Alcohol Use Disorder
Conditions
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.
Interventions
1 mg/day oral dutasteride (2 x 0.5 mg capsules)
DRUGPlacebo Capsules
Placebo capsules with matching appearance as Dutasteride Capsules
Sponsors
National Institute on Alcohol Abuse and Alcoholism (NIAAA)
UConn Health
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
QUADRUPLE (Subject, Caregiver, Investigator, Outcomes Assessor)
Masking description
UConn Health Investigational Pharmacy will randomize to dutasteride vs. placebo for phase 1 at baseline
Intervention model description
The study consists of two 12-week phases, the first being a 12-week parallel-groups comparison of dutasteride and placebo to evaluate the safety and efficacy of dutasteride 1 mg/day in reducing the likelihood of drinking and heavy drinking in treatment-seeking men and women with alcohol use disorder. 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 in phase 1 will be given dutasteride during phase 2, and non-responder subjects treated with dutasteride in phase 1 will receive naltrexone daily in phase 2. This design maintains double blind conditions in both phases 1 and 2.
Eligibility
Sex/Gender
ALL
Age
35 Years to 70 Years
Healthy volunteers
No
Inclusion criteria
* men and women age 35 to 70 yo inclusive * 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 * current DSM-5 AUD * no evidence of significant cognitive impairment * 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.
Exclusion criteria
* history of serious alcohol withdrawal symptoms (e.g., perceptual distortions, seizures, delirium, or hallucinations) * 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) * current, clinically significant physical disease 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 (the investigators 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) * 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) * have a current DSM-5 diagnosis of moderate drug use disorder (other than caffeine or nicotine dependence) * currently taking finasteride, dutasteride, medication for treatment of AUD, or chronic use of opioid pain medication * are considered by the investigators to be an unsuitable candidate for an investigational drug
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Change in Heavy Drinking Days Per Week for Dutasteride vs. Placebo Groups | 12 weeks (from initiation to end of treatment phase 1) | The number of heavy drinking days per week (i.e., four or more drinks in a day for women and five or more drinks in a day for men). The values listed in outcome table are the average HDD per week for the last 4 weeks (9-12) of phase 1 treatment. The generalized linear mixed model analysis considered all data from the ITT sample (75 dutasteride and 80 placebo participants) |
| Change in Drinks Per Week in Dutasteride vs. Placebo Groups | 12 weeks (from initiation to end of treatment phase 1) | Change in the number of drinks per week during treatment phase 1 of study (week 1-12). The values listed in the outcome table are the average drinks per week for the last 4 weeks of treatment (week 9-12). The generalized linear mixed model analysis considered all data from the ITT sample (75 dutasteride and 80 placebo participants) |
Other
| Measure | Time frame | Description |
|---|---|---|
| Change in Heavy Drinking Days Per Week for Phase 2 Naltrexone vs Dutasteride Groups | 12 weeks (week 13 to end of treatment phase 2, week 24) | The number of heavy drinking days per week (i.e., four or more drinks in a day for women and five or more drinks in a day for men) for phase 1 non-responders (\<60% reduction in drinks per week) during phase 2 comparing naltrexone 50 mg and dutasteride 1 mg daily. The values listed in outcome table are the mean change in HDD per week for the last 4 weeks (wk 21-24) of phase 2 relative to drinking at beginning of phase 2 treatment. treatment. |
| Change in Drinks Per Week in Phase 2 Naltrexone vs. Dutasteride Groups | 12 weeks (week 13 to end of treatment phase 2, week 24) | The number of drinks per week for phase 1 non-responders (\<60% reduction in drinks per week) during phase 2 comparing naltrexone 50 mg and dutasteride 1 mg daily. The values listed in outcome table are the mean change in drinks per week for the last 4 weeks (wk 21-24) relative to drinking at beginning of phase 2 treatment. |
Countries
United States
Participant flow
Recruitment details
Via postings at UConn Health and radio advertisements
Pre-assignment details
Of the 180 consented, 10 were screen failures and 3 withdrew after screening visit. Five participants did not attend baseline visit to receive medication and 7 did return after baseline visit leaving 155 as the phase 1 modified intention to treat sample (75 dutasteride arm and 80 placebo arm).
