Clinical trial NCT02634320
Conditions: Schizophrenia
Keywords: Alkermes ARISTADA Aripiprazole Lauroxil Schizophrenia
Sponsor: Alkermes, Inc.
Start date: 2015-12-01; Completion date: 2017-07-11
Enrollment: 51 participants; Allocation: NA; Intervention model: SINGLE_GROUP

Brief summary:
This study will evaluate the safety and tolerability of aripiprazole lauroxil (also known as ARISTADA, ALKS 9070).

Detailed description:

Arms: arm 1: Intramuscular (IM) injection
Interventions: intervention 1: Aripiprazole Lauroxil
Intervention descriptions: intervention 1: Monthly IM injection

Protocol documents:
Prot_000.pdf: 
Safety and Tolerability of Initiating Aripiprazole Lauroxil in 
Subjects with Schizophrenia who are Inadequately Treated 
with Paliperidone Palmitate or Risperidone Long Acting 
Injection 
 
 
Unique Protocol ID: 
ALK9072-A401 
NCT Number: 
NCT02634320 
Date of Protocol:  
07 September 2016 
 


TITLE PAGE 
 
CLINICAL STUDY PROTOCOL 
ALK9072-A401 
Study Title 
Safety and Tolerability of Initiating Aripiprazole Lauroxil in 
Subjects with Schizophrenia who are Inadequately Treated 
with Paliperidone Palmitate or Risperidone Long Acting 
Injection 
Document Status 
Final 
Document Date 
Original Protocol: 18 Sep 2015 
v1.0 (incorporates Amendment 1): 07 Sep 2016 
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. 


 
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CONTACT INFORMATION 
Role in Study 
Name 
Address and Telephone 
Alkermes Medical Monitor  
 
Alkermes, Inc. 
852 Winter Street 
Waltham, MA 02451 USA 
Office telephone: 
 
 Medical Monitor 
 
 
 
Raleigh, North Carolina 27604 
Office telephone: 
 
Mobile telephone: 
 
 
Alkermes Drug Safety 
Specialist 
 
Alkermes, Inc. 
852 Winter Street 
Waltham, MA 02451 USA 
Office telephone: 
 
 
PPD
PPD
PPD
PPD
PPD
PPD
PPD
PPD
PPD
PPD


 
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1. 
SYNOPSIS 
Name of Sponsor/Company: Alkermes, Inc. 
Name of Product: Aripiprazole lauroxil 
Name of Active Ingredient: Aripiprazole 
Title of study: Safety and Tolerability of Initiating Aripiprazole Lauroxil in Subjects with Schizophrenia 
who are Inadequately Treated with Paliperidone Palmitate or Risperidone Long Acting Injection 
Study Center Multicenter study (United States [US]) 
Study Period: 
Estimated date of first subject’s consent: Q4 2015 
Estimated date of last subject’s last visit: Q3 2017 
Phase of Study: 
4 
Objectives: 
Primary: 
• 
To evaluate the safety, tolerability, and efficacy of aripiprazole lauroxil in subjects with 
schizophrenia who are inadequately treated with paliperidone palmitate or risperidone long 
acting injection 
Secondary: 
• 
To evaluate quality of life, including daily and social functioning, after treatment with 
aripiprazole lauroxil 
• 
To characterize the caregiver and healthcare burden 
Methodology: 
This is an open-label study in subjects who are switched to aripiprazole lauroxil from paliperidone 
palmitate or risperidone long acting injection. Subjects will participate for approximately 7 months, 
including a screening period of up to 30 days, and will be administered 4 to 6 doses of intramuscular (IM) 
aripiprazole lauroxil. Dosing may occur in monthly (441 mg, 662 mg, or 882 mg) or 6-week (882 mg 
only) intervals. The dose and frequency of dosing will be at the discretion of the investigator, based on the 
dose selected, and on dosing instructions. 
Potential subjects will be evaluated for eligibility according to the inclusion and exclusion criteria at a 
screening visit and again on Day 1. The first dose of aripiprazole lauroxil will be administered on Day 1. 
Subjects will receive their first dose of aripiprazole lauroxil no earlier than one week and not later than 
6 weeks following their previous injection of paliperidone palmitate or risperidone long acting injection. 
For subjects who have never taken aripiprazole, two test doses of oral aripiprazole 5 mg will be 
administered during the screening period. Only subjects who exhibit tolerability to oral aripiprazole 
(either following test doses or by past experience) are eligible to enroll in the study. 
On Day 1, qualified subjects will be administered a single IM injection of aripiprazole lauroxil into the 
gluteal (441 mg, 662 mg, or 882 mg) or deltoid (441 mg only) muscle, according to the dosing 
instructions. Following the first injection, subjects will return to the study site monthly or every 6 weeks 
for IM aripiprazole lauroxil administration and outpatient assessments. Additional outpatient assessments 
may be scheduled at the discretion of the investigator. 
If a subject must withdraw from the study early, an early termination (ET) visit should be completed 


 
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using the assessments scheduled for Day 169. 
Number of Subjects Planned: 
This study will enroll approximately 50 subjects. 
Main Criteria for Inclusion: 
Men and women 18 through 65 years of age (inclusive) with a diagnosis of schizophrenia at screening 
and who have been taking paliperidone palmitate or risperidone long acting injection with inadequate 
results for at least 3 doses prior to screening may be eligible for this study. 
Product, Dosage, Duration and Mode of Administration: 
Aripiprazole lauroxil in doses of 441 mg (via deltoid or gluteal muscle), 662 mg (via gluteal muscle), or 
882 mg IM (via gluteal muscle) will be administered monthly or every 6 weeks (882 mg only). The dose 
and frequency of dosing will be at the discretion of the investigator, based on the dose selected, and on 
dosing instructions (as depicted in the table below). 
Dose 
Dosing Frequency 
Site of Intramuscular Injection 
441 mg 
Monthly 
Deltoid or Gluteal 
662 mg 
Monthly 
Gluteal 
882 mg 
Monthly or every 6 weeks 
Gluteal 
 
Reference Therapy, Dosage, Duration and Mode of administration: 
Not applicable. 
Duration of Study: 
Approximately 7 months. 
Criteria for Evaluation: 
Efficacy: 
The following scales will be used to assess efficacy: 
• 
CGI-S and BPRS 
Safety and Tolerability: 
The following safety and tolerability measures will be assessed: 
• 
AEs 
• 
Injection site reactions 
• 
Vital signs (blood pressure, heart rate, respiratory rate, and body temperature), weight, and 
waist circumference 
• 
Clinical laboratory parameters (chemistry [including prolactin], hematology, and urinalysis) 
• 
C-SSRS responses 
• 
ESRS-A scores 
Quality of Life, Daily and Social Functioning 
The following assessments will be conducted to characterize any change in quality of life, including daily 
and social functioning: 
− 
Quality of Life Scale (QLS) 
− 
Negative Symptom Assessment-16 (NSA-16) 


 
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− 
Sexual functioning subscale from UKU Side Effect Rating Scale and CSFQ-14 scores 
− 
Personal and Social Performance scale (PSP) 
− 
Total and individual items scores of the Modified -MSQ 
Other Assessments 
The following assessments will be collected to explore potential changes in healthcare burden, cognition, 
insight, and psychosocial care needs: 
• 
Health economics 
− 
Total healthcare costs as measured by Treatment Services Review (TSR-6) (Modified for 
Mental Health) 
• 
Functional Assessment 
− 
Birchwood Insight Scale (BIS) 
• 
Family Measures 
− 
Caregiver Quality of Life – Burden Dimensions (CarerQOL–7D) and VAS 
− 
Burden Assessment Scale 
• 
Investigator- and Caregiver-Rated Cognition 
− Respective New York Assessment of Adverse Cognitive Effects of Neuropsychiatric 
Treatment (NY-AACENT) subscales 
• 
Substance Use 
− 
Mini International Neuropsychiatric Interview (M.I.N.I.) Module I (alcohol use disorder) 
− Mini International Neuropsychiatric Interview (M.I.N.I.) Module J (substance use 
disorder) 
Statistical Methods: 
The safety population will include all subjects who received at least one dose of aripiprazole lauroxil 
injection. All analyses will be carried out using the safety population. 
Efficacy: 
The change from baseline in CGI-S and BPRS scores at each post-baseline visit will be summarized. 
Safety and Tolerability: 
The number and percentage of treatment emergent adverse events (TEAEs) will be summarized by 
treatment group and overall by system organ class, and preferred terms within each system organ class. 
Serious adverse events (SAEs) and AEs resulting in treatment discontinuation will also be summarized. 
Observed values and change from baseline in vital signs, clinical laboratory data, and ESRS scores will be 
summarized 
Shift tables and potential clinical significance tables, along with supporting listings, will be provided for 
selected parameters. 
Analyses of Other Assessments 
Data on quality of life and functional domains including personal, social, and family measures will be 
summarized using the safety population. 
 


 
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Sample Size Considerations: 
No formal sample size calculations have been performed. The sample size is based on clinical 
considerations. 


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2.
TABLE OF CONTENTS
TITLE PAGE ...................................................................................................................................1 
CONTACT INFORMATION ..........................................................................................................2 
1. 
SYNOPSIS ...................................................................................................................3 
2. 
TABLE OF CONTENTS .............................................................................................7 
3. 
LIST OF ABBREVIATIONS.....................................................................................12 
4. 
INTRODUCTION ......................................................................................................14 
5. 
OBJECTIVES .............................................................................................................15 
5.1. 
Primary Objective .......................................................................................................15 
5.2. 
Secondary Objectives .................................................................................................15 
6. 
SELECTION AND WITHDRAWAL OF SUBJECTS ..............................................16 
6.1. 
Subject Inclusion Criteria ...........................................................................................16 
6.2. 
Subject Exclusion Criteria ..........................................................................................17 
6.3. 
Subject Withdrawal ....................................................................................................18 
6.4. 
Replacement of Subjects .............................................................................................19 
7. 
STUDY DESIGN .......................................................................................................20 
7.1. 
Overall Study Design and Plan ...................................................................................20 
7.2. 
Schedule of Visits and Assessments ...........................................................................21 
7.3. 
Study Procedures Descriptions ...................................................................................26 
7.3.1. 
Informed Consent .......................................................................................................26 
7.3.2. 
Eligibility Review .......................................................................................................26 
7.3.3. 
Demographics and Medical History ...........................................................................26 
7.3.4. 
Concomitant Medication Review ...............................................................................26 
7.3.5. 
Vital Signs, Weight, and Waist Circumference ..........................................................26 
7.3.6. 
Physical Examination .................................................................................................26 
7.3.7. 
12-Lead Electrocardiogram ........................................................................................26 
7.3.8. 
Columbia Suicide Severity Rating Scale ....................................................................27 
7.3.9. 
Extrapyramidal Symptom Rating Scale – Abbreviated ..............................................27 
7.3.10. 
Laboratory Assessments .............................................................................................27 
7.3.10.1. 
Drug Testing ...............................................................................................................27 
7.3.10.2. 
Hematology, Biochemistry, and Urinalysis ................................................................27 


 
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7.3.10.3. 
Pregnancy Testing ......................................................................................................28 
7.3.11. 
Drug Dispensation and Reconciliation .......................................................................28 
7.3.12. 
Adverse Event Monitoring .........................................................................................28 
7.3.13. 
Efficacy Assessments .................................................................................................29 
7.3.13.1. 
Clinical Global Impressions-Severity .........................................................................29 
7.3.13.2. 
Brief Psychiatric Rating Scale ....................................................................................29 
7.3.14. 
Quality of Life, Daily, and Social Functioning Assessments .....................................29 
7.3.14.1. 
Sexual Functioning Subscale from Udvalg for Kliniske Undersøgelser Side 
Effect Rating Scale .....................................................................................................29 
7.3.14.2. 
Changes in Sexual Functioning Questionnaire Short Form .......................................29 
7.3.14.3. 
Personal and Social Performance Scale ......................................................................29 
7.3.14.4. 
Heinrichs-Carpenter Quality of Life Scale .................................................................29 
7.3.14.5. 
Negative Symptom Assessment-16 ............................................................................30 
7.3.14.6. 
Modified Medication Satisfaction Questionnaire .......................................................30 
7.3.15. 
Other Assessments ......................................................................................................30 
7.3.15.1. 
Sixth edition of the Treatment Services Review (TSR-6)-Modified for 
Mental Health .............................................................................................................30 
7.3.15.2. 
Caregiver Quality of Life – Burden Dimensions (7D) and Visual Analog 
Scale ............................................................................................................................30 
7.3.15.3. 
Burden Assessment Scale ...........................................................................................30 
7.3.15.4. 
Birchwood Insight Scale (BIS) ...................................................................................31 
7.3.15.5. 
New York Assessment of Adverse Cognitive Effects of Neuropsychiatric 
Treatment subscales ....................................................................................................31 
7.3.15.6. 
MINI International Neuropsychiatric Interview – Modules I and J ...........................31 
7.4. 
Study Requirements and Restrictions .........................................................................31 
7.4.1. 
Prohibited Medications ...............................................................................................31 
7.4.2. 
Contraception and Pregnancy .....................................................................................31 
8. 
TREATMENT OF SUBJECTS ..................................................................................33 
8.1. 
Study Drug Dose and Administration .........................................................................33 
8.2. 
Missed Doses ..............................................................................................................34 
8.3. 
Early Dosing ...............................................................................................................34 
8.4. 
Dose Adjustments for CYP450 Considerations .........................................................35 
8.5. 
Oral Aripiprazole Test Doses .....................................................................................36 


 
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8.6. 
Treatment Adherence ..................................................................................................36 
8.7. 
Blinding ......................................................................................................................36 
9. 
STUDY DRUG MATERIALS AND MANAGEMENT ...........................................37 
9.1. 
Study Drugs ................................................................................................................37 
9.2. 
Accountability .............................................................................................................37 
9.3. 
Handling and Disposal ................................................................................................37 
10. 
ASSESSMENT OF EFFICACY ................................................................................38 
11. 
QUALITY OF LIFE, DAILY AND SOCIAL FUNCTIONING ...............................39 
12. 
OTHER ASSESSMENTS ..........................................................................................40 
13. 
ASSESSMENT OF SAFETY AND TOLERABILITY .............................................41 
13.1. 
Definition of Adverse Event .......................................................................................41 
13.2. 
Definition of Serious Adverse Event ..........................................................................41 
13.3. 
Relationship to Study Drug ........................................................................................42 
13.4. 
Monitoring and Recording of Adverse Events ...........................................................43 
13.5. 
Reporting of Serious Adverse Events .........................................................................44 
14. 
STATISTICS ..............................................................................................................45 
14.1. 
Sample Size Considerations .......................................................................................45 
14.2. 
General Statistical Methodology ................................................................................45 
14.2.1. 
Study Population .........................................................................................................45 
14.3. 
Demographics and Baseline Data ...............................................................................45 
14.4. 
Efficacy Analyses .......................................................................................................45 
14.5. 
Safety and Tolerability Analysis ................................................................................45 
14.6. 
Analyses of Other Assessments ..................................................................................46 
15. 
DIRECT ACCESS TO SOURCE DATA/DOCUMENTS.........................................47 
15.1. 
Study Monitoring ........................................................................................................47 
15.2. 
Audits and Inspections ................................................................................................47 
15.3. 
Institutional Review Board/ Independent Ethics Committee .....................................47 
16. 
QUALITY CONTROL AND QUALITY ASSURANCE .........................................48 
16.1. 
Case Report Forms .....................................................................................................48 
16.2. 
Confidentiality of Data ...............................................................................................48 
17. 
ETHICAL CONSIDERATIONS................................................................................49 
17.1. 
Ethics Review .............................................................................................................49 


 
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17.2. 
Ethical Conduct of the Study ......................................................................................49 
17.3. 
Written Informed Consent ..........................................................................................49 
18. 
DATA HANDLING AND RECORDKEEPING .......................................................51 
18.1. 
Data Capture ...............................................................................................................51 
18.2. 
Inspection of Records .................................................................................................51 
18.3. 
Retention of Records ..................................................................................................51 
18.4. 
Use of Information and Publication Policy ................................................................52 
19. 
REFERENCES ...........................................................................................................53 
 
 
LIST OF TABLES 
Table 1: 
Schedule of Visits and Assessments ...........................................................................22 
Table 2: 
Clinical Laboratory Assessments ...............................................................................28 
Table 3: 
Aripiprazole Lauroxil Dosing Frequency and Site of Injection .................................33 
Table 4: 
Aripiprazole Lauroxil Doses Based on Oral Aripiprazole Total Daily Dose .............34 
Table 5: 
Recommendation for Concomitant Oral Aripiprazole Supplementation 
Following Missed Dosesa ...........................................................................................34 
Table 6: 
Aripiprazole Lauroxil Dose Adjustments with Concomitant CYP450 
Modulator Use ............................................................................................................35 
Table 7: 
Adverse Event Causality Guidelines ..........................................................................43 
 
 
LIST OF FIGURES 
Figure 1: 
Study Design (ALK9072-A401).................................................................................20 
 


 
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LIST OF APPENDICES 
Appendix A. 
Columbia Suicide Severity Rating Scale (Sample) 
Appendix B. 
Extrapyramidal Symptom Rating Scale – Abbreviated (ESRS-A) (Sample) 
Appendix C. 
Clinical Global Impressions-Severity (CGI-S) (Sample) 
Appendix D. 
Brief Psychiatric Rating Scale (BPRS) (Sample) 
Appendix E. 
Sexual Functioning Subscale from Udvalg for Kliniske Undersøgelser (UKU) Side Effect 
Rating Scale (Sample) 
Appendix F. 
Changes in Sexual Functioning Questionnaire (Sample) 
Appendix G. 
Personal and Social Performance Scale (PSP) (Sample) 
Appendix H. 
Heinrichs-Carpenter Quality of Life Scale (QLS) (Sample) 
Appendix I. 
Negative Symptom Assessment-16 (NSA-16) (Sample) 
Appendix J. 
Modified Medication Satisfaction Questionnaire (Modified MSQ) (Sample) 
Appendix K. 
Sixth Edition of the Treatment Services Review (TSR-6) (Sample) 
Appendix L. 
Caregiver Quality of Life (CarerQOL) – Burden Dimensions (7D) [Brouwer WBF, 2006] 
and Visual Analog Scale (VAS) (Sample) 
Appendix M. 
Burden Assessment Scale (Sample) 
Appendix N. 
Birchwood Insight Scale (BIS) (Sample) 
Appendix O. 
New York Assessment of Adverse Cognitive Effects of Neuropsychiatric Treatment 
(NY-AACENT) Subscales (Sample) 
Appendix P. 
Mini International Neuropsychiatric Interview (M.I.N.I.) – Modules I and J (Sample) 
Appendix Q. 
List of Potent Cytochrome P450 3A4 (CYP3A4) Inducers and Moderate-to-Strong 
Inhibitors of 3A4 or 2D6 
 


 
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3. 
LIST OF ABBREVIATIONS 
The following abbreviations are used in this study protocol. 
Abbreviation or Term 
Explanation or Definition 
AE 
adverse event 
ALK-P 
alkaline phosphatase 
ALT 
alanine aminotransferase 
AST 
aspartate aminotransferase 
ATC 
Anatomical Therapeutic Chemical [classification system] 
BIS 
Birchwood Insight Scale 
BPRS 
Brief Psychiatric Rating Scale 
CarerQOL-7D 
Caregiver Quality of Life – Burden Dimensions 
CGI-S 
Clinical Global Impressions-Severity 
CPK 
creatine phosphokinase 
CSA 
Clinical Study Agreement 
CSFQ-14 
Changes in Sexual Functioning Questionnaire Short Form 
CRO 
contract research organization 
C-SSRS 
Columbia Suicide Severity Rating Scale 
DSM-5 
Diagnostic and Statistical Manual of Mental Disorders – Fifth Edition 
EC 
Ethics Committee 
ECG 
electrocardiogram 
eCRF 
electronic case report form 
EPS 
Extrapyramidal symptoms 
ESRS-A 
Extrapyramidal Symptom Rating Scale - Abbreviated 
ET 
early termination 
FDA 
Food and Drug Administration 
GCP 
Good Clinical Practice 
GGP 
gamma-glutamyl transferase 
HIV 
human immunodeficiency virus 
HR 
heart rate 
IB 
Investigator’s Brochure 
ICF 
informed consent form 
ICH 
International Conference on Harmonisation of Technical Requirements 
for Registration of Pharmaceuticals for Human Use 


 
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Abbreviation or Term 
Explanation or Definition 
IRB 
Institutional Review Board 
ISR 
injection site reaction 
LAI 
long acting injectable antipsychotic 
LDH 
lactic dehydrogenase 
MedDRA 
Medical Dictionary for Regulatory Activities 
M.I.N.I. 
Mini International Neuropsychiatric Interview 
NSA-16 
Negative Symptom Assessment-16 
NY-AACENT 
New York Assessment of Adverse Cognitive Effects of Neuropsychiatric 
Treatment 
PANSS 
Positive and Negative Syndrome Scale 
PK 
pharmacokinetics 
QLS 
Quality of Life Scale 
RR 
respiratory rate 
SAE 
serious adverse event 
SAP 
statistical analysis plan 
SD 
standard deviation 
TEAE 
treatment-emergent adverse event 
TSR-6 
Sixth edition of the Treatment Services Review 
UKU 
Udvalg for Kliniske Undersøgelser 
ULN 
upper limit of normal 
VAS 
Visual Analog Scale 
WHO 
World Health Organization 


 
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4. 
INTRODUCTION 
Aripiprazole lauroxil is a covalently bonded, non-ester modification of aripiprazole, a second 
generation atypical antipsychotic agent, 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. Conversion of aripiprazole lauroxil to aripiprazole is 
governed by dissolution of the aripiprazole lauroxil drug crystal from the injection site and 
subsequent enzyme-mediated cleavage, generating lauric acid and N-hydroxymethyl 
aripiprazole; the covalently bonded hydroxymethyl group N-hydroxymethyl aripiprazole 
dissociates, releasing aripiprazole and formaldehyde. 
In clinical trials, treatment with aripiprazole lauroxil 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 being insomnia, akathisia, and headache. This study is designed to demonstrate that 1) the 
transition from treatment with other long acting injectable antipsychotics (LAIs) to aripiprazole 
lauroxil is clinically feasible, and that 2) comparative assessments of the safety and tolerability 
profiles of the respective treatments is clinically important. 
Paliperidone palmitate (Invega® Sustenna®) or risperidone long acting injection (Risperdal® 
Consta®) are commonly prescribed long-acting injectable antipsychotics. Paliperidone palmitate 
is a prodrug of paliperidone (9-hydroxy risperidone), the active metabolite of risperidone. As 
potent D2 antagonists, risperidone and paliperidone are pharmacologically distinct from 
aripiprazole’s hypothesized principal mechanism of antipsychotic action, one of high affinity, 
partial dopamine agonism. 
This study is an open label, 7-month prospective evaluation of the safety, tolerability, and 
efficacy of aripiprazole lauroxil in subjects with schizophrenia inadequately treated with 
risperidone long acting injection or paliperidone palmitate. 


 
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5. 
OBJECTIVES 
5.1. 
Primary Objective 
The primary objective of this study is to evaluate the safety, tolerability, and efficacy of 
aripiprazole lauroxil in subjects with schizophrenia who are inadequately treated with 
paliperidone palmitate or risperidone long acting injection. 
5.2. 
Secondary Objectives 
The secondary objectives of this study are to: 
• Evaluate quality of life, including daily and social functioning, after treatment with 
aripiprazole lauroxil 
• Characterize the caregiver and healthcare burden 


 
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6. 
SELECTION AND WITHDRAWAL OF SUBJECTS 
Each subject must meet all of the eligibility criteria to be qualified to participate in this study. 
6.1. 
Subject Inclusion Criteria 
Each subject must meet all of the following inclusion criteria to be qualified to participate in this 
study. 
1. Is willing and able to provide informed consent 
2. Is between 18 and 65 years of age, inclusive, at screening 
3. Meets either of the following aripiprazole tolerability criteria: 
• Has demonstrated tolerability to test doses of oral aripiprazole during screening; OR 
• Has a history of tolerated use of aripiprazole 
4. Has a diagnosis of schizophrenia as defined by Diagnostic and Statistical Manual of 
Mental Disorders, 5th Edition [DSM-5] (American Psychiatric Association 2013) criteria 
at screening 
5. Is clinically stable as evidenced by no hospitalizations for acute psychiatric exacerbations 
within the 2 months prior to screening and prior to initiation on Day 1. Social 
hospitalizations are not applicable and should not disqualify subjects 
6. Has a BPRS score of ≥30 and ≤45 at screening 
7. Has received at least 3 doses of risperidone long acting injection (Risperdal Consta®) or 
paliperidone palmitate (Invega Sustenna®) prior to screening (may include the ‘loading’ 
dose). Has no antipsychotic medication regimen change for 4 weeks prior to Day 1 
(medication or dose level, unless due to tolerability). 
8. In the judgment of the investigator, is inadequately responding to or not tolerating long 
acting injectable (risperidone or paliperidone), and is likely to benefit from a transition to 
aripiprazole lauroxil 
9. Agrees to abide by the contraceptive requirements of the protocol (as defined in 
Section 7.4.2) 
10. Has an identified reliable informant (caregiver), in the opinion of the investigator 
11. Resides in a stable living situation, in the opinion of the investigator 
12. Is fluent (oral and written) in the language in which standardized tests will be 
administered, and can be reliably rated 


 
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6.2. 
Subject Exclusion Criteria 
Each subject must not have any of the following conditions to be qualified to participate in this 
study. 
1. Is currently pregnant or breastfeeding, or is planning to become pregnant during the study 
2. Has received Invega Trinza® (3-month formulation of paliperidone palmitate), 
aripiprazole lauroxil or IM depot aripiprazole within 6 months of screening 
3. Has a history of poor or inadequate response to oral or injectable aripiprazole 
4. Has participated in a clinical trial involving any investigational product (ie, drug, device, 
biologic) within the past 3 months, or is currently participating in a clinical trial involving 
an investigational product 
5. Has a history of psychopathology other than schizophrenia as indicated by any of the 
following: 
• Has a DSM-5 (American Psychiatric Association 2013) diagnosis of moderate to 
severe substance use disorder (except tobacco use disorder), within the 12 months 
prior to screening 
• Has any primary DSM-5 diagnosis other than schizophrenia within the 12 months 
prior to screening or upon admission (depression, schizoaffective disorder, bipolar 
disorder, or neurocognitive disorder) 
6. In the opinion of the investigator, the subject is a danger to himself/herself or others at 
screening or upon admission or meets one of the following criteria for elevated suicidal 
ideation or behavior: 
• At screening (using “Baseline” version of the C-SSRS): 
− Answers “Yes” to items 4 or 5 of the C-SSRS “Suicidal Ideation” section with the 
most recent episode occurring within the 6 months prior to screening 
− Answers “Yes” to any of the 5 items C-SSRS “Suicidal Behavior” with an 
episode occurring within the 1 year prior to screening 
• Upon entry (on Day 1) (using “Since Last Visit” version of the C-SSRS): 
− Answers “Yes” to items 4 or 5 of the C-SSRS “Suicidal Ideation” 
− Answers “Yes” to any of the 5 items of the C-SSRS “Suicidal Behavior” 
7. Has a history or current evidence of a clinically significant condition or abnormality 
(including clinical laboratory test results or ECG findings) that in the investigator’s 
opinion could preclude safe participation in this study, or prevent, limit, or confound 
protocol specified assessments 
8. Has any of the following conditions or abnormalities at screening: 
• In the opinion of the investigator or sponsor has uncontrolled diabetes, heart disease 
or stroke 


 
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• Aspartate aminotransferase (AST) or alanine aminotransferase (ALT) levels ≥3 times 
the upper limit of the laboratory reference range at screening 
• An absolute neutrophil count ≤1.5 × 103 μL (or for black patients with history of 
“benign neutropenia” , a sustained count of ≤1 × 103 μL) 
• A platelet count ≤100 × 103 μL 
• Has a QT interval (corrected using the Fridericia formula; QTcF) >450 milliseconds 
for men or >470 milliseconds for women at screening 
9. Has a history of neuroleptic malignant syndrome or clinically significant tardive 
dyskinesia 
10. Is taking both strong CYP2D6 and strong CYP3A4 inhibitors. In addition, patients who 
are known CYP2D6 poor metabolizers taking strong CYP3A4 inhibitors are excluded 
11. Has a positive urine drug test for illicit use of amphetamines, barbiturates, cocaine, 
methadone, opiates, phencyclidine, at screening. Repeat testing may be performed if 
positive results cannot be confirmed by a history of presumed active substance use, or use 
of prescribed medications which may account for the positive urine drug test results 
12. Is employed by Alkermes, 
 the investigator, the study center (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 family of an employee of 
Alkermes, 
 the investigator, the study center, or other third-party agent 
• Immediate family is defined as a spouse, parent, child, or sibling, whether biological 
or legally adopted. 
6.3. 
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: 
• AE 
• Lost to follow-up 
• Lack of Efficacy 
• Withdrawal by subject 
• Non-compliance with study drug 
• Other 
• Pregnancy 
• Protocol deviation 
• Study terminated by sponsor 
Subjects completing all visits up to and including Day 169 will be considered completers. 
PPD
PPD


 
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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 final study visit, the study period may be extended as necessary. In 
such instances, the sponsor and the investigator will agree to an acceptable 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. Subjects are to be asked to return to the clinic for an ET visit. If the subject fails or refuses 
to return to the study center, 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 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. 
6.4. 
Replacement of Subjects 
Subjects who withdraw before completion of the study will not be replaced. 


 
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7. 
STUDY DESIGN 
7.1. 
Overall Study Design and Plan 
This is an open-label study in approximately 50 subjects who are switched to aripiprazole 
lauroxil from long acting injectable risperidone or paliperidone palmitate. In total, subjects will 
participate for approximately 7 months, including a screening period of up to 30 days, and will 
be administered 4 to 6 doses of IM aripiprazole lauroxil (Figure 1). Dosing may occur in 
monthly (441 mg, 662 mg, or 882 mg) or 6-week (882 mg only) intervals. The dose and 
frequency of dosing will be at the discretion of the investigator, based on the subject’s history, 
dose selected, and on dosing instructions (Section 8.1). 
Figure 1: 
Study Design (ALK9072-A401) 
 
Potential subjects will be evaluated for eligibility according to the inclusion and exclusion 
criteria at a screening visit and again on Day 1. The first dose of aripiprazole lauroxil will be 
administered on Day 1. Subjects will receive their first dose of aripiprazole lauroxil no earlier 
than one week and not later than six weeks following their previous injection of paliperidone 
palmitate or risperidone. The cross-tapering from risperidone or paliperidone to aripiprazole 
lauroxil is facilitated by the gradual disappearance of plasma risperidone/paliperidone while 
aripiprazole is concomitantly released from the initial IM aripiprazole lauroxil injection. 
For subjects who have never taken aripiprazole, two test doses of oral aripiprazole 5 mg will be 
administered during the screening period. Only subjects who exhibit tolerability to oral 
aripiprazole (either following test doses or by past experience) are eligible to enroll in the study. 
On Day 1, qualified subjects will be administered a single IM injection of aripiprazole lauroxil 
into the gluteal (441, 662 or 882 mg) or deltoid muscle (441 mg), according to the dosing 
instructions (Section 8.1). Following the first injection, subjects will return to the study site 
monthly or every 6 weeks (882 mg, gluteal IM only) for IM aripiprazole lauroxil administration 
and outpatient assessments. Additional outpatient assessments may be scheduled at the discretion 
of the investigator. 
Efficacy will be evaluated based on Clinical Global Impressions-Severity (CGI-S) and Brief 
Psychiatric Rating Scale (BPRS) responses. 
Day
(127)
Monthly AL injection
Q 6 weeks AL injection 
(882 mg)
Screening 
1
29
57
85
113
141 
169 
EOT/ET
Treatment Period 
-30 to -1
(43)
AL = aripiprazole lauroxil 
EOT = end of treatment; ET = early termination


 
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Safety and tolerability will be evaluated based on adverse events (AEs), injection site reactions 
(ISRs), clinical laboratory data, vital sign data, Columbia Suicide Severity Rating Scale 
(C-SSRS) responses, and Abbreviated Extrapyramidal Symptom Rating Scale (ESRS-A) scores. 
Potential changes in informant-rated cognition, insight, treatment satisfaction, quality of life, 
daily and social functioning, caregiver and healthcare burden, and psychosocial care needs 
following a transition to aripiprazole lauroxil will be examined. Total healthcare costs as 
measured by TSR-6-(Modified for Mental Health) survey will also be evaluated. 
7.2. 
Schedule of Visits and Assessments 
The schedules of visits and assessments are shown in Table 1. 
For a missed visit, the site should attempt to contact the subject to reschedule. 
Premature discontinuation procedures are provided in Section 6.3. 


