Clinical trial NCT02634346
Conditions: Schizophrenia
Keywords: Alkermes ALKS 3831 Samidorphan Schizophrenia Acute Exacerbation of Schizophrenia
Sponsor: Alkermes, Inc.
Start date: 2015-12-01; Completion date: 2017-06-07
Enrollment: 403 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
This study will evaluate the efficacy of ALKS 3831 in adult subjects with acute exacerbation of schizophrenia.

Detailed description:

Arms: arm 1: Administered as a coated bilayer tablet arm 2: Administered as a coated bilayer tablet arm 3: Administered as a coated bilayer tablet
Interventions: intervention 1: ALK3831 intervention 2: Olanzapine intervention 3: Placebo
Intervention descriptions: intervention 1: Daily dosing intervention 2: Daily dosing intervention 3: Daily dosing

Protocol documents:
Prot_000.pdf: 
A Phase 3 Study to Determine the Antipsychotic Efficacy 
and Safety of ALKS 3831 in Adult Subjects with Acute 
Exacerbation of Schizophrenia 
 
 
Unique Protocol ID: 
ALK3831-A305 
NCT Number: 
NCT02634346  
EudraCT Number:  
2015-003373-15 
Date of Protocol:  
22 September 2016 
 


1. 
TITLE PAGE 
 
CLINICAL STUDY PROTOCOL 
ALK3831-A305 
 
Study Title 
A Phase 3 Study to Determine the Antipsychotic Efficacy 
and Safety of ALKS 3831 in Adult Subjects with Acute 
Exacerbation of Schizophrenia 
Document Date 
Amendment 1.0: 22 September 2016 
Original Protocol: 05 August 2015 
Sponsor 
Alkermes, Inc. 
852 Winter Street 
Waltham, MA 02451 
USA 
 
 
 
 
 
 
CONFIDENTIAL 
Information and data in this protocol contain trade secrets and privileged or confidential information, 
which is the property of Alkermes, Inc. No person is authorized to make it public without the written 
permission of Alkermes, Inc. These restrictions or disclosures will apply equally to all future information 
supplied to you that is indicated as privileged or confidential. 


 
 
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CONTACT INFORMATION 
Role in Study 
Name 
Address and Telephone 
Alkermes Clinical Program 
Manager 
 
Alkermes, Inc. 
852 Winter Street 
Waltham, MA 02451 
Phone: 
 
Alkermes Medical Monitor  
 
Alkermes Pharma Ireland, Ltd. 
Connaught House 
1 Burlington Road 
Dublin 4, Ireland 
Phone: 
 
Alkermes Drug Safety 
Specialist 
 
Alkermes, Inc. 
852 Winter Street 
Waltham, MA 02451 
Phone: 
 
CRO Medical Monitor and 
24-Hour Emergency Contact 
 
Phone: 
 
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 Study to Determine the Antipsychotic Efficacy and Safety of ALKS 3831 in 
Adult Subjects with Acute Exacerbation of Schizophrenia 
Investigator(s): This is a multinational multicenter study 
Study Period: 
Estimated date of first subject’s consent: Q4 2015 
Estimated date of last subject’s last visit: Q1 2018 
Phase of Development: 3 
Objectives: 
Primary: 
• 
To evaluate the antipsychotic efficacy of ALKS 3831 (a fixed-dose combination of 
olanzapine and samidorphan) in adult subjects with acute exacerbation of schizophrenia. 
Secondary: 
• 
To evaluate the safety and tolerability of ALKS 3831 in adult subjects with acute 
exacerbation of schizophrenia  
Methodology: This is a Phase 3, multinational, multicenter, randomized, double-blind, placebo-
controlled study in subjects experiencing an acute exacerbation of schizophrenia. Subjects will be 
screened up to 10 days prior to randomization. Upon completion of screening assessments, subjects 
meeting eligibility criteria will be admitted to an inpatient unit on Day -1, if they are not already inpatient. 
Currently prescribed antipsychotics will be discontinued at screening. 
On Day 1 (Visit 2), subjects meeting eligibility criteria will be randomized in a 1:1:1 fashion to one of the 
following 3 treatment groups: ALKS 3831, olanzapine, or placebo, and will receive double-blind 
treatment for up to 4 weeks. 
On Days 1 and 2, subjects randomized to ALKS 3831 will receive 10/10 [10 mg olanzapine/10 mg 
samidorphan] and subjects randomized to olanzapine will receive 10 mg. On Day 3, the dose will be 
increased to 20/10 [20 mg olanzapine/10 mg samidorphan] for subjects randomized to ALKS 3831 or 20 
mg for subjects randomized to olanzapine. Following the increase on Day 3, the dose may be decreased to 
10/10 (ALKS 3831) or 10 mg (olanzapine) at end of week 1 (Day 7) or week 2 (Day 15) if there are 
tolerability problems based on judgment of the investigator. No further dose adjustments will be allowed 
Day 15 onward for the remaining 2 weeks of the treatment period. All subjects will receive 1 tablet daily 
in a blinded manner. 
Subjects are required to be inpatient for the first 2 weeks of the treatment period (until Day 15). 
Following the mandatory 2-week inpatient stay, subjects can either continue the study as inpatients for the 
full 4-week treatment period or be discharged at the end of Week 2 or end of Week 3 if they meet the 
discharge criteria specified in Section 8.1.1. 
Subjects completing 4 weeks of treatment with study drug will be eligible to continue in the open-label, 
long-term safety study (ALK3831-A306) and continue to receive ALKS 3831 for up to 52 weeks. 
Subjects not continuing in the long term safety study will enter a 2-week safety follow-up period. During 


 
 
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this follow-up period subjects may be treated with any antipsychotic medication according to physician 
recommendations. 
Subjects who are inpatient at the end of the 4-week treatment period and are not continuing in the 
extension study (ALK3831-A306) may continue as inpatients for up to 1 additional week of the 2-week 
safety follow-up period. These subjects may be discharged from the inpatient unit at any time during this 
week based on investigator’s judgment. For subjects continuing in the safety extension study 
(ALK3831-A306), details regarding the additional inpatient week will be provided in the ALK3831-A306 
protocol. 
Study Design Schematic 
 
 
Number of Subjects Planned: Approximately 390 subjects will be randomized in a 1:1:1 ratio to each of 
the following 3 treatment groups: ALKS 3831, Olanzapine, and Placebo 
Main Criteria for Inclusion: 
Men and women 18 through 70 years of age (inclusive) with DSM-5 diagnosis of schizophrenia who 
meet pre-specified symptom severity criteria, meet sponsor criteria for an acute exacerbation of 
schizophrenia symptoms, and have a stable living environment (when not hospitalized) as well as a 
designated caregiver or informant in countries where a caregiver is required. 
Main Criteria for Exclusion: 
Subjects may be excluded based on diagnosis of additional psychiatric conditions, use of prohibited or 
contraindicated drugs and medications, pre-existing medical conditions, abnormal lab results during 
screening, participation in any recent clinical trials or previous clinical trials of ALKS 3831 or 
samidorphan, pregnancy, and relationship to an employee of the study sponsor or CRO. 
Investigational Product, Dosage, Duration and Mode of Administration: ALKS 3831 will be supplied 
as a coated bilayer tablet containing either 10 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: Olanzapine will be supplied as 
an identical bilayer tablet containing either 10 mg or 20 mg of olanzapine only and no additional active 
ingredients. Placebo will be supplied as a bilayer tablet identical to the ALKS 3831 and olanzapine tablets 


 
 
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but with no active ingredients. Olanzapine or placebo tablets will be taken by mouth once daily, 
preferably at bedtime. 
Duration of Study: The total duration of this study is approximately 7.5 weeks, including a 10-day 
screening period (Days -10 to -1), a 4-week treatment period (Days 1-29), and 1 follow-up visit 2 weeks 
after EOT (Day 43). 
Criteria for Evaluation: 
Efficacy: Evaluation of efficacy will be based on the following measures: 
• 
Positive and Negative Syndrome Scale (PANSS) 
• 
Modified Overt Aggression Scale (MOAS) 
• 
Clinical Global Impressions-Severity (CGI-S) 
• 
Clinical Global Impressions-Improvement (CGI-I) 
Pharmacokinetics/ pharmacodynamics: Concentrations of olanzapine, samidorphan, and metabolites of 
interest will be determined from plasma samples collected according to the schedule in Table 1. PK data 
from these samples may be included in a subsequent population PK analysis or other post-hoc analyses 
conducted outside of this study. 
Safety: Evaluation of safety will be based on the following measures: 
• 
Adverse events 
• 
Columbia-Suicide Severity Rating Scale (C-SSRS) 
• 
Abnormal Involuntary Movement Scale (AIMS) 
• 
Barnes Akathisia Rating Scale (BARS) 
• 
Simpson-Angus Scale (SAS) 
• 
Vital signs (oral temperature, respiratory rate, pulse, orthostatic blood pressure) 
• 
Electrocardiogram parameters (heart rate, RR, PR, QRS, and QT) 
• 
Clinical laboratory parameters (chemistry, hematology, and urinalysis) 
• 
Weight and Waist Circumference 
Efficacy Endpoints: 
Primary Endpoint 
The primary efficacy endpoint is change from baseline in PANSS total score at Week 4. 
Key Secondary Endpoint 
Change from baseline in CGI-S score at Week 4 
Other Secondary Endpoints 
• 
Change from baseline in PANSS total score and PANSS subscales (positive, negative, 
general psychopathology) by visit 
• 
Change from baseline in MOAS score by visit 
• 
Change from baseline in CGI-S by visit 
• 
CGI-I at each postbaseline visit 


 
 
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• 
PANSS responders ( ≥ 30% improvement from baseline in PANSS total score) by visit 
• 
CGI-I responders (CGI-I score of 2 [much improved] or 1 [very much improved]) by visit 
• 
Overall Response defined as: PANSS total score ≥ 30% improvement from baseline or CGI-I 
score of 1 or 2 by visit 
• 
Change from baseline in PANSS-Excited Component (EC) score (comprised of 5 items, 
excitement, tension, hostility, uncooperativeness, and poor impulse control) by visit 
Statistical Methods: 
Efficacy: Efficacy analyses will be based on the full analysis set (FAS) population defined as all 
randomized subjects who receive at least one dose of study drug and at least one postbaseline PANSS 
assessment. All statistical tests will be 2-sided hypothesis tests performed at the 5% significance level. All 
confidence intervals will be 2-sided 95% confidence intervals, unless otherwise specified. 
Pharmacokinetics/ pharmacodynamics: PK data may be included in a subsequent population PK 
analysis or other post-hoc analyses conducted outside of this study. Concentrations of olanzapine, 
samidorphan, and metabolites of interest will be provided as by-subject listings. 
Safety: The safety analysis will be carried out using the Safety Population, defined as all randomized 
subjects who receive at least one dose of study drug. All safety analyses will be based on observed data 
only, and no missing values will be imputed. 
Reported adverse event terms will be coded using the Medical Dictionary for Regulatory Activities 
(MedDRA) and summarized by preferred term and system organ class categories. 
Observed values and change from baseline in laboratory parameters, weight, BMI, waist circumferences, 
vital signs, and ECG parameters will be summarized by treatment group and study visit. 
Prior and concomitant medication use will be summarized by World Health Organization Drug 
Dictionary Anatomical Therapeutic Class code and treatment group. 
Sample Size Considerations: The planned sample size is 390 subjects in total, 130 subjects per treatment 
group. This sample size will provide at least 90% power to show superiority for ALKS 3831 group when 
compared to placebo at the 2-sided alpha level of 0.05, assuming a 10-point improvement of PANSS total 
score at week 4, a standard deviation (SD) of 20, and a dropout rate of 30%. 


 
 
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3. 
TABLE OF CONTENTS 
1. 
TITLE PAGE ................................................................................................................1 
CONTACT INFORMATION ..........................................................................................................2 
2. 
SYNOPSIS ...................................................................................................................3 
3. 
TABLE OF CONTENTS .............................................................................................7 
4. 
LIST OF ABBREVIATIONS.....................................................................................12 
5. 
INTRODUCTION ......................................................................................................14 
5.1. 
Background .................................................................................................................14 
5.2. 
Study Drugs ................................................................................................................15 
5.2.1. 
Samidorphan ...............................................................................................................15 
5.2.2. 
Olanzapine ..................................................................................................................15 
5.3. 
Study Rationale ...........................................................................................................16 
5.4. 
Dose Rationale ............................................................................................................16 
6. 
OBJECTIVES .............................................................................................................17 
6.1. 
Primary Objective .......................................................................................................17 
6.2. 
Secondary Objective ...................................................................................................17 
7. 
SELECTION AND WITHDRAWAL OF SUBJECTS ..............................................18 
7.1. 
Subject Inclusion Criteria ...........................................................................................18 
7.2. 
Subject Exclusion Criteria ..........................................................................................19 
7.2.1. 
Psychiatric Exclusion Criteria ....................................................................................19 
7.2.2. 
Exclusion Criteria Based on Treatment History .........................................................19 
7.2.3. 
Exclusion Criteria Based on Drug/Alcohol Use and Concomitant Meds ...................20 
7.2.4. 
Exclusion Criteria Based on Medical Conditions/Medical History ...........................20 
7.2.5. 
Exclusion Criteria Based on Laboratory Assessments at Screening ..........................21 
7.2.6. 
General Exclusion Criteria .........................................................................................21 
7.3. 
Subject Withdrawal ....................................................................................................22 
7.4. 
Replacement of Subjects .............................................................................................23 
7.5. 
Identification of Informant or Caregiver ....................................................................23 
7.6. 
Withdrawal and Replacement of Caregiver ................................................................23 
8. 
STUDY DESIGN .......................................................................................................24 
8.1. 
Overall Study Design and Plan ...................................................................................24 


 
 
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8.1.1. 
Discharge Criteria .......................................................................................................25 
8.2. 
Schedule of Visits and Assessments ...........................................................................26 
8.3. 
Study Procedures Descriptions ...................................................................................30 
8.3.1. 
Informed Consent .......................................................................................................30 
8.3.2. 
Eligibility Review .......................................................................................................30 
8.3.3. 
Demographics and Medical History ...........................................................................30 
8.3.4. 
Concomitant Medication Review ...............................................................................30 
8.3.5. 
Vital Signs ..................................................................................................................30 
8.3.6. 
Physical Examination .................................................................................................31 
8.3.7. 
Height, Body Weight, and Waist Circumference .......................................................31 
8.3.8. 
12-Lead Electrocardiogram ........................................................................................31 
8.3.9. 
Structured Interviews and Questionnaires ..................................................................31 
8.3.9.1. 
Diagnostic Assessments ..............................................................................................31 
8.3.9.2. 
Efficacy Assessments .................................................................................................32 
8.3.9.3. 
Safety Assessments .....................................................................................................32 
8.3.10. 
Clinical Validation Inventory for Study Admission and Ongoing Rater 
Review ........................................................................................................................33 
8.3.11. 
Laboratory Assessments .............................................................................................33 
8.3.11.1. 
Drug Testing ...............................................................................................................33 
8.3.11.2. 
Hematology, Biochemistry, and Urinalysis ................................................................33 
8.3.11.3. 
Pregnancy Testing ......................................................................................................35 
8.3.11.4. 
Serology Testing .........................................................................................................35 
8.3.12. 
Pharmacokinetic Assessments ....................................................................................35 
8.3.13. 
Genotype Sampling ....................................................................................................35 
8.3.14. 
Randomization ............................................................................................................35 
8.3.15. 
Drug Dispensation and Reconciliation .......................................................................35 
8.3.16. 
Emergency Treatment Card ........................................................................................36 
8.3.17. 
Adverse Event Monitoring .........................................................................................36 
8.4. 
Study Requirements and Restrictions .........................................................................36 
8.4.1. 
Contraception and Pregnancy .....................................................................................36 
8.4.2. 
Prohibited Medications ...............................................................................................37 
8.4.3. 
Permitted Therapy ......................................................................................................38 
8.4.4. 
Non-medication Therapy ............................................................................................38 


 
 
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8.4.5. 
Pain Management .......................................................................................................38 
8.4.6. 
Fasting.........................................................................................................................39 
8.4.7. 
Inpatient Stay ..............................................................................................................39 
8.4.8. 
Other Restrictions and Requirements .........................................................................39 
9. 
TREATMENT OF SUBJECTS ..................................................................................41 
9.1. 
Study Drug Dose and Administration .........................................................................41 
9.2. 
Treatment Adherence ..................................................................................................41 
9.3. 
Randomization/ Method of Assigning Subjects to Treatment ....................................41 
9.4. 
Blinding ......................................................................................................................41 
10. 
STUDY DRUG MATERIALS AND MANAGEMENT ...........................................43 
10.1. 
Study Drug ..................................................................................................................43 
10.2. 
Packaging and Labeling ..............................................................................................43 
10.3. 
Storage ........................................................................................................................43 
10.4. 
Accountability .............................................................................................................43 
10.5. 
Handling and Disposal ................................................................................................43 
11. 
ASSESSMENT OF EFFICACY ................................................................................44 
11.1. 
Efficacy Measures ......................................................................................................44 
12. 
ASSESSMENT OF PHARMACOKINETICS AND 
PHARMACODYNAMICS ........................................................................................45 
13. 
ASSESSMENT OF SAFETY .....................................................................................46 
13.1. 
Definition of Adverse Event .......................................................................................46 
13.2. 
Definition of Serious Adverse Event ..........................................................................46 
13.3. 
Relationship to Study Drug ........................................................................................47 
13.4. 
Monitoring and Recording of Adverse Events ...........................................................49 
13.5. 
Reporting of Serious Adverse Events .........................................................................49 
14. 
STATISTICS ..............................................................................................................50 
14.1. 
Sample Size Considerations .......................................................................................50 
14.2. 
General Statistical Methodology ................................................................................50 
14.2.1. 
Study Populations .......................................................................................................50 
14.2.1.1. 
Safety Population ........................................................................................................50 
14.2.1.2. 
Efficacy Population ....................................................................................................50 
14.3. 
Demographics and Baseline Data ...............................................................................50 
14.4. 
Efficacy Analyses .......................................................................................................51 


 
 
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14.4.1. 
Primary Endpoint ........................................................................................................51 
14.4.2. 
Key Secondary Endpoint ............................................................................................51 
14.4.3. 
Other Endpoints ..........................................................................................................51 
14.5. 
Pharmacokinetic Analyses ..........................................................................................52 
14.6. 
Safety Analyses ..........................................................................................................52 
15. 
DIRECT ACCESS TO SOURCE DATA/ DOCUMENTS........................................53 
15.1. 
Study Monitoring ........................................................................................................53 
15.2. 
Audits and Inspections ................................................................................................53 
15.3. 
Institutional Review Board/Independent Ethics Committee ......................................53 
16. 
QUALITY CONTROL AND QUALITY ASSURANCE .........................................54 
16.1. 
Case Report Forms .....................................................................................................54 
16.2. 
Confidentiality of Data ...............................................................................................54 
17. 
ETHICAL CONSIDERATIONS................................................................................55 
17.1. 
Ethics Review .............................................................................................................55 
17.2. 
Ethical Conduct of the Study ......................................................................................55 
17.3. 
Written Informed Consent ..........................................................................................55 
18. 
DATA HANDLING AND RECORDKEEPING .......................................................57 
18.1. 
Data Capture ...............................................................................................................57 
18.2. 
Inspection of Records .................................................................................................57 
18.3. 
Retention of Records ..................................................................................................57 
18.4. 
Use of Information and Publication Policy ................................................................58 
19. 
REFERENCES ...........................................................................................................59 
20. 
APPENDICES ............................................................................................................61 
 
LIST OF TABLES 
Table 1: 
Schedule of Visits and Assessments ...........................................................................27 
Table 2: 
Clinical Laboratory Assessments ...............................................................................34 
Table 3: 
Adverse Event Causality Guidelines ..........................................................................48 
 
LIST OF FIGURES 
Figure 1: 
Study Design Schematic .............................................................................................25 
 


 
 
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LIST OF APPENDICES 
Appendix A 
Partial list of prohibited cytochrome P450 (CYP) 3A4 inducers and moderate-
to-strong inhibitors 
Appendix B 
Clinical Global Impression 
• Severity 
− Structured Interview Guide for Global Impression (SIGGI) 
• Improvement 
Appendix C 
Modified Overt Aggression Scale 
Appendix D 
Positive and Negative Syndrome Scale 
Appendix E 
Abnormal Involuntary Movement Scale 
Appendix F 
Barnes Akathisia Rating Scale 
Appendix G 
Simpson-Angus Scale 
Appendix H 
Columbia-Suicide Severity Rating Scale 
• Baseline/ Screening 
• Since Last Visit 