Participants by arm
| Arm | Count |
|---|---|
| Dutasteride two 0.5 mg capsules of dutasteride daily for 12 weeks | 75 |
| Placebo Capsule inactive placebo matched in appearance with dutasteride capsules daily for 12 weeks | 80 |
| Total | 155 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 | FG002 | FG003 |
|---|---|---|---|---|---|
| Wk 1-12 Phase 1 Dutasteride or Placebo | Lack of Efficacy | 2 | 3 | 0 | 0 |
| Wk 1-12 Phase 1 Dutasteride or Placebo | Lost to Follow-up | 5 | 0 | 0 | 0 |
| Wk 1-12 Phase 1 Dutasteride or Placebo | Withdrawal by Subject | 3 | 11 | 0 | 0 |
| Wk 13-24 for Phase 1 Non-responders | Adverse Event | 0 | 0 | 1 | 1 |
| Wk 13-24 for Phase 1 Non-responders | Lack of Efficacy | 0 | 0 | 0 | 1 |
| Wk 13-24 for Phase 1 Non-responders | Lost to Follow-up | 0 | 0 | 3 | 3 |
| Wk 13-24 for Phase 1 Non-responders | Protocol Violation | 0 | 0 | 0 | 1 |
| Wk 13-24 for Phase 1 Non-responders | Withdrawal by Subject | 0 | 0 | 1 | 0 |
Baseline characteristics
| Characteristic | Dutasteride | Total | Placebo Capsule |
|---|---|---|---|
| Age, Continuous | 57.1 years STANDARD_DEVIATION 9.3 | 56.3 years STANDARD_DEVIATION 91 | 55.5 years STANDARD_DEVIATION 8.9 |
| Drinks per week | 43.2 drinks per week STANDARD_DEVIATION 21.9 | 43.4 drinks per week STANDARD_DEVIATION 20.2 | 43.5 drinks per week STANDARD_DEVIATION 18.5 |
| Ethnicity (NIH/OMB) Hispanic or Latino | 1 Participants | 4 Participants | 3 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 74 Participants | 151 Participants | 77 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants | 0 Participants |
| Number of heavy drinking days per week | 5.4 Heavy drinking days per week STANDARD_DEVIATION 1.8 | 5.5 Heavy drinking days per week STANDARD_DEVIATION 1.7 | 5.6 Heavy drinking days per week STANDARD_DEVIATION 1.7 |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Asian | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Black or African American | 7 Participants | 8 Participants | 1 Participants |
| Race (NIH/OMB) More than one race | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) White | 68 Participants | 147 Participants | 79 Participants |
| Region of Enrollment United States | 75 Participants | 155 Participants | 80 Participants |
| Sex: Female, Male Female | 35 Participants | 67 Participants | 32 Participants |
| Sex: Female, Male Male | 40 Participants | 88 Participants | 48 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk | EG003 affected / at risk |
|---|---|---|---|---|
| deaths Total, all-cause mortality | 0 / 75 | 0 / 80 | 0 / 49 | 0 / 59 |
| other Total, other adverse events | 46 / 75 | 41 / 80 | 34 / 49 | 33 / 59 |
| serious Total, serious adverse events | 0 / 75 | 0 / 80 | 0 / 49 | 2 / 59 |
Outcome results
Primary
Change in Drinks Per Week in Dutasteride vs. Placebo Groups
Change in the number of drinks per week during treatment phase 1 of study (week 1-12). The values listed in the outcome table are the average drinks per week for the last 4 weeks of treatment (week 9-12). The generalized linear mixed model analysis considered all data from the ITT sample (75 dutasteride and 80 placebo participants)
Time frame: 12 weeks (from initiation to end of treatment phase 1)
Population: Participants who attended and provided outcome data for at least one study visit following baseline session.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Dutasteride | Change in Drinks Per Week in Dutasteride vs. Placebo Groups | -14.16 Drinks per week | Standard Error 2.49 |
