Conditions: Cocaine-Related Disorders
Allocation: RANDOMIZED | Intervention model: PARALLEL
Enrollment: 118
Healthy volunteers: no

Brief summary:
First, the investigators will determine whether Acceptance and Commitment Therapy in combination with Contingency Management increases initial treatment response rates.

Second, for patients who do not respond to initial treatment, the investigators will examine whether dopamine-targeted pharmacotherapy is an effective augmentation strategy.

Third, for patients who respond to initial treatment, the investigators will assess the relative benefit of continued treatment with Acceptance and Commitment Therapy in combination with Contingency Management, as compared to Drug Counseling in combination with Contingency Management, to prevent relapse.

Detailed description:
Drug addiction is a chronic, devastating, but treatable disorder, for which there exists a growing armamentarium of evidence-based interventions, including pharmacotherapies and psychotherapies. A core principle of drug addiction treatment, however, states that no single treatment is appropriate for everyone; rather, treatments need to be adjusted based on patient characteristics and response in order to be maximally effective. Ideally, clinicians would identify a sequence of interventions that works best across different stages of addiction treatment, from abstinence initiation to relapse prevention. Adaptive treatment interventions have been used successfully to inform this sequential clinical decision-making process. For cocaine use disorders (CUD), the most potent intervention currently available for initiating abstinence is behavior therapy using contingency management (CM) procedures. Intensive CM has been shown to produce initial cocaine abstinence rates of 40%, unmatched by all other forms of behavioral or pharmacological treatment, making it a prototypical first-line therapy for CUD. Importantly, achievement of initial abstinence predicts future abstinence. For the clinician, these research findings translate into a straightforward question: Can the investigators drive CM response rates even higher with targeted adjunctive interventions?

The proposed sequential, multiple assignment, randomized trial (SMART) will provide the data needed to answer this question. First, the investigators will determine whether Acceptance and Commitment Therapy (ACT) in combination with CM increases initial treatment response rates. The investigators hypothesize that four weeks of treatment with ACT+CM will produce higher abstinence rates than initial treatment combining standard Drug Counseling with CM (DC+CM). The hypothesized synergism of ACT+CM on primary treatment mechanisms of experiential avoidance and reward sensitivity, respectively, will be examined. Second, for patients who do not respond to initial treatment, the investigators will examine whether dopamine-targeted pharmacotherapy is an effective augmentation strategy. Specifically, the investigators hypothesize that continued ACT+CM treatment with modafinil augmentation will be most effective in promoting abstinence relative to treatment combinations involving continued DC and/or placebo. Third, for patients who respond to initial treatment, the investigators will assess the relative benefit of continued treatment with ACT+CM, as compared to DC+CM, to prevent relapse. ACT emphasizes goal-directed actions based on values that are intrinsically motivating, and is thereby expected to be a more effective intervention for extending the duration of abstinence following initial treatment with intensive CM.

Arms:
arm 1: Acceptance and Commitment Therapy along with Contingency Management for cocaine use will be administered to help decrease experiential avoidance while increasing acceptance and willingness to experience unpleasant thoughts, feelings, and physical symptoms. arm 2: Acceptance and Commitment Therapy along with Contingency Management for cocaine use will be administered and augmented with a placebo capsule during Phase 2 (weeks 5-12). arm 3: Acceptance and Commitment Therapy along with Contingency Management for cocaine use will be administered and augmented with a Modafinil (300mg) capsule during Phase 2 (weeks 5-12). arm 4: Drug Counseling and Contingency Management for cocaine use will be administered to help educate patients about important concepts in addiction recovery. arm 5: Drug Counseling and Contingency Management for cocaine use will be administered and augmented with a placebo capsule during Phase 2 (weeks 5-12). arm 6: Drug Counseling and Contingency Management for cocaine use will be administered and augmented with a Modafinil (300mg) capsule during Phase 2 (weeks 5-12).

Interventions: intervention 1: Acceptance and Commitment Therapy (ACT) intervention 2: Drug Counseling (DC) intervention 3: Contingency Management (CM) intervention 4: Placebo intervention 5: Modafinil
Intervention descriptions: intervention 1: ACT will assist cocaine patients to notice internal cravings and triggers, abandon attempts to manage these triggers via active avoidance, suppression or other control-based strategies, and to make commitments to engage in behaviors consistent with chosen values or goals. ACT encourages clients to experience thoughts and feelings from an observer perspective, and helps clients not to believe distressing thoughts and feelings as if those thoughts and feelings are literally true and in need of action. ACT treatment will be based on the ACT therapy manual developed and tested previously. intervention 2: The investigators will use the manual-guided individual DC modeled after the NIDA Collaborative Cocaine Treatment Study and used as the active control therapy in previous studies. DC approximates clinical practice as it is considered the most common type of evidence-based treatment in the community for patients actively using cocaine. intervention 3: The investigators will use the same high-magnitude CM schedule shown previously to be feasible and effective in facilitating initial cocaine abstinence. Subjects will earn vouchers for cocaine-negative urine samples collected at scheduled clinic visits each week. Under an escalating reinforcement schedule, voucher values will begin at $15 and increase by $10 for each consecutive negative urine. Bonus vouchers of $10 will be given for three consecutive negative urines. Provision of a cocaine-positive urine or failure to provide a scheduled sample will result in no vouchers earned and will reset the schedule to the initial value of $15. intervention 4: The placebo capsule will be filled with corn starch and riboflavin. intervention 5: Modafinil capsules will start at 200 mg (day 1) and increase to the fixed dose of 300 mg (day 2) and will also contain riboflavin.

Protocol document:
Prot_SAP_000.pdf: 
IRB NUMBER: HSC-MS-15-0595 
IRB APPROPaVgAeL1DoAf 2T8E: 06/15/2020 
UT Houston Protocol Template 
Adapted from NIH protocol template and ICH Guidelines 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Developing adaptive interventions for cocaine cessation and relapse prevention; Using 
event-related potentials to predict treatment outcomes in cocaine use disorder (“Adaptive 
trial”) 
 
NCT02896712 
 
Version Date: 06/15/2020 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


IRB NUMBER: HSC-MS-15-0595 
IRB APPROPaVgAeL2DoAf 2T8E: 06/15/2020 
UT Houston Protocol Template 
Adapted from NIH protocol template and ICH Guidelines 
 
Protocol Title: 
Developing adaptive interventions for cocaine cessation and relapse 
prevention; Using event-related potentials to predict treatment outcomes in 
cocaine use disorder (“Adaptive trial”) 
Principal Investigator: 
Dr. Joy Schmitz 
 
Co-Investigators: 
Dr. Michael Weaver, Dr. Anka Vujanovic, Dr. Jin Yoon, Dr. Angela Stotts, Dr. 
Angela Heads, Dr. Charles Green, Dr. Scott Lane, Dr. Heather Soder 
Study Coordinator: 
Jessica Vincent 
 
Population: 
N = 160 adults (18-60 years old) with cocaine use disorder recruited from the 
Houston metropolitan area 
Number of Sites: 
Single site 
 
Study Duration: 
Four years 
 
Study Duration per 
subject: 
14 weeks, with 3 visits per week for a total of 42 study visits 
 
 
 
Project Summary 
Drug addiction is a chronic, devastating, but treatable disorder, for which there exists a growing 
armamentarium of evidence-based interventions, including pharmacotherapies and psychotherapies. A 
core principle of drug addiction treatment, however, states that no single treatment is appropriate for 
everyone; rather, treatments need to be adjusted based on patient characteristics and response in order 
to be maximally effective. Ideally, clinicians would identify a sequence of interventions that works best 
across different stages of addiction treatment, from abstinence initiation to relapse prevention. 
Adaptive treatment interventions have been used successfully to inform this sequential clinical decision- 
making process. For cocaine use disorders (CUD), the most potent intervention currently available for 
initiating abstinence is behavior therapy using contingency management (CM) procedures. Intensive CM 
has been shown to produce initial cocaine abstinence rates of 40%, unmatched by all other forms of 
behavioral or pharmacological treatment, making it a prototypical first-line therapy for CUD. 
Importantly, achievement of initial abstinence predicts future abstinence. For the clinician, these 
research findings translate into a straightforward question: Can we drive CM response rates even higher 
with targeted adjunctive interventions? 
The proposed sequential, multiple assignment, randomized trial (SMART) will provide the data 
needed to answer this question. First, we will determine whether Acceptance and Commitment Therapy 
(ACT) in combination with CM increases initial treatment response rates. We hypothesize that four 
weeks of treatment with ACT+CM will produce higher abstinence rates than initial treatment combining 
standard Drug Counseling with CM (DC+CM). The hypothesized synergism of ACT+CM on primary 
treatment mechanisms of experiential avoidance and reward sensitivity, respectively, will be examined. 
Second, for patients who do not respond to initial treatment, we will examine whether dopamine- 
targeted pharmacotherapy is an effective augmentation strategy. Specifically, we hypothesize that 
continued ACT+CM treatment with modafinil augmentation will be most effective in promoting 
abstinence relative to treatment combinations involving continued DC and/or placebo. Third, for 
patients who respond to initial treatment, we will assess the relative benefit of continued treatment 
with ACT+CM, as compared to DC+CM, to prevent relapse. ACT emphasizes goal-directed actions based 


IRB NUMBER: HSC-MS-15-0595 
IRB APPROPaVgAeL3DoAf 2T8E: 06/15/2020 
UT Houston Protocol Template 
Adapted from NIH protocol template and ICH Guidelines 
 
on values that are intrinsically motivating, and is thereby expected to be a more effective intervention 
for extending the duration of abstinence following initial treatment with intensive CM. 
In summary, results from this Stage II (PA-13-078) project should support a Go/No Go decision 
about further Phase III, confirmatory studies. The primary aims of this project address an important 
NIDA research priority and have the potential to significantly impact how we tailor treatment of CUD to 
maximize outcomes. 
 
