Clinical trial NCT03424681
Conditions: Alcohol Use Disorder
Sponsor: The Mind Research Network
Start date: 2017-12-11; Completion date: 2018-08-31
Enrollment: 12 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
Alcohol use disorder (AUD) is a major cause of morbidity and mortality and more treatments are needed, especially pharmacotherapies. There are a variety of efficacious treatments for AUD, but effect sizes are small, and vary from study to study. Medications may be more effective if particular subgroups of AUD are targeted. Identifying the mechanisms of action of a particular medication will help identify the subtypes more likely to respond to therapy. Global impulse control is a rational treatment target, and improving it is a likely mechanisms by which some medications for AUD work, especially in subtypes of AUD with impaired impulse control at baseline. Modafinil is a medication that is FDA approved for the treatment of narcolepsy, and is relatively safe and tolerable. There is reason to believe it may improve impulse control, and underlying neural circuitry, and may work best to improve alcohol use outcomes in AUD with poor impulse control. The overall aim of this study is to investigate the effects of modafinil on task performance and the integrity of neural circuits mediating response inhibition in treatment-seeking AUD with poor response inhibition, to establish target engagement. Secondary aims are to measure whether target engagement mediates improvement in alcohol use outcomes, and to utilize machine learning to identify neural and behavioral markers which best predict treatment outcomes. Twenty-four individuals with AUD and impaired response inhibition will be enrolled in the study, randomized to modafinil or placebo, and treated for 6 weeks. Functional magnetic resonance imaging brain scans during a response inhibition task and during rest will be obtained at baseline and 2 weeks. Aversive stimuli will be included in the response inhibition task to assure that efficacy generalizes to several conditions. Diffusion imaging and arterial spin labeling sequences will also be obtained. Investigators predict that modafinil will significantly increase brain activity in the medial and lateral prefrontal cortex during response inhibition, thereby establishing target engagement, and that it will improve alcohol use outcomes. Findings will provide information about whether or not a larger R01 trial investigating the efficacy of modafinil for individuals with AUD and impaired response inhibition is warranted.

Detailed description:
see above.

Arms: arm 1: Modafinil 300 mg by mouth each day arm 2: Identical looking capsule/number of capsules by mouth each day without active medication
Interventions: intervention 1: Modafinil intervention 2: Placebo
Intervention descriptions: intervention 1: Modafinil 300 mg by mouth daily intervention 2: Placebo

Protocol documents:
Prot_SAP_000.pdf: 
1 
 
 Protocol Title (01/30/2018) 
Modafinil for the treatment of alcohol use disorder: targeting impaired response inhibition 
(Version 01/30/2018) 
 Principal Investigator 
Claire Wilcox MD, Mind Research Network, 505-633-8102, cwilcox@mrn.org 
 Funding Agency 
National Institutes of Health (NIH) [specifically, National Institute of General Medical 
Sciences (NIGMS), a subdivision of NIH] 
 IRB Review History 
Previously approved by University of New Mexico, Human Resources and Review 
Committee, transferred due to change of employer of the Principal Investigator. At the 
time of transfer, 5 participants have been consented, 4 discontinued (deemed ineligible 
based on stop signal reaction time), 1 enrolled but not yet initiated on treatment or 
randomized. 
 Objectives 
Hypotheses and Specific Aims:  
Alcohol use disorders (AUD) are pervasive and have significant individual and societal costs1. 
While three FDA approved medications are available for the treatment of AUD, effect sizes tend 
to be modest, and results frequently inconsistent2-6. Important to recognize, AUD medication 
effects may be masked by heterogeneity in patient samples and by specific sub-types within the 
AUD spectrum2,4-17. An NIH-wide initiative, Precision Medicine18, has recently embraced the 
importance of patient-treatment matching to produce optimal patient outcomes, a central theme 
of the Mechanisms of Behavior Change conference in 2016 at the Research Society on 
Alcoholism. Responding to this initiative, this application seeks to prospectively investigate the 
promising moderating effects of response inhibition on a new medication for the treatment of 
AUD.  
Modafinil is FDA-approved to treat narcolepsy, is safe, and works by increasing synaptic 
dopamine and norepinephrine19,20. In the only study in which modafinil was tested for the 
treatment of AUD, no main effect was found supporting that modafinil reduced alcohol 
consumption21. Likewise, in the treatment of other SUD, studies of this medication have shown 
mixed effects on substance use22-32. However, preliminary evidence suggests that modafinil 
matches to the particular characteristic of impaired response inhibition (i.e., a reduced ability to 
withhold a pre-potent response)21 which is a characteristic of approximately 60% of individuals 
with AUD21(C.1). Specifically, in a post hoc analyses of the single study of modafinil in AUD21, 
individuals with impaired response inhibition [as defined by a stop signal reaction time (SSRT) 
of > 233] had a reduction in drinking with a fairly large effect size [effect size time to relapse 
(TTR) d=.84, percent days abstinent (PDA) d=.50] which are much larger than effect sizes of 
naltrexone (FDA-approved for the treatment of AUD) on heavy drinking observed from a meta-
analysis (0.19)5. The primary goal of this study is to offer the first prospective test of the 
effect of modafinil on drinking in individuals with AUD with impaired response inhibition 
compared to individuals with normal response inhibition.  
Establishing biological mechanisms of treatment (target engagement) in clinical trials is also an 
NIMH-wide initiative33 endorsed by NIAAA; response inhibition is a likely target for SUD34. To be 
a mechanism, a target must both be 1) mobilized by the treatment, and 2) changes in the target 
must predict changes in the outcome of interest33. Regarding the former (1), there is evidence 
that modafinil improves response inhibition35-38 and related metrics such as working memory 
and attention37-44 in a variety of populations. However, curiously, while response inhibition was a 


2 
 
matching variable (predicted response to treatment) in the aforementioned modafinil trial in 
AUD21, response inhibition was not altered by active treatment, even in the impaired response 
inhibition subgroup, although self-reported impulse control improved. Further work using a wider 
array of potentially more sensitive measures (response inhibition in the presence of 
emotional/alcohol cues), and other related metrics of cognitive function (working memory), 
obtained at a higher frequency are needed to test for target engagement in AUD undergoing 
treatment with modafinil. Regarding the latter (2), although individuals with impaired response 
inhibition do worse in treatment45-47, improvements in response inhibition correlate with drinking 
reductions48,49 and treatments targeting response inhibition predict drinking reductions in heavy 
drinkers50 no study has demonstrated that improvement in response inhibition predicts 
reductions in drinking in AUD. Our second set of goals will be to explore the mechanisms 
of effect of modafinil on alcohol use outcomes in AUD. 
There is reason to believe that blood-oxygen-level dependent (BOLD) signal during response 
inhibition [obtained by performing a task while undergoing a brain functional MRI (fMRI) scan] 
may be a more sensitive predictor of substance use51,52 and other clinically-relevant outcomes53 
than task performance. Hypoactivation in dorsomedial prefrontal cortex (dmPFC) and lateral 
prefrontal cortex (lPFC) are markers of impaired response inhibition in a variety of 
populations46,54-56. Moreover, modafinil increases dmPFC activation during response inhibition 
tasks after a single dose in AUD38. 
 
25 treatment seeking adults with AUD will be recruited from local treatment centers and 
randomized to treatment with either placebo or 300 mg of modafinil daily for 6 weeks in a 
double-blind placebo-controlled trial. Measures of response inhibition21, other cognitive 
domains, impulsivity, and drinking will be collected at baseline, 2 and 4 weeks. fMRI scans will 
be obtained at baseline and 2 weeks after initiation of either medication or placebo (2 scans per 
participant) while performing an emotional Go/No-Go (GNG) task57. 
Aim 1: To investigate the effects of modafinil on alcohol use outcomes in treatment-
seeking AUD. Modafinil will improve alcohol use outcomes relative to placebo in individuals 
with impaired response inhibition (SSRT>233) with a larger effect size than individuals with 
normal response inhibition (SSRT<233). If effect size calculations show a moderate to large 
effect in the expected direction, this will provide pilot data for an NIH application. 
Aim 2: To investigate the mechanisms of effect of modafinil on relevant self-report, 
neuropsychological testing, and fMRI measures and to establish the most robust 
measure of its mechanism in AUD with poor response inhibition. Modafinil will improve 
response inhibition relative to placebo and improvements in these metrics will predict reductions 
in alcohol use and will mediate the beneficial effect of modafinil on alcohol use outcomes, in 
individuals with impaired response inhibition.  Modafinil treatment relative to placebo treatment 
will improve response inhibition (performance) and increase dmPFC and lPFC activation during 
response inhibition (No-Go vs Go trials) to both neutral and aversive stimuli. 
 Background 
The promise of Precision Medicine in AUD: Alcohol dependence accounts for 4% of the global 
disease burden1, and, although effective pharmacotherapies for AUD exist, effect sizes are 
often small5 and findings do not replicate from study to study3-6. AUD is heterogeneous, and 
medications for the treatment of AUD may be more effective if particular subgroups are 
targeted2,4-17. Indeed, Precision Medicine18 is an initiative that is being pushed not only in AUD, 
but across NIH divisions, with the recognition that heterogeneity may be masking treatment 
effects across a variety diagnoses. 
Modafinil as a medication for which client heterogeneity may be masking effects during AUD 
treatment: Modafinil has been most studied in SUD populations as a treatment for stimulant use 
disorder (StimUD). In these studies, effects of modafinil on substance use outcomes were 
mixed22-32, with only 3 studies showing effects of treatment on substance use in the whole 


