Extending Long-term Outcomes Through an Adaptive Aftercare Intervention
Phase: NA
Conditions: Cocaine Use Disorder, Contingency Management
Sponsor: UConn Health

 
Extending long-term outcomes through an adaptive aftercare intervention 
NCT02143063 
Protocol 
IRB Approval Version: 3/31/2020 

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Protocol:  Extending long-term outcomes through an adaptive aftercare intervention
Principal Investigator: Sheila Alessi, Ph.D.
Reinforcement interventions have pronounced effects on reducing cocaine use. We developed and 
evaluated a low-cost reinforcement intervention, systematically moving it through the Stages of development 
to dissemination and broad clinical implementation. In an ongoing project, reinforcement interventions are 
yielding benefits when reinforcers are provided at treatment initiation and for longer durations. However, less 
than half of patients remain engaged for 12 weeks with traditional reinforcement interventions, which require 
frequent attendance for monitoring and reinforcing abstinence. Interventions that extend into aftercare and 
that are acceptable to and efficacious in preventing long-term relapse are critically needed. 
      
Reinforcement interventions are efficacious during periods they are in effect, and pilot data show that 
variable interval (VI) reinforcement schedules, once behavior change occurs, hold potential for maintaining 
gains when administered infrequently. Assessing methods to extend benefits of these interventions is of 
paramount scientific and clinical concern. This study will evaluate a novel approach in which reinforcement 
frequency varies by patient performance. In this intervention, reinforcement will be available for 24 weeks, on 
a progressive VI schedule, that adapts according to patient status. Patients who maintain abstinence earn 
maximum reinforcers as infrequently as every three weeks on average, while frequency of monitoring and 
reinforcing abstinence will increase in those who relapse until abstinence is re-instated. 
 
 To test efficacy, 280 patients with cocaine use disorder will be randomly assigned to: standard care 
(SC), SC+traditional twice weekly reinforcement, or SC+adaptive VI reinforcement. Evaluations will be 
completed at baseline and throughout 18 months to assess objective and self-reported indices of drug use, 
psychosocial problems, and HIV risk behaviors. Primary hypotheses are (1) the adaptive VI reinforcement 
intervention will improve outcomes relative to standard care during the treatment period and throughout 
follow-up, and (2) the adaptive VI reinforcement intervention will improve outcomes relative to the traditional 
reinforcement system. This study will also evaluate the roles of cognitive control and treatment outcome. 
Patients with better cognitive control are expected to maintain longer durations of abstinence across 
conditions. If these measures differentially relate to outcomes across treatments, such results suggest the 
potential of pairing reinforcement interventions to individuals most likely to benefit from them; they may also 
indicate possible markers of response in a treatment-specific manner. If cognitive indices mediate treatment 
response, future studies can refine interventions to improve cognitive processes and long-term outcomes. 
Specific aims
Designed and tested using the NIH Stage Model of psychotherapy development (Onken et al., in press), 
reinforcement interventions hold great potential to improve drug abuse treatment outcomes. Community 
clinics are increasingly applying these interventions, but methods to maintain their benefits long-term are 
needed. Extending the effects of reinforcement interventions would be a major step forward in increasing 
the efficacy and acceptability of this approach. Traditional approaches toward reinforcement, requiring 
frequent clinic attendance, limit acceptability among both patients and providers, especially when applied over 
long durations. We have pilot data suggesting the efficacy of a gradually increasing variable interval (VI) 
reinforcement schedule in maintaining behavior gains. This study will evaluate this approach for improving 
short- and long-term drug use outcomes. It will also address potential cognitive mechanisms of action.
In total, 280 patients initiating treatment for cocaine use will be randomized to: standard care (SC), SC + 
traditional reinforcement, or SC + progressive variable interval (VI) reinforcement. The two reinforcement 
interventions will provide the same overall average maximum magnitudes of expected earnings. Patients in the 
traditional reinforcement condition will earn reinforcers twice weekly for submitting stimulant negative 
samples. Patients in the progressive VI reinforcement condition will earn reinforcers for providing cocaine-
negative urine samples according to an increasing VI schedule; monitoring and reinforcement will occur 
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relatively infrequently when abstinence is maintained but increase in frequency if drug use occurs. Cell phones 
will maintain contact with patients in all conditions to inform them of randomly selected urine testing days 
throughout a 24-week period to provide, for one of the first times, objective indicators of relapse following 
treatment cessation. All patients will complete cognitive assessments pre, mid and post-treatment. 
Primary study aims are to:
1. Determine the efficacy of an adaptive progressive VI reinforcement intervention for reducing cocaine use 
in the short- and long-term.The hypothesis is that patients assigned to the adaptive progressive VI 
reinforcement intervention will achieve longer periods of abstinence than patients in standard care during the 
period reinforcement is in effect (24 weeks). We will also evaluate how well this reinforcement intervention 
maintains benefits throughout follow-up (18 months). 
2. Compare the relative efficacy of adaptive progressive VI reinforcement to a traditional reinforcement 
intervention. Patients receiving adaptive progressive VI reinforcement are hypothesized to achieve greater 
during and post-treatment abstinence than those receiving traditional twice-weekly reinforcement. 
Secondary and exploratory aims of the study are to:
a. Evaluate relations between behavioral and measures of cognitive control and response to monetary 
rewards and treatment outcomes. Patients with better cognitive control are expected to achieve longer 
durations of abstinence, regardless of treatment assignment. Patients who are more sensitive to monetary 
rewards are expected to achieve longer duration of abstinence, particularly when assigned to a reinforcement 
intervention. We also expect that sensitivity to monetary rewards and cognitive control may increase among 
those who are assigned to a reinforcement intervention, and that changes in these processes may mediate 
drug use outcomes.
b. Assess the impact of reinforcement interventions on HIV risk and other outcomes. Compared to SC, 
reinforcement interventions are expected to reduce high risk sexual behaviors that spread infectious diseases. 
Reinforcement interventions are also hypothesized to decrease psychiatric symptoms and improve quality of 
life. Both short-term and long-term effects will be examined. Gender effects will also be explored. 
c. Estimate costs and cost-effectiveness. We will examine costs and cost-effectiveness of interventions and 
estimate conditions under which, and patients for whom, these interventions may be most cost-effective. 
Results from this study will be highly relevant for policy decisions as reinforcement interventions move into 
practice settings.  If adaptive progressive VI schedules are efficacious, this would be a major advance because 
this approach could be applied on a long-term basis to prevent relapse. This procedure minimizes patient and 
provider burden relative to traditional reinforcement interventions, and even relative to typical aftercare 
interventions. Moreover, as effective as reinforcement interventions may be, little is known regarding the 
types of individuals who do and do not respond to them. Inclusion of cognitive measures is likely to greatly 
enhance our understanding of predictors of patient response, which could lead to more efficient patient-
treatment matching strategies. If this project yields evidence of pre- to post-treatment changes in cognition 
that mediate effects of reinforcement interventions, this information has the potential to revolutionize our 
understanding of how these very effective interventions exert their beneficial effects.  
RESEARCH STRATEGY
Of all psychosocial treatments for drug use disorders, reinforcement interventions have the largest effect size 
(Dutra et al., 2008). Independent meta-analyses, spanning scores of studies, find reinforcement interventions 
consistently reduce drug use (Lussier et al, 2006; Prendergast et al, 2006). Given their strong evidence base, 
clinics across the US and internationally are beginning to implement these interventions. We have been at the 
forefront of addressing issues that impact dissemination of these interventions. Methods to reduce costs, 
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including the prize approach that we developed and assessed (Petry et al., 2000,2004,2005a) and tested in the 
NIDA Clinical Trials Network (CTN; Peirce et al., 2006; Petry et al., 2005b), have allowed integration in 
multitudes of settings. For example, Hospital and Health Corp. in NY successfully applied prize reinforcers in its 
clinics (Kellogg et al. 2005), RI, NY and SC have integrated reinforcers into drug abuse treatment (Henggler et 
al., 2008; McCorry et al., 2010; Squires et al., 2008), and England introduced reinforcers into its national health 
care system (Ballard & Radley, 2009; NICE, 2007; Pilling et al., 2007). 
In support of these and other adoption efforts, we developed training materials, as well as adherence and 
competence indices, and demonstrated their relationships to patient outcomes (Petry et al., 2011a,2012bc). 
Clinicians readily can be taught to administer these interventions competently (Petry et al., 2010a, 2012bc; 
Squires et al., 2008), and prize reinforcement interventions are not only efficacious but also cost-effective 
when implemented clinically (Lott & Jencius, 2009; Olmstead et al, 2007abc, 2009; Sindelar et al, 2007ab). 
A major development during our last period of support is that the Veteran’s Administration (VA) called for use 
of reinforcement interventions nationwide (Schoenhard, 2011) and contracted with us to provide training and 
implementation support in >100 clinics. We trained clinicians (Rash et al., 2013), and >1000 veterans have 
received reinforcement, with clinician-- and patient-- response overwhelmingly positive (Petry et al., in press 
a). 
Although highly efficacious while in effect, reinforcement typically ceases once patients discontinue care, 
when resumption of drug use is most likely. Methods to efficiently and effectively continue benefits after 
formal care ends are needed to prevent relapse and maintain effects.  This is a critical scientific issue the 
present study is designed to address in that it will evaluate a novel reinforcement approach to extend long-
term benefits. 
Even though reinforcement interventions are notably efficacious, about 30%-50% of patients never achieve 
abstinence when exposed to them (Preston et al., 1998; Silverman et al., 1996; Weinstock et al., 2010).  Little 
attention has been paid to evaluating variables related to response to these interventions.  We will investigate 
predictors of response to these interventions, focusing on impulsivity and cognitive control. 
Innovation
1. Extending benefits of reinforcement interventions.  Reinforcement interventions are applied primarily 
during early stages of treatment. While clearly efficacious in this regard, a criticism has been that effects 
weaken once reinforcement stops. This is an issue with treatments in general, because most are provided on a 
brief and acute basis (McLellan et al., 2000).  National guidelines recommend continuing care or aftercare after 
initial care (ASAM, 2001), but many patients do not present to aftercare or stop attending after few sessions 
and experience high rates of relapse (Dennis et al., 2003; Humphreys & Tucker, 2002; McKay, 2005; McKay et 
al., 2004; Simpson, 2004; SAMHSA, 2008). In community clinics, <15% of patients receiving standard aftercare 
complete 8 weeks, and over 75% relapse within 3 months of leaving care (Petry et al 2004,2005a,2006a).
Studies have investigated approaches to improve aftercare access and outcomes, including group sessions 
based on cognitive-behavioral (CB) principles and phone interventions (McKay, 2005). Although about half of 
aftercare studies found benefits relative to control or no interventions (McKay, 2009), more intensive and in-
person interventions are not more effective than briefer or phone interventions (Coviello et al, 2001; McKay et 
al., 1997, 2005), and all suffer from poor adherence. McKay (2009, 2010) noted that key components of 
effective aftercare models are ones that: are low burden and convenient for patients; include aggressive 
attempts to stay in contact with patients; systematically monitor drug use; and use reinforcement. 
Very few studies have evaluated reinforcement interventions as a means extending the benefits of care.  Van 
Horn et al. (2011) used reinforcers to enhance participation in telephone care. They randomized 195 patients 
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who completed intensive outpatient care to telephone continuing care with or without reinforcers for 
participating in phone sessions. Patients receiving reinforcers completed 67% of calls versus only 39% for those 
without.  