Background Information 
Cocaine use disorders comprise a public health problem in need of new treatment approaches. 
Cocaine affects multiple brain circuits, with prolonged exposure compromising cognitive and behavioral 
processes associated with reward, motivation, learning, and inhibitory control.1-3 The complexity of the 
disorder has presented treatment challenges. Controlled studies have demonstrated effectiveness for 
several types of behavioral therapies, including cognitive-behavioral therapy (CBT), motivational 
interviewing (MI), and CM,4,5 along with promising pharmacotherapies.6,7 Despite the growing 
armamentarium of CUD interventions available, the treatment field continues to rely on fixed- 
intervention models (all patients offered the same type or dosage of intervention) which has fallen short 
of substantially improving clinical care and outcomes.8 Adaptive intervention methodology responds to 
the call for new behavioral and integrative treatment development research to improve effectiveness by 
allowing for greater individualization or “tailoring” of treatment to the needs of the individual (PA-13- 
077; NIDA Principles of Drug Addiction Treatment, 2012).9 
An adaptive treatment intervention (ATI) for CUD aims to answer the ultimate clinical question - 
- what sequence of interventions work best for each individual across the stages of addiction treatment, 
from abstinence initiation to relapse prevention? The sequential multiple assignment trial (SMART) is an 
experimental design used for constructing empirically-supported ATIs. The first decision stage of the 
SMART provides data for identifying the best initial treatment. The second decision stage of the SMART 
compares second treatment options for initial treatment responders/non-responders. We propose a 
SMART design to find the sequence of integrated therapies that will achieve the best possible outcomes 
for both responders and non-responders over the course of CUD treatment. The following sections 
summarize the conceptual framework along with supporting data for the hypothesized ATIs, shown 
below. 
 
 Initial Treatment  
 Initial Response  
 Second Treatment  
Abstinent 
Continue ACT+CM 
ACT+CM 
Non abstinent 
Continue ACT+CM 
Augment with pharmacotherapy 
Figure B.1.2. Hypothesized adaptive treatment interventions using integrated   therapies. 


IRB NUMBER: HSC-MS-15-0595 
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UT Houston Protocol Template 
Adapted from NIH protocol template and ICH Guidelines 
 
CM is an efficacious intervention for initiating abstinence from cocaine. Based on operant 
learning principles, CM interventions seek to increase availability of reinforcement derived from non- 
drug alternatives, increase constraints on reinforcement derived from substance use, and deliver these 
environmental contingencies to accommodate the temporal discounting behavior that is characteristic 
of substance use disorders.10 An extensive literature of controlled-studies documents the success of 
these interventions.11 We 12 and others 13-15 have implemented high-magnitude CM interventions during 
initial weeks of CUD treatment to produce abstinence rates as high as 40%. To our knowledge, CM is 
currently the most reliably effective method for facilitating initial abstinence. Given the robustness of 
initial abstinence in predicting long-term abstinence, e.g.16,17 it behooves practitioners and treatment 
researchers to find new approaches to increase the number of CM “responders”. 
Adding acceptance and mindfulness-based treatment strategies with CM may lead to improved 
abstinence outcomes. While highly effective, CM response is variable with significant rates of non- 
response, even to high-magnitude rewards. Little is known about individual-level characteristics 
associated with CM response, with the exception of intake urine status considered a marker of disorder 
severity.15,18,19 To our knowledge, we reported the first study examining modifiable cognitive-affective 
characteristics associated with CM response.20  Ninety-nine treatment-seeking patients with CUD 
received 4 weeks of high-magnitude CM-based treatment targeting abstinence initiation.12 A post-hoc 
comparison of responders, i.e., those achieving two consecutive weeks of cocaine-negative urine 
screens, and non-responders was performed on pretreatment measures of negative affect, experiential 
avoidance, cocaine craving/withdrawal symptoms, and impulsivity. Notably, while the groups reported 
similar levels of negative affect, impulsivity, and craving/withdrawal, the non-responder subgroup had 
higher levels of experiential avoidance (EA).  In other words, non-responders differed from responders 
in their approach to handling negative internal experiences (e.g., craving, negative emotions). EA, or the 
tendency to avoid or respond inflexibly with drug use behaviors when experiencing aversive states, is 
thought to provide negative reinforcement for continued use despite the availability of competing non- 
drug rewards. These findings suggest that targeting problems in EA and behavioral flexibility may prove 
to be effective in enhancing response to CM. 
Acceptance and Commitment Therapy (ACT) is a third generation CBT intervention, emphasizing 
the role of EA and inflexibility as key mechanisms underlying and positively correlated with 
psychopathology including drug use.21,22 ACT uses experiential exercises and metaphors to change the 
function of distressing thoughts and feelings, essentially helping clients make decisions and choices 
based on personal goals and values rather than on 
avoidance or control through substance use.23 By 
reducing EA and improving distress tolerance, ACT 
may help facilitate sensitivity to, and contact with, 
non-drug sources of reward made available via CM. 
As shown in Figure B.1.3, these purported dual 
mechanisms of action provide a highly plausible 
rationale for combining ACT with CM as a way to 
strengthen treatment response, especially for CUD 
adults who exhibit high levels of EA and relatively 
low sensitivity to reward contingencies. 
 
Potential mediators 
Experiential Avoidance 
Reward Sensitivity 
 
 
 
ACT+CM 
 
Initial 
abstinence 
Figure B.1.3. Hypothetical model of experiential avoidance and 
reward sensitivity as mediators of the effect of ACT+CM on 
achievement of initial abstinence. 
 
Patients who do not respond to initial treatment may arguably be most in need of adjunctive 
pharmacotherapy as a secondary treatment. Studies investigating the neurochemistry of CUD have 
shown that low dopamine transmission is associated with poor response to CM treatment,24 suggesting 
that fundamental biological differences in the functioning of the brain reward system explain the 
inability of some patients to respond to alternative reinforcers.25   The recommendation follows that 


IRB NUMBER: HSC-MS-15-0595 
IRB APPROPaVgAeL5DoAf 2T8E: 06/15/2020 
UT Houston Protocol Template 
Adapted from NIH protocol template and ICH Guidelines 
 
pharmacological interventions that target striatal dopamine signaling might serve as a therapeutic 
adjunct for enhancing CM responding in this subset of patients. Modafinil has both dopaminergic and 
glutamatergic activity that may be useful for cocaine dependence. In three independent human 
laboratory studies, modafinil has been shown to reduce cocaine induced euphoria.26-28 Modafinil was 
found to reduce cocaine self-administration in the Hart et al study.27 In an initial outpatient clinical trial 
of 62 cocaine-dependent patients modafinil was superior to placebo in achieving abstinence and 
reducing cocaine-positive urines 29, however subsequent trials have found this benefit limited to subsets 
of patients, including male participants 30 and those without a history of alcohol dependence 31. 
Kampman recently presented data showing that modafinil-treated subjects were significantly more 
likely than placebo-treated subjects to be abstinent throughout the entire trial, and continuously 
abstinent from cocaine by self-report (supported by at least two negative and no positive or missing 
urine drug screens each week) during the last 3-weeks of the trial 32. Thus, of the numerous candidate 
pharmacotherapeutics evaluated to promote cessation of cocaine use, modafinil appears to be the most 
promising. 
Patients who respond to initial ACT+CM treatment may benefit from continued ACT to prevent 
relapse.   Achieving early cocaine abstinence is a robust predictor of longer term cocaine abstinence.33 
In our previous feasibility study, patients who achieved two consecutive weeks of abstinence under 
high-magnitude CM used less cocaine during subsequent treatment, regardless of medication received, 
compared with subjects who failed to achieve initial abstinence.12 However 15 of the 33 initial 
responders (46%) “relapsed” during second treatment, as indicated by the first cocaine-positive urine 
after achieving initial abstinence. Using 46% as a benchmark for measuring improvement, the goal of 
the proposed study is to construct an optimal adaptive treatment intervention that reduces relapse 
(<46%) within this subgroup of initial responders with an otherwise good prognosis. 
As mentioned, CM interventions that provide high-magnitude alternative sources of 
reinforcement have been quite effective in promoting initial, externally-motivated, changes in behavior. 
The long-term efficacy of incentive-based treatments in reducing relapse is less clear. For CM, like most 
interventions, the magnitude of the treatment effect declines over time.11 Indeed, one of the most oft- 
cited concerns with CM has to do with maintenance of behavior change after reinforcement is 
discontinued or faded. The notion of extending CM according to an “incentives maintenance model”, 
has been suggested, 34 however studies of longer CM interventions have shown lower effect sizes on 
average than shorter CM interventions.11 Rather, the common clinical practice is to combine CM with 
other interventions that focus on sustaining initial treatment gains and minimize relapse risk. 
Relapse is commonly triggered by aversive internal experiences such as negative affect, stress, craving, 
and other withdrawal symptoms that can occur during and well beyond the acute phase of cessation.35 
To the extent that avoidant responding to these aversive states is a mechanism underlying cocaine 
relapse, acceptance-based therapy goals, as described above, are well-suited for relapse prevention. 
Another major goal of ACT is to help the patient develop sustainable, value driven, goal-directed 
approach behaviors as an alternative to avoidance.36 Learning and practicing to choose behaviors based 
on important personal values and goals rather than choosing to focus on the immediate reduction of 
craving, negative affect, or stress, will decrease relapse risk. ACT-based strategies may play an essential 
role in the maintenance of drug abstinence by shifting patients’ motivation from external (e.g., CM) to 
internal incentives or sources of motivation. 
In summary, the proposed SMART design represents a significant departure from standard 
randomized clinical trial paradigms that fail to address the heterogeneity of treatment response seen 
among individuals with chronic CUD. Continued progress in treatment development research must 
overcome this barrier with novel trial designs that formalize clinical decision making, thus having a real- 
world impact on the treatment of cocaine addiction and other chronic substance use disorders. 


