Clinical trial NCT02696096
Conditions: Opioid Addiction
Sponsor: Butler Hospital
Start date: 2016-08-01; Completion date: 2020-02-01
Enrollment: 21 participants; Allocation: NA; Intervention model: SINGLE_GROUP

Brief summary:
This study proposes to use functional magnetic resonance imaging (FMRI) to observe brain activity and behavior associated with decision-making about rewards (DD task), working memory and working memory cognitive persistence (WM task), and craving (CR task) in 72 opiate dependent participants initiating buprenorphine. While stably using opiates (initial study appointment) and again during withdrawal (approximately 3 days later), participants will receive an FMRI scan with behavioral challenges; immediately after the second FMRI, they will receive their first dose of buprenorphine. Buprenorphine treatment will continue for twelve weeks, followed by a four week taper. Urine toxicological analysis will be performed prior to the first scanning session, weekly for two weeks and biweekly thereafter.

Participation for all individuals will last 4 months. Assessments will occur at baseline, and weeks 1, 2, 4, 8, and 12. Buprenorphine induction will begin at the completion of the second scan; follow-up medical visits will align with study assessments on weeks 1, 2, 4, 8 and 12. All participants will receive 16 weeks of buprenorphine (the final 4 of these 16 weeks will include a taper).

Detailed description:

Arms: arm 1: FMRI Suboxone
Interventions: intervention 1: FMRI intervention 2: Suboxone
Intervention descriptions: intervention 1: all participants will complete 2 FMRIs intervention 2: all participants will be prescribed Suboxone for 4 months during their study participation

Protocol documents:
Prot_000.pdf: 
 
 
 
 
 
 
 
 
 
 
Neuroimaging predictors of relapse during treatment for Opiate dependence 
NCT: 02696096 
June 22, 2017 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


C1.  Brief Description of Subjects 
The study sample will consist of 72 opiate dependent persons, 21-50 years old, who want to 
initiate buprenorphine treatment. 
 
C2.  Study Design 
Participation for all individuals will last 4 months.  Assessments will occur at baseline, and 
weeks 1, 4, 8, and 12.  FMRI scans will occur on the initial study day (consent and BL 
assessment are also completed on this day) or within a week of the initial study day, and 
approximately 2-3 days later.  Buprenorphine induction will begin at the completion of the 
second scan; follow-up medical visits will align with study assessments on weeks 1, 4, 8 and 
12.  All participants will receive 16 weeks of buprenorphine (the final 4 of these 16 weeks 
will include a taper).  
 
C3.  Specific Procedures or Treatments 
Assessments: Participants will meet with the Research Assistant (RA) at the baseline visit, 
during the scanning sessions, and prior to the medical visit at weeks 1, 4, 8, and 12 after 
beginning buprenorphine. The goal of the follow-up contacts will be to assess drug and 
buprenorphine use using the TLFB, dispense buprenorphine, and biochemically confirm 
acute abstinence with urine toxicological analysis.  
 
During the baseline (first study visit) day, participants will be cabbed to Butler Hospital to 
complete informed consent, meet with the study physician to confirm study eligibility, and 
complete the baseline assessment.  If their FMRI is the same day, they will then be cabbed to 
the FMRI facility, where they will meet with a second research staff member and complete 
the FMRI session.  At the conclusion of this first day, they will be cabbed home.  If their FMRI 
is on a separate day from the BL appointment, they will be cabbed home from the BL 
appointment, then cabbed back and forth to the FMRI facility for the first FMRI.  For all 
participants, for the second FMRI day, they will be cabbed directly to and from the FMRI 
facility.  For the study visits during weeks 1-12, which all take place only at Butler Hospital, 
they will be asked to provide their own transportation. 
 
Assessments will include the following measures: general demographic information, social 
support (Duke Social Support Index78), self-efficacy (Thoughts About Abstinence Scale79), 
other drug use (Addiction Severity Index section on drug use80, self-report by TLFB, and 
urine toxicology), alcohol use, craving81 (Brief Substance Craving Scale82), withdrawal 
symptoms (Clinical Opiate Withdrawal Scale83), delayed discounting (paper version), and 
service utilization (The Treatment Services Review which quantifies types of treatment 
services received by participants84 during treatment, including the number of 12-step 
groups attended). 
 
