Clinical trial NCT03345979
Conditions: Schizophrenia
Keywords: Alkermes schizophrenia aripiprazole lauroxil ARISTADA ARISTADA INITIO
Sponsor: Alkermes, Inc.
Start date: 2017-11-15; Completion date: 2019-03-12
Enrollment: 200 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
This study will evaluate the efficacy of initiating treatment of schizophrenia with ARISTADA INITIO plus 30 mg oral aripiprazole followed by a 2-month dose of AL.

Detailed description:

Arms: arm 1: Regular injections arm 2: Regular injections
Interventions: intervention 1: Aripiprazole Lauroxil intervention 2: Paliperidone Palmitate
Intervention descriptions: intervention 1: Intramuscular injection; study drug provided using a pre-filled syringe intervention 2: Intramuscular injection

Protocol documents:
Prot_000.pdf: 
Q-LES-Q-SDage 
1. 
TITLE PAGE 
 
CLINICAL STUDY PROTOCOL 
ALK9072-A306 
 
Study title: 
A Phase 3b, Multicenter, Randomized, Double-blind Study to 
Evaluate the Efficacy and Safety of Aripiprazole Lauroxil or 
Paliperidone Palmitate for the Treatment of Schizophrenia in 
Subjects Hospitalized for Acute Exacerbation 
Document date: 
v 2.0 (incorporates Amendment 1.0): 04 Jan 2018 
Original Protocol: 24 Aug 2017 
Sponsor: 
Alkermes, Inc. 
852 Winter Street 
Waltham, MA 02451 
USA 
 
 
 
 
 
 
 
CONFIDENTIAL 
Information and data in this protocol contain trade secrets and privileged or confidential information, 
which is the property of Alkermes, Inc. No person is authorized to make it public without the written 
permission of Alkermes, Inc. These restrictions or disclosures will apply equally to all future information 
supplied to you that is indicated as privileged or confidential. 


 
 
Alkermes, Inc. 
Protocol ALK9072-A306 v 2.0 (Amendment 1.0) 
CONFIDENTIAL 
Page 2 of 72 
PROCEDURES IN CASE OF EMERGENCY 
Table 1: 
Study Contact Information 
Role in Study 
Name 
Address and Telephone Number 
Alkermes Medical Monitor  
 
Alkermes, Inc. 
852 Winter Street 
Waltham, MA 02451 USA 
Office: 
 
Mobile: 
 
Alkermes Global Safety 
Officer  
 
Alkermes, Inc. 
852 Winter Street 
Waltham, MA 02451 USA 
Office: 
 
 
CRO Medical Monitor and 
24-Hour Emergency Contact 
Raleigh, NC 27604 USA 
Office: 
 
Mobile: 
 
 
24-hour Emergency Hotline:  
 
CRO Unblinded Medical 
Monitor 
 
 
 
Raleigh, NC 27604 USA 
Office: 
 
 
SAE and Pregnancy 
Reporting 
 Drug Safety  
Email: 
 
Phone Number: 
 
FAX Number: 
 
Abbreviations: CRO=contract research organization; SAE=serious adverse event 
PPD
PPD
PPD
PPD
PPD
PPD
PPD
PPD
PPD
PPD
PPD
PPD
PPD
PPD
PPD
PPD
PPD
PPD
PPD
PPD
PPD


 
 
Alkermes, Inc. 
Protocol ALK9072-A306 v 2.0 (Amendment 1.0) 
CONFIDENTIAL 
Page 3 of 72 
2. 
SYNOPSIS 
Name of Sponsor/Company: Alkermes, Inc. 
Name of investigational product: aripiprazole lauroxil (AL; ARISTADA®), aripiprazole lauroxil 
NanoCrystal® Dispersion (AL-NCD) 
Name of active ingredient: aripiprazole lauroxil 
Title of study: A Phase 3b, multicenter, randomized, double-blind study to evaluate the efficacy and 
safety of aripiprazole lauroxil or paliperidone palmitate for the treatment of schizophrenia in subjects 
hospitalized for acute exacerbation 
Investigator(s): This study will be conducted at multiple sites in the United States. 
Study period (years):  
Estimated date first patient enrolled: November 2017 (First Subject First Visit) 
Estimated date last patient completed: August 2019 (Last Subject Last Visit) 
Phase of development: 
Phase 3b 
 
Objectives:  
Primary: 
 
To evaluate the efficacy of AL-NCD initiation regimen (30 mg oral aripiprazole + 662 mg 
AL-NCD intramuscular [IM]) followed by AL 1064 mg IM during the first 4 weeks of 
treatment of patients hospitalized for an acute exacerbation of schizophrenia. 
Secondary: 
 
To compare the efficacy of AL-NCD initiation regimen followed by AL 1064 mg IM with 
paliperidone palmitate initiation dosing (PP; Invega® Sustenna®; 234 mg + 156 mg IM) 
during the first 4 weeks of treatment of patients hospitalized for an acute exacerbation of 
schizophrenia 
 
To evaluate the safety, efficacy, and tolerability of AL 1064 mg IM after 6 months of 
treatment with AL for schizophrenia 
 
To compare the safety, efficacy, and tolerability of AL 1064 mg IM with monthly PP 156 mg 
IM after 6 months of treatment with AL or PP for schizophrenia 
Exploratory: 
 
To characterize subject and caregiver centered outcomes, such as quality of life, work 
readiness, satisfaction with medication, resource utilization, and caregiver burden after 
6 months of treatment with AL or PP for schizophrenia 
Methodology: This is a multicenter, randomized, double-blind study evaluating the efficacy and safety of 
AL and PP in approximately 180 subjects experiencing an acute exacerbation of schizophrenia. In total, 
subjects will participate for approximately 26 weeks, including up to 1 week of inpatient screening and 
25 weeks of treatment (which includes an initial 2-week inpatient stay). Potential subjects will be 
evaluated for eligibility according to the inclusion and exclusion criteria at a Screening visit (up to a 7 day 
period) and Baseline visit prior to randomization. Prior antipsychotic medications should be discontinued 
after screening upon inpatient admission. Subjects will be randomized to either the AL Treatment Group 
or the PP Treatment Group and receive dosing with AL or PP. 


 
 
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Protocol ALK9072-A306 v 2.0 (Amendment 1.0) 
CONFIDENTIAL 
Page 4 of 72 
Number of subjects planned: Approximately 180 subjects (90 subjects per group) 
Main criteria for inclusion: Men and women 18 through 65 years of age (inclusive) with a diagnosis of 
schizophrenia, who are experiencing an acute exacerbation or relapse of symptoms requiring 
hospitalization with onset less than 2 months prior to screening may be eligible for this study. Subjects 
must be willing and able to be confined to an inpatient study unit for up to 3 or 4 weeks (clinically 
dependent). 
Investigational product, dosage, duration, and mode of administration: 
Aripiprazole lauroxil (AL) is a covalent non-ester modification of aripiprazole to form 
N-lauroyloxymethyl aripiprazole. The AL drug product is a white to off-white aqueous extended-release 
suspension for IM provided as single-use prefilled syringes (PFS) in a dose strength of 1064 mg every 
2 months. Aripiprazole lauroxil NanoCrystal Dispersion (AL-NCD) is an alternative formulation of AL 
designed to provide faster dissolution than the AL formulation and is provided in single-use PFS 
containing a dose strength of 662 mg. Aripiprazole lauroxil NanoCrystal Dispersion (AL-NCD) is 
intended as a starting dose to initiate treatment with AL. 
For subjects with no history of tolerated exposure to aripiprazole, oral test doses will be commercially 
available aripiprazole 5 mg tablets, provided in commercial packaging provided to the site by Alkermes. 
Oral aripiprazole for use in dose initiation will be aripiprazole 30 mg tablets (overencapsulated to 
maintain study blind), which will be provided in bottles to the site by Alkermes. 
On Day 1, subjects randomized to the AL Treatment Group will receive 662 mg AL-NCD (single IM 
gluteal injection) plus IM placebo (PBO; single IM deltoid injection) plus a 30 mg oral aripiprazole tablet. 
On Day 8, subjects will receive AL 1064 mg (single IM gluteal injection) plus IM PBO (single IM deltoid 
injection). On Days 64 and 120, subjects will receive AL 1064 mg (single IM gluteal injection), and on 
Days 36, 92, and 148 will receive IM PBO (single IM gluteal injection).  
Reference therapy, dosage, duration, and mode of administration: Paliperidone palmitate is available 
as a white to off-white aqueous extended-release injectable suspension for IM injection provided as a 
single-use PFS in dose strengths of 156 mg and 234 mg. 
For subjects with no history of tolerated exposure to risperidone or paliperidone, risperidone for use as 
oral test doses will be commercially available risperidone 1.0 mg tablets, provided in commercial 
packaging provided to the site by Alkermes. 
Oral PBO for use in dose initiation will be empty gelatin capsules that visually match the 
overencapsulated aripiprazole 30 mg tablets (to maintain study blind), which will be provided in bottles to 
the site by Alkermes. 
On Day 1, subjects randomized to the PP Treatment Group will receive PP 234 mg (single IM deltoid 
injection) plus IM PBO (single IM gluteal injection) plus an oral PBO tablet. On Day 8, subjects will 
receive PP 156 mg (single IM deltoid injection) plus IM PBO (single IM gluteal injection). Subjects 
randomized to the PP Treatment Group will receive PP 156 mg (single IM gluteal injection) on Days 36, 
64, 92, 120, and 148. 
Duration of study: The overall study duration is approximately 26 weeks and includes up to 1 week of 
inpatient screening and 25 weeks of treatment (which includes an initial 2-week inpatient stay post 
randomization/baseline). 


 
 
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Protocol ALK9072-A306 v 2.0 (Amendment 1.0) 
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Criteria for evaluation:  
Efficacy: 
Primary efficacy endpoint:  
 
Change from baseline in the Positive and Negative Syndrome Scale (PANSS) total score at 
Week 4 (within treatment groups) 
Secondary efficacy endpoints:  
 
Change from baseline in PANSS total score at Week 4 (between treatment groups) 
 
Change from baseline in PANSS total score at Week 9 and Week 25 (within treatment 
groups) 
 
Change from baseline in PANSS total score at Week 9 and Week 25 (between treatment 
groups) 
Other efficacy endpoints: 
 
Change from baseline in PANSS total score at each visit 
 
Change from baseline in PANSS subscales (positive, negative, general, or other subscales) at 
each visit 
 
Change from baseline in Clinical Global Impression-Severity Scale (CGI-S) at each visit 
 
Time from randomization to Readiness for Discharge 
Safety endpoints:  
 
Incidence of treatment-emergent adverse events (TEAEs) 
 
Change from baseline in clinical laboratory parameters (chemistry, hematology, and 
urinalysis), vital signs, and electrocardiograms (ECGs) 
 
Number and percentage of subjects with potentially clinically significant values in chemistry, 
hematology, vital signs and ECGs  
 
Change from baseline in abnormal movement scales scores (Abnormal Involuntary 
Movement Scale [AIMS], Barnes Akathisia Rating Scale [BARS], and Simpson-Angus Scale 
[SAS])  
 
Columbia-Suicide Severity Rating Scale (C-SSRS) scores  
 
Number and percentage of injection site reactions (ISRs)  
 
Udvalg for Kliniske Undersøgelser Side Effect Self-Rating Scale - Patient (UKU-SERS-PAT) 
 Sexual Side Effects Subscale score  
 
Epworth Sleepiness Scale (ESS) total score  
Other subject or caregiver centered endpoints: 
 
Quality of Life Enjoyment and Satisfaction Questionnaire - Short Form (Q-LES-Q-SF) total 
score  
 
Number and percentage of response to each modified Medication Satisfaction Questionnaire 
(MSQ) question  
 
Change from baseline in total Burden Assessment Score  
 
Number and percentage of response to Work Readiness Questionnaire (WoRQ) question 
 
Total resource utilization value  


 
 
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 
Handwriting Movement Kinematics score 
 
Wrist actigraphy scores from each collection period 
Statistical methods: 
Efficacy analysis will be based on the Full analysis set (FAS), which will include all subjects in the Safety 
population who have at least one postbaseline assessment of PANSS. 
The Safety population will include all subjects who received at least one dose of study drug (AL injection, 
AL-NCD injection, 30 mg oral aripiprazole, oral PBO, PBO injection, or PP injection). Safety analysis 
will be based on the Safety population.  
Efficacy:  
Primary endpoint:  
The change from baseline in PANSS total score at Week 4 will be tested against no improvement using 
the one-sample T test for the AL and PP Treatment Groups separately. 
Secondary endpoints:  
The change from baseline in PANSS total score at Week 9 and Week 25 will be tested against no 
improvement using the one-sample T test for the AL and PP groups separately. 
The change from baseline in PANSS total score at Week 4, Week 9, or Week 25 will be compared 
between the two treatment groups using an analysis of covariance (ANCOVA) with last observation 
carried forward (LOCF) imputation for missing data. The ANCOVA model will include treatment group, 
baseline PANSS total score, stratification factor, and the pooled study sites as covariates.  
Other efficacy endpoints: 
The continuous outcomes (change from baseline in PANSS subscales, CGI-S) will be analyzed using the 
same ANCOVA with LOCF model. The time from randomization to Readiness for Discharge will be 
summarized using a Kaplan-Meier plot. 
Safety endpoints: 
Evaluation of safety will be based on adverse events (AEs), vital signs, clinical laboratory parameters 
(chemistry, hematology, and urinalysis), ECGs, abnormal movement scales scores (AIMS, BARS, and 
SAS), C-SSRS scores, ISRs, UKU-SERS-PAT  Sexual Side Effects Subscale scores, and ESS total 
scores. Reported AE terms will be coded using the Medical Dictionary for Regulatory Activities 
(MedDRA) preferred terms and system organ classes. Concomitant medications will be categorized using 
the World Health Organization Anatomical Therapeutic Chemical (WHO-ATC) classification system. 
Analysis of other subject or caregiver centered endpoints: 
The change from baseline at each visit in Q-LES-Q-SF total score will be summarized by treatment 
group. The Burden Assessment Score will be summarized by treatment group or by caregiver type. The 
number and percentage of response for the modified MSQ and WoRQ will be summarized by treatment 
group. The number and percentage of subjects who had an ER visit, arrest, or have been incarcerated will 
be summarized by treatment group. Handwriting Movement Kinematics and wrist actigraphy results will 
be summarized by treatment group. Further analysis details will be specified in the Statistical Analysis 
Plan (SAP). 
Sample size considerations: 
No formal sample size calculations have been performed. The sample size is based on practical and 
clinical considerations. 
 


 
 
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3. 
TABLE OF CONTENTS, LIST OF TABLES, AND LIST OF 
FIGURES  
TABLE OF CONTENTS 
1. 
TITLE PAGE ................................................................................................................1 
2. 
SYNOPSIS ...................................................................................................................3 
3. 
TABLE OF CONTENTS, LIST OF TABLES, AND LIST OF FIGURES .................7 
4. 
LIST OF ABBREVIATIONS AND DEFINITIONS OF TERMS.............................13 
5. 
INTRODUCTION ......................................................................................................15 
5.1. 
Disease Overview .......................................................................................................15 
5.2. 
Study Rationale ...........................................................................................................16 
5.3. 
Dose Selection ............................................................................................................16 
6. 
STUDY OBJECTIVES ..............................................................................................17 
6.1. 
Primary Objective .......................................................................................................17 
6.2. 
Secondary Objectives .................................................................................................17 
6.3. 
Exploratory Objective .................................................................................................17 
7. 
SELECTION AND WITHDRAWAL OF SUBJECTS ..............................................18 
7.1. 
Subject Inclusion Criteria ...........................................................................................18 
7.1.1. 
General Criteria ..........................................................................................................18 
7.1.2. 
Psychiatric Criteria .....................................................................................................18 
7.2. 
Subject Exclusion Criteria ..........................................................................................19 
7.2.1. 
Psychiatric Criteria .....................................................................................................20 
7.2.2. 
Criteria Based on Treatment History ..........................................................................20 
7.2.3. 
Criteria Based on Drug/Alcohol Use and Concomitant Medications .........................20 
7.2.4. 
Criteria Based on Medical Conditions/Medical History ............................................21 
7.2.5. 
Criteria Based on Laboratory Assessments ................................................................22 
7.2.6. 
General Criteria ..........................................................................................................22 
7.3. 
Subject Withdrawal ....................................................................................................22 
7.4. 
Replacement of Subjects .............................................................................................23 
8. 
STUDY DESIGN .......................................................................................................24 
8.1. 
Overall Study Design and Plan ...................................................................................24 
8.2. 
Schedule of Visits and Assessments ...........................................................................25 
8.3. 
Study Procedures Descriptions ...................................................................................33 


 
 
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8.3.1. 
Informed Consent .......................................................................................................33 
8.3.2. 
Eligibility Review .......................................................................................................33 
8.3.3. 
Identification of Informant/Caregiver .........................................................................33 
8.3.4. 
Demographics and Medical/Psychiatric History ........................................................33 
8.3.5. 
Resource Utilization Form ..........................................................................................34 
8.3.6. 
Mini-International Neuropsychiatric Interview 7.0.2 for Schizophrenia and 
Psychotic Disorder Studies (MINI v 7.0.2) ................................................................34 
8.3.7. 
Concomitant Medication Review ...............................................................................34 
8.3.8. 
Vital Signs ..................................................................................................................34 
8.3.9. 
Physical Examination, Body Height, and Weight ......................................................35 
8.3.10. 
12-Lead Electrocardiogram ........................................................................................35 
8.3.11. 
Injection Site Evaluation .............................................................................................36 
8.3.12. 
Wrist Actigraphy ........................................................................................................36 
8.3.13. 
Structured Interviews and Questionnaires ..................................................................36 
8.3.13.1. 
Positive and Negative Syndrome Scale ......................................................................36 
8.3.13.2. 
Abnormal Movement Scales .......................................................................................36 
8.3.13.3. 
Columbia-Suicide Severity Rating Scale ....................................................................37 
8.3.13.4. 
Epworth Sleepiness Scale ...........................................................................................37 
8.3.13.5. 
Readiness for Discharge Questionnaire ......................................................................37 
8.3.13.6. 
Quality of Life Enjoyment and Satisfaction Questionnaire - Short Form ..................37 
8.3.13.7. 
Modified Medication Satisfaction Questionnaire .......................................................37 
8.3.13.8. 
Work Readiness Questionnaire ...................................................................................38 
8.3.13.9. 
Udvalg for Kliniske Undersøgelser-Side Effect Self-Rating Scale - Patient, 
Sexual Side Effects Subscale ......................................................................................38 
8.3.13.10. Burden Assessment Scale ...........................................................................................38 
8.3.13.11. Handwriting Movement Kinematics ...........................................................................38 
8.3.13.12. Clinical Global Impression–Severity ..........................................................................38 
8.3.14. 
Laboratory Assessments .............................................................................................38 
8.3.14.1. 
Drug Testing ...............................................................................................................38 
8.3.14.2. 
Hematology, Biochemistry, and Urinalysis ................................................................39 
8.3.14.3. 
Pregnancy Testing ......................................................................................................39 
8.3.14.4. 
Cytochrome P450 Genotype Testing ..........................................................................39 
8.3.14.5. 
Serology Testing .........................................................................................................40 


 
 
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8.3.15. 
Randomization ............................................................................................................40 
8.3.16. 
Drug Dispensation and Reconciliation .......................................................................40 
8.3.17. 
Adverse Event Monitoring .........................................................................................40 
8.4. 
Study Requirements and Restrictions .........................................................................40 
8.4.1. 
Contraception and Pregnancy .....................................................................................40 
8.4.2. 
Permitted Therapy ......................................................................................................41 
8.4.3. 
Non-medication Therapy ............................................................................................41 
8.4.4. 
Prohibited Medications ...............................................................................................42 
8.4.5. 
Dietary Restrictions ....................................................................................................42 
9. 
TREATMENT OF SUBJECTS ..................................................................................43 
9.1. 
Study Drug Dose and Administration .........................................................................43 
9.2. 
Oral Test Doses ...........................................................................................................43 
9.3. 
Treatment Adherence ..................................................................................................44 
9.4. 
Randomization/Method of Assigning Subjects to Treatment .....................................44 
9.5. 
Blinding ......................................................................................................................45 
9.6. 
Study Drug Dose Adjustment and Stopping Rules .....................................................45 
10. 
STUDY DRUG MATERIALS AND MANAGEMENT ...........................................46 
10.1. 
Study Drug ..................................................................................................................46 
10.2. 
Packaging and Labeling ..............................................................................................46 
10.3. 
Storage ........................................................................................................................47 
10.4. 
Accountability .............................................................................................................47 
10.5. 
Handling and Disposal ................................................................................................47 
11. 
ASSESSMENT OF EFFICACY ................................................................................48 
12. 
ASSESSMENT OF SUBJECT OR CAREGIVER CENTERED 
ENDPOINTS ..............................................................................................................49 
13. 
ASSESSMENT OF PHARMACOKINETICS AND 
PHARMACODYNAMICS ........................................................................................50 
14. 
ASSESSMENT OF SAFETY .....................................................................................51 
14.1. 
Definition of Adverse Event .......................................................................................51 
14.2. 
Definition of Serious Adverse Events ........................................................................52 
14.3. 
Relationship to Study Drug ........................................................................................52 
14.4. 
Monitoring and Recording of Adverse Events ...........................................................53 
14.5. 
Reporting of Serious Adverse Events and Pregnancy ................................................54 


 
 
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15. 
STATISTICS ..............................................................................................................55 
15.1. 
Sample Size Considerations .......................................................................................55 
15.2. 
General Statistical Methodology ................................................................................55 
15.2.1. 
Study Populations .......................................................................................................55 
15.2.1.1. 
Safety Population ........................................................................................................55 
15.2.1.2. 
Efficacy Population ....................................................................................................55 
15.3. 
Demographics and Baseline Data ...............................................................................55 
15.4. 
Efficacy Analyses .......................................................................................................55 
15.4.1. 
Primary Efficacy Endpoint .........................................................................................55 
15.4.2. 
Secondary Efficacy Endpoints ....................................................................................56 
15.4.3. 
Other Efficacy Endpoints ...........................................................................................56 
15.5. 
Pharmacokinetic/Pharmacodynamic Analyses ...........................................................56 
15.6. 
Safety and Tolerability Analyses ................................................................................56 
15.7. 
Analysis of Other Subject or Caregiver Centered Endpoints .....................................57 
16. 
DIRECT ACCESS TO SOURCE DATA/ DOCUMENTS........................................58 
16.1. 
Study Monitoring ........................................................................................................58 
16.2. 
Audits and Inspections ................................................................................................58 
16.3. 
Institutional Review Board/Independent Ethics Committee ......................................58 
17. 
QUALITY CONTROL AND QUALITY ASSURANCE .........................................59 
17.1. 
Case Report Forms .....................................................................................................59 
17.2. 
Confidentiality of Data ...............................................................................................59 
18. 
ETHICAL CONSIDERATIONS................................................................................60 
18.1. 
Ethics Review .............................................................................................................60 
18.2. 
Ethical Conduct of the Study ......................................................................................60 
18.3. 
Written Informed Consent ..........................................................................................60 
19. 
DATA HANDLING AND RECORDKEEPING .......................................................62 
19.1. 
Data Capture ...............................................................................................................62 
19.2. 
Inspection of Records .................................................................................................62 
19.3. 
Retention of Records ..................................................................................................62 
19.4. 
Use of Information and Publication Policy ................................................................63 
20. 
REFERENCES ...........................................................................................................64 
21. 
APPENDIX A: PARTIAL LIST OF PROHIBITED CYP3A INHIBITORS 
AND INDUCERS .......................................................................................................67 


 
 