McKay et al. (2010) randomized 100 cocaine dependent patients who completed intensive care to 4 conditions 
using a 2 x 2 design: reinforcers for cocaine negative samples or not, and CB relapse prevention therapy or 
standard aftercare. Reinforcers significantly reduced positive samples and self reports of cocaine use, but no 
main or interactive effect of CB therapy was noted. Thus, reinforcement appears efficacious in preventing 
relapse during less structured phases of care.  The addition of CB therapy failed to improve outcomes beyond 
reinforcers alone, suggesting that additional psychosocial interventions may not be necessary. However, 
access to reinforcers required frequent (3x/week) attendance, and patients find aftercare interventions that 
do not require frequent attendance to be more acceptable (McKay, 2009). Our progressive VI reinforcement 
intervention, outlined below, will allow for fairly infrequent attendance. 
2. Adaptive progressive VI reinforcement should sustain effects. The progressive VI reinforcement 
intervention proposed here is novel because it adapts frequency of monitoring and reinforcing abstinence to 
the patient’s progress as a means of sustaining benefits. Typically, monitoring and reinforcement schedules 
remain pre-set (e.g., twice weekly) and then are removed completely. However, basic behavioral research 
demonstrates that variable interval (VI) schedules of reinforcement are most likely to sustain change after 
reinforcers are removed (Ferster & Skinner, 1957; Nevin & Grace, 2000). In this study, patients initially will be 
reinforced for abstinence according to a usual twice-weekly monitoring system, validated in multiple trials 
(e.g., Petry et al., 2005b,2007a,2012bc). As long as patients maintain abstinence, the frequency of monitoring 
and reinforcing abstinence will decrease according to a VI schedule, gradually down to once every three weeks 
on average. If a patient submits a positive sample or fails to submit a sample, reinforcement will reset and 
frequency of monitoring increase until abstinence is re-instated.
This adaptive intervention is expected to increase the proportion of patients who receive large or full “doses” 
of reinforcement therapy. Less than half of patients in reinforcement interventions complete intended 
durations of care, even when they are only 12 weeks (Petry et al., 2004,2005ab,2006a,2011a,2012ab). In part, 
attrition from reinforcement interventions mimics discontinuation from standard care. Although 
reinforcement interventions enhance participation in clinical care relative to non-reinforcement treatments 
(Petry et al., 2005ab,2006,2011a,2012ab), patients stop providing samples and no longer receive reinforcers 
for abstinence once they cease attending groups. By encouraging patients who no longer attend group therapy 
to continue earning reinforcers for abstinence on their own self-selected and relatively minimal schedule, this 
progressive VI reinforcement intervention is likely to engage patients for longer durations.  If efficacious, a VI 
schedule that adjusts to patient progress has the potential to change the course of how reinforcement 
interventions are implemented. 
3. Cell phone technology will maintain contact with patients and inform them of testing schedules. Cell phones 
are increasingly applied in the context of health behaviors, and this study will use a novel approach to 
integrate cell phones into reinforcement interventions. Patients will receive unlimited cell service, highly 
desired because most patients with free plans use up allotted monthly minutes quickly. According to 
procedures worked out in prior trials (see prelim studies), patients will maintain use of study cell phones so 
long as they submit samples when contacted and asked to do so, regardless of results of the samples. This 
technology also provides a means by which staff can prompt sample submission and assess the natural course 
of relapse, and how it is impacted by reinforcement interventions, using objective indices even after patients 
cease attending treatment.
4. Neurocognitive assessment. This study is also novel in that it will evaluate neural processes underlying 
cognitive control and reward processing in the context of reinforcement interventions. Many neurobiological 
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models of addiction highlight the interaction between subcortical structures that mediate reward and cortical 
structures that support cognitive control (Everitt & Robbins, 2004; Everitt et al., 2008; Goldstein & Volkow, 
2011; Koob & Le Moal, 2001; Volkow et al., 2003). We will investigate these processes and their relation to 
outcomes.  
a.) Cognitive control. Deficits in cognitive control are a defining feature of addiction (Ersche et al., 2012; 
Goldstein & Volkow, 2011; Hyman, 2005), and the functions most commonly impaired (e.g., cognitive 
flexibility, inhibition, control, and attention) are the ones many treatments attempt to enhance (Sofuoglu et 
al., 2013). For example, learning new cognitive responses (e.g., to cravings) are critical aspects of cognitive-
behavioral, motivational, and even 12-step approaches (Ersche & Sahakian, 2007; Garavan & Hester, 2007) 
(see Project #1). Reinforcement interventions, in contrast, rely on very basic learning principles. Such 
treatments have been applied for decades to individuals with severe cognitive dysfunction and mental 
retardation, for whom they are a standard of care (e.g., Bijou & Orlando, 1961). Because individuals with 
severely impaired cognitive functioning respond to reinforcement interventions, these treatments may be 
beneficial even among drug abusing patients with cognitive deficits, and data indicate that contingent rewards 
reliably and robustly sway decision making toward clinically desired behaviors (Dutra et al., 2008; Lussier et al., 
2006). Nevertheless, drug using patients make choices between the alternate reinforcers provided by these 
interventions and the reinforcement provided by drug use. Such choices are made in patients’ natural 
environments, where they experience cravings for drugs; when drugs become suddenly available, these 
choices rely on cognitive control, and the function of the prefrontal cortex  (Kober et al., 2010; Volkow et al., 
2010). Although cognitive control is not the primary tenet of reinforcement interventions, it may predict and 
contribute to treatment outcomes. Furthermore, patients practice acts of cognitive control by choosing to 
attend treatment and regulate craving, inhibit drug use, and maintain abstinence (DeVito et al., 2012; 
Muraven, 2010). Reinforcement interventions, especially if they result in continued use of these cognitive 
strategies while maintaining abstinence, may lead to greater cognitive control. Thus, cognitive control may be 
both a moderator and mediator of treatment outcomes (see prelim studies). 
b.) Response to monetary rewards. Contemporary theories on addiction point to abnormalities in reward 
circuitry in regions such as the ventral striatum and ventromedial prefrontal cortex (e.g., Chau et al., 2004; 
Volkow et al., 2003). Volkow et al. (2003) have proposed that, in addiction, the reward value of drugs increases 
while the reward value of other reinforcers (such as money) decreases. Many studies have shown deficits in 
reward processing, reflected by reduced response to monetary rewards in the ventral striatum, in substance 
using patients relative to healthy controls (Balodis et al, 2012; Beck et al, 2009; Peters et al, 2011; Wrase et al, 
2007). These findings appear especially relevant to reinforcement interventions, because they provide 
monetary rewards as alternatives to those derived from drugs. By their nature, these interventions may be 
particularly beneficial for those who are sensitive to monetary rewards. Therefore, we expect that individuals’ 
neurocognitive responses to monetary rewards pre-treatment may predict treatment outcomes in 
reinforcement conditions, serving as a potential moderator of treatment effects. Further, because monetary 
rewards appear to serve as effective reinforcers at least as long as they are in effect, we expect that sensitivity 
to monetary rewards may increase during treatment, and that this increase may mediate outcomes.
5. Cost-effectiveness. We will not only evaluate the efficacy and moderators and mediators of these 
interventions, but also their cost-effectiveness, as we have done previously (Olmstead et al. 2007abc, 2009). 
These data will help inform decisions about for whom and under what circumstances funders or society may 
be willing to pay for their increased costs. As more private providers, state systems (NY, SC), and federal 
agencies (the VA) are integrating these interventions, this study will provide important and timely data 
regarding the conditions under which and patients for whom reinforcement interventions engender benefits. 
 
Preliminary studies
We have conducted numerous studies showing benefits of reinforcement interventions, and data indicate-- 
with great consistency--  that longer durations of abstinence are associated with long-term benefits. We 
completed a pilot study showing progressive VI schedules can maintain gains, and we have applied cell phones 
to prompt sample submission. Our pilot data also indicate that cognitive control and sensitivity to rewards 
relate to treatment outcomes during reinforcement interventions. Together, the data suggest that the 
proposed study is likely to yield hypothesized effects, and if so, an adaptive progressive VI schedule may have a 
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major impact on the future science and practice of reinforcement interventions. 
A common criticism of reinforcement interventions is that effects wane once reinforcement ceases. These 
concerns, while valid, often do not acknowledge that some studies from our group (Alessi et al, 2007; Petry & 
Martin, 2002; Petry et al, 2005c; prelim studies) and others (Iguchi et al, 1997; Higgins et al, 2000a, 2003, 2007) 
do show benefits can persist after reinforcers are removed. Further, Higgins et al. (2000b,2007) and we (Petry 
et al, 2005a, 2006a,2007a,2010b,2011a,2012a) have consistently shown that a robust predictor of outcomes 
after reinforcers end is the longest duration of abstinence achieved. 
An analysis of reinforcement studies from psychosocial/non-methadone clinics (Petry et al, 2004, 2005a, 
2006a,2011a,2012a) suggests that longer durations of abstinence during treatment yield greater long-term 
benefits. Of 1074 patients randomized to a standard care or a standard care plus reinforcement intervention 
for 12 weeks, 1011 (94.1%) completed a 9-month follow-up and were coded as abstinent throughout 12 weeks 
of treatment and 9 months of follow-up (via urinalysis and self reports) or not (either index indicating use). 
Controlling for site, demographics (age, gender, education, race), and baseline drug use, longest duration of 
abstinence was significantly related to abstinence throughout the 9 month follow-up, Beta(SE)=.18(.02), 
Wald=91.61, p<.001, with each additional week of abstinence associated with a 19% increased chance of 
abstinence post-treatment (95%CI=1.15-1.24). Longer term exposure to reinforcement (24 in the proposed 
study vs 12 weeks in completed studies), in conjunction with the extended effects noted with VI schedules in 
general, should further increase durations of abstinence, arguably the best predictor of long-term outcomes. 
We have pilot data suggesting that providing reinforcement for longer durations should increase abstinence. A 
total of 238 alcohol-dependent patients have been randomized to standard care (SC), SC+12 weeks of 
reinforcement for submitting negative breath samples, or SC+24 weeks of reinforcement for submitting 
negative breath samples. There is a strong linear association between time receiving reinforcement and 
longest duration of abstinence, whether abstinence is defined by negative samples alone, F(2,235) = 6.75, 
p<.001, or with self reports, F(2,235)=6.75, p<.001. On average, patients in SC achieved 7.8 + 6.8 weeks of 
abstinence vs 10.5 + 7.4 and 12.4 + 8.5 weeks for those assigned to the 12 and 24 week reinforcement 
conditions, respectively. 
Our ongoing RCT was designed to isolate the best timing and duration of reinforcement. Preliminary analyses 
of 206 patients whose time in the study has elapsed reveal that longest duration of abstinence (LDA) is 
significantly greater in those receiving 12 weeks of reinforcement compared to those who were never 
reinforced (p < .05). Neither of the short-term (6 week) reinforcement interventions increased durations of 
abstinence compared to standard care. Results related to % negative samples submitted vary depending on 
how missing data are included. When number of submitted samples is the denominator, no differences exist 
between groups with >80% testing negative. When expected samples are included in the denominator, % 
negative samples is higher in patients receiving reinforcement throughout 12 weeks, or just for the first 6 
weeks (ps < .05) relative to those in SC. These between-group differences depending on how missing samples 
are considered likely relate to differential sample submission rates across groups. Patients in all conditions 
receive $2/sample submitted, and mean samples obtained is 10.5, 11.5, 13.7 and 14.8 in the SC 1-6/SC 7-12, SC 
1-6/Reinf 7-12, Reinf 1-6/SC 7-12, and Reinf 1-6/Reinf 7-12 conditions, respectively. The latter two conditions 
differ from patients receiving SC for the entire 12 weeks in sample 
submission rates (p < .05). To more fully identify potential benefits, 
it is critical to obtain higher and equal rates of sample submission 
across groups, which provision of cell phones should do.