IRB NUMBER: HSC-MS-15-0595 
IRB APPROPaVgAeL6DoAf 2T8E: 06/15/2020 
UT Houston Protocol Template 
Adapted from NIH protocol template and ICH Guidelines 
 
Aims and Hypotheses 
 
1. To determine if ACT enhances response to a high-magnitude CM procedure targeting cocaine- 
negative urines. It is hypothesized that initial treatment (4 weeks) with ACT and CM (ACT+CM) will 
produce higher response (abstinence) rates than initial treatment that combines standard Drug 
Counseling with CM (DC+CM). 
1.a. To determine if pretreatment EA level moderates the effects of ACT+CM on initial response. It is 
hypothesized that the benefit of ACT+CM over DC+CM on initial response (abstinence) rates will 
be greater in the subgroup of individuals with higher pretreatment EA scores. 
1.b. To determine if the effects of ACT+CM are mediated by changes in EA and reward sensitivity. It 
is hypothesized that ACT+CM effects on initial treatment response will be mediated by the 
primary hypothesized treatment mechanisms, EA and reward sensitivity. 
 
Secondary Aims/Hypotheses: 
2. To determine the best sequencing of treatment for initial non-responders. For initial non-responders, 
it is hypothesized that continued ACT+CM treatment with pharmacotherapy (modafinil) augmentation 
will be most effective in promoting abstinence relative to treatment combinations involving DC and/or 
placebo. 
 
3. To determine the best sequencing of treatment for initial responders. For initial responders, it is 
hypothesized that continued ACT+CM will be more effective (higher abstinence rates; < 46% relapse 
rate) than continued DC+CM. 
 
Study Design 
Overall Research Strategy. We propose an adaptive, two-stage SMART design to test the primary 
research hypothesis that ACT, when used in combination with CM, will increase initial treatment 
response rates. Secondary hypotheses will determine the probability of benefit associated with two 
sequences of treatments, specifically, continued ACT+CM for initial treatment responders (dashed lines 
in Figure B.3.2.i) and continued ACT+CM with modafinil augmentation for initial treatment non- 
responders (double lines in Figure B.3.2.i). 


IRB NUMBER: HSC-MS-15-0595 
IRB APPROPaVgAeL7DoAf 2T8E: 06/15/2020 
UT Houston Protocol Template 
Adapted from NIH protocol template and ICH Guidelines 
 
 
 
Overview of Study Design. Note: SR=stratified randomization; R=randomization; ACT=Acceptance and 
Commitment Therapy; DC=Drug Counseling; CM=Contingency Management; PLA=placebo; MOD=modafinil. 
Abstinent=6 consecutive (2 wks) cocaine-negative (BE<150 ng/ml) urines  samples. 
 
Participants. The study will enroll treatment-seeking individuals, 18 to 60 years old, who meet current 
DSM-5 criteria for CUD of at least moderate severity (≥4 symptoms). Eligible subjects must submit at 
least one positive urine toxicology screen for the cocaine metabolite (BE ≥ 150 ng/mL) during intake; a 
standard requirement in most cocaine trials to ensure enrollment of patients actively using cocaine. 
Subjects meeting moderate or severe criteria for substances other than cocaine, marijuana, alcohol, or 
nicotine will be excluded. Subjects whose alcohol use meets for physiological dependence requiring 
detoxification or use that makes participation medically unsafe as determined by the medical director 
will be excluded. Other exclusion criteria will include the presence of significant and unstable psychiatric 
disorders, including active psychosis, dementia, or other axis I psychiatric or neurological conditions 
requiring ongoing treatment and/or making study participation unsafe. Individuals with a past 
psychiatric history but without symptoms reported within the past 12 months prior to assessment, and 
who meet other inclusion criteria, may be eligible to participate. Individuals having medical conditions 
(e.g., severe cardiovascular disease, severe liver impairment) or taking medications (e.g., propranolol, 
phenytoin, warfarin, or diazepam) known to be contraindicated for modafinil pharmacotherapy will be 
excluded. To be eligible, females of childbearing potential must agree to use an acceptable method of 
birth control during study participation and for one month after discontinuation of the study 
medication. Non-hormonal methods of contraception are recommended, including barrier 
contraceptives (e.g., diaphragm, cervical cap, male condom) or intrauterine device (IUD). Steroid 
contraceptives if used with non-hormonal methods are acceptable. No pregnant women will be 
permitted in study. There will be separate inclusion/exclusion criteria for the Electroencephalogram 
(EEG) sub-study. Individuals with hairstyles that are incompatible with an EEG net (e.g., tight braids, 
ponytails, wigs, weaves, dreadlocks, or head scarves, etc.) and are unwilling to change the hairstyle will 
be excluded only from the EEG portion of the study. Individuals will also be excluded if they have a 
history of epilepsy or seizure disorder or head injury with loss of consciousness in the past 5 years. 
 
Eligibility criteria (described above) will be evaluated as part of the General Evaluation protocol for all 
treatment research studies at our clinic. All potential subjects are invited to first participate in this 


IRB NUMBER: HSC-MS-15-0595 
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UT Houston Protocol Template 
Adapted from NIH protocol template and ICH Guidelines 
 
separate CPHS-approved protocol (HSC-MS-05-0322 - "General Evaluation of Eligibility for Substance 
Abuse/Dependence Research). Intake evaluation procedures will include a complete psychiatric 
diagnosis using the Structured Clinical Interview for DSM-5 (SCID-5) administered by trained licensed 
professional counselors under the supervision of a licensed clinical psychologist. Medical screening will 
include a history and physical examination, a blood draw for serum chemistry and blood count, urine 
sample for urinalysis and an electrocardiogram (EKG), and urine testing for drugs of abuse and 
pregnancy. Lab tests will include a Comprehensive Metabolic Panel (CMP) with tests of liver enzymes: 
alkaline phosphatase (ALP), alanine amino transferase (ALT), aspartate amino transferase (AST), 
Prothrombin time (PT), partial thromboplastin time (PTT), and bilirubin. We will apply the Child-Pugh 
criteria to exclude subjects with stage B or C scores, indicating severe liver disease. Upon completion of 
this intake evaluation, eligible participants will be invited to participate in 
the current study. 
 
Study Site, Recruitment, Projected Enrollment.  The study site is the Treatment Research Clinic 
of the Center for Neurobehavioral Research on Addictions (CNRA), a university-supported center of 
excellence within the UT-Houston Department of Psychiatry and Behavioral Sciences and a NIDA-funded 
Medications Development Center (P50 DA 009262). Since 1995, the CNRA has been the site for more 
than 20 randomized clinical trials, enrolling over 1,000 patients with substance use disorders, most of 
these with CUD. Established and effective recruitment strategies have been identified 37  and will be 
used, including newspaper/newsletter articles, public service announcements on TV and radio, notices 
mailed to local professionals, and billboards located throughout the local community. We will reach our 
projected enrollment of N=160 subjects within 40 months, based on our established record of enrolling 
4 new subjects per month on average; a rate we have maintained for the past 5 years. 
 
Phase 1 treatments. Consenting subjects will be assigned to one of the two 4-week Phase 1 treatments, 
ACT+CM or DC+CM, using urn randomization to ensure balance between groups on baseline EA level, 
coded as “high” if AIS score > 45, or “low”≤ 45. Subjects in both treatments will be scheduled to attend 
three clinic visits per week (MWF) during the 4-week period. Two of these weekly visits will include 1- 
hour therapy sessions (ACT or DC). 
 
Acceptance and Commitment Therapy-Cocaine Use (ACT). The overarching goal of ACT is to decrease 
experiential avoidance while increasing acceptance and willingness to experience unpleasant thoughts, 
feelings, and physical symptoms. More specifically, ACT will assist cocaine patients to notice their 
internal cravings and triggers, abandon their attempts to manage these triggers via active avoidance, 
suppression or other control-based strategies, and to make commitments to engage in behaviors 
consistent with their chosen values or goals. ACT encourages clients to experience thoughts and feelings 
from an observer perspective, and helps them not to believe distressing thoughts and feelings as if they 
are literally true and in need of action. ACT treatment will be based on the therapy manual developed 
and tested previously.38, 39 The manual covers 10 core topics listed in Table B.3.2.vi.  Our experienced 
ACT therapists will be taught to use the manual as a map with flexibility to “go with the client” so long as 
issues of acceptance, diffusion, values, and committed action are thoroughly covered. Mindfulness 
exercises, metaphors, and homework sheets will be used to pursue therapeutic goals, more so than 
didactic instruction. Masters-level therapists with ACT experience from our previous trial 38  will be 
trained and supervised by Dr. Angela Stotts (Co-I) and Dr. Kelly Wilson (Consultant). 
 
Drug Counseling (DC). We will use the manual-guided individual DC modeled after the NIDA 
Collaborative Cocaine Treatment Study 40 and used as the active control therapy in our previous 
studies.38, 41, 42   DC approximates clinical practice as it is considered the most common type of evidence- 


IRB NUMBER: HSC-MS-15-0595 
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UT Houston Protocol Template 
Adapted from NIH protocol template and ICH Guidelines 
 
based treatment in the community for patients actively using cocaine. DC educates patients about 
important concepts in addiction recovery based on the underlying philosophy that physical, emotional, 
spiritual, and interpersonal needs must all be addressed to support recovery. Accordingly, the DC 
manual covers the core topics listed in Table B.3.2.vi. Masters-level therapists with DC experience from 
our previous trials 41, 42 will be trained and supervised by Dr. Anka Vujanovic (Co-I). 
 