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Table 1: 
Schedule of Visits and Assessments 
 
Screening 
Treatment Period1) 
Day 1 
Month 1 
Month 2 
Month 32) 
Month 4 
Month 5 
Month 6 
EOT/ET 
V1 
V2 
V3 
V4 
V5 
V6 
V7 
V8 
Visit windows 
(days) 
 
Day 1 
22-36 
37-64 
65-92 
93-120 
121-148 
149-183 
4 week dosing target day 
 
1 
29 
57 
85 
113 
141 
169 
6 week dosing target day 
 
1 
May skip 
Visit3) 
43 
85 
May skip 
Visit3) 
127 
169 
Study Drug Administration  
 
Injections are to be given monthly (6 total injections) or every 6 weeks (4 total injections) based on 
the dosing regimen selected; After Day 1, subsequent injections will occur 28 or 42 days following 
the previous injection  
 
Informed Consent 
X 
 
 
 
 
 
 
 
Eligibility Criteria 
Review4) 
X 
X 
 
 
 
 
 
 
Oral Aripiprazole Test 
Dose Administration5) 
X 
 
 
 
 
 
 
 
Drug Screen6) 
X 
 
 
 
 
 
 
 
12-Lead ECG 
X 
 
 
 
 
 
 
 
Demographics and Medical 
History 
X 
 
 
 
 
 
 
 
Reason for switching 
paliperidone/risperidone 
X 
 
 
 
 
 
 
 
MINI (Modules I & J)  
X 
 
 
 
 
 
 
X 
Height 
X 
 
 
 
 
 
 
 
Pregnancy Testing7) 
X 
X 
 
 
 
 
 
 


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Table 1: 
Schedule of Visits and Assessments (Continued) 
 
Screening 
Treatment Period1) 
Day 1 
Month 1 
Month 2 
Month 32) 
Month 4 
Month 5 
Month 6 
EOT/ET 
V1 
V2 
V3 
V4 
V5 
V6 
V7 
V8 
Visit windows 
(days) 
 
Day 1 
22-36 
37-64 
65-92 
93-120 
121-148 
149-183 
Physical Exam8) 
X 
X 
 
 
 
 
 
 
Adverse Event Monitoring 
X 
X 
X 
X 
X 
X 
X 
X 
Concomitant Medication 
Review 
X 
X 
X 
X 
X 
X 
X 
X 
Vital Signs, Weight, Waist 
Circumference9) 
X 
X 
X 
X 
X 
X 
X 
X 
ESRS-A 
 
X 
 
 
X 
 
 
X 
Clinical Lab Tests10) 
X 
X 
X11) 
X11) 
X11) 
 
 
X 
Modified MSQ 
X12) 
 
 
 
 
 
 
X12) 
Modified UKU  
X 
X 
 
 
 
 
 
X 
CSFQ-14 
X 
X 
 
 
 
 
 
X 
Injection Site Evaluation13) 
 
X 
X 
X 
X 
X 
X 
X 
C-SSRS14) 
X 
X 
X 
X 
X 
X 
X 
X 
TSR-6-Modified 
X 
X 
X 
X 
X 
X 
X 
X 
CGI-S 
X 
X 
X 
X 
X 
X 
X 
X 
BPRS 
X 
X 
X 
X 
X 
X 
X 
X 
QLS 
X 
 
 
 
X 
 
 
X 
NSA-16 
X 
 
 
 
X 
 
 
X 
NY-AACENT 
X 
 
 
 
 
 
 
X 


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Table 1: 
Schedule of Visits and Assessments (Continued) 
 
Screening 
Treatment Period1) 
Day 1 
Month 1 
Month 2 
Month 32) 
Month 4 
Month 5 
Month 6 
EOT/ET 
V1 
V2 
V3 
V4 
V5 
V6 
V7 
V8 
Visit windows 
(days) 
 
Day 1 
22-36 
37-64 
65-92 
93-120 
121-148 
149-183 
PSP 
X 
 
 
 
X 
 
 
X 
BIS 
X 
 
 
 
 
 
 
X 
Burden Assessment Scale 
X 
 
 
 
 
 
 
X 
CarerQOL-7D+VAS 
X 
 
 
 
 
 
 
X 
EOT= end of treatment; ET= early termination; ECG= electrocardiogram; MINI = Mini International Neuropsychiatric Interview; ESRS-A=Abbreviated 
Extrapyramidal Symptom Rating Scale; MSQ= Medication Satisfaction Questionnaire; UKU= Udvalg for Kliniske Undersøgelser Side Effect Rating Scale; 
CSFQ-14=Changes in Sexual Functioning Questionnaire Short Form; C-SSRS= Columbia Suicide Severity Rating Scale; TSR-6= Sixth edition of the 
Treatment Services Review; CGI-S= Clinical Global Impressions-Severity; BPRS= Brief Psychiatric Rating Scale; QLS = Quality of Life Scale; NSA-16 = 
Negative Symptom Assessment-16; NY-AACENT= New York Assessment of Adverse Cognitive Effects of Neuropsychiatric Treatment; PSP= Personal and 
Social Performance scale; BIS= Birchwood Insight Scale; CarerQOL-7D+VAS= Caregiver Quality of Life – burden dimensions and visual analog scale 
1) For all visits other than Screening and Day 1, the visit will be anchored to the previous visit (based on dosing regimen schedule) 
2) In the event the Month 3 visit is missed or skipped, the additional assessments required at the Month 3 visit (ESRS-A, prolactin, QLS, NSA-16, PSP) should be 
conducted (via unscheduled assessment) at the subject’s next visit 
3) Visits may be skipped for subjects on a 6 week dosing regimen 
4) Eligibility Review Form must be reviewed by 
 Clinical Surveillance Team (CST) prior to enrolling a subject on Day 1 
5) Only for prospective subjects who have never received aripiprazole. The oral aripiprazole test doses will consist of 5 mg/day for 2 consecutive days during the 
screening period. The first test dose should be administered at the clinic. 
6) Urine drug screen via dipstick at screening. The urine drug screen includes amphetamines, barbiturates, cocaine, methadone, opiates, and phencyclidine. 
Rescreening may be performed if positive results cannot be confirmed by a history of presumed active substance use or use of prescribed medications, which 
may account for the positive urine drug test results. 
7) Urine pregnancy testing will be completed for ALL women. At screening, pregnancy test should be completed prior to the administration of the first oral 
aripiprazole test dose, where applicable. On Day 1, testing will be performed before dosing. 
8) Full physical examination at screening; brief physical examination on Day 1; symptom directed physical exams may be performed as needed at the 
Investigator’s discretion. 
9) Vital signs include blood pressure, heart rate, respiratory rate, and body temperature, 
10)Includes biochemistry (including prolactin), hematology, and urinalysis. 
11)Prolactin only will be measured at Month 1, Month 2 and Month 3. 
PPD


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12)Modified MSQ question #1 only at screening; the entire modified MSQ will be completed at Visit 8 (EOT) 
13)The injection site and surrounding area will be evaluated following each injection and monitored so long as there are reactions to be monitored; if there are no 
observed reactions, continuing evaluation is not necessary 
14)“Baseline” version used at screening; “since last visit” used at all subsequent visits 


 
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7.3. 
Study Procedures Descriptions 
Details of the study procedures are described below. The overall schedules of assessments are 
provided in Table 1. 
7.3.1. 
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 17.3. 
Prior to the administration of any study-specific procedures, authorized study personnel will 
obtain written informed consent from each potential subject and caregiver. 
7.3.2. 
Eligibility Review 
An eligibility review will be conducted by the investigator at the visits specified in Table 1 using 
the subject inclusion criteria in Section 6.1 and exclusion criteria in Section 6.2. 
7.3.3. 
Demographics and Medical History 
Subject’s demographic data and medical history will be reviewed and documented at the time 
point(s) specified in Table 1. 
7.3.4. 
Concomitant Medication Review 
At the time point(s) specified in Table 1, prospective subjects will be asked about the 
medications they have taken since the last visit and are currently taking, including prescription 
and nonprescription medications, vitamins, and supplements. 
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. 
7.3.5. 
Vital Signs, Weight, and Waist Circumference 
Vital signs (blood pressure, heart rate, respiratory rate, and body temperature), waist 
circumference, and weight will be assessed at the time point(s) specified in Table 1. Blood 
pressure, heart rate, and respiratory rate will be measured after the subject has been resting in a 
seated or supine position for at least 5 minutes. 
7.3.6. 
Physical Examination 
A full physical examination will be performed at screening and a brief physical exam performed 
on Day 1. Symptom-directed physical exams may be performed as needed at the Investigator’s 
discretion. 
7.3.7. 
12-Lead Electrocardiogram 
A 12-lead electrocardiogram (ECG) will be conducted at screening only. 


 
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7.3.8. 
Columbia Suicide Severity Rating Scale 
The PI or designee will administer the C-SSRS (Appendix A) according to the schedule in 
Table 1. At screening, the “Baseline” version will be administered (Posner, Brent et al. 2009), 
and at all other visits, the “Since Last Visit” version will be administered (Posner, Brent et al. 
2009). For “Since Last Visit” versions, subjects should be asked to report on ideation and 
behavior since the last scheduled C-SSRS assessment. The C-SSRS should be administered by a 
clinician trained to assess and manage suicidal ideation and behavior. 
7.3.9. 
Extrapyramidal Symptom Rating Scale – Abbreviated 
The ESRS-A is a questionnaire that assesses the severity and/or frequency of drug induced 
movement disorders (eg. Parkinsonism, dystonia, dyskinesia, and akathisia) (Chouinard and 
Margolese 2005). The investigator or designee will administer the ESRS-A scale at time points 
specified in Table 1. A sample of the ESRS-A can be found in Appendix B. 
7.3.10. 
Laboratory Assessments 
7.3.10.1. Drug Testing 
Subjects will complete a urine drug test for illicit amphetamines, barbiturates, cocaine, 
methadone, opiates, phencyclidine, at screening. A positive drug test will exclude the subject 
from the study. Repeat testing may be performed if positive results cannot be confirmed by a 
history of presumed active substance use or use of prescribed medications which account for the 
positive urine drug test results. 
7.3.10.2. Hematology, Biochemistry, and Urinalysis 
Blood and urine samples will be collected at the time points specified in Table 1 for specific 
hematology, biochemistry, and urinalysis assessments that are listed in Table 2. Samples will be 
analyzed by a central laboratory. Laboratory assessments may be repeated at the investigator’s 
discretion. 


 
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Table 2: 
Clinical Laboratory Assessments 
Hematology  
Biochemistry 
Urinalysis 
• Hematocrit 
• Hemoglobin 
• Platelets 
• Red blood cell count 
• Total and differential 
(absolute) white blood 
cell count  
• Albumin 
• Creatine phosphokinase(CPK) 
• Glucose 
• Lactic dehydrogenase (LDH) 
• Potassium 
• Sodium 
• Total protein 
• Alanine aminotransferase(ALT) 
• Alkaline phosphatase(ALK-P) 
• Aspartate 
aminotransferase(AST) 
• Gamma-glutamyl transferase 
(GGT) 
• Total bilirubin 
• Prolactin 
• Blood urea nitrogen 
• Creatinine 
• HbA1c 
• Total cholesterol 
• LDL 
• HDL 
• Triglycerides 
• TSH, at screening only 
• Bilirubin 
• Color and appearance 
• Glucose 
• Nitrite 
• Occult blood 
• pH 
• Protein 
• Specific gravity 
• Urobilinogen 
7.3.10.3. Pregnancy Testing 
Urine pregnancy testing will be completed for all women at the time points specified in Table 1. 
Pregnancy testing will be performed before administration of the first 5 mg aripiprazole test dose 
(where required) at Screening and before dosing on Day 1. 
Results must be negative for initial study eligibility and continued participation. 
7.3.11. 
Drug Dispensation and Reconciliation 
Section 8 provides information related to drug dispensing procedures. Study drug will be 
administered at the time point(s) specified in Table 1 and reviewed with the subject. 
7.3.12. 
Adverse Event Monitoring 
AEs will be monitored continuously from the time a subject signs the informed consent 
document until the completion of the final study visit (see Table 1). AEs and serious adverse 


 
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events (SAEs) are defined in Section 13.1 and 13.2, respectively. Section 13.4 provides guidance 
on the monitoring and reporting requirements for AEs. Section 13.5 provides guidance on the 
reporting requirements for SAEs. 
7.3.13. 
Efficacy Assessments 
7.3.13.1. Clinical Global Impressions-Severity 
The investigator or designee will complete the Clinical Global Impression – Severity (CGI-S) 
(Appendix C) scale (Guy 2000) at screening and at every time point as identified in Table 1. 
7.3.13.2. Brief Psychiatric Rating Scale 
The investigator or designee will complete the Brief Psychiatric Rating Scale (BPRS) 
(Appendix D) at screening and at every time point as identified in Table 1. 
7.3.14. 
Quality of Life, Daily, and Social Functioning Assessments 
7.3.14.1. Sexual Functioning Subscale from Udvalg for Kliniske Undersøgelser Side Effect 
Rating Scale 
The sexual functioning subscale from the UKU Side Effect Rating Scale (Appendix E) contains 
7 items for males and 9 items for females (Lingjaerde, Ahlfors et al. 1987, Lindstrom, Lewander 
et al. 2001). 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 patient at the time points specified in Table 1. 
7.3.14.2. Changes in Sexual Functioning Questionnaire Short Form 
The CSFQ-14 (Appendix F) is a 14-item rating scale that evaluates sexual functioning in each 
domain of the sexual response cycle (Keller, McGarvey et al. 2006). The subjects rate their 
sexual functioning on a 5-point Likert scale. Higher scores indicate more sexual dysfunction. 
The CSFQ will be completed by the patient at the time points specified in Table 1. 
7.3.14.3. Personal and Social Performance Scale 
The investigator or designee will complete the 5-point Personal and Social Performance (PSP) 
(Appendix G) scale (Patrick, Burns et al. 2009) at the time points identified in Table 1. 
7.3.14.4. Heinrichs-Carpenter Quality of Life Scale 
The QLS is a clinician-rated scale that is used to assess health-related quality of life and 
functioning in patients with schizophrenia during the preceding 4 weeks (Heinrichs, Hanlon et al. 
1984) (Appendix H). The QLS consists of 21 items in 4 major domains (Intrapsychic 
Foundations, Interpersonal Relations, Instrumental Role, and Common Objects and Activities). 
Following a semi-structured interview, each item is rated on a 7-point scale, from 0 (severe 
impairment) to 6 (normal or unimpaired functioning). The QLS will be completed at the time 
points specified in Table 1. 


 
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7.3.14.5. Negative Symptom Assessment-16  
The Negative Symptom Assessment is a clinician-rated scale that is used to evaluate the 
presence, severity, and range of the negative symptoms that often impact the quality of life of 
those with schizophrenia (Axelrod, Goldman et al. 1993) (Appendix I). The NSA-16 consists of 
16 items with 5 domains (Communication, Emotion/Affect, Social Involvement, Motivation, and 
Retardation). Each item is rated on a 6-point scale that ranges from 1 to 6 with higher scores 
indicating more severe pathology. The NSA-16 will be completed at the time points specified in 
Table 1. 
7.3.14.6. Modified Medication Satisfaction Questionnaire 
The Modified MSQ (Appendix J) is a 3-item self-report 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 versus the one taken prior 
to the study, and their opinion on the side effects of their current medication versus the one taken 
prior to the study. Ratings are on a 5-point Likert scale. The Modified MSQ will be collected at 
the time points identified in Table 1. 
7.3.15. 
Other Assessments 
7.3.15.1. Sixth edition of the Treatment Services Review (TSR-6)-Modified for Mental 
Health 
The modified TSR-6 (Appendix K) is a brief structured interview to assess specific services 
provided to patients; this version was modified for use in a patient population for chronic mental 
illness. The modified TSR-6 focuses on services for five potential problem areas: medical 
condition, employment and support, legal status, family/social relations, and psychiatric 
function. Patients are asked about the services that they received in the past 28-42 days. The 
modified TSR-6 consists of 22 items; it will be administered at the time points identified in 
Table 1. 
7.3.15.2. Caregiver Quality of Life – Burden Dimensions (7D) and Visual Analog Scale 
The CarerQOL-7D and VAS (Brouwer, van Exel et al. 2006) (Appendix L) measures care-
related quality of life in informal caregivers. The burden component utilizes 7 items to assess 
burden, and the valuation component uses a VAS to ascertain level of happiness. The burden 
items require caregivers to indicate whether they have ‘no’, ‘some’ or ‘a lot’ of problems or 
fulfillment/ support regarding the given dimension. For problem-related items, ‘no, ‘some’ and 
‘a lot’ are scored 3, 2, and 1, respectively. For fulfillment/support items, reverse scoring applies, 
so a high score indicates a high level of burden. The valuation component allows for the 
calculation of a score from 0 (completely unhappy) to 10 (completely happy). The CarerQOL-7D 
and VAS will be completed by the designated caregiver at the time points identified in Table 1. 
7.3.15.3. Burden Assessment Scale 
The Burden Assessment Scale (Appendix M) is a 19-item scale completed by the caregiver that 
focuses on specific subjective and objective consequences of families caring for individuals with 
severe mental disorders (Reinhard, Gubman et al. 1994). Respondents are required to indicate 


 
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whether they have experienced each of the types of burden - ‘Not at all’, ‘A little’, ‘Some’ or ‘A 
lot’ - in the past four weeks. These are scored 1, 2, 3, and 4 respectively. A higher score indicates 
more perceived burden. The Burden Assessment Scale will be completed by the designated 
caregiver at the time points identified in Table 1. 
7.3.15.4. Birchwood Insight Scale (BIS) 
The BIS (Appendix N) is an 8-item self-report measure addressing the three components of 
insight: awareness of illness, relabeling of symptoms (ie, attribution of one's symptoms as part of 
one's disorder), and need for treatment (Birchwood, Smith et al. 1994). Possible responses of 
"agree," "unsure," or "disagree" are scored on a Likert-type scale ranging from 0 to 2. The total 
score will be summed for a BIS total score (range = 0-16), with higher scores indicating greater 
insight. The BIS will be completed by the subject at the time points identified in Table 1. 
7.3.15.5. New York Assessment of Adverse Cognitive Effects of Neuropsychiatric 
Treatment subscales 
The NY-AACENT subscales (Appendix O) are used to detect changes in cognitive function 
subsequent to pharmacological or similar treatments for neurological or psychiatric problems 
(Opler, Antonius et al. 2015). It is comprised of seven items for the patient, seven items for the 
caregiver, and seven items for the clinician derived from these seven domains: speed of 
processing, attention/vigilance, working memory, verbal learning, visual learning, reasoning and 
problem solving, and social cognition. The NY-AACENT will be administered at the time points 
identified in Table 1. 
7.3.15.6. MINI International Neuropsychiatric Interview – Modules I and J 
The MINI is a short, clinician-administered, structured diagnostic interview for making DSM-5 
diagnoses (Appendix P). The MINI has been validated against the much longer Structured 
Clinical Interview for DSM diagnoses (SCID-5). Modules I (Alcohol Use Disorder) and J 
(Substance Use Disorder) from the MINI will be administered as shown in Table 1.  
7.4. 
Study Requirements and Restrictions 
7.4.1. 
Prohibited Medications 
Concomitant use of potent oral CYP3A4 inhibitors and CYP2D6 inhibitors is to be avoided. In 
addition, subjects with known CYP2D6 poor metabolism should not receive strong oral CYP3A4 
inhibitors during the study. During the study, dose adjustment may be necessary in the event of 
potent oral CYP2D6 inhibitor, or a CYP3A4 inhibitor or inducer, use. For example, the use of 
CYP3A4 inducers may require dose escalation. Investigators should consult the Medical Monitor 
for questions regarding any such dose adjustments. A list of common CYP3A4 inducers or 
inhibitors and CYP2D6 inhibitors is provided in Appendix Q. 
7.4.2. 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 post-menopausal (see below). The 
following are considered acceptable methods of contraception: 


 
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1. Double-barrier protection (eg, a condom with spermicide or a diaphragm with 
spermicide) 
2. Intrauterine device (IUD) 
3. Oral contraceptive pills or other hormonal methods (eg, a vaginal ring, contraceptive 
patch, contraceptive implant) 
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 or 
bilateral orchiectomy are considered surgically sterile. Partner vasectomy is not considered an 
approved acceptable method of contraception for a female subject. 
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. Pregnancy is not considered an AE, however pregnancy, whether a 
female study subject or the partner of a male study subject, must be immediately documented on 
a Pregnancy Form and faxed to 
 at the SAE reporting fax number (Section 13.5) 
within 24 hours of the investigator becoming aware of the pregnancy. Additional follow-up may 
be required. 
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8. 
TREATMENT OF SUBJECTS 
8.1. 
Study Drug Dose and Administration 
The initial dose of aripiprazole lauroxil will be selected according to the investigator's judgment 
and will be prepared and administered in accordance with the Directions for Use. 
Depending on individual patient’s needs, treatment with aripiprazole lauroxil can be initiated at a 
dose of 441 mg, 662 mg or 882 mg administered monthly, which corresponds to 300 mg, 450 mg 
and 600 mg of aripiprazole, respectively. Treatment may also be initiated with the 882 mg dose 
every 6 weeks. 
Subjects will receive their first dose of aripiprazole lauroxil no earlier than one week and not 
later than 6 weeks following their previous dose of injectable risperidone or paliperidone. Due to 
safety concerns and the potential for rapid emergence of adverse events including akathisia, 
dystonia and EPS, oral aripiprazole dosing for 21 days after the initial dose of aripiprazole 
lauroxil is not recommended. Cross-tapering patients from long acting injectable risperidone or 
paliperidone palmitate to aripiprazole lauroxil is facilitated by the gradual disappearance of 
plasma risperidone/paliperidone while aripiprazole is concomitantly released from the initial IM 
aripiprazole lauroxil injection. 
Administer aripiprazole lauroxil either in the deltoid muscle (441 mg dose only) or gluteal 
muscle (441 mg, 662 mg or 882 mg). See Table 3. 
Table 3: 
Aripiprazole Lauroxil Dosing Frequency and Site of Injection 
Dose 
Dosing Frequency 
Site of Intramuscular Injection 
441 mg 
Monthly 
Deltoid or Gluteal 
662 mg 
Monthly 
Gluteal 
882 mg 
Monthly or every 6 weeks 
Gluteal 
During the course of the study, the PI may adjust the dose of aripiprazole lauroxil. Stepwise dose 
decreases will be allowed for tolerability, accounting for the slow and prolonged release of 
aripiprazole lauroxil. Increased dose or frequency (e.g. to monthly from every 6 weeks) may be 
considered for inadequate efficacy. To allow for the gradual stepwise increase in aripiprazole 
levels with initial injections, dose increases may be performed after the second injection. 
Schedule changes, from monthly to every 6 weeks (or the reverse) will also be allowed after the 
second injection. Dose changes due to the medical need to initiate concomitant CYP modulators 
may be performed at any time if the concomitant medication is necessary for more than 2 weeks. 
After the first change, further dose or schedule changes should be made in consultation with the 
 Medical Monitor and must account for the gradual increase in plasma aripiprazole levels 
following the initial monthly doses. 
PPD


 
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Table 4 outlines the recommended starting dose for subjects who have been historically 
stabilized on oral aripiprazole: 
Table 4: 
Aripiprazole Lauroxil Doses Based on Oral Aripiprazole Total Daily Dose 
Oral Aripiprazole Dose 
Intramuscular Aripiprazole Lauroxil Dose 
10 mg 
441 mg 
15 mg 
662 mg 
20 mg or higher 
882 mg 
8.2. 
Missed Doses 
When a dose is missed, administer the next injection of aripiprazole lauroxil as soon as possible. 
If the time elapsed since the last aripiprazole lauroxil injection exceeds the length of time noted 
in Table 5, use oral aripiprazole supplementation with the next aripiprazole lauroxil injection as 
recommended below. 
Table 5: 
Recommendation for Concomitant Oral Aripiprazole Supplementation 
Following Missed Dosesa 
Dose of Patient’s Last 
Aripiprazole Lauroxil 
Injection 
Length of Time Since Last Injection 
No Oral 
Supplementation 
Required 
Supplement with 
7 Days Oral 
Aripiprazole 
Supplement with 
21 Days Oral 
Aripiprazole 
Monthly 441 mg 
≤ 6 weeks 
> 6 and ≤ 7 weeks 
> 7 weeks 
Monthly 662 mg 
≤ 8 weeks 
> 8 and ≤ 12 weeks 
> 12 weeks 
Monthly 882 mg 
≤ 8 weeks 
> 8 and ≤ 12 weeks 
> 12 weeks 
882 mg every 6 weeks 
≤ 8 weeks 
> 8 and ≤ 12 weeks 
> 12 weeks 
a Oral aripiprazole supplementation dosage may be per Table 4. 
8.3. 
Early Dosing 
The aripiprazole lauroxil injection should not be given earlier than 14 days after the previous 
injection. 


 
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8.4. 
Dose Adjustments for CYP450 Considerations 
In subjects taking strong CYP2D6 or CYP3A4 modulators the initial and subsequent dose of 
aripiprazole lauroxil should be selected based upon the recommendations of Table 6 below. 
Once stabilized on aripiprazole lauroxil, refer to the dosing recommendations below for patients 
taking CYP2D6 inhibitors, CYP3A4 inhibitors, or CYP3A4 inducers: 
• No dosage changes recommended for aripiprazole lauroxil, if CYP450 modulators are 
added for less than 2 weeks. 
• Make dose changes to aripiprazole lauroxil if CYP450 modulators are added for greater 
than 2 weeks (see Table 6). 
Table 6: 
Aripiprazole Lauroxil Dose Adjustments with Concomitant CYP450 
Modulator Use 
Concomitant Medicine 
Dose Change for ARIPIPRAZOLE LAUROXILa 
Strong CYP3A4 Inhibitor 
Reduce the dose of ARIPIPRAZOLE LAUROXIL to the next lower 
strength. No dosage adjustment is necessary in patients taking 441 mg 
ARIPIPRAZOLE LAUROXIL, if tolerated. 
For patients known to be poor metabolizers of CYP2D6: Reduce dose to 
441 mg from both higher doses. No dosage adjustment is necessary in 
patients taking 441 mg ARIPIPRAZOLE LAUROXIL, if tolerated. 
Strong CYP2D6 Inhibitor 
Reduce the dose of ARIPIPRAZOLE LAUROXIL to the next lower 
strength. No dosage adjustment is necessary in patients taking 441 mg 
ARIPIPRAZOLE LAUROXIL, if tolerated. 
For patients known to be poor metabolizers of CYP2D6: No dose 
adjustment required. 
Both Strong CYP3A4 
Inhibitor and Strong 
CYP2D6 Inhibitor 
Avoid use for patients at 662 mg or 882 mg dose. No dosage adjustment is 
necessary in patients taking 441 mg ARIPIPRAZOLE LAUROXIL, if 
tolerated. 
For patients known to be poor metabolizers of CYP2D6: Same as for 
extensive metabolizers. 
CYP3A4 Inducers 
No dose adjustment for 662 mg and 882 mg dose, increase the 441 mg dose 
to 662 mg. 
For patients known to be poor metabolizers of CYP2D6: Same as for 
extensive metabolizers. 
a For the 882 mg dose administered every 6 weeks, the next lower strength should be 441 mg administered every 
4 weeks. 
Augmentation with oral antipsychotics is permitted per clinical judgment and should be recorded 
as a concomitant medication separately from other concomitant medications. 
Sites must have written procedures in place detailing the healthcare personnel required to be on 
site during subject dosing, the availability of equipment and medications necessary to treat an 
emergency (should it occur), and the process for transferring a subject to a medical facility if 
necessary. 


 
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8.5. 
Oral Aripiprazole Test Doses 
Oral aripiprazole for use as test doses during screening is an approved antipsychotic marketed 
under the trade name Abilify® (Bristol-Myers Squibb 2016). The first test dose will be 
administered in the clinic. 
Oral test doses of aripiprazole are in 5 mg tablet form. 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 Abilify. 
Aripiprazole for use as oral aripiprazole test doses will be commercially available Abilify® 5 mg 
tablets (Bristol-Myers Squibb 2016) or aripiprazole obtained from a local commercial source, 
provided in commercial packaging provided to the site by Alkermes. 
8.6. 
Treatment Adherence 
All study drug injections will be directly administered by clinical study staff. Study staff will 
address non-adherence with the subject as needed. 
8.7. 
Blinding 
Not applicable. The study is open-label. 


 
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9. 
STUDY DRUG MATERIALS AND MANAGEMENT 
9.1. 
Study Drugs 
The product in this study is aripiprazole lauroxil, a covalently bonded modification of 
aripiprazole to form N-lauroyloxymethyl aripiprazole. 
Detailed information about aripiprazole lauroxil can be found in the Aripiprazole Lauroxil 
Investigator’s Brochure (IB). 
9.2. 
Accountability 
The clinical 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. 
9.3. 
Handling and Disposal 
Following completion and verification of accountability logs, all unused and used packages must 
be destroyed. Packages may be destroyed on site according to Good Clinical Practice (GCP) and 
site practice. Alternatively, the sponsor may arrange for destruction with a third party vendor 
operating in accordance with GCP and/or Good Manufacturing Practice (GMP), as applicable. 


 
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10. 
ASSESSMENT OF EFFICACY 
Efficacy will be evaluated based on Clinical Global Impressions-Severity (CGI-S) and Brief 
Psychiatric Rating Scale (BPRS) responses. 


 
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11. 
QUALITY OF LIFE, DAILY AND SOCIAL FUNCTIONING 
The following assessments will be collected to characterize any change in quality of life, 
including daily and social functioning, after treatment with aripiprazole lauroxil: 
− Heinrichs-Carpenter Quality of Life Scale (QLS) 
− Negative Symptom Assessment-16 (NSA-16) 
− Sexual functioning subscale from UKU Side Effect Rating Scale and CSFQ 
scores 
− Personal and Social Performance scale (PSP) 
− Total and individual items scores of the Modified MSQ 


 
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12. 
OTHER ASSESSMENTS 
The following assessments will be collected to explore potential changes in healthcare burden, 
cognition, insight, and psychosocial care needs following a transition to aripiprazole lauroxil: 
• Health economics 
− Total healthcare costs as measured by TSR-6-Modified for Mental Health 
• Functional Assessment 
− BIS 
• Family Measures 
− CarerQOL–7D and VAS 
− Burden Assessment Scale 
• Investigator- and Caregiver-Rated Cognition 
− Respective NY-AACENT subscales 
• Substance Use 
− M.I.N.I. Module I (alcohol use disorder) 
− M.I.N.I. Module J (substance use disorder) 


 
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13. 
ASSESSMENT OF SAFETY AND TOLERABILITY 
The following safety and tolerability measures will be assessed throughout the study and 
summarized: 
• AEs 
• Injection site reactions 
• Vital signs (blood pressure, heart rate, respiratory rate, and body temperature), and 
waist circumference and weight 
• Clinical laboratory parameters (chemistry [including prolactin], hematology, and 
urinalysis) (Table 2) 
• C-SSRS responses 
• ESRS-A scores 
13.1. 
Definition of Adverse Event 
An AE is any untoward medical occurrence in a patient or clinical investigation subject 
administered a pharmaceutical product. The occurrence, which may or may not have a causal 
relationship with the 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 informed consent form (ICF) are considered to 
be pre-existing 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 recorded 
as such on the eCRFs. 
Pregnancy alone is not considered an AE, although a female subject will be withdrawn from 
study drug treatment if a pregnancy occurs. If a pregnancy occurs in the partner of a male 
subject, it is not required that the male be withdrawn from study drug; however, contraceptive 
requirements should be revisited. As described in Section 7.4.2, the pregnancy must be reported 
to Alkermes and additional follow-up may be required. 
13.2. 
Definition of Serious Adverse Event 
An SAE is any AE, occurring at any dose and regardless of causality that: 
• 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. 


