Conditions: Opioid Dependence
Keywords: naltrexone buprenorphine neuroimaging
Allocation: RANDOMIZED | Intervention model: PARALLEL
Enrollment: 3
Healthy volunteers: yes

Brief summary:
This study will investigate the mechanisms of cognitive-behavioral response to medications used for relapse prevention in opioid use disorder (opioid addiction, OUD), through investigation of the neural circuits underlying key cognition functions. The study will use previously validated cognitive probes, functional Magnetic Resonance Imaging (fMRI), and novel extended-release injectable preparations of opioid partial agonist buprenorphine and antagonist naltrexone, in OUD patients to explain the individual heterogeneity of OUD treatment response.

Detailed description:
This proposal seeks to identify the neural circuits underlying the cognitive effects of medication assisted therapy (MAT) for OUD. The study will examine the neurocognitive effects of MAT by comparing two preparations with different pharmacodynamic properties (extended release buprenorphine and naltrexone, XRBUP, XRNTX) in three key domains (incentive salience, executive functioning, and emotion processing) using task functional Magnetic Resonance Imaging (MRI). In the 1st phase of the study, forty treatment-seeking OUD patients will be randomized to XRNTX or XRBUP groups after detoxification. Participants will undergo medication induction followed by monthly injections and urine toxicology monitoring for 120 days. Neuroimaging will follow completion of detoxification (pre-treatment) and 15 days after the second injection (on-treatment). The second study phase will extend the paradigm to an independent sample of 160 additional participants and test the explanatory value of MAT-induced changes in the neuroimaging signal in the classification of OUD treatment outcomes.

Arms:
arm 1: Participants assigned to treatment with extended-release buprenorphine arm 2: Participants assigned to treatment with extended-release naltrexone

Interventions: intervention 1: Brixadi intervention 2: Vivitrol
Intervention descriptions: intervention 1: Extended release injectable Buprenorphine intervention 2: Extended release injectable Naltrexone

Protocol document:
Prot_SAP_000.pdf: 
Protocol Number 843403 
Brixadi and Vivitrol  
CAM2038/Brixadi/Buvidal 
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CLINICAL RESEARCH PROTOCOL 
STUDY NUMBER(S): 
843403 
PROTOCOL(S) TITLE: 
Open label comparison of injectable 
buprenorphine (CAM2038, Brixadi®) 
and naltrexone (Vivitrol®) for opioid 
use disorder  
IND NUMBER: 
151811 
REGULATORY SPONSOR: 
Daniel Langleben, MD 
FUNDING SPONSOR(S): 
National Institute on Drug Abuse 
MEDICAL DIRECTOR: 
STUDY PHYSICIAN: 
PRINCIPAL INVESTIGATOR: 
CO-INVESTIGATOR: 
Daniel Langleben, MD 
Kyle Kampman, MD. 
Addiction Treatment Center 
3535 Market St. Philadelphia PA, 19104 
(215) 746-2764
kampman@pennmedicine.upenn.edu 
James Loughead, Ph.D. 
3535 Market St. 4th Floor 
Philadelphia PA, 19104 
(215) 746-0107
loughead@pennmedicine.upenn.edu
Daniel Langleben, MD 
Addiction Treatment Center 
3535 Market St. Philadelphia PA, 19104 
(215) 746-0107
langlebe@pennmedicine.upenn.edu
ORIGINAL PROTOCOL DATE: 
06/15/2020 


 
 
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VERSION NUMBER: 
 V5.0 
VERSION DATE: 
 17 August 2023 
 
 
 
 


 
 
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1 
Study Summary .......................................................................................................... 7 
1.1 
Synopsis .................................................................................................................. 7 
2 
Introduction and RationalE .................................................................................... 10 
2.1 
Study Rationale ................................................................................................... 10 
2.2 
Background .......................................................................................................... 10 
2.2.1 
Pharmacokinetics, Pharmacodynamics and Toxicology ........................... 11 
2.2.2 
Dosing Rationale ............................................................................................ 12 
2.2.3 
Clinical Adverse Event Profile ..................................................................... 12 
2.2.4 
Dosing Rationale ............................................................................................ 12 
2.3 
Risk/Benefit Assessment ..................................................................................... 12 
2.3.1 
Known Potential Risks .................................................................................. 12 
2.3.2 
Known Potential Benefits ............................................................................. 16 
2.3.3 
Assessment of Potential Risks and Benefits ................................................ 16 
3 
Study Objectives and Endpoints ............................................................................. 18 
3.1 
General Design .................................................................................................... 18 
3.2 
Primary Study Endpoints (see Table in the Schedule of Activities (SoA), 
Appendix Section 12.1. ........................................................................................ 18 
3.3 
Secondary Study Endpoints (abbreviations spelled out on Page 27, 
“STUDY MEASURES”): ................................................................................... 20 
3.4 
Primary Safety Endpoints .................................................................................. 20 
4 
Study Plan ................................................................................................................. 20 
4.1 
Study Design: ....................................................................................................... 20 
4.2 
Scientific Rationale for Study Design ................................................................ 21 
4.3 
Justification for Dose .......................................................................................... 22 
4.4 
End of Study Definition ...................................................................................... 22 
5 
Study Population ...................................................................................................... 23 
5.1 
Inclusion Criteria ................................................................................................ 23 
5.2 
Exclusion Criteria ............................................................................................... 23 
5.3 
Strategies for Recruitment and Retention ........................................................ 24 
6 
Study InterventionS ................................................................................................. 25 
6.1 
Study Procedures: ............................................................................................... 25 
6.1.1 
Study Intervention Description .................................................................... 29 
6.2 
XRNTX (Vivitrol): .............................................................................................. 30 
6.2.1 
Acquisition and accountability ..................................................................... 30 
6.2.2 
Formulation, Appearance, Packaging, and Labeling ................................ 30 
6.2.3 
Product Storage and Stability ...................................................................... 30 
6.2.4 
Preparation .................................................................................................... 30 
6.3 
Measures to Minimize Bias: Randomization and Blinding ............................. 31 
6.4 
Study Intervention Compliance ......................................................................... 31 
6.5 
Concomitant Therapy ......................................................................................... 31 
7 
Study Intervention Discontinuation and Participant 
Discontinuation/Withdrawal ................................................................................... 32 
7.1 
Discontinuation of Study Intervention .............................................................. 32 
 


 
 
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7.2 
Participant Discontinuation/Withdrawal from the Study ............................... 32 
7.3 
Lost To Follow-Up ............................................................................................... 33 
8 
Study Assessment and Procedures ......................................................................... 34 
8.1 
Efficacy Assessments: ......................................................................................... 36 
8.2 
Safety and Other Assessments: .......................................................................... 37 
8.3 
Adverse Events and Serious Adverse Events .................................................... 39 
8.3.1 
Definition of Adverse Events (AE) ............................................................... 39 
8.3.2 
Definition of Serious Adverse Events (SAE) ............................................... 39 
8.3.3 
Classification of an Adverse Event .............................................................. 40 
8.3.4 
Time Period and Frequency for Event Assessment and Follow-Up ......... 40 
8.3.5 
Adverse Event Reporting ............................................................................. 41 
8.3.6 
Serious Adverse Event Reporting ................................................................ 41 
8.3.7 
Reporting of Pregnancy ................................................................................ 42 
9 
Statistical Considerations ........................................................................................ 42 
9.1 
Statistical Hypotheses ......................................................................................... 42 
9.2 
Sample Size Determination: ............................................................................... 45 
9.3 
Populations for Analyses .................................................................................... 45 
9.4 
Statistical Analyses .............................................................................................. 45 
9.4.1 
General Approach ......................................................................................... 45 
10 Supporting Documentation and Operational Considerations ............................. 47 
10.1 
Regulatory, Ethical, and Study Oversight Considerations ............................. 47 
10.1.1 
Informed Consent Process ............................................................................ 47 
10.1.2 
Study Discontinuation and Closure ............................................................. 48 
10.1.3 
Confidentiality and Privacy ......................................................................... 48 
10.1.4 
Safety Oversight ............................................................................................ 49 
10.1.5 
Quality Assurance and Quality Control ..................................................... 49 
10.1.6 
Data Handling and Record Keeping ........................................................... 49 
10.1.7 
Protocol Deviations ....................................................................................... 51 
10.1.8 
Publication and Data Sharing Policy ........................................................... 51 
10.1.9 
Conflict of Interest Policy ............................................................................. 52 
10.2 
LIMITATIONS ................................................................................................... 52 
11 Research staff ........................................................................................................... 52 
12 References ................................................................................................................. 53 
13 APPENDIX ............................................................................................................... 57 
13.1 
Schedule of Activities (SoA) ............................................................................... 57 
 
 
 
 


 
 
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Abbreviations 
 
AE 
Adverse Event 
ANCOVA 
Analysis of Covariance 
CFR 
Code of Federal Regulations 
CLIA 
Clinical Laboratory Improvement Amendments 
MP 
Monitoring Plan 
COC 
Certificate of Confidentiality 
CONSORT 
Consolidated Standards of Reporting Trials 
CRF 
Case Report Form 
DCC 
Data Coordinating Center 
DHHS 
Department of Health and Human Services 
DSMB 
Data Safety Monitoring Board 
DRE 
Disease-Related Event 
EC 
Ethics Committee 
eCRF 
Electronic Case Report Forms 
FDA 
Food and Drug Administration 
FDAAA 
Food and Drug Administration Amendments Act of 2007 
FFR 
Federal Financial Report 
GCP 
Good Clinical Practice 
GLP 
Good Laboratory Practices 
GMP 
Good Manufacturing Practices 
GWAS 
Genome-Wide Association Studies 
HIPAA 
Health Insurance Portability and Accountability Act  
IB 
Investigator’s Brochure 
ICH 
International Conference on Harmonization  
ICMJE 
International Committee of Medical Journal Editors 
IDE 
Investigational Device Exemption 
IND 
Investigational New Drug Application 
IRB 
Institutional Review Board 
ISM 
Independent Safety Monitor 
ISO 
International Organization for Standardization 


 
 
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ITT 
Intention-To-Treat 
LSMEANS 
Least-Squares Means 
MedDRA 
Medical Dictionary for Regulatory Activities 
MOP 
Manual of Procedures 
MSDS 
Material Safety Data Sheet 
NCT 
National Clinical Trial 
NIH  
National Institutes of Health 
NIH IC 
NIH Institute or Center 
OHRP 
Office for Human Research Protections 
PI 
Principal Investigator 
QA 
Quality Assurance 
QC 
Quality Control 
SAE 
Serious Adverse Event 
SAP 
Statistical Analysis Plan 
DSMC 
Data Safety Monitoring Committee 
SoA 
Schedule of Activities 
SOC 
System Organ Class 
SOP 
Standard Operating Procedure 
UADE 
Unanticipated Adverse Device Effect 
UP 
Unanticipated Problem 
US 
United States 
 
 
 
 


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1 STUDY SUMMARY 
1.1 
Synopsis 
Title: 
Open label comparison of injectable extended release 
buprenorphine (CAM2038, Brixadi®) and naltrexone (Vivitrol®) for the 
treatment of opioid use disorder 
Short Title: 
Brixadi and Vivitrol 
Study 
Description: 
This study will elucidate the cognitive mechanisms of response to opioid 
agonists and antagonists used to prevent relapse in OUD through 
investigation of the underlying neural circuits. We shall use previously 
validated cognitive probes, functional Magnetic Resonance Imaging 
(fMRI), and extended-release injectable preparations of opioid partial 
agonist buprenorphine (XRBUP, Brixadi) and opioid antagonist 
naltrexone (XRNTX, Vivitrol), in OUD patients. Using two medications 
with opposing mu opioid receptor action will allow a comprehensive 
evaluation of the mechanisms of response to relapse prevention 
pharmacotherapy in OUD. The study will determine the presence of 
treatment effects in the domains of executive function, incentive salience, 
and resting functional connectivity and the interaction that will indicate a 
difference between the two medications. Then we will evaluate the ability 
of the brain fMRI signal to explain relapse defined by % of opioid-positive 
urine tests and adherence to the study interventions. Participants will be 
recently detoxified treatment-seeking patients with OUD who will receive  
3 monthly injections of XR-NTX or XR-BUP and have weekly urine 
toxicology monitoring. The project will enroll 200 participants over 6 
years. The proposal would be the first neural systems’ level investigation 
of the cognitive effects of the next generation extended release 
preparation of buprenorphine and naltrexone to explain the individual 
heterogeneity of OUD treatment response and failure. This project has 
the potential to advance the theory and personalized treatment of OUD 
by elucidating the brain mechanisms of vulnerability to relapse in OUD 
and in SUD in general.  
The proposal is similar to an existing UPenn IRB protocol 814234 and 
Biomarkers of disease and response to treatment in opioid addiction in 
all aspects except the addition of XRBUP, Brixadi.  
Objectives: 
Compare brain fMRI response to injectable extended-release 
buprenorphine (Brixadi, XR-BUP) and naltrexone (XR-NTX, 
Vivitrol) 


 
 
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Medications 
and 
Interventions 
XRBUP (CAM2038, Brixadi) is a subcutaneous (SC) injectable extended-release 
formulation of buprenorphine that has been developed by Camurus AB (Sweden) 
and licensed in the US by Braeburn Pharmaceuticals. Brixadi is available in a 
range of weekly and monthly doses (8,16,24 and 32 mg weekly and 64 and 96 
mg monthly) (Lofwall et al 2018). CAM2038 was approved under brand name 
Buvidal for OUD by the European Medicines Agency and approved as Brixadi by 
the FDA.This creates a unique window of opportunity for research. Braeburn, the 
US licensee of Brixadi has agreed to provide the study medication at no cost (See 
Letter of support).   
 
XRNTX (Vivitrol): is a monthly extended-release intramuscular injection of 380 
mg of naltrexone manufactured by Alkermes Inc, that has been approved by the 
FDA for OUD since 2010 (Lee et al 2017) XRNTX maintains therapeutic levels of 
naltrexone and its active metabolites for approximately 4 weeks after each 
injection.  
Functional magnetic resonance imaging (fMRI): is an established method of 
clinical medical imaging. Combined with neurocognitive testing, standard 
clinical MRI scanner can be used as an accurate and robust means of 
evaluation of brain response to medications such as opioid agonists and 
antagonists, that modulate cognitive and motivational processes in addiction 
(Davis et al 2017, Moningka et al 2019). 
Neurocognitive testing: Psychological tasks are a well-established means to 
evaluate a particular cognitive or emotional domain. We shall use established 
tasks probing four domains: motivation, response inhibition, emotional controls 
and awake rest during the fMRI sessions, to simultaneously assess domain- 
specific behavioral performance and brain activity.    
Primary 
Endpoint:  
Group (XRNTX, XRBUP) by Session (PRE, ON) interaction in the brain 
fMRI signal in 4 cognitive domains 
Secondary 
Endpoints: 
Domain-specific cognitive performance, Urine toxicology, Adherence to 
follow up and treatment visits.  
Study 
Population: 
200 individuals between the ages of 18 and 65 who have a diagnosis of 
Opioid Use Disorder (OUD). 
Phase: 
Phase 2a/b 
Description of 
Sites/Facilities  
UPenn Department of Psychiatry, Center for the Study of Addictions, 
3535 Market St., Suite 500, Philadelphia, PA 19104 
Enrolling 
Participants: 
UPenn Center for the Study of Addictions  


 
 
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Description of 
Study 
Intervention: 
XRBUP (CAM2038) or XRNTX (Vivitrol) 
Study 
Duration: 
Six years (72 months) 
Participant 
Duration: 
20 weeks 
 
 
 
 
 


 
 
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2 INTRODUCTION AND RATIONALE 
This document is a protocol for a human research study. This study is to be conducted according 
to US and international standards of Good Clinical Practice (FDA Title 21 part 312 and 
International Conference on Harmonization guidelines), applicable government regulations and 
Institutional research policies and procedures. This proposal brings four main innovations: It 
would be the first neural systems’ level investigation of the cognitive effects of extended-release 
preparations of a partial opioid agonist (XRBUP) and an antagonist (XRNTX). These formulations 
remove the pharmacokinetic and motivational imbalance between the monthly injectable 
naltrexone and daily sublingual buprenorphine that were compared in prior research (Wang et al 
2015). In addition to differences in pharmacokinetics, long acting formulations are likely to have 
a different effect on patients’ expectations of possible reward, which directly impacts 
dopaminergic signaling that regulates salience of drug and non-drug stimuli. Second, it would be 
one of the first comprehensive investigations of the cognitive effects of buprenorphine in OUD. 
Third, it would apply machine-learning algorithms to the integrated brain-behavior models to 
explain the individual heterogeneity of treatment response to MAT. Last, this would be the 1st 
study of the next generation injectable buprenorphine (Brixadi) that is expected to appear on the 
US market by September 2023 but is already approved by the FDA in terms of safety and efficacy.  
The significance of this project is in its potential to advance OUD theory and treatment by 
elucidating the brain mechanisms of vulnerability to relapse. Further, the results of this study could 
lay the foundation for improving treatment outcomes in OUD and in SUD in general. Project goals 
also directly address national public health priorities recently outlined by the directors of NIDA 
and the NIH: finding novel and increasing the effectiveness of available OUD treatment strategies 
(Volkow et al 2017). 
 