Contingency Management (CM). We will use the same high-magnitude CM schedule shown previously 
to be feasible and effective in facilitating initial cocaine abstinence.12 Subjects will earn vouchers for 
cocaine-negative urine samples collected at scheduled clinic visits (MWF) each week. Under an 
escalating reinforcement schedule, voucher values will begin at $15 and increase by $10 for each 
consecutive negative urine. Provision of a cocaine-positive urine or failure to provide a scheduled 
sample will result in no vouchers earned and will reset the schedule to the initial value ($15). Bonus 
vouchers ($10) will be given for completing all study-related tasks in a given week. Subjects will redeem 
their earned vouchers for cash loaded to the ClinCard, a reloadable debit card. 
 
Initial response and re-randomization. Following Phase 1 treatment, the primary outcome of 
response/non-response will be determined. Subjects who submit 6 consecutive (2 weeks) cocaine 
negative urine samples by week 4 will be classified as responders. Those who fail to meet response 
criteria will be classified as non-responders. 
During second (Phase 2) treatment: 
• 
Responders will continue to receive their assigned initial treatment, as described below. 
• 
Non-responders in each initial treatment arm will be re-randomized to a second treatment 
consisting of pharmacotherapy augmentation with either modafinil or placebo. 
All subjects will attend three clinic visits per week (MWF) during the 8 week second treatment period. 
 
Table B.3.2.vi. 10 Core Topics for ACT and DC 
Second (Phase 2) treatments 
Continued ACT or DC. Twice 
weekly 1-hour ACT and DC 
sessions will continue during 
the 8 weeks of second 
treatment, covering the core 
topics shown in Table 
B.3.2.vi. 
 
Contingency Management. 
 
Preparing to begin 
Planning my recovery 
Values 
Stages of recovery 
Making contact with the cost of using 
People, places, things 
Creative hopelessness 
Self-help groups & support systems 
Control v Willingness 
Establishing a support system 
Defusion & Deliteralization 
Spirituality 
Distinguishing the person from the programming 
Personal Inventory 
Barriers to valued action 
Character Defects 
Making a commitment 
Lifestyle evaluation 
Maintaining a commitment 
Employment and managing money 
CM during Phase 2 treatment will continue to offer subjects the opportunity to earn rewards for 
engaging in targeted behaviors for either cocaine abstinence or session attendance based on initial 
treatment response. 
Initial treatment non-responders will receive abstinence-based CM using the standard prize bowl 
method described by Petry who switched to this lower-cost procedure after one month of high- 
magnitude CM for patients who initiated treatment with cocaine-positive urines.15 Patients will earn 
draws every time they submit a cocaine-negative urine at clinic visits (MWF). Draws will escalate by one 
for each consecutive negative urine sample, up to a maximum of 7 draws per day.  Missed visits without 
a valid excuse will reset draws to one the next time attended. Reset value will return to the highest 
previously achieved value if patients attend fully for 3 consecutive visits. The standard prize bowl will 
contain 500 slips with 50% associated with small prizes. Of these, 209 will be small ($5) prizes, 40 will be 
large ($20) prizes, and one will be a jumbo ($100) prize.  Patients will receive earned prizes immediately 
in the form of cash loaded to the ClinCard, a reloadable debit card provided by UTHealth. 
ACT 
DC 


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Phase 1 treatment responders will receive attendance-based CM using the same prize bowl method 
described above. The Petry study found that for initially cocaine-negative patients, reinforcing 
attendance was as efficacious as an abstinence-based CM in promoting longer durations of abstinence.15 
 
Pharmacotherapy augmentation. We chose modafinil as the pharmacotherapy augmentation strategy 
for non-responders based on growing and encouraging evidence from numerous clinical trials in cocaine 
dependent treatment-seeking patients.29, 31, 32, 43 Its dopaminergic and glutamatergic activity make sense 
theoretically for non-responders who likely represent a subgroup with greater biological/neurochemical 
impairment and for whom behavioral interventions alone may not sufficiently change dopamine 
transmission.24 Modafinil will start at 200 mg (day 1) and increase to the fixed dose of 300 mg (day 2). 
Placebo capsules will be identical in size, color, coating and shape. Participants in both conditions will 
take the same number of capsules at the same scheduled times (morning/evening) per day throughout 
treatment. Capsules will be packaged in blister cards with emergency replacement cards provided in the 
event that a subject forgets to bring their weekly card to the clinic or to replace lost cards. On clinic visits 
(MWF) the morning dose on the blister card will be taken by the subject at the dispensing window under 
observation by study staff. Additional standard methods for monitoring medication compliance will be 
followed, including pill counts and analysis of urine samples for riboflavin. Compliance will be defined 
using a cutoff level ≥ 20 fluorescence units, consistent with Mooney et al. 44  and our previous 
medication trials.12, 45, 46 
 
Counselor training and evaluation of treatment integrity. Masters-level licensed professional counselors 
with > 5 years of experience in treatment of CUD at our clinic will be trained as needed on each of the 
therapy manuals (ACT, DC). Two counselors with prior training will provide ACT; a second set of two 
counselors with relevant prior training will provide DC. The two sets of counselors will be matched for 
number of years of experience. While this design choice does not control for differential counselor 
effects across conditions, it does prevent cross-contamination of treatment elements. Co-Investigators, 
Drs. Stotts, and Vujanovic, will provide a review training and ongoing supervision of the ACT and DC 
manuals, respectively. Dr. Kelly Wilson, co-developer and international trainer of ACT, along with Dr. 
Stotts will provide an initial ACT training consisting of 2 days of didactics and experiential exercises and 
audiotaped and rated practice sessions. ACT competency per Dr’s. Wilson (Consultant) and Stotts must 
be demonstrated by relevant study therapists prior to beginning the trial. Several methods used in our 
previous trials38, 47 will be used to ensure fidelity of treatment delivery. To monitor deviation or drift 
from the study protocol, all sessions will be audiotaped and reviewed; remediation will follow, if 
necessary. Furthermore, randomly selected videos erased of specific identifying information will be 
reviewed by Dr. Vujanovic (DC) and Dr. Stotts (ACT). In addition, Dr. Wilson will provide group 
supervision, as needed, and travel to our research site once per year to conduct booster sessions with 
therapists, and problem-solve particularly difficult cases. A checklist will be adapted from past studies 
for therapists to use at each session. The checklist will serve as a cue for the therapist to provide each 
component as designed, and it will be used to measure the “dose” of the intervention delivered to each 
client. Treatment adherence will be checked by independent raters (who themselves are skilled in the 
performance of the treatment) who will rate randomly selected audiotaped samples according to 
adherence rating scales. These scales will list core elements prescribed in the manual. The rater will 
indicate on a scale from 1 (none) to 5 (very much) the extent to which the treatment element was 
present in the recorded session. 
 
Safety Follow-Up Visit. A safety follow-up visit will occur 7-10 days post treatment to ensure there are 
no new or worsening side effects or psychiatric symptoms. For completing the follow-up visit 
assessments, subjects will be compensated $25. 


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Assessment Schedule 
 
Treatment mechanisms. A multi-modal measurement strategy will be used, where possible, to minimize 
method bias in evaluating putative mechanisms as predictors of treatment outcome (Aim 1a) and 
mediators of treatment effects (Aims 1b). 
 
Experiential Avoidance: The Avoidance and Inflexibility Scale (AIS) is a 13-item self-report measure, on 
which respondents indicate, using a 5-point Likert-style scale, their level of avoidance and inflexibility 
with regard to internal experiences. The AIS has been adapted for several substance-using and other 
populations,38, 48 and in our previous study was modified for cocaine users. Higher scores indicate more 
avoidant and inflexible responses to internal states associated with cocaine use. The internal consistency 
of the AIS in our past studies was .89. The AIS will be used as the stratification variable for initial 
randomization.  High avoidance will be defined as AIS scores > 45, based on our preliminary data, 
showing that this cutoff score distinguished CM responders from non-responders with good sensitivity 
and specificity indices. The Acceptance and Action Questionnaire for Substance Abuse (AAQ-SA) is an 18- 
item self-report measure on which respondents rate their urges on a 7-point Likert-type scale (1 = 
“never true” to 7 = “always true”). The AAQ is the standard measure of psychological flexibility. The 
AAQ-SA is the substance abuse focused version of this measure and has demonstrated good internal 
consistency, factor structure, and construct validity. 102 The Valuing Questionnaire (VQ) is a 10-item self- 
report measure that assesses the effectiveness of ACT interventions using a 6-point Likert-type scale (1 = 
“Not at all true” to 6 = “Completely true”). The VQ should provide ACT researchers a convenient, 
reliable, valid measure for evaluating ACT interventions.103 The Five Facet Mindfulness Questionnaire 
(FFMQ) is a 39-item self-report consisting of five subscales (observing, describing, acting with 
awareness, non-judging of inner experience, and non-reactivity to inner experience) that assess a 
participant’s mindfulness based on a 5-point Likert-type scale (1 = “Never or very rarely true” to 5 = 
“Very often or always true”). Mindfulness facets have been found to be significantly related to 
meditation experience, psychological symptoms and well-being.104 The PTSD checklist (PCL-5) is a 20- 
item self-report checklist of traumatic events, PTSD symptoms and severity rated on a 5-point Likert- 
type scale (0 = “Not at all” to 4 = “Extremely”) and will be used to assess new or worsening trauma 
symptoms. The Distress Tolerance Scale (DTS) is a 15-item self-report measure on which respondents 
indicate, on a 5-point Likert-type scale (1 = “strongly agree” to 5 = “strongly disagree”), the extent to 
which they believe they can experience and withstand distressing emotional states (e.g., “I can’t handle 
feeling distressed or upset”). The internal consistency of the DTS is ≥ .82.49 A Cold Pressor Task (CPT) will 
be implemented as an index of physical distress tolerance, otherwise conceptualized as EA of physical 
distress.50 This task involves continual application of a cold stimulus, intended to be safe but aversive, to 
the hand up to the wrist. Consistent with prior work, we will use ice water (1°C; 33°F) and instruct 
participants to keep hands still while submerged. 51  Pain threshold is defined as the length of time (in 
sec) until a self-report of pain is made by the participant. Tolerance is defined as the length of time (in 
sec) until participant reports that the pain or discomfort is no longer tolerable and/or spontaneous 
termination of the procedure. Endurance is defined as tolerance minus threshold. 52 It should be noted 
that, in the absence of gold standard self-report or behavioral measures of experiential avoidance or 
emotional tolerance, the measures selected have shown the most relevance to the mechanisms of 
interest in the present study based on past work. 
 
