Conditions: Schizophrenia
Keywords: Alkermes ALKS 3831 Samidorphan Schizophrenia Safety
Allocation: NA | Intervention model: SINGLE_GROUP
Enrollment: 266
Healthy volunteers: no

Brief summary:
The primary objective of this study is to evaluate the long-term safety and tolerability of ALKS 3831 in subjects with schizophrenia.

Detailed description:

Arms:
arm 1: Oral tablet, daily dosing

Interventions: intervention 1: ALKS 3831
Intervention descriptions: intervention 1: Coated bilayer tablet containing 10 mg, 15 mg or 20 mg olanzapine and 10 mg samidorphan

Protocol document:
Prot_000.pdf: 
A Phase 3, Multicenter Study to Assess the Long Term 
Safety and Tolerability of ALKS 3831 in Subjects with 
Schizophrenia 
 
 
Unique Protocol ID: 
ALK3831-A304 
NCT Number: 
NCT02873208 
Date of Protocol:  
26 Apr 2018 
 


1. 
TITLE PAGE 
 
CLINICAL STUDY PROTOCOL 
ALK3831-A304 
 
 
Study Title 
A Phase 3, Multicenter Study to Assess the Long Term 
Safety and Tolerability of ALKS 3831 in Subjects with 
Schizophrenia 
Document Status 
Final 
Document Date 
v 4.0 (incorporates Amendment 3.0): 26 Apr 2018 
v 3.0 (incorporates Amendment 2.0): 06 Jul 2017 
v 2.0 (incorporates Amendment 1.0): 24 Jun 2016 
Original Protocol: 01 Feb 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 
Table 1: 
Study Contact Information 
Abbreviations: SAE=serious adverse event 
Role in Study 
Name 
Address and Telephone 
Alkermes Medical Monitor  
 
Alkermes Pharma Ireland, Ltd 
Connaught House 
1 Burlington Road 
Dublin 4, Ireland 
Phone: 
 
Alkermes Global Safety 
Officer 
 
Alkermes, Inc. 
852 Winter Street 
Waltham, MA 02451 
Phone: 
 
CRO Medical Monitor and 
24-Hour Emergency Contact 
 
 
 
 
Del Mar, CA 92014 
Mobile: 
 
Office: 
 
SAE and Pregnancy Reporting 
 Safety Medical Monitor 
US Email:
EU/Rest of World (ROW) Email: 
 
US Fax Number.: 
 
EU Fax Number: 
 
 
PPD
PPD
PPD
PPD
PPD
PPD
PPD
PPD
PPD
PPD
PPD
PPD
PPD
PPD
PPD


 
 
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2. 
SYNOPSIS 
Name of Sponsor/Company: Alkermes, Inc. 
Name of Investigational Product: ALKS 3831 
Name of Active Ingredient: olanzapine and samidorphan 
Title of study: A Phase 3, Multicenter Study to Assess the Long Term Safety and Tolerability of 
ALKS 3831 in Subjects with Schizophrenia 
Investigator(s): This is a multicenter study 
Study Period: 
Estimated date of first subject’s consent: Q3 2016 
Estimated date of last subject’s last visit: Q4 2018 
Phase of Development: 3 
 
Objectives: 
Primary: The primary objective of this study is to evaluate the long term safety and tolerability of 
ALKS 3831 in subjects with schizophrenia. 
Methodology: Subjects that have completed the 24-week treatment period of the antecedent study 
ALK3831-A303 within the past 7 days are eligible to be enrolled in this study. 
Subjects enrolled in the study will be started on the same olanzapine dose that they had maintained at 
the end of ALK3831-A303. Subjects taking 20 mg olanzapine (either as OLZ 20 or ALKS 3831 20/10 
[20 mg olanzapine/10 mg samidorphan]) will start on ALKS 3831 20/10 in this study and subjects 
taking 10 mg olanzapine (either as OLZ 10 or ALKS 3831 10/10 [10 mg olanzapine/10 mg 
samidorphan) will start on ALKS 3831 10/10 in this study. An intermediate dose, ALKS 3831 15/10 
(15 mg olanzapine/10 mg samidorphan), will also be available, and subjects may be titrated to this dose 
any time after the start of the study at the investigator’s discretion. Dosing is flexible throughout the 
study; however, frequent adjustments are discouraged. Dose adjustments can only be performed on-site 
at the study center. Subjects requiring dose adjustments between scheduled visits should arrange an 
unscheduled visit for the following procedures: study drug return, adherence review, adverse event 
monitoring, and study drug dispensation.  
At eligible sites opting to participate in an additional substudy, subjects may be interviewed regarding 
their burden of disease and their treatment experiences; some of their caregivers also will be 
interviewed regarding their experiences in caring for a subject in the study.  
Subjects completing 52 weeks of treatment with study drug will be eligible to continue in the open 
label, long-term safety study (ALK3831-A308) and will continue to receive ALKS 3831. Subjects not 
continuing in the ALK3831-A308 long term safety study will enter a 4-week safety follow-up period. 
Number of Subjects Planned: Approximately 540 subjects are planned to be enrolled in this study.  
Main Criteria for Inclusion: 
To enroll in this study, a subject must be willing and able to provide informed consent; the subject 
must sign the informed consent form before initiation of any study specific procedures. The subject 
must agree to use an acceptable method of contraception for the duration of the study, be willing and 
able to follow the study procedures as outlined in the protocol, and have the potential to benefit from 
the administration of ALKS 3831, in the opinion of the investigator. The subject must have completed 
the 24-week treatment period of the antecedent study ALK3831-A303 within 7 days. 


 
 
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Investigational Product, Dosage, Duration and Mode of Administration: ALKS 3831 will be 
supplied as a coated bilayer tablet containing 10 mg, 15 mg or 20 mg olanzapine and 10 mg 
samidorphan. The tablet is to be taken by mouth once daily, preferably at bedtime. 
Reference Therapy, Dosage, Duration and Mode of administration: N/A 
Duration of Study: The study duration will be up to 56 weeks, which includes a 52-week treatment 
period and a 4-week safety follow-up period. 
Criteria for Evaluation: 
Safety: 
Safety will be assessed on the basis of: 
• 
Adverse events (AEs) 
• 
Clinical laboratory parameters (chemistry, hematology, and urinalysis) 
• 
Vital signs (oral temperature, respiratory rate, orthostatic blood pressure and pulse) 
• 
Weight/Body Mass Index (BMI) and Waist circumference 
• 
Electrocardiogram parameters (Uncorrected QT, QTcF, QTcB, PR, RR, and QRS 
intervals) 
• 
Columbia Suicide Severity Rating Scale (C-SSRS) 
• 
Abnormal Involuntary Movement Scale (AIMS) 
• 
Barnes Akathisia Rating Scale (BARS) 
• 
Simpson-Angus Scale (SAS) 
Efficacy: 
Efficacy assessments used to measure durability of treatment effect include: 
• 
Positive and Negative Syndrome Scale (PANSS) 
• 
Clinical Global Impression – Severity (CGI-S) 
Other: 
The following assessments will be used to obtain information regarding subject experience throughout 
the study: 
• 
Impact of Weight on Quality of Life –Lite Questionnaire (IWQOL-Lite) 
• 
EuroQol five dimensions questionnaire (EQ-5D) 
• 
Cigarette Use 
Statistical Methods: 
The safety population is defined as all enrolled subjects who receive at least one dose of ALKS 3831 in 
this study. All analyses will be carried out using the safety population. 
Safety: 
Incidence of AEs will be analyzed as a safety endpoint. Reported adverse event terms will be coded 
using the Medical Dictionary for Regulatory Activities (MedDRA) and summarized by system organ 
class and preferred term categories. Serious adverse events (SAEs) and AEs leading to study 
discontinuation will also be summarized. 


 
 
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Observed values and change from baseline in weight, BMI, waist circumference, laboratory 
parameters, vital signs, and ECG parameters will be summarized by study visit. 
The number and percentage of subjects who have met potentially clinically significant (PCS) criteria at 
any postbaseline visit will be summarized for laboratory, vital signs, weight, and ECG parameters. 
Supporting listings will be provided. 
The number and percentage of subjects with shifts in laboratory and extrapyramidal symptom (EPS) 
parameters (AIMS, BARS, and SAS) will be summarized. Supporting listings will be provided. 
The number and percentage of subjects with C-SSRS assessments of suicidal ideation and behavior 
will be summarized. 
Prior and concomitant medication use will be summarized by World Health Organization (WHO) Drug 
Dictionary Anatomical Therapeutic Class (ATC) code. 
Efficacy: 
The following efficacy endpoints will be analyzed to evaluate the durability of treatment effect for 
ALKS 3831: 
• 
Change from baseline in Positive and Negative Syndrome Scale (PANSS) total score and 
subscales by visit 
• 
Change from baseline in Clinical Global Impression – Severity (CGI-S) by visit 
• 
Time to discontinuation 
The PANSS (total and subscale scores) and CGI-S scores, and appropriate changes from baseline, will 
be summarized using descriptive statistics. 
The discontinuation rate will be estimated using the Kaplan-Meier (KM) Method and the KM plot will 
be provided. 
Sample Size Considerations: Approximately 540 subjects are planned to be enrolled in this study. 


 
 
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3. 
TABLE OF CONTENTS 
1. 
TITLE PAGE ................................................................................................................1 
CONTACT INFORMATION ..........................................................................................................2 
2. 
SYNOPSIS ...................................................................................................................3 
3. 
TABLE OF CONTENTS .............................................................................................6 
4. 
LIST OF ABBREVIATIONS.....................................................................................10 
5. 
INTRODUCTION ......................................................................................................12 
5.1. 
Background .................................................................................................................12 
5.2. 
Study Drugs ................................................................................................................13 
5.2.1. 
Samidorphan ...............................................................................................................13 
5.2.2. 
Olanzapine ..................................................................................................................13 
5.3. 
Study Rationale ...........................................................................................................13 
5.4. 
Dose Rationale ............................................................................................................14 
6. 
OBJECTIVES .............................................................................................................15 
6.1. 
Primary Objective .......................................................................................................15 
7. 
SELECTION AND WITHDRAWAL OF SUBJECTS ..............................................16 
7.1. 
Subject Inclusion Criteria ...........................................................................................16 
7.2. 
Subject Exclusion Criteria ..........................................................................................16 
7.3. 
Subject Withdrawal ....................................................................................................16 
7.4. 
Replacement of Subjects .............................................................................................17 
8. 
STUDY DESIGN .......................................................................................................18 
8.1. 
Overall Study Design and Plan ...................................................................................18 
8.2. 
Schedule of Visits and Assessments ...........................................................................19 
8.3. 
Study Procedures Descriptions ...................................................................................23 
8.3.1. 
Informed Consent .......................................................................................................23 
8.3.2. 
Eligibility Review .......................................................................................................23 
8.3.3. 
Demographics and Medical History ...........................................................................23 
8.3.4. 
Concomitant Medication Review ...............................................................................23 
8.3.5. 
Vital Signs ..................................................................................................................23 
8.3.6. 
Physical Examination .................................................................................................24 
8.3.7. 
Body Weight and Waist Circumference .....................................................................24 


 
 
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8.3.8. 
12-Lead Electrocardiogram ........................................................................................24 
8.3.9. 
Structured Interviews and Questionnaires ..................................................................24 
8.3.9.1. 
Antipsychotic Efficacy Assessments ..........................................................................24 
8.3.9.2. 
Safety Assessments .....................................................................................................25 
8.3.9.3. 
Other Assessments ......................................................................................................25 
8.3.10. 
Laboratory Assessments .............................................................................................26 
8.3.10.1. 
Drug Testing ...............................................................................................................26 
8.3.10.2. 
Hematology, Biochemistry, and Urinalysis ................................................................26 
8.3.10.3. 
Pregnancy Testing ......................................................................................................27 
8.3.11. 
Drug Dispensation and Reconciliation .......................................................................28 
8.3.12. 
Emergency Treatment Card ........................................................................................28 
8.3.13. 
Adverse Event Monitoring .........................................................................................28 
8.4. 
Study Requirements and Restrictions .........................................................................28 
8.4.1. 
Contraception and Pregnancy .....................................................................................28 
8.4.2. 
Prohibited Medications ...............................................................................................29 
8.4.3. 
Permitted Therapy ......................................................................................................30 
8.4.4. 
Pain Management .......................................................................................................30 
8.4.5. 
Other Restrictions and Requirements .........................................................................31 
9. 
TREATMENT OF SUBJECTS ..................................................................................32 
9.1. 
Study Drug Dose and Administration .........................................................................32 
9.2. 
Treatment Adherence ..................................................................................................32 
9.3. 
Randomization/Method of Assigning Subjects to Treatment .....................................32 
9.4. 
Blinding ......................................................................................................................32 
10. 
STUDY DRUG MATERIALS AND MANAGEMENT ...........................................33 
10.1. 
Study Drug ..................................................................................................................33 
10.2. 
Packaging and Labeling ..............................................................................................33 
10.3. 
Storage ........................................................................................................................33 
10.4. 
Accountability .............................................................................................................33 
10.5. 
Handling and Disposal ................................................................................................34 
11. 
ASSESSMENT OF EFFICACY ................................................................................35 
12. 
ASSESSMENT OF PHARMACOKINETICS AND 
PHARMACODYNAMICS ........................................................................................36 
13. 
ASSESSMENT OF SAFETY .....................................................................................37 


 
 
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13.1. 
Definition of Adverse Event .......................................................................................37 
13.2. 
Definition of Serious Adverse Event ..........................................................................37 
13.3. 
Relationship to Study Drug ........................................................................................38 
13.4. 
Monitoring and Recording of Adverse Events ...........................................................40 
13.5. 
Reporting of Serious Adverse Events and Pregnancy ................................................40 
14. 
STATISTICS ..............................................................................................................42 
14.1. 
Sample Size Considerations .......................................................................................42 
14.2. 
General Statistical Methodology ................................................................................42 
14.2.1. 
Study Population .........................................................................................................42 
14.2.1.1. 
Safety Population ........................................................................................................42 
14.3. 
Demographics and Baseline Data ...............................................................................42 
14.4. 
Safety and Tolerability Analyses ................................................................................42 
14.5. 
Efficacy Analysis ........................................................................................................43 
14.6. 
Pharmacokinetic/Pharmacodynamic Analyses ...........................................................43 
15. 
DIRECT ACCESS TO SOURCE DATA/ DOCUMENTS........................................44 
15.1. 
Study Monitoring ........................................................................................................44 
15.2. 
Audits and Inspections ................................................................................................44 
15.3. 
Institutional Review Board/Independent Ethics Committee ......................................44 
16. 
QUALITY CONTROL AND QUALITY ASSURANCE .........................................45 
16.1. 
Case Report Forms .....................................................................................................45 
16.2. 
Confidentiality of Data ...............................................................................................45 
17. 
ETHICAL CONSIDERATIONS................................................................................46 
17.1. 
Ethics Review .............................................................................................................46 
17.2. 
Ethical Conduct of the Study ......................................................................................46 
17.3. 
Written Informed Consent ..........................................................................................46 
18. 
DATA HANDLING AND RECORDKEEPING .......................................................48 
18.1. 
Data Capture ...............................................................................................................48 
18.2. 
Inspection of Records .................................................................................................48 
18.3. 
Retention of Records ..................................................................................................48 
18.4. 
Use of Information and Publication Policy ................................................................49 
19. 
REFERENCES ...........................................................................................................50 
APPENDICES ...............................................................................................................................52 
 


 
 
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LIST OF TABLES 
Table 1: 
Study Contact Information ...........................................................................................2 
Table 2: 
List of Abbreviations and Definition of Terms ..........................................................10 
Table 3: 
Schedule of Visits and Assessments ...........................................................................20 
Table 4: 
Clinical Laboratory Assessments ...............................................................................27 
Table 5: 
Adverse Event Causality Guidelines ..........................................................................39 
 
LIST OF FIGURES 
Figure 1: 
Study Design Schematic .............................................................................................19 
 
LIST OF APPENDICES 
Appendix A 
Partial List of Prohibited Cytochrome P450 (CYP) 3A4 Inducers and Inhibitors 
Appendix B 
Positive and Negative Syndrome Scale 
Appendix C 
Clinical Global Impression 
• 
Severity 
Appendix D 
Abnormal Involuntary Movement Scale 
Appendix E 
Barnes Akathisia Rating Scale 
Appendix F 
Simpson-Angus Scale 
Appendix G 
Columbia-Suicide Severity Rating Scale 
• 
Since Last Visit 
Appendix H 
Impact of Weight on Quality of Life - Lite 
Appendix I 
EuroQol Five Dimensions Questionnaire 
Appendix J 
Substudy to Protocol ALK3831-A304 (Participating Sites Only) 


 
 
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4. 
LIST OF ABBREVIATIONS 
Table 2: 
List of Abbreviations and Definition of Terms 
Abbreviation or Term 
Full Form or Definition 
AE 
adverse event 
AIMS 
Abnormal Involuntary Movement Scale 
ATC 
Anatomical Therapeutic Chemical [classification system] 
BARS 
Barnes Akathisia Rating Scale 
BMI 
body mass index 
CGI-S 
Clinical Global Impression - Severity 
CRO 
contract research organization 
CSA 
Clinical Study Agreement 
C-SSRS 
Columbia-Suicide Severity Rating Scale 
EC 
Ethics Committee 
ECG 
electrocardiogram 
eCRF 
electronic case report form 
EQ-5D 
EuroQol five dimensions questionnaire 
EOT 
end of treatment 
EPS 
extra pyramidal symptoms 
ET 
early termination 
GCP 
Good Clinical Practice 
HbA1c 
Hemoglobin A1c 
ICF 
informed consent form 
ICH 
International Conference on Harmonisation of Technical Requirements 
for Registration of Pharmaceuticals for Human Use 
IWQOL 
Impact of Weight on Quality of Life 
IRB 
Institutional Review Board 
KM 
Kaplan-Meier 
MedDRA 
Medical Dictionary for Regulatory Activities 
OLZ 
olanzapine 
PANSS 
Positive and Negative Syndrome Scale 
PCP 
phencyclidine 


 
 
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Table 2: 
List of Abbreviations and Definition of Terms (Continued) 
Abbreviation or Term 
Full Form or Definition 
PCS 
potentially clinically significant 
QTcB 
QT corrected with Bazett formula 
QTcF 
QT corrected with Fridericia formula 
SAE 
serious adverse event 
SAS 
Simpson-Angus Scale 
SCI-PANSS 
Structured Clinical Interview for the PANSS 
TEAE 
treatment-emergent adverse event 
WHO 
World Health Organization 


 
 
