HLAB-002 of ANS-6637 for Alcohol Use Disorder
Condition: Alcohol Use Disorder
MeSH terms: Alcoholism; Alcohol Drinking
Intervention: ANS-6637; Placebo oral tablet
Intervention description: 200 mg (given as 2 x 100 mg tablet) and 600 mg (given as 2 x 300 mg tablet) once a day; Placebo oral tablet
Phase: Phase 2
Study type: Interventional
Primary purpose: Treatment
Allocation: Randomized
Intervention model: Parallel Assignment
Intervention model description: This study is a 3-arm, double-blind, randomized, placebo-controlled, parallel group, 3-site study designed to assess the effects of ANS-6637 as compared with placebo on responses to in vivo alcohol cue exposure in the human laboratory setting.
Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
Masking description: Double-blind
Enrollment: 43.0
Sex: All
Minimum age: 21 Years
Healthy volunteers: No
Keywords: pharmacotherapy; human laboratory study; novel medication

Summary:

      Primary: The primary objective of this study was to evaluate the effects of 2 different doses
      of ANS-6637, 200 mg (given as 2 x 100 mg tablets) and 600 mg (given as 2 x 300 mg tablets)
      once a day, and matched placebo, on alcohol cue-elicited alcohol craving during a human
      laboratory paradigm after 1 week of daily dosing among subjects with moderate to severe
      alcohol use disorder (AUD) as confirmed by the Diagnostic and Statistical Manual of Mental
      Disorders - Fifth Edition (DSM-5™).

      Secondary: Secondary objectives included evaluation of ANS-6637 200 mg, ANS-6637 600 mg, and
      matched placebo on reduction of alcohol consumption, alcohol craving, cigarette smoking
      (among smokers) and nicotine use (among nicotine users), mood, sleep, alcohol use negative
      consequences, study retention, and safety and tolerability throughout the last 4 weeks of the
      treatment phase of the study.
    

Eligibility criteria:

        Inclusion criteria:

          1. Be at least 21 years of age.

          2. Meet the DSM-5 criteria for alcohol use disorder of at least moderate severity.

          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. Have at least 1 heavy drinking day (4 or more drinks for women/5 or more drinks for
             men) during the 7-day period prior to randomization.

          5. Be seeking treatment for AUD and desire a reduction or cessation of drinking.

          6. Be able to verbalize an understanding of the consent form, able to provide written
             informed consent, verbalize willingness to complete study procedures, able to
             understand written and oral instructions in English and able to complete the
             questionnaires required by the protocol.

          7. Agree (if the subject is female and of child bearing potential) to use at least one of
             the following methods of birth control to at least 7 days post the last dose of study
             drug, unless she is surgically sterile, partner is surgically sterile or she is
             postmenopausal (one year):

               1. oral contraceptives,

               2. contraceptive sponge,

               3. patch,

               4. double barrier (diaphragm/spermicidal or condom/spermicidal),

               5. intrauterine contraceptive system,

               6. etonogestrel implant,

               7. medroxyprogesterone acetate contraceptive injection,

               8. complete abstinence from sexual intercourse, and/or hormonal vaginal
                  contraceptive ring.

          8. Agree (if male) to use acceptable methods of contraception if the male participant's
             partner could become pregnant from the time of the first administration of the study
             drug until 7 days following the final administration of the study drug. One of the
             following acceptable methods of contraception must be utilized:

               1. Surgical sterilization (vasectomy);

               2. The participant's female partner uses oral contraceptives (combination
                  estrogen/progesterone pills), injectable progesterone or sub dermal implants
                  (commenced at least 14 days prior to study drug administration to the male
                  participant)

               3. The participant's female partner uses a medically prescribed topically applied
                  transdermal contraceptive patch (commenced at least 14 days prior to study drug
                  administration to the male participant);

               4. The participant's female partner has undergone tubal ligation (female
                  sterilization) or is postmenopausal (one year);

               5. The participant's female partner has undergone placement of an intrauterine
                  device or intrauterine system;

               6. True abstinence: when this is in line with the preferred and usual lifestyle of
                  the participant.

          9. Agree (if male) to refrain from sperm donation from the randomization visit to at
             least 7 days after the last dose of study drug.

         10. Be able to take oral medication and be willing to adhere to the medication regimen.

         11. Complete all assessments required at screening and baseline.

         12. Have a place to live in the 2 weeks prior to randomization and not be at risk that
             s/he will lose his/her housing in the next 2 months.

         13. Not anticipate any significant problems with transportation arrangements or available
             time to travel to the study site over the next 2 months.

         14. Not have any unresolved legal problems that could jeopardize continuation or
             completion of the study.

         15. 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.

         16. Have a BAC by breathalyzer equal to 0.000 when s/he signed the informed consent
             document.

         17. If taking a medication for depression or anxiety, must have been taking a stable dose
             in the 2-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)

         18. Be someone who in the opinion of the investigator would be expected to complete the
             study protocol.

         19. 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 scheduled events or a job that may substantially interfere with study
             participation.

         20. Be willing to use a smartphone's video capability to record daily oral ingestion of
             tablets for the entire 5-week treatment period (subject's own smartphone or one
             provided by AiCure).

