Conditions: Alcohol Use Disorder
Allocation: RANDOMIZED | Intervention model: PARALLEL
Enrollment: 180
Healthy volunteers: no

Brief summary:
The purpose of this study is to evaluate the safety and efficacy of dutasteride in reducing drinking and heavy drinking in men and women with alcohol use disorder. The investigators hypothesize that dutasteride 1 mg per day will be well tolerated in this patient population and that, compared to placebo treatment, dutasteride will result in a greater reduction in drinks per week and in the frequency of heavy drinking days.

Detailed description:
Heavy drinking remains a significant public health problem and is frequently under treated. Although several medications have been shown to help patients stop or reduce drinking, additional medication options are needed as there is considerable variability in effectiveness or tolerability of existing medications for individual patients. Additionally, identification of individual subject level predictors of efficacy are needed to better personalize pharmacotherapy treatment recommendations. This study will seek to replicate and extend our results showing efficacy of a novel medication dutasteride for reducing drinking and will examine potential easily measured predictors of response.

Dutasteride is a widely prescribed medication for benign prostatic hypertrophy and androgenic hair loss that also modulates the elimination of cortisol and the production of some neuroactive steroids. Changes in the regulation of cortisol and neuroactive steroids have each been suggested as factors which may contribute to the maintenance of alcohol dependence. Data from a recently completed first randomized placebo controlled trial of dutasteride for AUD in a sample of male drinkers, indicates that dutasteride is well tolerated in alcoholics and has efficacy in helping subjects reduce drinking. Additionally, results indicate that dutasteride may be particularly helpful for patients who drink to cope with anxiety and negative emotions, a group of patients with poor response to other treatments.

This 24-week treatment study will use an innovative randomized placebo controlled step therapy design to examine the safety and efficacy of dutasteride to reduce drinking by treatment seeking women and men with hazardous levels of alcohol use. At 12-weeks placebo non-responders will transition to dutasteride and dutasteride non-responders will transition to naltrexone, an FDA approved medication with demonstrated efficacy for reducing heavy drinking. 12-week responders (reduction in drinks/week of 60% or greater compared with screening) will continue for an additional 12-weeks on their initial study medication assignment (dutasteride or placebo).

Additionally, the investigators will examine several baseline measures as predictors of dutasteride efficacy, including drinking to cope, anxiety, adverse child events, and perceived life stress as well as stress resilient vs. reactive genotypes of FKBP5 a chaperone protein involved in regulation of glucocorticoid, androgen and progesterone receptor function.

Arms:
arm 1: two 0.5 mg capsules of dutasteride daily arm 2: inactive placebo matched in appearance with dutasteride capsules

Interventions: intervention 1: Dutasteride Capsules intervention 2: Placebo Capsules
Intervention descriptions: intervention 1: 1 mg/day oral dutasteride (2 x 0.5 mg capsules) intervention 2: Placebo capsules with matching appearance as Dutasteride Capsules

Protocol document:
Prot_SAP_001.pdf: 
 
Document title: IRB approved study protocol at time of study initiation 
 
NCT04098302:    Dutasteride Treatment for Reducing Heavy Drinking in 
AUD: Predictors of Efficacy 
    
 
 