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5. 
INTRODUCTION 
5.1. 
Background 
Schizophrenia is a chronic, severe disease with debilitating psychotic symptoms, physical and 
psychiatric comorbidities and increased mortality. Despite the availability of a range of 
FDA-approved medicines, the disease is still inadequately treated and associated with enormous 
human and economic cost. Life expectancy is reduced by 19 years in men and 16 years in 
women with schizophrenia compared to the general population (Harris and Barraclough 1998; 
Lambert et al, 2010; Tiihonen et al, 2009). The decreased life expectancy is due to a combination 
of direct effects of the disease, eg increased rates of suicide and violence (Hodgins 2008; Kuo et 
al, 2005), as well as indirect causes including increased incidence of obesity and cardiovascular 
disease (Nasrallah et al, 2006; Saha et al, 2007). 
The goal of treatment in schizophrenia is to achieve the maximal reduction in positive and 
negative symptoms and increase functionality. Unfortunately, even with regular administration 
of currently available antipsychotic medications at full therapeutic dose levels, the overwhelming 
majority of patients continue to exhibit residual active symptomatology. For physicians and 
patients, in many cases the current treatment paradigm involves an efficacy/tolerability trade-off, 
where use of the most efficacious agents is avoided or delayed in order to avoid known safety 
issues. As such, there is a need for more efficacious therapies with better tolerability. 
Olanzapine is regarded as one of the most effective antipsychotic agents with well-recognized 
efficacy and decreased incidence of extrapyramidal symptoms. However, its efficacy is 
compromised by safety and tolerability limitations that affect compliance and retention of 
patients on olanzapine therapy (Lieberman et al, 2005). In particular, results of the Clinical 
Antipsychotic Trials of Intervention Effectiveness (CATIE), identify olanzapine as an effective 
atypical antipsychotic associated with the highest weight gain (9.4 kg over a treatment period up 
to 18 months and ≥7% body weight in 30% of subjects) and a comparatively higher 
discontinuation rate relative to other antipsychotic agents due to weight gain and metabolic 
effects. As a result of these limitations surrounding safety, tolerability, adherence and retention, 
the risk of olanzapine therapy can outweigh the benefit and patients are often switched to 
alternative antipsychotic agents even if they are less effective. 
ALKS 3831 is a fixed-dose combination product of olanzapine and samidorphan (an opioid 
modulator, see Section 5.2.1 for more information) under investigation for the treatment of 
schizophrenia. Phase 1 and Phase 2 studies demonstrated that coadministration of samidorphan 
with olanzapine attenuates the weight gain experienced with olanzapine alone. ALKS 3831 may 
have the further benefit of controlling substance abuse in patients with schizophrenia. Comorbid 
substance use disorder is a well-recognized obstacle to patient care. An estimated 1 out of 
every 3 patients with schizophrenia (33.7%) meet or have met criteria for alcohol use disorder 
(Regier et al, 1990). Patients with both schizophrenia and alcohol use disorder represent a 
common variant within the schizophrenia spectrum that is difficult to treat and is associated with 
an extremely poor prognosis (Dixon 1999; Koekkoek et al, 2006). In clinical studies, 
samidorphan has been shown to block both the subjective and physiological effects of the opioid 
agonist remifentanil (ALK33-004) and it is correlated with reduced drinking behavior in adults 


 
 
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with alcohol dependence (ALK33-005). ALK3831-401 is an ongoing clinical study designed to 
evaluate the effect of ALKS 3831 on drinking behavior in adult subjects with schizophrenia and 
alcohol use disorder. 
In summary, ALKS 3831 is being explored as a therapeutic agent for the treatment of 
schizophrenia designed to combine the antipsychotic efficacy of olanzapine with a reduced risk 
of weight gain and associated metabolic deficits. Development of ALKS 3831 as a fixed-dose 
combination of olanzapine and samidorphan has the potential to improve upon the benefit/risk 
profile of olanzapine alone and address a significant clinical need for patients that are currently 
forced to choose between treatment efficacy and safety. 
5.2. Study Drugs 
In this study, a fixed-dose combination of olanzapine and samidorphan will be administered in a 
single bilayer tablet. The following sections provide an overview of samidorphan and 
olanzapine. Detailed information about the study drugs can be found in the current ALKS 3831 
Investigator’s Brochure (IB). 
5.2.1. 
Samidorphan 
Samidorphan (also referred to as ALKS 33 or RDC-0313) is a new molecular entity in clinical 
development by Alkermes that functions as an antagonist at μ-opioid receptors and as a low 
intrinsic activity agonist at κ- and δ-opioid receptors. It is currently being investigated in 
combination with buprenorphine for the treatment of major depressive disorder (ALKS 5461) 
and in combination with olanzapine for the treatment of schizophrenia. Based on its chemical 
structure, samidorphan is considered a Schedule II controlled substance according to the US 
Drug Enforcement Agency and will require proper handling (see Section 10). At least ten clinical 
studies of samidorphan have been conducted to date, 8 of which included subjects that received 
samidorphan alone (not in combination with another product). Commonly reported adverse 
events (AEs) observed across all studies included nausea, fatigue, and somnolence. Overall, no 
trends or clinically meaningful changes have been observed in clinical laboratory analytes, vital 
sign parameters, or electrocardiogram (ECG) data. 
5.2.2. 
Olanzapine 
Olanzapine has been available in the US since 1996 (Zyprexa®) and was originally approved for 
the treatment of schizophrenia. It has since been approved for other indications including the 
treatment of schizophrenia in adolescents and bipolar disorder. The safety and tolerability profile 
of olanzapine is well documented, and adverse event labeling is supported by an extensive safety 
database that includes over 8,500 adult patients (Eli Lilly and Company 2017) . Commonly 
reported AEs consistent across all or most dosage forms in short-term, placebo controlled trials 
include somnolence, constipation, dry mouth, accidental injury, weight gain, postural 
hypotension, dizziness, asthenia, fever and abnormal gait. 
5.3. Study Rationale 
This is a Phase 3 open-label extension of study ALK3831-A303 to evaluate the long-term safety 
and tolerability of ALKS 3831 in adults with schizophrenia. Safety and tolerability data from the 
completed 24-week study (ALK3831-302) found ALKS 3831 to have a safety and tolerability 


 
 
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profile similar to olanzapine. Results from this study and from a parallel safety study 
(ALK3831-A306) will extend these findings and evaluate the safety and tolerability of 
ALKS 3831 over a 52-week period. 
5.4. 
Dose Rationale 
The selected doses of ALKS 3831 (20/10 [20 mg olanzapine/10 mg samidorphan], 15/10 [15 mg 
olanzapine/10 mg samidorphan] 10/10 [10 mg olanzapine/10 mg samidorphan]) are within the 
approved olanzapine therapeutic dose range for the treatment of schizophrenia (Eli Lilly and 
Company 2017). These doses span the intended commercial maintenance dose range of 
ALKS 3831, 10–20 mg. 
The 10 mg samidorphan dose was identified as the minimally effective dose based on the robust 
efficacy with optimal safety profile observed in ALK3831-302 at this dose. A fixed dose of 
samidorphan was selected due to the fact that data from this study demonstrated no correlation 
between the ratio of samidorphan/olanzapine dose and percent change from baseline in body 
weight, indicating that even with higher olanzapine doses, a fixed dose of samidorphan is 
sufficient to achieve maximal effect on reducing olanzapine-induced weight gain. 


 
 
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6. 
OBJECTIVES 
6.1. 
Primary Objective 
The primary objective of this study is to evaluate the long term safety and tolerability of 
ALKS 3831 in subjects with schizophrenia. 


 
 
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7. 
SELECTION AND WITHDRAWAL OF SUBJECTS 
7.1. 
Subject Inclusion Criteria 
Each subject must meet all of the following inclusion criteria to be qualified to participate in this 
study. 
1. Subject is willing and able to provide informed consent; subject has signed the informed 
consent form before initiation of any study specific procedures 
2. Subject agrees to use an acceptable method of contraception for the duration of the study 
(please refer to Section 8.4.1 for additional details regarding contraception) 
3. Subject is willing and able to follow the study procedures as outlined in the protocol 
4. Subject has the potential to benefit from the administration of ALKS 3831, in the opinion 
of the investigator 
5. Subject has completed the 24-week treatment period in the antecedent study 
ALK3831-A303 within 7 days 
7.2. 
Subject Exclusion Criteria 
Each subject must not meet any of the following criteria to be qualified to participate in this 
study. 
1. Subject has any finding that in the view of the investigator or medical monitor would 
compromise the safety of the subject or affect their ability to fulfill the protocol visit 
schedule or visit requirement 
2. Subject is currently taking medications that are contraindicated with olanzapine use or 
exhibit drug-interaction potential with olanzapine. Such medications will be defined and 
prohibited at the discretion of the PI 
3. Subject has a positive test for drugs of abuse at study entry 
4. Subject is pregnant, planning to become pregnant, or breastfeeding during the study 
5. Subject is employed by Alkermes, [CRO], or study site (permanent, temporary contract 
worker, or designee responsible for the conduct of the study) or is immediate family* of 
an Alkermes, [CRO], or study site employee (* Immediate family is defined as a spouse, 
parent, sibling or child, whether biological or legally adopted) 
7.3. 
Subject Withdrawal 
A subject may be discontinued from the study at any time if the subject, investigator, or the 
sponsor determines that it is not in the best interest of the subject to continue participation. If a 
subject has an absolute neutrophil count (ANC) < 1.0 × 103 per µL or glycosylated hemoglobin 
(HbA1c) ≥ 6.5% at any time during this extension study, the subject will be discontinued from 
the study. Other reasons for discontinuation include the following: 


 
 
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• Adverse Event (AE) 
• Lack of Efficacy 
• Lost to follow-up 
• Withdrawal by subject 
• Protocol Deviation (non-compliance with study drug or study procedures) 
• Pregnancy 
• Study terminated by sponsor 
• Other 
If a subject withdraws from the study for any reason, he or she will be asked to return to the 
clinic for an early termination (ET) visit. The ET visit should be scheduled as close as possible to 
the subject’s last dose and will mimic the assessments scheduled to be conducted at the end of 
treatment (EOT) visit (Visit 27, Table 3). Following the ET visit, subjects who discontinue study 
drug but are willing to come in for further assessments will be asked to complete 2 safety follow-
up visits 2 and 4 weeks after the ET visit (same assessments as Visits 28 and 29 in Table 3). 
They will then be asked to return to the study center for monthly visits according to the schedule 
outlined in Table 3 for follow-up weight assessments, adverse events, and documentation of any 
new antipsychotic medications the subject is taking. 
Following ET, any ongoing AEs will be followed until resolution, or 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 safety follow-up visit, 
the follow-up period may be extended as necessary. In such instances, the sponsor and the 
investigator will agree to an acceptable follow- up schedule. 
In the event that a subject chooses to withdraw from the study, the investigator should make a 
reasonable effort to ascertain the reason(s) for withdrawal, while fully respecting the subject’s 
rights. 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 documented and entered on the appropriate electronic 
case report form (eCRF). If a subject is lost to follow-up, a reasonable attempt to contact the 
subject must be made and documented. 
7.4. 
Replacement of Subjects 
Subjects prematurely discontinued from the study will not be replaced. 


 
 
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8. 
STUDY DESIGN 
8.1. 
Overall Study Design and Plan 
Subjects that have completed the 24-week treatment period of the antecedent study  
ALK3831-A303 within the past 7 days are eligible to be enrolled in the study. 
Subjects enrolled in the study will be started on the same olanzapine dose that they had 
maintained at the end of ALK3831-A303. Subjects taking 20 mg olanzapine (either as OLZ 20 or 
ALKS 3831 20/10 [20 mg olanzapine/10 mg samidorphan]) will start on ALKS 3831 20/10 in 
this study and subjects taking 10 mg olanzapine (either as OLZ 10 or ALKS 3831 10/10 [10 mg 
olanzapine/10 mg samidorphan]) will start on ALKS 3831 10/10 in this study. An intermediate 
dose, ALKS 3831 15/10 (15 mg olanzapine/10 mg samidorphan), will also be available, and 
subjects may be titrated to this dose any time after the start of the study at the investigator’s 
discretion. Dosing is flexible throughout the study; however, frequent adjustments are 
discouraged. Dose adjustments can only be performed on-site at the study center. Subjects 
requiring dose adjustments between scheduled visits should arrange an unscheduled visit for the 
following procedures: study drug return, adherence review, AE monitoring and study drug 
dispensation. 
Safety assessments will include AE monitoring, clinical laboratory testing, vital signs, weight/ 
BMI and waist circumference assessments, 12-lead electrocardiograms (ECGs), movement 
disorder assessments including the Abnormal Involuntary Movement Scale (AIMS), Barnes 
Akathisia Rating Scale (BARS), and Simpson Angus Scale (SAS), and the Columbia-Suicide 
Severity Rating Scale (C-SSRS). 
Efficacy assessments to evaluate the durability of treatment effect will include Positive and 
Negative Syndrome Scale (PANSS) and Clinical Global Impressions- Severity (CGI-S). 
Additional assessments include Impact of Weight on Quality of Life – Lite Questionnaire 
(IWQOL-Lite), Cigarette Use, and EuroQol five dimensions questionnaire (EQ-5D). 
Subjects completing 52 weeks of treatment with study drug will be eligible to continue in the 
open-label, long-term safety study (ALK3831-A308) and will continue to receive ALKS 3831. 
Subjects not continuing in the ALK3831-A308 long-term safety study will enter a 4-week safety 
follow-up period.  
Sites with subjects completing or prematurely discontinuing treatment in this study may 
participate in an additional substudy to explore treatment experiences of subjects and their 
caregivers (Appendix J). At participating sites, subjects who agree to be interviewed will be 
asked to provide feedback regarding their burden of disease and their treatment experiences; 
some of their caregivers also will be interviewed regarding their experience in caring for a 
subject in the study.  
The overall schedule of visits and assessments is provided in Table 3. 
A schematic of the study design is provided in Figure 1. 


 
 
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Figure 1: 
Study Design Schematic 
Within 7 days of 
ALK3831-A303 
Study Completion
ALKS 3831 10/10, 15/10, or 20/10 mg*
52-week open-label Treatment Period*
Safety 
Follow-up 
4 weeks
*Visits will occur biweekly throughout the 52-week Treatment Period. Subjects will start the study on the 
equivalent olanzapine dose to what they maintained at the end of ALK3831-A303. The dose may be adjusted 
to either 10/10, 15/10, or 20/10 mg throughout the Study Period based on Investigator discretion, and such 
dose adjustments will require subjects to visit the study site.
Long Term 
Safety Study
 
8.2. 
Schedule of Visits and Assessments 
The schedule of visits and assessments is shown in Table 3. 
A visit window of ±2 days is allowed throughout the treatment period and during the follow-up 
period. For a missed visit, the site must contact the subject to reschedule. 
Premature discontinuation procedures are provided in Section 7.3. Subjects who discontinue 
study drug but are willing to come in for further assessments will be asked to complete the ET 
visit (same assessments as Visit 27, Table 3) followed by 2 safety follow-up visits 2 and 4 weeks 
after the ET visit (same assessments as Visits 28 and 29 in Table 3). They will then be asked to 
return to the study center for monthly visits according to the schedule outlined in Table 3, to 
collect the following information: weight assessments, any new antipsychotic medications the 
subject is taking, and adverse events. 


 
 
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Table 3: 
Schedule of Visits and Assessments 
Visita 
Treatment Period 
Follow-Up 
Period 
1b 
2 
3 
4 
5 
6 
7 
8 
9 
10 
11 
12 
13 
14 
15 
16 
17 
18 
19 
20 
21 
22 
23 
24 
25 
26 
27/ 
ET 
28c 
29 
Study week 
- 
2 
4 
6 
8 
10 
12 
14 
16 
18 
20 
22 
24 
26 
28 
30 
32 
34 
36 
38 
40 
42 
44 
46 
48 
50 
52 
54 
56 
Informed 
Consent 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Eligibility 
Criteria 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Pregnancy 
Testingd 
X 
 
 
 
 
 
X 
 
 
 
 
 
X 
 
 
 
 
 
X 
 
 
 
 
 
 
 
 
 
 
Urine Drug 
Screene 
X 
 
 
 
 
 
X 
 
 
 
 
 
X 
 
 
 
 
 
X 
 
 
 
 
 
 
 
X 
 
 
Weightf 
 
X 
X 
X 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
Waist 
Circumference 
 
X 
X 
X 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
Vital Signsg 
 
X 
X 
X 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
Laboratory 
Samplesh 
 
 
X 
 
 
 
X 
 
 
 
 
 
X 
 
 
 
 
 
X 
 
 
 
 
 
 
 
X 
 
 
ECG 
 
 
X 
 
 
 
X 
 
 
 
 
 
X 
 
 
 
 
 
X 
 
 
 
 
 
 
 
X 
 
 
Physical 
Exam 
 
 
X 
 
 
 
X 
 
 
 
 
 
X 
 
 
 
 
 
X 
 
 
 
 
 
 
 
X 
 
 
PANSSi 
 
X 
X 
 
X 
 
X 
 
 
 
 
 
X 
 
 
 
 
 
X 
 
 
 
 
 
 
 
X 
 
 
CGI-S 
 
X 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
 
AEj 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
ConMed 
Reviewj 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
C-SSRSk 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 


 
 
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Table 3: 
Schedule of Visits and Assessments (Continued) 
Visita 
Treatment Period 
Follow-Up 
Period 
1b 
2 
3 
4 
5 
6 
7 
8 
9 
10 
11 
12 
13 
14 
15 
16 
17 
18 
19 
20 
21 
22 
23 
24 
25 
26 
27/ET 
28c 
29 
Study week 
- 
2 
4 
6 
8 
10 
12 
14 
16 
18 
20 
22 
24 
26 
28 
30 
32 
34 
36 
38 
40 
42 
44 
46 
48 
50 
52 
54 
56 
Abnormal 
Movement 
Scalesl 
 
 
X 
 
 
 
X 
 
 
 
 
 
X 
 
 
 
 
 
X 
 
 
 
 
 
 
 
X 
 
 
IWQOL 
 
 
X 
 
 
 
X 
 
 
 
 
 
X 
 
 
 
 
 
X 
 
 
 
 
 
 
 
X 
 
 
EQ-5D 
 
 
X 
 
 
 
X 
 
 
 
 
 
X 
 
 
 
 
 
X 
 
 
 
 
 
 
 
X 
 
 
Cigarette 
Use 
 
 
X 
 
 
 
X 
 
 
 
 
 
X 
 
 
 
 
 
X 
 
 
 
 
 
 
 
X 
 
 
Emergency 
Treatment 
Cardm 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
 
Study Drug 
Dispensation 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
 
 
Study Drug 
Adherence 
Review 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
 
Abbreviations: AE=adverse event; CGI-S=Clinical Global Impression-Severity; ConMed=concomitant medications; C-SSRS=Columbia-Suicide Severity Rating 
Scale; EOT=end of treatment; ECG=electrocardiogram; EQ-5D=EuroQol five dimensions questionnaire; IWQOL=impact of weight on quality of life; 
PANSS=Positive and negative syndrome scale 
a A visit window of ±2 days is allowed throughout the treatment period and during the follow-up period. 
b Visit 1 must occur within 7 days of the end of treatment visit (Visit 17) of the antecedent study, ALK3831-A303, and may occur on the same day. Assessments 
from ALK3831-A303 Visit 17 will constitute the baseline/screening assessments for this extension study. 
c Follow-up visits (Visits 28 and 29) are not required for subjects who enroll in ALK3831-A308 
d Urine pregnancy test at Visit 1 and at all subsequent specified visits. 
e Urine drug screen via dipstick prior to study drug dispensation at Visit 1, Visit 7, Visit 13, Visit 19 and Visit 27. Urine drug screen tests include, tests for 
opiates (including codeine, hydrocodone, hydromorphone, methadone, morphine, oxycodone, and oxymorphone) and drugs of abuse (including amphetamine/ 
methamphetamine, phencyclidine [PCP], and cocaine) 
f Subjects that prematurely discontinue study drug will be asked to come in for monthly follow-up assessments of weight, adverse events and any new 
antipsychotic medications following an early termination (ET) visit and two safety follow-up visits. 


 
 
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g Vital signs include orthostatic blood pressure and heart rate, respiratory rate, and oral body temperature. Orthostatic blood pressure and pulse rate will be taken 
after the subject has been supine for 5 minutes and once again after the subject has stood for 2 minutes. 
h Subjects must fast (no food or drink except water) for at least 8 hours before lab draws. Lab draws are to be conducted in the morning for all specified visits. 
i PANSS should be administered before other psychiatric assessments at each specified study visit. 
j Adverse events ongoing at the end of trial or concomitant medications continuing from the antecedent study will be carried over and followed through until 
resolution 
k The “Since Last Visit” version to be used at all visits. 
l Abnormal movement scales include the following: Abnormal Involuntary Movement Scale (AIMS), Barnes Akathisia Rating Scale (BARS), and 
Simpson-Angus Scale (SAS). 
m Emergency treatment card to be dispensed at Visit 1, confirmed at subsequent timepoints, and collected at Visit 27, EOT. 


