Supplementary Appendix 1:Inclusion/Exclusion Criteria

Inclusion Criteria

To be eligible, the subject must:

1.Be at least 21 years of age and no more than 65 years of age

2.Have a current (past 12 months) DSM-IV-TR diagnosis of alcohol dependence

3.If male, report drinking a weekly average of at least 35 drinks per week or if female report drinking a weekly average of at least 28 drinks per week for the 28-day period prior to consent

4.Be seeking treatment for alcohol dependence and desire a reduction or cessation of drinking

5.Be able to verbalize an understanding of the consent form, provide written informed consent, verbalize willingness to complete study procedures, understand written and oral instructions in English, and complete the questionnaires required by the protocol

6.Agree (if the subject is female and of child bearing potential) to use at least one of the following methods of birth control, unless she is surgically sterile, male partner is surgically sterile or she is postmenopausal (amenorrheic for longer than 1 year and age appropriate) from the time of signing informed consent until 90 days after completing study drug administration:

  1. oral contraceptives
  2. contraceptive sponge
  3. patch
  4. double barrier (diaphragm withspermicide or condom with spermicide)
  5. intrauterine contraceptive system
  6. etonogestrelimplant
  7. medroxyprogesterone acetate contraceptive injection
  8. complete abstinence from sexual intercourse with male partners, and/or
  9. hormonal vaginal contraceptive ring

7.Agree, (if male) to not donate sperm from the time of the start of study drug administration to 90 days after the last dose of study drug, and to use at least one of the following methods of birth control:

  1. abstinence from sexual intercourse with female partners
  2. double barrier (condom with spermicide)
  3. surgically sterile
  4. female partner is surgically sterile or postmenopausal
  5. female partner uses an acceptable method of birth control

8.Verbally confirm the ability to take oral medication and be willing to adhere to the medication regimen

9.Voluntarily provide Informed Consent and sign the Informed Consent Form

10.Complete all assessments required at screening and baseline

11.Have a stable residence during the 2 weeks prior to randomization, have no plans to move to a location which would make continued participation in the study impractical, and not be at risk that s/he will lose his/her housing in the next 4 months

12.Not anticipate any significant problems with transportation arrangements or available time to travel to the study site over the next 4 months

13.Not have any unresolved legal problems that could jeopardize continuation or completion of the study

14.Provide contact information of someone, such as a family member, spouse, or significant other, who may be able to contact the subject in case of a missed clinic appointment

15.Have a BAC by breathalyzer equal to 0.000 when s/he signed the informed consent document (either just prior to or immediately after signing consent)

16.Be someone, who in the opinion of the investigator, would be expected to complete the study protocol (e.g., adequate venous access)

17.Agree to the schedule of visits, verbally acknowledge that s/he will be able to attend each scheduled visit, participate in phone visits and that s/he does not have any already or potentially scheduled events or medical procedures, or a job that may substantially interfere with study participation

18.If taking a medication for depression or anxiety, the subject must have been taking a stable dose in the 3-months prior to randomization and plan to continue during the study. This includes drugs such as the following:

  1. selective serotonin reuptake inhibitors (SSRIs)
  2. dual uptake inhibitors
  3. serotonin-norepinephrine reuptake inhibitors (SNRIs)
  4. tricyclic antidepressants
  5. monoamine oxidase inhibitors (MAOIs)
  6. Wellbutrin

Exclusion Criteria

To be eligible, the subject must not:

  1. Have current (past 12 months) abuse or dependence on any psychoactive substance other than alcohol, nicotine,or marijuana (abuse is acceptable but dependence is not) including sedatives and hypnotics, as defined by DSM-IV-TR criteria
  2. Have a positive urine toxicology screen performed during screening or baseline for any of the following substances:
  1. benzodiazepines
  2. cocaine
  3. opioids
  4. amphetamines
  5. buprenorphine
  6. methadone
  7. barbiturates
  8. oxycodone
  9. methamphetamines

Note: Testing for tetrahydrocannabinol (THC) is included in the urine drug screen; however, subjects who test positive for THC are still eligible to participate in the study unless they are found to have marijuana dependence, as indicated by DSM-IV-TR criteria as assessed by the MINI. The results for THC will be recorded for information only. If the subject is positive for opioids or oxycodone, but recent opiate use for acute pain is reported by the subject, then the subject can be re-screened.