 
Protocol date 05/18/2022   
IRB Number: 19-147-2 
IRB approval date 2/27/2024 


Dutasteride AUD#2 protocol V9 (05-18-2022)
Page 1 of 44
Alcohol Research Center
Department of Psychiatry
University of Connecticut School of Medicine
Farmington, CT 06030-1410
Protocol Title:  Dutasteride treatment for reducing heavy drinking in AUD: Predictors of 
efficacy. 
Principal Investigator:  Jonathan Covault, MD, PhD
Co-investigators: Howard Tennen, Ph.D., Surita Rao, MBBS, 
Abstract
Heavy drinking remains a significant public health problem and is frequently under 
treated.  Although several medications have been shown to help patients stop or reduce 
drinking, additional medication options are needed as there is considerable variability in 
effectiveness or tolerability of existing medications for individual patients.  Additionally, 
identification of individual subject level predictors of efficacy are needed to better 
personalize pharmacotherapy treatment recommendations. This study will seek to 
replicate and extend our results showing efficacy of a novel medication dutasteride for 
reducing drinking and will examine potential easily measured predictors of response.
Dutasteride is a widely prescribed medication for benign prostatic hypertrophy and 
androgenic hair loss that also modulates the elimination of cortisol and the production of 
some neuroactive steroids.  Changes in the regulation of cortisol and neuroactive steroids 
have each been suggested as factors which may contribute to the maintenance of alcohol 
dependence.  Data from a recently completed first randomized placebo controlled trial of 
dutasteride for AUD in a sample of male drinkers, indicates that dutasteride is well 
tolerated in alcoholics and has efficacy in helping subjects reduce drinking. Additionally, 
results indicate that dutasteride may be particularly helpful for patients who drink to cope 
with anxiety and negative emotions, a group of patients with poor response to other 
treatments. 
This 24-week treatment study will use an innovative randomized placebo controlled step 
therapy design to examine the safety and efficacy of dutasteride to reduce drinking among 
a sample of 190 treatment seeking women and men with hazardous levels of alcohol use. 
At 12-weeks placebo non-responders will transition to dutasteride and dutasteride non-
responders will transition to naltrexone, an FDA approved medication with demonstrated 
efficacy for reducing heavy drinking.  12-week responders (reduction in drinks/week of 
60% or greater compared with screening) will continue for an additional 12-weeks on their 
initial study medication assignment (dutasteride or placebo). 
 Additionally, we will examine several baseline measures as predictors of dutasteride 
efficacy, including drinking to cope, anxiety, adverse child events, and perceived life stress 
as well as stress resilient vs. reactive genotypes of FKBP5 a chaperone protein involved in 
regulation of glucocorticoid, androgen and progesterone receptor function.
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Section 1. 
Alcohol has multiple biological effects, each of which are potential targets for 
pharmacotherapy of alcohol use disorder (AUD).  Human and animal studies indicate that 
alcohol-induced generation of GABAA receptor neuroactive steroid agonists mediates 
some of alcohol’s effects and that chronic alcohol use leads to disturbances in HPA axis 
function.  Dutasteride, a widely used medication to treat benign prostatic hypertrophy, is an 
inhibitor of 5-alpha reductase (5AR) enzymes, which play a central role in the production of 
neuroactive steroids as well as in the elimination pathway for cortisol. Thus, dutasteride 
represents a potential pharmacologic treatment for AUD. Results from the first placebo 
(pbo)-controlled, randomized study of dutasteride for treating AUD conducted at UConn 
Health Alcohol Center show that dutasteride 1 mg/day was efficacious in reducing the 
number of heavy drinking days and drinks per week in treatment-seeking, non-smoking 
men.  During the final 4 weeks of the 12-week treatment phase, 49% of subjects in the 
dutasteride arm had reduced their drinking by ≥60% compared with 20% of pbo-treated 
subjects [2=8.3, p=0.004; OR=3.8 (95% CI=1.5-9.8)] and 33% of subjects in the 
dutasteride arm had zero heavy drinking days compared with 11% of pbo-treated subjects 
[2=6.7, p=0.01; OR = 4.1 (95% CI=2.0-12.5)].  This treatment response represents a 
moderate effect size comparable to that observed in a previous study led by Dr. Kranzler 
and Covault of topiramate for reducing heavy drinking previously conducted at UCONN 
Health Alcohol Research Center (Kranzler, Covault et al. 2014).  We also identified 
potential predictors of dutasteride treatment efficacy.  Subjects with elevated baseline 
drinking to cope motivation and anxiety showed a greater dutasteride vs. pbo treatment 
response.  This finding suggests that dutasteride may facilitate reduced drinking in part by 
modulating HPA stress response pathways as hepatic 5-reductase and 5-reductase and 
adipose 5-reductase are important components of the cortisol elimination pathway. 
These findings warrant additional study of dutasteride as a new treatment option for AUD.  
This proposal seeks to extend these findings by: 
a) examining the safety, tolerability and efficacy of dutasteride to reduce drinking in a 
sample including both men and women in a 12-week pbo-controlled, randomized study 
phase 1;          
b) examine whether the reduction of drinking in phase 1 initial 12-week treatment 
responders (defined as ≥60% reduction in drinks/wk during weeks 9-12) can be maintained 
in a 12-week double blind phase 2 extension of the initial treatment condition to help 
identify the clinical utility of dutasteride as a treatment for AUD, which is a chronic 
relapsing disorder; 
c) examine whether pbo arm non-responders during phase 1 experience a reduction in 
drinking when crossed over to dutasteride during the 12-week phase 2 extension; and 
d) examine the moderating effects on treatment outcomes of baseline self-reports of 
drinking to cope, trait anxiety, perceived stress, adverse child experiences and a 
polymorphism (rs1360780) in the FKBP5 gene encoding a key chaperone protein 
regulating functions of androgen, progesterone and glucocorticoid receptors that has been 
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associated with negative behavioral responses to life stressors, including increased heavy 
drinking in college students (Lieberman, Armeli et al. 2016) and a stronger linkage 
between drinking to cope and next day emotional depletion.
Specific Aims.
Aim 1.  To examine the safety, tolerability and efficacy of dutasteride in helping patients 
with AUD to reduce or stop drinking, 190 treatment-seeking men and women with AUD 
who drink heavily on a regular basis (≥24 standard drinks / week for men and ≥18 
drinks/week for women) will be randomly assigned to treatment with either dutasteride or 
pbo for 12 weeks.   A biological marker (PEth phosphatidylethanol) will be used as a 
secondary measure of change in alcohol use and the dihydrotestosterone (DHT) 
metabolite 3-androstanediol glucuronide will be used to monitor dutasteride inhibition of 
5-reductase enzyme activity.  We hypothesize that dutasteride 1 mg/day will be well 
tolerated by both male and female heavy drinkers, will produce ≥80% reduction in the 
serum marker of 5-reductase enzyme activity and will result in a greater reduction in the 
number of heavy drinking days and drinks per week than pbo and that treatment effects 
will be greater for women as they are expected to more frequently experience drinking to 
cope, higher anxiety and a history of childhood adversity/trauma.
Aim 2. Aim 2A: To examine whether the reduction in drinking in treatment responders 
(defined as ≥60% reduction during weeks 9-12) is maintained in a 12-week, phase 2 
extension of the initial treatment condition (pbo or dutasteride). This will help to determine 
the clinical utility of dutasteride as a treatment for AUD, which is a chronic, relapsing 
disorder.  Aim 2B: Increase the number of dutasteride double-blind treated subjects by 
including in the 12-week phase 2 a cross-over for pbo non-responders to dutasteride and 
for dutasteride non-responders to naltrexone, a medication with a different mechanism of 
action compared with dutasteride.  
We hypothesize that reductions in drinking for dutasteride responders in phase 1 will be 
maintained during the 12-week extension period. Additionally, we hypothesize that phase 1 
non-responders on pbo will have significant reductions in drinking when crossed over to 
dutasteride in the second 12-week phase.  Further, we expect that a portion of dutasteride 
non-responders will have significant reductions in drinking when treated with naltrexone, 
consistent with models of individual genetic and environmental factors producing 
differences in individual subject responses to medications with different mechanisms of 
action.
Aim 3.  To examine baseline measures of drinking to cope, trait anxiety, perceived life 
stress, or early life adversity predict dutasteride treatment efficacy, and secondarily, 
whether a common genetic variation, rs1360780, in the FKBP5 gene, which encodes a 
modulator of the intra-cellular steroid hormone signaling system and HPA stress response 
system, moderates dutasteride treatment response as an interactive effect with these 
negative affect/life stress measures. We hypothesize that dutasteride treatment benefits 
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relative to placebo will be greatest for subjects reporting more drinking to cope, greater 
anxiety, perceived stress or a history of trauma/adversity, particularly for those who are 
carriers of the FKBP5 rs1360780 T-allele.
Section 2.  RESEARCH STRATEGY
2.A. Significance.    Alcohol use disorder is highly prevalent, frequently chronic and has 
significant negative effects on the health and quality of life for affected individuals and their 
families.  Alcohol use has been estimated to account for 4.6% of lost global disability-
adjusted life-years (Rehm, Mathers et al. 2009). Alcohol use disorder (AUD) has a point 
prevalence of 14% in the U.S. (Grant, Goldstein et al. 2015) and is notably undertreated. 
Most problem drinkers do not seek treatment and those who do are frequently more 
interested in reducing rather than stopping drinking.  Primary care providers often feel 
hesitant or ill-prepared to intervene using psychosocial treatments other than referral to AA 
and may be more willing to provide medical therapies.  Pharmacotherapy options for 
alcohol use disorder include only three FDA-approved compounds (disulfiram, naltrexone 
and acamprosate), which have modest effect sizes compared with placebo (Zindel and 
Kranzler 2014).  Recent studies highlight the potential for medications approved for the 
treatment of other indications (e.g., topiramate, ondansetron, zonisamide, baclofen) to be 
applied to the treatment of AUD (reviewed in references (Edwards, Kenna et al. 2011, 
Zindel and Kranzler 2014, Akbar, Egli et al. 2018)).  Study of additional agents, particularly 
those that act through novel mechanisms, is needed to expand the range of 
pharmacotherapy options for AUD.  The neuroactive steroid system represents one such 
novel mechanism, and dutasteride, a widely prescribed medication that blocks a key step 
in the production of 5-reduced neuroactive steroids, is a promising candidate for treating 
AUDs.  In the first RCT of dutasteride (section 2.B.2) we observed that patients reporting 
drinking to cope, higher levels of anxiety or taking medications for depression or anxiety 
may particularly benefit from dutasteride.  Co-morbid symptoms of anxiety and/or 
depression are common among treatment seeking drinkers and are associated with worse 
treatment outcomes (Smith and Randall 2012).  Drinking to self-medicate anxiety and 
mood symptoms increases the risk of AUD incidence and persistence (Menary, Kushner et 
al. 2011, Crum, Mojtabai et al. 2013) and drinking to cope appears to be a keystone 
feature linking internalizing symptoms with adverse drinking-related outcomes (Armeli, 
Sullivan et al. 2015, Anker, Forbes et al. 2017). Women drinkers are more commonly 
affected by anxiety/depression and drinking to cope (Smith and Randall 2012).  
This study aims to extend our findings by examining effects in both men and 
women, extending treatment period to 24 weeks and to examine baseline measures, 
including drinking to cope, perceived stress, anxiety and childhood adversity alone or 
combined with a polymorphism in the gene encoding the steroid hormone receptor 
chaperone protein FKBP5, to predict patient groups most likely to benefit from dutasteride 
compared with placebo.  Identification of phenotypic and genetic predictors of medication 
response offers the potential to personalize alcohol treatment (Jones, Comer et al. 2015, 
Seneviratne and Johnson 2015) as it is common experience in clinical practice that 
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medications have limited benefit for the average patient, but in a subset of patients can 
have large effects.
2.B. Innovation.  The study is innovative in examining a novel medication, dutasteride, for 
AUD and for identifying predictors of response to advance the personalized treatment of 
the disorder.  The study design is innovative, as it employs a 24-week pharmacotherapy 
protocol with a sequenced medication treatment algorithm to allow a naturalistic approach 
to treatment and enhance retention. Specifically, patients who respond to their initial 
treatment during the initial 12 weeks (phase 1), will continue on that assigned treatment 
with continued blinded conditions.  However, patients who fail to respond during phase 1 
will transition in a pre-planned fashion to either dutasteride for those who received pbo in 
phase 1, or naltrexone for those who received dutasteride in phase 1.  Naltrexone is an 
FDA approved medication for AUD with a completely distinct mechanism of action 
compared with dutasteride and which has been reported to have greatest benefits for 
smokers (Fucito, Park et al. 2012, Schacht, Randall et al. 2017) and patients with greater 
drinking to enhance compared with drinking to cope (Mann, Roos et al. 2018) 
characteristics which complement those we have identified for dutasteride (see 2.B.2). 
This design provides a blinded and ethical solution for retaining patients in a 6-month 
treatment study for those who fail to respond in the initial 3-month phase and provides 
additional information on the utility of the investigational medication dutasteride by 
exploring the effects of crossing placebo non-responder to dutasteride for phase 2 of the 
study.
2.B.1. Neuroactive steroids, dutasteride and alcohol.  An extensive body of pre-clinical 
research supports the hypothesis that endogenous neuroactive steroids produced in 
response to alcohol mediate some of the behavioral and electrophysiological effects of 
alcohol [reviewed in (Kumar, Porcu et al. 2009).  5 reduced 3-hydroxy-pregnane and 
3-hydroxy-androstane neuroactive steroid metabolites of progesterone and testosterone 
respectively are endogenous, highly potent, positive allosteric modulators of GABAA 
receptors (Paul and Purdy 1992) that are produced both peripherally and in the brain.  
Immunostaining studies examining rodent and cynomolgus monkey brain tissue indicate 
that levels of 3-reduced neurosteroids are dynamically regulated in the CNS and show 
regional variation (Saalmann, Kirkcaldie et al. 2007, Beattie, Maldonado-Devincci et al. 
2017, Beattie, Reguyal et al. 2017).  While 53-reduced steroids have been more widely 
examined as they are the prevalent form in rodents, in humans 53-reduced steroids are 
also present and are also positive allosteric modulators of GABAA receptors (levels of 
these would not be reduced by 5-reductase inhibitors).
In rat models, alcohol increases levels of neuroactive steroids in the plasma and 
brain of intact animals and in brain slice preparations (Barbaccia, Affricano et al. 1999, 
Morrow, Janis et al. 1999, VanDoren, Matthews et al. 2000, O'Dell, Alomary et al. 2004, 
Sanna, Talani et al. 2004).  Blockade of ethanol-induced increases of neuroactive steroids 
in rats using the 5-alpha reductase (5AR) inhibitor finasteride attenuates several 
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behavioral effects of alcohol (VanDoren, Matthews et al. 2000, Hirani, Khisti et al. 2002, 
Hirani, Sharma et al. 2005) and blocks the effects of alcohol on GABAA currents in brain 
slice preparations (Sanna, Talani et al. 2004). Other studies have examined the effects of 
neuroactive steroids and their inhibitors on alcohol self-administration in rodents.  In mice 
and rats trained to self-administer 10% ethanol, treatment with low doses of the 
endogenous GABAA neurosteroid agonist allopregnanolone (5α-pregnan-3α-ol-20-one) 
(Ford, Nickel et al. 2005) or the synthetic neurosteroid agonist ganaxolone (Besheer, 
Lindsay et al. 2010) increase alcohol self-administration.  In contrast, treatment with the 
GABAA inhibitory neuroactive steroid epipregnanolone (5-pregnan-3-ol-20-one) reduces 
alcohol self-administration in rats (O'Dell, Purdy et al. 2005).  Additionally, blockade of 
neuroactive steroid production by the 5AR  inhibitor finasteride attenuates the acquisition 
of alcohol preference in mice (Ford, Yoneyama et al. 2008) and reduces alcohol self-
administration in mice previously trained to self-administer it (Ford, Nickel et al. 2005), as 
well as in naïve mice (Ramaker, Ford et al. 2011).  Together, these results from pre-clinical 
studies suggest that 1) alcohol-related changes in neuroactive steroid levels or patterns of 
metabolism contribute to the reinforcing aspects of alcohol in self-administration paradigms 
and 2) that blockade of these processes by inhibitors of 5AR may be useful in reducing 
alcohol consumption in humans.
Data from human studies supporting neuroactive steroids as mediators of alcohol’s 
effects are more limited.  In humans, the plasma concentration of allopregnanolone has 
been reported to be increased following severe intoxication (Torres and Ortega 2003, 
Torres and Ortega 2004), but not moderate doses of alcohol (Holdstock, Penland et al. 
2006, Pierucci-Lagha, Covault et al. 2006, Porcu, O'Buckley et al. 2009).  We provided 
indirect evidence of a role of neuroactive steroids in human alcohol consumption by 
showing that polymorphisms in two key neuroactive steroid biosynthetic enzymes, 5AR 
type I (encoded by SRD5A1), and 3-hydroxysteroid reductase type 2 (encoded by 
AKR1C3) are associated with AUD (Milivojevic, Kranzler et al. 2011).  Further, we found 
that His5Gln AKR1C3*2 C-allele (an AUD risk allele) homozygotes reported lower 
effects of acute alcohol in a human laboratory study (Milivojevic, Feinn et al. 2014).
Finasteride, which has been widely used as a pharmacological tool in animal 
studies of neuroactive steroids, blocks both type I and II 5AR in rodents.  However, in 
humans, finasteride at clinical doses blocks only type II 5AR, the 5AR isoenzyme most 
abundant in prostate and skin but absent in adult brain.  Dutasteride, a second FDA-
approved 5AR inhibitor for the treatment of prostatic hyperplasia, irreversibly inhibits both 
type I (brain, adrenal, liver and adipose tissue) and type II (liver, skin and prostate) 5AR 
enzymes at clinically relevant dosages, leading to a greater reduction in 5-
dihydrotestosterone (DHT) levels than finasteride without suppressing testosterone (Clark, 
Hermann et al. 2004). This broader 5AR inhibition profile, together with good tolerability 
and safety, make dutasteride an excellent candidate medication for reducing drinking in 
humans.  Published reports of the behavioral effects of dutasteride in humans support the 
potential clinical utility of dutasteride beyond effects on DHT levels in prostatic hyperplasia 
and alopecia.   In a study of male social drinkers, we reported that a single 4-mg dose of 
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dutasteride reduced the sedative effects of alcohol consumed 2-4 days later and also 
reduced drinking in the natural environment for 1-2 weeks following this short treatment 
(Covault, Pond et al. 2014).  A pilot study in women with pre-menstrual dysphoria showed 
that dutasteride 2.5 mg daily for 30 days was well tolerated and attenuated pre-menstrual 
dysphoria symptoms (Martinez, Rubinow et al. 2016).
In addition to the well-known role of 5AR enzymes in conversion of testosterone to 
dihydrotestosterone, 5AR (and 5-reductase) enzymes inactivate cortisol to 5-
dihydrocortisol, which is then converted to the inactive elimination cortisol metabolite 5-
tetrahydrocortisol (5a/b-THF) by 3-hydroxysteroid dehydrogenase.  5-THF and 5-THF 
each represent ≈20% of total urinary excretion of cortisol metabolites (Finken, Andrews et 
al. 1999).  Dutasteride and finasteride treatment for 3 months in healthy subjects reduces 
levels of 5-reduced cortisol urinary metabolites by over 95% without an increase in 5-
reduced cortisol metabolites resulting in an overall reduction of urinary cortisol metabolites 
but without a change in morning plasma or salivary cortisol (Upreti, Hughes et al. 2014).  
This recent finding suggests that 5AR inhibitors reduce overall adrenal cortisol output by 
reduction in rates of elimination with compensatory cortisol feedback reductions in further 
HPA axis activation and suggests that dutasteride would be expected to reduce the 
plasma ACTH to cortisol ratio.  HPA effects are thus a second mechanism by which 
dutasteride could moderate alcohol intake which may be most relevant to patients with 
elevated stress, stress reactivity, anxiety or trauma (Blaine and Sinha 2017).  
2.B.2. Preliminary studies.
We recently completed the first RCT of Dutasteride for the reduction of heavy 
drinking in men.  Results support further examination of dutasteride as a treatment option 
for AUD.   In total 189 treatment seeking men were enrolled of which 24 were screen 
failures and 23 failed to return for the baseline visit leaving 142 subjects randomized to 
medication (dutasteride n=74).  Seven subjects did not return after the baseline 
randomization visit providing a modified intention to treat sample of 135 subjects  (68 
dutasteride and 67 placebo) who provided drinking data post-randomization.  One hundred 
seven subjects completed the entire 12-week treatment.  The mean number of treatment 
weeks completed were not different between arms (dut 10.2 vs. pbo 10.7).  3-
androstanediol glucuronide levels were decreased by 80% in the dutasteride group at both 
6 and 12 weeks vs. 0% in pbo treated subjects confirming the anticipated pharmacological 
effect for our study design. There were no significant differences between groups 
(dutasteride vs. pbo) for measures of alcohol consumption during the 60-days prior to 
screening including the number of standard drinks (SD) per week (48.8 vs. 47.3), number 
of heavy drinking days (HDD, 5 or more drinks for men) per week (5.2 vs. 5.2), or abstinent 
days per week (0.67 vs. 0.62).  While the dutasteride group were more likely to have had a 
prior episode of treatment for alcohol use (59% vs. 40%, p=0.03) the number of DSM-IV 
AD criteria did not significantly differ between groups (4.3 vs. 4.0). 
Safety. There were no study related serious adverse effects.  The proportion of 
subjects exposed to study medication who reported at least one non-serious adverse 
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effect was not significantly different for the dutasteride vs. pbo groups 71.6% vs. 67.1% 
similarly, the number of side effects per subject was not different between dutasteride and 
placebo groups, 1.36 ± 1.46 vs. 1.03 ± 1.10.  Adverse events that were reported by more 
patients in the dutasteride compared with the placebo arm included stomach discomfort 
(16.4% vs. 4.5%, p=0.04) and reduced libido (9.0% vs. 0%; p=0.03). More subjects in the 
dutasteride arm (n=4) than the pbo arm (n=1) stopped medication due to side effects. Beck 
Depression Inventory scores were low in both treatment arms at baseline (10.4 dut vs. 7.5 
pbo) and reduced to a similar degree during the 12-week treatment (-3.3 dut vs. -2.4 pbo, 
t=0.6; p=0.5).
Drinking outcomes. Comparison of treatment groups for the modified intention to 
treat sample (N=135) on the primary outcomes of HDD/week and drinks/ week using 
generalized linear mixed models (GLMM) showed significant treatment x time interactions 
(HDD F=9.2; df=1,1406, p=0.002 and SD/wk F=4.8, df=1,1406, p= 0.028). 
While a minority of our subjects smoke, in view of prior reports of differential medication 
effects among smokers vs. non-smokers for naltrexone we examined GLMM models that 
included smoking status, treatment condition, treatment x time, and treatment x smoking 
as predictors, and identified significant 2-way interactions of treatment x time (F=9.1, 
df=1,1404, p=0.003 and F=4.4, df=1,1403, p=0.035 for HDD and SD/wk, respectively), and 
treatment x smoking (F=8.4, df=1,1404, p=0.004 and F=10.9, df=1,1403, p=0.001 for HDD 
and SD/wk, respectively), such that smokers (n=12) treated with dutasteride drank more 
throughout the treatment period than smokers treated with pbo (n=12), while the opposite 
response was observed for non-smokers (dutasteride=56; pbo=55).  Smokers and non-
smokers did not differ on baseline drinking, age, Spielberger State Anxiety (SAI) or Beck 
Depression Inventory (BDI) scores. The interaction of drug x smoking status may relate to 
the induction by tobacco of phase I metabolism cytochrome P450 and aldo-keto reductase 
enzymes (Nagaraj, Beckers et al. 2006), the latter of which are involved in neuroactive 
steroid biosynthesis and metabolism. A prior study showed a positive correlation between 
serum cotinine levels and the neuroactive steroid allopregnanolone in a sample of 28 men 
(Marx, Trost et al. 2006). Somewhat surprisingly, with limited exceptions (Fucito, Park et 
al. 2012, Litten, Ryan et al. 2013, Schacht, Randall et al. 2017) reports for recent RCTs for 
AUD either did not report the proportion of smokers (Johnson, Ait-Daoud et al. 2003, 
Johnson, Rosenthal et al. 2007, Johnson, Ait-Daoud et al. 2011, Johnson, Seneviratne et 
al. 2013, Kranzler, Covault et al. 2014) or did not include smoking status in the analysis of 
outcomes (Anton, O'Malley et al. 2006, Anton, Myrick et al. 2011, Fertig, Ryan et al. 2012, 
Litten, Fertig et al. 2012).  Interestingly, in the reports by Fucito et al. (Fucito, Park et al. 
2012) and Schacht et al.(Schacht, Randall et al. 2017) naltrexone only benefited drinkers 
who also smoked while our results with dutasteride indicated only non-smokers were 
responsive, presumably reflecting distinct mechanisms of change.  We will include 
smokers in the proposed study to further evaluate our initial findings.  Dutasteride non-
responsive smokers in phase 1 may experience treatment responsive to naltrexone in 
phase 2 of the proposed study which would support use of smoking as a factor in 
individualized treatment recommendations.
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For the majority non-smoker group (n=111) there was a significant interaction of 
medication group by treatment week (HDD/wk F=6.2, df=1,1183, p=0.013; and SD/wk 
F=4.7, df=1,1183, p=0.031) Figure 1, such that dutasteride treated subjects reduced 
drinking over time more than placebo subjects.  During the last 4 weeks of the 12-week 
treatment period, the proportion of subjects with a ≥60% reduction in SD/wk compared with 
screening (which represents a clinically meaningful reduction from a group average of 48 
SDs/wk to less than 20) was significantly greater for the dutasteride vs. the pbo group 
[49% vs. 20%; 2=8.3, p=0.004; OR=3.8 (95% CI=1.5-9.8)].  Additionally, among the 91 
per protocol completers, during the last month of treatment 33% of subjects in the 
dutasteride arm had no heavy drinking and 27% no hazardous drinking (no HDDs and no 
more than 14 SD/wk) compared with 11% and 2% of pbo- treated subjects respectively [no 
HDD days [2=6.7, p=0.01; OR = 4.1, NNT=5]; and no hazardous drinking [2=11.1, 
p=0.001; OR = 16.4, NNT=4]. The additional analysis described below focuses on the 
group of 111 non-smokers.
Figure 1. Heavy 
Drinking Days 
per week (left) 
and Standard 
Drinks per week 
(right) for pbo vs 
dutasteride 
treated non-
smokers 
(mean±SEM).
Potential predictors of response:  In an effort to identify potential drinking related 
markers associated with treatment response we examined several measures collected at 
study entry including drinking motives (CDMQ), self-reported alcohol cravings, and family 
history of AD (a surrogate for genetic loading).  Among these features, only the CDMQ 
drinking to cope score significantly interacted with medication group.  There was a 
significant interaction of medication with baseline drinking to cope score for HDD/wk 
(F=10.2, df=1,1155, p=0.001) and for SD/wk (F=4.9, df=1,1155, p=0.027) such that 
contrasting subjects above and below the median drinking to cope groups, there were 
limited reductions in drinking in the higher DTC group among placebo subjects but 
significant drinking reductions in dutasteride treated patients, Fig. 2.  For the high drinking 
to cope group there was a significant medication x time interaction for the HDD/wk 
measure (F=5.6, df=1,535, p=0.017) and a significant main effect of medication for SD/wk 
(F=5.2, df=1,535, p=0.023).  For the 41 subjects in high DTC group who completed all 12 
weeks of treatment, 45.5% of dutasteride treated subjects had no heaving drinking during 
the last month of treatment compared with 10.5% of placebo treated subjects [2=6.0, 
p=0.014; OR = 7.1 (95% CI=1.3-38.3) NNT=3]. 
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Figure 2.  Mean heavy 
drinking days per week for 
dutasteride vs. placebo 
subjects stratified by a 
median split for low vs. 
high drinking to cope as a 
proportion of total drinking 
motives score (0-25% vs. 
26-63%).  Low DTC group 
(left) - 31 placebo and 25 
dutasteride subjects; high 
DTC group (right) - 23 
placebo and 30 
dutasteride. The standard 
error of the mean is 
represented.
  