 
 
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8.3. 
Study Procedures Descriptions 
Details of the study procedures are described below. The overall schedule of assessments is 
provided in Table 3. Information collected with the following assessments will be carried 
forward from the antecedent study, ALK3831-A303, for screening/baseline: demographics and 
medical history, vital signs, physical exam, height, body weight and waist circumference, 
12-lead ECG, CGI-S, PANSS, abnormal movement scales, IWQOL, EQ-5D, and cigarette use. 
8.3.1. 
Informed Consent 
The nature of the study and its risks and benefits will be explained to the subject 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. 
8.3.2. 
Eligibility Review 
An eligibility review will be conducted by the investigator at the visits specified in Table 3 using 
the subject inclusion criteria in Section 7.1 and exclusion criteria in Section 7.2. 
8.3.3. 
Demographics and Medical History 
Subjects’ demographic data and medical history will be carried over from the antecedent study, 
ALK3831-A303. 
8.3.4. 
Concomitant Medication Review 
At the time points specified in Table 3 subjects will be asked about the medications they have 
taken since their last visit, 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. 
8.3.5. 
Vital Signs 
Vital signs (ie, blood pressure, heart rate, respiratory rate, and oral body temperature) will be 
assessed at the time points specified in Table 3. An effort will be made to consistently use the 
same arm (preferably the subject’s dominant arm) to measure blood pressure and heart rate 
throughout the study. The blood pressure cuff will be calibrated per study site standard operating 
procedures (SOP). Automated measurement is preferred, but if performed manually, heart rate 
will be measured in the brachial artery for at least 30 seconds. Orthostatic blood pressure and 
heart rate will be collected in the following manner: 
• Allow subject to be in a supine position for at least 5 minutes 
• Measure blood pressure and heart rate 
• Have subject stand for 2 minutes 
• Measure blood pressure and heart rate 
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Vital signs may be collected at any time during a scheduled visit, unless otherwise noted. 
8.3.6. 
Physical Examination 
A physical examination will be performed at the timepoints specified in Table 3. 
8.3.7. 
Body Weight and Waist Circumference 
Body weight and waist circumference will be measured at all the timepoints specified in Table 3. 
For weight measurements, subjects should be asked to void immediately prior to measurement 
and should be dressed in a hospital gown with consistent under-attire for each measurement. 
Subjects should remove all personal items such as watches and jewelry and they should be 
weighed on the same scale for each measurement under the same conditions. 
Both weight and waist circumference will be measured three consecutive times at each 
assessment and all measurements will be recorded in the eCRF. 
8.3.8. 
12-Lead Electrocardiogram 
A 12-lead electrocardiogram (ECG) will be conducted at the timepoints specified in Table 3. All 
scheduled ECGs must be performed after the subject has rested quietly for at least 5 minutes in 
the supine position. 
A qualified clinician will conduct ECGs and assess ECG results using equipment that has been 
calibrated according to the site’s standard operating procedures. The following ECG parameters 
will be collected: pulse, RR, PR, QRS, QT, QT interval corrected using the Fridericia formula 
(QTcF), and QT interval corrected using the Bazett formula (QTcB). 
ECGs will also be evaluated by a central reader. 
8.3.9. 
Structured Interviews and Questionnaires 
Brief descriptions of each of the interviews and questionnaires to be distributed are available 
below. All interviews and questionnaires will be administered by trained and qualified study 
personnel. 
For assessments performed at multiple visits, every effort should be made to pair the same 
clinician/rater with the same subject across visits. 
Table 3 provides information on the time points at which each assessment should be 
administered. For all visits where assessments overlap, the PANSS should be administered first 
before any other psychiatric assessment. 
8.3.9.1. 
Antipsychotic Efficacy Assessments 
8.3.9.1.1. Positive and Negative Syndrome Scale 
The PI or designee will complete the PANSS (Appendix B) (Kay et al, 1987) according to the 
schedule in Table 3. The Structured Clinical Interview for the PANSS (SCI-PANSS) will be 
used to administer the PANSS. 
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8.3.9.1.2. Clinical Global Impression-Severity 
The PI or designee will complete the CGI-Severity (CGI-S, Appendix C) scale at the timepoints 
specified in Table 3. The CGI-S measures mental illness severity. Clinicians are asked to rate 
subjects based on their prior experience working with individuals in a similar patient population 
(Guy 1976). 
8.3.9.2. 
Safety Assessments 
8.3.9.2.1. Abnormal Movement Rating Scales 
The PI or designee will complete the following abnormal movement rating scales: The Abnormal 
Involuntary Movement Scale (AIMS, Appendix D) (Guy 1976), the Barnes Akathisia Rating 
Scale (BARS, Appendix E) (Barnes 1989), and the Simpson-Angus Scale (SAS, Appendix F) 
(Simpson and Angus 1970) at the timepoints specified in Table 3. 
After administration of the first dose of study drug, if a subject complains of extrapyramidal 
symptoms on a day when abnormal movement scale assessments are not scheduled, an 
unscheduled abnormal movement assessment should be performed. 
8.3.9.2.2. Columbia-Suicide Severity Rating Scale 
The PI or designee will administer the C-SSRS (Appendix G) according to the schedule in 
Table 3. The “Since Last Visit” version is to be completed at all scheduled time points. The 
C-SSRS should be administered by a qualified clinician trained in assessing and managing 
suicidal ideation and behavior (Posner et al, 2011). 
8.3.9.3. 
Other Assessments 
8.3.9.3.1. Cigarette Use 
Data on cigarette use will be collected using the question: “How many packs of cigarettes did 
you smoke over the past 7 days?” at the timepoints specified in Table 3. 
8.3.9.3.2. Impact of Weight on Quality of Life – Lite 
Subjects will complete the IWQOL-Lite questionnaire (Appendix H) at the timepoints specified 
in Table 3. 
8.3.9.3.3. EuroQol Five Dimensions Questionnaire 
Subjects will complete the EQ-5D (Appendix I) at the timepoints specified in Table 3. This scale 
provides an indication of health status based on self-rating in the following five categories: 
mobility, self-care, usual activities, pain/discomfort, and anxiety/depression. Additionally, it asks 
subjects to rank their health status on a visual analogue scale (VAS) from “worst imaginable 
health state” to “best imaginable health state.” 
8.3.9.3.4. Patient Voice Substudy (Only at Participating Study Sites) 
Substudy (Appendix J): At a subset of study sites, subject concept elicitation interviews to 
explore patient experience will be conducted with subjects who have completed or discontinued 
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early from the main protocol and who agree to participate. Caregivers will also be interviewed to 
gain their perspectives. 
8.3.10. 
Laboratory Assessments 
8.3.10.1. Drug Testing 
A drug screen for opiates (including codeine, hydrocodone, hydromorphone, methadone, 
morphine, oxycodone, and oxymorphone) and drugs of abuse (including amphetamine/ 
methamphetamine, phencyclidine [PCP], and cocaine) will be performed at the timepoints 
specified in Table 3. Urine drug screens may be repeated based on investigator judgment. The 
test may also be repeated at any time during the study, should the investigator feel it is 
warranted. Subjects are not eligible for participation if the results are positive at screening. If a 
subject is determined to be using any of these substances during the treatment period, the 
investigator should contact the medical monitor to discuss the course of action. 
8.3.10.2. Hematology, Biochemistry, and Urinalysis 
Fasting blood and urine samples will be collected at the timepoints specified in Table 3 for 
specific hematology, biochemistry, and urinalysis assessments listed in Table 4. Subjects will be 
instructed not to eat or drink anything (except water) for 8 hours before each visit where blood 
samples for biochemistry and hematology assessments will be collected. Samples will be 
collected in accordance with the site’s standard procedures and analyzed by a central laboratory. 
Laboratory assessments may be repeated at the investigator’s discretion. 
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Table 4: 
Clinical Laboratory Assessments 
Hematology 
Biochemistry 
Urinalysis 
Hematocrit 
Hemoglobin 
Platelet count 
Red blood cell count 
Total and differential 
(absolute) white blood cell 
count 
General Chemistry 
Albumin 
Bicarbonate 
Calcium 
Chloride 
Creatine phosphokinase 
Glucose 
Lactic dehydrogenase 
Potassium 
Sodium 
Total protein 
Uric acid 
Endocrine Function Test 
HbA1c 
Prolactin 
Insulin 
Liver Function Tests 
Alanine aminotransferase 
Alkaline phosphatase 
Aspartate aminotransferase 
Gamma-glutamyl transferase 
Total bilirubin 
Renal Function Tests 
Blood urea nitrogen 
Creatinine 
Lipid Panel 
High-density lipoprotein 
Low-density lipoprotein 
Total cholesterol 
Triglycerides 
Bilirubin 
Color and appearance 
Glucose 
Ketones 
Leukocytes 
Nitrite 
Occult blood 
pH 
Protein 
Specific gravity 
Urobilinogen 
Cotinine 
 
Microscopic examination of 
sediment, only if urinalysis 
dipstick results are abnormal 
8.3.10.3. Pregnancy Testing 
A urine pregnancy test will be administered to all women at the timepoints specified in Table 3. 
At the screening visit, results must be negative for the subject to be eligible for the study. As 
highlighted in Section 7.3 a positive pregnancy test result at any time will necessitate the 
subject’s immediate withdrawal from the study. Additional follow-up may be necessary as 
indicated in Section 8.4.1. 
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8.3.11. 
Drug Dispensation and Reconciliation 
Section 9 provides information related to drug dispensing procedures. Study drug will be 
dispensed at the timepoints specified in Table 3. The study drug use and storage information will 
be explained to/reviewed with the subject. 
Whether or not samidorphan is classified as a controlled substance varies from country to 
country; some countries have classified samidorphan as a controlled substance, while others have 
not. Sites will be given storage, handling, and reconciliation instructions applicable to their 
country to ensure compliance with local regulations for controlled substances. 
8.3.12. 
Emergency Treatment Card 
An emergency treatment card will be distributed to each subject and collected from each subject 
at the timepoints indicated in Table 3. The card will indicate that the subject is receiving an 
opioid antagonist and olanzapine and will include the PI’s contact information, a suggested pain 
management plan and information regarding opiate blockade. Subjects will be instructed to keep 
the card with them at all times. Study personnel will confirm that subjects have the card in their 
possession at each study visit as indicated in Table 3. 
8.3.13. 
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 3). AEs and serious adverse 
events (SAEs) are defined in Section 13.1 and 13.2, respectively. Section 13.4 provides guidance 
on the monitoring and recording requirements for AEs. Section 13.5 provides guidance on the 
reporting requirements for SAEs. 
8.4. 
Study Requirements and Restrictions 
8.4.1. 
Contraception and Pregnancy 
All male and female subjects must agree to use an acceptable method of contraception for the 
duration of the study unless they are surgically sterile or post-menopausal (see below). The 
following are considered acceptable methods of contraception: 
1. Double-barrier protection (eg, a condom with spermicide or a diaphragm with 
spermicide) 
2. Intrauterine device (IUD) 
3. Oral contraceptive pills and 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 are 
considered surgically sterile. Partner vasectomy is not considered an approved acceptable 
method of contraception for a female subject. 
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Women who are postmenopausal are also exempt from the requirement to use contraception. For 
the purpose of this study, postmenopausal is defined as the permanent cessation of menstruation 
for at least 12 months prior to screening in women who are 45 years of age or older. 
If a subject becomes pregnant while participating in the study, she will be discontinued from 
study drug immediately. Pregnancies in female subjects and female partners of male subjects 
should be handled in the same manner. The investigator must fill out a Pregnancy Report Form 
and submit the information to the sponsor within 24 hours of awareness of the pregnancy, 
irrespective of whether an adverse event has occurred. The early termination and safety follow-
up visits will be scheduled. The investigator will follow the pregnancy until completion or until 
pregnancy termination and notify the outcome to the sponsor. If the outcome of the pregnancy 
meets the criteria for immediate classification as an SAE the investigator should follow the 
procedure of reporting SAEs (see Section 13.5). Additional follow-up may be required. 
8.4.2. 
Prohibited Medications 
The prohibited medications include the following: 
• Monoamine oxidase inhibitors (eg, phenelzine, tranylcypromine, selegiline, or 
moclobemide) 
• Long-acting formulations of any antipsychotic agent 
• Use of antipsychotic sleep aids (eg, Seroquel) is prohibited. However, use of 
benzodiazepines to treat some symptoms is permissible 
• In general, the use of psychotropic medications other than study drug is prohibited 
with the exception of the following (these medications should only be administered 
after all assessments have been completed for that visit): 
− Beta-blockers (eg, propranolol or pinodolol), antihistamines, and anticholinergics 
may be used for treatment-emergent akathisia 
− Anticholinergics may be used for extrapyramidal symptoms 
• Chantix® (varenicline) is not permitted. However, nicotine replacement therapy 
including nicotine replacement patch and oral nicotine gum is permitted 
• All prescription or over-the-counter (OTC) agents taken for the purpose of weight 
reduction 
• Systemic steroids administered by oral, intravenous, or intramuscular route 
• Topiramate (Topamax®) and combination products containing topiramate; Calcitonin 
(eg, Miacalcin®) 
• Diabetes treatments and hypoglycemic agents including Metformin and Insulin 
Medications that are contraindicated with olanzapine use or exhibit drug-interaction potential 
with olanzapine are prohibited (see ALKS 3831 Investigator Brochure). 
Use of moderate to strong inducers or inhibitors of cytochrome P450 (CYP) 3A4 (prescription 
medications, OTC medications, or dietary supplements) was prohibited in the antecedent study 
(ALK3831-A303) and will be prohibited in this study from Visit 1 through follow-up. Refer to 
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Appendix A for a list of CYP3A4 inhibitors and inducers (Food and Drug Administration 2016; 
University of Washington: School of Pharmacy 2017a; University of Washington: School of 
Pharmacy 2017b). 
The CRO medical monitor should be consulted for any questions about use of any psychotropic 
medications during a subject’s participation in this study. 
Use of opioid antagonists, including naltrexone (any formulations) and naloxone throughout the 
study period is prohibited. Note: during the study period, opioid agonists should be avoided as 
they may be rendered ineffective by samidorphan. 
8.4.3. 
Permitted Therapy 
Permissible medications to treat extrapyramidal symptoms may include benzodiazepines, 
antihistamines, and anticholinergics. Benzodiazepines should be utilized for treatment-
emergent akathisia. While insomnia may be treated with a variety of agents, short half-life 
benzodiazepines should be utilized due to the potential for lingering effects on daytime 
functioning and study assessments (eg, triazolam). Non-benzodiazepine medication may be used 
to treat insomnia (eg, zolpidem, eszopiclone). Treatment of agitation and/or anxiety with 
benzodiazepines is permissible. 
8.4.4. 
Pain Management 
Because ALKS 3831 contains samidorphan, a μ-opioid antagonist, patients may experience 
reduced or ineffective analgesia when taking an opioid analgesic agent concurrently with 
ALKS 3831, including several days after last dosing of ALKS 3831. 
In the event of an emergency, pain management of the subject should include the following: 
• Regional analgesia or use of non-opioid analgesics 
• If opiate anesthesia or analgesia is required, the subject should be continuously 
monitored, in an anesthesia care setting, by persons not involved in the conduct of the 
surgical or diagnostic procedure. The opioid therapy must be provided by individuals 
specifically trained in the use of anesthetic drugs and the management of the 
respiratory effects of potent opioids, specifically the establishment and the 
maintenance of a patent airway and assisted ventilation. 
• Close monitoring by appropriately trained personnel in a setting equipped and staffed 
for cardiopulmonary resuscitation 
For subjects requiring emergency opioid analgesics prior to dosing, the study drug should not be 
administered. If opioid analgesics are required after the study drug has been dosed, it may take 
several days for opiate sensitivity to be restored, since samidorphan functions as a μ-opioid 
antagonist and could interfere with opioid-mediated pain management. 
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8.4.5. 
Other Restrictions and Requirements 
Additional restrictions and requirements include: 
• Prohibited substances include amphetamines (including methamphetamine), cocaine, 
barbiturates, methadone, opiates (including morphine, oxycodone, methadone, and 
buprenorphine), and phencyclidine 
• Subjects will be required to abstain from blood or blood product donation during the 
study and for 30 days following the follow-up visit 
• Subjects will be instructed to maintain their normal caffeine intake and/or tobacco use 
as well as normal activity/ exercise throughout the study. Subjects will be asked to 
abstain from strenuous physical activity for 48 hours prior to each study visit 
• Subjects will be asked to refrain from driving, operating machinery, or engaging in 
hazardous activities until they and the investigator are sure the study drug is not 
impairing their judgment and/or ability to perform skilled tasks 
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9. 
TREATMENT OF SUBJECTS 
9.1. 
Study Drug Dose and Administration 
Study drugs include 
• ALKS 3831 10/10 (10 mg olanzapine/10 mg samidorphan) 
• ALKS 3831 15/10 (15 mg olanzapine/10 mg samidorphan) 
• ALKS 3831 20/10 (20 mg olanzapine/10 mg samidorphan) 
ALKS 3831 will be supplied as a coated bilayer tablet for oral administration. 
At Visit 1 and all subsequent visits until EOT, subjects will be given blister cards containing 
study drug to take at home. Subjects will be instructed to take one tablet by mouth each day, 
preferably at bedtime. Dosing may be switched to another time at the investigator’s discretion if 
there are tolerability problems; however, frequent switching is discouraged. 
Subjects will be instructed to keep all unused tablets in their blister card and to return unused 
tablets to the study site at their next visit. If dosing is to occur at that visit, the dose should be 
taken from the subject’s next blister card, not from the card they are returning. 
If a dose is missed or forgotten, subjects will be instructed to resume regular dosing the 
following night. Subjects will be instructed not to take a double dose to try to “make up” for the 
missed dose. 
9.2. 
Treatment Adherence 
Subjects will undergo a study drug adherence review at the time points indicated in Table 3. 
Subjects will be instructed to keep all unused tablets in their original containers and to return the 
original containers with any unused study drug at each visit following dispensation. Study drug 
accountability will be documented as the number of tablets dispensed, dosed, lost/missing, or 
remaining. If applicable, the site will discuss non-adherence with the subject. 
9.3. 
Randomization/Method of Assigning Subjects to Treatment 
Not Applicable. 
9.4. 
Blinding 
Not Applicable. Study is open-label. 
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10. 
STUDY DRUG MATERIALS AND MANAGEMENT 
10.1. 
Study Drug 
The ALKS 3831 drug product will be supplied as a coated bilayer tablet in three fixed-dose 
combinations: 
• ALKS 3831 10/10 (10 mg olanzapine/10 mg samidorphan) 
• ALKS 3831 15/10 (15 mg olanzapine/10 mg samidorphan) 
• ALKS 3831 20/10 (20 mg olanzapine/10 mg samidorphan) 
Samidorphan is a Schedule II controlled substance. Thus, ALKS 3831 should be treated as a 
Schedule II controlled substance in the US and any other country in which it is controlled. 
10.2. 
Packaging and Labeling 
ALKS 3831 will be supplied in blister cards. Blister cards will be in biweekly configurations. 
Biweekly blister cards will contain 16 tablets, enough for 2 weeks of dosing plus sufficient 
overage for 2 additional once daily doses. 
10.3. 
Storage 
Product should be stored at not more than 25°C. 
Under the US Controlled Substances Act, samidorphan is considered a Schedule II substance 
because it is derived from opium alkaloids. Therefore, ALKS 3831 must be stored in accordance 
with restrictions related to Schedule II substances. The site will take adequate precautions, 
including storage of the investigational drug in a securely locked, substantially constructed 
cabinet, or other securely locked, substantially constructed enclosure, access to which is limited, 
to prevent theft or diversion of the substance. 
10.4. 
Accountability 
The investigator will be responsible for the oversight of recording the receipt and administration 
of study drug, and for insuring the supervision of the storage and allocation of these supplies. 
The investigator is required to maintain current drug dispensing and accountability logs 
throughout the study. The investigator may delegate accountability duties to an appropriate and 
qualified pharmacist or staff member who is under the supervision of the investigator. The 
investigator or designee must allow the Clinical Research Associate or equivalent to perform 
drug reconciliation during each study monitoring visit. All unused supplies will be checked 
against the study drug movement records before investigational drug is returned or destroyed. 
Refer to Section 8.3.11 for additional study drug reconciliation procedures. 
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10.5. 
Handling and Disposal 
Following completion and verification of accountability logs, all unused and used blister cards 
must be destroyed. The sponsor will arrange for destruction with a third party vendor operating 
in accordance with GCP and/or Good Manufacturing Practice (GMP). 
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11. 
ASSESSMENT OF EFFICACY 
The following efficacy assessments will be used to analyze the durability of treatment effect: 
• Positive and Negative Syndrome Scale (PANSS) 
• Clinical Global Impression – Severity (CGI-S) 
Other Assessments: 
The following assessments will be used to obtain information regarding subject experience 
throughout the study: 
• Impact of Weight on Quality of Life – Lite (IWQOL-Lite) Questionnaire 
• Cigarette Use Questionnaire 
• EQ-5D 
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12. 
ASSESSMENT OF PHARMACOKINETICS AND 
PHARMACODYNAMICS 
Not applicable 
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13. 
ASSESSMENT OF SAFETY 
Safety will be assessed on the basis of: 
• Adverse events (AEs) 
• Clinical laboratory parameters (chemistry, hematology, and urinalysis) 
• Vital signs (oral temperature, respiratory rate, orthostatic blood pressure and pulse) 
• Weight/BMI and Waist Circumference 
• Electrocardiogram parameters (Uncorrected QT, QTcF, QTcB, PR, RR, and 
QRS intervals) 
• Columbia Suicide Severity Rating Scale (C-SSRS) 
• Abnormal Involuntary Movement Scale (AIMS) 
• Barnes Akathisia Rating Scale (BARS) 
• Simpson-Angus Scale (SAS) 
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 investigational treatment, may include any clinical or laboratory change that 
does not commonly occur in that subject and is considered clinically significant. 
Illnesses present prior to the subject signing the 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 is not considered an AE, although a subject will be withdrawn from the study if a 
pregnancy occurs. As described in Section 8.4.1, the pregnancy 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 meets one or more of 
the following criteria: 
• Results in death 
• Is life-threatening. The subject is at immediate risk of death from the reaction as it 
occurs. This does not include reaction that, had it occurred in a more severe form, 
might have caused death. 
• Requires inpatient hospitalization or prolongation of existing hospitalization. 
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• Results in persistent or significant disability/incapacity (eg, a substantial disruption of 
a person’s ability to conduct normal life functions) 
• Is a congenital anomaly/birth defect 
Important medical events that may not result in death, be immediately life threatening, or require 
hospitalization may be considered to be SAEs when, based upon appropriate medical judgment, 
they may jeopardize the patient or subject and may require intervention to prevent one of the 
other outcomes listed above. 
Admission to a hospital or an inpatient unit for a nonmedical reason (ie, social stay admission) 
during the study in the absence of untoward medical occurrence will not be considered as an 
SAE, but will be captured as an AE. 
Hospitalization due to worsening of behavioral health related issues should be reported as 
an SAE. 
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 5 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 5: 
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. 
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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 safety follow-up visit (Visit 29) or 28 days after the final dose of study drug. Any AE or SAE 
having an onset after the safety follow-up 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. 
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 and Pregnancy 
All SAEs and pregnancies must be reported to Alkermes via 
 