2.1 
Study Rationale 
Investigation of brain and behavioral mechanisms of the effects of the two injectable extended 
release preparations for the treatment of opioid use disorder with the ultimate goal of improving 
treatment outcomes in opioid use disorder. Both of these preparations are   FDA-approved. One 
is opioid antagonist (Vivitrol, XRNTX), and other is a partial opioid agonist (Brixadi, XRBUP). 
 
2.2 
Background 
Opioid use disorder (OUD) has reached epidemic proportions in the US, with devastating public 
health consequences (Compton et al 2016, Hedegaard et al 2017, Jiang et al 2017). Since 
1999, the number of deaths due to opioid overdose has more than quadrupled (Jones 2013), 
and it is now among the leading causes of death in adolescents and young adults (Jones et al 
2015). Treatment of OUD has three distinct targets: (i) prevention of opioid overdose in users of 
illicit drugs, (ii) detoxification from physiological dependence, and (iii) prevention of relapse. Of 
these, relapse presents the greatest treatment challenge because it persists after protracted 
abstinence and even a brief relapse can be fatal. There are two efficacious classes of 
medication-assisted therapies (MAT) for OUD: opioid agonists (e.g. methadone and 


 
 
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buprenorphine) and antagonists (e.g. naltrexone). Both have high affinity for the mu-opioid 
receptor (MOR) with antagonists lacking inherent opioid-like activity. Both MAT agonists and 
antagonists are well tolerated and highly effective at preventing relapse and withdrawal when 
taken (Lee et al 2017, Tanum et al 2017, Latif et al 2018). Nevertheless, in the clinic, MAT is 
associated with significant rates of continued illicit use that is on a continuum with non-
adherence to MAT and relapse (Soyka et al 2008, Tkacz et al 2012, Hser et al 2014, Schuman-
Olivier et al 2014). Vulnerability to relapse is a multidimensional phenotype comprised of pre-
treatment characteristics and treatment response. Understanding the individual variability in 
treatment response is critical for elucidating the mechanisms of relapse.  Although motivational 
and cognitive factors are ultimately responsible for relapse, cognitive assessments have not 
provided robust explanation of MAT effects (Nunes et al 2015). fMRI allows probing the 
cognitive mechanisms of MAT by studying the underlying neural circuitry. Studies indicate that 
incentive salience and executive functioning are key cognitive-behavioral domains that exhibit 
abnormalities in established OUD (Kwako et al 2016). Our preliminary studies have identified 
probes of executive function and incentive salience with well-established normative brain fMRI 
signatures that are sensitive to oral methadone or extended-release naltrexone (XRNTX) 
(Langleben et al 2014, Wang et al 2015, Shi et al 2018, Wang et al 2018). Comparable data on 
sublingual (transmucosal) buprenorphine/naloxone (Suboxone) is extremely limited and is 
lacking entirely on the recently approved extended-release injectable buprenorphine  (XRBUP) 
preparations (Becerra et al 2013, Pujol et al 2018). comparisons between buprenorphine and 
naltrexone introduced by the differences in routes of administration (Lee et al 2017, Tanum et al 
2017). 
2.2.1 
Pharmacokinetics, Pharmacodynamics and Toxicology  
For the present proposal, we will use injectable extended release naltrexone Vivitrol (XRNTX) 
that has been FDA approved since 2010 for the treatment of OUD and CAM2038 or Brixadi, 
manufactured by Camurus AB (Sweden) and Braeburn Pharmaceuticals (USA) (Lofwall et al 
2018). XRNTX is a monthly IM injection of naltrexone. XRBUP is a weekly or monthly injection 
of buprenorphine. The active ingredients of Vivitrol and Brixadi are naltrexone and 
buprenorphine, both of which have been in clinical FDA-approved use for over 30 years. Brixadi 
and Vivitrol are injectable extended release preparations of these two well known drugs. 
Complete PK, PD and Toxicology profile for Vivitrol is available from attached package insert 
and at https://www.vivitrol.com/. Complete PK, PD and Toxicology profile for Brixadi is available 
from Braeburn Website: 
https://braeburnrx.com/braeburns-brixadi-buprenorphine-extended-release-subcutaneous-
injection-ciii-receives-fda-approval-for-moderate-to-severe-opioid-use-disorder/ 
  
 
Opioid receptor actions of buprenorphine include analgesia, alleviation of withdrawal-like 
symptoms, and antidepressant effects. Opioid receptor actions of naltrexone include opioid 
receptor blockade. The main potential side effect of both medications is precipitated opioid 
withdrawal when administered to an individual who has not been sufficiently detoxified from 
opioids. Buprenorphine may rarely lead to over-sedation and respiratory depression in overdose, 
although because of its mixed agonist/antagonist properties, it is very unlikely. Other important 
side effects of naltrexone include prevention of action of opioid analgesics and hepatotoxicity 
when given to patients with compromised liver function. This is avoided by testing liver function 
prior to and during treatment.  


 
 
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Urine drug screen (UDS) and self-report of past use have long been the two main outcomes 
variables in SUD treatment studies. XRNTX and XRBUP differ from the traditional 
pharmacotherapies because once administered, the patient cannot terminate their effect for 
approximately one month (Dunbar et al 2007). During this time, continued illicit opioid use has 
more psychological that pharmacological significance (Sullivan et al 2013). Moreover, receiving 
an injection is 100% verifiable and not subject to interpretation. Thus, adherence is an additional 
valid measure of treatment response to injectable extended-release medications. Concurrent use 
of non-opioid medications, which XR MAT does not prevent, has been shown to be associated 
with unfavorable outcomes (Grella et al 2011, Wang et al 2015). This justifies its inclusion as an 
exploratory outcome variable in the clinical-behavioral model.  
2.2.2 
Dosing Rationale 
Dosing will be in the range approved by the FDA. For Vivitrol only one dose strength of 380 mg 
of naltrexone is available. For Brixadi, a combination of weekly (8mg, 16mg, and 24mg) and 
monthly doses of 64mg, 96mg, or 128mg will be used in the range and manner approved in 
accordance with the FDA and EMA] 
2.2.3 
 Clinical Adverse Event Profile 
Vivitrol® (XRNTX) is naltrexone for extended-release injectable suspension. Vivitrol is 
approved by the FDA for the treatment of opioid use disorder. It is manufactured and marketed 
in the US by Alkermes plc. Full prescribing information is available at https://www.vivitrol.com/  
Brixadi® (CAM 2038, XRBUP), is prolonged-release buprenorphine solution for injection. On 
May 23, 2023, the U.S. FDA granted approval of Brixadi to Braeburn Inc for the treatment of 
Opioid Use Disorder . . Information on safety and adverse events profile for Brixadi is available 
at https://braeburnrx.com/braeburns-brixadi-buprenorphine-extended-release-subcutaneous-
injection-ciii-receives-fda-approval-for-moderate-to-severe-opioid-use-disorder/ 
2.2.4 
Dosing Rationale 
Dosing will be in the range approved by the FDA. For Vivitrol only one dose strength of 380 mg 
of naltrexone is available. For Brixadi, a combination of weekly doses (8mg, 16mg, and 24mg) 
and monthly doses of 64mg, 96mg, or 128mg mg will be used in the range and manner 
approved in accordance with the FDA and EMA] 
2.3 
Risk/Benefit Assessment  
2.3.1 
Known Potential Risks 
Medications (please see Sections 2.2.1 and 2.2.2):  
Participants who are opioid-positive upon screening will undergo office-based treatment using 
FDA-approved generic medications to alleviate opioid withdrawal symptoms as determined by 
the study physicians, following symptom-triggered approach that includes clonidine 0.1 mg tid, 
dicyclomine 20 mg qid, clonazepam 0.5 mg q12 hrs PRN, diphenhydramine PRN, non-steroidal 


 
 
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anti-inflammatory drugs (NSAID’s) PRN, trazodone 50 mg qhs and oral hydration solutions. 
Common side effects of these medications include over sedation and hypotension. These will 
be prevented by proper patient education and communication, and frequent medical monitoring.  
Investigational Agent:  
XRBUP (Brixadi) is an extended-release formulation of buprenorphine.  It is known as CAM 
2038 and brand name Buvidal (EU) and Brixadi (US). CAM 2038 has been approved as Buvidal 
for opioid use disorder by the European Medicines Agency (MEA) and on May 23, 2023, The 
U.S. Food and Drug Administration granted approval of Brixadi to Braeburn Inc. It is 
administered by subcutaneous (SC) injection. It is available in multiple concentration and 
duration of action. For the present proposal we will use either the 64mg, 96mg, or the 128mg 
monthly dose. Braeburn, the US manufacturer of CAM 2038, has agreed to provide the study 
medication at no cost (See letter of support).   
The most important and nevertheless rare side effects of buprenorphine are (1) precipitated 
opioid withdrawal; (2) anxiety; (3) pain and infection at the injection side, (4) liver toxicity in 
cases of compromised liver function. These will be minimized by the following steps:   
Although complete lack of physiological dependence is not required for buprenorphine induction 
in the clinic, in order to avoid selection bias between XRNTX and XRBUP, all participants will 
undergo complete detoxification from opioids. This will be confirmed by an opioid-negative urine 
test or self-report of no opioid use in the last 5-7 days. Naloxone challenge test would not be 
necessary for CAM 2038 induction.  
Anxiety is usually self-limited and will be treated symptomatically, initially with the weekly 
psychotherapy and if necessary, with medications indicated for this purpose.   
Daytime sedation is uncommon and usually temporary. If it persists, patient will be interviewed 
again about concomitant sedative medications or alcohol. If these or other unrelated causes 
such as insomnia are not identified, the PI will determine whether it is necessary to exclude the 
participants from the study.   
Meticulous injection technique: our experienced personnel who has administered thousands of 
Vivitrol injections without ANY complications over a decade, psychoeducation  
Applying the exclusion criterion regarding elevated liver function tests labs described in the 
Exclusion Criteria section above.  
Opioid overdose is a feared complication of OUD in general. In the context of the present study, 
overdose needs to be considered in two settings: during treatment and after participation ended. 
Individuals receiving buprenorphine or naltrexone are unlikely to experience opioid overdose 
during treatment, because buprenorphine is a partial agonist whose antagonist properties 
increase in a dose-dependent fashion and naltrexone is an antagonist that blocks the effects of 
illicit opioids. Buprenorphine treatment discontinuation does not lead to precipitous increase in 
sensitivity to illicit opioids. Individuals formerly treated with XRNTX do lose their tolerance to 
opioids and are therefore at an increased risk of opioid overdose if they discontinue MAT 


 
 
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treatment abruptly and usually against medical advice. Nevertheless, studies found that the rate 
of opioid overdoses after XRNTX discontinuation is actually lower than in the control groups. 
However, to minimize the risk of overdose, participants completing the study will be referred to 
the clinical program of their choice using a “warm-handoff” procedure that will include (1) 
beginning to make arrangements for post-study referral before the effects of XRNTX or XRBUP 
wear off allowing one month for the project coordinator and the participant to establish clinical 
treatment (2) monitoring and assisting participants in making their follow up appointment and 
escorting them to their first appointment as needed (3) Providing psycho-education about opioid 
overdose risk and provide prescriptions for the nasal Naloxone spray used as a rescue in case 
of an overdose.  
XRNTX (Vivitrol) is an FDA-approved medication for opioid relapse prevention 
(https://www.vivitrol.com/content/pdfs/prescribing-information.pdf.) It is a suspension of 380 mg 
of naltrexone in a nanoparticle slow release vehicle, for intramuscular injection. The most 
important and nevertheless rare side effects are (1) precipitated opioid withdrawal; (2) anxiety; 
(3) pain and infection at the injection side, (4) liver toxicity in cases of compromised liver 
function and (5) loss of opioid tolerance and therefore greater risk of opioid overdose after study 
completion or in case of drop out. These will be minimized by the following measures:   
Ensuring that the participant is not physiologically opioid dependent, by obtaining an opioid-
negative urine test, self-report of no opioid use in the last 5 days (7 days for buprenorphine and 
methadone) and a negative naloxone challenge test (Langleben et al Addiction Biology 2014).  
Anxiety is usually self-limited and will be treated symptomatically, initially with the weekly 
psychotherapy and if necessary, with medications indicated for this purpose.   
Meticulous injection technique: our experienced personnel who has administered thousands of 
Vivitrol injections without ANY complications over a decade, psychoeducation  
Applying the exclusion criterion regarding elevated liver function tests labs described in the 
Exclusion Criteria section above.  
Risks of the study unrelated to the investigational product:  
1) Exposure to high magnetic fields: The Siemens Magnetom Prisma 3 Tesla MRI scanner 
we will use in the study is a clinical MRI system approved by the FDA. Information about 
this scanner is available on manufacturers website: https://www.siemens-
healthineers.com/en-us/magnetic-resonance-imaging/3t-mri-scanner/magnetom-prisma 
2) FDA guidelines and the IRB committees consider this scanner to be a minimal risk 
device. Specific Absorption Rates (SAR) of electromagnetic energy by the body is 
controlled by a directional coupler that serves as a circuit breaker that switches the 
magnet off, if the local SAR exceeds the FDA limit of 8 watt/kg in any gram of tissue. 
The exposure characteristics are kept on file with a copy of the consent form at the 
University of Pennsylvania Center for MRI and Spectroscopy (CAMRIS). Although 
pregnancy is not a contraindication for MRI, pregnant women will not be eligible for 
XRNTX and therefore, screened out prior to them being considered for our study. 


 
 
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3) Participants who successfully complete detoxification, will undergo a neuroimaging 
session immediately followed by induction to XRNTX or XRBUP over a period of up to 
14 days, which will include oral Naltrexone 50 mg for the XRNTX group followed by the 
1st injection of XRNTX, or by injection of one or more weekly XRBUP in 8mg, 16mg or 
24 mg strength with the total weekly dose not to exceed 32mg, followed by an injection 
of monthly XRBUP in 64, mg, 96mg, or 128mg strength (Figure 1). If deemed clinically 
necessary, induction to XRBUP may be extended by up to one week, using the same 
weekly Brixadi schedule. Buprenorphine/naloxone (Suboxone) is an FDA-approved 
sublingual form of buprenorphine that may be used during the induction if clinically 
indicated. Total duration of induction onto XRBUP will not exceed 14 days. Participants 
who are unable to complete the detoxification or induction will be excluded from the 
study and referred to a clinical addiction program for continuation of treatment as 
indicated. Suspected adverse reactions to any of the medications used in the study will 
be reported appropriately to the IRB, FDA at 1-800-FDA-1088 or 
www.fda.gov/medwatch, Alkermes, plc at 1-800-VIVITROL (1-800-848-4876) or email: 
usmedinfo@alkermes.com or both or Braeburn Inc at 1-833-274-9234 .  
4) Emotional discomfort and drug craving: Viewing drug-related images (cues) can 
sometimes trigger drug-related craving in participants with a drug-use history. This 
craving may cause some emotional and physiological arousal, but it does not pose a 
medical risk. Our standard practice is to have a trained clinician available in the event 
that the participant is still experiencing continued arousal or discomfort, either from the 
images or for any other reason, at the end of the imaging session. If the participant is still 
aroused, the clinician has a number of psychological strategies (deep relaxation, 
imagery, distraction, consequences tools, etc.) that can quickly help the subject inhibit 
craving and feel more comfortable and in control of her/his feelings. Taking these 
precautions increases the participant’s level of comfort and safety. After testing 
hundreds of participants over more than a decade, none has ever dropped out as a 
consequence of drug-related images exposure session. We have demonstrated 
sessions handled with these precautions do not lead to an increase in drug use. There is 
a small chance that participants may become upset when discussing their history of drug 
use or other behaviors. We will discontinue administration of research instruments if a 
subject shows discomfort. If necessary, the investigators who are clinicians with 
expertise in addictions, will work with the participant to alleviate any concerns. 
5) Confidentiality: There is a potential risk of a loss of confidentiality in any research 
participation. As our subjects carry a substance abuse diagnosis, this is a risk we take 
especially seriously. Following completion of an imaging session, raw data will 
immediately be transferred to electronic storage by the MR technician for later 
processing. This storage is in a locked room with access limited to the investigators and 
data processors. Subjective and physiological data are likewise kept in a locked area 
accessible only to the investigators/data processors. No published or presented 
materials will identify subjects by names, initials, or any other means that could be used 
to identify the participant. As part of consent procedures, patients will be advised of 
precautions taken to preserve confidentiality. Further, all participants in the data 
collection procedures have been instructed to not divulge any information concerning 
subjects to any person or agency without the written and explicit consent of the subject. 