This study will use Care New England’s instance of REDCap for the collection and storage of 
data. The study will not collect or store any actual data within REDCap until the project has 
been moved into REDCap’s production environment. 
 
REDCap is a secure, web-based application developed by Vanderbilt University for building 
and managing surveys and databases. It is primarily designed to support online or offline 
data capture for research studies, quality improvement, and operations. REDCap provides 
easy data manipulation (with audit trails for reporting, monitoring and querying patient 
records), real-time data entry validation, and an automated export mechanism to common 
statistical packages.  


 
Care New England’s instance of REDCap is hosted within the Care New England data center 
in Warwick, RI. This REDCap instance is role-based and is fully integrated with CNE’s Active 
Directory structure. It enjoys 24/7/365 enterprise-level support and security inherit to 
CNE’s HIPAA-compliant data center. Network transmissions (data entry, survey submission, 
and web browsing) to and from REDCap are protected via TLS 1.2 encryption.  REDCap’s 
data is stored on encrypted servers within CNE’s data center.  
 
The REDCap Consortium is composed of thousands of active institutional partners in over 
one hundred countries who utilize and support REDCap. REDCap was developed specifically 
around HIPAA-Security guidelines, and more information about the consortium and system 
security can be found at http://www.projectredcap.org/. 
 
Buprenorphine: The participant will meet with the study physician (Dr. Stein) at the first 
study visit at Butler Hospital, prior to buprenorphine induction. During this visit, he will 
take a medical history, confirm the participant’s eligibility for buprenorphine and explain 
how to use the buprenorphine medication.  Participants will be told at this first visit that 
they need to be in mild to moderate opiate withdrawal when they complete the second 
FMRI scan at the upcoming study visit (2-3 days later) in order to be eligible to receive their 
initial buprenorphine dose.  At the conclusion of this second scan, research staff at the FMRI 
facility will complete the COWS to confirm withdrawal symptoms, remind the participant 
how to self-dose the buprenorphine, and provide the participant with enough 
buprenorphine to last until the next study visit in about a week. 
 
As their initial buprenorphine dose, the participant will receive four milligrams of 
buprenorphine (with 1 mg of naloxone) sublingually14. Following this protocol, which Dr. 
Stein has used in multiple prior studies14,15, additional buprenorphine will be taken home 
for use later in the day, with the usual first day dose of 16 milligrams (with 4mg naloxone), 
and 16 mg administered daily throughout the 12 weeks of maintenance for standardization. 
Participants will be seen and dosed by Dr. Stein thereafter with only enough buprenorphine 
provided at each study visit to reach the next scheduled medical visit. Buprenorphine 
dosing will be done with the understanding that a total of 16 weeks of treatment will be 
offered. Thus, at the week 12 visit, a buprenorphine taper will begin, with a reduction of half 
the week 12 dose during week 12-14, and the remaining taper during weeks 14-16. Upon 
request, participants will be provided with a complete list of buprenorphine providers in 
the area to continue buprenorphine assisted therapy (maintenance) if participants wish to 
continue treatment beyond the study period. For those participants continuing 
buprenorphine assisted therapy with a buprenorphine provider arranged post-study, a 
stable dose of buprenorphine will be provided during weeks 12-16 in lieu of taper. If the 
participant’s appointment with this outside buprenorphine provider is after, but within 
approximately 10 days of, the 4-month study date, when the study medication is completed, 
the participant can be eligible to receive a “bridge prescription” to maintain continuity of 
medication between the end of the study and the start of outside care.  Urine toxicology will 
be performed at each medical visit. No participant will be discharged for use of illicit 
opiates. Thus, the incentive to misrepresent opiate use behavior at follow-up assessments is 
relatively low since use does not result in discontinuation of buprenorphine or from the 
study, or loss of monetary compensation for assessment.  
 