 immediately, within 24 hours of discovery, by emailing or faxing the report to the 
following: 
Attention: Safety 
 Medical Monitor 
US Email: 
 
EU/Rest of World (ROW) Email: 
 
US Fax Number: 
 
EU/ROW 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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The written report for pregnancies in female subjects and in female partners of male subjects 
should be submitted on the Pregnancy Report Form provided for this purpose. 
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14. 
STATISTICS 
14.1. 
Sample Size Considerations 
No formal sample size calculation is performed for this extension study. A sample size of 
approximately 540 is based on the estimated maximum number of subjects who might be 
expected to continue from the ALK3831-A303 study. 
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. 
The statistical analysis methods are described below. Additional details will be provided in the 
Statistical Analysis Plan to be finalized before database lock. 
14.2.1. 
Study Population 
14.2.1.1. Safety Population 
The Safety Population includes all enrolled subjects who received at least 1 dose of ALKS 3831. 
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, and BMI will be 
summarized with descriptive statistics. 
14.4. 
Safety and Tolerability Analyses 
Incidence of AEs will be analyzed as a safety endpoint. Reported adverse event terms will be 
coded using the Medical Dictionary for Regulatory Activities (MedDRA) and summarized by 
system organ class and preferred term categories. 
SAEs and AEs contributing to study discontinuation will also be summarized. 
Observed values and change from baseline in weight, BMI, waist circumference, laboratory 
parameters, vital signs, and ECG parameters will be summarized by study visit. 
The number and percentage of subjects who have met potentially clinically significant (PCS) 
criteria at any post-baseline visit will be summarized for laboratory, vital signs, weight, and ECG 
parameters. Supporting listings will be provided. 
The number and percentage of subjects with shifts in laboratory and EPS parameters (AIMS, 
BARS, and SAS) will be summarized. Supporting listings will be provided. 
The number and percentage of subjects with C-SSRS assessments of suicidal ideation and 
behavior will be summarized. 
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Prior and concomitant medication use will be summarized by World Health Organization 
(WHO) Drug Dictionary Anatomical Therapeutic Class (ATC) code. 
Listings will be provided for all safety endpoints. 
14.5. 
Efficacy Analysis 
The following endpoints will be used to evaluate durability of treatment effect: 
• Change from baseline in Positive and Negative Syndrome Scale (PANSS) total score 
and subscales by visit 
• Change from baseline in Clinical Global Impression – Severity (CGI-S) by visit 
• Time to discontinuation 
The PANSS (total and subscale scores) and CGI-S scores, and appropriate changes from 
baseline, will be summarized using descriptive statistics. 
The discontinuation rate will be estimated using the Kaplan-Meier (KM) Method and the KM 
plot will be provided. 
14.6. 
Pharmacokinetic/Pharmacodynamic Analyses 
Not Applicable 
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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 an investigational 
new drug safety report must be immediately reported. 
All relevant correspondence from the IRB/IEC will be forwarded by the respective study site to 
the sponsor in a timely fashion. 
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 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 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 must not include any language that waives the 
subject’s legal rights. Prospective subjects must also be informed of their right to withdraw 
consent without prejudice at any time during the study. If the subject chooses to participate, 
he/she must sign the ICF before any study-specific procedures are conducted. 
All subjects will be informed of their rights to privacy and will be made aware that the study data 
will be submitted to Alkermes, the IRB, the 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 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. 
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The time that informed consent is obtained must be documented. The investigator must maintain 
the original, signed ICF in the subject’s source documents. A copy of the signed ICF must be 
given to the subject. 
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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. 
All electronic source data collected outside of the eCRF will be transferred directly to Alkermes 
for incorporation into the final datasets. 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 all essential clinical study documents shall be governed by the terms 
and conditions of the site’s CSA and in accordance with ICH guidelines/local regulatory 
requirements as follows: 
Essential documents should be retained until at least 2 years after the last approval of a 
marketing application in an ICH region and until there are no pending or contemplated marketing 
applications in an ICH region or at least 2 years have elapsed since the formal discontinuation of 
clinical development of the investigational product. These documents should be retained for a 
longer period, however, if required by the applicable regulatory requirements or by the terms of 
the CSA. It is the responsibility of the sponsor to inform the investigator/institution as to when 
these documents no longer need to be retained. 
Subjects’ medical files should be retained in accordance with the applicable legislation and in 
accordance with the maximum period of time permitted by the hospital, institution, or private 
practice. 
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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. 
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19. 
REFERENCES
Barnes TR. A rating scale for drug-induced akathisia. Br J Psychiatry. 1989;154:672-676. 
Corbin J, Strauss A. Basics of Qualitative Research: Techniques and Procedures for Developing 
Grounded Theory. 3rd ed. California. Sage Publications; 2008. 
Dixon L. Dual diagnosis of substance abuse in schizophrenia: prevalence and impact on 
outcomes. Schizophr Res. 1999;35 Suppl:S93-100. 
Zyprexa [package insert]. Indianapolis, IN: Eli Lilly and Company; 2017. 
Food and Drug Administration. Drug Development and Drug Interactions: Table of Substrates, 
Inhibitors and Inducers. 2016; 
http://www.fda.gov/Drugs/DevelopmentApprovalProcess/DevelopmentResources/DrugInteractio 
nsLabeling/ucm093664.htm. 
Guy W. ECDEU Assessment Manual for Psychopharmacology. Rockville, MD: Department of 
Health, Education, and Welfare; 1976. 
Harris EC, Barraclough B. Excess mortality of mental disorder. Br J Psychiatry. 1998;173:11-
53. 
Hodgins S. Violent behaviour among people with schizophrenia: a framework for investigations 
of causes, and effective treatment, and prevention. Philos Trans R Soc Lond B Biol Sci. 
2008;363(1503):2505-2518. doi: 10.1098/rstb.2008.0034. 
Kay S, Fiszbein A, Opler L. The Positive and Negative Syndrome Scale (PANSS) for 
Schizophrenia. Schizophr Bull. 1987;13(2):261-276. 
Koekkoek B, van MB, Hutschemaekers G. "Difficult patients" in mental health care: a review. 
Psychiatr Serv. 2006;57(6):795-802. doi: 10.1176/appi.ps.57.6.795. 
Kuo CJ, Tsai SY, Lo CH, Wang YP, Chen CC. Risk factors for completed suicide in 
schizophrenia. J Clin Psychiatry. 2005;66(5):579-585. 
Lambert M, Conus P, Cotton S, Robinson J, McGorry PD, Schimmelmann BG. Prevalence, 
Predictors, and Consequences of Long-Term Refusal of Antipsychotic Treatment in First-
Episode Psychosis. J Clin Psychopharmacol. 2010;30(5):565-572. doi: 
10.1097/JCP.0b013e3181f058a0. 
Lieberman JA, Stroup TS, McEvoy JP, et al. Effectiveness of antipsychotic drugs in patients 
with chronic schizophrenia. N Engl J Med. 2005;353(12):1209-1223. 
Nasrallah HA, Meyer JM, Goff DC, et al. Low rates of treatment for hypertension, dyslipidemia 
and diabetes in schizophrenia: data from the CATIE schizophrenia trial sample at baseline. 
Schizophr Res. 2006;86(1-3):15-22. doi: 10.1016/j.schres.2006.06.026. 
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CONFIDENTIAL 
Patrick DL, Burke LB, Gwaltney CJ, et al. Content validity--establishing and reporting the 
evidence in newly developed patient-reported outcomes (PRO) instruments for medical product 
evaluation: ISPOR PRO good research practices task force report: part 1--eliciting concepts for a 
new PRO instrument. Value Health. 2011;14(8):967-977. doi: 10.1016/j.jval.2011.06.014. 
Posner K, Brown GK, Stanley B, et al. The Columbia-Suicide Severity Rating Scale: initial 
validity and internal consistency findings from three multisite studies with adolescents and 
adults. Am J Psychiatry. 2011;168(12):1266-1277. doi: 10.1176/appi.ajp.2011.10111704. 
Regier DA, Farmer ME, Rae DS, et al. Comorbidity of mental disorders with alcohol and other 
drug abuse. Results from the Epidemiologic Catchment Area (ECA) Study. JAMA. 
1990;264(19):2511-2518. 
Saha S, Chant D, McGrath J. A systematic review of mortality in schizophrenia: is the 
differential mortality gap worsening over time? Arch Gen Psychiatry. 2007;64(10):1123-1131. 
doi: 10.1001/archpsyc.64.10.1123. 
Simpson GM, Angus JW. A rating scale for extrapyramidal side effects. Acta Psychiatr Scand 
Suppl. 1970;212:11-19. 
Tiihonen J, Lonnqvist J, Wahlbeck K, et al. 11-year follow-up of mortality in patients with 
schizophrenia: a population-based cohort study (FIN11 study). Lancet. 2009;374(9690):620-627. 
doi: 10.1016/S0140-6736(09)60742-X. 
University of Washington: School of Pharmacy. In Vivo CYP3A Inducers. Seattle, WA: M and 
T Drug Interaction Database; 2017a. 
University of Washington: School of Pharmacy. In Vivo Inhibitors of CYP3A Probes. Seattle, 
WA: M and T Drug Interaction Database; 2017b. 
 
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Alkermes, Inc. 
Protocol ALK3831-A304 v 4.0 (Amendment 3.0) 
CONFIDENTIAL 
APPENDICES 
Appendix A 
Partial List of Prohibited Cytochrome P450 (CYP) 3A4 Inducers and Inhibitors 
Appendix B 
Positive and Negative Syndrome Scale 
Appendix C 
Clinical Global Impression 
• 
Severity 
Appendix D 
Abnormal Involuntary Movement Scale 
Appendix E 
Barnes Akathisia Rating Scale 
Appendix F 
Simpson-Angus Scale 
Appendix G 
Columbia-Suicide Severity Rating Scale 
• 
Since Last Visit 
Appendix H 
Impact of Weight on Quality of Life - Lite 
Appendix I 
EuroQol Five Dimensions Questionnaire 
Appendix J 
Substudy to Protocol ALK3831-A304 (Participating Sites Only) 
Page 52 of 97


 
 
Alkermes, Inc. 
Protocol ALK3831-A304 v 4.0 (Amendment 3.0) 
CONFIDENTIAL 
APPENDIX A. PARTIAL LIST OF PROHIBITED CYTOCHROME P450 
(CYP) 3A4 INHIBITORS AND INDUCERS 
The following is a list of CYP3A4 inhibitors and inducers that subjects are to avoid within 
30 days of Screening and throughout the study. This list is not comprehensive. 
Table 1:  Partial List of CYP3A4 Inhibitors and Inducers 
Moderate-to-Strong Inhibitors 
Moderate-to-Strong Inducers 
Aprepitant 
Idelalisib 
Avasimibe 
Boceprevir 
Indinavir/Ritonavira 
Bosentan 
Cimetidine 
Itraconazole 
Carbamazepine 
Ciprofloxacin 
Ketoconazole 
Efavirenz 
Clarithromycin 
Lopinavir/Ritonavira 
Enzalutamide 
Clotrimazole 
Mibefradil 
Etravirine 
Cobicistat 
Nefazodone 
Mitotane 
Conivaptan 
Nelfinavir 
Modafinil 
Crizotinib 
Paritaprevir/Ritonavir and 
(Ombitasvir and/or Dasabuvir)a 
Phenobarbital 
Cyclosporine 
Posaconazole 
Phenytoin 
Danoprevir/Ritonavira 
Ritonavira 
Rifabutin 
Diltiazem 
Saquinavir/Ritonavira 
Rifampin 
Dronedarone 
Telaprevir 
St. John’s Wort 
Elvitegravir/Ritonavira 
Telithromycin 
— 
Erythromycin 
Tipranavir/Ritonavira 
— 
Fluconazole 
Tofisopam 
— 
Fluvoxamine 
Troleandomycin 
— 
Grapefruit juice 
Verapamil 
— 
Imatinib 
Voriconazole 
— 
a Ritonavir is usually given in combination with other anti-human immunodeficiency virus (HIV) or anti-hepatitis C 
virus (HCV) drugs in clinical practice. Caution should be used when extrapolating the observed effect of ritonavir 
alone to the effect of combination regimens on CYP3A activities. 
Source: (Food and Drug Administration 2016; University of Washington: School of Pharmacy 2017a; University of 
Washington: School of Pharmacy 2017b) 
Page 53 of 97


 
 
Alkermes, Inc. 
Protocol ALK3831-A304 v 4.0 (Amendment 3.0) 
CONFIDENTIAL 
APPENDIX B. POSITIVE AND NEGATIVE SYNDROME SCALE  
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SAMPLE
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Alkermes, Inc. 
Protocol ALK3831-A304 v 4.0 (Amendment 3.0) 
CONFIDENTIAL 
APPENDIX C. CLINICAL GLOBAL IMPRESSION 
•
Severity
Page 71 of 97


Clinical Global Impressions- Severity
Instructions: Circle the appropriate number after the following item.
This document is provided by Wyeth Pharmaceuticals Inc.
244260-01
SEVERITY OF ILLNESS 
Considering your total clinical experience with this particular population, how mentally ill is the patient at this time? 
Not assessed
Normal, not at all ill
Borderline mentally ill
Mildly ill
Moderately ill
Markedly ill
Severely ill
Among the most extremely ill patients
0
1
2
3
4
5
6
7
Name or ID: 
Date:
This tool should be used to supplement, not to replace, clinical judgement.
SAMPLE
Page 72 of 97


Alkermes, Inc. 
Protocol ALK3831-A304 v 4.0 (Amendment 3.0) 
CONFIDENTIAL 
APPENDIX D. ABNORMAL INVOLUNTARY MOVEMENT SCALE 
Page 73 of 97


Guy, W. ed. ECDEU Assessment Manual for Psychopharmacology. US Dept 
of HEW, Publication No. (Adm): 76-338, 1976 
Clintara Version 1.6 June, 2011 
Page 1 of 1 
Abnormal Involuntary Movement Scale (AIMS) 
Movement ratings: Rate highest severity observed. Rate movements that occur upon activation 
one less than those observed spontaneously. 
Code: 
0 = None 
1 = Minimal, may be extreme normal 
2 = Mild 
3 = Moderate 
4 = Severe 
(Circle One) 
FACIAL AND 
ORAL 
MOVEMENTS: 
1.
MUSCLES OF FACIAL EXPRESSION e.g movements of forehead, eyebrows,
periorbital area, cheeks, including frowning, blinking, smiling, grimacing
0 
1 
2 
3 
4 
2.
LIPS AND PERIORAL AREA e.g. puckering, pouting, smacking
0 
1 
2 
3 
4 
3.
JAW e.g. biting, clenching, chewing, mouth opening, lateral movement
0 
1 
2 
3 
4 
4.
TONGUE Rate only increases in movement both in and out of mouth. NOT
inability to sustain movement
0 
1 
2 
3 
4 
EXTREMITY 
MOVEMENTS: 
5.
UPPER (ARMS, WRISTS, HANDS, FINGERS) Include choreic movements (i.e.
rapid, objectively purposeless, irregular, spontaneous), athetoid movements (i.e.
slow, irregular, complex, serpentine). Do NOT include tremor (i.e. repetitive,
regular, rhythmic)
0 
1 
2 
3 
4 
6.
LOWER (LEGS, KNEES, ANKLES, TOES) e.g. lateral knee movement, foot
tapping, heel dropping, foot squirming, inversion and eversion of foot
0 
1 
2 
3 
4 
TRUNK 
MOVEMENTS: 
7.
NECK, SHOULDERS, HIPS e.g.rocking, twisting, squirming, pelvic gyrations
0 
1 
2 
3 
4 
GLOBAL 
JUDGMENT: 
8.
SEVERITY OF ABNORMAL MOVEMENTS
None, normal     0 
Minimal     1 
Mild     2 
Moderate     3 
Severe     4 
9.
INCAPACITATION DUE TO ABNORMAL MOVEMENTS
None, normal     0 
Minimal     1 
Mild     2 
Moderate     3 
Severe     4 
10. PATIENT’S AWARENESS OF ABNORMAL MOVEMENTS. RATE ONLY
PATIENT’S REPORT
No awareness     0 
Aware, no distress     1 
Aware, mild distress     2 
Aware, moderate distress     3 
Aware, severe distress     4 
DENTAL 
STATUS: 
11. Current problems with teeth and/or dentures?
No     0 
Yes    1 
12. Does patient usually wear dentures?
No     0 
Yes    1 
Rater Signature: _______________________ 
Date: _________________________ 
SAMPLE
Page 74 of 97


Alkermes, Inc. 
Protocol ALK3831-A304 v 4.0 (Amendment 3.0) 
CONFIDENTIAL 
APPENDIX E. BARNES AKATHISIA SCALE 
Page 75 of 97