The high drinking to cope group had higher baseline Spielberger Anxiety Inventory 
scores (SAI, t= 2.6, df=107, p=.010) which were moderately correlated with DTC scores 
(r=.36, p<0.01).  When patients were contrasted based on median baseline SAI score, 
there was a main effect of drug in the high but not low anxiety group for both HDD/wk 
(F=5.7, df=1,557, p=0.017) and SD/wk and (F=10.7, df=1,557, p=0.001) with the form of 
interaction similar to that illustrated in Fig 2 for high vs. low DTC score.
We did not exclude subjects with concomitant use of medications for anxiety or 
depression, 20% of subjects were taking such medications at baseline. Patients in the high 
DTC group were more likely to take medication for anxiety or depression than the low DTC 
group 28.3% vs. 12.5% [2=4.2, p=0.04; OR = 2.7].
Figure 3.  Mean drinks per week 
contrasting subjects taking or not 
taking concominant medications for 
anxiety or depression stratified by 
placebo (left) vs. dutasteride 
treatment (right). The standard error 
of the mean is represented.  
Reductions in drinks per week among dutasteride treated subjects was not impacted by 
concurrent medication use for anxiety or depression (Fig 3 right), while among placebo 
subjects there were very limited reductions in drinking for subjects taking medication for 
anxiety or depression compared with placebo treated subjects without ongoing use of such 
medications (SD/wk F=7.8, df=1,596, p=0.005), Fig 3 left.
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Summary: Results from the first study of dutasteride for AUD conducted in men indicate 
that dutasteride is well tolerated and significantly reduced alcohol use compared with 
placebo in moderate to heavy drinkers.  Further, dutasteride-treated subjects with elevated 
baseline self-reported DTC motives and anxiety showed the largest reductions in drinking 
compared with placebo.  Drinking to cope with negative affect and anxiety are common 
clinical challenges in the treatment of AUD (Smith and Randall 2012) (Menary, Kushner et 
al. 2011, Crum, Mojtabai et al. 2013).  These results suggest that dutasteride may have 
particular benefit for patients with these characteristics. The associations of dutasteride 
response with baseline measures related to stress suggest that the effects of dutasteride 
to reduce drinking may include a mechanism of action involving the HPA stress response 
system.  
The proposed study will extend these results by including both sexes and extend our 
analysis of the relationship of baseline drinking to cope (DTC) and anxiety by adding 
baseline standardized questionnaires measuring trait anxiety (STAI), early life adversity 
(ACES), and a perceived stress scale (PSS) which in other settings was more predictive of 
health care utilization than stressful life event counts (Cohen, Kamarck et al. 1983). 
Women are expected to have a greater likelihood of elevated DTC, ACES, trait anxiety 
scores (Smith and Randall 2012) which will enrich our sample in subjects potentially more 
responsive to dutasteride vs. pbo.  We will use separate randomizations for women vs. 
men and include dichotomized scores for DTC and FKBP5 risk allele carrier status in our 
URN randomization to balance for these potential predictors of efficacy.  This study may 
identify easy to score pre-treatment measures such as the CDMQ, ACES, STAI, PSS and 
genotype that could be clinically useful for making personalized treatment 
recommendations regarding use of dutasteride to reduce heavy drinking.
2.C. Experimental Approach / Research Plan 
2.C.1.  General Design:  The study will be conducted in the UCHC Clinical Research 
Center (CRC) clinic.  Random assignment to initial treatment group and double-blind 
conditions will be maintained throughout the study.  The study consists of two 12-week 
phases (Table 1), the first being a 12-week parallel-groups comparison of dutasteride and 
pbo to evaluate the safety and efficacy of dutasteride 1 mg/day in reducing the likelihood of 
drinking and heavy drinking in a sample of treatment-seeking men and women with AUD.  
In the second 12-week phase, responders in phase 1 (defined as a ≥60% reduction in 
SD/wk for weeks 9-12 compared with screening) will continue on their initial medication 
assignment, while non-responder subjects treated with placebo will cross over to 
dutasteride, and non-responder subjects treated with dutasteride will cross over to 
naltrexone.  This design maintains double blind conditions in both phases 1 and 2 and is 
innovative. This design will: i) promote retention and recruitment, as subjects who do not 
respond to treatment in phase 1 will cross-over to an active FDA approved medication for 
AUD, ii) provide two comparisons to examine dutasteride efficacy, a between-subjects 
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comparison in phase 1 and a within-subjects test in phase 2 for patients treated with pbo in 
phase 1 and dutasteride in phase 2, iii) allow evaluation of whether reductions in drinking 
are maintained with ongoing treatment for phase 1 dutasteride responders, and iv) provide 
preliminary data on whether dutasteride non-responders show reductions in drinking when 
crossed over to naltrexone, an established medication for AUD with a different mechanism 
of action compared with dutasteride.
Three and six-month follow-up visits following the completion of the 24-week treatment 
phase will evaluate the durability of treatment effects, allow measurement of the degree to 
which dutasteride effects on 5AR inhibition have been reversed following 12- or 24-week 
exposures and to maintain contact with female participants to remind them of the 
importance of effective contraception for 6 months following treatment.
Table 1. Expected Patient Distribution for Phase 1 and 2.
Phase 1 
Treatment
Phase 1 
Statistical 
contrasts
Phase 1 
Expected Tx 
response groups
Phase 2 
Treatment
Phase 2 Statistical contrasts
Dutasteride 
n=95
(grp A)
Dut-R (wk 9-12 
Response n=40)
Dut-NR (wk 9-
12 
Non-Response 
n=40)
Dut-R 
dutasteride
Dut-NR 
naltrexone 
Within-subject interrupted 
time series regression using 
mixed models.
Dut-R: Is dut response 
maintained? 
Dut-NR: Do dut NRs 
respond to naltrexone?
Pbo 
n=95 
(grp B)
Between-subject 
contrasts using 
GLMM 
Dut vs. Pbo for 
DVs HDD/wk and 
SD/wk;.
Moderating 
effects of 
genotype, 
baseline state vs. 
trait anxiety, 
perceived stress 
and interaction 
with FKBP5 
genotype 
Pbo-R (wk 9-12   
Response n=16)
Pbo-NR (wk 9-
12
Non-Response 
n=64)
Pbo-R 
pbo
Pbo-NR
dutasteride
Pbo-R: insufficient sample 
for statistical comparison.
Pbo-NR: Do pbo NRs 
respond to Dut?  
Phase 1 response ≥ 60% reduction SD/wk for wk 9-12 vs baseline (current study 49% 
response rate for dut vs. 20% pbo). dutasteride 1 mg/day; naltrexone 50 mg/day.
2.C.2.  Patients:  Drinkers who want to reduce or stop drinking will be recruited using 
advertisements in radio and print media, by posting/distributing recruitment materials in 
community settings, informational mailings to area clinicians and by referral from UConn 
Health medical and dental clinics in at our main campus in Farmington CT together with 
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satellite outpatient clinics in Canton, East Hartford, Putnam, Simsbury, Southington, Storrs, 
and West Hartford CT. Based on prior UConn ARC pharmacotherapy trials open to men 
and women (Kranzler, Tennen et al. 2009, Kranzler, Armeli et al. 2011, Kranzler, Covault 
et al. 2014) we anticipate that 35% of subjects will be female.  Approximately 260 subjects 
will be enrolled (in person screening visit) with the goal of randomizing 190 to medication 
with 160 completing the initial 12 weeks of treatment.  In the current study limited to men 
only, we enrolled 189 men and of these randomized 142.  At least four factors will 
contribute to success in enhancing our recruitment in order to randomize 190 subjects in 
the proposed study: i) inclusion of women (35% of subjects), ii) UCONN Health has 
recently adopted the EPIC electronic medical record system which includes clinical trial 
notice pop up feature on clinicians’ patient management screens with link to information 
about our clinical trial for patients with a clinic problem list entry of alcohol use disorder, iii) 
involvement of Dr. Surita Rao as a co-investigator who is the past-president and current 
board member of the CT Chapter of the American Society for Addiction Medicine and has 
agreed to send an informational letter and recruitment flyers for the study to all central CT 
members of ASAM, and iv) the PI’s greater experience in recruitment compared with the 
current study which was the first clinical trial for which he served as Principal Investigator. 
2.C.2.a.  Temporal Sequence of Screening:  Prospective participants will first undergo 
phone screening including the AUDIT-C three-item screener (Dawson, Grant et al. 2005) 
to assess key inclusion / exclusion criteria.  Patients who appear to be eligible will be 
invited for an in-person screening.  After informed consent is obtained, staff will administer 
several questionnaires, obtain a medical history, collect urine and blood specimens for 
clinical screening and for genotyping the FKBP5 rs1360780 polymorphism to allow 
balanced genotype distributions in the dutasteride and pbo treatment arms. Patients will 
receive a physical examination by a study physician and if no exclusions are identified will 
be randomized to receive study medication.  
2.C.2.b. Inclusion Criteria: a) men and women age 35 to 70 yo inclusive; b) have an 
average weekly ethanol consumption of >24 SD for men and >18 for women and at least 2 
HDD/wk over the 8 weeks prior to screening [i.e., substantially in excess of non-hazardous 
drinking levels (Sanchez-Craig, Wilkinson et al. 1995)]; c) current DSM-5 AUD, d) Have a 
goal to reduce or stop drinking, e) no evidence of significant cognitive impairment; and f) 
for women of child-bearing potential (i.e., no hysterectomy, bilateral oophorectomy, or 
tubal ligation; or <2 years postmenopausal) must be non-lactating, practicing a reliable 
method of birth control and agree to continue such throughout the study and for 6 months 
following participation , and have a negative serum pregnancy test prior to initiation of 
treatment.   
We are limiting participation to patients >35 yo to minimize the risk to female 
participants in a phase of life when pregnancy is more common (<35 yo).  In our prior 
studies, only 5% of subjects have been younger than 35. Overall, patients for this study 
are anticipated to have a moderate level of AUD severity.  They will be asked to affirm a 
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treatment goal of either stopping drinking or reducing their drinking to non-hazardous 
levels including no heavy drinking days (≤4 SD/day men ≤3 SD/day women). 
2.C.2.c. Exclusion Criteria:  Although we will not set a specific upper limit of drinks per 
week, we will exclude subjects with either a) history of serious alcohol withdrawal 
symptoms (e.g., perceptual distortions, seizures, delirium, or hallucinations), or b) subjects 
who on clinical examination by a physician are deemed to be too severely alcohol 
dependent to permit them to participate in a pbo-controlled study (e.g., evidence of serious 
adverse medical or psychiatric effects that are exacerbated by heavy drinking and would, 
for safety reasons, lead the physician to urge the patient to be totally abstinent and engage 
in an empirically supported treatment); other exclusions include: c) current, clinically 
significant physical disease, body weight >340 lbs or abnormality on the basis of medical 
history, physical examination, or routine laboratory evaluation, including direct bilirubin 
more than 2.5 times the upper limit of normal or transaminase elevations 5 times the upper 
limit of normal (we will not exclude patients with hypertension, diabetes, asthma or other 
common medical conditions, if these are adequately controlled and the patient has an 
ongoing relationship with a primary care provider), d) have a serious psychiatric illness on 
the basis of history or psychiatric examination (i.e., schizophrenia, active clinically 
significant mood episode of bipolar disorder or major depression, organic mental disorder, 
current clinically significant eating disorder, or substantial suicide or violence risk); e) have 
a current DSM-5 diagnosis of moderate drug use disorder (other than caffeine or nicotine 
dependence); f) currently taking finasteride, dutasteride, medication for treatment of AUD, 
or chronic use of opioid pain medication; g) are considered by the investigators to be an 
unsuitable candidate for an investigational drug.
2.C.3. Study Drugs: 
2.C.3.a. Dutasteride is FDA approved to treat prostatic hypertrophy and is a competitive 
and specific inhibitor of both type I and type II steroid 5-reductase enzymes with which it 
forms a stable enzyme complex with very slow dissociation. In humans, type I 5AR is 
present in the brain, liver, adrenal gland, and adipose tissue and is responsible for one-
third of circulating DHT.  Type II 5AR is present in the liver and prostate, and is responsible 
for two-thirds of circulating DHT.  For studies of alcohol use, inhibition of type I 5AR may 
be of particular importance, as type I 5AR, but not type II enzyme, is present in the adult 
brain (Lephart, Lund et al. 2001) where local generation of neuroactive steroids is thought 
to occur in addition to peripherally generated neuroactive steroids. The dutasteride dose of 
1 mg/day proposed for this study is expected to achieve a >90% inhibition of peripheral 
type II 5AR and a 60% inhibition of  type 1 5AR by 4 weeks for a total reduction in DHT of 
 80% by 4 wks based on pharmacokinetic models (Gisleskog, Hermann et al. 1998) and 
consistent with our observed 80% reduction in 3-adiol glucuronide at 6 wks in our 
recently completed initial study in men using this dose. Dutasteride will be purchased 
commercially and over encapsulated using opaque capsules by the UConn Health 
Research Pharmacy Service.  Pbo will be formulated to match the active medication. 
Subjects will take one 0.5 mg capsule of dutasteride or matching pbo during the first 
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treatment visit (baseline study visit 2) and at home on day 2 followed by two capsules daily 
for either 12 or 24 weeks (depending on treatment response).  Similarly, subjects 
transitioning from placebo or dutasteride based on phase 1 non-response will be given one 
capsule of medication (dutasteride 0.5 mg or naltrexone 25 mg) during their first phase 2 
study visit and day 2 of phase 2 followed by two capsules daily for 12 weeks.   
Dutasteride is contraindicated for use in pregnant women due to the potential 
effects of dutasteride in utero on the normal development of external male genitalia 
secondary to reduced fetal DHT (Avodart, Prescribing information 2012, GlaxoSmithKline).  
As noted in the inclusion criteria and in human subject protections, we will limit 
participation to women >35 who are either not sexually active with men, are practicing 
effective contraception or are without reproductive capacity.  Female participants must 
have a negative serum -HCG at study entry and will be monitored every 6 weeks during 
treatment using urinary HCG.  Dutasteride has been safely used off label to treat alopecia 
(Boersma, Oranje et al. 2014, Seale, Eglini et al. 2016) in pre- and post-menopausal 
women in clinical practice and pre-menstrual dysphoria in a placebo controlled clinical trial 
(Martinez, Rubinow et al. 2016).  Dr. Covault has an IND 74,222 for the study of 
dutasteride for AUD which includes a protocol including women.     
2.C.3.b. Naltrexone  is FDA approved both as an oral daily treatment (50 mg, Revia) and a 
long-acting depot IM formulation (Vivitrol) for the treatment of alcohol use disorder.  
Naltrexone has been shown to reduce heavy drinking in multiple RCTs (Maisel, Blodgett et 
al. 2013, Jonas, Amick et al. 2014). Naltrexone is an antagonist of the -opioid and -
opioid receptors is thought to reduce alcohol craving and heavy drinking by blocking 
endogenous opioid induced dopamine release in response to the anticipation of drinking or 
use of alcohol. Naltrexone will be purchased commercially and over encapsulated using 
opaque capsules by the UConn Health Research Pharmacy Service. Naltrexone, 
dutasteride and placebo capsules will be identical in appearance.  Subjects assigned to 
naltrexone in study phase 2 will take 1 capsule of naltrexone 25 mg on phase 2 day 1 and 
2 and then 2 capsules each day containing in total 50 mg naltrexone for the remainder of 
phase 2.  All subjects who transition to a different study medication at end of phase 1 will 
be required to have a negative urine test for opioids and report no opioid use for at least 5 
days. 
2.C.3.c.  Pbo drug will consist of lactose powder formulated by the UCONN Health 
Research Pharmacy Service in gelatin capsules indistinguishable from the capsules 
containing dutasteride or naltrexone.
2.C.3.d. Medication Randomization and Drug Accountability: Urn randomization (Stout, 
Wirtz et al. 1994) will be used to assign subjects 1:1 to dutasteride or pbo for treatment 
phase 1, balancing for number of DSM5 AUD criteria (2-5 vs.>5), DTC relative to total 
motives score (0-25% vs. >25%), FKBP5 genotype (CC vs. T-carrier), current smoking 
status, and use of medication for treatment of co-morbid psychiatric condition.  Separate 
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randomizations will be done for women and men to ensure balance on these variables in 
both sex groups. At the end of phase 1, patients who have reduced drinks/week by at least 
60% will continue for the second 12 wks on the originally randomized treatment taking 2 
capsules per day.  Subjects who have reduced drinks/wk by less than 60%, will be 
informed that they will be transitioning to an active study medication (either dutasteride or 
naltrexone), and will be interviewed to confirm they have not used opioid medication for 5 
days prior which will be verified by urine testing, subjects testing positive for opioids will not 
be eligible for starting phase 2.  For non-responder subjects in the phase 1 pbo arm, the 
pharmacy will begin dispensing 0.5 mg dutasteride capsules with instructions to take 1 
capsule per day for 2 days, then 2 capsules daily for 12 weeks.  For subjects in the initial 
dutasteride arm and reducing less than 60%, the pharmacy will dispense 25 mg naltrexone 
capsules with the same instructions of 1 capsule for days 1 and 2 followed by 2 capsules 
each day (50 mg naltrexone per day) to match the dutasteride capsule dosing. Medication 
vials including any unused medication will brought to each follow-up visit. Unused pill 
counts will be recorded by the study nurse at each bi-weekly visit and medication use 
recorded daily by patients on their drink log.
2.C.4.  Study Visits:
At the screening visit, the patient's breath alcohol or salivary alcohol level will be 
measured as a surrogate for blood alcohol concentration (BAC).  In order to sign the study 
informed consent the BAC must be <0.021. At each subsequent visit, a clinical 
assessment for signs of alcohol intoxication will be done by a member of the study team 
including unexplained drowsiness, euphoria / disinhibition or failing standard field sobriety 
tests (horizontal gaze nystagmus test, finger-to-nose pointing and one-leg stand).  If this 
assessment reveals two or more positive signs of alcohol intoxication, a breath alcohol or 
salivary alcohol test will be done as a surrogate measure of BAC.If a subject has an 
estimated BAC over 0.08% (the legal limit for driving in Connecticut) they will be asked to 
turn their car keys over to research staff to hold until their BAC has dropped to below 0.08 
and has been evaluated by a research clinic nurse or physician to assess subject safety.  
Intoxicated subjects who did not drive to the clinic may leave in the company of a friend or 
other responsible person after evaluation by clinician for safety.  If a subject is impaired 
and refuses to cooperate with these safety procedures, the UCONN Health Police will be 
called 679-2121 for assistance.  Additionally, at each study visit subjects will be screened 
for alcohol withdrawal symptoms using the Clinical Institute Withdrawal Assessment 
(CIWA) with a threshold score of 10 triggering evaluation by clinic physician for appropriate 
treatment/management. 
2.C.4.a.  Visit 1 (Screening Visit):  After informed consent is obtained, a medical and 
psychiatric history will be obtained by a study nurse which will be reviewed with the 
participant by a study physician and any medication or study related questions reviewed. 
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Relevant portions of the Structured Clinical Interview for DSM-5 will be administered by a 
research assistant to exclude subjects with active major mental illness or current moderate 
to severe substance dependence other than alcohol, caffeine or tobacco.  A Timeline 
Follow-Back (TLFB) interview will be performed to collect daily alcohol consumption for the 
90 days prior to screening. Blood and urine samples will be taken for routine clinical 
laboratory evaluations, drug screening, DNA extraction and for measurement of the 
alcohol use biomarker phosphatidylethanol (PEth, which will be used as a secondary 
measure of drinking), the steroid metabolite 3-diolG to monitor 5AR inhibition and ACTH 
and cortisol to examine for the effects of dutasteride on the ACTH/cortisol ratio.  Efforts will 
be made to schedule individual subjects at the same time of day for each of their visits 
involving blood draws to reduce the within subject effects of diurnal variation in hormone 
levels (based on our prior studies, a majority of our subjects are anticipated to be 
employed with consistent times requested for study visits). Finally, subjects will be 
provided a stool sample collection kit and instructed on its use at home for obtaining stool 
samples to be returned at Visit 2. Stool samples will be collected at baseline and end of 
