Clinical trial NCT02901041: Interdisciplinary Study of A Novel Anticonvulsant in Alcoholism
Official title: Interdisciplinary Study of Two Novel Anticonvulsants in Alcoholism
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE3
Conditions: Alcohol Dependence
Lead sponsor: Boston University Charles River Campus
Sponsor class: OTHER
Collaborators: name: Mclean Hospital
name: University of Houston
First posted: 2016-09-15
Enrollment: 81
Sex: ALL
Minimum age (years): 21
Maximum age (years): 65
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

Brief summary: Alcoholism is the third leading cause of preventable death in the US, accounting for 80,000 deaths annually. Almost 18 million US adults have alcohol use disorder (AUD); however, approved medications for the treatment of AUD has shown limited effectiveness.

Zonisamide (ZON), a broad spectrum anticonvulsant, has proven to be more effective than a placebo in reducing alcohol intake in individuals with alcohol dependence. ZON's mechanism of action seems to be quite distinct from currently approved anti-alcoholism medications, which holds promise for treatment of individuals who are not responsive to conventional medications. However, much remains unknown about ZON's therapeutic mechanisms and ZON's efficacy in treating patients with a diagnosis of AUD.

To fill in these gaps, the investigators will conduct a double-blind randomized controlled study that assesses ZON's treatment mechanisms and effectiveness in reducing alcohol consumption in patients with AUD. Participants will be randomized to one of two conditions: 1) treatment with ZON and a computerized psychotherapy platform called Take Control (TC); 2) treatment with a placebo (PLC) and TC. To understand the neurobiology behind ZON's potential therapeutic effects on AUD, fMRI will be used to compare the brain activity of the ZON+TC versus PLC+TC group while participants perform an alcohol and emotional-word Stroop task, as well as an alcohol related cues task.

Detailed description: Potential participants will complete a telephone and an in-clinic screening to determine eligibility for this study. Eligible participants will be randomized to receive one of two treatment conditions: 1) Zonisamide plus Take Control (a computerized alcohol reduction and medication compliance program developed by the National Institute on Alcohol Abuse and Alcoholism (NIAAA)); 2) a placebo plus Take Control. For both conditions, participants will receive 12 treatment sessions. Participants will receive medication at each session, and they should have two weeks worth of medication on hand at any given time. Participants will take the medication as prescribed at home. The first 11 treatment sessions will include Take Control. The 12 treatment sessions will be followed by two drug dose taper sessions, and a follow up phone interview immediately following the final session.

Participants will also undergo two scans of less than 2 hours duration, one before they begin study sessions and the second near the end of the study (12th study week and before the medication taper). At the in-clinic screening session, participants will receive a "MRI Information for Research Participants" handout that answers some commonly asked questions about MRI and tells participants what they can expect while undergoing an MRI scan. Both scans will be conducted at BU CILSE. Participants will be screened before each scan session for pregnancy (urine sample, women of childbearing potential only), recent smoking or alcohol use (breathalyzers), and illicit substance use (urine sample). Participants will be asked to complete the Alcohol Urge Questionnaire (AUQ) before and after the scan. Eligible participants will complete a 1-hour 3 Tesla MRI scan involving structural imaging (MRI) and functional imaging (fMRI). The fMRI scans include a resting-state scan (no task involved) a cognitive (Stroop) task, and an alcohol cue reactivity task. The latter two scans involve presentation of visual images to participants while they are in the scanner. No contrast agent or invasive procedures are used. Only personnel trained in working in high magnetic field environments will work on this project. Imaging data will be analyzed on secure networks using only encrypted files. All data obtained will be coded to protect participant privacy and confidentiality.

Starting on March 23, 2020, all study procedures have been moved to HIPAA compliant, remote platforms and can be performed from home due to the COVID-19 pandemic. Screenings will take place over the phone or Zoom, neurocognitive assessments will take place on Inquisit 5 at sessions 1 and 12, female participants of child-bearing potential will be directed to take a pregnancy test at all sessions, and patients will use a breathalyzer provided by Boston University at the start of each session to show they are within study-specified limits of blood alcohol content.

One month following completion of study treatment (study week 16), participants will be asked to complete a follow-up telephone assessment.

The entire study is estimated to be completed in five years. The first six months to nine months of the project will be dedicated to hiring, training and certifying staff. Recruitment will begin within three months of obtaining IRB approval, during Year 1 of the study. Approximately 3-4 new participants will be recruited per month. We anticipate recruiting a total of 5 participants in Year 1, 25 participants in Years 2 and 3, 30 participants in year 4, and 15 participants in Year 5. The last third of Year 5 will be devoted to completion of data entry and data management procedures, preliminary analyses, and the preparation of manuscripts

Eligibility criteria: Inclusion Criteria:

* DSM-5 diagnosis of an Alcohol Use Disorder (AUD)
* Adults ages 21 to 65 years old
* Expressed desire to stop drinking alcohol completely or to reduce alcohol consumption
* Reported drinking an average of at least 14 standard drinks per week for males, or 7 for females occurring over a 28-consecutive day period during the 90 day-long time window that preceded the screening session
* Must be willing to discontinue psychotherapy for substance use disorder (except A.A.)