3 
 
sample. However, subgroup analyses showed that poor adherence28,29,32, too high of a dose27,29-
31, and comorbid other SUD28 may have contributed to negative findings. Especially important, 
however, is that none of the trials in StimUD reported on whether response inhibition was 
a predictor of response to modafinil. There has only been a single treatment trial of modafinil 
in AUD thus far21. In this study, individuals undergoing residential treatment also received 
300mg modafinil treatment for 10 weeks. Individuals were still in residential treatment during 
most of the trial. Although there was no significant effect of modafinil in when the whole sample 
was analyzed, SSRT predicted treatment response, such that individuals with poor response 
inhibition (SSRT>233) had greater increases in PDA on modafinil relative to placebo (p=.07, 
d=.50) and prolonged TTR (p=.02, d=.84). Targeting AUD with poor response inhibition may 
significantly enhance effects of modafinil on alcohol use outcomes. 
The importance of establishing target engagement early on in treatment studies: Identifying the 
mechanisms by which a treatment works, which involves establishing that the treatment 
improves a measure of the mechanism, and that changes in the mechanism predict changes in 
the disorder, is another incentive within NIH33,34. Establishing target engagement during 
early phases of pharmacotherapeutic treatment studies in AUD will inform future 
research and clinical practice. Successful target engagement (i.e., modulation of response 
inhibition by modafinil) even in conjunction with a failed trial (i.e., no change in drinking) would 
suggest that the proposed mechanism is not related to outcome. Moreover, the absence of 
target engagement with a concurrent positive clinical effect would indicate that the treatment is 
not working via the hypothesized mechanism. Response inhibition falls within the Cognitive 
Systems domain of the Research Domain Criteria (an NIMH-initiative to organize functional 
dimensions of behavior and treatment targets)58. 
Response inhibition, cognitive control, and impulsivity: In SUD, response inhibition is impaired. 
Furthermore, it is considered to be a biological mechanism, and is therefore a likely treatment 
target34,46. Defined as the ability to withhold a pre-potent behavior, it is commonly measured with 
Stop Signal (SST) or a Go No-Go (GNG) task46 . Response inhibition falls into the broader 
category of cognitive control, which includes working memory, and has been found to be related 
to response inhibition in terms of task performance and the neural circuitry involved 34,41,46. 
Furthermore, response inhibition is often correlated with self-reported impulsivity and delay 
discounting, the latter a measure of the ability to delay reward46,59-61. In summary, response 
inhibition, cognitive control, and impulsivity are related constructs, but the relative importance of 
their roles in AUD is still not entirely clear. 
Response inhibition as a likely target of modafinil treatment: Modafinil is FDA-approved to treat 
narcolepsy and works, in part, by increasing synaptic dopamine and norepinephrine19,20,62-64, 
neurotransmitter systems which regulate response inhibition65-67. Modafinil improves response 
inhibition in rodent models with low levels of response inhibition68 and in single-dose studies in 
non-substance disordered humans35,36. The beneficial effects of modafinil on response 
inhibition37,38, impulsive decision making41, and other cognitive control tasks40,42-44,69 carry over 
into AUD and other SUD both in single dose studies37-41 and in studies where the medication is 
given over days to weeks42-44. This is especially true for individuals with more room for 
improvement 
(greater 
SUD 
severity, 
higher 
impulsivity, 
or 
poorer 
baseline 
task 
performance)37,40,42,43,69. In single-dose studies modafinil normalizes the neural circuitry recruited 
during tasks of response inhibition38 and related cognitive functions39,41 in AUD and StimUD70, 
changes which were also associated with improvements in performance. Modafinil may 
improve response inhibition and related metrics in AUD especially in individuals with poor 
response inhibition. Notably, although baseline SSRT was a matching variable in the single 
clinical trial of modafinil in AUD21, SSRT did not decrease even when the subgroup with poor 
response inhibition was targeted. However, working memory, when targeting those with the 
lowest levels worst working memory at baseline, did improve in this same population on 
modafinil42 and in other populations43,44. The absence of an effect of medication on SSRT may 
have been due either to the fact that the SSRT was obtained too infrequently (every 5 weeks), 
that abstinence-related effects on response inhibition in the whole sample masked medication 


4 
 
effects and/or that the task was not sensitive enough to measure the underlying construct of 
interest. To address these, we will test cognitive function more frequently, and we will include a 
larger array of measures, which will include tests of working memory and tests of response 
inhibition during exposure to alcohol or aversive stimuli. Response inhibition performance can 
be profoundly affected by environmental cues such as drug/ alcohol cues or during emotional 
arousal56,71-86. By obtaining more sensitive measures of response inhibition at more 
frequent intervals, we will improve our chances of finding effects, if present.  
Brain activation during response inhibition as an important target for AUD treatment: Response 
inhibition is defined as the ability to withhold a pre-potent behavior and is most commonly 
measured with stop signal, go no-go or continuous performance tasks46. There is reason to 
believe that blood-oxygen-level dependent (BOLD) signal during response inhibition may be a 
more sensitive predictor of substance use51,52 and other clinically-relevant outcomes53 than task 
performance. These tasks activate lateral PFC (lPFC) [dorsolateral prefrontal cortex (dlPFC), 
ventrolateral prefrontal cortex (vlPFC)/inferior frontal gyrus (IFG) (BA 44/45)], inferior parietal 
lobe (IPL), dorsomedial prefrontal cortex (dmPFC), [dorsal anterior cingulate cortex (dACC), 
pre-supplementary motor area (pre-SMA) and supplementary motor area (SMA)], dorsal 
striatum, and thalamus46,54,55,57. Decreased activation in lPFC and dmPFC during response 
inhibition is observed in clinical groups with higher impulsivity, higher rates of past and future 
substance use and poor response inhibition46,51,54,55,87,88. In addition, individuals with AUD 
compared to controls, or with greater AUD severity, demonstrate lower activation in dmPFC and 
lPFC46,88-90  and in subcortical regions (putamen38 and thalamus88). Therefore, for our purposes, 
an increase in dmPFC and lPFC activation during response inhibition will indicate 
normalization of brain function in this subgroup with known behavioral deficits.  
Change in response inhibition as a likely mechanism by which treatments for AUD work: 
Impaired response inhibition theoretically contributes to greater AUD severity by increasing 
sensitivity to drug cue-induced craving91,92 or by globally impairing the ability to withhold a pre-
potent response, like reaching for a drink, in the context of cue-exposure93. Indeed, impaired 
response inhibition is predictive of later development of SUD94,95 as well as poorer response to 
treatment in AUD45-47. Relatedly, brain activation during response inhibition96-98predicts worse 
treatment outcome. Importantly, treatments or trainings which increase response inhibition are 
also associated with improvements in drinking in AUD48,49and heavy drinkers50,99, but whether 
these associations are driven by reductions in response inhibition (establishing it as a 
mechanism) or whether the drinking reductions are driving the improvements in performance in 
AUD48,49 is not clear. Therefore, although studies indicate it is a good mechanistic candidate, no 
study has definitively established response inhibition as a mechanism. 
 Preliminary Data: Our previous work demonstrates we can successfully carry out the 
proposed project. First, in terms of retention, the PI has recently completed a 6-week 
randomized placebo-controlled clinical trial of prazosin for the treatment of AUD in which 
individuals received a battery of self-report, neuropsychological tests, and an fMRI scan before 
and after 3 weeks of treatment (K23 AA021156; PI Dr. Wilcox). 78% of the 36 individuals 
initiated on medication were available for collection of follow-up data at 6 weeks. Second, data 
was collected from 10 participants with AUD who underwent a SST identical to the task which 
identified response inhibition as a moderator21 and the task we will use as our matching variable 
in the proposed study. Approximately 60% of participants had a SSRT>233, which is similar to 
what was seen in the clinical trial in AUD21. Third, we are well-prepared to do the study and the 
analyses, having conducted two definitive reviews on the roles of cognitive control and emotion 
regulation in SUD46,84, and treatment implications. A manuscript is in preparation for the clinical 
outcomes analyses on the prazosin dataset, and analyses are complete. Fourth, together the 
three Intensive Outpatient Treatment Programs (IOPs) we will be recruiting from enroll 
approximately 50 AUD per month, 30 of which would likely meet criteria for screening, of which 
60% would be likely to have impaired response inhibition. 