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22. 
APPENDIX B: PARTIAL LIST OF PROHIBITED CYP2D6 INHIBITORS ..........68 
23. 
APPENDIX C: CAREGIVER INTAKE FORM ........................................................69 
24. 
APPENDIX D: RESOURCE UTILIZATION FORM ...............................................70 
25. 
APPENDIX E: PROLACTIN BLINDING ................................................................72 
 


 
 
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LIST OF TABLES 
Table 1: 
Study Contact Information ...........................................................................................2 
Table 2: 
List of Abbreviations and Definition of Terms ..........................................................13 
Table 3: 
Schedule of Assessments ............................................................................................26 
Table 4: 
Vital Signs: Assessment Timing from Screening through 
Visit 11(EOT/EOS/ET) ..............................................................................................35 
Table 5: 
Clinical Laboratory Assessments ...............................................................................39 
Table 6: 
Dosing Schedule .........................................................................................................43 
Table 7: 
Treatment Groups .......................................................................................................44 
Table 8: 
Stratification Factors ...................................................................................................45 
Table 9: 
Adverse Event Causality Guidelines ..........................................................................53 
Table 10: Partial List of CYP3A Inhibitors and Inducers ...........................................................67 
Table 11: Partial List of CYP2D6 Inhibitors ..............................................................................68 
 
LIST OF FIGURES 
Figure 1: 
Study Design Schematic .............................................................................................25 
 


 
 
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4. 
LIST OF ABBREVIATIONS AND DEFINITIONS OF TERMS 
Table 2: 
List of Abbreviations and Definition of Terms 
Abbreviation or Term 
Full Form of Definition 
AE 
Adverse event 
AIMS 
Abnormal Involuntary Movement Scale 
AL 
Aripiprazole lauroxil 
AL-NCD 
Aripiprazole lauroxil NanoCrystal Dispersion 
ANCOVA 
Analysis of covariance 
BARS 
Barnes Akathisia Rating Scale 
BMI 
Body mass index 
CGI-S 
Clinical Global Impression-Severity Scale 
CSA 
Clinical Study Agreement 
CRO 
Contract research organization 
C-SSRS 
Columbia-Suicide Severity Rating Scale 
C-VISA 
Clinical-Validation Inventory for Study Admission 
CYP 
Cytochrome P450 
DSM-5 
Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition 
ECG 
Electrocardiogram 
eCRF 
Electronic case report form 
EOS 
End of study 
EOT 
End of treatment 
End of Trial 
Date of last subject’s last visit 
EPS 
Extrapyramidal symptoms  
ESS 
Epworth Sleepiness Scale 
ET 
Early termination 
FAS 
Full analysis set 
FDA 
Food and Drug Administration 
GCP 
Good Clinical Practice 
HIV 
Human immunodeficiency virus 
ICF 
Informed consent form 
ICH 
International Conference on Harmonisation 
IEC 
Independent Ethics Committee 


 
 
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Table 2: 
List of Abbreviations and Definition of Terms (Continued) 
Abbreviation or Term 
Full Form of Definition 
IM 
Intramuscular 
IRB 
Institutional Review Board 
ISR 
Injection site reactions 
LAI 
Long-acting injectable 
LOCF 
Last observation carried forward 
MDMA 
3,4-methylendioxymethamphetamine 
MedDRA 
Medical Dictionary for Regulatory Activities 
MINI v 7.0.2 
Mini-International Neuropsychiatric Interview-7.0.2 for Schizophrenia 
and Psychotic Disorder Studies 
MSQ 
Medication Satisfaction Questionnaire 
PANSS 
Positive and Negative Syndrome Scale 
PBO 
Placebo 
PFS 
Prefilled syringe 
PP 
Paliperidone palmitate 
Q-LES-Q-SF 
Quality of Life Enjoyment and Satisfaction Questionnaire - Short 
Form 
QTcF 
QT interval corrected for heart rate using Fridericia’s formula 
RDQ 
Readiness for Discharge Questionnaire 
SAS 
Simpson-Angus Scale 
SAE 
Serious adverse event 
SAP 
Statistical Analysis Plan 
TEAE 
Treatment-emergent adverse event 
UKU-SERS-PAT 
Udvalg for Kliniske Undersøgelser Side Effect Self-Rating Scale – 
Patient 
US 
United States 
WHO-ATC 
World Health Organization-Anatomical Therapeutic Chemical  
WoRQ 
Work Readiness Questionnaire 


 
 
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5. 
INTRODUCTION 
Schizophrenia is a severe mental disorder characterized by abnormalities in the perception or 
expression of reality. Aripiprazole is a second generation, atypical antipsychotic with 
demonstrated efficacy for the symptoms of schizophrenia (Abilify USPI, 2017). Although 
aripiprazole and other antipsychotics are effective for managing schizophrenia when used 
regularly, poor adherence to oral antipsychotic treatment regimens is widespread and presents a 
major limitation to successful treatment (Keith and Kane 2003). Nonadherence has been 
associated with relapse and worsening long-term functional and mental outcomes (Ascher-
Svanum et al, 2006; Ascher-Svanum et al, 2010). Long-acting injectable (LAI) antipsychotic 
formulations, such as risperidone (Risperdal® Consta®), paliperidone palmitate (PP; Invega® 
Sustenna®), olanzapine (Zyprexa® Relprevv®), and aripiprazole (Abilify® Maintena®; 
ARISTADA®), were developed to promote treatment adherence, and have been demonstrated to 
improve adherence relative to oral medication, and thus improve outcomes and reduce long term 
costs (Kane et al, 2013). 
Aripiprazole lauroxil (AL; ARISTADA) is a covalently bonded, non-ester modification of 
aripiprazole to form N-lauroyloxymethyl aripiprazole. It is formulated as an extended-release 
suspension to be administered via intramuscular (IM) injection into the gluteal or deltoid muscle. 
In clinical trials, treatment with AL demonstrated statistically significant reductions from 
baseline in Positive and Negative Syndrome Scale (PANSS) total scores at Week 12, compared 
with placebo. Aripiprazole lauroxil was generally well tolerated for patients with schizophrenia 
at monthly IM dosing of 441 mg and 882 mg with the most common adverse events (AEs) being 
insomnia, akathisia, and headache.  
Due to the delayed appearance of aripiprazole in systemic circulation following AL 
administration, treatment with AL currently requires a concurrent 21-day oral lead-in regimen 
(oral initiation regimen; ie, oral aripiprazole once daily for 21 days after AL administration) to 
ensure adequate pharmacological activity to cover the initial lag of aripiprazole appearance with 
the first IM injection. Aripiprazole lauroxil NanoCrystal Dispersion® (AL-NCD) is an alternative 
IM formulation of AL under investigation that has been developed for the initiation of treatment 
with AL in order to eliminate the need for the current oral initiation regimen. This study is 
designed to 1) evaluate the efficacy of the AL-NCD initiation regimen followed by the 
AL 1064 mg/every 2 months dose regimen for acute symptoms of schizophrenia, and 2) compare 
the safety and efficacy of AL to PP (ie, ARISTADA and Invega Sustenna). 
This study is a double-blind, 25-week evaluation of the safety and efficacy of AL or PP for the 
treatment of schizophrenia in subjects hospitalized for acute exacerbation. 
5.1. 
Disease Overview 
Schizophrenia is a chronic, severe mental disorder characterized by debilitating psychotic 
symptoms, physical and psychiatric comorbidities, and increased mortality. Symptoms are 
characterized by a mix of “positive symptoms” such as hallucinations, delusions, and thought 
disorders, and by “negative symptoms” such as flat or blunted affect, poverty of speech, inability 
to experience pleasure, lack of desire to form relationships, and reduced motivation (American 
Psychiatric Association 2013). Effective antipsychotic medications are available to treat this 


 
 
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condition; for example, in patients with schizophrenia, aripiprazole has demonstrated efficacy for 
both the positive and negative symptoms of schizophrenia (Abilify USPI, 2017). Although 
aripiprazole and other antipsychotics are effective for managing schizophrenia when used 
regularly, poor adherence to oral antipsychotic treatment regimens is widespread and presents a 
major barrier to achieving optimal pharmacologic outcomes (Keith and Kane 2003). 
5.2. 
Study Rationale 
Aripiprazole lauroxil is an injectable extended-release formulation of an atypical antipsychotic 
developed by Alkermes for the treatment of schizophrenia. Five dose regimens of AL are 
currently approved by the United States (US) Food and Drug Administration (FDA) for the 
treatment of schizophrenia as follows: 441 mg/monthly, 662 mg/monthly, 882 mg/monthly, 
882 mg/every 6 weeks, and 1064 mg/every 2 months. 
Aripiprazole lauroxil NanoCrystal Dispersion (AL-NCD) is an alternative IM formulation of AL 
under investigation that has been developed for the initiation of treatment with AL in order to 
eliminate the need for the current 21-day oral initiation regimen. The AL-NCD initiation regimen 
comprises a single 662 mg IM dose of AL-NCD coadministered with a single 30 mg oral dose of 
aripiprazole. This regimen was developed based on pharmacokinetic modeling, and AL-NCD 
was found to be well tolerated when tested in a clinical study in subjects with schizophrenia. 
This study is being conducted to evaluate the efficacy of the AL-NCD initiation regimen for 
acute symptoms followed by initiation of the 1064 mg/every 2 months dose regimen. It will also 
compare the safety and efficacy of AL to PP (ie, ARISTADA and Invega Sustenna), two atypical 
LAI antipsychotics with different mechanisms of action. Paliperidone palmitate is approved by 
the US FDA for the treatment of schizophrenia. In multiple clinical studies, PP has been found to 
be efficacious in patients with an acute exacerbation of schizophrenia (Gopal et al, 2010; 
Nasrallah et al, 2010; Pandina et al, 2010). An active drug with a known efficacy profile is a 
useful comparator for evaluating new drugs while avoiding the ethical dilemmas associated with 
placebo.  
Therefore, this study is being conducted to assess the efficacy, safety, and tolerability of AL and 
PP in subjects hospitalized for acute exacerbation of schizophrenia. 
5.3. 
Dose Selection 
The AL dose of 1064 mg IM every 2 months and the PP doses of 234 mg IM initiation and 
156 mg IM monthly were selected because they are approved doses used for the treatment of 
patients with schizophrenia.  
For the AL-NCD initiation regimen, the dose of 662 mg IM coadministered with a single 30 mg 
oral aripiprazole dose has been shown to provide aripiprazole concentrations comparable to daily 
administration of 15 mg oral aripiprazole administered during the first 21 days of AL treatment. 


 
 
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6. 
STUDY OBJECTIVES 
6.1. 
Primary Objective 
The primary objective of this study is to evaluate the efficacy of AL-NCD initiation regimen 
(30 mg oral aripiprazole + 662 mg AL-NCD IM) followed by AL 1064 mg IM during the first 
4 weeks of treatment of patients hospitalized for an acute exacerbation of schizophrenia. 
6.2. 
Secondary Objectives 
The secondary objectives of this study are to: 
 Compare the efficacy of AL-NCD initiation regimen followed by AL 1064 mg IM 
with PP initiation dosing (Invega® Sustenna®; 234 mg + 156 mg IM) during the first 
4 weeks of treatment of patients hospitalized for an acute exacerbation of 
schizophrenia 
 Evaluate the safety, efficacy, and tolerability of AL 1064 mg IM after 6 months of 
treatment with AL for schizophrenia 
 Compare the safety, efficacy, and tolerability of AL 1064 mg IM with monthly 
PP 156 mg IM after 6 months of treatment with AL or PP for schizophrenia 
6.3. 
Exploratory Objective 
The exploratory objective of this study is to characterize subject and caregiver centered 
outcomes, such as quality of life, work readiness, satisfaction with medication, resource 
utilization, and caregiver burden after 6 months of treatment with AL or PP for schizophrenia. 


 
 
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7. 
SELECTION AND WITHDRAWAL OF SUBJECTS 
Each subject must meet all of the inclusion and none of the exclusion criteria to be qualified to 
participate in this study.  
7.1. 
Subject Inclusion Criteria 
Each subject must meet all of the following inclusion criteria to be qualified to participate in this 
study. 
7.1.1. 
General Criteria 
1. Subject is willing and able to give informed consent; subject has signed the informed 
consent form (ICF) before initiation of any study-specific procedures 
2. Subject is ≥18 and ≤65 years of age and is willing and able to provide government-issued 
identification at screening 
3. Subject has a body mass index (BMI) between 18.0 kg/m2 and 40.0 kg/m2, inclusive, at 
screening 
4. Subject is willing to abide by the contraception requirements that will be defined in the 
protocol for the duration of the study (males and females; please refer to Section 8.4.1 in 
the protocol) 
5. Subject is fluent (oral and written) in the language of the Investigator and study site staff 
in order to be reliably evaluated and rated using standardized tests 
6. Subject is willing and able to follow the study procedures as outlined in the protocol 
7.1.2. 
Psychiatric Criteria 
7. Subject has a diagnosis of schizophrenia per the Diagnostic and Statistical Manual of 
Mental Disorders, Fifth Edition (DSM-5) (American Psychiatric Association 2013) 
criteria as confirmed by Mini International Neuropsychiatric Interview 7.0.2 for 
Schizophrenia and Psychotic Disorder Studies (MINI v 7.0.2)  
8. Subject is experiencing an acute exacerbation or relapse of symptoms, with onset less 
than 2 months prior to screening 
a. The subject requires hospitalization for this acute exacerbation or relapse of 
symptoms 
b. If already inpatient at screening, has been hospitalized for less than 2 weeks for the 
current exacerbation at the time of screening  
 Involuntarily hospitalized subjects who request and are granted voluntary status 
prior to signing informed consent may participate, provided criteria above are met 
9. Subject is willing and able to be confined to an inpatient study unit for up to 3 or 4 weeks 
(clinically dependent) 
10. PANSS that meets the following criteria at screening and baseline: 


 
 
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a. Total score between 80 and 120, inclusive 
b. Score of ≥4 (moderate or greater) for ≥2 of the following Positive Scale (P) items: 
 Item 1 (P1; delusions) 
 Item 2 (P2; conceptual disorganization) 
 Item 3 (P3; hallucinatory behavior) 
 Item 6 (P6; suspiciousness/persecution) 
11. Clinical Global Impression-Severity Scale (CGI-S) score ≥4 at screening and baseline 
12. Subject has experienced at least one previous hospitalization for schizophrenia 
13. Subject has had a past history of clinically significant beneficial response (improvement 
in schizophrenia symptoms), as determined by the Investigator, to treatment with an 
antipsychotic medication other than clozapine 
14. Subject meets either one of the two tolerability criteria below for aripiprazole: 
a. Has a history of tolerated use of aripiprazole  
b. If there is no tolerability history, then has demonstrated tolerability to oral test doses 
of aripiprazole during screening 
15. Subject meets either one of the two tolerability criteria below for either risperidone or 
paliperidone: 
a. Has a history of tolerated use of risperidone or paliperidone (Note: history of 
tolerating either medication will fulfill this criteria) 
b. If there is no tolerability history, then has demonstrated tolerability to oral test doses 
of risperidone during screening 
16. Subject has been able to achieve outpatient status for more than 3 consecutive months in 
the past year  
17. Subject resides in a stable living situation when not hospitalized, in the opinion of the 
Investigator 
18. Subject has an identified reliable informant (caregiver) who is willing and able to provide 
informed consent by signing the caregiver ICF 
7.2. 
Subject Exclusion Criteria 
Each subject must not have any of the following conditions to be qualified to participate in this 
study. 
1. Subject has any finding that in the view of the Investigator may compromise the safety of 
the subject or affect their ability to adhere to the protocol visit schedule or fulfill visit 
requirements 


 
 
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7.2.1. 
Psychiatric Criteria 
2. Subject has a history of psychopathology other than schizophrenia as indicated by any of 
the following: 
a. Has any current primary DSM-5 diagnosis other than schizophrenia within the 
12 months prior to screening (confirmed using MINI v 7.0.2 at screening) 
b. Has a DSM-5 diagnosis of moderate to severe substance use disorder (except tobacco 
or cannabis use disorder) within the 12 months prior to screening (confirmed using 
MINI v 7.0.2 at screening) 
3. Subject poses a current suicide risk in the opinion of the Investigator or as confirmed by 
the following:  
a. Answers “Yes” on items 4 or 5 (Columbia-Suicide Severity Rating Scale 
[C-SSRS]-ideation) with the most recent episode occurring within the 2 months prior 
to screening, or answers “Yes” to any of the 5 items (C-SSRS-behavior) with an 
episode occurring within the 12 months prior to screening. Non-suicidal self-injurious 
behavior is not exclusionary. 
7.2.2. 
Criteria Based on Treatment History 
4. Subject has a history of treatment resistance defined as failure to respond to 2 adequate 
courses of pharmacotherapy (a minimum of 4 weeks at an adequate dose per the label) or 
required clozapine within the last 12 months 
5. Subject has a known or suspected hypersensitivity, or history of intolerable side effects 
attributed to one or more of the following: aripiprazole, risperidone, or paliperidone, per 
the Investigator’s judgment 
6. Subject has a history of poor or inadequate clinical response to one or more of the 
following: aripiprazole, risperidone, or paliperidone, when subject was known to be 
adherent to the antipsychotic for a full course (a minimum of 4 weeks at an adequate dose 
per the label) per the Investigator’s judgment 
7. Subject has received a LAI antipsychotic (eg, paliperidone palmitate) in the past 
3 months or received ARISTADA 1064 mg or Invega Trinza® in the past 6 months 
8. Subject initiated first antipsychotic treatment within the past 12 months or <1 year has 
elapsed since the initial onset of the active-phase of schizophrenia symptoms 
9. Current involuntary hospitalization or incarceration 
10. Subject has had psychiatric hospitalization(s) for more than 30 days (cumulative) during 
the 90 days before screening 
7.2.3. 
Criteria Based on Drug/Alcohol Use and Concomitant Medications 
11. Subject has a positive urine drug test for illicit use of amphetamines, methamphetamines, 
3,4-methylenedioxymethamphetamine (MDMA), barbiturates, benzodiazepines, cocaine, 
opioids, or phencyclidine at screening (cannabinoids are not exclusionary). Use of 
prescribed medications (eg, benzodiazepines or opioids) that account for the positive 
urine drug test results are not exclusionary.  


 
 
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12. Subject has used potent oral cytochrome P450 (CYP) 3A inducers or inhibitors or 
CYP2D6 inhibitors (prescription medications, over-the-counter medications, or dietary 
supplements) over the 14 days prior to Day 1 (Section 21 and Section 22). 
13. Subject requires treatment with a prohibited medication (refer to Section 8.4.4)  
7.2.4. 
Criteria Based on Medical Conditions/Medical History 
14. Subject has a history or current evidence of a clinically significant medical illness, 
condition, or disorder that would be anticipated to potentially compromise subject safety 
or adversely affect the evaluation of efficacy, including, but not necessarily limited to, the 
following: 
a. Clinically significant hypotension or hypertension not stabilized by medical therapy 
per the Investigator’s judgment  
b. Unstable thyroid dysfunction in the past 6 months (eg, hypothyroidism, 
hyperthyroidism, or thyroiditis that was untreated or discovered, and treatment was 
initiated within the 6 months prior to screening)  
c. Malignant tumor within the last 5 years (exception: dermal squamous or basal cell 
carcinoma or cervical carcinoma in situ allowable)  
d. Neurologic conditions including the following: 
 History of seizure disorder or condition associated with seizures, with the 
exception of febrile seizure history 
 History of brain tumor, subdural hematoma, or other clinically significant 
neurological condition within the past 12 months 
 Head trauma with loss of consciousness within 12 months before screening 
 Active acute or chronic central nervous system infection  
 Stroke within 6 months before screening 
 History of neuroleptic malignant syndrome or clinically significant tardive 
dyskinesia 
e. Clinically significant cardiac arrhythmia, cardiomyopathy, or cardiac conduction 
defect; history of myocardial infarction or unstable angina within the last 3 months 
before screening; or clinically significant abnormality on screening or baseline 
electrocardiogram (ECG), including but not limited to: 
 A QT interval corrected using the Fridericia’s formula (QTcF) >450 milliseconds 
for men or >470 milliseconds for women 
15. Subject is pregnant, planning to become pregnant, or breastfeeding during the study 
16. Subject has participated in a clinical study involving any investigational product (ie, drug, 
device, or biologic) within the past 3 months or is currently participating in a clinical 
study involving an investigational product 
17. Inadequate muscle mass or excessive subcutaneous fat, as determined by the Investigator, 
that would interfere with a successful IM injection by either the deltoid or gluteal route 


 
 
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7.2.5. 
Criteria Based on Laboratory Assessments 
18. Subject has any of the following conditions or abnormalities at screening: 
a. Uncontrolled diabetes (HbA1c >7%),  
b. Aspartate aminotransferase or alanine aminotransferase levels ≥3 times the upper 
limit of the laboratory reference range at screening 
c. Absolute neutrophil count ≤1.5 × 103 per μL 
d. Platelet count ≤100 × 103 per μL  
e. Positive test result for Human Immunodeficiency Virus (HIV) antibody and/or 
antigen, hepatitis B surface antigen, or anti-hepatitis C virus antibody  
f. Serum creatinine >2.5 mg/dL 
7.2.6. 
General Criteria 
19. Subject is employed by Alkermes, the Investigator, the study site (includes permanent or 
temporary contract workers and designees responsible for the conduct of the study), or a 
third-party agent of this study or is immediate family1 of an employee of Alkermes, the 
Contract Research Organization (CRO), the Investigator, the study site, or other 
third-party agent 
20. If, in the opinion of the Investigator (and/or Sponsor), is unsuitable for enrollment in the 
study 
7.3. 
Subject Withdrawal 
A subject may be discontinued from the study at any time if the subject, Investigator, or Sponsor 
determines that it is not in the best interest of the subject to continue participation. Reasons for 
discontinuation include: 
 Adverse event 
 Lack of efficacy 
 Loss to follow-up 
 Withdrawal of consent 
 Noncompliance with study drug (including missed dose by >2 weeks) 
 Physician decision 
 Pregnancy 
 Protocol deviation 
 Study terminated by Sponsor 
 Other 
 
1 Immediate family is defined as a spouse, parent, sibling, or child, whether biological or legally adopted. 


 
 
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If a subject withdraws from the study for any reason, any ongoing AEs will be followed until 
resolution, until deemed stable by the Investigator, or until the subject is deemed by the 
Investigator to be lost to follow-up. If, in the opinion of the Investigator, it is necessary to 
monitor a subject beyond the Early Termination (ET)/End of Study (EOS)/End of Treatment 
(EOT) visit, the Follow-up period may be extended as necessary. In such instances, the Sponsor 
and the Investigator will agree to an acceptable follow-up schedule. 
In the event that a subject chooses to withdraw from the study, the Investigator should make a 
reasonable effort to ascertain the reason(s) for withdrawal, while fully respecting the subject’s 
rights. Randomized subjects are to be asked to return to the clinic for an ET visit. The ET visit 
should be scheduled as close as possible to the subject’s last dose, and ET assessments and will 
mimic the assessments scheduled to be conducted at Visit 11/EOT/EOS.  
For subjects discontinuing early, any untoward medical condition occurring within 30 days after 
the last dose should be considered an AE. An unscheduled visit should be captured in the EDC 
and documented in the source should the subject require a visit to the investigational site. 
If the subject fails or refuses to return to the study site, an attempt must be made to contact the 
subject by telephone in order to assess as many safety and efficacy parameters as possible. All 
data collected over the telephone must be documented and kept in the subject’s record. 
The Investigator must maintain a record of all subjects who fail to complete the study. The 
reason for study discontinuation will be documented and made on the appropriate electronic case 
report form (eCRF). If a subject is lost to follow-up, a reasonable attempt to contact the subject 
must be made and documented. 
7.4. 
Replacement of Subjects 
Subjects who withdraw from the study after randomization will not be replaced. 