 
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• Requires inpatient hospitalization or prolongation of existing hospitalization. Hospital 
admission for elective surgery scheduled prior to study entry is not considered an 
SAE. 
• Results in 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, 
they may jeopardize the patient or subject and may require intervention to prevent one of the 
other outcomes listed above. 
13.3. 
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 
sub-investigator) according to his/her best clinical judgment. The criteria listed in Table 7 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 7: 
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. 
13.4. 
Monitoring and Recording of Adverse Events 
AE data collection will begin after a subject signs the ICF and will continue until completion of 
the End of Treatment/Early Termination visit (Day 169). Any AE or SAE having an onset after 
the End of Treatment/Early Termination 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 13.3), 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. 
13.5. 
Reporting of Serious Adverse Events 
All SAEs must be reported to Alkermes, via 
 within 1 business day of 
discovery, by faxing the report to the following: 
Attention: 
 Drug Safety 
PHONE Number: 
 
FAX Number: 
 
FAX Number: 
 
 
The written report should be submitted on the SAE form provided for this purpose. The 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. 
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14. 
STATISTICS 
14.1. 
Sample Size Considerations 
No formal sample size calculations have been performed. The sample size is based on clinical 
considerations. 
14.2. 
General Statistical Methodology 
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. 
14.2.1. 
Study Population 
The safety population will include all subjects who received at least one dose of aripiprazole 
lauroxil injection. All analyses will be carried out using the safety population. 
14.3. 
Demographics and Baseline Data 
Demographics and baseline characteristics such as gender, age, race, weight, height, and BMI 
will be summarized using descriptive statistics. Medical history will be summarized using the 
number of observations and percentage of subjects reporting each category. 
14.4. 
Efficacy Analyses 
The change from baseline in CGI-S and BPRS scores at each post-baseline visit will be 
summarized. 
14.5. 
Safety and Tolerability Analysis 
The safety analysis will be carried out using the safety population. Reported AE terms will be 
coded using the Medical Dictionary for Regulatory Activities (MedDRA). 
The number and percentage of TEAEs will be summarized by treatment group and overall by 
system organ class, and preferred terms within each system organ class. Serious adverse events 
(SAEs) and AEs resulting in treatment discontinuation will also be summarized. 
Observed values and change from baseline in vital signs, clinical laboratory data, and ESRS 
scores will be summarized 
Shift tables and potential clinical significance tables, along with supporting listings, will be 
provided for selected parameters. 
Prior and concomitant medication use will be summarized by World Health Organization Drug 
Dictionary Anatomical Therapeutic Class code and treatment group. 
Listings will be provided for all safety endpoints. 
Additional details on the safety analysis will be provided in the Statistical Analysis Plan. 


 
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14.6. 
Analyses of Other Assessments 
Data on quality of life, social functioning, functional assessment, and family measures will be 
summarized using the safety population. 


 
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15. 
DIRECT ACCESS TO SOURCE DATA/DOCUMENTS 
15.1. 
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. 
15.2. 
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 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, 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 Conference on Harmonisation (ICH), and any applicable regulatory requirements. 
The investigator should contact Alkermes immediately if contacted by a regulatory agency 
regarding an inspection. 
15.3. 
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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16. 
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 15.2 for details regarding the audit process. 
16.1. 
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. 
16.2. 
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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17. 
ETHICAL CONSIDERATIONS 
17.1. 
Ethics Review 
The clinical 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 drug will be released to 
the investigator. The protocol must be re-approved 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 a drug safety report 
must be immediately reported. For this study, submissions to the central IRB will be completed 
on behalf of the sites by 
 as outlined in the study-specific regulatory and safety 
management plans. 
All relevant correspondence from the IRB/IEC will be filed at the site and collected by the 
Alkermes monitor or designated representative for inclusion in the Trial Master File (TMF) in a 
timely fashion. 
17.2. 
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. GCP 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. 
17.3. 
Written Informed Consent 
The investigator (or authorized designee) at each center will ensure that the subject (or the 
subject’s legal representative) and reliable informant is given full and adequate oral and written 
information about the nature, purpose, potential and possible risks and benefits of the study. 
Each prospective subject and informant will receive an IRB-approved informed consent form 
(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 informant and must not include any language that waives the 
subject’s/informant’s legal rights. Prospective subjects/informants must also be informed of their 
right to withdraw consent without prejudice at any time during the study. If the subject/informant 
chooses to participate, he/she must sign the ICF before any study-specific procedures are 
conducted. 
All subjects/informants 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 contract research organization (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 
PPD


 
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will also be informed that the study 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. 
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/informant. 


 
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18. 
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. 
18.1. 
Data Capture 
As stated in Section 16.1, 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 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 recorded 
as such on the eCRFs. 
AEs will be coded using MedDRA. Concomitant medications will be categorized using the 
WHO-ATC classification system. 
18.2. 
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 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. 
18.3. 
Retention of Records 
Retention and storage of essential clinical study documents (eg, worksheets, drug accountability 
forms, and other administrative documentation) shall be governed by the terms and conditions of 
the site’s CSA. If the CSA does not state specific document retention terms, then the site shall 
keep essential clinical study documentation for the longer of: 
• Ten years after discontinuation of the study, or 
• Two years following the date a marketing application is approved for the study drug 
for the indication for which it is being investigated pursuant to the study, or 
• If no application is to be filed or if the application is not approved for such indication, 
until 2 years after the date the study is terminated. 
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. 


 
Alkermes, Inc. 
Protocol ALK9072-A401 1.0 (Amendment 1.0) 
CONFIDENTIAL 
 
Page 52 
18.4. 
Use of Information and Publication Policy 
Data generated in this study are proprietary information that is 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. 


 
Alkermes, Inc. 
Protocol ALK9072-A401 1.0 (Amendment 1.0) 
CONFIDENTIAL 
 
Page 53 
19. 
REFERENCES 
American Psychiatric Association (2013). Diagnostic and Statistical Manual of Mental Disorders 
(DSM-5). Washington, DC. 
Axelrod, B. N., R. S. Goldman and L. D. Alphs (1993). "Validation of the 16-item Negative 
Symptom Assessment." J Psychiatr. Res 27(3): 253-258. 
Birchwood, M., J. Smith, V. Drury, J. Healy, F. Macmillan and M. Slade (1994). "A self-report 
Insight Scale for psychosis: reliability, validity and sensitivity to change." Acta Psychiatr Scand 
89(1): 62-67. 
Bristol-Myers Squibb, O. P. C. (2016, 2016). "Prescribing Information: Abilify (aripiprazole), 
2016-08." 
Brouwer, W. B., N. J. van Exel, G. B. van and W. K. Redekop (2006). "The CarerQol 
instrument: a new instrument to measure care-related quality of life of informal caregivers for 
use in economic evaluations." Qual Life Res 15(6): 1005-1021. 
Chouinard, G. and H. C. Margolese (2005). "Manual for the Extrapyramidal Symptom Rating 
Scale (ESRS)." Schizophr Res 76(2-3): 247-265. 
Guy, W. (2000). Clinical Global Impressions (CGI) Scale. Handbook of Psychiatric Measures. J. 
Rush, H. A. Pincus, M. B. First et al. Washington, DC, APA: 100-102. 
Heinrichs, D. W., T. E. Hanlon and W. T. Carpenter, Jr. (1984). "The Quality of Life Scale: an 
instrument for rating the schizophrenic deficit syndrome." Schizophr Bull 10(3): 388-398. 
Keller, A., E. L. McGarvey and A. H. Clayton (2006). "Reliability and construct validity of the 
Changes in Sexual Functioning Questionnaire short-form (CSFQ-14)." J Sex Marital Ther 32(1): 
43-52. 
Lindstrom, E., T. Lewander, U. Malm, U. F. Malt, H. Lublin and U. G. Ahlfors (2001). "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)." Nord J Psychiatry 
55 Suppl 44: 5-69. 
Lingjaerde, O., U. G. Ahlfors, P. Bech, S. J. Dencker and K. Elgen (1987). "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 Psychiatr Scand Suppl 334: 1-100. 
Opler, M., D. Antonius and C. Correll (2015). New York Assessment of Adverse Cognitive 
Effects of Neuropsychiatric Treatment - Revised (NY-AACENT-R), Unpublished Rating 
Instrument. 
Patrick, D. L., T. Burns, P. Morosini, M. Rothman, D. D. Gagnon, D. Wild and I. Adriaenssen 
(2009). "Reliability, validity and ability to detect change of the clinician-rated Personal and 


 
Alkermes, Inc. 
Protocol ALK9072-A401 1.0 (Amendment 1.0) 
CONFIDENTIAL 
 
Page 54 
Social Performance scale in patients with acute symptoms of schizophrenia." Curr. Med. Res. 
Opin 25(2): 325-338. 
Posner, K., D. Brent, C. Lucas, M. Gould, B. Stanley, G. Brown, P. Fisher, J. Zelazny, A. Burke, 
M. Oquendo and J. Mann (2009). Columbia-Suicide Severity Rating Scale (C-SSRS): 
Baseline/Screening Version. New York, NY, New York State Psychiatric Institute. 
Posner, K., D. Brent, C. Lucas, M. Gould, B. Stanley, G. Brown, P. Fisher, J. Zelazny, A. Burke, 
M. Oquendo and J. Mann (2009). Columbia-Suicide Severity Rating Scale (C-SSRS): Since last 
visit. New York, NY, New York State Psychiatric Institute. 
Reinhard, S. C., G. D. Gubman, A. V. Horwitz and S. Minsky (1994). "Burden assessment scale 
for families of the seriously mentally ill." Evaluation and Program Planning 17(3): 261-269. 
 


 
Alkermes, Inc. 
Protocol ALK9072-A401 1.0 (Amendment 1.0) 
CONFIDENTIAL 
 
Page 55 
APPENDICES 
Appendix A. 
Columbia Suicide Severity Rating Scale (Sample) 
Appendix B. 
Extrapyramidal Symptom Rating Scale – Abbreviated (ESRS-A) (Sample) 
Appendix C. 
Clinical Global Impressions-Severity (CGI-S) (Sample) 
Appendix D. 
Brief Psychiatric Rating Scale (BPRS) (Sample) 
Appendix E. 
Sexual Functioning Subscale from Udvalg for Kliniske Undersøgelser (UKU) Side Effect 
Rating Scale (Sample) 
Appendix F. 
Changes in Sexual Functioning Questionnaire (Sample) 
Appendix G. 
Personal and Social Performance Scale (PSP) (Sample) 
Appendix H. 
Heinrichs-Carpenter Quality of Life Scale (QLS) (Sample) 
Appendix I. 
Negative Symptom Assessment-16 (NSA-16) (Sample) 
Appendix J. 
Modified Medication Satisfaction Questionnaire (Modified MSQ) (Sample) 
Appendix K. 
Sixth Edition of the Treatment Services Review (TSR-6) (Sample) 
Appendix L. 
Caregiver Quality of Life (CarerQOL) – Burden Dimensions (7D) [Brouwer WBF, 2006] 
and Visual Analog Scale (VAS) (Sample) 
Appendix M. 
Burden Assessment Scale (Sample) 
Appendix N. 
Birchwood Insight Scale (BIS) (Sample) 
Appendix O. 
New York Assessment of Adverse Cognitive Effects of Neuropsychiatric Treatment 
(NY-AACENT) Subscales (Sample) 
Appendix P. 
Mini International Neuropsychiatric Interview (M.I.N.I.) – Modules I and J (Sample) 
Appendix Q. 
List of Potent Cytochrome P450 3A4 (CYP3A4) Inducers and Moderate-to-Strong 
Inhibitors of 3A4 or 2D6 
 


 
CONFIDENTIAL 
Clinical Protocol Amendment 1.0 (Amendment 1.0) 
Alkermes, Inc. 
 
APPENDIX A. COLUMBIA SUICIDE SEVERITY RATING SCALE 
(SAMPLE) 
Page 56


For Review Only
COLUMBIA-SUICIDE SEVERITY
RATING SCALE
(C-SSRS) 
Baseline 
Version 1/14/09 
Posner, K.; Brent, D.; Lucas, C.; Gould, M.; Stanley, B.; Brown, G.; Fisher, P.; Zelazny, J.; 
Burke, A.; Oquendo, M.; Mann, J.
 
Disclaimer: 
This scale is intended to be used by individuals who have received training in its administration. The questions contained 
in the Columbia-Suicide Severity Rating Scale are suggested probes. Ultimately, the determination of the presence of 
suicidal ideation or behavior depends on the judgment of the individual administering the scale. 
Definitions of behavioral suicidal events in this scale are based on those used in The Columbia Suicide History 
Form, developed by John Mann, MD and Maria Oquendo, MD, Conte Center for the Neuroscience of Mental Disorders 
(CCNMD), New York State Psychiatric Institute, 1051 Riverside Drive, New York, NY, 10032. (Oquendo M. A., 
Halberstam B. & Mann J. J., Risk factors for suicidal behavior: utility and limitations of research instruments. In M.B. First 
[Ed.] Standardized Evaluation in Clinical Practice, pp. 103 -130, 2003.) 
 
For reprints of the C-SSRS contact 
 New York State Psychiatric Institute, 1051 Riverside Drive, New 
York, New York, 10032; inquiries and training requirements contact 
© 2008 The Research Foundation for Mental Hygiene, Inc. 
Page 57
PPD
PPD


For Review Only
SUICIDAL IDEATION 
Ask questions 1 and 2.  If both are negative, proceed to “Suicidal Behavior” section. If the answer to question 2 is “yes”, 
ask questions 3, 4 and 5.  If the answer to question 1 and/or 2 is “yes”, complete “Intensity of Ideation” section below.
Lifetime:  
Time He/She 
Felt Most 
Suicidal
1.  Wish to be Dead
Subject endorses thoughts about a wish to be dead or not alive anymore, or wish to fall asleep and not wake up.  
Have you wished you were dead or wished you could go to sleep and not wake up?  
 
 
 
If yes, describe: 
 
Yes       No 
      
2.  Non-Specific Active Suicidal Thoughts
General, non-specific thoughts of wanting to end one’s life/commit suicide (e.g., “I’ve thought about killing myself”) without thoughts of ways to kill 
oneself/associated methods, intent, or plan.  
Have you actually had any thoughts of killing yourself? 
If yes, describe: 
 Yes      No 
     Κ
3.  Active Suicidal Ideation with Any Methods (Not Plan) without Intent to Act 
Subject endorses thoughts of suicide and has thought of at least one method during the assessment period. This is different than a specific plan with time, 
place or method details worked out (e.g., thought of method to kill self but not a specific plan).  Includes person who would say, “I thought about taking an 
overdose but I never made a specific plan as to when, where or how I would actually do it…and I would never go through with it.”
Have you been thinking about how you might do this? 
If yes, describe: 
 
 Yes      No 
     Κ
4.  Active Suicidal Ideation with Some Intent to Act, without Specific Plan 
Active suicidal thoughts of killing oneself and subject reports having some intent to act on such thoughts, as opposed to “I have the thoughts but I 
definitely will not do anything about them.” 
Have you had these thoughts and had some intention of acting on them?
If yes, describe: 
 
Yes       No 
     Κ
5.  Active Suicidal Ideation with Specific Plan and Intent 
Thoughts of killing oneself with details of plan fully or partially worked out and subject has some intent to carry it out. 
Have you started to work out or worked out the details of how to kill yourself? Do you intend to carry out this plan? 
If yes, describe: 
 Yes      No 
     Κ
INTENSITY OF IDEATION 
The following features should be rated with respect to the most severe type of ideation (i.e., 1-5 from above, with 1 being the least severe 
and 5 being the most severe). Ask about time he/she was feeling the most suicidal.  
                                             
Most Severe Ideation:         
                                                 _____                      _________________________________________________ 
                                                                                                    Type # (1-5)                                         Description of  Ideation
Most 
Severe 
Frequency 
How many times have you had these thoughts?  
(1) Less than once a week    (2) Once a week   (3)  2-5 times in week    (4) Daily or almost daily    (5) Many times each day
____
Duration 
When you have the thoughts, how long do they last? 
(1) Fleeting - few seconds or minutes                                                 (4) 4-8 hours/most of day 
(2) Less than 1 hour/some of the time                                                 (5) More than 8 hours/persistent or continuous
(3) 1-4 hours/a lot of time 
____
Controllability 
Could/can you stop thinking about killing yourself or wanting to die if you want to? 
(1) Easily able to control thoughts                                                      (4) Can control thoughts with a lot of difficulty 
(2) Can control thoughts with little difficulty                                     (5) Unable to control thoughts 
(3) Can control thoughts with some difficulty                                    (0) Does not attempt to control thoughts
____
Deterrents 
Are there things - anyone or anything (e.g., family, religion, pain of death) - that stopped you from wanting to die or acting on
thoughts of committing suicide? 
(1) Deterrents definitely stopped you from attempting suicide            (4) Deterrents most likely did not stop you  
(2) Deterrents probably stopped you                                                    (5) Deterrents definitely did not stop you
(3) Uncertain that deterrents stopped you                                             (0) Does not apply 
____
Reasons for Ideation 
What sort of reasons did you have for thinking about wanting to die or killing yourself?  Was it to end the pain or stop the way
you were feeling (in other words you couldn’t go on living with this pain or how you were feeling) or was it to get attention, 
revenge or a reaction from others? Or both? 
(1) Completely to get attention, revenge or a reaction from others       (4) Mostly to end or stop the pain (you couldn’t go on
(2) Mostly to get attention, revenge or a reaction from others                     living with the pain or how you were feeling)
(3) Equally to get attention, revenge or a reaction from others               (5) Completely to end or stop the pain (you couldn’t go on  
       and to end/stop the pain.                                                                        living with the pain or  how you were feeling) 
                                                                                                                 (0)  Does not apply 
____
Version 1/14/09 
Page 58


For Review Only
SUICIDAL BEHAVIOR
(Check all that apply, so long as these are separate events; must ask about all types) 
 
Lifetime  
Actual Attempt:
A potentially self-injurious act committed with at least some wish to die, as a result of act. Behavior was in part thought of as method to kill oneself. Intent 
does not have to be 100%.  If there is any intent/desire to die associated with the act, then it can be considered an actual suicide attempt. There does not 
have to be any injury or harm, just the potential for injury or harm. If person pulls trigger while gun is in mouth but gun is broken so no injury results, 
this is considered an attempt.   
Inferring Intent: Even if an individual denies intent/wish to die, it may be inferred clinically from the behavior or circumstances. For example, a highly lethal 
act that is clearly not an accident so no other intent but suicide can be inferred (e.g., gunshot to head, jumping from window of a high floor/story). Also, if 
someone denies intent to die, but they thought that what they did could be lethal, intent may be inferred.  
Have you made a suicide attempt? 
Have you done anything to harm yourself? 
Have you done anything dangerous where you could have died? 
What did you do? 
Did you______ as a way to end your life?  
Did you want to die (even a little) when you_____?  
Were you trying to end your life when you _____? 
Or did you think it was possible you could have died from_____? 
Or did you do it purely for other reasons / without ANY intention of killing yourself (like to relieve stress, feel better, get sympathy,
or get something else to happen)? (Self-Injurious Behavior without suicidal intent)
If yes, describe: 
 
 
Has subject engaged in Non-Suicidal Self-Injurious Behavior? 
 
Yes      No 
   Κ
Total # of 
Attempts 
______
 
 
 
 
 
 
Yes    No 
   Κ
Interrupted Attempt:
When the person is interrupted (by an outside circumstance) from starting the potentially self-injurious act (if not for that, actual attempt would have 
occurred).
Overdose: Person has pills in hand but is stopped from ingesting.  Once they ingest any pills, this becomes an attempt rather than an interrupted attempt. 
Shooting: Person has gun pointed toward self, gun is taken away by someone else, or is somehow prevented from pulling trigger. Once they pull the trigger, 
even if the gun fails to fire, it is an attempt. Jumping: Person is poised to jump, is grabbed and taken down from ledge. Hanging: Person has noose around neck 
but has not yet started to hang - is stopped from doing so. 
Has there been a time when you started to do something to end your life but someone or something stopped you before you 
actually did anything? 
If yes, describe: 
 
Yes      No 
    
 
 
Total # of 
interrupted
______
Aborted Attempt:   
When person begins to take steps toward making a suicide attempt, but stops themselves before they actually have engaged in any self-destructive behavior. 
Examples are similar to interrupted attempts, except that the individual stops him/herself, instead of being stopped by something else. 
Has there been a time when you started to do something to try to end your life but you stopped yourself before you actually did
anything?
If yes, describe: 
 
Yes      No 
    
 
Total # of 
aborted 
______
Preparatory Acts or Behavior: 
Acts or preparation towards imminently making a suicide attempt. This can include anything beyond a verbalization or thought, such as assembling a specific 
method (e.g., buying pills, purchasing a gun) or preparing for one’s death by suicide (e.g., giving things away, writing a suicide note).  
Have you taken any steps towards making a suicide attempt or preparing to kill yourself (such as collecting pills, getting a gun,
giving valuables away or writing a suicide note)?
If yes, describe: 
 
Yes      No 
   Κ
Suicidal Behavior:
Suicidal behavior was present during the assessment period? 
Yes      No 
   Κ
Answer for Actual Attempts Only
Most Recent
Attempt 
Date:
Most Lethal         
Attempt 
Date:
Initial/First
Attempt 
Date:
Actual Lethality/Medical Damage:   
0.  No physical damage or very minor physical damage (e.g., surface scratches). 
1.  Minor physical damage (e.g., lethargic speech; first-degree burns; mild bleeding; sprains). 
2.  Moderate physical damage; medical attention needed (e.g., conscious but sleepy, somewhat responsive; second-degree 
burns; bleeding of major vessel). 
3.  Moderately severe physical damage; medical hospitalization and likely intensive care required (e.g., comatose with 
reflexes intact; third-degree burns less than 20% of body; extensive blood loss but can recover; major fractures). 
4.  Severe physical damage; medical hospitalization with intensive care required (e.g., comatose without reflexes; third-
degree burns over 20% of body; extensive blood loss with unstable vital signs; major damage to a vital area). 
5.  Death 
Enter Code 
______
Enter Code 
______
Enter Code 
______
Potential Lethality: Only Answer if Actual Lethality=0 
Likely lethality of actual attempt if no medical damage (the following examples, while having no actual medical damage, 
had potential for very serious lethality: put gun in mouth and pulled the trigger but gun fails to fire so no medical damage; 
laying on train tracks with oncoming train but pulled away before run over). 
0 = Behavior not likely to result in injury 
1 = Behavior likely to result in injury but not likely to cause death 
2 = Behavior likely to result in death despite available medical care  
Enter Code 
______
Enter Code 
______
Enter Code 
______
Page 59


For Review Only
COLUMBIA-SUICIDE SEVERITY
RATING SCALE
(C-SSRS) 
Since Last Visit 
Version 1/14/09 
Posner, K.; Brent, D.; Lucas, C.; Gould, M.; Stanley, B.; Brown, G.; Fisher, P.; Zelazny, J.; 
Burke, A.; Oquendo, M.; Mann, J.
 
Disclaimer: 
This scale is intended to be used by individuals who have received training in its administration. The questions contained in 
the Columbia-Suicide Severity Rating Scale are suggested probes. Ultimately, the determination of the presence of suicidal 
ideation or behavior depends on the judgment of the individual administering the scale. 
Definitions of behavioral suicidal events in this scale are based on those used in The Columbia Suicide History Form, 
developed by John Mann, MD and Maria Oquendo, MD, Conte Center for the Neuroscience of Mental Disorders 
(CCNMD), New York State Psychiatric Institute, 1051 Riverside Drive, New York, NY, 10032. (Oquendo M. A., 
Halberstam B. & Mann J. J., Risk factors for suicidal behavior: utility and limitations of research instruments. In M.B. First 
[Ed.] Standardized Evaluation in Clinical Practice, pp. 103 -130, 2003.) 
 
For reprints of the C-SSRS contact 
 New York State Psychiatric Institute, 1051 Riverside Drive, New 
York, New York, 10032; inquiries and training requirements contact 
 
© 2008 The Research Foundation for Mental Hygiene, Inc. 
Page 60
PPD
PPD


For Review Only
SUICIDAL IDEATION
Ask questions 1 and 2.  If both are negative, proceed to “Suicidal Behavior” section. If the answer to question 2 is “yes”,
ask questions 3, 4 and 5.  If the answer to question 1 and/or 2 is “yes”, complete “Intensity of Ideation” section below.
Since Last 
Visit
1.  Wish to be Dead
Subject endorses thoughts about a wish to be dead or not alive anymore, or wish to fall asleep and not wake up. 
Have you wished you were dead or wished you could go to sleep and not wake up? 
If yes, describe:
Yes
No
□  □
2.  Non-Specific Active Suicidal Thoughts
General, non-specific thoughts of wanting to end one’s life/commit suicide (e.g., “I’ve thought about killing myself”) without thoughts of ways to kill 
oneself/associated methods, intent, or plan during the assessment period. 
Have you actually had any thoughts of killing yourself?
If yes, describe:
Yes      No
□    □
3.  Active Suicidal Ideation with Any Methods (Not Plan) without Intent to Act
Subject endorses thoughts of suicide and has thought of at least one method during the assessment period. This is different than a specific plan with time, 
place or method details worked out (e.g., thought of method to kill self but not a specific plan).  Includes person who would say, “I thought about taking an
overdose but I never made a specific plan as to when, where or how I would actually do it…and I would never go through with it.”
Have you been thinking about how you might do this?
If yes, describe:
Yes      No
□  □
4.  Active Suicidal Ideation with Some Intent to Act, without Specific Plan
Active suicidal thoughts of killing oneself and subject reports having some intent to act on such thoughts, as opposed to “I have the thoughts but I 
definitely will not do anything about them.”
Have you had these thoughts and had some intention of acting on them?
If yes, describe:
Yes    No
□   □
5.  Active Suicidal Ideation with Specific Plan and Intent
Thoughts of killing oneself with details of plan fully or partially worked out and subject has some intent to carry it out.
Have you started to work out or worked out the details of how to kill yourself? Do you intend to carry out this plan?
   
If yes, describe:
Yes     No
□  □
INTENSITY OF IDEATION
The following features should be rated with respect to the most severe type of ideation (i.e., 1-5 from above, with 1 being the least severe 
and 5 being the most severe). 
                                            
Most Severe Ideation:             _____                      _________________________________________________
                                             
                                                                                                          Type # (1-5)                                         Description of  Ideation
Most
Severe
Frequency
How many times have you had these thoughts?
(1) Less than once a week    (2) Once a week   (3)  2-5 times in week    (4) Daily or almost daily    (5) Many times each day
____
Duration
When you have the thoughts, how long do they last?
(1) Fleeting - few seconds or minutes                                             
(4) 4-8 hours/most of day
(2) Less than 1 hour/some of the time                                                 (5) More than 8 hours/persistent or continuous
(3) 1-4 hours/a lot of time                                                                   
____
Controllability
Could/can you stop thinking about killing yourself or wanting to die if you want to?
(1) Easily able to control thoughts                                                      (4) Can control thoughts with a lot of difficulty
(2) Can control thoughts with little difficulty                                   (5) Unable to control thoughts
(3) Can control thoughts with some difficulty                                   (0) Does not attempt to control thoughts
____
Deterrents
Are there things - anyone or anything (e.g., family, religion, pain of death) - that stopped you from wanting to die or acting on 
thoughts of committing suicide?
(1) Deterrents definitely stopped you from attempting suicide            (4) Deterrents most likely did not stop you 
(2) Deterrents probably stopped you                                                
(5) Deterrents definitely did not stop you 
(3) Uncertain that deterrents stopped you                                            (0) Does not apply
____
Reasons for Ideation
What sort of reasons did you have for thinking about wanting to die or killing yourself?  Was it to end the pain or stop the way 
you were feeling (in other words you couldn’t go on living with this pain or how you were feeling) or was it to get attention,
revenge or a reaction from others? Or both?
(1) Completely to get attention, revenge or a reaction from others       (4) Mostly to end or stop the pain (you couldn’t go on
(2) Mostly to get attention, revenge or a reaction from others                     living with the pain or how you were feeling)
(3) Equally to get attention, revenge or a reaction from others               (5) Completely to end or stop the pain (you couldn’t go on 
       and to end/stop the pain                                                                         living with the pain or  how you were feeling)
                                                                                                                 (0) Does not apply
____
© 2008 Research Foundation for Mental Hygiene, Inc.
C-SSRS—Since Last Visit (Version 1/14/09)   
Page 61


For Review Only
SUICIDAL BEHAVIOR
(Check all that apply, so long as these are separate events; must ask about all types)
Since Last 
Visit
Actual Attempt:
A potentially self-injurious act committed with at least some wish to die, as a result of act. Behavior was in part thought of as method to kill oneself. Intent 
does not have to be 100%.  If there is any intent/desire to die associated with the act, then it can be considered an actual suicide attempt. There does not 
have to be any injury or harm, just the potential for injury or harm. If person pulls trigger while gun is in mouth but gun is broken so no injury results,
this is considered an attempt.  
Inferring Intent: Even if an individual denies intent/wish to die, it may be inferred clinically from the behavior or circumstances. For example, a highly 
lethal act that is clearly not an accident so no other intent but suicide can be inferred (e.g., gunshot to head, jumping from window of a high floor/story). 
Also, if someone denies intent to die, but they thought that what they did could be lethal, intent may be inferred. 
Have you made a suicide attempt?
Have you done anything to harm yourself?
Have you done anything dangerous where you could have died?
What did you do?
Did you______ as a way to end your life? 
Did you want to die (even a little) when you_____? 
Were you trying to end your life when you _____?
Or did you think it was possible you could have died from_____?
Or did you do it purely for other reasons / without ANY intention of killing yourself (like to relieve stress, feel better, get
sympathy, or get something else to happen)? (Self-Injurious Behavior without suicidal intent)
If yes, describe:
Has subject engaged in Non-Suicidal Self-Injurious Behavior?
Yes      No
□   □
Total # of
Attempts
______
Yes
No
□   □
Interrupted Attempt:
When the person is interrupted (by an outside circumstance) from starting the potentially self-injurious act (if not for that, actual attempt would have 
occurred).
Overdose: Person has pills in hand but is stopped from ingesting.  Once they ingest any pills, this becomes an attempt rather than an interrupted attempt. 
Shooting: Person has gun pointed toward self, gun is taken away by someone else, or is somehow prevented from pulling trigger. Once they pull the trigger, 
even if the gun fails to fire, it is an attempt. Jumping: Person is poised to jump, is grabbed and taken down from ledge. Hanging: Person has noose around 
neck but has not yet started to hang - is stopped from doing so.
Has there been a time when you started to do something to end your life but someone or something stopped you before you 
actually did anything?
If yes, describe:
Yes      No
□   □
Total # of 
interrupted
______
Aborted Attempt:  
When person begins to take steps toward making a suicide attempt, but stops themselves before they actually have engaged in any self-destructive behavior. 
Examples are similar to interrupted attempts, except that the individual stops him/herself, instead of being stopped by something else.
Has there been a time when you started to do something to try to end your life but you stopped yourself before you 
actually did anything?
If yes, describe:
Yes      No
□   □
Total # of
aborted
______
Preparatory Acts or Behavior:
Acts or preparation towards imminently making a suicide attempt. This can include anything beyond a verbalization or thought, such as assembling a 
specific method (e.g., buying pills, purchasing a gun) or preparing for one’s death by suicide (e.g., giving things away, writing a suicide note). 
Have you taken any steps towards making a suicide attempt or preparing to kill yourself (such as collecting pills, getting a gun, 
giving valuables away or writing a suicide note)?
If yes, describe:
Yes      No
□   □
Suicidal Behavior:
Suicidal behavior was present during the assessment period?
Yes      No
□   □
Suicide:
Yes    No
□   □
Answer for Actual Attempts Only
Most Lethal
Attempt
Date:
Actual Lethality/Medical Damage:  
0.  No physical damage or very minor physical damage (e.g., surface scratches).
1.  Minor physical damage (e.g., lethargic speech; first-degree burns; mild bleeding; sprains).
2.  Moderate physical damage; medical attention needed (e.g., conscious but sleepy, somewhat responsive; second-degree burns; bleeding of major vessel).
3.  Moderately severe physical damage; medical hospitalization and likely intensive care required (e.g., comatose with reflexes intact; third-degree burns 
less than 20% of body; extensive blood loss but can recover; major fractures).
4.  Severe physical damage; medical hospitalization with intensive care required (e.g., comatose without reflexes; third-degree burns over 20% of body; 
extensive blood loss with unstable vital signs; major damage to a vital area).
5.  Death
Enter Code
______
Potential Lethality: Only Answer if Actual Lethality=0
Likely lethality of actual attempt if no medical damage (the following examples, while having no actual medical damage, had potential for very serious 
lethality: put gun in mouth and pulled the trigger but gun fails to fire so no medical damage; laying on train tracks with oncoming train but pulled away 
before run over).
0 = Behavior not likely to result in injury
1 = Behavior likely to result in injury but not likely to cause death
2 = Behavior likely to result in death despite available medical care 
Enter Code
______
© 2008 Research Foundation for Mental Hygiene, Inc. 
 