Thus, reinforcement interventions—when applied during early 
stages of care—are efficacious, with the most consistent and long-
term benefits in those exposed to reinforcers for longer durations. 
0
20
40
60
80
100
LDA (days)
% Neg of submitted % Neg of expected 
M
ean
SC 1-6, SC 7-12
SC 1-6, Reinf 7-12
Reinf 1-6, SC 7-12
Reinf 1-6, Reinf 7-12
*
*
*
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Although reinforcement is beneficial, only 33% of patients assigned to the longest duration reinforcement 
condition completed a full course of 12 weeks of treatment, with median time in treatment being 5 weeks. 
Nevertheless, 82.1% of patients continued submitting samples beyond their time in treatment when a modest 
$2 per sample was provided. These results suggest that the proposed study, which will arrange greater overall 
compensation for sample submission via cell phone service, will be able to obtain even higher rates of sample 
submission and more accurately gauge drug use. Further, willingness to submit samples after discontinuing 
formal treatment bodes well for an adaptive reinforcement intervention that maintains contingent 
reinforcement  even after patients cease attending group therapy sessions. By requiring less frequent 
attendance with a progressive VI schedule, we expect to increase the proportion of patients who remain 
involved in the reinforcement intervention.
We have data showing that a progressive VI schedule can maintain behavioral gains when delivered 
relatively infrequently.  Exercise, similarly to drug abstinence, is a behavior that is difficult to initiate and 
sustain. We provided pedometers to sedentary adults (mean steps/day at baseline was 4,400) and encouraged 
them to walk >10,000 steps/day. For 3 weeks, participants attended the clinic 2-3 times/week according to a 
set schedule, similar to those used in drug abuse treatment studies that reinforce abstinence. As in our drug 
abuse treatment trials, these participants earned draws with chances of winning prizes each day they walked 
>10,000 steps. At week 4, participants (N=61) were randomized to no further reinforcers or progressive VI 
reinforcers, in which frequency of monitoring and reinforcing walking decreased down to once every three 
weeks on average. In weeks 4-15, each participant selected two potential monitoring days (M-Th, M-F, or T-F) 
and they were phoned each of those mornings and informed whether or not they needed to attend the clinic 
that day for pedometer uploads (identical to procedures planned herein). Participants attended 88.6%+18.7% 
of requested sessions, with no differences in attendance or days of pedometer data available between groups, 
p = .58. At sessions, participants randomized to the progressive VI condition earned prize draws if the past 4 
days of pedometer data indicated walking >10,000 steps per day. A missed session or a day in the past 4 days 
with <10,000 steps resulted in no draws, and a reset in draws the next time they were randomly selected to 
attend. As shown, participants randomized to VI reinforcement maintained gains more than participants who 
ceased earning reinforcers after the initial reinforcement phase, p<.01. Thus, this progressive VI reinforcement 
procedure was efficacious in maintaining high rates of behavior even 
when infrequent (and low magnitude) reinforcers were arranged. 
Over the 12-week randomized phase, a mean of $77+$68 in prizes 
($6/week) was sufficient to sustain high rates of walking. Given 
promising results in altering physical activity and its strong basis in 
basic behavioral research generally, a similar progressive VI schedule 
is likely to be efficacious in maintaining abstinence in cocaine 
dependent patients, a hypothesis this study will test directly. 
We have fMRI pilot data from Carroll et al.’s (under review) trial relevant to reinforcement interventions. Pre- 
and post- treatment imaging data from the Stroop task (described in DeVito et al., 2012) were obtained from 
22 cocaine dependent patients. Eleven were randomized to a reinforcement intervention, and 11 to a non-
reinforcement intervention; all 22 received placebo medication. Two main findings emerged: 1) Greater pre-
treatment Stroop activity in the dorsolateral prefrontal cortex (dlPFC) was positively correlated with 
reinforcers earned in those receiving the reinforcement intervention, suggesting that better cognitive-control 
pre-treatment may be related to better response to treatment (Fig 1).  2) Stroop activity decreased in dmPFC 
and dlPFC from pre- to post-treatment in those receiving the reinforcement intervention, and these effects 
were greater among those in the reinforcement than the non-reinforcement condition (Fig 2).  We reported 
similar decreases in these regions in concert with improvements in Stroop performance, suggesting greater 
efficiency in these PFC circuits (DeVito et al., 2012) and consistent with findings noted with working memory 
training (Klingberg, 2010). Together, these data suggest that Stroop-related activation in the PFC may relate to 
outcomes, and that reinforcement interventions may be associated with changes in brain functioning in these 
0
2000
4000
6000
8000
10000
12000
BL
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
Mean steps
Weeks
No further reinforcement
Progressive VI reinforcement
On average 
every 2 weeks
On average 
>3 weeks
Reinforcement available
Reinforce-
ment
phase
Randomization Phase
On average 
weekly
p < .01
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regions. 
      The Monetary Incentive Delay (MID) 
task is commonly used to assess neural activity during anticipation and receipt of monetary rewards (Balodis et 
al., 2012). Neural activity is compared between no reward ($0) and reward conditions ($5) during a period of 
anticipation, and once the outcome is revealed (winning $5 or $0). Compared to controls, those with drug use 
disorders have reduced neural response to monetary rewards in regions including the ventral striatum (VS; 
Andrews et al., 2011; Balodis et al., 2012; Goldstein et al., 2007).  MID data are available from the 11 cocaine-
dependent participants above who received a reinforcement intervention. As expected, greater pre-treatment 
activity in the VS during receipt of monetary rewards (outcome phase) was associated with longer abstinence 
during treatment (Fig 3). We also observed increases in activity in the VS pre- to post-treatment in patients 
receiving the reinforcement intervention (Fig 4). 
        These data suggest that 
reward-related activation in the 
ventral striatum, which has 
been implicated in drug effects 
and reward processing more 
generally, may predict 
treatment outcomes in 
reinforcement interventions, and these interventions may be associated with increased sensitivity to monetary 
rewards over time. These data, however, are from a small sample, and MID data were only available from 
participants randomized to the reinforcement intervention (Unfortunately, multiple subjects assigned to the 
non-reinforcement intervention experienced technical difficulties or excessive movement during participation 
in the MID task, problems we have since corrected). The proposed study will examine these associations with 
an adequately powered sample, comparing patients receiving reinforcement and standard care interventions. 
Methods
Design: This 3-group randomized design will address two primary scientific questions: (1) will adaptive 
progressive VI reinforcement improve short- and long-term abstinence outcomes compared to standard care, 
and (2) will adaptive progressive VI reinforcement yield benefits beyond that of traditional reinforcement? 
Subjects and setting: Patients will be recruited from admissions to intensive outpatient care at Alcohol & Drug 
Recovery Centers (Hartford, CT), Hospital of Central CT and Farrell Center (both New Britain, CT), Carlson 
Recovery Centers (Springfield, MA), Regional Network of Programs (Bridgeport, CT), and The Village (Hartford, 
CT). Use of multiple clinics enhances generalization of findings and has worked well (Petry et al., 
2011a,2012ab). Clinics provide comprehensive services, including intensive day programs and long-term 
aftercare. They were selected because they have similar treatment approaches and intensities of care, and 
treat analogous populations. 
A subset of patients assigned to SC and SC+adaptive VI reinforcement groups (n=30 per group) who do not 
meet exclusion criteria for imaging will be offered participation in an fMRI sub-study. Pre- and post-treatment 
scans will be conducted at Hartford Hospital Institute of Living’s Olin Neuropsychiatry Research Center. 
Fig 1. Pretreatment Stroop-related activity in dlPFC relates to 
reinforcement intervention outcome
-0.5
0
0.5
1
1.5
0
500
1000
1500
% Signal Change
INC>CON
$ earned
dlPFC
N=11
pFWE=.05
X=26
Fig 4. MID reward sensitivity increases 
pre- to post-treatment
Y=10
Ventral Striatum
pFWE=.05
-4
-2
0
2
4
0
50
100
% Signal Change
Outcome $$ > $0
Longest duration of abstinence (days)
Fig 3. Pre-treatment MID activity relates to 
reinforcement treatment outcome
pFWE=.05
Y=10
N=11
N=11
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Inclusion criteria: Each subject must: (1) be age > 18 years, (2) have a current DSM-5 cocaine use disorder 
diagnosis, and (3) be willing to sign informed consent and able to pass an informed consent quiz.  
Exclusion criteria: are (1) serious, uncontrolled psychiatric illness (e.g., schizophrenia, bipolar disorder, or 
suicide risk), (2) in recovery from pathological gambling, or (3) do not speak English. 
Exclusion criteria for the fMRI sub-study are: (1) current use of any medication that affects blood flow (e.g., for 
hypertension) and (2) any conditions that are contra-indicated for fMRI scanning: claustrophobia, presence of 
ferromagnetic metallic implants, prior severe head trauma, color blindness, left handedness and pregnancy 
(assessed via urinalysis on day of scanning). See Human Subjects. 
Informed Consent: Patients who meet inclusion, but not exclusion, criteria will be offered the chance to 
participate in the study within 7 business days of clinic admission. Research assistants (RA), under PI 
supervision, will obtain consent, prior to collection of any study data. Anyone who does not participate in the 
study will receive standard care (Human Subjects). A separate consent will be used for the fMRI sub-study and 
the decision to participate in the sub-study will have no bearing on participation in the main study.
Assessments.  After informed consent, subjects will undergo a 2-3 hr evaluation (that may be split over 2 days) 
to evaluate inclusion and exclusion criteria, primary and secondary outcomes, and possible moderators and 
mediators of effects. Assessments were selected based on their psychometric properties and theoretical 
and/or empirical association with reinforcement interventions and drug use treatment outcomes. Measures 
will be collected at BL, and those that change over time throughout months 1,3,6,9,12,15, and 18 as shown. 
Patients receive $35 in gift cards for the BL assessment, and $50 for all others, plus $25 in gift cards for 
computer/impulsivity assessments (as well as the chance to win an additional $5 based on task responses). 
Those eligible for fMRI will receive $100 for the pre- and post-treatment scan. 
DSM-5 criteria Checklist (DSM) (APA, 2013) assesses alcohol, cocaine, methamphetamine, opiate, 
benzodiazepine and marijuana use disorder.
The NODS assesses DSM-IV pathological gambling with good reliability and validity (Gerstein et al, 1999).
Shipley Institute of Living Scale (Zachary, 1991) is included as a measure of general intelligence.
The Addiction Severity Index (ASI; McLellan et al., 1988) provides ratings on alcohol, drug, medical, legal, 
psychiatric, employment, and social functioning. Psychometric properties are well established (Cacciola et 
al., 1997; McLellan et al., 1985; Zanis et al., 1994). Brief sections on cigarette smoking and demographics 
are also included. An abbreviated version will be administered at follow-up.