Exclusion Criteria:

* Bipolar disorder, schizophrenia, current bulimia/anorexia, dementia, or other substance use disorder, with the exception of nicotine, marijuana, and caffeine
* Clear and current suicidal risk
* Significant medical problem (e.g. uncontrolled diabetes)
* Medical contraindication to the use of ZON (e.g. history of significant renal disease, kidney stones, liver problems, metabolic acidosis, etc), as indicated by the FDA Zonisamide medication guide
* History of anticonvulsant-induced rash
* Currently taking:

  1. acamprosate, naltrexone, topiramate, disulfiram, or benzodiazepines
  2. a medication that is a moderate or major inhibitor or inducer of cytochrome P450 3A4 enzymes
  3. an amphetamine or other psychomotor stimulant
  4. opioids or have been treated chronically with opioids
  5. antipsychotic agents, anticonvulsants, or sedative hypnotics
  6. drugs with "sulfa" moiety (e.g. sulfonamides, sulfonylureas, carbonic anhydrase inhibitors, thiazides, and loop diuretics), except ethacrynic acid
  7. anxiolytics or antidepressants
* Previously received ZON for the treatment of an AUD
* Known allergy to sulfonamides
* Implantation of anything containing magnetically sensitive material including metal plates, aneurysm clips, and cardiac pacemakers, stents
* Non-English speakers
* Pregnant women or women who are lactating (breastfeeding)

Exclusion from Screening:

* Reduction in the mean number of drinks consumed per week for the pre-screening period by 50% or more during the screening period or report of average drinks per day fall within safe levels of alcohol consumption (i.e. 2 drinks/day for males and 1 drink/day for females by the HHS standard) two weeks prior to screening
* Women of child bearing potential (not postmenopausal for at least one year) will not be admitted into this study unless they are found to have a negative HCG test during screening. If they pass the HCG screening, they will be asked to maintain the use of an effective means of contraception during the course of the study
* Blood test shows lower than average red or white blood cell count or higher than average level of acid in blood

Primary outcomes:
measure: Average Standard Drinking Units Per Day
timeFrame: Pre-treatment
measure: Average Standard Drinking Units Per Day
timeFrame: Post-treatment (Week 12)
measure: Percentage of Drinking Days
timeFrame: Pre-treatment
measure: Percentage of Drinking Days
timeFrame: Post-treatment (Week 12)
measure: Percent Heavy Drinking Days
timeFrame: Pre-treatment
measure: Percent Heavy Drinking Days
timeFrame: Post-treatment (Week 12)
measure: Average Weekly Standard Drinking Units (SDUs)
timeFrame: Pre-treatment
measure: Average Weekly Standard Drinking Units (SDUs)
timeFrame: Post-treatment (Week 12)
Secondary outcomes:
measure: Balloon Analogue Risk Task: Total Pump Count
timeFrame: Pre-treatment
measure: Balloon Analogue Risk Task: Total Pump Count
timeFrame: Post-treatment (Week 12)
measure: Cued Go/No-go Task: Inhibition Error
timeFrame: Pre-treatment
measure: Cued Go No-Go: Inhibition Error
timeFrame: Post-treatment (Week 12)
measure: Connor's Continuous Performance Task (CPT) - X Test Omission Rate
timeFrame: Pre-treatment
measure: Connor's Continuous Performance Task (CPT): X Test Omission Rate
timeFrame: Post-treatment (Week 12)
measure: Connor's Continuous Performance Task (CPT): X Test Commission Rate
timeFrame: Pre-treatment
measure: Connor's Continuous Performance Task (CPT): X Test Commission Rate
timeFrame: Post-treatment (Week 12)
measure: Connor's Continuous Performance Task (CPT): AX Test Omission Rate
timeFrame: Pre-treatment
measure: Connor's Continuous Performance Task (CPT): AX Test Omission Rate
timeFrame: Post-treatment (Week 12)
measure: Connor's Continous Performance Task: AX Test Commission Rate
timeFrame: Pre-treatment
measure: Connor's Continuous Performance Task: AX Test Commission Rate
timeFrame: Post-treatment (Week 12)
measure: Roger's Risk Task: Mean Percent Bet
timeFrame: Pre-treatment
measure: Roger's Risk Task: Mean Percent Bet
timeFrame: Post-treatment (Week 12)
measure: Roger's Risk Task: Risk Adjustment
timeFrame: Pre-treatment
measure: Roger's Risk Task: Risk Adjustment
timeFrame: Post-treatment (Week 12)
measure: Roger's Risk Task: Delay Aversion
timeFrame: Pre-treatment
measure: Roger's Risk Task: Delay Aversion
timeFrame: Post-treatment (Week 12)
Other outcomes:
Locations:
city: Boston
country: United States
facility: Center for Anxiety and Related Disorders - Boston University
state: Massachusetts
Study officials:
affiliation: Boston University
name: David H Barlow, PhD
role: PRINCIPAL_INVESTIGATOR
References: