 
 
 
 
3.1.3 Rationale of Study Design  
In Part A, the screening/baseline period permits evaluation of the laboratory and ECG 
assessments and enables confirmation of eligibility for inclusion into the study.  The 
screening/baseline period will be no longer than 14 days, and is encouraged to be less than 
7 days in an effort to retain patients and reduce caregiver burden.  The screening/baseline 
period is appropriate to ensure washout of excluded medication, under the supervision of the 
investigator before baseline.  During the screening/baseline period, baseline data will be 
collected for caregiver diaries and actigraphy.  Patients will be randomly assigned in a 1:1 
ratio to one of two treatment groups at the baseline visit and will receive treatment for up to 4 
weeks.  In order to ensure patient safety, a 14-day follow-up visit will be performed after 
administration of the last dose of study drug.  Any ongoing AEs at the follow-up visit must be 
followed until resolution, until the AE stabilizes, until it is determined to be non-clinically 
significant, or until the patient is lost to follow-up.  


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The dose to be administered in the present study, 9 mg ITI-007, was shown to be well 
tolerated in a prior study (ITI-007-200) with no evidence of a need for drug titration.  
Therefore, a fixed-dose design will be employed in this study.  
In Part A, the placebo control group is needed to establish the efficacy of a new compound. 
The Part A  treatment duration of 4 weeks has been chosen because this is considered an 
appropriate duration to demonstrate efficacy in this patient population.  Though not approved 
for the treatment of agitation in patients with dementia, a previous efficacy trial with 
risperidone showed statistically significant reduction in agitation compared to placebo after 4 
weeks of treatment (Brodaty, 2003).  It is desired to have rapid reduction in agitation to 
reduce patient distress, caregiver burden, and delay placement into nursing care facilities.  
Moreover, the primary endpoint clinical measure, CMAI, is validated looking at agitated and 
aggressive behavior over the previous 2 weeks (Cohen-Mansfield, 1989; Cohen-Mansfield, 
1995).  Capturing data after 2 weeks and again after 4 weeks of treatment allows for an 
interim measurement of efficacy in the case of early discontinuation by patients.  
In Part A of the study, one interim analysis is planned to be performed.  The interim data will 
allow evaluation of the validity of the assumptions used in the study design for which reliable 
prior information does not exist.  If the assumptions appear inaccurate, a mid-study 
adjustment, such as sample size re-estimation, will improve the chance that the study will 
reach a definitive conclusion. 


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4 Patient Selection and Withdrawal Criteria 
4.1 Selection of Study Population 
Approximately 292 patients (in Part A, approximately 146 patients/treatment group) will be 
enrolled at approximately 60 study sites in the United States.  In Part A patients will be 
randomly assigned to study treatment only if they meet all of the inclusion criteria and none 
of the exclusion criteria.  
 
  
 
 
 
 
 
 
 
 
 
 
4.1.1 Part A Inclusion Criteria 
Each patient must meet all of the following criteria to be enrolled in this study: 
1. Has ability to provide written informed consent or have written informed consent 
provided on behalf of the patient by a legally authorized representative (LAR); 
2. Patients able to attend clinic visits who have a primary caregiver with the ability to 
provide written informed consent for joint participation in study.  
 
 
 
 
 
 
 


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3. Is a male or female, > 55 years of age at the time of screening; 
4. Has a clinical diagnosis of probable AD according to the National Institute on Aging- 
Alzheimer's Association (NIA-AA) guidelines (McKhann, 2011; Appendix A); 
5, Has an MMSE score of 8 to 26 (inclusive) at screening; 
6. Has clinically significant symptom(s) of agitation secondary to probable AD, 
consistent with the International Psychogeriatric Association consensus definition (see 
Appendix B); 
7. At screening, according to NPI-C, has verbally agitated behavior, physically agitated 
nonaggressive behavior, or physical aggressive behavior occurring at least several 
times a week defined as ratings of frequency scores on items comprising the domains 
of Agitation and/or Aggression i.e., at least one behavior occurring at a frequency of 3 
(several times a week but less than every day) or 4 (once or more per day), or at least 
two behaviors occurring at a frequency of 2 (about once per week), or at least three 
behaviors occurring at a frequency of 1 (less than once per week).  This will be 
assessed over the past 4 weeks before screening; 
8. At baseline according to the CMAI-C, has agitation and/or aggressive behavior as 
measured by any of the items in the Factor Composite occurring at least several times 
a week, i.e., at least one behavior occurring at a frequency of 4, or two behaviors 
occurring at a frequency of 3, or three behaviors occurring at a frequency of 2, at 
baseline (as assessed over the past 2 weeks before baseline); 
9. In the opinion of the investigator, has frequent agitation that is clinically significant 
and warrants treatment with a pharmacological agent; 
10. Has a CGI-S of Agitation or CGI-S of Aggression score of ≥ 4 (moderately ill) at 
screening and baseline; 
11. Is maintained on a stable dose of any allowed standard of care medications for at least 
3 months prior to Day 1 (baseline) [unless a shorter duration is reviewed and approved 


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by the medical monitor] and for the duration of study participation.  This includes 
stable doses of cholinesterase inhibitors and memantine; 
12. Has a body mass index (BMI) between 19.0 and 38.0 kg/m2, inclusive, and a minimum 
body weight of 46 kg at screening; 
13. Has a score of ≤ 4 on a modified Hachinski Ischemia Scale; 
14. Has normal serum B12 and folate levels (patients with abnormally low serum B12 and 
folate levels at screening can be re-screened following supplementation). 
4.1.2 Part A Exclusion Criteria 
A patient meeting any of the following criteria will be excluded from the study: 
1. Is bedridden; 
2. Is, in the opinion of the investigator, unable to comply with study procedures; 
3. Has clinical symptoms suggestive of other neurological disease such as evidence of 
infection, tumor, infarction, or other focal (e.g., subdural hematoma) or generalized 
lesions (e.g., hydrocephalus) that could account for the subject’s dementia; 
[Note: if magnetic resonance imaging (MRI) or computed tomography (CT) scan of 
the head is available within the last 12 months, it should be negative]; 
4. Has, in the opinion of the investigator, and/or as assessed by the C-SSRS at screening 
(suicidal ideation of type 4 or 5 on the C-SSRS within 6 months prior to screening or 
any suicidal behavior in the last 2 years prior to screening, as indicated by any “yes” 
answers on the suicidal behavior section of the C-SSRS), a significant risk for suicidal 
behavior during the course of their participation in the study or is considered to be an 
imminent danger to themselves or others; 
5. Has any clinically significant systemic illness or unstable or severe medical 
condition(s) that could put the patient at risk during the study, interfere with outcome 
measures, or affect compliance with the protocol procedures, such as: 
a. History of myocardial infarction within 3 months prior to screening, unstable or 
severe cardiovascular disease including uncontrolled angina or congestive heart 
failure with symptoms at rest within 2 years before enrollment or history of a 
clinically significant cardiac arrhythmia including antipsychotic drug-induced 
QTc prolongation; 
b. Endocrine-related disease (including insulin-requiring diabetes or poorly 
controlled diabetes); uncorrected hypothyroidism within the last 2 years)  


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[Note: if on thyroid replacement medication, dose should be stable for at least 3 
months prior to screening and remain stable during trial participation, unless a 
shorter duration is reviewed and approved by the medical monitor]; 
c. Uncontrolled hypertension (systolic blood pressure > 180 mmHg or diastolic 
blood pressure > 110 mmHg); 
d. History of clinically significant liver disease, coagulopathy or Vitamin K 
deficiency within the last 2 years prior to screening; 
e. History of clinically significant renal disease;  
f. Clinically significant obstructive pulmonary disease or asthma; 
g. Clinically significant and unstable gastrointestinal disorder; 
h. Documented and confirmed clinically significant neurological or psychiatric 
disease (e.g., Parkinson’s disease, multi-infarct dementia, Huntington’s disease, 
normal pressure hydrocephalus [based upon clinical judgment], brain tumor, 
progressive supranuclear palsy, seizure disorder including epilepsy, subdural 
hematoma, schizophrenia, major depressive disorder, significant anxiety and/or 
phobic disorder(s), multiple sclerosis, arteriovenous malformation or history of 
significant head trauma and/or subdural hematoma followed by persistent 
neurologic deficits or known structural abnormalities, substance-induced 
persisting dementia, dementia due to multiple etiologies or dementia not 
otherwise specified) [Note: with the exception of rapid eye movement (REM) 
sleep behavior disorder, sleep disorders are allowed, but should be carefully 
documented, including but not limited to insomnia (sleep induction and/or sleep 
maintenance insomnia), periodic limb movements of sleep, and sleep apnea as 
determined by the STOP-bang questionnaire]; 
i. Malignancy (including any malignancy and/or chemotherapy within the 2 years 
prior to screening; malignancy more than 2 years prior to screening must have 
been local and without metastasis and/or recurrence, and if treated with 
chemotherapy, without nervous system complications; some malignancies, such 
as basal cell carcinoma, may not preclude participation and will be individually 
reviewed); 
j. Metabolic, psychiatric or other condition that might be detrimental to the patient 
if he or she participates in the study in the opinion of the investigator;  
6. Has abnormal laboratory values or clinical findings at screening that are judged 
clinically significant by the investigator (one re-test is allowed to confirm 
reproducibility of results; results must be available prior to the baseline visit and must 
have returned to non-clinically significant range). Absolute value exclusions are listed 
in items 6b and 6c below: 


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a. Thyroid stimulating hormone (TSH) outside of the normal limits and clinically 
significant as determined by the investigator.  Free thyroxine (T4) levels may be 
measured if TSH level is high.  Patient will be excluded if Free T4 level is judged 
clinically significant by investigator; 
b. 12-lead ECG (in a supine position at rest at screening or baseline visit; note: 
baseline ECG measures for determining inclusion into the study are based on the 
investigator/site read ECG data, though the database will reflect centrally read 
ECG data) mean of triplicate QTcF > 500 ms (independent from sex) and/or heart 
rate (HR) ≤50 beats per minute. Bundle branch blocks deemed clinically 
significant by investigator will be excluded. [Note: If it is the opinion of the 
investigator that a lower HR is physiological in a well-fit subject or due to stable 
concomitant medications, this will be reviewed and approved by the medical 
monitor on a case by case basis];  
c. Alanine transaminase (ALT), aspartate transaminase (AST), or creatine 
phosphokinase values > 3 times the upper limit of normal (ULN); 
d. Any other clinically significant abnormal laboratory result at the time of the 
screening as determined by the investigator;   
7. Is a female of childbearing potential as determined by the investigator;   
8. Has a history of neuroleptic malignant syndrome induced by any antipsychotic 
medication; 
9. Has a history of human immunodeficiency virus (HIV) infection or demonstration of 
HIV antibodies; 
10. Has a history of Hepatitis B or C infection AND evidence of active disease defined as 
elevated ALT, AST or bilirubin levels > 2 × ULN; 
11. Has demonstrated Hepatitis B surface antigen or Hepatitis C antibodies at screening 
AND evidence of active disease defined as elevated ALT, AST or bilirubin levels > 2 × 
ULN; 
12. Meets Diagnostic and Statistical Manual – 5th Edition (DSM-5) criteria for moderate 
to severe substance use disorder; 
13. Has a positive urine drug or alcohol test at screening  or evidence of either withdrawal 
from, or acute intoxication with cocaine, (meth) amphetamines, alcohol, barbiturates, 
or hallucinogens or similar compounds; 
 