C-SSRS—Since Last Visit (Version 1/14/09)    
 
 
  
Page 62


 
CONFIDENTIAL 
Clinical Protocol Amendment 1.0 (Amendment 1.0) 
Alkermes, Inc. 
 
APPENDIX B. EXTRAPYRAMIDAL SYMPTOM RATING SCALE – 
ABBREVIATED (ESRS-A) (SAMPLE) 
Page 63


For Review Only
Extrapyramidal Symptom Rating Scale-Abbreviated 
Scoring Sheet-Long Form (NOT FOR COMPLETION) 
Parkinsonism 
Rigidity 
Upper limbs
0
No rigidity
1
Minimal
Very mild, barely perceptible
2
Mild 
Some resistance to passive movements
3
Moderate 
Definite resistance to passive movements, still easy to move limb, full range motion achieved
4
Severe 
Marked resistance to passive movements, difficulty to move limb with full range of motion
5
Extreme 
Lead pipe rigidity, limb nearly frozen; motion achieved with difficulty
Lower limbs
0
No rigidity
1
Minimal
Very mild, barely perceptible
2
Mild 
Some resistance to passive movements
3
Moderate 
Definite resistance to passive movements, still easy to move limb, full range motion achieved
4
Severe 
Marked resistance to passive movements, difficulty to move limb with full range of motion
5
Extreme 
Lead pipe rigidity, limb nearly frozen; motion achieved with difficulty
Neck 
0
No rigidity
1
Minimal
Very mild, barely perceptible
2
Mild 
Some resistance to passive movements
3
Moderate 
Definite resistance to passive movements, still easy to move neck, full range motion achieved
4
Severe 
Marked resistance to passive movements, difficulty to move neck within full range of motion
5
Extreme 
Lead pipe rigidity, neck nearly frozen; motion achieved with difficulty
Tremor
Face, jaw/chin, lips, head
0
No tremor
Absent at rest and during action/posture
1
Minimal
Tremor with action/posture. Absent at rest; rare (<10% of the time)
2
Mild 
Small amplitude tremor with action/posture; occasional (<50% of the time). Absent at rest
3
Moderate 
Moderate amplitude tremor with action/posture; noticeable (>50% of the time). May be absent at 
rest
4
Severe 
Large amplitude tremor at rest or during action/posture; occasional (<50% of the time)
5
Extreme 
Large amplitude tremor at rest and during action/posture; noticeable (>50% of the time)
Upper limbs/hands
0
No tremor
Absent at rest and during action/posture
1
Minimal
Tremor with action/posture. Absent at rest; rare (<10% of the time)
2
Mild 
Small amplitude tremor with action/posture; occasional (<50% of the time) Absent at rest
3
Moderate 
Moderate amplitude tremor with action/posture; noticeable (>50% of the time). May be absent at 
rest
4
Severe 
Large amplitude tremor at rest or during action/posture; occasional (<50% of the time)
5
Extreme 
Large amplitude tremor at rest and during action/posture; noticeable (>50% of the time)
Lower limbs/feet
0
No tremor
Absent at rest and during action/posture
1
Minimal
Tremor with action/posture. Absent at rest; rare (<10% of the time)
2
Mild 
Small amplitude tremor with action/posture (<50% of the time); absent at rest
3
Moderate 
Moderate amplitude tremor with action/posture; noticeable (>50% of the time); may be absent at 
rest
4
Severe 
Large amplitude tremor at rest or during action/posture; occasional (<50% of the time)
5
Extreme 
Large amplitude tremor at rest and during action/posture; noticeable (>50% of the time)
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For Review Only
Parkinsonism (continued)  
Reduced facial expression/speech 
0
Normal
1
Minimal
Very mild decrease in facial expressiveness
2
Mild 
Mild decrease in facial expressiveness; hypomania
3
Moderate 
Rare spontaneous smile, decreased blinking, voice monotonous
4
Severe 
Difficulty to frown, slurred speech, staring gaze
5
Extreme 
Unable to frown, unintelligible speech, fixed facial expression, lips parted
Impaired Gait/Posture 
0
Normal
1
Minimal
Very mild decreased pendular arm movement, not quite erect normally: stooped posture
2
Mild 
Mild decrease of pendular arm movement, mildly stooped posture
3
Moderate 
No pendular arm movement, head flexed, can be leaning to one side
4
Severe 
Small step (shuffling gait), stiff posture (neck, back), moderate leaning to one side
5
Extreme 
Festination/freezing on turning, barely able to walk, triple flexion: posture extreme abnormal
Postural Instability 
0
No postural instability
1
Minimal
Hesitation when suddenly pushed or pulled but no latero, antero nor retropulsion
2
Mild 
Latero, antero or retropulsion but recovers unaided
3
Moderate 
Absence of postural response, would fall if not caught
4
Severe 
Unstable while standing, even without pushing
5
Extreme 
Unable to stand without assistance
Bradykinesia/ Hypokinesia
0
No slowness of movement
1
Minimal
Minimally/questionably slowed movements, hesitancy
2
Mild 
Mildly slowed movements, mild poverty of movements
3
Moderate 
Moderate difficulty in initiating or stopping movements
4
Severe 
Rare voluntary movements, small amplitude movements
5
Extreme 
Almost completely immobile
Page 65


For Review Only
 
 
Dystonia 
Tongue
0
None
No contraction at rest or during action
1
Minimal
Very mild contraction partial tongue protrusion; rare (<10% of the time)
2
Mild 
Mild contraction partial tongue protrusion; occasional (<50% of the time) 
3
Moderate 
Sustained min effort contraction partial tongue protrusion; noticeable (>50% of the time) 
4
Severe 
Forceful effort contraction near complete tongue protrusion; occasional (<50% of the time) 
5
Extreme 
Forceful effort near complete tongue protrusion; noticeable (>50% of the time) 
Jaw
0
None
No contractions at rest or during action
1
Minimal
Very mild contraction partial jaw opening or clenching; rare (<10% of the time) 
2
Mild 
Mild contraction partial jaw opening or clenching; occasional (<50% of the time) 
3
Moderate 
Sustained min effort partial jaw opening or clenching; noticeable (>50% of the time) 
4
Severe 
Forceful effort complete jaw opening or clenching/bruxism; occasional (<50% of the time) 
5
Extreme 
Forceful effort complete jaw opening or clenching/bruxism; noticeable (>50% of the time) 
Eyes, upper face, lower face, larynx
0
None
No contractions at rest or during action
1
Minimal
Very mild blepharospasm, oculogyration, choked voice or grimacing; rare (<10% of the time) 
2
Mild 
Mild blepharospasm, oculogyration, choked voice or grimacing; occasional (<50% of the time) 
3
Moderate 
Sustained min effort blepharospasm, oculogyration, choked voice or grimacing; predominant (>50% 
of the time) 
4
Severe 
Forceful effort blepharospasm, oculogyration, choked voice or grimacing; occasional (<50% of the 
time) 
5
Extreme 
Forceful effort blepharospasm, oculogyration, choked voice or grimacing; noticeable (>50% of the 
time) 
Shoulders, upper limbs, hands
0
None
No contraction at rest or during action
1
Minimal
Very mild contraction of shoulder, upper limb or hand; rare (<10% of the time) 
2
Mild 
Mild contraction of shoulder, upper limb or hand; occasional (<50% of the time) 
3
Moderate 
Sustained min effort contraction of shoulder, upper limb or hand; noticeable (>50% of the time) 
4
Severe 
Forceful effort contraction of shoulder, upper limb or hand; occasional (<50% of the time) 
5
Extreme 
Forceful effort contraction of shoulder, upper limb or hand; noticeable (>50% of the time) 
Hips, lower limbs, feet
0
None
No contraction at rest or during action 
1
Minimal
Very mild contraction of hip, lower limb or foot; rare (<10% of the time) 
2
Mild 
Mild contraction of hip, lower limb or foot; occasional (<50% of the time) 
3
Moderate 
Sustained min effort contraction of hip, lower limb or foot; noticeable (>50% of the time) 
4
Severe 
Forceful effort contraction of hip, lower limb or foot; occasional (<50% of the time) 
5
Extreme 
Forceful effort contraction of hip, lower limb or foot; noticeable (>50% of the time) 
Trunk, neck 
0
None
No contraction at rest or during action 
1
Minimal
Very mild contraction trunk bending or head turning; rare (<10% of the time) 
2
Mild 
Mild contraction trunk bending or head turning; occasional (<50% of the time) 
3
Moderate 
Sustained min effort trunk bending or head turning; noticeable (>50% of the time) 
4
Severe 
Forceful effort contraction trunk bending or head turning; occasional (<50% of the time) 
5
Extreme 
Forceful effort contraction trunk bending or head turning; noticeable (>50% of the time) 
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For Review Only
Dyskinesia 
Tongue
0 Absent
No dyskinesia at rest or during action
1 Minimal
Very mild dyskinetic lateral or torsion movement of tongue; rare (<10% of the time)
2 Mild
Lateral or torsion tongue dyskinesia within oral cavity; occasional (<50% of the time)
3 Moderate
Lateral or torsion tongue dyskinesia within oral cavity; noticeable (>50% of the time)
4 Severe
Near complete tongue protrusion dyskinesia (fly catching); occasional (<50% of the time)
5 Extreme
Near complete tongue protrusion dyskinesia (fly catching); noticeable (>50% of the time)
Jaw
0 Absent
No dyskinesia at rest or during action
1 Minimal
Very mild dyskinetic lateral, chewing or biting jaw movement; rare (<10% of the time)
2 Mild
Lateral, chewing or biting dyskinesia without jaw opening; occasional (<50% of the time)
3 Moderate
Lateral, chewing or biting dyskinesia without jaw opening; noticeable (>50% of the time)
4 Severe
Near complete jaw opening dyskinesia; occasional (<50% of the time)
5 Extreme
Near complete jaw opening dyskinesia; noticeable (>50% of the time)
Eyes, upper face, lower face
0 Absent
No dyskinesia at rest or during action
1 Minimal
Very mild dyskinetic blinking, or pouting; rare (<10% of the time)
2 Mild
Blinking, or pouting dyskinesia; occasional (<50% of the time)
3 Moderate
Blinking, or pouting dyskinesia; noticeable (>50% of the time)
4 Severe
Marked blinking, or pouting dyskinesia; occasional (<50% of the time)
5 Extreme
Marked blinking, or pouting dyskinesia noticeable (>50% of the time)
Shoulders, upper limbs, hands
0 Absent
No dyskinesia at rest or during action
1 Minimal
Very mild dyskinetic shoulder, limb or hand movement; rare (<10% of the time)
2 Mild
Unilateral dyskinesia of shoulder, limb or hand; occasional (<50% of the time)
3 Moderate
Unilateral dyskinesia of shoulder, limb or hand; noticeable (>50% of the time)
4 Severe
Bilateral dyskinesia of shoulder, limb or hand; occasional (<50% of the time)
5 Extreme
Bilateral dyskinesia of shoulder, limb or hand; noticeable (>50% of the time)
Hips, lower limbs, feet
0 Absent
No dyskinesia at rest or during action
1 Minimal
Very mild dyskinetic hip, limb or foot movement; rare (<10% of the time)
2 Mild
Unilateral dyskinesia of hip, limb or foot; occasional (<50% of the time)
3 Moderate
Unilateral dyskinesia of hip, limb or foot; noticeable (>50% of the time)
4 Severe
Bilateral dyskinesia of hip, limb or foot; occasional (<50% of the time)
5 Extreme
Bilateral dyskinesia of hip, limb or foot; noticeable (>50% of the time)
Trunk, neck
0 Absent
No dyskinesia at rest or during action
1 Minimal
Very mild dyskinetic trunk bending or head turning; rare (<10% of the time)
2 Mild
Mild trunk bending or head turning dyskinesia; occasional (<50% of the time)
3 Moderate
Moderate trunk bending or head turning dyskinesia; noticeable (>50% of the time)
4 Severe
Marked trunk bending or head turning dyskinesia; occasional (<50% of the time)
5 Extreme
Marked trunk bending or head turning dyskinesia; noticeable (>50% of the time)
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For Review Only
 
 
Akathisia 
Subjective (reported by the patient)
0 None
No feelings of restlessness/urge to move, nor distress reported.
1 Minimal
Slight vague feelings of restlessness/urge to move, minimally aware or distressed.
Rare (<10% of the time)
2 Mild
Clearly identifiable feelings of restlessness/urge to move that are manageable, do not require treatment, 
mildly aware or distressed. No impact on daily activities. Occasional (<50% of the time)
3 Moderate
Feelings of restlessness/urge to move require effort to manage, interfere with some daily activities, 
moderately aware or distressed. Patient may seek treatment. Noticeable (>50% of the time)
4 Severe
Feelings of restlessness/urge to move with significant impact on daily activities, intensely aware or 
distressed. Medications may not completely control symptoms. Occasional (<50% of the time)
5 Extreme
Feelings of restlessness/urge to move with severe impact on all daily activities, extremely aware or 
distressed. Medications have minimal effects. Noticeable (>50% of the time)
Objective (observed during patient examination)
0 None
No overt signs of restlessness or fidgeting.
1 Minimal
Slight restless movements, fidgeting or crossing-uncrossing of leg. Rare (<10% of the time)
2 Mild
Mild restless movements. Need to move at least one extremity, fidgets in his/her chair, rocks or crosses 
and uncrosses his/her legs. Occasional (<50% of the time)
3 Moderate
Noticeable restless movements, but can remain seated. Need to move one extremity or to change 
position, fidgets in his/her chair, may rock back and forth, may need to stand up and walk. Noticeable 
(>50% of the time)
4 Severe
Evident restless movements, unable to sit down for more than a short period of time.
Rocking, need to get up and leave his/her seat, or to pace back and forth, or shift from foot to foot when 
standing. Occasional (<50% of the time)
5 Extreme
Unremitting severe restless movements, moves or walks constantly with no apparent control. Rocks 
uncontrollably, cannot sit still, paces back and forth, marches in place. Noticeable (>50% of the time) 
Page 68


For Review Only
Clinical Global Impression of Movement Severity (CGI-S)
Parkinsonism
0 Absent 
1 Minimal
2 Mild
3 Moderate 
4 Severe 
5 Extreme
Dystonia
0 Absent 
1 Minimal
2 Mild
3 Moderate 
4 Severe 
5 Extreme
Dyskinesia
0 Absent 
1 Minimal
2 Mild
3 Moderate 
4 Severe 
5 Extreme
Akathisia
0 Absent 
1 Minimal
2 Mild
3 Moderate 
4 Severe 
5 Extreme
Page 69


 
CONFIDENTIAL 
Clinical Protocol Amendment 1.0 (Amendment 1.0) 
Alkermes, Inc. 
 
APPENDIX C. CLINICAL GLOBAL IMPRESSIONS-SEVERITY (CGI-S) 
(SAMPLE) 
Page 70


For Review Only
Page 1 of 2
Clinical Global Impression – Severity (CGI-S) Scale 
Considering your total clinical experience with this particular population, how mentally ill is the 
patient at this time? 
□ 1 = Normal, not at all ill 
□ 2 = Borderline mentally ill 
□ 3 = Mildly ill 
□ 4 = Moderately ill 
□ 5 = Markedly ill 
□ 6 = Severely ill 
□ 7 = Among the most extremely ill patients 
Rater Signature: ________________________    
Busner, J., Targum, S. (2007), as adapted from Kay, Stanley R., Positive and Negative Symptoms in 
Schizophrenia:Assessment and Research.  Clinical and Experimental Psychiatry, Monograph No. 5.  Brunner/Mazel, 1991.
Modified from Guy W. Clinical Global Impressions: In ECDEU Assessment Manual for Psychopharmacology. 1976; 218-222.  
Revised DHEW Pub. (ADM) Rockville, MD: National Institute for Mental Health 
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Page 2 of 2
CGI-S Scoring Guidelines  
1
Normal, not at all ill
Symptoms of disorder have not been present in the past seven 
days
2
Borderline mentally ill
Subtle or suspected pathology present within the past seven 
days 
3
Mildly ill
Clearly established symptoms causing minimal, if any, distress 
for the subject or difficulty in social and occupational function 
4
Moderately ill
Overt symptoms causing noticeable, but modest, functional 
impairment or distress for the subject; 
Some symptoms may warrant adjustment of medication 
5
Markedly ill
Intrusive symptoms that distinctly impair social/occupational 
function or cause intrusive levels of distress for the subject; 
There is overt behavioral or social dysfunction that is obvious 
to others 
6
Severely ill
Disruptive pathology; behavior and function are frequently 
influenced by symptoms; 
Extent of overt dysfunction may require intervention from 
others 
7
Among the most 
extremely ill patients
Pathology drastically interferes in many life functions; patient
may be hospitalized
Rater Signature: ________________________    
Busner, J., Targum, S. (2007), as adapted from Kay, Stanley R., Positive and Negative Symptoms in 
Schizophrenia:Assessment and Research.  Clinical and Experimental Psychiatry, Monograph No. 5.  Brunner/Mazel, 1991.
Modified from Guy W. Clinical Global Impressions: In ECDEU Assessment Manual for Psychopharmacology. 1976; 218-222.  
Revised DHEW Pub. (ADM) Rockville, MD: National Institute for Mental Health 
Page 72


 
CONFIDENTIAL 
Clinical Protocol Amendment 1.0 (Amendment 1.0) 
Alkermes, Inc. 
 
APPENDIX D. BRIEF PSYCHIATRIC RATING SCALE (BPRS) 
(SAMPLE) 
Page 73


For Review Only
 
Form ID: BPRSA082801  
Form Date: 8/28/01  
          
 
                
 
 
1 of 8 
Hillside Hospital Psychiatry Research - Departmental Form                                    
BPRS-A (Brief Psychiatric Rating Scale - Anchored)                     DIRECTIONS: There are 18 items to be rated.  
The starred items (Items 3, 4, 6, 7, 13, 14, 16, 17 and 18) should be rated on the basis of observations made during the 
interview. For these items, 1 = Not observed. The remaining items should be rated on the basis of reported (i.e., subjective) 
information pertaining to the past week. For these items, 1 = Not reported. 
1. SOMATIC CONCERN: Degree of concern over present bodily health. Rate the degree to which physical health is 
perceived as a problem by the patient, whether complaints have a realistic basis or not. Do not rate mere reporting of 
somatic symptoms. Rate only concern for (or worrying about) physical problems (real or imagined). Rate on the basis 
of reported (i.e., subjective) information pertaining to the past week. 
-7 = Cannot be assessed adequately because of severe formal thought disorder, uncooperativeness, or marked 
evasiveness/guardedness; or Not assessed 
   1 = Not Reported 
   2 = Very Mild: occasionally is somewhat concerned about body, symptoms or physical illness 
   3 = Mild: occasionally is moderately concerned, or often is somewhat concerned 
   4 = Moderate: occasionally is very concerned, or often is moderately concerned 
   5 = Moderately Severe: often is very concerned 
   6 = Severe: is very concerned most of the time 
   7 = Very Severe: is very concerned nearly all of the time 

During the past week how has your physical health been? 

Do you feel you are physically ill in any way? (What do you think is wrong?) (How serious is it?) 

Have you worried about your health recently? 
2. ANXIETY: Worry, fear or overly concerned for present or future. Rate solely on the basis of verbal report of patient’s 
own subjective experiences. Do not infer anxiety from physical sign or from neurotic defense mechanisms. Do not rate 
if restricted to somatic concern. 
-7 = Cannot be assessed adequately because of severe formal thought disorder, uncooperativeness, or marked 
evasiveness/guardedness; or Not assessed 
   1 = Not Reported 
 2 = Very Mild: occasionally feels somewhat anxious 
   3 = Mild: occasionally feels moderately anxious, or often feels somewhat anxious 
   4 = Moderate: occasionally feels very anxious, or often feels moderately anxious 
   5 = Moderately Severe: often feels very anxious 
   6 = Severe: feels very anxious  most of the time 
   7 = Very Severe: feels very anxious nearly all of the time 

During the past week have you felt very frightened or anxious? 

Have you worried a lot? (What do you worry about?) 

Have you had the feeling that something terrible might happen? 
 
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Form ID: BPRSA082801  
Form Date: 8/28/01  
          
 
 
 
 
             2 of 8 
*3. EMOTIONAL WITHDRAWAL: Deficiency in relating to the interviewer and to the interview situation. Overt 
manifestations of this deficiency include poor/absence of eye contact, failure to orient oneself physically toward the 
interviewer, and a general lack of involvement or engagement in the interview. Distinguish from BLUNTED  
AFFECT, in which deficits in facial expression, body gesture, and voice pattern are scored.  
-7 = Cannot be assessed (e.g., scored from audio tape) 
   1 = Not observed 
   2 = Very Mild: e.g., occasionally exhibits poor eye contact 
   3 = Mild: e.g., as above, but more frequent 
   4 = Moderate: e.g., exhibits little eye contact, but still seems engaged in the interview and is appropriately 
responsive to all questions 
   5 = Moderately Severe: e.g., stares at floor or orients self away from interviewer, but still seems moderately 
engaged 
   6 = Severe: e.g., as above, but more persistent or pervasive 
   7 = Very Severe: e.g., appears “spacey” or “out of it” (total absence of emotional relatedness), and is 
disproportionately uninvolved or unengaged in the interview 
*4. CONCEPTUAL DISORGANIZATION: Degree of speech incomprehensibility. Include any type of formal thought 
disorder (e.g., loose associations, incoherence, flight of ideas, neologisms). DO NOT include mere circumstantiality or 
pressured speech, even if marked. DO NOT rate on the basis of the patient’s subjective impressions (e.g., “my 
thoughts are racing. I can’t hold a thought,” “my thinking gets all mixed up.). Rate ONLY on the basis of observations 
made during the interview. 
-7 = Not assessed 
 1 = Not observed 
   2 = Very Mild: e.g., somewhat vague, but of doubtful clinical significance 
   3 = Mild: e.g, frequently vague, but the interview is able to progress smoothly 
   4 = Moderate: e.g., occasional irrelevant statements, infrequent use of neologisms, or moderate loosening of 
associations 
   5 = Moderately Severe: as above, but more frequent 
   6 = Severe: format thought disorder is present for most of the interview, and the interview is severely strained 
   7 = Very Severe: very little coherent information can be obtained 
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For Review Only
 
Form ID: BPRSA082801  
Form Date: 8/28/01  
          
 
 
 
 
             3 of 8 
5. GUILT FEELINGS: Overly concerned or remorseful for past behavior. Rate on the basis of the patient’s subjective 
experiences of guilt as evidenced by verbal report. Do not infer guilt feelings from depression, anxiety or neurotic 
defenses. 
 -7 = Cannot be assessed adequately because of severe formal thought disorder, uncooperativeness, or marked 
evasiveness/guardedness; or Not assessed 
   1 = Not Reported 
   2 = Very Mild: occasionally feels somewhat guilty 
3 = Mild: occasionally feels moderately guilty, or often feels somewhat guilty 
   4 = Moderate: occasionally feels very guilty, or often feels moderately guilty 
   5 = Moderately Severe: often feels very guilty 
   6 = Severe: feels very guilty most of the time, or encapsulated delusion of guilt 
   7 = Very Severe: agonizing constant feelings of guilt, or pervasive delusions of guilt 

During the past week have you been blaming yourself for anything? 

Have you been feeling guilty? (Do you feel that you deserve punishment?) (Have you been thinking 
about this a lot?) 
*6. TENSION: Rate motor restlessness (agitation) observed during the interview. DO NOT rate on the basis of subjective 
experiences reported by the patient. Disregard suspected pathogenesis (e.g., tardive dyskinsia). 
-7 = Cannot be assessed (e.g., scored from audiotape) 
   1 = Not observed 
   2 = Very Mild: e.g., occasionally fidgets 
   3 = Mild: e.g., frequently fidgets 
   4 = Moderate: e.g., constantly fidgets, or frequently fidgets, wrings hands and pulls clothing 
   5 = Moderately Severe: e.g., constantly fidgets, wrings hands and pulls clothing 
   6 = Severe: e.g., cannot remain seated (i.e., must pace) 
   7 = Very Severe: e.g., paces in a frantic manner 
*7. MANNERISMS AND POSTURING: Unusual and unnatural motor behavior. Rate only abnormality of movements; 
do not rate simple heightened motor activity here. Consider frequency, duration, and degree of bizarreness. Disregard 
suspected pathogenesis. 
-7 = Cannot be assessed (e.g., scored from audiotape) 
   1 = Not observed 
   2 = Very Mild: odd behavior but of doubtful clinical significance, e.g. occasional unprompted smiling, infrequent 
lip movements 
   3 = Mild: strange behavior but not obviously bizarre, e.g., infrequent head-tilting (side to side) in a rhythmic 
fashion, intermittent abnormal finger movements 
   4 = Moderate: e.g., assumes yoga position for a brief period of time, infrequent tongue protrusions, rocking 
   5 = Moderately Severe: e.g., assumes and maintains yoga positions throughout interview, unusual movements in 
several body areas 
   6 = Severe: as above, but more frequent, intense, or pervasive 
   7 = Very Severe: e.g., bizarre posturing throughout most of the interview, continuous abnormal movements in 
several body areas 
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For Review Only
 
Form ID: BPRSA082801  
Form Date: 8/28/01  
          
 
 
 
 
             4 of 8 
8. GRANDIOSITY: Inflated self-esteem (self-confidence), or inflated appraisal of one’s talents, powers, abilities, 
accomplishments, knowledge, importance, or identity. Do not score mere grandiose quality of claims (e.g., “I’m the 
worst sinner in the world,. ‘The entire country is trying to kill me”) unless the guilt/persecution is related to some 
special, exaggerated attributes of the individual. Also, the patient must claim exaggerated attributes: e.g., if patient 
denies talents, powers, etc., even if he or she states that others indicate that he/she has these attributes, this item should 
not be scored. 
-7 = Cannot be assessed adequately because of severe formal thought disorder, uncooperativeness, or marked 
evasiveness/guardedness, or Not assessed 
   1 = Not reported 
   2 = Very Mild: e.g., is more confident than most people, but of only possible clinical significance 
   3 = Mild: e.g., definitely inflated self-esteem or exaggerates talents somewhat out of proportion to the 
circumstances 
   4 = Moderate: e.g., inflated self-esteem clearly out of proportion to the circumstances, or suspected grandiose 
delusion(s) 
   5 = Moderately Severe: e.g., a single (definite) encapsulated grandiose delusion, or multiple (definite) 
fragmentary grandiose delusions 
   6 = Severe: e.g., a single (definite) grandiose delusion/delusional system, or multiple (definite) grandiose 
delusions that the patient seems preoccupied with 
   7 = Very Severe: e.g., as above, but nearly all conversation is directed toward the patient’s grandiose delusion(s)

During the past week have you felt more self-confident than usual? 

Do you have any special abilities or talents? 

Do you feel there is a special purpose or mission to your life? (Have you thought you might be 
somebody rich or famous?) 
9. DEPRESSIVE MOOD: Subjective report of feeling depressed, blue, “down in the dumps,” etc. Rate only degree of 
reported depression. Do not rate on the basis of inferences concerning depression based upon general retardation and 
somatic complaints. 
-7 = Cannot be assessed adequately because of severe formal thought disorder, uncooperativeness, or marked 
evasiveness/guardedness, or Not assessed 
   1 = Not reported 
   2 = Very Mild: occasionally feels somewhat depressed 
   3 = Mild: occasionally feels moderately depressed, or often feels somewhat depressed 
   4 = Moderate: occasionally feels very depressed, or often feels moderately depressed 
   5 = Moderately Severe: often feels very depressed 
   6 = Severe: feels very depressed most of the time 
   7 = Very Severe: feels very depressed nearly all of the time 

In the past week have you had less interest in your usual activities? 

Have you felt sad or depressed? (Have you cried at all?) (How bad is the feeling?) (How long does it 
last?) 
Page 77


For Review Only
 
Form ID: BPRSA082801  
Form Date: 8/28/01  
          
 
 
 
 
             5 of 8 
10. HOSTILITY: Animosity, contempt, belligerence, disdain for other people outside the interview situation. Rate solely 
on the basis of the verbal report of feelings and actions of the patient toward others during the week. Do not infer 
hostility from neurotic defenses, anxiety or somatic complaints. 
-7 = Cannot be assessed adequately because of severe formal thought disorder, uncooperativeness, or marked 
evasiveness/guardedness, or Not assessed 
   1 = Not reported 
   2 = Very Mild: occasionally feels somewhat angry 
   3 = Mild: often feels somewhat angry, or occasionally feels moderately angry 
   4 = Moderate: occasionally feels very angry, or often feels moderately angry or occasionally yells at others 
   5 = Moderately Severe: often feels very angry; often yells at others or occasionally threatens to harm others 
   6 = Severe: has acted on his anger by becoming physically abusive on one or two occasions or makes frequent 
threats to harm other 
   7 = Very Severe: has been physically aggressive and/or has required intervention to prevent assaultiveness on 
several occasions; or any serious assaultive act. 

During the past week have you been feeling irritable? 

How have you been getting along with other people? (Have you gotten in any arguments or fights?) 

Have you been easily annoyed or angered? (How strongly have you felt this way?) (How much of the 
time?) 
11. SUSPICIOUSNESS: Belief (delusional or otherwise) that others have now, or have had in the past, malicious or 
discriminatory intent toward the patient. On the basis of verbal report, rate only those suspicions that are currently held 
whether they concern past or present circumstances. 
-7 = Cannot be assessed adequately because of severe formal thought disorder, uncooperativeness, or marked 
evasiveness/guardedness, or Not assessed 
1 = Not reported 
   2 = Very Mild: rare instances of suspiciousness that may or may not be warranted by the situation 
   3 = Mild: occasional instances of suspiciousness that are definitely not warranted by the situation 
   4 = Moderate: more frequent suspiciousness, or transient ideas of reference 
   5 = Moderately Severe: pervasive suspiciousness, or frequent ideas of reference 
   6 = Severe: definite, delusion(s) of reference or persecution that is (are) not wholly pervasive (e.g., an 
encapsulated delusion)
   7 = Very Severe: as above, but more widespread, frequent or intense 

How did you get along with people in general, during the past week? 