treatment phase 1 and archived at -80C for batch processing to catalog each subjects gut 
microbiome via DNA sequencing as part of a Center pilot project in order to contrast the 
gut microbiome sampled at baseline between subjects who reduce or do not reduce their 
drinking during phase 1 of the study.  Prior reports suggest that gut colonization with pro-
inflammatory microorganisms may be associated with greater difficultly in reducing 
drinking (Leclercq, Matamoros et al. 2014, Leclercq, de Timary et al. 2017, Leclercq, 
Starkel et al. 2018).  We will also contrast the change in the gut microbiome comparing 
baseline and endpoint stool samples as a function of reduction in alcohol use. We have 
had good acceptance rates in pilot use of this stool collection method in other clinical 
studies.  Subjects will be paid a nominal amount of money in consideration of their time 
and inconvenience for visits beyond the baseline visit (e.g., visits 3-16) as well as for 
completing the IVR daily calls.  Total potential compensation is $620 for completing all 16 
visits and all IVR calls.
2.C.4.b.  Visit 2 (Baseline Visit): 3-21 days after the screening visit, eligible subjects will 
return for their baseline visit.  Subjects will be instructed in the use of study medication and 
will take one capsule study medication (0.5 mg dutasteride or pbo) at the baseline visit and 
again on study day 2, followed by 2 capsules daily for the remainder of the phase 1 12-
week treatment period (in order to match capsule number for 2 day naltrexone titration in 
phase 2). Finally, subjects will be trained to use a paper calendar provided by staff to 
record their daily drinking and use of the IVR system to record their mood, desire to drink, 
self-efficacy and daily drinking during weeks 1-4 and 9-12 of phase 1 and 21-24 of phase 
2.  We considered asking subjects to use the IVR report daily for the 168 days of treatment 
but considered that this would be an excessive subject burden.
Study visits beyond visit 2, may be conducted remotely by telephone if a participant is 
unable to come to the clinic due to illness, travel, or other valid concerns (e.g. about 
exposure to COVID-19) related to traveling to UConn Health.  Participants will be sent a 
one-time use REDCap secure link via email to complete study visit surveys. In the event a 
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participant is unable to attend an in person scheduled visit, backup supply of medication 
previously provided may be used or additional medication (up to 8 weeks) will be provided 
at an earlier visit if inability to attend future scheduled visit is anticipated in advance.  Study 
staff will consult with study physician regarding whether study medication should be 
continued if a participant reports illness as reason for a missed in person visit.  All unused 
medications will be brought to the next in person study visit.
2.C.4.c.  Bi-weekly Clinic or remote Visits 3-14: A brief Timeline Follow-Back (TLFB) 
interview will be performed to track participants’ daily alcohol consumption and medication 
use since the last study visit, and a trained staff member will deliver the medical 
management intervention.  
At the end of phase 1 treatment week 12 (visit 8) and phase 2 treatment week 24 
(visit 14), subjects will complete a series of questionnaires and be interviewed by research 
staff concerning their alcohol consumption and alcohol-related symptomatology. For 
subjects who withdraw early and do not wish to continue with study visits/procedures, end-
of-treatment evaluations will be administered at the time of withdrawal. Such subjects will 
also be invited to participate in-person or by telephone to provide drinking data for the 12-, 
24-week time points in order to include this data in intent to treat analysis of the treatment 
phase.  
2.C.4.d.  Visits 15 and 16 (3- and 6-month Post-treatment Assessment):  To evaluate the 
durability of treatment effects, patients will be invited to return to the clinic for a post-
treatment assessment 3 and 6 months after completion of treatment (if unable to come in 
person a telephone interview will be conducted).  Subjects will be contacted 6-8 weeks 
after end of treatment and following the 3-month follow-up visit to remind them of their 
follow-up appointment dates, reinforce maintaining their written drinking diary and to 
remind female subjects of the importance of continued use of effective contraception for 6 
months following treatment. At each follow-up visit, subjects will complete self-report 
questionnaires and will be interviewed by the research staff.  Blood samples for 
measurement of serum PEth, and 3-diolG will be obtained.  Subjects will be paid $50 for 
participating in each post treatment visit. 
2.C.5.  Medical Management:  A study physician will meet with each subject at the 
beginning of treatment. The PI will consult at least weekly with study staff to monitor 
potential study-related side effects and will be available to personally evaluate subjects 
with severe or persistent adverse effects.  At each treatment encounter, subjects will 
receive brief counseling as part of medical management, described below.
2.C.5.a.  Medical Management (MM) [Adapted from (Pettinati, Weiss et al. 2004)]:  The 
manual for this intervention was developed for use in the Combine Study (Anton, O'Malley 
et al. 2006) to provide a basic clinical intervention supporting medication use and 
monitoring of progress in reducing drinking that could be easily implemented by medically 
trained practitioners in non-specialty settings.  A modified MM protocol that includes both 
abstinence or reduced drinking as an individual’s stated goal will be used in the present 
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study.  An important goal of MM is to enhance medication adherence and treatment 
participation through education and support. 
The first MM session (study visit 2) will consist of a review of the results of the initial 
evaluation, to identify any medical concerns related to drinking and to reinforce subjects’ 
treatment goal of stopping or reducing drinking to non-hazardous levels.  This session will 
also use a self-help handout developed at the UConn ARC to encourage drinkers to self-
evaluate their drinking and set goals to stop or reduce drinking. At the end of the session 
patients are given the opportunity to ask any questions or express any concerns that they 
may have about the study procedures. 
Subsequent MM sessions will be conducted biweekly for the 24 weeks of active 
treatment.  During these sessions, the study nurse will perform a review of the subject’s 
general functioning, obtain vital signs, weight, and perform a brief assessment of the 
subject’s drinking, monitor the subject’s medication adherence, and make 
recommendations for the subject to follow until the next visit.  For subjects who are not 
drinking at sensible levels, the recommendation will be made that they try different 
behavioral strategies for reducing drinking (e.g., spacing drinks, drinking drinks with lower 
alcohol content) that are outlined in the NIAAA Clinician's Guide (NIAAA 2007). 
2.C.6.  Assessments:
2.C.6.a.  Laboratory/Medical Assessments:  A physical examination, urinalysis, urine 
toxicology, serum bHCG (for women), CBC, and a chemistry panel (which includes 
electrolytes, liver enzymes [ASAT, ALAT, GGT], direct bilirubin, BUN, and creatinine) will 
be used to screen subjects for medical exclusion criteria. ASAT, ALAT will be repeated for 
subjects with elevations at baseline greater than 3x normal at weeks 6, 12, 18 and 24 (or 
until reduced to less than 3x normal). Weight, blood pressure and pulse will be obtained at 
each treatment visit.  Urine will be tested every 6 weeks for drugs of abuse and HCG for 
women of reproductive potential. Blood will be archived for measurement of 
phosphatidylethanol (PEth) by a commercial testing lab as an objective measure of alcohol 
use.  PEth is an alcohol-specific adduct catalyzed by phospholipase D from ethanol and 
phosphatidylcholine in membranes of red blood cells and is not affected by liver or kidney 
disease, age or sex.  It is a sensitive and specific metabolite which is produced in direct 
response to use of alcohol during the past 20-30 days (Viel, Boscolo-Berto et al. 2012).  
PEth levels are correlated with the amount of alcohol consumed (Aradottir, Asanovska et 
al. 2006) and correlate better with daily diary drinking reports than carbohydrate deficient 
transferrin or gamma glutamyl transferase (de Bejczy, Lof et al. 2015, Walther, de Bejczy 
et al. 2015).  Blood for PEth will be collected at screening, and weeks 6, 12, 18 and 24.  
Serum 3-diolG will be measured using a commercial ELISA kit as a biochemical measure 
of 5AR inhibition by dutasteride.  3-diolG is a major metabolite of testosterone and is 
more abundant that DHT especially in women and has been shown to decrease in parallel 
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with DHT following finasteride treatment in men (Rittmaster, Stoner et al. 1989, Gormley, 
Stoner et al. 1990) and has been used to monitor the reduction of 5AR activity in women 
treated with finasteride (Wong, Morris et al. 1995, Falsetti, Gambera et al. 1999).  Serum 
testosterone, estradiol, progesterone, cortisol, ACTH and sex hormone binding globulin will 
be measured using commercial immunoassays to evaluate changes in these steroid 
hormones during treatment with dutasteride.  Blood for 3-diolG and steroid hormones will 
be collected at screening and weeks 6, 12, 18 and 24.
2.C.6.b.  Psychological/Behavioral Assessments:  The assessments listed below were 
chosen because they: a) are widely used assessments which will facilitate comparison of 
findings with prior treatment studies, b) include measures drinking motives, both trait and 
state anxiety, developmental adversity and perceived stress as potential predictors of 
treatment outcome,  c) measure multiple outcome criteria, since a reduction in drinking 
may or may not result in improvement in other domains, and d) assess for potential 
change in depression or anxiety related to treatment as additional safety measures.  The 
majority of patient report questionnaires will utilize the REDCap software package 
developed at Vanderbilt University. REDCap is a secure, web-based application for 
capturing data from participant self-reports or from staff interactions with study participants. 
Similarly, an online application NetSCID-5™ (Telesage) will be used by study staff to 
administer the structured clinical interview for DSM-5.
2.C.6.b.1.  Areas assessed only at Visit 1 (in person screening):  a) 
Medical/Sociodemographic information:  Medical history, marital status, educational and 
occupational information. b) NetSCID-5™ a web based version of the Structured Clinical 
Interview for DSM-5 (First, Williams et al. 2016) will be used to classify subjects according 
to the presence or absence of psychiatric disorders including AUD. The alcohol portion of 
the SCID will be administered at the 12 and 24 week (end phase 1 and B) and the 3- and 
6-month follow-up visits to evaluate presence of current alcohol dependence criteria. c) 
Family history of alcohol dependence: We will use the alcohol section of the Family History 
Assessment Module FHAM (Rice, Reich et al. 1995) , subjects will be asked to provide 
information concerning thier biological relatives’ history of alcohol use, however, names of 
family members will not be obtained. d). Alcohol Use Disorders Identification Test (AUDIT) 
(Saunders, Aasland et al. 1993) is a widely used instrument to screen for hazardous 
drinking, AUDIT scores will provide a measure of alcohol involvement for our study sample 
to allow comparison with other research samples and clinical populations.  It will be 
administered by the study nurse during review of medical history and provides a frame for 
nurse engagement of subjects during medical management sessions. e) Traumatic Events 
Screening Inventory (TESI) (Ford, Grasso et al. 2013) has 18 items that assess various 
types of trauma that with a total of nine trauma categories (i.e., accident/illness/disaster, 
traumatic loss/separation, traumatic physical victimization, traumatic sexual victimization, 
traumatic emotional victimization, traumatic domestic violence victimization, witnessed 
trauma, traumatic war victimization, or other traumatic events).  Subjects indicate (yes/no) 
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as to whether events occurred before age 6, between ages 6 and 17, above age 18 or 
within the past year.  We previously reported an interaction of FKBP5 genotype and 
trauma measured with the TESI on drinking in a large college student sample (Lieberman, 
Armeli et al. 2016). Presence or absence of childhood trauma will be evaluated for main 
and interactive effects with FKBP5 genotype on predicting treatment outcomes; g) Adverse 
Child Experiences Scale (ACES) The ACES assesses early life stress in the form of 
childhood exposure to adverse experiences and a risky family environment (Felitti, Anda et 
al. 1998). This 17 item questionnaire probes childhood exposures including psychological 
abuse, physical abuse, sexual abuse, substance abuse within the family, mental illness 
within the family, violence toward mother, and criminal behavior in the household. Felitti et 
al. (Felitti, Anda et al. 1998) found that in a large sample of adults belonging to a HMO, 
more than half endorsed at least one category of childhood exposure. Individuals who had 
experienced four or more categories of childhood exposure had 4 to 12-fold increased risk 
for alcoholism, drug abuse, depression and risky sexual behavior. Scores for the ACES will 
be evaluated for main and interactive effects with the FKBP5 genotype on predicting 
treatment outcomes.
2.C.6.b.2.  Areas assessed daily during the active treatment period:  IVR will be used 
to collect daily subjective ratings of alcohol-related expectancies, craving, anxiety/tension, 
and self-efficacy to reduce drinking, as well as drinking amounts. To reduce subject burden 
for daily IVR in this 24-wk study, we will use IVR to capture daily data for the first 4 study 
weeks and the last 4 weeks of both phase 1 and phase 2.  The IVR daily drinking data will 
be used together with bi-weekly drinking reports to determine treatment response (60% 
reduction in drinks/wk) during the last 4 weeks of phase 1 to inform treatment assignment 
for phase 2. Daily IVR reports will also enable us to address whether study medication 
moderates associations between daily mood, drinking motives, self-efficacy or daily events 
and drinking as has been reported using IVR methods for treatment with naltrexone and 
topiramate (Kranzler, Armeli et al. 2004, Armeli, Feinn et al. 2006). Moderation of 
relationships between daily mood reports and drinking by medication will be contrasted 
between baseline and end of phase 1 or 2.
Table 2:  Schedule of Assessments
Study Visit
V1 
Screen
V2 
Baseline
V 3-7
phase 2 
baseline
V 9-13
V14
V15-16
Time relative to Medication
Start 
medication
wks 2, 
4,6,8,10 
wk 12 
end 
phase 1 
wks 14, 
16,18,20,22 
wk 24 
end 
phase 2
3- and 6-
mo follow-
up
Medical History, demographics, 
AUDIT, SCID, FHAM, ACES, 
TESI, STAI-trait, 
Clinical screening labs, blood for 
DNA and research analytes
Physical Exam & Clinician 
review of Medical History
X
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TLFB, PHQ-9, CIWA, MTR
X
X
X
X
X
X
X
Vital signs & weight
X
X
X
X
X
X
X
 DMQ, AEQ, SIP
X
X
X
X
Study outcome blood samples
X
wk 6
X
wk 18
X
X
Urine drug screen, HCG 
(women), PACS
X
wk 6
X
wk 18
X
X
STAI-state, PSS
X
STAI-trait, PSS
X
X
X
Daily IVR call
X
wk 1-4
wk 9-12
wk 21-24
Side Effect Checklist (SAFTEE)
X
X
X
X
X
X
Medical Management 
X
X
X
X
X
Alcohol SCID past 1 month
X
X
X
The IVR system will use the same procedures we have used in the recently 
completed dutasteride study and prior UConn Health studies of topiramate (Kranzler, 
Armeli et al. 2016).  a) Daily drinking diary:  Every evening, as part of the IVR daily diary, 
patients will record their alcohol consumption as the number of standard drinks in each of 
three categories of alcoholic beverages:  beer, wine, liquor. Patients are asked to report 
separately drinking from yesterday and any drinking during the current day, up until the 
time of the IVR report.  This allows us to examine lagged associations with mood and life 
event triggers.   b)  Daily mood:  Patients will be asked to rate as part of the daily IVR their 
mood using an adjective checklist.  The checklist consists of 9 adjectives (Larsen and 
Diener 1992) with each rated on a 5-point scale (0 = "not at all" to 4 = "extremely").  Three 
adjectives for each of three mood state dimensions provide measures of positive mood, 
negative mood and activated mood. Subjects will also be asked to report their self-efficacy 
for managing life problems. c) Daily Events:  Participants will be asked whether they 
experienced a list of nine possible daily events (3 stressful, 3 pleasant, and 3 situations 
where someone might drink).  These measures will be used to assess the influence of 
positive and negative current life events on drinking. d) Drinking motives: Participants will 
be asked to respond to 3-items for each of three drinking motives as to why they drank 
today and yesterday;  to cope, to enhance or to socialize on a 3-point scale (1= “not at all”, 
2=”somewhat” and 3=”definitely).
2.C.6.b.3. Assessed at intake, end of treatment phase 1 and 2, and at 3-mo follow-up: 
Psychological symptoms  The Physician’s Health Questionnaire (PHQ-9), is a validated 
9-item self-report measure of depressive symptoms with a total score of 0-27 (Ware, 
Kosinski et al. 1996, Kroenke, Spitzer et al. 2001).  It will also be administered at each bi-
weekly treatment visit.  Spielberger State-Trait Anxiety Inventory (STAI), a 40-item self-
report questionnaire (Spielberger 1983) containing 20-items each measuring Trait-anxiety 
vs. State-anxiety. The trait anxiety component will be administered at screening and the 
state anxiety at the baseline visit 2. The pre-treatment trait and state anxiety scores will be 
examined as predictors of dutasteride treatment efficacy.  The trait-anxiety items will be 
asked again at the 12 and 24-week visits to monitor anxiety symptoms over time. 
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Perceived Stress Scale (PSS), a  10-item scale measuring perceived stress for the past 
month (Cohen, Kamarck et al. 1983).  It has been reported to have better predictive value 
for health symptoms and health care utilization than life stress counts. Based on our 
current study interim results, we anticipate that similar to the STAI, the baseline PSS score 
may identify subjects most likely to benefit from dutasteride.  
Drinking-motives, self-efficacy and alcohol problems: Drinking Motives will be 
measured with the Cooper Drinking Motives Questionnaire (DMQ); (Cooper, Russell et al. 
1992, Cooper 1994)).  This instrument contains 20 items with 4 drinking motives 
subscales:  a) to cope motives (e.g., “Because it helps when you are feeling nervous or 
depressed”), b) conformity motives (e.g., “Because it helps me fit in”), c) enhancement 
motives (e.g., “Because it’s fun”), and d) social motives (e.g., “Because it makes a social 
occasion more enjoyable”).  The DMQ will be administered at baseline and for those 
subjects who continue to drink again at end of phase 1 and 2 treatment periods. Alcohol 
expectancies will be assessed with 24 items from the Alcohol Effects Questionnaire (AEQ; 
(George, Frone et al. 1995)) probing 4 positive expectancy subscales (social and physical 
pleasure, aggression and power, social expressiveness, and relaxation and tension 
reduction) and 1 negative subscales (cognitive/physical impairment) to explore potential 
changes as a result of treatment with dutasteride.   The Short Inventory of Problems (SIP). 
The SIP is a 15-item instrument derived from the Drinker Inventory of Consequences 
(DrInC), to measure alcohol-related medical, psychological, social, occupational, and legal 
consequences (Feinn, Tennen et al. 2003). The Penn Alcohol Craving Scale (PACS) is a 
5-item self-report measure that includes questions regarding the frequency, intensity, and 
duration of craving over the past week (Flannery, Volpicelli et al. 1999).   
Integrity of the double blind: A Medication Questionnaire (MED-Q) will be completed by 
the subject at the end of phase 1 and 2 treatment periods (or at the time of treatment 
discontinuation for subjects who do not complete either treatment period).  It includes an 
indication of which medication group the subject believes to have been in, their level of 
confidence in that assessment and the reasons for this belief.
2.C.6.b.4.  Areas assessed biweekly during the active treatment period and follow up 
visits:  
The timeline follow back (TLFB) (Sobell and Sobell 1992) will be used to estimate drinking 
at intake, at each biweekly study visit during the active treatment period and at the 3- and 
6-month follow-up evaluation.  This interview procedure will provide quantity/frequency of 
alcohol consumption data for each day since the last study visit.  Time since onset of last 
menses will be collected at each treatment visit for women to examine as a co-variate for 
medication effects and safety monitoring for pre-menstrual women.  Medication adverse 
effects:  Subjects will provide reports of side effects at each bi-weekly study visit and the 3- 
and 6-month follow-ups using the widely used Systematic Assessment for Treatment 
Emergent Effects (SAFTEE) (Levine and Schooler 1986, Johnson, Ait-Daoud et al. 2005). 
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Measures of treatment received (MTR): All medication taken will be recorded.  The study 
staff will also record the number of contact hours subjects have been exposed to for any 
treatment outside of the study that is related to their drinking to identify if this variable 
might need to be considered as a covariate in outcomes analysis.
  