  1. Have been hospitalized for alcohol intoxication delirium, alcohol withdrawal delirium, alcohol-induced persisting dementia or amnestic disorder, or have had an alcohol withdrawal seizure, alcohol-induced psychotic disorder with a primary diagnosis of alcohol dependence or a history of any seizure disorder
  2. Have participated in any behavioral or pharmacological intervention research study for the treatment of alcoholism within 1 year prior to signing the informed consent
  3. Be mandated by the court to obtain treatment for alcohol-dependence, or have probation or parole requirements that might interfere with study participation
  4. Be currently undergoing psychotherapy by a licensed therapist or psychiatrist for alcohol problems

NOTE: Current psychotherapy should be considered on a case-by-case basis. Psychotherapy for a disorder that may be related to the subject’s use of alcohol should be exclusionary. However, shorter term focused behavioral therapy for defined problems for non-alcohol related problems may be acceptable.

  1. Be anyone who in the opinion of the investigator could not be safely withdrawn from alcohol without medical detoxification
  2. Have undergone medical detoxification (e.g., reports using a benzodiazepine) during the screening phase (prior to randomization)
  3. Have been treated with a pharmacotherapy for alcohol dependence within 6 months prior to randomization
  4. Have taken any herbal supplements, hypnotics, barbiturates, psychomotor stimulants (such as methylphenidate), buprenorphine or methadone in the last 30 days prior to the date of randomization.
  5. Have taken any strong or moderate CYP 3A inhibitors or inducers ofP-glycoprotein 1 (also known as P-gp or multidrug resistance protein 1) in the last 30 days prior to the date of randomization
  6. Have taken any medications that target the HPA axis (systemic or inhaled steroids, glucocorticoid antagonists, cortisol synthesis inhibitors, aldosterone antagonists) in the last 30 days prior to the date of randomization
  7. Have taken any medications contraindicated with CORTROSYN, including anticoagulants (e.g., warfarin), interleukin-2, or mifepristone, in the last 30 days prior to the date of randomization or quinolones (e.g., levofloxacin) within 5 half-lives of the date of the ACTH challenge test.
  8. Have taken any anti-convulsants oranti-psychotics within 3 months of randomization.
  9. Have any of the following, based on DSM-IV-TR criteria as assessed using the MINI:
  1. current, past, or lifetime diagnosis of psychotic disorders
  2. current or past diagnosis of bipolar disorder
  3. current or past year major depressive episode
  4. current (past 3 months) eating disorder (anorexia or bulimia),
  5. current (within past year) diagnosis of panic disorder with or without agoraphobia, or
  6. anti-social personality disorder

Note: Subjects diagnosed with psychiatric disorders not specifically excluded above may be included at the discretion of the PI as long as the concurrent treatment for the comorbid psychiatric condition does not compromise the study integrity by virtue of its type, duration, or intensity.

  1. Have any of the following:
  1. attempted suicide in the past year
  2. current (past year) suicidality risk as assessed using the MINI (see note below about assessment of subjects diagnosed at low risk)
  3. current (since screening MINI) suicidality risk as indicated during the conduct of the C-SSRS with concurrence after a study physician’s evaluation if the response to C-SSRS questions 1 or 2 is “yes”)

Note: The MINI suicidality module rates scores of 1 to 8 as a diagnosis of low risk of suicidality. As the MINI questions that could result in a low risk score are considered inadequate to fully determine the potential suicidal risk of an individual (e.g., “Feel hopeless” and “Think that you would be better off dead or wish you were dead?” responses of “yes” dictates a score of 1 for each question), any subject who scores in the low risk category should be evaluated further by a study physician who should document whether the subject is appropriate for study inclusion based on his/her clinical judgment of the potential suicide risk of the subject. Likewise, if the subject responds “yes” to either the first two questions on the screening C-SSRS performed on the day of randomization as a final eligibility check, the subject should also evaluated by a study physician for current suicidality risk, who should document the subject’s suitability for study inclusion.

  1. Have dementia as assessed by clinical exam
  2. Have any underlying medical condition that could exacerbate during trial participation causing hospitalization, surgery, or the need to use exclusionary medications to treat the conditionat the discretion of the investigator
  3. Be pregnant or breast-feeding or have plans to become pregnant at any time during the study
  4. History of sensitivity to CORTROSYN
  5. Did not achieve plasma cortisol ≥ 18µg/dL within 60 minutes after CORTROSYN challenge (ACTH stimulation test)
  6. Have a clinically significant abnormal laboratory values; specifically excluded are:
  1. elevation of liver enzymes (AST or ALT) 3-fold above the upper limit of normal (ULN), OR,
  2. total bilirubin greater than 2 times the ULN OR,
  3. elevation of liver enzymes (AST or ALT) 2-fold above ULN ANDtotal bilirubin greater than 1.5 times the ULN
  1. Have serum creatinine > ULN
  2. Have a hemoglobin A1c value > 7%
  3. Have HIV or hepatitis B or Cas determined by medical historyor positive serology for hepatitis B or C

Note: Hepatitis B testing may be repeated with an appropriate test if the subject reports having had the Hepatitis B vaccine.