FMRI: For FMRI session 1, research staff will be certain that participants are not in opiate 
withdrawal (scoring <7 on the Clinical Opiate Withdrawal Scale83). For FMRI session 2, 


participants will be instructed to stop using opiates 12-24 hours prior to the session so they 
arrive at the Brown University FMRI facility at the time of their scan in a state of mild opiate 
withdrawal, scoring 7-12 on the Clinical Opiate Withdrawal Scale (COWS)83. This COWS 
score range will allow standardization of withdrawal symptoms across opiate types (e.g., 
heroin, oxycodone). If they appear at the FMRI appointment and are not in withdrawal, 
participants will need to reschedule their scan. Participants will remain in withdrawal 
throughout the FMRI session 2 procedures, and after this FMRI will receive their first dose 
of buprenorphine. This plan is in keeping with the fact that withdrawal symptoms are 
essential for buprenorphine to be initiated.  
 
After administration of pre-scan measures, participants will be “trained” to perform each of 
the three FMRI tasks, that is, made aware of what they will see and be asked to do when in 
the FMRI scanner. This training takes 15 minutes. Despite training, performance below 
chance level on the WM task and invalid responses on the DD task are expected in a small 
minority of participants, making the data from these individuals unusable. Resting state 
scans are not based on performance levels or subjective responses and therefore (unless 
data are lost to movement) always analytically adequate. Based on our experience 
administering these paradigms and the careful participant screening procedures that we 
have developed, we expect that analytic exclusions based on head movement and the 
inability of the participants to complete any particular FMRI portion of the study will be 
approximately 20%. 
 
Participants will then apply earplugs and FMRI-compatible vision correction, if needed, and 
lie on the MR scanner table. Stimuli will be back-projected with a LCD projector onto a 
screen that the participant will view through mirrors fixed to the scanner. High-resolution 
T1 scans will be acquired before FMRI. During FMRI, participants will respond using a 
response box. The FMRI scan process will last approximately 60 minutes.  
 
During both FMRI sessions, we will administer three FMRI behavioral challenges and a 
resting scan during the 60-minute protocol (see Table 1). Research staff will be overseen by 
co-Investigator Dr. Jerskey, who will be responsible for administering the paradigms during 
FMRI data acquisition.  
 
 
Delay Discounting Paradigm. This paradigm will be presented to examine decision-making 
for smaller immediate rewards versus larger delayed rewards. Thus, this task will assay 
impulsive choice preferences and the relative activity of both motivational drive and 
inhibitory control prior to entering buprenorphine treatment. Using an event-related 
design, participants make choices between smaller immediate rewards or larger delayed 
rewards over 72 trials (e.g., “Would you rather have $25 today or $35 in 29 days”). Each 
item has a temporal discounting function and the overall array of responses permits 
calculation of an individuals’ discounting level.  
Table 1. FMRI Paradigms and domains challenged 
Paradigm 
Relapse Risk Domain(s) 
Time 
Bilateral ROIs 
Delay Discounting (DD) 
Reward, Impulsivity, Restraint 
16 min 
MFG, anterior insula, ACC, PCC, MedFG 
Working Memory (WM) 
WM, WM Cognitive Persistence 
8 min 
MFG, IPL, SMA 
 Inhibitory Control (IC) 
 Inhibitory Control 
12 min 
 
Rest 
Default Network  
6 min 
PCC, MedFG 
     Abbreviations: Middle frontal gyrus (MFG), anterior insula (AI), anterior cingulate (ACC), posterior cingulate (PCC),  
     medial frontal gyrus (MedFG), inferior parietal lobule (IPL), supplementary motor area (SMA), ventral striatum (VS). 


 
Working Memory Paradigm. The 2-Back version of the n-Back has been widely used in FMRI 
experiments as a WM challenge (i.e., a construct that refers to the process of short-term 
storage and management of information). This task challenges persistence during a 
sustained cognitive set since information is constantly maintained and updated over six 45s 
blocks of time. During the 2-Back WM challenge a series of 15 consonants are presented 
visually, one every 3000 ms. Participants make a yes/no response following each consonant 
- whether it is the same as, or different from, the consonant presented two earlier. Each 
consonant block contains 33% stimulus-target consonants pairs, which randomly overlap 
(e.g., F, N, B, N, B, K, B, K, N…). The 0-Back task (a control task for the 2-Back) will include 
nine consonants presented at the standard 3000 ms rate. Subjects respond “yes” when a 
predetermined target consonant appears and “no” for other consonants. In total, there will 
be two runs of six 2-Back blocks each, requiring 4.8 minutes to complete (including control 
blocks). Three blocks of the 0-Back and three blocks of the rest will be included in each run. 
Accuracy and reaction time will be used as dependent measures of cognitive performance.  
 