| Placebo Capsule | Change in Drinks Per Week in Dutasteride vs. Placebo Groups | -7.72 Drinks per week | Standard Error 2.16 |
p-value: 0.019Mixed Models Analysis
Primary
Change in Heavy Drinking Days Per Week for Dutasteride vs. Placebo Groups
The number of heavy drinking days per week (i.e., four or more drinks in a day for women and five or more drinks in a day for men). The values listed in outcome table are the average HDD per week for the last 4 weeks (9-12) of phase 1 treatment. The generalized linear mixed model analysis considered all data from the ITT sample (75 dutasteride and 80 placebo participants)
Time frame: 12 weeks (from initiation to end of treatment phase 1)
Population: Participants who attended and provided outcome data for at least one study visit following baseline session.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Dutasteride | Change in Heavy Drinking Days Per Week for Dutasteride vs. Placebo Groups | -2.24 Heavy Drinking Days per week | Standard Error 0.33 |
| Placebo Capsule | Change in Heavy Drinking Days Per Week for Dutasteride vs. Placebo Groups | -1.41 Heavy Drinking Days per week | Standard Error 0.28 |
p-value: 0.012Mixed Models Analysis
Other Pre-specified
Change in Drinks Per Week in Phase 2 Naltrexone vs. Dutasteride Groups
The number of drinks per week for phase 1 non-responders (\<60% reduction in drinks per week) during phase 2 comparing naltrexone 50 mg and dutasteride 1 mg daily. The values listed in outcome table are the mean change in drinks per week for the last 4 weeks (wk 21-24) relative to drinking at beginning of phase 2 treatment.
Time frame: 12 weeks (week 13 to end of treatment phase 2, week 24)
Population: Phase 2 completers (wk 13-24). The generalized linear mixed model analysis considered all data from the phase 2 ITT sample (phase 1 non-responders. 49 phase 1 dutasteride-phase 2 naltrexone and 59 phase 1 placebo-phase 2 dutasteride participants).
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Dutasteride | Change in Drinks Per Week in Phase 2 Naltrexone vs. Dutasteride Groups | -7.29 drinks per week | Standard Error 1.37 |
| Placebo Capsule | Change in Drinks Per Week in Phase 2 Naltrexone vs. Dutasteride Groups | -5.31 drinks per week | Standard Error 1.48 |
p-value: 0.29Mixed Models Analysis
Other Pre-specified
Change in Heavy Drinking Days Per Week for Phase 2 Naltrexone vs Dutasteride Groups
The number of heavy drinking days per week (i.e., four or more drinks in a day for women and five or more drinks in a day for men) for phase 1 non-responders (\<60% reduction in drinks per week) during phase 2 comparing naltrexone 50 mg and dutasteride 1 mg daily. The values listed in outcome table are the mean change in HDD per week for the last 4 weeks (wk 21-24) of phase 2 relative to drinking at beginning of phase 2 treatment. treatment.
Time frame: 12 weeks (week 13 to end of treatment phase 2, week 24)
Population: Phase 2 (wk13-24) completers. The generalized linear mixed model analysis considered all data from the phase 2 ITT sample (phase 1 non-responders with \<60% reduction in drinks per week (49 phase 1 dutasteride-phase 2 naltrexone and 59 phase 1 placebo-phase 2 dutasteride participants).
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Dutasteride | Change in Heavy Drinking Days Per Week for Phase 2 Naltrexone vs Dutasteride Groups | -1.45 Heavy drinking days per week | Standard Error 0.26 |
| Placebo Capsule | Change in Heavy Drinking Days Per Week for Phase 2 Naltrexone vs Dutasteride Groups | -0.54 Heavy drinking days per week | Standard Error 0.25 |
p-value: <0.001Mixed Models Analysis