         21. Have sitting (3 to 5 minutes) vital signs at the screening visit within the following
             limits:

               1. Systolic blood pressure 90 to 160 mmHg

               2. Diastolic blood pressure of 50 to 95 mmHg

               3. Heart rate of 40 to 90 beats per minute Note: Vital signs may be repeated once if
                  outside the limits above and if within the limits on a second evaluation, the
                  subject may be included.

        Exclusion Criteria:

          1. Current (past 12 months) substance use disorder of at least moderate severity (4 or
             more criteria) for any psychoactive substance other than alcohol and nicotine,
             including sedatives and hypnotics, as defined by DSM-5 criteria.

          2. Urine drug test positive performed during screening or baseline for any of the
             following substances:

               1. benzodiazepines,

               2. cocaine,

               3. opioids,

               4. amphetamines,

               5. methamphetamine,

               6. buprenorphine,

               7. methadone,

               8. barbiturates,

               9. oxycodone,

              10. and/or MDMA. Note: Testing for THC was included in the urine drug test; however,
                  subjects who tested positive for THC were still eligible to participate in the
                  study unless they had moderate or greater severity for cannabis use disorder as
                  indicated by DSM-5 criteria. The results for THC were recorded for information
                  only. If positive for opioids or oxycodone but recent opiate use for acute pain
                  was reported by the subject, then the subject could be included at the discretion
                  of the investigator.

          3. VAS craving rating ("How strong is your craving to drink alcohol") during first
             presentation of alcohol cue <5 during the screening cue reactivity session.

          4. 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 AUD
             or a history of any seizure disorder.

          5. Have participated in any behavioral and/or pharmacological intervention research study
             for the treatment of alcoholism where the last intervention was within 3 years prior
             to signing the informed consent.

          6. Be mandated by the court to obtain treatment for alcohol-dependence, or has probation
             or parole requirements that might interfere with study participation.

          7. Be anyone who in the opinion of the investigator could not be safely withdrawn from
             alcohol without medical detoxification.

          8. Have undergone medical detoxification (e.g., reports using a benzodiazepine) during
             the screening phase (prior to randomization).

          9. Have been treated with a pharmacotherapy for alcohol use disorder within 6 months
             prior to randomization.

         10. Have any of the following, based on DSM-5 criteria as assessed using theMINI:

               1. Current or lifetime diagnosis of psychotic disorders,

               2. Current bipolar disorder,

               3. Current major depressive episode,

               4. Current (past 3 months) eating disorder (anorexia or bulimia), or

               5. Within past year diagnosis of panic disorder with or without agoraphobia. Note:
                  Subjects diagnosed with psychiatric disorders not specifically excluded above
                  could 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.

         11. Have any of the following:

               1. attempted suicide past year,

               2. current (past year) suicide behavior disorder in accordance with DSM-5 criteria
                  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 responded "yes" to either the first 2 questions on the
                  screening C-SSRS performed on the day of randomization as a final eligibility
                  check, the subject should also have been evaluated by a study physician for
                  current suicidality risk, who should document the subject's suitability for study
                  inclusion.

         12. Have moderate or serious dementia as assessed by clinical exam.

         13. Be pregnant or breast-feeding or have plans to become pregnant at any time during the
             study or within 7 days after the last dose of IP.

         14. Have clinically significant abnormal laboratory values, including elevation of liver
             enzymes (AST or ALT > 2.5 x upper limit of normal or total bilirubin > 1.5 x the upper
             limit of normal).

         15. Have abnormal calculated creatinine clearance defined as < 80 mL/minute for subjects ≤
             55 years of age and < 65 mL/minute for subjects > 55 years of age.

         16. Have a serious or unstable medical illness or any potentially life-threatening or
             progressive medical condition other than addiction that may compromise subject safety
             or study conduct.

         17. Be currently undergoing psychotherapy by a licensed therapist or psychiatrist for
             alcohol problems. NOTE: Current psychotherapy was to be considered on a case-by-case
             basis. Psychotherapy for a disorder that could 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 could be acceptable.

         18. Have data suggesting cirrhosis of the liver (albumin < 3.2 g/dL, or ascites by
             physical exam).

         19. Have been previously treated with ANS-6637 for any reason.

         20. Have had gastric bypass surgery.

         21. Have had a severe reaction to disulfiram while drinking alcohol requiring medical
             attention.

         22. Have a history of atherosclerotic cardiovascular disease including angina pectoris,
             myocardial infarction, stroke, transient ischemic attack, peripheral vascular disease
             or revascularization procedures or clinically significant ECG indicative of
             cardiovascular disease. Note: medically controlled hypertension is not exclusionary.

         23. History of syncope, palpitations, or unexplained dizziness at screening.

         24. Had a prior history of any severe adverse reactions to ethanol [e.g., flushing
             (noticeable redness of the neck or throat) and/or increased heart rate (subject
             reports sensation of increased heart rate or palpitations) after drinking alcohol].

         25. Report heavy drinking of alcohol within 2 days on TLFB prior to screening and have a
             negative result on EtG urine test.

         26. Have Parkinson's Disease or a family history of Parkinson's Disease.

         27. Have restless legs syndrome and receiving dopamine agonist treatment.

         28. Have attention-deficit disorder and receiving dopamine stimulant treatment.

         29. Are taking a prohibited medication.