2.C.7.  Genotyping:  Genotyping for urn randomization will be done using Cells-to-Ct 
assay reagent (Applied Biosystems, Inc) to allow genotyping at the FKBP5 rs1360780 
SNP directly from blood.  The anticipated genotype distribution frequency based on our 
study of 1845 college students (Lieberman, Armeli et al. 2016) and the 1000 genomes 
project is CC 0.48 and T-carrier 0.52 for Caucasians and 0.37 and 0.63 for African-
Americans.  Reference DNA samples representing each of the three possible genotypes at 
rs1360780 will be included with each subject sample.  Additional DNA will be purified from 
whole blood using the PureGene kit (GentraSystems, Minneapolis, MN) to allow 
confirmation of initial rapid genotyping for urn randomization using batched purified DNA 
samples.  In view of advances in knowledge during the time of this study we anticipate that 
DNA will also be used to examine genotypes at other candidate markers related to alcohol 
use and related behaviors.
2.C.8 Exploratory microbiome analysis Leclercq et al (Leclercq, Matamoros et al. 2014, 
Leclercq, de Timary et al. 2017) have reported that as many as 40% of alcohol dependent 
subjects may harbor pro-inflammatory gut microbiota contributing to increased gut 
permeability which was associated with higher anxiety and alcohol craving after 3 weeks of 
abstinence.  Our hypothesis is that participants with higher levels of pro-inflammatory gut 
microbes at baseline will have less success in reducing drinking.  Stool samples will be 
collected by participants at home and transported to the CRC in a small cooler with freezer 
packs.  Samples will be stored at -80C until batch processed.  DNA will be prepared from 
stool samples and used for metagenomics whole genome shotgun sequencing of microbial 
DNA.  This method allows species and strain level identification of the gut microbiome.  
Analysis of sequence data and comparison of strains by treatment response will be done 
by Dr. Yanjiao Zhou Assistant Professor of Medicine at UConn Health who is an 
experienced investigator in molecular characterization of human microbiomes.  
Correlations of the relative abundance of microbes in baseline stool samples with 
participant success and in reducing weekly drinking will be examined.  We will also 
examine change in microbiome between baseline and endpoint as a function of change in 
drinking.
2.C.9.  Data Analysis:
2.C.9.a.1.  Safety:  Safety will be analyzed using categorical outcomes, defined by the 
type and severity of adverse effects.  Summary measures of adverse effects (AEs) will be 
developed by organ system from the SAFTEE adverse event checklist and will be 
compared for patients receiving dutasteride or pbo using  analysis in phase 1 and 
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comparing patients switched to dutasteride vs. naltrexone in phase 2.  Comparisons will be 
conducted on 1) the proportion of patients in each of the comparison groups who report 
AEs, 2) the proportion of patients in each of the comparison groups who report moderate-
to-severe AEs, and 3) the proportion of patients in each comparison group who 
discontinue treatment due to AEs.  Individual AEs that occur in > 5% of patients in either 
medication condition will be examined using  analysis.
2.C.9.a.2.  Efficacy:  Primary treatment outcomes will be defined in terms of HDD/wk and 
SD/wk based on TLFB reports of drinking.  Reduction in these measures is related to 
health benefits of reduced drinking.  These are the measures that are used to define non-
hazardous drinking.  Secondary outcomes will include proportion of days abstinent (PDA), 
% of subjects with no HDDs, % of subjects with non-hazardous drinking (no HDD and 
SD/week <15 men/<8 women) during the last 4 weeks of each treatment phase, and 
change in PEth at end of each treatment phase relative to baseline.  
For the phase 1 comparison of dutasteride and pbo over time, efficacy analyses will 
be performed using generalized linear mixed (GLMM) models implemented in SPSS. 
GLMM incorporates within subject correlation effects important in examination of repeated 
measures, can incorporate multiple covariates, interactions, random and fixed effects, non-
normal distributions, and is often recommended for designs such as proposed 
(Mallinckrodt C 2017).  Medication group will be treated as a factor and treatment week as 
a continuous covariate.  Sex, smoking status, treatment goal (stop vs. reduce drinking), 
and use of concurrent medication for co-morbid psychiatric conditions will also be 
examined as baseline between-subject covariates.  Medication group, week, and the other 
covariates will be modeled as fixed effects, and the intercept will be modeled as random 
effects. For the outcome HDD/wk a binomial distribution with logit link will be used where 
the number of HDD during the week will be the numerator and number of observed days 
the denominator. For the outcome SD/wk a negative binomial distribution with log link will 
be used. An interaction term between medication group and the week term(s) will be used 
to evaluate whether the efficacy of dutasteride compared to pbo in reducing drinking varies 
over time. Interaction effects of sex and treatment condition will also be examined. 
Pretreatment drinking will be controlled using baseline TLFB drinking data as a covariate.  
The robustness of results will be evaluated by running the model under three different 
conditions: 1) modified intention to treat using all available outcome information from 
subjects with at least 1 post-randomization visit, 2) data from 12-week per protocol 
completers, and 3) multiple imputation using 10 imputed data sets with weekly drinking 
and baseline covariates thought predictive of the outcomes or missingness included in the 
imputation phase. 
For aim 2, phase 2 outcomes, the within-subjects analysis will compare drinking 
during phase 1 against phase 2 for three groups: a) patients responsive to dutasteride in 
phase 1 and continuing on dutasteride for an additional 12-weeks in phase 2, to examine 
whether the response is maintained with continued treatment; b) phase 1 non-responders 
crossed over from pbo in phase 1 to dutasteride in phase 2 to provide a second contrast 
using an A-B design of the efficacy of dutasteride compared with pbo; and c) phase 1 
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dutasteride arm non-responders switched to naltrexone to determine whether naltrexone is 
effective in reducing drinking in dutasteride non-responders. An interrupted time series 
regression using mixed models will be used (Wagner, Soumerai et al. 2002, mallinckrodt 
and Lipkovich 2017), where in addition to a variable for week an indicator variable for 
phase, a second weekly variable that is sequentially coded beginning at phase 2 and the 
interaction of the two variables will be included in the model. The phase indicator variable 
will measure change when entering phase 2 and the second weekly variable will measure 
change in trajectory deviating from phase 1. In addition, a restricted period analysis 
focusing on the average of the last 4 weeks of phase 1 compared to average of the last 4 
weeks of phase 2 will be conducted.  This may be more sensitive if the first few weeks of 
each phase show limited initial response, which would dilute the effects for phase and the 
interaction for the interrupted regression model. For the first group, dutasteride 
responders, a non-inferiority test will be used where the non-inferior margin will be 20% 
above the drinking levels during phase 1. For the latter two groups of non-responders a 
superiority test will be used.
For aim 3, analysis of drinking outcomes will be repeated including baseline 
measures of DTC, trait anxiety, perceived stress, adverse child event count and genotype 
for the FKBP5 rs1360780 SNP (CC vs. T-carrier) as additional between-subject factors 
together with the 2- and 3-way interactions of medication condition with DTC, SAI, PSS or 
ACES measures and FKBP5 genotype. We will include both Blacks and Caucasians in the 
pharmacogenetics analysis as our prior study showed similar interactions of FKBP5 
genotype with life stress on drinking measures in both Black and Caucasian college 
students (Lieberman, Armeli et al. 2016).
     
