Clinical trial NCT02111798
Conditions: Substance Abuse Cocaine Dependence
Keywords: substance abuse treatment cocaine dependence contingency management; abstinence incentives medication-enhanced behavioral therapy
Sponsor: Johns Hopkins University
Start date: 2014-07-01; Completion date: 2021-01-01
Enrollment: 83 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
This project will examine effects of bupropion extended release (XL) at a dose of 300mg/day for cocaine abstinence among persons receiving methadone for the treatment of opioid use disorder. Participants also earned financial incentives for providing urine samples that tested negative for cocaine. Bupropion was examined for this purpose because of its previously demonstrated efficacy and safety as well as its pharmacological actions at dopamine systems. Participants were randomly assigned to bupropion XL vs. placebo and received different incentive schedules depending on whether they demonstrated abstinence from cocaine early in the study. Outcomes were tracked over a 6-month time frame and the overarching hypothesis was that bupropion (as compared to placebo) would increase the number of urine samples testing negative for cocaine, independent of whether participants demonstrated abstinence from cocaine early in the study.

Detailed description:
The efficacy of behavior therapies may be enhanced by certain medications, particularly those that act on dopaminergic systems. The purpose of this project is to examine effects of bupropion on initiation and maintenance of cocaine abstinence in a population of persons being treated with methadone for the treatment of opioid use disorder who are concurrently using cocaine. Bupropion appears to be the most promising medication for this purpose because of its previously demonstrated efficacy and safety as well as its pharmacological actions at dopamine systems.

Participants will be eligible for inclusion in the study if they are 1) enrolled in methadone maintenance treatment, having previously met the criteria for opioid dependence; 2) between the ages of 18 and 65; 3) provide evidence of cocaine dependence (DSM-IV criteria, self-report, and/or urine tests positive for cocaine during the intake process); and 4) are willing to take study medications and adhere to reporting and data collection schedules.

They will be excluded if they have 1) a history of epilepsy or seizure, including alcohol- or cocaine-related seizure; 2) conditions with increased risk of seizure (e.g. head trauma with loss of consciousness \> 30 mins), 3) current use (past 30 days) of antidepressants, antipsychotics, theophyllines, systemic steroids, MAO-A inhibitors, 4) recent use (past 30 days of any medication containing bupropion or budeprion (Wellbutrin®, Zyban®), 5) allergy to bupropion or budeprion, 6) liver enzyme levels greater than 3x upper limit of normal (ULN); 7) uncontrolled diabetes mellitus (glucose \> 200mg%); 8) severe psychiatric diagnosis: schizophrenia, psychosis, major depression, mania, current suicidal ideation with plan; cognitive impairment severe enough to preclude informed consent or valid responses on questionnaires; 9) severe renal insufficiency (eGFR \< 30 ml/min), 10) pregnant, breast feeding or unwilling to use birth control, 11) medical illness that in the view of the investigators would compromise participation in research, 12) advanced HIV infection requiring HAART 13) current eating disorder (anorexia or bulimia), 14) uncontrolled hypertension with blood pressure ( BP) \>140/90.

All participants will be randomly assigned to receive bupropion XL (300mg/day) or placebo. In addition, study participants will also receive an add-on incentive-based intervention depending upon whether they provide 6 consecutive-urine samples that test negative for cocaine. Those who provide 6 consecutive negative urine samples will earn incentives for continuing to provide negative sample (Relapse Prevention group) and those who do not achieve this threshold will earn a different schedule of incentives to promote abstinence (Abstinence Initiation). Our hypothesis is that bupropion as compared to placebo treatment will both enhance the number of urine samples testing negative for cocaine. All participants will be eligible to earn $675 in incentives and cocaine use will be monitored via thrice weekly urine samples collected for a 6 month period.

Overall, this research will provide new and valuable information about the use of bupropion XL to enhance provision of cocaine-negative urine samples in persons independent of their early abstinence behaviors. If hypothesized synergies can be demonstrated, the study will point the way to a significant advance in improved treatment outcomes for this critical group of drug abusers. The proposed study is compelling because it conceptually differentiates the two key clinical issues in treatment of stimulant abusers- abstinence initiation and relapse prevention. It uses a design that efficiently and effectively tests a combined treatment approach for each clinical issue and as well examines cognitive function and reinforcement-based mediators. The research will add to understanding of the interplay between brain reinforcement systems and drug-seeking behavior. Finally, it will make an important contribution to behavioral therapy development by exploring a novel solution to limitations previously noted for CM that include lack of response in some patients and relapse after withdrawal of incentives.

Arms: arm 1: In week 2 participants will randomly assigned to receive twice daily capsules filled with placebo powder. At the end of week 6, participants who did not provide \>/=3 consecutive negative urine samples during weeks 1-6 of the trial will be assigned to the Abstinence Initiation incentive arm. arm 2: In week 2 participants will randomly assigned to receive bupropion 150mg capsules filled with placebo powder. At the end of week 6, participants who did not provide \>/=3 consecutive negative urine samples during weeks 1-6 of the trial will be assigned to the Abstinence Initiation incentive arm. arm 3: In week 2 participants will randomly assigned to receive twice daily capsules filled with placebo powder. At the end of week 6, participants who did provide \>/=3 consecutive negative urine samples during weeks 1-6 of the trial will be assigned to the Abstinence Initiation incentive arm. arm 4: In week 2 participants will randomly assigned to receive bupropion 150mg capsules filled with placebo powder. At the end of week 6, participants who did provide \>/=3 consecutive negative urine samples during weeks 1-6 of the trial will be assigned to the Abstinence Initiation incentive arm.
Interventions: intervention 1: Placebo intervention 2: Bupropion XL intervention 3: Abstinence Initiation intervention 4: Relapse Prevention
Intervention descriptions: intervention 1: Participants will be randomly assigned to receive placebo powder in twice-daily capsules at the end of week 2. intervention 2: Participants will be randomly assigned to receive bupropion XL 150mg/day in twice-daily capsules at the end of week 2. intervention 3: Participants will provide urine samples thrice weekly during weeks 1-6 of the study. Urine samples will be tested immediately onsite for evidence of recent cocaine exposure. Participants who do not provide 3 urine samples that test negative for cocaine by the end of week 6 will be assigned to an Abstinence Incentive condition. intervention 4: Participants will provide urine samples thrice weekly during weeks 1-6 of the study. Urine samples will be tested immediately onsite for evidence of recent cocaine exposure. Participants who provide 3 urine samples that test negative for cocaine will be promptly assigned to a Relapse Prevention incentive condition.

Protocol documents:
Prot_SAP_000.pdf: 
 
 
JHMIRB eFormA  01 
Version 7 Dated:   01/2016 
 
Page 1 of 19 
 
Official Title: Medication Enhanced CM for Cocaine 
Dependence 
 
NCA Number: 02111798 
 
Document Date: January 2, 2019


 
 
JHMIRB eFormA  01 
Version 7 Dated:   01/2016 
 
Page 2 of 19 
 
 
Date: January 2, 2019  
Principal Investigator: Kelly E. Dunn, Ph.D. 
Application Number: NA00090062 
 
 
 
JHM IRB - eForm A – Protocol 
 
 
 
• 
Use the section headings to write the JHM IRB eForm A, inserting the appropriate material 
in each. If a section is not applicable, leave heading in and insert N/A. 
• 
When submitting JHM IRB eForm A (new or revised), enter the date submitted to the field at 
the top of JHM IRB eForm A. 
 
*************************************************************************************************** 
 
1. 
Abstract 
Provide no more than a one page research abstract briefly stating the problem, the research hypothesis, 
and the importance of the research. 
 
The efficacy of behavior therapies may be enhanced by certain medications, particularly those that act on 
dopaminergic systems.  This project will examine effects of bupropion on initiation and maintenance of 
cocaine abstinence in a population of cocaine dependent methadone maintenance patients.   Bupropion 
appears to be the most promising medication for this purpose because of its previously demonstrated 
efficacy and safety as well as its pharmacological actions at dopamine systems.    
 
Methadone maintained cocaine dependent study participants (N = 100) will be stratified according to 
whether or not they stop their cocaine use during initial exposure to an abstinence incentive (contingency 
management) procedure and will be randomly assigned to receive bupropion XL (300mg/day) versus 
placebo for the remainder of the study. Our hypothesis is that bupropion as compared to placebo 
treatment will both enhance rates of abstinence initiation in those who have difficulty stopping cocaine and 
retard rates of relapse in those who initially stopped their cocaine use.   
 
Participants will receive a CM schedule that is tailored to their initial CM response and outcomes will be 
tracked over a 6-month time frame that includes assessment of drug use outcomes after incentives have 
stopped.  In addition, the project will provide novel information about mechanisms of medication effects by 
measuring subjective drug effects, drug vs money choices, and self-reports of pleasure derived from daily 
non-drug activities.   We hypothesize that bupropion compared to placebo participants will report non-drug 
activities as more pleasurable (reinforcing), will engage in more of them and that measures of non-drug 
reinforcement will mediate abstinence outcomes.   
 
Overall, this research will provide new and valuable information about combined behavioral-
pharmacological treatments and specifically the conditions under which medication may enhance effects 
of CM.  If hypothesized synergies can be demonstrated, the study will point the way to a significant 
advance in improved treatment outcomes for this critical group of drug abusers.  The proposed study is 
compelling because it conceptually differentiates the two key clinical issues in treatment of stimulant 
abusers- abstinence initiation and relapse prevention.  It uses a design that efficiently and effectively tests 
a combined treatment approach for each clinical issue and as well examines cognitive function and 
reinforcement-based mediators.  The research will add to understanding of the interplay between brain 
reinforcement systems and drug-seeking behavior.  Finally, it will make an important contribution to 
behavioral therapy development by exploring a novel solution to limitations previously noted for CM that 
include lack of response in some patients and relapse after withdrawal of incentives.   


 
 
JHMIRB eFormA  01 
Version 7 Dated:   01/2016 
 
Page 3 of 19 
 
 
2. 
Objectives (include all primary and secondary objectives) 
 
Specific aims of the project are the following: 
a. Examine in those who initially achieve abstinence with CM the effects of bupropion XL  (300    
mg/day) versus placebo on 24-week abstinence outcomes during and after CM.   
Hypothesis: Among participants who achieve initial abstinence, those treated with 
bupropion compared to placebo will have significantly longer delays to resumption of drug 
use and higher rates of abstinence at 24-weeks.  
b. Examine in those who initially fail to achieve abstinence with CM the effects of active bupropion 
XL (300 mg/day) versus placebo medication on subsequent abstinence initiation outcomes.  
 
Hypothesis: Among participants who failed to achieve initial abstinence, those treated with 
     bupropion vs placebo will have significantly higher rates of abstinence at 12 and 24 weeks. 
c. Identify mechanisms of bupropion-enhanced outcomes by administering self-report instruments 
      that assess response to non-drug reinforcement. 
Hypothesis1: Bupropion compared to placebo participants will report both money and non-drug 
activities as more reinforcing and will engage in more of the latter. 
Hypothesis 2: Enhanced non-drug reinforcement will mediate abstinence outcomes 
d. Determine whether response to abstinence-contingent reinforcers can be predicted by pre- 
            treatment response to measures of drug vs non-drug relative reinforcing efficacy. 
e. Explore the effects of bupropion XL (300 mg) vs placebo on secondary outcome measures of 
cognition, impulsivity, HIV risk behaviors and tobacco smoking. 
Hypothesis: Bupropion compared to placebo will improve attention, short-term memory and 
other cognitive processes and may decrease risky behaviors and tobacco smoking. 
 