 
 
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8. 
STUDY DESIGN 
8.1. 
Overall Study Design and Plan 
This is a multicenter, randomized, double-blind study evaluating the efficacy and safety of AL 
and PP in approximately 180 subjects experiencing an acute exacerbation of schizophrenia. In 
total, subjects will participate for approximately 26 weeks, including up to 1 week of inpatient 
screening and 25 weeks of treatment (which includes an initial 2-week inpatient stay). Potential 
subjects will be evaluated at a Screening visit (up to 7 days) prior to randomization. If a subject 
does not have historical exposure to aripiprazole and/or risperidone and paliperidone, test doses 
will be administered during the first 2 days of inpatient stay during the Screening period, prior to 
randomization, to assess tolerability, as described in Section 9.2.  
All subjects should be in an inpatient setting when discontinuing prior antipsychotic medication. 
The washout of antipsychotics would be at the discretion of the Investigator based on evolving 
clinical picture. Allowable washout period is 2 to 5 days. 
On Day 1, qualified subjects will be randomized to either the AL Treatment Group or the PP 
Treatment Group and receive dosing with AL or PP as described in Section 9.1. Subjects will 
remain in the inpatient study unit during the Screening period and for at least 2 weeks after 
administration of the first dose of study drug on Day 1. Subjects will be discharged from the 
inpatient unit upon assessment as clinically stable and appropriate for discharge as determined by 
the Investigator. Subjects will receive their final injection of study drug on Day 148 and will be 
considered to be on treatment until Day 176. A schematic of the study design is provided in 
Figure 1. 


 
 
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Figure 1: 
Study Design Schematic 
 
Abbreviations: AL-NCD=aripiprazole lauroxil NanoCrystal Dispersion; PBO=placebo 
a Subjects randomized into the AL Treatment Group will receive IM PBO (deltoid) on Days 1 and 8 and 30 mg oral 
aripiprazole on Day 1 
b Subjects randomized into the PP Treatment Group will receive IM PBO (gluteal) on Days 1 and 8 and oral PBO 
on Day 1 
Safety and tolerability assessments will include AE monitoring, clinical laboratory testing, vital 
signs, body weight, 12-lead ECGs, monitoring, abnormal movement scales (Abnormal 
Involuntary Movement Scale [AIMS], Barnes Akathisia Rating Scale [BARS], and 
Simpson-Angus Scale [SAS]), C-SSRS, injection site reactions (ISRs), the Udvalg for Kliniske 
Undersøgelser Side Effect Self-Rating Scale - Patient (UKU-SERS-PAT)  Sexual Side Effects 
Subscale, and Epworth Sleepiness Scale (ESS). 
Efficacy assessments will include PANSS, Clinical Global Impression–Severity (CGI-S), and 
Readiness for Discharge Questionnaire (RDQ). 
Subject or caregiver-centered assessments will include Quality of Life Enjoyment and 
Satisfaction Questionnaire - Short Form (Q-LES-Q-SF), modified Medication Satisfaction 
Questionnaire (MSQ), the Work Readiness Questionnaire (WoRQ), Handwriting Movement 
Kinematics, wrist actigraphy, and Resource Utilization Form. Caregivers who meet criteria will 
also complete the Burden Assessment Scale. 
8.2. 
Schedule of Visits and Assessments 
The schedule of assessments is shown in Table 3. 
For a missed visit, the study site should attempt to contact the subject to reschedule. A subject 
who is late for a scheduled injection by more than 2 weeks will be discontinued from treatment. 
Premature discontinuation procedures are provided in Section 7.3. 
Day
-7
1
8
15
22
29
36
64
92
120
148
176
End of Treatment/End 
of Study (at Day 176)
Subjects 
Admitted
Subjects 
Discharged
Randomization
1:1
Aripiprazole lauroxil group (n=90)
Paliperidone Palmitate group (n=90)
Dose 
Administered
PBO
1064 mg
PBO
1064 mg
PBO
156 mg
156 mg
156 mg
156 mg
156 mg
234 mg
156 mg
AL-NCD
1064 mg
Inpatient
Outpatient
a
b
Week
1
2
3
4
5
9
13
17
21
25


 
 
 
 
 
 
 
 
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Table 3: 
Schedule of Assessments 
Procedure/Study Day 
Screening 
Double-blind Treatment Period 
Required Inpatient Staya 
Outpatient Visits 
V1 
Screeningb 
V2 
Baseline 
V3 
V4 
V5 V6 V7 V8 V9 
V10 
V11/EOT/EOS/ 
ETc 
-7 to -1 
1 
2-3 
4 
5-7 
8 
9-14 
15 
22 
29 
36 
64 
92 120 148 
176 
±1 day 
±3 day window, anchored to the prior injection 
Informed Consent 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Clinical-Validation Inventory for 
Study Admission (C-VISA)d 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Eligibility Criteria Review 
X 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Demographics, 
Medical/Psychiatric History  
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Caregiver Consente 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Caregiver Intake Forme 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Resource Utilization Form 
X 
 
 
 
 
 
 
 
 
 
X 
X 
X 
X 
X 
X 
Mini-International 
Neuropsychiatric Interview 7.0.2 
for Schizophrenia and Psychotic 
Disorder Studies (MINI v 7.0.2) 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Physical Examinationf 
X 
 
 
 
 
 
 
X 
 
 
 
 
 
 
 
X 
Height 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Weight 
X 
X 
 
 
 
 
 
X 
 
X 
 
X 
 
X 
 
X 


 
 
 
 
 
 
 
 
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Table 3: 
Schedule of Assessments (Continued) 
Procedure/Study Day 
Screening 
Double-blind Treatment Period 
Required Inpatient Staya 
Outpatient Visits 
V1 
Screeningb 
V2 
Baseline 
V3 
V4 
V5 V6 V7 V8 V9 
V10 
V11/EOT/EOS/ 
ETc 
-7 to -1 
1 
2-3 
4 
5-7 
8 
9-14 
15 
22 
29 
36 
64 
92 120 148 
176 
±1 day 
±3 day window, anchored to the prior injection 
Urine Drug Screeng 
X 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Pregnancy Test 
(All Women) 
Xh 
X 
 
 
 
 
 
 
 
X 
X 
X 
X 
X 
X 
 
Biochemistry, Hematology, and 
Urinalysis Samples (Including 
Prolactin)i 
X 
X 
 
 
 
X 
 
X 
 
 
X 
X 
X 
X 
X 
X 
Genotype Sampling 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Serologyj 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Vital Signsk 
X 
X 
 
 
 
X 
 
X 
 
 
X 
X 
X 
X 
X 
X 
12-lead Electrocardiogram 
(ECG)l 
X 
X 
 
 
 
X 
 
X 
 
 
X 
X 
X 
X 
X 
X 
Admission to Inpatient Facilitya 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Administer Test Dosesm 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Randomization 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Administer 30 mg Oral 
Aripiprazole or oral PBO Dose 
 
Xn 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


 
 
 
 
 
 
 
 
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Table 3: 
Schedule of Assessments (Continued) 
Procedure/Study Day 
Screening 
Double-blind Treatment Period 
Required Inpatient Staya 
Outpatient Visits 
V1 
Screeningb 
V2 
Baseline 
V3 
V4 
V5 V6 V7 V8 V9 
V10 
V11/EOT/EOS/ 
ETc 
-7 to -1 
1 
2-3 
4 
5-7 
8 
9-14 
15 
22 
29 
36 
64 
92 120 148 
176 
±1 day 
±3 day window, anchored to the prior injection 
IM Injection of AL-NCD 662 mg 
or PP 234 mg, and IM PBO Dose 
 
Xn 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
IM Injection of AL 1064 mg or 
PP 156 mg, and/or PBO Dose 
 
 
 
 
 
Xn 
 
 
 
 
X 
X 
X 
X 
X 
 
Injection Site Evaluationo 
 
X 
X 
 
 
X 
X 
X 
 
 
X 
X 
X 
X 
X 
 
Discharge From the Inpatient 
Facilitya 
 
 
 
 
 
 
 
X 
 
 
 
 
 
 
 
 
Positive and Negative Syndrome 
Scale (PANSS)p 
X 
X 
 
X 
 
X 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Abnormal Involuntary Movement 
Scale (AIMS) 
 
X 
 
 
 
 
 
 
 
X 
 
 
 
 
 
X 
Akathisia/Movement Disorder 
Rating (BARS/SAS) 
X 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
 
 
X 
Columbia-Suicide Severity 
Rating Scale (C-SSRS)q 
X 
X 
 
 
 
X 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Epworth Sleepiness Scale (ESS) 
 
 
 
 
 
 
 
X 
X 
X 
 
X 
X 
 
 
X 
Readiness for Discharge 
Questionnaire (RDQ) 
 
 
 
X 
Xr 
X 
Xr 
X 
 
 
 
 
 
 
 
 


 
 
 
 
 
 
 
 
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Table 3: 
Schedule of Assessments (Continued) 
Procedure/Study Day 
Screening 
Double-blind Treatment Period 
Required Inpatient Staya 
Outpatient Visits 
V1 
Screeningb 
V2 
Baseline 
V3 
V4 
V5 V6 V7 V8 V9 
V10 
V11/EOT/EOS/ 
ETc 
-7 to -1 
1 
2-3 
4 
5-7 
8 
9-14 
15 
22 
29 
36 
64 
92 120 148 
176 
±1 day 
±3 day window, anchored to the prior injection 
Quality of Life Enjoyment and 
Satisfaction Questionnaire - Short 
Form (Q-LES-Q-SF) 
 
 
 
 
 
 
 
 
 
 
X 
 
X 
 
 
X 
Modified Medication Satisfaction 
Questionnaire (MSQ) 
 
 
 
 
 
 
 
 
 
X 
 
X 
 
X 
 
X 
Work Readiness Questionnaire 
(WoRQ) 
 
 
 
 
 
 
 
X 
 
X 
 
X 
 
X 
 
X 
Udvalg for Kliniske 
Undersøgelser Side Effect 
Self-Rating Scale - Patient 
(UKU-SERS-PAT)  Sexual Side 
Effects Subscale  
 
X 
 
 
 
 
 
 
 
X 
 
X 
 
X 
 
X 
Burden Assessment Scales 
X 
 
 
 
 
 
 
 
 
 
 
X 
 
 
 
X 
Handwriting Movement 
Kinematics 
X 
 
 
 
 
 
 
X 
 
X 
 
X 
 
X 
 
 
Clinical Global 
Impression-Severity Scale 
(CGI-S) 
X 
X 
 
X 
 
X 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Distribute Wrist Actigraph 
 
 
 
 
 
 
 
 
X 
 
 
Xt 
 
 
 
 


 
 
 
 
 
 
 
 
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Table 3: 
Schedule of Assessments (Continued) 
Procedure/Study Day 
Screening 
Double-blind Treatment Period 
Required Inpatient Staya 
Outpatient Visits 
V1 
Screeningb 
V2 
Baseline 
V3 
V4 
V5 V6 V7 V8 V9 V10 
V11/EOT/EOS/ 
ETc 
-7 to -1 
1 
2-3 
4 
5-7 
8 
9-14 
15 
22 
29 
36 
64 
92 120 148 
176 
±1 day 
±3 day window, anchored to the prior injection 
Collect Wrist Actigraph 
 
 
 
 
 
 
 
 
 
 
X 
 
X 
 
 
 
Adverse Event Monitoring 
X 
Prior and Concomitant 
Medication Review 
X 
Abbreviations: AE=adverse event; AIMS=Abnormal Involuntary Movement Scale; AL=aripiprazole lauroxil; AL-NCD=aripiprazole lauroxil NanoCrystal 
Dispersion; BARS=Barnes Akathisia Rating Scale; CGI-S=Clinical Global Impression-Severity Scale; C-SSRS=Columbia-Suicide Severity Rating Scale; 
C-VISA=Clinical-Validation Inventory for Study Admission; ECG=electrocardiogram; EOS=end of study; EOT=end of treatment; ESS=Epworth Sleepiness 
Scale; ET=early termination; HIV=human immunodeficiency virus; IM=intramuscular; ISR=injection site reaction; MINI v 7.0.2=Mini-International 
Neuropsychiatric Interview 7.0.2 for Schizophrenia and Psychotic Disorder Studies; PANSS=Positive and Negative Syndrome Scale; PBO=placebo; 
PP=paliperidone palmitate; Q-LES-Q-SF=Quality of Life Enjoyment and Satisfaction Questionnaire - Short Form; RDQ=Readiness for Discharge 
Questionnaire; SAS=Simpson-Angus Scale; UDS=urine drug screen; UKU-SERS-PAT=Udvalg for Kliniske Undersøgelser Side Effect Self-Rating 
Scale- Patient; V=visit; WoRQ=Work Readiness Questionnaire 
a Subjects meeting initial screening eligibility criteria, who are not already inpatient, will be admitted to an inpatient study unit for completion of Screening visit 
assessments or as soon as possible thereafter. After randomization on Day 1, 2 weeks of inpatient hospitalization is required. Subjects are to be returned to 
outpatient status when assessed by the Investigator as safe and medically ready for discharge on Day 15. Note: With Medical Monitor approval prior to Day 15, 
the Investigator may retain the subject in the inpatient unit for up to 1 additional week (to Day 22) if the Investigator deems the subject not safe or medically 
ready for discharge on Day 15 
b Screening assessments may be conducted over 2 consecutive days (Inclusion/Exclusion eligibility criteria review must be conducted on the first day of 
screening); up to 7 days is allowed for screening to ensure availability of safety laboratory assessments, etc; however the shortest Screening period is 
recommended 
c The End of Treatment (EOT)/End of Study (EOS) visit is to occur 28 ± 3 days after the previous dose of IM study drug was administered (Visit 10/ Day 148). 
If a subject terminates early from the study, an Early Termination (ET) visit should occur as close as possible to the subject’s last dose, and ET assessments and 
will mimic the assessments scheduled to be conducted at Visit 11/EOT/EOS. For subjects discontinuing early, any untoward medical condition occurring 
within 30 days after the last dose and deemed related to study drug should be considered an AE. An unscheduled visit should be captured in the EDC and 
documented in the source should the subject require a visit to the investigational site 


 
 
 
 
 
 
 
 
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d The C-VISA uses audio-digital recordings of key screening assessments as the basis for site-independent eligibility review, which includes study measures such 
as PANSS, CGI-S, and MINI v 7.0.2 
e Information about a subject’s caregiver will be collected at screening and in the event of a change in a subject’s caregiver during the study. Caregiver Consent, 
and Intake Form can be conducted anytime within the 7 day screening period 
f Full physical examination is performed at screening and brief examination at all other time points. A symptom-driven physical examination can be completed 
at other study visits as clinically indicated 
g At screening, a urine sample for urine drug screen (UDS) will be sent to the central laboratory for analysis (a UDS via dipstick will also be performed). A UDS 
(via dipstick) will also be performed at V2 predose. At the Investigator’s discretion, a UDS (via dipstick) may be performed at any time as an unscheduled 
assessment 
h If positive urine pregnancy test (via dipstick) at screening, serum confirmation is required. Urine pregnancy test (via dipstick) at all other applicable visits 
i Fasting laboratory assessments are performed at screening and on Day 1; all other laboratory sample collections may be performed non-fasting 
j Serology testing includes anti-human immunodeficiency virus (HIV) antibody and/or antigen, hepatitis B surface antigen, and anti-hepatitis C antibody 
k Vital signs (ie, blood pressure, pulse, respiratory rate, and body temperature) will be measured at the time points identified in Table 4. During screening, 
Day 15 , and Visit 11 (EOT/EOS/ET), all vital signs are to be measured anytime during the visit. On Day 1, blood pressure and pulse are to be measured both 
within 1 hour predose and within 2 to 4 hours postdose and respiratory rate and body temperature are to be measured within 1 hour predose. On days 8, 36, 64, 
92, 120, and 148, blood pressure and pulse are to be measured both within 1 hour predose and within 2 to 4 hours postdose, respiratory rate is to be measured 
within 1 hour predose, and body temperature is to be measured within 2 to 4 hours post. On study days when multiple doses are administered (Day 1 and 
Day 8), predose assessment timing is relative to the first dose given, and postdose assessment timing is relative to the last dose given 
l A 12-lead electrocardiogram (ECG) is to be performed at the study visits identified in the schedule of assessments. On days when a subject receives study drug, 
an ECG will be performed both before and after dosing. Predose ECG should be completed within 1 hour prior to dosing. The postdose ECG should be 
completed within 2 to 4 hours postdose. On study days when multiple doses are administered (Day 1 and Day 8), predose assessment timing is relative to the 
first dose given, and postdose assessment timing is relative to the last dose given  
m Test doses are only distributed if a subject does not have historical exposure to aripiprazole, or if a subject does not have historical exposure to risperidone or 
paliperidone. For subjects without historical exposure to aripiprazole, oral test doses will consist of 5 mg/day aripiprazole during the first 2 days of inpatient 
stay to assess tolerability. For subjects without historical exposure to risperidone and paliperidone, oral test doses will consist of 1 mg/day risperidone 
administered during the first 2 days of inpatient stay to assess tolerability. For subjects who require test doses of both aripiprazole and risperidone, the oral test 
doses should be administered 8 hours apart on the first 2 days of the inpatient Screening period (eg, administer aripiprazole test dose in the morning and 
risperidone test dose in the evening, or vice versa). 
n On study days when multiple doses are administered (Day 1 and Day 8), predose assessment timing is relative to the first dose given, and postdose assessment 
timing is relative to the last dose given 
o The injection site(s) and surrounding areas will be inspected for possible ISRs within 2 to 6 hours after last injection. During the inpatient stay, the injection 
site(s) will also be inspected daily for 2 days post-injection (ie, on Days 2 and 3 and Days 9 and 10) and on Day 15. All ISRs, whether by objective physical 
finding or subjective report, will also be recorded as AEs and will be followed until resolution 
p The PANSS assessment should be performed first before any other psychiatric assessment at applicable study visits, with the exception of the Screening visit, 
where the MINI v 7.0.2 will be conducted first 
q “Baseline/Screening” version at screening (Visit 1); “Since Last Visit” version at all subsequent visits  
r  Readiness for Discharge scale will be administered daily from Day 4 to Day 15 
s The Burden Assessment Scale will only be completed by caregivers who are family or friends (ie, nonprofessional caregivers) and the screening Burden 
Assessment Scale can be conducted anytime within the 7 day screening period 
t Only two weeks of data will be collected following distribution of actigraph 


 
 
 
 
 
 
 
 
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Notes: For details regarding the timing of the structured interviews and questionnaires, refer to Section 8.3.13. Study drug is administered on Days 1, 8, 36, 64, 
92, 120, and 148, as indicated by the gray shading in the column headers. 
 
 


 
 
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8.3. 
Study Procedures Descriptions 
Details of the study procedures are described below. The overall schedule of assessments is 
provided in Table 3. 
8.3.1. 
Informed Consent 
The nature of the study and its risks and benefits will be explained to the subject and caregiver 
by the Principal Investigator or designated study personnel as outlined in Section 18.3. 
Prior to the administration of any study-specific procedures, authorized study personnel will 
obtain written informed consent from each potential subject and caregiver. 
8.3.2. 
Eligibility Review 
An eligibility review using the Clinical-Validation Inventory for Study Admission (C-VISA) will 
be conducted by the Investigator at the visits specified in Table 3 using the subject inclusion 
criteria in Section 7.1 and exclusion criteria in Section 7.2. Ratings will be reviewed at screening 
by raters employed by Bracket, with additional reviews taking place at baseline and on various 
visits throughout the study according to a prespecified schedule (subject to change based on rater 
accuracy). Rater review is being carried out for providing an unbiased “second” opinion on 
critical inclusion/exclusion assessments and efficacy assessments. Additionally, other key 
eligibility criteria (including medical and psychiatric history) will be reviewed by 
 clinical 
surveillance team. 
8.3.3. 
Identification of Informant/Caregiver 
Each subject enrolled in this study will need a reliable informant/caregiver. The caregiver will be 
required to sign a caregiver ICF and may withdraw consent at any time, in which case he/she can 
no longer fill the caregiver role for this study. If a caregiver can no longer fill the caregiver role, 
he/she should be replaced if possible. If the caregiver cannot be replaced, most subjects will be 
able to continue in the study. If the subject must also withdraw from the study (eg, the caregiver 
provided transportation to the site and no other travel arrangements can be made for the subject), 
the Investigator should make a reasonable effort to ascertain the reason(s) for the caregiver’s 
withdrawal, while fully respecting the caregiver’s and subject’s rights. The reason for the 
caregiver’s withdrawal and explanation of the subject’s discontinuation should be documented in 
the appropriate eCRF. 
Information about a subject’s caregiver will be collected at screening and in the event of a 
change in a subject’s caregiver during the study. Please refer to the Caregiver Intake Form 
located in Section 23. 
8.3.4. 
Demographics and Medical/Psychiatric History 
Each subject’s demographic data and medical/psychiatric history will be reviewed and 
documented at the time point(s) specified in Table 3.  
PPD


 
 
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8.3.5. 
Resource Utilization Form 
At the time points specified in Table 3, subjects will report resource use, such as emergency 
room visits and criminal justice involvement, over the time specified. When available, caregiver 
report and medical records will be used to confirm hospitalizations. This information will be 
collected in the Resource Utilization Form located in Section 24. 
8.3.6. 
Mini-International Neuropsychiatric Interview 7.0.2 for Schizophrenia and 
Psychotic Disorder Studies (MINI v 7.0.2) 
The MINI v 7.0.2 is a clinician-administered, structured diagnostic interview, with an 
administration time of approximately 15 minutes (Sheehan et al, 1998). The MINI v 7.0.2 has 
been validated against the much longer Structured Clinical Interview for DSM Diagnoses that 
corresponds to the DSM-5. The MINI v 7.0.2 will be used at screening only as indicated in 
Table 3. The MINI v 7.0.2 is required to be done before any other diagnostic assessments at 
screening. 
8.3.7. 
Concomitant Medication Review 
All medications (prescription and nonprescription, including vitamins and herbal supplements) 
taken by a given subject within 30 days prior to screening through follow-up will be recorded. 
The Investigator will record the following data on all medications used by the subject: name, 
dose, regimen, route of administration, start and stop dates, and the indication for use.  
8.3.8. 
Vital Signs 
Vital signs (ie, blood pressure, pulse, respiratory rate, and body temperature) will be measured at 
the time point(s) identified in Table 3 and Table 4 . Blood pressure and pulse and respiratory rate 
will be measured after the subject has been comfortably seated for at least 5 minutes. Efforts 
should be made to take all blood pressure and pulse measurements from the same arm 
(preferably the subject’s dominant arm) throughout the study. Automated measurement is 
preferred. The method of measuring body temperature for a given subject should remain constant 
throughout the subject’s participation in the study. 