 
 
 


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14. Has a likely allergy or sensitivity to ITI-007 or any psychoactive drug based on 
history; 
15. Has used any of the following agents under the specified conditions:  
a. Lifetime exposure to ITI-007 
 
 or, who has had exposure to any investigational product 
within 3 months of baseline visit or participated in the past 4 years in > 2 clinical 
studies of an investigational product with a central nervous system indication; 
b. Any strong or moderate CYP450 3A4 inhibitor or inducer within 7 days (or 5 
half-lives, whichever is greater) prior to the baseline visit;  
c. Certain drugs with known psychotropic properties or any non-psychotropic drugs 
with known or potential significant central nervous system effects within 5 half-
lives before the baseline visit unless noted below to be discontinued by the 
baseline with taper, if appropriate (see Section 5.8), including:  
i. Anxiolytics (except lorazepam as described in Table 5-7) 
ii. Sedative hypnotics  
iii. Central opioid agonists/antagonists including tramadol (Ultram). 
Except: following review by medical monitor for treatment of stable 
condition on case by case basis  
iv. Antipsychotics may be tapered and must be discontinued by the 
baseline visit  
v. Methotrexate 
vi. Any known 5-HT2A receptor antagonist or inverse agonist including 
but not limited to mianserin, mirtazapine, nefazodone, cyproheptadine, 
pimavanserin, or fluvoxamine 
vii. Immunosuppressants 
viii. St. John’s Wort must be discontinued by the baseline visit  
[Notes: Anticonvulsants, mood stabilizers, and antidepressants (such 
as SSRI or SNRI) may be allowed, but the dose should be stable for at 
least 3 months prior to screening and remain stable during trial 
participation, unless a shorter duration is reviewed and approved by 
the medical monitor.  Dietary supplements, medical foods, or 
pharmaceuticals used specifically for the treatment of dementia, 


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agitation, or sleep, containing omega3 fatty acids, melatonin, kava 
kava, Vitamin B12, folate, or valerian root may be allowed, but the 
dose should be stable for at least 3 months prior to screening and 
remain stable during trial participation, unless a shorter duration is 
reviewed and approved by the medical monitor.  Multivitamin as daily 
supplement is allowed.  All stable psychotropic medications or 
supplements require review and approval by the medical monitor.]; 
16. Is unable to be safely discontinued from current above-mentioned psychotropic 
medications; 
17. Is unable to swallow oral medication; 
18. Is judged by the investigator to be inappropriate for the study; 
19. Is an immediate family (i.e., spouse, parent, child, or sibling, whether biological or 
legally adopted) of the investigator, ITI or CROs conducting the study. 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 


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4.2 Withdrawal of Patients from the Study 
In Part A, the planned overall duration of the study for each patient is up to up to 8 weeks 
(7 visits): a screening/baseline period of up to 2 weeks, an on-treatment period of 4 weeks, 
 there will be a follow-up period of 
approximately 2 weeks.  The duration of the study is defined for each patient as the date 
signed written informed consent is provided through the last follow-up visit on Day 43 for 
patients who participate in Part A only.   
 
 
 
 
 
 
  
 
4.2.1 Reasons for Withdrawal/Discontinuation 
Patients may withdraw from the study at any time and for any reason without prejudice to 
their future medical care by the investigator or at the study site.  Every effort should be made 
to keep patients in the study.  The reasons for patients not completing the study will be 
recorded.  A patient may be withdrawn from the study for any of the following reasons: 
1. Does not meet the protocol inclusion criteria or meets the protocol exclusion criteria. 
2. Noncompliance with the protocol. 
3. A serious or intolerable AE that, in the investigator’s opinion, requires withdrawal 
from the study.   
4. Laboratory safety assessments that reveal clinically significant hematological or 
biochemical changes from baseline values, or baseline laboratory safety assessments 
that are returned after randomization in Part A
 
 
 


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5. Symptoms or an intercurrent illness not consistent with the protocol requirements or 
that justify withdrawal. 
6. Lost to follow-up. 
7. Other (e.g., pregnancy, development of contraindications of use of study drug). 
8. The investigator or sponsor decide to discontinue the patient’s participation in the 
study.  
[Note: Patients may be discontinued from study treatment, at the request of the 
Sponsor, if they experience adverse events that are unexpected based on previous ITI-
007 clinical trials that might indicate an allergy or sensitivity to ITI-007 (e.g., rash or 
respiratory distress) and/or might indicate underlying neurological toxicity (e.g., any 
new instance of tremor, including treatment-emergent mild tremor, or worsening of 
existing tremor) and/or might indicate liver function impairment (e.g., elevated liver 
function tests such as AST or ALT), or for other reasons.]   
9. The patient withdraws consent.  If consent is withdrawn, the patient must be 
questioned by the investigator or study site staff whether the withdrawal is due to an 
AE, lack of efficacy, personal or family reasons, or whether the patient withdrew 
consent and refused all end-of-study procedures, including refusing to give a reason; 
these reasons must be documented in the electronic case report form (eCRF). 
The investigator will also withdraw a patient if ITI terminates the study.  Upon occurrence of 
a serious or intolerable AE, the investigator will confer with the sponsor or medical monitor 
as the sponsor’s designee.  If a patient is discontinued because of an AE, the event will be 
followed until it is resolved, stabilizes, is determined to be non-clinically significant, or the 
patient is lost to follow-up.  Any patient may withdraw his or her consent at any time.  
4.2.2 Handling of Withdrawals 
Patients are free to withdraw from the study or study treatment at any time.  Patient 
participation in the study may be stopped at any time at the discretion of the investigator or at 
the request of the sponsor. 
Patients who discontinue study treatment or active participation in the study will no longer 
receive study drug.  When a patient withdraws from the study, the reason(s) for withdrawal 
shall be recorded by the investigator on the relevant screen of the eCRF.  Whenever possible, 
all patients who discontinue study treatment or withdraw from the study prematurely will 
undergo all end-of-study assessments.  Patients who fail to return for final assessments will 


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be contacted by the study site in an attempt to have them comply with the protocol.  A 
minimum of 2 documented telephone calls should be made on different days over the course 
of 2 weeks.  If the patient is unreachable by telephone, a registered letter should be sent to the 
patient requesting him or her to contact the study site. 
It is vital to obtain follow-up data on any patient withdrawn as a result of an AE or serious 
AE (SAE).  In every case, efforts must be made to undertake protocol-specified, safety, 
follow-up procedures.  All data collected from all patients, including early withdrawals, will 
be used in the reporting and analysis of the study. 
4.2.3 Replacements 
In Part A, patients who have been randomly assigned to study drug and prematurely 
discontinue from the study will not be replaced.   
A patient who fails to satisfy inclusion criteria and exhibits any of the exclusion criteria at 
screening/baseline may be rescreened with the permission of the medical monitor.  In Part A 
any patient who is rescreened within 28 days of an initial screen 
may have some screening procedures waived by the medical monitor on a case by case basis; 
any patient who is rescreened more than 28 days following the previous screen (as defined by 
the date of informed consent) will need to have all screening procedures repeated.  In all 
cases, a new informed consent must be obtained for a rescreen.  A patient may not be 
screened more than 2 times.   


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5 Study Treatments 
5.1 Method of Assigning Patients to Treatment Groups 
In Part A,  patients who continue to meet all eligibility criteria at baseline (Visit 2) will be 
randomly assigned to one of the two treatment groups for a 4-week, double-blind on-
treatment period.  Patients will be randomly assigned to one of the following groups: 9 mg 
ITI-007 or matching placebo.  The on-treatment period will be a total of 4 weeks.   
An interactive voice response system (IVRS)/interactive web response system (IWRS) 
(English only) will be used to administer the randomization schedule.  Unblinded 
biostatistics personnel not participating in the conduct of the study will generate a permuted 
block randomization schedule using SAS software Version 9.2 or higher (SAS Institute Inc, 
Cary, North Carolina) for IVRS/IWRS, which will link sequential patient randomization 
numbers to treatment codes.  In the event that the blind needs to be broken because of a 
medical emergency, the investigator may unblind an individual patient’s treatment allocation 
(Section 5.6.1).  The randomization schedule will be stratified by MMSE score at screening. 
Each patient will be assigned a randomization number, which will be separate from the 
patient identification number.  Once a randomization number has been allocated to a patient, 
it may not be assigned to another patient.   
The IVRS/IWRS will send visit notifications to the study center personnel, confirming the 
patient data that were entered.  The IVRS/IWRS notifications should be filed securely at the 
study site.   
 
 
 
 
  
 
  


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5.2 Treatments Administered 
In Part A, patients will be assigned to receive either 9 mg ITI-007 or placebo.  
 
 
 
 
 
   
 
 
 
 
 
  
 
5.3 Identity of Investigational Product 
5.3.1 Investigational Product for Study Part A 
In Part A, ITI-007 will be supplied as 4.5 mg over-encapsulated tablets (capsules) 
  
 
  
 
 
 
 
 
 
 
 
 












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5.4.2 Test Article Accountability 
The investigator will maintain accurate records of receipt of all test articles, including dates 
of receipt.  In addition, accurate records will be kept regarding when and how much test 
article is dispensed and used by each patient in the study.  Reasons for departure from the 
expected dispensing regimen must also be recorded.  At the completion of the study, to 
satisfy regulatory requirements regarding drug accountability, all study drug will be 
reconciled and retained or destroyed according to applicable regulations. 
5.5 Overdose Management 
An overdose is any dose of study treatment given to a patient or taken by a patient that 
exceeds the dose described in the protocol.  Any overdose, with or without associated AEs, 
must be promptly reported to the medical monitor.  Overdoses without signs or symptoms do 
not need to be recorded as AEs; in case of any AEs associated with the overdose, these 
should be reported on relevant AE/SAE sections in the eCRF. 
 
 
 
 
 
 
 
  
 
 
 
  
5.5.2 Medication Errors 
Dispensing study treatment to be taken by patients in an outpatient study increases risk for 
medication errors.  All errors in medication dispensing or administration must be carefully 
documented.  These errors may include, but are not limited to, providing the wrong dose (in 
Part A, not taking 2 capsules per dose or taking too many capsules per dose
 


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 losing medication, or administration at the wrong time of the 
day.  Medication adherence will be emphasized at every visit.  Written instructions will be 
provided to the patients with the treatment cards in order to minimize medication error.  
Additional adherence procedures may be implemented.   
5.5.3 Treatment of Medication Errors 
The treatment of medication errors should be discussed with the Medical Monitor on a 
case-by-case basis.  In the case of overdose, see Section 5.5.1. 
5.6 Blinding 
Part A  will be performed in a double-blind manner.  All study drug will be supplied in 
identical treatment cards and packaging, and will be similar in color, odor, taste, and 
appearance, thereby enabling double-blind conditions. 
 
  
5.6.1 Breaking the Blind 
In Part A, a patient’s treatment assignment will not be broken until the end of the study unless 
medical treatment of the patient depends on knowing the study treatment the patient received.  
In the event that the blind needs to be broken because of a medical emergency, the 
investigator may unblind an individual patient’s treatment allocation.  As soon as possible, 
the investigator should first contact the medical monitor to discuss the medical emergency 
and the reason for revealing the actual treatment received by that patient.  The treatment 
assignment will be unblinded through IVRS/IWRS.  Reasons for treatment unblinding must 
be clearly explained and justified in the eCRF.  The date on which the code was broken 
together with the identity of the person responsible must also be documented. 
 