 
 
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4. 
LIST OF ABBREVIATIONS 
The following abbreviations are used in this study protocol. 
Abbreviation or Term 
Explanation or Definition 
AE 
adverse event 
AIMS 
Abnormal Involuntary Movement Scale 
ALT 
alanine aminotransferase 
AST 
aspartate aminotransferase 
ATC 
Anatomical Therapeutic Chemical [classification system] 
BARS 
Barnes Akathisia Rating Scale 
BMI 
body mass index 
CGI-I 
Clinical Global Impressions - Improvement 
CGI-S 
Clinical Global Impressions - Severity 
CNS 
central nervous system 
CSA 
Clinical Study Agreement 
C-SSRS 
Columbia-Suicide Severity Rating Scale 
C-VISA 
Clinical Validation Inventory for Study Admission 
DSM-5 
Diagnostic and Statistical Manual of Mental Disorders – Fifth Edition 
EC 
Ethics Committee 
ECG 
Electrocardiogram 
ECT 
electroconvulsive therapy 
eCRF 
electronic case report form 
EOT 
end of treatment 
EPS 
extra pyramidal symptom 
ET 
early termination 
FAS 
full analysis set 
GCP 
Good Clinical Practice 
GI 
gastrointestinal 
GMP 
Good Manufacturing Practice 
HbA1c 
Hemoglobin A1c 
HDPE 
high density polyethylene 
HIV 
human immunodeficiency virus 


 
 
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Abbreviation or Term 
Explanation or Definition 
ICF 
informed consent form 
ICH 
International Conference on Harmonisation of Technical Requirements 
for Registration of Pharmaceuticals for Human Use 
IEC 
Independent Ethics Committee 
IRB 
Institutional Review Board 
IUD 
intrauterine device 
IWRS 
interactive web response system 
LOCF 
last observation carried forward 
MedDRA 
Medical Dictionary for Regulatory Activities 
MINI 
Mini International Neuropsychiatric Interview 
MMRM 
mixed model with repeated measures 
MOAS 
Modified Overt Aggression Scale 
OLZ 
Olanzapine 
OTC 
over-the-counter 
PANSS 
Positive and Negative Syndrome Scale 
PCS 
Potentially Clinically Significant 
PK 
pharmacokinetic 
QTcB 
QT interval corrected using the Bazett formula 
QTcF 
QT interval corrected using the Fridericia formula 
SAE 
serious adverse event 
SAP 
statistical analysis plan 
SAS 
Simpson-Angus Scale 
SCID 
Structured Clinical Interview for DSM Diagnoses 
SD 
Standard Deviation 
TEAE 
treatment-emergent adverse event 
ULN 
upper limit of normal 
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, 
Tiihonen, Lonnqvist et al. 2009, Lambert, Conus et al. 2010). The decreased life expectancy is 
due to a combination of direct effects of the disease, eg increased rates of suicide and violence 
(Kuo, Tsai et al. 2005, Hodgins 2008), as well as indirect causes including increased incidence of 
obesity and cardiovascular disease (Nasrallah, Meyer et al. 2006, Saha, Chant 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, Stroup 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 lbs over a treatment 
period up to 18 months and >7% body weight in 30% of subjects) and a comparatively higher 
discontinuation rate compared 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 (a μ-opioid 
antagonist) under investigation for the treatment of schizophrenia. Phase 1 and Phase 2 studies 
demonstrated that coadministration of samidorphan with olanzapine mitigates the weight gain 
experienced with olanzapine alone. A Phase 1 study conducted in healthy males 
(Study ALK33-301), demonstrated that 3 weeks of treatment with ALKS 3831 resulted in 29% 
less weight gain compared with subjects who received olanzapine alone. Based on the results of 
this study, a two-part (Part A and Part B), Phase 2 study (ALK3831-302) was conducted to 
evaluate the antipsychotic efficacy and body weight effect of ALKS 3831 in subjects with 
schizophrenia. In Part A (a 12-week, double-blind, randomized, olanzapine-controlled phase), 
ALKS 3831 demonstrated similar antipsychotic efficacy compared with olanzapine based on 
Positive and Negative Syndrome Scale (PANSS) total score. ALKS 3831 also led to clinically 
and statistically significant less body weight gain compared to olanzapine. Data from Part B 


 
 
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(a 12-week all-active, extension) indicated maintenance of the beneficial effect on weight 
observed in Part A, while maintaining stable PANSS scores over the 12 week extension period. 
In addition, 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, Farmer et al. 1990). Patients with both schizophrenia and 
alcohol use disorder represent a common variant of the schizophrenia spectrum that is difficult to 
treat and is associated with an extremely poor prognosis (Dixon 1999, Koekkoek, van et al. 
2006). Samidorphan (also referred to as ALKS 33 or RDC-0313), is structurally derived from 
naltrexone and is a potent μ-opioid antagonist. In clinical studies, it 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 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 has the potential as an improved 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 versus 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 is a new chemical entity in clinical development by Alkermes. Samidorphan is a µ-
opioid receptor antagonist. 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). Overall, approximately 600 subjects have been exposed to 
samidorphan. 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 and was originally approved for the 
treatment of schizophrenia, but has since been approved for other indications including the 
treatment of schizophrenia in adolescents and bipolar disorder. The safety and tolerability profile 


 
 
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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 2015). 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 
Schizophrenia is a lifelong illness with evolving symptoms that can fluctuate in severity over 
time and with changes in treatment regimen. A major goal in designing treatments for 
schizophrenia is to effectively stabilize symptoms, keep them stable over the long term, and 
minimize side effects. In a Phase 2 study, ALK3831-302, ALKS 3831 exhibited similar 
antipsychotic efficacy to olanzapine as well as a significant attenuation of olanzapine-induced 
weight gain. ALK3831-302 was conducted in subjects with schizophrenia that were classified as 
psychiatrically stable. The present study is designed to assess the ability of ALKS 3831 to 
stabilize symptoms in a subject population with unstable symptomology experiencing an acute 
exacerbation of schizophrenia. The study will evaluate the efficacy of ALKS 3831 on psychiatric 
symptoms, including aggression, relative to placebo. It will also assess the safety and tolerability 
of ALKS 3831 in subjects with an acute exacerbation of schizophrenia. 
5.4. 
Dose Rationale 
The selected doses of ALKS 3831 (20/10 and 10/10) are within the approved olanzapine 
therapeutic dose range for the treatment of schizophrenia (Eli Lilly and Company 2015). 
Olanzapine doses of 10 and 20 mg will bracket the lowest and highest approved maintenance 
doses for the treatment of schizophrenia and provide adequate coverage for 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 antipsychotic efficacy of ALKS 3831 
(a fixed-dose combination of olanzapine and samidorphan) in adult subjects with an acute 
exacerbation of schizophrenia. 
6.2. 
 Secondary Objective 
The secondary objective of this study is to evaluate the safety and tolerability of ALKS 3831 in 
adult subjects with an acute exacerbation of 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. Is willing and able to provide written informed consent 
2. Is age 18–70 years, inclusive, at screening 
3. Has a body mass index (BMI) of 18.0–40.0 kg/m2, inclusive at screening 
4. Agrees to abide by the contraception requirements specified in the protocol 
5. Meets criteria for the DSM-5 diagnosis of schizophrenia, confirmed with the Mini 
International Neuropsychiatric Interview (MINI): 
− Is currently experiencing an acute exacerbation or relapse 
− If inpatient at screening, has been hospitalized for less than two weeks for the 
current exacerbation 
6. Total PANSS Score ≥80 at screening and baseline (Visits 1 and 2) 
7.  A score ≥4 on at least three of the following PANSS Positive Scale (P) Items at Visits 1 
and 2: 
− Item 1 (P1; delusions) 
− Item 2 (P2; conceptual disorganization) 
− Item 3 (P3; hallucinatory behavior) 
− Item 6 (P6; suspiciousness/persecution) 
8. CGI-S Score ≥4 at screening and Visits 1 and 2 
9. Resides in a stable living situation when not hospitalized 
10. Subjects at some sites may be required to have an informant or caregiver who meets 
some or all of the following criteria in accordance with the locally approved informed 
consent form (ICF): 
a. Informant or caregiver will be in contact with the subject several times per week 
b. If necessary, the informant or caregiver will accompany the subject to visits 
c. Informant or caregiver will help ensure maximum subject adherence to study 
procedures 
d. The informant or caregiver must be willing and able to provide informed consent by 
signing the caregiver ICF. 
11. Is willing and able to provide government-issued identification 


 
 
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7.2. 
Subject Exclusion Criteria 
Each subject must not meet any of the following criteria to be qualified to participate in this 
study. 
7.2.1. 
Psychiatric Exclusion Criteria 
1. Subject has had a psychiatric hospitalization for more than 30 days during the 90 days 
before screening 
2. Subject initiated first antipsychotic treatment within the past 12 months, or <1 year has 
elapsed since the initial onset of active-phase of schizophrenia symptoms. 
3. Subject has any of the following psychiatric conditions per DSM-5 criteria, as assessed 
by the MINI. Conditions not assessable by the MINI should be assessed by clinical 
judgment 
− Diagnosis of schizoaffective disorder or bipolar I or II disorder, or current, 
untreated or unstable major depressive disorder (according to DSM-5 Criteria) 
− Clinically significant cognitive difficulties including dementia, delirium, or 
amnestic syndromes, or any other cognitive disorder present within the past 
2 years that could interfere with participation in the study 
− Drug-induced or toxic psychosis 
− Any other psychiatric condition that could interfere with participation in the study 
4.  Subject poses a current suicide risk in the opinion of the investigator or as confirmed by 
the following: 
− Answers “Yes” on items 4 or 5 (C-SSRS-ideation) with the most recent episode 
occurring within the past 2 months, or answers “Yes” to any of the 5 items 
(C-SSRS-behavior) with an episode occurring within the last year 
5. Subject’s PANSS score improves ≥30% from Visit 1 to Visit 2 
7.2.2. 
Exclusion Criteria Based on Treatment History 
6. Subject has a history of treatment resistance, defined as failure to respond to 2 adequate 
trials of different antipsychotic medications (a minimum of 4 weeks at the subject’s 
maximum tolerated dose) 
7. Subject has used clozapine within 6 months prior to screening or has a history of 
clozapine use for treatment-resistant schizophrenia 
8. Subject has a history of poor or inadequate response to treatment with olanzapine 
9. Subject received olanzapine, mesoridazine, chlorpromazine, or thioridazine at any time 
during the past 6 months or long-acting injectable antipsychotic medication in the last 
6 months with the exception of 3-month paliperidone which must not have been received 
within the past 12 months 
10. Subject requires or has had electroconvulsive therapy (ECT) treatment in the 2-month 
period prior to screening 


 
 
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7.2.3. 
Exclusion Criteria Based on Drug/Alcohol Use and Concomitant Meds 
11. Subject has a diagnosis (based on DSM-5 criteria) of moderate or severe alcohol or drug 
use disorder currently or at any time during the 3 months prior to screening. 
12. Subject has a positive urine drug screen for opioids, amphetamine/ methamphetamine, 
phencyclidine, or cocaine at screening 
13. Subject has taken opioid agonists (eg, codeine, oxycodone, tramadol, or morphine) within 
the 14 days prior to screening and/or anticipates a need to take opioid medication during 
the study period (eg, planned surgery) or has taken opioid antagonists within 60 days 
prior to screening 
14. Subject is taking any weight loss agents or hypoglycemic agents at screening 
15. Subject is currently on a statin medication (an HMG-CoA reductase inhibitor) that was 
initiated or has had a dose adjustment within the 3 months prior to screening 
7.2.4. 
Exclusion Criteria Based on Medical Conditions/Medical History 
16. Subject has known risk of narrow-angle glaucoma 
17. Subject has a clinically significant or unstable medical illness, condition, or disorder that 
would be anticipated to potentially compromise subject safety or adversely affect the 
evaluation of efficacy, including (but not necessarily limited to) the following: 
• Clinically significant hypotension or hypertension not stabilized by medical therapy 
• Unstable thyroid dysfunction in the past 6 months (eg, hypothyroidism, 
hyperthyroidism, or thyroiditis that was untreated, or discovered and treatment was 
initiated within the 6 months prior to screening) 
• Personal or family history of neuroleptic malignant syndrome, has a history of 
clinically significant extrapyramidal symptoms when taking olanzapine, or has had 
clinically significant tardive dyskinesia or tardive dystonia within 30 days of 
screening 
• Inflammatory bowel disease or any other gastrointestinal (GI) disorder associated 
with weight loss, anorexia nervosa, bulimia nervosa, or binge eating disorder 
• Neurologic conditions including the following: 
− History of seizure disorder or a condition associated with seizures (exception: 
history of febrile seizures) 
− History of brain tumor, subdural hematoma or other clinically significant 
neurological condition within the 12 months prior to screening 
− Head trauma with loss of consciousness within the 12 months prior to screening 
− Active acute or chronic central nervous system (CNS) infection 
− Stroke within the 6 months prior to screening 


 
 
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• A cardiac condition that might confound the results of the study or pose additional 
risk when administering the investigational agents to the subject or preclude 
successful completion of the study including the following: 
− Clinically significant cardiac arrhythmia, cardiomyopathy, or cardiac conduction 
defect, a history of myocardial infarction or unstable angina within 3 months prior 
to screening 
18. Subject has a history of diabetes 
19. Subject has undergone a significant blood loss (>500 mL) or blood product donation 
(including platelets or plasma) within 60 days of screening or anticipates blood or blood 
product donation at any time during the trial 
7.2.5. 
Exclusion Criteria Based on Laboratory Assessments at Screening 
20. Subject has any of the following lab results at screening: 
• Hemoglobin A1c (HbA1c) ≥ 6.0% 
• Dyslipidemia, defined for this study as total fasting cholesterol >280 mg/dL or fasting 
triglycerides >500 mg/dL 
• Aspartate aminotransferase (AST) or alanine aminotransferase (ALT) value ≥2 times 
the upper limit of the laboratory normal reference range 
• Absolute neutrophil count ≤1.5 × 103 μL 
• Platelet count ≤75 × 103 μL 
• Serum creatinine >2.5 mg/dL 
• Positive pregnancy test result 
21. Positive serology test for hepatitis B surface antigen, hepatitis C antibody (confirmed by 
RNA testing), or human immunodeficiency virus (HIV) antibody at screening 
22. Clinically significant ECG abnormality at Visit 1 or baseline Visit 2 
23. QT interval >450 msec for men and >470 msec for women, as corrected by the Fridericia 
formula (QTcF), observed at Visit 1 or baseline Visit 2 
7.2.6. 
General Exclusion Criteria 
24. Subject is currently pregnant or breastfeeding, or is planning to become pregnant during 
the study period. 
25. Subject has any finding that, in the view of the investigator, would compromise the 
subject’s ability to fulfill the protocol visit schedule or study requirements 
26. Subject is currently under involuntary hospitalization or incarceration 
27. Subject has participated in another clinical trial in which the subject received an 
experimental or investigational drug or agent within 6 months before screening by 
self-report or through confirmation using an clinical trial subject registry 
28. Subject has participated in a clinical study with ALKS 3831 or samidorphan at any time 


 
 
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29. Subject is employed by Alkermes, 
 or study site (permanent, 
temporary contract worker, or designee responsible for the conduct of the study) or is 
immediate family* of an Alkermes, 
 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 sponsor 
determines that it is not in the best interest of the subject to continue participation. Reasons for 
discontinuation include: 
• Adverse Event 
• Lack of Efficacy 
• Lost to Follow-up 
• Withdrawal by Subject 
• Protocol Deviation (non-compliance with study drug or study procedures) 
• Pregnancy 
• Study Terminated by Sponsor 
• Other 
Additionally, if a subject has an ANC<1.0 × 103µL or HbA1c ≥6.5% at any time from Visit 2 to 
Visit 6, the PI (or designee) should discontinue the subject from participation immediately. 
If a subject withdraws from the study for any reason, any ongoing AEs will be followed until 
resolution, until deemed stable by the investigator, or until the subject is deemed by the 
investigator to be lost to follow-up. If, in the opinion of the investigator, it is necessary to 
monitor a subject beyond the 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. Randomized subjects are to be asked to return to the clinic for an early termination (ET) 
visit and to complete a subsequent safety follow-up period. The early termination visit should be 
scheduled as close as possible to the subject’s last dose and will mimic the assessments 
scheduled to be conducted at Visit 6. 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. A full 
explanation of the reason for study discontinuation will be made on the appropriate electronic 
case report form (eCRF). 
PPD
PPD


 
 
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A subject will be deemed lost to follow-up after 3 attempts at contact have been made and it has 
been at least 1 month since the last subject contact. The 3rd attempt at contact must be a certified 
letter accompanied by a survey inquiring the reason for study discontinuation. All attempts at 
contact will be documented. The reason for discontinuation will be documented. If the PI 
becomes aware of a change in the subject’s status or receives more information about a subject’s 
disposition, this information will be documented. 
7.4. 
Replacement of Subjects 
Subjects prematurely discontinued from the study post randomization will not be replaced. 
7.5. 
Identification of Informant or Caregiver 
In some cases a caregiver may be required for a subject to join the study (eg, by a local 
institutional review board [IRB]). This person should be in contact with the subject, able to help 
with adherence to study procedures (including attending study visits when needed), and able to 
report on the subject’s safety and behavior. 
7.6. 
Withdrawal and Replacement of Caregiver 
Some sites may require the caregiver to sign a caregiver ICF (separate from a subject ICF). A 
caregiver who is required to sign a caregiver ICF may withdraw consent at any time, in which 
case he/she can no longer fill the caregiver role for this study. Any other caregiver may decide to 
stop cooperating with study staff or be lost to follow-up, in which case he/she can no longer fill 
the caregiver role for this study. If a caregiver can no longer fill the caregiver role, he/ she should 
be replaced if possible. If the caregiver cannot be replaced, most subjects will be able to continue 
in the study. If the subject must also withdraw from the study (eg, the caregiver provided 
transportation to the site and no other travel arrangements can be made for the subject), the PI 
should make a reasonable effort to ascertain the reason(s) for the caregiver’s withdrawal, while 
fully respecting the caregiver’s and subject’s rights. A full explanation about the caregiver’s 
withdrawal should be included with explanation of the subject’s discontinuation in the 
appropriate eCRF. 


 
 
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8. 
STUDY DESIGN 
8.1. 
Overall Study Design and Plan 
This is a Phase 3, multinational, multicenter, randomized, double-blind, placebo-controlled study 
in subjects experiencing an acute exacerbation of schizophrenia. Subjects will be screened up to 
10 days prior to randomization. Upon completion of screening assessments, subjects meeting 
eligibility criteria will be admitted to an inpatient unit on Day -1, if they are not already 
inpatient. Currently prescribed antipsychotics will be discontinued at screening. 
Study design and timeline are summarized in the schematic shown in Figure 1. 
On Day 1 (Visit 2), subjects meeting eligibility criteria will be randomized in a 1:1:1 fashion to 
one of the following 3 treatment groups: ALKS 3831, olanzapine, or placebo, and will receive 
double-blind treatment for up to 4 weeks. 
On Days 1 and 2, subjects randomized to ALKS 3831 will receive 10/10 [10 mg olanzapine/ 
10 mg samidorphan] and subjects randomized to olanzapine will receive 10 mg. On Day 3, the 
dose will be increased to 20/10 [20 mg olanzapine/10 mg samidorphan] for subjects randomized 
to ALKS 3831 or 20 mg for subjects randomized to olanzapine. Following the increase on Day 3, 
the dose may be decreased to 10/10 (ALKS 3831) or 10 mg (olanzapine) at end of week 1(Day 
7) or week 2 (Day 15) if there are tolerability problems based on judgment of the investigator. 
No further dose adjustments will be allowed Day 15 onward for the remaining 2-weeks of the 
treatment period. All subjects will receive 1 capsule daily in a blinded manner. 
Subjects are required to be inpatient for the first 2 weeks of the treatment period (until Day 15). 
Following the mandatory 2-week inpatient stay, subjects can either continue the study as 
inpatients for the full 4-week treatment period or be discharged at the end of Week 2 or end of 
Week 3 if they meet the discharge criteria specified in Section 8.1.1. 
Following discharge, subjects will be contacted by study staff at least once between their weekly 
site visits to monitor their status and determine if there are any safety concerns that would 
precipitate re-admission to the inpatient facility. If subjects are re-admitted to the inpatient 
facility due to safety concerns, it will be recorded as an SAE. 
Subjects completing 4 weeks of treatment with study drug will be eligible to continue in the 
open-label, long-term safety study (ALK3831-A306) and receive ALKS 3831 for up to 
52 weeks. Subjects not continuing in the long term safety study will enter a 2-week safety 
follow-up period. During this follow-up period subjects may be treated with any antipsychotic 
medication according to physician recommendations. 
Subjects who are inpatient at the end of the 4-week treatment period and are not continuing in 
the extension study (ALK3831-A306) may continue as inpatients for up to 1 additional week of 
the 2-week safety follow-up period. These subjects may be discharged from the inpatient unit at 
any time during this week based on investigator’s judgment. For subjects continuing in the safety 
extension study (ALK3831-A306), details regarding the additional inpatient week will be 
provided in the ALK3831-A306 protocol. 