5 
 
 Inclusion and Exclusion Criteria 
Inclusion Criteria. Participants will be required to meet the following criteria to be eligible for 
enrollment: 1) males and females age 18-65 meeting DSM-V criteria for moderate or severe 
AUD in the past year; 2) interested in reducing or quitting drinking; 3) able to provide voluntary 
informed consent; 4) have at least 4 heavy drinking days (≥ 5 drinks per day for men, and 4 for 
women) in the past 60 days.  
Exclusion Criteria. Participants will not be eligible for enrollment (excluded) if they meet the 
following criteria: 1) severe neurological conditions (severe TBI100/stroke/active seizure 
disorder); 2) heart disease [mitral valve prolapse, left ventricular hypertrophy, cardiac 
arrhythmias, angina, myocardial infarction, unstable angina, cardiac syncope or pre-syncope, 
any electrocardiogram (ECG) finding that suggests the presence of one of these conditions]; 3) 
uncontrolled hypertension (SBP >160, DBP >100); 4) heart rate greater than 70% of the 
maximum expected for age [0.70(220-age)]; 5) chronic renal or hepatic failure; 6) recent 
pancreatitis; 7) insulin-dependent diabetes; 8) other urgent medical problems; 9) elevated liver 
function tests (AST or ALT greater than 4 times normal; modafinil is metabolized primarily by the 
liver101); 10) schizophrenia, schizoaffective disorder, Bipolar I disorder, suicidal thoughts in the 
last month; 11) current moderate or severe other SUD (except nicotine or marijuana); 12) active 
legal problems with the potential to result in incarceration; 13) pregnancy or lactation, or child 
bearing age and not on birth control; 14) current daily use of anti-craving medications, 
stimulants, benzodiazepines, 
opiates, anti-psychotics; 
current daily 
use 
of 
tricyclic 
antidepressants, bupropion, monoamine oxidase inhibitors, serotonin and norepinephrine 
reuptake inhibitors, or therapeutic doses (for bipolar disorder) of mood stabilizers; 15) taking a 
medication contraindicated for use with modafinil; 16) meet safety criteria to undergo an MRI 
scan; 17) taking the following medications: acebrophylline, asunaprevir, axitinib, bedaquiline, 
bosutinib, cobimetinib, dasabuvir, deflazacort, elbasvir, flibanserin, grazoprevir, iobenguane I, 
neratinib, nisoldipine, olaparib, ranolazine, simeprevir, sofosbuvir, sonidegib, velpatasvir, 
venetoclax. 
Modafinil can interact with metabolism of several medications, either increasing or decreasing 
the levels of these medications. Some of these are listed in the exclusion criteria because they 
are exclusionary for other reasons (psychiatric medications that could affect the fMRI signal or 
impulse control such as tricyclic antidepressants, monoamine oxidase inhibitors, antipsychotics, 
benzodiazepines). For each participant, prior to initiating study medication, the study physician 
will research all possible interactions with any medications a participant is taking, and on a 
case-by-case basis, determine whether it is safe to proceed with initiating the study medication, 
whether increased vigilance is needed during monitoring for side effects, and, if necessary, 
whether medication doses need to be adjusted (of either study medication or of the medications 
they are taking for other conditions, in collaboration with the participant’s prescribing physician, 
with participant permission).  
In addition, modafinil can decrease concentrations of hormonal contraception. Therefore, 
participants will be required to utilize additional modes of contraception (e.g. barrier methods) 
while on study medication.  
Criteria for undergoing the MRI scan: All participants must have a negative urine pregnancy test 
and no contraindications to receiving an MRI scan (MRI safety screening form) in order to 
undergo the MRI scans. Participants with positive urine drug screen for marijuana, cocaine, 
amphetamine, opiates or benzodiazepines plus reported use within the last 24 hours; for alcohol 
use within the last 24 hours; or who have a CIWA102 >= 8 will be asked to reschedule their 
assessment visit within the next 4 days. 


6 
 
 
Multi-Site Research 
N/A 
 
Study Timelines 
Individual participant’s involvement will last a total of 14.5 hours over approximately 11 weeks. It 
is estimated to take approximately a year to complete enrollment.   
 Study Endpoints 
Primary endpoints occur at week 2, 6 and 10.  The study will close to enrollment after at 
least 25 participants have completed all study procedures.   
 
Study Methods  
 
Study Overview Table:  
Week 
 
-1 
-.5 
0 (baseline) 
1 
2 
3 
4 
6 
10 
Intervention 
Phone 
Scree
n 
Consent, 
SST, 
SCID 
I, 
TLFB, 
Vitals 
History 
& 
Physical, 
Lab Draw, 
ECG, 
Vitals 
Initiate Meds, 
Assessment, 
Vitals 
Med 
Visit, , 
Vitals 
Med 
Visit, 
Assessment, 
Vitals 
Med 
Visit, 
Vitals 
Med Visit, 
Assessment, 
Vitals 
Assessment 
Phone 
assessment 
Compensation 
($) 
0 
30 
30 
60 
 
70 
 
70 
40 
40 
Time (hours) 
.25 
2.5 
1.5 
3.5 
.5 
3.0 
.5 
1.5 
1 
.5 
Adverse Events will be evaluated for at week 1,2,3,4,6,10. 
SST: Screening stop signal task. 
TLFB: Timeline follow-back for daily alcohol and other drug use history. 
SCID: Interview for exclusionary psychiatric diagnoses and other substance use disorder 
diagnoses.  
• 
Initiate Meds: Symptom checklist, BAL, urine drug screen, urine pregnancy test, CIWA102 
for alcohol withdrawal. 
• 
Med Visit: Symptom checklist, BAL, urine drug screen, adherence and pill counts, 
CIWA102 for alcohol withdrawal, urine pregnancy test. 
• 
Week 0 Assessment: TLFB between screening visit and current date, impaired control103 
and craving104. Emotional and Alcohol Go No-Go, digit span task42,105, Kirby Delay 
Discounting task106, the PROMIS anxiety, depression, and anger scales107,the State 
Difficulties in Emotion Regulation Scale108 an emotional n-back task109, and the 
Pittsburgh Sleep Quality Index110 and Epworth Sleepiness Scale111.  Rivermead Post-
Concussion Symptoms Questionnaire112, Alcohol Dependence Scale113, Fagerstrom 
Test 
for 
Nicotine 
Dependence114, 
AUDIT115, 
intelligence 
(WTAR116), 
Barratt 
Impulsiveness Scale (BIS)59, UPPS117, the Adult ADHD Self-report scale21,29, motivation 
(Stages of Change Readiness and Treatment Eagerness Scale118), Treatment Services 
Review119, Difficulties in Emotion Regulation Questionnaire120 and Emotion Regulation 
Questionnaire121, urine pregnancy test, urine drug test, MRI safety screening form, fMRI 
scan. 
• 
Week 2 Assessment: TLFB between Week 0 and current date, impaired control103 and 
craving104. Emotional and Alcohol Go No-Go, digit span task42,105, Kirby Delay 
Discounting task106, the PROMIS anxiety, depression, and anger scales107,the State 
Difficulties in Emotion Regulation Scale108, the stop signal task, an emotional n-back 
task109, and the Pittsburgh Sleep Quality Index110 and Epworth Sleepiness Scale111, urine 
pregnancy test, urine drug test, MRI safety screening form, fMRI scan. 
• 
Week 4 Assessment: TLFB between Week 2 and current date, impaired control103 and 
craving104. Emotional and Alcohol Go No-Go, digit span task42,105, Kirby Delay 
Discounting task106, the PROMIS anxiety, depression, and anger scales107,the State 
Difficulties in Emotion Regulation Scale108 an emotional n-back task109, and the 


7 
 
Pittsburgh Sleep Quality Index110 and Epworth Sleepiness Scale111, urine pregnancy 
test. 
• 
Week 6 Assessment: TLFB between Week 4 and current date, impaired control103 and 
craving104. PROMIS anxiety, depression, and anger scales107,the State Difficulties in 
Emotion Regulation Scale108 Pittsburgh Sleep Quality Index110 and Epworth Sleepiness 
Scale111, urine pregnancy test. 
• 
Phone Assessment: TLFB between Week 6 and Week 10, impaired control103 and 
craving104. 
 
Screening/Consent Visit (Week -1) 
At the first visit, participants will undergo a consent process. Participants will meet with the 
coordinator if they pass the phone screen and will go over any questions about the consent and 
study with the coordinator at this first in-person visit. Individuals will indicate their consent to 
participate in the study by signing and returning the informed consent form. If they consent to be 
in the study, they will then undergo the Screening SST to establish which response inhibition 
subgroup they belong to (impaired=SSRT>23321, normal=SSRT<233) followed by a Structured 
Clinical Interview (SCID) for Psychotic, Anxiety, Mood, and Drug and Alcohol Use Disorders122 
to establish whether they have moderate to severe AUD and/or exclusionary SUD and 
psychiatric disorders. A 90 day timeline follow-back (TLFB)123 will also be performed to establish 
adequate drinking levels for inclusion. If participants are experiencing clinically significant active 
alcohol withdrawal (CIWA>8102) they will be asked to have their withdrawal treated before 
returning to initiate treatment in the study. All participants will complete the safety screening 
form for fMRI to determine eligibility for undergoing the fMRI portion of the study. All research 
forms will be labeled with a code and all identifiers will be securely kept separate from the 
research forms. 
Screening Physical (Week -.5) 
All participants will then undergo a screening physical at which they will have a medical history 
and physical exam by the study physician to determine safety for initiation of modafinil. Blood 
work, EKG, vital signs, and a urine pregnancy test will be obtained at this visit. 
Randomization 
All individuals who pass the screening will be randomized to receive: 1) modafinil, or 2) placebo. 
Urn randomization procedures will be utilized to ensure groups are matched on recruitment site 
and response inhibition subgroup (impaired: SSRT > 233, normal: SSRT < 233). The PI will 
generate the randomization scheme and the pharmacist will perform the randomization. Besides 
the pharmacist, all study personnel will be blinded to condition. 
 