The Brief Symptom Index (BSI: Derogatis, 1992) is a widely used 53-item inventory of psychiatric symptoms 
that asks participants to rate items on a 5-point scale of distress and is used across protocols to monitor 
psychiatric symptoms.   
State-Trait Anxiety Inventory (STAI) is a widely used measure of both consistent and transient stress and 
anxiety (Kendell et al., 1976) and is included as a potential moderator of treatment effects. 
Quality of Life Inventory (QOL; Frisch et al., 1992) assesses satisfaction with and importance of life areas 
(work, health, recreation, etc) and is positively impacted by reinforcement interventions (Petry et al., 2007b).
HIV Risk Behavior Scale (HRBS;Darke et al., 1991) measures injection and sexual risk behaviors reliably and 
validly (Petry, 2001b), which decrease in reinforcement interventions (Hanson et al, 2008; Petry,et al., 
2010a,2011a). Non-overlapping items on the Risk Assessment Battery (Navaline et al., 1994) will be included. 
The HRBS will assess lifetime at baseline, past month at the Month 1 interview and the past 3 months at all 
other timepoints, including baseline.
The Risk Assessment Battery (RAB; Navaline et al., 1994) is a comprehensive assessment of risk behaviors 
(e.g., Chaudhury et al., 2010; Disney et al., 2006; Takizawa et al., 2007; Tourian et al., 1997). Questions from 
the RAB (that do not overlap with the HRBS) will assess lifetime and past 3 months at baseline, the past 
month at the Month 1 interview and the past 3 months at all other timepoints.
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The Service Utilization Form (SU; Olmstead et al., 2007) will be used to evaluate services received and costs. 
An abbreviated version will be administered at follow-up.
The Timeline Follow-back (TLFB; Sobell et al., 1980) uses calendar prompts to elicit specific information 
about the frequency and intensity of substance use over time intervals with good test-retest reliability and 
validity (Sobell & Sobell, 1992). It will assess days and quantity of alcohol use and days of cocaine, 
amphetamine, methamphetamine, opioid, benzodiazepine, marijuana or other drug use 3 months before 
treatment, throughout treatment, and since the last interview at follow-up. 
CANTAB:  Our principal set of cognitive tasks is drawn primarily from the Cambridge Automated 
Neuropsychological Test Battery (CANTAB) (www.cambridgecognition.com). CANTAB is a well-validated 
computerized battery designed to be sensitive to a broad range of cognitive abilities, ages, education levels 
and cultures (e.g., primarily language-independent; Robbins et al., 1998).  The software allows for accurate 
timing, secure data storage, quick data access and processing. For many tasks, age-, gender-, and IQ-adjusted 
normative databases are available, and reports as to a subject’s performance relative to such norms can be 
immediately generated at the end of testing.   
Balloon Analog Risk Task (BART) is a computerized measure of risk-taking (Lejuez et al., 2003).  We have 
found it to be predictive of response to specific treatments in several projects (Carroll et al., 2011).
Personality inventories include Barratt Impulsiveness Scale (BIS;Patton et al., 1995), which contains three 
subscales (cognitive, non-planning and motor impulsivity), and 
Eysenck Personality Inventory (EPI;Eysenck et al., 1985). 
Delay discounting (DD) is assessed by choices between immediate and delayed money (Bickel et 
al.,1999;Petry, 2001ac). 
Probability discounting (PD) evaluates preferences for certain vs probabilistic money (Andrade & Petry, 
2011; Kirby & Marakovic, 1996; Madden et al., 2009). (One of six possible versions of the PD (versions A-F) 
will be randomly selected by the roll of a die for each participant at baseline and post-treatment evaluation.)
For Iowa Gambling Task (IGT;Bechara et al., 1994), in a computer-administered format, subjects select from 
card decks that vary in probabilities and magnitudes of gains and losses, and main outcome is choices from 
gain decks with smaller short-term rewards. 
Urine and breath samples will be tested for alcohol, cocaine, amphetamine, methamphetamine, marijuana, 
benzodiazepine and opioids via standardized procedures, and clinic records will be accessed to validate days 
attended treatment. 
fMRI tasks will include the Stroop Color-Word Interference Task to assess cognitive control as well as neural 
activity (Egner & Hirsch, 2005; MacLeod, 1991; Streeter et al., 2008) and 
the Monetary Incentive Delay Task (MIDT) to assess responsivity to monetary rewards (Andrews et al., 2011; 
Balodis et al., 2012; Jia et al,, 2011).
fMRI Task
Primary 
Domain
Description
Relevance
Neural 
Correlates
Hypothesized 
Pharmacological  
Moderators
Monetary 
Incentive 
Delay Task 
(MIDT)
Reward 
Processing
Respond with button 
press to target on screen 
in order to win or avoid 
losing money 
Individuals with addictions 
(cocaine, tobacco, alcohol, 
gambling) show differences from 
those without in brain function 
during MIDT with links to 
treatment outcome 
Ventral striatum, 
vmPFC, insula, 
amygdala and 
others
DA, NE, ACh, 
GABA, Glu, 5-HT
Stroop Color-
Word 
Interference 
Task
Cognitive 
Control
Appropriately name color 
of ink when it is matched 
(“blue” in blue ink) or 
mismatched (“blue” in red 
ink) to spelled work.
Individuals with cocaine 
dependence show differences in 
performance and brain activations 
linked to treatment outcomes 
ACC, dlPFC, insula, 
thalamus, 
striatum, 
midbrain and 
other regions
DA, NE, ACh, 
GABA, Glu, 5-HT
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Assessment
 BL
During Tx 
(wk 1-24)
M1
M3
M6
M9
M12 M15 M18
DSM,NODS,Shipley
X
ASI,BSI,STAI,QOL,HRBS, RAB, SU
X
X
X
X
X
X
X
X
BART, BIS, EPI,DD, PD, IGT
X
X
X
X
CANTAB
X
X
X
TLFB
X
X
X
X
X
X
X
X
X
Urine and breath samples
X
Up to 2x wkly
X
X
X
X
X
X
X
Clinic attendance 
X
Up to daily
X
X
X
X
X
X
X
fMRI (subset; n=60)
X
X
Follow-up assessments will be scheduled to take place about 1, 3, 6, 9, 12, 15 or 18 months from study intake 
and other study visits will be scheduled as described below. However, in this study population, patients are often 
difficult to contact (e.g., homelessness, unstable housing) or become unavailable to meet (e.g., in controlled 
environment). We have many procedures in place to address these issues (e.g., collection of contact 
information, reminder calls and cards, etc.). Given these difficulties, some flexibility in scheduling is required to 
protect participants from unnecessarily limiting study procedures to a specific calendar day. If a participant 
misses a study visit or follow-up evaluation, research staff will attempt to contact and reschedule, but, we 
anticipate late and missed appointments. Study visits may be conducted over the phone or by mail if needed.  
During the COVID-19 outbreak and until exposure risks to participants and research assistants are reduced, 
study visits will be completed over the phone. Participants who complete follow-up visits over the phone will 
miss some components (i.e. sample submission) but will receive the full $50 follow-up payment. If the interval 
between the remote follow-up and opportunity to collect samples/measures is minimal, participants may be 
able to submit these missed components after risk decreases. Payments for completed mailed packets will 
remain $30.
Incarceration:  This is a minimal risk study that recruits non-prisoner patients from substance abuse treatment 
programs. However, a portion of the study patients are likely to be incarcerated during the study period due to 
illegal activities that are common in this population. If a patient is incarcerated during study participation, all 
study procedures are suspended except the evaluations. In the ICF, patients indicate whether or not they 
would like the evaluation questionnaires sent to them in prison. The mailing delivered to the incarcerated 
patient only contains the evaluation questionnaires and a cover letter indicating the questionnaires are follow-
up to a study the patient participated in at the University of Connecticut Health Center. A stamped and 
addressed return envelope is also provided with the questionnaires. If the patient completes and returns the 
questionnaires for Month 1, 3, 6, 9, 12, 15 or 18, they will receive $30 in the form of a check. The patient will 
receive the check after their release from incarceration or they may designate a person to whom the check 
should be sent during their incarceration. The patient is notified in the ICF that their participation in this study 
while incarcerated will have no effect on their eligibility for parole.
Randomization: Patients will be randomly assigned to one of the three conditions. An urn randomization 
program (Stout et al., 1994), will balance patients based upon baseline sample results (cocaine positive or 
negative) and whether or not they were in a controlled environment in the past month (e.g. jail, inpatient 
detoxification). These variables are used because initial toxicology results are a strong predictor of outcomes 
(Petry et al., 2004; Preston et al., 1998; Stitzer et al., 2007), and controlled environments impact drug use. A 
separate ‘urn’ will be employed in each clinic, thereby stratifying on clinic as well.
A. Standard treatment (weeks 1-24): Patients assigned to this condition will receive standard care, consisting 
of group therapy, including daily planning, 12-Step therapy, relapse prevention, coping and life skills training, 
recreation training, focus groups for depression and anxiety, and AIDS education. Intensity starts at 3-4 groups 
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Adapt Version 3/20                                                          Page 12 of 32
per day 3-5 days per week and is gradually reduced to 1 aftercare group per week. Individual and family 
counseling is provided on an as-needed basis, usually only for crises. Groups are led by recovering individuals, 
nurses, and MA level counselors. Format and intensity of care is similar across clinics. 
Study patients will undergo regular urine and breath sample monitoring for 24 weeks. In the first three 
weeks, twice weekly testing will be arranged, coinciding with early and late weekdays of clinic attendance (M-
Th, M-F, Tu-Fri). Thereafter, days selected for sample collection will be randomly selected from patients’ twice 
weekly preferred schedule (M-Th, M-F, or T-F), which may or may not coincide with group therapy, as some 
patients will have ceased attending groups. RAs will phone or text (patient’s preference) on the morning of 
each testing day to inform them whether or not to leave a sample that day. For example, in weeks 4-9, a 
patient with a M-F schedule may be asked to come in on Mon, Mon, Fri, Mon, Fri, Mon in the respective 
weeks. Patients will be told to plan to leave a sample on each of their test days, and will be phoned or texted 
on average every other possible test day in weeks 4-9 and told they need not leave a sample that day. In weeks 
10-24, days for sample collection will reduce to once every 2-3 weeks on average. Patients need only avail 
themselves for sample collection on two days per week (beginning and end of each week), and the schedule of 
availability can change over the 24-week period (e.g., from M-Th to T-F) so long as patients give at least one 
week notice. Patients will receive $2 per requested sample submitted, plus a $20 bonus if they submit all 
requested samples in a four week period (regardless of results). In the case of an excused absence, patients 
can come in the next day to submit a sample and still be eligible for the $20 bonus.  
To ensure contact and submission of samples on requested days, patients will receive a study cell 
phone (allowing unlimited calls and texting) as long as they do not miss more than one requested sample in a 
row. If a patient fails to submit a sample on a testing day, the RA will phone the patient that afternoon/evening 
and remind him/her that if s/he fails to provide a sample the next selected testing day, the phone will be 
turned off. After a missed sample, the next two test days will be prompted for sample submission. For 
example, if a patient failed to submit a sample when requested on a Mon, that patient would be prompted for 
another sample that Thur, and the following Mon. If the patient missed the Thur sample (or any two prompted 
samples in a row), cell service would be discontinued. The goal is to obtain on average >18 samples from 
patients across 24 weeks and equivalent samples relative to Group C, so that objective indices of drug use will 
be available similarly across conditions. (To accommodate for the potential of higher test days that may occur 
in Group C patients who relapse, additional test days will be randomly selected based on running averages of 
samples obtained from patients in the adaptive condition; Dr. Andrade has developed and maintained 
programs to automate sample selection days in ongoing and pilot trials). This system encourages submission of 
samples to accurately and consistently gauge drug use, without being unduly burdensome. 