 
 
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Table 4: 
Vital Signs: Assessment Timing from Screening through Visit 11 
(EOT/EOS/ET) 
Visit 
Assessment 
Assessment Timing 
Screening, Day 15, Visit 11 
(EOT/EOS/ET) 
Blood pressure 
Pulse 
Body temperature 
Respiratory Rate 
Anytime during visit 
Day 1a 
Blood pressure  
Pulse 
Within 1 hour predose and  
within 2 to 4 hours postdose 
Body temperature 
Respiratory rate 
Within 1 hour predose 
Days 8a, 36, 64, 92, 120, 148 
Blood pressure  
Pulse 
Within 1 hour predose and  
within 2 to 4 hours postdose 
Body temperature 
Within 2 to 4 hours postdose 
Respiratory rate 
Within 1 hour predose 
a On study days when multiple doses are administered (Day 1 and Day 8), predose assessment timing is relative to 
the first dose given and postdose assessment timing is relative to the last dose given. 
8.3.9. 
Physical Examination, Body Height, and Weight 
A physical examination will be performed at the time point(s) specified in Table 3. A full 
physical examination (including a neurological examination) is performed at screening and brief 
examinations (including HEENT inspection [no otoscopic or fundoscopic examination], chest 
inspection, percussion and auscultation, abdominal inspection, auscultation, and palpitation) at 
all other time points. Pelvic and rectal examinations are not required unless clinically needed and 
then would be referred. A symptom-driven physical examination can be completed at other study 
visits as clinically indicated. 
8.3.10. 
12-Lead Electrocardiogram 
A 12-lead ECG will be conducted at the time point(s) specified in Table 3. On days when 
subjects receive injections of IM study drug, an ECG will be performed both before and after 
dosing. Predose ECG should be completed within 1 hour prior to dosing. The postdose ECG 
should be completed within 2 to 4 hours postdose. On study days when multiple doses are 
administered (Day 1 and Day 8), predose assessment timing is relative to the first dose given, 
and postdose assessment timing is relative to the last dose given. All scheduled ECGs should be 
performed after the subject has rested quietly for at least 5 minutes in the supine position. QT 
intervals will be automatically corrected for heart rate by the ECG machine using QTcF. The 
ECGs will be evaluated by a central facility. Additional details regarding recording and 
evaluation of ECGs will be described in a manual provided to the study site. 


 
 
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8.3.11. 
Injection Site Evaluation 
The injection site(s) and surrounding areas will be inspected for possible ISRs by the Investigator 
or designee at the time points identified in Table 3, within 2 to 6 hours after last injection. During 
the inpatient stay, the injection site(s) will also be inspected daily for 2 days postinjection (on 
Days 2 and 3 and Days 9 and 10) and on Day 15. All ISRs, whether by objective physical finding 
or subjective report, will also be recorded as AEs and will be followed until resolution.  
8.3.12. 
Wrist Actigraphy 
Investigators or designees will distribute the actigraphy device at the time points identified in 
Table 3. The device is meant to be worn by each subject on the wrist of the non-dominant arm 
for around 14 consecutive days after it is distributed. The device will monitor and record the 
physical activity of each subject. Subjects should be instructed to wear the device at all times. 
The device should then be collected by sites at the time points identified in Table 3 and returned 
to the Sponsor/designee for data analysis. 
8.3.13. 
Structured Interviews and Questionnaires 
With regard to the structured interviews and questionnaires, when the administration of these 
rating scales coincide, they should be administered in the following order: 
1. MINI v 7.0.2 
2. PANSS 
3. C-SSRS 
4. Abnormal movement scales (AIMS, BARS, and SAS) 
5. CGI-S 
6. RDQ 
It is important that assessments are performed in the proper order. Subject and caregiver reported 
scales can be collected at any time during the visit, when applicable.  
Other assessments that are not structured interviews or questionnaires can be performed as 
needed. 
8.3.13.1. Positive and Negative Syndrome Scale 
The PANSS is a scale used to assess positive and negative symptoms in patients with 
schizophrenia (Kay et al, 1987). Patients are rated on a scale of 1 to 7 on 30 different symptoms. 
The Investigator or designee will complete the PANSS at time points identified in Table 3. The 
Structured Clinical Interview for the PANSS will be used to administer the PANSS. 
8.3.13.2. Abnormal Movement Scales 
Abnormal Movement Scales will include AIMS, BARS, and SAS. 
The Investigator or designee will complete the set of abnormal movement rating scales at time 
points identified in Table 3. 


 
 
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After administration of the first dose of study drug, if a subject complains of extrapyramidal 
symptoms (EPS) on days when the abnormal movement scales are not scheduled to be 
performed, an unscheduled assessment should be performed. 
8.3.13.3. Columbia-Suicide Severity Rating Scale 
The Investigator or designee will administer the C-SSRS according to the schedule in Table 3. At 
screening, the “Baseline/Screening” version will be administered (Posner et al, 2009a), and at all 
other visits, the “Since Last Visit” version will be administered. For “Since Last Visit” versions, 
subjects should be asked to report on ideation and behavior since the last scheduled C-SSRS 
assessment (Posner et al, 2009b). The C-SSRS should be administered by a clinician trained to 
assess and manage suicidal ideation and behavior. 
8.3.13.4. Epworth Sleepiness Scale 
The ESS is a self-reported questionnaire with 8 questions that provides a measure of a person’s 
level of daytime sleepiness (Johns 1991). The ESS assesses, on a 4-point scale (0–3), a person’s 
usual chances of dozing off or falling asleep in 8 different situations or activities. This scale will 
be completed by the subject at the time points specified in Table 3. 
8.3.13.5. Readiness for Discharge Questionnaire 
The RDQ is a questionnaire used to assess a patient’s readiness for discharge, independent of 
socio-economic factors (Potkin et al, 2005). The RDQ consists of 6 items assessing 
suicidality/homicidality, control of aggression/impulsivity, activities of daily living, medication-
taking, delusions/hallucinations interfering with functioning and global status. The 6 items 
ultimately inform a “yes/no” indication of whether the subject is clinically appropriate for 
discharge. The Investigator or designee will complete the RDQ at time points identified in 
Table 3. Subjects who are determined to be “ready for discharge” prior to Day 15 are still 
required to remain inpatient until Day 15. 
8.3.13.6. Quality of Life Enjoyment and Satisfaction Questionnaire - Short Form 
The Q-LES-Q-SF is a self-reported measure used to assess the degree of enjoyment and 
satisfaction experienced by subjects in various areas of daily functioning (Stevanovic 2011). 
Responses are evaluated on a 5-point scale (“not at all to never” to “frequently or all the time”), 
with higher scores indicating more enjoyment and satisfaction. Subjects will complete the 
Q-LES-Q-SF at time points identified in Table 3. 
8.3.13.7. Modified Medication Satisfaction Questionnaire 
The modified MSQ is a 3-item self-reported patient satisfaction questionnaire which assesses the 
level of patient satisfaction with medication. Subjects rate their satisfaction with their current 
medication, their preference for their current medication vs previous medications, and their 
opinion on the side effects of their current medication vs previous medications. Ratings are on a 
5-point Likert scale. The modified MSQ will be collected at the time points identified in Table 3. 


 
 
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8.3.13.8. Work Readiness Questionnaire 
The WoRQ is a questionnaire used to assess a patient’s ability to engage in socially useful 
activity, independent of work availability (Potkin et al, 2016). The Investigator or designee will 
complete the WoRQ at time points identified in Table 3. 
8.3.13.9. Udvalg for Kliniske Undersøgelser-Side Effect Self-Rating Scale - Patient, Sexual 
Side Effects Subscale 
The sexual functioning subscale from the UKU-SERS-PAT contains 7 items for males and 
9 items for females (Lindstrom et al, 2001; Lingjaerde et al, 1987). Each item is rated on a 
4-point scale (0=none or doubtful, 1=present to a mild degree, 2=present to a moderate degree, 
and 3=present to a severe degree). This scale will be completed by the subject at the time points 
specified in Table 3. 
8.3.13.10. Burden Assessment Scale 
The Burden Assessment Scale is a 19-item scale administered to caregivers who are family or 
friends (ie, nonprofessional caregivers) that focuses on specific subjective and objective 
consequences of families caring for individuals with severe mental disorders (Reinhard et al, 
1994). Respondents are required to indicate whether they have experienced each of the types of 
burden ‘Not at all,’ ‘A little,’ ‘Some,’ or ‘A lot’ in the past 4 weeks. These are scored 1, 2, 3, and 
4, respectively. A higher score indicates more perceived burden. The Burden Assessment Scale 
will be administered to the designated caregiver at the time points identified in Table 3.  
8.3.13.11. Handwriting Movement Kinematics 
A quantitative analysis of handwriting kinematics is used to evaluate effects of antipsychotic 
medication in patients with schizophrenia (Caligiuri et al, 2009). The Investigator or designee 
will administer the handwriting tests to the subjects at time points identified in Table 3. 
Instructions will be provided separately to the site. 
8.3.13.12. Clinical Global Impression–Severity 
The CGI-S is a 7-point scale used to assess the rate of severity of a patient’s illness (Guy 2000). 
The Investigator or designee will complete the CGI-S scale at time points identified in Table 3. 
8.3.14. 
Laboratory Assessments 
8.3.14.1. Drug Testing 
Subjects will complete a urine drug test for illicit use of amphetamines, methamphetamines, 
MDMA, barbiturates, benzodiazepines, cocaine, opioids (including oxycodone, methadone, and 
buprenorphine), and phencyclidine at screening and baseline. Results must be negative for the 
subject to be eligible for the study. Use of cannabinoids is not exclusionary but THC levels will 
be collected as part of the standard urine drug screen. Use of prescribed medications 
(eg, benzodiazepines or opioids) that account for the positive urine drug test results are not 
exclusionary. Use of prescribed barbiturates must be stopped 14 days prior to Day 1. Repeat 
testing may be performed if positive urine drug test results cannot be confirmed by a history of 
presumed active substance use or use of prescribed medications. 


 
 
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8.3.14.2. Hematology, Biochemistry, and Urinalysis 
Blood and urine samples for laboratory assessments will be collected at the time points specified 
in Table 3. Specific hematology, biochemistry, and urinalysis assessments are listed in Table 5. 
Samples will be collected in accordance with the study site’s usual procedures and analyzed by a 
central laboratory. Laboratory assessments may be repeated at the Investigator’s discretion. The 
process for the review of prolactin levels is discussed in Section 25. 
Table 5: 
Clinical Laboratory Assessments 
Hematology 
Biochemistry 
Urinalysis 
Hematocrit 
Hemoglobin 
Red blood cell count 
Total and differential (absolute) 
white blood cell count 
Platelets 
Sodium 
Potassium 
Glucose 
Creatinine 
Total protein 
Blood urea nitrogen  
Albumin 
Total bilirubin 
Alanine transferase  
Aspartate transferase  
Lactic dehydrogenase  
Gamma-glutamyl transferase  
Alkaline phosphatase  
Creatine phosphokinase  
HbA1c 
TSH 
Free T3a 
Free T4a 
Prolactin  
Color and appearance 
pH 
Specific gravity 
Ketones 
Protein 
Glucose 
Bilirubin 
Nitrite 
Urobilinogen 
Occult blood 
Microscopic examination of 
sediment, only if urinalysis 
dipstick results are abnormal 
a _ Free T3 and free T4 levels will be measured if TSH levels are abnormal. 
8.3.14.3. Pregnancy Testing 
At the screening visit, results must be negative for the subject to be eligible for the study. If there 
is a positive urine pregnancy test (via dipstick) at screening, serum confirmation is required. 
A urine pregnancy test (via dipstick) will be administered at all other applicable visits as 
specified in Table 3. 
Section 14.5 provides guidance on the reporting requirements for pregnancies. 
8.3.14.4. Cytochrome P450 Genotype Testing 
A blood sample will be collected from each subject for determination of CYP2D6 genotype on 
Day 1. 


 
 
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8.3.14.5. Serology Testing 
A blood sample for a serology panel testing for hepatitis B surface antigen, anti-hepatitis C 
antibodies, and HIV antibody and/or antigen will be performed at screening only. 
8.3.15. 
Randomization 
On Day 1, subjects will be randomized as outlined in Section 9.4. 
8.3.16. 
Drug Dispensation and Reconciliation 
Section 9 provides information related to drug dispensing procedures. Study drug will be 
administered at the time points specified in Table 3. 
8.3.17. 
Adverse Event Monitoring 
Adverse events will be monitored continuously from the time a subject signs the informed 
consent document until the completion of the final study visit (see Table 3). Adverse events and 
serious adverse events (SAEs) are defined in Section 14.1 and Section 14.2, respectively. 
Section 14.4 provides guidance on the monitoring and recording requirements for AEs. 
Section 14.5 provides guidance on the reporting requirements for SAEs. 
In the event that a subject experiences an AE of akathisia or seizure during the treatment period, 
a PK blood sample should be collected at the next visit and shipped frozen to the lab for storage. 
At the Sponsor’s discretion, sites may be instructed to collect PK samples for additional AEs. 
8.4. 
Study Requirements and Restrictions 
8.4.1. 
Contraception and Pregnancy 
All male and female subjects must agree to use an acceptable method of contraception for the 
duration of the study unless they are surgically sterile or postmenopausal (see below). The 
following are considered acceptable methods of contraception: 
1. Double-barrier protection (eg, a condom with spermicide or a diaphragm with 
spermicide) 
2. Intrauterine device  
3. Oral contraceptive pills and other hormonal methods (eg, a vaginal ring, contraceptive 
patch, or contraceptive implant); oral contraceptives should have been initiated at least 
30 days prior to screening 
Subjects who are abstinent are eligible, provided they agree to use an acceptable contraceptive 
method should they become sexually active. 
Subjects who are surgically sterile are exempt from the requirement to use contraception. 
Women who have undergone a hysterectomy, bilateral tubal ligation, or bilateral 
salpingo-oophorectomy are considered surgically sterile. Men who have undergone a vasectomy 
are considered surgically sterile. Partner vasectomy is not considered an approved acceptable 
method of contraception for a female subject.  


 
 
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Women who are postmenopausal are also exempt from the requirement to use contraception. 
For the purpose of this study, postmenopausal is defined as the permanent cessation of 
menstruation for at least 12 months prior to screening in women who are 45 years of age or 
older. 
If a subject becomes pregnant while participating in the study, she will be discontinued from 
study drug immediately. The ET visit will be scheduled and the pregnancy will be reported to 
Alkermes. Additional follow-up may be required. Pregnancies in female partners of male 
subjects should also be reported and will be followed in the same manner. 
A Pregnancy Report Form must be submitted to Alkermes via 
 Drug Safety 
(per Section 14.5) immediately within 24 hours of awareness of the pregnancy, irrespective of 
whether an AE has occurred. The pregnancy will be followed until completion or termination. 
If the outcome of the pregnancy meets the criteria for classification as a SAE, it should be 
reported following the SAE procedure (see Section 14.5). 
8.4.2. 
Permitted Therapy 
Permissible potential medications to treat EPS may include benzodiazepines, antihistamines, 
beta-blockers, and anticholinergics. While insomnia may be treated with a variety of agents, 
short half-life benzodiazepines are preferable to longer half-life benzodiazepines due to the 
potential for lingering effects on daytime functioning and study assessments. Treatment of 
agitation and/or anxiety with benzodiazepines is permissible, but the dose should be kept as 
stable as possible throughout the study as clinically indicated, so as not to interfere with daytime 
functioning and study assessments. Use of antidepressants other than CYP inhibitors/inducers 
(Section 21 and Section 22) may be continued during the study if dosage has been stable for 
30 days before Day 1 and should be kept as stable as possible throughout the study as clinically 
indicated.  
Therapies based upon the Clinical Investigator’s medical judgment to be in the best interest of 
the patient’s safety are permissible after consultation with the Sponsor/CRO Medical Monitor.  
8.4.3. 
Non-medication Therapy 
Psychotherapy should not be started or changed during a subject’s participation in the study. It is 
acceptable for a subject already receiving psychotherapy to participate in the study; however, 
subjects receiving cognitive-behavioral therapy should not be enrolled. While on the inpatient 
study unit during participation in the study, initiation of augmenting psychotherapies (ie, group 
therapy) deemed by the Clinical Investigator to be of clinical benefit is discouraged, although 
standard milieu-related activities are acceptable. Partial hospitalization after discharge from the 
inpatient study unit is allowed, and the level of care after discharge from the inpatient study unit 
ultimately should be made based on the Investigator’s judgment. 
Therapies based upon the Clinical Investigator’s medical judgment to be in the best interest of 
the patient’s safety are permissible after consultation with the Sponsor/CRO Medical Monitor. 
PPD


 
 
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8.4.4. 
Prohibited Medications 
With the exception of those specifically prohibited, medications are allowed. In this study, the 
medications listed below are prohibited; the Medical Monitor should be consulted regarding any 
questions on allowed and prohibited medications: 
 Use of potent inducers or inhibitors of CYP3A or inhibitors of CYP2D6, whether as 
prescription medications, over-the-counter medications, or dietary supplements, 
within 14 days before dosing and during the course of the study is prohibited 
 A list of common CYP3A inducers or inhibitors and CYP2D6 inhibitors is 
provided in Section 21 and Section 22, respectively. This list is not exhaustive 
 Use of antipsychotic medications during the course of the study is prohibited. Prior 
antipsychotic medications should be discontinued after screening upon inpatient 
admission. All subjects should be in an inpatient setting when discontinuing prior 
antipsychotic medication. The washout of antipsychotics would be at the discretion of 
the Investigator based on evolving clinical picture. Allowable washout period is 
2 to 5 days 
 If administration of a psychotropic medication during a subject’s participation in 
the study is being considered (eg, an antipsychotic as rescue medication during 
the Treatment period), the Investigator must contact the Medical Monitor to 
discuss the appropriate course of action 
 Monoamine oxidase inhibitors (eg, phenelzine, tranylcypromine, selegiline, 
moclobemide) are strictly prohibited  
 Lithium, valproic acid (divalproex sodium), carbamazepine and lamotrigine are not 
permitted  
 IM medications other than the study drug should be administered contralateral to IM 
study drug injections to avoid confounding safety assessments of study drug 
injections sites and surrounding areas 
See Section 8.3.7 for details regarding the concomitant medication review. 
8.4.5. 
Dietary Restrictions 
Foods and beverages that are inducers or inhibitors of CYP3A or inhibitors of CYP2D6, such as 
grapefruit, grapefruit juice, Earl Grey tea, etc, are prohibited. 


 
 
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9. 
TREATMENT OF SUBJECTS 
9.1. 
Study Drug Dose and Administration 
Study drug dosing schedule is shown in Table 6. 
Subjects randomized to the AL Treatment Group will receive 662 mg AL-NCD (single IM gluteal injection) 
plus IM placebo (PBO; single IM deltoid injection) plus a 30 mg oral aripiprazole tablet on Day 1. On 
Day 8, these subjects will receive AL 1064 mg (single IM gluteal injection) plus IM PBO (single IM deltoid 
injection). On Days 36, 92, and 148,  
these subjects will receive IM PBO (single IM gluteal injection), and on Days 64 and 120,  
these subjects will receive AL 1064 mg (single IM gluteal injection). 
Subjects randomized to the PP Treatment Group will receive PP 234 mg (single IM deltoid 
injection) plus IM PBO (single IM gluteal injection) plus an oral PBO tablet on Day 1. 
On Day 8, these subjects will receive PP 156 mg (single IM deltoid injection) plus IM PBO 
(single IM gluteal injection). On Days 36, 64, 92, 120, and 148, these subjects will receive 
PP 156 mg (single IM gluteal injection).  
Placebo for IM injection is phosphate buffered saline. Placebo will be provided in a single-use 
prefilled syringe (PFS) with a volume of 2.4 mL. Placebo will be administered via gluteal or 
deltoid IM injection. It is recommended that all study drugs should be given within 30 minutes. 
If a dose is missed by >2 weeks, the subject must discontinue study drug. 
Table 6: 
Dosing Schedule 
 
Day 1 
Day 8 
(Week 1) 
Day 36 
(Week 5) 
Day 64 
(Week 9) 
Day 92 
(Week 
13) 
Day 120 
(Week 17) 
Day 148 
(Week 
21) 
AL 
30 mg oral 
aripiprazole + 
AL-NCD 662 mg 
(gluteal) + IM 
PBO (deltoid) 
AL 
1064 mg 
(gluteal) + 
IM PBO 
(deltoid) 
IM PBO 
(gluteal) 
AL 
1064 mg  
(gluteal) 
IM PBO 
(gluteal) 
AL 
1064 mg  
(gluteal) 
IM PBO 
(gluteal) 
PP 
Oral placebo + 
PP 234 mg 
(deltoid) + IM 
PBO (gluteal) 
PP 156 mg 
(deltoid) + 
IM PBO 
(gluteal) 
PP 
156 mg 
(gluteal) 
PP 156 mg 
(gluteal) 
PP 
156 mg 
(gluteal) 
PP 156 mg 
(gluteal) 
PP 
156 mg 
(gluteal) 
Abbreviations: AL=aripiprazole lauroxil; AL-NCD=aripiprazole lauroxil NanoCrystal Dispersion; 
IM=intramuscular; PBO=placebo; PP=paliperidone palmitate  
9.2. 
Oral Test Doses 
If a subject does not have historical exposure to aripiprazole, oral test doses of aripiprazole will 
be administered during the first 2 days of inpatient stay during the Screening period. If a subject 
does not have historical exposure to risperidone or paliperidone, oral test doses of risperidone 
will be administered during the first 2 days of inpatient stay during the Screening period. All test 


 
 
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doses are administered prior to randomization in order to assess tolerability as observed by the 
study site staff.  
For subjects with no history of tolerated exposure to aripiprazole, aripiprazole for use as oral test 
doses will be commercially available aripiprazole 5 mg tablets, provided in commercial 
packaging provided to the site by Alkermes. Oral aripiprazole tablets must be kept in a locked 
storage area before dosing and must be stored in accordance with the full prescribing information 
for aripiprazole. For all women, a urine pregnancy test will be conducted and the results must be 
negative prior to administration of aripiprazole test doses. The date and time of test dose 
administration will be recorded.  
For subjects with no history of tolerated exposure to risperidone or paliperidone, risperidone for 
use as oral test doses will be commercially available risperidone 1.0 mg tablets, provided in 
commercial packaging provided to the site by Alkermes. Oral risperidone tablets must be kept in 
a locked storage area before dosing and must be stored in accordance with the full prescribing 
information for risperidone. For all women, a urine pregnancy test will be conducted and the 
results must be negative prior to administration of risperidone test doses. The date and time of 
test dose administration will be recorded. 
For subjects who require test doses of both aripiprazole and risperidone, the oral test doses 
should be administered 8 hours apart on the first 2 days of the inpatient Screening period 
(eg, administer aripiprazole test dose in the morning and risperidone test dose in the evening, 
or vice versa). 
9.3. 
Treatment Adherence 
All study drug will be directly administered by study site staff.  
9.4. 
Randomization/Method of Assigning Subjects to Treatment 
Subjects meeting all eligibility criteria will be randomized to one of two Treatment Groups, as 
described in Table 7. 
Table 7: 
Treatment Groups 
Treatment Group 
Aripiprazole lauroxil 
Paliperidone palmitate 
Day 1 
662 mg AL-NCD (IM gluteal) +  
PBO (IM deltoid) + 30 mg oral aripiprazole 
PP 234 mg (IM deltoid) +  
PBO (IM gluteal) + oral PBO 
Day 8 
AL 1064 mg (IM gluteal) +  
PBO (IM deltoid) 
PP 156 mg (IM deltoid) +  
PBO (IM gluteal) 
Days 36, 92, and 148 
PBO (IM gluteal) 
PP 156 mg (IM gluteal) 
Days 64 and 120 
AL 1064 mg (IM gluteal) 
PP 156 mg (IM gluteal) 
Abbreviations: AL=aripiprazole lauroxil; AL-NCD=aripiprazole lauroxil NanoCrystal Dispersion; 
IM=intramuscular; PBO=placebo; PP=paliperidone palmitate 
To minimize potential response bias based on antipsychotic medication exposure history, 
randomization will be stratified by the status of prior exposure to aripiprazole or risperidone/ 
paliperidone. There are two stratification levels, as described in Table 8. After the stratification 
level (either Level 1 or Level 2) is determined for the subject, he or she will be randomized to 


 
 
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one of two treatment groups in a 1:1 ratio. Stratification will ensure a balance of the two 
treatment groups within each stratification level. 
Table 8: 
Stratification Factors 
 
Prior Risperidone/Paliperidone Exposure 
Yes 
No 
Prior Aripiprazole 
Exposure 
Yes 
Level 1 
Level 2 
No 
Level 2 
Level 1 
9.5. 
Blinding 
This is a double-blind study; the Investigator and study site staff, subject and caregiver, Sponsor, 
and CRO will remain blinded throughout the conduct of the study, with two exceptions: 
1. All study drugs (IM and Day 1 oral doses) will be administered in a double-blind 
fashion by a trained unblinded pharmacist (or designee) who is not involved in any 
efficacy or safety assessments of the subject 
2. The CRO unblinded Medical Monitor will monitor postbaseline prolactin values 
throughout the study (refer to Section 25 for details) and will be a resource to the 
Investigator/study site staff in the event of the need for emergency unblinding 
If the Investigator deems it necessary to break the study blind in the interest of a subject’s 
medical safety, he or she must make every effort to contact the CRO/Sponsor Medical Monitor 
before the blind is broken. If the site is unable to contact the Medical Monitor prior to breaking 
the blind, the Medical Monitor must be contacted within 24 hours following disclosure of study 
drug assignment.  
The Investigator is responsible for all study-related medical decisions. When the Investigator 
deems it necessary, emergency unblinding may be done without contacting a Medical Monitor. 
Any premature unblinding should be promptly documented and explained to the Medical 
Monitor. 
Breaking the blind for a single subject will not affect the blind for the remaining subjects. 
9.6. 
Study Drug Dose Adjustment and Stopping Rules 
Study drug doses cannot be adjusted. Subjects who meet the criteria for study drug 
discontinuation should be withdrawn from the study as described in Section 7.3. 