   
 
l clinical data have 
been entered into the database and all data queries have been resolved.   


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5.7 Treatment Compliance 
Patient compliance will be assessed by  counts of unused study drug at each visit during the 
double-blind on-treatment period for Part A 
 
Table 6-1 
   
In Part A, any irregularities in medication adherence should be discussed with the patient.  
Any patient who misses 2 doses of study drug per week in any 2 weeks of the study on-
treatment period or who misses 3 or more doses of study drug in any single week should be 
considered for early discontinuation.  Any exceptions due to unusual circumstances should be 
discussed on a case-by-case basis with the medical monitor to determine whether a patient 
may continue despite apparent treatment compliance issues.  
 
 
 
5.8 Prior and Concomitant Therapy  
Patients who are maintained on a stable dose of any allowed standard of care medications for 
at least 3 months prior to Day 1 (baseline) [unless a shorter duration is reviewed and 
approved by the medical monitor] and for the duration of study participation may be eligible 
for participation in this study.  This includes stable doses of cholinesterase inhibitors and 
memantine. 
Patients are required not to use the following during the study: alcohol, cannabis, any known 
5-HT2A receptor antagonist or inverse agonist, any strong or moderate cytochrome P450 3A4 
inhibitor or inducer, any short-acting anxiolytic (except use of lorazepam described in 
Table 5-7 and Table 5-8 below), or certain drugs with known psychotropic properties or any 
non-psychotropic drugs with potential central nervous system effects, including: 
i. Anxiolytics (except lorazepam as described in Table 5-7 and 
Table 5-8) 
ii. Sedative hypnotics  
iii. Central opioid agonists/antagonists including tramadol (Ultram). 
Except: following review by medical monitor for treatment of stable 
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6 Study Assessments and Procedures 
Before participating in any study procedures, all potential study patients must sign an 
informed consent form (ICF) or have written informed consent provided on behalf of the 
patient by a LAR.  Patients (or LAR) will have the opportunity to have any questions 
answered before signing the ICF.  The investigator must address all questions raised by the 
patient (or LAR).  The investigator will also sign the ICF and a signed copy will be provided 
to the patient (or LAR).  Separate written informed consent must be provided for each part of 
the study.  
The schedules of events are presented in Table 6-1 
  
 
 
   
 


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Table 6-1 
Part A Schedule of Events 
Study Period 
Screening 
Baseline 
Double-Blind On-Treatment Period 
Follow-up  
Visit No. 
1 
2 
3 
4 
5 
6  
7 or ET1 
Study Week 
- 2 
0 
1 
2 
3 
4 
6 
Study Day 
Up to – 142 
1 
8 (±1) 
15 (±1) 
22 (±1) 
29 (±1) 
43 (±2) 
 
Clinic Visit 
Clinic Visit 
Phone 
contact 
Clinic 
Visit 
Phone 
contact 
Clinic 
Visit 
Clinic Visit 
Informed Consent 
Before Any Study-Specific 
Procedures are Conducted 
 
 
 
 
 
 
Review Patient/Caregiver 
Information Sheet  
X 
 
 
 
 
 
 
Medical History incl. 
Demography and STOP-
bang Questionnaire 
X 
 
 
 
 
 
 
Modified Physical & 
Neurological Examination 
including Calculation of 
BMI (height and Modified 
Hachisnki Ischemia Scale at 
screening only) 
X 
 
 
 
 
X 
X 
12-lead ECG3 
X 
X 
 
 
 
X 
X 
Vital Signs4  
X 
X 
 
X 
 
X 
X 
Hepatitis/HIV Testing 
X 
 
 
 
 
 
 
Drug and Alcohol Screen 
X 
X 
 
 
 
 
 
Laboratory Assessments5 
X 
 
 
 
 
X 
X 
Dementia Diagnosis 
X 
 
 
 
 
 
 
MMSE 
X 
 
 
 
 
X 
 
C-SSRS 
X 
X 
 
 
 
X 
X 
CMAI-C10 
 
X 
 
X 
 
X 
 
CGI-S of Agitation10 
X 
X 
 
X 
 
X 
 
CGI-S of Aggression10 
X 
X 
 
X 
 
X 
 
Caregiver Diary6 
X 
X 
 
X 
 
X 
 


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Study Period 
Screening 
Baseline 
Double-Blind On-Treatment Period 
Follow-up  
Visit No. 
1 
2 
3 
4 
5 
6  
7 or ET1 
Study Week 
- 2 
0 
1 
2 
3 
4 
6 
Study Day 
Up to – 142 
1 
8 (±1) 
15 (±1) 
22 (±1) 
29 (±1) 
43 (±2) 
 
Clinic Visit 
Clinic Visit 
Phone 
contact 
Clinic 
Visit 
Phone 
contact 
Clinic 
Visit 
Clinic Visit 
Day/Night Actigraphy7 
X 
X 
 
X 
 
X 
 
Review Inclusion/ 
Exclusion Criteria 
X 
X 
 
 
 
 
 
 Eligibility Adjudication8 
X 
 
 
 
 
 
 
NPI-C   
X 
 
 
 
 
X 
 
SAS & BARS & AIMS 
 
X 
 
 
 
X 
 
Blood Draw for 
Pharmacokinetic 
Assessments9 
 
X 
 
 
 
X 
X 
Blood Draw for 
Biomarker Assessments 
 
X 
 
 
 
 
 
Randomization 
 
X 
 
 
 
 
 
Medication Dispensed 
 
X 
 
X 
 
 
 
Unused Medication 
Returned 
 
 
 
X 
 
X 
 
Treatment Compliance 
Assessment 
 
 
 
X 
 
X 
 
AEs / SAEs 
X 
X 
X 
X 
X 
X 
X 
Prior/ Concom Med 
X 
X 
X 
X 
X 
X 
X 
1 An attempt should be made to collect as many Day 43 assessments as possible upon early discontinuation / early termination from study treatment. 
2 Extension to the screening period may be approved by the Sponsor or representative in extenuating circumstances related to the patient or caregiver.  
3   Each ECG assessment will comprise of triplicate 10 second epochs from 12-lead ECGs recorded 5 minutes apart.  One triplicate ECG will be performed during 
screening, at baseline and on Days 29 and 43 (or Early Termination Visit).  In all cases, ECGs are conducted before other assessments scheduled in the same 
time window; for example, when ECG, vital signs, and blood sample collection for PK measures are scheduled for the same time window, ECG measures 
should be conducted first, followed by vital signs and then blood sample collection. 


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4  Vital sign assessments will include 3-positional blood pressure and pulse rate, respiratory rate, and oral temperature.  The 3-positional blood pressure and pulse 
rate will be measured after 10 minutes in the supine position, 1 minute sitting, immediately after standing, and 3 minutes after standing.  Pulse will be 
measured by counting pulse over 60 seconds.  Height will be measured only at screening.  Body weight will be measured during screening, at baseline and on 
Days 15 29 and 43 (or Early Termination Visit).  Vital signs are always taken after conducting the ECGs, as applicable, and prior to any other assessments, 
including needle sticks for labs or PK samples, scheduled in the same time window.  
5 Clinical laboratory samples are to be taken after an overnight fast of at least 10 hours, after any scheduled ECG or vital signs have been recorded. Screening 
clinical laboratory may be fasting or non-fasting. 
6  Diaries will be dispensed at screening (Visit 1).  Caregivers will be asked to fill out a daily diary during the screening/baseline period and throughout the study 
on-treatment period.  The period between the screening visit (Visit 1) and the Baseline visit (Visit 2) will serve as baseline for the data collected in the diary 
and will serve to ascertain diary compliance before randomization.  The diary will be reviewed by the investigator or approved clinical rater at the site to 
facilitate caregiver interviews and inform the clinical ratings.  
7Actigraphy units will be provided at screening (Visit 1) to patients and to caregivers who provide optional consent for the caregiver actigraphy data collection.  
Actigraphy units will be worn during the screening/baseline period and throughout the study on-treatment period; data will be downloaded from units at 
scheduled visits.  The period between the screening visit (Visit 1) and the baseline visit (Visit 2) will serve as baseline for the data collected by actigraphy and 
will serve to ascertain actigraphy compliance before randomization. 
8  Screening adjudication process to confirm eligibility will take place between screening and baseline and will be administered by remote, independent expert 
raters and/or medical monitor(s) who are approved for this role by the sponsor and with the adjudication conducted in conjunction with the sponsor.  This 
includes the Qualitative Assessment of Biopsychosocial Conditions (Qual-ABC) to confirm subject suitability and caregiver appropriateness for participation 
in the study. 
9   Blood sample collection for pharmacokinetic analysis will be collected pre-dose at baseline (Visit 2) and on Study Days 29 (Visit 6) and on Day 43 at the final 
safety follow-up visit (Visit 7 or Early Termination Visit if a patient does not complete the on-treatment period) for determination of ITI-007 (IC200056 
parent) and its metabolites (IC200131, IC200161, IC200565, IC201308, and IC201309) concentrations in plasma. 
10 CGI-S assessments should be completed by the same site rater on the same day after the NPI-C at screening and after the CMAI-C assessment at other visits. 
 
 
 
 


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6.1 Screening Assessments and Procedures 
After obtaining written informed consent, the following assessments are to be performed 
within 2 weeks prior to baseline (Day 1), according to the schedule of events in Table 6-1 
for Part A 
 assessments can be conducted on different days 
within the screening period. 
6.1.1 Informed Consent 
For Part A 
 before any study-related activities the patient or LAR must sign and 
date an ICF approved by the responsible institutional review board (IRB).  The format and 
content of the ICF must have been agreed upon by the investigator, the appropriate IRB, and 
ITI.   
 
 
 
 
 
 
 
 
 
 
 
6.1.2 Medical History and Other Information 
Medical history information will be collected at screening and should include (but not be 
limited to) demographic information, current and past medical conditions, and current and 
past medications.  The medical history must be documented in the patient’s study chart prior 
to study treatment administration and also recorded in the appropriate eCRF.  In addition to 
conventional medical history, information pertaining to the patient’s average alcohol and 
caffeine consumption and average tobacco usage should be recorded in the eCRF.  
Demographic information will also be collected.  


