Clinical trial NCT03610048
Conditions: Refractory Major Depressive Disorder
Keywords: Alkermes Major depressive disorder Depression ALKS 5461
Sponsor: Alkermes, Inc.
Start date: 2018-08-09; Completion date: 2020-05-01
Enrollment: 175 participants; Allocation: NA; Intervention model: SINGLE_GROUP

Brief summary:
This study will assess the long-term safety and tolerability of ALKS 5461 as an adjunctive treatment for refractory MDD.

Detailed description:

Arms: arm 1: Sublingual tablets
Interventions: intervention 1: ALKS 5461
Intervention descriptions: intervention 1: samidorphan + buprenorphine administered sublingually

Protocol documents:
Prot_000.pdf: 
A Phase 3b Extension Study of Adjunctive ALKS 5461 in the 
Treatment of Refractory Major Depressive Disorder 
 
 
Unique Protocol ID: 
ALK5461-218 
NCT Number: 
NCT03610048 
Date of Protocol:  
14 Nov 2019 
 


 
 
1. 
TITLE PAGE 
 
 
CLINICAL STUDY PROTOCOL 
ALK5461-218 
 
Study title: 
A Phase 3b Extension Study of Adjunctive ALKS 5461 in the 
Treatment of Refractory Major Depressive Disorder 
Document date: 
v 3.0 (incorporates Amendment 2.0): 14 Nov 2019 
v 2.0 (incorporates Amendment 1.0): 01 Aug 2018 
Original Protocol: 25 Jun 2018 
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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PROCEDURES IN CASE OF EMERGENCY 
 
Table 1: 
Study Contact Information 
Role in Study 
Name 
Address and Telephone Number 
Alkermes Medical Monitors 
 
Alkermes, Inc. 
852 Winter Street 
Waltham, MA 02451 USA 
Telephone: 
 
Alkermes Global Safety 
Officer 
 
Alkermes, Inc. 
852 Winter Street 
Waltham, MA 02451 USA 
Telephone: 
 
CRO Medical Monitor and 
24-Hour Emergency Contact 
 
 
 
Raleigh, NC 27604 USA 
Telephone: 
 
Mobile Phone: 
 
SAE and Pregnancy 
Reporting 
 Safety 
and Pharmacovigilance 
FAX Number: 
 
E-mail: 
 
Abbreviations: CRO=contract research organization; SAE=serious adverse event 
PPD
PPD
PPD
PPD
PPD
PPD
PPD
PPD
PPD
PPD
PPD
PPD


 
 
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2. 
SYNOPSIS 
Name of Sponsor/Company: Alkermes, Inc. 
Name of investigational product: ALKS 5461 
Name of active ingredient: Buprenorphine (BUP) and samidorphan (SAM) 
Title of study: A Phase 3b Extension Study of Adjunctive ALKS 5461 in the Treatment of Refractory 
Major Depressive Disorder 
Investigators: Multicenter, multicountry study to be conducted at approximately 35 sites in the US and 
Australia.  
Study Period:  
Estimated date first patient enrolled: Q3 2018 
Estimated date last patient completed: Q1 2020 
Phase of development: 3b 
 
Objectives: The objective of this study is to evaluate the long-term safety and tolerability of adjunctive 
ALKS 5461 in adults who have treatment-refractory major depressive disorder (MDD). 
Methodology:  
This is a Phase 3b extension study to Study ALK5461-217 to evaluate the long-term safety and 
tolerability of adjunctive ALKS 5461 in adults who have treatment-refractory MDD. 
Number of subjects planned: All subjects who complete Study ALK5461-217 and meet eligibility 
criteria will be allowed to participate. It is estimated that up to 250 subjects may participate in this 
study. 
Sample size considerations: No formal sample size calculation has been performed for this extension 
study. A sample size of up to 250 subjects is based on an estimated number of subjects who may wish 
to continue from Study ALK5461-217. 
Main criteria for subject inclusion: Subjects who have completed scheduled participation in 
Study ALK5461-217 who are willing and able to follow the study procedures as outlined in the 
protocol, including adherence with approved antidepressant therapy and study drug regimen, are 
eligible for participation in the study. 
Investigational product, dosage, duration, and mode of administration: ALKS 5461 consists of 
BUP and SAM in a 1:1 ratio. ALKS 5461 2/2 (2 mg BUP:2 mg SAM) will be administered as a 
once-daily sublingual tablet. 
Reference therapy, dosage, duration, and mode of administration: Not applicable 
Duration of study: The study is planned to be open until approximately Q1 2020. Therefore, 
depending on when a subject is enrolled, the duration of participation in this study will vary. Subjects 
are expected to receive approximately 16 weeks to 68 weeks of ALKS 5461 within this protocol. There 
will be one Safety Follow-up visit, occurring 2 weeks after the last dose of ALKS 5461. 
The study may continue for a planned period of up to 68 weeks and/or until regulatory approval has 
been obtained in the United States, and the product is commercially available and reimbursed in the 
United States. 
Criteria for evaluation:  
Safety: The following assessments will be used to evaluate safety and tolerability throughout the study 
and during a 2-week post-discontinuation follow-up period: 


 
 
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• 
Adverse events 
• 
Serious adverse events 
• 
Columbia-Suicide Severity Rating Scale (C-SSRS)  
Statistical methods: 
Safety: Summary statistics (n, mean, standard deviation, median, minimum, and maximum values for 
continuous variables, and number and percentage of subjects in each category for categorical variables) 
will be provided for evaluated variables. All individual subject level data will be presented as data 
listings.  
 


 
 
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3. 
TABLE OF CONTENTS, LIST OF TABLES, AND LIST OF 
FIGURES  
TABLE OF CONTENTS 
1. 
TITLE PAGE ................................................................................................................1 
2. 
SYNOPSIS ...................................................................................................................3 
3. 
TABLE OF CONTENTS, LIST OF TABLES, AND LIST OF FIGURES .................5 
4. 
LIST OF ABBREVIATIONS AND DEFINITIONS OF TERMS...............................9 
5. 
INTRODUCTION ......................................................................................................10 
5.1. 
Study Rationale and Selection of Study Design .........................................................11 
5.2. 
Study Dose Selection ..................................................................................................11 
6. 
STUDY OBJECTIVES ..............................................................................................12 
7. 
SELECTION AND WITHDRAWAL OF SUBJECTS ..............................................13 
7.1. 
Subject Inclusion Criteria ...........................................................................................13 
7.2. 
Subject Exclusion Criteria ..........................................................................................13 
7.3. 
Subject Withdrawal ....................................................................................................14 
7.4. 
Replacement of Subjects .............................................................................................15 
8. 
STUDY DESIGN .......................................................................................................16 
8.1. 
Overall Study Design and Plan ...................................................................................16 
8.2. 
Schedule of Visits and Assessments ...........................................................................16 
8.3. 
Study Procedures Descriptions ...................................................................................19 
8.3.1. 
Informed Consent .......................................................................................................19 
8.3.2. 
Eligibility Review .......................................................................................................19 
8.3.3. 
Demographics and Medical History ...........................................................................19 
8.3.4. 
Concomitant Medication Review ...............................................................................19 
8.3.5. 
Study Drug Adherence Review ..................................................................................19 
8.3.6. 
Safety Assessments .....................................................................................................19 
8.3.7. 
Pregnancy Testing.......................................................................................................20 
8.3.8. 
Drug testing ................................................................................................................20 
8.4. 
Study Requirements and Restrictions .........................................................................20 
8.4.1. 
Contraception and Pregnancy .....................................................................................20 
8.4.2. 
Concomitant Medications ...........................................................................................21 
8.4.3. 
Prohibited Medications ...............................................................................................21 


 
 
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8.4.4. 
Pain Management .......................................................................................................22 
9. 
TREATMENT OF SUBJECTS ..................................................................................23 
9.1. 
Study Drug Dose and Administration .........................................................................23 
9.1.1. 
Description of ALKS 5461 .........................................................................................23 
9.1.2. 
Study Drug Dose and Dosing Regimen ......................................................................23 
9.2. 
Treatment Adherence ..................................................................................................23 
9.3. 
Method of Assigning Subjects to Treatment ..............................................................23 
9.4. 
Blinding ......................................................................................................................23 
9.5. 
Study Drug Dose Adjustment and Stopping Rules .....................................................23 
10. 
STUDY DRUG MATERIALS AND MANAGEMENT ...........................................24 
10.1. 
Study Drug ..................................................................................................................24 
10.2. 
Packaging and Labeling ..............................................................................................24 
10.3. 
Storage ........................................................................................................................24 
10.4. 
Accountability .............................................................................................................24 
10.5. 
Handling and Disposal ................................................................................................25 
11. 
ASSESSMENT OF EFFICACY ................................................................................26 
12. 
ASSESSMENT OF PHARMACOKINETICS ...........................................................27 
13. 
ASSESSMENT OF SAFETY .....................................................................................28 
13.1. 
Definition of Adverse Event .......................................................................................28 
13.2. 
Definition of Serious Adverse Events ........................................................................28 
13.3. 
Relationship to Study Drug ........................................................................................29 
13.4. 
Monitoring and Recording of Adverse Events ...........................................................30 
13.5. 
Reporting of Serious Adverse Events and Pregnancy ................................................30 
14. 
STATISTICS ..............................................................................................................31 
14.1. 
Sample Size Considerations .......................................................................................31 
14.2. 
General Statistical Methodology ................................................................................31 
14.2.1. 
Study Populations .......................................................................................................31 
14.3. 
Demographics and Baseline Characteristic Data ........................................................31 
14.4. 
Efficacy Analyses .......................................................................................................31 
14.5. 
Pharmacokinetic Analyses ..........................................................................................31 
14.6. 
Patient Questionnaire ..................................................................................................31 
14.7. 
Safety and Tolerability Analyses ................................................................................31 
15. 
DIRECT ACCESS TO SOURCE DATA/DOCUMENTS.........................................33 