Although some patients have their own cell phones, >90% of those with phones have pre-paid or 
government-limited plans, resulting in highly unreliable service (most quickly use up all their minutes). In an 
informal survey, 93% stated that patients would submit samples up to twice weekly for 6 months in exchange 
for unlimited cell service. Patients who prefer to use their own cell may elect to receive a $25 gift card for each 
month during which they do not miss more than one randomly selected test day in a row. (Patients with their 
own phones may switch to study phones at any time to ensure contact). If a study phone is turned off, it will 
be reinstated as soon as the patient submits a sample (i.e., the patient comes to the clinic or UCHC to submit a 
sample on their own, without being prompted to do so). After discontinuation of cell service, patients will be 
informed in writing about how to reinstate it. Once cell service is reinstated, similar rules related to continued 
use will be applied (and service discontinued if they miss >1 prompted test day in a row).
As in all our studies, research will be separate from clinical care. The clinics rarely test for drug use, and 
only upon suspicion. Clinic-requested samples will occur separately from research samples, and results not 
shared, as arranged previously (Petry et al., 2011a,2012a). RAs will congratulate patients for each drug for 
which they test negative, and if positive, encourage them to discuss any use in group (Human Subjects). 
We expect that most patients will not continue in treatment at the clinics for 24 weeks, and median 
length of stay is <5 weeks. Although prompting sample submission via cell phones will increase sample 
submission, we expect any effect related to enhancing clinic group attendance will be modest. For >15 years, 
patients in our studies have been returning to clinics for study procedures (sample submission, follow-ups), 
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IRB APPROVAL DATE: 03/31/2020

Adapt Version 3/20                                                          Page 13 of 32
which are clearly differentiated from treatment procedures. Even if these procedures do enhance clinical 
services received, the effects will be similar across groups as all receive the same incentives for sample 
submission (i.e., cell service). 
B. Standard care + twice weekly reinforcement for abstinence: Patients assigned to this condition will receive 
standard care and urine sample monitoring as above. As in Group A, patients will receive $2 per requested 
sample submitted, plus a $20 bonus if they submit all requested samples in a four week period (regardless of 
results). In the case of an excused absence, patients can come in the next day to submit a sample and still be 
eligible for the $20 bonus.  These patients will also draw from an urn and have a chance to win prizes each day 
they provide a stimulant negative urine sample according to their twice-weekly testing schedule. For the first 
stimulant negative sample provided, they will earn one draw from a prize bowl, and the number of draws 
earned will increase by one for each consecutive negative sample submitted up to a maximum of 5 draws per 
negative sample (after 3 weeks of abstinence). If ever a patient fails to leave any of their twice weekly samples 
or submits a positive sample, draws earned the next time they leave a negative sample will reset to 1, and then 
escalate as before. Excused absences (medical or court appointment arranged in advance with therapist, and 
verified emergencies, e.g., car broke down with tow receipt) will not reset draws. 
The urn will contain 500 cards, and 50% of them will be winning cards. Of these, 204 will be small 
prizes (patient’s choice of $1 coupons, toiletries, food items, or bus tokens); 45 will be large prizes, worth up to 
$20 in value (choice of CDs, gift cards, watches), and one will be a jumbo prize up to $100 (choice of stereo, TV, 
or five larges). Cards are replaced after each draw, so that chances of winning remain constant. A variety of 
prizes will be kept in a locked cabinet, and when patients win they chose a prize from that category. This 
schedule provides similar probabilities and magnitudes of prizes as our prior studies (Petry et al., 
2004,2005abc,2006a, 2007a,2011a,2012abc). Patients have an expected maximum average earning of 229 
draws (mean expected earnings of $460 in prizes) if they submit all 48 negative urine samples over 24 weeks. 
Patients in this condition, as in Group A, will receive a study cell phone (or $25/month toward their 
own cell phone service) if they maintain contact with research staff and submit samples when requested to do 
so. Because the reinforcement schedule for abstinence is set at twice weekly for 24 weeks, there is little 
reason to inform patients of reinforcement days throughout the study period. However, RAs will phone or text 
patients at the same frequency in this condition as in Groups A and C to inform them when “a sample is due to 
maintain cell phone service.” If they fail to submit a sample when prompted, additional samples will be 
requested within the next week, as described in Group A. If two requested samples in a row are missed, then 
cell service will be discontinued. Reinstatement of cell service will be as described above. 
In this manner, reinforcement for submission of negative samples is similar to that provided in 
traditional reinforcement interventions (pre-determined frequent urine testing). At the same time, prompting 
of urine sample submission (along with cell phone service for complying with submission) will be similar to 
other groups so that overall the same minimum number of samples should be obtained across conditions. In 
this manner, objective indicators of relapse to drug use will be obtained similarly across groups (see also 
Analyses). 
Patients in this group can earn draws for providing negative samples in response to a cell phone 
prompt, and they may not have submitted these samples had they discontinued care in a traditional 
reinforcement intervention. In this sense, Group B is somewhat enhanced relative to traditional reinforcer 
interventions, and allows for a conservative test of Aim 2. Nevertheless, maximum draws per sample is only 1 
when patients fail to submit negative samples twice weekly in this condition. Thus, the additional 
reinforcement for submission of samples by integrating cell phone prompted samples appears modest and 
unlikely to impact outcomes. 
 
C. Standard care + progressive VI reinforcement. These patients receive standard care and earn draws with 
chances of winning prizes for submitting negative urine samples. However, relative to Group B, the frequency 
with which they are expected to submit samples to earn abstinence reinforcement decreases over time so long 
as they maintain abstinence. In the first phase, twice weekly samples are expected just like the other groups, 
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Adapt Version 3/20                                                          Page 14 of 32
with sample collection days occurring at the beginning and end of the week and coinciding with regular clinic 
attendance (when applicable) and patient preference for days (M-Th, M-F, or T-F). Once patients in this group 
achieve ~3 weeks of continuous abstinence, they will be expected to submit samples on average once a week 
for the next 6 weeks (phase 2). After 9 full weeks of abstinence, sample collection will decrease to every other 
week on average for the next six weeks (phase 3), and finally patients who maintain abstinence will be 
transitioned to a testing and reinforcement schedule of every three weeks on average for the final 9 weeks of 
the 24-week treatment period (phase 4). In total, an average of >18 samples will be scheduled over 24 weeks 
in patients maintaining abstinence. As in Groups A and B, patients will receive $2 per requested sample 
submitted, plus a $20 bonus if they submit all requested samples in a four week period (regardless of results). 
In the case of an excused absence, patients can come in the next day to submit a sample and still be eligible for 
the $20 bonus.
 As in Group B, patients earn 1 draw per negative sample, and draws earned increase by one draw for 
consecutive negative samples during the twice-weekly testing phase (phase 1). To accommodate for the 
reduced overall number of samples submitted relative to Group B and to maintain overall equal maximum 
reinforcement between conditions, once a patient moves to the phase 2 sample schedule (once a week) draws 
per negative sample increase by 2 draws for each consecutive negative sample provided. Draws continue to 
increase by 2 up to a cap of 25 draws per negative sample, which would be achieved after about 15 weeks of 
abstinence.
If a patient fails to provide a sample or submits a positive sample, draws earned for the next negative 
sample reset to one, and then increase by one per consecutive negative sample. The frequency of testing and 
reinforcement also increases after a reset to rapidly reinstate abstinence. After a missed or positive sample, 
the patient will be asked to submit samples on all scheduled testing days for 2 consecutive testing days, 
earning 1 and then 2 draws if negative. Then, sample collection will resume to weekly on average for about 
another 2-3 weeks (earning 3, 4 and 5 draws if negative). Upon achieving 5 draws (~4 weeks of abstinence), 
number of draws earned will reinstate back to the highest level previously attained for the next negative 
sample, and sample collection frequency will coincide with whatever level the patient was previously at. In 
other words, a patient who had previously achieved 13 weeks of abstinence and was at every other week 
random testing would resume 21 draws per negative sample and every other week random testing once he 
has attained a month of abstinence following a lapse or missed sample.  Using this schedule, patients who test 
negative on all test days will earn about 231 draws over the 24-week period, similar to Group B. As in other 
conditions, RAs will congratulate patients for each substance for which they test negative, and encourage 
them to discuss any use in group.  
Design considerations: 
Why these reinforcement parameters? The parameters were chosen to be consistent with reinforcement 
schedules found previously efficacious and to equally reinforce abstinence in the two reinforcement 
conditions. The total number of draws possible is nearly identical (+2 draw) across conditions, and within each 
phase of reduced monitoring and reinforcement in Group C, overall possible reinforcement is similar to that in 
Group B. The continued escalating feature of reinforcement in Group C accommodates for the reduced 
frequency of testing and reinforcement, such that instead of earning 5 draws per negative sample twice a 
week, patients earn about 10 draws once per week. When further tapered to less than weekly testing, draws 
possible remain at about 20-25 draws every 2-3 weeks. Although this number of draws may appear to be a lot, 
it takes only about 2 min to select and open 25 slips, which translates to an expected average earning of about 
$40 in prizes.  
Why this testing frequency? A gradually decreasing frequency was selected to balance clinical, practical, and 
scientific considerations. In the first few weeks, some patients will not yet have achieved abstinence, and 
twice-weekly testing will detect all (or most all) drug use. Once abstinence is achieved, it does not appear 
necessary to monitor drug use as frequently, and random tests will ensure that use does not occur around 
known testing times. The schedule outlined should detect relapse as mean frequency of cocaine use is 10 
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IRB APPROVAL DATE: 03/31/2020

Adapt Version 3/20                                                          Page 15 of 32
days/month (Petry et al., 2012a), i.e., 2.5 days/week, which is likely to be detected at the next randomly 
selected testing day even during infrequent testing phases. Importantly, informing about testing and 
reinforcement days could be automated (computerized phone systems prompting samples) and continue long 
term (e.g., for >1 year) as a cost effective method to maintain abstinence if this study finds this intervention 
effective while it is in place. In contrast, requiring patients to come to a clinic twice weekly for 24 weeks (or 
longer), while also potentially efficacious, adds substantially to staffing and testing costs, as well as 
reinforcement costs. 
Will patients submit samples after leaving treatment, and will compensating sample submission confound 
results?  We have conducted studies in which patients were compensated for providing samples after leaving 
formal care (Petry et al., 2011a; prelim studies), and patients continued providing samples even when no 
longer engaged in clinical care. In an informal survey, 93% stated that patients would submit samples up to 
twice weekly for 6 months in exchange for unlimited cell service. Strict separation of treatment and research is 
maintained, with clinic staff encouraging engagement in research activities after treatment ends. If a patient 
were uncomfortable returning to the clinic after ending care, alternate locations for sample collection or 
evaluations can be arranged (see Human Subjects). Compensating patients for leaving samples or attending 
follow-ups increases those specific behaviors, but it has not impacted clinic attendance when research and 
clinical aspects are kept distinct; further, compensation for study procedures will be identical across groups. 