  1. Have a clinically significant ECG as determined by the investigator, or abnormal ECG heart rate (<45 or > 100 bpm), or QTc interval corrected for heart rate using the Fridericia formula (QTcF) > 450 msec
  2. Have a history of clinically significant cardiac disease, including family history of long-QT syndrome or unexplained sudden deaths
  3. Have sittingdiastolic blood pressure of <50 or > 95 mmHg or sitting systolic blood pressure of < 90 or > 145 mmHg
  1. Have a serious or unstable medical illness or any potentially life-threatening or progressive medical condition other than alcohol addiction that may compromise subject safety or study conduct.
  2. Have a history of cancer (except basal cell carcinoma of the skin) within the past 5 years
  3. Have a history of any clinically significant renal (including hyperoxaluria, oxalate calcinosis, or nephrolithiasis), hepatic, muscular (including hereditary or drug-induced myopathy), endocrinological or neurological disease or disorder, or family history of primary hyperoxaluria
  4. History of any clinically significant infection or any surgical procedure within 4 weeks prior to screening
  5. Have a history of serioussensitivity or allergy to any drug
  6. Have data suggesting cirrhosis of the liver (e.g., albumin < 3.2 g/dL, clinically significant INRor ascites by physical exam
  7. Have had gastric bypass surgery
  8. Have irritable bowel syndrome (current), Crohn’s Disease, ulcerative colitis, or history of varices

Supplementary Appendix 2:Schedule of Visits and Assessments

Screen / Randomize / Maintenance / Safety Follow-up
Study Week / 1 / 2 / 3 / 4 / 5 / 6 / 7 / 8 / 9 / 10 / 11 / 12 / 13 / 15
Target Study Daysa / -14 to-1 / 1 / 8-
10 / 15-17 / 22-28 / 29-31 / 36-42 / 43-45 / 50-56 / 57-59 / 64-70 / 71-77 / 78-84 / 85-91b / 99-105
Clinic Visit # / 0 / 1 / 2 / 3 / 4 / 5 / 6 / 7 / 8
Informed Consent / X
Alcohol Breathalyzer / X / X / X / X / X / X / X / X / X
Urine Drug Screen / X / X / X / X / X / X / X / X / X
Locator Form c / X
Demographics / X
Medical History / X / Xd
Physical Exam / X / Xd / Xe / Xe / Xe / Xe / Xe / Xe
Family History of Alcohol Problems / X
MINI V 6.0 / X
Clinical Chemistry f / X / X / X / X / X / X / X
Hematology f / X / X / X / X / X / X / X
Urinalysis f / X / X / X / X / X / X / X
ACTH stimulation / X / X / X
Copeptin / X
Saliva Cortisol Sampleg / X / X / X / X / X / X
Blood for Genetics Testingh / X
Blood for Medication Compliance / X / X / X / X / X / X
Blood for hepatitis B & C serology / X
Pregnancy Testi+ birth control / X / X / X / X / X
Orthostatic Vital Signs j / X / X / X / X / X / X / X / X / X
Weight / X / X / X
ECG / X / X / X / X / X / X
Thoughts About Abstinence Scale / X
ImBIBe / X / X / X / X
Time-line Follow Backk / X / X / X / X / X / X / X / X
Brief Drinking Questionnaire / X / X
Prior and Concomitant Meds / X / X / X / X / X / X / X / X / X / X / X / X / X / X / X / X
Eligibility Checklistl / X / X
CIWA-AR / X / X / X / X / X / X / X / X / X / X / X / X / X / X
C-SSRS / X / X / X / X / X / X / X
Penn Alcohol Craving Scale (PACS) / X / X / X / X / X / X / X
Modified Fagerström Test for Nicotine Dependence / X
Smoking quantity/frequency / X / X / X / X / X / X / X
POMS / X / X / X / X / X / X / X
Spielberger Trait Questionnaire / X
Alcohol Dependence Scale / X
RANDOMIZATION / X
Drug dose (total mg & # of capsules) / 400/2 / 800/4 / 4 / 4 / 4 / 4 / 4 / 4 / 4 / 4 / 4 / 4
Drug accountability/compliance / X / X / X / X / X / X / X
Week 1 safety telephone contact / Days 2 to 7
Brief Telephone Interviewm / X / X / X / X / X / X
Take Control / X / X / X / X / X / X / X
AEs / X / X / X / X / X / X / X / X / X / X / X / X / X / X
Gastrointestinal AE Assessment formsn / ANo / AN / AN / AN / AN / AN / AN / AN / AN / AN / AN / AN / AN
Exit Interview / X
Treatment Referral / X
Follow-Up Telephone Interview / X
Final Subject Disposition / X

aVisit 1 occurs on Study Day 1. Other visits should ideally occur on the same day of the week as Visit 1 but may occur on any day of the week within the range of study days.

