OLANI PK/Safety Study in Healthy Volunteers
Phase: PHASE1
Conditions: Opioid Use Disorder
Sponsor: Go Medical Industries Pty Ltd

A PILOT PHARMACOKINETIC TRIAL OF THE O’NEIL LONG ACTING NALTREXONE IMPLANT 
CONFIDENTIAL  
 
 
 
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A PILOT PHARMACOKINETIC TRIAL OF THE O’NEIL LONG 
ACTING NALTREXONE IMPLANT 
 
 
Protocol Identifying Number: GM0017  
Principal Investigator: Dr. Adam Bisaga 
Sponsor: Go Medical Industries Pty Ltd 
Funded by: NIDA 1UG3DA047720-01 
Version Number: GM0017 v 0.13 
11 June 2020 
 
 
 

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I. 
TABLE OF CONTENTS 
I. 
TABLE OF CONTENTS ............................................................................................................. ii 
II. 
INDEX OF TABLES AND FIGURES ........................................................................................ vi 
III. 
LIST OF ABBREVIATIONS AND DEFINITION OF TERMS ....................................................vii 
IV. 
STATEMENT OF COMPLIANCE ............................................................................................. ix 
V. 
PROTOCOL SUMMARY ........................................................................................................... x 
VI. 
SCHEMATIC OF STUDY DESIGN ..........................................................................................XII 
1 
KEY ROLES ............................................................................................................................. 13 
1.1 
SPONSOR ............................................................................................................................... 13 
1.2 
PRINCIPAL INVESTIGATOR .................................................................................................. 13 
1.3 
INSTITUTE .............................................................................................................................. 13 
1.3.1 
SATELLITE LOCATION 1 .............................................................................................. 13 
1.3.2 
SATELLITE LOCATION 2 .............................................................................................. 13 
1.4 
CLINICAL LABORATORY ....................................................................................................... 13 
1.5 
CENTRAL CLINICAL LABORATORY ..................................................................................... 13 
1.6 
RESPONSIBLE CLINICIAN ..................................................................................................... 13 
1.7 
IMPLANTATION PROCEDURE SURGEON ........................................................................... 13 
1.8 
SPONSOR REPRESENTATIVE ............................................................................................. 14 
1.9 
INSTITUTE REPRESENTATIVE ............................................................................................. 14 
1.9.1 
SATELLITE LOCATION 1 REPRESENTATIVE ............................................................ 14 
1.9.2 
SATELLITE LOCATION 2 REPRESENTATIVE ............................................................ 14 
1.10 
CLINICAL TRIAL CO-ORDINATOR ........................................................................................ 14 
1.11 
STATISTICIAN ......................................................................................................................... 14 
1.12 
CLINICAL RESEARCH ASSOCIATE ...................................................................................... 14 
2 
INTRODUCTION: BACKGROUND INFORMATION AND SCIENTIFIC ................................. 15 
2.1 
BACKGROUND INFORMATION ............................................................................................. 15 
2.1.1 
Metabolism of Naltrexone .............................................................................................. 15 
2.1.2 
Clinical Use of Naltrexone .............................................................................................. 15 
2.1.3 
Sustained Release Preparations ................................................................................... 16 
2.1.4 
Investigational Product: O’Neil Long Acting Naltrexone Implant (OLANI) – In Vitro 
Information ..................................................................................................................... 16 
2.1.5 
OLANI: Clinical Trials ..................................................................................................... 18 
2.1.6 
Clinical Use Summary .................................................................................................... 19 
2.2 
STUDY RATIONALE ............................................................................................................... 24 
2.3 
POTENTIAL RISKS AND BENEFITS ...................................................................................... 24 
2.3.1 
Known Potential Risks ................................................................................................... 24 
2.3.2 
Known Potential Benefits ............................................................................................... 25 
3 
OBJECTIVES AND PURPOSE ............................................................................................... 26 
3.1 
PRIMARY OBJECTIVES ......................................................................................................... 26 
3.2 
SECONDARY OBJECTIVES ................................................................................................... 26 

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4 
STUDY DESIGN AND ENDPOINTS ....................................................................................... 27 
4.1 
DESCRIPTION OF THE STUDY DESIGN .............................................................................. 27 
4.2 
STUDY ENDPOINTS ............................................................................................................... 27 
4.2.1 
Primary Endpoint............................................................................................................ 27 
4.2.2 
Secondary Endpoints ..................................................................................................... 27 
4.2.3 
Primary Efficacy Endpoint: ............................................................................................. 27 
4.2.4 
Secondary Efficacy Endpoints: ...................................................................................... 27 
4.2.5 
Exploratory Efficacy Endpoints: ..................................................................................... 27 
5 
STUDY ENROLMENT AND WITHDRAWAL ........................................................................... 28 
5.1 
PARTICIPANT INCLUSION CRITERIA ................................................................................... 28 
5.2 
PARTICIPANT EXCLUSION CRITERIA ................................................................................. 28 
5.3 
STRATEGIES FOR RECRUITMENT AND RETENTION ........................................................ 29 
5.3.1 
Target Sample Size: ...................................................................................................... 29 
5.3.2 
Recruitment .................................................................................................................... 29 
5.3.3 
Retention ........................................................................................................................ 30 
5.4 
PARTICIPANT WITHDRAWAL OR TERMINATION ............................................................... 30 
5.4.1 
Reasons for Withdrawal or Termination ........................................................................ 30 
5.4.2 
Handling of Participant Withdrawals or Termination ...................................................... 30 
5.5 
PREMATURE TERMINATION OR SUSPENSION OF STUDY .............................................. 31 
6 
STUDY AGENT ....................................................................................................................... 32 
6.1 
STUDY AGENT(S) AND CONTROL DESCRIPTION ............................................................. 32 
6.1.1 
Acquisition ...................................................................................................................... 32 
6.1.2 
Formulation, Appearance, Packaging and Labelling ..................................................... 32 
6.1.3 
Product Storage and Stability ........................................................................................ 34 
6.1.4 
Preparation ..................................................................................................................... 34 
6.1.5 
Dosing and Administration ............................................................................................. 34 
6.1.6 
Route of Administration .................................................................................................. 34 
6.1.7 
Starting Dose and Dose Escalation Schedule ............................................................... 35 
6.1.8 
Dose Adjustments/Modifications/Delays ........................................................................ 35 
6.1.9 
Duration of Therapy ....................................................................................................... 35 
6.1.10 
Tracking of Dose ............................................................................................................ 35 
6.1.11 
Device Specific Considerations ..................................................................................... 35 
6.2 
STUDY AGENT ACCOUNTABILITY PROCEDURES ............................................................ 35 
7 
STUDY PROCEDURES AND SCHEDULE ............................................................................. 36 
7.1 
STUDY PROCEDURES/EVALUATIONS ................................................................................ 36 
7.1.1 
Study Specific Procedures ............................................................................................. 36 
7.2 
LABORATORY PROCEDURES/EVALUATIONS ................................................................... 42 
7.2.1 
Clinical Laboratory Evaluations ...................................................................................... 42 
7.2.2 
Other Assays or Procedures .......................................................................................... 43 
7.2.3 
Total amount of Blood to be collected ........................................................................... 43 

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7.2.4 
Specimen Preparation, Handling and Storage .............................................................. 44 
7.2.5 
Specimen Shipment ....................................................................................................... 44 
7.3 
STUDY SCHEDULE ................................................................................................................ 44 
7.3.1 
Screening Visit 1 ............................................................................................................ 44 
7.3.2 
Screening Visit 2 ............................................................................................................ 45 
7.3.3 
Recruitment Visit ............................................................................................................ 45 
7.3.4 
Day -1 to Day 2 (‘Admission’ Days) ............................................................................... 45 
7.3.5 
Follow-Up Day 4 to 540 ................................................................................................. 46 
7.3.6 
Final Study Visit ............................................................................................................. 47 
7.3.7 
Early Termination Visit ................................................................................................... 47 
7.3.8 
Unscheduled Visit .......................................................................................................... 47 
7.3.9 
PK Follow-up Visit .......................................................................................................... 47 
7.3.10 
AE Follow-up Visit .......................................................................................................... 47 
7.3.11 
Assessment Time Point Tables ..................................................................................... 48 
7.4 
CONCOMITANT MEDICATIONS, TREATMENTS AND PROCEDURES .............................. 51 
7.5 
PROHIBITED MEDICATIONS, TREATMENTS AND PROCEDURES ................................... 51 
7.6 
PROPHYLACTIC MEDICATIONS, TREATMENTS AND PROCEDURES ............................. 51 
7.6.1 
Prophylactic Medications ............................................................................................... 51 
7.6.2 
Management of Infection/ Inflammatory Responses to the Wound/Implant Site ........... 51 
7.7 
RESCUE MEDICATIONS, TREATMENTS AND PROCEDURES .......................................... 53 
7.8 
PARTICIPANT ACCESS TO STUDY AGENT AT STUDY CLOSURE ................................... 53 
7.9 
REIMBURSEMENT COSTS .................................................................................................... 54 
8 
ASSESSMENT OF SAFETY ................................................................................................... 55 
8.1 
SPECIFICATION OF SAFETY PARAMETERS ...................................................................... 55 
8.1.1 
Definition of Adverse Events (AE).................................................................................. 55 
8.1.2 
Definition of Serious Adverse Events (SAE) .................................................................. 55 
8.2 
CLASSIFICATION OF AN ADVERSE EVENT ........................................................................ 56 
8.2.1 
Severity of Event ............................................................................................................ 56 
8.2.2 
Relationship to Study Medication and Surgical Procedure ............................................ 56 
8.2.3 
Expectedness................................................................................................................. 57 
8.3 
TIME PERIOD AND FREQUENCY FOR EVENT ASSESSMENT AND FOLLOW-UP .......... 58 
8.4 
REPORTING PROCEDURES ................................................................................................. 58 
8.4.1 
Adverse Event Reporting ............................................................................................... 58 
8.4.2 
Serious Adverse Event Reporting .................................................................................. 58 
8.4.3 
Reporting of Pregnancy ................................................................................................. 59 
8.5 
STUDY HALTING RULES ....................................................................................................... 59 
8.5.1 
Study Termination .......................................................................................................... 59 
8.5.2 
On-Site Audits ................................................................................................................ 60 
8.6 
DATA AND SAFETY MONITORING PLAN ADMINISTRATION ............................................. 60 
8.6.1 
Responsibility for data and safety monitoring (DSM) ..................................................... 60 

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8.6.2 
Frequency of DSM ......................................................................................................... 60 
8.6.3 
DSMB Plan ..................................................................................................................... 60 
9 
CLINICAL MONITORING ........................................................................................................ 61 
10 
STATISTICAL CONSIDERATIONS ......................................................................................... 62 
10.1 
STATISTICAL AND ANALYTICAL PLANS.............................................................................. 62 
10.2 
STATISTICAL HYPOTHESES ................................................................................................ 62 
10.3 
ANALYSIS DATASETS ........................................................................................................... 62 
10.4 
DESCRIPTION OF STATISTICAL METHODS ....................................................................... 62 
10.4.1 
General Approach .......................................................................................................... 62 
10.4.2 
Analysis of the Primary Endpoint ................................................................................... 62 
10.4.3 
Analysis of the Secondary and Exploratory Endpoint(s) ............................................... 62 
10.4.4 
Safety Analyses ............................................................................................................. 62 
10.4.5 
Adherence and Retention Analyses............................................................................... 63 
10.4.6 
Baseline Descriptive Statistics ....................................................................................... 63 
10.4.7 
Planned Interim Analyses .............................................................................................. 63 
10.4.8 
Additional Sub-Group Analyses ..................................................................................... 63 
10.4.9 
Multiple Comparison/ Multiplicity .................................................................................... 63 
10.4.10 
Tabulation of Individual Response Data ........................................................................ 63 
10.4.11 
Exploratory Analyses ..................................................................................................... 63 
10.5 
SAMPLE SIZE ......................................................................................................................... 64 
10.6 
MEASURES TO MINIMIZE BIAS ............................................................................................ 64 
10.6.1 
Enrolment/ Randomization/ Masking Procedures .......................................................... 64 
10.6.2 
Evaluation of Success of Blinding .................................................................................. 64 
10.6.3 
Breaking the Study Blind/Participant Code .................................................................... 64 
11 
SOURCE DOCUMENTS AND ACCESS TO SOURCE DATA/DOCUMENTS ....................... 64 
12 
QUALITY ASSURANCE AND QUALITY CONTROL .............................................................. 64 
13 
ETHICS/PROTECTION OF HUMAN PARTICIPANTS ........................................................... 65 
13.1 
ETHICAL STANDARD ............................................................................................................. 65 
13.2 
INSTITUTIONAL REVIEW BOARD ......................................................................................... 65 
13.3 
INFORMED CONSENT PROCESS ........................................................................................ 65 
13.3.1 
Consent/Assent and Other Informational Documents Provided to Participants ............ 65 
13.3.2 
Consent Procedures and Documentation ...................................................................... 65 
13.4 
PARTICIPANT AND DATA CONFIDENTIALITY ..................................................................... 65 
13.4.1 
Research Use of Stored Human Samples, Specimens or Data .................................... 66 
13.5 
FUTURE USE OF STORED SPECIMENS.............................................................................. 66 
14 
DATA HANDLING AND RECORD KEEPING ......................................................................... 67 
14.1 
DATA COLLECTION AND MANAGEMENT RESPONSIBILITIES.......................................... 67 
14.2 
STUDY RECORDS RETENTION ............................................................................................ 67 
14.3 
PROTOCOL DEVIATIONS ...................................................................................................... 67 
14.4 
PUBLICATION AND DATA SHARING POLICY ...................................................................... 68 

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STUDY ADMINISTRATION ..................................................................................................... 68 
15.1 
STUDY LEADERSHIP ............................................................................................................. 68 
16 
CONFLICT OF INTEREST POLICY ........................................................................................ 68 
17 
REVISION HISTORY ............................................................................................................... 69 
18 
SUMMARY OF CHANGES FROM PREVIOUS VERSION ..................................................... 69 
18.1 
Version 0.6 ............................................................................................................................... 69 
18.2 
Version 0.7 ............................................................................................................................... 72 
18.3 
Version 0.8 ............................................................................................................................... 72 
18.4 
Version 0.9 ............................................................................................................................... 73 
18.5 
Version 0.10 ............................................................................................................................. 74 
18.6 
Version 0.11 ............................................................................................................................. 75 
18.7 
Version 0.12 ............................................................................................................................. 76 
19 
LITERATURE REFERENCES ................................................................................................. 77 
 