2.C.9.b.  Sample size considerations:  For Aim 1, the proposed sample size of 160 
completing the phase 1 12-week treatment (80 per arm), has 80% power to show 
statistical significance (=0.05) for medium-size effects, d=0.4, such as observed in our 
initial RCT of dutasteride in men (d=0.38 for change in SDs/wk from baseline to last month 
of treatment comparing dutasteride and pbo n=91].   For Aim 2a, assuming 80% power 
and =0.05 and a sample of 40 responder subjects continuing on dutasteride, the non-
inferior margin limit would be an increase of 0.67 HDD/wk or 5 SDs/wk during the second 
12 weeks dutasteride treatment. For Aim 2b, a sample of 64 placebo non-responders 
crossing over to dutasteride for phase 2 would have 90% power to detect a medium effect 
size for reduction in drinking in phase 2 using a within-subjects t-test.  For Aim 3, using the 
GLMPOWER procedure and the between cell effects for the preliminary data presented 
above (section 2.B.2) for the 2-way interaction of drinking to cope x drug, a sample of 160 
subjects in phase 1 would have 80% power to detect the magnitude of this interaction seen 
in the preliminary dataset.  
 
Table 3.  Timeline for recruitment and other study objectives:
Activity
Year 1
Year 2
Year 3
Year 4
Year 5
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Staff training & study prep
Patient enrollment & 
randomizing 5/mo
3- and 6-month follow-up
Data entry & cleaning 
Data analysis & Report writing
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Section 3.  PROTECTION OF HUMAN SUBJECTS 
3.A  Risks to Human Subjects
3.A.1  Patient population: Outpatient male and female problem drinkers identified 
through advertisements and referral from UConn Health clinics, area mental health clinics 
or area providers will be randomized to study medication.  We anticipate enrolling 260 
subjects for screening visits in order to randomize 190 subjects to medication with a goal 
of 160 subjects completing the phase 1 12 weeks of study medication.  Patients must be 
heavy drinkers (ages 35-70) who affirm a desire to stop or reduce their drinking to non-
hazardous levels.  Research subjects will all be in good physical health who are competent 
to provide consent.  Subjects will be paid a nominal amount of money in consideration of 
their time and inconvenience for visits beyond the baseline visit (e.g. visit 3-16) as well as 
for completing the IVR daily calls.  Total potential compensation is $620 for completing all 
16 visits and IVR calls [$20/visit 3-14 paid at 6, 12, 18 and 24 weeks as well as $50 for 
attending the 3- and 6-month follow up visits 15-16; IVR daily phone calls weeks 1-4, 9-12, 
and 21-24: $2 per completed phone call plus $6 for each week where all calls are 
completed during phase 1 (up to $20/wk) and $3 per completed phone call plus $9 for 
each week where all calls are completed during phase 2 weeks 21-24 (up to $30/wk).
TABLE 2: Schedule of subject payments:
Visit 5, 6 wks, midpoint phase 1
$60
Visit 8, 12 wks, endpoint phase 1
$60
Visit 11, 18 wks, midpoint phase 2
$60
Visit 14, 24 wks, endpoint phase 2
$60
Visit 15 and 16, 3- and 6-month follow-up
$50 each
IVR
Up to 
$280
Maximum Total compensation for all visits and IVR phone 
calls
    