 
 
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The total duration of this study is approximately 7.5 weeks, including a 10-day screening period 
(Days -10 to -1), a 4-week treatment period (Days 1-29), and 1 follow-up visit 2 weeks after 
EOT (Day 43). 
Figure 1: 
Study Design Schematic 
 
8.1.1. 
Discharge Criteria 
Subjects are eligible to be discharged at end of Week 2, Week 3, or Week 4 if they meet ALL of 
the following criteria: 
1. Subjects are judged clinically suitable for discharge by the investigator: 
a. Subjects have shown a sustained pattern of improvement relative to their condition on 
Day 1 within the past week. 
b. Subjects are not a danger to themselves or others 
c. Subjects can be discharged into a supervised living environment deemed suitable by 
the investigator. 
2. Subjects show stabilization of symptoms as confirmed by PANSS: 
a. PANSS total score <70 
b. Score <4 on selected PANSS positive items (Item 1 [P1; delusions], item 2 
[P2; conceptual disorganization], item 3 [P3; hallucinatory behavior], and item 6 
[P6; suspiciousness/persecution]) 
3. Subjects answer “No” on items 4 or 5 of the Columbia-Suicide Severity Rating Scale 
(C -SSRS-ideation), and “No” to all 5 items of (C-SSRS-behavior) 
Subjects not meeting the discharge criteria will continue as inpatients for the remainder of the 
study and for up to 1 additional week if they do not meet discharge criteria at EOT. 


 
 
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8.2. 
Schedule of Visits and Assessments 
The schedule of visits and assessments is shown in Table 1. 
For a missed visit, the site should attempt to contact the subject to reschedule. 
Premature discontinuation procedures are provided in Section 7.3. 


 
 
 
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Table 1: 
Schedule of Visits and Assessments 
Period 
Screening 
Double-Blind Treatment Period 
Follow-Up1 
Visit Number 
1 
2 
3 
4 
5 
6 
7 
Study Day 
-10 to -1 
1 
8 
15 
222 
29/ET2 
432 
Informed Consent 
X 
 
 
 
 
 
 
Demographics 
X 
 
 
 
 
 
 
Medical/ Psychiatric History 
X 
 
 
 
 
 
 
Mini International Neuropsychiatric 
Interview (MINI) 
X 
 
 
 
 
 
 
Eligibility Criteria Review 
X 
X3 
 
 
 
 
 
Genotype Sample 
X 
 
 
 
 
 
 
Height 
X 
 
 
 
 
 
 
Weight and waist circumference 
(conducted 3 times each visit) 
X 
X3 
 
 
 
X 
X 
Physical Exam4 
X 
X3 
 
 
 
X 
X 
Randomization 
 
X 
 
 
 
 
 
Urine Drug Screen5 
X 
X3 
 
 
X6 
X6 
 
Pregnancy Testing 
X 
X3 
 
 
 
 
 
Serology Testing7 
X 
 
 
 
 
 
 
Laboratory Samples8 (refer to Table 2) 
X 
X3 
 
X 
 
X 
 
PK Sample9 
 
X3 
 
X 
 
X 
 
Vital Signs10 
X 
X3 
X 
X 
X 
X 
X 
12-Lead Electrocardiogram 
X 
X3 
X 
X 
X 
X 
X 
Adverse Event Monitoring 
X 
X 
X 
X 
X 
X 
X 


 
 
 
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Table 1: 
Schedule of Visits and Assessments (Continued) 
Period 
Screening 
Double-Blind Treatment Period 
Follow-Up1 
Visit Number 
1 
2 
3 
4 
5 
6 
7 
Study Day 
-10 to -1 
1 
8 
15 
222 
29/ET2 
432 
Concomitant Medication Review 
X 
X 
X 
X 
X 
X 
X 
Columbia-Suicide Severity Rating Scale 
(C-SSRS)11 
X 
X3 
X 
X 
X 
X 
X 
Abnormal Movement Scales12 
 
X3 
X 
X 
X 
X 
X 
Positive and Negative Syndrome Scale 
(PANSS)13 
X 
X3 
X 
X 
X 
X 
 
Modified Overt Aggression Scale14 
 
X 
X 
X 
X15 
X15 
 
Clinical Global Impression – Severity 
(CGI-S) 
X16 
X 
X 
X 
X 
X 
 
Clinical Global Impression – 
Improvement (CGI-I) 
 
 
X 
X 
X 
X 
 
Informed Consent for ALK3831-A306 
 
 
 
 
 
X17 
 
Emergency treatment card18 
 
X 
 
 
 
X 
 
Admission to Inpatient Unit19 
X 
 
 
 
 
 
 
Discharge from Inpatient Unit20 
 
 
 
X 
X 
X 
 
Study Drug Dispensation21 
 
X 
X 
X 
X 
 
 
Study Drug Return and Adherence 
Review 
 
 
X 
X 
X 
X 
 
1 Follow-up Visit (V7) is not required for subjects who enroll in ALK3831-A306 
2 A visit window of ±2 days (anchored to Day 1) is allowed 
3 Predose 
4 Full physical exam at screening; brief physical exam at all subsequent time points. 


 
 
 
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5 Urine drug screen via dipstick at screening and prior to randomization on Day 1. Drug screen at Visits 5 and 6 applies to outpatient subjects only. Urine drug 
screen includes opiates, phencyclidine (PCP), amphetamine/methamphetamine, and cocaine. 
6 For outpatient subjects only 
7 Serology testing includes anti-human immunodeficiency virus (HIV) antibody, hepatitis B surface antigen, and anti-hepatitis C antibody. 
8 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. 
9 One PK sample will be collected at the specified visits to measure plasma levels of olanzapine, samidorphan, and metabolites of interest 
10 Vital signs include orthostatic blood pressure and heart rate, respiratory rate, and oral body temperature. Blood pressure, pulse rate, and respiratory rate will be 
taken after the subject has been supine for 5 minutes and once again after the subject has stood for 2 minutes. 
11 The “Baseline/Screening” version of the C-SSRS will be used at screening; the “Since Last Visit” version to be used at all other scheduled visits. 
12 Abnormal movement scales include the following: Abnormal Involuntary Movement Scale (AIMS), Barnes Akathisia Rating Scale (BARS), and Simpson-
Angus Scale (SAS). 
13 With the exception of the screening visit, the PANSS should be administered before other psychiatric assessments at each specified study visit. 
14The MOAS will be performed on all subjects at Visits 2, 3 and 4 and only on inpatient subjects at Visits 5 and 6. 
15 Only for inpatient subjects 
16CGI-S will be administered at the Screening Visit using the structured interview guide for global impressions (SIGGI) 
17 The informed consent form for the open-label extension, ALK3831-A306, must be distributed to subjects by the end of treatment. However, the form may be 
distributed to subjects earlier at the investigator's discretion. 
18 Emergency treatment card to be dispensed at randomization (Visit 2), confirmed at subsequent time points, and collected at Visit 6, EOT. 
19 Subjects will be admitted to the inpatient unit on the same day as their screening assessments if they are not already inpatient. 
20 Subjects may be discharged at Day 15, Day 22, or Day 29 if they meet discharge criteria. Subjects not meeting discharge criteria at Day 29 may remain 
inpatient for up to 1 additional week and may be discharged from the inpatient unit at any point during this week at the investigator’s discretion. 
21 During the inpatient stay, study drug will be administered daily by study staff, preferably at bedtime. Upon discharge, subjects will be given study drug to take 
daily, preferably at bedtime though dose timing may be adjusted at the investigator’s discretion based on tolerability. 


 
 
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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 1. 
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 1 using 
the subject inclusion criteria in Section 7.1 and exclusion criteria in Section 7.2. 
8.3.3. 
Demographics and Medical History 
Subject’s demographic data and medical history will be reviewed and documented at the time 
point(s) specified in Table 1. 
8.3.4. 
Concomitant Medication Review 
All medications (prescription and non-prescription, including vitamins and herbal supplements) 
taken by a given subject within 60 days of screening through follow-up will be recorded. 
At each study visit (see Table 1), the investigator or designee 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 point(s) specified in Table 1. 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 
Vital signs may be collected at any time during a scheduled visit, unless otherwise noted. 


 
 
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8.3.6. 
Physical Examination 
A physical examination will be performed at the time points specified in Table 1. A full physical 
will be performed at screening and a brief physical at subsequent visits. 
8.3.7. 
 Height, Body Weight, and Waist Circumference 
Height will be measured at screening only and body weight and waist circumference will be 
measured at all the time points specified in Table 1. 
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 time points specified in Table 1. 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. 
Table 1 provides information on the time points at which each assessment should be 
administered. 
At screening the medical and psychiatric history and MINI diagnostic interview must be 
conducted prior to the PANSS. For all other visits where assessments overlap, the PANSS should 
be administered first before any other psychiatric assessment. Structured Interview Guide for 
Global Impression (SIGGI, Appendix B) will be used to administer the CGI-S. 
8.3.9.1. 
Diagnostic Assessments 
8.3.9.1.1. Mini International Neuropsychiatric Interview 
The MINI is a short, clinician-administered, structured diagnostic interview, with an 
administration time of approximately 15 minutes (Sheehan, Lecrubier et al. 1998). The MINI has 
been validated against the much longer Structured Clinical Interview for DSM Diagnoses 
(SCID). The MINI will be used at screening only as indicated in Table 1. 


 
 
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8.3.9.2. 
Efficacy Assessments 
8.3.9.2.1. Clinical Global Impression-Severity 
The PI or designee will complete the CGI-Severity (CGI-S, Appendix B) scale at the time points 
specified in Table 1. 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). For the Screening Visit, the Structured Interview Guide for Global Impression 
(SIGGI, Appendix B) will be used to administer the CGI-S. 
8.3.9.2.2. Clinical Global Impression-Improvement 
The PI or designee will complete the CGI-Improvement (CGI-I, Appendix B) at the time points 
specified in Table 1. The CGI-I measures improvement from the first assessment(Guy 1976). 
8.3.9.2.3. Modified Overt Aggression Scale 
The PI or designee will complete the MOAS (Appendix C) (Kay, Wolkenfeld et al. 1988). The 
MOAS provides a weighted measure of aggression based on four primary components (verbal 
aggression, aggression against property, auto-aggression, and physical aggression). It is a recall 
assessment based on behavior observed over a defined period of time, for the purposes of this 
study, the past week, and therefore, to maintain consistency in observation and rating, the 
assessment will be performed only on subjects that are inpatient according to the schedule 
indicated in Table 1. 
8.3.9.2.4. Positive and Negative Syndrome Scale 
The PI or designee will complete the PANSS (Appendix D) (Kay, Fiszbein et al. 1987) 
according to the schedule in Table 1. The Structured Clinical Interview for the PANSS (SCI-
PANSS) will be used to administer the PANSS. 
8.3.9.3. 
Safety Assessments 
8.3.9.3.1. Abnormal Movement Rating Scales 
The PI or designee will complete the following abnormal movement rating scales: The Abnormal 
Involuntary Movement Scale (AIMS, Appendix E) (Guy 1976), the Barnes Akathisia Rating 
Scale (BARS, Appendix F) (Barnes 1989), and the Simpson-Angus Scale (SAS, Appendix G) 
(Simpson and Angus 1970) at the time points specified in Table 1. 
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. 
8.3.9.3.2. Columbia-Suicide Severity Rating Scale 
The PI or designee will administer the C-SSRS (Appendix H) according to the schedule in 
Table 1. The “Baseline/Screening” version (Posner, Brent et al. 2009) is to be completed at Visit 
1 and the “Since Last Visit” version (Posner, Brent et al. 2009) is to be completed at all 
subsequent scheduled time points. The C-SSRS should be administered by a qualified clinician 
trained in assessing and managing suicidal ideation and behavior. 


 
 
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8.3.10. 
Clinical Validation Inventory for Study Admission and Ongoing Rater Review 
Rater (ie, study staff) accuracy at screening on pre-specified study measures (ie, PANSS) will be 
reviewed by central raters employed by Clintara, LLC using the C-VISA™. 
Later reviews will take place according to a pre-specified schedule (subject to change based on 
rater accuracy) after the measure has been administered using an audio recording of the 
screening interview. Rater review is necessary for mitigating inaccurate inclusion/exclusion 
assessments and inaccurate efficacy assessments. 
Rater assessments require subject interviews to be audio recorded. The audio recording will be 
disclosed and explained to the subject by study staff and will be disclosed in the ICF during the 
informed consent process. No subject will be recorded without the knowledge that a recording is 
being made. 
8.3.11. 
Laboratory Assessments 
8.3.11.1. Drug Testing 
A urine drug screen for opiates (including codeine, hydrocodone, hydromorphone, methadone, 
morphine, oxycodone, and oxymorphone) and drugs of abuse (including amphetamine/ 
methamphetamine, phencyclidine and cocaine) will be performed at the time points specified in 
Table 1. 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. 
8.3.11.2. Hematology, Biochemistry, and Urinalysis 
Fasting blood and urine samples will be collected at the time points specified in Table 1 for 
specific hematology, biochemistry, and urinalysis assessments listed in Table 2. 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 2: 
Clinical Laboratory Assessments 
Hematology  
Biochemistry 
Urinalysis 
Hematocrit 
Hemoglobin 
Platelets 
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 
HbgA1c1 
Insulin 
Thyroid Stimulating Hormone2 
Prolactin 
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 
1 At screening, predose on Day 1, and EOT 
2 At screening only; if the TSH results indicate the value is outside of normal limits, the central lab will 
automatically test the same screening visit sample and provide a free T4 and T3 analysis 


 
 
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8.3.11.3. Pregnancy Testing 
As described in Section 8.4.1, a urine/ serum pregnancy test will be administered to all women at 
the time points specified in Table 1. 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. 
8.3.11.4. Serology Testing 
A blood sample for a serology panel testing for hepatitis B surface antigen, anti-hepatitis C 
antibodies, and human immunodeficiency virus (HIV) will be performed at screening only. 
8.3.12. 
Pharmacokinetic Assessments 
Concentrations of olanzapine, samidorphan, and metabolites of interest will be determined from 
plasma samples collected according to the schedule in Table 1. The time of last study drug 
administration (when applicable) and the time of each PK blood draw must be documented in the 
subject’s source documents. Samples for PK analysis will be stored at -20°C ±10°C. PK data 
from these samples may be included in a subsequent population PK analysis or other post-hoc 
analyses conducted outside of this study. 
8.3.13. 
Genotype Sampling 
A blood sample may be collected (at the time point indicated in Table 1) for evaluation of 
genotypes that are potentially related to response and to explore potential genetic associations 
with efficacy, adverse effects, symptoms or outcomes. No other tests will be performed with 
these samples. 
8.3.14. 
Randomization 
At the time point specified in Table 1, subjects will be randomized as outlined in Section 9.3. 
8.3.15. 
Drug Dispensation and Reconciliation 
Section 9.1 provides information related to drug dispensing procedures. Study drug will be 
dispensed/ administered at the time points specified in Table 1. 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. 
Study drug will be supplied as oral, bilayer tablets for once daily dosing in high-density 
polyethylene (HDPE) bottles with desiccant. 
While subjects are inpatient, study drug will be administered by study staff daily, preferably at 
bedtime. If/when subjects are discharged from the inpatient facility, they will be given study 
drug to take at home. 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 


 
 
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dispensed, dosed, lost/ missing, or remaining. If applicable, the site will discuss non-compliance 
with the subject. 
8.3.16. 
Emergency Treatment Card 
An emergency treatment card will be distributed to each subject and collected from each subject 
at the time points indicated in Table 1. The card will indicate that the subject may be receiving 
an opioid antagonist and/or 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 indicated in Table 1. 
8.3.17. 
Adverse Event Monitoring 
AEs will be monitored continuously from the time a subject signs the informed consent 
document until the completion of the final study visit (see Table 1). AEs and serious adverse 
events (SAEs) are defined in Section 13.1 and 13.2, respectively. Section 13.4 provides guidance 
on the monitoring and reporting requirements for AEs. Section 13.5 provides guidance on the 
reporting requirements for SAEs. 
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. 
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 


 
 
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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 use of any antipsychotic other than study drug is prohibited. Prior antipsychotic medication 
should be discontinued at screening (at Visit 1). All subjects should be in an inpatient setting 
when discontinuing prior antipsychotic medication, at the investigator’s discretion. Allowable 
washout period is 2-5 days starting at Visit 1. If administration of an antipsychotic during a 
subject’s participation in the study is being considered (eg, as rescue treatment), the investigator 
should contact the medical monitor to discuss the appropriate course of action. 
Prohibited medications include the following: 
• Monoamine oxidase inhibitors (eg, phenelzine, tranylcypromine, selegiline, or 
moclobemide) 
• Long-acting formulations of any antipsychotic agent 
• Antipsychotic agents 
− Use of antipsychotic sleep aids (eg, Seroquel) is prohibited. However, use of 
benzodiazepines to treat some symptoms is permissible (see Section 8.4.3 for 
permitted therapy) 
• In general, the use of psychotropic medications other than study drug is prohibited 
with the exception of the following: 
− Beta-blockers (eg, propranolol or pinodolol), antihistamines, and anticholinergics 
may be used for treatment-emergent akathisia 
− Anticholinergics may be used for extrapyramidal symptoms 
• Nicotine replacement therapy including nicotine replacement patch and oral nicotine 
gum is permitted. However, Chantix® (varenicline) is not 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®), Exenatide (Byetta®); Sulfonylureas (eg, Diamicron®, Amaryl®, 
Glucotrol®, Micronase®); Meglitinides (eg, Starlix®, Prandin®); Metformin or other 
hypoglycemic agent 
• Antidepressants that have been started within 30 days of screening are prohibited. An 
antidepressant should not be started during a subject’s participation in the study. 


 
 
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Subjects who have been on a stable dose of an antidepressant for at least 30 days 
before screening may be allowed to participate in the study if it is anticipated that the 
dose will not change during the subject’s participation in the study 
Medications that are contraindicated with olanzapine use or exhibit drug-interaction potential 
with olanzapine are prohibited. 
Use of moderate to strong inducers or inhibitors of cytochrome P450 (CYP) 3A4 (prescription 
medications, OTC medications, or dietary supplements) within 30 days before randomization 
through follow-up is prohibited. See Appendix A for a list of P450 (CYP) 3A4 inhibitors and 
inducers. 
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 agonists (eg, codeine, oxycodone, tramadol, or morphine) within 14 days before 
screening is prohibited. Use of opioid antagonists, including naltrexone (any formulations) and 
naloxone within 60 days before screening and throughout the study duration is prohibited. 
Note: during the study period, opioid agonists should be avoided as they may be rendered 
ineffective by samidorphan. 
See Section 8.3.4 for details regarding the concomitant medication review. 
8.4.3. 
Permitted Therapy 
Permissible medications to treat extrapyramidal symptoms may include benzodiazepines, 
antihistamines, and anticholinergics. Continuous use of these medications should be avoided if 
possible and they should only be given to the patient after all study assessments have been 
performed. 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. However, doses should be restricted to no more than a 2 mg 
lorazepam equivalent per day and should be kept as stable as possible throughout study so as not 
to interfere with daytime functioning and study assessments. 
8.4.4. 
Non-medication Therapy 
Psychotherapy should not be started or changed during a subject’s participation in the study. It is 
acceptable for a subject already receiving psychotherapy to participate in the study. While on the 
inpatient study unit during participation in the study, initiation of augmenting psychotherapies 
(ie, group therapy) deemed by the clinical investigator to be of clinical benefit while on the 
inpatient study unit is discouraged, though standard milieu-related activities are acceptable. 
8.4.5. 
Pain Management 
Because ALKS 3831 contains samidorphan, a μ-opioid receptor 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. 