3. 
Background (briefly describe pre-clinical and clinical data, current experience with procedures, 
drug or device, and any other relevant information to justify the research) 
 
There are few efficacious treatments for stimulant abuse, but those that have been identified are behavior 
therapies.  In particular, the most effective behavior therapy approach available arguably involves the 
addition to counseling of contingency management procedures in which tangible incentives are offered for 
evidence of sustained abstinence from stimulant drugs (e.g. Dutra et al., 2008).  On a background of 
extensive efficacy testing, two large clinical trials conducted in the CTN verified the effectiveness of this 
approach when applied with stimulant users enrolled in either methadone maintenance (Peirce et al., 
2006) or psychosocial counseling (Petry et al., 2005) treatments.  There are nonetheless two areas in 
which abstinence incentive therapies fall short.  One is that only about half or fewer of the drug users 
exposed to these interventions respond by initiating prolonged periods of abstinence (Silverman et al., 
1996; 2004).   Secondly, many who do stop use during incentive interventions return to drug use after 
withdrawal of the interventions (Silverman et al., 1996; 2004).  Methods that could counter these shortfalls 
and further improve treatment outcome for stimulant users would be very valuable. 
   
There is also a growing body of evidence suggesting that certain medications can boost the efficacy of 
abstinence-focused contingency management.  One of the first studies reported was by Kosten and 
colleagues (Kosten et al., 2003) who randomly assigned 160 buprenorphine-maintained cocaine abusers 
to receive desipramine (150mg/day) or placebo crossed with abstinence-contingent versus non-contingent 
voucher reinforcement (maximum earnings of $738 over 12 weeks).   A significant interaction was 
observed.  Overall percent of opiate and cocaine-free urines during weeks 3-12 of the intervention was 
50% for the combined therapy group versus 25-29% for each of the other groups, with no significant 
differences between control and single therapy conditions.  This was a convincing demonstration of a 
medication-CM interaction, especially since the CM did not appear to have any beneficial effects on its 
own   Another convincing study was published by Schmitz and colleagues (Schmitz et al., 2008) who 


 
 
JHMIRB eFormA  01 
Version 7 Dated:   01/2016 
 
Page 4 of 19 
 
randomly assigned 161 cocaine dependent patients to receive levodopa/carbidopa (400/100mg bid) 
crossed with one of 3 behavior therapy interventions (clinical management, cognitive-behavior therapy or 
voucher-based abstinence reinforcement; maximum earnings of approximately $1000 over 12 weeks).  As 
in the Kosten et al. study, the largest intervention effect was seen with the group that received the 
medication combined with abstinence incentives.  Further, the abstinence incentive condition was the only 
behavior therapy condition in which a significant effect of medication versus placebo was observed in 
planned post-hoc testing.  Specifically, 60% versus 23% cocaine negative urines were delivered by 
participants in the levodopa/carbidopa vs placebo conditions when background therapy was abstinence-
contingent CM.   Although levo-dopa is not especially practical for clinical use, it has precise 
pharmacological specificity for enhancing dopaminergic neurotransmission.   Thus, Schmitz et al (2008) 
were able to put forth an hypothesis and convincing argument that the mechanism of the interaction was 
likely enhanced response to rewarding stimuli (in this case, the CM intervention). 
  
Bupropion is another anti-depressant medication that works in part by enhancing dopamine 
neurotransmission.  In several prior trials, this medication did not show benefits when given on its own with 
a psychosocial counseling therapy as background (Elkashof et al., 2008; Margolin et al., 1995; Shoptaw et 
al., 2008a,b), although a recent re-analysis of the Elkashof study (McCann & Li, 2012) with 
methamphetamine abusers receiving CBT as a background therapy used a novel analysis approach to 
show that bupropion produced longer durations of abstinence among those who initiated abstinence (i.e. a 
relapse prevention or relapse delay effect).  Bupropion in two studies has had a synergistic effect in 
combination with abstinence incentive interventions. Poling and colleagues (Poling et al., 2006) randomly 
assigned 106 methadone maintained cocaine users to receive bupropion (300mg/day) or placebo crossed 
with a behavior therapy that did or did not reinforce opiate and cocaine-free urine samples (maximum 
earnings of $462 over 12 weeks).  Two outcome measures were significantly different for CM bupropion vs 
CM placebo groups: consecutive weeks of cocaine abstinence (6.7 CMB vs 4.3 CMP) and probability of a 
cocaine positive sample in weeks 24-25 (.33 CMB vs .57 CMB).  This drug vs placebo difference is 
impressive considering the relatively small sample sizes studied and the multiple behavioral targets for the 
CM intervention (opiates, cocaine and abstinence-related goal activities) that could have diluted effects of 
CM on cocaine use specifically.  Additional evidence of the apparent synergy between contingent 
incentives and bupropion comes from a smoking cessation study recently reported by Gray et al. (2010) in 
which adolescents who received bupropion (300 mg/day) plus abstinence incentives ($275 available over 
a 6-week program) had a 27% smoking abstinence rate at end of treatment compared with abstinence 
rates of 8-10% for groups that received either of the treatments alone or no treatment.   
 
While pharmacological specificity of the interaction has not been explicitly researched, it is notable that 
one published study using tryptophan (Jones et al., 2004) another using the glutaminergic antagonist 
memantine (Bisaga et al., 2010) and an unpublished study using topiramate (Umbricht, personal 
communication) have failed to find an advantage for the combination of medication and abstinence 
incentives in the treatment of cocaine dependence.   Findings for serotonergic medications tested in 
combination with CM have been mixed.  In two trials with SSRI medications, one with fluoxetine (Schmitz 
et al., 1998) and one with citalopram (Moeller et al, 2007), positive treatment effects (medication vs. 
placebo) were observed when the background behavior therapy included an abstinence reinforcement 
intervention.  However, an older study by Shoptaw et al. (2006) treating methamphetamine abusers failed 
to find a significant treatment interaction when abstinence-based incentives were combined with sertraline 
(50 mg bid).   Further, a recent study by Winstanley et al. (2011) failed to find an interaction between 
fluoxetine and abstinence-contingent reinforcers in methadone maintained cocaine users.  Thus, it 
appears that there may be some important pharmacological specificity related to drug actions on 
dopamine systems that supports the use of specific medications in combination with behavior therapies 
that rely on response to alternative positive reinforcement. 
 
While the trials demonstrating a CM-medication interaction have been quite varied in the populations 
studied as well as the medications and methodologies employed, there is a striking consistency across 
them that supports the use of a dopaminergic medication for continued research on this interaction.   


 
 
JHMIRB eFormA  01 
Version 7 Dated:   01/2016 
 
Page 5 of 19 
 
Further, although there are several possible explanations for this therapeutic interaction, the most 
intriguing and plausible is that the interaction occurs at a cellular level in dopaminergic brain systems that 
mediate response to rewarding stimuli such that dopamine levels are enhanced by the medication, which 
in turn allows the behavior therapy to be more efficacious than it otherwise would be.  An exciting study 
proving additional support for this theory was recently published by Martinez et al. (2011).  The study used 
PET imaging to examine dopamine signaling in the limbic striatum of cocaine users before and during the 
administration of a contingency management intervention.  They found that both striatal dopamine 
receptor binding and presynaptic dopamine release were lower in volunteers who failed to respond to the 
abstinence reinforcement intervention.  Thus, the study suggests that low dopamine transmission is 
associated with treatment failure and supports the hypothesis that a medication such as bupropion that 
increases striatial dopamine signaling may enhance response to a reward-based therapy.  
   
Further support for a synergistic interaction between bupropion and abstinence incentives could 
significantly change clinical practice by offering a novel new paradigm for clinical treatment of stimulant 
abusers.  Bupropion is the best candidate medication based on prior evidence for efficacy (Poling et al., 
2006; Gray et al., 2010), recent positive findings from a laboratory drug versus money choice study by 
Stoops et al. (2012) and feasibility of use in clinical practice (e.g. low cost and low risk for significant side 
effects).  The present proposed study will go well beyond previously published findings on this interaction 
to provide information that is both scientifically and clinically valuable.  Specifically, the proposed study 
design is uniquely crafted to allow examination of patient-level mediators of the therapy interaction and to 
simultaneously answer two critically important clinical questions: 1) Does the medication help individuals 
with on-going stimulant use to stop  that use initially?  2) Does the medication help with relapse prevention 
in those who have stopped stimulant use prior to medication exposure?  
 
Overall, the proposed study is compelling because it conceptually differentiates the two key clinical issues 
in treatment of stimulant abusers- abstinence initiation and relapse prevention- and uses a design that 
efficiently and effectively tests a combined treatment approach on each.  If successful, the study will point 
the way to a significant advance in improved treatment outcomes for this critical group of drug abusers. 
 
4. 
Study Procedures 
a. Study design, including the sequence and timing of study procedures   
(distinguish research procedures from those that are part of routine care). 
 
Features of the study design are presented in detail below. All procedures including the study 
assessments, frequent urine testing schedule, and contingency management incentives will be 
conducted either at a methadone maintenance clinic site or at the BPRU with participants 
enrolled in methadone maintenance elsewhere.  Background usual care consists of daily 
methadone dosing with medical management, and expectations of regular (usually once 
weekly) attendance at face to face individual and/or group counseling sessions.  
 
b. Study duration and number of study visits required of research participants. 
 
The study lasts for 30 weeks during which time participants are expected to report to their 
normal methadone clinic 7 days per week for methadone dosing (take home privileges, official 
holidays, and clinically determined take-home days excluded) and 3 times per week to study 
staff members either at REACH, Addiction Treatment Services, Glenwood Life Center, or at 
the BPRU for urine testing.  Study visits include up to 3 screening visits (brief screen, full 
screen, medical exam), a baseline assessment, once weekly brief assessment visits (N = 20) 
and five longer assessment visits at weeks 6, 12, 18, 24, and 30. 
  


 
 
JHMIRB eFormA  01 
Version 7 Dated:   01/2016 
 
Page 6 of 19 
 
c. Blinding, including justification for blinding or not blinding the trial, if applicable. 
 
Medication condition (active versus placebo bupropion) will be blinded to research and 
counseling staff who interact with participants in order to eliminate any potential biases from 
their interaction with participants.  
  
d. Justification of why participants will not receive routine care or will have current therapy 
stopped.  
 
NA; participants will receive routine methadone maintenance. 
 
e. Justification for inclusion of a placebo or non-treatment group. 
 
Placebo is included for scientific validity in a clinical trial needed to answer study questions 
related to medication efficacy. 
 
f. Definition of treatment failure or participant removal criteria. 
 
There is no clear definition of treatment failure for this study sample of methadone maintained 
patients since long-term methadone maintenance is standard care for their chronic relapsing 
disorder.  Patients could potentially be dismissed from treatment for violating clinic rules 
particularly those relating to violence, firearms possession, drug sales or or other 
unacceptable behavior at the clinic.  Participants could be removed from the study if severe or 
persistent medication side-effects were observed or if new medical conditions developed 
including pregnancy or concomitant medications were started that made their continued 
participation unsafe.  
  
g. Description of what happens to participants receiving therapy when study ends or if a 
participant’s participation in the study ends prematurely. 
 
Study participants will continue on usual care methadone maintenance treatment at their 
normal methadone clinic after the study or in the event of premature withdrawal from the 
study. 
 