Do you feel that you have to be on guard with people? 

Has anyone been giving you a hard time, or accusing you of things? 

Has anyone deliberately tried to annoy you? 

Tried to harm you? 
Page 78


For Review Only
 
Form ID: BPRSA082801  
Form Date: 8/28/01  
          
 
 
 
 
             6 of 8 
12. HALLUCINATORY BEHAVIOR: Perceptions (in any sensory modality) in the absence of an identifiable external 
stimulus. Rate only those experiences that have occurred during the last week. DO NOT rate “voices in my head,” or 
“visions in my mind” unless the patient can differentiate between these experiences and his or her thoughts.
-7 = Cannot be assessed adequately because of severe formal thought disorder, uncooperativeness, or marked 
evasiveness/guardedness, or Not assessed 
   1 = Not reported 
   2 = Very Mild: suspected hallucinations only 
 3 = Mild: definite hallucinations, but insignificant, infrequent, or transient (e.g., occasional formless visual 
hallucinations, a voice calling the patient’s name)
   4 = Moderate: as above, but more frequent or extensive (e.g., frequently sees the devil’s face, two voices carry on 
lengthy conversations)
   5 = Moderately Severe: hallucinations are experienced nearly every day, or are a source of extreme distress 
   6 = Severe: as above, and has had a moderate impact on the patient’s behavior (e.g., concentration difficulties 
leading to impaired work functioning) 
   7 = Very Severe: as above, and has had a severe impact (e.g., attempts suicide in response to command 
hallucinations) 

Have you had any unusual experiences during the past week? 

Do you seem to hear noises or voices when there’s no one around and nothing else to explain it?

Have you had visions, or seen things that others couldn’t see? 

Is there anything unusual about the way things feel, or taste, or smell? 

How often do you [hear voices]? (Do the voices make it hard to concentrate?) (Do they tell you to do 
things?)
*13. MOTOR RETARDATION: Reduction in energy level evidenced in slowed movements. Rate on the basis of 
observed behavior of the patient only; do not rate on the basis of the patient’s subjective impression of his or her own 
energy level. 
-7 = Cannot be assessed (e.g., scored from audiotape) 
1 = Not observed 
   2 = Very Mild and of doubtful clinical significance 
   3 = Mild: e.g. conversation is somewhat retarded, movements somewhat slowed 
   4 = Moderate: e.g., conversation is noticeably retarded, but not strained  
   5 = Moderately Severe: e.g., conversation is strained, moves very slowly 
   6 = Severe: e.g., conversation is difficult to maintain, hardly moves at all 
   7 = Very Severe: e.g., conversation is almost impossible, does not move at all throughout the interview 
Page 79


For Review Only
 
Form ID: BPRSA082801  
Form Date: 8/28/01  
          
 
 
 
 
             7 of 8 
*14. UNCOOPERATIVENESS: Evidence of resistance, unfriendliness, resentment, and lack of readiness to cooperate 
with the interviewer. Rate only on the basis of the patient’s attitude and responses to the interviewer and the interview 
situation; do not rate on the basis of reported resentment or uncooperativeness outside the interview situation. 
-7 = Not assessed 
   1 = Not observed 
   2 = Very Mild: e.g., does not seem motivated 
   3 = Mild: e.g., seems evasive in certain areas 
   4 = Moderate: e.g., monosyllabic, fails to elaborate spontaneously 
   5 = Moderately Severe: e.g., expresses resentment and is unfriendly throughout the interview 
   6 = Severe: e.g., refuses to answer a number of questions 
   7 = Very Severe: e.g., refuses to answer most questions 
15. UNUSUAL THOUGHT CONTENT: Severity of delusions of any type – consider conviction, and effect on actions. 
Assume full conviction if patient has acted on his or her beliefs. Rate on the basis of reported (i.e., subjective) 
information pertaining to the past week. 
-7 = Cannot be assessed adequately because of severe formal thought disorder, uncooperativeness, or marked 
evasiveness/guardedness, or Not assessed 
   1 = Not reported 
   2 = Very Mild: delusion(s) suspected or likely 
   3 = Mild: at times, patient questions his or her belief(s) (partial delusion) 
   4 = Moderate: full delusional conviction, but delusion(s) has little or no influence on behavior 
   5 = Moderately Severe: full delusional conviction, but delusion(s) has only occasional impact on behavior 
   6 = Severe: delusion(s) has significant effect, e.g. neglects responsibilities because of preoccupations with belief 
the he/she is God 
   7 = Very Severe: delusion(s) has major impact, e.g., stops eating because believes food is poisoned 

Have you had any difficulty with your thinking in the past week? 

Do certain things have special meaning for you? (Give me an example.) 

Is there any interference with your thoughts? 

Is there anything controlling your thoughts or movements? 

Do you see references to yourself in surprising places, like on TV? 
Page 80


For Review Only
 
Form ID: BPRSA082801  
Form Date: 8/28/01  
Rater Signature: ______________________________  
 
 
Date: ______________ 
          
 
 
 
 
               8 of 8
*16. BLUNTED AFFECT: Diminished affected responsivity, as characterized by deficits in facial expression, body 
gesture, and voice pattern. Distinguish from EMOTIONAL WITHDRAWAL, in which the focus is on the 
interpersonal impairment rather than affect. Consider degree and consistency of impairment. 
-7 = Cannot be assessed (e.g., scored from audiotape) 
   1 = Not observed 
   2 = Very Mild: e.g., occasionally seems indifferent to material that is usually accompanied by some show of 
emotion 
   3 = Mild: e.g., somewhat diminished facial expression, or somewhat monotonous voice or somewhat restricted 
gestures 
   4 = Moderate: e.g., as above, but more intense, prolonged or frequent 
   5 = Moderately Severe: e.g., flattening of affect, including at least two of the three features: severe lack of facial 
expression, monotonous voice, or restricted body gestures 
   6 = Severe: e.g., profound flattening of affect 
   7 = Very Severe: e.g., totally monotonous voice, and total lack of expressive gestures throughout the evaluation 
*17. EXCITEMENT: Heightened emotional tone, including irritability and expansiveness (hypomanic affect). Do not 
infer affect from statement of grandiose delusions. 
-7 = Not assessed 
   1 = Not observed 
   2 = Very Mild and of doubtful clinical significance 
   3 = Mild: e.g., irritable or expansive at times 
   4 = Moderate: e.g., frequently irritable or expansive 
   5 = Moderately Severe: e.g., constantly irritable or expansive;or, at times, enraged or euphoric 
   6 = Severe: e.g., enraged or euphoric throughout most of the interview 
   7 = Very Severe: e.g., as above, but to such a degree that the interview must be terminated prematurely 
*18. DISORIENTATION: Confusion or lack of proper association for person, place or time. 
-7 = Cannot be assessed adequately because of severe formal thought disorder, uncooperativeness, or marked 
evasiveness/guardedness, or Not assessed 
   1 = Not observed 
   2 = Very Mild: e.g., seems somewhat confused 
   3 = Mild: e.g., indicates 2000 when, in fact, it is 2001
   4 = Moderate: e.g. indicates 1998 
   5 = Moderately Severe: e.g., is unsure where he/she it 
   6 = Severe: e.g., has no idea where he/she is 
   7 = Very Severe: e.g., does not know who he/she is 

Now I want to ask you some standard questions that we usually ask at this point. What is today’s 
date? (What day of the week is it? What month? What day of the month? What year?) 

Where are we now? 
Page 81


 
CONFIDENTIAL 
Clinical Protocol Amendment 1.0 (Amendment 1.0) 
Alkermes, Inc. 
 
APPENDIX E. SEXUAL FUNCTIONING SUBSCALE FROM UDVALG 
FOR KLINISKE UNDERSØGELSER (UKU) SIDE 
EFFECT RATING SCALE 
Page 82


For Review Only
UKU-SERS-Pat, Summ Form + Patient Form Eng 2001-04-22
The UKU Side Effect Rating Scale, Self-rating version Modified  
4.9  
Have you noticed milk from your nipples? 
 Not at all 
 Some 
 Yes, but not troublesome 
 Much, stains my underwear 
4.10
Have you experienced tension or swelling in your breasts? 
 Not at all 
 Some tension and swelling 
 Breasts are tense and larger than normal 
 Breasts clearly enlarged 
4.11
Have you experienced increased sexual interest or increased sexual desire? 
 Not at all 
 Somewhat more than normal 
 More than normal 
 Much more than normal
4.12
Have you experienced decreased sexual interest or decreased sexual desire? 
 Not at all 
 A little less than normal
 Less than normal 
 Much less than normal 
Page 83


For Review Only
UKU-SERS-Pat, Summ Form + Patient Form Eng 2001-04-22
Females only
4.7a 
Have you noticed more discharge/bleeding when menstruating? 
 Not at all 
 Somewhat more than normally 
 More than normally 
 Profuse discharge/bleeding 
4.7b 
Have you noticed discharge/bleeding between periods? 
 Not at all 
 Occasional discharge/bleeding 
 Substantial discharge/bleeding, occasionally 
 Frequent discharge/bleeding between periods 
4.8 
Have you noticed less discharge/bleeding when menstruating? 
 Not at all 
 Slightly less than normal 
 Less than normal 
 Menstruation has not occurred 
4.15
Have you experienced difficulty in reaching orgasm? 
 Not at all 
 Some difficulty 
 More difficult than normal 
 Rarely have orgasm 
4.16
Do you have problems with a dry vagina during intercourse? 
 Not at all 
 Some dryness
 More problems than normal 
 Severe problems, must use lubrication 
Page 84


For Review Only
UKU-SERS-Pat, Summ Form + Patient Form Eng 2001-04-22
Males only 
4.13
Have you experienced difficulty in reaching erection? 
 Not at all 
 Slightly more difficult than normal 
 More difficult than normal 
 Cannot get erection 
4.14a Have you experienced difficulties in ejaculation? 
 Not at all 
 Ejaculation slightly delayed
 Ejaculation delayed
 Cannot ejaculate 
4.14b Have you experienced early (premature) ejaculation? 
 Not at all 
 Ejaculation slightly early
 Ejaculation early 
 Spontaneous ejaculations 
Page 85


 
CONFIDENTIAL 
Clinical Protocol Amendment 1.0 (Amendment 1.0) 
Alkermes, Inc. 
 
APPENDIX F. CHANGES IN SEXUAL FUNCTIONING 
QUESTIONNAIRE 
Page 86


For Review Only
Copyright © 1998 (Rev. 11/99) A. Clayton, Dept. of Psychiatric Medicine, University of Virginia Health System. All rights reserved. 
CHANGES IN SEXUAL FUNCTIONING QUESTIONNAIRE (CSFQ-F-C)
Patient Name __________________________________ 
         Today’s Date __________________
NOTE: This is a questionnaire about sexual activity and 
sexual function. By sexual activity, we mean sexual 
intercourse, masturbation, sexual fantasies and other activity. 
1.  Compared with the most enjoyable it has ever been, how 
enjoyable or pleasurable is your sexual life right now? 
 1-No enjoyment or pleasure 
 2-Little enjoyment or pleasure 
 3-Some enjoyment or pleasure 
 4-Much enjoyment or pleasure 
 5-Great enjoyment or pleasure
2.  How frequently do you engage in sexual activity (sexual 
intercourse, masturbation, etc.) now? 
 1-Never
 2-Rarely (once a month or less) 
 3-Sometimes (more than once a month, up to twice a week) 
 4-Often (more than twice a week) 
 5-Every day 
3.  How often do you desire to engage in sexual activity? 
 1-Never
 2-Rarely (once a month or less) 
 3-Sometimes (more than once a month, up to twice a week) 
 4-Often (more than twice a week) 
 5-Every day 
4. How frequently do you engage in sexual thoughts (thinking 
about sex, sexual fantasies) now? 
 1-Never
 2-Rarely (once a month or less) 
 3-Sometimes (more than once a month, up to twice a week) 
 4-Often (more than twice a week)
 5-Every day 
5.  Do you enjoy books, movies, music or artwork with sexual 
content? 
 1-Never
 2-Rarely (once a month or less) 
 3-Sometimes (more than once a month, up to twice a week) 
 4-Often (more than twice a week) 
 5-Every day 
6.  How much pleasure or enjoyment do you get from thinking 
about and fantasizing about sex? 
 1-No enjoyment or pleasure 
 2-Little enjoyment or pleasure 
 3-Some enjoyment or pleasure 
 4-Much enjoyment or pleasure 
 5-Great enjoyment or pleasure
7.  How often do you become sexually aroused? 
 1-Never
 2-Rarely (once a month or less) 
 3-Sometimes (more than once a month, up to twice a week) 
 4-Often (more than twice a week) 
 5-Every day 
8.  Are you easily aroused? 
 1-Never
 2-Rarely (much less than half the time) 
 3-Sometimes (about half the time) 
 4-Often (much more than half the time) 
 5-Always 
9.  Do you have adequate vaginal lubrication during sexual 
activity? 
 1-Never
 2-Rarely (much less than half the time) 
 3-Sometimes (about half the time) 
 4-Often (much more than half the time) 
 5-Always 
10.  How often do you become aroused and then lose interest? 
 5-Never
 4-Rarely (much less than half the time) 
 3-Sometimes (about half the time) 
 2-Often (much more than half the time) 
 1-Always 
11. How often do you experience an orgasm? 
 1-Never
 2-Rarely (much less than half the time) 
 3-Sometimes (about half the time) 
 4-Often (much more than half the time) 
 5-Always 
12.  Are you able to have an orgasm when you want to? 
 1-Never
 2-Rarely (much less than half the time) 
 3-Sometimes (about half the time) 
 4-Often (much more than half the time) 
 5-Always 
13.  How much pleasure or enjoyment do you get from your 
orgasms? 
 1-No enjoyment or pleasure 
 2-Little enjoyment or pleasure 
 3-Some enjoyment or pleasure 
 4-Much enjoyment or pleasure 
 5-Great enjoyment or pleasure
14.  How often do you have painful orgasm? 
 5-Never
 4-Rarely (once a month or less) 
 3-Sometimes (more than once a month, up to twice a week) 
 2-Often (more than twice a week) 
 1-Every day 
____ = Pleasure (Item 1)
____ = Desire/Frequency (Item 2 + Item 3)
____ = Desire/Interest (Item 4 + Item 5 + Item 6)
____ = Arousal/Excitement (Item 7 + Item 8 + Item 9)
____ = Orgasm/Completion (Item 11 + Item 12 + Item 13)
____ = Total CSFQ Score (Items 1 to 14)
Page 87


For Review Only
Copyright © 1998 A. Clayton, Dept. of Psychiatric Medicine, University of Virginia Health Sciences Center. All rights reserved.
CHANGES IN SEXUAL FUNCTIONING QUESTIONNAIRE (CSFQ-M-C)
Patient Name __________________________________ 
Today’s Date __________________
NOTE: This is a questionnaire about sexual activity and 
sexual function. By sexual activity, we mean sexual 
intercourse, masturbation, sexual fantasies and other activity. 
1.  Compared with the most enjoyable it has ever been, how 
enjoyable or pleasurable is your sexual life right now? 
 1-No enjoyment or pleasure 
 2-Little enjoyment or pleasure 
 3-Some enjoyment or pleasure 
 4-Much enjoyment or pleasure 
 5-Great enjoyment or pleasure
2.  How frequently do you engage in sexual activity (sexual 
intercourse, masturbation, etc.) now? 
 1-Never 
 2-Rarely (once a month or less) 
 3-Sometimes (more than once a month, up to twice a week) 
 4-Often (more than twice a week) 
 5-Every day 
3.  How often do you desire to engage in sexual activity? 
 1-Never 
 2-Rarely (once a month or less) 
 3-Sometimes (more than once a month, up to twice a week) 
 4-Often (more than twice a week) 
 5-Every day 
4. How frequently do you engage in sexual thoughts (thinking 
about sex, sexual fantasies) now? 
 1-Never 
 2-Rarely (once a month or less) 
 3-Sometimes (more than once a month, up to twice a week) 
 4-Often (more than twice a week) 
 5-Every day 
5.  Do you enjoy books, movies, music or artwork with sexual 
content? 
 1-Never 
 2-Rarely (once a month or less) 
 3-Sometimes (more than once a month, up to twice a week) 
 4-Often (more than twice a week) 
 5-Every day 
6.  How much pleasure or enjoyment do you get from thinking 
about and fantasizing about sex? 
 1-No enjoyment or pleasure 
 2-Little enjoyment or pleasure 
 3-Some enjoyment or pleasure 
 4-Much enjoyment or pleasure 
 5-Great enjoyment or pleasure
7.  How often do you have an erection related or unrelated to 
sexual activity? 
 1-Never 
 2-Rarely (once a month or less) 
 3-Sometimes (more than once a month, up to twice a week) 
 4-Often (more than twice a week) 
 5-Every day 
8.  Do you get an erection easily? 
 1-Never 
 2-Rarely (much less than half the time) 
 3-Sometimes (about half the time) 
 4-Often (much more than half the time) 
 5-Always 
9.  Are you able to maintain an erection? 
 1-Never 
 2-Rarely (much less than half the time) 
 3-Sometimes (about half the time) 
 4-Often (much more than half the time) 
 5-Always 
10.  How often do you experience painful, prolonged 
erections? 
 5-Never 
 4-Rarely (once a month or less) 
 3-Sometimes (more than once a month, up to twice a week) 
 2-Often (more than twice a week) 
 1-Every day 
11.  How often do you have an ejaculation? 
 1-Never 
 2-Rarely (once a month or less) 
 3-Sometimes (more than once a month, up to twice a week) 
 4-Often (more than twice a week) 
 5-Every day 
12.  Are you able to ejaculate when you want to? 
 1-Never 
 2-Rarely (much less than half the time) 
 3-Sometimes (about half the time) 
 4-Often (much more than half the time) 
 5-Always 
13.  How much pleasure or enjoyment do you get from your 
orgasms? 
 1-No enjoyment or pleasure 
 2-Little enjoyment or pleasure 
 3-Some enjoyment or pleasure 
 4-Much enjoyment or pleasure 
 5-Great enjoyment or pleasure
14.  How often do you have painful orgasm? 
 5-Never 
 4-Rarely (once a month or less) 
 3-Sometimes (more than once a month, up to twice a week) 
 2-Often (more than twice a week) 
 1-Every day 
____ = Pleasure (Item 1)
____ = Desire/Frequency (Item 2 + Item 3)
____ = Desire/Interest (Item 4 + Item 5 + Item 6)
____ = Arousal/Erection (Item 7 + Item 8 + Item 9)
____ = Orgasm/Ejaculation (Item 11 + Item 12 + Item 13)
____ = Total CSFQ Score (Items 1 to 14)
Page 88


 
CONFIDENTIAL 
Clinical Protocol Amendment 1.0 (Amendment 1.0) 
Alkermes, Inc. 
 
APPENDIX G. PERSONAL AND SOCIAL PERFORMANCE SCALE 
(PSP) (SAMPLE) 
Page 89


For Review Only
  
Page 1 of 2
Personal and Social Performance Scale (PSP) – Worksheet 
 
The rating is based on four main areas: (a) socially useful activities, including work and study; (b) personal and social 
relationships; (c) self-care; and (d) disturbing and aggressive behaviors. 
Data will be captured in the following format using the PSP descriptions provided below: 
 
Absent 
Mild 
Manifest 
Marked 
Severe 
Very 
Severe 
a. Socially useful activities, including work and study
 
 
 
 
 
 
b. Personal and social relationships






c. Self-care






d. Disturbing and aggressive behaviors






The levels of functioning in other areas should be taken into account to adjust the rating inside the decimal level (for 
instance, from 31 to 40).  Suicidal risk is not included in the scale.
10-point 
intervals
PSP descriptions
100-91
Excellent functioning in all four main areas*.  He/she is held in high consideration for 
his/her good qualities, copes adequately with life problems, is involved in a wide range 
of interests and activities
90-81
Good functioning in all four main areas, presence of only common problems or 
difficulties
80-71
Mild difficulties in 1 or more of areas a-c
70-61
Manifest, but not marked difficulties in 1 or more areas a-c, or mild difficulties in d
60-51
Marked difficulties in 1 of areas a-c, or manifest difficulties in d
50-41
Marked difficulties in 2 or more, or severe difficulties in 1 of areas a-c, with or 
without manifest difficulties in d
40-31
Severe difficulties in 1 and marked difficulties in at least 1of areas a-c, or marked 
difficulties in d
30-21
Severe difficulties in 2 of areas a-c, or severe difficulties in d, with or without 
impairment in areas a-c
20-11
Severe difficulties in all areas a-d, or very severe in d with or without impairment in 
general areas a-c.  If the person reacts to external prompts the suggested scores are 20-
16; if not, the suggested scores are 15-11.
10-1
Lack of autonomy in basic functioning with extreme behaviors but without survival 
risk (ratings 6-10) or with survival risk, eg, death risk due to malnutrition, dehydration, 
infections, inability to recognize situation of manifest danger (ratings 5-1).
Overall score |___|___|___| 
For main areas a-c, the degrees of severity are:
Absent
Mild
Not manifest difficulties, known only to someone who is very familiar with the 
person
Manifest, but not 
marked
Difficulties clearly noticeable by everyone, but not interfering substantially with 
the person’s ability to perform his/her role in that area, given the person’s socio-
cultural context, age, sex and educational levels
Marked
Difficulties heavily interfering with role performance in that area; however, the 
person is still able to do something without professional or social help, although 
inadequately and/or occasionally; if helped by someone, he/she may be able to 
reach the previous level of functioning
Severe
Difficulties that make the person unable to any role performance in that area, if 
not professionally helped, or lead the person to a destructive role; however, there 
are no survival risks.
Very severe
Impairments and difficulties of such intensity to endanger person’s survival.
Page 90


For Review Only
Rater Signature: _____________________________  
Date: _________________ 
 
      Page 2 of 2
For general area d, the degrees of severity are:
Absent
Mild
Mild rudeness, unsociability or whingeing
Manifest, but not 
marked
Speaking too loudly or speaking to others in a too-familiar manner, or eating in a 
socially unacceptable manner
Marked
Insulting other in public, breaking or wrecking objects, acting frequently in a 
socially inappropriate but not dangerous way (eg, stripping in public or urinating 
in public).
Severe
Frequent verbal threats or frequent physical assaults, without intention or 
possibility of severe injuries.
Very severe
Frequent aggressive acts, aimed at or likely to cause severe injuries.
Occasional is defined as occurring three or more times in the reference period or occurring even less than three times 
but in circumstances and/or with such a previous history to convince the rater that there is a risk of recurrence in the 
near future.  If the aggressive behavior has been present occasionally, the rating may be decreased by one degree, eg, 
from severe to marked. 
* Main areas: a=socially useful activities, including work and study; b=personal and social relationships; c=self-care; 
d=disturbing and aggressive behaviors. 
Guidelines for PSP Total Score 
Ratings from 71-100 reflect only mild difficulties. 
Ratings from 31-70 reflect manifest disabilities of various degrees. 
Ratings from 1-30 reflect functioning so poor that intensive support or supervision is needed. 
Morosini, P.L., Magliano, L., Brambilla, L., Ugolini, S., Pioli, R. (2000). Development, reliability, and acceptability of 
a new version of the DSM-IV Social and Occupational Functioning Assessment Scale (SOFAS) to assess routine social 
functioning. Acta Psychiatrica Scandinavica 101(4), 323-329.
Page 91


 
CONFIDENTIAL 
Clinical Protocol Amendment 1.0 (Amendment 1.0) 
Alkermes, Inc. 
 
APPENDIX H. HEINRICHS-CARPENTER QUALITY OF LIFE SCALE 
(QLS) (SAMPLE) 
Page 92


For Review Only
April 10, 1992 
QUALITY OF LIFE SCALE
This instrument is designed to evaluate the current functioning of 
nonhospitalized schizophrenic persons apart from the presence or absence of florid 
psychotic symptomatology or need for hospitalization. It assesses the richness of 
their personal experience, the quality of their interpersonal relations, and their 
productivity in occupational roles. 
It is intended to be administered as a semi-structured interview. Each item 
consists of three parts. First, a brief statement is provided to help the interviewer 
understand and focus on the parameter to be assessed. Second, a number of 
suggested questions are provided that may help the interviewer begin his 
exploration with the subject. Finally, a seven-point scale is provided for each item, 
with a brief description at four points to help the interviewer make his judgment 
and unlabeled points. 
The questions provided are just suggestions. They are to be altered or 
supplemented as needed. Each item should be explored as much as required to 
allow the rater to make a good clinical judgment. The intent of the schedule is to 
assess limitations due to psychopathology or personality deficits. Adjustments 
should be made by the rater when extraneous factors are clearly and 
unambiguously involved (e.g., decreased social contact due to serious physical 
illness).
All items should be rated. Circle the appropriate number on each item scale. 
SCORING: Mean scores of the following subsca1es and total (prorate items 1 and 12 for missing data as 
indicated in the manual). 
Subscale Scores: 
I. Interpersonal Relations (1-8): ______  
   
 II. Instrumental Role (9-12): ______
III. Intrapsychic Foundations (13-17,20,21): _____
IV. Common Objects and Activities (18,19):___ 
III plus IV (13 thru 20):  ______  
 
        Total Score (Items 1-21): ______ 
Page 93


For Review Only
1. RATE INTIMATE RELATIONSHIPS WITH HOUSEHOLD MEMBERS 
This item is to rate close relationships with significant mutual caring and sharing 
with immediate family or members of the subject's current household. 
Suggested questions:
Are you especially close with any of 
the people you currently live with or 
your immediate family? 
Can you discuss personal matters 
with them? 
How much have you talked with 
them?
What are these relationships like? 
Can they discuss personal matters 
with you? 
What sorts of things have you done 
together?
When at home, have you spent much 
time around your family or were you 
generally alone? 
0 - Virtually no intimacy 
1 - 
2 - Only sparse and intermittent 
intimate interactions 
3 - 
4 - Some consistent intimate 
interactions but reduced in extent 
or intensity; or intimacy only 
present erratically 
5 - 
6 - Adequate involvement in intimate 
relations with household members 
or immediate family 
9 - Score here if lives alone and no 
immediate family nearby 
Note:  (For Factor and Total Scores, 
prorate this item on the basis of 
Items 2 through 8.) 
Page 94


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2. RATE INTIMATE RELATIONSHIPS 
This item is to rate close relationships with significant mutual caring and sharing, 
with people other than immediate family or household members. Exclude 
relationships with mental health workers.
Suggested questions:
Do you have friends with whom you 
are especially close other than your 
immediate family or the people you 
live with? 
Can you discuss personal matters 
with them? 
How many friends do you have? 
How often have you spoken with 
them recently, in person or by phone? 
What have these relationships been 
like?
Can they discuss personal matters 
with you? 
0 - Virtually absent 
1 - 
2 - Only sparse intermittent relations 
3 - 
4 - Some consistent intimate relations 
but reduced in number or 
intensity; or intimacy only present 
erratically
5 - 
6 - Adequate involvement with 
intimate relationships with more 
than one other person 
 
 
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3. RATE ACTIVE ACQUIANTANCES 
This item is to rate relationships with people based on liking one another and 
sharing common activities or interests but without the intimate emotional 
investment of the above item. Exclude relationships with mental health workers 
and other household members. 
Suggested questions:
Apart from close personal friends, are 
there people you know with whom 
you have enjoyed doing things? 
How many? 
How often have you gotten together 
with them? 
What things have you done together? 
Have you been with people as a part 
of clubs or organize activities? 
Have you had extra social contact 
with co-workers, such as going to 
lunch together or going out after  
0 - Virtually absent 
1 - 
2 - Few active acquaintances and 
      only infrequent contact 
3-
4 - Some ongoing active 
acquaintance but reduced contact 
and limited shared activity 
5 - 
6 - Adequate involvement with active 
acquaintances
work? 
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4. RATE LEVEL OF SOCIAL ACTIVITY 
This item is to rate involvement in activities with other people done for enjoyment. 
Exclude social activity that is primarily instrumental for other goals, for example, 
work and school. Exclude psychotherapy. 
Suggested questions:
How often have you done things for 
enjoyment that involve other people? 
What sort of things? 
Have you participated in clubs or 
other organized social groups? 
0 - Virtually absent 
1 - 
2 - Occasional social activity but lack 
of regular pattern of such activity, 
or limited only to activity with 
immediate family or members of 
household
3 - 
4 - Some regular social activity but 
reduced in frequency or diversity 
5 - 
6 - Adequate level of regular social 
activity
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5. RATE INVOLVED SOCIAL NETWORK 
This item is to rate the extent to which other people concern themselves with the 
person, care about his fortunes or know about his activities. Exclude mental health 
workers. 
Suggested questions:
Are there people who have been 
concerned about your happiness and 
well being? 
How many? 
How did they show it? 
If some important and exciting thing 
happened to you, who would you 
contact or inform? 
Are there people who often provided 
you emotional support or help in day-
to-day matters such as food, 
transportation, and practical advice? 
Are there people you could turn to or 
depend on for help if anything 
happened? 
0 - Virtually absent 
1 - 
2 - Minimal in number or degree of 
involvement, and/or limited to 
immediate family 
3 -
4 - Presence of some involved social 
network but reduced in number of 
degree of involvement 
5 - 
6 - Adequate involved social network 
in both extent and in degree of 
involvement
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6. RATE SOCIAL INITIATIVES 
This item is to rate the degree to which the person is active in directing his social 
interactions - what, how much, and with whom. 
Suggested questions:
Have you often asked people to do 
something with you, or have you 
usually waited for others to ask you? 
When you have had an idea for a 
good time, have you sometimes 
missed out because it's hard to ask 
others to participate? 
Have you contacted people by 
phone?
Have you tended to seek people out? 
Have you usually done things alone 
or with other people? 
0 - Social activity almost completely 
dependent on initiatives of others 
1 - 
2 - Occasional social initiative, but 
social life significantly 
impoverished due to his pattern of 
social passivity, or initiative 
limited to immediate family 
3 - 
4 - Evidence of some reduction of 
social initiative, but with only 
minimal adverse consequences on 
his social activity 
5 - 
6 - Adequate social initiative 
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7. RATE SOCIAL WITHDRAWAL 
This item is to rate the degree to which the person actively avoids social 
interaction due to his discomfort or disinterest. 
Suggested questions:
Have you felt uncomfortable with 
people?
Have you turned down offers to do 
things with other people? Would you 
if you were asked? 
Have you done this even when you 
have had nothing to do? 
Have you avoided answering the 
phone?
How has this interfered with your 
life?
Have you dealt with people only 
when it's necessary to accomplish 
something you want? 
Have you stayed to yourself at home? 
Have you preferred to be alone? 
0 - Active avoidance of virtually all 
social contact 
1 -
2 - Tolerates that social contact 
required for meeting other needs, 
but very little social contact for its 
own sake, or lack of withdrawal 
only with immediate family 
3 - 
4 - Some satisfying and enjoyable 
social engagement, but reduced 
due to avoidance 
5 - 
6 - No evidence of significant social 
withdrawal 
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8. RATE SOCIOSEXUAL RELATIONS 
This item is to rate the capacity for mature intimate relations with members of the 
opposite sex and satisfying sexual activity. The wording assumes a heterosexual 
preference. In clear cases of consistent homosexual preference, reword 
accordingly and rate these same capacities. 
Suggested questions if single:
Have your social activities involved  
women (men)? 
Have you avoided them or found it 
too uncomfortable to deal with them? 
Have you dated? 
Did you have one or more 
girlfriends? (boyfriends?) 
Have the relationships been 
satisfying?
Have emotionally involved were 
you?
Were you in love? 
Were you having sexual activity? 
Was it satisfying? 
Did you show physical signs of 
affection, such as hugging and 
kissing?
0 - No interest in opposite sex, or 
active avoidance
1 - 
2 - Some limited contact with 
opposite sex but superficial with 
avoidance of intimacy; or sexual 
activity as just physical release 
without emotional involvement; 
or relationships marked by severe 
and chronic disruption, 
dissatisfaction or affective chaos 
3 - 
4 - Relationships with some intimacy 
and emotional investment, 
predominantly satisfying, and 
perhaps some sexual expression 
or physical signs of affection 
5 - 
6 - Usually has satisfying 
relationships, emotionally rich 
and intimate and appropriate 
sexual expression and physical 
signs of expression 
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Suggested questions if married or living 
with someone:
Were you happy in your relationship 
with your partner? 
Have you done many things together? 
Did you talk together much? 
Did you discuss personal thoughts and 
feelings?
Did you fight much? 
Has your sex life been satisfying? 
Did you show physical signs of 
affection such as hugging and  
kissing?
Did you feel close to her (him)? 
0 - No interest in opposite sex, or active 
avoidance
1 - 
2 - Some limited contact with opposite 
sex but superficial with avoidance of 
intimacy; or sexual activity as just 
physical release without emotional 
involvement; or relationships 
marked by severe and chronic 
disruption, dissatisfaction or 
affective chaos 
3 - 
4 - Relationships with some intimacy 
and emotional investment, 
predominantly satisfying, and 
perhaps some sexual expression or 
physical signs of affection 
5 - 
6 - Usually has satisfying relationships, 
emotionally rich and intimate and 
appropriate sexual expression and 
physical signs of expression 
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9. RATE OF EXTENT OF OCCUPATIONAL ROLE FUNCTIONING 
This item is to rate the amount of role functioning the person is attempting, not 
how well nor how completely he is succeeding. For homemakers, consider 
whether for a person with normal efficiency the responsibilities would represent a 
full-time job seeking activity.  
Suggested questions:
Have you had a job? 
 