 
 
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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 is an opioid antagonist and 
could interfere with opioid-mediated pain management. 
8.4.6. 
Fasting 
Subjects are required to fast for at least 8 hours (no food or drink except water) prior to lab blood 
draws. 
8.4.7. 
Inpatient Stay 
Eligible subjects must be admitted to the inpatient study facility on the same day as their 
screening assessments and are required to remain inpatient for the first 2 weeks of the treatment 
period (until Day 15). Subjects may be discharged on Day 15, Day 22, or Day 29 if they meet 
discharge criteria (See Section 8.1.1). Subjects who are inpatient at the end of the 4-week 
treatment period and are not continuing in the extension study (ALK3831-A306) may continue 
as inpatients for up to 1 additional week of the 2-week safety follow-up period. These subjects 
may be discharged from the inpatient unit at any time during this week based on investigator’s 
judgment. For subjects continuing in the safety extension study (ALK3831-A306), details 
regarding the additional inpatient week will be provided in the ALK3831-A306 protocol. 
8.4.8. 
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 


 
 
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• Subjects are prohibited from participating in a weight management program or from 
entering a smoking cessation program for the duration of the study 
• 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 
• Subjects will be required to follow the clinic's in-house rules 


 
 
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9. 
TREATMENT OF SUBJECTS 
9.1. 
Study Drug Dose and Administration 
Study drugs include: 
• ALKS 3831 10/10 or 20/10 (10 mg olanzapine/10 mg samidorphan or 20 mg 
olanzapine/10 mg samidorphan respectively) administered as a coated bilayer tablet 
• Olanzapine 10 mg or 20 mg administered as a coated bilayer tablet 
• Placebo matching 10 mg and 20 mg tablets. 
During the inpatient period, subjects will be administered study drug orally, once daily 
preferably at bedtime. Following discharge on Day 15 or later, subjects will be given study drug 
to take home and instructed to take one tablet orally preferably at bedtime. If there are 
tolerability problems, dosing may be switched to another time based on the judgment of the 
investigator; frequent switching is discouraged. 
9.2. 
Treatment Adherence 
Subjects will undergo a study drug adherence review at the time points indicated in Table 1. In 
addition to these scheduled adherence reviews, for subjects discharged on Day 15 or 22, study 
staff will check in with them or a caregiver (if applicable) between assessment visits to monitor 
treatment adherence. 
9.3. 
Randomization/ Method of Assigning Subjects to Treatment 
Subjects meeting eligibility criteria at baseline (Day 1) will be randomized in a 1:1:1 ratio to one 
of the following treatment groups: 
• ALKS 3831 
• Olanzapine 
• Placebo 
Randomization will be performed centrally through an Interactive Web Response System 
(IWRS). A unique randomization number will be assigned by the IWRS once eligibility has been 
determined. Once a randomization number has been assigned, that number must not be used 
again if, for example, a subject is withdrawn from the study. Codes will be prepared by an 
independent biostatistician who is not otherwise involved in this study. 
9.4. 
Blinding 
All Alkermes staff, clinical staff, subjects and caregivers will be blinded to treatment assignment 
until database lock. 
The principal investigator is responsible for all trial-related medical decisions. If the investigator 
deems it necessary to break the study blind in the interest of a subject’s medical safety, he or she 
must make every effort to contact the CRO/ sponsor medical monitor before the blind is broken. 


 
 
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If the site is unable to contact the medical monitor prior to breaking the blind, the medical 
monitor must be contacted within 24 hours following disclosure of study drug assignment. Any 
premature unblinding should be promptly documented. 
Breaking the blind for a single subject will not affect the blind for the remaining subjects. 


 
 
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10. 
STUDY DRUG MATERIALS AND MANAGEMENT 
10.1. 
Study Drug 
ALKS 3831 drug product will be supplied as a coated bilayer tablet in two fixed-dose 
combinations: 
• ALKS 3831 10/10 (10 mg olanzapine/10 mg samidorphan) 
• ALKS 3831 20/10 (20 mg olanzapine/10 mg samidorphan) 
Matching olanzapine-only drug will be supplied as a coated bilayer tablet in two dose strengths: 
• OLZ 10 (10 mg olanzapine) 
• OLZ 20 (20 mg olanzapine) 
Matching placebo will be supplied in two dose strengths: 
• Placebo to match 10/10 ALKS 3831 and 10 mg olanzapine comparator 
• Placebo to match 20/10 ALKS 3831 and 20 mg olanzapine comparator 
10.2. 
Packaging and Labeling 
All tablets will be packaged in HDPE bottles with desiccant. Bottle labels will meet all 
applicable local and regulatory requirements. 
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, samidorphan and/or blinded study drug 
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 clinical site is required to maintain current drug dispensation and accountability logs 
throughout the study. All unused supplies will be checked against the drug movement records 
during the study and/or at the end of the study. 
Refer to Section 8.3.15 for additional study drug reconciliation procedures. 
10.5. 
Handling and Disposal 
Following completion and verification of accountability logs, all unused and used packages must 
be destroyed. Packages may be destroyed on site according to Good Clinical Practice (GCP) and 
site practice. Alternatively, the sponsor may arrange for destruction with a third party vendor 
operating in accordance with GCP and/or Good Manufacturing Practice (GMP), as applicable. 


 
 
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11. 
ASSESSMENT OF EFFICACY 
11.1. 
Efficacy Measures 
• Positive and Negative Syndrome Scale (PANSS) (Kay, Fiszbein et al. 1987) 
• Modified Overt Aggression Scale (MOAS) (Kay, Wolkenfeld et al. 1988) 
• Clinical Global Impression of Severity (CGI-S) (Guy 1976) 
• Clinical Global Impression of Improvement (CGI-I) (Guy 1976) 
See Section 8.3.9.2 for details regarding efficacy assessments. 


 
 
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12. 
ASSESSMENT OF PHARMACOKINETICS AND 
PHARMACODYNAMICS 
Concentrations of olanzapine, samidorphan, and metabolites of interest will be determined from 
plasma samples collected according to the schedule in Table 1. Pharmacokinetic (PK) data from 
these samples may be included in a subsequent population PK analysis conducted outside of this 
study. By-subject listings of plasma concentrations will be provided. 


 
 
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13. 
ASSESSMENT OF SAFETY 
Safety will be assessed on the basis of: 
• Adverse events 
• Abnormal Involuntary Movement Scale (AIMS) 
• Barnes Akathisia Rating Scale (BARS) 
• Simpson-Angus Scale (SAS) 
• Columbia-Suicide Severity Rating Scale (C-SSRS) 
• Vital signs (oral temperature, respiratory rate, pulse, systolic and diastolic blood 
pressure) 
• Electrocardiogram parameters (heart rate, RR, PR, QRS, and QT) 
• Clinical laboratory parameters (chemistry, hematology, and urinalysis; see Table 2) 
• Weight/BMI and Waist Circumference 
See Section 8.3.9.3 for more details on the AIMS, BARS, SAS and C-SSRS. 
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 


 
 
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• Requires inpatient hospitalization or prolongation of existing hospitalization. Hospital 
admission for elective surgery scheduled prior to study entry is not considered an 
SAE 
• Results in disability/incapacity (eg, a substantial disruption of a person’s ability to 
conduct normal life functions) 
• Is a congenital anomaly/birth defect 
Important medical events that may not result in death, be immediately life threatening, or require 
hospitalization may be considered to be SAEs when, based upon appropriate medical judgment, 
they may jeopardize the patient or subject and may require intervention to prevent one of the 
other outcomes listed above. 
13.3. 
Relationship to Study Drug 
The assessment of study drug relationship to each AE will be reported on the appropriate source 
document (and SAE form, in the event of an SAE) by the investigator (or designated 
sub-investigator) according to his/her best clinical judgment. The criteria listed in Table 3 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 3: 
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 7). 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 
All SAEs must be reported to 
 within 1 business day of 
discovery, by emailing 
 or faxing the report to the 
following: 
Attention: 
 Medical Monitor 
US Fax Number.: 
 
EU 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. 
PPD
PPD
PPD
PPD
PPD


 
 
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14. 
STATISTICS 
14.1. 
Sample Size Considerations 
The planned sample size is 390 subjects in total, randomized 1:1:1to ALKS 3831, olanzapine and 
placebo arms. This sample size will provide at least 90% power to show superiority for 
ALKS 3831 group when compared to placebo at the 2-sided alpha level of 0.05, assuming a 
10-point improvement of PANSS total score at week 4, a standard deviation (SD) of 20, and a 
dropout rate of 30%. 
14.2. 
General Statistical Methodology 
The statistical analysis methods are described below. Additional details will be provided in the 
Statistical Analysis Plan to be finalized before database lock and unblinding. 
In general, summary statistics (n, mean, standard deviation [SD], median, minimum and 
maximum for continuous variables, and number [%] of subjects in each category for categorical 
variables) will be provided by treatment group for all variables. 
Source data for the summary tables and statistical analyses will be presented as subject data 
listings. 
All statistical tests and confidence intervals, unless stated otherwise, will be 2-sided and will be 
set at α = 0.05. 
14.2.1. 
Study Populations 
14.2.1.1. Safety Population 
The safety population includes all randomized subjects who receive at least 1 dose of study drug 
during the double-blind treatment period. 
14.2.1.2. Efficacy Population 
The full analysis set (FAS) population will be used for efficacy analysis and includes all subjects 
in the safety population who have at least one post-baseline PANSS assessment. 
14.3. 
Demographics and Baseline Data 
Demographics and baseline characteristics such as gender, age, race, weight, BMI, and 
psychiatric history will be summarized by treatment group. If there are heterogeneities between 
study groups in any of the subject characteristics that are of clinical importance or could affect 
the treatment outcome, the impact of the imbalances will be investigated and, if necessary, 
appropriate adjustments made in the efficacy and safety analyses. 
Medical history will be summarized for the safety population using the number of observations 
and percentage of subjects reporting each category. 


 
 
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14.4. 
Efficacy Analyses 
Efficacy analyses will be based on the FAS population. Baseline for efficacy analysis is defined 
as the last non-missing efficacy assessment before the first dose of study drug in the double-blind 
treatment period. All statistical tests will be 2-sided hypothesis tests performed at the 5% 
significance level. All confidence intervals will be 2-sided 95% confidence intervals, unless 
specified otherwise. 
14.4.1. 
Primary Endpoint 
The primary efficacy endpoint is change from baseline in PANSS total score at Week 4. 
For the primary efficacy endpoint, change from baseline in PANSS total score at week 4, 
analysis will be carried out using a mixed model with repeated measurements (MMRM) with an 
unstructured variance-covariance matrix based on the observed data. The model will include 
visit, treatment, and interaction term of visit and treatment as categorical variables, and baseline 
PANSS total score as a covariate. The statistical test will be carried out as follows: 
The change from baseline in PANSS total score at Week 4 in ALKS 3831 group will be 
compared to that in the placebo group using superiority testing at two-sided alpha level of 0.05. 
14.4.2. 
Key Secondary Endpoint 
The key secondary endpoint is change from baseline in CGI-S score at Week 4. 
The analysis will be carried out using MMRM as described for the primary endpoint. 
14.4.3. 
Other Endpoints 
• Change from baseline in PANSS total score and PANSS subscales (positive, 
negative, general psychopathology) by visit 
• Change from baseline in MOAS score by visit 
• Change from baseline in CGI-S by visit 
• CGI-I at each postbaseline visit 
• PANSS responders ( ≥ 30% improvement from baseline in PANSS total score) by 
visit 
• CGI-I responders (CGI-I score of 2 [much improved] or 1 [very much improved]) by 
visit 
• Overall Response defined as: PANSS total score ≥ 30% improvement from baseline 
or CGI-I score of 1 or 2 by visit 
• Change from baseline in PANSS-Excited Component (EC) score (comprised of 
5 items, excitement, tension, hostility, uncooperativeness, and poor impulse control) 
by visit 
For proportion of subjects exhibiting improvement on CGI-I assessment, a logistic regression 
based on last observation carried forward (LOCF) imputation for missing data will be used to 


 
 
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compare ALKS 3831 with placebo. The model will include treatment group, and baseline 
PANSS total score as covariates. 
For all other endpoints, each point will be summarized by treatment groups for all visits. Each 
active group (ALKS 3831 or olanzapine) will be compared to placebo. For continuous outcome, 
a similar approach to that for PANSS total score will be used. For dichotomous outcome, a 
similar approach to that used for CGI-I improvement scores will be used. More details will be 
provided in the statistical analysis plan (SAP). 
14.5. 
Pharmacokinetic Analyses 
Listings will be provided for concentrations of olanzapine, samidorphan, and metabolites of 
interest. PK concentrations may be used in a subsequent population PK analysis conducted 
outside of this study. 
14.6. 
Safety Analyses 
The safety analysis will be carried out using the Safety Population. For each safety parameter, 
the last assessment of the parameter before the first dose of randomized study drug will be used 
as the baseline for all analyses of that safety parameter. Safety endpoint will include adverse 
events (AEs), clinical laboratory parameters, vital signs, electrocardiographic (ECG) parameters, 
Columbia–Suicide Severity Rating Scale (C-SSRS) scores, body weight, BMI, waist 
circumference, AIMS, BARS, and SAS. All safety analyses will be based on observed data only, 
and no missing values will be imputed. 
Reported adverse event terms will be coded using the Medical Dictionary for Regulatory 
Activities (MedDRA) and summarized by preferred term and system organ class categories. 
Safety assessments will be summarized using descriptive statistics along with supportive listings. 
The number and percentage of TEAEs will be summarized by treatment group and overall by 
system organ class, and preferred terms within each system organ class. SAEs and AEs resulting 
in treatment discontinuation will also be summarized. 
Observed values and change from baseline in laboratory parameters, weight, BMI, waist 
circumference, vital signs, and ECG parameters will be summarized by treatment group and 
study visit. 
The number and percentage of subjects who have met potentially clinically significant (PCS) 
criteria at any post-baseline visit will be summarized by treatment group labs, vitals, weight, and 
ECG parameters. Supporting listings will be provided. 
The number and percentage of subjects with shifts in laboratory and extra pyramidal symptom 
(EPS) parameters (AIMS, BARS, and SAS) will also be summarized by treatment group. 
Prior and concomitant medication use will be summarized by World Health Organization 
(WHO) Drug Dictionary Anatomical Therapeutic Class (ATC) code and by treatment group. 
The number and percentage of subjects with C-SSRS assessments of suicidal ideation and 
behavior will also be summarized. 
Listings will be provided for all safety endpoints. 


 
 
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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 (or the 
subject’s legal representative) 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. 


 
 
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Significant changes to the protocol or product safety information may require a revision of the 
ICF, which must be reviewed and approved by the IRB, and then signed by all applicable study 
participants. 
The time that informed consent is obtained must be documented. The investigator must maintain 
the original, signed ICF in the subject’s source documents. A copy of the signed ICF must be 
given to the subject. 


 
 
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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 such as central laboratory data 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. 
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, T. R. (1989). "A rating scale for drug-induced akathisia." Br J Psychiatry 154: 672-676. 
Dixon, L. (1999). "Dual diagnosis of substance abuse in schizophrenia: prevalence and impact 
on outcomes." Schizophr Res 35 Suppl: S93-100. 
Eli Lilly and Company (2015). Prescribing Information: Zyprexa, 2015-07. Indianapolis, IN, 
Lilly USA, LLC. 
Guy, W. (1976). ECDEU Assessment Manual for Psychopharmacology. Rockville, MD, 
Department of Health, Education, and Welfare. 
Harris, E. C. and B. Barraclough (1998). "Excess mortality of mental disorder." Br J Psychiatry 
173: 11-53. 
Hodgins, S. (2008). "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 363(1503): 2505-2518. 
Kay, S., A. Fiszbein and L. Opler (1987). "The Positive and Negative Syndrome Scale (PANSS) 
for Schizophrenia." Schizophr Bull 13(2): 261-276. 
Kay, S. R., F. Wolkenfeld and L. M. Murrill (1988). "Profiles of aggression among psychiatric 
patients. I. Nature and prevalence." J Nerv. Ment. Dis 176(9): 539-546. 
Koekkoek, B., M. B. van and G. Hutschemaekers (2006). ""Difficult patients" in mental health 
care: a review." Psychiatr Serv 57(6): 795-802. 
Kuo, C. J., S. Y. Tsai, C. H. Lo, Y. P. Wang and C. C. Chen (2005). "Risk factors for completed 
suicide in schizophrenia." J Clin Psychiatry 66(5): 579-585. 
Lambert, M., P. Conus, S. Cotton, J. Robinson, P. D. McGorry and B. G. Schimmelmann (2010). 
"Prevalence, Predictors, and Consequences of Long-Term Refusal of Antipsychotic Treatment in 
First-Episode Psychosis." J. Clin. Psychopharmacol 30(5): 565-572. 
Lieberman, J. A., T. S. Stroup, J. P. McEvoy, M. S. Swartz, R. A. Rosenheck, D. O. Perkins, R. 
S. Keefe, S. M. Davis, C. E. Davis, B. D. Lebowitz, J. Severe and J. K. Hsiao (2005). 
"Effectiveness of antipsychotic drugs in patients with chronic schizophrenia." N Engl J Med 
353(12): 1209-1223. 
Nasrallah, H. A., J. M. Meyer, D. C. Goff, J. P. McEvoy, S. M. Davis, T. S. Stroup and J. A. 
Lieberman (2006). "Low rates of treatment for hypertension, dyslipidemia and diabetes in 
schizophrenia: data from the CATIE schizophrenia trial sample at baseline." Schizophr Res 86(1-
3): 15-22. 


 
 
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Posner, K., D. Brent, C. Lucas, M. Gould, B. Stanley, G. Brown, P. Fisher, J. Zelazny, A. Burke, 
M. Oquendo and J. Mann (2009). Columbia-Suicide Severity Rating Scale (C-SSRS): 
Baseline/Screening Version. New York, NY, New York State Psychiatric Institute. 
Posner, K., D. Brent, C. Lucas, M. Gould, B. Stanley, G. Brown, P. Fisher, J. Zelazny, A. Burke, 
M. Oquendo and J. Mann (2009). Columbia-Suicide Severity Rating Scale (C-SSRS): Since last 
visit. New York, NY, New York State Psychiatric Institute. 
Regier, D. A., M. E. Farmer, D. S. Rae, B. Z. Locke, S. J. Keith, L. L. Judd and F. K. Goodwin 
(1990). "Comorbidity of mental disorders with alcohol and other drug abuse. Results from the 
Epidemiologic Catchment Area (ECA) Study." JAMA 264(19): 2511-2518. 
Saha, S., D. Chant and J. McGrath (2007). "A systematic review of mortality in schizophrenia: is 
the differential mortality gap worsening over time?" Arch. Gen. Psychiatry 64(10): 1123-1131. 
Sheehan, D. V., Y. Lecrubier, K. H. Sheehan, P. Amorim, J. Janavs, E. Weiller, T. Hergueta, R. 
Baker and G. C. Dunbar (1998). "The Mini-International Neuropsychiatric Interview (M.I.N.I.): 
the development and validation of a structured diagnostic psychiatric interview for DSM-IV and 
ICD-10." J Clin Psychiatry 59 Suppl 20: 22-33. 
Simpson, G. M. and J. W. Angus (1970). "A rating scale for extrapyramidal side effects." Acta 
Psychiatr Scand Suppl 212: 11-19. 
Tiihonen, J., J. Lonnqvist, K. Wahlbeck, T. Klaukka, L. Niskanen, A. Tanskanen and J. Haukka 
(2009). "11-year follow-up of mortality in patients with schizophrenia: a population-based cohort 
study (FIN11 study)." Lancet 374(9690): 620-627. 