Study Procedures: Urine Testing.  Primary outcomes will be based on qualitative (pos/neg) urinalysis 
testing results using standard detection cut-off values.  In order to detect recent use of cocaine, urine 
samples will be collected three times per week on non-consecutive days throughout the study, usually on 
Mon, Wed, and Fri.  Sample collection will be observed if possible and all samples will additionally be 
tested for temperature and adulterants.  A second sample will be requested if the original sample fails 
these tampering tests.  
Study Procedures: CM Lead-In.  Participants will enter the study following an intensive screening during 
which eligibility is determined, informed consent is signed and baseline assessment is completed.  The 
study itself begins with a 6-week contingency management lead-in during which vouchers can be earned 
for submission of cocaine negative urine samples under an escalating schedule with reset to the original 
value in the case of missing or positive urines.  A participant who stops cocaine use on the first day of the 
study and remains continuously cocaine abstinent would earn $145 by the end of week 6.  However, many 
participants may start earning later than week 1 or experience resets and thus earn less.  
Stratification and Random Assignment.  A key feature of abstinence incentive programs is that 
participants tend to clearly dichotomize into responders and non-responders.  The former initiate and 
sustain abstinence early in the program, while non-responders, either never initiate abstinence or do so 
intermittently or for only short periods of time before relapsing.   In this study, participants will be stratified 
into CM responders versus non-responders based on submission of two consecutive weeks of cocaine-


 
 
JHMIRB eFormA  01 
Version 7 Dated:   01/2016 
 
Page 7 of 19 
 
free urines (6 samples) during study weeks 1- 6.  Considerable experience with implementing these types 
of interventions suggests that there will be close to a 50/50 split between responders and non-responders 
by the end of the first month of the CM program.   
By the end of study week 6, all participants still active in the study (and independent of exactly where they 
may be in the abstinence-contingent lead-In earnings plan) will be randomly assigned to bupropion vs 
placebo medication from within the responder vs non-responder strata and introduced to their tailored 
earnings schedule for the remainder of the study (see graphs below).  Those who qualify for relapse 
prevention by submitting 2 weeks of negative urines will be randomized on the day they submit the 6th 
negative urine, while those who will clearly not qualify for relapse prevention will be randomized at the 
start of week 6.   
Medication: Bupropion.   
Commercially available sources of Bupropion XL and Microcrystalline Cellulose (placebo) will be obtained 
by the BPRU pharmacy.   Qualified pharmacy staff will prepare double blind dosages by over-
encapsulation of bupropion tablets.  The inert substance in both active and placebo capsules will be 
Microcrystalline Cellulose.  Active or placebo capsules will be placed in one-week blister pack kits 
compatible with daily dispensing requirements of the protocol. When a medication order is provided to the 
pharmacy, the blister packs will be labeled with a subject number and dispensed to the study site.  Study 
medication blister-packs may be dispensed to participants by nursing staff at the methadone clinic 
dispensary window or by BPRU research staff.  Each kit would contain an accountability log for clinic or 
study staff to document distribution of capsules from the kit to the study participant.  Medication will be 
stored either in a secure vault at the methadone clinic site or in a pharmacy-approved safe within a locked 
room. 
Medication dispensing will begin in study week 1 at which time all participants will begin receiving double 
blind capsules containing placebo. The advantage of this “placebo run-in” is that it stabilizes the 
medication taking regimen early in the study, precludes “placebo effects” at the time of random 
assignment and allows for a smooth transition into the post-random assignment study period without any 
change in study procedures.  Participants may be randomized and potentially switched to active bupropion 
after giving their 6th cocaine negative urine following placebo initiation (week 3 randomization at the 
earliest) or at the start of study week 6 for those who provide urinalysis evidence of continued active drug 
use. Consistent with clinical practice for those randomized to active bupropion, there will be a brief (3-day) 
induction period followed by maintenance dosing at 300mg/day   Medication dispensing will continue 
through week 30. Typically, only a one week supply will be given, but additional medication may be 
dispensed for holidays, weather-related or other emergencies.  
Abstinence incentive schedule initially drug-negative.   
The schematic below (left panel) depicts total weekly earnings for accelerating and decelerating phases 
for those who submit 6 or more negative urines during the CM run-in. The gradual escalation of voucher 
values begun in week 1 continues for a total of 12 weeks, which includes the Lead-in phase.  Reset 
contingencies have been included for the relapse prevention participants to forestall early relapse.  Once 
randomized to this condition, a cocaine positive or missing sample submitted prior to week 26 will result in 
reset to the $3 value.  Following a reset, the participant will earn $3 then $3.50 for the first two cocaine 
negative samples then will return to the most recently achieved point in their earning schedule (e.g. $11 
per sample) after the third consecutive cocaine negative sample.  Extending the earning period from 24 to 
26 weeks allows for completion of the entire earning schedule with 2 brief (single urine positive) slips 
during which an additional total of $13 could be earned.  


 
 
JHMIRB eFormA  01 
Version 7 Dated:   01/2016 
 
Page 8 of 19 
 
.  
Following completion of the 10 week stable earning phase at $11 per negative urine, payment escalation 
reverses and the per urine payment schedule begins to decelerate.  Note that the schedule is shown 
ending at study week 24.  However, participants will be enrolled in the study for 30 weeks and allowed to 
continue earning through week 26.  This allows time for those who may qualify later during Lead-In or 
have brief slips to complete the schedule and also time to track drug use and relapse measures after all 
reinforcement is withdrawn.  Gradual pay reduction schedules have been used successfully in our clinical 
laboratory as relapse tests in cocaine self-administration (Donny et al., 2003, 2004) and smoking (Juliano 
et al., 2006) studies.  Under this schedule, relapse will be delayed to the extent that the money alternative 
is perceived as more motivating and/or motivation for abstinence has shifted to reinforcers in the natural 
environment other than the monetary payments.  Thus, bupropion is expected to slow or prevent relapse 
because the saliency of non-drug reinforcers maintaining abstinence will be enhanced.  A maximum total 
of $688 can be earned  by those who are continuously abstinent with the exception of no more than two 
single cocaine positive urines. 
Abstinence incentive schedule: initially drug-positive.   
The schematic above (right panel) depicts total weekly earnings for accelerating and decelerating phases 
for those who fail to reliably initiate abstinence during the initial 5 weeks.  They will be randomly assigned 
at the start of study week 6 to begin taking double blind bupropion or placebo and will be able to earn 
abstinence incentives through week 26 of the trial while taking study medications.  During week 5 they will 
be shown their new earnings schedule and encouraged to renew their efforts to become abstinent as soon 
as possible.  The schedule under which they can earn abstinence-contingent vouchers has been adjusted 
so that total earnings for continuous abstinence are approximately equal to that of the initially abstinent 
relapse prevention group ($653 plus whatever might be earned during the lead-in phase). There will be a 
reset back to the original voucher value in this study to discourage relapse using the same rules described 
above. There is no decelerating payment phase as described for the Relapse Prevention group since the 
issue here is whether participants will initiate abstinence and for how long they will remain abstinent under 
a typical escalating schedule of payment.  
Note that bonuses are included for both groups that are paid following submission of 3 consecutive 
cocaine negative urines.  The number of bonuses that can be earned is fixed; once a bonus is dispersed it 
cannot be earned again following resets.  It is important to note that there should be no biases developed 
among clinic patients as to which study earnings schedule is preferable since the total amount of money 
that can be earned during the study is comparable for those in the relapse prevention and abstinence 
initiation studies.  Note, for example, that $114 is included in each schedule for bonus payments denoting 
achievement of 3 consecutive cocaine negative urines.  Further, each schedule has features that may be 
perceived by participants as desirable (e.g. earnings escalation) and undesirable (declining values in 
Study Week
   6      12      18      24      30
   6      12      18      24      30
Relapse Prevention
Abstinence Initiation
Abstinence Reinforcement Schedules
  10       20         30      40
Weekly Earnings ($)


 
 
JHMIRB eFormA  01 
Version 7 Dated:   01/2016 
 
Page 9 of 19 
 
Relapse Prevention).  Finally, participants will understand that they cannot choose, but will be assigned to 
their final earning schedule at or before study week 7.  All these procedures circumvent any real or 
perceived inequities in the study stratification and assignment procedures.  
Voucher redemption.  Throughout the study, participants will be regularly updated on the amount of 
money in their voucher account. Once earned, voucher money is never taken away.  Participants will be 
able to trade in vouchers at any time for a variety of tangible items and gift cards that will be kept on-site, 
to request that specific items be brought in for immediate trade-in or to save their voucher money for larger 
items that will be redeemed at a later time.  The only restriction is on purchase of weapons, cigarettes or 
alcohol. 
Contingency management summary.  In addition to the schedules outlined above, participants will be 
reinforced for attendance of the short-assessment visit which occurs once-weekly. Participants can earn 1 
bus token (good for a one-way trip) each time they attend and complete the short assessment. 
Participants may also receive other incentives for session attendance. The abstinence reinforcement 
schedules developed for this study are specially tailored to the study questions and subpopulations being 
addressed.  Those who can stop their cocaine use before receiving medication may have higher 
dopamine function than those who do not (Martinez et al., 2011) but may still benefit from a dopamine-
boosting medication for delaying or circumventing relapse.  Their CM schedule, that incorporates a 
decelerating payment phase, is tailored for a time-to relapse assessment. In those who struggle to initiate 
abstinence, the escalating CM schedule will provide an appropriate background for detecting reinforcer 
boosting effects of a dopaminergic medication. 
Study Measures (all but standard screening tools are appended in application) 
 
Screening measures.  Screening for stimulant and alcohol use disorders will be conducted using 
the DSM-5 checklist (American Psychiatric Association, 2013).  Psychiatric screening will be conducted 
using the MINI International Neuropsychiatric Interview (Sheehan et al., 1998), a validated instrument that 
yields psychiatric diagnoses based on DSM-IV criteria.  We will not administer the entire instrument.  
Rather, it will be used to screen for current major depression, mania/hypomania, psychosis, eating 
disorders and suicidality. We will continue to employ the Beck Depression Inventory as a measure of 
depressed mood and will conduct urine screen for cocaine and other drugs. 
Weekly assessments include 3 X per week cocaine urine screen; periodic full drug screen, cocaine 
use self-report (7 day time line follow back), assessment of alcohol and tobacco use, the Cocaine Effects 
Scale visual analog measures of the pleasurable subjective effects of cocaine, and a depression symptom 
assessment.   
Additional assessments administered at baseline and study weeks 6, 12, 18, 24, and 30:  
Multiple Choice Drug vs Money scale (Griffiths et al., 1993) to assess relative reinforcement 
potency of cocaine; In this hypothetical task developed by Griffiths and colleagues (Griffiths et al., 1993), 
participants are presented with a series of choices between drug and money.  The amount of drug 
remains constant across choices while the amount of money escalates.  Amounts shown below 
incorporate the values of the actual per-urine payment schedule participants will later encounter (from 
$1.00 to $11) as well as values above and below this range.   Outcome from the Multiple Choice 
Procedure is a “cross-over point”.  This is the point at which the participant’s choice switches reliably from 
drug to money.  The hypothesis is that those taking bupropion will switch their preference from drug to 
money at lower monetary values than will those taking placebo.  
The Quick Inventory of Depressive Symptomatology (Rush et al., 2003) to further assess 
depression and depressive symptoms, including sleep and appetite changes which may also 
inform us about effects of cocaine withdrawal. 
Snaith-Hamilton Pleasure Scale (Nakonezny et al., 2010) well suited for any population to assess 
pleasure derived from activities in the natural environment  
Life Style Changes Scale (Silverman, 1998) to assess activities related to giving up drugs  
Activities Assessment interview to probe in more depth for life style changes.  