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Medical history of sleep disorders are allowed, with the exception of rapid eye movement 
sleep disorder, but should be carefully documented, including but not limited to insomnia 
(sleep induction and/or sleep maintenance insomnia), sleep apnea (as determined by the 
STOP-bang questionnaire; Chung, 2008 for Part A) and periodic limb movements during 
sleep. 
6.1.3 Modified Physical and Neurological Examination  
A modified physical examination, including neurological and excluding genital/rectal 
examinations, will be performed.  The examination should include evaluation of height (at 
screening only [m]); body weight (kg); appearance and skin; head and neck; eyes, ears, 
nose, and throat; chest and lungs; heart; abdomen; and extremities.  Neurological 
examinations include an assessment of motor function, sensory function, reflexes, and gait.  
All physical and neurological examination findings must be documented in the patient’s 
study chart and also recorded in the eCRF.  The Modified Hachinski Ischemia Scale should 
be conducted at Screening Visit only.  Physical and neurological examinations will be 
conducted according to the schedule of events in Table 6-1 
 
6.1.4 Electrocardiogram Assessments 
In Part A, each ECG assessment will be comprised of triplicate 10-second epochs from 
12-lead ECGs recorded 5 minutes apart.  Electrocardiogram parameters to be measured 
include HR, QRS, PR, QT, QTcF, and RR intervals.  
The ECG recordings will be made on ECG machines supplied by a central ECG laboratory.  
Electrocardiogram data will be transferred to the central ECG laboratory on the same day as 
collected and interpretation will be provided to the study site within approximately 48 hours.  
If any 12-lead ECG recording shows an arrhythmia other than a sinus arrhythmia, sinus 
tachycardia, or sinus bradycardia, an additional 12-lead ECG will be recorded to confirm the 
original tracing.  Any other clinically significant treatment-emergent cardiac conduction 
abnormalities will be followed until no longer deemed necessary by the investigator. 
Central interpretations of ECG recordings obtained at screening will be the basis for 
determination that a patient is eligible for inclusion in the study.  Similarly, central 
interpretations of ECG recordings at baseline and other visits will be included in the final 
study data.  However, given that interpretations of recordings will not be available for up to 
48 hours, investigators are to use machine generated parameters and clinical judgment to 


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assess cardiac function for the purposes of immediate safety concerns and baseline ECG 
measures for determining inclusion into the study are based on the investigator/site clinical 
judgement based on machine generated ECG data.  ECG recordings will be made according 
to the schedule of events in Table 6-1. 
 
 
 
 
 
  
 
 
6.1.5 Vital Sign Measurements 
In Part A, vital sign assessments will include 3-positional blood pressure and pulse rate, 
respiratory rate, and oral temperature.  The 3-positional blood pressure and pulse rate will be 
measured after 10 minutes in the supine position, 1-minute sitting, immediately after 
standing, and 3 minutes after standing.  Pulse will be measured by counting pulse over 
60 seconds.  Height will be measured only at screening.  Vital signs, including body weight 
will be measured at scheduled clinic visits according to the schedule of events in Table 6-1.  
Each patient’s BMI will be calculated before Baseline to ensure that the patient meets the 
BMI inclusion criterion.   
 
 
 
  
 
 
   


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6.1.6 Hepatitis Screening 
Blood samples will be collected at screening from all patients in order to perform hepatitis B 
surface antigen and hepatitis C antibody (immunoglobulin G) testing.  Test results will be 
sent to the screening site and must be reviewed before the Baseline visit (Visit 2).  Any 
patient with active disease as evidence by LFT elevation for hepatitis B or C will be 
excluded from participating in the study.  Details regarding sample collection, processing, 
and shipping can be found in the study reference manual. 
6.1.7 HIV Screening 
Patients are required to provide blood samples for HIV virus types 1 and 2 testing.  Test 
results will be sent to the screening site and must be reviewed before the Baseline visit 
(Visit 2).  Any patient positive for HIV will be excluded from participating in the study.  
Patients will be informed of positive HIV results and referred for follow-up testing and 
counseling, and health authorities will be notified of positive HIV results consistent with 
federal, state, and local laws.  Details regarding sample collection, processing, and shipping 
can be found in the study reference manual.  
6.1.8 Drug and Alcohol Screening 
Urine drug (amphetamines, barbiturates, benzodiazepines, cannabinoids [THC], cocaine 
metabolites, methadone, opiates, phencyclidine, propoxyphene) and alcohol tests will be 
performed.  Any patient with a positive urine drug or alcohol test at screening or evidence of 
either withdrawal from, or acute intoxication with cocaine, (meth) amphetamines, alcohol, 
barbiturates, or hallucinogens or similar compounds will be excluded from participating in 
the study. 
Previous occasional use of alcohol or cannabis (but not synthetic marijuana/K2/Spice) or 
prescribed psychotropic (e.g., benzodiazepine, opiate) is allowed as long as the level of use 
does not meet DSM-5 criteria for any moderate or severe substance use disorder within the 
12 months prior to screening and the use of alcohol or cannabis is not considered by the 
investigator to be the precipitating factor of the current agitation, and any prescribed 
psychotropic is accompanied by evidence of prescription; patients are required to abstain 
from alcohol and cannabis use during the study. 


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When urine collection is not feasible to collect, missing urine drug screen data and risk for 
substance use will be reviewed as part of the screening adjudication process.  
Further information regarding sample collection, processing, and shipping can be found in 
the study reference manual. 
6.1.9 Laboratory Assessments 
Laboratory assessments performed at screening are described in Section 6.5. 
6.1.10 Dementia Diagnosis 
The major clinical criterion for inclusion in the study is that the patient be diagnosed with 
probable AD according to the NIA-AA guidelines (McKhann, 2011; Appendix A).  The 
NIA-AA guidelines will be used in this study at screening only to confirm the diagnosis of 
probable AD in patients evaluated for inclusion in the study.  Diagnosis will be performed 
by the investigator or an expert site-based rater approved by the sponsor.   
6.1.11 Mini Mental State Examination  
The MMSE is a brief cognitive test assessing general cognitive function (Folstein, 1975) 
that has been employed in numerous clinical trials of Food and Drug Administration (FDA) 
products approved for the treatment of AD.  The MMSE consists of 5 components: 1) 
orientation to time and place, 2) registration of 3 words, 3) attention and calculation, 4) 
recall of 3 words, and 5) language.  The scores from each of the five components are 
summed to obtain the overall MMSE score.  The score can range from 0 to 30, with lower 
scores indicating greater impairment in function.  This will be used to assess severity at 
screening (Visit 1) and at the end of the study on-treatment period (Visit 6).  The MMSE 
takes about 5 to 10 minutes to administer.  The MMSE will be administered by the 
investigator or an expert site-based rater approved by the sponsor and results will be 
reviewed by an independent expert as a component of the systematic patient eligibility 
adjudication process for participation in Part A.   
6.1.12 Columbia Suicide Severity Rating Scale 
The C-SSRS is a questionnaire developed and validated by Kelly Posner and colleagues 
(2011) for the assessment of suicidal ideation and behavior.  Several versions have been 
developed including the “Baseline” and “Screening” versions and a combined 


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“Baseline/Screening” version of the scale which assesses suicidal ideation and behavior in a 
patient’s lifetime and during a predefined time period.  This version can assess a patient’s 
lifetime suicidality as well as eligibility based on inclusion/exclusion criteria.  A separate 
“Since Last Visit” version of the scale has been developed which is used to assess suicidality 
since the patient’s last visit.  This version is meant to assess patients who have completed at 
least 1 initial C-SSRS assessment, and should be used at every subsequent visit.  The “Since 
Last Visit” version of the C-SSRS addresses any suicidal thoughts or behaviors the 
patient/participant may have had since the last time the C-SSRS was administered.   
The C-SSRS will be administered by the investigator or an expert site-based rater, as 
indicated in the Schedule of Events (Table 6-1 and Table 6-2).   
At screening, a potential study participant will not be eligible if he or she reports suicidal 
ideation of type 4 or 5 on the C-SSRS within 6 months prior to screening or any suicidal 
behavior in the last 2 years prior to screening, as indicated by any “yes” answers on the 
suicidal behavior section of the C-SSRS. 
6.1.13 Neuropsychiatric Inventory Clinician  
The NPI-C is structured to allow clinician input to assessments of neuropsychiatric 
symptoms (Cummings, 1994).  The NPI-C can be used to rate the presence of 
neuropsychiatric symptoms across many domains, as in the original NPI, as a standalone 
measure for specific symptom domains (e.g., dysphoria, agitation), or a combination of both 
(presence of neuropsychiatric symptoms across domains plus particular focus on one or 
more specific domains).  Unlike the original NPI, the NPI-C allows the rater to obtain 
additional caregiver and patient information to inform the rating for each item within a 
domain.  The NPI-C is completed following a caregiver interview (rating each item for 
frequency on a scale of 0 to 4, severity on a scale of 0 to 3, and distress on a scale of 0 to5), 
a patient interview (rating each item for frequency on a scale of 0 to 4) and a clinical 
assessment (rating each item for clinical impression of severity on a scale of 0 to 3).  The 
NPI-C is validated looking back over the past 4 weeks.  In the present study, the NPI-C will 
be used as a secondary endpoint, assessed at screening and endpoint, after 4 weeks of 
treatment.  The score for each domain is the sum of clinical impression ratings for all items. 
The NPI-C will be assessed at screening and again after four weeks of treatment according 
to the schedule of events in Table 6-1 for Part A 
 


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6.1.14  Clinical Global Impression scale for Severity of Illness 
The CGI scale for Severity of Illness (Guy, 1976) is a standardized assessment tool that the 
clinician can use to rate the overall severity of illness and efficacy of medication.  CGI-S of 
Agitation and CGI-S of Aggression will be used in this study at screening and baseline (as a 
criterion for inclusion or exclusion) and throughout the study as a measure of efficacy 
(Table 6-1 and Table 6-2).  Scores on the CGI-S range from 1 (not ill at all) to 7 (among the 
most extremely ill).  A CGI-S assessment will be completed by the investigator or another 
ITI-approved expert site-based rater, the same person who completes the CMAI-C 
assessment, following and informed by the CMAI-C and all other available clinical 
information at all visits except screening.  At screening, the CGI-S assessments will be 
completed following and informed by the NPI-C and all other available clinical information.   
6.1.15 Caregiver Daily Diary 
 
Caregivers will be asked to record the frequency of patient agitation and aggressive 
behaviors on a daily basis in order to inform the caregiver’s input to the clinician at the 
study visits.  A formal structure for the diary will be provided in order to collect daily 
reports in a systematic and consistent way across caregivers.  Caregivers and clinicians will 
review the daily diary together at the study visits.  The intent is to reduce the reliance on 
caregiver memory of frequency of events that occurred over the past two weeks by 
recording events daily. 
Diaries will be dispensed at screening (Visit 1).  Caregivers will be asked to fill out a daily 
diary during the screening/baseline period and throughout the study on-treatment period.  
The period between the screening visit (Visit 1) and the baseline visit (Visit 2) will serve as 
baseline for the data collected in the diary and will serve to ascertain diary compliance 
before randomization.  The diary will be reviewed by the investigator or approved clinical 
rater at the site to facilitate caregiver interviews and inform the clinical ratings (Table 6-1). 
6.1.16 Actigraphy 
  
Actigraphy is a non-invasive method of monitoring human rest/activity cycles.  A small 
actigraph unit, also called an actimetry sensor or actigraphy device, is worn for a week or 
more to measure gross motor activity.  The unit is usually, in a wrist-watch-like package, 
worn on the wrist.  The movements the actigraph unit undergoes are continually recorded 
and some units also measure physiological measures (e.g., HR) and environmental measures 