Study Intervention and Assessment Procedures: (Week 0-10) 
 
Intervention: At the screening visit, if the participants are likely to qualify pending lab test results, 
the physician will describe in detail the possible side effects with modafinil, dosing regimen, and 
will develop a medication adherence plan. Once labs confirm they meet study criteria, 
participants will be randomized to active treatment or placebo using an urn technique (stratified 
by recruitment site). The placebo group will receive capsules which look identical to capsules 
filled with active treatment, and will receive the same number of capsules. Only the study 
pharmacist will be un-blinded, and the pharmacist will not interact with any of the participants. 
Modafinil will be given at 100mg orally per day for the first 4 days, then 200mg for 4 days, and 
then 300mg for the remainder of the treatment based on previous work21.  
The dose will be adjustable at the discretion of the medical practitioners (Dr. Wilcox or covering 
provider) and dispensed weekly (See IDS plan). Specifically, at the Week 0 visit, the participant 


8 
 
will receive the first 11 days of study medication, at the Week 1 visit the participant will receive 
the subsequent 7 days of study medication, at the Week 2 visit the participant will receive the 
subsequent 7 days of study medication, at the Week 3 visit the participant will receive the 
subsequent 7 days of study medication, and at the Week 4 visit, the participant will receive the 
final 10 days of study medication. If we adjust the dose at a particular medication visit we will 
simply inform the participant to take the appropriate dose from their bottle (all capsules are 100 
mg modafinil and so we will just inform them to take 2 capsules instead of 3 capsules if we are 
suggesting a dose decrease from 300 mg to 200 mg for example), and we will also call the 
pharmacist to tell them that for the next prescription the participant should have a lesser quantity 
dispensed. We will note any dose adjustments at that visit, and will expect the participants to 
return the appropriate number of pills to us at the subsequent visit. All non-consumed pills will 
be returned to the pharmacist. If we make an adjustment in the dose before the medication has 
been prepared by the pharmacist, for example following a phone consultation initiated by the 
participant, then we will call the study pharmacist to request that she dispense the lower dose at 
the next dispensation.  
Dose adjustments will only be made at the discretion of either Dr. Wilcox or covering provider 
based on participant symptoms and signs. Dose adjustments cannot be made by the research 
coordinator or nurse, but the research coordinator or nurse will be expected to report any and all 
participant complaints, side effects, vitals, physical signs, and adverse events to study 
physicians for final dosing decisions to be made at each medication visit. 
Adherence will be monitored with pill counts at all med visits, primarily by the research 
coordinator or nurse, but also by study physicians if needed. All participants will be asked to 
record adherence in a daily log, and to bring in their pill bottles for pill counts at all visits. 
Unused pills will be returned to the pharmacist. Study personnel (nurse, research coordinators, 
study physicians) and the pharmacy will count pills remaining in bottles and record these values. 
All individuals will be screened for side effects at the weekly visit (Med Visit) with a nurse or 
research coordinator. During these four follow-up Med Visits (15 minutes), individuals will 
undergo a review of side effects, and an assessment of alcohol consumption and medication 
adherence.  Serious adverse events will be documented on the serious adverse events form 
and will be followed with the serious adverse events follow-up forms until resolution.  
Note: for community recruited participants, we will provide individuals who are not currently in 
treatment for their AUD 4 sessions of a widely-accepted evidence-based psychosocial 
intervention for AUD called Motivational Enhancement Therapy (MET)124. Specifically, all 
individuals who are not undergoing active treatment will be offered 4 sessions of this 
intervention at Week 0, 2, 4, and 6, and the therapy will be administered by the PI. 
Assessment Measures: Clinical Measures: Based on their association with modafinil treatment 
in past work27-29,125, rash [with a possibly, but not definitively increased frequency over 
background rates of Stevens Johnson Syndrome (SJS), Toxic Epidermal Necrolysis (TEN), and 
Drug Rash with Eosinophilia and Systemic Symptoms (DRESS)], euphoria, craving for the 
medication, chest pain, tachycardia, headache, nausea, dizziness, depression, anxiety, 
psychosis, irritability, insomnia, arthralgia, dry mouth, appetite changes will be assessed at each 
Med Visit and at week 6 using a standardized form126. Vitals, breath alcohol (BAL), urine drug 
screen (UDS) and CIWA102 will be checked at each visit and urine pregnancy will be checked at 
the screening physical exam visit, baseline, and at each in-person follow-up visit, including prior 
to each MRI scan. At week 4 participants will be asked whether they think they were in the 
placebo or the modafinil group to test blinding. Screening SST: Designed after the SST used in 
the single clinical trial in AUD, this will be used to distinguish those with impaired response 
inhibition (SSRT>233)21 from those without impaired response inhibition. Go trials require the 
participants to perform a two-choice reaction time task on a computer screen. Stop trials are 
identical to go trials but in addition a visual stop signal (screen turns from black to red) cues 
participants to inhibit their response. An adaptive tracking algorithm accomplishes 50% 
successful inhibition for each participant by varying the delay [stop signal delay; (SSD)] between 


9 
 
presentation of the arrow and the stop signal. The dependent variable (SSRT) is calculated by 
subtracting the SSD (the mean time between the appearance of the arrow and the stop signal) 
from the mean reaction time to go stimuli. Primary Outcome Variables: We will derive PDA, 
TTR, drinks per drinking day (DPDD) and drinks per week (DPW) at every assessment visit 
using the TLFB123; even though effects on DPDD were not seen in in previous work we will still 
measure it21. We will also measure impaired control103 and craving104 at every assessment. 
Primary Mediators, response Inhibition: The task we will use to measure target engagement 
(obtained at every assessment) is a validated emotional Go No-Go task57,127,128 and will have 
additional trials preceded by aversive74 alcohol72,129 or neutral stimuli. Exploratory Mediators: At 
every assessment participants will also perform a digit span task42,105, Kirby Delay Discounting 
task106, the PROMIS anxiety, depression, and anger scales107,the State Difficulties in Emotion 
Regulation Scale108 an emotional n-back task109, and the Pittsburgh Sleep Quality Index110 and 
Epworth Sleepiness Scale111. Nuisance Variables:  At baseline, we will obtain the Rivermead 
Post-Concussion Symptoms Questionnaire112, Alcohol Dependence Scale113, Fagerstrom Test 
for Nicotine Dependence114, AUDIT115, intelligence (WTAR116), Barratt Impulsiveness Scale 
(BIS)59, UPPS117, the Adult ADHD Self-report scale21,29, motivation (Stages of Change 
Readiness and Treatment Eagerness Scale118), Treatment Services Review119, Difficulties in 
Emotion Regulation Questionnaire120 and Emotion Regulation Questionnaire121. Adherence 
(self-report/pill counts), and presence of moderate TBI (loss of consciousness >30 minutes and 
<24 hours) will be controlled for. Treatment site will be a nuisance variable. 
Magnetic Resonance Imaging (MRI): MRI scan(s) taking less than an hour will involve 
performing a cognitive task (emotional GNG task designed after previous work57, approximately 
20 minutes), a resting state task during which they are asked to gaze at a fixation cross and 
think about nothing in particular for 6 minutes, and a structural, diffusion weighted imaging and 
arterial spin labeling scan during which they are not required to perform any task. Participants 
will lie down on a table and be placed into a long donut-shaped magnet.  
 
If a participant appears to a visit intoxicated (BAL >.08%) the assessment (both research 
assessments and clinical assessments) will not proceed, and the participant will not receive 
their medication refill until they can be assessed under the legal limit. Furthermore the 
participant will not be allowed to drive home until under the legal limit. In cases of intoxication, 
the assessment will be rescheduled to occur as quickly as possible. There will be a 4-day flex 
window for rescheduling an assessment for intoxication. Similarly, there will be a 4-day flex 
window for rescheduling for no-shows. If it is impossible to reschedule an assessment or a no-
show within that period of time, then participants will be given one chance to restart the study 
from the day after the baseline visit if the lapse occurred between Week 0 and Week 2 (redoing 
all subsequent research and clinical assessments and re-initiation of modafinil up-titration if it 
has been more than 3 days since their last modafinil dose). If the lapse occurs between Week 2 
and Week 4, they will be given one chance to restart the study from the day after the Week 2 
visit, but they will be required to restart the modafinil up-titration at 100 mg if it has been more 
than 3 days since their last modafinil dose. If a lapse happens a second time, they will be 
discontinued from the study.  
 