 
 
JHMIRB eFormA  01 
Version 7 Dated:   01/2016 
 
Page 10 of 19 
 
Health Risk Behavior Scale (Darke et al., 1991) to assess drug and sex-related HIV risk behaviors. 
Fagerstrom Test of Nicotine Dependence (Heatherton et al., 1991) for assessment of current 
smoking dependence. 
Physical status assessment of blood pressure; body weight.  
Monetary-Choice Questionnaire to assess delay discounting (Epstein et al., 2003). 
The Barratt Impulsiveness Scale to assess impulsiveness and impulsive personal traits (Patton et 
al., 1995). 
Kirby Discounting Questionnaire  
Neurocognitive assessment.  A battery of tasks designed to measure neurocognitive performance 
has been developed at the BPRU (Mintzer and Stitzer, 2002) and will be adapted for this study.  Functions 
to be tested include psychomotor speed/pattern recognition (e.g. digit symbol substitution), set 
shifting/conceptual flexibility (e.g.; trail making tests), divided attention, long-term/episodic memory (e.g. 
recognition and free recall) and short-term/working memory and focused attention (e.g. N-back task). The 
Conners Continuous Performance Test will also be used to assess performance in areas of 
inattentiveness, impulsivity, sustained attention, and vigilance (Epstein et al., 2002). 
 
Inclusion/Exclusion Criteria 
Inclusion Criteria:  
• 
Over 18 years old 
• 
Enrolled or meets federal requirements for enrollment in methadone maintenance 
treatment, and willing to visit the clinic daily 
• 
Evidence of current cocaine dependence (DSM-5 criteria, self-report, urine test positive for 
cocaine during the intake process or by clinical record during the past 3 months). 
• 
Willingness to swallow a capsule daily 
• 
Willing to provide observed urine samples three times a week and participate in 
assessment procedures 
 
Exclusion Criteria:   
 
•  Any history of epilepsy or seizure, including alcohol-, sedative-, or cocaine-related seizure; 
•  Any increased risk of seizure such as serious head trauma with a loss of consciousness of    
more than an hour duration, brain tumor, or other brain pathology increasing risk of seizure. 
•  Current eating disorder including anorexia or bulimia 
•  Current use (last 30 days) of medication that is contraindicated with bupropion or other 
bupropion products (e.g. antidepressants, antipsychotics, MAO-A inhibitors, theophyllines, 
systemic steroids, etc) 
•  Allergy to bupropion or budeprion 
•  Liver enzymes greater than 3x ULN 
•  Uncontrolled diabetes mellitus, or h/o diabetic coma 
•  Uncontrolled hypertension with BP > 140/90 
•  Current psychiatric diagnosis: schizophrenia, psychosis, major depression, mania, current 
suicidal ideation as determined by MINI psychiatric interview, cognitive impairment severe 
enough to preclude informed consent or valid responses on questionnaires 
• Severe renal insufficiency (eGFR < 30 ml/min) 
• Pregnancy or current breast feeding,  
• Medical illness that in the view of the investigators would compromise participation in 
research, such as uncompensated congestive heart failure, recent history of myocardial 
infarction (<1year), or urologic conditions that inhibit urine collection.   
• Advanced HIV infection requiring the use of HAART, or with CD4 T cell < 200/uL 
 


 
 
JHMIRB eFormA  01 
Version 7 Dated:   01/2016 
 
Page 11 of 19 
 
5. 
Drugs/ Substances/ Devices 
a. The rationale for choosing the drug and dose or for choosing the device to be used. 
b. Justification and safety information if FDA approved drugs will be administered for non-FDA 
approved indications or if doses or routes of administration or participant populations are 
changed. 
c. Justification and safety information if non-FDA approved drugs without an IND will be 
administered.  
 
Bupropion was selected as the best candidate medication for this trial based on prior evidence for its 
synergistic interaction with contingency management to enhance treatment outcomes for substance users 
(Poling et al., 2006; Gray et al., 2010), recent positive findings from a laboratory drug versus money 
choice study by Stoops et al. (2012) and feasibility of use in clinical practice including low cost and low risk 
for significant side effects. Dose selection (300 mg/day) is based on clinical guidelines, safety 
considerations and prior research in substance users.  Selection of the slow release dosage form supports 
feasibility and compliance by allowing the majority of dose ingestions to be observed at the clinic. 
 
We believe use of this medication is exempt from IND application requirements under CFR 312.2 as the 
study is not intended to provide data that would influence indications, labeling or advertising.  Further, The 
investigation involves a standard dose (300mg/day) and route of administration (oral).  Neither the dose, 
route of administration, study population or other factors significantly increases the risks (or acceptability 
of the risks) associated with use of this product.  
 
6. 
Study Statistics 
a. Primary outcome variable. 
b. Secondary outcome variables. 
c. Statistical plan including sample size justification and interim data analysis. 
d. Early stopping rules. 
 
Sample size and power.    
 
The aim of this study is to evaluate whether bupropion will enhance cocaine abstinence among 
methadone-maintained patients who are abusing cocaine. This is being evaluated in a double-blind 
context. Further, based on evidence that individuals with cocaine use disorder typically present to the 
clinic with a urine sample that is positive for cocaine (which predicts continued use) or negative for cocaine 
(which predicts abstinence), we had originally proposed to treat those individuals as two separate groups 
and run 2 parallel studies (presented as Primary Aims 1 and 2), using contingency management as a 
background platform to support either abstinence or relapse prevention, respectively. Each aim was 
intended to enroll 100 individuals (N=200) total, to enable equal distribution of bupropion (n=50) and 
placebo (n=50) within each aim.  
Based on unanticipated difficulties with recruitment, we are now collapsing the two parallel studies into the 
same overarching study, such that Primary Aim 1 will now be examining the effects of bupropion XL vs. 
placebo on 24-week abstinence outcomes during and after exposure to a behavioral intervention (CM). 
We are reducing our sample size to 100 individuals, which still preserves the required 50 participants per 
medication group that was identified in our power analyses as necessary to detect an effect of the 
medication. This approach will allow us to achieve our primary aim of determining whether bupropion will 
enhance cocaine abstinence despite challenges with recruitment and will enable this study to still provide 
clinically important information to advance the treatment of cocaine use disorder. 
We are modifying our statistical plan to accommodate this change in sample size. We will retain the 
original primary outcome measure (biochemically-confirmed abstinence from cocaine), which will be 
assessed across all participants (independent of abstinence group) in the same statistical model. The 
endpoint will be binary (abstinent yes or no), and the treatment effect will be assessed using a repeated-
measures logistic regression model having two main effects: medication and time, plus their interaction, as 


 
 
JHMIRB eFormA  01 
Version 7 Dated:   01/2016 
 
Page 12 of 19 
 
well as any necessary covariates, including cocaine positive vs negative urine tests prior to random 
assignment as a covariate. Generalized linear mixed models (GLMM) will be used to analyze repeated 
measures data, since this technique can include participants with incomplete data without resorting to 
imputation.  This approach has been found to minimize bias and maximize power in cases of incomplete 
follow-up (see Hedden et al, 2009).  Data will then be examined using the nonbinary method described by 
McCann and Li (2012) in which participants who meet an end of study threshold of success (1 week EOS 
abstinence) are assigned values indicating their number of beyond threshold weeks of success (in our 
case 1-24).  This distribution will be analyzed as a function of drug condition using a two-sided Vander 
Waerden two-sample test (Permutt and Berger, 2000). 
All other analyses will be conducted in the overarching group that includes those abstinent and actively 
using at baseline. This approach will allow us to preserve all study Aims with a reduced sample size that 
will ensure the study can be completed in the time allowed. 
The data analysis plan consists of the following: 
 
1) Comparison of groups for baseline differences. Participants will be compared as a function of 
medication group on baseline characteristics to determine whether they are comparable with respect to 
general demographic features, baseline drug use, and reinforcement measures (drug vs. money relative 
reinforcing potency scale, Snaith-Hamilton Pleasure scale).  Groups will be compared using t tests for 
continuous measures and chi-square tests for categorical characteristics.  If medication groups are found 
to differ on baseline measures, then these characteristics will be used as covariates in subsequent 
analyses assessing treatment effect. 
 
2) Primary outcome analyses:  (see above) 
 
3) Secondary outcome analyses:  The main secondary outcome measure will be biochemically-
confirmed abstinence from opiates.  We hypothesize that participants receiving bupropion will have a 
higher proportion of opiate abstinent samples as well as for cocaine. Analyses conducted to assess the 
treatment effect for opiate use will be identical to those used for cocaine use (described above). 
 
 
4) Other Secondary Outcome Analyses:  Other secondary outcomes are reinforcement measures, 
such as the drug vs. money relative reinforcing potency scale, the Snaith-Hamilton Pleasure scale, as well 
as time engaging in non-drug-related activities and changes in neurocognitive performance.  These 
measures will be collected at baseline and throughout the study.  Analyses will be the same as those 
described for cocaine (GEE with medication group X time as factors).  Participants receiving bupropion are 
hypothesized to find non-drug activities to be more reinforcing than participants receiving placebo, and to 
engage in more of them.   
          5) Exploratory mediation analysis.  Measures collected at baseline including demographic 
characteristics, intake drug use severity, non-drug reinforcement, non-drug activities and neurocognitive 
performance will be examined separately to determine whether any predicts outcome independently of 
treatment. Next, we will add each of these measures to the models that assessed treatment effect, used 
for primary outcome analyses.  If the treatment effect becomes diminished by addition of a third variable, 
this will be considered preliminary evidence that the third variable may mediate the effect of the treatment.   
7. 
Risks 
a. Medical risks, listing all procedures, their major and minor risks and expected frequency. 
b. Steps taken to minimize the risks. 
c. Plan for reporting unanticipated problems or study deviations. 
d. Legal risks such as the risks that would be associated with breach of confidentiality. 
e. Financial risks to the participants. 
 
Bupropion XL is an FDA-approved antidepressant and smoking cessation pharmacotherapy and will be 
used in accordance with the prescription labeling instructions during this study.  The extended release 
(XL) preparation allows for once-daily dosing and thus improved adherence.  The medication will be 
titrated to an oral dose of 300 mg after 3 days at 150 mg daily.  With a half-life of 21 hours, steady state is 


 
 
JHMIRB eFormA  01 
Version 7 Dated:   01/2016 
 
Page 13 of 19 
 
reached after 8 days.  Methadone maintenance is a long-standing and effective usual care treatment for 
opioid dependence but does not directly impact the concurrent use of stimulants alcohol or other drugs. 
 