 
 
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15.1. 
Study Monitoring ........................................................................................................33 
15.2. 
Audits and Inspections ................................................................................................33 
15.3. 
Institutional Review Board/Independent Ethics Committee ......................................33 
16. 
QUALITY CONTROL AND QUALITY ASSURANCE .........................................34 
16.1. 
Case Report Forms .....................................................................................................34 
16.2. 
Confidentiality of Data ...............................................................................................34 
17. 
ETHICAL CONSIDERATIONS................................................................................35 
17.1. 
Ethics Review .............................................................................................................35 
17.2. 
Ethical Conduct of the Study ......................................................................................35 
17.3. 
Written Informed Consent ..........................................................................................35 
18. 
DATA HANDLING AND RECORDKEEPING .......................................................37 
18.1. 
Data Capture ...............................................................................................................37 
18.2. 
Inspection of Records .................................................................................................37 
18.3. 
Retention of Records ..................................................................................................37 
18.4. 
Use of Information and Publication Policy ................................................................37 
19. 
REFERENCES ...........................................................................................................38 
20. 
APPENDIX A: CHECKLIST USED TO REVIEW KEY ELIGIBILITY 
CRITERIA WITH SUBJECTS ENTERING ≥30 DAYS AFTER 
COMPLETING ALK5461-217 ..................................................................................39 
21. 
APPENDIX B: PARTIAL LIST OF PROHIBITED CYTOCHROME P450 
(CYP) 3A4 INHIBITORS AND INDUCERS ............................................................44 


 
 
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LIST OF TABLES 
Table 1: 
Study Contact Information ...........................................................................................2 
Table 2: 
List of Abbreviations and Definition of Terms ............................................................9 
Table 3: 
Schedule of Assessments ............................................................................................17 
Table 4: 
Adverse Event Causality Guidelines ..........................................................................29 
Table 5: 
Partial List of Cytochrome P450 (CYP) 3A4 Inhibitors and Inducers .......................44 
 
 


 
 
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4. 
LIST OF ABBREVIATIONS AND DEFINITIONS OF TERMS 
Table 2: 
List of Abbreviations and Definition of Terms  
Abbreviation or Term 
Full Form or Definition 
ADT 
Antidepressant therapy 
AE 
Adverse event 
BUP 
Buprenorphine 
CSA 
Clinical Study Agreement 
C-SSRS 
Columbia-Suicide Severity Rating Scale  
CYP 
Cytochrome P450 
eCRF 
Electronic case report form 
GCP 
Good Clinical Practice 
ICF 
Informed consent form 
ICH 
International Conference on Harmonisation 
IEC 
Independent Ethics Committee 
IRB 
Institutional Review Board 
MADRS 
Montgomery-Åsberg Depression Rating Scale 
MDD 
Major depressive disorder 
MedDRA 
Medical Dictionary for Regulatory Activities  
SAE 
Serious adverse event 
SAM 
Samidorphan 
SL 
Sublingual 
TEAE 
Treatment-emergent adverse event 
WHO 
World Health Organization 
 


 
 
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5. 
INTRODUCTION 
Major depressive disorder (MDD) is a serious, and in some cases life-threatening, condition. 
Current therapy is limited and insufficient for many patients. Selective serotonin reuptake 
inhibitors or serotonin-norepinephrine reuptake inhibitors are recommended as first-line therapy; 
however, the large majority of patients do not experience an adequate response (Rush et al, 
2006). For patients with MDD who have an inadequate response to approved first-line 
antidepressant therapy (ADT), the only currently approved agents for adjunctive treatment are 
atypical antipsychotics. However, this class of medicines is associated with serious toxicity, 
including tardive dyskinesia, which may be irreversible, as well as neuroleptic malignant 
syndrome and agranulocytosis, both of which are potentially fatal. Further, metabolic adverse 
effects of some antipsychotics contribute to significant long-term comorbidity (eg, increased 
adiposity, insulin-resistance, cardiovascular disease, etc.) (Newcomer 2006). These conditions 
and other side effects of the atypical antipsychotics commonly lead to discontinuation of 
treatment (Spielmans et al, 2013). 
The development of an adjunctive treatment that avoids the toxicity associated with atypical 
antipsychotics is an important step toward addressing the suboptimal treatment of MDD and the 
related public health consequences. The Sponsor is developing ALKS 5461, a fixed-dose, 
combination tablet consisting of buprenorphine (BUP) and samidorphan (SAM) in a 
1:1 (weight/weight) ratio for once-daily, sublingual (SL) administration as an adjunctive therapy 
to antidepressants for the treatment of MDD. 
ALKS 5461 consists of a combination of BUP, a μ-opioid receptor partial agonist and κ-opioid 
receptor antagonist, and SAM, a potent μ-opioid receptor antagonist. ALKS 5461 offers a unique 
mechanism of action for the treatment of MDD: modulation of the opioid system. From 1982 to 
the present, there have been several published studies of BUP in depressed patients (Bodkin et al, 
1995; Emrich et al, 1982; Karp et al, 2014; Nyhuis et al, 2008). These studies demonstrated 
antidepressant effects with BUP treatment, particularly in patients with MDD who have had 
multiple prior inadequate responses to therapy. Despite this evidence of efficacy with BUP, the 
risk of diversion, abuse, and dependence have precluded routine clinical use of BUP, and opioids 
in general, in the treatment of depression. ALKS 5461 was specifically designed to confer 
therapeutic benefits in the treatment of depression through the opioid system, while addressing 
the risk of abuse or addiction and dependence potential normally associated with opioids. 
SAM is a new molecular entity optimized for high potency and high SL bioavailability, which 
facilitates coformulation with BUP for SL administration. 
Efficacy of ALKS 5461 2/2 was demonstrated in a Phase 2 study (ALK5461-202) and a Phase 3 
study (ALK5461-207). These placebo-controlled clinical studies specifically focused on patients 
continuing therapeutic doses of ADT who had an inadequate response to treatment. All subjects, 
including subjects assigned to placebo treatment, remained on background ADT throughout the 
Treatment period. For another Phase 3 study (ALK5461-205), post hoc analyses of multiple time 
points for Montgomery-Åsberg Depression Rating Scale (MADRS) score changes from baseline 
demonstrated that the changes for Weeks 3 through 6, and at the last visit of the Treatment 
period, were significantly lower among subjects in the ALKS 5461 2/2 group than with placebo. 
In another Phase 3 study (ALK5461-206), ALKS 5461 2/2 showed improvement vs baseline; 
however, the net treatment effect was obscured by a large placebo effect.  


 
 
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ALKS 5461 was generally well tolerated across all placebo-controlled studies. This was 
confirmed in a clinically complete Phase 3 long-term safety study (ALK5461-208). There has 
been no evidence to suggest that ALKS 5461 is associated with motor disorders or metabolic 
dysregulation, which are toxicities associated with atypical antipsychotics.  
There is minimal evidence of abuse potential based on data from a human abuse potential study 
(ALK5461-212) and data from the ALKS 5461 clinical development program to-date. 
Taken together, these findings indicate that ALKS 5461 has the potential to address an unmet 
medical need in this serious condition. 
Results from nonclinical and clinical investigations available to date on the pharmacokinetics, 
safety, and efficacy of ALKS 5461, as well as of SAM and BUP as individual and 
co-administered therapeutic agents, are summarized in the ALKS 5461 Investigator’s Brochure. 
5.1. 
Study Rationale and Selection of Study Design 
Safety and tolerability data from clinical studies to date show that ALKS 5461 was 
well-tolerated. In Phase 2 and Phase 3 studies, data on the short-term and long-term safety and 
tolerability of ALKS 5461 have been and are being collected. This is an open-label, Phase 3b, 
multicenter extension study of Study ALK5461-217 designed to assess safety and tolerability for 
up to an additional 68 weeks of treatment. 
5.2. 
Study Dose Selection 
This is an extension study for subjects who have completed Study ALK5461-217 (11 weeks of 
treatment plus the 1-week Follow-up period). Thus, the dose level selected for this study (ALKS 
5461 2/2) is the same as the dose administered in Study ALK5461-217.  


 
 
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6. 
STUDY OBJECTIVES 
The objective of this study is to assess the long-term safety and tolerability of ALKS 5461 as an 
adjunctive treatment for refractory MDD. 