 
 
0 – Virtually no role functioning 
How many hours a week did you work?  
1 -  
Were you involved in school in   
 
2 – Less than half-time 
addition to work? 
 
 
 
 
 
 
 
3 -  
Suggested questions:
4 – Half-time or more, but less    
       than full time
What sort of education program were 
you pursuing? 
 
 
How many classes were you taking? 
How much time did school take per  
week?
Were you also working, caring for  
children or responsible for 
housekeeping? 
Suggested questions for homemakers:
How much was involved in taking care 
of your home and family? 
Were you raising children? 
What were your responsibilities in the 
home? 
How much did other people help with  
these responsibilities? 
5 –
6 - Full-time or more 
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10. RATE LEVEL OF ACCOMPLISHMENT 
This item is to rate the level of success and achievement in fulfilling the particular 
role the person has chosen to attempt. 
Question the subject regarding salary and 
raises, the challenge and responsibility of 
the job, praise or reprimands from employer, 
adequacy of interaction with co-workers, 
absenteeism, promotions or demotions. For 
students, question regarding grades, the 
difficulty of the curriculum, praise or 
criticism from teachers, adequacy of 
interaction with other classmates, class 
attendance, completion of assigned work, 
and extracurricular activities. For 
homemakers, question regarding the 
adequate performance of required tasks such 
as cooking, shopping, washing dishes, 
cleaning, dusting, laundry, management of 
household budget, physical care of children, 
and meeting the emotional needs of 
children. Question further regarding praise 
or criticism by family members about either 
housekeeping or child raising. 
0 - Attempting no role function or 
performing at level so poor as to 
imminently threaten the ability to 
continue in that role 
1 - 
2 - Functioning just well enough to keep 
position with very low level of 
accomplishment 
3 - 
4 - Generally adequate functioning 
5 - 
6 - Very good functioning with evidence of 
new or progressive accomplishments 
and/or very good functioning in some 
areas
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11. RATE DEGREE OF UNDEREMPLOYMENT 
This item is to rate the degree to which the existing extent of and accomplishment in 
occupational role functioning reflects full utilization of the potentiality and opportunities 
available to the person. Consider innate abilities, physical handicaps, education, economic 
and social culture factors. Obviously, limitations directly reflecting any mental illness or 
personality disorder should not be considered in estimating the person's potential. 
Suggested questions:
This item requires a complex judgment. 
Ask any further questions needed to clarify 
the abilities and opportunities of this 
individual.
0 - Almost complete failure to actualize 
potentials
1 - 
2 - Significant underemployment of abilities 
or unemployed but looking for work 
actively.
3 - 
4 - Somewhat below the person's capacity 
5 - 
6 - Role functioning commensurate with 
person's abilities and opportunities 
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12. RATE SATISFACTION WITH OCCUPATIONAL ROLE FUNCTIONING 
This item is to rate the extent to which the person is comfortable with his choice of role, the 
performance of it, and the situation in which he performs it. It also is to rate the extent to 
which it provides a sense of satisfaction, pleasure, and fulfillment to him. 
Suggested questions:
Did you like your work or schooling? 
Would you have preferred to be doing 
something else? 
Do you plan a change? Why? 
Did you get good feelings from doing     
your work – pleasure, fulfillment, etc. 
Did your work or school make you feel  
good about yourself? 
Are you enthusiastic about your job? 
Do you look forward to going to work? 
0 - Pervasive unhappiness and 
dissatisfaction with occupational role 
1 - 
2 - Little or no definite evidence of 
unhappiness or dissatisfaction, but role 
does not provide any positive pleasure or 
fulfillment. Perhaps boredom is evident. 
3 - 
4 - Little or no discontent and some limited 
pleasure in work 
5 - 
6 - Rather consistent sense of fulfillment and 
satisfaction, perhaps in spite of some 
limited complaints 
9 - Not applicable if patient not involved in 
any occupational role functioning 
Note:  (This item should be rated 2 if item 
#9 is rated less than 3. For Factor and 
Total scores, prorate this item on the 
basis if items 9 through 11.) 
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13. RATE SENSE OF PURPOSE 
This item is to rate the degree to which the person posits realistic, integrated goals for his 
life. If the person's current life reflects such goals, it is not necessary that he (she) be 
planning a change in order to be judged to have a good sense of purpose. 
Suggested questions:
What makes life worth living for you? 
Do you think much about the future? 
Have you set any goals for yourself? 
What do you anticipate your living and 
working situation to be a few months from 
now?
What plans do you have for your life over 
the next year or so – personal as well as job 
related ones?
0 - No plans, or plans are bizarre, delusional, 
or grossly unrealistic 
1 - 
2 - Has plans, but they are vague, somewhat 
unrealistic, poorly integrated with one 
another, or of little consequence to the 
person's life 
3 - 
4 - Realistic and concise plans for next year 
or so but little integration into long-range 
life plan 
5 - 
6 - Realistic, concise, and integrated plans, 
both short- and long-range 
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14. RATE DEGREE OF MOTIVATION 
This item is to rate the extent to which the person is unable to initiate or sustain goal-
directed activity due to inadequate drive. 
Suggested questions:
How have you been going about 
accomplishing your goals? 
What other things have you worked on or 
accomplished recently? 
Have there been tasks in any area that you 
wanted to do but didn't because you 
somehow didn't get around to it? 
Has this experience of just not getting 
around to it interfered with your regular 
daily activities? 
How motivated have you been? 
Have you had much enthusiasm, energy,  
and drive? . 
Have you tended to get into a rut? 
Have you tended to put things off? 
0 - Lack of motivation significantly 
interferes with basic routine 
1 - 
2 - Able to meet basic maintenance demands 
of life, but lack of motivation 
significantly impairs any progress or new 
accomplishments 
3 - 
4 - Able to meet routine demands of life and 
some new accomplishments, but lack of 
motivation results in significant 
underachievement in some areas 
5 - 
6 - No evidence of significant lack of 
motivation
 
 
 
 
.
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15. RATE CURIOSITY 
This item is to rate the degree to which the person is interested in his surroundings and 
questions those things he doesn't understand. Exclude interest in hallucinations or delusions 
or other psychotic products. However, pathological preoccupation with psychotic products 
or other themes may limit curiosity or interest in other things.
Suggested questions:
How often have you seen or heard about 
something that you wanted to know more 
about or understand better? 
What sorts of things? 
Have you done anything to learn more  
about them? Please specify. 
Have you read the newspapers, or listened  
to the news on TV or radio? 
Were you interested in any issues in
current events or sports? 
How curious about things have you been? 
0 - Very little curiosity or interest in new 
topics or events 
1 - 
2 - Some sporadic curiosity, but not pursued 
in thought or action 
3 - 
4 - Some curiosity and time spent thinking 
about topics or interest and some actual 
effort to learn more about them 
5 - 
6 - Curiosity about a number of topics and 
some effort to learn more about some of 
them such as reading, asking questions 
and planned observation 
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16. RATE ANHEDONIA 
This item is to rate the person's capacity to experience pleasure and humor. Do not rate 
anhedonia that presents as the result of a clear and observable depressive syndrome, e.g., 
agitation, crying, marked feelings of wickedness and worthlessness, etc. However, 
anhedonia accompanied by apathy and withdrawal from which depression may be inferred 
should be rated. Ask any questions necessary to determine the presence of depression and 
its effect on hedonic capacity. This is to be distinguished from the capacity to display 
affect, which is not rated here. 
Suggested questions:
Have you been able to enjoy yourself? 
How often have you really enjoyed or
gotten satisfaction from something you
were doing? 
How often did you choose to do something 
that struck you as amusing or made you  
feel like laughing? 
Did you have trouble getting enjoyment 
from things that seemed like they should
be fun? Do other people seem to get more 
enjoyment in things than you do? 
Did you often spend the better part of the 
day bored or disinterested in things? 
0 - Nearly complete inability to experience 
pleasure or humor
1 - 
2 - Some sporadic and limited experiences 
of pleasure or humor but a predominant 
lacking of these capacities 
3 - 
4 - Some regular experiences of pleasure & 
humor but reduced in extent & intensity 
5 - 
6 - No evidence of anhedonia or can be 
explained completely by concurrent 
depression or anxiety
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17. RATE TIME UTILIZATION 
This item is to rate the amount of time passed in aimless inactivity -sleeping during the 
day, lying in bed, sitting around doing nothing or in front of the TV or radio when not 
particularly interested. 
Suggested questions:
Did you spend much time doing nothing  
Just sitting around or in bed? 
Did you spend much time watching TV or 
listening to music - were you really 
interested or just had nothing better to do? 
Did you sleep much during the day? 
How much of your days were spent in  
these ways? 
How have you utilized your time? 
Did you tend to waste time? 
0 - Spends the vast majority of his day in 
aimless activity 
1 - 
2 - Spends about half of his days in aimless 
activity
3 - 
4 - Some excessive aimless inactivity but 
less than half his day 
5 - 
6 - No excessive aimless inactivity beyond 
the normal amount required for 
relaxation
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18. RATE COMMONPLACE OBJECTS 
This item assumes that basic participation in living in this culture nearly always requires a 
person to possess certain objects. 
Suggested questions:
For this question, inquire about each of
the 12 items listed below. 
Are you wearing or carrying the following? 
(1) 
a wallet or purse 
(2) 
keys 
(3) 
a driver's license 
(4) 
a watch 
(5) 
a credit card 
(6) 
a Social Security or 
Medical Assistance card 
Do you have with you at your place of 
residence the following? 
(1) 
a map of the city or area 
(2) 
your own alarm clock 
(3) 
a comb or hair brush 
(4) 
an overnight bag 
(5) 
a library card 
(6) 
postage stamps 
0 - Absence of nearly all commonplace 
objects (0 items) 
1 - 
2 - Major deficit of commonplace 
objects (3-4 items) 
3 - 
4 - Moderate deficit (7-8 items) 
5 - 
6 - Little or no deficit (11-12 items) 
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19. RATE COMMONPLACE ACTIVITIES 
This item assumes that basic participation in living in this culture nearly always requires a 
person to engage in certain activities. 
Suggested questions:
For this item inquire about each of the 
8 items listed below. Which of the 
following have you done in the past two 
weeks? (1) read a newspaper, (2) paid a 
bill, (3) wrote a letter, (4) gone to a 
movie or play, (5) driven a car or 
ridden public transportation alone, 
(6) shopped for food, (7) shopped for other 
than food, (8) eaten in a restaurant, 
(9) taken a book or record out of the 
library, (10) participated in a public 
gathering, (11) attended a sporting event, 
(12) visited a public park or other 
recreational facility. 
0 - Absence of nearly all activities (0 items) 
1 - 
2 - Major deficit (3-4 items) 
3 - 
4 - Moderate deficit (7-8 items) 
5 - 
6 - Little or no deficit 
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20. RATE CAPACITY FOR EMPATHY
This item is to rate the person's capacity to regard and appreciate the other person's 
situation as different from his own - to appreciate different perspectives, affective states 
and points of view. It is reflected in the person's description of interactions with other 
people and how he views such interactions. Specific probing to elicit the person's 
description and assessment of relevant situations can be done at this time if sufficient data 
has not emerged thus far in the interview. 
Suggested questions:
Consider someone you are close to or  
spend a lot of time with. What about
them irritates or annoys you? What 
about you irritates or annoys them? 
What things do they like? What 
things that you do please them? If 
they appear upset, how do you usually 
react? If you have an argument or 
difference of opinion with them, how 
do you handle it? 
Are you usually sensitive to the 
feelings of others? 
Are you affected very much by how 
other people feel? 
0 - Shows no capacity to consider the views 
and feelings of others 
1 - 
2 - Shows little capacity to consider the 
views and feelings of others 
3 - 
4 - He can consider other people's views and 
feelings but tends to be caught up in his 
own world. 
5 - 
6 - He spontaneously considers the other 
person's situation in most instances, can 
intuit the other person's affective 
responses, and uses this knowledge to 
adjust his own responses. 
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21. RATE CAPACITY FOR ENGAGEMENT AND EMOTIONAL INTERACTION 
WITH INTERVIEWER 
This item is to rate the person's ability to engage the interviewer, to make him feel 
affectively in touch and acknowledge him as a participant individual in the encounter, and 
to react in a give and take way. 
This is a global judgment based on the  
entire interview. 
0 - Interviewer feels virtually ignored with 
essentially no sense of engagement, with 
very little reactivity 
1 - 
2 - Very limited engagement 
3 - 
4 - Engagement somewhat limited or present 
erratically
5 - 
6 - Consistently good engagement and 
reactivity
Page 115


 
CONFIDENTIAL 
Clinical Protocol Amendment 1.0 (Amendment 1.0) 
Alkermes, Inc. 
 
APPENDIX I. NEGATIVE SYMPTOM ASSESSMENT-16 (NSA-16) 
(SAMPLE) 
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June 22, 2015 
 
10 
Negative Symptom Assessment-16  (NSA-16)—Long Form 
 
 
 
1. Prolonged time to respond.  After asking the subject a question, he/she pauses for 
inappropriately long periods before answering.  Rate severity of the frequency of these 
pauses. 
 
 
1. No abnormal pauses before speaking 
2. Minimal evidence of inappropriate pauses, may be extreme of normal 
3. Occasionally pauses long enough before answering the question to cause you to 
wonder whether he/she heard it 
4. Long pauses occur frequently (20-40% of responses) 
5. Long pauses occur most of the time (40-80% of responses) 
6. Long pauses occur with almost every response (80-100% of responses) 
9.   Not ratable (use only when all efforts to rate this item have failed)  
 
2. Restricted speech quantity.  This item assesses the amount of speech the subject provides 
in the course of the interview.  Ratings on this item suggest that the subject gives brief 
answers to questions and/or provides elaborating details only after the interviewer prods him. 
 
1. Normal speech quantity 
2. Minimal reduction in quantity, may be extreme of normal 
3. Speech seems reduced, but more can be obtained with minimal prodding 
4. Speech is maintained only by regularly prodding the subject 
5. Responses are usually limited to a few words and/or details are only obtained by 
prodding or bribing 
6. Responses are usually non-verbal or limited to 1 or 2 word answers (despite one’s 
best efforts to get the subject to elaborate)   
9.   Not ratable (use only when all efforts to rate this item have failed) 
 
3. Impoverished speech content.  The subject may talk a lot or a little but the information 
conveyed is very limited.  If this symptom is pronounced, you will feel you have little more 
information at the end of the conversation than at the beginning.  For subjects who give 
minimal responses, rate item based on what the interviewer knows after asking probing 
questions. 
 
1. Normal speech content 
2. Minimal reduction in content, may be extreme of normal 
3. Ideas are sometimes vague 
4. Ideas are vague and/or some ideas remain vague even after the interviewer asks for 
clarification 
5. Ideas remain vague even after the interviewer asks for clarification 
6. No ideas can be clarified beyond vague 
9.   Not ratable (use only when all efforts to rate this item have failed) 
 
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June 22, 2015 
 
11 
4. Inarticulate speech.  The subject’s speech cannot be understood because enunciation is 
poor.  Do not rate psychotic sub-vocalizations if the rest of the subject’s speech is normal and 
these utterances are not addressed to the interviewer.  For subjects with a strong dialect, rate 
on the basis of the subject’s ability to articulate and not on their competence with the 
language.   
 
1. Clear speech, not mumbled  
2. Minimal garbled speech, may be extreme of normal  
3. A few words slurred, but can be understood in context 
4. The subject must occasionally be asked to repeat mumbled words 
5. Many words are difficult to understand; the subject must frequently be asked to 
repeat, but on repeating can usually be understood 
6. Little language can be understood even after repeating 
9.   Not ratable (use only when all efforts to rate this item have failed) 
 
5. Emotion: Reduced range.  Emotion is the feeling content of a person’s inner life.  This item 
assesses the range of emotion experienced by the subject during the last week (or other 
specified time period).  Base ratings on the subject’s answers to queries of whether he/she 
has felt happy, sad, etc. during the last week, as well as any reports of having these emotions 
later in the interview.  A full range of emotions would include, but not be limited to happiness, 
sadness, pride, fear, surprise, and anger.  This item should be distinguished from the 
capacity to display affect, which is rated elsewhere.  (If you sense that a subject’s emotional 
life is autistic and not contextually validated, rate his/her emotional range according to your 
interpretations of his/her experience.) 
 
1. Normal range of emotion 
2. Minimal reduction in range, may be extreme of normal 
3. Range seems restricted relative to a normal person, but during the specified time 
frame subject convincingly reports at least 4 emotions.   
4. Subject convincingly identifies 2 or 3 emotional experiences 
5. Subject convincingly identifies only 1 emotional experience  
6. Subject reports little or no emotional range 
9.   Not ratable (use only when all efforts to rate this item have failed) 
 
6. Affect: Reduced modulation of intensity.  This item assesses the subject’s modulations of 
intensity of affect shown during the interview while discussing matters that would be expected 
to elicit significantly different affective intensities in a normal person 
 
1. Normal modulations of affect 
2. Minimal reduction of modulation, may be extreme of normal 
3. Affective intensity is muted relative to normal, but some spontaneous change in 
affective intensity appropriate to the content of conversation is observed 
4. Affective responses are clearly blunted; but by asking more pointed questions, 
appropriate changes in affective intensity can be elicited  
5. Intensity of affect is modulated only slightly, even after prodding 
6. Affective responses are never modulated, even after prodding  
9.   Not ratable (use only when all efforts to rate this item have failed) 
 
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June 22, 2015 
 
12 
7. Affect: Reduced display on demand.  Affect is the outward expression of a person’s 
feelings.  This items assesses the subject’s ability to display a range of affect as expressed 
by changes in his/her facial expression and gestures when asked by the interviewer to show 
how his/her face appears when he/she feels happy, sad, proud, scared, surprised, and angry.  
(Although capable, some subjects are reticent about making facial expressions on demand.  
The interviewer may encourage the subject until convinced that he/she is unable, or unwilling 
to assume the expression.  Do not accept correct affective expressions that are half-hearted 
and unconvincing, and do not accept descriptions of affective expressions.)  
 
1. Subject convincingly displays all requested affective expressions 
2. Subject convincingly displays 5 of 6 requested affective expressions   
3. Subject displays any 4 of 6 requested affective expressions 
4. Subject displays any 2 or 3 of 6 requested affective expressions 
5. Subject displays any 1 of 6 requested affective expressions  
6. Subject is unable to display any of the affective expressions 
9.   Not ratable (use only when all efforts to rate this item have failed) 
 
8. Reduced social drive.  This item assesses how much the subject desires to initiate social 
interactions.  Desire may be measured in part by the number of actual or attempted social 
contacts with others.  To rate severity probes the type of social interactions, and their 
frequency.  Remember the reference range is a normal 20 year old.  Many subjects may be 
rated 2 to 3. 
 
1. Normal social drive 
2. Minimal reduction in social drive, may be extreme of normal 
3. Desire for social interactions seems somewhat reduced 
4. Obvious reduction in desire to initiate social contacts, but a number of contacts are 
initiated each week 
5. Marked reduction in the subject’s desire to initiate social contacts, but a few contacts 
are maintained at subject’s initiation (as with family) 
6. No desire to initiate any social interactions 
9.   Not ratable (use only when all efforts to rate this item have failed) 
 
 
9. Poor rapport with interviewer.  This item assesses the interviewer’s subjective sense that 
he/she and the subject are actively engaged in communication with one another.  Evaluate 
both verbal and nonverbal aspects of communication.  Do no rate hostility as lack of rapport.   
 
1. Normal rapport 
2. Minimal reduction in rapport, may be extreme of normal 
3. Interviewer sometimes has to carry the conversation because the subject’s interest 
seems reduced 
4. Interchanges are generally dull and uninspiring; interviewer must often lead the 
conversation because subject is detached  
5. Interviewer must prod to engage the subject in the interview 
6. Prodding does not result in engagement with the interviewer 
9.   Not ratable (use only when all efforts to rate this item have failed) 
 
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June 22, 2015 
 
13 
10. 
Interest in emotional and physical intimacy. This item assesses how much the subject 
retains interest in emotional and/or physical intimate activities.  Do not exclusively rate 
actual performance even though in many instances performance might indicate desire 
and non-performance the absence of it.  Take the subject’s marital and environmental 
situations into account when rating this item.  (Because of his/her illness, he/she may be 
unable to find a suitable partner; if hospitalized, he/she may be discouraged from being 
intimate with others.)  Emotional and physical intimacy interest can be expressed by a 
wide variety of activities.  If the subject claims to be interested in emotional and physical 
intimacy interest but his/her performance is not consistent with his/her claim, the rater 
should ask him/her to account for this discrepancy.   
 
1. Desires to engage in some form of emotional and/or physical intimate activity once a 
day or more 
2. Desires to engage in some form of emotional and/or physical intimate activity 3-6 
times a week 
3. Desires to engage in some form emotional and/or physical intimate activity once or 
twice a week 
4. Desires to engage in some form of emotional and/or physical intimate activity 1-3 
time a month 
5. Desires to engage in some form of emotional and/or physical intimate activity several 
times a year 
6. No emotional and/or physical intimate interest is reported 
9.   Not ratable (use only when all efforts to rate this item have failed) 
 
11. Poor grooming and hygiene.  The subject presents with poorly groomed hair, disheveled 
clothing, etc.  Do not rate grooming as poor if it is simply done in what a middle-class 
observer might consider poor taste (e.g.; wild hairdo or excessive facial makeup).   
 
1. Normal grooming and hygiene 
2. Minimal reduction of grooming and hygiene, may be extreme of normal 
3. Clean but untidy, or clothes are mismatched 
4. Clothes are unkempt and unbuttoned (looks as if subject just got out of bed) 
5. Clothes are dirty or stained, or has an odor   
6. Clothes are badly soiled and/or subject has a foul odor 
9.   Not ratable (use only when all efforts to rate this item have failed) 
 
12. Reduced sense of purpose.  This item assesses whether the subject posits integrated goals 
for his/her life.  If the subject already has what seems to be a satisfactory and well-integrated 
life, it is not necessary that he/she be planning a change to be judged as having a good 
sense of purpose. 
 
1. Normal sense of purpose 
2. Minimal reduction in purpose, may be extreme of normal 
3. Life goals somewhat vague, but current activities suggest purpose 
4. Subject has difficulty coming up with life goals, but activities are directed toward 
limited goal or goals 
5. Goals are very limited or have to be suggested, and activities are not focused toward 
achieving any of them 
6. No identifiable life goals 
9.   Not ratable (use only when all efforts to rate this item have failed) 
 
13. Reduced hobbies and interest.  This item assesses the range and intensity of the subject’s 
interests. 
 
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June 22, 2015 
 
14 
1. Normal interests  
2. Minimal reduction in interests, may be extreme of normal 
3. Range of interests and/or commitment to them seems diminished 
4. Range of interests is clearly diminished and is not particularly committed to interests 
held 
5. Only 1 or 2 interests reported, and these pursued superficially   
6. No identifiable goals   
9.   Not ratable (use only when all efforts to rate this item have failed) 
 
14. Reduced daily activity.  This item assesses the level of the subject’s daily activity and 
his/her failure to take advantage of the opportunities his/her environment offers.  Get a 
complete account of what the subject does from the time he/she gets up until he goes to bed.  
Compare his/her activities with those of a young person who is not mentally ill.  If the subject 
participates as an outpatient in a mental health program, determine the level of his/her 
participation, i.e. whether he/she is actively involved, or just passes time there.  If the subject 
is hospitalized rate his/her daily activity as you would for a young person who is not 
hospitalized and without regard for the limitations that the hospital routine may place on 
him/her.   
 
1. Normal daily activity 
2. Minimal reduction in activity, may be extreme of normal 
3. Employed, attends school or volunteers, but is underachieving; few hobbies  
4. Not involved in the activities expected of a normal young person (may be 
unemployed, or minimally employed for education, but may be involved in a mental 
health program one or more days a week) 
5. Most of day spent doing activities, things that require minimal mental or physical 
exertion (watches TV, smokes, drinks coffee, walks to store, but may be involved in a 
mental health program one or more days a week)   
6. Most of day is spent sitting in a chair or lying in bed; has little or no regard for what 
goes on in immediate environment 
9.   Not ratable (use only when all efforts to rate this item have failed) 
 
15. Reduced expressive gestures.  Gestures and body movements that normally facilitate 
communication during speech are less than normal, or are not observed at all.  Do not rate 
involuntary movement disorders. 
 
1. Normal expressive gestures 
2. Minimal reduction in gestures, may be extreme of normal 
3. Hand and head gestures normally seen during conversation are reduced 
4. Hand or head gestures are infrequent; gestures may be limited to periods when the 
subject is discussing topics of special interest 
5. Gestures infrequent even during discussion of highly emotional topics 
6. Gestures are never observed 
9.   Not ratable (use only when all efforts to rate this item have failed) 
 
16. Slowed movements.  This item assesses how much the subject’s voluntary movements are 
slowed.  At a minimum one should rate movements as gait and those of rising from a chair.  
Rate these movements in comparison to a normal young person 
 
1. Normal speed of movements  
2. Minimal reduction in speed of movements, may be extreme of normal 
3. Voluntary movements are slightly retarded or slowed 
4. Movements are generally sluggish 
5. Most movements are retarded and made with effort 
6. All movements are made with extreme effort; subject must be assisted from chair 
9.   Not ratable (use only when all efforts to rate this item have failed) 
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June 22, 2015 
 
15 
 
Page 122


June 22, 2015 
 
16 
GLOBAL NEGATIVE SYMPTOMS RATING.  Rate this item on the basis of overall impression of 
negative symptoms in the subject, not on the basis of a single item or total score. 
 
1. No evidence of negative symptoms  
2. Minimal evidence of negative symptoms  
3. Mild evidence of negative symptoms 
4. Moderate evidence of negative symptoms apparent to the casual observer 
5. Marked evidence of negative symptoms readily apparent to the casual observer 
6. Severe evidence of negative symptoms marked and obvious impact on functioning 
7. Extremely severe negative symptoms (incapacitating) 
 
 
Page 123


 
CONFIDENTIAL 
Clinical Protocol Amendment 1.0 (Amendment 1.0) 
Alkermes, Inc. 
 
APPENDIX J. PATIENT SATISFACTION WITH MEDICATION 
QUESTIONNAIRE (PSMQ)-MODIFIED (SAMPLE) 
Page 124


 
MODIFIED MEDICATION SATISFACTION QUESTIONNAIRE (MSQ) 
 
 
  
Overall, how satisfied are you with your current medication? 
 
Very 
Dissatisfied 
Somewhat 
Dissatisfied 
Neither 
Dissatisfied 
nor Satisfied 
Somewhat 
Satisfied 
Very 
Satisfied 
    □      □      □      □      □  
1 
2 
3 
4 
5 
 
 
Overall, do you prefer your current LAI medication or your previous LAI medication 
for the treatment of Schizophrenia (prior to your participation in this study)? 
 
 
Much 
Prefer 
Previous LAI 
Prefer 
Previous LAI 
Neither 
Prefer 
Previous nor 
Current LAI 
Prefer 
Current LAI 
Much Prefer 
Current LAI 
    □      □      □      □      □  
1 
2 
3 
4 
5 
 
 
How would you rate the side effects of your current LAI medication, compared with 
previous LAI medication for the treatment of Schizophrenia (prior to your participation 
in this current study)? 
 
Much Less 
Side Effects 
Less Side 
Effects 
The Same  
as Previous 
More Side 
Effects 
Much More 
Side Effects 
    □      □      □      □      □  
1 
2 
3 
4 
5 
 
 
 
 
 
© International Society for CNS Drug Development (ISCDD)  
 
Page 125


 
CONFIDENTIAL 
Clinical Protocol Amendment 1.0 (Amendment 1.0) 
Alkermes, Inc. 
 
APPENDIX K. SIXTH EDITION OF THE TREATMENT SERVICES 
REVIEW (TSR-6) (SAMPLE) 
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Page 1 of 7 
ALK9072-A401 
TREATMENT SERVICES REVIEW (Version 6) – Modified for Mental Health 
This interview asks about different services you may have received over the past ___ days, since DATE.  It 
includes medical services, emotional or psychological services, family, marital or parenting services, 
financial or housing services, and legal services.  Do you have any questions before we get started? 
 
TIME STARTED: 
 
 
DEMOGRAPHIC INFORMATION 
 
 
 
 
Patient initials: 
 
Interviewer Name: 
 
 
 
 
 
Patient Number: 
 
Date of Interview: 
 
 
 
 
 
Patient Marital Status 
(circle one): 
1. Married 
2. Living as married 
3. Widowed 
4. Divorced 
5. Separated 
6. Never married 
7. No reply 
 
 
Coverage Period 
From: 
To: 
 
NUMBER OF DAYS IN RECALL PERIOD: 
 
 
G1 
Where did you stay for the past ___ days? 
 
# of Days 
 
1. Alone (in private house, apartment, hotel, etc.) 
 
__ __ __ 
 
2. With others (in private house, apartment, hotel, group home, 
assisted living residence, etc.) 
 
 
__ __ __ 
 
3. Institution, e.g. hospital, jail, prison (controlled environment) 
 
 
 
(a) Hospital/Residential treatment 
 
__ __ __ 
 
(b) Jail or prison 
 
__ __ __ 
 
(c) Day treatment or partial hospital program 
 
__ __ __ 
 
4. Homeless shelter 
 
__ __ __ 
 
5. Homeless, i.e. on the street, in an abandoned building, in a car 
 
__ __ __ 
 
 
 
 
 
 
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Page 2 of 7 
ALK9072-A401 
MEDICAL SERVICES 
Questions about any medical treatment you have received over the past ___ days 
 
 
 
 
M1 
How many nights were you an inpatient in a medical hospital, nursing 
home, or medical rehabilitation facility? 
 
 
__ __ __ 
 
1a) Specify: 
 
 
 
Medical hospital 
 
__ __ __ 
 
Nursing home or medical rehab 
 
__ __ __ 
 
If 0, Skip to M2 
 
 
 
1b) Diagnosis/major problem ________________________ 
1c) Major procedures or evaluations __________________ 
 
 
 
 
 
 
? 
ON PAST ___ DAYS WHEN NOT IN A MEDICAL HOSPITAL: 
 
 
 
 
 
 
M2 
How many times did you visit an emergency room? 
 