 
 
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These procedures have been effective in completely protecting patient information in 
past studies. All study staff receive Good Clinical Practice and Human Subjects 
Protection training as well as HIPAA privacy training before working with any subjects. 
All medical records and research information will be kept confidential.  
2.3.2 
Known Potential Benefits 
The study offers significant benefits to participants and to society, both of which have enabled 
highly successful recruitment into our prior similar studies. The direct benefits from participation 
in the study is undergoing opioid detoxification, receiving relapse prevention treatment for OUD, 
referral for continued treatment of OUD and incidental clinically relevant findings identified from 
the psychiatric, neuropsychological, and/or brain MRI procedures conducted during the study.  
There is also a strong benefit to society from understanding mechanisms that could potentially 
alter the way we treat opioid dependence and overdose.  
Participant Retention: Participants will have numerous motives to remain in the study. First are 
the significant benefits of participation described in the previous section. Second, they will 
receive significant monetary compensation for their time. Third, the study team includes 
experiences clinicians who will make all efforts to create rapport with participants that will help 
them maintain contact even if they decided to end their pharmacotherapy. Last, the study 
coordinator and technician have been specially trained to maintain ongoing contact with OUD 
patients.  
Protection of Participants: All medical records and research information will be kept confidential. 
Medical records, and research data may only be accessed by staff engaged in the research 
project or clinical care of the subjects, or by representatives of the National Institute on Drug 
Abuse, the Food and Drug Administration, or other government agencies as required and 
permitted by law. Prior to every session subjects will be reminded that should they become 
uncomfortable for any reason, the study can be terminated with no penalties. Participation will 
not have any effect on subject’s legal status or medical care.  
2.3.3 
Assessment of Potential Risks and Benefits 
Rationale for the necessity of exposing participants to risks and a summary of the ways 
that risks to participants were minimized in the study design: The project involves two 
medications that have been FDA approved for OUD in USand are in active clinical use in the US 
(Vivitrol, XRNTX) and Brixadi will be available on market by September 2023.  . Active 
ingredients of both medications are off patent medications that have been used for OUD for 
over 30 years in the US. Dosages, risks and benefits of both medications are well known in the 
literature and have been described in detail in Sections 2.2.1, 2.2.2, and 2.2.3. They are both 
among the safest medications in their class and their use clearly outweighs the risks entailed in 
not providing these treatments to patients with OUD, first and foremost fatal opioid overdose, 
spread of infections such as HIV and Hepatitis C and criminal activity. Risks are minimized by 
inclusion and exclusion criteria that ensure enrollment of only participants with OUD and 
excluding all categories of patients at above usual risk of AE from either medication.  


 
 
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Justification as to why the benefits of participation in the study outweigh the risks of the 
information to be gained: Participation in the study benefits the participant directly as follows:  
Directly to the participant: Free expert evaluation and initiation of state-of-the-art treatment for 
OUD and monitoring of its effects. Both medications are among the safest medications in their 
class and their use clearly outweighs the risks entailed in not providing these treatments to 
patients with OUD, first and foremost fatal opioid overdose, spread of infections such as HIV 
and Hepatitis C and criminal activity.  
Benefit to society: as detailed in section 2.1 (Study Rationale), investigation of brain and 
behavioral mechanisms of the effects of the two injectable extended release preparations for the 
treatment of opioid use disorder with the ultimate goal of improving treatment outcomes in 
opioid use disorder.  
 


 
 
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3 STUDY OBJECTIVES AND ENDPOINTS 
3.1 General Design 
Study Design: The proposed study is a prospective open label 2-group study to compare the 
brain and behavioral responses of individuals with OUD receiving XRBUP and XRNTX 
treatments. The study will be conducted in two phases – Phase 1 = feasibility and Phase 2 = 
confirmation. Study interventions (XRNTX and XRBUP) and their duration will be same in both 
phases. Phase 1 (2 years) will have more cognitive and behavioral probes, some of which may 
not survive into Phase 2 (3 years) if found to not yield significant discrimination between the study 
interventions (groups). Participants will be men and women with current DSM-5 diagnoses of 
opioid use disorder (OUD) who will be randomized to XRBUP or XRNTX. Phase 1 will recruit 60 
participants and Phase 2 will recruit 200 participants. The study length for each participant is 
comprised of up to 30 days of screening and baseline evaluations (called “week 1”), a 12-week 
open label trial (medication phase), and one follow-up visit 4 weeks after end of medication phase. 
The overall duration of the project will be 5 years (60 months). We intend to recruit 4 subjects per 
month for 40 months. 
Table 1. Study timeline  
Year/Phase    
Year 1 (Phase 1) 
Year 2 (Phase 1) 
Year 3 (Phase 2) 
Year 4 (Phase 2) 
Year 5 (Phase 2) 
Quarter 
Q1 
Q2 
Q3 
Q4 
Q1 
Q2 
Q3 
Q4 
Q1 
Q2 
Q3 
Q4 
Q1 
Q2 
Q3 
Q4 
Q1 
Q2 
Q3 
Q4 
Preparation 
x 
x 
x 
x 
 
 
 
 
x 
x 
 
 
 
 
 
 
 
 
 
 
Recruitment 
 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
 
 
 
 
Data 
Collection 
 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
 
 
 
Data 
Analysis/QC 
 
 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
Publication 
 
 
 
x 
x 
 
 
x 
x 
 
 
x 
x 
 
 
x 
x 
x 
x 
x 
 
Figure 1: Outline of study interventions 
 
 
3.2 Primary Study Endpoints (see Table in the Schedule of Activities (SoA), Appendix 
Section 12.1. 
Clinical:  


 
 
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1) percent of the urine drug screen (UDS) tests positive for opioids during the last month of 
participation.  
2) The number of study interventions (1,2 or 3) participant adhered to.  
Surrogate: Brain fMRI response in three cognitive domains:  
1) Response inhibition (Go-NoGo task) 
2) Drug cue reactivity (Opioid Cues task) 
3) Emotional identification (IDemo Task) 
4)  
Primary Hypothesis:  
Aim 1 (Phase 1): Estimate the differential brain fMRI response between XRNTX and XRBUP in 
OUD treatment groups. We hypothesize that (H1) XRBUP and XRNTX will modulate the 
regional brain activity in the two-key cognitive-behavioral domains and measures of brain 
connectivity from pre-treatment (PRE) to on-treatment (ON) and this response will differ 
between the two medications. Milestone for transition to Phase 2: The MAT group (XRNTX, 
XRBUP) by Session (PRE, ON) interaction will have at least small (d’ =/> 0.2) effect size in all 
brain measures.  
 
H1a: Incentive salience (opioid cue-reactivity task): The decrease in the brain response 
to drug related stimuli (ON minus PRE) in the medial prefrontal cortex (mPFC) and the ventral 
striatum (VS) will be greater in the XRNTX than in the XRBUP group.  
 
H1b: Executive function (Go-NoGo task): XRNTX will improve the efficiency of 
response inhibition more than XRBUP, leading to a greater decrease in the brain signal (ON vs 
PRE) during the NoGo trials in the inferior frontal cortex in the XRNTX group (see A.2.b).   
 
H1c: Resting state functional connectivity (rsFC): change (ON vs PRE) in the rsFC 
between the VS and the right inferior frontal gyrus (rtIFG) and the mPFC will be greater in the 
XRNTX (vs. XRBUP group). 
 
 
Aim 2 (Phase 2): Confirm in the full sample (n=200), the significance of MAT (XRNTX, XRBUP) 
by Session (PRE, ON) interaction in all domains from Aim 1. Test the explanatory value of 
integrated brain-behavior models of relapse vulnerability, identify differences in variable loading 
between MAT group, and explore potential mechanism of individual variability in treatment 
outcome. 
 
H2a: Using logistic regression, we will test the explanatory value of brain signal in 
modeling treatment failure (Section C.5.c) and identify specific variables that differentiate MAT 
groups (interaction).  
 
H2b (Exploratory): Test if the models that include brain response better explain treatment 
success or failure when compared to those fitted solely with demographic and clinical measures: 
demographic + clinical measures vs. demographic + clinical measures + brain response).  


 
 
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3.3 
Secondary Study Endpoints (abbreviations spelled out on Page 27, “STUDY 
MEASURES”):  
Depression (HAM-D2); Anxiety (HAM-A); Opioid Withdrawal (COWS); Opioid Craving  (Opioid 
Craving Scale); TLFB interview; Percent UDS positive for cocaine (Ten-drug urine screen)  
3.4 Primary Safety Endpoints 
Brixadi adverse events: Brixadi has been shown to be safe and well tolerated in a number of 
Phase I, II and III trials, involving approximately 120 subjects. The most common side effects of 
Brixadi noted in clinical trials include: Adverse reactions most frequently reported for 
buprenorphine are headache, nausea, hyperhidrosis, insomnia, drug withdrawal syndrome and 
pain. Uncommon (between 1 and 0.01%) adverse events reported include Infection, Influenza, 
Pharyngitis, Rhinitis, injection site cellulitis, Lymphadenopathy, Hypersensitivity and Decreased 
appetite.  
There were no medication-related Serious Adverse Events in any of the clinical trials conducted 
thus far.  . In the proposed trial, patients will be monitored remotely twice a week for adverse 
events and weekly in person by a nurse or trained research staff for presence of adverse events 
or clinical deterioration. 
 
Clinical deterioration and/or suicide risk management:  All of the investigators have had 
experience managing and referring subjects under these conditions.  The TRC follows standing 
emergency policy when managing clinical deterioration related to addiction or psychiatric 
symptomatology for all of our subjects.  At the weekly visit, subjects are evaluated for the presence 
or persistence of any symptoms, indicative of clinical deterioration due to a rapidly increasing 
problem with cocaine use, alcohol use, and/or psychiatric symptoms, including suicidality. 
Between visits, subjects are instructed to contact the study physician or an authorized research 
staff member in the event that disturbing symptoms become evident. In all cases, these subjects 
are immediately evaluated, and if deemed appropriate, are referred to clinical treatment.  If 
possible, they will be maintained in the trial as long as it is deemed safe to do so. Also, any 
additional treatment is recorded for data analysis purposes.  At any time, subjects who are 
severely suicidal or at high risk of medical or physical harm will be immediately discontinued from 
the trial and appropriate medical treatment instituted.  All subjects who are discontinued from the 
trial are still encouraged to attend the follow-up visits. 
4 STUDY PLAN 
4.1 
Study Design:  
Single-blind, prospective study with Phase 1 (N = 60) to show feasibility and Phase 2 (N = 200) 
to confirm Phase 1 findings if they meet the milestones of effect size. This is to comply with the 
structure of the two-phase R61/R33 NIH funding mechanism.  Both Phases will use the same 
sequence of data collection (Section 3.1, Figure 2).   


 
 
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Rationale for the study duration:  Early medication effects are considered to be strong 
predictors of long term effectiveness both at the clinical (e.g. tolerability and symptom relief) and 
at the neural systems and pharmacodynamic levels (McDermott et al 2015). XRNTX exhibits high 
drop-out rate in the first 2 months of treatment, with 50% to 75% retention at the 3rd XRNTX 
injection (Wang et al 2015, Lee et al 2017). In a trial of sublingual buprenorphine, retention at 3 
months was approximately 75% and relapse rates defined as repeated opioid positive urines were 
almost unchanged between 3 and 6 months time points (Lee et al 2017). Thus, a 70-day follow 
up period provided by two monthly XRNTX or XRBUP injections is a necessary and sufficient time 
window for a neurobiological evaluation of the mechanisms of relapse vulnerability while 
minimizing the effect of unrelated variables such as change in family, employment or medical 
status, on the outcome variable. We optimize the two-phase design by designing experiments 
that would generate data that could serve two purposes: the initial Phase 1 exploratory and 
milestone target and then part of the Phase 2 sample that would address confirmatory questions 
that require a sample size that neither phase could reach separately.    
Summary of preliminary findings as rationale for primary hypotheses: Our preliminary and 
published data show that the proposed neurocognitive measures (e.g. neural response) have 
the potential to provide a neural systems level mechanistic explanation for the effects and the 
differences between agonist and antagonists MAT as presented in Aim 1. Our preliminary data 
also suggest that the proposed fMRI probes could explain early treatment failure which in this 
context is a close approximation of relapse, independently 
from demographic and clinical-behavioral predictors. In 
addition, each of the three sets of neural measures 
increased the AUC of the best demographics + clinical 
measures model (Figure 3). Examining the different sets 
of variables gives information on the brain mechanisms 
underlying treatment outcome. Combining all available 
neural measures yields a substantial increase in AUC, 
from 0.76 to 0.92, relative to the best non-neural model. 
While the preliminary dataset was too small to provide 
definitive results, these results suggest that combining 
variables from the behavioral and neural domains may 
further improve their value in explaining the 
mechanisms of individual variability in treatment 
response and relapse vulnerability in OUD.  
4.2 
Scientific Rationale 
for Study Design 
OVERVIEW 
OF 
DESIGN 
AND PROCEDURES:  
Design: This is a 
prospective, open-label, 
randomized study in 
individuals with OUD (Figure 
1). The goals of the study are 
Fig 2. Response to drug minus non-drug 
stimuli. PFC/ACC activation greater in 
adherent vs. non-adherent patients 
(N=14) 
Fig 3. Brain response to drug vs. non-drug stimuli in the VS (left) and 
mOFC (right) among patients not on MAT (PRE), on Suboxone, and on 


 
 
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to confirm hypotheses about neural mechanisms of response to MAT in OUD and to evaluate 
their association with MAT treatment outcomes (at 2 months.  
Overview of Procedures: Recruitment, screening, consent, demographics, detoxification, and 
recurring assessments and post-participation referrals will be performed at the UPenn Center 
for Studies of Addiction (3535 Market Street, Philadelphia, PA 19104). Screening and initial 
intake measures  may be conducted at participant’s treatment facilities. Neuroimaging will be 
performed at the UPenn Center for MRI and Spectroscopy (CAMRIS) equipped with a Siemens 
3 Tesla whole-body Prisma MRI system (See Resources section). The team will maintain phone 
contact with participants via the coordinators to address any clinical or other issues that may 
arise during participation. Refer to Section 2.1 for Study Design. 
4.3 
Justification for Dose 
See Section 2.2.3 and refer to the Product package inserts 
4.4 
End of Study Definition 
A participant is considered to have completed the study if he or she has completed all phases of 
the study including the last visit or the last scheduled procedure shown in the Schedule of 
Activities (SoA), Appendix Section 12.1. Proper referral and continuation of treatment after study 
discontinuation, with an option to continue the same medication for Vivitrol group and options to 
switch to oral preparation of buprenorphine or a biosimilar injectable extended release 
preparation that is available on the US market.. Participants will be offered referrals 
commensurate with their treatment preferences and the medication they received in the study. 
Individuals who drop out of study pharmacotherapy will be offered to continue their follow up 
visits. Individuals who drop out of study pharmacotherapy will be offered to continue their follow 
up visits. Participants completing the study will be referred to the clinical program of their choice 
using a “warm-handoff” procedure that will include (1) beginning to make arrangements for post-
study referral before the effects of XRNTX or XRBUP wear off allowing one month for the 
project coordinator and the participant to establish clinical treatment (2) monitoring and assisting 
participants in making their follow up appointment and escorting them to their first appointment 
as needed (3) Providing psycho-education about opioid overdose risk and provide prescriptions 
for the nasal Naloxone spray used as a rescue in case of an overdose. 