Risks associated with Bupropion XL side-effects 
Major risks of bupropion are summarized below; a complete list of potential side-effects is included 
in the consent form. 
 Allergic reactions.  Participants may experience allergic reactions to bupropion characterized by a 
rash, itching, swelling of the face, mouth, and throat.  Allergic reactions are rare but can be life-threatening 
and can cause trouble breathing (anaphylactic reaction).  Participants will be informed of this risk and 
instructed to stop taking the study medication and immediately contact medical staff if they experience any 
swelling or tingling in the mouth, develop a rash, or observe swelling, redness and/or peeling of the skin.   
Seizures.  The most relevant risk of bupropion is dose-dependent seizures, especially at doses 
higher than those proposed for this study (e.g. 450 mg daily).  Bupropion is contra-indicated in patients 
with a seizure disorder, in those taking other medications containing bupropion, those taking monoamine 
oxidase A inhibitors (MOA-AI, e.g., phenelzine, risk of hypertensive crisis due to enhanced norepinephrine 
release), and those undergoing abrupt cessation of alcohol or sedative-hypnotic medications.  These risks 
are managed by appropriate exclusion criteria and close medical monitoring described below. 
Cardiovascular effects. While generally safe for use even in people with cardiovascular disease, 
review of the literature suggests that bupropion may increase blood pressure slightly. 
Other side-effects and drug accumulation.  Other side-effects associated with Bupropion XL 
include anxiety, agitation, insomnia, vivid or abnormal dreams, and weight loss.  Less common side-
effects include headache, hypertension, constipation, flatulence, nausea.  All of these will be monitored 
during the study.  Drug accumulation can occur in cases of severe liver disease and renal insufficiency.  
Patients with transaminases > 3 x ULN and an eGFR < 30 mL/min are excluded from participation.  
Neuropsychiatric risks: The risk of suicidal thinking and behaviors, including completed suicide has 
been associated with antidepressants especially in children, adolescents, and young adults (< 25 yrs). The 
population targeted in this study may include young adults.  While the incidence of neuropsychiatric 
symptoms among patients taking bupropion is of serious concern, it is expected to be rare.  All participants 
will be closely monitored for any changes in mood, thought disturbance or agitation. 
Potential drug-drug interactions:  There is a general risk that Bupropion might have an adverse 
reaction with other medications, including methadone.  The main causes of drug-drug interactions with 
bupropion are due to induction or inhibition of CYP2B6 dependent enzymatic pathways and potentiation of 
norepinephrine availability by MAO-A inhibitors.  
Alcohol interaction.  Bupropion may decrease tolerance for alcohol and high alcohol intake may 
enhance metabolism of bupropion through Interaction with CYP2B6 dependent enzymatic pathways.  
Drug interactions are also found with ritonavir, nelfinavir and efavirenz, Highly Active Antiretroviral Therapy 
drugs (HAART), with a reduction in the activity of HAART and/or a reduction in bupropion concentration 
(Robertson SM et al, 2008).  Pre-clinical studies demonstrate acute exacerbation of bupropion toxicity by 
the non-selective MAOI phenelzine, most likely due to increase in norepinephrine release mediated by 
MAO-A.  These potential interactions are handled by excluding participants taking HAART medications or 
MAO inhibitors and by monitoring alcohol intake. 
 Methadone interaction.  Bupropion is unlikely to influence methadone metabolism: five studies of 
bupropion in methadone maintenance context showed no adverse reactions as a result of bupropion 
administration in conjunction with methadone and/or cocaine use (Poling et al., 2006 & 2007; Margolin et 
al., 1990 &1995, Levin FR et al., 2006). 
 
Risks associated with methadone maintenance 
This study will not be experimentally manipulating methadone doses and usual clinic policies and medical 
oversight will determine methadone doses.  Methadone maintenance is associated with some risks 
including over sedation and QT prolongation.  Any complaints of over-sedation will be evaluated by 
medical staff and methadone dose adjusted accordingly. 
 
Other study-related risks 


 
 
JHMIRB eFormA  01 
Version 7 Dated:   01/2016 
 
Page 14 of 19 
 
Diversion of study medication    
Take-home doses of Bupropion XL will be provided for days when patients are given take-home 
(TH) methadone medication according to clinic policy.  These will be for the most part single day TH on 
holidays, and for patients’ unforeseeable emergencies.  There is a small potential risk that study 
participants will divert or attempt to abuse the medication.  However, bupropion is a Schedule V 
medication and is not associated with significant abuse liability.  The limited take-home dosing and low 
abuse potential pose minimal risk of diversion. 
Continued abuse of illicit drugs   
 
Many participants who are enrolled in MM continue to abuse illicit drugs, and continued cocaine 
abuse is the targeted behavior of this study. Although there is no specific pharmacological risk of using 
cocaine and Bupropion concurrently, use of cocaine (or other illicit drugs) while enrolled in MM treatment 
is strongly discouraged and will be addressed by counselors during the study.  Bupropion could affect the 
rate of cocaine and other drug use and this will be monitored as part of the study.  Money or tangible 
goods earned in the contingency management program could supply funds for drug purchase.  This is no 
different from the danger associated with funds secured in any other fashion.  However, the process is 
self-limiting in contingency management since submission of a positive urine test immediately stops the 
dispersal of incentive payments.  
 
Removal to controlled environment  
 
Participants may experience a gap in research participation due to a period of non study-related 
hospitalization or incarceration.  These individuals may be able to re-enter the research.  However, such 
events will be handled on an individual basis according to best clinical judgment, and will take into account 
the safety and tolerability of inducting the participant back onto the study medication, the ability of the 
participant to resume reasonable compliance with the study requirements, and any marked changes in 
baseline cocaine use following the incident.  
 
Pregnancy  
 
There is a possibility that female participants may become pregnant while enrolled in the study and 
taking methadone and bupropion. Methadone is approved for use among pregnant women.while 
bupropion XL has been assigned to pregnancy category C where potential risks must be balanced by 
potential benefits in prescribing the medication.  Urine pregnancy tests will be administered at 6-week 
intervals during the study as part of the health assessment.  Study participation will be stopped for any 
woman who becomes pregnant.  
 
 
Legal risks: Breach of confidentiality 
Although staff members are highly trained to maintain participant confidentiality, there is always a 
risk that some of the confidential information collected could be revealed to people who are not involved in 
the research study. This could be embarrassing or risky to the participant and confidentiality breaches are 
considered to be very serious and are guarded against by standard precautions that include using only 
study ID’s on CRF’s and in data bases, using adequate password protection for data stored on computers 
and keeping identifying information (e.g. consent forms and PHI) in locked cabinets accessible only to 
research staff,   
 
Financial risks.  Participants who earn more than $600 in the study may have this income reported 
to the IRS (pending IRB approval of an exception for drug abuse-related research at the BPRU). 
 
 
Risks Management 
Risks inherent in exposure to the study medication, Bupropion XL, are managed first by application of 
appropriate study exclusion criteria that minimize risk, second by on-going in-person monitoring of study 
participants by methadone nursing and/or research staff and third by periodic administration of 
questionnaires that address changes in mood and suicidal ideations including assessment 1-2 weeks after 
starting study medication, which is a critical time for emergence of neuropsychiatric symptoms.  
Participants will be evaluated during the 6-week baseline phase of the protocol for excessive alcohol or 
sedative use. If medical staff judges that continued use of alcohol or sedatives is unsafe for interaction 
with bupropion, the individuals study participation will be terminated prior to randomization.   Blood 
pressure will be monitored at baseline, 1-2 weeks after medication starts and at 6-week intervals 


 
 
JHMIRB eFormA  01 
Version 7 Dated:   01/2016 
 
Page 15 of 19 
 
thereafter. Blood pressure criteria for medication adjustment or discontinuation would be as per clinical 
guidelines, i.e, BP > 140/90.  Naturally, we will also be alert to any other cardiovascular adverse events as 
well with clinical judgment being used to determine dose adjustment or medication discontinuation.     
 
In addition, study participants will receive periodic (e.g. every 6 weeks) assessment, for the presence of 
inter current health problems and for new concurrent medications that may pose a risk of drug-drug 
interactions.  No specific laboratory monitoring is recommended for patients on bupropion. Participants will 
not be allowed to take any other antidepressants while they are on the study and will be discharged from 
the study if they need to begin taking any excluded medications that pose a risk of drug-drug interaction.  
 
Experienced research, counseling, nursing, and medical staff will be readily available on-site as needed to 
assess and manage AE’s and SAE’s and research staff will be trained to report any responses indicating 
risk to medical and/or nursing personnel immediately for review and follow-up. Medical staff will evaluate 
participants who report clinically significant side effects possibly related to Bupropion (e.g., headache, 
agitation, insomnia) or who experience neuropsychiatric symptoms (e.g. depression, agitation).  A code to 
break the drug blinds is available 24/7 if needed in response to a medical emergency.  A participant may 
be put on close monitoring and/or referred for treatment if warranted in the judgment of medical staff.  A 
participant may also be promptly withdrawn from the study protocol if medical staff indicates it is in the 
best interest of the patient.  In all cases of persistent complaints, referral or study withdrawal, the case will 
be followed by medical staff until the complaint is resolved and the incident will be fully documented in 
study records and reported to IRB and NIDA.  
 
Responsibility for monitoring data and safety during this clinical trial resides with the Principal Investigator 
(PI) Dr. Dunn and co-investigator Dr. Umbricht, M.D.  AE’s and SAE’s are generally discovered through 
careful and frequent monitoring of participants by research and clinical staff using open-ended questions 
about how the participant has been feeling recently.  Any complaint is probed for information about 
frequency, duration and severity, coded on a side-effects checklist and described in a written summary 
report.  The Principal Investigator coordinates the preparation of semi-annual summary reports on the 
prevalence of side effects and adverse events observed during the course of the study.  These reports will 
be provided annually to the local IRB and to the NIDA Program Official with the annual progress report.  
The PI will also be responsible for promptly notifying in writing the local Institutional Review Board if a 
serious adverse event (SAE) occurs.  A SAE is defined as either: death; a life-threatening occurrence; 
hospitalization; new onset significant medical disorder; or significant exacerbation of an existing medical 
disorder.  
 
In addition an independent panel of consultants will be contracted for bi-annual review of the risks-benefits 
ratio of the study.  At mid-point during enrollment (when 100 randomized participants have completed the 
study) this panel will be provided with reports of adverse events and with participant outcome data (urine 
sample results) by unlabeled medication groups (A vs. B), as a function of study assignment (relapse 
prevention vs abstinence initiation).  This information will be used to assess whether the risks reported are 
considered to be of unusual magnitude or frequency across any specific groups and to determine whether 
the study should be ended prematurely due to participant safety concerns.  It is unlikely that such a small 
study would be interrupted because of an uneven distribution of adverse events experienced by any one 
group, however we will ensure that a qualified panel of reviewers makes this decision.   
 
9. Benefits 
a. 
Description of the probable benefits for the participant and for society. 
 
Study participation will directly benefit participants by providing them with methadone maintenance for 
opioid dependence, with increased urine monitoring beyond that available in usual care and with 
contingency management that is likely to reduce the amount of cocaine they use.  
 


 
 
JHMIRB eFormA  01 
Version 7 Dated:   01/2016 
 
Page 16 of 19 
 
The study will provide important information about the efficacy of bupropion XL for reducing cocaine use in 
the context of methadone maintenance and background contingency management. The results of this 
study will provide valuable scientific information regarding the effects of dopamine systems activation on 
the saliency of non-drug monetary and non-monetary reinforcers as alternative to drug reinforcers.  Study 
findings could also have direct clinical application for combined behavioral and pharmacological treatment 
of cocaine dependence should the hypotheses be borne out.  
 
10. Payment and Remuneration 
Detail compensation for participants including possible total compensation, proposed bonus, and 
any proposed reductions or penalties for not completing the protocol. 
 
Each participant can earn $50 for screening, $210 for 6 longer assessment visits, and up to $688 in 
abstinence-contingent incentives based on cocaine negative urine screens for a total of $948 maximum 
earnings per participant. Participants can also earn Baltimore City Bus Tokens or be offered other 
incentives for attendance and/or other study related activities. There are no completion bonuses.  Partial 
payment for study non-completers would be disbursed based on study assessments completed and 
contingent incentives earned.  
 
11. Costs 
a. 
Detail costs of study procedure(s) or drug (s) or substance(s) to participants and identify 
who will pay for them. 
 
Participants may be required to pay treatment costs according to policies of the clinical performance site.  
All research-related costs including study medication and placebo, urine testing and abstinence incentive 
costs will be supported by the research grant. Any up-front fees associated with new participants entering 
ATS methadone treatment will be covered by the study. 
 