 
 
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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. Be willing and able to provide informed consent 
2. Be willing to abide by the contraception requirements for the duration of the study 
(please refer to Section 8.4.1 for additional details regarding contraception) 
3. Be willing and able to follow the study procedures and visits as outlined in the protocol  
4. Have the potential to benefit from the administration of ALKS 5461, in the opinion of the 
Investigator 
5. Have completed treatment in Study ALK5461-217. The following criteria are to be met 
based on the time between completing Study ALK5461-217 and enrolling in this study: 
 <30 days: Investigator attestation that no changes have occurred with the subject 
that would compromise safety  
 ≥30 days: Investigator should review key criteria to ensure subject still meets 
eligibility requirements1. Discussion with the Medical Monitor will occur as 
necessary 
7.2. 
Subject Exclusion Criteria 
Each subject must not have any of the following conditions to be qualified to participate in this 
study: 
1. Has any finding that, in the view of the Investigator or Medical Monitor, would 
compromise the safety of the subject or affect his or her ability to adhere to the protocol 
visit schedule or fulfill visit requirements 
2. Is pregnant, planning to become pregnant, or is breastfeeding during the study 
3. Poses a current suicide risk, as evidenced by any of the following:  
a. In the opinion of the Investigator, the subject may be at risk for suicide  
b. The subject responds “Yes” to Question 4 (“Active Suicidal Ideation with Some 
Intent to Act, Without Specific Plan”) or Question 5 (“Active Suicidal Ideation with 
Specific Plan and Intent”) on the Screening Columbia-Suicide Severity Rating Scale 
(C-SSRS) 
c. The subject has attempted suicide at any time after enrollment in Study 
ALK5461-217 
 
1 Investigators will be provided with a checklist to ensure review of key criteria. A sample checklist is provided in 
Section 20 (Appendix A). 


 
 
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4. Has used opioid agonists (eg, codeine, oxycodone, tramadol, morphine) or opioid 
antagonists (eg, naloxone, naltrexone) within 14 days prior to Screening, has an 
anticipated need for opioid use at any point during the study (eg, planned surgery), or has 
used an extended-release formulation of an opioid antagonist within 2 months prior to 
Visit 1 
5. Has a positive test for drugs of abuse at Visit 1 
7.3. 
Subject Withdrawal 
Subjects who are screen failures may be eligible for rescreening only if rescreening is approved 
by the Medical Monitor. 
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 
• Lost to follow-up 
• Withdrawal by subject 
• Non-compliance with study drug 
• Physician decision 
• Pregnancy 
• Protocol deviation 
• Study terminated by Sponsor 
• Other 
If a subject withdraws from the study for any reason, any ongoing adverse events (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. Subjects are to be asked to return to the clinic for an Early Termination visit and a 2-week 
postdiscontinuation Safety Follow-up visit. The Early Termination visit should be scheduled as 
close as possible to the subject’s last dose of study drug. If the subject fails or refuses to return to 
the study site, an attempt must be made to contact the subject by telephone in order to assess as 
many safety parameters as possible. All data collected over the telephone must be documented 
and kept in the subject’s record. 
The Investigator must maintain a record of all subjects who fail to complete the study. The 
reason for study discontinuation will be documented and made on the appropriate electronic case 


 
 
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report form (eCRF). If a subject is lost to follow-up, a reasonable attempt to contact the subject 
must be made and documented. 
The study may continue for a planned period of up to 68 weeks and/or until regulatory approval 
has been obtained, and the product is commercially available and reimbursed. 
7.4. 
Replacement of Subjects 
Subjects who withdraw after receiving the first dose of study drug in this study will not be 
replaced. 


 
 
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8. 
STUDY DESIGN 
8.1. 
Overall Study Design and Plan 
This is an open-label, Phase 3b, multicenter extension study to evaluate the long-term safety and 
tolerability of ALKS 5461 administration for use as an adjunctive therapy to antidepressants for 
the treatment of refractory MDD. Subjects who completed treatment in Study ALK5461-217 will 
be eligible for enrollment into the study. 
At Visit 1, all eligible, consenting subjects will begin the Treatment period. Dosing is described 
in detail in Section 9.1.2. From Day 1 onward, all participating subjects will take ALKS 5461 2/2 
and an approved ADT. 
Study staff will administer the first dose of ALKS 5461 on Day 1. From that point on during the 
Treatment period, the staff will dispense ALKS 5461 for subjects’ self-administration. Subjects 
will be advised to take the study drug at bedtime. 
During the Treatment period, subjects will return to the clinic for periodic scheduled visits, at 
which safety and tolerability will be assessed, as well as a 2-week postdiscontinuation Follow-up 
visit. 
8.2. 
Schedule of Visits and Assessments 
Eligibility criteria and assessments described in Section 8.3 will occur on Day 1 of the study. 
For a missed visit, the study site should attempt to contact the subject to reschedule. 
Subjects who discontinue from the study prematurely will be encouraged to return for an Early 
Termination visit and a 2-week postdiscontinuation Follow-up visit. See Section 7.3 for 
additional details. 
See Table 3 for a full schedule of assessments. 
 


 
 
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Table 3: 
Schedule of Assessments 
 
Screening 
Visit 
Transition 
from 
Previous 
Studya, b, c 
Week 1 
Week 2 
Week 6 
Week 12 
Visits every 8 
Weeks  
(Weeks 20, 
28, 36, 44, 52, 
60) 
Week 68 
EOT/ET 
Visitd 
 
Safety 
Follow-Up 
Visit 
 
Day 
SCN/1 
8 (±4) 
15 (±4) 
43 (±4) 
85 (±4) 
Every 56 (±4) 
days 
 477 (±4)  
14 (±4) 
days after 
the final 
dose of 
study drug 
Visit 
 
1 
2 
3 
4 
5 
 6, 7, 8, 9, 10, 
11 
12 
13 
Informed Consent 
X 
 
 
 
 
 
 
 
Qualification/ Diagnostic Assessments  
Eligibility Review 
X 
 
 
 
 
 
 
 
Medical and Psychiatric History Updates 
X 
 
 
 
 
 
 
 
Qualification/ Safety Assessments  
Symptom-driven Physical Examination 
X 
 
 
 
 
 
 
 
Urine Pregnancy Test (all women) 
X 
X 
X 
X 
X 
X 
X 
X 
Urine Drug Screene 
X 
 
 
 
 
 
 
 
C-SSRS (since last visit) 
X 
X 
X 
X 
X 
X 
X 
X 
Adverse Event Monitoring 
X 
X 
X 
X 
X 
X 
X 
X 
Concomitant Medication Review 
X 
X 
X 
X 
X 
X 
X 
X 
Additional Study Procedures  
Dispensation of Study Drugf 
X 
X 
X 
X 
X 
X 
 
 
Study Drug Adherence Reviewg 
 
X 
X 
X 
X 
X 
X 
 
Abbreviations: AE=adverse event; C-SSRS=Columbia-Suicide Severity Rating Scale; EOT=end of treatment; ET=early termination; SCN=Screening  


 
 
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a Screening (Visit 1) may occur on the same day as the Safety Follow-up Visit of the preceding Study ALK5461-217, in which case the procedures of these two 
visits may be combined.  
b Procedures already performed in ALK5461-217 do not need to be repeated in ALK5461-218. Information from the antecedent study will be re-entered into the 
electronic data capture system for Study ALK5461-218. 
c If the subject is screened ≥30 days after completing ALK5461-217, Investigators will review key eligibility criteria in order to ensure subject still meets 
requirements (Sample checklist is provided in Section 20, Appendix A). 
d ET visit should occur as close as possible to subject’s last dose. 
e Urine drug screen testing will be performed at Visit 1 and at subsequent visits as needed based on the Investigator’s judgment. 
 
f At each specified dispensing visit, subjects will receive a supply of ALKS 5461 to last until the following visit. 
g Adherence for study drug based on subject query. 
 


 
 
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8.3. 
Study Procedures Descriptions 
Details of the study procedures are described below. 
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 on Screening/Day 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 carried over from the antecedent study. 
If ≥30 days have elapsed since end-of-treatment in ALK5461-217, medical history for the 
interval period will be queried and updated as necessary.  
8.3.4. 
Concomitant Medication Review 
At each visit, subjects will be asked about the medications they have taken since the last visit, 
including prescription and nonprescription medications, vitamins, and supplements. In particular, 
use of opioid agonists (eg, codeine, oxycodone, tramadol, or morphine) should be queried. 
The Investigator will record the following data on all medications used by the subject: name, 
dose, regimen, route of administration, start and stop dates, and indication for use. 
8.3.5. 
Study Drug Adherence Review 
At each specified dispensing visit, subjects will receive a supply of ALKS 5461 to last until the 
following visit. Subjects will be instructed to bring the blister pack (see Section 10.4) with them 
to each subsequent visit. Drug adherence for ALKS 5461 will be reviewed with subjects at each 
visit. 
8.3.6. 
Safety Assessments 
8.3.6.1. 
Adverse Event Monitoring 
Adverse events will be monitored continuously from the time a subject signs the informed 
consent document until the completion of the final study visit. Adverse events and serious 
adverse events (SAEs) are defined in Sections 13.1 and 13.2, respectively. Section 13.4 provides 
guidance on the monitoring and recording requirements for AEs. Section 13.5 provides guidance 
on the reporting requirements for SAEs. 