Reproduced from: Barnes TR: A Rating Scale for Drug-Induced Akathisia. 
British Journal of Psychiatry 154:672-676, 1989.  
Clintara Version 1.6 June, 2011 
Page 1 of 1 
Barnes Akathisia Rating Scale (BARS) 
Instructions: Patient should be observed while they are seated, and then standing while engaged in neutral conversation (for a 
minimum of two minutes in each position). Symptoms observed in other situations, for example, while engaged in activity on the 
ward, may also be rated. Subsequently, the subjective phenomena should be elicited by direct questioning.  
Please circle the appropriate scores. 
Objective 
0 
Normal, occasional fidgety movements of the limbs 
1 
Presence of characteristic restless movements: shuffling or tramping movements of the legs/feet, or swinging of 
one leg while sitting, and/or rocking from foot to foot or “walking on the spot” when standing, but movements 
present for less than half the time observed 
2 
Observed phenomena, as described in (1) above, which are present for at least half the observation period 
3 
Patient is constantly engaged in characteristic restless movements, and/or has the inability to remain seated or 
standing without walking or pacing, during the time observed 
Subjective 
Awareness of restlessness 
0 
Absence of inner restlessness 
1 
Non-specific sense of inner restlessness 
2 
The patient is aware of an inability to keep the legs still, or a desire to move the legs, and/or complains of inner 
restlessness aggravated specifically by being required to stand still 
3 
Awareness of an intense compulsion to move most of the time and/or reports strong desire to walk or pace most 
of the time 
Distress related to restlessness 
0 
No distress 
1 
Mild 
2 
Moderate 
3 
Severe 
Global Clinical Assessment of Akathisia 
0 
Absent. No evidence of awareness of restlessness. Observation of characteristic movements of akathisia in the 
absence of a subjective report of inner restlessness or compulsive desire to move the legs should be classified 
as pseudoakathisia 
1 
Questionable. Non-specific inner tension and fidgety movements 
2 
Mild akathisia. Awareness of restlessness in the legs and/or inner restlessness worse when required to stand 
still. Fidgety movements present, but characteristic restless movements of akathisia not necessarily observed. 
Condition causes little or no distress 
3 
Moderate akathisia. Awareness of restlessness as described for mild akathisia above, combined with 
characteristic restless movements such as rocking from foot to foot when standing. Patient finds the condition 
distressing 
4 
Marked akathisia. Subjective experience of restlessness includes a compulsive desire to walk or pace. 
However, the patient is able to remain seated for at least five minutes. The condition is obviously distressing. 
5 
Severe akathisia. The patient reports a strong compulsion to pace up and down most of the time. Unable to sit 
or lie down for more than a few minutes. Constant restlessness which is associated with intense distress and 
insomnia. 
Rater Signature: _______________________ 
Date: _________________________ 
Scoring the Barnes Akathisia Rating Scale (BARS) 
The Barnes Akathisia Rating Scale is scored as follows:  
Objective Akathisia, Subjective Awareness of Restlessness and Subjective Distress Related to Restlessness are rated on a 
4-point scale from 0 – 3 and are summed yielding a total score ranging from 0 to 9.  
The Global Clinical Assessment of Akathisia uses a 5-point scale ranging from 0 – 4. 
SAMPLE
Page 76 of 97


Alkermes, Inc. 
Protocol ALK3831-A304 v 4.0 (Amendment 3.0) 
CONFIDENTIAL 
APPENDIX F. SIMPSON-ANGUS SCALE 
Page 77 of 97


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Alkermes, Inc. 
Protocol ALK3831-A304 v 4.0 (Amendment 3.0) 
CONFIDENTIAL 
APPENDIX G. COLUMBIA SUICIDE SEVERITY RATING SCALE 
•
Since Last Visit
Page 81 of 97


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 for use by trained clinicians. The questions contained in the Columbia-Suicide Severity Rating Scale 
are suggested probes. Ultimately, the determination of the presence of suicidality depends on clinical judgment. 
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 
 
SAMPLE
Page 82 of 97
PPD
PPD


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 
____ 
Version 1/14/09 
SAMPLE
Page 83 of 97


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 
□   □ 
Completed 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 
 
 
 
______ 
 
SAMPLE
Page 84 of 97


 
 
Alkermes, Inc. 
Protocol ALK3831-A304 v 4.0 (Amendment 3.0) 
CONFIDENTIAL 
APPENDIX H. IMPACT OF WEIGHT ON QUALITY OF LIFE – LITE 
Page 85 of 97


© Copyright 2000. Duke University Medical Center. Direct all correspondence to 
 Obesity 
and Quality of Life Consulting, 1004 Norwood Avenue, Durham, NC 27707, USA; 
 Fax: 
 (email address: 
 
IWQOL-Lite – English (US). 
Impact of Weight on Quality of Life Questionnaire—Lite Version (IWQOL-Lite) 
Please answer the following statements by circling the number that best applies 
to you in the past week. Be as open as possible. There are no right or wrong 
answers. 
Physical Function 
ALWAYS 
TRUE 
USUALLY 
TRUE 
SOMETIMES 
TRUE 
RARELY 
TRUE 
NEVER 
TRUE 
1.
Because of my weight I have trouble
picking up objects.
5 
4 
3 
2 
1 
2.
Because of my weight I have trouble tying
my shoes.
5 
4 
3 
2 
1 
3.
Because of my weight I have difficulty
getting up from chairs.
5 
4 
3 
2 
1 
4.
Because of my weight I have trouble using
stairs.
5 
4 
3 
2 
1 
5.
Because of my weight I have difficulty
putting on or taking off my clothing.
5 
4 
3 
2 
1 
6.
Because of my weight I have trouble with
mobility.
5 
4 
3 
2 
1 
7.
Because of my weight I have trouble
crossing my legs.
5 
4 
3 
2 
1 
8.
I feel short of breath with only mild exertion.
5 
4 
3 
2 
1 
9.
I am troubled by painful or stiff joints.
5 
4 
3 
2 
1 
10.
My ankles and lower legs are swollen at
the end of the day.
5 
4 
3 
2 
1 
11.
I am worried about my health.
5 
4 
3 
2 
1 
Self-esteem 
ALWAYS 
TRUE 
USUALLY 
TRUE 
SOMETIMES 
TRUE 
RARELY 
TRUE 
NEVER 
TRUE 
1.
Because of my weight I am self-conscious.
5 
4 
3 
2 
1 
2.
Because of my weight my self-esteem is
not what it could be.
5 
4 
3 
2 
1 
3.
Because of my weight I feel unsure of
myself.
5 
4 
3 
2 
1 
4.
Because of my weight I don’t like myself.
5 
4 
3 
2 
1 
5.
Because of my weight I am afraid of being
rejected.
5 
4 
3 
2 
1 
6.
Because of my weight I avoid looking in
mirrors or seeing myself in photographs.
5 
4 
3 
2 
1 
7.
Because of my weight I am embarrassed to
be seen in public places.
5 
4 
3 
2 
1 
Page 86 of 97
PPD
PPD
PPD
PPD


© Copyright 2000. Duke University Medical Center. Direct all correspondence to 
 Obesity 
and Quality of Life Consulting, 1004 Norwood Avenue, Durham, NC 27707, USA; 
 Fax: 
 (email address: 
 
IWQOL-Lite – English (US). 
Sexual Life 
ALWAYS 
TRUE 
USUALLY 
TRUE 
SOMETIMES 
TRUE 
RARELY 
TRUE 
NEVER 
TRUE 
1.
Because of my weight I do not enjoy sexual
activity.
5 
4 
3 
2 
1 
2.
Because of my weight I have little or no
sexual desire.
5 
4 
3 
2 
1 
3.
Because of my weight I have difficulty with
sexual performance.
5 
4 
3 
2 
1 
4.
Because of my weight I avoid sexual
encounters whenever possible.
5 
4 
3 
2 
1 
 
Public Distress 
ALWAYS 
TRUE 
USUALLY 
TRUE 
SOMETIMES 
TRUE 
RARELY 
TRUE 
NEVER 
TRUE 
1.
Because of my weight I experience ridicule,
teasing, or unwanted attention.
5 
4 
3 
2 
1 
2.
Because of my weight I worry about fitting
into seats in public places (e.g. theaters,
restaurants, cars, or airplanes).
5 
4 
3 
2 
1 
3.
Because of my weight I worry about fitting
through aisles or turnstiles.
5 
4 
3 
2 
1 
4.
Because of my weight I worry about finding
chairs that are strong enough to hold my
weight.
5 
4 
3 
2 
1 
5.
Because of my weight I experience
discrimination by others.
5 
4 
3 
2 
1 
Work  (Note: For homemakers and 
retirees, answer with respect 
to your daily activities.) 
ALWAYS 
TRUE 
USUALLY 
TRUE 
SOMETIMES 
TRUE 
RARELY 
TRUE 
NEVER 
TRUE 
1.
Because of my weight I have trouble getting
things accomplished or meeting my
responsibilities.
5 
4 
3 
2 
1 
2.
Because of my weight I am less productive
than I could be.
5 
4 
3 
2 
1 
3.
Because of my weight I don’t receive
appropriate raises, promotions or
recognition at work.
5 
4 
3 
2 
1 
4.
Because of my weight I am afraid to go on
job interviews.
5 
4 
3 
2 
1 
Page 87 of 97
PPD
PPD
PPD
PPD


 
 
Alkermes, Inc. 
Protocol ALK3831-A304 v 4.0 (Amendment 3.0) 
CONFIDENTIAL 
APPENDIX I. EUROQOL FIVE DIMENSIONS QUESTIONNAIRE 
Page 88 of 97


USA (English) © 2009 EuroQol Group EQ-5D™ is a trade mark of the EuroQol Group
Health Questionnaire
English version for the USA
SAMPLE
Page 89 of 97


2
USA (English) © 2009 EuroQol Group EQ-5D™ is a trade mark of the EuroQol Group
Under each heading, please check the ONE box that best describes your health TODAY.
MOBILITY
I have no problems walking

I have slight problems walking

I have moderate problems walking

I have severe problems walking

I am unable to walk

SELF-CARE
I have no problems washing or dressing myself

I have slight problems washing or dressing myself

I have moderate problems washing or dressing myself

I have severe problems washing or dressing myself

I am unable to wash or dress myself

USUAL ACTIVITIES (e.g. work, study, housework, family or 
leisure activities)
I have no problems doing my usual activities

I have slight problems doing my usual activities

I have moderate problems doing my usual activities

I have severe problems doing my usual activities

I am unable to do my usual activities

PAIN / DISCOMFORT
I have no pain or discomfort

I have slight pain or discomfort

I have moderate pain or discomfort

I have severe pain or discomfort

I have extreme pain or discomfort

ANXIETY / DEPRESSION
I am not anxious or depressed

I am slightly anxious or depressed

I am moderately anxious or depressed

I am severely anxious or depressed

I am extremely anxious or depressed

SAMPLE
Page 90 of 97


3
USA (English) © 2009 EuroQol Group EQ-5D™ is a trade mark of the EuroQol Group
The worst health 
you can imagine

We would like to know how good or bad your health is TODAY.

This scale is numbered from 0 to 100.

100 means the best health you can imagine.
0 means the worst health you can imagine.

Mark an X on the scale to indicate how your health is TODAY.

Now, please write the number you marked on the scale in the box
below.
The best health 
you can imagine
YOUR HEALTH TODAY =
10
0
20
30
40
50
60
80
70
90
100
5
15
25
35
45
55
75
65
85
95
SAMPLE
Page 91 of 97


 
 
Alkermes, Inc. 
Protocol ALK3831-A304 v 4.0 (Amendment 3.0) 
CONFIDENTIAL 
APPENDIX J. SUBSTUDY TO PROTOCOL ALK3831-A304 
(PARTICIPATING SITES ONLY)  
Introduction and Rationale for the Substudy 
In addition to standard efficacy and safety endpoints collected in a clinical trial of a new 
therapeutic treatment, patient and caregiver perspectives are useful in further describing the 
overall patient experience. Patients’ and caregivers’ experiences with the disease or with specific 
therapies can provide information on important disease concepts, including impacts on quality of 
life and preferences with regard to treatment options. Such data are valuable to inform clinical 
development of new therapies.  
Patient and caregiver experience data may be collected using quantitative, qualitative, or mixed 
methodology. An important advantage of qualitative methodology is its ability to discover 
information not covered in standard structured questionnaires or rating scales.  
To obtain patient experience data from subjects treated with ALKS 3831, this substudy will use 
in-depth, qualitative interviews to collect subjects’ and caregivers’ feedback on their experiences 
in study ALK3831-A304. The interviews will follow semi-structured interview guides to capture 
spontaneous, as well as probed, descriptions of treatment experience. This exploratory qualitative 
approach is intended both to assess a priori concepts of interest and to explore the disease burden 
and treatment experiences of patients and caregivers with schizophrenia prior to and during 
participation in study ALK3831-A304. 
Substudy Objectives 
The main objectives of this substudy are to explore the burden of living with schizophrenia and 
the treatment experiences of subjects who have completed or discontinued prematurely from 
study ALK3831-A304. Additionally, experiences of subjects’ caregivers will be examined. 
Interviews will focus on concepts relevant to the subject’s and caregiver’s experience with the 
burden of disease, impacts of treatment with ALKS 3831 on daily life, and impacts of 
participation in the ALK3831-A304 Study. The interviews will also probe on specific treatment 
attributes liked/disliked by subjects, the degree of patient satisfaction/dissatisfaction with the 
ALKS 3831 treatment and study, and subjects’ and caregivers’ comparisons of the ALKS 3831 
treatment experience with previous treatment experiences. 
Selection and Withdrawal of Subjects 
Substudy Sites 
A subset of sites with subjects enrolled in ALK3831-A304 will be eligible to participate in the 
substudy. Approval from the appropriate IEC/IRB must be obtained for each site participating in 
the substudy. 
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Alkermes, Inc. 
Protocol ALK3831-A304 v 4.0 (Amendment 3.0) 
CONFIDENTIAL 
Substudy Participants 
Approximately 50 subjects who participated in ALK3831-A304 and approximately 15 of their 
caregivers are expected to participate in the substudy. Subjects who enroll in the substudy will 
have completed study procedures for the end of treatment/early discontinuation visit described in 
Section 8.2 and will meet the criteria for inclusion in the substudy.   
Subject Inclusion Criteria 
Selection of subjects to be interviewed will be based on the following inclusion criteria: 
1. Subject is willing and able to provide written informed consent. 
2. Subject has completed or prematurely discontinued from study ALK3831-A304.  
3. Subject speaks English fluently. 
4. Subject is willing and able to participate in a 60-minute interview. 
5. If not participating in study ALK3831-A308, subject agrees to schedule an interview 
within 60 days of completing or prematurely discontinuing from study ALK3831-A304. 
If subject is participating in study ALK3831-A308, the interview may be conducted at 
any time after completing study ALK3831-A304. 
There is no exclusion criterion for participants of this substudy; any subject who meets the 
inclusion criteria may participate. 
Caregiver Inclusion Criteria 
Caregivers of subjects participating in the ALK3831-A304 substudy will be selected for 
interview based on the following inclusion criteria: 
6. Subject has provided written informed consent to allow caregiver to be interviewed 
regarding subject’s condition and treatment experience. 
7. Caregiver must be willing and able to provide written informed consent to participate in 
the substudy. 
8. Caregiver is in contact several times per week with the subject participating in the 
substudy. Caregivers can be family members, friends, or paid professional caregivers. 
Caregivers may provide full- or part-time help to the person with schizophrenia. 
9. Caregiver speaks English fluently.  
10. Caregiver is willing and able to participate in a 60-minute interview, either in person or 
via telephone. 
There is no exclusion criterion for caregivers participating in this substudy; any caregiver who 
meets the inclusion criteria may participate. 
Subject or CaregiverWithdrawal 
A subject or caregiver may withdraw consent to participate in this substudy at any time. A 
subject who chooses to withdraw consent to participate in the substudy may continue full 
participation in any other ongoing ALKS 3831 study, as eligible. 
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Alkermes, Inc. 
Protocol ALK3831-A304 v 4.0 (Amendment 3.0) 
CONFIDENTIAL 
Substudy Design 
This is a qualitative study involving interviews with approximately 50 subjects who have either 
completed or prematurely terminated participation in ALK3831-A304, and with approximately 
15 of their caregivers. Subjects will return to the clinical site for an interview within 60 days of 
completing Visit 27, or at any time if continuing in study ALK3831-A308. Interviewers will 
follow standardized, semi-structured Interview Guides developed specifically for the study. 
Caregivers will be interviewed by phone/webcam to explore their perspectives of subjects’ 
treatment and study experience. Qualitative analysis will involve scoring transcribed interviews 
for concepts that emerge during the substudy.  
Substudy Procedures 
Informed consent for participation in substudy 
Each subject and caregiver must provide written informed consent to participate in the substudy 
prior to scheduling an interview. In addition, for each participating caregiver, written informed 
consent for the caregiver to be interviewed regarding the subject’s condition and treatment 
experience must be obtained from the subject.  
Concept Elicitation Interviews  
Interviewers 
All interviews will be conducted by qualitative researchers with experience and training in 
conducting qualitative interviews.  
Patient Concept Elicitation Interviews 
The goal of the Patient Concept Elicitation interview is to gain insight into how living with and 
being treated for schizophrenia impacts the way the subjects feel and function in daily life, and to 
document preferences and comparative information about current and prior treatment 
experiences.  
Interviewers will follow the Subject Interview Guide containing questions designed to document 
concepts related to schizophrenia including, but not limited to burden of disease, physical 
function, role function, social function, and overall treatment experiences, as well as satisfaction 
and preferences regarding treatment received during and prior to participation in study 
ALK3831-A304.  
Questions in the interview guide will utilize a standardized methodology for collecting subjects’ 
responses to open-ended questions, and following up by probing to elicit more specific and 
nuanced detail.  
Interviews will be conducted with the subject present at the clinical site. The interviewer may 
participate either in person or by videoconference. At the start of the interview, the interviewer 
will confirm that each participant understands and has signed the ICF.  
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Alkermes, Inc. 
Protocol ALK3831-A304 v 4.0 (Amendment 3.0) 
CONFIDENTIAL 
Each interview will last approximately 60 minutes and will include an introduction 
(approximately 5 minutes), a concept elicitation portion (approximately 50 minutes), and a 
conclusion (approximately 5 minutes). After several interviews have been completed and 
transcripts have been reviewed, the Subject Interview Guide may be revised to capture emergent 
concepts and to pose questions more effectively. 
Caregiver Concept Elicitation Interviews 
Each subject will be asked during the in-person concept elicitation interview whether the 
subject’s caregiver might be agreeable to participating in a separate telephone interview. If so, 
the subject will be asked for written consent for the subject’s caregiver to be interviewed, and 
will be provided with contact information to share with the caregiver for the purpose of 
scheduling a telephone interview.   
Caregivers of subjects participating in this substudy will be interviewed by telephone or 
videoconference/telephone. The design of the concept elicitation interview with caregivers will 
mirror that for concept elicitation interviews of subjects; however, questions in the Caregiver 
Interview Guide will be designed to elicit a caregiver’s feedback on a subject’s experiences with 
schizophrenia, particularly the burden of disease, as well as treatment preferences and treatment 
satisfaction. Additionally, caregivers will be asked to share experiences around the burden of 
caring for someone with schizophrenia, impact of this burden on quality of life, and impressions 
of treatment successes and challenges, as well as experiences in caring for a clinical trial 
participant. Although all caregiver interviews will be conducted remotely, other aspects of 
interview procedures will be similar to those for subject interviews. 
Statistics 
Data Coding  
Interview transcripts will be independently coded using content thematic analysis, in accordance 
with Grounded Theory methods [(Corbin and Strauss 2008), Chapters 8 through 11; (Patrick et 
al, 2011)]. Coding will be verified by two trained qualitative researchers until saturation (the 
point at which no new information emerges) is reached. Coding will occur after each round of 
interviews, enabling results to inform refinement of subsequent interviews.  
Data Analysis 
To identify patterns in responses and confirm important concepts reported by subjects with 
schizophrenia and their caregivers (eg, burden of disease, areas of impact related to patients’ 
quality of life, overall treatment experiences, treatment satisfaction, and treatment preferences), 
coded transcripts will be reviewed for emerging themes [(Corbin and Strauss 2008), Chapter 8]. 
This methodology allows identification of new concepts emerging from interviews with patients 
or caregivers, rather than limiting inquiry to concepts imposed by a predetermined theory. All 
qualitative data obtained from substudy interviews will be analyzed using NVivo qualitative 
research software, version 11.0 (NVivo qualitative data analysis software; QSR International 
PTY Ltd. Version 11, 2015). Final details of the analysis will be captured in a substudy data 
analysis plan. Results from this substudy will be provided in an addendum to the clinical study 
report for ALK3831-A304.  
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Alkermes, Inc. 
Protocol ALK3831-A304 v 4.0 (Amendment 3.0) 
CONFIDENTIAL 
Safety Reporting 
The interview guide will not include any question regarding a specific adverse event (AE). 
Interviewers will be trained to inform the Principal Investigator of any unsolicited AE reported 
during the interview upon conclusion of the interview. Adverse events and serious AEs (SAEs) 
will be reported in accordance with Section 13 of the protocol.  
Ethical Considerations 
Institutional Review Board 
The responsible IRB (Section 17.1 of the protocol) for each site participating in the substudy 
must review and approve protocol sections describing the substudy, the Subject Interview Guide, 
and any revisions made, as well as information on the substudy to be provided to participating 
subjects and caregivers in obtaining written informed consent. 
Ethical Conduct of the Substudy 
This substudy will be conducted in accordance with the protocol, the ICH Guideline E6, and all 
applicable local regulatory requirements. 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. 
Written Informed consent 
In addition to written informed consent previously obtained from subjects to participate in the 
main study ALK3831-A304, all subjects and caregivers who voluntarily agree to participate in 
this substudy must provide separate written consent to the interview, to interview recording, and 
to subsequent analysis of interview responses.  
Data Handling and Recordkeeping 
Data Capture 
Subjects will be interviewed at the clinical trial site by interviewers participating either in person 
or through videoconference. Caregivers will be interviewed via telephone or videoconference/ 
telephone.  
In-person interviews will be audiotaped using digital audio-recorder equipment and later 
transcribed verbatim. Telephone interviews will be recorded using WebEx and a back-up audio 
recorder. Recordings will be sent to a qualitative research vendor via a secure file transfer system 
to be transcribed verbatim. The qualitative vendor will redact all personal information from the 
transcript before submitting back via the secure file transfer system. 
Interview transcripts will be independently content-coded and verified by two trained qualitative 
researchers. Coding will be reviewed by a senior qualitative scientist. Any identified discrepancy 
between coders will be reviewed, discussed, and resolved by the substudy research team. 
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Alkermes, Inc. 
Protocol ALK3831-A304 v 4.0 (Amendment 3.0) 
CONFIDENTIAL 
Retention of Records 
All participant records will be archived consistent with International Council for Harmonisation 
Good Clinical Practice (ICH-GCP) and Health Insurance Portability and Accountability Act 
(HIPAA) regulations. All paper copies of documents, audio recordings, and electronic files will 
be saved in a secure system following HIPAA regulations. Any written or printed study 
documents will be collected and filed in a locked filing cabinet. Records, including the electronic 
versions of the responses and scores, will be maintained indefinitely or until the sponsor requests 
destruction. 
Subject Confidentiality 
All transcripts will be labeled only with the unique participant subject or caregiver identification 
number; no identifying information will be included in the transcript. Alkermes will not receive 
any identifying information from the study participants. Auditors and other authorized agents of 
Alkermes will be granted direct access to the study participant data, without violating the 
confidentiality of the participant, to the extent permitted by law and applicable regulations. 
Participants’ identities will remain confidential in any presentation of the results of this substudy 
at meetings or in publications. 
Page 97 of 97