II. 
INDEX OF TABLES AND FIGURES 
Table 2-1: List of Clinical Trials Performed During the Development of OLANI ................. 18 
Table 2-2: Total number of second generation OLANI used sorted by treatment .................. 19 
Table 2-3: Opiate Treatments ADRs and SAEs reported between February 2016 and January 
2018 for GM 2nd Generation OLANI’s ................................................................. 20 
Table 2-4: Opiate Treatment ADRs by ICD10 description. .................................................... 21 
Table 2-5: Opiate Treatment SAE’s by ICD10 description. .................................................... 22 
Table 2-6: Treatment of AEs & SAE’s reported as ‘Inflammatory reaction due to implants’ 23 
Table 7-1: Assessment Time Points ......................................................................................... 48 
 
Figure 2.1: Comparison of release rate of spray coated (second generation) vs dip coated (first 
generation), release specification limits highlighted ............................................. 17 
Figure 2.2: Causality Groups ................................................................................................... 20 
Figure 6.1: Applicator with OLANI pellets ............................................................................. 32 
Figure 6.2: Applicator with tablets exposed for delivery ........................................................ 33 
Figure 6.3: First layer packaging ............................................................................................. 33 
Figure 6.4: Second layer packaging ......................................................................................... 34 
Figure 7.1: Usual OLANI placement ....................................................................................... 37 
Figure 7.2: Target insertion of local anesthetic ....................................................................... 38 
Figure 7.3: Correct holding of syringe applicator .................................................................... 39 
Figure 7.4: Syringe applicator insertion................................................................................... 40 
Figure 7.5: Insertion of OLANI using Syringe plunger ........................................................... 41 
Figure 7.6: Correct positioning of OLANI .............................................................................. 41 
 
 

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III. 
LIST OF ABBREVIATIONS AND DEFINITION OF TERMS 
Term or Abbreviation 
Description 
6βN 
6-β-naltrexol 
ADR 
Adverse Drug Reaction 
AE 
Adverse Event 
AMPRF 
Australian Medical Procedures Research Foundation 
AUC 
Area Under the Curve 
BDI 
Beck Depression Inventory-II 
CMP 
Clinical Monitoring Plan 
COWS 
Clinical Opiate Withdrawal Scale 
CRF 
Case Report Form 
CRO 
Contract Research Organization 
CUMC 
Columbia University Medical Center 
DSMB 
Data Safety Monitoring Board 
ECG 
Electrocardiography 
eCRF 
Electronic Case Report Forms 
EUC 
Electrolytes, Urea, Creatinine 
FBC 
Full Blood Count 
FCP 
Full Chemistry Panel 
GCP 
Good Clinical Practice 
GLP 
Good Laboratory Practices 
GMP 
Good Manufacturing Practices 
HREC 
Human Research Ethics Committee 
IB 
Investigator’s Brochure 
ICH 
International Conference on Harmonisation 
IP 
Investigational Product 
IRB 
Institutional Review Board 
LFT 
Liver Function Tests 
MEC 
Minimum Effective Concentration 
MSDS 
Material Safety Data Sheet 
NCT 
Naloxone Challenge Test 
NTX 
Naltrexone 
NYSPI 
New York State Psychiatric Institute 
OLANI 
O’Neil Long Acting Naltrexone Implant 
PHQ 
Patient Health Questionaire 
PI 
Principal Investigator 
QC 
Quality Control 

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Term or Abbreviation 
Description 
UA 
Urinalysis 
UDS 
Urine Drug Screen 
SAE 
Serious Adverse Event 
SAP 
Statistical Analysis Plan 
SLV 
Since Last Visit 
SMC 
Safety Monitoring Committee 
SOP 
Standard Operating Procedure 
SURC 
Substance Use Research Center 
 
 

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V. 
PROTOCOL SUMMARY 
Title: 
A PILOT PHARMACOKINETIC TRIAL OF THE O’NEIL 
LONG ACTING NALTREXONE IMPLANT 
Overview: 
A Phase I/II, Single Arm, Open Label study measuring the 
Pharmacokinetics of the O’Neil Long Acting Naltrexone Implant 
(OLANI).  
This study will examine the pharmacokinetic profile of OLANI over 
540 days in participants without a DSM 5 - Substance Related 
Disorders classification. Participants will be required to undergo a 
Naloxone Challenge Test (NCT) to confirm opiate naivety before 
administration of the study medication. All participants will be treated 
with a double administration of a 1.8g (
) OLANI in an open label 
manner. No randomization will occur. 
Objectives: 
Primary: 
 
 
To characterize the pharmacokinetic profile (Cmax, Tmax, AUC, 
T>MEC, where MEC = 1.33 ng/mL NTX, Time to C0 for naltrexone) 
of the OLANI (2 units).  
Primary outcomes used to determine these properties will be based on 
results from plasma concentration of naltrexone and 6-β-naltrexol as 
ascertained from blood samples taken at the following time points:  
- 0, 3, 6, 12, 24, 48 hours  
- 4, 8, 14, 21, 28, 35, 42, 49, 56, 90, 120, 150, 180, 210, 240, 
270, 300, 330, 360, 390, 420, 450, 480, 510 & 540 days. 
Note: 1.33 ng/mL is a target MEC for this protocol. The MEC will be 
further developed over time. 
Secondary:  
• To characterize the safety profile (i.e. adverse events, laboratory 
results, wound site and inflammatory response rates) of the 
OLANI.  
Endpoint: 
Primary: 
The collection of at least 75% pharmacokinetic blood time points 
including 2 consecutive monthly naltrexone blood levels recorded at 
<0.1 ng/mL in 10 participants.  
Primary Efficacy Endpoint: 
Proportion of participants who tolerate OLANI and maintain blood 
level of naltrexone of at least 1.33 ng/mL at all collected time points to 
≥180 day time point.  
Population: 
20 healthy participants (10 male, 10 female), aged between 18 and 55 
years old, without a DSM 5 - Substance Related Disorders 
classification. 

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Phase: 
I/II 
Number of 
Sites: 
One site: Substance Use Research Centre (SURC), New York State 
Psychiatric Institute, 1051 Riverside Drive, New York, NY 10032, 
USA (initial assessment, follow up to 48 hours, Final Visit or Early 
Termination Visit, and additional follow up visits as appropriate) 
Satellite Location 1: Columbia University Medical Center (CUMC), 
177 Fort Washington Ave., New York, NY 10032, USA (IP 
administration) 
Satellite Location 2: Clinilabs, 423 West 55th St, New York, 10019 
(post 48 hour follow-up) 
Investigation
al Product: 
The investigational product is the O’Neil Long Acting Naltrexone 
Implant (1.8g, 
) x 2 units. The investigational product is a 
biodegradable implant which is administered subcutaneously using a 
minor surgical procedure under local anesthetic. 
Study 
Duration: 
Estimated 22 months 
Participant 
Duration: 
540 days 
 
 

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1 
KEY ROLES 
1.1 
SPONSOR 
Go Medical Industries Pty Ltd,  
200 Churchill Ave, Subiaco, Perth, WA 6008, Australia 
 
 
1.2 
PRINCIPAL INVESTIGATOR 
Adam Bisaga M.D. 
New York State Psychiatric Institute, 1051 Riverside Dr., New York, NY 10032 
 
1.3 
INSTITUTE  
Substance Use Research Center (SURC), New York State Psychiatric Institute, 1051 
Riverside Dr., Unit 120, New York, NY 10032 (Initial assessment, follow up to 48 hours, 
Final Visit or Early Termination Visit, and additional follow up visits as appropriate) 
1.3.1 SATELLITE LOCATION 1 
Columbia University Medical Center (CUMC), 177 Fort Washington Ave., New York, NY 
10032 (IP administration) 
1.3.2 SATELLITE LOCATION 2 
Clinilabs, 423 West 55th St, New York, 10019 (post 48 hour follow-up) 
 
1.4 
CLINICAL LABORATORY 
PK analysis of naltrexone and 6- -naltrexol will be performed by a qualified bioanalytic 
laboratory. No other clinical labs will be performed.  
 
1.5 
CENTRAL CLINICAL LABORATORY 
(LFT, FBC, EUC, URINE DRUG SCREEN AND ROUTINE PATHOLOGY) 
Laboratory Corporation of America 
 
1.6 
RESPONSIBLE CLINICIAN 
Adam Bisaga M.D. 
New York State Psychiatric Institute, 1051 Riverside Dr., New York, NY 10032 
 
 
1.7 
IMPLANTATION PROCEDURE SURGEON 
Christine Rohde, MD, MPH, FACS 
Associate Professor of Surgery at CUMC 
Board Certified in Plastic Surgery 
Chief of Microvascular Services, Department of Surgery 
Columbia University Medical Center 
 

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1.8 
SPONSOR REPRESENTATIVE 
Mr Chin-Tark Chan BSc (IT) BEng (Mech) Hons 
Operations Manager, Pharmaceutical Division 
Go Medical Industries Pty Ltd 
 
1.9 
INSTITUTE REPRESENTATIVE  
Adam Bisaga M.D. 
New York State Psychiatric Institute, 1051 Riverside Dr., Unit 120, New York, NY 10032 
1.9.1 SATELLITE LOCATION 1 REPRESENTATIVE 
Christine Rohde, MD, MPH, FACS 
Columbia University Medical Center (CUMC), 177 Fort Washington Ave., New York, NY 
10032 
1.9.2 SATELLITE LOCATION 2 REPRESENTATIVE 
Provided by Clinilabs, 423 West 55th St, New York, 10019 
 
1.10 CLINICAL TRIAL CO-ORDINATOR 
Kaitlyn Mishlen M.A. New York State Psychiatric Institute, 1051 Riverside Dr., New York, 
NY 10032 
 
1.11 STATISTICIAN 
Provided by Clinilabs, 423 West 55th St, New York, 10019 
 
1.12 CLINICAL RESEARCH ASSOCIATE 
Provided by Clinilabs, 423 West 55th St, New York, 10019 
 
 

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2 
INTRODUCTION: BACKGROUND INFORMATION AND SCIENTIFIC  
2.1 
BACKGROUND INFORMATION 
Naltrexone (NTX) is a synthetic derivative of thebaine, a minor constituent of opium. It is a 
nonspecific pure opioid antagonist. NTX binds competitively to all classes of opioid 
receptors with the following order of preference µ>κ>δ, with a high affinity for the µ-opioid 
receptor. It blocks the effects of opioids by competitive binding at opioid receptors. NTX is 
approved by the FDA for the treatment of opioid dependence/opioid use disorder (OUD) and 
is also approved for the treatment of alcohol use disorder. NTX is currently registered in USA 
as a once daily oral formulation containing 50 mg of NTX and as a once-monthly injectable 
formulation containing 380 mg of NTX.  
2.1.1 Metabolism of Naltrexone  
NTX is well absorbed orally (96%), but it undergoes a significant first pass metabolism 
resulting in only 5 to 40% oral bioavailability. Naltrexone is extensively metabolized in 
humans1. Production of the primary metabolite, 6β-naltrexol (6-BN), is mediated by 
dihydrodiol dehydrogenase, a cytosolic family of enzymes. Two other minor metabolites are 
2-hydroxy-3-methoxy-6β-naltrexol and 2-hydroxy-3-methoxy-naltrexone2. NTX and 6-BN 
terminal half-life values have been reported as ranging from 2 to 10 hours for naltrexone3–5 
and 7.5 to 13 hours for 6-BN3,5,6. Both NTX and 6-BN are excreted primarily by the kidneys. 
There is a large amount of variation in the metabolism and pharmacokinetics of NTX. In one 
study, the enzyme kinetics of the formation of 6-BN from NTX using human liver cytosol 
preparation showed a 2.9 fold variability in Vmax, a 3.2 fold variability in Km and a 7.7 fold 
variability in intrinsic clearance7. The systemic clearance of NTX supersedes the hepatic 
blood flow, suggesting the NTX is highly extracted and extra hepatic sites of drug 
metabolism exist. 
2.1.2 Clinical Use of Naltrexone  
While NTX is a potent antagonist and efficiently blocks the effects of exogenous opioids 
such as heroin, the success of NTX for the treatment of opioid dependence has been limited 
by poor patient compliance with the oral formulation8. Unlike alternative pharmacotherapies 
for opioid dependence such as methadone and buprenorphine, NTX has no positive 
reinforcing effects, ceasing NTX has no withdrawal or negative consequences. Thus there is 
little incentive to continue taking the oral formation, with patients often stopping the 
medication and returning to opioid use. After opioid detoxification, patients are likely to have 
reduced tolerance to opioids. As the blockade of exogenous opioids provided by NTX wanes 
and eventually dissipates completely, patients who have been treated with NTX may respond 
to lower doses of opioids than previously used, just as they would shortly after completing 
detoxification. This could result in potentially life-threatening opioid intoxication (respiratory 
compromise or arrest, circulatory collapse, etc.) if the patient uses previously tolerated doses 
of opioids9. 
Better NTX compliance has been observed when a responsible adult is available to supervise 
daily NTX dosing10. It has been reported that the method of daily oral NTX treatment is not 
an affective long term treatment in most patients11,12. Clinical data has indicated that poor 
medication compliance occurs with daily oral NTX maintenance treatment for opioid 
dependence8,10,13. It has been proposed that the development of a sustained release NTX 
preparation would combat these issues and lead to improved outcomes for opioid users. 
 