Reward Sensitivity: Reward sensitivity will be assessed using two behavior economic measures, Delay 
Discounting (DD) and demand curve analyses via the Cocaine-Purchasing Task (CPT). DD describes how 
a reward loses value as a function of increasing delay to its receipt. 53-56 Steeper discounting has been 


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Adapted from NIH protocol template and ICH Guidelines 
 
positively associated with vulnerability to substance use disorders, including CUDs. 57-61  The 
computerized DD task presents the participants with repeated choices between hypothetical monetary 
outcomes. The two choices will be $1,000 after a fixed delay or a smaller, immediate option ranging 
from $5 to $955. The value of the immediate option will be titrated to a point of subjective equality 
using a heuristic based on the participant’s responding. The delay values will range from 1 day to 25 
years, allowing for a complete characterization of the DD function. Dr. Yoon (Co-I) has successfully 
utilized the DD task in a number of previous studies involving substance use disorders including 
cocaine.53, 55, 56, 59, 62 Purchasing tasks such as the CPT simulate changes in price and consumption of drug 
in order to assess demand curves associated with drug consumption. 63-67 Using demand curves, one can 
assess the elasticity of demand associated with changes in drug cost. The CPT asks participants how 
much cocaine they would purchase at the beginning of a hypothetical day as the cost of cocaine 
increases from $0 to $10,000 assuming that: their income and savings are as they usually are; the 
quality/type of cocaine is the kind they normally purchase; no other sources of cocaine are available and 
if they do not buy any cocaine they will not have any to use; any cocaine they purchase must be used 
that day and cannot be saved or sold to others; and their craving and desire for cocaine is similar to how 
they feel that day. Purchasing tasks have been shown to have good test-retest reliability 68, 69 and track 
changes in drug reward sensitivity resulting from treatment. 70 
 
Cue reactivity: Attention bias (AB) task is a saccade-based eye-tracking measurement, developed by Dr. 
Lane to assess attentional bias to drug cues. Eye movements (saccades) have advantages over other 
variables because they are directly observable, ecologically valid, and typically stable across repeated 
measures. AB measures utilizing eye movements have produced moderate to robust effects for a broad 
class abused substances, including cocaine. Using our drug specific anti-saccade task, the between- 
group effect size for anti-saccade error rates in the presence of cocaine cues was large: CUD vs. control 
Cohen’s dav = 0.6 (see Lane protocol HSC-MS-16-0120). A baseline eye tracking session will occur before 
treatment begins and a follow-up session will occur in week 12, at the end of treatment. 
 
Hedonic Capacity. Recent research has developed a neurobiological measure of hedonic (e.g., 
rewarding) capacity through brain responses to pleasant, unpleasant, and drug-cue images that is 
predicative of treatment outcomes in smokers105, 106. Specifically, using cluster analysis, it is possible to 
identify subjects groups with higher and lower likelihood of successful treatment outcomes: smokers 
with a higher Late Positive Potential (LPP) to pleasant images compared to drug-cue images achieve 
more long-term smoking abstinence than smokers with a higher LPP to drug-cue images. There is also 
evidence that a similar effect exists in cocaine use disorder populations, but there are limited studies, 
none of which has applied cluster analysis technique107-110. Picture Viewing Task: Participants will view 
emotional images while we record their EEG. Four categories of images will be displayed including: 
pleasant, unpleasant, neutral and cocaine-related images. The pleasant, unpleasant, and neutral images 
will be selected from the International Affective Picture System (IAPS)111 and cocaine-related images will 
be taken from images previously used for cocaine-cue craving research. The images will be displayed for 
a few seconds followed by a random inter-trial interval that will consist of a black screen with a white 
fixation cross. The trials will be divided into equivalent blocks, separated by a short pauses in which 
participants will have the possibility to relax. The picture viewing task will take approximately 30 
minutes. Self-Assessment Manikin (SAM): Following the picture viewing task, the participants will be 
asked to rate hedonic valence and arousal of the images that they viewed 112. The SAM will take 
approximately 15 minutes to complete. This portion of the study will be taken at baseline and will 
include a separate consent form due to additional exclusion criteria and minor risks for participating in 
an EEG study. Oddball Task: Participants will view a series of letters (English and Chinese) and will be 
asked to respond when the letter “O” appears. This task will task about 10 minutes. Doors Task: During 


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this task, the participants will play a guessing game. They are asked to guess which door has a prize 
behind it. Every time they guess correctly, the participant wins $0.50 and when they guess incorrectly, 
they lose $0.25. The participants can will a total of $7.50 on this task. The task will last about 10 
minutes. 
 
Cocaine Craving. Cocaine craving plays an important role in addiction recovery and relapse. A newer 
brief measure will be used to assess change in craving as a function of treatment at each clinic visit. The 
Brief Substance Craving Scale (BSCS) divides cocaine craving into three domains: intensity, duration and 
frequency. Each domain is measured on a 0–4 likert scale. By adding the three scores a craving 
composite measure can be derived116. An additional cocaine craving measure will be used at baseline 
after consent on the EEG sub-study. The Cocaine Craving Questionnaire-Brief is a shortened version of 
the Cocaine Craving Questionnaire-Now originally created to test the 5 factors of craving (i.e., desire, 
intent, positive expectations, relief, and lack of control)113, 114. The brief form includes items that loaded 
onto “general craving”114. The brief form has established good reliability and validity and predicts time 
to relapse across several demographic populations114, 115. 
 
Salivary biomarkers. Saliva (buccal cell) samples will be collected at repeated time points (baseline and 
treatment weeks 4, 8, and 12) according to a standard commercial kit protocol. Recent studies have 
shown that saliva constituents, i.e., molecular and microbial analytes, may be effective markers of 
disease detection, monitoring, and prognosis. Compared to blood, collection of saliva has advantages in 
terms of being easy to administer, noninvasive, safer to handle, economical, and easy to store. 
Correlations between cocaine use levels during treatment and changes in biomarkers measured in saliva 
will be conducted. 
 
Cocaine use outcomes. The primary outcome measure of cocaine use/nonuse will be based on 
qualitative urine drug screen levels of cocaine metabolite BE, coded as “positive” for cocaine use if BE ≥ 
150 ng/mL. While this objective measure is considered by some to be the gold standard, we realize that 
there is no established, “optimal” outcome measure and that urine-based definitions of cocaine 
use/nonuse have limitations in terms of data loss and carryover effect. Recent procedures for combining 
self-report and urine BE have been recommended.71-73 As a secondary measure of cocaine use/nonuse, 
we will apply the SRPHK1 (SelfReportPHarmacoKinetic1) coding method that classifies daily cocaine 
use/nonuse based on evaluation of self-report using a Timeline Follow-Back (TLFB) 74 method, 
quantitative urine BE levels, and the participant’s concordance rate (agreement between self-report and 
urine result). The SRPHK1 is expected to produce fewer missing data and lower use estimates than 
urine-based only outcomes. 72 We will take advantage of available software programs for applying the 
SRPHK1 conversion. 
 
Safety monitoring. Vital signs assessed at each study visit will include oral temperature, sitting blood 
pressure, pulse, respiratory rate, and weight. If blood pressure is > 140/90, or resting heart rate is above 
100bpm, hold medication and consult with study physician, who will make the determination about 
length of hold, and any additional monitoring or referrals needed prior to continuation. Patients with 
blood pressure readings with either the systolic or diastolic outside the range of 140/90 or resting heart 
rate above 100bpm over 3 consecutive visits will be discontinued from the study medication and 
referred for medical follow-up. There is no protocol for dose reduction with retention in the study, only 
discontinuation. If other AEs are reported, the study nurse will hold medication and consult with the 
study physician, who will make the determination about length of hold, and any additional monitoring 
or referrals needed prior to continuation. Any SAE will result in discontinuation of the study medication 
and referral for medical or psychiatric follow up. AEs that do not meet these criteria (e.g. severe 


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headache) but interfere with the participant’s daily activities and are persistent across 3 consecutive 
visits will also result in discontinuation of study medication and referral for medical or psychiatric follow 
up. The Systematic Assessment for Treatment and Emergent Events (SAFTEE) will be administered by 
trained research staff at each study visit to document patient-reported adverse events, serious adverse 
events, and/or treatment-emergent symptoms. The Concomitant Medications Tracking Log will be used 
to record any medications taken during the study. The study nurse completing the form will enter the 
name of the medication, dose/unit, route of administration, date started/stopped, and indication. 
Reported use of prohibited concomitant medications will be reviewed by the study physician (Dr. 
Weaver, Co-I) who will make a reasonable judgement about continued participation in the study. 
Additional measures will be used to monitor treatment-emergent psychiatric symptoms, including the 
Clinical Global Impression (CGI) scale, a well-established research rating tool for tracking clinical progress 
over study period and evaluating any change in the severity of psychopathology; and the Beck 
Depression Inventory-II, a 21-item, self-report rating inventory that measures symptoms of depression. 
The study physician (Dr. Weaver, Co-I) will be alerted of any psychiatric adverse events or reactions of 
treatment such as suicidality or worsening of mood symptoms. If clinically indicated in cases of 
significant worsening or deterioration of patient’s functioning, appropriate actions will be taken, 
including study termination with proper referral. The Patient-Reported Outcomes Measurement 
Information System short form (PROMIS-10) is a global health assessment tool made publically available 
that allows measurements of general domains of health functioning including overall health, mental 
health, social health, pain, fatigue, and overall perceived quality of life using a 10-item Likert-type scale 
(5 = “Excellent/Completely/Never/None” to 1 = “Poor/Not At All/Always/Very Severe”). 
Suicide ideation and behavior assessment. The Columbia-Suicide Severity Rating Scale (C-SSRS: 
http://www.cssrs.columbia.edu) will be used to assess suicidal ideation and behavior occurrence. The 
CSSRS involves a series of probing questions asked in the patient interview, integrated with information 
from other sources, to classify suicidal ideation and behavior into 11 preferred categories. The full 
assessment will be conducted at the initial intake evaluation for screening and eligibility determination. 
The initial screening questions will be completed at every study visit for every patient by the trained 
study nurse. The study site has physicians (Co-I: Michael Weaver, MD), psychiatrists, and licensed clinical 
psychologist (Investigators: Joy Schmitz, PhD, Angela Stotts, PhD, Angela Heads, PhD, Anka Vujanovic, 
PhD) on site with extensive experience in managing suicidal ideation and behavior according to 
established protocols in our outpatient treatment research clinic. 
 