There will be no change if the participant drops out of SOC treatment (IOP’s or study-provided 
motivational interviewing) and we will be happy to provide the participant with further referral 
information to explore at their discretion, and they are more than welcome to engage in other 
non-pharmacologic alcohol use disorder treatment options and self-help group attendance 
(Alcoholics Anonymous etc.) while also still undergoing the study protocol. 
 
Data Analysis 
1. Neuroimaging Methods: Task: All participants will complete the emotional GNG task 
designed after previous work57 at baseline, and at 2 weeks.  


10 
 
2. Neuroimaging Acquisition and Analyses: Standard pulse sequences will be utilized to collect 
high-resolution anatomical (T1) and whole brain echo-planar images. Functional images will 
be generated using similar methods previously published by the PI and mentor, and evoked 
analyses will follow standard pre-processing techniques130-133. Deconvolution analyses will 
be performed (AFNI, 3dDeconvolve) and individual-subject percent signal change (PSC) 
maps will be generated for four trial types (aversive NoGo, neutral Go trials, neutral NoGo, 
aversive Go), regressing out error-related signal. No-Go minus Go contrasts will be 
calculated at the individual-subject level for both aversive and neutral stimuli. DTI: To probe 
for effects of modafinil on neuroinflammation, we will also obtain fractional anisotropy and 
axial diffusivity measures using DTI134,135. Analyses methods will mirror those performed in 
previous work by Dr. Mayer136-138. Arterial Spin Labeling (ASL): A pulsed Arterial Spin 
Labeling (pASL) image will be collected to measure mean cerebral blood flow (CBF) in 
significant clusters, which can be used to correct for vascular effects of modafinil (modafinil 
has weak cardiostimulatory effects, and could globally effect CBF125,139,140) and to distinguish 
those from the neural effects141-146. Analysis methods will mirror those performed in previous 
work by Dr. Wilcox130,147.   
3. Statistical Analyses: Data will be inspected for normality and outliers; when appropriate, 
slight deviations from normality will be transformed whereas rank analyses will be performed 
for severe violations. Aim 1: First, we will test the effects of medication in the whole sample 
in which medication, response inhibition subgroup and an interaction term (medication 
condition*response inhibition subgroup) will be entered as a predictor, to test for a matching 
effect. Because the sample size is small, regardless of whether the interaction term or 
condition term are significant in the whole sample, we will also test for an effect of 
medication in the sample with impaired response inhibition separately from the sample with 
normal response inhibition. Using latent growth curve modeling (LGCM), we will be able to 
examine the main effects of medication on PDA, DPDD, and DPW at baseline, 1, 2, 3, and 4 
weeks.  LGCM is an extremely flexible modeling approach that allows the examination of 
linear and non-linear changes over time amongst both normally and non-normally distributed 
outcome measures. To test for medication effects on TTR, a Cox regression analysis will be 
performed for the time to first heavy drinking day (≥ 4 drinks/day for women, 5 for men)8. 
Aim 2: To test our hypothesis that modafinil will improve response inhibition (GNG errors of 
commission) relative to placebo a series of 2x3x3 ANCOVAs will be performed with fixed 
factors for treatment group (modafinil vs. placebo) time (baseline, 2, 4) GNG trial type 
(alcohol cue vs. aversive cue vs. neutral cue), and the nuisance variables as covariates. 
Similar analyses will be performed for exploratory targets/mediators, and repeated in the 
non-impaired group. To test for mediation we will use parallel process LGCMs which 
examine simultaneous growth (i.e., change) in the mediators and outcomes and can be 
used to examine both concomitant and prospective mediation models. In these models, the 
total, direct, and indirect effects of treatment on alcohol outcomes via putative mediators will 
be estimated using the bias-corrected bootstrap based on 10,000 bootstrapped samples148, 
which provides a powerful test of mediation149, and is robust to small departures from 
normality150. For both aims, baseline drinking quantities and medication group will be 
entered as main effect predictors, as will nuisance variables that differ between active and 
placebo groups at baseline, and missing data will be handled using full information 
maximum likelihood procedures151,152. For fMRI analyses, contrast images (No-Go minus 
Go) will be entered into a 2x2x2 mixed measures ANOVA [Group(modafinil, placebo), Time 
(baseline, week 2), Stimulus(aversive, non-aversive)] which will permit examination of Aim 1 
hypotheses (i.e., GroupxTime interaction with null effect for Stimulus). Appropriate measures 
will be enacted (i.e., parametric thresholding and spatial clustering) as we have done in 
previous work130-133 to correct for false positives for all voxel-wise comparisons. For all 
analyses, the null hypothesis will be rejected in the event of a significant GroupxTime 
interaction.  Additional Analyses: Chi square analyses and t-tests will be used to compare 
rates of individual and overall number of reported side effects and adherence (pill counts) in 
each treatment arm.  


11 
 
4. Power Analyses: Based on our previous studies (Preliminary Data), we expect 20% attrition, 
leaving a total of 20 participants completing the study. Approximately 12 of these will have 
impaired response inhibition based on preliminary data (see above). Our primary test will be 
whether or not modafinil reduces percent days abstinent and time to relapse in those with 
impaired response inhibition with a larger effect size than those with normal response 
inhibition. Previous studies21 have demonstrated effect sizes of .5 and .8, respectively, for 
effects of modafinil on these metrics in individuals with impaired response inhibition. The 
other tests are essentially secondary aims and we will not expand on this here. Using 1-
tailed hypotheses, we will have 80% power to detect an effect of size of .8 with an alpha of 
.2. We will first be able to determine whether the directionality of effects are in the expected 
direction (e.g. if modafinil increases time to relapse and percent days abstinent rather than 
reducing it). Then we will be able to determine if there is evidence of benefit of similar effect 
size comparable to that seen in previous work, and whether or not pursuing further funding 
is worthy with our sample size. We acknowledge that this study is not powered to definitively 
determine whether or not the medication is effective for the treatment of AUD, and that 
modafinil is not minimal risk. However, in general it is a relatively safe medication, and the 
potential benefits to the participants who get assigned to active treatment and the potential 
value to the field and future patients with AUD outweigh the risks of being on this 
medication. Aim 1: We would require 24 participants per medication group in the impaired 
response inhibition subgroup to be adequately powered (80%) to detect an effect of the size 
seen for TTR (d=.84 using a pooled SD of .37) and 64 per medication group to be 
adequately powered to detect a similar effect for PDA (effect size .50)21 in the previous 
modafinil study. We are not adequately powered to detect an effect, but we will test 
medication effects by measuring effect sizes. However, previous pilot studies of other 
pharmacotherapeutic agents in AUD have measured effects sizes as large as d=2.8, 
which we would be adequately powered to detect with 6 per group153.  Aim 2: We have 
mentioned that in the previous trial of modafinil in AUD, that SSRT was not altered by 
treatment21; however, there was a medication effect on working memory in individuals with 
impaired working memory at baseline42 (d=.52). Moreover, previous work has shown a 
correlation (r=.39, d=.85) between changes in response inhibition and changes in alcohol 
use during pharmacotherapeutic treatment48. If there is a large effect, as defined by d>.59, 
for medication on mediator, and for changes in mediator and alcohol use outcome, then we 
would need total sample sizes of 34 to have 80% power using bias-corrected bootstrapping 
to detect a significant (p<.05) mediating effect149. We will therefore be underpowered to 
detect an effect, but we will have 80% power to detect a trend (p<.15) with 20 participants 
completing. Moreover, our design (more frequent testing of potential mediators, and 
participants being in their natural environments, amongst drinking triggers) may further 
increase effects from those observed in previous work. Power analyses for fMRI task: The 
only single-dose study of effects of modafinil on brain activation during response inhibition 
did not include means and standard deviations from which to derive effect sizes38. In 
StimUD, modafinil elicited activation in lPFC and dmPFC (learning task) with effect sizes 
ranging from 0.7 to 1.070. Our sustained dosing approach should result in larger effects20. 
We will be adequately powered (80%) to detect similar effects (effect size 1.0) of medication 
on BOLD signal with our sample size of 25 if we use a liberal alpha of 0.15 for our spatial 
clustering procedure during the whole brain analysis and a 2x2 mixed measures ANOVA, 
leaving stimulus type out of the model. In summary, we will certainly have enough 
participants to determine if an R01 application is warranted and project necessary sample 
sizes.  
 
 
Compensation 
 


12 
 
Participants will compensated for their time for research visits as follows: Consent and screen 
visit $30, history, physical, and screen visit $30, baseline assessment $60, second assessment 
(week 2) $70, third assessment (week 4) $70, fourth assessment (week 6) $40, Phone 
assessment ($40). Participants will not be compensated for medication visits that don’t co-occur 
with an assessment. Payments will be in the form of merchandise gift cards, pre-paid visa cards 
(or similar) or cash to equal a total of $340 (if all visits are completed). If participants do not 
complete the study, they are paid for visits completed and all payments occur immediately at the 
conclusion of a study visit.   
 