 
 
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5 STUDY POPULATION 
PARTICIPANTS:  
Inclusion/Exclusion criteria:  
Inclusion: Treatment-seeking men and women between 18 and 65 years of age, with OUD 
confirmed by history and physical including urine toxicology, medical records and self-report, and 
interested in injectable extended-release agonist or antagonist treatment. Eligible candidates may 
have concurrent non-opioid substance use disorders, but opioids must be their drug of choice.  
Mild to moderate Depressive and Anxiety disorders and Attention Deficit Hyperactivity Disorder 
that do not require prescription stimulants and DSM Cluster B and C personality disorders are 
also included. Participants must have a stable address, working command of the English 
language, and telephone access. Exclusion: (1) Major current DSM V psychiatric disorders 
except those listed in the inclusion criteria and lifetime history of psychotic disorders (American 
Psychiatric Association 2013); (2) Medical and surgical conditions such as a malignancy that may 
affect patients’ ability to receive XRNTX or XRBUP treatment because it may interfere with opioid 
analgesia; (3) Women of child-bearing potential who are pregnant or contemplating pregnancy in 
the next 6 months, nursing or not using an effective contraception.  
5.1 
Inclusion Criteria 
1. Males and Females 
2. 18-65 Years old 
3. 
OUD by DSM5 Criteria, confirmed by history and physical examination including 
urine toxicology, medical records and self-report 
4. 
Opioids are the drug of choice 
5. 
Interested in injectable extended release agonist or antagonist treatment 
6. 
Have a stable address, working command of English language, and telephone 
access. 
7. 
Women of childbearing age must use an effective contraceptive 
5.2 
Exclusion Criteria 
1. Psychiatric Co-morbidities:  
a) Lifetime diagnoses of any psychotic disorder, e.g. schizophrenia, schizoaffective 
disorder, bipolar affective disorder type 1.  
b) Psychiatric co-morbidities: Psychiatric disorders requiring current medication 
treatment, e.g. moderate to severe depression. Mild to moderate Depressive and 
Anxiety disorders and Attention Deficit Hyperactivity Disorder that do not require 
prescription stimulants and DSM Cluster B and C personality disorders are also 
allowed.  
c) Polysubstance users whose drug of choice is not an opioid.  
2. Contraindications for XRNTX or XRBUP e.g. active liver disease.  
8. 
Medical and surgical conditions such as malignancy that may affect patients’ 
ability to receive XRNTX or XRBUP treatment because it may interfere with opioid 
analgesia 
9. 
Contraindications for MRI, e.g. claustrophobia, indwelling foreign magnetic 
agents.  
 


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5.3 
Strategies for Recruitment and Retention 
Recruitment: The project team has an established track record of recruiting for and conducting 
neuroimaging studies of OUD that include office-based detoxification and induction to XRNTX or 
XRBUP (Langleben et al 2014, Wang et al 2015, Shi et al 2018, Wang et al 2018). The team has 
established relationship with a network of addiction treatment facilities in the metro Philadelphia 
area, from which we have been recruiting participants with OUD for over a decade. This network 
includes two full-service academic opioid treatment programs as well as six community inpatient 
facilities and numerous office-based practices. The network guarantees access to a diverse and 
representative population spanning urban, suburban, and rural settings. Finally, our community 
and media outreach, (Bender 2013) as well as social media advertising, have been highly 
effective means of supplementing the clinical referrals of participants. From all these combined 
sources, we expect to recruit a total of 200 participants. Approximately 75% will achieve the opioid 
abstinence status to receive the 1st monthly XR MAT injection, to a total of 160 anticipated by the 
power analysis. We budget an additional 10% of scanner time to account for data loss due to 
motion artifacts and technical problems.  Access is a challenge in health care and a research 
confound. Insufficient transportation could impose selection bias against individuals with lower 
SES, disabilities and history of impaired driving which are all overrepresented among individuals 
with OUD. We will address this issue by reimbursing for private or public transportation expenses 
and access to cost-effective prepaid car services and substituting some in-person visits by 
telephone and electronic communications. 


 
 
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6 STUDY INTERVENTIONS 
Medications: 
Investigational Agent XRBUP (CAM 2038, Brixadi) is a subcutaneous (SC) extended-
release formulation of buprenorphine that has been developed by Camurus AB (Sweden) and 
licensed in the US by Braeburn Pharmaceuticals. Differences between Brixadi and the alternative 
FDA-approved injectable XRBUP Sublocade and will be used in a weekly doses comprised of 
8mg,  16mg, and 24mg not exceeding 32mg and monthly doses or 64mg, 96mg, or 128mg, and 
unlike Sublocade, it does not require abdominal SC injection and is expected to be less expensive 
than Sublocade (Lofwall et al 2018). Brixadi was approved under brand name Buvidal for OUD 
by the European Medicines Agency and On May 23, 2023, The U.S. Food and Drug 
Administration granted approval of Brixadi to Braeburn Inc.,. Braeburn, the US licensee of Brixadi 
has agreed to provide the study medication at no cost (See Letter of support).   
XRNTX (Vivitrol): is a monthly extended-release intramuscular injection of 380 mg of 
naltrexone manufactured by Alkermes Inc, that has been approved by the FDA for OUD since 
2010 (Lee et al 2017) XRNTX maintains therapeutic levels of naltrexone and its active metabolites 
for approximately 4 weeks after each injection. We plan to purchase Vivitrol required for the 
proposal.  
 
6.1 
Study Procedures:  
will be administered by a clinician with appropriate level of clinical training and certification (RN, 
CRNP, RT, MD): 
 
Screening (Appendix Section 12.1): Candidates will be screened by phone or in person at a 
referral site. Contact information of perspective participants will be kept in a secured password-
protected computer file accessible only by study personnel. After obtaining perspective participant 
contact information from voicemails left on the study recruitment hotline (phone number 
distributed via flyers) or in-person, study staff will enter their contact information for screening into 
a secured computer file. After screening, study staff will mark study eligibility status within the file 
so candidates are not repeatedly contacted. Those eligible and interested in participation will 
undergo informed consent procedure and intake. 
 
Intake and Informed Consent 
  Participants who pass Screening will be invited to attend Intake session at UPenn Center for 
Studies of Addiction (3535 Market Street, Philadelphia, PA 19104). An IRB (UPENN) approved 
Informed Consent will be read verbatim by a trained research staff. At the end of the consent 
session, a quiz is given. Subjects scoring below 100% correct will receive additional instruction 
regarding the study and consent form.  Incorrect questions from the quiz will be administered 
again until all questions are answered correctly. All participant questions will be answered as 
appropriate after which the Informed Consent will be completed (signed and dated).  
After signing the consent, participants would also be asked to grant access to their medical 
records at University of Pennsylvania and other institutions to share their health information that 
may include diagnoses, medications, hospital admissions, laboratory and imaging studies and 
participation in treatment programs including substance use disorder. This will be done by 
signing a “RESEARCH PARTICIPANT AUTHORIZATION TO OBTAIN AND REVIEW HIPAA- 


 
 
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PROTECTED MEDICAL RECORDS AND COMMUNICATION WITH THEIR HEALTH CARE 
PROVIDERS” 
Participants’ eligibility for fMRI and XRNTX and XRBUP will be determined by history and physical 
examination and laboratory testing, e.g. Blood chemistry including Liver Functions and Complete 
Blood Count (CBC) (Cornish et al 1997). Additional tests relevant to the specific detoxification 
setting, such as 12 lead Electrocardiogram (ECG), Xray will be performed if clinically indicated. 
 
Intake Procedures at Treatment Facilities: 
Participants found to be eligible at screening who are unable to attend intake at our center 
because they are currently inpatient, will undergo intake procedures at their inpatient treatment 
facility. Private space for the intake sessions will be secured in coordination with inpatient clinical 
staff. 
 
The following procedures will be done at the inpatient facilities to reduce the delay in enrolling 
eligible participants. 
• 
Informed consent, informed consent quiz and HIPAA authorization form administered by 
the trained study member. 
Non-invasive assessments and measures will be administered by the trained study members 
using portable tablets.  
Opioid withdrawal management (detoxification) and induction to monthly MAT injections: 
The clinical management of XRBUP is similar to XRNTX except that induction to XRBUP requires 
partial detoxification followed a weekly dose of injectable XRBUP, while induction on XRNTX 
requires complete abstinence (Lofwall et al 2018). The goal of the detoxification and induction 
phase of the experiment is to establish a uniform starting point for both monthly formulations. To 
achieve it, we will detoxify all participants to abstinence and randomize after abstinence from illicit 
opioids has been achieved. Outpatient detoxification to abstinence takes between 5 and 10 days. 
Following detoxification, the XRBUP participants will receive a combination of 8mg,16mg, and 
24mg strengths of weekly XRBUP, not to exceed 32 mg/week, followed by the injection of 64mg, 
96mg, or 128mg of monthly XRBUP. If clinically indicated, supplemental doses of sublingual 
buoprenorphine/naloxone (Suboxone) may be used. If clinically indicated, the induction procedure 
may be extended by up to one week, using the same approach. The total duration of induction to 
Brixadi will not exceed 14 days. The XRNTX participants will receive 50 mg of oral naltrexone for 
7-10 days after detoxification followed by the 1st XRNTX (380 mg naltrexone IM) injection. The 
use of symptom-driven titration of weekly XRBUP during induction reflects current best practices 
in administration of the drug and increases participant safety and comfort.  The XRBUP induction 
period is also intended to synchronize the timepoint at which both cohorts begin their monthly 
treatments. The non-opioid detoxification will follow the procedure described in our previous 
neuroimaging studies (Langleben et al 2014, Langleben 2015, Wang et al 2018). Participants who 
are opioid-positive upon screening will undergo office-based withdrawal management (detox) by 
the study physicians using FDA-approved generic medications to alleviate opioid withdrawal 
symptoms following a symptom-triggered approach that includes clonidine 0.1 mg tid, dicyclomine 
20 mg qid, clonazepam 0.5 mg q12 hrs PRN, diphenhydramine 25 mg PRN, non-steroidal anti-
inflammatory medicines PRN, Trazodone 50 mg qhs and oral hydration solutions (Molenberghs 
et al 2005). The induction to XRNTX or XRBUP will commence immediately after the baseline 
MRI session. The 1st monthly injection will be administered by an experienced nurse practitioner 
after induction is completed (approximately 7-14 days later).   
 


 
 
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Neuroimaging (MRI): The MRI session will take place after detoxification and immediately before 
MAT induction (Table 1, Figure 1). This baseline time-point has been used successfully in our 
prior studies (Langleben et al 2014, Wang et al 2015) Participants will be escorted to the MRI 
facility where the investigator will meet them, review the consent and MRI screening form, and 
answer any remaining questions. Participants will be placed in the scanner in a supine position. 
The stimuli are rear projected to the center of the visual field using a PowerLite 7300 Video 
projector system (Epson America, Inc.) and viewed through a mirror mounted on the head coil. 
Participants will be given a non-ferromagnetic scroll wheel (FORP™, Current Design Inc., 
Philadelphia, PA) to respond during the tasks. Neuroradiologists will review the scans for clinically 
significant abnormalities. fMRI data will be acquired during (a) MPRAGE T1 image acquisition (5 
min), (b) resting-state fMRI (5 min), (c) Go-NoGo task (5.5 min), (d) visual opioid cue task (10.5 
min).  The Go-NoGo and the visual opioid cue task will be counterbalance between scan 1 and 2. 
The total time in the scanner, including time for positioning removal and structural imaging, will 
not exceed 60 minutes.  
 
STUDY MEASURES: will be administered by the study coordinator or psychologist with 
appropriate level of clinical training and certification (MA, PsyD or PhD): 
 
Demographic and Clinical (Appendix Section 12.1): We use PhenX protocols 
(phenxtoolkit.org).  
Demographical Information: Standard demographical information will be collected during 
phone screening and baseline study appointments, such as height, weight, preliminary fMRI 
eligibility, contact information, years of education etc.  
MINI International Neuropsychiatric Interview (MINI) (Sheehan DV, 1998; 59(suppl 20)). 
The MINI is a clinician administered neuropsychiatric interview for symptoms across 17 of the 
most common mental health disorders. The DSM-5 version of the MINI will be administered.  
Addiction Severity Scale Lite (ASI-Lite) (McLellan, 1997) The Addiction Severity Scale 
Lite is a shortened version of the full clinical interview. The measure collects information on 
demographics, employment, legal status, alcohol/drugs, family/social relationships, and 
psychiatric status. This measure is administered by a clinician. 
 
Shipley Institute of Living Scale (SILS) (Zachary, 1985 ) The Shipley institute of living 
scale is a 20-minute administered measure arriving at an estimate of IQ. The scale is divided 
into two sections, verbal and logic-based and is administered by study staff. 
 
State Trait Anxiety Inventory (STAI-6) (Marteau, 1992) The STAI-6 is a 6 item self-report 
inventory design to evaluate anxiety.  
 
Subjective Opiate Withdrawal Scale (SOWS) (Dijkstra, 2007) The SOWS is a self-report 
16-tem scale measuring motoric, autonomic, gastrointestinal, and musculoskeletal opiate 
withdrawal symptoms as well as psychological symptoms like anxiety and craving due to opiate 
use.  
 


 
 
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Opiate Withdrawal Scale – Elman (OWSE) (Elman, 2001) The opiate withdrawal scale 
from Elman is an adapted 6-item self-report questionnaire looking to examine five aspects of 
opiate craving- currently intensity, projected intensity, resistance, responsiveness to drug-
related stimuli, and imagined likelihood of use in a setting with access to the drug. The 
questionnaire was initially designed to assess cocaine craving. The measure shows good 
consistency being used to assess opiate craving. 
Hamilton Anxiety Rating Scale (HAM-A) (Hamilton 1967). The HAM-A is a 15-minute, 14-
item, clinician-administered instrument that measures current anxiety and changes in anxiety 
symptoms.  
Hamilton Depression Rating Scale (HAM-D) (Hamilton 1959). The HAM-D is a 20-
minute, 24-item interview that measures the severity of depression and changes in depressive 
symptoms.  
Clinical Opiate Withdrawal Scale (COWS) (Wesson et al 2003). The COWS is a clinician-
administered instrument that measures eleven common opioid withdrawal symptoms. 
Short Form-McGill Pain Questionnaire-2 (SF-MPQ-2) (Dworkin et al 2015) (PhenX 
#190901) is a 22-item self-administered questionnaire that asks about the different qualities of 
pain and related symptoms. Respondents are asked to rate the intensity of each type of pain 
they felt during the past week on a scale from 0 to 10 
Timeline Follow-Back Interview (TLFB) (Sobell et al 1992).  The TLFB is a 15-30-minute, 
semi-structured interview designed to measure self-reported drug use. It will be used at baseline 
to capture all drug use in the past 30 days including prescribed concomitant medications 
(PhenX 27016266).   
Weekly online self-reported TLFB is a modified TLFB interview that uses a calendar-
based format to record participants’ self-report of past week drug use. 
Experimental Assessments: 
Biochemical Assessments:  
Urine Toxicology: Rapid semi-quantitative ELISA urine drug screen test for morphine, oxycontin, 
methadone, 
buprenorphine, 
fentanyl, 
cocaine, 
amphetamine, 
methamphetamine, 
benzodiazepines, PCP and THC. Urine sample collection procedure has been described in a 
recent paper (Wang et al 2015).  
Neuroimaging and cognitive: Overview of BOLD fMRI paradigms design: BOLD fMRI is a 
relative (non-absolute) measure, and experimental results are typically reported as contrast 
between conditions. Two main strategies are event-related and block designs (Aguirre et al 1999, 
Laurienti et al 2003).  
Resting-state fMRI (rs-fMRI): During the 5-min rs-fMRI, participants will be instructed to stay 
awake, still, and to keep their eyes open. A fixation crosshair will be shown on a black 
background throughout the scan. No task performance will be required. 
Visual Opioid Cue Task: Forty-eight drug-related and 48 control stimuli are presented randomly 
for 500 msec, separated by variable inter-trial intervals (ITI, 0–18 s). The stimuli sets are tailored 
to a specific pattern of OUD: prescription opioids only, heroin (IV and IN) only, and mixed 
prescription opioids and heroin (Shi 2016). The control stimuli that depict household objects and 


 
 
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CAM2038/Brixadi/Buvidal 
Page 29 of 60 
 