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(e.g., light exposure).  The data can be later read to a computer and analyzed offline; in 
some brands of sensors the data is transmitted and analyzed in real time.  Actigraphy will be 
measured for the patient and the primary caregiver, by way of separate, optional consent of 
the primary caregiver.  The actigraph unit will be secured in place at the initial screening 
visit (Visit 1) and worn throughout the on-treatment period (through Visit 6); data will be 
downloaded from the unit at scheduled visits.  The period between the screening visit 
(Visit 1) and the baseline visit (Visit 2) will serve as baseline for the data collected by 
actigraphy and will serve to ascertain actigraphy compliance before randomization.  If 
wearing the actigraph unit is not tolerated and is removed by the patient, the data will not be 
collected after the second attempt of securing the device in place; such data will be handled 
as missing data as described in the statistical analysis plan.  Re-securing of the actigraph 
unit will not be repeatedly attempted so as not to further agitate the patient or increase the 
burden to the caregiver. 
6.1.17 Eligibility Adjudication 
 
Eligibility of potential patients will be confirmed through a formal adjudication process, in 
which screening data obtained to evaluate patient diagnosis, severity of illness, medical 
appropriateness for participation in the clinical study, and appropriateness of the designated 
caregiver for participation in the clinical study.  Adjudication of patient eligibility will be 
administered by remote, independent expert raters and/or medical monitor(s) who are 
approved for this role by the sponsor and adjudication will be conducted in conjunction with 
the sponsor.  Further information regarding the screening adjudication can be found in the 
study reference manual.   
6.2 Efficacy Assessments and Procedures 
6.2.1 CMAI-C 
The purpose of the CMAI is to measure the frequency of agitated behaviors 
(Cohen-Mansfield, 1989).  The CMAI has been validated in measuring behavior over the 
past 2 weeks.  Recall of frequency is a reasonably objective, quantifiable and reliable 
measure.  In the present study, recall of frequency of agitated behavior will be supported by 
a structured clinical interview performed by the clinician and the use of a daily caregiver 
diary that will be referred to before and during the course of the standardized interview.  
Frequent individual agitation behavior is troubling for the patient and disruptive to the 
caregiver; physically aggressive behavior is particularly troublesome for the patient and 


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distressful to the caregiver.  The Community version (CMAI-C; 37 items rated 1-7 for 
frequency) (Cohen-Mansfield, 1991; Cohen-Mansfield, 1995) will be utilized in the present 
study.  The 37 CMAI-C items are specifically worded to ensure the rater’s standardization, 
consistency and specific shared understanding in the interview of the community-based non-
professional primary caregiver for each specific agitation behavior item.  Items that do not 
apply to the patient are skipped.  The 1 to 7 scoring range of the CMAI-C offers 
significantly finer granularity than other versions that utilize a 1 to 5 scoring range with 
regards to the taxonomy of specific agitated behaviors, while maintaining the objectivity of 
the frequency-based rating of each item.  
The CMAI-C Factor Composite score (Appendix C) includes key symptom items from the 
CMAI-C that have been demonstrated to reliably cluster in meaningful symptom domains 
associated with agitation and aggression according to factor analyses (Rabinowitz, 2005).   
The CMAI-C is the primary efficacy measure which will be administered in its full 
validated form (but only a subset of items will be included in the primary efficacy analysis, 
Appendix C) and will be assessed according to the schedule of events in Table 6-1 for Part A 
 
6.2.2 Clinical Global Impressions 
The CGI-S of Agitation and CGI-S of Aggression (Section 6.1.14) will be a clinical efficacy 
assessment by the investigator of each patient’s severity of illness.  The CGI-S assessments 
will be measured after 2 and 4 weeks of treatment according to the schedule of events in 
Table 6-1 for Part A 
  
6.2.3 Neuropsychiatric Inventory Clinician  
The NPI-C (Section 6.1.13) will be assessed at screening and again after four weeks of 
treatment according to the schedule of events in Table 6-1 for Part A 
 
   
6.2.4 Caregiver Daily Diary (Part A only) 
The caregiver daily diary will be administered as described in Section 6.1.15. 


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6.3 Safety and Tolerability Assessments 
All patients who receive study drug will be evaluated for safety (Table 6-1 and Table 6-2).  
6.3.1 Adverse Events 
The investigator is responsible for reporting all AEs that are observed or reported during the 
study, regardless of their relationship to study drug or their clinical significance. 
6.3.1.1 Definition of Adverse Event 
An AE is any untoward medical occurrence in a study patient administered a study drug, 
whether or not considered drug related.  This can be any unfavorable and unintended sign 
(such as an abnormal laboratory finding), symptom, or disease temporally associated with 
the use of a study drug, without any judgment of causality. 
The AE may be: 
• A new illness; 
• A worsening sign or symptom of the condition under treatment, or of a concomitant 
illness; 
• An effect of the study drug, including comparator; or 
• A combination of 2 or more of these factors. 
 
No causal relationship with the study drug or with the clinical study itself is implied by the 
use of the term AE. 
Surgical procedures themselves are not AEs; they are therapeutic measures for conditions 
that require surgery.  The condition for which the surgery is required may be an AE.  
Planned surgical measures, if permitted by the clinical study protocol and the conditions 
leading to those measures are not AEs. 


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TEAEs will be defined as any AEs, regardless of the relationship to study drug, that occur or 
worsen in intensity after the first dose of study drug and on or before the last date of study 
drug. 
All AEs fall into the categories of “nonserious” or “serious (Sections 6.3.1.2 and 6.3.1.3). 
6.3.1.2 Definition of Serious Adverse Event 
An SAE is defined as any untoward medical occurrence that at any dose: 
• Results in death; 
• Is life threatening;  
• Requires hospitalization or prolongation in existing hospitalization; 
• Results in persistent or significant disability or incapacity; or 
• Is a congenital anomaly or birth defect. 
The term “life threatening” refers to an event in which the patient is at risk of death at the 
time of the event; it does not refer to an event, which hypothetically might have caused 
death if it were more severe. 
Medical and scientific judgment should be exercised in deciding whether an AE is serious.  
Some important medical events that may not result in death, be life threatening, or require 
hospitalization may be considered SAEs when they may jeopardize the patient such that 
medical or surgical intervention is needed to prevent 1 of the outcomes previously listed.  
Examples of such medical events include intensive emergency treatment for an allergic 
reaction, blood dyscrasias or convulsions that do not result in inpatient hospitalization, and 
the development of drug dependency or drug abuse. 
If either the sponsor or principal investigator believes that any event is serious, the event 
must be considered and evaluated by the sponsor for possible expedited reporting. 
Clarification of the difference between "serious" and "severe": 
The term “severe” is often used to describe the intensity (severity) of a specific event (as in 
mild, moderate, or severe myocardial infarction); the event itself, however, may be of 
relatively minor medical significance (such as a severe headache).  This is not the same as 
“serious,” which is based on patient/event outcome or action criteria usually associated with 


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events that pose a threat to a patient’s life or functioning.  Seriousness (not severity) serves 
as a guide for defining regulatory reporting obligations. 
6.3.1.3 Nonserious Adverse Event 
A nonserious AE is any AE not meeting the SAE criteria.  
6.3.1.4 Definition of Relationship to Study Drug 
By definition, any AE that starts before the first dose of study drug administration is 
considered to be “unrelated.” 
The investigator will assess the causality/relationship between the study drug and the AE 
(Table 6-3).  One of the following categories should be selected based on medical judgment, 
considering the following definitions and all contributing factors. 


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Table 6-3 
Causality Categories 
Category 
Definition 
Definitely related 
 
A clinical event, including laboratory test abnormality, occurs in a 
plausible time relationship to treatment administration, and which 
concurrent disease or other drugs or chemicals cannot explain.  The 
response to withdrawal of the treatment (dechallenge1) should be 
clinically plausible.  The event must be definitive pharmacologically or 
phenomenologically, using a satisfactory rechallenge2 procedure if 
necessary. 
Probably related 
 
A clinical event, including laboratory test abnormality, with a reasonable 
time sequence to administration of the treatment, unlikely to be 
attributed to concurrent disease or other drugs or chemicals, and which 
follows a clinically reasonable response on withdrawal (dechallenge).  
Rechallenge information is not required to fulfill this definition. 
Possibly related 
 
A clinical event, including laboratory test abnormality, with a reasonable 
time sequence to administration of the treatment, but which could also 
be explained by concurrent disease or other drugs or chemicals.  
Information on treatment withdrawal may be lacking or unclear. 
Unlikely to be 
related 
 
A clinical event, including laboratory test abnormality, with a temporal 
relationship to treatment administration which makes a causal 
relationship improbable, and in which other drugs, chemicals or 
underlying disease provide plausible explanations. 
Unrelated 
 
A clinical event, including laboratory test abnormality, with little or no 
temporal relationship with treatment administration.  May have negative 
dechallenge and rechallenge information.  Typically, explained by 
extraneous factors (e.g., concomitant disease, environmental factors, or 
other drugs or chemicals). 
1 Dechallenge is when a drug suspected of causing an adverse event (AE) is discontinued.  If the symptoms of 
the AE disappear partially or completely, within a reasonable time from drug discontinuation, this is termed a 
positive dechallenge.  If the symptoms continue despite withdrawal of the drug, this is termed a negative 
dechallenge.  Note that there are exceptions when an AE does not disappear upon discontinuation of the drug, 
yet drug-relatedness clearly exists (e.g., bone marrow suppression, fixed drug eruptions, tardive dyskinesia). 


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2 Rechallenge is when a drug suspected of causing an AE in a specific patient in the past is readministered to 
that patient.  If the AE recurs upon exposure, this is termed a positive rechallenge.  If the AE does not recur, 
this is termed a negative rechallenge. 
 
6.3.1.5 Definition of Intensity 
The principal investigator will assess all AEs for intensity (severity) in accordance with the 
following standard ratings (Table 6-4): 
Table 6-4 
Intensity Categories 
Category 
Definition 
Mild 
Ordinarily transient symptoms, does not influence performance of 
patient’s daily activities.  Treatment is not ordinarily indicated. 
Moderate 
Marked symptoms, sufficient to make the patient uncomfortable.  
Moderate influence on performance of patient’s daily activities.  
Treatment may be necessary. 
Severe 
Symptoms cause considerable discomfort.  Substantial influence on 
patient’s daily activities.  May be unable to continue in the study and 
treatment may be necessary. 
Life threatening 
Extreme limitation in activity, significant assistance required; 
significant medical intervention/therapy required, hospitalization or 
hospice care probable. 
 
When changes in the intensity of an AE occur more frequently than once a day, the 
maximum intensity for the event should be noted for that day.  Any change in intensity of 
signs and symptoms will be captured by recording a new AE, with the amended intensity 
grade and the date (and time, if known) of the change.  
6.3.1.6 Period of Observation for Adverse Events 
For the purposes of this study, the period of observation extends from the time the patient 
gives his study-specific informed consent until the end of study procedures are completed. 