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2.1.3 Sustained Release Preparations 
Wise (1984) developed a NTX (70%)-poly(D,L-lactide-co-glycolide) copolymer (30%) 
implant14, which was the first biodegradable drug delivery system approved by the Food and 
Drug Administration (FDA) for clinical testing, but was limited by “burst release” in human 
trials. Previous findings also suggested that polymeric NTX sustained release systems are 
biocompatible formulations15,16. Additionally, several dosage forms have also been proposed. 
For example, a NTX-poly(lactic acid) composite17, which had an effective blocking action to 
morphine in rats for 24 days; NTX-copolymer (90% L-lactic acid and 10% glycolic acid) 
beads18,which would provide constant NTX levels for one month, and a NTX pamoate linear 
poly(ortho esters) disk19, which released NTX pamoate for 21 days. In 2006, Alkermes 
registered a 30 day NTX intramuscular injection known as Vivitrol with the FDA for 
treatment of alcohol dependence, and it was also approved by FDA in 2010 for the treatment 
of opioid dependence20,21. Vivitrol consists of a NTX PLGA microsphere suspension 
delivered intramuscularly via an injection. Some studies revealed that a 380 mg injection can 
produce a blood NTX level of 1.2 ng/mL for approximately four weeks22. However, Vivitrol 
has been found to give dose-dependent effects with some adverse events23. 
2.1.4 Investigational Product: O’Neil Long Acting Naltrexone Implant (OLANI) – In 
Vitro Information 
Basic composition of the OLANI formulations is a proprietary combination of 
 
 
. 
The manufacturing process has been developed from its original laboratory scale and refined 
to more commercial Good Manufacturing Practice (GMP) techniques via a process of 
upscaling. Therefore, the investigational product has evolved into two generations of product. 
The first generation of investigational product was manufactured under smaller scale R&D 
production. Initially the manufacturing tolerances for early investigational product were 
reflective of manufacturing capability and were set as 
 
. 
During product development and upscaling, the manufacturing process was improved to 
allow for more commercially sized manufacturing equipment to be implemented and a 
reduction in residual solvent levels in the final product. The variation itself consists of 
 
 
 
 
 
.  
The second generation of product using the 
 
 
 
 
 
 
 
 
. 

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Continual product improvement has now allowed for the second generation spray coated 
product specification 
 
. 
Preliminary water bath data demonstrates that the release rates for both generations of 
implants are very similar 
 
. Data 
generated from water bath experiments that demonstrates similar release rates between the 
old and new formulations, suggests that the risk of variations to the efficacy and safety of the 
new product is low. 
The biodegradable polylactic based polymer is used in a variety of products e.g. 
 
 
 
 
 
, 
with the authors estimating an incidence of foreign body reaction of 4.9%, from accumulated 
data from 412 patients. 
In-vitro dissolution experiments were conducted with a standardized method. 
 
 
 
 Figure 
2.1 includes a comparison between the initial release rates of the first and second generation 
products.  
Figure 2.1: Comparison of release rate of spray coated (second generation) vs dip coated (first 
generation), release specification limits highlighted 
 
Dissolution data indicates appropriate sustained release characteristics maintained for over 
six months and satisfactory batch-to-batch consistency. The variation between manufacturing 
formulation for first and second generation implants is not considered to be significant as 

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‘fluid drainage/site cleaned’ 0.97% (5 in 515), ‘non-surgical removal’ 0.58% (3 in 515) or 
surgical removal 0.38% (2 in 515).  
The majority of inflammatory reports occur within the first 60 days of implantation with peak 
values around the 56 day mark. It should also be noted that this data represents reports of 
inflammatory reactions received by AMPRF either through proactive follow up 
questionnaires or patients reporting issues to the clinic. Natural attrition of follow up will 
occur over a period of 365 days and thus the reported inflammatory responses may be under 
reported in the latter period of the follow up.  
After inflammatory reactions, the next most common ADR was related to withdrawal state - 
opiate 6.21% (32 in 515) and other associated drug withdrawal symptoms (Insomnia, 
Anxiety, Depression and Nausea) 7.96% (41 in 515). 
Overall it can be concluded that the OLANI is safe and that the perception of efficacy 
amongst patients has outweighed any perceived inconvenience arising from the mild 
inflammatory reactions that have been observed. A method for treatment of inflammatory 
responses is effective with only a small amount of procedures requiring removal of an 
implant for an unresolved inflammatory response. It is also important to have good treatment 
plans in place to help patients post implantation to deal with the expected withdrawal 
symptoms and adjustment to a change in lifestyle from opiate dependence. 
 
2.2 
STUDY RATIONALE 
To date, a number of studies have been carried out on the first generation of the OLANI 
measuring PK, efficacy and safety data. The current study seeks to collect pilot PK data on 
the second generation OLANI in healthy participants without a DSM 5 - Substance Related 
Disorders classification. The use of healthy non-substance dependent volunteers for this 
protocol greatly reduces the risk of opioid withdrawal related AE’s and opioid overdose due 
to sub-therapeutic naltrexone blood levels being recorded. This pilot data will be used in the 
planning and design of a large bioequivalence study on the OLANI.  
 
2.3 
POTENTIAL RISKS AND BENEFITS 
2.3.1 Known Potential Risks 
1. 
When the local anesthetic used during OLANI insertion wears off, the site of 
implantation may be tender. 
2. 
The OLANI may cause irritation or inflammation at or near the site of administration 
as a result of an allergic response or other inflammatory process.  
3. 
There is a risk of infection with any surgical procedure of this type. The risk is 
minimized by use of appropriate sterile technique and ensuring that the formulation 
meets normal pharmaceutical standards for sterility.  
4. 
In the unlikely event the participant requires narcotic painkillers for severe pain; most 
will have a greatly reduced effect whilst naltrexone is still being released from the 
OLANI and higher doses of high potency opioids may need to be used. In instances 
where pain cannot be controlled by other means (such as regional blocks or 
alternative drugs see section 7.7) the OLANI may have to be removed surgically.  

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5. 
Known side-effects from naltrexone include difficulty sleeping, anxiety, nervousness, 
abdominal pain/cramps, nausea and/or vomiting, low energy, join and muscle pain, 
headache, loss of appetite, diarrhea, constipation, increased thirst, increased energy, 
depressive mood, irritability, dizziness, skin rash, delayed ejaculation, erection 
dysfunction, reduced sexual desire, and chills. 
6. 
Naltrexone has been associated with reversible hepatocellular injury indicated by 
elevated liver enzymes when administered at doses substantially greater than the 
doses expected in this study. When used in the lower dose range in opiate dependent 
patients, this risk is remote26,27. Naltrexone is therefore contraindicated in participants 
with acute hepatitis or liver failure, and such participants are excluded from the study. 
Participants with hepatic enzyme levels greater than three times the upper limit of 
normal are excluded. Implantable naltrexone achieves lower blood levels than oral 
naltrexone initially, and blood level should remain lower throughout treatment period 
than levels associated with hepatitis. If naltrexone induced hepatitis were to occur in 
the setting of long-acting preparation, where the naltrexone would be only very 
slowly eliminated, this would prolong exposure to the offending agent. However, the 
experience with injectable and implantable naltrexone also suggests it is safe. In 
studies with injectable naltrexone several participants experienced elevation in liver 
enzymes, which were determined to be related to hepatitis C. Several recent reports 
with injectable naltrexone showed that it poses significantly lower risk of 
hepatotoxicity than previously suspected, even among alcohol and opioid-dependent 
persons including those with HCV and/or HIV infection28–31. In July of 2013, the 
Boxed Warning on the hepatotoxicity was removed from the Vivitrol Package Insert.” 
7. 
Naloxone injection may cause withdrawal symptoms such as nausea, vomiting, 
diarrhea, stomach pain, fever, sweating, body aches, weakness, running nose, 
goosebumps, shivering, increased heart rate, and anxiety. 
 
2.3.2 Known Potential Benefits 
1. 
There are no known potential benefits of this treatment in the study cohort.  
2. 
There is a large potential benefit to the opiate addicted community should the PK pilot 
study provide strong pharmacokinetic data which would aid in getting a long term 
naltrexone product through the registration process and onto the market. 
 
 

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3 
OBJECTIVES AND PURPOSE 
3.1 
PRIMARY OBJECTIVES 
To characterize the pharmacokinetic profile (Cmax, Tmax, AUC, T>MEC, where 
MEC = 1.33 ng/mL NTX, Time to C0 for naltrexone) of the OLANI (2 units).  
Primary outcomes used to determine these properties will be based on results from plasma 
concentration of naltrexone and 6-β-naltrexol as ascertained from blood samples taken at the 
following time points:  
• 0, 3, 6, 12, 24, 48 hours  
• 4, 8, 14, 21, 28, 35, 42, 49, 56, 90, 120, 150, 180, 210, 240, 270, 300, 330, 360, 390, 420, 
450, 480, 510 & 540 days. 
Note: 1.33 ng/mL is a target MEC for this protocol. The MEC will be further developed over 
time. 
3.2 
SECONDARY OBJECTIVES 
• To characterize the safety profile (i.e. AEs, laboratory results, wound site and 
inflammatory response rates) of the OLANI. 
 
 

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4 
STUDY DESIGN AND ENDPOINTS 
4.1 
DESCRIPTION OF THE STUDY DESIGN 
This pilot study is a phase I/II, open label, single-arm pharmacokinetic trial of the OLANI in 
healthy participants without a DSM 5 - Substance Related Disorders classification. PK data 
will be collected in all participants until 2 consecutive monthly naltrexone blood levels 
recorded at <0.1 ng/mL, it is anticipated that this will occur by Day 540. Participants will be 
required to undergo a Naloxone Challenge Test (NCT) to confirm absence of physiological 
dependence on opioids before administration of the study medication. Participants will be 
recruited, treated and followed up at the SURC clinic at the NYSPI. 
All participants will be treated with a double administration of a 1.8g (
) OLANI. 
 
4.2 
STUDY ENDPOINTS 
4.2.1 Primary Endpoint 
• The collection of at least 75% pharmacokinetic blood time points including 2 consecutive 
monthly naltrexone blood levels recorded at <0.1 ng/mL, in 10 participants.  
 
4.2.2 Secondary Endpoints 
• Detailed PK characteristics of the product. 
• The collection of safety information and AEs information over 540 days in participants 
treated with the OLANI. 
 
4.2.3 Primary Efficacy Endpoint: 
• Proportion of participants who tolerate OLANI and maintain blood level of naltrexone of 
at least 1.33 ng/mL at all collected time points to 180 day time point. 
 
4.2.4 Secondary Efficacy Endpoints: 
• Mean Cmax, Tmax, AUC for naltrexone blood level 
• Mean T>MEC for naltrexone, where MEC = 1.33 ng/mL  
• Mean Cmax, Tmax, AUC for 6β-naltrexol blood level 
• Frequency of AEs and SAEs  
 
4.2.5 Exploratory Efficacy Endpoints: 
• Use of drugs (opioids, cocaine, marijuana) and alcohol, as reported by participants and 
detected using urine drug screen (UDS). 
 

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5 
STUDY ENROLMENT AND WITHDRAWAL 
5.1 
PARTICIPANT INCLUSION CRITERIA 
Healthy participants without a DSM 5 - Substance Related Disorders classification will be 
recruited for this study. Participants will be assessed for their general health and mental 
health status. 
Participants will be required to undergo a NCT to confirm opiate naivety before 
administration of the study medication. Participants will be required to not have had a 
naltrexone implant or any other extended release naltrexone preparation administered within 
the last year. A naltrexone blood sample will be taken at baseline to confirm zero naltrexone 
levels for data analysis.  
 
To qualify for the study participation, participants must also be: 
1. Men or women between the ages of 18 and 55 years old (inclusive) 
2. Without DSM 5 - Substance Related Disorders classification; in sustained remission is 
not exclusionary 
3. Able and willing to comply with the requirements of the protocol 
4. Able and willing to provide written informed consent 
5. Willing to undergo a minor surgical procedure under local anesthetic to allow for 
investigational drug administration in the subcutaneous tissue 
6. Have an initial weight between 45.3 and 81.6 kilograms (inclusive) or have a BMI 
inclusive of 18.5 to 30.0 
 
5.2 
PARTICIPANT EXCLUSION CRITERIA 
An individual who meets any of the following criteria will be excluded from participation in 
this study:  
1. Positive UDS at screening for illicit substances. 
2. Is currently on naltrexone medication. 
3. Has had a naltrexone implant in the past 24 months. 
4. Has received treatment with an extended naltrexone product (e.g. Vivitrol) in the past 12 
months. 
5. Has a condition which requires treatment with opioid based medication. 
6. Has a known hypersensitivity to naltrexone. 
7. Has a known hypersensitivity to poly-lactic based materials e.g. biodegradable sutures, 
surgical implants or previous biodegradable implants. 
8. Has a known hypersensitivity to local anesthesia. 
9. Is prone to skin rashes, irritation or has a skin condition such as recurrent eczema that is 
likely to impact the implant site area, or as determined by the evaluating physician. 
10. Demonstrates any abnormal skin tissue in the proposed implantation area. 

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11. Is pregnant or planning to be. Women need to have negative blood pregnancy test at 
screening. Women need to agree to practice dual contraceptives. 
12. Participant is breastfeeding or planning to be.  
13. Has a current significant neurological (including cognitive and psychiatric disorders), 
hepatic, renal, endocrine, cardiovascular, gastrointestinal, pulmonary, hematological or 
metabolic disease unless currently controlled and stable with protocol-allowed medication 
30 days prior to proposed investigational product administration. 
14. Any clinically important abnormal finding as determined by medical history, physical 
examination, ECG or clinical laboratory tests. 
15. Any additional condition(s) that in the investigator’s opinion would prohibit the 
participant from completing the study or would not be in the best interest of the 
participant. 
16.  ALT or AST > 3 times the upper end of the laboratory normal range. 
17. Any methadone use 14 days prior to screening, and up to Study Day 0. 
18. Current DSM 5 diagnosis of schizophrenia, bipolar, anxiety, or depressive disorder, 
confirmed by MINI assessment, or currently treated with medications for anxiety or 
depression.  Past history (in remission DSM 5 classification) of anxiety or depression is 
not exclusionary.   
19. Any elevated risk for suicide measured using the Columbia Suicide Severity Rating 
Scale, endorsing any of the items in the past month (C-SSRS, Lifetime) 
20. Is participating or intending to participate in any other clinical trial during the duration of 
this study. 
 