SAP_001.pdf: 
A Phase 3, Multicenter Study to Assess the Long Term 
Safety and Tolerability of ALKS 3831 in Subjects with 
Schizophrenia 
 
 
Unique Protocol ID: 
ALK3831-A304 
NCT Number: 
NCT02873208 
Date of Statistical Analysis 
Plan:  
11 June 2019 
 


 
 
 
 
 
STATISTICAL ANALYSIS PLAN  
 
ALK3831-A304 
NCT02873208 
 
Study Title: 
A Phase 3, Multicenter Study to Assess the Long Term Safety and 
Tolerability of ALKS 3831 in Subjects with Schizophrenia 
Document Status: 
Final Version 1.0  
Document Date: 
11 June 2019 
Based on: 
ALK3831-A304 Protocol Amendment 3.0 Date: 26 Apr 2018 
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 - ALK3831-A304                                                                                                 11 June 2019 
 
 
 
 
Page 2 of 36 
 
 
 
TABLE OF CONTENTS 
TABLE OF CONTENTS .................................................................................................................2 
LIST OF TABLES ...........................................................................................................................4 
LIST OF FIGURES .........................................................................................................................4 
ABBREVIATIONS .........................................................................................................................5 
1. 
INTRODUCTION ........................................................................................................7 
1.1. 
Study Objectives ...........................................................................................................7 
1.1.1. 
Primary Objective .........................................................................................................7 
1.2. 
Summary of the Study Design ......................................................................................7 
2. 
SAMPLE SIZE CONSIDERATION ............................................................................8 
3. 
DATA ANALYSIS ......................................................................................................8 
3.1. 
General Statistical Methodology ..................................................................................8 
3.2. 
Definitions of Analysis Populations .............................................................................9 
3.2.1. 
Safety Population ..........................................................................................................9 
3.2.2. 
Follow-up Safety Population ........................................................................................9 
3.2.3. 
Post-discontinuation Safety Population ........................................................................9 
3.3. 
Disposition ....................................................................................................................9 
3.4. 
Protocol Deviation ......................................................................................................10 
3.5. 
Demographics and Baseline Characteristics ...............................................................10 
3.6. 
Prior and Concomitant Medication .............................................................................10 
3.7. 
Treatment Adherence Rate and Extent of Exposure to Study Drug ...........................10 
3.7.1. 
Treatment Adherence Rate .........................................................................................10 
3.7.2. 
Extent of Exposure to Study Drug ..............................................................................11 
3.8. 
Efficacy Analyses .......................................................................................................11 
3.8.1. 
General Considerations ...............................................................................................11 
3.8.2. 
Efficacy Analysis ........................................................................................................11 
3.8.3. 
Other Endpoints ..........................................................................................................12 
3.8.4. 
Multiple Comparison / Multiplicity ............................................................................13 
3.9. 
Safety Analysis ...........................................................................................................13 
3.9.1. 
Adverse Events ...........................................................................................................13 


Alkermes, Inc.                                                                                                                                     
Statistical Analysis Plan - ALK3831-A304                                                                                                 11 June 2019 
 
 
 
 
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3.9.1.1. 
Deaths, Serious and Other Significant AEs ................................................................14 
3.9.1.2. 
Other Significant AEs .................................................................................................14 
3.9.1.3. 
Analysis of Abuse Potential, Withdrawal, and Dependence ......................................14 
3.9.2. 
Clinical Laboratory Parameters ..................................................................................15 
3.9.3. 
Vital Signs, Body Weight, and ECG ..........................................................................18 
3.9.3.1. 
Vital Signs ..................................................................................................................18 
3.9.3.2. 
Weight and Body Mass Index .....................................................................................19 
3.9.3.3. 
Electrocardiograms .....................................................................................................20 
3.9.4. 
Abnormal Movement Scales .......................................................................................20 
3.9.5. 
Columbia-Suicide Severity Rating Scale (C-SSRS) ...................................................21 
3.10. 
Pharmacokinetic/ Pharmacodynamic Data Analysis ..................................................21 
4. 
INTERIM ANALYSES ..............................................................................................21 
5. 
CHANGES IN CONDUCT OR PLANNED ANALYSES FROM THE 
PROTOCOL ...............................................................................................................22 
6. 
DEFINITIONS AND CONVENTIONS FOR HANDLING OF THE DATA ..........22 
6.1. 
Analysis Visit Windows .............................................................................................22 
6.2. 
Handling of Partial Dates of Concomitant Medication ..............................................23 
6.3. 
Handling of Safety Data .............................................................................................23 
7. 
GENERAL STATISTICAL METHODOLOGY .......................................................24 
7.1. 
Reporting Precision ....................................................................................................24 
8. 
PROGRAMMING SPECIFICATIONS .....................................................................24 
9. 
MOCK TABLES, LISTINGS AND FIGURES (TLFS) ............................................24 
10. 
REFERENCES ...........................................................................................................25 
APPENDIX 1. AESI - MOVEMENT DISORDERS (INCLUDING 
EXTRAPYRAMIDAL SYNDROME AND TARDIVE DYSKINESIA; 
STANDARDIZED MEDDRA QUERY) ...................................................................26 
APPENDIX 2. AESI - SUICIDAL IDEATION AND BEHAVIOR (CUSTOM 
MEDDRA QUERY) ...................................................................................................30 
APPENDIX 3. AE TERMS - ABUSE POTENTIAL (CUSTOM MEDDRA QUERY)............31 
APPENDIX 4. AE TERMS – DEPENDENCE (CUSTOM MEDDRA QUERY) .....................34 
APPENDIX 5. AE TERMS – WITHDRAWAL (CUSTOM MEDRA QUERY) ......................35 
 


Alkermes, Inc.                                                                                                                                     
Statistical Analysis Plan - ALK3831-A304                                                                                                 11 June 2019 
 
 
 
 
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LIST OF TABLES 
Table 1: 
Definition of CGI-S Categories ..................................................................................11 
Table 2: 
Shift Categories for CGI-S response ..........................................................................12 
Table 3: 
Criteria of Potentially Clinically Significant (PCS) Abnormality for Selected 
Analytes ......................................................................................................................16 
Table 4: 
Shifts Categories from Baseline to Any Postbaseline for Selected Lipid 
Parameters ...................................................................................................................17 
Table 5: 
Shift Categories from Baseline to Any Postbaseline in Glucose and HbA1c ............18 
Table 6: 
Shift Categories from Baseline to Any Postbaseline in Liver Function Test .............18 
Table 7: 
Criteria for Potentially Clinically Significant (PCS) Blood Pressure or Pulse 
Rate .............................................................................................................................19 
Table 8: 
Criteria for Potentially Clinically Significant (PCS) Changes from Baseline 
in Body Weight ...........................................................................................................20 
Table 9: 
Criteria for Potentially Clinically Significant (PCS) QTcF ........................................20 
Table 10: C-SSRS Categories for Analysis ................................................................................21 
Table 11: Visit Window for All Efficacy and Safety Assessments Excluding PANSS .............22 
Table 12: Visit Window for PANSS Assessments .....................................................................23 
Table 13: Degree of Precision .....................................................................................................24 
 
LIST OF FIGURES 
Figure 1: Study Design Schematic ...................................................................................................8 


Alkermes, Inc.                                                                                                                                     
Statistical Analysis Plan - ALK3831-A304                                                                                                 11 June 2019 
 
 
 
 
Page 5 of 36 
 
 
 
ABBREVIATIONS 
Abbreviation or Term 
Explanation or Definition 
AE 
Adverse event 
AIMS 
Abnormal Involuntary Movement Scale 
BARS 
Barnes Akathisia Rating Scale 
BMI 
Body mass index 
CGI-S 
Clinical Global Impression - Severity 
C-SSRS 
Columbia Suicide Severity Rating Scale 
CMQ 
Customized MedDRA queries 
ECG 
Electrocardiogram 
eCRF 
Electronic case report form 
EPS 
Extra pyramidal symptoms 
EQ-5D 
EuroQOL-5D 
HbA1C 
Hemoglobin A1c 
IWQOL 
Impact of Weight on Quality of Life 
MedDRA 
Medical Dictionary for Regulatory Activities 
OLZ 
Olanzapine 
PANSS 
Positive and Negative Syndrome Scale 
PCS 
Potentially clinically significant 
PK 
Pharmacokinetics 
PT 
Preferred term 
KM 
Kaplan-Meier 
QTcF 
QT corrected with Fridericia formula 
SAE 
Serious adverse event 
SAP 
Statistical analysis plan 
SAS 
Simpson-Angus Scale 
SD 
Standard deviation 
SMQ 
Standardized MedDRA queries 
SOC 
System organ class 
TEAE 
Treatment-emergent adverse event 


Alkermes, Inc.                                                                                                                                     
Statistical Analysis Plan - ALK3831-A304                                                                                                 11 June 2019 
 
 
 
 
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Abbreviation or Term 
Explanation or Definition 
ULN 
Upper limit of normal 
VAS 
Visual analogue scale 
WHO 
World Health Organization 


Alkermes, Inc.                                                                                                                                     
Statistical Analysis Plan - ALK3831-A304                                                                                                 11 June 2019 
 
 
 
 
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1. 
INTRODUCTION 
This statistical analysis plan (SAP) describes the statistical methods to be used for analyses and 
presentation of safety and efficacy data for the study ALK3831-A304. ALK3831-A304 is a 52-
week, open-label safety extension study of ALK3831-A303. This document has been prepared 
based on Alkermes ALK3831-A304 Study Protocol Amendment 3.0 (dated 26 April 2018)1. 
1.1. 
Study Objectives 
1.1.1. 
Primary Objective 
The primary objective of this study is to evaluate the long-term safety and tolerability of 
ALKS 3831 in subjects with schizophrenia.  
1.2. 
Summary of the Study Design 
Subjects are eligible to be enrolled in the study within 7 days after completing the 24-week 
treatment period of the antecedent study, ALK3831-A303.  
Subjects enrolled in the study will be started on the same olanzapine dose that they had 
maintained at the end of ALK3831-A303. Subjects taking 20 mg olanzapine (either as OLZ 20 or 
ALKS 3831 20/10 [20 mg olanzapine/10 mg samidorphan]) will start on ALKS 3831 20/10 in 
this study and subjects taking 10 mg olanzapine (either as OLZ 10 or ALKS 3831 10/10 [10 mg 
olanzapine/10 mg samidorphan) will start on ALKS 3831 10/10 in this study. An intermediate 
dose, ALKS 3831 15/10 (15 mg olanzapine/10 mg samidorphan), will also be available, and 
subjects may be titrated to this dose any time after the start of the study at the investigator’s 
discretion. Dosing is flexible throughout the study; however, frequent adjustments are 
discouraged. Dose adjustments can only be performed on-site at the study center. Subjects 
requiring dose adjustments between scheduled visits should arrange an unscheduled visit for the 
following procedures: study drug return, adherence review, adverse event monitoring, and study 
drug dispensation. Safety assessments will include AE monitoring, clinical laboratory testing, 
vital signs, weight and waist circumference assessments, 12-lead ECGs, movement disorder 
assessments, including the Abnormal Involuntary Movement Scale (AIMS), Barnes Akathisia 
Rating Scale (BARS), Simpson Angus Scale (SAS), and the Columbia-Suicide Severity Rating 
Scale (C-SSRS). 
Efficacy assessments to evaluate the durability of treatment effect will include Positive and 
Negative Syndrome Scale (PANSS) and Clinical Global Impressions-Severity (CGI-S). 
Additional assessments include Impact of Weight on Quality of Life–Lite Questionnaire 
(IWQOL-Lite), Cigarette Use, and EuroQOL-5D (EQ-5D). 
Subjects completing 52 weeks of treatment with study drug will be eligible to continue in another 
open-label, long-term safety study (ALK3831-A308) and will continue to receive ALKS 3831. 
Subjects not continuing in the ALK3831-A308 long-term safety study will enter a 4-week Safety 
Follow-up Period. 


Alkermes, Inc.                                                                                                                                     
Statistical Analysis Plan - ALK3831-A304                                                                                                 11 June 2019 
 
 
 
 
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A schematic of the study design is provided in Figure 1 . 
Figure 1: Study Design Schematic  
 
 
*Visits will occur biweekly throughout the 52-week Treatment Period. Subjects will start the study on the 
equivalent olanzapine dose to what they maintained at the end of ALK3831-A303. The dose may be adjusted 
to either 10/10, 15/10, or 20/10 mg throughout the study period, based on Investigator discretion, and 
such dose adjustments will require subjects to visit the study site. 
2. 
SAMPLE SIZE CONSIDERATION 
No formal sample size calculation is performed for this extension study. A sample size of 
approximately 540 is based on the estimated maximum number of subjects who might be 
expected to continue from the ALK3831-A303 study. 
3. 
DATA ANALYSIS 
3.1. 
General Statistical Methodology 
Baseline for efficacy or safety analysis is defined as the last non-missing assessment before the 
first dose of ALKS 3831 in the ALK3831-A304 study, and it will be used for all efficacy and 
safety analysis, unless specified otherwise.  
Baseline of precedent study (A303) is defined as the last non-missing assessment before the first 
dose of study drug in the ALK3831-A303 study. It will be used for the summary of the PANSS 
total score and subscales and body weight results.  
Treatment sequence is defined according to the treatment assignment in antecedent and current 
studies as ALKS 3831/ALKS 3831 (ALKS 3831 in both ALK3831-A303 study and ALK3831-
A304 study) and OLZ/ALKS 3831 (olanzapine in ALK3831-A303 study and ALKS 3831 in 


Alkermes, Inc.                                                                                                                                     
Statistical Analysis Plan - ALK3831-A304                                                                                                 11 June 2019 
 
 
 
 
Page 9 of 36 
 
 
 
ALK3831-A304 study). All efficacy and safety analysis will be presented by treatment sequence 
and overall. 
In general, descriptive statistics: n, mean, standard deviation (SD), median, minimum, and 
maximum, for continuous variables and number and percentage of subjects in each category for 
categorical variables will be provided. 
All source data will be presented as subject data listings. 
3.2. 
Definitions of Analysis Populations 
3.2.1. 
Safety Population 
The Safety Population will include all subjects who enrolled and received at least one dose of 
ALKS 3831 in the ALK3831-A304 study. All analyses will be conducted using the Safety 
Population except for AEs in the safety follow-up period and AE to evaluate the potential for 
drug withdrawal and dependence. The populations used for the analyses of these events are 
specified below. 
3.2.2. 
Follow-up Safety Population 
Follow-up Safety Population will be defined with respect to the 5 half-lives of the product as 
subjects in the Safety Population and met any of the following criteria: 
• Completed at least one follow-up visit after >7 days of the last dose of ALKS 3831 
• Reported at least one AE reported after >7 days of the last dose of ALKS 3831 
This population will be used to analyze the AEs in the safety follow-up period. 
3.2.3. 
Post-discontinuation Safety Population 
Post-discontinuation Safety Population will be defined as subjects in the Safety Population 
and met any of the following criteria: 
• Completed at least one follow-up visit after >2 day within 16 days of the last dose of 
ALKS 3831 
• Reported at least one AE reported after >2 day after the last dose of ALKS 3831 
AE to evaluate potential for drug withdrawal and dependence emerging following 
discontinuation of ALKS 3831 will be assessed for this population, during the period of >2 days 
to 16 days after the last dose of drug for subjects with at least 4 weeks study drug exposure. 
3.3. 
Disposition 
The number and percentage of subjects completing or prematurely discontinuing the study 
including reasons for discontinuation will be summarized for the following: 
• Subjects who enrolled in the study  


Alkermes, Inc.                                                                                                                                     
Statistical Analysis Plan - ALK3831-A304                                                                                                 11 June 2019 
 
 
 
 
Page 10 of 36 
 
 
 