__ __ __ 
 
IF 0, SKIP to M3 
 
 
 
2a) What was your reason(s) for visiting the ER?  Check all that apply: 
 
 
 
Medical 
 
1 – Yes 
2 – No 
 
Psychological 
 
1 – Yes 
2 – No 
 
Substance Use 
 
1 – Yes 
2 – No 
 
2b) Diagnosis/major problem ________________________ 
 
 
 
2c) Major procedures or evaluations __________________ 
 
 
 
 
 
 
M3 
How many times did you visit a medical doctor (physician, psychiatrist) 
for testing, examination, treatment, or care of medical 
concerns/problems? 
Note: we will ask you about visits for psychological or emotional 
concerns later. 
 
 
 
 
 
__ __ __ 
 
If 0, SKIP TO M4 
 
 
 
3a) Diagnosis/major problem ________________________ 
 
 
 
3b) Major procedures or evaluations __________________ 
 
 
 
 
 
 
M4 
How many times did you visit any other medical professional (e.g. 
dentist, optometrist, nurse, physical therapist, X-ray or lab technician) 
for testing, examination, or treatment of medical concerns/problems? 
 
 
 
__ __ __ 
 
If 0, SKIP TO M5 
 
 
 
4a) Diagnosis/major problem ________________________ 
 
 
 
4b) Major procedures or evaluations __________________ 
 
 
 
 
 
 
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Page 3 of 7 
ALK9072-A401 
M5 
How many (individual or group) counseling sessions did you attend 
with non-medical personnel during which medical concerns/problems 
were the main focus (exclude all previously recorded visits)? 
 
 
 
__ __ __ 
 
If 0, SKIP TO M6 
 
 
 
5a) Number of sessions with: 
 
__ __ __ 
 
Non-medical doctor (e.g. psychologist – Ph.D./Psy. D) 
 
__ __ __ 
 
Physician assistant, Nurse prescriber (Practitioner, APNP) 
 
__ __ __ 
 
Nurse 
 
__ __ __ 
 
Other clinician (e.g. counselor, social worker, case manager, 
clergy) 
 
__ __ __ 
 
Group member(s) (i.e. a support group not professionally led) 
 
__ __ __ 
 
Don’t know 
 
__ __ __ 
 
5b) On average, how long did a session last? (record # of minutes) 
 
__ __ mins 
 
5c) How many of these were group sessions? 
 
__ __ __ 
 
PSYCHOLOGICAL SERVICES 
Questions about any emotional or psychological services received over the past ___ days 
P1  
How many nights were you an inpatient in a psychiatric hospital or 
psych treatment unit (i.e., stayed overnight)? Where? ______________ 
 
 
__ __ __ 
 
1a) Diagnosis/major problem ________________________ 
 
 
 
1b) Major procedures or evaluations __________________ 
 
 
 
 
 
 
? 
On past ___ days NOT in psychiatric inpatient treatment: 
 
 
 
 
 
 
P2 
On how many days did you attend any treatment for mental health, 
emotional or psychological problems? 
 
 
__ __ __ 
 
Where? ________________________ 
 
 
 
2a) How many of these were day hospital or intensive outpatient 
programs? 
 
 
__ __ __ 
 
 
 
 
P3 
How many individual (one-on-one) sessions did you attend during 
which your mental health, emotional or psychological problems were 
the main purpose of the discussion (not including inpatient or day 
hospital/intensive outpatient programs)? 
 
 
 
 
__ __ __ 
 
If 0, SKIP TO P4 
 
 
 
3a) Number of individual sessions with: 
 
 
 
Medical doctor (e.g. psychiatrist or physician) 
 
__ __ __ 
 
Non-medical doctor (e.g. psychologist – Ph.D./Psy. D.) 
 
__ __ __ 
 
Physician assistant, Nurse prescriber (Practitioner, APNP) 
 
__ __ __ 
 
Nurse 
 
__ __ __ 
 
Other clinician (e.g. counselor, social worker, case manager, 
clergy) 
 
__ __ __ 
 
Group member(s) (i.e. a support group not professionally led) 
 
__ __ __ 
 
Don’t know 
 
__ __ __ 
 
3b) On average, how long did each individual session last? (# of 
minutes) 
 
 
__ __ mins 
 
 
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Page 4 of 7 
ALK9072-A401 
P4 
How many group sessions did you attend for mental health, emotional 
or psychological problems? 
 
 
__ __ __ 
 
If 0, SKIP TO FAMILY SERVICES 
 
 
 
4a) Number of group sessions with: 
 
 
 
Medical doctor (e.g. psychiatrist or physician) 
 
__ __ __ 
 
Non-medical doctor (e.g. psychologist – Ph.D./Psy. D.) 
 
__ __ __ 
 
Physician assistant, Nurse prescriber (Practitioner, APNP) 
 
__ __ __ 
 
Nurse 
 
__ __ __ 
 
Other clinician (e.g. counselor, social worker, case manager, 
clergy) 
 
__ __ __ 
 
Group member(s) (i.e. a support group not professionally led) 
 
__ __ __ 
 
Don’t know 
 
__ __ __ 
 
4b) On average, how long did a group session last? (# of minutes) 
 
__ __  mins 
 
4c) On average, how many other patients were in a group? 
 
__ __ __ 
 
4d) On average, how many group leaders were present in each session? 
 
__ __ __ 
 
FAMILY SERVICES 
Questions about family or parenting services received over past ___ days. 
 
 
 
 
F1 
How many classes or sessions did you attend to help with parenting or 
problems with children?   
 
__ __ __ 
 
 
If 0, SKIP TO F3 
 
 
 
1a) Number of sessions with: 
 
 
 
Medical doctor (e.g. psychiatrist or physician) 
 
__ __ __ 
 
Non-medical doctor (e.g. psychologist – Ph.D./Psy. D.) 
 
__ __ __ 
 
Physician assistant, Nurse prescriber (Practitioner, APNP) 
 
__ __ __ 
 
Nurse 
 
__ __ __ 
 
Other clinician (e.g. counselor, social worker, case manager, 
clergy) 
 
__ __ __ 
 
Group member(s) (i.e. a support group not professionally led) 
 
__ __ __ 
 
Don’t know 
 
__ __ __ 
 
1b) On average, how long did a session last? 
 
__ __ mins 
 
1c) In how many of these sessions were members of other families 
present? 
 
 
__ __ __ 
 
 
 
 
F2 
How many treatment sessions did you attend with some member(s) of 
your family or significant other? (exclude those recorded in previous 
sections) 
 
 
 
__ __ __ 
 
2a) Number of those with: 
 
 
 
Medical doctor (e.g. psychiatrist or physician) 
 
__ __ __ 
 
Non-medical doctor (e.g. psychologist – Ph.D./Psy. D.) 
 
__ __ __ 
 
Physician assistant, Nurse prescriber (Practitioner, APNP) 
 
__ __ __ 
 
Nurse 
 
__ __ __ 
 
Other clinician (e.g. counselor, social worker, case manager, 
clergy) 
 
__ __ __ 
 
Group member(s) (i.e. a support group not professionally led) 
 
__ __ __ 
 
Don’t know 
 
__ __ __ 
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Page 5 of 7 
ALK9072-A401 
 
2b) On average, how long did a session last? (# of minutes) 
 
__ __  mins 
 
2c) In how many of these sessions were members of other families 
present? 
 
 
__ __ __ 
 
 
 
 
F3 
How many sessions did you attend to deal with relationship issues (e.g. 
domestic violence, communication issues) where no other family 
member was present? (exclude any previously recorded) 
 
 
 
__ __ __ 
 
3a) Number of those with: 
 
 
 
Medical doctor (e.g. psychiatrist or physician) 
 
__ __ __ 
 
Non-medical doctor (e.g. psychologist – Ph.D./Psy. D.) 
 
__ __ __ 
 
Physician assistant, Nurse prescriber (Practitioner, APNP) 
 
__ __ __ 
 
Nurse 
 
__ __ __ 
 
Other clinician (e.g. counselor, social worker, case manager, 
clergy) 
 
__ __ __ 
 
Group member(s) (i.e. a support group not professionally led) 
 
__ __ __ 
 
Don’t know 
 
__ __ __ 
 
3b) On average, how long did a session last? (# of minutes) 
 
__ __ mins 
 
3c) How many of these were group sessions? 
 
__ __ __ 
 
FINANCIAL/EMPLOYMENT/HOUSING SERVICES 
Questions about any specialized educational, financial, employment, or housing services received over 
the past ___ days. 
 
 
 
 
E1 
How many days did you attend school or formal training (e.g. 
apprenticeship, internship)? 
 
 
__ __ __ 
 
 
 
 
E2 
How many days did you work in a therapeutic work setting/sheltered 
workshop? 
 
 
__ __ __ 
 
 
 
 
E3 
How many sessions did you attend where job/education counseling or 
placement was the main focus? 
 
 
__ __ __ 
 
3a) Number of those with: 
 
 
 
Job or education counselor 
 
__ __ __ 
 
Anyone else (i.e. non-specialist) 
 
__ __ __ 
 
 
 
 
E4  
 
How many sessions did you attend where specific housing services 
were the main focus? 
 
__ __ __ 
 
4a) Number of those with: 
 
 
 
Any housing specialist 
 
__ __ __ 
 
Anyone else (i.e., non-specialist) 
 
__ __ __ 
 
 
 
 
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Page 6 of 7 
ALK9072-A401 
E5 
How many sessions or classes did you attend where financial/benefits 
issues were main focus? 
 
 
__ __ __ 
 
5a) Number of those with: 
 
 
 
Benefits or financial counselor, or any other financial specialist? 
 
__ __ __ 
 
Anyone else (i.e. non-specialist) 
 
__ __ __ 
 
LEGAL SERVICES 
Following questions concern any legal or correctional involvement over past ___ days. 
 
L1 
Have you been arrested, picked up, or transported by police in the 
last ___ days?  YES OR NO 
 
1 – Yes 
2 – No 
 
1a) If yes, why? (Check all that apply) 
 
 
 
           Vagrancy (street person/begging/homelessness/transient) 
 
1 – Yes 
2 – No 
 
           Related to Drug/Alcohol use or possession 
 
1 – Yes 
2 – No 
 
           Disorderly conduct/disturbing the peace 
 
1 – Yes 
2 – No 
 
           Public endangerment 
 
1 – Yes 
2 – No 
 
           Other:  ___________________________________________ 
 
1 – Yes 
2 – No 
 
1b) If yes, for how many days were you incarcerated? 
 
__ __ __ 
 
OTHER SERVICES 
 
O1 
Did you receive any other services during past ___ days (e.g. food bank, 
soup kitchen)? 
 
1 – Yes 
2 – No 
 
1a) Specify: _______________________ 
 
 
 
1b) Specify: _______________________ 
 
 
 
1c) Specify: _______________________ 
 
 
 
1d) Specify: _______________________ 
 
 
 
 
 
 
O2 
In the past ___ days, did someone help you manage your overall 
condition – including your physical health, mental health, social, 
housing, financial and legal situation – by giving you information about 
the kind of help that is available or by putting you in touch with others 
who could help you? (e.g. case management) [not including services 
already recorded] 
 
 
1 – Yes 
2 – No 
 
2a) On how many days did you meet/speak with him/her? 
 
__ __ __ 
 
 
 
 
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Page 7 of 7 
ALK9072-A401 
O3 
Throughout this interview, you’ve told me about different services you’ve received over the past 
___ days [give examples of services patient has described].  I realize things aren’t that cut and 
dried – I know, for example, that you don’t just talk about medical issues; you can talk about 
social or emotional or family or medical problems.  The same is true when you go to the doctor – 
you don’t just talk about medical problems; you can talk about emotional issues or a lot of other 
things.  What I’d like to do now is to get a sense of that.  Given all the services and treatments and 
contacts you’ve had in the past ___ days, how much of all of that dealt with: 
 
3a) Your physical health or medical problems? 
 
 
 
0 
1 
2 
3 
4 
 
 
None 
A little bit 
Some 
Quite a bit 
A lot 
 
 
 
 
 
 
 
 
3b) Your mental health or psychological problems and issues? 
 
 
 
 
 
 
 
 
0 
1 
2 
3 
4 
 
 
None 
A little bit 
Some 
Quite a bit 
A lot 
 
 
3c) Your family problems and issues? 
 
 
 
 
 
 
 
 
0 
1 
2 
3 
4 
 
 
None 
A little bit 
Some 
Quite a bit 
A lot 
 
 
 
 
 
 
 
 
3d) Your employment, education, finances, or house? 
 
 
 
 
 
 
 
 
0 
1 
2 
3 
4 
 
 
None 
A little bit 
Some 
Quite a bit 
A lot 
 
 
 
 
 
 
 
 
3e) Your legal or criminal problems and issues? 
 
 
 
 
 
 
 
 
0 
1 
2 
3 
4 
 
 
None 
A little bit 
Some 
Quite a bit 
A lot 
 
 
 
 
 
 
 
 
 
TIME ENDED: 
 
 
Page 133


 
CONFIDENTIAL 
Clinical Protocol Amendment 1.0 (Amendment 1.0) 
Alkermes, Inc. 
 
APPENDIX L. CAREGIVER QUALITY OF LIFE (CARERQOL) – 
BURDEN DIMENSIONS (7D) [BROUWER WBF, 2006] 
AND VISUAL ANALOG SCALE (VAS) (SAMPLE) 
Page 134


For Review Only
CarerQol-7D
Please draw an “X” to indicate which description best fits your current care giving situation
no
some
a lot of
a.
I have
fulfillment with carrying out my care tasks.
b.
I have
relational problems with the care receiver (e.g., he/she is very demanding,
he/she behaves differently, we have communication problems).
c.
I have
problems with my own mental health (e.g., stress, fear, gloominess, depression,
concern about the future).
d.
I have
problems combining my care tasks with my daily activities (e.g., household 
activities, work, study, family and leisure activities).
e.
I have
financial problems because of my care tasks.
f.
I have
support with carrying out my care tasks, when I need it (e.g., from family,
friends, neighbors, acquaintances).
g.
I have
problems with my own physical health (e.g., more often sick, tiredness,
physical stress).
CarerQol-VAS
Please draw an “X” on the scale below to indicate how happy you feel at this moment 
Completely 
unhappy
Completely 
happy
0
1
2
3
4
5
6
7
8
9
10
Derived from Brouwer WB, van Exel NJ, van Gorp B, Redekop WK. The CarerQol instrument: a new 
instrument to measure care-related quality of life of informal caregivers for use in economic evaluations. Qual 
Life Res. 2006 Aug;15(6):1005-21.
Page 135


 
CONFIDENTIAL 
Clinical Protocol Amendment 1.0 (Amendment 1.0) 
Alkermes, Inc. 
 
APPENDIX M. BURDEN ASSESSMENT SCALE (SAMPLE) 
Page 136


For Review Only
Burden Assessment Scale (BAS) 
 
I am going to read a list of things which other people have found to happen to them because of their 
relative’s illness. Would you tell me to what extent you have had any of the following experiences in the 
past six months.  
Not at all
1
A little
2
Some
3
A lot
4
N/A
9
 
Because of (name’s) illness, to what extent have you:  
1.
Had financial problems  
2.
Missed days at work (or school) 
3.
Found it difficult to concentrate on your own activities  
4.
Had to change your personal plans like taking a new job, or going on vacation  
5.
Cut down on leisure time  
6.
Found the household routine was upset  
7.
Had less time to spend with friends  
8.
Neglected other family members’ needs  
9.
Experienced family frictions and arguments  
10. Experienced frictions with neighbors, friends, or relatives outside the home  
11. Became embarrassed because of (name’s) behavior  
12. Felt guilty because you were not doing enough to help  
13. Felt guilty because you felt responsible for causing (name’s) problem  
14. Resented (name) because s/he made too many demands on you  
15. Felt trapped by your caregiving role  
16. Were upset about how much (name) had changed from his or her former self  
17. Worried about how your behavior with (name) might make the illness worse  
18. Worried about what the future holds for (name)  
19. Found the stigma of the illness upsetting 
 
 
 
 
Burden Assessment Scale, 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. 
Page 137


 
CONFIDENTIAL 
Clinical Protocol Amendment 1.0 (Amendment 1.0) 
Alkermes, Inc. 
 
APPENDIX N. BIRCHWOOD INSIGHT SCALE (BIS) (SAMPLE) 
Page 138


IS – (present)
Please read the following statements carefully and then tick the box 
which best applies to you.
Agree
Disagree
Unsure
1. Some of the symptoms were 
made by my mind 
 
2. I am mentally well 
 
 
3. I do not need medication 
 
 
4. My stay in hospital was 
necessary 
 
5. The doctor is right in 
prescribing medication for me 
 
6. I do not need to be seen by a 
doctor or psychiatrist 
 
7. If someone said I had a nervous 
or mental illness then they would 
be right 
8. None of the unusual things I 
experienced are due to an illness 
 
 
 
 
 
For 
For
For
ew 
Revie
Revie
Revie
Only
O y
Page 139


Insight Scale (IS) 
(Coding Schedule) 
 
 
Agree 
Disagree 
Unsure 
1. Some of the symptoms were 
made by my mind 
 
2 
0 
1 
2. I am mentally well 
 
 
0 
2 
1 
3. I do not need medication 
 
 
0 
2 
1 
4. My stay in hospital was 
necessary
 
2 
0 
1 
5. The doctor is right in 
prescribing medication for me 
 
2 
0 
1 
6. I do not need to be seen by a 
doctor or psychiatrist 
 
0 
2 
1 
7. If someone said I had a 
nervous or mental illness then 
they would be right 
2 
0 
1 
8. None of the unusual things I 
experienced are due to an illness 
 
0 
2 
1 
 
Maximum Score  
= 12   -  Full insight 
Minimum Score   
= 0     -  No insight 
(9 and above = good insight) 
 
Subscales 
Items
Possible Total
1, 8
Awareness of symptoms
4
(3or 4 = good insight,
1 or 2 = poor insight)
2, 7
Awareness of illness 
4
(3or 4 = good insight, 
1 or 2 = poor insight)
3, 4, 5, 6
Need for treatment 
(items need to be added and divided by 2)
4
(3or 4 = good insight, 
1 or 2 = poor insight)
For
e saidFor
mental illness
For 
be right
eview 
Re
Re
Re
henRe
2
e
w Only
0
y
Page 140


 
CONFIDENTIAL 
Clinical Protocol Amendment 1.0 (Amendment 1.0) 
Alkermes, Inc. 
 
APPENDIX O. NEW YORK ASSESSMENT OF ADVERSE COGNITIVE 
EFFECTS OF NEUROPSYCHIATRIC TREATMENT 
(NY-AACENT) SUBSCALES (SAMPLE) 
Page 141


 
SMPL/RA Version 
Sept-2015 
NY-AACENT-R, ©2012, M. Opler, D. Antonius, C. Correll. All Rights Reserved.  
Not to be reproduced or distributed without express written permission of the authors. 
New York Assessment of Adverse Cognitive Effects of Neuropsychiatric Treatment 
 
Description: The NY-AACENT is intended to be used to detect changes in cognitive function subsequent to pharmacological or 
similar treatments for neurological or psychiatric problems. It is originally designed to be used in pediatric populations, but can be 
utilized with other age groups as appropriate. Each of the seven items is derived from the seven domains identified by MATRICS1. 
When coupled with similar adverse event assessments (such as the PAERS2) that are intended to be used in drug treatment 
studies, data on select items on the NY-AACENT (e.g. item #2, Attention/Vigilance) may be imputed from other, identical items 
(e.g. item #9 on the PAERS.)  
 
Instructions: It is recommended that the patient and caregiver forms be completed first as a brief interview, conducted 
separately with subjects and parents. After this has been completed, the forms should be reviewed and the clinician form 
completed, summarizing best judgment. If specific symptoms are reported to be present, please determine: 
 
 
- 
Whether the symptoms are likely due to a study medication or concomitant medication (if used in the context of a 
research study); 
- 
The time-frame of the symptoms, i.e. whether or not they have only emerged or changed subsequent to beginning 
treatment; 
- 
The extent to which the symptom does or does not have an impact on functioning. 
 
After all information has been collected, the clinician or researcher is instructed to complete the Clinician Form, scoring each 
section accordingly.  
 
Conducting the Interviews. Brief, separate interviews with both patients and caregivers are recommended. For certain subjects, it 
is advisable to interview the patient prior to interviewing the caregiver. In cases where the patient is a poor historian or presents 
with other impairments that reduce the validity of side effect reporting, both the patient and caregiver may be interviewed 
together. The interview should cover each domain of cognition and focus on eliciting specific examples, determining the extent to 
which social, academic or role functioning are impaired, and the emergence of symptoms in relation to the administration of a 
specific medication. If etiology is unclear, it is advisable to ask follow-up questions. 
 
Domains: Seven domains of cognition are covered in the NY-AACENT. These include –  
 
1. Working memory 
2. Attention/Vigilance 
3. Verbal Learning/Memory 
4. Visual Learning/Memory 
5. Reasoning & Problem Solving  
6. Speed of Processing 
7. Social Cognition  
 
It is strongly advised that prior to conducting the interviews, investigators review the domains of cognition carefully and ensure 
that when querying patients or caregivers, that the proper aspects of cognition and functioning are being considered. 
                                                          
1 Green MF, Nuechterlein KH, Gold JM, Barch DM, Cohen J, Essock S, Fenton WS, Frese F, Goldberg TE, Heaton RK, Keefe RS, Kern RS, Kraemer 
H, Stover E, Weinberger DR, Zalcman S, Marder SR. Approaching a consensus cognitive battery for clinical trials in schizophrenia: the NIMH-
MATRICS conference to select cognitive domains and test criteria. Biol Psychiatry. 2004; 56(5):301-7. 
2 March J, Karayal O, Chrisman A. CAPTN: The Pediatric Adverse Event Rating Scale. Paper presented at: Scientific Proceedings of the 2007 
Annual Meeting of the American Academy of Child and Adolescent Psychiatry; October 23-28, 2007, 2007; Boston, MA. 
Page 142


 
SMPL/RA Version 
Sept-2015 
NY-AACENT-R, ©2012, M. Opler, D. Antonius, C. Correll. All Rights Reserved.  
Not to be reproduced or distributed without express written permission of the authors. 
Patient Form: Please focus on the past week. (If you have experienced one of these problems, but not in the past week, check 
“Not Present.”) If present in the past week, indicate the extent to which the described symptom bothered you or was a problem 
for you. 
 
1. Do you have trouble remembering things that people (co-workers, clinicians, caregivers, friends, relatives) have said to 
you, immediately after you hear them? 
 Not 
Present  
 A little bit 
bothersome/ 
a mild 
problem 
 Somewhat 
bothersome/ 
a moderate 
problem 
 Quite 
bothersome/   
a severe 
problem 
 Very 
bothersome
/ an 
extreme 
problem 
 Not applicable 
 Not medication related 
 Possibly due to a specific medication/medications 
(please list:) 
__________________________________________ 
Quite likely due to a specific medication/medications 
(please list:) 
______________________________________________ 
 Almost definitely due to a specific 
medication/medications (please list:) 
_____________________________________________ 
2. Do you have trouble paying attention in different settings (home, work, clinic, day programs etc), watching TV, browsing 
the internet or using computers? 
 Not 
Present  
 A little bit 
bothersome/ 
a mild 
problem 
 Somewhat 
bothersome/ 
a moderate 
problem 
 Quite 
bothersome/   
a severe 
problem 
 Very 
bothersome
/ an 
extreme 
problem 
 Not applicable 
 Not medication related 
 Possibly due to a specific medication/medications 
(please list:) 
______________________________________________ 
Quite likely due to a specific medication/medications 
(please list:) 
_____________________________________________ 
 Almost definitely due to a specific 
medication/medications (please list:) 
_____________________________________________ 
3. Is it difficult for you to learn or remember words to things (books, songs, TV shows)? Are you able to come up with 
words in conversation? 
 Not 
Present  
 A little bit 
bothersome/ 
a mild 
problem 
 Somewhat 
bothersome/ 
a moderate 
problem 
 Quite 
bothersome/   
a severe 
problem 
 Very 
bothersome
/ an 
extreme 
problem 
 Not applicable 
 Not medication related 
 Possibly due to a specific medication/medications 
(please list:) 
_____________________________________________ 
Quite likely due to a specific medication/medications 
(please list:) 
_____________________________________________ 
 Almost definitely due to a specific 
medication/medications (please list:) 
_____________________________________________ 
4. Do you have difficulty recalling how things look, including shapes, colors? 
 Not 
Present  
 A little bit 
bothersome/ 
a mild 
problem 
 Somewhat 
bothersome/ 
a moderate 
problem 
 Quite 
bothersome/   
a severe 
problem 
 Very 
bothersome
/ an 
extreme 
problem 
 Not applicable 
 Not medication related 
 Possibly due to a specific medication/medications 
(please list:) 
______________________________________________ 
Quite likely due to a specific medication/medications 
(please list:) 
_____________________________________________ 
 Almost definitely due to a specific 
medication/medications (please 
list:)________________________________________ 
 
Page 143


 
SMPL/RA Version 
Sept-2015 
NY-AACENT-R, ©2012, M. Opler, D. Antonius, C. Correll. All Rights Reserved.  
Not to be reproduced or distributed without express written permission of the authors. 
5. Do you have trouble managing money, solving problems, doing puzzles, dealing with new challenges? 
 Not 
Present  
 A little bit 
bothersome/ 
a mild 
problem 
 Somewhat 
bothersome/ 
a moderate 
problem 
 Quite 
bothersome/   
a severe 
problem 
 Very 
bothersome
/ an 
extreme 
problem 
 Not applicable 
 Not medication related 
 Possibly due to a specific medication/medications 
(please list:) 
______________________________________________ 
Quite likely due to a specific medication/medications 
(please list:) 
_____________________________________________ 
 Almost definitely due to a specific 
medication/medications (please list:) 
_____________________________________________ 
6. Do you feel “slowed down”, does it take you longer than usual to do things? 
 Not 
Present  
 A little bit 
bothersome/ 
a mild 
problem 
 Somewhat 
bothersome/ 
a moderate 
problem 
 Quite 
bothersome/   
a severe 
problem 
 Very 
bothersome
/ an 
extreme 
problem 
 Not applicable 
 Not medication related 
 Possibly due to a specific medication/medications 
(please list:) 
_____________________________________________ 
Quite likely due to a specific medication/medications 
(please list:) 
_____________________________________________ 
 Almost definitely due to a specific 
medication/medications (please list:) 
____________________________________________ 
7. Do you have trouble understanding what other people intend or want from you, participating in social situations, or 
interacting with others? 
 Not 
Present  
 A little bit 
bothersome/ 
a mild 
problem 
 Somewhat 
bothersome/ 
a moderate 
problem 
 Quite 
bothersome/   
a severe 
problem 
 Very 
bothersome
/ an 
extreme 
problem 
 Not applicable 
 Not medication related 
 Possibly due to a specific medication/medications 
(please list:) 
_____________________________________________ 
Quite likely due to a specific medication/medications 
(please list:) 
_____________________________________________ 
 Almost definitely due to a specific 
medication/medications (please list:) 
_____________________________________________ 
 
Page 144


 
SMPL/RA Version 
Sept-2015 
NY-AACENT-R, ©2012, M. Opler, D. Antonius, C. Correll. All Rights Reserved.  
Not to be reproduced or distributed without express written permission of the authors. 
Caregiver Form: Please focus on the past week. If the patient has experienced one of these problems, but not in the past week 
check “Not Present.” If present in the past week, indicate the extent to which the item bothered him/her by checking one of the 
boxes marked 1 through 4. 
 
1. Patient has trouble remembering things that people (co-workers, clinicians, caregivers, friends, relatives) have just said 
immediately after hearing them? 
 Not 
Present  
 A little bit 
bothersome/ 
a mild 
problem 
 Somewhat 
bothersome/ 
a moderate 
problem 
 Quite 
bothersome/   
a severe 
problem 
 Very 
bothersome
/ an 
extreme 
problem 
 Not applicable 
 Not medication related 
 Possibly due to a specific medication/medications 
(please list:) 
_____________________________________________ 
Quite likely due to a specific medication/medications 
(please list:) 
_____________________________________________ 
 Almost definitely due to a specific 
medication/medications (please list:) 
______________________________________________ 
2. Patient has trouble paying attention in in different settings (home, work, clinic, day programs etc) or while playing games, 
watching TV, browsing the internet or using computers? 
 Not 
Present  
 A little bit 
bothersome/ 
a mild 
problem 
 Somewhat 
bothersome/ 
a moderate 
problem 
 Quite 
bothersome/   
a severe 
problem 
 Very 
bothersome
/ an 
extreme 
problem 
 Not applicable 
 Not medication related 
 Possibly due to a specific medication/medications 
(please list:) 
_____________________________________________ 
Quite likely due to a specific medication/medications 
(please list:) 
_____________________________________________ 
 Almost definitely due to a specific 
medication/medications (please list:) 
_____________________________________________ 
3. Is it difficult to for the patient to learn or remember words to things (book, songs, TV shows)? Is the patient able to come 
up with words in conversation? 
 Not 
Present  
 A little bit 
bothersome/ 
a mild 
problem 
 Somewhat 
bothersome/ 
a moderate 
problem 
 Quite 
bothersome/   
a severe 
problem 
 Very 
bothersome
/ an 
extreme 
problem 
 Not applicable 
 Not medication related 
 Possibly due to a specific medication/medications 
(please list:) 
____________________________________________ 
Quite likely due to a specific medication/medications 
(please list:) 
____________________________________________ 
 Almost definitely due to a specific 
medication/medications (please list:) 
____________________________________________ 
4. Does the patient have difficulty recalling how things look, such as shapes and colors? 
 Not 
Present  
 A little bit 
bothersome/ 
a mild 
problem 
 Somewhat 
bothersome/ 
a moderate 
problem 
 Quite 
bothersome/   
a severe 
problem 
 Very 
bothersome
/ an 
extreme 
problem 
 Not applicable 
 Not medication related 
 Possibly due to a specific medication/medications 
(please list:) 
____________________________________________ 
Quite likely due to a specific medication/medications 
(please list:) 
_____________________________________________ 
 Almost definitely due to a specific 
medication/medications (please list:) 
_____________________________________________ 
 
Page 145


 
SMPL/RA Version 
Sept-2015 
NY-AACENT-R, ©2012, M. Opler, D. Antonius, C. Correll. All Rights Reserved.  
Not to be reproduced or distributed without express written permission of the authors. 
5. Does the patient have trouble managing money, solving problems, doing puzzles, dealing with new challenges? 
 Not 
Present  
 A little bit 
bothersome/ 
a mild 
problem 
 Somewhat 
bothersome/ 
a moderate 
problem 
 Quite 
bothersome/   
a severe 
problem 
 Very 
bothersome
/ an 
extreme 
problem 
 Not applicable 
 Not medication related 
 Possibly due to a specific medication/medications 
(please list:) 
____________________________________________ 
Quite likely due to a specific medication/medications 
(please list:) 
_____________________________________________ 
 Almost definitely due to a specific 
medication/medications (please list:) 
_____________________________________________ 
 
6. Does the patient feel “slowed down”, does it take him/her longer than usual to do things? 
 Not 
Present  
 A little bit 
bothersome/ 
a mild 
problem 
 Somewhat 
bothersome/ 
a moderate 
problem 
 Quite 
bothersome/   
a severe 
problem 
 Very 
bothersome
/ an 
extreme 
problem 
 Not applicable 
 Not medication related 
 Possibly due to a specific medication/medications 
(please list:) 
_____________________________________________ 
Quite likely due to a specific medication/medications 
(please list:) 
_____________________________________________ 
 Almost definitely due to a specific 
medication/medications (please list:) 
_____________________________________________ 
 
7. Does the patient have trouble understanding what other people intend, participating in social situations, or interacting 
with others? 
 Not 
Present  
 A little bit 
bothersome/ 
a mild 
problem 
 Somewhat 
bothersome/ 
a moderate 
problem 
 Quite 
bothersome/   
a severe 
problem 
 Very 
bothersome
/ an 
extreme 
problem 
 Not applicable 
 Not medication related 
 Possibly due to a specific medication/medications 
(please list:) 
____________________________________________ 
Quite likely due to a specific medication/medications 
(please list:) 
____________________________________________ 
 Almost definitely due to a specific 
medication/medications (please list:) 
____________________________________________ 
Page 146


 
SMPL/RA Version 
Sept-2015 
NY-AACENT-R, ©2012, M. Opler, D. Antonius, C. Correll. All Rights Reserved.  
Not to be reproduced or distributed without express written permission of the authors. 
Clinician Form: Please complete each section below:  
 
1. Working memory: Trouble remembering things that people (co-workers, clinicians, caregivers, friends, relatives) have just 
said? 
 Present 
during past 
week 
 Not present 
in past week 
 Evident During 
Visit 
 Not Evident 
During Visit 
 Not drug related  
 Due to study drug  
 Other drug 
 Drug/drug interaction 
 Not applicable 
 Mild 
 Moderate 
 Severe 
 Extreme 
 Not applicable 
 Functional/ Role 
Impairment 
 No Functional/ 
Role Impairment 
 Not applicable 
 
2. Attention/Vigilance: Trouble paying attention in in different settings (home, work, clinic, day programs etc) or while 
playing games, watching TV, browsing the internet or using computers? 
 Present 
during past 
week 
 Not present 
in past week 
 Evident During 
Visit 
 Not Evident 
During Visit 
 Not drug related  
 Due to study drug  
 Other drug 
 Drug/drug interaction 
 Not applicable 
 Mild 
 Moderate 
 Severe 
 Extreme 
 Not applicable 
 Functional/ Role 
Impairment 
 No Functional/ 
Role Impairment 
 Not applicable 
 
3. Verbal Learning/Memory: Difficulty remembering or learning words to things (book, songs, TV shows)? Trouble coming 
up with words in conversation? 
 Present 
during past 
week 
 Not present 
in past week 
 Evident During 
Visit 
 Not Evident 
During Visit 
 Not drug related  
 Due to study drug  
 Other drug 
 Drug/drug interaction 
 Not applicable 
 Mild 
 Moderate 
 Severe 
 Extreme 
 Not applicable 
 Functional/ Role 
Impairment 
 No Functional/ 
Role Impairment 
 Not applicable 
 
4. Visual Learning/Memory: Patient has difficulty recalling how things look, such as shapes and colors? 
 Present 
during past 
week 
 Not present 
in past week 
 Evident During 
Visit 
 Not Evident 
During Visit 
 Not drug related  
 Due to study drug  
 Other drug 
 Drug/drug interaction 
 Not applicable 
 Mild 
 Moderate 
 Severe 
 Extreme 
 Not applicable 
 Functional/ Role 
Impairment 
 No Functional/ 
Role Impairment 
 Not applicable 
 
5. Reasoning & Problem Solving: Trouble managing money, solving problems, doing puzzles, dealing with new challenges? 
 Present 
during past 
week 
 Not present 
in past week 
 Evident During 
Visit 
 Not Evident 
During Visit 
 Not drug related  
 Due to study drug  
 Other drug 
 Drug/drug interaction 
 Not applicable 
 Mild 
 Moderate 
 Severe 
 Extreme 
 Not applicable 
 Functional/ Role 
Impairment 
 No Functional/ 
Role Impairment 
 Not applicable 
 
6. Speed of Processing: Feeling “slowed down”, does it take you longer than usual to do things? 
 Present 
during past 
week 
 Not present 
in past week 
 Evident During 
Visit 
 Not Evident 
During Visit 
 Not drug related  
 Due to study drug  
 Other drug 
 Drug/drug interaction 
 Not applicable 
 Mild 
 Moderate 
 Severe 
 Extreme 
 Not applicable 
 Functional/ Role 
Impairment 
 No Functional/ 
Role Impairment 
 Not applicable 
 
7. Social Cognition: Trouble understanding what other people intend, participating in social situations, or interacting with 
others? 
 Present 
during past 
week 
 Not present 
in past week 
 Evident During 
Visit 
 Not Evident 
During Visit 
 Not drug related  
 Due to study drug  
 Other drug 
 Drug/drug interaction 
 Not applicable 
 Mild 
 Moderate 
 Severe 
 Extreme 
 Not applicable 
 Functional/ Role 
Impairment 
 No Functional/ 
Role Impairment 
 Not applicable 
Notes: 
Page 147


 
CONFIDENTIAL 
Clinical Protocol Amendment 1.0 (Amendment 1.0) 
Alkermes, Inc. 
 