Literature cited 
 
American Psychiatric Association. (2013). Diagnostic and statistical manual of mental disorders (5th ed.). 
Arlington, VA: American Psychiatric Publishing. 
 
Bisaga, A, Aharonovich, E, Cheng, WY, Levin, FR, Mariani, JJ, Raby, WN, Nunes, EV. A placebo-
controlled trial of memantine for cocaine dependence with high-value voucher incentives during a pre-
randomization lead-in period.  Drug Alcohol Depend, 2010 111: 97-104. PMCID: PMC2930076 
 
Darke S, Hall W, Heather N, Ward J, Wodak A. The reliability and validity of a secale to measure HIV risk-
taking behaviour among intravenous drug users. AIDS, 1991; 5:181-185.   
 
Donny EC, Bigelow GE, Walsh SL. Choosing to take cocaine in the human laboratory: Effects of cocaine 
dose, inter-choice interval, and magnitude of alternative reinforcement. Drug Alcohol Depend. 2003 69(3): 
289-301. 
  
Donny EC, Bigelow GE, Walsh SL. Assessing the initiation of cocaine self-administration in humans during 
abstinence: Effects of dose, alternative reinforcement, and priming. Psychopharmacology. 2004 172(3): 
316-323.  
 
Dutra, L, Stathopoulou, G, Basden, SL, Leyro, TM, Powers, MB, Otto, MW. A meta-analytic review of 
psychosocial interventions for substance use disorders.  Am J Psychiatry. 2008 165: 179-87. 
 
Elkashef, AM, Rawson, Ra, Anderson, AL, Li, SH, Holmes, T, Smith, EV, Chiang, N,  Kahn, R, Vocci, F, 
Ling, W, Pearce, VJ, McCann, M, Campbell, J, Gorodetzky, C, Haning, W, Carlton, B, Mawhinney, J, 
Weiss, D (2008) Bupropion for the treatment of methamphetamine dependence.  


 
 
JHMIRB eFormA  01 
Version 7 Dated:   01/2016 
 
Page 17 of 19 
 
Neuropsychopharmacology, 33, 1162-70.    
 
Epstein JN, Erkanli A, Conners CK, Klaric J, Costello JE, Angold A. Relations between continuous 
performance test performance measures and ADHD behaviors. Journal of Abnormal Child Psychology. 
2002; 31(5):543-554. 
 
Epstein LH, Richards JB, Saad FG, Paluch RA, Roemmich JN, Lerman C. Comparison between two 
measures of delay discounting in smokers. Experimental and Clinical Psychopharmacology. 2003; 
11(2):131-138. 
 
Gray, KM, Carpenter, MJ, Baker, NL, Hartwell, KJ, Lewis, AL, Hiott, DW, Deas, D, Upadhyaya, HP. 
Bupropion SR and contingency management for adolescent smoking cessation.  J Subst Abuse Treat. 
2010 40: 77-86. PMCID: PMC2997899 
 
Griffiths, RR, Troisi, JR, Silverman, K, Mumford, GK (1993)  Multiple-choice procedure: an efficient 
approach for investigating drug reinforcement in humans.  Behavioral Pharmacology, 4, 3-13. 
 
Heatherton TF, Kozlowski LT, Frecker RC, Fagerström KO. The Fagerström Test for Nicotine 
Dependence: a revision of the Fagerström Tolerance Questionnaire. British Journal of Addiction (1991); 
86:1119-1127. 
 
Hedden, SL, Woolson, RF, Carter, RE, Palesch Y, Upadhyaya HP, Malcolm RJ. The impact of loss to 
follow-up on hypothesis tests of the treatment effect for several different statistical methods in substance 
abuse clinical trials.  J Subst Abuse Treat. 2009 37: 54-63. PMCID: PMC2707817 
 
Jones, HE, Johnson, RE, Bigelow, GE, Silverman, K, Mudric, T, Strain, EC. Safety and efficacy of l-
tryptophan and behavioral incentives for treatment of cocaine dependence: A randomized clinical trial.  Am 
J Addict. 2004 13: 421-37.  
 
Juliano, L.M., Donny, E.C., Houtsmuller, E.J., & Stitzer, M.L.  Experimental evidence for a casual 
relationship between smoking lapse and relapse.  J Abnorm Psychol. 2006 115: 166-173.  
 
Kosten, T, Oliveto, A, Feingold, A, Poling, J, Sevarino, K, McCance-Katz, E, Stine, S, Gonzalez, G, 
Gonsai, K . Desipramine and contingency management for cocaine and opiate dependence in 
buprenorphine maintained patients.  Drug Alcohol Depend. 2003 70: 315-25. 
 
Margolin, A, Kosten, Tr, Avants, K, Wilkins, J, Ling, W, Beckson, M, Arndt, IO, Cornish, J, Ascher, JA, Li, 
SH, Bridge, P. A multicenter trial of bupropion for cocaine dependence in methadone-maintained patients.  
Drug Alcohol Depend. 1995 40: 125-131. 
 
Martinez, D, Carpenter, KM, Liu, F, Slifstein, M, Broft, A, Friedman, AC, Kumar, D, Heertum, RV, Kleber, 
HD, Nunes, E. Imaging dopamine transmission in cocaine dependence: Link between neurochemistry and 
response to treatment.  Am J Psychiatry, 2011 168: 634-41. 
 
McCann, DJ, Li, SH (2012) A novel, nonbinary evaluation of success and failure reveals bupropion 
efficacy vs methamphetamine dependence: Re-analysis of a multi site trial . CNS Neuroscience & 
Therapeutics, 18, 414-18. 
Mintzer MZ, Stitzer ML. Cognitive impairment in methadone maintenance patients. Drug Alcohol Depend. 
2002 Jun 1; 67(1): 41-51.  
Moeller, FG, Schmitz, JM, Steinberg, JL, Green, CM, Reist, C, Lai, LY, Swann, AC, Grabowski, J. 
Citalopram combined with behavioral therapy reduces cocaine use: A double-blind, placebo-controlled 
trial. Am J Drug  Alcohol Abuse. 2007 33: 367-78. 


 
 
JHMIRB eFormA  01 
Version 7 Dated:   01/2016 
 
Page 18 of 19 
 
 
Nakonezny PA, Crmody TJ, Morris DW, Kurian BT, Trivedi MH. Psychometric evaluation of the Snaith-
Hamilton pleasure scale in adult outpatients with major depressive disorder.  Int Clin Psychopharmacol. 
2010 25: 328-333. PMCID: PMC2957191 
 
Patton JH, Stanford MS, Barratt ES. Factor structure of the barratt impulsiveness scale. Journal of Clinical 
Psychology. 1995; 51(6)768-774. 
 
Peirce JM, Petry NM, Stitzer ML, Blaine J, Kellogg S, Satterfield F, Schwartz M, Kraznansky J, Pencer E, 
Silva-Vasquez L, Kirby KC, Royer-Malvestuto C, Roll JM, Cohen A, Copersino ML, Kolodner K, Li R. 
Effects of lower-cost incentives on stimulant abstinence in methadone maintenance treatment.  Arch Gen 
Psychiatry. 2006 63: 201-208. 
 
Petry NM, Peirce JM, Stitzer ML, Blaine J, Roll JM, Cohen A, Obert J, Killeen T, Saladin ME, Cowell M, 
Kirby KC, Sterling R, Royer-Malvestuto C, Hamilton J, Booth RE, Macdonald M, Liebert M, Rader L, Burns 
R, DiMaria J, Copersino M, Stabile PQ, Kolodner K, Li R. Effect of prize-based incentives on outcomes in 
stimulant abusers in outpatient psychosocial treatment programs: a national drug abuse treatment clinical 
trials network study.  Arch Gen Psychiatry. 2005 62: 1148-1156. 
Poling J, Oliveto A, Petry N, Sofuoglu M, Gonsai K, Gonzalez G, Martell B, Kosten TR. Six-month trial of 
bupropion with contingency management for cocaine dependence in a methadone-maintained population. 
Arch Gen Psychiatry. 2006 Feb; 63(2): 219-228.  
Poling J, Pruzinsky R, Kosten TR, Gonsai K, Sofuoglu M, Gonzalez G, Oliveto A. Clinical efficacy of 
citalopram alone or augmented with bupropion in methadone-stabilized patients. Am J Addict. 2007 May-
Jun; 16(3): 187-194.  
Rush, A. J., Trivedi, M. H., Ibrahim, H. M., Carmody, T. J., Arnow, B., Klein, D. N., et al. (2003). The 16-
item quick inventory of depressive symptomatology (QIDS), clinician rating (QIDS–C), and self-report 
(QIDS–SR): A psychometric evaluation in patients with chronic major depression. Biological Psychiatry, 
54(5), 573–583. 
Sheehan, D et al. (1998) the MINI-International Neuropsychiatric Interview (M.I.N.I.): Development and 
validation of a structured diagnostic psychiatric interview for DSM-IV and ICD-10.  Journal of Clinical 
Psychiatry, 59, suppl 20: 22-33.  
Schmitz, JM, Mooney, ME, Moeller, FG, Stotts, AL, Green, C, Grabowski, J. Levodopa pharmacotherapy 
for cocaine dependence: Choosing the optimal behavioral therapy platform.  Drug Alcohol Depend. 2008 
94: 142-50. PMCID: PMC2293271 
Schmitz JM, Rhoades HM, Elk R, Creson D, Hussein I, Grabowski J. Medication take-home doses and 
contingency management.  Exp Clin Psychopharmacol. 1998 6: 162-68.  
 
Shoptaw S, Heinzerling KG, Rotheram-Fuller E, Kao UH, Wang PC, Bholat MA, Ling W. Bupropion 
hydrochloide versus placebo in combination with cognitive behavioral therapy for the treatment of cocaine 
abuse/dependence.  J Addict Dis. 2008a  27: 13-23. 
 
Shoptaw S, Heinzerling KG, Rotheram-Fuller E, Steward T, Wang J, Swanson AN, De La Garza R, 
Newton T. Ling W. Randomized, placebo-controlled trial of bupropion for the treatment of 
methamphetamine dependence.  Drug Alcohol Depend. 2008b 96: 222-232. 
 
Shoptaw S, Huber A, Peck J, Yang X, Liu J, Dang J, Roll J, Shapiro B, Rotheram-Fuller E, Ling W.  
Randomized placebo-controlled trial of sertraline and contingency management for the treatment of 
methamphetamine dependence.  Drug Alcohol Depend. 2006 85: 12-18. 
 
Silverman K, Higgins ST, Brooner R, Montoya ID, Cone EJ, Schuster CR, Preston KL. Sustained cocaine 


 
 
JHMIRB eFormA  01 
Version 7 Dated:   01/2016 
 
Page 19 of 19 
 
abstinence in methadone maintenance patients through voucher-based reinforcement therapy.  Arch Gen 
Psychiatry. 1996 53: 409-415.  
 
Silverman K, Robles E, Mudric T, Bigelow GE, Stitzer ML. A randomized trial of long-term reinforcement of 
cocaine abstinence in methadone –maintained patients who inject drugs.  J Consult Clin Psychol. 2004 
72: 839-54. 
 
Silverman K, Wong CJ, Umbricht-Schneiter A, Montoya ID, Schuster CR, Preston KL. Broad beneficial 
effects of cocaine abstinence reinforcement among methadone patients. J Consult Clin Psychol. 1998 66: 
811-24. 
Stoops, WW, Lile, JA, Glaser, PE, Hays, LR, Rush, CR (2012) Influence of acute bupropion pre-treatment 
on the effects of intranasal cocaine.  Addiction, 107, 1140-47. 
Stitzer, M.L. and Walsh, S.L. (1997) Psychostimulant abuse: The case for combined behavioral and 
pharmacological treatments.  Pharmacology, Biochemistry & Behavior, 57, 457-470. 
 