 
 
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8.3.6.2. 
Columbia-Suicide Severity Rating Scale  
The C-SSRS is a clinician-administered instrument that assesses suicidal ideation and behavior 
(Posner et al, 2011). The C-SSRS will be administered at each visit as specified in Table 3 and will 
be assessed for the period since the last visit.  
8.3.7. 
Pregnancy Testing 
A urine pregnancy test will be administered to all participating female subjects predosing and at 
all subsequent visits during the Study period. Results must be negative prior to administration of 
study drug. 
A positive pregnancy test result at any time will necessitate the subject’s immediate withdrawal 
from the study. Additional follow-up may be required as detailed in Section 8.4.1. 
8.3.8. 
Drug testing 
Urine drug screen testing will be performed (via dipstick) at Visit 1. Following that, screening 
will be performed based on the Investigator’s judgment. 
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 and 30 days after the final dose of study drug unless they are surgically 
sterile or postmenopausal (see below). The following are considered acceptable methods of 
contraception: 
1. Double-barrier protection (eg, a condom with spermicide or a diaphragm with 
spermicide) 
2. Intrauterine device 
3. Oral contraceptive pills and other hormonal methods (eg, a vaginal ring, contraceptive 
patch, and contraceptive implant); oral contraceptives should have been initiated at least 
30 days prior to screening 
Subjects who are abstinent are eligible, provided they agree to use an acceptable contraceptive 
method should they become sexually active. 
Subjects who are surgically sterile are exempt from the requirement to use contraception. 
Women who have undergone a hysterectomy, bilateral tubal ligation, or bilateral 
salpingo-oophorectomy are considered surgically sterile. Men who have undergone a vasectomy 
are considered surgically sterile. Partner vasectomy is not considered an approved acceptable 
method of contraception for a female subject. 
Women who are postmenopausal are also exempt from the requirement to use contraception. For 
the purpose of this study, postmenopausal is defined as the permanent cessation of menstruation 
for at least 12 months prior to screening in women who are 45 years of age or older. 
If a subject becomes pregnant while participating in the study, she will be discontinued from 
study drug immediately. The Early Termination and Safety Follow-up visits will be scheduled 


 
 
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and the pregnancy will be reported to Alkermes. Additional follow-up may be required. 
Pregnancies in female partners of male subjects should also be reported and will be followed in 
the same manner. 
A Pregnancy Report Form must be submitted to Alkermes (per Section 13.5) immediately, 
within 24 hours of awareness of the pregnancy, irrespective of whether an AE has occurred. The 
pregnancy will be followed until delivery or termination. If any AE that occurred during 
pregnancy and/or the outcome of the pregnancy meets the criteria for classification as an SAE, it 
should be reported following the SAE procedure (see Section 13.5). 
8.4.2. 
Concomitant Medications 
All medications taken by a given subject between the completion of ALK5461-217 and the first 
dose of ALKS 5461 in this study will be recorded, as detailed in Section 8.3.4. 
Subjects are permitted to continue taking concomitant medications during the study provided that 
these medications are clinically appropriate and are not prohibited. The Investigator may 
discontinue or adjust the dose of any of these concomitant medications to ensure subject safety. 
At the Investigator’s discretion, new concomitant medications may be administered during the 
course of the study for the treatment of an AE or a change in disease state. If a prohibited 
medication is needed, the Investigator should notify the Medical Monitor as soon as possible to 
discuss the continued participation of the subject in the study. 
Dose adjustment of approved ADT during the Treatment period is permitted for optimal 
therapeutic effect within the recommended dose range. Further, subjects are not permitted to 
change ADTs during the course of the study period. 
8.4.2.1. 
Antidepressant Therapy 
Subjects must use the ADT pharmacy card provided during the study and may not seek 
reimbursement from their private insurance and/or local, state or federally funded healthcare 
programs for ADT utilized in the study. 
8.4.3. 
Prohibited Medications 
If a prohibited medication is needed, the Investigator should notify the Medical Monitor as soon 
as possible to discuss the continued participation of the subject in the study. 
Prohibited medications include antipsychotics, additional antidepressants other than the assigned 
background antidepressant, mood stabilizers, varenicline, anxiolytics, and CYP3A4 inhibitors 
and inducers (see Section 21 [Appendix B] for a list of prohibited inducers and 
moderate-to-strong inhibitors of CYP3A4). This is not an exhaustive list of prohibited 
medications. The Investigator should consult with the Medical Monitor regarding other 
potentially prohibited medications. 
Prohibited medication or treatment categories include, but are not restricted to, the following: 
• Agents that might have antidepressant or related pharmacodynamics effects. This 
includes but is not restricted to: 
 Monoamine oxidase inhibitors (eg, phenelzine, tranylcypromine, selegiline) 


 
 
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 Lithium 
 Tricyclic antidepressants (eg, amitriptyline, nortriptyline, desipramine) 
 Psychostimulants (eg, methylphenidate, dextroamphetamine/amphetamine) 
 Bupropion 
 Additional agents (prescription or over-the-counter) for purpose of treating MDD 
or augmenting the effects of the ADT 
• Anti-epileptic medications (eg, topiramate, gabapentin, lamotrigine, or 
oxcarbazepine) at any dose or duration for any indication 
• Opioid agonists (eg, codeine, oxycodone, tramadol, or morphine) or opioid 
antagonists (eg, naloxone or naltrexone) 
• Use of systemic corticosteroids 
• Antipsychotics 
Hypnotic agents will be permitted within the dose range approved by the Food and Drug 
Administration for insomnia. 
8.4.4. 
Pain Management 
Because the ALKS 5461 coformulation contains SAM, a μ-opioid receptor antagonist, subjects 
may experience reduced or ineffective analgesia when taking an opioid analgesic agent 
concurrently with ALKS 5461, including several days after the last dosing of ALKS 5461. 
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, study drug should not be 
administered. If opioid analgesics are required after study drug has been administered, it may 
take several days for opiate sensitivity to be restored, since SAM is an opioid antagonist and 
could interfere with opioid-mediated pain management. 


 
 
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9. 
TREATMENT OF SUBJECTS 
9.1. 
Study Drug Dose and Administration 
9.1.1. 
Description of ALKS 5461 
The ALKS 5461 drug product will be formulated as tablets for SL administration and will 
contain a ratio of 1:1 BUP:SAM as free base equivalents by weight.  
9.1.2. 
Study Drug Dose and Dosing Regimen 
Dosing begins on Day 1. One tablet will be taken SL on each dosing day. The tablet should be 
placed under the tongue and kept under the tongue until completely dissolved. The tablet must 
not be swallowed. Eating and drinking should be avoided for 15 minutes after dosing. At the 
first visit, study site personnel will administer the tablet and visually confirm that the tablet has 
dissolved completely. Subjects will then self-administer the daily SL dose; it is recommended 
that subjects take ALKS 5461 at bedtime. 
9.2. 
Treatment Adherence 
As indicated in Table 3, subjects will receive at each specified dispensing visit a supply of study 
drug (ALKS 5461) that will last until the following visit. Study drug adherence will be reviewed 
with the subject at each visit as specified in Table 3. Subjects will be instructed to bring each 
dispensed blister pack with them to each subsequent visit to return any remaining study drug. 
Full site-level accountability will be carried out as described in Section 10.4.  
9.3. 
Method of Assigning Subjects to Treatment 
All participating subjects will receive ALKS 5461. 
9.4. 
Blinding 
Not applicable. 
9.5. 
Study Drug Dose Adjustment and Stopping Rules 
Beginning on Day 1, all participating subjects will receive open-label ALKS 5461 2/2. No dose 
titration will be allowed. 
Section 7.3 outlines procedure for when a subject discontinues from the study. 


 
 
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10. 
STUDY DRUG MATERIALS AND MANAGEMENT 
10.1. 
Study Drug 
The investigational product for this study is ALKS 5461, a fixed-dose combination of BUP, a 
μ-opioid receptor partial agonist and κ-opioid receptor antagonist, and SAM, a μ-opioid receptor 
antagonist. 
The ALKS 5461 drug product is formulated as tablets for SL administration and will contain a 
ratio of 1:1 BUP:SAM (2 mg BUP:2 mg SAM) as free base equivalents by weight.  
Buprenorphine is a Schedule III narcotic in the United States, and SAM is a Schedule II 
controlled substance in the United States. Therefore, ALKS 5461 must be handled in accordance 
with restrictions related to Schedule II controlled substances in the United States. In Australia, 
ALKS 5461 should be handled according to local regulations. See Section 10.3 and Section 10.5 
for information on storage and handling of controlled substances, respectively. 
Study drug is white-to-off-white in color, non-debossed, triangle-shaped tablet. The SL tablet 
formulation contains excipients commonly used in products approved by the United States Food 
and Drug Administration, and accepted for use as food additives in Europe, including lactose 
monohydrate, microcrystalline cellulose, crospovidone, sucralose, citric acid, sodium citrate, and 
magnesium stearate. 
10.2. 
Packaging and Labeling 
Study drug will be packaged in child-resistant blister packs. All packaging will be labeled in a 
manner that meets applicable local and regulatory requirements. 
Subjects will receive child-resistant blister packs containing 9 tablets at each dispensing visit to 
supply a sufficient number of tablets to last until the next scheduled visit. 
Subjects should follow the dosing instructions as printed on the packaging. 
10.3. 
Storage 
In the US and Australia, ALKS 5461 must be stored in accordance with local controlled 
substance requirements and restrictions related to Schedule II controlled substances. 
The Investigator will take adequate precautions, including storage of the investigational product 
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 
into illegal channels of distribution. 
Complete details on storage condition requirements can be found in the Investigator’s Brochure. 
10.4. 
Accountability 
The Investigator will be responsible for the oversight of recording the receipt and administration 
of study drug, and for insuring the supervision of the storage and allocation of these supplies. 