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If the investigator detects an SAE in a study patient after the end of the period of 
observation and considers the event possibly related to prior study treatment, he or she 
should contact the sponsor to determine how the AE should be documented and reported. 
6.3.1.7 Documenting, Reporting, and Eliciting Adverse Events  
All AEs reported or observed during the study will be collected and recorded on the AE 
page of the eCRF for each patient from the date the ICF was signed until the end of study 
procedures are completed. 
Adverse events may be volunteered spontaneously by the patient, or discovered by the study 
staff during physical examinations or by asking an open, non-leading question such as, 
“How have you been feeling since you were last asked?”  All AEs and any required remedial 
action will be recorded.  The nature of the AE, date (and time, if known) of the AE onset, 
date (and time, if known) of the AE outcome to date, severity, and action taken for the AE 
will be documented together with the investigator’s assessment of the seriousness of the AE 
and causal relationship to study drug and/or study procedure.  
All AEs should be recorded individually in the study patient’s own words (verbatim) unless, 
in the opinion of the investigator, the AEs constitute components of a recognized condition, 
disease or syndrome.  In the latter case, the condition, disease or syndrome should be named 
rather than each individual symptom.  The AEs will subsequently be coded using the latest 
version of Medical Dictionary for Regulatory Activities (MedDRA).  
6.3.1.8 Notification About Serious or Unexpected Adverse Events 
The investigator will review each SAE (Section 6.3.1.2) and evaluate the intensity and the 
causal relationship of the event to study drug.  All SAEs will be recorded from signing of 
informed consent until the end of study procedures are completed.   
The investigator is responsible for providing notification to the sponsor or designee of any 
SAE, whether deemed related to study drug or not, that a patient experiences during their 
participation in study within 24 hours of becoming aware of the event. 
As a minimum requirement, the initial notification should provide the following 
information: 
• Study number 


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• Patient number 
• Gender 
• Date of birth 
• Name of investigator and full study site address 
• Details of SAE 
• Criterion for classification as “serious” 
• Study drug code, or name if unblinded, and treatment start date and stop date, if 
applicable 
• Date of SAE onset 
• Causality assessment (if sufficient information is available to make this classification) 
The sponsor will request clarification of omitted or discrepant information from the initial 
notification.  The investigator or an authorized delegate is responsible for faxing the 
requested information to the sponsor within 24 hours of the sponsor’s request. 
Initial reports of SAEs must be followed later with detailed descriptions, including clear 
photocopies of other documents as necessary (e.g., hospital reports, consultant reports, 
autopsy reports), with the study patient’s personal identifiers removed.  All relevant 
information obtained by the investigator through review of these documents will be 
recorded and faxed to the sponsor within 24 hours of receipt of the information.  If a new 
SAE Report Form is faxed, then the investigator must sign and date the form.  The sponsor 
may also request additional information on the SAE, which the investigator or an authorized 
delegate must fax to the sponsor within 24 hours of the request. 
The SAE reporting contact information will be provided to all participating study sites by 
the contract research organization (CRO) before study initiation.   
6.3.1.9 Exceptions 
Visits to urgent care or emergency room facilities may not warrant reporting as SAEs unless 
the patient is admitted to the hospital or the event meets other “serious” criteria.  As 
discussed in Section 6.3.1.2, medical and scientific judgment should be exercised in 
deciding whether an AE is serious.  Events that are not clearly meeting “serious” criteria can 
be discussed on a case-by-case basis with the medical monitor to help the investigator 
determine whether the event meets “serious” criteria. 


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6.3.1.10 Follow-Up of Adverse Events 
All AEs must be reported in detail on the appropriate page in the eCRF and followed to 
satisfactory resolution, until the investigator deems the event to be chronic or not clinically 
significant, or until the patient is considered to be stable. 
A follow-up telephone call will be performed for those patients with an ongoing AE which 
the investigator believes to be not related to study drug administration.  A follow-up visit to 
the study site may occur for those patients with an ongoing AE which the investigator 
believes to be possibly related to study drug administration. 
All AEs must be reported in detail on the appropriate page in the eCRF and followed until 
they are resolved or stable, or judged by the investigator to be not clinically significant. 
6.3.2 Safety Assessments 
Safety assessments scheduled through the course of the study (Table 6-1 and Table 6-2) will 
include suicidality assessment by the C-SSRS, cognitive status assessment by the MMSE, 
movement disorder assessment by the AIMS, BARS and SAS, vital sign measurements, 
ECG evaluations, and physical and neurological examination.  
6.3.2.1 C-SSRS 
The C-SSRS will be completed at visits according to the schedule of events (Table 6-1 
 
  Details of the C-SSRS are presented in Section 6.1.12.   
6.3.2.2 MMSE 
The MMSE will be completed at screening and after 4 weeks of treatment according to the 
schedule of events (Table 6-1 and Table 6-2).  Details of the MMSE are presented in 
Section 6.1.11.   
6.3.2.3 Abnormal Involuntary Movement Scale 
The AIMS (Guy, 1976) measures facial and oral movements, extremity movements, and 
trunk movements.  Seven items are rated on a scale from none (0) to severe (4).  A score of 
“mild” (2) in 2 or more categories or a score of “moderate” or “severe” in any 1 category 
results in a positive AIMS score (i.e., the scores are not averaged).  Additionally, overall 
severity is scored on the basis of severity of abnormal movements and incapacitation due to 


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abnormal movements.  The patient’s awareness of and distress caused by the abnormal 
movements are also noted.  The AIMS is to be completed at baseline and as specified in the 
schedule of events (Table 6-1 and Table 6-2).  
6.3.2.4 Barnes Akathisia Rating Scale 
The BARS is a rating scale for drug-induced akathisia developed by Barnes (1989).  It 
includes the rating of observable restless movements, the subjective awareness of 
restlessness, and the distress associated with the akathisia.  There is also a global rating for 
severity.  The scale is completed by the investigator or an expert site-based rater after a 
standard examination.  Objective akathisia, subjective awareness and subjective distress are 
rated on a 4-point scale from 0 to 3, yielding a total score from 0 to 9.  The Global Clinical 
Assessment of Akathisia is rated separately, on a 6-point scale from 0 to 5.  The BARS is to 
be completed at baseline and as specified in the schedule of events (Table 6-1 and 
Table 6-2).   
6.3.2.5 Simpson-Angus Scale 
The SAS is a measure of extrapyramidal side effects (Simpson, 1970).  Ten items including 
rating gait, arm dropping, shoulder shaking, elbow rigidity, wrist rigidity, leg pendulousness, 
head rotation, glabella tap, tremor, and salivation are rated on a scale from 0 (normal) to 4 
(extreme in severity).  The SAS should be conducted by the investigator or an expert site-
based rater in a room where the patient can walk a sufficient distance to allow a natural pace 
(e.g., 15 paces).  Each side of the body should be examined.  In the case of patients with 
more advanced dementia, certain items may be difficult or almost impossible to rate such as 
arm and leg drop; in the event that an item cannot be assessed in an individual patient, the 
reason should be noted and the item will be counted as missing data.  The SAS is to be 
completed at baseline and as specified in the schedule of events (Table 6-1 and Table 6-2).   
6.3.2.6 Vital Sign Measurements 
Vital signs will be measured at screening and at every subsequent scheduled clinic visit 
(Table 6-1 
  Details of the vital sign measurements are presented in 
Section 6.1.5.  


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6.3.2.7 ECG Assessments 
The ECG assessments will be performed at screening and periodically throughout the study, 
as scheduled (Table 6-1 
).  Details of the ECG assessments are presented in 
Section 6.1.4.  
6.3.2.8 Modified Physical and Neurological Examination  
The modified physical and neurological examinations will be conducted at screening and as 
scheduled (Table 6-1
).  Details of the physical and neurological examinations 
are presented in Section 6.1.3.   
6.4 Safety Monitoring Committee 
No safety monitoring committee will be used for the study.   
6.5 Laboratory Analyses 
Blood samples collected from patients will be forwarded to a central laboratory for analysis.  
Further details regarding sample collections, processing and specific testing can be found in 
the study reference manual.  
All samples for clinical laboratory analysis will be collected after an overnight fast 
(≥10 hours), after any scheduled ECG or vital signs have been recorded, and prior to dosing 
with study drug.  Samples for clinical laboratory analysis will be used only for the 
evaluation of safety and tolerability.   
Any abnormal laboratory test results (hematology, clinical chemistry) or other safety 
assessments (e.g., ECGs, vital sign measurements), including those that worsen from 
baseline, felt to be clinically significant, in the medical and scientific judgment of the 
investigator, are to be recorded as AEs or SAEs. 
However, any clinically significant safety assessments that are associated with the 
underlying disease, unless judged by the investigator to be more severe than expected for the 
patient’s condition, are not to be reported as AEs or SAEs. 
The following clinical analytes will be determined:  


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Hematology: hematocrit; hemoglobin; red blood cell count with indices (mean corpuscular 
volume, mean corpuscular hemoglobin, and mean corpuscular hemoglobin concentration); 
reticulocytes; white blood cell count and differential (neutrophils, lymphocytes, monocytes, 
eosinophils, and basophils) reported as percent (%) and absolute values; and platelets 
(platelet count, prothrombin time and partial thromboplastin time).  
Clinical chemistry: albumin; alkaline phosphatase; blood urea nitrogen; gamma-glutamyl 
transferase; calcium; creatinine; glucose; insulin; HbA1c (Part A at screening and Day 29 
 
, if applicable, at screening and on Study Days 25, 100, 175, and 189); cholesterol 
(high-density lipoprotein and low-density lipoprotein [LDL] [calculated] and homogenous 
LDL will be reported, and homogenous LDL will be reflexed if a patient’s triglycerides are 
>400); triglycerides; phosphate; potassium; prolactin; ALT; AST; lactate dehydrogenase; 
sodium; chloride; bilirubin (total, direct); total protein; serum B12/folate (at screening only); 
uric acid; creatine phosphokinase; and thyroid panel (at screening only, thyroid-stimulating 
hormone will be assayed and if the result is abnormal, the free thyroxine and free 
triiodothyronine will be assayed).  
Serology: anti-HIV antibodies, hepatitis B surface antigen, and hepatitis C antibody (only 
during screening). 
Laboratory assessments will be conducted according to the schedule of events (Table 6-1 
and Table 6-2). 
  
 
 
  
 
 
 
 
 
   


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Further details regarding sample collections, processing and specific testing can be found in 
the study reference manual. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
   




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medication.  Any pregnancy of a study participant or partner of a study participant that 
occurs during study participation must be reported using a clinical study pregnancy form.  
To ensure patient safety, each pregnancy must be reported to ITI within 2 weeks of learning 
of its occurrence.  The pregnancy must be followed up to determine outcome (including 
spontaneous miscarriage, elective termination, normal birth, or congenital abnormality) and 
status of mother and child, even if the patient was discontinued from the study.  Pregnancy 
complications and elective terminations for medical reasons should not be reported as an AE 
or SAE.  Spontaneous miscarriages must be reported as an SAE. 
Any SAE occurring in association with a pregnancy, brought to the investigator’s attention 
after the patient has completed the study, and considered by the investigator as possibly 
related to the study treatment, must be promptly reported to ITI. 


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7 Statistical and Analytical Plan 
Formal and detailed statistical analysis plans  will be finalized prior to database lock (Parts 
A and B), which will provide further details regarding the definition of analysis endpoints 
and analysis methodology to address all study objectives.  Changes made to the data 
analysis methods as described in the protocol will be documented in the statistical analysis 
plans and will not necessitate a protocol amendment.  All departures from the statistical 
analyses described in the approved protocol, whether made before or after database lock, 
will be documented, and justified in the final clinical study report.   
Blinded (Part A) 
 data reviews will be conducted prior to unblinding 
the patients’ treatment assignments (Part A) 
  The reviews will 
assess the accuracy and completeness of the study database, patient evaluability, and 
appropriateness of the planned statistical methods.  An unblinded review of the Part A 
interim data will be conducted by the DMC, based on the interim analysis plan. 
7.1 Analysis Endpoints 
7.1.1 Primary Efficacy Endpoints – Part A 
The multiple primary efficacy endpoint(s) of Part A are the change from baseline to Day 29 in 
the CMAI-C three Factor scores related to aggressive behavior, non-aggressive agitated 
behavior, and verbally agitated behavior.  
7.1.2 Secondary 
Efficacy Endpoints 
 
7.1.2.1 Key Secondary Efficacy Endpoint – Part A 
The key secondary efficacy endpoint for Part A is the change from baseline to Day 29 in 
the CGI-S of illness (e.g., CGI-S of Agitation and/or CGI-S of Aggression). 
 