 
 
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20. 
APPENDICES 
Appendix A 
Partial list of prohibited cytochrome P450 (CYP) 3A4 inducers and moderate-
to-strong inhibitors 
Appendix B 
Clinical Global Impression 
• Severity 
− Structured Interview Guide for Global Impression (SIGGI) 
• Improvement 
Appendix C 
Modified Overt Aggression Scale 
Appendix D 
Positive and Negative Syndrome Scale 
Appendix E 
Abnormal Involuntary Movement Scale 
Appendix F 
Barnes Akathisia Rating Scale 
Appendix G 
Simpson-Angus Scale 
Appendix H 
Columbia-Suicide Severity Rating Scale 
• Baseline/ Screening 
• Since Last Visit 
 


 
 
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APPENDIX A. PARTIAL LIST OF PROHIBITED CYTOCHROME P450 
(CYP) 3A4 INDUCERS AND MODERATE-TO-STRONG 
INHIBITORS 
Partial List of CYP3A4 Inhibitors and Inducers (This is not an all-inclusive list.) 
Moderate to Strong CYP3A4 inhibitors: 
Partial List of Moderate to Strong CYP3A4 inducers: 
Amprenavir 
Bosentan 
Aprepitant 
Carbamazepine 
Atazanavir 
Efavirenz 
Boceprevir 
Etravirine 
Ciprofloxacin 
Modafinil 
Clarithromycin 
Nafcillin 
Conivaptan 
Nevirapine 
Crizotinib 
Phenobarbital 
Darunavir/ ritonavir 
Phenytoin 
Diltiazem 
Rifampin 
Erythromycin 
Rifabutin 
Fosamprenavir 
St. John’s Wort 
Fluconazole 
 
Imatinib 
 
Indinavir 
 
Itraconazole 
 
Ketoconazole 
 
Lopinavir/ ritonavir 
 
Nefazodone 
 
Nelfinavir 
 
Posaconazole 
 
Ritonavir 
 
Saquinavir 
 
Telaprenavir 
 
Telithromycin 
 
Troleandomycin 
 
Verapamil 
 
Voriconazole 
 


 
 
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CONFIDENTIAL 
 
APPENDIX B. CLINICAL GLOBAL IMPRESSION 
• Severity 
− Structured Interview Guide for Global Impression (SIGGI) 
• Improvement 


Clinical Global Impression – Severity of Illness and Improvement of 
Illness (CGI-S and CGI-I) 
 
Severity of Illness (CGI-S) 
Considering your total clinical experience with this particular population, how 
mentally ill is the patient at this time? 
0 = Not assessed 
1 = Normal, not at all ill 
2 = Borderline mentally ill 
3 = Mildly ill 
4 = Moderately ill 
5 = Markedly ill 
6 = Severely ill 
7 = Among the most extremely ill 
patients 
Global Improvement (CGI-I) 
Rate total improvement whether or not in your judgment it is due entirely to drug 
treatment.  Compared to his/her condition at admission, how much has he/she 
changed? 
0 = Not assessed 
1 = Very much improved 
2 = Much improved 
3 = Minimally improved 
4 = No change 
5 = Minimally worse 
6 = Much worse 
7 = Very much worse 
 
Reproduced from Guy W, editor. ECDEU Assessment Manual for Psychopharmacology. 
1976. Rockville, MD, U.S. Department of Health, Education, and Welfare 
SAMPLE


Source Document ALKERMES ALK3831-A305: SIGGI 
Rater Initials 
Time Performed (24 hours) 
Has the rater changed from the previous assessment? 
 
 
 
___ ___ : ___ ___ 
Yes □                         No □                         N/A □             
Site No. / Subject ID No. 
Date of Assessment (DD/MMM/YYYY) 
Visit No. 
 
 
 
 
 
 
 
 
 
___ ___/___ ___ ___/___ ___ ___ ___ 
 
 
 
SIGGI for ALK3831‐A305  
Version 2.0  
SIGGI Page 1 of 3 
Structured Interview Guide for Global Impression (SIGGI) 
ALK3831‐A305 
Clintara LLC, 2015 
Instructions for Raters 
This interview guide applies the clinical global impression of severity (CGI‐S) to explore the global impact of identified 
“targeted” symptoms of schizophrenia on behavior and function within the PAST SEVEN DAYS. In this study, subjects 
must meet DSM‐5 criteria for Schizophrenia and have moderate symptoms of schizophrenia that have at least a 
moderate impact on behavior and/or function overall. 
 
Generally, the  SIGGI  interview  follows  a  review  of  the  psychiatric history,  the  administration of  a symptomatic 
questionnaire that identifies current clinically relevant symptoms, and collection of any collateral information from 
reliable informants.  USE ALL AVAILABLE CLINICAL INFORMATION TO COMPLETE THIS FORM. 
 
The interview proceeds as follows: 
1. 
EXPLANATION: Explain the purpose of the interview and obtain the subjects consent to participate. 
2. 
SYMPTOM IDENTIFICATION: Inquire about (and/or confirm) the presence of relevant symptoms of 
Schizophrenia that have been present within the past week (PAST 7 DAYS). 
3. 
IMPACT ASSESSMENT: Inquire about the amount of current distress (if any) or interference that the 
specific “targeted” symptoms have caused for the subject in the past week (PAST 7 DAYS). 
4.  SCORE AND DOCUMENT: Using the scoring anchors provided, determine the most appropriate global 
score and provide written documentation to support the derived score. 
 
1. EXPLANATION AND CONSENT 
I’d like to ask you some questions about some of the symptoms that you have experienced within the past week. 
Some of these questions may have already been asked and others will be new questions. 
 
I’m interested in how much the symptoms that you’ve experienced in the past week have affected you at home, at 
work, at school, in your relationships with others, or while you pursue your usual interests or activities (such as 
hobbies). 
Is that okay with you? 
 
 
2. SYMPTOM IDENTIFICATION (focus on symptoms of schizophrenia)
Let’s begin by listing the most troubling symptoms that you have experienced within the past week (7 days).  Can you 
describe them?  How long have you had these symptoms (describe each specific symptom)?  SYMPTOM LISTING (Identify 
SYMPTOM and DURATION) 
 
1.   
 
Duration:   
 
 
2.   
 
Duration:   
 
 
3.   
 
Duration:   
 
 
4.   
 
Duration:   
 
 
5.   
 
Duration:   
 
 
NOTE TO RATER:  Please include any relevant symptoms identified from any other sources beyond this interview that may be 
present within the PAST SEVEN days. Summarize and confirm each symptom and its duration before proceeding 


Subject ID:______________ 
Visit:______________ 
Date:______________ 
SIGGI for ALK3831‐A305 
Version 2.0 
 SIGGI Page 2 of 3 
 
3. IMPACT ASSESSMENT 
A. Have any of these symptoms interfered with your ability to function? 
YES 
NO 
 
 
INQUIRE ABOUT RELEVANT ACTIVITIES: work, study, pursuit of hobbies or interests, participation in social events, 
or attending school. 
IF SUBJECT RESPONDS YES, ASK:  In what way have the symptoms interfered?  
DOCUMENT RESPONSES IN THE SUBJECT’S OWN WORDS (with examples): 
B. Have any of these symptoms interfered with your relationships? 
YES 
NO 
INQUIRE ABOUT: friendships, social or work relationships, and interactions with family members. 
IF SUBJECT RESPONDS YES, ASK:  In what way have the symptoms interfered with your relationships in the past week? 
DOCUMENT RESPONSES IN THE SUBJECT’S OWN WORDS (with examples): 
IF THE SUBJECT RESPONDS YES TO EITHER OF THE ABOVE IMPACT QUERIES (A or B), ASK THE FOLLOWING 
QUESTIONS: 
 
Regarding these symptoms, how troubling or distressing have these symptoms been for you? 
  Can you give me an example? DOCUMENT RESPONSES IN THE SUBJECT’S OWN WORDS (with examples): 
QUANTIFICATION (RATER: refer to queries A or B above) 
 
How many DAYS in the past week have these symptoms disturbed you or interfered with your behavior or 
function?   
days 
 
How much of the time during the day (or night) have these symptoms disturbed you or interfered with your 
behavior or function?   
 % 
4. SCORE AND DOCUMENT 
CGI SEVERITY ASSESSMENT:   
(1‐7) 
 
(use scoring guide/anchors provided for specific study/evaluation) 
 
PLEASE DOCUMENT BELOW THE JUSTIFICATION FOR DERIVED SCORE FROM ALL AVAILABLE CLINICAL DATA: 


Subject ID:______________ 
Visit:______________ 
Date:______________ 
SIGGI for ALK3831‐A305 
Version 2.0 
 SIGGI Page 3 of 3 
 
 
CGI‐S Scoring Guidelines 
 
1 
Normal, not at all 
ill 
Symptoms of disorder have not been present in the past seven days 
2 
Borderline 
mentally ill 
Subtle or suspected pathology present within the past seven days 
3 
Mildly ill 
Clearly established symptoms causing minimal, if any, distress for the subject or 
difficulty in social and occupational function can be documented within the past 
seven days 
4 
Moderately ill 
Overt symptoms causing noticeable, but modest, functional impairment or distress 
for the subject; 
 
Some symptoms may warrant adjustment of medication 
5 
Markedly ill 
Intrusive symptoms that distinctly impair social/occupational function or cause 
intrusive levels of distress for the subject; 
 
There is overt behavioral or social dysfunction that is obvious to others 
6 
Severely ill 
Disruptive pathology; behavior and function are frequently influenced by symptoms; 
Extent of overt dysfunction may require intervention from others 
7 
Among the most 
extremely ill 
patients 
Pathology drastically interferes in many life functions; patient may be hospitalized 
 


 
 
Alkermes, Inc. 
Protocol ALK3831-A305 v2.0 (Amendment 1.0) 
CONFIDENTIAL 
 
APPENDIX C. MODIFIED OVERT AGGRESSION SCALE 
Taken from: Kay SR, Wolkenfeld F, Murrill LM (1988) Profiles of aggression among 
psychiatric patients. I. Nature and prevalence. J Nerv Ment Dis 176:539-546 


546 
KAY et al. 
Association (p. 69-70). Wuhington. DC: American Psychiatric 
Press. 
' 
Tardiff K. Sweillam A (1980) Assault, suicide, and mental illness. 
Arch Gen P!1Ichiatry 37:164-169. 
Tardiff K. Sweillam A (1982) Assaultive behavior among chronic 
patients. Am J P3Ychiatry 139:212-215. 
Werner PO, Rose TL, Yesavage JA (1983a) Reliability, accuracy, 
and deeision-making strategy in clinical predictiolUl of imminent 
dangerousness. J Comult Clin Psychol 51:81&-825. 
Werner PO, Yesavage JA, BeekerJMT, et al (l983b) Hostile words 
and assaultive behavior on an acute inpatient psychiatric unit. J 
Ne"} Ment Dis 171:385-387. 
Yudofsky'SC. SilverJM. Jackson W, et al (1986) The Overt Aggres-
sion Scale for the objective rating of verbal and physical aggres-
sion. A.m J P3Ychiatry 143:3&-39. 
APPENDIX: MODIFIED OVERT AGGRESSION SCALE 
Patient's name 
Rater _______ _ 
Ward __ Shift __ Date ______ _ 
Hospital no. _ 
Sex _ 
Period of observation __ 
Directions: For each category of aggressive behavior, 
check the highest applicable rating point to describe 
the most serious act of aggression committed by the 
patient during the specified observation period. 
Verbal aggression. Verbal hostility, such as state-
ments or invectives that seek to inflict psychological 
harm on another through devaluation/degradation, and 
threats of physical attack. 
-_ O. No verbal aggression 
-_ 1. Shouts angrily, curses mildly, or makes 
personal insults 
-_ 2. Curses viciously, is severely insulting, has 
temper outbursts , 
-_ 3. Impulsively threatens violence toward oth-
ers or self 
__ 4. Threatens violence toward others or self 
repeatedly or deliberately (e.g., to gain 
money or sex) 
Aggression against property. Wanton and reckless de-
struction of ward paraphernalia or others' possessions. 
__ O. No aggression against property 
__ 1. Slams door angrily, rips clothing, urinates 
on floor 
__ 2. Throws objects down, kicks furniture, de-
o. ,_ faces walls 
__ 3. Breaks objects, smashes windows 
__ 4. Sets fires, throws objects dangerously 
Autoaggression. Physical injury toward oneself, such 
as self-mutilation or suicide attempt. 
__ O. No autoaggression 
__ 1. Picks or scratches skin, pulls out hair, hits 
self (without injury) 
__ 2. Bangs head, hits fists into walls, throws 
self on floor 
__ 3. Inflicts minor cuts, bruises, burns, or welts 
on self 
' 
__ 4. Inflicts major injury on self or makes a su-
icide attempt 
Physical aggression. Violent action intended to inflict 
pain, bodily harm, or death upon another. 
__ O. No physical aggression 
__ 1. Makes menacing gestures, swings at pe0-
ple, grabs at clothing 
__ 2. Strikes. kicks, pushes, scratches, pulls hair 
of others (without injury) 
__ 3. Attacks others, causing mild injury 
(bruises, sprains, welts, etc.) 
__ 4. Attacks others, causing serious injury 
(fracture, loss of teeth, deep cuts, loss of 
consciousness, etc.) 
Rating summary 
Scale 
Verbal aggression 
Aggression against 
property 
Autoaggression 
Physical aggression 
Total weighted score 
Scaled scare Weighted scare 
xl 
x2 = 
x3 
x4 
SAMPLE


 
 
Alkermes, Inc. 
Protocol ALK3831-A305 v2.0 (Amendment 1.0) 
CONFIDENTIAL 
 
APPENDIX D. POSITIVE AND NEGATIVE SYNDROME SCALE 


Lewis A. Opler, M.D., Ph.D.
Stanley R. Kay, Ph.D.
J.P. Lindenmayer, M.D., &
Abraham Fiszbein, M.D.
Structured Clinical Interview –
Positive and Negative
Syndrome Scale
S C I - P A N S S
SCI-PANSS
SAMPLE


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Copyright © 1992, 1999, Multi-Health Systems Inc. All rights reserved. In the U.S.A., P.O. Box 950, North Tonawanda, NY 14120-0950, 1-800-456-3003.
In Canada, 3770 Victoria Park Ave., Toronto, ON  M2H 3M6, 1-800-268-6011. Internationally, +1-416-492-2627. Fax, +1-416-492-3343 or 1-888-540-4484.
SAMPLE