5.3 
STRATEGIES FOR RECRUITMENT AND RETENTION 
5.3.1 Target Sample Size: 
A total of 20 participants (10 females and 10 males) will be recruited. We expect that 10 of 
the 20 participants will complete the study (50%), which is providing at least 75% valid 
pharmacokinetic blood samples including 2 monthly naltrexone blood levels recorded at 
<0.1 ng/mL. 
 
5.3.2 Recruitment 
After reading the study consent participants will be seen by a research psychiatrist or 
psychologist for a screening evaluation and mental status examination as part of routine 
admission procedures at SURC. Final informed consent for the study will be obtained after 
full psychiatric and medical workup is complete. The research staff knows the protocol well 
and is able to explain study to the participant. Procedures for training staff physicians in each 
protocol and consent form include initial presentations by the Principal Investigator (PI) at 
weekly staff meetings, and weekly discussion of inclusion/exclusion criteria and study 
eligibility for each screening participant. 
The use of the Contract Research Organization (CRO) Clinilabs, will also allow access to 
their participant database where the majority of healthy volunteers are expected to be 
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5.3.3 Retention 
All participants will be reimbursed as per section 7.9 for each clinic visit to compensate them 
for the time spent doing research assessments as well as the cost of transportation. We will 
maintain a close phone contact with participants to confirm each visit, and to reschedule in 
case of the missed visit. 
 
5.4 
PARTICIPANT WITHDRAWAL OR TERMINATION 
5.4.1 Reasons for Withdrawal or Termination 
• A participant may withdraw from the study at any time or for any reason without being 
obliged to divulge their reason for doing so to the investigators or clinic staff.  
• A participant may be withdrawn from the study if there are unacceptable AEs, laboratory 
abnormality or any other medical condition or situation including distress due to effects 
of any study procedure or medication.  
• A participant may be withdrawn from the study if in the opinion of the treating clinician 
the participant’s interests are best served by withdrawing from the study.  
• A participant may be withdrawn from the study if the participant meets an exclusion 
criterion (either newly developed or not previously recognized) that precludes further 
study participation. 
• Participant will be withdrawn from the study if they fail the naloxone challenge test. 
 
5.4.2 Handling of Participant Withdrawals or Termination 
Participants, who do not receive the study medication (OLANI), for any reason, are not 
considered treatment failures. A participant may be discontinued from the study at any time if 
the participant, investigator, or sponsor determines that it is not in the best interest of the 
participant to continue participation. Reasons for discontinuation may include:  
• Adverse event 
• Withdrawal of participant 
• Lost to follow-up 
• Study terminated by investigator 
• Pregnancy 
• Clinical worsening  
• Other 
• Screen Failure 
 
5.4.2.1 Participant Monitoring and Removal from Study 
Medical staff will assess and communicate with the study PI the appropriateness for 
continuation in the research study on a continuous basis and will remove from the trial 
participants with significant clinical deterioration or noncompliance of a type which could be 
dangerous. Criteria for removal from the study will include: 
1. 
Clinical deterioration which cannot be managed safely in the context of outpatient 
treatment. This would include a participant who becomes suicidal, or a participant 

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who goes on severe drug binges (including non-opiate drugs), endangering 
him/herself. 
2. 
Elevation of liver enzymes > 3 times normal. The PI or a study physician is available 
24 hours/day by phone and/or beeper in case of emergency. 
3. 
Participant becomes pregnant. In case of incidental pregnancy, the participant will 
remain in the study and will be followed until the resolution of pregnancy. To reduce 
unnecessary procedures, we will stop PK blood draws, unless clinically indicated, 
however the safety monitoring will continue.  In addition, we will collect safety 
information related to the pregnancy and birth outcomes. After finding an 
incidental pregnancy the removal of the implant will be offered to the participant and 
the participant will decide how best to proceed in consultation with her 
obstetrician.  The decision regarding the pregnancy will affect the decision whether or 
not to remove the implant at any point during the pregnancy. The risk of anesthesia 
differs during different times during pregnancy, however the risks of anesthesia and 
the risks of removal are both minimal. 
If a participant becomes pregnant, PK labs will no longer be collected, but the participant will 
be followed for safety monitoring for the remainder of the study.  
For those who withdraw from the study, (data collection and / or treatment) there are two 
main options: 
Option 1: Withdrawing from data collection and no further contact with study personnel. 
This carries the least amount of risk, with option 2 carrying some risk.  
Option 2: Removal of the study medication via surgical procedure. Whilst removal of the 
study medication is straightforward in the early stages (up to about 10 days), 
removal after this becomes more complex as the OLANI biodegrades. Later 
procedures require a general anesthetic (with access to OR facilities) and may 
result in a large scar – certainly larger than not removing the implant but the extent 
depends on the amount of tissue to be excised. The risks associated with general 
anesthetic vary between people, but about 20% of those receiving general 
anesthesia have minor AEs and 0.2% have major AEs including death. If removal 
of the implant is the only acceptable option to the participant, this will be arranged 
through either Columbia University Medical Center or another local hospital.  
 
5.5 
PREMATURE TERMINATION OR SUSPENSION OF STUDY 
This study may be temporarily suspended or prematurely terminated if there is sufficient 
reasonable cause. Written notification, documenting the reason for study suspension or 
termination, will be provided by the suspending or terminating party to PI and sponsor. If the 
study is prematurely terminated or suspended, the PI will promptly inform the NYSPI IRB, 
(DSMB), FDA and will provide the reason(s) for the termination or suspension. 
Circumstances that may warrant termination or suspension include, but are not limited to: 
• Determination of unexpected, significant, or unacceptable risk to participants 
• Insufficient compliance to protocol requirements 
• Data that are not sufficiently complete and/or evaluable 
• Determination of futility 
 
Study may resume once concerns about safety, protocol compliance, data quality are 
addressed; and satisfy the Sponsor, NYSPI IRB, DSMB and FDA. 
 

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6 
STUDY AGENT 
6.1 
STUDY AGENT(S) AND CONTROL DESCRIPTION 
6.1.1 Acquisition 
The OLANI will be supplied by Go Medical to the PI. 
6.1.2 Formulation, Appearance, Packaging and Labelling  
6.1.2.1 Manufacturing and Sterility 
The OLANI is manufactured by Go Medical Industries Pty Ltd, 200 Churchill Ave, Subiaco, 
Perth, Western Australia, Australia 6008.  
Tel: +61 (0)8 9388 1700, Email: info@gomedical.com.au 
The OLANI is manufactured under the code of GMP. Sterilization (gamma) validation of the 
product at 25KGy is performed in accordance with ISO 11173. Implants are sterilized with 
gamma radiation between a minimum of 25KGy and no more than 40KGy. Regular crushed 
bioburden tests are also conducted on randomly selected samples from each batch. Pyrogen 
testing is also performed on sterilized product at routine periods. 
 
6.1.2.2 Packaging 
The OLANI is packed 10 pellets to one applicator device (Figure 6.1 and Figure 6.2). The 
applicator device is then sealed in a small foil pouch –Figure 6.3. This small foil pouch is 
then in turn sealed in another larger foil pouch –Figure 6.4. The double foiled pouch and 
applicator is labeled with a gamma indicator dot and the product label and sent for gamma 
sterilization. The gamma indicator dot will turn red when exposed to gamma radiation. 
 
 
Figure 6.1: Applicator with OLANI pellets 

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Figure 6.2: Applicator with tablets exposed for delivery 
 
 
Figure 6.3: First layer packaging 
 
 

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Figure 6.4: Second layer packaging 
 
6.1.2.3 Disposal 
The active implants shall be inserted into the subcutaneous tissue; however, the applicator 
device will be removed during the procedure and should be disposed of as per standard 
clinical protocols for biological specimens. The packaging can be disposed of in general 
waste. 
 
6.1.3 Product Storage and Stability 
The investigational product is supplied sterile in a double layer of foil packaging. Storage 
conditions require temperature to be maintained between 8-30°C. Expiration dates are 24 
months from date of sterilization by manufacturer and are listed on the second layer of 
packaging. 
 
6.1.4 Preparation 
The investigational product is supplied sterile in foil packaging. The product will be prepared 
by the treating clinician using aseptic techniques to remove the applicator from the sterile 
packaging.  
 
6.1.5 Dosing and Administration 
All participants will be administered a double dose (two syringes with 10 tablets (1.8 g) each) 
of the OLANI (
). Investigational product will be administered surgically by the trial 
surgeon under local anesthetic. Subcutaneous insertion of the investigational product shall be 
documented as time = 0 for the purposes of pharmacokinetic blood collection. 
 
6.1.6 Route of Administration 
Subcutaneous implant via small surgical procedure conducted under local anesthetic. 

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6.1.7 Starting Dose and Dose Escalation Schedule 
All participants will be administered the same starting dose of 2 x OLANI (
, 1.8g).  
 
6.1.8 Dose Adjustments/Modifications/Delays 
Not applicable 
 
6.1.9 Duration of Therapy 
The duration of therapy will be 540 days. 
 
6.1.10 Tracking of Dose 
All participants will be implanted with the study dose. At each scheduled follow-up visit an 
implant site evaluation will take place. 
 
6.1.11 Device Specific Considerations 
Not applicable. 
 
6.2 
STUDY AGENT ACCOUNTABILITY PROCEDURES 
Go Medical will supply all study medication. The PI (or delegated study personnel) will sign 
that they have received all investigational product. Investigational product will be kept in a 
securely locked, temperature monitored cabinet and a drug inventory maintained. All unused 
supplies must be accounted for and returned to the sponsor in the event it is not used. 
 
 
 

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7 
STUDY PROCEDURES AND SCHEDULE 
7.1 
STUDY PROCEDURES/EVALUATIONS  
7.1.1 Study Specific Procedures 
7.1.1.1 Baseline Evaluation 
Baseline evaluations will take place at the SURC, with two screening assessments being 
carried out, followed by a recruitment visit. The nature of the study and its risks and benefits 
will be explained to the participant by the PI who will also obtain a written informed consent 
from each potential participant prior to the administration of any study-specific procedures. 
The most important aspects of the protocol such as the implant procedure are discussed in 
great detail. The PI confirms that the participant is capable of providing informed consent. 
At the first screening visit, informed consent for collecting information for screening will be 
obtained along with inclusion/exclusion criteria being assessed. The research physician will 
then perform tests as outlined in section 7.3.1.  
At the second screening visit, medical staff or certified research assistants will collect blood 
and urine samples as outlined in section 7.3.2.  
A recruitment visit will then be scheduled, where the research physician confirms that a 
participant meets all inclusion/exclusion criteria, is medically healthy to participate in the 
study. The physician also reviews and signs the inclusion/exclusion checklist and signs off on 
enrollment documentation. A procedure note for the medical chart will be included and 
signed verifying that the study physician reviewed results of the evaluation and obtained 
informed consent. Following study enrollment, the study physician assumes medical 
responsibility and arranging hospitalization for investigational product (IP) administration at 
CUMC followed by hospitalization at SURC. 
 
7.1.1.2 Naloxone challenge test (NCT) 
All participants will undergo a NCT at SURC prior to IP administration. Prior to 
administration of the NCT, a baseline Clinical Opiate Withdrawal Scale (COWS) assessment 
will be obtained. Participants will receive 0.8 mg naloxone, IM, followed by q10 minutes 
observation by research psychiatrist or nurse over 30 minutes for signs and symptoms of 
opiate withdrawal. A COWS assessment will be repeated 10, 20, and 30 minutes after the 
administration of the NCT. If any COWS score increases more than 2 points from baseline, 
the participant will be considered a NCT failure and will not receive the IP. 
Naloxone injection may cause withdrawal symptoms such as nausea, vomiting, diarrhea, 
stomach pain, fever, sweating, body aches, weakness, running nose, goosebumps, shivering, 
increased heart rate, and anxiety. Most of these effects will wear off after 20-30 minutes and 
treatment is usually not needed but in case of severe symptoms, participants will be offered a 
dose of clonidine 0.1 mg and/or clonazepam 0.5 mg. In that case, participants will be 
monitored for up to 6 hours until all symptoms resolve, and they can be released. 
If a participant passes the NCT then they will progress to the IP administration with the 
implantation procedure 7.1.1.3.  

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7.1.1.3 Implantation Procedure 
The investigational product will be administered via a minor surgical procedure conducted at 
CUMC by the study surgeon Dr. Christine Rohde who is a board certified plastic surgeon. 
Prior to the procedure participants will be fitted with an intravenous cannula to aid blood 
collection during the first 48 hours of sampling. The surgical procedure will take 
approximately 30 minutes and will be performed under local anesthesia. The surgical 
procedure will be carried out by the study plastic surgeon trained in the implantation 
procedure (see 1.7) supported by a clinical nurse and another support staff. 
 
Step 1: Have the participant lie on their back on an appropriate operating table 
Step 2: Disinfect hands with approved validated procedures for the institution where the 
procedure is being carried out then apply non-sterile gloves. 
Step 3: Administration of intra-operative prophylactic antibiotic. There is good literature 
evidence for intra-operative prophylactic antibiotics with breast and other implants. 
For this reason, the participant will be given 2g of IV cefazolin (600 mg clindamycin 
if allergic to cephalosporins or penicillin) within 30 minutes preceding the surgery.  
Step 4: The participant’s abdomen is carefully observed and palpated with a view to defining 
the most ideal surgical site. The usual placement of the OLANI is in V-shape (see 
Figure 7.1) with one implant on either side.  
 
 
Figure 7.1: Usual OLANI placement 
 
Step 5: Using a new disposable marker pen, define the area that the local anesthetic will be 
injected into (Figure 7.2). The outer limit of the anesthetic is defined by the outer lines 
and two single lines mark the center of the site. The two central lines guide the position 
that the original lidocaine is inserted into. The outer lines indicate the area that the 
40 mL of bupivacaine is inserted into. 

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again and puts on sterile gloves. The site should then be allowed to dry before 
surrounding the operative site with sterile towels or drapes. 
Step 9: Surgical procedure 
The surgical procedure commences by using a scalpel, blade size 15, where the skin 
at the center of the site is stretched and a 10-12 mm incision approximately 1-2 mm 
deep is created. This initial incision will simply be partially through the skin and so 
the blade is then reversed, and a firm incision is made approximately 5-10 mm deep 
while the reverse blade is used to cut completely through the skin along the 10-12 mm 
incision line. 
 