 
 
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10. 
STUDY DRUG MATERIALS AND MANAGEMENT 
10.1. 
Study Drug 
The investigational product is a covalent non-ester modification of aripiprazole to form 
N-lauroyloxymethyl aripiprazole. Aripiprazole lauroxil is a white to off-white aqueous 
extended-release suspension for IM injection provided as single-use PFS in a dose strength of 
1064 mg. Aripiprazole lauroxil NanoCrystal Dispersion (AL-NCD) is a white to off-white 
aqueous extended-release suspension, which is an alternative formulation of AL designed to 
provide faster dissolution than the AL formulation, provided in single-use PFS containing a dose 
strength of 662 mg. Additional information is provided in the AL IB. 
Oral aripiprazole is a tablet for oral administration in dose strengths of 5 mg (test dose) and 
30 mg (oral initiation regimen dose). Additional information is provided in the full prescribing 
information for aripiprazole.  
Paliperidone palmitate (Invega Sustenna) (Invega Sustenna USPI, 2017) is a white to off-white 
aqueous extended-release injectable suspension for IM injection in dose strengths of 156 mg and 
234 mg. Additional information is provided in the paliperidone prescribing information. 
Risperidone (Risperdal Consta) (Risperdal Consta USPI, 2017) is a white capsule-shaped tablet 
provided in a dose strength of 1 mg. Additional information is provided in the risperidone 
prescribing information. 
Placebo for IM injection is phosphate buffered saline. Placebo will be provided in a single-use 
PFS with a volume of 2.4 mL. Placebo will be administered via gluteal or deltoid IM injection 
per the Instructions for Use. 
The Sponsor will provide all study drugs and PBO to the clinical study sites. 
10.2. 
Packaging and Labeling 
Aripiprazole lauroxil and AL-NCD are supplied in a 5 mL PFS. Primary packaging consists of a 
sterilized, siliconized, cyclo-olefin copolymer plastic syringe barrel with a bromobutyl rubber 
plunger and bromobutyl rubber tip cap. The clinical kit will contain the PFS, needles, and 
labeling packaged in a pre-formed tray and carton.  
Aripiprazole for oral administration on Day 1 will be provided as 15 count community bottles 
containing 30 mg aripiprazole or PBO over-encapsulated tablets.  
Oral aripiprazole test doses in 5 mg tablet form will be commercially available aripiprazole 
provided in 30 count community bottles. 
Oral risperidone test doses in 1 mg tablet form will be commercially available risperidone 
provided in 60 count community bottles. 
Paliperidone palmitate (Invega Sustenna) will be provided in a PFS (cyclic-olefin-copolymer) 
with a plunger stopper and tip cap (bromobutyl rubber).  


 
 
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10.3. 
Storage 
Aripiprazole lauroxil, AL-NCD, and PBO must be stored in a locked area at 20°C to 25°C (68°F 
to 77°F); excursions between 15°C and 30°C (59°F and 86°F) are permitted. Oral aripiprazole 
tablets must be kept in a locked storage area before dosing and must be stored in accordance with 
the full prescribing information for aripiprazole.  
Paliperidone palmitate (Invega Sustenna) must be stored at room temperature (25°C [77°F]); 
excursions between 15°C and 30°C (59°F and 86°F) are permitted. 
Risperidone (Risperdal) tablets must be stored at controlled room temperature (15°C and 25°C 
[59°F and 77°F]) and protected from light and moisture. 
10.4. 
Accountability 
The study site is required to maintain current drug dispensation and accountability logs 
throughout the study. All unused supplies will be checked against the drug movement records 
during the study and/or at the end of the study. 
Refer to Section 9 for additional study drug reconciliation procedures. 
10.5. 
Handling and Disposal 
Following completion and verification of accountability logs, all unused and used packages must 
be destroyed. The Sponsor will arrange for destruction with a third-party vendor operating in 
accordance with GCP and/or Good Manufacturing Practice. 


 
 
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11. 
ASSESSMENT OF EFFICACY 
The primary and secondary efficacy endpoints will be evaluated based on PANSS responses. 
Additional efficacy endpoints will be evaluated by CGI-S and RDQ. 


 
 
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12. 
ASSESSMENT OF SUBJECT OR CAREGIVER CENTERED 
ENDPOINTS 
The subject or caregiver centered endpoints will be evaluated by Q-LES-Q-SF, modified MSQ, 
Burden Assessment Score, WoRQ responses/measurements, Handwriting Movement 
Kinematics, wrist actigraphy, and resource utilization value. 


 
 
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13. 
ASSESSMENT OF PHARMACOKINETICS AND 
PHARMACODYNAMICS 
Not applicable. 


 
 
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14. 
ASSESSMENT OF SAFETY 
The following safety and tolerability measures will be assessed throughout the study and 
summarized: 
 AEs 
 ISRs (eg, pain, tenderness, induration, pain, ecchymosis, pruritus, redness, 
swelling, etc) 
 Clinical laboratory parameters (chemistry, hematology, and urinalysis) 
 Vital signs (blood pressure, pulse, respiratory rate, and body temperature) 
 ECGs (heart rate, RR, PR, and QT) 
 C-SSRS responses  
 Abnormal movement scales scores (AIMS, BARS, and SAS) 
 ESS responses 
 UKU-SERS-PAT  Sexual Side Effects Subscale responses 
14.1. 
Definition of Adverse Event 
An AE is any untoward medical occurrence in a patient or clinical investigation subject who has 
been administered a pharmaceutical product. The occurrence, which may or may not have a 
causal relationship with the investigational treatment, may include any clinical or laboratory 
change that does not commonly occur in that subject and is considered clinically significant. 
Illnesses present prior to the subject signing the ICF are considered to be preexisting conditions 
and are documented on the medical history eCRF. Pre-existing conditions that worsen during the 
study are entered on the AE eCRF. 
All out-of-range laboratory values will be deemed as clinically significant or not clinically 
significant by the Investigator. Clinically significant values will be considered AEs and will be 
recorded as such on the eCRFs. The process for the review of prolactin levels is discussed in 
Section 25. 
Pregnancy is not considered an AE, although a subject will be withdrawn from the study if a 
pregnancy occurs. As described in Section 8.4.1, the pregnancy, including a partner’s pregnancy, 
must be reported to Alkermes, and additional follow-up may be required.  


 
 
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14.2. 
Definition of Serious Adverse Events 
An SAE is any AE, occurring at any dose and regardless of causality that meets one or more of the 
following criteria: 
 Results in death 
 Is life-threatening. The subject is at immediate risk of death from the reaction as it 
occurs. This does not include reaction that, had it occurred in a more severe form, 
might have caused death 
 Requires inpatient hospitalization or prolongation of existing hospitalization 
 Results in persistent or significant disability/incapacity (eg, a substantial disruption of 
a person’s ability to conduct normal life functions) 
 Is a congenital anomaly/birth defect 
Important medical events that may not result in death, be immediately life threatening, or require 
hospitalization may be considered to be SAEs when, based upon appropriate medical judgment, 
may jeopardize the patient or subject and may require intervention to prevent one of the other 
outcomes listed above. 
Admission to a hospital or an inpatient unit for a non-medical reason (ie, social stay admission) 
during the study in the absence of untoward medical occurrence will not be considered as an 
SAE, but will be captured as an AE. Hospitalization due to worsening of behavioral health 
related issues should be reported as an SAE. 
14.3. 
Relationship to Study Drug 
The assessment of study drug relationship to each AE will be reported on the appropriate source 
document (and SAE form, in the event of an SAE) by the Investigator (or designated 
subinvestigator) according to his or her best clinical judgment. The criteria listed in Table 9 
should be used to guide this assessment. Please note that not all criteria must be present to be 
indicative of a particular drug relationship. All study drugs are considered “test drugs” for the 
purposes of the definitions listed in the table. 


 
 
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Table 9: 
Adverse Event Causality Guidelines 
Relationship 
Criteria for Assessment 
Definitely Related 
There is evidence of exposure to the test drug 
AND 
The temporal sequence of the AE onset relative to administration of the test drug is 
reasonable 
The AE is more likely explained by the test drug than by another cause 
Dechallenge (if performed) is positive 
Rechallenge (if feasible) is positive 
The AE shows a pattern consistent with previous knowledge of the test drug or test drug 
class 
Probably Related 
There is evidence of exposure to the test drug 
AND 
The temporal sequence of the AE onset relative to administration of the test drug is 
reasonable 
The AE is more likely explained by the test drug than by another cause 
Dechallenge (if performed) is positive 
Possibly Related 
There is evidence of exposure to the test drug 
AND 
The temporal sequence of the AE onset relative to administration of the test drug is 
reasonable 
The AE could have been due to another equally likely cause 
Dechallenge (if performed) is positive 
Probably Not 
Related 
There is evidence of exposure to the test drug 
AND 
There is another more likely cause of the AE 
Dechallenge (if performed) is negative or ambiguous 
Rechallenge (if performed) is negative or ambiguous 
Definitely not 
Related 
The subject did not receive the test drug 
OR 
Temporal sequence of the AE onset relative to administration of the test drug is not 
reasonable 
OR 
There is another obvious cause of the AE 
Abbreviation: AE=adverse event 
14.4. 
Monitoring and Recording of Adverse Events 
Adverse event data collection will begin after a subject signs the ICF and will continue until 
completion of the End of Treatment (EOT)/EOS visit (Visit 11). Any AE or SAE having an 
onset after the EOT/EOS visit will not be collected or reported unless the Investigator feels that 
the event may be related to the study drug. 
Subjects will be instructed by the Investigator or designee to report the occurrence of any AE. 
All volunteered, elicited, and observed AEs are to be recorded on the AE eCRFs. 


 
 
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The Investigator will assess all AEs regarding any causal relationship to the study drug 
(see Section 14.3), the intensity (severity) of the event, action taken, and subject outcome. 
The following criteria should be used to guide the assessment of intensity (severity): 
 Mild: Causes awareness of sign or symptom, but is easily tolerated; does not interfere 
with usual activities 
 Moderate: Causes discomfort enough to interfere with usual activities 
 Severe: Is incapacitating; results in inability to work or perform usual activities 
All AEs will be followed until resolution, until deemed stable by the Investigator, or until the 
subject is deemed by the Investigator to be lost to follow-up. 
For clinical study safety reporting purposes, the most recent version of the Investigator’s 
Brochure will be used as the reference document to designate event expectedness. 
Withdrawal from the study as a result of an AE and any therapeutic measures that are taken shall 
be at the discretion of the Investigator. If a subject withdraws from the study for any reason, any 
ongoing AEs will be followed until resolution, until deemed stable by the Investigator, or until 
the subject is deemed by the Investigator to be lost to follow-up. 
14.5. 
Reporting of Serious Adverse Events and Pregnancy 
All SAEs and pregnancies must be reported to Alkermes via 
 Drug Safety 
immediately within 24 hours of discovery by emailing or faxing the report to the 
following: 
Attention: 
 Drug Safety 
FAX Number: 
 
Phone Number: 
 
Email: 
 
The written report for SAEs should be submitted on the SAE form provided for this purpose.  
The SAE report must include the Investigator’s opinion as to whether the event is study drug-
related. If this relationship is determined to be possibly, probably, or definitely related to study 
drug, evidence to support this assessment must also be provided. 
The written report for pregnancies in female subjects and in female partners of male subjects 
should be submitted on the Pregnancy Report Form provided for this purpose. 
PPD
PPD
PPD
PPD
PPD


 
 
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15. 
STATISTICS 
15.1. 
Sample Size Considerations 
No formal sample size calculations have been performed. The sample size of 180 subjects is 
based on practical, clinical considerations. 
15.2. 
General Statistical Methodology 
The statistical analysis methods are described below. Additional details will be provided in the 
Statistical Analysis Plan (SAP) to be finalized before database lock. 
In general, summary statistics (n, mean, standard deviation, median, minimum and maximum 
values for continuous variables and number and percentage of subjects in each category for 
categorical variables) will be provided for evaluated variables. All individual subject level data 
will be presented as data listings. All statistical tests and confidence intervals, unless otherwise 
stated, will be two sided and will be set at alpha=0.05. 
15.2.1. 
Study Populations 
15.2.1.1. Safety Population 
The Safety population will include all subjects who received at least one dose of study drug  
(AL injection, AL-NCD injection, 30 mg oral aripiprazole, oral PBO, PBO injection, or  
PP injection). Safety analyses will be based on the Safety population. 
15.2.1.2. Efficacy Population 
The Full analysis set (FAS) will include all subjects in the Safety population who have at least 
one postbaseline assessment of PANSS. Efficacy analyses will be based on the FAS. 
15.3. 
Demographics and Baseline Data 
Baseline for each variable will be the last non-missing assessment before the first dosing of 
randomized study drug on Day 1. 
Demographics and baseline characteristics such as gender, age, race, weight, BMI, prior 
exposure to aripiprazole or risperidone/paliperidone, baseline PANSS, and CGI-S score will be 
summarized with descriptive statistics to assess the comparability of the study groups. If there 
are heterogeneities between study groups in any of the subject characteristics that are of clinical 
importance or could affect the treatment outcome, the impact of the imbalances will be 
investigated and, if necessary, appropriate adjustments made in the efficacy and safety analyses. 
15.4. 
Efficacy Analyses 
15.4.1. 
Primary Efficacy Endpoint 
The change from baseline in the PANSS total score at Week 4 will be tested against no 
improvement using the one-sample T test for the AL and PP Treatment Groups separately.  


 
 
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15.4.2. 
Secondary Efficacy Endpoints 
The change from baseline in the PANSS total score at Week 9 and Week 25 will be tested 
against no improvement using the one-sample T test for the AL and PP Treatment Groups 
separately. 
The change from baseline in the PANSS total score at Week 4, at Week 9 or at Week 25 will be 
compared between the two treatment groups using an analysis of covariance (ANCOVA) with 
last observation carried forward (LOCF) imputation for missing data. The ANCOVA model will 
include treatment group, baseline PANSS total score, stratification factor, and the pooled study 
sites as covariates. 
PANSS response based on the observed data or LOCF will also be summarized by treatment 
group at each visit. A logistic regression model will be used to compare two groups, the model 
will include the treatment group, baseline PANSS total score, stratification factor, and the pooled 
study sites as covariates. 
Additional imputation approaches will be explored. 
15.4.3. 
Other Efficacy Endpoints 
The continuous outcome endpoints (eg, change from baseline in PANSS subscales, CGI-S) will 
be analyzed using the same ANCOVA with LOCF model. Time from randomization to 
Readiness for Discharge will be summarized using a Kaplan-Meier plot. 
15.5. 
Pharmacokinetic/Pharmacodynamic Analyses 
Not applicable. 
15.6. 
Safety and Tolerability Analyses 
Safety will be evaluated based on the occurrence of AEs, vital signs, results of clinical laboratory 
tests, and ECG findings, as well as ISRs, AIMS, BARS, SAS, C-SSRS, UKU-SERS-PAT –
Sexual Side Effects Subscale, and ESS scores. Reported AE terms will be coded using the 
Medical Dictionary for Regulatory Activities (MedDRA) Version 20.1 or higher. 
Treatment-emergent AEs (TEAEs) are defined as AEs that occur or worsen after the first dose of 
study drug.  
All AEs will be listed. The incidence of TEAEs will be summarized for each study group and 
overall, by severity and by relationship to study drug. The summary tables will include the 
number and percentage of subjects with TEAEs overall, by system organ class, and by preferred 
terms within each system organ class. Similar tables will be prepared for SAEs, TEAEs leading 
to discontinuation, as well as additional categories of AEs as defined in the SAP. 
Concomitant medications will be categorized and presented using the World Health Organization 
Anatomical Therapeutic Chemical (WHO-ATC) drug classification system. 
Change from baseline in vital signs measurements, laboratory test results, and ECG parameters 
will be summarized by treatment group. The number and percentage of subjects with potentially 
clinically significant values or shift tables will also be summarized by treatment group. 
Subjects with suicidal ideation and/or behavior will be summarized. 


 
 
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Injection site reactions reported as AEs and associated information (eg, injection site pain, 
redness, swelling, etc) will be summarized by treatment group and injection sequence. 
The change from baseline in abnormal movement rating scale (ie, AIMS, BARS, and SAS)  
total scores and subcategory scores will be summarized by treatment group and visit. 
Number (percentage) of subjects meeting the criteria treatment-emergent EPS, 
treatment-emergent akathisia, or treatment-emergent dyskinesia at any postbaseline visits will be 
summarized.  
The UKU-SERS-PAT  Sexual Side Effects Subscale will be summarized by gender and 
treatment group. 
Epworth Sleepiness Scale results will be summarized by treatment group.  
Listings will be provided for all safety endpoints. Supporting listings for potentially clinically 
significant tables will also be provided. 
15.7. 
Analysis of Other Subject or Caregiver Centered Endpoints 
The Q-LES-Q-SF total score will be summarized by treatment group.  
The Burden Assessment Score and change from baseline will be summarized by treatment group 
or by caregiver type.  
The number and percentage of response for the modified MSQ and WoRQ will be summarized 
by treatment group. 
The number and percentage of subjects who had an ER visit, arrest, or have been incarcerated 
will be summarized by treatment group. 
Handwriting Movement Kinematics and wrist actigraphy results will be summarized by 
treatment group. 
Further analysis details will be specified in the SAP. 


 
 
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16. 
DIRECT ACCESS TO SOURCE DATA/ DOCUMENTS 
16.1. 
Study Monitoring 
Monitoring of the study site (including, but not limited to, reviewing eCRFs for accuracy and 
completeness) will be performed by an Alkermes Monitor or designee.  
16.2. 
Audits and Inspections 
By signing the protocol, the Investigator agrees that, within local regulatory restrictions and 
institutional and ethical considerations, authorized representatives of Alkermes, a regulatory 
authority, and/or an institutional review board (IRB)/independent ethics committee (IEC) may 
visit the study site to perform audits or inspections, including the drug storage area, study drug 
stocks, drug accountability records, subject charts and source documents, and other records 
relative to study conduct. The purpose of an Alkermes audit or inspection is to systematically 
and independently examine all study-related activities and documents (eg, laboratory reports, 
x-rays, workbooks, and subjects’ medical records) to determine whether these activities were 
conducted and data recorded, analyzed, and accurately reported according to the protocol,  
GCP guidelines of the International Council on Harmonisation (ICH), and any applicable 
regulatory requirements. 
The Investigator should contact Alkermes immediately if contacted by a regulatory agency 
regarding an inspection. 
16.3. 
Institutional Review Board/Independent Ethics Committee 
The Investigator must obtain IRB/IEC approval for the investigation. Initial IRB/IEC approval, 
as well as all materials approved by the IRB/IEC for this study, including the subject consent 
form and recruitment materials, must be maintained by the Investigator and made available for 
inspection. 


 
 
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17. 
QUALITY CONTROL AND QUALITY ASSURANCE 
This study will be conducted under GCP and all applicable regulatory requirements. To ensure 
data accuracy, completeness, and compliance, the study site should have processes in place for 
data review and quality control. Alkermes may also conduct a quality assurance audit. Please see 
Section 16.2 for details regarding the audit process. 
17.1. 
Case Report Forms 
This study will use eCRFs. All eCRF data must be based on source documents or approved to be 
the original data (ie, data directly reported on the eCRF). All eCRFs will be completed by the 
clinic staff prior to review by the Alkermes Monitor or designated representative. 
The Alkermes Monitor or designated representative will review all source records on site and 
compare them to the data collected on the eCRF. 
17.2. 
Confidentiality of Data 
By signing this protocol, the Investigator affirms to Alkermes that he or she will maintain in 
confidence information furnished to him or her by Alkermes and will divulge such information 
to his or her respective IRB or IEC under an appropriate understanding of confidentiality with 
such board. All data will be considered the sole property of Alkermes. Please refer to the Clinical 
Study Agreement (CSA) for details. 


 
 
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18. 
ETHICAL CONSIDERATIONS 
18.1. 
Ethics Review 
The study site’s IRB/IEC must meet all relevant regulatory requirements. The study protocol and 
ICF will be reviewed by the IRB/IEC prior to enrolling subjects into the study; written approval 
from the committee must be received by Alkermes before study drug will be released to the 
Investigator. The protocol must be reapproved by the IRB/IEC upon receipt of amendments and 
annually, as local regulatory requirements require. 
The Investigator is responsible for submitting all protocol changes and SAE reports to the 
IRB/IEC according to local procedures. At a minimum, all SAEs requiring an investigational 
new drug safety report must be immediately reported. 
All relevant correspondence from the IRB/IEC will be forwarded by the respective study site to 
the Sponsor in a timely fashion. 
18.2. 
Ethical Conduct of the Study 
This study will be conducted in accordance with the protocol, the ICH Guideline E6, and all 
applicable local regulatory requirements. Good Clinical Practice is an international ethical and 
scientific quality standard used for designing, conducting, recording, and reporting studies 
involving the participation of human subjects. Alkermes is committed to complying with this 
standard to provide assurance that the rights, safety, and well-being of study subjects will be 
protected, consistent with the principles having their origin in the Declaration of Helsinki.  
18.3. 
Written Informed Consent 
The Investigator (or authorized designee) at each study site will ensure that the subject (or the 
subject’s legal representative) is given full and adequate oral and written information about the 
nature, purpose, and the potential and possible risks and benefits of the study. Each prospective 
subject will receive an IRB-approved ICF that summarizes the pertinent study information and 
will be given ample time to read the form and ask questions about the study. All information is to 
be provided in a language understandable to the subject and must not include any language that 
waives the subject’s legal rights. Prospective subjects must also be informed of their right to 
withdraw consent without prejudice at any time during the study. If the subject chooses to 
participate, he or she must sign the ICF before any study-specific procedures are conducted.  
All subjects will be informed of their rights to privacy and will be made aware that the study data 
will be submitted to Alkermes, the IRB, the CRO, if applicable, and to regulatory authorities for 
review and evaluation for the duration of the study and until the project has been approved for 
marketing or is withdrawn from investigation. They will also be informed that the Alkermes 
Medical Monitor may inspect their medical records to verify the accuracy and completeness of 
the study records and results. 
Significant changes to the protocol or product safety information may require a revision of the 
ICF, which must be reviewed and approved by the IRB and then signed by all applicable study 
participants. 


 
 
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The time that informed consent is obtained must be documented. The Investigator must maintain 
the original signed ICF in the subject’s source documents. A copy of the signed ICF must be 
given to the subject. 