What if reinforcement is effective in the short- but not long-term? We anticipate adaptive progressive VI 
reinforcement will be more likely than standard care (and even typical reinforcement procedures) to yield 
post-treatment benefits because it is likely to engage more patients in the reinforcement intervention longer 
and engender longer periods of abstinence, which is consistently linked with post-treatment outcomes 
(Higgins et al., 2000b; Petry et al., 2005a,2007a,2010b,2011a,2012ab). However, if long-term benefits do not 
occur, the adaptive reinforcement intervention could be maintained (even indefinitely in high-risk populations) 
to sustain benefits. Reinforcement once every 3 weeks on average is a low intensity intervention that may 
ultimately be a highly effective, relatively low cost maintenance approach applicable to a wide range of 
behaviors, including weight loss, medication adherence, exercise, and diabetes management (Petry et 
al,2011b,2012d, in press de).  It is also less intensive than other forms of aftercare (1 hour weekly groups), 
requiring only 10 min of staff time.
Are interventions generalizable? Twice-weekly reinforcement interventions are already being implemented in 
clinics, as noted earlier. Although this adaptive progressive VI schedule is more complex, schedules of testing 
and reinforcing can be computerized and reminders set via cell phones, as we are doing (R21-DA029215, R01-
HD075630). This system reduces frequency of monitoring as patients achieve more sustained periods of 
abstinence, similarly to methods of monitoring patient outcomes in other chronic diseases. For example, when 
blood pressure or A1cs remain in clinically accepted ranges, medical appointments are minimized, but when 
objective indices indicate difficulties in maintaining goals, intensities and frequencies of treatment increase. 
The National Business Group on Health (2013) reported that 85% of employers are now using reinforcers to 
promote health behaviors, and section 2705 of the Affordable Care Act allows employers to use up to 50% of 
total premiums for outcome-based incentives. Thus, insurers and society are recognizing the potential of 
reinforcement interventions to positively impact outcomes of diseases with behavioral components. Clinics, if 
appropriately reimbursed, could prompt, collect, test, and reinforce samples every 3 weeks from patients, 
even after they discontinue participation in traditional group therapy. This VI reinforcement intervention 
minimizes patients’ and providers’ time, thereby ultimately increasing potential for generalization. 
Data Quality Control: Separation of clinical (treatment) and research components (structured evaluations) is 
critical. One RA will manage the reinforcement system, and another, blind to treatment conditions when 
possible, will conduct structured evaluations when possible. The project director will supervise implementation 
of treatments, assessing adherence and competence, and ensure equal and appropriate sample prompts 
IRB Review
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IRB APPROVAL DATE: 03/31/2020

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across conditions. Checksheets will be kept, listing data collected, draws earned and prizes won; sessions are 
audiotaped and reviewed for competence (Petry et al,2010a,2012bc).
Data Analysis. An important issue preceding analyses is to identify baseline differences between groups 
despite random assignment.  Differences between groups that may be related to outcome (e.g., psychiatric 
diagnoses, dependence severity, clinic services received) will be used as covariates or fixed factors, as 
appropriate.  Analysis will be conducted on an intent-to-treat basis, using all randomized patients, and both 
short-term (changes from baseline to month 6) and longer-term (throughout the 18-month follow-up) efficacy 
will be evaluated. The primary outcome is longest duration of cocaine abstinence, a continuous variable that 
can be transformed if needed.  Groups will be compared using t-tests for normally distributed data, or 
ANCOVA if covariates are included. The design includes 3 treatment groups, allowing for analyses of two main 
effects. 
Primary aim # 1 is to examine the efficacy of adaptive progressive VI reinforcement. We will compare those 
randomized to Group C vs Group A with respect to longest duration of abstinence during the 24-week 
intervention period and throughout the 18-month follow-up period.  
Primary aim #2 is to assess if adaptive reinforcement improves duration of abstinence achieved relative to 
traditional reinforcement. We will compare those randomized to the two reinforcement conditions with 
respect to during treatment and long-term abstinence outcomes. 
Secondary aims are to evaluate the impact of the interventions on other indices of stimulant and 
secondary drug use outcomes. Using the same contrasts above, we will compare groups with respect to: 
proportions of submitted and expected samples that test negative for stimulants and other drugs (alcohol, 
opioids, THC), and subjective reports of use (SUC % abstinent days). The first rely on objective indicators and 
such data will be available from all randomized patients. Subjective reports will supplement objective indices, 
and patients can be considered using if either index is positive. In terms of proportional data, missing samples 
will be considered missing (not impacting the denominator) in one analysis, and positive in another to consider 
the range of possibilities with respect to drug use outcomes. Because Group B has more expected samples (48) 
than the other groups (>18), proportional data for expected samples will rely upon the cell phone prompted 
samples (>18), designed to be similar across conditions, to conservatively test group differences. 
Power analyses for primary aims. Our studies reinforcing abstinence generally find Cohen’s d effect 
sizes of 0.6 to > 1.0 for during treatment drug use outcomes (Petry et al, 2000, 2002,2004,2005abc,2006a, 
2007a,2010b,2011a,2012abc). In terms of post-treatment effects, our ongoing study is finding an effect size of 
0.46 for a 12-week reinforcement intervention in enhancing post-treatment abstinence relative to standard 
care. Although we expect a larger effect size when 24 weeks of reinforcement is provided, and especially if 
more patients engage in the adaptive progressive VI reinforcement intervention for greater durations, we will 
conservatively power this study to detect a similar effect size of 0.46 between the VI reinforcement 
intervention and standard care for long-term outcomes. Using a Type I error rate of =.05, a Type II error rate 
of =.20, and power=0.80 (Cohen, 1988), 60 patients/ group are needed to detect d=0.46 between the 
standard care and reinforcement interventions (Aim 1). For Aim 2, the study is powered to detect a lower, but 
still clinically meaningful, effect size of 0.35 between the two active reinforcement conditions, similar to effect 
sizes found between reinforcement conditions in other studies (Petry et al., 2004, 2006a). Using the same 
power analyses outlined above, 110 patients/group are needed to detect d > .35 between the traditional and 
adaptive reinforcement conditions with respect to during treatment and long-term outcomes. Thus, we will 
recruit 280 patients (60 in standard care and 110 each for the reinforcement interventions). 
Secondary aims are to evaluate if reinforcement improves other indices of drug use, psychosocial functioning 
(ASI, BSI scores), quality of life, and HIV risk behaviors, as found in other studies (Ghitza et al., 2008; Hanson et 
al, 2008; Petry et al., 2007b,in press b). These are continuous measures, with missing data likely. If no 
systematic differences in missing data are noted (the case in our prior studies), hierarchial linear models (HLM; 
Gibbons et al., 1993) using MIXREG (Hedeker, 1993) will analyze differences between groups over time. These 
analyses have advantages over repeated measures ANOVA as they estimate missing data via model parameter 
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estimates and use real time, rather than scheduled time, of assessments. Two contrasts will be explored. One 
will evaluate Aim 1, assigning a contrast weight of +1 to patients in VI reinforcement and –1 to standard care. 
For aim 2, we will assign contrast weights of +1 to those receiving adaptive reinforcement and –1 to traditional 
reinforcement. Analyses will be conducted for both short- (BL to M6, with up to 4 data points/ patient: 
BL,M1,M3,M6) and long-term effects (BL through M18, with up to 8 data points/patient: BL,M1,3,6,9,12, 
15,18). The model will include factors for group (using contrasts above), time, and the interaction of group by 
time. These analyses will ascertain whether the interventions impact areas of functioning beyond drug use.
Changes in other drug use over time can also be examined using urinalysis data. Means of >18 samples 
will be scheduled for collection over 24 weeks, and >22 samples through the M18 follow-up.  Samples will be 
coded as positive for any illicit drug or negative for all substances. HLM using MIXOR (Hedeker, 1996), an HLM 
program for dichotomous measures, will examine group changes over time, using contrasts above. 
 
Moderators of effects will be explored. To date, we have investigated gender as a moderator of effects 
but never observed gender effects on drug use outcomes in reinforcement studies (e.g., Petry et al., 2005ac, 
2006a,2010b,2011a,2012a), perhaps in part because we provide highly desired prizes for both men and 
women (Petry, 2012). Nonetheless, effects of gender will be explored, as will interactions between gender, 
treatment condition, and other characteristics that may impact outcomes. Although we do not anticipate 
gender differences in main outcomes, we expect to find gender-specific HIV risk behaviors (Barry et al., 2008; 
Rash & Petry, 2009). We have also found that women show greater heritability of impulsive responding on 
cognitive tasks than men (Petry et al., 2002) and women with addictive disorders and ASPD are particularly 
impulsive (Andrade et al., under review). 
To determine if patient factors predict outcome, multiple regression analyses will be used to find 
predictors of continuous measures (e.g., longest duration of abstinence, percent negative samples), and 
logistic regressions for dichotomous dependent variables (e.g., presence or absence of stimulant use at follow-
up). Cox regression analyses may also be used to determine what factors predict time to event outcomes, such 
as time to first positive sample after study initiation. Independent variables will include treatment condition, 
site, days attended groups at the clinic, drug use severity (ASI-drug scores, baseline positive samples), scores 
on cognitive control tasks at baseline (computer task or impulsivity scores), and demographics, including 
gender and race. Analyses will be conducted for the entire sample and with interactions of predictors with 
condition to assess if certain characteristics are more predictive of outcomes in the different treatment 
conditions.
Behavioral changes that result from treatment may also be a function of improving cognitive control, 
and reinforcement interventions may lead to reductions in drug use by enhancing cognitive functioning. If 
effects of reinforcement on drug use outcomes are significant, cognitive control as assessed via computer and 
impulsivity tasks will be evaluated as a potential mediator of effects. A latent growth model using structural 
equation modeling can be built. Models will be built sequentially, starting with a basic latent growth model 
comprising drug use days over time, modeled as slope and intercept. Important cognitive performance indices 
can be tested as mediators in turn. A bootstrapping resampling procedure will estimate model test statistic p 
values and parameter standard errors (Arbuckle, 2006).  Models will be considered to fit the data if the chi-
square is not significant, Comparative Fit Index (CFI) is >.97, and root mean square error of approximation 
(RMSEA) is <.10 (Bollen & Long, 1993) using an iterative basis, with individual paths added or deleted on the 
basis of modification indices (Jöreskog & Sörbom, 1984). Once a basic latent growth model is determined, 
treatment group will be added as a predictor of slope and intercept. Then, cognitive variables (pre to post 
change scores) included in the model. Beta weights of the full model can be tested using a product of 
coefficients test to determine if mediation is significant (MacKinnon 2007a,b).
The fMRI sub-study will provide refined tests of hypotheses related to cognitive control in a subsample. The 
Stroop effect is calculated as the difference in reaction time between incongruent and congruent trials. In fMRI 
data, it is defined as difference in neural activity between incongruent and congruent trials. 
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1.
To evaluate relationships between pre-treatment behavioral and neural measures of cognitive 
control during the Stroop task and treatment outcome, we will assess the Stroop effect and 
related neural activity and correlate these indices with treatment outcomes (e.g., longest duration 
of abstinence, % negative urines).  
2. To assess changes in behavioral and neural measures of cognitive control, we will compare indices 
pre- to post-treatment (e.g., (Incongruent(pre) > congruent (pre)) > (Incongruent(post) > 
congruent (post)). We will also compare these indices between groups to identify treatment-
specific changes. 
The MID task allows examination of neural activity during anticipation and receipt of monetary rewards. 