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chores are graphically and contextually matched to the drug-related stimuli (Langleben et al 2008, 
Wang et al 2015). Opiate craving is assessed with a subjective craving score (SCS), before and 
after each MRI session on a 0–9 Likert scale. There is no response requirement in the task, 
avoiding the possible confounds of individual differences in motor coordination/reaction time. 
fMRI Go-NoGo task (GNG): The Go-NoGo fMRI task is a validated task testing cognitive control 
aspect of executive functions adopted from previous research (Goldman et al 2015). The Go 
stimuli included 122 positively valanced pictures (e.g. sweets), and the No-go stimuli were 38 
negatively valanced pictures (e.g. snakes). Each trial consisted of a stimulus displayed for 300 
ms, followed by 1700-ms baseline period during which a crosshair was displayed. Pseudo-
random order of the stimuli and baseline periods was generated. Total Task Time: ~8 min. Our 
preliminary task performance data indicate that Go-NoGo task performance predicted XRNTX 
treatment failure (p<0.01). Performance will be coded by the number of errors of commission. 
Emotion regulation: We will use the Face Emotion Identification (IDEMO) task, a validated (Gur 
et al. 2002a,b, 2007; Loughead et al. 2008; Satterthwaite et al. 2010) probe using appraisal of 
emotional valence of facial expressions to evaluate emotional state and bias. Briefly, participants 
view 60 faces displaying neutral, happy, sad, angry or fearful expressions presented in a fast 
event-related fashion. Each face is displayed for 5.5 seconds followed by a variable inter-stimulus 
interval (0.5–18.5 seconds) during which a complex crosshair (matched to the faces’ perceptual 
qualities) is displayed. While viewing the stimuli, participants are asked to select one of five labels 
(happy, sad, anger, fear, neutral) for each face presented, using a custom scroll wheel response 
device (Current Designs; Philadelphia, PA, USA). Accuracy and correct reaction time were 
assessed as secondary measures. Total task duration is 10.5 minutes. 
MRI Image Acquisition: Neuroimaging will be performed on a 3-Tesla Siemens Prisma scanner 
equipped with a 64-channel head coil. Prior to scanning, participants review instructions and 
practice all fMRI tasks. An MR-compatible button-box is used to record task responses (Current 
Designs, Philadelphia, PA). A T1-weighted multi-echo magnetization-prepared, rapid acquisition 
gradient echo (MPRAGE) structural image is acquired using standard parameters at 1-mm 
resolution. Resting fMRI BOLD will be obtained after structural imaging, followed by task 
paradigms. fMRI T2*-weighted BOLD images will be acquired using a whole-brain, single-shot 
gradient-echo (GE) echo-planar imaging (EPI) sequence, using the following parameters: 
TR/TE=1500/32 ms, flip angle 90°, field of view (FOV)=192 mm, matrix= 96X96, isotropic voxel 
resolution 2.5 mm, slice thickness/gap=2.5/0mm, 38 slices axial-oblique parallel to AC-PC. We 
find that these parameters produce robust signal in ventral brain regions including ventral striatum, 
orbital/ventral prefrontal cortex and amygdala, with little distortion or signal loss.  
6.1.1 
Study Intervention Description 
Medications: 
Investigational Agent XRBUP (CAM 2038, Brixadi) is a subcutaneous (SC) extended-
release formulation of buprenorphine that has been developed by Camurus AB (Sweden) and 
licensed in the US by Braeburn Pharmaceuticals. Differences between Brixadi and the alternative 
FDA-approved injectable XRBUP Sublocade it that it is available in a range of weekly and monthly 
doses (8,16,24 and 32 mg weekly and 64mg and 96mg and 128mg monthly), unlike Sublocade, 
it does not require abdominal SC injection and is expected to be less expensive than Sublocade 
(Lofwall et al 2018). Weekly Brixadi doses for the study will use a combination of 8mg, 16mg, and 
24mg doses not exceeding 32mg. Monthly Brixadi does will be either 64mg, 96mg, or 128mg. 


 
 
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Brixadi was approved under brand name Buvidal for OUD by the European Medicines Agency 
and On May 23, 2023, The U.S. Food and Drug Administration granted approval of Brixadi to 
Braeburn Inc. . Braeburn, the US licensee of Brixadi has agreed to provide the study medication 
at no cost (See Letter of support).   
6.2 
XRNTX (Vivitrol):  
is a monthly extended-release intramuscular injection of 380 mg of naltrexone manufactured by 
Alkermes Inc, that has been approved by the FDA for OUD since 2010 (Lee et al 2017) XRNTX 
maintains therapeutic levels of naltrexone and its active metabolites for approximately 4 weeks 
after each injection. We plan to purchase Vivitrol required for the proposal. 
Preparation/Handling/Storage/Accountability 
6.2.1 
Acquisition and accountability 
Investigational agent (Brixadi, XRBUP) is manufactured and supplied by Braeburn. It will be 
stored and dispensed by the Research Pharmacy at the Hospital of the University of Pennsylvania 
consistent with regulations governing a DEA Schedule III medication.  
Upon receipt of the of the study treatment supplies, an inventory will be performed, and a drug 
receipt log filled out and signed by the person accepting the shipment.  It is important that the 
designated study staff counts and verifies that the shipment contains all the items noted in the 
shipment inventory.  Any damaged or unusable study drug in a given shipment (active drug or 
comparator) will be documented in the study files. 
6.2.2 
Formulation, Appearance, Packaging, and Labeling 
Please refer to the Vivitrol and Brixadi product package insert 
6.2.3 
Product Storage and Stability 
In compliance with Office of Clinical Research guidelines for outpatient clinical trials using industry 
drug, study medications will be received, packaged and stored at PENN’s Investigational Drug 
Service (IDS). Upon receipt of the study medication, an inventory will be performed and a drug 
receipt log filled out and signed by the person accepting the shipment. IDS staff will verify that the 
shipment contains all the items noted in the shipment inventory. Any damaged or unusable study 
medication in a given shipment will be documented in the study files. IDS will oversee assigning 
and labeling of all study medication.Study medications will be kept separate from all other 
samples, and drugs and clearly labelled as investigational product. XRNTX and XRBUP will be 
stored at the appropriate temperatures as determined by the manufacturer. Both cold and room 
temperature storage (if applicable) will be kept secured locked and accessible only to those 
working on the study. Accountability logs (subject level & study-wide) will be kept ensuring 
thorough documentation of shipping, handling, storage, preparation, and dispensing of study 
medication.  
6.2.4 
Preparation 
Study medication will be prepared at PENN’s Investigational Drug Service (IDS) and administered 
by clinical research staff (RNs) on-site at the Addiction Treatment Center (3535 Market St.) who 
have received documented and thorough training on the knowledge of the study medications, 
purpose, side effects, and precautions. Inventory, dispensing, and logging of study medications 


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will be conducted on a trial-level and individual subject basis. As per OCR guidelines, study 
medications are not re-packaged prior to administration. A separate study medication destruction 
log will be kept if unused medication is not returned to the manufacturer as per manufacturer’s 
specifications for the trial. All procedures, instructions and documentation requirements as 
defined by the Office of Clinical Research for management of investigation sites using FDA 
regulated drugs using IDS will be followed.   
6.3 
Measures to Minimize Bias: Randomization and Blinding 
Urn Randomization. We plan to use urn randomization to stratify subjects across the two 
treatment conditions. We will stratify subjects on sex on the day of randomization.  
An off-site statistician will work with clinical research staff in setting up the urn randomization 
sequences and will ensure that the codes linking subject’s ID numbers to treatments are secure. 
Randomization uses an electronic emergency-unmasking database in Microsoft Access 
accessible to the off-site statistician 24 hours a day.. Randomization tables are secured within 
Microsoft Access and are managed by an off-cite statistician and data management study 
personnel, who do not work directly with study participants. The system only provides access for 
one subject at a time and all transactions are recorded. If a subject is prematurely discontinued 
from the trial, all attempts will be made to not break the blind. If an emergency necessitates that 
the blind be broken, only the off-site statistician will have access to the blind to do so. They will 
be given the name of the staff members who have authority to request that the blind be broken. 
The off-site statistician can be reached 24 hours a day and can access a subject’s code rapidly. 
6.4 
Study Intervention Compliance 
Medication adherence.  There will be observed medication injection on day 10 and 40. 
6.5 
Concomitant Therapy 
Concomitant medications will be recorded for the time period of one month before the initial 
screening visit throughout the follow up phase.  
Prohibited medications include: benzodiazepines, barbiturates, antipsychotics, 
antidepressants, psychomotor stimulants (such as methylphenidate and amphetamine), 
antianxiety medications, naltrexone, disulfiram, modafinil, anticonvulsants, GABAergic 
drugs. Gabapentin prescribed for pain and not for a seizure disorder is acceptable. 
Acceptable forms of birth control are: 
•
Oral contraceptives (“the pill”)
•
Contraceptive sponge,
•
Barrier (diaphragm or condom),
•
Intrauterine contraceptive system (Mirena®, Paragard®)
•
Levonorgestrel implant (Norplant®)
•
Etonogestrel implant (Implanon®)


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•
Medroxyprogesterone acetate contraceptive injection (Depo-Provera®)
•
Complete abstinence from sexual intercourse
•
Hormonal vaginal contraceptive ring (NuvaRing®)
•
Patch (Ortho Evra®)
Surgically sterile
•
Partner surgically sterile
Additional psychosocial therapies including self-help groups will be allowed during the 
randomized medication phase but will be measured using the Treatment Services Review (TSR). 
7 STUDY INTERVENTION DISCONTINUATION AND PARTICIPANT 
DISCONTINUATION/WITHDRAWAL 
7.1 
Discontinuation of Study Intervention  
Stopping rules will be having SAEs or unexpected AEs attributable to study medication in 10% 
or more patients, or 3X as many SAEs or unexpected AEs in a single arm. Mild irritation at an 
injection site that resolves with treatment in 3-7 days will not be counted as an unexpected AE’s; 
an infection that does not resolve in 7 days or progresses to an abscess that needs surgical 
intervention will be counted as an unexpected AE or SAE depending on the need for hospital 
treatment. 
7.2 
Participant Discontinuation/Withdrawal from the Study 
Participants are free to withdraw from participation in the study at any time upon request. 
An investigator may discontinue or withdraw a participant from the study for the following 
reasons: 
•
Pregnancy
•
Significant study intervention non-compliance
•
If any clinical adverse event (AE), laboratory abnormality, or other medical condition or 
situation occurs such that continued participation in the study would not be in the best 
interest of the participant
•
If the participant meets an exclusion criterion (either newly developed or not previously 
recognized) that precludes further study participation
•
Participant missing a due injection for more than 14 days.
The reason for participant discontinuation or withdrawal from the study will be recorded on the 
study Case Report Form (CRF) along with a note to file. Subjects who sign the informed 
consent form and are randomized but do not receive the injection may be replaced. Subjects 


 
 
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who sign the informed consent form and are randomized and receive the injection, and 
subsequently withdraw, or are withdrawn or discontinued from the study, will not be replaced. 
7.3 
Lost To Follow-Up 
A participant will be considered lost to follow-up if he or she fails to return for more than 2 
consecutive scheduled visits and is unable to be contacted by the study site staff. 
The following actions must be taken if a participant fails to return to the clinic for a required 
study visit: 
• 
The site will attempt to contact the participant and reschedule the missed visit and 
counsel the participant on the importance of maintaining the assigned visit schedule and 
ascertain if the participant wishes to and/or should continue in the study. 
• 
Before a participant is deemed lost to follow-up, the investigator or designee will make 
every effort to regain contact with the participant (where possible, 3 telephone calls and, 
if necessary, a certified letter to the participant’s last known mailing address or local 
equivalent methods). These contact attempts should be documented in the participant’s 
medical record or study file.  
• 
Should the participant continue to be unreachable, he or she will be considered to have 
withdrawn from the study with a primary reason of lost to follow-up. 


 
 
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8 STUDY ASSESSMENT AND PROCEDURES 
STUDY MEASURES: 
Demographic and Clinical (Appendix Section 12.1): We use PhenX protocols 
(phenxtoolkit.org).  
Demographical Information: Standard demographical information will be collected during 
phone screening and baseline study appointments, such as height, weight, preliminary fMRI 
eligibility, contact information, years of education etc.  
MINI International Neuropsychiatric Interview (MINI) (Sheehan DV, 1998; 59(suppl 20)). 
The MINI is a clinician administered neuropsychiatric interview for symptoms across 17 of the 
most common mental health disorders. The DSM-5 version of the MINI will be administered.  
Addiction Severity Scale Lite (ASI-Lite) (McLellan, 1997) The Addiction Severity Scale 
Lite is a shortened version of the full clinical interview. The measure collects information on 
demographics, employment, legal status, alcohol/drugs, family/social relationships, and 
psychiatric status. This measure is administered by a clinician. 
 
Shipley Institute of Living Scale (SILS) (Zachary, 1985 ) The Shipley institute of living 
scale is a 20-minute administered measure arriving at an estimate of IQ. The scale is divided 
into two sections, verbal and logic-based and is administered by study staff. 
 
State Trait Anxiety Inventory (STAI-6) (Marteau, 1992) The STAI-6 is a 6 item self-report 
inventory design to evaluate anxiety.  
 
Subjective Opiate Withdrawal Scale (SOWS) (Dijkstra, 2007) The SOWS is a self-report 
16-tem scale measuring motoric, autonomic, gastrointestinal, and musculoskeletal opiate 
withdrawal symptoms as well as psychological symptoms like anxiety and craving due to opiate 
use.  
 
Opiate Withdrawal Scale – Elman (OWSE) (Elman, 2001) The opiate withdrawal scale 
from Elman is an adapted 6-item self-report questionnaire looking to examine five aspects of 
opiate craving- currently intensity, projected intensity, resistance, responsiveness to drug-
related stimuli, and imagined likelihood of use in a setting with access to the drug. The 
questionnaire was initially designed to assess cocaine craving. The measure shows good 
consistency being used to assess opiate craving. 
Hamilton Anxiety Rating Scale (HAM-A) (Hamilton 1967). The HAM-A is a 15-minute, 14-
item, clinician-administered instrument that measures current anxiety and changes in anxiety 
symptoms.  
Hamilton Depression Rating Scale (HAM-D) (Hamilton 1959). The HAM-D is a 20-
minute, 24-item interview that measures the severity of depression and changes in depressive 
symptoms.  
Clinical Opiate Withdrawal Scale (COWS) (Wesson et al 2003). The COWS is a clinician-
administered instrument that measures eleven common opioid withdrawal symptoms. 


 
 
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Short Form-McGill Pain Questionnaire-2 (SF-MPQ-2) (Dworkin et al 2015) (PhenX 
#190901) is a 22-item self-administered questionnaire that asks about the different qualities of 
pain and related symptoms. Respondents are asked to rate the intensity of each type of pain 
they felt during the past week on a scale from 0 to 10 
Timeline Follow-Back Interview (TLFB) (Sobell et al 1992).  The TLFB is a 15-30-minute, 
semi-structured interview designed to measure self-reported drug use. It will be used at baseline 
to capture all drug use in the past 30 days including prescribed concomitant medications 
(PhenX 27016266).   
Weekly online self-reported TLFB is a modified TLFB interview that uses a calendar-
based format to record participants’ self-report of past week drug use. 
 