 
 
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19. 
DATA HANDLING AND RECORDKEEPING 
An overview of study data handling and recordkeeping procedures and restrictions is provided in 
the subsequent sections; please refer to the CSA for further details. 
19.1. 
Data Capture 
As stated in Section 17.1, this study will use eCRFs for capturing data. All entries, corrections, 
and alterations will be made by the Investigator or other authorized study personnel. All data 
entries will be verified for accuracy and correctness by independent monitors. The electronic 
data capture system maintains a full audit trail.  
A paper copy of all laboratory reports will remain with the source documents at the study site. 
All electronic source data collected outside of the eCRF, such as e-diaries, and central 
laboratory, central ECG, or central MRI data, will be transferred directly to electronic data 
capture or directly to Alkermes for incorporation into the final datasets. All out-of-range 
laboratory values will be deemed as clinically significant or not clinically significant by the 
Investigator. Clinically significant values will be considered AEs and will be recorded as such on 
the eCRFs.  
Adverse events will be coded using MedDRA. Concomitant medications will be categorized 
using the WHO-ATC classification system. 
19.2. 
Inspection of Records 
Alkermes or its representative will be allowed to conduct site visits to the investigational 
facilities for the purpose of monitoring any aspect of the study. The Investigator agrees to allow 
the Alkermes Medical Monitor to inspect the drug storage area, study drug stocks, drug 
accountability records, subject charts and source documents, and other records relative to study 
conduct. 
19.3. 
Retention of Records 
Retention and storage of all essential clinical study documents shall be governed by the terms 
and conditions of the study site’s CSA and in accordance with ICH guidelines/local regulatory 
requirements as follows: 
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 until 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 the terms of the CSA. It is the responsibility of the Sponsor to inform the Investigator/ 
institution as to when these documents no longer need to be retained. 
Subjects’ medical files should be retained in accordance with the applicable legislation and in 
accordance with the maximum period of time permitted by the hospital, institution, or private 
practice. 


 
 
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19.4. 
Use of Information and Publication Policy 
Data generated in this study are proprietary information that are the sole property of Alkermes. 
Results of the study are to be held in confidence by both the Investigators and the Sponsor. 
Please refer to the CSA for details on the procedures for publishing and presenting data. 


 
 
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20. 
REFERENCES 
Abilify US Prescribing Information. Rockville, MD: Otsuka America Pharmaceutical, Inc; February 2017. 
American Psychiatric Association. Diagnostic and Statistical Manual of Mental Disorders (DSM-5). 5th 
ed. Washington, DC. American Psychiatric Association; 2013. 
Ascher-Svanum H, Faries DE, Zhu B, Ernst FR, Swartz MS, Swanson JW. Medication adherence and long-
term functional outcomes in the treatment of schizophrenia in usual care. The Journal of clinical 
psychiatry. 2006;67(3):453-460. 
Ascher-Svanum H, Zhu B, Faries DE, et al. The cost of relapse and the predictors of relapse in the 
treatment of schizophrenia. BMC psychiatry. 2010;10:2. doi: 10.1186/1471-244x-10-2. 
Caligiuri MP, Teulings HL, Dean CE, Niculescu AB, Lohr J. Handwriting movement analyses for monitoring 
drug-induced motor side effects in schizophrenia patients treated with risperidone. Human movement 
science. 2009;28(5):633-642. doi: 10.1016/j.humov.2009.07.007. 
Food and Drug Administration. Drug Development and Drug Interactions: Table of Substrates, Inhibitors 
and Inducers. 2016; 
http://www.fda.gov/Drugs/DevelopmentApprovalProcess/DevelopmentResources/DrugInteractionsLab
eling/ucm093664.htm. Accessed 22 Aug 2017. 
Gopal S, Hough DW, Xu H, et al. Efficacy and safety of paliperidone palmitate in adult patients with 
acutely symptomatic schizophrenia: a randomized, double-blind, placebo-controlled, dose-response 
study. International clinical psychopharmacology. 2010;25(5):247-256. doi: 
10.1097/YIC.0b013e32833948fa. 
Guy W. Clinical Global Impressions (CGI) Scale. In: Rush J, Pincus HA, First MB, et al., eds. Handbook of 
Psychiatric Measures. Washington, DC: American Psychiatric Press; 2000:100-102. 
Invega Sustenna US Prescribing Information. Titusville, NJ: Janssen Pharmaceuticals, Inc; February 2017. 
Johns MW. A new method for measuring daytime sleepiness: the Epworth sleepiness scale. Sleep. 
1991;14(6):540-545. 
Kane JM, Sanchez R, Zhao J, et al. Hospitalisation rates in patients switched from oral anti-psychotics to 
aripiprazole once-monthly for the management of schizophrenia. Journal of medical economics. 
2013;16(7):917-925. doi: 10.3111/13696998.2013.804411. 
Kay SR, Fiszbein A, Opler LA. The positive and negative syndrome scale (PANSS) for schizophrenia. 
Schizophrenia bulletin. 1987;13(2):261-276. 
Keith SJ, Kane JM. Partial compliance and patient consequences in schizophrenia: our patients can do 
better. The Journal of clinical psychiatry. 2003;64(11):1308-1315. 


 
 
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Lindstrom E, Lewander T, Malm U, Malt UF, Lublin H, Ahlfors UG. Patient-rated versus clinician-rated 
side effects of drug treatment in schizophrenia. Clinical validation of a self-rating version of the UKU Side 
Effect Rating Scale (UKU-SERS-Pat). Nordic journal of psychiatry. 2001;55 Suppl 44:5-69. doi: 
10.1080/080394801317084428. 
Lingjaerde O, Ahlfors UG, Bech P, Dencker SJ, Elgen K. The UKU side effect rating scale. A new 
comprehensive rating scale for psychotropic drugs and a cross-sectional study of side effects in 
neuroleptic-treated patients. Acta psychiatrica Scandinavica Supplementum. 1987;334:1-100. 
Nasrallah HA, Gopal S, Gassmann-Mayer C, et al. A controlled, evidence-based trial of paliperidone 
palmitate, a long-acting injectable antipsychotic, in schizophrenia. Neuropsychopharmacology : official 
publication of the American College of Neuropsychopharmacology. 2010;35(10):2072-2082. doi: 
10.1038/npp.2010.79. 
Pandina GJ, Lindenmayer JP, Lull J, et al. A randomized, placebo-controlled study to assess the efficacy 
and safety of 3 doses of paliperidone palmitate in adults with acutely exacerbated schizophrenia. 
Journal of clinical psychopharmacology. 2010;30(3):235-244. doi: 10.1097/JCP.0b013e3181dd3103. 
Posner K, Brent D, Lucas C, et al. New York, NY: Columbia-Suicide Severity Rating Scale (C-SSRS): 
Baseline/Screening Version; 1/14/2009 2009a. 
Posner K, Brent D, Lucas C, et al. Columbia-Suicide Severity Rating Scale (C-SSRS): Since last visit. New 
York, NY: New York State Psychiatric Institute; 2009b. 
Potkin SG, Bugarski-Kirola D, Edgar CJ, et al. Psychometric evaluation of the Work Readiness 
Questionnaire in schizophrenia. CNS spectrums. 2016;21(2):199-206. doi: 10.1017/s1092852914000352. 
Potkin SG, Gharabawi GM, Greenspan AJ, et al. Psychometric evaluation of the Readiness for Discharge 
Questionnaire. Schizophrenia research. 2005;80(2-3):203-212. doi: 10.1016/j.schres.2005.06.021. 
Reinhard SC, Gubman GD, Horwitz AV, Minsky S. Burden assessment scale for families of the seriously 
mentally ill. Evaluation and Program Planning. 1994;17(3):261-269. 
Risperdal Consta US Prescribing Information. Titusville, NJ: Janssen Pharmaceuticals , Inc; February 2017. 
Sheehan DV, Lecrubier Y, Sheehan KH, et al. The Mini-International Neuropsychiatric Interview (M.I.N.I.): 
the development and validation of a structured diagnostic psychiatric interview for DSM-IV and ICD-10. 
The Journal of clinical psychiatry. 1998;59 Suppl 20:22-33;quiz 34-57. 
Stevanovic D. Quality of Life Enjoyment and Satisfaction Questionnaire-short form for quality of life 
assessments in clinical practice: a psychometric study. Journal of psychiatric and mental health nursing. 
2011;18(8):744-750. doi: 10.1111/j.1365-2850.2011.01735.x. 
University of Washington: School of Pharmacy. In Vivo CYP3A Inducers. Seattle, WA: M and T Drug 
Interaction Database; 2017a. 


 
 
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University of Washington: School of Pharmacy. In Vivo Inhibitors of CYP3A Probes. Seattle, WA: M and T 
Drug Interaction Database; 2017b. 


 
 
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21. 
APPENDIX A: PARTIAL LIST OF PROHIBITED CYP3A 
INHIBITORS AND INDUCERS  
The following is a list of CYP3A inhibitors and inducers that are prohibited 14 days prior to 
Day 1 and throughout the study. The list is not comprehensive. 
Table 10: 
Partial List of CYP3A Inhibitors and Inducers 
Moderate-to-Strong Inhibitors 
Moderate-to-Strong Inducers 
Aprepitant 
Idelalisib 
Avasimibe 
Boceprevir  
Indinavir/Ritonavira 
Bosentan 
Cimetidine 
Itraconazole 
Carbamazepine 
Ciprofloxacin 
Ketoconazole 
Efavirenz 
Clarithromycin 
Lopinavir/Ritonavira 
Enzalutamide 
Clotrimazole 
Mibefradil 
Etravirine 
Cobicistat 
Nefazodone 
Mitotane 
Conivaptan 
Nelfinavir 
Modafinil 
Crizotinib 
Paritaprevir/Ritonavir and 
(Ombitasvir and/or Dasabuvir)a 
Phenobarbital 
Cyclosporine 
Posaconazole 
Phenytoin 
Danoprevir/Ritonavir
a 
Ritonavira 
Rifabutin 
Diltiazem 
Saquinavir/Ritonavira 
Rifampin 
Dronedarone 
Telaprevir 
St. John’s Wort 
Elvitegravir/Ritonavira 
Telithromycin 
— 
Erythromycin 
Tipranavir/Ritonavira 
— 
Fluconazole  
Tofisopam 
— 
Fluvoxamine 
Troleandomycin 
— 
Grapefruit juice 
Verapamil 
— 
Imatinib 
Voriconazole 
— 
a Ritonavir is usually given in combination with other anti-HIV or anti-HCV drugs in clinical practice. Caution 
should be used when extrapolating the observed effect of ritonavir alone to the effect of combination regimens on 
CYP3A activities. 
References: (Food and Drug Administration 2016; University of Washington: School of Pharmacy 2017a; 
University of Washington: School of Pharmacy 2017b) 


 
 
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22. 
APPENDIX B: PARTIAL LIST OF PROHIBITED CYP2D6 
INHIBITORS 
The following is a list of CYP2D6 inhibitors that are prohibited 14 days prior to Day 1 and 
throughout the study. The list is not comprehensive. 
Table 11: 
Partial List of CYP2D6 Inhibitors  
Moderate-to-Strong Inhibitors 
Bupropion 
Fluoxetine  
Cimetidine 
Mirabegron 
Cinacalcet 
Paroxetine 
Duloxetine  
Quinidine 
Fluvoxamine 
Terbinafine 
Reference: (Food and Drug Administration 2016) 


 
 
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23. 
APPENDIX C: CAREGIVER INTAKE FORM 
Instructions: Collect the following information for each subject’s identified caregiver at the 
Screening visit. In the event a caregiver changes during the study for a given subject, this 
information should be collected from the newly identified caregiver. 
1. Relationship to Subject: 
a. Spouse/Partner/Girlfriend/Boyfriend 
b. Child 
c. Parent/Guardian 
d. Sibling 
e. Friend 
f. Caseworker 
g. Residential Setting Representative 
h. Other, please specify: _________________ 
2. How many hours per week does the caregiver/informant spend with the subject, on 
average? 
a. < 5 hours per week 
b. 5-9 hours per week 
c. ≥10 hours per week 
3. How long has the caregiver/informant known the subject? 
a. < 8 weeks from screening 
b. 8 weeks to 1 year from screening 
c. 1 to 5 years 
d. 5 years or more but less than a lifetime 
e. Lifetime 
4.  
Can the caregiver/informant comply with the study’s obligations? 
a. Complete questionnaires required by the study and follow study site 
staff’s instructions 
Yes 
No 
b. Be available to accompany the subject to required study visits 
Yes 
No 
c. Observe the subject for study related side illness or injury and report 
them to the study doctor 
Yes 
No 
5.  
Did the Investigator meet with the caregiver/informant? 
Yes 
No 


 
 
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24. 
APPENDIX D: RESOURCE UTILIZATION FORM 
Instructions: Please complete this form with the subject. When possible, confirm information 
with caregivers. At screening, inquire about the past 3 months. At subsequent visits, the recall 
period is since the last visit. 
 
1. Since [date/last visit], has the subject visited the ER? (Y/N) 
a. If yes, how many times ( __ __ ) 
i. For each time, what was the date? 
1. Episode 1: (dd MMM yyyy) 
2. Episode 2: (dd MMM yyyy) 
3. Episode 3: (dd MMM yyyy) 
ii. For each time, what was the reason? 
1. Episode 1: (___________) 
2. Episode 2: (___________) 
3. Episode 3: (___________) 
2. Since [date/last visit], has the subject been arrested? (Y/N) 
a. If yes, how many times ( __ __ ) 
i. For each time, what was the date? 
1. Episode 1: (dd MMM yyyy) 
2. Episode 2: (dd MMM yyyy) 
3. Episode 3: (dd MMM yyyy) 
ii. For each time, what was the reason? 
1. Episode 1: (___________) 
2. Episode 2: (___________) 
3. Episode 3: (___________) 
3. Since [date/last visit], has the subject been incarcerated (in a jail or prison)? (Y/N) 
a. If yes, how many times ( __ __ ) 
i. For each time, what was the date? 
1. Episode 1 Start Date: (dd MMM yyyy)/End Date: (dd MMM yyyy) 
2. Episode 2 Start Date: (dd MMM yyyy)/End Date: (dd MMM yyyy) 
3. Episode 3 Start Date: (dd MMM yyyy)/End Date: (dd MMM yyyy) 
ii. For each time, what was the reason? 
1. Episode 1: (___________) 
2. Episode 2: (___________) 
3. Episode 3: (___________) 


 
 
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4. For recording rater: how did you collect this information? (circle all that apply) 
a. Medical records 
b. Provider report 
c. Subject report 
d. Other (specify): _______________ 
 
 
 
 


 
 
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25. 
APPENDIX E: PROLACTIN BLINDING 
To prevent functional unblinding due to the known differential influence on prolactin levels 
between aripiprazole and paliperidone, postbaseline prolactin levels will be blinded to 
Investigators and study site staff, Alkermes, and 
 (with the exception of the 
designated unblinded Medical Monitor).  
The unblinded Medical Monitor will remain blinded to treatment assignment, but will receive 
and monitor prolactin levels for all subjects throughout the study. The unblinded Medical 
Monitor will contact the Investigator when the pre-defined gender-specific threshold alerts are 
triggered (see below) to determine if the alert value is clinically significant in the Investigator’s 
opinion.   
Alert Thresholds: 
 Males: >100 ng/mL 
 Females: >150 ng/mL 
The alert threshold may be re-evaluated when 50% of subjects have been randomized. Any 
update to the alert thresholds will not require a protocol amendment, but will be addressed via an 
administrative change memo. 
Investigators may request postbaseline prolactin levels from the unblinded Medical Monitor at 
their clinical discretion (eg, if a subject has clinical symptoms that may be related to 
hyperprolactinemia). 
Treatment assignments and prolactin levels will be shared with the Investigator at study end 
when unblinded. 
 
PPD

SAP_001.pdf: 
 
 
 
 
 
STATISTICAL ANALYSIS PLAN 
 
ALK9072-A306 
 
Study Title: 
A Phase 3b, Multicenter, Randomized, Double-blind Study to Evaluate 
the Efficacy and Safety of Aripiprazole Lauroxil or Paliperidone 
Palmitate for the Treatment of Schizophrenia in Subjects Hospitalized 
for Acute Exacerbation  
Document Status: 
Final Version 
Document Date: 
05 Feb 2019 
Based on: 
ALK9072-A306 Protocol v 2.0 (incorporates Amendment 1.0), Date: 04 
Jan 2018, Original Protocol: 24 Aug 2017 
Sponsor: 
Alkermes, Inc. 
852 Winter Street 
Waltham, MA 02451 
USA 
 
 
 
 
 
CONFIDENTIAL 
Information and data in this document contain trade secrets and privileged or confidential information, 
which is the property of Alkermes, Inc. No person is authorized to make it public without the written 
permission of Alkermes, Inc. These restrictions or disclosures will apply equally to all future information 
supplied to you that is indicated as privileged or confidential. This study is being conducted in 
compliance with good clinical practice, including the archiving of essential documents. 


Alkermes, Inc.                                                                                                                                     
Statistical Analysis Plan-ALK9072-A306                                                                                            Final Version 
 
 
 
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Alkermes, Inc.                                                                                                                                     
Statistical Analysis Plan-ALK9072-A306                                                                                            Final Version 
 
 
 
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TABLE OF CONTENTS 
TABLE OF CONTENTS .................................................................................................................3 
LIST OF TABLES ...........................................................................................................................5 
LIST OF FIGURES .........................................................................................................................6 
ABBREVIATIONS .........................................................................................................................7 
1. 
INTRODUCTION ........................................................................................................9 
1.1. 
Study Objectives ...........................................................................................................9 
1.1.1. 
Primary Objective .........................................................................................................9 
1.1.2. 
Secondary Objectives ...................................................................................................9 
1.1.3. 
Exploratory Objectives .................................................................................................9 
1.2. 
Summary of the Study Design ....................................................................................10 
2. 
SAMPLE SIZE CONSIDERATION ..........................................................................12 
3. 
DATA ANALYSIS ....................................................................................................12 
3.1. 
General Statistical Methodology ................................................................................12 
3.2. 
Definitions of Analysis Populations ...........................................................................12 
3.2.1. 
Safety Population ........................................................................................................12 
3.2.2. 
Efficacy Population ....................................................................................................12 
3.3. 
Disposition ..................................................................................................................13 
3.4. 
Protocol Deviation ......................................................................................................13 
3.5. 
Demographics and Baseline Characteristics ...............................................................13 
3.6. 
Prior and Concomitant Medication .............................................................................13 
3.7. 
Treatment Adherence Rate and Duration of Study Drug Administration ..................14 
3.7.1. 
Treatment Adherence Rate .........................................................................................14 
3.7.2. 
Duration of Study Drug Administration .....................................................................14 
3.8. 
Efficacy Analyses .......................................................................................................14 
3.8.1. 
General Considerations ...............................................................................................14 
3.8.1.1. Primary Efficacy Endpoint ...............................................................................................14 
3.8.1.2. Primary Analysis ...............................................................................................................14 
3.8.1.3. Secondary Efficacy Endpoints ..........................................................................................15 


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3.8.1.4.  Secondary Analysis ..........................................................................................................15 
3.8.1.5. 
Other Efficacy Endpoints ...........................................................................................16 
3.8.2. 
Exploratory Analyses of Other Subject or Caregiver-Centered Assessments ............16 
3.8.2.5. 
Quality of Life Enjoyment and Satisfaction Questionnaire - Short Form ..................16 
3.8.2.6. 
Burden Assessment Scale ...........................................................................................16 
3.8.2.7. 
Modified Medication Satisfaction Questionnaire .......................................................17 
3.8.2.8. 
Work Readiness Questionnaire ...................................................................................17 
3.8.2.9. 
Resource Utilization ...................................................................................................17 
3.8.2.10. 
Handwriting Kinematics .............................................................................................17 
3.8.2.11. 
Wrist Actigraphy ........................................................................................................18 
3.8.3. 
Multiple Comparison/Multiplicity ..............................................................................20 
3.8.4. 
Pooling Sites ...............................................................................................................20 
3.9. 
Safety Analysis ...........................................................................................................20 
3.9.1. 
General Considerations ...............................................................................................20 
3.9.2. 
Adverse Events ...........................................................................................................20 
3.9.3. 
Death, Serious and Other Significant Adverse Events ...............................................22 
3.9.4. 
Clinical Laboratory Parameters ..................................................................................22 
3.9.5. 
Vital Signs, Body Weight, and Electrocardiograms ...................................................28 
3.9.5.1. 
Vital Signs ..................................................................................................................28 
3.9.5.2. 
Weight and Body Mass Index .....................................................................................29 
3.9.5.3. 
Electrocardiograms .....................................................................................................29 
3.9.6. 
Abnormal Movement Scales .......................................................................................30 
3.9.7. 
Injection Site Reactions ..............................................................................................30 
3.9.8. 
Columbia-Suicide Severity Rating Scale ....................................................................31 
3.9.9. 
Epworth Sleepiness Scale ...........................................................................................31 
3.9.10. 
UKU-SERS-PAT-Sexual Side Effects .......................................................................31 
3.9.11. 
Genotyping data ..........................................................................................................32 
3.10. 
Pharmacokinetic/ Pharmacodynamic Data Analysis ..................................................32 
4. 
INTERIM ANALYSES ..............................................................................................32 


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5. 
CHANGES IN CONDUCT OR PLANNED ANALYSES FROM THE 
PROTOCOL ...............................................................................................................32 
6. 
DEFINITIONS AND CONVENTIONS FOR HANDLING OF THE DATA ..........32 
6.1. 
Analysis Visit Windows .............................................................................................33 
6.2. 
Handling of Partial Dates of Concomitant Medication ..............................................33 
6.3. 
Handling of Safety Data .............................................................................................33 
7. 
GENERAL STATISTICAL METHODOLOGY .......................................................33 
7.1. 
Reporting Precision ....................................................................................................33 
8. 
PROGRAMMING SPECIFICATIONS .....................................................................34 
9. 
MOCK TABLES, LISTINGS AND FIGURES .........................................................34 
10. 
REFERENCES ...........................................................................................................34 
 
LIST OF TABLES 
Table 1: 
Treatment Groups .......................................................................................................10 
Table 2: 
Stratification Factors ...................................................................................................11 
Table 3: 
Subgroup Definitions ..................................................................................................19 
Table 4: 
Criteria of Potentially Clinically Significant (PCS) Abnormality for Selected 
Analytes ......................................................................................................................24 
Table 5: 
Shifts Category from Baseline to Any Postbaseline for Selected Lipid 
Parameters ...................................................................................................................26 
Table 6: 
Shift Category from Baseline to Any Postbaseline in Glucose and HbA1c ...............27 
Table 7: 
Shift Category from Baseline to Any Postbaseline in Liver Function Test ...............28 
Table 8: 
Criteria for Potentially Clinically Significant  Blood Pressure or Pulse Rate ............29 
Table 9: 
Criteria for Potentially Clinically Significant Changes from Baseline in 
Body Weight ...............................................................................................................29 
Table 10: Criteria for Potentially Clinically Significant (PCS) QTcF ........................................30 
Table 11: C-SSRS Categories for Analysis ................................................................................31 
Table 12: Degree of Precision .....................................................................................................34 
 


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LIST OF FIGURES 
Figure 1: Study Design Schematic .................................................................................................11 