 
 
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The Investigator is required to maintain current drug dispensing and accountability logs 
throughout the study. The Investigator may delegate accountability duties to an appropriate and 
qualified pharmacist or staff member who is under the supervision of the Investigator. 
The Investigator or designee must allow the Clinical Research Associate or equivalent to 
perform drug reconciliation during each study monitoring visit. All unused supplies will be 
checked against the study drug movement records before investigational product is returned or 
destroyed. 
Subject-level study drug accountability will be documented in the subjects’ source documents. If 
study drug cannot be accounted for, actions will be taken that are appropriate for a drug 
containing controlled substances. These actions may include, but are not limited to, re-training 
subject on adherence or discontinuation of subject from the study. 
The study site is required to maintain current drug dispensation and accountability logs 
throughout the study. All unused supplies will be checked against the drug movement records 
during the study and/or at the end of the study. Any broken or chipped tablets should be stored at 
the sites until drug accountability is completed. 
10.5. 
Handling and Disposal 
In both the US and Australia, all unused study drug must be handled and disposed of in 
accordance with Good Clinical Practice (GCP), Good Manufacturing Practice, and Schedule II 
controlled substance requirements, as applicable. At the end of the study, the Sponsor will 
provide additional instruction as to the disposition of unused study drug. Until instructions have 
been provided, each study site must store unused materials on site in the manner described in 
Section 10.3. All study drug must be accounted for in a drug accountability record. 


 
 
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11. 
ASSESSMENT OF EFFICACY 
No formal efficacy assessments will be conducted in the study. Based on the Investigator’s 
judgment, efficacy assessments consistent with the local clinical practice will be documented. 


 
 
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12. 
ASSESSMENT OF PHARMACOKINETICS 
No pharmacokinetic sampling is planned in this study. 


 
 
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13. 
ASSESSMENT OF SAFETY 
Safety and tolerability will be assessed on the basis of: 
• Adverse events 
• Serious adverse events 
• C-SSRS results  
13.1. 
Definition of Adverse Event 
An AE is any untoward medical occurrence in a patient or clinical investigation subject who has 
been administered a pharmaceutical product. The occurrence, which may or may not have a 
causal relationship with the investigational treatment, may include any clinical or laboratory 
change that does not commonly occur in that subject and is considered clinically significant. 
Illnesses present prior to the subject signing the informed consent form (ICF) are considered to 
be preexisting conditions and are documented on the medical history eCRF. Preexisting 
conditions that worsen during the study are entered on the AE eCRF. 
Pregnancy is not considered an AE although a subject will be withdrawn from the study if a 
pregnancy occurs. As described in Section 8.4.1, the pregnancy, including a partner’s pregnancy, 
must be reported to Alkermes, and additional follow-up may be required. 
13.2. 
Definition of Serious Adverse Events 
An SAE is any AE, occurring at any dose and regardless of causality, that: 
• Results in death 
• Is life-threatening. The subject is at immediate risk of death from the reaction as it 
occurs. This does not include a reaction that, had it occurred in a more severe form, 
might have caused death 
• Requires inpatient hospitalization or prolongation of existing hospitalization 
• Results in persistent or significant disability/incapacity (eg, a substantial disruption of 
a person’s ability to conduct normal life functions) 
• Is a congenital anomaly/birth defect 
Important medical events that may not result in death, be immediately life-threatening, or require 
hospitalization may be considered to be SAEs when, based upon appropriate medical judgment, 
may jeopardize the patient or subject and may require intervention to prevent one of the other 
outcomes listed above. 
Admission to a hospital or an inpatient unit for a nonmedical reason (ie, social stay admission) 
during the study in the absence of untoward medical occurrence will not be considered as an 
SAE but will be captured as an AE. Hospitalization due to worsening of behavioral 
health-related issues should be reported as an SAE. 


 
 
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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 
Subinvestigator) according to his or her best clinical judgment. The criteria listed in Table 4 
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. 
Table 4: 
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 
Adverse event data collection will begin after a subject signs the ICF and will continue until 
completion of the Safety Follow-up visit or 2 weeks after the final dose of study drug. Any AE 
or SAE having an onset after the Safety Follow-up visit will not be collected or reported unless 
the Investigator feels that the event may be related to the study drug. 
Subjects will be instructed by the Investigator or designee to report the occurrence of any AE. 
All volunteered, elicited, and observed AEs are to be recorded on the AE eCRFs. 
The Investigator will assess all AEs regarding any causal relationship to the study drug (see 
Section 13.3), the intensity (severity) of the event, action taken, and subject outcome. 
The following criteria should be used to guide the assessment of intensity (severity): 
• Mild: causes awareness of sign or symptom but is easily tolerated; does not interfere 
with usual activities 
• Moderate: causes discomfort enough to interfere with usual activities 
• Severe: is incapacitating; results in inability to work or perform usual activities 
All AEs will be followed until resolution, until deemed stable by the Investigator, or until the 
subject is deemed by the Investigator to be lost to follow-up. 
For clinical study safety reporting purposes, the most recent version of the Investigator’s 
Brochure will be used as the reference document to designate event expectedness. 
Withdrawal from the study as a result of an AE, and any therapeutic measures that are taken, 
shall be at the discretion of the Investigator. If a subject withdraws from the study for any reason, 
any ongoing AEs will be followed until resolution, until deemed stable by the Investigator, or 
until the subject is deemed by the Investigator to be lost to follow-up. 
13.5. 
Reporting of Serious Adverse Events and Pregnancy 
All SAEs and pregnancies must be reported to 
 within 24 hours of 
discovery by sending an email or facsimile of the report to the following: 
Attention: 
 Safety and Pharmacovigilance 
FAX Number: 
 
In case of fax issues, e-mail: 
 
The written report for SAEs should be submitted on the SAE form provided for this purpose. The 
SAE report must include the Investigator’s opinion as to whether the event is study drug-related. 
If this relationship is determined to be possibly, probably, or definitely related to study drug, 
evidence to support this assessment must also be provided. 
The written report for pregnancies in female subjects and in female partners of male subjects 
should be submitted on the Pregnancy Report Form provided for this purpose. 
 
PPD
PPD
PPD
PPD


 
 
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14. 
STATISTICS 
This extension study is not designed to formally assess ALKS 5461. Data collection will be 
limited to information needed to determine eligibility, describe patient demographics and 
exposure, collect safety information, and meet regulatory reporting requirements. 
14.1. 
Sample Size Considerations 
No formal sample size calculation has been performed for this extension study. A sample size of 
up to 250 subjects is based on an estimated number of subjects who may wish to continue from 
Study ALK5461-217. 
14.2. 
General Statistical Methodology 
Summary statistics (n, mean, standard deviation, median, minimum, and maximum values for 
continuous variables, and number and percentage of subjects in each category for categorical 
variables) will be provided for evaluated variables. All individual subject level data will be 
presented as data listings. 
14.2.1. 
Study Populations 
14.2.1.1. Safety Population 
The Safety Population will consist of all enrolled subjects who received at least one dose of 
study drug (ALKS 5461). 
14.3. 
Demographics and Baseline Characteristic Data 
Demographics and baseline characteristics such as gender, age, race, and weight will be 
summarized with descriptive statistics to assess the comparability of the study groups.  
14.4. 
Efficacy Analyses 
No formal efficacy analysis will be performed for this study.  
14.5. 
Pharmacokinetic Analyses 
No pharmacokinetic analysis will be performed for this study.  
14.6. 
Patient Questionnaire 
Not applicable for this study. 
14.7. 
Safety and Tolerability Analyses 
All safety assessments will be summarized using descriptive statistics. Reported AE terms will 
be coded using the Medical Dictionary for Regulatory Activities (MedDRA).  
Treatment-emergent AEs (TEAEs) will be defined as AEs that occur or worsen after the first 
dose of study drug. The incidence of TEAEs will be summarized by System Organ Classes and 


 
 
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Preferred Terms and by severity and relationship to study drug. Subjects with SAEs and AEs 
leading to discontinuation from the study will be summarized. The number and percentage of 
subjects with C-SSRS assessments at post-baseline will be summarized. Concomitant 
medications will be categorized using the World Health Organization (WHO) Anatomical 
Therapeutic Chemical (ATC) classification system. Listings will be provided for all concomitant 
medications. 
Further details will be described in the Statistical Analysis Plan. 
 