bThis visit should be a close to Day 85 as possible so that assessment of HPA axis integrity is performed as close to the end of dosing as possible.

cUpdate as needed.

dThe medical history and physical exam are updated at screening prior to randomization.

eA symptom directed physical exam will be conducted at this visit.

fSamples collected for the clinical laboratory tests are outlined in Error! Reference source not found..

gAwakening saliva only.

hIf for any reason the genetics sample is not collected at the Week 1 visit, it may be collected at any other visit after this that a blood sample is collected for any reason.

iA urine pregnancy test will be performed.

jBlood pressure and pulse (sitting for 3 minutes, then supine for 3 minutes, then standing), and temperature.

kThe period of assessment at screening is 28 days.

lEligibility is initially checked during screening with the final determination of eligibility on the day of randomization.

mBrief Telephone Interview consists of assessing the subject’s concomitant medication use, encouragement for medication compliance, assessment of AEs, CIWA-AR, and visit reminder, including reminder to collect the saliva cortisol sample and bring the Salivette to their next visit.

nThe gastrointestinal AE assessment forms are completed after an irregular bowel movement AE is reported. The baseline scale is completed only once after the first report of an irregular bowel movement AE and after the gastrointestinal AE assessment has been completed.

oAN = As Needed.

Supplementary Appendix 3: Clinical Sites and Oversight

The four academic sites where data were collected included:

  • University of Virginia
  • Johns Hopkins University School Medicine
  • Boston Medical Center
  • University of Pennsylvania Treatment Research Center

The study was conducted in accordance with the Declaration of Helsinki and the International Conference on Harmonisation Guideline for Good Clinical Practice: E6 (International Conference on Harmonisation, 1997). All participants provided voluntary, written informed consent prior to the initiation of any study procedures. The protocol, consent, and all study-related materials were reviewed and approved by the Institutional Review Board at each participating site and the Data and Safety Monitoring Board. The study was conducted under an Investigational New Drug application.

Supplementary Appendix 4: Randomization and Blinding Details

The Contract Research Organization, FastTrack Drugs and Biologics, generated the random allocation sequence. If a participant was determined to be eligible for trial participation, authorized clinical site personnel, who had completed training for the IWRS, logged onto the system and provided the site number, STAI score, unique Subject ID and Alpha Code, and the participant’s date of birth. The IWRS provided the randomized group kit number and assigned the subject to one of the two interventions. All participants, care providers, study staff, and sponsors were blinded to the intervention assignment until the study was complete and the database was locked. The block size for randomization was two participants per block.

Supplementary Appendix 5:Statistical Analysis Details

For the mixed-effects models with continuous outcomes, all covariates were treated as fixed effects, except participants treated as the random effect. A toeplitz covariance matrix best fit the data and was used to model the correlations between repeated measures among participants.

All fully adjusted models of continuous outcomes included a base set of covariates: the baseline value of the outcome, clinical site, study week, treatment group, and the treatment group by study week interaction. Models of continuous drinking outcomes also included the following covariates: treatment goal (permanent abstinence from alcohol vs. other), trait anxiety (STAI score >39), years of regular drinking, and pre-randomization reducer status (any reduction in drinks per day between the 28-day screening period and the week before randomization). The baseline value of each drinking outcome was computed for the 28-day period prior to the first screening visit. Clinical site and trait anxiety were selected as covariates because they were stratification factors. Treatment goal, years of regular drinking, and pre-randomization reducer status were included as covariates because they were consistently correlated with the drinking outcomes in bivariate analyses. Models of continuous non-drinking outcomes included additional covariates beyond the base set that were correlated with outcome. These added covariates included: treatment goal, years of regular drinking, and Alcohol Dependence Severity for the model of alcohol craving (PACS) outcome; as well as another covariate, any prior alcohol treatment history (including Alcoholics Anonymous), for the model of alcohol-related consequences (ImBIBe) outcome.

Cohen’s d and p-values were based on the fully adjusted models with the appropriately transformed outcome variables as follows: square root transformations (drinks per day, drinks per drinking day, cigarettes per week, ImBIBe, POMS); and inverse transformation (percentage of very heavy drinking days and CIWA-Ar). The percentage of heavy drinking days, percentage of days abstinent and PACS were not transformed because they were not skewed.

Cohen’s d=(µTreatment – µPlacebo) /σ, where µTreatment – µPlacebo is the difference between the means for the treatment and placebo groups, and σ is the pooled standard deviation. The following are offered as cut-offs for interpreting the effect size: small=.20, medium=.50, and large=.80 (Cohen, 1992).