Experimental Assessments: 
Urine Toxicology: Rapid semi-quantitative ELISA urine drug screen test for morphine, oxycontin, 
methadone, 
buprenorphine, 
fentanyl, 
cocaine, 
amphetamine, 
methamphetamine, 
benzodiazepines, PCP and THC. (Urine sample collection procedure has been described in a 
recent paper (Wang et al 2015).  
Neuroimaging and cognitive: Overview of BOLD fMRI paradigms design: BOLD fMRI is a 
relative (non-absolute) measure, and experimental results are typically reported as contrast 
between conditions. Two main strategies are event-related and block designs (Aguirre et al 1999, 
Laurienti et al 2003).  
Resting-state fMRI (rs-fMRI): During the 5-min rs-fMRI, participants will be instructed to stay 
awake, still, and to keep their eyes open. A fixation crosshair will be shown on a black 
background throughout the scan. No task performance will be required. 
Visual Opioid Cue Task: Forty-eight drug-related and 48 control stimuli are presented randomly 
for 500 msec, separated by variable inter-trial intervals (ITI, 0–18 s). The stimuli sets are tailored 
to a specific pattern of OUD: prescription opioids only, heroin (IV and IN) only, and mixed 
prescription opioids and heroin (Shi 2016). The control stimuli that depict household objects and 
chores are graphically and contextually matched to the drug-related stimuli (Langleben et al 2008, 
Wang et al 2015). Opiate craving is assessed with a subjective craving score (SCS), before and 
after each MRI session on a 0–9 Likert scale. There is no response requirement in the task, 
avoiding the possible confounds of individual differences in motor coordination/reaction time. 
fMRI Go-NoGo task (GNG): The Go-NoGo fMRI task is a validated task testing cognitive control 
aspect of executive functions adopted from previous research (Goldman et al 2015). The Go 
stimuli included 122 positively valanced pictures (e.g. sweets), and the No-go stimuli were 38 
negatively valanced pictures (e.g. snakes). Each trial consisted of a stimulus displayed for 300 
ms, followed by 1700-ms baseline period during which a crosshair was displayed. Pseudo-
random order of the stimuli and baseline periods was generated. Total Task Time: ~8 min. Our 
preliminary task performance data indicate that Go-NoGo task performance predicted XRNTX 
treatment failure (p<0.01). Performance will be coded by the number of errors of commission. 
MRI Image Acquisition: Neuroimaging will be performed on a 3-Tesla Siemens Prisma scanner 
equipped with a 64-channel head coil. Prior to scanning, participants review instructions and 
practice all fMRI tasks. An MR-compatible button-box is used to record task responses (Current 
Designs, Philadelphia, PA). A T1-weighted multi-echo magnetization-prepared, rapid acquisition 
gradient echo (MPRAGE) structural image is acquired using standard parameters at 1-mm 


 
 
Protocol Number 843403 
Brixadi and Vivitrol  
 
CAM2038/Brixadi/Buvidal 
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resolution. Resting fMRI BOLD will be obtained after structural imaging, followed by task 
paradigms. fMRI T2*-weighted BOLD images will be acquired using a whole-brain, single-shot 
gradient-echo (GE) echo-planar imaging (EPI) sequence, using the following parameters: 
TR/TE=1500/32 ms, flip angle 90°, field of view (FOV)=192 mm, matrix= 96X96, isotropic voxel 
resolution 2.5 mm, slice thickness/gap=2.5/0mm, 38 slices axial-oblique parallel to AC-PC. We 
find that these parameters produce robust signal in ventral brain regions including ventral striatum, 
orbital/ventral prefrontal cortex and amygdala, with little distortion or signal loss.  
fMRI Image Processing will utilize standard image processing procedures (Langleben et al 2008, 
Langleben et al 2014, Wang et al 2015). Briefly, functional image analysis will utilize FSL platform 
(Functional MRI of the Brain Software Library) (Jenkinson et al 2012) and will include: B0 
correction using FUGUE; slice time correction, motion correction (Jenkinson et al 2002), high-
pass filter (120 sec), spatially smoothing (6 mm FWHM, isotropic) and mean-based intensity 
normalization. Resulting translational motion parameters will be examined to ensure that there is 
not excessive motion (i.e. >3 mm in any plane) and will be included in the General Linear Model 
(GLM). BET is used to remove non-brain areas (Smith 2002). Subject-level time-series statistical 
analysis will be executed with FSL’s improved linear model (Woolrich et al 2001).  Contrasts of 
interest are: drug vs. control stimuli (Cue Task); No-Go vs. Go (GNG); correct vs. incorrect No-
Go (GNG). Preprocessed rs-fMRI data will undergo linear de-trending, band-pass filtering 
(.01–.08 
Hz), 
and 
regression 
of 
confound 
variables 
(motion 
parameters, 
white 
matter/cerebrospinal fluid signals). The bilateral NAcc will serve as the seed region, and the 
connectivity with the NAcc will be indexed by the Fisher-transformed correlation coefficients 
between the time series of the NAcc and other brain regions as defined by the Power nodes 
(Power et al 2011). Subject level statistical maps will be co-registered to the T1 image using 
boundary-based registration (Greve et al 2009) and normalized to the MNI 2mm template using 
a highly accurate, deformable registration via attribute matching and mutual-saliency weighting 
(DRAMMS) (Ou et al 2011). Given our strong apriori hypotheses based on preliminary data and 
current literature, we will utilize a combination of hypothesis-driven regional analyses as well as 
follow-up whole-brain voxel-wise analyses.  
Hypothesis-driven regional analyses: For each subject, regions of interest (see H1a) will be 
defined anatomically using the Harvard-Oxford Probabilistic Atlas (Hayasaka et al 2003) as well 
as by using in-house templates. For regional analyses, the signal to noise ratio will be maximized 
by averaging voxels within the region prior to extraction of mean percent signal change for entry 
to a hypothesis-specific statistical model as detailed in section C5.  
Whole brain voxel-wise analyses: In order to identify significant effects beyond the a priori 
regions, an exploratory whole-brain voxel-wise analysis will also be conducted for each task.  
Voxel-wise analyses will be conducted using FSL’s FLAME tool. For all voxel-wise analyses, type 
I error control will be achieved using cluster correction as implemented with Gaussian Random 
Field Theory (Desikan et al 2006) using a cluster height of z>3.09 and a corrected cluster 
probability of p<0.01. Functional clusters of activation will be anatomically labeled using the 
Harvard-Oxford Probabilistic Atlas (Hayasaka et al 2003).  
8.1 
Efficacy Assessments:  
The following study measures will serve as primary and secondary efficacy endpoints:  
Opioid withdrawal management (detoxification) and induction to monthly MAT injections 
will be performed by the study physicians. The 1st monthly injection will be administered by an 
experienced nurse practitioner after induction (7-14 days) is complete. 
 


 
 
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Neuroimaging (MRI): The MRI session will take place after detoxification and immediately 
before MAT induction (Appendix Section 12.1) by a trained and authorized technician. 
   
Addiction Severity Scale Lite (ASI-Lite) (McLellan, 1997) The Addiction Severity Scale 
Lite is a shortened version of the full clinical interview. The measure collects information on 
demographics, employment, legal status, alcohol/drugs, family/social relationships, and 
psychiatric status. This measure is administered by a clinician 
 
Opiate Withdrawal Scale – Elman (OWSE) (Elman, 2001) The opiate withdrawal scale 
from Elman is an adapted 6-item self-report questionnaire looking to examine five aspects of 
opiate craving- currently intensity, projected intensity, resistance, responsiveness to drug-
related stimuli, and imagined likelihood of use in a setting with access to the drug. The 
questionnaire was initially designed to assess cocaine craving. The measure shows good 
consistency being used to assess opiate craving. 
 
Hamilton Anxiety Rating Scale (HAM-A) (Hamilton 1967). The HAM-A is a 15-minute, 14-
item, clinician-administered instrument that measures current anxiety and changes in anxiety 
symptoms.  
Hamilton Depression Rating Scale (HAM-D) (Hamilton 1959). The HAM-D is a 20-
minute, 24-item interview that measures the severity of depression and changes in depressive 
symptoms.  
Short Form-McGill Pain Questionnaire-2 (SF-MPQ-2) (Dworkin et al 2015) (PhenX 
#190901) is a 22-item self-administered questionnaire that asks about the different qualities of 
pain and related symptoms. Respondents are asked to rate the intensity of each type of pain 
they felt during the past week on a scale from 0 to 10 
Timeline Follow-Back Interview (TLFB) (Sobell et al 1992).  The TLFB is a 15-30-minute, 
semi-structured interview designed to measure self-reported drug use. It will be used at baseline 
to capture all drug use in the past 30 days including prescribed concomitant medications 
(PhenX 27016266).   
Weekly online self-reported TLFB is a modified TLFB interview that uses a calendar-
based format to record participants’ self-report of past week drug use. 
Urine Toxicology: is a standard procedure using commercial clinically approved kits that will be 
administered by trained staff member.  
8.2 
Safety and Other Assessments:  
the following assessments will serve as safety measures when their results indicate change 
from baseline indicative of AE or baseline reading indicating that a participant meets an 
exclusion criterion.  
Screening & Intake (Appendix Section 12.1): Candidates will be screened by phone or in person 
at a referral site by a trained staff member(research assistant, coordinator, RN, psychologist or 
physician). History and physical as well as basic chemistry and blood count will be done at Intake.  
[see section 6.1 above].   
Opioid withdrawal management (detoxification) and induction to monthly MAT injections 


 
 
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will be performed by the study physicians. The 1st monthly injection will be administered by an 
experienced nurse practitioner after induction (7-14days) is complete.   
 
Neuroimaging (MRI): The MRI session will take place after detoxification and immediately before 
MAT induction (Appendix Section 12.1) by a trained and authorized technician.   
 
MINI International Neuropsychiatric Interview (MINI) (Sheehan DV, 1998; 59(suppl 20)). 
The MINI is a clinician administered neuropsychiatric interview for symptoms across 17 of the 
most common mental health disorders. The DSM-5 version of the MINI will be administered.  
Addiction Severity Scale Lite (ASI-Lite) (McLellan, 1997) The Addiction Severity Scale 
Lite is a shortened version of the full clinical interview. The measure collects information on 
demographics, employment, legal status, alcohol/drugs, family/social relationships, and 
psychiatric status. This measure is administered by a clinician. 
 
Shipley Institute of Living Scale (SILS) (Zachary, 1985 ) The Shipley institute of living 
scale is a 20-minute administered measure arriving at an estimate of IQ. The scale is divided 
into two sections, verbal and logic-based and is administered by study staff. 
 
State Trait Anxiety Inventory (STAI-6) (Marteau, 1992) The STAI-6 is a 6 item self-report 
inventory design to evaluate anxiety.  
 
Subjective Opiate Withdrawal Scale (SOWS) (Dijkstra, 2007) The SOWS is a self-report 
16-tem scale measuring motoric, autonomic, gastrointestinal, and musculoskeletal opiate 
withdrawal symptoms as well as psychological symptoms like anxiety and craving due to opiate 
use.  
 
Opiate Withdrawal Scale – Elman (OWSE) (Elman, 2001) The opiate withdrawal scale 
from Elman is an adapted 6-item self-report questionnaire looking to examine five aspects of 
opiate craving- currently intensity, projected intensity, resistance, responsiveness to drug-
related stimuli, and imagined likelihood of use in a setting with access to the drug. The 
questionnaire was initially designed to assess cocaine craving. The measure shows good 
consistency being used to assess opiate craving. 
Hamilton Anxiety Rating Scale (HAM-A) (Hamilton 1967). The HAM-A is a 15-minute, 14-
item, clinician-administered instrument that measures current anxiety and changes in anxiety 
symptoms.  
Hamilton Depression Rating Scale (HAM-D) (Hamilton 1959). The HAM-D is a 20-
minute, 24-item interview that measures the severity of depression and changes in depressive 
symptoms.  
Clinical Opiate Withdrawal Scale (COWS) (Wesson et al 2003). The COWS is a clinician-
administered instrument that measures eleven common opioid withdrawal symptoms. 


 
 
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Short Form-McGill Pain Questionnaire-2 (SF-MPQ-2) (Dworkin et al 2015) (PhenX 
#190901) is a 22-item self-administered questionnaire that asks about the different qualities of 
pain and related symptoms. Respondents are asked to rate the intensity of each type of pain 
they felt during the past week on a scale from 0 to 10 
Timeline Follow-Back Interview (TLFB) (Sobell et al 1992).  The TLFB is a 15-30-minute, 
semi-structured interview designed to measure self-reported drug use. It will be used at baseline 
to capture all drug use in the past 30 days including prescribed concomitant medications 
(PhenX 27016266).   
Weekly online self-reported TLFB is a modified TLFB interview that uses a calendar-
based format to record participants’ self-report of past week drug use. 
 
8.3 
Adverse Events and Serious Adverse Events 
8.3.1 
Definition of Adverse Events (AE) 
An adverse event (AE) is any symptom, sign, illness or experience that develops or worsens in 
severity during the course of the study.  Intercurrent illnesses or injuries should be regarded as 
adverse events.  Abnormal results of diagnostic procedures are considered to be adverse events 
if the abnormality: 
• 
results in study withdrawal 
• 
is associated with a serious adverse event 
• 
is associated with clinical signs or symptoms 
• 
leads to additional treatment or to further diagnostic tests 
• 
is considered by the investigator to be of clinical significance 
8.3.2 
Definition of Serious Adverse Events (SAE)  
Adverse events are classified as serious or non-serious.  A serious adverse event is any AE 
that is:  
• 
fatal 
• 
life-threatening 
• 
requires or prolongs hospital stay 
• 
results in persistent or significant disability or incapacity 
• 
a congenital anomaly or birth defect 
• 
an important medical event 
 
Important medical events are those that may not be immediately life threatening but are clearly of 
major clinical significance.  They may jeopardize the subject and may require intervention to 
prevent one of the other serious outcomes noted above.  For example, drug overdose or abuse, 
a seizure that did not result in in-patient hospitalization, or intensive treatment of bronchospasm 
in an emergency department would typically be considered serious.  
 
All adverse events that do not meet any of the criteria for serious should be regarded as non-
serious adverse events.  


 
 
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8.3.3 
Classification of an Adverse Event 
8.3.3.1 
Severity of Event 
For adverse events (AEs) not included in the protocol defined grading system, the following 
guidelines will be used to describe severity. 
• 
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. Of note, the term “severe” does not necessarily equate to “serious”. 
8.3.3.2 
Relationship to Study Intervention 
All adverse events (AEs) must have their relationship to injection assessed by the clinician who 
examines and evaluates the participant based on temporal relationship and his/her clinical 
judgment. The degree of certainty about causality will be graded using the categories below. In 
a clinical trial, the study product must always be considered. 
• 
Related – The AE is known to occur with the injection there is a reasonable possibility 
that the injection caused the AE, or there is a temporal relationship between the injection 
and event. Reasonable possibility means that there is evidence to suggest a causal 
relationship between the injection and the AE. 
• 
Not Related – There is not a reasonable possibility that the administration of the injection 
caused the event, there is no temporal relationship between the injection and event 
onset, or an alternate etiology has been established. 
 
8.3.3.3 
Expectedness  
The Medical Director will be responsible for determining whether an adverse event (AE) is 
expected or unexpected. An AE will be considered unexpected if the nature, severity, or 
frequency of the event is not consistent with the risk information previously described for the 
injection. 
8.3.4 
Time Period and Frequency for Event Assessment and Follow-Up 
Safety will be assessed by monitoring and recording potential adverse events by medical history 
and physical examination and formal instruments [see section Safety Measures, above].  


 
 
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The severity of mild, moderate, severe, life-threatening, and death, corresponding to Grades 1-
5, will be used whenever possible. Once an adverse event is detected, it should be followed 
until its resolution or until it is judged to be permanent, and assessment should be made at each 
visit (or more frequently, if necessary) of any changes in severity, the suspected relationship to 
the study treatment, the interventions required to treat it, and the outcome. 
8.3.5 
Adverse Event Reporting 
Once per week, a medical sub-investigator must seek information on adverse events by specific 
questioning and, as appropriate, by examination.  However, research staff should notify a medical 
sub-investigator any time an adverse event is reported by a subject. Information on all adverse 
events should be recorded immediately in the source document, and also in the appropriate 
adverse event module of the case report form (CRF).  All clearly related signs, symptoms, and 
abnormal diagnostic procedures results should recorded in the source document, though should 
be grouped under one diagnosis. 
 
8.3.6 
All adverse events occurring during the study period must be recorded.  The 
clinical course of each event should be followed until resolution, stabilization, 
or until it has been determined that the study treatment or participation is not 
the cause.  Serious adverse events that are still ongoing at the end of the 
study period must be followed up to determine the final outcome.  Any serious 
adverse event that occurs after the study period and is considered to be 
possibly related to the study treatment or study participation should be 
recorded and reported immediately.Serious Adverse Event Reporting  
Adverse event reporting to the FDA will follow the study IRB protocol. Briefly, a serious 
adverse event will be reported to the study sponsor (Dr. Langleben) by email or telephone within 
72 hours of when the event is reported to any of the study staff.  A Serious Adverse Event 
(SAE) form must be completed by the investigator and faxed to the study sponsor within 72-
hours.  The investigator will keep a copy of this SAE form on file at the study site.  Report 
serious adverse events by phone and facsimile to the study regulatory sponsor: Daniel D. 
Langleben, M.D. (o) 215-746-0107, (f) 215-746-7358, langlebe@pennmedicine.upenn.edu 
 
At the time of the initial report, the following information would be provided: 
Study identifier 
Study Center 
Subject number 
A description of the event 
Date of onset 
Current status 
Whether study treatment was 
discontinued 
The reason why the event is classified as 
serious 
Investigator assessment of the 
association between the event and study 
treatment 
 
 
Within the following 48 hours, the investigator must provide further information on the serious 
adverse event in the form of a written narrative.  This should include a copy of the completed 
Serious Adverse Event form, and any other diagnostic information that will assist the 
understanding of the event.  Significant new information on ongoing serious adverse events 
should be provided promptly to the study sponsor. 