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ABBREVIATIONS 
Abbreviation or Term 
Explanation or Definition 
AE 
Adverse event 
AIMS 
Abnormal Involuntary Movement Scale 
ATC 
Anatomical Therapeutic Chemical [classification system] 
AL 
Aripiprazole lauroxil 
AL-NCD 
Aripiprazole lauroxil NanoCrystal Dispersion 
ANCOVA 
Analysis of covariance 
BARS 
Barnes Akathisia Rating Scale 
BMI 
Body mass index 
CGI-I 
Clinical Global Impression - Improvement 
CGI-S 
Clinical Global Impression - Severity 
CI 
Confidence interval 
C-SSRS 
Columbia Suicide Severity Rating Scale 
C-VISA 
Clinical-Validation Inventory for Study Admission 
CYP 
Cytochrome P450 
DSM-5 
Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition 
EC 
Excited Component 
ECG 
Electrocardiogram 
eCRF 
Electronic case report form 
EOT 
End of treatment 
EPS 
Extra pyramidal symptoms 
ESS 
Epworth Sleepiness Scale 
EQ-5D 
EuroQOL-5D 
ET 
Early termination 
FAS 
Full analysis set 
HbA1C 
Hemoglobin A1c 
IM 
Intramuscular 


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Abbreviation or Term 
Explanation or Definition 
IRB 
Institutional Review Board 
ISR 
Injection site reactions 
LAI 
Long-acting injectable 
LOCF 
Last observation carried forward 
IWQOL 
Impact of Weight on Quality of Life 
MedDRA 
Medical Dictionary for Regulatory Activities 
MINI v 7.0.2 
Mini-International Neuropsychiatric Interview-7.0.2 for Schizophrenia and 
Psychotic Disorder Studies 
MSQ 
Medication Satisfaction Questionnaire 
PANSS 
Positive and Negative Syndrome Scale 
PBO 
Placebo 
PCS 
Potentially clinically significant 
PFS 
Prefilled syringe 
PK 
Pharmacokinetic 
PP 
Paliperidone palmitate 
PT 
Preferred term 
KM 
Kaplan-Meier 
QTcB 
QT corrected with Bazett formula 
QTcF 
QT corrected with Fridericia formula 
Q-LES-Q-SF 
Quality of Life Enjoyment and Satisfaction Questionnaire - Short Form  
RDQ 
Readiness for Discharge Questionnaire 
SAE 
Serious adverse event 
SAP 
Statistical analysis plan 
SAS 
Simpson-Angus Scale 
SD 
Standard deviation 
SMQ 
Standardized MedDRA queries 
SOC 
System organ class 
TEAE 
Treatment-emergent adverse event 
UKU-SERS-PAT 
Udvalg for Kliniske Undersøgelser Side Effect Self-Rating Scale – Patient 


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Abbreviation or Term 
Explanation or Definition 
ULN 
Upper limit of normal 
VAS 
Visual analogue scale 
WHO 
World Health Organization 
WoRQ 
Work Readiness Questionnaire 
1. 
INTRODUCTION 
This statistical analysis plan (SAP) describes the statistical methods to be used for analyses and 
presentation of safety and efficacy data for the study ALK9072-A306. This document has been 
prepared based on Alkermes ALK9072-A306 Study Protocol Amendment 1.0 (dated 04 Jan 
2018). 
1.1. 
Study Objectives 
1.1.1. 
Primary Objective 
The primary objective of this study is to evaluate the efficacy of the aripiprazole lauroxil 
NanoCrystal® Dispersion (AL-NCD) initiation regimen (30 mg oral aripiprazole + 662 mg AL-
NCD intramuscular [IM]) followed by aripiprazole lauroxil (AL) 1064 mg IM during the first 4 
weeks of treatment of patients hospitalized for an acute exacerbation of schizophrenia.  
1.1.2. 
Secondary Objectives 
 To compare the efficacy of AL-NCD initiation regimen followed by AL 1064 mg IM 
with paliperidone palmitate initiation dosing (PP; Invega® Sustenna®; 234 mg + 
156 mg IM) during the first 4 weeks of treatment of patients hospitalized for an acute 
exacerbation of schizophrenia 
 To evaluate the safety, efficacy, and tolerability of AL 1064 mg IM after 6 months of 
treatment with AL for schizophrenia 
 To compare the safety, efficacy, and tolerability of AL 1064 mg IM with monthly PP 
156 mg IM after 6 months of treatment with AL or PP for schizophrenia 
1.1.3. 
Exploratory Objectives 
To characterize subject and caregiver centered outcomes, such as quality of life, work readiness, 
satisfaction with medication, resource utilization, and caregiver burden after 6 months of 
treatment with AL or PP for schizophrenia. 


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1.2. 
Summary of the Study Design 
This is a multicenter, randomized, double-blind study evaluating the efficacy and safety of AL 
and PP in approximately 180 subjects experiencing an acute exacerbation of schizophrenia. In 
total, subjects will participate for approximately 26 weeks, including up to 1 week of inpatient 
screening and 25 weeks of treatment (which includes an initial 2-week inpatient stay). Potential 
subjects will be evaluated for eligibility according to the inclusion and exclusion criteria at a 
Screening visit (up to a 7 day period) and Baseline visit prior to randomization. Prior 
antipsychotic medications should be discontinued after screening upon inpatient admission. If a 
subject does not have historical exposure to aripiprazole and/or risperidone and paliperidone, test 
doses with aripiprazole and/or risperidone will be administered during the first 2 days of 
inpatient stay during the Screening period, prior to randomization, to assess tolerability.  
On Day 1, qualified subjects will be randomized to either the ALtreatment group or the PP 
treatment group. Subjects will remain in the inpatient study unit during the Screening period and 
for at least 2 weeks after administration of the first dose of study drug on Day 1. Subjects will be 
discharged from the inpatient unit upon assessment as clinically stable and appropriate for 
discharge as determined by the Investigator. Subjects will receive their final injection of study 
drug on Week 21 (Day 148) and will be considered to be on treatment until Week 25 (Day 176).  
Subjects meeting all eligibility criteria will be randomized to one of two treatment groups, as 
described in Table 1. 
Table 1: 
Treatment Groups 
Treatment Group 
Aripiprazole lauroxil (AL) 
Paliperidone palmitate (PP) 
Day 1 
662 mg AL-NCD (IM gluteal) +  
PBO (IM deltoid) + 30 mg oral aripiprazole 
PP 234 mg (IM deltoid) +  
PBO (IM gluteal) + oral PBO 
Day 8 
AL 1064 mg (IM gluteal) +  
PBO (IM deltoid) 
PP 156 mg (IM deltoid) +  
PBO (IM gluteal) 
Days 36, 92, and 148 
PBO (IM gluteal) 
PP 156 mg (IM gluteal) 
Days 64 and 120 
AL 1064 mg (IM gluteal) 
PP 156 mg (IM gluteal) 
Abbreviations: AL=aripiprazole lauroxil; AL-NCD=aripiprazole lauroxil NanoCrystal Dispersion; 
IM=intramuscular; PBO=placebo; PP=paliperidone palmitate 
To minimize potential response bias based on antipsychotic medication exposure history, 
randomization will be stratified by the status of prior exposure to aripiprazole or risperidone/ 
paliperidone. There are two stratification levels, as described in Table 2. After the stratification 
level (either Level 1 or Level 2) is determined for the subject, he or she will be randomized to 
one of two treatment groups in a 1:1 ratio. Stratification will ensure a balance of the two 
treatment groups within each stratification level. 


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Table 2: 
Stratification Factors 
 
Prior Risperidone/Paliperidone Exposure 
Yes 
No 
Prior Aripiprazole 
Exposure 
Yes 
Level 1 
Level 2 
No 
Level 2 
Level 1 
Safety and tolerability assessments will include adverse event (AE) monitoring, clinical 
laboratory testing, vital signs, body weight, 12-lead electrocardiogram (ECG) monitoring, 
abnormal movement scales (Abnormal Involuntary Movement Scale [AIMS], Barnes Akathisia 
Rating Scale [BARS], and Simpson-Angus Scale [SAS]), Columbia Suicide Severity Rating 
Scale (C-SSRS), injection site reactions (ISRs), the Udvalg for Kliniske Undersøgelser Side 
Effect Self-Rating Scale - Patient (UKU-SERS-PAT) − Sexual Side Effects Subscale, and 
Epworth Sleepiness Scale (ESS).  
Efficacy assessments will include Positive and Negative Syndrome Scale (PANSS), Clinical 
Global Impression–Severity (CGI-S), and Readiness for Discharge Questionnaire (RDQ).  
Subject or caregiver-centered assessments will include Quality of Life Enjoyment and 
Satisfaction Questionnaire - Short Form (Q-LES-Q-SF), modified Medication Satisfaction 
Questionnaire (MSQ), the Work Readiness Questionnaire (WoRQ), Handwriting Movement 
kinematics, Wrist actigraphy, and Resource Utilization Form. Caregivers who meet criteria will 
also complete the Burden Assessment Scale. 
A schematic of the study design is provided in Figure 1. 
Figure 1: Study Design Schematic  
 
Day
-7
1
8
15
22
29
36
64
92
120
148
176
End of Treatment/End 
of Study (at Day 176)
Subjects 
Admitted
Subjects 
Discharged
Randomization
1:1
Aripiprazole lauroxil group (n=90)
Paliperidone Palmitate group (n=90)
Dose 
Administered
PBO
1064 mg
PBO
1064 mg
PBO
156 mg
156 mg
156 mg
156 mg
156 mg
234 mg
156 mg
AL-NCD
1064 mg
Inpatient
Outpatient
a
b
Week
1
2
3
4
5
9
13
17
21
25


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Abbreviations: AL-NCD=aripiprazole lauroxil NanoCrystal Dispersion; PBO=placebo 
a Subjects randomized into the AL Treatment Group will receive IM PBO (deltoid) on Days 1 and 8 and 30 mg oral 
aripiprazole on Day 1 
b Subjects randomized into the PP Treatment Group will receive IM PBO (gluteal) on Days 1 and 8 and oral PBO 
on Day 1 
2. 
SAMPLE SIZE CONSIDERATION 
No formal sample size calculations have been performed. The sample size of 180 subjects is 
based on practical, clinical considerations. 
3. 
DATA ANALYSIS 
3.1. 
General Statistical Methodology 
Baseline for efficacy or safety analysis is defined as the last non-missing assessment before the 
first dose of study drug in ALK9072-A306 study on Day 1, and it will be used for all efficacy 
and safety analysis unless specified otherwise.  
In general, descriptive statistics: n, mean (±standard deviation [SD]), median, minimum, and 
maximum, for continuous variables and number and percentage of subjects in each category for 
categorical variables will be provided. 
All statistical tests and confidence intervals (CIs), unless stated otherwise, will be 2-sided and 
will be set at an alpha level of 0.05. 
All source data will be presented as subject data listings. 
3.2. 
Definitions of Analysis Populations 
3.2.1. 
Safety Population  
The Safety population will include all subjects who received at least one dose of study drug  
(AL injection, AL-NCD injection, 30 mg oral aripiprazole, oral placebo (PBO), PBO injection, 
or PP injection). Safety analyses will be based on the Safety population. 
3.2.2. 
Efficacy Population 
The Full Analysis set (FAS) will include all subjects in the Safety population who have at least 
one postbaseline assessment of PANSS. Efficacy analyses will be based on the FAS. Subjects 
identified as duplicate subjects are not included in the FAS Populations.  


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3.3. 
Disposition 
The number and percentage of subjects completing or prematurely discontinuing the study 
including reasons for discontinuation will be summarized by treatment group and overall for the 
following: 
 Subjects who enrolled in the study  
 Subjects in the Safety Population  
 Subject in the Efficacy Population 
 Subjects who completed the 4-week Treatment period 
 Subjects who completed the entire Treatment period 
 Subjects who discontinued treatment along with reasons for discontinuation 
3.4. 
Protocol Deviation 
Subjects with major protocol deviations in the following categories will be summarized by 
treatment group and overall. A supportive listing will be provided as well. 
 Did not meet the inclusion/exclusion criteria 
 Received prohibited medications 
 Lack of adherence with study medication, as defined by subjects taking 1 injection 
less than they were supposed to receive. A subject who missed the injection by > 2 
weeks will also be considered as lack of adherence. 
 Dosing error 
 Others 
3.5. 
Demographics and Baseline Characteristics 
Demographics and baseline characteristics such as gender, age, race, ethnicity, weight, body 
mass index (BMI), prior antipsychotic medication, CYP2D6 phenotype, PANSS total and 
subscale scores, and CGI-S will be summarized by treatment group and overall for the Safety 
population.  
3.6. 
Prior and Concomitant Medication 
Prior medications are defined as medications taken prior to the first dose of study drug in 
ALK9072-A306 study. Concomitant medications are defined as medications taken on or after the 
first dose of study drug in ALK9072-A306 study. All medications will be coded using the World 
Health Organization Drug Dictionary (WHO-DD Enhanced + Herbal [version: March 2016 or 
higher]). 


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Concomitant medications taken during the Treatment period will be summarized by the preferred 
drug name for the Safety population. All reported medications (including prior medicatios and 
those initiated after the last dose of study medication) will be included in listing. For the 
summary table, if a subject has taken a concomitant medication more than once, the subject will 
be counted only once for that medication. 
3.7. 
Treatment Adherence Rate and Duration of Study Drug 
Administration 
3.7.1. 
Treatment Adherence Rate 
All dosing and exposure information will be included in supportive listings. Cumulative number 
of injections by treatment group and overall for the safety population will be summarized.  
3.7.2. 
Duration of Study Drug Administration 
The duration of study administration will be defined as the last injection date minus the first 
dosing date + 30 days.  
3.8. 
Efficacy Analyses 
3.8.1. 
General Considerations 
All statistical analysis will be performed at the 5% significance level. All CI will be 2-sided 95% 
confidence intervals. Efficacy analysis will be carried out using the FAS population. PANSS 
total and subscale scores, CGI-S, PANSS response analyses and body weight will be based on 
both observed data and the last observation carried forward (LOCF) imputation, that is, the last 
observed non-missing postbaseline value will be carried forward for missing postbaseline 
assessments.  
In general, continuous and categorical endpoints will be summarized using descriptive statistics 
by treatment group and overall. 
3.8.1.1. Primary Efficacy Endpoint 
The primary efficacy endpoint is the change from baseline in PANSS total score at Week 4 
(Day 29). 
3.8.1.2. Primary Analysis  
The primary analysis is to compare the PANSS total score at Week 4 (Day 29) vs the total score at 
baseline within each treatment group separately. The two statistical hypotheses to be tested for the 
primary efficacy endpoints are: 
1. For AL group: H0:  dal_week4 = 0 versus Ha: dal_week4 ≠ 0 


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2. For PP group: H0:  dpp_week4 = 0 versus Ha: dpp_week4 ≠ 0,  
where dal_week4 is the change from baseline in PANSS total score at Week 4 (Day 29) for AL 
treatment group, and dpp_week4 is the change from baseline in PANSS total score at Week 4 for PP 
treatment group. 
One-sample t-test will be used to assess the change from baseline in the PANSS total score at 
Week 4 (Day 29) against no improvement for the AL and PP treatment groups separately based 
on the observed data without imputation.  Each analysis will be a 2-sided test with p–value = 
0.05. No adjustments for multiplicity will be made for the primary analysis.  
3.8.1.3. Secondary Efficacy Endpoints 
The secondary efficacy endpoints are:   
 The change from baseline in PANSS total score at Week 4 (Day 29), Week 9 
(Day 64) and Week 25 (Day 176).  
 PANSS response  by treatment group at each visit. PANSS response is defined as 
PANSS total score >=30% improvement from baseline.  
3.8.1.4.  Secondary Analysis 
The first secondary analysis will be within treatment group comparison.The change from 
baseline in the PANSS total score at Week 9 (Day 64) and Week 25 (Day 176) will be tested 
against no improvement using the same approach outlined for the primary efficacy endpoint. 
The second secondary analysis will be between treatment group comparison. Separate mixed 
models repeated measures (MMRM) will be used to analyze the results from baseline though 
either: Week 4 (Day 29), Week 9 (Day 64) or Week 25 (Day 176). The analyses will be based on 
the observed data. The model will include treatment group, visits, interaction term of treatment 
group and visit, baseline PANSS total score, stratification factor, and the pooled study sites as 
covariates. The model will assume an unstructured variance-covariance matrix for within-subject 
variability. If the model cannot converge due to the unstructured matrix, the heterogeneous 
autoregressive of order 1 will be used.   
The change from baseline in PANSS total score will be plotted for each treatment group from the 
MMRM. 
The third secondary analysis will be between treatment group comparison for PANSS response. 
PANSS response at each visit based on both the observed data and LOCF will be summarized by 
treatment group at each visit. A logistic regression model will be used to compare the two 
treatment groups at Week 4 (Day 29), Week 9 (Day 64) and Week 25 (Day 176); the model will 
include the treatment group, baseline PANSS total score, stratification factor, and the pooled 
study sites as covariates.   
Additional imputation approaches will be explored. 


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3.8.1.5. 
Other Efficacy Endpoints 
The observed values and change from baseline in PANSS subscale scores and CGI-S will be 
summarized. The change from baseline for the other efficacy endpoints will be analyzed using an 
analysis of covariance (ANCOVA) model with LOCF and the same MMRM as summarized 
above for the primary and secondary endpoints. 
The change from baseline in PANSS subscale scores, and CGI-S will be plotted for each 
treatment group from the MMRM based on observed data, as well as from the ANCOVA model 
based on LOCF data. 
Time from randomization to Readiness for Discharge will be analyzed using a Kaplan-Meier 
method. The log rank test will be used to compare two treatment groups. 
Time to treatment discontinuation will be analyzed similarly using the Kaplan-Meier method by 
treatment group. Both, all cause discontinuation and medication related discontinuation (defined 
as due to AE or lack of efficacy) will be summarized. For prematurely discontinued subjects, 
time to discontinuation is defined as time from the date of first dose of study drug to the date of 
discontinuation.  Subjects who compeleted the study will be considered censored at the end of 
treatment (EOT) visit. For medication related discontinuation analysis, early discontinued 
subjects due to other reasons will be considered censored at the discontinuation date.  
3.8.2. 
Exploratory Analyses of Other Subject or Caregiver-Centered Assessments 
3.8.2.5. 
Quality of Life Enjoyment and Satisfaction Questionnaire - Short Form  
The Q-LES-Q-SF is a 16-item self-reported measure used to assess the degree of enjoyment and 
satisfaction experienced by subjects in various areas of daily functioning. Responses are 
evaluated on a 5-point scale (“very poor” to “very good”), with higher scores indicating more 
enjoyment and satisfaction. The scoring of the Q-LES-Q-SF involves summing only the first 14 
items to yield a raw total score. The last two items are not included in the raw total score, but are 
standalone items. The raw total score is transformed into a percentage maximum possible (% 
Maximum) score using the following formula: (raw total score −14)/56. Subjects will complete 
the Q-LES-Q-SF at Week 5 (Day 36) , Week 13 (Day 92), and Week 25 (Day 176).The total raw 
score, % maximum score, and scores of item 15, 16 at each visit will be summarized by 
treatment group.  
3.8.2.6. 
Burden Assessment Scale 
The Burden Assessment Scale is a 19-item scale administered to caregivers who are family or 
friends (ie, nonprofessional caregivers) that focuses on specific subjective and objective 
consequences of families caring for individuals with severe mental disorders. Respondents are 
required to indicate whether they have experienced each of the types of burden ‘Not at all,’ ‘A 
little,’ ‘Some,’ or ‘A lot’ in the past month. These are scored 1, 2, 3, and 4, respectively. A 
higher score indicates more perceived burden. The Burden Assessment Scale will be 


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administered to the designated caregiver at Screening, Week 9 (Day 64), and Week 25 (Day 
176).  The change from baseline in Burden score will be summarized by treatment group. 
3.8.2.7. 
Modified Medication Satisfaction Questionnaire  
The modified MSQ is a 3-item self-reported patient satisfaction questionnaire which assesses the 
level of patient satisfaction with medication. Subjects rate their satisfaction with their current 
medication, their preference for their current medication vs previous medications, and their 
opinion on the side effects of their current medication vs previous medications. Ratings are on a 
5-point Likert scale. MSQ was assessed on Day 29 (Week 4), 64 (Week 9), 120 (Week 17), and 
176 (Week 25).  The number and percentage of response for the modified MSQ will be 
summarized by treatment group. 
3.8.2.8. 
Work Readiness Questionnaire  
The WoRQ is a questionnaire (7-item and a global assessment) used to assess a patient’s ability 
to engage in socially useful activity, independent of work availability. The Investigator or 
designee will complete the WoRQ at Day 15 (Week 2), 29, (Week 4), 64 (Week 9), 120 (Week 
17), 176 (Week 25). The global assessment (yes or no on ready to work) will be summarized by 
treatment group. 
3.8.2.9. 
Resource Utilization 
The number and percentage of subjects who had an emergency room visit, arrest, hospitalization 
(based on the serious adverse events [SAEs] that led to hospitalization), or have been 
incarcerated will be summarized by treatment group. 
3.8.2.10. Handwriting Kinematics 
A quantitative analysis of handwriting kinematics is used to evaluate effects of antipsychotic 
medication in patients with schizophrenia. The Investigator or designee will administer the 
handwriting tests to the subjects at screening, Week 2 (Day 15), Week 4 (Day 29), Week 9 (Day 
64), and Week 17 (Day 120). The following endpoints related to extrapyramidal syndrome (EPS) 
will be summarized by treatment group.  
 Stroke duration 
 Stroke amplitude or size  
 Peak and average velocity  
 Frequency of secondary movements  
 Average normalized jerk  
 Number of acceleration peaks  
 Pen pressure variability  


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Peak and average velocity and frequency of secondary movements (but not limited to) will be 
analyzed separately for a subset of patients with signs of EPS by treatment group. The subset of 
patients for this analysis will be selected based on the baseline SAS score of ≥5. 
3.8.2.11. Wrist Actigraphy 
Wrist actigraphy will be analyzed using the derived activity and sleep parameters collected 
during the two 14-days monitoring Cycles following the distribution of actigraph. The actigraph 
device will be distributed on Week 3 (Day 22) and Week 9 (Day 64). For each collection period, 
actigraphy parameters will include: total time sleep (min), sleep efficiency (%), sleep onsets 
(min), number of wakes after sleep onset, wakes after sleep onset (min), mean wake duration 
after sleep onset (min), deep rest time (min), deep rest sleep time (min), nap rest time (min), nap 
rest sleep time (min), day hour of peak activity, day mean activity in peak hour, day standard 
deviation of activity within peak hour, circadian rhythm period (min), circadian rhythm mesor, 
circadian rhythm amplitude.  
Length of daytime activity will be calculated based on the the following rules: 
1. Sleep onset is defined as the first recorded instance of sleep occurring at or after 9 pm 
and if the subject was asleep at 9 pm, using the latest transition from wake to sleep prior 
to 9 pm.  
2. Sleep offset is defined as the last instance of transitioning from sleep to wake before 9am 
on the following day and if the person was still labelled as asleep at 9am, considering the 
next transition from sleep to wake as the sleep offset.  
3. All activity that falls outside of this ‘sleep window’ is defined as daytime activity. 
In each cycle, for each subject, the average of 14 days data  will be calculated based on the 
available individual data. Average for the two monitoring cycles and for the combined total will 
be used in the summary statistics. 
Wrist actigraphy parameters will be summarized by the treatment group, and by subgoups. 
Definitions of the subgroups are provided in Table 3. 