$620
Recruitment and informed consent procedures:  Patients recruitment will use IRB-
approved recruitment materials, which advertise for regular or daily drinkers who want to 
reduce or stop their drinking.  Distribution methods will include: informational brochures in 
UCONN Health and affiliated primary care and dental clinics; informational mailings to area 
clinics; advertisements in local media (including text ads in newspapers; radio ads; web 
ads and web postings on community message boards); through broadcast email 
messages at institutions (such as UCONN Health, community agencies, local college 
campuses, etc.) that offer that type of service; by posting/distributing recruitment materials 
in community settings with public posting areas or other means of providing community 
access to materials (such as hospitals, town halls, public libraries, YMCA, health 
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fairs/organizations).  A partial waiver of consent and HIPAA Authorization will be obtained 
from the IRB to allow for preliminary phone screening for calls initiated by potential 
patients.  Those individuals deemed eligible for in-person screening will sign a HIPAA 
Authorization and study consent form at their first visit.  During the in-person screening 
visit each patient will receive an explanation of the study protocol, its risks, potential 
benefits, and alternative treatment by a study staff member.  Following resolution of any 
questions, patients who appear to understand the nature of the study and consent will be 
asked to sign the study consent form.  An entire copy of the informed consent form will be 
given to each patient.  Because we will be recruiting patients from throughout the Greater 
Hartford area, including outreach to the minority communities in the area, we anticipate 
that approximately 10% of patients enrolled in the study will be African-American and 8% 
will be Latino.  
3.A.2  Sources of Research materials:  Research material will include information 
obtained from patients.  Other data will be obtained by physical examination, clinical and 
research laboratory evaluation, and data from observation of patients by study staff.  All 
data will be obtained exclusively for research purposes and will be at no cost to patients.  
All research data and biological specimens will be stored in coded fashion without direct 
identifiable information.  Personally identifiable information will be stored in separate 
secure files.  Links between study IDs and personal information will be destroyed following 
data verification and cleaning to generate a de-identified dataset.  
3.A.3  Potential risks:  
General Procedures:  There is some risk that patients will be identified as participants in a 
study of treatment for heavy drinking or that the clinical assessments will adversely affect 
patients' well-being.
  
Counseling:  Medical management brief counseling has been used safely with alcohol-
dependent patients in the COMBINE Study and in prior clinical trials at the UConn ARC.  
Psychological risks are minimal and not different from those of equivalent non-study 
treatments.
Medications:
   
Dutasteride is not reinforcing and is therefore not a drug of abuse. There are few adverse 
effects associated with dutasteride use (Hirshburg, Kelsey et al. 2016).  Based on 
extensive clinical studies in men, dutasteride is well tolerated.  In a series of three 2-year 
long treatment trials including 4,300 men aged 47-94 years (mean = 66 years), a 0.5 mg 
daily dose of dutasteride for treatment of enlarged prostate resulted in the following 
adverse effects compared with pbo: impotence (4.7% vs. 1.7%), decreased sex drive 
(3.0% vs. 1.4%), problems with ejaculation (1.4% vs. 0.5%), and enlargement of breast 
tissue (0.5% vs. 0.2%).  4% of dutasteride and 3% of pbo patients ended treatment due to 
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a side effect concern.  In other clinical studies, daily doses of 5 mg (i.e., 5 times the daily in 
the proposed study for alcohol problems) were administered to 60 men for 6 months with 
no adverse effects beyond those seen at the more commonly used daily dose of 0.5 mg 
(Avodart, Prescribing information 2012, GlaxoSmithKline).  Depression has been reported 
as a potential side effect of the 5AR inhibitor finasteride in several small retrospective case 
series (Hirshburg, Kelsey et al. 2016).  In the only prospective study examining mood in 
128 men treated with finasteride for alopecia, the Beck Depression Inventory (BDI) score 
increased minimally from 12.11 to 12.80 after 2 months treatment (Rahimi-Ardabili, 
Pourandarjani et al. 2006).  In our current study of dutasteride in men we observed a 
decrease in BDI scores over the 12-week study period in both dutasteride and placebo 
arms.  A recent large retrospective study of 90,000 men who initiated treatment with a 5-
reductase inhibitor (finasteride or dutasteride) during the period 2003-2013 and matched 
controls found no increased risk of suicide associated with medication but an increased 
risk of self-harm events (18 per 10,000 exposed vs. 14 per 10,000) and incident 
depression (194 per 10,000 exposed vs. 137 per 10,000) during the initial 18 months of 
treatment (Welk, McArthur et al. 2017).  In view of these reports of the potential for 5-
reductase inhibitors to increase depressive symptoms, we will use the physician’s health 
questionnaire (PHQ-9) to screen for clinical depression at every study visit. The PHQ-9 is 
a validated 9-item self-report measure of depressive (Ware, Kosinski et al. 1996, Kroenke, 
Spitzer et al. 2001), a response of 1 or greater on item 9 related to suicidal thoughts will 
trigger a clinical evaluation by study physician or nurse regarding safety.    
A large treatment trial involving over 6,000 men, “Reduction by Dutasteride of Prostate 
Cancer Events (REDUCE)” evaluated the daily use of dutasteride 0.5 mg versus pbo for 4 
years to examine the effects of long-term treatment with dutasteride on the risk of prostate 
cancer in men over 50 years of age (Andriole, Bostwick et al. 2010). The trials 
demonstrated an overall reduction in prostate cancer diagnosis with dutasteride compared 
with pbo treatment (20% vs. 25% with pbo) but an increased incidence of high-grade 
(Gleason score 8-10) prostate cancer (1% for dutasteride vs. 0.5% for pbo) after 4 years.  
The increased incidence of high-grade cancer was not observed after 2 years exposure 
(0.5% for dutasteride vs. 0.5% for pbo). Long-term treatment with dutasteride may 
increase the risk for the development of high-grade prostate cancer. The short-term use of 
dutasteride in this study of alcohol use is not expected to alter participants’ risk of prostate 
cancer. 
Dutasteride (and finasteride) is contraindicated for use by pregnant women due to the 
potential risk of a specific birth defect (reduced size of male external genitalia and potential 
for hypospadias) (Avodart, Prescribing information 2011, GlaxoSmithKline).  There is no 
known risk to non-pregnant women. The 5-reductase inhibitors finasteride and 
dutasteride have been used off-label in clinical practice for the long term treatment of 
alopecia in women without serious side effects (Boersma, Oranje et al. 2014, Hirshburg, 
Kelsey et al. 2016, Seale, Eglini et al. 2016).  Side effects of 5AR inhibitors in women have 
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been reported to include headache, gastrointestinal discomfort and decreased libido in 
uncontrolled retrospective reports (Hirshburg, Kelsey et al. 2016).  In a long-term placebo 
controlled study involving 137 women ages 41-60 yo who were treated for 1 year with 
finasteride or placebo for alopecia there were no statistically significant differences in rates 
of side effects for finasteride vs. placebo (Price, Roberts et al. 2000).  Dutasteride was well 
tolerated and effective in reducing pre-menstrual dysphoria in a clinical research study in 
which women were treated daily with 2.5 mg of dutasteride for 1 month (Martinez, Rubinow 
et al. 2016).  Women of reproductive potential should practice effective contraception while 
using dutasteride and for 6 months following discontinuation of medication to prevent 
unintended exposure to a male fetus consistent with package label recommending that 
men refrain from donating blood for 6 months following use of dutasteride.
While it is theoretically possible to expose a pregnant woman to dutasteride via semen, 
exposure of pregnant non-human primates intravenously with16x the potential exposure 
from 5 ml of semen daily (assuming 100% absorption of dutasteride) was without adverse 
effect on the offspring (Avodart, Prescribing information 2011, GlaxoSmithKline).  No 
precautions are listed in the package insert regarding exposure of female partners to 
semen of men taking dutasteride.  As recommended in the package insert, subjects will be 
warned to not donate blood products for 6 months following study treatment to prevent 
unintended exposure to dutasteride to pregnant women.
Naltrexone is FDA approved for the treatment of alcohol dependence as well as for opioid 
dependence. Naltrexone has also been shown to reduce heavy drinking in multiple RCTs 
(Maisel, Blodgett et al. 2013, Jonas, Amick et al. 2014). Naltrexone is an antagonist of the 
-opioid and -opioid receptors is thought to reduce alcohol craving and heavy drinking by 
blocking the endogenous opioid system and thereby reducing dopamine release in 
response to the anticipation of or use of alcohol.  Naltrexone has no abuse potential.  In 
subjects with dependence on opioids who have recently used opiates naltrexone will 
precipitate withdrawal symptoms.  The most common side effects of naltrexone in a large 
open label safety study (Croop, Faulkner et al. 1997) in 570 subjects with alcoholism 
(Revia, Prescribing information 2013, Barr Pharmaceuticals) were: nausea (10%), 
headache (7%), dizziness (4%), nervousness (4%), fatigue (4%) insomnia (3%), vomiting 
(3%), anxiety (2%) and somnolence (2%). A prior FDA black box warning related to 
possible hepatotoxicity based on naltrexone use at 300 mg / day for obesity has 
subsequently been removed based on extensive experience with naltrexone 50-100 
mg/day for alcohol dependence.  Naltrexone is a pregnancy class C medication (animal 
data suggest teratogenic potential, but no human data available).  To be eligible for 
participating in this study women of reproductive potential will be required to agree to use 
effective contraceptive practices.    
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Interaction of Medications and Alcohol:  Neither dutasteride or naltrexone produce clinically 
significant additive interactions with alcohol on CNS depressant effects.  Dutasteride and 
naltrexone are both safe in the setting of ongoing alcohol use.  
Blood and Urine Collection:  These procedures are performed in large measure for 
baseline screening to safeguard that patients with untreated medical conditions are not 
enrolled and at subsequent visits to monitor medication safety, document urine drug use 
screening and verify absence of pregnancy.  Additional bloods are drawn for research 
measures of alcohol use and dutasteride effects. These procedures should add no risks 
other than those normally associated with these procedures, e.g., pain and bruising as a 
consequence of venipuncture.  
Rating Scales and Questionnaires:  These are non-invasive and add no special risk, 
although they do cover sensitive areas.  The major disadvantages are the time taken to 
complete them, and possible breach of confidentiality.  Our past experience indicates that 
these measures are acceptable to patients.  Careful efforts to maintain confidentiality have 
been effective in our previous research and will be continued.
Genetic Testing.  The principal risk of genetic testing is the potential for breach of 
confidentiality, with information concerning the patient’s genetic risk for disease becoming 
known.  Such information, if available to the patient, could cause distress and if available 
to health or life insurers could adversely affect the patient’s access to insurance or its 
benefits.  To guard against these risks, patients will not be provided with genetic test 
results and confidentiality will be closely protected as described below.  At the conclusion 
of the study, links between personal identifiers and the study ID associated with genetic 
test results and DNA / biological samples will be destroyed to generate de-identified 
samples and datasets.  Given the small likelihood of breach of confidentiality (NB: in over 
15 years of genetic research by our ARC research group, we are not aware of a single 
instance of such a breach), the potential benefits accruing to the research (namely, a 
greater understanding of the genetic basis of alcohol use disorders and related psychiatric 
conditions and potentially of the genetic moderators of the response to treatment with 
dutasteride), and the complex nature of the disorders (limiting the impact that knowledge of 
any single genetic variant may have on disease risk), the potential benefit-to-risk ratio is 
favorable.
3.B  Protection Against Risks
3.B.1. Procedures to minimize potential risks:  Inclusion/ criteria and the use of 
experienced research assistants in initial screening and review of phone screens with 
study investigator(s) will minimize acceptance of patients with either insufficient or 
currently highly hazardous alcohol use into the study.  Careful pre-treatment laboratory 
testing and evaluation by trained, experienced staff will minimize the risk of including 
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individuals with contraindicated medical and/or psychiatric conditions.  Experienced 
phlebotomists will minimize venipuncture risk.  During treatment, patients' substance use 
and medical and psychiatric status will be closely monitored.  Patients with breath or 
salivary alcohol levels over the legal driving limit or clinical evidence of intoxication will be 
examined by a study physician and monitored until no longer intoxicated, or referred for 
appropriate treatment, as clinically appropriate.
Identifying subjects who are inappropriate for study entry because of current alcohol 
withdrawal: Subjects with prominent signs of physical dependence, and/or medical 
comorbidities such that study physicians feel they should consider immediate 
detoxification, will be referred for medical detoxification in a normal treatment setting. The 
Clinical Institute Withdrawal Assessment (CIWA-Ar) will be used to facilitate assessment of 
withdrawal, and decisions regarding appropriateness for study entry with respect to 
physical dependence will be made based on the judgment of study physicians using the 
CIWA-Ar score of 10 for an approximate cutoff level. All our study physicians have 
extensive experience in assessing and triaging patients with alcohol withdrawal. Subjects 
that need detoxification will be referred for detoxification, and may be eligible to begin the 
study following successful completion of detoxification.  
Medication risks:  Frequent contact will help identify patients with adverse treatment 
effects.  Patients will be given a card identifying themselves as participants in a study 
involving dutasteride or naltrexone, and containing the contact numbers of the PI and 
study nurse.  The medication blind will be broken if necessary for emergency assessment 
or treatment.  For example, if the PI determines that an adverse event is serious, 
unexpected, possibly related to the study drug, and medical intervention is needed, the PI 
will request from research pharmacy the medication assignment for the subject so that the 
patient can receive proper treatment.  Adverse medication effects will be systematically 
evaluated and recorded.  If serious, patients will be withdrawn from the study and given 
appropriate treatment and/or referral.
Study staff may request that pharmacy provide medication assignment after completing 
the 6 month follow-up or if information needed by patient for clinical discussion with their 
physician, it may requested after completing medication phase of study.
Procedures to minimize potential exposure of pregnant women to active study medication 
(dutasteride or naltrexone) include 1) excluding subjects younger than 35 who may have a 
greater likelihood of considering pregnancy after starting the study and would need to 
avoid pregnancy for 6 months following treatment with dutasteride, 2) inclusion 
requirement of a negative serum bHCG at screening together with monitoring of urine 
HCG during the 24-week treatment,  3) review of teratogenic risks by study physician with 
female subjects, 4) agreement by women of reproductive potential to use effective 
contraception during the study and for 6 months following completion of medication use, 5) 
monthly contact by study nurse during 6 month follow-up to remind women of importance 
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of effective contraception.  If a patient reports being pregnant or tests positive, she will be 
immediately withdrawn from study medication treatment, referred for obstetric evaluation, 
informed as to the study medication she had taken and advised to discontinue drinking 
alcohol.
Confidentiality:  To avoid breach of confidentiality, patients' names will appear only on a 
consent form, a telephone screening form, the study nurses visit contact information sheet 
and a "key" form kept by study staff in a locked cabinet.  All forms that contain identifying 
information will be kept double locked (i.e., in a locked cabinet, in a locked room) to 
maintain their security.  All study data forms will contain only the patient's unique study 
identification number.  Prior to final study closure, any links between personal identifiers 
and each subject’s unique study ID will be deleted to generate a de-identified dataset.  
Patient visits will be scheduled by study staff and no information about the patient will be 
provided to anyone outside the study team (except in emergencies as defined above) in 
person or by telephone, except as required by law.  The study will be conducted in an 
outpatient clinic in which treatment is provided to patients who have a variety of problems, 
not limited to substance abuse.  To further help protect participant privacy, a Certificate of 
Confidentiality from the National Institutes of Health will be in force for this study. This 
certificate will protect the investigator and immediate study staff from being forced to 
release any research data that would identify a participant in this study, even under a court 
order or subpoena.
  