 
 
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Suspected adverse reactions to any of the medications used in the study will be reported 
appropriately to the IRB, FDA at 1-800-FDA-1088 or www.fda.gov/medwatch, Alkermes, plc at 
1-800-VIVITROL (1-800-848-4876) or email: usmedinfo@alkermes.com or both or Braeburn Inc 
at 1-833-274-9234 . 
 
8.3.7 
Reporting of Pregnancy 
Pregnancy and not using effective contraception are exclusion criteria for participation. 
Medications used in the study are Class C, i.e. their effects on pregnancy are not well known. In 
addition to pregnancy urine test conducted as part of screening, pregnancy will be monitored 
using betaHCG test prior to MRI scans and by self-report during follow up and treatment visits. 
When a pregnancy has been confirmed in a subject, and the fetus is exposed to study drug 
and/or process maternally, participant will be excluded from participation and referred to her 
treating physician for monitoring.  
 
9 STATISTICAL CONSIDERATIONS 
9.1 
Statistical Hypotheses 
Overview of primary hypotheses: Our primary response will be a binary indicator of treatment 
failure on the XRNTX or XRBUP regimen, defined as ≥ 2 weekly UDS positive for opioids, or self-
report of ≥ 2 periods of three of more days of opioid use, or refusing XRNTX or XRBUP, or 
dropping out of study entirely. In hypotheses H1a and H1b, we are examining the effects of small, 
pre-specified, sets of measures, so our analyses will focus on model fit and prediction, and not 
on model selection. In hypothesis H1c, we search for best sets of predictors among demographic 
and clinical-behavioral variables, and over sets of brain/neural measures, so our focus is on model 
selection and on avoiding overfitting to the available data.  
R61 Phase:  
Hypothesis H1 (fMRI): For each of the cue reactivity (H1a), response inhibition (H1b), and 
connectivity (H1c) brain measured, we have a small number of neural responses associated with 
one or two regions of interest. These variables are continuously distributed, so we will test 
Hypotheses 1a, 1b and 1c using a repeated measures analysis of variance (rm-anova). The 
models will include a within-subject factor for Session (PRE vs ON) and a between-subject factor 
Group (XRNTX vs XRBUP), and their interaction. To accommodate the anticipated non-normal 
distributions of the response, we will use a generalized estimating equation (GEE) approach, 
using robust standard errors, using a compound symmetry working correlation structure for the 
within-subject correlations between the PRE and ON fMRI scans (Diggle PJ et al 2002). We will 
perform the rm-anova separately for each ROI (mPFC and VS for H1a, IFC for H1b, and VS-rtIFG 
and VS-mPFC for H1c). The hypotheses will be addressed by the Session by Group interaction, 
and we will obtain estimates and standard errors of the PRE vs ON change within each of the two 
groups, along with the size, standard error and significance of the differences between these 
estimates.  


 
 
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Sample size considerations for sample: The sample size is adequate for application 
of the GEE methods to obtain robust standard error (Lipsitz et al 1994). For a test of the PRE vs 
ON effect, our sample yields 80% power for a one-sided test that the ON levels will be Cohen’s 
d=0.4 lower than the PRE levels, consistent with a decrease of Cohen’s d=0.5 observed in our 
preliminary data and a decrease of Cohen’s d=0.3 in the Suboxone sample.  
Milestone for transition from Phase 1 to Phase 2: Using the models described above, 
we will obtain (model-based) estimates of the Session (PRE vs ON) by Group (XRNTX vs XRBUP 
effects for the five hypotheses described above. If these estimates show at least small effects 
(Cohen’s d ≥0.2) in at least two of the three domains, then we will continue to the R33 phase.  
Primary Analyses for Phase 2: Session by Group interaction effects on neural response: First, 
we will formally test the interaction effects explored in the R61 phase. We will rerun the analyses 
described for H1a, H1b and H1c in the R61 phase, for the full sample of n=140 obtained through 
the R61 and R33 phases. The models will be exactly as described in the R61 phase.  
Effects of neural response on relapse vulnerability: Our primary outcome combines 
adherence to treatment and frequency of illicit opioid use during treatment. The primary outcome 
is a binary indicator of treatment success: if a patient provides ≥ 2 weekly UDS positive for opioids, 
or self-report of ≥ two or more periods of ≥ 3 days of opioid use, or refuses XRNTX or XRBUP, 
or drops out of treatment entirely, then they will be classified as a treatment failure; otherwise they 
will be classified as a treatment success. We will calculate the PRE-ON change in %-signal-
change for each of the regions and neural responses described in the R61 phase. We will use 
logistic regression models to predict the log-odds of treatment success (Aitkin et al 2009). The 
predictors in the model will be a binary factor for Group (XRNTX vs. XRBUP), and the neural 
change scores. We anticipate that there will be some greater PRE to ON changes in the XRNTX 
group than in the XRBUP group, so there will be some confounding between the effects of change 
score and the effects of Group on the rates of positive UDS. Thus, we will include Group first in 
our model, so evaluating the Group effect separate from the change-score effects, and then 
include the change scores in a model including Group, so evaluating the additional effect of 
change-scores in addition to the existing effects of Group. To assess whether the effects of the 
change scores differ between the XRNTX and XRBUP groups, we will also test for interaction 
effects between Group and each of the change-scores, by adding the interaction terms to the 
model that includes the group and neural change score main effects. We will check the 
assumptions underlying the logistic regression models (e.g. linearity of covariates effects on log-
odds, outliers, influential observations) using standardized residuals, influence diagnostics, and 
graphical displays. 
Sample size considerations for the sample: Analyses of Session by Group effects on 
neural response: For a one-sided test that the PRE vs ON effect is larger in the XRNTX group 
than in the XRBUP group, our sample of 70 per group yields 81% power for an effect of d=0.42 
or greater. This effect is similar to the effects observed in the preliminary data. On the basis of 
the preliminary data we anticipate Group by Session effects of approximately d=0.38 in the VS 
and d=0.42 in the mOFC.  
Analyses of effects of neural response on relapse vulnerability: We consider the effect for an 
individual neural change variable, in a model where Group is included, assuming a small effect 
for Group (odds ratio = 1.25). We have three domains, with two neural variables in two domains 
and one in the other, so we provide power for alpha=0.05 and for alpha=0.025. For alpha=0.05 
we have 80% power for an odds ratio of 1.75 or higher per standard deviation increase in a neural 
variable; for alpha=0.025, we have 80% for an odds ratio of 1.86 or higher.  


 
 
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Analyses of polysubstance use outcomes: We will also examine the effects of Group and neural 
change variables on other substance use outcomes, including self-report and UDS measures of 
opioid, stimulant, and benzodiazepine use. Here, we will use the self-report and UDS measures 
to create binary weekly measures of use for each substance, and use GEE repeated measures 
logistic regression models, with Group and the neural change measures as predictors, to estimate 
and test effects. These secondary analyses will be subject to missing data. We anticipate 25% 
dropout rates. To assess possible effects of nonignorable missingness on inference, we will 
perform sensitivity analyses using pattern-mixture models and selection models. For pattern 
mixture models, subjects are grouped on the basis of their pattern of missing data, and the 
resulting categorical factor is included in the analyses as a main effect and interaction with 
predictors of interest. Overall predictor effects may be found by averaging over the patterns 
(Molenberghs et al 2005). Selection models (Molenberghs et al 2005) take a different approach, 
by explicitly modeling the probability of drop out, and incorporating the predicted probabilities into 
the main longitudinal analysis, with the dropout and response processes included in a single 
bivariate model. Comparisons between the predictions of the primary analyses, and each set of 
pattern mixture and selection models, provides some evidence for assessing the sensitivity of 
results to missing data. 
Predictive modeling: The models for relapse/treatment-success addressed the effects of neural 
responses, in isolation from demographic and clinical measures. In further analyses, we will 
examine their effects in combination with demographic and non-imaging clinical predictors. As we 
can expect overlap between the effects of these sets of variables, we compare the effects of these 
domains on prediction of treatment success. Thus, we will compare models using various sets of 
predictors on the basis of AUC comparisons, rather than on goodness of fit (Sullivan Pepe 2003). 
In our model search, we will compare models containing interactions between Group and the 
various predictors, with the constraint that an interaction is included only in models where the 
corresponding main effects are also included. First, we will find the best fitting demographic model, 
searching over a set including age, race, gender, and educational status. Next, with the predictors 
from the best demographic model included, we will search over the clinical predictors (depression 
and anxiety scores, measures of withdrawal and craving, and the ASI composite scores) to find 
the set that most improves the predictive utility of the best demographic model. Third, with the 
predictors from the best demographic/clinical model included, we will search over the measures 
of neural change to find the set that most improves the fit of the best demographic/clinical model. 
We will then perform goodness of fit and ROC comparisons between the best demographic, 
demographic/clinical, and demographic/clinical/brain models. This process involves three 
searches over various sets of variables, and unconstrained searches are likely to yield complex 
models involving many predictors, resulting in a prediction rule that performs poorly in new 
samples. To avoid this, we will use a lasso approach to fitting the logistic regression models for 
this hypothesis. The usual algorithms for logistic regression estimate the model parameters by 
minimizing a measure of lack of fit of the model to the data, but do not penalize models for 
complexity. The lasso approach selects a best fitting model subject to the constraint that the sum 
of the magnitudes of the regression coefficients in the model is less than a small positive threshold 
value. The threshold is chosen adaptively from the data, by minimizing an estimate of the 
prediction error for the model, using ten-fold cross validation. Then, a best fitting model is chosen 
with the estimated threshold used in the penalty. The best fitting model is usually one in which a 
number of the coefficients are set to zero, i.e. a number of predictors are dropped from the model.  
 


 
 
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9.2 
Sample Size Determination:  
Analyses of Session by Group effects on neural response: For a one-sided test that the PRE vs 
ON effect is larger in the XRNTX group than in the XRBUP group, our sample of 80 per group 
yields 81% power for an effect of d=0.42 or greater. This effect is similar to the effects observed 
in the preliminary data. On the basis of the preliminary analysis, we anticipate Group by Session 
effects of approximately d=0.38 in the VS and d=0.42 in the mOFC.  
9.3 
Populations for Analyses 
 
All-treated population:  Any subject randomized into the study that received at least one dose 
of study drug. 
9.4 
Statistical Analyses 
9.4.1 
General Approach 
Data Management.  Data will be gathered using Penn’s REDcap data collection system, a direct-
entry data system where subjects can directly enter responses. REDcap is HIPAA compliant and 
data is secured on Penn Medicine’s data management unit (DMU) network. Interview data and 
self-report data are entered directly into REDcap at the research sites, by research technicians 
and study subjects respectively. Field validation (eg, no out of range or otherwise invalid 
responses will be accepted) and form validation (e.g. logically impossible responses to different 
questions will not be accepted) are built into this entry process. Data are transmitted (128-bit 
encrypted form) over the internet to the DMU servers. After online reviews, the data are archived 
on the servers. Certain DMU staff members have permission to modify the archived data. Audit 
logs record any modification to the original entry. Password protection allows members of the 
research team appropriate levels of data access. At time of data collection clinical research staff 
will review data collected for completeness (field and form validation). Weekly routine data 
inspections will be performed by clinical research staff to ensure data integrity. Subject brain scan 
data are extracted via CAMRIS web-servers and are archived to lab-specific, encrypted servers 
for standard cleaning and analysis.  
 
Data Analyses. Kevin Lynch, PhD, the CSA Statistician, and his staff will perform the data 
analyses.  Prior to analyses, standard data screening/cleaning procedures will be applied 53.  
These procedures will screen the data for data-entry errors, check for outliers, assess the extent 
and pattern of missing data, and check that appropriate assumptions of normality are met 
whenever necessary.  Due to sample size, it is unlikely that the randomization will result in 
significant imbalance of the distributions of demographic or other variables across treatment 
groups. Additional covariates will be considered for inclusion in the analyses, to improve the 
precision of estimation for the treatment effects.  Covariates describing levels of cocaine use 
prior to the study may be included.  Assumptions underlying the application of statistical 
methods will be examined, through use of standardized residuals, influence diagnostics, and 
graphical displays.   
 
Primary Hypothesis: Estimate the differential brain fMRI response between XRNTX and 
XRBUP in OUD treatment groups. We hypothesize that (H1) XRBUP and XRNTX will modulate 


 
 
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the regional brain activity in the two-key cognitive-behavioral domains and measures of brain 
connectivity from pre-treatment (PRE) to on-treatment (ON) and this response will differ 
between the two medications. Milestone for transition to Phase 2: The MAT group (XRNTX, 
XRBUP) by Session (PRE, ON) interaction will have at least small (d’ =/> 0.2) effect size in all 
brain measures.  
 
H1a: Incentive salience (opioid cue-reactivity task): The decrease in the brain response 
to drug related stimuli (ON minus PRE) in the medial prefrontal cortex (mPFC) and the ventral 
striatum (VS) will be greater in the XRNTX than in the XRBUP group.  
 
H1b: Executive function (Go-NoGo task): XRNTX will improve the efficiency of 
response inhibition more than XRBUP, leading to a greater decrease in the brain signal (ON vs 
PRE) during the NoGo trials in the inferior frontal cortex in the XRNTX group.   
 
H1c: Resting state functional connectivity (rsFC): change (ON vs PRE) in the rsFC 
between the VS and the right inferior frontal gyrus (rtIFG) and the mPFC will be greater in the 
XRNTX (vs. XRBUP group). 
 
Secondary Hypotheses:  Confirm in the full sample (n=140), the significance of MAT (XRNTX, 
BUP-NTX) by Session (PRE, ON) interaction in all domains from Aim 1. Test the explanatory 
value of integrated brain-behavior models of relapse vulnerability, identify differences in variable 
loading between MAT group, and explore potential mechanism of individual variability in treatment 
outcome. 
 
H2a: Using logistic regression, we will test the explanatory value of brain signal in 
modeling treatment failure and identify specific variables that differentiate MAT groups 
(interaction).  
 
H2b (Exploratory): Test if the models that include brain response better explain treatment 
success or failure when compared to those fitted solely with demographic and clinical measures: 
demographic + clinical measures vs. demographic + clinical measures + brain response).  
 
Missing Data and Nonadherence:  For the longitudinal analyses described above, premature 
discontinuation from treatment and occasional missing daily use indicators will lead to 
incomplete data. The mixed effects models described above can make use of all available data 
provided by subjects, but the inferences drawn from them will be unaffected by the missing data 
only if the missing data can be regarded as ignorable, in the sense of Laird 55. To assess the 
sensitivity of our analyses to this assumption, we will use shared parameter models, which allow 
for correlated random effects underlying the cocaine use measurements and the pattern of 
dropout 56.  We will also use selection models to examine the effects of missing data 57,58. We 
will explicitly model the probability of premature discontinuation at a time point as a function of 
baseline characteristics and responses at previous time points, using a logistic regression 
model, and incorporate the predicted probabilities into a weighted analysis of the main 
hypotheses. We will do analyses in a range of assumptions and assess the sensitivity of results 
to them 58. We will use urine drug screens, record of clinic visits and receipt of injectable 
medications as measures of compliance with assigned medication regime. We will use the 
methods of Nagelkerke et al 59 and Small et al 60, to obtain estimates of the intervention effect in 
a population compliant with treatment i.e. the Complier Average Causal Effect (CACE).  
 