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Copyright © 1992, 1999, Multi-Health Systems Inc. All rights reserved. In the U.S.A., P.O. Box 950, North Tonawanda, NY 14120-0950, 
In Canada, 3770 Victoria Park Ave., Toronto, ON  M2H 3M6, 
 Internationally, 
 Fax, 
Structured Clinical Interview for the Positive and Negative Syndrome Scale
SCI-PANSS
L. A. Opler, M.D., Ph.D.        S. R. Kay, Ph.D.        J. P. Lindenmayer, M.D.      A. Fiszbein, M.D.
Patient Name or ID: ______________________________________________________________________
Interviewer: ____________________________________________________   Date: _____ / _____ / _____
Data on “Lack of Spontaneity and Flow of Conversation” (N6),
“Poor Rapport” (N3), and “Conceptual Disorganization” (P2)
Hi, I’m ... We’re going to be spending the next 30 to 40 minutes talking about you and your reasons for being here. Maybe you
can start out by telling me something about yourself and your background?
(Instruction to interviewer: Allow at least 5 minutes for a non-directive phase serving to establish rapport in the context of an
overview before proceeding to the specific questions listed below.)
Data on “Anxiety” (G2)
1.
Have you been feeling worried or nervous in the past week? _________________________________
IF YES, skip to question 3. IF NO, continue.
2.
Would you say that you’re usually calm and relaxed? ______________________________________
IF YES, skip to question 8. IF NO, continue.
3.
What’s been making you feel nervous (worried, not calm, not relaxed)? ________________________
4.
Just how nervous (worried, etc.) have you been feeling? ____________________________________
5.
Have you been shaking at times, or has your heart been racing? ______________________________
6.
Do you get into a state of panic? _______________________________________________________
7.
Has your sleep, eating, or participation in activities been affected? ____________________________
Data on “Delusions (General)” (PI) and “Unusual Thought Content” (G9)
8.
Have things been going well for you? ___________________________________________________
9.
Has anything been bothering you lately? _________________________________________________
10.
Can you tell me something about your thoughts on life and its purpose? ________________________
SAMPLE
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Copyright © 1992, 1999, Multi-Health Systems Inc. All rights reserved. In the U.S.A., P.O. Box 950, North Tonawanda, NY 14120-0950, 
In Canada, 3770 Victoria Park Ave., Toronto, ON  M2H 3M6, 
 Internationally, 
 Fax, 
11.
Do you follow a particular philosophy (any special rules, teachings, or religious doctrine)? ____________
12.
Some people tell me they believe in the Devil; what do you think? ____________________________
IF NO (i.e., he/she doesn’t believe in the Devil), skip to question 14.
IF YES (i.e., he/she does believe), continue.
13.
Can you tell me more about this?_______________________________________________________
14.
Can you read other people’s minds? ____________________________________________________
IF NO, skip to question 16. IF YES, continue.
15.
How does that work? ________________________________________________________________
16.
Can others read your mind? ___________________________________________________________
IF NO, skip to question 19. IF YES, continue.
17.
How can they do that? _______________________________________________________________
18.
Is there any reason that someone would want to read your mind? _____________________________
19.
Who controls your thoughts? __________________________________________________________
Data on “Suspiciousness/Persecution” (P6) and “Poor Impulse Control” (GI4)
20.
How do you spend your time these days? ________________________________________________
21.
Do you prefer to be alone? ____________________________________________________________
22.
Do you join in activities with others? ___________________________________________________
IF YES, skip to question 25. IF NO, continue.
23.
Why not? ... Are you afraid of people, or do you dislike them? _______________________________
IF NO, skip to question 26. IF YES, continue.
24.
Can you explain?
__________________________________________________________________
Skip to question 26.
25.
Tell me about it.
__________________________________________________________________
26.
Do you have many friends? ___________________________________________________________
IF YES, skip to question 30. IF NO, continue.
27.
Just a few?
__________________________________________________________________
IF YES, skip to question 29. IF NO, continue.
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Copyright © 1992, 1999, Multi-Health Systems Inc. All rights reserved. In the U.S.A., P.O. Box 950, North Tonawanda, NY 14120-0950, 
In Canada, 3770 Victoria Park Ave., Toronto, ON  M2H 3M6, 
 Internationally, 
 Fax, 
28.
Any? .... Why?
__________________________________________________________________
Skip to question 32.
29.
Why just a few friends? ______________________________________________________________
30.
Close friends?
__________________________________________________________________
IF YES, skip to question 32. IF NO, continue.
31.
Why not?
__________________________________________________________________
32.
Do you feel that you can trust most people? ______________________________________________
IF YES, skip to question 34. IF NO, continue.
33.
Why not?
__________________________________________________________________
34.
Are there some people in particular who you don’t trust? ____________________________________
IF NO to question 34 and YES to question 32, skip to question 41.
IF NO to question 34 and NO to question 32, skip to question 36.
IF YES to question 34, continue.
35.
Can you tell me who they are? _________________________________________________________
36.
Why don’t you trust people (or name specific person)? _____________________________________
IF “DON’T KNOW” OR “DON’T WANT TO SAY,” continue. Otherwise, skip to question 41.
37.
 Do you have a good reason not to trust ...?
               ______________________________________________________________________________
38.
Is there something that .... did to you? ___________________________________________________
39.
Perhaps something that ... might do to you now? __________________________________________
IF NO, skip to question 41. IF YES, continue.
40.
Can you explain to me? ______________________________________________________________
41.
Do you get along well with others? _____________________________________________________
IF YES, skip to question 43. IF NO, continue.
42.
What’s the problem? ________________________________________________________________
43.
Do you have a quick temper? __________________________________________________________
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Copyright © 1992, 1999, Multi-Health Systems Inc. All rights reserved. In the U.S.A., P.O. Box 950, North Tonawanda, NY 14120-0950, 
In Canada, 3770 Victoria Park Ave., Toronto, ON  M2H 3M6, 
 Internationally, 
 Fax, 
44.
Do you get into fights? _______________________________________________________________
IF NO, skip to question 48. IF YES, continue.
45.
How do these fights start? ____________________________________________________________
46.
Tell me about these fights. ____________________________________________________________
47.
How often does this happen? __________________________________________________________
48.
Do you sometimes lose control of yourself? ______________________________________________
IF NO, skip to question 50. IF YES, continue.
49.
What happens when you lose control of yourself? _________________________________________
50.
Do you like most people? _____________________________________________________________
IF YES, skip to question 52. IF NO, continue.
51.
Why not?
__________________________________________________________________
52.
Are there perhaps some people who don’t like you? ________________________________________
IF NO, skip to question 54. IF YES, continue.
53.
For what reason?
__________________________________________________________________
54.
Do others talk about you behind your back? ______________________________________________
IF NO, skip to question 57. IF YES, continue.
55.
What do they say about you? __________________________________________________________
56.
Why?_____________________________________________________________________________
57.
Does anyone ever spy on you or plot against you? _________________________________________
58.
Do you sometimes feel in danger? ______________________________________________________
IF NO, skip to question 64. IF YES, continue.
59.
Would you say that your life is in danger? _______________________________________________
60.
Is someone thinking of harming you or even perhaps thinking of killing you? ___________________
61.
Have you gone to the police for help? ___________________________________________________
62.
Do you sometimes take matters into your own hands or take action against those who might harm you?
__________________________________________________________________________________
IF NO, skip to question 64. IF YES, continue.
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Copyright © 1992, 1999, Multi-Health Systems Inc. All rights reserved. In the U.S.A., P.O. Box 950, North Tonawanda, NY 14120-0950, 
In Canada, 3770 Victoria Park Ave., Toronto, ON  M2H 3M6, 
 Internationally, 
 Fax, 
63.
What have you done? ________________________________________________________________
Data on “Hallucinatory Behavior” (P3) and associated delusions
64.
Do you once in a while have strange or unusual experiences? ________________________________
65.
Sometimes people tell me that they can hear noises or voices inside their head that others can’t hear.
What about you?
__________________________________________________________________
IF YES, skip to question 68. IF NO, continue.
66.
Do you sometimes receive personal communications from the radio or TV? _____________________
IF YES, skip to question 68. IF NO, continue.
67.
From God or the Devil?: _____________________________________________________________
IF NO, skip to question 83. IF YES, continue.
68.
What do you hear? __________________________________________________________________
69.
Are these as clear and loud as my voice?_________________________________________________
70.
How often do you hear these voices, noises, messages, etc.? _________________________________
71.
Does this happen at a particular time of day or all the time? __________________________________
IF HEARING NOISES ONLY, skip to question 80. IF HEARING VOICES, continue.
72.
Can you recognize whose voices these are? ______________________________________________
73.
What do the voices say? ______________________________________________________________
74.
Are the voices good or bad? ___________________________________________________________
75.
Pleasant or unpleasant? ______________________________________________________________
76.
Do the voices interrupt your thinking or your activities? ____________________________________
77.
Do they sometimes give you orders or instructions? ________________________________________
IF NO, skip to question 80. IF YES, continue.
78.
For example?
__________________________________________________________________
79.
Do you usually obey these orders (instructions)? __________________________________________
80.
What do you make of these voices (or noises); where do they really come from? _________________
81.
Why do you have these experiences?____________________________________________________
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Copyright © 1992, 1999, Multi-Health Systems Inc. All rights reserved. In the U.S.A., P.O. Box 950, North Tonawanda, NY 14120-0950, 
In Canada, 3770 Victoria Park Ave., Toronto, ON  M2H 3M6, 
 Internationally, 
 Fax, 
82.
Are these normal experiences?_________________________________________________________
83.
Do ordinary things sometimes look strange or distorted to you?_______________________________
84.
Do you sometimes have “visions” or see things that others can’t see? __________________________
IF NO, skip to question 88. IF YES, continue.
85.
For example?
__________________________________________________________________
86.
Do these visions seem very real or life-like? ______________________________________________
87.
How often do you have these experiences? _______________________________________________
88.
Do you sometimes smell things that are unusual or that others don’t smell? _____________________
IF NO, skip to question 90. IF YES, continue.
89.
Please explain.
__________________________________________________________________
90.
Do you get any strange or unusual sensations from your body? _______________________________
IF NO, skip to question 92. IF YES, continue.
91.
Tell me about this. __________________________________________________________________
Data on “Somatic Concern” (GI)
92.
How have you been feeling in terms of your health?________________________________________
IF OTHER THAN “GOOD,” skip to question 94. IF “GOOD,” continue.
93.
Do you consider yourself to be in top health? _____________________________________________
IF YES, skip to question 95. IF NO, continue.
94.
What has been troubling you? _________________________________________________________
95.
Do you have any medical illness or disease? ______________________________________________
96.
Has any part of your body been troubling you? ____________________________________________
IF YES, skip to question 98. IF NO, continue.
97.
How is your head?  Your heart?  Stomach?  The rest of your body? ___________________________
98.
Could you explain?__________________________________________________________________
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Copyright © 1992, 1999, Multi-Health Systems Inc. All rights reserved. In the U.S.A., P.O. Box 950, North Tonawanda, NY 14120-0950, 
In Canada, 3770 Victoria Park Ave., Toronto, ON  M2H 3M6, 
 Internationally, 
 Fax, 
99.
Has your head or body changed in shape or size? __________________________________________
IF NO, skip to question 102. IF YES, continue.
100. Please explain.
__________________________________________________________________
101. What is causing these changes? ________________________________________________________
Data on “Depression” (G6)
102. How has your mood been in the past week: mostly good, mostly bad? _________________________
IF “MOSTLY BAD,” skip to question 104. IF “MOSTLY GOOD,” continue.
103. Have there been times in the past week when you were feeling sad or unhappy? _________________
IF NO, skip to question 114. IF YES, continue.
104.  Is there something in particular that is making you sad? ____________________________________
105. How often do you feel sad? ___________________________________________________________
106. Just how sad have you been feeling? ____________________________________________________
107. Have you been crying lately? __________________________________________________________
108. Has your mood in any way affected your sleep? ___________________________________________
109. Has it affected your appetite?__________________________________________________________
110. Do you participate less in activities on account of your mood? _______________________________
111. Have you had any thoughts of harming yourself? __________________________________________
IF NO, skip to question 114. IF YES, continue.
112. Any thoughts about ending your life? ___________________________________________________
IF NO, skip to question 114. IF YES, continue.
113. Have you attempted suicide? __________________________________________________________
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Copyright © 1992, 1999, Multi-Health Systems Inc. All rights reserved. In the U.S.A., P.O. Box 950, North Tonawanda, NY 14120-0950, 
In Canada, 3770 Victoria Park Ave., Toronto, ON  M2H 3M6, 
 Internationally, 
 Fax, 
Data on “Guilt Feelings” (G3) and “Grandiosity” (P5)
114. If you were to compare yourself to the average person, how would you come out: a little better, maybe
a little worse, or about the same? _______________________________________________________
IF “BETTER,” skip to question 117.
IF “ABOUT THE SAME,” skip to question 118.
IF “WORSE,” continue.
115. Worse in what ways? ________________________________________________________________
116. Just how do you feel about yourself? ____________________________________________________
Skip to question 120.
117. Better in what ways? ________________________________________________________________
Skip to question 120.
118. Are you special in some ways? ________________________________________________________
IF NO, skip to question 120. IF YES, continue.
119. In what ways?
__________________________________________________________________
120. Would you consider yourself gifted? ____________________________________________________
121. Do you have talents or abilities that most people don’t have?_________________________________
IF NO, skip to question 123. IF YES, continue.
122. Please explain.
__________________________________________________________________
123. Do you have any special powers? ______________________________________________________
IF NO, skip to question 126. IF YES, continue.
124. What are these?
__________________________________________________________________
125. Where do these powers come from? ____________________________________________________
126. Do you have extrasensory perception (ESP), or can you read other people’s minds?_______________
127. Are you very wealthy? _______________________________________________________________
IF NO, skip to question 129. IF YES, continue.
128. Explain please.
__________________________________________________________________
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SCI–PANSS BOOKLET
PAGE 11
Copyright © 1992, 1999, Multi-Health Systems Inc. All rights reserved. In the U.S.A., P.O. Box 950, North Tonawanda, NY 14120-0950, 
In Canada, 3770 Victoria Park Ave., Toronto, ON  M2H 3M6, 
 Internationally, 
 Fax, 
129. Can you be considered to be very bright? ________________________________________________
IF NO, skip to question 131. IF YES, continue.
130. Why would you say so? ______________________________________________________________
131. Would you describe yourself as famous?_________________________________________________
132. Would some people recognize you from TV, radio, or the newspaper? _________________________
IF NO, skip to question 134. IF YES, continue.
133. Can you tell me about it? _____________________________________________________________
134. Are you a religious person? ___________________________________________________________
IF NO, skip to question 140. IF YES, continue.
135. Are you close to God? _______________________________________________________________
IF NO, skip to question 140. IF YES, continue.
136. Did God assign you some special role or purpose? _________________________________________
137. Can you be one of God’s messengers or angels? ___________________________________________
IF NO, skip to question 139. IF YES, continue.
138. What special powers do you have as God’s messenger (angel)? _______________________________
139. Do you perhaps consider yourself to be God? _____________________________________________
140. Do you have some special mission in life? _______________________________________________
IF NO, skip to question 143. IF YES, continue.
141. What is your mission? _______________________________________________________________
142. Who assigned you to that mission? _____________________________________________________
143. Did you ever do something wrong — something you feel bad or guilty about? ___________________
IF NO, skip to question 149. IF YES, continue.
144. Just how much does that bother you now?________________________________________________
145. Do you feel that you deserve punishment for that? _________________________________________
IF NO, skip to question 149. IF YES, continue.
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PAGE 12
Copyright © 1992, 1999, Multi-Health Systems Inc. All rights reserved. In the U.S.A., P.O. Box 950, North Tonawanda, NY 14120-0950, 
In Canada, 3770 Victoria Park Ave., Toronto, ON  M2H 3M6, 
 Internationally, 
 Fax, 
146. What kind of punishment would you deserve? ____________________________________________
147. Have you at times thought of punishing yourself?__________________________________________
IF NO, skip to question 149. IF YES, continue.
148. Have you ever acted on those thoughts of punishing yourself? ________________________________
 Data on “Disorientation” (GlO)
149. Can you tell me today’s date (i.e., the day, month, and year)? ________________________________
IF YES, skip to question 151. IF NO, continue.
150. Can you tell me what day of the week it is? ______________________________________________
151. What is the name of the place that you are in now?_________________________________________
IF NOT HOSPITALIZED, skip to question 154. IF HOSPITALIZED, continue.
152. What ward are you on?_______________________________________________________________
153. What is the address of where you’re now staying? _________________________________________
IF ABLE TO TELL, skip to question 155. IF NOT ABLE TO TELL, continue.
154. Can you tell me your home address? ____________________________________________________
IF NOT HOSPITALIZED, skip to question 156. IF HOSPITALIZED, continue.
155. If someone had to reach you by phone, what number would that person call? ____________________
156. If someone had to reach you at home, what number would that person call? _____________________
157. What is the name of the doctor who is treating you? ________________________________________
IF NOT HOSPITALIZED, skip to question 159. IF HOSPITALIZED, continue.
158. Can you tell me who else is on the staff and what they do? __________________________________
159. Do you know who is currently the president (prime minister, etc.)? ____________________________
160. Who is our governor (premier, etc.)? ____________________________________________________
161. Who is the mayor (town supervisor, etc.) of this city (town, etc.)? _____________________________
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SCI–PANSS BOOKLET
PAGE 13
Copyright © 1992, 1999, Multi-Health Systems Inc. All rights reserved. In the U.S.A., P.O. Box 950, North Tonawanda, NY 14120-0950, 
In Canada, 3770 Victoria Park Ave., Toronto, ON  M2H 3M6, 
 Internationally, 
 Fax, 
Data on “Difficulty in Abstract Thinking” (N5)
I’m going to now say a pair of words, and I’d like you to tell me in what important way they’re alike.  Let’s start, for example, with the words
“apple” and “banana.” How are they alike — what do they have in common? IF THE RESPONSE IS THAT “THEY’RE BOTH FRUIT”,
THEN SAY:  Good.  Now what about ...?  (Select three other items from the Similarities list at varying levels of difficulty from Appendix A.)
IF AN ANSWER IS GIVEN THAT IS CONCRETE, TANGENTIAL, OR IDIOSYNCRATIC (E.G., “THEY BOTH HAVE SKINS,”
“YOU CAN EAT THEM,” “THEY’RE SMALL,” OR “MONKEYS LIKE THEM”), THEN SAY:  OK, but they’re both fruit.  Now
how about ... and ... : how are these alike?  (Select three other items from the Similarities list at varying levels of difficulty from Appendix A.)
APPENDIX A
Items for Similarities in the evaluation of “Difficulty in Abstract Thinking”
1. How are a ball and an orange alike?
2. Apple and banana ?
3. Pencil and pen?
4. Nickel and dime?
     ______________
5. Table and chair?
6. Tiger and elephant?
7. Hat and shirt?
8. Bus and train?
     ______________
9.  Arm and leg?
10. Rose and tulip?
11. Uncle and cousin?
12. The sun and the moon?
      _______________
13. Painting and poem?
14. Hilltop and valley?
15. Air and water?
16. Peace and prosperity?
You’ve probably heard the expression, “Carrying a chip on the shoulder.” What does that really mean? There’s a very old saying,
“Don’t judge a book by its cover.” What is the deeper meaning of this proverb? (Select two other proverbs from the list in Appendix
B at varying levels of difficulty.)
APPENDIX B
Items for assessing PROVERB INTERPRETATION in the evaluation of “Difficulty in Abstract Thinking”
What does the saying mean:
1. “Plain as the nose on your face”
2. “Carrying a chip on your shoulder”
3. “Two heads are better than one”
4. “Too many cooks spoil the broth”
      ___________________
5. “Don’t judge a book by its cover”
6. “One man’s food is another man’s poison”
7. “All that glitters is not gold”
8. “Don’t cross the bridge until you come to it”
     ____________________
9.  “What’s good for the goose is good for the gander”
10. “The grass always looks greener on the other side”
11. “Don’t keep all your eggs in one basket”
12. “One swallow does not make a summer”
     ____________________
13. “A stitch in time saves nine”
14. “A rolling stone gathers no moss”
15. “The acorn never falls far from the tree”
16. “People who live in glass houses should not throw stones at others”
Note on Appendix A: Similarities are generally assessed by sampling
four items at different levels of difficulty (i.e., one item selected from
each quarter of the full set). When using the PANSS longitudinally,
items should be systematically altered with successive interviews so
as to provide different selections from the various levels of difficulty
and thus minimize repetition.
Notes on Similarities responses:
________________________________________________
________________________________________________
________________________________________________
________________________________________________
Circle the Similarities Used
Note on Appendix B: Proverb interpretation is generally assessed by
sampling four items at different levels of difficulty (i.e., one item
selected from each quarter of the full set). When using the PANSS
longitudinally, items should be systematically altered with succes-
sive interviews so as to provide different selections from the various
levels of difficulty and thus minimize repetition.
Notes on Proverb responses:
________________________________________________
________________________________________________
________________________________________________
________________________________________________
Circle the Proverbs Used
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PAGE 14
Copyright © 1992, 1999, Multi-Health Systems Inc. All rights reserved. In the U.S.A., P.O. Box 950, North Tonawanda, NY 14120-0950, 
In Canada, 3770 Victoria Park Ave., Toronto, ON  M2H 3M6, 
 Internationally, 
 Fax, 
Data on “Lack of Judgment and Insight” (G12)
162. How long have you been in the hospital (clinic, etc.)?__________________________________________
163. Why did you come to the hospital (clinic, etc.)? ___________________________________________
164. Did you need to be in a hospital (clinic, etc.)? _____________________________________________
IF YES, skip to question 167. IF NO, continue.
165. Did you have a problem that needed treatment? ___________________________________________
IF NO, skip to question 169. IF YES, continue.
166. Would you say that you had a psychiatric or mental problem? ________________________________
IF NO, skip to question 169. IF YES, continue.
167. Why?....would you say that you had a psychiatric or mental problem? _________________________
IF NO, skip to question 169. IF YES, continue.
168. Can you tell me about it and what it consisted of? _________________________________________
169. In your own opinion, do you need to be taking medicine? ___________________________________
IF YES, skip to question 171.
IF NO and unmedicated, skip to question 172.
IF NO and medicated, continue.
170. Why then are you taking medicines? ____________________________________________________
Skip to question 172.
171. Why?... Does the medicine help you in any way? __________________________________________
172. Do you at this time have any psychiatric or mental problems? ________________________________
IF YES, skip to question 174. IF NO, continue.
173. For what reason are you at the hospital (clinic, etc.)? _______________________________________
Skip to question 175.
174. Please explain
__________________________________________________________________
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PAGE 15
Copyright © 1992, 1999, Multi-Health Systems Inc. All rights reserved. In the U.S.A., P.O. Box 950, North Tonawanda, NY 14120-0950, 
In Canada, 3770 Victoria Park Ave., Toronto, ON  M2H 3M6, 
 Internationally, 
 Fax, 
175. Just how serious are these problems? _____________________________________________________
IF UNHOSPITALIZED, skip to question 178.
IF HOSPITALIZED, continue.
176. Are you ready yet for discharge from the hospital? _________________________________________
177. Do you think you’ll be taking medicine for your problems after discharge? _____________________
178. What are your future plans? ___________________________________________________________
179. What about your longer-range goals? ___________________________________________________
Well, that’s about all I have to ask of you now.  Are there any questions that you might like to ask of me?
Thank you for your cooperation.
SAMPLE
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Multi-Health Systems Inc.
In the U.S.A...
P.O. Box 950
North Tonawanda, NY 14120-0950
In Canada...
3770 Victoria Park Avenue
Toronto, ON  M2H 3M6
Local and International: 
Fax: 
www.mhs.com
SAMPLE
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Alkermes, Inc. 
Protocol ALK3831-A305 v2.0 (Amendment 1.0) 
CONFIDENTIAL 
 
APPENDIX E. ABNORMAL INVOLUNTARY MOVEMENT SCALE 


 
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


 
 
Alkermes, Inc. 
Protocol ALK3831-A305 v2.0 (Amendment 1.0) 
CONFIDENTIAL 
 
APPENDIX F. BARNES AKATHISIA SCALE 


 
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


 
 
Alkermes, Inc. 
Protocol ALK3831-A305 v2.0 (Amendment 1.0) 
CONFIDENTIAL 
 
APPENDIX G. SIMPSON-ANGUS SCALE 


Modified from: Simpson GM, Angus JWS: A rating scale for 
extrapyramidal side effects. Acta Psychiatrica Scandinavica 212:11-19, 
1970. Revised 
Clintara Version 1.5 June, 2011 
 
Page 1 of 3 
 
SIMPSON ANGUS RATING SCALE  
 
Circle the appropriate score for each item
 
: 
1. 
GAIT 
The patient is examined as he walks into the examining room: his gait, the swing of arms, his 
general posture; all form the basis for an overall score for this item. This is rated as follows: 
0 
Normal 
1 
Mild diminution in swing while the patient is walking 
2 
Obvious diminution in swing suggesting shoulder rigidity 
3 
Stiff gait with little or no arm swing noticeable 
4 
Rigid gait with arms slightly pronated; or stopped-shuffling gait with propulsion and retropulsion 
2. 
ARM DROPPING 
The patient and the examiner both raise their arms to shoulder height and let them fall to their 
sides. In a normal subject a stout slap is heard as the arms hit the sides. In the patient with 
extreme Parkinson’s syndrome, the arms fall very slowly. 
0 
Normal, free fall with loud slap and rebound 
1 
Fall slowed slightly with less audible contact and little rebound 
2 
Fall slowed, no rebound 
3 
Marked slowing, no slap at all 
4 
Arms fall as though against resistance; as though through glue 
3. 
SHOULDER SHAKING 
The subject’s arms are bent at a right angle at the elbow and are taken one at a time by the 
examiner who grabs one hand and also clasps the other around the patient’s elbow. The subject’s 
upper arm is pushed to and fro and the humerus is externally rotated. The degree of resistance 
from normal to extreme rigidity is scored as follows: 
0 
Normal 
1 
Slight stiffness and resistance 
2 
Moderate stiffness and resistance 
3 
Marked rigidity with difficulty in passive movement 
4 
Extreme stiffness and rigidity with almost a frozen joint 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
SAMPLE


Subject ID No.________    Visit No.________ 
Modified from: Simpson GM, Angus JWS: A rating scale for 
extrapyramidal side effects. Acta Psychiatrica Scandinavica 212:11-19, 
1970. Revised 
Clintara Version 1.6 June, 2011 
 