 
 
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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 Council 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 study site’s IRB/IEC must meet all relevant regulatory requirements. The study protocol and 
ICF will be reviewed by the IRB/IEC prior to enrolling subjects into the study; written approval 
from the committee must be received by Alkermes before the drug will be released to the 
Investigator. The protocol must be reapproved by the IRB/IEC upon receipt of amendments and 
annually, as local regulatory requirements require. 
The Investigator is responsible for submitting all protocol changes and SAE reports to the 
IRB/IEC according to local procedures. At a minimum, all SAEs requiring an investigational 
new drug safety report must be immediately reported. 
All relevant correspondence from the IRB/IEC will be forwarded by the respective study site to 
the Sponsor in a timely fashion. 
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. Good Clinical Practice is an international ethical and 
scientific quality standard used for designing, conducting, recording, and reporting studies 
involving the participation of human subjects. Alkermes is committed to complying with this 
standard to provide assurance that the rights, safety, and well-being of study subjects will be 
protected, consistent with the principles having their origin in the Declaration of Helsinki. 
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 ICF that summarizes the pertinent study information and will be 
given ample time to read the form and ask questions about the study. All information is to be 
provided in a language understandable to the subject and must not include any language that 
waives the subject’s legal rights. Prospective subjects must also be informed of their right to 
withdraw consent without prejudice at any time during the study. If the subject chooses to 
participate, he or she must sign the ICF before any study-specific procedures are conducted. 
All subjects will be informed of their rights to privacy and will be made aware that the study data 
will be submitted to Alkermes, the IRB, the contract research organization, 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 in the United States or is withdrawn from investigation. They 
will also be informed that the study Monitor may inspect their medical records to verify the 
accuracy and completeness of the study records and results. 
Significant changes to the protocol or product safety information may require a revision of the 
ICF, which must be reviewed and approved by the IRB and then signed by all applicable study 
participants. 


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


 
 
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18. 
DATA HANDLING AND RECORDKEEPING 
An overview of study data handling and recordkeeping procedures and restrictions is provided in 
the subsequent sections; please refer to the CSA for further details. 
18.1. 
Data Capture 
As stated in Section 16.1, this study will use eCRFs for capturing data. All entries, corrections, 
and alterations will be made by the Investigator or other authorized study personnel. All data 
entries will be verified for accuracy and correctness by independent monitors. The electronic 
data capture system maintains a full audit trail. 
Adverse events will be coded using MedDRA. Concomitant medications will be categorized 
using the WHO-Anatomical Therapeutic Chemical classification system. 
18.2. 
Inspection of Records 
Alkermes or its representative will be allowed to conduct site visits to the investigational 
facilities for the purpose of monitoring any aspect of the study. The Investigator agrees to allow 
the Monitor to inspect the drug storage area, study drug stocks, drug accountability records, 
subject charts and source documents, and other records relative to study conduct. 
18.3. 
Retention of Records 
Retention and storage of all essential clinical study documents shall be governed by the terms 
and conditions of the site’s CSA and in accordance with ICH Guidelines/local regulatory 
requirements as follows: 
Essential documents should be retained until at least 2 years after the last approval of a 
marketing application in an ICH region and until there are no pending or contemplated marketing 
applications in an ICH region, or until at least 2 years have elapsed since the formal 
discontinuation of clinical development of the investigational product. These documents should 
be retained for a longer period, however, if required by the applicable regulatory requirements or 
by the terms of the CSA. It is the responsibility of the Sponsor to inform the 
Investigator/institution as to when these documents no longer need to be retained. 
Subjects’ medical files should be retained in accordance with the applicable legislation and in 
accordance with the maximum period of time permitted by the hospital, institution, or private 
practice. 
18.4. 
Use of Information and Publication Policy 
Data generated in this study are proprietary information that are the sole property of Alkermes. 
Results of the study are to be held in confidence by both the investigators and the Sponsor. 
Please refer to the CSA for details on the procedures for publishing and presenting data. 


 
 
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19. 
REFERENCES 
Bodkin JA, Zornberg GL, Lukas SE, Cole JO. Buprenorphine treatment of refractory depression. 
J Clin Psychopharmacol. 1995;15(1):49-57. doi: 10.1097/00004714-199502000-00008. 
 
Emrich HM, Vogt P, Herz A. Possible antidepressive effects of opioids: Action of 
buprenorphine. Ann N Y Acad Sci. 1982;398:108-112. 
 
Karp J, Butters  MA, Begley AE, et al. Safety, tolerability, and clinical effect of low-dose 
buprenorphine for treatment-resistant depression in midlife and older adults. J Clin Psychiatry. 
2014;75(8):e785-e793. 
 
Newcomer JW. Medical risk in patients with bipolar disorder and schizophrenia. J Clin 
Psychiatry. 2006;67 Suppl 9:25-30. 
 
Nyhuis PW, Gastpar M, Scherbaum N. Opiate treatment in depression refractory to 
antidepressants and electroconvulsive therapy. J Clin Psychopharmacol. 2008;28(5):593-595. 
doi: 10.1097/JCP.0b013e31818638a4. 
 
Posner K, Brown GK, Stanley B, et al. The Columbia-Suicide Severity Rating Scale: initial 
validity and internal consistency findings from three multisite studies with adolescents and 
adults. Am J Psychiatry. 2011;168(12):1266-1277. doi: 10.1176/appi.ajp.2011.10111704. 
 
Rush AJ, Trivedi MH, Wisniewski SR, et al. Acute and longer-term outcomes in depressed 
outpatients requiring one or several treatment steps: A STAR*D report. Am J Psychiatry. 
2006;163(11):1905-1917. 
 
Spielmans GI, Berman MI, Linardatos E, Rosenlicht NZ, Perry A, Tsai AC. Adjunctive atypical 
antipsychotic treatment for major depressive disorder: a meta-analysis of depression, quality of 
life, and safety outcomes. PLoS Med. 2013;10(3). doi: 10.1371/journal.pmed.1001403. 
 
Wesson DR, Ling W. The Clinical Opiate Withdrawal Scale (COWS). J Psychoactive Drugs. 
2003;35(2):253-259. 
Food and Drug Administration. Drug Development and Drug Interactions: Table of Substrates, 
Inhibitors and Inducers. 2016; 
http://www.fda.gov/Drugs/DevelopmentApprovalProcess/DevelopmentResources/DrugInteractio
nsLabeling/ucm093664.htm. Accessed 12 Jun 2018. 


 
 
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20. 
APPENDIX A: CHECKLIST USED TO REVIEW KEY 
ELIGIBILITY CRITERIA WITH SUBJECTS ENTERING 
≥30 DAYS AFTER COMPLETING ALK5461-217 
 
 


 
 
 
 
 
 
 
 
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PPD


 
 
 
 
 
 
 
 
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PPD
PPD


 
 
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21. 
APPENDIX B: PARTIAL LIST OF PROHIBITED 
CYTOCHROME P450 (CYP) 3A4 INHIBITORS AND INDUCERS 
A list of CYP3A4 inhibitors and inducers that subjects are to avoid is presented in Table 5 
below. This list is not comprehensive. 
Table 5: 
Partial List of Cytochrome P450 (CYP) 3A4 Inhibitors and Inducers 
Moderate-to-Strong Inhibitors 
Moderate-to-Strong Inducers 
Aprepitant 
Imatinib 
Bosentan 
Boceprevir 
Ketoconazole 
Carbamazepine 
Ciprofloxacin 
Lopinavir/Ritonavir 
Efavirenz 
Clarithromycin 
Nefazodone 
Enzalutamide 
Conivaptan 
Nelfinavir 
Etravirine 
Crizotinib 
Posaconazole 
Modafinil 
Danoprevir/Ritonavir 
Ritonavir 
Phenobarbital 
Diltiazem 
Saquinavir/Ritonavir 
Phenytoin 
Erythromycin 
Telaprevir 
Rifampin 
Fluconazole 
Troleandomycin 
Rifabutin 
Indinavir/Ritonavir 
Verapamil 
St. John’s Wort 
Itraconazole 
Voriconazole 
 
Source: (Food and Drug Administration, 2016). 

SAP_001.pdf: 
A Phase 3b Extension Study of Adjunctive ALKS 5461 in the 
Treatment of Refractory Major Depressive Disorder 
 
 
Unique Protocol ID: 
ALK5461-218 
NCT Number: 
NCT03610048 
Date of Statistical Analysis 
Plan:  
19 Feb 2020 
 


 
 
STATISTICAL ANALYSIS PLAN  
ALK5461-218 
 
Study Title: 
A Phase 3b Extension Study of Adjunctive ALKS 5461 in the Treatment 
of Refractory Major Depressive Disorder  
Document Status: 
Final Version 1.0 
Document Date: 
19 February 2020 
Based on: 
Study protocol v3.0 (incorporates Amendment 2.0, dated 14 Nov 2019)  
Study protocol v2.0 (incorporates Amendment 1.0, dated 01 August 2018) 
Original study protocol (dated 25 June 2018) 
Sponsor: 
Alkermes, Inc. 
852 Winter Street 
Waltham, MA  02451 
USA 
 
CONFIDENTIAL 
Information and data in this document contain trade secrets and privileged or confidential information, 
which is the property of Alkermes, Inc. No person is authorized to make it public without the written 
permission of Alkermes, Inc. These restrictions or disclosures will apply equally to all future information 
supplied to you that is indicated as privileged or confidential. This study is being conducted in 
compliance with good clinical practice, including the archiving of essential documents. 
 