Go/No-Go: The Go/No-Go is an inhibitory control task.  The version used in this study is 
similar to the version used previously by Kiehl and colleagues (2000), except that the Go 
stimuli are randomly selected letters other than “X”.  Specifically, letters will be presented 
for 100 ms each, with an interstimulus interval of 900 ms.  A total of 240 letters will be 
presented consisting of 80% “Go” stimuli (all letters other than “X”) and 20% “no-go” 
stimuli (“X”). Participants will be instructed to press a button for each “Go” stimulus in 
order to establish a pre-potent response, and inhibit their response when an “X” appears on 
the screen.  Total percentage correct, percentage of false alarms (commission errors), and 
reaction times for correct go stimuli will be used as behavioral measures of performance. 
 
 

SAP_001.pdf: 
 
 
 
 
 
 
 
 
 
 
Neuroimaging predictors of relapse during treatment for Opiate dependence 
NCT: 02696096 
June 22, 2017 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


C4.  Data Analysis  
A priori ROI analyses will be our primary method for quantifying task-related effects for 
hypothesis testing, while analyses involving the functionally defined ROIs will serve to validate 
our a priori findings.  
 
We will test hypotheses using lapse as the grouping variable and then with relapse. Three 
markers (altered response, disorganized response, and compensatory mechanisms; see Aim 1) 
will be evaluated in both the stable opiate use state and during opiate withdrawal. 
 
We will compare lapsers and nonlapsers on pre-quit behavioral and FMRI measures 
hypothesized to predict lapse (Aim 1) followed by application of Cox regression models 
predicting time to relapse among the full sample to determine if neuroimaging measures 
provide additional utility in predicting lapse (Aim 2). Although Aim 1 hypotheses are designed to 
be tested as group contrasts based on lapse within 1 week of quitting, we will group by median 
split of time to lapse if this results in unacceptable differences in group size.  
 
Aim 1. 1) Altered response to targeted challenges. These hypotheses will be tested using 
independent samples t-tests using mean task-associated activity in each ROI (listed in Table 1) as 
the dependent measure. For contrasts of cognitive persistence during the WM challenge, a 
linear mixed effects model for repeated measures will be conducted that allows estimates of 
contrasts of group over time and interactions. Parallel contrasts of behavioral measures will also 
be conducted for each task. 2) Disorganization of neural networks. Functional connectivity 
analyses will be conducted to determine the strength of relationships between the nodes of 
each network listed in Table 1. These will be converted to z-scores using Fisher’s transformation 
and contrasted across groups using independent samples t-tests. 3) Compensatory mechanisms. 
Compensatory overactivation will be assessed using voxel-wise independent samples t-tests. 
Voxel threshold will be <.05 corrected for multiple comparisons. We expect more recruitment of 
regions outside of the a priori ROIs among the lapsers during all FMRI paradigms. Although 
assessed qualitatively due to a lack of a priori spatial extent, we will count both clusters of 
significant activity and total volume of significant activity outside of a priori ROIs in order to 
perform exploratory group contrasts. Compensatory underactivation will be assessed using 
independent samples t-tests of mean task-related responses (i.e., DD, WM, WMCP, IC) in 
regions identified as the DN in the independent functional connectivity analyses of the resting 
state imaging run. We expect that while FMRI predictors for lapse and relapse will be related, 
they will not be identical. We plan primary analyses to separately examine both lapse and 
relapse. Although they are strongly associated, this permits identification of differential 
relationships between each and FMRI challenges, if present. Prediction and prevention of 
relapse is the most important goal of this line of research; however, we still include lapse, since 
it has been used as the outcome measure in most relevant studies. 
 
Aim 2. For each targeted relapse-risk domain, comparisons of behavioral and FMRI markers will 
be examined per ROI using logistic regression (lapse) and Cox proportional hazards survival 
models predicting time to relapse conditional on planned covariates including gender, age, 
social support, self-efficacy, comorbid alcohol and drug use, and mood. The unique explanatory 
contribution of FMRI responses will be evaluated by comparing a full model (including FMRI 
response, behavioral data acquired during the FMRI challenges, and covariates) to a reduced 
model, which includes only the behavioral data and covariates.