• Subjects in the Safety Population  
• Subjects who completed the treatment period 
• Subjects who discontinued treatment along with reason for discontinuation (as 
indicated in case report form) 
3.4. 
Protocol Deviation 
Subjects with major protocol deviations in the following categories will be summarized. A 
supportive listing will be provided as well. 
• Did not meet the study entry criteria 
• Received prohibited medications 
• Lack of adherence with study medication, as defined by subjects taking less than 70% 
of protocol specified amount of study medication 
• Dosing error 
3.5. 
Demographics and Baseline Characteristics 
Demographics and baseline characteristics such as sex, age, race, ethnicity, weight, and body 
mass index (BMI) will be summarized for the Safety Population and for the subset of subjects 
who participated in the patient voice substudy.  
3.6. 
Prior and Concomitant Medication 
Prior medications will be defined as medications taken prior to the first dose of study drug in 
ALK3831-A304 study. Concomitant medications will be defined as medications taken on or 
after the first dose of study drug in ALK3831-A304 study. All medications will be coded using 
the World Health Organization WHO-DD Enhanced + Herbal (version: March 2016) or higher. 
Concomitant medications taken during the treatment period will be summarized by the preferred 
drug name. All reported medications (including those initiated after the last dose of study 
medication) will be included in the listing. For the summary table, if a subject has taken a 
concomitant medication more than once, the subject will be counted only once for that 
medication. 
3.7. 
Treatment Adherence Rate and Extent of Exposure to Study Drug 
3.7.1. 
Treatment Adherence Rate 
Treatment adherence to the daily dosing schedule during treatment period will be summarized. 
Treatment adherence will be calculated as follows: 
100 × Total tablets dispensed −total tablets returned −total tablets lost
Total tablets scheduled to be taken
 


Alkermes, Inc.                                                                                                                                     
Statistical Analysis Plan - ALK3831-A304                                                                                                 11 June 2019 
 
 
 
 
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3.7.2. 
Extent of Exposure to Study Drug 
Duration of exposure to study drug (ALKS 3831) is defined as the number of days from the date 
of the first dose of study drug of this study (ALK3831-A304) to the date of the last dose of study 
drug, inclusive (ie, last dose date – first dose date + 1 day). Duration of study drug administration 
will be summarized. 
The overall mean and modal dose of olanzapine will be summarized  
3.8. 
Efficacy Analyses 
3.8.1. 
General Considerations 
In general, continuous and categorical endpoints will be summarized using descriptive statistics 
based on observed data.  
3.8.2. 
Efficacy Analysis 
The following endpoints will be used to evaluate durability of treatment effect:  
• Change from baseline in PANSS total score, and subscales (positive, negative, and 
general psychopathology subscales) by visit 
• Change from baseline in CGI-S by visit 
• Shift analysis in CGI-S 
• Time to treatment discontinuation  
Summary statistics will be provided for all continuous endpoints based on observed data.  
Change from current (A304) and precedent (A303) study baseline in PANSS total score and 
subscales will be summarized for the subset of subjects who participated in the patient voice 
substudy.  
CGI-S response will be categorized into the categories summarized in Table 1. The number and 
percentage of subjects in each category and with shifts from baseline will be summarized based 
on the observed data by descriptive statistics at 4, 12, 24 and 52 weeks. The shift categories are 
summarized in Table 2.  
Time to treatment discontinuation will be analyzed using the Kaplan-Meier method. Both all-
cause discontinuation and discontinuation due to AE will be summarized. For prematurely 
discontinued subjects (all-cause or due to AE), time to discontinuation is defined as time from 
the date of first dose of study drug to the date of last dose of study drug. Other subjects will be 
censored at the last dose of the study drug.  
Table 1: 
Definition of CGI-S Categories 
Response Category 
CGI-S Score 
Markedly to Extremely Ill 
≥5 


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Response Category 
CGI-S Score 
Moderately Ill 
4 
Normal to Mildly Ill 
≤3 
Table 2: 
Shift Categories for CGI-S response 
Shift from Baseline Category for CGI-S Response 
Baseline Category 
    Shift Category 
Markedly to Extremely Ill 
    No change 
    ≥1 level improvement 
    2 level improvement 
Moderately Ill 
    No change 
   1 level improvement 
   1 level worsening    
Normal to Mildly Ill 
   No change 
   ≥1 level worsening 
   2 level worsening     
3.8.3. 
Other Endpoints 
• Change from baseline in IWQOL-Lite scales (total score, physical function, self-
esteem, sexual life, public distress, and work) by visit 
• Change from baseline in EQ-5D-5L index value and visual analogue scale (VAS) 
score by visit 
Descriptive statistics of IWQOL-Lite scales and EQ-5D-5L, including n, mean, SD, median, 
minimum, and maximum, will be summarized by visit based on observed data. 
The IWQOL-Lite scale is a 31-item self-report measure of obesity-specific quality of life. 
IWQOL-Lite provides an overall total score as well as scores on five domains: (1) physical 
function, (2) self-esteem, (3) sexual life, (4) public distress, and (5) work. The raw scores will be 
transformed as follows (Tessier et al, 2012)3: the transformed scores range from 0 to 100, with 
100 representing the best, and 0 representing the most impaired quality of life. 
𝑇𝑟𝑎𝑛𝑠𝑓𝑜𝑟𝑚𝑒𝑑 𝑆𝑐𝑜𝑟𝑒= 𝑚𝑎𝑥𝑖𝑚𝑢𝑚 𝑡ℎ𝑒𝑜𝑟𝑒𝑡𝑖𝑐𝑎𝑙 𝑠𝑐𝑜𝑟𝑒−𝑎𝑐𝑡𝑢𝑎𝑙 𝑠𝑐𝑜𝑟𝑒
𝑡𝑒𝑠𝑡 𝑠𝑐𝑜𝑟𝑒 𝑟𝑎𝑛𝑔𝑒
𝑋100 


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The EQ-5D-5L is a validated quality of life questionnaire developed by the EuroQol Group in 
order to provide a simple, generic utility measure for characterizing current health states of 
patients. EQ-5D-5L is designed for self-completion by subjects. It consists of 2 parts – the EQ-
5D-5L descriptive system and the VAS. 
The EQ-5D-5L descriptive system comprises 5 dimensions: mobility, self-care, usual activities, 
pain/discomfort, and anxiety/depression. Each dimension has 5 levels. 
The 5 dimensional 5-level systems are converted into an index value. Values for theoretically 
possible health states are calculated using a regression model and weighted according to the 
social preferences of the U.S. population (Van Hout et al, 2012)4. The VAS records the 
respondent’s self-rated health on a vertical VAS. The VAS has 100 (Best health you can 
imagine) at the top, and 0 (Worst health you can imagine) at the bottom. This information can be 
used as a quantitative measure of health outcomes as judged by the individual respondents. EQ-
5D-5L self-reported VAS data generates information on the self-perceived overall health-related 
quality of life. Change from baseline in EQ-5D-5L index value and VAS score will be analyzed. 
3.8.4. 
Multiple Comparison / Multiplicity 
Not applicable. 
3.9. 
Safety Analysis 
3.9.1. 
Adverse Events 
Incidence of treatment emergent AEs (TEAEs) will be analyzed as a safety endpoint. Adverse 
events will be coded by System Organ Class and Preferred Term using the Medical Dictionary 
for Regulatory Activities (MedDRA®) Version 21.0 or higher. The verbatim term will be 
included in the AE listings. 
An AE (coded by preferred term) will be considered as a TEAE if the event is newly occurring 
or worsening on or after the date of first dose of study drug and within 7 days after the last dose 
of study drug in this study.  
An overview table, including number of subjects with TEAEs, AEs leading to treatment 
discontinuation, study drug related TEAEs, and SAEs will be provided. 
The incidence (number and percentage) of subjects reporting TEAEs during the treatment period 
will be presented for the following categories:  
• System organ class and preferred term  
• Preferred term, and including the following subset: 
 TEAEs experienced by ≥2% of subjects (in any group)  
• System organ class, preferred term, and severity  
• System organ class, preferred term for severe TEAEs  


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• System organ class, preferred term, and relationship  
• System organ class, preferred term for study drug related TEAEs  
If the same preferred term occurred more than once for the same subject, the subject will be 
counted only once for that preferred term using the most severe and most related occurrence for 
the summarization by severity and by relationship to the study drug. 
In addition, the number and percentage of subjects reporting AEs during the safety follow-up 
period will be tabulated by the system organ class and preferred term. 
Subgroup analysis by age (<40 years vs ≥40 years), sex (Female vs Male) and race (Black or 
African American, White, and Other) will be performed for TEAEs during the treatment period 
by preferred term.  
3.9.1.1. 
Deaths, Serious and Other Significant AEs  
The number and percentage of subjects who have serious adverse events (SAEs) and AEs 
leading to premature discontinuation from the treatment will be summarized by system organ 
class and preferred term. 
By-subject listings will be provided for SAEs, AEs leading to treatment discontinuation and AEs 
leading to death. 
3.9.1.2. 
Other Significant AEs 
In addition, incidence of a selected subset of relevant AEs in this class of drugs (e.g., 
Extrapyramidal symptoms [EPS) TEAEs, TEAE to evaluate potential of suicidal ideation and 
behavior, etc.) will be summarized by preferred term. The selection of AEs per subset will be 
based on the preferred terms from Standardized MedDRA queries (SMQs) or Customized 
MedDRA queries (CMQ’s).  
3.9.1.3. 
Analysis of Abuse Potential, Withdrawal, and Dependence 
3.9.1.3.1. Analysis of Abuse Potential 
Number and percentage subjects with TEAEs to evaluate abuse potential will be summarized by 
category (abuse behavior, euphoria related, and non-specific) and preferred term. The selection 
of AEs per subset will be based on the preferred terms from Customized MedDRA queries 
(CMQs). 
3.9.1.3.2. Analysis of Withdrawal and Dependence 
Adverse events with an onset date within 2 weeks (>2 to ≤16 days) after the last dose of the 
study drug in those subjects who have received at least 4 weeks of study drug will be included in 
the evaluation of the potential for withdrawal and dependence. The selection of AEs per subset 
will be based on the preferred terms from Customized MedDRA queries (CMQs). 


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The number and percentage of subjects with such AEs will be summarized in the Post-
discontinuation Safety Populations by preferred term for subjects with a duration of study drug 
exposure ≥4 weeks.  
3.9.2. 
Clinical Laboratory Parameters 
Laboratory parameters will be presented in conventional (ie, US) units. Only scheduled 
laboratory parameters will be included in the summaries, unless specified otherwise. All 
laboratory data, including those collected at unscheduled visits, will be included in the listings. 
Laboratory results including baseline and change from baseline during the treatment period for 
chemistry and hematology parameters will be summarized by visit. 
Clinical laboratory test values, scheduled or unscheduled, will be considered potentially 
clinically significant (PCS) if they meet PCS criteria listed in Table 3. The number and 
percentage of subjects who have postbaseline PCS clinical laboratory values will be summarized. 
The percentages will be calculated based on the number of subjects with non-PCS baseline value 
and have at least one postbaseline assessment. All PCS values including baseline PCS values 
will be included in supportive listings. 
For selected metabolic parameters (fasting total cholesterol, fasting high density 
lipoprotein[HDL], fasting low density lipoprotein[LDL], fasting triglycerides, fasting glucose, 
and hemoglobin A1c[HbA1c]), an analysis of sustained PCS values will also be conducted. The 
percentage of subjects with sustained PCS values through the treatment period will be 
summarized. The denominator is all subjects with non-PCS at baseline and at least two 
postbaseline assessments, and the numerator is the number of subjects who met PCS criteria at 
the last 2 assessments within the treatment period.  
Shift tables for selected fasting metabolic parameters (total cholesterol, LDL, HDL, triglycerides, 
glucose and HbA1c) and liver function tests will be presented. The criteria are summarized in 
Table 4, Table 5 and Table 6.  


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Table 3: 
Criteria of Potentially Clinically Significant (PCS) Abnormality for Selected 
Analytes 
Parameter 
Criteria 
Chemistry 
Albumin 
<2.5 g/dL 
Alkaline Phosphatase (U/L) 
≥3 × ULN 
Alanine Aminotransferase (U/L) 
≥3 × ULN 
Aspartate Aminotransferase (U/L) 
≥3 × ULN 
Bilirubin, Total 
≥2.0 mg/dL 
Blood Urea Nitrogen 
>30 mg/dL 
Cholesterol, Random 
>300 mg/dL 
Cholesterol, Fastinga 
≥240 mg/dL 
Cholesterol, Fasting 
Increase ≥40 mg/dL 
Cholesterol, HDL Fasting 
<40 mg/dL 
Cholesterol, HDL Fasting 
Decrease ≥20 mg/dL 
Cholesterol, LDL Fasting 
≥160 mg/dL 
Cholesterol, LDL Fasting 
Increase ≥30 mg/dL 
Creatine Kinase (U/L) 
≥3 × ULN 
Creatinine 
≥2.0 mg/dL 
Glucose, Random 
<50 mg/dL or  
≥200 mg/dL 
Glucose, Fasting 
<50 mg/dL or  
≥126 mg/dL 
Glucose, Fasting 
Increase ≥10 mg/dL 
HbA1c  
≥ 5.7% 
Potassium 
<3 mmol/L or 
>5.5 mmol/L 
Lactate Dehydrogenase (U/L) 
>3 × ULN 
Prolactin (Female) 
>30 ng/mL 
Prolactin (Male) 
>20 ng/mL 
Sodium 
<130 mmol/L or 
>150 mmol/L 


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Table 3: 
Criteria of Potentially Clinically Significant (PCS) Abnormality for Selected 
Analytes (Continued) 
Triglycerides, Fasting  
≥200 mg/dL 
Triglycerides, Fasting 
Increase ≥50 mg/dL 
Hematology 
Eosinophils 
>1.0 × 103/μL 
Hematocrit (Female) 
≤32% 
Hematocrit (Male) 
≤37% 
Neutrophils, Absolute 
<1.5 × 103/μL 
Platelets 
<75.0 × 103 cells/μL or 
≥ 700.0 × 103 cells/μL 
Leukocytes 
≤ 2.8 × 103/μL or 
≥ 16.0 ×103/μL 
a reported fasting. 
 
Table 4: 
Shifts Categories from Baseline to Any Postbaseline for Selected Lipid 
Parameters 
Total Cholesterol (fasting) mg/dL 
Normal (<200) to High (≥240) 
Borderline (≥200 and < 240) to High (≥240) 
Normal (<200) to Borderline (≥200 and <240) 
LDL Cholesterol (fasting) mg/dL 
Normal (<100) to High (≥160) 
Borderline (≥100 and <160) to High (≥160) 
Normal (<100) to Borderline (≥100 and <160) 
HDL Cholesterol (fasting) mg/dL 
Normal (≥40) to Low (<40) 
Triglycerides (fasting) mg/dL 
Normal (<150) to High (≥200) 
Borderline (≥150 and <200) to High (≥200) 
Normal (<150) to Borderline (≥150 and <200) 


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Table 5: 
Shift Categories from Baseline to Any Postbaseline in Glucose and HbA1c 
Glucose (fasting) mg/dL 
Normal (<100) to Impaired (≥100 and <126) 
Normal (<100) to High (≥126) 
Impaired (≥100 and <126) to High (≥126) 
HbA1c % 
Normal (<5.7%) to Borderline (≥5.7% and <6.5%) 
Borderline (≥5.7% and <6.5%) to High (≥6.5%) 
Normal (<5.7%) to High (≥6.5%) 
 
Table 6: 
Shift Categories from Baseline to Any Postbaseline in Liver Function Test 
Alanine Aminotransferase (ALT) (U/L)  
Shift from Normal to ≥3 x ULN   
Shift from Normal to ≥5 x ULN   
Shift from Normal to ≥10 x ULN   
Aspartate Aminotransferase (AST) (U/L) 
Shift from Normal to ≥3 x ULN   
Shift from Normal to ≥5 x ULN   
Shift from Normal to ≥10 x ULN   
Bilirubin, Total (mg/dL) 
Shift from Normal to >1 x ULN   
Shift from Normal to ≥2 x ULN   
3.9.3. 
Vital Signs, Body Weight, and ECG 
3.9.3.1. 
Vital Signs 
Descriptive statistics for vital signs and changes from baseline values at each scheduled time 
point will be presented. 
Vital sign values will be considered PCS if they meet both the observed-value criteria and the 
change-from-baseline criteria listed in Table 7. The number and percentage of subjects with PCS 
postbaseline values will be tabulated. The percentages will be calculated based on the number of 
subjects with non-PCS baseline values and at least one postbaseline assessment. The numerator 


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will be the number of subjects with non-PCS baseline values and at least one postbaseline PCS 
value. A supportive listing of subjects with PCS postbaseline values will be provided. 
All vital signs will be presented in the subject data listing. 
Orthostatic hypotension (20/10 mmHg) is defined as a fall in systolic blood pressure of at least 
20 mmHg and a fall in the diastolic blood pressure of at least 10 mmHg upon standing from 
supine. Orthostatic hypotension (30 mmHg) is defined as a fall in systolic blood pressure of at 
least 30 mmHg upon standing from supine. 
Orthostatic tachycardia is defined as a heart rate increase of 30 beats per minute (bpm) or more 
upon standing from supine, or over 120 bpm upon standing. 
The number and percentage of subjects with orthostatic hypotension or orthostatic tachycardia 
occurring at any postbaseline visit will be summarized. 
Table 7: 
Criteria for Potentially Clinically Significant (PCS) Blood Pressure or Pulse 
Rate 
Parameter 
Criteria 
Supine Systolic Blood Pressure 
≤90 and decrease ≥20 mm Hg 
≥180 and increase ≥20 mm Hg 
Supine Diastolic Blood Pressure 
≤50 and decrease ≥15 mm Hg 
≥105 and increase ≥15 mm Hg 
Supine Heart Rate 
≤50 and decrease ≥15 bpm 
≥120 and increase ≥15 bpm 
3.9.3.2. 
Weight and Body Mass Index 
Body weight (kg), BMI (kg/m2) and waist circumferences (cm) (baseline and change from 
baseline) will be summarized using observed data. Absolute (kg) and percent change from 
baseline in body weight will be summarized by visit.  
Absolute and percent change from current (A304) and precedent (A303) study baseline in body 
weight will also be summarized for the subset of subjects who participated in the patient voice 
substudy.  
Number and percentage of subjects with ≥7% or ≥10% weight gain from baseline based on the 
observed data will be summarized by visit. In addition, number and percentage of subjects with 
weight change values considered as PCS occurring at any postbaseline visit will be summarized. 
Criteria for PCS are presented below. The percentages will be calculated relative to the number 
of subjects in the Safety Population with at least one postbaseline value. A supportive listing will 
be provided for subjects with PCS values. 