 
 
 
 
 
 
 


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7.2 Sample Size Calculations 
In Part A, approximately 292 patients (if no sample size adjustment is made after the 
interim analysis) will be randomly assigned in a 1:1 ratio to 1 of the 2 treatment groups.  A 
sample size of 292 patients will provide approximately 264 patients assuming an 
approximately 9% discontinuation rate before the first post baseline assessment of the 
primary efficacy outcome measure (CMAI-C). 132 patients per treatment group will 
provide approximately 90% power, assuming an effect size of 0.4 at a two-sided 
significance level of 5%.  
The power calculations for the primary and key secondary efficacy endpoints were 
performed using the R software.  
 
 
 
 
 


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7.3 Analysis Sets 
In Part A the following analysis sets will be used in the statistical analyses: 
All Enrolled (ENR) Set:  The All Patients Enrolled (ENR) Set will contain all patients who 
signed informed consent for this study. 
All Randomized (RND) Set:  The All Patients Randomized (RND) Set will contain all 
patients who provided informed consent and were randomized to study medication. 
Full Analysis Set (FAS):  The Full Analysis Set (FAS) will contain all randomized patients 
who received at least one dose of study drug and who had a valid (pre-dose) baseline and at 
least one valid post baseline measurement of CMAI-C.  All analyses using the FAS will 
group patients according to the randomized treatment, regardless of the treatment received 
during the course of the study.  FAS will be used in the analysis of the primary, key 
secondary and exploratory efficacy endpoints.  
Per-protocol Set (PPS):  The PPS is defined as all randomized patients who completed the 
study on-treatment period and did not have any major protocol deviations.  The major 
protocol deviation criteria will be specified in the SAP and finalized as part of the blinded 
data review prior to the final database lock.  All analyses using the PPS will group patients 
according to the randomized treatment.  
Safety Analysis Set:  The Safety Analysis Set is defined as all patients who received at least 
1 dose of study drug.  All analyses using the safety set will group patients according to the 
treatment actually received.  
PK Set:  The PK Set will contain of all patients who received at least one dose of study 
drug, had a baseline measurement and at least one post baseline measurement of CMAI-C, 
and had at least one PK sample collected and analyzed.  Analyses using the PK Set will 
group patients according to the treatment actually received. 
 
 
   




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All statistical analysis will be performed using SAS® software Version 9.2 or higher.  
Additional details regarding the statistical analysis methodology will be provided in the 
SAP.   
7.5.1 
Patient Disposition, Analysis of Demographics and Other Baseline 
Characteristics 
Patient disposition and withdrawals will be summarized by visit and by treatment group 
(Part A), when applicable.  The incidence of patients who were screened, screen failed,  
randomized, completed or discontinued treatment and completed or discontinued study, 
including the corresponding reasons for early withdrawal, will be presented overall, by Part, 
and by treatment group (Part A).  Time to discontinuation due to all reasons, AEs, lack of 
efficacy, or due to any reason of special interest will be summarized by Part, evaluated using 
the Kaplan-Meier method and will be compare between the ITI-007 9 mg the placebo 
groups (Part A) using the Log-rank test.  
Demographic and baseline characteristics, including efficacy parameters and safety 
assessments, will be summarized by part and by treatment group (Part A).  No formal statistical 
testing will be carried out for comparing demographic or other baseline characteristics between 
treatment groups (Part A). 
7.5.2 Analysis of Primary and Key Secondary Efficacy Endpoints – Part A 
Part A of the study is designed to evaluate the efficacy profile of ITI-007 9 mg based on the 
following primary and key secondary endpoints: 
• Primary Endpoint(s) – Change from baseline to Day 29 in the CMAI-C three Factor 
scores related to aggressive behavior, non-aggressive agitated behavior, and/or 
verbally agitated behavior. 
• Key Secondary Endpoint(s) – Change from baseline to Day 29 in the CGI-S of 
Agitation and/or CGI-S of Aggression. 
A multiplicity adjustment based on a parallel gatekeeping procedure will be applied at the 
interim and final analyses to control the overall Type I error rate (familywise error rate) in the 
strong sense across the primary and key secondary endpoints at alpha=0.05 (two-sided).  The 
primary efficacy endpoints (Primary Family) will serve as a parallel gatekeeper for the key 
secondary efficacy endpoints (Secondary Family) in the sense that the treatment effect on the 


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key secondary efficacy endpoints will be evaluated if and only if the treatment effect on at 
least one primary efficacy endpoint is significant.  A stepwise multiple testing procedure that 
applies a truncated Holm test will be applied to the primary efficacy endpoints and a regular 
Holm test will be applied to the key secondary efficacy endpoints.  Details of this 
gatekeeping procedure will be provided in the statistical analysis plan. 
Each of the primary efficacy endpoints will be evaluated using a mixed model repeated 
measures (MMRM) analysis.  The model will include the change from baseline of CMAI-C 
score to each pre-specified time points (Weeks 2 and 4) as the response variable, and 
treatment (ITI-007 9 mg and placebo), site (or pooled site), visit, corresponding baseline 
CMAI-C score, the stratification variable, defined by the MMSE score at screening, and 
interaction terms for baseline CMAI-C score-by-visit, and treatment-by-visit as fixed effects 
and the patient term will be included in the model as a random effect.  Model parameters 
will be estimated using restricted maximum likelihood.  An unstructured covariance matrix 
will be used to model the correlation among repeated measurements within patient.  The 
Kenward-Roger’s correction will be used to estimate the denominator degrees of freedom in 
the model.  Least-squares means (LSMs) and the corresponding standard errors will be 
presented by treatment group and visit.  Contrast estimates (LSMs) for between-treatment 
group comparisons (ITI-007 9 mg vs. placebo) and the corresponding standard errors, effect 
sizes, and p-values will also be presented.  In the event the convergence cannot be attained 
with the unstructured correlation matrix, the following alternative structures will be 
attempted in the specified order: heterogeneous Toeplitz structure (TOEPH), heterogeneous 
autoregressive(1) (ARH(1)), heterogeneous compound symmetry (CSH), No Diagonal 
Factor Analytic (FA0(q), with q equal to the number of time points), Toeplitz structure 
(TOEP), autoregressive(1) (AR(1)), and compound symmetry (CS).  
The key secondary efficacy endpoint(s), change from baseline to Day 29 in the CGI-S of 
Agitation and/or CGI-S of Aggression, will be analyzed similarly to the primary efficacy 
endpoint(s), using an MMRM method similar to the one specified for the analysis of the 
primary efficacy endpoint(s) while substituting CMAI-C score related variables in the model 
with the corresponding CGI-S related variables, such as baseline score and baseline score-
by-visit interaction.  
The primary and key secondary efficacy analyses described above will also be conducted on 
the PPS as a supportive analysis. 


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Additional exploratory analyses of the primary and key secondary efficacy endpoints may 
be conducted if deemed necessary and will be detailed in the SAP.  
7.5.3 Sensitivity Analyses of Primary Efficacy Endpoint – Part A 
The purpose of sensitivity analyses is to to explore the robustness of the MMRM results for 
the primary efficacy analysis under a different assumption on the mechanism of missing 
data.  The MMRM method assumes a Missing At Random (MAR) mechanism for missing 
data.  That is, the probability that measurements are missing depends on the set of observed 
measurements, but is unrelated to the specific unobserved missing values that, in principle, 
should have been obtained.  Sensitivity analyses for this study will be based on different 
assumptions on the mechanism of missing data.  
A pattern-mixture model (PMM) using a placebo-based multiple imputation (MI) method 
assumes a Missing Not At Random (MNAR) mechanism for the missing data.  Applying 
PMM using a placebo-based MI assumes that patients who discontinue early from the ITI-
007 treatment will follow the trajectory of outcomes similar to the one in the placebo group, 
after discontinuation of the ITI-007 treatment, taking into account observed measurements 
prior to discontinuation.  Patients who discontinue early from the placebo group will be 
assumed to have unobserved outcomes similar to the observed ones in placebo patients who 
remain on study.  This strategy is conservative with respect to the experimental treatment 
because it minimizes the difference between treatment and placebo groups.  
A responder analysis will be conducted to support the evidence of the existence of a 
treatment effect.  Patients who discontinue early from the study treatment will be considered 
as failures and will be classified as non-responders. 
Details on implementing the sensitivity analyses will be provided in the SAP.   
 
 
 
 
 
 


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7.5.8 Interim Analyses – Part A 
One interim analysis (IA) is planned during Part A of the study after 140 patients have 
completed the 28-day On-Treatment Period or confirmed to have discontinued study after at 
least one post-baseline assessment of the primary efficacy outcome measure (CMAI-C).  
The IA will be conducted such that the ongoing study integrity is maintained, and will be 
reviewed by an independent Data Monitoring Committee (DMC). 
The interim analysis will be used to reassess the assumptions of variability and effect size.  
The interim data may be used for a decision to terminate the study due to superior efficacy 
or futility or to adjust the sample size, at the discretion of the Sponsor. 
The statistical details of the Part A interim analysis will be provided in the SAP.  The 
operational details of the interim analysis will be provided in the DMC Charter. 
An additional interim analysis will report on the completion of Part A of the study, with the 
final analysis including data from both Parts A and B.  
7.6 Data Quality Assurance 
To ensure compliance with Good Clinical Practice (GCP) and all applicable regulatory 
requirements, ITI or its designee may conduct a quality assurance audit of the study site 
records and regulatory agencies may conduct a regulatory inspection at any time during or 
after the study.  In the event of an audit or inspection, the investigator (and institution) must 
agree to grant the auditor(s) and inspector(s) direct access to all relevant documents and to 
allocate their time and the time of their staff to discuss any findings/relevant issues.  
Responsibility for the accuracy, completeness, and reliability of the study data presented to 
the sponsor lies with the investigator generating the data. 
7.6.1 Data Management 
As part of the responsibilities assumed by participating in the study, the investigator agrees 
to maintain adequate case histories for the patients treated as part of the research under this 
protocol.  The investigator agrees to maintain accurate eCRFs and source documentation as 


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part of the case histories.  These source documents may include records of screening 
assessments such as the clinical scales (Table 6-1), laboratory reports, and ECG strips.  
Investigative site personnel will enter patient data into electronic data capture (EDC).  All 
eCRF fields are to be filled in.  If an item is not available or is not applicable, this fact 
should be indicated.  Blank fields should not be present unless otherwise directed.  The 
analysis data sets will be a combination of these data and data from other sources (e.g., 
laboratory data). 
Clinical data management will be performed in accordance with applicable ITI standards 
and data cleaning procedures to ensure the integrity of the data, e.g., removing errors and 
inconsistencies in the data.  Adverse events and concomitant medication terms will be coded 
using MedDRA, an internal validated medication dictionary. 
After database lock, each study site will receive a CD-ROM containing all of their study 
site- specific eCRF data as entered into the EDC, including full discrepancy and audit 
history.  Additionally, a CD-ROM copy of all of the study site’s data will be created and sent 
to the sponsor for storage.  The CRO will maintain a duplicate CD-ROM copy for their 
records.  In all cases, patient initials will not be collected or transmitted to the sponsor. 