 
 
List of Appendices 
Impaired Control Scale initial  
Impaired Control Scale followup 
Difficulties in Emotion regulation questionnaire  
Barratt Impulsivity Scale  
AUDIT  
Emotion Regulation Questionnaire (ERQ)  
StateDERS 
Promis Anger/Anxiety/Depression 
SOCRATES – alcohol questions 
UPPS 
FTND 
PACS 
PSQI  
Adult ADHD self report scale (ASRS) 
ESS  
Drinker Inventory of Consequences (pages 43-46 in the pdf) 
ADS (Alcohol Dependence Scale) 
CondMedsMod 
CIWA 
Demographic Form 
Edinburgh Handedness Questionnaire 
MedHx2 
MRI Screening Form no contrast 
Phone Screen Modafinil 12_31_17 
Physical Exam 
Post Scan Questionnaire 
Pre Scan Questionnaire 
Rivermead Post Concussion Symptoms Questionnaire 
SAE report 
SAE f/u 
SAFTEEmodafinil 
SCID V 
Treatment Review Questionnaire 
WTAR recording 
WTAR word card 
 
2015ModafinilPrescribing Info 
IDS Plan 9/12/17 


13 
 
PIND 
 
Online ad Mod 12_31_17 
Modafinil for Alcohol Use Disorder MRN Website 12_31_17 
Modafinil Flyer 12_31_17 
Narrative Modafinil 12_31_17 
Newspaper Add Modafinil 12_31_17 
Newspaper Color Add Modafinil 12_31_17 
 
 
 
Data and Specimen Banking 
No specimens will be banked as part of this protocol.  Participants will be given the option of 
having their data stored in the MRN Data Repository (see HRRC# 06-387, PI: Roberts). 
 
Data Management 
 
Consent Forms: Signed consent forms are stored in a locked cabinet in a locked office at MRN. 
 
Questionnaire Data: All data are coded with a unique research subject identifier (URSI) number.  
Electronic data is stored on a drive only accessible by the research team on a secure MRN 
server.  For non-computer based forms, such as the neuropsychological assessments, the data 
collection sheets are stored in a locked cabinet in a locked office at MRN. 
 
Behavioral and Imaging Data: All data is coded with the URSI, and collected and stored 
electronically.  Electronic data is stored on a drive only accessible by the research team on a 
secure MRN server (any standardized forms/assessments that have a space for “name” are 
labeled with URSI only, e.g. Epworth sleepiness scale and PSQI). The MRI screening form is 
labeled with name and date of birth, and stored separately from any research data which is 
necessary for safety screening by the MRI technologists. De-identified data resulting from this 
study may also be presented at meetings, published in journals/books, used in classrooms for 
training/teaching purposes, and may be shared with other researchers including scientists at 
other universities and institutions. 
 
Study Closure: At the time of study closure, all participant identifiers (name, address, etc.) will 
be made inaccessible to the research team. MRN retains the link between identifiers and URSI 
indefinitely for the potential future benefit to the research participant. Specifically, it may become 
medically advantageous in the future for a former participant to have access to the clinical 
information that may be present in radiological scans and reviews. For example, if a participant 
has been diagnosed with a neurological condition (e.g., multiple sclerosis, glioblastoma, etc.) it 
may be clinically beneficial for the participant’s physician to have access to a research scan that 
was performed at an earlier time-point to determine disease course and severity. 
 
 
Provisions to Monitor the Data to Ensure the Safety of Participants 
 
General Considerations: The risks are greater than minimal risk. Although the safety profile of 
modafinil is reasonably well established, modafinil has only been studied in alcohol dependent 
populations in a single study, and there were no serious adverse study-related events. The data 
and safety monitoring plan is therefore designed both to ensure that the risks of medications 
and study-related procedures are minimized for patients, and to minimize any doubt that there 


14 
 
are adequate safeguards in place to minimize this risk. The FDA has determined this medication 
to be exempt from needing an IND (see attached IND exemption letter).  
 
Every effort will be made to address adverse events as they arise from the medication 
treatment. The study physician will be allowed to decrease the dose, or discontinue the study 
medication as deemed necessary. Similarly, every effort will be made to address adverse 
events as they arise from the assessments including anxiety from exposure to the affective 
stimuli. If there are any serious adverse events we will take appropriate measures. 
 
If a participant does experience excessive craving or anxiety as a result of the assessments, or 
neuropsychological testing, or expresses suicidal thoughts, Dr. Wilcox or covering medical 
provider will be available at any time to assess safety and make an attempt to help the patient. 
Although no aspects of the study are expected to be unduly upsetting or risky, established 
procedures are in place for the occurrence of such an emergency. Support will be available to 
deal with any anxiety, fatigue or increased urge to use drugs associated with behavioral testing. 
There will a physician available any time by phone to talk with participants for any emergent 
medical adverse events from the medication. A standardized suicide risk assessment protocol is 
in-use by this team to assess for safety when participants report past or current suicidal 
thoughts, and Dr. Wilcox or covering medical provider will be called, and one of them will be 
available at any time to respond, if the protocol warrants their involvement. 
 
Every effort will be made to protect the confidentiality of participants’ records. However, 
complete confidentiality of records cannot be guaranteed as records may be examined by 
authorized personnel from the approving IRB. Participants will be informed of this possibility 
prior to signing the consent forms. Otherwise, records will be kept strictly confidential and will 
not be inspected by any other agency unless required by law. Loss of confidentiality will be 
minimized by assigning a randomized number to each participant upon entry into the study. This 
number will be used for all correspondence between study investigators and all data collection 
and analysis after the initial screening visit. MRN has state-of-the art IT networks with all 
necessary security mechanisms in place for data storage. Any personal information entered into 
computers is password protected and monitored for suspicious activity. Moreover, all 
information will be in double-locked rooms per privacy specifications. The results of this 
research may be presented at meetings or in publications; however, participants’ identity will not 
be disclosed. This research study has a Certificate of Confidentiality from the National Institutes 
of Health (NIH). 
 
Participants will be clearly informed of their right to withdraw from the study at any time and still 
receive full compensation. 
 
Adverse events (AEs) will be collected on an AE case report form when they come to the 
awareness of study staff. The form will include an assessment of clinical significance and study 
relatedness.  AEs will be reported in accordance with federal law and policies and the IRB.  
Reporting procedures vary depending on the severity of the AE, and will follow the policies in 
the IRB manual.  In particular, adverse events and other reportable events that are 
unanticipated and deemed related to research procedures will be reported to the IRB within 7 
days of discovery, regardless of whether they qualify as SAEs.  In addition, information on 
adverse events will be captured in the study data system as follows. 
 
There are no known health risks associated with the proposed MRI aspect of the study. A two-
way intercom system and a video monitoring system provide continual monitoring of the 
participant’s condition at all times. If discomfort or concern is expressed, or detected, the 


15 
 
experiment will be stopped and the participant will be given the option to discontinue at any 
time. Absolute caution will be implemented to ensure that only non-ferrous objects are present 
during all of the MRI sessions. Participants will be asked to change into hospital scrubs prior to 
being placed in the scanner to ensure that they do not introduce any metallic objects into the 
imaging environment. Participants will also be screened for the presence of a pacemaker or any 
other metallic objects in their body, such as an aneurysm clip, ear implant, or nerve stimulator. 
Participants with these or other metallic devices will not be allowed to participate in any of the 
previously described studies. Ambient scanner noise will be below the current recommended 
guidelines. 
 
Data Safety Monitoring Committee 
 
Data and Safety Monitoring Committee: Data and Safety Monitoring Committee will be 
established comprising the study physician, the research coordinator, and an external physician 
reviewer who is not otherwise affiliated with the study and does not report directly or indirectly to 
the PI. This committee will meet at least quarterly to review data quality, recruitment and 
retention, and to review all serious or clinically significant adverse events.  In addition, the 
committee will review safety data before each dose increase in the study, and following any 
serious adverse event that appears to be study related. The DSMC members will be blinded for 
participants who are currently enrolled, but not blinded for participants who have been informed 
about what group they were assigned to (e.g. once the participants knows what group they were 
assigned to, which will occur after their final assessment, all study team members and the 
DSMC members will know what group a particular participant was assigned to). For all SAE’s, 
investigators will consider and discuss the need for unblinding, based on the nature of the SAE, 
and based on whether or not knowing the group assignment would alter treatment of the SAE, 
within 48 hours. Patterns of adverse events as well as individual events may indicate the need 
for operational changes, protocol modifications, a decrease in dose, or, conceivably, 
discontinuation of the trial. An example of a pattern of adverse event that could result in 
discontinuation would be greater rates of cardiac events (severe tachycardia) in the active 
treatment group compared to the placebo group. Either the PI, or a single member of the DSMC 
could recommend protocol modifications or discontinuations. 
 
All side effects and adverse event information will be monitored for using a standardized 
checklist at all medication visits with the nurse or research coordinator. Study data will be 
reviewed quarterly, or more frequently as deemed necessary by the PI.  
 