Note: The following part of the procedure is described for a right-handed 
surgeon. 
Step 10: The surgeon uses their left hand to lift the subcutaneous tissues to the left of the 10 mm 
incision and uses a pair of disposable sterile forceps in their right hand to break 
through into the subcutaneous tissues that they have exposed with their left hand. The 
procedure is then repeated with the opposite hands when inserting the same forceps 
into the subcutaneous tissue on the participant’s right side of the abdomen. 
Pick up the applicator device and remove the applicators cover on the front of the 
instrument, ensuring that the syringe applicator is held correctly (Figure 7.3). Do not 
open the back end of the device as there is a risk of tablets escaping if this is opened 
prematurely.  
 
Figure 7.3: Correct holding of syringe applicator 
 
 
 

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Note: The following description applies to a right-handed surgeon inserting the 
first implant into the participant’s left side of the abdomen.  
Step 11: The surgeon uses their left hand to lift the subcutaneous tissues of the abdominal wall 
just 1-2cm to the left of the incision. The bevel of the applicator should be facing 
upwards and the applicator is inserted carefully into the incision, ensuring that the 
applicator is placed under the adipose tissue but above the muscle sheath (Figure 7.4) 
until firm resistance from the subcutaneous tissues is felt.  
 
Figure 7.4: Syringe applicator insertion 
 
Step 12: Using the surgeons left hand it is then possible to push the subcutaneous tissues against 
the applicator until the applicator advances for 5-10 mm. The surgeon’s left hand is 
then moved 5-10 mm away from the incision and lifts up the adjacent subcutaneous 
tissues. The procedure of then pushing the subcutaneous tissues firmly against the 
bevel of the applicator will allow another 10 mm of movement along the marked 
central line. This procedure is repeated a series of times until the applicator is fully 
inserted and sitting just above the sheath with a significant covering of subcutaneous 
tissues above the applicator. The applicator’s trocar can then be picked up in the 
surgeon’s right hand and the opening of the applicator’s rear cap can then occur 
providing the participant is leaning a little to the left so that there is no risk of tablets 
being lost from the applicator. The trocar is then inserted firmly (Figure 7.5) so that 
the tablets are slowly pushed forward while the applicator is slowly withdrawn.  

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Figure 7.5: Insertion of OLANI using Syringe plunger 
 
If this is carried out carefully then tablets will be in a line rather than pushed into one 
ball (Figure 7.6). It is preferable that the tablets be pushed gently in a line to ensure 
correct placement. 
 
Figure 7.6: Correct positioning of OLANI 
 
Step 13: The procedure is then repeated through the same incision using a second applicator 
syringe to position the OLANI tablets on the other side of the abdomen. The site of 
each OLANI’s will be recorded on the CRF.  
Step 14: Closure of the incision 
It is important that closure be carried out in two layers. The first involves closure of 
the subcutaneous tissues. This should usually be carried with an absorbable suture. 
We recommend a 3-0 monocryl or biosyn deep dermal suture layer. The second layer 
of closure requires the skin to be closed using a cyanoacrylate medical glue. In the 
practical care of those with addictions the glue has proved to be very acceptable as 

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participants who fail to return for routine assessment following their procedures do 
not have the risk of a stitch abscess. Following the application of glue, steri-strips are 
applied, and the wound is covered with a dressing. 
7.1.1.4 Wound Site/Implant Site Assessment 
7.1.1.4.1 SURC Clinic (Initial 48 hours) 
Wound Site/Implant Site Assessment will be carried out by the study PI Dr. Bisaga (trained 
in the evaluation by the study surgeon Dr. Rohde), using the Implant Site Evaluation Form 
(ISEF). The wound/implant site will be assessed at 24 2 hours and 48 hours 2 hours after 
the procedure and more frequently if clinical indicated. Any concerns that are identified by 
the ISEF will be referred to the study surgeon for evaluation and treatment as per 7.6.2.  
 
7.1.1.4.2 Clinilabs Clinic (Post 48 hours) 
Wound Site/Implant Site Assessment will be carried out by a research nurse (trained by the 
study surgeon Dr. Rohde), using the ISEF as per the protocol time points outlined in Table 
7-1. Any concerns that are identified by the ISEF will be initially referred to the Clinilabs 
doctor for evaluation and treatment as per 7.6.2. The Clinilabs doctor will consult with the 
study surgeon if required.  
If there are any concerns to the wound/implant site by the participants outside of regular 
study visits, they will be asked to come to the Clinilabs clinic for evaluation as above. All 
evaluations will be documented using the ISEF.  
Note: As appropriate, participants may be seen for follow-up visits at the SURC clinic (i.e. if 
clinically indicated or if traveling to the Clinilabs clinic presents a hardship to a participant). 
 
7.2 
LABORATORY PROCEDURES/EVALUATIONS 
7.2.1 Clinical Laboratory Evaluations 
Samples will be collected and sent for analysis to Lab Corp. 
 
For the following test, 4.5 mL of blood will be collected in 1 tube (lavender top EDTA tube): 
• [FBC] Full Blood Count: RBC, WBC, Hematocrit, Hemoglobin, Platelet Count, 
Eosinophils, Basophils, Monocytes, Neutrophils, Lymphocytes, Mean Corpuscular 
Volume (MCV), Mean Corpuscular Hemoglobin Concentration (MCHC), Mean 
Corpuscular Hemoglobin (MCH), Reticulocytes, Red cell distribution width (RDW), 
immature granulocytes 
 
For the following tests, 5 mL of blood will be collected in 1 tube (red/grey mottled top gel 
barrier SST tube): 
• [FCP] Full Chemistry Panel with Liver Function Tests: Glucose, Uric Acid, Blood 
Urea Nitrogen (BUN), Creatinine, Sodium, Potassium, Chloride, Calcium , 
Phosphorus, Protein Total, Albumin, Globulin, Albumin/Globulin A/G Ratio, 
Bilirubin (total), Bilirubin (direct), Bilirubin (indirect), Alkaline Phosphatase, Lactate 
Dehydrogenase (LDH) , AST (SGOT), ALT (SGPT), GGT, Iron, Total Cholesterol, 
Triglycerides, HDL Cholesterol, LDL Cholesterol (calculated), Magnesium, CO2, 
CPK, Amylase , Lipase 

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For the following tests, 5 mL of blood will be collected in 1 tube (lavender top EDTA tube): 
• Hepatitis A IGG 
• Hepatitis B Serology 
• Hepatitis C Serology 
 
For the following test, 5 mL of blood will be collected in 1 tube (red/grey mottled top gel 
barrier SST tube): 
• HIV Serology 
 
For the following tests, a sample of urine is collected:  
• UA (Urinalysis) including urine color, appearance, bilirubin, urobilinogen, WBC 
esterase and a microscopic examination (WBC, RBC, epithelial cells, mucus threads, 
bacteria) 
• LEU (Leucocytes), NIT (Nitrite), PRO (Protein), pH, BLD (Blood), SG (Specific 
Gravity), KET (Ketones), GLU (Glucose) 
• [UDS] Full drug screen including morphine, oxycodone, methadone, cocaine, 
amphetamines, hydromorphone, hydrocodone, codeine, methamphetamines, thc, 
benzodiazepines, fentanyl and buprenorphine assay. 
 
Pregnancy test: For all female participants, a blood test is done initially, with urine tests 
done monthly afterwards. A blood test will be used to confirm a positive urine result. 
 
7.2.2 Other Assays or Procedures 
7.2.2.1 Naltrexone Blood Level Assay 
9 mL of whole blood will be collected into 10cc Na Heparin (green top) tubes (see Section 
7.2.4.1 for more details regarding the procedure). 
 
7.2.3 Total amount of Blood to be collected  
The amount of blood drawn for the study is: 
• HIV and Hepatitis screening = 10 mL. 
• FCP and FBC = 180.5 mL (18 x 9.5 mL) 
• Pregnancy testing (Female participants only) = 4 mL (during the trial, a blood test will 
be used to confirm a positive urine result) 
• Total blood samples for naltrexone / naltrexol = 288 mL (32 x 9 mL) 
• There is also the potential for further bloods to be taken on any un-scheduled visit for 
PK bloods (10 mL) and follow-up visit for outstanding AEs (FCP and FBC 9.5 mL) 
post end of trial.  
 
Note: that the total blood samples for naltrexone / naltrexol have been calculated for the 
worst case of participants going out to Day 540. In the event that a participant registers two 
consecutive monthly naltrexone blood levels recorded at <0.1 ng/mL, then the participant will 
be withdrawn from the study and the blood collection will be reduced by 10 mL for every 
monthly time point not required. 

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7.2.4 Specimen Preparation, Handling and Storage 
7.2.4.1 Naltrexone Blood Level Assay 
All naltrexone blood samples will be collected in 1 x 10 mL Na Heparin tubes (9 mL) and 
stored in the refrigerator at 0-4°C until specimen preparation. Specimen preparation will be 
carried out within 30 minutes of collection. This will involve centrifugation of the blood 
sample in an ambient centrifuge for 15 min at 2,000 rpm within 30 minutes of collection to 
enable plasma separation. The plasma will be extracted and transferred into two 2 mL 
cryovials (2 aliquots total). Cryovials with aliquot will be stored in a freezer at no 
warmer than -70°C until shipment. 
All plasma samples up to 48 hours will be collected, processed and stored at NYSPI. All 
plasma samples scheduled after 48 hours will be collected, processed and stored at Clinilabs. 
When batches of greater than 50 samples are available these can then be shipped on dry ice to 
the PK analysis laboratory for free (unconjugated) naltrexone and free (unconjugated) 6-β-
naltrexol analysis. Backup samples will remain stored at Clinilabs and NYSPI for the 
duration of the trial.  
 
7.2.5 Specimen Shipment 
Plasma will be stored for batch shipment to the PK analysis laboratory for analysis. Storage 
of samples at no warmer than -70°C will be done at Clinilabs and NYSPI. Shipment of 
samples to the PK laboratory will be done under dry ice. 
 
7.3 
STUDY SCHEDULE 
7.3.1 Screening Visit 1 
Participant shall be screened for inclusion and exclusion criteria and overall suitability for the 
study.  
• Obtain informed consent for screening. 
• Review medical history to determine eligibility based on inclusion/exclusion criteria. 
• Review medications history to determine eligibility based on inclusion/exclusion criteria. 
• Perform medical and psychiatric examinations, including Patient Health Questionnaire 
(PHQ) and Beck Depression Inventory (BDI-II), MINI-International Neuropsychiatric 
Interview (MINI), needed to determine eligibility based on inclusion/exclusion criteria. 
• Concomitant medication review. 
• Physical (Record BMI) and mental status exam. 
• Vital signs. 
• A 12-lead ECG will be conducted for each measurement, the subject should be resting 
during the 10 minutes prior to the measurement time point and in a semi-recumbent or 
supine position at the measurement timepoint. RR, PR, QRS, QT, QTcF and QTcB will 
be collected. ECGs will be measured with equipment calibrated as per site standard 
operating procedures and will be assessed by a qualified clinician. 
• C-SSRS-Lifetime. 
• Breathalyzer Assessment 

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7.3.2 Screening Visit 2 
Review of inclusion and exclusion criteria and overall suitability for the study. 
• Collect blood for FBC, FCP. 
• Collect urine for UA, and UDS. 
• Collect blood for Hepatitis and HIV tests. 
• Collect blood for baseline naltrexone and 6-β-naltrexol measurement. 
• Collect blood for pregnancy test in female participants. 
• Self-reported substance use (using the Recent Drug Use-Baseline [RDU]). 
• Concomitant medication review. 
• AE Monitoring. 
 
7.3.3 Recruitment Visit 
At the Recruitment visit the following will take place; 
• Review of screening assessments and study inclusion exclusion criteria. All screening 
assessments must be collected within 30 days prior to the Recruitment visit, 
• Obtain informed consent for IP administration. 
• Concomitant medication review. 
• AE Monitoring. 
• Breathalyzer Assessment 
 
7.3.4 Day -1 to Day 2 (‘Admission’ Days) 
7.3.4.1 Admission Day -1 
Participants will be admitted to the SURC clinic at the NYSPI where they will complete the 
PHQ, BDI-II, Substance Use assessment, urine drug screen, concomitant medication review 
and AE monitoring. Each participant will then undergo the NCT to confirm opiate naivety 
based on COWS score. 
 
7.3.4.2 Admission Day 0 
Participants will be scheduled for administration of the OLANI as outlined in section 7.1.1.3. 
After a review of concomitant medications and vital signs are obtained, participants will be 
fitted with the iv cannula to aid in the collection of blood sample for the first 48 hours. There 
shall be no use of heparin to keep the cannula clear as this may affect the blood analysis of 
naltrexone and 6-β-naltrexol. Processing and storage of blood samples shall be done as per 
section 7.2.4.1. 
The recorded dose time (0 hour) will be the time at which the procedure will be completed. 
Naltrexone blood samples (see section 7.2.4.1) will be collected at the following time points: 
3 hours 60 min, 6 hours 60 min, and 12 hours 60 min. The actual time of each PK sample 
collection shall be recorded. 
Participants will also be monitored for AEs. 

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7.3.4.3 Admission Day 1 
Naltrexone blood samples (see section 7.2.4.1) will be collected at 24 hours 2 hours after the 
OLANI procedure. The actual time of each PK sample collection shall be recorded. 
Participants will also be monitored for AEs, have a review of concomitant medications and 
have a Wound Site/ Implant Site Assessment as per 7.1.1.4. 
At this time, participants will have the option of remaining an inpatient or being discharged 
from the SURC clinic and returning for the 48-hour observation (Admission Day 2). 
 