Page 2 of 3 
4. 
ELBOW RIGIDITY 
The elbow joints are separately bent at right angles and passively extended and flexed, with the 
subject’s biceps observed and simultaneously palpated. The resistance to this procedure is rated. 
(The presence of cogwheel rigidity is noted separately.) 
0 
Normal 
1 
Slight stiffness and resistance 
2 
Moderate stiffness and resistance 
3 
Marked rigidity with difficulty in passive movement 
4 
Extreme stiffness and rigidity with almost a frozen joint 
5. 
WRIST RIGIDITY OR FIXATION OF POSITION 
The wrist is held in one hand and then the fingers held by the examiner’s other hand with the wrist 
moved to extension, and both ulnar and radial deviation. The resistance to this procedure is rated: 
 
0 
Normal 
1 
Slight stiffness and resistance 
2 
Moderate stiffness and resistance 
3 
Marked rigidity with difficulty in passive movement 
4 
Extreme stiffness and rigidity with almost a frozen joint 
6. 
LEG PENDULOUSNESS 
The patient sits on a table with his legs hanging down and swinging free. The ankle is grasped by 
the examiner and raised until the knee is partially extended. It is then allowed to fall. The 
resistance to falling and the lack of swinging form the basis for the score on this item: 
0 
The legs swing freely 
1 
Slight diminution in the swing of the legs 
2 
Moderate resistance to swing 
3 
Marked resistance and damping of swing 
4 
Complete absence of swing 
7. 
HEAD ROTATION 
The patient sits or stands and is told that you are going to move his head side to side, that it will 
not hurt and that he should try and relax. (Questions about pain in the cervical area or difficulty in 
moving his head should be obtained to avoid causing any pain.) Clasp the patient’s head between 
the two hands with fingers on back of the neck. Gently rotate the head in a circular motion 3 times 
and evaluate the muscular resistance to the movement. 
0 
Loose, no resistance 
1 
Slight resistance to movement although the time to rotate may be normal 
2 
Resistance is apparent and time of rotation is slowed 
3 
Resistance is obvious and rotation is slowed 
4 
Head appears stiff and rotation is difficult to carry out 
 
 
 
 
SAMPLE


Subject ID No.________    Visit No.________ 
Modified from: Simpson GM, Angus JWS: A rating scale for 
extrapyramidal side effects. Acta Psychiatrica Scandinavica 212:11-19, 
1970. Revised 
Clintara Version 1.6 June, 2011 
 
Page 3 of 3 
8. 
GLABELLA TAP 
Subject is told to open his eyes and not to blink. The glabella region is tapped at a steady, rapid 
speed. The number of times patient blinks in succession is noted: 
0 
0-5 blinks 
1 
6-10 blinks 
2 
11-15 blinks 
3 
16-20 blinks 
4 
21 and more blinks 
9. 
TREMOR 
Patient is observed walking into examining room and then is examined for this item: 
0 
Normal 
1 
Mild finger tremor, obvious to sight and touch 
2 
Tremor of hand or arm occurring spasmodically 
3 
Persistent tremor of one or more limbs 
4 
Whole body tremor 
10. 
SALIVATION 
Patient is observed while talking and then asked to open his mouth and elevate his tongue. The 
following ratings are given: 
0 
Normal 
1 
Excess salivation so that pooling takes place if the mouth is open and the tongue raised 
2 
Excess salivation is present and might occasionally result in difficulty in speaking 
3 
Speaking with difficulty because of excess salivation 
4 
Frank drooling 
 
 
Rater Signature: _______________________ 
Date: _________________________ 
 
 
 
SAMPLE


 
 
Alkermes, Inc. 
Protocol ALK3831-A305 v2.0 (Amendment 1.0) 
CONFIDENTIAL 
 
APPENDIX H. COLUMBIA-SUICIDE SEVERITY RATING SCALE 
• Baseline/Screening 
• Since Last Visit 


 
 
 
 
 
 
 
 
 
COLUMBIA-SUICIDE SEVERITY 
RATING SCALE 
(C-SSRS)  
Baseline/Screening Version 
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
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SUICIDAL IDEATION 
Ask questions 1 and 2.  If both are negative, proceed to “Suicidal Behavior” section. If the answer to 
question 2 is “yes,” ask questions 3, 4 and 5.  If the answer to question 1 and/or 2 is “yes”, complete 
“Intensity of Ideation” section below. 
Lifetime: Time 
He/She Felt 
Most Suicidal 
Past __ 
Months 
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 
□    □ 
 
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 
   □    □ 
 
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 
 □    □ 
 
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 
□    □ 
 
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 
 □    □ 
 
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 ). For prior to study entry, ask about time he/she was feeling the most 
suicidal.  
                                   
Lifetime -           Most Severe Ideation:  _______                  ________________________________________ 
                                                                       Type # (1-5)                                                 Description of  Ideation 
 
Past X Months - Most Severe Ideation:  _______                   ________________________________________ 
                                                                      Type # (1-5)                                                 Description of  Ideation 
Most  
Severe 
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


SUICIDAL BEHAVIOR 
(Check all that apply, so long as these are separate events; must ask about all types) 
Lifetime 
Past __ 
Years 
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 
□   □ 
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 
 
______ 
 
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 
 
______ 
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 
□   □ 
 
 
Yes     No 
□   □ 
Suicidal Behavior: 
Suicidal behavior was present during the assessment period? 
Yes      No 
□   □ 
Yes     No 
□   □ 
Answer for Actual Attempts Only 
Most Recent 
Attempt 
Date: 
Most Lethal        
Attempt 
Date: 
Initial/First 
Attempt 
Date: 
Actual Lethality/Medical Damage:   
0.  No physical damage or very minor physical damage (e.g. surface scratches). 
1.  Minor physical damage (e.g. lethargic speech; first-degree burns; mild bleeding; sprains). 
2.  Moderate physical damage; medical attention needed (e.g. conscious but sleepy, somewhat responsive; second-degree 
burns; bleeding of major vessel). 
3.  Moderately severe physical damage; medical hospitalization and likely intensive care required (e.g. comatose with reflexes 
intact; third-degree burns less than 20% of body; extensive blood loss but can recover; major fractures). 
4.  Severe physical damage; medical hospitalization with intensive care required (e.g. comatose without reflexes; third-degree 
burns over 20% of body; extensive blood loss with unstable vital signs; major damage to a vital area). 
5.  Death 
 
Enter Code 
 
 
 
______ 
 
 
 
 
Enter Code 
 
 
 
______ 
 
 
 
 
Enter Code 
 
 
 
______ 
 
 
 
Potential Lethality: Only Answer if Actual Lethality=0 
Likely lethality of actual attempt if no medical damage (the following examples, while having no actual medical damage, had 
potential for very serious lethality: put gun in mouth and pulled the trigger but gun fails to fire so no medical damage; laying 
on train tracks with oncoming train but pulled away before run over). 
 
0 = Behavior not likely to result in injury 
1 = Behavior likely to result in injury but not likely to cause death 
2 = Behavior likely to result in death despite available medical care 
 
Enter Code 
 
 
 
______ 
 
 
Enter Code 
 
 
 
______ 
 
 
Enter Code 
 
 
 
______ 
 
SAMPLE


 
 
 
 
 
 
 
 
 
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
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


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

SAP_001.pdf: 
A Phase 3 Study to Determine the Antipsychotic Efficacy 
and Safety of ALKS 3831 in Adult Subjects with Acute 
Exacerbation of Schizophrenia 
 
 
Unique Protocol ID: 
ALK3831-A305 
NCT Number: 
NCT02634346 
EudraCT Number:  
2015-003373-15 
Date of Statistical Analysis 
Plan:  
23 June 2017 
 


 
 
 
 
 
STATISTICAL ANALYSIS PLAN 
 
ALK3831-A305 
 
Study Title: 
A Phase 3 Study to Determine the Antipsychotic Efficacy and Safety of 
ALKS 3831 in Adult Subjects with Acute Exacerbation of Schizophrenia 
Document Status: 
Final Version 1.0 
Document Date: 
23 June 2017 
Based on: 
ALK3831-A305 Protocol Amendment 1.0 Date: 22 September 2016 
Sponsor: 
Alkermes, Inc. 
852 Winter Street 
Waltham, MA 02451 
USA 
 
 
 
 
 
CONFIDENTIAL 
Information and data in this document contain trade secrets and privileged or confidential information, 
which is the property of Alkermes, Inc. No person is authorized to make it public without the written 
permission of Alkermes, Inc. These restrictions or disclosures will apply equally to all future information 
supplied to you that is indicated as privileged or confidential. This study is being conducted in 
compliance with good clinical practice, including the archiving of essential documents. 


Alkermes, Inc. 
 
Statistical Analysis Plan-ALK3831 - A305 
Final Version 1.0 
 
 
Page 2 of 24 
 
TABLE OF CONTENTS 
ABBREVIATIONS .........................................................................................................................5 
1. 
INTRODUCTION ........................................................................................................7 
1.1. 
Study Objectives ...........................................................................................................7 
1.1.1. 
Primary objective ..........................................................................................................7 
1.1.2. 
Secondary objective ......................................................................................................7 
1.2 
Summary of the Study Design ......................................................................................7 
2. 
SAMPLE SIZE CONSIDERATION ............................................................................8 
3. 
DATA ANALYSIS ......................................................................................................9 
3.1. 
General Statistical Methodology ..................................................................................9 
3.2. 
Definitions of Analysis Populations .............................................................................9 
3.2.1. 
Safety Population ..........................................................................................................9 
3.2.2. 
Efficacy Population ......................................................................................................9 
3.3. 
Disposition ....................................................................................................................9 
3.4. 
Protocol Deviation ........................................................................................................9 
3.5. 
Demographics and Baseline Characteristics ...............................................................10 
3.6. 
Prior and Concomitant Medication .............................................................................10 
3.7. 
Treatment Adherence Rate and Extent of Exposure ...................................................10 
3.7.1. 
Treatment Adherence Rate .........................................................................................10 
3.7.2. 
Duration of Study Drug Administration .....................................................................10 
3.8. 
Efficacy Analyses .......................................................................................................11 
3.8.1. 
General Considerations ...............................................................................................11 
3.8.2. 
Primary Efficacy Endpoint .........................................................................................11 
3.8.2.1. 
Primary Analysis ........................................................................................................11 
3.8.2.2. 
Sensitivity Analysis ....................................................................................................11 
3.8.2.3. 
Examination of Subgroups .........................................................................................12 
3.8.3. 
Key Secondary Endpoint ............................................................................................12 
3.8.4. 
Multiple Comparison / Multiplicity ............................................................................12 
3.8.5. 
Other Endpoints ..........................................................................................................13 
3.9. 
Safety Analysis ...........................................................................................................13 
3.9.1. 
Adverse Events ...........................................................................................................13 
3.9.1.1. 
Other significant AEs .................................................................................................14 


Alkermes, Inc. 
 
Statistical Analysis Plan-ALK3831 - A305 
Final Version 1.0 
 
 
Page 3 of 24 
 
3.9.2. 
Clinical Laboratory Parameters ..................................................................................14 
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 ANALYSIS ...............................................................................................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 ..............................................22 
6.3. 
Handling of Safety Data .............................................................................................22 
7. 
GENERAL STATISTICAL METHODOLOGY .......................................................23 
7.1. 
Reporting Precision ....................................................................................................23 
8. 
PROGRAMMING SPECIFICATIONS .....................................................................23 
9. 
MOCK TABLES, LISTINGS AND FIGURES (TLFS) ............................................23 
10. 
REFERENCES ...........................................................................................................23 
 
LIST OF TABLES 
Table 1: 
Criteria of Potentially Clinically Significant (PCS) Abnormality for Selected 
Analytes ......................................................................................................................16 
Table 2: 
Shifts Category from Baseline to Any Post-Baseline for Selected Lipid 
Parameters ...................................................................................................................17 
Table 3: 
Shift Category from Baseline to Any Post-Baseline in Glucose and Hba1c ..............18 
Table 4: 
Shift Category from Baseline to Any Post-Baseline in Liver Function Test .............18 
Table 5: 
Criteria for Potentially Clinically Significant (PCS) Blood Pressure or Pulse 
Rate .............................................................................................................................19 
Table 6: 
Criteria for Potentially Clinically Significant (PCS) Changes from Baseline 
in Body Weight ...........................................................................................................20 
Table 7: 
Criteria for Potentially Clinically Significant (PCS) QTcB and QTcF ......................20 
Table 8: 
C-SSRS Categories for Analysis ................................................................................21 


Alkermes, Inc. 
 
Statistical Analysis Plan-ALK3831 - A305 
Final Version 1.0 
 
 
Page 4 of 24 
 
Table 9: 
Degree of Precision .....................................................................................................23 
 
LIST OF FIGURES 
Figure 1: 
Study Design Schematic ...............................................................................................8 


Alkermes, Inc. 
 
Statistical Analysis Plan-ALK3831 - A305 
Final Version 1.0 
 
 
Page 5 of 24 
 
ABBREVIATIONS 
Abbreviation or Term 
Explanation or Definition 
AE 
adverse event 
AIMS 
Abnormal Involuntary Movement Scale 
ANCOVA 
analysis of covariance 
ATC 
Anatomical Therapeutic Chemical [classification system] 
BARS 
Barnes Akathisia Rating Scale 
BMI 
body mass index 
CGI-I 
Clinical Global Impression - Improvement 
CGI-S 
Clinical Global Impression - Severity 
CI 
confidence interval 
C-SSRS 
Columbia Suicide Severity Rating Scale 
ECG 
electrocardiogram 
eCRF 
electronic case report form 
EOT 
end of treatment 
EPS 
extra pyramidal symptoms 
ET 
early termination 
FAS 
full analysis set 
HbA1C 
Hemoglobin A1c 
IWQOL 
Impact of Weight on Quality of Life 
LOCF 
last observation carried forward 
MedDRA 
Medical Dictionary for Regulatory Activities 
MI 
multiple imputation 
MMRM 
mixed model with repeated measurements 
MOAS 
Modified Overt Aggression Scale 
OLZ 
olanzapine 
PANSS 
Positive and Negative Syndrome Scale 
PCS 
potentially clinically significant 
PK 
pharmacokinetic 
QTcB 
QT corrected with Bazett formula 
QTcF 
QT corrected with Fridericia formula 


Alkermes, Inc. 
 
Statistical Analysis Plan-ALK3831 - A305 
Final Version 1.0 
 
 
Page 6 of 24 
 
Abbreviation or Term 
Explanation or Definition 
SAE 
serious adverse event 
SAP 
statistical analysis plan 
SAS 
Simpson-Angus Scale 
TEAE 
treatment-emergent adverse event 
ULN 
upper limit of normal 
WHO 
World Health Organization 


Alkermes, Inc. 
 
Statistical Analysis Plan-ALK3831 - A305 
Final Version 1.0 
 
 
Page 7 of 24 
 
1. 
INTRODUCTION 
This statistical analysis plan (SAP) describes the statistical methods to be used for analyses and 
presentation of  efficacy and safety data for the study ALK3831-A305. This document has been 
prepared based on Alkermes ALK3831-A305 Study Protocol Amendment 1.0 (dated 22 Sep 
2016). 
1.1. 
Study Objectives 
1.1.1. 
Primary objective 
The primary objective of this study is to evaluate the antipsychotic efficacy of ALKS 3831 (a 
fixed-dose combination of olanzapine and samidorphan) in adult subjects with an acute 
exacerbation of schizophrenia.  
1.1.2. 
Secondary objective 
The secondary objective of this study is to evaluate the safety and tolerability of ALKS 3831 in 
adult subjects with an acute exacerbation of schizophrenia. 
1.2 
Summary of the Study Design 
ALK3831-A305 is a Phase 3, multinational, multicenter, randomized, double-blind, placebo-
controlled study in subjects experiencing an acute exacerbation of schizophrenia. Subjects will 
be screened up to 10 days prior to randomization. Upon completion of screening assessments, 
subjects meeting eligibility criteria will be admitted to an inpatient unit on Day -1, if they are not 
already inpatient. Currently prescribed antipsychotics will be discontinued at Screening. 
On Day 1 (Visit 2), subjects meeting eligibility criteria will be randomized in a 1:1:1 fashion to 
one of the following 3 treatment groups: ALKS 3831, olanzapine, or placebo, and will receive 
double-blind treatment for up to 4 weeks. 
On Days 1 and 2, subjects randomized to ALKS 3831 will receive 10/10 [10 mg olanzapine/10 
mg samidorphan] and subjects randomized to olanzapine will receive 10 mg. On Day 3, the dose 
will be increased to 20/10 [20 mg olanzapine/10 mg samidorphan] for subjects randomized to 
ALKS 3831 or 20 mg for subjects randomized to olanzapine. Following the increase on Day 3, 
the dose may be decreased to 10/10 (ALKS 3831) or 10 mg (olanzapine) at end of Week 1 (Day 
7) or Week 2 (Day 15) if there are tolerability problems based on judgment of the investigator. 
No further dose adjustments will be allowed Day 15 onward for the remaining 2 weeks of the 
treatment period. All subjects will receive 1 tablet daily in a blinded manner. 
Subjects are required to be inpatient for the first 2 weeks of the treatment period (until Day 15). 
Following the mandatory 2-week inpatient stay, subjects can either continue the study as 
inpatients for the full 4-week treatment period or be discharged at the end of Week 2 or end of 
Week 3 if they meet the discharge criteria specified in Protocol Section 8.1.1.  
Visits during the double-blind period will be every week. Each weekly visit will consist of 
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Subjects completing 4 weeks of treatment with study drug will be eligible to continue in the 
open-label, long-term safety study (ALK3831-A306) and continue to receive ALKS 3831 for up 
to 52 weeks. Subjects not continuing in the long term safety study will enter a 2-week Safety 
Follow-up Period. During this follow-up period subjects may be treated with any antipsychotic 
medication according to physician recommendations. 
Subjects who are inpatient at the end of the 4-week treatment period and are not continuing in 
the extension study (ALK3831-A306) may continue as inpatients for up to 1 additional week of 
the 2-week safety follow-up period. These subjects may be discharged from the inpatient unit at 
any time during this week based on Investigator’s judgment. For subjects continuing in the safety 
extension study (ALK3831-A306), details regarding the additional inpatient week will be 
provided in the ALK3831-A306 protocol. 
Figure 1: 
Study Design Schematic 
 
2. 
SAMPLE SIZE CONSIDERATION 
The planned sample size is 390 subjects in total, 130 subjects per treatment group. This sample 
size will provide at least 90% power to show superiority of the ALKS 3831 group compared to 
placebo group at a 2-sided alpha level of 0.05, assuming a 10-point improvement of PANSS total 
score at week 4, a standard deviation (SD) of 20, and a dropout rate of 30%. 


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3. 
DATA ANALYSIS 
3.1. 
General Statistical Methodology 
Baseline for efficacy or safety analysis is defined as the last non-missing efficacy or safety 
assessment on or before the first dose of study drug in the Double-blind Treatment Period. 
In general, descriptive statistics: n, mean (SD), median, minimum, and maximum, for continuous 
variables and number and percentage of subjects in each category for categorical variables will 
be provided by treatment group for all variables. 
All statistical tests and confidence intervals (CIs), unless stated otherwise, will be 2-sided and 
will be set at an alpha level of 0.05. 
Unless specified otherwise, all formal comparisons will be between ALKS 3831 and placebo 
groups. An exploratory analysis will be conducted between olanzapine and placebo groups.  
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 randomized subjects who receive at least 1 dose of study 
drug during the double-blind treatment period. The Safety Population will be used for the safety 
analyses. 
3.2.2. 
Efficacy Population 
The full analysis set (FAS) will include all subjects in the Safety Population who have at least 
one post-baseline PANSS assessment. The FAS will be used for the efficacy analyses. 
3.3. 
Disposition 
The number and percentage of subjects completing or prematurely discontinuing the study 
including reasons for discontinuation will be summarized overall and  by treatment group for the 
following: 
 Subjects who were randomized 
 Subjects in the Safety Population  
 Subjects in the FAS Population  
 Subjects who completed the double-blind treatment period 
 Subjects who discontinued the study during the double-blind treatment period along 
with reasons for discontinuation 
3.4. 
Protocol Deviation 
Subjects with major protocol deviations using the following categories will be summarized by 
treatment group along with supportive listings for each category.  