On a quarterly basis, just before each DSMC, we will review the literature, searching PubMed 
for new studies of “modafinil + alcohol use disorder”, and “modafinil + safety” and if any new 
information about risks or benefits is found on such a search that was not included in the 
consent, and that might change the participants’ mind about participating, we will inform all 
participants who are currently enrolled in the study. 
 
Adverse Events 
For the purpose of this study, the following AEs will not require reporting in the data system but 
will be captured in the source documentation (progress note) as medically indicated:  
All adverse events due to study medication will be captured at weekly visits with the nurse or 
research coordinator, or more frequently, on a validated form designed to capture adverse 
events. The following symptoms will be directly asked about at each visit: rash, euphoria, 
craving for the medication, chest pain, tachycardia, headache, nausea, dizziness, depression, 
anxiety, psychosis, irritability, arthralgia, dry mouth, appetite changes. These and those listed on 
the consent would be deemed expected. Adverse events that are unanticipated and deemed 


16 
 
related to research procedures will be reported to the IRB within 7 days of discovery, regardless 
of whether they qualify as SAEs.  
 
Serious Adverse Events 
Adverse events (AEs), when present, will be collected on an AE case report form at the end of 
each drug administration session and at all subsequent visits. The form will include an 
assessment of clinical significance and study relatedness.  Serious Adverse Events (SAEs) will 
be documented on a separate SAE form. SAEs will be reviewed by the Data and Safety 
Monitoring Committee at its quarterly meetings. These will also be reported to IRB within 48 
hours.  
 
 
Participant Complaints 
If a participant wishes to issue a complaint or request information about the research, they may 
notify the research coordinator at 505-510-4351 or the PI, Dr. Claire Wilcox, at 505-633-8105 
(Dr. Wilcox will be available 24/7 for patients to call regarding side effects). Participants may 
also contact the UNM Office of the IRB, (505) 277-2644, irbmaincampus@unm.edu. Website: 
http://irb.unm.edu/ 
Depending on the nature of the complaint, the problem will be resolved directly with the 
participant, if possible, in a confidential and timely manner. Complaints that constitute a 
reportable event will be submitted to the IRB within 7 days. Participant complaints will be coded 
with a unique research subject identifier (URSI) and kept in their respective study folder in a 
locked office for record-keeping purposes.  
 
 
Withdrawal of Participants 
It is not anticipated that circumstances will arise during the course of the study for which the 
participants will need to withdraw from the study.  The consent form will fully inform the 
participants that they can refuse to answer any questions, participate in any procedures (e.g., 
neuropsychological testing), or withdraw from the study at any time.  If a participant refuses to 
participate in a portion of the research, they can still participate in the other parts of the study.  If 
a participant withdrawals from the study completely, they will be informed in the consent that the 
data they have provided up to that date will be maintained as a part of their study record. 
Participants can withdraw from the study at any time. 
 Risks to Participants 
The risks of the interventions used in this study are greater than minimal risk.  
 
Risks of Modafinil 
The main risks of this study are probably related to possible effects from modafinil which are: 
rash [with a possibly, but not definitively increased frequency over background rates of Stevens 
Johnson Syndrome (SJS), Toxic Epidermal Necrolysis (TEN), and Drug Rash with Eosinophilia 
and Systemic Symptoms (DRESS)], euphoria, craving for the medication, chest pain, 
tachycardia, headache, nausea, dizziness, depression, anxiety, psychosis, irritability, arthralgia, 
dry mouth, appetite changes. Additionally, in the consent we have listed the following potential 
risks: 
 
Occasional (Between 5-20% more often than placebo) side effects include: headache, nausea. 


17 
 
Rare (2-4% more often than placebo) side effects include: nervousness, anxiety, vasodilation 
(orthostatic dizziness), paresthesia (tingling), high blood pressure, chest pain, dry mouth, sore 
throat, decreased appetite, insomnia. 
Extremely Rare (1% or less) side effects include: rhinitis (runny nose), back pain, diarrhea, 
dizziness, dyspepsia (stomach upset or reflux), liver function test changes, constipation, 
depression, palpitation, sleepiness, rapid heart rate, vision changes, agitation, asthma, chills, 
confusion, movement changes (dyskinesia, hyperkinesia, hypertonia), edema, emotional lability, 
high eosihophil levels on blood count, bloody nose, flatulence, risk of death, mouth ulcers, 
sweating, changes in taste, thirst, tremor, changes in urination, vertigo, rash, euphoria, craving 
for the medication, depression, psychosis, irritability, body aches. 
http://www.rxlist.com/provigil-drug/side-effects-interactions.htm 
 
Risks of Assessment Procedures 
It is possible that discussion of substance use and consequences may cause emotional 
discomfort in some participants.  The only risk associated with the assessments and 
neuropsychological testing is fatigue or anxiety. In particular, the affective stimuli in the 
emotional GNG are emotionally intense and the alcohol stimuli could trigger craving. To 
minimize such discomfort, the following steps will be taken.  The consent form will fully inform 
the participants about the nature of the information to be disclosed in the protocol, the nature of 
the cognitive tasks they will be undertaking, and the participants will be informed in the consent 
form that they can refuse to answer any questions or withdraw from the study at any time.  
Participants will be informed that all information is confidential, and the steps taken to guard 
confidentiality, as well as the limits to confidentiality, will be described.  One of the study 
investigators will be available to meet with any participant who becomes distressed about any 
aspect of the protocol and wishes to discuss this.  
 
Risks to Confidentiality and Potential Legal Consequences 
Records which identify participants and the consent form signed by participants may be 
inspected by the IRB.  Because of the need to release information to this party, absolute 
confidentiality cannot be guaranteed.  The results of this research project may be presented at 
meetings or in publications.  However, the identity of individual participants will not be disclosed 
in those presentations. 
 
MRI:  Radio and magnetic waves associated with MRI scans are not associated with any known 
adverse effects. MRI is non-invasive and considered minimal risk by the FDA and OHRP. 
However, the scanner is a large magnet, so it could move objects containing ferrous metal in 
the room during the scan.  All participants are screened using the MRI safety screening form 
prior to be being scanned.  Participants may be bothered by feelings of claustrophobia 
(uncommon). The MRI also makes loud ‘drum’ beating noises during the study.  Headphones or 
earplugs are provided for protection. Rarely, large or recent tattoos can heat up during an MRI 
scan and cause skin irritation like a sunburn (uncommon). No long-term harmful effects from 
MRI are known. However, since the effect of MRI on early development of the fetus is unknown, 
participants who are pregnant will not be allowed to go in the MRI. All females will undergo a 
urine pregnancy test prior to scanning. The test results will only be shared with participant. All 
MRI sequences used are within FDA approved parameters, including specific absorption rate. 
Due to the very high sensitivity of MRI in detecting abnormalities, there is a risk of false-positive 
findings, identifying something on imaging studies that may or may not be important.  This may 
result in anxiety and a referral for additional medical testing, possibly including a 
recommendation for clinical scans at the participant’s cost. 
 


18 
 
Another main risk of this study, especially given the questions regarding drug use and 
psychiatric symptoms and disorders, would concern confidentiality, so we will de-identify data as 
appropriate. Although we do not intend them to be, such questions could also be upsetting to 
individuals.  
 
As with any study that collects personal information, there is a risk of loss of confidentiality.  
 
There may also be side effects or risks to study participation that are unforeseen and not known 
at this time. 
 
 Potential Benefits to Participants 
Participants may or may not have benefit from the study. Knowledge gained through this study 
may aid the development of more effective treatments for individuals with alcohol dependence 
and other addictive disorders. There are also potential direct benefits to participants in this 
study. All individuals (whether assigned to the active treatment with modafinil or placebo group) 
are receiving treatment (either in the intensive outpatient program upon enrollment or will be 
offered four sessions of motivational interviewing by the PI), and will also be offered a referral 
list upon completion of the study. If the medication being tested works, then individuals assigned 
to the intervention group may also benefit from the treatment. Also, being in a research study 
may provide benefit, as may taking a placebo pill; individuals who undergo a series of 
assessments in a research study oftentimes reduce their drinking even if they are not on active 
treatment. Moreover, at the end of the study, individuals will be informed about whether they 
were assigned to active treatment or placebo. If assigned to active treatment, and if they 
experience benefit, they are welcome to approach their primary care provider to explore the 
possibility of off-label treatment.  Other aspects of study participation that may be beneficial 
include receiving free medical and psychiatric evaluations and the attention and support of 
participating in a clinical trial. 
 
 
Vulnerable Populations 
This study will not include vulnerable populations. Incidentally, we have chosen to keep the 
monetary compensation levels low to avoid undue coercion. As is discussed in the previous 
sections, potential participants will be informed of the purpose of the study, voluntary nature of 
participation, and ensured that their decision to participate (or not) will have no effect on their 
treatment.   
 