Anticipation of reward is assessed by comparing neural activity during the reward anticipation phase, and 
contrasting conditions of $0 and $5 (Anticipation of $5>$0). Responses to receipt of monetary rewards are 
assessed by comparing neural activity during the outcome phase (Receipt of $5>$0). 
1.
To examine relationships between pre-treatment behavioral and neural measures of reward 
processing and treatment outcome, we will assess neural responses during anticipation and 
receipt of reward ($5>$0) and correlate these indices with treatment outcomes (longest duration 
of abstinence, % negative urines). 
 
2. To evaluate the change in response to monetary rewards from pre- to post- treatment, we will 
compare indices from this task from pre- to post-treatment (e.g., anticipation of $5 pre>post, and 
receipt of $5 pre>post). We will also compare differences in these indices between groups to 
identify treatment-specific changes. 
For cost and feasibility issues, the fMRI study is limited to patients in groups most likely to show treatment 
differences, Groups A and C. This design most cost-effectively addresses the issue of if, and how, the 
availability of monetary based reinforcers alter brain functioning. Based on our earlier work (Devito et al., 
2012; Kober et al., 2010) and pilot data, we estimate a medium effect size for changes in regions such as VS 
and PFC regions. Thirty participants per group is sufficient to determine correlations of r>.30 between neural 
activity in Stroop and MID task and outcome variables. We estimate 25 participants post treatment will be 
sufficient to assess treatment-related changes in neural activity over time (see Devito et al., 2012). 
If effects of reinforcement interventions are moderated by cognitive control, future studies may target 
these interventions toward patients based on cognitive functioning. As reinforcers add known costs, being able 
to determine those who will be most positively affected will help direct scarce resources toward patients most 
likely to benefit. If cognitive function mediates outcomes, future research may refine and test therapies that 
reduce impulsive choices, and improve cognitive flexibility, inhibition and/or control (Bickel et al., 2011). 
Combining reinforcement with an intervention that improves cognitive control may result in even more 
durable effects, which may reduce personal-- and societal—harms related to drug abuse. 
 
Economic Evaluation. If primary hypotheses are supported, we will conduct cost-benefit analyses. These 
interventions can be costly, even when reinforcers are relatively modest. Not only must costs of reinforcers be 
included, but so must administration costs, which include staff time for managing and delivering reinforcers. 
Despite costs, these interventions may provide benefits to (1) clinics in terms of enhanced reimbursements 
(Lott & Jencius, 2009), and (2) society in terms of reductions in healthcare services (hospitalizations, ER visits) 
and criminal justice system costs, and improvements in workplace productivity (Petry et al., in press c). Using 
data from the PAC-SAT, this study will determine the net benefit of adding reinforcers, from both clinic and 
societal perspectives. It will also estimate costs of each week of abstinence attributable to the reinforcement 
conditions. 
a. Comprehensive administrative costs of interventions will be quantified (Olmstead et al., 2007abc; 
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Rosenheck et al, 1995; Sindelar et al. 2007ab), including costs of prizes, mileage for purchasing them, and 
toxicology tests and management (personnel time to arrange testing and reinforcers in both reinforcement 
conditions, along with costs of cell phone service in the adaptive reinforcement condition only). Costs related 
exclusively to data collection (arranging for collection and testing of urine samples when it is not reinforced, RA 
salaries for data collection) will not be included, as they would not be relevant if interventions were applied 
clinically. Costs for usual clinical services and clinic reimbursement for same will be ascertained.
b. General healthcare costs will be estimated by multiplying service units used per patient by average unit 
costs. In- and out-patient, day hospital, aftercare and emergency room services will be estimated from CT 
claims data, and nationally from the Market Scan database, which estimates service costs. 
c. Criminal justice (CJ) system costs. Patients receiving reinforcement interventions may have reduced 
involvement with the CJ system. The PAC-SAT assesses services provided as well as police contacts, court 
hearings, and incarceration, along with timing of events that resulted in service use so acts occurring before 
study participation can be separated from those occurring during it in terms of resource utilization. Unit costs 
of services will be estimated from national reports (Pastore & Maguire, 2003; US Dept. of Justice 2006).
Other societal costs will be obtained on productivity (earnings and workdays affected by drug use) and 
automobile crashes (including property damage, injuries, and fatalities).
Calculation of net benefits. First, resource utilization and cost data will be used to estimate the average net 
benefit (i.e., benefits – costs) per patient in each intervention from clinic and societal perspectives (Drummond 
et al., 2005; Zarkin et al., 2008). Second, average net benefits, and confidence intervals around estimates, will 
be calculated by subtracting average net benefit of adaptive reinforcement from standard care, or adaptive 
from traditional reinforcement. Finally, sensitivity analyses (Olmstead et al., 2007a; Drummond et al., 2005) 
will determine the robustness of the net benefit to alternative assumptions about a variety of cost parameters 
(e.g., unit costs of services, reimbursements received). If reimbursements rise by maximizing the number of 
patients attending groups via reinforcement treatment, net benefits are higher as shown by Lott and Jencius 
(2009). 
Cost-effectiveness ratios. If reinforcement engenders net benefits, then it ought to be adopted. However, 
even in the absence of a net benefit, the incremental cost-effectiveness ratio (ICER) is critical to eventual policy 
decisions. The ICER is calculated as: (i) incremental costs to (ii) incremental effectiveness (difference between 
average effectiveness of treatments in terms of weeks of abstinence). Using expert panel recommendations 
(Gold, 1996; Johanneson, 1996; Weinstein, 1996), we will present traditional ICERs and uncertainty of the 
ratios (Gold, 1996; O’Brien et al., 1994) and derive a single synthetic measure of multiple indicators of 
effectiveness, including quality of life (Hargreaves et al., 1997; Rosenheck et al., 1998). We will also conduct 
acceptability curve analysis to provide policy relevant interpretations (Fenwick et al, 2001,2004; Lothgren & 
Zethraeus, 2000; Polsky et al., 1997; vanHout et al., 1994). Multiple samples are selected randomly 
(bootstrapped), with replacement, from the original sample to approximate the larger population. These 
analyses can also be performed with important subsamples, such as patients with greater sensitivity to 
rewards if this is determined to be an important predictor of response to reinforcement interventions.  
Incremental cost and effectiveness values and ICERs can be calculated for each new sample and compared 
with theoretical “willingness to pay” values for an outcome, such as days abstinent. Such analyses inform 
policy makers in decision-making (Olmstead et al, 2007ab; Sindelar et al, 2007b) and can be conducted with 
samples even smaller than those herein (Olmstead et al., 2007c,2009; Sindelar et al., 2007a).
          In sum, this study allows for rigorous determination of costs and benefits of interventions that accrue to 
clinics and society. A clinic perspective is crucial because, at least in the immediate future, agencies are 
unlikely to fund expanded services unless they are cost beneficial. Societal perspectives (ICER analyses) are 
critical for future policy that might allocate state and federal funding to further support reinforcement 
interventions, as is now being done on a limited basis for substance abuse care as well as in some other health 
care arenas. Only a comprehensive study such as this can address multiple perspectives, ranging from 
individual differences in cognitive response to treatments, to clinical and societal effects. The ultimate goal of 
this proposal, which integrates these perspectives, is to optimize benefits of reinforcement interventions and 
extend them to the patients most likely to derive clinically significant, and durable, reductions in drug use. 
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Human Subjects
1.
RISKS TO THE SUBJECTS
a.
Human Subjects Involvement and Characteristics.
i.
Inclusion Criteria.
Subjects will be 280 men and women, age 18 and older, who meet DSM-5 criteria for cocaine use 
disorder and who are beginning intensive outpatient treatment at a community-based substance abuse 
treatment clinic. All subjects must be willing to sign informed consent and must be able to pass (6 or 
more correct responses) a brief, 8-item quiz inquiring about study procedures, such as “Do you get to 
choose which treatment group you go into?” and “Can you drop out of the study at any time and still 
come to regular treatment at this clinic?” In our past studies, only rarely have potential subjects failed 
to pass this quiz, which ensures understanding of study procedures. 
Participants with substance use disorders in addition to cocaine may participate in this trial to 
enhance generalization of findings; the vast majority of patients with cocaine use disorders have more 
than one substance use diagnosis. These clinics do not offer outpatient treatment services to patients 
experiencing physiological withdrawal symptoms, and such patients will have been referred to, and 
completed, an alcohol detoxification prior to initiating the intensive outpatient treatment program 
from which this study will recruit. 
ii.
Exclusion Criteria.
Exclusion criteria are serious uncontrolled psychiatric illness (acute bipolar disorder, schizophrenia, or 
suicidal behavior); in recovery from pathological gambling or current pathological gambling diagnosis 
and desiring to stop or reduce gambling (because of potential concerns of similarity of prize reinforcers 
and gambling even though no increases in gambling have been reported; Petry & Alessi, 2010; Petry, 
Kolander et al., 2006); and do not speak English (all treatment is provided in English at these clinics so 
we expect no patients who present to these clinics to be disqualified based on the language criteria; 
local clinics provide substance abuse treatment services in other languages). 
Participants in the main trial will be invited to participate in the fMRI sub-study associated with this 
project following randomization to Groups A or C. Only patients assigned to these two groups will be 
offered participation in the fMRI sub-study to conserve costs associated with fMRI; these two groups 
are expected to show the greatest differences with respect to treatment outcomes and hence are also 
expected to show the greatest pre to post differences with respect to neural changes during treatment. 
Participants interested in the fMRI sub-study will be screened and excluded from the fMRI sub-study 
for current use of any medication that affects blood flow (e.g., for hypertension) and for any conditions 
that are contra-indicated for fMRI scanning: claustrophobia, presence of ferromagnetic metallic 
implants, prior severe head trauma, color blindness, left handedness, and pregnancy (assessed via 
urinalysis on day of scanning).  
iii.
Ineligible Patients.
Some patients will choose not to enroll or will not qualify for the main study. These patients 
may continue receiving standard services at the clinic in which they are enrolled, and they may also be 
referred to their treatment provider or other facilities (e.g., other substance abuse treatment clinics, 
mental health treatment facilities, or to a gambling treatment clinic such as Problem Gambling 
Services in CT) as appropriate.
Similarly, some participants in the main trial will be ineligible for or not want to participate in 
the fMRI sub-study. Prospective participants will be informed that declining the invitation to 
participate in the neuroimaging component will not affect their ability to participate in the main trial 
or their ability to receive treatment at the clinic or elsewhere.  
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iv.
Treatment Clinics, Services, and Patient Population.
Patients will be recruited from Alcohol & Drug Recovery Centers (Hartford, CT), Hospital of 
Central CT and Farrell Center (both New Britain, CT), Carlson Recovery Centers (Springfield, MA), 
Regional Network of Programs (Bridgeport, CT), and The Village (Hartford, CT). These centers all 
provide comprehensive substance abuse treatment services, including an intensive day program and 
long-term aftercare. The clinics were selected because they have similar treatment approaches, 
provide equal intensities of care, and treat analogous patient populations. 