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Table 8: 
Criteria for Potentially Clinically Significant (PCS) Changes from Baseline 
in Body Weight 
Parameter 
Criteria 
Body Weight 
Decrease from Baseline ≥7% 
Increase from Baseline ≥7% 
3.9.3.3. 
Electrocardiograms 
Descriptive statistics for ECG parameters (heart rate, PR interval, RR interval, QRS interval, 
QT interval, and QTc interval) at baseline and change from baseline values at each scheduled 
assessment timepoint and at the end of the treatment period will be presented. QTc interval will 
be calculated using Fridericia (QTcF = QT/(RR)⅓) corrections; if RR is not available, it will be 
replaced with 60/HR in the correction formula. 
Electrocardiogram parameter values are considered PCS if they meet or exceed the higher-limit 
PCS criteria listed in Table 9. The number and percentage of subjects with PCS postbaseline 
ECG values will be tabulated. The percentages will be calculated based on the number of 
subjects with non-PCS baseline values and at least one postbaseline assessment. The numerator 
is the number of subjects with non-PCS baseline values and at least one postbaseline PCS value. 
A supportive listing of subjects with PCS values will be provided. 
Table 9: 
Criteria for Potentially Clinically Significant (PCS) QTcF 
Parameter 
Criteria 
QTcF 
>450 to ≤480 msec 
>480 to ≤500 msec 
>500 msec 
Change from baseline >30 to ≤60 msec 
Change from baseline >60 msec 
3.9.4. 
Abnormal Movement Scales 
Extra pyramidal symptoms (EPS) will be evaluated as AEs and also as assessed by abnormal 
movement scales. Abnormal movement scales will include the following: Abnormal Involuntary 
Movement Scale (AIMS), Barnes Akathisia Rating Scale (BARS), and Simpson-Angus Scale 
(SAS). 
Change from baseline in all abnormal movement scales, total scores and subscale scores will be 
summarized by visit. 
Number and percentage of subjects meeting the criteria for treatment emergent Parkinsonism 
(SAS total score>3), for treatment emergent akathisia (BARS global clinical assessment of 
akathisia score ≥2), for treatment emergent dyskinesia (AIMS score ≥3 on any of the first 


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7 items, or a score ≥2 on two or more of any of the first 7 items) at any postbaseline visit will be 
summarized. 
A listing will be provided for every abnormal movement scale. Listing for treatment emergent 
EPS will be provided. 
3.9.5. 
Columbia-Suicide Severity Rating Scale (C-SSRS) 
The C-SSRS is a questionnaire used to measure the presence and intensity of suicidal ideation 
and behavior. Suicidal behavior and suicidal ideation will be summarized descriptively 
(Table 10). The number of subjects with suicidal ideation and suicidal behavior will be 
summarized. 
Supportive tabular display of subjects with all values will be provided. 
Table 10: 
C-SSRS Categories for Analysis  
Category 
C-SSRS Item response is “YES” 
Suicidal behaviora 
Preparatory acts or behavior 
Aborted attempt 
Interrupted attempt 
Actual attempt 
Complete suicide 
Suicidal ideationa 
Wish to be dead 
Non-specific active suicidal thoughts 
Active suicidal ideation with any methods (not plan) without 
intent to act 
Active suicidal ideation with some intent to act, without specific 
plan 
Active suicidal ideation with specific plan and intent 
Non-Suicidal Self-Injurious 
Behavior 
Non-Suicidal Self-Injurious 
Behavior 
a Derived based on responses to individual items listed within the category  
3.10. 
Pharmacokinetic/ Pharmacodynamic Data Analysis 
Not applicable. 
4. 
INTERIM ANALYSES 
No interim analysis is planned for this study. 


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5. 
CHANGES IN CONDUCT OR PLANNED ANALYSES FROM 
THE PROTOCOL 
To further assess the long-term durability, the following analysis was added in SAP but were not 
specified in protocol.  
• Shift analysis in CGI-S 
6. 
DEFINITIONS AND CONVENTIONS FOR HANDLING OF THE 
DATA 
Dataset specifications will be provided in a separate document. 
6.1. 
Analysis Visit Windows 
Scheduled analysis visits are visits at scheduled timepoints as specified in the protocol 
(Table 3 Schedule of Visits and Assessments). 
Scheduled analysis visits during the study period will be the same as the nominal visits collected 
in eCRF. There will be one valid value of assessment kept for each scheduled analysis visit 
in summary/analysis statistics. 
Unscheduled visits are visits with data not collected on the scheduled time point. Unscheduled 
visits will not be used for by-visit summary/analysis statistics, unless specified otherwise. 
All unscheduled visits as collected in eCRF will be included in listings. 
Last postbaseline values are defined as the last valid postbaseline values collected for each 
subject during the treatment period.  
An early termination (ET) visit during the on-treatment period can be mapped to a scheduled 
visit, if there is no valid value already at that visit. Visit windows are defined in Table 11 and 
Table 12. An ET visit that is not mapped will not be summarized in the tables or figures, but will 
be included in the listing.  
Table 11: 
Visit Window for All Efficacy and Safety Assessments Excluding PANSS 
Analysis Visit to be 
Mapped to 
Target Study Week 
Target Visit Daya 
Visit Window 
Visit 1 
Week 0 
Day 1 
1 
Visit 2 
Week 2 
Day 15 
[2, 21] 
Visit 3 
Week 4 
Day 29 
[22, 35] 
Visit 4 
Week 6 
Day 43 
[36, 49] 
Visit 5 
Week 8 
Day 57 
[50, 70] 
Visit 7 
Week 12 
Day 85 
[71, 98] 


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Analysis Visit to be 
Mapped to 
Target Study Week 
Target Visit Daya 
Visit Window 
Visit 9 
Week 16 
Day 113 
[99, 126] 
Visit 11 
Week 20 
Day 141 
[127, 154] 
Visit 13 
Week 24 
Day 169 
[155, 182] 
Visit 15 
Week 28 
Day 197 
[183, 210] 
Visit 17 
Week 32 
Day 225 
[211, 238] 
Visit 19 
Week 36 
Day 253 
[239, 266] 
Visit 21 
Week 40 
Day 281 
[267, 294] 
Visit 23 
Week 44 
Day 309 
[295, 322] 
Visit 25 
Week 48 
Day 337 
[323, 350]  
Visit 27 
Week 52 
Day 365 
[351, 371] 
a Visit Day is calculated as date of visit – date of the first dose of study drug + 1 day. 
Table 12: 
Visit Window for PANSS Assessments 
Analysis Visit to be 
Mapped to 
Target Study Week 
Target Visit Day 
Visit Window 
Visit 2 
Week 2 
Day 15 
[2, 21] 
Visit 3 
Week 4 
Day 29 
[22, 42] 
Visit 5 
Week 8 
Day 57 
[43, 70] 
Visit 7 
Week 12 
Day 85 
[71, 126] 
Visit 13 
Week 24 
Day 169 
[127, 210] 
Visit 19 
Week 36 
Day 253 
[211, 308] 
Visit 27 
Week 52 
Day 365 
[309, 371] 
6.2. 
Handling of Partial Dates of Concomitant Medication 
Partial start dates of prior and concomitant medications will be assumed to be the earliest 
possible date consistent with the partial date. Partial stop dates of prior and concomitant 
medications will be assumed to be the latest possible date consistent with the partial date. In 
the case of completely missing stop date, medication will be assumed to be ongoing. 
6.3. 
Handling of Safety Data 
All efforts should be made to obtain the missing information from the investigator. For C-SSRS, 
vital signs, laboratory testing (chemistry, hematology, urinalysis), and 12-lead ECGs, only 
observed data will be used for analyses, and missing data will not be imputed. 


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7. 
GENERAL STATISTICAL METHODOLOGY 
In general, summary statistics (n, mean, SD, median, minimum, and maximum for continuous 
variables, and number and percentage of subjects in each category for categorical variables) will 
be provided by treatment sequence and overall. All summary tables will be based on observed 
data, and missing values will not be imputed. Measurements collected from unscheduled visits or 
repeated assessments will not be included in the by-visit summary tables or figures, but will be 
included in the analyses for the PCS postbaseline values, and subject listings. Source data for the 
summary tables will be presented as subject data listings. 
7.1. 
Reporting Precision 
Summary statistics will be presented to the following degree of precision, unless otherwise 
specified: 
Table 13: 
Degree of Precision 
Statistics 
Degree of Precision 
 
Mean, Median, Confidence limit 
boundaries 
One more than the raw data, up to 3 decimal places. 
Standard deviation, Standard error 
One more than the mean, up to 3 decimal places 
Minimum, Maximum 
The same as the raw data, up to 2 decimal places 
P-value 
Rounded to 3 decimal places and therefore presented as 
0.xxx; P-values smaller than 0.001 as ‘<0.001’; P-values 
greater than 0.999 as ‘>0.999’. 
Percentage 
One decimal place. A percentage of 100% will be 
reported as 100%. Percentages of zero will be reported 
as 0. 
Fractional numeric values will be presented with a zero to the left of the decimal point (for 
example, 0.12 – 0.30). 
For weight, height, and BMI, one decimal place will be used for summary statistics, unless 
otherwise specified. 
8. 
PROGRAMMING SPECIFICATIONS 
Programming specifications will be provided in a separate document. 
9. 
MOCK TABLES, LISTINGS AND FIGURES (TLFS) 
Mock-up tables and listings will be provided in a separate document. 


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10. 
REFERENCES 
1. Alkermes ALK3831-A304 Study Protocol Amendment 3.0 Date: 26 April 2018 
2. Marder SR, Davis JM, Chouinard G. The effects of risperidone on the five dimensions of 
schizophrenia derived by factor analysis: combined results of the North American trials. J 
Clin Psychiatry. 1997; 58(12): 538-546. 
3. Tessier A et al. Understanding the Determinants of Weight-Related Quality of Life 
among Bariatric Surgery Candidates. Journal of Obesity 2012; 2012: 713426  
4. Van Hout B, Janssen MF, et al. Interim scoring for the EQ-5D-5L: Mapping the EQ-5D-
5L to EQ-5D-3L value sets. Value in Health 2012 Jul-Aug;15(5):708-15 
 


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APPENDIX 1. AESI - MOVEMENT DISORDERS (INCLUDING 
EXTRAPYRAMIDAL SYNDROME AND TARDIVE 
DYSKINESIA; STANDARDIZED MEDDRA QUERY) 
Preferred Term (SMQ [#20000095] of Extrapyramidal syndrome) 
PT Code 
Abnormal involuntary movement scale 
10075002 
Action tremor 
10072413 
Akathisia 
10001540 
Akinesia 
10001541 
Athetosis 
10003620 
Ballismus 
10058504 
Blepharospasm 
10005159 
Bradykinesia 
10006100 
Bradyphrenia 
10050012 
Buccoglossal syndrome 
10006532 
Chorea 
10008748 
Choreoathetosis 
10008754 
Chronic tic disorder 
10076661 
Cogwheel rigidity 
10009848 
Complex tic 
10076663 
Dopamine dysregulation syndrome 
10067468 
Dopa-responsive dystonia 
10080034 
Drooling 
10013642 
Dyskinesia 
10013916 
Dyskinesia neonatal 
10013922 
Dyskinesia oesophageal 
10013924 
Dysphonia 
10013952 
Dystonia 
10013983 
Dystonic tremor 
10073210 
Early onset primary dystonia 
10076668 
Emprosthotonus 
10014566 
Extrapyramidal disorder 
10015832 


Alkermes, Inc.                                                                                                                                     
Statistical Analysis Plan - ALK3831-A304                                                                                                 11 June 2019 
 
 
 
 
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Preferred Term (SMQ [#20000095] of Extrapyramidal syndrome) 
PT Code 
Facial spasm 
10063006 
Fine motor skill dysfunction 
10076288 
Freezing phenomenon 
10060904 
Gait disturbance 
10017577 
Gait inability 
10017581 
Grimacing 
10061991 
Hyperkinesia 
10020651 
Hyperkinesia neonatal 
10020652 
Hypertonia 
10020852 
Hypertonia neonatal 
10048615 
Hypokinesia 
10021021 
Hypokinesia neonatal 
10021022 
Laryngeal tremor 
10078751 
Laryngospasm 
10023891 
Meige's syndrome 
10027138 
Micrographia 
10057333 
Mobility decreased 
10048334 
Motor dysfunction 
10061296 
Movement disorder 
10028035 
Muscle contractions involuntary 
10028293 
Muscle rigidity 
10028330 
Muscle spasms 
10028334 
Muscle spasticity 
10028335 
Muscle tightness 
10049816 
Muscle tone disorder 
10072889 
Muscle twitching 
10028347 
Musculoskeletal stiffness 
10052904 
Oculogyric crisis 
10030071 
Oesophageal spasm 
10030184 
On and off phenomenon 
10030312 


Alkermes, Inc.                                                                                                                                     
Statistical Analysis Plan - ALK3831-A304                                                                                                 11 June 2019 
 
 
 
 
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Preferred Term (SMQ [#20000095] of Extrapyramidal syndrome) 
PT Code 
Opisthotonus 
10030899 
Oromandibular dystonia 
10067954 
Oropharyngeal spasm 
10031111 
Parkinsonian crisis 
10048868 
Parkinsonian gait 
10056242 
Parkinsonian rest tremor 
10056437 
Parkinsonism 
10034010 
Parkinsonism hyperpyrexia syndrome 
10071243 
Parkinson's disease 
10061536 
Parkinson's disease psychosis 
10074835 
Pharyngeal dyskinesia 
10070912 
Pleurothotonus 
10035628 
Postural reflex impairment 
10067206 
Postural tremor 
10073211 
Posture abnormal 
10036436 
Posturing 
10036437 
Protrusion tongue 
10037076 
Provisional tic disorder 
10076694 
Psychomotor hyperactivity 
10037211 
Rabbit syndrome 
10068395 
Reduced facial expression 
10078576 
Respiratory dyskinesia 
10057570 
Resting tremor 
10071390 
Restlessness 
10038743 
Risus sardonicus 
10039198 
Secondary tic 
10076702 
Spasmodic dysphonia 
10067672 
Tardive dyskinesia 
10043118 
Tic 
10043833 
Tongue spasm 
10043981 


Alkermes, Inc.                                                                                                                                     
Statistical Analysis Plan - ALK3831-A304                                                                                                 11 June 2019 
 
 
 
 
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Preferred Term (SMQ [#20000095] of Extrapyramidal syndrome) 
PT Code 
Torticollis 
10044074 
Torticollis psychogenic 
10044076 
Tremor 
10044565 
Tremor neonatal 
10044575 
Trismus 
10044684 
Uvular spasm 
10050908 
Walking disability 
10053204 
Writer's cramp 
10072249 
 


Alkermes, Inc.                                                                                                                                     
Statistical Analysis Plan - ALK3831-A304                                                                                                 11 June 2019 
 
 
 
 
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APPENDIX 2. AESI - SUICIDAL IDEATION AND BEHAVIOR 
(CUSTOM MedDRA QUERY) 
Preferred Term 
PT Code 
Columbia suicide severity rating scale abnormal 
10075616 
Completed suicide 
10010144 
Depression suicidal 
10012397 
Intentional overdose 
10022523 
Intentional self-injury 
10022524 
Overdose 
10033295 
Poisoning deliberate 
10036000 
Self-injurious ideation 
10051154 
Suicidal behaviour 
10065604 
Suicidal ideation 
10042458 
Suicide attempt 
10042464 
Suicide threat 
10077417 


Alkermes, Inc.                                                                                                                                     
Statistical Analysis Plan - ALK3831-A304                                                                                                 11 June 2019 
 
 
 
 
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APPENDIX 3. AE TERMS - ABUSE POTENTIAL (CUSTOM MedDRA 
QUERY) 
Category 
Preferred Term 
PT Code 
Abuse behavior 
Accidental overdose 
10000381 
Drug abuse 
10013654 
Drug abuser 
10061111 
Drug detoxification 
10052237 
Drug diversion 
10066053 
Drug level above therapeutic 
10061132 
Drug level increased 
10013722 
Drug screen 
10050837 
Drug screen positive 
10049177 
Drug use disorder 
10079381 
Drug use disorder, antepartum 
10079382 
Drug use disorder, postpartum 
10079383 
Intentional overdose 
10022523 
Intentional product misuse 
10074903 
Intentional product use issue 
10076308 
Maternal use of illicit drugs 
10026938 
Needle track marks 
10028896 
Neonatal complications of substance abuse 
10061862 
Overdose 
10033295 
Prescription drug used without a prescription 10076639 
Prescription form tampering 
10067669 
Product tampering 
10069330 
Reversal of opiate activity 
10039004 
Substance abuse 
10066169 
Substance abuser 
10067688 
Substance use 
10070964 
Substance use disorder 
10079384 
Substance-induced mood disorder 
10072387 


Alkermes, Inc.                                                                                                                                     
Statistical Analysis Plan - ALK3831-A304                                                                                                 11 June 2019 
 
 
 
 
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Category 
Preferred Term 
PT Code 
Substance-induced psychotic disorder 
10072388 
Toxicity to various agents 
10070863 
Euphoria related 
Euphoric mood 
10015535 
Feeling abnormal 
10016322 
Feeling drunk 
10016330 
Feeling of relaxation 
10016352 
Hallucination 
10019063 
Hallucination, auditory 
10019070 
Hallucination, gustatory 
10019071 
Hallucination, olfactory 
10019072 
Hallucination, synaesthetic 
10062824 
Hallucination, tactile 
10019074 
Hallucination, visual 
10019075 
Hallucinations, mixed 
10019079 
Inappropriate affect 
10021588 
Mood altered 
10027940 
Mood swings 
10027951 
Thinking abnormal 
10043431 
Non-specific 
Acute psychosis 
10001022 
Aggression 
10001488 
Cognitive disorder 
10057668 
Confusional state 
10010305 
Delirium 
10012218 
Delusional disorder, unspecified type 
10012255 
Depersonalisation/derealisation disorder 
10077805 
Disorientation 
10013395 
Dissociation 
10013457 
Disturbance in attention 
10013496 
Disturbance in social behaviour 
10061108 
Dizziness 
10013573 


Alkermes, Inc.                                                                                                                                     
Statistical Analysis Plan - ALK3831-A304                                                                                                 11 June 2019 
 
 
 
 
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Category 
Preferred Term 
PT Code 
Dopamine dysregulation syndrome 
10067468 
Emotional disorder 
10014551 
Flight of ideas 
10016777 
Medication overuse headache 
10072720 
Mental impairment 
10027374 
Narcotic bowel syndrome 
10072286 
Paranoia 
10033864 
Psychotic behaviour 
10037249 
Psychotic disorder 
10061920 
Sedation 
10039897 
Somnolence 
10041349 
Stupor 
10042264 


Alkermes, Inc.                                                                                                                                     
Statistical Analysis Plan - ALK3831-A304                                                                                                 11 June 2019 
 
 
 
 
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APPENDIX 4. AE TERMS – DEPENDENCE (CUSTOM MedDRA 
QUERY) 
Preferred Term  
PT Code 
Dependence 
10012335 
Drug dependence 
10013663 
Drug dependence, antepartum 
10013675 
Drug dependence, postpartum 
10013676 
Drug tolerance 
10052804 
Drug tolerance decreased 
10052805 
Drug tolerance increased 
10052806 
Substance dependence 
10076595 
 


Alkermes, Inc.                                                                                                                                     
Statistical Analysis Plan - ALK3831-A304                                                                                                 11 June 2019 
 
 
 
 
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APPENDIX 5. AE TERMS – WITHDRAWAL (CUSTOM MedRA 
QUERY) 
Preferred Term  
PT Code 
Abdominal pain 
10000081 
Agitation 
10001497 
Anhedonia 
10002511 
Anxiety 
10002855 
Arthralgia 
10003239 
Chills 
10008531 
Depressed mood 
10012374 
Depression 
10012378 
Diarrhoea 
10012735 
Drug detoxification 
10052237 
Drug rehabilitation 
10064773 
Drug withdrawal convulsions 
10013752 
Drug withdrawal headache 
10013753 
Drug withdrawal maintenance therapy 
10052970 
Drug withdrawal syndrome 
10013754 
Drug withdrawal syndrome neonatal 
10013756 
Dysphoria 
10013954 
Dyssomnia 
10061827 
Feeling of despair 
10016344 
Headache 
10019211 
Hyperhidrosis 
10020642 
Insomnia 
10022437 
Irritability 
10022998 
Morose 
10027977 
Mydriasis 
10028521 
Nausea 
10028813 
Negative thoughts 
10058672 
Nervousness 
10029216 


Alkermes, Inc.                                                                                                                                     
Statistical Analysis Plan - ALK3831-A304                                                                                                 11 June 2019 
 
 
 
 
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Preferred Term  
PT Code 
Obsessive thoughts 
10029897 
Pain 
10033371 
Persistent depressive disorder 
10077804 
Piloerection 
10035039 
Poor quality sleep 
10062519 
Rebound effect 
10038001 
Restlessness 
10038743 
Reversal of opiate activity 
10039004 
Rhinorrhoea 
10039101 
Steroid withdrawal syndrome 
10042028 
Syncope 
10042772 
Tachycardia 
10043071 
Terminal insomnia 
10068932 
Tremor 
10044565 
Vomiting 
10047700 
Withdrawal arrhythmia 
10047997 
Withdrawal syndrome 
10048010 
Yawning 
10048232