Community-Based Participatory Research/Field Research 
N/A 
 Sharing of Results with Participants/Incidental Findings 
Incidental Findings: Regarding incidental findings from blood draws, all blood work will be done 
at CLIA certified labs. We will communicate all abnormal results to the participant, by phone if 
possible. If the participant is unreachable by phone (3 tries) we will mail them a letter asking 
them to contact us about their blood work. If the participant requests, we will also call 
participants’ providers with abnormal blood work results at the participant’s request after having 
them sign a release of information. Regarding incidental findings from MRI scans, all research 
MRI scans will be read by a neuroradiologist (a doctor with experience reading MRI scans) 
unless the participant has been scanned at MRN in the previous six months. If the scan is read, 
an e-mail notification is sent to the participant letting them know new results are available. The 
participant can securely log in to the Collaborative Informatics and Neuroimaging Suite (COINS) 


19 
 
Homepage to access their MRI radiology report. No sensitive or identifying information is sent 
via e-mail. If an abnormality that requires follow-up is identified, such as a Doctor Referral 
recommendation, a hard copy of the report may be mailed to the participant in addition to the e-
mail notification. In these cases, the MRN Medical Director may also attempt to contact the 
participant by phone to explain the information and help answer questions. There is no plan to 
share study progress and results will not be shared with participants except for lab results and 
MRI results as described above. 
 
Research Setting 
 
All study procedures will take place at the Mind Research Network with the exception of the 
University of New Mexico research pharmacy. 
 
UNMH research pharmacy: 
 
Research at the University of New Mexico Health Sciences Center (HSC) is supported by the 
Investigational Drug Services (IDS) Pharmacy. By responsibly managing and dispensing 
investigational drugs for clinical trials, IDS enhances the smooth functioning and compliant 
operation of these studies. In many cases, this process spans the entire study life-cycle, 
beginning in the early design and planning stages and continuing through study close-out.  
  
IDS activities may include, but are not limited to inventory management, maintenance of drug 
accountability records, blinding and/or randomization of study medication, development and 
preparation of matching placebo, procurement, dispensation of study medication to research 
staff, and the secure, temperature-monitored storage of investigational product.  
 
 Resources Available 
Five private, closed door rooms are available to research staff for study visits at MRN. These 
assessment rooms have white noise generators outside of the doors to prevent conversations 
from being overheard. These are reserved by investigators as needed, and are easily 
accessible.  The imaging facilities also have private changing rooms with lockers for personal 
items. All MRN research staff are trained in regards to the HIPAA Privacy Rule. All individuals 
will be trained to administer the same consenting and study procedures. Further, all study 
personnel will have current CITI and HIPAA training throughout the period of the study. 
John Phillips serves as MRN Medical Director. UNM hospital is less than a mile away and, as a 
public hospital, will serve as a treatment facility for unexpected participant emergencies. 
Located on UNM’s north campus, MRN is a 501(c)3 non-profit organization consisting of an 
interdisciplinary association of scientists focused on state-of-the-art imaging technology and its 
emergence as an integral element of neuroscience investigation.  
 
 
Prior Approvals/Attachments Requiring Signatures 
A COBRE pilot grant (PI Dr. Vince Calhoun, MRN) has been awarded for this study by the NIH. 
Also MRN Departmental Review is included with the submission. 
 
Recruitment Methods  
Recruitment: Individuals with AUD (N=25) will be recruited from local treatment centers with 
flyers and by word of mouth or from the community through newspaper advertisements, flyers 


20 
 
posted in the community, posting on online community websites, Johnny Boards etc. If recruited 
from treatment programs, potential participants will be recruited from one of three intensive 
outpatient treatment programs (IOPs) (Sage Neurosciences or Presbyterian or Turning Point; 
letters of support attached). Through collaborations with site staff and flyers posted at the site, 
potential participants will be identified and asked if they are interested in participating in this 
study.  If an individual is interested in participating in the study, they will be given the phone 
number to speak with the study coordinator to then undergo a phone screen. All existing 
treatment facility clients and subsequent new enrollees will be informed about the study. 
Interested participants will be given a study flyer and study description with contact information. 
They will call the coordinator at which point they will undergo a phone screen. Up to 100 
participants will be recruited over the course of the study to achieve a final sample of 25 
participants (12-13 per group). 
 
Local Number of Participants 
As many as 100 participants will be enrolled in this study locally to obtain a final sample size of 
20 people who complete the treatment with either placebo or active medication (accounting for 
20% attrition). Specifically, we will only be initiating participants on treatment who pass the 
screening history and physical examination. Individuals will initially be consented, then undergo 
some further screening with a computerized task (stop signal task) and assessment for 
comorbid psychiatric disorders and recent drinking history to assure that they qualify for the 
study. Preliminary data (see above) indicates that 60% of participants screened will qualify 
based on the stop signal task. 
 
 
Confidentiality 
All participants are assigned a study ID (URSI) that links their data with their name and other 
identifying information. All study data (with the exception of the consent form and payment 
receipt) are coded only with this number. The information is maintained in a secure, restricted 
access database (COINS). After completion of data analysis, the linking code will be made 
inaccessible to the research team. De-identified data will be retained until data analysis 
activities are complete.  
 
Provisions to Protect the Privacy of Participants 
Five private, closed door rooms are available to research staff for study visits at MRN. These 
assessment rooms have white noise generators outside of the doors to prevent 
conversations from being overheard. These are reserved by investigators as needed, and are 
easily accessible. The imaging facilities also have private changing rooms with lockers for 
personal items. 
  Compensation for Research-Related Injury 
No commitment is made by the MRN to provide free medical care or money for injuries to 
participants in this study. This is clearly stated in the consent form. Within the consent, 
participants will be informed that if they have an injury or illness that is caused by participation in 
this study, reimbursement for all related costs of care will be sought from their insurer, managed 
care plan, or other benefits program. Within the consent they will be informed that if they do not 
have insurance, they may be responsible for these costs and that they will also be responsible 
for any associated co-payments or deductibles required by their insurance. 


21 
 
 
Economic Burden to Participants 
Participants will not be charged for any of the experimental study procedures, including MRI 
scans. If incidental findings from the study result in the need for further evaluation/treatment, the 
participant or their insurance company will be responsible for additional clinical 
evaluation/treatment that may be needed. Also, incidental finding information is disclosed only 
to the individual participant. However, if a participant chooses to disclose such information also 
to their personal physician, this may become part of their medical record which may or may not 
have an effect in the future on getting health or life insurance.  
 Consent Process  
Upon initial contact, the study will be briefly introduced to the participant by a member of 
the study team. Participants will then be screened over the phone. We are requesting a 
waiver of consent for screening purposes only to screen and recruit for potential 
participants. It would not be practicable to carry out the study if we did not have this 
waiver. We will need to ask a variety of questions including questions about 
substance use and psychiatric history to determine if the participant is eligible to be in 
the study before inviting them for the first in-person visit, and the numbers we will 
need to screen over the phone will likely greatly exceed the number that qualify for 
the study, making in-person post-consent initial screening infeasible. We are 
requesting permission to save data for people who screen out of the study to review 
reasons for exclusion for future studies, and to keep identifying information for people 
who were ruled out to avoid the same people calling back and changing answers.  
If the participant meets inclusion criteria, the study visit will be scheduled and 
documented consent will be obtained from all participants.  Trained study staff will 
review the consent with participants and be available to answer any questions that arise 
as a potential participant reads the consent.  The consent process will take place at 
MRN in a private room with a study team member only. The consent form will fully inform 
the participants about the nature of the information to be disclosed in the assessments, 
and the participants will be informed in the consent form that they can refuse to answer 
any questions or withdraw from the study at any time. Participants will be informed that 
all information is confidential, and the steps taken to guard confidentiality, as well as the 
limits to confidentiality, will be described.  One of the investigators of the project will be 
available to meet with any participant who becomes distressed about any aspect of the 
protocol and wishes to discuss this. Patients indicate their consent to participate in the 
study by signing and returning the informed consent form.  Interested patients can 
choose to keep the consent to review, there is no time limit on how long they have to 
decide if they are interested in participation. All participants are required to sign consent 
prior to participation in any aspect of the study. If there are any changes to the consent 
during the course of the study, these changes will be submitted to the IRB.  No coercion 
or undue influence will be used.   If there are no further questions, the consent form is 
signed and stored in a locked cabinet in a locked office at MRN. A copy will be given to 
the participant. Source documents will be stored in locked cabinets in an office which will 
be locked when the office is not in use.   
Name, address, phone number and email are routinely collected from all study 
participants for the purpose of providing the radiology review letter and future contact, if 
needed. 
Participants not fluent in English Potential participants must be fluent in English to participate 
in the study as many of the assessments are only available in English.   


22 
 
Cognitively Impaired Adults/Adults Unable to Consent/Use of a Legally Authorized 
Representative Individuals who have significant impairment of cognition or judgment (as 
observed by study staff) rendering the person incapable of informed consent. (e.g., traumatic 
brain injury, delirium, intoxication) are not eligible to participate.   
Participants who are not yet adults (infants, children, teenagers) All participants will be 18 
and older.   
 
Drugs or Devices 
All medications will be stored and handled by the research pharmacy and only the pharmacy 
personnel or staff trained to dispense medications including research coordinator or nurse, or 
study physicians will dispense medications.  
 
 
 
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