7.3.4.4 Admission Day 2 
Naltrexone blood samples (see section 7.2.4.1) will be collected at 48hours 2 hours after the 
OLANI procedure. The actual time of each PK sample collection shall be recorded. 
Participants will also be monitored for AEs, have a review of concomitant medications and 
have a Wound Site/ Implant Site Assessment as per 7.1.1.4. 
Remaining inpatient participants will be discharged from the SURC clinic. 
All participants will be provided with a timetable for their follow-up visits, which will be 
carried out at the Clinilabs clinic. 
7.3.5 Follow-Up Day 4 to 540 
Participants will be instructed to attend the Clinilabs clinic to continue study procedures on 
an outpatient basis as per the protocol time points outlined in Table 7-1. There are allowable 
variations in actual day of collection as long as the variation is recorded. The following will 
be collected at all time points: Concomitant medical review, PK blood collection, AE 
monitoring, vital signs (Blood pressure, heart rate, respiratory rate, and oral body 
temperature) and a Wound Site/Implant Site assessment (see section 7.1.1.4).  
The following will also be collected on day 28 and then monthly as outlined in Table 7-1, 
PHQ & BDI-II, C-SSRS, FBC, FCP, UA, Pregnancy test (initial with urine with serum 
testing used to confirm positive results), substance use reporting (self-report using the 
Quantitative Substance use Inventory) and UDS. 
Note: As appropriate, participants may be seen for follow-up visits at the SURC clinic (i.e. if 
clinically indicated or if traveling to the Clinilabs clinic presents a hardship to a participant). 
SARS-CoV-2 Note: This study is being conducted in New York, NY; a location heavily 
impacted by the COVID-19 pandemic. Therefore, for the safety of study participants, the IRB 
requested on 21 April 2020 that in-persons study visits be stopped and replaced with 
telephone or video visits. Thus, where in-person study visits are not possible, safety will be 
monitored remotely. This change means that for some participants, certain procedures (e.g. 
PK blood draws), may be missed during the time of the public health emergency. Table 7-1 
has been updated to indicate which procedures will be captured by telephone/video visits and 
which procedures may be missed due to COVID-19. In case there are safety concerns that 
need in-person evaluation to determine best course of action, such as new-onset implant site-
reaction or site drainage, then an in-person visit at the clinic will be conducted.  
 
This change was implemented on 27 April 2020 and all missed visits/procedures are being 
tracked. In person visit will resume immediately when deemed safe and appropriate by the 
IRB. 

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7.3.6 Final Study Visit 
All participants will be required to attend the SURC clinic for a final visit with a study PI as 
outlined in Table 7-1.  The final visit will be scheduled as soon as possible after two non-
detectable PK samples have been obtained, or after Day 540 visit has occurred.  
7.3.7 Early Termination Visit  
Any participants that are withdrawn will be required to attend the SURC clinic for an early 
termination /withdrawal visit as outlined in Table 7-1. Participants will be advised of their 
options as outlined in in section 5.4.2. 
A follow-up visit may be conducted 30 days after the last scheduled on-study visit and is 
required only if a participant has ongoing AEs or laboratory abnormalities at the last on-study 
visit. An in-clinic follow-up visit must be conducted 30 days after the last scheduled on-study 
visit for an AE requiring laboratory testing for participants with the following conditions at 
the last on-study visit: ongoing AEs, SAEs regardless of attributability, any laboratory 
abnormalities considered to be AEs or potentially harmful to the participant. For in-clinic 
follow-up visits, assessments performed should reflect what is considered medically 
necessary to assess the event(s). 
7.3.8 Unscheduled Visit 
It is anticipated that some participants may miss or be delayed to some of their appointments. 
Every effort will be made to obtain blood samples at the scheduled dates, but blood samples 
will be accepted if they are taken late, with allowances made in the statistical analysis for 
this. Participants who miss appointments will be contacted by phone to encourage them to 
return for as many appointments as possible. However, some dropouts are also anticipated so 
additional participants will be recruited to get the correct totals for analysis. 
Participants will be asked to complete the following; vital signs, concomitant medication 
review, wound site/implant site assessment and AE monitoring (see Table 7-1). Additional 
assessments performed at Unscheduled visits are at the discretion of a study physician. 
 
7.3.9 PK Follow-up Visit 
PK follow-up visit may be conducted 30 days after the last monthly PK visit 540 days, if the 
participant has detectable naltrexone plasma levels. Follow-up visits will continue until two 
consecutive monthly naltrexone blood levels recorded at <0.1 ng/mL are received from the 
lab and recorded. If the latest PK levels are pending, participants will continue to make 
follow-up visits (see Table 7-1). 
7.3.10 AE Follow-up Visit 
A follow-up visit will be conducted 30 days after the last scheduled on-study visit. This visit 
is required only if a participant has ongoing AEs or laboratory abnormalities at the last on-
study visit (see Table 7-1). An in-clinic follow-up visit must be conducted 30 days after the 
last scheduled on-study visit for an AE requiring laboratory testing for participants with the 
following conditions at the last on-study visit: ongoing AEs, SAEs regardless of 
attributability, any laboratory abnormalities considered to be AEs or potentially harmful to 
the participant. For in-clinic follow-up visits, assessments performed should reflect what is 
considered medically necessary to assess the event(s). All other participants that will have 
additional questions or concerns about the fate of the implant will also be encouraged to 
come for a follow-up meeting with a study physician. 

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12. Satellite Location 1 = Columbia University Medical Center (CUMC), 177 Fort Washington Ave., New York, NY 10032, USA 
13. Satellite Location 2 = Clinilabs, 423 West 55th St, New York, 10019 for all visits after the initial 48-hour time-point 
14. Changes Due to COVID-19: During the public health emergency, some of the monthly follow-up visits may occur by telephone/video only. The following safety assessments will occur during 
these remote study visits: concomitant medication review, PHQ (BDI-II), C-SSRS1 (since last visit), AE monitoring, Qualitative Substance Use Inventory and wound site/implant site assessment 
(self-reported) done via video link, if possible. Conversely, the following assessments/procedures may be missed because of having remote study visits: safety labs, PK blood collection, pregnancy 
test, urine drug screen, vital signs/weight.  
15. Unscheduled Visits: Vital signs, concomitant medication review, wound site/implant site assessment and AE monitoring are to occur at all Unscheduled Visits. Additional assessments performed 
are at the discretion of a study physician. 
16. Vital Signs: Blood pressure, heart rate, respiratory rate, and oral body temperature will be measured after the subject has been in a seated position for at least 5 minutes. 
Note: After a subject’s last visit, the Disposition CRF must be completed. 

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7.4 
CONCOMITANT MEDICATIONS, TREATMENTS AND PROCEDURES 
All concomitant prescription medications taken during study participation will be recorded on 
the case report forms (CRFs). For this protocol, a prescription medication is defined as a 
medication that can be prescribed only by a properly authorized/licensed clinician. 
Medications to be reported in the CRF are concomitant prescription medications, over-the-
counter medications and non-prescription medications. 
 
7.5 
PROHIBITED MEDICATIONS, TREATMENTS AND PROCEDURES  
The medications and substances listed below are prohibited for the specified time periods: 
• Buprenorphine, either as part of a maintenance program or any illicit/non prescribed is 
prohibited for the duration of the study. 
• Methadone is prohibited at least 14 days prior to Day 0 and for the duration of the Study.  
• All other opioids are prohibited for the duration of the study unless approved by the PI or 
study clinician (see section 7.7)  
• Oral naltrexone is prohibited for at least 30 days prior to Day 0 and for the duration of 
the study 
• Other forms of extended release naltrexone (e.g. Vivitrol) is prohibited for at least 
24 months prior to Day 0 and for the duration of the study 
 
7.6 
PROPHYLACTIC MEDICATIONS, TREATMENTS AND PROCEDURES 
7.6.1 Prophylactic Medications 
One dose of IV antibiotic within 30 minutes of the surgical procedure is given as part of the 
implantation procedure (7.1.1.3): 
2g cefazolin IV If allergic to cephalosporins or penicillin, then alternative is 600 mg 
clindamycin  
7.6.2 Management of Infection/ Inflammatory Responses to the Wound/Implant Site 
All Participants will have their wound site / implant site regularly assessed as per 7.1.1.4 for 
signs of infection and/or inflammatory reactions. Particular attention shall be paid during 
follow-up visits at day 4, 8, 14 and 21 (as per 7.3.11) for signs of infection to the wound site 
or early signs of an inflammatory reaction to the implant. Symptoms and signs relating to 
redness, excessive itchiness and/or increasing pain at the implant or wound site may be 
attributed to the inflammatory response. Symptoms relating to edema, spreading cellulitis, 
fever and general feeling of malaise are likely to be attributed to infection of the implant or 
wound site. Inflammatory reactions tend to occur much more frequently than infections. 
Treatment for inflammatory reactions or infections should be performed as specified below.  
 
Infection treatment protocol 
Infections present in participants as spreading cellulitis with other clinical indicators such as 
fever or general malaise.  Spreading cellulitis involves redness of the skin which may extend 
several centimetres around the wound and extend over the area of the implant. Participants 

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with spreading cellulitis should be treated immediately with antibiotics (e.g., cephalexin) with 
physical exam and/or laboratory results used to monitor treatment response. If the infection 
does not resolve with oral antibiotics, a course of IV antibiotics may be necessary.  
 
Inflammatory responses without an infection 
Signs of redness, swelling, tenderness, itchiness or pain as identified from the ISEF after day 
14 without the presence of fever or general feeling of malaise, suggests the onset of a mild 
inflammatory response to the implant only and the treatment regime described below (level 1 
to level 4) should be implemented.  
 
Level 1 treatment (25 mg prednisone) 
Participants should be prescribed prednisone at 25 mg daily for the first 7 days followed by a 
tapered dose of 12.5 mg for an additional 14-days. The participant should be evaluated 3 days 
after the start of prednisone. If symptoms have not improved after 3 days then participants 
shall progress to Level 2 treatment. 
 
Level 2 treatment (50 mg prednisone) 
If Level 1 treatment is not resolving the pain and swelling, the dose of prednisone shall be 
increased to 50 mg per day. The participant should be re-assessed after 3 days. If after 3 days 
symptoms are improving, then the participant should return to the Level 1 treatment protocol.  
If after 3 days the symptoms have not improved, then participant shall progress to Level 3 
treatment protocol. 
 
Level 3 treatment (betamethasone and fluid assessment) 
Participants who have failed to respond to Level 2 treatment, shall stop their oral prednisone 
and be given an injection of betamethasone, with 1 mL diluted in saline or local anesthetic 
(1% lidocaine, 3mL) injected around the implant site where inflammation is occurring in the 
absence of fluid build-up.   
 
If there is fluid present prior to the betamethasone injection, the fluid must be aspirated. To 
achieve aspiration of the fluid, a needle with a wide bore is required to aspirate what can be 
quite thick viscous pus-like fluid. The aim of the drainage is to a) relieve tension and b) 
remove the fluid build-up. It is therefore important to lavage the fluid space until a CLEAR 
ASPIRATE is obtained. Lavage the space with normal saline or Hartman's solution. This 
normally requires multiple lavages, usually about 10mL each time. The final drainage(s) 
is/are performed without suction, to avoid dislodging/damaging the implant. Drainage and 
lavage are followed with a brief course of oral prophylactic antibiotic.   
   
Where there are two implant sites, a second injection will be required for the second site (if it 
is also affected by the inflammatory process). The participants should rest for 30 min 
following the procedure to maximize the chance of the betamethasone remaining in place.  
Note: betamethasone should not be substituted for any other steroidal injection with an 
alcohol base carrier as this will affect the implant composition. 
 

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After 3 days of review, if inflammatory symptoms have fully resolved and there are no signs 
of an infection then no further treatment is required and participant is observed only.  If 
inflammatory symptoms have improved significantly but not fully resolved then participant 
should return to Level 1 treatment protocols.  If inflammatory symptoms have slightly 
improved but not fully resolved a second round of betamethasone injections can be 
commenced.  
 
Level 4 treatment (removal of implants) 
In participants that do not respond adequately to the treatment regime, the implant(s) should 
be surgically removed. This can be achieved by a surgical incision over the implant site and 
should be done by the study surgeon when possible. 
 
Inflammatory response with secondary infection 
Some participants will develop fluid around their implant as an inflammatory response to the 
implant. The build-up of fluid causes pressure and symptoms such as pain which can result in 
the fluid tracking through the line of least resistance and be expelled through the initial 
surgical incision. This can lead to the wound opening and the risk of secondary infection, as 
well as implant expulsion. If the implant and wound site is treated according to level 1 to 
level 4 protocols for inflammatory responses then the risk of this occurring is reduced. 
Where the fluid build-up is great enough to cause rupture and discharge, the open wound is at 
risk of secondary infections.  This clinical situation is actually primarily due to an 
inflammatory response to the implant with a secondary outcome of an infection as a result of 
an open wound.  In such cases, the inflammatory response should be treated as per the 
inflammatory response protocol starting at level 3 with the addition of oral antibiotics. 
Treatment with appropriate oral antibiotics should be initiated on the diagnosis and modified 
if necessary based upon results of culture swabs from the surface of the wound.   
Most of the wounds close within a few days of the treatment resulting in the process settling 
as the fluid drainage no longer keeps the wound open. If the infection is not resolving after 3 
days of oral antibiotics, then IV antibiotics should be introduced. In participants that do not 
respond adequately to the treatment regime, the implant(s) should be surgically removed. 
This can be achieved by a surgical incision over the implant site and should be done by the 
study surgeon when possible. Antibiotics shall be continued after surgical removal to treat the 
remaining infection until all symptoms have resolved. 
 
7.7 
RESCUE MEDICATIONS, TREATMENTS AND PROCEDURES 
As naltrexone acts as an opioid blocker participants requiring pain relief during the study 
period will be offered appropriate pain medications e.g. tramadol, reginal blocks or partial 
opioid agonist such as buprenorphine.  
 
7.8 
PARTICIPANT ACCESS TO STUDY AGENT AT STUDY CLOSURE 
N/A 
 

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7.9 
REIMBURSEMENT COSTS 
Participants will receive reimbursement as follows.  
• $50 for each of the two screening visit (2 visits) 
• $50 for the consent visit (1 visit) 
• $400 for Day -1 to Day 2, the Admission Days (either 1 or 2 visits) 
• $50 for each scheduled outpatient visit (25 visits). Participants will receive an additional 
incremental bonus of $10 for each subsequent visit attended (Visit 1: $50, visit 2: 
$50+$10, Visit 3: $50+$20, Visit 4: $50 +$30 …). In case the scheduled visit is missed 
the value of the bonus is reset to the starting value of $10. This schedule is designed to 
reinforce adherence to all study safety assessments. Participants will not be penalized for 
missed visits during the COVID-19 pandemic as long as they attend telephone/video 
visits in place of the scheduled clinic visit.  
• Travel reimbursements – in addition to the amounts specified above, participants will 
receive $20 for travel at each visit, and up to $50 in travel if participants provide receipts. 
The total amount of reimbursement should a participant attend every scheduled visit is $4,800 
plus a maximum of $1500 in travel reimbursements depending on provided receipts.  
If a participant is required to return for further PK or AE follow-up visits, then they will 
receive $50 plus the incremental bonus, plus $20 for travel, or up to $50 in travel if 
participants provide receipts.  
 