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 Did not meet the inclusion/exclusion criteria  
 Received prohibited medications  
 Lack of adherence with study medication, as defined by subjects taking less than 70% 
of the protocol specified amount of study medication 
 Randomization or 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 overall and by treatment group for the Safety and FAS 
Population.  
Baseline efficacy characteristics, eg, PANSS and CGI-S, will be summarized by treatment group 
for the FAS Population to assess the comparability of the treatment groups.  
Medical and psychiatric history will be summarized for the Safety Population by treatment 
group and overall. 
3.6. 
Prior and Concomitant Medication 
Prior medications are defined as medications taken prior to the first dose of study drug. 
Concomitant medications are defined as medications taken on or after the first dose of study 
drug. All medications as documented by the investigator will be coded using the World Health 
Organization Anatomical Therapeutic Chemical (WHO-ATC) drug dictionary Enhanced 
Extended with Herbal version WHODRUG_C / 161E+H. 
Prior and concomitant medications will be summarized by the preferred drug name for the Safety 
population. Concomitant medications that are taken during the double-blind treatment period will 
be included in the summary table. For the summary tables, if a subject has taken a prior or 
concomitant medication more than once, the subject will be counted only once for the 
medication. All reported medications (including those initiated after the last dose of double-blind 
study medication) will be included in the listing. 
3.7. 
Treatment Adherence Rate and Extent of Exposure 
3.7.1. 
Treatment Adherence Rate 
Treatment adherence to the daily dosing schedule during the double-blind treatment period will 
be summarized by treatment group for the Safety Population. Treatment adherence will be 
calculated as follows: 
100 × Total tablets dispensed −total tablets returned −total tablets lost
Total tablets scheduled to be taken
 
3.7.2. 
Duration of Study Drug Administration 
Duration of study drug administration is defined as the number of days from the date of the first 
dose of study drug taken to the date of the last dose taken, inclusive (ie, last dose date – first dose 


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date + 1). Duration of study drug administration will be summarized for the Safety Population by 
treatment group. 
The overall prescribed mean and modal dose of olanzapine will be summarized by treatment 
group for relevant treatment groups. Number and percentage of subjects will be summarized by 
their final dose level. 
3.8. 
Efficacy Analyses 
3.8.1. 
 General Considerations 
All statistical tests will be 2-sided hypothesis tests performed at the 5% significance level. All 
confidence intervals will be 2-sided 95% confidence intervals. 
Baseline is defined as the last non-missing observation on or before the first dose of study drug 
in the double-blind treatment period.  
Unless specified otherwise, all formal comparisons will be between ALKS 3831 and placebo 
groups. An exploratory analysis will be conducted between olanzapine and placebo groups.  
3.8.2. 
Primary Efficacy Endpoint 
The primary efficacy endpoint is change from baseline in PANSS total score at Week 4.  
3.8.2.1. 
Primary Analysis 
For the primary efficacy endpoint, change from baseline in PANSS total score at Week 4, 
primary analysis will be carried out using a mixed model with repeated measurements (MMRM) 
with an unstructured variance-covariance matrix based on the observed data for the FAS 
population. The model will include region (US vs. non-US), visit, treatment, and interaction term 
of visit and treatment as categorical variables, and baseline PANSS total score as a covariate. 
The Kenward-Roger approximation2 will be used to adjust the denominator degree of freedom. 
The change from baseline in PANSS total score at Week 4 in the ALKS 3831 group will be 
compared to that in the placebo group using superiority testing at two-sided alpha level of 0.05. 
The least squares (LS) mean, standard error (SE), and LS mean difference between ALKS 3831 
and placebo along with the 95% CI, will be summarized.  
3.8.2.2. 
Sensitivity Analysis 
To assess the robustness of the primary analysis of the primary endpoint, the following 
sensitivity analyses will be performed: 
 Delta-adjusted Pattern Mixture Model3 will be conducted to assess the impact of 
missing data. It incorporates the clinical assumption that ALKS 3831 subjects who 
discontinue at a given time point would have, on average, their unobserved PANSS 
worsened by some amount δ compared with the observed PANSS of subjects on the 
same treatment arm who continue to the next timepoint. Subjects who discontinue 
from the placebo arm would have the same PANSS trajectory as the placebo subjects 
who stay on the study. A sequential regression-based multiple imputation (MI) 
procedure will be used to incorporate the assumption and to allow uncertainty in the 
imputations to be reflected appropriately in the analysis. The imputation model will 


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include the measurement at the current timepoint as the response variable, and region 
(US vs. non-US) as factor, the measurements at the previous timepoints and the 
baseline as covariates. Twenty imputations will be carried out. For each of the 20 
imputed data sets, the ANCOVA model with region (US vs. non-US) and treatment 
group as factors and baseline PANSS as covariate will be fitted to the change from 
baseline at Week 4 to obtain the treatment effect estimate and standard error. Rubin’s 
rule will be used to combine the treatment effect estimates and standard errors across 
imputations. The shift parameters to be used in the sensitivity analysis will accounts 
for 10%, 20%, 30%, 40%, and 50% of the observed treatment difference between 
ALKS 3831 and placebo. 
 The MMRM model may adjust for additional covariates and/or factors.  
3.8.2.3. 
Examination of Subgroups 
Subgroup analyses of the primary endpoint will be performed for each of the following 
subgroup. 
 Sex (male, female) 
 Age (<55 years, ≥55 years) 
 Race (white, black or African American, other) 
 Region (US, non-US) 
 Baseline PANSS  total  score (<95 points, ≥95 points) 
The forest plot of the least squares mean difference along with 95% CI between ALKS 3831 and 
placebo will be provided by the subgroup factors listed above. 
3.8.3. 
Key Secondary Endpoint 
The key secondary efficacy endpoint is change from baseline in CGI-S at Week 4.  
Primary Analysis 
An MMRM analysis, similar to the primary analysis on primary endpoint (Section 3.8.2.1) will 
be conducted to analyze the difference between ALKS 3831 and placebo groups.  
Sensitivity Analysis 
To assess the impact of missing data, a Delta-adjusted Pattern Mixture Model3 similar to the 
sensitivity analysis of the primary endpoint in Section 3.8.2.2 will be conducted. 
3.8.4. 
Multiple Comparison / Multiplicity 
If the primary analysis of the primary endpoint is statistically significant between ALKS 3831 
and placebo, the statistical test will be performed on the key secondary efficacy endpoint 
between ALKS 3831 and placebo at two-sided alpha of 0.05. 


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3.8.5. 
Other Endpoints 
 Change from baseline in PANSS total score and PANSS subscales (positive, 
negative, general psychopathology) by visit 
 Change from baseline in CGI-S by visit 
 CGI-I at each post-Baseline visit 
 PANSS responders ( ≥30% improvement from baseline in PANSS total score) by 
visit 
 CGI-I responders (CGI-I score of 2 [much improved] or 1 [very much improved]) by 
visit 
 Overall Response defined as: PANSS total score ≥30% improvement from baseline or 
CGI-I score of 1 or 2 by visit 
 Change from baseline in PANSS-Excited Component (EC) score (comprised of 5 
items, excitement, tension, hostility, uncooperativeness, and poor impulse control) by 
visit 
 Change from baseline in MOAS score by visit 
The CGI-I score at each postbaseline visit will be summarized by descriptive statistics.  
For proportion of subjects exhibiting improvement on the CGI-I assessment (CGI-I score of ≤2), 
a logistic regression based on LOCF imputation for missing data will be used to compare ALKS 
3831 with placebo. The model will include the region (US vs. non-US) and treatment group as 
factors, and baseline PANSS total score as covariates. 
All other endpoints will be summarized by treatment group for all visits. Each active group 
(ALKS 3831 or olanzapine) will be compared to placebo. For continuous outcome, a similar 
approach to that for the primary endpoint will be used (Section 3.8.2.1). For dichotomous 
outcomes, a similar approach to that used for CGI-I improvement scores will be used, using 
LOCF to impute for missing data and adjusting for their corresponding baseline values.  
For subjects with MOAS total score of at least 1 at baseline, the change from baseline in MOAS 
score and subscales will be analyzed using a similar MMRM model as Section 3.8.2.1, adjusting 
for baseline value as covariate. 
3.9. 
Safety Analysis 
3.9.1. 
Adverse Events 
Adverse events will be coded by System Organ Class and Preferred Term using the Medical 
Dictionary for Regulatory Activities (MedDRA®) Version 19.0 or higher. The verbatim term will 
be included in the AE listings. 
An AE (classified by preferred term) will be considered as treatment-emergent AE (TEAE) if the 
event is newly occurring or worsening on or after the date of first dose of study drug. 
The number and percentage of subjects reporting TEAEs in each treatment group during the 
double-blind period will be presented by treatment group for the following categories: 


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 System organ class and preferred term 
 Preferred terms in decreasing frequency, and also including the following subsets: 
 Experienced by ≥2% of subjects in any treatment group 
 Experienced by ≥5% of subjects in any treatment group and ≥2 times of placebo 
group 
 System organ class, preferred term, and severity 
 System organ class, preferred term for severe TEAEs 
 System organ class, preferred term, and relationship 
 System organ class, preferred term for drug-related TEAEs 
If more than one AE is coded to the same preferred term 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 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, preferred term and treatment group.  
The number and percentage of subjects who have serious adverse events (SAE) and AEs leading 
to premature discontinuation from the treatment will be summarized by preferred term and 
treatment group and will be sorted by decreasing frequency for ALKS 3831 group.  
3.9.1.1. 
Other significant AEs 
In addition, incidence of a selected subset of relevant AEs in this class of drugs (eg, 
extrapyramidal symptoms (EPS) TEAEs, AEs associated with abuse potential, AEs associated 
with drug withdrawal, and suicide related events, etc.) will be summarized by treatment group 
and preferred term. The selection of AEs per subset will be based on the preferred term and 
Standardized MedDRA queries (SMQs).  
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. All laboratory data, including those 
collected at unscheduled visits, will be included in the listings. 
Laboratory results (baseline and change from baseline) for the Safety population for chemistry 
and hematology parameters will be summarized by treatment group and by visit. 
Number (percentage) of subjects with potentially clinically significant (PCS) values at any post-
baseline visit, will be summarized by treatment group. PCS criteria are presented in Table 1. 
The denominator is all subjects with non-PCS baseline and at least one post-baseline assessment 
in the Safety Population and the numerator is the number of subjects with non-PCS baseline and 
PCS at post-baseline. All PCS values including baseline PCS values will be included in 
supportive listings. 


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Shift tables for selected metabolic parameters (glucose, total cholesterol, LDL, HDL, 
tryglyceride, and HbA1c) and liver function tests will be presented. The criteria are summarized 
in Table 2, Table 3 and Table 4.  
 


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Table 1: 
Criteria of Potentially Clinically Significant (PCS) Abnormality for Selected 
Analytes 
Parameters 
Criteria 
Chemistry 
Albumin 
<2.5 g/dL 
Alkaline Phosphatase (U/L) 
≥3 × ULN 
Alanine Aminotransferase (U/L) 
≥3 × ULN 
Aspartate Aminotransferase (U/L) 
≥3 × ULN 
Bilirubin, Total 
≥2.0 mg/dL 
Blood Urea Nitrogen 
>30 mg/dL 
Cholesterol, Random 
>300 mg/dL 
Cholesterol, Fasting 
≥240 mg/dL 
Cholesterol, HDL Fasting 
≤30 mg/dL 
Cholesterol, LDL Fasting 
≥160 mg/dL 
Creatine Kinase (U/L) 
≥3 × ULN 
Creatinine 
≥2.0 mg/dL 
Glucose, Random 
<50 mg/dL or  
≥200 mg/dL 
Glucose, Fasting 
<50 mg/dL or  
≥126 mg/dL 
Potassium 
<3 mmol/L or 
>5.5 mmol/L 
Lactate Dehydrogenase (U/L) 
>3 × ULN 
Prolactin (Female) 
>30 ng/mL 
Prolactin (Male) 
>20 ng/mL 
Sodium 
<130 mmol/L or 
>150 mmol/L 
Triglycerides, Fasting (Female) 
≥120 mg/dL 
Triglycerides, Fasting (Male) 
≥160 mg/dL 


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Table 1: 
Criteria of Potentially Clinically Significant (PCS) Abnormality for Selected 
Analytes (Continued) 
Parameters 
Criteria 
Hematology 
Eosinophils 
>1.0 × 103/μL 
Hematocrit (Female) 
≤32% 
Hematocrit (Male) 
≤37% 
Neutrophils, Absolute 
<1.5 × 103/μL 
Platelets 
<75.0 × 103 cells/μL or 
≥700.0 × 103 cells/μL 
Leukocytes 
≤2.8 × 103/μL or 
≥16.0 ×103/μL 
Table 2: 
Shifts Category from Baseline to Any Post-Baseline for Selected Lipid 
Parameters 
Total cholesterol (fasting) mg/dL 
  Normal (<200) to high (≥240) 
  Borderline (≥200 and < 240) to high (≥240) 
  Normal/Borderline (<240) to high (≥240) 
  Normal (<200) to borderline/high (≥200) 
  Increase ≥40 mg/dL 
LDL Cholesterol (fasting) mg/dL 
  Normal (<100) to high (≥160) 
  Borderline (≥100 and <160) to high (≥160) 
  Normal/borderline (<160) to high (≥160) 
  Normal (<100) to borderline/high (≥100) 
  Increase ≥30 mg/dL 
HDL Cholesterol (fasting) mg/dL 
  Normal (≥40) to low (<40) 
  Decrease ≥20 mg/dL 
Triglycerides (fasting) mg/dL 
  Normal (<150) to high (≥200) 
  Normal (<150) to very high (≥500) 
  Borderline (≥150 and <200) to high (≥200) 


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  Borderline (≥150 and <200) to very high (≥500) 
  Normal/borderline (<200) to high (≥200) 
  Normal/borderline (<200) to very high (≥500) 
  Normal (<150) to borderline/high/very high (≥150) 
  Increase ≥50 mg/dL 
Table 3: 
Shift Category from Baseline to Any Post-Baseline in Glucose and Hba1c 
Serum glucose (fasting) mg/dL 
  Normal (<100) to high (≥126) 
  Impaired (≥100 and <126) to high (≥126) 
  Normal/Impaired (<126) to high (≥126) 
  Increase ≥10 mg/dL 
HbA1c % 
  Shift from baseline (<5.7%) to post-baseline ≥5.7% 
  Shift from baseline (<5.7%) to post-baseline ≥5.7% and <6.5% 
  Shift from baseline (<5.7%) to post-baseline ≥6.5% 
Table 4: 
Shift Category from Baseline to Any Post-Baseline 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 xULN 
  Shift from Normal to ≥2 xULN 
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 by treatment group. 


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Vital sign values will be considered PCS if they meet both the observed-value criteria and the 
change-from-baseline criteria listed in Table 5. The number and percentage of subjects with PCS 
post-baseline values will be tabulated by treatment group. The percentages will be calculated 
relative to the number of subjects with available non-PCS baseline values and at least 1 post-
baseline assessment. The numerator will be the total number of subjects with available non-PCS 
baseline values and at least 1 PCS post-baseline value. A supportive tabular display of subjects 
with PCS post-baseline values will be provided, including the subject ID number, baseline, and 
all post-baseline (including non-PCS) values. 
All vital signs will be presented in the subject data listing. 
Orthostatic hypotension (20/10) 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) is defined as a fall in systolic blood pressure of at least 
30 mm Hg 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 post-baseline visit will also be summarized by treatment group for the 
double-blind period. 
Table 5: 
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 
Weight (kg), BMI (kg/m2) and waist circumference (baseline and change from baseline) will be 
summarized by treatment group. Height (cm) will be measured at the screening visit and this 
value will be used for the calculation of the BMI. All weight, BMI and waist circumference data 
will be listed. 
Number and percentage of subjects with weight change values considered as PCS occurring at 
any post-baseline visit will be summarized by treatment group. 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 post-baseline value. A supportive listing will be provided for 
subjects with PCS values. 


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Table 6: 
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 assessment 
timepoint and at the end of the double-blind treatment period will be presented by treatment 
group. QTc interval will be calculated using both Bazett (QTcB = QT/(RR)½) and Fridericia 
(QTcF = QT/(RR)⅓) corrections; if RR is not available, it will be replaced with 60/HR in the 
correction formula. 
Electrocardiogram parameter values are considered PCS if they meet or exceed the higher-limit 
PCS criteria listed in Table 7. The number and percentage of subjects with PCS post-baseline 
ECG values will be tabulated by treatment group. The percentages will be calculated relative to 
the number of subjects with normal baseline values and at least 1 post-baseline assessment. The 
numerator is the total number of subjects with normal baseline values and at least 1 PCS post-
baseline value. A supportive tabular display of subjects with PCS post-baseline values will be 
provided, including the subject ID number, study center number, baseline, all post-baseline 
(including non-PCS) values, and change from baseline. 
Table 7: 
Criteria for Potentially Clinically Significant (PCS) QTcB and QTcF 
Parameter 
Criteria 
QTcB and 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 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). 
For all abnormal movement scales, total scores and subscale scores will be summarized by 
treatment group at each visit for the absolute value and for changes from baseline. 
Number and percentage of subjects meeting the criteria for treatment emergent Parkinsonism 
(SAS total score>3), for treatment emergent akathisia (BARS global clinical assessment of 
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items, or a score ≥2 on two or more of any of the first 7 items) at any postbaseline visit will be 
summarized by treatment group.  
A listing will be provided for every abnormal movement scale. Listing for treatment emergent 
EPS will be provided.  
3.9.5. 
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. The number of 
subjects with suicidal ideation and suicidal behavior during the double-blind treatment period 
will be summarized by treatment group when applicable. 
Supportive tabular display of subjects with all values will be provided, including subject ID 
number, treatment group, visit number, intensity of suicidal ideation, suicidal behavior type, and 
lethality of suicidal behavior. 
Table 8: 
C-SSRS Categories for Analysis  
Category 
C-SSRS Item response is “YES” 
Suicidal behavior 
Preparatory acts or behavior 
Aborted attempt 
Interrupted attempt 
Actual attempt 
Complete suicide 
Suicidal ideation 
Wish to be dead 
Non-specific active suicidal thoughts 
Active suicidal ideation with any methods (not plan) without intent to act 
Active suicidal ideation with some intent to act, without specific plan 
Active suicidal ideation with specific plan and intent 
3.10. 
Pharmacokinetic/ Pharmacodynamic Data Analysis 
Subject listings for the PK sampling time and concentrations of olanzapine, samidorphan, and 
metabolites of interest will be provided. PK data obtained from plasma samples collected in this 
study may be included in a subsequent population PK analysis or other post-hoc analyses 
conducted outside the scope of this SAP. 
4. 
INTERIM ANALYSIS 
No interim analysis is planned for this study. 


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5. 
CHANGES IN CONDUCT OR PLANNED ANALYSES FROM 
THE PROTOCOL 
Changes have being made to the analyses specified in the Protocol1 Section 14.4 to include the 
region (US vs. non-US) as a factor in the analysis model for all the relevant efficacy endpoints as 
described above.  
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 1 Schedule of Visits and Assessments). 
Scheduled analysis visits during the study period will be the same as the nominal visits collected 
in eCRF. There will be one valid value of assessment kept for each scheduled analysis visit 
in summary/analysis statistics. 
Unscheduled visits are visits with data not collected on the scheduled time point. Unscheduled 
visits will not be used for by-visit summary/analysis statistics unless specified otherwise. 
All unscheduled visits will be included as collected in eCRF in listings. 
Visit Day is calculated as (visit date) – (date of the first dose of study drug) +1. 
Last postbaseline values are defined as the last valid postbaseline values collected for each 
subject during the double-blind treatment period.  
Any post-baseline values are defined as any valid values collected from scheduled visits if 
applicable. 
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, 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 by treatment group. All summary tables will be based on 
observed data, and missing values will not be imputed unless otherwise indicated. Measurements 
collected from unscheduled visits or repeated assessments will not be included in the by-visit 
summary tables or figures, but will be included in the analyses for the PCS postbaseline values, 
and subject listings. Source data for the summary tables and statistical analyses 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 9: 
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. 
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. 
10. 
REFERENCES 
1. Alkermes ALK3831-A305 Study Protocol Amendment 1.0 Date: 22 September 2016 


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Statistical Analysis Plan-ALK3831 - A305 
Final Version 1.0 
 
 
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2. Kenward MG and Roger JH. Small sample inference for fixed effects from restricted 
maximum likelihood. Biometrics 1997; 53: 983–997 
3. Ratitch B, O’Kelly M, and Tosiello R. Missing data in clinical trials: from clinical 
assumptions to statistical analysis using pattern mixture models. Pharmaceutical 
statistics 2013; 12: 337-347