At each clinic, about 8-12 patients enter the intensive day program each month from which 
subjects for this study will be recruited. Intensive outpatient care (up to about 6 hours/day, 3-5 
days/week) is provided for 3-4 weeks (depending on need), and then partial care (2-6 hours/day, 2-3 
days/week) for another 2-4 weeks.  Level of care is gradually reduced to 1-2 group/week during 
aftercare. Aftercare is recommended for 12 months, although very few patients continue attending 
treatment for this duration of time. About 40-60% of patients entering each clinic have a cocaine use 
disorder; the remainder have primarily an alcohol or marijuana use disorder. For over 15 years, we 
have been conducting similar studies at these and other community based clinics and the clinics have 
never encountered a problem meeting recruitment goals or integrating studies in the context of 
standard care; non-study patients are intermixed with study patients within the same group sessions 
without problems because the reinforcement intervention and study procedures are implemented on 
an individual basis, and at least half the patients in treatment at the clinics are not involved with the 
study. 
b.
Sources of Materials.  Research material includes interviews, questionnaires, audiorecordings of 
interviews and sessions, abstraction of attendance data from clinical charts, and observation of 
patients by study staff.  Breath samples and urine samples will be tested for evidence of alcohol 
and illicit drugs, e.g., stimulants (cocaine, amphetamine and methamphetamine), opioids, 
benzodiazepine and THC.  None of these materials will be available to legal, educational, or 
employer representatives. Data obtained for research purposes will be at no cost to patients. 
Urine and breath samples obtained for study purposes will not be shared with clinical staff except 
in the case of an emergency (patient deemed a threat to himself or others). Electronic data are 
stored on password-protected secured computers in locked facilities.
Sources of material for the fMRI portion (for those eligible) will include performance measures on 
the tasks (e.g., Stroop, MID), and the MRI data collected.  The performance measures will be 
collected via computer as will the MRI data during scanning on a 3T magnet.  Electronic data are 
stored on password-protected secured computers in locked facilities.
c.
Potential Risks.  Risks associated with participation in this research study include the following:
i.
Disappointment if participants are not assigned to their preferred treatment group;
ii.
Discomfort from being asked questions about alcohol and drug use, medical problems and 
histories, HIV risk behaviors, psychosocial problems, and submitting breath and urine 
samples;
iii.
Difficulties that may arise from discontinuation of study cellular phone service if patients 
fail to submit requested urine samples.
iv.
Potential breach of confidentiality.
v.
Risks associated with participating in the fMRI sub-study are considered minor as it is a 
non-invasive procedure and does not involve any radiation, but include the hazard 
from loose metal objects and feelings of claustrophobia associated with all MR imaging of 
the head.  
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2.
ADEQUACY OF PROTECTION AGAINST RISKS
a.
Recruitment and Informed Consent.
Study patients will be recruited from individuals initiating treatment at one of the participating 
centers. All potential clients will receive an explanation of the study protocol, its potential risks and 
benefits, and alternative treatment available.  Following resolution of any questions, patients who pass 
a brief quiz regarding the nature of the study and consent to participate will be asked to sign the study 
consent form and HIPAA document.  A signed copy of the consent and HIPAA forms will be given to 
each patient.  As noted above, patients who choose not to participate in the study or who are deemed 
ineligible for it will receive standard services at the center and may also be referred elsewhere for 
services if indicated.
An opt-in statement regarding audiorecording in the consent form will be utilized for recording 
of the interactions between research assistants and study participants, including baseline and follow-
up interviews. These audiorecordings are utilized only for quality insurance procedures, to rate 
research assistants according to set standards in interview and treatment administration. Patients may 
participate in the study even if they do not choose to allow audiorecording of the interviews (in our 
prior studies, less than 10% of patients refuse audiorecording). The audiorecording consent form will 
explain that the purpose is to rate the research assistants’ interviewing skills.
Recruitment for the fMRI sub-study will be separate from the main study, utilizing a unique 
informed consent form as relates to this sub-study. After completing the baseline assessment and 
being randomized as part of the main study, those who are assigned to Groups A and C, and who 
appear to possibly be eligible for fMRI will be screened for the fMRI sub-study, and additional fMRI 
exclusionary criteria assessed. Those who do not meet fMRI exclusionary criteria, and who choose to 
participate in the fMRI sub-study after receiving full informed consent for the fMRI study, will then be 
scheduled for fMRI. Patients may choose not to participate in the fMRI sub-study and still continue in 
the main study, as well as receive standard care at the clinic. Decisions whether or not to do the fMRI 
study will have no bearing on the primary study, or non-study, procedures.  
b.
Protection Against Risks.  The following will protect against potential risks:
i.
Random group assignment is used so that patients have about a 78% chance (220 of 280) 
of being assigned to a reinforcement group (60 of 280 are in the standard care condition; 
see power analyses), and patients may voluntarily end study participation if they are 
dissatisfied with their assignment.
ii.
The interviews and sample collections are brief, patients may skip questions or take a 
break if uncomfortable, and the particular sample assays chosen are intended to minimize 
discomfort. All participants will be informed (in the informed consent form and at each 
visit) that in weeks 1-3, they will be expected to submit urine samples twice weekly, 
according to their own pre-set schedule at the beginning and end of each week (M-Th, M-
F, or T-Th). To maintain cellular phone service, they cannot miss more than one requested 
sample in a 7-day period. Participants will be informed that in weeks 4-24, they will be 
phoned or texted (their preference) each morning of their twice weekly possible testing 
days and told whether they need to submit a sample that day.  If they fail to submit a 
requested sample, they will be phoned and/or texted later that same afternoon and told 
that they MUST submit a sample when requested at the next testing day to maintain 
cellular service. The consent form will state explicitly that all study participants will be 
asked to submit between 15 and 35 samples in weeks 4-24 to maintain cellular service, 
that failing to provide a sample when requested will result in the need to provide samples 
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on the next two consecutive testing days, and that missing two requested samples in a row 
will result in a discontinuation of cellular service.
iii.
 Participants will be informed of how to reinstate cellular service in the consent form and 
after any missed sample (i.e., if they submit a sample, discontinued service will be 
reinstated within about 24 hours). Additionally, if cellular service is discontinued, they will 
be contacted, informing them of the process about how to restore cellular phone service 
(i.e., submit a sample). If patients are uncomfortable returning to the treatment clinics to 
submit samples, they can also submit samples at UCHC, which is on the bus lines from 
Hartford and New Britain. Patients will be also informed in the consent form that if they 
wish to alter testing days they can do so at any time with one week’s notice.  
iv.
All data will be coded by number, not name, and a "key" form will be kept in a separate 
locked file cabinet.  No information will be provided about the patients enrolled in this 
study to anyone outside of the clinical and research teams, except in emergency situations 
(e.g., severe intoxication, participant deemed a threat to him/herself or others) or as 
required by law.  Locators (identified by patients to assist in finding them if needed for 
follow-ups) will not be given any information regarding the participant’s treatment status, 
only that we are trying to reach them regarding their participation in a health study.
Digital audio recordings of interviews and sessions will be stored as .wma files. All 
recordings will be labeled by number, not name, and the “key” form will be kept separate 
in a locked file cabinet. These files will be transferred from the digital recorder to a 
secured folder on the UCHC network drive after the recording is completed. This folder will 
only be accessible to research staff. Once files are transferred to the secure folder, they 
will be deleted from the recorder itself. When not in use, recorders will be stored in locked 
cabinets with data. Subjects will not be identified by name on recordings. Only study 
personnel will review the recordings for training, supervision, and adherence monitoring 
purposes. We will obtain consent to audiorecord, and patients may participate in the study 
without allowing audiorecording. The .wma files will be permanently deleted at the end of 
the study.
Any study participant who arrives at the clinics grossly intoxicated is not provided any 
clinic services that day. This project will strictly adhere to these clinic rules, and patients 
who appear to be intoxicated or smell strongly of alcohol will not be allowed to participate 
in group or individual therapy, or complete follow-up evaluations. Such patients will be 
immediately referred to clinic staff (e.g., clinic director) and/or asked to leave the center. If 
the patient is deemed a threat to him/herself or others, police or emergency personnel 
will be contact to assist in the situation as required by law. Almost none of the patients 
who attend these centers have automobiles, but any patient who may have driven to the 
center will be requested to provide their keys to clinic personnel. If they refuse, police or 
emergency services may be contacted, as required by law.
v.
To protect participants who are eligible and agree to participate in the fMRI portion of the 
trial, all participants will be screened for appropriateness for fMRI using a screening form. 
All participants will be screened using a screening form for any metallic objects that they 
may be holding or have implanted in their bodies and all potential participants with 
metallic implants will be excluded. Individuals with occupational histories that might pose 
problems for MRI will be required to undergo additional safety procedures (e.g., 
individuals who have performed welding without eye protection will be required to obtain 
orbital x-rays prior to scanning).  Similarly, other potential sources of metal (e.g., tattoos 
that contain magnetically sensitive metals), along with pregnancy will be investigated for 
compatibility with MRI.  The Screener will be repeated prior to imaging to ensure that 
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participants are not bringing any metallic materials into close proximity of the magnet, 
where they might be pulled toward the magnet or heated by the magnet. As a routine part 
of neuroimaging, individuals are also required to walk through a metal detector prior to 
entering the room with the scanner.
Further, on the day of scanning, information about menstrual cycle (for women), 
tobacco use (for smokers, including pre- and post-scan carbon monoxide (CO) 
assessments), alcohol use (pre- and post-scan breathalyzer measures) and substance use 
(urine toxicology and self-report) will be obtained.  Participants who are smokers will be 
given the opportunity to smoke about one hour prior to scanning in order to avoid acute 
intoxication or withdrawal effects from tobacco. Consistent with our prior fMRI studies, 
participants who are experiencing acute drug intoxication or withdrawal will not be 
scanned.  Similarly to data from the main trial, all fMRI data will be coded by a unique 
code, and not names. Electronic data are stored on password-protected secured 
computers and paper information with PHI linked to the computerized data is kept 
secured in locked file cabinets in locked facilities
c.
Potential Benefits of the Proposed Research to the Subjects and Others.  The anticipated 
benefits to patients in the study include careful evaluation of their medical and psychiatric status, drug 
and alcohol use, and a potential for reducing their cocaine use. Patients in all groups will receive $35 in 
gift cards for the baseline assessment, and $50 for all others, plus $25 in gift cards for 
computer/impulsivity assessments (as well as the chance to win an additional $5 based on task 
responses). Patients will receive $25 for returning the cell phone in working condition. They will 
receive a study-paid cell phone (or $25 per month in the form of gift cards to be given at the 3 and 6 
month assessments, if they choose to use their own phone, for a total of $150) so long as they provide 
study-requested samples, estimated average of 18-23 per patient. Depending on group assignment, 
patients may also receive prizes for submitting stimulant negative samples. 
Payment for participation in the fMRI sub-study is $100 per completed session, pro-rated to $20 per 
hour for incompleted sessions, to a maximum of $200 in total for two completed sessions. 
Benefits to society include a potential improvement in the effectiveness of treatment for 
patients with substance use disorders.
d.
Importance of the Knowledge to be Gained.  The potential risks of these treatments are minor 
compared to the risk incurred by patients with cocaine use disorder.  The risk/benefit ratio appears 
favorable.
e.
Women/Minorities/Children.  We expect the gender and racial composition to reflect the 
demographics of the clinic members.  About 50% of patients at each clinic are female, and >45% 
are members of ethnic minorities (30% African American and 15% Hispanic, all of whom are fluent 
in English as treatment is only provided in English at these clinics, and 2% Native American, Asian 
American, or other). These proportions allow for exploratory analyses of gender and 
racial/ethnicity effects, as we have done previously (e.g., Montgomery et al., 2012).
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IRB Review
IRB NUMBER: 14-090H-2
IRB APPROVAL DATE: 03/31/2020