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Table 3: 
Subgroup Definitions 
# 
Target subjects 
Criteria 
A Subjects with prominent 
negative symptoms 
Baseline score of ≥ 4 on at least 3, or ≥ 5 on at least 2, of the 7 Negative 
PANSS Subscale Scores 
B Subjects with Lack of 
efficacy or psychiatric 
AEs (treatment failure) 
Subjects with Lack of efficacy, OR 
Subjects with Psychiatric SAEs or AE leading to discontinuation 
(AEDC) of (PT):  
Schizophrenia 
Acute psychosis 
Suicidal behaviour 
Suicidal ideation 
Suicide attempt, OR 
Subjects who experienced worsening of psychosis defined as increase 
of PANSS (>30%) and CGI-S (2-point worsening) scores from baseline 
at any point 
C Subjects with Akathisia  
BARS score of ≥ 3 at Week 4 (Day 29), OR 
Subjects with AEs of (PT) ongoing during the recording cycle:  
Akathisia 
Restlesness 
 
D Subjects with marked 
daytime sleepiness and 
sedation  
ESS scale >16 at Week 4 (Day 29) and at Week 9 (Day 64) for Cycle 1 
and Cycle 2, respectively, OR 
Subjects with AEs of (PT) ongoing during the recording cycle:  
Somnolence 
Sedation 
Hypersomnia 
Lethargy 
E 
Subjects on 
Benzodiazepines  
Received the drugs with the following WhoDD codes during the 
recording cycle  
N05 PSYCHOLEPTICS 
N05CD Benzodiazepine derivatives 
N05CF Benzodiazepine related drugs 
F 
Subjects with Insomnia 
Patients with ongoing Medical History of Insomnia (PT), OR 
Patients with AEs of Insomnia (PT) ongoing during the recording cycle 
D Severity of Psychiatric 
Illness 
Subjects will be separated onto two subsets based on the CGI-S scale 
score on Day 22: mildly ill subgroup with the score of 3 and below, and 


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# 
Target subjects 
Criteria 
moderately ill subgroup – with the score of 4 and greater. Actigraphy 
parameters of the recording Cycle 1 (Day 22 to Day 36) are used in this 
table. 
3.8.3. 
Multiple Comparison/Multiplicity 
Primary endpoints for both treatment groups will each be tested at a full α level of 0.05. The study 
will be claimed positive when both of the the primary analyses  are statistically significant. Only if 
both primary endpoints are statistically significant will the secondary endpoints be further tested at 
an alpha level of 0.05.  
3.8.4. 
Pooling Sites 
Approximately 16 US sites are involved in this study. To insure the precision of the estimation, a 
minimum of 10 subjects per treatment group within each site may be pursued by pooling the 
actual sites as following:  rank the sites by the number of subjects at end of study from largest to 
smallest. If the smallest site has less than 10 subjects in one treatment group, pool this site with 
the second smallest site. If the pooled site has at least 10 subjects per treatment group, stop 
pooling. Otherwise, continue pooling with the third smallest site until each treatment group has 
at least 10 subjects within pooled site. However, in order to avoid a dominant center due to 
pooling, the pooling shall be stopped if the number of subjects within pooled site exceeds 20% of 
the total number of subjects. 
3.9. 
Safety Analysis 
3.9.1. 
General Considerations 
All safety endpoints will be summarized by treatment group and overall for the Safety 
Population. 
3.9.2. 
Adverse Events 
Incidence of treatment emergent AEs will be analyzed as a safety endpoint. Adverse events will 
be coded by System Organ Class (SOC)  and Preferred Term (PT) using the Medical Dictionary 
for Regulatory Activities (MedDRA) Version 21.1 or higher. The verbatim term will be included 
in the AE listings. 
An AE (coded by PT) will be considered as treatment emergent AE (TEAE) if the event is newly 
occurring or worsening on or after the date of first dose of study drug in this study.  
An overview table, including number of subjects with TEAEs, AEs leading to study 
discontinuation (AEDCs), SAEs, study drug related TEAEs, will be provided. 


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The number and percentage of subjects reporting TEAEs during the Treatment period will be 
presented by treatment group and overall for the following categories:  
 SOC and PT  
 PT, and including the following subset: 
 TEAEs experienced by ≥5% of subjects (in any group)  
 SOC, PT, and severity  
 SOC, PT for severe TEAEs  
 SOC, PT, and relationship  
 SOC, PT for study drug related TEAEs  
 SOC, PT for SAE 
If the same PT occurred more than once for the same subject, the subject will be counted only 
once for that PT using the most severe and most related occurrence for the summarization by 
severity and by relationship to the study drug. 
In additional, the following AE tables will be summarized by the cumulative 4-week and 9-week 
periods separately: 
 Overall summary of AE  
 All AE by SOC and PT    
 SAE by SOC and PT  
 AEDC by SOC and PT 
The onset and duration of following individual AEs will be displayed graphically: 
 Akathisia (including PTs of Akathisia, Extrapyramidal disorders, Hyperkinesia, 
Hyperkinesia neonatal, Motor dysfunction, Movement disorder, Psychomotor 
hyperactivity, Restlessness) for each treatment group 
 Sedation (including PTs of Sedation, Somnolence, Hypersomnia, Lethargy) on 
benzodiazepines vs. non-benzodiazepines for each treatment group 
 Hypotension/orthostasis (including PTs of Hypotension, Blood pressure orthostatic, 
Orthostatic hypotension, Presyncope, Syncope, Dizziness, Tachycardia) in 
antihypertensive vs. not for each treatment group 
 ISRs for each treatment group 


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3.9.3. 
Death, Serious and Other Significant Adverse Events 
The number and percentage of subjects who have SAE and AEDCs will be summarized by 
system organ class, preferred term, and treatment group and overall.  Any deaths, subjects with 
serious AEs, and subjects who discontinue due to AEs will be listed.  
3.9.3.1 Adverse Events of Special Interest 
In addition, incidence of a selected subset of relevant AEs in this class of drugs will be 
summarized by preferred term and treatment group and overall for cumulative 4-week, 9-week 
and entire Treatment period separately.  AEs will include the following: 
 Akathisia 
 Dyskinesia 
 Dystonia 
 Parkinson-like events 
 Suicidal Ideation and Behavior 
The selection of AEs per subset will be based on the PT and customized or Standardized 
MedDRA queries (SMQs). The list of PTs will be provided as an Appendix. 
3.9.4. 
Clinical Laboratory Parameters 
Laboratory parameters will be presented in conventional (ie, US) units. Only scheduled 
laboratory parameters will be included in the summaries, unless specified otherwise. All 
laboratory data, including those collected at unscheduled visits, will be included in the listings. 
Laboratory results including baseline and change from baseline for the Safety Population during 
the Treatment period for chemistry and hematology parameters will be summarized by treatment 
group, overall, and by visit. 
Clinical laboratory test values, scheduled or unscheduled, will be considered potentially 
clinically significant (PCS) if they meet PCS criteria listed in Table 4. The number and 
percentage of subjects who have postbaseline PCS clinical laboratory values will be summarized 
by treatment group and overall. The percentages will be calculated based on the number of 
subjects with non-PCS baseline value and have at least one postbaseline assessment. All PCS 
values including baseline PCS values will be included in supportive listings. 
Shift tables for selected metabolic parameters (glucose, total cholesterol, LDL, HDL, 
tryglyceride, and HbA1c) and liver function tests will be presented. The criteria are summarized 
in Table 5, Table 6, and Table 7 .  
In addition, the number (percentage) of subjects who had a prolactin value >1 × ULN, >2 × 
ULN, >3 × ULN at any post-baseline will be also summarized by gender, visit, and treatment 
group. Baseline prolactin will be summarized by prior treatment for each gender.  


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The selected lab parameters will be presented by figures. The prolactin and change from baseline 
over time will be plotted by gender and treatment group. The weight and vital signs and changes 
from baseline will be plotted over time.  
Number of subjects who meet Hy’s Law criteria (ALT or AST >3xULN, along with total 
Bilirubin >2xULN and a non-elevated ALP<2xULN) will be summarized by treatment group. 


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Table 4: 
Criteria of Potentially Clinically Significant (PCS) Abnormality for Selected 
Analytes 
Parameters 
Criteria 
Chemistry 
Albumin 
<2.5 g/dL 
Alkaline Phosphatase (U/L) 
≥3 × ULN 
Alanine Aminotransferase (U/L) 
≥3 × ULN 
Aspartate Aminotransferase (U/L) 
≥3 × ULN 
Bilirubin, Total 
≥2.0 mg/dL 
Blood Urea Nitrogen (BUN) 
>30 mg/dL 
Creatinine Kinase (CK)  
> 3 x ULN  
Creatinine  
≥ 2.0 mg/dL  
Creatine phosphokinase  
(CPK), Total  
≥ 3 x ULN  
Cholesterol, Random 
>300 mg/dL 
Cholesterol, Fasting 
≥240 mg/dL 
Cholesterol, HDL Fasting 
≤30 mg/dL 
Cholesterol, LDL Fasting 
≥160 mg/dL 
Creatine Kinase (U/L) 
≥3 × ULN 
Creatinine 
≥2.0 mg/dL 
Glucose, Random 
<50 mg/dL or  
≥200 mg/dL 
Glucose, Fasting 
<50 mg/dL or  
≥126 mg/dL 
Potassium 
<3 mmol/L or 
>5.5 mmol/L 
HbA1c% 
>6.5% 
Lactate Dehydrogenase (U/L) 
>3 × ULN 
Prolactin by gender 
>1 × ULN 
>2 × ULN 
>3 × ULN 


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Parameters 
Criteria 
Sodium 
<130 mmol/L or 
>150 mmol/L 


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Table 4: 
Criteria of Potentially Clinically Significant (PCS) Abnormality for Selected 
Analytes (Continued) 
Parameters 
Criteria 
Hematology 
Eosinophils 
>1.0 × 103/μL 
Hematocrit (Female) 
≤32% 
Hematocrit (Male) 
≤37% 
Neutrophils, Absolute 
<1.5 × 103/μL 
Platelets 
<75.0 × 103 cells/μL or 
≥ 700.0 × 103 cells/μL 
Leukocytes 
≤ 2.8 × 103/μL or 
≥ 16.0 ×103/μL 
Table 5: 
Shifts Category from Baseline to Any Postbaseline for Selected Lipid 
Parameters 
Total Cholesterol (fasting) mg/dL 
Normal (<200) to High (≥240) 
Borderline (≥200 and < 240) to High (≥240) 
Normal/Borderline (<240) to High (≥240) 
Normal (<200) to borderline/High (≥200) 
Increase ≥40 mg/dL 
LDL Cholesterol (fasting) mg/dL 
Normal (<100) to high (≥160) 
Borderline (≥100 and <160) to high (≥160) 
Normal/borderline (<160) to high (≥160) 
Normal (<100) to borderline/high (≥100) 
Increase ≥30 mg/dL 
HDL Cholesterol (fasting) mg/dL 
Normal (≥40) to low (<40) 
Decrease ≥20 mg/dL 


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Table 5: 
Shifts Category from Baseline to Any Postbaseline for Selected Lipid 
Parameters (Continued) 
Total Cholesterol (fasting) mg/dL 
Triglycerides (fasting) mg/dL 
Normal (<150) to high (≥200) 
Normal (<150) to very high (≥500) 
Borderline (≥150 and <200) to high (≥200) 
Borderline (≥150 and <200) to very high (≥500) 
Normal/borderline (<200) to high (≥200) 
Normal/borderline (<200) to very high (≥500) 
Normal (<150) to borderline/high/very high (≥150) 
Increase ≥50 mg/dL 
 
Table 6: 
Shift Category from Baseline to Any Postbaseline in Glucose and HbA1c 
Serum glucose (fasting) mg/dL 
Normal (<100) to High (≥126) 
Impaired (≥100 and <126) to High (≥126) 
Normal/Impaired (<126) to High (≥126) 
Increase ≥10 mg/dL 
HbA1c % 
Shift from baseline (<5.7%) to postbaseline ≥5.7% 
Shift from baseline (<5.7%) to postbaseline ≥5.7% and <6.5% 
Shift from baseline (<5.7%) to postbaseline ≥6.5% 
 
 
 
 
 
 


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Table 7: 
Shift Category from Baseline to Any Postbaseline in Liver Function Test 
Alanine Aminotransferase (ALT) (U/L)  
Shift from Normal to ≥3 x ULN   
Shift from Normal to ≥5 x ULN   
Shift from Normal to ≥10 x ULN   
Aspartate Aminotransferase (AST) (U/L) 
Shift from Normal to ≥3 x ULN   
Shift from Normal to ≥5 x ULN   
Shift from Normal to ≥10 x ULN   
Bilirubin, Total (mg/dL) 
Shift from Normal to >1 x ULN   
Shift from Normal to ≥2 x ULN   
3.9.5. 
Vital Signs, Body Weight, and Electrocardiograms 
3.9.5.1. 
Vital Signs 
Descriptive statistics for vital signs and changes from baseline values at each scheduled time 
point will be presented by treatment group for the Treatment period. 
Vital sign values will be considered PCS if they meet both the observed-value criteria and the 
change-from-baseline criteria listed in Table 8. The number and percentage of subjects with PCS 
postbaseline values will be tabulated by treatment group. The percentages will be calculated 
based on the number of subjects with non-PCS baseline values and at least one postbaseline 
assessment. The numerator will be the number of subjects with non-PCS baseline values and at 
least one postbaseline PCS value. A supportive listing of subjects with PCS postbaseline values 
will be provided. 
All vital signs will be presented in the subject data listing. 
Orthostatic hypotension can be defined in two ways. The first is defined as a fall in systolic 
blood pressure of at least 20 mmHg and a fall in the diastolic blood pressure of at least 10 mmHg 
upon standing from supine. The other Orthostatic hypotension is defined as a fall in systolic 
blood pressure of at least 30 mmHg upon standing from supine. 
Orthostatic tachycardia is defined as a heart rate increase of 30 beats per minute (bpm) or more 
upon standing from supine, or over 120 bpm upon standing. 
The number and percentage of subjects with orthostatic hypotension or orthostatic tachycardia 
occurring at any postbaseline visit will be summarized for by treatment group. 


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Table 8: 
Criteria for Potentially Clinically Significant  Blood Pressure or Pulse Rate 
Parameter 
Criteria 
Supine Systolic Blood Pressure 
≤90 and decrease ≥20 mm Hg 
≥180 and increase ≥20 mm Hg 
Supine Diastolic Blood Pressure 
≤50 and decrease ≥15 mm Hg 
≥105 and increase ≥15 mm Hg 
Supine Heart Rate 
≤50 and decrease ≥15 bpm 
≥120 and increase ≥15 bpm 
3.9.5.2. 
Weight and Body Mass Index 
Weight (kg), BMI (kg/m2) (baseline and change from baseline) will be summarized by treatment 
group and overall.  
In addition, number and percentage of subjects with weight change values considered as PCS 
occurring at any post-baseline visit will be summarized by treatment group and overall. Criteria 
for PCS are presented in Table 9. The percentages will be calculated relative to the number of 
subjects in the Safety Population with at least one post-baseline value. A supportive listing will 
be provided for subjects with PCS values.  The PCS increase in weight will also be summarized 
by baseline BMI category: 
  Underweight [<18.5 kg/m
2]; 
 Normal [≥18.5 to <25 kg/m
2]; 
 Overweight [≥25 to <30 kg/m
2]; and 
 Obese [≥30 kg/m
2]. 
Table 9: 
Criteria for Potentially Clinically Significant Changes from Baseline in Body 
Weight 
Parameter 
Criteria 
Body Weight 
Decrease from Baseline ≥7% 
Increase from Baseline ≥7% 
3.9.5.3. 
Electrocardiograms 
Descriptive statistics for ECG parameters (heart rate, PR interval, RR interval, QRS interval, 
QT interval, and QTc interval) at baseline and change from baseline values at each scheduled 
assessment timepoint and at the end of the Treatment period will be presented by treatment 
group for the Treatment period. QTc interval will be calculated using both Bazett (QTcB = QT/ 


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(RR)½) and Fridericia (QTcF = QT/ (RR)⅓) corrections; if RR is not available, it will be replaced 
with 60/HR in the correction formula. 
Electrocardiogram parameter values are considered PCS if they meet or exceed the higher-limit 
PCS criteria listed in Table 10. The number and percentage of subjects with PCS postbaseline 
ECG values will be tabulated by treatment group. The percentages will be calculated based on 
the number of subjects with non-PCS baseline values and at least one postbaseline assessment. 
The numerator is the number of subjects with non-PCS baseline values and at least one 
postbaseline PCS value. A supportive listing of subjects with PCS values will be provided. 
Table 10: 
Criteria for Potentially Clinically Significant (PCS) QTcF 
Parameter 
Criteria 
QTcF 
>450 to ≤480 msec 
>480 to ≤500 msec 
>500 msec 
Change from baseline >30 to ≤60 msec 
Change from baseline >60 msec 
3.9.6. 
Abnormal Movement Scales 
Extra pyramidal symptoms will be evaluated as AEs and also as assessed by abnormal movement 
scales. Abnormal movement scales will include the following: AIMS, BARS, and SAS. 
For all abnormal movement scales, total scores and subscale scores will be summarized by 
treatment group at each visit for the absolute value and for changes from baseline. 
Number and percentage of subjects meeting the criteria for treatment emergent Parkinsonism 
(SAS total score>3), for treatment emergent akathisia (BARS global clinical assessment of 
akathisia score ≥2), for treatment emergent dyskinesia (AIMS score ≥3 on any of the first 
7 items, or a score ≥2 on two or more of any of the first 7 items) at any postbaseline visit will be 
summarized by treatment group. 
A listing will be provided for every abnormal movement scale. Listing for treatment emergent 
EPS will be provided. 
3.9.7. 
Injection Site Reactions 
All ISR will be reported as AEs. Injection site reaction AE preferred terms (injection site pain, 
injection site erythema, injection site swelling, etc.) will be summarized by treatment group and 
overall. 


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3.9.8. 
Columbia-Suicide Severity Rating Scale  
The C-SSRS is a questionnaire used to measure the presence and intensity of suicidal ideation 
and behavior. 
Suicidal behavior and suicidal ideation will be summarized for the Safety population. The 
number of subjects with suicidal ideation and suicidal behavior will be summarized by treatment 
group when applicable. 
Supportive tabular display of subjects with all values will be provided. 
Table 11: 
C-SSRS Categories for Analysis  
Category 
C-SSRS Item response is “YES” 
Suicidal behavior 
Preparatory acts or behavior 
Aborted attempt 
Interrupted attempt 
Actual attempt 
Complete suicide 
Suicidal ideation 
Wish to be dead 
Non-specific active suicidal thoughts 
Active suicidal ideation with any methods (not plan) without 
intent to act 
Active suicidal ideation with some intent to act, without specific 
plan 
Active suicidal ideation with specific plan and intent 
3.9.9. 
Epworth Sleepiness Scale  
The ESS is a self-reported questionnaire with 8 questions that provides a measure of a person’s 
level of daytime sleepiness. The ESS assesses, on a 4-point scale (0–3), a person’s usual chances 
of dozing off or falling asleep in 8 different situations or activities. This scale will be completed 
by the subject at Week 2 (Day 15), Week 3 (Day 22), Week 4 (Day 29), Week 9 (Day 64), Week 
13 (Day 92), and Week 25 (Day 176).  The sum of 8-item score will be summarized by treatment 
group. 
3.9.10. 
 UKU-SERS-PAT-Sexual Side Effects 
The sexual functioning subscale from the UKU-SERS-PAT contains 7 items for males and 
9 items for females. Each item is rated on a 4-point scale (0=none or doubtful, 1=present to a 
mild degree, 2=present to a moderate degree, and 3=present to a severe degree). This scale will 
be completed by the subject at the time points specified at Day 1, Week 4 (Day 29), Week 9 


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(Day 64), Week 17 (Day 120), and Week 25 (Day 176).  The UKU score will be summarized by 
the following way:  
 Total score and change from baseline will be summarized by treatment group and 
gender  
 The number and percentage of subjects with ≥1 score on any item at each visit will be 
summarized by treatment group and gender (all items) 
 The number and percentage of subjects with ≥1 score on each item at any visit will be 
summarized by treatment group and gender (each item reported separately) 
3.9.11. 
Genotyping data 
CYP2D6 phenotype will be summarized by treatment group and overall. The change from 
baseline in PANSS and CGI-S at Week 4 (Day 29), Week 9 (Day 64), and Week 25 (Day 176) 
will be analyzed by each phenotype status (extensive metabolizer, intermediate metabolizer, or 
poor metabolizer). In addition, the AE incidence rate will be also summarized by phenotype 
status and treatment group. 
 
3.10. 
Pharmacokinetic/ Pharmacodynamic Data Analysis 
Not applicable. 
4. 
INTERIM ANALYSES 
There was no interim analysis for this study. 
5. 
CHANGES IN CONDUCT OR PLANNED ANALYSES FROM 
THE PROTOCOL 
The ANCOVA with LOCF for the secondary efficacy endpoint (the change of PANSS total 
score from baseline at Week 4 [Day 29], Week 9 [Day 64], and Week 25 [Day 176]) was 
replaced by MMRM approach to better address the missingness assumption. 
6. 
DEFINITIONS AND CONVENTIONS FOR HANDLING OF THE 
DATA 
Dataset specifications will be provided in a separate document. 


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6.1. 
Analysis Visit Windows 
Scheduled analysis visits are visits at scheduled timepoints as specified in the protocol 
(Table 1 Schedule of Visits and Assessments). 
Scheduled analysis visits during the study period will be the same as the nominal visits collected 
in eCRF. There will be one valid value of assessment kept for each scheduled analysis visit 
in summary/analysis statistics. 
Unscheduled visits are visits with data not collected on the scheduled time point. Unscheduled 
visits will not be used for by-visit summary/analysis statistics, unless specified otherwise. 
All unscheduled visits as collected in eCRF will be included in listings. 
Visit Day is calculated as date of visit – date of the first dose of study drug + 1 day. 
Last postbaseline values are defined as the last valid postbaseline values collected for each 
subject during the Treatment period.  
6.2. 
Handling of Partial Dates of Concomitant Medication 
Partial start dates of prior and concomitant medications will be assumed to be the earliest 
possible date consistent with the partial date. Partial stop dates of prior and concomitant 
medications will be assumed to be the latest possible date consistent with the partial date. In 
the case of completely missing stop date, medication will be assumed to be ongoing. 
6.3. 
Handling of Safety Data 
All efforts should be made to obtain the missing information from the investigator. For C-SSRS, 
vital signs, laboratory testing (chemistry, hematology, urinalysis), and 12-lead ECGs, only 
observed data will be used for analyses, and missing data will not be imputed. 
7. 
GENERAL STATISTICAL METHODOLOGY 
In general, summary statistics (n, mean, SD, median, minimum, and maximum for continuous 
variables, and number and percentage of subjects in each category for categorical variables) will 
be provided by treatment group. All summary tables will be based on observed data, and missing 
values will not be imputed, unless otherwise indicated. Measurements collected from 
unscheduled visits or repeated assessments will not be included in the by-visit summary tables or 
figures, but will be included in the analyses for the PCS postbaseline values, and subject listings. 
Source data for the summary tables will be presented as subject data listings. 
7.1. 
Reporting Precision 
Summary statistics will be presented to the following degree of precision, unless otherwise 
specified: 


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Table 12: 
Degree of Precision 
Statistics 
Degree of Precision 
 
Mean, Median, Confidence limit boundaries 
One more than the raw data, up to 3 decimal places. 
Standard deviation, Standard error 
One more than the mean, up to 3 decimal places 
Minimum, Maximum 
The same as the raw data, up to 2 decimal places 
P-value 
Rounded to 3 decimal places and therefore presented as 
0.xxx; P-values smaller than 0.001 as ‘<0.001’; P-values 
greater than 0.999 as ‘>0.999’. 
Percentage 
One decimal place. A percentage of 100% will be reported 
as 100%. Percentages of zero will be reported as 0. 
Fractional numeric values will be presented with a zero to the left of the decimal point (for 
example, 0.12 – 0.30). 
For weight, height, and BMI, one decimal place will be used for summary statistics, unless 
otherwise specified. 
8. 
PROGRAMMING SPECIFICATIONS 
Programming specifications will be provided in a separate document. 
9. 
MOCK TABLES, LISTINGS AND FIGURES  
Mock-up tables and listings will be provided in a separate document. 
10. 
REFERENCES 
1. Alkermes ALK9072-A306 Study Protocol Amendment  Date: 04 Jan 2018