Winstanley EL, Bigelow GE, Silverman K, Johnson RE, Strain EC. A randomized controlled trial of 
fluoxetine in the treatment of cocaine dependence among methadone-maintained patients. J Subst Abuse 
Treat. 2011 40(3): 255-264. PMCID: PMC3078567 
 
 

ICF_001.pdf: 
 
 
JHMIRB eFormA  01 
Version 7 Dated:   01/2016 
 
Page 1 of 19 
 
Official Title: Medication Enhanced CM for Cocaine 
Dependence 
 
NCA Number: 02111798 
 
Document Date: February 11, 2019  


 
 Approved February 11, 2019 
Date: February 11, 2019 
Principal Investigator: Kelly Dunn, Ph.D. 
Application No.: NA_00090062 
 
Page 1 of 9 
Combined Informed Consent/Authorization June 2015 Version 15 
 
 
 
 
 
 
 
 
 
RESEARCH PARTICIPANT INFORMED CONSENT AND PRIVACY 
AUTHORIZATION FORM 
 
Protocol Title: 
 
Medication Enhanced CM for Cocaine Dependence 
 
Application No.: 
NA_00090062 
 
Sponsor: 
National Institute on Drug Abuse 
 
Principal Investigator: Kelly Dunn, Ph.D. 
Behavioral Pharmacology Research Unit 
Johns Hopkins Bayview Medical Center 
5510 Nathan Shock Drive 
Baltimore, MD 21224 
410 550-2254 (phone) 
410 550-0030 (fax)  
  
1. 
What you should know about this study: 
• You are being asked to join a research study. This consent form explains the research study and your 
part in it. Please read it carefully and take as much time as you need. Ask your study doctor or the 
study team to explain any words or information that you do not understand. 
• You are a volunteer.  If you join the study, you can change your mind later.  There will be no penalty 
or loss of benefits if you decide to quit the study.   
• During the study, we will tell you if we learn any new information that might affect whether you 
wish to continue to participate. 
• If we think your participation in this study may affect your clinical care, information about your 
study participation will be included in your medical record, which is used throughout Johns Hopkins.   
Doctors outside of Johns Hopkins may not have access to this information.  You can ask the research 
team to send this information to any of your doctors. 
• When Johns Hopkins is used in this consent form, it includes The Johns Hopkins University, The 
Johns Hopkins Hospital, Johns Hopkins Bayview Medical Center, Howard County General Hospital, 
Johns Hopkins Community Physicians, Suburban Hospital, Sibley Memorial Hospital and All 
Children’s Hospital.  
• Biospecimens will be collected in this study.  Biospecimens may include any of the following: 
blood, tissue, saliva, urine, bone marrow, cells, etc.  Most biospecimens contain DNA, which is the 
genetic code for each person. 
If you are using Epic for this study, fax a copy 
of the signed consent form to 410-367-7382. 
 
 
 
 
 
Patient I.D. plate 
 
 
 
 
                                
          
 
 
 
 
 


 
 Approved February 11, 2019 
Date: February 11, 2019 
Principal Investigator: Kelly Dunn, Ph.D. 
Application No.: NA_00090062 
 
Page 2 of 9 
Combined Informed Consent/Authorization June 2015 Version 15 
• A description of this clinical trial will be available on http://www.ClinicalTrials.gov, as required by 
U.S. Law.  This Web site will not include information that can identify you. At most, the Web site 
will include a summary of the results. You can search this Web site at any time.  
• If you would like to review the information for this study, or a summary of the results, ask the study 
team doctor for the ClinicalTrials.gov study registration number. 
 
2. 
Why is this research being done? 
This research is being done to find out whether a particular medication called bupropion can help 
participants when they try to reduce or stop cocaine use.   The results may identify new strategies for 
helping people stop using cocaine. 
 
Bupropion is approved by the Food and Drug Administration (FDA) for the treatment of Major 
Depressive Disorder.  It is not approved for use in the treatment of cocaine dependence and is still being 
tested in research studies. 
   
Some methadone maintenance patients from participating methadone clinics as well as community 
members willing to enter methadone treatment who qualify for the study may join. 
 
How many people will be in this study? 
A total of 150 people are expected to participate. 
 
3. 
What will happen if you join this study? 
If you agree to be in this study, we will ask you first to complete a screening visit.  Signing the consent 
does NOT mean that you are automatically invited to participate in the whole study.  This will depend 
on whether you are eligible based on information from the screening visit.    
 
Screening Visit 
If you agree to participate in the screening session after signing this consent form, you will be asked to 
do the things listed below.  The screening visit usually takes about 1 1/2 to 2 hours.   
 
• We will ask you questions about your medical history, medication use, current and past drug use, 
and your mood.   
 
• We will measure your blood pressure. We will take a blood sample from your arm for laboratory 
analyses that tell us how well your liver and kidneys are working. 
 
• We will ask you to give us a sample of your urine that will tell us whether you have recently used 
illicit drugs.  If these tests suggest that this study may not be right for you, we may ask you to come 
back a second time for urine testing to make sure.  
 
• If you are a woman, we will do a urine pregnancy test. Women who are pregnant will not be able to 
participate in the study.  
 
Your participation in this screening is voluntary, which means that you can leave at any time if you lose 
interest or are uncomfortable.  
 
After we finish the screening and get the laboratory results, we will decide whether you are eligible for 
the study.   If you are eligible, a research assistant will contact you and schedule your first (baseline) 
study visit.   In the event that the Principal Investigator and/or medical staff decide later that this study is 
 


 
 Approved February 11, 2019 
Date: February 11, 2019 
Principal Investigator: Kelly Dunn, Ph.D. 
Application No.: NA_00090062 
 
Page 3 of 9 
Combined Informed Consent/Authorization June 2015 Version 15 
not right for you, the research assistant will contact you to tell you about this. 
 
You will receive up to $50 in gift cards for completing this screening session, even if you are not 
eligible for the study or decide that you do not want to participate.   
 
Daily visits to the methadone clinic 
If you are eligible and join the study, you will be expected to visit your methadone clinic daily as usual 
to swallow your regular methadone dose, unless you have a take-home privilege.   
 
Study medication 
After the study starts, you will also be given a capsule to swallow daily. You will not know what is in 
the capsule; it will be either active study medication or placebo.  A placebo is an inactive substance that 
looks like the study drug, but contains no active drug.  The daily capsules will continue for the entire 30-
week study and may be swallowed at the methadone clinic along with your methadone dose, at the 
BPRU research office or at home.  
 
 
Study Visits: 3 times per week brief visits 
You will be asked to make a brief visit to the research staff office located at your methadone clinic for 
ATS, REACH, Glenwood Life Center or at the BPRU for others 3 times per week for 6-7 months to 
leave a urine sample and report about your recent drug use. 
 
 
Study visits: 6 longer visits 
You will also be scheduled for 6 longer assessment sessions at study weeks 1 (baseline), 6, 12, 18, 24, 
and 30.  At these sessions, you will give urine samples, complete questionnaires and interviews and take 
a series of cognitive tests on a computer.  These longer visits may take up to 3 hours.  You can earn up 
to $210 for completing all study assessments. 
 
Abstinence incentives 
Throughout this study you will have the chance to earn points worth money for giving cocaine-negative 
urine samples.  The total amount that you could earn during the study for cocaine negative urines is 
$688.  We will explain later the details of how points are earned. Maximum earnings depend on giving 
all requested urine samples and achieving continuous abstinence from cocaine; the longer you are 
abstinent, the more money you will earn. 
 
The money you earn for cocaine negative urines can be used to buy goods at local stores of your 
choosing. Money can be used as soon as it is earned or saved for larger purchases later. 
 
 
 
 
 
 
How long will you be in the study? 
You will be in this study for 30 weeks (a little over 6 months). 
 
4. 
What are the risks or discomforts of the study? 
1) Screening and Baseline Procedures. The screening and baseline interviews will include questions 
about your medical and psychiatric histories, drug and alcohol use, urine tests of drug use and 
pregnancy, and questionnaires about your mood.  Answering personal questions could make you 
uncomfortable.  You may get tired or bored when we are asking you questions or you are completing 
questionnaires. You do not have to answer any question you do not want to answer. There is no 
discomfort from the urine tests.  The cognitive tests could make you feel frustrated if you find them 
difficult to accomplish.  
 
2) Blood Pressure and Blood Draws. The blood pressure cuff and/or the needle stick needed to draw 


 
 Approved February 11, 2019 
Date: February 11, 2019 
Principal Investigator: Kelly Dunn, Ph.D. 
Application No.: NA_00090062 
 
Page 4 of 9 
Combined Informed Consent/Authorization June 2015 Version 15 
blood may cause a small amount of discomfort.  The medical tests could reveal that you have abnormal 
blood pressure or something abnormal with your heart, liver, or kidney function.  In this case, you may 
not be eligible to continue in the study and we would ask that you see your doctor. 
 
 
3) Medication side effects.     The most serious potential side-effect from the study medication is an 
allergic reaction.  If you get a rash, itching, swelling in your face, mouth, or throat, or have trouble 
breathing you should tell the research staff right away and stop taking the study medicine.  There is also 
a small risk that the research medicine could cause a seizure or convulsion.  Again, if anything like this 
happens to you, you should tell the research staff immediately and stop taking the medicine.  You will 
not be allowed to take any other anti-depressants while you are in the study.  If your doctor wants you to 
start an anti-depressant, you should discuss this with the research medical staff.   
 
There are many other side-effects that could happen from taking study medications.  These are listed 
below along with the percent of people who may experience each one.   
 
Common  
• Hypertension (high blood pressure) (2.5% to 4.3% ) 
• Tachyarrhythmia (abnormal heart rate) (10.8% ) 
• Pruritus (itching) (2% to 4% ) 
• Rash (3% to 5% ) 
• Urticaria (hives) (1% to 2% ) 
• Constipation (5% to 26% ) 
• Nausea (9% to 24% ) 
• Arthralgia (joint pain) (1% to 5% ) 
• Myalgia (muscle pain) (2% to 6% ) 
• Confusion (8.4% ) 
• Dizziness (6% to 22.3% ) 
• Headache (about 25% ) 
• Insomnia (sleeplessness) (11% to 40% ) 
• Tremor (2% to 21.1% ) 
• Tinnitus (hearing noises) (3% ) 
• Agitation (2% to 31.9% ) 
• Anxiety (3.1% to 8% ) 
• Hostile behavior (6% ) 
• Disorder of menstruation (5% ) 
• Pharyngitis (sore throat) (3% to 11% ) 
• Xerostomia (dry mouth) (10% to 27.6% ) 
 
Serious  
• Cardiac dysrhythmia (irregular heartbeat) (5.3% ) 
• Seizure (0.1% to 0.4% ) 
 
Other rare, but serious reactions include:  
• Anaphylaxis (severe allergic reaction) 
• Stevens-Johnson Syndrome (life-threatening skin condition) 
• Depression 
• Exacerbation (worsening of symptoms) 


 
 Approved February 11, 2019 
Date: February 11, 2019 
Principal Investigator: Kelly Dunn, Ph.D. 
Application No.: NA_00090062 
 
Page 5 of 9 
Combined Informed Consent/Authorization June 2015 Version 15 
• Mania 
• Psychotic disorder 
• Suicidal thoughts 
 
Additional Risks while taking the study drug: 
There have been reported increases in the risk of seizures when drinking alcohol while taking the study 
drug.  Additionally, taking the study drug with a history of an eating disorder (such as anorexia or 
bulimia) can also place you at increased risk of seizures. 
 