 
 


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TABLE OF CONTENTS 
TABLE OF CONTENTS .................................................................................................................2 
LIST OF TABLES ...........................................................................................................................4 
LIST OF FIGURES .........................................................................................................................4 
LIST OF ABBREVIATIONS ..........................................................................................................5 
1. 
INTRODUCTION ........................................................................................................6 
1.1. 
Study Objectives ...........................................................................................................6 
1.2. 
Summary of the Study Design and Schedule of Assessments ......................................6 
1.3. 
Criteria for Evaluation ..................................................................................................7 
2. 
SAMPLE SIZE CONSIDERATION ............................................................................7 
3. 
DATA ANALYSIS ......................................................................................................8 
3.1. 
General Statistical Methodology ..................................................................................8 
3.2. 
Study Population ...........................................................................................................8 
3.2.1. 
Definitions of Analysis Populations .............................................................................8 
3.2.2. 
Definitions of Baseline and Analysis Periods ..............................................................8 
3.2.3. 
Disposition ....................................................................................................................9 
3.2.4. 
Protocol Deviations ......................................................................................................9 
3.3. 
Demographic Characteristics ........................................................................................9 
3.4. 
Prior and Concomitant Medications .............................................................................9 
3.5. 
Treatment Adherence Rate and Extent of Exposure ...................................................10 
3.6. 
Safety Analysis ...........................................................................................................10 
3.6.1. 
General Considerations ...............................................................................................10 
3.6.2. 
Adverse Events ...........................................................................................................10 
3.6.3. 
Columbia Suicide Severity Rating Scale (C-SSRS) ...................................................11 
3.6.4. 
Other Safety Assessments ...........................................................................................12 
4. 
INTERIM ANALYSES ..............................................................................................13 
5. 
CHANGES IN CONDUCT OR PLANNED ANALYSES FROM THE 
PROTOCOL ...............................................................................................................13 
6. 
DEFINITIONS AND CONVENTIONS FOR HANDLING OF THE DATA ..........13 
6.1. 
Analysis Visit Windows .............................................................................................13 
6.2. 
Handling of Partial Dates of Prior and Concomitant Medications .............................13 
7. 
GENERAL STATISTICAL METHODOLOGY .......................................................13 
7.1. 
Statistical Conventions ...............................................................................................13 


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7.2. 
Reporting Precision ....................................................................................................13 
7.3. 
PROGRAMMING SPECIFICATIONS .....................................................................14 
8. 
MOCK TABLES, LISTINGS AND FIGURES (TLFS) ............................................14 
9. 
REFERENCES ...........................................................................................................14 
 
 
 
 


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LIST OF TABLES 
Table 1: 
Schedule of Safety Assessments ...................................................................................7 
Table 2: 
C-SSRS Summary Categories for Analysis ................................................................12 
Table 3: 
Degree of Precision .....................................................................................................13 
 
LIST OF FIGURES 
Figure 1: 
Study Design Schematic ...............................................................................................7 
 
 
 
 


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LIST OF ABBREVIATIONS 
The following abbreviations are used in the statistical analysis plan. 
Abbreviation 
Definition 
ADT 
Antidepressant Therapy 
AE  
Adverse Event  
BUP 
Buprenorphine 
CRF 
Case Report Form 
C-SSRS 
Columbia Suicide Severity Rating Scale 
EOT 
End of Treatment  
EOS 
End of Study  
ET 
Early Termination 
MDD 
Major Depressive Disorder 
MedDRA 
Medical Dictionary for Regulatory Activities 
PDEAE 
Post-discontinuation Emergent Adverse Event 
PT 
Preferred Term 
SAE 
Serious Adverse Event 
SAP 
Statistical Analysis Plan 
SD 
Standard Deviation 
SOC 
System Organ Class 
TEAE 
Treatment-Emergent Adverse Events 


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1. 
INTRODUCTION 
This statistical analysis plan (SAP) describes the statistical methods and data presentation to be 
used at study completion for analyzing and reporting ALKS 5461 data for Study ALK5461-218, 
A Phase 3b Extension Study of Adjunctive ALKS 5461 in the Treatment of Refractory Major 
Depressive Disorder (MDD). This document has been prepared based on Alkermes ALK5461-
218 study protocol v3.0 (dated 19 November 2019) [1]. 
1.1. 
Study Objectives 
The objective of this study is to evaluate the long-term safety and tolerability of adjunctive 
ALKS 5461 in adults who have treatment-refractory MDD. 
1.2. 
Summary of the Study Design and Schedule of Assessments 
This is an open-label, Phase 3b, multicenter extension study to evaluate the long-term safety and 
tolerability of ALKS 5461 administration for use as an adjunctive therapy to antidepressants for the 
treatment of refractory MDD. Subjects who complete participation in the ALK5461-217 study will 
be eligible for enrollment into the study.  
At Visit 1 (day 1), all eligible, consenting subjects will begin the treatment period. One tablet will be 
taken sublingual on each dosing day. From Day 1 onward, all participating subjects will take 
ALKS 5461 2/2 mg and an approved antidepressant therapy (ADT).  
Study staff will administer the first dose of ALKS 5461 on Day 1. From that point on during the 
treatment period, the staff will dispense ALKS 5461 for subjects’ self-administration. Subjects will 
be advised to take the study drug at bedtime.  
During the treatment period, subjects will return to the clinic for periodic scheduled visits, at which 
time safety and tolerability will be assessed, as well as a 2-week post-discontinuation Follow-up 
visit.  
For a missed visit, the study site should attempt to contact the subject to reschedule. Subjects who 
discontinue from the study prematurely will be encouraged to return for an Early Termination visit 
and a 2-week post-discontinuation Follow-up visit.  
Subjects’ demographic data will be carried over from the ALK5461-217 study. If ≥30 days have 
elapsed since end-of-treatment in ALK5461-217, medical and psychiatric history for the intervening 
period will be queried and updated in the ALK5461-218 database as necessary.  
At each visit, subjects will be asked about the medications they have taken since the last visit. 
Drug adherence for ALKS 5461 will be reviewed with subjects at each visit. 
Please refer to the protocol for a detailed schedule of assessments. A brief schematic of study 
design is provided in Figure 1. A summary of the schedule of safety assessments is presented in  


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Table 1.  
 
 
 
Figure 1: 
Study Design Schematic 
 
 
 
 
 
 
 
Table 1: 
Schedule of Safety Assessments  
Procedure or Assessment 
Schedule 
Dispensation of study drug 
All scheduled visits prior to End of Treatment or Early Termination Visit (i.e., Screening 
[Day 1], weeks 1, 2, 6, 12, 20, 28, 36, 44, 52, 60) 
• Adverse Event  
• C-SSRS (since last visit) 
• Drug Adherence 
• Concomitant Medications 
• Urine Pregnancy Test  
Screening (Day 1), weeks 1, 2, 6, 12, 20, 28, 36, 44, 52, 60, 68 (ET/EOT), 14 days after 
last dose (Follow-up visit) 
Urine Drug Screen 
Screening (Day 1), at subsequent visits as needed based on the investigator’s judgment 
Abbreviations: C-SSRS=Columbia-Suicide Severity Rating Scale; EOT=end of treatment; ET=early termination 
1.3. 
Criteria for Evaluation 
Safety and Tolerability: 
The following assessments will be collected to measure safety and tolerability throughout the 
study: 
• Adverse events (AEs) 
• Serious adverse events (SAEs) 
• Columbia Suicide Severity Rating Scale (C-SSRS) 
Up to 68 weeks 
ALK5461-217 
Treatment 
Period 
Follow-up 
Period 
2 weeks 
Visit 12 
(ET/EOT) 
Follow-up Visit 
(EOS) 
Visit 1 
(Baseline) 
Abbreviations: EOS=end of study; EOT=end of treatment; ET=early termination 


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2. 
SAMPLE SIZE CONSIDERATION 
No formal sample size calculation has been performed. A sample size of up to 250 subjects is based 
on an estimated number of subjects who may wish to continue from Study ALK5461-217. 
3. 
DATA ANALYSIS 
3.1. 
General Statistical Methodology  
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 for subjects receiving one or more doses on ALKS 5461. Summary 
statistics will be based on observed data. In general, only data collected during the ALK5461-218 
study will be summarized even though baseline demographic data may have been assessed in study 
ALK5461-217.    
Source data for the summary tables will be presented as subject data listings.  
3.2. 
Study Population 
3.2.1. 
Definitions of Analysis Populations 
Safety Population will consist of all enrolled subjects who received at least 1 dose of study drug 
in the ALK5461-218 study.  
Post-discontinuation Safety Population will consist of subjects who received at least 1 dose of 
study drug in the ALK5461-218 study, and met one of the following criteria: 
• Subjects who entered the Post-discontinuation Period and had a Post-discontinuation 
Follow-up Visit  
• Subjects who did not enter the Post-discontinuation Period (i.e., final visit was last visit 
in treatment period), but had at least 1 PDEAE reported 
• Subjects who died after either completing the treatment or having an Early Termination 
(ET) Visit 
3.2.2. 
Definitions of Baseline and Analysis Periods 
Baseline 
For demographics and baseline disease characteristics, baseline will be defined as assessments 
recorded at Visit 1. Note that the actual assessment for some variables was made in the 
antecedent study, ALK5461-217. For adverse events, baseline will be defined as prior to Visit 1 
(i.e., the period from completion of ALK5461-217 to first dose received in ALK5461-218).  For 
the Columbia-Suicide Severity Rating Scale (C-SSRS) baseline will be defined as the assessment 
made during Visit 1.  
Treatment Period 
The treatment exposure period (i.e., Treatment Period) will be defined as the interval between 
Visit 1 and the last dose date plus 1 day, inclusive. 