APPENDIX P. MINI INTERNATIONAL NEUROPSYCHIATRIC 
INTERVIEW (M.I.N.I.) – MODULES I AND J (SAMPLE) 
Page 148


 
CONFIDENTIAL 
Clinical Protocol Amendment 1.0 (Amendment 1.0) 
Alkermes, Inc. 
 
APPENDIX Q. LIST OF POTENT CYTOCHROME P450 3A4 (CYP3A4) 
INDUCERS AND MODERATE-TO-STRONG 
INHIBITORS OF 3A4 OR 2D6 
 
3A4 
2D6 
Inducers 
Inhibitors 
Inhibitors 
• 
Carbamazepine 
• 
Barbiturates  
(eg, Phenobarbital) 
• 
Phenytoin 
• 
Rifampin 
• 
Modafinil 
• 
Cyproterone (eg, 
antiandrogen, progestin, 
Diane-35) 
• 
Non-nucleotide reverse 
transcriptase inhibitors  
(eg, efavirenz, 
nevirapine, etravirine) 
• 
Hyperforin; St. John’s 
Wort 
• 
Ketoconazole 
• 
Itraconazole 
• 
Fluconazole 
• 
Clarithromycin 
• 
Erythromycin 
• 
Telithromycin 
• 
Nefazodone 
• 
Fluvoxamine 
• 
Protease inhibitors 
(ritonavir, indinavir, 
nelfinavir) 
• 
Verapamil 
• 
Grapefruit juice 
• 
Bergamottin 
• 
Quercetin 
• 
Quinidine 
• 
Selective serotonin reuptake 
inhibitors 
(eg, fluoxetine, paroxetine) 
• 
Duloxetine 
• 
Bupropion 
• 
MDMA 
(3,4-Methylenedioxymeth-
amphetamine; Ecstasy) 
• 
Terbinafine  
• 
Goldenseal  
(Hydrastis canadensis) 
 
Page 149

SAP_001.pdf: 
Safety and Tolerability of Initiating Aripiprazole Lauroxil in 
Subjects with Schizophrenia who are Inadequately Treated 
with Paliperidone Palmitate or Risperidone Long Acting 
Injection 
 
 
Unique Protocol ID: 
ALK9072-A401 
NCT Number: 
NCT02634320 
Date of Statistical Analysis 
Plan:  
18 July 2017 
 


Alkermes, Inc. 
 
Statistical Analysis Plan 
ALK9072-A401                                                                                                                                           Confidential 
 
1 
 
 
STATISTICAL ANALYSIS PLAN 
PHASE 4 
ALK9072-A401 
 
Study Title: 
Safety and Tolerability of Initiating Aripiprazole Lauroxil in Subjects 
with Schizophrenia who are Inadequately Treated with Paliperidone 
Palmitate or Risperidone Long Acting Injection 
Document Status: 
Final 
Version: 
1.0 
Document Date: 
July 18, 2017 
Based on: 
Study Protocol Amendment 1 (dated 07 September 2016) 
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-A401 
 
Confidential 
 
 
 
Page 2 of 14 
TABLE OF CONTENTS 
ABBREVIATIONS .........................................................................................................................4 
1. 
INTRODUCTION ........................................................................................................6 
1.1. 
Study Objectives ...........................................................................................................6 
1.1.1. 
Primary Objectives .......................................................................................................6 
1.1.2. 
Secondary Objectives ...................................................................................................6 
1.2. 
Summary of the Study Design and Schedule of Assessments ......................................6 
2. 
SAMPLE SIZE AND STATISTICAL POWER CONSIDERATION .........................7 
3. 
DATA ANALYSIS ......................................................................................................7 
3.1. 
General Statistical Methodology ..................................................................................7 
3.2. 
Study Population ...........................................................................................................8 
3.2.1. 
Definitions of Analysis Populations (Analysis Sets) ....................................................8 
3.2.1.1. 
Safety Population ..........................................................................................................8 
3.2.2. 
Disposition ....................................................................................................................8 
3.2.3. 
Protocol Deviations ......................................................................................................8 
3.3. 
Demographics and Baseline Characteristics .................................................................8 
3.4. 
Treatment Adherence Rate and Extent of Exposure .....................................................8 
3.5. 
Efficacy Analyses .........................................................................................................9 
3.5.1. 
Clinical Global Impressions-Severity (CGI-S) .............................................................9 
3.5.2. 
Brief Psychiatric Rating Scale (BPRS).........................................................................9 
3.6. 
Quality of Life Analyses ...............................................................................................9 
3.6.1. 
Personal and Social Performance Scale (PSP) .............................................................9 
3.6.2. 
Negative Symptom Assessment-16 (NSA-16) .............................................................9 
3.6.3. 
Quality of Life Scale (QLS) .........................................................................................9 
3.7. 
Safety and other Analysis .............................................................................................9 
3.7.1. 
Adverse Events .............................................................................................................9 
3.7.2. 
Prior and Concomitant Medications ...........................................................................10 
3.7.3. 
Clinical Laboratory Parameters ..................................................................................10 
3.7.4. 
Vital Signs ..................................................................................................................11 
3.7.5. 
Body Weight, Waist Circumferences, and Body Mass Index (BMI) .........................12 
3.7.6. 
Injection Site Reactions ..............................................................................................12 
3.7.7. 
Columbia Suicide Severity Rating Scale (C-SSRS) ...................................................12 


Alkermes, Inc. 
 
Statistical Analysis Plan 
ALK9072-A401 
 
Confidential 
 
 
 
Page 3 of 14 
3.7.8. 
Extrapyramidal Symptom Rating Scale – Abbreviated (ESRS-A) ............................12 
3.7.9. 
Modified Medication Satisfaction Questionnaire (Modified –MSQ) .........................12 
3.7.10. 
Sexual Functioning Subscale from UKU Side Effect Rating Scale and 
CSFQ-14 .....................................................................................................................12 
3.7.11. 
Burden Assessment Scale (BAS)................................................................................13 
3.7.12. 
Birchwood Insight Scale (BIS) ...................................................................................13 
3.7.13. 
Mini International Neuropsychiatric Interview (M.I.N.I.) Module I & J ...................13 
3.7.14. 
Other Assessments ......................................................................................................13 
4. 
INTERIM ANALYSES ..............................................................................................13 
5. 
CHANGES IN CONDUCT OR PLANNED ANALYSES FROM THE 
PROTOCOL ...............................................................................................................13 
6. 
DEFINITIONS AND CONVENTIONS FOR HANDLING OF THE DATA ..........13 
6.1. 
Analysis Visit Windows .............................................................................................14 
6.2. 
Safety Data Handling ..................................................................................................14 
6.3. 
Handling of Partial Dates of Concomitant Medication ..............................................14 
7. 
PROGRAMMING SPECIFICATIONS .....................................................................14 
8. 
MOCK TABLES, LISTINGS AND GRAPHS (TLGS) ............................................14 
9. 
REFERENCES ...........................................................................................................14 
 
LIST OF TABLES 
Table 1: 
List of Abbreviations ....................................................................................................4 
Table 2: 
Clinical Laboratory Parameters - PCS Criteria ..........................................................10 
Table 3: 
Vital Signs - Clinical Laboratory Parameters - PCS Criteria .....................................12 
 
 


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Statistical Analysis Plan 
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ABBREVIATIONS 
The following abbreviations are used in this statistical analysis plan. 
Table 1: 
List of Abbreviations  
Abbreviation or term 
Explanation 
AE 
adverse event 
ALK-P 
alkaline phosphatase 
ALT 
alanine aminotransferase 
AST 
aspartate aminotransferase 
ATC 
Anatomical Therapeutic Chemical [classification system] 
BAS 
Burden Assessment Scale 
BIS 
Birchwood Insight Scale 
BPRS 
Brief Psychiatric Rating Scale 
CarerQOL-7D 
Caregiver Quality of Life – Burden Dimensions 
CGI-S 
Clinical Global Impressions-Severity 
CPK 
creatine phosphokinase 
CSA 
Clinical Study Agreement 
CSFQ-14 
Changes in Sexual Functioning Questionnaire Short Form 
CRO 
contract research organization 
C-SSRS 
Columbia Suicide Severity Rating Scale 
DSM-5 
Diagnostic and Statistical Manual of Mental Disorders – Fifth Edition 
EC 
Ethics Committee 
ECG 
electrocardiogram 
eCRF 
electronic case report form 
ESRS-A 
Extrapyramidal Symptom Rating Scale - Abbreviated 
ET 
early termination 
FDA 
Food and Drug Administration 
GCP 
Good Clinical Practice 
GGP 
gamma-glutamyl transferase 
HR 
heart rate 
IB 
Investigator’s Brochure 
ICF 
informed consent form 


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Abbreviation or term 
Explanation 
ICH 
International Conference on Harmonisation of Technical Requirements for 
Registration of Pharmaceuticals for Human Use 
IRB 
Institutional Review Board 
ISR 
injection site reaction 
LAI 
long acting injectable antipsychotic 
LDH 
lactic dehydrogenase 
MedDRA 
Medical Dictionary for Regulatory Activities 
M.I.N.I. 
Mini International Neuropsychiatric Interview 
MSQ 
Medication Satisfaction Questionnaire 
NSA-16 
Negative Symptom Assessment-16 
NY-AACENT 
New York Assessment of Adverse Cognitive Effects of Neuropsychiatric 
Treatment 
PK 
pharmacokinetics 
PSP 
Personal and Social Performance 
QLS 
Quality of Life Scale 
RR 
respiratory rate 
SAE 
serious adverse event 
SAP 
statistical analysis plan 
SD 
standard deviation 
TEAE 
treatment-emergent adverse event 
TSR-6 
Sixth edition of the Treatment Services Review 
UKU 
Udvalg for Kliniske Undersøgelser 
ULN 
upper limit of normal 
VAS 
Visual Analog Scale 
WHO 
World Health Organization 


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1. 
INTRODUCTION 
This statistical analysis plan (SAP) describes the statistical methods and data presentation to be 
used for analyzing and reporting safety, tolerability, and efficacy data for study ALK9072-A401. 
This document has been prepared based on Alkermes ALK9072-A401 Study Protocol 
Amendment 1 (dated 07 September 2016) [1]. 
1.1. 
Study Objectives 
1.1.1. 
Primary Objectives 
To evaluate the safety, tolerability, and efficacy of aripiprazole lauroxil in subjects with 
schizophrenia who are inadequately treated with paliperidone palmitate or risperidone long 
acting injection (LAI). 
1.1.2. 
Secondary Objectives 
To evaluate quality of life, including daily and social functioning, after treatment with 
aripiprazole lauroxil. 
To characterize the caregiver and healthcare burden. 
1.2. 
Summary of the Study Design and Schedule of Assessments 
ALK9072-A401 is a Phase 4, multicenter, open-label study in approximately 50 subjects who are 
transitioned to aripiprazole lauroxil from long acting injectable risperidone or paliperidone 
palmitate. In total, subjects will participate for approximately 7 months, including a screening 
period of up to 30 days, and will be administered 4 to 6 doses of IM aripiprazole lauroxil 
(Figure 1). Dosing may occur in monthly (441 mg, 662 mg, or 882 mg) or 6-week (882 mg only) 
intervals. The dose and frequency of dosing will be at the discretion of the investigator, based on 
the subject’s history, dose selected, and on dosing instructions. 
Figure 1: 
Study Design (ALK9072-A401) 
 
Potential subjects will be evaluated for eligibility according to the inclusion and exclusion 
criteria at a screening visit and again pre-dose on Day 1. The first dose of aripiprazole lauroxil 
will be administered on Day 1. Subjects will receive their first dose of aripiprazole lauroxil no 
Day
(127)
Monthly AL injection 
Q 6 weeks AL injection
(882 mg)
Screening
1
29
57
85
113 
141
169
EOT/ET
Treatment Period 
-30 to -1
( 43)
AL =
aripiprazole lauroxil
EOT = end of treatment; ET = early termination


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earlier than one week and not later than six weeks following their previous injection of 
paliperidone palmitate or risperidone. The cross-tapering from risperidone or paliperidone to 
aripiprazole 
lauroxil 
is 
facilitated 
by 
the 
gradual 
disappearance 
of 
plasma 
risperidone/paliperidone while aripiprazole is concomitantly released from the initial IM 
aripiprazole lauroxil injection.  
For subjects who have never taken aripiprazole, two test doses of oral aripiprazole 5 mg will be 
administered during the screening period. Only subjects who exhibit tolerability to oral 
aripiprazole (either following test doses or by past experience) are eligible to enroll in the study. 
On Day 1, qualified subjects will be administered a single IM injection of aripiprazole lauroxil 
into the gluteal (441, 662 or 882 mg) or deltoid (441mg) muscle , according to the dosing 
instructions. Following the first injection, subjects will return to the study site monthly or every 6 
weeks (882 mgonly) for IM aripiprazole lauroxil administration and outpatient assessments. 
Additional outpatient assessments may be scheduled at the discretion of the investigator. 
Efficacy will be evaluated based on Clinical Global Impressions-Severity (CGI-S) and Brief 
Psychiatric Rating Scale (BPRS) responses. 
Safety and tolerability will be evaluated based on adverse events (AEs), injection site reactions 
(ISRs), clinical laboratory data, vital sign data, Columbia Suicide Severity Rating Scale 
(C-SSRS) responses, and Abbreviated Extrapyramidal Symptom Rating Scale (ESRS-A) scores.  
Potential changes in informant-rated cognition, insight, treatment satisfaction, quality of life, 
daily and social functioning, caregiver and healthcare burden, and psychosocial care needs 
following a transition to aripiprazole lauroxil will be examined.  
The sixth edition of the Treatment Services Review (TSR-6)-Modified for Mental Health survey 
will also be listed.  
2. 
SAMPLE SIZE AND STATISTICAL POWER CONSIDERATION  
No formal sample size calculations have been performed.  The sample size is based on clinical 
considerations. 
3. 
DATA ANALYSIS 
3.1. 
General Statistical Methodology 
Descriptive statistics for continuous variables include n, mean, standard deviation, median, 
minimum, and maximum. Descriptive statistics for categorical variables include subject counts 
and percentages. All data summarized will have a corresponding listing created as well. All data 
listings, summaries, and statistical analyses will be generated using SAS® version 9.3 or higher.  
Baseline is defined as the last non-missing value before study drug administration. 
Study days will be numbered relative to the first day of study drug administration.  The start of 
treatment (Day 1) is defined as the date on which a patient takes study drug.  Days will be 
numbered relative to study start (i.e., ..., -2, -1, 1, 2, ...; with day 1 being the start of study drug 
and day -1 being the day before the start of study drug). 


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By visit summarization will be tabulated nominally at the visit information was collected. 
Treatment groups will be categorized into the following 3 groups based on the primary switch 
reasons: 
1. Due to tolerability or metabolic effect 
2. Due to suboptimal efficacy in negative symptoms 
3. Due to suboptimal efficacy in positive symptoms 
 
3.2. 
Study Population 
3.2.1. 
Definitions of Analysis Populations (Analysis Sets) 
3.2.1.1. 
Safety Population 
The safety population will include all subjects who received at least one aripiprazole lauroxil 
injection. All analyses will be carried out using the safety population. 
3.2.2. 
Disposition 
The number and percentage of subjects enrolled, subjects in the safety population, subjects who 
completed the study, and subjects who were prematurely terminated from the study will be 
summarized by treatment group and overall. For subjects who discontinued from the study, the 
reasons for discontinuation as recorded in the disposition page will also be presented. Percentage 
will be calculated based on safety population. 
3.2.3. 
Protocol Deviations 
All major protocol deviations will be summarized and listed. 
3.3. 
Demographics and Baseline Characteristics 
Demographics and baseline characteristics (age, sex, race, ethnicity, weight, height, body mass 
index [BMI]), will be summarized by treatment group and overall. Categories for missing data 
will be provided as necessary. Prior antipsychotic medications (risperidone LAI or paliperidone 
palmitate) and its associated dose level or frequency count at last dose, primary and secondary 
transition reasons, aripiprazole lauroxil dose at initial injection and last injection, caregiver paid 
or non-paid will also be summarized by overall subjects. 
Medical and psychiatric history will be summarized and listed by treatment group and overall.  
3.4. 
Treatment Adherence Rate and Extent of Exposure 
All dosing and exposure information will be included in supportive listings. Cumulative number 
of injection by treatment group and overall for the safety population will be summarized. The 
categories of dose change will be also summarized. 


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3.5. 
Efficacy Analyses 
3.5.1. 
Clinical Global Impressions-Severity (CGI-S) 
The Clinical Global Impressions – Severity (CGI-S) and the change from baseline at each visit 
will be summarized by treatment group and overall using descriptive statistics. A plot of mean 
(SE) of CGI-S score over time will be displayed for all subjects. The one-sample T test at the end 
of treatment period will be conducted to see if the change from baseline is different from zero. 
The T-test will be only applied to all subjects. 
3.5.2. 
Brief Psychiatric Rating Scale (BPRS) 
The Brief Psychiatric Rating Scale (BPRS) total score and the change from baseline at each visit 
will be summarized by treatment group and overall using descriptive statistics. A plot of mean 
(SE) of BPRS total score over time will be displayed for all subjects. The one-sample T test at 
the end of treatment period will be conducted to see if the change from baseline is different from 
zero. The T-test will be only applied to all subjects. The score of unreported item will be imputed 
with the average of all other items at the same visit. 
3.6. 
Quality of Life Analyses 
3.6.1. 
Personal and Social Performance Scale (PSP) 
Observed values and changes of PSP total score and subscale from baseline values will be 
summarized by treatment group and overall at each visit using descriptive statistics. 
3.6.2. 
Negative Symptom Assessment-16 (NSA-16) 
Global rating and total score of Negative Symptom Assessment-16 (NSA-16) and the changes 
from baseline will be summarized by treatment group and overall using descriptive statistics.  
3.6.3. 
Quality of Life Scale (QLS) 
Each 6 subscale of Quality of Life Scale (QLS), total score of 21-items, and the changes from 
baseline will be summarized by treatment group and overall using descriptive statistics. The 
score of unreported item will be imputed with the average of all other items at the same visit. 
3.7. 
Safety and other Analysis 
3.7.1. 
Adverse Events 
Summaries will be presented by treatment group and overall. 
Adverse events will be coded using the Medical Dictionary for Regulatory Activities (MedDRA) 
version 19.0. Treatment-emergent AEs (TEAEs) are defined as AEs that are newly occurring or 
worsening from the time of the first dose of study drug.  
An overview table, including number of subjects with any TEAEs, serious adverse events 
(SAEs), study drug related TEAEs, TEAE by severity, and AE leading to discontinuation will be 
summarized.  
In addition, the TEAEs will be summarized for the following: 


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• 
TEAEs by System Organ Class (SOC) and Preferred Term (PT) 
• 
TEAEs by SOC, PT, and severity 
• 
Drug Related TEAEs by System Organ Class and Preferred Term 
• 
SAEs by System Organ Class and Preferred Term 
• 
AEs leading to discontinuation by System Organ Class and Preferred Term 
A subject having the same AE (as determined by the coded MedDRA preferred term) more than 
once will be counted only once in the number and percentage of subjects' calculation for that AE. 
Similarly, if a subject had more than one AE in a System Organ Class, the subject will be 
counted only once in the number of subjects with an AE for that System Organ Class. If a subject 
has the same AE on multiple occasions, the highest severity (severe > moderate > mild) recorded 
for the event will be presented in the AEs by severity table. Treatment-related AEs are defined as 
those events with a ‘Relationship to Study Treatment’ recorded on CRF as ‘Definitely Related’, 
‘Probably Related’ or ‘Possibly Related’, others will be not related AEs. 
Listings for all AEs, SAEs, and AEs leading to discontinuation will be presented. 
3.7.2. 
Prior and Concomitant Medications 
Prior medications are defined as medications that started and stopped prior to the first dose of 
study drug. Concomitant mediations are defined as medications that started after or were ongoing 
at the time of the first dose of study drug. All medications will be coded using the World Health 
Organization Anatomical Therapeutic Chemical (WHO-ATC) Drug dictionary version March 
2016 of medical codes (WHO Drug). All prior and concomitant medications will be summarized 
and listed. 
3.7.3. 
Clinical Laboratory Parameters 
Laboratory parameters will be presented in conventional (CN) units. Only scheduled lab 
parameters will be included in the laboratory results summaries. 
Observed values and change from baseline will be summarized by treatment group and overall at 
each visit for chemistry and hematology parameters. Additionally, the number and percentage of 
subjects with potentially clinically significant (PCS) results will be presented (and by sex for 
prolactin). Only subjects with non-PCS values at baseline and PCS at any post-baseline visit will 
be included in the summary table. All PCS values (including baseline) will be included in 
supportive listings. For urinalysis, rate of abnormalities will be summarized. 
Criteria for PCS are listed in  Table 2: 
  
 Table 2: 
Clinical Laboratory Parameters - PCS Criteria 
Lab Parameters  
Criteria (Conventional units) 
Chemistry 
 
Albumin 
< 2.5 g/dL 
Alkaline phosphatase(ALK-P) ≥ 3 x ULN    
Alanine aminotransferase 
≥ 3 x ULN 


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Lab Parameters  
Criteria (Conventional units) 
ALT  
Aspartate aminotransferase 
AST   
≥ 3 x ULN 
Bilirubin, Total  
≥ 2.0 mg/dL 
Blood Urea Nitrogen (BUN) 
> 30mg/dL 
Creatinine Kinase (CK) 
> 3 x ULN 
Creatinine  
≥ 2.0 mg/dL 
Creatine phosphokinase  
(CPK), Total  
≥ 3 x ULN 
Cholesterol, Total, fasting  
≥ 240 mg/dL 
Cholesterol, HDL, fasting 
≤ 30 mg/dL 
Cholesterol, LDL, fasting 
≥ 160 mg/dL 
Glucose  
< 50mg/dL or ≥ 200 mg/dL  
Lactic Dehydrogenase (LDH) 
> 3 x ULN 
Potassium 
< 3 mEq/L or > 5.5 mEq/L 
Prolactin by gender 
> 1 x ULN 
> 2 x ULN 
> 3 x ULN 
Sodium  
< 130 mEq/L or > 150 mEq/L 
Triglycerides, fasting 
Female ≥120 mg/dL 
Male ≥ 160 mg/dL 
Hematology 
 
Eosinophils   
> l x 103 /μL 
Hematocrit  
Female ≤ 32% and 3 point decrease from baseline 
Male ≤ 37% and 3 point decrease from baseline 
WBC 
≤ 2.8 x 103 /μL or ≥ 16.0 x 103 /μL 
Neutrophils, absolute  
< 1.5  x 103 /μL 
Platelet count  
< 75,100 cells/μL or ≥ 700,000 cells/μL 
3.7.4. 
Vital Signs 
Observed values and changes from baseline values will be summarized by treatment group and 
overall and assessment time point for each vital sign parameter. Additionally, the number and 
percentage of subjects with potentially clinically significant (PCS) results will be presented. 
Criteria for PCS are listed in Table 3. 


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Table 3: 
Vital Signs - Clinical Laboratory Parameters - PCS Criteria 
Parameter 
PCS Criteria 
Supine Systolic blood pressure 
Low: ≤ 90mm Hg and decrease ≥ 20 mm Hg 
 
High: ≥180 mm Hg and increase ≥ 20 mm Hg 
Supine Diastolic blood pressure 
Low: ≤ 50mm Hg and decrease ≥ 15 mm Hg 
 
High: ≥105 mm Hg and increase ≥ 15 mm Hg 
Supine Pulse 
Low: ≤ 50 bpm and decrease ≥ 15 bpm 
 
High: ≥120 bpm and increase ≥ 15 bpm 
3.7.5. 
Body Weight, Waist Circumferences, and Body Mass Index (BMI) 
Body weight (kg) and waist circumferences (baseline and change from baseline) will be 
summarized by treatment group and overall. The number and percentage of subjects with PCS 
values (≥7% increase or ≥7% decrease at any post-baseline visit will be summarized by 
treatment group and overall. The PCS increase in weight will also be summarized by baseline 
BMI category (Underweight [<18.5 kg/m2], Normal [≥18.5 to <25 kg/m2], Overweight [≥25 to 
<30 kg/m2], and Obese [≥30 kg/m2]). 
3.7.6. 
Injection Site Reactions 
All injection site reactions 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. 
3.7.7. 
Columbia Suicide Severity Rating Scale (C-SSRS) 
The number and percentage of subjects with suicidal ideation and/or behavior (overall and for 
each subcategory) as assessed by the C-SSRS scale during the overall treatment period will be 
summarized by treatment group and overall using descriptive statistics. 
3.7.8. 
Extrapyramidal Symptom Rating Scale – Abbreviated (ESRS-A) 
Each subcategory (Parkinsonism, Dystonia, Dyskinesia, Akathisia), and total score of the 
Abbreviated Extrapyramidal Symptom Rating Scale (ESRS-A) will be summarized by treatment 
group and overall using descriptive statistics. 
3.7.9. 
Modified Medication Satisfaction Questionnaire (Modified –MSQ) 
The proportion of subjects for each category for each question at each visit will be summarized 
by treatment group and overall . 
3.7.10. 
Sexual Functioning Subscale from UKU Side Effect Rating Scale and CSFQ-14 
Observed values and changes of each CSFQ subscale and total score from baseline values will be 
summarized by gender and overall using descriptive statistics. 
The proportion of subjects with each UKU side effect will be summarized by treatment group 
and overall using descriptive statistics.  


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3.7.11. 
Burden Assessment Scale (BAS) 
Observed values and changes of BAS total score from baseline values will be summarized by 
treatment group and overall using descriptive statistics. In addition, the BAS will also be 
summarized by paid or non-paid caregivers. 
3.7.12. 
Birchwood Insight Scale (BIS) 
Observed values and changes of each BIS subscale and total score from baseline values will be 
summarized by treatment group and overall using descriptive statistics.  
3.7.13. Mini International Neuropsychiatric Interview (M.I.N.I.) Module I & J 
The proportion of subjects with Mini International Neuropsychiatric Interview (M.I.N.I.) Module 
I (alcohol use disorder) and Module J (substance use disorder) will be summarized by treatment 
group and overall.  
3.7.14. 
Other Assessments 
Caregiver Quality of Life – Burden Dimensions (CarerQOL–7D) and VAS happiness score, and 
the changes from baseline will be summarized using descriptive statistics as appropriate by 
treatment group, as well as by paid or non-paid caregivers. 
New York Assessment of Adverse Cognitive Effects of Neuropsychiatric Treatment (NY-
AACENT) subscales clinician will be summarized for at least one occurrence, each domain. For 
each domain, the severity, drug related, or functional/role impairment will be summarized. Data 
from patients and caregiver will be listed only. 
Treatment Services Review (TSR-6)-Modified for Mental Health will be listed. 
4. 
INTERIM ANALYSES 
Not applicable 
5. 
CHANGES IN CONDUCT OR PLANNED ANALYSES FROM 
THE PROTOCOL 
Not applicable 
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 
For all analyses for this study, the scheduled visit and/or time point from the CRF (ie, CRF visit) 
will be used as the analysis visit and/or time point. There would be one valid value of assessment 
kept for each scheduled analysis visit in summary/analysis statistics. 
Unless specified otherwise, measurements collected from unscheduled visits, will not be 
included in the summary tables, except for PCS analysis, and will be included in the subject 
listings. 
6.2. 
Safety Data Handling 
All efforts should be made to obtain the missing information from the investigator. 
6.3. 
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 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. 
7. 
PROGRAMMING SPECIFICATIONS 
Programming specifications will be provided in a separate document. 
8. 
MOCK TABLES, LISTINGS AND GRAPHS (TLGS) 
Mock-up tables and listings will be provided in a separate document. 
9. 
REFERENCES 
1. Alkermes ALK9072-A401 Study Protocol Amendment 1 (dated 07 September 2016)