 

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8 
ASSESSMENT OF SAFETY 
8.1 
SPECIFICATION OF SAFETY PARAMETERS  
Safety will be assessed on the basis of: 
• the incidence of death 
• the incidence of SAEs 
• the incidence AEs leading to discontinuation  
• the incidence common AEs 
• the incidence complications of insertion  
• the incidence implantation site reactions  
• laboratory abnormalities indicating hepatic problems (absolute values and changes over 
time)  
 
8.1.1 Definition of Adverse Events (AE) 
AEs will be identified from the telephone interviews, face to face visits or from the CRF. 
They will be recorded on an AE form. 
Definitions 
An AE is any untoward medical occurrence in a clinical investigational participant 
administered a pharmaceutical product and which does not necessarily have a causal 
relationship with this treatment. An AE can therefore be any unfavorable or unintended sign 
(including an abnormal laboratory finding), symptom, or disease temporally associated with 
the use of a medicinal investigational product, whether or not considered related to the 
medicinal product. An adverse event is any adverse change (developing or worsening) from 
the patient’s pre-treatment condition, including concurrent illness. 
The investigator must make the distinction between exacerbation of pre-existing illness and 
lack of therapeutic efficacy. 
 
8.1.2 Definition of Serious Adverse Events (SAE) 
A SAE is any adverse experience occurring during the study period that: 
• results in death; 
• is life-threatening; 
• results in inpatient hospitalization or prolongation of existing hospitalization; 
• results in a persistent or significant disability/incapacity; or 
• results in congenital anomaly/birth defect. 
A life-threatening AE is one that actually places the participant at immediate risk of death. A 
participant’s reaction is not classified as life-threatening simply because more severe 
manifestations of the same adverse reaction can be fatal, e.g. mild airway obstruction is not 
life threatening but severe airway obstruction is. 
Hospitalization includes any inpatient admission, any transfer within a hospital for the 
purpose of treatment (for example, transfer of a participant from a psychiatric unit to a 
general medical unit) and prolongation of admission. Prolongation of hospitalization is 

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defined as any extension of an inpatient hospitalization beyond the stay anticipated/ required 
in relation to the original reason for the initial admission, as determined by the investigator or 
treating physician.  
Study coordinators will report any new SAEs to the PI, NYSPI IRB, DSMB and sponsor 
within 24 hours of first knowledge. 
 
8.2 
CLASSIFICATION OF AN ADVERSE EVENT 
8.2.1 Severity of Event 
• Mild – Events require minimal or no treatment and do not interfere with the participant’s 
daily activities. 
• Moderate – Events result in a low level of inconvenience or concern with the therapeutic 
measures. Moderate events may cause some interference with functioning. 
• Severe – Events interrupt a participant’s usual daily activity and may require systemic 
drug therapy or other treatment. Severe events are usually potentially life-threatening or 
incapacitating. 
 
8.2.2 Relationship to Study Medication and Surgical Procedure 
The clinician’s assessment of an AE's relationship to the study medication (i.e. OLANI) or 
the surgical procedure is part of the documentation process, but it is not a factor in 
determining what is or is not reported in the study. If there is any doubt as to whether a 
clinical observation is an AE, the event should be reported. All AEs must have their 
relationship to study agent assessed. In a clinical trial, the study product must always be 
suspect. To help assess, the following guidelines are used. 
• Definitely Related – There is clear evidence to suggest a causal relationship, and other 
possible contributing factors can be ruled out. The clinical event, including an abnormal 
laboratory test result, occurs in a plausible time relationship to drug administration and 
cannot be explained by concurrent disease or other drugs or chemicals. The response to 
withdrawal of the drug (dechallenge) should be clinically plausible. The event must be 
pharmacologically or phenomenologically definitive, with use of a satisfactory 
rechallenge procedure if necessary. 
• Probably Related – There is evidence to suggest a causal relationship, and the influence 
of other factors is unlikely. The clinical event, including an abnormal laboratory test 
result, occurs within a reasonable time after administration of the drug, is unlikely to be 
attributed to concurrent disease or other drugs or chemicals, and follows a clinically 
reasonable response on withdrawal (dechallenge). Rechallenge information is not 
required to fulfil this definition. 
• Possibly Related – There is some evidence to suggest a causal relationship (e.g., the 
event occurred within a reasonable time after administration of the trial medication). 
However, other factors may have contributed to the event (e.g., the participant’s clinical 
condition, other concomitant events). Although an AE may rate only as “possibly related” 
soon after discovery, it can be flagged as requiring more information and later be 
upgraded to “probably related” or “definitely related,” as appropriate. 

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• Unlikely to be related – A clinical event, including an abnormal laboratory test result, 
whose temporal relationship to drug administration makes a causal relationship 
improbable (e.g., the event did not occur within a reasonable time after administration of 
the trial medication) and in which other drugs or chemicals or underlying disease 
provides plausible explanations (e.g., the participant’s clinical condition, other 
concomitant treatments). 
• Not Related – The AE is completely independent of study drug administration, and/or 
evidence exists that the event is definitely related to another etiology. There must be an 
alternative, definitive etiology documented by the clinician. 
 
8.2.3 Expectedness  
8.2.3.1 Adverse Drug Reactions Commonly Seen from Naltrexone (MIMS) 
• Difficulty sleeping 
• Anxiety 
• Nervousness 
• Abdominal pain/cramps 
• Nausea and/or vomiting 
• Low energy 
• Join and muscle pain 
• Headache 
• Loss of appetite 
• Diarrhea 
• Constipation 
• Increased thirst 
• Increased energy 
• Depressive mood 
• Irritability 
• Dizziness 
• Skin rash 
• Delayed ejaculation 
• Erectile dysfunction 
• Reduced sexual desire 
• Chills
 
8.2.3.2 Adverse Events Commonly Seen Following Implantation procedure 
• Local inflammatory reaction; itchiness, redness, heat or swelling 
• Wound site Infections 
• Hematoma 
 
8.2.3.3 Adverse Events Rarely Seen Following Implantation procedure 
• Allergic reactions to suture material 
• Implant removal for infections or allergic responses 
• Implant removal for psychological reasons. 
 
8.2.3.4 Adverse Events Commonly Seen from Poly Lactide Polymer 
• Local inflammatory reaction; itchiness, redness, heat or swelling 
 
 
 

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8.3 
TIME PERIOD AND FREQUENCY FOR EVENT ASSESSMENT AND 
FOLLOW-UP  
The occurrence of an AE or SAE may come to the attention of study personnel during study 
visits and interviews of a study participant presenting for medical care, or upon review by a 
study monitor. 
All AEs including local and systemic reactions not meeting the criteria for SAEs will be 
captured on the appropriate CRF. Information to be collected includes event description, time 
of onset, clinician’s assessment of severity, relationship to study product (assessed only by 
those with the training and authority to make a diagnosis), and time of resolution/stabilization 
of the event. All AEs occurring while on study must be documented appropriately regardless 
of relationship. All AEs will be followed to adequate resolution. 
Any medical condition that is present at the time that the participant is screened will be 
considered as baseline and not reported as an AE. However, if the study participant’s 
condition deteriorates at any time during the study, it will be recorded as an AE. 
Changes in the severity of an AE will be documented to allow an assessment of the duration 
of the event at each level of severity to be performed. AEs characterized as intermittent 
require documentation of onset and duration of each episode. 
The PI will record all reportable events with start dates occurring any time after informed 
consent is obtained until 7 (for non-serious AEs) or 30 days (for SAEs) after the last day of 
study participation. At each study visit, the investigator will inquire about the occurrence of 
AE/SAEs since the last visit. Events will be followed for outcome information until 
resolution or stabilization. 
In the event of study discontinuation for any reason, any ongoing AEs will be followed until 
resolution, or in the event of removal of the OLANI for at least 4 weeks after the removal, 
until deemed stable by the PI, or until the participant is deemed by the PI to be lost to follow-
up. If, in the opinion of the PI, it is necessary to monitor a participant beyond the safety 
follow-up visit, the follow-up period may be extended as necessary. In such instances, the 
sponsor and the PI will agree to an acceptable follow-up schedule. The PI must maintain a 
record of all participants who fail to complete the study. The reason for study discontinuation 
will be made on the appropriate CRF. 
 
8.4 
REPORTING PROCEDURES  
8.4.1 Adverse Event Reporting 
The sponsor will inform the investigator of any new information that may impact the conduct 
of the trial or have an impact on the ethical acceptability of the trial. 
Investigator shall report all AE’s on a monthly basis to sponsor and Data Safety Monitoring 
Board (DSMB) for review.  
The sponsor will update the Investigator Brochure regularly with any new safety information 
relating to the drug.  
 
8.4.2 Serious Adverse Event Reporting 
All SAEs should be reported immediately to the sponsor, NYSPI IRB, FDA, DSMB except 
for those SAEs that the protocol or other document (e.g. Investigator's Brochure) identifies as 

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not needing immediate reporting. The immediate reports should be followed promptly by 
detailed, written reports. The immediate and follow-up reports should identify participants by 
unique code numbers assigned to the trial participants rather than by the participants' names 
personal identification numbers, and/or addresses.  
 
8.4.2.1 Management of SAE’s  
SAEs, as defined by the FDA, will be systematically evaluated at each clinic visit. Any SAE, 
whether or not related to study medication, will be reported to the NYSPI IRB, FDA & 
DSMB. The initial SAE report will be followed by submission of a completed SAE report to 
both institutions. 
In the event that a participant either withdraws from the study or the investigator decides to 
discontinue a participant due to SAE, the participant will have appropriate follow-up medical 
monitoring. Monitoring will continue until the problem requiring hospitalization has resolved 
or stabilized with no further change expected, is clearly unrelated to study medication, or 
results in death. Outcome of SAEs will be reported to the NYSPI IRB, FDA & DSMB as 
soon as this information becomes available. A summary of the SAEs that occurred during the 
previous year will be included in the annual progress report to the NYSPI IRB, FDA & 
DSMB. 
 
8.4.3 Reporting of Pregnancy 
Reporting of pregnancy will be to the treating physician, PI, NYSPI IRB and DSMB. After 
finding an incidental pregnancy the removal of the implant will be offered to the participant 
and the participant will decide how best to proceed in consultation with her obstetrician.  The 
decision regarding the pregnancy will affect the decision whether or not to remove the 
implant at any point during the pregnancy. The risk of anesthesia differs during different 
times during pregnancy, however the risks of anesthesia and the risks of removal are both 
minimal. 
 
8.5 
STUDY HALTING RULES 
8.5.1 Study Termination 
The Sponsor reserves the right to close the investigational sites or terminate the study at any 
time. The Investigator may initiate site closure at any time, provided there is reasonable 
cause and sufficient notice is given in advance of the intended termination. Reasons for the 
early closure of an investigational site by the Sponsor or Investigator, or termination of a 
study by the Sponsor, may include but are not limited to:  
• failure of the Investigator to comply with the protocol, the Sponsor’s procedures, or 
GCP guidelines 
• safety concerns 
• inadequate recruitment of participants by the Investigator 
Study termination will be reported to, NYSPI IRB, DSMB and FDA. 
 

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8.5.2 On-Site Audits 
Representatives of the Sponsor’s quality assurance department may visit the site to carry out 
an audit of the study in compliance with regulatory guidelines and the Sponsor’s standard 
operating procedures. Audits and clinical trial monitoring will also be carried out by the 
CRO, Clinilabs during the trial period. These audits will require access to all study records, 
including source documents, for inspection and comparison with the CRFs. Participant 
privacy must, however, be respected. Similar auditing procedures may also be conducted by 
agents of any regulatory body reviewing the results of this study in support of a regulatory 
submission. The Investigator should immediately notify the Sponsor if they have been 
contacted by a regulatory agency concerning an upcoming inspection.  
 
8.6 
DATA AND SAFETY MONITORING PLAN ADMINISTRATION 
8.6.1 Responsibility for data and safety monitoring (DSM) 
The study PI, Dr. Adam Bisaga, is required to be present for all DSMB meetings to provide 
reports for all accumulated data from the trial. The PI will also be primarily responsible for the 
implementation of any recommendations from the DSMB. The PI will be assisted in this duty 
by Dr. Edward Nunes, study Medical Monitor.  
 
8.6.2  Frequency of DSM 
Ongoing data and safety monitoring will be conducted weekly during research team meetings 
of the PI with the investigative team. Every three months, the PI and the medical monitor will 
review the number of participants enrolled, the number who completed the protocol, the 
number who dropped out of the protocol prior to completion (and reason why), any AEs, 
procedures for assuring participants privacy and confidentiality, and the quality and integrity 
of the data collected.  Corrective action will be taken if needed. IRB study protocols and 
informed consent documents will be reviewed annually by the IRB. Reports of enrollment 
and retention and reporting of AEs are required with these renewals.  
 
In addition, all studies involving human participants are periodically and systematically 
reviewed by the New York State Quality Assurance Staff. These procedures assure protocol 
compliance by conducting unannounced reviews of participants' research charts, comparing 
research charts to the IRB protocol. All SAEs will be reported to the FDA (as appropriate) 
and the DSMB in a timely fashion. 
 
A separate DSMB (See 8.6.3 for details) will meet quarterly and within a week of any SAEs 
occurring. Ad hoc meetings may also occur if any study related issues arise during the course 
of the study. 
 