Analysis Plan 
Bayesian framework. The Bayesian approach addresses the following study questions: 1) What is the 
probability that ACT+CM confers benefit relative to DC+CM on abstinence at end of first treatment; 
what is the best estimate of this effect and what is its precision? 2) Among non-responders at end of 
first treatment, what are the relative probabilities that pharmacotherapy augmentation confers benefit 
at end of second treatment for those initially receiving ACT+CM versus DC+CM; what are the best 
estimates of these effects and what is their precision? 3) Among responders at end of first treatment, 
what is the probability that continued ACT+CM confers benefit relative to continued DC+CM at end of 
second treatment; what are the best estimates of these effects and what is their precision? By 
estimating the probability that such effects exists, we are assessing the probability that the alternative 
hypothesis is true, a probability that is, by definition, not accessible to Frequentist methods. The FDA 
has discussed the use of Bayesian statistical methods to make decisions regarding the efficacy of new 
treatments as an alternative to Frequentist methods in developing clinical applications.75-80 The current 
proposal will provide the best, unbiased estimates for the benefit conferred across treatment 
sequences, conditional upon initial response, while also estimating the probability that such effects 


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exist. Posterior distributions can then be used as informative priors for continued monitoring in 
expansions of treatments and treatment strategies exhibiting initial promise. 
 
Analytic strategy. Broadly, the analytic strategy will use generalized linear modeling. Continuous, 
dichotomous and time-to-event data will utilize linear, logistic, and proportional hazards regression 
respectively. Longitudinal analyses will employ generalized linear mixed models. All of these SAS (ver 
9.3) procedures permit Bayesian analyses. Primary analyses will use intention-to-treat principles, with 
missing observations imputed as positive. Secondary analyses will implement joint modeling of observed 
outcomes and the missing data which is robust to ignorable missingness.81, 82 Sensitivity analyses will 
evaluate robustness of analytic conclusions to missing data. Non-ignorable missing data patterns will be 
addressed through pattern-mixture modeling methods.81 Prior distributions for comparison of 
proportions will use ~Beta(a = 1, b = 1) priors. Linear, logistic and Cox Proportional Hazards regression 
coefficient priors will take the form ~N (mean = 0, var = 1 x 106) in the linear, log (odds) and log scales 
respectively. Level one error variances will be specified as ~Inverse Gamma (shape = 0.001, scale = 
0.001); level two variances will use ~Uniform(0,1000) distributions. Sensitivity analyses using optimistic 
and pessimistic, skeptical priors will evaluate prior assumptions.83, 84 Inverse probability weight will 
permit unbiased effect size estimates in the context of re-randomization. Finally, coding procedures will 
permit identification of each salient effect. Specifically, at the initial randomization ACT+CM and DC+CM 
will be coded as 1 and -1 respectively. For the re-randomization: 1) non-responders receiving 
continuation therapy will be coded 1 while all other participants will be coded 0; 2) non-responders 
receiving augmentation will be coded 1 versus 0 for all other participants. 
 
Hypothesis testing. 
Hyp. 1. Initial treatment with ACT+CM will produce higher response (abstinence) rates than initial 
treatment with DC+CM. Logistic regression will evaluate cocaine-abstinence rates at week 4 as a 
function of treatment assignment. 
Hyp. 1.a. The benefit of ACT+CM over DC+CM on initial response (abstinence) rates will be greater in 
the subgroup of individuals with higher pretreatment EA scores. Adding the interaction term (EA-by 
treatment) to the logistic regression model will evaluate the moderating effect of EA. 
Hyp. 1.b. ACT+CM effects on initial treatment response will be mediated by the primary hypothesized 
treatment mechanisms, EA and reward sensitivity. In the context of the direct effect of treatment on 
response, mediational modeling will evaluate the indirect effect of treatment on response via EA and 
reward sensitivity variables, using the product moment method with bootstrapped 95% CI and Bayesian 
posterior distributions. 
Hyp. 2. For initial non-responders, continued ACT+CM treatment with pharmacotherapy (modafinil) 
augmentation will be most effective in promoting abstinence relative to treatment combinations 
involving DC and/or placebo. Logistic regression will evaluate cocaine abstinence at the end of second 
treatment in a set of contrasts: (1) modafinil versus placebo within each initial treatment; (2) the 
sequence of ACT+CM with modafinil augmentation versus DC+CM with modafinil augmentation. 
Hyp. 3. For initial responders, continued ACT+CM will be more effective (higher abstinence rates; < 
46% relapse rate) than continued DC+CM. Logistic regression will evaluate cocaine abstinence/relapse 
at end of second treatment as a function of initial treatment (ACT+CM vs DC+CM). 
 
Power. Power estimates for Hypotheses 1, 2 and 3 will use as the primary outcome (i.e., “response”), 
two consecutive weeks of cocaine abstinence (BE ≤ 150 ng/mL). Initial treatment response (abstinence) 
rates are expected to be ~40%, based on our previous study 12 and pooled data across cocaine clinical 
trials85; however we predict a difference in response rates, favoring ACT+CM over DC+CM by about 20%, 
constituting a clinically meaningful treatment effect. Among initial non responders, we expect at least a 


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Adapted from NIH protocol template and ICH Guidelines 
 
nherent in pre-e isting empirical evi
ent 
Initial respon 
x 
ater uncertainty 
dence and even gr e
e 
Second Treat 
(8 weeks) 
small treatment effect favoring augmentation with modafinil, based on our previous trials. 29, 31, 32, 43 
Among initial responders, we previously observed that approximately 54% remain abstinent (46% 
“relapse”) over an extended period of treatment, up to 12 weeks. Using this estimate for the control 
group (DC+CM), we predict a difference in response rates, favoring continued ACT+CM by about 15%, 
translating into a relapse rate of about 30%. Importantly, these effect size estimates are derived from 
data in which missing data is counted as non-abstinence, which mirrors the way we will be treating 
missing data for our primary analyses. 
 
Finally, given the uncertainty i 
for conditional probabilities of 
response, prudence dictated 
that robust trial planning rely 
upon probability distributions 
of plausible effects that take 
into account the uncertainty of 
 
 
 
Initial Treatm 
(4 weeks) 
 
 
 
 
 
ACT+CM 
 
 
 
 
s 
(% abstinent) 
 
 
Response 
0.50, 0.39-0.60 
~Beta(a=47.2,b=47.2) 
 
 
 
 
ment 
 
End of treatment 
response (% abstinence) 
 
Continue ACT+CM 
 
Response 
0.70, 0.61-0.78 
~Beta(a=47.3,b=47.3) 
 
 
our predictions of effect, rather 
than simple point-estimates. 
Adoption of distributional 
specification of effect sizes and 
their associated uncertainty 
required implementation of a 
Bayesian statistical approach. 
 
Data Simulation Model. Using 
the above outcome estimates, 
we conducted a Monte Carlo 
simulation study to determine 
predicted power for the 
planned analyses, taking into 
account uncertainty in 
parameter estimates. Figure 
B.3.2.x depicts the trial design 
with probability point-estimates 
and 95% Credible Limits for 
each treatment cell, derived 
from logistic regression models 
with vague neutral priors, 
 
 
 
 
 
 
 
 
 
 
 
DC+CM 
 
Non-Response 
 
 
 
 
 
 
 
Response 
0.30, 0.21-0.40 
~Beta(a=29.7,b=47.9) 
Non-Response 
Continue ACT+CM 
Augment with PLA 
 
Continue ACT+CM 
Augment with MOD 
 
 
 
Continue DC+CM 
 
 
 
Continue DC+CM 
Augment with PLA 
 
Continue DC+CM 
Augment with MOD 
Response 
0.29, 0.22-0.37 
~Beta(a=8.25,b=18.82) 
 
Response 
0.46, 0.37-0.54 
~Beta(a=5.68,b=6.87) 
 
Response 
0.54, 0.43-0.64 
~Beta(a=8.58,b=7.36) 
 
Response 
0.17, 0.12-0.23 
~Beta(a=4.35,b=23.1) 
 
Response 
0.30, 0.23-0.37 
~Beta(a=8.25,b=18.82) 
averaged across K = 500 
simulations.  Simulated results 
*Contrast numbers correspond to numbers in black boxes on Figure B.3.2.x. 
for anticipated cell sizes are shown in italics. Table B.3.2.x displays estimates of power to detect any 
benefit (HA: θ > 0) conferred by the treatment hypothesized as being superior. All primary hypotheses 
demonstrate a > 80% chance of detecting 0.90 probability of benefit for a sample of N = 160. Also 
shown in Table B.3.2.x are the point-estimates and 95% Credible Intervals of specified effects averaging 
over the K = 500 simulations. 
 