Alternative Treatments:  The alternative procedures available are counseling by other 
clinicians, self-help groups such as Alcoholics Anonymous, or more intensive treatment for 
heavy drinking, including treatment with oral or long-acting injectable naltrexone, 
disulfiram, or acamprosate, which are FDA-approved medications widely available for 
treatment of AD.  Subjects requesting additional treatment for alcohol problems following 
completion of the study protocol or withdrawal from the study will be referred to local 
treatment centers.   
3.B.2. Potential benefits to patients and society:  Benefits to patients include careful 
evaluation of their medical and psychiatric status and alcohol use. Benefits to participants 
also include the potential for reduction in their alcohol consumption with associated 
improvements in their physical and psychological health, functioning at work and in their 
family/relationships. Benefits to society include a potential improvement in the 
effectiveness of treatment for problem drinking, which may reduce the personal and 
societal burdens associated with heavy drinking.  In addition, clinicians and scientists may 
better understand the effects of dutasteride to reduce alcohol consumption.  An improved 
understanding of phenotypic and genetic predictors and/or moderators of dutasteride 
response will offer the potential for individualized treatment and enhanced the clinical utility 
of dutasteride for alcohol use problems.
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3.B.3. Importance of Knowledge to be Gained:   Alcohol dependence has a major 
impact on society, families and individuals affected.  AUD remains a major health concern, 
additional treatment options are needed.  Results from our recently completed first study of 
dutasteride for reducing alcohol use indicate is well tolerated and may represent a very 
effective treatment options especially for subjects who drink to cope with negative 
emotions. The proposed study seeks to better identify predictors of efficacy to potentially 
advance medication treatment match for alcohol use treatment. 
3.B.4.  Comparison of risks and anticipated benefits to patients and society:  The 
risks associated with the study counseling are minimal.  Although the study medication 
presents some risk, dutasteride has been shown to be safe when administered for benign 
prostatic hypertrophy for long periods of time (years) in men and in more limited off-label 
treatments of women for alopecia for up to 3 years.  Naltrexone is widely prescribed for 
treatment of alcohol use disorders in men and women with an excellent safety record.  The 
potential risks of these treatments are low compared to the risk incurred by individuals who 
continue to drink heavily.  The study design provides ongoing bi-weekly monitoring and 
support for reducing alcohol use such that placebo subjects may benefit from contact with 
study staff.  Placebo non-responders will also be transitioned after 12-weeks to the active 
study medication providing potential additional benefit. In view of the potential for 
advancing treatment options for future patients and potential benefit to participants for 
reducing drinking, the risk/benefit ratio appears favorable for the proposed treatments.
3.C  Data and Safety Monitoring Plan (DSMP):  
The DSMP is established to ensure the safety of research participants and the integrity of 
the study data.  Dr. Jonathan Covault, M.D., the principal investigator of this project [or in 
his absence or one of the other study physicians – Dr. Oncken or Rao], will be charged 
with the duty of determining the severity rating of adverse events. The study staff (P.I., co-
investigators, clinical research assistants) are responsible for collecting and recording all 
clinical data.  As these results are collected, any toxicities and adverse events will be 
identified, graded for severity and assigned causality, reported to the required entities, and 
compiled for periodic review.  Dr. Covault or one of the other study investigator/physicians 
will review with study staff on a weekly basis the treatment status and any side effects for 
active study patients and the outcome of AEs and SAEs over time and need for 
intervention.  Dr. Covault and study staff will meet on a semi-annual basis to review 
summary information regarding patient flow in the study, reasons for dropout and adverse 
events.  This summary information will then be sent to the study’s Data and Safety 
Monitoring Board (DSMB) for review.   
AE monitoring.  The study nurse will use the SAFTEE instrument to screen for adverse 
events at each treatment visit.  The P.I. will evaluate every moderate or severe adverse 
event and determine whether it affects the risk/benefit ratio of the study and whether 
modifications to the protocol or informed consent form are required.  The principal 
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investigator (and, in his absence, physician co-investigators) will differentiate serious from 
non-serious adverse events.  
A Serious Adverse Events Monitoring Form will be used by study staff to provide 
information about all serious adverse events (expected and unexpected including not study 
related), how they were handled, and their potential relationship to study participation and 
a sign-off by appropriate supervisory personnel.  Patients who experience a significant 
psychiatric or medical problem requiring an overnight hospitalization at an acute care 
facility will be considered to have experienced an SAE. Serious Adverse Events also 
include adverse events that result in death, a persistent or significant disability/incapacity 
or result in a congenital anomaly/birth defect.
Serious adverse events (SAEs) and other serious unanticipated events that are possibly 
related to the study interventions will be reported within 48 hours of study team knowledge 
of the SAE to the 1) UCHC IRB / Office of the Vice President for Research, 2) the study 
DSMB, and 3) the NIAAA project officer. All other SAEs, unanticipated events and non-
serious adverse events (AEs) during the treatment will be reported to the UCHC IRB, as 
well as to the NIAAA on an annual basis. SAEs, AEs, and unanticipated problems will be 
managed consistent with UConn Health IRB guidelines. 
Other adverse events will be monitored during study visits or phone calls with participants 
and reviewed weekly at study staff meeting.  An ongoing database of adverse events will 
be maintained by the study staff.   Aggregate data on reports of adverse events will be 
provided to the DSMB members on a semi-annual basis as part of their semi-annual 
review with the study staff and PI of data and patient safety monitoring.   The following 
information will be considered in the periodic safety report:
 
• Number of patients who have completed the study.
• Dropout rates and reasons for the dropouts.
• Summary of adverse events.
• Any other relevant information
The annual report to the NIAAA program officer will include

Confirmation of adherence to the data and safety monitoring plan;

Summary of all AEs;

Summary of any data and safety monitoring issues that occurred since the previous 
reporting period;

Description of any changes in the research protocol or the data and safety 
monitoring plan that potentially affect risk;

Summary of all new IRB approvals during the report period.
Any patients thought to be at risk from drinking or psychiatric or medical disorders during 
treatment or the follow-up period will be referred to services at UCONN Health or to other 
local health service providers.  
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Data Monitoring.  Data entry will occur at the time of visit via REDCap directly by staff or 
study subjects (with supervision by staff).  Other data not entered at time of visit will be 
doubly entered via REDCap feature to assure accuracy of entry.  All study staff involved in 
data entry are blind to treatment condition.  The PI will have primary responsibility for data 
accuracy and compliance with protocol.
A Data Safety and Monitoring Board (DSMB) for the study will be established prior to 
enrollment of patients.  This committee will be asked to review semi-annually study data 
regarding enrollment, safety and adverse events. The committee may make 
recommendations for early stoppage of the trial based on review of study data. DSMB 
members will be provided with semi-annual reports to include data that inform progress of 
the study, including recruitment data, and adverse events data. These data will be used to 
decide whether to 1) continue recruitment as planned, 2) continue with a protocol 
amendment, or 3) stop recruitment pending investigation.  The DSMB will typically hold 
meetings electronically or by conference call.
Study suspension / stopping.  A decision to discontinue the study will be based primarily 
on consideration by the DSMB of study related serious adverse events (SAE’s).  DSMB 
members will receive a copy of the Serious Adverse Events Monitoring Form within 48 
hours of study team knowledge of the SAE, at which point DSMB members will make one 
of two recommendations: 1) continue recruitment and treatment as planned; 2) schedule a 
formal meeting within one week to determine if the study should: a) continue study 
unchanged; b) continue recruitment after a protocol amendment; or c) stop recruiting and if 
appropriate treatment pending further investigation. 
If safety concerns warrant, upon request from DSMB members the pharmacy will provide 
un-blinding information regarding drug assignment.
If it has been determined, for any reason, that the study should be suspended, we will 
discontinue enrollment of new patients, while continuing the treatment and monitoring of 
patients already enrolled in the study, unless to do so would create a risk that is not 
justified by any potential benefit to patients.
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IRB Review
IRB NUMBER: 19-147-2
IRB APPROVAL DATE: 02/27/2024