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8 Ethics 
8.1 Independent Ethics Committee or Institutional Review Board 
Federal regulations and the International Council for Harmonisation (ICH) guidelines 
require that approval be obtained from an IRB before participation of human patients in 
research studies.  Before study onset, the protocol, informed consent, advertisements to be 
used for the recruitment of study patients, and any other written information regarding this 
study to be provided to the patient or the patient’s legal guardian must be approved by the 
IRB.  Documentation of all IRB approvals and of the IRB compliance with ICH harmonised 
tripartite guideline E6(R1): GCP will be maintained by the study site and will be available 
for review by the sponsor or its designee. 
All IRB approvals should be signed by the IRB chairman or designee and must identify the 
IRB name and address; the clinical protocol by title, protocol number, or both; and the date 
approval or a favorable opinion was granted. 
The investigator is responsible for providing written summaries of the progress and status of 
the study at intervals not exceeding 1 year or otherwise specified by the IRB.  The 
investigator must promptly supply the sponsor or its designee, the IRB, and, where 
applicable, the institution, with written reports on any changes significantly affecting the 
conduct of the study or increasing the risk to patients. 
8.2 Ethical Conduct of the Study 
The study will be performed in accordance with the ethical principles that have their origin 
in the Declaration of Helsinki, ICH GCP, and all applicable regulations. 
8.3 Patient Information and Consent 
A written informed consent in compliance with US Title 21 Code of Federal Regulations 
(CFR) Part 50 shall be obtained from each patient before entering the study or performing 
any unusual or nonroutine procedure that involves risk to the patient.  An informed consent 
template may be provided by the sponsor to study sites.  If any institution-specific 
modifications to study-related procedures are proposed or made by the study site, the 
consent should be reviewed by the sponsor, its designee, or both before IRB submission.  
Once reviewed, the consent will be submitted by the investigator to his or her IRB for 


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review and approval before the start of the study.  If the ICF is revised during the course of 
the study, all active participating patients must sign the revised form. 
Before recruitment and enrollment, each prospective patient or his or her legal guardian will 
be given a full explanation of the study and be allowed to read the approved ICF(s).  Once 
the investigator is assured that the patient/legal guardian understands the implications of 
participating in the study, the patient/legal guardian will be asked to give consent to 
participate in the study by signing the ICF(s). 
The investigator shall retain the signed original ICF(s) and give a copy of the signed original 
form to the patient or legal guardian. 


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9 Investigator’s Obligations 
The following administrative items are meant to guide the investigator in the conduct of the 
study but may change based on industry and government standard operating procedures, 
working practice documents, or guidelines.  Changes will be reported to the IRB and will 
not result in protocol amendments. 
9.1 Confidentiality 
All laboratory specimens, evaluation forms, reports, and other records will be identified in a 
manner designed to maintain patient confidentiality.  All records will be kept in a secure 
storage area with limited access.  Clinical information will not be released without the 
written permission of the patient (or the patient’s legal guardian), except as necessary for 
monitoring and auditing by the sponsor, its designee, the US FDA, or the IRB. 
The investigator and all employees and coworkers involved with this study may not disclose 
or use for any purpose other than performance of the study any data, record, or other 
unpublished, confidential information disclosed to those individuals for the purpose of the 
study.  Prior written agreement from the sponsor or its designee must be obtained for the 
disclosure of any said confidential information to other parties. 
9.2 Financial Disclosure and Obligations 
Investigators are required to provide financial disclosure information to allow the sponsor to 
submit the complete and accurate certification or disclosure statements required under 
21 CFR 54.  In addition, the investigator must provide to the sponsor a commitment to 
promptly update this information if any relevant changes occur during the course of the 
investigation and for 1 year following the completion of the study. 
Neither the sponsor nor the CRO is financially responsible for further testing or treatment of 
any medical condition that may be detected during the screening process.  In addition, in the 
absence of specific arrangements, neither the sponsor nor the CRO is financially responsible 
for further treatment of the patient’s disease. 


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9.3 Investigator Documentation 
Prior to beginning the study, the investigator will be asked to comply with ICH E6(R1) 8.2 
and Title 21 of the CFR by providing the following essential documents, including but not 
limited to: 
• IRB approval 
• Original investigator-signed investigator agreement page of the protocol 
• Form FDA 1572, fully executed, and all updates on a new fully executed Form FDA 
1572 
• Curriculum vitae for the investigator and each subinvestigator listed on Form 
FDA 1572 
• Financial disclosure information to allow the sponsor to submit complete and accurate 
certification or disclosure statements required under 21 CFR 54.  In addition, the 
investigators must provide to the sponsor a commitment to promptly update this 
information if any relevant changes occur during the course of the investigation and 
for 1 year after study completion. 
• IRB-approved informed consent, samples of site advertisements for recruitment for 
this study, and any other written information regarding this study that is to be provided 
to the patient or legal guardian, and 
• Laboratory certifications and normal ranges for any local laboratories used by the 
study site, in accordance with 42 CFR 493 
9.4 Study Conduct 
The investigator agrees that the study will be conducted according to the principles of 
ICH E6(R1).  The investigator will conduct all aspects of this study in accordance with all 
national, state, and local laws or regulations.  Study information from this protocol will be 
posted on publicly available clinical trial registers before enrollment of patients begins. 
9.5 Adherence to Protocol 
The investigator agrees to conduct the study as outlined in this protocol in accordance with 
ICH E6(R1) and all applicable guidelines and regulations. 


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9.6 Adverse Events and Study Report Requirements 
By participating in this study, the investigator agrees to submit reports of SAEs according to 
the time line and method outlined in the protocol.  In addition, the investigator agrees to 
submit annual reports to the study site IRB, as appropriate. 
9.7 Investigator’s Final Report 
Upon completion of the study, the investigator, where applicable, should inform the 
institution; the investigator/institution should provide the IRB with a summary of the study’s 
outcome and the sponsor and regulatory authority(ies) with any required reports. 
9.8 Records Retention 
Essential documents should be retained until at least 2 years after the last approval of a 
marketing application in an ICH region and until there are no pending or contemplated 
marketing applications in an ICH region or at least 2 years have elapsed since the formal 
discontinuation of clinical development of the investigational product.  These documents 
should be retained for a longer period, however, if required by the applicable regulatory 
requirements or by an agreement with the sponsor.  It is the responsibility of the sponsor to 
inform the investigator/institution as to when these documents no longer need to be retained. 
9.9 Publications 
After completion of the study, the data may be considered for reporting at a scientific 
meeting or for publication in a scientific journal.  In these cases, the sponsor will be 
responsible for these activities and will work with the investigators to determine how the 
manuscript is written and edited, the number and order of authors, the publication to which 
it will be submitted, and other related issues.  The sponsor has final approval authority over 
all such issues. 
Data are the property of the sponsor and cannot be published without prior authorization 
from the sponsor, but data and publication thereof will not be unduly withheld. 


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10  Study Management 
10.1 Monitoring 
10.1.1 External Data Monitoring Committee 
See Section 7.5.8 for details on DMC for the interim analysis.   
10.1.2 Monitoring of the Study 
The clinical monitor, as a representative of the sponsor, has the obligation to closely follow 
the study.  In doing so, the monitor will visit the investigator and study site at periodic 
intervals, in addition to maintaining necessary telephone and letter contact with the 
investigator and study site.  The monitor will maintain current personal knowledge of the 
study through observation, review of study records and source documentation, and 
discussion of the conduct of the study with the investigator and personnel. 
All aspects of the study will be carefully monitored, by the sponsor or its designee, for 
compliance with applicable government regulation with respect to current GCP and current 
standard operating procedures. 
10.1.3 Inspection of Records 
Investigators and institutions involved in the study will permit study-related monitoring, 
audits, IRB review, and regulatory inspections by providing direct access to all study 
records.  In the event of an audit, the investigator agrees to allow the sponsor, 
representatives of the sponsor, or a regulatory agency (e.g., FDA or other regulatory agency) 
access to all study records. 
The investigator should promptly notify the sponsor and the CRO of any audits scheduled 
by any regulatory authorities and promptly forward copies of any audit reports received to 
the sponsor. 
10.2 Management of Protocol Amendments and Deviations 
10.2.1 Modification of the Protocol 
Any changes in this research activity, except those necessary to remove an apparent, 
immediate hazard to the patient, must be reviewed and approved by the sponsor or its 


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designee.  Amendments to the protocol must be submitted in writing to the investigator’s 
IRB for approval before patients can be enrolled into an amended protocol. 
10.2.2 Protocol Deviations 
The investigator or designee must document and explain in the patient’s source 
documentation any deviation from the approved protocol.  The investigator may implement 
a deviation from, or a change of, the protocol to eliminate an immediate hazard to study 
patients without prior IRB approval.  As soon as possible after such an occurrence, the 
implemented deviation or change, the reasons for it, and any proposed protocol amendments 
should be submitted to the IRB for review and approval, to the sponsor for agreement, and 
to the regulatory authorities, if required. 
A deviation from the protocol is an unintended or unanticipated departure from the 
procedures or processes approved by the sponsor and the IRB and agreed to by the 
investigator.  A significant deviation occurs when there is nonadherence to the protocol by 
the patient or investigator that results in a significant, additional risk to the patient.  
Significant deviations can include nonadherence to inclusion or exclusion criteria, 
enrollment of the patient without prior sponsor approval, or nonadherence to FDA 
regulations or ICH GCP guidelines, and will lead to the patient being withdrawn from the 
study (Section 4.2). 
Protocol deviations will be documented by the clinical monitor throughout the course of 
monitoring visits.  Principal investigators will be notified in writing by the monitor of 
deviations.  The IRB should be notified of all protocol deviations in a timely manner. 
10.3 Study Termination 
Although ITI has every intention of completing the study, ITI reserves the right to 
discontinue the study at any time for clinical or administrative reasons.  
The end of the study is defined as the date on which the last patient completes the last visit 
(includes follow-up visit).  
10.4 Final Report 
Whether the study is completed or prematurely terminated, the sponsor will ensure that the 
clinical study reports are prepared and provided to the regulatory agency(ies) as required by 


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the applicable regulatory requirement(s).  The sponsor will also ensure that the clinical study 
reports in marketing applications meet the standards of the ICH harmonised tripartite 
guideline E3: Structure and content of clinical study reports. 
Upon completion of the clinical study report, the study results will be posted on publicly 
available clinical trial registers, as required by the applicable regulatory requirement(s). 


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SAP_001.pdf: 
NCT02817906 
 
Study ID: ITI-007-201 
 
Title: A Randomized, Double-Blind, Placebo-Controlled, Multi-Center Study with an Open-Label 
Extension to Assess the Efficacy and Safety of ITI-007 in the Treatment of Agitation in Subjects with 
Dementia, Including Alzheimer’s Disease 
 
Statistical Analysis Plan Date: 23 October 2018