Summary. Using data-driven effect sizes that take into account uncertainty, simulation results indicate 
that with a sample size N=160, we have roughly 80% power for all primary hypotheses. Further, we 
stipulate a priori that a > 80% chance of treatment conferring benefit (i.e. Pr (Pr θ > 0|data) > 0.80) 
Table B.3.2.x. 
Posterior 
Power to 
Average 
Average 
Effect 
Probability 
Detect 
Point 
Interval (95% 
Pr(θ>0) 
Pr(θ>0) 
Estimate 
C.I.) Estimate 
Effect of Initial Treatment 
Hypothesis Test Aim 1: 
Contrast 1 vs 2* 
0.90 
0.83 
0.20 
0.05-0.34 
Effect of Second Treatment (Initial non-responders) 
Hypothesis Test Aim 2
Contrast 5 vs 6* 
0.80 
0.81 
0.17 
0.06-0.27 
Contrast 7 vs 8* 
0.80 
0.81 
0.13 
0.05-0.21 
Contrast 6 vs 8* 
0.85 
0.80 
0.16 
0.07-0.25 
Effect of Second Treatment (Initial responders) 
Hypothesis Test Aim 3: 
Contrast 3 vs 4* 
0.85 
0.80 
0.16 
0.07-0.25 


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constitutes sufficient evidence for results from this Stage II project to support a “Go” decision to 
advance to Phase III confirmatory studies. 
 
 
Protection of Human Subjects 
 
Selection Criteria 
Eligible participants will: 
1. 
be between 18 and 60 years of age 
2. 
meet DSM-5 criteria for current cocaine use disorder of at least moderate 
severity (≥ 4 symptoms) 
3. 
have at least 1 positive urine BE specimen (≥ 150 ng/mL) during intake 
4. 
be in acceptable health on the basis of interview, medical history and physical 
exam 
5. 
a agree to use an acceptable method of birth control during study participation 
and for one month after discontinuation of the study medication. Non- 
hormonal methods of contraception are recommended, including barrier 
contraceptives (e.g., diaphragm, cervical cap, male condom) or intrauterine 
device (IUD). Steroid contraceptives if used with non-hormonal methods are 
acceptable. 
6. 
be able to understand the consent form and provide written informed consent 
7. 
be able to provide the names of at least 2 persons who can generally locate 
their whereabouts. 
Exclusion criteria include: 
8. 
current DSM-5 diagnosis for substance use disorder (of at least moderate 
severity) other than cocaine, marijuana, alcohol, or nicotine 
9. 
current alcohol use that meets for physiological dependence requiring 
detoxification or makes participation medically unsafe as determined by the 
medical director. 
10. 
have a DSM-5 axis I psychiatric disorder or neurological disease or disorder 
requiring ongoing treatment and/or making study participation unsafe (e.g., 
psychosis, dementia). 
11. 
significant current suicidal or homicidal ideation 
12. 
medical conditions contraindicating modafinil pharmacotherapy (e.g., major 
cardiovascular disease, severe liver disease based on Child-Pugh score of B or C, 
serious kidney problems) 
13. 
taking medications that could adversely interact with modafinil (e.g., 
propranolol, phenytoin, warfarin, diazepam) 
14. 
having conditions of probation or parole requiring reports of drug use to officers 
of the court 
15. 
impending incarceration 
16. 
pregnant or nursing for female patients 
17. 
inability to read, write, or speak English 
18. 
hair style that is incompatible with EEG nets (for EEG sub-study only) 
19. 
history of epilepsy or seizure disorder (for EEG sub-study only) 
20. 
head injury with loss of consciousness in the last 5 years (for EEG sub-study 
only) 


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All patients who are excluded will be given referral information on other local treatment programs. 
Potential Risks 
 
Medication. Modafinil will be initiated at 300 mg as a single morning dose, as administered in previous 
trials e.g., 30, 32. Standard methods for monitoring medication compliance will be followed, including pill 
counts, analysis of urine samples for riboflavin, observed pill taking at thrice-weekly clinic visits, and 
blister-package pill counts by the study nurse at weekly clinic visits. 
Available safety data suggest a highly favorable risk/benefit profile for this agent. Modafinil is an 
FDA approved medication for treatment of excessive daytime sleepiness or narcolepsy and has been 
administered safely to humans in doses of up to 800 mg 86, 87. In sleep-deprived subjects, modafinil has 
been shown to improve mood, fatigue, sleepiness, reaction time, logical reasoning, and short-term 
memory 88. In addition to its wakefulness-promoting effects, modafinil produces psychoactive and 
euphoric effects typical of other CNS stimulants in humans. Modafinil is partially discriminated as 
stimulant-like 86 and is self-administered by non-human primates 89, but has low abuse potential 86, 87, 
and a neurochemical profile distinct from that of cocaine and amphetamine 90-93. Its safety when 
coadministered with other drugs, including dextroamphetamine 94, 95, methylphenidate 96, and cocaine 
26, 28   has been established. The dose of modafinil to be used in the proposed study is 300 mg/d. This 
dose is in the range recommended for the treatment of narcolepsy. Similar dosages have been 
evaluated in studies of modafinil for the treatment of CUD 32 with favorable safety and efficacy results. 
Modafinil is generally well tolerated, with reported adverse experiences in the mild-to-moderate range. 
Common side effects reported (> 5%) more frequently than placebo include headache, infection, 
nausea, nervousness, anxiety, and insomnia. 
Use of modafinil is contraindicated in individuals with advanced arteriosclerosis, symptomatic 
CVD, moderate to severe hypertension, hyperthyroidism, known hypersensitivity or idiosyncrasy to the 
sympathomimetic amines, and glaucoma. The above conditions will be assessed and treated as 
exclusionary. Modafinil is extensively metabolized by the liver and should be used cautiously in patients 
with impaired hepatic function. Eligibility screening for this study will include a Comprehensive 
Metabolic Panel (CMP) with tests of liver enzymes: alkaline phosphatase (ALP), alanine amino 
transferase (ALT), aspartate amino transferase (AST), Prothrombin time (PT), partial thromboplastin 
time (PTT), and bilirubin. We will apply the Child-Pugh criteria to exclude subjects with stage B or C 
scores, indicating severe liver disease. 
Modafinil is Category C for use during pregnancy. There are no adequate and well-controlled 
trials to describe the full spectrum of potential toxic effects of modafinil on the fetus. No pregnant 
women will be permitted in study. Modafinil interacts with steroid contraceptives such as ethinyl 
estradiol, thus reducing the effectiveness of such methods when used with modafinil and for one month 
after discontinuation of treatment. Inclusion criteria will require that females of child-bearing potential 
use one of the following forms of contraception while participating in the study and for one month after 
discontinuation of medication treatment: non-hormonal methods of contraception, including barrier 
contraceptives (e.g., diaphragm, cervical cap, male condom) or intrauterine device (IUD). Steroid 
contraceptives if used with non-hormonal methods are acceptable. Pregnancy tests will be performed at 
intake and be repeated monthly thereafter. 
Because of the risk of treatment-emergent psychiatric reactions, including mania, delusions, 
hallucinations, suicidal ideation, and aggression, modafinil should be used cautiously in patients with 
history of psychosis, depression, or mania. Eligibility screening for this study will include a complete 
psychiatric diagnosis using the Structured Clinical Interview for DSM-5 (SCID-5) administered by trained 
licensed professional counselors under the supervision of a licensed clinical psychologist. Psychiatric 
exclusion criteria include active psychosis, dementia, or other axis I psychiatric disorders or neurological 


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disease or disorders requiring ongoing treatment and/or making study participation unsafe. In the 
absence of current (past 12 months) symptoms, the study will not exclude individuals reporting a history 
of psychiatric disorders. Such patients, along with all participants, will be monitored weekly during the 
study for treatment-emergent psychiatric symptoms. At each study visit monitoring procedures will 
include (1) The Systematic Assessment for Treatment and Emergent Events (SAFTEE), administered by 
trained research staff at each study visit to document patient-reported adverse events and/or 
treatment-emergent symptoms; (2) the Clinical Global Impression (CGI) scale, a well-established 
research rating tool for tracking clinical progress over study period and evaluating any change in the 
severity of psychopathology; (3) the Beck Depression Inventory-II, a 21-item, self-report rating inventory 
that measures symptoms of depression. Weekly individual therapy sessions conducted by trained 
licensed professional counselors under the supervision of a licensed clinical psychologist will provide 
additional monitoring of treatment-emergent psychiatric symptoms. The study physician (Dr. Weaver, 
Co-I) will be alerted of any psychiatric adverse events or reactions of treatment such as suicidality or 
worsening of mood symptoms. If clinically indicated in cases of significant worsening or deterioration of 
patient’s functioning, appropriate actions will be taken, including study termination with proper referral. 
 
Behavioral Treatment. All participants will receive evidence-based and manual-guided behavioral 
therapies according to their assigned condition. These therapies include Drug Counseling (DC), 
Acceptance and Commitment Therapy (ACT), and Contingency Management (CM) procedures.  CM will 
be used to reinforce abstinence and attendance using the well-established prize-bowl method with 
escalating number of draws for continuous performance of the target behavior. Earned vouchers will be 
redeemed with cash loaded to the ClinCard, a reloadable debit card provided by UTHealth to be used in 
lieu of gift cards. Every ClinCard will be assigned to an individual participant with no identifying 
information made available to outside entities. Subjects will be responsible for replacement card fees 
which reduces the risk of trading cards on the street in exchange for drugs. However, there is always a 
risk of subjects exchanging goods bought with money earned in research studies for drugs or alcohol. All 
efforts will be made to encourage subjects to not participate in this kind of activity. 
 