8.6.3 DSMB Plan  
The DSMB, will be chaired by Dr. Jonathan Stewart a Professor of Psychiatry at Columbia 
University College of Physicians and Surgeons and a senior expert in mood disorder 
pharmacotherapy. Three additional faculty members from the division will join the DSMB;  
• Dr. Richard Foltin Ph.D, a senior researcher in the division, with more than 30 years of 
experience in the early phases of medication development for substance use disorders;  
• Dr. Elias Dakwar, an opioid dependence treatment investigator in the division, and  
• Dr. Arthur R. Williams, another research psychiatrist in the division.  

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Finally, Dr Jeffery Ascherman, Site Chief of the Division of Plastic Surgery and a Professor of 
Surgery at Columbia University Medical Center, will be on the DSMB and will provide 
surgical expertise. 
 
The DSMB will meet before the study launch and quarterly afterwards to conduct initial and 
ongoing study review and review all AEs that occurred in the study. The DSMB will meet 
within a week of the occurrence of any SAE. For each SAE, the PI and covering physician 
will present a synopsis of how it occurred and how the incident was handled clinically so that 
DSMB can assess how the event was managed and if there are any recommendations that will 
maintain the high quality of the care that we provide to our research participants. Ad hoc 
meetings may also occur as needed to address study related issues. 
 
All DSMB members will be asked to submit in writing any potential conflict of interest 
pertaining to the study. The DSMB will prepare a report in response to any SAE review 
meetings and will submit a DSM report annually. Reports will be submitted to the Sponsor 
and other authorities as appropriate. This report will include the following:  
a) Brief description of the trial,  
b) Baseline socio-demographic characteristics,  
c) Retention and disposition of study participants,  
d) Quality assurance issues,  
e) Regulatory issues,  
f) AEs,  
g) SAEs 
h) Efficacy. 
 
9 
CLINICAL MONITORING 
This study may be participant to audit or inspection by representatives from the NYSPI IRB, 
DSMB or FDA.  
Data from this study will be monitored by staff from the CRO, Clinilabs, for compliance with 
GCP principals. Monitoring will include review of CRFs and other study documents for 
protocol compliance, data accuracy and completeness. Monitoring will include review of the 
investigator’s site file and drug handling records. Clinilabs will be given direct access to 
source documents, CRFs and other study-related documents. By signing the informed consent 
form, the participant authorizes Clinilabs staff direct access to their medical records and the 
study data.  
 
 
 

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10 STATISTICAL CONSIDERATIONS 
10.1 STATISTICAL AND ANALYTICAL PLANS  
The statistical analysis will be collected in two stages, first at the interim stage (See 10.4.7), 
and second after the conclusion of all study procedures and database lock. 
 
10.2 STATISTICAL HYPOTHESES 
N/A 
 
10.3 ANALYSIS DATASETS 
 
The analysis will be performed based on Intention-to-Treat and Per-Protocol in all 
participants enrolled. Assessment of primary outcomes will be performed on participants who 
complete at least 75% of applicable time points. 
 
10.4 DESCRIPTION OF STATISTICAL METHODS 
10.4.1 General Approach 
Pharmacokinetic parameters will be expressed as a mean, standard deviation and co-efficient 
of variation for the group total. Similarly, the mean, standard deviation and co-efficient of 
variation plasma naltrexone and 6-beta-naltrexol will be calculated and tabulated for each 
time point.  
 
10.4.2 Analysis of the Primary Endpoint 
Participants who submitted at least 75% valid pharmacokinetic blood samples including 2 
consecutive monthly naltrexone blood levels recorded at <0.1 ng/mL will be analyzed.  
 
10.4.3 Analysis of the Secondary and Exploratory Endpoint(s) 
Pharmacokinetic parameters (Cmax, Tmax and AUC0-∞, the period of time from insertion that 
naltrexone plasma concentrations remain above 1.33 ng/mL) will be calculated using a non-
compartmental approach. Naltrexone plasma profiles will be plotted graphically for each 
individual and the study group (concentration-versus-time profile). 
Use of opioids, cocaine, marijuana, and alcohol for each day of the study will be determined 
based on results of urine toxicology and self-report. Proportion of days with substance use for 
each participant will be summarized.  
 
10.4.4 Safety Analyses 
The frequency of AEs including wound site and inflammatory response rates will be 
recorded. Any SAEs, adverse drug reactions, and suspected unexpected serious AE will be 
collated for the combined group. Additionally, counts of the number of laboratory values that 
fall outside of the normal range will be used to assess safety.  

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10.4.5 Adherence and Retention Analyses 
The percentage of participants that complete the desired number of follow up blood 
collection points will be calculated and presented with 95% confidence intervals.  
 
10.4.6 Baseline Descriptive Statistics 
Baseline characteristics will be calculated using mean, standard deviation, median, 
interquartile range, percentages and 95% confidence intervals (where appropriate).  
 
10.4.7 Planned Interim Analyses 
10.4.7.1 Safety Review 
As per AE reporting, AEs will be collated and reviewed quarterly by the Safety Committee. 
This may include crude rates of type specific AEs; however, no formal interim analysis will 
be conducted.  
 
10.4.7.2 Efficacy Review 
An interim analysis will be carried out once at least 10 participants have completed their 
Day 180 PK blood time point. Participants, who submitted at least 14 of 19 valid blood 
samples (including the Day 180 sample) and safety data will be evaluated whether or not they 
met the MEC criteria (naltrexone blood level above 1.33 ng/mL). The analyzed interim data 
will be used in the planning and design of a bioequivalence/safety study of the OLANI 
against a reference extended release naltrexone product.  
 
10.4.8 Additional Sub-Group Analyses 
No sub-group analysis will be performed.  
 
10.4.9 Multiple Comparison/ Multiplicity 
No adjustment will be made for multiple comparisons.  
 
10.4.10Tabulation of Individual Response Data 
Individual pharmacokinetic and safety data will be tabulated for each time point and included 
in the appendices of the final study report.  
 
10.4.11Exploratory Analyses 
No exploratory analysis will be conducted.  
 

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10.5 SAMPLE SIZE  
At the completion of the study it is desirable that a minimum of 10 participants complete a 
minimum of 75% blood collection time points, including 2 consecutive undetectable values 
(defined as naltrexone blood levels of <0.1 ng/mL). 
 
10.6 MEASURES TO MINIMIZE BIAS 
10.6.1 Enrolment/ Randomization/ Masking Procedures  
N/A as there is no blinding 
 
10.6.2 Evaluation of Success of Blinding 
N/A as there is no blinding 
 
10.6.3 Breaking the Study Blind/Participant Code 
N/A as there is no blinding 
 
11 SOURCE DOCUMENTS AND ACCESS TO SOURCE DATA/DOCUMENTS 
Direct access to source data/documents will be provided to the sponsor, trial-related 
monitoring, audits, NYSPI IRB, and regulatory inspection(s). 
 
12 QUALITY ASSURANCE AND QUALITY CONTROL 
QC procedures will be implemented beginning with the data entry system and data QC 
checks that will be run on the database will be generated. Any missing data or data anomalies 
will be communicated to the site(s) for clarification/resolution. 
Following written SOPs, the monitors will verify that the clinical trial is conducted and data 
are generated, documented (recorded) and reported in compliance with the protocol, GCP and 
the applicable regulatory requirements (e.g. Good Laboratory Practices (GLP), Good 
Manufacturing Practices (GMP). 
The investigational site will provide direct access to all trial related sites, source 
data/documents and reports for the purpose of monitoring and auditing by the Sponsor, CRO 
(Clinilabs) and inspection by local and regulatory authorities. 
 
 
 

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13 ETHICS/PROTECTION OF HUMAN PARTICIPANTS 
13.1 ETHICAL STANDARD 
The study will be conducted in accordance with the guidelines and principles outlined in the 
International Conference on Harmonization - Standards of Good Clinical Practice32 and the 
Declaration of Helsinki33.Compliance with these standards ensures that the rights, safety and 
well-being of participants are consistent with the above principles. 
 
13.2 INSTITUTIONAL REVIEW BOARD  
The investigator will obtain NYSPI IRB approval for this study. Initial IRB approval as well 
as all materials approved by the IRB for this study, including the participant consent form and 
recruitment materials.  
Annual Reports describing the study progress and all AEs will be provided to the NYSPI 
IRB, along with a final study report by the PI. A copy of this report will also be provided to 
the sponsor. 
 
13.3 INFORMED CONSENT PROCESS 
13.3.1 Consent/Assent and Other Informational Documents Provided to Participants  
All study participants will be provided with a Participant Information Sheet (PIS) describing 
the study and providing sufficient information so that they are able to make an informed 
decision about their participation in the trial. Both the PIS and the Participant Informed 
Consent (PIC) form will be submitted with the research application for review and approval 
by the IRB.  
 
13.3.2 Consent Procedures and Documentation  
The investigator (or authorized designee) will ensure that the participant (or the participant’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 participant 
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 participant and must not include any 
language that waives the participant’s legal rights. Prospective participants must also be 
informed of their right to withdraw consent without prejudice at any time during the study. If 
the participant chooses to participate, he/she must sign the ICF before any study-specific 
procedures are conducted. 
 
13.4 PARTICIPANT AND DATA CONFIDENTIALITY 
All data generated in this study will remain confidential. All information will be stored 
securely. participant information will only be disclosed to authorized individuals i.e. research 
personnel listed on the Delegation of Duties List who have signed a confidentiality agreement 
with the PI to undertake research related procedures.  
All participant data will be de-identified by use of an alphanumeric study coding system. 

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Participant identification will be recorded on a Master Participants List held in-confidence by 
the PI in a locked cabinet separate to the de-identified data sheets. 
Personal information recorded in study documentation or an electronic database will only be 
accessed by authorized study personnel. Personal computer access will be password protected 
and also limited to authorized study personnel. 
Additionally, a Federal Certificate of Confidentiality will be obtained. 
 
13.4.1 Research Use of Stored Human Samples, Specimens or Data  
13.4.1.1 Naltrexone blood level 
Samples collected up to and including the 48 hour time point will be prepared by study 
personnel from NYSPI for storage at -70ºC before shipment in batches to the PK analysis 
laboratory. Samples collected after the 48 hour time point will be processed by Clinilabs and 
stored until suitable batch sizes are available for shipment to the PK laboratory on dry ice. All 
samples will be analyzed for free (unconjugated) naltrexone and free (unconjugated) 6-β-
naltrexol quantification. It is anticipated that samples will prepared and split into 2 aliquots, 
with 1 being used for analysis and 1 serving as a backup being stored de-identified in a -70°C 
freezer. Samples will be kept for 5 years after the completion of the trial, after which time 
they will be destroyed.  
 
13.5 FUTURE USE OF STORED SPECIMENS  
Data collected for this study will be analyzed and stored at NYSPI, as per local standard 
protocols.  
 
 
 

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14 DATA HANDLING AND RECORD KEEPING 
14.1 DATA COLLECTION AND MANAGEMENT RESPONSIBILITIES  
An electronic Case Report Form (eCRF) will be designed to record data required by the 
protocol and collected by the Investigator. An eCRF will be completed for each participant.  
A confidential list of participant names, contact details, and screening numbers will be kept 
by the the Clinilabs and SURC clinics. eCRF data removed from the study site will be 
identified by the screening number and will not contain participant names or contact details. 
Data collection is the responsibility of the clinical trial staff at the site under the supervision 
of the site PI. The investigator is responsible for ensuring the accuracy, completeness, 
legibility and timeliness of the data reported. All source documents should be completed in a 
neat, legible manner to ensure accurate interpretation of data. 
 
14.2 STUDY RECORDS RETENTION  
Retention and storage of essential clinical study documents (e.g. worksheets, drug 
accountability forms, and other administrative documentation) shall be governed by the terms 
and conditions of NYSPI.  
• 
Ten years after discontinuation of the study, or  
• 
Two years following the date a marketing application is approved for the study drug for 
the indication for which it is being investigated pursuant to the study, or 
• 
If no application is to be filed or if the application is not approved for such indication, 
until 2 years after the date the study is terminated.  
Participants’ 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 
 
14.3 PROTOCOL DEVIATIONS  
A protocol deviation is any noncompliance with the clinical trial protocol, SOP’s and GCP 
requirements. The noncompliance may be either on the part of the participant, the 
investigator, or the study site staff at the SURC clinic, CUMC, or Clinilabs clinic. As a result 
of deviations, corrective actions are to be developed by the site and implemented promptly. 
The PI should not implement any deviation from, or changes of the protocol without 
agreement by the sponsor and prior review and documented approval/favorable opinion from 
NYSPI IRB, except where necessary to eliminate an immediate hazard(s) to trial participants, 
or when the change(s) involves only logistical or administrative aspects of the trial (e.g., 
change in monitor(s), change of telephone number(s)). 
If the PI implements a deviation from, or a change of, the protocol to eliminate an immediate 
hazard(s) to trial participants, without prior approval/favorable opinion from NYSPI IRB. As 
soon as possible, the implemented deviation or change, the reasons for it, and, if appropriate, 
the proposed protocol amendment(s) should be submitted:  
• To NYSPI IRB for review and approval/favorable opinion,  
• To the sponsor for agreement and, if required,  
• To the regulatory authority. 

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The PI, or person designated by the PI, should document and explain any deviation from the 
approved protocol. 
 
14.4 PUBLICATION AND DATA SHARING POLICY 
 
The data will be entered and analyzed by a PI, Clinilabs, and additional study personnel from 
NYS Psychiatric Institute. A Clinical Study Report will be issued which may form the basis 
of a manuscript intended for publication. Any publications arising from this study will be 
published by a process of peer review. 
 
15 STUDY ADMINISTRATION 
15.1 STUDY LEADERSHIP 
The study leadership will be composed of the PI, the Responsible Clinician, Sponsor 
Representative, and site representative (See section 1) 
 
16 CONFLICT OF INTEREST POLICY 
The independence of this study from any actual or perceived influence is critical. Therefore, 
any actual conflict of interest of persons who have a role in the design, conduct, analysis, 
publication, or any aspect of this trial will be disclosed and managed. Furthermore, persons 
who have a perceived conflict of interest will be required to have such conflicts managed in a 
way that is appropriate to their participation in the trial. The study leadership in conjunction 
with the IRB has established policies and procedures for all study group members to disclose 
all conflicts of interest and will establish a mechanism for the management of all reported 
dualities of interest. 
 
 
 

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