Safety: The adverse event responses will be analyzed as a measure of safety.  Total number of 
adverse events, adverse events leading to discontinuation (in the judgment of the study physician), 
% of patients reporting at least one adverse event, clinical lab assessments, vital signs and 


 
 
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evidence of clinical worsening (by urine drug screen results and TLFB results) will be considered 
in assessment of safety.  In a manner parallel to the analysis for therapeutic response, medication 
group, gender, age and other clinical variables will be entered into a generalized linear mixed 
effects model to predict adverse events.  
10 SUPPORTING DOCUMENTATION AND OPERATIONAL 
CONSIDERATIONS 
10.1 Regulatory, Ethical, and Study Oversight Considerations 
10.1.1 
Informed Consent Process and HIPAA Authorization 
10.1.1.1 
Consent/Assent and Other Informational Documents Provided To 
Participants 
Consent forms describing in detail the injections, study procedures, and risks are given to the 
participant and written documentation of informed consent is required prior to starting 
intervention. The following consent materials are submitted with this protocol:  
• 
XRBUP vs XRNTX Consent form. 
• 
Informed consent quiz 
• 
HIPAA Authorization form  
10.1.1.2 
Consent Procedures and Documentation 
Informed Consent: 
 
Study procedures will be described in detail  to the subjects by a trained study staff member  
during the informed consent session..  The consent form and session will include  detailed 
information about the study medication; that is, a description of the medication, rationale for why 
it is being studied, frequency of dosing and length of treatment, potential side effects, 
safeguards and emergency procedures. Information will also be provided about the 
psychosocial treatment, frequency of visits and length of treatment, safeguards and emergency 
procedures, etc. Collection of lab specimens (number of venipunctures and urine specimens 
required) will be reviewed.  Eligibility will be reviewed.  The number and frequency of the 
research interviews and self-assessments will be reviewed 
In addition, subjects will be assured that their participation is voluntary and that withdrawal from 
the study does not jeopardize current or future treatment.  Patients will also be told that if at any 
time during the study the research team and the clinical treatment team feel that the patient needs 
more intensive, standard treatment, the patient will be referred to one of the available inpatient 
treatment programs in Philadelphia.  All subjects will be informed of potential risks and benefits 
involved in the study.  Potential medication side effects will be described to all subjects.  Patients 
will be informed that their participation in the treatment trial may be discontinued at any time 
because of serious medication side effects, their noncompliance with treatment, missing 
appointments or if continued participation is considered an endangerment to their welfare. 


 
 
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Informed Consent quiz: 
At the end of the consent session, a quiz is given. Subjects scoring below 100% correct will 
receive additional instruction regarding the study and consent form.  Incorrect questions from 
the quiz will be administered again until all questions are answered correctly. All participants are 
provided with a hard copy of the consent form that includes the name and telephone numbers of 
the investigative team, and the Chair of Penn’s Institutional Review Board (IRB).  A 24-hour 
Emergency contact is provided in case of an adverse consequence or any other emergency. 
HIPAA Authorization Form: 
After signing the consent, participants would also be asked to grant access to their medical 
records at University of Pennsylvania and other institutions to share their health information that 
may include diagnoses, medications, hospital admissions, laboratory and imaging studies and 
participation in treatment programs including substance use disorder. This will be done by 
signing a “RESEARCH PARTICIPANT AUTHORIZATION TO OBTAIN AND REVIEW HIPAA- 
PROTECTED MEDICAL RECORDS AND COMMUNICATION WITH THEIR HEALTH CARE 
PROVIDERS”).  
 
Intake Procedures at Treatment Facilities: 
Participants found to be eligible at screening who are unable to attend intake at our center 
because they are currently inpatient, will undergo intake procedures at their inpatient treatment 
facility. Private space for the intake sessions will be secured in coordination with inpatient clinical 
staff. 
 
The following procedures will be done at the inpatient facilities to reduce the delay in enrolling 
eligible participants. 
• 
Informed consent, informed consent quiz and HIPAA authorization form administered by 
the trained study member. 
• 
Non-invasive assessments and measures will be administered by the trained study 
members using portable tablets.  
10.1.2 
Study Discontinuation and Closure 
The study may be discontinued at any time by the IRB, the Sponsor, the FDA, or other 
government agencies as part of their duties to ensure that research subjects are protected. 
10.1.3 
Confidentiality and Privacy 
Information about study subjects will be kept confidential and managed according to the 
requirements of the Health Insurance Portability and Accountability Act of 1996 (HIPAA).  Those 
regulations require a signed subject authorization informing the subject of the following:  
• 
What protected health information (PHI) will be collected from subjects in this study 
• 
Who will have access to that information and why 


 
 
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• 
Who will use or disclose that information 
• 
The rights of a research subject to revoke their authorization for use of their PHI.  
In the event that a subject revokes authorization to collect or use PHI, the investigator, by 
regulation, retains the ability to use all information collected prior to the revocation of subject 
authorization.  For subjects that have revoked authorization to collect or use PHI, attempts should 
be made to obtain permission to collect at least vital status (i.e. that the subject is alive) at the 
end of their scheduled study period. 
10.1.4 
Safety Oversight 
DATA AND SAFETY MONITORING: 
10.1.5 
During the course of the study, data and safety monitoring will be performed on an 
ongoing basis by the Principal Investigator- James Loughead, PhD, Medical 
Director & Regulatory Sponsor- Daniel Langleben, MD, Study Physician- Kyle 
Kampman, MD, research staff, and the site IRB. The PI James Loughead PhD will 
have overall responsibility for data analysis and management, as well as overall 
responsibility for safety and data monitoring on a day-to-day basis. The PI will be 
responsible for reporting the adverse events and serious adverse events. This study 
will be monitored according to the monitoring plan as noted in DSMP. The study 
physician will be available to review medical issues related to participation for 
each participant on an ongoing basis as outlined in this protocol. The internal 
monitoring will be conducted on site at Center for Studies of Addiction by the study 
coordinator appointed by the PI. The study coordinator is qualified by education, 
experienced and have completed training on GCP. See their certifications and 
qualifications in the e-regulatory binder for the study. The study coordinator will 
be responsible for collecting and recording all clinical data. This includes ensuring 
that all source documents exist for the data on the case report forms, ensuring all 
fields are completed appropriately, and all corrections are done according to GCP. 
Any inconsistencies/deviations will be documented. The study coordinator will 
perform regular chart reviews to verify data integrity. Quality Assurance and 
Quality Control 
This study will be monitored according to the monitoring plan as noted above.  The investigator 
will allocate adequate time for such monitoring activities.  The Principal Investigator will also 
ensure that the monitor or other compliance or quality assurance reviewer is given access to all 
the above noted study-related documents and study related facilities (e.g. pharmacy, diagnostic 
laboratory, etc.), and has adequate space to conduct the monitoring visit. 
10.1.6 
Data Handling and Record Keeping  
 
Subject Confidentiality 


 
 
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This study will utilize directly identifiable protected health information (PHI). PHI, as defined by 
HIPAA, means individually identifiable health information about an individual that is transmitted 
or maintained by electronic media or in any other form or medium. PHI includes demographic 
information that is created or received by a health care provider, health plan, employer, or health 
clearinghouse. PHI relates to the past, present, or future physical or mental health or condition of 
an individual; the provisions of health care to an individual; or the past, present, or future payment 
for the provision of health care to an individual; and identifies the individual or can reasonably be 
used as a basis to identify an individual. The following PHI will be collected for this study: 
 
• 
Name 
• 
Postal address information 
• 
All elements of dates, such as birthdate and date of visit, (except year) for dates directly 
related to an individual and all ages over 89) 
• 
Telephone and fax number 
• 
Electronic mail addresses 
• 
Social security numbers (for study compensation) 
• 
Medical record numbers (for ordering MRIs, medications,  
• 
Access to medical records to determine eligibility and safety for participation 
 
In accordance to University of Pennsylvania’s policy regarding how PHI is handled, managed, 
and disseminated, study personnel will utilize an institutionally secured and managed network 
drive.  
 
Institutionally secured and managed network drive: The CSA/TRC utilizes a departmental shared 
drive to securely store PHI. The CSA/TRC shared drive is managed and secured by The Penn 
Medicine Academic Computing Services (PMACS). Access to the shared drive requires password 
access to a departmental device (CSA/TRC desktop or laptop) then additional password access 
to the departmental shared drive. After being granted access to the shared drive, one must have 
an encryption code to access the files storing PHI. Therefore, the only CSA/TRC employees that 
will have access to the PHI connected to this study will be the approved study personnel (Principal 
Investigator, Project Supervisor, Clinical Research Coordinators).  
 
Any paperwork that includes PHI (such as SSN on subject compensation forms) will be kept in a 
locked draw within a locked office. To reduce the possibility of breaches in subject confidentiality, 
subjects will be given a unique identifier to place on their demographic information, questionnaires, 
behavioral ratings, and data from scan sessions. Only the study personnel will have access to the 
code. Five years after completion of the study, the subject code will be destroyed.  Data will be 
destroyed 8 years after study completion. 
 
 
Subject Privacy 
The study personnel will maintain a high level of privacy for this research study. To respect those 
boundaries, several safeguards will be in place. Subjects will be screened and interviewed in a 
private office at the CSA/TRC offices located at 3535 Market Street or at participant’s treatment 
facilities. When contacting subjects, information about mental and physical health will not be 


 
 
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disclosed; telephone messages or voicemails will be worded so as to not reveal the subjects study 
status, diagnoses, or any other confidential information. 
 
 
10.1.7 
Protocol Deviations   
Exception 
A one-time, intentional action or process that departs from the IRB-approved study protocol, 
intended for one occurrence. If the action disrupts the study progress, such that the study design 
or outcome (endpoints) may be compromised, or the action compromises the safety and welfare 
of study subjects, advance documented approval from the Regulatory Sponsor, IRB, and other 
local regulatory review committees per institutional guidelines is required. Approval from the 
Regulatory Sponsor must be received prior to submission to the IRB and local regulatory review 
committees for approval. 
  
Deviation 
A one time, unintentional action or process that departs from the IRB-approved study protocol, 
involving one incident and identified retrospectively, after the event occurred. If the impact on the 
protocol disrupts the study design, may affect the outcome (endpoints) or compromises the safety 
and welfare of the subjects, the deviation must be reported to the Regulatory Sponsor within 10 
business days of PI knowledge, and to local regulatory review committees per institutional 
guidelines.  Acknowledgement from the Regulatory Sponsor must be received prior to submission 
to local regulatory review committees. 
  
Other deviations should be appropriately documented (such as a subject missing a visit unless a 
critical/important treatment or procedure was missed and must have been done at that specific 
time) per site policies/procedures.  
  
We will include the following information on the Sponsor-supplied exception/deviation 
form:  protocol number, subject study number, comprehensive description of the 
exception/deviation from the protocol, rationale and corrective and preventative action plan 
(deviations only).  All completed exception/deviation forms will be signed by the Principal 
Investigator (or physician sub-investigator) and submitted to the Sponsor Project Manager for 
review.    
 
Once approval of the exception request or acknowledgement of the deviation has been granted 
by the Regulatory Sponsor, the exception or deviation will be submitted to all applicable 
committees for review and approval. 
10.1.8 
Publication and Data Sharing Policy 
Neither the complete nor any part of the results of the study carried out under this protocol, nor 
any of the information provided by the sponsor for the purposes of performing the study, will be 
published or passed on to any third party without the consent of the study sponsor.  Any 
investigator involved with this study is obligated to provide the sponsor with complete test results 
and all data derived from the study. 


 
 
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10.1.9 
Conflict of Interest Policy 
Any investigator who has a conflict of interest with this study (patent ownership, royalties, or 
financial gain greater than the minimum allowable by their institution, etc.) must have the conflict 
reviewed by a properly constituted Conflict of Interest Committee with a Committee-sanctioned 
conflict management plan that has been reviewed and approved by the study sponsor prior to 
participation in this study.  All University of Pennsylvania investigators will follow the University 
conflict of interest policy. 
10.2 LIMITATIONS 
LIMITATIONS AND ALTERNATIVE RESULTS: We have carefully considered potential 
limitations of our study and alternate designs. Several domains that may be of interest are 
not included (e.g., Affect Regulation) because task selection is based on a conceptual model and 
to optimize subject burden.  In our past experience, scanning participants for > 1-hour results in 
substantial movement artifact that can bias imaging results.  Regarding affect regulation, we are 
including a well-validated self-report measure and other psychological measures as baseline 
predictors/covariates in the analysis. We have focused on a model-driven analysis. However, this 
sample may allow a data-driven, model-free approach.  This limitation can be addressed by 
exploratory analyses using advanced methods (e.g. machine learning). Although our proposed 
sample size provides ample power to test our primary hypotheses and model building, validation 
will likely require an independent sample rather than resampling techniques for cross validation. 
Strengths of Proposed Research: To our knowledge, this would be the first investigation of the 
use of = BOLD fMRI signal during cognitive tasks and connectivity to characterize treatment 
outcomes for two extended release MAT medications. The study is carefully designed and 
powered to evaluate the outcomes of interest. The use of larger sample sizes than previous 
research and novel medication will provide the strongest possible test of our hypotheses. We 
have demonstrated the feasibility of recruitment to studies with similar requirements, have 
identified brain regions of interest through our prior research, and have performed extensive pilot-
testing of all paradigms. The significance of this project is its potential to advance theory and 
treatment by elucidating brain-behavior mechanisms.  
 
11 RESEARCH STAFF 
The following research staff will be directly involved with the implementation and execution of 
the study: 
• 
James Loughead, Ph.D., Principal Investigator 
• 
Daniel Langleben, MD., Co-Principal Investigator,  
• 
Kyle Kampman, MD., Study Physician 
• 
Kevin Lynch, Ph.D., CSA Statistician 
• 
Susan Ware, Database Developer/Manager 
• 
Joseph Smith, Data Management Specialist 
• 
Urooj Iqbal, Research Staff 
• 
Dominique Spence, Research Staff 


 
 
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13 APPENDIX  
13.1  Schedule of Activities (SoA) 
Psychiatric and 
medical   
Screening 
detox and 
randomization 
(Day -14) 
 
MRI 
Scan 1 
Baseline 
(day 0) 
 
Induction 
to XRBUP 
or XRNTX 
(day 0-10) 
 
Injection 
1 
(day 10) 
+ weekly 
follow up 
Injection 
2 
(day 40) 
 
 MRI Scan 
2 On 
Treatment 
 (day 55) 
Injection 
3 
(Day 70 
 
 
Weekly  
Follow-
up 
End of 
study 
and 
referral 
(Day 
100) 
Demographics (age1, 
sex1, edu.1) 
X 
 
 
 
 
 
 
 
History, physical and 
labs (C.4.a) 
X 
 
 
 
 
 
 
 
SILS 
X 
 
 
 
 
 
 
 
MINI (EOS* – end of 
study) 
X 
 
 
 
 
 
 
X EOS* 
Addiction Severity 
Index1 
X 
 
 
 
 
 
 
X EOS* 
 Clinical/Behavioral 
(C.3.a) 
 
 
 
 
 
 
 
 
HAM-D2, HAM-
A2,COWS2 
X 
X 
X 
 
X 
X 
 
X 
SOWS, Opioid 
Craving Scale2 ,SF-
MPQ-22, STAI-6 
X 
X 
X 
 
X 
X 
 
X 
TLFB interview 
X 
X 
X 
 
X 
X 
 
X 
Ten-drug urine drug 
screen (UDS) 
X 
X 
        X 
X 
X 
X 
 
X 
Go-NoGo errors of 
commission2 
 
X 
 
 
X 
 
 
 
Neuroimaging 
(Section C.3.b) 
 
 
 
 
 
 
 
 
Go-NoGo fMRI3 
 
X 
 
 
X 
 
 
 
Opioid Cue task 
fMRI3 
 
X 
 
 
X 
 
 
 
Resting-state fMRI3 
 
X 
 
 
X 
 
 
 
MPRAGE (anatomical 
MRI scan) 
 
X 
 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


 
 
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PRINCIPAL INVESTIGATOR SIGNATURE 
 
STUDY 
SPONSOR: 
Daniel Langleben, MD 
STUDY TITLE: 
Open label comparison of injectable extended release preparations of 
buprenorphine (Brixadi®) and naltrexone (Vivitrol®) for the treatment of 
opioid use disorder 
STUDY ID 
PROTOCOL 
VERSION 
843403 
V5.0 
I have read the referenced protocol. I agree to conduct the study in accordance to this 
protocol, in compliance with the Declaration of Helsinki, Good Clinical Practices (GCP), 
and all applicable regulatory requirements and guidelines. 
Principal 
Investigator Name  James Loughead, Ph.D 
 
Signature 
 
Affiliation: 
University of Pennsylvania 
 
Date 
7/17/2023 
 
 
 
 
 


 
 
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END OF DOCUMENT


 
 
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