Psychological. Items on certain questionnaires and interviews might be perceived as psychologically 
discomforting to some subjects. While subjects may be uncomfortable reporting these issues, the risks 
of serious sequelae are extremely low. 
 
EEG Computer Session. Participants in the EEG session may experience skin irritation from the 
placement of the sensors, which is usually treatable and goes away after a few hours. The presentation 
of emotional images may cause an affective response, which typically subsides rapidly after image 
presentation. Participants can chose not to participate in the EEG sub-study and can ask to stop the 
slideshow at any time. 
 
Alternative Treatments. We believe that our therapeutic interventions provide treatment that is 
considerably superior to most, if not all treatment opportunities in the community. Nevertheless, we 
will refer patients to other facilities upon request or when required by other circumstances. 
 
Adequacy of Protection against Risks 
 
Recruitment and Informed Consent 
Participants will be self-referred in response to various study advertisements via newspaper and 
radio.  Individuals who call for information will be given a brief description of the study.  Those 
interested will then be asked to answer questions about their current substance use. A trained research 


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Adapted from NIH protocol template and ICH Guidelines 
 
assistant will conduct this telephone-screening interview. Eligible subjects will be scheduled for an in- 
person intake visit at the Treatment Research Clinic (TRC), the outpatient research and treatment facility 
of the UT Department of Psychiatry and Behavioral Sciences, Center for Neurobehavioral Research on 
Addiction (CNRA).  The first intake appointment will begin with the presentation of the informed 
consent form. The consent form will detail the requirements of study participation (e.g., # of visits, type 
of data collected, time commitment, etc.). 
Subjects will be told that the purpose of the study is to evaluate a strategy for adapting treatments 
for improving cocaine cessation and relapse prevention outcomes. Information about the treatment 
components being studied will be explained. This discussion will include details of the different behavior 
therapies and how CM rewards will be made available during treatment. Subjects will be informed that 
they will attend thrice weekly clinic sessions. Other information on the consent form will include a full 
description of study requirements, reimbursement, risks, benefits, alternatives, and the role of the local 
IRB.  All questions will be answered before written consent is requested. 
Once written consent is given, eligible participants will also be asked if they are interested in 
participating in an optional EEG sub-study. These eligible participants will be informed that participation 
in the sub-study will not affect their treatment or participation in the main study. Interested participants 
will then be given an additional informed consent form that describes the purpose, reimbursement, 
risks, benefits, and alternatives specific to the sub-study to review and sign. 
All research conducted at the Substance Abuse Research Center requires approval by the 
Committee for the Protection of Human Subjects (CPHS) of the University of Texas Health Science 
Center - Houston.  The trial will be registered and updated on clinicaltrials.gov. 
 
Protection Against Risk 
The following procedures will be taken to safeguard against adverse medication events: (1) careful initial 
intake evaluation to determine eligibility based on inclusion/exclusion criteria; (2) thorough physical 
evaluation prior to treatment, consisting of physical examination, standard laboratory tests, 
electrocardiogram, urine toxicology screen, pregnancy test and vital signs; (3) weekly review of 
treatment response, adverse events, concomitant medication use, and medication compliance; (4) 
regular evaluation by the study physician and Medical Director of the CNRA, Dr. Michael Weaver (Co-I). 
Modafinil interacts with CYP3A4/5 and CYP2C19 substrates. At the initial intake evaluation, the 
study coordinator and/or nurse will screen potential subjects against the list of prohibited concomitant 
medications (“conmeds”) including those metabolized by CYP3A4/5 (e.g., steroidal contraceptives, 
cyclosporine, midazolam, triazolam, quetiapine) and CYP2C19 (e.g., phenytoin, diazepam, propranolol, 
omeprazole, clomipramine). Enrolled subjects will meet with the study nurse weekly during treatment 
to assess for any new medications. The Concomitant Medications Tracking Log will be used to record 
any medications taken during the study. The study nurse completing the form will enter the name of the 
medication, dose/unit, route of administration, date started/stopped, and indication. Reported use of 
prohibited conmeds will be reviewed by the study physician (Dr. Weaver, Co-I) who will make a 
reasonable judgement about continued participation in the study. 
All participants will be monitored weekly during the study for treatment-emergent psychiatric 
symptoms. At each study visit monitoring procedures will include (1) The Systematic Assessment for 
Treatment and Emergent Events (SAFTEE), administered by trained research staff at each study visit to 
document patient-reported adverse events and/or treatment-emergent symptoms; (2) the Clinical 
Global Impression (CGI) scale, a well-established research rating tool for tracking clinical progress over 
study period and evaluating any change in the severity of psychopathology; (3) the Beck Depression 
Inventory-II, a 21-item, self-report rating inventory that measures symptoms of depression. Weekly 
individual therapy sessions conducted by trained licensed professional counselors under the supervision 
of a licensed clinical psychologist will provide additional monitoring of treatment-emergent psychiatric 


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Adapted from NIH protocol template and ICH Guidelines 
 
symptoms. The study physician (Dr. Weaver, Co-I) will be alerted of any psychiatric adverse events or 
reactions of treatment such as suicidality or worsening of mood symptoms. If clinically indicated in cases 
of significant worsening or deterioration of patient’s functioning, appropriate actions will be taken, 
including study termination with proper referral. 
Modafinil is a schedule IV controlled substance. Our research pharmacy holds a current DEA 
Certificate of Registration (DEA Form 223) and complies with DEA Security Requirements regarding the 
storage of controlled substances in securely locked and substantially constructed cabinets. Inventory 
and recordkeeping requirements adhere to the DEA practitioner’s manual. To prevent diversion, the 
pharmacists dispense one weeks’ worth of study medications directly to the Research Nurse, who 
administers the medications directly to each study participant. Unused pills are returned by the patient 
to the study nurse at weekly scheduled clinic visits. 
Confidentiality will be protected in several ways. All information collected solely for research 
purpose will be kept in locked, restricted access files. Subject records will be coded and filed by a 
number code. Subject identities will not be revealed in any publication of the data. Individual subject 
information will be transferred to outside sources only with the express written request of the subject. 
Subjects will receive a copy of their signed consent form. 
 
Potential Benefits of the Proposed Research to the Subject and Others 
All assessment and treatment services provided in this study will be at no cost to the subject. The 
treatments should help in stopping cocaine use and preventing relapse. Subjects will be told if unusual 
information is discovered during the study that will make a difference in treatment for this or other 
problems. By taking part in this research subjects will help others with similar problems because this 
study is likely to identify what types of treatment work best and for whom. 
 
Importance of the Knowledge to be Gained 
Research participation may assist subjects in abstaining from cocaine during treatment and beyond. 
Cocaine dependence is highly prevalent and leads to devastating consequences on a personal and 
societal level. Current treatment approaches are delivered using a fixed-intervention approach. This 
project aims to develop newer adaptive treatment approaches that “tailor” interventions according to 
individual patient response. We predict this adaptive approach will optimize outcome and more closely 
mirror actual clinical practice. 
The above stated risks are relatively mild in degree and procedures have been designed to minimize 
their probability. We believe this protocol has an extremely favorable risk/benefit ratio. Our research 
center has an excellent track record in conducting controlled trials with the utmost attention to safety. 
 
Data and Safety Monitoring Plan 
This plan describes the general data and safety monitoring procedures for the proposed study. A 
detailed DSM plan will be submitted for approval prior to starting the study. 
 
1. 
The Principal Investigator (Schmitz) will be responsible for knowing the policies of the local IRB 
(the UT – Houston Committee for the Protection of Human Subjects, CPHS). The PI will adhere to CPHS 
policies and maintain accurate documentation of CPHS correspondence and reports (e.g., annual 
report). The PI will be responsible for documentation and handling of all possible study-related adverse 
events. The Treatment Research Clinic (TRC) within our Center for Neurobehavioral Research on 
Addictions (CNRA) has longstanding data collection and safety monitoring systems in place that will be 
available for the proposed study. These include staff training, manual driven processes, weekly audit of 
data collection/entry, medical screening with results reviewed by on-site nurse and physician, use of 
standardized assessments, continued medical monitoring during treatment, use of a certified (CLIA) 


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analytical laboratory to perform urine toxicology testing, procedures to monitor medication compliance 
(e.g., riboflavin), collaboration with Dr. Green (Co-I) who oversees data analysis and system 
management. Dr. Schmitz will assure that the above systems are in place and functioning properly for 
the duration of the study. 
 
2. 
A DSM Board will be formed to provide additional, independent oversight of data related to 
patient safety. Membership will include Drs. Marianne Marcus (UT-School of Nursing), Edward Fann 
(Baylor College of Medicine-Psychiatry, Anne Dougherty (UT-Department of Internal Medicine, 
Cardiology) and Tom Newton (Baylor College of Medicine). These individuals have served previously on 
the DSMB for our P50 grant and thus have the relevant expertise and experience in monitoring clinical 
trials.  This committee will perform the following activities:  (a) review the research protocol and plans 
for data and safety monitoring; (b) evaluate study progress, including data quality, participant 
recruitment rates, retention rates, outcome and adverse experience data, and risk versus benefit profile; 
(c) make recommendations to terminate the trial because of safety concerns; and (d) protect the 
confidentiality of the trial data and the results of monitoring. 
 
3. 
Adverse events (AE) will be reported to the UT-CPHS on an annual basis. Serious adverse events 
will be reported immediately (verbally within 24 hours) to the UT-CPHS, the DSMB, and to the NIDA. A 
written report will follow as soon as possible but in no more than three days. The written report will be 
in the format required by the CPHS and will contain information regarding the date of the AE, 
description of the AE, severity rating (Grade 1 to 4), assessment of cause, whether the AE indicates an 
increased risk for current or future subjects, and whether changes to the informed consent form are 
necessary. 
 
 
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