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Visit 1 is the first scheduled visit during the scheduled treatment period and Visit 12 is the last 
scheduled visit including ET visit during treatment. 
Post-Discontinuation Period 
Post-discontinuation Safety Period will be defined as the interval starting from the last dose date 
plus 2 days to the end of study date, inclusive.  
3.2.3. 
Disposition 
Subject disposition will be summarized for all subjects. The number and percentage of subjects 
will be summarized for the following: 
• Subjects who enrolled in the study 
• Subjects in the Safety Population 
• Subject who completed treatment (as indicated on the case report form (CRF)) 
• Subjects who completed the study (as indicated on the CRF)  
• Subjects who discontinued from the study  
For subjects who prematurely discontinue from the study, the reasons for discontinuation as 
recorded on the disposition CRF will be presented. Percentage will be calculated based on Safety 
Population.  
A listing of disposition for all subjects will be provided. 
3.2.4. 
Protocol Deviations 
Subjects with major protocol deviations will be summarized along with supportive listings for 
each of the following categories: 
• Did not meet the inclusion / exclusion criteria 
• Received prohibited medications 
• Dosing error 
• Other major protocol deviation 
3.3. 
Demographic Characteristics 
Demographic characteristics data (i.e., age, gender, primary race, ethnicity and region (United 
States [US], non-US)) will be summarized for the Safety Population. Categories for missing data 
will be provided as necessary.  
Medical history collected since the completion of the antecedent study will be summarized using 
the number of observations and percentage of subjects reporting each category for the Safety 
Population. 
Demographic and baseline listings will be provided for all subjects.  


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3.4. 
Prior and Concomitant Medications 
Prior medications are defined as medications taken between the completion of study ALK5461-
217 and the first dose of ALKS 5461 in this study. Concomitant medications are defined as 
medications taken during the treatment period (defined as first dose date and the last dose date of 
study drug plus 1 day, inclusive). All medications as documented by the investigator will be 
coded using the WHODrug Format C, Version March 2017, WHO DDE + Herbal.  
Prior medications and concomitant medications will be summarized by Preferred Term (PT) for 
the Safety Population. 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.  
Listings will be provided for all prior and concomitant medications.  
3.5. 
Treatment Adherence Rate and Extent of Exposure 
Treatment adherence to the daily dosing schedule of study drug is measured as the rate of actual 
compared to intended number of doses to be taken during the ALK5461-218 study. Percentage 
of treatment adherence will be calculated during the treatment period for the Safety Population as 
follows:  
100 ×
Total tablets taken
Total tablets subject should have taken from the first dose date to the last dose date, inclusive 
Duration of exposure to study drug is defined as the number of days from the first dose date of 
study drug taken to the date of the last dose taken during the ALK5461-218 study, inclusive.    
Treatment adherence and exposure of study drug will be summarized for the Safety Population. 
Treatment adherence will be summarized as a continuous measure and as a categorical measure 
for each adherence rate category (rounded to the whole number): <70%; ≥70% to 80%; >80% to 
90%; >90% to 100%; >100% to 110%; >110% to 120%; and >120%.   
The number of subjects exposed to study drug and the extent of exposure (i.e., days of treatment) 
will be summarized as a continuous measure using descriptive statistics.    
3.6. 
Safety Analysis 
3.6.1. 
General Considerations 
All safety endpoints will be summarized based on observed data for the Safety Population during 
the Treatment Period / during the Post-discontinuation Safety Period.  
3.6.2. 
Adverse Events 
Adverse events will be coded by System Organ Class (SOC) and Preferred Term using the 
Medical Dictionary for Regulatory Activities (MedDRA, version 20.0). The verbatim term will 
be included in the AE listings.  
An AE will be considered as a treatment-emergent adverse event (TEAE) if it starts or worsens 
(if present during baseline period) on or after first dose date during the treatment period (defined 
as the period between the first dose date and last dose date +1). An AE will be considered as a 
PDEAE if it starts during the Post-discontinuation Safety Period (defined as after the period after 
last dose date plus 2 days, inclusive, and include AEs with preferred terms that may have also 


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been TEAEs during the Treatment Period. For the determination of TEAEs during the treatment 
period, AEs with the greatest severity before the baseline will be used as the benchmark for the 
comparison of the AEs occurring during the treatment period. For PDEAEs, all AEs starting 
during the Post-discontinuation Safety Period will be summarized.  
All AEs will be listed by subject. TEAEs / PDEAEs, deaths, serious adverse events (SAEs), and 
AEs leading to study discontinuation will be included in the summary tables. For AEs leading to 
study discontinuation or deaths, the AEs will be summarized in the period in which the 
discontinuation or death occurred. Drug-related TEAEs include those scored as definitely 
related, probably related, and possibly related by the investigator. 
The following summary tables will be produced for the treatment period / Post-discontinuation 
Safety Period for the Safety Population: 
•   Overview AE summary tables (TEAEs / PDEAEs) 
•   TEAEs / PDEAEs by System Organ Class and Preferred Term 
•   TEAEs / PDEAEs by Preferred Term  
•   TEAEs / PDEAEs experienced by ≥5% of subjects by Preferred Term  
•   TEAEs / PDEAEs by System Organ Class, Preferred Term, and Severity 
•   Drug-related TEAEs by Preferred Term 
•   SAEs (fatal and non-fatal) by Preferred Term  
•   AEs leading to study discontinuation by System Organ Class and Preferred Term 
•   AEs leading to study discontinuation by Preferred Term 
A subject having the same AE (as determined by the coded MedDRA preferred term) more than 
once will be counted only once in the calculation of the number and percentage of subjects for 
that AE. Similarly, if a subject has more than one AE in a System Organ Class, the subject will 
be counted only once in the number of subjects with an AE for that System Organ Class. If a 
subject has the same AE on multiple occasions, the highest severity (severe > moderate > mild) 
recorded for the event will be presented in the AE by severity summary. Similarly, if a subject 
has the same AE on multiple occasions, the closest relationship (related > not related, where 
related includes definitely related, probably related, and possibly related; and not related includes 
probably not related and definitely not related) recorded for the event will be presented in the AE 
by relationship summary.  
Subgroup analyses are planned for TEAEs only. Subgroups to include:  
• Demographics (age [<55 years, ≥55 years], race [white, all other races], gender [female, 
male]) 
• Region (US, non-US) 
Subject listings for AEs will be included. 


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3.6.3. 
Columbia Suicide Severity Rating Scale (C-SSRS) 
Columbia Suicide Severity Rating Scale items of suicidal behavior and suicidal ideation will be 
summarized at baseline (Visit 1) and post-baseline for the Safety Population. The proportion of 
subjects who meet the criterion for each of these four categories (suicidal behavior, suicidal 
ideation, suicidal behavior or ideation, and self-injurious behavior without suicidal intent) as 
described in Table 2:  will be summarized. In addition, each item will be presented separately 
within each category. Data will be presented for baseline, any post-baseline during the treatment 
period, at last post-baseline visit during the treatment period, and any post-discontinuation values. 
Any behaviors experienced will be listed with a brief narrative. Any completed suicides will be 
presented with full narrative.  
Table 2: 
C-SSRS Summary Categories for Analysis 
Category 
C-SSRS item response is "YES"  
Suicidal ideation 
1) Wish to be dead 
2) Non-specific active suicidal thoughts  
3) Active suicidal ideation with any methods 
(not plan) without intent to act  
4) Active suicidal ideation with some intent to 
act, without specific plan 
5) Active suicidal ideation with specific plan 
and intent 
Suicidal behavior 
6) Preparatory acts or behavior 
7) Aborted attempt  
8) Interrupted attempt  
9) Actual attempt 
10) Completed suicide 
Suicidal behavior or ideation 
Including 10 items above 
Self-injurious behavior without suicidal intent 
Purely for other reasons / without any intention of 
killing yourself 
3.6.4. 
Other Safety Assessments 
 
Listings for urine pregnancy test and urine drug screen will be provided.  


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4. 
INTERIM ANALYSES  
No interim analysis is planned.   
5. 
CHANGES IN CONDUCT OR PLANNED ANALYSES FROM 
THE PROTOCOL 
Not applicable. 
6. 
DEFINITIONS AND CONVENTIONS FOR HANDLING OF THE 
DATA 
Dataset specifications will be provided in a separate document. 
6.1. 
Analysis Visit Windows 
Not applicable. Longitudinal analysis is not planned. 
6.2. 
Handling of Partial Dates of Prior and Concomitant Medications 
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. 
7. 
GENERAL STATISTICAL METHODOLOGY 
7.1. 
Statistical Conventions 
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. All summary tables will be based on observed data, and 
missing values will not be imputed. Source data for the summary tables and statistical analyses 
will be presented as subject data listings. 
7.2. 
Reporting Precision 
Summary statistics will be presented to the degree of precision in 5, unless otherwise specified. 
Table 3: 
Degree of Precision 
Statistics 
Degree of Precision 
Mean, Median, Quartiles 
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. 
Percentage 
One decimal place. A percentage of 100% will be 


Alkermes, Inc.                                                                                                                ALKS 5461  
 
CONFIDENTIAL                                                                                              SAP-ALK5461-218 
 
 
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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).  
7.3. 
PROGRAMMING SPECIFICATIONS 
Programming specifications will be provided in a separate document. 
8. 
MOCK TABLES, LISTINGS AND FIGURES (TLFS) 
Mock-up tables, listings, and figures will be provided in a separate document. 
9. 
REFERENCES