4) Stopping cocaine use.  You may experience temporary discomfort from stopping cocaine use with 
symptoms including lethargy, disturbed sleep, and poor appetite.  These symptoms should be gone in a 
week or two. 
 
5) Risk of placebo. There is the risk that you may not receive any benefit from the medication and that 
your cocaine use may worsen. 
 
6) Breach of Confidentiality.  One risk of the study is your loss of privacy if other people find out 
about interview answers, health information, or urine test results.  We do everything we can to protect 
your research information, as described in the Confidentiality section below. 
 
5. 
Are there risks related to pregnancy? 
Pregnant women will not be recruited at part of this study. Pregnancy tests will be given before a woman 
is allowed to be in the study and while she is in the study. If a woman becomes pregnant during the 
study, she will be excused from participation and referred to services at their methadone clinic or 
elsewhere.  
 
6. 
Are there benefits to being in the study? 
You will continue to receive standard methadone maintenance during this study, but your methadone 
treatment is controlled by your methadone clinic policies and is not part of the study.  You may benefit 
from the study by stopping or reducing your cocaine use. 
 
7. 
What are your options if you do not want to be in the study? 
If you decide not to join this study, other options are available.  You do not have to join this study to get 
treatment.  Other treatments include standard drug abuse treatment and counseling 
 
You do not have to join this study.  If you do not join, your care at Johns Hopkins will not be affected. 
 
8. 
Will it cost you anything to be in this study?   
No.  But if you don’t have Medicaid or insurance, you may be asked to pay for your methadone 
treatment according to the policies of your methadone clinic. Any up-front fees associated with new 
participants entering ATS methadone treatment will be covered by the study. 
 
9. 
Will you be paid if you join this study? 
The total possible amount of money that you can earn for this study is $948.  This includes $50 in gift 
cards for the screening session, $210 for completing the baseline and 5 other longer assessment sessions, 
and up to $688 for giving cocaine negative urines.  If you start but do not finish the study, you will be 
paid for the sessions that you have completed and for any incentive earnings.  You may also earn bus 
tokens or other incentives for completing a scheduled study visit.  
 


 
 Approved February 11, 2019 
Date: February 11, 2019 
Principal Investigator: Kelly Dunn, Ph.D. 
Application No.: NA_00090062 
 
Page 6 of 9 
Combined Informed Consent/Authorization June 2015 Version 15 
You may be required to provide your social security number to be paid for taking part in this study. 
Federal tax law requires that you report your research payments when you file your taxes. If your total 
payments from Johns Hopkins exceed $600 per year, Johns Hopkins will report these payments to the 
Internal Revenue Service and you will receive a 1099-MISC form from us. 
 
10. 
Can you leave the study early? 
• You can agree to be in the study now and change your mind later. 
• If you wish to stop, please tell us right away. 
• Leaving this study early will not stop you from getting regular medical care.  
 
If you leave the study early, Johns Hopkins may use or give out your health information that it has 
already collected if the information is needed for this study or any follow-up activities.  
 
11. 
Why might we take you out of the study early?  
The Principal Investigator also reserves the right to remove you from the study at any time. 
You may be taken out of the study if: 
• Staying in the study would be harmful. 
• You need treatment not allowed in the study. 
• You fail to follow instructions. 
• You become pregnant. 
• The study is cancelled. 
• There may be other reasons to take you out of the study that we do not know at this time.  
 
If you are taken out of the study early, Johns Hopkins may use or give out your health information that it 
has already collected if the information is needed for this study or any follow-up activities. 
 
12. 
How will your privacy be protected?  
We have rules to protect information about you.  Federal and state laws and the federal medical Privacy 
Rule also protect your privacy.  By signing this form you provide your permission, called your 
“authorization,” for the use and disclosure of information protected by the Privacy Rule. 
 
The research team working on the study will collect information about you.  This includes things learned 
from the procedures described in this consent form.  They may also collect other information including 
your name, address, date of birth, and information from your medical records (which may include 
information about HIV status, drug, alcohol or STD treatment, genetic test results, or mental health 
treatment). 
 
The research team will know your identity and that you are in the research study.  Other people at Johns 
Hopkins, particularly your doctors, may also see or give out your information. We make this information 
available to your doctors for your safety.    
 
People outside of Johns Hopkins may need to see or receive your information for this study.  Examples 
include government agencies (such as the Food and Drug Administration), safety monitors, other sites in 
the study and companies that sponsor the study.  
 
If you are in a cancer study that receives federal funding, the National Cancer Institute (NCI) now 
requires that we report identifiable information (such as, zip code) about your participation.  You may 
contact the NCI if you have questions about how this information is used.  
 


 
 Approved February 11, 2019 
Date: February 11, 2019 
Principal Investigator: Kelly Dunn, Ph.D. 
Application No.: NA_00090062 
 
Page 7 of 9 
Combined Informed Consent/Authorization June 2015 Version 15 
We cannot do this study without your authorization to use and give out your information.  You do not 
have to give us this authorization.  If you do not, then you may not join this study. 
 
We will use and disclose your information only as described in this form and in our Notice of Privacy 
Practices; however, people outside Johns Hopkins who receive your information may not be covered by 
this promise or by the federal Privacy Rule.  We try to make sure that everyone who needs to see your 
information keeps it confidential – but we cannot guarantee that your information will not be re-
disclosed. 
 
The use and disclosure of your information has no time limit. You may revoke (cancel) your permission 
to use and disclose your information at any time by notifying the Principal Investigator of this study by 
phone or in writing.  If you contact the Principal Investigator by phone, you must follow-up with a 
written request that includes the study number and your contact information.  The Principal 
Investigator’s name, address, phone and fax information are on page one of this consent form.  
 
If you do cancel your authorization to use and disclose your information, your part in this study will end 
and no further information about you will be collected. Your revocation (cancellation) would not affect 
information already collected in the study, or information we disclosed before you wrote to the Principal 
Investigator to cancel your authorization. 
 
13. 
Will the study require any of your other health care providers to share your health 
information with the researchers of this study? 
As a part of this study, the researchers may ask to see your health care records from your other health 
care providers.   
 
14. 
What if there is a Certificate of Confidentiality for this study?  
The National Institutes of Health has given us a Certificate of Confidentiality for this study.  This 
Certificate provides some additional protection for research information that identifies you. The 
Certificate allows us, in some circumstances, to refuse to give out information that could identify you as 
a research subject without your consent, when such information is sought in a federal, state, or local 
court or public agency action. Still, we may disclose identifying information about you if, for example, 
you need medical help. 
 
We may also disclose identifiable information about you as described in Section 12 of this form or in 
other cases. For example, the government may see your information if it audits us, and the research team 
will voluntarily comply with reporting requirements to the appropriate local or state authorities: 
 
• if they suspect abuse, neglect or abandonment of a child or vulnerable or dependent adult; 
• if certain diseases are present; and 
• if the team learns that you plan to harm someone. In this case, the team also may warn the person 
who is at risk. 
 
Even with this Certificate in place, you and your family members must continue to protect your own 
privacy.  If you voluntarily give your written consent for an insurer, employer, or lawyer to receive 
information about your participation in the research, then we may not use the Certificate to withhold this 
information. 
 
This Certificate does not mean the government approves or disapproves of this research project. 
 


 
 Approved February 11, 2019 
Date: February 11, 2019 
Principal Investigator: Kelly Dunn, Ph.D. 
Application No.: NA_00090062 
 
Page 8 of 9 
Combined Informed Consent/Authorization June 2015 Version 15 
15. 
What treatment costs will be paid if you are injured in this study?  
Johns Hopkins and the federal government do not have programs to pay you if you are hurt or have 
other bad results from being in the study. However, medical care at Johns Hopkins is open to you as it is 
to all sick or injured people.   
The costs for any treatment or hospital care you receive as the result of a study-related injury that are not 
covered by a health insurer will be billed to you. 
 
By signing this form you will not give up any rights you have to seek compensation for injury.  
 
16. 
What other things should you know about this research study? 
a. What is the Institutional Review Board (IRB) and how does it protect you?  
The Johns Hopkins Medicine IRB is made up of: 
• Doctors 
• Nurses 
• Ethicists 
• Non-scientists 
• and people from the local community.  
 
The IRB reviews human research studies. It protects the rights and welfare of the people taking part 
in those studies.  You may contact the IRB if you have questions about your rights as a participant or 
if you think you have not been treated fairly.  The IRB office number is 410-955-3008. You may 
also call this number for other questions, concerns or complaints about the research. 
 
When the Johns Hopkins School of Medicine Institutional Review Board (IRB) reviews a study at 
another site, that site (institution) is solely responsible for the safe conduct of the study and for 
following the protocol approved by the Johns Hopkins IRB.   
 
b. What do you do if you have questions about the study?    
Call the principal investigator, Dr. Kelly Dunn at 410-550-2254. If you wish, you may contact the 
principal investigator by letter or by fax.  The address and fax number are on page one of this 
consent form. If you cannot reach the principal investigator or wish to talk to someone else, call the 
IRB office at 410-955-3008.   
 
c. What should you do if you are injured or ill as a result of being in this study?  
If you think you are injured or ill because of this study, call Dr. Annie Umbricht, MD at 410 550-
1917 during regular office hours.  
 
If you have an urgent medical problem related to your taking part in this study, call the BPRU 
emergency line at 410- 550-0052 which is available at any time. 
 
d. What happens to Data and Biospecimens that are collected in the study?  
Johns Hopkins and our research partners work to understand and cure diseases. The biospecimens 
and/or data you provide are important to this effort. 
 
If you join this study, you should understand that you will not own your biospecimens or data, and 
should researchers use them to create a new product or idea, you will not benefit financially.  
 
With appropriate protections for privacy, Johns Hopkins may share your biospecimens and 
information with our research sponsors and partners.    


 
 Approved February 11, 2019 
Date: February 11, 2019 
Principal Investigator: Kelly Dunn, Ph.D. 
Application No.: NA_00090062 
 
Page 9 of 9 
Combined Informed Consent/Authorization June 2015 Version 15 
 
 
17. 
What does your signature on this consent form mean?  
Your signature on this form means that: You understand the information given to you in this form, you 
accept the provisions in the form and you agree to join the study. You will not give up any legal rights 
by signing this consent form.  
 
WE WILL GIVE YOU A COPY OF THIS SIGNED AND DATED CONSENT FORM 
 
 
________________________________________________________________________________________________________________________ 
Signature of Participant                                                                           (Print Name)                                                 
 
Date/Time  
 
 
________________________________________________________________________________________________________________________ 
Signature of Person Obtaining Consent                                                  (Print Name)                                               
 
Date/Time 
 
NOTE: A COPY OF THE SIGNED, DATED CONSENT FORM MUST BE KEPT BY THE PRINCIPAL INVESTIGATOR; 
A COPY MUST BE GIVEN TO THE PARTICIPANT; IF YOU ARE USING EPIC FOR THIS STUDY A COPY MUST BE 
FAXED TO 410-367-7382; IF YOU ARE NOT USING EPIC A COPY MUST BE PLACED IN THE PARTICIPANT’S 
MEDICAL RECORD (UNLESS NO MEDICAL RECORD EXISTS OR WILL BE CREATED).  
 
ONLY CONSENT FORMS THAT INCLUDE THE JOHNS HOPKINS MEDICINE LOGO CAN BE USED TO OBTAIN 
THE CONSENT OF RESEARCH PARTICIPANTS.